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利伐沙班衍生物的合成及Ⅹa因子抑制活性

Synthesis and factor Xa inhibitory activity of rivaroxaban derivatives

  • 摘要: 利伐沙班是噁唑烷酮类选择性Ⅹa因子抑制剂,本文在利伐沙班的结构基础上设计并合成了一系列新的噁唑烷酮类化合物,并对这些化合物的Ⅹa因子抑制活性进行了测定。2-苯胺基乙醇经过酰化,再依次经过硝化、还原、与环氧化合物缩合、CDI缩合、脱除保护基制得中间体4-4-(5S)-5-(氨基甲基)-2-氧代-1,3-噁唑烷-3-基苯基吗啉-3-酮,再与噻吩酰氯缩合制得利伐沙班,或者与噻唑类酰氯缩合生成目标衍生物,共合成了10个利伐沙班衍生物( 11a~11j ),其结构均经IR、1H NMR、13C NMR和MS确证,然后测定了目标衍生物的Ⅹa因子抑制活性,初步研究表明:所合成的化合物具有一定的Ⅹa因子抑制活性,但活性低于利伐沙班。

     

    Abstract: Rivaroxaban is the first launched drug as a potent factor Xa inhibitor.Based on current SAR study results of rivaroxaban and its derivatives,we designed and synthesized a series of new oxazolidinone derivatives,and tested their anti-factor Xa activity.Rivaroxaban derivatives were synthesized starting from 2-phenylaminoethanol via acylation,nitrification,reduction,and then cyclization to afford (S)-4-(4-(5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl)phenyl)morpholin-3-one,which was condensed with 5-chlorothiophene-2-carbonyl chloride or thiazole carboxylic acid to afford the target compounds.Ten novel rivaroxaban derivatives( 11a-11j ) were synthesized,and their structures were identified by IR,1H NMR,13C NMR and MS.Preliminary results of factor Xa inhibition assays showed that most of the test compounds exhibited factor Xa inhibitory activity,yet with less potency than rivaroxaban.

     

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