Organic Chemistry: Current Research
Open Access

Synthesis of 6-oxomorphinan derived novel C-heterocycle-fused compounds: Potential compounds with mixed opioid receptor binding profile

10^th European Organic Chemistry Congress

March 21-22, 2019 | Rome, Italy

Mate J. Vajda and Sandor Hosztafi

Semmelweis University, Hungary

Posters & Accepted Abstracts: Organic Chem Curr Res

Abstract :

Introduction: Opioids are generally used in medicine as the most potent analgesics. Besides their ability to relieve pain, the currently used analgesics have serious side-effects such as respiratory depression, constipation, development of tolerance, physical dependence and addiction liabilities. It is also well known that modulation of the endogen opioid system plays a key role in psychological and behavioral responses, such as feeling of content, motivation and positive reinforcement (reward). One possible approach in developing agents which possess potent analgesic properties without the undesired side-effects is to create compounds with mixed receptor binding profile. It has been proven that DOR agonists can significantly increase the efficacy of MOR agonists, thus the effective dose can be significantly lowered. DOR antagonists can prevent or diminish the development of tolerance and physical dependence by MOR agonists. Based on several previous reports of heterocycle-fused morphinan compounds through the C-ring (emphasizing oxymorphazole, an oxymorphone derived 6,7:3’,4’-pyrazolomorphinan), a great number of them shows the desired receptor binding profiles as described.

Aims: Our goal in the first part of work is the synthesis of a series of substituted oxycodone, oxymorphone and hydrocodone derived pyrazolo- and isoxazolomorphinans, structural characterization with NMR spectroscopy and in vitro biological evaluation through opioid receptor binding assays. Later we are planning to synthesize the compound series with antagonist starting materials, like naloxone and naltrexone.

Method: For the building of unsubstituted pyrazolo- and isoxazolomorphinan skeletons, we utilized N,Ndimethylformamide dimethyl acetal, a one carbon atom building block commonly used in heterocyclic chemistry, to synthesize 7-(N,N-dimethylaminomethylene)morphinan intermediates. For substituted compounds we synthetized 14-O-acylated compounds using acetyl, propionyl- and benzoyl-anhydride, and used the 14-O → 7-C acyl migration method reported by Nagase and Portoghese (1990) to create the 1,3-dioxo intermediates. The initial purity examination was carried out using thin-layer chromatography, for full structural evaluation and confirmation Varian 600 MHz NMR Spectometer was used for the recording of 1H, 13C, g-HMBCAD and g-HSQCAD spectra, as well as mass spectrometry.

Results: So far by the date of the abstract submission 15 end product have been synthesized with high purity out of the planed 18.

Conclusion: As the work is not finished yet, biological data is not yet available about the synthetized products, although based on similar structural moieties of previously reported compounds it is likely that some of our molecules may exhibit the desired receptor binding profile and may be a valuable compounds for opioid drug design with better side-effect profile.

Biography :

Mate J. Vajda has graduated in 2017 at Semmelweis University, Hungary as a pharmacist. He’s currently a PhD Student at the Department of Pharmaceutical Chemistry of Semmelweis University. He’s research field is opioid chemistry, especially research and development of novel analgesics with interesting and clinically relevant pharmacological profile. His work has been awarded at the Hungarian Scientific Days in 2018. Beside scientific work, he also works in pharmacies in his hometown.