Note: Descriptions are shown in the official language in which they were submitted.
COMPOSITIONS, COMBINATIONS, AND METHODS THEREOF FOR
TREATMENT OF NEUROLOGICAL DISORDERS
TECHNICAL FIELD
[001] This disclosure relates to Targeted Drug Rescue (TDR)Tm with novel
compositions,
combinations, therapeutic formulations, symptomatic and disease-modifying
treatments, therapies,
kits thereof, and methods thereof.
BACKGROUND
[002] Excess weight changes the body, increasing certain hormones and levels
of inflammation that
can lead to metabolic disorders, cancer, and brain disorders, including
developmental, psychiatric and
neurodegenerative diseases, which represent an enormous disease burden,
regarding human suffering
and economic cost, and causing the rapid rise in healthcare spending. Diseases
affecting the brain and
central nervous system represent one of the largest global healthcare
challenges and greatest medical
needs due to the devastating personal and economic consequences for patients,
caregivers and society.
An estimated 55 million people worldwide suffer from neurodegenerative
diseases with no currently
approved disease-modifying therapies available. As modern therapeutic
interventions increase life
expectancy, the number of patients suffering from these diseases is expected
to double every 20 years.
Just nine of the most common neurological diseases such as Alzheimer's disease
and other dementias,
low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple
sclerosis, spinal cord injury,
and Parkinson's disease is staggering, totaling $789 billion in 2014 dollars,
currently estimated at $818
billion, and estimated to be more than $1 trillion by 2030. Total European
2010 cost of brain disorders
was Ã798 billion, of which direct health care cost 37%, direct non-medical
cost 23%, and indirect cost
40% (Oleson et al., The economic cost of brain disorders in Europe, EJN, 19,
1,155-162 (2012).
[003] Progress in specifically addressing therapeutic needs in dementia has
been slow in the past two
decades, and all development projects in Alzheimer's Disease have failed since
the approval of
memantine by the EMA (2002) and the FDA (2003). Rather than insisting on
"treatment" indications,
regulators have addressed the persisting high medical need by opening up the
range of approvable
medications to therapies with syndromal indication labels. Such a syndromal
indication label could
cover, e.g., Behavioral and Psychiatric Symptoms in Dementia (BPSD), sub-
syndromal indications
like aggression or apathy in Alzheimer's Disease, hallucinations and delusions
in Parkinson's Disease
Dementia (PDD). Accordingly, there is need for development of such new
therapies with syndromal
indication labels for novel compositions, combinations, therapeutic
formulations, symptomatic and
disease-modifying treatments, and therapies using EXCIVA TDRIm technology.
Date Recue/Date Received 2022-05-04
SUMMARY OF THE INVENTION
[004] Various embodiments of the disclosure relate to Targeted Drug Rescue
(TDR)Tm with novel
compositions, combinations, therapeutic formulations, symptomatic and di sease-
modifying
treatments, therapies, kits thereof, and methods of making such compositions,
combinations,
therapeutic formulations, treatments, therapies, and kits comprising
biologics, chemicals, nutritionals,
pharmaceuticals, compositions, treatments, therapies, cures, prophylactics,
supplements, and
formulations; including allopathic, alternative, ayurvedic, herbal, holistic,
homeopathic, natural,
medicinal, pharmaceutical, unnatural agents, adjuvants, aids, brews,
chemicals, compositions,
combinations, concoctions, drugs, elements, extracts, extractions,
formulations, kits, mechanisms,
medications, medicines, mixtures, potions, preparations, prophylactics,
recipes, solutes, solutions,
solvents, substances, systems, teas, therapies, tinctures, and treatments;
biologics and vaccines; cures;
diagnostic kits, reagents and assays; dietary, gastronomical, and nutritional
agents, potions, and
supplements; healthcare products; and neutraceuticals; and related products
and services thereof; for
administering, cleansing, curing, diagnosing, healing, disinfecting,
medicating, preventing, and
treating the acute or chronic situations namely: addictions, conditions,
deficiencies, disabilities,
diseases, disorders, dysfunctions, infections, problems, poisonings,
pollutions, and maladies thereof;
due to and related to, namely, accidental, allergic, auditory, anti-cancer,
cardiovascular,
cardiopulmonary, chemotherapeutic, cognitive, congenital, dermatological,
endocrinal,
gastrointestinal, genetical, genital, genitourinary, hereditary, hormonal,
hepatological, immunological,
incidental, intellectual, karmic, lymphatic, metabolic, mental, muscular,
musculoskeletal,
neurological, oncological, optical, ophthalmic, osteological, osteopathic,
psychiatric, psychological,
psychopathic, psychosomatic, physical, physiological, respiratory,
reproductive, sexual, skeletal,
urological, virtual, and visual functions, systems, and causes thereof.
[005] In various embodiments, the invention is a composition comprising a
combination of one or
more agents, each having a unique Therapeutic Mode of Action (TMA), wherein
the agent is NMDA
Receptor Antagonist, 5-11T2A Receptor Antagonist, 5-11T2A Receptor Inverse
Agonist, 5-11T2c
Receptor Antagonist, and/ or CYP2D6 Inhibitor.
[006] An embodiment of the invention is a composition comprising a compound of
Formula I:
2
Date Recue/Date Received 2021-04-14
R2
Rr
R4
Formula I, wherein, Ri and R2 are independently H, substituted or
unsubstituted C1_10 alkyl,
substituted or unsubstituted C5-10 aryl, substituted or unsubstituted C3-10
cycloalkyl-Cs_io aryl,
substituted or unsubstituted C4_10 bicycloalkyl, substituted or unsubstituted
C4_10 bicycloalkyl-05-11)
aryl, substituted or unsubstituted C4_10 bicycl oalkyl-C 5-10 heteroaryl,
substituted or unsubstituted C4_10
tricycloalkyl, substituted or unsubstituted C4_10 tricycloalkyl-0510 aryl,
substituted or unsubstituted C4-
tricycloalkyl-05-10 heteroaryl, or substituted or unsubstituted C5_10
heteroaryl, or Ri and R2 together
with the nitrogen form a saturated or unsaturated heterocycle having one or
more hetero atoms selected
from N, 0, and S;
R3 is independently H, substituted or unsubstituted C1_10 alkyl, substituted
or unsubstituted C5-10 aryl,
10 substituted or unsubstituted C5_10 heteroaryl, substituted or
unsubstituted C3-10 cycloalkyl-Cs_io aryl,
substituted or unsubstituted C4_10 bicycloalkyl, substituted or unsubstituted
C4_10 bicycloalkyl-05-11)
aryl, substituted or unsubstituted C4_10 bicycl oalkyl-C 5-10 heteroaryl,
substituted or unsubstituted C4_10
bicycloalkyl-C1_ lo-alkyl-05-lo aryl, substituted or unsubstituted C4_10
bicycloalkyl-C1_10-alkyl-C 5-
loheteroaryl, substituted or unsubstituted C4_10 tricycloalkyl, substituted or
unsubstituted C4-
1 5 iotricycloalkyl-C1_ l 0- alkyl-C s_lo aryl, substituted or
unsubstituted C4_10 tricycl o alkyl-C 1_ 10- alkyl-Cs- 11)
heteroaryl, substituted or unsubstituted C4_10 tricycloalkyl-Cs_io aryl,
substituted or unsubstituted C4_10
tricycloalkyl-Cs_io heteroaryl, or substituted or unsubstituted Cs_io
heteroaryl, or substituted or
unsubstituted C5_10 heteroaryl;
n is an integer from 0 to 5; R4 is H, NH-Rs, S-Rs, -OH, 0-R5, ¨CO-Rs, ¨0-CO-
R5, or ¨00-0-R5,
wherein R5 is an acyl radical; or R5 and R2 form a heterocycle; or enantiomers
thereof, metabolites
thereof, derivatives thereof, and/or prodrugs thereof, pharmaceutically
acceptable salts thereof, N-
oxides thereof, or a combination thereof.
[007] Some embodiments include a composition comprising an effective amount
of: 1) a composition
comprising a compound of Formula I, as defined above, enantiomers thereof,
metabolites thereof,
derivatives thereof, and/or prodrugs thereof, pharmaceutically acceptable
salts thereof, N-oxides
thereof, or a combination thereof; or 2) a compound of Formula II
3
Date Recue/Date Received 2021-04-14
0
Rs
Rio
Wa. H
Ra
Formula H, wherein, R6, R7, and R8 are independently H, D, Ci_io-alkyl, halo
Ci_io-alkyl wherein
halogen is F, Cl, or Br; R9 and Rio are independently H; Ci_io-alkyl; halo
Ci_io-alkyl wherein halogen
is F, Cl, or Br; OH; or R9 and Rio together form a five-membered heterocycle
wherein the hetero atom
is 0, S, or N; enantiomers, metabolites, derivatives, prodrugs, salts,
diastereomers, pharmaceutically
acceptable salts, or N-oxides thereof, or a combination thereof; or 3) a
combination of 1 and 2; or a
combinations thereof.
[008] Some embodiments include a method of treating a disease or disorder in a
subject in need
thereof comprising an effective amount of: 1) a composition comprising a
compound of Formula I, as
defined above; enantiomers thereof, metabolites thereof, derivatives thereof,
and/or prodrugs thereof,
pharmaceutically acceptable salts thereof, N-oxides thereof, or a combination
thereof ; or 2) a
compound of Formula II, as defined above, enantiomers, metabolites,
derivatives, prodrugs, salts,
diastereomers, pharmaceutically acceptable salts, or N-oxides thereof, or a
combination thereof; or 3)
a combination of 1 and 2.
[009] Some embodiments include a method of treating a disease or disorder in a
subject in need
thereof comprising an effective amount of a composition comprising
dextromethorphan, enantiomers,
metabolites, derivatives, or prodrugs thereof, or a combination thereof; salts
and diastereomers thereof,
pharmaceutically acceptable salts thereof, N-oxides thereof, processes and
intermediates for
preparation thereof, compositions thereof, and uses thereof.
[0010] In an embodiment, the method is a method of decreasing the number of
doses and/or total daily
dose of the compound of Formula II that can be administered while increasing
efficacy and
safeguarding tolerability and safety; a method of reducing an adverse event
associated with treatment
by the compound of Formula II, wherein the subject is at risk of experiencing
the adverse event as a
result being treated with the compound of Formula II; a method of decreasing
metabolites of the
compound of Formula II plasma levels, a method of treating a neurological
disorder, a method of
increasing the compound of Formula II plasma levels in a subject in need of
treatment with the
compound of Formula II, wherein the subject is an extensive metabolizer of the
compound of Formula
II; a method of inhibiting the metabolism of the compound of Formula II; a
method of increasing the
metabolic lifetime of the compound of Formula II; a method of correcting
extensive metabolism of
4
Date Recue/Date Received 2021-04-14
the compound of Formula II; a method of improving the antitussive properties
of the compound of
Formula II; a method of treating cough. Another embodiment is the method,
wherein the disease or
disorder is a neurological disorder, wherein the composition is administered
at least once a day for at
least I day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 8 days.
[0011] Some embodiments include a method of treating a neurological disorder
comprising
administering about 5 mg/day to about 600 mg/day, about 5 mg/day to about 300
mg/day, about 5
mg/day to about 400 mg/day, about 5 mg/day to about 500 mg/day, about 5 mg/day
to about 600
mg/day, about 5 mg/day to about 1,000 mg/day, about 50 mg/day to about 1000
mg/day, about 100
mg/day to about 1000 mg/day, about 150 mg/day to about 1000 mg/day, about 150
mg/day to about
5000 mg/day, about 150 mg/day to about 300 mg/day, or about 150 mg/day to
about 100 mg/day, or
an amount as required of a compound of Formula I, and about 0.1 mg/day to
about 1 mg/day, about
0.5 mg/day to about 15 mg/day, about 15 mg/day to about 60 mg/day, about 15
mg/day to about 120
mg/day, about 0.1 mg/day to about 200 mg/day, or an amount as required of the
compound of Formula
II to a subject in need thereof.
[0012] Another embodiment is a pharmaceutical composition comprising the
compound of Formula
II and one or more agents selected from the group comprising 5-HT2A receptor
antagonist /inverse
agonist, and CYP2D6 inhibitor. In another embodiment, the agent is an agent
having properties of
both 5-HT2A receptor antagonist/inverse agonist and CYP2D6 inhibitor. In
another embodiment, the
agent is a dual agent (DA) haying properties of both 5-HT2A receptor inverse
agonist and CYP2D6
inhibitor. In another embodiment, the DA is a compound of Formula I.
BRIEF DESCRIPTION OF FIGURES
[0013] FIGURES 1A, 1B, and 1C represent Dixon plots to determine Ki values for
CYP2D6 of
compounds of Formula I exemplified by Sarpogrelate and M-1, and quinidine. The
concentrations of
dextromethorphan were determined 2.5 (filled circles), 5 (open circles), and
10 (triangles) mM,
respectively. V represents formation rate of dextrorphan (pmol/min/mg
protein). Data are the mean
values of triplicate determinations. The solid lines of a compound of Formula
I, exemplified by
Sarpogrelate and M-1, and quinidine fit well to all competitive inhibition
types (Cho et al., Effect of
the potent CYP2D6 inhibitor on the pharmacokinetics and phannacodynamics of
metoprolol in
healthy male Korean volunteers. Xenobiotica, 45(3):256-63 (2015 March),
incorporated in entirety by
reference).
[0014] FIGURES 2A, 2B, and 2C represent Mean Neuropsychiatric Inventory
Agitation/ Aggression
5
Date Recue/Date Received 2021-04-14
Domain Scores by Stage and Visit for Patients Included in the Sequential
Parallel Comparison Design
and 10-Week Analyses. A, Stage 1 (weeks 1-5); B, stage 2 (weeks 6-10) for
placebo nonresponders
rerandomized after stage 1; C, 10-week results (the 10-week secondary analysis
includes only patients
who continued the same treatment assignment throughout study participation;
ie, were randomized to
receive only dextromethorphan-quinidine or only placebo [excludes patients who
were rerandomized
from placebo to dextromethorphan-quinidine in stage 2], thus simulating a
parallel-group design).
Analysis-of-covariance models with treatment as fixed effect and baseline as
covariate were used to
compare mean change from baseline between groups at each time point. Baseline
for stage 2 is the
patients' scores at the start of stage 2. Least squares mean treatment
differences are as follows: for
stage 1, week 1, ¨0.8 (95%CI, ¨1.5 to ¨0.03; P = .04), week 3, ¨1.0 (95%CI,
¨1.8 to ¨0.2; P = .01),
and week 5, ¨1.5 (95%CI, ¨2.3 to ¨0.7; P < .001); for stage 2, week 6, 0.7
(95%CI, ¨0.4 to 1.9; P =
.19), week 8, ¨0.1 (95%CI, ¨1.3 to 1.2; P = .93), and week 10, ¨1.6 (95%CI,
¨2.9 to ¨0.3; P = .02);
for 10-week analysis, week 1, ¨0.9 (95%CI, ¨1.8 to ¨0.04; P = .047), week 3,
¨1.3 (95%CI, ¨2.2 to
¨0.3; P = .01), week 5, ¨1.8 (95%CI, ¨2.7 to ¨0.9; P < .001), week 6, ¨0.9
(95%CI, ¨2.0 to 0.1; P =
.06), week 8, ¨1.3 (95%CI, ¨2.4 to ¨0.3; P= .01), and week 10, ¨1.8 (95%CI,
¨2.8 to ¨0.7; P = .003).
a Observed cases (Cummings et al., Effect of dextromethorphan quinidine on
agitation in patients with
Alzheimer Disease dementia: a randomized clinical trial. JAMA 314(12):1242-
1254 (2015),
incorporated in entirety by reference).
[0015] FIGURES 3A, 3B, and 3C show treatment effects on psychosis severity
reduction in the 6
week study period in the full analysis set. The full analysis set includes all
patients who received >1
dose and had a SAPS assessment at baseline and at least one afterward. Data
points show least squares
means (standard error). (A) SAPS-PD improvement. (B) Change in CGI-severity
score. (C) CGI-
improvement scores. SAPS=scale for assessment of positive symptoms.
CGI=clinical global
impression (Cummings et al., Pimavanserin for patients with Parkinson's
disease psychosis: a
randomized, placebo-controlled phase 3 trial. Lancet, 383(9916):533-40 (8
February 2014),
incorporated in entirety by reference).
[0016] FIGURES 4A, 4B, and 4C represent Lineweaver-Burk plots for the
inhibition of CYP2D6
and human liver microsomes (HLMs) by Compound 847 (canabiodiol, CBD).
Recombinant
CYP2D6 was incubated with (A) 3-[2-(N,N-Diethyl-N-methylammonium) ethyl]-7-
methoxy-4-
methylcoumarin (AMMC) in the presence of CBD (FIGURE 4A), (B) dextromethorphan
in the
presence of CBD (FIGURE 4B), and (C) in the absence of CBD (FIGURE 4C), HLMs
were
6
Date Recue/Date Received 2021-04-14
incubated with dextromethorphan in the presence or absence of CBD. Each point
is the mean of
duplicate determinations.
[0017] FIGURES 4D, 4E, and 4F represent effects of the major phytocannabinoids
A9-tetrahydro
cannabinol (A9-THC), CBD, and cannabinol (CBN) on AMMC and the
dextromethorphan 0-
demethylase activities of CYP2D6 and HLMs. Recombinant CYP2D6 was
incubated with (D) 0.6 M AMMC (FIGURE 4D), (E) 0.6 M dextromethorphan
(FIGURE 4E) in
the presence of various amounts of A9-THC, CBD, and CBN; and (F) HLMs were
incubated with 4
M dextromethorphan in the presence of various amounts of A9-THC, CBD, and CBN
(FIGURE
4F). Each point is the mean of two determinations (Yamaori et al.,
Cannabidiol, a Major
Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6, Drug Metabolism
and Disposition,
Vol. 39, No. 11(2011) incorporated in entirety by reference).
[0018] FIGURE 5 shows effects of(-) and (+) enantiomers of M1 as well as M-
100,907 on MK-801-
induced hyperactivity in rats. Data are presented as mean ( SEM) average
activity over a 60-min test
session. N=5-9 per group.
[0019] FIGURE 6 shows effects of sarpogrelate on motor activity in rats after
olfactory bulbectomy
(OBX) or sham surgery (SHAM). Data are presented as mean ( SEM) average
activity over a 5-min
test session. N=12 per group.
[0020] FIGURE 7 shows plasma level curves of sarpogrelate and M1 in male
Wistar rats after single
intravenous administrations of sarpogrelate hydrochloride (2 mg/kg). Data are
presented as mean
( SD) concentration (ng/ml). N=4.
[0021] FIGURE 8 shows plasma level curves of dextromethorphan in male Wistar
rats that received
dextromethorphan (50 mg/kg, per os) immediately followed by intravenous bolus
injection of
sarpogrelate (1, 3 or 10 mg/kg; racemate or one of the enantiomers) or vehicle
via vascular access port
at t = 0 h. Data are presented as mean ( SD) concentration (ng/ml). N=2-3.
[0022] FIGURE 9A, 9B, and 9C show effects of a combination of dextromethorphan
with Compound
50 racemate (upper panel), (-) Compound 51 (middle panel) or (+) Compound 52
on PCP-induced
hyperactivity in rats.
[0023] FIGURE 10 shows effects of dextromethorphan and sarpogrelate racemate
on blood glucose
level. Data are presented as area under the curve (mean+SEM) for blood glucose
level over the period
of time 30-180 min after oral glucose (2 g/kg) challenge. N=8 per group.
7
Date Recue/Date Received 2021-04-14
[0024] FIGURE 11A and 11B show the mean (SEM) concentrations of (a) buspirone
and (b) 1-PP
after administration of 20 mg buspirone after an 8-day pretreatment with
either 60 mg Compound 829
(closed square; n=10) or placebo (closed circle; n=10) once daily.
[0025] FIGURE 12A and 12B show the mean (SEM) plasma prolactin concentrations
(a) after
treatment with Compound 829, 60 mg (closed square; n=16), or placebo (closed
circle; n=16) once
daily for 7 days and (b) after concomitant administration of 20 mg of
buspirone after an 8-day
pretreatment with either 60 mg Compound 829 (closed square; n=16) or placebo
(closed circle; n=16)
once daily.
[0026] FIGURE 13 shows prodrug strategies for the most common functional
groups on parent drug
compounds of Formula I and II representd by R with general schemes
representing various
embodiments of prodrugs of compounds of Formulae I and II.
[0027] FIGURE 14A and 14B show the effect of compound 829 on discriminative
stimulus effects
of NMDA receptor channel blockers. Data are presented as mean ( S.E.M.)
percent of drug-lever
responses (upper panel) and response rate (responses per second; lower panel).
N=6.
[0028] FIGURE 15A shows the effect of compound 829 in combination with
memantine and in
combination dextromethorphan in the tail suspension test. Data are presented
as mean ( S.E.M.)
immobility time. N=8.
[0029] FIGURE 15b shows the effect of ritanserin in combination with memantine
in the tail
suspension test. Data are presented as mean ( S.E.M.) immobility time. N=7-8.
[0030] FIGURE 16A shows the effect of compound 829 and memantine on punlished
responding in
the Geller-Seiffer test. Data are presented as mean ( S.E.M.) number of
responses per session. N=4.
[0031] FIGURE 16B shows the effect of compound 829 and memantine on
unpunlished responding
in the Geller-Seiffer test. Data are presented as mean ( S.E.M.) number of
responses per session.
N=4.
[0032] FIGURE 17 shows the effect of compound 829 in combination with
memantine, and ritanserin
in combination with memantine on isolation-induced aggression. Data are
presented as mean (
S.E.M.) latency to the first attack. N=7.
[0033] FIGURE 18 shows the total concentration of compound 146 (M1) in plasma
and brain tissue.
The total brain and plasma concentration after intraperitonial administration
of a composition of the
invention comprising a compound of the Formula I, exemplified by Compound 146.
Data are
presented as mean ( S.E.M.) amount of compound in brain tissue extracts
measured using the
8
Date Recue/Date Received 2021-04-14
UPLC/MS analysis. N=4.
DETAILED DESCRIPTION OF THE INVENTION
[0034] Various embodiments of the inventive Targeted Drug Rescue (TDR)Tm
comprising novel
compositions, and combinations, therapeutic formulations, symptomatic and
disease-modifying
treatments, therapies, kits thereof, and methods of making such compositions,
combinations,
therapeutic formulations, treatments, therapies, and kits comprising
biologics, chemicals, nutritionals,
pharmaceuticals, compositions, treatments, therapies, cures, prophylactics,
supplements, and
formulations, including the disclosures of patent applications US 62/501,693
filed 05/04/2017,
PCT/US2017/048748 filed 08/25/2017 published WO 2018/039642 Al 03/01/2018, TW
106129169
filed 08/28/2017, US 62/634,162 filed 02/22/2018, US 62/636,171
filed
02/22/2018, US 62/635,554 filed 02/27/2018, and US 62/636,099 filed
02/27/2018.
[0035] An embodiment of the invention is a composition comprising a compound
of formula I:
R2
R( (CH2)õ
R4 R3
Formula I' wherein, Ri and R2 are independently H, substituted or
unsubstituted C1_10 alkyl,
substituted or unsubstituted C5-10 aryl, substituted or unsubstituted C3-10
cycloalkyl-05-10 aryl,
substituted or unsubstituted C4_10 bicycloalkyl, substituted or unsubstituted
C4_10 bicycloalkyl-05-10
aryl, substituted or unsubstituted C4_10 bicycloalkyl-05_10 heteroaryl, or
substituted or unsubstituted C5-
10 heteroaryl, or Ri and R2 together with the nitrogen form a saturated or
unsaturated heterocycle
having one or more hetero atoms selected from N, 0, and S;
R3 is independently H, substituted or unsubstituted Ci_io alkyl, substituted
or unsubstituted C5_10 aryl,
substituted or unsubstituted C5-10 heteroaryl, substituted or unsubstituted C3-
10 cycloalkyl-05_10 aryl,
substituted or unsubstituted C4_10 bicycloalkyl, substituted or unsubstituted
C4_10 bicycloalkyl-05-10
aryl, substituted or unsubstituted C4_10bicycloalkyl-05_10heteroaryl or
substituted or unsubstituted C5
-
heteroaryl; n is an integer from 0 to 5; R4 is H, NH-R5, S-R5, -OH, O-R5, ¨CO-
R5,-0-CO-R5, or ¨
C0-0-R5, wherein R5 is an acyl radical; or R5 and R2 form a heterocycle; or
enantiomers thereof,
metabolites thereof, derivatives thereof, and/or prodrugs thereof,
pharmaceutically acceptable salts
thereof, N-oxides thereof, or a combination thereof.
9
Date Recue/Date Received 2021-04-14
[0036] An embodiment is a compound of Formula I, wherein the substituted or
unsubstituted C4-10
cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl,
or cyclodecyl radical. In another embodiment, the cycloalkyl comprises one or
more heteroatoms N,
S, or O.
[0037] Another embodiment is a compound of Formula I, wherein the substituted
or unsubstituted C3-
bicycloalkyl is bicyclobutyl, bicyclopentyl, bicyclohexyl, bicycloheptyl,
bicyclooctyl, bicyclononyl,
or bicyclodecyl radical. In another embodiment, the bicycloalkyl comprises one
or more heteroatoms
N, S, or O.
[0038] Another embodiment is a compound of Formula I, wherein the aryl is
phenyl, naphtyl,
10 anthracenyl, or phenanthrenyl.
[0039] In another embodiment, the compound is a compound of Formula I wherein
R5 is an acyl
radical selected from the group consisting of mono, di, and tri carboxylic
acid radicals.
[0040] In another embodiment, the compound is a compound of Formula I wherein
R5 is an acyl
radical selected from the group consisting of acetate, acetyl salicylate,
adipate, N-acyl-aspartate,
aspartate, butyrate, caprate, caproate, caprylate, enanthate, formate,
fumarate, N-acyl-glutarate,
glutarate, isophthallate, maleate, malonate, methionate, N-acyl-methionate
oxalate, pelargonate,
pimelate, propionate, phthallate, salicylate, sebacate, succinate,
terephthallate, tyrosinate, N-acyl-
tyrosinate, tryptophanate, N-acyl-tryptophanate, and valerate.
[0041] Another embodiment is a compound of Formula
-127 R7 't)
R9
RIO RIO
H H Rs
Ro Re
Formula Ila Formula II b wherein, R6, R7, and R8 are independently H, D,
Ci_to-alkyl, halo Ci-to-
alkyl wherein halogen is F, Cl, or Br; R9 and Rio are independently H; CI-to-
alkyl; halo CI-to-alkyl
wherein halogen is F, Cl, or Br; OH; or R9 and Rio together form a five-
membered heterocycle
wherein the hetet. atom is 0, S, or N.
[0042] Another embodiment is a compound of Formula I, wherein R5 and R2 form a
heterocycle
selected from the radicals such as morpholine, dihydrooxazine, oxazine,
piperazine, dihydropiperzine,
and tetrahydropirazine. Compounds of this embodiment include, but not limited
to, the following
compounds 10-24:
Date Recue/Date Received 2021-04-14
R30
_tsc7T HN- FENT-
p
0
,,.,õ,131a. la
Compound 10 Compound 11 Compotmd 12 Compound 13 Compound 14 Compound 15
Compound 16 Compotmd 17 Pura- I nsntiomer
CL62,_Hsi_%11µ=13.1-4 052H p, Rye RZ
Formula Ib
Compound 18 Compotmd 19 Compound 20 Compound 21
Compound 22 Compound 23 Compotmd 24
Pure Enantiomer
[0043] Another embodiment is a pure enantiomer of Formula I selected from
Formula Ia or lb.
[0044] In another embodiment, the compound of Formula I, wherein Ri, R2, and
R3 are methyl,
provided X is not ethyl.
[0045] In another embodiment, the composition comprising Formula I is
sarpogrelate (SARPO),
wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is succinoyl radical,
having the following
compounds SGL, SGL-El, and SGL-E2.
[0046] In another embodiment, the composition comprising formula I is
sarpogrelate metabolite Ml,
wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is OH, having the
following compounds Ml,
Ml-El, and Ml-E2.
[0047] In another embodiment, the composition comprising formula I is
sarpogrelate metabolite Ml,
wherein Ri and R2 together with the nitrogen form a saturated or unsaturated
heterocycle having one
or more hetero atoms selected from N, 0, and S; and R3 is methyl, X is ethyl,
and R4 is OH. In another
embodiment, the heterocycle is a five-membered ring. Another embodiment is
where the heterocycle
is a six-membered ring. In another embodiment, the heterocycle is saturated.
Another embodiment has
the unsaturated heterocycle. In one embodiment the heterocycle has one hetero
atom. In another, the
heterocycle has two hetero atoms.
[0048] In another embodiment, the compound of formula I, wherein the
heterocycle formed from Ri
and R2 together with the nitrogen is selected from the heterocycles listed
below:
9 /-? 9 2' 9 "9 9 C37 9 9 cP 20 9 9
[0049] The term "DEX" represents a compound of Formula II, such as
dextromethorphan,
enantiomers thereof, metabolites thereof, derivatives thereof, and/or prodrugs
thereof, or a
combination thereof. Derivatives include, but not limited to, deuterated
derivatives, e.g., DEX-H3,
DEX-D3, DO, and DO-D3.
[0050] The term "SARPO," represents one or more compounds selected from the
group consisting of
sarpogrelate (SGL), enantiomers thereof, a metabolite thereof, Ml, SG1, SG2,
SMG1, SMG2, SMG3,
a derivative thereof, a prodrug thereof, and a combination thereof.
11
Date Recue/Date Received 2021-04-14
[0051] The term SARPODEXTm represents a combination of DEX and a compound of
Formula I. An
embodiment of the invention is a composition comprising a compound of formula
I and
dextromethorphan. An embodiment of the invention is a composition comprising a
compound of
formula I and DEX-H3, DEX-D3, DO, or DO-D3. An embodiment of the invention is
a composition
comprising: Ml, Ml-El, Ml-E2, SGL, SGL-El, or SGL-E2; and DEX-H3, DEX-D3, DO,
or DO-D3.
100521 The term DERADEXTM or DERAPHANTm represents a combination of DEX and a
compound
of Formula I, wherein the compound is a derivative of bicyclo[2.2.1]heptanol
having the Formula I:
R2
Rj (CH2).
R4)N"
R3
Formula I, wherein R3 is a bicyclic system and the rest of the Formula I
represented by R7: as
shown in Formula If
R6
0
R7
Formula lf, wherein, R6 is H, substituted or unsubstituted -C1_10 alkyl,
substituted or
unsubstituted -C3_10 cycloalkyl, substituted or unsubstituted -05_10 aryl,
substituted or unsubstituted -
C1_10 alkyl- C5-10 aryl, substituted or unsubstituted -05_10 heteroaryl, or
substituted or unsubstituted -
C1_10 alkyl- C5_10 heteroaryl;
cag.
R7 is 10alkyl-X-00., -C3 10 cycloalkyl-X-(Y)., -0510 aryl-X-
(Y)m, or -05 10 heteroaryl-
1 5 X-(Y)m; wherein X is a bond, N, 0, S, -C1_10 alkyl, -C3_10 cycloalkyl, -
05_10 aryl, -CO-Cm alkyl, -CO-
C3-10 cycloalkyl, -0005_10 aryl, -CO-05_10 heteroaryl, -CO-NH-C11 alkyl, -CO-
NH-C3_10 cycloalkyl, -
CO-NH- C5_10 aryl, Or -CO-NH-05_10 heteroaryl; Y is H, C1_10 alkyl, C3_10
cycloalkyl, C5_10 aryl, -CO-
Ci-m alkyl, -CO- C3-10 cycloalkyl, -C005_10 aryl, CO-05_10 heteroaryl, -CO-NH-
C1-10 alkyl, -CO-NH-
C3-10 cycloalkyl, -CO-NH- C5-10 aryl, or -CO-NH-05_10 heteroaryl; and m is an
integer 1 or 2; or
pharmaceutically acceptable salts or N-oxides thereof; or prodrugs thereof.
[0053] The term DERATINETm represents a combination of an NMDA receptor
antagonist and and a
compound of Formula I, as defned above.
100541 The term SARPOTINETm represents a combination of an NMDA receptor
antagonist and and
a compound of Formula I, as defned above.
12
Date Recue/Date Received 2021-04-14
[0055] An embodiment of the invention is a composition comprising a compound
of Formula I and
DEX-H3, DEX-D3, DO, or DO-D3.
100561 In another embodiment, a compound of Formula I or analogs can be made
using the following
carboxylic acids: Malic Acid HO2C-CH2-CH(OH)-CO2H (Compounds 25-29),
Methionine H3C-S-
(CH2)2-CH(NH2)-CO2H (Compounds 30-34), Phthallic Acid C6114(CO2H)2 (Compounds
35-37),
MaIonic Acid HO2C-CH2-CO2H (Compounds 38-40), Tyrosine HO-C6H4-CH2-CH(NH2)-
CO2H
(Compounds 41-43), Tryptophan C8H6N-CH2-CH(NH2)-CO2H (Compounds 44-46), Maleic
Acid
HO2C-CH=CH-CO2H (Compounds 47-49), Succinic Acid HO2C-(CH2)2-CO2H (Compounds
50-52),
Glutaric acid HO2C-(CH2)3-CO2H (Compounds 53-55), Adipic Acid 1102C-(CH2)4-
CO2H
(Compounds 56-58), Pimelic acid HO2C-(CH2)5-CO2H (Compounds 59-61), Sebacic
acid HO2C-
(CH2)6-CO2H (Compounds 62-64), Formic acid HCO2H (Compounds 65-67), Acetic
acid CH3CO2H
(Compounds 68-70), Propionic acid CH3CH2CO2H (Compounds 71-73), Butyric acid
CH3(CH2)2CO211 (Compounds 74-76), Valeric acid CH3(CH2)3CO2H (Compounds 77-
79), Caproic
acid CH3(CH2)4CO2H (Compounds 80-82), Enanthic acid CH3(CH2)5CO2H (Compounds
83-85),
Caprylic acid CH3(CH2)6CO2H (Compounds 86-88), Pelargonic acid CH3(CH2)7CO2H
(Compounds
89-91), Capric acid CH3(CH2)8CO2H (Compounds 92-94), Oxalic Acid HO-CO-CO2H
(Compounds
95-97), Isophthallic Acid C6H4(CO2H)2 (Compounds 98-100), Terephthallic Acid
C6H4(CO2H)2
(Compounds 101-103), Salicylic Acid HO-C6H4-CO2H (Compounds 104-106), Acetyl
Salicylic Acid
CH3-00-0-C6H4-CO2H (Compounds 107-109).
[0057] An embodiment of the invention is a compound of formula I, wherein the
compound is
sarpomalate, wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is malate;
compounds 25-29. An
embodiment of the invention is a compound of formula I, wherein the compound
is sarpomethionate,
wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is methionate; compounds
30-34. An
embodiment of the invention is a compound of formula I, wherein the compound
is sarpophthallate,
wherein Ri, R2, and R3 are methyl, X is ethyl, and R4 is phthalate; compounds
35-37. An embodiment
of the invention is a compound of formula I, wherein the compound is
sarpomalonate, wherein R1, R2,
and R3 are methyl, X is ethyl, and R4 is malonate' compounds 38-40. An
embodiment of the invention
is a compound of formula I, wherein the compound is sarpotyrosinate, wherein
Ri, R2, and R3 are
methyl, X is ethyl, and R4 is tyrosinate; compounds 41-43. An embodiment of
the invention is a
compound of formula I, wherein the compound is sarpotryptophanate, wherein Ri,
R2, and R3 are
methyl, X is ethyl, and R4 is tryptophanate; compounds 44-46. In an
embodiment, the composition is
13
Date Recue/Date Received 2021-04-14
a combination of DEX and at least one compound selected from compounds 10-46,
SGL, SGL-El,
SGL-E2, Ml, MI-El, Ml-E2. An embodiment of the invention is a composition
comprising a
compound of formula I, wherein the compound is sarpogrelate, and
dextromethorphan.
[0058] An embodiment of the invention is a composition comprising a compound
of formula I,
wherein the compound is sarpogrelate, and dextromethorphan, wherein
sarpogrelate and
dextromethorphan form diastereomeric mixture.
:c0H)hA0) ii4 ¨fuV UW(A ,41,L A SI j(z Jo
)-0 IL s HIT
-) I 0¨/ ' L uH D¨/ OH H "H
H
compound 25 6
OH
Compound 26 Command 27 Compound 28
Compound 29 0 Compound 30 ,Ilv
0/ S¨
ry
i_ HO
ix.\
0¨)¨D)C15 \ IV Hj \- L / b( 0¨/¨D / \' ¨(2-113
ampoimd 3L 2 37 7\to
6 Compound 33 ¨2
6 conwom N'12 u
¨ Compound 35 D¨/-
13) \DC( õ
OCompound 36
[0059] An embodiment of the invention is a composition comprising a compound
of formula I,
wherein the compound is sarpogrelate, and dextromethorphan, wherein
sarpogrelate and
dextromethorphan form a salt, wherein the salt is a diastereomeric mixture. An
embodiment of the
invention is a composition comprising a compound of formula I, wherein the
compound is
sarpogrelate, and dextromethorphan, wherein sarpogrelate and dextromethorphan
form a salt, wherein
the salt is a pure diastereomer. An embodiment of the invention is a
composition comprising a
compound of formula I, wherein the compound is sarpogrelate metabolite Ml, and
dextromethorphan.
An embodiment of the invention is a composition comprising dextromethorphan
and a compound of
formula I, wherein the compound is sarpomalate, forming a salt comprising
diastereomeric mixture or
a pure diastereomer thereof. An embodiment of the invention is a composition
comprising a compound
of formula I, wherein the compound is sarpomethionate, and dextromethorphan,
forming a salt
comprising diastereomeric mixture or a pure diastereomer thereof. An
embodiment of the invention is
a composition comprising a compound of formula I, wherein the compound is
sarpophthallate, and
dextromethorphan, forming a salt comprising diastereomeric mixture or a pure
diastereomer thereof.
An embodiment of the invention is a composition comprising a compound of
formula I, wherein the
compound is sarpomalonate, and dextromethorphan, forming a salt comprising
diastereomeric mixture
or a pure diastereomer thereof. An embodiment of the invention is a
composition comprising a
compound of formula I, wherein the compound is sarpotyrosinate, and
dextromethorphan, forming a
14
Date Recue/Date Received 2021-04-14
salt comprising diastereomeric mixture or a pure diastereomer thereof. An
embodiment of the
invention is a composition comprising a compound of formula I, wherein the
compound is
sarpotryptophanate, and dextromethorphan, forming a salt comprising
diastereomeric mixture or a
pure diastereomer thereof.
[0060] An embodiment of the invention is a composition comprising a compound
of formula I,
wherein the compound is SGL, and dextromethorphan HC1, forming a salt
comprising diastereomeric
mixture or a pure diastereomer thereof. An embodiment of the invention is a
composition comprising
a compound of formula I, wherein the compound is SGL, and dextromethorphan
HBr, forming a salt
comprising diastereomeric mixture or a pure diastereomer thereof. An
embodiment of the invention is
a composition comprising a compound selected from the group consisting of SGL,
enantiomers
thereof, a metabolite thereof, Ml, SG1, SG2, SMG1, SMG2, SMG3, a derivative
thereof, a prodrug
thereof, and a combination thereof. An embodiment of the invention is a
composition comprising a
compound selected from the group consisting of SGL, enantiomers thereof, a
metabolite thereof, Ml,
SG1, SG2, SMG1, SMG2, SMG3, a derivative thereof, a prodrug thereof, and a
combination thereof,
and dextromethorphan.
[0061] Another embodiment is a compound of Formula 1, wherein the Ra and R2
form a five- or six-
membered heterocyclic moiety, exemplary compounds are compounds 110-145. An
embodiment of
the invention is a composition comprising a compound selected from the group
consisting of SGL,
enantiomers thereof, a metabolite thereof, Ml, SG1, SG2, SMG1, SMG2, SMG3, a
derivative thereof,
a prodrug thereof, and a combination thereof, and dextromethorphan.
Date Recue/Date Received 2021-04-14
00 Oil d
N- d
4-b
d , d eN_ d
4b 3-CCEk-81-11,00.12
11:2-h_pi,_ ins P__63)411.V.)ty
If
Ifs.
If
110 11Cr.
110
Compound 38 Compound 39 Compound 40 Compound 41 Compound
42 Compound 43 Compound 44 Compound 45 Command 46
d N_ d d N_ d N- let N- IQ co- in-
% (Zo % 14-Zo .-----6 )-Zo .4443/11 --j 111 --d tr
g-84:1)gil cE--4.311k-
c,,,,,,,,,,,d 47 co.peu..4 48 Compound 49 Compound 50
compound 51 Compound 52 Compound 53 Compound 54 Q.v.., 5,
qb __
--\ :1%t
CM>
0 .4-011 t -011 ci
(-011
Compound 56 Compound 57 ........ couwouna 54 Compound 59 Comp I
60 ( pound ol Compound 62 Compound 61 Compolod 64
17 0%to 0%14\1.6-1 4 _ 00 -
µ311)4)0_,õ _õ(--
_4c3D
Compound 65
Compound 66 Compound 67 Compound 68 Compound 69 Coo1P0ood 70 Compound 71
ComPouud n Compound 73 Compound 74 Compound 73
Compound 76 Compound /7 Compound 78 Compound 79 Compound SO Compound SI
Compound 62 Compound 113 Compound 64 Compound 85 Compound 86 Compound 87
0' 0L 6 I 0'I 01
d_4 OH
d
H 6'01?3
0 H
Compound 88 Compoomd 89 Cannoned 90 Compound 91 Compound 92 Compound 93
Compound 94 Compound 95 Compoold 96 Compound 97 Compound 104
0
Oil ()XII 04,6'4 0 11 0 0 011 0, KI1 0 Ho
. Tr
1() 44 ?I: A491. )1' 1 (?611V1 I.Yr
Compound 98 Compost! 99 Commend 100 Compost! 101 Compound 102 Commend 103
Compound 105 Compound 106 Compound 107 Compound 108 Compound 109
o o UN S
C,), 0
Q d Qd si), d 0, d Q d IT_7), 0 -,..) d HZ!), d 4
t!), d d)..,
110 110-S 110. liff 1 1 t p 1 1 110j) 1 110-$ )-1
d 8
Compound 110 Compound 111 Compound 112 Compound 113 Compound 114 Compound 115
Compound 116 Compound 117 Comma 118 Compound 119 Compound120 Compound 121
r) d t), d Z,), d HQN d It), d
fro d
Q d Q d
1 Bio..g). H?:r pic,: 110-T 1110.. P 110 P 110- r HO-cT 1104:r no- r
0 D D
0
Compound 122 Compound 123 Compound 124 Cawood 125 Compound 126 Compound 127
Compound 128 Compound 121 Compound i30 Compound 131 Compound 132 Compound
133
fl)? d d
d 4 4
Q d Q d q ,
V II N 6 IIA d HN2 0 N\ d
ts1 0 17:1 11
HO:r= HOS HO. HO HO- 110X
110 .1 ' ' io-o=T lIt) HO .i, 110-?:r 110.. p
0 0
c.) d
Compound 134 Compound 135 Compound 136 Common 137 Compound 138 Compound 139
Compound 140 Compound 141 Compound 142 Compound 143 Compound 144 Compound 145
16
Date ecue/Date Received 2021-04-14
[0062] In another embodiment, examples of the compound of formula I, wherein
the heterocycle
formed from R1 and R2 together with the nitrogen, represented by the compounds
having Formulae
Ic-Is comprising saturated (shown below) and unsaturated heterocycles:
R3¨ ¨ R3.0 kli R30 s R30 R30 = R30 R30
R30
Q ou (u)
N 0 CND 0 CN) 0 iry- b c) a n rs
N,,N1H 0 <NI) b
(Nox ; x=( x=r xR,rcc,x Lox
R7u) ,1 L X
R4------ot 0 R4 'a '
IW R4 t
Formula Is Formula lh Formula li
Formula k Formula Id Formula le
Formula If Formula lj
R30 R30 R30 R30 R30 R3.0 R30
R30
lc b c-,,,NH a cS ash, H14\1N-Ir H1µ1N-D ) H1U ?IT (õ1
UH
x K- x x x).) xJ.) x Wi K xJ.)
R4ot R.,,rot R4,ot RyCot R4,0,6 R4,0,6 R4Ø10
Formula 1 Formula II Formula Im Formula In
Formula To Fomiula Ip Formula Ir Formula Is
100631 In another embodiment, the compound is a compound of Formulae Ic-Is,
wherein the 5-
membered heterocycle is unsaturated.
[0064] In another embodiment, the composition comprises DEX and a compound of
formula I and/or
prehexiline, flecainide, quinidine, (R)-propaphenone, (S)-propaphenone,
isoniazid, (R)fluoxetine,
(S)fluoxetine, nefazodone, paroxetine, ketoconazole, chloroquine, oxamniquine,
primaquine, quinine,
acetbutolol, betaxolol, bufuralol, oxprenolol, pindolol, propranolol,
budipine, simvastatin, fluvastatin,
lovastatin, pravastatin, perazine, ajamlicine, corynanthine, loheline, or
derivatives thereof_
[0065] In another embodiment, the composition comprising formula I, wherein
Ri, R2, and R3 are
methyl, X is ethyl, and R4 is OH, represented by the following compounds Ml,
Ml-El, and Ml-E2.
OH 1 0 rN 0
N
OH
r 1
,,õõ .,
Ior. 0
Compound 146 Compound 147 Compound 148
Racemate MI Enantiomer I (MI-El) Enantiomor 2 (M1 L-E2)
(R)-1-(dimethylamino)-3-(2-(3-
1-(dimethylamino)-3-(2-(3- (S)-1-
(dimethylamino)-3-(2-(3- methoxyphenethyl)phenoxy)propan-2-ol
methoxyphenethyl)phenoxy)propan-2-ol methoxyphenethyl)phenoxy)propan-2-ol
,C11
-- 0--
H
_
'N")r o ICo "II'. u
I I
Compound 50 Compound 51 Compound 52
Sarpogretate Racemate (SGL) Sarpogrelate Enantiomer 1 (SGL-E1)
Sarpogrelate Enantiomer 2 (SGL-E2)
4-((1-(dimethylamino)-3-(2-(3- (S)-4-((1-(dimethylamino)-3-(2-(3- (R)-4-
((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy)propa
methoxyphenethyl)phenoxy)propan- methoxyphenethyl)phenoxy)propan-2-
n-2-yl)oxy)-4-oxobutanoic acid 2-y1)oxy)4-oxobutanoic acid yl)oxy)-
4-oxobutanoic acid
17
Date Recue/Date Received 2021-04-14
[0066] In another embodiment, the composition comprising formula I, wherein
RI, R2, and R3 are
methyl, X is ethyl, and R4 is succinoyl radical, represented by the following
compounds SGL, SGL-
El, and SGL-E2.
[0067] In one embodiment, the composition comprises a formula I, wherein R5 is
¨0(C0)-C112-CH2-
(CO)O-Y, wherein an alkyl, cycloalkyl, aryl, heteroaryl, -akenyl-aryl, -
aralkyl, alkyl-0NO2,
cycloalkyl-0NO2, aryl-0NO2, heteroaryl-0NO2, -akenyl-aryl-0NO2, and -aralkyl-
0NO2, as
exemplified, but not limited to, the following: 1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy)propan-2-y1 methyl succinate, 1-
(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy)propan-2-y1 ((nitrooxy)methyl) succinate, 1-
(dimethylamino)-3-(2-(3-
methoxyphenethyl) phenoxy)propan-2-y1 (2-(nitrooxy)ethyl) succinate, 1-
(dimethyl amino)-3-(2-(3-
methoxyphenethyl)phenoxy)propan-2-y1(3-(nitrooxy)propyl)succinate, 1-(dimethyl
amino)-3-(2-(3-
methoxyphenethyl) phenoxy)propan-2-y1 (4-(nitrooxy)butyl) succinate, 4-((1-
(dimethylamino)-3-(2-
(3-methoxyphenethyl) phenoxy)propan-2-y0oxy)-4-oxobutanoic nitric anhydride,
etc.
0
...0_I0 G';.178Ør.,_
jito ,No(H.)20...x..._Jc OzNO(HzCh0..rj--.0 cozNO(Hze),0 0 OZNOr------
L-0
0 õO
õ0 so
- le õo so _oX.)
Compound 177 Compound 178 Compound 179 Compound 180
Compound 181 Compound 182
OH
Air 0
0
#11141110-
FICe
"
DEX-H3 DEX-03 DO-143 n0-D3
Compound 154 Compound 155 Compound
Compound 149 Compound 150 Compound 151 Compound 153
156
¨N
0 OH
H N\
¨N Hz Nil
HO \
Ketamme Methadone Dextro-propoxyphene Ketobemidone Memantine A-mwnwii'v
Compound 157Compound 159 Compound 160 Compound 161 Compound 162
Compound 898 Compound 899
[0068] In one embodiment, the composition comprises DEX-113, DEX-D3, DO, DO-
D3,
levomethorphan, morphine, codeine, thebaine, benzocaine, ketamine, methadone,
memantine (3,5-
dimethyladamantan- 1 -amine), amantadine, dextropropoxyphene 42R)-4-
(dimethylamino)-3-methy1-
1,2-diphenylbutan-2-y1 propionate), ketobemidone (1-(4-(3-hydroxypheny1)-1-
methylpiperidin-4-
yl)propan-1 -one), tropane alkaloids such as cocaine, atropine, scopolamine,
etc.
[0069] In another embodiment, the composition comprises a combination of a
compound of Formula
I and a compound of Formula II comprising DEX-113, DEX-D3, DO, DO-D3,
levomethorphan,
morphine, codeine, thebaine, or benzocaine; and /or ketamine, methadone,
memantine, amantadine,
dextropropoxyphene, ketobemidone, cocaine, atropine, or scopolamine.
[0070] In another embodiment, the composition comprises a combination of a
compound of Formula
18
Date Recue/Date Received 2021-04-14
I and ketamine, methadone, memantine, amantadine, dextropropoxyphene,
ketobemidone, cocaine,
atropine, or scopolamine, wherein the compound of Formula I is racemic
compound 50 (sarpogrelate),
racemic compound 146 ( M1), or compound 829 (deramciclane). In another
embodiment, the
composition comprises memantine. In another embodiment, the composition
comprises sarpogrelate
and memantine. In another embodiment, the composition comprises enatimerically
pure S-compound
51 (S-sarpogrelate) and R-compound 52 ( R-sarpogrelate)) and memantine. In
another embodiment,
the composition comprises enatimerically pure S-compound 147 (S-M1), R-
compound 148 (R-M1),
and memantine. In another embodiment, the composition comprises
enantiomerically pure
deramciclane and memantine.
[0071] In another embodiment, the compound of the invention is a compound
Formula I, wherein, R1,
R2, and R3 are independently substituted with one, two or three halogens,
wherein the halogen is F,
Cl, or Br. Examples of fluorine derivatives of Formula I:
F _ F¨i:_ _r FV )4¨
F i -
' -µ' 0
H7 1-1,3 1-15--/-4-3 11 110'--/--µ-µ: H :?S¨P-
C30 HO)'--/-4
'Ir H Ir
.1WV F .1WV 4W
C xupond 167 Compound 168
Compound 169 Compound 170 Compound 171 Compound 172 Ca-441,4,41d 173
co.,..,.....1 174 c.1 175
[0072] In another embodiment, a compound of Formula I or analogs can be made
using the following
carboxylic acids: difluorosuccinicacid, HO2C-CF2-C112-CO2H (201-206),
trifluorosuccinic acid,
1102C-CF2-CHF-0O211 (207-212), tetrafluorosuccinic acid,
HO2C-(CF2)2-CO2H,
difluorosuccinicacid (213-215), HO2C-CHF-CHF-CO2H (216-219), difluoroglutaric
acid, 1102C-
(C112)2-CF2-0O214 (219-221), difluoroglutaric acid, H02C- CF2- (CH2)2-0O2H
(222-225),
difluoroacetic acid, 1102C-CF211 (226-228), and trifluoroacetic acid, HO2C-CF3
(229-231).
Compounds 201-203 Compounds 207-209 8 Comzunds 216-218
Compounds 219-221 b Compounds 226-228
o b
iv- iv-
-14
0 F Nca)::-Ncc_I F0 F
Fl b
F ) d
0
r..
F FF-0
Compounds 204-206 Compounds 210-212
Compounds 213-215 Compounds 222-224 Compounds 229-231
[0073] In another embodiment, a compound of Formula I is Formula Ic or Formula
Id, as defined
above, and derivatives thereof comprising acid addition salts selected from:
acetate, acetyl salicylate,
adipate, aspartate, butyrate, caprate, caproate, caprylate, enanthate,
formate, fumarate, glutamate
glutarate, isophthallate, maleate, malonate, methionate, oxalate, pelargonate,
pimelate, propionate,
19
Date Recue/Date Received 2021-04-14
phthallate, salicylate, sebacate, succinate, terephthallate, tyrosinate,
tryptophanate, valerate, N-acyl-
aspartate, N-acyl-glutamate, N-acyl-tyrosinate, N-acyl-tryptophanate, N-acyl-
methionate, citrate,
galactonate, glucaric acid (saccharic acid), mannonate, mucate, rhamnonate,
and tartrate.
[0074] In another embodiment, a compound of Formula I is Formula Ic or Formula
Id, as defined
above, and derivatives thereof comprising acid addition salts formed from di
and tri carboxylic acids
selected from: adipic acid, aspartic acid, N-acyl aspartic acid, citric acid,
fumaric acid, galactonic acid,
glutaric acid, glutamic acid, N-acyl glutamic acid, glucaric acid (saccharic
acid), malic acid, maleic
acid, mannonic acid, mucic acid, oxalic acid, pimelic acid, phthallic acid,
isophthallic acid,
terephthallic acid, rhamnonic acid, sebacic acid, succinic acid, and tartaric
acid.
[0075] Another embodiment is a composition comprising a derivative of a
compound of Fonnula Ic
or Formula Id, and a derivative of a compound of Fonnula II, wherein the
derivative of Formula Ic,
Formula Id, and Formula II thereof is independently an acid addition salt:
hydrogen acetate, hydrogen
acetyl salicylate, hydrogen adipate, hydrogen aspartate, hydrogen butyrate,
hydrogen caprate,
hydrogen caproate, hydrogen caprylate, hydrogen enanthate, hydrogen formate,
hydrogen fumarate,
hydrogen glutamate, hydrogen glutarate, hydrogen isophthallate, hydrogen
maleate, hydrogen
malonate, hydrogen methionate, hydrogen oxalate, hydrogen pelargonate,
hydrogen pimelate,
hydrogen propionate, hydrogen phthallate, hydrogen salicylate , hydrogen
sebacate, hydrogen
succinate, hydrogen terephthallate, hydrogen tyrosinate, hydrogen
tryptophanate, hydrogen valerate,
hydrogen N-acyl-aspartate, hydrogen N-acyl-glutamate, hydrogen N-acyl-
tyrosinate, hydrogen N-
acyl-tryptophanate, hydrogen N-acyl-methionate, hydrogen citrate, hydrogen
galactonate, hydrogen
glucaric acid (saccharic acid), hydrogen mannonate, hydrogen mucate, hydrogen
rhamnonate, and
hydrogen tartrate.
[0076] Another embodiment is a composition comprising an acid addition salt of
dextromethorphan
and M1 selected from: dextromethorphan and M1 dihydrogen adipate,
dextromethorphan and M1
dihydrogen aspartate, dextromethorphan and M1 dihydrogen fumarate,
dextromethorphan and M1
dihydrogen glutamate, dextromethorphan and M1 dihydrogen glutarate,
dextromethorphan and M1
dihydrogen isophthallate, dextromethorphan and M1 dihydrogen maleate,
dextromethorphan and M1
dihydrogen malonate, dextromethorphan and M1 dihydrogen oxalate,
dextromethorphan and M1
dihydrogen pimelate, dextromethorphan and M1 dihydrogen phthallate,
dextromethorphan and M1
dihydrogen sebacate, dextromethorphan and M1 dihydrogen succinate,
dextromethorphan and M1
dihydrogen terephthallate, dextromethorphan and M1 dihydrogen N-acyl-
aspartate, dextromethorphan
Date Recue/Date Received 2021-04-14
and Ml dihydrogen N-acyl-glutamate, dextromethorphan and Ml dihydrogen
citrate,
dextromethorphan and Ml dihydrogen galactonate, dextromethorphan and Ml
dihydrogen glucarate,
dextromethorphan and M1 di hydrogen saccharate, dextromethorphan and M1
dihydrogen mannonate,
dextromethorphan and Ml dihydrogen mucate, dextromethorphan and Ml dihydrogen
rhamnonate,
and dextromethorphan and Ml dihydrogen tartrate.
100771 In another embodiment, a compound of Formula I is Formula Ic or Formula
Id, as defined
above, and fluoro derivatives thereof. In another embodiment, a compound of
Formula I is a compound
of Formula Ic or Formula Id, wherein the compound is Fluoro Derivative (FD) of
Formula Ic (FDIc)
or Formula Id (FDId), selected from compounds 221 ¨ 269, and dextromethorphan
or a compound of
Formula II as defined above.
[0078] Another embodiment is a composition comprising an acid addition salt of
dextromethorphan
and FDIc selected from: dextromethorphan and FDIc dihydrogen adipate,
dextromethorphan and FDIc
dihydrogen aspartate, dextromethorphan and FDIc dihydrogen fumarate,
dextromethorphan and FDIc
dihydrogen glutamate, dextromethorphan and FDIc dihydrogen glutarate,
dextromethorphan and FDIc
dihydrogen isophthallate, dextromethorphan and FDIc dihydrogen maleate,
dextromethorphan and
FDIc dihydrogen malonate, dextromethorphan and FDIc dihydrogen oxalate,
dextromethorphan and
FDIc dihydrogen pimelate, dextromethorphan and FDIc dihydrogen phthallate,
dextromethorphan and
FDIc dihydrogen sebacate, dextromethorphan and FDIc dihydrogen succinate,
dextromethorphan and
FDIc dihydrogen terephthallate, dextromethorphan and FDIc dihydrogen N-acyl-
aspartate,
dextromethorphan and FDIc dihydrogen N-acyl-glutamate, dextromethorphan and
FDIc dihydrogen
citrate, dextromethorphan and FDIc dihydrogen galactonate, dextromethorphan
and FDIc dihydrogen
glucarate, dextromethorphan and FDIc di hydrogen saccharate, dextromethorphan
and FDIc
dihydrogen mannonate, dextromethorphan and FDIc dihydrogen mucate,
dextromethorphan and FDIc
dihydrogen rhamnonate, and dextromethorphan and FDIc dihydrogen tartrate.
21
Date Recue/Date Received 2021-04-14
F F
F
1 *1 91 0
* 7=
F; N n;;171"
I F
1 H 40 4 . 1 77N irPITI 4 õ 1
-11.-T'T 1''''',.--0 * Fl7FF 44* F.... õ*
11-6; 0 * 140 õ OHCon 10 õ
Pound 231-233 F 4 Compound 234-236 FA 1 F 4
F.11r 6 Al; F 1
Compound 737-9 Compound 240-2 Compound
243-5 Compound 246-8
4"Th---10 * 14F Air FT ,.-,
¨2-a7 4 o " -- OH 41 - N OF--1 * 4
F i N sr.p" 4 0 I 7N -'t.p9 .11 41 0 ' -,tic---,--g." 4 o
Compound 249-251 F ti1F Compound 252-4 Ft Compound 255-7 111
Compound 258-60 1 -k r-. Compound 261-3 1 -4 Compound 264-6 F AFF:
F F 74 0 * F /4 F._ N.....6,460 0
7 .-''P,, 4. 7 -'1C'eF., * 4 õ c... 40 õ -N-
CG), 1.1 4 , -N rDeg * 4 0 -N-C., 11" 0
FAFF: FA; 1 -1-F
I. 1, PP Ft
11F
Compound 267-9 Compound 270-2 Compound 273-5
Compound 276-278 Compound 279-81 Compound 282-4
F4,. F F
*
1,....:,F 0
Fil ip P' 10 I Am
FiN......za, ois 0 , N ocii:F78 40 0 pfr.......,icr,,osca, 040 o
F7Nni...-aci7F 40 0 FIN._,..yaca:1114, 4 F....N......7.6-011.2 it 0
Ft.F F--13; FA; FP FIF
Compound 285-7 Compound 288-90 Compound 291-73
Compound 294-96 Compound 297-99 Compound 300-2
N. N----'11CW3 2*141 0 . '' 411 0 -14-nrei-
.24P *no 1+1-6-0.F Fi* 4 IYL--1¨ zF 00,[7`µI-----r¨ 2:1" *
F t L i "F 14F F F
5c.F.
Compound 303-5 Compound 306-8 Compound 309-11
Compotmd 312-14 1 ".'F. Compoid 315-7 Compound 318-20
, u ,
FiHs1V1* 0 0 F;IHO2F1* 4 . r
0H7F1.4OC'H 2F1.1 40 (õi, 'NI MCH2F 011
' -Nrneli-6F. 41 õ
Compound 321-3 ' -kl. Compound 324-326 F' Compound 327-
329 F tr. Compound 330-32 1 TF Compound 333-3, 1 li Compound 336-8 LI
F4F i.iiii, r;
r,,I,;/ F714-.,6.-cx* 4 F,, N .,,,s-c5g,
F; -'.1Z ." 4 . F7, 023-1:W. 4 , F; sICCZ131 41 7 ,1=1 4 0 FIFF
Compound 239-41 F4 Compound 342-4 6. -11. r C und
345-114U Compmmd 348-350 F 1/41; Compound 351-353 1 Compound 354-356
FP
6-1-ZISM 4 0 411 -14111 IP 41.
C ompound 357-359F t F Compound 360-362 F-. compoõ1 767 365 '- F
[0079] Another embodiment is a composition comprising an acid addition salt of
dextromethorphan
and FDId selected from: dextromethorphan and FDId dihydrogen adipate,
dextromethorphan and
FDId dihydrogen aspartate, dextromethorphan and FDId dihydrogen fumarate,
dextromethorphan and
FDId dihydrogen glutamate, dextromethorphan and FDId dihydrogen glutarate,
dextromethorphan
and FDId dihydrogen isophthallate, dextromethorphan and FDId dihydrogen
maleate,
dextromethorphan and FDId dihydrogen malonate, dextromethorphan and FDId
dihydrogen oxalate,
dextromethorphan and FDId dihydrogen pimelate, dextromethorphan and FDId
dihydrogen phthallate,
dextromethorphan and FDId dihydrogen sebacate, dextromethorphan and FDId
dihydrogen succinate,
dextromethorphan and FDId dihydrogen terephthallate, dextromethorphan and FDId
dihydrogen N-
acyl-aspartate, dextromethorphan and FDId dihydrogen N-acyl-glutamate,
dextromethorphan and
FDId dihydrogen citrate, dextromethorphan and FDId dihydrogen galactonate,
dextromethorphan and
FDId dihydrogen glucarate, dextromethorphan and FDId di hydrogen saccharate,
dextromethorphan
and FDId dihydrogen mannonate, dextromethorphan and FDId dihydrogen mucate,
dextromethorphan
and FDId dihydrogen rhamnonate, and dextromethorphan and FDId dihydrogen
tartrate.
[0080] In another aspect of the inventions, the compound is a compound of
Formula I derivatives
include the following compounds:
22
Date Recue/Date Received 2021-04-14
0,,cvacroc_Noli
01S)H 010 6\ ,-I,oa >11nrtya
365-367 368-370 3 7 1-3 73 374-376 377-379 380-382 383-
385
k..=.' ''')
386-388 389-391 392-394 395-397 398-400 401-403 404-
406
0
Tr.
407-409 410-412 413-415 416-418 422-424
1.11,
0)315P\ 3 1164õir.......Ø4)
'''Cli'L'
H21,111*-rP '11:1--
H
425-527 428.430 431-433 434436 437439 440-442
443.445 446448
10,0 7-A'
IT 3
:100-0 N ....A:Tir
449-451 452-454 455-457 458-460 461-463 464466 467-
469 470-472
0-
1,1cly cro,,,01 44 ,r)14,,,,cca (.479.48 rrl Sa
:Do 'YCJI I{ 'r,&I'CjH 'r CI
''SLO
ilv -
11 T-
482484 485.487 480490 491.493
494496
473.475 476-478
OH OH
croMy
509-511 512-514 515-
517
497-499 500-502 503-505 506.508
Cjill
1414A)._0-0 4_41 _I '(3-0,---'N-N
.--)-0-- \ -N,µ= Z-b-0-\_ l'"1 \3'c <14711,1,
527-529 530-532 533-535
518-520 521-522 524-526
1,
al ,a, , ''' &;= n
536438 ..._ 0 539-541 542-544 545.547_ _ õ11 \511448:550
551.553 554556 557-559
2 OH H I C. 014
HO
) ,10-0---601-V
560-562 563-565 566.568 569-571 572474 '601 ¨6
NH2 OH L77 575-577
C-S--eH 711-Z 578-5e2a 581-583
...i.,5,0 HO.--
?
