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: 
 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 3  where R 5  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 11 R 12  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 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 5  where R 5  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  which is 1-(4-methylphenyl)-4-morpholin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-6-carbonitrile, or a pharmaceutically acceptable salt 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.