WO2007036781A1

WO2007036781A1 - Diphenyl ether monoamine reuptake inhibitor

Info

Publication number: WO2007036781A1
Application number: PCT/IB2006/002650
Authority: WO
Inventors: Harry Ralph Howard, Jr.
Original assignee: Pfizer Products Inc.
Priority date: 2005-09-30
Filing date: 2006-09-18
Publication date: 2007-04-05

Abstract

The present invention relates to a compound of the formula (I) wherein R1 is hydrogen or C1-C6 alkyl; X and Y are independently selected from the group consisting of fluoro, chloro and bromo; its enantiomers, racemate and mixtures of enantiomers and the pharmaceutically acceptable salts thereof, which exhibit activity as serotonin, norepinephrine and dopamine reuptake inhibitors, and are therefore useful in the treatment of central nervous system and other disorders.

Description

DIPHENYL ETHER MONOAMINE REUPTAKE INHIBITOR 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 Psvchopharmacologv. 1995, 9(3), 284-286). This invention relates to a novel biaryl ether derivative that exhibits activity as a monoamine (e.g.. serotonin, dopamine, norepinephrine) reuptake inhibitor, to pharmaceutical compositions containing this compound and to methods of using this compound to treat central nervous system (CNS) and other disorders.

The present invention specifically relates to 1-[2-(3,4-dichlorophenoxy)-5-fluorophenyl]- ethylamine and its enantiomers and pharmaceutically acceptable salts thereof, to processes for their preparation, to pharmaceutical compositions comprising them and to their medicinal use.

More particularly, these compounds are selective inhibitors of the monoamine reuptake transporters. The racemic and enantiomeric compounds of the invention are useful in treating depression, obsessive-compulsive disorder (OCD) and other diseases, disorders or conditions for which an selective inhibitor of monoamine reuptake transporters is therapeutically indicated.

United States Patent No. 4,018,830 refers to phenylthioaralkylamines and 2- phenylthiobenzylamines which are active as antiarrhythmics.

PCT Publication WO97/17325, published on May 15, 1997, refers to derivatives of N₁N- dimethyl-2-(arylthio)benzylamine which selectively influence serotonin transport in the central nervous system and are useful as antidepressants.

United States Patent No. 5,190,965 and United States Patent No. 5,430,063 refer to phenoxyphenyl derivatives which have utility in the treatment of depression.

United States Patent No. 4,161,529 refers to pyrrolidine derivatives which possess anticholesteremic and hypolipemic activity. Summary of the Invention

The present invention relates to a compound of the formula -Z-

wherein Ri is hydrogen or C₁-C₆ alkyl; X and Y are independently selected from the group consisting of fluoro, chloro and bromo; and, the pharmaceutically acceptable salts thereof. In one embodiment, the invention relates to the compound, wherein X and Y are different, and R is methyl or ethyl. In another embodiment, the invention relates to an enantiomer of the compound above selected from the (+) enantiomer of the compound having the S configuration at the benzylic carbon, the (-) enantiomer of the compound having the R configuration at the benzylic carbon, and pharmaceutically acceptable salts thereof.

The present invention also relates to a compound of the formula

and pharmaceutically acceptable salts thereof. The (+) enantiomer which has the S configuration at the benzylic carbon, and the pharmaceutically acceptable salts thereof, is preferred

In addition, the present invention relates to a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight. In addition, the present invention relates to mixtures of the (+)-(S) enantiomer of the compound of formula I with its (-)-(R) antipode, wherein the ratio of (+)-(S)- to (-)-(R)-enantiomers is about 2:1. More preferred is a mixture wherein the ratio of (+)-(S)- to (-)-(R)-enantiomers is about of 5:1. Most preferred is the mixture wherein the ratio of (+)-(S)- to (-)-(R)-enantiomers is about 99:1.