Y`y. yl..-c_ckac cv1-(i:x4:1 1,11700 Ack"13,0_,T J cc
'C H
584486
587-589 590-592 593-595 596-598
'() 599.401 602j 605407
I . tr OH
1-116* dyNN OH ,µ)-11415 OH
NCI'
= , 614 11 -N 'Cr'X'A 1
,44 - 6111 sC-C)-1491 -1111 -a-. ,
H
608410 6 '
61 I 413 614616 617419 620422 623425 6264V5
629.631 Cr 632-634 635437 vp
OH
.1, 01,_,470HH 21,), 0 1-
.67)0p11.....o.0
ci,..)._/-ti H 4.0 C..)
638448 H ,_6:::)0,0,51 J---
641 644646 Cr 64 7449 ')..')31::::) 1.== 650452
653455 --)-Ci 659461 662464
VI'''r'62 OHO=6 11?)1S -"-
lei 6H vni 1,-ry.9,.. jo t A trwrO
\--.,
665467 --- =-= 668470 671473 674476 677-679 (-
680"682 683'685 686488 689.691
j:
6
0 0"
'0
14
k1(41492 149 11'9
H2Nõ..jori,-- 14 o...õ..li Hvcro .0 ,5,4¨%.õ_.\_4
695497 698.7000 701- 0704-706 170 ,
"
7.709 710.712 H o_r
' Y
71 3.71 5'716.718
I. ReRs":.,0 "-' R2 Y
Ø313,13 14)- c,ji n-0-0 0.,,c_1 -0,q50 .,(4.9,,,aL i(stio
'-'11 H 11
Rf141.}16-1:::y5
He'
722.724 725-727 719-721 722.724 Nam ta k
Ramada Id
011111=Earmesur
Obrige hummer
23
Date ecue/Date Received 2021-04-14
[0081] In some embodiments, the compound of Fonnula I is Fonnula Ic or Formula
Id:
[0082] In some embodiments, the compound of Fonnula Ic or Fommla Id is Ml,
wherein, Y is CH3;
R4 is OH. In some embodiments, the compound of Formula Ic or Formula Id, as
defined above is a
fluoro derivative wherein R4 is OCF3.
J-1
0OH 9" 1, 0
N
(S 1111 (II) MI (S) Compound 219 (R)
Compound 220
(S)-1-(Mme mino)-3-(2-(3-
(R)-1-(clirnethylamino)-3-(2-(3- (5)-3-(2-(3-methozyphenethyl)phenoxy)-
(R)-3-(2-(3-methoxyphenei I tyl)phenoxy)-
methozypheno I Ophenoxy)propa methoxyphenethyl)phenoxy)pro
.&N-dimethy1-2- .N,N-dimethy1-2-(nifluerom..thoxy)propan-
pan-2-o1 (trifluorometboxy)propan-1 -amine 1-amine
100831 In an embodiment of the invention is a composition comprising a
compound having a Formula
R2
LCH2),,
Formula', wherein R3 is a bicyclic system and the rest of the Formula I
represented by R7: as shown
in Fonnula If
R6
0
7 Formula If, wherein, R6 is H, substituted or unsubstituted -C1_10 alkyl,
substituted or
unsubstituted -C3_10 cycloalkyl, substituted or unsubstituted -05_10 aryl,
substituted or unsubstituted -
C1_10 alkyl- C5_10 aryl, substituted or unsubstituted -05_10 heteroaryl, or
substituted or unsubstituted -
C1_10 alkyl- C5_10 heteroaryl;
R7 is R(''Fh-- -clloalkyl-X-(Y)n, -C3-10 cycloalkyl-X-(Y)m, -05_10 aryl-X-
(Y)m, or -05-10 heteroaryl-
X(Y)m; wherein X is a bond, N, 0, S, -Ci_10 alkyl, -C3_10 cycloalkyl, -05_10
aryl, -CO-Cm alkyl, -CO-
C3-10 cycloalkyl, -0005_10 aryl, -CO-05_10 heteroaryl, -CO-NH-C1_10 alkyl, -CO-
NH-C3_10 cycloalkyl, -
CO-NH- C5_10 aryl, or -CO-NH-05_10 heteroaryl; Y is H, C1_10 alkyl, C3_10
cycloalkyl, C5_10 aryl, -CO-
C1_10 alkyl, -CO- C3_10 cycloalkyl, -0005_10 aryl, CO-05_10 heteroaryl, -CO-NH-
Cm alkyl, -CO-NH-
C3-10 cycloalkyl, -CO-NH- C5-10 aryl, or -CO-NH-05_10 heteroaryl; and m is an
integer 1 or 2; or
phalmaceutically acceptable salts or N-oxides thereof; or prodmgs thereof.
[0084] In certain embodiments, the compound is a compound of Formula If
wherein R6 is an aryl, and
R7 is substituted or unsubstituted -C1_10 alkyl-X-(Y). In certain embodiments,
R6 is substituted or
24
Date Recue/Date Received 2021-04-14
unsubstituted C1-10 alkyl- C5_10 aryl, and R7 is substituted or unsubstituted -
C1_10 alkyl-X-(Y).. In
certain embodiments, R6 is phenyl, R7 is -C1-10 alkyl-N-( Ci_io alky02.
100851 In an embodiment, the compound of Formula I includes, but not limited
to, the following
examples:
RS4-((4-(dim ethyl amino)- 1-(2-(3 -methoxyphenethyl)phenoxy)butan-2-
y0oxy)-3 ,3 -
di fluoro-4-ox obutanoi c acid; S4-((4-(dimethylamino)- 1-(2-(3 -
methoxyphenethyl)phenoxy)butan-2-
yl)oxy)-3,3-difluoro-4-oxobutanoic acid; R4-((4-(dimethylamino)-1-(2-(3-
methoxyphenethyl)
phenoxy)butan-2-yl)oxy)-3 ,3 -di fluoro-4- oxobutan oi c
acid; RS4-((4-(dimethylamino)- 1-(2-(3 -
methoxyphenethyl)phenoxy) butan-2-yl)oxy)-2,2- difluoro-4-oxobutanoic acid; S4-
((4-
(dim ethyl amino)- 1 -(2-(3-methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2-
difluoro-4-oxobutanoic
acid; R444-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan-2-yl)oxy)-
2,2-difluoro-4-
oxobutanoic acid; RS4- ((4-(dimethylamino) -1-(2-(3-methoxyphenethyl)
phenoxy)butan-2-yl)oxy)-
2,2,3-trifluoro-4-oxobutanoic acid; S4-((4-(dimethylamino)-1-(2-(3-
methoxyphenethyl)phenoxy)
butan-2-y0oxy)-2,2,3-trifluoro-4-oxobutanoic acid;
R4-((4-(dimethylamino) -14243-
methoxyphenethyl) phenoxy)butan-2-yl)oxy)-2,2,3 -trifluoro-4-oxobutanoic acid;
RS4- ((4-
(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan-2-yl)oxy)-2,3,3-
trifluoro-4-
oxobutanoic acid; S4-((4- (dimethylamino) -1-(2-(3-methoxyphenethyl)
phenoxy)butan-2-yl)oxy)-
2,3 ,3 -trifluoro-4-oxobutanoic acid;
R444-(dim ethyl amino)- 1-(2-(3 -
methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,3 ,3 -trifluoro-4-oxobutanoic
acid; RS4-((4-
(dim ethyl amino)- 1-(2-(3 - methoxyphenethyl) phenoxy) butan-2-yl)oxy)-2,3 -
di fluoro-4-ox obutanoi c
acid; S4-((4-(dim ethyl amino)- 1-(2-(3 -methoxyphenethyl)phenoxy)butan-2-
y0oxy)-2,3 -di fluoro-4-
ox obutanoi c acid; R4-((4-(dim ethyl amino)- 1-(2-(3 -methoxyphenethyl)
phenoxy)butan-2-yl)oxy)-2,3 -
di fluoro-4-ox obutanoi c acid; RS4-((4-(dim ethyl amino)- 1-(2-(3 -
methoxyphenethyl) phenoxy)butan-
2-yl)oxy)-2,2,3 ,3-tetrafluoro-4-oxobutanoic acid;
S444-(dim ethyl amino)- 1-(2-(3 -
methoxyphenethyl)phenoxy)butan-2-yl)oxy)-2,2,3 ,3 -tetrafluoro-4- oxobutanoic
acid; R4-((4-
(dim ethyl amino)- 1-(2-(3 -methoxyphenethyl)phenoxy)butan-2-y1)
oxy)-2,2,3 ,3 - tetrafluoro-4-
oxobutanoic acid; RS5- ((4-(dimethylamino) -1-(2-(3-
methoxyphenethyl)phenoxy)butan-2-yl)oxy)-
4,4-di fluoro-5 - oxopentan oi c acid; S 5 -((4-(dimethyl amino)
- 1 -(243 -methoxyphenethyl)
phenoxy)butan-2-yl)oxy) -4,4-difluoro-5-oxopentanoic acid; R5- ((4-
(dimethylamino) -1-(2-(3-
methoxyphenethyl) phenoxy) butan-2-yl)oxy)-4,4- difluoro-5- oxopentanoic acid;
RS5-((4-
3 0 (dim ethyl amino)- 1-(2-(3 -methoxyphenethyl)phenoxy)butan-2-y0oxy)-4,4-
di fluoro-5 - oxopentanoic
acid; S 5 44-(dim ethyl amino)- 1-(2- (3 -methoxyphenethyl) phenoxy) butan-2-
yl)oxy) -4,4-di fluoro-5 -
Date Recue/Date Received 2021-04-14
oxopentanoic acid; R5-((4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)
butan-2-yl)oxy) -
4,4- difluoro-5- oxopentanoic acid; RS5-((4- (dimethylamino) -1-(2-(3-
methoxyphenethyl) phenoxy)
butan-2-yl)oxy) -2,2-di fluoro -5 - oxopentanoi c
acid; S 5 -((4-(di m ethylamino)- 1 -(2- (3 -
methoxyphenethyl) phenoxy) butan-2-y1) oxy)-2,2-difluoro-5-oxopentanoic acid;
R5-((4-
(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy) butan-2-y1) oxy) -2,2-
difluoro-5-
oxopentanoic acid; RS4- (dimethylamino) -1-(2-(3-methoxyphenethyl)
phenoxy)butan-2-y1 2,2-
di fluoroac etate ; S4-(dim ethyl amino) -1 -(243 -m ethoxyph enethyl)
phenoxy)butan-2-y1 2,2-
di fluoroac etate ; R4-(dim ethyl amino)-1-(2-(3 -m ethoxyphen ethyl)
phenoxy)butan-2-y1 2,2-
difluoroacetate; RS4-(dim ethyl amino)- 1-(2-(3 -m ethoxyphen ethyl) ph
enoxy)butan-2-y1 2,2,2-
trifluoroacetate;
S4-(dim ethyl amino)-1 -(243 -methoxyphenethyl) phenoxy)butan-2-y1 2,2,2-
trifluoroacetate; R4-(dimethylamino) -1-(2-(3-methoxyphenethyl) phenoxy)butan-
2-y1 2,2,2-
trifluoroacetate;
RS4-((difluoromethyl)(trifluoromethyl)amino)-1-(2-(3-
(trifluoromethoxy)
phenethyl)phenoxy) butan-2-ol; S4-((difluoromethyl) (trifluoromethyl) amino) -
1- (2- (3-
(trifluoromethoxy)phenethyl)phenoxy)butan-2-ol; R4-((difluoromethyl)
(trifluoromethyl) amino)-1-
(2-(3-(trifluoromethoxy) phenethyl) phenoxy)butan-2-ol; RS4-((fluoromethyl)
(trifluoromethyl)
amino)- 1-(2-(3 -(trifluoromethoxy) phenethyl)phenoxy)butan-2-ol;
S4-((fluorom ethyl)
(trifluoromethyl) amino)-1-(2 -(3 -(trifluoromethoxy) phenethyl)phenoxy) butan-
2 -ol ; R4-
((fluoromethyl) (trifluoromethyl)amino) -1-(2-(3-(trifluoromethoxy)
phenethyl)phenoxy)butan-2-ol;
RS4- (methyl (trifluoromethyl) amino)-1-(2-(3- (trifluoromethoxy) phenethyl)
phenoxy) butan-2-ol;
S4-(methyl (trifluoromethyl)amino)- 1 -(243 -(trifluoromethoxy)
phenethyl)phenoxy)butan-2-ol; R4-
(m ethyl (tri fluorom ethyl)amino)-1 -(243 -(trifluoromethoxy)
phenethyl)phenoxy)butan-2-ol; RS4-
((difluoromethyl) (methyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl)
phenoxy) butan-2-ol; S4-
((difluoromethyl)(methyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)
butan-2-ol; R4-
((di fluorom ethyl) (m ethyl)ami no)-1 -(2 -(3 -(trifluoromethoxy)
phenethyl)phenoxy) butan-2-ol; RS4-
((fluoromethyl) (methyl)amino)-1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)
butan-2-ol; S4-
((fluorom ethyl)(m ethyl)amino)-1 -(243 -(trifluoromethoxy) phenethyl)
phenoxy)butan-2-ol; R4-
((fluorom ethyl) (m ethyl)amino)-1 -(243 -(trifluoromethoxy)phenethyl)phenoxy)
butan-2-ol; RS4-
(dimethylamino) -1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; S4-
(dimethylamino) -
1-(2-(3-(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; R4-(dimethylamino)-
1-(2-(3-
(trifluoromethoxy) phenethyl) phenoxy) butan-2-ol; R Si- (2-(3-
(difluoromethoxy) phenethyl)
phenoxy) -4-(dim ethyl amino) butan-2-ol; Si -(243 -(di fluorom
ethoxy)phenethyl)phenoxy)-4-
26
Date Recue/Date Received 2021-04-14
(dim ethyl amino)butan-2-ol ;
R1 -(243 -(di fluorom ethox y)phenethyl)phenox y)-4-
(dimethylamino)butan-2-ol; RS4-(dimethylamino) -1-(2-(3-(fluoromethoxy)
phenethyl) phenoxy)
butan-2-ol; S4-(dim ethyl amino)- 1 -(2-(3 -(fluoromethoxy) ph
enethyl)phenoxy)butan-2-ol ; R4-
(dim ethyl amino)-1 -(243 -(fluorom ethoxy)phenethyl)phenoxy)butan-2 -ol ; RS3
-(trifluoro methoxy) -
4-(2-(3- (trifluoromethoxy) phenethyl) phenoxy)-N,N- bis(trifluoromethyl)
butan-1- amine; S3-
(trifluoromethoxy) -4-(2-(3 -(trifluoromethoxy) phenethyl)phenoxy) -N,N-bis
(trifluoro methyl)
butan-1 -amine; R3 -(trifluoromethoxy)-4-(2-(3 -
(trifluoromethoxy)phenethyl) phenoxy)-N,N-
bi s(trifluorom ethyl)butan-1 -amine; RSN-(difluoromethyl)-3-
(trifluoromethoxy)-4- (2-(3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)-N-(tri fluorom ethyl)butan-1 -amine;
SN-(difluoromethyl)-3 -
(trifluoromethoxy)-4-(2-(3 -(tri fluorom ethoxy)phenethyl)phenoxy)-N-(tri
fluoromethyl)butan-1-
amine; RN-(difluoromethyl)-3 -(trifluoromethoxy)-4-(2-(3 -
(trifluoromethoxy)phenethyl)phenoxy) -
N-(tri fluorom ethyl)butan- 1 -amine; RSN-(fluoromethyl)-3 -
(trifluoromethoxy)-4-(2-(3 -(trifluoro
methoxy) phenethyl)phenoxy)-N-(tri fluorom ethyl)butan-1 -amine; SN-(fluorom
ethyl)-3 -(trifluoro
m ethoxy)-4-(2-(3-(tri fluorom ethoxy)phenethyl)ph enoxy)-N-(tri fluorom
ethyl)butan-1 -amine; RN-
(fluoro methyl) -3 -(trifluoromethoxy)-4-(2-(3 -(tri fluorom
ethoxy)phenethyl)phenoxy)-N -(trifluoro
methyl) butan-l-amine; RSN-methyl-3-(trifluoromethoxy)-4-(2-(3-
(trifluoromethoxy) phenethyl)
phenoxy)-N-(tri fluorom ethyl)butan-1 -amine;
SN-methy1-3-(trifluoromethoxy)-4-(2-(3-
(trifluoromethoxy) phenethyl)phenoxy)-N -(tri fluorom ethyl)butan-1 -
amine; RN -m ethy1-3 -
(trifluoromethoxy)-
44243 -(tri fluorom ethoxy)ph enethyl)phenoxy)-N-(tri fluorom
ethyl)butan-1-
amine; RSN-(di fluorom ethyl) -
N-methyl-3-(trifluoromethoxy)-4-(2-(3-(trifluoromethoxy)
phenethyl)phenoxy)butan-1 -amine;
SN-(di fluorom ethyl)-N-methy1-3 -(trifluoromethoxy)-4-(2-(3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)butan-1 -am ine; RN-(difluoromethyl)- N-
m ethy1-3 -(trifluoro
m ethoxy)-4-(2-(3-(tri fluorom ethoxy)phenethyl)ph enoxy)butan-1 -amine; RSN-
(fluoromethyl)- N-
m ethy1-3 -(trifluoromethoxy)-4-(2-(3 -(trifluoromethoxy) phenethyl)phenoxy)
butan-1 -amine; SN-
(fluorom ethyl)-N-m ethy1-3 -(trifluoromethoxy)-4-(2-(3 -(trifluoromethoxy)
phenethyl)
phenoxy)butan-l-amine;
RN-(fluoromethyl)-N-m ethy1-3 -(trifluoromethoxy)-4-(2-(3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)butan-1 -am ine; RSN,N-dim ethy1-3 -
(trifluoromethoxy)-4-(2-
(3 -(tri fluorom ethoxy)phenethyl)phenoxy)butan-1 -amine; SN,N-dimethy1-3-
(trifluoromethoxy) -4-(2 -
(3 -(tri fluorom ethoxy)phenethyl)phenoxy)butan-1 -amine; RN,N-dimethy1-3-
(trifluoromethoxy) -4-(2-
(3- (tri fluorom ethoxy)phenethyl)phenoxy)butan-1 -amine;
RS4-(2-(3 -
(di fluorom ethoxy)phenethyl)phen oxy)-N,N-dim ethy1-3-(tri fluorom
ethoxy)butan-l-amine; S4-(2-(3 -
27
Date Re9ue/Date Received 2021-04-14
(di fluorom ethoxy)phenethyl)phen oxy)-N,N-dim ethy1-3- (tri fluorom
ethoxy)butan-1 - amine ; R4- (2-(3 -
(di fluorom ethoxy) phenethyl)phenoxy) -N,N-dimethy1-3- (trifluoromethoxy)
butan-1-amine; RS4-(2-
(3 - (fluoromethoxy) ph enethyl)ph enoxy)-N,N-dim ethy1-3 -(trifluoromethoxy)
butan-1 -amine; S4- (2 -
(3-(fluoromethoxy) phenethyl)phenoxy) -N,N-dimethy1-3-(trifluoromethoxy) butan-
1-amine; R4-(2-
(3 - (fluoromethoxy)phenethyl)phenoxy)-N,N-dim ethy1-3- (tri fluorom
ethoxy)butan-1 - amine ; RS3 -
(difluoromethoxy)-4-(2-(3-(trifluoromethoxy) phenethyl) phenoxy)-N,N-
bis(trifluoromethyl)butan-
1 -am i n e ; S3 -(di fluorom eth oxy) -4-(2-(3 - (tri
fluoro methoxy) ph en ethyl)ph en oxy)-N,N-
bi s(trifluorom ethyl)butan -1 - amine ;
R3 -(di fluorom eth oxy)-4-(2- (3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)-N,N-bi s(trifluoromethyl)butan -1-
amine; RS3-
(di fluorom ethoxy)-N-(di fluorom ethyl)-4- (2-(3 -
(trifluoromethoxy)phenethyl) phenoxy)-N-
(trifluoromethyl) butan-1 -amine ;
S3 -(di fluorom eth oxy)-N-(di fluorom ethyl)-4- (2 -(3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)-N-(tri fluorom ethyl)butan-1 -amine ;
R(- (di fluorom ethoxy)-N-
(di fluorom ethyl)-4- (2 -(3 - (tri fluorom ethoxy)phen ethyl)phen oxy)-N-
(trifluorom ethyl)butan-1 - amine ;
RS 3-(di fluorom eth oxy)-N- (fluorom ethyl)-4- (2 -(3 - (tri fluorom eth
oxy)ph en ethyl)ph en oxy)-N-
(tri fluorom ethyl )butan-1 - amine ;
S3 -(di fluorom eth oxy)-N - (fluorom ethyl)-4- (2 -(3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)-N-(tri fluorom ethyl)butan-1 -amine ;
R3 - (di fluorom ethoxy) -N-
(fluorom ethyl)-4- (2-(3 - (trifluorom ethoxy)phenethyl )phenoxy)-N-
(trifluorom ethyl)butan -1 - amine ;
RS3- (di fluorom ethoxy) -N -m ethy1-4- (2- (3 -
(trifluoromethoxy)phenethyl) phenoxy)-N -
(tri fluorom ethyl ) butan-1-amine;
S3 -(di fluoromethoxy)-N-m ethy1-4-(2-(3 - (tri fluorom ethoxy)
phenethyl)phenoxy) -N- (tri fluorom ethyl) butan-1 -amine ; R3 -(di fluorom
ethoxy)-N-methy1-4-(2- (3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)-N-(tri fluorom ethyl)butan-1-amine;
RS3-(difluoro methoxy) -
N-(di fluorom ethyl)-N-m ethy1-4 -(243 - (tri fluorom ethoxy)phenethyl)ph
enoxy)butan -1 - amine ; S3 -
(difluoromethoxy)-N- (difluoromethyl) -N-methyl -4-(2-(3- (trifluoromethoxy)
phenethyl) phenoxy)
butan-1 - amine ; R3 - (di fluorom ethoxy) -N-
(di fluorom ethyl)- N-methyl-4-(2- (3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)butan-1 -am ine; RS3 - (di fluorom
ethoxy) -N-(fluorom ethyl) -N-
methyl-4-(2-(3 -(tri fluorom ethoxy)phenethyl)phenoxy)butan-1 - amine ; S3 -
(di fluor methoxy) -N-
(fluorom ethyl)-N-m ethy1-4-(2- (3 - (tri fluorom ethoxy)ph enethyl)
phenoxy)butan-1 -amine ; R3 -
(di fluorom ethoxy) -N-(fluoromethyl)- N-m ethy1-4- (2- (3 -
(trifluoromethoxy) phenethyl)
phenoxy)butan-1- amine ;
RS3 - (di fluorom eth oxy)-N,N-di m ethy1-4-(2- (3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)butan-1 -am ine ; S3 -(di fluorom
ethoxy)-N,N-dim ethy1-4- (2-(3 -
(trifluoromethoxy) phenethyl)phenoxy)butan-1 - amine ; R3 -(di fluorom ethoxy)-
N,N-dim ethy1-4-(2-(3 -
28
Date Re9ue/Date Received 2021-04-14
(tri fluorom ethoxy)phen ethyl)phenoxy)butan-1 -am ine ; RS3 - (di fluorom
ethoxy) -44243-
(di fluorom ethoxy) phen ethyl)phenoxy)-N,N-dim ethylbutan-1 - amine
S3 -(di fluorom ethoxy)-4- (2- (3- (di fluorom ethoxy)phenethyl)phenoxy)-N,N-
dim ethylbutan-1 - amine ;
R3-(difluoromethoxy) -4-(2-(3-(difluoromethoxy) phenethyl)phenoxy) -N,N-
dimethylbutan -1-
amine; RS3 - (di fluorom ethoxy)-4- (2- (3 -(fluorom ethoxy)phenethyl)ph
enoxy)-N,N-dim ethylbutan-1 -
amine; S3-(difluoromethoxy)-4-(2-(3-(fluoromethoxy)phenethyl) phenoxy)- N,N-
dimethyl butan-1-
amine ; R3 - (di fluorom ethoxy)-4- (2- (3 -(fluorom ethoxy)phenethyl)ph
enoxy)-N,N-dim ethylbutan-1 -
amine; RS3 -(fluorom ethoxy)-4- (243-
(trifluoromethoxy)phenethyl)phenoxy)-N,N-
bi s(trifluorom ethyl)butan -1 - amine ; S3-(fluoro methoxy) -4-
(2- (3-
(trifluoromethoxy)phenethyl)phenoxy)-N,N-bi s(tri fluorom ethyl)butan-1 -
amine ; R3-
(fluoromethoxy)- 4-(2-(3-(trifluoromethoxy) phenethyl)phenoxy) -N,N-bis
(trifluoromethyl) butan-1-
amine; RSN-(difluoromethyl)-3-(fluoromethoxy)-4-(2-(3-(trifluoro methoxy)
phenethyl)phenoxy)-N-
(trifluoromethyl)butan-1 - amine ; SN- (di fluorom ethyl)-3 -(fluoro
methoxy)- 44243-
(tri fluorom ethoxy)phen ethyl)phenoxy)-N-(tri fluorom ethyl)butan-1 -amine ;
RN- (di fluorom ethyl)-3 -
(fluorom ethoxy)-4-(2- (3 - (trffluorom ethoxy)phenethyl)phen oxy)-N - (tri
fluor methyl) butan-1 -amine;
RS3-(fluoromethoxy)-N-(fluoromethyl)-4-(2-(3-(trifluoromethoxy)
phenethyl)phenoxy)-N-
(tri fluorom ethyl )butan-1 - amine ; S3 -(fluoromethoxy)-N-
(fluoromethyl)-4-(2-(3-
(tritluoromethoxy)phenethyl)phenoxy)-N -(trifluoromethyl)butan-1 -amine ; R3 -
(fluorom ethoxy)-N -
(fluorom ethyl)-4- (2-(3 - (trifluorom ethoxy)phenethyl )phenoxy)-N-
(trifluorom ethyl)butan -1 - amine ;
RS3-(fluoromethoxy)- N-m ethy1-4 - (2-(3 -(tri fluorom
ethoxy) phenethyl) phenoxy)-N-
(trifluoromethyl) butan-1 - amine ;
S3 -(fluorom ethoxy)-N-m ethy1-4- (2-(3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)-N-(tri fluorom ethyl)butan-1 -amine ;
R3 - (fluorom ethoxy)-N-
m ethy1-4- (2- (3 -(tri fluorom ethoxy)phenethyl)phenoxy)-N- (tri fluorom
ethyl)butan-1 -amine ; RSN-
(di fluorom ethyl)-3 - (fluorom ethoxy)-N-m ethy1-4-(2-(3 -(tri fluorom
ethoxy)phenethyl) phenoxy)butan-
1-amine; SN- (di fluorom ethyl)-3- (fluoromethoxy)- N-m ethy1-4- (2 -(3 -(tri
fluorom ethoxy) phenethyl)
phenoxy)butan-1- amine ;
RN- (difluorom ethyl)-3 - (fluorom ethoxy)-N-m ethy1-4-(2- (3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)butan-1 -am ine ; RS3 -(fluorom ethoxy)-
N-(fluorom ethyl)-N-
m ethy1-4- (2- (3 -(tri fluorom ethoxy)phenethyl)phenoxy)butan-1 - amine ;
S3 -(fluorom ethoxy)-N-
(fluorom ethyl)-N-m ethy1-4-(2- (3 - (tri fluorom ethoxy)ph enethyl)phenoxy)
butan-1 - amine ; R3 -
(fluoromethoxy)-N-(fluoromethyl)-N-methyl-4-(2-(3-(trifluoromethoxy)
phenethyl) phenoxy) butan-
1 -amine; RS3 -(fluorom ethoxy) -N,N-dimethy1-4-(2-(3-(trifluorom ethoxy)
phenethyl) phenoxy)butan -
29
Date Re9ue/Date Received 2021-04-14
1-amine; S3 -(fluoromethoxy)-N,N-dim ethy1-4- (2-(3 -(tri fluorom
ethoxy)phenethyl)phenoxy)butan-1 -
amine ; R3 - (fluorom ethoxy)-N,N-dim ethy1-4- (2-(3 -(tri fluorom
ethoxy)phenethyl)phenoxy)butan-1 -
amine; RS4-(2-(3-(difluoromethoxy) phen ethyl) phenoxy)-3- (fluoromethoxy)-N,N-
dimethylbutan-
1-amine; S4-(2-(3-(difluoro methoxy) phenethyl)phenoxy)-3- (fluoromethoxy)-
N,N-dimethyl butan-
1-amine; R4-(2-(3- (difluoro methoxy) phenethyl) phenoxy)-3-(fluoromethoxy)-
N,N-dimethylbutan-
1 -amine;
RS3 -methoxy-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N,N-
bi s(trifluorom ethyl)butan -1 - amine ; S3 -methoxy -4-(2-(3 - (tri fluorom
ethoxy) phenethyl)phenoxy)-
N,N-bi s(tri fluorom ethyl)butan-1 - amine ;
R3 -m ethoxy-4-(2- (3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)-N,N-bi s(tri fluorom ethyl)
butan-1 -amine ; RSN-
(di fluorom ethyl) -3 -m ethoxy-4- (2- (3 -
(trifluoromethoxy) phenethyl) phenoxy) -N-
(tri fluorom ethyl)butan-1 - amine ; SN- (di fluorom ethyl) -3 -methoxy-4-(2-
(3 - (tri fluorom ethoxy)
phenethyl) phenoxy)-N-(trifluoromethyl)butan- 1 -amine; RN-(difluorom ethyl)-3
-methoxy-4-(2-(3 -
(trifluoromethoxy) phenethyl)phenoxy)-N- (tri fluorom ethyl)butan-1 -amine
RSN- (fluoromethyl)
-3 -m ethoxy-4- (2- (3 - (tri fluorom ethoxy)phen ethyl)phenoxy)-N-
(tri fluor
methyl) butan-1-amine; SN ifluoromethyl)- 3-methoxy-4-(2-(3-(trifluoromethoxy)
phenethyl)
phenoxy)-N- (tri fluorom ethyl) butan-1 - amine ;
RN- (fluorom ethyl) -3 -m ethoxy-4- (2-(3 -
(trifluoromethoxy) phenethyl) phenoxy)-N- (trifluoromethyl)butan-1 -amine; R53-
methoxy-N-
m ethyl -442 -(3 -(trifluoromethoxy)phenethyl)phenoxy)-N -
(trifluoromethyl)butan- 1 -amine; S3-
methoxy-N-methy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-
(trifluoromethyl)butan-1-
amine; R3-methoxy-N-methy1-4-(2-(3-(trifluoromethoxy)phenethyl)phenoxy)-N-
(trifluoro methyl)
butan-1 - amine ; RS4- (2- (3 -(di fluorom ethoxy)phenethyl)ph enoxy)-3 -m
ethoxy-N,N-dim ethylbutan-1 -
amine ; 54-(2-(3 (di fluorom ethoxy) phenethyl)phenoxy) -3 -m ethoxy-N,N-
dimethylbutan -1 - amine ;
R4-(2-(3 - (di fluorom ethoxy)ph enethyl)phenoxy)-3 -m ethoxy-N,N-dim
ethylbutan-1 -amine ; RSN-
(fluoromethyl)-3-methoxy-N-methy1-4-(2-(3-(trifluoromethoxy) phenethyl)
phenoxy)butan -1 - amin e ;
SN-(fluoromethyl)-3 -m ethoxy-N-m ethy1-4- (2- (3 - (tri fluorom
ethoxy)phenethyl)phenoxy)butan-1 -
amine;
RN-(fluoromethyl)-3 -m ethoxy-N-m ethy1-4-(2- (3 -
(tri fluorom ethoxy)phen ethyl)phenoxy)butan- 1 -amine; R54-(2-(3-
(difluoromethoxy) phen ethyl)
phenoxy)-3-methoxy-N,N-dimethylbutan-1-amine;
54-(2-(3-(difluoromethoxy) .. phen
ethyl)phenoxy)-3-m ethoxy-N,N-dim ethylbutan-1 - amine ; R4- (2-(3- (di
fluorom ethoxy) phenethyl)
phen oxy)-3-m ethoxy-N,N-dim ethylbutan-1 -amine ;
R54-(2-(3 -(fluoromethoxy) phen
ethyl)phenoxy)-3-m ethoxy-N,N-dim ethylbutan-1 - amine ; 54-(2-(3 -
(fluoromethoxy) phen ethyl)
Date Re9ue/Date Received 2021-04-14
phenoxy)-3-methoxy-N,N-dimethylbutan- 1 -amine; R4-(2-(3-(fluoromethoxy)
phenethyl) phenoxy) -
3-methoxy-N,N-dimethylbutan-1-amine;RS4-(2-(3 (fluoromethoxy) phenethyl)
phenoxy) -3-
methoxy-N,N- dimethylbutan- 1 -amine; S4-(2-(3-(fluoromethoxy)
phenethyl)phenoxy ) -3-methoxy-
N,N- dimethylbutan-1-amine; R4-(2-(3-(fluoromethoxy) phenethyl) phenoxy)-3-
methoxy-N,N-
dimethylbutan-1-amine;RS1-(piperidin-1-y1)-3-(m-toly1 oxy) propan-2-ol; S1-
(piperidin-1-y1)-3-(m-
tolyloxy)propan-2-ol; RI -(piperidin-1-y1)-3-(m-tolyloxy)
propan-2-ol; RS 1 -(4-(3-
methoxyphenyl)piperazin-l-y1)-3-phenoxypropan-2-ol
S1-(4-(3- methoxyphenyl) piperazin-l-y1)-3- phenoxypropan-2-ol; R1-(4-(3-
methoxyphenyl)
piperazin -1-y1)-3- phenoxypropan-2-ol; RS 1 -(2,2,5,5-tetramethy1-2,5-dihydro-
IH-pyrrol- 1 -y1)-3 -(m-
1 0 tolyloxy)propan-2-ol;S1-(2,2,5,5-tetramethy1-2,5-dihydro-1H-pyrrol-1-
y1)-3-(m-tolyloxy) propan -2-
01; R1-(2,2,5,5-tetramethy1-2,5-dihydro-1H-pyrrol-1-y1)-3-(m-tolyloxy) propan-
2-ol; RS1-
morpholino-3-(m-tolyloxy)propan-2-ol; Si -morpholino-3- (m-tolyloxy) propan-2-
ol; R1 -
morpholino-3-(m-tolyloxy)propan-2-ol; RS3,3'-(pheny1azanediy1)bis(1-
phenoxypropan-2-ol); S3,3'-
(pheny1az anedi yl)bi s(1-phenoxypropan-2-ol); R3,3'-(phenylazanediy1) bis(1-
phenoxypropan-2-01);
RS1-(2,2,5,5-tetramethylpyrrolidm-1-y1)-3-(m-tolyloxy)propan-2-ol;
S1-(2,2,5,5-
tetramethylpyrrolidin-l-y1)-3-(m-tolyloxy)propan-2-ol; R1-(2,2,5,5-tetramethyl
pyrrolidine -1-y1)-3 -
(m-tolyloxy) propan-2-ol; RS1-(tert-butylamino)-3-(3,4-dimethylphenoxy) propan-
2-ol; S1-(tert-
butylamino)-3-(3,4-dimethylphenoxy)propan-2-ol; R1-(tert-butylamino)-3-(3,4-
dimethylphenoxy)
propan-2-ol; RS1-(4-(3-chlorophenyl) piperazin-l-y1)-3-phenoxypropan-2-ol; S1-
(4-(3-chlorophenyl)
piperazin-l-y1)-3-phenoxypropan-2-ol; R1-(4-(3-chlorophenyl) piperazin-l-y1) -
3-phenoxypropan-2-
ol; RS1-(dimethylamino)-3-(2-phenoxy phenoxy) propan-2-ol; S1-(dimethylamino) -
3-(2-
phenoxyphenoxy)propan-2-ol; R1-(dimethyl amino)-3-(2-phenoxy phenoxy) propan-2-
ol; RS1-
(pyrrolidin-l-y1)-3-(m-tolyloxy)propan-2-ol; S1-(pyrrolidin-l-y1)-3-(m-
tolyloxy)propan-2-ol; R1 -
(pyrrolidin-l-y1)-3-(m-tolyloxy)propan-2-ol; RS1-amino-3-(3,5-
dimethylphenoxy)propan-2-ol; Sl-
amino-3-(3,5-dimethylphenoxy)propan-2-ol; R1-amino-3-(3,5-
dimethylphenoxy)propan-2-ol; RS1-
(dimethylamino)-3-(2-phenethylphenoxy)propan-2-ol;
S1-(dimethylamino)-3 -(2-
phenethylphenoxy)propan-2-ol; R1-(dimethyl amino)-3- (2-phenethyl phenoxy)
propan-2-ol; RS1-
(benzylamino)-3-(3-(trifluoromethyl) phenoxy) propan-2-ol;
S1-(benzylamino)-3-(3-
(trifluoromethyl) phenoxy) propan-2-ol; R1-(benzylamino)-3 -(3-
(trifluoromethyl)phenoxy)propan-2-
ol; RS1-amino-3-phenoxypropan-2-ol; Sl-amino-3-phenoxy propan-2-ol; R1-amino-3-
phenoxypropan-2-ol; RS1-((3-chloro-2- methylphenyl) amino)-3-phenoxy propan-2-
ol; S1-((3 -
31
Date Recue/Date Received 2021-04-14
chloro-2-methylphenyl)amino) -3-phenoxypropan-2-ol; R1-((3-chloro-2-
methylphenyl) amino)-3-
phenoxypropan-2-ol; RS14(24(2,4-dichloro phenyl)amino) ethyl)amino)-3-
phenoxypropan-2-ol; Si -
((2-((2,4-dichlorophenyl) amino) ethyl)amino)-3-phenoxypropan-2-ol;
RI -((2-((2,4-
dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol;
RS1-((3-
(aminomethyl)phenyl)(methyl)amino)-3-phenoxypropan-2-ol;
51- ((3-(aminomethyl) phenyl)
(methyl)amino)-3-phenoxypropan-2-ol; RI -((3-(aminomethyl)phenyl)
(methyl)amino)-3-
phenoxypropan-2-ol; RS1-((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3-
phenoxypropan-2-ol; S1-
((242,6-dichlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((2,6-
dichloro phenyl)
amino) ethyl)amino)-3 -phenoxypropan-2-ol; RS 1 -((2-((4-nitrophenyl)amino)
ethyl)amino)-3 -
1 0 phenoxypropan-2-ol; S14(244-nitrophenyl)amino)ethyl) amino) -3-phenoxy
propan-2-ol; R1-((2-
((4-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; RS1-((3-methoxy
propyl) amino)-3-
phenoxybutan-2-ol; Si -((3 -methoxypropyl)amino)-3 -phenoxybutan-2-ol; RI -((3
-methoxypropyl)
amino)-3-phenoxybutan-2-ol; RS1-(isopropylamino)-3-((2-methy1-1H-indo1-4-
y1)oxy)propan-2-ol;
S1-(isopropylamino)-342-methy1-1H-indo1-4-y1)oxy)propan-2-ol;
R1-(i sopropyl amino)-3-((2-
methy1-1H-indo1-4-y1)oxy)propan-2-ol;
RS1-(isopropylamino)-3-((6-methylfuro[3,2-cipyridin-4-
y0oxy)propan-2-ol; S1-(isopropylamino)-34(6-methylfuro[3,2-c]pyridin-4-
y0oxy)propan-2-ol; R1 -
(i sopropyl amino)-3-((6-methylfuro [3,2-c]pyridin-4-yl)oxy) propan -2-ol; RS1-
(isopropylamino)-3-
(naphthalen-l-ylmethoxy)propan-2-ol; S1-(isopropyl amino)-3-(naphthalen-1-
ylmethoxy) propan-2-
ol; R 1 -(i sopropylamino)-3-(naphthalen-l-ylmethoxy) propan-2-ol; RS1-(i
sopropylamino)-34(3-(4-
methylpiperazin-l-y1) pyrazin -2-yl)oxy)propan-2-ol; S1-(isopropylamino)-3-((3-
(4-methylpiperazin-
l-yl)pyrazin-2-yl)oxy) propan-2-ol; R1- (isopropylamino) -3-((3-(4-
methylpiperazin -1-yl)pyrazin-2-
yl)oxy) propan -2-ol; RS1-(2-nitro-1H-imidazol-1-y1)-3-phenoxypropan-2-ol; S1-
(2-nitro-1H-
imidazol-1-y1)-3-phenoxypropan-2-ol; R1-(2-nitro-1H-imidazol-1-y1)-3-
phenoxypropan-2-ol; RS1-
(6-amino-2- ethoxy-9H-purin-9-y1)-3-phenoxypropan-2-ol; S1-(6-amino-2-ethoxy-
9H-purin-9-y1)-3-
phenoxy propan-2-ol; R1-(6-amino-2-ethoxy-9H-purin-9-y1)-3-phenoxypropan-2-ol;
RS1-
(i sopropyl amino )-3-((2-methylfuro[3,2-c]pyridin-4-yl)oxy)propan-2-ol; S1-
(isopropylamino)-3-((2-
methylfuro [3,2-c]pyridin-4-yl)oxy)propan-2-ol;
R1-(i sopropylamino)-3-((2-methylfuro [3,2-
c]pyridin-4-yl)oxy) propan-2-ol; RS1-(isopropylamino)-3-(p-
tolyloxy)propan-2-ol; S1-
(isopropylamino)-3-(p-tolyloxy)propan-2-ol; R1-(isopropylamino)-3-(p-
tolyloxy)propan-2-ol; RS1-
(isopropylamino)-34(5-methy1-3-morpholinopyrazin-2-y0oxy)propan-2-ol; S1-
(isopropy lamino) -3-
((5-methy1-3-morpholinopyrazin-2-y0oxy) propan-2-ol; R1-(isopropylamino) -3 -
((5-methyl-3 -
32
Date Recue/Date Received 2021-04-14
morpholinopyrazin-2-yl)oxy)propan-2-ol; RS1-(4-(2-chlorophenyl) piperazin-l-
y1)-3-phenoxy
propan-2-ol; S1-(4-(2-chlorophenyl) piperazin-l-y1)-3-phenoxypropan-2-ol; R1-
(4-(2-chloro phenyl)
piperazin- 1 -y1)-3-phenoxypropan-2-ol; RS 1 -(isopropylamino)-3 -((2-
methylthieno [3,2-c]pyridin-4-
y0oxy)propan-2-ol; S1-(isopropyl amino)-342-methylthieno[3,2-c]pyridin-4-
yl)oxy) propan-2-ol;
R1-(isopropylamino)-342-methylthieno[3,2-c]pyridin-4-y0oxy)propan-2-ol;
RS1-
(i sopropyl amino)-3-(pyrimidin-2-yloxy)propan-2-ol;
Si -(isopropylamino)-3-(pyrimidin-2-
yloxy)propan-2-ol; R1-(isopropylamino)-3-(pyrimidin-2-yloxy)propan-2-
ol; RS1-((3,4-
dimethoxyphenethyl)amino)-3-phenoxypropan-2-ol;
S1-((3,4-dimethoxyphenethyl)amino)-3-
phenoxypropan-2-ol; RI -((3 ,4-dimethoxyphenethyl)amino)-3 -phenoxypropan-2-
ol; RS 1 -(4-(3 -(IH-
1 0 1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; S1-
(4-(3 -(1H-1,2,4-triazol-1-
yl)propoxy)phenoxy)-3-(i sopropylamino)propan-2-ol;
R1-(4-(3-(1H-1,2,4-triazol-1-
yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS 1 -(isopropylamino)-3 -
phenoxypropan-2-ol;
S 1-(i sopropylamino)-3-phenoxypropan-2-ol; R1-(isopropylamino)-3-
phenoxypropan-2-ol;
RS1-(4-(3-(1H-1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-
ol; S1-(4-(3-(1H-
1,2,4-triazol-1-yl)propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-(3-
(1H-1,2,4-thazol-1-
y0propoxy)phenoxy)-3-(isopropylamino)propan-2-ol; RS1-(isopropylamino)-3-(o-
tolyloxy)propan-
2-ol; S1-(isopropylamino)-3-(o-tolyloxy)propan-2-ol; R1-(isopropylamino)-3-(o-
tolyloxy)propan-2-
01; RS2-(isopropylamino)-1-(4-methoxyphenoxy)ethan-1-ol;
S2-(isopropylamino)-1-(4-
methoxyphenoxy)ethan-l-ol; R2-(isopropylamino)-1-(4-methoxyphenoxy)ethan-l-ol;
RS(Z)-1-
(i sopropyl amino) -3-(2-methoxy-4- (prop-I-en-1-y phenoxy) propan-2-ol; S(Z)-
1-(isopropylamino)-
3-(2-methoxy-4-(prop-1-en-l-y1)phenoxy) propan-2-ol; R(Z)-1-(isopropylamino)-3-
(2-methoxy-4-
(prop-1-en-l-y1)phenoxy) propan -2-ol;
RS1-(isopropylamino)-3-(4-(2-
(methylthio)ethoxy)phenoxy)propan-2-ol;
S1-(isopropylamino)-3-(4-(2-
(methylthio)ethoxy)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(4-(2-
(methylthio) ethoxy)
phenoxy)propan-2-ol; RS(E)-1-(i sopropylamino)-3-(2-methoxy-4-(prop-1-en-l-
yOphenoxy)propan-
2-01; S(E)-1-(isopropylamino)-3-(2-methoxy-4-(prop-1-en-l-y1)phenoxy)p ropan-2-
ol; R(E)-1-
(isopropylamino)-3-(2-methoxy-4-(prop-1-en-l-y1)phenoxy)propan-2-ol; RS1-
(isopropylamino)-3-
(mesityloxy)propan-2-ol; S1-(isopropylamino)-3-(mesityloxy)propan-2-ol; R1-
(isopropylamino)-3-
(mesityloxy)propan-2-ol; RS1-(isopropylamino)-3-(4-((1-(m ethyl
thi o)propan-2-
yl)oxy)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(441-(methylthio)propan-2-
y0oxy) phenoxy)
propan-2-ol; R1-(i sopropylamino)-3 -(4-((1-(methylthio)propan-2-yl)oxy)
phenoxy) propan-2-ol;
33
Date Recue/Date Received 2021-04-14
RS1-(isopropylamino)-3-(4-(3-methy1-1H-indo1-2-yOphenoxy)propan-2-ol; S1-
(isopropylamino)-3-
(4-(3-methy1-1H-indo1-2-yOphenoxy)propan-2-ol; R1-(isopropyl amino )-3-(4-(3-
methy1-1H-indo1-2-
yOptienoxy)propan-2-ol;
RS 1 -(isopropylamino)-3 -(24(5-methylisoxazol-3-
yOmethoxy)phenoxy)propan-2-ol; S1-(isopropylamino)-3-(2-((5-methyl
isoxazol -3-y1)
methoxy)phenoxy)propan-2-ol; R1-(isopropylamino)-3-(245-methyl isoxazol
-3-
yl)methoxy)phenoxy)propan-2-ol;
RS 1 -(i sopropylamino)-3 424(3 -methyli soxazol-5-yl)methoxy)
phenoxy)propan-2-ol; S1-(isopropylamino)-3-(2-((3-methylisoxazol-5-
yOmethoxy)phenoxy) propan-
2-ol; R1-(isopropylamino)-3-(243-methylisoxazol-5-yl)methoxy)phenoxy)propan-2-
ol;
RS 1-(4-((2H- 1,2,3 -tri azol-2-yl)m ethoxy)phenoxy)-3 -(i
sopropylamino)propan-2-ol; Si -(4-((2H-
1 0 1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol;
R1-(4-((2H-1,2,3-triazol-2-
yOmethoxy)phenoxy)-3-(isopropylamino)propan-2-ol;
RS1-(isopropylamino)-3-(4-(2-
methoxyethyl)phenoxy)propan-2-ol; Si -(isopropylamino)-3-(4-(2-
methoxyethyl)phenoxy) propan-2-
01; R1 -(isopropylamino)-3 -(4-(2-methoxyethyl)phenoxy) propan-2-ol; RS1-(4-(2-
(2H-1,2,3-triazol-2-
yOethoxy)phenoxy)-3-(isopropylamino)propan-2-ol;
S1-(4-(2-(2H-1,2,3-tri azol-2-
yl)ethoxy)phenoxy)-3-(isopropylamino)propan-2-ol;
R1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy)
phenoxy) -3-(i sopropylamino)propan-2-ol; RS1-(isopropylamino)-3-(3-
methoxyphenoxy) propan -2-
ol; S1-(isopropylamino)-3-(3-methoxyphenoxy)propan-2-ol; R1-(isopropylamino)-3-
(3-methoxy
phenoxy)propan-2-ol; RS1-(4-(2-(1H-1,2,4-tri az ol-1-yl)ethyl)phenoxy)-3-(i
sopropylamino) propan-
2-ol; S1-(4-(2-(1H-1,2,4-tri az ol-1-y1) ethyl)phenoxy)-3-(isopropylamino)
propan-2-ol; R1-(4-(2-(1H-
1,2,4-triazol-1-ypethyl)phenoxy)-3-(isopropyl amino) propan-2-ol; RS1-(4-(2-
(1H-pyraz 01-1 -
yl)ethyl)phenoxy)-3 -(i sopropylamino) propan -2-ol; S1-(4-(2-(1H-pyrazol-1-
yl)ethyl)phenoxy)-3-
(isopropylamino)propan-2-ol; R1-(4-(2-(1H-pyraz ol-1-yl)ethyl)phenoxy)-3 -(i
sopropyl amino)propan-
2-01; RS1-(4-(2-(1H-1,2,4-triazol-1-yl)ethyl) phenoxy)-3-
(isopropylamino)propan-2-ol; S1-(4-(2-
(1H-1,2,4-triazol-1-yl)ethyl) phenoxy) -3-(i sopropylamino)propan-2-ol; R1-(4-
(2-(1H-1,2,4-tri az ol-
1-yl)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
RS1-(4-(2-(1H-1,2,4-triazol-1-
yOethoxy)phenoxy)-3-(isopropyl amino) propan-2-ol;
S1-(4-(2-(1H-1,2,4-triazol-1-
yOethoxy)phenoxy)-3-(isopropylamino) propan- 2-ol;
R1-(4-(2-(1H-1,2,4-triazol-1-
yOethoxy)phenoxy)-3-(isopropylamino)propan-2-ol
RS1-(4-((2H-1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol;
S1-(4-((2H-
1,2,3-triazol-2-yl)methoxy)phenoxy)-3-(isopropylamino)propan-2-ol; R1-(4-((2H-
1,2,3-triazol-2-
yOmethoxy)phenoxy)-3-(isopropylamino)propan-2-ol;
RS1-(4-(2-(2H-1,2,3-triazol-2-yl)ethoxy)
34
Date Re9ue/Date Received 2021-04-14
-170-1=ZOZ paneoe apcuari5a ele0
SE
E
tio-z-uedoicI(Axouacdatip-z-Vipaul-E)-E-(owurepCinci-1101)- is
p-z-uedoic1(Axouagdatip-z-pCipaul- E)-E-(ou!utepCinci-Ini)- I S-21 tio-z-
uedoid(ou!utepCdoidos!) 0
-E-(Axo(pc-E-upiAdou!ute-Z))- ii is
io-z-uedoid(ou!utepCdoidos!)-E-(Axo( jA-E-upiAdou!itte-Z))- I SI1
-uedoid(ou!uteiAdoidos!)- E-(Axotnqd(pCifla (IA- lo zeiAd-HI )- tio-z-
uedoid(ou!utepCdoidos!)
-
E-(Axotioqd(pCipa (pC- i lozeiAd-HI)-z)--fr)- is tio-z-
uedoid(ou!uteiAdoidos!)- E-(Cxotioqd(pCipa (IA
-
I -IozmAd-H )-Z)--10- I S-21 jo--uinq(oiqijAjoi-d)-i7-
(ornunjAdoidosi)- ia 10- z-ueinci(o !tp.pCiol-d) SZ
--17-(oulute pCdoidos!)- is tio-z-uelnci(omAim-d)-4,-(ou!utelAdoidos!)-is tio-
z-uudoicI(Axouagdatip
-
E-(ou!ute pCdoidos!)- i >j io-z-uedoicI(Axouatidatip- E-(ou!ure Vdoidos!)-
iS
io-z-uedoid(AxouNdoiip-E-V9aul
-z)- E-(ou!ute pCdoido s!)- i g>j io-z-uedoid(Axo(pC-E-u!zeNJAd ou!iotpthoul-
9))-E-(ou!utepCdo1dos!)
tio-z-uedoid(Axo(pC-E-u!zumiAdoullotidioul-9))-E-(ou!uteiAdoidos!)- is
io-z-uedoid(Axo (IA .. oz
-
E-u!z2miAdou!iotic1oul-9))-E-(ou!utepCdoidos!)-is tio-z-uedoid(Axopqm-m)-E-
(ou!utepCdoidos!)
- ia io-z-uudoicI(Axovqm-u1)- -(outuluiAdoidos!)- is tio-z-uudoicI(Axovq0).-
0-E-(outumiAdoidos!)
- I S-21
tio-z-uedoicIpCuaqd-E-(ou!utepCdoidos!)-I-u tio-z-uedoicIpCuaqd-E-
(ou!urepCdoidos!)- is
io-z-ttedoidiAuaqd-E-(ou!ute pCdoido s!)- i satpuedoid (pCuagdAxotpow-E-
(Axodoid(ou!utepCdoidos!)
- -Axa1pATZ)-17)- j
puedoid (pCuaffdAxotflow-E-(Axodoid(ou!uteiAdoidos!) ci
-
-AxaMAII-Z)-10- S tieuedoid(pCuogdAxotpul-E-(Axodoid(ou!urepCdoidos!)-E-
AxcupAq-z)
--fr)-Esu tio-z-uedoic1(Axo(pC-z-u!zeJAd(o!tplCuaqd)-E))-E-(ou!uteiAcIaidos!)-
ii io-z-uedoid(Axo (IA
-z-u!zalAd(omliAuatid)- -(ouTuluiAdoidos!)- is tio-z-uudoid(Axo(IA-z-
uvuiAd(omliAuaffd)- ))-
-(ou!tue pCdoidos!)- s>j 10- z-uedoid(Axo fetpqdeu)-E-(ou!ute pCdoido s!)-
ia jo--udoid(AxojA
-z-uopipmdeu)-E-(ou!utepCdoidos!)- is
tio-z-uedoid(AxopC-z-uatetpmdeu)-E-(ou!utepCdoidos!) 0i
- I S2I tio-z-uudoid(icxo(vcivupuipAd(o!toIA1P-00-z))- -(ou!um vCdoidos!)-
i >j io-z-uudoid(Axo (IA
-4,-uptu!JAd(omAg)aul)-z))-E-(ou!uteiAdoidos!)- is tio-z-uedoic1(Axo0A-4,-
uput!JAd(o!tpiAtpaul)
-z))- E-(ou!ute pCdoido s!)- is-u tio-z-uedoid(Axo(pC-i-uatetpqdeuVipaul-
t))-E-(ou!utepCdoidos!)
- ii
t io-z-uudaKI(Axo (IA- I -1,13 tfuldeuIA11131-u-17))- -(ffiqurevCdoidos!)- I
S io-z-uudoicI(Axo (IA
-i-uoptiNdeupCipaul-4,))-E-(ou!urepCdoidos!)-is>j
mumuo!doic1(pCuaqd(Axodoid(ou!utepCdoidos!)
-E-AxamAq-z)--fr)-Nu tomateuo!doid(pCuaqd(Axodoid(ou!utepCdozdos!)-E-
AxatpAq
-Z)-17)-KS tamulguo!doid (jAuNd(Axodoid (otmugiAdoidos!) -E-Axamk
tio-z-uudoid
(ou!tuviAdoidos!)-E-(AxouNd(Axotpa(jA--jozui- 'Z' I -1-1Z)-Z)-10- ia ic)-z-
uedoic1 (ou!utepCdoidos!)
