Synthesis and Evaluation of N-(Phenylacetyl)trifluoromethanesulfonamides as Anticonvulsant Agents

Abstract

A series of N-(phenylacetyl)trifluoromethanesulfonamides (3a-g) was prepared according to the Topliss scheme in order to determine if aryl substituents would influence anticonvulsant activity. In initial (phase I) screening and quantitative (phase II) evaluation, all seven compounds exhibited significant activity against MES- and scMet-induced seizures. N-(Phenylacetyl)trifluoromethanesulfonamide (3a) was then advanced through five additional testing phases (phases III-VII). Compound 3a displayed good oral bioavailability, low toxicity, and a larger protective index in mice than the prototype drugs, phenytoin, phenobarbital, valproate, and ethosuximide. Additionally, 3a exhibited a longer time to peak effect in all tests and a greater 24-h margin of safety (HD(50)/ED(50)) than the prototypes. Compound 3a blocked picrotoxin-induced seizures but was ineffective against seizures induced by bicuculline or strychnine. In vitro receptor binding studies revealed that 3a did not displace [(3)H]-labeled gamma-aminobutyric acid or [(3)H]-labeled flunitrazepam, and tolerance did not develop during a 5-day chronic administration.

Trifluoromethanesulfonamide derivatives of azoles

“…Sulfonylation of substituted and unsubstituted amines with trifluoromethanesulfonyl halide or trifluoromethanesulfonic anhydride in the presence of a base is carried out for the synthesis of the corresponding trifluoromethanesulfonamides [3]. A large number of trifluoromethanesulfonamidophenyl-substituted compounds have been found to exhibit anti-inflammatory [3,4] and anticonvulsant properties [5] which have enhanced their use in the research and development of new medicines. Trifluoromethanesulfanilides are also known to show insecticidal and nematicidal properties [6,7].…”

Synthesis and Evaluation of New 2-(Substituted Phenyl)- 3-[5'-(2'-Oxo-2H-chromen-3'-yl)-1,3,4-Oxadiazol-2-yl]-1, 3-Thiazolidin-4-Ones as Anticonvulsants

“…[14][15][16] showed protection were 4, 7, 9 and 11 after 0.5 h. These compounds also showed protection against MES test after 4 h but at a higher dose of 300 mg/kg. Compounds, which showed protection against MES test at 300 mg/ kg after 0.5 h and 4 h, were 5, 10 and 16.…”

“…Physical data of compounds (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) a Elemental analysis for C, H, N and S were within 0.4% and 0.3% respectively of the theoretical values. b Eluents used in TLC were Toluene: Ethyl acetate: Formic acid (5:4:1) for compounds.…”

Synthesis and anticonvulsant activity of 6,7,8,9-tetra hydro-5H-5-(2′-hydroxy phenyl)-2-(4′-substituted benzylidine)-3-(4-nitrophenyl amino) thiazolo quinazoline derivatives

“…Neurotoxicity (NT) in mice was measured by the rotarod test. Initial anticonvulsant activity and NT data for the thiazolo quinazoline derivatives (4a-f and 5a-f) are given in Table 1 along with literature data on phenytoin and ethosuximide (Porter et al 1984;Dimmock et al 1996;Flaherty et al 1996). The derivatives were injected intraperitoneally into mice using doses of 30, 100, and 300 mg kg À1 , and the tests to evaluate anticonvulsant efficacy were carried out 0.5 and 4 h after dosage.…”