Synthesis and anticonvulsant activity of 6­alkil(aralkil)­3­R­4H­[1,2,4]triazin­5­ons

Abstract

Epilepsy is one of the most widespread serious brain diseases. Over 70 millions of people around the

worlds suffer from it. Epilepsy has bimodal distribution with highest risk in babies and older age groups. Use of antiepileptic drugs (AEDs) is the primary approach in epilepsy treatment and helps to prevent sei- zures in two thirds of patients. Since 1990s, over 15 second generation AEDs have been presented, which expands possibilities of individual treatment for each patient. Pharmacotherapy as a rule, is sufficient, however, approximately 20–30 % of patients turn out to be resistant to it, which significantly worsens their general quality of life and substantiates search for new, more effective drugs.

The aim of the research is to synthesize, prove structure of synthesized compounds and study anticon- vulsant activity of 6(tret-butil)-3-R-4H-[1,2,4]triazin-5-ons and 6-(41-methoxibenzil)-3-R-4H-[1,2,4]tri- azin-5-ons in comparison to known anticonvuilsant drug (lamotrigine) on the stage of primary pharmaco- logical screening.

Anticonvulsant, muscle relaxation and sedative activities have been estimated respectively on model of «pentylenetetrazole convulsions», «wire» test and «open field» test in mice after administration of new compounds at doses equimolar to ED50 of lamotrigine (10 mg/kg).

It was established, that 6(tret-butil)-3-R-4H-[1,2,4]triazin-5-ons and 6-(41-methoxibenzil)-3-R- 4H-[1,2,4]triazin-5-ons derivatives are characterized by anticonvulsant activity, moderate sedative action and absence of muscle relaxation effect. Such peculiarities of pharmacological action of new compounds and structural similarity to lamotrigine suggest the absence of GABA-ergic component in their specific activity. Anticonvulsant and behavioral activities of compounds depend on modification of substitutes in both third and sixth position of heterocyclic 1,2,4-triazine ring.

Regarding anticonvulsant activity, studied compounds show reliable effects, according to which some of them are not inferior to reference drug, lamotrigine.