Cross‐Coupling‐Cyclocondensation Reaction Sequence to Access a Library of Ring‐C Bridged Pyrimidino‐tetrahydrothebaines and Pyrimidinotetrahydrooripavines

Abstract

Ring‐C bridged 1‐(pyrimidinyl)tetrahydrothebaines were convenience synthesized by a consecutive three‐component alkynylation–cyclocondensation sequence starting from 1‐ethynyl‐7α,8α‐(2,5‐dioxo‐N‐phenylpyrrolidino)‐[3,4‐h]‐6,14‐endo‐etheno‐tetrahydrothebaine, aroyl chlorides, and amidinium hydrochlorides. Several derivatizations and transformations of selected 1‐pyrimidinyl substituted tetrahydrothebaines were carried out. The analgesic activity of new type of hybrid compounds in the tail‐flick test in rats was evaluated. The data revealed that the antinociceptive potency was stroungly depended on the nature of the substituent in the C‐6 position of the pyrimidine nucleus. Docking study was undertaken to gain insight into the possible binding mode with the μ‐opioid receptor.

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

“…The 18R-hydroxy (185, 46%) and 19S-hydroxy (186, 43%) isomers were separated by preparative TLC, and the structure of the 18R-hydroxy compound (185) was verified by X-ray analysis. Selective protection of the least hindered 7α-hydroxymethyl group of the 19-OH compound (186) via benzylation provided the 7α-benzyloxymethyl derivative (188).…”

“…For the successful 6-O-demethylations, an OR (R = H, alkoxy) or an NH 2 group was required in the 20 position. Shults et al [187,188] investigated the O-demethylation reactions of thebaine-succinimide adducts with boron tribromide, in which demethylation of alkyl methyl ether (6-O-demethylation) and/or demethylation of aryl methyl ether (3-O-demethylation) was observed, depending on the character of the substrate. Coop et al [159] reported on the unusual 6-O-demethylation of 20-methylthevinol through hydroboration (BH 3 /H 2 O 2 ), whereas Husbands et al studied the reactions of buprenorphine (96) with N-halosuccinimide derivatives in an acidic milieu [189].…”

“…Recently, the Shults research group [188] thoroughly investigated the feasibility of the introduction of various pyrimidine substituents in the position one of the morphinan aromatic A-ring. From a pharmacologically convergent point of view, the pharmacophore 2-substituted 4-arylpyrimidine group with adenosine receptor antagonist properties was combined with a 6,14-ethenomorphinan scaffold.…”

“…The analgesic activity of selected compounds (440, 442, R 1 = CH 3 , X = F, Br, OCH 3 ) was evaluated in the rat tail-flick test after intraperitoneal (i.p.) administration [188]. The authors concluded that the antinociceptive potency of the 1-pyrimidin-4-yl derivatives (442, R 1 = CH 3 , X = F, Br, and OCH 3 ) depended heavily on the character of the substituent introduced in position six of the pyrimidine ring.…”