NOVEL HETEROCYCLIC-ANALOGS OF THE NEW POTENT CLASS OF CALCIUM ENTRY BLOCKERS - 1-[[4-(AMINOALKOXY)PHENYL]SULFONYL]INDOLIZINES

Several heterocyclic analogues of the potent 1-[[4-(aminoalkoxy)phenyl ]sulfonyl]indolizines were synthesized and evaluated for their antagon istic calcium activities in comparison with the 1-sulfonylindolizine S R 33557 and the usual calcium antagonist references verapamil, cis-(+) -diltiazem, and nifedipine. The bicyclic nine-membered rings were, in general, more potent than the bicyclic 10-membered or five-membered ri ngs. Among the bicyclic nine-membered rings, the indole nucleus appear ed to be extremely favorable to support the calcium antagonistic activ ity. In particular, compound 36, with an IC50 value for the inhibition of [H-3]nitrendipine equal to 0.072 nM, is among the most potent calc ium antagonist known. This compound has been selected for clinical dev elopment.