Arylpiperazines having activity at the serotonin 1A receptor

Abstract

A series of aryl piperazine compounds are effective pharmaceuticals for the treatment of conditions related to or affected by the serotonin 1 A receptor; the compounds are particularly effective antagonists at that receptor, and are particularly useful for alleviating the symptoms of nicotine and tobacco withdrawal.

1 . A method for treating obesity, the method comprising administering to a patient in need of such treatment of an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar′ is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 R 1  is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio;  
 R 2  is phenyl, naphthyl or (C 3 -C 12 )cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 R 3  is selected from the group consisting of hydrogen (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 X is —(C═O)—;  
 or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof.  
 
     
     
         2 . The method of  claim 1 , wherein Ar′ is phenyl substituted with (C 1 -C 6 )alkoxy.  
     
     
         3 . The method of  claim 1 , wherein R 2  is phenyl or (C 3 -C 12 )cycloalkyl.  
     
     
         4 . The method of  claim 1 , wherein the compound has a formula:  
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the pharmaceutically acceptable salt is a dihydrochloride salt or a monohydrochloride salt.  
     
     
         6 . The method of  claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of an oxalate salt, a maleate salt, and a phosphate salt.  
     
     
         7 . A method for treating sexual dysfunction, the method comprising administering to a patient in need of such treatment of an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar′ is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 R 1  is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio;  
 R 2  is phenyl, naphthyl or (C 3 -C 12 )cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 R 3  is selected from the group consisting of hydrogen (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 X is —(C═O)—;  
 or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof.  
 
     
     
         8 . The method of  claim 7 , wherein Ar′ is phenyl substituted with (C 1 -C 6 )alkoxy.  
     
     
         9 . The method of  claim 7 , wherein R 2  is phenyl or (C 3 -C 12 )cycloalkyl.  
     
     
         10 . The method of  claim 7 , wherein the compound has a formula:  
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 7 , wherein the pharmaceutically acceptable salt is a dihydrochloride salt or a monohydrochloride salt.  
     
     
         12 . The method of  claim 7 , wherein the pharmaceutically acceptable salt is selected from the group consisting of an oxalate salt, a maleate salt, and a phosphate salt.  
     
     
         13 . A method for treating an eating disorder, the method comprising administering to a patient in need of such treatment of an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar′ is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 R 1  is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio;  
 R 2  is phenyl, naphthyl or (C 3 -C 12 )cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 R 3  is selected from the group consisting of hydrogen (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylhalo, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl or halo;  
 X is —(C═O)—;  
 or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof.  
 
     
     
         14 . The method of  claim 13 , wherein Ar′ is phenyl substituted with (C 1 -C 6 )alkoxy.  
     
     
         15 . The method of  claim 13 , wherein R 2  is phenyl or (C 3 -C 12 )cycloalkyl.  
     
     
         16 . The method of  claim 13 , wherein the compound has a formula:  
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 13 , wherein the pharmaceutically acceptable salt is a dihydrochloride salt or a monohydrochloride salt.  
     
     
         18 . The method of  claim 13 , wherein the pharmaceutically acceptable salt is selected from the group consisting of an oxalate salt, a maleate salt, and a phosphate salt.