Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS AND METHODS FOR SUPPRESSION OF CARBONIC ANHYDRASE ACTIVITY
PRIORITY
10001] The present application claims the benefit of Indian Provisional -
Patent
Application No. '1810101E12012 filed on 08-May-2012, the entire disclosure of
which is
relied on for all purposes and is incorporated into this application by
reference.
FIELD OF THE 1...NVENTION
tow2.1 This disclosure generally relates to compounds and compositions for the
suppression of carbonic anhydrase activity. More particularly,. this iriventí
on relates to
treating subjects with a pharmaceutically acceptable dose of compounds,
stereoisomers,
enantiomers, crystals, esters, salts, hydrates, prodrugs, or mixtures thereof
BACKGROUND OF THE INVENTION
['WW1 Carbonic anhydrases (CAs, also known as carbonate dehydratases EC
4.2.1.1)
are ubiquitous metalloenzy.mes present in prokaryotes and eukaryotes that are
encoded by
four evolutionarily unrelated gene families. CAs catalyse a simple
physiological rea.etiori.
the conversion of CO2 to the bicarbonate ion and protons. The active site of
most CAs
contains a zinc ion (2n2+), which is essential for catalysis. The CA reaction
is involved
in many physiological and pathological processes, including respiration and
transport of
CO, and bicarbonate between metabolizing .tissues and lungs; pli and CO,
homeostasis;
electrolyte secretion in various tissues and organs; biosynthetic reactions
(such as
gluconeogenesis, lipogenesis and ureagenesis); bone resorption; calcification,
and
tumorigenieity,
j0004-1 Many of the CA isozymes involved in these processes are important
therapeutic
targets with the potential to be .inhibited to treat a range of disorders
.including oedema;
glaucoma.; obesity, cancer, epilepsy and osteoporosis. Two main classes of CA
inhibitors
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(C.Als) are known: the Metal-complexing anions and the unsubstituted
.,sulphonamide.s and
their bioisosteres. CAls include the classical inhibitors aeetazolamide,
methazolatnide,
ethoxzolamide , sulthiame and dichlorophenamide
10005] The reduced compounds (thiots) are less bulky and show excellent CA
inhibitory
activity (in the low nanomolar range.) compared with the corresponding
sterically
hindered di sul phi des, N.vhich have di fficul ty entering the limi ted space
of the enzy me.
active site and also NVith low bioavailability as well as poor
pharmacdkinetics with very
COMMOD side effects such as numbness in toes, taste, ataxia,. paraesthesia of
face and
limbs and blurred visim.
f00061 I\4anaging acute pathology of often relies on the addressing underlying
pathology
and symptoms of the disease. There is currently a need in the art for new
compositions to
treatment or delay of the onset of carbonic anhydrase enzyme actvity and its
associated
complications progression.
SUMINIA.RY OF T.H.E. :INVENTION
[0007" The present invention provides compounds, compositions containing.
these
compounds and methods for using. the same to treat, prevent andfor ameliorate
the
effects of the conditions such as complications or diseases manifested from
carbonic
anhydrase enzyme activity..
100081 The invention herein provides compositions comprising of .formula 1 or
pharmaceutical acceptable salts thereof. The in.vention also provides
pharmaceutical
compositions comprising one or more compounds of .formul a l or intermediates
thereof
and one or more of phannaceutically acceptable carriers, vehicles or diluents.
These.
compositions may be used in the suppression of carbonic anhydrase activity and
its
associated complications.
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R2
- 0
S
H N Nsr
NH2
N¨N
R3
Formula 1
j00091 In certain embodiments, the present invention relates to the compounds
and
compositions of t7ormula or pharmaceutically acceptable salts thereof,
R2 0
HN 0
NH2
N-N
R3
Formula I
Wherein,
Ri each independently represents D,
0 0
o
NH2 0 0
0 0 et,
111/C\0/ \s,cr -1\
0
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0 0
0
H \:s
0 0 0 0
-=-.. ,..... '1.1.L.," LI
csS5
0 õrµ
NH2 NH2
H H
N "It.a
¨0.-
-A*0
H ,
H H
N
0
H H
.;22;INN's=...,,,,NN,.o,,.-N-..,%.õ.-- s' ¨
{2Z, 0 0 sSS
OH
0
H H i
or H
,
R2 each independently represents
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0 N CHI
".....,
SH
H2
..,---
0 N/ s
H3C .,,,,,.
4,, 0
...../...N'e
H 0
1 ,HS H2N
, .
..7,N.,,,NNs,..õ...7.CH 3
N CH3
1
OH
HO
OH
0
l'N'...../..
H
H
0 0 N õsS
\esS:\ HO
OH HS \\........õ,.......... ....... \
H 40 N
N1-12 H H
0 0
H
OH
: =
0
0
0 .2..
0 e S -...,,,
S
,
i'
4 7 1 0 13 16
0 t
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0
..i.sS5
0
12 20
,
:SS'S
-
i 9
4 7 1 0 1 3
0 ,
H. OH 0
1:-
1,
HO ...o
0 0
S s
NHCOCH3
.1 0 0
0 c., 100 CO2 H
OH A to rss. ococH3 coNH2
0.,..
o=??...
. ,
r CH 3 C1-E3 OH 0
0
0
14. 10
01 CH;
11,5C ¨N........._õ7-N.N.,...",s5' 0 0
H3C 0
1
C H3
CH3 OH 0
OH
o
tiVI\ NH
Ea 0
H 1-3
Matt
s
HN if
0 , NH2
,
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0
'
a
d
or
a is independently 2,3 or 7;
each b is independently 3, 5 or 6;
e is independently 1, 2 or 6;
e and d are each independently H. D, -OH., -OD, C1-C6-a1kyl, -NH 2 or -COCH3;
R3 independently represents H, D, methyl, F. CI, ethyl or acetyl.
100101 In the illustrative embodiments, examples of compounds of formula I are
as set
forth below:
0
NH
H2N
0
- 1 )
0
N/ y
,,s%
0
(1-2)
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0
HN
s,s
0
'0
(1-3)
100111 'Herd n the application also provides a kit comprising any of the
pharmaceutical
compositions disclosed herein. The kit may comprise instructions for use in
the
suppression of carbonic anhydrase activity or -its related complications.
100121 The application also discloses a pharmaceutical composition comprising
a
pharmaceutically acceptable earlier and any of the compositions herein. in
some aspects,
the pharmaceutical composition is formulated .for systemic .administrationõ
oral
administration, .sustained rel ease, parenteral admi in strati on, inj ecti
on, sub derm
admini strati on, or transdermal ad mi ni strati on.
100131 Herein, the application additionally provides kits comprising the
pharmaceutical
compositions described herein. The kits may further comprise instructions for
use in the
suppression of carbonic anhydrase activity or its related complications.
1001.41 The compositions described herein have several uses. The present
application
provides, for example, methods of treating a patient suffering from carbonic
anhydrase
modulation activity or its related complications manifested from ne-
urodegeneration,
neurological dysilinction, metabolic conditions or disorders, metabolic
syndrome, chronic
diseases or disorders; Hyperinsulinemia. Insulin resistance, Glucose
intolerance,
.Hepatology, Cancer, Respiratory, Hematological, Orthopedic, Cardiovascular,
Renal,
Skin, N e pivot ogi cal , or Ocular complications.
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.DETAILED DESCRIPTION OF THE INVENTION
=Lefiiiì ti ons
100151 As used herein, the following terms and phrases shall have the meanings
set. forth
below. -Unless defined otherwise, all technical and scientific terms used
hefeill have the
same meaning as comnionly understood to one of ordinary skill in the art.
