U.S. patent application number 13/570412 was filed with the patent office on 2012-11-29 for derivatives of venlafaxine and methods of preparing and using the same.
Invention is credited to Nandkumar N. Bhongle, Thomas P. Jerussi, Chrisantha H. Senanayake.
Application Number | 20120302794 13/570412 |
Document ID | / |
Family ID | 26826101 |
Filed Date | 2012-11-29 |
United States Patent
Application |
20120302794 |
Kind Code |
A1 |
Jerussi; Thomas P. ; et
al. |
November 29, 2012 |
Derivatives of venlafaxine and methods of preparing and using the
same
Abstract
Methods of preparing, and compositions comprising, derivatives
of venlafaxine are disclosed. Also disclosed are methods of
treating and preventing diseases and disorders including, but not
limited to, affective disorders such as depression, bipolar and
manic disorders, attention deficit disorder, attention deficit
disorder with hyperactivity, Parkinson's disease, epilepsy,
cerebral function disorders, obesity and weight gain, incontinence,
dementia and related disorders.
Inventors: |
Jerussi; Thomas P.;
(Framingham, MA) ; Senanayake; Chrisantha H.;
(Shrewsbury, MA) ; Bhongle; Nandkumar N.;
(Shrewsbury, MA) |
Family ID: |
26826101 |
Appl. No.: |
13/570412 |
Filed: |
August 9, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10720134 |
Nov 25, 2003 |
8269040 |
|
|
13570412 |
|
|
|
|
09527442 |
Mar 17, 2000 |
|
|
|
10720134 |
|
|
|
|
60127938 |
Apr 6, 1999 |
|
|
|
60167906 |
Nov 30, 1999 |
|
|
|
Current U.S.
Class: |
564/336 |
Current CPC
Class: |
A61P 25/08 20180101;
A61P 25/06 20180101; A61P 25/16 20180101; A61P 9/10 20180101; A61P
25/14 20180101; C07D 295/192 20130101; A61P 43/00 20180101; A61P
25/20 20180101; A61P 15/10 20180101; C07C 255/36 20130101; C07C
215/64 20130101; A61P 13/00 20180101; C07C 2601/14 20170501; A61P
25/22 20180101; A61P 25/30 20180101; A61K 9/2059 20130101; A61K
31/135 20130101; A61P 25/00 20180101; A61P 3/04 20180101; A61P
25/04 20180101; A61K 9/4866 20130101; C07C 217/74 20130101; A61K
9/2054 20130101; A61P 25/24 20180101; A61P 23/00 20180101; C07C
255/37 20130101; C07C 233/18 20130101; A61P 25/28 20180101 |
Class at
Publication: |
564/336 |
International
Class: |
C07C 211/27 20060101
C07C211/27 |
Claims
1-59. (canceled)
60. A compound which is O-desmethylvenlafaxine succinate.
Description
1. FIELD OF INVENTION
[0001] The invention relates to derivatives of racemic venlafaxine,
methods of their synthesis, compositions comprising them, and
methods of their use.
2. BACKGROUND OF THE INVENTION
[0002] A number of nontricyclic antidepressants have recently been
developed that diminish the cardiovascular and anticholinergic
liability characteristic of tricyclic antidepressants. Some of
these compounds are used as anti-obesity agents and have shown
promise in the treatment of cerebral function disorders such as
Parkinson's disease and senile dementia. See, e.g., WO 94/00047 and
WO 94/00114. The nontricyclic compound venlafaxine, chemically
named
(.+-.)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol,
is an antidepressant which has been studied extensively and which
is described in, for example, U.S. Pat. No. 4,761,501 and Pento, J.
T. Drugs of the Future 13(9):839-840 (1988). Its hydrochloride salt
is currently commercially available in the United States under the
trade name Effexor.RTM.. Effexor.RTM., which is a racemic mixture
of the (+) and (-) enantiomers of venlafaxine, is indicated for the
treatment of depression.
[0003] Although venlafaxine contains an asymmetric carbon atom and
is sold as a racemate, it has been reported that its (-) enantiomer
is a more potent inhibitor of norepinephrine synaptosomal uptake
while its (+) enantiomer is more selective in inhibiting serotonin
uptake. Howell, S. R. et al. Xenobiotica 24(4):315-327 (1994).
Furthermore, studies have shown that the ratio of the two isomers'
metabolism varies not only among species, but between subjects as
well. Klamerus, K. J. et al. J. Clin. Pharmacol. 32:716-724 (1992).
In humans, venlafaxine is transformed by a saturable metabolic
pathway into two minor metabolites, N-desmethylvenlafaxine and
N,O-didesmethylvenlafaxine, and one major metabolite,
O-desmethylvenlafaxine, as shown in Scheme I(a):
##STR00001##
Klamerus, K. J. et al. J. Clin. Pharmacol. 32:716-724 (1992). In
vitro studies suggest that O-desmethylvenlafaxine is a more potent
inhibitor of norepinephrine and dopamine uptake than the parent
compound venlafaxine. Muth, E. A. et al. Drug Develop. Res.
23:191-199 (1991). O-desmethylvenlafaxine has also been reported to
have a half-life (t1/2) of about 10 hours, which is approximately
2.5 times as long as that of venlafaxine. Klamerus, K. J. et al. J.
Clin. Pharmacol. 32:716-724 (1992). Studies directed at
understanding the activity of O-desmethylvenlafaxine as compared to
its parent have been hampered, however, by the metabolic difference
between laboratory animals and man in their exposure to
venlafaxine. Howell, S. R. et al. Xenobiotica 24(4):315-327
(1994).
[0004] Despite the benefits of venlafaxine, it has adverse effects
including, but not limited to, sustained hypertension, headache,
asthenia, sweating, nausea, constipation, somnolence, dry mouth,
dizziness, insomnia, nervousness, anxiety, blurred or blurry
vision, and abnormal ejaculation/orgasm or impotence in males.
Physicians' Desk Reference pp. 3293-3302 (53.sup.rd ed., 1999); see
also Sinclair, J. et al. Rev. Contemn. Pharmacother. 9:333-344
(1998). These adverse effects can significantly limit the dose
level, frequency, and duration of drug therapy. It would thus be
desirable to find a compound with the advantages of venlafaxine
while avoiding its disadvantages.
3. SUMMARY OF THE INVENTION
[0005] This invention relates to novel pharmaceutical compositions
comprising derivatives of venlafaxine such as
(.+-.)-O-desmethylvenlafaxine. The invention also relates to
methods of preparing derivatives of venlafaxine with high purity
and in high yield, and to methods of treating and preventing
diseases and disorders which comprise the administration of one or
more derivatives of venlafaxine to a human in need of such
treatment or prevention.
[0006] Methods and compositions of the invention can be used to
treat or prevent depression and affective disorders such as, but
not limited to, attention deficit disorder and attention deficit
disorder with hyperactivity. Methods and compositions of the
invention are also useful in treating obesity and weight gain in a
human. The invention also encompasses the treatment of cerebral
function disorders including, but not limited to, senile dementia,
Parkinson's disease, epilepsy, Alzheimer's disease,
amnesia/amnestic syndrome, autism and schizophrenia; disorders
ameliorated by inhibition of neuronal monamine reuptake; and pain,
particularly chronic pain. The invention further encompasses the
treatment or prevention of obsessive-compulsive disorder, substance
abuse, pre-menstrual syndrome, anxiety, eating disorders and
migraines. The invention finally encompasses the treatment or
prevention of incontinence in humans.
[0007] The compounds and compositions of the invention possess
potent activity for treating or preventing the above-described
disorders while reducing or avoiding adverse effects including, but
not limited to, sustained hypertension, headache, asthenia,
sweating, nausea, constipation, somnolence, dry mouth, dizziness,
insomnia, nervousness, anxiety, blurred or blurry vision, and
abnormal ejaculation/orgasm or impotence in males. In particular;
adverse effects associated with the administration of racemic
venlafaxine are reduced or avoided by the use of derivatives of
venlafaxine. Compositions of the invention can also exhibit long
half lives as compared to racemic venlafaxine.
[0008] Although a variety of pharmaceutical salts, solvates,
clatherates and/or hydrates (including anhydrous forms) of the
active ingredients disclosed herein are suitable for use in the
methods and compositions of the invention, the derivatives of
venlafaxine are typically prepared as hydrochloride salts, and
preferably as the monohydrates.
3.1. DEFINITIONS
[0009] As used herein, the terms "venlafaxine" and
"(.+-.)-venlafaxine" mean the racemic compound (.+-.)-1-[2-(di
methylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol.
[0010] As used herein, the terms "venlafaxine derivative" and
"derivative of venlafaxine" encompass, but are not limited to,
human metabolites of racemic venlafaxine. In particular, the terms
"venlafaxine derivative" and "derivative of venlafaxine" mean a
compound selected from the group that includes, but is not limited
to: (.+-.)-N-desmethylvenlafaxine, chemically named
(.+-.)-1-[2-(methylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol;
(.+-.)-N,N-didesmethylvenlafaxine, chemically named
(.+-.)-1-[2-(amino)-1-(4-methoxyphenyl)ethyl]cyclohexanol;
(.+-.)-O-desmethylvenlafaxine, chemically named
(.+-.)-1-[2-(dimethylamino)-1-(4-phenol)ethyl]cyclohexanol;
(.+-.)-N,O-didesmethylvenlafaxine, chemically named
(.+-.)-1-[2-(methylamino)-1-(4-phenol)ethyl]cyclohexanol; and
(.+-.)-O-desmethyl-N,N-didesmethylvenlafaxine, chemically named
chemically named
(.+-.)-1-[2-(amino)-1-(4-phenol)ethyl]cyclohexanol.
[0011] As used herein, the term "pharmaceutically acceptable salts"
refers to salts prepared from pharmaceutically acceptable non-toxic
acids, including inorganic acids and organic acids. Suitable
non-toxic acids include inorganic and organic acids such as acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid,
p-toluenesulfonic and the like. Particularly preferred are
hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most
particularly preferred is the hydrochloride salt.
[0012] As used herein, the term "affective disorder" includes
depression, attention deficit disorder, attention deficit disorder
with hyperactivity, bipolar and manic conditions, and the like. The
terms "attention deficit disorder" (ADD) and "attention deficit
disorder with hyperactivity" (ADDH), or attention
deficit/hyperactivity disorder (AD/HD), are used herein in
accordance with the accepted meanings as found in the Diagnostic
and Statistical Manual of Mental Disorders, 4.sup.th Ed., American
Psychiatric Association (1997) (DSM-IV.TM.).
[0013] As used herein, the term "a method of treating depression"
means relief from the symptoms of depression which include, but are
not limited to, changes in mood, feelings of intense sadness,
despair, mental slowing, loss of concentration, pessimistic worry,
agitation, and self-deprecation. Physical changes may also be
relieved, including insomnia, anorexia, weight loss, decreased
energy and libido, and abnormal hormonal circadian rhythms.
[0014] As used herein, the term "a method for treating obesity or
weight gain" means reduction of weight, relief from being
overweight, relief from gaining weight, or relief from obesity; all
of which are usually due to extensive consumption of food.
[0015] As used herein, the term "a method of treating disorders
ameliorated by inhibition of neuronal monoamine reuptake" means
relief from symptoms of disease states associated with abnormal
neuronal monoamine levels; such symptoms are reduced by way of
neuronal monoamine reuptake inhibition. Monoamines, the reuptake of
which are inhibited by the compounds or compositions of the present
invention, include, but are not limited to, noradrenaline (or
norepinephrine), serotonin and dopamine. Disorders treated by
neuronal monoamine reuptake inhibition include, but are not limited
to, Parkinson's disease and epilepsy.
[0016] As used herein, the term "method of treating Parkinson's
disease" means relief from the symptoms of Parkinson's disease
which include, but are not limited to, slowly increasing disability
in purposeful movement, tremors, bradykinesia, rigidity, and a
disturbance of posture in humans.
[0017] As used herein, the term "a method for treating cerebral
function disorders" means relief from the disease states associated
with cerebral function disorders involving intellectual deficits
which include but are not limited to, senile dementia, Alzheimer's
type dementia, memory loss, amnesia/amnestic syndrome, disturbances
of consciousness, coma, lowering of attention, speech disorders,
Parkinson's disease, Lennox syndrome, autism, hyperkinetic syndrome
and schizophrenia. Also within the meaning of cerebral function
disorders are disorders caused by cerebrovascular diseases
including, but not limited to, cerebral infarction, cerebral
bleeding, cerebral arteriosclerosis, cerebral venous thrombosis,
head injuries, and the like and where symptoms include disturbances
of consciousness, senile dementia, coma, lowering of attention,
speech disorders, and the like.
[0018] The terms "obsessive-compulsive disorder," "substance
abuse," "pre-menstrual syndrome," "anxiety," "eating disorders" and
"migraine" are used herein in a manner consistent with their
accepted meanings in the art. See, e.g., DSM-IV.TM.. The terms
"method of treating or preventing," "method of treating" and
"method of preventing" when used in connection with these disorders
mean the amelioration, prevention or relief from the symptoms
and/or effects associated with these disorders. Without being
limited by any theory, the treatment or prevention of certain of
these disorders may be related to the activity of the active
ingredient(s) as inhibitors of serotonin uptake.
[0019] As used herein, the term "a method of treating or preventing
incontinence" means prevention of or relief from the symptoms of
incontinence including involuntary voiding of feces or urine, and
dribbling or leakage or feces or urine which may be due to one or
more causes including but not limited to pathology altering
sphincter control, loss of cognitive function, overdistention of
the bladder, hyper-reflexia and/or involuntary urethral relaxation,
weakness of the muscles associated with the bladder or neurologic
abnormalities.
4. DETAILED DESCRIPTION OF THE INVENTION
[0020] This invention relates to derivatives of venlafaxine such
as, but not limited to, (.+-.)-O-desmethylvenlafaxine,
(.+-.)-N-desmethylvenlafaxine, and
(.+-.)-N,O-didesmethylvenlafaxine. This invention further relates
to the synthesis of venlafaxine derivatives and to compositions
(e.g., pharmaceutical compositions) comprising them. The invention
also relates to novel uses of the compounds disclosed herein, which
constitute improvements over the use of racemic venlafaxine as well
as over the optically pure isomers of venlafaxine.
[0021] One embodiment of the invention encompasses a method of
treating an affective disorder in a human which comprises
administering to a human in need of such treatment a
therapeutically effective amount of a venlafaxine derivative,
preferably (.+-.)-O-desmethylvenlafaxine, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof. Venlafaxine
derivatives, preferably (.+-.)-O-desmethylvenlafaxine, can be used
to treat an affective disorder while exhibiting a longer half life
than venlafaxine and/or while avoiding or reducing adverse effects
that are associated with the administration of venlafaxine.
[0022] Another embodiment of the invention encompasses a method of
treating weight gain or obesity in a human which comprises
administering to a human in need of weight loss or obesity therapy
a therapeutically effective amount of a venlafaxine derivative,
preferably (.+-.)-O-desmethylvenlafaxine, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof, said amount being
sufficient to reduce or prevent weight gain or obesity. Venlafaxine
derivatives, preferably (.+-.)-O-desmethylvenlafaxine, can be used
to treat weight gain or obesity disorder while exhibiting a longer
half life than venlafaxine and/or while avoiding or reducing
adverse effects that are associated with the administration of
venlafaxine.
[0023] Another embodiment of the invention encompasses a method of
treating disorders ameliorated by neuronal monoamine reuptake
inhibition in a human which comprises administering to a human a
therapeutically effective amount of a venlafaxine derivative,
preferably (.+-.)-O-desmethylvenlafaxine, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof, said amount being
sufficient to treat such disorders. Disorders which are ameliorated
by neuronal monoamine reuptake include, but are not limited to,
Parkinson's disease, epilepsy, and depression. The derivative of
venlafaxine may be used to treat such disorders while avoiding or
reducing adverse effects associated with the administration of
venlafaxine.
