New calcium antagonists: synthesis, X-ray analysis, and smooth muscle relaxing effect of 3-[O-(Benzyl-substituted)-oximino-ethers]-hexahydroazepin-2,3-diones Original Research Article

A series of new Z and E 3-[O-(benzyl-substituted)-oximino-ether]-hexahydroazepin-2,3-diones was prepared from the corresponding hexahydroazepin-2,3-diones and examined as smooth muscle relaxants. E and Z structures were assigned by NMR analysis and confirmed for (E and Z) by an X-ray diffraction using synchrotron radiations. The nitrobenzyl derivative was the most potent in vitro as relaxant of rat trachea precontracted with acetylcholine. The E isomer was more potent than the Z isomer . E isomer is more potent than aminophylline to relax both rat trachea and human bronchus.This derivative acts mainly by inhibiting cellular influx of extracellular calcium since it inhibits potently and dose-dependently the contractions of rat trachea to high concentrations of KCl and to CaCl2 in a depolarizing medium. It appears to act weakly by inducing cGMP and cAMP synthesis. Moreover, its relaxing activity is not related to an inhibition of phosphodiesterases, to opening of potassium channels or to induction of prostaglandin synthesis. Therefore, appears to work mainly as a potent calcium antagonist.