Xu P, Wang S Y, Liu W Q
Department of Medicinal Chemistry, Beijing Medical University.
Yao Xue Xue Bao. 1991;26(9):650-5.
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).
近年来，人们相当重视这样一种假说，即增强γ-氨基丁酸（GABA）传递在某些类型的癫痫中可能是有益的。通过芳基醛、吗啉和氰化钾相互作用得到的α-（芳基）-4-吗啉乙腈，已被用于通过对丙烯腈或丙烯酸酯进行1,4-加成来合成3-（芳酰基）-丙酸及其酯。3-（芳酰基）丙酸与肼反应可生成6-芳基-4,5-二氢-3（2H）哒嗪酮，该哒嗪酮经溴（通过溴化脱溴化氢）脱氢得到6-芳基-3（2H）哒嗪酮。通过用三氯氧磷进行氯化，然后与GABA反应，将后一种化合物转化为3-（N-GABA）-6-（取代苯基）哒嗪和3-（N-丁酰内酰胺基）-6-（取代苯基）哒嗪。通过这种方法合成了十七种6-（取代苯基）哒嗪的3-GABA衍生物。还测试了这些化合物的抗惊厥活性（最大电休克发作，MES）。3-（N-GABA）-6-（2'，4'-二氯）苯基哒嗪；强效抗惊厥剂（半数有效剂量ED50 = 21.05毫克/千克）。
