小分子c-Met激酶抑制剂丙二酰胺类及脲类关键中间体的合成

发布时间：2018-05-18 13:39

本文选题：肿瘤 + 分子靶向　；参考：《安徽医科大学》2014年硕士论文

【摘要】：近年来人类健康一直深受多种疾病的威胁,其中肿瘤威胁较大,其治疗一直都是世界性的大难题。目前现有抗肿瘤药物大都是细胞毒类药物,该药物存在毒性大、易产生耐药性等缺点。但随着分子生物学的发展,抗肿瘤药物的研究已经由传统的随机筛选过渡到合理的根据作用机制而靶向于特异细胞功能异常的药物研究。蛋白酪氨酸激酶(Protein tyrosine kinase,PTK)在多种疾病,特别是肿瘤发生发展过程中起重要作用。在各种受体酪氨酸激酶中,肝细胞生长因子受体(c-Met)对促进细胞生长、降低细胞凋亡、改变细胞骨架功能、增加转移和其它生物学改变起关键作用。靶向于HGF/c-Met通路可改善依赖c-Met的肿瘤的治疗。在研究以HGF/c-Met信号通路为靶点的抗肿瘤药物过程中,小分子c-Met激酶抑制剂的研究起步较晚,但随着c-Met晶体结构的公开,越来越多的小分子c-Met激酶抑制剂被开发,根据这些化合物的结构特点,可知有效的c-Met激酶抑制剂至少应包含1个六元疏水的芳香环,同时六元环上必须有1个氨基,其与相隔2个化学键范围内的1个氢键受体一起提供2个氢键作用位点。本文主要研究结果如下:1、合成了2个关键中间体,分别为N-(3-氟-4-羟基苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺和N-(3-氟-4-羟基苯基)-2-氧代-3-苯基咪唑烷-1-甲酰胺,二者包含丙二酰胺类及脲类结构并且脲末端连接含氟取代的苄基或苯基,根据小分子c-Met激酶抑制剂构效关系规律,此类结构有助于小分子c-Met激酶抑制剂的活性提高。另外合成了化合物5-羟基-4-甲氧基-2-硝基苯甲醛、2-羟基-5-硝基苯甲醛,将二者分别与上述二中间体连接,可合成新的小分子c-Met激酶抑制剂。2、对1-[(4-氟苯基)氨基甲酰基]环丙烷羧酸进行酰胺化,合成小分子c-Met激酶抑制剂类似物N-(4-氟苯基)-N-(4-苯氧基苯基)环丙烷-1,1-二甲酰胺,为进一步优化小分子c-Met激酶抑制剂的设计与合成奠定了基础。
[Abstract]:In recent years, human health has been threatened by many diseases, among which tumor is a great threat, and its treatment has always been a worldwide problem. At present, most of the existing anti-tumor drugs are cytotoxic drugs, which have many disadvantages, such as high toxicity, easy to produce drug resistance and so on. However, with the development of molecular biology, the research of anti-tumor drugs has been transferred from traditional random screening to the study of drugs with abnormal function of specific cells according to the mechanism of action. Protein tyrosine kinase (PTK) plays an important role in many diseases, especially in tumorigenesis and development. Among various receptor tyrosine kinases, hepatocyte growth factor receptor c-Meta plays a key role in promoting cell growth, reducing cell apoptosis, changing cytoskeleton function, increasing metastasis and other biological changes. Targeting the HGF/c-Met pathway can improve the treatment of c-Met-dependent tumors. In the process of studying anti-tumor drugs targeting HGF/c-Met signaling pathway, the study of small molecular c-Met kinase inhibitors started late, but with the disclosure of c-Met crystal structure, more and more small molecule c-Met kinase inhibitors were developed. According to the structural characteristics of these compounds, effective c-Met kinase inhibitors should contain at least one hexagonal hydrophobic aromatic ring and one amino group on the six-member ring. It provides two hydrogen bond interaction sites together with a hydrogen bond receptor in a range of 2 chemical bonds. In this paper, the main results are as follows: 1: 1. Two key intermediates were synthesized, namely, N-fluoro-3-fluoro-4-hydroxyphenyl -N-N-fluorophenyl-4-fluorophenyl) cyclopropane-1-diformamide and N--3-fluoro-4-hydroxyphenyl carbon-2-oxo-3-phenylimidazole-1-formamide. They contain malonamide and urease structures and end with fluorinated benzyl or phenyl. According to the structure-activity relationship of small molecule c-Met kinase inhibitors, this kind of structure can improve the activity of small molecule c-Met kinase inhibitors. In addition, the compound 5-hydroxy-4-methoxy-2-nitrobenzaldehyde, 2-hydroxy-5-nitrobenzaldehyde, was synthesized and connected with the two intermediates. A new small molecular inhibitor of c-Met kinase, .2., can be synthesized by amidation of 1- [4-fluorophenyl) carbamate] cyclopropane carboxylic acid, and synthesis of a small molecular c-Met kinase inhibitor analogues N-4-fluorophenyl-N-(4-phenoxyphenyl)-cyclopropane-1-diformamide. It lays a foundation for further optimization of the design and synthesis of small molecular c-Met kinase inhibitors.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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