-
E-(Axouaqd(Axotpa 'Z' I -1-1Z)-Z)-10- is tio-z-uedoid(ou!utepCdoidos!)-E-
(Axouaqd
nitrophenoxy)propan-2-ol; RS1-(2-cyclohexylphenoxy)-3-(isopropylamino)propan-2-
ol
S1-(2-cyclohexylphenoxy)-3-(isopropylamino)propan-2-ol;
R1-(2-cyclohexylphenoxy)-3-
(isopropylamino)propan-2-ol;
RS 1 -(441 -hydroxy-2-methoxyethyl)phenoxy)-3 -(i sopropylamino)
propan-2-ol; S1-(4-(1-hydroxy-2-methoxyethyl)phenoxy)-3-(isopropylamino)
propan-2-ol; R1-(4-(1-
hydroxy-2-methoxyethyl)phenoxy)-3-(isopropylamino) propan-2-ol;RS1-(3-amino
phenoxy) -3-(2-
methyl- I H-benzo [d]imidaz ol- I -yl)propan-2-ol;
Si -(3 -aminophenoxy)-3 -(2-methyl- I H-
benzo [d]imidazol-1-yl)propan-2-ol;R1-(3-aminophenoxy)-3-(2-methy1-111-benz
o[d] I midazol-1-
yl)propan-2-ol;RS1-(4-(2-(cyclobutylmethoxy)ethoxy)phenoxy)-3(isopropyl amino)
propan-2-ol; Sl-
(4-(2-(cyclobutylmethoxy)ethoxy)phenoxy)-3 -(i sopropylamino) propan-2-ol;
R1-(4-(2-
i 0 (cyclobutylmethoxy)ethoxy)phenoxy)-3-(isopropyl amino)propan-2-ol;
RS14(246-chloropyridazin-
3-yl)oxy)ethyl)amino)-3-phenoxy propan -2-ol; S14(246-chloropyridazin-3-
yl)oxy)ethyl)amino)-3-
phenoxypropan-2-ol;
R1((24(6-chloropyridazin-3-yl)oxy)ethyl)amino)-3-phenoxypropan-2-ol;
RS1-(4-(2-(cyclo propyl methoxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
S1-(4-(2-
(cyclopropyl methoxy) ethyl)phenoxy)-3-(isopropylamino)propan-2-
ol; R1-(4-(2-
(cyclopropylmethoxy) ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; RS3,3'-
(butylazanediy1)bis
(1-phenoxypropan-2-ol); S3,3'-(butylazanediy1)bi s(1-phenoxypropan-
2-ol); R3,3'-
(butylazanediyObis(1-phenoxypropan-2-01);
RS1-(4-((2-i sopropoxyethoxy)m ethyl)phenoxy)-3-
(i sopropyl amino)propan-2-ol;S1-(4-((2-i so propoxyethoxy)
methyl)phenoxy)-3-
(isopropylamino)propan-2-ol; R1-(4-((2-isopropoxyethoxy) methyl)
phenoxy)-3-
(isopropylamino)propan-2-ol; RS1-(3,4-dimethylphenoxy) - 3-(2,2,5,5-tetra
methy1-2,5-dihydro-1H-
pyrrol-1-yl)propan-2-ol; S1-(3,4-dimethyl phenoxy)- 3-(2,2,5,5-tetra methy1-
2,5-dihydro-1H-pyrrol-
1-yl)propan-2-ol; R1-(3,4-dimethyl phenoxy)- 3-(2,2,5,5-tetra methyl -2,5-
dihydro-1H-pyrrol-1-
yl)propan-2-ol; R5342-hydroxy- 3-phenoxypropyl) amino) propan-l-ol; S3-((2-
hydroxy-3-
phenoxypropyl)amino)propan-l-ol; R34(2-hydroxy-3-phenoxypropyl)amino)propan-l-
ol; R55-(2-
hydroxy-3-(isopropylamino)propoxy)chroman-3-y1 nitrate;
55-(2-hydroxy-3-
(isopropylamino)propoxy)chroman-3-y1 nitrate;
R5-(2-hydroxy-3-
(isopropylamino)propoxy)chroman-3-y1 nitrate;
RS1-(i sopropylamino)-3-((6-methylpyrazin-2-
yl)oxy)propan-2-ol; S1-(isopropylamino)-346-methylpyrazin-2-
y0oxy)propan-2-ol; R1-
(i sopropyl amino)-34(6-methylpyrazin-2-yl)oxy)propan-2-ol;
RS1-(isopropylamino)-3-((3-
morpholinopyrazin-2-y0oxy)propan-2-ol;
S1-(isopropylamino)-343-morpholinopyrazin-2-
y0oxy)propan-2-ol; R1-(isopropylamino)-3-((3-morpholinopyrazin-2-yl)oxy)propan-
2-ol; RS1 -
36
Date Recue/Date Received 2021-04-14
(i sopropyl amino)-34(6-m ethylpyrazin-2-yl)oxy)propan-2-ol;
S1-(isopropylamino)-346-
methylpyrazin-2-yl)oxy)propan-2-ol; R1-(isopropylamino)-346-methylpyrazin-2-
y0oxy)propan-2-
ol;
RSN-(8-(2-hydroxy-3 -(isopropyl amino)propoxy)- 1,2,3 ,4,4a,7,8,8 a-
octahydro- 1,4-
etharionaphthalen-5-yOm ethanesulfonamide;
SN-(8-(2-hydroxy-3 -(i sopropylamino)propoxy)-
1,2,3,4,4a,7,8,8a-octahydro-1,4-ethanonaphthalen-5-yl)m ethane sulfonamide; RN-
(8-(2-hydroxy-3-
(isopropylamino)propoxy)- 1,2,3 ,4,4a,7,8, 8a-octahydro-1,4-ethanonaphthalen-5-
yl)m ethanesulfonamide; RS1-(isopropylamino)-3-((6-methoxy pyridazin-3-
y0oxy)propan-2-ol; Sl-
(i sopropyl amino)-3-((6-m ethoxypyridazin-3-yl)oxy)propan-2-ol;
R1-(isopropylamino)-3-((6-
methoxypyridazin-3-yl)oxy)propan-2-ol; RS1- (is opropylamino)-3 -(thi az ol-2-
yloxy)propan-2-ol; Si -
1 0 (i sopropyl amino)-3-(thi az ol-2-yloxy) propan -2-ol; R1-(i
sopropylamino)-3 -(thi azol-2-yloxy)propan-
2-01; RS1-(isopropylamino)-3-(4-nitrophenyl)
propan-2-ol; S1-(isopropylamino)-3-(4-
nitrophenyl)propan-2-ol; RI -(isopropylamino)-3-(4-nitrophenyl)propan-2-ol; RS
1 -(i sopropylamino)-
3-(4-nitrophenyl)propan-2-ol; S1-(isopropylamino)-3-(4-
nitrophenyl)propan-2-ol; R1-
(i sopropyl amino)-3-(4-nitrophenyl)propan-2-ol;
RS1-(4-ally1-2-m ethoxyphenoxy)-3-
(isopropyl ammo)propan-2-ol; S1-(4-ally1-2-methoxy phenoxy)-3-
(isopropylammo)propan-2-ol; R1 -
(4-ally1-2-m ethoxyphenoxy)-3-(isopropyl amino) propan-2-ol; RS1-
(isopropylamino)-3-(2,4,5-
trimethylphenoxy)propan-2-ol; S1-(isopropylamino) -3-(2,4,5-
trimethylphenoxy)propan-2-ol; R1-
(i sopropyl amino)-3-(2,4,5-trim ethylphenoxy) propan-2-ol;
RS1-(isopropylamino)-3-(2-
methoxyphenoxy)propan-2-ol; S1-(isopropylamino)-3-(2-methoxyphenoxy)propan-2-
ol; R1-
(isopropylamino)-3-(2-methoxyphenoxy)propan-2-ol;
RS1-(4-(2-methoxyethyl)phenoxy)-3-((3-
phenylpropyl)amino)propan-2-ol; S1-(4-(2-m ethoxy ethyl)
phenoxy)-3-((3-
phenylpropyl)amino)propan-2-ol; R1-(4-(2-m ethoxyethyl)
phenoxy)-3-((3-
phenylpropyl)amino)propan-2-ol; RS1-(2-(methylthio)phenoxy)-3-(2,2,5,5-
tetramethylpyrrolidin -1-
yl) propan-2-ol; S1-(2-(methylthio)phenoxy)-3-(2,2,5,5-tetramethylpyrrolidin-l-
yl)propan-2-ol
R1-(2-(methylthio)phenoxy)-3-(2,2,5,5-tetramethylpyrrolidin-l-yl)propan-2-ol;
R53,3'42-
hydroxyethyl)azanedi yObi s(1-phenoxypropan-2-01); S3,3'-((2-hydroxyethyl)
azanedi yl) bi s(1 -
phenoxy propan-2-01); R3,3'42-hydroxyethyl)azanediyObis(1-phenoxypropan-2-01);
RS1-(2-
(methylthio)phenoxy)-3-(2,2,6,6-tetramethylpiperidin-l-yl)propan-2-ol;
S1-(2-(methylthio)
phenoxy) -3-(2,2,6,6-tetramethylpiperidin-1-yl)propan-2-ol; R1-(2-
(methylthio)phenoxy) -3-(2,2,6,6-
tetram ethyl piperidin-l-yl)propan-2-ol; RS1-(3,6-dihydropyridin-1(2H)-y1)-3-
(o-tolyloxy)propan-2-
ol; S1-(3,6-dihydropyridin-1(2H)-y1)-3-(o-tolyloxy)propan-2-ol; R1-(3,6-
dihydropyridin-1(2H)-y1)-
37
Date Recue/Date Received 2021-04-14
3-(o-tolyloxy)propan-2-ol; RS144-methoxyphenyl)amino)-3-phenoxy propan-2-ol;
S144-
methoxyphenyl)amino)-3 -phenoxypropan-2-ol; R1-((4-m ethoxyphenyl) amino)-3-
phenoxypropan-2-
ol;
RS1 -((2-((2,6-dichlorophenyl)amino)ethyl)amino)-3 -(m-tolyloxy)propan-2-ol;
Si 4(24(2,6-
dichlorophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol;
R1-((2-((2,6-
dichlorophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol;
RS1-(4-(2-
methoxyphenyl)piperazin- I -y1)-3 -(m-tolyloxy)propan-2-ol;
Si -(4-(2-methoxyphenyl)piperazin- 1-
y1)-3-(m-tolyloxy)propan-2-ol; R1-(4-(2-methoxyphenyl)piperazin-l-y1)-3-(m-
tolyloxy) propan-2-ol;
RS1-((2-((2,5-dimethylphenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol;
S14(242,5-
dimethylphenyl)amino)ethyl)amino)-3 -(m-tolyloxy)propan-2-ol;
R1 -((2-((2,5-dimethyl
I 0
phenyl)amino) ethyl)amino)-3-(m-tolyloxy)propan-2-ol; RS1-(((l-benzy1-3,5-
dimethyl-1H-pyrazol-
4-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol;
S1-(((l-benzyl-3,5-dimethyl-1H-pyrazol-4-
yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol;
RI-((( I -benzy1-3,5-dimethyl- I H-pyraz ol- 4-
yl)methyl) (methyl)amino)-3-phenoxypropan-2-ol; RS1-(tert-butylamino)-343-
methyl- 1H-indol- 4-
yl)oxy)propan-2-ol; S1-(tert-butylamino)-343-methy1-1H-indo1-4-y0oxy)propan-2-
ol; R1-(tert-
butylamino)-3-((3-methy1-1H-indo1-4-yl)oxy)propan-2-ol; RS1-(methyl amino) -3-
phenoxypropan-2-
ol; S1-(methylamino)-3-phenoxypropan-2-ol; R1-(methyl amino) -3-phenoxypropan-
2-ol; RS142-
hydroxyethyl)amino)-3-phenoxypropan-2-ol; S142-hydroxyethyl)amino)-3-
phenoxypropan-2-ol;
R1((2-hydroxyethyl)amino)-3-phenoxypropan-2-ol;
RS14(4-methylthiazol-5-yl)oxy)-3-(4-(2-
(neopentyloxy)phenyl)piperazin-l-yl)propan-2-ol;
S144-methylthi az ol-5-yl)oxy)-3-(4-(2-
(neopentyloxy)phenyl)piperazin-l-yl)propan-2-ol;
R144-methylthiazol-5-y0oxy)-3-(4-(2-
(neopentyloxy)phenyl)piperazin-l-y1)propan-2-ol;
RS1-(4-(2-ethoxyphenyl)piperazin-l-y1)-34(4-
methylthi az ol-5-yl)oxy)propan-2-ol; S1-(4-(2-ethoxy phenyl) piperazin-l-y1)-
344-methylthiazol-5-
y0oxy)propan-2-ol; R1-(4-(2-ethoxyphenyl) piperazin-l-y1)-344-methylthiazol-5-
y0oxy)propan-2-
ol; RS1-phenoxy-3-(quinuclidin-3-ylamino)propan-2-ol;
Sl-phenoxy-3-(quinucli din-3-
ylamino)propan-2-ol; Rl-phenoxy-3-
(quinuclidin-3-ylamino)propan-2-ol; RS1-(4-(3-
chlorophenyl)piperazin-l-y1)-344-methylthiazol -5-
yl)oxy)propan-2-ol; S1-(4-(3-
chlorophenyl)piperazin-l-y1)-34(4-methylthiazol-5-y0oxy) propan -2-
ol; R1-(4-(3-
chlorophenyl)piperazin-l-y1)-344-methylthiazol-5-y0oxy)propan-2-ol;
RS14(6,7-
dimethoxyi sochroman-l-yOmethyl)(methyl)amino)-3-phenoxypropan-2-ol;
S1-(((6,7-
dimethoxyisochroman-l-yOmethyl)(methyl)amino)-3-phenoxypropan-2-ol;
R1-(((6,7-dimethoxy
isochroman-l-yl)methyl)(methyl)amino)-3-phenoxypropan-2-ol;
RS142-aminoethyl)amino)-3 -
38
Date Recue/Date Received 2021-04-14
phenoxy propan-2-ol; S142-aminoethyl)amino)-3-phenoxypropan-2-ol; R142-
aminoethyl)amino)-
3-phenoxypropan-2-ol;
RS1-(4-(2-(isopentyloxy)phenyl)piperazin-l-y1)-344-methylthiazol-5-
y0oxy)propan-2-ol; Si -(4-(2-(is opentyloxy)phenyl)piperazin- 1-y1)-
3 -((4-methyl thiaz ol-5-
yl)oxy)propan-2-ol; R1-(4-(2-(isopentyloxy)phenyl)piperazin-1-y1)-344-
methyl thiazol-5-
yl)oxy)propan-2-ol; RS1-(4-(2-
isobutoxyphenyl)piperazin-l-y1)-344-methyl thiazol-5-
yl)oxy)propan-2-ol; S 1 -(4-(2-i sobutoxyphenyl)piperazin- 1-y1)-3 -((4-m
ethylthi az ol-5-yl)oxy) propan-
2-ol; R1-(4-(2-isobutoxyphenyl)piperazin-1-y1)-344-methylthiazol-5-y0oxy)
propan-2-ol; RS142-
((2,6-dimethylphenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol;
S1-((2-((2,6-dimethyl
phenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol;
RI -((2-((2,6-dimethylphenyl)
amino)ethyl)amino)-3-phenoxypropan-2-ol;
RS1-((2-((2-chlorophenyl)amino)ethyl)amino)-3-
phenoxypropan-2-ol; S142-((2-chlorophenyl)amino)ethyl)amino)-3-phenoxypropan-2-
ol; R142-
((2-chlorophenyl)amino)ethyl)amino)-3 -phenoxypropan-2-ol;
RS 1 -phenoxy-34(2-(o-
tolylamino)ethyl)amino)propan-2-ol; Sl-phenoxy-3-((2-(o-
tolylamino)ethyl)amino)propan-2-ol
Rl-phenoxy-3-((2-(o-tolylamino)ethyl)amino)propan-2-ol;
RS1-((4-methoxybutyl)amino)-3-
phenoxypropan-2-ol; Sli(4-
methoxybutyl)ammo)-3-phenoxypropan-2-ol; R1-((4-
methoxybutyl)amino)-3-phenoxypropan-2-ol;
RS1-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-
tolyloxy)propan-2-ol; S1-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-
tolyloxy)propan-2-ol
R1-((2-((3-nitrophenyl)amino)ethyl)amino)-3-(m-tolyloxy)propan-2-ol;
RS1-((2-((3-nitrophenyl)
amino) ethyl)amino)-3-(m-tolyloxy)propan-2-ol; S14(243-
nitrophenyl)amino)ethyl)amino)-3-(m-
tolyloxy)propan-2-ol; R142-((3-nitrophenyl)amino)ethyl)amino)-3-(m-
tolyloxy)propan-2-ol; RS1-
((242-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol; S14(2-((2-
nitrophenyl) amino)
ethyl)amino)-3-phenoxypropan-2-ol; R1-((2-((2-nitrophenyl)amino)ethyl)amino)-3-
phenoxypropan-
2-ol; RS14(242-nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-
ol; S14(242-
nitrophenyl)amino)ethyl)amino)-3-phenoxypropan-2-ol;
R1-((2-((2-nitrophenyl)amino)
ethyl)amino)-3-phenoxypropan-2-ol;RS1-(isopropylamino)-3-((l-tosyl-1H-indo1-4-
y0oxy) propan -
2-ol; S1-(isopropylamino)-3-((l-tosyl-1H-indo1-4-y0oxy)propan-2-ol; R1-
(isopropylamino) -3-((l-
tosy1-1H-indo1-4-y0oxy)propan-2-ol.
[0086] Another embodiment is a compound of Formula If, wherein R6 and R7 are
independently
substituted with one, two or three halogens, wherein the halogen is F, Cl, or
Br. Examples of
halogenated compounds of Formula I include, but not limited to:
39
Date Recue/Date Received 2021-04-14
N-methyl-N-(trifluoromethyl)-2-41,7,7-trimethyl-2-phenylbicyclo[2.2.1]heptan-2-
y0oxy) ethan-1-
amine,
N,N-bis(trifluoromethyl)-24(1,7,7-trimethy1-2-phenylbicyclo[2.2.1]heptan-2-
yl)oxy)ethan-1-amine,
2-((1,7-dimethy1-2-pheny1-7-(trifluoromethyl)bicyclo[2.2.1]heptan-2-y1)oxy)-
N,N-bis
(trifluoromethyl)ethan-1-amine,
2-(0-methyl-2-phenyl-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-ypoxy)-N,N-
bis(trifluoromethyl)ethan-1-amine,
N-methy1-24(1-methyl-2-pheny1-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-
y0oxy)-N-
(trifluoromethyl)ethan-1-amine,
N,N-dimethy1-2-((1-methy1-2-phenyl-7,7-
bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-y0oxy)ethan-1-
amine,
2-((1,7-dimethy1-2-pheny1-7-(trif1uoromethyl)bicyclo[2.2.1]heptan-2-y1)oxy)-
N,N-dimethylethan-1-
amine, and
N,N-dimethy1-2-((1,7,7-trimethy1-2-(4-
(trifluoromethoxy)phenyObicyclo[2.2.1]heptan-2-
yl)oxy)ethan-l-amine.
[0087] Another embodiment is a composition comprising a compound of Formula If
listed below:
2-phenyl-2-(3'-dim ethyl aminopropoxy)-1,7,7-trim ethylbi cycl o [2,2,1]
heptane ;
2-phenyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(p-methoxy-phenyl)-2-(3'-dimethylaminopropoxy)-1,7,7-trimethyl-
bicyclo(2,2,1) heptane; 2-
b enzy1-2-(3'-dim ethyl aminopropoxy)-1,7,7-trim ethylbi cycl o
[2,2,1]heptane;
2-benzy1-2-(3'-dimethylamino-2'-methylpropoxy)-1,7,7-trimethyl-bicyclo[2,2,1]
heptane;
2-benzy1-2-(2-diisopropylaminoethoxy)-1,7,7-trimethyl-bicyclo[2,2,1]heptane;
2-benzy1-2-1'-(4'-benzylpiperaziny1)-propoxy1,7,7-trimethylbicyclo[2,2,1]
heptane;
2-b enzy1-2-(3 '-dii sopropyl aminopropoxy)-1,7,7-trim ethylbi cycl o [2,2,1]
heptane ;
2-b enzy1-2-(3 '-di ethyl aminopropoxy)-1,7,7-trim ethylbi cycl o [2,2,1]
heptane ;
2-b enzy1-2-(3 '-dim ethyl aminopropoxy)-1,7,7-trim ethyl-bi cyclo [2,2,1]
heptane ;
2-b enzy1-2-(2'-di ethyl aminoethoxy)-1,7,7-trim ethylbi cycl o
[2,2,1]heptane;
2-benzy1-2-(3'-dimethylamino propoxy) -1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(3'-dimethylaminopropoxy)-2-(4'-methoxypheny1)-1,7,7-trimethylbicyclo[2,2,1]
heptane;
2-(p-chloro-benzy1)-2-(3'-dimethylaminopropoxy)-1,7,7- trimethylbicyclo[2,2,1]
heptane;
2-(p-chloro-benzy1)-2-(2'-dimethylaminoethoxy)-1,7,7-
trimethylbicyclo[2,2,1]heptane;
Date Recue/Date Received 2021-04-14
2-(3'-dimethylamino-2'-methyp-propoxy-2-(p-chloro-pheny1)-1 ,7,7-
trimethylbicyclo [2,2,1]heptane;
2-(3'-dimethylaminopropoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(21-dimethylaminoethoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(3-diethylaminopropoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(2'-diethylaminoethoxy)-2-(2'-thieny1)-1,7,7-
trimethylbicyclo[2,2,1]heptane;
2-(3'-dimethylaminopropoxy)-2-(2'-thieny1)-1,7,7-
trimethylbicyclo[2,2,1]heptane;
2-(3'-diethylaminopropoxy)-2-(2'-thieny1)-1,7,7-
trimethylbicyclo[2,2,1]heptane;
2-benzy1-2-3'-(N-cyclohexyl-N-methyl)aminopropoxy]-1,7,7-
trimethylbicyclo[2,2,1] heptane;
2-(p-methoxypheny1)-2-(3'-dimethylaminopropoxy)-1,7,7- trimethylbicyclo[2,2,1]
heptane;
(1R,2 S,4R)-(-)-2-[(2'- {N,N-dimethylamino -ethoxy)]-2-[phenyl]- 1,7,7-
trimethylbicyclo [2,2,1]heptane;
(1R,2S,4R)-(+2-benzy1-2-(3'-dimethylaminopropoxy)-1,7,7-
trimethylbicyclo[2,2,1] heptane;
(1R,2S,4R)-(+2-benzy1-2-(2'-methy1-3'-dimethy1aminopropoxy)-1,7,7-
trimethylbicyclo [2,2,1] heptane;
(1RS,2RS,4RS)-2-pheny1-2-(2'-dimethylaminoethoxy)-1,7,7
trimethylbicyclo[2,2,1] heptane;
(1S,2R,4S)-(+)-2-pheny1-2-(2'-dimethylaminoethoxy)-1,7,7-
trimethylbicyclo[2,2,1] heptane; N,N-
chmethy1-2-[[(1R,3S,4R)-4,7,7-trimethy1-3-phenyl-3-bicyclo[2.2.1] heptanyl]
oxy] ethanamine
(deramciclane); N-methyl-N-(trifluoromethyl)-241,7,7-trimethyl-2-phenylbicyclo
[2.2.1]heptan-2-
yl)oxy) ethan-l-amine,
N,N-bis(trifluoromethyl)-24(1,7,7-trimethy1-2-phenylbicyclo[2.2.1]heptan-2-
yl)oxy)ethan-1-amine,
2-((1,7-dimethy1-2-pheny1-7-(trifluoromethyl)bicyclo[2.2.1]heptan-2-y0oxy)-N,N-
bis(trifluoromethyl)ethan-l-amine,
2-((1-methy1-2-phenyl-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-y1)oxy)-
N,N-
bis(trifluoromethyl)ethan-1-amine,
N-methy1-24(1-methyl-2-pheny1-7,7-bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-
y0oxy)-N-
(trifluoromethyl)ethan-1-amine,
N,N-dimethy1-2-((1-methyl-2-phenyl-7,7-
bis(trifluoromethyl)bicyclo[2.2.1]heptan-2-y0oxy)ethan-1-
amine,
24(1,7-dimethy1-2-pheny1-7-(trifluoromethyl)bicyclo[2.2.1]heptan-2-y0oxy)-N,N-
dimethylethan-1-
amine, and
N,N-dimethy1-2-((1,7,7-trimethy1-2-(4-
(trifluoromethoxy)phenyObicyclo[2.2.1]heptan-2-
yl)oxy)ethan-l-amine.
[0088] Another embodiment is a composition comprising an acid addition salt of
a compound of
41
Date Recue/Date Received 2021-04-14
Formula If comprising hydrogen acetate, hydrogen acetyl salicylate, hydrogen
adipate, hydrogen
aspartate, hydrogen butyrate, hydrogen caprate, hydrogen caproate, hydrogen
caprylate, hydrogen
enanthate, hydrogen formate, hydrogen fumarate, hydrogen glutarate, hydrogen
isophthallate,
hydrogen maleate, hydrogen malonate, hydrogen oxalate, hydrogen pelargonate,
hydrogen pimelate,
hydrogen propionate, hydrogen phthallate, hydrogen salicylate , hydrogen
sebacate, hydrogen
succinate, hydrogen terephthallate, hydrogen tyrosinate, hydrogen
tryptophanate, hydrogen
methionate; hydrogen N-acyl-methionate; and hydrogen valerate.
[0089] Another embodiment is a composition comprising an acid addition salt of
N,N-dimethy1-2-
[[(1R,3S,4R)-4,7,7-trimethy1-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]ethanamine
(deramciclane)
comprising deramciclane hydrogen acetate, deramciclane hydrogen acetyl
salicylate, deramciclane
hydrogen adipate, deramciclane hydrogen aspartate, deramciclane hydrogen
butyrate, deramciclane
hydrogen caprate, deramciclane hydrogen caproate, deramciclane hydrogen
caprylate, deramciclane
hydrogen enanthate, deramciclane hydrogen formate, deramciclane hydrogen
fumarate,
deramciclane hydrogen glutarate, deramciclane hydrogen isophthallate,
deramciclane hydrogen
maleate, deramciclane hydrogen malonate, deramciclane hydrogen oxalate,
deramciclane hydrogen
pelargonate, deramciclane hydrogen pimelate, deramciclane hydrogen propionate,
deramciclane
hydrogen phthallate, deramciclane hydrogen salicylate , deramciclane hydrogen
sebacate,
deramciclane hydrogen succinate, deramciclane hydrogen terephthallate,
deramciclane hydrogen
tyrosinate, deramciclane hydrogen tryptophanate, deramciclane hydrogen
methionate; deramciclane
hydrogen N-acyl-methionate; or deramciclane hydrogen valerate.
[0090] An embodiment of the invention is a composition comprising
dextromethorphan or its acid
addition salt and a compound of Formula I selected from the group consisting
of:
2-phenyl-2-(2-dimethylaminoethoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-phenyl-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-phenyl-2-(3'-diethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(p-methoxy-pheny1)-2-(3'-dimethylaminopropoxy)-1,7,7-
trimethylbicyclo[2,2,1]heptane;
2-benzy1-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-benzy1-2-(3'-dimethylamino-2'-methylpropoxy)-1,7,7-trimethyl-bicyclo[2,2,1]
heptane;
2-benzy1-2-(2-diisopropylaminoethoxy)-1,7,7-trimethyl-bicyclo[2,2,1]heptane;
2-benzy1-2-1'-(4'-benzylpiperaziny1)-propoxy1,7,7-trimethylbicyclo[2,2,1]
heptane;
2-benzy1-2-(3'-diisopropylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
42
Date Recue/Date Received 2021-04-14
2-b enzy1-2-(3'-di ethyl aminopropoxy)-1,7,7-trim ethylbi cycl o
[2,2,1]heptane ;
2-b enzy1-2-(3'-dim ethyl aminopropoxy)-1,7,7-trim ethyl-bi cyclo
[2,2,1]heptane;
2-benzy1-2-(2'-diethylaminoethoxy)- 1,7,7-trimethylbicyclo [2,2, l]heptane;
2-benzy1-2-(3'-dimethylaminopropoxy)-1,7,7-trimethylbicyclo[2,2,1]heptane;
2-(3'-dim ethyl aminopropoxy)-2-(4'-m ethoxypheny1)-1,7,7-trim ethylbi cycl o
[2,2,1]heptane;
2-(p-chloro-benzy1)-2-(3'-dimethylaminopropoxy)-1,7,7- trimethylbicyclo[2,2,1]
heptane;
2-(p-chloro-benzy1)-2-(2'-dimethylaminoethoxy)-1,7,7-
trimethylbicyclo[2,2,1]heptane;
2-(3'-dimethylamino-2'-methyl)-propoxy-2-(p-chloro-pheny1)-1,7,7-
trimethylbicyclo [2,2,1] heptane;
2-(3'-dimethylaminopropoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(2'-dimethylaminoethoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(3-diethylaminopropoxy)-2-pheny1-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(2'-diethylaminoethoxy)-2-(T-thieny1)-1,7,7- trimethylbicyclo[2,2,1]heptane;
2-(3'-dimethylaminopropoxy)-2-(2'-thieny1)-1,7,7-
trimethylbicyclo[2,2,1]heptane;
2-(3'-diethylaminopropoxy)-2-(2'-thieny1)-1,7,7-
trimethylbicyclo[2,2,1]heptane;
2-benzy1-2-3'-(N-cyclohexyl-N-methyl)aminopropoxy]-1,7,7-
trimethylbicyclo[2,2,1] heptane;
2-(p-methoxypheny1)-2-(3'-dimethylaminopropoxy)-1,7,7- trimethylbicyclo[2,2,1]
heptane;
(1R,2S,4R)-(-)-2-[(2'- {N,N-dim ethylamino} -ethoxy)] -2- [phenyl] -1,7,7-trim
ethylbicyclo [2,2,1]
heptane;
(1R,2S,4R)-(+2-benzy1-2-(3'-dimethylaminopropoxy)-1,7,7-
trimethylbicyclo[2,2,1] heptane;
(1R,2S,4R)-(-)-2-benzy1-2-(2'-methyl-3'-dimethylaminopropoxy)-1,7,7-
trimethylbicyclo [2,2,1]
heptane;
(1RS,2RS,4RS)-2-pheny1-2-(2'-dimethylaminoethoxy)-1,7,7 trimethylbicyclo
[2,2,1] heptane;
(1S,2R,4S)-(+)-2-pheny1-2-(2'-dimethylaminoethoxy)-1,7,7-
trimethylbicyclo[2,2,1]heptane; N,N-
dimethy1-2-[[(1R,3S,4R)-4,7,7-trimethy1-3-phenyl-3-
bicyclo[2.2.1]heptanyl]oxy]ethanamine
(deramciclane); or an acid addition salt thereof.
[0091] An embodiment of the invention is a composition comprising
dextromethorphan or its acid
addition salt, and deramciclane, deramciclane acetate, deramciclane acetyl
salicylate, deramciclane
adipate, deramciclane butyrate, deramciclane caprate, deramciclane caproate,
deramciclane caprylate,
deramciclane enanthate, deramciclane formate, deramciclane fumarate,
deramciclane glutarate,
deramciclane isophthallate, deramciclane maleate, deramciclane malonate,
deramciclane oxalate,
deramciclane pelargonate, deramciclane pimelate, deramciclane propionate,
deramciclane phthallate,
43
Date Recue/Date Received 2021-04-14
deramciclane salicylate , deramciclane sebacate, deramciclane succinate,
deramciclane terephthallate,
deramciclane tyrosinate, deramciclane tryptophanate, or deramciclane valerate;
or a combination
thereof.
[0092] In some embodiments, the compound of Formula II is a fluoro- derivative
such as, but not
limited to:
(4bS,8aS,9S)-11-methy1-3-(trifluoromethoxy)-6,7,8,8a,9,10-hexahydro-5H-9,4b-
(epiminoethano)phenanthrene;
(4bS, 8 aS,9 S)-3 -(trifluoromethoxy)-11-(trifluoromethyl)-
6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene;
(4b S,8aS,9S)-3-methoxy-11-
(trifluoromethyl)-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene.
[0093] In some embodiments, the compound of Formula II is an acid addition
salt selected from
acetate, acetyl salicylate, adipate, aspartate, butyrate, caprate, caproate,
caprylate, enanthate, formate,
fumarate, glutamate glutarate, isophthallate, maleate, malonate, methionate,
oxalate, pelargonate,
pimelate, propionate, phthallate, salicylate, sebacate, succinate,
terephthallate, tyrosinate,
tryptophanate, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-
tyrosinate, N-acyl-tryptophanate,
N-acyl-methionate, citrate, galactonate, glucaric acid (saccharic acid),
mannonate, mucate,
rharnnonate, and tartrate.
[0094] In another embodiment, dextromethorphan or a compound of Formula II as
defined above, and
a derivative of a compound of Formula I, wherein the derivative is an acid
addition salts selected from:
acetate, acetyl salicylate, adipate, aspartate, butyrate, caprate, caproate,
caprylate, enanthate, formate,
fumarate, glutamate glutarate, isophthallate, maleate, malonate, methionate,
oxalate, pelargonate,
pimelate, propionate, phthallate, salicylate, sebacate, succinate,
terephthallate, tyrosinate,
tryptophanate, valerate, N-acyl-aspartate, N-acyl-glutamate, N-acyl-
tyrosinate, N-acyl-tryptophanate,
N-acyl-methionate, citrate, galactonate, glucaric acid (saccharic acid),
mannonate, mucate,
rhamnonate, and tartrate.
[0095] In some embodiments, the compound of Formula II is an acid addition
salt selected from N-
acyl-aspartate, N-acyl-glutarate, N-acyl-tyrosinate, N-acyl-tryptophanate, and
N-acyl-methionate.
[0096] Examples include addition salts of base of formula II represented by
dextromethorphan, such
as dextromethorphan hydrogen acetate, dextromethorphan hydrogen acetyl
salicylate,
dextromethorphan hydrogen adipate, dextromethorphan hydrogen aspartate,
dextromethorphan
hydrogen butyrate, dextromethorphan hydrogen caprate, dextromethorphan
hydrogen caproate,
dextromethorphan hydrogen caprylate, dextromethorphan hydrogen enanthate,
dextromethorphan
hydrogen formate, dextromethorphan hydrogen fumarate, dextromethorphan
hydrogen glutarate,
44
Date Recue/Date Received 2021-04-14
dextromethorphan hydrogen isophthallate, dextromethorphan hydrogen maleate,
dextromethorphan
hydrogen malonate, dextromethorphan hydrogen oxalate, dextromethorphan
hydrogen pelargonate,
dextromethorphan hydrogen pimelate, dextromethorphan hydrogen propionate,
dextromethorphan
hydrogen phthallate, dextromethorphan hydrogen salicylate , dextromethorphan
hydrogen sebacate,
dextromethorphan hydrogen succinate, dextromethorphan hydrogen terephthallate,
dextromethorphan
hydrogen tyrosinate, dextrornethorphan hydrogen tryptophanate, and
dextromethorphan hydrogen
valerate.
[0097] Another embodiment of the invention is a composition comprising an acid
addition salt of
compound of Formula I and an acid addition salt of a compound of Formula II.
Another embodiment
of the invention is a composition comprising an acid addition salt of
deramciclane and an acid addition
salt of dextromethorphan.
[0098] Another embodiment of the invention is a composition comprising an acid
addition salt of a
halogenated compound of Formula I and an acid addition salt of
dextromethorphan. Another
embodiment is a composition comprising the halogenated compound of Formula I
is trifluoromethyl
derivative of Ml.
[0099] aspartate, benzenesulfonate, besylate, benzoate, bicarbonate,
bitartrate, bromide, camphor
sulfonate, camsylate, chloride, citrate, decanoate, edetate, lauryl sulfate,
estolate, ethanesulfonate,
esylate, lumarate, gluceptate, gluconate, glutamate, glycolate,
glycollylarsandate, hexanoate,
hexylresorcinol, hydroxynaphthoate, isethionate, iodide, lactate,
galactopyranosyl-d-gluconate,
lactobionate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate,
mucate, napsylate, nitrate, octanoate, oleate, pamoate, 4,4'-methylenebis(3-
hydroxy-2-naphthoate,
pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate,
succinate, sulfate, tartrate,
teoclate, 8-chloro-1,3-dimethy1-7h-purine-2,6-di one, tosylate, malate,
methionate, phthallate,
malonate, tyrosinate, tryptophanate, maleate, fumarate,
[00100] An embodiment of the invention is an addition salt of Formula I,
wherein with organic acid
such as aspartic acid, benzenesulfonic acid, besylic acid, benzoic acid,
bicarbonic acid, tartaric acid,
bromide, camphor sulfonic acid, camsylic acid, chloride, citric acid, decanoic
acid, edetate, lauryl
sulfonic acid, estolic acid, ethanesulfonic acid, esylic acid, fumaric acid,
gluceptic acid, gluconic acid,
glutamic acid, glycolic acid, glycollylarsanilic acid, hexanoic acid,
hexylresorcinol, hydroxynaphthoic
acid, isethionic acid, iodide, lactic acide, galactopyranosyl-d-gluconic acid,
lactobionic acid, malic
acid, maleic acid, mandelic acid, methanesulfonic acid, methylbromide,
methylnitric acid,
Date Recue/Date Received 2021-04-14
methylsulfonic acid, mucic acid, napsylic acid, nitric acid, octanoic acid,
oleic acid, pamoic acid, 4,4'-
methylenebis(3-hydroxy-2-naphthonic acid, pantothenic acid, phosphoric acid,
polygalacturonic acid,
propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid,
tartaric acid, teoclic acid, 8-
chloro-1,3-dimethy1-7h-purine-2,6-dione, tosylic acid, malic acid, methionic
acid, phthallic acid,
malonic acid, tyrosine, tryptophan, maleic acid, fumaric acid, succinic acid,
glutaric acid, adipic acid,
pimelic acid, sebacic acid, formic acid, acetic acid, propionic acid, butyric
acid, valeric acid, caproic
acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, oxalic acid,
isophthallic acid,
terephthallic acid, salicylic acid, difluorosuccinicacid, trifluorosuccinic
acid, tetrafluorosuccinic acid,
difluoroglutaric acid, difluoroacetic acid, trifluoroacetic acid; and
dextromethorphan; or a combination
thereof.
[00101] In some aspects of the invention, the compound of Formula I is a
prodrug according to wherein
the compound is an ester or an addition formed from the following acids: 3-
(nitrooxy)propanoic acid
(Vendors: AKos (AK0S006377427), and 1717 CheMall (0R235109)), 4-
nitrooxybutanoic acid
(Vendors: AKos (AKOS006378268) and iChemical (EBD3415162)), 3-
(nitrooxy)butanoic acid
(AKos (AK0S006376331, AK0S016035558), MolMall (21929)). Examples include, but
not limited
to, 3-nitrooxy derivatives of Compounds 71-73, 4-nitrooxy derivatives of
Compounds 74-76, and 3-
nitrooxy derivatives of Compounds 74-76. In some embodiments, the compounds of
Formula I form
addition salts a 3-(nitrooxy)propanoic acid, 3-(nitrooxy)butanoic acid, and 4-
(nitrooxy)butanoic acid.
In another embodiment, the acid addition salt is of 3-(nitrooxy)propanoic
acid, 3-(nitrooxy)butanoic
acid, and 4-(nitrooxy)butanoic acid.
[00102] In another embodiment, the pharmaceutically acceptable acid addition
salts of the compounds
of the Formula I can be formed with inorganic acids such as hydrochloric acid,
hydrogen bromide,
sulfuric acid, phosphoric acid and nitric acid.
[00103] Other anion salts of compounds of Formulas I and II include the salts
formed from the
following acidic groups:
46
Date Recue/Date Received 2021-04-14
,...xicTrOH
Aspartate Thr
.,151õ. H
0 Galactopyranosyl-D-
0 NH, gluconic acid (Lactobionate)=\C'H
Benzenesulfonate
HO
(Besylate) 111, ?,--
0 maiate C)..'rrij'.. HO
0 0 OH OH
Benzoate 0 maieate 4t. .... 0
o 0_,7--.
Bicarbonate
HO)L0
OH 0 Mandelate 49 cr
OH
B i tartrate HO yyt,OH 0
0 OH Mesylate -OH
Bromide Br- g
o Methylbromide ¨Br o
Camphor sulfonic acid 0";)11 II
Me
(Camsylate) 0 thylnitrate -..õ. . o-
(Cain
Ntµµ.
0
Chloride Cl- . 0....0- . 0 Methylsulfate -- -A
o' -
Citrate
OH Galactaric Acid (Mucate)
0 OH Ho 1
I:r).,h':)hri.klo 0H
1Decanoate o
Napsylate H 00, o
0 ('OH 0
Edetate Ho -II, N ,.....-.. N ..-,õnõOH 0 Nitrate
, N',
0
HO ,r? 0 o_g-o Octanoate0 _.---....,--,..--,,J10 o
Lauryl sulfate (Estolate) -......,-,. `,--........-:--,r1 b Oleate
¨ o
Pamoate (4,4'-
Ethanesulfonate (Esylate) ,----../ methylenebis(3-
cc, --o,,,
hydroxy-2- -o
Fumarate -0_Tr.--õyõ0 o cl-,I,
naphthoate))
0 OH OH 0 HO >L1,1
*-XI ------I0
Gluceptate HO '...."Thr3C----1k0H Pantothenate 0
OH H
EH OH EH Phosphate -IT-
Gluconate
rio...5.1,11,1,, 1,o- .51-0
polygalacturonate --i!,/,0 1-.2, '0 .C.2, 10H
EH EH HO OH HO OH HO- OH
Glutamate 0 y Propionate 0 ......k,' _
0,Lc.........xko
Salicylate CI"
0t,lhi
Glycolate 0
HO ........}...... õK. Stearate 0
0
Glycollylarsanilate Ho.,..IN 1100 (' - Succinate
H 00
H ne o ci ol ^^5k0- '1
Heexxyan'roaster Sulfate II
-0 -6 -0-
II
I- --.----------------- ---H
Tartrate 0 (--,1 c
0 0-
OH c,-
Hydroxynaphthoate OM H 0 OH
H ...-1r
o
os Teoclate (8-chloro-1,3-dimethy1-
7H-purine-2,6-dione)
Isethionate H0..-.,õ:6,6
1
Iodide I-
O Tosylate ,4*. -OH
HO
Lactate
[00104] Acid addition salts of Formula I described are represented by the
below formulae:
1 4 OH4
31 0 ,z,
.,z_icl õ H ,) lor.o,
'Pli E4 cy .440
i
1.1 1 l
-HMO I H
li _13 1 e __ I II-F110 I "gipb OH . f{ I H ,,= OH I
il))
Formula I-Acid-Formula It _ r
- d , _ . _
[00105] Another embodiment is a composition comprising a compound of Formula
I, and at least one
compound selected from thioridazine, perphenazine, fluphenazine,
zuclopenthixol, risperidone,
sertindole, nortriptyline, amitriptyline, imipramine, fluoxetine, paroxetine,
ajmaline, amiodarone,
amitriptyline, aprindine, azelastine, celecoxib, chlorpheniramine,
chlorpromazine, diphenhydramine,
doxorubicin, fluphenazine, fluvastatin, haloperidol, imipramine, indinavir,
lasoprazole,
levomepromazine, lopinavir, loratadine, mequitazine, methadone,
metoclopramide, mibefradil,
47
Date Recue/Date Received 2021-04-14
moclobemide, nelfinavir, nevirapine, nicardipine, norfluoxetine, perphenazine,
pimozide, terfenadine,
thioridazine, cimetidine, quinidine, cisapride, citalopram, clozapine,
cocaine, desipramine, ranitidine,
risperidone, ritonavir, saquinavir, sertraline, terbinafine, ticlopidine,
trifluperidol, yohimbine,
clomipramine, doxepin, mianserin, imipramine, 2-chloroimipramine,
amitriptyline, amoxapine,
protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine,
isocarboxazid, tranylcypromine,
trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine,
escitalopram, fluvoxamine,
venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline,
sibutramine,
milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, nialamide,
iproniazid, iproclozide,
toloxatone, butriptyline, dosulepin, dibenzepin, iprindole, lofepramine,
opipramol, and dapoxetine.
[00106] Another embodiment of the invention is a composition comprising a
compound of Formula I,
a compound of Formula II, and at least one compound selected from
thioridazine, perphenazine,
fluphenazine, zuclopenthixol, risperidone, sertindole, nortriptyline,
amitriptyline, imipramine,
fluoxetine, paroxetine, ajmaline, amiodarone, amitriptyline, aprindine,
azelastine, celecoxib,
chlorpheniramine, chlorpromazine, diphenhydramine, doxorubicin, fluphenazine,
fluvastatin,
haloperidol, imipramine, indinavir, lasoprazole, levomepromazine, lopinavir,
loratadine, mequitazine,
methadone, metoclopramide, mibefradil, moclobemide, nelfinavir, nevirapine,
nicardipine,
norfluoxetine, perphenazine, pimozide, terfenadine, thioridazine, cimetidine,
quinidine, cisapride,
citalopram, clomipramine, clozapine, cocaine, ranitidine, risperidone,
ritonavir, saquinavir, sertraline,
terbinafine, ticlopidine, trifluperidol, yohimbine, doxepin, mianserin,
imipramine, 2-
chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline,
trimipramine, nortriptyline,
maprotiline, phenelzine, isocarboxazid, tranylcypromine, trazodone,
citalopram, sertraline, aryloxy
indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine,
desvenlafaxine, duloxetine,
mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine,
brasofensine,
moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone,
butriptyline, dosulepin,
dibenzepin, iprindole, lofepramine, opipramol, and dapoxetine.
[00107] In one embodiment, the composition comprises a compound of Formula I,
wherein the
compound wherein le is a conjugate or covalent compound formed either by
etherification or
esterification with derivatives of one or more of AChIs such as 24(1-
Benzylpiperidin-4-yOmethyl)-
5,6-dim ethoxy-2,3 -dihydro-1H-inden-1 -one (Donepezil), (S)-3 -(1 -(di m
ethyl amino)ethyl)ph enyl
ethyl(methyl) carbamate (Rivastigmine), dimethyl (2,2,2-trichloro- 1 -
hydroxyethyl)phosphonate
(Metrifonate),
(4aS,6R,8aS)-3 -methoxy-11 -m ethy1-4a,5,9,10,11,12-hexahydro-6H-
48
Date Recue/Date Received 2021-04-14
b enzo [2,3]b enz ofuro [4,3 -cd] az epin-6-ol (Gal antamine), and 1,2,3,4-
tetrahydroacridin-9-amine
(Tacrine), 0,S-dimethyl acetylphosphoramidothioate, 0,0-dimethyl S44-
oxobenzo[d][1,2,3]triazin-
3 (411)-yOmethyl) phosphorodithioate, 2,2-dimethyl-2,3-dihydrobenzofuran-7-y1
methylcarbamate, S-
(((4-chl orophenyl)thi o)m ethyl) 0,0-diethyl
phosphorodithioate, 2-chl oro-1 -(2,4-
di chl orophenyl)vinyl diethyl phosphate,
0,0-diethyl 0-(3,5,6-tri chl oropyri din-2-y
phosphorothioate, 043 -chloro-4-methyl-2-oxo-2H-chrom en -7 -y1) 0,0 -di ethyl
phosphorothioate,
phenylethyl (E)-3-((dimethoxyphosphoryl)oxy)but-2-enoate,4-(tert-buty1)-2-
chlorophenyl methyl
methylphosphoramidate, 0,0-diethyl 0-(2-(ethylthio)ethyl) phosphorothioate,
0,0-diethyl S-(2-
(ethylthi o)ethyl) phosphorothioate, 0,0-diethyl
0-(2-isopropyl-6-methylpyrimidin-4-y1)
phosphorothioate, 2,2-dichlorovinyl dimethyl phosphate, (E)-4-(dimethylamino)-
4-oxobut-2-en-2-y1
dimethyl phosphate, 0,0-dimethyl S-(2-(methylamino)-2-oxoethyl)
phosphorodithioate, S,S'-(1,4-
di oxane-2,3 -diyl) 0,0,0, 0'-tetraethyl bis(phosphorodithioate), 0,0-diethyl
S-(2-(ethylthio)ethyl)
phosphorodithioate, 0-ethyl 0-(4-nitrophenyl) phenylphosphonothioate,
0,0,0',0'-tetraethyl S,S'-
methylene bis(phosphorodithioate), 0-ethyl S,S-dipropyl phosphorodithioate, 0-
(4-(N,N-
1 5 chmethylsulfamoyl)phenyl) 0,0-dimethyl phosphorothioate, ()-(4-(N ,N -
thmethylsulfamoyl)phenyl)
0,0-dimethyl phosphorothioate, ethyl (3-methy1-4-(methylthio)phenyl)
isopropylphosphoramidate,
0,0-dimethyl 0-(3-methy1-4-nitrophenyl) phosphorothioate,
0-ethyl S-phenyl
ethylphosphonodithioate, isopropyl 2-
((ethoxy(isopropylamino)phosphorothioyl)oxy)benzoate,
diethyl 2-((dim ethoxyphosphorothi oyl)thi o)succ inate, 0, S-dim ethyl
phosphoramidothioate, 0, S-
dim ethyl phosphoramidothioate, S-((5-m ethoxy-2-oxo-1,3,4-thi adi az 01-3
(2H)-yl)m ethyl) 0,0-
dimethyl phosphorodithioate, methyl 3-((dimethoxyphosphoryl)oxy)but-2-enoate,
(E)-dimethyl (4-
(methylamino)-4-oxobut-2-en-2-y1) phosphate, 1,2-dibromo-2,2-dichloroethyl
dimethyl phosphate,
isopropyl (S)-methylphosphonofluoridate, 3,3-dimethylbutan-2-y1 (S)-
methylphosphonofluoridate,
0,0-diethyl 0-(4-nitrophenyl) phosphorothioate, S-(2-(ethylsulfinyl)ethyl) 0,0-
dimethyl
phosphorothioate, 0,0-diethyl S-((ethylthi o)m ethyl)
phosphorodithioate, S-((6-chl oro-2-
ox ob enz o [d] oxazol-3 (2H)-yl)m ethyl) 0,0-diethyl phosphorodithioate, S-
((1,3-di oxoi s oindolin-2-
yl)m ethyl) 0,0-dimethyl phosphorodithioate, (E)-3-chl oro-4-(di ethyl amino)-
4-ox obut-2-en-2-y1
dim ethyl phosphate, 0,0,0', 0'-tetram ethyl 0,0'-(thi obi s (4,1 -phenyl en
e)) bis(phosphorothioate),
tetraethyl diphosphate, S-((tert-butylthio)methyl) 0,0-diethyl
phosphorodithioate, 2-chloro-1-(2,4,5-
trichlorophenyl)vinyl dimethyl phosphate, and
dimethyl (2,2,2-trichloro-1-
hydroxyethyl)phosphonate, or pharmaceutically acceptable derivatives,
metabolites, analogs, or salts
49
Date Recue/Date Received 2021-04-14
thereof, prepared using prodrug strategies described in FIGURE 13 wherein the
parent drug
compounds of Formula I and II are represented by R with general schemes
representing various
embodiments of prodrugs of compounds of Formula I and II (see for example,
Rautio et al., The
expanding role of prodrugs in contemporary drug design and development, Nature
Reviews Drug
Discovery, published online at http://dx.doi.org/10.1038/nrd.2018.46 (27 April
2018); Stella,
Prodrugs: Some thoughts and current issues. J. Pharm. Sci. 99, 4755-4765
(2010); Clas et al.,
Chemistry-enabled drug delivery (prodrugs): recent progress and challenges.
Drug Discov.
Today 19, 79-87 (2014); Rautio et al., Prodrugs ¨ Recent approvals and a
glimpse of the
pipeline. Eur. J. Pharm. Sci. 109, 146-161 (2017); Rautio et al. Prodrugs:
design and clinical
applications. Nat. Rev. Drug Discov. 7, 255-270 (2008);Stella et al., Prodrug
strategies to
overcome poor water solubility. Adv. Drug Deliv. Rev.59, 677-694 (2007);
Kumpulainen et
al. Synthesis, in vitro and in vivo characterization of novel ethyl dioxy
phosphate prodrug of
propofol. Eur. J. Pharm. Sci. 34, 110-117 (2008); Hale et al. Phosphorylated
morpholine acetal
human neurokinin-1 receptor antagonists as water-soluble prodrugs. I Med.
Chem. 43, 1234-1241
(2000); Ishikawa et al. TAK-599, a novel N-phosphono type prodrug of anti-MRSA
cephalosporm
T-91825: synthesis, physicochemical and pharmacological properties. Bioorg.
Med. Chem. 11,
2427-2437 (2003); Mehellou et al., Aryloxy phosphoramidate triesters: a
technology for delivering
monophosphorylated nucleosides and sugars into cells. ChemMedChem 4, 1779-1791
(2009);
Thornton et al., Nucleoside phosphate and phosphonate prodrug clinical
candidates. I Med.
Chem. 59, 10400-10410 (2016); Pradere etal., Synthesis of nucleoside phosphate
and phosphonate
prodrugs. Chem. Rev.114, 9154-9218 (2014); Starrett et al. Synthesis and in
vitro evaluation of a
phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)
adenine. Antiviral
Res.19, 267-273 (1992); Starrett et al. Synthesis, oral bioavailability
determination, and in vitro
evaluation of prodrugs of the antiviral agent 9-[2-
(phosphonomethoxy)ethyl]adenine (PMEA). I
Med. Chem. 37, 1857-1864 (1994); McGuigan et al. Synthesis, anti-human
immunodeficiency
virus activity and esterase lability of some novel carboxylic ester-modified
phosphoramidate
derivatives of stavudine (d4T). Antivir. Chem. Chemother. 9, 473-479 (1998);
McGuigan et al.,
Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate
derivatives of d4T
(stavudine): esterase hydrolysis as a rapid predictive test for antiviral
potency. Antivir. Chem.
Chemother. 9, 109-115 (1998); Erion et al. Design, synthesis, and
characterization of a series of
cytochrome P(450) 3A-activated prodrugs (HepDirect prodrugs) useful for
targeting
Date Recue/Date Received 2021-04-14
phosph(on)ate-based drugs to the liver. J. Am. Chem. Soc. 126, 5154-5163
(2004); Yuan et al.,
Evaluation of in vitro models for screening alkaline phosphatase-mediated
bioconversion of
phosphate ester prodrugs. Drug Metab. Dispos. 37, 1443-1447 (2009); Heimbach
et
al., Absorption rate limit considerations for oral phosphate prodrugs. Pharm.
Res. 20, 848-856
(2003); Kadow et al., Inhibitors of human immunodeficiency virus type 1 (HIV-
1) attachment 6.
Preclinical and human pharmacokinetic profiling of BMS-663749, a
phosphonooxymethyl prodrug
of the HIV-1 attachment inhibitor 2-(4-benzoy1-1 -piperaziny1)-1 -(4,7-dim
ethoxy-1H-pyrrolo [2,3 -
c]pyridin-3-y1)-2-oxo ethanone (BMS-488043). J. Med. Chem. 55, 2048-2056
(2012); Heimbach
et al., Enzyme-mediated precipitation of parent drugs from their phosphate
prodrugs. Int. J.
Pharm. 261, 81-92 (2003).
51
Date Recue/Date Received 2021-04-14
PHOSPHATE AND PHOSPHONATE PRODRUGS OF FORMULA I
)14CH/1. RI RI Ity
RI Niwn
it'''41114). \ 4 =,<-4e4). / ----0
P.<
K,----(.... \0 OH iv, ...., ,....,..047. Rht-if 0 4 )¨No )-- i 4
Iti 4 )---\.
ro b:riel, R, __.-ov_o
I t _.)--r--)r.
ri ? ¨\ d 70 -----)r
<, \ 0
P-1 P-2 P-3 P-4 p_5 0 , \ P-6 P-7
it ci ci
3
4N-1C11,).
RI 'THAL a
<, I 7
R. 0,-4,
0 )......sc: I ,0 0 .,,,,,, I, 4 \
),, 0 ,
--11, /........ 0,--Ø----..y..AllsA wc", . R' Nii '/Pc1 14
P-8 1 . \___ k P-10 P-11 1 ¨o)---..7 ¨KB PA-1
PA-2 _
Ri
Pk' RI F F F
k I/ \c, --)-0 )f Il
a a ¨<
N-0 F M-0 I4 -0
R.)...... O. 1..._. "P-0 R. TilL0 N
7 \
CI --3 n
\ -4 P'
i iN. IC.
RI H
4 ¨11' d\--14)-:,, 1. SC CIr
Alc -N
i SR, Cl
\
PF-1 PF-2 PF-3 PF-4 PP-3 PF-6 )---" PF-7 PF-8
RI Rt at RI RI Pt t!1
ii -(C1% 0- \WEI ___c tIl RI'. a k
¨__ Fier -(CRI ._/H \ .......5,,, stay. 1,0
ICHR=
0, ,R 4 /,ISc,,6 ) C'1:5 RA
\ I 0
0 'PP % , tS2q) RI
---J S /0A
R,
PT-1 PT-2 PT-3 PT-4I )< A) PT-5 s
PT-6 / PT-f
k /-0
RI
(I
FN C
i .. , .A.,
0 :1 pwc, 7.1 $ " NI rC076.8 C...._
)¨\ (1'0_1_, Ak....,,r...,,..,1:õ.,,,
PT-8 _....1,...0-n . R., por-sc,_/\ ,>--/,4,yr. _fo ir 111_ RI r PT-11 i
p.. ) , T-12 itYT-b L
N--,--"Noi
CI
IR, P.
RI RI
RI Ir1-0
µ..õ./1 =R_(00,..). R" \ I,
/¨. II R /¨ ,_(e.õ). ,,,---,05) -1-
7,0,
4 .
R. -1-0 4
Rn 01Ip IP') 0 I IL R. .ij
L? )
PT-14 1 PT-15 P1-16 PT-17 PT-18 .-A(\ P1-19 deo-
PT-20
.....i
R'N-ceiv.
it, )----\0F ---NrRfol,--)_\ ,-.KNAro-c"1,-. 11!
N -(C1h). PI
,...,11,..,T,
ss¨ \ ...... RI / H 1.1-(a11)=
fir _cõ).;.0
OP 'N.' NII
' 141 1 \211
R. µ, .k
Pi PT -21 PT-22 , PT-23 0 PT-24 \ h-25 j
s PT-2
if
, -(CRF= RI
RI
0 0 0
---HfiRa I \ j
'4II IkT"
R, no_ _. K....,-- 4 )Z-p_ . 4
.,....pr
4 1:-N.--,N. / g \¨N/ 1
)''. Ri dr, i
.------\N----- 4 )¨,,_,P% ZeRs)a
R4 rd S-'\ -, \ 114--
µ =IIS._ci__
./2 0 It
/SO < I
PT-27 PT-28 PT-29 PT-30 P1-31 PT-32 )
El
RI
i, u,
RI' 109. ),r
IV' 'KAI
I P -= Phosphate PA = PhosphorAmidate PF = PhosphonoFluoridate
PT=PhosphoroThioate
PT-33 PT-34
[00108] In another embodiment, the prodrug compounds of of Fommla I include,
but not limited to:
52
Date Recue/Date Received 2021-04-14
õ, * 0, ,
-' '-->, õ, -
c_. . IP 9,-L/ -
7
,-----V-( y...-,,-
Le¨r
, ,s%
Compound 901 Compound 902 Compound 903 Compound
904 Compound 905 Compound 906 Compound 907
,
41 ,
,,, 1* 1 c co,r,>¨ \o
-0-% 0 0-141-' L - ,'''' - 1¨ t,")'-
eu . Y,,, -
L.)..__ (c'-'' --7- . C.)._:). C',''' 'LX,
1 ) 7
Compound 908 Compound 909 Compound 11 \ =1
Compound 913
Compound 910 Compound 912
, '
4
,_os
õ..--
, ri,.....k- 0 . ,..-
i...o.,.Ø, i ?......,õ== rx,.........),= ;..._........\=
Lõ. 1,,-0,,,õLõ. , _/-. '1, -\__.0 µ
n
'1÷ CC µ",71' \_ ,, \ _ ,,
111'
Compound 914 Compound 915 Compound 916 Compound 917
Compound 918 Compound 919 Compound 920 Compound 921
* * . ec\_.4 so. .._ * *ec-
S_ * .**- * *._ * *., Cc-i3C-
_
V-0;=1:Cra:er 1/-..,," I-i-r. -)--N- 1 V'-'-'9'-+C)-`1,-, -..."
_ta-')r-s
.) ) .),- 1 sr- .*',=-\ 4_
Compound 922 Compound 923 Compound 924
Compound 925 Compound 926 Compound 927 Compound 928 Compound 929
Compound 930
..
,,..r6c 0A--S, \¨<..dµ ,1:',/µ ' # =--C:dsb' --Ls ¨.,_,<
Compound 931 Compound 932 Compound 933 Compound 934 Compound 935
Compound 936 Compound 937 Compound 938 Compound 939
* 4 '. 10 4., 0H1,,,, 40 ....4.1" _ 41 ....pl. 0 4.*, 4
'
LC-Viik CC2,16,k Y:- ;rcfL cc-...."1:;.-/- 'c-.., 17.-/- (,- -, -
.='0-i- L,õ..,7- y----4,-õn,õ ,µ_.zo--L.
1 1 1 (1- l'-'1,- 'r" I''' -LI- c'?..--
-7 -6 '4'6 - \''Pr "MM." 940 Compound 941 Compound 942 Compound
9431*11 Compound 944 Compound 945 Racemate, S, mil 'so Romanic., S. and
R Racemate, S. and R
Compounds 946-948 Compounds 949-951 Compounds 952-954
42,i=X * '\¨Cfs. . 'i-' 42:1-' 4 ' -C" -"( _)- 1
''µ.__ orf,f;-\
Rac,..te, S. and R Romanic., S, and R Romanic., S, and R
Itnounate, S. and R Romanic., S. and R Romanic, S. and R Racemate, S.
and R Romanic, S. andllt
Compounds 955-957 Compounds 958-960 Compounds 961-963 Compound
964-966 Compound 967-969 Compound 970-972 Compound 973-975 Compound
976-978
[00109] In another embodiment, the prodrugs of Formula I, exemplified by, but
not limited to,
compounds 901- 978 representating Formulas P1-P1, PA-1 and 2, PF-1 to PF9, PT-
1 to PT34,
wherein P = Phosphate, PA = PhosphorAmidate,
PF = PhosphonoFluoridate, and
PT=PhosphoroThioate, are also acetylcholinesterase inhibitors due to the
phosphate,
phorphoramidate, phosphofuoridate, and phosphothioate moieties that confer
such activity
(McGleenon et al., Acetylcholinesterase inhibitors in Alzheimer's disease, Br
J Clin Pharmacol, 48,
471-480 (1999); Acetylcholinesterase Inhibitors and Memantine,
Acetylcholinesterase Inhibitors for
the Treatment of Mild to Moderate Dementia, and Memantine for the Treatment of
Moderate to Severe
Dementia in Alzheimer's disease(AD) (June 2013).
METHODS OF USE
[00110] The five most costly brain disorders (Ã million) were: dementia:
Ã22,164; psychotic disorders:
53
Date Re9ue/Date Received 2021-04-14
Ã16,717; mood disorders: Ã19,238; addiction: Ã11,719; anxiety disorders:
Ã11,687. Apart from
psychosis, these five disorders ranked amongst those with the lowest direct
medical expenditure per
subject (<Ã3000) (Feinberg et al., The size, burden and cost of disorders of
the brain in the UK, J
Psychopharmacol. 27(9): 761-770 (2013 September); Projections of the Cost of
Cancer Care in the
United States: 2010-2020, J Natl Cancer Inst. 103(2): 117-128 (2011 Jan 19)).
It was estimated that the total cost of bipolar disorder (BP), also known as
manic-
depressive illness, made more than a decade ago was as high as $ 45 billion
per year. Most of this cost
is accounted for by indirect costs related to the reduced functional capacity
and lost work. Patients
with BP have higher rates of utilization of healthcare resources compared with
the general population
and compared with patients with other types of psychiatric conditions.
Comorbidity contributes to the
heavy burden that BP imposes on society. Brain diseases represent a
considerable social and economic
burden in Europe. With yearly costs of about 800 billion euros and an
estimated 179 million people
afflicted in 2010, brain diseases are an unquestionable emergency and a grand
challenge for
neuroscientists. The global cost of mental health conditions alone was
estimated at US$ 2.5 trillion in
2010, with a projected increase to over US $6 trillion in 2030. Glioblastoma
multiform is the most
common malignant primary brain tumor in adults, with an estimated incidence of
4.43 per 100,000
person-years in the United States and a median age at presentation of 64
years. Symptoms often
include headaches; nausea and vomiting, and progressive memory, personality,
or neurologic deficits.
While Alzheimer and other dementias are projected to show a 66% increase from
2005 to 2030. In the
United States, depression is the second highest source of disability among
women, and antidepressant
non-responders are among the heaviest users of health care resources. Despite
the clear decrease in
quality of life and decreased productivity associated with depression, it is
often underdiagnosed and
inadequately treated.
[00111] Drug and alcohol dependence is a severe public health problem. It is
estimated that between
26.4 million and 36 million people abuse opioids worldwide (UNODC, World Drug
Report 2012),
with an estimated 2.1 million people in the United States suffering from
substance use disorders related
to prescription opioid pain relievers in 2012 and an estimated 467,000
addicted to heroin (Substance
Abuse and Mental Health Services Administration, Results from the 2012
National Survey on Drug
Use and Health: Summary of National Findings, NSDUH Series H-46, HHS
Publication No. (SMA)
13-4795. Rockville, MD: Substance Abuse and Mental Health Services
Administration, 2013). The
number of unintentional overdose deaths from prescription pain relievers has
soared in the United
54
Date Recue/Date Received 2022-05-04
States, more than quadrupled since 1999. There is also growing evidence to
suggest a relationship
between increased non-medical use of opioid analgesics and heroin abuse in the
United States (Pradip
et al., Associations of Nonmedical Pain Reliever Use and Initiation of Heroin
Use in the US, Center
for Behavioral Health Statistics and Quality Data Review, SAMILS'A (2013)).
[00112] Links between a chronic diabetic metabolic situation and the risk and
emergence of AD
pathophysiology have long been suspected and substantiated in the recent years
(Goldwaser et al.,
Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic
Link between Diabetes
Mellitus and Alzheimer's Disease. J Alzheimers Dis. (2016 Aug 1)). In several
large post-mortem
series, more than a third of all subjects clinically diagnosed with typical AD
showed evidence of
cerebrovascular disease and had to be re-classified as mixed dementia (Grandal
et al., Prevalence and
concordance between the clinical and the post-mortem diagnosis of dementia in
a psychogeriatric
clinic, Neurologia (2016)). From a clinical perspective, it is therefore
desirable to extend AD therapy
beyond currently approved drugs and mechanisms, and also address the cognitive
impairment by
optimizing a latent diabetic metabolic situation or the fairly frequent Type 2
diabetes in the elderly
subjects. Indeed, glycemic control is thought to have an impact on the
severity of cognitive impairment
(Zilliox et al., Diabetes and Cognitive Impairment. Curr Diab Rep, 16 (9):87
(2016)). Due to the
specific anti-diabetic actions of a compound of Formula I described above, in
one embodiment, the
present inventon provides benefit on both, symptoms and disease progression in
AD, and in cognitive
impairment of mainly vascular origin (multi-infarct dementia, vascular
dementia, vascular cognitive
impairment, etc.).
[00113] In Parkinson's Disease, the anticholinergic effects of neuroleptics
are highly unwanted as they
inevitably worsen, in addition the motor condition and symptoms of the
vegetative nervous system. In
all dementias, lowering the seizure threshold is another infrequent but highly
unwanted potential
adverse effect of neuroleptics. About 10 million people worldwide have
Parkinson's disease.
Parkinson's disease is a synucleinopathy resulting in progressive
neurodegeneration marked by motor
dysfunction and non-motor symptoms including psychosis. More than 50% of
patients with
Parkinson's disease have psychosis at some time. Psychosis affects up to 75%
of patients with
Parkinson's disease dementia, and symptoms are more intractable in this group.
Such psychosis is
expressed primarily as hallucinations and delusions, which can cause great
distress for patients and
their caregivers. These episodes present a major challenge for treatment and
care, increase the
likelihood of placement in nursing homes, and are associated with increased
mortality. Best-practice
Date Recue/Date Received 2021-04-14
treatment guidelines promote initial consideration of comorbidities and
reduction of dopaminergic
therapy. However, these approaches are often insufficient, and few other
therapeutic options exist.
1001141 The morbidity and mortality associated with depression are
considerable and continue to
increase. Depression currently ranks fourth among the major causes of
disability worldwide, after
lower respiratory infections, perinatal conditions, and HIV/AIDS. Seventeen
percent of people will
suffer from depression during their lifetime; making matters worse, people
already suffering either
from acute or chronic illness are even more likely to suffer from depression,
where the incidence of
depression may be 30% to 50% in patients depending on the specific medical
condition.
1001151 The monoamine hypothesis has been the prevailing hypothesis of
depression over the last
several decades. It states that depression is associated with reduced
monoamine function. Hence efforts
to increase monoamine transmission by inhibiting serotonin (5-HT) and
norepinephrine (NE)
transporters has been a central theme in depression research since the 1960s.
The selective 5-HT
reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) that
have emerged from
this line of research are currently first line treatment options for major
depressive disorder (MDD).
One of the recent trends in antidepressant research has been to refine
monoaminergic mechanisms by
targeting monoaminergic receptors and additional transporters (e.g. with
multimodal drugs and triple
re-uptake inhibitors) or by adding atypical antipsychotics to SSRI or SNRI
treatment. In addition,
several other hypotheses a depression have been brought forward in pre-
clinical and clinical research
based on biological hallmarks of the disease and efficacy of pharmacological
interventions. A central
strategy has been to target glutamate receptors (for example, with intravenous
infusions of the N-
methyl-D-aspartate (NMDA) receptor antagonist ketamine). Other strategies have
been based on
modulation of cholinergic and gamma-aminobutyric acid (GABA)ergic
transmission, neuronal
plasticity, stress/hypothalamic pituitary adrenal (HPA)-axis, the reward
system and
neuroinflammation. Thus, there is a need to develop novel medications with
complex pharmacological
profiles derived from targeting several neurotransmitter and neuromodulator
systems simultaneously.
[00116] BP frequently occurs together with other psychiatric disorders,
especially anxiety disorders
and substance abuse. In addition, BP has been associated with a variety of
general medical conditions,
which further complicate management of the psychiatric disorder (Am J Manag
Care,11: S85-S90
(2005)).
[00117] BP is a brain disorder that causes unusual shifts in mood, energy,
activity levels, and the ability
to carry out day-to-day tasks. BP is characterized by a dysregulation of mood,
impulsivity, risky
56
Date Recue/Date Received 2021-04-14
behavior and interpersonal problems. BP is a recurrent and often chronic
psychiatric illness,
associated with functional impairment, elevated suicide rates and utilization
of mental health systems.
BP is commonly under-recognized and as many as 40% of patients with BPs are
initially
misdiagnosed, resulting in increased risk for suicide, mania and chronic
psychosocial suffering. When
correctly diagnosed, successful treatment is possible <50% of diagnosed
patients and as many as 10-
15% of patients eventually die as a result of suicide (NIMH 2002).
[00118] While the pharmacological guidelines for treatment are well
established, treatment for BP
remains less than ideal. Most individuals still have breakthrough episodes or
significant residual
symptoms while on medication (NIMH 2002). In addition, functional deficits
often remain even when
patients are in remission (NIMH 2002). Because many patients with BP remain
symptomatic, even
while fully adherent to their medication regimens, the need for greater
understanding of the
pathogenesis of this illness from the research on the pharmacological
mechanisms of bipolar
medications is all the more urgent. The major medication therapy of BPs is
mood stabilizers unless
the pharmacology mechanisms are not clear yet. Common neuroprotective effects
of mood stabilizers
play a role of brain cell dysfunction in BP, and the dysfunction may
eventually cause neuron loss.
Volumetric neuroimaging, now increasingly assessing potential involvement of
different brain
structures in mood regulation, could be applied to test neuroanatomical models
of mood disorders.
