Compounds for proteasome enzyme inhibition

Abstract

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Nn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

1 .- 49 . (canceled) 
     
     
         50 . A method of synthesizing compound 8 
       
         
           
           
               
               
           
         
       
       comprising
 (a) admixing compound (B), or salt thereof, and 2-morpholinoacetic acid to form compound (M): 
 
       
         
           
           
               
               
           
         
         (b) reacting compound (M) with hydrogen and palladium on carbon to form compound (N): 
       
       
         
           
           
               
               
           
         
         (c) admixing compound (N) and compound (E), or a salt thereof, to form compound 8 
       
       
         
           
           
               
               
           
         
       
     
     
         51 . The method of  claim 50 , wherein compound (B) is admixed as a salt. 
     
     
         52 . The method of  claim 51 , wherein compound (B) is admixed as the trifluoroacetate salt. 
     
     
         53 . The method of  claim 50 , wherein step (a) is performed in the presence of a peptide coupling agent. 
     
     
         54 . The method of  claim 53 , wherein the peptide coupling agent comprises PyBOP. 
     
     
         55 . The method of  claim 50 , wherein compound (E) is admixed as a trifluoroacetate salt. 
     
     
         56 . The method of  claim 50 , wherein step (c) is performed in the presence of a peptide coupling agent. 
     
     
         57 . The method of  claim 56 , wherein the peptide coupling agent comprises PyBOP, HOBT, or both. 
     
     
         58 . The method of  claim 50 , further comprising (d) isolating compound 8 via filtration.