Orally Active .beta.-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure-Activity Relationships for 3,3-Dialkylazetidin-2-ones

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Abstract

The stereospecific synthesis of several 4-[(4-carboxyphenyl)oxy]- 3,3-dialkyl-1-[[(1-phenylalkyl)-amino]carbonyl]azetidin-2-on es 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 beta-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) (kobs/[I] = 91,000 M-1 s-1) were confirmed with an X-ray structure determination, which was also utilized to develop an HLE inhibition model.

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