Treatment of kidney disease or renal failure using interleukin-1beta-converting enzyme (ICE)/CED-3 family inhibitors

Abstract

The present invention provides methods and compositions for treating infectious disease or suppressing inflammation associated therewith or ameliorating symptoms thereof by the suppression of the activity of a member of the interleukin-1β-converting enzyme (ICE)/CED-3 family of proteases. Also provided are compositions useful for these purposes. Exemplary compounds useful in the methods of the invention are provided herein.

We claim:  
     
         1 . A method for ameliorating or treating infectious disease, comprising contacting a cell population with an inhibiting effective amount of a reagent that suppresses the protease activity of at least one member of the interleukin-1β-converting enzyme (ICE)/CED-3 family, thereby ameliorating or treating infectious disease.  
     
     
         2 . The method of  claim 1 , wherein said infectious disease is viral.  
     
     
         3 . The method of  claim 1 , wherein said contacting is in vitro.  
     
     
         4 . The method of  claim 1 , wherein said contacting is in vivo.  
     
     
         5 . The method of  claim 1 , wherein the reagent suppresses the protease activity in an irreversible manner.  
     
     
         6 . The method of  claim 1 , wherein the reagent suppresses the protease activity in a reversible manner.  
     
     
         7 . The method of  claim 1 , wherein the reagent is a compound of formula 1:  
       
         
           
           
               
               
           
         
       
       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 and 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), CH 2 OCO(heteroaryl); or CH 2 OPO(R 7 )R 8    
 where Z is an oxygen or a sulfur atom;  
 R 6  is phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, heteroaryl, or (heteroaryl)alkyl; and  
 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 thereof.  
 
     
     
         8 . The method of  claim 1 , wherein the reagent is a compound of formula 3:  
       
         
           
           
               
               
           
         
         wherein: 
 n is 1 or 2;  
 m is 1 or 2;  
 A is R 2 CO—, R 3 —O—CO—, or R 4 SO 2 —;  
 a group of the formula:  
                     
 further wherein: 
 R 1  is a hydrogen atom, alkyl or phenylalkyl;  
 R 2  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl;  
 R 3  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted phenyl)alkyl;  
 R 4  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl;  
 R 5  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl;  
 R 6  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted phenyl)alkyl;  
 R 7  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl;  
 R 8  is an amino acid side chain chosen from the group consisting of natural and unnatural amino acids;  
 B is a hydrogen atom, a deuterium atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, (heteroaryl)alkyl, or halomethyl;  
 a group of the formula:  
 —CH 2 XR 9 ;  
 wherein R 9  is phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl; and X is an oxygen or a sulfur atom;  
 a group of the formula:  
 —CH 2 —O—CO-(ARYL);  
 a group of the formula:  
 —CH 2 —O—CO-(HETEROARYL);  
 a group of the formula:  
 —CH 2 —O—PO(R 10 )R 11    
 wherein R 10  and R 11  are independently selected from a group consisting of alkyl, cycloalkyl, phenyl, substituted phenyl, phenylalkyl and (substituted phenyl) alkyl; and the pharmaceutically-acceptable salts thereof.  
 
 
       
     
     
         9 . A method for preventing or ameliorating inflammation due to an infectious disease comprising contacting a population of cells exposed to an infectious agent with an inhibiting effective amount of a reagent that suppresses the protease activity of at least one member of the interleukin-1β-converting enzyme (ICE)/CED-3 family.  
     
     
         10 . The method of  claim 9 , wherein said contacting is in vitro.  
     
     
         11 . The method of  claim 9 , wherein said contacting is in vivo.  
     
     
         12 . The method of  claim 9 , wherein the reagent suppresses the protease activity in an irreversible manner.  
     
     
         13 . The method of  claim 9 , wherein the reagent suppresses the protease activity in a reversible manner.  
     
     
         14 . The method of  claim 9 , wherein the reagent is a compound of formula 1:  
       
         
           
           
               
               
           
         
         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 and 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), CH 2 OCO(heteroaryl); or CH 2 OPO(R 7 )R 8    
 where Z is an oxygen or a sulfur atom;  
 R 6  is phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, heteroaryl, or (heteroaryl)alkyl; and  
 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 thereof.  
       
     
     
         15 . The method of  claim 9 , wherein the reagent is a compound of formula 3:  
       
         
           
           
               
               
           
         
         wherein: 
 n is 1 or 2;  
 m is 1 or 2;  
 A is R 2 CO—, R 3 —O—CO—, or R 4 SO 2 —;  
 a group of the formula:  
                     
 further wherein: 
 R 1  is a hydrogen atom, alkyl or phenylalkyl;  
 R 2  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl;  
 R 3  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted phenyl)alkyl;  
 R 4  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl;  
 R 5  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl;  
 R 6  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted phenyl)alkyl;  
 R 7  is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl;  
 R 8  is an amino acid side chain chosen from the group consisting of natural and unnatural amino acids;  
 B is a hydrogen atom, a deuterium atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, phenylalkyl, substituted phenyl, (substituted phenyl)alkyl, heteroaryl, (heteroaryl)alkyl, or halomethyl;  
 a group of the formula:  
 —CH 2 XR 9 ;  
 wherein R 9  is phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, heteroaryl, or (heteroaryl)alkyl; and X is an oxygen or a sulfur atom;  
 a group of the formula:  
 —CH 2 —O—CO-(ARYL);  
 a group of the formula:  
 —CH 2 —O—CO-(HETEROARYL);  
 a group of the formula:  
 CH 2 —O—PO(R 10 )R 11    
 wherein R 10  and R 11  are independently selected from a group consisting of alkyl, cycloalkyl, phenyl, substituted phenyl, phenylalkyl and (substituted phenyl) alkyl; and the pharmaceutically-acceptable salts thereof.