Pyrrole derivatives

Abstract

Pyrrole derivatives represented by the following formula: wherein Ring Z is an optionally substituted pyrrole ring, etc.; W 2 is —CO—, —SO 2 —, an optionally substituted C 1 -C 4 alkylene, etc.; Ar 2 is an optionally substituted aryl, etc.; W 1 and Ar 1 mean the following (1) and (2): (1) W 1 is an optionally substituted C 1 -C 4 alkylene, etc.; Ar 1 is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms: (2) W 1 is an optionally substituted C 2 -C 5 alkylene, an optionally substituted C 2 -C 5 alkenylene, etc.; and Ar 1 is an aryl or monocyclic heteroaryl, which are substituted by carboxyl, an alkoxycarbonyl, etc. at the ortho- or meta-position thereof with respect to the binding position of W 1 , or a pharmaceutically acceptable salt thereof. These compounds are useful as medicaments such as a fibrosis inhibitor for organs or tissues.

1 . A compound, a prodrug thereof, or a pharmaceutically acceptable salt thereof, of the formula:  
       
         
           
           
               
               
           
         
         wherein Ring Z is an optionally substituted pyrrole ring or an optionally substituted indole ring;  
         W 2  is —OC—, —SO 2 —, —CONR—, an optionally substituted C 1 -C 4  alkylene or an optionally substituted C 2 -C 4  alkenylene, and R is a hydrogen or an alkyl;  
         Ar 2  is an optionally substituted aryl or an optionally substituted heteroaryl;  
         W 1  and Ar 1  mean the following (1) or (2):  
         (1) W 1  is an optionally substituted C 1 -C 4  alkylene or an optionally substituted C 2 -C 4  alkenylene; and Ar 1  is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms;  
         (2) W 1  is an optionally substituted C 2 -C 5  alkylene, an optionally substituted C 2 -C 5  alkenylene, an optionally substituted C 2 -C 5  alkynylene, or —Y—W 3 —, wherein Y is an oxygen atom or a cycloalkanediyl, and W 3  is an optionally substituted C 1 -C 5  alkylene, an optionally substituted C 2 -C 5  alkenylene, or an optionally substituted C 2 -C 5  alkynylene; and Ar 1  is an aryl or monocyclic heteroaryl, which is substituted at the ortho- or meta-position thereof with respect to the binding position of W 1  by a group selected from the group consisting of a carboxyl, an alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s), a cyclic aminocarbonyl, an alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl, a sulfamoyl having optionally alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said aryl or monocyclic heteroaryl being optionally further substituted;  
         provided that when Ring Z is an optionally substituted pyrrole ring of the formula:  
         
           
             
             
                 
                 
             
           
         
         wherein the number of R 1  is one or more, and each is independently hydrogen, a halogen or an optionally substituted alkyl, then Ar 1  is not an aryl.  
       
     
     
         2 . The compound, prodrug thereof, or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein the divalent group including said Ring Z may be any one of the following divalent groups (any direction of bonds are included):  
       
         
           
           
               
               
           
         
       
       wherein the number of R 1  is one or more and each is independently hydrogen, a halogen or an optionally substituted alkyl.  
     
     
         3 . The compound, prodrug thereof, or pharmaceutically acceptable salt thereof according to  claim 1 , said compound having the formula:  
       
         
           
           
               
               
           
         
       
       wherein W 1 , W 2 , Ar 1 , Ar 2  and R 1  are as defined in  claim 1 .  
     
     
         4 . The compound, prodrug thereof, or pharmaceutically acceptable salt thereof according to  claim 1 , wherein W 2  is —CO—, —SO 2 —, —CONR—, methylene, or hydroxymethylene.  
     
     
         5 . The compound, prodrug thereof, or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Ar is a substituted phenyl.  
     
     
         6 . The compound, prodrug thereof, or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Ar 2  is a phenyl which is substituted by a member selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, hydroxy or morpholino.  
     
     
         7 . The compound, prodrug thereof, or pharmaceutically acceptable salt thereof according to  claim 1 , wherein W 1  is an optionally substituted C 1 -C 4  alkylene or an optionally substituted C 2 -C 4  alkenylene, and Ar 1  is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms.  
     
     
         8 . The compound, prodrug thereof, or pharmaceutically acceptable salt thereof according to  claim 7 , wherein the bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms is selected from the group consisting of indolyl, isoindolyl, inolidinyl, indazolyl, puryl, 4-H-quinolidinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridyl, quinoxalyl and quinazolyl.  
     
     
         9 . The compound, prodrug thereof, or pharmaceutically acceptable salt thereof according to  claim 7 , wherein the bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms is selected from the group consisting of indolyl, indazolyl, quinolinyl and quinoxalyl.  
     
     
         10 . A pharmaceutical composition comprising: 
 the compound, prodrug thereof, or pharmaceutically acceptable salt thereof, according to  claim 1;  and    a pharmaceutically acceptable carrier or diluent.    
     
     
         11 . A pharmaceutical composition comprising: 
 the compound, prodrug thereof, or pharmaceutically acceptable salt thereof, according to  claim 2;  and    a pharmaceutically acceptable carrier or diluent.    
     
     
         12 . The pharmaceutical composition according to  claim 10 , which is a TGF-β inhibitor.  
     
     
         13 . The pharmaceutical composition according to  claim 10 , which is a fibrosis inhibitor.