[0024] Venlafaxine derivatives, preferably
(.+-.)-O-desmethylvenlafaxine, and compositions containing them are
also useful in treating cerebral function disorders. Such disorders
include, but are not limited to, senile dementia, Alzheimer's type
dementia, memory loss, amesia/amnestic syndrome, disturbance of
consciousness, coma, lowering of attention, speech disorders,
Parkinson's disease, Lennox syndrome, autism, hyperkinetic syndrome
and schizophrenia. Cerebral function disorders may be induced by
factors including, but not limited to, cerebrovascular diseases
such as cerebral infarction, cerebral bleeding, cerebral
arteriosclerosis, cerebral venous thrombosis, head injuries and the
like and where symptoms include disturbances of consciousness,
senile dementia, coma, lowering of attention, speech disorders and
the like. Thus, the invention encompasses a method of treating
cerebral function disorder in a human which comprises administering
to a human in need of such therapy a therapeutically effective
amount of venlafaxine derivative, preferably
(.+-.)-O-desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, or clathrate thereof. The use of a venlafaxine
derivative, preferably (.+-.)-O-desmethylvenlafaxine, is intended
to provide an improvement over the use of the parent drug
venlafaxine. The derivatives of the invention are more potent and
yet provide an overall improved therapeutic index over
venlafaxine.
[0025] Another embodiment of the invention encompasses a method of
treating pain, including chronic pain, in a human which comprises
administering to a human in need of such therapy a therapeutically
effective amount of venlafaxine derivative, preferably
(.+-.)-O-desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, or clathrate thereof, said amount being sufficient
to alleviate the human's pain.
[0026] Another embodiment of the invention encompasses a method of
treating an obsessive-compulsive disorder in a human, which
comprises administering to a human in need of such therapy a
therapeutically effective amount of a venlafaxine derivative,
preferably (.+-.)-O-desmethylvenlafaxine, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof.
[0027] Another embodiment of the invention encompasses a method of
treating or preventing substance abuse in a human, which comprises
administering to a human in need of such therapy a therapeutically
effective amount of a venlafaxine derivative, preferably
(.+-.)-O-desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, or clathrate thereof.
[0028] Another embodiment of the invention encompasses a method of
treating or preventing pre-menstrual syndrome in a human, which
comprises administering to a human in need of such therapy a
therapeutically effective amount of a venlafaxine derivative,
preferably (.+-.)-O-desmethylvenlafaxine, or a pharmaceutically
acceptable salt, solvate, or clathrate thereof.
[0029] Another embodiment of the invention encompasses a method of
treating anxiety in a human, which comprises administering to a
human in need of such therapy a therapeutically effective amount of
a venlafaxine derivative, preferably (.+-.)-O-desmethylvenlafaxine,
or a pharmaceutically acceptable salt, solvate, or clathrate
thereof.
[0030] Another embodiment of the invention encompasses a method of
treating an eating disorder in a human, which comprises
administering to a human in need of such therapy a therapeutically
effective amount of a venlafaxine derivative, preferably
(.+-.)-O-desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, or clathrate thereof.
[0031] Another embodiment of the invention encompasses a method of
treating or preventing a migraine, or migraine headaches, in a
human, which comprises administering to a human in need of such
therapy a therapeutically effective amount of a venlafaxine
derivative, preferably (.+-.)-O-desmethylvenlafaxine, or a
pharmaceutically acceptable salt, solvate, or clathrate
thereof.
[0032] Another embodiment of the invention encompasses a method of
treating or preventing incontinence in a human which comprises
administering to a human in need of such therapy a therapeutically
effective amount of a venlafaxine derivative, preferably
(.+-.)-O-desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, or clathrate thereof. In particular, a venlafaxine
derivative can be used to treat fecal incontinence, stress urinary
incontinence ("SUI"), urinary exertional incontinence, urge
incontinence, reflex incontinence, passive incontinence and
overflow incontinence. In a preferred embodiments the human is an
elder person of an age greater than 50 or a child of an age less
than 13. Further, the invention encompasses the treatment of
incontinence in patients with either loss of cognitive function,
sphincter control or both. The invention is particularly well
suited for the treatment or prevention of fecal incontinence and
stress urinary incontinence.
[0033] Another embodiment of the invention encompasses a method of
preparing (.+-.)-N-desmethylvenlafaxine which comprises contacting
a compound of Formula 5:
##STR00002##
with a reductant for a time and at a temperature sufficient to form
(.+-.)-N-desmethylvenlafaxine. A preferred reductant is
BH.sub.3.Me.sub.2S.
[0034] Another embodiment of the invention encompasses a method of
preparing (.+-.)-N,N-didesmethylvenlafaxine which comprises
contacting a compound of Formula 2:
##STR00003##
with a reductant for a time and at a temperature sufficient to form
(.+-.)-N,N-didesmethylvenlafaxine. A preferred reductant is
CoCl.sub.2/NaBH.sub.4.
[0035] Another embodiment of the invention encompasses a method of
preparing (.+-.)-O-desmethylvenlafaxine which comprises contacting
venlafaxine with lithium diphenylphosphide for a time and at a
temperature sufficient to form (.+-.)-O-desmethylvenlafaxine.
[0036] Another embodiment of the invention encompasses
substantially pure (.+-.)-O-desmethylvenlafaxine and
pharmaceutically acceptable salts, solvates, and clathrates
thereof.
[0037] Another embodiment of the invention encompasses
substantially pure (.+-.)-N,O-didesmethylvenlafaxine and
pharmaceutically acceptable salts, solvates, and clathrates
thereof.
[0038] Another embodiment of the invention encompasses
substantially pure (.+-.)-O-desmethyl-N,N-didesmethylvenlafaxine
and pharmaceutically acceptable salts, solvates, and clathrates
thereof.
[0039] Another embodiment of the invention encompasses
(.+-.)-N-desmethylvenlafaxine and pharmaceutically acceptable
salts, solvates, and clathrates thereof.
[0040] A final embodiment of the invention encompasses
(.+-.)-N,N-didesmethylvenlafaxine and pharmaceutically acceptable
salts, solvates, and clathrates thereof.
[0041] Compounds of the invention, which can be used and prepared
as described herein, are shown below in Scheme I(b):
##STR00004##
[0042] The synthesis of some venlafaxine derivatives has been
described by Yardley, J. P. et al. J. Med. Chem. 33:2899-2905
(1990), the disclosure of which is hereby incorporated by
reference. This method, which may be adapted for the synthesis of
the compounds of this invention, is shown in Scheme II:
##STR00005##
wherein R is methoxy or hydroxy, R.sub.1 is hydrogen or methyl, and
the reaction conditions are as follows: (a) LDA in cycloalkanone at
-78.degree. C.; (b) Rh/Al.sub.2O.sub.3; and (c) HCHO, HCOOH,
H.sub.2O, reflux. The final product yielded by step (c) may be
isolated by any method known to those skilled in the art, including
high performance liquid chromatography (HPLC). As used herein, the
term "isolate" encompasses the isolation of a compound from a
reaction mixture and the purification of the compound.
[0043] In a preferred method of the invention,
(.+-.)-N,N-didesmethylvenlafaxine is prepared according to the
method shown in Scheme III:
##STR00006##
According to this method, cyclohexanone is reacted with compound 1
to provide compound 2. This reaction is preferably done in the
presence of a catalyst such as, but not limited to, lithium
diisopropylamide (LDA), and in an aprotic solvent such as, but not
limited to, THF. The cyano group of compound 2 is subsequently
contacted with a reductant to provide compound 3,
(.+-.)-N,N-didesmethylvenlafaxine. A preferred reductant is
CoCl.sub.2/NaBH.sub.4 in methanol, although other reductants known
to those skilled in the art can also be used. Salts of
(.+-.)-N,N-didesmethylvenlafaxine, such as the HCl salt (compound
4), can then be formed using reaction conditions well known in the
art.
[0044] In another preferred method of the invention,
(.+-.)-N-desmethylvenlafaxine is prepared from
(.+-.)-N,N-didesmethylvenlafaxine according to the method shown in
Scheme IV:
##STR00007##
According to this method, (.+-.)-N,N-didesmethylvenlafaxine
(compound 3) is converted to compound 5 using, for example,
HCO.sub.2H in a solvent such as, but not limited to, toluene. The
aldehyde of compound 5 is subsequently reduced to provide compound
6, (.+-.)-N-desmethylvenlafaxine. A preferred reductant is
BH.sub.3.Me.sub.2S in an aprotic solvent such as, but not limited
to, THF. Salts of (.+-.)-N-desmethylvenlafaxine, such as the HCl
salt (compound 7), can then be formed using reaction conditions
well known in the art.
