MONOAMINE REUPTAKE INHIBITORS FOR TREATMENT OF CNS DISORDERS

Abstract: The present invention relates to compounds that are a useful exhibit activity as serotonin, norepinephrine and dopamine reuptake inhibitors, and their pharmaceutically acceptable salts, and their use in the treatment of central nervous system and other disorders.

Description: MONOAMINE REUPTAKE INHIBITORS FOR TREATMENT OF CNS DISORDERS 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 United States Patent 4,018,830, published on April 19, 1997, refers to phenylthioaralkylamines and 2-phenylthιobenzylamιnes which are active as antiarrhythmics PCT publication 97/17325, published on May 15, 1997, refers to derivatives of N,N- dιmethyl-2-(arylthιo)benzylamιne which selectively influence serotonin transport in the central nervous system and are useful as antidepressants United States Patent 5,190,965, published on March 2, 1993, and United states Patent 5,430,063, issued July 4, 1995, refer to phenoxyphenyl derivatives which have utility in the treatment of depression United States Patent 4,161 ,529, published on July 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, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, 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 (0,-0 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 carbocyc c 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, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, 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 (ι_e_, chloro, fluoro, bromo or lodo), (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, ammo, (C r C 4 )alkylamιno, dι-[(C r C 4 )alkyl]amιno, NR 5 (C=0)(C r C 4 )alkyl, S0 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 r 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, (n) R 1 and R 2 are selected, independently, from hydrogen and (C 1 -C 4 )alkyl, and (in) 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, pediatπc 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-mduced parkinsonism and tardive dyskmesias), 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 norepmephrine 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, pediatπc 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 dyskmesias), 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, tπchotillomania, 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 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 norepmephrine 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 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, pediatπc 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 persona ty 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 dyskmesias), 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 norepmephrine reuptake inhibiting effective amount of a compound of the formula I, 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, norepmephrine or dopamine in a mammal, preferably a human, comprising serotonin, dopamine or norepmephrine reuptake inhibiting effective amount of a compound of the formula I 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 (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 dyskmesias), 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 norepmephrine reuptake inhibiting effective amount of a compound of the formula I, 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, norepmephrine or dopamine in a mammal, preferably a human, comprising administering to a mammal requiring such treatment a serotonin, dopamine or norepmephrine reuptake inhibiting effective amount of a compound of the formula I, 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 norepmephrine in a mammal, preferably a human, comprising a) a pharmaceutically acceptable carrier, b) a compound of the formula I or a pharmaceutically acceptable salt thereof, and c) an NK-1 receptor antagonist or a 5HT 1D receptor antagonist, or a pharmaceutically acceptable salt thereof, wherein the amount of the active compounds (i e , the compound of formula I and the NK-1 receptor antagonist or 5HT 1D receptor antagonist) are such that the combination 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 norepmephrine in a mammal, preferably a human, comprising administering to a mammal requiring such treatment a) a compound of the formula I, defined above, or a pharmaceutically acceptable salt thereof, and b) an NK-1 receptor antagonist or a 5HT 1D receptor antagonist, or a pharmaceutically acceptable salt thereof, wherein the amounts of the active compounds (i e , the compound of formula I and the NK-1 receptor antagonist or 5HT 1D receptor antagonist) are such that the combination 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, fumaπc acid, citric acid, succimc acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartanc acid, maleic acid, di-p-toluoyl tartanc acid, acetic acid, sulfuπc acid, hydroiodic acid and mandelic acid Unless otherwise indicated, the term "halo", as used herein, includes fluoro, chloro, bromo and lodo Unless otherwise indicated, the term "alkyl", as used herein, may be straight, branched or cyclic, and may include straight and cyclic moieties as well as branched and cyclic moieties The term "treatment", as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such condition or disorder The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above The compounds of formula I may have optical centers and therefore may occur in different enantiomenc configurations The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula I, as well as racemic and other mixtures thereof The present invention also relates to all radiolabelled forms of the compounds of the formula I Preferred radiolabelled compounds of formula I are those wherein the radiolabels are selected from as 3 H, 11 C, 14 C, 18 F, 1 3 l and 25 l Such radiolabelled 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 (trademark)) "Treating a chemical dependency," as used herein, means reducing or alleviating such dependency Preferred embodiments of this invention include the following compounds of the formula I and their pharmaceutically acceptable salts [2-(3,4-Dιchlorophenoxy)-5-fluorobenzyl]-dιmethylamιne, [2-(3,4-Dιchlorophenoxy)-5-fluorobenzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-5-trιfluoromethylbenzyl]-dιmethylamιne, N-[4-(3,4-Dιchlorophenoxy)-3-dιmethylamιnomethylphenyl]-acetamιde, {1 -[2-(3,4-Dιchlorophenoxy)phenyl]-ethyl}-dιmethylamιne, [2-(3,4-Dιchlorophenoxy)-4-trιfluoromethylbenzyl]-dιmethylamιne, [2-(3,4-Dιchlorophenoxy)-4-tπfluoromethylbenzyl]-methylamιne, [4-Chloro-2-(3,4-dιchlorophenoxy)-benzyl]-methylamιne, {1 -[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-ethyl}-methylamme, {1 -[2-(3,4-Dιchlorophenoxy)phenyl}-ethyl}-methylamιne, {1-[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamιne, [2-(3,4-Dιchlorophenoxy)-5-methoxybenzyl]-methylamιne, [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamιne, and {1 -[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamιne [2-(3,4-Dιchlorophenoxy)-5-methylbenzyl]-dιmethylamιne, [4-Bromo-2-(3,4-dιchlorophenoxy)-benzyl]-methylamιne, [5-Bromo-2-(3,4-dιchlorophenoxy)-benzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-4,5-dιmethoxybenzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-4-methoxybenzyl]-dιmethylamιne, 4-(3,4-Dιchlorophenoxy)-3-methylamιnomethyl-benzonιtrιle, [2-(3,4-Dιchlorophenoxy)-4,5-dιmethylbenzyl]-methylamιne, 3-(3,4-Dιchlorphenoxy)-4-methylamιnomethyl-benzonιtrιle, (+)-{1 -[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-ethyl}-methylamιne, (-)-{1 -[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-ethyl}-methylamme, [2-(3,4-Dιchlorophenoxy)-5-tπfluoromethyl-benzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-4-methoxybenzyl]-methylamιne, [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyl]-methylamιne, [2-(3-Chloro-4-fluorophenoxy)-5-fluorobenzyl]-methylamιne, (+/-)-2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-pyrrolιdιne, (-)-2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-pyrrolιdιne, (+)-2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-pyrrolιdιne, and 2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-N-methylpyrrolιdιne Other embodiments of this invention include the following compounds and their pharmaceutically acceptable salts {1 -[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-1 -methylethyl}-methylamme, {1 -[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-1 -methylethyl}-dιmethylamιne, [4-Chloro-2-(4-chlorophenoxy)-5-fluorobenzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-5-fluoro-4-methoxybenzyl]-methylamιne, [4-(3,4-Dιchlorophenoxy)-3-(dιmethylamιnomethyl)-phenyl]-dιmethylamιne [5-Fluoro-2-(4-fluoro-3-methoxyphenoxy)-benzyl]-dιmethylamιne, [2-(4-Chlorophenoxy)-5-ιsopropylbenzyl]-methylamιne, {1 -[2-(4-Chlorophenoxy)-5-trιfluoromethylphenyl]-ethyl}-methylamιne; [2-(4-Chlorophenoxy)-4,5-dιmethylbenzyl]-methylamιne; {1 -[5-Chloro-2(3,4-dιchlorophenoxy)phenyl]-propyl}-methylamιne; [2-(3,4-Dιchlorophenoxy)-5-methylsulfanyl-benzyl]-methylamine; {1 -[2-(3,4-Dιchlorophenoxy)-5-methylsulfanyl-phenyl]-ethyl}-methylamιne; {1 -[2-(3,4-Dιchloro-phenoxy)-5-methylsulfanyl-phenyl]-1 -methylethyl}-methylamιne; [2-(3,4-Dιchlorophenoxy)-5-methylsulfanyl-benzyl]-dιmethylamιne; [2-(3,4-Dιchlorophenoxy)-5-methanesulfιnyl-benzyl]-dιmethylamιne ; [2-(3,4-Dιchlorophenoxy)-5-methanesulfιnyl-benzyl]-methylamιne; [2-(3,4-Dιchlorophenoxy)-5-methanesulfonyl-benzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-5-methanesulfonyl-benzyl]-dιmethylamine; [2-(3,4-Dιchlorophenoxy)-5-(propane-2-sulfonyl)-benzyl]-methylamιne; 2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-pιpeπdιne, 2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-1-methyl-pιperιdine; 3-[2-(3,4-Dιchlor-phenoxy)-5-fluorophenyl]-4-methyl-morpholιne; 2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-1 ,2-dιmethyl-pιperιdιπe; {1 -t2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-cyclopropyl}-dιmethylamιne, 2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-1 ,5-dιmethyl-pyrrolιdιne, 3-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-4-methyl-thιomorpholιne, {1 -[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-cyclopentyl}-methylamιne, {1 -[2-(3,4-Dιchlorophenoxy)-5-(propane-2-sulfonyl)-phenyl]-ethyl}-methylamιne; and [4-Chloro-2-(3,4-dιchlorophenoxy)-5-methanesulfonyl-benzyl]-methylamιne Other embodiments of this invention relate to the compound of the formula I wherein m is zero, n is one, R 3 and R 4 are hydrogen, X is chloro, bromo, lodo or methyl, R 1 is hydrogen and R 2 ιs methyl This invention also relates to compounds of the formula XVIII wherein Q is -C(=0)H, cyano, -C(=0)OH or -C(=0)NR 1 R 2 wherein R 1 and R 2 are selected, independently, from hydrogen and (C,-C 4 )alkyl, 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, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C r C 6 )alkyl These compounds are useful as intermediates in the synthesis of certain compounds of the formula I This invention also relates to compounds having the formula and the pharmaceutically acceptable salts thereof These compounds and their pharmaceutically acceptable salts also exhibit activity as monoamme reuptake inhibitors and are useful for treating the disorders and conditions referred to above The compounds of formula XVIII may have optical centers and therefore may occur in different enantiomenc configurations The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula XVIII, as well as racemic and other mixtures thereof Detailed Description of the Invention Compounds of the formula I may be prepared according to the following reaction Schemes and discussion Unless otherwise indicated, A, B, R\ R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, m and n, and structural formulas I and XVIII, in the reaction schemes and discussion that follows are as defined above SCHEME 1 SCHEME 2 y I (R 3 ,R 4 = H) VIII SCHEME 3 SCHEME4 IV XI I(R 3 ,R 4 not = H) SCHEME5 XII IV SCHEME 6 XIII XIV IV SCHEME7 IV, R 3 = O-alkyl XXI XXIII XXII Scheme 1 refers to the preparation of compounds of the formula I from compounds of the formulas II and III Compounds of the formulas II and III are commercially available or can be made by methods well known to those of ordinary skill in the art For example, compounds of general formulas lla and lib wherein R 3 is H may be prepared by introducing an aldehyde functional group (CHO) to a compound of formula XV or XVI, respectively, using methods well known to those of skill in the art XV XVI When L = F, the procedure of A J Bridges et al_, Tetrahedron Letters, 1992, 33(49), 7499- 7502, is particularly useful for the synthesis of substituted ortho-fluorobenzaldehydes Other such transformations have been described by C F H Allen et al_, Organic Synthesis, 1951 , 31 , 92, T DePaulis et al, J Med Chem , 1986, 29, 61 , I M Godfrey et al_, J Chemical Society, Perkin Transactions 1 , 1974, 1353, K M Tramposil et al_, J Med Chem , 1983, 26(2), 121 , and M E Cracknell et al , Chem Ind , (London), 1985, (9), 309 Referring to Scheme 1 , a compound (i e , an aldehyde or ketone) of the formula lla, wherein L is a suitable leaving group such as fluoro, chloro, nitro or triflate, is reacted with a compound (i e , a phenol) of the formula Ilia in the presence of a base to form the corresponding compound of formula IV This reaction is generally carried out at a temperature from about 0°C to about 150°C for about 1 hour to about 3 days, preferably at about 90-95°C for about 18 hours, in a polar solvent such as dimethyl sulfoxide (DMSO), N,N- dimethylformamide (DMF), N,N-dιmethylacetamιde (DMA) or N-methyl-2-pyrrolιdιnone (NMP), preferably DMF Suitable bases include anhydrous sodium carbonate (Na 2 C0 3 ), potassium carbonate (K 2 C0 3 ), sodium hydroxide (NaOH), potassium hydroxide (KOH) and amines such as pyrrolidme, tπethylamine and pyridine, with anhydrous K 2 C0 3 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 Alternatively, phenols of the formula lib and compounds of the formula lllb may be converted into aldehydes or ketones of the general formulae IV according to the procedures described by K Tomisawa et al_ Chemical and Pharmaceutical Bulletin , 1984, 32(8), 3066-3074 Compounds of the formula IV can be converted into compounds of the formula I by subjecting them to reductive amination conditions For example, a compound of the formula IV can be reacted with a compound of the formula HNR 1 R 2 to form an intermediate of the formula XVII XVI I which may be isolated or converted directly in the same reaction step into a compound of the formula I This conversion, whether in situ or starting with the isolated compound of formula XVII, can be performed using one or more methods known to those skilled in the art For example, the compound of formula IV and the appropriate compound of formula HNR'R 2 can be combined in the presence of a dehydrating reagent such as titanium (IV) tetrachlonde or titanium (IV) isopropoxide, in a reaction inert solvent such as benzene, toluene, ethanol or a like solvent, 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 IV and the compound of formula HNR 1 R 