5-取代-4-甲基-1,3-二氢-2H-咪唑-2-酮类化合物的合成及其强心作用

本文设计并合成了5-取代-4-甲基-1,3-二氢-2 H-咪唑-2-酮类化合物23个,其中19个尚未见报道。中间体5-(4-溴甲基苯甲酰基)-4-甲基-1,3-二氢-2H-咪唑-2-酮(Ⅴ)为一新化合物。在关键中间体4-甲基-1,3-二氢-2H-咪唑-2-酮(Ⅳ)的合成中,设计了由β-羟基丙胺一步氧化直接合成氨基丙酮的新方法。药理初筛表明:Ⅱ₁,Ⅱ₂,Ⅱ₄,Ⅲ₄,Ⅲ₆,Ⅲ₇,Ⅲ₈和RMI 82,249(1)具有不同程度的正性肌力作用,其中4个未知化合物Ⅱ₁,Ⅱ₂,Ⅱ₄和Ⅲ₄的最大效应高于已知对照物(1)。Ⅱ₄既增加心肌收缩力,又减慢心率,值得进一步研究。

SYNTHESIS AND CARDIOTONIC ACTIVITIES OF 5-SUBSTITUTED-4-METHYL-1, 3-DIHYDRO-2H-IMIDAZOL-2-ONES

Twenty-three derivatives of 5-substituted-4-methyl-1,3-dihydro-2 H-imidazol-2-one were designed and synthesized for searching of more potent and less toxic cardiotonic agents. The key intermediate, 4-methyl-1,3-dihydro-2H-imidazol-2-one(Ⅳ), was prepared by a method of one-step oxidation of β-hydroxy propylaminc, a new synthesis of aminoacetone.Preliminary pharmacologic tests on isolated male guinca pig atria showed that eight of the synthetic compounds (Ⅱ₁, Ⅱ₂, Ⅱ₄, Ⅲ₄, Ⅲ₆, Ⅲ₇, Ⅲ₈ and 1) exhibited significant positive inotropic activities. The maximum inotropic effects of four of them (Ⅱ₁, Ⅱ₂, Ⅱ₄ and Ⅲ₄) were higher than those of the known cardiotonic agent, RMI 82,249(1). It is interesting that Ⅱ₄ showed both positive inotropic and negative chronotropic effects significantly.