Orally active beta-lactam inhibitors of human leukocyte elastase. 3. Stereospecific synthesis and structure-activity relationships for 3,3-dialkylazetidin-2-ones.

The stereospecific synthesis of several 4-[(4-carboxyphenyl)oxy]-3,3-dialkyl-1-[[(I-phenylalkyl)-amino]carbonyl]azetidin-2-ones 3 is described in which the C-3 alkyl groups were varied from methyl to butyl as well as allyl, benzyl and methoxymethyl. The structure-activity relations for these compounds are discussed in terms of the hydrolytic stability of the β-lactam ring, their in vitro inhibitory potency for human leukocyte elastase (HLE), and their in vivo oral efficacy in an HLE-mediated hamster lung hemorrhage assay. Further alkyl substitution on the benzylic urea moiety, especially in the R configuration, afforded enhanced HLE inhibition and in vivo efficacy. The stereochemical assignments for (3R,4S)-4-[(4-carboxyphenyl)oxy]-3-ethyl-3-methyl-1-[[((R)-1-phenylpropyl)amino]carbonyl]azetidin-2-one (42a) (k obs /[I] = 91000 M -1 s -1 ) were confirmed with an X-ray structure determination, which was also utilized to develop an HLE inhibition model.