2 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 XVII The degree of completion of the conversion of compounds of the formula IV into the above ιntermedιate(s) of formula XVII can be assessed using one or more known analytical techniques, including 1 H-NMR spectroscopy In some instances, it may be possible or desirable to isolate the ιntermedιate(s) of formula XVII, or they may be further reacted with a reducing agent selective for the reduction of the intermediate to the desired compounds of formula I Such reducing agents are widely known to those skilled in the art and include, for example, sodium borohydπde (NaBH 4 ), sodium cyanoborohydπde (NaBH 3 CN) and sodium triacetoxy-borohydπde (NaBH(OAc) 3 ), as described by A F Abdel-Magid et aj_ in Tetrahedron Letters, 1990, 31_, 5595) This reduction is generally carried out in a polar solvent such as methanol, ethanol, isopropanol or a like solvent, and at temperatures of about 0°C to about 100°C, preferably at room temperature In the procedure described by Bhattarcharyya, the intermediate of formula XVII is formed in an ethanol solvent and, without isolation, is reduced to the product of formula I using NaBH 4 As an alternative to the aldehyde or ketone intermediates of formula IV, one skilled in the art can also prepare compounds of formula VI (ι_e_, nitriles), as illustrated in Scheme 2, for use as intermediates in the syntheses of the desired compounds of formula I, using a diphenyl ether formation procedure analogous to that described in Scheme 1 Procedures for preparation of compounds of formula VI can be adapted from those found in the literature (See, e ^, D. C Remy et al_, J Med Chem , 1975, 18(2), 142-148, E A Schmittling et al_, Journal of Organic Chemistry, 1993, 58(12), 3229-3230) The conversion of the nitriles of formula VI so obtained into the desired products of formula I can be achieved by several routes, as depicted in Scheme 2 For example, the nitπle group of VI can be hydrolyzed under acidic conditions using methods well known to those of skill in the art, to produce a carboxyhc acid derivative of formula VII (See, e_gκ A I Meyers et al , Tetrahedron Letters, 1984, 25 (28), 2941 , and R W Higgins et al , J Organic Chemistry, 1951 , 16, 1275) This carboxyhc acid derivative, in turn, can be converted into a carboxamide derivative having the formula VIII using one or more standard methods which are disclosed in the chemical literature, e g , via reaction of an acid halide prepared from compounds of the formula VII with an amme of general formula HNR 1 R 2 (See R E Kent et al_, Organic Synthesis, Coll Vol III, 1955, 490, and R M Herbst et al_, Organic Synthesis, Coll, Vol II, 1943, 1 1 for discussions of the Schotten-Bauman reaction) The resulting carboxamides of the formula VIII, wherein R 1 and R 2 are hydrogen, can also be prepared directly from the corresponding nitriles of formula VI by specific hydrolysis methods, employing, for example, hydrogen peroxide or strong aqueous alkalis metal salts (See Chemistry & Industry, 1961 , 1987, C R Noller, Organic Synthesis, Coll Vol II, 1943, 586, and J H Hall and M Gisler, J Organic Chemistry, 1976, 41 , 3769) Subsequently, the carboxamide derivatives of formula VIII may can be reduced using one of a variety of reducing agents available for such conversion, to produce the desired compounds of formula I (See, e g , A C Cope et al , Organic Synthesis, Coll Vol IV, 1963, 339, for use of lithium aluminum hydride in a diethyl ether or THF solvent ) Alternatively, the nitriles of formula VI can be reduced to form the desired compounds of general formula I, wherein R 1 and R 2 are hydrogen, by using one of a variety of reducing agents disclosed in the chemical literature which are selective for this transformation (including catalytic hydrogenation using hydrogen gas and platinum (II) oxide, as described by J A Secπst, III and M W Logue in J Organic Chemistry, 1972, 37, 335, hydrazine hydrate and Raney nickel in ethanol, as described by W W Zajac, Jr et al in J Organic Chemistry, 1971 , 36, 3539, and sodium tπfluoroacetoxy borohydπde in THF, as described by N Umino et al in Tetrahedron Letters, 1976, 2875) Such reducing agents can also include lithium aluminum hydride in a nonreactive solvent such as diethyl ether or tetrahydrofuran Finally, the nitriles of formula VI may be converted to the corresponding aldehydes of general formula IV, wherein R 3 is hydrogen, using reaction conditions specific for this transformation, such as lithium tπethoxyaluminum hydride in a solvent such as THF or diethyl ether, as described by H C Brown and C P Garg in J American Chemical Society, 1964, 86, 1085 and by J Malek and M Cerny in Synthesis, 1972, 217 Using an alternative synthetic pathway, the intermediate carboxyhc acids of formula VII (or their methyl or ethyl ester derivatives) can be reduced to their corresponding benzyiic alcohols of formula IX This process is well precedented in the literature and can be accomplished using selective reducing agents such as sodium borohydπde (see, e g , J V B Kanth et al_, J Organic Chemistry, 1991 , 56, 5964), diborane in THF (see, e j_, M N Moon et al_, J Organic Chemistry, 1973, 38, 2786), and similar reducing agents The alcohols of formula IX so obtained can then be selectively re-oxidized to form the corresponding aldehydes of formula IV (R 3 = H), for example, using pyπdinium chlorochromate in methylene chloride, according to the procedure of E J Corey et al_, Tetrahedron Letters, 1975, 31 , 2647-2650, or C -G Huang, Journal of Organic Chemistry, 1991 , 56(16), 4846-4853 The hydroxyl group of the compound of formula IX may be also converted into a more reactive leaving group L 2 (e g , mesylate, triflate), as described in the scientific literature (see, e g , M S Newman et al_, J Organic Chemistry, 1974, 39, 1036, and E K Anderson et al_, Synthesis, 1974, 665), to generate intermediates of the formula X, which can then be reacted with the appropriate amines of formula HNR 1 R 2 to produce the corresponding desired compounds of formula I Schemes 3 and 4 illustrate processes that can be used to introduce substituents (R 3 , R 4 ) at the alpha position of the benzylamine side chain In Scheme 3, according to the procedure of D J Calderwood et al_, (Tetrahedron Letters, 1997, 38(7), 1241 -1244), a nitπle of the formula VI or an amide of the formula VIII can be treated with a reagent of the formula R 3 MJ 2 (wherein M is a metal such as cerium and J is a halogen such a Cl or Br) to produce a compound of the formula I wherein R 1 =R 2 =hydrogen Such compounds can then be converted to compounds of formula I wherein R 1 and R 2 are other than hydrogen, for example, via the reductive amination procedures described herein Alternatively, according to Scheme 4, intermediates of the formula IV can be reacted with, for example, a Gπgnard reagent (i_e_, R 4 MgJ) under well established conditions to generate the intermediate alcohols of formula XI Such alcohols of formula XI may be converted in one of several manners For example, the alcohol may be reacted with NaN 3 in aqueous DMF, replacing the OH in formula XI with N 3 , according to the procedure of Sharpless et al_, Tetrahedron Letters, 1996, 37(19), 3219-3222 The azide derivative thus formed can then be reduced to the primary amine of formula I (R 1 =R 2 =H) under a variety of conditions, for example, using hydrogen and barium sulfate in ethanol, (A Guy et al_, Synthesis, 1988, 11 , 900-904), lithium aluminum hydride in ether (M Saito et al_, Journal of Medicinal Chemistry, 1980, 23(12), 