(S)-2-(1,3-dioxoisoindolin-2-yl)-N-(2-oxo-2-phenylethyl)-3-phenylpropanamide | 872017-63-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-(1,3-dioxoisoindolin-2-yl)-N-(2-oxo-2-phenylethyl)-3-phenylpropanamide
• 英文别名: (S)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-oxo-2-phenyl-ethyl)-3-phenyl-propionamide；(s)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-n-(2-oxo-2-phenyl-ethyl)-3-phenyl-propionamide；(2S)-2-(1,3-dioxoisoindol-2-yl)-N-phenacyl-3-phenylpropanamide
• CAS: 872017-63-5
• 化学式: C₂₅H₂₀N₂O₄
• 分子量: 412.445
• InChiKey: JXIYRYXJQCFMOL-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  83.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-2-(1,3-dioxoisoindolin-2-yl)-N-(2-oxo-2-phenylethyl)-3-phenylpropanamide 在 肼 、 三氯氧磷 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.83h， 生成 (S)-2-phenyl-1-(5-phenyloxazol-2-yl)ethanamine
  参考文献：
  名称：

  Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity

  摘要：

  Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (K-i = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.

  DOI：

  10.1021/jm5010607
• 作为产物：
  描述：

  2-氨基苯乙酮 、 N-邻苯二甲酰基-L-苯丙氨酸 在 吡啶 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 作用下， 反应 16.0h， 以100%的产率得到(S)-2-(1,3-dioxoisoindolin-2-yl)-N-(2-oxo-2-phenylethyl)-3-phenylpropanamide
  参考文献：
  名称：

  Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity

  摘要：

  Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (K-i = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.

  DOI：

  10.1021/jm5010607

文献信息

• Five-membered heterocycles useful as serine protease inhibitors
  申请人：Hangeland J. Jon

  公开号：US20050282805A1

  公开（公告）日：2005-12-22

  The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V): or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R 3 , R 4 , R 6 , R 11 , X 1 , X 2 , and X 3 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.

  本发明提供了一种治疗血栓性或炎症性疾病的方法，即向需要治疗的患者施用至少一种公式（I）或公式（V）化合物的治疗有效量，或其立体异构体或药学上可接受的盐或溶剂形式，其中变量A、L、Z、R3、R4、R6、R11、X1、X2和X3如本文所定义。公式（I）化合物可用作凝血级联和/或接触激活系统中丝氨酸蛋白酶酶的选择性抑制剂；例如凝血酶、Xa因子、XIa因子、IXa因子、VIIa因子和/或血浆激肽。特别是，涉及到选择性因子XIa抑制剂的化合物。本发明还提供了公式I范围内的化合物，并涉及包含这些化合物的制药组合物。
• FIVE-MEMBERED HETEROCYCLES USEFUL AS SERINE PROTEASE INHIBITORS
  申请人：Hangeland Jon J.

  公开号：US20090036438A1

  公开（公告）日：2009-02-05

  The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V): or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R 3 , R 4 , R 6 , R 11 , X 1 , X 2 , and X 3 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.

  本发明提供了一种治疗血栓性或炎症性疾病的方法，该方法向需要治疗的患者施用至少一种公式（I）或公式（V）中的化合物的治疗有效量：或其立体异构体或药学上可接受的盐或溶剂形式，其中变量A、L、Z、R3、R4、R6、R11、X1、X2和X3如本文所定义。公式（I）的化合物可用作凝血级联和/或接触激活系统的丝氨酸蛋白酶酶的选择性抑制剂；例如凝血酶、因子Xa、因子XIa、因子IXa、因子VIIa和/或血浆激肽。特别是，涉及到选择性因子XIa抑制剂的化合物。本发明还提供了公式I范围内的化合物，并涉及包含这些化合物的制药组合物。
• [EN] FIVE-MEMBERED HETEROCYCLES USEFUL AS SERINE PROTEASE INHIBITORS<br/>[FR] HETEROCYCLES A CINQ CHAINONS UTILISES COMME INHIBITEURS DE LA SERINE PROTEASE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2005123050A3

  公开（公告）日：2007-01-04
• US7453002B2
  申请人：——

  公开号：US7453002B2

  公开（公告）日：2008-11-18
• US8101778B2
  申请人：——

  公开号：US8101778B2

  公开（公告）日：2012-01-24