Synthesis and biological activity of novel calcium channel blockers: 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid esters and 2,5-dihydro-4-methyl-2-phenyl-1,5-benzodiazepine-3-carboxylic acid esters.

摘要: 2,5-Dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid esters, based on the structures of dihydropyridines and diltiazem, were synthesized from o-aminothiophenol 2-(phenylmethylene)- 3-oxobutanoic esters. Biological evaluation in potassium-depolarized rabbit aorta suggests that these compounds are calcium channel blockers. The vitro activity was further confirmed by electrophysiological techniques. Structure-activity studies for aromatic substitution showed 2-nitro derivative most potent (IC50 = 0.3 microM) compound while ethyl ester slightly better than corresponding methyl ester. Replacement sulfur with nitrogen atom provided 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1,5-benzodiazepine-3-carboxylic ester, which only less active benzothiazepine. Derivatization 2,5-dihydro-4-methyl- 2-(3-nitrophenyl)-1,5-benzothiazepine-3-carboxylic a (dimethylamino)ethyl group (present diltiazem) 2,5-dihydro-5-[(dimethylamino)ethyl]- 4-methyl-2-(3-nitrophenyl)-1,5-benzo-thiazepine-3-carboxylic found to be equipotent diltiazem vitro. Radioligand binding using [3H]nitrendipine [3H]diltiazem free binds competitively into dihydropyridine site molecule is alkylated interacts both sites. Our results therefore show 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic good starting point designing as well mimics.