Synthesis and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine derivatives

Abstract

A novel series of 8-alkoxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine derivatives were synthesized and characterized by IR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis. The newly synthesized compounds were screened for their anticonvulsant activities by the maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxic effects were determined by the rotarod neurotoxicity test. Compound 8-pentyloxy-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine (3d) besides being one of the most active compounds had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED50) of 17.5 mg/kg, and had protective index (PI) value of 6.5, which is slightly less than that of the prototype drug carbamazepine (PI = 8.1). Its value of ED50 and PI in the anti-scPTZ test were 21.2 and 5.4, respectively, the latter value (PI) of which is much greater than that of the prototype drug carbamazepine (ED50 >100, PI <0.72). Possible structure–activity relationship has been discussed.