[0045] It is also possible to prepare the compounds of the
invention from racemic venlafaxine, which can be prepared according
to methods disclosed, for example, by U.S. Pat. No. 4,761,501 and
Pento, J. T. Drugs of the Future 13(9):839-840 (1988), both of
which are incorporated herein by reference.
[0046] Alternative methods of preparing (.+-.)-venlafaxine.HCl and
(.+-.)-O-desmethyl-venlafaxine are shown in Scheme V:
##STR00008##
According to Scheme V, (.+-.)-venlafaxine (compound 8) is prepared
by reacting (.+-.)-N,N-didesmethylvenlafaxine (compound 3) with,
for example, HCHO/HCO.sub.2H. Compound 8 can then be converted to
(.+-.)-O-desmethylvenlafaxine (compound 13) using, for example,
lithium diphenylphosphide. Alternatively, salts of
(.+-.)-venlafaxine, such as the HCl salt (compound 12), can be
formed using reaction conditions well known in the art.
[0047] Utilizing derivatives of venlafaxine in the treatment and/or
mitigation of the conditions described herein results in clearer
dose-related definitions of efficacy, diminished adverse effects,
and accordingly an improved therapeutic index as compared to
venlafaxine itself.
[0048] The magnitude of a prophylactic or therapeutic dose of a
venlafaxine derivative (herein also referred to as an "active
ingredient"), preferably (.+-.)-O-desmethylvenlafaxine, in the
acute or chronic management of a disease will vary with the
severity of the condition to be treated and the route of
administration. The dose, and perhaps the dose frequency, will also
vary according to age, body weight, response, and the past medical
history of the individual patient. In general, the recommended
daily dose range for the conditions described herein lie within the
range of from about 10 mg to about 1000 mg per day, given as a
single once-a-day dose in the morning but preferably as divided
doses throughout the day taken with food. Preferably, a daily dose
range should be from about 50 mg to about 500 mg per day, more
preferably, between about 75 mg and about 350 mg per day. In
managing the patient, the therapy should be initiated at a lower
dose, perhaps about 50 mg to about 75 mg, and increased if
necessary up to about 250 mg to about 325 mg per day as either a
single dose or divided doses, depending on the patient's global
response. If a dosage is increased, it is preferably done in
intervals of about 75 mg separated by at least 4 days.
[0049] Because elimination of venlafaxine derivatives from the
bloodstream is dependant on renal and liver function, it is
recommended that the total daily dose be reduced by at least 50% in
patients with moderate hepatic impairment, and that it be reduced
by 25% in patients with mild to moderate renal impairment. For
patients undergoing hemodialysis, it is recommended that the total
daily dose be reduced by 5% and that the dose be withheld until the
dialysis treatment is completed. Because some adverse reactions
have been reported for patients who took venlafaxine concurrently
with, or shortly after, a monamine oxidase inhibitor, it is
recommended that the venlafaxine derivatives of this invention not
be administered to patients currently taking such inhibitors. In
general, the concurrent administration of the compounds of this
invention with other drugs, particularly other serotonin uptake
inhibitors, should be done with care. See, e.g., von Moltke, L. L.
et al. Biol. Psychiatry 41:377-380 (1997); and Sinclair, J. et al.
Rev. Contemp. Pharmacother. 9:333-344 (1998).
[0050] The various terms "said amount being sufficient to alleviate
the affective disorder," "said amount being sufficient to alleviate
depression," "said amount being sufficient to alleviate attention
deficit disorder," "said amount being sufficient to alleviate an
obsessive-compulsive disorder", "said amount being sufficient to
prevent or alleviate substance abuse", "said amount being
sufficient to prevent or alleviate pre-menstrual syndrome", "said
amount being sufficient to prevent or alleviate anxiety", "said
amount being sufficient to prevent or alleviate an eating
disorder", "said amount being sufficient to prevent or alleviate or
prevent migraine", "said amount being sufficient to alleviate
Parkinson's disease," "said amount being sufficient to alleviate
epilepsy," "said amount being sufficient to alleviate obesity or
weight gain," "an amount sufficient to achieve weight loss," "said
amount being sufficient to bring about weight reduction in a
human," "said amount being sufficient to alleviate pain," "said
amount being sufficient to alleviate dementia," "said amount
sufficient to alleviate said disorders ameliorated by inhibition of
neuronal monoamine reuptake," "said amount is sufficient to
alleviate cerebral function disorders" wherein said disorders are
selected from the group consisting of senile dementia, Alzheimer's
type dementia, memory loss, amnesia/amnestic syndrome, disturbance
of consciousness, coma, lowering of attention, speech disorders,
Parkinson's disease, Lennox syndrome, autism, hyperkinetic
syndrome, schizophrenia, and cerebrovascular diseases, such as
cerebral infarction, cerebral bleeding, cerebral arteriosclerosis,
cerebral venous thrombosis, head injuries, and the like, "said
amount being sufficient to treat or prevent incontinence" wherein
said incontinence includes but is not limited to fecal, stress,
urinary, urinary exertional, urge, reflex, passive and overflow
incontinence, are encompassed by the above described dosage amounts
and dose frequency schedule. Similarly, amounts sufficient to
alleviate each of the above disorders but insufficient to cause
adverse effects associated with venlafaxine are also encompassed by
the above described dosage amounts and dose frequency schedule.
[0051] Any suitable route of administration can be employed for
providing the patient with a therapeutically or prophylactically
effective dose of an active ingredient. For example, oral, mucosal
(e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral
(e.g., intravenous, intramuscular), transdermal, and subcutaneous
routes can be employed. Preferred routes of administration include
oral, transdermal, and mucosal. Suitable dosage forms for such
routes include, but are not limited to, transdermal patches,
ophthalmic solutions, sprays, and aerosols. Transdermal
compositions can also take the form of creams, lotions, and/or
emulsions, which can be included in an appropriate adhesive for
application to the skin or can be included in a transdermal patch
of the matrix or reservoir type as are conventional in the art for
this purpose. A preferred transdermal dosage form is a "reservoir
type" or "matrix type" patch, which is applied to the skin and worn
for a specific period of time to permit the penetration of a
desired amount of active ingredient. The patch can be replaced with
a fresh patch when necessary to provide constant administration of
the active ingredient to the patient.
[0052] Other dosage forms of the invention include, but are not
limited to, tablets, caplets, troches, lozenges, dispersions,
suspensions, suppositories, ointments, cataplasms (poultices),
pastes, powders, dressings, creams, plasters, solutions, capsules,
soft elastic gelatin capsules, and patches.
[0053] In practical use, an active ingredient can be combined in an
intimate admixture with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques. The carrier can
take a wide variety of forms depending on the form of preparation
desired for administration. In preparing the compositions for an
oral dosage form, any of the usual pharmaceutical media can be
employed as carriers, such as, for example, water, glycols, oils,
alcohols, flavoring agents, preservatives, coloring agents, and the
like in the case of oral liquid preparations (such as suspensions,
solutions, and elixirs) or aerosols; or carriers such as starches,
sugars, micro-crystalline cellulose, diluents, granulating agents,
lubricants, binders, and disintegrating agents can be used in the
case of oral solid preparations, preferably without employing the
use of lactose. For example, suitable carriers include powders,
capsules, and tablets, with the solid oral preparations being
preferred over the liquid preparations.
[0054] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid pharmaceutical carriers are employed. If desired,
tablets can be coated by standard aqueous or nonaqueous
techniques.
[0055] In addition to the common dosage forms set out above, an
active ingredient can also be administered by controlled release
means or delivery devices that are well known to those of ordinary
skill in the art, such as those described in U.S. Pat. Nos.
3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719,
5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476,
5,354,556, and 5,733,566, the disclosures of which are incorporated
herein by reference. These dosage forms can be used to provide slow
or controlled-release of one or more active ingredients using, for
example, hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, or microspheres or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the pharmaceutical compositions of the
invention. The invention thus encompasses single unit dosage forms
suitable for oral administration such as, but not limited to,
tablets, capsules, gelcaps, and caplets that are adapted for
controlled-release.
