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

Abstract A new series of anticonvulsant 3-carboalkoxy-2-methyl-2,3-dihydro-1 H -phenothiazin-4[10 H ]-ones is herein reported. 2-Aminothiophenols underwent cyclocondensation with 4-carboalkoxy-5-methylcyclohexane-1,3-diones in refluxing dimethylsulfoxide (DMSO) to yield 3-carboalkoxy-2-methyl-2,3-dihydro-1 H -phenothiazin-4[10 H ]-ones, 4a–k . In the case of the carbo- tert -butoxy derivatives ( 4c and 4k ) prolonged reaction times led to the isolation of the respective 3-unsubstituted-2-methyl-2,3-dihydro-1 H -phenothiazin-4[10 H ]-ones ( 4l and 4m ) instead. Significant anticonvulsant activity was displayed by these analogues, most particularly 4 k, which was active at 30 mg/kg intraperitoneally (ip) 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 4k in the MES evaluation provided an ED 50 of 17.60 mg/kg, with no toxicity noted at dosages up to 500 mg/kg, providing a protective index (PI = TD 50 /ED 50 ) > 28.40. These compounds represent the first reported series of phenothiazines which possess anticonvulsant activity.