3-(2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile | 245425-39-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 3-(2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile
• 英文别名: 3-(3-cyanophenyl)-1,2,3,4-tetrahydro-2-quinolinone；3-(2-oxo-3,4-dihydro-1H-quinolin-3-yl)benzonitrile
• CAS: 245425-39-2
• 化学式: C₁₆H₁₂N₂O
• 分子量: 248.284
• InChiKey: IBRWGSMCJWWSCP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  52.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-(2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 64.25h， 生成 3-{1-[5-(2R,6S)-2,6-dimethylpiperidin-1-yl]pentyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinyl}benzenecarbonitrile
  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：

  3-羟基苯乙酸 在 palladium on activated charcoal 四(三苯基膦)钯 、 氢气 、 乙酸酐 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0~150.0 ℃ 、310.26 kPa 条件下， 反应 6.33h， 生成 3-(2-oxo-1,2,3,4-tetrahydro-3-quinolinyl)benzenecarbonitrile
  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

• Quinolones as serine protease inhibitors
  申请人：Dudley Danette Andrea

  公开号：US06855726B1

  公开（公告）日：2005-02-15

  The invention discloses quinolinones 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 a therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.

  本发明公开了喹诺酮类化合物，这些化合物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。本发明还公开了这些化合物的药物可接受的盐和前药，包含这些化合物的药物可接受组合物，以及使用它们作为治疗或预防哺乳动物异常血栓形成疾病状态的治疗剂的方法。
• QUINOLONES AS SERINE PROTEASE INHIBITORS
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP1091955A1

  公开（公告）日：2001-04-18
• US6855726B1
  申请人：——

  公开号：US6855726B1

  公开（公告）日：2005-02-15
• [EN] QUINOLONES AS SERINE PROTEASE INHIBITORS<br/>[FR] QUINOLONES COMME INHIBITEURS DE SERINES-PROTEASES
  申请人：WARNER-LAMBERT COMPANY

  公开号：WO1999050263A1

  公开（公告）日：1999-10-07

  (EN) This invention discloses quinolinones 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.(FR) L'invention concerne des composés de quinolinones qui ont des effets inhibiteurs sur des sérines-protéases telles que le facteur Xa, la thrombine et le facteur VIIa. L'invention concerne également des sels et des promédicaments pharmaceutiquement acceptables de ces composés, des compositions pharmaceutiquement acceptables contenant ces composés, leurs sels ou leurs promédicaments, ainsi que des méthodes pour les utiliser comme agents thérapeutiques pour traiter ou prévenir chez des mammifères des états pathologiques caractérisés par une thrombose anormale.
• Design, Synthesis, and Biological Activity of Potent and Selective Inhibitors of Blood Coagulation Factor Xa
  作者：J. Adam Willardsen、Danette A. Dudley、Wayne L. Cody、Liguo Chi、Thomas B. McClanahan、Thomas E. Mertz、Ronald E. Potoczak、Lakshmi S. Narasimhan、Debra R. Holland、Stephen T. Rapundalo、Jeremy J. Edmunds

  DOI：10.1021/jm0497491

  日期：2004.7.1

  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.