Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION THERAPY FOR TREATMENT OF DEPRESSION
In the mammalian central nervous system (CNS), the transmission of
nerve impulses is controlled by the interaction between a neurotransmitter,
that is
released by a sending neuron, and a surface receptor on a receiving neuron,
which causes either an excitation or inhibition of this receiving neuron. L-
Glutamate, which is the most abundant neurotransmitter in the CNS, mediates
the majority of excitatory transmission in mammals, and is referred to as an
excitatory amino acid (EAA). The receptors that respond to glutamate are
1 o generally referred to as excitatory amino acid receptors (EAA receptors).
See
Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981 ); Monaghan,
Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins,
Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The
excitatory amino acids are of great physiological importance, playing a role
in a
variety of physiological processes, such as long-term potentiation (learning
and
memory), the development of synaptic plasticity, motor control, respiration,
cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types.
Receptors that are directly coupled to the opening of cation channels in the
cell
2 o membrane of the neurons are termed "ionotropic". This type of receptor has
been subdivided into at least three subtypes, which are defined by the
selective
agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-
methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second
general type of receptor is the G-protein or second messenger-linked
25 "metabotropic" excitatory amino acid receptor. This second type of EAA
receptor
is coupled to multiple second messenger systems that lead to enhanced
phosphoinositide hydrolysis, activation of phospholipase D, increases or
decreases in c-AMP formation, and changes in ion channel function. Schoepp
and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors
3 o appear not only to mediate normal synaptic transmission along excitatory
pathways, but also participate in the modification of synaptic connections
during
development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in
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Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research
Reviev~rs, 15, 41 (1990).
The AMPA subtype of glutamate receptors are assembled from four
protein subunits known as GIuR1 to GIuR4, (also referred to as GIuRA-GIuRD)
while kainic acid receptors are assembled from the subunits GIuR5 to GIuR7,
and KA-1 and KA-2. Wong and Mayer, Molecular Pharmacology 44: 505-510,
1993. It is not yet known how.these sub-units are combined in the natural
state.
However, the structures of certain human variants of each subunit have been
elucidated, and cell lines expressing individual subunit variants have been
cloned
so and incorporated into test systems designed to identify compounds which
bind to
or~ interact with them, and hence which may modulate their function. Thus,
European patent application, publication number EP-A2-0574257 discloses the
human sub-unit variants GIuR1 B, GIuR2B, GIuR3A and GIuR3B. European
patent application, publication number EP-A1-0583917 discloses the human
15 subunit variant GIuR4B
One distinctive property of AMPA and kainic acid receptors is their rapid
deactivation and desensitization in response to application of glutamate.
Yamada and Tang, The Journal of Neuroscience, September 1993, 13(9): 3904-
3915 and Kathryn M. Partin, J. Neuroscience, November 1, 1996, 16(21 ): 6634-
2 0 6647. The physiological implications of rapid desensitization, and
deactivation if
any, are not fully understood.
It is known that the rapid desensitization and deactivation of AMPA and/or
kainic acid receptors to glutamate may be inhibited using certain compounds.
This action of these compounds is often referred to in the alternative as
25 "potentiation" of the receptors. One such compound, which selectively
potentiates AMPA receptor function, is cyclothiazide. Partin et al., Neuron.
Vol.
11, 1069-1082, 1993.
In addition, certain sulfonamide derivatives which potentiate glutamate
receptor function in a mammal have been disclosed in the following
International
3 0 Patent Application Publications: WO 98/33496 published August 6, 1998; WO
99/43285 published September 2, 1999; and WO 00/06539; WO 00/06537, WO
00/06176, WO 00/06159, WO 00/06158, WO 00/06157, WO 00/06156, WO
00/06149, WO 00/06148, and WO 00/06083, all published February 10, 2000.
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Furthermore, International Patent Application Publication WO 97/39750,
published October 30, 1997 discloses a method of treating depression in a
human suffering from a mental disorder comprising the selective potentiation
of
AMPA brain receptors of the patient to natural ligands thereof, the selective
potentiation being sufficient to amplify the effects of the natural ligands in
an
amount adequate to improve thedepression.
Depression in its many variations has recently.become much more visible
to the general public than it has previously been. It is now recognized as an
extremely damaging disorders and one that afflicts a surprisingly large
fraction of
1o the population. Suicide is the most extreme symptom of depression, but
millions
of people, not quite so drastically afflicted, live in misery and partial or
complete
uselessness, and afflict their families as well by their affliction. The
introduction
of fluoxetine, a serotonin reuptake inhibitor (SRI), was a breakthrough in the
treatment of depression, and depressives are now much more likely to be
15 diagnosed and treated than they were only a decade ago..
Depression is often associated with other diseases and conditions, or
caused by such other conditions. For example, it is, associated with
Parkinson's
disease; with HIV; with Alzheimer's disease; and with. abuse of anabolic
steroids.
Depression may also be.associated with abuse of any substance, or may be
2 o associated with behavioral problems resulting from or occurring in
combination
with head injuries, mental retardation or stroke.
Despite the breakthrough nature of serotonin reuptake inhibitors in the
treatment of depression, a number of patients suffering from depression do not
respond, or respond only partially to treatment with serotonin reuptake
inhibitors,
25 for example, or other traditional modes of treating depression, including
the older
tricyclic class of compounds referred to as monoamine oxidase inhibitors
(MAOI's). Additionally, there is often a significant period of time before
treatment
wifih serotonin reuptake inhibitors provide a therapeutic effect. Furthermore,
various side effects are sometimes associated with current antidepressant
o therapy, for example with serotonin reuptake inhibitors the gastrointestinal
system may be affected wherein symptoms are often manifested as nausea and
occasional vomiting. An additional troubling side effect associated with
serotonin
reuptake inhibitors is sexual dysfunction. It has been estimated that such
sexual
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dysfunction is as high as 34%. [See F.M. Jacobsen, J. Clin. Psychiatry, 53,
119,
(1992)]. These side effects often result in depressed patients not maintaining
the
SRI therapy for a period that is long enough in duration to recognize any
.significant improvement in the patient's condition.
The present invention provides a method for treating depression,
comprising administering to a patient an effective amount of a first component
which is a suitable antidepressant, in combination with an effective amount of
a
second component which is a suitable AMPA receptor potentiator.
The present invention further provides a method for treating refractory
~ depression, comprising administering to a patient an effective amount of a
first
component which is a suitable antidepressant, in combination with an effective
amount of a second component which is a suitable AMPA receptor potentiator.
This invention provides, further, a method for attenuating adverse events
associated with depression comprising administering to a patient an effective
s5 amount of a first component which is a suitable antidepressant, in
combination
with an effective amount of a suitable AMPA receptor potentiator.
This invention also provides a method of providing rapid onset treatment
of depression to a patient which comprises administering to said patient an.
efFective amount of a first component which is a suitable antidepressant, in
combination with an effective amount of a second component which is_a suitable
AMPA receptor potentiator.
The invention also provides a pharmaceutical composition which
comprises a first component which is a suitable antidepressant, and a second
corriponent which is a suitable AMPA receptor potentiator, the two components-
being present in an amount effective in the treatment of depression.
The present invention further provides an article of manufacture
comprising packaging material and a pharmaceutical composition which
comprises a first component which is a suitable antidepressant, and a second
component which is a suitable AMPA receptor potentiator, contained within said
3 o packaging material, wherein said packaging material comprises a label
which
indicates.that said pharmaceutical composition can be used for treating
depression.
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BRIEF DESCRIPTION OF THE DRAWING
Figure 1 discloses the effect of the combination of imipramine and
N-2-(4-(3-thienyl)phenylpropyl 2-propanesulfonamide (392098 in the Forced
Swim Test in the mouse. More specifically, low doses of 392098 by itself
produced no effect in the Forced Swim Test. Figure 1 further reveals that when
392098 was combined at a dose as low as 25 micrograms/kg with a subeffective
dose of imipramine (5 mg/kg), a statistically significant reduction in
immobility of
the mouse resulted.
zo DETAILED DESCRIPTION OF THE INVENTION
As used herein the term "potentiating glutamate receptor function" refers
to any increased responsiveness of glutamate receptors, for example AMPA
receptors, to glutamate or an agonist, and includes but is not limited to
inhibition
of rapid desensitization or deactivation of AMPA receptors to glutamate.
15 , As.used herein the term "AMPA receptor potentiator" refers to a
compound which inhibits the rapid desensitization or deactivation of AMPA
receptors to glutamate.
As used herein the term "attenuating" means decreasing the number,
severity or frequency of side effects or adverse events associated with
treatment
2 0 of depression with conventional antidepressant medication, such as an
SRI's,
when such products are used at dosages that yield beneficial effects on the
symptoms of the disease.
As used herein the number "392098" refers to the compound N-2-(4-(3-
thienyl)phenylpropyl 2-propanesulfonamide of example 2.
25 As used herein the term "1M1" refers to imipramine.
As used herein the term "FST" refers to Forced Swim Test.
As used herein the term "i.p." refers to intraperitoneal or intraperitoneally.
It is understood by one of ordinary skill in the art that the present
invention
includes the pharmaceutically acceptable salts of either or both of the first
and
o second components. The compounds used in this invention can possess a
sufficiently acidic group, a sufficiently basic group, or both functional
groups, and
accordingly react with any of a number of organic and inorganic bases, and
inorganic and organic acids, to form a pharmaceutically acceptable salt.
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The term "pharmaceutically acceptable salt" as used herein, refers to salts
of the compounds used in the present invention which are substantially non-
toxic
to living organisms. Typical pharmaceutically acceptable salts include those
salts
prepared by reaction of the compounds of the present invention with a
s pharmaceutically acceptable mineral or organic acid. Such salts are also
known
as acid addition salts. Such salts include the pharmaceutically acceptable
salts
fisted in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known
to
the skilled artisan.
Acids commonly employed to form acid addition salts are inorganic acids
1 o such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid,
phosphoric acid, and the like, and organic acids such as p-toluenesulfonic,
methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic
acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid,
and the
like. Examples of such pharmaceutically acceptable salts are the sulfate,
15 pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate; bromide, iodide, acetate,
propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate,
hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate,
propionate, phenylpropionate, salicylate, oxalate, malonate, succinate,
suberate,
20 sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate,
isonicotinate, cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-
1,4-
dioate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, hexyne-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate,
dinitrobenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, phthalate, p-
25 toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate,
xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, a-hydroxybutyrate, glycolate, tartrate,
benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,
hydroxyethanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate,
o mandelate, tartarate, and the like. Preferred pharmaceutically acceptable
acid
addition salts are those formed with mineral acids such as hydrochloric
acid.and
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hydrobromic acid, and those formed with organic acids such as malefic acid,
oxalic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as
ammonium or alkali or alkaline earth metal hydroxides, carbonates,
bicarbonates,
and the like. Such bases useful in preparing the salts of this invention thus
include sodium hydroxide, potassium hydroxide, ammonium hydroxide,
potassium carbonate, sodium carbonate, sodium bicarbonate, potassium
bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium
and sodium salt forms are particularly preferred.
so It should be recognized that the particular counterion forming a part of
any
salt of this invention is usually not of a critical nature, so long as the
salt as a
whole is pharmacologically acceptable and as long as the counterion does not
contribute undesired qualities to the salt as a whole. It is further
understood that
the above salts may form hydrates or exist in a substantially anhydrous form.
As used herein, the term "stereoisomer" refers to a compound made up of
the same atoms bonded by the same bonds but having different three-
dimensional structures which are not interchangeable. The three-dimensional
structures are called configurations. As used herein, the term "enantiomer"
refers to two stereoisomers whose molecules are nonsuperimposable mirror
2 o images of one another. The term "chiral center" refers to a carbon atom to
which
four different groups are attached. As used herein, the term "diastereomers"
refers to stereoisomers which are not enantiomers. In addition, two
diastereomers which have a different configuration at only one chiral center
are
referred to herein as "epimers". The terms "racemate", "racemic mixture" or
"racemic modification" refer to a mixture of equal parts of enantiomers.
