Design,Synthesis And Antitumor Activities Of Thieno[2,3-d]Pyrimidine Derivatives

As one of the serious health problems worldwide, the mortality of cancer is second only to cardiovascular disease. Consequently, researches and developments of new anticancer drugs have attracted much attention. The study found that Tyrosine Kinase Inhibitors(TKIs) can inhibit the growth, differentiation and metastasis of tumor cells through blocking or modulating the abnormal signaling pathways generated by Tyrosine Kinase. The research of the quinazoline tyrosine kinase has been a hotspot. Thieno[2,3-d]pyrimidine ring, as a bioisostere of the quinazoline ring,which has been widely used in the field of new antitumor drugs' mechanism-based design and synthesis due to its unique structure and pharmacological activity. In addition, the asymmetric unit substituted urea structure has highly biological activity due to its inclusion of different peptide bond, and as the common structure of many enzyme inhibitors, it occupies an important position in the pharmaceutical aspect.Moreover, because of the high activity and the low toxicity of the fluorine-containing derivatives, trifluoromethyl is often introduced in the procedure of drugs design and synthesis to enhanced the potential activity of drugs. In this paper, according to the principles of bioisostere and superposition, 56 new thienopyrimidine derivatives are designed and synthesized by modifying the main structure of thieno[2,3-d]pyrimidines in three series, and the preliminary in vitro antitumor activity tests of these compounds is evaluated.The first chapter, reviews the latest research progress of thienopyrimidine derivatives, asymmetric substituted ureas and fluorine-containing derivatives,respectively. The second chapter, sixteen fluorinated thieno[2,3-d]pyrimidine derivatives were synthesized by the SNAr reaction of substituted benzylamines with important intermediate 4-chloro-2-trifluoromethyl-5,6-dimethylthieno[2,3-d]pyridine,in which was prepared directly from 2-amino-4,5-dimethylthiophene-3-carbonitrile via “one-pot” procedure, and the synthesis of 2-amino-4,5-dimethyl-3-cyanothiophene via a modified Gewald reaction. All the target products were confirmed by MS, 1H NMR, 13 C NMR and elemental analysis, and the crystal structure of compounds Ia was determined by single-crystal X-ray diffraction. Preliminary activity results indicates that some of the tilte compounds have better inhibitory activity against HepG2 and MCF-7 and the inhibitory activity of compound Ia, Ic on HepG2 and MCF-7 were superior to the reference substance gefitinib. The third chapter, in order to investigate the influence of urea unit's antitumor activity, ureastructure-activity unit were introduced into thieno[2,3-d]pyrimidine 4-position, in order to obtain antitumor agent with novel structure and better inhibitor activity.Twenty fluorinated thieno[2,3-d]pyrimidine derivatives were synthesized starting with2-butanone through the Gewald reaction, the Cyclization, Chloride, Aromatic Nucleophilic substitution, Nucleophilic addition, and discussion of physicochemical properties and synthesis conditions of the target compounds, as well as the important chemical intermediaries were carried. Preliminary activity tests results indicates that some of the tilte compounds have good inhibitory activity against MCF-7. The fourth chapter, in order to study the influence of trifluoromethyl about inhibitory activity,considering substitute trifluoromethyl group on 2-position of the5,6-dimethyl-2-trifluoromethyl-thieno[2,3-d]pyrimidine on the bases of the series III. Twenty thieno[2,3-d]pyrimidine urea derivatives were synthesized through Gewald reaction,One-step chloride, Nucleophilic substitution and Nucleophilic addition reaction.Preliminary activity tests results indicates that the tilte compounds have the best inhibitory activity against HepG2 and MCF-7 and compound IIIk, IIIr exhibit the best inhibitory activity. The fifth chapter analysyzing the three series of target products I, II, III. Preliminary activity tests results indicates that some of the tilte compounds of series I, III have better inhibitory activity against HepG2 and MCF-7,and the series II have good inhibitory activity against MCF-7.