Ibrance(palbociclib)-已获美国FDA加速批准，用于治疗晚期（转移性）乳腺癌。
批准日期：2015年2月3日；公司：Pfizer Inc.
——加速批准，突破性治疗指定和优先审评
近日，乳腺癌新药Palbociclib（商品名Ibrance）已获得美国食品药品监督管理局（FDA）的加速批准，用于治疗晚期（转移性）乳腺癌。
Palbociclib可抑制与癌症细胞增殖相关的细胞周期激酶CDK4和CDK6，与来曲唑联用用于治疗尚未接受过激素疗法的绝经后ER阳性HER2阴性的转移性乳腺癌患者。
FDA 药物评估与研究中心血液和肿瘤药物办公室主任 Richard Pazdur 教授称，palbociclib 和来曲唑联用可为转移性乳腺癌患者提供一个新的治疗选择，FDA 是基于加速批准通道授予其上市许可。Ibrance曾获得FDA授予的突破性治疗药物资格，也获得了优先审评资格。此次获得FDA的加速批准，比PDUFA预定的2015年4月13日的审批期限提前了2个月。
Ibrance的疗效在165例未经治疗的绝经后ER 阳性 HER2 阴性晚期乳腺癌患者中得到了证实。临床研究中患者被随机分配至Ibrance+来曲唑联合治疗组或letrozole单药治疗组。Ibrance+来曲唑治疗组无进展生存期（PFS）为22.2个月，来曲唑单药组为10.2个月。总生存期数据尚未获得。
最常见的药物副作用包括中性粒细胞减少、白细胞减少症、疲劳、贫血、上呼吸道感染、恶心呕吐、口腔黏膜炎症性口炎、脱发、腹泻、血小板减少、食欲下降、无力、周围神经损伤以及鼻出血等。医疗保健人员应告知患者这些风险。
药物的起始治疗剂量为 125 mg，持续 21 天，随后停止服药7 天。医疗保健人员应根据患者临床表现，在开始治疗前、每个治疗周期开始前以及在前2个周期的第 14 天监测全血细胞计数。
Ibrance（Palbociclib）帕博西尼 帕博西林|イブランス|パルボシクリブ
Pfizer’s potential mega-blockbuster breast cancer drug palbociclib(brand name: Ibrance, Chinese Name: 帕博西尼, 帕博西林, Japanese Names: パルボシクリブ, イブランス) was granted accelerated approval on February 3, 2015 by the U.S. Food and Drug Administration (FDA) in combination with cancer drug Femara (letrozole) as first-line systemic treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, based on findings from the phase II PALOMA-1 trial. Ibrance(Palbociclib) is the first medicine in a new class of anti-cancer agents, cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, to be approved by the FDA. Analysts have estimated that Ibrance (palbociclib), priced at $9,850 for a month’s supply, could eventually generate annual sales of more than $5 billion.. Analysts at Morgan Stanley have predicted that Palbociclib (Ibrance) could top Pfizer’s blockbuster Lipitor drug at its peak if successful.
