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WO2007036781A1 - Inhibiteur de la recapture de la monoamine diphenylether - Google Patents

Inhibiteur de la recapture de la monoamine diphenylether Download PDF

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Publication number
WO2007036781A1
WO2007036781A1 PCT/IB2006/002650 IB2006002650W WO2007036781A1 WO 2007036781 A1 WO2007036781 A1 WO 2007036781A1 IB 2006002650 W IB2006002650 W IB 2006002650W WO 2007036781 A1 WO2007036781 A1 WO 2007036781A1
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compound
formula
enantiomer
pharmaceutically acceptable
amount
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Harry Ralph Howard, Jr.
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Pfizer Products Inc
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Pfizer Products Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Serotonin Selective Reuptake Inhibitors 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).
  • DRIs dopamine reuptake inhibitors
  • SRI and DRI may haveten 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.
  • CNS central nervous system
  • 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.
  • 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.
  • OCD obsessive-compulsive disorder
  • 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 N 1 N- 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.
  • the present invention relates to a compound of the formula -Z-
  • Ri is hydrogen or C 1 -C 6 alkyl
  • X and Y are independently selected from the group consisting of fluoro, chloro and bromo; and, the pharmaceutically acceptable salts thereof.
  • the invention relates to the compound, wherein X and Y are different, and R is methyl or ethyl.
  • 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
  • (+) enantiomer which has the S configuration at the benzylic carbon, and the pharmaceutically acceptable salts thereof, is preferred
  • 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.
  • 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:
  • 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.
  • 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
  • the compound of formula III is prepared by treating the compound of formula
  • 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.
  • ADHD attention deficit hyperactivity disorder
  • 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.
  • 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.
  • 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.
  • 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.
  • 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...
  • 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,
  • 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
  • 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...
  • 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,
  • 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
  • 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 I 1 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
  • 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
  • R 1 is a group of the formula G 1 or G 2 depicted below,
  • G 1 G2 a is zero to eight; m is one to three;
  • R 6 is selected from the group consisting of hydrogen, (Ci-C 6 )alkyl optionally substituted with (Ci-C 6 )alkoxy or one to three fluorine atoms, or ((C r C 4 )alkyl)aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH 2 ) 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 r C 6 )alkyl, (Ci-C 6 )alkoxy, triflu
  • X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C 1 -C 6 )alkyl, hydroxy, (CrC 6 )alkoxy, -SOt(C r C 6 )alkyl wherein t is zero, one or two, -CO 2 R 10 or -CONR 11 R 12 ; each of R 10 , R 11 and R 12 is selected, independently, from hydrogen, (C ⁇ -C 4 )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-C 3 )alkyl, (C 1 -C 6 JaIkOXy, trifluoromethyl, cyano and -SOt(C 1 -C 6 )alkyl wherein t is zero, one or two; or R 11 and R 12 ,
  • R 3 is -(CH 2 ) g B, 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- C 8 )hydroxyalkyl-, (C 1 -C 8 )alkoxy-(C 1 -C 8 )alkyl-, (C 3 -C 8 )hydroxycycloalkyl-, (C 3 -C 8 )CyClOaIkOXy-, (C 1 - C 8 )alkoxy-(C 3 -C 8 )cycloalkyl-, heterocycloalkyl, hydroxy
  • each said ring may be optionally substituted with one to three substituents independently selected from (a) lactone formed from -(CH 2 ) t OH with an ortho -COOH 1 wherein t is one, two or three; (b) -CONR 14 R 15 , wherein R 14 and R 15 are independently selected from (C-rC ⁇ )alkyl and benzyl, or R 14 and R 15 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
  • R 18 and R 19 are selected, independently, from hydrogen and (Ci-C 4 )alkyl, or R 18 and R 19 , 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
  • This invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I.
  • 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.
  • 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.
  • 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 3 H, 11 C, 14 C, 18 F, 123 I and 125 I.
  • 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., ValiumTM). "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.
  • 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 0 0 C to about 15O 0 C for about 1 hour to about 7 days, preferably at about 90-95 0 C 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.
  • 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 (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ), sodium hydroxide (NaOH), potassium hydroxide (KOH) and organic amines such as pyrrolidine, triethylamine and pyridine, with anhydrous K 2 CO 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.
  • 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 20 0 C to about 25 0 C, 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).
  • a dehydrating reagent such as titanium (IV) tetrachloride or titanium (IV) isopropoxide
  • 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.
  • an inert solvent such as benzene or toluene
  • a water scavenger such as molecular sieves
  • 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 1 H-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.
  • reducing agents include, for example, sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN) and sodium triacetoxy-borohydride (NaBH(OAc) 3 , as described by A. F. Abdel-Magid et aL in Tetrahedron Letters, 1990, 31. 5595).
  • NaBH 4 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 0 0 C to about 100 0 C 1 preferably at about 20 0 C to about 25 0 C, for about 0.5 hour to about 24 hours, preferably about 1 hour to about 16 hours.
  • a polar solvent such as methanol, ethanol, isopropanol or a like solvent
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • additional ingredients such as flavorings, binders, excipients and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • 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.
  • 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.
  • 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.
  • 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 TeflonTM 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 4 0 C. The final pellet is resuspended in an appropriate volume of sucrose buffer that yielded less than 10% uptake.
  • the buffer
  • 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).
  • 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.
  • 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 C 14 H 12 CI 2 FNO-HCI: C, 49.95, H, 3.89, N, 4.16. Found: C 1 49.82, H, 3.85, N, 4.14.

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Abstract

La présente invention concerne un composé de formule (I), dans laquelle R1 est hydrogène ou alkyle C1-C6 et X et Y sont indépendamment choisis dans le groupe constitué par fluoro, chloro et bromo, ses énantiomères, un racémate et des mélanges d'énantiomères ainsi que les sels pharmaceutiquement acceptables correspondants, ces composés agissant comme inhibiteurs de la recapture de la sérotonine, de la norépinéphrine et de la dopamine, d'où leur utilité dans le traitement de troubles du système nerveux central et d'autres troubles.
PCT/IB2006/002650 2005-09-30 2006-09-18 Inhibiteur de la recapture de la monoamine diphenylether Ceased WO2007036781A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7767666B2 (en) 2006-06-29 2010-08-03 Janssen Pharmaceutica Nv Butyl and butynyl benzyl amine compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5190965A (en) * 1991-05-29 1993-03-02 Akzo N.V. Phenoxyphenyl derivatives, compositions and methods of use thereof
WO2000050380A1 (fr) * 1999-02-23 2000-08-31 Pfizer Products Inc. Inhibiteurs de recaptage de monoamine destines au traitement de troubles du systeme nerveux central

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5190965A (en) * 1991-05-29 1993-03-02 Akzo N.V. Phenoxyphenyl derivatives, compositions and methods of use thereof
WO2000050380A1 (fr) * 1999-02-23 2000-08-31 Pfizer Products Inc. Inhibiteurs de recaptage de monoamine destines au traitement de troubles du systeme nerveux central

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7767666B2 (en) 2006-06-29 2010-08-03 Janssen Pharmaceutica Nv Butyl and butynyl benzyl amine compounds

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