新型双环吡啶类化合物的合成及其抗血小板活性  

Synthesis and Antiplatelet Activities of Novel Bicyclic Pyridine Compounds

作　　者：曹阳芷 孔德瑜 杨玉社 CAO Yang-zhi;KONG De-yu;YANG Yu-she(Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100094,China)

机构地区：[1]中国科学院上海药物研究所,上海201203 [2]中国科学院大学,北京100049

出　　处：《合成化学》2021年第10期813-821,共9页Chinese Journal of Synthetic Chemistry

基　　金：中国科学院青年创新促进会项目(2016262)。

摘　　要：以卤代物(1a~1d、5a~5j)为起始原料,经硫脲盐酸盐(2a~2d)、磺酸钠(6a~6e)或磺酸(6f~6j)的氯代和氨解反应,制得相应的磺酰胺片段(4a~4d、8a~8j)。1-Boc-4-甲基-4-哌啶甲酸(9)脱保护基后与吡啶类化合物(11)发生亲核取代反应制得中间体1-(3-氰基-5-氧代-5,7-二氢呋喃[3,4-b]吡啶-2-基)-4-甲基哌啶-4-羧酸(12);12与磺酰胺片段发生缩合反应合成了相应的双环吡啶类化合物(13a~13n),其结构经1 H NMR,13 C NMR和MS(ESI)表征。采用比浊法血小板聚集试验研究了13a~13n对人源血小板聚集的抑制作用。结果表明:13c和13g具有一定的抗血小板聚集活性,其中化合物13g的IC 50值为44.08μM。Sulfonamide fragments(4a~4d,8a~8j)were prepared by the reaction of chlorination and ammonolysis from the corresponding thiourea hydrochloride(2a~2d),sodium sulfonate(6a~6e)or sulfonic acid(6f~6j)using halide(1a~1d,5a~5j)as starting material.1-Boc-4-methyl-4-piperidinecarboxylic acid(9)was deprotected and then nucleophilically substituted with pyridine compound 11 to obtain intermediate 1-(3-cyano-5-oxo-5,7-dihydrofuran[3,4-b]pyridin-2-yl)-4-methylpiperidine-4-carboxylic acid(12).12 were respectively condensed with sulfonamide fragments to prepare the corresponding bicyclic pyridine compounds(13a~13n).The structures were characterized by ^(1)H NMR,^(13)C NMR and MS(ESI).The turbidimetric platelet aggregation test was used to study the inhibitory effects of 13a~13n on human platelet aggregation.The results showed that 13c and 13g exhibited inhibition of platelet aggregation in vitro.Among these new bicyclic pyridine compounds,13g displayed potent and dose-dependent inhibition of platelet aggregation with IC 50 of 44.08μM.

关 键 词：双环吡啶 血栓 硫脲 磺酸 抗血小板活性 比浊法 合成 

分 类 号：O626.32[理学—有机化学] O625.11[理学—化学]