Abstract
Synthetic and pharmacological studies of diltiazem hydrochloride, a representative calcium antagonist widely used for the treatment of ischemic heart disease all over the world, have been reviewed. 3-Hydroxy-1, 5-benzothiazepine derivatives were synthesized for evaluting central nervous system (CNS) activities, but our original random screening test revealed that these compounds have a potent coronary vasodilating effect without significant influence on CNS. Out of them, diltiazem ((+)-(2S, 3S)-2, 3-dihydro-3-acetoxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]-1, 5-benzothiazepin-4(5H)-one hydrochloride) was selected as the compound to be developed. As a result of various investigations, 2-3-cis-2, 3-dihydro-2-(4-methoxyphenhyl)-3-hydroxy-1, 5-benzothiazepin-4(5H)-one, a key intermediate for the synthesis of diltiazem, has been successfully synthesized in high yield via regio- and stereo-selective opening of the oxirane ring of 3-(4-methoxyphenyl)glycidic ester with 2-nitrothiophenol in the presence of tin-catalyst. In the course of studies on the mechanism of its vasodilating action, we found that diltiazem has a calcium antagonistic property. We reviewed the pharmacological bases or features of diltiazem for its anti-anginal, anti-hypertensive and antiarrythmic effects. Its effects on calcium channels, as well as on renal and cerebral circulation, were also mentioned. In addition, new possible indications, and domestic and international development of diltiazem were briefly described.