1364) or tπbutyltin hydride in benzene (J Wasserman et al, Journal of American Chemical Society, 1985, 107(2), 519) The primary amine (-NH 2 ) compound of formula I so obtained can be converted to compounds of formula I wherein R 1 and R 2 are other than hydrogen, as described previously In addition to the methods described above in Schemes 1 and 2 for the preparation of the intermediate aldehydes and ketones of formula IV, other methods exist which can provide compounds of the formula IV For example, a compound of formula XII, in which the group Z is a hydrogen atom, can be reacted, under conditions of Fπedel-Crafts acylation (e g , AICI 3 /CH 2 CI 2 /R 3 COCI), to produce ketones of the formula IV in which R 3 is not hydrogen This procedure is depicted in Scheme 5 and is well precedented in the scientific literature and familiar to those skilled in the art The location of the acyl group (COR 3 ) can be determined by the nature and location of the X and/or Y substituents present, as well as the conditions employed for the reaction In instances where it is desireable to prepare compounds of formula IV (R 3 =H), from XII (Z=H), introduction of the aldehyde functional group (CHO) may be achieved using conditions described above for the preparation of the intermediates lla and lib in Scheme 1 Preparation of compounds of the formula IV wherein R 3 = H (ι_e_, aldehydes) can be achieved using one or more of the known procedures for the formylation of aromatic rings, including reacting dichloromethyl methyl ether and titanium (IV) tetrachlonde in methylene chloride according to the procedure described by M L Mancini et al_, Synthetic Communications, 1989, 2001 -2007, or H Chikashita et al_, J Organic Chemistry, 1991 , 56, 1692 Alternatively, reaction of the compounds of formula XII wherein Z is a halogen (e g , Br, I) with a strong base (e g , n-sec- or tert-butyl lithium, lithium dnsopropylamide) in an inert solvent such as hexane or THF, followed by reaction with a reagent such as N,N- dimethylformamide (DMF), will produce aldehydes like those of formula IV (See G Voss et al_, Chemishe Beπchte, 1989, 122, 1199, M P Hoyer et al_, J Organic Chemistry, 1986, 51 (26), 5106, and N Eisen et al , Angew Chem International Edition, 1986, 25(11 ), 1026) Another method for the preparation of compounds of formula IV relies on the oxidation of an alkyl group (e g , CH 3 , C 2 H 5 ) at the Z position of compounds of the formula XII The oxidation can progress to the formation of the aldehyde of the formula IV, wherein R 3 = H (e g , F M Hauser et al_, Synthesis, 1987, 723, S D Carter et al_, Synthesis, 1983, (12), 1000, European Patent 451650, 1991 , Bayer AG), or, under more vigorous conditions, can proceed to the formation of a carboxyhc acid compound of formula VII, from which it can then be converted into compounds of the formula I, as depicted in Scheme 2 The success of this oxidation procedure will, of course, depend upon the nature and location of any additional substituents X and Y on the compounds of formula XII Yet another alternative for the preparation of the intermediates of formula IV is illustrated by Scheme 6 Compounds of the formula XIII, containing a nitro group and prepared according to procedures described by R Beugelmans et al_ (Tetrahedron Letters, 1994, 35(31 ), 5649-5652), J H Clark et al , (Tetrahedron Letters, 1987, 28(31 ), 3627) and E Roberts et al_, (Journal of the Chemical Society, 1925, 127, 2004), can be reduced under conditions disclosed in the chemical literature to the corresponding amine compounds of formula XIV There reductions can be accomplished using gaseous hydrogen (H 2 ) and a catalyst (e g , Pd/C, Raney nickel) in an alcohol solvent such as ethanol, at pressures of about one to about 5 atmospheres of H 2 , or using an in situ reduction using an iron/acetic acid or tin/hydrochloric acid system to produce the corresponding compounds of formula XIV These latter intermediates of formula XIV can then be converted, via their diazonium salts (prepared, for example, using NaN0 2 and aqueous HCI) into the nitriles of formula VI (i e , see H T Clarke and R R Read, Organic Synthesis, 1941 , 514) which may then be converted via the corresponding carboxyhc acids of formula VII as shown in Scheme 2 into aldehydes of the general formula IV wherein R 3 = H The intermediates of formula XIV can also be converted directly into the corresponding aldehydes of formula IV by reacting them with formaldoxime, followed by acid hydrolysis, as described by R B Woodward et al_, Tetrahedron, 1958, 2, 1 and W F Beech in J Chemical Society, 1954, 1297 For the preparation of compounds of the general formula I wherein R 2 and R 3 taken together with the nitrogen to which R 2 is attached and the carbon to which R 3 is attached form a nitrogen containing ring, an adaptation of the procedure described by L S Bleicher et al (J Organic Chemistry, 1998, 63, 1109) can be employed, as shown in Scheme 7 Thus, an ester of the general formula IV (R 3 = O-alkyl) is reacted with a cyclic lactam of the general formula XXX XXX where L 4 is a reaction labile group such as -CH=CH 2 , in the presence of a strong base such as sodium methoxide, to produce the intermediate of general formula XXI This intermediate can then be converted to the corresponding cyclic imine of formula XXII in the presence of a strong acid, such as hydrochloric acid, usually under reflux conditions Subsequently, the compounds of formula XXII can be reduced to form the cyclic amines of formula XXIII (wherein R 1 = H) using, for example, sodium borohydnde in methanol as described previously Such compounds of formula XXIII can further be converted into compounds of the formula XXIII (wherein R 1 is as defined for compounds of formula I) as previously discussed The in vitro activity of the compounds of the present invention at the individual monoamme reuptake sites can be determined using rat synaptosomes or HEK-293 cells transfected with the human serotonin, dopamine or norepmephrine 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 Neurochemistry, 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 stπata 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 1 mg/ml glucose, 0 1mM ethylenediamine tetraacetic acid (EDTA) adjusted to pH 7 4 with trιs(hydroxymethyl)-amιnomethane (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 m at 4°C The resulting supernatant is recentπfuged at 17,000 x g for 20 m at 4°C 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), norepmephrine (NE) or dopamine (DA) transporter are grown in DMEM (Dulbecco's Modified Eagle Medium, Life Technologies Ine , 9800 Medical Center Dr , Gaithersburg, MD, catalog no 1 1995-065)) supplemented with 10% dialyzed FBS (Fetal Bovine Serum, from Life Technologies, catalog no 26300-053), 2 mM L-glutamme and 250 ug/ml G418 for the 5-HT and NE transporter or 2ug/ml puromycm 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 10uM sertrahne, desipramine or nomifensme 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 pargyhne and glucose (1 mg/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 mm (5-HT, DA) or 10 mm (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 EXPERIMENTAL EXAMPLES PREPARATION 1 2-(3,4-DICHLOROPHENOXY)-5-TRIFLUOROMETHYLBENZALDEHYDE Under N 2 in a 50 mL round-bottomed flask fitted with a reflux condenser and magnetic stirrer were placed 0 829 g (6 0 mmol) of K 2 C0 3 and 0 342 g (2 1 mmol) of 3,4-dιchlorophenol (Aldπch Chem Co , Milwaukee, WI) in 10 mL of anhydrous N,N-dιmethylformamιde (DMF) After stirring the mixture for 5 mm , 0 384 g (2 0 mmol) of 2-fluoro-5- tπfluoromethylbenzaldehyde (Aldrich) was added and the mixture was heated to 90-95° C overnight After allowing the reaction to cool to room temperature, the mixture was diluted with water and EtOAc, the aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with H 2 0 and saturated NaCl and dried over MgS0 4 Removal of the solvent in vacuo gave a light amber colored oil, 0680 g 1 H-NMR (CDCI 3 , 400 MHz) d 10 46 (s, 1 H), 8 18 (s, 1 H), 7 74 (m, 1 H), 7 48 (m, 1 H), 7 23 (m 1 H), 6 97 (m, 2H) Mass spectrum (GCMS, m/z) 334 (m + ) In the same manner the following aldehyde and ketone intermediates of the formula IV were prepared PREPARATION 32 5-CYANO-2-(3,4-DICHLOROPHENOXY)-BENZALDEHYDE Under N 2 in a flame-dried 3-neck round bottomed flask fitted with a reflux condenser and magnetic stirrer, a mixture of 5-bromo-2-(3,4-dιchlorophenoxy)-benzaldehyde (3 0 g, 8 7 mmol), zinc (II) cyanide (1 5 g, 13 mmol) and tetrakιs(trιphenylphosphιne) palladium (0) (1 5 g, 1 3 mmol) in anhydrous DMF (145 ml) was stirred at room temperature while degassing with N 2 for 5 mm After heating at approximately 80 °C for 90 m , the reaction was judged complete by thin layer chromatography (50% CH 2 CI 2 hexanes) and was allowed to cool to room temperature The reaction mixture was then diluted with water and ethyl acetate (EA) and stirred another 10 mm The water layer was separated, extracted twice with EA and combined with the original EA layer, and washed with an aqueous solution of Rochelle salt (potassium sodium tartrate tetrahydrate) followed by aqueous NaCl The organic layer was dried with Na 2 S0 4 , filtered and concentrated in vacuo to an oil The oil was flash chromatographed on a 15 X 5 cm column of silica gel, eluting with CH 2 CI 2 hexanes (1 1 ) to obtain the title product as a white solid, 1 5 g (60%), m p 122-126 °C Mass spectrum (GC/MS, m/z) 291 (m + ), 262 1 H-NMR (CDCI 3 , d) 10 47 (s, 1 H), 8 22 (d, 1 H), 7 75 (dd, 1 H), 7 53 (d, 1 H), 7 25 (m, 1 H), 6 98 (dd, 1 H), 6 92 (d, 1 H) In the same manner, 4-cyano-2-(3,4-dichlorophenoxy)-benzaldehyde was prepared from the corresponding 4-bromo-2-(3,4-dιchlorophenoxy)-benzaldehyde, clear oil, 16% Mass spectrum (GC/MS, m/z) 291 (m + ) 1 H-nmr (CDCI 3 , d) 10 45 (s, 1 H), 8 02 (d, 1 H), 7 55 (m, 2H), 7 23 (m, 1 H), 7 14 (m, 1 H), 6 96 (dd, 1 H) PREPARATION 33 4,5-DIMETHOXY-2-FLUOROBENZALDEHYDE In a flame-dried, round-bottomed flask fitted with a magnetic stirrer and N 2 inlet was placed 4-fluoroveratrole (0 78 g, 5 0 mmol, Aldnch Chemical Co ) in 20 ml of anhydrous CH 2 CI 2 After cooling to 0° C, titanium (IV) chloride (0 91 ml, 1.57 g, 8.3 mmol) was added, followed after 10 mm by a,a-dιchloromethyl methyl ether (0.45 ml, 0.575 g, 5.0 mmol). The mixture was allowed to warm to room temperature and after 2 hr it was quenched with an excess of aqueous saturated NaHC0 3 . The suspension was filtered through a pad of d.e. (diatomaceous earth), the aqueous phase was extracted with additional amounts of CH 2 CI 2 and the organic phases were combined and washed with water followed by saturated aqueous NaCl After drying with MgS0 4 , the organic solvent was removed in vacuo to give the title compound as a white solid, 910 mg 1 H-NMR (CDCI 3 , d) * 10.2 (s, 1 H), 7.26 (d, 1 H), 6.64 (d, 1 H), 3.93 (s, 3H), 3.89 (s, 3H). PREPARATION 34 2-(3,4-DICHLOROPHENOXY)-5-BENZONITRILE Under N 2 in a single-neck round bottomed flask with a reflux condenser and magnetic stirrer, a mixture of 3,4-dιchlorophenol (1.96 g, 12 mmol) and anhydrous potassium carbonate (4 14 g, 30 mmol) in anhydrous N,N-dιmethylformamιde (DMF, 50 ml) was treated with 2,5- difluorobenzonitrile (1 39 g, 10 mmol, Aldrich Chemical Co., Milwaukee, WI) and heated to 95- 100 °C for 18 hr The mixture was then cooled to room temperature and diluted with water and ethyl acetate (EA), the water layer was extracted with additional quantities of EA and the EA layers were combined, washed with water, 2N NaOH, water and finally saturated aqueous NaCl After drying over MgS04, the solvent was removed in vacuo to give a tan solid. • Mass spectrum (GC/MS) m/z 281 (m + ) 1 H-NMR (CDCI 3 , 300 MHz, d) 7.43 (d, 1 H), 7 37 (dd, 1 H), 7 26 (m, 1 H), 7.12 (d, 1 H), 6 92 (m, 2H) In a similar fashion, the following benzonitnles of the formula VI were prepared, isolated after flash chromatography (silica gel, elution with 20% CH 2 CI 2 in hexanes): PREPARATION 38 2-(3,4-DICHLOROPHENOXY)-5-FLUORO-N-METHYL-BENZAMIDE A mixture of 0 602 g (2 0 mmol) of 2-(3,4-dιchlorophenoxy)-5-fluoro-benzoιc acid in 20 mL of anhydrous benzene was treated with 2 drops of N,N-dιmethylformamιde (DMF), followed by slow addition of 0 785 g (481 μL, 6 6 mmol) of thionyl chloride After heating to reflux for 3.5 hr, the solution was stirred at room temperature overnight and concentrated in vacuo to a tan oil that was further azeotroped twice with fresh benzene The residue was re-dissolved in 4 mL of benzene and added to 15 mL of 1 0 M CH 3 NH 2 in CH 3 OH (Aldrich Chem Co ) at 25 °C After 12 hr, the mixture was concentrated in vacuo and partitioned between water and EtOAc The aqueous layer was then extracted with additional EtOAc and the combined organic extracts were washed with water followed by saturated aqueous NaCl, dried with MgS0 4 , filtered and concentrated to a brown oil which slowly solidified on standing, 0 654 g 1 H-nmr (CDCI 3 , 400 MHz, δ) 7 89 (dd, 1 H), 7 41 (d, 1 h), 7 30 (bs, 1 H, NH), 7 09 (m, 2H), 6 83 (m, 2H), 2 95 (d, 3H) PREPARATION 39 2-(3,4-DICHLOROPHENOXY)-5-FLUORO-BENZONITRILE A flame-dried flask containing N 2 inlet and magnetic stirrer was charged with 2 9 g (18 mmol) of 3,4-dιchlorophenol, 6 2 g (45 mmol) of potassium carbonate and 50 mL of anhydrous DMF With stirring, 2 08 g (15 mmol) of 2,5-dιfluorobenzonιtrιle (Aldrich Chem Co ) was added and the mixture was heated overnight at 105 °C, cooled to room temperature and partitioned between water and EtOAc The aqueous layer was reextracted with EtOAc and the combined organic layers were successively washed with 2N NaOH, water and saturated aqueous NaCl After drying with MgS04, the solvent was removed to give the title product as a light brown oil which slowly solidified, 3 5 g Mass spectrum (APCI, m/z) 281 (m + ) 1 H-nmr (CDCI 3 , 400 MHz, δ) 7 43 (d, 1 H), 7 37 (dd,1 H), 7 26 (m, 1 H), 7 12 (d, 1 H), 6 92 (m, 2H) PREPARATION 40 2-(3,4-DICHLOROPHENOXY)-5-FLUORO-BENZALDEHYDE A flame-dried flask containing N 2 inlet and magnetic stirrer was charged with 1 24 g (9 0 mmol) of potassium carbonate and 20 mL of anhydrous DMF, followed by 0 513 g (3 15 mmol) of 3,4-dιchlorophenol, with stirring at room temperature After 5 m , 0 426 g (3 0 mmol) of 2,5-dιfluorobenzaldehyde (Aldrich Chem Co ) was added and the mixture was heated at 95 °C for 18 hr After cooling to room temperature, the mixture was diluted with water, twice extracted with EtOAc and the organic extracts were washed with water and saturated NaCl and dried over MgS04 Removal of the solvent gave a brown oil, 963 mg, which was chromatographed on 230-400 mesh silica eluted with 5% EtOAc 95% hexanes The title product was isolated from the appropriate fractions as a white low-melting solid, 0 572 g 1 H-nmr (CDCI 3 , 400 MHz, δ) 7 60 (dd, 1 H), 7 42 (d,1 H), 7 28 (m, 1 H), 7 10 (d, 1 H), 6 95 (dd, 1 H), 6 87 (dd, 1 H) EXAMPLE 1 2-FLUORO-6-(P-TOLYLOXY)BENZYLAMINE A flame-dried flask containing N 2 inlet and magnetic stirrer was charged with 6 0 mL of 1 0 M lithium aluminum hydride in THF (6 0 mmol, Aldrich Chem Co ), followed by an additional 10 mL of anhydrous THF at room temperature