Synthesis Of Nitrogen-containing Bisphosphonate Derivatives Based On The Michael Reaction

As China gradually entering the stage of aging, osteoporosis has become multiple diseases among elderly patients. In addition, the tumors as well as various viral diseases are the main cause of human death in our country. These invisible killers have been paid widespread attentions and have turned into a global problem of health.Bisphosphonates (BPs) and their ester derivatives have been widely used clinically for the treatment of osteoporosis, Paget’s inflammation and various diseases caused by bone metastases etc.. The research on bisphosphonates is one of the most important issues in the field of Biochemistry. The structure-activity relationship study of bisphosphonates showed that the side chain containing a nitrogen atom, especially nitrogen heterocyclic, could enhance drug’s biological activity. As a named organic reaction, Michael addition reaction is one of the efficient methods for synthesis of bisphosphonate derivatives with the side chain containing nitrogen.. We made the structural modification about the amine compounds to synthesize bis-phosphonate derivatives using Michael addition reaction, based on the principle of drug design.The specific research contents are as follows.In chapter1of this paper, the biological activity and the synthetic methods of bisphosphonate derivatives were reviewed. Then in chapter2, the Michael addition reaction between aniline and ethenylidenebisphosphonates was selected as a model reaction in order to explore the optimal reaction conditions. The results showed that the best yield of the product would be obtained if the reaction conditions were as follows:solvents (CHCl3), temperature (65℃), and time (6h). To study the activity effect of different nitrogen atom compounds,12bisphosphhonate derivatives were synthesized from aromatic primary amine and ethenylidene bisphosphonates in the optimal reaction conditions. These compounds were characterized by IR, and NMR and the structures of compound1-1was further confirmed by X-ray diffraction. The bisphosphonate derivatives were investigated through the electrospray ionization tandem mass spectrometry (ESI-MS), The characteristic fragment was summarized:. The selective reactivity of Michael addition reaction between-SH or-NH2group in the same substrute and ethenylidene bisphosphonates were further discussed in chapter2.In chapter3and4, the optimal reaction conditions established in chapter2was applied to the synthesis of8bisphosphonate derivatives obtained from aromatic secondary amines or amides with ethenylidene bisphosphonates. Nucleoside drugs, which have good antiviral activities, have been used to treat AIDS and other diseases on the clinical.6nucleoside bisphosphonate derivatives were further synthesized. These compounds were characterized by IR, and NMR. The bisphosphonate derivatives were investigated through the electrospray ionization tandem mass spectrometry (ESI-MS), The characteristic fragment was summarized. Because the starting matiral of quinoxaline (3-g) has a possible opportunity of tautomerism, the structure of the target compound was further confirmed by2D NMR.