The term "enantiomeric enrichment" as used herein refers to the increase
in the amount of one enantiomer as compared to the other. A convenient
method of expressing the enantiomeric enrichment achieved is the concept of
enantiomeric excess, or "ee", which is found using the following equation:
ee = E~ - E2 X 100
E
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_$_
wherein E~ is the amount of the first enantiomer and E2 is the amount of the
second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50,
such
as is present in a racemic mixture, and an enantiomeric enrichment sufficient
to
produce a final ratio of 70:30 is achieved, the ee with respect to the first
enantiomer is 40%. However, if the final ratio is 90:10, the ee with respect
to the
' first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of
greater
than 95% is most preferred and an ee of greater than 99% is most especially
preferred.
Enantiomeric enrichment is readily determined by one of ordinary skill in
so the art using standard techniques and procedures, such as gas or high
penformance liquid chromatography with a chiral column. In addition,
separation
and isolation of the compounds of the present invention into the individual
enantiomers is similarly performed by one of ordinary skit( in the art using
standard techniques and procedures, such as gas or high performance liquid
chromatography with a chiral column, or other standard resolving techniques.
Choice of the appropriate chiral column, eluent and conditions necessary to
effect separation of the enantiomeric pair is well within the knowledge of one
of
ordinary skill in the art. In addition, the enantiomers of compounds of the
present
invention can be resolved using standard techniques such as those described by
2 o J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley
and
Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,"Stereochemistry of Organic
Compounds", (Wiley-Interscience 1994), and European Patent Application No.
EP-A-838448, published April 29, 1998.
Some of the compounds of the present invention have one or more chiral
centers and may exist in a variety of stereoisomeric configurations. As a
consequence of these chiral centers, the compounds of the present invention
occur as racemates, mixtures of enantiomers and as individual enantiomers, as
well as diastereomers and mixtures of diastereomers. All such racemates,
enantiomers, and diastereomers are within the scope of the present invention.
3 o The terms "R" and "S" are used herein as commonly used in organic
chemistry to denote specific configuration of a chiral center. The term "R"
(rectus) refers to that configuration of a chiral center with a clockwise
relationship
of group priorities (highest to second lowest) when viewed along the bond
toward ,
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_g_
the lowest priority group. The term "S" (sinister) refers to that
configuration of a
chiral center with a counterclockwise relationship of group priorities
(highest to
second lowest) when viewed along the bond toward the lowest priority group.
The priority of groups is based upon their atomic number (in order of
decreasing
atomic number). A partial list of priorities and a discussion of
stereochemistry is
contained in "Nomenclature of Organic Compounds: Principles and Practice",
(J.H. Fletcher, et al., eds., 1974) at pages 103-120
The designation " ~ " refers to a bond that protrudes forward out of
the plane of the page.
so The designation " w~~~~~~~ " refers to a bond that protrudes backward out
of
the plane of the page.
The designation " -"~"'~~' " refers to a bond wherein the stereochemistry is
not defined.
As used herein the term "CX516" refers to a compound of the following
is structure:
o
N
\ N
N
The first component is a compound which functions as a suitable
antidepressant. As used herein the term "suitable antidepressant" includes but
is
2 o not limited to serotonin reuptake inhibitors (SRI's), norepinephrine
reuptake
inhibitors (NERI's), combined serotonin-norepinephrine reuptake inhibitors
(SNRI's), monoamine oxidase inhibitors (MAOI's), phosphodiesterase-4
inhibitors
(PDE-4), and the like. SRI's and SNRI's are the preferred suitable
antidepressants, with SRI's being most preferred.
25 More specifically, examples of suitable antidepressants include, but are
not limited to:
Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, is
marketed in the hydrochloride salt form, and as the racemic mixture of its two
enantiomers. U.S. Patent 4,314,081 is an early reference on the compound.
3 o Robertson et al., J. Med. Chem. 31, 1412 (1988), taught the separation of
the R
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and S enantiomers of fluoxetine and showed that their activity as serotonin
uptake inhibitors is similar to each other. In this document, the word
"fluoxetine"
will be used to mean any acid addition salt or the free base, and to include
either
the racemic mixture or either of the R and S enantiomers;
Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, is
usually administered as the hydrochloride salt and as the (+) enantiomer. It
was
first taught by U.S. Patent 4,956,388, which shows its high potency. The word
"duloxetine" will be used here to refer to any acid addition salt or the free
base of
the molecule;
so Venlafaxine is known in the literature, and its method of synthesis and ifs
activity as an inhibitor of serotonin and norepinephrine uptake are taught by
U.S.
Patent 4,761,501. Venlafaxine is identified as compound A in that patent;
Milnacipran (N,N-diethyl-2-aminomethyl-1-
phenylcyclopropanecarboxamide) is taught by U.S. Patent 4,478,836, which
15 prepared milnacipran as its Example 4. The patent describes its compounds
as
antidepressants. Moret et al., Neuropharmacology 24, 1211-19 (1985), describe
its pharmacological activities as an inhibitor of serotonin and norepinephrine
reuptake;
Citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-
2o isobenzofurancarbonitrile, is disclosed in U.S. Patent 4,136,193 as a
serotonin
reuptake inhibitor. Its pharmacology was disclosed by Christensen et al., Eur.
J.
Pharmacol. 41, 153 (1977), and reports of its clinical effectiveness in
depression
may be found in Dufour et al., Int. Clip. Psychopharmacol. 2, 225 (1987), and
Timmerman et al., ibid., 239;
25 Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone O-(2-
aminoethyl)oxime, is taught by U.S. Patent 4,085,225. Scientific articles
about
the drug have been published by Claassen et al., Brit. J. Pharmacol. 60, 505
(1977); and De Wilde et al., J. Affective Disord. 4, 249 (1982); and Benfield
et al.,
Drugs 32, 313 (1986);
3o Paroxetine, traps-(-)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-
fluorophenyl)piperidine, may be found'in U.S. Patents 3,912,743 and 4,007,196.
Reports of the drug's activity are in Lassen, Eur. J. Pharmacol. 47, 351
(1978);
Hassan et al., Brit. J. Clip. Pharmacol. 19, 705 (1985); Laursen et al., Acta
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Psychiat. Scand. 71, 249 (1985); and Battegay et al., Neuropsychobioloqy 13,
31
(1985);
Sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-
naphthylamine hydrochloride, is a serotonin reuptake inhibitor which is
.marketed
as an antidepressant. It is disclosed by U.S. Patent 4,536,518;
Buproprion (Wellbutrin°), (~)-1-(3-chlorophenyl)-2-[(1,1-
dimethylethyl)amino]-1-propanone is indicated for treatment of depression. The
term "buproprion" " will be used here to refer to any acid addition salt or
the free
base of the molecule existing as the racemate or either enantiomer; The HCI
salt
z o is particularly preferred;
Reboxetine (EdronaxT""), 2-[a-(2-ethoxy)phenoxy-benzyl]morpholine, is
usually administered as the racemate. It was first taught by U.S. Patent
4,229,449, which describes its utility for the treatment of depression.
Reboxetine
is a selective norepinephrine reuptake inhibitor. The term "reboxetine" will
be
15 used here to refer to any acid addition salt or the free base of the
molecule
existing as the racemate or either enantiomer;
Moclobemide, 4-chloro-N-[2-(4-morpholinyl)-ethyl]benzamide, see U.S.
Patent No. 4,210,754;
Imipramine, see U.S. Patent No. 2,554,736; and
2o Rolipram, see U.S. Patent No. 4,193,926.
The second component is a compound which is a suitable AMPA
potentiator. Examples of suitable AMPA receptor potentiators include but are
not
limited to those disclosed in:
25 WO 98/33496 published August 6, 1998;
WO 99/43285 published September 2, 1999;
WO 00/06539 published February 10, 2000;
WO 00/06537 published February 10, 2000;
WO 00/06176 published February 10, 2000;
3 o WO 00/06159 published February 10, 2000;
WO 00/06158 published February 10, 2000;
WO 00/06157 published February 10, 2000;
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WO 00/06156 published February 10, 2000;
WO 00/06149 published February 10, 2000;
WO 00/06148 published February 10, 2000;
WO 00/06083 published February 10, 2000;
U.S. Patent No. 5,891,871, issued April 6, 1999;
U.S. Patent No. 5,852,008, issued December 22, 1998;
U.S. Patent No. 5,747,492, issued May 5, 1998; and
U.S. Patent No. 5,650,409, issued July 22, 1997; the disclosures of which
are all hereby incorporated by reference. The above suitable AMPA receptor
so potentiators are readily prepared by one of ordinary skill in the art
following, for
example, the procedures set forth therein.
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Specific examples of suitable AMPA receptor potentiators are listed in
table I.
Table I. Suitable AMPA Receptor Potentiators
Example Compound
1 [(Methylethyl)sulfonyl]~2-[4-(4-~2-
j(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl~a
mine
1 a {(2R)-2-[4-(4-~2-
[(Methylsulfonyl)amino]ethyl~phenyl)phenyl]propyl~[(
meth leth I sulfon I amine
2 N-2-(4-(3-thienyl)phenylpropy) 2-
ro anesulfonamide
3 [2-fluoro-2-(4-~3-
[(methylsulfonyl)amino]phenyl}phenyl)propyl][(meth
leth I sulfon I amine
3a [2-fluoro-2-(4-~3-
[(methylsulfonyl)amino]phenyl}phenyl)propyl][(meth
leth I sulfon I amine enantiomer 1
4 CX516
. Aniracetam
6 Piracetam
7 PEPA
8 IDRA-21
9 S18986
All of the U.S. patents which have been mentioned above in connection
with compounds used in the present invention are incorporated herein by
reference.
1o While all combinations of first and second components are useful and
valuable, certain combinations are particularly valued and are preferred, as
set
forth in table II:
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Table II Particularly Preferred Combinations.
First ComponentSecond Component
Fluoxetine Suitable AMPA receptor potentiator
Venlafaxine Suitable AMPA receptor potentiator
Citralopram Suitable AMPA receptor potentiator
Fluvoxamine Suitable AMPA receptor potentiator
Paroxetine Suitable AMPA receptor potentiator
Sertraline Suitable AMPA receptor potentiator
Milnacipran Suitable AMPA receptor potentiator
Duloxetine Suitable AMPA receptor potentiator
Fluoxetine [(Methylethyl)sulfonyl]~2-[4-(4-~2-
[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}a
mine
Fluoxetine ~(2R)-2-[4-(4-{2-
[(Methylsulfonyl)amino]ethyl}phenyl)phenyl]propy1)[(
meth leth I sulfon I amine
Fluoxetine CX516
Paroxetine {(2R)-2-[4-(4-(2-
[(Methylsulfonyl)amino]ethyl}phenyl)phenyl]propy1}[(
meth leth I sulfon I amine
Paroxetine CX516
Citalopram {(2R)-2-[4-(4-{2-
[(Methylsulfonyl)amino]ethyl)phenyl)phenyl]propy1}[(
meth leth I sulfon I amine
Citalopram CX516 ,
Sertraline ~(2R)-2-[4-(4-~2-
[(Methylsulfonyl)amino]ethyl}phenyl)phenyl]propy1}[(
meth leth I sulfon I amine
Sertraline CX516
Imipramine {(2R)-2-[4-(4-{2-
[(Methylsulfonyl)amino]ethyl}phenyl)phenyl]propy1)[(
meth leth J sulfon ! amine
Imipramine CX516
Imipramine N-2-(4-(3-thienyl)phenylpropyl2-
ro anesulfonamide
Imipramine (2-fluoro-2-(4-{3-
[(methylsulfonyl)amino]phenyl}phenyl)propyl][(meth
leth I sulfon I amine enantiomer 1
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The following examples and preparations represent typical syntheses of
certain AMPA receptor potentiators as described generally above. These
examples are illustrative only and are not intended to limit the invention in
any
way. The reagents and starting materials are readily available to one of
ordinary
s skill in the art. As used herein, the following terms have the meanings
indicated:
"eq" refers to equivalents; "g" refers to grams; "mg" refers to milligrams;
"L" refers
to liters; "mL" refers to milliliters; "~L" refers to microliters; "mol"
refers to moles;
"mmol" refers to millimoles; "psi" refers to pounds per square inch; "min"
refers
to minutes; "h" or "hr" refers to hours; "°C" refers to degrees
Celsius; "TLC" refers
Zo to thin layer chromatography; "HPLC" refers to high performance liquid
chromatography; "Rf' refers to retention factor; "Rt" refers to retention
time;
"8"refers to part per million down-field from tetramethylsilane; "THF" refers
to
tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to
methyl sulfoxide; "LDA" refers to lithium diisopropylamide; "EtOAc" refers to
ethyl
15 acetate; "aq" refers to aqueous; "iPrOAc" refers to isopropyl acetate;
"methyl
DAST" refers to dimethylaminosulfur trifluoride, "DAST" refers to
diethylaminosulfurtrifluoride, "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-
ene;
as used herein "Pd(dppf)2CI2catalyst" refers to ([1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2CI2; as
2 o used herein the terms "Me", "Et", "Pr", "iPr", and "Bu" refer to methyl,
ethyl,
propyl, isopropyl, and butyl respectively, and "RT" refers to room
temperature.
