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  • Title: Synthesis, characterization, and anticonvulsant activity of enaminones. Part 5: investigations on 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothizin-4[10H]-one derivatives.
    Author: Laws ML, Roberts RR, Nicholson JM, Butcher R, Stables JP, Goodwin AM, Smith CA, Scott KR.
    Journal: Bioorg Med Chem; 1998 Dec; 6(12):2289-99. PubMed ID: 9925291.
    Abstract:
    A new series of anticonvulsant 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-on es 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-1H-phenothiazin-4[10H]-on es, 4ak. 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-1H-phenothiazin-4[10H]-ones (41 and 4m) instead. Significant anticonvulsant activity was displayed by these analogues, most particularly 4k, 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 (p.o.) rat evaluation of 4k in the MES evaluation provided an ED50 of 17.60 mg/kg, with no toxicity noted at dosages up to 500 mg/kg, providing a protective index (PI = TD50/ED50) > 28.40. These compounds represent the first reported series of phenothiazines which possess anticonvulsant activity.
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