吡酮酸类抗菌药物的研究——Ⅵ.7-氯-6-氟-1-乙基-1,4-二氢-4-氧吡啶(2,3-c)并哒嗪-3-羧酸及其衍生物的合成与抗菌活性

STUDIES ON PYRIDONECARBOXYLIC ACIDS AS ANTIBACTERIAL AGENTS——Ⅵ. SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF 7-CHLORO-6-FLUORO-1-ETHYT-1, 4-DIHYDRO-4-OXOPYRIDO(2, 3-c)PYRIDAZINE-3-CARBOXYLIC ACID AND DERIVATIVES

摘要: 由2,6-二氯-5-氟-3-氰基吡啶出发,经氰基水解、酰氯化、与重氮乙酸乙酯缩合、重氮基还原、环化五步反应合成了一个新的杂环体系,即取代的吡啶(2,3-c)并哒嗪Ⅵ。由Ⅵ为原料经不同途径制得21个新衍生物,其中10个游离酸进行了体外抗菌活性筛选。对金葡-15、大肠-1515、绿脓-29的MIC(μg/ml),除化合物Xa和Xb对大肠-1515为50外,其余均大于100。

Abstract: The synthesis and in vitro antibacterial activity of 7-chloro-6-fluoro-1-ethyl-1, 4-dihydro-4-oxopyrido (2,3-c) pyridazine-3-carboxylic acid and derivatives were reported. Ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxopyrido (2,3-c) pyridazine-3-carboxylate Ⅵ was obtained from 2,6-dichloro-5-fluoronicotinitrile Ⅰ through hydrolysis, carboxylic chlorination, condensation with ethyl diazoacetate, reduction of diazo group and cyclization. Compound Ⅵ reacted by different pathways to provide ten free acids which had a minimum inhibitory concentration >100 μg/ml against S. aureus-15, E. coli-1515 and P. aeruginosa-29, while those of compounds Xa and Xb against E. coli-1515 were 50μg/ml.The structures of twenty-four new compounds Ⅳ, Ⅴ, Ⅵ, Ⅶ, Ⅷa～b, Ⅸ a～h and Ⅹa～f, ⅰ～1 were determined by IR; MS; IHNMR and elemental analysis.