[0056] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include: 1) extended activity of
the drug; 2) reduced dosage frequency; and 3) increased patient
compliance. In addition, controlled-release formulations can be
used to affect the time of onset of action or other
characteristics, such as blood levels of the drug, and thus can
affect the occurrence of side effects.
[0057] Most controlled-release formulations are designed to
initially release an amount of drug that promptly produces the
desired therapeutic effect, and to gradually and continually
release of other amounts of drug to maintain this level of
therapeutic effect over an extended period of time. In order to
maintain this constant level of drug in the body, the drug must be
released from the dosage form at a rate that will replace the
amount of drug being metabolized and excreted from the body.
Controlled-release of an active ingredient can be stimulated by
various inducers, including, but not limited to, pH, temperature,
enzymes, water, or other physiological conditions or compounds.
[0058] Pharmaceutical compositions of the invention suitable for
oral administration can be presented as discrete dosage forms, such
as capsules, cachets, or tablets, or aerosol sprays each containing
a predetermined amount of an active ingredient as a powder or in
granules, a solution, or a suspension in an aqueous or non-aqueous
liquid, an oil-in-water emulsion, or a water-in-oil liquid
emulsion. Such dosage forms can be prepared by any of the methods
of pharmacy, but all methods include the step of bringing the
active ingredient into association with the carrier, which
constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation.
[0059] For example, a tablet can be prepared by compression or
molding, optionally with one or more accessory ingredients.
Compressed tablets can be prepared by compressing in a suitable
machine the active ingredient in a free-flowing form such as powder
or granules, optionally mixed with an excipient such as, but not
limited to, a binder, a lubricant, an inert diluent, and/or a
surface active or dispersing agent. Molded tablets can be made by
molding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent.
[0060] This invention further encompasses lactose-free
pharmaceutical compositions and dosage forms. Lactose is used as an
excipient in venlafaxine formulations. See, e.g., Physician's Desk
Reference.RTM. 3294 (53.sup.rd ed., 1999). Unlike the parent drug,
however, N-demethylated derivatives of venlafaxine (e.g.,
(.+-.)-N-desmethylvenlafaxine and
(.+-.)-N,N-didesmethylvenlafaxine), are secondary or primary amines
and may thus decompose over time when exposed to lactose.
Consequently, compositions of the invention that comprise
N-demethylated derivatives of venlafaxine preferably contain
little, if any, lactose or other mono- or di-saccharides. As used
herein, the term "lactose-free" means that the amount of lactose
present, if any, is insufficient to substantially increase the
degradation rate of an active ingredient.
[0061] Lactose-free compositions of the invention can comprise
excipients which are well known in the art and are listed in the
USP (XXI)/NF (XVI), which is incorporated herein by reference. In
general, lactose-free compositions comprise an active ingredient, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free dosage
forms comprise an active ingredient, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0062] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising an active ingredient,
since water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate
decomposition. Thus the effect of water on a formulation can be of
great significance since moisture and/or humidity are commonly
encountered during manufacture, handling, packaging, storage,
shipment, and use of formulations.
[0063] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms of the invention which
contain lactose are preferably anhydrous if substantial contact
with moisture and/or humidity-during manufacturing, packaging,
and/or storage is expected.
[0064] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous-nature is maintained.
Accordingly, anhydrous compositions are preferably packaged-using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils, plastic
or the like, unit dose containers, blister packs, and strip
packs.
[0065] In this regard, the invention encompasses a method of
preparing a solid pharmaceutical formulation comprising an active
ingredient which method comprises admixing under anhydrous or low
moisture/humidity conditions the active ingredient and an excipient
(e.g., lactose), wherein the ingredients are substantially free of
water. The method can further comprise packaging the anhydrous or
non-hygroscopic solid formulation under low moisture conditions. By
using such conditions, the risk of contact with water is reduced
and the degradation of the active ingredient can be prevented or
substantially reduced.
[0066] Binders suitable for use in pharmaceutical compositions and
dosage forms include, but are not limited to, corn starch, potato
starch, or other starches, gelatin, natural and synthetic gums such
as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium,
sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl
cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
(e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and
mixtures thereof.
[0067] Suitable forms of microcrystalline cellulose include, for
example, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL
RC-581, and AVICEL-PH-105 (available from FMC Corporation, American
Viscose Division, Avicel Sales, Marcus Hook, Pa., U.S.A.). An
exemplary suitable binder is a mixture of microcrystalline
cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
Suitable anhydrous or low moisture excipients or additives include
AVICEL-PH-103.TM. and Starch 1500 LM.
[0068] Examples of suitable fillers for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder/filler in pharmaceutical
compositions of the present invention is typically present in about
50 to about 99 weight percent of the pharmaceutical
composition.
[0069] Disintegrants are used in the compositions of the invention
to provide tablets that disintegrate when exposed to an aqueous
environment. Too much of a disintegrant will produce tablets which
may disintegrate in the bottle. Too little may be insufficient for
disintegration to occur and may thus alter the rate and extent of
release of the active ingredient(s) from the dosage form. Thus, a
sufficient amount of disintegrant that is neither too little nor
too much to detrimentally alter the release of the active
ingredient(s) should be used to form the dosage forms of the
compounds disclosed herein. The amount of disintegrant used varies
based upon the type of formulation and mode of administration, and
is readily discernible to those of ordinary skill in the art.
Typically, about 0.5 to about 15 weight percent of disintegrant,
preferably about 1 to about 5 weight percent of disintegrant, can
be used in the pharmaceutical composition.
[0070] Disintegrants that can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums or mixtures
thereof.
[0071] Lubricants which can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, calcium stearate, magnesium stearate, mineral oil,
light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other glycols, stearic acid, sodium lauryl sulfate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil),
zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures
thereof. Additional lubricants include, for example, a syloid
silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of
Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed
by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon
dioxide product sold by Cabot Co. of Boston, Mass.), or mixtures
thereof. A lubricant can optionally be added, typically in an
amount of less than about 1 weight percent of the pharmaceutical
composition.
[0072] Desirably, each tablet contains from about 25 mg to about
150 mg of the active ingredient and each cachet or capsule contains
from about 25 mg to about 150 mg of the active ingredient. Most
preferably, the tablet, cachet, or capsule contains either one of
three dosages, e.g., about 25 mg, about 50 mg, or about 75 mg of
active ingredient (as scored tablets, the preferable dose
form).
[0073] The invention is further defined by reference to the
following examples describing in detail the preparation of the
compositions of the invention. It will be apparent to those skilled
in the art that many modifications, both to materials and methods,
may be practiced without departing from the purpose and interest of
this invention.
5. EXAMPLES
[0074] As discussed above, at least two different synthetic
approaches may be utilized to obtain the compounds of this
invention. A first is based upon the isolation of venlafaxine,
followed by selective demethylation. In a second approach, the
compounds are prepared directly.
5.1. Example 1
Synthesis of Venlafaxine
1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol
[0075] A solution of 4-methoxybenzylnitrile (53.5 g, 0.36 mol) in
400 mL THF was cooled to -78.degree. C. followed by slow addition
of a 2.0 M THF solution of lithium diisopropylamide (200 mL, 0.40
mol) maintaining the reaction temperature below -65.degree. C. The
reaction was stirred at -78.degree. C. for 30 minutes.
Cyclohexanone (39.5 g, 0.40 mol) was added at a rate such that the
reaction temperature did not rise above -65.degree. C. After the
addition reaction was stirred at -78.degree. C. for 2 hours, then
was poured into 1 L saturated aqueous NH.sub.4Cl containing ice.
The mixture was stirred for 15 minutes and was extracted with ethyl
acetate (4.times.200 mL). Combined ethyl acetate layer was washed
with water (3.times.100 mL), brine (1.times.100 mL) and dried
(Na.sub.2SO.sub.4). Ethyl acetate was evaporated in vacuo to give
colorless solid that was trichurated with hexane. The precipitate
was filtered, washed with hexane, dried in vacuo to give colorless
solid (72.0 g, 80.7% yield). .sup.1H (CDCl.sub.3): 7.30 and 6.90
(q, 4H), 3.80 (s, 3H), 3.75 (s, 1H), 1.55 (m, 10H); .sup.13C
(CDCl.sub.3): 159.8, 130.8, 123.8, 120.0, 114.1, 72.9, 55.5, 49.5,
34.9, 25.3, 21.6.
