Imidazo[1,2-α]pyridines. I. Synthesis and Inotropic Activity of New 5-Imidazo[1,2-α]pyridinyl-2(1H)-pyridinone Derivatives

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概要

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• A series of 1,2-dihydro-5-imidazo[1,2-α]pyridinyl-2(1H)-pyridonones was synthesized and evaluated for positive inotropic activity. 1,2-Dihydro-5-imidazo[1,2-α]pyridin-6-yl-6-methyl-2-oxo-3-pyridinecarbonitrile (11a) hydrochloride monohydrate (E-1020) was found to be a potent and selective inhibitor of phosphodiesterase III and a long-acting, potent, orally active positive inotropic agent. Additional imidazo[1,2-α]pyridin-2-yl (3a), -3-yl (16), -7-yl (20) and -8-yl (24a) compounds were also prepared. Altering the pyridine substitution from the 2-position to the 6-position produced a 2-fold increse in the i.v. cardiotonic potency (ED_<50>) from 52 to 23 μg/kg, while substitution at the 3-, 7- or 8-position reduced potency. In the 2-positional isomers, introduction of halogen groups enhanced the activity and 3-chloro-1,2-dihydro-5-(6-fluoroimidazo[1,2-α]pyridin-2-yl)-6-methyl-2(1H)-pyridinone (3u) was the most potent (i.v. ED_<50> 11 μg/kg) in this series. E-1020 is presently under development for the treatment of congestive heart failure.

• 公益社団法人日本薬学会の論文
• 1991-06-25

著者

• 山中 基資

  Eisai Tsukuba Research Laboratories

• 須田 眞次

  Eisai Tsukuba Research Laboratories

• 小川 利明

  Eisai Tsukuba Research Laboratories

• 大原 秀人

  Eisai Tsukuba Research Laboratories

• 三宅 一俊

  Eisai Tsukuba Research Laboratories

• 山中 基資

  Eisai Co. Ltd. Tsukuba Research Laboratories

関連論文

• Imidazo[1,2-α]pyridines. III. Synthesis and Bradycardic Activity of New 5-Imidazo[1,2-a]pyridin-6-ylpyridine Derivatives
• A Practical Synthetic Method for 3-(N, N-Disubstituted Carbamoyloxy)-methyl Cephems without Generating the Δ^2-Isomers
• Imidazo[1,2-α]pyridines. I. Synthesis and Inotropic Activity of New 5-Imidazo[1,2-α]pyridinyl-2(1H)-pyridinone Derivatives
• 正常及び実験的心不全犬の左室径並びにモルモット摘出心筋及び洞房結節の活動電位に対する新規強心薬塩酸Loprinone(E-1020)の作用
• Studies on the Stability of Δ^2 and Δ^3 Cephem Esters. I. Marked Difference in Stability between Δ^2 and Δ^3 Cephem Prodrug Esters and Application to the Preparation of Key Intermediates for Oral Cephem Synthesis
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• Imidazo[1,2-α]pyridines. II. Ozonolysis of Imidazo[1,2-α]pyridines and Synthesis of Carfiotonic Agents
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