Dipeptide nitrile cathepsin K inhibitors

Abstract

Dipeptide nitrile Cathepsin K inhibitors of formula I, and pharmaceutically acceptable salts or esters thereof In which R 1 and R 2 are independently H or C 1 -C 7 lower alkyl, or R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 8 cycloalkyl ring, and Het is an optionally substituted nitrogen-containing heterocyclic substituent, are provided, useful e.g. for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated.

1 - 9 . (canceled)  
   
   
       10 . A compound of formula I, or a pharmaceutically acceptable salt or ester thereof  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  and R 2  are independently H or C 1 -C 7 lower alkyl; or R 1  and R 2  together with the carbon atom to which they are attached form a C 3 -C 8 cycloalkyl ring; and  
 Het is a saturated nitrogen-containing heterocyclic ring containing at least one nitrogen atom and from 2 to 10 carbon atoms, optionally substituted at nitrogen by C 1 -C 7 lower alkyl, C 1 -C 7 lower alkoxy-C 1 -C 7 lower alkyl, C 5 -C 10 aryl-C 1 -C 7 lower alkyl or C 3 -C 8 cycloalkyl.  
 
   
   
       11 . A compound according to  claim 10  of formula II, or a pharmaceutically acceptable salt or ester thereof  
     
       
         
         
             
             
         
       
     
     wherein 
 X is CH or N, and  
 R is C 1 -C 7 lower alkyl, C 1 -C 7 lower alkoxy-C 1 -C 7 lower alkyl, C 5 -C 10 aryl-C 1 -C 7 lower alkyl, or C 3 -C 8 cycloalkyl.  
 
   
   
       12 . A pharmaceutical composition comprising a compound according to  claim 10  as an active ingredient.  
   
   
       13 . A compound according to  claim 10 , wherein the saturated nitrogen-containing heterocyclic ring system contains from 3 to 7 carbon atoms.  
   
   
       14 . A compound according to  claim 10 , wherein the saturated nitrogen-containing heterocyclic ring system contains 4 or 5 carbon atoms.  
   
   
       15 . A compound according to  claim 10 , wherein R 1  and R 2  are H.  
   
   
       16 . A compound according to  claim 10 , in which the saturated nitrogen-containing heterocyclic ring is optionally substituted at nitrogen by C 1 -C 7 lower alkyl.  
   
   
       17 . A compound according to  claim 10 , in which the saturated nitrogen-containing heterocyclic ring is substituted at nitrogen by C 1 -C 7 lower alkyl.  
   
   
       18 . A compound according to  claim 10 , in which the saturated nitrogen-containing heterocyclic ring is substituted at nitrogen by C 1 -C 7 lower alkoxy-C 1 -C 7 lower alkyl.  
   
   
       19 . A compound according to  claim 10 , in which the saturated nitrogen-containing heterocyclic ring is substituted at nitrogen by C 5 -C 10 aryl-C 1 -C 7 lower alkyl.  
   
   
       20 . A compound according to  claim 10 , in which the saturated nitrogen-containing heterocyclic ring is substituted at nitrogen by C 3 -C 8 cycloalkyl.  
   
   
       21 . A compound according to  claim 10 , wherein Het is piperazinyl or piperidinyl each of which is optionally substituted at nitrogen by C 1 -C 7 lower alkyl, C 1 -C 7 lower alkoxy-C 1 -C 7 lower alkyl, C 5 -C 10 aryl-C 1 -C 7 lower alkyl or C 3 -C 8 cycloalkyl.  
   
   
       22 . A compound according to  claim 21 , in which Het is piperazin-1-yl or piperidin-4-yl optionally substituted at nitrogen by C 1 -C 7 lower alkyl.  
   
   
       23 . A compound according to  claim 21 , which is N-[1-cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-methyl-piperazin-1-yl)-benzamide.  
   
   
       24 . A method of treating a mammal suffering from a disease or medical condition which involves elevated levels of cathepsin K, such disease or medical condition being selected from hypercalcemia of malignancy, excessive bone loss, excessive cartilage degradation and excessive matrix degradation, comprising administering to said mammal an effective cathepsin K inhibiting amount of a compound according to  claim 10 .  
   
   
       25 . A method of treating osteoporosis in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 10 .  
   
   
       26 . A method of treating rheumatoid arthritis in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 10 .  
   
   
       27 . A method of treating osteoarthritis in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 10 .  
   
   
       28 . A method of treating gingival diseases in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 10 .  
   
   
       29 . A method of treating Paget's disease in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 10 .  
   
   
       30 . A method of treating hypercalcemia of malignancy in a mammal comprising administering to said mammal an effective amount of a compound according to  claim 10 .  
   
   
       31 . A method of selectively inhibiting cathepsin K activity in a mammal with elevated levels of cathepsin K which comprises administering to a mammal in need thereof an effective cathepsin K inhibiting amount of a compound according to  claim 10.