1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol
[0076] A 3-L, three-neck flask equipped with a mechanical stirrer
and a thermocouple was charged with
1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (40.0 g, 0.16 mol) and
1 L methanol. To the resulting stirred solution was added cobalt
chloride (42.4 g, 0.32 mol) and the reaction was stirred until a
clear dark blue solution was obtained. Sodium borohydride (62.0 g,
1.63 mol) was added in small lots maintaining the reaction
temperature below 35.degree. C. A dark black precipitate was formed
along with vigorous evolution of gas as soon as sodium borohydride
was added. After completion of addition the slurry was stirred at
room temperature for 2 hours. TLC examination indicated complete
disappearance of the starting material. The reaction was cooled in
ice/water and 1 L 3N HCl was added slowly. Reaction temperature was
maintained below 25.degree. C. Reaction was stirred for 30 minutes
after completion of the addition. Small amount of black precipitate
was still observed. Methanol was removed in vacuo followed by
extraction of the aqueous layer with ethyl acetate (3.times.300
mL). The aqueous layer was cooled in ice/water and was basified (pH
paper) by slow addition of concentrated NH.sub.2OH (-600 mL).
Reaction temperature was maintained below 25.degree. C. Reaction
was extracted with ethyl acetate (4.times.200 mL). Combined ethyl
acetate layer was washed with water (3.times.100 mL), brine
(1.times.100 mL), and dried (Na.sub.2SO.sub.4). Ethyl acetate was
evaporated in vacuo to give yellow gum (34.0 g, 83.6% yield).
.sup.1H (CDCl.sub.3): 7.20 and 6.85 (q, 4H), 3.80 (s, 3H), 3.20 (m,
2H), 2.70 (t, 3H), 2.35 (br s, 3H), 1.40 (m, 10H); .sup.13C
(CDCl.sub.3): 158.4, 132.6, 130.6, 113.7, 73.7, 56.7, 55.3, 42.4,
37.3, 34.5, 26.0, 21.9.
(.+-.)-Venlafaxine
[0077] 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (33.0 g,
0.13 mol) was dissolved in 88% formic acid (66.0 g, 55 mL, 1.43
mol) and water (330 mL) followed by addition of 37% aqueous
formaldehyde (44.4 g, 41 mL, 1.48 mol). The resulting solution was
refluxed for 20 hours, cooled to room temperature and was
concentrated to 150 mL, adjusted to pH 2.0 with 3N HCl, and
extracted with ethyl acetate (--6.times.50 mL) until pink impurity
was removed. The aqueous layer was cooled in ice/water and was
basified by slow addition of 50% NaOH. The aqueous layer was
extracted with ethyl acetate (3.times.75 mL). Combined ethyl
acetate layer was washed with water (3.times.25 mL), brine
(1.times.25 mL) and dried (Na.sub.2SO.sub.4). Ethyl acetate was
evaporated in vacuo to give yellow gum that turned slowly in to
pale yellow solid (34.0 g, 92.6% yield). .sup.1H (CDCl.sub.3): 7.05
and 6.80 (q, 4H), 3.80 (s, 3H), 3.30 (t, 1H), 2.95 (dd, 1H), 2.35
(s, 6H), 2.30 (dd, 1H), 1.30 (m, 10H); .sup.13C (CDCl.sub.3):
158.4, 132.9, 130.3, 113.5, 74.4, 61.4, 55.3, 51.8, 45.6, 38.2,
31.3, 26.2, 21.8, 21.5. MS (277, M+).
(.+-.)-Venlafaxine.HCl Salt
[0078] A solution of (.+-.)-venlafaxine (1.0 g, 3.6 mmol) in 100 mL
MTBE was cooled to 0.degree. C. and 2 mL of 15% HCl in MTBE was
added to it. A colorless precipitate was formed. The reaction was
stirred at 0.degree. C. for 10 minutes. Solid was filtered, washed
with MTBE, dried in vacuo to give the product as colorless solid
(0.700 g, 61.9% yield). .sup.1H (CDCl.sub.3): 11.40 (s, 1H), 7.15
and 6.85 (q, 4H), 4.05 (d, 1H), 3.80 (s, 3H), 3.35 (t, 1H), 3.20
(m, 2H), 2.80 (s, 3H), 2.60 (s, 3H), 1.30 (m, 10H); .sup.13C
(CDCl.sub.3): 159.0, 131.4, 130.3, 114.2, 73.7, 60.4, 55.4, 52.7,
45.3, 42.8, 36.7, 31.5, 25.5, 21.7, 21.3. MS (277, M+ for free
base). % purity (HPLC): 99.62.
5.2. Example 2
Synthesis of (.+-.)-O-desmethylvenlafaxine
[0079] A solution of diphenylphosphine (3.0 g, 16.1 mmol) in 20 mL
THF was cooled to -10.degree. C. followed by slow addition of a 1.6
M THF solution of n-BuLi (123 mL, 20.2 mmol) at a rate such that
reaction temperature did not rise above 0.degree. C. The reaction
was stirred at 0.degree. C. for 30 minutes. A solution of
(.+-.)-venlafaxine (1.0 g, 3.6 mmol) in 10 mL THF was added slowly
at 0.degree. C. The reaction was stirred at 0.degree. C. for 15
minutes and allowed to warm to room temperature and stirred for 1
hour. It was then refluxed overnight. The reaction was cooled to
room temperature and was poured slowly into 30 mL cold 3N HCl
maintaining the temperature below 15.degree. C. After stirring for
10 minutes, the aqueous layer was extracted with ethyl acetate
(3.times.30 mL). The aqueous layer was adjusted to pH 6.8-6.9 by
slow addition of solid NaHCO.sub.3. It was then saturated by adding
NaCl and was extracted with ethyl acetate (6.times.30 mL). Combined
ethyl acetate layer was dried (Na.sub.2SO.sub.4), ethyl acetate was
evaporated in vacuo to give colorless solid. The solid was
trichurated with cold ethyl acetate, filtered, washed with cold
ethyl acetate to give colorless solid (0.700 g, 73.8% yield).
.sup.1H (DMSO, d.sub.6): 9.30 (br s, 1H), 7.10 and 6.80 (q, 4H),
5.60 (br s, 1H), 3.15 (dd, 1H), 2.88 (t, 1H), 2.50 (dd, 1H), 2.30
(s, 6H), 1.35 (m, 10H); .sup.13C (DMSO, d.sub.6): 155.5, 131.7,
130.1, 114.4, 72.6, 60.4, 51.6, 45.3, 37.2, 32.4, 25.7, 21.2. MS:
(264, M+1). % purity (HPLC): 99.9.
5.3. Example 3
Synthesis of (.+-.)-N-desmethylvenlafaxine
[0080] To a solution of 1-[amino(4-methoxyphenyl)ethyl]cyclohexanol
(1.0 g, 4.0 mmol) in 8 mL of toluene, 96% formic acid (0.37 g, 8.0
mmol) was added and the reaction was refluxed for 4 hours. It was
cooled to room temperature and poured into 40 mL saturated aqueous
NaHCO.sub.3. Toluene layer was separated and aqueous layer was
extracted with toluene (3.times.15 mL). Combined toluene layer was
washed with water (3.times.15 mL), brine (1.times.15 mL) and dried
(Na.sub.2SO.sub.4). Toluene was evaporated in vacuo to give crude
N-formyl compound as yellow gum (0.930 g, 83.8% yield). .sup.1H
(CDCl.sub.3): 7.95 (s, 1H), 7.15 and 6.85 (q, 4H), 5.80 (s, 1H),
4.10 (m, 1H), 3.80 (s, 3H), 3.50 (s, 1H), 2.80 (dd, 1H), 1.50 (m,
10H); .sup.13C (CDCl.sub.3): 161.4, 158.8, 131.0, 130.7, 113.9,
73.0, 55.3, 54.2, 38.1, 36.1, 35.6, 25.6, 21.9, 21.8. (Impurity:
164.5, 129.0, 128.0, 125.0, 56.5, 42.0, 36.5, 35.5). MS (277,
M+).
