Yamada T, Nobuhara Y, Shimamura H, Tsukamoto Y, Yoshihara K, Yamaguchi A, Ohki M
J Med Chem. 1983 Mar;26(3):373-81. doi: 10.1021/jm00357a012.
In an effort to develop new types of antiulcer agents, we synthesized a series of novel 2-[omega-(thioureido)alkyl]- and 2-[omega-(cyanoguanidino)alkyl]-3(2H)-pyridazinone derivatives. All target compounds were evaluated for gastric antisecretory activity in the pylorus-lygated rat by the method of Shay, and selected compounds were evaluated in the stress-induced ulcer test in rats. Structure-activity relationships were established. Two series of the compounds had significant activity in antisecretory and/or antiulcer tests. The molecular features essential for the activities are a thiourea group or a 2-cyanoguanidine group, a phenyl group in the C-6 position of the 3(2H)-pyridazinone ring, a four-carbon chain length between the 3(2H)-pyridazinone ring and the functional group, and a methyl group at the N-3 position of the functional group. Among them, the three thiourea derivatives (24, 26, and 38) and the six 2-cyanoguanidine derivatives (61, 62, 65, 75, 85, and 86) had the most potent antisecretory and/or antiulcer activities. These compounds are not histamine H2-receptor antagonists.
为了开发新型抗溃疡药物，我们合成了一系列新型的2-[ω-(硫脲基)烷基]-和2-[ω-(氰基胍基)烷基]-3(2H)-哒嗪酮衍生物。采用Shay法在幽门结扎大鼠中对所有目标化合物进行胃泌酸抑制活性评估，并在大鼠应激性溃疡试验中对选定的化合物进行评估。建立了构效关系。这两个系列的化合物在泌酸抑制和/或抗溃疡试验中具有显著活性。这些活性所必需的分子特征包括一个硫脲基团或一个2-氰基胍基团、3(2H)-哒嗪酮环C-6位上的一个苯基、3(2H)-哒嗪酮环与官能团之间四个碳的链长以及官能团N-3位上的一个甲基。其中，三种硫脲衍生物（24、26和38）以及六种2-氰基胍衍生物（61、62、65、75、85和86）具有最强的泌酸抑制和/或抗溃疡活性。这些化合物不是组胺H2受体拮抗剂。