The present invention also relates to racemic mixtures of the compound of formula I. Further, the present invention relates to a process for the preparation of a compound of formula I comprising:

Treating a compound of the formula

wherein formula Il represents both syn and anti stereochemical configurations of said imine and any mixture thereof, with a reducing agent, either in-situ during the preparation of said imine of formula III or in a separate step after isolation.

In another aspect of the invention, the imine of formula II, wherein formula Il represents both syn and anti stereochemical configurations of said imine and any mixture thereof, is prepared by treating the compound of the formula

with ammonia. In yet another aspect of the invention the compound of formula III is prepared by treating the compound of formula

IV

with the compound of formula

V

in the presence of base. In a further aspect, the present invention relates to the resolution of a racemic mixture of the compound of formula I into its (+) and (-) enantiomers.

The present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from hypertension, depression

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 (e.g.. 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 the aforementioned disorders or conditions comprising an amount of the (+)-(S) enantiomer of the compound of formula I or an amount of the (-)-(R) enantiomer of the compound of formula I or an amount of a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof effective in treating such disorder or condition and a pharmaceutically acceptable carrier. In a preferred embodiment, the present invention relates to the (+)-(S) enantiomer of the compound of formula I.

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 above.

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 the (+)-(S) enantiomer of the compound of formula I or an amount of the (-)-(R) enantiomer of the compound of formula I or an amount of a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, 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 above.

The present invention also relates to a method for treating a disorder or condition selected from hypertension, depression (e^, 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 (ex[., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g.. 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 (ag.., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (O-i, 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 administering to a mammal in need of such treatment an amount of a compound of the formula I, or an amount of the (+)-(S) enantiomer of the compound of formula I or an amount of the (-)-(R) enantiomer of the compound of formula I or an amount of a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition. The present invention also relates to a method 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 administering to a mammal in need of such treatment an amount of a compound of the formula I, or an amount of the (+)-(S) enantiomer of the compound of formula I or an amount of the (-)-(R) enantiomer of the compound of formula I or an amount of a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.

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 (e.g.. 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 a serotonin, dopamine or norepinephrine reuptake inhibiting effective amount of a compound selected from the compound of formula I, the (+)-(S) enantiomer of the compound of formula I, the (-)-(R) enantiomer of the compound of formula I or a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof, 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, norepinephrine or dopamine in a mammal, preferably a human, comprising serotonin, dopamine or norepinephrine reuptake inhibiting effective amount of a compound selected from the compound of formula I, the (+)-(S) enantiomer of the compound of formula I₁ the (-)-(R) enantiomer of the compound of formula I or a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 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 induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (e^g., premature ejaculation), eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (ej^, addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e^L, 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 administering to a mammal requiring such treatment a serotonin, dopamine or norepinephrine reuptake inhibiting effective amount of a compound selected from the compound of formula I, the (+)-(S) enantiomer of the compound of formula I, the (-)-(R) enantiomer of the compound of formula I or a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, norepinephrine or dopamine in a mammal, preferably a human, comprising administering to a mammal requiring such treatment a serotonin, dopamine or norepinephrine reuptake inhibiting effective amount of a compound selected from the compound of formula I, the (+)-(S) enantiomer of the compound of formula I, the (-)-(R) enantiomer of the compound of formula I or a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight,, or a pharmaceutically acceptable salt thereof.

The present invention relates to a pharmaceutical composition for treating a condition or disorder that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, preferably a human, comprising: a) a pharmaceutically acceptable carrier; b) an amount of compound selected from the compound of formula I, the (+)-(S) enantiomer of the compound of formula I, the (-)-(R) enantiomer of the compound of formula I or a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof; and c) an amount of a NK-1 receptor antagonist or a 5HT_1B receptor antagonist, or a pharmaceutically acceptable salt thereof, where the 5HT_1B receptor antagonist is selected from elzasonan and benzyl(idene)-!actams of the formula I

wherein R¹ is a group of the formula G¹ or G² depicted below,

_G1 G2 a is zero to eight; m is one to three;

