Synthesis and analgesic properties of some conformationally restricted analogues of profadol.
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.
D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D051379:Mice; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000700:Analgesics; D011759:Pyrrolidines