title: Pyridazinones. 1. Synthesis and 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 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.
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis*; D001241:Aspirin; D055598:Chemical Phenomena; D002621:Chemistry; D005753:Gastric Mucosa / Q000378:metabolism; D006168:Guinea Pigs; D006635:Histamine H2 Antagonists / Q000138:chemical synthesis; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010276:Parasympatholytics; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000139:chemically induced; D013315:Stress, Psychological / Q000150:complications
chemical_list: D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D010276:Parasympatholytics; D011724:Pyridazines; D001241:Aspirin