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-[[(1-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 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) (k(obs)/[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.