含三氟甲基三氮嗪酪氨酸激酶抑制剂设计合成及生物活性研究  

Synthesis of 6-CF_(3)-1,2,4-triazine-based Tyrosine Kinase Inhibitors and The Evaluation of Biological Activities

作　　者：秦沛 马海 张发光 马军安[1] Qin Peia;Ma Hai;Zhang Fa-Guang;Ma Jun-An(Department of Chemistry,School of Science,Tianjin Key Laboratory of Molecular Optoelectronic Sciences,Tianjin University,Tianjin 300072;Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700)

机构地区：[1]天津大学理学院化学系,天津市分子光电科学重点实验室,天津300072 [2]中国中医科学院中药研究所,北京100700

出　　处：《化学学报》2023年第7期697-702,共6页Acta Chimica Sinica

基　　金：国家自然科学基金(Nos.92156025,22271212,21961142015);国家重点研发计划(2019YFA0905100)资助。

摘　　要：三氟甲基是一类重要的有机官能团,将其引入生物活性分子已经成为药物开发中一种常见的策略,目前发展的多种蛋白激酶抑制剂中均含有三氟甲基芳烃单元.从三氟乙胺出发,发展了甘氨酸亚胺与原位生成的三氟重氮乙烷的[3+3]环加成反应,以良好收率得到了系列3-酯基-5-芳基-6-三氟甲基-1,2,4-三氮嗪,随后经过水解→氯化→酰胺化三步化学转化反应,并引入酪氨酸激酶抑制剂伊马替尼和尼洛替尼的核心片段,得到了14个含有三氟甲基三氮嗪骨架的小分子化合物,初步生物活性测试发现了部分化合物对细胞凋亡蛋白Caspase 9具有较好的促进作用.Trifluoromethyl group has strong electron-withdrawing ability and stable C—F bond,and its introduction into organic molecules could often significantly modify the acidity,dipole moment,lipophilicity and metabolic stability of parent compounds.Therefore,the incorporation of trifluoromethyl group into bioactive molecules has become a common strategy for drug development.Trifluoromethylated arene moiety is the important unit of many drugs and related candidates,such as Nilotinib,Radotinib,Ponatinib,Regorafenib,Pexidartinib,Bimiralisi,and Defactinib.Therefore,it is of great interest to design new compounds containing trifluoromethyl group and explore their potential applications in the development of protein kinase inhibitors.Imatinib is the first-generation tyrosine kinase inhibitor and the first small molecule targeting anti-tumor drug that inspires the synthesis of a large number of excellent anti-tumor drugs.Therefore,in this study,we aimed to design new trifluoromethyl-containing tyrosine kinase inhibitors via combining the aniline-pyrimidine structure of Imatinib with 1,2,4-triazines.In particular,we developed a one-pot[3+3]cycloaddition sequence to construct a series of 3-ester-5-aryl-6-CF_(3)-1,2,4-triazines in good yields.Subsequently,a series of new compounds containing the trifluoromethyl 1,2,4-triazine skeleton were obtained via a sequence of hydrolysis,chlorination,and amidation reactions.Finally,a preliminary evaluation of biological activity was conducted and a hit compound 4a was found with good activity in promoting apoptosis protein Caspase 9.A representative procedure for the synthesis of model product 4a is described as following:Starting from trifluoroethylamine(9.91 g,100 mmol),tert-butyl nitrite(11.34 g,110 mmol)and AcOH(1.2 g,20 mmol)were used to generate trifluorodiazoethane in situ in tetrahydrofuran(THF,20 mL)at 55℃ for 30 min.Then the CF3CHN2 solution was added to the mixture of glycine imine 1(50 mmol),silver fluoride catalyst(0.64 g,5 mmol)and cesium carbonate(20.36 g,62.5 mmol)in TH

关 键 词：三氟甲基 三氮嗪 激酶抑制剂 含氟药物 

分 类 号：TQ460.6[化学工程—制药化工]