Inhibitors of cruzipain and other cysteine proteases

Abstract

Compounds of general formula (I) or general formula (II):— wherein R 1 , P 1 , P 2 , Q, Y, (X) o , (W) n , (V) m , Z and U are as defined in the specification, are inhibitors of cruzipain and other cysteine protease inhibitors and are useful as therapeutic agents, for example in Chagas' disease, or for validating therapeutic target compounds.

1 . A compound according to general formula (I) or general formula (II):— 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 =C 0-7 -alkyl (when C=0, R 1  is simply hydrogen), C 3-6 -cycloalkyl or Ar—C 0-7 -alkyl (when C=0, R 1  is simply an aromatic moiety Ar); 
 Z=O, S, CR 2 R 3  or NR 4 , where R 4  is chosen from C 0-7 -alkyl, C 3-6 -cycloalkyl or Ar—C 0-7 -alkyl; 
 P 1 =CR 5 R 6 , 
 P 2 =CR 7 R 8 , 
 Q=CR 9 R 10  or NR 11 , where R 11  is chosen from C 0-7 -alkyl, C 3-6 -cycloalkyl or Ar—C 0-7 -alkyl; 
 Each of R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10  is independently chosen from C 0-7 -alkyl, C 3-6 -cycloalkyl, Ar—C 0-7 -alkyl, O—C 0-7 -alkyl, O—C 3-6 -cycloalkyl, O—Ar—C 0-7 -alkyl, S—C 0-7 -alkyl, S—C 3-6 -cycloalkyl, S—Ar—C 0-7 -alkyl, NH—C 0-7 -alkyl, NH—C 3-6 -cycloalkyl, NH—Ar—C 0-7 -alkyl, N(C 0-7 -alkyl) 2 , N(C 3-6 -cycloalkyl) 2  or N(Ar—C 0-7 -alkyl) 2 ; 
 Y=CR 12 R 13 —CO, where R 12 , R 13  are chosen from C 0-7 -alkyl, C 3-6 -cycloalkyl or Ar—C 0-7 -alkyl; 
 (X) o =CR 14 R 15 , where R 14  and R 15  are independently chosen from C 0-7 -alkyl, C 3-6 -cycloalkyl and Ar—C 0-7 -alkyl and o is a number from zero to three; 
 (W) n =O, S, C(O), S(O) or S(O) 2  or NR 16 , where R 16  is chosen from C 0-7 -alkyl, C 3-6 -cycloalkyl and Ar—C 0-7 -alkyl and n is zero or one; 
 (V) m =C(O), C(S), S(O), S(O) 2 , S(O) 2 NH, OC(O), NHC(O), NHS(O), NHS(O) 2 , OC(O)NH, C(O)NH or CR 17 R 18 , where R 17  and R 18  are independently chosen from C 0-7 -alkyl, C 3-6 -cycloalkyl, Ar—C 0-7 -alkyl and m is a number from zero to three, provided that when m is greater than one, (V) m  contains a maximum of one carbonyl or sulphonyl group; 
 U=a stable 5- to 7-membered monocyclic or a stable 8- to 11-membered bicyclic ring which is either saturated or unsaturated and which includes zero to four heteroatoms (as detailed below): 
 
       
         
           
           
               
               
           
         
         wherein R 19  is:
 C 0-7 -alkyl, C 3-6 -cycloalkyl, Ar—C 0-7 -alkyl, O—C 0-7 -alkyl, O—C 3-6 -cycloalkyl, O—Ar—C 0-7 -alkyl, S—C 0-7 -alkyl, S—C 3-6 -cycloalkyl, S—Ar—C 0-7 -alkyl, NH—C 0-7 -alkyl, NH—C 3-6 -cycloalkyl, NH—Ar—C 0-7 -alkyl, N(C 0-7 -alkyl) 2 , N(C 3-6 -cycloalkyl) 2  or N(Ar-C 0-7 -alkyl) 2 ; or, when part of a CHR 19  or CR 19  group, R 19  may be halogen; 
 
         A is chosen from:
 CH 2 , CHR 19 , O, S and NR 20 ;
 where R 19  is as defined above; and R 20  is chosen from: 
 C 0-7 -alkyl, C 3-6 -cycloalkyl and Ar—C 0-7 -alkyl; 
 
 
         B, D and G are independently chosen from:
 CR 19 , where R 19  is as defined above, or N; 
 
         E is chosen from:
 CH 2 , CHR 19 , O, S and NR 20 , where R 19  and R 20  are defined as above; 
 
         J, L, M, R, T, T 2 , T 3  and T 4  are independently chosen from:
 CR 19  and N, where R 19  is as defined above; 
 
         T 5  is chosen from:
 CH or N; 
 
         q is a number from one to three, thereby defining a 5-, 6- or 7-membered ring. 
       
     
     
         2 . A compound as claimed in  claim 1  wherein independently or in combination:
 Z is O, S, CH 2 , NH or NR 4 , where R 4  is a Ar—C 1-4 -alkyl or a substituted carbonyl or sulphonyl group;   P 1  and P 2  are CH 2 ; and   Q is CH 2  or NH.   
     
     
         3 . A compound as claimed in  claim 1  wherein R 1  comprises C 0-7 -alkyl or Ar—C 0-7 -alkyl. 
     
