Synthesis and antinociceptive activity of long-known but unexplored nitro-fentanyl derivatives

Abstract

Fentanyl and related 4-anilidopiperidines are the most potent and clinically important analgesics for the treatment of severe acute and chronic pain. Many fentanyl derivatives have been made so far to obtain new analgesics with improved pharmacological profile. However, of simple nitro fentanyl derivatives only the meta isomer was reported, while ortho and para isomers proved to be synthetically challenging. We report here for the first time the synthesis of ortho and para-nitro-fentanyl. The most arduous step in the synthesis was the acylation of nitroaniline precursor, where the ortho and para positioned nitro group with strong electron-withdrawing and/or steric effects led to an extremely low nucleophilicity of anilino nitrogen. To address this problem electrophilic conditions had to be enhanced using strong acylating agent i.e. propionyl chloride or bromide, and bases such as Et₃N or pyridine in a polar, aprotic solvent such as N,N-dimethylformamide (DMF). Indeed, under these conditions, acylation step afforded title products in excellent yields. The in vivo pharmacological evaluation demonstrated that regioisomerism plays a role in the potency and the onset of action of these compounds. The ortho-nitro derivative emerged as the most effective analgesic, exhibiting approximately 50 times less potency than fentanyl, comparable to morphine. Furthermore, it demonstrated a faster onset of action than fentanyl while maintaining a similar duration of effect. These traits indicate that it may be well-suited for treating severe acute pain and breakthrough pain in chronic pain conditions. Ortho-nitro fentanyl is henceforth worthy of further evaluation in toxicity and safety pharmacology studies.