Study Of Synthesis And Anti-inflammation Of 1-Pyrrolizinones

The synthesis and structure-activity relationship (SAR) of the novel nonsteroidal anti-inflammatory agents, 1H-2,3-dihydro-l-pyrrolizinones are studied in this dissertation.Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of acute and chronic inflammation and moderate pain. However, most of NSAIDs used in clinic now tend to induce gastrointestinal damage, nephrotoxicity and hepatotoxicity. Therefore, the discovery of novel anti-inflammatory and analgesic agents with lower toxicities has been an important research field.It has been found that pyrrolizinones showed remarkable anti-inflammatory and analgesic activities. Based on the SAR of anti-inflammatory and analgesic activities of pyrrolizinones summarized before, three types of new pyrrolizinones were designed and synthesized for further study of the SAR. The new pyrrolizinones are thirty-four aminocarbonylpyrrolizinones, nineteen 5-amidopyrrolizinones and three pyrrolizinone-5-carboxylic esters. Among them, fifty-three compounds were not found in literatures.With trichloroacetylpyrrolizinone as starting materials, a new synthetic scheme was developed for the synthesis of 5-aminocarbonylpyrrolizinones. Trichloroacetylpyrrolizinone can be transformed to amides directly by aminolysis. It can also be hydrolyzed into l,2-dihydro-l-pyrrolizinone-5-carboxilic acid, and then, chlorinated, acylated into 5-aminocarbonylpyrrolizinones. Also a facile scheme was designed for the synthesis of 5-aminopyrrolizinone, the key intermediate for the synthesis of 5-aroylaminopyrrolizinones.Anti-inflammatory and analgesic activities were evaluated with xylene-induced ear edema and acetic acid-induced writhing in mice, respectively. The results showed that mostof the compounds prepared had notably anti-inflammatory and/or analgesic activities. The anti-inflammatory and analgesic activities of compounds ZS408, ZS424, ZS425, ZS430, ZS431 and ZS453 were comparable to ibuprofen, the positive control. Therefore, they are regarded as valuable compounds for further study to develop new anti-inflammatory agents.In the acute ulcerogenic test in rats, 5-aminopyrrolizinone (YZ240) did not cause any ulcer. The compound, ZS453 formed by combinating YZ240 and ibuprofen did not cause any ulcer, too. Excitingly, the anti-inflammatory and analgesic activities of ZS453 are stronger than ibuprofen.Some new SAR of pyrrolizinones have been summarized. For aminocarbonylpyrrolizinones, o-substituted phenylamino derivatives showed stronger anti-inflammatory and analgesic activities than m- or p- substituted phenylamino derivatives. Anti-inflammatory and analgesic activities remarkably increase when N atom of amide has an alkyl group.Three dimensional quantitative structure-activity relationship (3D-QSAR) of the compounds prepared was studied with Comparative molecular field analysis (CoMFA). The results suggest that 5-amido derivatives are superior to 5-aminocarbonyl derivatives in augmenting anti-inflammatory and analgesic activities; o-substituted phenyl of 5-amido and 5-aminocarbonyl derivatives tend to increase anti-inflammatory and analgesic activities.In conclusion, most of the compounds prepared have definite anti-inflammatory and analgesic activities, and some of them are promising for developing new anti-inflammatory and analgesic agents.