Synthesis and antiarrhythmic activity of new 3-[2-(.omega.-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds

A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an electrical stimulus in isolated rabbit atria). The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation.