Dipeptide nitriles

Abstract

N-terminal substituted dipeptide nitrites 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 nitrites 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 . A cathepsin inhibiting pharmaceutical composition comprising a dipeptide nitrile in which the C-terminal carboxy group of the dipeptide is replaced by a nitrile group (—C≡N) and in which the N-terminal nitrogen atom is substituted via a peptide or pseudopeptide linkage which optionally additionally comprises a -methylene-hetero atom-linker or an additional hetero atom, directly by aryl, lower alkyl, lower alkenyl, lower alkynyl or heterocyclyl or a physiologically-acceptable and -cleavable ester or a salt thereof, in combination with a pharmaceutically acceptable carrier.  
     
     
         2 . A cathepsin inhibiting pharmaceutical composition according to  claim 1  comprising a compound of formula I, or a physiologically-acceptable and -cleavable ester or a salt thereof  
       
         
           
           
               
               
           
         
         wherein: 
 R is optionally substituted (aryl, lower alkyl, lower alkenyl, lower alkynyl, or heterocyclyl);  
 R 2  and R 3  are independently hydrogen, or optionally substituted [lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-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 atom to which they are attached 
 wherein R 6  is hydrogen, lower alkyl or aryl-lower alkyl; or  
 
 either R 2  or R 3  are linked by lower alkylene to the adjacent nitrogen to form a ring;  
 R 4  and R 5  are independently H, or optionally substituted (lower alkyl, aryl-lower alkyl), —C(O)OR 7 , or —C(O)NR 7 R 8 , 
 wherein 
 R 7  is optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), and  
 R 8  is H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), 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 
 wherein R 6  is hydrogen, lower alkyl or aryl-lower alkyl, or  
 
 R 4  is H or optionally substituted lower alkyl and R 5  is a substituent of formula —X 2 —(Y 1 ) n -(Ar) p -Q-Z  
 wherein 
 Y 1  is O, S, SO, SO 2 , N(R 6 )SO 2 , N—R 6 , SO 2 NR 6 , CONR 6  or NR 6 CO;  
 n is zero or one;  
 p is zero or one;  
 X 2  is lower alkylene; or when n is zero, X 2  is also C 2 -C 7 -alkylene interrupted by O, S, SO, SO 2 , NR 6 , SO 2 NR 6 , CONR 6  or NR 6 CO; 
 wherein R 6  is hydrogen, lower alkyl or aryl-lower alkyl;  
 
 Ar is arylene;  
 Z is hydroxy, acyloxy, carboxyl, esterified carboxyl, amidated carboxyl, aminosulfonyl, (lower alkyl or aryl-lower alkyl)aminosulfonyl, or (lower alkyl or aryl-lower alkyl)sulfonylaminocarbonyl; or Z is tetrazolyl, triazolyl or imidazolyl;  
 Q is a direct bond, lower alkylene, Y 1 -lower alkylene or C 2 -C 7 -alkylene interrupted by Y 1 ;  
 
 X 1  is —C(O)—, —C(S)—, —S(O)—, —S(O) 2 —, or —P(O)(OR 6 )—, 
 wherein R 6  is as defined above;  
 
 Y is oxygen or sulphur;  
 L is optionally substituted -Het-, -Het-CH 2 — or —CH 2 -Het-, 
 wherein Het is a hetero atom selected from O, N or S, and  
 
 x is zero or one;  
 and aryl in the above definitions represents carbocyclic or heterocyclic aryl;  
 in combination with a pharmaceutically acceptable carrier.  
 
       
     
     
         3 . A compound of formula I, or a physiologically-acceptable and -cleavable ester or a salt thereof  
       
         
           
           
               
               
           
         
         wherein: 
 R is optionally substituted (aryl, lower alkyl, lower alkenyl, lower alkynyl, or heterocyclyl);  
 R 2  and R 3  are independently hydrogen, or optionally substituted [lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-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 atom to which they are attached 
 wherein R 6  is hydrogen, lower alkyl or aryl-lower alkyl; or  
 
 either R 2  or R 3  are linked by lower alkylene to the adjacent nitrogen to form a ring;  
 R 4  and R 5  are independently H, or optionally substituted (lower alkyl, aryl-lower alkyl), —C(O)OR 7 , or —C(O)NR 7 R 8 , 
 wherein 
 R 7  is optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), and  
 R 8  is H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, cycloalkyl, bicycloalkyl or heterocyclyl), 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 
 wherein R 6  is hydrogen, lower alkyl or aryl-lower alkyl, or  
 
