title: 8-Amino-3-benzyl-1,2,4-triazolo[4,3-a]pyrazines. Synthesis and anticonvulsant activity.
abstract: Eleven substituted 8-amino-3-benzyl-1,2,4-triazolo[4,3-a] pyrazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. The compounds were prepared in four stages from the phenylacetonitriles. I. The intermediate (2,2,2-triethoxyethyl)benzenes III were condensed with 2-chloro-3-hydrazinopyrazine (IV) to provide the 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazines V. The latter were converted to the 8-amine targets VI with methylamine or ammonia. Several compounds exhibited potent activity against MES; the 3-(2-fluorobenzyl)-8-(methylamino) and 3-(2,6-difluorobenzyl)-8-(methylamino)congeners (4 and 12) exhibited the best anticonvulsant activity with oral ED50S of 3 mg/kg. The 1,2,4-triazolo[4,3-a]pyrazine ring system serves as a bioisostere of the purine ring for anticonvulsant activity; however, these agents exhibit less propensity to cause emesis.
authors.affiliation: Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 22709, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Kelley
authors.forename: J A
authors.initials: JA
authors.lastname: Linn
authors.forename: D D
authors.initials: DD
authors.lastname: Bankston
authors.forename: C J
authors.initials: CJ
authors.lastname: Burchall
authors.forename: F E
authors.initials: FE
authors.lastname: Soroko
authors.forename: B R
authors.initials: BR
authors.lastname: Cooper
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D004558:Electric Stimulation; D008297:Male; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D011719:Pyrazines