Metalloproteinase inhibitor compounds

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 a phenyl group monosubstituted at the 3- or 4-position by halogen or trifluoromethyl, or disubstituted at the 3- and 4-positions by halogen (which may be the same or different); or B is a 2-pyridyl or 2-pyridyloxy group monosubstituted at the 4-, 5- or 6-position by halogen, trifluoromethyl, cyano, or C 1-4 alkyl; or B is a 4-pyrimidinyl group optionally substituted at the 6-position by halogen or C 1-4 alkyl;  
 X is a carbon or nitrogen atom;  
 R 1  is a trimethyl-1-hydantoin C 2-4 alkyl or a trimethyl-3-hydantoin C 2-4 alkyl group; or R 1  is phenyl or C 2-4 alkylphenyl monosubstituted at the 3- or 4-position by halogen, trifluoromethyl, thio, C 1-3 alkyl; or C 1-3 alkoxy; or R 1  is phenyl-SO 2 NHC 2 -4alkyl or R 1  is 2-pyridyl or 2-pyridyl C 2 -4alkyl; or R 1  is 3-pyridyl or 3-pyridyl C 2-4 alkyl; or R 1  is 2-pyrimidine-SCH 2 CH 2 ; or R 1  is 2- or 4-pyrimidinyl C 2-4 alkyl optionally monosubstituted by one of halogen, trifluoromethyl, C 1-3 alkyl, C 1-3 alkyloxy, 2-pyrazinyl optionally substituted by halogen, or 2-pyrazinyl C 2-4 alkyl optionally substituted by halogen.  
 
   
   
       2 . A compound as claimed in  claim 1 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein: 
 B is a phenyl group monosubstituted at the 3- or 4-position by halogen or trifluoromethyl, or disubstituted at the 3- and 4-positions by halogen (which may be the same or different); or B is a 2-pyridyl or 2-pyridyloxy group monosubstituted at the 5- or 6-position by halogen, trifluoromethyl or cyano; or B is a 4-pyrimidinyl group optionally substituted at the 6-position by halogen or C 1-4 alkyl;    X is a carbon or nitrogen atom;    R 1  is a trimethyl-1-hydantoin C 2-4 alkyl or a trimethyl-3-hydantoin C 2-4 alkyl group; or R 1  is phenyl or C 2-4 alkylphenyl monosubstituted at the 3- or 4-position by halogen, trifluoromethyl, thio, C 1-3 alkyl, or C 1-3 alkoxy; or R 1  is phenyl-SO 2 NHC 2-4 alkyl or R 1  is 2-pyridyl or 2-pyridyl C 2-4 alkyl; or R 1  is 3-pyridyl or 3-pyridyl C 2-4 alkyl; or R 1  is 2-pyrimidine-SCH 2 CH 2 ; or R 1  is 2- or 4-pyrimidinyl C 2-4 alkyl optionally monosubstituted by one of halogen, trifluoromethyl, C 1-3 alkyl, C 1-3 alkyloxy, or 2-pyrazinyl or 2-pyrazinyl C 2-4 alkyl.    
   
   
       3 . A compound as claimed in  claim 11  or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein B is selected from 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluorophenyl, 5-chloro-2-pyridyl, 5-bromo-2-pyridyl, 5-fluoro-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 5-cyano-2-pyridyl, and 5-methyl-2-pyridyl.  
   
   
       4 . A compound as claimed in  claim 3 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein B is 4-fluorophenyl, 5-chloro-2-pyridyl, or 5-trifluoromethyl-2-pyridyl.  
   
   
       5 . A compound as claimed in any one of the previous claims, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein X is a nitrogen atom.  
   
   
       6 . A compound as claimed in any one of the previous claims, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof wherein R 1  is selected from 3-chlorophenyl, 4-chlorophenyl, 3-pyridyl, 2-pyridylpropyl, 2- or 4-pyrimidinylethyl (optionally monosubstituted by fluorine), 2- or 4-pyrimidinylpropyl, and 2-(2-pyrimidinyl)propyl (optionally monosubstitued by fluorine).  
   