 R 4  is H or optionally substituted lower alkyl and R 5  is a substituent of formula —X 2 —(Y 1 ) n -(Ar) p -Q-Z  
 wherein 
 Y 1  is O, S, SO, SO 2 , N(R 6 )SO 2 , N—R 6 , SO 2 NR 6 , CONR 6  or NR 6 CO;  
 n is zero or one;  
 p is zero or one;  
 X 2  is lower alkylene; or when n is zero, X 2  is also C 2 -C 7 -alkylene interrupted by O, S, SO, SO 2 , NR 6 , SO 2 NR 6 , CONR 6  or NR 6 CO; 
 wherein R 6  is hydrogen, lower alkyl or aryl-lower alkyl;  
 
 Ar is arylene;  
 Z is hydroxy, acyloxy, carboxyl, esterified carboxyl, amidated carboxyl, aminosulfonyl, (lower alkyl or aryl-lower alkyl)aminosulfonyl, or (lower alkyl or aryl-lower alkyl)sulfonylaminocarbonyl; or Z is tetrazolyl, triazolyl or imidazolyl;  
 Q is a direct bond, lower alkylene, Y 1 -lower alkylene or C 2 -C 7 -alkylene interrupted by Y 1 ;  
 
 X 1  is —C(O)—, —C(S)—, —S(O)—, —S(O) 2 —, or —P(O)(OR 6 )—, 
 wherein R 6  is as defined above;  
 
 Y is oxygen or sulphur;  
 L is optionally substituted -Het-, -Het-CH 2 — or —CH 2 -Het-, 
 wherein Het is a hetero atom selected from O, N or S, and  
 
 x is zero or one;  
 and aryl in the above definitions represents carbocyclic or heterocyclic aryl;  
 provided that when R is lower alkyl not substituted by aryl, 
 one of R 4  or R 5  is a substituent of formula —X 2 -(Y 1 ) n -(Ar) p -Q-Z;  
 
 provided that when x is one, L is —O—, or —CH 2 —O— and X 1  is —C(O)—, 
 either one of R 4  or R 5  is a substituent of formula —X 2 —(Y 1 ) n -(Ar) p -Q-Z, or R is not unsubstituted phenyl;  
 
 provided that when R 2 =R 4 =R 5 =H, x is zero and X 1  is —C(O)—, 
 R 3  is not H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —CH—(CH 3 ) 2 , —CH 2 —COOH, or —CH 2 —COO—CH 2 —CH 3 , when R is unsubstituted phenyl,  
 R 3  is not H, —CH(CH 3 ) 2 , or —CH 2 —CH—(CH 3 ) 2 , when R is 4-aminophenyl or 4-nitrophenyl,  
 R 3  is not H when R is 3-aminophenyl, 3-nitrophenyl 2-chloropyridin-4-yl, or vinyl or  
 R 3  is not —CH 2 —CH 2 —S—CH 3  when R is pyridin-3-yl or 2-chloropyridin-4-yl,  
 
 provided that when R 2 =R 3 =R 4 =H, x is zero and X 1  is —C(O)— and R is phenyl, 
 R 5  is not —CH(CH 3 ) 2 ,  
 
 provided that when R 3 =R 4 =H, R 5  is —CH 2 —CH 2 —COOH, x is zero and X 1  is —C(O)—, 
 R 2  does not form a heterocyclic ring with the adjacent nitrogen atom, and  
 
 provided that when R 2 =R 3 =R 4 =R 5 =H, x is zero and X 1  is —SO 2 —, 
 R is not 4-methylphenyl.  
 
 
       
     
     
         4 . A compound according to  claim 3 , of formula II, or a physiologically-acceptable and -cleavable ester or a salt thereof  
       
         
           
           
               
