Novel Compounds

Abstract

The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases S, K, F, L and B. Of particular interest are diseases associated with Cathepsin S. In addition this invention also discloses processes for the preparation of such inhibitors.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         in which: 
         X is CH or CH 2 ; 
         Y is CH, CO, CH 2  or :CNR 2 R 3 , where R 2  and R 3  are independently hydrogen, C 1-6  alkyl or 
         C 3-6  cycloalkyl; 
         R is aryl or heteroaryl optionally substituted by halogen, amino, hydroxy, cyano, nitro, trifluoromethyl, carboxy, CONR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , NHSO 2 R 4 , NHCOR 4 , ethylenedioxy, methylenedioxy, C 1-6  alkyl, C 1-6  alkoxy, SR 4  or NR 5 R 6  where R 4  is hydrogen, C 1-6  alkyl or C 3-6  cycloalkyl, R 5  and R 6  are independently hydrogen, C 1-6  alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR 4  group; 
         or R is hydrogen, C 1-6  alkyl or C 3-6  cycloalkyl, 
         R 1  is a group Y(CH 2 ) p R 7  where p is 0, 1 or 2 and Y is O or NR 8  where R 8  is hydrogen, C 1-6  alkyl or C 3-6  cycloalkyl; 
         and R 7  is a 5- or 6-membered saturated ring containing one or more O, S or N atoms, aryl or a heteroaryl group containing one to four heteroatoms selected from O, S or N, the saturated ring, aryl and heteroaryl groups all being optionally substituted by halogen, amino, hydroxy, cyano, nitro, trifluoromethyl, carboxy, CONR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , NHSO 2 R 4 , NHCOR 4 , C 1-6  alkyl, C 1-6  alkoxy, SR 4  or NR 5 R 6  where R 4  is hydrogen, C 1-6  alkyl or C 3-6  cycloalkyl, R 5  and R 6  are independently hydrogen, C 1-6  alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR 4  group; 
         or R 1  is a group NR 9 R 10  where R 9  and R 10  are independently hydrogen or C 1-6  alkyl, or R 9  and R 10  together with the nitrogen atom to which they are attached form a 5 or 6-membered saturated ring optionally containing a further O, S or N atom and optionally substituted by a second NR 9 R 10  where R 9  and R 10  are independently hydrogen or C 1-6  alkyl or R 9  and R 10  together with the nitrogen atom to which they are attached form a 5 or 6-membered saturated ring optionally containing a further O, S or NR 4 , CO 2 C 1-6  alkyl, CONR 1 R 2  where R 11  and R 12  are independently hydrogen or C 1-6  alkyl, aryl or heteroaryl group optionally substituted by halogen, amino, hydroxy, cyano, nitro, trifluoromethyl, carboxy, CONR 5 R 6 , SO 2 NR 5 R 6 , SO 2 R 4 , NHSO 2 R 4 , NHCOR 4 , C 1-6  alkyl, C 1-6  alkoxy, SR 4  or NR 5 R 6  where R 4  is hydrogen, C 1-6  alkyl or C 3-6  cycloalkyl, R 5  and R 6  are independently hydrogen, C 1-6  alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR 4  group; 
         and pharmaceutically acceptable salts or solvates thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein R 1  is C 1-4 alkyl, or phenyl substituted by halogen, SO 2 Me, C 1-6 alkoxy or C 1-4 alkyl. 
     
     
         3 . A compound according to  claim 1 , wherein R 1  is a group Y(CH 2 ) p R 7  where p is 0 and Y is NR 8  where R 8  is hydrogen and R 7  is substituted phenyl. 
     
     
         4 . A compound according to  claim 1 , wherein R 1  is NR 9 R 10  where R 9  and R 10  are hydrogen or C 1-3  alkyl or together with the nitrogen atom to which they are attached form a 5 or 6-membered saturated ring optionally containing a further O, S or NR 4 . 
     
     
         5 . A compound of formula (I) according to  claim 1  selected from: 
       7-(4-Chlorophenyl)-4-morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 
       7-(4-Chlorophenyl)-4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 
       4-[(4-Chlorophenyl)amino]-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 
       1-[7-(4-Chlorophenyl)-2-cyano-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-L-prolinamide, 
       1-[2-Cyano-7-(4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-L-prolinamide, 
       7-(4-Methoxyphenyl)-4-pyrrolidin-1-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 
       7-(4-Methoxyphenyl)-4-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 
       and pharmaceutically acceptable salts thereof. 
     
     
         6 . A pharmaceutical composition which comprises a compound of the formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. 
     
     
         7 . A method for producing inhibition of at least one cysteine protease chosen from cathepsins S, K, L, F and B in a mammal comprising administering to said mammal an effective amount of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A method for treating pain in a mammal in need of such treatment comprising administering to said mammal an effective amount of a compound as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A method for inhibiting Cathepsin S in a warm blooded animal comprising administering a compound of the formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt thereof to a warm blooded animal.