Design and synthesis of 10-alkoxy-5, 6-dihydro-triazolo[4,3-d]benzo[f][1,4] oxazepine derivatives with anticonvulsant activity

A series of novel 10-alkoxy-5, 6-dihydro-triazolo[4,3-d]enzo[f][1,4]oxazepine derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). In the MES test, compound 10-Heptyloxy-5, 6-dihydro-triazolo[4,3-d]benzo[f][1,4]oxazepine (8f) was found to possess better anticonvulsant activity and higher safety than marketed drugs carbamazepine and phenytoin with an ED50 value of 6.9 mg/kg a PI value of 9.5. To explain the possible mechanism of anticonvulsant activity, compound 8f was tested in pentylenetetrazole, isoniazid, thiosemicarbazide, 3-mercaptopropionic acid and Bicuculline induced seizures tests. The results suggest that compound 8f exerts anticonvulsant activity through GABA-mediated mechanism. (c) 2010 Elsevier Masson SAS. All rights reserved.