4-取代-3-烷基-4,5-二氢-1-(3-氯-4-氟苯基)-1,2,4-三唑-5-酮的合成及生物活性  

Synthesis and Biological Activities of 4-Substituted-3-alky-4,5-dihydro-1-(3-chloro-4-fluorophenyl)-1,2,4-triazol-5-one Derivatives

作　　者：徐进宜[1] 贺乾辉[1] 魏臻[1] 曾翼[1] 华维一[1] 吴晓明[1] 王秋娟[2] 胡松[2] 张静[2] 

机构地区：[1]中国药科大学药物化学教研室,南京210009 [2]中国药科大学生理学教研室,南京210009

出　　处：《有机化学》2006年第1期123-128,共6页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.30371688);教育部科技研究重点基金(No.03089)资助项目.

摘　　要：为寻找活性强、作用时间长的新型非肽类血管紧张素IIAT1受体拮抗剂,从易得原料3-烷基-4,5-二氢-1-(3-氯-4-氟苯基)-1,2,4-三唑-5-酮出发,经过N-烃化反应、1,3-偶极反应、氢解、水解和酰化等反应,合成得到一系列4-取代-3-烷基-4,5-二氢-1-(3-氯-4-氟苯基)-1,2,4-三唑-5-酮类衍生物,总收率为58%～87%,其结构经IR,1HNMR,MS和元素分析确证.初步药理试验结果表明:所有目标化合物均有一定的AT1受体拮抗活性,其中化合物12d抑制AII诱导的兔主动脉环收缩的IC50值为4.0×10-9mol/L,与阳性药坎地沙坦(candesartan)相当,具有进一步的研究意义.In order to search for the novel angiotensin II （All） AT1 receptor antagonists with high potency and long duration, with triazolinone as the core, a series of 4-substituted-3-alky-4,5-dihydro-l-（3-chloro-4- fluorophenyl）-l,2,4-triazol-5-one derivatives have been synthesized in over 58%-87% yields from readily available starting material 3-alkyl-4,5-dihydro-l-（3-chloro-4-fluorophenyl）-l,2,4-triazol-5-ones via N-alkyl- ation, 1,3-dipolar cycloaddition, hydrogenolysis, saponification and acylation reactions. All the products were identified by IR, 1H NMR, MS spectra and elemental analysis, and evaluated for their antagonism of AII-induced contractions of the rabbit thoracic aortic rings. The assay results showed that the most potent compound 12d had the IC50 value of 4.0× 10^-9 mol/L, which is comparable to that of positive drug candesartan.

关 键 词：3-氯-4-氟苯基 三唑啉酮 AT1受体拮抗剂 合成 降压 心衰 

分 类 号：O626.26[理学—有机化学]