| This dissertation is about the study of synthesis and structure-activity relationship (SAR) of a new type of nonsteroidal anti-inflammatory agent, 3H-1,2-dihydro-1-pyrrolizinone compounds.The nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat many acute and chronic inflammations and moderate pain in clinic. Since sodium salicylate was used to treat rheumatoid arthritis around 120 years ago, scientists have carried out comprehensive researches on the NSAIDs both in theory and exploiting in order to strengthen their active potencies and reduce their toxicities. Many new NSAIDs have been developed, and now, NSAIDs have become the biggest family in all medicines and are widely used in clinic.In last century, the most outstanding achievement on the inflammation research was the elucidation of the relationship between inflammation and the metabolites of arachidonic acid (AA). Based on the mechanism, most anti-inflammatory agents currently used in clinic are active as the inhibitors of metabolites of AA. Several new types nonsteroidal anti-inflammatory agents have been developed in last 20 years, such as selective cyclooxygenase-2 (COX-2) inhibitor, 5-lipoxygenase (5-LO) inhibitor, COX/5-LO dual inhibitor, phospholipase A2 (PLA2) inhibitor. The discovery of COX-2 and the synthesis of many selective COX-2 inhibitors in last decade have added new energy to the developing of new anti-inflammatory agents. Recent years, several COX-2 inhibitors were launched, and were said that their gastrointestinal toxicities were lower. Nevertheless, the search of new anti-inflammatory andanalgesic agents with lower toxicities remains the dominating aim in this research field because all the present NSAIDs have some toxicity, and they are hard to be monitored and controlled in use.It has been found in our laboratory that derivatives of pyrrolizinone show marked anti-inflammatory and analgesic activities. Some compounds of the kind proved to be promising agents to develop new anti-inflammatory drugs. Based on the SAR summarized, the main aim of this research is to design new anti-inflammatory agents of pyrrolizinones with new type of structures, and search for more potential activity and low toxicity agents. Also this should add new rules to the SAR.It was found that the compounds of 2-aminomethyl, 5-aminomethyl and 5-acyl-pyrrolizinones have marked anti-inflammatory and analgesic activities. However, the substituted aminomethyl derivatives are instable, and their water-solubility is poor. So, 8 of 5-acyl and 5-alkylpyrrolizinones were synthesized. Instead of the aminomethyl and acyl, 5-aminosulfonyl and 5-amidopyrrolizinones were designed. So, 34 of 5-aminosulfonyl-pyrrolizinones, 3 of aminopyrrolizinones and 11 of 5-amidopyrrolizinones Were synthesized.Also 2-substituted derivatives of pyrrolizinone were designed since the substituents on 2 position of the pyrrolizinone were found to take important part in the activities. 20 of 2-alkylpyrrolizinones were synthesized. Totally, 76 compounds belonging to four series were synthesized, and 70 of them have not been found in literature.Some interesting chemical problems were found during the synthesis.Pyrrolizinone undergoes normal aldol condensation with aromatic aldehydes in aqueous sodium hydroxide at room temperature, but, with 2-phenylethanal, the reaction could not take place under same conditions. Heating the reaction solution, a reaction occurred, instead of the prospective product, two bimolecular self-condensation products of the pyrrolizinone were obtained. They are geometric isomers, and their configurations were primary evaluated by H-H NOESY: YZ-254 was designated as Z-isomer and YZ-255 as E-isomer.Pyrrolizinone treated with HNO3-Ac2O, three products were obtained with moderate yields. They are proved to be the isomers of nitropyrrolizinone, 5, 6 and 7-nitropyrrolizinone, and structure of each was determined by 1H-NMR. Reduced by catalytic hydrogenation, 5, 6and 7-aminopyrrolizinone were obtained. Aminopyrrole is unstable, but...
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