三氮唑骈吡啶类JAK抑制剂的合成及体外活性评价  

Synthesis and in vitro activity evaluation of triazolidipyridine JAK inhibitors

作　　者：梁欢[1] 常先磊 邓晓东[3] 杨洋[4] 刘思凡 张宇[1] 李庶心[1,2,4] LIANG Huan;CHANG Xian-lei;DENG Xiao-dong;YANG Yang;LIU Si-fan;ZHANG Yu;LI Shu-xin(Department of Postgraduates ,Jiangxi University of Traditional Chinese Medicine ,Nanchang 330006, China;Institute of Radiation and Irradiation Medicine ,Academy of Military Medicine Science ,Beifing 100850, China;Sichuan Entry-Exit Inspection and Quarantine Bureau, Chengdu 610041, China;School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China)

机构地区：[1]江西中医药大学研究生部,江西南昌330006 [2]军事医学科学院放射与辐射医学研究所,北京100850 [3]四川省出入境检验检疫局,四川成都610041 [4]广东药科大学药科学院,广东广州510006

出　　处：《中国药物化学杂志》2018年第2期97-104,共8页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(30973616)

摘　　要：目的设计合成一系列三氮唑骈吡啶类Janus激酶(JAK)抑制剂并进行初步体外激酶活性评价。方法选择filgotinib为先导化合物,通过结构优化改造,设计合成一系列新型三氮唑骈吡啶类JAK抑制剂。以2-氨基-6-溴-吡啶为起始原料,经过亲核加成、亲核取代、水解、Suzuki偶联、Michael加成等重要反应步骤合成目标化合物。以filgotinib为阳性对照物,采用毛细管电泳方法通过检测底物肽段磷酸化转化率来进行化合物激酶活性评价。结果与结论合成了10个未见文献报道的新化合物,其结构经1H-NMR、MS谱鉴定。初步体外活性评价结果表明,所设计的化合物均表现出一定程度的JAK亚型抑制倾向,其中Ⅰe、Ⅱe两个化合物表现出良好的激酶亚型选择性,具有进一步研究的价值。Rheumatoid arthritis is a common autoimmune disease. Studies have shown that,in the pathogenesis of RA,JAK/STAT signal transduction pathway is active,and participates in the occurrence and development of the disease. Therefore,the use of JAK inhibitor by blocking JAK/STAT signal transduction pathway,can improve rheumatoid arthritis. However,due to the pathogenesis of RA is not yet fully clear,and JAK is widely distributed in the human body,the JAK inhibitor lack of subtype selectivity,then the treatment of the disease at the same time there may be serious adverse reactions. Therefor,there is still an urgent need to develop a subtypes kinase selective JAK inhibitors. In this paper,filgotinib was selected as the lead compound and baricitinib as the reference compound. The 1,2,4-triazolo [1,5-a] pyridine structure in the filgotinib molecule was used to replace the 7H-pyrrolo[2,3-d] pyrimidine structure. The tail ethylsulfonyl group is converted to an arylsulfonyl group or an arylcarbonyl group to give the target compounds Ⅰa-Ⅰe.In addition,the cyano-methylidine N-heterocyclobutane was replaced with the cyanomethylidene piperazine ring to give the target compounds Ⅱa-Ⅱe. 2-Anmino-6-bromopyridine was used as the starting material,and the key intermediate 6 was obtained by nucleophilic adtion,Suzuki coupling reaction and hydrolysis.Then,3-oxazetidine-1-carboxyl acid tert-butyl ester and 4-oxopiperidine-1-carboxylic acid tert-butyl ester as the starting materials to obtain the key intermediates 8 a-8 e and 8 a’-8 e’. Finally,the target compoundsⅠa-Ⅰe and Ⅱa-Ⅱe were obtained through the way of Michael’addition. We choose the filgotinib as a positive control,the activity of the compounds was evaluated by detecting the phosphorylation conversion of the substrate peptide by capillary electrophoresis. By means of data analysis,the designed compounds were more susceptible to inhibition of JAK1,and the inhibition of JAK was lower than that of aynomethylidene piperazine ring compared with cyanomethylidine

关 键 词：类风湿关节炎 JAK抑制剂 毛细管电泳法 合成 

分 类 号：R914[医药卫生—药物化学]