单-和双（氨甲基）苯乙酸酯作为短效抗心律失常药。2.

Mono- and bis(aminomethyl)phenylacetic acid esters as short-acting antiarrhythmic agents. 2.

作者信息

Chorvat R J, Black L A, Ranade V V, Barcelon-Yang C, Stout D M, Brown B S, Stampfli H F, Quon C Y

机构信息

Department of Medicinal Chemistry, Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880.

出版信息

J Med Chem. 1993 Aug 20;36(17):2494-8. doi: 10.1021/jm00069a007.

DOI:10.1021/jm00069a007

PMID:8355250

Abstract

The synthesis, antiarrhythmic activity, and blood hydrolysis properties of a series of mono- and bis(aminomethyl)phenylacetic acid esters related to a previously reported class Ic antiarrhythmic agent (ACC-9358) are described. Of the various oxa-, aza-, thia-, and carbacyclic esters initially prepared in the bis(pyrrolidinomethyl)-4-hydroxyphenylacetic acid series, the 1,4-benzodioxanyl-2-methyl(3q) and the thienyl-2-methyl(31) esters were evaluated in vivo for antiarrhythmic efficacy. In addition, a number of monoappended phenylacetic esters of 3q with or without the 4-hydroxy group were also prepared for evaluation of antiarrhythmic, lipophilic, and metabolic properties. Of these compounds, 3q possessed the most desirable pharmacological and pharmacokinetic profile.

摘要

描述了一系列与先前报道的Ic类抗心律失常药物（ACC-9358）相关的单（氨基甲基）苯基乙酸酯和双（氨基甲基）苯基乙酸酯的合成、抗心律失常活性及血液水解特性。在最初制备的双（吡咯烷甲基）-4-羟基苯基乙酸系列的各种氧杂、氮杂、硫杂和碳环酯中，对1,4-苯并二氧杂环戊烯基-2-甲基（3q）酯和噻吩基-2-甲基（31）酯进行了体内抗心律失常疗效评估。此外，还制备了一些带有或不带有4-羟基的3q单取代苯基乙酸酯，以评估其抗心律失常、亲脂性和代谢特性。在这些化合物中，3q具有最理想的药理和药代动力学特征。