While stirring, 0 341 g (1 5 mmol) of 2-fluoro-6-(p-tolyloxy)benzonιtrιle (Maybπdge Chem Co Ltd , Trevillett, Tmtagel, Cornwall, UK) was added slowly via syringe, causing some mild foaming After 4 hr, a tic (CHCI 3 CH 3 OH, 95 5) showed no starting material and two new very polar spots With ice bath cooling, the reaction was quenched using 230 mL H 2 0, 230 mL 15% NaOH and then 690 mL H 2 0 After 15 m stirring at room temperature, the mixture was filtered through a d e pad, the pad was washed further with small amounts of CH 2 CI 2 and the combined organic filtrate was concentrated in vacuo to a yellow oil, 0 287 g The oil was chromatographed on 10 g silica gel (230-400 mesh) eluting first with CH 2 CI 2 , then adding increasing percentages of CH 3 OH The less polar of the two spots, 2-Fluoro-6-(p-tolyloxy)benzylamine eluted as a yellow oil, 0 120 g Mass spectrum (APCI, m/z) 232 (m + ), 215 (m + -NH 3 ) 1 H-NMR (CDCI 3 , 400 MHz) d 7 12 (m, 3H), 6 86 (m, 2H), 6 78 (t, 1 H), 6 60 (dd, 1 H), 3 92 (s, 2H), 2 32 (s, 3H), 1 72 (bs, 2H, NH 2 ) Further elution of the chromatography provided the more polar component, 2-(p- tolyloxy)benzylamine, as a yellow oil, 0.082 g. 1 H-NMR (CDCI 3 , 400 MHz): d 7.34 (d, 1 H), 7.12 (m, 4H), 6.86 (m, 3H), 3.87 (s, 2H), 2.31 (s, 3H), 1.80 (bs, 2H, NH 2 ). By the same method, the following benzylamino compounds of formula I (where R 1'4 = H) were prepared from the corresponding benzonitriles VI: EXAMPLE 6 [2-(3,4-DICHLOROPHENOXY)-5-TRIFLUOROMETHYLBENZYL]-DIMETHYLAMINE MALEATE In a round-bottomed flask fitted with a magnetic stirrer and N 2 inlet was placed 0 331 g (4 06 mmol) of dimethylamine hydrochloride (Aldrich) and 0 410 g (4 06 mmol) triethylamme in 25 mL ethanol while stirring until the solution was clear At room temperature, 1 15 g titanium (IV) isopropoxide (1 2 mL, 4 06 mmol) was added via syringe, followed by 0 680 g (2 03 mmol) of 2-(3,4-dιchlorophenoxy)-5-tπfluoromethyl-benzaldehyde to give a yellow-brown solution which was stirred overnight To the resulting cloudy solution was added 0 115 g (3 05 mmol) of sodium borohydπde, and stirring was continued for 24 hr The reaction was then quenched with 6N HCI (~pH = 10), stirred another 2 hr and diluted with EtOAc The aqueous layer was made basic with saturated aqueous Na 2 C0 3 , layered with additional EtOAc and the two-layered mixture was filtered through a pad of diatomaceous earth (d e ), washing the d e pad well with EtOAc and H 2 0 The EtOAc layer was combined with additional extracts of the water layer and the combined organics were washed with saturated aqueous NaCl, dried with MgS0 4 and concentrated in vacuo to a yellow oil, 0 626 g Mass spectrum (APCI, m/z) 366, 364 (m + ) 1 H-NMR (CDCI 3 , 400 MHz) d 7 78 (s, 1 H), 7 47 (dd, 1 H), 7 39 (s, 1 H), 7 04 (s, 1 H), 6 90 (dd 1 H), 6 80 (dd, 1 H), 3 48 (s, 2H), 2 26 (s, 6H) The preceding oil dissolved in anhydrous diethyl ether was treated with 0 199 g of maleic acid in 2 mL of acetone The mixture was filtered through a thin pad of d e to clarify the solution and then was stirred at room temperature for 8 hr The resulting solids were filtered and washed with Et 2 0 and dried under vacuum, m p 127-128 °C Elemental analysis for C 16 H 14 CI 2 F 3 NO.C 4 H 4 0 4 calculated C, 50 01 , H, 3 77, N, 2 92 Found C, 49 93, H, 3 85, N, 3 04 In the same manner the following compounds of formula I, wherein R 4 is hydrogen, were prepared EXAMPLE 52 (2-FLUORO-6-(P-TOLYLOXY)BENZYL)-PIMETHYLAMINE MALEATE (I, R 1 *2 = CH 3 ) Under N 2 , a solution of 0 120 g (0 52 mmol) of 2-fluoro-6-(p-tolyloxy)benzylamιne (from example 3) in 2 mL of CH 3 OH was treated with 215 mL (2 86 mmol) of 37% aqueous formaldehyde (Aldrich), producing a solid precipitate Sodium triacetoxyborohydride (0 319 g, 1 43 mmol) was then added, producing some foaming before becoming a clear solution After stirring at room temperature overnight, H 2 0 and EtOAc were added, the aqueous layer was further extracted with EtOAc, and the organic layers were combined and washed with H 2 0 and saturated NaCl After drying over MgS0 4 , the solvent was removed in vacuo to give a light yellow film, 0 110 g Mass spectrum (APCI, m/z) 260 (m +1 ) 1 H-NMR (CDCI 3 , 400 MHz) d 7 28 (m, 1 H), 7 14 (m, 2H), 6 91 (m, 2H), 6 83( t, 1 H), 6 56 (d, 1 H), 4 38 (s, 2H), 2 79 (s, 6H), 2 32 (s, 3H) The crude amine (84 mg) was dissolved in Et 2 0 and treated with 38 mg (1 equiv ) of maleic acid in 2 mL of acetone After stirring at room temperature for 18 hr, the white solid salt was filtered and washed with small amounts of Et 2 0 and dried under high vacuum to give 0 048 g of the title product, m p 147-148 °C Elemental analysis for C 16 H 18 FNO-»C 4 H 4 0 4 calculated C, 63 99, H, 5 90, N, 3 73 Found C, 63 97, H, 5 91 , N, 3 67 EXAMPLE 53 4-(3,4-DICHLOROPHENOXY)-3-(DIMETHYLAMINOMETHYL)-PHENYLAMINE HYDROCHLORIDE Under N 2 , in a 250 mL Parr apparatus bottle, 0 265 g of 10% Pd on carbon was treated with 30 mL of EtOAc and 0 53 g (1 55 mmol) of [2-(3,4-dιchlorophenoxy)-5- nιtrobenzyl]-dιmethylamιne (prepared as in Preparation 1 ) followed by 2 drops of acetic acid The mixture was hydrogenated at 40-45 psi of H 2 for 90 mm, at which time no starting material was visible by tic (90 10 CHCI 3 CH 3 OH) Saturated NaHC0 3 was added to adjust the pH>7 and the solution was filtered through a pad of d e , washing the pad with H 2 0 and EtOAc The organic layers were combined, washed with H 2 0 and saturated NaCl, dried over MgS0 4 and concentrated in vacuo to a tan oil, 0 325 g Mass spectrum (APCI, m/z) 313, 311 1 H-NMR (CDCI 3 , 400 MHz) d 7 39 (m, 2H), 7 21 (m, 3H), 6 70 (dd, 1 H), 4 52 (s, 2H), 2 89 (s, 6H) The oil was dissolved in Et 2 0 and treated with 2 1 mL of 1 0 M HCI in Et 2 0 (Aldrich), stirred at room temperature for 2 hr and filtered After drying in vacuo, the title product weighed 0 286 g, m p 228 °C EXAMPLE 54 N-[4-(3,4-DICHLOROPHENOXY)-3-DIMETHYLAMINOMETHYLPHENYL]-ACETAMIDE HYDROCHLORIDE To a suspension of 0 130 g (0 375 mmol) of 4-(3,4-dιchlorophenoxy)-3- (dιmethylamιnomethyl)-phenylamιne hydrochloride (from example 53) in 3 mL of toluene at room temperature, under N 2 , was added 110 mL of triethylamme After 2 hr, 28 mL (0 394 mmol) of acetyl chloride was added and the mixture was stirred another 1 hr before being diluted with EtOAc and saturated aqueous NaHC0 3 The aqueous layer was further extracted with EtOAc and the organic layers were combined, washed with H 2 0 and saturated NaCl, dried with MgS0 4 and concentrated to a tan oil, 0 1 16 g Mass spectrum (APCI, m/z) 355, 353 The crude product was dissolved in Et 2 0 and treated with 330 L of 1 0 M HCI in Et 2 0 After stirring at room temperature, the solids were filtered and washed with small amounts of Et 2 0, then dried in vacuo to give the title product, 88 mg, m p 199-202 °C Elemental Analysis calculated for C 17 H 18 CI 2 N 2 0 2 HCUV* H 2 0 C, 50 64, H, 5 12, N, 6 95 Found C, 50 51 , H 5 19, N, 6 66 EXAMPLE 55 2-[2-(3,4-DICHLOROPHENOXY)-5-FLUOROPHENYL]-PYRROLIDINE HYDROCHLORIDE A. 2-(3,4-DICHLOROPHENOXY)-5-FLUORO-BENZOIC ACID Under N 2 in a round-bottomed flask fitted with a reflux condenser and magnetic stirrer were placed 6 37 g (19 55 mmol) of cesium carbonate and 3 2 g (19 55 mmol) of 3,4-dιchlorophenol (both from Aldrich Chem Co , Milwaukee, WI) in 60 mL of anhydrous toluene After stirring the mixture for 5 mm , 89 mg (0 24 mmol) of copper (II) tπfluoromethansulfonate (copper triflate) and 0 26g (9 78 mmol) of 5-fluoro-2-ιodobenzoιc acid (prepared according to the method in Collection of Czechoslovakian Chemical Communications, 1975, vol 