4-benzyloxy-3-[4-(5-bromopentyl)-3-oxo-3,4-dihydroquinoxalin-2-yl]benzonitrile | 245554-90-9

• 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: 4-benzyloxy-3-[4-(5-bromopentyl)-3-oxo-3,4-dihydroquinoxalin-2-yl]benzonitrile
• 英文别名: 3-[4-(5-Bromopentyl)-3-oxoquinoxalin-2-yl]-4-phenylmethoxybenzonitrile
• CAS: 245554-90-9
• 化学式: C₂₇H₂₄BrN₃O₂
• 分子量: 502.41
• InChiKey: QKFSAMSXNCTQND-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  65.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-benzyloxy-3-[4-(5-bromopentyl)-3-oxo-3,4-dihydroquinoxalin-2-yl]benzonitrile 在 盐酸 、 乙醇 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 42.0h， 生成 3-(4-(5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl)-3-oxo-3,4-dihydro-2-quinoxalinyl)-4-hydroxybenzenecarboximidamide
  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 、 四(三苯基膦)钯 、 草酰氯 、 caesium carbonate 、 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 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.5h， 生成 4-benzyloxy-3-[4-(5-bromopentyl)-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

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：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
• US6916805B2
  申请人：——

  公开号：US6916805B2

  公开（公告）日：2005-07-12
• [EN] QUINOXALINONES AS SERINE PROTEASE INHIBITORS SUCH AS FACTOR XA AND THROMBIN<br/>[FR] QUINOXALINONES COMME INHIBITEURS DE SERINES-PROTEASES TELLES QUE LE FACTEUR XA ET LA THROMBINE
  申请人：WARNER-LAMBERT COMPANY

  公开号：WO1999050254A1

  公开（公告）日：1999-10-07

  (EN) This invention discloses quinoxalinones according to Formula (I) or stereoisomers or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, 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 quinoxalinones représentées par la formule (I), ou des stéréo-isomères ou leurs sels, esters, amides ou promédicaments pharmaceutiquement acceptables, lesquelles 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 promédicaments pharmaceutiquement acceptables des composés, des compositions pharmaceutiquement acceptables contenant ces composés, leurs sels ou 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.