辉瑞突破性乳腺癌药物Ibrance(Palbociclib, 帕博西尼, 帕博西林)于2015年2月3日获FDA批准，用作联合芳香化酶抑制剂来曲唑用于ER+/HER2–绝经后转移性乳腺癌的一线治疗。Ibrance(Palbociclib, 帕博西尼, 帕博西林)是全球上市的首个CDK4/6抑制剂。该药的获批是基于一项II期研究PALOMA-1的数据，与标准治疗药物曲唑（letrozole）相比，palbociclib联合曲唑使无进展生存期（PFS）取得了统计学意义的显著延长（20.2个月 vs 10.2个月，p=0.0004）。华尔街分析师认为该药的销售峰值将达到30-50亿美元。

Synthesis of Palbociclib Isethionate (Ibrance) – Pfizer’s First-In-Class CDK4/6-targeting Drug For Breast Cancer  辉瑞乳腺癌药物帕博西尼(palbociclib, 帕博西林)的合成

Trade Name:Ibrance
Generic Name:Palbociclib
Synonym:PD-0332991
Chinese Names: 帕博西林, 帕博西尼, 帕波克利, 帕布昔利布
Japanese Name: パルボシクリブ, イブランス
Chemical Name: 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl) amino) pyrido[2,3-d] pyrimidin-7(8H)-one
CAS number:571190-30-2((palbociclib), 827022-33-3 (palbociclib isethionate)
Mechanism of action: selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6
Indication: Estrogen receptor-positive (ER+), HER2-negative (HER2 -) breast cancer
Route, Dosage Form: Oral, Capsule
Strength:75mg, 100MG, 125 mg
US patent number: US6936612, US7208489, US7456168
Patent Expiration Date:  Jan 22, 2023 (US6936612, download pdf file from yaopha.com)； Jan 16, 2023 (US7208489, US7456168 )
Cost:$9,850 a month, or $118,200 per year
Date of Approvel: February 3, 2015
Potential Sales(peak):$5 billion
Company:Pfizer
商品名：Ibrance
通用名：Palbociclib
别名:GPD-0332991
中文名： 帕博西尼, 帕博西林, 帕波克利
英文化学名:6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl) amino) pyrido[2,3-d] pyrimidin-7(8H)-one
CAS 登录号:571190-30-2((palbociclib, 帕博西尼), 827022-33-3 (palbociclib isethionate, 帕博西尼羟乙基磺酸盐)
适应症： 乳腺癌
作用机制: 全球首个CDK4/6激酶抑制剂
批准时间： 2015年2月3日 (美国)
费用: 每月$9850
销售额(2020年)：50亿美元
美国专利号码:  US6936612(从yaopha.com下载US6936612专利), US7208489, US7456168
知识产权情况: 专利到期 : 2023年1月22日 (US6936612), 2023年1月16日 (US7208489, US7456168)
药物公司： 辉瑞
Sources:
Dhillon, Sohita. Palbociclib: First Global Approval.Drugs (2015), 75(5), 543-551.
Xu, Xuenong.Method for preparing palbociclib. Faming Zhuanli Shenqing (2015), CN104496983 A 20150408
[发明公布]一种帕博西尼的制备方法. 申请公布号：CN104496983A. 申请公布日：2015.04.08. 申请号：2014106930911 申请日：2014.11.26. 申请人：苏州明锐医药科技有限公司. 发明人：许学农 地址：江苏省苏州市工业园区联丰商业广场1幢1305室 215000
摘要： 本发明揭示了一种帕博西尼(Palbociclib，I)的制备方法，其制备步骤包括：通过易得原料1-(4-氨基-2-取代基-5-嘧啶)乙酮(II) 与乙酰乙酸酯(III)发生环合反应生成6-乙酰基-5-甲基-2-取代基-吡啶并[2，3-d]嘧啶-7(8H)-酮(IV)；该中间体(IV)与卤代 环戊烷(V)发生取代反应生成6-乙酰基-8-环戊基-5-甲基-2-取代基-吡啶并[2，3-d]嘧啶-7(8H)-酮(VI)；中间体(VI)与4- (6-氨基-吡啶-3-基)-哌嗪-1-甲酸叔丁基酯(VII)发生缩合和水解反应制得帕博西尼(I)。该制备方法原料易得，工艺简洁，经济环保，适合工 业化生产
Xu, Xuenong.Method for preparation of palbociclib. Faming Zhuanli Shenqing (2015), CN104447743 A 20150325.
