Peptoid and nonpeptoid containing alpha-keto oxadiazoles as serine protease inhibitors

Abstract

The present invention relates to certain substituted oxadiazole peptoids and nonpeptoids useful as inhibitors of serine proteases, especially human neutophil elastase (HNE). Compounds of the present invention are useful for the treatment or amelioration of symptoms of adult respiratory distress syndrome, septic shock, and multiple organ failure. Processes mediated by HNE are also implicated in conditions such as arthritis, periodontal disease, glomerulonephritis, and cystic fibrosis.

What is claimed is:  
     
         1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from tert-butyl, α,α-dimethylbenzyl, and α,α-dimethyl-3,4-methylenedioxybenzyl.  
     
     
         2 . A compound of  claim 1 , to wit: methyloxycarbonyl-L-valyl-N-[1-(2-[5-α,α-dimethylbenzyl]oxadiazolyl)carbonyl-2-(S)-methylpropyl]-L-prolinamide.  
     
     
         3 . A compound of  claim 1 , to wit: methoxycarbonyl-L-valyl-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxy)benzyl]oxadiazolyl)carbonyl-2-(S)-methylpropyl]-L-prolinamide.  
     
     
         4 . A compound of  claim 1 , to wit: methyloxycarbonyl-L-valyl-N-[1-(2-[5-tert-butyl]oxadiazolyl)carbonyl-2-(S)-methylpropyl]-L-prolinamide.  
     
     
         5 . A compound of formula II  
       
         
           
           
               
               
           
         
       
       wherein RI is selected from tert-butyl and α,α-dimethyl-3,4-methylenedioxybenzyl.  
     
     
         6 . A compound of  claim 5  selected from: 
 2-[5-methyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrirnidinyl]-N-[1-(2-[5-tert-butyl]oxadiazolyl)carbonyl-2-(R,S)-methylpropyl]acetamide;  
 2-[5-methyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl]oxadiazolyl)carbonyl-2-(R)-methylpropyl]acetamide; or  
 2-[5-methyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl]oxadiazolyl)carbonyl-2-(S)-methylpropyl]acetamide;  
 
     
     
         7 . A compound of  claim 5  selected from: 
 2-[5-methyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-(α,α-dimethyl-3,4-methylenedioxy)benzyl]oxadiazolyl)carbonyl-2-(R,S)-methylpropyl]acetamide;  
 2-[5-methyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl]oxadiazolyl)carbonyl-2-(R)-methylpropyl]acetamide; or  
 2-[5-methyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[1-(2-[5-tert-butyl]oxadiazolyl)carbonyl-2-(S)-methylpropyl]acetamiide.