Synthesis and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives.

A series of novel 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The results of these tests demonstrated that 8-heptyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3f) and 8-hexyloxy -5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3e) were the most promising compounds, with median effective dose (ED(50)) of 17.6 and 17.9 mg/kg, and protective index (PI) of greater than 63.4 and 62.4 in the MES test, respectively. These PI values were higher than the PI value of the prototype antiepileptic drug carbamazepine. The scPTZ test showed that 8-pentyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3d) was the most potent with ED(50) value of 38.0 mg/kg and PI value of greater than 29.4, which is much safer than marketed drug carbamazepine. The possible structure-activity relationship was discussed.