Yamada T, Nobuhara Y, Yamaguchi A, Ohki M
J Med Chem. 1982 Aug;25(8):975-82. doi: 10.1021/jm00350a018.
In an effort to develop new types of antiulcer agents, a series of novel 3(2H)-pyridazinone derivatives and related analogues was synthesized. Substituted 3(2H)-pyridazinones and their 4,5-dihydro analogues were alkylated by omega-haloalkyl cyanides at the N-2 position under phase-transfer catalytic reaction, and the nitrile group was converted to the thio amide group by treatment with hydrogen sulfide alone or with the appropriate primary or secondary amines. Various substituents were introduced on the nitrogen of thio amide, on the carbon in the side chains, and on the 3(2H)-pyridazinone ring. The synthesized compounds were evaluated for gastric antisecretory activity in the pylorus-ligated rat, and selected compounds were applied to experimental ulcer models, such as Shay's, aspirin-induced, and stress-induced ulcers in the rat. Structure-activity relationships are discussed. 3(2H)-Pyridazinones with a C-6 phenyl group and an N-2 alkyl side chain with a terminal thio amide group (48, 49, 51, and 52) were the most potent among the compounds tested.
为了开发新型抗溃疡药物，合成了一系列新型3(2H)-哒嗪酮衍生物及相关类似物。在相转移催化反应条件下，用ω-卤代烷基氰化物将取代的3(2H)-哒嗪酮及其4,5-二氢类似物在N-2位进行烷基化反应，然后单独用硫化氢或与适当的伯胺或仲胺反应，将腈基转化为硫代酰胺基。在硫代酰胺的氮原子、侧链的碳原子以及3(2H)-哒嗪酮环上引入了各种取代基。对合成的化合物在幽门结扎大鼠中进行胃分泌抑制活性评估，并将选定的化合物应用于实验性溃疡模型，如大鼠的 Shay 溃疡模型、阿司匹林诱导的溃疡模型和应激诱导的溃疡模型。讨论了构效关系。在测试的化合物中，具有C-6苯基和带有末端硫代酰胺基的N-2烷基侧链的3(2H)-哒嗪酮（48、49、51和52）活性最强。