Imaging studies suggested that ongoing neuronal atrophy accompanies BP. For
instance, PET images
of the cerebral blood flow and the rate of glucose metabolism regarding as
brain activity detected the
reduced activity in the subgenual prefrontal cortex during the bipolar
depression. This decrement in
activity was, in part, at least explained by a corresponding reduction of
cortical volume, as same as
magnetic resonance imaging demonstration of the mean gray matter volume. In
BP, abnormalities of
the third ventricle, frontal lobe, cerebellum, and possibly the temporal lobe
are also noted.
[00119] Brain tumors are formed by abnormal growths and can appear in
different areas of the brain.
Benign (not cancerous) tumors may grow and press on nearby areas of the brain,
but rarely spread into
other tissues. Malignant (cancerous) tumors are likely to grow quickly and
spread into other brain
tissue. A tumor that grows into or presses on an area of the brain may stop
that part of the brain from
working the way it should, whether the tumor itself is benign or malignant,
and will then require
treatment. The most common type of brain tumor seen does not originate from
the brain tissue itself,
but rather are metastases from extracranial cancers such as lung cancer and
breast cancer. Brain tumors
include neurofibromatosis type 1 or 2, von Hippel-Lindau disease, tuberous
sclerosis, Li-Fraumeni
57
Date Recue/Date Received 2021-04-14
syndrome, Turcot syndrome type 1 and type 2, Klinefelter syndrome, and Nevoid
basal cell carcinoma
syndrome. Neuroblastoma is cancer found in developing nerve cells, usually in
children under 10 years
of age. Almost 90% of cases are diagnosed by the age of 5. Different factors
can affect the type of
neuroblastoma a child has and their prognosis.
[00120] Specific treatment for neurological cancer is based on several factors
including a patient's
overall health and medical history; the type, location, and size of the tumor;
the extent of the condition;
and other individual factors. Generally, treatment for patients with cancer of
the brain or spinal cord
includes surgery, chemotherapy, radiation therapy, and/or steroids to treat
and prevent swelling,
especially in the brain; anti-seizure medication to treat and prevent seizures
associated with
intracranial pressure; placement of a shunt (to help drain excess fluid in the
brain); lumbar
puncture/spinal tap (to measure pressure in the spinal cord and brain); bone
marrow transplantation;
rehabilitation (to regain lost motor skills and muscle strength); and/or
antibiotics (to treat and prevent
infections). Chemotherapy is the use of anticancer drugs to treat cancerous
cells. In most cases,
chemotherapy works by interfering with the cancer cell's ability to grow or
reproduce. These drugs
may be given into a vein or by mouth, as a tablet.
[00121] Neuropsychiatric symptoms are a common burden in patients suffering
from Alzheimer's
disease (AD), Parkinson's disease dementia (PDD), and many other
neurodegenerative disorders,
including but not limited to dementia with Lewy bodies (DLB), vascular
dementia (VaD), and
frontotemporal lobar degeneration (FTLD) (Kazui H et al. Differences of
Behavioral and
Psychological Symptoms of Dementia in Disease Severity in Four Major
Dementias. PLoS ONE
11(8): e0161092 (2016); Van der Schyf CJ. Psychotropic Drug Development
Strategies that Target
Neuropsychiatric Etiologies in Alzheimer's and Parkinson's Diseases. Drug Dev
Res. 77: 458-468
(2016)).
[00122] Many neuropsychiatric symptoms manifest very early in
neurodegenerative disease stages, and
are even considered prodromal indicators or indicators for disease progression
(Kazui H et al.
Differences of Behavioral and Psychological Symptoms of Dementia in Disease
Severity in Four
Major D em enti as. PLoS ONE 11(8): e0161092 (2016); Peters ME et al.
Neuropsychiatric Symptoms
as Predictors of Progression to Severe Alzheimer's Dementia and Death: The
Cache County Dementia
Progression Study. Am J Psychiatry 172: 460-465 (2015)).
[00123] Behavioral and psychological symptoms of dementia (BPSD), also known
as neuropsychiatric
symptoms, in neurodegenerative diseases and disease states including but not
limited to AD have a
58
Date Recue/Date Received 2021-04-14
multifactorial origin (McClam TD et al. Interventions for neuropsychiatric
symptoms in
neurocognitive impairment due to Alzheimer's disease: a review of the
literature. Hary Rev Psychiatry
23: 377-393 (2015)). Therefore, a strategy aimed at simultaneously targeting
multiple etiologies of a
disease (hence, multiple drug targets) constitutes the best approach in the
development of treatment
strategies for a range of diseases including but not limited to AD (Nikolic K
et al. Drug design for
CNS diseases: polypharmacological profiling of compounds using cheminformatic,
3D-QSAR and
virtual screening methodologies. Front Neurosci 10: 265 (2015)).
[00124] Individual BPSD symptoms may appear as mutually exclusive but can
nevertheless share the
underlying mechanisms. This shared mechanism similarity can occur at the
neurochemical and/or
neuroanatomical levels and serves as a basis for developing targeted, but not
mechanism-specific
therapies addressing more than one BPSD symptom.
[00125] Shared mechanisms are illustrated by similar neurochemical
organizations of the projections
from cortical areas to basal ganglia to thalamus and back to the cortex. For
example, the dorsolateral
prefrontal cortex projects to the dorsolateral caudate which in turn targets
lateral dorsomedial parts of
internal globus pallidus that sends projections to the principal part of the
ventral anterior or
mediodorsal thalamus which returns projections to the cortex. In contrast, the
orbitofrontal cortex
projects to the ventromedial caudate that projects to medial dorsomedial parts
of internal globus
pallidus that sends projections to the magnocellular part a ventral anterior
or mediodorsal thalamus
which returns projections to the cortex. Thus, different parts of cortex may
be responsible for different
functions but there are common principles according to which cortical networks
operate (Aouizerate
B et al. Pathophysiology of obsessive-compulsive disorder: a necessary link
between phenomenology,
neuropsychology, imagery and physiology. Prog Neurobiol 72(3):195-221 (2004)).
Therefore,
impairments in different circuits underlie the emergence of different BPSD
symptoms. Heterogeneity
of the clinical presentations of neurodegenerative disorders is determined by
the predominant location
of the pathology (i.e. by affected networks). For example, the dorsal anterior
cingulate cortex and
dorsolateral prefrontal cortex are more affected in apathetic patients, and
the medial orbital frontal
cortex in disinhibited patients with byFTLD (e.g., Massimo et al. Dement
Geriatr Cogn Disord 27:96-
104 (2009)).
[00126] For 5-HT2A receptors that are targeted by compounds of Formula I, it
is well established that
serotonin via 5-HT2A receptors increases glutamatergic spontaneous excitatory
postsynaptic currents
in apical dendrites of layer V pyramidal cells of prefrontal cortex
(Aghajanian GK, Marek GJ.
59
Date Recue/Date Received 2021-04-14
Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of
prefrontal cortex by
an asynchronous mode of glutamate release. Brain Res 825:161-71 (1999)). Such
excessive
asynchronous transmission may be functionally expressed in a variety of forms
dependent on which
part of the cerebral cortex is affected ¨ from auditory or visual
hallucinations to disinhibition and
apathy ¨ but in most cases, will be sensitive to manipulations involving 5-
HT2A receptors that are
present across various cortical areas (van Dyck CH et al. PET quantification
of 5-HT2A receptors in
the human brain: a constant infusion paradigm with [18F]altanserin. J Nucl Med
41(2):234-41 (2000)).
[00127] For glutamatergic signaling that is targeted by dextromethorphan and
memantine, it is well
established that it mediates thalamocortical signaling, causing the activation
of corresponding areas of
the cortex (Kharazia VN, Weinberg RJ. Glutamate in thalamic fibers terminating
in layer IV of
primary sensory cortex. J Neurosci 14(10):6021-6032 (1994); Sherman SM.
Thalamus plays a central
role in ongoing cortical functioning. Nat Neurosci 19(4):533-41 (2016)).
[00128] Diseases like Alzheimer's disease are characterized by systematic,
progressive, probably trans-
synaptic spread of neurodegeneration. That does not only mean more cell loss
in a certain area of the
brain but also spreading of the pathology to other brain areas. As different
brain areas have different
functional roles, this explains why more advanced stages of the disease are
accompanied by a wider
spectrum of symptoms (Kazui et al. Differences of Behavioral and Psychological
Symptoms of
Dementia in Disease Severity in Four Major Dementias. PLoS ONE 11(8): e0161092
(2016)).
[00129] Behavioral and psychological symptoms of dementia, also known as
neuropsychiatric
symptoms, are commonly studied in the clinic using research tools such as the
Neuropsychiatric
Inventory (NPI; Cummings JL. The Neuropsychiatric Inventory: Assessing
psychopathology in
dementia patients. Neurology 48:S10-S16 (1997)). The NPI scale recognizes 12
sub-domains of
behavioral functioning: delusions, hallucinations, agitation/aggression,
dysphoria, anxiety, euphoria,
apathy, disinhibition, irritability/lability, aberrant motor activity, night-
time behavioral disturbances,
and appetite and eating abnormalities.
[00130] Patients rarely display each and every of these NPI symptoms at once
as there are NPI items
like euphoria that are rare, even at a CDR score of 3. Conversely, clinical
experience indicates that
there is rarely a patient showing just one specific item, and none of the
rest. Instead, BPSD symptoms
occurs in various combinations or clusters. For example, a frequent AD cluster
could e.g. be
aggression, agitation, wandering, repetitiveness, while a frequent Vascular
Dementia cluster could e.g.
be confusion and restlessness, but the frequency and severity of NPI items is
subject to change, e.g.
Date Recue/Date Received 2021-04-14
from day to day, but especially during disease progression (Kazui etal.
Differences of Behavioral and
Psychological Symptoms of Dementia in Disease Severity in Four Major
Dementias. PLoS ONE
11(8): e0161092 (2016); Johnson DK et al. Neuropsychiatric profiles in
dementia. Alzheimer Dis
Assoc Disord 25(4): 326-332 (2011)). As a given patient may present such a
cluster of several
symptoms of clinical relevance at once, there is a high medical need in
treatments that can target
various clusters of symptoms or the entire range of BPSD symptoms,
irrespective of any currently
prevailing pathophysiological hypothesis on the disease.
[00131] The prevalence of delusions is rather low in general population, in
people with normal
cognitive aging (0.4-2.4%) but is increased in subjects with mild cognitive
impairment (MCI; 3.1-
3.4%) and markedly increased in dementia (18.0-31.0%) (Geda YE et al. The
Prevalence of
Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive
Aging: A
Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos
CG et al.
Prevalence of neuropsychiatric symptoms in dementia and mild cognitive
impairment: results from
the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al.
The prevalence of
neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-
analysis. J Affect
Disord 190:264-71 (2016)). Prevalence of hallucinations is also low in the
general population, in
people with normal cognitive aging (0.4-0.6%) but is increased in subjects
with MCI (0.6-1.3%) and
dementia (10.5-16.0%) (Geda YE et al. The Prevalence a Neuropsychiatric
Symptoms in Mild
Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study.
Arch Gen Psychiatry
65(10): 1193-1198 (2008); Lyketsos CG et al. Prevalence of neuropsychiatric
symptoms in dementia
and mild cognitive impairment: results from the cardiovascular health study.
JAMA 288(12):1475-83
(2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in
Alzheimer's disease:
Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
[00132] Both delusions and hallucinations are part or symptoms of psychosis in
various neurological
and psychiatric diseases and disease states. Neuroleptics have traditionally
been used off-label to treat
such symptoms faute-de-mieux in dementia; however, with very few exceptions
both "typical" and
"atypical" neuroleptics increase the incidence of CV adverse events and showed
a markedly increased
death rate when used off-label in dementia. Hence, the FDA issued a "black
box" warning against
their off-label use outside schizophrenia which leaves little therapeutic
options to treat such BPSD
symptoms in dementia. On this background, a completely different class, namely
5-HT2A receptor
antagonists and inverse agonists demonstrated an antipsychotic-like efficacy
profile in preclinical
61
Date Recue/Date Received 2021-04-14
studies (Weiner et al. 5-hydroxytryptamine2A receptor inverse agonists as
antipsychotics. J Pharmacol
Exp Ther 299(1):268-76 (2001)). Several 5-HT2A receptor antagonists and
inverse agonists have been
in development for neuropsychiatric indications and there were reports of
beneficial antipsychotic
effects obtained with compounds such as eplivanserin (Meltzer HY et al.
Placebo-controlled
evaluation of four novel compounds for the treatment of schizophrenia and
schizoaffective disorder.
Am J Psychiatry 161: 975-84 (2004)). 5-HT2A receptor inverse agonist
pimavanserin significantly
reduced psychotic symptoms, which includes hallucinations and delusions, in
patients with moderate
to severe Parkinson's disease (Cummings J et al. Pimavanserin for patients
with Parkinson's disease
psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383: 533-40
(2014)) and has been
FDA approved specifically for the treatment of these symptoms in PDD. In
patients with Alzheimer's
disease dementia, HTR2A T102C polymorphism is a significant risk factor for
psychosis with an
allelic OR of 2.191 for C allele that increased to 5.143 for the homozygous CC
genotype (Ramanathan
S, Glatt SJ. Serotonergic system genes in psychosis of Alzheimer dementia:
meta-analysis. Am J
Geriatr Psychiatry 17(10):839-46 (2009)).
1001331 Dextromethorphan has NMDA receptor channel blocking properties and
NMDA receptor
channel blockers such as phencyclidine or ketamine are known to possess
psychotomimetic rather than
antipsychotic properties. There are reports of psychosis induced by
dextromethorphan in humans
(Miller SC. Dextromethorphan psychosis, dependence and physical withdrawal.
Addict Biol
10(4):325-7 (2005)). These psychoactive properties of dextromethorphan may be
a function of its
metabolic degradation resulting in production of dextrorphan (Zawertailo LA et
al. Effect of metabolic
blockade on the psychoactive effects of dextromethorphan. Hum Psychopharmacol
25(1):71-9
(2010)). Psychoactive effects of dextromethorphan observed in some subjects do
not exclude a
possibility that dextromethorphan also has antipsychotic properties under
certain circumstances.
Indeed, dextromethorphan, but not its metabolite dextrorphan, was reported to
attenuate
phencyclidine-induced motor behaviors in rats (Szekely JI et al. Induction of
phencyclidine-like
behavior in rats by dextrorphan but not dextromethorphan. Pharmacol Biochem
Behav 40(2):381-6
(1991)). Meta-analysis of the randomized controlled studies of another NMDA
receptor channel
blocker, memantine, in patients with Alzheimer's disease indicated that
memantine induces significant
improvement in delusions (Kishi T et al. The effects of memantine on
behavioral disturbances in
patients with Alzheimer's disease: a meta-analysis. Neuropsychiatr Dis
Treatment 13: 1909-1928
(2017)).
62
Date Recue/Date Received 2021-04-14
[00134] Agitation and aggression are grouped together as one item on the NPI
scale. Prevalence of
agitation and aggression is low in general population, in people with normal
cognitive aging (2.8-
2.9%) but is increased in subjects with MCI (9.1-11.3%) and dementia (30.3-
40%) (Geda YE et al.
The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and
Normal Cognitive
Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008);
Lyketsos CG et
al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive
impairment: results from
the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al.
The prevalence of
neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-
analysis. J Affect
Disord 190:264-71 (2016)). So this NPI item is one the most prevalent and at
the same time difficult
to treat clinical BPSD symptom.
[00135] Preclinical studies indicate that blockade of 5-HT2A receptors reduces
aggression in laboratory
rodents (Sakaue M et al. Modulation by 5-h-f2A receptors of aggressive
behavior in isolated mice. Jpn
J Pharmacol 89(1):89-92 (2002)). Human genetics data indicate that scores on
three out of four
subscales of the Buss-Perry Aggression Questionnaire (Hostility, Anger and
Physical Aggression)
show significant association with HIK2A rs7322347 I allele (Banlaki Z et al.
Polymorphism in the
serotonin receptor 2a (HTR2A) gene as possible predisposal factor for
aggressive traits. PLoS One
10(2):e0117792 (2015)). In a case-control study in Chinese subjects with AD,
aggression in AD was
significantly associated with 5-HT2A receptor polymorphism such as T102C (Lam
LC et al. 5-HT2A
T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer's
disease. Int J Geriatr
Psychiatry 19(6):523-6 (2004)).
[00136] Various NMDA receptor channel blockers have been shown to attenuate
aggressive behaviors
in mice and these effects may be difficult to separate from sedative action
(Belozertseva IV, Bespalov
AY. Effects of NMDA receptor channel blockade on aggression in isolated male
mice. Aggr Behav
25:381-396 (1999)). In patients with probable Alzheimer disease and clinically
significant agitation,
dextromethorphan-quinidine combination reduced Agitation/Aggression scores of
the NPI
(Cummings JL et al. Effect of Dextromethorphan-Quinidine on Agitation in
Patients With Alzheimer
Disease Dementia: A Randomized Clinical Trial. JAMA 314(12):1242-54 (2015))).
A meta-analysis
of randomized controlled studies of another nonselective NMDA receptor channel
blocker,
memantine, in patients with Alzheimer's disease indicated that also memantine
induces significant
improvement in agitation/aggression (Kishi T et al. The effects of memantine
on behavioral
disturbances in patients with Alzheimer's disease: a meta-analysis.
Neuropsychiatr Dis Treatment 13:
63
Date Recue/Date Received 2021-04-14
1909-1928 (2017)).
[00137] The prevalence of dysphoria/depression is moderate in general
population, in people with
normal cognitive aging (7.2-11.4%) but is increased in subjects with MCI (20.1-
27.0%) and it is one
of the most prevalent problems in dementia (32.3-42%) (Geda YE et al. The
Prevalence of
Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive
Aging: A
Population-Based Study. Arch Gen Psychiatry 65(10): 1193-1198 (2008); Lyketsos
CG et al.
Prevalence of neuropsychiatric symptoms in dementia and mild cognitive
impairment: results from
the cardiovascular health study. JAMA 288(12):1475-83 (2002); Zhao QF et al.
The prevalence of
neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-
analysis. J Affect
Disord 190:264-71 (2016)).
[00138] Preclinical studies using brain stimulation reward indicated that 5-
HT2A receptor antagonism
may counteract dysphoria induced by conventional neuroleptics such as
haloperidol (Benaliouad F et
al. Blockade of 5-HT2a receptors reduces haloperidol-induced attenuation of
reward.
Neuropsychopharmacology 32(3):551-61 (2007)). 5-HT2A receptor antagonists
exert antidepressant-
like effects in preclinical models sensitive to clinically used antidepressant
drugs (Marek et al. The
selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like
behavioral effects of the
SSRI fluoxetine. Neuropsychopharmacology 30: 2205-2215 (2005); Patel JG et al.
The highly
selective 5-hydroxytryptamine (5-HT)2A receptor antagonist, EMD 281014,
significantly increases
swimming and decreases immobility in male congenital learned helpless rats in
the forced swim test.
Synapse 52: 73-75 (2004)).
[00139] NMDA receptor channel blockers such as dextromethorphan have been
shown to possess
antidepressant-like properties in preclinical models (Sakhaee E et al. The
role of NMDA receptor and
nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like
effect of
dextromethorphan in mice forced swimming test and tail suspension test. Biomed
Pharmacother
85:627-634 (2017)). Of the NMDA receptor channel blockers, ketamine, is proven
to have rapid and
robust antidepressant activity in patients with treatment-resistant major
depressive disorder (Singh JB
et al. A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of
Intravenous
Ketamine in Patients With Treatment-Resistant Depression. Am J Psychiatry
173(8):816-26 (2016)).
Dextromethorphan given in combination with quinidine also exerts
antidepressant action in humans
(Murrough JW et al. Dextromethorphan/quinidine pharmacotherapy in patients
with treatment
resistant depression: A proof of concept clinical trial. J Affect Disord
218:277-283 (2017)).
64
Date Recue/Date Received 2021-04-14
Dextromethorphan is not a selective NMDA receptor channel blocker and is more
potent at serotonin
and norephinephrine transporters as well as sigma-1 receptors that may
contribute to therapeutic
effects of dextromethorphan (Stahl SM. Mechanism of action of
dextromethorphan/quinidine:
comparison with ketamine. CNS Spectrums 18: 225-227 (2013)). While monoamine
transporters are
targeted by most currently used antidepressants, sigma-1 receptors have also
been found to contribute
to antidepressant-like effects of dextromethorphan in laboratory animals
(Nguyen L et al. Involvement
of sigma-1 receptors in the antidepressant-like effects of dextromethorphan.
PLoS One 9(2):e89985
(2014)).
[00140] The prevalence of apathy is low in general population, in people with
normal cognitive aging
(3.2-4.8%) but is increased in subjects with MCI (14.7-18.5%) and dementia
(35.9-49%) (Geda YE et
al. The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment
and Normal
Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-
1198 (2008);
Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and
mild cognitive
impairment: results from the cardiovascular health study. JAMA 288(12):1475-83
(2002); Zhao QF
et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease:
Systematic review and
meta-analysis. J Affect Disord 190:264-71 (2016)). In a case-control study in
Chinese subjects with
AD, apathy in AD was significantly associated with 5-HT2A receptor
polymorphism such as T102C
(Lam LC et al. 5-1-IT2A Ti 02C receptor polymorphism and neuropsychiatric
symptoms in Alzheimer's
disease. Int J Geriatr Psychiatry 19(6):523-6 (2004)). Apathy is a symptom
frequently seen in patients
with schizophrenia and belongs to the group of negative symptoms. 5-HT2A
receptor antagonists
reduce the severity of negative symptoms in patients with schizophrenia
(Davidson M et al. Efficacy
and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled
Trial of a New
Drug in Development for the Treatment of Negative Symptoms in Schizophrenia.
Am J Psychiatry
DOI: 10.1176/appi.ajp.2017.17010122 (2017); Meltzer HY et al. Placebo-
controlled evaluation of
four novel compounds for the treatment of schizophrenia and schizoaffective
disorder. Am J
Psychiatry 161(6):975-84 (2004)).
[00141] NMDA receptor channel blockers such as memantine are reported to
reduce apathy in certain
patients with neurodegenerative diseases (Links KA et al. A case of apathy due
to frontotemporal
dementia responsive to memantine. Neurocase 19(3):256-61 (2013)) or with the
negative symptoms
in schizophrenia (Paraschakis A. Tackling negative symptoms of schizophrenia
with memantine. Case
Rep Psychiatry 2014:384783 (2014)).
Date Recue/Date Received 2021-04-14
[00142] The prevalence of anxiety is low in general population, in people with
normal cognitive aging
(5.0-5.8%) but is increased in subjects with MCI (9.9-14.1%) and dementia
(21.5-39%) (Geda YE et
al. The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment
and Normal
Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-
1198 (2008);
Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and
mild cognitive
impairment: results from the cardiovascular health study. JAMA 288(12):1475-83
(2002); Zhao QF
et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease:
Systematic review and
meta-analysis. J Affect Disord 190:264-71 (2016)).
[00143] 5-HT2A receptor antagonists exert anxiolytic in various preclinical
models, particularly models
of conditioned fear (Adamec R et al. Prophylactic and therapeutic effects of
acute systemic injections
of EMD 281014, a selective serotonin 2A receptor antagonist on anxiety induced
by predator stress in
rats. Eur J Pharmacol 504(1-2):79-96 (2004); Millan MJ. The neurobiology and
control of anxious
states. Progr Neurobiol 70: 83-244 (2003)). In humans, 5-HT2A receptor
blockade attenuates
emotional processing in the orbitofrontal cortex involved in the evaluation of
socially relevant stimuli
(Homboll B et at. Pharmacological blockade of 5-H12A receptors reduces
orbitofrontal activation
during processing of fearful and angry faces in healthy subjects. NeuroImage
47: S39¨S41 (2009)).
5-HT2 receptor antagonist serazepine (CGS-15040A) has shown efficacy in
clinical trials in patients
with generalized anxiety disorder (Katz RJ et al. Serotonergic (5-HT2)
mediation a anxiety-
therapeutic effects of serazepine in generalized anxiety disorder. Biol
Psychiatry 34: 41-44 (1993)).
[00144] Like other members of the NMDA receptor antagonist class (Chojnacka-
Wojcik E et al.
Glutamate receptor ligands as anxiolytics. Curr Opin Investig Drugs 2(8):1112-
9 (2001)),
dextromethorphan was observed to induce anxiolytic-like effects in laboratory
animals within a certain
dose range (Dere E et al. NMDA-receptor antagonism via dextromethorphan and
ifenprodil modulates
graded anxiety test performance of C57BL/6 mice. Behav Pharmacol 14(3):245-9
(2003)). Preclinical
anxiolytic effects of dextromethorphan may be related not only to the
inhibition of NMDA receptor
function but also to interaction with the sigma-1 receptors (Kamei H et al.
(+)-SKF-10,047 and
dextromethorphan ameliorate conditioned fear stress through the activation of
phenytoin-regulated
sigma 1 sites. Eur J Pharmacol 299(1-3):21-8 (1996)). In patients with AD,
treatment with another
nonselective NMDA receptor channel blocker, memantine, significantly decreases
in the scores of NPI
subscale for anxiety (Ishikawa I et al. The effect of memantine on sleep
architecture and psychiatric
symptoms in patients with Alzheimer's disease. Acta Neuropsychiatr 28(3):157-
64 (2016)).
66
Date Recue/Date Received 2021-04-14
[00145] The prevalence of euphoria / elation is very low in general
population, and in people with
normal cognitive aging (0.3-0.4%) but is increased in subjects with MCI (0.6-
1.3%) and dementia
(3.1-7%) (Geda YE et al. The Prevalence of Neuropsychiatric Symptoms in Mild
Cognitive
Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen
Psychiatry 65(10):
1193-1198 (2008); Lyketsos CG et al. Prevalence of neuropsychiatric symptoms
in dementia and mild
cognitive impairment: results from the cardiovascular health study. JAMA
288(12):1475-83 (2002);
Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's
disease: Systematic
review and meta-analysis. J Affect Disord 190:264-71 (2016)).
[00146] Human PET studies have established a positive correlation of the
psychostimulant drug-
induced-induced changes in euphoria analog scale scores with decreases in
[11C]raclopride receptor
binding potential (BP) in the caudate nucleus and putamen consistent with an
increase in endogenous
dopamine (Drevets WC. Amphetamine-induced dopamine release in human ventral
striatum correlates
with euphoria. Biol Psychiatry 49(2):81-96 (2001)). A nonselective 5-HT2A
receptor agonist
psilocybin significantly reduced [11C]raclopride BP in the ventral striatum
that correlated with
depersonalization associated with euphoria (Vollenweider FX et al. 5-HT
modulation of dopamine
release in basal ganglia in psilocybin-induced psychosis in man -- a PET study
with [11C]raclopride.
Neuropsychopharmacology 20(5):424-33 (1999)).
[00147] Preclinical data have indicated that the majority of prefrontal
cortical pyramidal neurons that
project to the dorsal raphe nuclei and ventral tegmental area express 5-HT2A
receptors (Vazquez-
Borsetti P. et al. Pyramidal neurons in rat prefrontal cortex projecting to
ventral tegmental area and
dorsal raphe nucleus express 5-HT2A receptors. Cereb Cortex 19:1678-86
(2009)). Consequently,
blockade of prefrontal 5-HT2A receptors may modulate pyramidal neurons
projecting to the midbrain
and thereby inhibit the dopaminergic system in the midbrain (Erbdrup BH et al.
Serotonin 2A receptor
antagonists for treatment of schizophrenia. Expert Opin Investig Drugs
20(9):1211-1223 (2011)).
DOpaminergic midbrain system is also under control of cholinergic projections
such as those
originating in habenula and activity of these projections are modulated by
a3134-containing nicotinic
acetylcholine receptors (McCallum SE et al. 0134 nicotinic acetylcholine
receptors in the medial
habenula modulate the mesolimbic dopaminergic response to acute nicotine in
vivo.
Neuropharmacology 63(3):434-40 (2012)). Antagonism at a3134-containing
nicotinic acetylcholine
receptors is associated with various effects ascribed to reduced dopamine tone
(Maisonneuve IM,
Glick SD. Anti-addictive actions of an iboga alkaloid congener: a novel
mechanism for a novel
67
Date Recue/Date Received 2021-04-14
treatment. Pharmacol Biochem Behav 75(3):607-18 (2003)). a3134-containing
nicotinic acetylcholine
receptors are one of the main targets of dextromethorphan (Taylor CP et al.
Pharmacology of
dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta0) clinical
use. Pharmacol
Ther 164:170-82 (2016)).
[00148] The prevalence of disinhibition is low in general population, in
people with normal cognitive
aging (0.9-1.6%) but is increased in subjects with MCI (3.1-4.7%) and dementia
(12.7-17%) (Geda
YE et al. The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive
Impairment and Normal
Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10): 1193-
1198 (2008);
Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia and
mild cognitive
impairment: results from the cardiovascular health study. JAMA 288(12):1475-83
(2002); Zhao QF
et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease:
Systematic review and
meta-analysis. J Affect Disord 190:264-71 (2016)).
[00149] Alterations in the balance of functional activity within the 5-HT
system underlie impulse
control and preclinical studies suggest that the 5-HT2A receptor regulates
impulsive behavior,
including both inherent and induced behavioral disinhibition (Anastasio NC et
al. Serotonin (5-
hydroxytryptamine) 5-HT(2A) receptor: association with inherent and cocaine-
evoked behavioral
disinhibition in rats. Behav Pharmacol 22(3):248-61 (2011)).
[00150] In humans, there are significant associations found between high
levels a behavioral
impulsivity and certain 5-HT2A polymorphisms such as the C/C genotype of
rs6313 (Jakubczyk A et
al. The CC genotype in HTR2A T102C polymorphism is associated with behavioral
impulsivity in
alcohol-dependent patients. J Psychiatr Res 46(1):44-9 (2012)). Humans with
the A/A genotype of
the HTR2A 1438A/G polymorphism have higher scores of maladaptive impulsivity
(Tomson K et al.
Effect of a human serotonin 5-HT2A receptor gene polymorphism on impulsivity:
Dependence on
cholesterol levels. J Affect Disord 206:23-30 (2016)). From a neuroanatomical
perspective, neocortex
is known to be rich in 5-HT2A receptors and behavioral disinhibition in
neurodegenerative diseases
such as behavioral variant frontotemporal dementia is correlated with the
cortical thickness of the right
parahippocampal gyms, right orbitofrontal cortex and right insula (Santillo AF
et al. Grey and White
Matter Clinico-Anatomical Correlates of Disinhibition in Neurodegenerative
Disease. PLoS One
11(10):e0164122 (2016)).
[00151] Combination of dextromethorphan and quinidine has positive therapeutic
effects in patients
with pseudobulbar affect (PBA), (Pioro EP. Review of Dextromethorphan 20
mg/Quinidine 10 mg
68
Date Recue/Date Received 2021-04-14
(NUEDEXTAO) for Pseudobulbar Affect. Neurol Ther 17;3(1):15-28 (2014)). PBA
may occur in
association with a variety of neurological diseases such as amyotrophic
lateral sclerosis,
extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain
injury, Alzheimer's
disease, stroke, and brain tumors. PBA is a disinhibition syndrome, in which
pathways involving
serotonin and glutamate are disrupted (Ahmed A, Simmons Z. Pseudobulbar
affect: prevalence and
management. Ther Clin Risk Manag 9:483-9 (2013)). Meta-analysis of the
randomized controlled
studies of another nonselective NMDA receptor channel blocker, memantine, in
patients with
Alzheimer's disease indicated that memantine induces significant improvement
in disinhibition (Kishi
T et al. The effects of memantine on behavioral disturbances in patients with
Alzheimer's disease: a
meta-analysis. Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)).
[00152] The prevalence of irritability/lability is low in general population,
in people with normal
cognitive aging (4.6-7.6%) but is increased in subjects with MCI (14.7-19.4%)
and dementia (27-36%)
(Geda YE et al. The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive
Impairment and
Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10):
1193-1198
(2008); Lyketsos CCi et al. Prevalence of neuropsychiatric symptoms in
dementia and mild cognitive
impairment: results from the cardiovascular health study. JAMA 288(12):1475-83
(2002); Zhao QF
et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease:
Systematic review and
meta-analysis. J Affect Disord 190:264-71 (2016)).
[00153] Animal and human functional magnetic resonance studies have pointed to
a specific
involvement of the 5-HT2A receptor in the prefrontal cortical (PFC) feedback
regulatory projection
onto the amygdala. As this receptor is highly expressed in the prefrontal
cortex areas, it affects
inhibitory control of emotion-based and emotion-controlled actions, such as
various impulse-related
behaviors (Aznar S, Klein AB. Regulating prefrontal cortex activation: an
emerging role for the 5-
HT2A serotonin receptor in the modulation of emotion-based actions? Mol
Neurobiol 48(3):841-53
(2013)).
[00154] Combination of dextromethorphan and quinidine has positive therapeutic
effects in patients
with pseudobulbar affect that is characterized by emotional lability,
uncontrolled crying or laughing
which may be disproportionate or inappropriate to the social context (Pioro
EP. Review of
Dextromethorphan 20 mg/Quinidine 10 mg (NUEDEXTAO) for Pseudobulbar Affect.
Neurol Ther
17;3(1):15-28 (2014)). In patients with AD, treatment with another
nonselective NMDA receptor
channel blocker, memantine, significantly decreases the scores of NPI item for
irritability/lability
69
Date Recue/Date Received 2021-04-14
(Ishikawa I et al. The effect of memantine on sleep architecture and
psychiatric symptoms in patients
with Alzheimer's disease. Acta Neuropsychiatr 28(3):157-64 (2016)). Meta-
analysis of the
randomized controlled studies of memantine in patients with Alzheimer's
disease indicated that
memantine was superior to control in irritability/lability (Kishi T et al. The
effects of memantine on
behavioral disturbances in patients with Alzheimer's disease: a meta-analysis.
Neuropsychiatr Dis
Treatment 13: 1909-1928 (2017)).
[00155] The prevalence of aberrant motor activity is low in general
population, in people with normal
cognitive aging (0.4-0.6%) but is increased in subjects with MCI (1.3-3.8%)
and dementia (16-32%)
(Geda YE et al. The Prevalence of Neuropsychiatric Symptoms in Mild Cognitive
Impairment and
Normal Cognitive Aging: A Population-Based Study. Arch Gen Psychiatry 65(10):
1193-1198
(2008); Lyketsos CG et al. Prevalence of neuropsychiatric symptoms in dementia
and mild cognitive
impairment: results from the cardiovascular health study. JAMA 288(12):1475-83
(2002); Zhao QF
et al. The prevalence of neuropsychiatric symptoms in Alzheimer's disease:
Systematic review and
meta-analysis. J Affect Disord 190:264-71 (2016)).
1001561 Aberrant motor behavior in All is found to be significantly associated
with 5-H12A receptor
polymorphism such as T102C (Lam LC et al. 5-HT2A T102C receptor polymorphism
and
neuropsychiatric symptoms in Alzheimer's disease. hit J Geriatr Psychiatry
19(6):523-6 (2004);
Pritchard AL et al. Role a 5HT 2A and 5HT 2C polymorphisms in behavioural and
psychological
symptoms of Alzheimer's disease. Neurobiol Aging 29(3):341-7 (2008)).
[00157] Aberrant motor behavior in various neurological disease state such as
Parkinson's disease are
due to abnormal plasticity processes in basal ganglia that may be expressed as
behavioral sensitization
that is sensitive to glutamate/NMDA receptor blockade (Chase TN et al.
Striatal glutamatergic
mechanisms and extrapyramidal movement disorders. Neurotox Res 5(1-2):139-46
(2003)) and
antagonism at a3134-containing receptors (Maisonneuve IM, Glick SD. Anti-
addictive actions of an
iboga alkaloid congener: a novel mechanism for a novel treatment. Pharmacol
Biochem Behav
75(3):607-18 (2003)), two of the receptor targets of dextromethorphan (Taylor
CP et al. Pharmacology
of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta0)
clinical use. Pharmacol
Ther 164:170-82 (2016)).
[00158] The prevalence of night-time behavioral disturbances is moderate in
general population, in
people with normal cognitive aging (10.9%) but is increased in subjects with
MCI (13.8-18.3%) and
dementia (27.4-39%) (Geda YE et al. The Prevalence of Neuropsychiatric
Symptoms in Mild
Date Recue/Date Received 2021-04-14
Cognitive Impairment and Normal Cognitive Aging: A Population-Based Study.
Arch Gen Psychiatry
65(10): 1193-1198 (2008); Lyketsos CG et al. Prevalence of neuropsychiatric
symptoms in dementia
and mild cognitive impairment: results from the cardiovascular health study.
JAMA 288(12):1475-83
(2002); Zhao QF et al. The prevalence of neuropsychiatric symptoms in
Alzheimer's disease:
Systematic review and meta-analysis. J Affect Disord 190:264-71 (2016)).
[00159] 5-HT2A receptors play a major role in regulation of sleep (Vanover KE,
Davis RE. Role of 5-
HT2A receptor antagonists in the treatment of insomnia. Nat Sci Sleep 2:139-50
(2010)). In a clinical
trial assessing safety and efficacy of 5-HT2A receptor inverse agonist
pimavanserin in patients with
moderate to severe Parkinson's disease, participants reported improvements on
night-time sleep and
daytime wakefulness for pimavanserin compared with placebo (Cummings J et al.
Pimavanserin for
patients with Parkinson's disease psychosis: a randomised, placebo-controlled
phase 3 trial. Lancet
383: 533-40 (2014)). Another 5-HT2A receptor inverse agonist, eplivanserin,
has demonstrated clinical
efficacy in patients with insomnia (European Medicines Agency. Withdrawal
Assessment Report for
Sliwens (Eplivanserin), March 18, 2010, London. EMA/CHMP/90435/2010).
[00160] Meta-analysis of the randomized controlled studies of another
nonselective NMDA receptor
channel blocker, memantine, in patients with Alzheimer's disease indicated
that memantine induces
significant improvement in nighttime disturbance/diurnal rhythm disturbances
(Kishi T et al. The
effects of memantine on behavioral disturbances in patients with Alzheimer's
disease: a meta-analysis.
Neuropsychiatr Dis Treatment 13: 1909-1928 (2017)). In patients with AD,
memantine was effective
in reducing fragmented sleep and polysomnography revealed longer total sleep,
increases in sleep
efficiency and time spent in stage II, and decreases in nocturnal awakening,
the periodic limb
movement index, and time spent in stage I (Ishikawa I et al. The effect of
memantine on sleep
architecture and psychiatric symptoms in patients with Alzheimer's disease.
Acta Neuropsychiatr
28(3):157-64 (2016)).
[00161] The prevalence of appetite and eating abnormalities is low in general
population, in people
with normal cognitive aging (5.3%) but is increased in subjects with MCI (10.4-
10.7%) and dementia
(19.6-34%) (Geda YE et al. The Prevalence of Neuropsychiatric Symptoms in Mild
Cognitive
Impairment and Normal Cognitive Aging: A Population-Based Study. Arch Gen
Psychiatry 65(10):
1193-1198 (2008); Lyketsos CG et al. Prevalence of neuropsychiatric symptoms
in dementia and mild
cognitive impairment: results from the cardiovascular health study. JAMA
288(12):1475-83 (2002);
Zhao QF et al. The prevalence of neuropsychiatric symptoms in Alzheimer's
disease: Systematic
71
Date Recue/Date Received 2021-04-14
review and meta-analysis. J Affect Disord 190:264-71 (2016)).
[00162] Serotonin plays a major role in emergence and maintenance of various
types of eating disorders
(Steiger H. Eating disorders and the serotonin connection: state, trait and
developmental effects. J
Psychiatry Neurosci 29(1):20-9 (2004)). The gene encoding 5-HT2A receptor
(HTR2A) has been
implicated as a functional candidate in many neuropsychiatric phenotypes
including eating disorders
(Norton N, Owen MJ. HTR2A: association and expression studies in
neuropsychiatric genetics. Ann
Med 37(2):121-9 (2005)). Eating behavior and appetite are also modulated by
one of the receptor
target's of dextromethorphan, serotonin transporter, that is affected in
patients with eating disorders
(Spies M et al. The serotonin transporter in psychiatric disorders: insights
from PET imaging. Lancet
Psychiatry 2(8):743-55 (2015)).
[00163] Thus, current evidence suggests that pathophysiology of
neurodegenerative diseases such as
Alzheimer's disease is complex, involves multiple neuroanatomic substrates,
neurochemical and
neuropharmacological mechanism resulting in the following: i) one Therapeutic
Mode of Action
(TMA) may be used to treat more than one clinically diagnosable BPSD item
(e.g. an NPI symptom
or symptom cluster); ii) one TMA may be used to treat symptoms of two or more
clinically distinct
neurodegenerative diseases (e.g. AD, PD, DLB, FTLD, etc.) as illustrated by
the emerging efficacy
profile of Nuplazid0; iii) a single TMA is unlikely to ever cover the full
spectrum of BPSD symptoms;
iv) a single TMA may not produce a maximally possible therapeutic benefit
against even a single
BPSD symptom or symptom cluster.
[00164] Thus, in contrast to the limited clinical efficacy exerted by a single-
MTA therapy with
pimavanserin (Nuplazid0; Ballard C et al. Evaluation of the safety,
tolerability, and efficacy of
pimavanserin versus placebo in patients with Alzheimer's disease psychosis: a
phase 2, randomised,
placebo-controlled, double-blind study. Lancet Neurology (2018) 17: 213-22),
combination therapy
comprising several MTAs represented by compounds of Formula I and compounds of
Formula II
delivers both a broader and stronger efficacy profile.
[00165] An embodiment is a method of treating behavioral and psychological
symptoms of dementia
in a patient in need thereof comprising the step of administering a
pharmaceutical composition
comprising a compound of Formula II (DEX) and one or more agents selected from
the group
comprising 5-HT2A receptor antagonist, 5-HT2A receptor inverse agonist, and
CYP2D6 inhibitor. In
another embodiment, the agent is a Dual Agent (DA) having properties of both 5-
HT2A receptor
antagonist and CYP2D6 inhibitor. In another embodiment, the agent is a DA
having properties of both
72
Date Recue/Date Received 2021-04-14
5-HT2A receptor inverse agonist and CYP2D6 inhibitor. In another embodiment,
the DA is a
compound of Formula I.
[00166] DEX is an agonist of the cy2 receptor, an N-methyl-D-aspartate (NMDA)
antagonist, and an
0134 nicotinic receptor antagonist. Uptake of norepinephrine and serotonin are
also inhibited. Several
neuropsychiatric diseases and syndromes such as Alzheimer's disease and
behavioral and
psychological symptoms of dementia involve dis-regulation of glutamatergic,
cholinergic,
serotoninergic and norepinephrinergic neurotransmitter systems. Accordingly,
In another
embodiment, the composition comprises an NMDA receptor antagonist such as
ketamine, methadone,
memantine, amantadine, dextropropoxyphene, ketobemidone and dextromethorphan
(Jamero et al.,
The Emerging Role of NMDA Antagonists in Pain Management, US Pharm. 36(5):HS4-
HS8 (2011);
Sang, NMDA-receptor antagonists in neuropathic pain: experimental methods to
clinical trials, J Pain
Symptom Manage. 19 (1 Suppl) S21-5 (2000)).
In
another embodiment, the composition is a combination of a compound of Formula
I, and ketamine,
methadone, memantine, amantadine, dextropropoxyphene, ketobemidone, or
dextromethorphan. The
compound of Formula I forms the combination as mixture, complex, conjugate,
compound with
covalent bond, or a salt.
[00167] In another embodiment, the pharmaceutical composition comprises a
compound of formula I
and a compound of formula II (exemplified by SARPODEXTm, DERADEXTm, or
DERAPHANTm).
Another embodiment is a method of treatment of a patient in need thereof
comprising the step of
administering a pharmaceutical composition comprising comprises SARPODEXTm,
DERADEXIm,
or DERAPHANIm.
[00168] Psychological symptoms of dementia involve disregulation of
glutamatergic, cholinergic,
serotoninergic and norepinephrinergic neurotransmitter systems. Therefore, an
embodiment is a
method of treating behavioral and psychological symptoms of dementia. Another
embodiment is a
treatment of a person in need thereof comprising administering a composition
comprising a compound
of Formula I and a compound of Formula II to improve EEG abnormalities,
behavior, cognition, and
reduce seizures, as well as improve breathing abnormalities, motor
capabilities, bone density, and GI
dysfunction. Another embodiment is the treatment of a person in need thereof
comprising
administering a composition comprising DERATINETm, SARPOTINETm, SARPODEXTm,
DERADEXTm, or DERAPHANTm to improve EEG abnormalities, behavior, cognition,
and reduce
seizures, as well as improve breathing abnormalities, motor capabilities, bone
density, and GI
73
Date Recue/Date Received 2022-05-04
dysfunction. Another embodiment is a treatment of a person in need thereof
comprising administering
a composition comprising DERATINETh, SARPOTINETm, SARPODEXTm, DERADEXTm, or
DERAPHANTM in the treatment of other diseases and conditions, including
involuntary emotional
expression disorder (TEED) or pseudobulbar affect (PBA), neurodegenerative
diseases, neuropathic
pain, and brain injuries.
1001691 Another embodiment is a composition comprising a compound of
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm alone or in combination with
other drugs such as analgesics (e.g. acetaminophen), antihistamines (e.g.
chlorpheniramine),
decongestants (e.g., pseudoephedrine) and/or expectorants (e.g., guaifenesin).
[00170] Dextromethorphan is metabolized into active metabolites in the liver
starting with 0-and N-
demethylation to form primary metabolites DO and 3-methoxy-morphinan are
further N- and 0-
demethylated respectively to 3-hydroxy-morphinan. A major metabolic catalyst
is the cytochrome
P450 enzyme 2D6 (CYP2D6), which is responsible for the 0-demethylation
reactions of
dextromethorphan and 3-methoxymorphinan. N-demethylation of dextromethorphan
and DO are
catalyzed by enzymes in the related C YP3A family. Conjugates of DO and 3-
hydroxymorphinan can
be detected in human plasma and urine within hours of its ingestion. DO is a
substance most notable
for its psychoactive effects.
[00171] SGL is a 5-HT2A receptor inverse agonist and CYP2D6 inhibitor. SGL
inhibits responses to
5-HT mediated by 5-HT2A receptors such as platelet aggregation,
vasoconstriction and vascular
smooth muscle proliferation. SGL (MCI-9042) was shown to have the same
affinity as ritanserin for
5-HT2A receptors (Nishio et al., Binding affinity of a compound of formula I
or sarpogrelate, a new
antiplatelet agent, and its metabolite for serotonin receptor subtypes. Arch
Int Pharmacoclyn Ther.
331(2):189-202 (1996 March-April)). The blockade of 5-HT2A receptors can
inhibit thrombus
formation, suppresses platelet aggregation and inhibits vascular smooth muscle
cell proliferation
(Pertz et al., In-vitro pharmacology of a compound of Formula I and the
enantiomers of its major
metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of
ritanserin-induced
depression of 5-FIT contractions in rat tail artery. J Pharm Pharmacol.
47(4):310-6 (1995 April)).
Accordingly, an embodiment is a method of treatment of a patient in need
thereof comprising
administering a composition comprising a compound of Formula I and a compound
of Formula II, or
DERATINElm, SARPOTINElm, SARPODEX'TM, DERADEX'TM, or DERAPHAN'TM.
[00172] Another embodiment is the method of treatment wherein the patient is
suffering from a disease
74
Date Recue/Date Received 2021-04-14
or disorder comprising peripheral arterial disease, e.g., Raynaud's Disease
and claudicatio
intermittens; pulmonary hypertension (Saini et al., 2004), angina pectoris
(Kinugawa et al., 2002),
and/or diabetes mellitus (Pietraszek et al., 1993; Ogawa et al., 1999). In
another embodiment, the
method of treatment of a patient after coronary stenting comprising a compound
of Formula I, to and
is useful in restenosis (Doggrell, sarpogrelate: cardiovascular and renal
clinical potential, Expert
Opinion on Investigational Drugs, Volume 13, Issue 7 (2004)).
[00173] DO is a substance most notable for its psychoactive effects that
likely arise from blockade of
NMDA receptors. DO has a substantially higher affinity for NMDA receptors
compared to that of
DEX. Adverse psychoactive effects of DEX have been associated with its
metabolism to DO (Taylor
et al., Pharmacology of dextromethorphan: Relevance to
dextromethorphan/quinidine (Nuedexta0)
clinical use. Pharmacol Ther. 164:170-82 (2016 August)). Therefore, another
embodiment is a method
of reducing adverse effects of DEX during treatment of a patient in need
thereof comprising the step
of administering a pharmaceutical composition comprising DEX and one or more
agents selected from
the group comprising 5-HT2A receptor antagonist/inverse agonist, and CYP2D6
inhibitor. In another
embodiment, the agent is an agent having properties of both 5-H'1'2A receptor
antagonist/inverse
agonist and CYP2D6 inhibitor. In another embodiment, the agent is an agent
having properties of both
5-HT2A receptor inverse agonist and CYP2D6 inhibitor. In another embodiment,
the agent is a
compound of Formula I and a compound of Formula 11, or DERAT1NE', SARPOT1NETm,
SARPODEXTm, DERADEX'TM, or DERAPHANTm.
[00174] Another embodiment is a composition comprising (6)-1-1242-(3-
methoxyphenil) ethyl]-
phenoxy} -3-(dimethylamino)-2-propanol (M-1) (Nagatomo et al., 2004; Saini et
al., 2004), a 5-HT2A
receptor inverse agonist and CYP2D6 inhibitor.
[00175] The genetically polymorphic cytochrome CYP2D6 has been implicated in
the metabolism of
many antipsychotic agents, including thioridazine, perphenazine,
chlorpromazine, fluphenazine,
haloperidol, zuclopenthixol, risperidone, and sertindole (Michalets, 1998).
This enzyme is also
important in the metabolism of other drugs that are commonly prescribed to
patients with psychiatric
disorders, e.g., tricyclic antidepressants (nortriptyline, desipramine,
amitriptyline, imipramine, and
clomipramine) and selective serotonin reuptake inhibitors, including
fluoxetine and paroxetine (Taylor
and Lader,1996; Sproule et al., 1997). Drugs that inhibit these enzymes would
be expected to cause
increases in the plasma concentration of co-administered antipsychotic drugs
(Goff, 1993; Ereshefsky,
1996; Michalets, 1998). These increases may, in turn, lead to the development
or aggravation of
Date Recue/Date Received 2021-04-14
antipsychotics-induced side effects including cardiac toxicity,
anticholinergic side effects, or
orthostatic hypotension (Ereshefsky, 1996; Desta et al., 1999).
1001761 Many antipsychotic drugs inhibited CYP2D6-catalyzed DEX 0-
demethylation. Among the
antipsychotic drugs tested, thioridazine and perphenazine were the most potent
inhibitors and
decreased the DO formation rate to 26.5 and 19.7% of control activity at 10
microM, and 11.4 and
10.7% of control activity at 25 micro M, respectively. The inhibitory potency
of these drugs on DEX
0-demethylation was comparable to the inhibitory effect of 10 to 25 microM
quinidine. The estimated
mean IC50 values for thioridazine and perphenazine were 2.7 + 0.5 and 1.5 0.3
micro M,
respectively. The IC50 of quinidine, a potent CYP2D6 inhibitor, was estimated
to be 0.52 + 0.2 micro
M under these conditions. The estimated IC50s of chlorpromazine, fluphenazine,
and haloperidol were
9.7, 16.3, and 14.4 micro M, respectively. Cisthiothixene, clozapine, and
risperidone exhibited weaker
inhibition than the other drugs tested, with mean IC5os estimated to be 136.6,
92.2, and 39.1 micro M,
respectively (Shin et al., Effect Of Antipsychotic Drugs on Human Liver
Cytochrome P-450 (Cyp)
Isoforms in Vitro: Preferential Inhibition of CYP2D6, Drug Metabolism And
Disposition, Vol. 27,
No. 9 (1999)).
[00177] In one embodiment, the pharmaceutical composition of the invention
comprise one or more of
the CYP2D6 inhibitors such as, but are not limited to, Ajmaline, Amiodarone,
Amitriptyline,
Aprindine, Azelastine, Celecoxib, Chlorpheniramine, Chlorpromazine,
Diphenhydramine,
Doxorubicin, Fluoxetine, Fluphenazine, Fluvastatin, Fluvoxamine, Haloperidol,
Imipramine,
Indinavir, Lasoprazole, Levomepromazine, Lopinavir, Loratadine, Mequitazine,
Methadone,
Metoclopramide, Mibefradil, Moclobemide, Nelfinavir, Nevirapine, Nicardipine,
Norfluoxetine,
Paroxetine, Perphenazine, Pimozide, Terfenadine, Thioridazine, Cimetidine,
Quinidine, Cisapride,
Citalopram, Clomipramine, Clozapine, Cocaine, Desipramine, Ranitidine,
Risperidone, Ritonavir,
Saquinavir, Sertraline, Terbinafine, Ticlopidine, Trifluperidol, Venlafaxine,
and Yohimbine.
[00178] In one embodiment, the invention is a combination of a 5HT2A receptor
antagonist and a
CYP2D6 inhibitor providing a therapeutic advantage of the simultaneous 5HT2A
receptor antagonism
and 2D6 inhibition. In another embodiment, the invention is a combination of a
5HT2A receptor
inverse agonist and a CYP2D6 inhibitor providing a therapeutic advantage of
the simultaneous 5HT2A
receptor inverse agonism and 2D6 inhibition. A compound of Formula I and a
compound of Formula
II; or DERATINElm, SARPOTINElm, SARPODEX'TM, DERADEX'TM, or DERAPHANIm
provides a
unique therapeutic advantage by combining both CYP2D6 inhibition and 5HT2A
receptor inverse
76
Date Recue/Date Received 2021-04-14
agonism to improve the magnitude of the therapeutic response to DEX. Thus,
Formula I and a
compound of Formula II; or DERATINErm, SARPOTINETm, SARPODEXIm, DERADEXIm, or
DERAPHANTm avoids potential health risks associated with the concomitant use
of an anti-
arrhythmic drug quinidine with DEX. Accordingly, an embodiment is a
composition comprising
Formula I and a compound of Formula II; or DERATINETm, SARPOTINElm,
SARPODEXTm,
DERADEXTm, or DERAPHANTm.
[00179] Some embodiments include a method of decreasing the number of doses
and/or total daily dose
of dextromethorphan, a metabolite, a derivative or a prodrug thereof (DEX)
that can be administered
while increasing efficacy and safeguarding tolerability and safety, comprising
orally administering an
effective amount of a compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXIm, DERADEXTm, or DERAPHANTm.
[00180] Some embodiments include a method of reducing an adverse event
associated with treatment
comprising co-administering a compound of Formula I and a compound of Formula
II; or,
DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm to a subject in
need of DEX and/or a compound of Formula 1, DERAT1NETm, SARPOTINE",
SARPODEXTm,
DERADEXTm, or DERAPHANTm treatment, wherein the subject is at risk of
experiencing the adverse
event as a result being treated with DEX and/or a compound of Formula I,
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHAN'.
[00181] Some embodiments include a method of decreasing DO plasma levels
comprising co-
administering a compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHAN' to a subject in need of
treatment
with DEX, wherein the compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTM is administered on the first
day
of at least two days of treatment with DEX, wherein a decrease in the DO
plasma level occurs on the
first day that a compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEX'TM, or DERAPHANIm are administered, as
compared
to the same amount of DEX administered without a compound of Formula I.
[00182] Another embodiment is a method of decreasing DO plasma levels
comprising co-administering
a compound of Formula I and a compound of Formula II; or DERATINElm,
SARPOTINETm,
SARPODEX'TM, DERADEX'TM, or DERAPHAN'TM, for at least eight consecutive days,
to a subject
in need of treatment with DEX, wherein, on the eighth day, the DO plasma level
is lower than the DO
77
Date Recue/Date Received 2021-04-14
plasma level that would have been achieved by administering the same amount of
DEX administered
without a compound of Formula I for eight consecutive days.
1001831 5-HT2A receptor antagonist/inverse agonists, such as a compound of
Formula I and a
compound of Formula II; or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXIm, or
DERAPHANTm, can be used to improve the therapeutic properties of DEX, such as
in the treatment
of neurological disorders. A compound of Formula I and a compound of Formula
II; or DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANIm regardless of
stereochemistry,
can be effective in inhibiting or reducing the metabolism of DEX in some
subjects, accomplished by
co-administering a compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm.
[00184] Another embodiment is a method of treating a neurological disorder
comprising administering
a 5-HT2A receptor antagonist/inverse agonist and DEX to a subject in need
thereof, wherein the
subject is an extensive metabolizer of DEX.
[00185] Another embodiment is a method of treating a neurological disorder
comprising administering
a 5-1-112A receptor inverse agonist, antagonist, and DEX to a subject in need
thereof, wherein the
subject is an extensive metabolizer of DEX.
[00186] Another embodiment is a method of increasing DEX plasma levels in a
subject in need of
treatment with DEX, wherein the subject is an extensive metabolizer a DEX,
comprising co-
administering a compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXIm, DERADEXTm, or DERAPHANTm to the subject.
[00187] Another embodiment is a method of inhibiting the metabolism of DEX,
comprising
administering a compound of formula I, or a compound of Formula I and a
compound of Formula II;
or DERATINETm, SARPOTINETm, SARPODEX'TM, DERADEXTm, or DERAPHANTm, to a
subject,
wherein the subject is an extensive metabolizer of DEX, and wherein DEX is
present in the body of
the subject at the same time as a compound of Formula I.
[00188] Another embodiment is a method of increasing the metabolic lifetime of
DEX, comprising
administering a compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm to a subject in need of
treatment
with DEX, wherein the subject is an extensive metabolizer of DEX, and wherein
DEX is present in
the body of the subject at the same time as a compound of Formula I.
[00189] Another embodiment is a method of correcting extensive metabolism of
DEX, comprising
78
Date Recue/Date Received 2021-04-14
administering a compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANThl, to a subject in need
thereof.
1001901 Another embodiment is a method of improving the antitussive properties
of DEX comprising
administering a compound of Formula I and a compound of Formula II; or
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEX'TM, or DERAPHANTm in conjunction with
administration of DEX to a subject in need of treatment for a cough.
[00191] Another embodiment is a method of treating cough comprising
administering a combination
of a compound of Formula I and a compound of Formula II; or DERATINElm,
SARPOTINETm,
SARPODEXTm, DERADEXTm, or DERAPHANTm to a subject in need thereof.
[00192] Another embodiment is a method of treating a neurological disorder
comprising administering
a compound of Formula I and a compound of Formula II; or DERATINElm,
SARPOTINETm,
SARPODEXTm, DERADEXTm, or DERAPHANTm to a subject in need thereof, wherein the
compound of Formula I and a compound of Formula II; or DERATINElm,
SARPOTINETm,
SARPODEXTm, DERADEXTm, or DERAPHANTm are administered at least once a day for
at least
eight days.
[00193] Another embodiment is a method of treating a neurological disorder
comprising administering
about 5 mg/day to about 600 mg/day, about 5 mg/day to about 300 mg/day, about
5 mg/day to about
400 mg/day, about 5 mg/day to about 500 mg/day, about 5 mg/day to about 600
mg/day, about 5
mg/day to about 1,000 mg/day, about 50 mg/day to about 1000 mg/day, about 100
mg/day to about
1000 mg/day, about 150 mg,/day to about 1000 mg/day, about 150 mg/day to about
5000 mg/day,
about 150 mg/day to about 300 mg/day, or about 150 mg/day to about 100 mg/day,
or an amount as
required of a compound of Formula I and about 0.1 mg/day to about 1 mg/day,
about 0.5 mg/day to
about 15 mg/day, about 15 mg/day to about 60 mg/day, about 15 mg/day to about
120 mg/day, about
0.1 mg/day to about 200 mg/day, or an amount as required of DEX to a subject
in need thereof.
[00194] Another embodiment is a method of increasing DEX plasma levels in a
subject in need of
treatment with DEX, wherein the subject is an extensive metabolizer of DEX,
comprising co-
administering a compound of Formula I with DEX to the subject.
[00195] Another embodiment is a method of inhibiting the metabolism of DEX,
comprising
administering a compound of Formula I, to a subject, wherein the subject is an
extensive metabolizer
of DEX, and wherein DEX is present in the body of the subject at the same time
as a compound of
Formula I.
79
Date Recue/Date Received 2021-04-14
[00196] Another embodiment is a method of increasing the metabolic lifetime of
DEX, comprising
administering a compound of formula I, to a subject in need of treatment with
DEX, wherein the
subject is an extensive metabolizer of DEX, and wherein DEX is present in the
body of the subject at
the same time as a compound of formula I.
[00197] Another embodiment is a method of increasing DEX plasma levels
comprising co-
administering a compound of formula land DEX to a subject in need of treatment
with DEX, wherein
the compound of formula I is administered on the first day of at least two
days of co-administration
of a compound of formula I, with DEX, wherein an increase in the DEX plasma
level occurs on the
first day that a compound of formula I and DEX are co-administered, as
compared to the same amount
of DEX administered without a compound of formula I.
[00198] Another embodiment is a method of increasing DEX plasma levels
comprising co-
administering a compound of formula I and DEX for at least five consecutive
days, to a subject in
need of treatment with DEX, wherein, on the fifth day, the DEX plasma level is
higher than the DEX
plasma level that would have been achieved by administering the same amount of
DEX administered
without a compound of formula 1, for five consecutive days.
[00199] Another embodiment is a method of increasing DEX plasma levels
comprising co-
administering a compound of formula I and DEX for at least six consecutive
days, to a subject in need
of treatment with DEX, wherein, on the sixth day, the DEX plasma level is
higher than the DEX
plasma level that would have been achieved by administering the same amount of
DEX administered
without a compound of formula I, for six consecutive days.
[00200] Another embodiment is a method of reducing a trough effect of DEX
comprising, co-
administering a compound of formula I, with DEX to a subject in need of
treatment with DEX, wherein
DEX has a plasma level 12 hours after co-administering a compound of formula
I, with DEX that is
at least twice the plasma level that would be achieved by administering the
same amount of DEX
without a compound of formula I.
[00201] Another embodiment is a method of reducing a trough effect of DEX
comprising, co-
administering a compound of formula I, with DEX to a subject in need of
treatment with DEX,
wherein DEX has a plasma level 12 hours after co-administering a compound of
formula I, with DEX
that is at least twice the plasma level that would be achieved by
administering the same amount of
DEX without a compound of Formula I.
[00202] Another embodiment is a method of reducing a trough effect of DEX
comprising, co-
Date Recue/Date Received 2021-04-14
administering a compound of formula I, with DEX to a subject in need of
treatment with DEX,
wherein DEX has a plasma level 12 hours after co-administering a compound of
formula I, with DEX
that is at least twice the plasma level that would be achieved by
administering the same amount of
DEX without a compound of Formula I.
[00203] Another embodiment is a method of reducing an adverse event or other
unwanted
consequences such as addiction associated with treatment by DEX, comprising co-
administering a
compound of Formula I, and DEX to a subject in need of DEX treatment, wherein
the subject is at risk
of experiencing the adverse event as a result of being treated with DEX.
[00204] Another embodiment is a method of reducing an adverse event associated
with treatment by a
compound of formula I, comprising co-administering DEX and a compound of
formula I, to a subject
in need of a compound of Formula I, treatment, wherein the subject is at risk
of experiencing the
adverse event as a result of being treated with a compound of formula I.
[00205] Another embodiment is a method of improving antitussive properties of
DEX comprising
administering a compound of formula I, in conjunction with administration of
DEX to a subject in
need of treatment for cough.
[00206] Another embodiment is a method of treating cough comprising
administering a combination
of a compound of formula I and DEX to a subject in need thereof.
[00207] Another embodiment is a method of treating a neurological disorder
comprising administering
a compound of formula I and DEX to a subject in need thereof, wherein the
compound of formula I
and DEX are administered at least once a day for at least 8 days.
[00208] Another embodiment is a method of treating a neurological disorder
comprising administering
a composition comprising DEX, Formula I, DERATINETm, SARPOTINETm, SARPODEX'TM,
DERADEXTm, or DERAPHANTm to a subject in need thereof, wherein the DEX,
Formula I,
DERATINE', SARPOTINE', SARPODEX', DERADEX', or DERAPHAN' is administered
at least once a day for at least 8 days.