100161 The compounds of the present invention can be present in the form of
pharmaceutically acceptable salts. The compounds of the present invention can
also be
present in the form. of pharmaceutically acceptable esters (i.e., the .methyl
and ethyl esters
of the acids of formula 1 to be used as prodrugq The compounds of the present
invention.
can also be solvated, -i.e. hydrated. The solvation can be affected in the
course of the
manufacturing process or can take place i.e. as a consequence of hygroscopic
propeAies
of an initially anhydrous compound .of formula 1 (hydration).
10017-] Compounds that have the same molecular .formula but differ in the
.nature or
sequence of bonding of their atoms or the arrangement of their atoms in space
are termed
"isomers," Isomers that differ in the arrangement of their .atoms in space are
termed
"stereoisome.rs." Dia.stereomers are stereoisomers with opposite configuration
at. one or
more chiral centers which are .not enantiomers. .Stereoisomers bearing one or
more
asymmetric centers that are non- superimposable mirror images of each other
are termed
"enantiomers." -When a compound has an asymmetric center, for example,. if a
carbon
atom is bonded to four different groups, a pair of enantiomers is possible. An
enamiomer
can ic thara.cterized by the absolute configuration of its a.symmetric center
or centers and.
is described by the R.- and S-sequencing rules of Cahn, lngold and Prelog, or
by the
manner in which the molecule,' rotates the plane of polarized light and
designated as
dextrorotatoly or levorotatory (i.e., as (3-) or (-)isomers respectively). A
chiral compound
can exist as either individual enantiomer or as a mixture .ihereof A IlliXtUte
containing
equal -proportions, of the enantiomers i called a "ra.cetnic mixture".
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100181 .As used herein, the term "metabolic, condition" refers to an Inborn
errors of
metabolism (or genetic metabolic conditions) are genetic disorders that result
from a
defect in one or inore metabolic pathways; specifically, the function of an
enzyme is
affected and is either deficient or completely absent.
[001.91 In some embodi men ts, a T11.01 ecu ar conjugate compri se& of COM pou
11 d S Se ected
from the group consisting of R-lipoic acid (CAS No. 120(3-22-2), salsalate
(CAS No.
552-94-3), acetylcysteine WAS No. 616-91-1), Eicosapentaenoic acid (CAS No. 1.
04 .17-
94-4), :Docosahexaenoic acid (CAS No. 6217-54-5).
10020] The term ".polymorph" as used herein is art-recognized and refers to
one crystal
structure of a given compound.,
10021" The phrases "parenteral administration" and "administered parenterally"
as used
herein refer to modes of administration other than enteral and topical
administration, ..such
as injections, and include without limitation intravenous, intramuscular,
intrapleural,
intravascular, intrapericardial, imraarterial, intrathecal, intraeapsular,
intraorbital,
intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous,
subcuticular, Ultra-
articular, subea.psular, subarachnoid, intraspinal and intrastemal injection
.and infusion..
10022] .A "patient," "subject," or "host" to be treated by the subject method
may mean
either a human or non-human animal, .such as prim.ates, mammals, and
vertebrates,
(00251 The phrase "pharmaceutically acceptable" is art-recognized. 1.ri
certain
embodiments, the term includes compositions, polymers and other niaterials
and/or
dosage forms which are, within the scope of sound medical judgment, suitable
for use in
contact with the tissues of mammals, huinan beings and animals without
excessive.
toxicity. rri tati on, allergic re spon se:, or other problem or
complication:, commensurate
with a reasonable benefit/risk ratio.
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100241 The phrase "pharmaceutically acceptable carrier" is art-recot.mi zed,
and includes,
for example, pharmaceutically acceptable materials, compositions or vehicles,
such as a
liquid or solid tiller, diluent solvent or encapsulating .material .involved
in carrying or
transporting any subject compo.siti on, from one organ, or portion of the
body, to another
organ, or portion of the body. Each carrier must be "acceptable" in the sense
of being
compatibile .with the other ingredients of a subject composition and not
injurious to the.
patient. in certain embodiments, a pharmaceutically acceptable carrier is non-
pyrogenic.
Some examples of materials which may serve as pharmaceutically, acceptable
carriers
include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such
as corn starch
and potato starch, (3) cellulose, and its derivatives, such as sodium
carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5)
malt; (6)
gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as
peanut. oil,
cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean
oil; (10) glycols,
such as propylene glycol.; (11) polyols, such as glycerin, sorbit.ol, mannitol
and
polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13)
agar; (14)
buffering agents, such as magnesiUM hydroxide and aluminum hydroxide; (15)
alginic
acid, (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl
alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible
substances
employed in pharmaceutical .formulations.
[00251 The term "prodrug" is intended to encompass compound.s that under
physiological conditions, are converted into the therapeutically active agents
of the
present invention. A common method for rnaking a prodrug is to include
selected
Moieties that are hydrolyzed under physiological conditions to reveal the
desired
molecule, .In other embodinients, the prodrug is converted by an enzymatic
activity of the
host animal.
1002611 The term "prophylactic or therapeutic" treatment is art-recognized and
includes
administration to the host of one or more of the subject compositions, if it
is
administered prior to clinical manifestation of the unwanted condition (e.g.,
disease. or
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other unwanted state of the host animal) then the treatment is prophylactic,
i.e.., it protects
the host against- developing the unwanted condition, whereas if it is
administered after
manifestation of .the unwanted condition, the treatment is therapeutic, (i.e.,
it is intended
to diminish, ameliorate, or stabilize the existing unwanted cnchtioii or side
effects
thereof).
100271 The term "predicting" as used herein refers to assessing the
probability related
di sea ses pati e.nt will suffe.c from ab norm ali ties or conipli cati on an
dlor term i nal plate" et
aggregation or failure andfor death (i.e. mortality) within a. defined tiine
window
(predictive -window) in the future. The mortality may be caused by .the
central nervous
system or complication. The predictive window is an interval in which the
subject will
develop one or more of the said complications according to the predicted
probability, The
predictive window may be the entire remaining lifespan of the subject upon
analysis by
the method of the present invendon.
100281 The term "treating" is art -recognized and .includes .preventing a
disease, disorder
or condition from occurring in an animal which may be predisposed .to the
disease,
disorder and/or condition but has not yet been diagnosed as having it;
inhibiting the
disease, disorder or condition, e.g., impeding its progress: and relieving the
disease,
disorder, or condition, e.g., causing regression of -the disease, disorder
andlor condition,
'Treating the disease or condition includes ameliorating at least one symptom
of the
particular disease or condition, even if the underlying pathophysiology is not
affected.,
such as treating the glaucoma, epileptic seizures., Idiopathic intracranial
hypertension
(pseud.otumor cerebri), altitude sickness, cystinuria.õ periodic paralysis and
(Jura! ectasia,
conge.stive heart failure, drug induce,d edema, intermittent claudication
resulting froni.
obstructed arteries in the limbs, and vascular dementia., improves blood flow
through
peripheral blood vessels and therefore helps with blood circulation in the
arms and legs
(e.g. intermittent claudication), and the brain (hence its use in vascular
dementia),
Peyronie's disease and .neuropathie injuries, prevent strokes and can be used
in managing.
sickle cell disease, .to treat nausea and headaches in. the mountains
(altitude sickness), and
has been shown to reduce mortality in acute alcoholic and non-alcoholic
steatohepatifis
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arid alcoholic liver disease, reduc.int.t, the extent of fibrotic lesions
.induced by radiation
therapy for breast cancer. IV treatment of cytokine release syndrome., type 1
diabetes and
type 2 diabetes, asthma.õ bronchodilation., neuroprotective properties,
vasodilation,
Alzheimer's disease, dementia, stroke, and treatment of endatiletriosis. It is
also used in
the treatment of venous disease of a subject by administration of an agent
even though
such agent does not treat the cause of the condition. The term "treating,
"treat" or
"treatment" as used herein includes curative, preventative (e,g.,
prophylactic), adjunct and
palliative. treatment.
