6-取代苯基哒嗪的3位γ-氨基丁酸衍生物的合成及抗惊活性

GABA的合成类似物是开发新型抗惊剂和抗癫痫药物的新领域。由芳香醛与吗啉、氰化钾反应形成的α-芳基-α-(4-吗啉)乙腈,可对α,β-不饱和腈或酯进行1,4-加成,生成1,4-酮酸型化合物。此物与肼缩合,再经芳构化即得6-芳基-3(2H)哒嗪酮。后者再经氯化后。与GABA缩合,制备3-(N-GABA)-6-芳基哒嗪类及其分子内脱水产物3-(N-丁内酰胺)-6-芳基哒嗪类化合物。本文应用此法合成了17个上述苯代哒嗪的GABA衍生物,并初步测验了它们的抗惊(MES)活性。活性最强的是3-(N-GABA)-6-(2′,4′-二氯苯基)哒嗪(ED₅₀=21.05mg/kg)。

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 alpha-(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).