   
       7 . A compound as claimed in  claim 6 , or a pharmaceutically acceptable salts or an in vivo hydrolysable ester thereof wherein R 1  is 2-pyrimidinylpropyl, 2-(2-pyrimidinyl)propyl (optionally monosubstitued by fluorine), or 5-fluoro-2-pyrimidinylethyl.  
   
   
       8 . A compound as claimed in  claim 1 , or a pharmaceutically acceptable salts or an in vivo hydrolysable ester thereof wherein the compound of the formula I is as exemplified herein.  
   
   
       9 . A compound as claimed in  claim 8 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein the compound is selected from N-[1-([4-(4-bromophenyl)piperazino]sulfonylmethyl)-4-pyrimidin-2-ylbutyl]-N-hydroxyformamide, N-[1-([4-(5-chloropyridin-2-yl)piperazino]sulfonylmethyl)-3-(5-fluoropyrimidin-2-yl)propyl]-N-hydroxyformamide, N-[(1S)-1-({[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}methyl)-4-(pyrimidin-2-yl)butyl]-N-hydroxyformamide, N-[(1S)-1-({[4-(5-bromopyridin-2-yl)piperazino]sulfonyl}methyl)-4-(pyridin-2-yl)butyl]-N-hydroxyformamide, N-[(1S)-1-({[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}methyl)-3-(5-fluoropyrimidin-2-yl)propyl]-N-hydroxyformamide, N-[(1S)-1-({[4-(4-fluorophenyl)piperazino]sulfonyl}methyl)-4-(pyrimidin-2-yl)butyl]-N-hydroxyformamide, N-[(1S)-1-({[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}methyl)-3-(pyrimidin-2-yl)propyl]-N-hydroxyformamide, N-[(1R)-1-({[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}methyl)-3-(pyrimidin-2-yl)propyl]-N-hydroxyformamide, N-[(1S)-1-({[4-(5-trifluoromethylpyridin-2-yl)piperazino]sulfonyl}methyl)-3-(pyrimidin-2-yl)propyl]-N-hydroxyformamide, N-[(1R)-1-({[4-(5-trifluoromethylpyridin-2-yl)piperazino]sulfonyl}methyl)-3-(pyrimidin-2-yl)propyl]-N-hydroxyformamide, N-[(1S)-1-({[4-(5-bromopyridin-2-yl)piperazino]sulfonyl}methyl)-4-(pyrimidin-2-yl)butyl]-N-hydroxyformamide, N-[(1R)-1-({[4-(5-bromopyridin-2-yl)piperazino]sulfonyl}methyl)-4-(pyrimidin-2-yl)butyl]-N-hydroxyformamide, N-[(1S)-1-({[4-(5-trifluoromethylpyridin-2-yl)piperazino]sulfonyl}methyl)-4-(pyrimidin-2-yl)butyl]-N-hydroxyformamide, N-({[4-fluorophenylpiperazino]sulfonyl}methyl)-3-[(5-fluoropyrimidin-2-yl)propyl]-N-hydroxyformamide, N-[(1R or 1S)-({[4-chlorophenylpiperazino]sulfonyl}methyl)-3-[(3R or 3S)-(5-fluoropyrimidin-2-yl)butyl]-N-hydroxyformamide, N-[(1R or 1S)-({[4-bromophenylpiperazino]sulfonyl}methyl)-3-[(3R or 3S)-(5-fluoropyrimidin-2-yl)butyl]-N-hydroxyformamide, N-[(1R or 1S)-({[4-chlorophenylpiperidino]sulfonyl}methyl)-3-[(3R or 3S)-(5-fluoropyrimidin-2-yl)butyl]N-hydroxyformamide, N-[(1R or 1S)-({[3,4-dichlorophenylpiperazino]sulfonyl}methyl)-3-[(3R or 3S)-(5-fluoropyrimidin-2-yl)butyl]-N-hydroxyformamide, N-[(1R or 1S)-({[4-(5-cyanopyridin-2-yl)piperazino]sulfonyl}methyl)-3-[(3R or 3S)-(5-fluoropyrimidin-2-yl)butyl]-N-hydroxyformamide, N-[(1S)-({[4-(4-fluorophenylpiperazino]sulfonyl}methyl)-3-[(3S)-(5-fluoropyrimidin-2-yl)butyl]-N-hydroxyformamide, 1-({[4-(4-chlorophenyl)piperazin-1-yl]sulfonyl}methyl)-3-(5-chloropyridin-3-yl)propyl(hydroxy)formamide.  
   
