抗癌药CBTN关键中间体合成开题报告

1. 研究目的与意义（文献综述包含参考文献）

1、卡博替尼的简介 2016年4月25日，exelixis药业公司的抗肿瘤新药 卡博替尼 经由fda批准用于已接受过抗血管生成治疗患者的晚期肾细胞癌。

卡博替尼(cabozantinib)，其（s）-苹果酸盐化学名为n-[4-[(6,7- 二甲氧基 -4- 喹啉基 ) 氧 基]苯基]-n'-(4-氟苯基)环丙烷-1,1-二甲酰胺(s)苹果酸盐，是受体酪氨酸激酶（包括met， vegfr-1，-2和-3; axl； ret; ros1; tyro3; mer; kit; trkb; flt-3和tie-2）的抑制剂，发挥抗肿瘤作用，杀死肿瘤细胞，减少转移并抑制肿瘤血管新生。

该药的主要目标人群是曾接受抗血管生成治疗的晚期肾癌。

2. 研究的基本内容、问题解决措施及方案

1、 课题研究内容本课题通过多种方法合成卡博替尼在对这几种方法从高效、节能、快捷、环保以及成本等多方面进行分析比较，从中找出相对最为环保高效快捷节能的合成路线。

2、 课题研究方案合成路线：1. 2. 3. 4. 5.参考文献1. National Cancer Institute. SEER Cancer Statistics Factsheets: Kidney and Renal Pelvis Cancer. Bethesda (MD): National Cancer Institute; [cited 2016 Jun 27]. Available from: http://seer.cancer.gov/statfacts/html/kidrp.html.Google Scholar2. U.S Food and Drug Administration. Highlights of prescribing information (AFINITOR). Silver Spring (MD): U.S. Food and Drug Administration; 2016 [cited 2016.Jun.27].Available.from:http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022334s038lbl.pdf.Google Scholar3. U.S Food and Drug Administration. Highlights of prescribing information (INLYTA). Silver Spring (MD): U.S. Food and Drug Administration; 2012 [cited 2016.Jun.27].Available.from:http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202324lbl.pdf.Google Scholar4. U.S Food and Drug Administration. Highlights of prescribing information (OPDIVO). Silver Spring (MD): U.S. Food and Drug Administration; 2015 [cited 2016.Jun.27].Available.from:http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125554s012lbl.pdf.Google Scholar5. U.S. Food and Drug Administration. Highlights of prescribing information (LENVIMA). Silver Spring (MD): U.S. Food and Drug Administration; 2016 [cited 2016.Jun.27].Available.from:http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206947s003lbl.pdf.Google Scholar6. U.S. Food and Drug Administration. Guidance for industry expedited programs for serious conditions drugs and biologics. Silver Spring (MD): U.S. Food and.Drug.Administration;.2014.[cited.2016.Jun.27].Available.from:http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.Google Scholar7. Katayama R, Kobayashi Y, Friboulet L, Lockerman EL, Koike S, Shaw AT, et al. Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer. Clin Cancer Res 2015;21:16674.Abstract/FREE Full TextGoogle Scholar8. Zhou L, Liu X-D, Sun M, Zhang X, German P, Bai S, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2016;35:268797.CrossRefPubMedGoogle Scholar9. U.S. Food and Drug Administration. Clinical pharmacology and biometrics review(s). Silver Spring (MD): U.S. Food and Drug Administration; 2012 [cited 2016.Jun.27].Available.from:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203756Orig1s000PharmR.pdf.Google Scholar10. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:181423.CrossRefPubMedGoogle Scholar11. Chouieri TK, Escudier B, Powles T, Tanner NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:91727.CrossRefPubMedGoogle Scholar12. U.S. Food and Drug Administration. Guidance for industry postmarketing studies and clinical trials implementation of Section 505 (o)(3) of the Federal Food, Drug, and Cosmetic Act. Silver Spring (MD): U.S. Food and Drug Administration;2011.[cited.2016.Jun.27].Available.from:http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm172001.pdf.Google Scholar13. Xu W, Donnelly DJ, Chow PL, et al. Method of preparing fluorine- 18 labeled cabozantinib and its analogs[P]. International patent,WO20 16019285.2016 -2-4.14. 郑希元, 姜汉杰, 浦小平．抗甲状腺髓样癌新药卡博替尼 [J]．中国新药杂志, 2013, 22(17): 1990-1993．15. 蔡建萍, 陈曾飞, 张李锋, 等．一种抗肿瘤治疗药物卡博替 尼的合成方法: 中国, 201310631287.3 [P]．2013-11-27．