Dipeptide nitriles

Abstract

N-terminal substituted dipeptide nitriles as defined are useful as inhibitors of cysteine cathepsins, e.g. cathepsins B, K, L and S, and can be used for the treatment of cysteine cathepsin dependent diseases and conditions, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization). Particular dipeptide nitriles are compounds of formula I, or physiologically-acceptable and -cleavable esters or a salts thereof wherein: the symbols are as defined. In particular it has been found that by appropriate choice of groups R, R 2 , R 3 , R 4 , R 5 , X 1 , Y and L, the relative selectivity of the compounds as inhibitors of the various cysteine cathepsin types, e.g. cathepsins B, K, L and S may be altered, e.g. to obtain inhibitors which selectively inhibit a particular cathepsin type or combination of cathepsin types.

1 - 20 . (canceled)  
   
   
       21 : A compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 R is substituted aryl selected from 4-(morpholin-1-yl)-phen-1-yl, 4-(morpholin-1-yl-methyl)-phen-1-yl, 4-(pyrrolidin-1-yl-methyl)-phen-1-yl), 4-(4-methylpiperazin-1-yl)-phen-1-yl and 4-(piperidinyl)-phenyl;  
 R 2  and R 3  are, independently, hydrogen or lower alkyl; or  
 R 2  and R 3 , together, represent lower alkylene, optionally interrupted by O, S or NR 6 , so as to form a ring with the carbon to which they are attached, and R 6  is hydrogen, lower alkyl or aryl-lower alkyl;  
 R 4  and R 5  are, independently, hydrogen or lower alkyl; or  
 R 4  and R 5 , together, represent lower alkylene, optionally interrupted by O, S or NR 6 , so as to form a ring with the carbon atom to which they are attached, and R 6  is hydrogen, lower alkyl or aryl-lower alkyl;  
 X 1  is —C(O)—;  
 Y is oxygen; and  
 x is zero;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       22 : A compound of formula (II):  
     
       
         
         
             
             
         
       
     
     wherein 
 R 20  is substituted aryl selected from 4-(morpholin-1-yl)-phen-1-yl, 4-(morpholin-1-yl-methyl)-phen-1-yl, 4-(pyrrolidin-1-yl-methyl)-phen-1-yl), 4-(4-methylpiperazin-1-yl)-phen-1-yl and 4-(piperidinyl)-phenyl;  
 R 22  is hydrogen or lower alkyl and R 23  is lower alkyl; or  
 R 22  and R 23 , together with the carbon atom to which they are attached, form a C 5 -C 8  cycloalkyl group or a heterocycloalkyl group of 3-10 ring atoms;  
 R 24  and R 25  are, independently, hydrogen or lower alkyl; or  
 R 24  and R 25 , together with the carbon atom to which they are attached, form a C 3 -C 7  cycloalkyl group;  
 X 1  is —C(O)—;  
 Y is oxygen; and  
 x is zero;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       23 : A compound according to  claim 22 , wherein R 22  and R 23 , together with the carbon to which they are attached, represent a C 6  cycloalkyl group.  
   
   
       24 : A compound according to  claim 22 , wherein R 24  and R 25  are both H or —CH 3 .  
   
   
       25 : A compound according to  claim 22 , wherein R 24  is H and R 25  is —CH 2 CH(CH 3 ) 2 .  
   
   
       26 : A method of inhibiting cathepsin activity in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound according to  claim 22 .  
   
   
       27 : A method of treating a cathepsin-dependent condition in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound according to  claim 22 .  
   
   
       28 : A method according to  claim 27 , wherein the condition is selected from inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.  
   
   
       29 : A method of treating a cathepsin-dependent condition in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound according to  claim 23 .  
   
   
       30 : A method according to  claim 29 , wherein the condition is selected from inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.  
   
   
       31 : A cathepsin-inhibiting pharmaceutical composition comprising a compound according to  claim 22  in combination with a pharmaceutically acceptable carrier.  
   
   
       32 : A compound according to  claim 22 , wherein 
 X 1  is —C(O)—;    Y is oxygen;    x is zero;    R 22  is H;    R 23  is —CH 2 CH(CH 3 ) 2 ; and    (a) R 20  is 4-(morpholin-1-ylmethyl)-phen-1-yl; and 
 R 24  and R 25  are H; or  
   (b) R 20  is 4-(pyrrolidin-1-ylmethyl)-phen-1-yl; and 
 R 24  and R 25  are H;  
 or a pharmaceutically acceptable salt thereof.  
   
   
   
       33 : A compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 R is phenyl substituted by hetero(C 3 -C 10 )cycloalkyl(C 1 -C 4 )alkyl or hetero(C 3 -C 10 )cycloalkyl;  
 x is zero;  
 X 1  is —C(O)—;  
 R 2  is hydrogen or lower alkyl;  
 R 3  is lower alkyl; or  
 R 2  and R 3  together represent lower alkylene optionally interrupted by O, S or NR 6 , wherein, so as to form a ring with the carbon atom to which they are attached, and R 6  is hydrogen or lower alkyl;  
 Y is oxygen;  
 R 4  and R 5  are hydrogen;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       34 : A compound according to  claim 33 , wherein R is selected from the group consisting of 4-(morpholin-1-yl)-phen-1-yl, 4-(morpholin-1-ylmethyl)-phen-1-yl, 4-(pyrrolidin-1-ylmethyl)-phen-1-yl, 4-(4-methylpiperazin-1-yl)-phen-1-yl and 4-(piperidinyl)phenyl.  
   
   
       35 : A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 33  in combination with a pharmaceutically acceptable excipient.  
   
   
       36 : A method of treating a disease in a mammal in which cathepsin K contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the mammal a therapeutically effective amount of a compound according to  claim 33 .  
   
   
       37 : A method according to  claim 36 , wherein the disease is osteoporosis.  
   
   
       38 : A method according to  claim 36 , wherein the mammal is a human.  
   
   
       39 : A method according to  claim 36 , wherein the human is a post-menopausal woman.