Example 1
25 Preparation ofl(methylethyl)sulfonyl]~2-f4-(4~2-
[(methylsulfonyl)amin~lethyl'[~henyl)phenyllaropLrl'~amine.
CH3
H3C-S-H
~S~ CH3
O O
CH3
The title compound can be prepared following the procedure disclosed in
3 o WO 98/33496 published August 6, 1998, Example 51 ). More specifically, to
a
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room temperature solution of 0.1 g (0.3 mmol) of N-2-(4-(4-(2-
aminoethyl)phenyl)phenyl)propyl 2-propanesulfonamide (prepared following
procedure disclosed in WO 98/33496 published August 6, 1998, Example 50)
and 0.06 mL (0.4 mmol) of triethylamine in 2 mL of dichloromethane was added
0.03 mL (0.4 mmol) of methanesulfonyl chloride. The mixture was stirred at
ambient temperature for 16 hours. Chromatography (10 g silica gel, 50% ethyl
acetate/hexane) of the reaction mixture afforded 0.1 g (94%) of the title
compound.
Analysis calculated for C2~H30N204S2
to Theory %C, 57.51; %H, 6.89; %N, 6.39.
Found: %C, 57.90; %H, 6.72; %N, 6.
Example 1 a
Preparation of ~(2R)-2-[4-(~2-
~methylsulfonyl)aminolet~il)phenyl}phenyllaropyl'~f(methyleth r~l
sulfony,amine.
CH3
p CH3
H3C-
Preparation of 2-Phenyl-1-aropylamine HCI.
CH3
NHZ HCI
2 o To an autoclave hydrogenation apparatus under nitrogen was charged
water-wet 5% palladium on carbon (453 g), ethanol (6.36 L), 2-
phenylpropionitrile
(636 g, 4.85 moles) and finally concentrated (12M} hydrochloric acid (613g,
5.6
mole). The mixture was stirred rapidly and pressurized to 75-78 psi with
hydrogen. The mixture was then heated to 50-64 °C for 3 hours. 1 H NMR
2 5 analysis of an aliquot showed less than 5% starting material. The reaction
mixture, was depressurized and filtered to afford two lots of filtrate that
were
concentrated under reduced pressure to 400 mL each. To each lot was added
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methyl tent-butyl ether (MTBE) (2.2 L each) and the precipitate solids were
allowed to stir overnight. Each lot was filtered and the collected solids were
each
washed with fresh MTBE (100 mL) and dried overnight. The lots were combined-
to afford 2-phenyl-1-propylamine HCI (634.4 g, 76.2%) as a white powder.
1 H NMR analysis of the free base: 1 H NMR (CDCI3, 300 MHz) b 7.32 (m,
2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m, 1 H), 1.25 (d, 3H, J=6.9), 1.02 (br
s,
2H).
Preaaration of (2R)-2-phenyprop~lamine malate.
H CHs
''~~ NHZ HOZC ~C02H
OH
2
To a dry 3-Liter round bottom flask under nitrogen was charged 2-phenyl-
1-propylamine HCI (317.2 g, 1.85 moles), dry ethanol (2.0 L) and NaOH beads
(75.4 g, 1.89 moles) that were washed in with additional ethanol (500 mL). The
mixture was stirred for 1.6 hours, and the resulting milky white NaCI salts
were
filtered. An aliquot of the filtrate was analyzed by gas chromatography to
provide
the amount of free amine, 2-phenyl-1-propylamine, (1.85 moles. A solution of L-
malic acid (62.0 g, 0.462 mole, 0.25 equivalents) in ethanol (320 mL) was
added
dropwise to the yellow filtrate and the solution was heated to 75 °C.
The solution
2 o was stirred at 75 °C for 30 minutes. The heat was removed and the
solution was
allowed to cool slowly. The resulting thick precipitate was allowed to stir
overnight. The precipitate was filtered and dried under vacuum after rinsing
with
ethanol (325 mL) to afford (2R)-2-phenylpropylamine malate (147.6 g, 39.5%) as
a white crystalline solid. Chiral GC analysis of the free base, 2-phenyl-1-
2 s propylamine revealed 83.2% e.e. enriched in the R-isomer (configuration
was
assigned via spectrometric comparison with commercial 2-phenyl-1-propylamine)
~H NMR (CDCI3, 300 MHz) 8 7.32 (m, 2H), 7.21 (m, 3H), 2.86 (m, 2H), 2.75 (m,
1 H), 1.25 (d, 3H, J=6.9), 1.02 (br s, 2H).
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A slurry of (2R)-2-phenylpropylamine malate (147.1 g, 83.2% e.e.) in 1325
mL ethanol and 150 mL deionized water was heated to reflux 079.2 °C)
until the
solids went into solution. The homogeneous solution was allowed to slowly cool
with stirring overnight. The precipitated white solids were cooled (0-5
°C) and
filtered. The collected solids were rinsed with ethanol (150 mL) and dried at
35
°C to afford (2R)-2-phenylpropylamine malate (125.3 g, 85.2% recovery)
as a
white powder. Chiral GC analysis of the free base, (2R)-2-phenylpropylamine,
revealed 96.7% e.e. enriched in the R-isomer.
1H NMR (CD30D, 300 MHz) S 7.32 (m, 10 H), 4.26 (dd, 1H, J=3.6, 9.9), 3.08 (m,
so 6H), 2.72 (dd, 1 H, J=9.3, 15.3), 2.38 (dd, 1 H, J=9.3, 15.6), 1.33 (d, 6H,
J=6.6).
Preparation of 1~2R~2-phenylproipyl)f(methylethyl)sulfony~amine.
H, CHs H O CHs
CCHs
To a stirred slurry of (2R)-2-phenylpropylamine malate (200 g, 0.494 mol)
I5 in CH2CI2 (1000 mL) was added 1.0 N NaOH (1050 mL, 1.05 moles). The
mixture was stirred at room temperature for 1 hour and the organic phase was
separated and gravity filtered into a 3.0 L round-bottom flask with a CH2CI2
rinse
(200 mL). The resulting free base, (2R)-2-phenylpropylamine, was dried via
azeotropic distillation. Accordingly, the clear filtrate was concentrated to
600 mL
2 o at atmospheric pressure via distillation through a simple distillation
head.
Heptane (1000 mL) was added and the solution was concentrated again at
atmospheric pressure to 600 mL using a nitrogen purge to increase the rate of
distillation. The final pot temperature was 109 °C.
The solution was cooled to room temperature under nitrogen with stirring
2 5 to give a clear, colorless heptane solution (600 mL) of (2R)-2-
phenylpropylamine.
To this solution was added 4-dimethylaminopyridine (6.04 g, 0.0494 moi),
triethylamine (200 g, 1.98 moles), and CH2CI2 (500 mL). The mixture was
stirred
at room temperature until a clear solution was obtained. This solution was
cooled to 5°C and a solution of isopropylsulfonyl chloride (148 g, 1.04
moles) in
3 o CH2CI2 (250 mL) was added dropwise with stirring over 2 hrs. The mixture
was
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allowed to warm gradually to room temperature over 16 h. GC analysis indicated
complete consumption of the (2R)-2-phenylpropylamine starting material.
The stirred mixture was cooled to 8 °C and 2 N HCI (500 mL) was
added
dropwise. The organic phase was separated and extracted with water (1 x 500
mL) and saturated NaHC03 (1 x 500 mL). The organic phase was isolated, dried
(Na2S04), and gravity filtered. The filtrate was concentrated under reduced
pressure to provide ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine (230g,
96%) as a pale yellow oil. 'H NMR (CDCI3, 300 MHz) 8 7.34 (m, 2H), 7.23 (m,
3H), 3.89 (br t, 1 H, J=5.4), 3.36 (m, 1 H), 3.22 (m, 1 H), 3.05 (m, 1 H),
2.98 (m,
zo 1 H), 1.30 (d, 3H, J=7.2), 1.29 (d, 3H, J=6.9), 7.25 (d, 3H, J=6.9).
Preparation of f(2RL~4-iodophenyl)propyl].[(methyleth rLl sulfonyllamine.
H, CH3 H O CH3
N o CH3
I
15 A stirred room temperature solution of ((2R)-2-
phenylpropyl)[(methylethyl)sulfonyl]amine (37.1 g, 0.154 mol) in glacial
acetic
acid (185 mL) was treated with concentrated H2S04 (16.0 g, 0.163 mol), added
dropwise in a slow stream, followed by a H20 rinse (37 mL). To this solution
(~30 °C) was added H5106 (8.29 g, 0.0369 mol), followed by iodine (17.9
g,
20 0.0707 mol). The resulting reaction mixture was heated and allowed to stir
for 3
h at 60 °C. After HPLC analysis verified the consumption of starting
material, the
reaction mixture was cooled to 30° C and a 10% aqueous solution of
NaHS03
(220 mL) was added dropwise while maintaining the temperature between 25
° C
and 30 ° C. The mixture crystallized to a solid mass upon cooling to 0-
5 °C.
2s The solids were suction filtered and rinsed with H20 to afford 61.,7 g of
crude solids that were redissolved into warm MTBE (500 mL). This solution was
extracted with H20 (2 x 200 mL) and saturated NaHC03 (1 x 200 mL) and the
organic phase was dried (MgS04), filtered, and concentrated under reduced
pressure to 200 mL. Heptane (100 mL) was added dropwise to the product
3 o solution with slow stirring until crystallization commenced. ~An
additional 100 mL
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of heptane was added and the resulting suspension was allowed to stir slowly
overnight at room temperature. The mixture was then cooled (0 °C),
filtered, and
the collected solids were rinsed with heptane. The solids were then air-dried
to
afford the intermediate title compound, [(2R)-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine (33.7 g, 59.8%) as a white
powder. Chiral Chromatography of this lot indicated 100 % e.e.
~ H NMR (CDCI3, 300 MHz) b 7.66 (d, 2H, J=8.1 ), 6.98 (d, 2H, J=8.4); 3.86 (br
t,
1 H, J=5.1 ), 3.33 (m, 1 H), 3.18 (m, 1 H), 3.06 (m, 1 H), 2.92 (m, 1 H), 1.30
(d, 3H,
J=6.6), 1.27 (d, 6H, J=6.6).
