塩酸ジルチアゼムの開発研究
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概要
- 論文の詳細を見る
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.
- 公益社団法人日本薬学会の論文
- 1988-08-25
著者
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井上 博純
Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd, .
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長尾 拓
Biological Research Laboratory:tanabe Seiyaku Co. Ltd. :(present Adress)department Of Toxicology And
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井上 博純
田辺製薬株式会社有機化学研究所
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井上 博純
Organic Chemistry Research Laboratory Tanabe Seiyaku Co. Ltd .
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阿部 久二
田辺製薬株式会社
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長尾 拓
田辺製薬株式会社
関連論文
- Enantioselective Reduction of meso-Cyclic-1,2-dicarboxylic Anhydrides and 1,2-Dicarboximides : Asymmetric Synthesis of Bicyclic Lactones and Hydroxylactams
- A New Enantioselective Synthesis of (2R, 3S)-3-(4-Methoxyphenyl)glycidic Ester via the Enzymatic Hydrolysis of erythro-N-Acetyl-β-(4-methoxyphenyl)serine
- A New Synthetic Route to 1,5-Benzothiazepines. Synthesis of Derivatives of Diltiazem
- Synthesis of the Metabolites of Clentiazem
- Asymmetric Reduction of Aromatic Ketones. II. An Enantioselective Synthesis of Methyl (2R, 3S)-3-(4-Methoxyphenyl)glycidate
- Synthesis of the Optically Active trans-Isomers of Diltiazem and Their Cardiovascular Effects and Ca-Antagonistic Activity
- Synthesis of N-Substituted C-Normorphinans and Their Pharmacological Properties
- Reactions of 3-Phenylglycidic Esters. V. Reaction of Methyl 3-(4-Methoxyphenyl) glycidate with 2-Nitroaniline and Synthesis of 1,5-Benzodiazepine Derivatives
- Reaction of 3-Phenylglycidic Esters. III. Reaction of cis-3-Arylglycidic Esters with Various Thiophenols
- Reaction of 3-Phenylglycidic Esters. IV. Reaction of Methyl 3-(4-Methoxyphenyl) glycidate with 2-Nitrophenol and Synthesis of 1,5-Benzoxazepine Derivatives
- Azabicycloalkanes as Analgetics. I. Synthesis of 1-Phenyl-6-azabicyclo [3,2,1] octane Derivatives
- Azabicycloalkanes as Analgetics. V. 4-Phenyl-2-azabicyclo [2,2,2] octanes
- Synthesis of 1,5-Benzothiazepine Derivatives. III
- Synthesis of 1,5-Benzothiazepine Derivatives. II
- Synthesis of 1,5-Benzothiazepine Derivatives. I
- Azabicycloalkanes as Analgetics. II. An Improved Synthesis of 1-Phenyl-6-azabicyclo [3,2,1] octane Derivatives
- 4-Acylaminophenol Derivatives as Novel Lipoxygenase Inhibitors : Synthesis and Inhibitory Effect on 5-Lipoxygenase and Leukotriene B_4 Production
- 1,5-Benzothiazepine誘導体の合成(第4報)dl-cis-3-Acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one Hydrochlorideの光学分割
- Synthesis and Pharmacological Properties of Azido Derivatives of 1,5-Benzothiazepine Ca Antagonist
- 塩酸ジルチアゼムの開発研究
- Synthesis of Bridged 2-Phenylcyclohexylamines as Potential Analgetics
- Synthesis of B/C trans-Fused Morphine Structures. VI. Mass Spectrum, Optical Rotatory Dispersion and Circular Dichroism of B/C trans-Morphine Derivatives
- Synthesis of B/C trans-Fused Morphine Structures. IV. Synthesis of B/C trans-Isomorphine
- Ca2+ 拮抗薬 Diltiazem の気管支拡張作用
- 麻酔犬の血行動態ならびに His 束心電図に及ぼす Diltiazem の影響