40, p728) were added and the mixture was heated to reflux overnight Progress of the reaction was monitored using thin layer chromatography (tic), eluting with CHCI 3 CH 3 OH AcOH (9 1 0 5) After allowing the reaction to cool to room temperature, the mixture was diluted with water and EtOAc, the aqueous layer was acidified with 6 N HCI and re-extracted with additional EtOAc The organic layers were combined, washed with H 2 0 and saturated NaCl and dried over MgS0 4 Removal of the solvent in vacuo gave a dark brown colored oil, 2 6 g, as a mixture of title product and unreacted 5-fluoro-2-ιodobenzoιc acid Alternatively, a solution of 4 28 g (15 mmol) of 2-(3,4-dιchloro-phenoxy)-5- fluorobenzaldehyde (Preparation no 5) in 25 mL of acetone was cooled to 5-10 °C and treated via syringe with 5 8 mL (15 6 mmol) of 2 67 M Jones reagent * After 1 hr at this temperature, the reaction was quenched with 8 mL of isopropanol, allowed to warm to 25 °C, and filtered through a pad of d e The filtrate was concentrated in vacuo to approximately Vi volume, diluted with water and extracted several times with CHCI 3 The organic layers were washed with water, then with saturated NaCl and finally dried over MgS0 4 and concentrated to provide 2-(3,4-dιchlorophenoxy)-5-fluoro-benzoιc acid as a tan solid, 4 19 g 1 H-nmr (CDCI 3 , 400 MHz, δ) 7 78 (dd, 1 H), 7 38 (d, 1 H), 7 27 (m, 1 H), 6 98 (m, 2H), 6 81 (dd, 1 H) * Jones reagent was prepared from 13 4 g of chromium tπoxide and 11 5 mL of concentrated H 2 S0 4 , diluted to a final volume of 50 mL with H 2 0 B 2-(3,4-DICHLOROPHENOXY)-5-FLUORO-BENZOIC ACID ETHYL ESTER The preceding mixture in 75 mL of ethanol was treated with 1 mL of H 2 S0 4 and heated to reflux for 7 hr, then stirred overnight at room temperature The solvent was removed in vacuo and the residue was dissolved in EtOAc, was with water, saturated aqueous Na 2 C0 3 and then water After drying with MgS0 4 , the solvent was evaporated to give a brown oil, 2 1 g 1 H- nmr (CDCI 3 , 400 MHz, δ) 7 64 (dd, 1 H), 7 31 (d, 1 H), 7 22 (m, 1 H), 7 03 (dd, 1 H), 6 92 (s, 1 H), 6 72 (dd, 1 H), 4 24 (q, 2H), 1 19 (t, 3H) C 3-[2-(3,4-DICHLOROPHENOXY)-5-FLUOROBENZOYL]-1 -VINYL- PYRROLIDIN-2-0NE Under N 2 , a solution of 12 2 mL (12 2 mmol) of 1 0M lithium bιs-(trιmethylsιlyl)amιde in THF (Aldrich Chem Co ) was stirred and cooled to -30 °C while 781 μL (0 812 g, 7 31 mmol) of 1- vιnyl-2-pyrrohdιnone (Aldrich Chem Co ) was added via syringe After stirring at this temperature for 1 hr, the preceding ethyl ester in 20 mL of THF was added to produce a nearly black solution This mixture was stirred at room temperature for 72 hr, then diluted with water and EtOAc The aqueous layer was further extracted with EtOAc and the organic layers were combined, washed with water and saturated NaCl, dried over MgS0 4 and concentrated in vacuo to a tan foam, 2 18 g This material was used without purification in the following step D 5-[2-(3,4-DICHLOROPHENOXY)-5-FLUOROPHENYL]-2J-DIHYDRO-1 H- PYRROLE The preceding material was combined with 40 mL of 6N HCI and refluxed for 30 mm , producing a gummy precipitate 1 ,4-Dιoxane (30 mL) was added and the resulting solution was refluxed an additional 30 hr to give a black solution The reaction was made basic with saturated aqueous K 2 C0 3 and extracted three times with EtOAc The combined organic extracts were washed with water and saturated NaCl, dried with MgS0 4 and treated with activated charcoal (Darco G60) Filtration through d e , washing the pad well with EtOAc and concentration of the filtrate provided a tan oil, 0 803 g, used without further purification in the next step Mass spectrum (m/e) 325, 323 (m + ) E 2-[2-(3,4-DICHLOROPHENOXY)-5-FLUOROPHENYLl-PYRROLIDINE HYDRO-CHLORIDE To 0 300 g (0 93 mmol) of the preceding material in 15 mL of absolute ethanol was added 70 mg (1 86 mmol) of sodium borohydπde at room temperature under an N 2 atmosphere (Caution foaming) After 24 hr, a tic (CHCI 3 CH 3 OH, 95 5) showed a new polar product had formed Water was added to quench residual sodium borohydπde and the mixture was evaporated to a clear oil which was redissolved in EtOAc and washed with water The organic layer was further washed with water, saturated NaCl and then dried with MgS0 4 Removal of the solvent in vacuo gave a clear film, 0 202g Mass Spectrum (m/e) 328, 326 (m +1 ) 1 H-nmr (CDCI 3 , 400 MHz, δ) 7 35 (dd, 1 H), 7 32 (d, 1 H), 6 96 (d, 1 H), 6 87 (m, 2H), 6 73 (dd, 1 H), 4 26 (t, 1 H), 3 11 (m, 1 H), 2 97 (m, 1 H), 1 78 (m, 2H), 1 52 (m, 1 H) The free base was dissolved in 5 mL Et 2 0 and treated with 622 mL of 1 0 M HCI in Et 2 0, then stirred for 1 5 hr to produce the title compound hydrochloride salt as pale yellow solids, 165 mg, m p 171 -173 °C Mass Spectrum (m/e) 328, 326 (m +1 ) Elemental analysis calculated for C 16 H 14 CI 2 FNO-»HCI C, 52 99, H, 4 17, N, 3 86 Found C, 53 23, H, 4 25, N, 3 89 EXAMPLE 56 [2-(3,4-DICHLOROPHENOXY)-5-FLUOROBENZYL]-METHYLAMINE Under N 2 , a mixture of 0 313g (1 0 mmol) of 2-(3,4-dιchlorophenoxy)-5-fluoro-N-methyl- benzamide in 5 0 mL of anhydrous tetrahydrofuran (THF) was treated via syringe with 4 0 mL (4 0 mmol) of 1 0 M BH 3 in THF (Aldrich Chem Co ) and the mixture was heated to reflux for a total of 48 hr The reaction was quenched by the addition of 25 mL of 6N HCI and heating to reflux until the free amine could be detected by tic (CHCI 3 CH 3 OH TEA, (95 5 1 )) The cooled mixture was then diluted with water, basified with K 2 C0 3 and extracted with EtOAc The combined organic layers were washed with water and saturated NaCl, then dried with MgS0 4 , filtered and concentrated in vacuo to the free base as a light brown oil, 0 164 g, 54%) This compound was converted to the hydrochloride salt as described previously, m p 200-202 ° EXAMPLE 57 2-(3,4-DICHLOROPHENOXY)-5-FLUORO-BENZYLAMINE A flame-dried flask containing N 2 inlet and magnetic stirrer was charged with 3 0 mL of 2 0 M borane methyl sulfide complex in THF (6 0 mmol, Aldrich Chem Co ), followed by an additional 10 mL of anhydrous THF at room temperature While stirring, 0 562 g (2 0 mmol) of 2-(3,4-dιchlorophenoxy)-5-fluoro-benzonιtπle (title compound of Preparation 37) was added slowly via syringe, causing some mild foaming After the addition, the reaction was heated at reflux for a total of 3 hr, and a tic (CHCI 3 CH 3 OH cone NH 4 OH, 95 5 1 ) showed no starting material remaining With ice bath cooling, the reaction was quenched using 10 mL of 6N HCI, heated to reflux an additional 1 hr to break the boron complex and slowly made basic with saturated aqueous Na 2 C0 3 The mixture was diluted with water and EtOAc, the organic layer was combined with a second EtOAc extraction of the aqueous layer and then washed with water and saturated aqueous NaCl After drying over MgS04, the solvent was removed in vacuo to give a yellow tan oil, 0.676 g. The oil was partitioned between Et z O and 6N HCI, the Et 2 0 layer was reextracted with 6N HCI and the aqueous layers were combined, made basic with aqueous Na 2 C0 3 and reextracted with Et 2 0. These latter organic extracts were dried (MgSO„) and concentrated in vacuo to a tan oil, 0.538 g. Mass spectrum (APCI, m/z): 286 (ιm + ), 288. The oil was dissolved in Et 2 0 and treated with 2.0 mL of 1.0 M HCI in Et 2 0. The resulting solids were stirred at room temperature for 2 hr, filtered, washed with Et 2 0 and dried under vacuum to give the hydrochloride salt of the title product, 0.434 g, m.p. 190-194 °C. Elemental Analysis calculated for C 13 H 10 CI 2 FNO»HCI: C, 48.40, H, 3.43, N, 4.34. Found: C, 48.22, H, 3.80, N, 4.28.

