Piperazine compounds and medicinal use thereof

Abstract

The present invention relates to a piperazine compound of the formula wherein R 1 and R 2 are each hydrogen, halogen, lower alkyl, lower alkoxy, amino, substituted amino, nitro, hydroxy or cyano, R 3 , R 4 and R 5 are each hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, substituted amino or hydroxy, R 6 and R 7 are each hydrogen, lower alkyl, lower alkyl substituted by halogen, aralkyl, acyl or lower acyl substituted by halogen, R 8 and R 9 are each hydrogen or lower alkyl, Y is lower alkylene and the like, and ring A is phenyl, pyrimidyl, thiazolyl, pyridyl, pyrazyl or imidazolyl, a pharmaceutically acceptable salt thereof and pharmaceutical agents containing these compounds. The compound of the present invention has superior TNF-α production inhibitory effect and/or IL-10 production promoting effect, and, since it is free of or shows only strikingly reduced expression of an effect on the central nervous system, the compound is useful as a highly safe and superior TNF-α production inhibitor an/or IL-10 production promoter and is useful as an agent for the prophylaxis or treatment of various diseases caused by abnormal TNF-α production, diseases curable with IL-10, such as chronic inflammatory diseases, acute inflammatory diseases, inflammatory diseases due to infection, autoimmune diseases, allergic diseases, and TNF-α mediated diseases.

What is claimed is:  
     
         1 . A piperazine compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;  
 R 3 , R 4  and R 5  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl;  
 R 6  and R 7  are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);  
 R 8  and R 9  are the same or different and each is hydrogen or lower alkyl;  
 Y is a group of the formula  
                     wherein R 10  and R 11  are the same or different and each is hydrogen or lower alkyl, R 12  and R 13  are the same or different and each is hydrogen or lower alkyl, or R 12  and R 13  in combination form alkylene, R 14  and R 15  are the same or different and each is hydrogen or lower alkyl, m is an integer of 0-2, n is an integer of 0-2, and 0≦m+n≦2; and    
 ring A is phenyl, pyrimidyl, thiazolyl, pyridyl, pyrazyl or imidazolyl, provided that when one of R 6  and R 7  is hydrogen and the other is butyl, in Y, both R 12  and R 13  are hydrogen, m and n are 0, R 1 , R 2 , R 8  and R 9  are hydrogen, and ring A is phenyl, one of R 3 , R 4  and R 5  should not be 2-isopropoxy and the remaining two should not be hydrogen, or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The piperazine compound of  claim 1 , which has the following formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;  
 R 3 , R 4  and R 5  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl;  
 R 6  and R 7  are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s); and  
 Y 1  is a group of the formula  
                     wherein R 12  and R 13  are the same or different and each is hydrogen or lower alkyl, or R 12  and R 13  in combination form alkylene, provided that when one of R 6  and R 7  is hydrogen and the other is butyl, in Y 1 , both R 12  and R 13  are hydrogen and R 1  and R 2  are hydrogen, one of R 3 , R 4  and R 5  should not be 2-isopropoxy and the remaining two should not be hydrogen, or a pharmaceutically acceptable salt thereof.    
 
     
     
         3 . The piperazine compound of  claim 1 , which has the following formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;  
 R 3 , R 4  and R 5  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl;  
 R 6  and R 7  are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);  
 R 8a  is lower alkyl; and  
 Y 1  is a group of the formula  
                     wherein R 12  and R 13  are the same or different and each is hydrogen or lower alkyl, or R 12  and R 13  in combination form alkylene, or a pharmaceutically acceptable salt thereof.    
 
     
     
         4 . The piperazine compound of  claim 3 , wherein R 8a  is methyl, or a pharmaceutically acceptable salt thereof.  
     
     
         5 . The piperazine compound of  claim 1 , which has the following formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;  
 R 3 , R 4  and R 5  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, hydroxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl;  
 R 6  and R 7  are the same or different and each is hydrogen, lower alkyl or lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);  
 R 8a  and R 9a  are the same or different and each is lower alkyl; and  
 Y 1  is a group of the formula  
                     wherein R 12  and R 13  are the same or different and each is hydrogen or lower alkyl, or R 12  and R 13  in combination form alkylene, or a pharmaceutically acceptable salt thereof.    
 
     
     
         6 . The piperazine compound of  claim 5 , wherein R 8a  and R 9a  are both methyl, or a pharmaceutically acceptable salt thereof.  
     
     
         7 . The piperazine compound of any of  claim 1  to  claim 6 , wherein R 3 , R 4  and R 5  are the same or different and each is hydrogen, halogen or lower alkoxy, or a pharmaceutically acceptable salt thereof.  
     
     
         8 . The piperazine compound of  claim 1 , which has the following formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;  
 ring A′ is a group of the formula  
                     wherein R 16  and R 17  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, and R 18  is hydrogen or lower alkyl;    
 R 6  and R 7  are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s); and  
 Y 1  is a group of the formula  
                     wherein R 12  and R 13  are the same or different and each is hydrogen or lower alkyl, or R 12  and R 13  in combination form alkylene, or a pharmaceutically acceptable salt thereof.    
 
     
     
         9 . The piperazine compound of  claim 1 , which has the following formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;  
 ring A′ is a group of the formula  
                     wherein R 16  and R 17  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, and R 18  is hydrogen or lower alkyl;    
 R 6  and R 7  are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);  
 R 8a  is lower alkyl; and  
 Y 1  is a group of the formula  
                     wherein R 12  and R 13  are the same or different and each is hydrogen or lower alkyl, or R 12  and R 13  in combination form alkylene, or a pharmaceutically acceptable salt thereof.    
 
