2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one | 1071540-03-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one
• 英文别名: 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindol-1-one
• CAS: 1071540-03-8
• 化学式: C₁₆H₁₇N₃O₂
• 分子量: 283.33
• InChiKey: QJPYXMLUMZZRAE-UHFFFAOYSA-N

物化性质

• 沸点：
  453.9±55.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  56.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one 在 肼 、 三氯氧磷 作用下， 以 乙醇 为溶剂， 反应 18.0h， 生成 1-chloro-4-(6-methylpyridin-2-yl)phthalazine
  参考文献：
  名称：

  通过3-取代的3-羟基异吲哚啉-1-酮合成4-取代的氯邻苯二甲酰肼，二氢苯并氮杂氮杂二酮，2-吡唑基苯甲酸和2-吡唑基苯甲酰肼

  摘要：

  在本文中，我们描述了以良好的总收率进行的4-取代的氯邻苯二甲腈的一般三步合成。在关键步骤中，N，N-二甲基氨基邻苯二甲酰亚胺（8a）指导烷基，芳基和杂芳基有机金属试剂的选择性单加成反应，得到3-取代的3-羟基异吲哚满酮9b，9i - 9am。通过与肼反应，然后用POCl 3氯化，许多羟基异吲哚啉酮可转化为氯酞嗪1b - 1v。我们还发现了3-乙烯基和3-炔基-3-羟基异吲哚满酮的两个新颖的转化。将乙烯基有机金属试剂添加到N，N-二甲基氨基邻苯二甲酰亚胺（8a）通过提议的3-乙烯基-3-羟基异吲哚满酮中间体的扩环作用提供了二氢苯并氮杂氮杂二酮15a - 15c。3-炔基-3-羟基异吲哚啉酮与肼和取代的肼反应，生成2-吡唑基苯甲酸16a - 16d和2-吡唑基苯并酰肼17a - 17g，而不是预期的炔基酞菁。

  DOI：

  10.1021/jo3000628
• 作为产物：
  描述：

  苯酐 在 正丁基锂 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 4.5h， 生成 2-(dimethylamino)-3-hydroxy-3-(6-methylpyridin-2-yl)isoindolin-1-one
  参考文献：
  名称：

  通过3-取代的3-羟基异吲哚啉-1-酮合成4-取代的氯邻苯二甲酰肼，二氢苯并氮杂氮杂二酮，2-吡唑基苯甲酸和2-吡唑基苯甲酰肼

  摘要：

  在本文中，我们描述了以良好的总收率进行的4-取代的氯邻苯二甲腈的一般三步合成。在关键步骤中，N，N-二甲基氨基邻苯二甲酰亚胺（8a）指导烷基，芳基和杂芳基有机金属试剂的选择性单加成反应，得到3-取代的3-羟基异吲哚满酮9b，9i - 9am。通过与肼反应，然后用POCl 3氯化，许多羟基异吲哚啉酮可转化为氯酞嗪1b - 1v。我们还发现了3-乙烯基和3-炔基-3-羟基异吲哚满酮的两个新颖的转化。将乙烯基有机金属试剂添加到N，N-二甲基氨基邻苯二甲酰亚胺（8a）通过提议的3-乙烯基-3-羟基异吲哚满酮中间体的扩环作用提供了二氢苯并氮杂氮杂二酮15a - 15c。3-炔基-3-羟基异吲哚啉酮与肼和取代的肼反应，生成2-吡唑基苯甲酸16a - 16d和2-吡唑基苯并酰肼17a - 17g，而不是预期的炔基酞菁。

  DOI：

  10.1021/jo3000628

文献信息

• [EN] AURORA KINASE MODULATORS AND METHOD OF USE<br/>[FR] MODULATEURS D'AURORA KINASE ET PROCÉDÉ D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2009117157A1

  公开（公告）日：2009-09-24

  The present invention relates to chemical compounds having a general formula (I) wherein A1-5 and 7-8, D', L1, L2, R1, R3, R6-8, n and o are defined herein, and synthetic intermediates, which are capable of modulating the activity of Aurora kinase proteins and, thereby, influencing various disease states and conditions related to the activities of Aurora kinases. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.

