Synthesis and histamine H2-receptor antagonist activity of 4-(1-pyrazolyl)butanamides, guanidinopyrazoles, and related compounds

Article abstract of DOI:10.1002/ardp.19953280411

A series of 4-(1-pyrazolyl)butanamides, pyrazolylalkyl cyanoguanidines, and related compounds with diverse functional groups (e.g. nitro, amino, guanidino groups) in the 3-position of the pyrazole ring was prepared via 4-(3-nitro-1-pyrazolyl)butanenitrile (5) and the corresponding carboxylic acid 7 as central intermediates. The amides 9a-d were prepared from the primary amines 8a-d which represent partial structures of the H₂-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine. The roxatidine-derived 4-(3-nitro-1-pyrazolyl)butanamide (9a) proved to be the compound with the highest H₂-receptor antagonist activity of 23 compounds tested at the isolated guinea pig right atrium preparation, achieving about 6 times famotidine's or 160 times cimetidine's potency. By contrast, in Ghosh-Schild rats 9a did not inhibit histamine-stimulated gastric acid secretion at a dosage of 0.1 μmol/kg i.v. Compounds 20a (the 3-(trifluoroethylguanidino)pyrazole analogue of 9a, 12a (the cyanoguanidine analogue) and N-{4-[3-(trifluoroethylguanidino)-1-pyrazolyl]butyl}cyanoguanidine (29), which are about as active as famotidine in the atrium, turned out to be very potent inhibitors of gastric acid secretion as well (e.g., 29: 74% inhibition at 0.025 μmol/kg). These compounds are comparable to famotidine in the rat stomach and by far superior to cimetidine and ranitidine in this test system.