Pyridazinones. 2. Synthesis and antisecretory and antiulcer activities of thiourea and 2-cyanoguanidine derivatives.
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.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006146:Guanidines; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D011724:Pyridazines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000209:etiology; D013312:Stress, Physiological / Q000150:complications; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives*
D006146:Guanidines; D011724:Pyridazines; D013890:Thiourea; C004711:dicyandiamido; D000109:Acetylcholine