100291 The phrase 'therapeutically effective .amount" is an art-recognized
term. in
certain embodiments, the term refers to an amotmt of a salt or composition
disclosed
herein that produces some desired effect at a reasonable benefit/risk ratio
applicable to
any medical treatment. In certain embodiments, the term refers to that amount
necessary
or sufficient to eliminate or reduce medical symptoms for a period of time.
The effective
amount may vary depending on such factors as the disease or condition being
treated, the
particular targeted constructs being administered, the size of the subject, or
the severity of
the disease or condition. One of ordinary skill in the art may empirically
detemine the
effective amount of a particular composition without .necessitating undue
experi inentati on.
100301 In certain embodiments, the pharmaceutical compositions described
herein are
.formulated in a manner such that said compositions will be delivered to a
patient in a.
therapeutically effective amount, as part cif a prophylactic or therapeutic
treatment. The
desired amount of the composition to be administered to a patient will depend
on
absorption, inactivation, and excretion rates of the drug as Iva as the
delivery rate of the
salts and com.positions from the subject compositions. It is to be noted that
dosage values
may also vary with the severity of the condition to be alleviated. It is to be
further
understood that far any particular subject, specific dosage regimens should be
adjusted
over time according to the individual need and the professional judgment of
the persolì.
admi.nistering or supervising the administration of the compositions..
Typically, dosing
will be determined -using techniques known to one skilled in the. art.
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100311 Additionally, the optimal concentration and/or quantities or amounts of
any
particular salt or composition may be adjusted -to accommodate variations in
the
treatment parameters. Such treatment parameters include the clinical use -to
which the
preparation is put, e.g.., the site treated, the type of patient, e.g., human
or non-human,
adult or child, and the nature of the disease or condition.
[0032] in certain embodiments, the dosage of .the subject compositions
provided herein
may be determined by reference to the plasma concentrations of the -
therapeutic
composition or other encapsulated materials. For example, the maximum plasma.
concentratio.n (Cmax) and .the area under .the plasma concentration-time curve
from time
0 to infinity may he used,
[00331 When used with respect to a. pharmaceutical composition or other
material, the
term "sustained release" is art-recognized. For example, a subject composition
which
releases a substance over time may exhibit sustained release characteristics,
in contrast to
a bolus type administration in )xhich the entire amount of the substance is
made
biologically available at one time. For example, in particular embodiments,
upon contact
with body fluids including blood, spinal fluid, mucus secretions, lymph or the
like, one or
more of the pharmaceutically acceptable excipients inay undergo gradual or
delayed
degradation (e.g., through hydrolysis) with concomitant release of any
material
incorporated therein, e.g., an therapeutic andlor biologically active salt
andfor
composition, for a sustained or extended period (as compared to the release
from a
bolus). This release may result in prolOn ged delivery of therapeutically
effective
amounts of any of the therapeutic a.gents disclosed herein.
100341 The phrases "systemic administration," "administered systemically,"
'peripheral
administration" and "administered peripherally" are art-recognized, and
include, the
administration of a subject composition, therapeutic or other material at a
site remote
from. the disease being treated. Administration of an agent for the disease
being treated,
even if .the agent is subsequently distributed systemically, may be .termed
"local or
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"topical" or 'regional' administration, other than directly into the central
nervous system,
e.g., by subcutaneous a_dministration, such that it enters the patient's
system and, thus, is
subject to metabolism and other like processes
10035] The phrase "therapeutically effective amount" is an art-recognized
term. In
certain embodiments, the term refers to an amount of a salt or co.mposition
disclosed
herein that produces some desired effect at a reasonable benefit/risk ratio
applicable to
any medical treatment. In certain embodiments., the term refers to that amount
necessary
or sufficient to eliminate or reduce medical symptoms for a period of time.
The effective
amount may vary depending on such factors as .the disease or condition being
treated, the
particular targeted constructs being. administered, the size of the subject,
or the severity of
the disease or condition. One of ordinary skill in the art may empirically
determine the
effective amount of a particular compositi on wi th out necessitating undue
experimentation.
100361 The present disclosure also contemplates prodrugs of the compositions
disclosed
herein, as well as phamiaceutically acceptable salts of -said prodrugs.
[0037] This application al so discloses a. pharmaceutical composition compri
sing a
pharmaceutically acceptable carrier and the composition of a compound of
Formula I
may be formulated for .63,,stemic or topical or oral administration. The
pharmaceutical
composition m.ay be also formulated for oral ad.ministrationõ oral solution,
injection,
subderin al administration, or trans& rm al ad mi ni strati on. The
pharmaceuti cal
composition may further comprise at least one of a pharmaceutically acceptable
stabilizer, diluent, surfactant, tiller, binder, and lubricant.
100381 In many em.bodiments, the pharmaceuticai compositions described herein
incorporate the disclosed compounds and compositions (Formula l) to be
delivered in an
amount sufficient to deliver to a patient a therapeutically effective amount
of a. compound
of formula 1 or composition as part of a prophylactic or therapeutic
treatment. The
desired concentration of .formula 1 or its pharmaceutical acceptable salts
will depend on
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ab.sorption, inactivation, and excretion rates of the drug as well as the
delivery rate of the
salts and compositions from the subject compositions. 1.t is to be noted that
dosage values
may also vary with the severity of .the condition to be alleviated. It is to
be further
understood thatt for any particular subject, specific dosage regillIEMS should
be adjusted
over time according .to the individual need and the professional ju4unent of
.the person
administering or supervising the administration of the compositions_
Typically, dosing
will be determined using techniques knowe to one skilled in the: art,
NO391 Additionally, the optimal concentration andfor quantities or amounts of
any
particular compound of formula I may be adjusted to accommodate variations in
the
treatment para.meters. Such treatment parameters include the clinical use to
which the
preparation is put, e.g., the site treated, the type of patient, e.g., human
o.r non-huma.n,
adult or child, and the nature of the disease or condition.
10040" The concentration andlor .amount of any compound of formula I may be
.readily
identified by routine screening in animals, e.g., rats, by screening a range
of
concentration andlor amounts of the material in question using appropriate
assays.
Known methods are also available to assay local tissue concentrations,
diffusion rates of
the salts or com.positions, and local blood flow before and after
administration of
therapeutic formulations disclosed .herein. One such method is micro:dialysis,
as
reVieWed by T. E. Robinson et al., 1991, mierodialysis in the neuroscienees,
Techniques,
volume 7, Chapter I. The methods reviewed by Robinson may be applied, in
brief, as
follows. A microdialysis loop is placed in. situ in a test animal. -Dialysis
fluid is pumped.
through the loop. When compounds with fomiula such as those disclosed herein
.are
injected adjacent to the loop, released drugs are collected in the di alysate
in proportion to
their local tissue concentrations. The progress of diffusion of the salts or
compositions
may be determined thereby with suitable calibration procedures using known
concentrations of salts or compositions.
10041] in certain embodiments., .the dosage of the subiect compounds of
formula
provided herein may be determined by reference to the plasma concentrations of
the
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therapeutic composition or other encapsulated materials. For example, the
maximum
pla.sma concentration (Cmax) and the area under the plasma concentration-tim.e
curve
from time 0 to infinity rnay be used.
