Therapeutic Combinations for the Treatment or Prevention of Depression

Abstract

Therapeutic combinations useful in the treatment or prevention of depression or other mood disorders, to pharmaceutical compositions containing said combinations, and to their use in the treatment or prophylaxis of depression or other mood disorders are provided. Such compounds are of formula I: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 3 , n, y, and Ar are as defined and described herein.

1 - 16 . (canceled) 
     
     
         17 . A method of treating a patient suffering from a depression or a mood disorder comprising administering to said patient a therapeutically effective amount of a a composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         n is one or two; 
         each of R 2  and R 3  is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl; 
         each R 1  is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN; 
         Ar is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more R x  substituents; 
         each R x  is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN; and 
         y is 0-3; 
         and an antidepressant. 
       
     
     
         18 . A method of treating a patient suffering from anxiety comprising administering to said patient a therapeutically effective amount of an anxiety-reducing composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         n is one or two; 
         each of R 2  and R 3  is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl; 
         each R 1  is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN; 
         Ar is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more R x  substituents; 
         each R x  is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN; and 
         y is 0-3; 
         and an antidepressant. 
       
     
     
         19 . A method of treating a patient suffering from a psychotic disorder comprising administering to said patient an therapeutically effective amount of a composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         n is one or two; 
         each of R 2  and R 3  is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl; 
         each R 1  is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN; 
         Ar is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more R x  substituents; 
         each R x  is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN; and 
         y is 0-3; 
         and an antidepressant. 
       
     
     
         20 . The method of  claim 19  wherein the patient is suffering from schizophrenia. 
     
     
         21 . A method of treating a patient suffering from bipolar disorder comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         n is one or two; 
         each of R 2  and R 3  is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl; 
         each R 1  is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN; 
         Ar is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more R x  substituents; 
         each R x  is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN; and 
         v is 0-3; 
         and an antidepressant. 
       
     
     
         22 . The method according to  claim 17 , wherein the antidepressant is selected from the group consisting of seratonin reuptake inhibitors (SRIs), norepinephrine reuptake inhibitors (NERIs), combined serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), phosphodiesterase-4 (PDE4) inhibitors, corticotropin releasing factor (CRF) antagonists, alpha.-adrenoreceptor antagonists, and combinations thereof. 
     
     
         23 . The method according to  claim 17 , wherein the antidepressant is selected from the group consisting of adinazolam, alaproclate, amineptine, amitriptyline, amitriptyline/chlordiazepoxide combination, amoxapine, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, buproprion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clomipramine, clovoxamine, dazepinil, deanol, demexiptiline, desipramine, O-desmethylvenlafaxine, dibenzepin, dothiepin, doxepin, droxidopa, duloxetine, enefexine, escitalopiam, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, fluoxetine, fluvoxamine, idazoxan, imipramine, indalpine, indeloxazine, iprindole, isocarboxazid, levoprotiline, lithium, litoxetine, lofepramine, maprotiline, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, montirelin, nebracetam, nefazodone, nefopam, netazodane, nialamide, nomifensine, norfluoxetine, nortriptyline, orotirelin, oxaflozane, paroxetine, phenelzine, pinazepam, pirlindone, pizotyline, protriptyline, reboxetine, ritanserin, rolipram, selegiline, sercloremine, sertraline, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, tranylcypromine, trazodone, trimipramine, venlafaxine, veralipride, viloxazine, viqualine, zimelidine, zometrapine, pharmaceutically acceptable salts thereof, and combinations thereof. 
     
     
         24 . The method according to  claim 17 , wherein administration of the compounds is oral. 
     
     
         25 . The method according to  claim 17 , wherein the patient is suffering from depression. 
     
     
         26 . The method according to  claim 17 , wherein the patient is suffering from anxiety. 
     
     
         27 . The method according to  claim 17 , wherein the patient is further suffering from a psychotic disorder. 
     
     
         28 . The method according to  claim 27 , wherein the patient is suffering from schizophrenia. 
     
     
         29 . The method of  claim 27  wherein the patient is suffering from bipolar disorder. 
     
     
         30 . The method according to  claim 17 , wherein the patient is suffering from a mood disorder selected from the group consisting of dysthymic disorder with early or late onset and with or without atypical features; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood, disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics; schizoaffective disorder of the depressed type; adjustment disorder with depressed mood; and combinations thereof.