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 . A compound of formula I, or a pharmaceutically acceptable salt or ester 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, provided that Het is not 4-pyrrol-1-yl.  
 
     
     
         2 . A compound according to  claim 1  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 -C8cycloalkyl.  
 
     
     
         3 . A compound according to  claim 1 , or a pharmaceutically acceptable salt or ester thereof, selected from 
 N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(piperazin-1-yl)-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-methyl-piperazin-1-yl)-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-ethyl-piperazin-1-yl)-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[4-(1-propyl)-piperazin-1-yl]-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4-isopropyl-piperazin-1-yl)-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(4--benzyl-piperazin-1-yl)-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(1-propyl-piperidin-4-yl)-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[1-(2-methoxy-ethyl)-piperidin-4-yl]-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(1-isopropyl-piperidin-4-yl)-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(1-cyclopentyl-piperidin-4-yl)-benzamide;    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(1-methyl-piperidin-4-yl)-benzamide, or    N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-(piperidin-4-yl)-benzamide.    
     
     
         4 . N-[1-(Cyanomethyl-carbamoyl)-cyclohexyl]-4-[4-(1-propyl)-piperazin-1-yl]-benzamide, or a pharmaceutically acceptable salt or ester thereof.  
     
     
         5 . A compound according to  claim 1  for use as a pharmaceutical.  
     
     
         6 . A pharmaceutical composition comprising a compound according to  claim 1  as an active ingredient.  
     
     
         7 . A method of treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated, comprising administering an effective amount of a compound according to  claim 1  to the patient.  
     
     
         8 . The use of a compound according to  claim 1  for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated.  
     
     
         9 . A process for the preparation of a compound of formula I or a salt or ester thereof which comprises coupling the corresponding Het substituted benzoic acid derivative of formula III  
       
         
           
           
               
               
           
         
       
       wherein Het is as defined in  claim 1 , with 1-amino-cyclohexanecarboxylic acid cyanomethyl-amide.