N¹-(3-cyanobenzoyl)-N²-(4-tert-butylbenzoyl)-5-methoxycarbonyl-1,2-benzenediamine | 219519-61-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N¹-(3-cyanobenzoyl)-N²-(4-tert-butylbenzoyl)-5-methoxycarbonyl-1,2-benzenediamine
• 英文别名: 5-methoxycarbonyl-N1-(3-cyanobenzoyl)-N2-(4-t-butylbenzoyl)-1,2-benzenediamine；Methyl 4-[(4-tert-butylbenzoyl)amino]-3-[(3-cyanobenzoyl)amino]benzoate
• CAS: 219519-61-6
• 化学式: C₂₇H₂₅N₃O₄
• 分子量: 455.513
• InChiKey: RVTLUZXHBOFYLM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N¹-(3-cyanobenzoyl)-N²-(4-tert-butylbenzoyl)-5-methoxycarbonyl-1,2-benzenediamine 在 lithium hydroxide 、 盐酸羟胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 为溶剂， 生成 N¹-(3-(amino(hydroxyimino)methyl)benzoyl)-N²-(4-tert-butylbenzoyl)-5-benzyloxycarbonyl-1,2-benzenediamine
  参考文献：
  名称：

  Structure-Based Design of Potent, Amidine-Derived Inhibitors of Factor Xa:  Evaluation of Selectivity, Anticoagulant Activity, and Antithrombotic Activity

  摘要：

  To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of Ma to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in Ma affinity and a refined model of the new inhibitors in the Ma active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of Ma relative to other trypsin-like serine proteases. Furthermore, the Ma affinity of compounds in this series (K-ass = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

  DOI：

  10.1021/jm9903287
• 作为产物：
  描述：

  3,4-二氨基苯甲酸甲酯 在 吡啶 作用下， 以 乙腈 为溶剂， 生成 N¹-(3-cyanobenzoyl)-N²-(4-tert-butylbenzoyl)-5-methoxycarbonyl-1,2-benzenediamine
  参考文献：
  名称：

  Structure-Based Design of Potent, Amidine-Derived Inhibitors of Factor Xa:  Evaluation of Selectivity, Anticoagulant Activity, and Antithrombotic Activity

  摘要：

  To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of Ma to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in Ma affinity and a refined model of the new inhibitors in the Ma active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of Ma relative to other trypsin-like serine proteases. Furthermore, the Ma affinity of compounds in this series (K-ass = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

  DOI：

  10.1021/jm9903287

文献信息

• Antithrombotic agents
  申请人：Eli Lilly and Company

  公开号：US06417200B1

  公开（公告）日：2002-07-09

  This application relates to a compound of formula (I), a pharmaceutically acceptable salt of the compound, or a prodrug thereof, as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its preparation and intermediates therefor.

  这种应用涉及到式(I)的化合物，该化合物的药用盐或其前药，如本文所定义的，以及其药物组合物，以及其作为Xa因子抑制剂的用途，以及其制备方法和中间体。
• EP1007037A4
  申请人：——

  公开号：EP1007037A4

  公开（公告）日：2004-10-06
• ANTITHROMBOTIC AGENTS
  申请人：ELI LILLY AND COMPANY

  公开号：EP1007037A1

  公开（公告）日：2000-06-14
• US6417200B1
  申请人：——

  公开号：US6417200B1

  公开（公告）日：2002-07-09
• US6677369B2
  申请人：——

  公开号：US6677369B2

  公开（公告）日：2004-01-13