Preparation of (met~lsulfonyl~(2-phenylethyl)amine.
i
0
H3C_S_H
O
To a 10 °C solution of phenethylamine (12.1 g, 0.100 mol) and
triethylamine (11.1 g, 0.110 mol) in CH2CI2 (50 mL) was added methanesulfonyl
chloride (12.6 g, 0.110 mol) dropwise over 10 min. The solution was stirred at
room temperature for 1.5 h and was then washed with 1 N HCI (5 x 20 mL). The
organic phase was directly concentrated to provide the intermediate title
compound, (methylsulfonyl)(2-phenylethyl)amine, (21.2 g, 93.3%) as an oil.
2 0 ~H NMR (CDCI3, 300 MHz) s7.32 (m, 2H), 7.23 (m, 3H), 4.30 (br s, 1 H),
3.40 (t,
2H, J=3.9), 2.88 (t, 2H, J=4.2), 2.81 (s, 3H}.
Preparation of f2-(4-iodophenyl)ethyll(methylsulfonyl)amine.
i
o
H3C-S-N ~~
O H
To a stirring room temperature solution of (methylsulfonyl)(2-
phenylethyl)amine (205 g, 1.03 moles), water (200 mL), 95% sulfuric acid (111
g,
1.08 moles) in acetic acid (1 L), was added iodine (111 g, 0.438 mol) and
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. periodic acid. (H5106, 45.6 g, 0.206 mol). The reaction mixture was warmed
to
70-75 °C for 3 h. The heat was removed and the dark violet reaction
mixture was
allowed to proceed overnight at room temperature. Potassium hydroxide pellets
(85%, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then
enough saturated aqueous sodium sulfite was added to decolorize the mixture to
afford a white suspension. The suspension was cooled to 15 °C and
filtered.
- The filter cake was triturated thoroughly with water and was then dissolved
in
CH2CI2 (1 L) and extracted with additional water (2 x 200 mL). The organic
phase was concentrated under reduced pressure to provide the intermediate
title
so compound, [2-(4-iodophenyl)ethyl](methylsulfonyl)amine, (201 g, 60.2%) as a
white powder.
~H NMR (CDCI3, 300 MHz) 8 7.64 (d, 2H, J=4.8), 6.97 (d, 2H, J=5.1 ), 4.37 (br
t,
1 H, J=4), 3.36 (app. q, 2H, J=3.9), 2.85 (s, 3H), 2.82 (t, 2H, J=3.9).
~5 Preaaration of (tert-butoxvl-N-f2-l4-iodoahenvllethvll-N-
(methylsulfonLrl)carboxamide.
0
H3C-S-N
O ~O
O
A room temperature solution of [2-(4-
iodophenyl)ethyl](methylsulfonyl)amine (201 g, 0.618 mol), 4-
2 o dimethylaminopyridine (3.8 g, 0.031 mol) and di-tert-butyl dicarbonate
(162 g,
0.744 mol) in CH2CI2 (1 L) was allowed to stir overnight. The reaction mixture
was washed with water (2 x 400 mL) and the organic phase was concentrated to
about 600 mL and hexanes (400 mL) was added. This combined solution was
washed again ~ivith water (400 mL) and was concentrated to a solid that was
2s suspended in hexanes (600 mL) and filtered. The collected solids were dried
under reduced pressure to afford the intermediate title compound, (tert-
butoxy)-
N-[2-(4-iodophenyl)ethyl]-N-(methylsulfonyl)carboxamide (241.5 g, 91.5%) as a
white solid.
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~H NMR (CDCI3, 300 MHz) 8 7.63 (d, 2H, J=7.8), 6.98 (d, 2H, J=7.8), 3.88 (t,
2H,
J=6.9), 3.10 (s, 3H), 2.88 (t, 2H, J=6.9), 1.51 (s, 9H).
Preparation of ~tert-butoxy)-N~methylsulfonyl)-N-j2-f4-(4,4,5,5-
tetramethyl(1,3,2-
dioxaborolan-2-yl) pheny~eth,Lrl)carboxamide.
0 ~
B-p' \
0 ' ~\~
H3C-S-N
O ~O
O
To a degassed solution of (tart-butoxy)-N-[2-(4-iodophenyl)ethyl]-N-
(methylsulfonyl)carboxamide (128 g, 0.300 mol), triethylamine (91.1 g, 0.900
mol), and 1,1'-bis(diphenylphosphino) ferrocenedichloropalladium (II)-CH2CI2
2o complex (2.9 g, 0.0035 mol) in acetonitrile (600 mL) was added
pinacolborane
(50 g, 0.391 mol) dropwise: The mixture was stirred at 70-74 °C for 8 h
and then
was cooled to room temperature. The reaction mixture was concentrated to a
fluid oil that was partitioned between MTBE (500 mL) and water (500 mL). The
organic phase was separated and washed with water (2 x 200 mL) and
i5 concentrated to a residue that was partially dissolved with heptane (1 L).
The
heptane soluble fraction was filtered through Celite~ 521 and concentrated to
an
oil (95 g). The residue was dissolved in acetone (600 mL) and heptane (600 mL)
and filtered through Celite° 521. The combined filtrates were
concentrated to 95
g of a mixture of a 3:1 molar ratio (~H NMR, 81.0% by weight) of intermediate
title
2o compound, (tart-butoxy)-N-(methylsulfonyl)-N-{2-[4-(4,4,5,5-
tetramethyl(1,3,2-
dioxaborolan-2-yl))phenyl]ethyl)carboxamide, (60.3% potency corrected yield)
and protio derivative.
~H NMR (CDCI3, 300 MHz) 8 7.75 (d, 2H, J=7.8), 7.23 (d, 2H, J=8.1), 3.87 (t,
2H,
J=8.1 ), 2.99 (s, 3H), 2.90 (t, 2H, J=7.5), 1.53 (s, 9H), 1.33 (s, 6H), 1.27
(s, 6H).
Preparation of methylsulfonyl)f2-j~4,4,5,5-tetramethy~1,3,2-dioxaborolan-2-
yl))phenyethyl~amine.
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O
I
O ' ~\ J
H3C-S-N
O H
To a 2 L flask charged with a stirring solution of (tert-butoxy)-N-
(methylsulfonyl)-N-~2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-
yl))phenyl]ethyl~carboxamide (98.7 g, 0.232 mol) in CH2CI2 (500 mL) was added
trifluoroacetic acid (82 mL, 121.4 g, 1.06 moles) dropwise from an addition
funnel. No exotherm was observed and the reaction solution was allowed to stir
at room temperature for 18 h.
HPLC analysis indicated 98% completion so the cooled (5 °C)
reaction
mixture was neutralized by the slow addition of 5N NaOH (175 mL). The pH of
1 o the aqueous phase was 10.5. The phases were separated and the aqueous
phase was extracted with CH2CI2 (50 mL). The combined CH~CI2 phases were
washed with brine (2 x 100 mL) and water (1 x 100 mL). The CHZCI2 phase was
diluted with heptane (300 mL) and was concentrated under reduced pressure to
afford a suspension that was isolated by filtration. The collected solids were
s5 washed with pentane (2 x 100 mL) and dried under vacuum to provide the
intermediate title compound, (methylsulfonyl)~2-[4-(4,4,5,5-tetramethyl(1,3,2-
dioxaborolan-2-yl))phenyl]ethyl}amine, (69.0g, 91.4%) as a white powder.
~H NMR (CDCI3, 300 MHz) 8 7.77 (d, 2H, J=8.1 ), 7.22 (d, 2H, J=7.8), 4.26 (br
t,
1 H, J=6), 3.40 (q, 2H, J=6.9), 2.89 (t, 2H, J=6.6), 2.82 (s, 3H), 1.34 (s,
12H).
Preparation of 4-~2-[(methylsulfonyl)aminoethvl]benzene boronic acid.
OH
B'OH
O ,~ ~\ J
H3C-S-N
O H
2 5 (Methylsulfonyl){2-[4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-
yl))phenyl]ethyl~amine (68.0 g, 0.209 mol) was placed into a 2L flask and
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combined with acetone (600 mL), 1 N ammonium acetate (600 mL), and Na104
(168.1 g, 0.786 mol). This mixture was stirred at room temperature overnight.
The reaction mixture was filtered to remove insoluble matter to afford
filtrate A.
The collected solids were washed with acetone (2 x 100 mL) and this filtrate
was
s combined with filtrate A. The combined filtrates were concentrated under
reduced pressure to 600 mL to afford a precipitate that was recovered by
filtration. The collected solids were air-dried to give 110g of crude
material. This
crude material was suspended in water (100 mL) and 5N NaOH was added until
the pH was 12.5. The resulting suspension was filtered and the filtrate was
to treated with decolorizing carbon (Darco 6-60). The mixture was filtered and
the
filtrate was diluted with 10N H2S04 until the pH was 5.0 to precipitate the
intermediate title compound. This precipitate was collected by filtration and
dried
under reduced pressure to provide the intermediate title compound, 4-{2-
[(methylsulfonyl)amino]ethyl)benzene boronic acid, (41.9 g, 82.5%) as a white
15 powder.
~H NMR (acetone-ds, 300 MHz) 8 7.82 (d, 2H, J=8.4), 7.27 (d, 2H, J=7.8), 7.11
(s, 2H), 6.03 (m, 1 H), 3.36 (m, 2H), 2.91 (m, 2H), 2.84 (s, 3H).
Pre~~aration of final title compound.
2 o An aqueous solution of potassium formate was prepared in the following
manner. To 15 mL of water was added KOH (85% flakes, 6.73 g, 0.102 mol),
then 98% formic acid (4.70 g, 0.102 mol). Alternatively, one may use
commercially available potassium formate. To this solution was then added
K~C03 (2.76 g, 0.0210 mol), 4-]2-[(methylsulfonyl)amino]ethyl}benzene boronic
25 acid (4.62 g, 0.190 mol), 1-propanol (100 mL), and [(2R)-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine (7.35 g, 0.200 mol). This
mixture
was deoxygenated via three vacuum/N2-refill cycles. Palladium black (0.0215 g,
0.0002 mol) was added and the mixture was again deoxygenated via three
vacuum/N2-refill cycles. The reaction flask was heated in a preheated oil bath
at
30 88 °C and the mixture was stirred overnight.
HPLC analysis showed complete consumption of 4-(2-
[(methylsulfonyl)amino]ethyl)benzene boronic acid, and the mixture was diluted
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with ethyl acetate and filtered through Celite~ to remove palladium. The
mixture
was concentrated under reduced pressure and the resulting residue was
partitioned between ethyl acetate and water. The organic phase was
concentrated and the solid residue was collected and recrystallized from 1:1
acetone / water to afford the final title compound, ~(2R)-2-[4-(4-{2-
[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine,
(6.2 g, 75%) as a white crystalline powder.
'H NMR (CDCI3, 300 MHz) ~ 7.54 (dd, 4H, J=1.8, 8.1 ), 7.29 (dd, 4H, J=1.8, 8.1
),
4.27 (t, 1 H, J=6.6), 3.91 (m, 1 H), 3.43 (q, 2H, J=6.6), 3.37 (dd, 1 H,
J=5.7, 7.5),
3.26 (m, 1 H), 3.07 (m, 2H), 2.93 (t, 2H, J=6.6), 2.87 (s, 3H), 1.34 (d, 3H,
J=7.2),
1.31 (d, 3H, J=6.9), 1.27 (d, 3H, J=6.6).
Additional preJ~aration of ~~2R)-2-f4-(4-f2-
~methylsulfonyl)amino]ethyl~,phenLrl phenyllpropyl~[(meth I~yl)sulfonyllamine.
Z5
Within a single-neck, 3L round bottom flask equipped with a magnetic stir
bar was placed potassium formate (112.8 g, 1.34 moles, 5.1 eq) and water (200
mL) to provide a pH 8 solution. Potassium carbonate (72.7g, 0.526 mol, 2.0
eq),
and 4-~2-[(methylsulfonyl)amino]ethyl}benzene boronic acid (60.8 g, 0.250 mol,
0.95 eq) was added to form a stirring suspension as 1-propanol (720 mL) was
added. [(2R)-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (96.6 g,
0.263
mol,~ 1.0 eq) was added followed by additional 1-propanol (600 mL). The
resulting mixture was stirred for 3 minutes while the reaction flask was
fitted with
a heating mantle and a glycol-cooled reflux condenser. Vacuum (10-20 torr) was
slowly applied to the system over 10 minutes. Stirring had stopped due to the
additional precipitation of the cooled system; nevertheless, after 30 minutes,
the
system was returned to atmospheric pressure with nitrogen. With gentle
heating,
the flask was evacuated and refilled with nitrogen two additional times.