100421 Generally, in carrying- out the methods detailed in this applicationõ
an effective
dosage for the compounds of Formulas'', is in the range of about 0,01
mg/kg/day to about
100 mg/kg/day in .single or divided doses, .for instance 0.01 mg/kg/day to
about 50
nigilerglday in single or divided doses. The compounds of Fonnullas I May be
administered
at a dose of, .for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0
ing/k1gday,. 5
mg/kg/day,. 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day.
Compounds of
Formula I may also be administered to a human patient at a dose of, fOr
example,
between 0,1 mg and 1000 mg, between 5 ma and 80 mg, or less than LO, 9.0,
12,0, 20.0õ
50,0, 75,0, 100, 300,, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain
embodiments, the compositions herein are administered at an amount that is
less than
95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 1 of the compound of formula
1 required for the same therapeutic 'benefit.
1.0043.1 An effective amount of the compounds of formula I described herein
refers to the
amount of one of said salts ar corn posi lions which is capable of inhi biting
or preventing a
di sea s e..
100441 An effective at/1mA may be sufficient to prohibit, treat, alleviate,
ameliorate, halt.,
restrain, slow or reverse the progression, or reduce the severity of a
complication
resulting .from nerve dam.age or demyelization andlor elevated reactive
oxidative-
nitrosative species andlor abnormalities in physiological homeosta.sis's, in
patients who
are at risk for such complications. As such., these methods include both
medical
therapeutic (acute) andlor prophylactic (prevention) administration as
appropriate. The.
amount and timing of compositions administered willõ of course:, be dependent
On the
subject being treated, on the severity of the affliction, on the manner of
administration
and on the judgment of the prescribing -physician, Thus, because of patient-to-
patient
variability, the dosages given above are a guideline and the. physician may
titrate doses of
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the drug to achieve the treatment that the physician considers appropriate for
the patient.
In considering the degree of treatment desired, the physician must balance a
variety of
factors such as age of the patient, presence of preexisting disease, as well
as presence of
other di sease.s.
[00451 The compositions provided by this application .may be administered to a
subject
in need of treatment by a variety of conventional routes of administration,
induding
orally, =topically, parenterally, e.g., intravenously, subcutaneously or
intramedullary.
Further, the compositions may be administered intranasally., as a rectal
suppository, or
using a "flash" formulation, i.e., allowing the medication to dissolve in the
mouth without
the need to use water. Furthermore, the compositions may be administered to a
subject in
need of treatment by controlled release dosage forms, site specific drug
delivery,
transdermal drug delivery, patch (active/passive) mediated drug delivery, by
.stereotactic
injection, or in nanoparticles.
10046" The compositions may be administered alone or in combination with
phamaceutically acceptable carriers, vehicles or diluents, in either single or
multiple
doses. Suitable pharmaceutical carriers., vehicles and diluents include inert
solid diluents
or fillers, sterile !aqueous solutions and various organic solvents,. The
pharmaceutical
compositions formed by combining the compositions and the pharmaceutically
acceptable carriers, vehicles or diluents are then, readily administered ìrî
a. variety of
dosage forms such as tablets, powders, lozermes, syrups, injectable .solutions
and the like.
These pharmaceutical compositions can, if desired, contain additional
ingredients such as
flavorings, binders, excipients and the like., Thus, for purposes of oral
administration,
tablets containing various excipients such as ,I...-arginine, sodium citrate,
calciwn
carbonate and calcium phosphate may be employed along with various
disintegrates such
as starch, alginic acid and certain complex silicates, together with binding
agents such as
polvvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating
agents such
as inagnesium stearate, sodium lauryl sulfate and talc. are often useful for
tabletting
purposes. Solid compositions of a similar type !nay also be employed a.s
.fillers in soft and
hard filled gelatin capsules. Appropriate materials for this include lactose
or milk sugar
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and .high molecular weight polyethyle.ne glycols. When aqueous suspensions or
elixirs are
desired for oral administration, the essential active ingredient therein may
be combined
with various sweetening or flavoring agents, coloring matter or dyes and, if
desired.,
emulsifying or suspending agents, together with diluents such as water,
ethanol,
propylene glycol, glycerin. and combinations thereof. The compound.s of
formula. 1 may
also cornprise emetically coated comprising of various excipients, as is well
known in the.
pharmaceutical art.
10047] For parenteral administration, SOILitiOnS of the compositions may be
prepared in
(for example) sesame or peanut oil, aqueous propylene glycol., or in sterile
aqueous.
solutions may be employed. Such aqueous solutions should be suitably buffered
if
necessary and the liquid diluent first rendered isotonic with sufficient
saline or glucose.
These particular aqueous solutions are especially suitable for intravenous,
intramuscular,
subcutaneous and intraperitoneal adnìinistratìoi't. n this connection, the
sterile aqueous.
media employed are all readily available by standard techniques known to those
skilled .in
the art.
10048.1 The formulations, for instance tablets, may contain e.g.. 10 to 100,
50 to 250, 150
to 5(X) ir.P/, or 350 to 800 nn, es. 10, 50, 100, 300, 500, 700, 800 mg of the
compounds of
formula I disclosed herein, for instance, compounds of .formula. II or
pharmaceutical
acceptable salts of a compound.s of Formula 1.
1.0049.1 Generally, a composition as described herein may be administered
orally, or
parenterally (e.g., intravenous, intram.uscular, subcutaneous or inttam ed ul
ary) 'Topical
adniinistration may also be indicated, for example., where the patient is
suffering fromgastrointestinal disorder that prevent oral administration, or
whenever .the medication is
best applied to the surface of a tissue or organ as determined by the
attending physician.
Localized administration may also be indicated, for example, when a high dose
is desired
at the target tissue or organ. For buccal administration the active
composition may take.
the form of .tablets or lozenges formulated in a. conventional .manner.
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100501 The dosage administered ì1l be dependent upon the identity of the
metabolic
disease; the type of host involved, including its age, health and weight; the
kind. of
concurrent. treatment, if any; the frequency of treatment and therapeutic
.ratio.
1005.1.1 Illustratively, dosage levels of' the administered active ingredients
are:
intravenous, 0.1 to about 200 ing/kg; intramuscular, 1 to about 500 mg/kg;
orally, 5 to
about 1.000 mg/kg; intranasal instillation; 5 to about 1000 mg/kg; and
il.CFOS01, 5 to about.
1000 m'lg. of host body weight.
10052] Expressed in terms of concentration, an active ingredient can be
present in the:
compositions of the present invention for localized use about the cutis,
intranasally,
pharyngol aryngeally,, bronchi ally:, intravagi nal ly; rectally, or ocularly
in a concentratioi'i.
of from about 0.01 to about 50% siew of the composition; preferably about 1 to
about:
20% w/w of the composition; and for parenteral use in a concentration of from
about 0.05
to about 50% w/v of the composition and preferably from About 5 to about 20%
w/v.
[00531 The compositions of the present invention are preferably presented for
administration to humans and animals in unit dosage fonns, such as tablets,
capsules,
pills, powders, granules, s-uppositories, sterile parenteral solutions or
suspensions, sterile
non-parenteral solutions of suspensions, and oral solutions or suspensions and
the like,
containing suitable quantities of an active ingredient. For oral
administratiOn either solid
or fluid unit dosage forms can be prepared.
100541 As discussed above, the tablet core contains one or more hydrophilic
polymers,
Suitable hydrophilic pol.ym.ers include, but are not limited to, water
swellable cellulose
derivatives, polyalkyiene glycols, thermoplastic polyalkylene oxides, acrylic
polymers,
hydrocolloids, clays, gelling.; starches, givellims cross-linked polymers, and
mixtures;
thereof. Examples of suitable -water swell a.ble cellulose derivatives
include, but are not
Finn ted to, sodium carboxy methylcell ulose, cross-linked hydro.xypropyl
cellulose,
hydroxypropyl ceiiut ose WPC),
h:ydroxypropylm ethyl cellul ose (IIPMC),
hydrctxyisopropyieeitul ose,
hydrox.ybutylcellul ose, hy droxyphenyl cellulose,
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hydroxyethy 1 cell those (HEC), hydroxypen ty cel tdose, hydroxypropy ethy 1
cell tiloseõ
hy droxy prop ylbutylc el 1 ul o se, and hydroxypropyl et hy 1 cel 1 ul ose,
and mixtures thereof
Examples of suitable polyalkylene glycols include, but are not limited to,
polyethylene
glycol. Examples of suitable thermoplastic polyallcylene oxides include, but
are not
limited to, poly(ethylene oxide). :Examples of suitable acrylic polymers
include, but are
not limited toõ potassium meth acryl atedi vinylbenzene copol
ymer,
pol meth eth ac
ry ate, h igh-mol eat! ar weight cross] inked acrylic acid homopolymers
and copolymers such as those commerciallly available from Noveon Chemicals
under the
tradename CARTIOPOLIm. Examples of suitable hydrocollolds include, but are not
limited to, alginates, agar, guar gum, locust bean pill, kappa carrageenan,
iota
carrageenan, tara, gum arabi c, tragacanth, pectin, xanthan gum, gellan gum,
maltodextrin,
galactomannan, pusstulan, laminarin, sclerogiucan, gum arabic, inulin, pectin,
gelatin,
whelan, rhainsan, zooglan, methylanõ chitin, cyclodextrin, chitosan, and
mixtures thereof.
Examples of suitable clays include, but are not limited to, smectites such as
bentonite,
kaolin, and laponite, magnesium trisilicateõ magnesium aluminum silicate; and
mixtures
thereof. Examples of suitable gelling starches include, but are not limited
to, acid
hydrolyzed starches, swelling starches such as sodium starch glycolate and
derivatives
thereof, and mixtures thereof. Examples of suitable swelling cross-linked
polymers
include, but are not limited to, cross-linked polyvinyl pyrrolidon e, cross-
linked agar, and
cross-linked carboxymethyleellulose sodium, and .mixtures thereof,
10055] The carrier may contain me or more suitable excipients for the
formulation of
tablets. Examples of suitable excipients include, but are not limited to,
fillers. adsorbents,
binders, di si ntegrants, lubricants, gl d
ants, release-modifying ex cipi en tsõ
superdisintegrants, antioxidants, and mixtures thereof.
100561 Suitable binders include, but are not limited to, dry binders such as
polyvinyl
pyrrol i done and hy d roxyp ropy! m eth yl cellul ose ; wet hi riders such as
water-soluble
polymers, including hydrocolloids such as acacia, alginates, agar, guar gum:,
locust bean,
earrageenan, carboxymethylcellulose, tara, gum arable, traQacanth, pectin,
xantlaan,
gellan, gelatin, maltodextrin, galactomannan; pusstdlan, laminarin,
selerogluean, inulin,
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when, rh a msan, zoogl an, in ethyl an, chitin, eye] od ex trin, chi tos a nõ
polyvinyl
pyrroli done, cellulois, sucrose, and starches; and mixtures thereof..
Suitable
disintegrants include, but are not limited to, .sodi um starch glycolate,
cross-1inked
polyvinylpyrrolidonc, cross-linked carboxymethylcellulose, starches,
microcrystalline
cellulose, and mixtures thereof.
[00571 Suitable lubricants include, but are not limited to, long chain tatty
acids and their
salts, such as magnesium stearate and stearic acid, talc, glycerides waxes,
and mixtures
thereof. Suitable glidants include, but are not limited to, colloidal silicon.
dioxide.
Suitable release-modifying excipients include, but are not limited .to,
insoluble edible
materials, pH-dependent polymers, and iiiixture.s thereof,
10058] Suitable insoluble edibl.e materials for -use as release-modifying
excipients
include, but are not limited to, water-insoluble polymers and low-melting
hydrophobic
materials, copolymers thereof, and mixtures thereof. Examples of suitable,
water-
insoluble polymers include, but are not limited to, ethylcellulose, polyvinyl
alcohols,
polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives,
aerylatesõ
meth.acrylates, acrylic a.cid copolymers, copolymers thereof, and mixtures
thereof.
Suitable low-melting hydrophobic materials include, but are not limited to,
fats, fatty acid
esters, phospholipids, waxes, and mixtures thereof Ex.amples of suitable fats
include, but
are not limited to, hydrogenated vegetable oils such as for example cocoa
butter,
hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated
sunflower oil,
and hydrogenated soybean oil, free fatty acids and their salts, and mixtures
thereof.
Examples of suitable fatty acid esters include, but are .not limited to,
sucrose fatty acid
esters, mono-, di.-, and triglycerides, glyceryl belienate, glyceryl
palmitostearate, glyceryl
monostearate, glyceryl tristearate, glyceryl uilaurylate, glyceryl myristate.
G1ycoWax-
:932, lauroyi acrogol-
32 glycerides, stearoyl macrogo1-32 glyce.rides, and mixtures
thereof. Examples cif suitable phospholipids include phosphotidyl choline,
phosphotidyl
serene, phosphotidyl enositolõ phosphotidic acid, and mixtures thereof.
Examples of
suitable waxes include, but are not limited to, camauba wax, spermaceti wax,
beeswax,
candelilla wax, shellac wax, micmcrystalline wax, and paraffin wax; fat-
containing.
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mixtures such as chocolates, and mixtures thereof. Examples of .super
disintegrants
include, but are not limited to, croscarmellose sodium, sodium starch
glycolate and cross-
linked povidone (crospovidone). In one e.mbodiment the tablet core contains up
to about
S percent by weight of such super disintegrant.
(00591 Examples of antioxidants include, but are not limited to, tocopherols,
ascorbic
acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole,
edetic acid, and
edetate salts, and mixtures -thereof Examples of preservatives include, but
are not limited
to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic
acid, and sorbic
acid, and mixtures =thereof.
(00601 In one embodiment, the immediate release coating has an average
thickness of at
least 50 microns, such as from about 50 microns to about 2500 microns; e.g.,
from about
250 microns to about 1000 microns. In embodiment, the immediate release
coating is
typically compressed at a density a more than about 0.9 Wee, as measured by
the weight
and volume of that specificlayer.
1.0061.1 In one embodiment, the immediate release coating contains a first
portion and a
second portion, ti=vh erei n at least one of the portions contains the second
pharmaceutically
active agent. In one embodinuint, the portions contact each other at a center
axis of the
tablet. In one embodiment, the first portion .includes the first
pharmaceutically active
agent and the .second portion includes the second pharmaceutically active
agent.
1.00621 in one embodim.ent, the first portion contains the first
pharm.aceutically active
agent and the second portion contains the second phartn.aceutically active
agent. In one
embodiment, one of the portions contains a third pharmaceutically active
agent, In one
embodiment one of the portions contains a second immediate release portion of
the same
ph armaceuti call y active agent as that contained in the tablet core.
10063] In one embodiment, the outer coating portion is prepared as a dry blend
of
materials prior to addition to the coated tablet core. in another embodi.ment
the outer
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coating portion is included of a dried granulation including the
pharmaceutically active
agent.
10064] Formuladons with different drug release mechanisms described above
could be.
combined in a final dosage form containing single or multiple units.. Examples
of
multiple units include multilayer tablets, capsules containing tablets, beads,
or granules in
a solid or liquid form. Typical, immediate release formulations include
compressed
tablets, .gels., Mills, coatings, liquids and particles that can be.
encapsulated, for example,
in a. gelatin capsule. Many methods for preparing coatings, covering or
incorporatiag
drugs, are known in -the art..
