Subject(s)
Anisomycin , Antifungal Agents , Ascomycota/metabolism , Pyrrolidines , Anisomycin/analogs & derivatives , Anisomycin/biosynthesis , Anisomycin/pharmacology , Antifungal Agents/biosynthesis , Antifungal Agents/pharmacology , Candida/drug effects , Chromatography, Thin Layer , Fermentation , Fungi/drug effects , Isomerism , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure , Pyrrolidines/analogs & derivatives , Pyrrolidines/biosynthesis , Pyrrolidines/pharmacologyABSTRACT
Aromatic hydroxylated derivatives of spiro[indan-1,3'-pyrrolidine], designed as conformationally restricted analogs of profadol, were synthesized and pharmacologically evaluated in mice for analgesia and other central nervous system activities. None of the compounds synthesized were as potent as profadol in writhing and hot plate tests, but the 4-hydroxy derivative exhibited codeine-level analgesia in the tests.
Subject(s)
Analgesics/chemical synthesis , Pyrrolidines/pharmacology , Animals , Anticonvulsants/chemical synthesis , Body Temperature/drug effects , Chemical Phenomena , Chemistry , Mice , Molecular Conformation , Motor Activity/drug effects , Postural Balance/drug effects , Pyrrolidines/analogs & derivativesABSTRACT
N-Methylspiro[5-hydroxytetralin-1,3'-pyrrolidine] (2j) and N-methylspiro[7-hydroxytetralin-1,3'-pyrrolidine] (2n), conformationally restricted analogues of profadol, were synthesized via initial reaction of the appropriately substituted 1-tetralone with ethyl cyanoacetate to give the ethyl 1-tetralylidenecyanoacetate derivative (3), which was then reacted with KCN to give the corresponding 1-cyano-1-(cyanomethyl)tetralin (4). Treatment of 4 with either HBr in dry ether-dichloromethane or acetic acid-sulfuric acid afforded the spiro[tetralin-1,3'-pyrrolidine-2',5'-dione] derivative (5), which was then reduced with LiAlH4-THF and N-methylated with HCHO-HCO2H to give the appropriately substituted spiro[tetralin-1,3'-pyrrolidine] (2). Both 2j and 2n and the isomeric 6-hydroxy derivative 21 all showed no significant analgesic activity in hot-plate and writhing tests. However, spiro[tetralin-1,3'-pyrrolidine] (2a) and its N-methyl derivative (2b) both possessed codeine-level analgesic activity.
