Absolute Conformation and Configuration of (2S, 3S)‐3‐Acetoxy‐5‐(dimethylaminoethyl)‐2‐(4‐methoxyphenyl)‐2,3‐dihydro‐1,5‐benzothiazepin‐4(5H)‐one Chloride (Dilthiazem Hydrochloride)

Abstract

SummaryResolution of racemic cis-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxypheny1)propionic acid (2) via the cinchonidine salt 3, and brucine salt 4, isolation of the calcium salts (+)-and (-)-5, as well as their cyclization to enantiomeric 1,s-benzothiazepines (+)-and (-)-1, are described. X-Ray single-crystal analysis reveals (2S, 3s) absolute configuration of (+)-1, and the existence of its 7-membered ring in a slightly twisted boat conformation in the solid state. M-absolute conformation in solution is assigned to (+)-1 on the basis of tentative comparison of CD data with those for the 1,4-benzodiazepine derivative (+)-8 of known absolute configuration.

Photochemical Identification of Transmembrane Segment IVS6 as the Binding Region of Semotiadil, a New Modulator for the L-type Voltage-dependent Ca2+ Channel

“…In contrast, the calcium antagonist activity of semotiadil depends, in part, on the long side chain of Ar-O-CH 2 CH 2 CH 2 -N(Me)-CH 2 CH 2 -O-Ar at the C-3 position of the 1,4-benzothiazine. This idea is supported by the comparison of the three-dimensional structures between semotiadil and diltiazem based on their conformational analyses by x-ray crystallography and spectroscopy in solution (7,8). There is no apparent similarity in the orientation of the side chains as well as in the common methoxyphenyl group between two drugs, when the phenyl ring of the benzothiazepine and 1,4-benzothiazine are overlaid by the computer.…”

cis-(±)-3-Acetoxy-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine 1-Oxide

“…The title compound, (I), is a drug intermediate of diltiazem, (II), an enantiomerically pure drug with calcium antagonist activity (Kojic-Prodic, Ruzic-Toros & Sunjic, 1984). The pharmacological action of compound (I) is unknown and so the present X-ray analysis was carried out in order to determine its exact conformation.…”

trans-(±)-2-(4-Methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl Acetate

“…drug with calcium antagonist activity (Kojic Prodic, Ruzic Toros & Sunjic, 1984). The pharmacological action of (I) is not yet confirmed, but enantiomorphic compounds of (I) behave as chiral solvating agents (Giordano & Restelli, 1991).…”