Synthesis, characterization, and anticonvulsant activity of enaminones. Part 5: Investigations on 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-one derivatives

A new series of anticonvulsant 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenot hiazin-4[10H]-ones is herein reported. 2-Aminothiophenols underwent cycloco ndensation with 4-carboalkoxy-5-methylcyclohexane-1,3-diones in refluxing d imethylsulfoxide (DMSO) to yield 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phen othiazin-4[10H]-ones, 4a-k. In the case of the carbo-tert-butoxy derivative s (4c and 4k) prolonged reaction times led to the isolation of the respecti ve 3-unsubstituted-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones (41 and 4m) instead. Significant anticonvulsant activity was displayed by these an alogues, most particularly 4k, which was active at 30 mg/kg intraperitoneal ly tip) in mice in the maximal electroshock seizure (MES) evaluation, with no toxicity noted at dosages up to 300 mg/kg. Oral (po) rat evaluation of 4 k in the MES evaluation provided an ED50 Of 17.60 mg/kg, with no toxicity n oted at dosages up to 500 mg/kg, providing a protective index (PI = TD50/ED 50) > 28.40. These compounds represent the first reported series of phenoth iazines which possess anticonvulsant activity. (C) 1998 Elsevier Science Lt d. All rights reserved.