R⁶ is selected from the group consisting of hydrogen, (Ci-C₆)alkyl optionally substituted with (Ci-C₆)alkoxy or one to three fluorine atoms, or ((C_rC₄)alkyl)aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_q-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C_rC₆)alkyl, (Ci-C₆)alkoxy, trifluoromethyl, cyano and -SO_t(Ci-C₆)alkyl, wherein t is zero, one or two; each R¹³ is, independently, (C₁-C₄)SlRyI or a (C₁-C₄)alkylene bridge from one of the ring carbons of the piperazine or piperidine ring of G¹ or G², respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G¹ or G², respectively, having an available bonding site, or to a ring carbon of R⁶, when R⁶ has a ring structure having an available bonding site;

X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C₁-C₆)alkyl, hydroxy, (CrC₆)alkoxy, -SOt(C_rC₆)alkyl wherein t is zero, one or two, -CO₂R¹⁰ or -CONR¹¹R¹²; each of R¹⁰, R¹¹ and R¹² is selected, independently, from hydrogen, (C<ι-C₄)alkyl, phenyl and naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (Ci-C₃)alkyl, (C₁-C₆JaIkOXy, trifluoromethyl, cyano and -SOt(C₁ -C₆)alkyl wherein t is zero, one or two; or R¹¹ and R¹², together with the nitrogen to which they are attached, form a 5- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;

R³ is vinyl, C(=O)R, wherein R is C₁-C₈ straight chain or branched alkyl, C₃-C₈ cycloalkyl, or aryl, wherein R is preferably terf-butyl, or,

R³ is -(CH₂)_gB, wherein g is zero to three and B is hydrogen, phenyl, naphthyl or a 5- to 6- membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein each of the foregoing phenyl, naphthyl and heteroaryl rings may optionally be substituted with one to three substituents independently selected from (Ci- C₈)hydroxyalkyl-, (C₁-C₈)alkoxy-(C₁-C₈)alkyl-, (C₃-C₈)hydroxycycloalkyl-, (C₃-C₈)CyClOaIkOXy-, (C₁- C₈)alkoxy-(C₃-C₈)cycloalkyl-, heterocycloalkyl, hydroxyheterocycloalkyl, and (Ci-C₈)alkoxy- heterocycloalkyl, wherein each (C₃-C₈)cycloalkyl or heterocycloalkyl moiety may be independently substituted with from one to three (CrCβJalkyl or benzyl groups; when B is a phenyl, naphthyl or heteroaryl ring, each said ring may be optionally substituted with one to three substituents independently selected from phenyl, naphthyl and a 5- to 6-membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, with the proviso that said heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from one to three (C_rC₈)alkyl or C₃-C₈ cycloalkyl substituents, wherein examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, ^

dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl; or, when B is a phenyl, naphthyl or heteroaryl ring, each said ring may be optionally substituted with one to three substituents independently selected from (a) lactone formed from -(CH₂)_tOH with an ortho -COOH₁ wherein t is one, two or three; (b) -CONR¹⁴R¹⁵, wherein R¹⁴ and R¹⁵ are independently selected from (C-rCβ)alkyl and benzyl, or R¹⁴ and R¹⁵ together with the nitrogen to which they are attached form a 5- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the

-CONR¹⁴R¹⁵ group, wherein when any of said heteroatoms is nitrogen it may be optionally substituted with (C_rC₈)alkyl or benzyl, with the proviso that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; (c) -(CH₂)_VNCOR¹⁶R¹⁷ wherein v is zero, one, two or three and -COR^1S and R¹⁷ taken together with the nitrogen to which they are attached form a 4- to

6-membered lactam ring; and, (d) ~(C1-C8)NR¹⁸R¹⁹ where each of R¹⁸ and R¹⁹ is selected, independently, from hydrogen and (Ci-C₄)alkyl, or R¹⁸ and R¹⁹, together with the nitrogen to which they are attached, form a 4- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; wherein the broken lines indicate optional double bonds; and, n is one, two, or three; or, a pharmaceutically acceptable salt or optical isomer thereof; wherein the amount of b) and the amount of c) are such that the combination of b) and c) is effective in treating such disorder or condition.

