Design, Synthesis Of6-Substituted-pyrido[2,3-d]Pyridazine Derivatives With Anticonvulsant Activity

Aim to find new compounds with stronger anticonvulsant activity and lower neurotoxicity, a novel series of6-substituted-[1,2,4]triazol[3,4-α]pyridazine derivatives(1-18) and6-substituted-[1,2,4]tetrazolo[3,4-a]pyridazine derivatives (19-21) 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 neurotoxicities were measured by the rotarod test. The results of these tests demonstrated that N-m-chlorophenyl-[1,2,4]triazolo-[4,3-b]-pyrido[2,3-d]pyridazin-6-amine (3) was the most potent anticonvulsant, with ED50value of13.6mg/kg and protective index (PI=TD50/ED50) values of7.2in the MES test. Compound N-m-chlorophenyltetriazolo[5,1-b]-pyrido[2,3-d]pyridazin-6-amine(19), exhibited a little weaker activity than compound3in controlling the seizure induced by MES test at the dose of15.9mg/kg, but it possessed lower neurotoxicity with PI value of13.4, which was safer than marketed drug carbamazepine.