               
           
         
         wherein: 
 R 20  is optionally substituted (aryl, aryl-lower alkyl, lower alkenyl, lower alkynyl, heterocyclyl, or heterocyclyl-lower alkyl);  
 R 22  is H, or optionally substitued lower alkyl, and  
 R 23  is optionally substituted (lower alkyl, aryl-lower alkyl, or cyloalkyl-lower alkyl) or  
 R 22  and R 23  together with the carbon atom to which they are attached form an optionally substituted (cycloalkyl group or heterocycloalkyl group);  
 R 24  and R 25  are independently H, or optionally substituted (lower alkyl, or aryl-lower alkyl), —C(O)OR 7 , or —C(O)NR 7 R 8 ,  
 wherein R 7  and R 8  are as defined above, or  
 R 24  and R 25  together with the carbon atom to which they are attached form an optionally substituted (cycloalkyl group or heterocycloalkyl group);  
 X 1  is as defined in  claim 2;   
 Y is oxygen or sulphur;  
 L′ is optionally substituted (-Het-CH 2 — or —CH 2 -Het-), 
 wherein Het is a a hetero atom selected from O, N or S, and  
 
 x is 1 or 0,  
 provided that when x is one, L is —CH 2 —O— and X 1  is —C(O)—, 
 R 20  is not unsubstituted phenyl,  
 
 provided that when R 22 =R 24 =R 25 =H, x is zero and X 1  is —C(O)—, 
 R 23  is not H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —CH—(CH 3 ) 2 , —CH 2 —COOH, or —CH 2 —COO—CH 2 —CH 3 , when R 20  is unsubstituted phenyl,  
 R 23  is not H, —CH(CH 3 ) 2 , or —CH 2 —CH—(CH 3 ) 2 , when R 20  is 4-aminophenyl or 4-nitrophenyl,  
 R 23  is not H when R 20  is 3-aminophenyl, 3-nitrophenyl 2-chloropyridin-4-yl, or vinyl, or  
 R 23  is not —CH 2 —CH 2 —S—CH 3  when R 20  is pyridin-3-yl or 2-chloropyridin-4-yl,  
 
 provided that when R 22 =R 23 =R 24 =H, x is zero and X 1  is —C(O)— and R 20  is phenyl, 
 R 25  is not —CH(CH 3 ) 2 ,  
 
 provided that when R 23 =R 24 =H, R 25  is —CH 2 —CH 2 —COOH, x is zero and X 1  is —C(O)—, 
 R 22  does not form a heterocyclic ring with the adjacent nitrogen atom, and  
 
 provided that when R 22 =R 23 =R 24 =R 25 =H, x is zero and X 1  is —SO 2 —, 
 R 20  is not 4-methylphenyl.  
 
 
       
     
     
         5 . A compound according to  claim 3 , of formula II′ or a physiologically-acceptable and -cleavable ester or a salt thereof  
       
         
           
           
               
               
           
         
         wherein: 
 R 20 ′ is optionally substituted (C 6 -C 18  aryl or C 4 -C 18  heteroaryl);  
 R 22 ′ is H, or optionally substitued C 1 -C 8  alkyl, and  
 R 23 ′ is optionally substituted (C 2 -C 8  alkyl, or C 7 -C 14  aralkyl), or  
 R 22 ′ and R 23 ′ together with the carbon atom to which they are attached form an optionally substituted (C 3 -C 8  cycloalkyl group or C 4 -C 7  heterocycloalkyl group);  
 R 24 ′ and R 25 ′ are independently H, or optionally substituted (C 1 -C 8  alkyl, C 7 -C 14  aralkyl, or C 5 -C 14  heteroaralkyl), —C(O)OR 6 ′, or —C(O)NR 6 ′R 7 ′, 
 wherein 
 R 6 ′ is optionally substituted (C 1 -C 8  alkyl, C 7 -C 14  aralkyl, C 3 -C 8  cycloalkyl, C 4 -C 7  heterocycloalkyl, C 5 -C 14  heteroaralkyl, C 6 -C 14  aryl, or C 4 -C 14  heteroaryl), and  
 R 7 ′ is H, or optionally substituted (C 1 -C 8  alkyl, C 7 -C 14  aralkyl, C 3 -C 8  cycloalkyl, C 4 -C 7  heterocycloalkyl, C 5 -C 14  heteroaralkyl, C 6 -C 14  aryl, or C 4 -C 14  heteroaryl), or  
 
 
 R 24 ′ and R 25 ′ together with the carbon atom to which they are attached form an optionally substituted (C 3 -C 8  cycloalkyl group or C 4 -C 7  heterocycloalkyl group);  
 X 1  is —C(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —P(O)(OR 6 ′)—
 wherein R 6 ′ is as defined above;  
 
