Design, Synthesis of 6-Substituted-pyrido[3,2-d]pyridazine Derivatives with Anticonvulsant Activity

The aim of the present paper was to find new compounds with stronger anticonvulsant activity and lower neurotoxicity, a novel series of 6-substituted-pyrido[3,2-d]pyridazine derivatives was synthesized using furo[3,4-b]pyridine-5,7-dione as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and their neurotoxicity was measured by the rotarod test. The results of these tests demonstrated that N-m-chlorophenyl-[1,2,4]triazolo- [4,3-b]-pyrido[3,2-d]pyridazin-6-amine (3) was the most potent anticonvulsant, with ED50 value of 13.6 mg/kg and protective index (PI = TD50 / ED50) values of 7.2 in the MES test. Compound N-m-chlorophenyltetriazolo[5,1-b]-pyrido[3,2-d]pyridazin-6-amine (19), exhibited a little weaker activity than compound 3 in controlling the seizure induced by MES test at the dose of 15.9 mg/kg, but it possessed lower neurotoxicity with PI value of 13.4, which was safer than marketed drug carbamazepine.