5-(5-苯基-4-((吡啶-2-甲基)氨基)喹唑啉-2-基)吡啶-3-磺酰胺 | 1272353-82-8

• 物质功能分类: 有机原料 - 杂环化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 5-(5-苯基-4-((吡啶-2-甲基)氨基)喹唑啉-2-基)吡啶-3-磺酰胺
• 英文名称: 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridine-3-sulfonamide
• 英文别名: 3-Pyridinesulfonamide, 5-(5-phenyl-4-((2-pyridinylmethyl)amino)-2-quinazolinyl)-；5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide
• CAS: 1272353-82-8
• 化学式: C₂₅H₂₀N₆O₂S
• 分子量: 468.539
• InChiKey: XGKULQQVQWCASY-UHFFFAOYSA-N

物化性质

• 沸点：
  662.6±65.0 °C(Predicted)
• 密度：
  1.393±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  132
• 氢给体数：
  2
• 氢受体数：
  8

制备方法与用途

BMS-919373是一种选择性和强效的IKur电流阻断剂，适用于心血管疾病的研宄。

反应信息

• 作为反应物：
  描述：

  5-(5-苯基-4-((吡啶-2-甲基)氨基)喹唑啉-2-基)吡啶-3-磺酰胺 在 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成
  参考文献：
  名称：

  Selective I_Kur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide

  摘要：

  We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent I-Kur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.

  DOI：

  10.1021/acs.jmedchem.6b01889
• 作为产物：
  描述：

  苯硼酸 在 bis-triphenylphosphine-palladium(II) chloride 盐酸 、 potassium acetate 、 三乙胺 、 sodium t-butanolate 作用下， 以 1,4-二氧六环 、 异丁酰胺 、 甲苯 为溶剂， 反应 22.0h， 生成 5-(5-苯基-4-((吡啶-2-甲基)氨基)喹唑啉-2-基)吡啶-3-磺酰胺
  参考文献：
  名称：

  [EN] QUINAZOLINES AS POTASSIUM ION CHANNEL INHIBITORS
  [FR] QUINAZOLINES COMME INHIBITEURS DES CANAUX IONIQUES POTASSIQUES

  摘要：

  其中A、X、Y、Z、R1和R24如所述的(I)式化合物。这些化合物作为钾通道功能的抑制剂以及用于治疗和预防心律不齐、IKur相关疾病和其他由离子通道功能介导的疾病是有用的。

  公开号：

  WO2011028741A1

文献信息

• Utilizing Native Directing Groups: Synthesis of a Selective I_Kur Inhibitor, BMS-919373, via a Regioselective C–H Arylation
  作者：Steven R. Wisniewski、Jason M. Stevens、Miao Yu、Kenneth J. Fraunhoffer、Evan O. Romero、Scott A. Savage

  DOI：10.1021/acs.joc.8b02254

  日期：2019.4.19

  BMS-919373 is a highly functionalized quinazoline under investigation as a selective, potent IKur current blocker. By utilizing the aminomethylpyridine side chain at C-4, a selective C–H functionalization at C-5 was invented, enabling the efficient synthesis of this molecule. The strategy of leveraging this inherent directing group allowed the synthesis of this complex heterocycle in only six steps from

  BMS-919373是一种高度功能化的喹唑啉，正在研究中，它是一种选择性的强效I Kur电流阻断剂。通过利用C-4处的氨基甲基吡啶侧链，发明了C-5处的选择性C–H功能化，从而使该分子得以有效合成。利用这种固有的导向基团的策略仅需六步即可从商品化学品合成这种复杂的杂环。进一步研究了C–H活化的范围，并探讨了一系列双环芳族杂环的转化一般性。
• [EN] PHOSPHORAMIDIC ACID PRODRUGS OF 5 - [5 - PHENYL- 4 - (PYRIDIN- 2 - YLMETHYLAMINO) QUINAZOLIN- 2 - YL] PYRIDINE- 3 - SULFONAMIDE<br/>[FR] PROMÉDICAMENTS D'ACIDE PHOSPHORAMIDIQUE DE 5-[5-PHÉNYL-4-(PYRIDIN-2-YLMÉTHYLAMINO)QUINAZOLIN-2-YLE]PYRIDINE-3-SULFONAMIDE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2013188254A1

  公开（公告）日：2013-12-19

  A compound of structural formula (I), wherein R is H or -PO3H or a pharmaceutically acceptable salt form thereof. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

  其中R是H或-PO3H或其药物可接受的盐形式的化合物结构式(I)。这些化合物作为钾通道功能的抑制剂，以及用于治疗和预防心律不齐、IKur相关疾病和其他由离子通道功能介导的疾病是有用的。
• Quinazolines as potassium ion channel inhibitors
  申请人：Johnson James A.

  公开号：US08575184B2

  公开（公告）日：2013-11-05

  A compound of formula (I) wherein A, X, Y, Z, R1 and R24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, IKur-associated disorders, and other disorders mediated by ion channel function.

  化合物的化学式为(I)，其中A、X、Y、Z、R1和R24的描述见本文。这些化合物可用作钾通道功能的抑制剂，用于治疗和预防心律失常、IKur相关疾病和其他离子通道功能介导的疾病。
• QUINAZOLINES AS POTASSIUM ION CHANNEL INHIBITORS
  申请人：Bristol-Myers Squibb Company

  公开号：US20140031345A1

  公开（公告）日：2014-01-30

  A compound of formula I wherein A, X, Y, Z, R 1 and R 24 are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, I Kur -associated disorders, and other disorders mediated by ion channel function.

  化合物I的化学式如下，其中A，X，Y，Z，R1和R24的描述在此处。这些化合物可用作钾通道功能的抑制剂，并用于治疗和预防心律失常，IKur相关疾病以及其他离子通道功能介导的疾病。
• PHOSPHORAMIDIC ACID PRODRUGS OF 5-[5-PHENYL-4-(PYRIDIN-2-YLMETHYLAMINO)QUINAZOLIN-2-YL]PYRIDINE-3-SULFONAMIDE
  申请人：Bristol-Myers Squibb Company

  公开号：US20150175641A1

  公开（公告）日：2015-06-25

  A compound of structural formula (I), wherein R is H or —PO3H or a pharmaceutically acceptable salt form thereof. The compounds are useful as inhibitors of potassium channel function and in the treatment and prevention of arrhythmia, I Kur associated disorders, and other disorders mediated by ion channel function.

  结构式（I）的化合物，其中R为H或—PO3H或其药学上可接受的盐形式。这些化合物可用作钾通道功能的抑制剂，并用于治疗和预防心律失常、IKur相关疾病和其他离子通道功能介导的疾病。