Pyrrolizidine Synthesis And Analgesic Activity, Triazine And Quinoline Compounds

This dissertation reports a study on the synthesis and structure-activity relationships(SAR) of anti-inflammatory and analgesic effect of tetrahydropyrrolizino[2, 1-c]quinoline derivatives.Tetrahydropyrrolizino[2, 1-c]quinoline derivatives, discovered by Department of Organic Chemistry of Shenyang Pharmaceutical University during the research of anti-inflammatory and analgesic effective of pyrrolizinones, is a new types of heterocyclic compounds. The structural feature of these compounds is similar to morphine, especially to pethidine. Generally, these compounds show higher analgesic effective than pyrrolizinones, but weaker anti-inflammatory activity.Based on the SAR of tetrahydropyrrolizino[2,1-c]quinoline derivatives and opiumid analgesic agents, forty-six new tetrahydropyrrolizino[2,1-c]quinolines were designed and synthesized. Their structures have been confirmed by NMR, IR and MS. None of them has been reported in literature before.The configuration of Tetrahydropyrrolizino[2,1-c] quinolines has been studied on nuclear magnetic resonance spectrum and X-ray single crystal diffraction. They are supposed to be cis-configuration. The stereochemistry of cyclization reaction and its mechanism were preliminarily studied.The analgesic activities were tested in acetic acid-induced mice writhing. Pharmacological studies showed that most of the synthesized compounds have notable analgesic activities at a dose of 200mg/kg. Furthermore, the activities of compounds HR15, HR19, HR30, HR31 are comparable to morphine at a dose of 10mg/kg, deserving further study. Some SAR of these compounds was discussed in the dissertation.The calculation of comparative molecular field analysis(CoMFA) was carried out on an SGI IRIX workstation with Tripos' Syby16.91. The result was applied to analyze the SAR of the compounds. The results show that tetrahydropyrrolizino[2,1-c]quinoline should be a type of promising compound for developing new analgesic agents. The findings can be used as important reference information in the further research of these compounds.