ISOCYTOSINE H(2)-RECEPTOR HISTAMINE-ANTAGONISTS .4. THE SYNTHESIS ANDBIOLOGICAL-ACTIVITY OF DONETIDINE (SK-AND-F-93574) AND RELATED-COMPOUNDS

The synthesis and biological activity of some novel 2-amino-4-pyrimido ne derivatives is described. Side-chains associated with H-2-antagonis t activity am attached through the 2-amino group, whilst a range of 2- hydroxypyridine containing moieties are substituted at the 5-position of the pyrimidone ring. Good H-2-receptor histamine antagonist activit y is observed with all the series and the majority of the compounds ar e selective for the H-2-receptor. High aqueous solubility and iv poten cy coupled with an extended duration of biological activity in animal models led to compound 16c, lamino]-5-(2-hydroxypyrid-4-ylmethyl)-4-py rimidone (donetidine, SK&F 93574) being selected for clinical investig ation as a potential parenterally administered therapeutic agent.