Study Of 10-alkoxy-5, 6-dihydro-triazolo[4, 3-d] Benzo[f][1, 4]oxazepine Derivatives With Anticonvulsant Activity

Series of 7-Substituted-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one derivatives (8a-8u) and 10-alkoxy-5,6-dihydro-triazolo[4,3-d]benzo[f] [1,4]oxazepine derivatives (13a-13s) were synthesized using 4-hydroxyquinolin-2(1H)-one as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and their neurotoxicities were measured by the rotarod test. Most of the compounds exhibit the anticonvulsant activities, and the series of 13a-13s possessing a better anticonvulsant activity compared with the series of 8a-8u.10-Heptyloxy-5,6-dihydro-triazolo[4,3-d]benzo[f] [1,4] oxazepine (13f) was found to be the most promising compound, possessing 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, the compound 13f was tested in pentylenetetrazole (PTZ), isoniazid (ISO), thiosemicarbazide (THIO),3-mercaptopropionic acid (3-MP) and Bicuculline (BIC) induced seizures tests, respectively. The results suggest that compound 13f exerts anticonvulsant activity through GABA-mediated mechanism.