The present invention also relates to a method 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 administering to a mammal requiring such treatment: a) an amount of compound selected from the compound of formula I, the (+)-(S) enantiomer of the compound of formula I, the (-)-(R) enantiomer of the compound of formula I or a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof; and b) an amount of a NK- 1 receptor antagonist or a 5HT_1B receptor antagonist, or a pharmaceutically acceptable salt thereof; wherein the amount of a) and the amount of b) are such that the combination of a) and b) is effective in treating such disorder or condition.

This invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleic acid, di-p-toluoyl tartaric acid, acetic acid, sulfuric acid, hydroiodic acid and mandelic acid. The term "treatment", when used herein in reference to a disorder or condition, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition or one or more symptoms of such condition or disorder to which such term refers. The term "treating", when used herein in reference to a disorder or condition, refers to the act of administering a "treatment" as "treatment" is defined immediately above.

The invention includes all enantiomers, and other stereoisomers of the compounds of formula I, as well as racemic and other mixtures thereof.

The present invention also relates to all radiolabeled forms of the compounds of the formula I. Preferred radiolabeled compounds of formula I are those wherein the radiolabels are selected from as ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I. Such radiolabeled compounds are useful as research and diagnostic tools in metabolism pharmacokinetics studies and in binding assays in both animals and man.

"Chemical dependency," as used herein, means an abnormal craving or desire for, or an addiction to a drug. Such drugs are generally administered to the affected individual by any of a variety of means of administration, including oral, parenteral, nasal or by inhalation. Examples of chemical dependencies treatable by the methods of the present invention are dependencies on alcohol, nicotine, cocaine, heroin, phenolbarbitol, and benzodiazepines (e.g., Valium™). "Treating a chemical dependency," as used herein, means reducing or alleviating such dependency. Detailed Description of the Invention

The compound of the formula I may be prepared according to Scheme 1 and the following discussion.

Scheme 1 refers to the preparation of the compound of formula I from the compounds of formulas IV and V. Compounds of formulas IV and V are commercially available or can be made by methods well known to those of ordinary skill in the art.

In step 1 of Scheme 1 the compound of formula III is prepared by treating the compound of formula IV with the phenol of the formula V in the presence of a base. Compound HI may also be prepared from compounds related to compound IV wherein the fluorine substituent ortho to the carbonyl is replaced with another suitable leaving group such as chloro, nitro or triflate. This reaction is generally carried out at a temperature from about 0⁰C to about 15O⁰C for about 1 hour to about 7 days, preferably at about 90-95⁰C for about 5 days, in a polar solvent such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or N-methyl-2- pyrrolidinone (NMP), preferably DMF. Suitable bases include anhydrous sodium carbonate (Na₂CO₃), potassium carbonate (K₂CO₃), sodium hydroxide (NaOH), potassium hydroxide (KOH) and organic amines such as pyrrolidine, triethylamine and pyridine, with anhydrous K₂CO₃ being preferred. Details for conducting this procedure can be found in G. W. Yeager et aL, Synthesis. 1995, 28-30; J. R. Dimmock et al. Journal of Medicinal Chemistry. 1996, 39(20), 3984-3997.