 Y is oxygen or sulphur;  
 L′ is optionally substituted (-Het-CH 2 — or —CH 2 -Het-), 
 wherein Het is a a hetero atom selected from O, N or S, and  
 
 x is 1 or 0,  
 provided that when x is one, L′ is —CH 2 —O— and X 1  is —C(O)—
 R 20 ′ is not unsubstituted phenyl,  
 
 provided that when R 22 ′=R 24 ′=R 25 ′=H, x is zero and X 1  is —C(O)—, 
 R 23 ′ is not H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —CH—(CH 3 ) 2 , —CH 2 —COOH, or —CH 2 —COO—CH 2 —CH 3 , when R 20 ′ is unsubstituted phenyl,  
 R 23 ′ is not H, —CH(CH 3 ) 2 , or —CH 2 —CH—(CH 3 ) 2 , when R 20 ′ is 4-aminophenyl or 4-nitrophenyl,  
 R 23 ′ is not H when R 20 ′ is 3-aminophenyl, 3-nitrophenyl, 2-chloropyridin-4-yl, or vinyl, or  
 R 23 ′ is not —CH 2 —CH 2 —S—CH 3  when R 20 ′ is pyridin-3-yl or 2-chloropyridin-4-yl,  
 
 provided that when R 22 ′=R 23 ′=R 24 ′=H, x is zero and X 1  is —C(O)— and R 20 ′ is phenyl, 
 R 25 ′ is not —CH(CH 3 ) 2 ,  
 
 provided that when R 23 ′=R 24 ′=H, R 25 ′ is —CH 2 —CH 2 —COOH, x is zero and X 1  is —C(O)—, 
 R 20 ′ does not form a heterocyclic ring with the adjacent nitrogen atom, and  
 
 provided that when R 22 ′=R 23 ′=R 24 ′=R 25 ′ H, x is zero and X 1  is —SO 2 —, 
 R 20 ′ is not 4-methylphenyl.  
 
 
       
     
     
         6 . A cathepsin inhibiting pharmaceutical composition comprising a compound of formula III  
       
         
           
           
               
               
           
         
         wherein 
 R 30  is an acyl group derived from an organic carboxylic, carbonic, carbamic or sulfonic acid;  
 R 32  and R 33  are independently hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-lower alkyl; or R 32  and R 33  together represent lower alkylene so as to form a ring together with the carbon to which they are attached;  
 R 34  is hydrogen or lower alkyl;  
 Y 1  is O, S, SO, SO 2 , N(R 6 )SO 2 , N—R 6 , SO 2 NR 6 , CONR 6  or NR 6 CO;  
 n is zero or one;  
 p is zero or one;  
 X 2  is lower alkylene; or when n is zero, X 2  is also C 2 -C 7 -alkylene interrupted by O, S, SO, SO 2 , NR 6 , SO 2 NR 6 , CONR 6  or NR 6 CO;  
 wherein R 6  is hydrogen, lower alkyl or aryl-lower alkyl;  
 Ar is arylene;  
 Z is hydroxy, acyloxy, carboxyl, esterified carboxyl, amidated carboxyl, aminosulfonyl, (lower alkyl or aryl-lower alkyl)aminosulfonyl, or (lower alkyl or aryl-lower alkyl)sulfonylaminocarbonyl; or Z is tetrazolyl, triazolyl or imidazolyl;  
 Q is a direct bond, lower alkylene, Y 1 -lower alkylene or C 2 -C 7 -alkylene interrupted by Y 1 ;  
 or a pharmaceutically acceptable salt or ester thereof;  
 in combination with a pharmaceutically acceptable carrier.  
 
       
     
     
         7 . A compound of formula III  
       
         
           
           
               
               
           
         
         wherein 
 R 30  is an acyl group derived from an organic carboxylic, carbamic or sulfonic acid;  
 R 32  and R 33  are independently hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, or (aryl, biaryl, cycloalkyl or bicycloalkyl)-lower alkyl; or R 32  and R 33  together represent lower alkylene so as to form a ring together with the carbon to which they are attached;  
 R 34  is hydrogen or lower alkyl;  
 Y 1  is O, S, SO, SO 2 , N(R)SO 2 , N—R 6 , SO 2 NR 6 , CONR 6  or NR 6 CO;  
 n is zero or one;  
 p is zero or one;  
 X 2  is lower alkylene; or when n is zero, X 2  is also C 2 -C 7 -alkylene interrupted by O, S, SO, SO 2 , NR 6 , SO 2 NR 6 , CONR 6  or NR 6 CO;  
 wherein k is hydrogen, lower alkyl or aryl-lower alkyl;  
 Ar is arylene;  
 Z is hydroxy, acyloxy, carboxyl, esterified carboxyl, amidated carboxyl, aminosulfonyl, (lower alkyl or aryl-lower alkyl)aminosulfonyl, or (lower alkyl or aryl-lower alkyl)sulfonylaminocarbonyl; or Z is tetrazolyl, triazolyl or imidazolyl;  
 Q is a direct bond, lower alkylene, Y 1 -lower alkylene or C 2 -C 7 -alkylene interrupted by Y 1 ;  
 
         or a pharmaceutically acceptable salt or ester thereof.  
       