[00209] Another embodiment is a method of treating a neurological disorder
comprising administering
a composition comprising DEX, Formula I, DERATINE', SARPOTINETm, SARPODEXTM,
DERADEXTm, or DERAPHANTm to a subject in need thereof, wherein the compound of
formula I
and DEX are administered at least once a day for at least 8 days.
[00210] Another embodiment is an oral sustained release delivery system for
DEX, comprising a
composition comprising DEX, Formula I, DERATINETm, SARPOTINEThl, SARPODEXTm,
81
Date Recue/Date Received 2021-04-14
DERADEXTm, or DERAPHANTm, and a vehicle.
[00211] Another embodiment is a method of decreasing the number of doses of
DEX that can be
administered without loss of efficacy, comprising orally administering an
effective amount of a
composition comprising DEX and Formula I, or DERATINETm, SARPOTINETh4,
SARPODEXTm,
DERADEXTm, or DERAPHANTm to a subject in need of treatment with DEX.
[00212] Another embodiment is a pharmaceutical composition, dosage form, or
medicament
comprising a therapeutically effective amount of DEX, a therapeutically
effective amount of a
compound of fommla I and a pharmaceutically acceptable excipient.
[00213] In an aspect, provided is a method of increasing the metabolic
lifetime of DEX, comprising
administering 5-HT2A receptor antagonist/inverse agonist to a subject in need
of treatment with DEX,
wherein 5-HT2A receptor antagonist/inverse agonist is an inhibitor of a CYP2D6
enzyme and wherein
DEX is present in the body of the subject at the same time as the inhibitor of
a CYP2D6. In another
embodiment, the composition comprises DEX and Formula I, or DERATINElm,
SARPOTINETm,
SARPODEXTm, DERADEX'TM, or DERAPHANTm.
[00214] In another aspect, provided is a method of preventing adverse events
associated with treatment
by DEX, comprising co-administering 5-HT2A receptor antagonist/inverse agonist
or such as a
compound of formula I, to a subject in need of treatment with DEX, wherein the
subject is at risk of
experiencing the adverse event as a result of being treated with DEX.
[00215] In another aspect, provided is a method for using 5HT2A receptor
antagonists such as a
compound of formula I, to improve the therapeutic properties of DEX in the
treatment of neurological
disorders.
[00216] In another aspect, provided is a method of treating a disorder or
disease comprising
administering a composition comprising 5HT2A receptor antagonist and DEX to a
subject in need
thereof. In another embodiment, the composition comprises DEX and Formula I,
or DERATINE',
SARPOTINETm, SARPODEXIm, DERADEXTm, or DERAPHANTm.
[00217] In another aspect, provided is a method for selecting a 5-HT2A
receptor antagonist/inverse
agonist for the use in combination with DEX in a subject in need thereof.
[00218] Another embodiment NMDA receptor antagonists reduce the physical
aspects of the
expression of morphine dependence as measured by naloxone-precipitated
withdrawal (Bristow et al.,
Competitive and glycine: NMDA receptor antagonists attenuate withdrawal-
induced behaviors and
increased hippocampal acetylcholine efflux in morphine-dependent rats.
Neuropharmacology. 36:
82
Date Recue/Date Received 2021-04-14
241-250 (1997); Popik etal., Inhibition of reinforcing effects of morphine and
motivational aspects of
naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor
antagonist, memantine. J.
Pharmacol. Exp. Ther. 280: 854-865 (1997); Popik etal., Inhibition of
reinforcing effects of morphine
and naloxone-precipitated opioid withdrawal by novel glycine site and
uncompetitive NMDA receptor
antagonists. Neuropharmacology. 37: 1033-1042 (1998)) and may attenuate not
only the physical but
also affective and motivational components of abstinence states, as well as
craving (Cornish et al. A
randomized, double-blind, placebo-controlled safety study of high-dose
dextromethorphan in
methadone-maintained male inpatients. Drug & Alcohol Dependence. 67(2): /77-
83(2002)). By
reducing withdrawal symptoms, such medications should be beneficial for the
patients during the acute
detoxification phase of treatment for opioid dependence (Cornish et al., A
randomized, double-blind,
placebo-controlled safety study of high-dose dextromethorphan in methadone-
maintained male
inpatients. Drug & Alcohol Dependence. 67(2): 177-83 (2002)).
[00219] Accordingly, an embodiment is a method of treating a subject in need
of treatment for disorders
or diseases associated with addiction and substance abuse comprising
administration of DEX and
Formula 1, or DERAT1NE, SARPOT1NETm, SARPODEXTm, DERADEXTm, or DERAPHANTm.
[00220] Chronic exposure to morphine results in a number of biochemical
adaptations of the
glutamatergic receptor system in the limbic system (Fitzgerald et al., Drugs
of abuse and stress
increase the expression a (HuR1 and NMDAR1 glutamate receptor subunits in the
rat ventral
tegmental area: common adaptations among cross-sensitizing agents. J.
Neurosci. 16: 274-282
(1996);). Excitatory amino acids are involved in the mediation of many
neurochemical and behavioral
effects resulting from chronic exposure to abusing drugs, some of which can be
prevented or reversed
using glutamatergic antagonists (Inturrisi, Preclinical evidence for a role of
glutamatergic systems in
opioid tolerance and dependence. Semin. Neurosci. 9: 110-119 (1997)).
Continued self-
administration of abusive drugs, including opioid, results in an
overstimulation of dopamine in the
brain reward centers and an increased release of excitatory amino acids
including glutamate leading
to the development of tolerance and dependence which could be blocked by
glutamate antagonists
(Herman et al., Clinical medication development for opiate addiction: focus on
nonopioids and opioid
antagonists for the amelioration of opiate withdrawal symptoms and relapse
prevention. Semin.
Neurosci. 9: 158-172 (1997)). Accordingly, an embodiment is a method of
treating a subject in need
of treatment for disorders or diseases associated with addiction and substance
abuse resulting from
opioid tolerance and dependence by amelioration of opiate withdrawal symptoms
and relapse
83
Date Recue/Date Received 2021-04-14
prevention comprising administration of DEX and Formula I, or DERATINElm,
SARPOTINETm,
SARPODEXTm, DERADEX'TM, or DERAPHANTm.
1002211 DEX affords neuroprotection on dopamine neurons in several
inflammation-based animal
Parkinson's disease models (Li et al., Protective effect of dextromethorphan
against endotoxic shock
in mice. Biochemical Pharmacology. 69(2): 233-40 (2005); Liu et al.,
Dextromethorphan protects
dopaminergic neurons against inflammation-mediated degeneration through
inhibition of microglial
activation. Journal of Pharmacology & Experimental Therapeutics. 305 (1):212-8
(2003); Zhang et
al., Neuroprotective effect of dextromethorphan in the MPTP Parkinson's
disease model: role of
NADPH oxidase. FASEB Journal. 18(3): 589-91 (2004); Zhang et al., 3-
hydroxymorphinan is
neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-
induced neurotoxicity.
FASEB Journal. 19(3): 395-7 (2005)). 1-10 micro M DEX protected dopamine
neurons against
lipopolysaccharide (LPS)-induced reduction of dopamine uptake in rat primary
mixed mesencephalic
neuron-glia cultures. Morphologically, in LPS-treated cultures, besides the
reduction of an abundance
of dopamine neurons, the dendrites of the remaining dopamine neurons were
significantly less
elaborative than those in the controls. In cultures pretreated with DEX (10
micro M) before LPS
stimulation, dopamine neurons were significantly more numerous and the
dendrites less affected.
Significant neuroprotection was observed in cultures with DEX added up to 60
minutes after the
addition a LPS. Thus, DEX significantly protects monoamine neurons not only
with pretreatment but
also with post-treatment (Zhang et al., Neuroprotective effect of
dextromethorphan in the MPTP
Parkinson's disease model: role of NADPH oxidase. FASEB Journal, 18(3): 589-91
(2004)). Animal
studies using both LPS and MPTP PD models also show potent protective effect
of DEX (Zhang et
al., Neuroprotective effect of dextromethorphan in the MPTP Parkinson's
disease model: role of
NADPH oxidase. FASEB Journal, 18(3): 589-91 (2004)). Accordingly, an
embodiment is a method
of treating a subject in need of a treatment for Parkinson's disease
comprising administration of DEX
and Formula I, or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEX'TM, or
DERAPHANTm.
[00222] The neuroprotective effect of DEX is associated with the inhibition of
microglia over-
activation by inhibition of superoxide anion production from NADPH-oxidase,
and this
neuroprotective effect of DEX is not associated with its NMDA receptor
antagonist property.There is
A correlation was observed between the anti-inflammatory potency and
neuroprotection of NMDA
receptor antagonists, such as MK801, AP5, and memantine, suggesting that the
dopamine
84
Date Recue/Date Received 2021-04-14
neuroprotection provided by DEX in the inflammation-related neurodegenerative
models is not
mediated through the NMDA receptor. This conclusion is not in conflict with
previous reports,
indicating that NMDA receptor blockade is associated with the neuroprotective
effects of DEX in the
acute glutamate-induced excitotoxicity models. Accordingly, an embodiment is a
method of treating
a subject in need of treatment for a disorder or disease thereof comprising
administration of DEX and
Formula I, or DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm
wherein the disorder or disease is an inflammation-related neurodegenerative
disorder.
[00223] GC-dependent effects of morphine activate the hypothalamic-pituitary-
adrenal (HPA) axis.
The activation of the HPA axis increases the products of GC as potent
immunomodulatory hormones
(Freier et al., A mechanism of action for morphine-induced immunosuppression:
corticosterone
mediates morphine-induced suppression of natural killer cell activity. J
Pharmacol Exp Ther 270(3):
1127-33 (1994); Mellon et al., Role of central opioid receptor subtypes in
morphine-induced
alterations in peripheral lymphocyte activity. Brain Res 789(1): 56-67
(1998)). Accordingly, an
embodiment is a method of treating a subject in need of treatment for a
disorder or disease thereof
comprising administration of DEX and Formula 1, or DERATINETh, SARPOTINETm,
SARPODEXTm, DERADEXTm, or DERAPHANTm wherein the disorder or disease is opioid
dependence. The dosage of up to about 500 mg/day DEX is suggested, including
doses of 120, 240,
and 480 mg/day a DEX for heroin addicts undergoing withdrawal. DEX at high
doses caused mild
elevations of heart rate, blood pressure, temperature, and plasma bromide
(Cornish et al., A
randomized, double-blind, placebo-controlled safety study of high-dose
dextromethorphan in
methadone-maintained male inpatients. Drug & Alcohol Dependence. 67(2): 177-83
(2002)).
Particularly among Han Chinese in Taiwan, DEX has been reported to have quite
different
"dextromethorphan metabolic enzyme CYP2D6" from that of Western population
(Yeh et al., Analysis
of pharmacokinetic parameters for assessment of dextromethorphan metabolic
phenotypes. I Biomed.
Sci. 10: 552-564 (2003)).
[00224] Significantly higher interleukin-6, interleukin-8, and TNF-alpha
levels are manifested in
bipolar disorder (BP) patients during manic and depressive episodes than
normal controls (Kim et al.,
Alexithymia and Stress Response Patterns among Patients with Depressive
Disorders in Korea.
Psychiatry Investig. 6(1): 13-8 (2009); O'Brien et al., Cytokine profiles in
bipolar affective disorder:
focus on acutely ill patients. J Affect Disord. 90(2-3): 263-7 (2006);
Brietzke et al., Comparison of
cytokine levels in depressed, manic and euthymic patients with bipolar
disorder. J Affect Disord.
Date Recue/Date Received 2021-04-14
116(3): 214-7 (2009)).
[00225] In postmortem frontal cortex from BP patients, the significantly
higher protein and mRNA
levels of IL-1 beta receptor and neuroinflammatory markers inducible nitric
oxide synthase (iNOS)
and c-fos were found (Rao et al., Increased excitotoxicity and
neuroinflammatory markers in
postmortem frontal cortex from bipolar disorder patients. MoL Psychiatry.
15(4): 384-92 (2010)).
Taken together, the imbalance of the immune system, subsequently leading to
the neuronal
inflammatory response, might be related to the progression of the brain
atrophy and aggravated BP
symptoms. BP treatment with immune-targeted therapies showed antidepressant
effects. For example,
open-label acetylsalicylic acid when added to fluoxetine led to increased
remission rates in individuals
with major depression who were previously non-responsive to fluoxetine
monotherapy (Mendlewicz
et al., Shortened onset of action of antidepressants in major depression using
acetylsalicylic acid
augmentation: a pilot open-label study. mt. Cl/n. PsychopharmacoL 21(4): 227-
31 (2006)).
[00226] Thus, using an anti-inflammatory agent combined with a mood stabilizer
improves the
treatment effect on BP. Mood stabilizers have been shown to activate
interconnected intracellular
signaling pathways that promote neurogenesis and synaptic plasticity. A
reduction in brain volume in
BP patients was found to be largely suppressed by chronic treatment with
Valproate (VPA) resulting
in neuroprotective effects, as VPA renders neurons less susceptible to a
variety of insults (Chen et al.,
Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by
stimulating the release
of neurotrophic factors from astrocytes. Mol Psychiatry. 11(12).1116-1125
(December 2006)) and
even stimulates neurogenesis in the adult rodent brain. VPA induces
cytoprotective proteins like Bcl-
2, glucose-regulated protein 78 (Grp78), brain-derived neurotrophic factor
(BDNF) and heat shock
protein 70. Moreover, VPA promotes neurite outgrowth, while VPA at therapeutic
levels was reported
to inhibit histone deacetylase (HDAC), an enzyme that catalyzes the removal of
the acetyl group from
lysine residues of histones, promoting local, neuronal BDNF biosynthesis.
Accordingly, an
embodiment is a method of treating a subject in need of treatment for a
disorder or disease thereof
comprising administration of DEX and a compound of Formula I, or DERATINE',
SARPOTINETm,
SARPODEXTm, DERADEX'TM, or DERAPHANTm, wherein the disorder or disease is BP.
[00227] Another embodiment is a method of reducing adverse events of DEX in a
subject in need
thereof comprising:
a. administering DEX; and
b. administering a compound of Formula I, to the subject.
86
Date Recue/Date Received 2021-04-14
[00228] Some embodiments include a method of treating neuropsychiatric
disorders comprising
administering a therapeutically effective amount of DEX and a therapeutically
effective amount of a
compound of formula I, to a person in need thereof.
[00229] Some embodiments include a method of enhancing the therapeutic
properties of DEX in
treating neuropsychiatric disorders, comprising co-administering DEX and a
compound of formula I.
1002301 Some embodiments include a method of increasing DEX plasma levels in a
subject that is an
extensive metabolizer of DEX, comprising co-administering a 5-HT2A receptor
antagonist/inverse
agonist, such as a compound of formula I and DEX to the subject.
[00231] Some embodiments include a method of inhibiting the metabolism of DEX,
comprising
administering a 5-HT2A receptor antagonist/inverse agonist, such as a compound
of formula I to a
subject, wherein the subject is an extensive metabolizer of DEX, and wherein
DEX is present in the
body of the subject at the same time as the 5-HT2A receptor antagonist/inverse
agonist.
[00232] Some embodiments include a method of increasing the metabolic lifetime
of DEX, including
increasing the elimination half-life (T1/2) of DEX. These embodiments may
comprise administering a
5-HT2A receptor antagonist/inverse agonist, such as a compound of formula Ito
a subject, wherein
the subject is an extensive metabolizer of DEX, and wherein DEX is present in
the body of the subject
at the same time as the 5-HT2A receptor antagonist/inverse agonist..
[00233] Some embodiments include a method a correcting extensive metabolism a
DEX, comprising
administering a 5-HT2A receptor antagonist/ inverse agonist, such as a
compound of formula I to a
subject in need thereof, such as a subject in need of treatment for pain.
[00234] Some embodiments include a method of improving the therapeutic
properties of DEX in
treating neuropsychiatric disorders comprising administering a 5-HT2A receptor
antagonist/inverse
agonist, such as a compound of formula Tin conjunction with administration of
DEX to a subject in
need of treatment for a neuropsychiatric disorder.
[00235] Some embodiments include a method of treating neuropsychiatric
disorders comprising
administering a combination of a 5-HT2A receptor antagonist/inverse agonist,
such as a compound of
formula I and DEX to a subject in need thereof.
[00236] DEX is used as a cough suppressant. According to the FDA's DEX product
labeling
requirement under the OTC Monograph [21CFR341.74], DEX should be dosed 6 times
a day (every
4 hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours).
[00237] DEX is rapidly metabolized in the human liver. This rapid hepatic
metabolism may limit
87
Date Recue/Date Received 2021-04-14
systemic drug exposure in individuals who are extensive metabolizers. Subjects
can be: 1) extensive
metabolizers of DEX--those who rapidly metabolize DEX; 2) poor metabolizers of
DEX--those who
only poorly metabolize DEX; or 3) intermediate metabolizers of DEX--those
whose metabolism of
DEX is somewhere between that of an extensive metabolizer and a poor
metabolizer. Extensive
metabolizers can also be ultra-rapid metabolizers. Extensive metabolizers of
DEX are a significant
portion of the human population. DEX can, for example, be metabolized to DO.
[00238] When given the same oral dose of DEX, plasma levels of DEX are
significantly higher in poor
metabolizers or intermediate metabolizers as compared to extensive
metabolizers of DEX. The low
plasma concentrations of DEX can limit its clinical utility as a single agent
for extensive metabolizers,
and possibly intermediate metabolizers, of DEX. Some antidepressants, such as
a compound of
Formula I inhibit the metabolism of DEX, and can thus improve its therapeutic
efficacy. Similarly,
antidepressants may allow DEX to be given less often, such as once a day
instead of twice a day, once
a day instead of three times a day, once a day instead of four times a day,
twice a day instead of three
times a day, or twice a day instead of four times a day, without loss of
therapeutic efficacy.
[00239] Pain or other neuropsychiatric disorders may be treated by a method
comprising administering
a therapeutically effective amount of DEX and a therapeutically effective
amount of a 5-HT2A
receptor antagonist/inverse agonist, such as a compound of formula Ito a
person in need thereof.
[00240] Examples a neuropsychiatric disorders that may be treated, or that may
be treated with
increased efficacy, by a combination of DEX and a 5-HT2A receptor
antagonist/inverse agonist a
compound of formula I include, but are not limited to: affective disorders,
psychiatric disorders,
cerebral function disorders, movement disorders, dementias, traumatic brain
injury, chronic traumatic
encephalopathy, PTSD, motor neuron diseases, neurodegenerative diseases,
seizure disorders, and
headaches.
[00241] Affective disorders that may be treated by a combination of DEX and a
5-HT2A receptor
antagonist/inverse agonist a compound of formula I include, but are not
limited to, depression, major
depression, treatment-resistant depression and treatment-resistant bipolar
depression, BPs including
cyclothymia, seasonal affective disorder, mania, anxiety disorders, attention
deficit disorder (ADD),
attention deficit disorder with hyperactivity (ADDH), and attention
deficit/hyperactivity disorder
(AD/HD), bipolar and manic conditions, obsessive-compulsive disorder, bulimia,
anorexia, obesity or
weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome,
substance addiction or
abuse, nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and
emotional lability.
88
Date Recue/Date Received 2021-04-14
[00242] Depression may be manifested by changes in mood, feelings of intense
sadness, despair, mental
slowing, sleep disturbances, loss of concentration, pessimistic worry,
agitation, and self- depreciation.
Physical symptoms of depression may include insomnia, anorexia, weight loss,
decreased energy and
libido, apathy, and abnormal hormonal circadian rhythms.
[00243] Psychiatric disorders that may be treated by a combination of DEX and
a 5-HT2A receptor
antagonist/inverse agonist such as a compound of formula I include, but are
not limited to, anxiety
disorders, including but not limited to, phobias, generalized anxiety
disorder, social anxiety disorder,
panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic
stress disorder
(PTSD); mania, manic depressive illness, hypomania, unipolar depression,
depression, stress
disorders, somatoform disorders, personality disorders, psychosis,
schizophrenia, delusional disorder,
schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's
disease, agitation, and
apathy in Alzheimer's disease.
[00244] Apathy, or loss of motivation, is the most common change in behavior
in Alzheimer's disease
(AD). It is common throughout the spectrum of cognitive decline from mild
cognitive impairment to
severe Alzheimer's disease (AD), as well as in a variety of other
neuropsychiatric disorders. Apathy
represents a form of executive cognitive dysfunction. Patients with apathy
suffer from decreased daily
function and specific cognitive deficits and rely on families to provide more
care, which results in
increased stress for families. Apathy is one of the primary syndromes
associated with frontal and
subcortical pathology, and apathy in AD appears to have multiple
neuroanatomical correlates that
implicate components of frontal subcortical networks. Despite the profound
effects of this common
syndrome, only a few instruments have been designed to specifically assess
apathy, and these
insfiuments have not been directly compared. Assessment of apathy in AD
requires clinicians to
distinguish loss of motivation from loss of ability due to cognitive decline.
Although apathy may be
misdiagnosed as depression because of an overlap in symptoms, current research
has shown apathy to
be a discrete syndrome. Distinguishing apathy from depression has important
treatment implications
because these disorders respond to different interventions.
[00245] The Apathy Inventory (IA), a rating scale for global assessment of
apathy and separate
assessment of emotional blunting, lack of initiative, and lack of interest, is
a reliable method for
assessing in demented and non-demented elderly subjects several dimensions of
the apathetic
syndrome, and also the subject's awareness of these symptoms. The IA assesses
apathy as effectively
as the Neuro Psychiatric Inventory apathy domain (Robert et al., The Apathy
Inventory: assessment
89
Date Recue/Date Received 2021-04-14
of apathy and awareness in Alzheimer's disease, Parkinson's disease and mild
cognitive impairment,
the Journal of Geriatric Psychiatry, Volume 17, Issue 12, Pages 1099-1105
(December 2002); Landes
et al., Apathy in Alzheimer's Disease, the Journal of American Geriatric
Society, Volume 49, Issue
12, Pages 1700-1707 (December 2001); Malloy et al., Apathy and Its Treatment
in Alzheimer's
Disease and Other Dementias, Psychiatric Times, Vol. XXII, Issue 13 (November
01, 2005)). Apathy
can be the result of damage to one or more areas of the brain such as the
frontal cortex, the thalamus,
striatum and the amygdala. In most cases direct damage to the frontal lobes or
the subcortical nuclei
that have connections to the frontal lobes, cause apathy. Apathy associated
with Alzheimer's disease
is very difficult to treat. Antidepressants, SSRIs, psychostimulants,
acetylcholinesterase inhibitors etc.
alleviated apathy only to some degree.
[00246] Accordingly, an embodiment of the invention is a combination of DEX
and Formula I, or
DERATINETm, SARPOTINErm, SARPODEXTm, DERADEXTm, or DERAPHANTm ; and one or
more of antidepressants, SSRIs, psychostimulants, acetylcholinesterase
inhibitors, dopaminergic
agents. Another embodiment is a combination of DEX and Formula I, or
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHAN' and one or more of donepezil,
memantine, amantanidine, bupropion, ropinirole, methylphenidate, amphetamine,
modafinil,
metrifonate, tacrine, galantamine, rivastigmine, nefiracetam, ginkgo biloba
extract, etc. (Ruthirakuhan
et al., Pharmacological interventions for apathy in Alzheimer's disease
(Protocol), Cochran Database
of Systemic Studies, 2016, Issue 5. Art. No.: CD012197, Published by John
Wiley & Sons, Ltd.;
Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer
Disease: A Systematic
Review Across Modalities, Journal of Geriatric Psychiatry and Neurology, Vol
30, Issue 1, 2017;
references are).
[00247] Acetylcholinesterase is one of the most prominent constituents of
central cholinergic pathways.
It terminates the synaptic action of acetylcholine through hydrolysis and
yields the choline moiety that
is necessary for transmitter recycling. The pathogenesis of Alzheimer's
disease (AD) has been linked
to a deficiency in the brain neurotransmitter acetylcholine. The efficacy of
acetylcholinesterase
inhibitors (AChEIs) is attained through their augmentation of acetylcholine-
medicated neuron to
neuron transmission. This is accomplished by increasing the concentration of
acetylcholine through
reversible inhibition of its hydrolysis by acetylcholinesterase. (USFDA
Reference ID: 3096907;
Guidance on Donepezil Hydrochloride, Finalized Aug 2017).
[00248] Accordingly, in one embodiment, the composition comprises AChIs such
as 2-((1-
Date Recue/Date Received 2021-04-14
Benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1 -one
(Donepezil), (S)-3 -(1 -
(dim ethylamino)ethyl)phenyl ethyl(methyl) carbamate (Rivastigmine), dimethyl
(2,2,2-trichloro-1-
hydroxyethyl)phosphonate (Metrifonate), dimethyl (2,2,2-trichloro-1-
hydroxyethyl)phosphonate
(Metrifonate),
(4aS,6R,8aS)-3-methoxy-11-m ethy1-4a,5,9,10,11,12-hex ahydro-6H-
b enzo [2,3] b enz ofuro [4,3 -cd] az epin-6- ol (Gal antamine), and 1,2,3 ,4-
tetrahydroacri din-9- ami ne
(Tacrine), 0,S-dimethyl acetylphosphoramidothioate, 0,0-dimethyl S-((4-
oxobenzo[d][1,2,3]triazin-
3(4H)-yl)methyl) phosphorodithioate, 2,2-dimethyl-2,3-dihydrobenzofuran-7-y1
methylcarbamate, S-
(((4-chlorophenyl)thi o)m ethyl) 0,0-diethyl phosphorodithioate,
2-chl oro-1 -(2,4-
di chl orophenyl)vinyl di ethyl phosphate, 0,0-diethyl
043 ,5,6-tri chl oropyri din-2-y1)
phosphorothioate, 0-(3-chloro-4-methy1-2-oxo-2H-chromen-7-y1) 0,0-diethyl
phosphorothioate, 1-
phenylethyl (E)-3-((dimethoxyphosphoryl)oxy)but-2-enoate,4-(tert-buty1)-2-
chlorophenyl methyl
methylphosphoramidate, 0,0-diethyl 0-(2-(ethylthio)ethyl) phosphorothioate,
0,0-diethyl S-(2-
(ethylthi o) ethyl) phosphorothioate, 0,0-diethyl
0-(2-i sopropy1-6-m ethylpyrimi din-4-y
phosphorothioate, 2,2-dichlorovinyl dimethyl phosphate, (E)-4-(dimethylamino)-
4-oxobut-2-en-2-y1
dimethyl phosphate, 0,0-dimethyl S-(24methylamino)-2-oxoethyl)
phosphorodithioate, S,S'-(1,4-
di oxane-2,3-diy1) 0,0,0',O'-tetraethyl bis(phosphorodithi oate), 0,0-diethyl
S-(2-(ethylthi o)ethyl)
phosphorodithioate, 0-ethyl 0-(4-nitrophenyl) phenylphosphonothioate,
0,0,0',0'-tetraethyl S,S'-
methylene bis(phosphorodithioate), 0-ethyl S,S-dipropyl phosphorodithioate, 0-
(4-(N,N-
dimethylsulfamoyl)phenyl) 0,0-dimethyl phosphorothioate, 0-(4-(N,N-
dimethylsulfamoyl)phenyl)
0,0-dimethyl phosphorothioate, ethyl (3-methy1-4-(methylthio)phenyl)
isopropylphosphoramidate,
0,0-dimethyl 0-(3-methy1-4-nitrophenyl) phosphorothioate,
0-ethyl S-phenyl
ethylphosphonodithi oate,
isopropyl 2-((ethoxy(isopropylamino)phosphorothi oyl)oxy)benzoate,
di ethyl 2-((dimethoxyphosphorothi oyl)thi o)succ inate, 0, S-dim ethyl
phosphorami dothi oate, 0, S-
dim ethyl phosphoramidothioate, S-((5-m ethoxy-2- oxo-1,3 ,4-thi adi az 01-3
(2H)-yl)m ethyl) 0,0-
dimethyl phosphorodithioate, methyl 3-((dimethoxyphosphoryl)oxy)but-2-enoate,
(E)-dimethyl (4-
(methylamino)-4-oxobut-2-en-2-y1) phosphate, 1,2-dibromo-2,2-dichloroethyl
dimethyl phosphate,
isopropyl (S)-methylphosphonofluoridate, 3,3-dimethylbutan-2-y1 (S)-
methylphosphonofluoridate,
0,0-diethyl 0-(4-nitrophenyl) phosphorothioate, S-(2-(ethylsulfinyl)ethyl) 0,0-
dimethyl
phosphorothioate, 0,0-diethyl S-((ethylthi o)m ethyl)
phosphorodithioate, S-((6-chl oro-2-
oxobenzo[d] oxazol-3 (2H)-yl)m ethyl) 0,0-diethyl phosphorodithioate, S-((1,3-
di oxoi s oindolin-2-
yl)m ethyl) 0,0-dimethyl phosphorodithioate, (E)-3-chloro-4-(di ethyl amino)-4-
ox obut-2- en-2-y1
91
Date Recue/Date Received 2021-04-14
dimethyl phosphate, 0,0,0',0'-tetramethyl 0,0'-(thiobis(4,1-phenylene))
bis(phosphorothioate),
tetraethyl diphosphate, S-((tert-butylthio)methyl) 0,0-diethyl
phosphorodithioate, 2-chloro-1-(2,4,5-
trichlorophenyl)vinyl dimethyl phosphate, and dimethyl
(2,2,2-trichloro-1-
hydroxyethyl)phosphonate, or pharmaceutically acceptable derivatives,
metabolites, analogs, or salts
thereof.
[00249] Substance abuse and addiction that may be treated by a combination of
DEX and a 5-HT2A
receptor antagonist/inverse agonist such as a compound of formula I includes,
but is not limited to,
drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine,
speed, meth), nicotine,
alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana),
amphetamines, hallucinogens,
phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction
includes nicotine addiction of
all known forms, such as smoking cigarettes, cigars and/or pipes, and
addiction to chewing tobacco.
[00250] Cerebral function disorders that may be treated by a combination of
DEX and a 5-HT2A
receptor antagonist/inverse agonist such as a compound of formula I include,
but are not limited to,
disorders involving intellectual deficits such as vascular dementia,
Alzheimer's type dementia, Lewy
Body Dementia, Fronto-Temporal Lobar Degeneration, memory loss,
amnesia/amnestic syndrome,
epilepsy, disturbances of consciousness, coma, lowering of attention, speech
disorders, voice spasms,
Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome,
and schizophrenia.
Cerebral function disorders also include disorders caused by cerebrovascular
diseases including, but
not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral
arteriosclerosis, cerebral venous
thrombosis, head injuries, and the like where symptoms include disturbance of
consciousness,
dementia, coma, lowering of attention, apathy, and speech disorders.
[00251] Movement disorders that may be treated by a combination of DEX and a 5-
HT2A receptor
antagonist/inverse agonist such as a compound of formula I include, but are
not limited to, akathisia,
akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus,
bradykinesia, cerebral
palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea,
dyskinesia, tardive
dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-
responsive dystonia,
Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor,
Tourette's syndrome, and
Wilson's disease.
[00252] Dementias that may be treated by a combination of DEX and a 5-HT2A
receptor
antagonist/inverse agonist such as a compound of formula I include, but are
not limited to, Alzheimer's
disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies,
mixed dementia, fronto-
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temporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,
Huntington's disease,
Wernicke-Korsakoff Syndrome, and Fronto-Temporal Lobar Degeneration (FTLD).
1002531 Motor neuron diseases that may be treated by a combination of DEX and
a 5-HT2A receptor
antagonist/inverse agonist such as a compound of formula I include, but are
not limited to,
amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral
sclerosis (PLS),
progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular
atrophy (SMA), spinal
motor atrophies, Tay-Sach's disease, Sandhoff disease, and hereditary spastic
paraplegia.
[00254] Neurodegenerative diseases that may be treated by a combination of DEX
and a 5-HT2A
receptor antagonist/inverse agonist such as a compound of formula I include,
but are not limited to
Alzheimer's disease, prion-related diseases, cerebellar ataxia,
spinocerebellar ataxia (SCA), spinal
muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia,
Huntington's disease, Lewy
body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou
Gehrig's disease),
multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome,
corticobasal degeneration,
progressive supranuclear palsy, Wilson's disease, Menkes disease,
adrenoleukodystrophy, cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL),
muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic
paraparesis,
neurofibromatosis, olivopontine cerebellar atrophy or degeneration,
striatonigral degeneration,
Guillain-Barre syndrome, and spastic paraplegia.
[00255] Seizure disorders that may be treated by a combination of DEX and a 5-
HT2A receptor
antagonist/inverse agonist such as a compound of formula I include, but are
not limited to, epileptic
seizures, nonepileptic seizures, epilepsy, febrile seizures; partial seizures
including, but not limited to,
simple partial seizures, Jacksonian seizures, complex partial seizures, and
epilepsia partialis continua;
generalized seizures including, but not limited to, generalized tonic-clonic
seizures, absence seizures,
atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and
infantile spasms; and status
epilepticus.
[00256] Types of headaches that may be treated by a combination of DEX and a 5-
HT2A receptor
antagonist/inverse agonist such as a compound of formula I include, but are
not limited to, migraine,
trigeminal cephalgia, tension, and cluster headaches including Bing-Horton-
Syndrome.
[00257] Other neurological disorders that may be treated by a combination of
DEX and a 5-HT2A
receptor antagonist/inverse agonist such as a compound of formula I, a
derivative, a metabolite or
prodrug of any of these compounds include, Rett Syndrome, autism, tinnitus,
disturbances of
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consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy,
cataplexy; voice
disorders due to uncontrolled laryngeal muscle spasms, including, but not
limited to, abductor
spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia,
and vocal tremor;
diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate
neurotoxicity;
incontinence including, but not limited, stress urinary incontinence, urge
urinary incontinence, and
fecal incontinence; and erectile dysfunction.
[00258] Pain relieving properties of DEX may be enhanced by a method
comprising co-administering
DEX and a 5-1-1T2A receptor antagonist/inverse agonist, such as a compound of
formula I, a
metabolite, a derivative, or prodrug of any of these compounds, with DEX.
[00259] Pain relieving properties of a compound of formula I, may be enhanced
by a method
comprising co-administering DEX with a compound of formula I.
[00260] These methods may be used to treat or provide relief to, any pain
including, but not limited to,
musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain,
nociceptive pain, etc.
[00261] Examples of musculoskeletal pain include low back pain (i.e.
lumbosacral pain), primary
dysmenorrhea, and arthritic pain, such as pain associated with rheumatoid
arthritis, juvenile
rheumatoid arthritis, osteoarthritis, osteoarthosis, axial spondyloarthritis
including ankylosing
spondylitis, etc.
[00262] In some embodiments, a combination a DEX and a 5-HT2A receptor
antagonist/inverse
agonist, such as a compound of formula I, is used for treating chronic
musculoskeletal pain.
[00263] Examples of neuropathic pain include idiopathic and diabetic
peripheral neuropathy, post-
herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb
pain, central pain, etc.
Other causes of neuropathic pain include cancer-related pain, lumbar nerve
root compression, spinal
cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated
neuropathy, and radio-
or chemo-therapy associated neuropathy, etc.
[00264] The term "treating" or "treatment" includes the diagnosis, cure,
mitigation, treatment, or
prevention of disease in man or other animals, or any activity that otherwise
affects the structure or
any function of the body of man or other animals.
[00265] Any 5-HT2A receptor antagonist/inverse agonist may be used in
combination with DEX to
improve the therapeutic properties of DEX. DEX and the 5-HT2A receptor
antagonist/inverse agonist
may be administered in separate compositions or dosage forms, or may be
administered in a single
composition or dosage form comprising both.
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[00266] 5-HT2A receptor antagonist/inverse agonists that can be co-
administered with DEX include,
but are not limited to, a compound of formula I, clomipramine, doxepin,
fluoxetine, mianserin,
imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine,
protriptyline, trimipramine,
nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine,
paroxetine, trazodone,
citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram,
fluvoxamine, venlafaxine,
desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine,
milnacipran,
tesofensine, brasofensine, moclobemide, rasagiline, nialamide, iproniazid,
iproclozide, toloxatone,
butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol,
norfluoxetine, dapoxetine, etc.,
or a metabolite or prodrug of any of these compounds, or a pharmaceutically
acceptable salt of any of
these compounds.
[00267] Combining a compound of formula I, with DEX may provide greater
efficacy, such as greater
pain relief, than would otherwise be achieved by administering either
component alone. In extensive
metabolizers, DEX can be rapidly and extensively metabolized, yielding low
systemic exposure even
at high doses. A compound of formula I, besides possessing antidepressant and
analgesic properties,
is an inhibitor of DEX metabolism. Metabolites of a compound of formula 1,
which include a
compound of formula I, a derivative, a metabolite are also inhibitors of DEX
metabolism. Thus, a
compound of fonnula I, including a form of a compound of formula I, that is
rapidly converted in the
body (such as a salt, hydrate, solvate, polymorph, etc.), is a prodrug a a
compound a formula I.
[00268] As explained above, this inhibition may augment DEX plasma levels,
resulting in additive or
synergistic efficacy such as relief of neurological disorders including pain,
depression, smoking
cessation, etc. Thus, while inhibition of DEX metabolism is only one of many
potential benefits of the
combination, co-administration of DEX with a compound of formula I may thereby
enhance the
efficacy of a compound of formula I, for many conditions. Co-administration of
DEX with a
compound of formula I may enhance the analgesic properties of a compound of
formula I for many
conditions. Co-administration of DEX with a compound of formula I may also
enhance the
antidepressant properties of a compound of formula I for many conditions,
including faster onset of
action.
[00269] Another potential benefit of co-administration of DEX and a compound
of formula I is that it
may be useful to reduce the potential for an adverse event, such as drowsiness
or confusion, associated
with treatment by DEX. This may be useful, for example, in subjects at risk of
experiencing an adverse
event as a result being treated with DEX.
Date Recue/Date Received 2021-04-14
[00270] Another potential benefit of co-administration of DEX and a compound
of formula I is that it
may be useful to reduce the potential for an adverse event, such as seizure,
associated with treatment
by a compound of Formula I. This may be useful, for example, in subjects at
risk of experiencing the
adverse event as a result being treated with a compound of formula I.
[00271] With respect to DEX, a compound of formula I, co-administration may
reduce a central
nervous system adverse event, a gastrointestinal event, or another type of
adverse event associated
with any of these compounds. Central nervous system (CNS) adverse events
include, but are not
limited to, nervousness, dizziness, sleeplessness, light-headedness, tremor,
hallucinations,
convulsions, CNS depression, fear, anxiety, headache, increased irritability
or excitement, tinnitus,
drowsiness, dizziness, sedation, somnolence, confusion, disorientation,
lassitude, incoordination,
fatigue, euphoria, nervousness, insomnia, sleeping disturbances, convulsive
seizures, excitation,
catatonic-like states, hysteria, hallucinations, delusions, paranoia,
headaches and/or migraine, and
extrapyramidal symptoms such as oculogyric crisis, torticollis,
hyperexcitability, increased muscle
tone, ataxia, and tongue protrusion.
[00272] Ciastrointestinal adverse events include, but are not limited to,
nausea, vomiting, abdominal
pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic
ulcers with bleeding,
loose stools, constipation, stomach pain, heartburn, gas, loss of appetite,
feeling of fullness in stomach,
indigestion, bloating, hyperacidity, dry mouth, gastrointestinal disturbances,
and gastric pain.
[00273] Co-administering DEX and a 5-HT2A receptor antagonist/inverse agonist,
such as a compound
of formula I does not necessarily require that the two compounds be
administered in the same dosage
form. For example, the two compounds may be administered in a single dosage
form, or they may be
administered in two separate dosage forms. Additionally, the two compounds may
be administered at
the same time, but this is not required. The compounds can be given at
different times as long as both
are in a human body at the same time for at least a portion of the time that
treatment by co-
administration is being carried out.
[00274] In some embodiments, co-administration of a combination of a compound
of formula I and
DEX results in pain relieving properties. For example, the combination may
have improved pain-
relieving properties as compared to a compound of formula I alone or compared
to DEX alone,
including potentially faster onset of action.
[00275] In some embodiments, the combination may have improved pain relieving
properties of at least
about 0.5%, at least about 1%, at least about 10%, at least about 20%, at
least about 30%, at least about
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Date Recue/Date Received 2021-04-14
50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about
1000%, about 10% to
about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about
50%, about 50%
to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to
about 90%, about
90% to about 100%, about 100% to about 110%, about 110% to about 120%, about
120% to about
130%, about 130% to about 140%, about 140% to about 150%, about 150% to about
160%, about
160% to about 170%, about 170% to about 180%, about 180% to about 190%, about
190% to about
200%, or any amount of pain relief in a range bounded by, or between, any of
these values, as
compared to a compound of formula I alone.
[00276] In some embodiments, the combination may have improved pain relieving
properties of at least
about 0.5%, at least about 1%, at least about 10%, at least about 20%, at
least about 30%, at least about
50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about
1000%, about 10% to
about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about
50%, about 50%
to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to
about 90%, about
90% to about 100%, about 100% to about 110%, about 110% to about 120%, about
120% to about
130%, about 130% to about 140%, about 140% to about 150%, about 150% to about
160%, about
160% to about 170%, about 170% to about 180%, about 180% to about 190%, about
190% to about
200%, or any amount of pain relief in a range bounded by, or between, any of
these values, as
compared to as compared to DEX alone.
[00277] Unless otherwise indicated, any reference to a compound herein, such
as DEX, a compound of
Formula I by structure, name, or any other means, includes pharmaceutically
acceptable salts; alternate
solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers;
deuterium-modified compounds,
such as deuterium-modified DEX and a compound of formula I; or any chemical
species that may
rapidly convert to a compound described herein under conditions in which the
compounds are used as
described herein. Examples of deuterium modified DEX and a compound of formula
I, include, but
are not limited to, those shown below.
[00278] A dosage form or a composition may be a blend or mixture of DEX and a
compound that
inhibits the metabolism of DEX, such as a compound of formula I, either alone
or within a vehicle.
For example, DEX and a compound of formula I, may be dispersed within each
other or dispersed
together within a vehicle. A dispersion may include a mixture of solid
materials wherein small
individual particles are substantially one compound, but the small particles
are dispersed within one
another, such as might occur if two powders of two different drugs are blended
with a solid vehicle
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Date Recue/Date Received 2021-04-14
material, and the blending is done in the solid form. In some embodiments, DEX
and a compound of
formula I, may be substantially uniformly dispersed within a composition or
dosage form.
Alternatively, DEX and a compound of formula I, may be in separate domains or
phases in a
composition or dosage form. For example, one drug may be in a coating, and
another drug may be in
a core within the coating. For example, one drug may be formulated for
sustained release and another
drug may be formulated for immediate release.
[00279] Some embodiments include administration of a tablet that contains a
compound of formula I
in a form that provides sustained release and DEX in a form that provides
immediate release or vice
versa. While there are many ways that sustained release of a compound of
formula I, may be achieved,
in some embodiments, a compound of formula I is combined with hydroxypropyl
methylcellulose.
For example, particles of a compound of formula I hydrochloride could be
blended with
microcrystalline cellulose and hydroxypropyl methylcellulose (e.g.,
METHOCELTm) to form an
admixture of blended powders. This could then be combined with immediate
release DEX in a single
tablet.
[00280] DEX and/or a 5-HT2A receptor antagonist/inverse agonist such as a
compound of formula 1
may be combined with a pharmaceutical carrier selected on the basis of the
chosen route of
administration and standard pharmaceutical practice as described, for example,
in Remington's
Pharmaceutical Sciences, 2005. The relative proportions a active ingredient
and carrier may be
determined, for example, by the solubility and chemical nature of the
compounds, chosen route of
administration and standard pharmaceutical practice.
[00281] Therapeutic compounds may be administered by any means that may result
in the contact of
the active agent(s) with the desired site or site(s) of action in the body of
a patient. The compounds
may be administered by any conventional means available for use in conjunction
with
pharmaceuticals, either as individual therapeutic agents or in a combination
of therapeutic agents. For
example, they may be administered as the sole active agents in a
pharmaceutical composition, or they
can be used in combination with other therapeutically active ingredients.
[00282] Therapeutic compounds may be administered to a subject in a variety of
forms adapted to the
chosen route of administration, e.g., orally or parenterally. Parenteral
administration in this respect
includes administration by the following routes: intravenous, intramuscular,
subcutaneous,
intraocular, intrasynovial, transepithelial, including transdermal,
ophthalmic, sublingual and buccal;
topically including ophthalmic, dermal, ocular, rectal and nasal inhalation
via insufflation, aerosol and
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Date Recue/Date Received 2021-04-14
rectal systemic.
[00283] The ratio of DEX to a compound of formula I may vary. In some
embodiments, the weight
ratio of DEX to a compound of formula I, may be about 0.1 to about 10, about
0.1 to about 2, about
0.2 to about 1, about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to
about 0.4, about 0.3 to about
0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about
0.4, about 0.45, about 0.6,
about 0.9, or any ratio in a range bounded by, or between, any of these
values. A ratio of 0.1 indicates
that the weight of DEX is 1/10 that of a compound of formula I. A ratio of 10
indicates that the weight
of DEX is 10 times that of a compound of formula I.
[00284] The amount of DEX in a therapeutic composition may vary. For example,
some liquid
compositions may comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01%
(w/v) to about
20% (w/v), about 0.01% to about 10% (w/v), about 0.001% (w/v) to about 1%
(w/v), about 0.1% (w/v)
to about 0.5% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about
5% (w/v), about 5%
(w/v) to about 7% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to
about 15% (w/v),
about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about
30% (w/v) to about
40% (w/v), or about 40% (w/v) to about 50% (w/v) of DEX.
[00285] Some liquid dosage forms may contain about 10 mg to about 500 mg,
about 30 mg to about
350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg
to about 50 mg,
about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about
42 mg, about 42 mg
to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about
48 mg to about 50
mg, about 80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to
about 190 mg,
about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of DEX,
or any amount of
DEX in a range bounded by, or between, any of these values.
[00286] Some solid compositions may comprise at least about 5% (w/w), at least
about 10% (w/w), at
least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at
least about 80%, about
10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20%
(w/w) to about
30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%
(w/w), about 40%
(w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w)
to about 60%
(w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90%
(w/w) of DEX.
[00287] Some solid dosage forms may contain about 10 mg to about 500 mg, about
30 mg to about 350
mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to
about 50 mg, about 40
mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg,
about 46 mg to about
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48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to
about 70 mg, about
80 mg to about 100 mg, about 110 mg to about 130 mg, about 170 mg to about 190
mg, about 60 mg,
about 90 mg, about 120 mg, or about 180 mg of DEX, or any amount of DEX in a
range bounded by,
or between, any of these values.
[00288] The amount of a compound of formula I, in a therapeutic composition
may vary. If increasing
the plasma level of DEX is desired, a compound of formula I should be
administered in an amount
that increases the plasma level of DEX. For example, a compound of formula
Iõmay be administered
in an amount that results in a plasma concentration of DEX in the subject, on
day 8, that is at least
about 2 times, at least about 5 times, at least about 10 times, at least about
15 times, at least about 20
times, at least about 30 times, at least about 40 times, at least about 50
times, at least about 60 times,
at least about 70 times, or at least about 80 times, the plasma concentration
of the same amount of
DEX administered without a compound of formula I.
[00289] In some embodiments, a compound of formula I, may administered to a
subject in an amount
that results in a 12 hour area under the curve from the time of dosing
(AUC0_12), or average plasma
concentration in the subject for the 12 hours following dosing (Cavg) of DEX,
on day 8, that is at least
about 2 times, at least about 5 times, at least about 10 times, at least about
15 times, at least about 20
times, at least about 30 times, at least about 40 times, at least about 50
times, at least about 60 times,
at least about 70 times, or at least about 80 times the plasma concentration
of the same amount of DEX
administered without a compound of formula I.
[00290] In some embodiments, a compound of formula I, may administered to a
subject in an amount
that results in a maximum plasma concentration (C.) of DEX in the subject, on
day 8, that is at least
about 2 times, at least about 5 times, at least about 10 times, at least about
15 times, at least about 20
times, at least about 30 times, or at least about 40 times the plasma
concentration of the same amount
of DEX administered without a compound of formula I.
[00291] For co-administration of a compound of formula I, an increase in the
DEX plasma level can
occur on the first day that a compound of formula I is administered, as
compared to the same amount
of DEX administered without a compound of formula I. For example, the DEX
plasma level on the
first day that a compound of formula I is administered may be at least about
1.5 times, at least about
at least 2 times, at least about 2.5 times, at least about 3 times, at least
about 4 times, at least about 5
times, at least about 6 times at least about 7 times, at least about 8 times,
at least about 9 times, or at
least about 10 times the level that would be achieved by administering the
same amount of DEX
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Date Recue/Date Received 2021-04-14
without a compound of formula I.
[00292] In some embodiments, the DEX AUC on the first day that a compound of
formula I is
administered may be at least twice the AUC that would be achieved by
administering the same amount
of DEX without a compound of formula I.
[00293] In some embodiments, the DEX Cmax on the first day that a compound of
formula I is
administered may be at least twice the Cmax that would be achieved by
administering the same amount
of DEX without a compound of formula I.
[00294] In some embodiments, the DEX trough level (e.g., plasma level 12 hours
after administration)
on the first day that a compound of formula I is administered may be at least
twice the trough level
that would be achieved by administering the same amount of DEX without a
compound of formula I.
[00295] In some embodiments, a compound of formula I is administered on the
first day of at least two
days of treatment with DEX, wherein a decrease in the DO plasma level occurs
on the first day that a
compound of formula I and DEX are co-administered, as compared to the same
amount of DEX
administered without a compound of formula I. For example, the DO plasma level
on the first day may
be reduced by at least 5% as compared to the DO plasma level that would be
achieved by administering
the same amount of DEX without a compound of formula I.
[00296] In some embodiments, a compound of formula I and DEX are co-
administered for at least five
consecutive days, to a subject in need a treatment with DEX, wherein, on the
fifth day, the DEX
plasma level is higher than the DEX plasma level that would have been achieved
by administering the
same amount of DEX administered without a compound of formula I, for five
consecutive days. For
example, the DEX plasma level on the fifth day (for example at 0 hours, 1
hour, 3 hours, 6 hours, or
12 hours after administration) may be at least 5 times, at least 10 times, at
least 20 times, at least 40
times, at least 50 times, at least 60 times, at least 65 times, or up to about
500 times, the level that
would be achieved by administering the same amount of DEX without a compound
of formula I, for
five consecutive days.
[00297] In some embodiments, a compound of formula I and DEX are co-
administered for at least six
consecutive days, to a subject in need of treatment with DEX, wherein, on the
sixth day, the DEX
plasma level is higher than the DEX plasma level that would have been achieved
by administering the
same amount of DEX administered without a compound of formula I, for six
consecutive days. For
example, the DEX plasma level on the sixth day (for example at 0 hours, 1
hour, 3 hours, 6 hours, or
12 hours after administration) may be at least 5 times, at least 10 times, at
least 20 times, at least 30
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Date Recue/Date Received 2021-04-14
times, at least 50 times, at least 60 times, at least 70 times, at least 75
times, or up to about 500 times,
the level that would be achieved by administering the same amount of DEX
without a compound of
formula I, for six consecutive days.
[00298] In some embodiments, a compound of formula I and DEX are co-
administered for at least
seven consecutive days, to a subject in need of treatment with DEX, wherein,
on the seventh day, the
DEX plasma level is higher than the DEX plasma level that would have been
achieved by
administering the same amount of DEX administered without a compound of
formula I, for seven
consecutive days. For example, the DEX plasma level on the seventh day (for
example at 0 hours, 1
hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5
times, at least 10 times, at
least 20 times, at least 30 times, at least 50 times, at least 70 times, at
least 80 times, at least 90 times,
or up to about 500 times, the level that would be achieved by administering
the same amount of DEX
without a compound of formula I, for seven consecutive days.
[00299] In some embodiments, a compound of formula I and DEX are co-
administered for at least eight
consecutive days, wherein, on the eighth day, DEX has a plasma level, for
example at 0 hours, 1 hour,
3 hours, 6 hours, or 12 hours, after co-administering a compound of formula 1
with DEX that is at least
5 times, at least 10 times, at least 20 times, at least 30 times, at least 50
times, at least 60 times, at least
70 times, at least 80 times, at least 90 times, at least 100 times, or up to
about 1,000 times, the plasma
level that would be achieved by administering the same amount a DEX without a
compound of
formula I for eight consecutive days.
[00300] In some embodiments, a compound of formula I and DEX are co-
administered for at least eight
consecutive days, to a subject in need of treatment with DEX, wherein, on the
eighth day, the DO
plasma level is lower than the DO plasma level that would have been achieved
by administering the
same amount of DEX administered without a compound of Formula I for eight
consecutive days. For
example, the DO plasma level on the eighth day (for example at 0 hours, 1
hour, 3 hours, 6 hours, or
12 hours after administration) may be reduced by at least 10%, at least 20%,
at least 30%, at least 40%,
or at least 50%, as compared to the DO plasma level that would be achieved by
administering the same
amount of DEX without a compound of formula I for eight consecutive days.
[00301] In some embodiments, a compound of formula I may be administered to a
subject in an amount
that results in an AUG42 of a compound of formula I in the subject, on day 8,
that is at least about
100 nghr/mL, at least about 200 nghr/mL, at least about 500 nghr/mL, at least
about 600 nghr/mL, at
least about 700 nghr/mL, at least about 800 nghr/mL, at least about 900
nghr/mL, at least about 1,000
102
Date Recue/Date Received 2021-04-14
nghr/mL, at least about 1,200 nghr/mL, at least 1,600 nghr/mL, or up to about
15,000 nghr/mL.
[00302] In some embodiments, a compound of formula I may be administered to a
subject in an amount
that results in a Cavg of a compound of formula I in the subject, on day 8,
that is at least about 10
ng/mL, at least about 20 ng/mL, at least about 40 ng/mL, at least about 50
ng/mL, at least about 60
ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90
ng/mL, at least about 100
ng/mL, at least 120 ng/mL, or up to about 1,500 ng/mL.
[00303] Some liquid compositions may comprise about 0.0001% (w/v) to about 50%
(w/v), about
0.01% (w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 1% (w/v)
to about 3% (w/v),
about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 5%
(w/v) to about 15%
(w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v),
about 15% (w/v) to
about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about
40% (w/v), or about
40% (w/v) to about 50% (w/v) of a compound of Formula I or any amount of a
compound of Formula
I, in a range bounded by, or between, any of these values.
[00304] Some liquid dosage forms may contain about 10 mg to about 1000 mg,
about 50 mg to about
1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg
to about 90 mg,
about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to
about 200 mg, about
105 mg to about 200 mg, about 110 mg to about 140 mg, about 180 mg to about
220 mg, about 280
mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of a compound
a Formula I, or
any amount of a compound of Formula I, in a range bounded by, or between, any
of these values.
[00305] Some solid compositions may comprise at least about 5% (w/w), at least
about 10% (w/w), at
least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at
least about 80%, about
10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20%
(w/w) to about
30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%
(w/w), about 40%
(w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w)
to about 60%
(w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90%
(w/w) of a compound
of Formula I, or any amount of a compound of Formula I, in a range bounded by,
or between, any of
these values.
[00306] Some solid dosage forms may contain about 10 mg to about 1000 mg,
about 50 mg to about
1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg
to about 90 mg,
about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to
about 200 mg, about
105 mg to about 200 mg, about 110 mg to about 140 mg, about 50 mg to about 150
mg, about 180 mg
103
Date Recue/Date Received 2021-04-14
to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or
about 300 mg of a
compound of Formula I, or any amount of a compound of Formula I, in a range
bounded by, or
between, any of these values.
[00307] In some embodiments, a compound of Formula I is administered at a dose
that results in a a
compound of Formula I, plasma level of about 0.1 M to about 10 M, about 0.1
M to about 5 M,
about 0.2 M to about 3 1.1M, 0.1 M to about 11.1M, about 0.2 1.1M to about 2
1.1M, 11.1M to about 10
1.1M, about 1 M to about 5 M, about 2 M to about 3 M, or about 2.8 M to
about 3 M, about 1.5
M to about 2 M, about 4.5 M to about 5 M, about 2.5 M to about 3 M, about
1.8 M, about
4.8 p4, about 2.9 M, about 2.8 M, or any plasma level in a range bounded by,
or between, any of
these values.
[00308] In some embodiments, a compound of Formula I may be administered to a
subject in an
amount that results in an AUC0_12 of a compound of Formula I in the subject,
on day 8, that is at least
about 200 nghr/mL, at least about 400 nghr/mL, at least about 700 nghr/mL, at
least about 1,000
nghr/mL, at least about 3,000 nghr/mL, at least about 7,000 nghr/mL, at least
about 10,000 nghr/mL,
at least about 15,000 nghr/mL, at least about 20,000 nghr/mL, at least about
30,000 nghr/mL, up to
about 50,000 nghr/mL, up to about 150,000 nghr/mL, or any AUC in a range
bounded by, or between,
any of these values.
[00309] In some embodiments, a compound a Formula I is administered to a
subject in an amount
that results in a C. of a compound of Formula I in the subject, on day 8, that
is at least about 20
ng/mL, at least about 60 ng/mL, at least about 90 ng/mL, at least about 100
ng/mL, at least about 150
ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up to about 1,000
ng/mL, at least about
4,000 ng/mL, up to about 10,000 ng/mL, up to about 50,000 ng/mL, or any C. in
a range bounded
by, or between, any of these values.
[00310] In some embodiments, a compound of Formula I is administered to a
subject in an amount
that results in a Cavg of a compound of Formula I in the subject, on day 8,
that is at least about 20
ng/mL, at least about 30 ng/mL, at least about 50 ng/mL, at least about 80
ng/mL, at least about 90
ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200
ng/mL, at least about
300 ng/mL, up to about 1,000 ng/mL, up to about 5,000 ng/mL, up to about
30,000 ng/mL, or any Cavg
in a range bounded by, or between, any of these values.
[00311] For compositions comprising both DEX and a compound of Formula I some
liquids may
comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01% (w/v) to about
20% (w/v), about
104
Date Recue/Date Received 2021-04-14
0.01% to about 10% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to
about 5% (w/v),
about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7%
(w/v) to about 10%
(w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v),
about 20% (w/v) to
about 30% (w/v), about 30% (w/v) to about 40% (w/v), about 40% (w/v) to about
50% (w/v) of DEX
and a compound of Formula I combined, or any amount in a range bounded by, or
between, any of
these values. Some solid compositions may comprise at least about 5% (w/w), at
least about 10%
(w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70%
(w/w), at least about
80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w),
about 20% (w/w)
to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to
about 40% (w/w),
about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about
50% (w/w) to
about 60% (w/w), about 70% (w/w) to about 80% (w/w), about 80% (w/w) to about
90% (w/w) of
DEX and a compound of Formula I combined, or any amount in a range bounded by,
or between, any
of these values. In some embodiments, the weight ratio of DEX to a compound of
Formula I in a
single composition or dosage form may be about 0.1 to about 2, about 0.2 to
about 1, about 0.1 to
about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about
0.7, about 0.8 to about 1,
about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any
ratio in a range bounded by,
or between, any of these values.
1003121 A therapeutically effective amount a a therapeutic compound may vary
depending upon the
circumstances. For example, a daily dose of DEX may in some instances range
from about 0.1 mg to
about 1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg,
about 60 mg to about
700 mg, about 100 mg to about 400 mg, about 15 mg to about 20 mg, about 20 mg
to about 25 mg,
about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about
40 mg, about 40 mg
to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about
55 mg to about 60
mg, about 20 mg to about 60 mg, about 60 mg to about 100 mg, about 100 mg to
about 200 mg, about
100 mg to about 140 mg, about 160 mg to about 200 mg, about 200 mg to about
300 mg, about 220
mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg to about 380
mg, about 400 mg to
about 500 mg, about 500 mg to about 600 mg, about 15 mg, about 30 mg, about 60
mg, about 120 mg,
about 180 mg, about 240 mg, about 360 mg, or any daily dose in a range bounded
by, or between, any
of these values. DEX may be administered once daily; or twice daily or every
12 hours, three times
daily, four times daily, or six times daily in an amount that is about half,
one-third, one-quarter, or
one-sixth, respectively, of the daily dose.
105
Date Recue/Date Received 2021-04-14
[00313] A daily dose of a compound of Formula I may in some instances range
from about 10 mg to
about 1000 mg, about 50 mg to about 600 mg, about 100 mg to about 2000 mg,
about 50 mg to about
100 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg
to about 200 mg,
about 100 mg to about 150 mg, about 150 mg to about 300 mg, about 150 mg to
about 200 mg, about
200 mg to about 250 mg, about 250 mg to about 300 mg, about 200 mg about 300
mg, about 300 mg
to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 600 mg,
about 360 mg to
about 440 mg, about 560 mg to about 640 mg, or about 500 mg to about 600 mg,
about 100 mg, about
150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or any daily
dose in a range
bounded by, or between, any of these values, a compound of Formula I may be
administered once
daily; or twice daily or every 12 hours, or three times daily in an amount
that is about half or one-third,
respectively, of the daily dose.
[00314] In some embodiments: 1) about 50 mg/day to about 100 mg/day, about 100
mg/day to about
150 mg/day, about 150 mg/day to about 300 mg/day, about 150 mg/day to about
200 mg/day, about
200 mg/day to about 250 mg/day, about 250 mg/day to about 300 mg/day of a
compound of Formula
1 or about 300 mg/day to about 500 mg/day of a compound of Formula 1; and/or
2) about 15 mg/day
to about 60 mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to
about 45 mg/day, about
45 mg/day to about 60 mg/day, about 60 mg/day to about 100 mg/day, about 80
mg/day to about 110
mg/day, about 100 mg/day to about 150 mg/day, or about 100 mg/day to about 300
mg/day of DEX,
are administered to a subject in need thereof.
[00315] In some embodiments, about 150 mg/day of a compound of Formula I and
about 30 mg/day
of DEX, about 150 mg/day of a compound of Formula I and about 60 mg/day of
DEX, about 150
mg/day of a compound of Formula I and about 90 mg/day of DEX, about 150 mg/day
of a compound
of Formula I and about 120 mg/day of DEX, about 200 mg/day of a compound of
Formula I and
about 30 mg/day of DEX, about 200 mg/day of a compound of Formula I and about
60 mg/day of
DEX, about 200 mg/day of a compound of Formula I and about 90 mg/day of DEX,
about 200 mg/day
of a compound of Formula I and about 120 mg/day of DEX, about 300 mg/day of a
compound of
Formula I and about 30 mg/day of DEX, about 300 mg/day of a compound of
Formula I and about
60 mg/day of DEX, about 300 mg/day of a compound of Formula I and about 90
mg/day of DEX, or
about 300 mg/day of a compound of Formula I and about 120 mg/day of DEX is
administered to the
subject.
[00316] In some embodiments, about 100 mg/day of a compound of Formula I and
about 15 mg/day
106
Date Recue/Date Received 2021-04-14
of DEX is administered to the subject for 1,2, or 3 days, followed by about
200 mg/day of a compound
of Formula I and about 30 mg/day of DEX. In some embodiments, about 100 mg/day
of a compound
of Formula I and about 30 mg/day of DEX is administered to the subject for 1,
2, or 3 days, followed
by about 200 mg/day of a compound of Formula I and about 60 mg/day of DEX.
[00317] In some embodiments, about 75 mg/day of a compound of Formula I and
about 15 mg/day of
DEX is administered to the subject for 1, 2, or 3 days, followed by about 150
mg/day of a compound
of Formula I and about 30 mg/day of DEX. In some embodiments, about 75 mg/day
of a compound
of Formula I and about 30 mg/day of DEX is administered to the subject for 1,
2, or 3 days, followed
by about 150 mg/day of a compound of Formula I and about 60 mg/day of DEX.
[00318] A 5-HT2A receptor antagonist/inverse agonist, such as a compound of
Formula I may be
administered for as long as needed to treat a neurological condition, such as
pain, depression or cough.
In some embodiments, a 5-HT2A receptor antagonist/inverse agonist, such as a
compound of Formula
I and DEX are administered at least once a day, such as once daily or twice
daily, for at least 1 day, at
least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14
days, at least 30 days, at least 60
days, at least 90 days, at least 180 days, at least 365 days, or longer.
[00319] Therapeutic compounds may be formulated for oral administration, for
example, with an inert
diluent or with an edible carrier, or it may be enclosed in hard or soft shell
gelatin capsules, compressed
into tablets, or incorporated directly with the food of the diet. For oral
therapeutic administration, the
active compound may be incorporated with an excipient and used in the form of
ingestible tablets,
buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and
the like.
[00320] Tablets, troches, pills, capsules and the like may also contain one or
more of the following: a
binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient,
such as dicalcium
phosphate; a disintegrating agent such as corn starch, potato starch, alginic
acid, and the like; a
lubricant such as magnesium stearate; a sweetening agent such as sucrose,
lactose, or saccharin; or a
flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
When the dosage unit form
is a capsule, it may contain, in addition to materials of the above type, a
liquid carrier. Various other
materials may be present as coating, for instance, tablets, pills, or capsules
may be coated with shellac,
sugar or both. A syrup or elixir may contain the active compound, sucrose as a
sweetening agent,
methyl and propylparabens as preservatives, a dye and flavoring, such as
cherry or orange flavor. It
may be desirable for material in a dosage form or pharmaceutical composition
to be pharmaceutically
pure and substantially nontoxic in the amounts employed.
107
Date Recue/Date Received 2021-04-14
[00321] Some compositions or dosage forms may be a liquid or may comprise a
solid phase dispersed
in a liquid.
[00322] Therapeutic compounds may be formulated for parenteral or oral
administration. Solutions of
the active compounds as free bases or pharmacologically acceptable salts can
be prepared in water
suitably mixed with a surfactant, such as hydroxypropylcellulose. A dispersion
can also have an oil
dispersed within, or dispersed in, glycerol, liquid polyethylene glycols, and
mixtures thereof. Under
ordinary conditions of storage and use, these preparations may contain a
preservative to prevent the
growth of microorganisms.
[00323] Although dementias such as Alzheimer's disease (AD) are characterized
by cognitive deficits,
neuropsychiatric symptoms (behavioral and psychological symptoms of dementia,
BPSD) are among
the main drivers for caregiver burden and hospitalization. Frequency of BPSD
symptoms increases
with the disease progression (e.g. up to 60% in mild and moderate AD and up to
90% in severe AD).
[00324] Currently marketed dementia therapies leave much room for improvement
when it comes to
treat BPSD but also other non-cognitive areas of concern. In the continued
absence of a disease-
modifying therapy, this is of increasing importance, as symptoms like
hostility, aggression, wandering,
sexually inappropriate behavior or incontinence pose major problems to
caregivers and families, and
are predictors for (costly) nursing home placement.
[00325] It is common global practice to prescribe (typical or atypical)
neuroleptics to facilitate nursing
and caregiving. However, the FDA has determined that off-label prescription of
neuroleptics poses a
major threat to the health of demented subjects, and has issued a black box
warning, citing severe
cardiovascular adverse events and an increased risk for death. EU approval of
risperidone allows for
short-term use in moderate-severe AD patients only in case of harm to self or
others. In Parkinson's
Disease, the anticholinergic effects of neuroleptics are highly unwanted as
they inevitably worsen, in
addition, the motor condition and symptoms of the vegetative nervous system.
In all dementias,
lowering the seizure threshold is another infrequent but highly unwanted
potential adverse effect of
neuroleptics. These concerns about the use of neuroleptic drugs in dementias
result in decreased use
of neuroleptics in this category of patients leaving BPSD symptoms in the vast
majority of mild-to-
moderate AD patients essentially untreated.
[00326] Accordingly, several embodiments are novel compositions and methods
useful in the
symptomatic and disease-modifying treatment of neurodegenerative diseases and
brain injuries
including sequelae thereof like organic brain syndrome and chronic traumatic
encephalopathies;
108
Date Recue/Date Received 2021-04-14
chronic or intractable pain, ophthalmologic indications associated with
retinopathies, anxiety
disorders, post-traumatic stress disorder, depression, diabetes mellitus and
it's complications like
peripheral neuropathies with or without neuropathic pain, Buerger's disease,
Raynaud's disease,
coronary artery disease, angina pectoris, atherosclerosis including CNS like
multi-infarct dementia,
Vascular Cognitive Impairment, Vascular Dementia or Binswanger's Disease, and
nephropathies.
1003271 In a first aspect, provided is a method of increasing the metabolic
lifetime of DEX, comprising
administering 5-HT2A receptor antagonist/inverse agonist of Formula I to a
subject in need of
treatment with DEX, wherein 5-HT2A receptor antagonist/inverse agonist is an
inhibitor of a CYP2D6
enzyme and wherein DEX is present in the body of the subject at the same time
as Ml.
[00328] In a second aspect, provided is a method of preventing adverse events
associated with treatment
by DEX, comprising co-administering 5-HT2A receptor antagonist/inverse agonist
of Formula Ito a
subject in need of treatment with DEX, wherein the subject is at risk of
experiencing the adverse event
as a result of being treated with DEX.
[00329] In a third aspect, provided is a method for using 5HT2A receptor
antagonists of Formula Ito
improve the therapeutic properties of DEX in the treatment of neuropsychiatric
disorders.
[00330] In a fourth aspect, provided is a method of treating a
neuropsychiatric disorder comprising
administering a 5HT2A receptor antagonist of Formula I and DEX to a subject in
need thereof.
[00331] In an embodiment of the first, second, third and fourth aspects, 5-
HT2A receptor
antagonist/inverse agonist is a prodrug of M1 such as a compound of Formula I
or pharmaceutically
acceptable salts thereof.
[00332] In an embodiment of the first, second and third aspects, 5-HT2A
receptor antagonist/inverse
agonist is an enantiomer of M1 such as (R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl) phenoxy)
propan-2-ol) or (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-
2-ol), or
pharmaceutically acceptable salts thereof.
[00333] In an embodiment of the third and fourth aspects, the neuropsychiatric
disorder is Alzheimer's
disease.
[00334] In a fifth aspect, provided is a method for selecting a 5-HT2A
receptor antagonist/inverse
agonist for the use in combination with DEX in subjects in need thereof.
[00335] In an embodiment of the fifth aspect, a specific enantiomer of a 5HT2A
receptor antagonist
with potent CYP2D6 inhibitory activity has higher blood-brain barrier
penetration.
109
Date Recue/Date Received 2021-04-14
[00336] In an embodiment of the fifth aspect, a specific enantiomer of an
5HT2A receptor antagonist
with potent CYP2D6 inhibitory activity has a better ratio of central vs
peripheral effects when
administered in combination with DEX, wherein central effects are assessed by
direct or indirect
5HT2A receptor engagement methods while peripheral effects are assessed by
methods based on blood
glucose measurement.
[00337] In an embodiment of the fifth aspect, DEX and the selected 5-HT2A
antagonist are
administered in a combined dose, and wherein the amount of DEX administered
comprises from about
20 mg/day to about 80 mg/day.
[00338] In an embodiment of the fifth aspect, DEX is administered in a
combined dose with a selected
enantiomer of Ml, wherein the amount of the M1 enantiomer administered
comprises from about 0.1
mg/day to about 1000 mg/day.
[00339] An embodiment of the invention is a method to augment therapeutic
properties of DEX by
administering it with a 5HT2A receptor antagonist that has potent CYP2D6
inhibitory activity, and
multiple therapeutic benefits of its own.
[00340] Some embodiments include a method of treating a disease or disorder
comprising
administering about 5 mg/day to about 600 mg/day, about 5 mg/day to about 300
mg/day, about 5
mg/day to about 400 mg/day, about 5 mg/day to about 500 mg/day, about 5 mg/day
to about 600
mg/day, about 5 mg/day to about 1,000 mg/day, about 50 mg/day to about 1000
mg/day, about 100
mg/day to about 1000 mg/day, about 150 mg/day to about 1000 mg/day, about 150
mg/day to about
5000 mg/day, about 150 mg/day to about 300 mg/day, or about 150 mg/day to
about 100 mg/day, or
an amount as required of a compound of Formula I and about 0.1 mg/day to about
1 mg/day, about
0.5 mg/day to about 15 mg/day, about 15 mg/day to about 60 mg/day, about 15
mg/day to about 120
mg/day, about 0.1 mg/day to about 200 mg/day, or any amount of a compound of
Formula I in a range
bounded by, or between, any of these values, or an amount as required of DEX
to a subject in need
thereof.
[00341] Borodkin, Book chapter: Ion-exchange resin delivery system, in
"Polymers for Controlled
Drug Delivery", Tarcha, P J, Ed., CRC Press, Boca Raton, 1990). The
composition of the present
invention can be formulated into any pharmaceutical dosage forms for oral,
topical, rectal, vaginal,
nasal, or ophthalmic administration, and include . syrups and suspensions,
usingcommonly known
ingredients and procedures and methods (US4,221,778, US4,762,709, US4,788,055,
US4,959,219,
US4,996,047, US5,071,646, and US5,186,930; Borodkin, Book chapter: Ion-
exchange resin delivery
110
Date Recue/Date Received 2021-04-14
system, in "Polymers for Controlled Drug Delivery", Tarcha, P J, Ed., CRC
Press, Boca Raton, 1990)
can be used to formulate the compositions of the invention.
[00342] The present invention can be formulated into any pharmaceutical dosage
forms for oral, topical,
rectal, vaginal, nasal, or ophthalmic administration, and include. syrups and
suspensions, and
ommonly known ingredients and procedures to formulate pharmaceutical
composition are within the
purview of a person skilled in the art, including various known methods
(US4,221,778, US4,762,709,
US4,788,055, US4,959,219, US4,996,047, US5,071,646, US4,221,778, and
US5,186,930 ),
can be used to formulate the composition of the
invention.
[00343] The oral formulations and the tablet formulations include enteric
coating layered formulations
that comprise a separating layer to separate the acidic enteric coating
material from omeprazole being
an acid susceptible substance. HPC or other suitable polymers disclosed herein
may be used in a layer
that separates the core material from the enteric coating layer in the
described formulations.
SYNTHETIC METHODS
[00344] SGL hydrochloride (CAS NO.: 135159-51-2), with its systematic name of
Butanedioic acid,
m on o(2-(di m ethyl am i n o)-1 -((2-(2-(3-m ethox yphen yl) ethyl) ph en
oxy) methyl) ethyl) ester,
hydrochloride, could be produced through many synthetic methods (Chen et al.,
A practical synthesis
of sarpogrelate hydrochloride and in vitro platelet aggregation inhibitory
activities of its analogues,
Chinese Chemical Letters, Volume 21, Issue 3, March 2010, Pages 287-28; J Med
Chem 33(6) (1990);
CN103242179 A; W02015008973).
[00345] The reaction of 2-hydroxy-3'-methoxybibenzyl with epichlorohydrin by
means of a base in a
suitable solvent gives 2-(2,3-epoxypropoxy)-3'-methoxybibenzyl, which by
reaction with
dimethylamine in refluxing in a suitable solvent yields 243-(dimethylamino)-2-
hydroxypropoxy]-3'-
methoxybibenzyl. Finally, this compound is treated with succinic anhydride
while refluxing in a
suitable solvent with an acid.
.1-
v ----
Skireme Sthemelb
17,NILTUF
H ja? OH
,,,,C0cf
N.PTIekt.
Cawood 50 Comromd 50
111
Date Recue/Date Received 2022-05-04
[00346] As shown in the scheme below, the reaction of 2-hydroxy-31-methoxybib
enzyl with
epichlorohydrin by means of a base NaH in DMF gives 2-(2,3-epoxypropoxy)-3'-
methoxybibenzyl,
which by reaction with dimethylamine in refluxing THF yields 2-[3-
(dimethylamino)-2-
hydroxypropoxy]-3'-methoxybibenzyl. Finally, this compound is treated with
succinic anhydride in
refluxing THF and with HC1 in acetone (J Med Chem 33(6) (1990)).
1003471 SGL hydrochloride was synthesized with about 46% overall yield from
salicylicaldehyde via
benzyl protection, reduction, chlorination, Arbuzov reaction, Wittig-Horner
reaction, catalytic
hydrogenation to give 2-2-(3-methoxyphenyl)ethyl phenol, which was subjected
to react with
epichlorohydrin, amination, esterification and salt formation.
[00348] SGL hydrochloride drug substance used in the preparation SGL
hydrochloride tablets needed
to achieve acceptable purity, single hetero content must meet the
corresponding requirements.
US4485258 discloses a synthesis method of the first SGL hydrochloride, and
recrystallized from
acetone to obtain, but the experiments show that SGL hydrochloride poor
solubility in acetone,
acetone, hydrochloric acid is not suitable as a recrystallization solvent SGL.
CN101239920A disclosed
as acetonitrile, propionitrile, 1,4-dioxane, tetrahydrofuran, dimethyl
formamide, dimethyl acetamide,
sulfolane, dimethyl sulfoxide or a mixture of more than two kinds thereof with
methanol, ethanol,
acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be
used as the recrystallization
solvent SGL hydrochloride, the purity of the product can reach 98%. And C2-10
alkanes, C3-10 ketones,
C2_10 carboxylic acid esters, C1_10 halogenated alkanes, aromatic hydrocarbons
or aromatic derivative
at room temperature to the reflux temperature of the hydrochloric acid
solubility is small should not
alone SGL as a recrystallization solvent, SGL hydrochloride, and water as a
recrystallization solvent
or an organic solvent, an aqueous 5% or more cannot be obtained a high purity
product. Existing
literature does not mention the issue of a single impurity content control.
[00349] Enantiomerically pure form of SGL can be produced using chiral ligands
to induce formation
of a single enantiomer of choice as shown below:
112
Date Recue/Date Received 2021-04-14
o'
6 14¨q3CAi, 0 '(;)
kel 0
1 ,C1c, _6¨)..
,,,.
Hocn_ L'elgylZol? SOCl2.
010i1 It ,a0, cs, 10,,c, It'le2
NH
- k.:I *OH X 'it HNC 0 ,--4 3 HO
0,
0 6. '
Scheme 11 = i i
_
_
2,y1ffi . 0 = R. JO-% ito'Y);
A rs? A- r 'Yxio õA 611-9
it 104
ildezNH Ai NAME MOH
same v
Scheme IV I=if NiezNivroF 0 A 9
ni
i Xfa I
ee
ii = 6 o_70
oi.o pyo-
i 0 tHailkomowTHE-1?..,09 t i r SchmIII co
'1 cri?0,9
i
o.o.o\ 0,2,:i:2, 0 ,,r,(RAT**
**at SQL-El r 1
powid 0'1,n1,2 , )1011 r = caipmd 50 empow,j5, N 't)o - 0
(s)sylwelltry
e ""O' 0 A CitriCibr ': 01
Compound ol
- - V-6
Com o I C:poundirE252A
Laf 111 If-
III lir
Compound 52 Compound 51
001
H0 kCI 0 MOH .--i'r 6
Me2NH 1 0,,o,,,3
1
¨' 4)"' ' I == . (F)DEE
Td0T04,1110011 = = $
\ i
HI $ . - \ A31' __ JOI .
CsF' 'Cl Scheme VI klz01 _______ \ n)
,o1.9 (.,DETT,õõ),...311 -a?
A cy,),(,),y ()_ri)
MOE , $1 , Sherpless Asyroludic
Epoxidahon
IIIII i __________________________ . Cln'ar )V1 Scheme VII
Ili o
0 0- n
T7, 7
MORD K2053 --0,1?)ao __ -
---Ii-coai
l Scheme Via \ I
Vle2NH 1 \<
I
MI, .DEAD
Mesyl chloride
I o o,?µõ0, ial Sharpless Asymmetric
Dihyoxylation Me2NR
Ji-ro-b,0 C14(Jc. = u d,, HVTH'''Y/C:L A
I '1 Samoreg late. SU, Conmound 50 rC1
T Scheme IX
MOTH Schetne VIII ,)? _ B*0 ).õ1.0,cti ,,c)
Mesyl chloride
0
Me2NH
,
. Scheme Vifib \C-c k
1
LC-- (R)
Sarpogrelate, SGL-El, Compound 51
, 0
(S) Sarpopulate, SGL-E2, Compound 52
I (R) Sarpomelate, SGL-El . Compound 51 I
0*0
(S) Sarpogrelate, SGL-E2, Compound 52
H ________________________________________
c-
Schetne Mc i 1
[00350] Chiral organic compounds play an important role in pharmaceuticals,
agrochemicals and other
materials which possess useful biological activity. Enzymes and other natural
binding sites recognize
substrates with particular chirality to generate a variety of biological
functions. These enzymes or
receptor sites are specific in their action, because the enantiomers may
exhibit different properties due
to the chirality. Hence for biologically active compounds, it is possible that
only one of the enantiomer
is active and the other is devoid of activity, both enantiomers are active but
they have different
potencies or both the enantiomers have similar or equal activities. Therefore,
the production of
113
Date Recue/Date Received 2021-04-14
enantiomerically pure molecules of drugs is of interest and the methodology
has three basic strategies,
1) resolution (2) use of chiral building blocks and (3) asymmetric synthesis.
Asymmetric synthesis
provides by far the most efficient use of one chiral material to prepare
another.
[00351] The preparation of enantiomerically pure molecules of biological
interest can be effectively
achieved by asymmetric synthesis. This method involves the creation of one or
more chiral centers
from prochiral starting materials under the influence of chiral substrates.
The preparation of
enantiomerically pure compounds involves use of chiral auxiliaries, chiral
reagents or chiral catalysts,
or a combination thereof.
[00352] In another embodiment, the compounds of the disclosure can be prepared
from (2R)-3-
(dimethylamino)-1, 2-propanediol and (2S)-3-(dimethylamino)-1,2-propanediol
(Scheme VIII).
[00353] Various versatile and convenient chiral carboxylic acid ligands are
available in the literature
such as mandelic acid, 2-metylmandelic acid, 2-chloromandelic acid, 3-
chloromandelic acid, 4-
methoxymandelic acid, 0-acetylmandelic acid, a-methoxyphenylacetic acid, malic
acid, tartaric acid,
etc. The chiral ligands can be prepared from readily available building
blocks. (Moloney et al., Chiral
carboxylic acid ligands derived from camphoric acid, rTetrahedron: Asymmetry,
Volume 7, Issue 9,
September 1996, Pages 2551-2562; U57230135 B2; Product: (S)-2-Amino-1,2,3,4-
tetrahydro-6-
methoxy-naphthalene, Chiral Quest Corp; Ager (Ed), CHAPTER I Chiral Hydroxy
Compounds As
Ligands In Asymmetric Synthesis, Handbook a Chiral Chemicals, Second Edition;
Hu et al.,
Adventure in Asymmetric Hydrogenation: Synthesis of Chiral Phosphorus Ligands
and Asymmetric
Hydrogenation of Heteroaromatics, Top Organomet Chem 36:313-354 (2011);
Ishihara et al., An
extremely simple, convenient and selective method for acetylating primary
alcohols in the presence
of secondary alcohols, J. Org. Chem., 58 (15), pp 3791-3793 (1993); Edwards et
al., The
stereoselective replacement of hydroxyl groups by chlorine, using the mesyl
chloride-N,N-
dimethylformamide reagent, Carbohydrate Research, Volume 35, Issue 1, Pages
111-129 (July 1974)).
[00354] Formation of the diastereomeric compounds and salts is carried out in
a suitable reaction
medium. Suitable reaction media include water, methanol, ethanol, 1-propanol,
2-propanol, diethyl
ether, methyl tert-butyl ether, tetrahydrofuran, acetic acid, methyl acetate,
ethyl acetate, isopropyl
acetate, butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone,
acetonitrile, methylene
chloride, chloroform, 1,2-dichloroethane, benzene, toluene and xylenes, and
/or mixtures thereof.
SARPODEXTERTm AND SARPODEXA1VIIDETm
[00355] Amidation/Acylation
114
Date Recue/Date Received 2021-04-14
[00356] Linkers that can be used in the synthesis of SARPODEXAMIDETm
Derivatives in the above
scheme include, but not limited to, linkers (described in Simplicio et al.,
Prodrugs for Amines,
Molecules 13, 519-547 (2008); Mahato et al., Prodrugs for Improving Tumor
Targetability and
Efficiency, Adv Drug Deliv Rev. 63(8): 659-670 (2011 Jul 18); Jornada et al.,
The Prodrug Approach:
A Successful Tool for Improving Drug Solubility, Molecules 21, 42 (2016); Jain
et al., Mutual
prodrugs containing bio-cleavable and drug releasable disulfide linkers,
Bioorganic Chemistry
49C:40-48 (July 2013); US20130053301, W02011089216A1; W02006136586 A2;
US7932294; US
20060046967 Al; US8357723; US8349901; US8354455; US9550734; US20160220694;
US20160002167; US20150328323; US9090563; US20140058063; US20130158271;
US8288557;
US20110274695; W01998043961).
[00357] Esterification Esters are derived from carboxylic acids. A carboxylic
acid contains the -COOH
group, and in an ester the hydrogen in this group is replaced by a hydrocarbon
group R' such as an
alkyl, cycloalkyl, an aryl, and a hetero-aryl group. Esters are produced when
carboxylic acids are
heated with alcohols in the presence of an acid catalyst. The catalyst is an
acid, usually concentrated
sulfuric acid. Dry hydrogen chloride gas can be used in some cases. rfsOH
(tosic acid) is also often
used.
[00358] The esterification reaction is both slow and reversible. The equation
for the reaction between
an acid RCOOH and an alcohol RUH (where R and R' can be the same or different)
is:
+ FIDH 171-C + H20
µ0.14
Scheme XI
[00359] The alcohol is generally used as solvent so is present in large
excess.
SARPODEXTER'
=
Scheme XII CI:nhorj9L-
Compound 165 H
jao, (S-1-(d ylDistremner Sarpodex-amide
D )imethemino)-3-(2-(3-
methoxyphenethyllthenoxy)prepan-2-y1
extrolphan
13(----X OH ____ ((4K8sA9S)-11-mcky1-
6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoetheno)
phenanduen-3-y1) succiont
10
Sarpogreldte Recemate SGL
Compomd 50 =0)(HL-0
Compound 166 H
Diabzenmer Samodex-amide
(S)-1-(dimelhylmuino)-3-(2-(3-methoxyphenethaphenoxy)promm-2-y1
((41,..VMS,95)-11-methyl-6,7,8,8a,9,10-hexahydro-5//-9,4b-(epimbloethano)
plummthren-3-y1) succinde
115
Date Recue/Date Received 2021-04-14
In another embodiment of preparation of the compositions of the application,
the diastereomerically
pure SARPODEXTER can be obtained by reacting the racemic sarpogrelate with
optically pure
dextrorphan (DO-H3, compound 151) under mild esterification conditions to
obtain a mixture of
diastereomeric esters, compounds 165-166, which can be separated by
crystallization and
chromatographic techniques mentioned above and the techniques described in
this specification to
obtain diastereornerically pure SARPODEXTERs 165 and 166.
EXAMPLES
Preparation of SARPODEXA1VIIDETm Derivatives
[00360] A compound of Formula I or Sarpodexamidem derivatives can be obtained
by reacting
dextromethorphan either as a single isomer or a mixture thereof with 2,2,2-
trichloroethyl
chloroformate in refluxing toluene thus obtaining the N-demethylated compound.
4,4,4-nichloro-1-(3-methoxy-
6,7,8,8a,9,10-hexahydro-5H-9,4b.-
1- (epiminoethano)phenanthren-
11-
yl)butan- 1-one
[00361] The trichloroethoxycarbonyl above can be converted to N-desmethyl
dextromethorphan by
heating to reflux in presence of powdered zinc in glacial acetic acid.
[00362] The N-desmethyl dextromethorphan obtained as described above or
purchased (CAS Number:
125-71-3) can be treated with trifluoromethansulfonic anhydride and pyridine
at room temperature (as
described in Liebigs Ann. Chem. 1986, 336, and W01998043961).
OPTICALLY PURE SARPODEXA1VIIDE
Compound 167
Diatoreomer Sarpodex-emide
(5)-1-(dimmhylamhio)-3-(2-(3-mothmphmethyl)phenm)
0,0, 0 N-Domnetb=3re_t!lorphan b,xaydro.Pr==::r=.1,7484;11...
separation of tointiomers
upogrelote
acr, o 9 Itijr
Racemate
Scheme MI
SGL
Compound 50
Compound 168
Dulteroomer Serpodex-anude
(R)-1-(dimethyleuuno)-3-(243-methowhenethylvbenoxvpropen-211 4-
((45,goS,96)-3-melhoxy-6,7,8)30,9.10-hexabydro-5H-9,4b-
(epunmoothano)phousudiren-11-y1)-4-oxolnnenoate
As shown in Scheme XIII, amides (S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl) phenoxy)
propan-2-y1 4-((4b5,
8a5,95)-3 -methoxy-6,7,8, 8a,9,10-hexahydro -5H-9,4b-(epiminoethano)
phenanthren-11-y1)-4-oxobutanoate
(Compound 167) and (R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy)propan-2-y1 4 -((4b S,8 aS,9 S)-3 -m eth oxy-6,7,8, 8
a,9,10-hex ahydro-5H-
9,4b-(epiminoethano)phenanthren-11-y1)-4-oxo butanoate (compound 168) can be
obtained from
116
Date Recue/Date Received 2022-05-04
sarpogrelate by amidation with N-desmethyl dextromethorphan using HBTU in
combination with
Hiinig's base in 1-2 h. Reagents such as uronium salt (1-cyano-2-ethoxy-2-
oxoethylidenaminooxy)
dimethylamino morpholino carbenium hexafluorophosphate (COMU), ethyl 2-cyano-2-
(2-
nitrobenzenesulfonyloxyimino) acetate (o-NosylOXY), EDCI and NaHCO3,
B(OCH2CF3)3,
trimethylaluminium, Lanthanum trifluoromethanesulfonate, ZrOC12 = 8 H20,
methanesulfonyl
chloride and N-methylimidazole, N,N'-carbonyldiimidazole (CDI), etc. can be
used.
OPTICALLY PURE DEX, Formula I, SARPODEXTM, DERADEXTM, or DERAPHAN' SALT
o
-11) +" H
0 rt Compound
169
Diatereomer (S) Sarpodex salt
- Dextromethorphan
40 , õi0
"S"-"-----)-OH aqueous medium
'N- 101 a,
= 0
Sarpogreiate Racemate (SGL)
Compound 50 0- I
Scheme XIV 0 *1-1 H
7
Compound 170
Diatereomer (R)Sarpodea salt
Compound 50 and compound 149 form a diastereomeric salt mixture of
dextromethorphan (S)-4-((1-
(dim ethyl amino)-3 -(243 -m ethoxyphenethyl)phenoxy)propan-2 -yl)oxy)-4- ox
obutanoate (S-
SAIIPODEXTM) salt and dextromethorphan
(R)-4-(( 1 -(dim ethyl amino)-3 -(243 -
methoxyphenethyl)phenoxy)propan-2-y0oxy)-4-oxobutanoate (R-SARPODEXTM) salt in
chloroform or other suitable solvents such as dichloromethane, DMF, etc.,
which can be separated by
crystallization and recrystallization in suitable solvents such DMF and/or
chromatographic techniques
referred to and described in this specification.
[00363] In one embodiment, provided is a process for separating the
diastereomers of a compound by
using an ionic liquid to increase separation efficiency. When the
diastereomers are separated, for
example, by a process such as liquid-liquid extraction, one or more ionic
liquids may be used as the
extractant.
1003641 In one embodiment, this separation process may be performed on a
compound containing a
mixture of at least one pair of diastereomers, and the diastereomers may be
separated by contacting
the mixture with at least one ionic liquid in which one of the diastereomers
is soluble to a greater
extent than the other diastereomer, and separating the lower-solubility
diastereomer from the mixture.
117
Date Recue/Date Received 2021-04-14
The inventions disclosed herein thus include processes for the separation of
diastereomers, the use of
such processes, and the products obtained and obtainable by such processes.
[00365] In another embodiment, this separation process may be performed on a
compound such as a
diastereomeric mixture of DERATINElm, SARPOTINETm, SARPODEXTm, DERADEXTm, or
DERAPHANTm salt wherein, the diastereomers are separated by contacting the
mixture with at least
one ionic liquid in which one of the diastereomers is soluble to a greater
extent than the other
diastereomer, and separating the lower-solubility diastereomer from the
mixture.
[00366] In yet another embodiment, there is provided a process for separating
the erythro or threo
diastereomers of DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm
from a mixture comprising both diastereomers by liquid-liquid extraction using
at least one ionic liquid
as an extractive solvent.
[00367] Another embodiment is a process for performing an industrial operation
selected from the
group consisting of a calibration operation, a cleaning operation, a rinsing
operation, a drying
operation, a particulate removal operation, a solvent operation, a dispersion
operation, a heat transfer
operation, and an insulating operation, comprising contacting a mixture
comprising a pair of
diastereomers of DERAT1NETm, SARPOT1NETm, SARPODEXTm,
DERADEX'TM, or
DERAPHANTm with at least one ionic liquid in which one of the diastereomers is
soluble to a greater
extent than the other diastereomer, separating the lower-solubility
diastereomer from the mixture, and
employing the separated diastereomer in the operation.
[00368] Another embodiment is a process for separating one diastereomer from
another diastereomer
in a pair of diastereomers in a compound. In such a process, an ionic liquid
is used to facilitate the
separation, and the diastereomers may be separated by contacting the mixture
with at least one ionic
liquid in which one of the diastereomers is soluble to a greater extent than
the other diastereomer, and
separating the lower-solubility diastereomer from the mixture.
[00369] The term "ionic liquid" is defined as an organic salt that is fluid at
or below about 100 C.
[00370] "Liquid-liquid extraction" is a process for separating components in
solution by their
distribution between two immiscible liquid phases. Liquid-liquid extraction
involves the transfer of
mass from one liquid phase into a second immiscible liquid phase, and is
carried out using an extractant
or solvent.
[00371] Components in a liquid mixture can be separated by a process such as
liquid-liquid extraction
using a single equilibrium (or theoretical) stage, or using multiple stages.
An equilibrium, or
118
Date Recue/Date Received 2021-04-14
theoretical, stage is a device that allows intimate mixing of a feed with an
immiscible liquid such that
concentrations approach equilibrium, followed by physical separation of the
two immiscible liquid
phases. A single stage device can be a separatory funnel, or an agitated
vessel, which allows for
intimate mixing of the feed with the immiscible extractant. Following intimate
mixing, one or both of
the liquid phases can be recovered, for example, by decantation.
1003721 Multiple stage devices for liquid separation can be crosscurrent or
countercurrent devices. In a
multiple stage device, the feed enters a first equilibrium stage and is
contacted with an extractant. The
two liquid phases are mixed, with droplets of one phase suspended in the
second phase, and then the
two phases are separated, and DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTm,
or
DERAPHANTm from the first stage is contacted with additional extractant, and
the separation process
is repeated. The process of (1) contacting DERATINETm, SARPOTINE', DERADEXTm,
DERAPHANTm, or SARPODEXTm with extractant, (2) allowing for equilibrium
concentrations to be
approached, and (3) separating the liquid phases is repeated until the desired
purity of the component
of interest is achieved. The number of equilibrium stages will depend on the
desired purity, as well as
the solubility of the components in the extractant and the flow rates of the
feed and extractant.
[00373] In a crosscurrent system (or device), the feed is initially contacted
with extractant in a first
equilibrium stage. DEX, Formula I, DERATINETm, SARPOTINETm, SARPODEXTm,
DERADEXTm,
or DERAPHAN' from this stage then cascades down through one or more additional
stages. At each
stage, the composition is contacted with fresh extractant, and further
purification of the desired
component in the composition is achieved. An example of a crosscurrent system
where the threo
isomer of the composition is purified using the ionic liquid 1-butyl-3-
methylimidazolium
tetrafluoroborate ([BMIM][BE4] as the extractant. In a countercurrent system
or device, the extractant
enters at the stage farthest from the feed, and the two phases are passed
through and across each other,
coming from the two different (e.g. opposite) directions.
[00374] Equipment used for liquid-liquid extraction can be classified as
"stagewise" or "continuous
(differential) contact" equipment. Stagewise equipment is also referred to as
"mixer-settlers". Mixing
the liquids occurs by contacting the feed with the extractant, and the
resultant dispersion is settled as
the two phases separate. Mixing can occur with the use of baffles or
impellers, and the separation
process may be carried out in batch fashion or with continuous flow. Settlers
can be simple gravity
settlers, such as decanters, or can be cyclones or centrifuges, which enhance
the rate of settling.
119
Date Recue/Date Received 2021-04-14
[00375] Continuous contact equipment is typically arranged for multistage
countercurrent contact of
the immiscible liquids, without repeated separation of the liquids from each
other between stages.
Instead, the liquids remain in continuous contact throughout their passage
through the equipment.
Countercurrent flow is maintained by the difference in densities of the
liquids and either the force of
gravity (vertical towers) or centrifugal force (centrifugal extractors).
Gravity-operated extractors can
be classified as spray towers, packed towers or perforated-plate (sieve-plate)
towers. Gravity-operated
towers also include towers with rotating stirrers and pulsed towers as is
known in the art.
[00376] When the diastereomers of a compound of the composition, and in
particular the threo and
erythro isomers of 2,3-dihydrodecafluoropentane, are separated by a process
such as liquid-liquid
extraction, any of the equipment described above can be used to perform the
separation. In one
preferred embodiment, the separation is carried out using a vertical tower
with perforated plates. After
separation of the phase containing the lower-solubility diastereomer from the
phase containing the
extractant and the higher-solubility diastereomer, the higher solubility
diastereomer may be separated
from the extractant by a process such as distillation.
1003771 The transfer of mass from one liquid phase into a separate immiscible
phase by liquid-liquid
extraction, and equipment for use therein, is discussed further in sources
such as Robbins and Cusack,
"Liquid-Liquid Extraction Operations and Equipment" in Perry's Chemical
Engineers' Handbook, 7th
Ed., (McGraw-Hill, 1997, Section 15). Known liquid-liquid extraction processes
that operate on
principles that are the same as or similar to those applicable to the
separations described herein include
the recovery of acetic acid from water using ethyl ether or ethyl acetate as
the extractant (Brown,
Chem. Engr. Prog. (1963) 59:65), and the recovery of phenolics from water with
methyl isobutyl
ketone as the extractant as described by Scheibel in "Liquid-Liquid
Extraction" (Perry and Weissburg
(eds), Separation and Purification, 3rd Ed. (1978) Chapter 3, John Wiley &
Sons, Inc., Hoboken, NJ).
[00378] The dielectrical constant of the solvent (if solvent is used at the
resolutions) changes the
formation, composition and enantiomer recognition of the crystalls (Sakai et
al., Tetrahedron:
Asymmetry, 14, 3716 (2003)). The composition of crystalline diastereoisomers
is also influenced by
the pH of the reaction mixture (Fogassy etal., J. Chem. Res., S 11, 346
(1981); Fogassy etal., J. Chem.
Soc. Perkin Trans. 2. (1988)). The purity (de) of the diastereoisomer can be
improved using a mixture
of structurally related resolving agents. It is often referred as "Dutch
resolution" in the literature
(Kellogg et al., Synthesis, 1626 (2003)). If the diastereoisomeric salt cannot
be separated by
fractionated precipitation, it is feasible to get its crystalline solvate by
fractionated precipitation from
120
Date Recue/Date Received 2021-04-14
a solvate forming solution (Schindler et al., Chirality, 19, 239 (2007)). When
the solvent, unsuitable
for separation of the diastereoisomers, contains structurally partly similar
compounds to the solvate
forming solution (US 214720, Chem. Abs. 124, 117097 (1995); U52133894; Chem.
Abs. 139, 90595
(2001)), the separation of enantiomers became feasiable by fractionated
precipitation of the
diastereoisomeric salt (Palovics et al., Separation of the Mixtures of Chiral
Compounds by
Crystallization, Advances in Crystallization Processes, pp 1-37 (2012)).
[00379] At the crystallization of melts of racemate forming enantiomeric
mixtures the eutectic
composition usually determinates the composition of the crystallized mixture
and the oily residue.
That eutectic composition can be known from the binary melting point phase
diagram. When the initial
isomeric composition (ee0) is higher than the eutectic composition, the pure
optical isomer cam be
crystallized.
[00380] An ionic liquid, or a mixture of two or more thereof, may be used in a
process hereof to separate
the diastereomers of a compound. When, for example, the diastereomers of
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm are separated by a process
such
as liquid-liquid extraction, the extractant used may be an ionic liquid or a
mixture of two or more ionic
liquids. Ionic liquids are organic compounds that are liquid at room
temperature (approximately 25
C). They differ from most salts in that they have very low melting points, and
they generally tend to
be liquid over a wide temperature range. They also generally tend to not be
soluble in non-polar
hydrocarbons; to be immiscible with water (depending on the anion); and to be
highly ionizing (but
have a low dielectric strength). Ionic liquids have essentially no vapor
pressure, most are air and water
stable, and they can either be neutral, acidic or basic.
[00381] A cation or anion of an ionic liquid useful herein can in principle be
any cation or anion such
that the cation and anion together form an organic salt that is liquid at or
below about 100 C. The
properties of an ionic liquid can, however, be tailored by varying the
identity of the cation and/or
anion. For example, the acidity of an ionic liquid can be adjusted by varying
the molar equivalents and
type and combinations of Lewis acids used.
[00382] Many ionic liquids are formed by reacting a nitrogen-containing
heterocyclic ring, preferably
a heteroaromatic ring, with an alkylating agent (for example, an alkyl halide)
to form a quaternary
ammonium salt, and performing ion exchange or other suitable reactions with
various Lewis acids or
their conjugate bases to form the ionic liquid. Examples of suitable
heteroaromatic rings include
substituted pyridines, imidazole, substituted imidazole, pyrrole and
substituted pyrroles. These rings
121
Date Recue/Date Received 2021-04-14
can be alkylated with virtually any straight, branched or cyclic C1-20 alkyl
group, but preferably, the
alkyl groups are C1-16 groups, since groups larger than this may produce low
melting solids rather than
ionic liquids. Various triarylphosphines, thioethers and cyclic and non-cyclic
quaternary ammonium
salts may also been used for this purpose. Counter ions that may be used
include chloroaluminate,
bromoaluminate, gallium chloride, tetrafluoroborate, tetrachloroborate,
hexafluorophosphate, nitrate,
triflaoromethane sulfonate, methylsulfonate, p-toluenesulfonate,
hexafluoroantimonate,
hexafluoroarsenate, tetrachloroaluminate, tetrabromoaluminate, perchlorate,
hydroxide anion, copper
dichloride anion, iron trichloride anion, zinc trichloride anion, as well as
various lanthanum,
potassium, lithium, nickel, cobalt, manganese, and other metal-containing
anions.
[00383] Ionic liquids may also be synthesized by salt metathesis, by an acid-
base neutralization reaction
or by quaternizing a selected nitrogen-containing compound; or they may be
obtained commercially
from several companies such as Merck (Darmstadt, Germany) or BASF (Mount
Olive, NJ).
[00384] Representative examples of useful ionic liquids are described in
sources such as J. Chem. Tech.
Biotechnol., 68:351-356 (1997); Chem. Ind., 68:249-263 (1996); J. Phys.
Condensed Matter, 5: (supp
34B):B99-B106 (1993); Chemical and Engineering News, Mar. 30, 1998, 32-37; J.
Mater. Chem.,
8:2627-2636 (1998); Chem. Rev., 99:2071-2084 (1999); and US 2004/0133058.
[00385] In one embodiment, a library of ionic liquids may be prepared, for
example, by preparing
various alkyl derivatives of a particular cation (such as the quaternary
ammonium cation), and varying
the associated anions (US 20090131728A1).
In another
embodiment, the diastereomers of the invention can be separated efficiently by
cation exchange with
mixed-mode sorbent in the solid phase extraction (SPE) procedure.
[00386] In one embodiment, diastereomers can be separated by extractive
distillation, wherein an
auxiliary which changes the partial pressure of the various diastereomers to
be separated to a different
degree allowing easier separation of the diastereomers by distillation in a
good yield. Separation can
be accomplished using fractionating columns, and preferably under reduced
pressure of about 10-3 bar
to about 1 bar (US 4874473 A, US 20070225505 Al).
[00387] In one embodiment, reversed (RP-HPLC) and normal phase chromatographic
(NP-HPLC)
separations can be used to separate the diastereomers of the invention Columns
that can be used in the
separation of enantiomers can be Primesep C, NUCLEOSIL, cellulose based chiral
HPLC columns,
SHISEIDO Chiral CD-Ph, etc. (Fekete et al., Compative Study Separation of
Diastereomers by HPLC,
Chromatographia, 57, No.3/4(2003 February), US 7119211 B2).
122
Date Recue/Date Received 2022-05-04
ADAMANTANYLAM INO-4-0X0BUTANOATE DERIVATIVES
[00388] Using the above protocols for amide and ester formation, the
derivatives of compounds 50-52
cn be prepared to obtain amide compounds 1001-1006, and ester compounds 1007-
1009:
p 14.crIti /:4
clo,-
Compound 1001 Compound 1002 Compound
1003 ,JfaS c(ND'
Compound 1007
4P H CI:jcCH CI: j 1'7:5' " ____________________________
Compound 1008
Compound 50 Compound 51 Compound 52
0-0*
Compound 1009
Compound 1004 Compound 1005 Compound 1006
Compound 100 1 1 -(chm ethyl ammo)-3 -(2-(3 -m ethoxyphenethyl)phenoxy)propan-
2-y1 4-(adam antan-
1 -ylamino)-4-oxobutanoate;
Compound 1002 (S)-1-(dimethylamino)-3-(2-(3-methoxy phenethyl) phenoxy) propan-
2-y1 4-
(adamantan -1- ylamino) -4- oxobutanoate;
Compound 1003 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-
2-y1 4-
(adamantan-l-ylamino)-4-oxobutanoate;
Compound 1004 (R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-
2-y1 44(3,5-
dimethyl adamantan-1-y1) amino) -4- oxo butanoate;
Compound 1005 1 -(dim ethyl amino)-3 -(2-(3 -m ethoxyphenethyl) phenoxy)
propan-2-y1 44(3 ,5-
dim ethyl adamantan-l-yl)amino) -4- oxobutanoate;
Compound 1006 (S)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl) phenoxy) propan-
2-y1
dimethyl adamantan-1-y1) amino) -4- oxobutanoate;
Compound 1007 1 -(dimethyl amino)-3 -(243 -m ethoxyphenethyl)phenoxy)propan-2-
y1 (2,2,2-
trichloro-1-(dimethoxyphosphoryl)ethyl) succinate;
123
Date Recue/Date Received 2021-04-14
Compound 1008 (S)-1-(dim ethyl amino)-3 -(243 -m ethoxyph
enethyl)phenoxy)propan-2 -yl (2,2,2 -
tri chl oro-1 -(dim ethoxyphosphoryl)ethyl) succinate; and
Compound 1008 (R)-1 -(dim ethyl amino)-3 -(243 -m
ethoxyphenethyl)phenoxy)propan-2-y1 (2,2,2-
tri chl oro-1 -(dim ethoxyphosphoryl)ethyl) succinate.
PHARMACEUTICAL FORMULATIONS
[00389] The compositions of this invention can be prepared by adding a
compound of Formula I,
DERATINETm, SARPOTINETm, SARPODEX'TM, DERADEXTm, or DERAPHANTm to, and
dissolved in, a suitable solvent. The solution, thus obtained, is added to the
complex magnesium
aluminum silicate to form a paste-like mass. While the foregoing steps are
carried out at about room
temperature, elevated temperatures can be employed if desired. Subsequently,
sodium chloride and
sodium saccharin are added to, and uniformly distributed throughout, the
paste. Edible coloring and
:flavoring materials can be incorporated into the system at any stage of the
ipreparative method. In
another embodiment, soluble ingredients are added to a compound of Formula I,
DERATINElm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm solution which is prepared
in the
first step. The paste which is thus obtained can be incorporated readily into
a conventional hard candy-
forming mass, which mass, in turn, can be worked up, by conventional
procedures, into attractive,
pleasant-tasting lozenges each containing therapeutically effective quantities
of a compound of
Formula I, DERATINElm, SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm
uniformly distributed throughout.
[00390] Variations in the preparative methods presented here are within the
scope of the present
invention. For example, in producing the compositions of the invention, one
can mix racemate or
enatiomerically pure compound of Formula I, DERATINETm, SARPOTINE'lm,
SARPODEXTm,
DERADEXTm, or DERAPHANTm and the complex magnesium aluminum silicate and
subsequently
add a suitable solvent thereto to form a paste therewith. Sodium chloride and
sodium saccharin can be
added to the dextromethorphan-complex magnesium aluminum silicate mixture
prior to forming the
mixture into a paste. In the alternative, sodium chloride and sodium saccharin
can be added to the
paste. Furthermore, suitable flavoring agents and coloring agents can be added
either to the dry mixture
or to the paste. In carrying out this invention, any medicinally acceptable
organic solvent which is
suitable for pharmaceutical use and in which a compound of Formula I,
DERATINElm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANIm is soluble can be employed.
Thus, for example, organic solvents, such as propylene glycol, glycerine, 1,3-
butylene glycol, benzyl
124
Date Recue/Date Received 2021-04-14
alcohol, etc., can be used. In an embodiment of compositions of the invention,
benzyl alcohol is
employed as the solvent for the saprodexTm.
1003911 Edible coloring agents and edible flavoring agents can be used in
preparing the present
compositions. Flavoring agents which are suitable for use include, for
example, licorice, ginger,
natural fruit extracts, etc. As the coloring agent one can use any color which
is suitable for use in foods
and drugs. The quantity of coloring and the quantity of flavoring agents used
in formulating the
composition of this invention is variable.
[00392] In an embodiment, the formulation contains about 0.3 g to about 1.5 g,
about 1.0 g, of thickener;
about 1 g to about 10 g, about 2.5 g, of 1,2-propylen glycol as a dissolving
agent; about 0.12 g to about
0.19 g, or 0.15 g, of at least one paraben preservative such as methyl
paraben; about 0.05 g to about
0.2 g, or about 0.1 g, of sorbic acid; about 30 g to about 60 g, or 40 g of a
sugar alcohol solution; about
0.05 to about 0.2 g, or 0.1 g of an artificial sweetener; a compound of
Formula I, DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm -resin complex in an amount
to
yield a desired strength of about 2.10 g (the amount of a 1:6 complex needed
to deliver equivalent to
60 mg of a compound of Formula 1, DERAT1NETm, SARPOTINETm, SARPODEXTm,
DERADEXTm,
or DERAPHANTM in a 20 ml adult 12 hour dose); and sufficient water to bring
the volume up to 100
ml.
[00393] In another embodiment, suitable thickeners include: tragacanth;
bentonite; acacia and lower
alkyl ethers of cellulose (including the hydroxy and carboxy derivatives of
the cellulose ethers).
Exemplary paraben preservatives are Cl -C4alkyl parabens namely methyl, ethyl,
propyl, and butyl
parabens. In one embodiment, both methyl and propyl paraben are present in the
formulation in a ratio
of methyl paraben to propyl paraben of from about 2.5:1 to about 7.5:1. In
another embodiment the
methyl and propyl paraben ratio is 4:1.
[00394] In one embodiment, the artificial sweetener is a form of saccharin or
aspartame. In one
embodiment, saccharin is sacharin sodium. In other embodiments, equivalent
sweetening amounts of
other known sweetening agents such as the sugar alcohol sorbitol may be
substituted therefor.
[00395] In another embodiment, the formulation comprises an amount of resinate
sufficient to deliver,
when administered at one dose every 12 hours, an antitussive effective amount
of a compound of
Formula I, DERATINETm, SARPOTINETm, SARPODEXTm, DERADEX'TM, or DERAPHAN'im
over
a period of approximately 12 hours to a patient in need of such
administration.
125
Date Recue/Date Received 2021-04-14
[00396] In an embodiment, the formulation comprises an adult dose of 20 ml
contains approximately
420 mg of resinate, to deliver equivalent to 60 mg of a compound of Formula I,
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTM, or DERAPHAN when the drug to resin ratio
is
1:6 and 2.10 g of resinate are present per 100 ml of formulation. The dosage
can be altered analogously
to that known for the administration of dextromethorphan which has not been
complexed with resin,
i.e. the typical 15 mg-30 mg/dose of dextromethorphan hydrobromide 1 to 4
times daily, becomes S-
20 ml once to twice daily.
[00397] In another embodiment, the formulation comprises the nontoxic
substances that block the
NMDA receptor in accordance with this invention are dextromethorphan (( + )-3-
hydroxy-
Nmethylmorphinan), a compound of Formula I, DERATINETm, SARPOTINETh4,
SARPODEXIm,
DERADEXTm, or DERAPHANTm or derivatives thereof, and saprodexterrm, mixtures
and
pharmaceutically acceptable salts thereof.
[00398] In another embodiment, the formulation comprises substances that block
the NMDA receptor
include di z oci 1pine (5-m ethyl-10,11 -dihydro-5H-5,10-epiminodib enz o [a,
d] [7] annul ene), ketamine
(2-(2-chloropheny1)-2-(methylamino)cyclohexan-1-one), magnesium, selfotel
((2S,4R)-4-
(phosphonomethyl)piperidine-2-carboxylic acid), aptiganel (P-1-(3-ethylpheny1)-
1-methy1-2-
(naphthalen-l-y1)guanidine), felbamate (2-phenylpropane-1,3-diy1 dicarbamate),
phencyclidine (1-(1-
phenylcyclohexyl)piperidine), amantadine (1-aminoadamantine),
memantine (3,5
dimethylaminoadamantone), pyrroloquinoline quinone (PQQ, 4,5-dioxo-4,5-dihydro-
1H-pyrrolo[2,3-
f] qui n olin e-2,7,9-tri carboxyl i c acid ), (R)-(E)-4-(3-phosph on oprop-2-
enyl)piperazin e-2-carboxyli c
acid, (R)-2-amino-5- phosphonopentanoate, (S) and (R)
6-(1HTetrazol-5-
ylmethyl)decahydroisoquinoline-3-carboxylic acid,
(S)-a-amino-5-(phosphonomethyl)[1,19-
bipheny1]-3-propanoic acid, (S) and (R) (6)-cis-4-(4-phenylbenzoyl) piperazine-
2,3-dicarboxylic
acid, cis-4-phosphonomethy1-2-piperidine carboxylic acid, 2R,4R,5S-(2-amino-
4,5-(1,2-cyclohexyl)-
7-phosphonoheptanoic acid), and cis-4-(phosphonomethyl)-2-piperidinecarboxylic
acid, mixtures and
pharmaceutically acceptable salts thereof. (US 5,891,885, Christie et al.,
Native N-Methyl-D-aspartate
Receptors Containing NR2A and NR2B Subunits Have Pharmacologically Distinct
Competitive
Antagonist Binding Sites, The Journal Of Pharmacology And Experimental
Therapeutics, Vol. 292,
No. 3, pp 1169-74 (2000)).
[00399] In another embodiment, the therapeutic composition comprises at least
one other
pharmacologically active substance e.g., caffeine (a stimulant), an antiemetic
drug such as
126
Date Recue/Date Received 2022-05-04
metoclopramide, domperidone, belladonna alkaloids and phenothiazines such as
chlorpromazine,
prochlorperazine, and promethazine, a nonnarcotic analgesic, e.g.,
acetaminophen or a nonsteroidal
anti-inflammatory drug such as aspirin, diclofenac, diflusinal, etodolac,
fenbufen, fenoprofen,
flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
meclofenamic acid,
mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam,
sulindac, tolmetin,
zomepirac, and the like.
SYNTHESIS OF COMPOUNDS OF THE INVENTION
[00400] All reactions were performed under an argon atmosphere with dry
solvents, unless otherwise
stated. Dry chloroform (CH3C1), methylene chloride (CH2C12), tetrahydrofuran
(THF), ethyl acetate,
DMF, DMSO, methanol, ethanol, and acetonitrile (CH3CN) were purchased or
prepared. All
commercially available reagents were purchased and used without further
purification. Reactions were
monitored by thin-layer chromatography (TLC) on silica gel plates (Merck TLC
Silica Gel 60 F254)
using UV light, PMA (an ethanolic solution of phosphomolybdic acid) or ANTS
(an ethanolic solution
of para-anisaldehyde) as visualizing agent. Purification of products was
conducted by column
chromatography through silica gel 60 (0.060-0.200 mm). NMR spectra were
obtained on Bruker
AVANCE III 500 MHz (Bruker Corporation, Billerica, MA, USA) using residual
undeuterated solvent
or TMS (tetramethylsilane) as an internal reference. High-resolution mass
spectra (HR-MS) were
recorded on a JEOL JMS-700 (JEOL, Tokyo, Japan) using El (electron impact).
[00401] EXAMPLE 1: Dextromethorphan has been synthesized from a
benzylisoquinoline (with a
planar structure) by Grewe's cyclization to give the corresponding morphinan,
wherein the
1,2,3,4,5,6,7,8-octahydro-1-(4-methoxybenzyl)isoquinoline is converted into
the N-formyl derivative,
cyclized to the N- formyl normorphinan, and the formyl group reduced to an N-
methyl group, to give
3-methoxy-17-methylmorphinan. Dextromethorphan is freely soluble in ethanol
96% and essentially
insoluble in water. Dextromethorphan can be monohydrated hydrobromide salt or
bound to an ion
exchange resin based on polystyrene sulfonic acid. Dextrometorphan's specific
rotation in water is +
27.6 (20 C, Sodium D-line).
[00402] EXAMPLE 2: Equimolar sarpogrelate (429.506 g/mol) and dextromethorphan
(271.40 g/mol)
were mixed in a suitable solvent, agitated and let crystallize. The compound
of Formula I and
dextromethorphan positive cation would form hydrogen bond to form a complex
and crystallize.
[00403] EXAMPLE 3: To a solution of 54.28 g of dextromethorphan in one liter
of chloroform is
added a solution of 85.9 g of sarpogrelate in chloroform at 70 C. The salt is
precipitated from the hot
127
Date Recue/Date Received 2021-04-14
solution by the addition of ethyl acetate. After cooling the salt is
collected, washed with ethyl acetate
and dried to yield d-3-methoxy-N-methylmorphinan 4-[1-dimethylamino-3-[2-[2-(3-
methoxyphenyl)
ethyl]phenoxy]propan-2-yl] oxy-4-oxobutanoate salt and recrystallized from
aqueous
dimethylformamide (DMF) to yield of 135 g of the compound of Formula I,
DERATINETm,
SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANThl.
1004041 EXAMPLE 4: Ingredients: 15 g of a compound of Formula I, DERATINETm,
SARPOT1NETm, SARPODEXTm, DERADEXTm, or DERAPHANTm; 15 g Glyceryl tristearate;
100
ml Carbon tetrachloride. Preparation: Glyceryl tristearate is dissolved in the
warm carbon
tetrachloride at 55-60 C. A compound of formula I, derivative thereof,
SARPODEX Tm or derivative
thereof is then added and suspended in the solution. The suspension is then
spray dried using an inlet
temperature of 90 C and an outlet temperature of 40 C. The resulting coated
a compound of Formula
I, DERATINETm, SARPOTINETm, SARPODEXTm, DERADEXTm, or DERAPHANTm having an
average particle size of from about 10 to about 200 microns is then suspended
in the following aqueous
vehicle.
Ingredients: 10.00 g Tragacanth, USP ; 1.20 g Methylparaben, USP; 0.20 g
Propylparaben, USP;
0.30 g Saccharin sodium, USP; 3.00 g Sucaryl sodium, USP; 250.00 mL Sorbic
acid; 1.00 g Methyl
cellulose, 15 cps; 2.00 mL Imitation black currant; and 1000.00 mL Distilled
water.
1004051 The parabens, saccharin sodium, sucaryl sodium and sorbic acid are
dissolved in a portion of
the distilled water which has been heated to 85 C. The tragacanth is then
added to this solution and
dispersed uniformly. The dispersion is again heated, cooled and the sorbitol
solution, a solution of the
methyl cellulose in water and the imitation black currant are then added with
mixing to form the
vehicle. The coated a compound of Formula I, DERATINETm, SARPOTINETh4,
SARPODEXTm,
DERADEXTm, or DERAPHANTm is then added to the above vehicle and mixed until
the particles are
thoroughly wetted and uniformly dispersed.
[00406] The controlled drug-release composition of the present invention is
characterized by
comprising 100 parts by weight of an organic polymeric material which is
soluble in an organic solvent
and insoluble in water; 5 to 60 parts by weight of a lipid-soluble, low
molecular weight release
auxiliary agent; and 1 to 70 parts by weight of a drug.
[00407] In one embodiment, the polymeric material is biodegradable or
biocompatible, or both, for
example, biodegradable aliphatic polyester, or an aliphatic poly(carbonate),
poly(lactic acid), lactic
acid-glycolic acid copolymer, poly(caprolactone), poly(hydroxybutyric acid)
and the like.
128
Date Recue/Date Received 2021-04-14
[00408] In one embodiment, the release auxiliary agent is a carboxylic acid
ester, a monoester or diester
of glycerin. In another embodiment, the release auxiliary agent is an ester of
an organic acid selected
from succinic acid, citric acid, tartaric acid, malic acid or the like, or
monoacetate ester or diacetate
ester of glycerin.
[00409] In one embodiment, the composition may further comprise a cell
adhesion material or an
endothelialization promoting agent on a surface of a medical device.
[00410] In one embodiment, in invention is a drug-releasable medical device
characterized by
containing the compositions of the present disclosure. The drug-releasable
medical device forms a
layer of the composition on the surface, and contacts with a living body, or
is incorporated or indwelled
in a living body. The device includes a stent, a catheter, a clip, an organ
replacement medical device,
a capsule sensor or an artificial organ. The stent in one embodiment is used
for treating coronary artery
stenosis and gradually releasing the composition from the surface. The release
rate is 1/103 mu
g/mm2/h to 1 mu g/mm2/h on 21 days after indwelling the stent. In addition,
the stent of the present
invention is characterized in that the drug to be gradually released is
carried in a polymeric material
coated on the surface of a metal forming the stent or in a porous stent
substrate.
[00411] The polymeric material coated on the surface of the stent is
amorphous. The polymeric
material coated on the surface of the stent is an amorphous biodegradable
polymeric material. The
polymeric material is a poly(lactic acid) or a lactic acid-glycolic acid
copolymer, which is
biodegradable. The polymeric material further comprises a release auxiliary
agent that promotes the
release of a drug to be carried. The auxiliary agent that promotes the release
of a drug is a tartrate
ester or a malate ester, or a monoester or diester of glycerin. The surface of
the metal forming the stent
may be a porous body and the above-mentioned drug to be gradually released may
be carried in the
porous body. In one embodiment, the porous body has a pore size of 0.01 nm to
300 nm in diameter.
[00412] EXAMPLE 5: OPTICALLY PURE SARPOMALATE: Malic acid is a component of
many
of the foods that we eat daily. Although it is found as a naturally occurring
organic compound in
various fruits, many choose to take malic acid supplements to increase their
overall health, as well as
treat various maladies. Today, the acid is most commonly used as a food
additive and preservative. It
is a mild and relatively harmless acid when used in appropriate amounts. As a
food supplement, it is
generally considered beneficial for health and is present in large amounts in
apple juices. As when
taking any supplement, however, you should not exceed the recommended amounts
for consumption.
129
Date Recue/Date Received 2021-04-14
[00413] Malic acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC,
0.55 mmol, 1.1 equiv.)
and 4-dimethylaminopyridine at 0 C are added to a stirred solution of
racemate or enantiomerically
pure M1 (0.50 mmol, 1.0 equiv.) in CH2C12 (5 mL), heated over 30 min to 25 C,
stirred the mixture
at 25 C for 18 to 24 h, and diluted with CH2C12 (50 mL) and sat. aq. NaliCO3
(30 mL). The organic
layer is separated, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude
residue is purified by column chromatography (silica gel, hexanes:Et0Ac) to
yield racemic or
diasteriomerically pure sarpomalate, respectively depending upon the M1 and
malic acid used
(compounds 25-29). Racemic sarpomalate can be purified by crystallization
and/or chiral
chromatography to obtain diasteriomerically pure sarpomalate.
[00414] EXAMPLE 6: OPTICALLY PURE SARPOMETHIONATE: Methionine (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure MI
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaliCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. 'the crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or
diasteriomerically pure
sarpomethionate, respectively depending upon the M1 and methionine used
(compounds 30-34).
Racemic sarpomethionate can be purified by crystallization and/or chiral
chromatography to obtain
diasteriomerically pure sarpomethionate.
[00415] EXAMPLE 7: OPTICALLY PURE SARPOPHTHALLATE: Phthallic acid (0.55 mmol,
1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at
0 C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.)
in CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C
for 18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaliCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpophthallate,
respectively depending upon the M1 and phthallic acid used to yield compounds
35-37. Racemic
sarpophthallate can be purified by crystallization and/or chiral
chromatography to obtain
diasteriomerically pure sarpomalate.
[00416] EXAMPLE 8: OPTICALLY PURE SARPOMALONATE: MaIonic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
130
Date Recue/Date Received 2021-04-14
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpomalonate,
respectively depending upon the MI to yield compounds 38-40. Racemic
sarpomalonate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpomalonate.
[00417] EXAMPLE 9: OPTICALLY PURE SARPOTYROSINATE: Tyrosine (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpotyrosinate,
respectively depending upon the M1 to yield compounds 41-43. Racemic
sarpotyrosinate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpotyrosinate.
[00418] EXAMPLE 10: OPTICALLY PURE SARPOTRYPTOPHANATE: Tryptophan (0.55
mmol, 1.1 equiv.), dicyclohexylcarbodnmide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0 C are added to a stirred solution of racemate or
enantiomerically pure
M1 (0.50 mmol, 1.0 equiv.) in CH2C12 (5 mL), heated over 30 min to 25 C,
stirred the mixture at 25
C for 18 to 24 h, and diluted with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL).
The organic layer
is separated, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude residue is
purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic
or optically pure
sarpotryptophanate, respectively depending upon the M1 to yield compounds 44-
46. Racemic
sarpotryptophanate can be purified by crystallization and/or chiral
chromatography to obtain optically
pure sarpotryptophanate.
[00419] EXAMPLE 11: OPTICALLY PURE SARPOMALEATE: Maleic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
131
Date Recue/Date Received 2021-04-14
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpomaleate,
respectively depending upon the M1 to yield compounds 47-49. Racemic
sarpomaleate can be purified
by crystallization and/or chiral chromatography to obtain optically pure
sarpomaleate.
[00420] EXAMPLE 12: OPTICALLY PURE SARPOGRELATE: Succinic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpogrelate,
respectively depending upon the MI to yield compounds 50-52. Racemic
sarpogrelate can be purified
by crystallization and/or chiral chromatography to obtain optically pure
sarpogrelate.
[00421] EXAMPLE 13: OPTICALLY PURE SARPOGLUTARATE: Glutaric acid (0.55 mmol,
1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at
0 C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.)
in CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C
for 18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpoglutarate,
respectively depending upon the M1 to yield compounds 53-55. Racemic
sarpoglutarate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpoglutarate.
[00422] EXAMPLE 14: OPTICALLY PURE SARPOADIPATE: Adipic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpoadipate,
respectively depending upon the M1 to yield compounds 56-58. Racemic
sarpoadipnate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpoadipate.
132
Date Recue/Date Received 2021-04-14
[00423] EXAMPLE 15: OPTICALLY PURE SARPOPIMELATE: Pimelic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpopimelate,
respectively depending upon the M1 to yield compounds 59-61. Racemic
sarpopimelate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpopimelate.
[00424] EXAMPLE 16: OPTICALLY PURE SARPOSEBACATE: Sebacic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. 'the crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarposebacate,
respectively depending upon the M1 to yield compounds 62-64. Racemic
sarposebacate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarposebacate.
[00425] EXAMPLE 17: OPTICALLY PURE SARPOFORMATE: Formic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpoformate,
respectively depending upon the M1 to yield compounds 65-67. Racemic
sarpoformate can be purified
by crystallization and/or chiral chromatography to obtain optically pure
sarpoformate.
[00426] EXAMPLE 18: OPTICALLY PURE SARPOACETATE: Acetic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
133
Date Recue/Date Received 2021-04-14
with CH2C12 (50 mL) and sat. aq. NaliCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpoacetate,
respectively depending upon the Ml to yield compounds 68-70. Racemic
sarpoacetate can be purified
by crystallization and/or chiral chromatography to obtain optically pure
sarpoacetate.
1004271 EXAMPLE 19: OPTICALLY PURE SARPOPROPIONATE: Propionic acid (0.55 mmol,
1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at
0 C are added to a stirred solution of racemate or enantiomerically pure Ml
(0.50 mmol, 1.0 equiv.)
in CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C
for 18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaliCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpopropionate,
respectively depending upon the Ml to yield compounds 71-73. Racemic
sarpopriopionate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpopropionate.
