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

Abstract

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

CuI nanoparticles as a remarkable catalyst in the synthesis of benzo[b][1,5]diazepines: an eco-friendly approach

“…So we carried out synthesis of benzo [b] [1,5]diazepine derivatives by use of various structures of o-phenylenediamines and isocyanides.…”

“…[1][2][3][4] In addition, some of the benzodiazepines have found as important drugs to treat some diseases such as cardiovascular disorders, cancer, diabetes and viral infection (HIV). [5][6][7][8] Some of the important 1,5-benzodiazepine structures with high medicinal activity such as, olanzapine 1 and clozapine 2 (schizophrenia treatment), 9 clobazam 3 (anxiolytic agents), 10 and 3-carbamoyl-1,5-benzodiazepine 4 (selective CCK-B antagonists as potential anxiolyticdrugs) 11 has been shown in Figure 1. Therefore, the synthesis of 1,5-benzodiazepine derivatives due to a broad range of applications have always been the most interesting fields in the organic synthesis.…”

“…21 Recently, copper nanoparticles were used as an active catalyst in many reactions including carbon-heteroatom coupling, 22,23 synthesis of phenols, anilines, and thiophenols, 24 Synthesis of 1,4-dihydropyridines, 25 alkyne-azide cycloadditions, 26 the Mannich reaction, 27 azaMichael reactions 28 and hydroxylation of phenol. 29 Recently, Shaabani et al have reported a novel and efficient method for the synthesis of some tetrahydro-2,4-dioxo-1H-benzo[b] [1,5]diazepine-3-yl-2-methylpropanamide derivatives. 30 This method has valuable advantages such as, mild reaction conditions, good yields and no undesirable byproducts.…”

“…In order to achieve more efficient synthetic processes, minimize by-products, decrease the number of separate reaction steps, and also in the following of our research on the application of nanocatalysts in MCRs, [31][32][33][34][35][36][37] we have tried to extend a clean and environment friendly approach to the synthesis of tetrahydro-2,4-dioxo-1H benzo[b] [1,5]diazepine-3-yl-2-methylpropanamide derivatives via treatment of aromatic diamines, Meldrum's acid and isocyanides with excellent yields and short reaction times using CuI NPs as a catalyst (scheme 1).…”

Microwave assisted synthesis of naphtho[2,1-b]furan-1, 3, 4-benzotriazepines: a potent antimicrobial agent

“…The area of biological interest of this family of compounds have been extended recently to various diseases such as cancer, 5 viral infections(HIV) 6 and cardiovascular disorders. 7,8 Such a versatile biological activity of the benzodiazepine pharmacophore has prompted investigations into nitrogen homologues, the benzotrizepines, 9,10 in order to find new therapeutical leads. In this lead a great number of publications are come out on 1,3,5 benzotriazepines, [11][12][13][14][15] but little work has been carried on 1,3,4-benzotrizepines.…”