Novel Benzofurans and Indols

Abstract

Compounds of formula (I) wherein X is a fluorine or a chlorine atom; the methyl groups located at the 2- and 5-position of the piperazine ring are in trans-configuration to each other; Y is NH or O; R 1 is selected from hydrogen, chloro, bromo, nitro, methyl or trifluoromethyl; R 2 is selected from hydrogen, halo, methyl, trifluoromethyl, methoxy or trifluoromethoxy; or a pharmaceutically acceptable salt or solvate thereof; The invention also relates to pharmaceutical compositions containing a compound of formula (I) together with a pharmaceutically acceptable carrier. Included are also processes for the preparation of compounds of formula (I), as well as methods for treating mammals suffering from inflammatory, autoimmune, proliferative or hyperproliferative diseases by administering a compound having the formula (I) to said mammal.

1 . A compound of general formula (I)  
       
         
           
           
               
               
           
         
         wherein:  
         X is a fluorine or a chlorine atom;  
         the methyl groups located at the 2- and 5-position of the piperazine ring are in trans-configuration to each other;  
         Y is NH;  
         R 1  is selected from hydrogen, chloro, bromo, nitro, methyl or trifluoromethyl;  
         R 2  is selected from hydrogen, halo, methyl, trifluoromethyl, methoxy or trifluoromethoxy;  
         or a pharmaceutically acceptable salt or solvate thereof.  
       
     
     
         2 . A compound according to  claim 1 , wherein X is a fluorine atom; 
 R 1  is selected from hydrogen, chloro or bromo;    R 2  is selected from hydrogen, chloro, bromo, methyl, trifluoromethyl, methoxy or trifluoromethoxy.    
     
     
         3 . A compound according to  claim 1 , which is: 
 (trans)-4-(4-Chlorobenzyl)-1-(5-chloro-indol-2-yl-carbonyl)-2,5-dimethylpiperazine.    
     
     
         4 . The method according to  claim 1  of treating a mammal suffering a disorder selected from rheumatoid arthritis; multiple sclerosis; systemic lupus erythematosus; inflammatory bowel disease; asthma.  
     
     
         5 . The method according to  claim 1  of treating a mammal in need of treatment to prevent allograft rejection.  
     
     
         6 . A compound according to  claim 1 , which is: 
 (trans)-1-(5-Bromo-6-chloro-indol-2-yl-carbonyl)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine.    
     
     
         7 . A compound according to  claim 1 , which is: 
 (trans)-1-(5-Chloro-6-trifluoromethyl-indol-2-yl-carbonyl)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine.    
     
     
         8 . A process for the preparation of a compound of formula (I) by  
       
         
           
           
               
               
           
         
       
       treating the piperazine derivative of formula (II) with a compound of formula (III), wherein L 1  is a leaving group, in an organic solvent, at a temperature of 0° C. to 120° C.  
     
     
         9 . A composition comprising a therapeutically effective amount of a compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein:  
         X is a fluorine or a chlorine atom;  
         the methyl groups located at the 2- and 5-position of the piperazine ring are in trans-configuration to each other;  
         Y is NH;  
         R 1  is selected from hydrogen, chloro, bromo, nitro, methyl or trifluoromethyl;  
         R 2  is selected from hydrogen, halo, methyl, trifluoromethyl, methoxy or trifluoromethoxy;  
         or a pharmaceutically acceptable salt or solvate thereof; and  
         pharmaceutically acceptable constituents.  
       
     
     
         10 . A method of treating a mammal suffering from inflammatory, autoimmune, proliferative or hyperproliferative disease, comprising administering to said mammal in need thereof a therapeutically effective amount of a compound formula (I)  
       
         
           
           
               
               
           
         
         wherein:  
         X is a fluorine or a chlorine atom;  
         the methyl groups located at the 2- and 5-position of the piperazine ring are in trans-configuration to each other;  
         Y is NH;  
         R 1  is selected from hydrogen, chloro, bromo, nitro, methyl or trifluoromethyl;  
         R 2  is selected from hydrogen, halo, methyl, trifluoromethyl, methoxy or trifluoromethoxy;  
         or a pharmaceutically acceptable salt or solvate thereof.  
       
     
     
         11 . The method according to  claim 10 , wherein: 
 X is a fluorine atom;    R 1  is selected from hydrogen, chloro or bromo;    R 2  is selected from hydrogen, chloro, bromo, methyl, trifluoromethyl, methoxy or trifluoromethoxy.    
     
     
         12 . A compound according to  claim 1 , selected from the group consisting of 
 (trans)-4-(4-Chlorobenzyl)-1-(5-chloro-indol-2-yl-carbonyl)-2,5-dimethylpiperazine;    (trans)-1-(5,6-Dichloro-indol-2-yl-carbonyl)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine;    (trans)-1-(6-Bromo-5-chloro-indol-2-yl-carbonyl)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine;    (trans)-1-(5-Bromo-6-chloro-indol-2-yl-carbonyl)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine; and    (trans)-1-(5-Chloro-6-trifluoromethyl-indol-2-yl-carbonyl)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine.