Antiulcer Agents. III. Synthesis and Antiulcer Activity of N-[3-(3-Piperidinomethylphenoxy)propyl]pentacyclo[4.2.0.0^{2, 5}.0^{3, 8}.0^{4, 7}]-octane Carboxamides and Related Compounds

Abstract

The synthesis and antiulcer activity of highly strained cage compounds such as pentacyclo[4.2.0.0^{2, 5}.0^{3, 8}.0^{4, 7}]-octane (cubane), pentacyclo[4.3.0.0^{2, 5}.0^{3, 8}.0^{4, 7}]nonane (homocubane) and pentacyclo[5.3.0.0^{2, 4}.0^{3, 6}.0<5, 8>]decane are described. Of the compounds obtained, N-[3-(3-piperidinomethylphenoxy)propyl]-4-piperidinocarbonylpentacyclo[4.2.0.0^{2, 5}.0^{3, 8}.0<4, 7>]octane carboxamide (26a) and N-[3'-(3'-piperidinomethylphenoxy)propyl]-1-bromo-9, 9-ethylenedioxypentacyclo[4.3.0.0^{2, 5}.0^{3, 8}.0^{4, 7}]nonane]-4-carboxamide (26q) showed more potent antiulcer activity with very good cytoprotective ability in the HCl·ethanol-treated rat model. Compounds 26a and 26q exhibited H₂-receptor antagonist potency (in vitro) comparable to that of ranitidine, but did not inhibit histamine-stimulated acid secretion (in vivo) in the gastric fistula rat model, when orally administered in the dose range at which antiulcer and cytoprotective activities were seen. The structure-activity relationships are discussed.