1004281 EXAMPLE 20: OPTICALLY PURE SARPOBUTYRATE: Butyric acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure Ml
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 'V, stirred the mixture at 25 'V for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaliCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpobutyrate,
respectively depending upon the Ml to yield compounds 74-76. Racemic
sarpobutyrate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpobutyrate.
[00429] EXAMPLE 21: OPTICALLY PURE SARPOVALERATE: Valeric acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure Ml
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaliCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpovalerate,
134
Date Recue/Date Received 2021-04-14
respectively depending upon the M1 to yield compounds 77-79. Racemic
sarpovalerate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpovalerate.
[00430] EXAMPLE 22: OPTICALLY PURE SARPOCAPROATE: Caproic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpocaproate,
respectively depending upon the M1 to yield compounds 80-82. Racemic
sarpocaproate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpocaproate.
[00431] EXAMPLE 23: OPTICALLY PURE SARPOENANTHATE: Enanthoic (heptanoic) acid
(0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.)
and 4-
dimethylaminopyridine at 0 C are added to a stirred solution of racemate or
enantiomerically pure
M1 (0.50 mmol, 1.0 equiv.) in CH2C12 (5 mL), heated over 30 min to 25 'V,
stirred the mixture at 25
C for 18 to 24 h, and diluted with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL).
The organic layer
is separated, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude residue is
purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic
or optically pure
sarpoenanthoate, respectively depending upon the M1 to yield compounds 62-64.
Racemic
sarpoenanthoate can be purified by crystallization and/or chiral
chromatography to obtain optically
pure sarpoenanthoateate.
[00432] EXAMPLE 24: OPTICALLY PURE SARPOCAPRYLATE: Caprylic acid (0.55 mmol,
1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at
0 C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.)
in CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C
for 18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpocaprylate,
respectively depending upon the M1 to yield compounds 86-88. Racemic
sarpocaprylate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpocaprylate.
135
Date Recue/Date Received 2021-04-14
[00433] EXAMPLE 25: OPTICALLY PURE SARPOPELARGONATE: Pelargonic acid (0.55
mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0 C are added to a stirred solution of racemate or
enantiomerically pure
M1 (0.50 mmol, 1.0 equiv.) in CH2C12 (5 mL), heated over 30 min to 25 C,
stirred the mixture at 25
C for 18 to 24 h, and diluted with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL).
The organic layer
is separated, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude residue is
purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic
or optically pure
sarpopelargonate, respectively depending upon the M1 to yield compounds 89-91.
Racemic
sarpopelargonate can be purified by crystallization and/or chiral
chromatography to obtain optically
pure sarpopelargonate.
[00434] EXAMPLE 26: OPTICALLY PURE SARPOCAPRATE: Capric acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpocaprate,
respectively depending upon the M1 to yield compounds 92-94. Racemic
sarpocaprate can be purified
by crystallization and/or chiral chromatography to obtain optically pure
sarpocaprate.
[00435] EXAMPLE 27: OPTICALLY PURE SARPOOXALATE: Oxalic acid (0.55 mmol, 1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarpooxalate,
respectively depending upon the M1 to yield compounds 95-97. Racemic
sarpooxalate can be purified
by crystallization and/or chiral chromatography to obtain optically pure
sarpooxalate.
[00436] EXAMPLE 28: OPTICALLY PURE SARPOISOPHTHALLATE: Isophthallic acid (0.55
mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0 C are added to a stirred solution of racemate or
enantiomerically pure
136
Date Recue/Date Received 2021-04-14
M1 (0.50 mmol, 1.0 equiv.) in CH2C12 (5 mL), heated over 30 min to 25 C,
stirred the mixture at 25
C for 18 to 24 h, and diluted with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL).
The organic layer
is separated, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude residue is
purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic
or optically pure
sarpoisophthallate, respectively depending upon the M1 to yield compounds 98-
100. Racemic
sarpoisophthallate can be purified by crystallization and/or chiral
chromatography to obtain optically
pure sarpoisophthallate.
[00437] EXAMPLE 29: OPTICALLY PURE SARPOTEREPHTHALLATE: Terephthallic acid
(0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.)
and 4-
dimethylaminopyridine at 0 C are added to a stirred solution of racemate or
enantiomerically pure
M1 (0.50 mmol, 1.0 equiv.) in CH2C12 (5 mL), heated over 30 min to 25 C,
stirred the mixture at 25
C for 18 to 24 h, and diluted with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL).
The organic layer
is separated, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude residue is
purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic
or optically pure
sarpoterephthallate, respectively depending upon the M1 to yield compounds 101-
103. Racemic
sarpoterephthallate can be purified by crystallization and/or chiral
chromatography to obtain optically
pure sarpoterephthallate.
[00438] EXAMPLE 30: OPTICALLY PURE SARPOSALICILATE: Salicilic acid (0.55 mmol,
1.1
equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1 equiv.) and 4-
dimethylaminopyridine at 0
C are added to a stirred solution of racemate or enantiomerically pure M1
(0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL), heated over 30 min to 25 C, stirred the mixture at 25 C for
18 to 24 h, and diluted
with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The organic layer is
separated, dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude residue is
purified by column
chromatography (silica gel, hexanes:Et0Ac) to yield racemic or optically pure
sarposalicilate,
respectively depending upon the M1 to yield compounds 104-106. Racemic
sarposalicilate can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarposalicilate.
[00439] EXAMPLE 31: OPTICALLY PURE SARPOACETYLSALICILATE: Acetylsalicilic
acid (0.55 mmol, 1.1 equiv.), dicyclohexylcarbodiimide (DCC, 0.55 mmol, 1.1
equiv.) and 4-
dimethylaminopyridine at 0 C are added to a stirred solution of racemate or
enantiomerically pure
M1 (0.50 mmol, 1.0 equiv.) in CH2C12 (5 mL), heated over 30 min to 25 C,
stirred the mixture at 25
C for 18 to 24 h, and diluted with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL).
The organic layer
137
Date Recue/Date Received 2021-04-14
is separated, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The crude residue is
purified by column chromatography (silica gel, hexanes:Et0Ac) to yield racemic
or optically pure
sarpoacetylsalicilate, respectively depending upon the M1 to yield compounds
107-109. Racemic
sarpoacetylsalicilate can be purified by crystallization and/or chiral
chromatography to obtain optically
pure sarpoacetylsalicilate. (Park et al., Aspirination of a-Aminoalcohol
(Sarpogrelate MD,
Molecules 21(9), 1126 (2016)).
[00440] EXAMPLE 32: To a stirred solution of M1 (0.50 mmol, 1.0 equiv.) in
CH2C12 (5 mL) or
CH3CN (5 mL) was added aspirin (0.55 mmol, 1.1 equiv.) and 1,1'-
carbonyldiimidazole (CDI, 0.60
mmol, 1.2 equiv.) at 25 C. The mixture was stirred for 12 h, and diluted with
CH2C12 (40 mL) and
sat. aq. NH4C1 (25 mL). The organic layer was separated, dried (Na2SO4),
filtered, and concentrated
under reduced pressure. The crude residue was purified by column
chromatography (silica gel,
hexanes:Et0Ac) to obtain compound 107. Racemic sarpoacetylsalicilate compound
107 can be
purified by crystallization and/or chiral chromatography to obtain optically
pure sarpoacetylsalicilates
108 and 109.
[00441] EXAMPLE 33: To a stirred solution of M1 (0.50 mmol, 1.0 equiv.) in THF
(5 mL) was
added acetylsalicylic acid (0.75 mmol, 1.5 equiv.), triphenylphosphine (0.75
mmol, 1.5 equiv.) and
diisopropyl azodicarboxylate (DIAD, 0.75 mmol, 1.5 equiv.) at 0 C. The
mixture was stirred at the
same temperature for 1 h, and the solvent was removed under reduced pressure.
The residue was
diluted with Et0Ac (30 mL) and sat. aq. NII4C1 (15 mL). The organic layer was
separated, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The crude residue
was purified by
column chromatography (silica gel, hexanes:Et0Ac) to obtain compound 107.
Racemic
sarpoacetylsalicilate compound 107 can be purified by crystallization and/or
chiral chromatography
to obtain optically pure sarpoacetylsalicilates 108 and 109.
[00442] EXAMPLE 34: To a stirred solution of acetyl salicylate (1.00 mmol, 2.0
equiv.) in CH2C12 (5
mL) was added oxalyl chloride (2 M in CH2C12, 0.60 mL, 1.20 mmol, 2.4 equiv.)
and
dimethylformamide (DMF, 8.0 uL, 0.10 mmol, 0.2 equiv.) at 0 C. Then, the
temperature was
gradually raised to 25 C. The mixture was stirred at the same temperature for
12 h. Then, to another
stirred solution of M1 3 (0.50 mmol, 1.0 equiv.) in CH2C12 (5 mL) was added
pyridine (0.24 mL, 3.0
mmol, 6.0 equiv.) and the previously prepared aspirinyl chloride solution. The
mixture was stirred for
another 12 h, and diluted with CH2C12 (50 mL) and sat. aq. NaHCO3 (30 mL). The
organic layer was
separated, dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude residue was
138
Date Recue/Date Received 2022-05-04
purified by column chromatography (silica gel, hexanes:Et0Ac) to obtain
compound 107. Racemic
sarpoacetylsalicilate compound 107 can be purified by crystallization and/or
chiral chromatography
to obtain optically pure sarpoacetylsalicilates 108 and 109.
[00443] EXAMPLE 35: To a stirred solution of salicylate ester (241 mg, 0.536
mmol, 1.0 equiv.) in
pyridine (2 mL) was added Ac20 (76 [iL, 0.81 mmol, 1.5 equiv.) at 0 C. The
temperature was raised
to 25 'C. The mixture was stirred at the same temperature for 12 h. Then, the
mixture was concentrated
under reduced pressure and diluted with ethyl acetate (30 mL) and washed with
H20 (10 mL). The
organic layer was separated, dried (Na2SO4), filtered, and concentrated under
reduced pressure. The
crude residue was purified by column chromatography (silica gel, hexanes:
Et0Ac = 1:2) to afford
compound 107 (239 mg, 90% yield). Racemic sarpoacetylsalicilate compound 107
can be purified by
crystallization and/or chiral chromatography to obtain optically pure
sarpoacetylsalicilates 108 and
109.
[00444] EXAMPLE 36
1-(dimelbylaromo)-3-(2-(3-
-' mehoWl.nethYlVh.n
y2;:=12; 1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y1 2-
acetary
benzoate (compound 163): colorless oil; Rf = 0.25 (silica gel, hexanes: Et0Ac
1:1); 11-1-NMR (500
MHz, CDC13): 6 = 7.99 (dd, Ji = 1.6 Hz, J2 = 7.9 Hz, 1H), 7.53-7.50 (m, 1H),
7.18 (ddd, Ji = 1.1
Hz, J2 = 7.9 Hz, J3 = 7.9 Hz, 1H), 7.18-7.14 (m, 2H), 7.10-7.06 (m, 2H), 6.89-
6.86 (m, 2H), 6.77
(d, J= 7.7 Hz, 1H), 6.72-6.71 (m, 2H), 5.56-5.51 (m, 1H), 4.28-4.22 (m, 2H),
3.75 (s, 3H), 2.92-
2.71 (m, 6H), 2.32 (s, 6H), 2.30 (s, 3H) ppm; 13C-NMR (125 MHz, CDC13): 6 =
169.7, 163.9, 159.7,
156.5, 150.9, 144.1, 134.0, 131.9, 130.5, 130.3, 129.3, 127.4, 126.1, 123.9,
123.4, 121.0, 120.9,
114.2, 111.39, 111.37, 71.2, 67.6, 59.4, 55.2, 46.4, 36.5, 32.8, 21.1 ppm;
HRMS (El): calcd for
C29H33N06 [Mt]: 491.2308, found 491.2310.
1004451 EXAMPLE 37
'0S= 1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-ylacetate
(compound
164): colorless oil; Rf = 0.19 (silica gel, hexanes:Et0Ac 1:2); 11-1-NMR (500
MHz, CDC13): 6 = 7.21
(t, J= 7.8 Hz, 111), 7.16 (ddd,Ji = 1.7 Hz, J2 =7.8Hz,J3= 7.8 Hz, 1H), 7.11
(dd, = 1.7 Hz, =
7.4 Hz, 1H), 6.87 (ddd, Ji = 1.0 Hz, J2 = 7.4 Hz, J3 = 7.4 Hz, 1H), 6.84 (t,
J= 8.9 Hz, 2H), 6.78
(t, J= 1.9 Hz, 111), 6.76-6.73 (m, 1H), 5.39-5.34 (m, 1H), 4.19-4.09 (m, 2H),
3.80 (s, 3H), 2.91-
2.84 (m, 4H), 2.69-2.61 (m, 2H), 2.30 (s, 6H), 2.05 (s, 3H) ppm; 13C-NMR (125
MHz, CDC13): 6 =
170.8, 159.7, 156.5, 144.2, 130.5, 130.3, 129.4, 127.4, 121.0, 120.9, 114.3,
111.3, 111.2, 70.4, 67.7,
139
Date Recue/Date Received 2021-04-14
59.7, 55.3, 46.4, 36.6, 33.2, 21.4 ppm; HRMS (El): calcd for C22H29N04 [Mt]:
371.2097, found
371.2095.
1004461 EXA.MPLE 38
,
4- 07boltt 1-(Dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y1-2-
hydroxy
benzoate (compound 165) colorless oil; Rf = 0.23 (silica gel, hexanes:Et0Ac
2:1); 111-NMR (500
MHz, CDC13): 6 = 10.69 (s, 1H), 7.83 (dd, Ji = 1.7 Hz, J2 = 8.0 Hz, 1H), 7.44-
7.41 (m, 1H), 7.20-
7.16 (m, 2H), 7.11 (dd, Ji = 1.6 Hz, J2 = 7.4 Hz, 1H), 6.96 (dd, Ji = 0.9 Hz,
J2 = 8.4 Hz, 1H), 6.91-
6.88 (m, 2H), 6.81-6.77 (m, 1H), 6.76-6.72 (m, 3H), 5.70-5.66 (m, 1H), 4.30-
4.29 (m, 2H), 3.76 (s,
3H), 2.91-2.82 (m, 6H), 2.40 (s, 6H) ppm; 13C-NMR (125 MHz, CDC13): 6 = 169.6,
161.8, 159.7,
156.3, 144.0, 136.0, 130.5, 130.4, 130.1, 129.4, 127.4, 121.2, 120.9, 119.4,
117.8,114.3, 112.5,111.3,
111.2, 71.2, 67.6, 59.4, 55.2, 46.1, 36.5, 32.8 ppm; HRMS (El): calcd for
C271131N05 [Mt]: 449.2202,
found 449.2200.
[00447] EXAMPLE 39
2-(dimetbvlamino)-342-0-
mdl'al=1P,""Y
"y= 2-(Dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy)propy12-acetoxybenzoate
(Compound 166): colorless oil; Rf = 0.20 (silica gel, hexanes:Et0Ac 1:1); 111-
NMR (500 MHz,
CDC13): 6 = 7.98 (dd, Ji = 1.6 Hz, J2 = 7.8 Hz, 1H), 7.55 (ddd, Ji = 1.7 Hz,
J2= 7.8 Hz, J3 = 7.8 Hz,
1H), 7.28 (ddd, Ii = 1.1 Hz, J2 = 7.7 Hz, J3 = 7.7 Hz, 1H), 7.21-7.17 (m, 2H),
7.13 (dd, Ji = 1.5
Hz, J2 = 7.4 Hz, 1H), 7.11 (dd, Ji = 1.0 Hz, J2 = 8.1 Hz, 1H), 6.92-6.88 (m,
2H), 6.81 (d, J= 7.7 Hz,
1H), 6.75-6.73 (m, 2H), 4.62-4.53 (m, 2H), 4.20-4.12 (m, 2H), 3.77 (s, 3H),
3.29-3.24 (m, 1H),
2.95-2.85 (m, 4H), 2.51 (s, 6H), 2.31 (s, 3H) ppm; 13C-NMR (125 MHz, CDC13): 6
= 169.9, 164.3,
159.7, 156.5, 150.9, 144.0, 134.1, 131.7, 130.4, 130.3, 129.4, 127.4, 126.1,
124.0, 123.2, 121.0,
120.9, 114.2, 111.4, 111.1, 65.7, 62.8, 62.0, 55.2, 42.6, 36.6, 32.6, 21.1
ppm; HRMS (El): calcd for
C29H33N06 [Mt]: 491.2308, found 491.2309.
[00448] EXAMPLE 40: DEUTERATION of H-COMPOUND to form D-COMPOUND: The H-
compound (a compound of the invention, about 1.25 mmol) is dissolved in 3 mL
of 100 mM pH=7
deuterated phosphate-buffered saline (D-PBS) diluted with 9.00 mL D20 to a
final concentration of
25 mM. 100 mM D-PBS pH=7 (pH paper) buffer is prepared by dissolving 259.5 mg
of K3PQ4 in D20
(12.00 mL) and adding 264 pL 20% DC! in D20. The reaction mixture is shaken at
room temperature
for 11 days while monitoring for completion of hydrogen/deuterium (HID)
exchange by LC/MS.
140
Date Re9ue/Date Received 2021-04-14
[00449] A small scale workup is performed to prepare the hydrochloride salt of
the deuterated
compound. Thus a 1.2 mL aliquot of the reaction mixture (10% of total volume)
is diluted with 5 mL
saturated NaHCO3 and extracted with Et0Ac (3 x 5mL). The organic layer is
dried over Na2SO4 and
filtered. Evaporation of the solvent gave 20 mg of a colorless oil which is
converted to the HC1 salt by
addition of a few drops of 4M HC1 in dioxane. The salt is triturated with
ether and the solvents were
evaporated to give deuterated compound HC1 salt. A 9.6 mL aliquot (80% of
total volume) is diluted
with 40 mL saturated NaHCO3 and extracted once with Et0Ac (200 mL). The
organic layer is quickly
dried over Na2SO4. Evaporation of the solvent gives the compound which is
stored in a freezer.
1004501 EXAMPLE 41: PREPARATION OF CRUDE SARPOGRELATE HYDROCHLORIDE:
1-dimethylamino-3-[242-(3-methoxyphenyl)ethyl]phenoxy]-2-propanol
hydrochloride A 250 ml
13.7 g and water 25 ml were taken in a single-neck flask and stirred to
dissolve. The solution is treated
with 20% aqueous sodium hydroxide to a pH about 9 to about 14, and was
extracted with 30 ml of
toluene, and the organic layer was concentrated at 50 C under reduced
pressure to give a brown oil,
which was dissolved in 30 mL of tetfahydrofuran. Then, butyryl anhydride 4.5 g
was added and heated
to reflux with stirring for about 1 to about 4 hours, and concentrated to
dryness under reduced pressure
at 40 C. Ethyl acetate (25 mL) is added to dissolve the residue and saturated
hydrogen chloride in
ethyl acetate solution is added dropwise to adjust PH 1 or lower while
stifling for about 50-60 min to
obtain sarpogrelate hydrochloride crude wet product, and dried under reduced
pressure (-0.08--
0.1MPa) at 45 to 55 C to yield crude sarpogrelate hydrochloride 14.7 g, yield
86%, HPLC purity 98.6
%.
[00451] EXAMPLE 42: PURIFICATION OF THE CRUDE HYDROCHLORIDE
SARPOGRELATE: The crude sarpogrelate hydrochloride 5g was dissolved in
butanone (20 mL),
heated while stiffing until dissolved, refluxed for 20-30 min, cooled to 25-35
C, continued stirring
40-60 min, filtered, and the filter cake was rinsed with a small amount of
methyl ethyl ketone to give
a white loose solid, 55-65 C and dried under reduced pressure to 24 h, to
give sarpogrelate
hydrochloride 4.6g, yield 92%, HPLC purity of 99.9%.
[00452] EXAMPLE 43: PURIFICATION OF THE CRUDE HYDROCHLORIDE
SARPOGRELATE: The crude sarpogrelate hydrochloride 5g in butanone 30m1 was
heated with
stirring until dissolved and refluxed 20-30min, cooling to 25-35 C, incubated
with stifling 40-60
min, filtered, and the filter cake was rinsed with a small amount of methyl
ethyl ketone to give a white
141
Date Recue/Date Received 2021-04-14
loose solid, 55-65 C and dried under reduced pressure to 24 h, to give 4.55
sarpogrelate
hydrochloride, yield 91 %, HPLC purity 99.7%.
1004531 EXAMPLE 44: PURIFICATION OF THE CRUDE HYDROCHLORIDE
SARPOGRELATE: The crude sarpogrelate hydrochloride 5 g in butanone 40m1 is
heated with
stirring until dissolved and refluxed 20-30 min, cooling to 25-35 C,
incubated with stifling 40-60
min, filtered, and the filter cake was rinsed with a small amount of methyl
ethyl ketone to give a white
solid, 55-65 C and dried under reduced pressure to 24 h, to give sarpogrelate
hydrochloride 4.5 g,
yield 90%, HPLC purity 99.8 %.
1004541 EXAMPLE 45: PURIFICATION OF THE CRUDE HYDROCHLORIDE
SARPOGRELATE: The crude product was sarpogrelate hydrochloride 5 g, join
butanone 20 ml,
heated with stirring until dissolved and refluxed 20-30 min, cooled slowly
with stirring to room
temperature, at -10 C stand for crystallization, filtration, The filter cake
was rinsed with a small
amount of methyl ethyl ketone to give a white fluffy solid, 55-65 C and dried
under reduced pressure
to 24 h, to give the hydrochloride sarpogrelate 4.62 g, yield 92.4%, HPLC
purity 99.2%, largest single
matter content of 0.09%.
[00455] SARPOGRELATE ENANTIOMERS: Enantiomers of compounds described here can
be
separated using chromatographic techniques. The preparative separation of
enantiomers by
chromatography on chiral stationary phases (CSPs) has been recognized as being
a useful alternative
to the more conventional approaches such as enantioselective synthesis and
enzymatically catalyzed
transformations (Francotte, Enantioselective chromatography as a powerful
alternative for the
preparation of drug enantiomers, Journal of Chromatography A, Volume 906,
Issues 1-2, Pages 379-
397 (12 January 2001); Raj endran, et al., Simulated moving bed chromatography
for the separation of
enantiomers, Journal of Chromatography A, Volume 1216, Issue 4, Pages 709-738
(23 January
2009);Maier et al., Separation of enantiomers: needs, challenges,
perspectives, Journal of
Chromatography A, Volume 906, Issues 1-2, Pages 3-33 (12 January 2001); Miller
et al.,
Chromatographic resolution of the enantiomers of a pharmaceutical intermediate
from the milligram
to the kilogram scale, Journal of Chromatography A, Volume 849, Issue 2, Pages
309-317 (23 July
1999); Andersson et al., Preparative chiral chromatographic resolution of
enantiomers in drug
discovery, Journal of Biochemical and Biophysical Methods, Volume 54, Issues 1-
3, Pages 11-23 (31
December 2002); Pirkle et al., Chapter 6 Separation of Enantiomers by Liquid
Chromatographic
Methods, Asymmetric Synthesis, pp 87-124, in Volume 1: Analytical Methods
covers the major
142
Date Recue/Date Received 2021-04-14
analytical methods used to determine enantiomeric ratios, by Morrison (ed),
Elsevier, (December 2,
2012)).
Racemates of the invention can be resolved from an
analytical to a preparative scale by this technique.
[00456] Simulated moving-bed chromatography can be used for the separation of
the enantiomers of
the compounds of the invention, feasible at all production scales, from
laboratory to pilot to production
plant (Juza et al., Simulated moving-bed chromatography and its application to
chirotechnology,
Trends in Biotechnology, Volume 18, Issue 3, Pages 108-118 (1 March 2000) .
[00457] EXAMPLE 46: SEPARATION OF ENANTIOMERS OF SARPOGRELATE
HYDROCHLORIDE ((-)-4((11-(dimethylamino)-3-(2-(3-ethoxyphenethyl)
phenoxy)propan-2-
yloxy) -4-oxobutanoic acid hydrochloride): Sarpogrelate hydrochloride was
separated with the
XBridge C18 3.5[tm, 2.1x50 mm column, using a mobile phase: gradient elution
from 10% MeCN
in 0.01% TFA to 95% MeCN in 0.01% TFA, with a flow rate of 0.5 ml/min, at UV
254 nm, to yield
5.30 mg of enantiomer (99% HPLC purity). NMR: 400 MHz 1H-NMR (C0300, ppm) 7.20-
7.14 (m,
2H) 7.11 (dd, J=7.4, 1.6 Hz, 1H) 6.94-6.87 (m, 2H) 6.79-6.71 (m, 3H) 5.70-5.62
(m, 1 H) 4.18 (dd,
J=10.6, 4.1 Hz, 1 H) 4.15 (dd, J=10.6, 4.7 Hz, 1H) 3.75 (S, 3H) 3.70 (dd,
J=13.8, 10.1Hz, 1H) 3.54
(dd, J=13.8, 2.3 Hz, 1H) 2.98 (s, 6H) 2.96-2.77 (m, 4H) 2.76-2.53 (m, 4H). ESI-
MS, m/z): 429
[M+H]+. Melting point ( C): 155-156. Optical rotation, alpha [D]: -20.0 (c
0.33, Me0H).
[00458] EXAMPLE 47: DEXTROMETHORPHAN MALATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the malic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00459] EXAMPLE 48: DEXTROMETHORPHAN METHIONATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the methionine or
N-acyl methionine (0.05 mole) in 60 ml of hot water, and then cool the
reaction mixture to separate
crystals by filtration and dry.
[00460] EXAMPLE 49: DEXTROMETHORPHAN PHTHALLATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the phthallic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
143
Date Recue/Date Received 2022-05-04
[00461] EXAMPLE 50: DEXTROMETHORPHAN MALONATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the malonic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00462] EXAMPLE 51: DEXTROMETHORPHAN TYROSINATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the tyrosine or N-
acyl tyrosine (0.05 mole) in 60 ml of hot water, and then cool the reaction
mixture to separate crystals
by filtration and dry.
[00463] EXAMPLE 52: DEXTROMETHORPHAN TRYPTOPHANATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the tryptophan or
N-acyl tryptophan (0.05 mole) in 60 ml of hot water, and then cool the
reaction mixture to separate
crystals by filtration and dry.
[00464] EXAMPLE 53: DEXTROMETHORPHAN MALEATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the maleic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00465] EXAMPLE 54: DEXTROMETHORPHAN SUCCINATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution a the succinic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00466] EXAMPLE 55: DEXTROMETHORPHAN GLUTARATE/GLUTAMATE: Dissolve the
free base dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution
to a solution of the
glutaric acid, glutamic acid or N-acyl glutamic acid (0.05 mole) in 60 ml of
hot water, and then cool
the reaction mixture to separate crystals by filtration and dry.
[00467] EXAMPLE 56: DEXTROMETHORPHAN ADIPATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the adiptic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00468] EXAMPLE 57: DEXTROMETHORPHAN PIMELATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the pimelic acid
144
Date Recue/Date Received 2021-04-14
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
1004691 EXAMPLE 58: DEXTROMETHORPHAN SEBACATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the sebacic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00470] EXAMPLE 59: DEXTROMETHORPHAN FORMATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the formic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00471] EXAMPLE 60: DEXTROMETHORPHAN ACETATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the acetic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
1004721 EXAMPLE 61: DEXTROMETHORPHAN PROPIONATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the propionic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00473] EXAMPLE 62: DEXTROMETHORPHAN BUTYRATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the butyric acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00474] EXAMPLE 63: DEXTROMETHORPHAN VALERATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the valeric acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00475] EXAMPLE 64: DEXTROMETHORPHAN CAPROATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the caproic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
145
Date Recue/Date Received 2021-04-14
[00476] EXAMPLE 65: DEXTROMETHORPHAN ENANTHATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the enanthoic
(heptanoic) acid (0.05 mole) in 60 ml of hot water, and then cool the reaction
mixture to separate
crystals by filtration and dry.
[00477] EXAMPLE 66: DEXTROMETHORPHAN CAPRYLATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of thecaprylic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00478] EXAMPLE 67: DEXTROMETHORPHAN PELARGONATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the pelargonic
acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by
filtration and dry.
[00479] EXAMPLE 68: DEXTROMETHORPHAN CAPRATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the capric acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00480] EXAMPLE 69: DEXTROMETHORPHAN OXALATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution a the oxalic acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry.
[00481] EXAMPLE 70: DEXTROMETHORPHAN ISOPHTHALLATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the isophthalic
acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by
filtration and dry.
[00482] EXAMPLE 71: DEXTROMETHORPHAN TEREPHTHALLATE: Dissolve the free base
dextromethorphan (0.05 mole) in 20 ml of acetone, add the solution to a
solution of the terephthalic
acid (0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by
filtration and dry.
[00483] EXAMPLE 72: DEXTROMETHORPHAN SALICYLATE: Dissolve the free base (0.05
mole) in 20 ml of acetone, add the solution to a solution of the salicylic
acid (0.05 mole) in 60 ml of
hot water, and then cool the reaction mixture to separate crystals by
filtration and dry.
146
Date Recue/Date Received 2021-04-14
[00484] EXAMPLE 73: DEXTROMETHORPHAN ACETYLSALICYLATE: Dissolve the free
base (0.05 mole) in 20 ml of acetone, add the solution to a solution of the
acetyl salicylic acid (0.05
mole) in 60 ml of hot water, and then cool the reaction mixture to separate
crystals by filtration and
dry.
[00485] EXAMPLE 74-96: DIACID ADDITION SALT OF DEXTROMETHORPHAN AND A
COMPOUND SELECTED FROM FORMULA I COMPOUNDS COMPRISING FDIc AND
FDId (COMPOUNDS 219-269): Dissolve the free base (FDIc or FDId) (0.25 mole)
and
dextromethorphan (0.25 mole) in 20 ml of acetone, add the solution to a
solution of a di or tri acid
(0.05 mole) in 60 ml of hot water, and then cool the reaction mixture to
separate crystals by filtration
and dry. The di and tri acids include, but not limited to adipic acid,
aspartic acid, N-acyl aspartic acid,
citric acid, fumaric acid, galactonic acid, glutaric acid, glutamic acid, N-
acyl glutamic acid, glucaric
acid (saccharic acid), malic acid, maleic acid, mannonic acid, mucic acid,
oxalic acid, pimelic acid,
phthallic acid, isophthallic acid, terephthallic acid, rhamnonic acid, sebacic
acid, succinic acid, and
tartaric acid. Thus, forming addition salts such as:
[00486] EXAMPLE 74 Adipic acid addition salt of (141)1c or FD1d) and
dextromethorphan
[00487] EXAMPLE 75 Aspartic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00488] EXAMPLE 76 N-Acyl aspartic acid, addition salt of (FDIc or FDId) and
dextromethorphan
[00489] EXAMPLE 77 Citric acid addition salt a (FDIc or FDId) and
dextromethorphan
[00490] EXAMPLE 78 Fumaric acid addition salt of (FDIc or FDId) and
dextromethorphan
[00491] EXAMPLE 79 Galactonic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00492] EXAMPLE 80 Glutaric acid addition salt of (FDIc or FDId) and
dextromethorphan
[00493] EXAMPLE 81 Glutamic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00494] EXAMPLE 82 N-Acyl glutamic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00495] EXAMPLE 83 Glucaric acid (saccharic acid) addition salt of (FDIc or
FDId) and
dextromethorphan
[00496] EXAMPLE 84 Malic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00497] EXAMPLE 85 Maleic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00498] EXAMPLE 86 Mannonic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00499] EXAMPLE 87 Mucic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00500] EXAMPLE 88 Oxalic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00501] EXAMPLE 89 Pimelic acid addition salt of (FDIc or FDId) and
dextromethorphan
147
Date Recue/Date Received 2021-04-14
[00502] EXAMPLE 90 Phthallic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00503] EXAMPLE 91 Isophthallic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00504] EXAMPLE 92 Terephthallic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00505] EXAMPLE 93 Rhamnonic acid addition salt of (FDIc or FDId) and
dextromethorphan,
[00506] EXAMPLE 94 Sebacic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00507] EXAMPLE 95 Succinic acid addition salt of (FDIc or FDId) and
dextromethorphan
[00508] EXAMPLE 96 Tartaric acid addition salt of (FDIc or FDId) and
dextromethorphan
[00509] EXAMPLE 97 Compound 901 ((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy)
propan-2-yl)oxy)methyl isopropyl (S)-phosphorofluoridate;
[00510] EXAMPLE 98 Compound 902 (((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl isopropyl (S)-phosphorofluoridate;
[00511] EXAMPLE 99 Compound 903
(((R)-1-(dimethylamino)-3-(2-(3-methoxyphenethyl)
phenoxy) propan-2-yl)oxy)methyl isopropyl (S)-phosphorofluoridate;
[00512] EXAMPLE 100 Compound 904 ((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)
phenoxy)
propan-2-yl)oxy)methyl (3,3-dimethylbutan-2-y1) (R)-phosphorofluoridate;
[00513] EXAMPLE 101 Compound 905 sec-butyl ((((S)-1-(dimethylamino)-3-(2-(3-
methoxy
phenethyl) phenoxy) propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
[00514] EXAMPLE 102 Compound 906 sec-butyl
((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
[00515] EXAMPLE 102 Compound 907 04(1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) 0-ethyl 0-(4-nitrophenyl) phosphorothioate;
[00516] EXAMPLE 103 Compound 908 0-((((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) 0-ethyl 0-(4-nitrophenyl) phosphorothioate;
[00517] EXAMPLE 104 Compound 909 0-((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) 0-ethyl 0-(4-nitrophenyl) phosphorothioate;
[00518] EXAMPLE 105 Compound 910 04(1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) S-((1,3-dioxoisoindolin-2-yl)methyl)
(dimethy1-13-
oxidaneyl)phosphonodithioate;
[00519] EXAMPLE 106 Compound 911 0-((((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl
)phenoxy)propan-2-yl)oxy)methyl) S-((1,3-dioxoisoindolin-2-yl)methyl)
(dimethy1-13-
oxidaneyl)phosphonodithioate;
148
Date Recue/Date Received 2021-04-14
[00520] EXAMPLE 107 Compound 912 0-((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) S-((1,3-dioxoisoindolin-2-yl)methyl)
(dimethy1-13-
oxidaneyl)phosphonodithioate;
[00521] EXAMPLE 108 Compound 913 (E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-
y1 (((1-
(dimethylamino) -3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y0oxy)methyl)
methyl phosphate;
[00522] EXAMPLE 109 Compound 914 (E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-
y1 ((((S)-1-
(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y0oxy)methyl) methyl
phosphate;
[00523] EXAMPLE 110 Compound 915 (E)-3-chloro-4-(diethylamino)-4-oxobut-2-en-2-
y1 ((((R)-1-
(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-yl)oxy)methyl)
methyl phosphate
[00524] EXAMPLE 111 Compound 916 0-(((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy) methyl) S-(2-(ethylsulfinyl)ethyl) 0-methyl
phosphorothioate;
[00525] EXAMPLE 112 Compound 917 0-((((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-y1) oxy) methyl) S-(2-(ethylsulfinyl)ethyl) 0-methyl
phosphorothioate;
[00526] EXAMPLE 113 Compound 918 0-((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-y1) oxy) methyl) S-(2-(ethylsulfinyl)ethyl) 0-methyl
phosphorothioate;
[00527] EXAMPLE 114 Compound 919 0-(((1-(dimethylamino) -3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl) 0-ethyl S-((ethyl thio)methyl)
phosphorodithioate;
[00528] EXAMPLE 115 Compound 920 0-(((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-y1) oxy) methyl) 0-ethyl S-((ethylthio)methyl)
phosphorodithioate;
[00529] EXAMPLE 116 Compound 921 0-(((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-y1) oxy) methyl) 0-ethyl S-((ethylthio)methyl)
phosphorodithioate;
[00530] EXAMPLE 117 Compound 922 S-((6-chloro-2-oxobenzo[d]oxazol-3(2H)-
yOmethyl) 04(1-
(dimethylamino) -3-(2-(3- methoxyphenethyl)phenoxy)propan-2-y0oxy)methyl) 0-
ethyl
phosphorodithioate;
[00531] EXAMPLE 118 Compound 923 S-((6-chloro-2-oxobenzo[d]oxazol-3(211)-
yOmethyl) 0-
((((S)-1-(dimethylamino) -3-(2-(3-methoxyphenethyl)phenoxy)propan-2-
y0oxy)methyl) 0-ethyl
phosphorodithioate;
[00532] EXAMPLE 119 Compound 924 S-((6-chloro-2-oxobenzo[d]oxazol-3(2H)-
yl)methyl) 0-
((((R)-1-(dimethyl lamino) -3-(2-(3-methoxyphenethyl)phenoxy)propan-2-
y0oxy)methyl) 0-ethyl
phosphorodithioate;
[00533] EXAMPLE 120 Compound 925 S-((tert-butylthio)methyl) 0-(((1-
(dimethylamino)-3-(2-(3-
149
Date Re9ue/Date Received 2021-04-14
methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) 0-ethyl phosphorodithioate;
[00534] EXAMPLE 121 Compound 926 S-((tert-butyl thio) methyl) 0-((((S)-1-
(dimethyl amino) -3-
(2- (3-methoxy phen ethyl) phenoxy) propan-2-yl)oxy)methyl) 0-ethyl
phosphorodithioate;
[00535] EXAMPLE 122 Compound 927 SAtert-butylthio) methyl) 0-((((R)-1-
(dimethyl amino)- 3-
(2-(3-methoxy phen ethyl) phenoxy) propan-2-yl)oxy)methyl) 0-ethyl
phosphorodithioate;
[00536] EXAMPLE 123 Compound 928 0-(4-((4-(((((1-
(dimethyl amino)-3-(2-(3-
methoxyphenethyl) phenoxy) propan-2-y1) oxy) methoxy) (methoxy)
phosphorothioyl) oxy) phenyl)
thio) phenyl) 0,0-dimethyl phosphorothioate;
[00537] EXAMPLE 124 Compound 929 0-(4-((4-((((((S)-1- (dimethylamino) -3-(2-(3-
methoxy
phenethyl) phenoxy) propan- 2-y1) oxy) methoxy) (methoxy) phosphorothioyl)
oxy) phenyl) thio)
phenyl) 0,0-dimethyl phosphorothioate;
[00538] EXAMPLE 125 Compound 930
0-(44(4-((((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl) phenoxy)propan-2-yl)oxy) methoxy) (methoxy) phosphorothioyl)
oxy) phenyl)
thio) phenyl) 0,0-dimethyl phosphorothioate;
[00539] EXAMPLE 126 Compound 931 ((1-(dimethylamino) -3-(2- (3-
methoxyphenethyl) phenoxy)
propan-2-yl)oxy) methyl triethyl diphosphate;
[00540] EXAMPLE 127 Compound 932 (((S)-1- (dimethylamino) -3-(2- (3-
methoxyphenethyl)
phenoxy) propan-2-y1) oxy) methyl triethyl diphosphate;
[00541] EXAMPLE 128 Compound 933 (((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-y1) oxy) methyl triethyl diphosphate;
[00542] EXAMPLE 129 Compound 934 ((1-(dimethylamino) -3-(2-(3-
methoxyphenethyl) phenoxy)
propan-2-y1) oxy) methyl methyl (2,2,2-trichloro- 1 -hydroxyethyl)phosphonate;
[00543] EXAMPLE 130 Compound 935 (((S)-1-(dimethylamino) -3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro- 1 -
hydroxyethyl)phosphonate;
[00544] EXAMPLE 131 Compound 936 (((R)-1-(dimethylamino) -3 -(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro- 1 -
hydroxyethyl)phosphonate;
[00545] EXAMPLE 132 Compound 937 2-chloro-1- (2,4,5-trichlorophenyl) vinyl
(((1-
(dimethylamino) -3-(2-(3-methoxy phenethyl) phenoxy) propan-2-yl)oxy) methyl)
hydrogen
phosphate;
[00546] EXAMPLE 133 Compound 938 2-chloro-1-(2,4,5-trichlorophenyl) vinyl
((((S)-1-(dimethyl
amino) -3-(2-(3-methoxy phenethyl) phenoxy) propan-2-y1) oxy) methyl) hydrogen
phosphate;
150
Date Re9ue/Date Received 2021-04-14
[00547] EXAMPLE 134 Compound 939 2-chloro-1-(2,4,5-trichlorophenyl) vinyl
((((R)-1-(dimethyl
amino)-3-(2-(3-methoxy phene thy!) phenoxy) propan-2-y1) oxy) methyl) hydrogen
phosphate;
[00548] EXAMPLE 135 Compound 940 0-(((1-(dimethylamino) -3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl) S-methyl acetylphosphoramidothioate;
[00549] EXAMPLE 136 Compound 941 0-((((S)-1-(dimethylamino) -3-(2- (3-
methoxyphenethyl)
phenoxy) propan-2-y1) oxy) methyl) S-methyl acetyl phosphoramidothioate;
[00550] EXAMPLE 137 Compound 942 0-((((R)-1- (dimethylamino) -3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl) S-methyl acetylphosphoramidothioate;
[00551] EXAMPLE 138 Compound 943 (0-(((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) 0-propyl phosphorothioic) (0,0-dipropyl
phosphorothioic)
anhydride;
[00552] EXAMPLE 139 Compound 944 (0-((((S)-1-(dimethylamino) -3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-y1) oxy) methyl) 0-propyl phosphorothioic) (0,0-dipropyl
phosphorothioic)
anhydride;
[00553] EXAMPLE 140 Compound 945 (0-((((R)-1-(dimethyl amino) -3-(2-(3-methoxy
phenethyl)
phenoxy) propan-2-y1) oxy) methyl) 0-propyl phosphorothioic) (0,0-dipropyl
phosphorothioic)
anhydride;
[00554] EXAMPLE 141
Compound 946 0-(((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)
phenoxy)propan-2-y1) oxy) methyl) S-methyl acetylphosphoramidothioate;
[00555] EXAMPLE 142 Compound 947 0-((((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-y1) oxy) methyl) S-methyl acetylphosphoramidothioate;
[00556] EXAMPLE 143 Compound 948
0-((((R)-1-(dimethylamino)-3-(2-(3-methoxy
phenethyl)phenoxy)propan-2-y1) oxy) methyl) S-methyl
acetylphosphoramidothioate;
[00557] EXAMPLE 144 Compound 949 0-(((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) 0-methyl S-((4-oxobenzo[d][1,2,3]triazin-3(4H)-
yl)methyl)
phosphorodithioate compound with methane (1:1);
[00558] EXAMPLE 145 Compound 950 0-((((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) 0-methyl S-((4-oxobenzo[d][1,2,3]triazin-3(4H)-
yl)methyl)
phosphorodithioate compound with methane (1:1);
[00559] EXAMPLE 146 Compound 951 0-((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yl)oxy)methyl) 0-methyl S-((4-oxobenzo[d][1,2,3]triazin-
3(411)-yOmethyl)
151
Date Re9ue/Date Received 2021-04-14
phosphorodithioate compound with methane (1:1);
[00560] EXAMPLE 147 Compound 952 2-chloroethyl (((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
[00561] EXAMPLE 148 Compound 953 2-chloroethyl ((((S)-1-(dimethylamino)-3-(2-
(3-
methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
[00562] EXAMPLE 149 Compound 954 2-chloroethyl ((((R)-1-(dimethylamino)-3-(2-
(3-methoxy
phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
[00563] EXAMPLE 150 Compound 955 3-chlorobutan-2-y1 (((1-(dimethylamino)-3-(2-
(3-methoxy
phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
[00564] EXAMPLE 151 Compound 956 3-chlorobutan-2-y1 ((((S)-1-(dimethylamino)-3-
(2-(3-
methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
[00565] EXAMPLE 152 Compound 957 3-chlorobutan-2-y1 ((((R)-1-(dimethylamino)-3-
(2-(3-
methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) (R)-phosphorofluoridate;
[00566] EXAMPLE 153 Compound 958 ((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy)
propan-2-yl)oxy)methyl (S)-((((E)-
chlorofluoromethylene)amino)oxy)phosphonofluoridate;
[00567] EXAMPLE 154 Compound 959
((((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl
(S)-((((E)-
chlorofluoromethylene)amino)oxy)phosphonolluoridate;
[00568] EXAMPLE 156 Compound 960
((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl
(S)-((((E)-
chlorofluoromethylene)amino)oxy)phosphonofluoridate;
[00569] EXAMPLE 157 Compound 961
2-chloroethyl (((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl)
(E)-(((chlorofluoromethylene)
amino)oxy)phosphorofluoridate;
[00570] EXAMPLE 158 Compound 962 2-chloroethyl ((((S)-1-(dimethylamino)-3-(2-
(3-
methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-
(((chlorofluoromethylene)amino)
oxy)phosphorofluoridate;
[00571] EXAMPLE 159 Compound 963 2-chloroethyl ((((R)-1-(dimethylamino) -34243-
methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-
(((chlorofluoromethylene)amino)
oxy)phosphorofluoridate;
[00572] EXAMPLE 160 Compound 964 1-chloropropan-2-y1 (((1-(dimethylamino)-3-(2-
(3-
152
Date Re9ue/Date Received 2021-04-14
methoxyphenethyl) phenoxy) propan-2-y1) oxy)methyl) (E)-
(((chlorofluoromethylene)amino)oxy)
phosphorofluoridate;
[00573] EXAMPLE 161 Compound 965 1-chloropropan-2-y1 ((((S)-1-(dimethylamino)-
3-(2-(3-
methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-
(((chlorofluoromethylene) amino)oxy)
phosphor fluoridate;
[00574] EXAMPLE 162 Compound 966 1-chloropropan-2-y1 ((((R)-1-(dimethylamino) -
3-(2-(3-
methoxy phenethyl) phenoxy) propan-2-y1) oxy)methyl) (E)-(((chlorofluoro
methylene) amino) oxy)
phosphor fluoridate;
[00575] EXAMPLE 163 Compound 967 3-chlorobutan-2-y1 (((1-(dimethylamino)-3-(2-
(3-
methoxyphenethyl)phenoxy) propan-2-yl)oxy)methyl)
(E)-(((chlorofluoromethylene)amino)
oxy)phosphorofluoridate;
[00576] EXAMPLE 164 Compound 968 3-chlorobutan-2-y1 ((((S)-1-(dimethylamino)-3-
(2-(3-
methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-
(((chlorofluoromethylene)amino)
oxy)phosphoro fluoridate;
[00577] EXAMPLE 165 Compound 969 3-chlorobutan-2-y1 ((((R)-1-(dimethylamino)-3-
(2-(3-
methoxyphenethyl) phenoxy) propan-2-yl)oxy)methyl) (E)-
(((chlorofluoromethylene) amino)oxy)
phosphor fluoridate.
[00578] EXAMPLE 166 Compound 970 ((1-(dimethylamino)-3-(2-(3-methoxyphenethyl)
phenoxy)
propan-2-yl)oxy) methyl methyl (2,2,2-trichloro-1-hydroxyethyl)phosphonate.
[00579] EXAMPLE 167 Compound 971 ((((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl methyl (2,2,2-trichloro- 1 -
hydroxyethyl)phosphonate;
[00580] EXAMPLE 168 Compound 972 ((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy)methyl methyl (2,2,2-trichloro- 1 -
hydroxyethyl)phosphonate.
[00581] EXAMPLE 169 Compound 973 4-(tert-butyl)-2-chlorophenyl (((1-(dim
ethylamino)-3-(2-(3-
methoxyphenethyl) phenoxy)propan-2-yl)oxy)methyl) methylphosphoramidate
compound with
methane (1:1);
[00582] EXAMPLE 170 Compound 974 4-(tert-butyl)-2-chlorophenyl ((((S)-1-
(dimethylamino)-3-(2-
(3-methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) methylphosphoramidate
compound with
methane (1:1).
[00583] EXAMPLE 171 Compound 975 4-(tert-butyl)-2-chlorophenyl ((((R)-1-
(dimethylamino)-3-
(2-(3-methoxy phenethyl) phenoxy)propan-2-yl)oxy)methyl) methylphosphoramidate
compound with
153
Date Recue/Date Received 2021-04-14
methane (1:1).
[00584] EXAMPLE 172 Compound 976 ((1-(dimethylamino) -3-(2-(3-
methoxyphenethyl) phenoxy)
propan-2-y1) oxy) methyl (3-methy1-4-(methylthio) phenyl)
isopropylphosphoramidate;
[00585] EXAMPLE 173 Compound 977 ((((S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl (3-methy1-4-(methylthio)phenyl)
isopropylphosphoramidate.
[00586] EXAMPLE 174 Compound 978 ((((R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yl)oxy) methyl (3-methy1-4-(methylthio)phenyl)
isopropylphosphoramidate.
[00587] EXAMPLE 175 Compound 829 ((2,(¨)-11R,2S,41Z1-2- (2-dimethyl amino
ethoxy) -2-
phenyl -1,7,7- trimethyl bicyclo [2.2.1] heptane) fumarate (US 4,342,762 A;
Laclanyi L et al.,
Stereochemistry and enantiomeric purity of a novel anxiolytic agent,
deramciclane fumarate. Chirality
11:689-93 (1999)). Fumarate of compound 829 can be prepared by a three-step
synthesis scheme
using readily available and low-cost starting materials (camphor) with very
high enantiomeric purity
(>99.9%). 3.9 g (0.1 g atom) of potassium metal are added to 100 ml of
anhydrous xylene, and the
mixture is reacted with 23.04 g (0.1 mole) of(+)-2-phenyl-1,7,7-trimethyl-bicy-
clo(2,2,1)heptan-2-ol
under vigorous stirring. When the formation of hydrogen gas has ceased, a
solution of 10.3 g (0.11
moles) of 1-dimethylamino-2-chloro-etheie in 30 ml of anhydrous xylene is
introduced, under further
stirring. The reaction mixture is kept at 100 C. for 6 hours, then washed
thrice with 50 ml of water,
and extracted with a solution of 15 g (0.1 mole) of tartaric acid in 80 ml of
water or with 0.11 mole of
diluted aqueous hydrochloric acid. The aqueous phase is made alkaline to pH 10
with an aqueous
solution of potassium hydroxide of 20% under cooling (at 0 to 5 C). The base
separated as an oil is
extracted with ether. After distilling off the solvent the residue is either
.purified with fractionated
distillation under vacuo or used for salt formation. Yield: 25.2 g (D.6%) of a
pale yellow oil, BP: 131 -
135 C./26.7 Pa, Hydrogen fumarate, m.p.: 180 -182 C.The enantiomeric
separation is accomplished
by HPLC on Chiralcel OD (250 x 4.6 mm; 10 [tm) and hexane-ethanol (99.5:0.5)
as mobile phase at
room temperature. Chemical Formula: C24H35N05. Molecular Weight: 417.55.
Elemental Analysis:
Calculated: C: 69.03%, H: 8.45%, N: 3.35%, Found: C: 69.05%, H: 8.59%, N:
3.44%;
[00588] Compound 829 is a dual 5-HT2A/5-HT2c receptors inverse agonist at
clinically relevant doses
and does not induce down-regulation of these receptors (Palvimaki EP et al.,
Deramciclane, a putative
anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to
induce 5-HT2C receptor
down-regulation. Psychopharmacology (1998) 136:99-104). Deramciclane is at
least 10-fold selective
against dopamine D2 receptors (Gacsalyi I et al., Receptor binding profile and
anxiolytic-type activity
154
Date Recue/Date Received 2021-04-14
of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997) 40:333-348).
Extensive
evaluation of Compound 829 in dopaminergic models has not revealed any
functional significance of
these receptor binding data. Compound 829 was not found to elevate prolactin ¨
at least within the
dose-range that covers therapeutically relevant exposures (Lame K et al.,
Effect of the novel anxiolytic
drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4
probe drug
buspirone. Eur J Clin Pharmacol (2003) 59: 761-766).
[00589] Compound 829 has been extensively characterized preclinically and a
large body of evidence
indicate CNS target(s) for the pharmacodynamic activity of deramciclane.
Gacsalyi and colleagues
(Gacsalyi I et al., Receptor binding profile and anxiolytic-type activity of
deramciclane (EGIS-3886)
in animal models. Drug Dev Res (1997) 40:333-348) described a profile of
effects induced by
deramciclane that are typical for 5-HT2A / 5-HT2c receptor inverse agonists. N-
desmethylderivative
of compound 829 is a biologically active metabolite having a profile similar
to that of to Compound
829.
[00590] Ability of Compound 829 to target 5-HT2A receptors in the CNS has been
directly demonstrated
in both animals (Palvimaki EP et al., Deramciclane, a putative anxiolytic
drug, is a serotonin 5-H12C
receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation.
Psychopharmacology
(1998) 136:99-104) and humans (Kanerva H et al., Brain 5-HT2A receptor
occupancy of deramciclane
in humans after a single oral administration--a positron emission tomography
study.
Psychopharmacology (1999) 145:76-81).
[00591] Ability of Compound 829 to target 5-HT2A receptors in the CNS has been
directly demonstrated
in rats using [3H]nesulergine binding to choroid plexus (Palvimaki EP et al.,
Deramciclane, a putative
anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to
induce 5-HT2C receptor
down-regulation. Psychopharmacology (1998) 136:99-104). Doses of Compound 829
that produce
near-maximal inhibition of [3H]mesulergine binding (0.5 mg/kg) are at the
lower range of doses
producing efficacy in animal models (Gacsalyi I et al., Receptor binding
profile and anxiolytic-type
activity of deramciclane (EGIS-3886) in animal models. Drug Dev Res (1997)
40:333-348).
Therefore, Compound 829 is expected to produce in humans antidepressant,
anxiolytic, appetite-
stimulating and other effects, all of which are therapeutically relevant in
patients with dementia
(Jensen NH et al., Therapeutic potential of 5-HT2C receptor ligands.
ScientificWorldJournal. 2010
Sep 14;10:1870-85; Meltzer BY et al., Serotonin receptors as targets for drugs
useful to treat psychosis
and cognitive impairment in schizophrenia. Curr Pharm Biotechnol. 2012
Jun;13(8):1572-86).
155
Date Recue/Date Received 2021-04-14
[00592] For Compound 829, there is evidence on therapeutic effects from
clinical studies in patients
with generalized anxiety disorder (Naukkarinen H et al., Deramciclane in the
treatment of generalized
anxiety disorder: a placebo-controlled, double-blind, dose-finding study. Eur
Neuropsychophannacol
(1999) 15:617-23), strengthening the claim that Compound 829 is a CNS-active
compound that is
capable of engaging its target(s). In the intent-to-treat population (n =
208), both deramciclane 30
mg/day and 60 mg/day doses provided clinically relevant improvements in
Hamilton Anxiety Rating
scale HAM-A total score after 8 weeks of treatment, reaching statistical
significance compared with
placebo (n=51) in the 60 mg,/day dose group (p = 0.024, n=54) and a clear
trend in the 30 mg/day
group (p = 0.059, n=53), but not in the 10 mg/day group (n=54). On the HAM-A
psychic anxiety
factor, significant improvements were seen in patients in the deramciclane 30
mg/day and 60 mg/day
treatment groups compared with those in the placebo group.
[00593] Compound 829 is also a CYP 2D6 inhibitor based on studies in humans
using desipramine as
a substrate. In this randomized double-blind, cross-over study, fifteen
healthy subjects received either
60 mg/day Compound 829 or placebo for 8 days. On day 8 of each study phase,
the subjects received
a 100-mg single dose of desipramine. Repeated administration of Compound 829
doubled the AUG
of desipramine (Lame K et al., Effect of the novel anxiolytic drug
deramciclane on cytochrome P(450)
2D6 activity as measured by desipramine pharmacokinetics. Eur J Clin Pharmacol
(2004) 59:893-
898).
[00594] EXAMPLE 176 Compound 1001 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)
phenoxy) propan-2-y1 4-(adamantan-1-ylamino)-4-oxobutanoate: Chemical Formula:
C34H46N205; Exact Mass: 562.34; Molecular Weight: 562.75; m/z: 562.34
(100.0%), 563.34
(36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); Elemental Analysis: C,
72.57; H, 8.24; N,
4.98; 0, 14.21; Boiling Point: 1300.87 [K]; Melting Point: 890.75 [K];
Critical Temp: 1176.29 [K];
Critical Pres: 8.99 [Bar]; Critical Vol: 1685.5 [cm3/mol]; Gibbs Energy: 126.8
[kJ/mol]; Log P: 5.06;
MR: 160.74 [cm3/mol]; Henry's Law: 16.03; Heat of Form: -719.51 [kJ/mol];
tPSA: 77.1; CLogP:
6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.
[00595] EXAMPLE 177 Compound 1002 (S)-1-(dimethylamino)-3-(2-(3-methoxy
phenethyl)
phenoxy) propan-2-y1 4-(adamantan -1- ylamino) -4- oxobutanoate: Chemical
Formula:
C34H46N205; Exact Mass: 562.34; Molecular Weight: 562.75; m/z: 562.34
(100.0%), 563.34
(36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); Elemental Analysis: C,
72.57; H, 8.24; N,
4.98; 0, 14.21; Boiling Point: 1300.87 [K]; Melting Point: 890.75 [K];
Critical Temp: 1176.29 [K];
156
Date Recue/Date Received 2021-04-14
Critical Pres: 8.99 [Bar]; Critical Vol: 1685.5 [cm3/mol]; Gibbs Energy: 126.8
[kJ/mol]; Log P: 5.06;
MR: 160.74 [cm3/mol]; Henry's Law: 16.03; Heat of Form: -719.51 [kJ/mol]l
tPSA: 77.1; CLogP:
6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.
[00596] EXAMPLE 178 Compound 1003 (R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yi 4-(adamantan-1-ylamino)-4-oxobutanoate: Chemical Formula:
C34H46N205; Exact Mass: 562.34; Molecular Weight: 562.75; m/z: 562.34
(100.0%), 563.34
(36.8%), 564.35 (3.9%), 564.35 (2.7%), 564.34 (1.0%); Elemental Analysis: C,
72.57; H, 8.24; N,
4.98; 0, 14.21; Boiling Point: 1300.87 [K]; Melting Point: 890.75 [K];
Critical Temp: 1176.29
[K];Critical Pres: 8.99 [Bar]; Critical Vol: 1685.5 [cm3/mol]; Gibbs Energy:
126.8 [kJ/mol]; Log P:
5.06; MR: 160.74 [cm3/mol]; Henry's Law: 16.03; Heat of Form: -719.51
[kJ/mol]l tPSA: 77.1;
CLogP: 6.5154; CMR: 16.1393; LogS: -6.845; pKa: 8.362.
1005971 EXAMPLE 179 Compound 1004 (R)-1-(dimethy1amino)-3-(2-(3-
methoxyphenethy1)
phenoxy) propan-2-yi 4-((3,5-dimethyl adamantan-1-y1) amino) -4- oxo
butanoate: Chemical
Formula: C36H50N205; Exact Mass: 590.37; Molecular Weight: 590.81; m/z: 590.37
(100.0%),
591.38 (38.9%), 592.38 (7.4%), 592.38 (1.0%); Elemental Analysis: C, 73.19; 1-
1, 8.53; N, 4.74; 0,
13.54; Boiling Point: 1347.11 [K]; Melting Point: 961.09 [K]; Critical Temp:
1191.88 [K]; Critical
Pres: 8.46 [Bar]; Critical Vol: 1793.5 [cm3/mol]; Gibbs Energy: 132.66
[kJ/mol]; Log P: 6; MR:
169.53 [cm3/mol]; Henry's Law: 15.78; Heat of Form: -730.31 [kJ/mol]; tPSA:
77.1; CLogP: 7.5534;
CMR: 17.0669; LogS: -7.773; pKa: 8.362.
[00598] EXAMPLE 180 Compound 1005 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)
phenoxy) propan-2-yi 4-((3,5- dimethyl adamantan-l-yi)amino) -4- oxobutanoate:
Chemical
Formula: C36H50N205; Exact Mass: 590.37; Molecular Weight: 590.81; m/z: 590.37
(100.0%),
591.38 (38.9%), 592.38 (7.4%), 592.38 (1.0%); Elemental Analysis: C, 73.19; H,
8.53; N, 4.74; 0,
13.54; Boiling Point: 1347.11 [K]; Melting Point: 961.09 [K]; Critical Temp:
1191.88 [K]; Critical
Pres: 8.46 [Bar]; Critical Vol: 1793.5 [cm3/mol]; Gibbs Energy: 132.66
[kJ/mol]; Log P: 6; MR:
169.53 [cm3/mol]; Henry's Law: 15.78; Heat of Form: -730.31 [kJ/mol]; tPSA:
77.1; CLogP: 7.5534;
CMR: 17.0669; LogS: -7.773; pKa: 8.362.
[00599] EXAMPLE 181 Compound 1005 (S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-yi 4-((3,5-dimethyl adamantan-1-y1) amino) -4- oxobutanoate:
Chemical
Formula: C36H50N205; Exact Mass: 590.37; Molecular Weight: 590.81; m/z: 590.37
(100.0%),
591.38 (38.9%), 592.38 (7.4%), 592.38 (1.0%); Elemental Analysis: C, 73.19; H,
8.53; N, 4.74; 0,
157
Date Re9ue/Date Received 2021-04-14
13.54; Boiling Point: 1347.11 [K]; Melting Point: 961.09 [K]; Critical Temp:
1191.88 [K]; Critical
Pres: 8.46 [Bar]; Critical Vol: 1793.5 [cm3/mol]; Gibbs Energy: 132.66
[kJ/mol]; Log P: 6; MR:
169.53 [cm3/mol]; Henry's Law: 15.78; Heat of Form: -730.31 [kJ/mol]; tPSA:
77.1; CLogP: 7.5534;
CMR: 17.0669; LogS: -7.773; pKa: 8.362
[00600] EXAMPLE 182 Compound 1007 1-(dimethylamino)-3-(2-(3-methoxyphenethyl)
phenoxy) propan-2-y1 (2,2,2-trichloro-1-(dimethoxyphosphoryl)ethyl) succinate:
Chemical
Formula: C28H37C13N09P; Exact Mass: 667.13; Molecular Weight: 668.93; m/z:
667.13 (100.0%),
669.12 (95.9%), 671.12 (30.6%), 668.13 (30.3%), 670.13 (29.0%), 672.12 (9.3%),
671.13 (4.2%),
673.12 (3.3%), 669.13 (2.7%), 669.13 (1.8%), 669.13 (1.7%), 671.13 (1.6%),
673.13 (1.4%);
Elemental Analysis: C, 50.28; H, 5.58; Cl, 15.90; N, 2.09; 0, 21.53; P, 4.63
[00601] EXAMPLE 183 Compound 1008 (S)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy) propan-2-y1 (2,2,2-trichloro-1-(dimethoxyphosphoryl)ethyl) succinate:
Chemical
Formula: C28H37C13N09P; Exact Mass: 667.13; Molecular Weight: 668.93; m/z:
667.13 (100.0%),
669.12 (95.9%), 671.12 (30.6%), 668.13 (30.3%), 670.13 (29.0%), 672.12 (9.3%),
671.13 (4.2%),
673.12 (3.3%), 669.13 (2.7%), 669.13 (1.8%), 669.13 (1.7%), 671.13 (1.6%),
673.13 (1.4%);
Elemental Analysis: C, 50.28; H, 5.58; Cl, 15.90; N, 2.09; 0, 21.53; P, 4.63
[00602] EXAMPLE 184 Compound 1009 (R)-1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)
phenoxy)propan-2-yi (2,2,2-trichloro-1-(dimethoxyphosphorypethyl) succinate:
Chemical
Formula: C28H37C13N09P; Exact Mass: 667.13; Molecular Weight: 668.93; m/z:
667.13 (100.0%),
669.12 (95.9%), 671.12 (30.6%), 668.13 (30.3%), 670.13 (29.0%), 672.12 (9.3%),
671.13 (4.2%),
673.12 (3.3%), 669.13 (2.7%), 669.13 (1.8%), 669.13 (1.7%), 671.13 (1.6%),
673.13 (1.4%);
Elemental Analysis: C, 50.28; H, 5.58; Cl, 15.90; N, 2.09; 0, 21.53; P, 4.63.
