Combinations of Eszopiclone and Trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-N-Methyl-1-Napthalenamine or Trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-1-Napthalenamine, and Methods of Treatment of Menopause and Mood, Anxiety, and Cognitive Disorders

Abstract

One aspect of the present invention relates to pharmaceutical compositions containing two or more active agents that when taken together can be used to treat, e.g., menopause, mood disorders, anxiety disorders, or cognitive disorders. The first component of the pharmaceutical composition is a sedative eszopiclone. The second component of the pharmaceutical composition is trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine. The present invention also relates to a method of treating menopause, perimenopause, mood disorders, anxiety disorders, and cognitive disorders.

1 . A pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       2 . A pharmaceutical composition comprising eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       3 . A method of treating a patient suffering from a menopause or perimenopause, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       4 . A method of treating a patient suffering from a menopause or perimenopause, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       5 . A method of treating a patient suffering from a mood disorder, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       6 . A method of treating a patient suffering from a mood disorder, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       7 . A method of treating a patient suffering from an anxiety disorder, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       8 . A method of treating a patient suffering from an anxiety disorder, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       9 . A method of treating a patient suffering from a cognitive disorder, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       10 . A method of treating a patient suffering from a cognitive disorder, comprising the step of co-administering to a patient in need thereof a therapeutically effective amount of eszopiclone, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof, and a therapeutically effective amount of trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, or co-crystal thereof. 
   
   
       11 . The method according to  claim 5  or  6 , wherein the mood disorder is selected from major depression, major depressive disorder, mild depression, severe depression without psychosis, severe depression with psychosis, melancholia, atypical depression, dysthymic disorder, manic depression, bipolar disorder, bipolar I disorder, bipolar II disorder, bipolar III disorder, cyclothymic disorder, chronic hypomania, premenstrual syndrome, premenstrual dysphoric disorder, prenatal depression, and postpartum depression. 
   
   
       12 . The method according to  claim 7  or  8 , wherein the anxiety disorder is selected from panic attacks, panic disorder, phobic disorders, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, and generalized Anxiety Disorder. 
   
   
       13 . The method according to  claim 9  or  10 , wherein the cognitive disorder is selected from delirium, dementia, Alzheimer's Disease, Lewy body dementia, vascular dementia, Binswanger's dementia, Parkinson's disease, progressive supranuclear palsy, Huntington's disease, Pick's disease, Klüver-Bucy syndrome, frontal lobe dementia syndromes, normal-pressure hydrocephalus, subdural hematoma, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, general paresis, AIDS dementia, decreased cognitive function and memory loss. 
   
   
       14 . A process for preparation of a compound of formula P 
     
       
         
         
             
             
         
       
     
     comprising:
 a) reacting a compound of formula 1 
 
     
       
         
         
             
             
         
       
       
         wherein Z is chosen from aryl, aryl substituted by alkyl, alkyl substituted by aryl, and —CR 4 R 5 R 6 , wherein R 4  is C 1 -C 6  alkyl, R 5  is C 1 -C 6  alkyl, and R 6  is C 1 -C 6  alkyl, 
         in presence of a dehydrating agent to obtain compound of formula 2a 
       
     
     
       
         
         
             
             
         
       
       
          and 
       
       b) reducing the compound of formula 2a with a hydride reducing agent followed by solvolysis. 
     
   
   
       15 . The process according to  claim 14  wherein solvolysis is catalyzed by acid. 
   
   
       16 . The process according to  claim 15  further comprising crystallizing an acid addition salt of the compound of formula P. 
   
   
       17 . The process according to any of  claims 14  through  16  further comprising a step of converting a product compound to a free base of compound P. 
   
   
       18 . The process according to  claim 14  wherein the dehydrating agent is selected from titanium alkoxide, boron trifluoride etherate, boron trifluoride etherate with magnesium sulfate, and molecular sieves. 
   
   
       19 . The process according to  claim 18  wherein the titanium alkoxide is selected from titanium ethoxide and titanium isopropoxide. 
   
   
       20 . The process according to  claim 14  wherein the reducing agent is selected from 9-borabicyclononane, sodium borohydride, catechol borane, borane, and diisobutylaluminum hydride with zinc halide. 
   
   
       21 . The process according to  claim 15  wherein the acid is hydrochloric acid. 
   
   
       22 . The process according to  claim 14  wherein each of R 4 , R 5 , and R 6  is methyl. 
   
   
       23 . The process according to  claim 17  wherein the converting step comprises treating with a base. 
   
   
       24 . The process according to  claim 16  further comprising recrystallizing an acid addition salt of the compound of formula P from a solvent selected from an alcohol and a mixture of alcohol and hydrocarbon solvent. 
   
   
       25 . The process according to  claim 20  wherein the reducing step is carried out in a solvent comprising tetrahydrofuran.