论文总字数：28568字

摘 要

人们生活水平逐渐提高，现代的作息习惯,饮食结构对人们的身体健康产生了越来越多的负面影响，自身免疫疾病的发生的可能性逐年上升。近现代医学研究发现, 自身免疫病的产生与机体内炎性细胞因子 (cytokines) 合成和释放的失衡密切相关, 该发现也推动越来越多自身免疫病相关细胞因子及信号通路的研究。JAKs (Janus kinases) 是许多下游炎性细胞因子必需的信号转导介质, 因此靶向JAKs 的小分子抑制剂能够通过影响下游炎性因子的信号转导而发挥抗炎和免疫调节的药理作用。研究表明, JAKs 为一类非受体型酪氨酸激酶, 包括JAK1、JAK2、TYK2 (tyrosine kinase 2) 和JAK3。目前，全球共有五款JAK抑制剂获批上市。2011年，首个由美国Incyte公司开发的JAK抑制剂鲁索利替尼（Ruxolitinib）在美国批准上市，是第一款专门用于治疗骨髓纤维化的药物。2012年，随着托法替布（Tofacitinib）被FDA批准用于治疗类风湿关节炎（RA）后，2017年，由Incyte和Eli Lilly合作开发的Baricitinib首先在欧洲获得上市许可。Peficitinib（商品名称：Smyraf®）于2019.3.29获得PMDA的批准用于上市治疗RA，适用于治疗中重度溃疡性皮炎，活动性类风湿关节症。Upadactinib于2019年8月16日被FDA批准上市用于治疗类风湿性关节炎。本次实验以Filgotinib为先导化合物，以期合成效果更好的JAK1抑制剂。

关键词：自身免疫疾病 JAKs 抑制剂 STAT

Design and Synthesis of selective JAK1 Inhibitors

Abstract

With the gradual improvement of people's living standards, modern work and rest habits and diet have more and more negative effects on people's health, and the possibility of autoimmune diseases is increasing year by year. Modern medical research has found that the production of autoimmune disease is closely related to the imbalance of (cytokines) synthesis and release of inflammatory cytokines in the body. This discovery also promotes the study of more and more autoimmune disease-related cytokines and signal pathways. JAKs (Janus kinases) is a necessary signal transduction medium for many downstream inflammatory cytokines, so small molecular inhibitors targeting JAKs can exert anti-inflammatory and immunomodulatory effects by affecting the signal transduction of downstream inflammatory cytokines. Studies have shown that JAKs is a class of non-receptor tyrosine kinases, including JAK1, JAK2, TYK2 (tyrosine kinase 2) and JAK3. At present, a total of five JAK inhibitors have been approved and put on the market worldwide. In 2011, (Ruxolitinib), the first JAK inhibitor developed by Incyte, was approved to be marketed in the United States, and it is the first drug specifically used to treat myelofibrosis. In 2012, after Topatib (Tofacitinib) was approved by FDA for the treatment of rheumatoid arthritis (RA), Baricitinib, jointly developed by Incyte and Eli Lilly, was first licensed in Europe in 2017. Pegicitinib (trade name: Smyraf ®) was approved by PMDA on March 29, 2019 for the treatment of RA, for the treatment of moderate to severe ulcerative dermatitis and active rheumatoid arthritis. Upadactinib Upatinib was approved by FDA for the treatment of rheumatoid arthritis on August 16, 2019. Filgotinib was used as the lead compound in this experiment to synthesize JAK1 inhibitors with better effect.

Key word: Autoimmune disease; JAKs ; inhibitor; STAT

目录

摘要 I

Abstract II

第一章文献综述 1

1.1研究背景 1

1.2 JAKs-STAT信号通路 2

1.2.1JAKs的结构 3

1.2.2JAKs-STAT通路 5

1.2.3STAT 7

1.2.4JAKs-STAT与自身免疫疾病 8

1.3JAKs抑制剂的研究 9

1.3.1 JAK抑制剂Tofacitinib 9

1.3.2 JAK抑制剂Ruxolitinib 9

1.3.3 JAK抑制剂Baricitinib 10

1.4新一代JAK抑制剂 12

1.4.1 Decernotinib (VX-509) 12

1.4.2 Solcitinib (GSK2586184) 13

1.4.3 NCB039110 13

1.4.4 Peficitinib 13

1.4.5 Filgotinib 14

1.5小结 15

第二章 Filgotinib 的合成 16

2.1合成路线分析 16

2.1.1溴化反应 17

2.1.2取代反应 17

2.1.3单酰化反应 18

2.1.4铃木偶联反应 18

2.1.5中间体M-9的合成 19

2.2实验仪器与材料 20

2.3 Filgotinib的合成实验步骤 20

2.3.1化合物138500-85-3的合成 20

2.3.2化合物l-2的合成 21

2.3.3化合物l-3的合成 21

2.3.4化合物l-1 Filgotinib的合成 22

第三章 总结与展望 23

3.1总结 23

3.2展望 23

参考文献 24

致谢 28

第一章 文献综述

1.1研究背景

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