     
     
         10 . The piperazine compound of  claim 9 , wherein R 8a  is methyl, or a pharmaceutically acceptable salt thereof.  
     
     
         11 . The piperazine compound of  claim 1 , which has the following formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, amino, amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, nitro, hydroxy or cyano;  
 ring A′ is a group of the formula  
                     wherein R 16  and R 17  are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy or amino mono- or di-substituted by a group selected from the group consisting of lower alkyl and lower acyl, and R 18  is hydrogen or lower alkyl;    
 R 6  and R 7  are the same or different and each is hydrogen, lower alkyl, lower alkyl substituted by 1 to 3 halogen(s), aralkyl, acyl or lower acyl substituted by 1 to 3 halogen(s);  
 R 8a  and R 9a  are the same or different and each is lower alkyl; and  
 Y 1  is a group of the formula  
                     wherein R 12  and R 13  are the same or different and each is hydrogen or lower alkyl, or R 12  and R 13  in combination form alkylene, or a pharmaceutically acceptable salt thereof.    
 
     
     
         12 . The piperazine compound of  claim 11 , wherein R 8a  and R 9a  are both methyl, or a pharmaceutically acceptable salt thereof.  
     
     
         13 . The piperazine compound of any of  claim 1  to  claim 12 , wherein one of R 6  and R 7  is hydrogen and the other is acyl, or a pharmaceutically acceptable salt thereof.  
     
     
         14 . The piperazine compound of any of  claim 1  to  claim 13 , wherein R 12  and R 13  are the same or different and each is hydrogen or methyl, or R 12  and R 13  in combination form ethylene, or a pharmaceutically acceptable salt thereof.  
     
     
         15 . The piperazine compound of any of claims  1 ,  2 ,  7 ,  13  and  14 , which is a member selected from the group consisting of 
 N-(4-((4-phenylpiperazin-1-yl)methyl)phenylmethyl)acetamide,  
 N-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,  
 N-(4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,  
 N-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,  
 N-(2-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide,  
 N-(2-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide,  
 N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)ethyl)acetamide,  
 N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide,  
 N-(1-(4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)phenyl)-ethyl)acetamide,  
 N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-1-methylethyl)acetamide,  
 N-(1-(4-((4-phenylpiperazin-1-yl)methyl)phenyl)cyclopropyl)-acetamide and  
 N-(1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)-cyclopropyl)acetamide, or a pharmaceutically acceptable salt thereof.  
 
     
     
         16 . The piperazine compound of any of claims  1 ,  3 ,  4 ,  7 ,  13  and  14 , which is a member selected from the group consisting of 
 N-(4-(1-(4-phenylpiperazin-1-yl)ethyl)phenylmethyl)acetamide,  
 N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetamide and  
 N-(4-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)phenylmethyl)-acetamide, or a pharmaceutically acceptable salt thereof.  
 
     
     
         17 . The piperazine compound of any of claims  1 ,  5 - 7 ,  13  and  14 , which is N-(4-(1-(4-(4-fluorophenyl)piperazin-1-yl)-1-methylethyl)phenylmethyl)acetamide, or a pharmaceutically acceptable salt thereof.  
     
     
         18 . The piperazine compound of any of claims  1 ,  7 ,  8 ,  13  and  14 , which is a member selected from the group consisting of 
 N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-acetamide,  
 N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)ethyl)-acetamide,  
 N-(1-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenyl)-cyclopropyl)acetamide,  
 N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-formamide,  
 N-(4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)-propionamide,  
 N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide and  
 N-(4-((4-(pyridin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide, or a pharmaceutically acceptable salt thereof.  
 
     
     
         19 . The piperazine compound of any of claims  1 ,  7 ,  9 ,  10 ,  13  and  14 , which is N-(1-(4-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)-phenyl)cyclopropyl)acetamide, or a pharmaceutically acceptable salt thereof.  
     
     
         20 . A pharmaceutical composition containing the piperazine compound of any of  claim 1  to  claim 19 , or a pharmaceutically acceptable salt thereof, as an active ingredient.  
     
     
         21 . A TNF-α production inhibitor and/or an IL-10 production promoter comprising the piperazine compound of any of  claim 1  to  claim 19 , or a pharmaceutically acceptable salt thereof, as an active ingredient.  
     
     
         22 . An agent for the prophylaxis or treatment of diseases caused by abnormal TNF-α production, TNF-α mediated diseases or a disease treatable with IL-10, which comprises the piperazine compound of any of  claim 1  to  claim 19 , or a pharmaceutically acceptable salt thereof, as an active ingredient.  
     
     
         23 . An agent for the prophylaxis or treatment of an inflammatory disease, which comprises the piperazine compound of any of  claim 1  to  claim 19 , or a pharmaceutically acceptable salt thereof, as an active ingredient.  
     
     
         24 . An agent for the prophylaxis or treatment of an autoimmune disease, which comprises the piperazine compound of any of  claim 1  to  claim 19 , or a pharmaceutically acceptable salt thereof, as an active ingredient.  
     
     
         25 . An agent for the prophylaxis or treatment of rheumatoid arthritis, which comprises the piperazine compound of any of  claim 1  to  claim 19 , or a pharmaceutically acceptable salt thereof, as an active ingredient.  
     
     
         26 . An agent for the prophylaxis or treatment of an allergic disease, which comprises the piperazine compound of any of  claim 1  to  claim 19 , or a pharmaceutically acceptable salt thereof, as an active ingredient.