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

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.

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

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.