Isocytosine H(2)-Receptor Histamine-Antagonists .4. The Synthesis And Biological-Activity Of Donetidine (Sk-And-F-93574) And Related-Compounds

The synthesis and biological activity of some novel 2-amino-4-pyrimidone derivatives is described. Side-chains associated with H-2-antagonist 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 activity is observed with all the series and the majority of the compounds are selective for the H-2-receptor. High aqueous solubility and iv potency coupled with an extended duration of biological activity in animal models led to compound 16c, 2-[2-(5-dimethylaminomethyl-2-furanylmethyl-thio)ethylamino]-5-(2-hydroxypyrid-4-ylmethyl)-4-pyrimidone (donetidine, SK&F 93574) being selected for clinical investigation as a potential parenterally administered therapeutic agent.