C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ice/ced-3 family of cysteine proteases

Abstract

This invention is directed to novel (N-substituted) indole ICE/ced-3-inhibitor compounds. The invention is also directed to pharmaceutical compositions of such indole compounds, plus the use of such compositions in the treatment of patients suffering inflammatory, autoimmune and neurodegenerative diseases, for the prevention of ischemic injury.

We claim:  
     
         1 . A compound of the following formula:  
       
         
           
           
               
               
           
         
         wherein: 
 n is 1 or 2:  
 R 1  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, (substituted)phenyl, phenylalkyl, (substituted)phenylalkyl, heteroaryl, (heteroaryl)alkyl or (CH 2 ) m CO 2 R 4 , wherein m=1-4, and R 4  is as defined below;  
 R 2  is a hydrogen atom, chloro, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, (substituted)phenyl, phenylalkyl, (substituted)phenylalkyl, heteroaryl, (heteroaryl)alkyl or (CH 2 ) p CO 2 R 5 , wherein p=0-4, and R 5  is as defined below;  
 R 3  is a hydrogen atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted)phenylalkyl;  
 R 4  is a hydrogen atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted)phenylalkyl;  
 R 5  is a hydrogen atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted)phenylalkyl;  
 A is a natural or unnatural amino acid;  
 B is a hydrogen atom, a deuterium atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, (substituted)phenyl, phenylalkyl, (substituted)phenylalkyl, heteroaryl, (heteroaryl)alkyl, halomethyl, CH 2 ZR 6 , CH 2 OCO(aryl), or CH 2 OCO(heteroaryl), or CH 2 OPO(R 7 )R 8 , where Z is an oxygen, OC(═O) or a sulfur atom;  
 R 6  is phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, heteroaryl or (heteroaryl)alkyl;  
 R 7  and R 8  are independently selected from a group consisting of alkyl, cycloalkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl and (cycloalkyl)alkyl; and  
 X and Y are independently selected from the group consisting of a hydrogen atom, halo, trihalomethyl, amino, protected amino, an amino salt, mono-substituted amino, di-substituted amino, carboxy, protected carboxy, a carboxylate salt, hydroxy, protected hydroxy, a salt of a hydroxy group, lower alkoxy, lower alkylthio, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and (substituted phenyl)alkyl;  
 or a pharmaceutically acceptable salt or stereoisomer thereof.  
 
       
     
     
         2 . The compound of  claim 1  wherein B is CH 2 ZR 6 .  
     
     
         3 . The compound of  claim 2  wherein B is CH 2 OC.(═O)R 6 .  
     
     
         4 . The compound of  claim 3  wherein R 6  is substituted phenyl.  
     
     
         5 . The compound of  claim 3  where R 6  is heteroaryl.  
     
     
         6 . The compound of  claim 2  wherein B is CH 2 OR 6 .  
     
     
         7 . The compound of  claim 6  wherein R 6  is substituted phenyl.  
     
     
         8 . The compound of  claim 7  wherein R 6  is tetra(halo)phenyl.  
     
     
         9 . The compound of  claim 8  wherein R 6  is optionally substituted naphthyl.  
     
     
         10 . The compound of  claim 9  wherein R 6  is naphthyl substituted with one or more heteroaryl groups.  
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically-acceptable carrier thereof.  
     
     
         12 . A method for treating an autoimmune disease comprising administering an effective amount of a pharmaceutical composition of  claim 11  to a patient in need of such treatment.  
     
     
         13 . A method of treating an inflammatory disease comprising administering an effective amount of the pharmaceutical composition of  claim 11  to a patient in need of such treatment.  
     
     
         14  A method of treating a neurodegenerative disease comprising administering an effective amount of the pharmaceutical composition of  claim 11  to a patient in need of such treatment.  
     
     
         15 . A method of preventing ischemic injury to a patient suffering from a disease associated with ischemic injury comprising administering an effective amount of the pharmaceutical composition of  claim 11  to a patient in need of such treatment.