Claims: CLAIMS A compound 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 and R 2 are attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C.,-C 6 )alkyl, R 3 and R 4 are selected, independently, from hydrogen and (C,-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 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, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, 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 (ι_e_, chloro, fluoro, bromo or lodo), (C 1 -C 4 )alkyl optionally substituted with from one to three fluorine atoms, (C r C 4 )alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, ammo, (C,- C alkylamino, dι-[(C r C 4 )alkyl]amιno, NR 5 (C=0)(C r C 4 )alkyl, S0 2 NR 5 R 6 and SO p (C r 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, 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, (n) R 1 and R 2 are selected, independently, from hydrogen and (C 1 -C 4 )alkyl, and (in) ring B is mono- or disubstituted with, respectively, one or two halo groups, or a pharmaceutically acceptable salt thereof 2 A compound or salt according to claim 1 , wherein n is one, X is fluoro, R 3 and R 4 are hydrogen, R 1 is hydrogen, R 2 is methyl, m is two and Y is Y m is 3,4-dιchloro 3 A compound or salt according to claim 1 , wherein m is zero, n is one, R 3 and R 4 are hydrogen, X is chloro, bromo, lodo or methyl, R 1 is hydrogen and R 2 ιs methyl 4 A compound or salt according to claim 1 , wherein said compound or salt is selected from the following compounds and their pharmaceutically acceptable salts [2-(3,4-Dιchlorophenoxy)-5-fluorobenzyl]-dιmethylamιne, [2-(3,4-Dιchlorophenoxy)-5-fluorobenzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-5-trιfluoromethylbenzyl]-dιmethylamme, N-[4-(3,4-Dιchlorophenoxy)-3-dιmethylamιnomethylphenyl]-acetamιde, {1-[2-(3,4-Dιchlorophenoxy)phenyl]-ethyl}-dιmethylamιne, [2-(3,4-Dιchlorophenoxy)-4-tπfluoromethylbenzyl]-dιmethylamιne, [2-(3,4-Dιchlorophenoxy)-4-tπfluoromethylbenzyl]-methylamιne, [4-Chloro-2-(3,4-dιchlorophenoxy)-benzyl]-methylamιne, {1 -[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-ethyl}-methylamιne, {1 -[2-(3,4-Dιchlorophenoxy)phenyl}-ethyl}-methylamιne, {1 -[2-(4-Chlorophenoxy)phenyl]ethyl}-methylamιne, [2-(3,4-Dιchlorophenoxy)-5-methoxybenzyl]-methylamιne, [2-(4-Chlorophenoxy)-5-fluorobenzyl]-methylamme, {1-[2-(4-Chlorophenoxy)-5-fluorophenyl]-ethyl}-methylamιne, [2-(3,4-Dιchlorophenoxy)-5-methylbenzyl]-dιmethylamιne, [4-Bromo-2-(3,4-dιchlorophenoxy)-benzyl]-methylamιne, [5-Bromo-2-(3,4-dιchlorophenoxy)-benzyl]-methyiamιne, [2-(3,4-Dιchlorophenoxy)-4,5-dιmethoxybenzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-4-methoxybenzyl]-dιmethylamιne, 4-(3,4-Dιchlorophenoxy)-3-methylamιnomethyl-benzonιtπle, [2-(3,4-Dιchlorophenoxy)-4,5-dιmethylbenzyl]-methylamιne, 3-(3,4-Dιchlorphenoxy)-4-methylamιnomethyl-benzonιtrιle, (+)-{1-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-ethyl}-methylamιne, (-)-{1 -[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-ethyl}-methylamιne, [2-(3,4-Dιchlorophenoxy)-5-trιfluoromethyl-benzyl]-methylamιne, [2-(3,4-Dιchlorophenoxy)-4-methoxybenzyl]-methylamιne, [2-(4-Chloro-3-fluorophenoxy)-5-fluorobenzyi]-methylamιne, [2-(3-Chloro-4-fluorophenoxy)-5-fluorobenzyl]-methylamιne, (+/-)-2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-pyrrohdιne, (-)-2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-pyrrolιdιne, (+)-2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-pyrrolιdιne, and 2-[2-(3,4-Dιchlorophenoxy)-5-fluorophenyl]-N-methylpyrrohdιne, 5 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 dyskmesias), 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 according to claim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier 6 A pharmaceutical composition for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, dopamine or norepmephrine 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 7 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, 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 dyskmesias), 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, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition 8 A method for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, dopamine or norepmephrine in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1 , that is effective in treating such disorder or condition 9 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 dyskmesias), 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, comprising a serotonin, dopamine or norepmephrine reuptake inhibiting effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier 10 A pharmaceutical composition for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, norepmephrine or dopamine in a mammal, comprising serotonin, dopamine or norepmephrine reuptake inhibiting effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier 1 1 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 (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 dyskmesias), 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 according to claim 1 or a pharmaceutically acceptable salt thereof. 12. A method for treating a disorder or condition that can be treated by inhibiting the reuptake of serotonin, norepinephrine or dopamine in a mammal, comprising administering to a mammal requiring such treatment a serotonin, dopamine or norepinephrine reuptake inhibiting effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof. 13 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) a compound according to claim 1 ; and c) an NK-1 receptor antagonist or a 5HT 1D receptor antagonist, or a pharmaceutically acceptable salt thereof; wherein the amount of the active compounds (i.e., the compound of formula I and the NK-1 receptor antagonist or 5HT 1D receptor antagonist) are such that the combination is effective in treating such disorder or condition. 14. 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 of the formula I, defined above, or a pharmaceutically acceptable salt thereof, and b) an NK-1 receptor antagonist or 5HT 1D receptor antagonist, or a pharmaceutically acceptable salt thereof; wherein the amounts of the active compounds (i.e., the compound of formula I and the NK-1 receptor antagonist or 5HT 1D receptor antagonist) are such that the combination is effective in treating such disorder or condition. 15. A compound of the formula wherein Q is -C(=0)H, cyano, -C(=0)OH, or -C(=0)NR 1 R 2 wherein R 1 and R 2 are selected, independently, from hydrogen and (C 1 -C 4 )alkyl, or R 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 16 A compound having the formula or a pharmaceutically acceptable salt thereof

Inventors: ELLIOTT MARK LEONARD, HOWARD HARRY RALPH JR, SCHMIDT CHRISTOPHER JOSEPH, SEEGER THOMAS FRANCIS, ELLIOTT, MARK, LEONARD, HOWARD, HARRY, RALPH, JR., SCHMIDT, CHRISTOPHER, JOSEPH, SEEGER, THOMAS, FRANCIS
Applicants: ELLIOTT MARK LEONARD, HOWARD HARRY RALPH JR, PFIZER PROD INC, SCHMIDT CHRISTOPHER JOSEPH, SEEGER THOMAS FRANCIS, ELLIOTT, MARK, LEONARD, HOWARD, HARRY, RALPH, JR., PFIZER PRODUCTS INC., SCHMIDT, CHRISTOPHER, JOSEPH, SEEGER, THOMAS, FRANCIS
Application year: 2000
Main classification: C07C217
IPC codes: A61K31, A61P25, C07C217, C07C235, C07C255, C07C311, C07C317, C07C323, C07D207, C07D211, C07D265, C07D279