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有机化学
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有机化学 ›› 2006, Vol. 26 ›› Issue (01): 123-128. 上一篇    下一篇

研究简报

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

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   

  1. (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)
  • 收稿日期:2005-02-05 修回日期:2005-07-18 发布日期:2005-12-31
  • 通讯作者: 吴晓明

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

XU Jin-Yi1,HE Qian-Hui1,WEI Zhen1,ZENG Yi1,HUA Wei-Yi1
WU Xiao-Ming*,1,WANG Qiu-Juan2,HU Song2,ZHANG Jin2   

  1. (1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009)
    (2 Department of Physiology, China Pharmaceutical University, Nanjing 210009)
  • Received:2005-02-05 Revised:2005-07-18 Published:2005-12-31
  • Contact: WU Xiao-Ming

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1208

被引次数

12

为寻找活性强、作用时间长的新型非肽类血管紧张素II AT1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, 1H NMR, 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4.0×10－9 mol/L, 与阳性药坎地沙坦(candesartan)相当, 具有进一步的研究意义.

关键词: 心衰, 3-氯-4-氟苯基, 降压, 三唑啉酮, 合成, AT1受体拮抗剂

In order to search for the novel angiotensin II (AII) AT1 receptor antagonists with high potency and long duration, with triazolinone as the core, a series of 4-substituted-3-alky-4,5-dihydro-1-(3-chloro-4- fluorophenyl)-1,2,4-triazol-5-one derivatives have been synthesized in over 58%～87% yields from readily available starting material 3-alkyl-4,5-dihydro-1-(3-chloro-4-fluorophenyl)-1,2,4-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.

Key words: triazolinone, 3-chloro-4-fluorophenyl, AT1 receptor antagonist, heart failure, antihypertensive, synthesis