Synthesis Of Malonamide Derivatives And Urea Derivatives As The Key Intermediates Of Micromolecular C-Met Kinase Inhibitor

Malignant tumor is a serious threat to the mankind and the therapy of it is still the most issue in the world. The drugs of antitumor mostly are cytotoxic drugs, which are toxic and easier to form drug resistance. Recently, with the development of molecular biological techniques and the cellular and molecular understanding of the pathogenic mechanism of cancer, the research of the drugs of the antitumor has been target to particular cells.Protein tyrosine kinase(PTK) are important mediators of signaling cascade determining key roles in diverse biological process. In this group of targets, the c-Met receptor tyrosine kinase plays an important role in increased cell growth,reduced apoptosis, altered cytoskeletal function, increased metastasis, and other biologic changes. Therefore, targeting of the HGF /c-Met pathway is likely to improve current therapies in c-Met dependent malignancies.The macromolecular c-Met kinase inhibitors have been new antitumors during the study of the HGF / c-Met signaling pathway as a target for anticancer drugs. With the disclosed in the crystal structure of c-Met, more and more s macromolecular c-Met kinase inhibitors had been developed. According to the characteristics of these compounds, it can be known thatthe effective macromolecular c-Met kinase inhibitors of c-Met kinase comprises at least one hydrophobic aromatic six-membered ring,and must have an amino group on the six-membered ring, which was separated two chemical bonds within the scope a hydrogen bond acceptor provides two hydrogen bonding sites together.The several parts of the presents research works were summarized blew:1 It had been synthesized two key intermediates which were selected the typeof structure of urea urea-containing with substituted of fluorinated benzyl or phenyl. By synthesizing the intermediates containing such the structure, it can be increased the c-Met inhibitory activity of the new design macromolecular inhibitors. Whatsmore, It had been synthesizedother compounds, suchas 5- hydroxy- 4- methoxy-2- nitrobenzaldehyde,2-hydroxy-5-nitrobenzaldehyde, which laysathe foundation of the design of novel small molecule inhibition of c-Met kinase agents.2 For the 1- [(4- fluorophenyl) carbamoyl] cyclopropanecarboxylic acid amidation, was synthesized small molecule c-Met kinase inhibitors like N-(4-fluo- rophenyl)-N-(4-phenoxy-phenyl) cyclopropane-1,1-dicarboxamide To further optimize the small molecule inhibition of c-Met kinase design and to lay the foundation of the two aromatic rings of etherification.