In step 2 the compound of formula Il is prepared by treating the compound of formula 111 with ammonia preferably in the presence of a dehydrating reagent such as titanium (IV) tetrachloride or titanium (IV) isopropoxide, at about 20⁰C to about 25⁰C, for about 1 hour to about 72 hours, preferably about 16 hours to about 48 hours, in a solvent such as benzene, toluene, ethanol methanol or a like solvent, preferably a polar solvent if the subsequent reduction is to be conducted in-situ, until the reaction is judged to be complete, according to the procedure of S. Bhattarcharyya (Journal of Organic Chemistry, 1995, 60(15), 4928-4929). Alternatively, the compound of formula III and ammonia can be combined in an inert solvent such as benzene or toluene, in the presence or absence of a water scavenger such as molecular sieves, and heated to eliminate water generated during the formation of the intermediate of formula II. The extent of the conversion of the compound of formula III into the imine of formula Il can be assessed using one or more known analytical techniques, including ¹H-NMR spectroscopy.

The imine of formula Il may be isolated and then reduced in step 3 to the compound of formula I or, preferably, step 3 may be conducted in-situ with a reducing agent selective for the reduction of the imine to the compound of formula I. Such reducing agents are widely known to those skilled in the art and include, for example, sodium borohydride (NaBH₄), sodium cyanoborohydride (NaBH₃CN) and sodium triacetoxy-borohydride (NaBH(OAc)₃, as described by A. F. Abdel-Magid et aL in Tetrahedron Letters, 1990, 31. 5595). For the instant reduction NaBH₄ is preferred. This reduction is generally carried out in a polar solvent such as methanol, ethanol, isopropanol or a like solvent, and at temperatures of about 0⁰C to about 100⁰C₁ preferably at about 20⁰C to about 25⁰C, for about 0.5 hour to about 24 hours, preferably about 1 hour to about 16 hours. In the procedure described by Bhattarcharyya, the intermediate of formula Il is formed in an ethanol solvent and, without isolation, is reduced to the product of formula I using NaBH₄.

SCHEME 1

NH,

The compound of formula I may be separated into its individual enantiomers by methods known to those skilled in the art such as treatment with an optically active acid to form salts of differing solubility or preferably separation by elution from a chiral chromatographic medium.

Pharmaceutically acceptable salts of a compound of formula I can be prepared in a conventional manner by treating a solution or suspension of the corresponding free base with one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration or crystallization techniques can be employed to isolate the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic, and related acids.

A compound of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.

The pharmaceutical compositions formed by combining a compound of formula I or a pharmaceutically acceptable salt thereof can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions containing a compound of this invention or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

A compound of formula I or a pharmaceutically acceptable salt thereof can be administered orally, transdermal^ (e.g., through the use of a patch), parenterally (e.g. intravenously or rectally) or topically. In general, the daily dosage for treating a disorder or condition according to the methods described above will generally range from about 0.01 to about 10.0 mg/kg body weight of the patient to be treated. As an example, a compound of the formula I or a pharmaceutically acceptable salt thereof can be administered for treatment of, for example, depression to an adult human of average weight (about 70kg) in a dose ranging from about 0.7 mg up to about 700 mg per day, preferably from about 1 mg to about 500 mg per day, in single or divided (i.e., multiple) portions. Variations based on the aforementioned dosage ranges may be made by a physician of ordinary skill taking into account known considerations such as the weight, age, and condition of the person being treated, the severity of the affliction, and the particular route of administration chosen. BIOLOGICAL ASSAY

The in vitro activity of the compounds of the present invention at the individual monoamine reuptake sites can be determined using rat synaptosomes or HEK-293 cells transfected with the human serotonin, dopamine or norepinephrine transporter, according to the following procedure adapted from those described by S. Snyder et aL, (Molecular Pharmacology, 1971 , 7, 66-80), D.T. Wong et aL, (Biochemical Pharmacology. 1973, 22, 311-322), H. F. Bradford (Journal of Neurochemistrv. 1969, 16, 675-684) and D. J. K. Balfour (European Journal of Pharmacology. 1973, 23, 19-26).

