3-(2-benzyloxy-5-bromophenyl)-1-quinoxalin-2-one | 245554-88-5

• 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: 3-(2-benzyloxy-5-bromophenyl)-1-quinoxalin-2-one
• 英文别名: 3-[2-(benzyloxy)-5-bromophenyl]-2(1H)-quinoxalinone；3-(5-bromo-2-phenylmethoxyphenyl)-1H-quinoxalin-2-one
• CAS: 245554-88-5
• 化学式: C₂₁H₁₅BrN₂O₂
• 分子量: 407.266
• InChiKey: MWWUJTUOZDTFAH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  50.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(2-benzyloxy-5-bromophenyl)-1-quinoxalin-2-one 在 四(三苯基膦)钯 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 4-benzyloxy-3-{4-[5-((2S,6R)-2,6-dimethylpiperidin-1-yl)pentyl]-3-oxo-3,4-dihydroquinoxalin-2-yl}benzonitrile
  参考文献：
  名称：

  Design, Synthesis, and Biological Activity of Potent and Selective Inhibitors of Blood Coagulation Factor Xa

  摘要：

  Factor Xa (FXa) has materialized as a key enzyme for the intervention of the blood coagulation cascade and for the development of new antithrombotic agents. FXa is the lone enzyme responsible for the production of thrombin and therefore is an attractive target for the control of thrombus formation. We have designed and synthesized a unique series of quinoxalinone FXa inhibitors. This series resulted in 3-{4-[5-((2S,6R)-2,6-dimethylpiperidin-1-yl)pentyl]-3oxo-3,4-dihydroquinoxolin-2-yl}benzamidine (35) with 0.83 nM activity against FXa and excellent selectivity over similar serine proteases. An X-ray crystal structure of compound 35 bound to trypsin along with molecular modeling has led to a predicted binding conformation of compound 35 in FXa. Compound 35 has also been proven to be efficacious in vivo in both the rabbit veno-venous shunt and dog electrolytic injury models. In addition, it was shown that compound 35 did not significantly increase bleeding times in a rabbit model except at the highest doses and plasma concentrations were elevated in a dose dependent manner following a bolus dose and continuous intravenous infusion.

  DOI：

  10.1021/jm0497491
• 作为产物：
  描述：

  2-[2-(benzyloxy)-5-bromophenyl]-2-hydroxyacetonitrile 在 盐酸 、 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 反应 5.5h， 生成 3-(2-benzyloxy-5-bromophenyl)-1-quinoxalin-2-one
  参考文献：
  名称：

  Design, Synthesis, and Biological Activity of Potent and Selective Inhibitors of Blood Coagulation Factor Xa

  摘要：

  Factor Xa (FXa) has materialized as a key enzyme for the intervention of the blood coagulation cascade and for the development of new antithrombotic agents. FXa is the lone enzyme responsible for the production of thrombin and therefore is an attractive target for the control of thrombus formation. We have designed and synthesized a unique series of quinoxalinone FXa inhibitors. This series resulted in 3-{4-[5-((2S,6R)-2,6-dimethylpiperidin-1-yl)pentyl]-3oxo-3,4-dihydroquinoxolin-2-yl}benzamidine (35) with 0.83 nM activity against FXa and excellent selectivity over similar serine proteases. An X-ray crystal structure of compound 35 bound to trypsin along with molecular modeling has led to a predicted binding conformation of compound 35 in FXa. Compound 35 has also been proven to be efficacious in vivo in both the rabbit veno-venous shunt and dog electrolytic injury models. In addition, it was shown that compound 35 did not significantly increase bleeding times in a rabbit model except at the highest doses and plasma concentrations were elevated in a dose dependent manner following a bolus dose and continuous intravenous infusion.

  DOI：

  10.1021/jm0497491

文献信息

• Efficient syntheses of isotopically labeled PD0198961, a novel synthetic coagulation factor Xa inhibitor
  作者：Yinsheng Zhang

  DOI：10.1002/jlcr.1595

  日期：2009.6.15

  absorption, distribution, metabolism and elimination studies of the compound in animals and for use as mass spectral internal standards in support of bioanalytical assays, respectively. [14C]PD0198961 was prepared from [14C]CuCN in four radiosynthetic steps in an overall yield of 48% with a radiochemical purity of >99%. The cyanation reaction of an aromatic bromide with inorganic [14C]cyanide as a key

  PD0198961 被研究为一种有效的、选择性的凝血因子 Xa 抑制剂，用于治疗血栓性疾病。合成了放射性和稳定同位素标记的 PD0198961，用于该化合物在动物中的吸收、分布、代谢和消除研究，并分别用作支持生物分析测定的质谱内标。[14C]PD0198961由[14C]CuCN通过四个放射合成步骤制备，总产率为48%，放射化学纯度>99%。研究了芳香族溴化物与无机 [14C] 氰化物的氰化反应作为关键的放射性标记步骤。氘标记是在与 14C 标记不同的反应顺序中完成的。这种收敛过程通过顺式-2,6-二甲基[2H5]哌啶引入了稳定的同位素标记，由 2,6-二甲基吡啶与氘气催化加氢合成。版权所有 © 2009 John Wiley & Sons, Ltd.
• Quinoxalinones as serine protease inhibitors such as factor XA and thrombin
  申请人：Warner-Lambert Company

  公开号：US06410536B1

  公开（公告）日：2002-06-25

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

  该发明揭示了对丝氨酸蛋白酶如凝血因子Xa、凝血酶和/或凝血因子VIIa具有抑制作用的喹诺酮类化合物。该发明还揭示了这些化合物的药学上可接受的盐和前药，包含这些化合物、它们的盐或前药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中由异常血栓形成特征的疾病状态的方法。
• Quinoxalinones as serine protease inhibitors
  申请人：——

  公开号：US20020086866A1

  公开（公告）日：2002-07-04

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

  这项发明公开了对丝氨酸蛋白酶（如Xa因子、凝血酶和/或VIIa因子）具有抑制作用的喹诺酮。该发明还公开了该化合物的药物可接受的盐和前药、包含该化合物、其盐或前药的药物可接受的组合物，以及将其作为治疗剂用于治疗或预防哺乳动物的疾病状态，这些状态以异常血栓形成为特征的方法。
• QUINOXALINONES AS SERINE PROTEASE INHIBITORS SUCH AS FACTOR XA AND THROMBIN
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP1068190A1

  公开（公告）日：2001-01-17
• US6410536B1
  申请人：——

  公开号：US6410536B1

  公开（公告）日：2002-06-25