   
       10 . A compound as claimed in any one of the previous claims, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein the compound of formula I is the most active enantiomer.  
   
   
       11 . A compound as claimed in any one of the previous claims, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, wherein the compound of formula I is the S enantiomer or the S,S enantiomer.  
   
   
       12 . A pharmaceutical composition which comprises a compound of the formula I as claimed in  claim 11  or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, and a pharmaceutically acceptable carrier.  
   
   
       13 . A compound of the formula I as claimed in  claim 11  or a pharmaceutically acceptable salt, or in vivo hydrolysable ester thereof, for use in a method of therapeutic treatment of the human or animal body.  
   
   
       14 . A compound of the formula I as claimed in  claim 1 , or a pharmaceutically acceptable salt, or in vivo hydrolysable ester thereof for use as a therapeutic agent.  
   
   
       15 . A method of treating a metalloproteinase mediated disease condition which comprises administering to a warm-blooded animal a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt, or in vivo hydrolysable ester thereof.  
   
   
       16 . A method of treating a metalloproteinase mediated disease condition as claimed in  claim 15  which comprises treating a disease condition mediated by one or more of the following enzymes: MMP13, aggrecanase, MMP9, and MMP12.  
   
   
       17 . The use of a compound of the formula I or a pharmaceutically acceptable salt, or in vivo hydrolysable precursor thereof, in the preparation of a medicament for use in the treatment of a disease condition medicated by one or more metalloproteinase enzymes.  
   
   
       18 . The use of a compound of the formula I, or a pharmaceutically acceptable salt, or in vivo hydrolysable precursor thereof, in the preparation of a medicament for use in the treatment of arthritis.  
   
   
       19 . The use of a compound of the formula I, or a pharmaceutically acceptable salt, or in vivo hydrolysable precursor thereof, in the preparation of a medicament for use in the treatment of atherosclerosis.  
   
   
       20 . The use of a compound of the formula I, or a pharmaceutically acceptable salt, or in vivo hydrolysable precursor thereof, in the preparation of a medicament for use in the treatment of chronic obstructive pulmonary diseases.  
   
   
       21 . A process for preparing a compound of the formula I, or a pharmaceutically acceptable salt, or in vivo hydrolysable ester thereof, which process comprises reacting a compound of the formula II with a compound of the formula R 1 CHO to yield an alkene of the formula III, converting the alkene to a compound of the formula IV, and then converting the compound of formula IV to a compound of the formula I, and optionally thereafter forming a pharmaceutically acceptable salt or in vivo hydrolysable ester of the compound of formula I, all as set out below:  
     
       
         
         
             
             
         
       
     
   
   
       22 . A process for preparing a compound of the formula I, or a pharmaceutically acceptable salt, or in vivo hydrolysable ester thereof, which process comprises reacting a compound of the formula II with a compound of the formula R 1 COOR to yield a compound of the formula VIII, converting the compound of formula VIII to a compound of the formula IX, converting the compound of formula IX to an alkene of the formula III, converting the alkene to a compound of the formula IV, and then converting the compound of formula IV to a compound of the formula I; and optionally thereafter forming a pharmaceutically acceptable salt or in vivo hydrolysable ester of the compound of formula I, all as set out below: