Peptide analogs as irreversible interleukin-1beta protease inhibitors

Abstract

Disclosed are compounds, compositions and methods for inhibiting interleukin-1β protease activity, the compounds having the formula (I).

What is claimed is:  
     
         1 . A compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 n=0-4;  
 Y= 
                     
 m=0,1;  
 R 3 =a singularly or multiply substituted aryl wherein aryl is a phenyl or naphthyl ring wherein the substituents are independently selected from the group consisting of: 
 (1) H  
 (2) halogen  
 (3) OH  
 (4) CF 3    
 (5) NO 2    
 (6) OR 5    
 (7) COR 9    
 (8) NR 6 COR 10    
 (9) CONR 5 R 6    
 (10) SO 2 NR 5 R 6    
 (11) SO 2 R 6    
 (12) COOR 11    
                     
 (14) lower alkyl and lower cycloalkyl  
 
 R 5 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 0-6 -aryl  
 (3) (CR 6 R 7 ) 0-6 -heteroaryl or  
 (4) (CR 6 R 7 ) 2-6 -R 8 ;  
 
 R 6  and R 7  are independently H, lower straight chain or branched alkyl, benzyl, aryl, cycloalkyl and aryl is defined as above and heteroaryl includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, benzimidazolyl, pyrazinyl, pyrimiidyl, quinolyl, isoquinolyl, isothiazolyl, benzofuranyl, isoxazolyl, triazinyl and tetrazolyl;  
 R 8 =
 (1) OCH 2 CH 2 OR 6    
 (2) OCH 2 CH 2 NR 6 R 7    
 (3) NR 6 CH 2 CO 2 R 6    
                     
 (6) NR 6 R 7  wherein R 6  and R 7  are as above defined;  
 
 R 9 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 0-6 -aryl;  
 (3) (CR 6 R 7 ) 0-6 -heteroaryl; or  
 (4) (CR 6 R 7 ) 0-6 -R 8 , wherein R 6 , R 7  and R 8  are as above defined;  
 
 R 10 =
 (1) R 9    
 (2) OR 11    
 (3) NR 6 R 11 ,  
 wherein  
 
 R 11 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 1-6 -aryl;  
 (3) (CR 6 R 7 ) 1-6 -heteroaryl; or  
 (4) (CR 6 R 7 ) 2-6 -R 8 , and R 6 , R 7  and R 8  are as above defined;  
 
 R 4 =H or deuterium;  
 R 2 =
 (1) OR 6    
 (2) NR 6 OR 7  or  
 (3) NR 6 R 7 , and R 6  and R 7  are as above-defined;  
 
 A=
 (1) an amino acid of the formula (II)  
                     
 wherein R 6  and R 7  are as defined above;  
 
 R 12  is independently 
 (1) H or  
 (2) (CR 6 R 7 ) 1-6 -R 13 , and R 6  and R 7  are as above-defined;  
 
 R 13 =
 (1) H  
 (2) F  
 (3) CF 3    
 (4) OH  
 (5) OR 11    
 (6) NR 6 R 14    
 (7) cycloalkyl  
 (8) aryl  
 (9) heteroaryl  
 (10) SH  
 (11) SR 11    
 (12) CONR 5 R 6    
 (13) COOR 5  or  
                     
 
 R 14 =
 (1) R 7    
 (2) COR 10    
 (3) SO 2 NR 5 R 6  or  
                     
 or  
 
 A=
 (2) an amino acid selected from the group consisting of  
                                       
 
 R 1  is an acyl group of the formula (III)  
                     
 wherein  
 R 12  is 
 (1) OR 5    
 (2) NR 5 R 6    
 (3) R 5    
 (4) —CH═CHR 5    
                     
 wherein R 15  single bond, (CH 2 ) 2-6 —NR 6 —, (CH 2 ) 2-6 —O— and  
 
 R 5  and R 6  are as above defined; or  
 a sulfonyl group of the formula (IV)  
                     
 wherein  
 R 16  is 
 (1) R 5    
                     
 wherein R 5  and R 6  are as above-defined.  
 
 
     
     
         2 . A compound according to  claim 1  selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-difluorophenoxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-ditrifluoromethylbenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichlorophenoxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 2-fluoro-4-(N-morpholinylsulfonamido)phenoxymethyl ketone.  
     
     
         3 . A compound according to  claim 1  selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2-chloro-4-(N-thiomorpholinyl sulfonamido)phenoxymethyl ketone, N-Benzyl oxycarbonyl-L-aspartic acid 2,6-dichloro-3-(2-N-morpholinylethoxy) benzyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dimethoxybenzoyloxy methyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(benzyloxy)benzyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 2-acetamido-6-chlorobenzoyloxymethyl ketone.  
     
     
         4 . A compound according to  claim 1  selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-difluorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 3-(N-butylsulfonamido)-2,6-dichlorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-sulfonamido benzoylmethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 3-(N-benzylsulfonamido)-2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 3-(N-[2-aminoacetamidoyl]sulfonamido)-2,6-dichlorobenzoyloxymethyl ketone.  
     
     
         5 . A compound according to  claim 1  selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(N-morpholinylsulfonamido)benzoyloxymethyl ketone, N-Methoxycarbonyl-L-alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-thienyl) carbonyl-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-Methoxycarbonyl-glycine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone and N-Methoxycarbonyl-L-phenylalanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.  
     
     
         6 . A compound according to  claim 1  selected from the group consisting of: N-Methoxycarbonyl-L-β-(2-thienyl)alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-valine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-histidine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-valine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.  
     
     
         7 . A compound according to  claim 1  selected from the group consisting of: N-Benzyloxycarbonyl-L-valine-L-alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-furonyl)carbonyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-furonyl)carbonyl-L-aspartic acid 2,6-dichloro-3-(N-morpholinylsulfonamido)-benzoyloxymethyl ketone, N-(3-phenylpropionyl)-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(4-(N,N-dimethylaminomethyl)benzoyl-L-aspartic acid 2,6-dichloro-benzyloxymethyl ketone, N-benzyloxycarbonyl-D-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-[2,6-dichlorobenzoyloxy])acetyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-valine-L-aspartic acid N-Benzyloxycarbonyl-L-valine-L-aspartic acid 4-(N,N-diethyl-sulfonamido)-2,3,5,6-tetrafluoro-phenoxymethyl ketone.  
     
     
         8 . A pharmaceutical composition for inhibiting interleukin 1β protease comprising a compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 n=0-4;  
 Y= 
                     
 m=0,1;  
 R 3 =a singularly or multiply substituted aryl wherein aryl is a phenyl or naphthyl ring wherein the substituents are independently selected from the group consisting of: 
 (1) H  
 (2) halogen  
 (3) OH  
 (4) CF 3    
 (5) NO 2    
 (6) OR 5    
 (7) COR 9    
 (8) NR 6 COR 10    
 (9) CONR 5 R 6    
 (10) SO 2 NR 5 R 6    
 (11) SO 2 R 6    
 (12) COOR 11    
                     
 (14) lower alkyl and lower cycloalkyl  
 
 R 5 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 0-6 -aryl  
 (3) (CR 6 R 7 ) 0-6 -heteroaryl or  
 (4) (CR 6 R 7 ) 2-6 -R 8 ;  
 
 R 6  and R 7  are independently H, lower straight chain or branched alkyl, benzyl, aryl, cycloalkyl and aryl is defined as above and heteroaryl includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, isothiazolyl, benzofuranyl, isoxazolyl, triazinyl and tetrazolyl;  
 R 8 =
 (1) OCH 2 CH 2 OR 6    
 (2) OCH 2 CH 2 NR 6 R 7    
 (3) NR 6 CH 2 CO 2 R 6    
                     
 (6) NR 6 R 7  wherein R 6  and R 7  are as above defined;  
 
 R 9 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 0-6 -aryl;  
 (3) (CR 6 R 7 ) 0-6 -heteroaryl; or  
 (4) (CR 6 R 7 ) 0-6 -R 8 , wherein R 6 , R 7  and R 8  are as above defined;  
 
 R 10 =
 (1) R 9    
 (2) OR 11    
 (3) NR 6 R 11 ,  
 wherein  
 
 R 11 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 1-6 -aryl;  
 (3) (CR 6 R 7 ) 1-6 -heteroaryl; or  
 (4) (CR 6 R 7 ) 2-6 -R 8 , and R 6 , R 7  and R 8  are as above defined;  
 
 R 4 =H or deuterium;  
 R 2 =
 (1) OR 6    
 (2) NR 6 OR 7  or  
 (3) NR 6 R 7 , and R 6  and R 7  are as above-defined;  
 
 A=
 (1) an amino acid of the formula (II)  
                     
 wherein R 6  and R 7  are as defined above;  
 
 R 12  is independently 
 (1) H or  
 (2) (CR 6 R 7 ) 1-6 -R 13 , and R 6  and R 7  are as above-defined;  
 
 R 13 =
 (1) H  
 (2) F  
 (3) CF 3    
 (4) OH  
 (5) OR 11    
 (6) NR 6 R 14    
 (7) cycloalkyl  
 (8) aryl  
 (9) heteroaryl  
 (10) SH  
 (11) SR 11    
 (12) CONR 5 R 6    
 (13) COOR 5  or  
                     
 
 R 14 =
 (1) R 7    
 (2) COR 10    
 (3) SO 2 NR 5 R 6  or  
                     
 or  
 
 A=
 (2) an amino acid selected from the group consisting of  
                                       
 
 R 1  is an acyl group of the formula (III)  
                     
 wherein  
 R 12  is 
 (1) OR 5    
 (2) NR 5 R 6    
 (3) R 5    
 (4) —CH═CHR 5    
                     
 wherein R 15 =single bond, (CH 2 ) 2-6 —NR 6 —, (CH 2 ) 2-6 —O— and  
 
 R 5  and R 6  are as above defined; or  
 a sulfonyl group of the formula (IV)  
                     
 wherein  
 R 16  is 
 (1) R 5    
                     
 wherein R 5  and R 6  are as above-defined.  
 
 
     
     
         9 . The pharmaceutical composition of  claim 8  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-difluorophenoxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-ditrifluoro methyl benzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichlorophenoxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 2-fluoro-4-(N-morpholinylsulfonamido)phenoxymethyl ketone.  
     
     
         10 . The pharmaceutical composition of  claim 8  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2-chloro-4-(N-thiomorpholinyl-sulfonamido )phenoxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(2-N-morpholinylethoxy)benzyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dimethoxybenzoyloxy methyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(benzyloxy)-benzyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 2-acetamido-6-chlorobenzoyloxymethyl ketone.  
     
     
         11 . The pharmaceutical composition of  claim 8  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-difluorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 3-(N-butylsulfonamido)-2,6-dichlorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-sulfonamido benzoylmethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 3-(N-benzylsulfonamido)-2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 3-(N-[2-aminoacetamidoyl]sulfonamido)-2,6-dichlorobenzoyloxymethyl ketone.  
     
     
         12 . The pharmaceutical composition of  claim 8  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(N-morpholinylsulfonamido) benzoyloxymethyl ketone, N-Methoxycarbonyl-L-alanine-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-(2-thienyl) carbonyl-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-Methoxycarbonyl-glycine-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone and N-Methoxycarbonyl-L-phenylalanine-L-aspartic acid 2,6-dichloro-benzoyloxymethyl ketone.  
     
     
         13 . The pharmaceutical composition of  claim 8  wherein said compound is selected from the group consisting of: N-Methoxycarbonyl-L-β-(2-thienyl)alanine-L-aspartic acid 2,6-di-chlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-valine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-histidine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-valine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.  
     
     
         14 . The pharmaceutical composition of  claim 8  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-valine-L-alanine-L-aspartic acid 2,6-di-chlorobenzoyloxymethyl ketone, N-(2-furonyl)carbonyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-furonyl)carbonyl-L-aspartic acid 2,6-dichloro-3-(N-morpholinylsulfonamido)-benzoyloxymethyl ketone, N-(3-phenylpropionyl)-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(4-(N,N-dimethylaminomethyl)benzoyl-L-aspartic acid 2,6-dichloro-benzoyloxymethyl ketone, N-benzyloxycarbonyl-D-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-[2,6-dichlorobenzoyloxy])acetyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-valine-L-aspartic acid 4-(N,N-diethyl-sulfonamido)-2,3,5,6-tetrafluorophenoxymethyl ketone.  
     
     
         15 . A method of inhibiting interleukin-1β protease activity in a mammal in need of such treatment comprising administering to said mammal an effective inhibitory amount of a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof  
       
         
           
           
               
               
           
         
       
       wherein 
 n=0-4;  
 Y= 
                     
 m=0,1;  
 R 3 =a singularly or multiply substituted aryl wherein aryl is a phenyl or naphthyl ring wherein the substituents are independently selected from the group consisting of: 
 (1) H  
 (2) halogen  
 (3) OH  
 (4) CF 3    
 (5) NO 2    
 (6) OR 5    
 (7) COR 9    
 (8) NR 6 COR 10    
 (9) CONR 5 R 6    
 (10) SO 2 NR 5 R 6    
 (11) SO 2 R 6    
 (12) COOR 11    
                     
 (14) lower alkyl and lower cycloalkyl  
 
 R 5 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 0-6 -aryl  
 (3) (CR 6 R 7 ) 0-6 -heteroaryl or  
 (4) (CR 6 R 7 ) 2-6 -R 8 ;  
 
 R 6  and R 7  are independently H, lower straight chain or branched alkyl, benzyl, aryl, cycloalkyl and aryl is defined as above and heteroaryl includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, isothiazolyl, benzofuranyl, isoxazolyl, triazinyl and tetrazolyl;  
 R 8 =
 (1) OCH 2 CH 2 OR 6    
 (2) OCH 2 CH 2 NR 6 R 7    
 (3) NR 6 CH 2 CO 2 R 6    
                     
 (6) NR 6 R 7  wherein R 6  and R 7  are as above defined;  
 
 R 9 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 0-6 -aryl;  
 (3) (CR 6 R 7 ) 0-6 -heteroaryl; or  
 (4) (CR 6 R 7 ) 0-6 -R 8 , wherein R 6 , R 7  and R 8  are as above defined;  
 
 R 10 =
 (1) R 9    
 (2) OR 11    
 (3) NR 6 R 11 ,  
 wherein  
 
 R 11 =
 (1) lower straight chain or branched alkyl, lower cycloalkyl  
 (2) (CR 6 R 7 ) 1-6 -aryl;  
 (3) (CR 6 R 7 ) 1-6 -heteroaryl; or  
 (4) (CR 6 R 7 ) 2-6 -R 8 , and R 6 , R 7  and R 8  are as above defined;  
 
 R 4 =H or deuterium;  
 R 2 =
 (1) OR 6    
 (2) NR 6 OR 7  or  
 (3) NR 6 R 7 , and R 6  and R 7  are as above-defined;  
 
 A=
 (1) an amino acid of the formula (II)  
                     
 wherein R 6  and R 7  are as defined above;  
 
 R 12  is independently 
 (1) H or  
 (2) (CR 6 R 7 ) 1-6 -R 13 , and R 6  and R 7  are as above-defined;  
 
 R 13 =
 (1) H  
 (2) F  
 (3) CF 3    
 (4) OH  
 (5) OR 11    
 (6) NR 6 R 14    
 (7) cycloalkyl  
 (8) aryl  
 (9) heteroaryl  
 (10) SH  
 (11) SR 11    
 (12) CONR 5 R 6    
 (13) COOR 5  or  
                     
 
 R 14 =
 (1) R 7    
 (2) COR 10    
 (3) SO 2 NR 5 R 6  or  
                     
 or  
 
 A=
 (2) an amino acid selected from the group consisting of  
                     
 
 R 1  is an acyl group of the formula (III)  
                     
 wherein  
 R 12  is 
 (1) OR 5    
 (2) NR 5 R 6    
 (3) R 5    
 (4) —CH═CHR 5    
                     
 wherein R 15 =single bond, (CH 2 ) 2-6 —NR 6 —, (CH 2 ) 2-6 —O— and  
 
 R 5  and R 6  are as above defined; or  
 a sulfonyl group of the formula (IV)  
                     
 wherein  
 R 16  is 
 (1) R 5    
                     
 wherein R 5  and R 6  are as above-defined.  
 
 
     
     
         16 . The method of  claim 15  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-difluorophenoxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-ditrifluoromethyl benzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichlorophenoxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 2-fluoro-4-(N-morpholinylsulfonamido)phenoxymethyl ketone.  
     
     
         17 . The method of  claim 15  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2-chloro-4-(N-thiomorpholinyl-sulfonamido)phenoxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(2-N-morpholinylethoxy)benzyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dimethoxybenzoyloxy methyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(benzyloxy)benzyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 2-acetamido-6-chlorobenzoyloxymethyl ketone.  
     
     
         18 . The method of  claim 15  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-difluorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 3-(N-butylsulfonamido)-2,6-dichlorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-sulfonamido benzoylmethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 3-(N-benzylsulfonamido)-2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-aspartic acid 3-(N-[2-aminoacetamidoyl]sulfonamido)-2,6-dichlorobenzoyloxymethyl ketone.  
     
     
         19 . The method of  claim 15  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(N-morpholinylsulfonamido) benzoyloxymethyl ketone, N-Methoxycarbonyl-L-alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-thienyl) carbonyl-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-Methoxycarbonyl-glycine-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone and N-Methoxycarbonyl-L-phenylalanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.  
     
     
         20 . The method of  claim 15  wherein said compound is selected from the group consisting of: N-Methoxycarbonyl-L-β-(2-thienyl)alanine-L-aspartic acid 2,6-di-chlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-valine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-histidine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-valine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone.  
     
     
         21 . The method of  claim 15  wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L-valine-L-alanine-L-aspartic acid 2,6-di-chlorobenzoyloxymethyl ketone, N-(2-furonyl)carbonyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-furonyl)carbonyl-L-aspartic acid 2,6-dichloro-3-(N-morpholinylsulfonamido)benzoyloxymethyl ketone, N-(3-phenylpropionyl)-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(4-(N,N-dimethylaminomethyl)benzoyl-L-aspartic acid 2,6-dichloro-benzoyloxymethyl ketone, N-benzyloxycarbonyl-D-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2-[2,6-dichlorobenzoyloxy])acetyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-valine-L-aspartic acid 4-(N,N-diethyl-sulfonamido)-2,3,5,6-tetrafluorophenoxymethyl ketone.