14-(Arylhydroxyamino)codeinones and derivatives as analgetics and antagonists

Diels-Alder reaction of thebaine (1) and N-(cyclopropylmethyl)northebaine with nitrosobenzene and p-fluoronitrosobenzene gave adducts [6,14-exo-(phenyloxyamino)codeine 6-methyl esther and derivatives, 2a-d] which yielded 14-(phenylhydroxyamino)codeinone and derivatives (3a-d) on acid hydrolysis. Rearrangement of 3 (NaOMe) afforded 5,14-exo-(phenyloxyamino)thebainone and derivatives (4a-d); reduction of 3 led to 14-(phenylamino)dihydrocodeinone and derivatives (5a-d). Thebaine also reacted with 1-halo-1-nitrosocyclohexane (halo = Cl, Br) and with benzohydroxamic acid under oxidizing conditions to give 14-(hydroxyamino)codeinone (6). All compounds, 3-6, were evaluated as analgetics and antagonists by the tail-flick, writhing, and Straub tail assays: compounds of types 3-5 were analgetics (N-Me), one-third to one-tenth as potent as morphine, or antagonists [N-(cyclopropylmethyl)], 50 to 100 times less potent than naloxone; 6 behaved as an antagonist in the tail-flick test but as an agonist in the other assays. Opiate receptor binding studies indicate that compounds of type 3 may be useful as opiate spin-label precursors.