New calcium antagonists: Synthesis, X-ray analysis, and smooth muscle relaxing effect of 3-[O-(benzyl-substituted)-oximino-ethers]-hexahydroazepin-2,3-diones

A series of new Z and E 3-[O-(benzyl-substituted)-oximino-ether]-hexahydroa zepin-2,3-diones was prepared from the corresponding hexahydroazepin-2,3-di ones and examined as smooth muscle relaxants. E and Z structures were assig ned by NMR analysis and confirmed for 16 (E and Z) by an X-ray diffraction using synchrotron radiations. The nitrobenzyl derivative 16 was the most po tent in vitro as relaxant of rat trachea precontracted with acetylcholine. The E isomer 16b was more potent than the Z isomer 16a. E isomer 16b is mor e potent than aminophylline to relax both rat trachea and human bronchus. T his derivative acts mainly by inhibiting cellular influx of extracellular c alcium since it inhibits potently and dose-dependently the contractions of rat trachea to high concentrations of KCl and to CaCl2 in a depolarizing me dium. It appears to act weakly by inducing cGMP and cAMP synthesis. Moreove r, its relaxing activity is not related to an inhibition of phosphodiestera ses, to opening of potassium channels or to induction of prostaglandin synt hesis. Therefore, 16b appears to work mainly as a potent calcium antagonist . (C) 1999 Elsevier Science Ltd. All rights reserved.