TNF-alpha production inhibitors

Abstract

A purpose of the present invention is to provide TNF-α production inhibitors being useful as therapeutic agents for autoimmune diseases such as rheumatoid arthritis. Novel compounds having the structure represented by the general formula [1] or salts thereof according to the present invention have excellent TNF-α production inhibitory activities, wherein A is —(NR 4 )—, —(CR 5 R 6 )— or —O—, B is alkylene or alkenylene, R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen, alkyl, alkenyl, adamantyl or the like, R 3 is aryl or an unsaturated heterocycle, and X is oxygen or sulfer respectively.

1 . A compound represented by the following formula [1] or a salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein A is —(CR 5 R 6 )— or —O—;
 B is alkylene or alkenylene optionally containing —O—, —S—, —(NR 7 )— or —CO—, 
 R 1  and R 2  being the same or different, are alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by halogen, cycloalkyl, aryl or adamantyl; 
 R 3  is a substituted or unsubstituted pyridine ring; 
 R 5  and R 6  being the same or different, are hydrogen or alkyl; 
 R 7  is hydrogen or alkyl; and 
 X is O or S. 
 
     
     
         2 . The compound or a salt thereof as claimed in  claim 1 , wherein at least one of R 1  and R 2  is adamantylalkyl. 
     
     
         3 . The compound or a salt thereof as claimed in  claim 1 , wherein
 A is —(CR 5 R 6 )— or —O—;   B is alkylene or alkenylene optionally containing —O—, —S—, —(NR 7 )—, —CO—, or —N═;   R 1  is alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by halogen, cycloalkyl, aryl, or adamantyl;   R 2  is adamantylalkyl;   R 3  is a substituted or unsubstituted pyridine ring;   R 5  and R 6 , being the same or different, are hydrogen, or alkyl;   R 7  is hydrogen or alkyl; and   X is O or S.   
     
     
         4 . The compound or a salt thereof as claimed in  claim 3 , wherein R 2  is adamantylalkyl and R 3  is a pyridine ring. 
     
     
         5 . The compound or a salt thereof as claimed in  claim 3 , wherein
 A is —(CR 5 R 6 )— or —O—;   B is alkylene or alkenylene which optionally contains —S—;   R 1  is alkyl or alkenyl, wherein the alkyl is optionally substituted by halogen;   R 2  is adamantylalkyl;   R 3  is a pyridine ring;   R 5  and R 6  are hydrogen; and   X is O.   
     
     
         6 . A compound selected from the group consisting of
 5-(4-pyridyl)valeric acid N-[2-(1-adamantyl)ethyl]-N-pentylamide,   3-(4-pyridylmethylthio)propionic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide,   2-[2-(4-pyridyl)ethylthio]acetic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide, and   6-(4-pyridyl)caproic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide or a salt thereof.   
     
     
         7 . The compound or a salt thereof as claimed in  claim 1 , wherein
 A is —(CR 5 R 6 )— or —O—;   B is alkylene or alkenylene optionally containing —O—, —S—, —(NR 7 )— or —N═;   R 1  is alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is optionally substituted by halogen, cycloalkyl, or aryl;   R 2  is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl or arylalkyl;   R 3  is a pyridine ring;   R 5  and R 6 , being the same or different, are hydrogen or alkyl;   R 7  is hydrogen or alkyl; and   X is O or S.   
     
     
         8 . The compound or a salt thereof as claimed in  claim 7 , wherein
 A is —(CR 5 R 6 )—;   B is alkylene or alkenylene;   R 1  is alkyl or alkenyl;   R 2  is arylalkyl;   R 3  is a pyridine ring;   R 5  and R 6  are hydrogen; and   X is O.   
     
     
         9 . The compound or a salt thereof as claimed in  claim 8 , wherein R 1  is alkyl and R 2  is arylalkyl. 
     
     
         10 . 5-(4-pyridyl)valeric acid N-pentyl-N-phenethylamide or a salt thereof. 
     
     
         11 . The compound or a salt thereof as claimed in  claim 7 , wherein
 A is —(CR 5 R 6 )—;   B is alkylene or alkenylene;   R 1  is alkyl, alkenyl or cycloalkyl, wherein the alkyl is optionally substituted by halogen, cycloalkyl, or aryl;   R 2  is cycloalkylalkyl;   R 3  is a pyridine ring;   R 5  and R 6  are hydrogen; and   X is O.   
     
     
         12 . A pharmaceutical composition comprising the compound or a salt thereof as claimed in  claim 1  as an active ingredient and a pharmacologically acceptable additive.