Studies on histamine H2 receptor antagonists. 2. Synthesis and pharmacological activities of N-sulfamoyl and N-sulfonyl amidine derivatives

A series of N-sulfamoyl and N-sulfonyl amidines have been prepared and tested in vitro for H2 antihistamine activity on guinea pig atrium. In addition, several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs. Structure-activity relat...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1987-10, Vol.30 (10), p.1787-1793
Main Authors: Yanagisawa, Isao, Hirata, Yasufumi, Ishii, Yoshio
Format: Article
Language:English
Subjects:
Amidines - chemical synthesis
Amidines - pharmacology
Animals
Chromatography, High Pressure Liquid
Dogs
Famotidine
Gastric Acid - drug effects
Gastric Acid - metabolism
Guinea Pigs
Heart - drug effects
Histamine H2 Antagonists - chemical synthesis
Histamine H2 Antagonists - pharmacology
Magnetic Resonance Spectroscopy
Models, Molecular
Structure-Activity Relationship
Thiazoles - chemical synthesis
Thiazoles - pharmacology
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Summary:A series of N-sulfamoyl and N-sulfonyl amidines have been prepared and tested in vitro for H2 antihistamine activity on guinea pig atrium. In addition, several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs. Structure-activity relationship studies showed that those compounds containing 2-[(diaminomethylene)amino]thiazole exhibited potent H2-receptor antagonist activity. Introduction of alkyl or aralkyl groups to the terminal nitrogen of the sulfamoyl moiety reduced biological activities. Sulfamoyl amidines were more potent in both tests than sulfonyl amidines. Of these compounds, 3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]- N2-sulfamoylpropionamidine (2e, famotidine) showed extremely high potency in both assays and was selected for clinical trials as an antiulcer agent. Acid-catalyzed hydrolysis of famotidine gave the sulfamoyl amide 6 at room temperature and the carboxylic acid 7 at elevated temperatures. 15N NMR spectrum showed that famotidine in solution existed in only one of several possible tautomers derived from the amidine and the guanidine moieties. Nitrosation of famotidine was performed under mild condition and proved to occur on the 5-position of the thiazole ring.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00393a018