STUDIES ON SYNTHESIS AND ANTICONVULSANT ACTIVITY OF 3- GABA DERIVATIVES OF 6-(SUBSTITUTEDPHENYL) PYRIDAZINES

In recent years considerable emphasis has been placed on the hypothesis that enhancement of GABA transmission could be beneficial in some types of epilepsy. The α-(aryl)-4-morpholineacetonitrile obtained by the interaction of aryl aldehydes, morpholine and potassium cyanide, have been used to synthesize 3- (aroyl) -propionic acids and esters by 1,4- additions to acrylonitrile or acrylic ester. 3-( Aroyl ) propionic acids reacting with hydrazine can yield 6- aryl- 4, 5-dihydro-3(2H ) pyridazinones which are dehydrogenated by bromine (via bromination dehydrobromination) to give 6-aryl-3 (2H) pyridazinones. The latter compounds were converted into 3-(N-GABA)-6-(substitutedphenyl) pyridazines and 3-(N- butyryllactamyl )-6-(substitutedphenyl) pyridazines by the chlorination (by means of phosphorus oxychloride) and then reaction with GABA. By this method seventeen 3-GABA derivatives of 6-(substituted-phenyl ) pyridazines were synthesized. The anticonvulsant activity (MES) of these compounds were also tested. 3-( N-GABA)-6-( 2', 4'- dichloro ) phenylpyridazine ; potent anticonvulsant (ED₅₀ = 21.05 mg/kg).