Sándor Berényi

Recent developments in the chemistry of thebaine and its transformation products as pharmacological targets

The most practical synthetic routes to the preparation of as important pharmaceuticals as oxycodone, naloxone, naltrexone, nalbuphine and buprenorphine have utilized the alkaloid, thebaine, as a starting material. This review intends to focus on chemical transformations of morphinans which resulted in morphinandiene derivatives with well-established and novel pharmacological potencies. These chemical transformations were mainly associated with the formation and substitution of the unique diene structure of the ring C of the morphinan backbone.

A new and efficient one-pot synthesis of apomorphine and its ring-A halogenated derivatives

Abstract Rearrangement and O-demethylation of codeine (2) and various 6-demethoxythebaine derivatives 6–11 with morphinane skeletone into apomorphine (3) and its halogenated derivatives 20–24 could be efficiently executed in a one-pot operation, by treatment with methanesulfonic acid/methionine.

Synthesis and neuropharmacological characterization of 2-O-substituted apomorphines

We have synthesized novel 2-O-substituted apomorphines with both different lengths of lipophilic alkyl chains and alkyl chains carrying free hydroxyl groups. Two bis-apomorphines formed as side products of the reactions with diols were isolated and characterized as well. The neuropharmacological profile of all these new compounds were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. The obtained data pointed to the fact that, in the examination of dopaminergic activities of 2-substituted apomorphines, the lipophilicity of the substituent is more important than its spatial parameters.

Synthesis and neuropharmacological evaluation of 2-aryl-and alkylapomorphines

A novel synthesis has been elaborated for the pharmacologically remarkable 2-arylapomorphines described and characterized in the last few years. This new procedure contains two alternative synthetic routes and has allowed the preparation of several hitherto unknown compounds as well. The pharmacological profile of the previously published and the novel 2-alkyl- and arylapomorphines has been determined with the application of in vitro and in vivo techniques. For 2-phenyl- (2) and 2-(4-hydroxyphenyl)apomorphines (3) the superior dopamine agonist profile has been confirmed and for the novel compounds some remarkable results have been observed.

Rearrangement of morphinandienes in methanesulfonic acid

Besides 2-fluoroapocodeine 7, the methanesulfonic acid-induced rearrangement of 6-fluoro-6-demethoxythebaine 2 gave the C-2 substituted apocodeines 8,11 and 20. Analogous rearrangement of thebaine 1 in the presence of alcohols offers a convenient and high-yielding route to the 2-alkoxymorphothebaine 6, 11, 12 and 13. Formation of the products has been explained in terms of nucleophilic substitution of the cationic intermediates 21 and 22 from the acid-catalysed reaction.

Synthesis of C-3 Halogene-Substituted Apocodeines and Apomorphines

Abstract A new effective method has been elaborated for the preparation of the hitherto unknown C-3 halogene derivatives (Cl, Br) of apocodeine and apomorphine, as well as of their N-demethyl-N-substituted (N-propyl, N-alkyl) analogues. These compounds are expected to possess an effect on the dopamine receptor system.

N-Substituted-2-alkyl- and 2-arylnorapomorphines: novel, highly active D2 agonists.

Two synthesis routes have been elaborated for the preparation of novel N-substituted-2-alkyl- and 2-arylnorapomorphines. The first one utilizes the traditional methodology of N-substitution of morphinans before acid-catalyzed rearrangements into aporphinoids, while our new approach involves the N-substitution directly on the aporphine backbone. The aimed compounds were obtained in similar overall yields in different synthesis routes and were investigated with respect to their binding affinities and activities to dopamine D(2) and D(1) receptors. These studies revealed remarkable affinity and selectivity of some compounds for D(2) over D(1) receptor subtypes. Partial or full agonist properties were confirmed for all tested compounds.

A new efficient method for the preparation of 2-fluoro-N-propylnorapomorphine

A new synthesis of the highly efficient, selective dopamine D2 agonist, 2-fluoro-N-propylnorapomorphine 1 has been accomplished, involving the transformation of thebaine 13 into 6-fluoro-6-demethoxythebaine 10, followed by sequential N-demethylation, N-alkylation, rearrangement with methanesulfonic acid into the apocodeine derivative 17, and subsequent O-demethylation with boron tribromide.

Microwave-Promoted Acid-Catalyzed Rearrangement of Morphinans : A High-Yield Synthesis of R(-)-Apomorphine

Abstract The microwave‐promoted acid‐catalyzed rearrangement of morphine (1), codeine (2), and thebaine (3) was investigated. In all cases, a significant improvement in the yields were achieved compared to the traditional techniques. R(‐)‐Apomorphine (4), which is a clinically important dopamine agonist, was synthesized from morphine (1) in 75% yield.

Novel Route to 2‐Arylapomorphines

Abstract The synthesis of 2‐arylapomorphines (1, 2) has been accomplished using a new method involving a Suzuki‐type cross‐coupling reaction of 2‐bromoapocodeine (8) and arylboronic acids.