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

Bioorg Med Chem. 1998 Dec;6(12):2289-99. doi: 10.1016/s0968-0896(98)80009-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology
  • Crystallography, X-Ray
  • Electroshock
  • Indicators and Reagents
  • Male
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Motor Activity / drug effects
  • Neurotoxins / toxicity
  • Phenothiazines / chemical synthesis*
  • Phenothiazines / chemistry
  • Phenothiazines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / drug therapy*
  • Structure-Activity Relationship

Substances

  • Anticonvulsants
  • Indicators and Reagents
  • Neurotoxins
  • Phenothiazines