[4-氨基-2-[(1-甲磺酰基哌啶-4-基)氨基]嘧啶-5-基](2,3-二氟-6-甲氧基苯基)甲酮 | 741713-40-6

• 物质功能分类: 生物化工 - 抑制剂 - 细胞周期(Cell Cycle)
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: [4-氨基-2-[(1-甲磺酰基哌啶-4-基)氨基]嘧啶-5-基](2,3-二氟-6-甲氧基苯基)甲酮
• 英文名称: Ro 4584820
• 英文别名: [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone；R-547；R547；[4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone；(4-Amino-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)(2,3-difluoro-6-methoxyphenyl)methanone；[4-amino-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone
• CAS: 741713-40-6
• 化学式: C₁₈H₂₁F₂N₅O₄S
• 分子量: 441.459
• InChiKey: JRNJNYBQQYBCLE-UHFFFAOYSA-N

物化性质

• 沸点：
  703.7±70.0 °C(Predicted)
• 密度：
  1.49
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  136
• 氢给体数：
  2
• 氢受体数：
  11

安全信息

• 储存条件：
  -20℃

制备方法与用途

生物活性

R547 (Ro 4584820) 是一种有效的ATP竞争性CDK1/2/4抑制剂，Ki值分别为2 nM、3 nM和1 nM。对CDK7和GSK3α/β的作用稍弱，但能显著抑制其他激酶活性。Phase 1。

目标

• CDK4/CyclinD1 (细胞自由体系): Ki = 1 nM
• CDK1/CyclinB (细胞自由体系): Ki = 2 nM
• CDK2/CyclinE (细胞自由体系): Ki = 3 nM

体外研究

R547是一种二氨基嘧啶化合物，是有效的选择性ATP竞争性CDK抑制剂。它能有效抑制CDK1/cyclinB、CDK2/cyclinE和CDK4/cyclinD1 (Ki = 1-3 nM)，而对超过120个非相关激酶无活性（Ki > 5,000 nM）。R547能有效抑制耐药的肿瘤细胞系增殖，与组织学类型、视网膜母细胞瘤蛋白或p53状态无关，并且IC50s < 0.60 μM。在相同浓度下诱导细胞周期阻滞时，降低特定CDK磷酸化位点上的成视网膜细胞瘤蛋白水平，显示出潜在的临床应用药物动力学标志物。

R547抑制肿瘤细胞系的增殖，在所有测试的19种细胞系中均有效，不受组织来源、多药耐药性（MDR）、p53或视网膜母细胞瘤状态的影响。R547具有5-氟和6-氟取代基，对CDKs（CDK1，CDK2，和CDK4的Ki分别为0.001，0.003，和0.001 μM）显示出低个位数纳摩尔级的抑制效能，并且具有优良的细胞内效能（IC50 = 0.08 μM，HCT116细胞系）。

体内研究

R547以口服和静脉注射剂量给药对多种成熟的人肿瘤表现出显著的抑制活性。在结肠癌、肺癌、乳腺癌、前列腺癌及黑色素瘤人肿瘤异种移植模型中（40 mg/kg，每天），表现出高达79-99%的TGI。在静脉注射40 mg/kg每周一次的剂量下同样有效（61-95% TGI）。R547这些剂量无毒性，并不会引起体重损失。

3周研究期间未观察到显著毒性信号，在尸检中没有明显病理学变化。在HCT116人结肠肿瘤异种移植裸鼠模型中，R547抑制肿瘤生长高达95%。以等于或低于最大耐受剂量口服或静脉注射给药时，在所有测试模型中引起显著的TGI。R547对肿瘤异种移植模型有效暴露会抑制肿瘤中成视网膜细胞瘤蛋白的磷酸化，这为临床应用提供了药效生物指标。

这些报道表明，R547对于固体肿瘤治疗是一个有希望的分子。

反应信息

• 作为反应物：
  描述：

  [4-氨基-2-[(1-甲磺酰基哌啶-4-基)氨基]嘧啶-5-基](2,3-二氟-6-甲氧基苯基)甲酮 在 phosphorous (V) sulfide 、 碳酸氢钠 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 2.0h， 以75%的产率得到[4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanethione
  参考文献：
  名称：

