Design, Synthesis And Evaluation Of 4-(2-Acet Oxybenzoylamino) Butyanamide As Antiepileptic Agents

Seizures are the clinical syndrome complex characterized by the dysfunction of central nervous system due to the spontaneous and synchronous electrical discharge in the brain.γ-aminobutyric acid (GABA) as the most important inhibitory neurotransmitter is able to inhibit the overexcitement of epilepsy focus of glial cells. However, GABA lacks the drug-like characteristics due to the easy ionization in the physiological pH condition, higher hydrophility, and lower penetrability through blood-brain barrier. So nine 4-(2-acetoxybenzoylamino) butyanamides (t1-t9) not reported in the literature, in which acetylsalicylic acid was the carrier to help transport them into the brain, were designed and synthesized in order to the investigation of in vivo antiepilepsy.GABA as the raw material in the present of methanol and the catalyst thionyl chloride produced the solid methylγ-aminobutyrate hydrochloride. The solid acylated with 2-acetoxybenzoic chloride under triethylamine as the acid binding agent gave 4-(2-acetoxybenzoylamino) butyrates. The treatment of the corespording ammine with the residue of the sequent evaporation gave the target compounds (tl-t9). Meanwhile, the investigation of acylation condision optimized the synthesis techonics with more than 50% of the yields. The terminal target compounds (t1-t9) were confirmed by IR, 13CNMR.1HNMR, and HRMS.In the epilepsy model induced by ignition method of 4-aminopyridine in mice, the systematic evaluation of antiepileptic action of the nine target compounds in shake of determination by modified Cole's method of ED50 and LD50 resulted in the potency of compound t5-t8 0.3 to 1.8 folds higher than the one of sodium valproate as the positive control drug. So compound t7 with 138.50mg·kg-1 of ED50 and 431.92mg·kg-1 of LD50 is worthy to be furtherly developed.