Synthesis And Antiepileptic Activity Of Rufinamide And Its Derivatives

Epilepsy is a syndrome of the disfunction of brain evoked by over-excitement of neurons in local part of the brain. It was characterized by recurrent unprovoked seizures and affected approximately 5‰ of our nations.Rufinamide is a new antiepileptic developed by Novartis Company of Switzerland and has finished Phase Ⅲ clinical trial. In this paper, starting from 2,6-difiuoro benzyl chloride, Rufinamide was prepared via reaction with sodium azide, cyclization with ethyl propiolate and amidation. And 16 derivatives were prepared using substituted benzyl chloride as the starting material. Structures of the synthesized compounds were confirmed by 1~H-NMR, MS, IR and elemental analysis. All the compounds were screened for activity against maximal electroshock (MES)-induced seizure. And the result showed that seven compounds (4, 8a, 8g, 8h, 8i, 8n, 8o) possessed anticonvulsant activity at dose less than 100 mg/kg. Among the tested compounds, compounds (4, 8g, 8h, 8i, 8n, 8o) containing fluoro substituted phenyl ring were more potent than those unsubstituted phenyl derivatives. And compound 4 was found to be the best, while introduction of chloro atoms to the phenyl ring (8d, 8e, 8f, 8j, 8k, 8l, 8m) reduced the activity. Furthermore, their activity decreased when there were substituent on the nitrogen atom of carboxamide, and the larger the substituent, the lesser the activity.