[发明公布]帕博西尼的制备方法. 申请公布号：CN104447743A. 申请公布日：2015.03.25. 申请号：2014106912330 申请日：2014.11.26. 申请人：苏州明锐医药科技有限公司. 发明人：许学农 地址：江苏省苏州市工业园区联丰商业广场1幢1305室 215000
摘要：本发明揭示了一种帕博西尼(PalbOciclib，I)的制备方法，其制备步骤包括：2-乙酰基-2-丁烯酸甲酯与丙二睛在碱性条件下发生环合反 应生成1，4，5，6-四氢-2-甲氧基-4-甲基-5-乙酰基-6-氧-3-吡啶甲腈(II)；中间体(II)与卤代环戊烷(III)在缚酸剂作用下发 生取代反应生成N-环戊基-1，4，5，6-四氢-2-甲氧基-4-甲基-5-乙酰基-6-氧-3-吡啶甲腈(IV)；中间体(IV)与N-[5-(1- 哌嗪基)-2-哌啶基]胍(V)发生缩合反应生成6-乙酰基-8-环戊基-5-甲基-2-[[5-(1-哌嗪基)-2-吡啶基]氨基]-5，6-二氢吡啶 并[2，3-d]嘧啶-7(8H)-酮(VI)；中间体(VI)与硒酸钠发生脱氢反应制得帕博西尼(I)。该制备方法原料易得，工艺简洁，经济环保，适合 工业化生产。
Wu, Yusheng; Niu, Chengshan; Zou, Dapeng; Zhang, Sen; Guo, Ruiyun; Li, Jingya. Deuterated palbociclib derivative, its preparation and application. Faming Zhuanli Shenqing (2015), CN104447739 A 20150325.
[发明公布] 一种氘代Palbociclib衍生物、制备方法及应用.申请公布号：CN104447739A. 申请公布日：2015.03.25.申请号：201410623485X. 申请日：2014.11.07.申请人：郑州泰基鸿诺药物科技有限公司. 发明人：吴豫生;牛成山; 邹大鹏; 张森; 郭瑞云; 李敬亚. 地址：450052 河南省郑州市大学路75号
摘要： 本发明公开了一种氘代Palbociclib衍生物、制备方法及应用，该氘代Palbociclib衍生物的结构式如式(I)、式(II)、式(III) 或式(IV)所示。本发明的氘代Palbociclib衍生物，通过对Palbociclib的选择性氘代，改善了药物的药代性质，进而提高了药物的疗 效、安全性和耐受性；本发明的氘代Palbociclib盐，提高了药物的溶解度和溶出速率；氘代Palbociclib衍生物的合成，为合成新型抗肿瘤 药物提供了新的化合物，其与Palbociclib具有类似的生物活性，具有良好的药物应用前景。
|Ibrance Palbociclib Synthesis Patent|帕博西尼的制备专利| Mark Barvian, Richard John Booth, John Quin, III, Joseph Thomas Repine, Derek J. Sheehan, Peter Laurence Toogood, Scott Norman Vanderwel, Hairong Zhou, 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. US patent number: US6936612 (download pdf file from yaopha.com), Also published as: CA2473026A1, CA2473026C, CN101001857A, CN101001857B, CN101906104A, CN101906104B, CN102295643A, CN102295643B, DE60303009D1, DE60303009T2, EP1470124A1, EP1470124B1, US7208489, US7456168, US20030149001, US20050137214, US20070179118, WO2003062236A1, WO2003062236A8. Publication date: Aug 30, 2005.Original Assignee: Warner-Lambert Company
Mark Barvian, Richard John Booth, John Quin, III, Joseph Thomas Repine, Derek J. Sheehan, Peter Laurence Toogood, Scott Norman Vanderwel, Hairong Zhou, 2-(pyridin-2-ylamino)-pyrido [2,3-d]pyrimidin-7-ones . US patent number: US7208489 (download pdf file from yaopha.com), Also published as: CA2473026A1, CA2473026C, CN101001857A, CN101001857B, CN101906104A, CN101906104B, CN102295643A, CN102295643B, DE60303009D1, DE60303009T2, EP1470124A1, EP1470124B1, US6936612, US7456168, US20030149001, US20050137214, US20070179118, WO2003062236A1, WO2003062236A8. Publication date: Apr 24, 2007. Original Assignee: Warner-Lambert Company
Finn, Richard S.; Crown, John P.; Lang, Istvan; Boer, Katalin; Bondarenko, Igor M.; Kulyk, Sergey O.; Ettl, Johannes; Patel, Ravindranath; Pinter, Tamas; Schmidt, Marcus; et al.  The cyclin-​dependent kinase 4​/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-​line treatment of oestrogen receptor-​positive, HER2-​negative, advanced breast cancer (PALOMA-​1​/TRIO-​18)​: a randomised phase 2 study. Lancet Oncology (2015), 16(1), 25-35.
