Monoamine reuptake inhibitors for treatment of CNS disorders

Details Monoamine reuptake inhibitors for treatment of CNS disorders Monoamine reuptake inhibitors for treatment of CNS disorders

2001-04-30

2004-01-13

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S336000

Reexamination Certificate

active

06677378

ABSTRACT:

BACKGROUND OF THE INVENTION
Serotonin Selective Reuptake Inhibitors (SSRIs) currently provide efficacy in the treatment of major depressive disorder (MDD) and are generally perceived by psychiatrists and primary care physicians as effective, well-tolerated and easily administered. However, they are associated with undesirable features, such as high incidence of sexual dysfunction, delayed onset of action and a level on non-responsiveness estimated to be as high as 30% (see M. J. Gitlin, Journal of Clinical Psychiatry, 1994, 55, 406-413 and R. T. Segraves, Journal of Clinical Psychiatry, 1992, 10(2), 4-10). Preclinical and clinical evidence has indicated that the sexual dysfunction associated with SSRI therapy can be reduced through the use of dopamine reuptake inhibitors (DRIs), such as bupropion (see A. K. Ashton, Journal of Clinical Psychiatry, 1998, 59(3), 112-115). Furthermore, the combination of SRI and DRI may hasten the onset of action as well as offering relief to refractory patients, possibly through a synergistic mechanism (see R. D. Marshall et al, Journal of Psychopharmacology, 1995, 9(3), 284-286).
This invention relates to novel biaryl ether derivatives that exhibit activity as monoamine (e.g., dopamine, serotonin) reuptake inhibitors, to pharmaceutical compositions containing such compounds and to methods of using such compounds to treat central nervous system (CNS) and other disorders.
U.S. Pat. No. 4,018,830, published on Apr. 19, 1997, refers to phenylthioaralkylamines and 2-phenylthiobenzylamines which are active as antiarrhythmics.
PCT publication 97/17325, published on May 15, 1997, refers to derivatives of N,N-dimethyl-2-(arylthio)benzylamine which selectively influence serotonin transport in the central nervous system and are useful as antidepressants.
U.S. Pat. No. 5,190,965, published on Mar. 2, 1993, and U.S. Pat. No. 5,430,063, issued Jul. 4, 1995, refer to phenoxyphenyl derivatives which have utility in the treatment of depression.
U.S. Pat. No. 4,161,529, published on Jul. 17, 1979, refers to pyrrolidine derivative which possess anticholesteremic and hypolipemic activity.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein phenyl ring A and phenyl ring B can each, independently, be replaced by a naphthyl group, and wherein when phenyl ring A is replaced by a naphthyl group, the ethereal oxygen of structure I and the carbon to which R
3
, R
4
and NR
1
R
2
are attached, are attached to adjacent ring carbon atoms of the naphthyl group and neither of said adjacent ring carbon atoms is also adjacent to a fused ring carbon atom of said naphthyl group;
n and m are, selected, independently, from one, two and three;
R
1
and R
2
are selected, independently, from hydrogen, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, and (C
2
-C
4
)alkynyl, or R
1
and R
2
, together with the nitrogen to which they are attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R
1
and R
2
are attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C
1
-C
6
)alkyl;
R
3
and R
4
are selected, independently, from hydrogen and (C
1
-C
4
)alkyl optionally substituted with from one to three fluorine atoms, or R
3
and R
4
together with the carbon to which they are attached, form a four to eight membered saturated carbocyclic ring, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C
1
-C
6
)alkyl;
or R
2
and R
3
, together with the nitrogen to which R
2
is attached and the carbon to which R
3
is attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R
2
is attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C
1
-C
6
)alkyl;
each X is selected, independently, from hydrogen, halo (i.e., chloro, fluoro, bromo or iodo), (C
1
-C
4
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
4
)alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, amino, (C
1
-C
4
)alkylamino, di-[(C
1
-C
4
)alkyl]amino, NR
5
(C═O)(C
1
-C
4
)alkyl, SO
2
NR
5
R
6
and SO
p
(C
1
-C
6
)alkyl, wherein R
5
and R
6
are selected, independently, from hydrogen and (C
1
-C
6
)alkyl, and p is zero, one or two; and
each Y is selected, independently, from hydrogen, (C
1
-C
6
)alkyl and halo;
with the proviso that: (a) no more than one of NR
1
R
2
, CR
3
R
4
and R
2
NCR
3
can form a ring; and (b) at least one X must be other than hydrogen when (i) R
3
and R
4
are both hydrogen, (ii) R
1
and R
2
are selected, independently, from hydrogen and (C
1
-C
4
)alkyl, and (iii) ring B is mono- or disubstituted with, respectively, one or two halo groups;
and the pharmaceutically acceptable salts thereof.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from hypertension, depression (e.g, depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (eg., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such disorder or condition and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, preferably a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier. Examples of such disorders and conditions are those enumerated in the preceding paragraph.
The present invention also relates to a method for treating a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse ind

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