Angiotensin converting enzyme inhibitors: 1,5-benzothiazepine derivatives

Abstract

The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an IC50 of 2.95 nM. The ester of 2c, i.e. 14c, was found to inhibit the AI pressor response by 75% at a dose of 0.05 mg/kg iv and by 39% at 1.0 mg/kg po. Additionally, 14c lowered blood pressure in the spontaneous hypertensive rat (SHR) by 35 mmHg, at a dose of 10 mg/kg po.

Syntheses and Biological Activities of Chalcone and 1,5-Benzothiazepine Derivatives: Promising New Free-Radical Scavengers, and Esterase, Urease, and?-Glucosidase Inhibitors

“…± Benzothiazepine derivatives exhibit diverse biological activities. They may act as calcium antagonists [1], angiotensin converting enzyme inhibitors [2], anticonvulsants and tranquilizers [3], anticancer drugs [4] [5], and possess endogenous natriuretic activities [6]. The coveted drug diltiazem, for example, is being used as calcium channel blocker [7], calcium channel modulator [8], calcium channel antagonist [9], vasodilator, antihypertensive [10 ± 12], blood platelet aggregation inhibitor [13], anti-arrhythmic [14], antithrombotic [15], antianginal [16], and antiischemic [17].…”

Synthesis of optically active 1,5-benzothiazepines

“…In this review, we discuss only the optically active 3-amino-2,3-dihydro-1,5-benzothiazepine type ACE inhibitors. The first representative of the optically active 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-ones was synthesized by Slade et al 19 Source of the chirality was the L-cysteine as a natural amino acid used as building block. o-Fluoronitrobenzene ( Solid-phase synthesis of optically active 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-ones, using cysteine derivatives as building blocks, has also been described in the literature.…”

Dioxirane Oxidation of Sulfur‐Containing Organic Compounds

“…For this reason, their chemical tansformations including the oxidation of the sulfur atom have been extensively studied. Several procedures were used for their sulfoxidation [64][65][66][67][68][69][70] but diastereomeric mixtures of sulfoxides were obtained in most cases. The isolated DMD (1) proved to be the oxidant of choice for diastereoselective sulfoxidation of 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones substituted at the C-2 atom 15 providing transsulfoxides 16 as single isolable product in most cases 71 (Scheme 7).…”