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 -1-[[(1-phenylalkyl)amino]carb onyl]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 methoxymethy l. 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 thei r in vivo oral efficacy in an HLE-mediated hamster lung hemorrhage ass ay. 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-carboxyphen yl)oxy]-3-ethyl-3 [((R)-1-phenylpropyl)amino]carbonyl]azetidin-2-one ( 42a) (k(obs)/[I] = 91 000 M(-1) s(-1)) were confirmed with an X-ray st ructure determination, which was also utilized to develop an HLE inhib ition model.