4-(4-烷氧基苯基)-3-乙基-1H-1,2,4-三唑-5(4H)-酮类化合物的合成及其抗惊厥活性

Synthesis and anticonvulsant activity evaluation of novel 4-( 4-alkoxyphenyl)-3-ethyl-1H-1,2,4-triazol-5(4H)-ones

目的设计合成一系列4-(4-烷氧基苯基)-3-乙基-1H-1,2,4-三唑-5(4H)-酮类化合物,并评价其抗惊厥活性和神经毒性。方法以对乙酰氨基酚为起始原料,经烷基化、水解、环合等反应合成1,2,4-三唑-5(4H)-酮类化合物。通过最大电惊厥实验(MES)和神经毒性实验(NT),分别测定目标化合物的抗惊厥活性和神经毒性。结果与结论合成了20个新化合物,其结构经IR、1H-NMR和ESI-MS确证。药理学实验结果表明,所有化合物在不同剂量下都显示出抗惊厥活性。其中,3-乙基-4-(4-戊氧基苯基)-1H-1,2,4-三唑-5(4H)-酮(4e)的活性最强,其半数有效量ED50值为26.9 mg·kg-1,保护指数(PI)为11.0,虽然该化合物的活性低于阳性对照药卡马西平,但其保护指数优于卡马西平(PI=6.4);3-乙基-4-(4-(3-氟苄氧基)苯基)-1H-1,2,4-三唑-5(4H)-酮(4n)的ED50值为61.1 mg·kg-1,但其PI大于17.0,明显优于卡马西平,具有进一步研究的价值。

In previous work, we have reported the synthesis and anticonvulsant activity evaluation of 7- alkoxy-4,5-dihydro-[ 1,2,4 ] triazolo 14,3-a ] quinoline-1 （2H） -ones. The majority of these compounds ex- hibited potent anticonvulsant activity. As part of our continuous efforts to find better anticonvulsant agents in this area, twenty new 4-（4-alkoxyphenyl）-3-ethyl-1H-1,2,4-triazol-5 （4H）-one derivatives were designed and synthesized to meet the structural requirements essential for anticonvulsant properties. 4-（4-Alkoxyphe- nyl）-3-ethyl-1H-1,2,4-triazol-5 （4H）-one（4a-4t） were obtained by alkylation,hydrolysis and cyclization. Their structures were characterized using IR, 1H-NMR,MS, and 13C-NMR techniques. All target compounds were evaluated experimentally against maximal electroshock test（MES） and the neurotoxicity test（NT）. All the compounds showed good anticonvulsant activity at 200 mg· kg-1 and some of them showed good anti- convulsant activity at 30 mg·kg - 1. Especially, 3 -ethyl-4- （ 4- （ pentyloxy ） phenyl ） -1H-1,2,4-triazol-5 （4H） - one（4e, R = n-C5 nil ）was one of the most potential compounds with the EDs0 value of 26.9 mg· kg-1, and protective index（PI） value of 11.0, which showed a significantly higher safety than the standard carbama- zepine （ PI = 6. 4）.