Morgan, Adam J. Deuterated palbociclib as therapeutic agents. PCT Int. Appl. (2014), WO 2014150925 A2 20140925
Peter L. Toogood, Patricia J. Harvey, Joseph T. Repine, Derek J. Sheehan, Scott N. VanderWel, Hairong Zhou, Paul R. Keller, Dennis J. McNamara, Debra Sherry, Tong Zhu, Joanne Brodfuehrer, Chung Choi, Mark R. Barvian, and David W. Fry;Discovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6; Journal of Medicinal Chemistry, 2005, 48(7),2388-2406;
Scott N. VanderWel, Patricia J. Harvey, Dennis J. McNamara, Joseph T. Repine, Paul R. Keller, John Quin III, R. John Booth, William L. Elliott, Ellen M. Dobrusin, David W. Fry, and Peter L. Toogood; Pyrido[2,3-d]pyrimidin-7-ones as Specific Inhibitors of Cyclin-Dependent Kinase 4; Journal of Medicinal Chemistry,2005,48(7),2371-2387;
Erdman, David Thomas et al;Preparation of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones;PCT Int. Appl., WO2008032157 (download PDF file from yaopha.com)
Sharpless, Norman E. et al;Hematopoietic protection against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors;PCT Int. Appl., WO2010039997 (download PDF file here)
Dirocco, Derek Paul et al;Protection of renal tissues from schema through inhibition of the proliferative kinases CDK4 and CDK6;PCT Int. Appl., WO2012068381 (download PDF file here)
Logan, Joshua E.et al.;PD- 0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity; Anticancer Research (2013), 33(8), 2997-3004.
Phase III Study Evaluating Palbociclib (PD-0332991), a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor in Patients With Hormone-receptor-positive, HER2-normal Primary Breast Cancer With High Relapse Risk After Neoadjuvant Chemotherapy “PENELOPEB”;ClinicalTrials.gov number:NCT01864746;currently recruiting participants(as of January 2, 2013)
A Randomized, Multicenter, Double-Blind Phase 3 Study Of PD-0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole For The Treatment Of Postmenopausal Women With ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti Cancer Treatment For Advanced Disease;ClinicalTrials.gov number:NCT01740427;currently recruiting participants(as of January 2, 2013)
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Of Fulvestrant (Faslodex®) With Or Without PD-0332991 (Palbociclib) +/- Goserelin In Women With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer Whose Disease Progressed After Prior Endocrine Therapy;ClinicalTrials.gov number:NCT01942135;currently recruiting participants(as of January 2, 2013)
A Randomized, Multicenter, Double-Blind Phase 3 Study Of PD-0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole For The Treatment Of Postmenopausal Women With ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti Cancer Treatment For Advanced Disease;ClinicalTrials.gov number:NCT01740427;currently recruiting participants(as of Feb 3, 2014)
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Of Fulvestrant (Faslodex®) With Or Without PD-0332991 (Palbociclib) +/- Goserelin In Women With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer Whose Disease Progressed After Prior Endocrine Therapy (PALOMA-3);ClinicalTrials.gov number:NCT01942135;currently recruiting participants(as of Feb 3, 2014)