  4-Aminopyrimidine-5-thione derivatives

  摘要：

  本发明揭示了一种新型的4-氨基嘧啶-5-硫酮衍生物。这些化合物抑制细胞周期依赖性激酶，特别是Cdk1、Cdk2和Cdk4。这些化合物及其药学上可接受的盐具有抗增殖活性，可用于治疗或控制癌症，特别是实体肿瘤。本发明还涉及含有这些化合物的制药组合物，以及治疗或控制癌症的方法，尤其是治疗或控制乳腺、肺、结肠和前列腺肿瘤的方法。

  公开号：

  US20070117821A1
• 作为产物：
  描述：

  1-MS-4-Boc-氨基哌啶 在 间氯过氧苯甲酸 、 三氟乙酸 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 反应 6.0h， 生成 [4-氨基-2-[(1-甲磺酰基哌啶-4-基)氨基]嘧啶-5-基](2,3-二氟-6-甲氧基苯基)甲酮
  参考文献：
  名称：

  Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), A Potent and Selective Cyclin-Dependent Kinase Inhibitor with Significant in Vivo Antitumor Activity

  摘要：

  The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K-i > 10 AM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K-i = 0.001, 0.003, and 0.001 AM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC50 = 0.08 mu M). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

  DOI：

  10.1021/jm0606138

文献信息

• METHODS FOR STABILIZING LITHIATED HALOGEN-SUBSTITUTED AROMATIC COMPOUNDS
  申请人：Ji Yaohui

  公开号：US20090118546A1

  公开（公告）日：2009-05-07

  The present invention provides novel methods for stabilizing lithiated halogen-substituted aromatic compounds. In particular, the method is useful for the preparation of 2-methoxy-5, 6-difluorobenzaldehyde, an important intermediate for the preparation of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino) pyrimidin-5-yl](2,3-difluoro-6methoxyphenyl)methanone, a potent and selective inhibitor of CDK4/Cyclin D1, CDK2/Cyclin E and CDK1/Cyclin B. The method is also useful for stabilizing other lithiated halogen-substituted aromatic compounds and is particularly useful for scale up reactions where the exothermic nature of the reaction can lead to reaction runway.

  本发明提供了一种稳定锂化卤代芳香化合物的新方法。特别是，该方法对于制备2-甲氧基-5,6-二氟苯甲醛非常有用，该化合物是制备[4-氨基-2-(1-甲磺酰基哌啶-4-基氨基)嘧啶-5-基](2,3-二氟-6-甲氧基苯基)甲酮的重要中间体，后者是CDK4 / Cyclin D1，CDK2 / Cyclin E和CDK1 / Cyclin B的有效选择性抑制剂。该方法还对于稳定其他锂化卤代芳香化合物非常有用，尤其适用于规模化反应，其中反应的放热性质可能导致反应失控。
• 4-Aminopyrimidine-5-one derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US07157455B2

  公开（公告）日：2007-01-02

  Novel 4-aminopyrimidine-5-one derivatives are disclosed. These compounds inhibit cyclin-dependent kinases, in particular cyclin-dependent kinase 4 (Cdk4). These compounds and their pharmaceutically acceptable salts and esters have antiproliferative activity and are useful in the treatment or control of cancer, in particular solid tumors. This invention is also directed to pharmaceutical compositions containing such compounds and to methods of treating or controlling cancer, most particularly the treatment or control of breast, lung, colon and prostate tumors. Also disclosed are intermediates useful in the preparation of these novel 4-aminopyrimidine-5-one derivatives.