[0081] To a solution of crude N-formyl compound (0.585 g, 2.1 mmol)
in 6 mL THF was added BH.sub.3-Me.sub.2S (0.480 g, 0.63 mL of 10 M
solution, 6.3 mmol) slowly at 0.degree. C. The reaction was allowed
to warm to room temperature and then was refluxed for 5 hours. It
was cooled to 0.degree. C. and 5 mL of methanol was added very
carefully controlling the temperature below 10.degree. C. The
reaction was stirred for 10 minutes and volatiles were evaporated
off. Residue was partitioned between 3N HCl (20 mL) and ethyl
acetate (20 mL). Organic layer was separated and aqueous layer was
extracted with ethyl acetate (3.times.15 mL). Aqueous layer was
cooled to 0.degree. C. and was basified by slow addition of conc.
NH.sub.4OH. Aqueous layer was saturated with NaCl and was extracted
with ethyl acetate (3.times.20 mL). Combined ethyl acetate layer
was dried (Na.sub.2SO.sub.4), ethyl acetate was evaporated in vacuo
to give colorless oil (0.493 g, 88.8% yield). .sup.1H (CDCl.sub.3):
7.15 and 6.85 (q, 4H), 3.80 (s, 3H), 3.25 (dd, 1H), 2.95 (dd, 1H),
2.82 (dd, 1H), 2.45 (s, 3H), 1.40 (m, 10H); .sup.13C (CDCl.sub.3):
158.4, 133.0, 130.5, 113.7, 73.9, 55.4, 53.8, 53.0, 37.8, 36.5,
33.7, 26.0, 21.9.
(.+-.)-N-desmethylvenlafaxine.HCl Salt
[0082] To a solution of crude (.+-.)-N-demethylvenlafaxine (0.450
g, 1.7 mmol) in 25 mL MTBE was added 1 mL of 15% HCl in MTBE at
0.degree. C. The resulting slurry was stirred at 0.degree. C. for
15 minutes, filtered, solid was washed with MTBE, dried in vacuo to
give the product as colorless solid (0.380 g, 74.2% yield). .sup.1H
(CDCl.sub.3): 9.10 (br d, 1H), 7.15 and 6.85 (q, 4H), 3.80 (m &
s, 4H), 3.35 (dd, 1H), 3.15 (m, 1H), 2.70 (t, 3H), 1.30 (m, 10H);
.sup.13C (CDCl.sub.3): 159.0, 130.71, 130.4, 114.0, 74.7, 55.4,
52.8, 50.9, 37.0, 34.1, 30.9, 25.5, 21.4. % Purity (HPLC):
98.81.
5.4. Example 4
Synthesis of (.+-.)-N,N-didesmethylvenlafaxine.HCl Salt
[0083] To a solution of 1-[amino(4-methoxyphenyl)ethyl]cyclohexanol
(0.750 g, 3.0 mmol) in 75 mL MTBE was added 2 mL of 15% HCl in
MTBE. The reaction was stirred at 0.degree. C. for 15 minutes. It
was then evaporated to dryness and the residue was trichurated with
MTBE/hexane (6:4). Solid was filtered, washed with MTBE/hexane
(6:4). The solid was suspended in cold MTBE, filtered, washed with
cold MTBE, dried in vacuo to give the product as colorless solid
(0.450 g, 52.3% yield). .sup.1H (DMSO, d.sub.6)): 7.80 (br s, 2H),
7.20 and 6.90 (q, 4H), 4.50 (br s, 1H), 3.80 (s, 3H), 3.40 (m, 1H),
3.10 (m, 1H), 2.90 (m, 1H), 1.35 (m, 10H); .sup.13C (DMSO,
d.sub.6): 158.3, 130.7, 130.0, 113.5, 71.7, 54.9, 52.6, 36.3, 33.6,
26.8, 25.3, 21.4, 21.1. % Purity (HPLC): 99.3.
5.5. Example 5
Synthesis of (.+-.)-O-desmethyl-N,N-didesmethylvenlafaxine
[0084] To a solution of diphenylphosphine (22.2 g, 0.12 mol) in 175
ml THF was added a 1.6 M THF solution of n-BuLi (94 mL, 0.15 mol)
slowly maintaining the reaction temperature between -10.degree. C.
to 0.degree. C. After the addition reaction was stirred at
0.degree. C. for 30 minutes. A solution of
(.+-.)-N,N-didemethylvenlafaxine 13 (5.4 g, 0.021 mol) in 55 mL THF
was added slowly at 0.degree. C. The reaction mixture was stirred
at 0.degree. C. for 30 minutes and allowed to warm to room
temperature and stirred at room temperature for 1 hour. It was then
refluxed overnight. After cooling the reaction mixture to room
temperature, it was poured slowly into 250 mL of 3N HCl while the
temperature was maintained below 15.degree. C. After stirring for
30 minutes, the aqueous layer was extracted with methylene chloride
(3.times.200 mL). The aqueous layer was adjusted to pH 6.8-6.9 by
slow addition of concentrated NH.sub.4OH at 15.degree. C. and was
extracted with methylene chloride (3.times.100 mL). The aqueous
layer was then evaporated to dryness to give a colorless solid.
This colorless solid was suspended in 400 mL methylene
chloride/methanol (7:3) and was stirred for 1 hour. The insolubles
were Filtered off, washed with methylene chloride/methanol (7:3).
The filtrate was evaporated off to give colorless solid. 6.0 g of
the colorless solid was chromatographed on silica gel. Elution with
methylene chloride/methanol (9:1.fwdarw.48.5:1.5) afforded the
product as a colorless solid (1.5 g,). (DMSO, d.sub.6): 8.1 (br s,
exchangeable, 1H), 6.95 and 6.75 (q, 4H), 4.6 (m, exchangeable,
2H), 3.3 (m, 1H), 2.9 (m, 2H), 1.2 (m, 10H); .sup.13C (DMSO,
d.sub.6): 156.8, 130.5, 128.5, 115.2, 72.0, 52.1, 48.6, 36.6, 33.6,
25.6, 21.7, 21.3. % Purity (HPLC): 97.4%.
5.6. Example 6
Determination of Potency and Specificity
[0085] Several methods useful for the determination of the potency
and specificity of the compounds of this invention are disclosed in
the literature. See, e.g., Haskins, J. T. et al. Euro. J.
Pharmacol. 115:139-146 (1985). Methods that have been found
particularly useful are disclosed by Muth., E. A. et al. Biochem.
Pharmacol. 35:4493-4497 (1986) and Muth, E. A. et al. Drug Develop.
Res. 23:191-199 (1991), both of which are incorporated herein by
reference.
5.6.1 Receptor Binding
[0086] Determination of receptor binding of the compounds of this
invention preferably is performed by the methods disclosed by Muth
et al., and using the protocols summarized below in Table I.
TABLE-US-00001 TABLE I Receptor Binding Protocols Ligand Specific
Incubation Molarity activity Temp. Receptor .sup.3H-Ligand (nM)
(Ci/mmol) Buffer Time (.degree. C.) Displacing agent Dopamine-2
Spiperone 0.3 20-40 * a 10 min 37.degree. 1 mM (+) butaclamol
Adrenergic WB 4101 0.5 15-30 50 mM 30 min 25.degree. 10 mM
norepinephrine Tris-HCl bitartrate pH 7.7 Muscarinic Quinuclindinyl
0.06 30-60 50 mM 1 hr 25.degree. 100 mM oxotremorine cholinergic
benzilate Tris-HCl pH 7.7 Histamine-1 Pyrilamine 2.0 <20 50 mM
30 min 25.degree. 10 mM chlorpheniramine Phosphate maleate pH 7.5
Opiate Naloxone 1.3 40-60 50 nM 30 min 0-4.degree. 2 mM morphine
Tris-HCl pH 7.4 a 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl,1 mM
CaCl.sub.2, 1 mM MgCl.sub.2, 0.1% ascorbic acid, 10 mM pargyline
HCl, pH 7.1.
The tissue homogenates used are preferably whole brain except
cerebellum (histamine-1 and opiate binding), cortex (.alpha..sub.1
adrenergic receptor binding, monoamine uptake); and striatum
(dopamine-2 and muscarinic cholinergic receptor binding).
5.6.2 Synaptosomal Uptake Studies
[0087] These studies may be performed using the modified
methodology of Wood, M. D., and Wyllie, M. G. J. Neurochem.
