Studies on New Antiulcer Agents. I. Synthesis and Antisecretory Activity of Pyridazine Derivatives

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The pyridine ring of 2-phenyl-2-(2-pyridyl) thioacetamide (Ia), the lead compound for the present study, was replaced by a pyridazine ring in the hope of obtaining more potent and less toxic drugs with long-lasting action, and a series of 2-phenyl-2-(3-pyridazinyl) thioacetamide derivatives (II) was synthesized from halopyridazines (III) and phenyl-acetonitriles via the key intermediates, 2-phenyl-2-(3-pyridazinyl) acetonitrile derivatives (IV). The chemical structure of II appears to be in equilibrium between the pyridazine form and the pyridazinone-methide form on the basis of nuclear magnetic resonance (NMR) and ultraviolet (UV) spectral data. The antisecretory activity and acute toxicity of II were investigated and the structure-activity relationships are discussed. Among the compounds tested, 2-Phenyl-2-(3-pyridazinyl) thioacetamide (IIa) and 2-(6-methyl-3-pyridazinyl)-2-phenylthioacetamide (IIb) possessed long-lasting, potent activity when administered to rats at 20 mg/kg. The acute toxicities of IIa and IIb were about half to one-third of that of Ia in mice.
1981-12-25