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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 find out the new non-peptide angiotensin IIAT1 receptor antagonist with strong activity and long-acting time, we obtained 3-alkyl-4,5-dihydro-1- ) -1,2,4-triazol-5-one, through N-alkylation reaction, 1,3-dipolar reaction, hydrogenolysis, hydrolysis and acylation reaction, a series of 4-substituted-3 -alkyl-4,5-dihydro-1- (3-chloro-4-fluorophenyl) -1,2,4-triazol-5-one derivatives in a total yield of 58% to 87% , The structure of which was confirmed by IR, 1HNMR, MS and elemental analysis.The preliminary pharmacological test results showed that all the target compounds had certain AT1 receptor antagonistic activity, and the IC50 value of compound 12d for inhibiting AII-induced contraction of rabbit aortic rings was 4.0 × 10-9mol / L, and the positive drug candesartan (candesartan), with further research significance.