37:795-797 (1981) as described in Muth et al. Biochem. Pharmacol.
35:4493-4497 (1986). Briefly a P2 pellet is prepared from fresh rat
brain tissue by sucrose density gradient centrifugation using a
vertical rotor. For uptake studies, all components are dissolved in
the following buffer: 135 mM NaCl, 5 mM KCl, 1.2 mM MgCl.sub.2, 2.5
mM CaCl.sub.2, 10 mM glucose, 1 mM ascorbic acid, 20 mM Tris, pH
7.4, gassed with O.sub.2 for 30 min prior to use. Various
concentrations of test drug are preincubated with 0.1 .mu.M
[.sup.3H]dopamine or 0.1 .mu.M [.sup.3H]norepinephrine (130,000
dpm/tube) and 0.1 .mu.M [.sup.14C]serotonin (7,500 dpm/tube) in 0.9
ml buffer for 5 min at 37.degree. C. One-tenth milliliter of
synaptosomal preparation is added to each tube and incubated for a
further 4 mM at 37.degree. C. The reaction is then terminated by
the addition of 2.5 ml buffer, after which the mixture was filtered
under vacuum using cellulose acetate filters (0.45 .mu.M pore
size). The filters are then counted in a scintillation counter, and
the results are expressed as pmoles uptake/mg protein/min. The
IC.sub.50 values for uptake inhibition are calculated by linear
regression of logit [percent of Na.sup.+-dependent uptake] vs. long
[concentration of test drug].
5.6.3. Reversal of Reserpine-Induced Hypothermia
[0088] Reversal of reserpine-induced hypothermia in male CF-1 mice
(20-25 g., Charles River) may be performed according to an
adaptation of the method of Askew, B. Life Sci. 1:725-730 (1963).
Test compounds, suspended or solubilized in 0.25% Tween80.RTM. in
water, are then administered i.p. at several dose levels to male
mice (8/dose level) who had been treated 18 hr previously with 45.0
mg/kg reserpine s.c. A vehicle control group is run simultaneously
with drug groups. Test compounds, vehicle, and reserpine are
administered at a volume of 0.01 ml/g. Reserpine is solubilized by
the addition of a small amount (approximately 4 drops) of
concentrated acetic acid and then brought to the proper volume by
the addition of distilled water. Rectal temperatures are recorded
by a Yellow Springs Instruments thermistor probe at a dept of 2 cm.
Measurements are taken 18 hr after reserpine pretreatment and at
hourly intervals for 3 hr following administration of either test
compound or vehicle.
[0089] Rectal temperatures for all time periods are subjected to a
two-way analysis of variance for repeated measures with subsequent
Dunnett's comparison to control values to determine the minimum
effective dose (MED) for antagonizing reserpine-induced
hypothermia.
5.6.4. Induction of Rat Pineal Noradrenergic Subsensitivity
[0090] Suitable rats are male Sprague-Dawley rats (250-300 g,
Charles River) which should be maintained in continuous light
throughout all experiments so as to attenuate the diurnal
fluctuation in beta-adrenergic receptor density in the pineal gland
and to maintain a consistent supersensitive response to
noradrenergic agonists. Moyer, J. A. et al. Soc. Neurosci. Abstract
10:261 (1984). After 2 days of continuous light exposure, the rats
are then injected twice daily with either saline or test compound
(10 mg/kg i.p.) for 5 days (total of 9 injections). Another group
of rats should receive saline injections twice daily for 4 days
followed by a single injection of test compound (10 mg/kg i.p.) on
the 5th day. One hour following the final injection of test
compound or saline, animals are administered either 0.1% ascorbic
acid (controls), or isoproterenol (2 .mu.mol/kg i.p. in 0.1%
ascorbic acid). Rats are decapitated 2.5 minutes later, the time at
which preliminary experiments have shown that the
isoproterenol-induced increases in cyclic AMP levels in pineal
glands are maximal. Moyer, J. A. et al. Mol. Pharmacol. 19:187-193
(1981). Pineal glands are removed and frozen on dry ice within 30
seconds to minimize any post-decapitation increase in cAMP
concentration.
[0091] Prior to radioimmunoassay for cAMP, the pineal glands are
placed in 1 ml of ice-cold 2.5% perchloric acid and sonicated for
approximately 15 seconds. The sonicate is then centrifuged at
49.000 g for 15 min at 4.degree. C. and then resulting supernatant
fluid is removed, neutralized with excess CaCO.sub.3, and
centrifuged at 12,000 g for 10 min at 4.degree. C. The cAMP content
of the neutralized extract may be measured by a standard
radioimmunoassay using .sup.125I-labeled antigen and antiserum (New
England Nuclear Corp., Boston, Mass.). Steiner, A. L. et al. J.
Biol. Chem. 247:1106-1113 (1972). All unknown samples should be
assayed in duplicate and compared to standard solutions of cAMP
prepared in a 2.5% perchloric acid solution that had been
neutralized with CaCO.sub.3. Results are expressed as pmol
cAMP/pineal, and statistical analyses are performed by analysis of
variance with subsequent Student-Newman-Keuls tests.
5.6.5. Single Unit Electrophysiology
[0092] The firing rates of individual neurons of the locus
coeruleus (LC) or dorsal raphe nucleus (DR) in the chloral-hydrate
anesthetized rat are measured using single-barreled glass
micro-electrodes as previously described for the LC. Haskins, J. T.
et al. Eur. J. Pharmacol. 115:139-146 (1985). Using the stereotaxic
orientation of Konig, J. F. R., and Klippel, R. A. The rat brain: A
stereotaxic atlas of the forebrain and lower parts of the brain
stem Baltimore: Williams and Wilkins (1963), the electrode tips
should be lowered via a hydraulic microdrive from a point 1.00 mm
above the locus coeruleus (AP 2.00 mm caudal to the interaural line
and 1.03 mm lateral to midline). Drugs are administered i.v.
through a lateral tail vein cannula. Only one cell should be
studied in each rat in order to avoid residual drug effects.
5.7. Example 7
Oral Formulation
[0093] The pharmaceutical compositions of this invention may be
administered in a variety of ways. Oral formulations are of the
easiest to administer.
5.7.1. Hard Gelatin Capsule Dosage Forms
[0094] Table II provides the ingredients of suitable capsule forms
of the pharmaceutical compositions of this invention.
TABLE-US-00002 TABLE II Component 25 mg capsule 50 mg capsule 100
mg capsule (.+-.)-O-desmethyl- 25 50 100 venlafaxine
Microcrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized Starch
100.3 97.8 82.8 Croscarmellose 7.0 7.0 7.0 Magnesium Stearate 0.2
0.2 0.2
[0095] The active ingredient (venlafaxine derivative) is sieved and
blended with the excipients listed. The mixture is filled into
suitably sized two-piece hard gelatin capsules using suitable
machinery and methods well known in the art. See Remington's
Pharmaceutical Sciences, 16th or 18th Editions, each incorporated
herein in its entirety by reference thereto. Other doses may be
prepared by altering the fill weight and, if necessary, by changing
the capsule size to suit. Any of the stable hard gelatin capsule
formulations above may be formed.
5.7.2. Compressed Tablet Dosage Forms
[0096] The ingredients of compressed tablet forms of the
pharmaceutical compositions of the invention are provided in Table
III.
TABLE-US-00003 TABLE III Compressed Tablet Unit Dosage Forms
Component 25 mg capsule 50 mg capsule 100 mg capsule
(.+-.)-O-desmethyl- 25 50 100 venlafaxine Microcrystalline 90.0
90.0 90.0 Cellulose Pre-gelatinized Starch 100.3 97.8 82.8
Croscarmellose 7.0 7.0 7.0 Magnesium Stearate 0.2 0.2 0.2
[0097] The active ingredient is sieved through a suitable sieve and
blended with the excipients until a uniform blend is formed. The
dry blend is screened and blended with the magnesium stearate. The
resulting powder blend is then compressed into tablets of desired
shape and size. Tablets of other strengths may be prepared by
altering the ratio of the active ingredient to the excipient(s) or
modifying the table weight.
[0098] While the invention has been described with respect to the
particular embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made without
departing from the spirit and scope of the invention as defined in
the claims. Such modifications are also intended to fall within the
scope of the appended claims.
* * * * *