Synthesis And Anticonvulsant Activities Of8-Substimted-6-Phenyl-[1,2,4]Triazlol[4,3-b]Pyridazine And7-Substied-5-Phenyl-[1,2,4]Triazolo[1,5-a]Pyrimidines Denvatives

Heterocyclic compounds represent a important class of compounds with various bioactivities. Among these, triazolo compounds are one of the most significant subclass which has been shown to possess several medicinal properties. Triazole was increasingly used by medicinal chemists in the design of drugs expecially in recent in the area of antiepileptic drugs due to its appropriate charge distribution and high affinity to receptor. In our previous studies, several series of compounds contained triazole frame displayed excellent anticonvulsant activity. As part of our research on antiepileptic compounds with a triazole nucleus, we designed and synthesized a series of novel8-substituted-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine and7-substituted-5-phenyl-[1,2,4] triazolo[1,5-a]pyrimidines derivatives in this study.In this paper, reaction of1-phenylpentane-1,3-dione (1) with1,2,4-triazole-4-amine afforded6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-8(7H)-one (2), which was the same as6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine-8-ol (2), Alkylation of compound (2) with appropriate alkyl bromide afforded8-alkoxy-6-phenyl-[1,2,4] triazolo [4,3-b]pyridazine derivatives (3a-3h). The others, intermediates8-chloro-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine (4) was obtained by compounds (2) with excessive POCl3.8-phenoxy-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine compounds (5a-5j) produced by the reaction between the compound (4) and appropriate substituted phenols. A total of18pyridazine series of derivatives are novel compounds that have not been reported.At the same time, we choose benzoyl ethyl acetate (1) and1,2,4-triazole-3-amine which obtained the intermediate5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-one (2) after the enol interaction becomes5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-ol (2). And then compound (2) with appropriate alkyl bromides can afford7-alkoxy- 5-phenyl-[1,2,4] triazolo [1,5-a] pyrimidine compounds (3a-3i). And the other, compounds (2) with POCI3reaction afforded7-chloro-5-phenyl-[1,2,4] triazolo[1,5-a] pyrimidine (4), then reaction of compounds (4) and appropriate substituted phenols to obtain7-phenoxy-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine derivatives (5a-5j),19new pyrimidine derivatives were obtained and not reported in the literature.Their structures were characterized by IR,1H-NMR,13C-NMR and MS. Their preliminary anticonvulsant activities and neurotoxicity were evaluated respectively by the maximal electroshock test (MES) and rotarod test (TOX).Some of the compounds prepared displayed anticonvulsant activity in the dose of100mg/kg. Among these,8-butoxy-6-phenyl-[1,2,4]triazolo[4,3-b]pyridazine and7-(heptyloxy)-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidine were found to be the most promising compound with the100%protection against the seizure at the dose of100mg/kg in mice. In two pharmacological experiments, the measured compounds7-(Heptyloxy)-5-phenyl-[1,2,4] triazolo [1,5-a] pyrimidine showed the best anticonvulsant activity (ED50=84.8mg/kg) and protection index (PI=TD50/ED50) was6.0. Security is better than the clinical drug, carbamazepine and sodium valproate, so it should be follow-up research and development.