Synthesis and Histamine H 2 ‐Receptor Antagonist Activity of 4‐(1‐Pyrazolyl)butanamides, Guanidinopyrazoles, and Related Compounds

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 H 2 ‐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 H 2 ‐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.