Novel Hydantoin Derivatives as Metalloproteinase Inhibitors

Abstract

The invention provides compounds of formula (I): wherein R 1 , R 2 , A, A 1 and B are as defined in the specification; processes for their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy. The compounds are useful as MMP inhibitors.

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents cyclobutyl or cyclopropyl; said cyclopropyl group being optionally further substituted by CH 3 , CN or one or two fluoro atoms; 
         R 2  represents C1 to 3 alkyl or cyclopropyl; and 
         A, A 1  and B independently represent CH or N; 
       
     
     
         2 . A compound according to  claim 1 , wherein R 1  represents cyclopropyl. 
     
     
         3 . A compound according to  claim 1  or  claim 2 , wherein R 2  represents methyl or ethyl. 
     
     
         4 . A compound according to any one of  claims 1  to  3 , wherein B 1  represents CH. 
     
     
         5 . A compound according to any one of  claims 1  to  4 , wherein A and A 1  each represent N. 
     
     
         6 . A compound according to  claim 1  which is selected from the group consisting of:
 (5S)-5-({[6-(2-cyclopropylpyrimidin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;   (5S)-5-({[6-(6-cyclopropylpyridin-3-yl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;   (5S)-5-({[6-(2-cyclopropylpyrimidin-5-yl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;   (5S)-5-({[6-(2-cyclopropylpyrimidin-5-yl)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]sulfonyl}methyl)-5-ethylimidazolidine-2,4-dione;   (5S)-5-({[6-(2-cyclopropylpyrimidin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-5-ethylimidazolidine-2,4-dione;   (5S)-5-({[6-(2-cyclobutylpyrimidin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)-5-methylimidazolidine-2,4-dione;   (5S)-5-methyl-5-({[6-[2-(1-methylcyclopropyl)pyrimidin-5-yl]-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;   (5S)-5-Cyclopropyl-5-({[6-(2-cyclopropylpyrimidin-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}methyl)imidazolidine-2,4-dione;   and pharmaceutically acceptable salts thereof.   
     
     
         7 . A process for the preparation of a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt thereof which comprises:
 a) reaction of a compound of formula (II)   
       
         
           
           
               
               
           
         
         wherein R 2  is as defined in formula (I) and L 1  represents a leaving group, with a compound of formula (III) (or a salt thereof) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , A, A 1  and B are as defined in formula (I); or 
         b) reaction of a compound of formula (V) 
       
       
         
           
           
               
               
           
         
         wherein R 2  and B are as defined in formula (I) and LG is a leaving group; with a boronic acid derivative of formula (XII) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , A and A 1  are as defined in formula (I); or 
         c) reaction of a compound of formula (IX) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , A, A 1  and B are as defined in formula (I); with ammonium carbonate and potassium cyanide; 
         and optionally thereafter forming a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of  claims 1  to  6  in association with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         9 . A process for the preparation of a pharmaceutical composition as claimed in  claim 8  which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of  claims 1  to  6  with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         10 . A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of  claims 1  to  6  for use in therapy. 
     
     
         11 . Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of  claims 1  to  6  in the manufacture of a medicament for use in the treatment of an obstructive airways disease. 
     
     
         12 . Use according to  claim 11 , wherein the obstructive airways disease is asthma or chronic obstructive pulmonary disease. 
     
     
         13 . Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1  to  6  in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, osteoarthritis, atherosclerosis, cancer or multiple sclerosis. 
     
     
         14 . A method of treating a disease or condition mediated by MMP12 and/or MMP9 which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of  claims 1  to  6 . 
     
     
         15 . A method of treating an obstructive airways disease which comprises administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of  claims 1  to  6 .