Stirring
was stopped and palladium black (0.28 g, 0.0026 mol, 0.01 eq) was quickly
3 o added to the flask. Stirring was resumed and the system was again
evacuated
and returned to atmospheric pressure with nitrogen over a 2 minute cycle. This
evacuation / nitrogen purge was repeated two more times over a 15 second cycle
and the mixture was heated to reflux.
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After 16 hours, an aliquot was removed and analyzed by HPLC (275nm
detection). Analysis showed 0.07% of achiral dimer, (methylsulfonyl){2-[4-(4-
{2-
[(methylsulfonyl)amino]ethyl)phenyl)phenyl]ethyl}amine, relative to the
desired
product, f(2R)-2-[4-(4-~2-
[(methylsulfonyl)amino]ethyl)phenyl)phenyl]propyl}[(methylethyl)sulfonyl~amine.
The reaction mixture was cooled to 50 °C and ethyl acetate (500 mL) was
added.
The reaction mixture was then cooled to room temperature and the product,
~(2 R)-2-[4-(4-~2-
[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine,
. o began to precipitate. Additional ethyl acetate (1 L) was introduced to
redissolve
the product and the upper organic phase was decanted and filtered through
Celite~ to remove palladium metal. The filter cake was rinsed with 1-propanol.
The homogeneous filtrate was concentrated under reduced pressure to remove
n-propanol and after removal of 1.5 L of distillate, the product suspension
was
~s filtered. The combined filter cakes were dried to afford 109.8g of crude
final title
compound.
Recrystallization: The crude final fiitle compound (109.8 g~was dissolved
in acetone (490 mL). This solution was filtered though a glass filter to
retain a
minor amount of dark insoluble material. To the slowly stirred Citrate was
added
2 0 water (300 mL) over 15 min. The resulting suspension was stirred for 15
minutes
and additional water (20 mL) was introduced over 10 minutes. The suspension
was subsequently stirred for 30 minutes at room temperature and was filtered.
The cake was washed with 1:1 acetone / water (600 mL) and was dried at 35
°C
overnight. This process afforded 80.3 g (81.1 %) of {(2R)-2-[4-(4-{2-
25
[(methylsulfonyl)amino]ethyl}phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine
as
a white crystalline powder with a mean particle size of about 29 to about 34
microns. HPLC analysis indicated 0.01 % achiral dimer, (methylsulfonyl)~2-[4-
(4-
~2-[(methylsulfonyl)amino]ethyl}phenyl)phenyl]ethyl)amine, and 0.02% chiral
dimer, ((2R)-2-~4-[4-((1 R)-1-methyl-2-
0
~[(methylethyl)sulfonyl]amino)ethyl)phenyl]phenyl}propyl)[(methylethyl)sulfonyl
]a
mine.
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Example 2
Alternative preparation of {(2R)-2-f4-(4-~2-
f(methylsulfonyl amino]ethyl'phenyl)pheny119~ro~pyl)f(methylethLrl
sulfonyllamine.
Preparation of 4-f2-f(tert-butoxv)-N-
(methvlsulfonvl)carbonvlaminolethvl3benzene
boronic acid.
OH
B'OH
O ,~ ~
H3C-S-N ~~
O ~O
O
To a room temperature solution of (tert-butoxy)-N-(methylsulfonyl)-N-f2-[4-
(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenyl]ethyl}carboxamide (81.0%
1 o potent, 95 g, 0.18 mol, prepared in example 1 ) in acetone (2 L) was added
1 N
ammonium acetate (1 L) and sodium periodate (145 g, 0.678 mol) with stirring.
The reaction was allowed to proceed overnight. The reaction mixture was
concentrated to remove the acetone, and the aqueous phase was decanted
away from the oily product. The aqueous phase was extracted with CH2CI2 (100
15 mL) and MTBE (2 x 100 mL). The combined oily product and organic phases
were adjusted to pH 12.5 with the addition of 1 N NaOH. The phases were
separated, and the organic phase was extracted with 1 N NaOH (100 mL) and
water (2 x 100 mL). HPLC analysis (60% CH3CN / 40% H20, 2 mL / min, Zorbax
C-18, 205 nm) of the organic phase indicated that the product had been removed
2 o from this phase. The aqueous phases (containing product) were finally
combined and washed with CH2CI2 (100 mL) and MTBE (2 x 100 mL). The
aqueous phase was added to CH2CI2 (450 mL) and 1 N H2S04 was added until
the aqueous phase was at pH 3.05. The phases were separated and the
aqueous phase was extracted with CH2CI2 (100 mL). The combined organic
25 extracts (containing product) were concentrated to an oil (58.5 g) that
crystallized
overnight. The resulting solid mass was triturated with 10% MTBE in heptane
(100 mL) to afford, after filtration and drying under reduced pressure, the
intermediate title compound, 4-{2-[(tert-butoxy)-N-
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(methylsulfonyl)carbonylamino]ethyl)benzene boronic acid , (47.7 g, 77.2%) as
a
white powder.
~H NMR (ds-DMSO, 300 MHz) 8 7.83 (d, 2H, J= 4.8), 7.24 (d, 2H, J=5.1 ), 7.12
(s,
2H), 3.90 (t, 2H, J=3.9), 3.12 (s, 3H), 2.95 (t, 2H, J=4.5), 1.52 (s, 9H).
Preparation of final title compound.
Run 1. Within a 3-neck, 1000 mL round-bottom flask was placed [(2R)-2-
(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (15.0 g, 0.0408 mol,
prepared
in example 1 ), 4-~2-[(tert-butoxy)-N-
(methylsulfonyl)carbonylamino]ethyl}benzene
so boronic acid (19.1 g, 0.0557 mol), KZC03 (6.8 g, 0.0490 mol) and 1-propanol
(300 mL). To this mixture was then added water (42 mL) and finally Pd(OAc)2
(18 mg, 8.17 x 10-5 mol, 0.2 mol %). The resulting clear, pale amber solution
was heated to reflux (87 °C) to become a dark amber, then a clear olive
solution
with stirring black particulates (Pd°). The reaction was allowed to
stir for 20 h
and was allowed to cool to room temperature. TLC analysis (1:9 EtOAc /
CH2Ch) of the resulting off white suspension indicated desired product (Rf
032),
complete consumption of [(2R)-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine (Rf 0.60) and only a trace of 4-
{2-
[(tert-butoxy)-N-(methylsulfonyl)carbonylamino]ethyl}benzene boronic acid (Rf
2 0 0.49). The suspension was diluted with EtOAc (300 mL) to give a clear,
pale
yellow solution that was filtered through Celite~ (presaturated with EtOAc).
After washing the Celite° through with EtOAc, the filtrate was
combined
with that of an identical Run 2 which was conducted identically as described
above. The combined filtrates from both runs were concentrated under reduced
pressure to afford white solids that were diluted with EtOAc (1 L) and 10%
K2CO3
(300 mL) to form a clear, amber biphasic solution that was agitated. The
aqueous phase (light pink) was separated and the organic phase was washed
with additional 10% KZC03 (4 x 300 mL). The aqueous phase was back
extracted with EtOAc (300 mL) and the combined organic phases (1500 mL)
3 o were dried (MgS04), filtered, and concentrated to a volume of about 620 mL
within a 3 L round-bottom flask. The clear, pale yellow solution was stirred
slowly
while heating to 60 °C. Heptane (400 mL) was added dropwise from a
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separatory funnel to the stirring EtOAc solution at 60 °C (17 volumes
of EtOAc /
11 volumes of heptane). The heptanes were added over a period of 1.5 h and
the clear, pale yellow solution was allowed to cool slowly with slow stirring
overnight. The resulting white crystalline solids were cooled to 0 °C,
filtered, and
washed with a minimum of 1:1 EtOAc / heptanes to afford the final title
compound, {(2R)-2-[4-(4-(2-
[(methylsulfonyl)amino]ethyl]phenyl)phenyl]propyl}[(methylethyl)sulfonyl]amine,
(27.1 g, 75.7%) as a white crystalline powder.
2o Alternative preparation of~~2R~2-phen
rLpropyl}[(methylethyl)sulfonyllamine.
H'~ CHs H_,O, CHs
,, N O~ Hs
Preparation of (2R)-2-phenylpropan-1-ol.
An oven dried 500.0 mL three necked round bottom flask equipped with a
15 mechanical stirrer, thermometer, addition funnel with a continuous nitrogen
blanket is charged with 2.0 M solution of trimethylaluminum (65.6 mL, 131.2
mmol} and toluene (75.0 mL). Reaction solution was then chilled to -
60°C with
dry ice/acetone bath. To this solution was then added R-styrene oxide
dissolved
in 100.0 mL of toluene over a period of 50.0 minutes (reaction is quite
exothermic
2 o and can be controlled by the rate of addition of substrate). After
stirring at this
temperature for 60.0 minutes, reaction was brought to room temperature and
stirred for 4.0 hours. Reverse quenched reaction at room temperature into a
slurry of THF (100.0 mL) and sodium sulfate decahydrate (46.0 g}very
cautiously
over a period of 90.0 minutes (quenching was quite exothermic with evolution
of
25 gas). Filtered the precipitate formed over hyflo, then concentrated
filtrate to
provide the intermediate title compound, (2R)-2-phenylpropan-1-ol, (11.03 g,
92.6%) as an oil; 1 H nmr (CDCI3) 8 1.28-1.29 (d, 3H, J = 6.9Hz), 1.5 (b, 1
H), 2.9-
3.0 (m, 1 H), 3.69-3.70 (d, 2H, J = 6.64Hz), 7.24-7.35 (aromatic}; 13C nmr
(CDCI3) 8 18.31, 43.15, 69.40, 127.38, 128.20, 129.26144.39.
Preparation of 2~(2R)-2-phenulproay1)isoindoline-1,3-dione
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An oven dried 250.0 mL three necked round bottom flask equipped with a
mechanical stirrer, thermometer, addition funnel with a continuous nitrogen
blanket is charged with (2R)-2-phenylpropan-1-of (2.0 mL, 14.32 mmol),
phthalimide (2.1 g, 14.32 mmol), triphenylphosphine (5.63 g, 21.48 mmol) and
THF (70.0 mL). To this solution at room temperature was then added a solution
of diethylazodicarboxylate (3.38 mL, 21.48 mmol) dissolved in THF (10.0 mL)
over a period of 15-20 minutes (reaction exothermed slightly to 50°C by
the end
of addition went from clear to reddish color). Stirred reaction to room
temperature
overnight). To the red solution was added water (50.0 mL) and the organic
Zo extracted with chloroform (140.0 mL). Dried the organic solution with
anhydrous
magnesium sulfate, filtered and concentrated under reduced pressure to an oil.
To the oil was added heptane (150.0 mL) with stirring. Filtered of
precipitates,
then concentrated filtrate to an oil. Plug filtration of the oil over silica
gel with 1:1
ethylacetate/hexane and concentrating product fractions afforded the
15 intermediate title compound, 2-((2R)-2-phenylpropy!)isoindoline-1,3-dione,
(4.27
g, 96%) as an oil which solidified on equilibrating to room temperature; 1 H
rimr
(CDCI3) b 1.3 (d, 3H), 3.3-4.0(m, 1 H), 3.7-3.9 (m, 2H), 7.1-7.3 (prompt. m,
2H),
7.63-7.7 (prompt. m, 2H), 7.8-7.85 (prompt, rn, 4H).
2o Preparation of~2R)-2-phenylpropylamine.
A 500 mL three necked round bottom flask equipped with a mechanical
stirrer, thermometer and addition funnel is charged with 2-((2R)-2-
phenylpropyl)isoindoline-1,3-dione (11.54 g, 43.49 mmol), toluene (200.0 mL)
and anhydrous hydrazine (2.73 mL, 86.99 mmol). Reaction is then stirred at
2s room temperature for 3.0 hours and then heated at 90°C-95°C
for 2.0 hours.
Cooled the slurry to room temperature, filtered precipitates, then
concentrated
filtrate to provide the intermediate title compound, (2R)-2-phenylpropylamine,
(5.58 g, 94.9%) an oil; 1 H nmr (CDCI3) 8 1.21 (d,3H), 1.40-1.60 (b, 2H), 2.68-
2.80 (m, 1H), 2.81-2.87 (m, 2H) 7.20 (m, 2H), 7.32 (m, 2H).
Preparation of final title compound.
To a solution of the (2R)-2-phenylpropylamine (1.2g, 8.87mmol) in hexane
(16.OmL) was added triethylamine (2.47 mL, 17.74 mmol) and
dimethylaminopyridine (0.30 g, 2.47 mmol). Cooled reaction to 5°C, then
added a
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solution of isopropylsulfonyl chloride (0.97 mL, 8.69 mmol) dissolved in
methylene chloride (6.0 mL) over a period of 15.0 minutes. Stirred for 45.0
minutes, then stirred at room temperature for 120.0 minutes. Quenched reaction
with 1 N HCI (20.0 mL) and extracted organic with methylene chloride (25.0
mL).
a
Dried organic layer with anhydrous magnesium sulfate, filtered and
concentrated
filtrate to provide the final title compound, ((2R)-2-
phenylpropyl)[(methylethyl)sulfonyl]amine, (1.93 g, 90.1 %) an oil; 1 H nmr
(CDCI3) 8 1.25 (d,3H, J=6.9Hz}-,, 1.29(d, 3H, J=6.9Hz), 1.30 (d, 3H, J=
7.2Hz),
2.98 (m, 1 H), 3.05 (m, 1 H), 3.22 (m, 1 H), 3.36 (m, 1 H), 3.89 (b, 1 H),
7.23 (m,
2H), 7.34 (m, 2H).
Example 2 .
Preparation of N-2-(4=(3-thienylZphenylproayl 2-propanesulfonamide (392098).
CH3
\-N~SO CH
,~ ~ 3
O
CH3
The title compound is prepared in a manner analogous to the procedure
set forth in WO 98/33496 published August 6, 1998, Example 28.
2 o Example 3
Preparation of [2-fluoro-2- 4-~3-
j(methylsulfonyl)aminolpheny~phenyl)propyllf methyleth r1 sulfonyl]amine.
H ~ CH3
N-S--
O CHs
NH
i
O=S=O
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Preparation of 1-amino-2-(4-iodophenyl)propan-2-ol.
H3C OH
NH2
I
The trimethylsilyl-protected cyanohydrin derivative of 4-iodoacetophenone
was prepared in situ following generally the method disclosed by Greenlee and
Hangauer, Tetrahedron Lett., 24(42), 4559 (1983). Accordingly,
cyanotrimethylsilane (21.4 g, 0.216 mol) was added dropwise over 5 minutes to
a
Zo dry, room temperature solution containing 4-iodoacetophenone (44.3 g, 0.180
mol), 18-crown-6 (1.6 g, 6.1 mmoles) and KCN (1.17g, 0.018 mol) in THF (100
mL). The resulting solution was allowed to stir for 2.5 h. TLC analysis (3:7
EtOAc / Hexanes) showed consumption of starting acetophenone.
A 10M solution of borane in dimethylsulfide (25 mL, 0.25 mol) was added
z5 rapidly to the reaction solution and the resulting mixture was heated at
reflux for
16 h. The mixture was cooled to room temperature and anhydrous 10% (by wt)
HCI in methanol was added slowly over 1 h (GAS EVOLUTION). The solution
was allowed to stir for an additional hour, and was concentrated under reduced
pressure to give the crude title compound as white solid and as the
hydrochloride
2 o salt. This salt was triturated with methyl t butyl ether and filtered. The
free base
was prepared by adding 1 N NaOH to a suspension of the HCI salt in CH2CI2
(150 mL) and THF (350 mL) until pH 12.3 was reached. The phases were
separated and the organic phase was washed with brine (25 mL). The organic
phase containing the free amine was concentrated under reduced pressure and
2s the resulting solids were triturated with diethyl ether (30 mL) to afford 1-
amino-2-
(4-iodophenyl)propan-2-of (35.6 g, 71.3%) as an off-white powder after vacuum
drying. ~H NMR (CD30D, 300 MHz): 8 7.68 (d, 2H, J = 8.4), 7.24 (d, 2H, J =
8.7),
2.78 (m, 2H), 1.46 (s, 3H).
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Preparation of f2-hydroxy-2-(4-iodophenyl~~ropyllf met~lethyl)sulfonyllamine.
H3C OH O CH
H n 3
N-S--C
O CHa
I
Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, was
added dropwise 2-propanesulfonyl chloride (1.60 g, 0.011 mol) to 1-amino-2-(4-
iodophenyl)propan-2-of (2.77 gm, 0.01 mol) in 125 mL CH2GI2 while stirring at
20 0°C under nitrogen. The reaction was then allowed to warm to room
temperature
and stirred overnight at this temperature. In the morning, the mixture was
poured
into H20 and the layers were separated. The organic layer was washed once
with HBO, dried over anhydrous Na2S04, filtered, and concentrated under
reduced vacuum . The resulting semi-solid was purified via silica gel
s5 chromatography employing the Prep. LC-2000 and eluting with a solvent of
HexanelEtOAc 3:1 to provide [2-hydroxy-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine (744 mg, 19%) as a solid
material.
FDMS 382 (M*).
Analysis for C~2H~gNO3 S I:
2 o Theory: C, 37.61 H, 4.73 N, 3.65
Found: C, 38.08 H, 4.26 N, 3.55
Alternative ipr~~aration of I[2-hydroxy-~4-
iodophenyl)propyl]j(methylethyl sulfonyllamine.
25 In a 250 mL-3 neck flask fitted with a stirrer and thermometer, 2.10 g. of
propanesulfonyl chloride was added dropwise to 2.77 g. of 1-amino-2-(4-
iodophenyl)propan-2-of and 2.30 g. of DBU in CH2CI2 (150 mL) while stirring at
0°C under a nitrogen atmosphere. The reaction was allowed to warm to
room
temperature and stirred overnight at this temperature. In the morning, the
3 o reaction was diluted with CH2Ch (100 mL) and the organic layer was washed
two
times with H20, dried over anhydrous Na2S04, filtered, and concentrated under
reduced vacuum to yield a viscous oil. This material was purified via silica
gel
chromatography employing the Chromatotron, using a 4000 micron rotor and
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eluting with a solvent of methylene chloride/methanol 19:1 to yield [2-hydroxy-
2-
(4-iodophenyl)propyl]j(methylethyl)sulfonyl]amine (1.0 g, 31 %) as a viscous
oil.
Ion spray M.S. 382 (M* - 1 ).
Preparation of f2-fluoro-2-(4-iodophenyl propyllj.(meth 1y ethyl
sulfonyllamine.
H3C F H ~ CH3
N
/ O CHs
I
Into a 10 mL single neck flask, a solution of [2-hydroxy-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine (158 mg, 0.41 mmol) in 1.7 mL
CH2CI2
was added syringe wise slowly to a solution of DAST (66 mg, 0.41 mmol) in 0.3
mL
s o CH2CI2 while stirring at -78°C under nitrogen. The reaction was
then allowed to warm
to room temperature and the mixture was diluted with H20 and CH2CI2. The
layers
were separated and the organic layer was washed twice with H20, dried over
anhydrous Na2S04, filtered, and concentrated under reduced vacuum to [2-fluoro-
2-
(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (113 mg) as a solid. Ion
spray M.S.
z5 384 (M*-1 ).
Additional preparation of f2-fluoro-2-1;4-
iodophenyl)prop~(methylethyl sulfon~lamine.
Into a 100 mL 3-neck flask fitted with a stirrer and thermometer, 1.0 g, of
2 0 [2-hydroxy-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine in CH2CI2
(15 mL)
was added dropwise to 0.3 mL DAST in CH2CL2 (10 mL) while stirring at -
78°C
under a nitrogen atmosphere. Reaction was allowed to warm to room
temperature and diluted with CH2CI2 (50 mL). This organic layer was washed
with H20, dried over anhydrous Na2S04, filtered, and concentrated under
25 reduced vacuum to yield an oil. This material was purified via silica gel
chromatography employing the Chromatotron and using a 4000 micron rotor
while eluting with a gradient solvent of hexane/ethyl acetate 9:1 to
hexane/ethyl
acetate 3:1 to yield [2-fluoro-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine
(0.906 g) as a white solid. Ion spray M.S. 384 (M* - 1 ).
o Analysis for C~2H'7N02SF1:
Theory: C, 37.42 H, 4.44 N, 3.64
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Found: C, 37.27 H, 4.33 N, 3.61
Preparation o~2-f4-(3-aminophenyl)phenyll-2-
fluoropropyl}[(methylethyl)sulfonyllamine.
NH2
H ~ CH3
N-S--
O CHs
Into a 50 mL single neck flask [2-fluoro-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine (200 mg, 0.53 mmol), 3-
aminobenzene boronic acid (188 mg, 0.76 mmol), potassium carbonate (104 mg,
l0 0.76 mmol) and tetrakis(triphenyl phosphine)palladium(0) (41 mg, 0.036
mmol)
were combined in dioxane/water (20 mL, 3:1 ). The mixture was heated at 100
°C
under stirring for 18 hours. The reaction was cooled to room temperature and
poured into H20. The desired product was extracted with ethyl acetate and the
organic layer was separated and washed twice with H20, dried over K2C03 , and
concentrated under reduced vacuum to yield the crude material (276 mg) as a
dark oil. The resulting oil was purified via silica gel chromatography
employing
the Chromatotron using a 4000 micron rotor and eluting with a solvent of
Hexane/Ethyl Acetate 1:1 to yield the title compound (164 mg, 90%) as a
viscous
oil. Ion spray M.S. 351.4 (M*+1 ).
2 o Analysis calculated for: C~8 H23 N2 02 S F:
Theory: C, 61.69 H, 6.62 N, 7.99
Found: C, 61.53 H, 6.55 N, 8.13
Preparation of final title compound.
A 50 mL flask fitted with a stirrer and thermometer was charged with DBU
(67 mg, 1.1 eq), {2-[4-(3-aminophenyl)phenyl]-2-
fluoropropyl}[(methylethyl)sulfonyl]amine (140 mg, 0.44 mmol) and methylene
chloride (10 mL) under an atmosphere of nitrogen, and cooled to 0°C. To
this
stirring solution was added dropwise chloro-methane sulfonyl chloride (69 mg,
3 0 1.5 eq). The reaction was allowed to warm to room temperature and stirred
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overnight at this temperature. In the morning, the mixture was poured into H2O
and the layers were separated. The organic layer was washed once with H20,
dried over anhydrous Na2S04, filtered, and concentrated under reduced vacuum
to yield the crude material (192 mg) as a yellow oil. This crude material was
purified via silica gel chromatography employing the Chromatotron using a 4000
micron rotor and eluting with a solvent of Methylene Chloride/ethyl acetate
9:1
to yield the final title compound, [2-fluoro-2-(4-{3-
[(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine, (50
mg, 29%) as a white foam. Ion spray mass spectra 427.1 (M*-1 ).
Analysis fOr Cog H25 N2 04 S2 F:
Theory: C, 53.25 H, 5.88 N, 6.54
Found: C, 53.56 H, 6.11 N, 6.29
Example 3a
Preparation of f2-Fluoro-2-(4-f3-
j(methylsulfonyl)aminolahenyl)phenyl propyll[~methyleth r~l sulfonYl]~amine
nantiomer 1~
Preparation of (,+)-[2-fluoro-2-(4-iodophenyl
propyll[(methylethyl)sulfonyl]amine
and -)-f2-fluoro-2-(4-iodophenyl)proptrl]'~methLrlethrl sulfonyllamine.
[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (2.0 g,
prepared in example 3) was dissolved into 3A ethanol (30 mL) and was further
diluted with heptane (20 mL). [As used herein the term "3A ethanol" refers to
ethanol containing 5% methanol.] The mixture was agitated via ultrasound to
form a clear, colorless solution. This lot was loaded upon a 8 x 28 cm
preparative Chiralpak AD chromatographic column that was pre-equilibrated with
60% 3A ethanol/40% heptane. Eluent flow was 300 mL/min and detection
wavelength was 240 nm. The first eluting substance was (+)-[2-fluoro-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine, [a]p = +18.5 (c=1.08, MeOH),
3 o and the subsequent eluting substance was (-)-[2-fluoro-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine, [a]~ _ -23.5 (c=1.02, MeOH).
The above procedure was repeated twice in an analogous manner with [2-fluoro-
2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (second run, 3.0 g
dissolved
in 50 mL 3A ethanol/heptane, 3:2 and a third run, 2.0 g dissolved in 0.8 g
dissolved in 40 mL 3A ethanol/heptane, 3:2). Thus, in three runs, a total of
5.8 g
of [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine was resolved
into
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its component enantiomers in the following yields after concentration (in
vacuo)
of fractions:
(+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (2.38 g,
41.0%);
(-)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (1.2 g,
20.7%).
Analysis conditions: 0.46 x 35 cm Chiralpak AD 60% ethanol (5% methanol)/40%
Heptane; Flow: 1.0 mL/min, detection wavelength: 240 nm.
For (+)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine: Rt= 5.4
1 o min, MS (ES+) 384 (M-1 ).
~H NMR (CDCI3, 300 MHz): 8 7.73 (d, 2H, J=8.1 ), 7.09 (d, 2H, J=8.4), 4.27 (t,
1 H,
J=6.2), 3.50 (m, 2H), 3.03 (m, 1 H)~, 1.69 (d, 3H, J=22), 1.30 (d, 3H, J=7),
1.27 (d,
3H, J=7).
Analysis for C~2H~7FIN02S:
Theory: C 37.41, H 4.45, N 3.64.
Found: C 37.54, H 4.43, N 3.64.
For (-)-[2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine: Rt =
10.1
min. MS (ES+) 384 (M-1 ).
~H NMR spectrum identical to that of (+)-[2-fluoro-2-(4-
iodophenyl)propyl][(methylethyl)sulfonyl]amine.
Analysis for C~2H~~FIN02S:
Theory: C 37.41, H 4.45, N 3.64.
Found: C 37.56, H 4.43, N 3.59.
(+)-[2-Fluoro-2-(4-iodophenyi)propyl][(methylethyl)sulfonyl]amine (300 mg,
0.78 mmol), the borate of formula:
O
B
O
O'~SNH
/ 'O
3 0 (347 mg, 1.5 eq.), potassium carbonate (156 mg, 1.5 eq),
tetrakis(triphenyl
phosphine)palladium(0) (75 mg, 0.06 mmol) and dioxane/water (36 mL, 3:1 ) were
mixed together in a 100 mL single neck flask and stirred at 80°C for 4
hours.
The reaction was cooled to room temperature and poured into H20 and the
desired product was extracted with ethyl acetate. The organic layer was
backwashed once with H20, dried over. K2C03, filtered, and concentrated under
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reduced pressure to yield 191 mg as a viscous oil. This material was purified
via
silica gel chromatography employing the chromatotron and using a 2000 micron
rotor while eluting with a solvent of hexane/ethyl acetate 1:1 to yield the
title
compound (86 mg, 26%) as a white solid. Ion spray M.S. 427.1 (M*-1 ).
Calculated for: C~gH25N2OøS2 F- H2O
Theory: C 51.08, H 6.09, N 6.27.
Found : C 51.29, H 5.63, N 6.29.
Example 3b
2 o Preparation of f2-Fluoro-2-(4-f3-
f(methvlsulfonvl)aminolahenvl)ahenvllaroavllf(methvlethvl)sulfonvllamine
(enantiomer 2~
(-)-[2-Fluoro-2-(4-iodophenyf)propyl][(methylethyl)sulfonyl]amine (493 mg,
1.28 mmol, prepared in example 3a), the borate of formula:
~ ~ SO
O
O'\SNH
~ ~O
(385 mg, 1.30 mmol), 2.O M Na2C03/H20 (2.2 mL, excess), tetrakis(triphenyl
phosphine)palladium(0) (100 mg, 0.09 mmol) and dioxane (15 mL) were mixed
together in a 50 mL single neck flask and stirred at 80°C overnight. In
the
2 o morning the reaction was cooled to room temperature and poured into H20
and
the desired product was extracted with ethyl acetate. The organic layer was
backwashed once with H20, dried over K2CO3, filtered, and concentrated under
reduced pressure to yield 571 mg as a foam. This material was purified via
silica
gel chromatography employing the chromatotron and using a 4000 micron rotor
while eluting with a solvent of hexane/ethyl acetate 1:1 to yield the title
compound (294 mg, 56%) as a brown solid. Ion spray M.S. 427.3 (M*-1 ).
Calculated for: C'9H25N2O4S2 F- H20:
Theory: C 51.08, H 6.09, N 6.27.
Found : C 51.29, H 5.63, N 6.29.
The ability of compounds to potentiate glutamate receptor-mediated
response may be determined using fluorescent calcium indicator dyes (Molecular
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Probes, Eugene, Oregon, Fluo-3) and by measuring glutamate-evoked efflux of
calcium into GIuR4 transfected HEK293 cells, as described in more detail
below.
In one test, 96 well plates containing confluent monolayers of HEK 293
cells stably expressing human GIuR4B (obtained as described in European
Patent Application Publication Number EP-A1-583917) are prepared. The tissue
culture medium in the wells is then discarded, and the wells are each washed
once with 200 p1 of buffer (glucose, 10mM, sodium chloride, 138mM, magnesium
chloride, 1 mM, potassium chloride, 5mM, calcium chloride, 5mM, N-[2-
hydroxyethyl]-piperazine-N-j2-ethanesulfonic acid], 10mM, to pH 7.1 to 7.3).
The
Zo plates are then incubated for 60 minutes in the dark with 20 pM FIuo3-AM
dye
(obtained from Molecular Probes Inc., Eugene, Oregon) in buffer in each well.
After the incubation, each well is washed once with 100 p1 buffer, 200 p1 of
buffer
is added and the plates are incubated for 30 minutes.
Solutions for use in the test are also prepared as follows. 30 pM, 10 pM, 3
z5 pM and 1 NM dilutions of test compound are prepared using buffer from a 10~
mM
solution of test compound in DMSO. 100 NM cyclothiazide solution is prepared
by adding 3 p1 of 100 mM cyclothiazide to 3 ml of buffer. Control buffer
solution
is prepared by adding 1.5 p1 DMSO to 498.5 p1 of buffer.
Each test is then performed as follows: 200 p1 of control buffer in each
2 o well is discarded and replaced with 45 p1 of control buffer solution. A
baseline
fluorescent measurement is taken using a FLUOROSKAN II fluorimeter
(Obtained from Labsystems, Needham Heights, MA, USA, a Division of Life
Sciences International Plc). The buffer is then removed and replaced with 45
p1
of buffer and 45 p1 of test compound in buffer in appropriate wells. A second
25 fluorescent reading is taken after 5 minutes incubation. 15 p1 of 400 pM
glutamate solution is then added to each well (final glutamate concentration
100
pM), and a third reading is taken. The activities of test compounds and
cyclothiazide solutions are determined by subtracting the second from the
third
reading (fluorescence due to addition of glutamate in the presence or absence
of
3 o test compound or cyclothiazide) and are expressed relative to enhance
fluorescence produced by 100 pM cyclothiazide.
In another test, HEK293 cells stably expressing human GIuR4 (obtained
as described in European Patent Application Publication No. EP-A1-0583917)
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are used in the electrophysiological characterization of AMPA receptor
potentiators. The extracellular recording solution contains (in mM): 140 NaCI,
5
KCI, 10 HEPES, 1 MgCl2, 2 CaCl2, 10 glucose, pH = 7.4 with NaOH, 295 mOsm
kg-1. The intracellular recording solution contains (in rnM): 140 CsCI, 1
MgCl2,
HEPES, (N-[2-hydroxyethyl}piperazine-N1-[2-ethanesulfonic acid}) 10 EGTA
(ethylene-bis(oxyethylene-nitrilo)tetraacetic acid), pH = 7.2 with CsOH, 295
mOsm kg-1. With these solutions, recording pipettes have a resistance of 2-3
MSZ. Using the whole-cell voltage clamp technique (Hamill et al.(1981)Pflugers
Arch., 391: 85-100), cells are voltage-clamped at -60mV and control current
1 o responses to 1 mM glutamate are evoked. Responses to 1 mM glutamate are
then determined in the presence of test compound. Compounds are deemed
active in this test if, at a test concentration of 10 pM or less, they produce
a
greater than 10% increase in the value of the current evoked by 1 mM glutamate
and this effect can be blocked by a specific AMPA receptor antagonist such as
NBQX.
In order to determine the potency of test compounds, the concentration of
the test compound, both in the bathing solution and co-applied with glutamate,
is
increased in half log units until the maximum effect was seen. Data collected
in
this manner are fit to the Hill equation, yielding an EC50 value, indicative
of the
2 o potency of the test compound. Reversibility of test compound activity is
determined by assessing control glutamate 1 mM responses. Once the control
responses to the glutamate challenge are re-established, the potentiation of
these responses by 100 pM cyclothiazide is determined by its inclusion in both
the bathing solution and the glutamate-containing solution. In this manner,
the
efficacy of the test compound relative to that of cyclothiazide can be
determined.
The diagnosis of depression is made primarily by quantification of
alterations in patients' mood. These evaluations of mood are generally
performed by a physician or quantified by a neuropsychologist using validated
rating scales, such as the Hamilton Depression Rating Scale or the Brief
3 o Psychiatric Rating Scale which are well known to one of ordinary skill in
the art.
Numerous other scales have been developed to quantify and measure the
degree of mood alterations in patients with depression, such as insomnia,
difficulty with concentration, lack of energy, feelings of worthlessness, and
guilt.
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The standards for diagnosis of depression as well as all psychiatric diagnoses
are collected in the Diagnostic and Statistical Manual of Mental Disorders
(Fourth
Edition) referred to as the DSM IV manual published by the American
Psychiatric
Association, 1994.
Certain behavioral despair animal models are predictive of antidepressant
activity in man, such as the Forced Swim Test and the Tail Suspension Test.
For
example, see "Experimental Approaches to Anxiety and Depression", Edited by
J.M. Elliott, et al., (1992), John Wiley & Sons Ltd., Chapter 5, Behavioural
Models of Depression, Porsolt and Lenegre, pages 73-85. The Forced Swim
Zo Test and the Tail Suspension Test are described in detail below.
Forced Swim Test (FST): A male mouse (for example, of the NIH-Swiss
strain supplied by Harlan Sprague-Dawley) typically weighing 25-30 g is placed
in
a clear plastic cylinder (diameter: 10 cm; height: 25 cm) filled with 6 cm of
water
(22-25°C) for six min. The duration of immobility during the last four
minutes of
the six minute test period is scored. A mouse is recorded as immobile when
floating motionless or making only those movements necessary to keep its head
above water. Administration of clinically effective antidepressants before
this test
(e.g. imipramine, 15 mg/kg, administered intraperitoneally 15 min prior to
testing)
typically produce a diminution in the time immobile (e.g. Trullas and
Skolnick,.