  本发明涉及具有一般式(I)的化合物，其中在此定义了A1-5和7-8，D'，L1，L2，R1，R3，R6-8，n和o，以及合成中间体，这些化合物能够调节枢纽激酶蛋白的活性，从而影响与枢纽激酶活动相关的各种疾病状态和病况。例如，这些化合物能够影响细胞周期和细胞增殖过程，以治疗癌症和与癌症相关的疾病。该发明还包括包括这些化合物的药物组合物，以及治疗与枢纽激酶活性相关的疾病状态的方法。
• Aurora Kinase Modulators and Method of Use
  申请人：Amgen Inc.

  公开号：US20140336182A1

  公开（公告）日：2014-11-13

  The present invention relates to chemical compounds having a general formula I wherein A 1-8 , D′, L 1 , L 2 , R 1 , R 6-8 and n are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中A1-8、D'、L1、L2、R1、R6-8和n在此处定义，并且具有调节各种蛋白激酶受体酶并因此影响与这些激酶活动相关的各种疾病状态和病况的能力的合成中间体。例如，这些化合物能够调节枢纽激酶，从而影响细胞周期和细胞增殖过程，以治疗癌症和与癌症相关的疾病。该发明还包括包括这些化合物的药物组合物，以及治疗与枢纽激酶活性相关的疾病状态的方法。
• Aurora kinase modulators and method of use
  申请人：Cee Victor

  公开号：US20090069297A1

  公开（公告）日：2009-03-12

  The present invention relates to chemical compounds having a general formula I wherein A 1-8 , D′, L 1 , L 2 , R 1 , R 6-8 and n are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中A1-8，D'，L1，L2，R1，R6-8和n在此定义，并且合成中间体，它们能够调节各种蛋白激酶受体酶，并因此影响与这些激酶活动相关的各种疾病状态和情况。例如，这些化合物能够调节极化激酶，从而影响细胞周期和细胞增殖过程，以治疗癌症和与癌症相关的疾病。本发明还包括包括这些化合物的药物组合物以及治疗与极化激酶活性相关的疾病状态的方法。
• AURORA KINASE MODULATORS AND METHOD OF USE
  申请人：Deak Holly

  公开号：US20100280008A1

  公开（公告）日：2010-11-04

  The present invention relates to chemical compounds having a general formula I wherein A 1-8 , D′, L 1 , L 2 , R 1 , R 6-8 and n are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.

  本发明涉及具有一般式I的化合物，其中A1-8、D'、L1、L2、R1、R6-8和n在此定义，并且合成中间体能够调节各种蛋白激酶受体酶，从而影响与这些激酶活动相关的各种疾病状态和条件。例如，这些化合物能够调节极化分裂激酶，从而影响细胞周期和细胞增殖的过程，以治疗癌症和与癌症相关的疾病。该发明还包括包括这些化合物的药物组合物以及治疗与极化分裂激酶活性相关的疾病状态的方法。
• Discovery of <i>N</i>-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines
  作者：Stephanie Geuns-Meyer、Victor J. Cee、Holly L. Deak、Bingfan Du、Brian L. Hodous、Hanh Nho Nguyen、Philip R. Olivieri、Laurie B. Schenkel、Karina R. Vaida、Paul Andrews、Annette Bak、Xuhai Be、Pedro J. Beltran、Tammy L. Bush、Mary K. Chaves、Grace Chung、Yang Dai、Patrick Eden、Kelly Hanestad、Liyue Huang、Min-Hwa Jasmine Lin、Jin Tang、Beth Ziegler、Robert Radinsky、Richard Kendall、Vinod F. Patel、Marc Payton

  DOI：10.1021/acs.jmedchem.5b00183

  日期：2015.7.9

  Efforts to improve upon the physical properties and metabolic stability of Aurora kinase inhibitor 14a revealed that potency against multidrug-resistant cell lines was compromised by increased polarity. Despite its high in vitro metabolic intrinsic clearance, 23r (AMG 900) showed acceptable pharmacokinetic properties and robust pharmacodynamic activity. Projecting from in vitro data to in vivo target coverage was not practical due to disjunctions between enzyme and cell data, complex and apparently contradictory indicators of binding kinetics, and unmeasurable free fraction in plasma. In contrast, it was straightforward to relate pharmacokinetics to pharmacodynamics and efficacy by following the time above a threshold concentration. On the basis of its oral route of administration, a selectivity profile that favors Aurora-driven pharmacology and its activity against multidrug-resistant cell lines, 23r was identified as a potential best-in-class Aurora kinase inhibitor. In phase 1 dose expansion studies with G-CSF support, 23r has shown promising single agent activity.