2-chloro-N-(3-(morpholinosulfonyl)phenyl)-5-phenylquinazolin-4-amine | 1272354-30-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-chloro-N-(3-(morpholinosulfonyl)phenyl)-5-phenylquinazolin-4-amine
• 英文别名: 2-chloro-N-(3-morpholin-4-ylsulfonylphenyl)-5-phenylquinazolin-4-amine
• CAS: 1272354-30-9
• 化学式: C₂₄H₂₁ClN₄O₃S
• 分子量: 480.975
• InChiKey: SOGWIWNKUJOJIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  92.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-chloro-N-(3-(morpholinosulfonyl)phenyl)-5-phenylquinazolin-4-amine 、 嘧啶-5-硼酸嚬哪醇酯 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 以28.1%的产率得到N-(3-(morpholinosulfonyl)phenyl)-5-phenyl-2-(pyrimidin-5-yl)quinazolin-4-amine
  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：

  2,4-dichloro-5-phenylquinazoline 、 2‘-三氟甲基联苯-3-羧醛 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 14.08h， 以8.61%的产率得到2-chloro-N-(3-(morpholinosulfonyl)phenyl)-5-phenylquinazolin-4-amine
  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

文献信息

• 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。
• Quinazolines as potassium ion channel inhibitors
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US10676460B2

  公开（公告）日：2020-06-09

  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.

  式 I 的化合物 其中 A、X、Y、Z、R1 和 R24 如本文所述。这些化合物可作为钾离子通道功能的抑制剂，用于治疗和预防心律失常、IKur 相关性疾病和其他由离子通道功能介导的疾病。
• US8575184B2
  申请人：——

  公开号：US8575184B2

  公开（公告）日：2013-11-05
• US9458114B2
  申请人：——

  公开号：US9458114B2

  公开（公告）日：2016-10-04
• US9822096B2
  申请人：——

  公开号：US9822096B2

  公开（公告）日：2017-11-21