Trials of phenanthrene opioids functionalization with hindered polycyclic carboxylic acids

In the last decades, the number of patients undergoing pain relief for chronic or degenerative diseases has observed a significant increase, also due to an increase in the average age of the population. Morphine, the widely used opioid in pain therapy, is known to produce over time tolerance with the appearance of hyperalgesia and allodynia, conditions which may affect patient compliance. These phenomena have been re-conducted to one of its metabolite, the 3-O-glucuronide (accounting in humans for 80% of the dose administered), which was found to be an effective neuro-excitatory and a potent activator of microglia, so resulting to be responsible of the development of both hyperalgesia and allodynia. Therefore, the inhibition of glucuronidation represents an interesting pharmacological target to achieve greater therapeutic efficacy by morphine and the synthesis of new active compounds useful in the pain control therapy is still in the limelight. In this context, we observed that codeine and some codeine derivatives (in particular the acetyl and pivaloyl esters) are able to inhibit the formation of morphine-3-O-glucuronide so, in continuation of the previous work, we projected new codeine derivatives as potential useful compounds in the modulation of morphine glucuronidation. In this paper, we report the optimization of the synthetic procedure to obtain codeine esters with hindered polycyclic carboxylic acids by using a suitable alcohol (allyl alcohol) with the same configuration of 6-OH function of the codeine skeleton. Together with the allyl ester derivatives of these acids also the 1-adamantaneacetic acid ester derivative of codeine (4), a new codeine derivative, was finally synthesized following the reported synthetic approach.