Synaptosomes: Male Sprague Dawley rats are decapitated and the brains rapidly removed. The cortex, hippocampi and corpus striata are dissected out and placed in ice cold sucrose buffer, 1 gram in 20 ml of buffer (the buffer is prepared using 320 mM sucrose containing 1mg/ml glucose, 0.1mM ethylenediamine tetraacetic acid (EDTA) adjusted to pH 7.4 with tris(hydroxymethyl)-arninomethane (TRIS) base). The tissues are homogenized in a glass homogenizing tube with a Teflon™ pestle at 350 rpm using a Potters homogenizer. The homogenate is centrifuged at 1000 x g for 10 min. at 4°C. The resulting supernatant is recentrifuged at 17,000 x g for 20 min. at 4⁰C. The final pellet is resuspended in an appropriate volume of sucrose buffer that yielded less than 10% uptake.

Cell Preparation: HEK-293 cells transfected with the human serotonin (5-HT), norepinephrine (NE) or dopamine (DA) transporter are grown in DMEM (Dulbecco's Modified Eagle Medium, Life Technologies Inc., 9800 Medical Center Dr., Gaithersburg, MD, catalog no. 11995-065)) supplemented with 10% dialyzed FBS (Fetal Bovine Serum, from Life Technologies, catalog no. 26300-053), 2 mM L-glutamine and 250 ug/ml G418 for the 5-HT and NE transporter or 2ug/ml puromycin for the DA transporter, for selection pressure. The cells are grown in Gibco triple flasks, harvested with Phosphate Buffered Saline (Life Technologies, catalog no. 14190- 136) and diluted to an appropriate amount to yield less than 10% uptake.

Neurotransmitter Uptake Assay: The uptake assays are conducted in glass tubes containing 50 uL of solvent, inhibitor or 1OuM sertraline, desipramine or nomifensine for the 5-HT, NE or DA assay nonspecific uptake, respectively. Each tube contains 400 uL of [3H]5-HT (5 nM final), [3H]NE (10 nM final) or [3H]DA (5 nM final) made up in modified Krebs solution containing 100 uM pargyline and glucose (1mg/ml). The tubes are placed on ice and 50 uL of synaptosomes or cells is added to each tube. The tubes are then incubated at 37° C for 7 min. (5-HT, DA) or 10 min. (NE). The incubation is terminated by filtration (GF/B filters), using a 96-well Brandel Cell Harvester, the filters are washed with modified Krebs buffer and counted using either a Wallac Model 1214 or Wallac Beta Plate Model 1205 scintillation counter. The following IC50 values were obtained for serotonin, dopamine and norepinephrine reuptake inhibition, respectively, using rat synaptosomes: racemic compound of formula I (3.3 nM, 5.3 nM, 7.5 nM), (-)-R isomer (225 nM, 3.2 nM, 3.2 nM) and (+)-S isomer (2.3 nM, 40.5 nM, 22.9 nM).

EXAMPLES PREPARATION 1

2-(3.4-DICHLOROPHENOXY)-S-FLUORO-ACETOPHENONE

Under N₂ in a 125 mL round-bottomed flask fitted with a reflux condenser and magnetic stirrer were placed 10.6 g (76.8 mmol) of K₂CO₃ and 5.0 g (30.74 mmol) of 3,4-dichlorophenol (Aldrich Chem. Co., Milwaukee, Wl) in 30 mL of anhydrous N,N-dimethylformamide (DMF). After stirring the mixture for 5 minutes, 4.0 g (25.6 mmol) of 2,5-difluoro-acetophenone (Aldrich) was added and the mixture was heated to 90-95⁰C. After heating for five days the reaction was allowed to cool to room temperature. The mixture was diluted with water and ethyl acetate, the aqueous layer was extracted with additional ethyl acetate and the organic layers were combined, washed with H₂O and saturated NaCI and dried over MgSO₄. Removal of the solvent in vacuo gave a black tar residue. This was partitioned between methylene chloride and 2N aqueous NaOH. The organic layer was separated and washed with water and saturated aqueous NaCI, dried over MgSO₄ and concentrated to 5.09 g of a black residue. The crude product was flash chromatographed (150 X 40 mm silica gel column), eluting with methylene chloride: hexanes (20:80). Fractions containing the product were concentrated in vacuo to give a light yellow solid, 3.29 g (43%), m.p. 90-91⁰C.

