Cyanophenyl derivative

Abstract

This application relates to a piperazino-substituted novel cyanophenyl derivative in which a substituted carbamoyl or substituted sulfamoyl group having an aryl, heterocyclic or the like group that may have a substituent group is bonded to one nitrogen atom on the piperazine ring. The compound of this application has an anti-androgen action and is useful in preventing or treating prostatic cancer, benign prostatic hyperplasia and the like diseases.

1 . A compound represented by general formula (II) or a salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein each symbol has the following meaning: 
 R: cyano or nitro group,  
 R 1 : a hydrogen atom, a halogen atom or a cyano, halogeno-lower alkyl, nitro, carboxyl, lower alkyl, R 6 -A-, R 7 —S(O) p —, lower alkyl-C(═O)— or lower alkyl-C(═O)— or lower alkyl-O—C(═O)— group,  
 R 2  and R 3 : these may be the same or different from one another and each means a hydrogen atom, a lower alkyl group, a carbamoyl group which may be substituted by 1 or 2 lower alkyl groups or a lower alkyl-C(═O)— or lower alkyl-O—C(═O)— group,  
 wherein R 2  and R 3  bind to optional carbon atoms on the ring,  
 R 6 : a halogeno-lower alkyl; aryl; or lower alkyl which may be substituted by N(R 9 )R 10 ,  
 OH or lower alkyl-O—,  
 R 7 : a lower alkyl, aryl or N(R 11 )R 12 —,  
 R 8 , R 9 , R 10 , R 11 , and R 12 :hydrogen, lower alkyl or aryl,  
 with the proviso that 
 (1) in the case where Z 1 =Z 2 =CH and n=1 and k=2: 
 i) when R is CN and R 1  is a halogen atom or a cyano group, at least one of R 2  and R 3 is a group other than a hydrogen atom,  
 ii) when R is CN and R 1  is a hydrogen atom, both of R 2  and R 3  are not hydrogen atoms or one of R 2  and R 3  is a methyl group and the other group is a group other than a hydrogen atom,  
 iii) when R is a nitro group and R 1  is a methyl group, a methoxy group, CF 3 , a carboxyl group, or SO 2 N(Me) 2 , at least one of R 2  and R 3  is a group other than a hydrogen atom,  
 iv) when R is a nitro group and R 1  is a hydrogen atom, at least one of R 2  and R 3  is a group other than a hydrogen atom and a methyl group,  
 v) when R and R 1  are nitro groups, at least one of R 2  and R 3  is a group other than a hydrogen atom, a methyl group, a carboxyl group, and COOMe;  
 
 (2) in the case where Z 1 =Z 2 =CH and n=1 and k=3 or n=2 and k=2: 
 when R is a cyano group and R 1  is a hydrogen atom, or when R is a nitro group and R 1  isahydrogen atom, a chlorine atom, a cyano group, COOMe, CF 3 , or a methyl group, at least one of R 2  and R 3  is a group other than a hydrogen atom;  
 
 (3) in the case where Z 1 -N, Z 2 =CH and n=1 and k=2: 
 when R and R′ are nitro groups, at least one of R 2  and R 3  is a group other than a hydrogen atom.  
 
 
 
     
     
         2 . A compound according to  claim 1  represented by general formula (II) or a salt thereof, wherein the compound is selected from the group consisting of trans-4-(2,5-dimethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile; 4-piperazin-1-yl-2-trifluoromethylbenzonitrile; trans-4-(2,5-dimethylpiperazin-1-yl)benzonitrile; trans-4-(2,5-dimethylpiperazin-1-yl)-2-fluorobenzonitrile; trans-2-chloro-4-(2,5-dimethylpiperazin-1-yl)benzonitrile; trans-2-bromo-4-(2,5-dimethylpiperazin-1-yl)benzonitrile; trans-4-(2,5-dimethylpiperazin-1-yl)-2-methylbenzonitrile; trans-4-(2,5-dimethylpiperazin-1-yl)-3-fluorobenzonitrile; trans-4-(2,5-dimethylpiperazin-1-yl)-3-trifluoromethylbenzonitrile; 4-(3-methylpiperazin-1-yl)-2-trifluoromethylbenzonitrile; trans-6-(2,5-dimethylpiperazin-1-yl)nicotinonitrile; 4-(hexahydro-1H-1,4-diazepin-1-yl)-2-trifluromethylbenzonitrile; cis-4-(3,5-dimethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile; and trans-2,5-dimethyl-1-[4-nitro-3-(trifluoromethyl)phenyl]piperazine.  
     
     
         3 . A compound according to  claim 1  represented by general formula (II) or a salt thereof, wherein the compound is 4-(2-methylpiperazin-1-yl)-2-trifluoromethylbenzonitrile.  
     
     
         4 . A compound according to  claim 1  represented by general formula (II) or a salt thereof, wherein the compound is selected from the group consisting of 4-(2-ethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile; 4-[2-(1-methylethyl)piperazin-1-yl]-2-trifluoromethylbenzonitrile; and 4-(2 ,2-dimethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile.  
     
     
         5 . A compound according to  claim 1  represented by general formula (II) or a salt thereof, wherein the compound is trans-4-(2,5-dimethylpiperazin-1-yl)phthalonitrile.  
     
     
         6 . A compound according to  claim 1  represented by general formula (II) or a salt thereof, wherein the compound is selected from the group consisting of 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-trifluoromethylbenzonitrile; and 4-[(2R,5S)-2,5-dimethylpiperazin-1-yl]-2-trifluoromethylbenzonitrile.  
     
     
         7 . A compound according to  claim 1  represented by general formula (II) or a salt thereof, wherein the compound is selected from the group consisting of trans-4-(2,5-dimethylpiperazin-1-yl)-2-methoxybenzonitrile; trans-4-(2,5-dimethylpiperazin-1-yl)-2-(2-methoxyethoxy)benzonitrile; and trans-4-(2,5-dimethylpiperazin-1-yl)-2-(2-morpholin-4-yl-ethoxy)benzonitrile.