Synthesis Of Tyrosine Kinase Inhibitor Ureide Connected Indole-Benzimidazole Compounds

The cancer is one of the diseases of serious threat to mankind’s health and life nowadays.The incidence of cancer is increasing with the population growth and the aged tendency of population. Tyrosine kinase is the largest kinase system in human body. It plays an important role in signal transduction pathway, regulates and controls cellular growth, proliferation, division. Aberrant expression of tyrosine kinase is usually involved in human cancers. Vascular endothelial growth factor (VEGF) is a member of the family of protein tyrosine kinase, which is intimately correlated with turmor angiogenesis. The growth of tumor cells need to generate new blood vessels to provide nutrients for the cells. Blocking vascular endothelial growth factor receptor (VEGFR) can inhibit angiogenesis and promote the apoptosis of tumor cells. Ureido radical connected indole-benzimidazole compounds are a class of VEGFR-2 tyrosine kinase inhibitors by using the method of computer aided drug design (CADD) designed. This paper mainly studied on the synthesis of ureido radical connected indole-benzimidazole compounds. The following works were accomplished:1 With indole as raw material, through "indole-indoline-indole" synthetic route to abtain 5-bromo-1H-indole,5-nitro-1H-indole and 5-amino-1H-indole.5-substituted-1H-indole-3-carboxaldehyde were synthesized from 5-substituted indole by Vilsmeier-Haack reaction.5-substituted-1H-indole-3-carboxaldehvde further reacted with hydroxylamine hydrochloride in the presence of DMF to obtain 5-substituted -1H-indole-3-carbonitrile.5-substituted-1H-indole-3-carboxamide were prepared from 5-substituted-1H-indole-3-carbonitrile and hydrogen peroxide, sodium hydroxide. Four compounds were mainly synthesized in this chapter including 1H-indole-3-carboxamide,5-bromo-1H-indole-3-carboxamide,5-nitro-1H-indole-3-carboxamide, 5-methoxy-1H-indole-3-carboxamide.2 Substituted o-phenylenediamine and glycine took place nucleophilic addition catalyzed by Hydrochloric acid or phosphoric acid, closed loop to generated 5-substituted-2-aminomethyl benzimidazole compounds. Three compounds were mainly synthesized in this chapter, including 2-aminomethyl benzimidazole, 5-methyl-2-aminomethyl benzimidazole and 5-nitro-2-aminomethyl benzimidazole.3 The first step was to protect the amino group of 5-substituted-1H-indole-3-carboxamide by using 4-methylbenzenesulfonyl chloride, then reacted with oxalyl chloride to form an important intermediate aroyl isocyanate. Aroyl isocyanate reacted with 5-substituted-2-aminomethyl benzimidazole, then hydrolyzing in alkaline solution to de-protection of the amino group to obtain target compounds. N-(((1H-benzoimidazol-2-yl) methyl) carbamoyl)-1H-indole-3-carboxamide was synthe-sized from 1H-indole-3-carboxamide and 2-aminomethyl benzimidazole. N-(((1H-benzoimidazol-2-yl) methyl) carbamoyl)-5-methoxy-1H-indole-3-carboxam-ide was synthesized from 5-methoxy-1H-indole-3-carboxamide and 2-aminomethyl benzimidazole.