BIOLOGICAL STUDIES
[00603] Biological studies were conducted using compounds of Formula I
exemplified by 4-((1-
(dimethylamino)-3-(2-(3-methoxyphenethyl)phenoxy)propan-2-y0oxy)-4-oxobutanoic
acid
(represented by compounds 50, 51, and 52);
1-(dimethylamino)-3-(2-(3 -
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Date Re9ue/Date Received 2021-04-14
methoxyphenethyl)phenoxy)propan-2-ol (represented by compounds 146,
147, 148);
OH OH OH
I
-
N¨
H
Compound 146 Compound 147 Compound 148
Compound 829
Raeemate MI Enantiomer 1 (MI-El)
Enantiomer 2 (M1L-E2) Enantiomer
-(dimethyl amino)-3-0-0- (5)- 1-(dimethylamino)-3-(2-(3- (R)-1-
(dimethylamino)-3-(2-(3- N,N-dimethy1-2-(((1 R,2SAR)-1,7,7-
methoxyphenethyDphenoxy) methoxyphenethyl)phenoxy) methoxyphenethypphenoxy)
trirnethy1-2-phenylbicyclo[2.2.1]
propan-2-ol propan-2-ol propan-2-ol heptan-2-yl)oxy)ethan-1 -
amine
o
o
jj- OH Oy yOHr)LOH
Compound 50 Compound 51 Compound
52
Sarpogrelate Racemate (SGL) Sarpogrelate Enantiomer 1 (SGL-E I)
Sarpogrelate Enantiomer 2 (SGL-E2)
4-((1-(dimethylamino)-3-(2-(3- (5')-4-(( 1 -(dunethylamino)-3-(2-(3-
(R)-4-((1-(dimethylamino)-3-(2-(3-
methoxyphenethyl)phenoxy)propa methoxyphenethyl)phenoxy)propan-
methoxyphenethyl)phenoxy)propan-2-
n-2-yl)oxy)-4-oxobutanoic acid 2-yboxy)-4-oxobutanoic acid yl)oxy)-
4-oxobutanoic acid
N,N-dimethy1-2- [[(1R,3S,4R)-4,7,7-trimethy1-3-pheny1-3-bicyclo [2.2.1]
heptanyl] oxy] ethanamine or N,N-dimethy1-2-
(01R,2S,4S)-1,7,7-trimethyl-2-phenylbicyclo [2.2.1]heptan-2-yl)oxy)ethan-1-
amine (Compound 829, deramciclane)
and compounds of Formula II, exemplified by dextromethorphan, derivatives and
metabolites
thereof.
[00604] EXAMPLE 185: DEX METABOLISM AND CENTRAL EFFECTS OF 5HT2A
RECEPTOR BLOCKADE: Antipsychotic drugs attenuate locomotor hyperactivity
induced by
psychostimulant and psychotomimetic drugs in laboratory rodents. While
hyperactivity induced by
dopaminergic agents such as d-amphetamine is reversed by both typical and
atypical antipsychotics
that are currently in the clinic use, 5HT2A receptor antagonists are more
effective against hyperactivity
induced by NMDA receptor antagonists such as phencyclidine-like channel
blockers (Carlsson et al.,
The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA
antagonist- than
dopamine agonist-induced hyperactivity in mice, J. Neural. Transm. 106(2):123-
9 (1999)).
Pimavanserin (ACP-103) is an example of a 5HT2A receptor antagonist that was
administered in mice
in combination with 0.3 mg/kg MK-801 (i.p.) 15 min before the test session
(Vanover et al.,
Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N- (1-
methylpiperidin-4-y1) -
N'- (4-(2- methylpropyloxy) phenylmethyl) carbamide (2R,3R)-
dihydroxybutanedioate (2:1) (ACP-
103), a novel 5-hydroxytryptamine (2A) receptor inverse agonist, J Pharmacol
Exp Ther. 317(2):910-
8 (2006 May)). Motor activity data were collected during a 15-min session in a
lit room. Mice had no
prior exposure to the motor cages. Immediately before placing the mice in the
locomotor chambers,
159
Date Recue/Date Received 2021-04-14
effects on myorelaxation/ ataxia were determined by placing each of the
mouse's forepaws in contact
with a horizontal wire while holding the mouse by the base of the tail. Mice
were required to bring at
least one hindpaw in contact with the wire within 10 s to be scored as a
"pass" and failure to do so was
considered ataxic. Each dose or dose combination was tested in a separate
group of mice. ACP-103
significantly attenuated MK-801-induced hyperactivity in mice at doses of 0.1
and 0.3 mg/kg s.c.
[F(7,63)=6.010; p<0 .0001] , consistent with an antipsychotic-like effect.
[00605] When given in combination with quinidine in patients with neurological
diseases (Schoedel et
al., Evaluating the safety and efficacy of dextromethorphan/quinidine in the
treatment of pseudobulbar
affect. Neuropsychiatric Disease and Treatment 2014:10 1161-1174),
dextromethorphan is used at the
dose of 10 mg that may be administered twice a day. Currently known clinical
dose of Sarpogrelate
is 100 mg that is typically given three times a day (Doggrell (2004)
sarpogrelate: cardiovascular and
renal clinical potential, Expert Opinion on Investigational Drugs, 13:7, 865-
874). Thus, current
clinical dose of Sarpogrelate significantly exceeds that of dextromethorphan.
Given that the molecular
weight of sarpogrelate is about 429 and molecular weight of dextromethorphan
is about 271, combined
use of dextromethorphan and sarpogrelate at the current clinical doses does
not result in a molar ratio
of 1:1. However, such molar ratio of 1:1 is a pre-requisite for preparing and
using sarpogrelate salts
of dextromethorphan. As the current clinical use of sarpogrelate is for
peripheral (non-CNS)
indications (Doggrell (2004) sarpogrelate: cardiovascular and renal clinical
potential, Expert Opinion
on Investigational Drugs, 13:7, 865-874), use of sarpogrelate for CNS
indications may require lower
doses and therefore enable co-administration with dextromethorphan as
sarpogrelate salt of
dextromethorphan or as a mixture in a molar ratio of 1:1. In laboratory
animals, sarpogrelate is
typically given at doses of 25 mg/kg and above to induce peripheral effects
(Ma et al., Effective
treatment with combination of peripheral 5-hydroxytryptamine synthetic
inhibitor and 5-
hydroxytryptamine 2 receptor antagonist on glucocorticoid-induced whole-body
insulin resistance
with hyperglycemia. J Diabetes Investig 7(6):833-844 (2016)). An example of
higher CNS activity
of sarpogrelate is provided by an example where sarpogrelate is given to
Sprague-Dawley rats at the
doses of 0.3, 1 and 3 mg/kg 30 min prior to a centrally acting 5-HT2A agonist
DOT (3 mg/kg; (1(2,5-
dimethoxy-4-iodopheny1)-2-aminopropane)hydrochloride) and frequency of DOT-
induced head
shakes is reduced by co-administration of a compound of Formula I, SARPODEXTM,
DERADEXTM,
or DERAPHANTM.
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Date Recue/Date Received 2021-04-14
[00606] A compound of Formula I as well as both enantiomers of its primary
metabolite M1 are 5HT2A
receptor antagonists (Pertz et al., In-vitro pharmacology of a compound of
Formula I and the
enantiomers of its major metabolite: 5-HT2A receptor specificity,
stereoselectivity and modulation of
ritanserin-induced depression of 5-HT contractions in rat tail artery, J Pharm
Pharmacol. 47(4):310-6
(1995 April)). To confirm the ability of M1 S- and R-enantiomers to reach
5HT2A receptors in the
CNS, rats are pretreated with 0.1 mg/kg of MK801 and attenuation of MK801-
stimulated locomotor
hyperactivity is monitored across a range of doses of both a compound of
Formula I during 120-min
test session conducted using conventional motor activity monitors.
[00607] DEX acts at a number of receptors and one of its targets is the NMDA
receptor (Taylor et al.,
Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine
(Nuedexta0) clinical
use. Pharmacol Ther. 164:170-82 (2016 August)). However, DEX is a less potent
NMDA receptor
antagonist than its metabolite, DO. Accordingly, DEX is less likely to induce
phencyclidine-like motor
activity than DO. The behavioral effects of DEX, DO and phencyclidine (PCP)
were compared in
rats. DO (15-120 mg/kg) was similar to PCP (1.25-20 mg/kg) in inducing dose-
dependent locomotor
hyperactivity, stereotypy and ataxia. DEX (15-120 mg/kg) induced moderate
hyperactivity only at the
higher doses about 45 min after treatment. DEX and DO modified the locomotor
facilitation induced
by 10 mg/kg PCP in opposite directions. Pretreatment with DO facilitated,
whereas DEX dose-
dependently inhibited PCP-elicited hyperactivity (Szekely et al., Induction of
phencyclidine-like
behavior in rats by DO but not DEX, Pharmacol Biochem Behav, 40(2):381-6 (1991
October)).
[00608] EXAMPLE 186: A compound of Formula I as well as both enantiomers of
its primary
metabolite are CYP2D6 inhibitors. DEX is a commonly used substrate in in vitro
metabolism studies
to reveal 2D6 inhibitory activity of biologically active substances and drugs.
In a dedicated set of
studies, a compound of Formula I are administered prior to DEX and rats'
locomotor activity is
monitored for 120 min in order to demonstrate that a compound of Formula I
prevents emergence of
hyperactivity in DEX -treated subjects. These studies are paralleled by
measurements plasma DEX
levels. The combination of pharmacokinetic (plasma DEX concentration) and
pharmacodynamic
(MK-801- and DEX -induced hyperactivity) studies are used to identify the M1
enantiomer and the
dose level(s) producing the most optimal ratio of anti-hyperactivity and DEX
metabolism-suppressing
effects.
[00609] EXAMPLE 187: BLOOD GLUCOSE AND INSULIN SENSITIVITY: In contrast to the
sulfonylurea drugs, which result in significantly higher basal insulin
secretion compared to vehicle
161
Date Recue/Date Received 2021-04-14
treatment, DO and its prodrug DEX did not significantly alter basal insulin
secretion from mouse or
human islets or in vivo (Marquard et al., Characterization of pancreatic NMDA
receptors as possible
drug targets for diabetes treatment. Nat Med 21(4):363-72 (2015)). More
specifically, application of
DEX via drinking water (4 mg/ml) overnight changed neither basal plasma
insulin nor fasting blood
glucose concentrations in mice, but led to significantly higher glucose-
induced plasma insulin
concentrations and glucose tolerance than were seen in non-DEX-treated
controls (glucose
administered intraperitoneally at 1.5 mg/kg body weight).
[00610] Marguard et al. (2015) suggested that effects of DEX are mediated via
NMDA receptor channel
blocker and specifically pointed at the rapid metabolism of DEX into DO, a
potent inhibitor of the
NMDA receptors. To prove NMDA receptor involvement, Marguard et al.
demonstrated that glucose-
stimulated insulin secretion and glucose tolerance are not observed in mice
genetically engineered to
lack NMDA receptor function.
[00611] To test whether DEX could lead to higher serum insulin concentrations
and lower blood
glucose concentrations in people with type 2 diabetes mellitus (T2DM), a Phase
2a, Double-blinded,
placebo-controlled, randomized, crossover, single-dose proof-of-concept study
was performed
(Marquard et al., Characterization of pancreatic NMDA receptors as possible
drug targets for diabetes
treatment. Nat Med 21(4):363-72 (2015)). Twenty males with T2DM on metformin
monotherapy (age
59 (46-66) years (mean (range)); mean body mass index (BMI) 29.2 (25.2-34.1)
kg m-2; glycated
hemoglobin (HbAlc) 6.9 (6.5-7.4)%) were recruited. Each received a single oral
dose of 60 mg DEX,
270 mg DEX, 100 mg amantadine or placebo, followed by an oral glucose
tolerance test (OGTT) 1 h
after drug intake on four treatment days, separated by a washout period of 7-
14 days. Consistent with
the results in mice, DEX led to neither higher fasting serum insulin
concentrations nor lower fasting
blood glucose concentrations compared to placebo and did not provoke any
severe hypoglycemic
events up to a dose of 270 mg. In contrast, following oral glucose intake,
both 60 and 270 mg DEX
dosages resulted in significantly (P <0.05) higher maximal serum insulin
concentrations compared to
those seen with placebo.
[00612] In addition, the primary endpoint was reached for 270 mg DEX; that is,
the area under the
curve of blood glucose concentrations within the first 2 h of the OGTT
(glucose AUC1-3 h) was
significantly (P <0.05) smaller in individuals who received 270 mg doses of
DEX than in the same
individuals receiving placebo on a different treatment day.
162
Date Recue/Date Received 2021-04-14
[00613] Blood glucose level is also under control of peripheral 5HT2A
receptors (Yamada et al.,
Hyperglycemia induced by the 5-HT receptor agonist, 5-methoxytryptamine, in
rats: involvement of
the peripheral 5-HT2A receptor. Eur J Pharmacol. 323(2-3):235-40 (1997)). More
specifically,
administration of non-selective 5HT receptor agonist such as 5-
methoxytryptamine induced
hyperglycemia that is prevented by pretreatment with 5-HT2A receptor
antagonist ketanserin as well
as peripherally acting 5-HT2 receptor antagonist, xylamidine. These results
suggested that 5-
methoxytryptamine-induced hyperglycemia is mediated by the peripheral 5-HT2A
receptors.
[00614] Second-generation antipsychotics with dual dopamine and serotonin
receptor antagonism have
been associated with an increased risk for impaired glucose tolerance and
diabetes mellitus. Though
this has been largely attributed to weight gain, there is also a direct,
receptor-mediated effect of
antipsychotics on glucose tolerance. Certain 5HT2A receptor antagonists such
as ketanserin impair
insulin sensitivity (Gilles et al., Antagonism of the serotonin (5-HT)-2
receptor and insulin sensitivity:
implications for atypical antipsychotics. Psychosom Med. 67(5):748-51
(2005))). In the study by
Gilles et al., ten healthy male volunteers were included in a double-blind,
placebo-controlled crossover
study of a single close of 40 mg of the 5-HT2 antagonist ketanserin versus
placebo. Insulin sensitivity
was measured by means of the euglycemic-hyperinsulinemic clamp technique.
Subjects were treated
with the alpha-1 adrenergic antagonist phenoxybenzamine in both parts of the
study to control for
ketanserin's effects at the level athis receptor. Compared with the placebo
condition, subjects showed
a significantly decreased insulin sensitivity after ketanserin (placebo: 9.4
+/- 3.6 mg/kg/min;
ketanserin: 7.7 +/- 2.1 mg/kg/min; p = .047).
[00615] Thus, combining DEX and 5-HT2A receptor antagonists may lead to
synergistic effects on
blood glucose and insulin sensitivity that may be undesired in case of a long-
term treatment as it may
have unwanted metabolic side-effects qualitatively similar to those observed
in patients treated with
antipsychotic drugs. These effects may limit the doses of DEX and 5-HT2A
receptor antagonists that
can be safely administered as a combination.
[00616] There are two approaches that are part of this invention and that
enable therapeutic use of
combinations of DEX and 5HT2A receptor antagonists while reducing the risks of
peripheral
metabolic adverse effects.
[00617] One approach is based on the use of 5HT2A receptor inverse agonist or
antagonist that inhibits
CYP2D6 and thereby reduces the conversion of DEX into DO. Both DEX and DO are
NMDA receptor
channel blockers, and NMDA receptor inhibition in pancreatic islets was
suggested to be responsible
163
Date Recue/Date Received 2021-04-14
for glucose-stimulated insulin secretion, and glucose intolerance enhanced by
DEX and DO (Marquard
et al., Characterization of pancreatic NMDA receptors as possible drug targets
for diabetes treatment.
Nat Med 21(4):363-72 (2015)). Since DO is more potent NMDA receptor channel
blocker than DEX
(Pechnick et al., Comparison of the Effects of DEX, DO, and Levorphanol on the
Hypothalamo-
Pituitary-Adrenal Axis, The Journal Of Pharmacology and Experimental
Therapeutics, 309:515-522
(2004)), inhibition of DEX metabolism via CYP2D6 may reduce the expression of
effects of DEX on
glucose-stimulated insulin secretion and glucose tolerance and, therefore,
risks of metabolic side-
effects.
[00618] The second approach is the selection of a 5HT2A receptor inverse
agonist or antagonist that
has the best ratio of central vs. peripheral 5HT2A receptor occupancy.
Accordingly, a 5HT2A receptor
inverse agonist or antagonist is chosen to produce therapeutically relevant
central 5HT2A receptor
occupancy at the doses that are at lowest risk of producing unwanted metabolic
effects such as, but
not limited to, glucose intolerance.
[00619] The compound of formula I is a 5HT2A receptor inverse agonist or
antagonist that has 2D6
inhibitory properties. Acute and chronic effects of a compound of Formula 1 on
glucose tolerance and
insulin resistance have been examined (Takishita et al., Effect of
sarpogrelate hydrochloride, a 5-HT2
blocker, on insulin resistance in Otsuka Long-Evans Tokushima fatty rats
(OLETF rats), a type 2
diabetic rat model. J Cardiovasc Pharmacol 43(2):266-70 (2004)). In these
studies, Otsuka Long-
Evans Tokushima Fatty rats, a model of type 2 diabetes, were randomly assigned
to 2 groups; those
with 30 mg/kg BW/d a compound of Formula I treatment of 4 weeks (HTB group)
and without (control
group). The glucose infusion rate was significantly increased in the HTB group
compared with the
control group. The blood glucose levels after oral glucose tolerance test and
levels of plasma insulin
and lipids were significantly lower in the HTB group than in the control
group. a compound of Formula
I was shown to reverse insulin resistance induced by various means including
glucocorticoid drug
treatment (Ma et al., Effective treatment with a combination of peripheral 5-
hydroxytryptamine
synthetic inhibitor and 5-hydroxytryptamine-2 receptor antagonist on
glucocorticoid-induced whole-
body insulin resistance with hyperglycemia. J Diabetes Investig 7: 833-844
(2016)).
[00620] Synergistic effects of a compound of Formula I on blood glucose and
insulin sensitivity have
been shown for several drugs including carbidopa (Ma et al., Effective
treatment with a combination
of peripheral 5-hydroxytryptamine synthetic inhibitor and 5-hydroxytryptamine-
2 receptor antagonist
on glucocorticoid-induced whole-body insulin resistance with hyperglycemia. J
Diabetes Investig 7:
164
Date Recue/Date Received 2021-04-14
833-844 (2016)) and pioglitazone (Iizuka et al., Beneficial effects of a
compound of sarpogrelate
hydrochloride, a 5-HT2A receptor antagonist, supplemented with pioglitazone on
diabetic model
mice. Endocr Res. 34(1-2):18-30 (2009)).
[00621] Insulin-sensitizing effects of a compound of Formula I have also been
confirmed in humans
(Kokubu et al., Persistent insulin-sensitizing effects of sarpogrelate
hydrochloride, a serotonin 2A
receptor antagonist, in patients with peripheral arterial disease. Circ J
70(11):1451-6 (2006)). Indices
of insulin resistance (fasting immunoreactive insulin) were measured before
and after 2 weeks of a
compound of Formula I administration (300 mg/day) in 24 patients (19 men, 76+/-
9 years) with
peripheral arterial disease. Sixteen of the 24 patients were also examined
after 3 months of treatment.
After 2 weeks of treatment, significant decreases in fasting immunoreactive
insulin (p=0.03) were
observed. After 3 months of treatment, significant decreases in fasting
immunoreactive insulin
(16.0+/-10.3 vs 9.2+/-2.0 microU/ml, p=0.03) were maintained.
[00622] A compound of Formula I is rapidly metabolized into metabolite that
also has both 5HT2A
receptor antagonist and 2D6 inhibitory properties. Both enantiomers of
metabolite are biologically
active and share the ability to block 5H12A receptors and 21)6. To establish
which of the enantiomers
has the most optimal properties for being combined with DEX, effects of these
substances alone and
in combination with DEX on oral glucose tolerance are assessed (Taniguchi et
al., Diabetes, 55, 2371-
2378 (2006)). This method is based on the measurement a whole blood glucose
and plasma insulin.
Test substances are administered to male Sprague-Dawley rats (group size: 8
per group). Animals are
tested after an overnight food deprivation and individually housed. Test
substance is administered 60
minutes before glucose challenge, i.e. after baseline blood glucose
measurement. Animals are
challenged with glucose at 2 g/kg as an oral gavage at TO, after blood glucose
measurement. Blood
glucose is measured from a drop of blood collected from the cut tip of the
tail, using a commercially
available glucose-meter at 8 time-points: baseline (before treatment), TO
(before glucose) and then 15,
30, 60, 90, 120 and 180 minutes post-glucose challenge.
[00623] EXAMPLE 188: EFFECTS OF FORMULA I ALONE ON AD PATHOPHYSIOLOGY:
Links between a chronic diabetic metabolic situation and the risk and
emergence of AD
pathophysiology have long been suspected and substantiated in the recent years
(Goldwasser et al.,
Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic
Link between Diabetes
Mellitus and Alzheimer's Disease. JAlzheimers Dis 54(2):445-56 (2016 Aug 1)).
In several large post-
mortem series, more than a third of all subjects clinically diagnosed with
typical AD showed evidence
165
Date Recue/Date Received 2021-04-14
of cerebrovascular disease and had to be re-classified as mixed dementia
(Grandal Leiros et al.,
Prevalence and concordance between the clinical and the post-mortem diagnosis
of dementia in a
psychogeriatric clinic, Neurologia S0213-4853(16)30070-6 (2016)). From a
clinical perspective, it is
desirable to extend AD therapy beyond currently approved drugs and mechanisms,
and also address
the cognitive impairment by optimizing a latent diabetic metabolic situation
or the fairly frequent Type
2 diabetes in the elderly subjects. Indeed, glycaemic control is thought to
have an impact o the severity
of cognitive impairment (Zilliox et al., Diabetes and Cognitive Impairment.
Curr Diab Rep, 16 (9):87
(2016)).
[00624] Due to the specific anti-diabetic actions of a compound of Formula I
described above, it is,
therefore, conceivable to attempt an added benefit on both, symptoms and
disease progression in AD,
and in cognitive impairment of mainly vascular origin (multi-infarct dementia,
vascular dementia,
vascular cognitive impairment, etc.).
[00625] Based on the Japanese regulatory label, the incidence of adverse
events with a compound of
Formula I therapy in internal medicine is quite low as compared to placebo and
the nature of AEs
reported found to be acceptable; therefore, the benefit-risk ratio of added a
compound of Formula 1
therapy seems defendable, also in an elderly, multimorbid population.
[00626] EXAMPLE 189: STEREOSELECTIVE REVERSAL OF PSYCHOSTIMULANT-
INDUCED HYPERACTIVITY IN VIVO BY COMPOUND: Motor activity data were collected
during a 15-min session in a lit room. Mice had no prior exposure to the motor
cages. Immediately
before placing the mice in the locomotor chambers, effects on
myorelaxation/ataxia were determined
by placing each of the mouse's forepaws in contact with a horizontal wire
while holding the mouse by
the base of the tail. Mice were required to bring at least one hindpaw in
contact with the wire within
10 s to be scored as a "pass" and failure to do so was considered ataxic. Each
dose or dose combination
was tested in a separate group of mice. ACP-103 significantly attenuated MK-
801-induced
hyperactivity in mice at doses of 0.1 and 0.3 mg/kg s.c. [F(7,63)=6.010;
p<0.0001], consistent with an
antipsychotic-like effect.
[00627] HEK-293 cells expressing human recombinant 5HT2A receptor were used in
the antagonist
radioligand binding studies. A compound of Formula I such as Compound 50
racemate and both
enantiomers were applied at concentrations ranging from 3.0E-11 M to 1.0E-07
M. M1 enantiomers
were applied at concentrations ranging from 1.0E-11 M to 3.0E-08 M. The IC50
values (concentration
causing a half-maximal inhibition of control specific binding) and Hill
coefficients (nil) were
166
Date Recue/Date Received 2021-04-14
determined by non-linear regression analysis of the competition curves
generated with mean replicate
values using Hill equation curve fitting. The inhibition constants (Ki) were
calculated using the Cheng
Prusoff equation. Both sarpogrelate enantiomers were potent inhibitors of
[3H]ketanserin binding
(Table 1). M1 enantiomers also potently bind to 5HT2A receptors with the Ki
values that are
approximately one order of magnitude higher than those of sarpogrelate
enantiomers (Table 1). There
are no meaningful differences between enantiomers in terms of 5-HT2A receptor
binding for
sarpogrelate or its main metabolite.
[00628] TABLE 3 Inhibitory effects of sarpogrelate (racemate and enantiomers)
and M-1 enantiomers
on 5-HT2A receptor binding
Compound IC50, nM pKi
50 9.6 8.3
(+) 51 7.5 8.4
(-) 52 11 8.2
(+) 147 1.2 9.1
(-) 148 1.3 9.2
1006291 To confirm the ability of M1 enantiomers to induce effects that are
relevant to CNS diseases
and that are known for 5-HT2A receptor agonists and inverse agonists, separate
groups of female
Wistar rats (n=6-9), housed 4-5 per cage under standard colony room conditions
with free access to
food and water, were pretreated intraperitoneally with varying doses of one of
the two MI enantiomers
(0, 3 or 10 mg/kg) followed 15 minutes later by 0.1 mg/kg of MK801 or its
vehicle and immediately
thereafter placed into computer-controlled motor activity recording chambers
(25 x 35.5 x 34 cm, L x
W x H; transparent Plexiglas walls and a non-transparent plastic floor;
enclosed within sound-
attenuating ventilated cubicles) for 60 minutes, during which infrared
photocell interruptions (5 cm
and 14 cm off the floor) were recorded as a measure of motor activity. MK-801
is a phencyclidine-
like NMDA receptor channel blocked commonly used in psychopharmacology
research on novel
therapies including novel antipsychotics. Analysis of variance (ANOVA) has
revealed main effects
of the M1 dose and the interaction between M1 dose and MK-801 treatment
factors for the (-) M1
enantiomer [F(2,39)=6.154; p=0.0048, F(2,39)=4.613; p=0.0159, respectively]
and not for the (+) M1
enantiomer [F(2,42)=0.5211; p=0.5977, F(2,42)=0.5229; p=0.5966, respectively].
As shown in Figure
7, both doses of the (-)M1 enantiomer as well as 3 mg/kg of a prototypical 5-
HT2A receptor antagonist
M-100,907 reduced hyperactivity induced by MK-801 (Dunnett's multiple
comparisons test). Thus,
despite no significant differences between M1 enantiomers in terms of binding
to 5-HT2A receptors,
167
Date Recue/Date Received 2021-04-14
surprisingly, only one of the enantiomers exerts efficacy in a preclinical
model of psychomotor
activation that is known to be sensitive to 5-HT2A receptor blockade.
1006301 EXAMPLE 190: REVERSAL OF MOTOR HYPERACTIVITY INDUCED BY
OLFACTORY BULBECTOMY IN RATS: In a dedicated set of studies, adult male
Sprague-
Dawley rats (Charles River, Germany) were subjected to bilateral olfactory
bulbectomy performed
under ketamine/xylasine anesthesia. The animals were allowed to recover for 14
days following
surgery while being handled daily to eliminate any aggressiveness that would
otherwise arise. Sham-
operated animals were treated in the same way but the olfactory bulbs were
left intact. Drugs
administration and locomotor activity testing were performed 4 times for each
rat with 72 hours break
between consecutive test sessions. Prior to each test session, animals were
first treated with
dextromethorphan (0, 15, 30 or 60 mg/kg. per os) followed 15 min later by
sarpogrelate (1, 3 and 10
mg/kg, intraperitoneal) and another 15 min later were placed into Opto-Varimex
cages for locomotor
activity recording over 30 min. Hyperactivity in rats after olfactory
bulbectomy is observed mostly
during the early portion of the test sessions. Figure 8 presents average
activity counted over the first
15 min of the test when activity of the bulbectomized animals was
significantly higher than that of the
sham controls. ANOVA revealed a significant main effects of both surgery and
sarpogrelate dose
factors [F(1,88)=5.04, p=0.0273; F(3,88)=5.02, p=0.0029, respectively].
Post hoc pairwise
comparisons (Sidak's multiple comparisons test) confirmed that significant
differences between
bulbectomized and sham-operated were observed only in rats that were
pretreated prior to the test with
vehicle instead of sarpogrelate. Bulbectomized rats pretreated with 3 or 10
mg/kg of sarpogrelate
spent less time in ambulations compared with the respective controls that
received vehicle instead of
sarpogrelate. These anti-hyperactivity effects of sarpogrelate are observed at
the doses that do not
affect activity of sham-operated rats and therefore do not reflect a
generalized non-specific impairment
of motor capabilities. Thus, surprisingly, despite being previously referred
to as a peripherally
restricted 5-HT2A receptor antagonist with only minimal penetration across the
blood-brain barrier
(Obata H et al. Antinociception in rat by sarpogrelate, a selective 5-HT(2A)
receptor antagonist, is
peripheral. Eur J Pharmacol 404(1-2):95-102 (2000)), sarpogrelate is observed
to exert behaviorally
specific anti-hyperactivity effects in rats after olfactory bulbectomy, a
model commonly used to study
CNS drugs such as antidepressants.
[00631] EXAMPLE 191: INHIBITION OF DEXTROMETHORPHAN METABOLISM IN
VITRO AND IN VIVO: Dextromethorphan 0-demethylase activity was determined in
human liver
168
Date Recue/Date Received 2021-04-14
microsomes. Sarpogrelate (1.0E-8 M to 3.0E-5 M) or M-1 (concentration: 3.0E-9
M to 1.0E-5 M) and
dextromethorphan were dissolved in acetonitrile and serially diluted with
acetonitrile to the required
concentrations to give a final organic solvent concentration of 1.0% in the
incubation mixture. The
incubation mixtures contained pooled human liver microsomes (final
concentrations: 0.25 mg/ml),
dextromethorphan, and a NADPH-generating system (1.3 mM NADP+, 3.3 mM glucose
6-phosphate,
3.3 mM MgCl2, and 0.4 U/ml glucose-6-phosphate dehydrogenase). After
incubation and
centrifugation, the supernatant was diluted 100-fold with acetonitrile and
then injected into the LC-
MS/MS system. All incubations were performed in triplicate, and mean values
were used for analysis.
The 1C50 values (concentration causing a half-maximal inhibition of control
specific binding) and Hill
coefficients (nH) were determined by non-linear regression analysis of the
competition curves
generated with mean replicate values using Hill equation curve fitting. Both
sarpogrelate enantiomers
inhibited CYP2D6-mediated dextromethorphan 0-demethylation (Table 4).
[00632] Table 4. Inhibitory effects of sarpogrelate (racemate and enantiomers)
and M-1 enantiomers
on CYP 2D6 activity.
Compound 1050, M
50 1.2
(+) 51 0.58
(-) 52 1.3
(+) 147 0.038
(-) 148 0.096
[00633] While both enantiomers of M1 markedly inhibited 2D6 activity with the
IC50 values of 0.038-
0.096 M, sarpogrelate enantiomers were approximately 10-15 times less potent
(Table 4). Based on
previous in vivo studies, sarpogrelate was classified as a weak 2D6 inhibitor.
This classification was
based on a less than 2-fold increase in the substrate AUC (i.e. per guidance
provided by the US Food
and Drug Administration, Draft guidance for industry: drug interaction studies
¨ study design, data
analysis, implication for dosing and labeling recommendations. Center for Drug
Evaluation and
Research, US FDA (2012).
[00634] Pharmacokinetic study was performed in male Wistar rats equipped with
the jugular vein
cannulas. Sarpogrelate hydrochloride was formulated in Pharmasolv: PBS buffer
(5:95) mixture and
administered at the dose of 2 mg/kg intravenously. Blood samples were
collected from the jugular
vein using heparin as anticoagulant at the scheduled time-points: 5 min, 15
min, 30 min, 1 h, 1.5 h, 2
h, 4 h, and 6 h. An LC-MS/MS bioanalytical method was used for the
simultaneous quantification of
169
Date Recue/Date Received 2021-04-14
sarpogrelate and M1 in plasma samples. Following 2 mg/kg intravenous bolus
administration the
plasma level curves showed small inter-individual variability (Figure 9).
Apparent terminal
elimination half-life was estimated at 1.21 0.159 h. Formation of M1
metabolite of sarpogrelate was
rapid as the highest M1 concentrations were measured at the first sampling
time points. In spite of the
rapid formation, concentrations of the free M1 metabolite were orders of
magnitude lower in the
circulation than those of the parent compound (MI/sarpogrelate ratio of 2.98
0.597 %). Thus,
although M1 enantiomers are significantly more potent 2D6 inhibitors than the
parent compound,
potential impact of M1 is mitigated by low relative exposure to M1 suggested
by the ratio of plasma
AUC for M1 and sarpogrelate.
[00635] EXAMPLE 191: In a separate set of studies, ability of sarpogrelate to
inhibit
dextromethorphan metabolism in vivo was studied in rats. Adult male Sprague
Dawley rats
(RjHan:SD) purchased from Janvier Labs (France) were housed in a climate-
controlled room under a
12h light/12h dark cycle with ad libitum access to food and water. Two-three
days prior to blood
sampling, rats were provided with a catheter in the jugular vein and,
thereafter, rats treated once with
Carprofen (5 mg/kg) directly after surgery and catheters were rinsed daily
with Heparin (500 1E/m1)
(20 pl/rat/day). On the day of the experiment, dextromethorphan (50 mg/kg) was
administered by oral
gavage, immediately followed by intravenous bolus injection of sarpogrelate
(1, 3 or 10 mg/kg;
racemate or one of the enantiomers) or vehicle via vascular access port at t =
0 h. Blood samples were
collected at four time points until 6 hours post dextromethorphan
administration. Sample size was 80
[t1 Li-heparin whole blood / time point, i.e. 40 ul Li-heparin plasma /time
point. Whole blood samples
were stored on ice until centrifugation (10 min at 3000 g, 4 C). Plasma was
prepared within 45 min
after collection, frozen at -20 C and stored at this temperature until
processed for LC-MS analysis.
[00636] As shown in Figure 10, in rats treated with sarpogrelate (racemate or
enantiomers) plasma
levels of dextromethorphan continued to be high even at the later time points
while, in vehicle-treated
rats, dextromethorphan levels declined towards the 6-h time point.
[00637] Surprisingly, quantification of the AUC for dextromethorphan indicated
that, at the highest
tested dose of 10 mg/kg, sarpogrelate increased the dextromethorhan AUC 5.3-
6.9 fold. Even at the
lower dose of 3 mg/kg, dextromethorphan AUC was increased 2.7 (for the (-)
enantiomer) to 3.3 fold
(for the (+) enantiomer).
[00638] Table 5. Area under the curve (0-6 h) analysis of dextromethorphan
plasma concentration in
rats treated with sarpogrelate (racemate and enantiomers)
170
Date Recue/Date Received 2021-04-14
Treatment Sarpogrelate dose Dextromethorphan Fold
increase (relative to
(mg/kg) AUC (ng*hr/m1)
vehicle)
Vehicle 605.8
Compound 50 1 2329.5 3.8
3 3356.1 5.5
3211.9 5.3
(+)Compound 51 1 827.0 1.4
202L5 13
10 4154.3 6.9
(-)Compound 52 1 921.4 1.5
3 1 649 .5 2.7
10 3195.9 5.3
[00639] EXAMPLE 192: INHIBITION OF PHENCYCLIDINE-INDUCED HYPERACTIVITY
IN RATS TREATED BY A COMBINATION OF SARPOGRELATE AND
DEXTROMETHORPHAN: The behavioral effects of DEX, DO and phencyclidine (PCP)
were
compared in rats. DO (15-120 mg/kg) was similar to PCP (1.25-20 mg/kg) in
inducing dose-dependent
5 locomotor hyperactivity, stereotypy and ataxia. DEX (15-120 mg/kg)
induced moderate hyperactivity
only at the higher doses about 45 min after treatment. DEX and DO modified the
locomotor facilitation
induced by 10 mg/kg PCP in opposite directions.
[00640] In a dedicated set of studies, Compound 50 racemate and enantiomers
were co-administered
with DEX to demonstrate the ability of such drug combination(s) to counteract
psychomotor activation
10 and hyperactivity. Male Sprague-Dawley rats were administered
intraperitoneally Compound 50
(sarpogrelate racemate), (-) sarpogrelate, (+) sarpogrelate or vehicle as well
as subcutaneous (racemate
experiment) or oral (enantiomer experiments) dextromethorphan or vehicle
(water) and were placed
individually into the Opto-Varimex-4 auto-tracks. Fifteen minutes later rats
were removed from the
boxes, injected with phencyclidine (PCP; 5 mg/kg, subcutaneous) and returned
to the auto-tracks for
additional 105 min (i.e. until a total recording time of 120 min). Data
analysis focused on the second
half of the test (60-120 min). ANOVA has revealed significant interaction
between the dose of
sarpogrelate and the dose of dextromethorphan (Figure 11, upper panel;
F(9,120)=2.38, P=0.015).
[00641] Similar statistically significant interaction with the dose of
dextromethorphan was observed
for (-) sarpogrelate (Figure 11, middle panel; F(9,141)=3.07, P=0.002) but not
for (+) sarpogrelate
(Figure 11, lower panel; F(9,120)=1.65, P=0.1). The post-hoc analysis
indicated that, in the presence
of dextromethorphan, 3 mg/kg of sarpogrelate racemate as well as 1 mg/kg or 3
mg/kg of (-)
sarpogrelate inhibited motor hyperactivity in PCP-treated rats (Dunnett's
multiple comparisons test).
This pattern of the results is surprising given that the (-) enantiomer of
sarpogrelate is less potent than
171
Date Recue/Date Received 2021-04-14
the (+) enantiomer in terms of inhibiting dextromethorphan metabolism both in
vitro (Table 4) and in
vivo (Table 5).
1006421 When given in the absence of dextromethorphan, neither sarpogrelate
racemate nor
sarpogrelate enantiomers reduced activity in PCP-treated rats. When given in
combination with
dextromethorphan, inhibitory effects of sarpogrelate were observed
irrespective of whether
dextromethorphan by itself reduced (subcutaneous administration, experiment
with sarpogrelate
racemate) or enhanced (oral administration, experiments with sarpogrelate
enantiomers) motor activity
in PCP-treated rats. Thus, presence of dextromethorphan may be required for
sarpogrelate exert
inhibitory effects in subjects with psychomotor activation such as rats with
hyperactivity after
exposure to a psychotomimetic drug PCP. Such pattern of supra-additive
interactions between
dextromethorphan and sarpogrelate is surprising.
1006431 EXAMPLE 193: METHOD OF ASSESSMENT OF BLOOD GLUCOSE LEVELS
AND ORAL GLUCOSE TOLERANCE: Test substances were administered to male Wistar
(Han)
rats (180-280 g at the beginning of the experiments; Janvier Labs) housed in
groups under free
access to food and water. After overnight food deprivation, the tip of the
tail was cut, each rat was
weighed, housed individually and left without stress in a quiet room.
Approximately 1 hour later,
baseline blood glucose was measured from a drop of blood collected from the
tail tip, using a
commercially available glucose-meter (OneTouch , Lifescan) and then rats
received intraperitoneal
injection of sarpogrelate and/or dextromethorphan and 30 min later blood
glucose was measured
again and rats immediately challenged with glucose at 2 g/kg by oral gavage.
Then, blood glucose
was measured at 6 time-points until 180 minutes post-glucose challenge. As
shown in Figure 12,
there was a main effect of drug treatment (F(4,59=12.0, p<0.0001). Post hoc
pairwise group
comparisons indicated that, when given alone, dextromethorphan has
significantly reduced blood
glucose level and this effect of dextromethorphan was reversed when it was
administered in
combination with sarpogrelate racemate or either of the enantiomers.
[00644] EXAMPLE 194: 52 WEEKS OF CHRONIC TOXICITY TEST AND 5 WEEKS OF
RECOVERY TEST USING BEAGLE DOGS (Suzuki et al., Pharmacology & Therapeutics
Vol
19 Supplement '91): Compound 50 hydrochloride was given orally to beagle dogs
at dose levels of
5, 20, 80 and 320 mg/kg/day for 52 consecutive weeks. No animal died or was
sacrificed in extremis
regardless of sex. As for general conditions, emesis was noted in males and
females receiving
320mg/kg/day and males receiving 80 mg/kg/day and salivation in females
receiving 320 mg/kg/day.
172
Date Recue/Date Received 2021-04-14
The body weight gain was inhibited in males and females receiving 320
mg/kg/day. Food consumption
was inhibited in females receiving 80mg/kg/day and over. Females receiving
320mg/kg/day also
showed an inhibition of water consumption. ln the recovery period, the general
conditions observed
showed no difference between the control and treated groups. There was no
treatment related change
at electrocardiographic or ophthalmoscopic examination. ln the urinalysis, an
increase in protein was
revealed in females receiving 320 mg/kg,/day, in the hematological
examination, an increase in a
platelet count in males receiving 320 mg/kg/day, and in the biochemical
examination, an increase in
potassium in males receiving 80 mg/kg/day and over, and females receiving 320
mg/kg/day. These
changes recovered after drug withdrawal. The relative weight of the thyroid
and liver was increased
in males receiving 80 mg/kg/day and over, but no treatment related change was
seen in the
histopathological examination. ln the histopathological examination, fatty
degeneration was revealed
in the cortico-medullary border zone of the kidney in males receiving 320
mg/kg/day. ln the recovery
period however this change was not found. The no effect dose level of compound
50 hydrochloride in
a 52-week study was estimated at 20 mg/kg.
[00645] While contain features of the invention have been illustrated and
described herein, many
modifications, substitutions, changes, and equivalents will now occur to those
of ordinary skill in the
art. It is, therefore, to be understood that the appended claims are intended
to cover all such
modifications and changes as fall within the true spirit of the invention. It
will be understood by those
skilled in the art that various changes in form and details may be made
therein without departing from
the spirit and scope of the invention as set forth in the appended claims.
Those skilled in the art will
recognize or be able to ascertain using no more than routine experimentation,
many equivalents to the
specific embodiments of the invention described herein. Such equivalents are
intended to be
encompassed in the scope of the claims. Reasonable variations are not to be
regarded as a departure
from the scope of the invention. It will be obvious that the thus described
invention may be varied and
that various modifications, additions, substitutions, and variations to the
illustrative examples set forth
herein can be made without departing from the spirit of the invention and are,
therefore, considered
within the scope of the invention.
[00646] EXAMPLE 195: REVERSAL OF MOTOR HYPERACTIVITY INDUCED BY NMDA
RECEPTOR BLOCKADE IN RATS: To confirm the ability of the present invention (a
compound
173
Date Recue/Date Received 2022-05-04
of Formula I) to induce antipsychotic-like effects that are relevant to
efficacy against behavioral and
psychological symptoms of dementia and that are known for 5-HT2A receptor
agonists and inverse
agonists, separate groups of rats, housed under standard colony room
conditions with free access to
food and water, are pretreated with varying doses of deramciclane (up to 30
mg/kg) followed by an
NMDA receptor channel blocker or its vehicle and immediately thereafter placed
into computer-
controlled motor activity recording chambers. NMDA receptor channel blockers
are commonly used
in psychopharmacology research on novel therapies including novel
antipsychotics. Analysis of
variance (ANOVA) is applied to reveal main effects of the deramciclane dose
and the interaction
between the deramciclane dose and NMDA receptor treatment factors.
[00647] EXAMPLE 196: REVERSAL OF MOTOR HYPERACTIVITY INDUCED BY
OLFACTORY BULBECTOMY IN RATS: In a dedicated set of studies, adult male rats
are
subjected to bilateral olfactory bulbectomy, a model commonly used to study
CNS drugs such as
antidepressants. The animals are allowed to recover for at least 14 days
following surgery. Sham-
operated animals are treated in the same way but the olfactory bulbs are left
intact. Prior to each test
session, animals are treated with dextromethorphan (up to 60 mg/kg per os)
combined with the
compound of Formula I (up to 30 mg/kg) and later placed into activitiy
monitors for locomotor activity
recording. Hyperactivity in rats after olfactory bulbectomy is observed mostly
during the early portion
a the test sessions. Results are presented as average activity counted over
the early portions a test
session when activity of the bulbectomized animals is significantly higher
than that of the sham
controls. ANOVA is applied to reveal significant main effects of both surgery
and treatment dose
factors. The anti-hyperactivity effects of deramciclane are observed at the
doses that do not affect
activity of sham-operated rats and therefore do not reflect a generalized non-
specific impairment of
motor capabilities.
[00648] EXAMPLE 197: INHIBITION OF DEXTROMETHORPHAN METABOLISM:
Dextromethorphan 0-demethylase activity is determined in human liver
microsomes. The compound
of Formula I (concentration: up to 3.0E-5 M) and dextromethorphan are
dissolved in acetonitrile and
serially diluted with acetonitrile to the required concentrations to give a
final organic solvent
concentration of about 1.0% in the incubation mixture. The incubation mixtures
contain pooled human
liver microsomes, dextromethorphan, and a NADPH-generating system. After
incubation and
centrifugation, the supernatant is diluted up to 100-fold with acetonitrile
and then injected into the LC-
MS/MS system. All incubations are performed in triplicate, and mean values are
used for analysis.
174
Date Recue/Date Received 2021-04-14
The IC50 values (concentration causing a half-maximal inhibition of control
specific binding) and Hill
coefficients (nH) are determined using methods such as non-linear regression
analysis of the
competition curves generated with mean replicate values using Hill equation
curve fitting.
Deramciclane is observed to inhibit CYP2D6-mediated dextromethorphan 0-
demethylation.
[00649] Based on previous human studies with desipramine as a substrate, the
compound of Formula I
can be classified as a weak 2D6 inhibitor (Lame K et al., Effect of the novel
anxiolytic drug
deramciclane on cytochrome P450 2D6 activity as measured by desipramine
pharmacokinetics. Eur J
Clin Pharmacol (2004) 59: 893-898). This classification was based on about 2-
fold increase in the
substrate AUC (i.e. per guidance provided by the US Food and Drug
Administration, Draft guidance
for industry: drug interaction studies ¨ study design, data analysis,
implication for dosing and labeling
recommendations. Center for Drug Evaluation and Research, US FDA (2012).
[00650] In a pharmacokinetic study performed in rats, ability of the compound
of Formula I to inhibit
dextromethorphan metabolism is studied in vivo. Adult rats are housed in a
climate-controlled room
under a 12h light/12h dark cycle with ad libitum access to food and water. On
the day of the
experiment, dextromethorphan (50 mg/kg) is administered by oral gavage,
immediately followed by
deramciclane (up to 30 mg/kg) or vehicle (t= 0 h). Blood samples are collected
at multiple time points
until 24 hours post dextromethorphan administration. Sample size is about 80
p.1 Li-heparin whole
blood / time point, i.e. 40 [t1 Li-heparin plasma / time point. Whole blood
samples are stored on ice
until centrifugation (10 min at 3000 g, 4 C). Plasma is prepared within 45
min after collection, frozen
at -20 C and stored at this temperature until processed for LC-MS analysis. In
rats treated with the
compound of Formula I, plasma levels of dextromethorphan continue to be high
even at the later time
points while, in vehicle-treated rats, dextromethorphan levels decline faster.
[00651] EXAMPLE 199: EFFECTS OF THE COMPOUND OF FORMULA I ON
DISCRIMINATIVE STIMULUS EFFECTS OF DEXTROMETHORPHAN AND
MEMANTINE: Drug discrimination is commonly used to assess interoceptive
stimulus control
produced by psychoactive drugs (Sukhotina IA et al., Effects of calcium
channel blockers on behaviors
induced by the N-methyl-D-aspartate receptor antagonist, dizocilpine, in rats.
Pharmacol Biochem
Behav (1999) 63:569-80). These methods are used to address ability of certain
classes of CNS active
drugs such as NMDA receptor channel blockers to produce adverse effects
(Nicholson KL et al.,
Evaluation of the reinforcing and discriminative stimulus properties of the
low-affinity N-methyl-D-
aspartate channel blocker memantine. Behav Pharmacol (1998) 9:231-43).
175
Date Recue/Date Received 2021-04-14
[00652] Adult male Wistar rats were housed individually with water available
ad lib. Food consumption
was restricted to 14-16 g/day given after behavioral testing to maintain a
constant body weight (300-
330 g). Behavioral training and testing was conducted using standard two-lever
operant conditioning
chambers connected to a microcomputer through an interface and controlled by
MED-PC software.
Each chamber was equipped with a food dispenser, which delivered 45-mg food
pellets. At the start
of each drug discrimination training session, rats were injected i.p. with
either 0.056 mg/kg of
dizocilpine or saline, returned to their home cages, and then 15 min later
were placed into the operant
chambers for a total of 15 min. During test sessions, 10 consecutive responses
on either lever produced
a pellet delivery. Prior to the test sessions, there were two injections
given; one i.p. with deramciclane
(3 mg/kg) or its vehicle (preinjection time 60 min) and one with dizocilpine
(0.056 mg/kg), memantine
(10 mg/kg), dextromethorphan (30 mg/kg) or saline (preinjection time 15 min).
The percentage of
responses on the dizocilpine-designated lever (DLR) and response rate
(responses's) were calculated
for each test session to establish that deramciclane significantly reduces the
intensity of discriminative
stimulus effects of NMDA receptor channel blockers (Figure 14A) at the dose
that had not
significantly impair operant performance (Figure 14B). Reduced intensity of
discriminative stimulus
effects of memantine in the presence of deramciclane (Figure 1, upper panel)
indicates that
deramciclane can control unwanted effects of NMDA receptor channel blockers
such as
dextromethorphan (Nicholson KL et al., Evaluation of the reinforcing
properties and phencyclidine-
like discriminative stimulus effects of dextromethorphan and dextrorphan in
rats and rhesus monkeys.
Psychopharmacology (1999) 146:49-59) not only by inhibiting dextromethorphan's
metabolism
(Zawertailo LA et al., Effect of metabolic blockade on the psychoactive
effects of dextromethorphan.
Hum Psychopharmacol (2010) 25:71-9) but also by pharmacodynamic mechanisms.
Thus, given the
2D6 inhibitory properties of deramciclane, deramciclane most efficiently
controls subjective effects
of NMDA receptor channel blockers that are metabized via CYP 2D6 such as
dextromethorphan.
[00653] EXAMPLE 200: ANTIDEPRESSANT-LIKE EFFECTS OF THE COMPOUND OF
FORMULA I GIVEN IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL
BLOCKER: Tail suspension is one of the classical tests used to study
antidepressant drugs and was
also applied to evaluate antidepressant-like effects of NMDA receptor channel
blockers (Kos T et al.,
Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine
in rats and mice.
European Neuropsychopharmacology (2006) 16:297-310). Mice were transferred
from the housing
room to the testing area in their home cages and allowed to adapt to the new
environment for at least
176
Date Recue/Date Received 2021-04-14
1 h before drug treatment. Immobility was induced by tail suspension whereby
mice were attached
individually on a paper adhesive tape, 65 cm above the table top. The tape was
placed approximately
1 cm from the tip of the tail. Animals were suspended for 6 min and the
duration of immobility was
recorded. Mice were considered immobile only when they were completely
motionless. Prior to the
test sessions, there were two injections given; one i.p. with deramciclane (3
mg/kg) or its vehicle
(preinjection time 60 min) and one with memantine (3 mg/kg), dextromethorphan
(10 mg/kg) or saline
(preinjection time 30 min). While given alone none of the treatments at these
dose levels had
statistically significant effects, combined administration of deramciclane
with dextrimethorphan
significantly reduced immobility time suggesting antidepressant-like potential
of this combination
(Figure 15A). Combination of deramciclane with memantine also reduced
immobility time by 57%
(P=0.1). Surprisingly, when a subeffective dose of memantine (3 mg/kg) was
given in a combination
with another 5-1-1T2A/2C receptor antagonist, ritanserin (1 mg/kg), no
reduction in immobility time
was observed (Figure 15B). Instead, ritanserin was able to reverse
antidepressant-like effects of an
effective dose of memantine (10 mg/kg). These results suggest that, when given
in a combination
with NMDA receptor channel blockers, deramciclane is capable of producing
pharmacodynamic
effects that distinguish it from at least some of the other representatives of
the class of 5-HT2A/2C
receptor antagonists and inverse agonists.
[00654] EXAMPLE 201: ANXIOLYTIC EFFECTS OF THE COMPOUND OF FORMULA I
GIVEN IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL BLOCKER: Conflict
tests such as the Geller-Seifter test are commonly used to study anxiolytic
effects of drugs and were
also applied to evaluate anxiolytic effects of glutamate receptor antagonists
(Pietraszek M et al.,
Anxiolytic-like effects of mGlul and mG1u5 receptor antagonists in rats. Eur J
Pharmacol (2005)
514:25-34).
[00655] Using standard operant conditioning chambers, connected to a computer
through an interface
and controlled by MED-PC software, rats were trained to lever press under a
multiple fixed ratio (FR)
20 (food only), FR 20 (food and shock) schedule in which three 7-min
unpunished components
alternated with three 3-min punished components for a total session length of
30 min. Shock amperage
and duration were adjusted for each individual rat. The data were analyzed as
response rates
(responses per second) during the punished and unpunished components of each
session. For analysis
purposes, the response rate data obtained during the drug tests were expressed
as a response rate
change relative to the 5-day baseline. Prior to the test sessions, there were
two injections given; one
177
Date Recue/Date Received 2021-04-14
i.p. with deramciclane (1 mg/kg) or its vehicle (preinjection time 60 min) and
one with memantine (3
mg/kg) or saline (preinjection time 30 min). Both deramciclane and memantine
were given at the dose
levels that had on its own any appreciable effects on either punished or
unpunished responding
(Figures 16A and 16B). However, when subeffective doses of memantine and
deramciclane were
given in combination, rats were observed to emit significantly more punished
responses, indicating
synergistic interactions between deramciclane and memantine that result in
reduced anxiety.
[00656] EXAMPLE 202: ANTI-AGGRESSIVE EFFECTS OF THE COMPOUND OF
FORMULA I GIVEN IN COMBINATION WITH AN NMDA RECEPTOR CHANNEL
BLOCKER: Male mice housed in isolation readily develop and demonstrate
aggression towards
intruders. Such paradigms have been applied to evaluate anti-aggressive of
NMDA receptor channel
blockers (Belozertseva IV, Bespalov AY, Effects of NMDA receptor channel
blockade on aggression
in isolated male mice, Aggressive Behavior (1999) 25: 381-396). In these
experiments, mice were
housed individually and, starting after the first two weeks of isolation, were
repeatedly (twice a week)
allowed to attack for 4 min a group-housed stimulus intruder mouse. Only the
resident mice that
consistently exhibit attack behavior toward intruders were used for the drug
tests. Drug tests began
when resident mice demonstrated attacks toward the intruder in at least three
consecutive tests and
lived in isolation for at least 35 days. Intruder mice were housed in groups
of five. Thirty minutes
prior to the test, mice were treated with memantine (10 mg/kg) combined with
deramciclane (3 mg/kg)
or ritanserin (1 mg/kg). When given alone, none of the compounds at the chosen
doses exerted any
appreciable effects on agonistic behaviors (attacks, bites, threats, tail
rattling, upright and sideways
posturing, pushing, and retreating). However, when memantine was combined with
deramciclane (but
not ritanserin), mice were significantly less likely to attack in the absence
of any visible ataxia (Figure
17). Thus, while deramciclane or NMDA receptor antagonists may not be
effective when given alone,
they can produce robust anti-aggressive properties when given in a
combination.
[00657] EXAMPLE 203: The activity of dextromethorphan 0-demethylation was
measured (Yu et al.,
Comparative contribution to dextromethorphan metabolism by cytochrome P450
isoforms in vitro:
can dextromethorphan be used as a dual probe for both CTP2D6 and CYP3A
activities? Drug Metab
Dispos, 29:1514-1520 ( 2001)) with minor modifications. Recombinant CYP2D6
(0.25 pmol) and
HLMs (12.5 itig of protein) were used as enzyme sources. An incubation mixture
consisted of an
enzyme source, dextromethorphan, an NADPH-generating system (500 pM NADP, 10
mM glucose
6-phosphate, 10 mM magnesium chloride, and 1 unit/ml glucose 6-phosphate
dehydrogenase), and
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Date Recue/Date Received 2021-04-14
100 mM potassium phosphate buffer (pH 7.4) in a final volume of 200 1.
Incubations were performed
at 37 C for 10 min and were terminated by adding 10 1 of 70% (w/v) perchloric
acid. After removal
of protein by centrifugation, 50 IA of the supernatant was subjected to a high-
performance liquid
chromatography (D7500 integrator, L-7100 pump, L-7200 autosampler, L-7300
column oven, and L-
7485 fluorescence detector) equipped with a Mightysil RP-18 GP column (4.6
250 mm, 5 pm). The
mobile phase was the mixture of acetonitrile/methanol: 10 mM potassium
phosphate buffer adjusted
to pH 3.5 with phosphoric acid (200:160:630). Elution was performed at a flow
rate of 1.0 ml/min.
The formation of dextrorphan was monitored at an excitation of 280 nm and an
emission of 310 nm.
[00658] The preincubation mixture contained recombinant CYP2D6 (2 pmol), each
major cannabinoid
(2.5-50 M), an NADPH-generating system (8.2 i_tM NADP, 0.41 mM glucose 6-
phosphate, 0.41 mM
magnesium chloride, and 1 unit/ml glucose 6-phosphate dehydrogenase), and 100
mM potassium
phosphate buffer (pH 7.4) in a final volume of 180 1. After prewarming at 37
C for 5 min, reactions
were initiated by the addition of the NADPH-generating system. After a 20-min
preincubation, 20 IA
of AMMC solution was added to the preincubation mixture (final substrate
concentration, 0.6 04).
Incubations were conducted under the same manner as described under Enzyme
Assays for AMMC
0-demethylase activity. Prediction of In Vivo Drug Interactions for CYP2D6. An
estimate of in vivo
inhibition potency was determined by the methods of Obach et al. (2006). The
maximal unbound
hepatic input concentration, Cmax, u, inlet, was determined using the
following equation:
Cmax"inkt = (Canna D Fa = WO
Cmax is defined as the maximal systemic concentration, fu is the fraction
unbound in the blood, D is
the oral dose, Fa is the fraction of the oral dose absorbed, ka is the first-
order absorption rate constant,
and Qh is the hepatic blood flow. In the case of marijuana smoking, absorption
from the
gastrointestinal tract is not taken into account. Thus, the Cmax, u, inlet for
inhaled cannabinoids is
equal to fu Cmax. The value of fu for cannabinoids is at most 0.05 because 95
to 99% of plasma THC
is bound to plasma proteins, mainly lipoproteins (Grotenhermen, 2003). A ratio
of the area under the
curve (AUC) with inhibitor to control AUC could be estimated using the
following equation:
A UCiaiii iatedi A U Coatbd = I If fincyp2D6/0 vivo/KA ¨ Liu C
YP2D6))
In the above equation, AUC inhibited is the area under the curve for a given
substrate probe
179
Date Recue/Date Received 2021-04-14
in the presence of an inhibitor, and AUCcontroi is the area under the curve
for the same probe substrate
without inhibitor. The fraction of metabolism of the probe substrate by CYP2D6
and the magnitude
of the potency of the inhibitor are represented by fm(CYP2D6) and Ki,
respectively. The value of
unity was used for the fm(CYP2D6) of dextromethorphan/dextrorphan urinary
ratio (Obach et al.,
2006). Thus, a ratio of AUCmhibited to AUCeontrui of dextromethorphan is equal
to 1 +
[00659] EXAMPLE 204: The time related distribution and pharmacokinetics of
double-labelled
compound 829 (compound 829-phenyl-C-14 and -ethyl-H-3) were studied in the
plasma, hypophysis
and 14 cerebral regions, including the spinal cord o f the rat after a single
oral treatment (acute
experiments) and after repeated administration of one dose daily for six days
(subacute experiments).
The tissue levels of compound 829 were calculated from the simultaneously
determined dpm values
and the specific activi ties of the two radioisomers present in the dose
administered. EG1S-38 85 was
rapidly absorbed from the gastrointestinal tract t(max)=1.0 h). The
concentration-time curves in the
tissues can be described by a two compartment open model. The H-3-activity
could be measured
during the whole period of the acute experiment (95 h), whereas C-14-
radioactivity fell below the
detection limit within 24 h. The AUC (0.96) values for H-3 were 10 to 15 times
higher than that for
C-14. I, all samples examined, on the concentration time curves a peak
characteristic of ent erohepatic
cycle can be seen at 12 h. The studies indicated that intact molecules entered
brain tissues from the
circulation. The results of the subacute experiments indicate that the C-14-
labelled compound 829, or
its metabolite(s) carrying the tracer, reach an equilibrium as early as on the
second to third day, whilst
the level of H-3-radioactivity continually increases during the six days of
repeated administration. In
the subacute experiments the peak concentrations were reached at 0. 5 h after
the final treatment.
However, their values for 3H were higher than in acute experiments. The last
tendency was not
observed in the case of C-14-tracer. The AUC values of H-3-labelled compound
829 determined in
subacute experiments predominated over C-14; the ratios were 50 to 60 in all
brain regions. The
enterohepatic cycle, seen after a single dose, also operated after repeated
dosage. The time related
concentrations of compound 829 in the hypophysis were at least two times
higher than that in the
plasma and the brain tissues. No significant difference was seen in the
concentrations of compound
829 in the symmetrical (left and right) regions of the brain (Magyar et al.,
Distribution Of
Deramciclane In Rat-Brain Regions, European journal of drug metabolism and
pharmacokinetics,
23(2), pp. 125-131 (1998).
180
Date Recue/Date Received 2022-05-04
[00660] EXAMPLE 205: 5HT2a ASSAY: Evaluation of the affinity of compounds for
the human 5-
HT2A receptor in transfected HEK-293 cells determined in a radioligand binding
assay. Cell
membrane homogenates (30-50 ug protein) were incubated 15 min at 37 C with 0.5
nM
[3H]ketanserin in the absence or presence of the test compound in a buffer
containing 50 mM Tris-
HC1 (pH 7.4). Nonspecific binding was determined in the presence of 1 uM
ketanserin. Following
incubation, the samples were filtered rapidly under vacuum through glass fiber
filters presoaked with
0.3% PEI and rinsed several times with ice- cold 50 mM Tris-HC1 using a 96-
sample cell harvester.
The filters were dried then counted for radioactivity in a scintillation
counter using a scintillation
cocktail (W02005013952A1, EP1500391A1).
[00661] EXAMPLE 206: Male NMRI mice (20-25 g bodyweight) were dropped on a hot
plate (56 0,5
C) and the latency time elapsed until licking the forepaws was measured. The
reaction time was tested
twice before treatment. Animals were discarded if the first basal latency time
>5 sec. or the difference
between the two control measurements was greater than 3 sec. Mice were treated
either with saline or
with morphine HC1 1 mg/kg subcutanously and at the same time either with
vehicle or with
deramciclane or buspirone, HC1 30 mg/kg intraperitoneally, respectively. After
the treatment (15, 30,
45 and 60 min.) the reaction time was measured again. Animals were regarded as
positive if they
produced a 2.5-fold reaction time increase at least twice compared to their
first control values.
Administration of a combination of morphine and compound 129 showed
statistically significant
analgesic effect over administration of either of the compounds alone
(EP1734940 B1).
[00662] EXAMPLE 207: CNS EFFICACY OF THE COMPOUND OF FORMULA I CAN BE
MEDIATED BY A BIOLOGICALLY ACTIVE METABOLITE: Compound 50 is a peripherally
acting 5-HT2A receptor antagonist (Obata H et al., Antinociception in rat by
sarpogrelate, a selective
5-HT(2A) receptor antagonist, is peripheral. Eur J Phamiacol (2000) 404:95-
102) and there is a direct
evidence generated using [14C] labeled Compound 50 that sarpogrelate may not
be able to cross the
blood-brain barrier in the rat (Komatsu T et al., Studies on the Metabolic
Fate of (+)-
2(Dim ethyl amino)-1 -C C o(m-m ethoxyph enethyl) phenoxyDmethyl] ethyl
hydrogen siccinate
hydrochloride (MCI-9042) (II) : Absorption, Distribution, Metabolism and
Excretion after a Single
Administration to Rats).
[00663] Adult male SD rats were pretreated with the compound 146 or M1 (10
mg/kg intraperitoneally)
and the brain and blood plasma were collected 30, 60, 120 and 240 min after M1
administration. The
181
Date Recue/Date Received 2022-05-04
amount of compound in brain tissue extracts was measured using the UPLC/MS
analysis. As shown
in Figure XYZ, total brain concentration of M1 significantly exceeded the
blood concentration. Thus,
unlike Compound 50, Ml readily penetrates into the brain and may be
responsible for surprising CNS
effects of Compound 50.
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Date Recue/Date Received 2021-04-14
