Pyridazinones. 1. Synthesis, antisecretory, and antiulcer activities of thio amide derivatives

Abstract

In an effort to develop new types of antiulcer agents, a series of novel 3(2H)-pyridazinone derivatives and related analogs was synthesized. Substituted 3(2H)-pyridazinones and their 4,5-dihydro analogs 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 HS alone or with the appropriate primary or secondary amines. Various substituents were inroduced on the N of thio amide, on the C in the side chain 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 [2-[2-methyl-2-(thiocarbamoyl)ethyl]-6-phenyl-3(2H)-pyridazinone], 49 [6-phenyl-2-[3-(thiocarbamoyl)propyl]-3(2H)-pyridazinone], 51 [6-phenyl-2-[5-(thiocarbamoyl)pentyl]-3(2H)-pyridazinone] and 52 [2-[5-(N-methylthiocarbamoyl)pentyl]-6-phenyl-3(2H)-pyridazinone]) were the most potent among the compounds tested.