Inhibitors of matrix metalloproteinase

Abstract

Compounds of formula (I): wherein R 1 represents optionally substituted C 4-12 alkyl, optionally substituted C 2-6 alkylaryl, or optionally substituted 5- or 6-membered aryl or heteroaryl; Z represents a bond, CH 2 , O, S, SO, SO 2 , NR 4 , OCR 4 R 5 , CR 4 R 5 O, or Z, R 1 and Q together form an optionally substituted fused tricyclic group; Q represents an optionally substituted 5- or 6-membered aryl or heteroaryl ring; X represents COR 3 or N(OR 8 )COR 9 ; R 2 represents SO 2 R 10 or SO 2 NR 10 R 11 ; R 3 represents OR 6 NR 6 R 7 or NR 6 OH; R 4 and R 5 each independently represents H, C 1-6 alkyl or C 1-4 alkylaryl; R 6 and R 7 each independently represents H, C 1-6 alkyl, or C 1-6 alkyl substituted with one or more heteroaryl groups, or R 6 and R 7 together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which may optionally include 1 or more further heteroatoms selected from O, S and N; R 8 and R 9 each independently represents H or C 1-6 alkyl; R 10 and R 11 each independently represents H or C 1-6 alkyl; and and physiologically functional derivatives thereof, with the exception of N-(ethoxycarbonyl)-N-[4-(1H-tetrazol-1-yl)phenyl]glycine, processes for their preparation, pharmaceutical formulations containing them and their use as inhibitors of matrix metalloproteinase enzymes (MMPs) are described.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  represents optionally substituted C 4-12  alkyl, optionally substituted C 2-6 alkylaryl, or optionally substituted 5- or 6-membered aryl or heteroaryl; 
 Z represents a bond, CH 2 , O, S, SO, SO 2 , NR 4 , OCR 4 R 5 , CR 4 R 50 , or Z, R 1  and Q together form an optionally substituted fused tricyclic group; 
 Q represents an optionally substituted 5- or 6-membered aryl or heteroaryl ring; 
 X represents COR 3  or N(OR 8 )COR 9 ; 
 R 2  represents SO 2 R 10  or SO 2 NR 10 R 9 ; 
 R 3  represents OR 6 , NR 6 R 7  or NR 6 OH; 
 R 4  and R 5  each independently represents H, C 1-6  alkyl or C 1-4  alkylaryl; 
 R 6  and R 7  each independently represents H, C 1-6  alkyl, or C 1-6  alkyl substituted with one or more heteroaryl groups, or R 6  and R 7  together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which may optionally include 1 or more further heteroatoms selected from O, S and N; 
 R 8  and R 9  each independently represents H or C 1-6  alkyl; 
 R 10  and R 11  each independently represents H or C 1-6  alkyl; and 
 and physiologically functional derivatives thereof, with the exception of N-(ethoxycarbonyl)-N-[4-(1H-tetrazol-1-yl)phenyl]glycine. 
 
     
     
         2 . A compound of formula (Ia): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 10  represents H or C 1-6  alkyl; 
 R 12  represents H, halo, CF 3 , cyano, OCF 3 , nitro, OR 3 , SR 3 , COR 13  or C 1-6  alkyl; 
 R 13  represents C 1-6  alkyl or C 1-4 alkylaryl; 
 and physiologically functional derivatives thereof. 
 
     
     
         3 . A method for treatment of a human or animal subject suffering from or susceptible to an autoimmune disorder or an inflammatory condition, which comprises administering to said human or animal subject an effective amount of a compound of  claim 1 . 
     
     
         4 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier therefor, and optionally one or more other therapeutic agents. 
     
     
         5 . A process for preparation of compounds of formula (I) according to  claim 1 , which comprises:
 (A) preparing a compound of formula (I), wherein Z represents a bond and R 1  represents an optionally substituted C 2-6 alkylaryl or an optionally substituted 5- or 6-membered aryl or heteroaryl, by reacting a compound of formula (II):   
       
         
           
           
               
               
           
         
       
       wherein R 2 , Q and X are as previously defined for formula (I) and L represents a leaving group, with a reagent suitable to introduce the group R 1 ; or
 (B) preparing a compound of formula (I), wherein Z represents a bond and R 1  represents an optionally substituted C 4-12 alkyl, by reacting a compound of formula (III): 
 
       
         
           
           
               
               
           
         
       
       wherein R 2 , Q and X are as previously defined for formula (I), with a reagent suitable to introduce the group R 1 ; or
 (C) preparing a compound of formula (I), wherein Z represents OS, SO, SO 2 , NR 4  or OCR 4 R 5 , and R 1  represents an optionally substituted C 4-12 alkyl, by reacting a compound of formula (IV): 
 
       
         
           
           
               
               
           
         
       
       wherein X, R 2  and Q are as previously defined for formula (I), and Y represents OH, SH, NR 4 H or HCR 4 R 5 , with a reagent suitable to introduce group R 1 , provided that when Y is SH it is followed by optional oxidation of sulphide to sulfoxide or sulfone; or
 (D) preparing a compound of formula (I), wherein Z represents OS, SO, SO 2 , or NR 4 , and R 1  represents an optionally substituted C 2-6 alkylaryl or an optionally substituted 5- or 6-membered aryl or heteroaryl, by reacting a compound of formula (IV): 
 
       
         
           
           
               
               
           
         
       
       wherein X, R 2  and Q are as previously defined for formula (I), and Y represents OH, SH or NR 4 H, with a reagent suitable to couple to group R 1 , provided that when Y is SH it is followed by optional oxidation of the sulphide to sulfoxide or sulfone; or
 (E) preparing a compound of formula (I), wherein Z represents OCR 4 R 5  and R 1  represents an optionally substituted C 2-6 alkylaryl or an optionally substituted 5- or 6-membered aryl or heteroaryl, by reacting a compound of formula (V): 
 
       
         
           
           
               
               
           
         
       
       wherein X, R 2  and Q are as defined for formula (I) and L 4  is a suitable leaving group, with a reagent suitable to introduce group R 1 —O; or
 (F) preparing a compound of formula (I), wherein Z represents CR 4 R 50 , by reacting a compound of formula (IV): 
 
       
         
           
           
               
               
           
         
       
       wherein R 2  and Q are as defined for formula (I), and Y represents OH, with a reagent suitable to introduce group R 1 CR 4 R 5 —; or
 (G) preparing a compound of formula (I), wherein Z represents CH 2 , by reacting a compound of formula (III): 
 
       
         
           
           
               
               
           
         
       
       wherein R 2 , Q and X are as defined for formula (I), with a reagent suitable to introduce group R 1 CH 2 ;
 (H) reacting a compound of formula (VI) 
 
       
         
           
           
               
               
           
         
       
       or a protected derivative thereof, wherein R 1 , Z, Q and X are as defined for formula
 (I), with a reagent suitable to introduce group R 2  as defined for formula (I): or 
 (J) carrying out a process selected from processes (A) to (G) followed by interconversion of one or more functional groups.