[00651 The immediate release dosage, unit of the dosage form, i.e.., a tablet,
a plurality of
drug-containing beads, granules or particles, or an outer layer of a coated
core dosage
form, contains a therapeutically effective quantity of the active. .ag,ent
with conventional
pharmaceutical excipients. The .immediate release dosage unit may or may not
be coated,
and may or may not be admixed with the delayed release dosage unit or units
(as in an.
encapsulated .mixture of immediate release drug-containing granules, particles
or beads
and delayed release drug-containing granules or beads),
100661 .Emended release formulations are generally prepared as diffusion or
osmotic
systems, for example, as described. in "Remington¨The Science and Practice of
Pharmacy", 20th, Ed., Lippincott. Williams & Wilkins, Baltimore, id.. MOO), A
diffusion .system typically consists of one of two types of devices, reservoir
and matrix,
which are -wellknown and described in die art. The matrix devices are
generally prepared
by compressing the drug with a slowly dissolving polymer carrier into a tablet
form.
[00671 An immediate release portion can be added to the extended release
system by
means of either ap-plying an immediate, release layer On top of the extended
release core;
using coating, or compression, processes or in a multiple unit system such as
a capsule.
containing .extended and immediate release beads.
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100681 Delayed release dosage formulations are created by coating a solid
dosage form
with a film of a polymer which is insoluble in the acid environment of the
stomach, but
soluble in the neutral environment of small intestines. The delayed .release
dosage .units
can be prepared, for example., by coating a dnig or a drug-containing
composition .with a
selected coating material. The drug-containing composition may be a tablet for
incorporation into a capsule, a. tablet for use as an inner core in a. "coated
core" dosage
fbritn or a plurality of drug-containing beads, particles or granules, for
incorporation into
either a. tablet or capsule.
loo691 A pulsed release dosage form is one that mimics a. multiple dosing
profile.
without repeated dosing and typically allows at least a .twofold .reduction in
dosing
frequency as compared to the drug presented as a conventional dosage form
(e.g., as a
solution or prompt drug-releasing, conventional solid dosage form). A .ptilsed
release
profile is characterized by a time period of no release (1.a.g time) or
reduced release
followed by rapid drug release.
100701 Each dosage form contains a therapeutically effective amount of active=
agent, in
one e.mbodiment of dosage forms that mimic a twice daily dosing profile,
approximately
M.. 4 to 70 wt. %õ preferably 40 wt. % to 60 \vt. Vo, of the total amount of
active auent.
in the dosage form is released in the initial pulse, and, correspondingly
approximately 70
wt. to 3.0 wt. %, preferably 60 .svt. to 40
wt. 'X), of the total amount of active agent in
the dosage fonn is relea.sed in the second pulse. For dosage forms mimicking
the twice
daily dosing profile, the second pulse is preferably released approximately 3
hours to less
than 14 hours, and more preferably approximately 5 hours to 12 hours,
following
admini stration.
100711 Another dosage form contains a compressed .ta.blet or a capsule having
a drug-
containing iffinlediate release dosage unit, a delayed release dosage unit and
an optional
second delayed release dosage unit. In this dosage form, the immediate release
dosage
unit contains a. plurality of beads, granules particles that release drug
substantially
immediately follosving oral administration to provide an initial dose, The
delayed release
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dosage unit contains a plurality of coated beads or granules, which release
drug
approximately 3 hours to .141 hours following oral administration to provide a
second
dose.
10072] For purposes of transdermal (e.g., topical) administration, dilute
sterile, aqueous;
or partially aqueous solutions (usually in about. 0..1% to 5% conce.ntration),
otherwise
similar to the above parenteral solutions, may be prepared.
10073] Methods of preparing vanous pharmaceutical compositions with a certain
amount of one or more compounds of formula 1 or other active agents are known,
or .wit.1
be apparent in light of this disclosure, to .those stilled in this art, For
examples of
methods of preparing pharmaceutical compositions, see Remi.ngton's
Pharmaceutical
Sciences, Mack. Publishing Company, Easton, Pa., 19th Editi on (1995).
100741 En addition, in certain embodiments, subject compositions of the
present
application maybe lyophilized or subjected to another appropriate drying
technique such
as spray drying. The subject compositions .may be administered once, or may be
divided
into a number of smaller doses to be administered at varying intervals of
time, depending
in part on the release rate of the compositions and the desired dosage
10075i Formulations useful in the methods provided herein include those
suitable for
oral, .nasal, topical (including buccal and sublingual), rectal, vaginal,
aerosol .and/or
parenteral administration. The fomulations may conveniently be presented in
unit
dosage form and may be prepared by any methods well known in the art of
.pharmacy,
The amount of a subject composition which may be combined with a carrier
material to
prod.uce a single dose .may vary depending upon the subject being treated, and
the
particular mode of administration.
(0076] -Methods of preparing these formulation.s or compositions include the
step of
196i-12;41g into association subject coinpositions with the carrier and.;
optionally, one or
more accessory ingredients in general, the formulations are prepared by
uniformly and
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intimately bringing into as.sociation a subject composition with liquid
carriers, or finely
divided solid carriers, or both, and then, if necessary, shaping the product,
10077] The compounds of .formula 1 described herein may be administered in
inhalant.
or aerosol formulations. The inhalant or aerosol formulations may comprise one
or more
agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic
agents useful
in inhalation therapy. The final aerosol formulation may for example contain
0.005-9Wo
wirw, for instance 0.005-50%, 0,005-5% \WIN-, or 0.01-1.0% wfw, of medicament
relative
to the total weight of the: formulation.
100781 In solid dosage thrills for oral administration (capsules, tablets,
pills, dragees,
powders, granules and the like), the subject composition is mixed with one or
mare
pharmaceutically acceptable carriers andlor any of the following: (I) fillers
or extenders,
such as starches, lactose, sucrose, glucose, rnannitol, and/or silicic acid;
(2) binders, such
as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl
.pyrrolidone,
sucrose andlor acacia; (3) humectants, such as glycerol; (4) disintegrating
agents, such as
agar-agar, cal.ci UM carbonate, potato or tapioca starch, alginic acid,
certain silicates, and
sodium carbonate; (5) solution retarding agents, such as paraffin; (6)
absorption
accelerators, such as quaternary ammonium compounds; (7) wetting agents, such
as, for
example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as
kaolin and
bentonite clay; (9) lubricants, such a tale, calcium .stearate, magnesium
stearate, solid.
polyethylene glycols, sodium lauryl sulfate,. and .mixtures thereof; and (10)
coloring,
agents. In the case of capsules, tablets and pills, the pharmaceutical
compositions may
also comprise buffering !agents. Solid. compositions of a similar type may
also be
employed as fillers in soli and hard-filled gelatin capsules using lactose or
mili-. sugars, as
weli as high mol e:cul.ar weight polyethylene glycols and the likeõ
10079" Liquid dosage fornis tor oral administration include pharmaceutically
acceptable
emulsions, microem ul si on s, solutions, suspensions, sy nips and elixirs. In
a.ddi tin to the
subj.ect compositions, the ii c1uid dosage forms .may contain inert diluents
COMMonly used
in the art, such as, for example, water or other solvents, solubilizing agents
and
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emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl
acetate,
benzyl alcohol., benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils
(in particular,
cottonseedõ COM, peanut, sunflower, soybean, oliveõ castor, and .sesame oils),
glycerol,
tetrahydrofuryl alcohol, polyethylene glycols and .fatty acid esters of
sorbitan, and
mi xtures thereof
10080.1 Suspensions, in addition to the subject compo.sitionsõ may contain
suspending
agents such as, for example, ethoxylated isosteatyl alcohols., polyoxyethylene
sorbitol,
and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide,
bentonite, agar-
agar and tragacanth, and mixtures thereof.
[0081] Formulations for rectal or vaginal administration may be presented as a
suppository, which may be prepared by mixing a subject composition with one or
more
suitable non-irritating carriers comprising, for example, cocoa butter,
polyethylene
glycol, a .suppository wax, or a salicylate, and which is solid at room
temperature, but.
liquid at body temperature and, therefore, will melt in the appropriate body
cavity and
release the encapsulated compound(s) and composition(s) Formulations which are
suitable for vaginal administration also include .pessaries, tampons, creams,
gels, pastes,
foams, or spray .formulations containing such. carriers as are known in the
art to be
appropriate.
10082] Dosage forms for transdermal administration include powders, sprqs,
ointments, pastes, creams, lotions, gels, solutions, patche.s, and inhalants.
A subject.
composition may be mixed under sterile conditions with a pharmaceutically
acceptable
carrier, and with any preservatives, buffers, or propellants .that may be
required. For
transdermal administration, the complexes may include lipophilic and
hydrophilic groups
to achieve the desired water solubility and -transport. properties.
[0083] The ointments, pastes, creams and gets may contain, in addition to
subject
compositions, other carriers, such as animal and -vegetable fats, oils, waxes,
paraffins,
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starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may
contain, in
addition to a subject composition, excipients such as lactose, talc, silicic
acid, aluminum
hydroxide, calcium silicates and polyamide powder, or mixtures of such
substances.
Sprays may a ddi t onal y con Lain cutithill a ry
propellants, such as
chlo.rofluorohydrocarhons a.nd volatile 13nsubsfituted hydrocarbons, such as
butane and
propane.
10084] Methods of delivering a composition or compositions via a transdermal
patch are
known in the art. Exemplary patches and methods of patch delivery are
described in US
Patent Nos. 6,974,588, 6,564;093, 6,312,716, 6,440454, 6,267,983, 6,239,180,
and
6,103,275.
100851 in another embodiment, a transdemal patch may comprise: a. substrate
sheet
comprising a composite :film formed of a resin composifion comprising 100
parts by
eiti,ht of a polyvinyl chloride-polyurethane composite and 2-10 parts by
weight of a
styreneeethylene-butylene-styrene copolymer, a first adhesive layer on the one
side of the
composite film, and a polyalkyiene terephthalate film adhered to the one side
of the
composite film by means of the first adhesive layer, a primer layer which
coinprises a.
saturated polyester resin and is formed on the surface of the polyalkylene
terephthalate
-film; and a second adhe.sìe layer comprising a styrene-diene-styrene block
copolymer
containing a pharmaceutical agent layered on the primer layer. A method for
the
manufacture of the above-mentioned substrate sheet comprises preparing -the
above resin
composition molding the resin composition into a composite film by a calendar
process,
and then adhering a polyalkylene terephthalate filin on one side of the
composite film by
means of an adhesive layer thereby forming the substrate sheet, and forming a
primer
layer comprising a saturated -polyester resin on the outer surface of the
polyalkylene
terep hth al ate film
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1.00861 Another type of patch comprises incorporating the drug directly in a
phannac eutical y acceptable adhesive and laminating the drug-containing
adhesive onto a
suitable backing member, eg. a polyester backing membrane. The drug should be
present
at a concentration which will not affect the adhesive properties, and at the
same time
deliver the required clinical dose.
100871 Transdermal patches may be passive or active. Passive transdermal drug
delivery systems currently available, such as the nicotine, estrogen and
nitroglycerine
patches, deliver small-molecule drugs. Many of the newly developed proteins
and peptide
drugs are too large to be delivered through passive transdermal patches and
may be
delivered using technology such as electrical assist( i on top hore si s) for
large-molecule
drugs.
10088j lontophoresis is a technique employed for enhancing the flux of ionized
substances through membranes by application of electric current. One example
of an
iontophoretic Membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The
principal
mechanisms by which iontophoresis enhances molecular transport across the skin
are (a)
repelling a charged ion from an electrode of the same charge, (b)
electroosmosis, the
convective movement of solvent that occurs through a charged pore in response
the
preferential passage of counter-ions when an electric field is applied or (c)
increase skin
permeability due to application of electrical current.
10089] In some cases, it may be desirable to administer in the form of a kit,
it may
comprise a container for containing the separate compositions such as a
divided bottle or
a divided foil p a c ket, Typically the lit com ph se s di recti ohs for the
ad.ininistralion of the
separate components. 717he kit form is particularly advantageous -when the
separate
components are preferably administered in different dosage forms (e.g., oral
and
parent:era:I). are administered at different dosage intervals, or when
titration of the
individual components athe combination is desired by the prescribing
physician.
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100901 An example of such a kit is a so-called blister pack. Blister packs are
well known
in the packaging Indus-by and are widely used for the packaging a
pharmaceutical unit.
dosag.e forms (tablets, capsules.,. and the like). Blister packs generally
consist of a sheet of
relative! V stiff material covered \vial, a foil of a plastic material that
may be transparent..
[00911 Methods and compositions for the suppression of carbonic anhydrase
activity.
Among other things, herein is provided a method of treating complications or
diseases
manifested from carbonic anhydrase enzyme activity, comprising administering
to a
pati.ent in need thereof a therapeutically effective amount of compound of
Formula
R2
HN
NH2
N¨N
Formula
'Wherein.,
R1 each independently represents D, H,
0 0
0
iSSN'OWNX
NH 2 0 0
c.<1\0/\sss _________________________ A...L0-
0
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0 0
0
H \:s
0 0 0 0
-=-.. ,..... '1.1.L.," LI
csS5
0 õrµ
NH2 NH2
H H
N "It.a
¨0.-
-A*0
H ,
H H
N
0
H H
.;22;INN's=...,,,,NN,.o,,.-N-..,%.õ.-- s' ¨
{2Z, 0 0 sSS
OH
0
H H i
or H
,
R2 each independently represents
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0 N CHI
".....,
SH
H2
..,---
0 N/ s
H3C .,,,,,.
4,, 0
...../...N'e
H 0
1 ,HS H2N
, .
..7,N.,,,NNs,..õ...7.CH 3
N CH3
1
OH
HO
OH
0
l'N'...../..
H
H
0 0 N õsS
\esS:\ HO
OH HS \\........õ,.......... ....... \
H 40 N
N1-12 H H
0 0
H
OH
: =
0
0
0 .2..
0 e S -...,,,
S
,
i'
4 7 1 0 13 16
0 t
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0
..i.sS5
0
12 20
,
:SS'S
-
i 9
4 7 1 0 1 3
0 ,
H. OH 0
1:-
1,
HO ...o
0 0
S s
NHCOCH3
.1 0 0
0 c., 100 CO2 H
OH A to rss. ococH3 coNH2
0.,..
o=??...
. ,
r CH 3 C1-E3 OH 0
0
0
14. 10
01 CH;
11,5C ¨N........._õ7-N.N.,...",s5' 0 0
H3C 0
1
C H3
CH3 OH 0
OH
o
tiVI\ NH
Ea 0
H 1-3
Matt
s
HN if
0 , NH2
,
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o
= b
a
d
or
a is independently 2,3 or 7;
each b is independently 3, 5 or 6;
e is independently 1, 2 or 6;
c and d are each independently H, D, -OH., -OD, C1-C6-a1kyl, or -COCH3;
R3 independently represents H, D, methyl, F. CI, ethyl or acetyi.
