3-(4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-N-hydroxybenzenecarboximidamide | 244618-40-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 3-(4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-N-hydroxybenzenecarboximidamide
• 英文别名: 3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-N-hydroxybenzenecarboximidamide；3-[4-[5-[(2S,6R)-2,6-dimethylpiperidin-1-yl]pentyl]-3-oxo-1,4-benzoxazin-2-yl]-N'-hydroxybenzenecarboximidamide
• CAS: 244618-40-4
• 化学式: C₂₇H₃₆N₄O₃
• 分子量: 464.608
• InChiKey: GBNBQTSYMGOUTA-WPUZRXDDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  91.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-N-hydroxybenzenecarboximidamide 在 palladium on activated charcoal 氢气 作用下， 20.0~23.0 ℃ 、344.75 kPa 条件下， 反应 50.0h， 生成 3-(4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-benzenecarboximidamide bis-trifluoroacetate
  参考文献：
  名称：

  Rational Design, Synthesis, and Biological Activity of Benzoxazinones as Novel Factor Xa Inhibitors

  摘要：

  Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development, From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1,4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC50 of 27 muM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2N)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC50 of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.

  DOI：

  10.1021/jm000074l
• 作为产物：
  描述：

  2-溴-2-(3-溴苯基)乙酸甲酯 在 四(三苯基膦)钯 、 盐酸羟胺 、 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 64.25h， 生成 3-(4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-N-hydroxybenzenecarboximidamide
  参考文献：
  名称：

  Rational Design, Synthesis, and Biological Activity of Benzoxazinones as Novel Factor Xa Inhibitors

  摘要：

  Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development, From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1,4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC50 of 27 muM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2N)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC50 of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.

  DOI：

  10.1021/jm000074l

文献信息

• Benoxazinones/benzothiazinones as serine protease inhibitors
  申请人：——

  公开号：US20030187256A1

  公开（公告）日：2003-10-02

  This invention discloses benzoxazinone and benzothiazinone compounds which display inhibitory effects on serine proteases such as factor Xa, thrombin, and/or factor VIIa. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.

  本发明揭示了苯并噁嗪和苯并噻嗪化合物，这些化合物对丝氨酸蛋白酶如Xa因子，凝血酶和/或VIIa因子具有抑制作用。本发明还揭示了这些化合物的药学上可接受的盐，包含这些化合物或其盐的药学上可接受的组合物，以及将它们用作治疗或预防哺乳动物异常血栓病状态的治疗剂的方法。
• US6509335B1
  申请人：——

  公开号：US6509335B1

  公开（公告）日：2003-01-21
• Rational Design, Synthesis, and Biological Activity of Benzoxazinones as Novel Factor Xa Inhibitors
  作者：Danette A. Dudley、Amy M. Bunker、Liguo Chi、Wayne L. Cody、Debra R. Holland、Diane P. Ignasiak、Nancy Janiczek-Dolphin、Thomas B. McClanahan、Thomas E. Mertz、Lakshmi S. Narasimhan、Stephen T. Rapundalo、Julia A. Trautschold、Chad A. Van Huis、Jeremy J. Edmunds

  DOI：10.1021/jm000074l

  日期：2000.11.1

  Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development, From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1,4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC50 of 27 muM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2,6-dimethyltetrahydro-1(2N)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC50 of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.