Study On Synthesis And Anti-inflammatory Activity Of Oxazine Derivatives

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs in the world. The major disadvantage of these drugs in long-term use is gastrotoxicity, thus design and research of new drugs free from gastric toxicity, heart attack and myocardial infarction becomes one of the great strategies for new drug discovery. In our previous work, we find some compounds such as 4-chromanones, 4-chromones and isoflavones exhibit anti-inflammatory. In this paper, the classification, mechanisms of action and development of anti-inflammatory drugs were summarized, and the anti-inflammatory activities of derivatives of 4-chromones, 4-chromanones and isoflavones were introduced.The Mannich base at 3-position of 4-chromanones synthesized in our laboratory exhibits the significant anti-inflammatory activity. On the base of our previous work, aminomethylation of 2’,4’-dihydroxyacetophenone, mono hydroxy-substituted 4-chromanone, chromone and isoflavone derivatives followed by cyclization was designed to yield 1,3-oxazine derivatives which include seven of 1,3-benzoxazines, fifteen of chromeno[8,7-e][1,3]oxazine-4-ones, and four of chromeno[5,6-e][1,3]oxazine-10-ones, and all of them were characterized by ~1H-NMR, EI-MS and IR. The heterocyclic chromeno[8,7-e][1,3]oxazine-4-one scaffold and chromeno[5,6-e][1,3] oxazine-10-one scaffold are the novel heterocyclic systems which are not reported in the literature based on search by SciFinder and other database.The reaction of 2’,4’-dihydroxyacetophenone and formaldehyde with a primary amine in a ratio 1:2:1 yielded 3-aryl-3,4-dihydro-5-hydroxy-6-acetyl-2H- 1,3-benzoxazine, not 3-aryl-3,4-dihydro-5-hydroxy-8-acetyl-2H-1,3-benzoxazine reported in literature.Using the inflammatory model of ear edema induced by croton oil in mice, the anti-inflammatory activity of 13 target compounds was tested. According to screening results, 9-(4-chlorophenyl)-2,3,4,8,9,10-hexahydrochromeno [8,7-e] [ 1,3] oxazine-4-one(WY- 11), 9-benzyl-2,3,4,8,9,10-hexahydrochromeno [8,7-e] [1,3]oxazine-4-one(WY- 14), 9-(2-chlorophenyl)-4,8,9,10-tetrahydrochromeno [8,7-e] [1,3] oxazine-4-one(WY- 18), 2-(4-methylphenyl)- 1,2,3,10-tetrahydrochromeno [5,6-e] [1,3] oxazine-10-one(WY-21), showed potent anti-inflammatory activity (P＜0.05).