  本发明揭示了新的4-氨基嘧啶-5-酮衍生物。这些化合物抑制细胞周期依赖性激酶，尤其是细胞周期依赖性激酶4(Cdk4)。这些化合物及其药学上可接受的盐和酯具有抗增殖活性，并且在治疗或控制癌症，特别是实体肿瘤方面具有用途。本发明还涉及含有这些化合物的制药组合物以及治疗或控制癌症的方法，尤其是治疗或控制乳腺、肺、结肠和前列腺肿瘤的方法。还揭示了在制备这些新的4-氨基嘧啶-5-酮衍生物方面有用的中间体。
• 4-aminopyrimidine-5-one derivatives
  申请人：——

  公开号：US20040162303A1

  公开（公告）日：2004-08-19

  Novel 4-aminopyrimidine-5-one derivatives are disclosed. These compounds inhibit cyclin-dependent kinases, in particular cyclin-dependent kinase 4 (Cdk4). These compounds and their pharmaceutically acceptable salts and esters have antiproliferative activity and are useful in the treatment or control of cancer, in particular solid tumors. This invention is also directed to pharmaceutical compositions containing such compounds and to methods of treating or controlling cancer, most particularly the treatment or control of breast, lung, colon and prostate tumors. Also disclosed are intermediates useful in the preparation of these novel 4-aminopyrimidine-5-one derivatives.

  本发明揭示了新型4-氨基嘧啶-5-酮衍生物。这些化合物抑制细胞周期蛋白依赖性激酶，特别是细胞周期蛋白依赖性激酶4（Cdk4）。这些化合物及其药学上可接受的盐和酯具有抗增殖活性，并可用于治疗或控制癌症，特别是实体瘤。本发明还涉及含有这些化合物的制药组合物以及治疗或控制癌症的方法，尤其是乳腺、肺、结肠和前列腺肿瘤的治疗或控制。此外，还揭示了制备这些新型4-氨基嘧啶-5-酮衍生物的中间体。
• NA CHANNELS, DISEASE, AND RELATED ASSAYS AND COMPOSITIONS
  申请人：Brown Milton L.

  公开号：US20110230442A1

  公开（公告）日：2011-09-22

  Disclosed are molecules and their synthesis, for use in blocking gated ion channels such as voltage-gated sodium channels (VGSCs) and prostate voltage sodium channels (PVSCs). These inhibitors have superior blocking efficacy, for instance in displacing the radioligand [ 3 H]-Batrachotoxin-B ([ 3 H]-BTX-B) that binds to site 2 of a VGSC. The molecules of the invention comprise a moiety which increases the binding affinity of molecules for the protein binding site in prostate cancer cells (PCs), and which is also fluorescent. In one embodiment the invention molecules are an inhibition system that can be used to target over-abundant or hyperactive VGSCs selectively in pain, epilepsy or prostate cancer, inhibiting the proliferation of PCs. The fluorescent moiety also facilitates screening, tracking, and pharmacodynamic studies of the drug in a biological system both in vitro and in vivo.

  本发明涉及分子及其合成，用于阻断门控离子通道，例如电压门控钠通道（VGSC）和前列腺电压钠通道（PVSC）。这些抑制剂具有卓越的阻断效力，例如在取代结合到VGSC的位点2的放射性配体[3H]-Batrachotoxin-B ([3H]-BTX-B)方面。本发明的分子包括一个基团，增加分子对前列腺癌细胞（PC）中蛋白质结合位点的结合亲和力，并且也是荧光的。在一种实施方式中，本发明的分子是一种抑制系统，可用于选择性地靶向过度丰富或过度活跃的VGSC，从而抑制疼痛、癫痫或前列腺癌的PC的增殖。荧光基团还有助于在体外和体内生物系统中筛选、跟踪和药效学研究药物。
• [EN] COVALENT CDK2-BINDING COMPOUNDS FOR THERAPEUTIC PURPOSES<br/>[FR] COMPOSÉS DE LIAISON À CDK2 COVALENTS UTILISÉS À DES FINS THÉRAPEUTIQUES
  申请人：UMBRA THERAPEUTICS INC

  公开号：WO2022187693A1

  公开（公告）日：2022-09-09

  Heteroaryl sulfonyl compounds and compositions that have a CDK2 Recognition Moiety bound to an electrophile for the selective covalent modification of CDK2 to treat CDK2-mediated disorders are described.

  本文描述了具有CDK2识别基团结合到亲电体的杂环磺酰化合物和组合物，用于选择性共价修饰CDK2以治疗CDK2介导的疾病。