8-AMINO-3-BENZYL-1,2,4-TRIAZOLO[4,3-A]PYRAZINES - SYNTHESIS AND ANTICONVULSANT ACTIVITY

Eleven substituted 8-amino-3-benzyl-1,2,4-triazolo[4,3-a]pyrazines wer e synthesized and tested for anticonvulsant activity against maximal e lectroshock-induced seizures (MES) in rats. The compounds were prepare d in four stages from the phenylacetonitriles I. The intermediate (2,2 ,2-triethoxyethyl)benzenes III were condensed with 2-chloro-3-hydrazin opyrazine (IV) to provide the 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]p yrazines V. The latter were converted to the 8-amine targets VI with m ethylamine or ammonia. Several compounds exhibited potent activity aga inst MES; the 3-(2-fluorobenzyl)-8-(methylamino) and 3-(2,6-difluorobe nzyl)-8-(methylamino) congeners (4 and 12) exhibited the best anticonv ulsant activity with oral ED(50)S of 3 mg/kg. The 1,2,4-triazolo[4,3-a ]pyrazine ring system serves as a bioisostere of the purine ring for a nticonvulsant activity; however, these agents exhibit less propensity to cause emesis.