Aletimxis fix using compoinds offortmila
10021 The invention .also includes methods for treating glaucoma, epileptic
seizures,
Idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness,
cystinuria,
periodic paralysis and dual ectasia, congestive heart failure, drug induced
edema.,
diuretic, intermittent claudication resulting from obstructed arteries in the
limbs, and
vascular dementia, improves blood flow through peripheral blood. vessels and
therefore
helps with blood circulation in the arms and legs (e.g. intermittent.
claudication), and the
brain (hence its use in vascular dementia), .VerlOUS disease, Peyronie's
disease,
neuropathic injuries, strokes, sickle celi disease, nausea and headaches in
the mountains
(altitude sickness), non-alcoholic steatohepatitis and alcoholic liver
disease, fibrotic
lesions induced by radiation therapy for breast cancer, cytokine release
syndrome, type I
diabetes and type 2 diabetes, asthma., bronchodilationõ kidney diseases.,
renal protection,
vascular ischemia, .neuroprotection, va.sodilation, Alzheimer's disease,
dementia, stroke,
and treatm ent of en dam etri o.si s.
METHO.DS OF MAKING
1009311 Examples of synthetic pathways useful for making compounds of formula
t are
set forth in example below and generalized in scheme -1:
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Scheme-I:
C6H5CH2C1
N -NN KOH -N
. (CH3C0)20 N -N
H2N S Et0H H H2N C 3COOH ZN S
Ph
H20
1 rt- 0 C ,30m in 2 60 C, 10 min 3
C0nc.HC1
50% aq.CH3000H Et0H
-N 0 reflux, 4.5 h - 0
C, 30 min 0 4/ NH7 NN .1/
2) Liquid NH3 /L-N"--S 0
2) 5M aq.NaOH
4 5
0
oxalyi chloride
CHC13
6
rt, 2h
01
7
0
K2C01
+
DMF
H2 N 0
5 7 100 C,
8 h
H2N
sS¨<
N
8
10094] Step-1: Synthesis of campou nd 2:
C6H5CH2M
N KOH N -N
õIL ¨S H j===-S\
H2N S Et0H H2N S
H20 Ph
12
rt- 0 C,30m
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100951 .Addition of 301 n of (5.36 moles) of 85%potassilIM hydroxide to a
slurry of 608
g(4.56 moles) of 2-amill0-1,3,4-thiadiazole-5-thio1 1 in 456 cc of water
produced a brown.
solution. This solution was clarified .with Darco (g-60 (for filtration) and
diluted .with
1300 cc of ethanol. Benzyl chloride (575 g, 4.56 moles) was added rapidly with
stirring.
The thick reaction mixture was tbrmed almost immediately was stirred and
cooled to 0 C.
for 30 minutes and then diluted with 2 1., of cold water_ The solid compound 2
was
removed by filtration and washed with water and ether..
10096] Step-2: Synthesis of com.pound
N --N (CH3C 0)20 N -N
0
H,N S
Phi
Phi
C H3C0 0 H
2 60 C. 10 min 3
(00971 A slurry of 4.0 moles of compound 2 in 4..4 .Moles of acetic anhydride
and 1500 cc
of acetic acid was heated at 60 C. for 10 minutes to get clear solution. The
solution was
gradually cooled and at the first appearance of ciy.stals, 2l. of µvater .was
added. 'The
suspension was cooled to 0 C and the solid compound 3 was collected by
filtration.
[00981 Step-3: Synthesis of compound 4:
C12
0 N-N 50% aciCH3COOH 0
5 C: 30 min C)11
NF¨S 0
Ph 2) Liquid NH3.
4
100991 A suspension of 0.50 g of compound. 3 in 40 cc of 50% aqueous acetic
acid was
chlorinated for 0.5 h at 5 0 C. The solid was filtered off after this time and
added to 20 cc
of liquid ammonia. After evaporation of ammonia and dilution of the dry
residue with
water, the aqueous solution was filtered. Acidification with hydrochloric acid
gave solid
compound 4 with nicking point 260
[001001 Step-4: Synthesis of compound SI
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1) Conc.FIC
Et.OH
-N 0 reflux.; 4.5 hN 0
N-
11"---'S
2) 51V1 aq,Na01-1 2N
4 5
1001011 A
solution of compound 4 (15 g, 67.5 mmol ,j) in a mixture of ethanol (100
nilL) and concentrated 'hydrochloride acid (30 ml.) was heated at reflux for
4_5 h, during
which time a solid slowly deposited. Upon cooling the solution, the solvents
were
removed in vacuo and the solid residue was redissolved in F120 (75 mt.). The
SO1101.011
\vas basified to pH 7 Ivith 5 IM sodium hydroxide, the precipitated product.
.was collected
by filtration, and then recrystallized from water to give =the product 5 (10.6
g, 58.9 minol,
87%), mp 228-229 C (lit15 mp 230-232 ()C),
1001.02j Step-5: Synthesis of compound 7:
O
otreylcIlloncte.
¨
HO
6 CH Clz
rt. 2h
0
1
7
(001031 To a
.soluti on of 605 nig of 5,8,11,14,17-eicosapentaenic acid 6 in 6 ml of
dry chloroform was added 0,25 1111 of oxalyi chloride under argon at room
temperature.
The mixture was reacted for 2 hours, From the reactio.n mixture were removed
the c.hloroform and the remaining oxaly1 chloride by distillation under
reduced pressure
to give 5,8,1 1,14,17-eicosapentaenoyl chloride 7, which was then directly
used for the
next step,
1001.041 Step-6: Synthesis of compound 8:
NH kloo;
+
H1N S O DMF
6 7 100 `t, 8 h
HA p N-1,4 0
0
8
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1001051 A solution of compound 5 (2 mmol.) in dry .DMF (I 0 mr) was suspended
in of
anhydrous potassium carbonate (2,2 nunol) at room. temperature. To the
reaction mixture
was added the .DMIF solution 2 mmol of of 5,8, 4,17-
eicosapentaenoy1 chloride 7 in 2
rul DIMIF prepared above d.ropwise over 15 min., and the mixture was heated at
iO C for
8 hours. From the reaction mixture was removed insolubles by filtration, and
water Was
added to the filtrate. The mixture was extracted two times with ethyl acetate
(2x10 .ml).
Organic laver of the extract was washed with water and dried over anhydrous
sodium
sulfate. Then, the solvent was removed by distillation under reduced pressure
to get the
residue was subjected to silica gel column chromatography to obtain the pure
compound
8.
1001061 The term
"sample" refers to a sample of a body flu-id, to a sample of
separated cells or to a sample from a tissue or an organ. Samples of body
fluids can be
obtained by vell known techniques and include, preferably, samples of blood,
plasma,
serum, or urine, more preferably, samples of blood, plasma or SertIM.
:EQUIVALENTS
[001.071 'The present disclosure provides among other things compositions and
methods for treating diseases manifested from carbonic anydrase enzyme
activity and
their complications. While specific embodiments of the subject disclosure have
been
discussed, the above specification is illustrative and not restrictive. :M.any
variations of
the systems and methods herein will become apparent to those skilled in the
art upon
review of this specification. The full scope of the claimed systems and
methods should
be determined by reference to the claims, along with their .full scope of
equivalents, and
the specification, along with such variations.
INCORPORATION BY REFER.ENCE
1.001081 All
publications and patents mentioned herein, including those .items listed.
above, are hereby incorporated by reference in their entirety as if each
individuai
publication or patent was specifically and individually indicated -to be
incorporated by
reference. hi case of conflict the present application, including any
definitions herein,
will control,
