Antiulcer Agents. III. Synthesis and Antiulcer Activity of N-[3-(3-Piperidinomethylphenoxy)propyl]pentacyclo[4.2.0.02, 5.03, 8.04, 7]-octane Carboxamides and Related Compounds

• Published in: Chemical & pharmaceutical bulletin Vol. 41; no. 10; pp. 1760 - 1768
• Main Authors: HASEGAWA, Takeshi, NIGO, Tomohiro, KAKITA, Takao, TOYODA, Hiromu, TOYA, Harumasa, UEDA, Ikuo
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.10.1993; Maruzen; Japan Science and Technology Agency
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Animals; Anti-Ulcer Agents - chemical synthesis; Anti-Ulcer Agents - pharmacology; antiulcer activity; Bridged-Ring Compounds - chemical synthesis; Bridged-Ring Compounds - pharmacology; Chemistry; cubane; cytoprotective action; Exact sciences and technology; Gastric Acid - metabolism; highly strained cage compound; homocubane; Magnetic Resonance Spectroscopy; Male; N-[3-(3-piperidinomethylphenoxy)propyl]pentacyclooctane carboxamide; Organic chemistry; Preparations and properties; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Hydrochloric acid; Pentacyclic compound; Prevention; Acetal; Cage compound; Cytoprotector; Ethanol; Structure activity relation; Saturated compound; Carboxamide; Antiulcer agent
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.41.1760

The synthesis and antiulcer activity of highly strained cage compounds such as pentacyclo[4.2.0.02, 5.03, 8.04, 7]-octane (cubane), pentacyclo[4.3.0.02, 5.03, 8.04, 7]nonane (homocubane) and pentacyclo[5.3.0.02, 4.03, 6.0<5, 8>]decane are described. Of the compounds obtained, N-[3-(3-piperidinomethylphenoxy)propyl]-4-piperidinocarbonylpentacyclo[4.2.0.02, 5.03, 8.0<4, 7>]octane carboxamide (26a) and N-[3'-(3'-piperidinomethylphenoxy)propyl]-1-bromo-9, 9-ethylenedioxypentacyclo[4.3.0.02, 5.03, 8.04, 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.