¹H-NMR (CDCI₃, 400 MHz): 57.54 (dd, 1H), 7.40 (d 1H), 7.19 (m, 1H), 7.05 (d, 1 H), 6.94 (dd, 1 H), 6.80 (dd, 1 H), 2.56 (s, 3H). Mass spectrum (GCMS, m/z): 298 (m⁺).

EXAMPLE 1

1-[2-(3.4-DICHLOROPHENOXYi-S-FLUOROPHENYLI-ETHYLAMINE A suspension of 6.0 g (0.02 mol) of 2-(3,4-dichlorophenoxy)-5-fluoroacetophenone and 100 mL of methanol in a 250-mL round-bottomed flask was stirred with a magnetic stirrer under a N₂ atmosphere at room temperature while adding 40 mL of 7N ammonia in methanol (Aldrich). After stirring overnight, 8.9 mL (0.03 mol) of titanium isopropoxide (Aldrich) was added dropwise and stirring was continued a further 24 hours at room temperature to give a clear orange solution. The solution was cooled in an ice bath and 1.13 g (0.03 mol) NaBH₄ was added over a 20 minute period and the mixture again stirred overnight at room temperature. Thin layer chromatography (tic) (95% CHCI3: 5% CH30H) showed only a new, more polar spot at Rf 0.15. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. The aqueous pH was adjusted to less than 4 by addition of 6N HCI. After an additional sixty minutes, the pH was readjusted to greater than 9 with 1 N NaOH. The organic layer was removed, the aqueous layer extracted twice with 50 mL portions of methylene chloride and all layers were combined, washed with water, followed by saturated aqueous NaCl and dried over MgSO₄. The solvent was removed in vacuo to give an amber-colored oil, 5.2 g.

1 H-NMR (CDCI₃, 400 MHz): δ 7.31 (d, 1H), 7.23 (m, 1H), 6.97-6.71 (m, 4H), 4.27 (m, 1 H), 1.85 (s, 2H). 1.30 (d, 3H).

Mass spectrum (m/z): 304, 302, 300 (m⁺¹). EXAMPLE 2

1+) and M 1-[2-(3.4-DICHLOROPHENOXY)-S-FLUOROPHENYLI-ETHYLAMINE

HYDROCHLORIDE

The above racemic material (5.1 g) was separated into its individual enantiomers on a Chiralpak AD column, 10 X 50 cm, eluting with heptanes:ethanol (98:2) at a flow rate of 275 mL/min (N₂ positive pressure).

Enantiomer 1 , eluting at 7.67 min, was isolated as an amber oil, 2.11 g, with 97.4% e.e. Enantiomer 2, eluting at 8.76 min, was isolated as an amber oil, 1.89 g, with 96.5% e.e.

EXAMPLE 3 (+) and (-) 1 -[2-(3.4-DICHLOROPHENOXYVS-FLUOROPHENYU-ETHYLAMINE

HYDROCHLORIDE

Enantiomer 1 was dissolved in 30 mL ethyl ether, treated with 7.0 mL (7.0 mmol) of 1.0 M HCI in ethyl ether (Aldrich) and left to stand at room temperature. After 24 hours, the hydrochloride salt was filtered, washed with ethyl ether and then dried in vacuo at 45° C to produce 1.539 g white needles; m.p. 142-144°C. Elemental analysis calculated for C₁₄H₁₂CI₂FNO-HCI: C, 49.95, H, 3.89, N, 4.16. Found: C₁ 49.82, H, 3.85, N, 4.14. Optical rotation: [a]²⁵ _D = +9.09° (c=1.05, CH₃OH). Based upon single crystal X-ray analysis, this enantiomer was assigned the S-configuration. Enantiomer 2 was dissolved in 30 mL ethyl ether, treated with 6.3 mL (6.3 mmol) of 1.0 M

