PhD Scientific Days 2026

Poster Session 1.F - Pharmaceutical Sciences and Health Technologies

Synthesis and characterization of novel noropiates containing amides and amines in the nitrogen substituent

Name of the presenter

Simon, Balázs

Institute/workplace of the presenter

Department of Pharmaceutical Chemistry, Semmelweis University

Authors

Balázs Simon¹
1: Department of Pharmaceutical Chemistry, Semmelweis University

Text of the abstract

Introduction
Chronic pain is one of the most debilitating medical issues, and treatment to this day is still suffers from many problems. Opiates are the best known group of compounds used to treat this condition, but their drawbacks are numerous. The substituent of the nitrogen in the morphinan skeleton can alter the biological behaviour of these compounds significantly. Heteroatom containing substituents can alter the way the compound interacts with the opioid receptors, which can prove advantageous.
Aims
We aimed to synthetize and characterize as many as possible amine or amide containing derivatives of morphine and other natural and semisynthetic opiates. We used codeine as a model substance to get a better understandning of the reaction set.
Method
Norpoiates were synthetized from the appropriate starting material using 1-chloroethyl chloroformate. Primary amines were acquired through the alkylation of the noropiates with trifluoroacetamide-protected bromoalkylamines, followed by the basic hydrolysis of the protecting group. Tertiary amines were reached with alkylation reactions as well. Carboxyethyl-noropiates were synthetized through the addition of ethyl acrylate to the starting material, in the presence of triethylamine. The resulting ester was then hydrolyzed with base. Amide formation was either mediated with HATU and diisopropyl-ethylamine in an appropriate solvent (usually dichloromethane, but acetonitrile and dimethylformamide were also used), or were done with the similar reaction with TCFH in the presence of N-methylimidazole. Characterization of the compounds was carried out with NMR spectroscopy and LC-MS techniques.
Results:
12 amines and 33 amides were already synthetized and characterized. The HATU mediated coupling was more successful, when the amine-bearing partner was the opiate, while in the reversed reaction, TCFC proved superior. For primary amines, other protecting groups and reaction conditions were also trialed, without much succes. Yields were ranging from 20% (in the case of N,N-dimethyl-2-chloro-ethylamine) to 95% (in some of the amide couplings between N-aminoalkyl-norcodeines and hippuric acid).
Conclusion
Many derivatives are already succesfully prepared, but more work is needed to produce a library of compounds on which a definitive SAR study can be done.
Funding
No outside funding was received.