米索前列醇的一种3E,5Z二烯类似物的合成及胃肠药理学

Synthesis and gastrointestinal pharmacology of a 3E,5Z diene analogue of misoprostol.

作者信息

Collins P W, Kramer S W, Gasiecki A F, Weier R M, Jones P H, Gullikson G W, Bianchi R G, Bauer R F

出版信息

J Med Chem. 1987 Jan;30(1):193-7. doi: 10.1021/jm00384a032.

Abstract

A stereospecific synthesis and the gastric antisecretory and diarrheal activity of a 3E,5Z diene analogue of misoprostol are described. The key intermediate in the synthesis was an alpha chain truncated acetylene that was obtained by a cuprate/enolate capture procedure on the corresponding cyclopentenone. Palladium-catalyzed coupling of the acetylene with methyl 4-iodo-3(E)-butenoate provided the conjugated enyne. Although selective hydrogenation of the enyne with Lindlar catalyst failed, the desired 3E,5Z diene was obtained with P-2 nickel as catalyst. The diene was about 3 times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.

摘要

描述了米索前列醇的一种3E,5Z二烯类似物的立体定向合成及其胃抗分泌和止泻活性。合成中的关键中间体是一种α链截短的乙炔，它是通过在相应的环戊烯酮上进行铜酸盐/烯醇盐捕获程序得到的。乙炔与甲基4-碘-3(E)-丁烯酸酯的钯催化偶联提供了共轭烯炔。尽管用林德拉催化剂对烯炔进行选择性氢化失败，但以P-2镍为催化剂得到了所需的3E,5Z二烯。该二烯在抑制犬胃酸分泌和引起大鼠腹泻方面的效力约为米索前列醇的3倍。