Synthesis and analgesic properties of some conformationally restricted analogues of profadol.

P A Crooks, R Szyndler

Journal of medicinal chemistry 1980 Jun

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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.

Citation

P A Crooks, R Szyndler. Synthesis and analgesic properties of some conformationally restricted analogues of profadol. Journal of medicinal chemistry. 1980 Jun;23(6):679-82