     
         4 . A compound as claimed in  claim 3  wherein R 1  is selected from hydrogen or one of the following moieties: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound as claimed in  claim 1  wherein Y is CR 12 R 13 CO where R 12 , R 13  are selected from C 0-7 -alkyl, C 3-6 -cycloalkyl or Ar—C 0-7 -alkyl. 
     
     
         6 . A compound as claimed in  claim 5  where Y is selected from one of the following moieties: 
       
         
           
           
               
               
           
         
       
       wherein R 19 , R 20  and Ar are as defined above. 
     
     
         7 . A compound as claimed in  claim 1  wherein Y is CHR 13 CO where R 13  is Ar—CH 2 — where the aromatic ring is an optionally substituted phenyl or monocyclic heterocycle. 
     
     
         8 . A compound as claimed in  claim 1  wherein Y is CHR 13 CO where R 13  is a simple branched alkyl group or a straight heteroalkyl chain. 
     
     
         9 . A compound as claimed in  claim 1  wherein Y is CHR 13 CO where R 13  comprises cyclohexylmethyl. 
     
     
         10 . A compound as claimed in  claim 1  wherein Y is selected from the following: 
       
         
           
           
               
               
           
         
       
       wherein R 19  and Ar are as defined previously. 
     
     
         11 . A compound as claimed in  claim 1  wherein, in the group (X) o , X is CR 14 R 15  and each of R 14  and R 15  is selected from C 0-7 -alkyl or Ar—C 0-7 -alkyl. 
     
     
         12 . A compound as claimed in  claim 1 , wherein (X) o  is one of the following moieties: 
       
         
           
           
               
               
           
         
       
       wherein R 19  and R 20  are as defined previously. 
     
     
         13 . A compound as claimed in  claim 1 , wherein (X) o  a simple alkyl group and where o=0 or 1. 
     
     
         14 . A compound as claimed in  claim 1  wherein, in the group (W) n :
 W is O, S, SO 2 , SO, C(O) or NR 16 , where R 16  is C 0-4 -alkyl; and n is 0 or 1.   
     
     
         15 . A compound as claimed in  claim 1  wherein, in the group (W) n :
 W is O, S, SO 2 , C(O) or NH where n is 0 or 1.   
     
     
         16 . A compound as claimed in  claim 1  wherein, in the group (W) n :
 W is NH where n is 1.   
     
     
         17 . A compound as claimed in  claim 1  wherein, in the group (V) m :
 V is C(O), C(O)NH or CHR 18 , where R 18  is C 0-4 -alkyl; and
 m is 0 or 1. 
   
     
     
         18 . A compound as claimed in  claim 1  wherein the combination of (V) m  and (W) m  is one of the following: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound as claimed in  claim 1  wherein the combination (X) o , (V) m  and (W) m  is one of the following: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound as claimed in  claim 1  wherein U comprises an optionally substituted 5- or 6-membered saturated or unsaturated heterocycle or an optionally substituted saturated or unsaturated 9- or 10-membered heterocycle. 
     
     
         21 . A compound as claimed in  claim 20  wherein U comprises one of the following: 
       
         
           
           
               
               
           
         
       
       wherein R 19  is as defined previously. 
     
     
         22 . A compound as claimed in  claim 1  wherein U comprises a bulky alkyl or aryl group at the para position of an aryl Ar. 
     
     
         23 . A compound as claimed in  claim 1  wherein U comprises a meta or para-biaryl Ar—Ar, where Ar is as previously defined. 
     
     
         24 . A compound as claimed in  claim 1  wherein U comprises a 6,6 or 6,5 or 5,6-fused aromatic ring. 
     
     
         25 . A compound as claimed in  claim 1 , wherein U represents a group: 
       
         
           
           
               
               
           
         
       
       wherein R 19 , D, E, G, J, L, M, R, T, T 2 , T 3  and T 4  are as defined previously. 
     
     
         26 . A compound as claimed in  claim 1 , wherein U represents a group 
       
         
           
           
               
               
           
         
       
       wherein R 19 , D, E, G, J, L, M, R and T are as defined previously. 
     
     
         27 . A compound as claimed in  claim 1 , wherein U represents a group 
       
         
           
           
               
               
           
         
       
       wherein R 19 , D, E, G, J and L are as defined previously. 
     
     
         28 . A method of validating a known or putative cysteine protease inhibitor as a therapeutic target, the method comprising:
 (a) assessing the in vitro binding of a compound as claimed in  claim 1  to an isolated known or putative cysteine protease, providing a measure of ‘potency’; and optionally, one or more of the steps of:   (b) assessing the binding of a compound as claimed in  claim 1  to closely related homologous proteases of the target and general house-keeping proteases (e.g. trypsin) to provides a measure of ‘selectivity’;   (c) monitoring a cell-based functional marker of a particular cysteine protease activity, in the presence of a compound as claimed in  claim 1 ; and   (d) monitoring an animal model-based functional marker of a particular cysteine protease activity, in the presence of a compound as claimed in  claim 1 .   
     
     
         29 . (canceled) 
     
     
         30 . A method for preventing or treating diseases in which the disease pathology may be modified by inhibiting a cysteine protease, the method comprising administering to a patient an effective amount of a compound according to  claim 1 . 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 30 , wherein the disease is Chagas' disease. 
     
     
         33 .- 35 . (canceled) 
     
     
         36 . A composition comprising one or more compounds as claimed in  claim 1  and a pharmaceutically or veterinarily acceptable carrier. 
     
     
         37 . (canceled)