Synthesis And Anti-Inflammatory And Analgesic Activities Of Pyrrolopyrazinone Derivatives

The synthesis and structure-activity relationship (SAR) of the novel nonsteroidal anti-inflammatory agents, pyrrolo[l,2-a]pyrazine-1-one derivatives were reported in this dissertation.Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of acute and chronic inflammation, and moderate pain in clinic. However, most of traditional NSAIDs could lead to the gastrointestinal damage, nephrotoxicity and hepatotoxicity. Therefore, it has been the interest in this research field to develop novel anti-inflammatory and analgesic agents with low toxicity.Since the study of the inflammatory mechanism has made great achievements in last century, great progresses on the research of NSAIDs have also been achieved recent years. Many novel anti-inflammatory agents with new anti-inflammatory mechanism have been developed, such as selective inhibitors of cyclooxygenase-2 (COX-2), dual inhibitors of cyclooxygenase and 5-lipoxygenase (COX/5-LOX) and nitric oxide-releasing NSAIDs (NO-NSAIDs), and so on. Some of them have been applied in clinic.It has been found that some pyrazinones showed remarkable anti-inflammatory and analgesic activities. Based on the SAR of pyrazinones and their analogues reported in our laboratory, three types of pyrazinones were designed and synthesized for further study of the SAR. Fifty-three new pyrazinone derivatives were prepared, including twenty-one 3-aryl-2-methyl-l-pyrrolo[l,2-a]pyrazinones, eleven 3-aryl-3,4-dihydro-2-methyl-l-pyrrolo[l,2-a]pyrazinones and twenty-one 3,4-diaryl-2-methyl-l-pyr-rolo[l,2-a]pyrazinones. Among them, fifty-three compounds have not been found inliteratures.With arylethanones and methyl pyrrole-2-carboxylate as starting materials, a new synthetic scheme was designed for the preparation of 3-aryl-2-methyl-1-pyrrolo[l,2-a] pyrazinones. An improved scheme was also found for the synthesis of 3,4-diaryl-2-me-thyl-l-pyrrolo[l,2-a]pyrazinones, in which phosphoric acid was found to be a powerful catalyst for the cyclization.Anti-inflammatory and analgesic activities were evaluated with xylene-induced ear edema and acetic acid-induced writhing in mice, respectively. The results show that most of the prepared compounds have notable anti-inflammatory and/or analgesic activities at a dose of 200mg/kg. The activities of compounds ZWF-506, ZWF-516, ZWF-518, ZWF-519, ZWF-526, ZWF-529, ZWF-539, ZWF-545 and ZWF-552 are comparable to ibuprofen, the positive control. Therefore, they could be regarded as valuable compounds for further study to develop novel anti-inflammatory and analgesic agents.Some new SAR is found from the results of pharmacological tests above. For 3-aryl-2-methyl-l-pyrrolo[l,2-a] pyrazinones, the substitutes of the benzene ring take an important part in anti-inflammatory and analgesic activities. ZWF-516 and ZWF-519 showed the most remarkable activities among all the compounds. Anti-inflammatory activities of 3,4-diaryl-2-methyl-l-pyrrolo[l,2-a]pyrazinones were lower than those of 3-aryl-2-methyl-l-pyrrolo[l,2-a] pyrazinones. This indicates that the aryl substitutes at 4 position of the pyrazinone ring make unfavourable contribution to anti-inflammatory activities.Three dimensional quantitative structure-activity relationship (3D-QSAR) was studied with Comparative Molecular Field Analysis (CoMFA).In conclusion, some new structure-activity relationship of anti-inflammatory and analgesic activities of pyrazinones is found, and these would be helpful for further studies in this field.