Arylpiperazines and arylpiperidines and their use as metalloproteinase inhibiting agents

Abstract

Compounds of the formula I useful as metalloproteinase inhibitors, especially as inhibitors of MMP 13.

1 . A compound of the formula I or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof,  
     
       
         
         
             
             
         
       
       wherein  
       B is selected from H, C 1-6 alkyl, up to C12 cycloalkyl, up to C12 aryl, and up to C12 heteroaryl; wherein  
       B is optionally substituted by up to three groups independently selected from OH, NO 2 , CF 3 , CN, halogen, SC 1-4 alkyl, SOC 1-4 alkyl, SO 2 C 1-4 alkyl, C 1-4 alkyl, and C 1-4 alkoxy;  
       L 1  and L 2  are each independently selected from a direct bond and C 1-6 alkyl;  
       M 1 , M 2 , M 3 , M 4  and M 5  are each independently selected from N and C;  
       R1 is the group —X—Y;  
       X is C 1-6 alkyl; and  
       Y is selected from up to C10 cycloalkyl, up to C10 aryl, and up to C10 heteroaryl; wherein  
       Y is optionally substituted by up to three groups independently selected from OH, NO 2 , CF 3 , CN, halogen, SC 1-4 alkyl, SOC 1-4 alkyl, SO 2 C 1-4 alkyl, C 1-4 alkyl, and C 1-4 alkoxy.  
     
   
   
       2 . A compound of the formula II or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof,  
     
       
         
         
             
             
         
       
     
     wherein 
 B is selected from H, C 1-6 alkyl, up to C12 cycloalkyl, up to C12 aryl, and up to C12 heteroaryl; wherein  
 B is optionally substituted by up to three groups independently selected from OH, NO 2 , CF 3 , CN, halogen, SC 1-4 alkyl, SOC 1-4 alkyl, SO 2 C 1-4 alkyl, C 1-4 alkyl, and C 1-4 alkoxy;  
 L 1  and L 2  are each independently selected from a direct bond and C 1-6 alkyl;  
 M 1 , M 2 , M 3 , M 4  and M 5  are each independently selected from N and C;  
 R1 is the group —X—Y;  
 X is C 1-6 alkyl; and  
 Y is selected from up to C10 cycloalkyl, up to C10 aryl, and up to C10 heteroaryl; wherein  
 Y is optionally substituted by up to three groups independently selected from OH, NO 2 , CF 3 , CN, halogen, SC 1-4 alkyl, SOC 1-4 alkyl, SO 2 C 1-4 alkyl, C 1-4 alkyl, and C 1-4 alkoxy.  
 
   
   
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       12 . (canceled)  
   
   
       13 . (canceled)  
   
   
       14 . (canceled)  
   
   
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       19 . (canceled)  
   
   
       20 . A method for treating a human or animal, comprising administering to the human or animal a compound of  claim 1  or  claim 2  or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.  
   
   
       21 . A method of treating a metalloproteinase mediated disease or condition, which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of  claim 1  or  claim 2  or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.  
   
   
       22 . A method of treating a metalloproteinase mediated disease or condition as claimed in  claim 21 , wherein the metalloproteinase is MMP13.  
   
   
       23 . A method for treating a disease or condition mediated by one or more metalloproteinase enzymes, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1  or  claim 2  or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof.  
   
   
       24 . A method for treating arthritis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1  or  claim 2  or a pharmaceutically acceptable salt or in vivo hydrolysable precursor thereof.