NEW BETA-LACTAM MONOCYCLIC INHIBITORS OF HUMAN ELASTASES - SYNTHESIS AND ANTI-ELASTASE PROPERTIES OF 1-CARBAMOYL-4-METHYLENEAMINOXYAZETIDINONE DERIVATIVES

Some monocyclic beta-lactam derivatives of types II (1a-5a) and III (1 b-5b), designed as analogs of type I derivatives, in which the C-4 ary loxy group of I is replaced by an oximate moiety, were synthesized and tested in vitro for their inhibitory activity towards porcine pancrea tic (PPE) and human leukocyte (HLE) elastases. All compounds were foun d to be inactive on PPE. While 1b-5b did not display any appreciable a ctivity towards HLE, compounds 1a-5a exhibited a marked inhibitory act ivity on this enzyme. The most active in vitro type-II compound 4a and the derivative 5a, whose molecular Structure presents a carboxylic mo iety like type-I reference drug 14, were tested in vivo for their huma n sputum elastase inhibitory activity in elastase-induced lung hemorrh age in mice: they proved to possess an appreciable inhibitory activity even if somewhat lower than might have been expected on the basis of their activity indices obtained in the in vitro tests.