Synthesis of novel benzo[1,3]oxazines based on monoterpenoid (–)-isopulegol and study of their analgesic activity

1,3-Oxazines, six-membered heterocyclic compounds containing one nitrogen and one oxygen atom, have been of great interest to medicinal chemists in recent decades, due to the wide range of biological activity they exhibit, including anticancer, antibacterial, antifungal and etc. We found that the Ritter reaction between monoterpenoid (–)-isopulegol and a number of aliphatic and aromatic nitriles in the presence of concentrated sulfuric acid led to a series of chiral 1,3-oxazine derivatives with 35–80 % yields. Carrying out the reaction of (–)-isopulegol with benzyl cyanide in the presence of CF₃SO₃H made it possible to increase the yield of the product from 40 %, achieved in the presence of H₂SO₄, to 60 %. Development of new analgesic agents with high activity and low toxicity is very important task. It is known that the heterocyclic compounds synthesized from (–)-isopulegol exhibit analgesic activity. When studying the analgesic activity of the synthesized compounds in vivo, it was found that 1,3-oxazine at a dose of 10 mg/kg exhibited high analgesic activity reliably increasing the latent time of animals being on the hot plate and not inferior in efficiency to the reference drug sodium diclofenac administered at a similar dose.