Systhesis And The Anticonvulsant Activity Evaluation Of Phthalazine Derivatives And Related Heterocycle

Epilepsy is a frequently-occurring disease in the central nervous system,whose characteristics are sudden,relapse,refractory and the high mortality rate.It can do serious harm to the human central nervous system,the existing AEDs(antiepileptic drugs)only benefit 70 percent of the patients,and the condition of the remaining 30 percent are out of control.What's more,the long-term use of AEDs can effects the central nervous and the blood system.Therefore,it is important to study and develop the new,safe and effective AEDs.Heterocyclic compounds are widely spread in the nature and exhibit broad-spectrum biological activities.As a representative heterocylic,1,2,4-triazole is well known not only because of the wide spectrum of therapeutic properties,but also the improvement of lipid-water partition coefficient.Thus,more and more derivatives containing 1,2,4-triazole are synthesised,especially in the research of anticonvulsant.Starting with 2,3-dihydrophthalazine-1,4-dione,though chlorination,hydrolys is,hydrazine,the cyclization of triazole,the substitution of triazole and alkylati on,get the 5-(substituted)-[1,2,4]triazolo[3,4-a]phthalazin-6(5H)-one(6a-y)and 2-(substituted)-4-(1H-1,2,4-triazol-1-yl)phthalazin-1(2H)-one(8a-w).Then,we synth esised 9a-b,10a-b,12a-b and 14a-b to evaluate the effect of different heterocyl ic.The structures were characterized by IR,1H-NMR,13C-NMR and MS.The anticonvulsant activity was evaluated by the maximal electroshock test(MES)in mice,the neurotoxicity was evaluated by the rotarod neurotoxicity test(Tox),and the activity against seizures induced by pentylenetetrazole(PTZ)and bicuculiane was also establish.The pharmacoligical analyses showed that 5-heptyl-[1,2,4]triazolo[3,4-a]phth alazin-6(5H)-one(6e)had the most potent anticonvulsant activity.After intraper itoneal administration,the median effective dose(ED50)of 6e was 10.2 mg/kg,and the protective index(PI=TD50/EDso)was 7.64,at the same time,the ED50 of the control drug(carbamazepine)was 11.8 mg/kg,and the PI was 6.4.Aft er intragastric administration,the ED50 of 6e was 24.89 mg/kg,and the PI was 23.84,the ED50 of carbamazepine was 27.3mg/kg,and the PI was 12.0.The r esult indicated that 6e are more effective and safer than carbamazepine.The m echanism research showed that 6e was effective for the seizures induced by PT Z and BIC.