噁唑烷酮类化合物的合成及其凝血因子Ⅹa抑制活性研究

Synthesis of oxazolidinone compounds as factor Ⅹa inhibitors

目的利用生物电子等排原理对利伐沙班进行结构改造,以便寻找活性更好的噁唑酮类凝血因子Ⅹa抑制剂。方法以(S)-4-(4-(5-(氨基甲基)-2-氧代噁唑烷-3-基)苯基)吗啉-3-酮盐酸盐为原料,依次经过酰化、烃化反应,设计合成了22个噁唑烷酮类化合物3a^3v,并通过ESI-MS、1H-NMR及IR谱对目标化合物进行结构确证。结果与结论Ⅹa因子抑制活性的体外实验表明,在100μg·mL-1浓度下,化合物3p表现出比利伐沙班更好的凝血因子Ⅹa抑制作用,而化合物3b、3e、3s的体外Ⅹa抑制作用与利伐沙班相当。

In order to find oxazolidone compounds with potent factorⅩa inhibitory activity,twenty-two rivaroxaban analogues 3 a-3 v were designed and synthesized based on the principle of bioisosterism,via acylation and alkylation reactions by using(S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride as the starting material.The structures of the target compounds were confirmed by ESI-MS,1H-NMR,and IR.The in vitroⅩa inhibitory activity study showed that compound 3 p possessed more potent inhibitory activity than positive control rivaroxaban at the concentration of 100μg·mL-1,while compounds 3 b,3 e,3 s exhibited comparable activity relative to rivaroxaban.