2 o European Journal of Pharmacology, 185, 1-10 (1990)).
To determine if augmentation of action is produced with a combination of
a suitable AMPA receptor potentiator and a suitable antidepressant, as defined
herein, mice can be injected intraperitoneally (in, e.g., 0.1 ml) with a
suitable
AMPA receptor potentiator and a suitable antidepressant (in e.g., 0.1 ml) at
2s doses that do not individually produce a significant reduction in
immobility. A
combination of these compounds, if an augmentation (synergism) exists, would
result in an effect greater than each agent alone. In variations of this
procedure,
increasing doses of either compound would be injected in the presence of a
fixed
(subeffective or marginally effective) dose of the second compound. An
3 o augmentation of action would be reflected by a reduction in immobility
that is
greater than the arithimetic sum of the effect of each agent alone. A
hypothetical
example follows: the vehicle injected animals have a mean immobility time of
130
seconds and animals injected with a standard dose of a clinically effective
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antidepressant have an immobility of 90 seconds. Injection of a suitable AMPA
receptor potentiator at a dose that by itself does not significantly alter
immobility
time (e.g. 128 seconds) reduces immobility time to 65 seconds when combined
with the standard dose of a clinically effective antidepressant. That is, the
predicted arithmetic change would be (130-90) + (130-128) = 42 seconds, but
the
combination of the agents yield a reduction of 130-65= 65 seconds. Standard
statistical tests can be used to determine if this difference is significant.
The
same general strategy can be applied to the forced swim test as carried out in
rats (below) as well as the tail suspension test, also described below.
.o In a variant of the forced swim test procedure using rats, a rat (for
example, a male Sprague Dawley rat from Harlan Sprague-Dawley) weighing
200-300 g is placed in a clear plastic cylinder (diameter: 18 cm; height: 40
cm)
filled with water (22-25°C) to a depth of 16 cm for fifteen min. After
testing, the
rat is dried with paper towels and placed in holding cages. Five minutes
later,
s5 animals receive intraperitoneal injections (0.1 ml) of drugs or vehicle,
and are
then returned to their home cages. On the following day, rats receive a second
dose of compounds) or vehicle 1 h prior to the test: The rats are placed in
cylinders as described above for 5 min and .the duration of immobility
recorded.
Figure 1 discloses that low doses of 392098 by itself (0.025-0.1 mg/kg)
20 produced no effect in the Forced Swim Test in mice. The minimum effective
dose (MED) of 392098 was 0.5 mg/kg, i.p. However, Figure 1 further reveals
that
when 392098 was combined at a dose as low as 25 micrograms/kg with a
subeffective dose of imipramine (5 mg/kg), a statistically significant
reduction in
immobility of the mouse resulted. Moreover, Figure 1 reveals an unexpected
25 shift in the dose response curve of 392098 of at least 20-fold when it was
administered in combination with a subeffective dose of imipramine.
Admininstration
The dosages of the drugs used in the present invention must, in the final
analysis, be set by the physician in charge of the case, using knowledge of
the
drugs, the properties of the drugs in combination as determined in clinical
trials,
and the characteristics of the patient, including diseases other than that for
which
the physician is treating the patient. As used herein the term "effective
amount"
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is the amount or dose of each component, the suitable antidepressant and the
suitable AMPA receptor potentiator, which provides the desired effect in the
patient under diagnosis or particular treatment, such as treatment for
depression.
An effective amount can be readily determined by the attending
s diagnostician, as one skilled in the art, by the use of known techniques and
by
observing results obtained under analogous circumstances. In determining the
effective amount or dose, a number of factors are considered by the attending
diagnostician, including, but not limited to: the species of mammal; its size,
age,
and general health; the specific disease or disorder involved; the degree of
or
z o involvement or the severity of the disease or disorder; the response of
the
individual patient; the particular compound administered; the mode of
administration; the bioavailability characteristics of the preparation
administered;
the dose regimen selected; the use of concomitant medication; and other
relevant circumstances.
General outlines of the dosages, and some preferred dosages are set
forth below.
A typical daily dose of the first component, which is a suitable
antidepressant will contain from about 0.01 mg/kg to about 100 mg/kg of the
first
component. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg,
2 o more preferably from about 0.1 mg/kg to about 25 mg/kg. More specific
dosages
of certain suitable antidepressants are as follows:
Fluoxetine: from about 1 to about 80 mg, once/day; preferred, from
about 10 to about 40 mg once/day;
Duloxetine: from about 1 to about 30 mg once/day; preferred, from
25 about 5 to about 20 mg once/day;
Venlafaxine: from about 10 to about 150 mg once-thrice/day;
preferred, from about 25 to about 125 mg thrice/day;
Milnacipran: from about 10 to about 100 mg once-twice/day;
preferred, from about 25 to about 50 mg twice/day;
3 0 Citalopram: from about 5 to about 50 mg once/day; preferred, from
about 10 to about 30 mg once/day;
Fluvoxamine: from about 20 to about 500 mg once/day; preferred,
from about 50 to about 300 mg once/day;
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Paroxetine: from about 20 to about 50 mg once/day; preferred,
from about 20 to about 30 mg once/day.
Sertraline: from about 20 to about 500 mg once/day; preferred,
from about 50 to about 200 mg once/day.
Reboxetine: from about 1 to about 30 mg, once to four times/day;
preferred, from about 5 to about 30 mg once/day.
Buproprion: from about 100 to about 300 mg/day.
A typical daily dose of the second component which is a suitable
AMPA receptor potentiator, will contain from about 5 micrograms to about 150
1o mg of the suitable AMPA receptor potentiator, preferably about 5 micrograms
to
about 50 mg of the suitable AMPA receptor potentiator.
In more general terms, one would create a combination of the
present invention by choosing a dosage of first and second components
according
to the spirit of the above guideline.
15 As used herein the term "patient" refers to a mammal such as a dog,
rat, mouse, human, and the like. The preferred patient is a human.
The adjunctive therapy of the present invention is carried out by
administering the first component together with the second component in any
manner which provides effective levels of the compounds in the body at the
2 o same time. The compounds concerned are normally administered orally, and
so
oral administration of the adjunctive combination is preferred. They may be
administered together, in a single dosage form, or may be administered
separately.
However, oral administration is not the only route or even the only
25 preferred route. For example, transdermal administration may be very
desirable
for patients who are forgetful or petulant about taking oral medicine. One of
the
drugs may be administered by one route, such as oral, and the others may be
administered by the transdermal, percutaneous, intravenous, intramuscular,
intranasal or intrarectal route, in particular circumstances. The route of
30 administration may be varied in any way, limited by the physical properties
of the
drugs and the convenience of the patient and the caregiver.
The adjunctive combination may be administered as a single
pharmaceutical composition, and so pharmaceutical compositions incorporating
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both compounds are important embodiments of the present invention. Such
compositions may take any physical form which is pharmaceutically acceptable,
but orally usable pharmaceutical compositions are particularly preferred. Such
adjunctive pharmaceutical compositions contain an effective amount of each of
the compounds, which effective amount is related to the daily dose of the
compounds to be administered. Each adjunctive dosage unit may contain the
daily doses of all compounds, or may contain a fraction of the daily doses,
such
as one-third of the doses. Alternatively, each dosage unit may contain the
entire
dose of one of the compounds, and a fraction of the dose of the other
to compounds. In such case, the patient would daily take one of the
combination
dosage units, and one or more units containing only the other compounds. The
amounts of each drug to be contained in each dosage unit depends on the
identity of the drugs chosen for the therapy, and other factors such as the
indication for which the adjunctive therapy is being given.
The inert ingredients and manner of formulation of the adjunctive
pharmaceutical compositions are conventional, except for the presence of the
combination of the present invention. The usual methods of formulation used in
pharmaceutical science maybe used here. All of the usual types of
compositions may. be used, including tablets, chewable-tablets, capsules,
2 o solutions, parenteral solutions, intranasal sprays or powders, troches,.
suppositories, transdermal patches and suspensions. In general, compositions
contain from about 0.5% to about 50% of the compounds in total, depending on
the desired doses and the type of composition to be used. The amount of the
compounds, however, is best defined as the effective amount, that is, the
amount
of each compound which provides the desired dose to the patient in need of
such
treatment. The activity of the adjunctive combinations do not depend on the
nature of the composition, so the compositions are chosen and formulated
solely
for convenience and economy. Any of the combinations may be formulated in
any desired form of composition. Some discussion of different compositions
will
3 o be provided, followed by some typical formulations.
Capsules are prepared by mixing the compound with a suitable
diluent and filling the proper amount of the mixture in capsules: The usual
diluents include inert powdered substances such as starch of many different
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kinds, powdered cellulose, especially crystalline and microcrystalline
cellulose,
sugars such as fructose, mannitol and sucrose, grain flours and similar edible
powders.
Tablets are prepared by direct compression, by wet granulation, or
5, by dry granulation. Their formulations usually incorporate diluents,
binders,
lubricants and disintegrators as well as the compound. Typical diluents
include,
for example, various types of starch, lactose, mannitol, kaolin, calcium
phosphate
or sulfate, inorganic salts such as sodium chloride and powdered sugar.
Powdered cellulose derivatives are also useful. Typical tablet binders are
so substances such as starch, gelatin and sugars such as lactose, fructose,
glucose
and the like. Natural and synthetic gums are also convenient, including
acacia,
alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene
glycol,
ethylcellulose and waxes can also serve as binders.
A lubricant is necessary in a tablet formulation to prevent the tablet
s5 and punches from sticking in the die. The lubricant is chosen from such
slippery
solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated
vegetable oils.
Tablet disintegrators are substances which swell when wetted to
break up the tablet and release the compound. They include starches, clays,
2 o celluloses, algins and gums. More particularly, corn and potato 'starches,
methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge,
cation-exchange resins, alginic acid, guar gum, citrus pulp and
carboxymethylcellulose, for example, may be used, as well as sodium lauryl
sulfate.
2 s Enteric formulations are often used to protect an active ingredient
from the strongly acid contents of the stomach. Such formulations are created
by coating a solid dosage form with a film of a polymer which is insoluble in
acid
environments, and soluble in basic environments. Exemplary films are cellulose
acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose
3 o phthalate and hydroxypropyl methylcellulose acetate succinate. It is
preferred to
formulate duloxetine and duloxetine-containing combinations as enteric
compositions, and even more preferred to formulate them as enteric pellets.
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A preferred duloxetine enteric formulation is a pellet formulation
comprising a) a core consisting of duloxetine and a pharmaceutically
acceptable
excipient; b) an optional separating layer; c) an enteric layer comprising
hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a
pharmaceutically acceptable excipient; d) an optional finishing layer. This
enteric
formulation is described in U.S. Patent No. 5,508,276, herein incorporated by
reference in its entirety.
Tablets are often coated with sugar as a flavor and sealant. The
compounds may also be formulated as chewable tablets, by using large amounts
Zo of pleasant-tasting substances such as mannitol in the formulation, as is
now
well-established practice. Instantly dissolving tablet-like formulations are
also
now frequently used to assure that the patient consumes the dosage form, and
to
avoid the difficulty in swallowing solid objects that bothers some patients.
When it is desired to administer the combination as a suppository,
s5 the usual bases may be used. Cocoa butter is a traditional suppository
base,
which may be modified by addition of waxes to raise its melting point
slightly.
Water-miscible suppository bases comprising, particularly, polyethylene
glycols
of various molecular weights are in wide use, also.
Transdermal patches have become popular recently. Typically.they
2 o comprise a resinous composition in which the drugs will dissolve, or
partially.
dissolve, which is held in contact with the skin by a film which protects the
composition. Many patents have appeared in the field recently. Other, more
complicated patch compositions are also in use, particularly those having a
membrane pierced with innumerable pores through which the drugs are pumped
25 by osmotic action.
