抗高血压β-肾上腺素能阻滞剂（S）-2-[3-（叔丁基氨基）-2-羟基丙氧基]-3-氰基吡啶的杂环类似物

Heterocyclic analogues of the antihypertensive beta-adrenergic blocking agent (S)-2-[3-(ter-butylamino)-2-hydroxypropoxy]-3-cyanopyridine.

作者信息

Baldwin J J, Engelhardt E L, Hirschmann R, Ponticello G S, Atkinson J G, Wasson B K, Sweet C S, Scriabine A

出版信息

J Med Chem. 1980 Jan;23(1):65-70. doi: 10.1021/jm00175a012.

Abstract

The synthesis of a series of isoelectronic analogues of (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1) are described; included in this group are examples of thiazole, isothiazole, thiadiazole, pyrazine, and the structurally related naphthyridines. All of the compounds are similar to 1 in that they contain a cyano group ortho to the aminohydroxypropoxy side chain and meta to the nitrogen heteroatom. In addition, several related examples, having additional nuclear substituents and/or groups other than CN in the position adjacent to the aminohydroxypropoxy group, were prepared, and beta-adrenoceptor antagonist activity and vasodilating potency were determined. Three compounds, thiazole 2 and isothiazoles 3 and 27, effectively lowered mean arterial pressure in the SH rat at 5 mg/kg. Compounds 2, 3, and 27 increased iliac blood flow and exhibited beta-adrenergic blocking properties in the dog.

摘要

描述了一系列(S)-2-[3-(叔丁基氨基)-2-羟基丙氧基]-3-氰基吡啶(1)的等电子类似物的合成；该组中包括噻唑、异噻唑、噻二唑、吡嗪以及结构相关的萘啶的实例。所有化合物与1相似之处在于，它们在氨基羟基丙氧基侧链的邻位以及氮杂原子的间位含有一个氰基。此外，制备了几个相关实例，它们在氨基羟基丙氧基基团相邻位置具有额外的核取代基和/或除CN以外的基团，并测定了β-肾上腺素能受体拮抗剂活性和血管舒张效力。三种化合物，噻唑2以及异噻唑3和27，在5mg/kg时可有效降低SH大鼠的平均动脉压。化合物2、3和27增加了髂血流量，并在犬中表现出β-肾上腺素能阻断特性。