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.

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,  
       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, then 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,  
       
       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  claim 1 , 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  claim 1 , 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  claim 1 , 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  claim 1 , 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  claim 1 , 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  claim 1 , 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  claim 1 , which is N-(4-((4-(thiazol-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide or a pharmaceutically acceptable salt thereof.  
   
   
       19 . (canceled)  
   
   
       20 . A pharmaceutical composition containing the piperazine compound of  claim 1 , or a pharmaceutically acceptable salt thereof, as an active ingredient.  
   
   
       21 .- 26 . (canceled)  
   
   
       27 . The piperazine compound of  claim 7 , wherein one of R 6  and R 7  is hydrogen and the other is acyl, or a pharmaceutically acceptable salt thereof.  
   
   
       28 . The piperazine compound of  claim 7 , 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.  
   
   
       29 . The piperazine compound of  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.  
   
   
       30 . 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 thiazolyl 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, then 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.