Synthesis and Anticonvulsant Activity of 9-Alkoxy-6,7-dihydro-2H-benzo[c][1,2,4]triazolo[4,3-a]azepin-3[5H]-ones

Abstract

A series of novel 9-alkoxy-6,7-dihydro-2H-benzo[c][1,2,4]triazolo[4,3-a]azepin-3(5H)-one derivatives was designed and synthesized starting from 2,3,4,5-tetrahydro-7-hydroxy-1H-2-benzazepin-1-one. The structures of these compounds were confirmed by mass, ¹H NMR infrared spectra, and elemental analysis. Their anticonvulsant activity was evaluated by maximal electroshock (MES) test, and their neurotoxic effects were determined by the rotarod neurotoxicity test. The results shown that 3k was the most active compound with median effective dose (ED₅₀) of 27.3 mg/kg, median toxicity dose (TD₅₀) of 118.3 mg/kg, and protective index (PI) of 4.3. Possible structure–activity relationship is discussed.

GRAPHICAL ABSTRACT

Keywords:

• 9-Alkoxy-6,7-dihydro-2H-benzo[c][1,2,4]triazolo[4,3-a]azepin-3(5H)-one
• anticonvulsant
• synthesis

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (No. 30760290 and No.30860340) and Important Item Foundation of Ministry of Education P.R. China (No. 20070422029).

Notes

^a All of tested compounds were dissolved in DMSO.

^b The maximal electroshock test was carried out 30 min after administration of the test compounds.

^c Doses are denoted in milligrams per kilogram.

^a Median effective dose required to assure anticonvulsant protection in 50% of animals.

^b 95% confidence limits given in parentheses.

^c Median toxic dose eliciting minimal neurological toxicity in 50% of animals.

^d Not tested.

^e Protective index (TD₅₀/ED₅₀).