Pyrazolecarboxylic acid derivatives, their preparation and pharmaceutical compositions containing them

Abstract

N-Piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide and its salts and solvates are powerful antagonists of the CB 1 cannabinoid receptors. They are prepared by reacting a functional derivative of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid with 1-aminopiperidine, optionally followed by salification.

1 . N-Piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide, of formula:  
       
         
           
           
               
               
           
         
       
       its pharmaceutically acceptable salts and the solvates thereof.  
     
     
         2 . Process for preparing N-piperidino-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxamide, its salts and the solvates thereof, characterized in that a functional derivative of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid, of formula:  
       
         
           
           
               
               
           
         
       
       is treated with 1-aminopiperidine, in an organic solvent and in the presence of a base; and the compound thus obtained is optionally converted into one of its salts or one of the solvates thereof.  
     
     
         3 . Process according to  claim 2 , for preparing an alkyl ester of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid by cyclization of an alkyl ester of 3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl)hydrazono)pentanoic acid (IX).  
     
     
         4 . Process according to  claim 3 , for preparing an alkyl ester of 3-(4-bromobenzoyl)-2-(2-(2,4-dichlorophenyl)hydrazono)pentanoic acid by the action of a 2,4-dichlorophenylhydrazine salt on an alkyl ester of 4-bromobenzoyl-2-oxopentanoic acid (VIII).  
     
     
         5 . Process according to  claim 4 , for preparing an alkyl ester of 4-bromobenzoyl-2-oxopentanoic acid by the action of LiHMDS and then an alkyl ester of 2-(1-imidazolyl)-2-oxoacetic acid on bromobutyrophenone.  
     
     
         6 . Process according to  claim 2 , for preparing an alkyl ester of 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethylpyrazole-3-carboxylic acid from 4-bromobenzoyl-2-oxopentanoic acid by the action of a 2,4-dichlorophenylhydrazine salt, followed by cyclization.  
     
     
         7 . Compound of formula:  
       
         
           
           
               
               
           
         
       
       in which Alk represents a (C 1 -C 6 )alkyl.  
     
     
         8 . Compound of formula  
       
         
           
           
               
               
           
         
       
       in which Alk represents a (C 1 -C 6 )alkyl.  
     
     
         9 . Pharmaceutical composition containing, as active principle, a compound according to  claim 1 .  
     
     
         10 . Pharmaceutical composition according to  claim 9 , containing from 0.1 to 1000 mg of active principle, in unit dosage form, in which the active principle is mixed with at least one pharmaceutical excipient.  
     
     
         11 . Use of a compound according to  claim 1  for the preparation of medicinal products intended for treating diseases involving the CB 1  cannabinoid receptors.  
     
     
         12 . Use of a compound according to  claim 11  for the treatment of psychotic disorders, for the treatment of appetite disorders and obesity, for the treatment of memory and cognitive disorders; for the treatment of alcohol dependency and for withdrawal from tobacco.