     
     
         8 . A compound according to  claim 7 , wherein 
 (a) p is one;    (b) Y 1  is O, S, SO, SO 2 , N(R)SO 2  or N—R 6 ; and    (c) X 2  is lower alkylene; or when n is zero, X 2  is also C 2 -C 7 -alkylene interrupted by O, S, SO, SO 2  or NR 6 ,    or a pharmaceutically acceptable salt or ester thereof.    
     
     
         9 . A compound according to  claim 3 , of formula IV  
       
         
           
           
               
               
           
         
         wherein 
 R 40  is substituted phenyl or heterocyclic aryl, (mono- or di-carbocyclic or heterocyclic aryl)-lower alkyl or lower alkenyl, or heterocyclyl;  
 R 42  is hydrogen or lower alkyl;  
 R 43  is carbocyclic or heterocyclic aryl-lower alkyl;  
 R 44  and R 45  are independently hydrogen or lower alkyl; or  
 R 44  and R 45  combined represent lower alkylene;  
 or a pharmaceutically acceptable salt or esters thereof.  
 
       
     
     
         10 . A compound according to  claim 4  of the formula V,  
       
         
           
           
               
               
           
         
         wherein the symbols are as defined in said claim, or a physiologically-acceptable and -cleavable ester or salt thereof.  
       
     
     
         11 . A compound according to  claim 7  of the formula V′ 
       
         
           
           
               
               
           
         
         wherein the symbols are as defined in said claim, or a physiologically-acceptable and -cleavable ester or salt thereof.  
       
     
     
         12 . A compound according to  claim 9  of the formula V″ 
       
         
           
           
               
               
           
         
         wherein the symbols are as defined in said claim, or a physiologically-acceptable and -cleavable ester or salt thereof.  
       
     
     
         13 . A process for the preparation of a compound of formula I as defined in  claim 3 , comprising 
 (a) converting an amide of the formula VI                           wherein R, R 2 , R 3 , R 4  and R 5  have meaning as previously defined in  claim 2  for the compounds of formula I to a nitrile of formula I; or    (b) condensing a compound of the formula VII                           wherein R 4  and R 5  have meaning as defined in  claim 1 , with an acid of formula VIII                           wherein R, R 2  and R 3  have meaning as defined in  claim 1;  or with a reactive derivative thereof; or    (c) condensing a compound of the formula Ia                           wherein R 2 , R 3 , R 4  and R 5  have meaning as defined in  claim 1  with an acid corresponding to the group R-[L] x -X 1 — or with a reactive derivative thereof; and in the above processes, if required, temporarily protecting any interfering reactive groups and then isolating the resulting compound of the invention; and, if desired, converting any resulting compound into another compound of the invention; and/or if desired, converting a resulting compound into a salt or a resulting salt into the free acid or base or into another salt.    
     
     
         14 . A method of inhibiting cathepsin activity in a mammal which comprises administering to a mammal in need thereof an effective amount of a pharmaceutical composition as defined in  claim 1 .  
     
     
         15 . A method of inhibiting cathepsin activity in a mammal which comprises administering to a mammal in need thereof an effective amount of a pharmaceutical composition as defined in  claim 2 .  
     
     
         16 . A method of inhibiting cathepsin activity in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I as defined in  claim 3 .  
     
     
         17 . A method of treating cathepsin dependent conditions in a mammal which comprises administering to a mammal in need thereof an effective amount of a pharmaceutical composition as defined in  claim 2 .  
     
     
         18 . A method according to  claim 17  of treating inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.  
     
     
         19 . A method of treating cathepsin dependent conditions in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound as defined in  claim 3 .  
     
     
         20 . A cathepsin inhibiting pharmaceutical composition comprising a compound of formula I as defined in  claim 3 , in combination with a pharmaceutically acceptable carrier.