摘要多发性骨髓瘤在全世界的发病率位居血液恶性肿瘤发病率的第二位，每年新增患者大约7。5万人，而在多数发达国家的发病率为4/10万。在新确诊的多发性骨髓瘤患者中大约有10%-30%的患者对化疗无反应。即使对初始治疗有反应的患者，几乎都会复发。近几年免疫调节剂来那度胺、沙利度胺及蛋白酶抑制剂硼替佐米等药物都有很好的治疗作用，硼替佐米作为第一个蛋白酶体抑制剂，开拓了新的治疗途径。它通过阻断蛋白质的降解，使肿瘤细胞凋亡。与传统化疗相比，硼替佐米达到更高的完全缓解，能显著延长复发难治性多发性骨髓瘤患者的生存时间。阿西佐米(Ixazomib)是FDA批准的首个口服蛋白酶体抑制剂,2015年11月20日由FDA批准上市的治疗多发性骨髓的药物。本研究以N-(2,5-二氯苯甲酰基)甘氨酸和1-氨基-3-甲基丁基硼酸蒎烷二醇酯三氟醋酸盐为原料，经过缩合反应得到2， 3- 二氯-N-[2-({(1R)-3-甲基-1-[3aR,4R,6R,7aS)-3a,5,5-三甲基六氢-4,6-亚甲基-1，3,2-苯并二氧硼烷-2-基]丁基}氨基）-2-氧代乙基]苯甲酰胺,再将其硼酸交换得到N，N'，N” - [环硼氧烷-2,4,6-三基三[[（1R）-3-甲基丁烷-1,1-二基]氨基（2-氧代乙基-2,1-二基）]三（2,5-二氯苯甲酰胺），再和柠檬酸反应得到Ixazomib。72385

AbstractThe incidence of multiple myeloma in the world's highest incidence of hematological malignancies second place, about 7。5 million new patients each year, and in most developed countries the incidence rate of 4/10 million。 In China, mostly in patients 60 years of age or older, the incidence rate is about 1/100 000, and similar to other East Asia and Japan。 In multiple myeloma patients newly diagnosed in approximately 10% -30% of patients unresponsive to chemotherapy。 Even if patients initially respond to treatment, almost always relapse。 In recent years, an immunomodulatory agent lenalidomide, thalidomide and bortezomib and other protease inhibitor drugs have a very good therapeutic effect, bortezomib as first proteasome inhibitor, a pioneering cancer treatment new way。 It blocked by protein degradation, leading to apoptosis of tumor cells to open the door。 Compared with conventional chemotherapy, bortezomib achieve higher complete remission, can significantly prolong relapsed or refractory multiple myeloma patients survive。 Ixazomib is November 20, 2015 approved for marketing by the FDA drug treatment of multiple myeloma (MM), is the first FDA-approved oral proteasome inhibitor。 In this study, N- (2,5- dichlorobenzoyl) glycine and 1-amino-3-methylbutyl pinanediol esters of boronic acid trifluoroacetate was synthesized by condensation reaction of 2, 3- dichloro -N- [2 - ({(1R) -3- methyl -1- [3aR, 4R, 6R, 7aS) -3a, 5,5- trimethyl-hexahydro-4,6-methylene benzo-1,3,2-dioxaborolan-2-yl] butyl} amino) -2-oxoethyl] benzamide, which then exchange borate obtained N, N ', N "- [ boroxine 2,4,6-tris [[(1R) -3- methyl-butane-1,1-diyl] amino (2-oxo-2,1-diyl oxoethyl) ] tris (2,5-dichloro benzamide), citric acid, and then reacting Ixazomib。

毕业论文关键词：阿西佐米；合成；优化；抗骨髓瘤药

Keywords: Ixazomib; synthesis; optimization ;anti-myeloma drugs

目   录

第一章 引言 5

1。1多发性骨髓瘤的现状 5

1。2抗多发性骨髓瘤药物研究进展 6

1。2。1免疫调节剂 6

1。2。2组蛋白去乙酰化酶抑制剂HDAC 7

1。2。3蛋白酶体抑制剂 7

1。3阿西佐米的作用机制及给药方法 8

1。3。1作用机制