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palbociclib合成路线

 2014年8 月 18 日,辉瑞宣布该公司已向美国 FDA 提交 Palbociclib 的新药申请。这项新药申请请求 FDA 批准 Palbociclib 与来曲唑合并用于治疗之前晚期疾病未接受过治疗的雌激素受体阳性 (ER+)、人表皮生长因子受体 2 阴性(HER2-) 晚期乳腺癌患者。

现整理palbociclib的合成路线如下,供大家研究参考:

合成路线1

合成路线2


Generic Name:Palbociclib
Synonym:PD-0332991
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: selecive inhibitor of the cyclin-dependent kinases CDK4 and CDK6
Indication: Estrogen receptor-positive (ER+), HER2-negative (HER2 -) breast cancer
Current Status: Phase III (US, UK, EU), (US Clinical trials numbers NCT01864746, NCT01740427, NCT01942135, NCT01740427, NCT01942135)
Expected Launch Date: 2015
Potential Sales(peak):$5 billion
Company:Pfizer


辉瑞公司决定在今年第三季度根据乳腺癌试验药物Palbociclib的2期临床试验结果即向美国食品药监局(FDA)申请上市批准,Palbociclib是近来备受关注的也是辉瑞最重要试验药物之一,在一项2期临床研究中,使晚期乳腺癌患者的无进展生存期(PFS)平均增加一倍,但对患者总生存期(OS)未显示有统计学意义上的明显改善。据研究人员2014年4月在圣地亚哥举行的美国癌症研究协会会议上发布的最新数据显示,雌激素受体阳性转移性乳腺癌患者在合并使用Palbociclib与抗雌激素药物来曲唑时,其PFS平均为20.2个月,相比之下,单独使用来曲唑的患者其PFS平均为10.2个月。

Palbociclib(又名PD-0332991)最早进入人们视野的是在2012年圣安东尼奥乳腺癌会议上(SABCS),一经发布就引起行业广泛关注。Palbociclib是一种口服的细胞周期素依赖性激酶4、6的抑制药物,主要通过调节细胞周期发挥作用。Palbociclib主要通过抑制CDK4/6活性来阻止细胞由G1期到S期进而抑制DNA的合成。

辉瑞的Palbociclib到底何时上市还不得而知。不过,辉瑞公司于决定在今年底三季度根据2期临床试验结果即向美国食品药监局申请上市批准,而不会等待3期临床试验结果。预计,如果这款药物能够获得批准,其年销售额可能会达到50亿美元(约合人民币309.98亿元)。
礼来公司表示,目前研究人员正在进行同机理药物的三期临床研究实验设计,今年7月份有望启动3期研究,预计在2017年完成。分析师预测Bemaciclib(LY2835219)到2026年的销售峰值会达到6.5亿美元。

Sources:
1)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 selecive Inhibitor of Cyclin-Dependent Kinase 4/6; Journal of Medicinal Chemistry, 2005, 48(7),2388-2406;

2)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;

3)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 here)

4)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)

5)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)

6)Logan, Joshua E.et al.;PD- 0332991, a potent and selecive 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.

7)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)

8)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)

9)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)

10)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)

11)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)

updat (February 3, 2014): Positive Results of the phase 2 PALOMA-1 trial show the addition of palbociclib to letrozole significantly improved Progression-free Survival (PFS) in post-menopausal women with estrogen receptor-positive, HER-2–negative locally advanced or newly diagnosed metastatic breast cancer, according to a Pfizer Inc. press release on February 3, 2014.

Letrozole is the chemical name of Femara, a Novartis AG drug that belongs to a class of treatments called aromatase inhibitors that block production of estrogen.

The positive news comes after a recent disappointment for Pfizer with its Phase III studies of the irreversible pan-HER kinase inhibitor dacomitinib in patients with advanced non-small cell lung cancer.

Detailed efficacy and safety data from PALOMA-1 will be submitted for presentation at the American Association for Cancer Research Annual Meeting, scheduled for April 5-9 in San Diego.

Paloma-2 (ClinicalTrials.gov Identifier: NCT01740427), a randomized, global phase 3 trial of the same drug combination of palbociclib and letrozole as an initial treatment for breast cancer, is currently enrolling patients.

Paloma-3 (ClinicalTrials.gov Identifier: NCT01942135) will evaluate palbociclib in combination with another hormone therapy, fulvestrant, in women whose cancer has progressed after hormonal therapy. The drug, sold under the brand name Faslodex by AstraZeneca Plc, is called an estrogen receptor antagonist.

Last updat (May 22, 2014): On May 16, 2014, Pfizer announced that it will submit a New Drug Application (NDA) with the United States Food and Drug Administration (FDA) for palbociclib, combined with letrozole, as first-line systemic treatment of post-menopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer. Pfizer expects to submit the NDA early in the third quarter of this year. This decision was based on discussions with the FDA regarding the final results of PALOMA-1, a randomized, Phase 2 trial comparing palbociclib plus letrozole versus letrozole alone in this population of patients.

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