Ethers of O-Desmethyl venlafaxine

Abstract

This invention provides O-α-acyloxyalkyl ethers of the venlafaxine metabolite 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, represented by Formula (I): wherein: the configuration at the steriogenic center (*) may be R, S, or RS (the racemate); R 1 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, or the moiety: R 2 is selected from H, or C 1 -C 6 alkyl; or, R 1 and R 2 may be concatenated such that  form a moiety having formula (b): R3 is selected from H or C 1 -C 6 alkyl; and R4 and R5 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, —CN, —OH, —CF 3 , —OCF 3 , halogen, —NH 2 , —NO 2 , or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or pharmaceutically acceptable salts or hydrates thereof, R, S, or RS forms thereof; as well as pharmaceutical compositions and methods treating central nervous system disorders.

What is claimed:  
     
         1 . A compound of the Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 the configuration at the steriogenic center (*) may be R, S, or RS (the racemate);  
 R 1  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, or the moiety:  
                     
 R 2  is selected from H, or C 1 -C 6  alkyl; or  
 R 1  and R 2  may be concatenated such that  
                     
  form a moiety having formula (b):  
                     
 R3 is selected from H or C 1 -C 6  alkyl; and  
 R4 and R5 are independently selected from H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  thioalkoxy, —CN, —OH, —CF 3 , —OCF 3 , halogen, —NH 2 , —NO 2 , or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or pharmaceutically acceptable salts or hydrates thereof.  
 
     
     
         2 . A compound of  claim 1  wherein R1 is C 1 -C 6  alkyl or C 1 -C 6  alkoxy.  
     
     
         3 . A compound of  claim 1  wherein R2 is C 1 -C 6  alkyl.  
     
     
         4 . A compound of  claim 1  wherein R1 and R2 are concatenated such that  
       
         
           
           
               
               
           
         
       
       form a moiety having formula (b):  
       
         
           
           
               
               
           
         
       
       and R4 and R5 are hydrogen.  
     
     
         5 . A compound of  claim 1  which is {4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl pivalate, or a pharmaceutically acceptable salt or hydrate thereof.  
     
     
         6 . A compound of  claim 1  which is 1-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}ethyl propionate, or a pharmaceutically acceptable salt or hydrate thereof.  
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of  claim 1  which is 3-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}-2-benzofuran-1(3H)-one, or a pharmaceutically acceptable salt or hydrate thereof.  
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 the configuration at the steriogenic center (*) may be R, S, or RS;  
 R 1  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, or the moiety:  
                     
 R 2  is selected from H, or C 1 -C 6  alkyl; or,  
 R 1  and R 2  may be concatenated such that  
                     
  form a moiety having formula (b):  
                     
 R3 is selected from H or C 1 -C 6  alkyl; and  
 R4 and R5 are independently selected from H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  thioalkoxy, —CN, —OH, —CF 3 , —OCF 3 , halogen, —NH 2 , —NO 2 , or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or pharmaceutically acceptable salts or hydrates thereof; and a pharmaceutically acceptable carrier or excipient.  
 
     
     
         9 . A method of treating disorders of the central nervous system in a mammal, the method comprising providing to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 the configuration at the steriogenic center (*) may be R, S, or RS;  
 R 1  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, or the moiety:  
                     
 R 2  is selected from H, or C 1 -C 6  alkyl; or,  
 R 1  and R 2  may be concatenated such that  
                     
  form a moiety having formula (b):  
                     
 R3 is selected from H or C 1 -C 6  alkyl; and  
 R4 and R5 are independently selected from H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  thioalkoxy, —CN, —OH, —CF 3 , —OCF 3 , halogen, —NH 2 , —NO 2 , or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or a pharmaceutically acceptable salt or hydrate thereof.  
 
     
     
         10 . The method of  claim 9  wherein the central nervous system disorder is depression.  
     
     
         11 . The method of  claim 9  wherein the central nervous system disorder is generalized anxiety disorder.  
     
     
         12 . The method of  claim 9  wherein the central nervous system disorder is panic disorder.  
     
     
         13 . The method of  claim 9  wherein the central nervous system disorder is post traumatic stress disorder.  
     
     
         14 . The method of  claim 9  wherein the central nervous system disorder is attention deficit disorder, with and without hyperactivity.  
     
     
         15 . The method of  claim 9  wherein the central nervous system disorder is anxiety.  
     
     
         16 . The method of  claim 9  wherein the central nervous system disorder is schizophrenia.  
     
     
         17 . The method of  claim 9  wherein the central nervous system disorder is cocaine and alcohol addiction.  
     
     
         18 . The method of  claim 9  wherein the central nervous system disorder is premenstrual dysphoric disorder.  
     
     
         19 . The method of  claim 9  wherein the central nervous system disorder is autism.  
     
     
         20 . The method of  claim 9  wherein the central nervous system disorder is anorexia nervosa, bulimia nervosa, vasomotor flushing, and chronic fatigue syndrome.  
     
     
         21 . The method of  claim 9  wherein the central nervous system disorder is urinary incontinence.  
     
     
         22 . The method of  claim 9  wherein the central nervous system disorder is pain.  
     
     
         23 . The method of  claim 9  wherein the central nervous system disorder is sexual dysfunction.  
     
     
         24 . A method of enhancing cognition in a mammal, the method comprising providing to a mammal in need thereof a pharmaceutically effective amount of a compound of Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 the configuration at the steriogenic center (*) may be R, S, or RS;  
 R 1  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, or the moiety:  
                     
 R 2  is selected from H, or C 1 -C 6  alkyl; or,  
 R 1  and R 2  may be concatenated such that  
                     
  form a moiety having formula (b):  
                     
 R3 is selected from H or C 1 -C 6  alkyl; and  
 R4 and R5 are independently selected from H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  thioalkoxy, —CN, —OH, —CF 3 , —OCF 3 , halogen, —NH 2 , —NO 2 , or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or a pharmaceutically acceptable salt or hydrate thereof.