HCI in ethyl ether (Aldrich) and left to stand at room temperature. After 24 hours, the hydrochloride salt was filtered, washed with ethyl ether and then dried in vacuo at 45⁰C to produce 1.075 g white needles; m.p. 142-144° C. Elemental analysis calculated for C₁₄H₁₂CI₂FNO-HCI: C, 49.95, H, 3.89, N, 4.16. Found: C, 49.82, H, 3.94, N, 4.09.

Claims

CLAIMSWhat is Claimed is:

1. A compound of the formula

wherein R₁ is hydrogen or C₁-C₆ alkyl; X and Y are independently selected from the group consisting of fluoro, chloro and bromo; and, the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein X and Y are different, and R is methyl or ethyl.

3. An enantiomer of the compound of claim 1 selected from the (+) enantiomer of said compound having the S configuration at the benzylic carbon, the (-) enantiomer of said compound having the R configuration at the benzylic carbon, and pharmaceutically acceptable salts thereof.

4. The compound of claim 1 having the formula

and the pharmaceutically acceptable salts thereof.

5. An enantiomer of the compound of formula I selected from the (+) enantiomer of the compound of formula I having the S configuration at the benzylic carbon, the (-) enantiomer of the compound of formula I having the R configuration at the benzylic carbon, and pharmaceutically acceptable salts thereof.

6. A mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight and the pharmaceutically acceptable salts thereof.

7. A racemic mixture of the compound of formula I and the pharmaceutically acceptable salts thereof.

8. 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 according to claim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 10 comprising an amount of the compound of formula I selected from the (+)-(S) enantiomer of the compound of formula I, the (-)-(R) enantiomer of the compound of formula I or an amount of a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof effective in treating such disorder or condition and a pharmaceutically acceptable carrier.

10. A method for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1 , or an enantiomer of the compound of formula I having the formula

selected from the (+) enantiomer of the compound of formula I having the S configuration at the benzylic carbon, the (-) enantiomer of the compound of formula I having the R configuration at the benzylic carbon, and pharmaceutically acceptable salts thereof, that is effective in treating such disorder or condition.

11. The method of claim 14 wherein the compound administered is selected from the (+)-(S) enantiomer of the compound of formula i, the (-)-(R) enantiomer of the compound of formula I or an amount of a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight.

12. A pharmaceutical composition for treating a condition or disorder that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) an amount of a compound according to claim 1 selected from the (+)-(S) enantiomer of the compound of formula I, the (-)-(R) enantiomer of the compound of formula I or a mixture of the (+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof; and c) an amount of a NK-1 receptor antagonist or a 5HT_1B receptor antagonist, or a pharmaceutically acceptable salt thereof; wherein the amount of b) and the amount of c) are such that the combination of b) and c) is effective in treating such disorder or condition.

13. A method for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, dopamine or norepinephrine in a mammal, comprising administering to a mammal requiring such treatment: a) a compound according to claim 1 selected from the (+)-(S) enantiomer of the compound of formula I, the (-)-(R) enantiomer of the compound of formula I or a mixture of the

(+)-(S) enantiomer of the compound of formula I with the (-)-(R) enantiomer of the compound of formula I wherein the amount of the (+)-(S) enantiomer within said mixture ranges from about 0% to about 100% by weight, or a pharmaceutically acceptable salt thereof; and b) an NK-1 receptor antagonist or 5HTi_B receptor antagonist, or a pharmaceutically acceptable salt thereof; wherein the amount of a) and the amount of b) are such that the combination of a) and b) is effective in treating such disorder or condition.