ethyl (2S)-2-{[{[(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl]methoxy}(4-chlorophenoxy)phosphoryl]amino}propanoate | 946511-13-3

• 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: ethyl (2S)-2-{[{[(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl]methoxy}(4-chlorophenoxy)phosphoryl]amino}propanoate
• 英文别名: 5'-O-[(4-chlorophenoxy)[[(1S)-2-ethoxy-1-methyl-2-oxoethyl]amino]phosphinyl]-2'-C-methylcytidine；ethyl (2S)-2-[[[(2R,3R,4R,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-3,4-dihydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-(4-chlorophenoxy)phosphoryl]amino]propanoate；ethyl (2S)-2-[[[(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxy-4-methyloxolan-2-yl]methoxy-(4-chlorophenoxy)phosphoryl]amino]propanoate
• CAS: 946511-13-3
• 化学式: C₂₁H₂₈ClN₄O₉P
• 分子量: 546.901
• InChiKey: UJVJXIDGFAFXMM-WOPWQOAWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  182
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  ethyl (2S)-2-{[{[(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl]methoxy}(4-chlorophenoxy)phosphoryl]amino}propanoate 在 水 、 三乙胺 作用下， 反应 15.0h， 以54%的产率得到5'-O-({[(1S)-1-carboxylatoethyl]amino}phosphinato)-2'-C-methylcytidine
  参考文献：
  名称：

  Phosphoramidate Prodrugs of 2′-C-Methylcytidine for Therapy of Hepatitis C Virus Infection

  摘要：

  The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.

  DOI：

  10.1021/jm900447q
• 作为产物：
  描述：

  ethyl N-[chloro(4-chlorophenoxy)phosphoryl]-L-alaninate 、 2'-C-甲基胞嘧啶核苷 在 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 以659 mg的产率得到ethyl (2S)-2-{[{[(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl]methoxy}(4-chlorophenoxy)phosphoryl]amino}propanoate
  参考文献：
  名称：

  Cyclic phosphoramidates as prodrugs of 2′-C-methylcytidine

  摘要：

  The currently approved treatment for hepatitis C virus infections is a combination of Ribavirin and pegylated Interferon. It leads to a sustained virologic response in approximately only half of the patients treated. For this reason there is an urgent need of new therapeutic agents. 2'-C-Methylcytidine is the first nucleoside inhibitor of the HCV NS5B polymerase that was efficacious in reducing the viral load in patients infected with HCV. The application of a monophosphate prodrug approach based on unprecedented cyclic phosphoramidates is reported. Our SAR studies led to compounds that are efficiently converted to the active triphosphate in human hepatocytes. (C) 2009 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2009.04.043

文献信息

• Nucleoside Aryl Phosphoramidates for the Treatment of RNA-Dependent RNA Viral Infection
  申请人：MacCoss Malcolm

  公开号：US20100234316A1

  公开（公告）日：2010-09-16

  The present invention provides nucleoside aryl phosphoramidates of structural formula (I) which are precursors to inhibitors of RNA-dependent RNA viral polymerase. These compounds are precursors to inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as precursors to inhibitors of hepatitis C virus (HCV) NS5B polymerase, as precursors to inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside aryl phosphoramidates alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside aryl phosphoramidates of the present invention.

  本发明提供了结构式（I）的核苷酸芳基磷酰胺酯，这些化合物是RNA依赖性RNA病毒聚合酶抑制剂的前体。这些化合物是RNA依赖性RNA病毒复制抑制剂的前体，对于治疗RNA依赖性RNA病毒感染非常有用。它们特别适用作为乙型肝炎病毒（HCV）NS5B聚合酶抑制剂的前体，作为HCV复制抑制剂的前体，和/或用于治疗乙型肝炎感染。本发明还描述了含有这种核苷酸芳基磷酰胺酯的药物组合物，单独或与其他针对RNA依赖性RNA病毒感染，特别是HCV感染的药剂结合使用。还公开了使用本发明的核苷酸芳基磷酰胺酯来抑制RNA依赖性RNA聚合酶、抑制RNA依赖性RNA病毒复制和/或治疗RNA依赖性RNA病毒感染的方法。
• NUCLEOSIDE CYCLIC PHOSPHORAMIDATES FOR THE TREATMENT OF RNA-DEPENDENT RNA VIRAL INFECTION
  申请人：Meppen Malte

  公开号：US20100022468A1

  公开（公告）日：2010-01-28

  The present invention provides nucleoside cyclic phosphoramidates of structural formula (I) which are precursors to inhibitors of RNA-dependent RNA viral polymerase. These compounds are precursors to inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as pre-cursors to inhibitors of hepatitis C virus (HCV) NS5B polymerase, as precursors to inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside cyclic phosphoramidates alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside cyclic phosphoramidates of the present invention.

  本发明提供了结构式（I）的核苷酸环磷酰胺，它们是RNA依赖性RNA病毒聚合酶抑制剂的前体。这些化合物是RNA依赖性RNA病毒复制的抑制剂的前体，并且可用于治疗RNA依赖性RNA病毒感染。它们特别适用于作为丙型肝炎病毒（HCV）NS5B聚合酶抑制剂的前体，作为HCV复制抑制剂的前体和/或用于治疗丙型肝炎感染。本发明还描述了仅含有这种核苷酸环磷酰胺或与其他对RNA依赖性RNA病毒感染，特别是HCV感染活性的药物组合的制药组合物。本发明还公开了使用本发明的核苷酸环磷酰胺抑制RNA依赖性RNA聚合酶，抑制RNA依赖性RNA病毒复制和/或治疗RNA依赖性RNA病毒感染的方法。
• US7879815B2
  申请人：——

  公开号：US7879815B2

  公开（公告）日：2011-02-01
• US8148349B2
  申请人：——

  公开号：US8148349B2

  公开（公告）日：2012-04-03
• Phosphoramidate Prodrugs of 2′-<i>C</i>-Methylcytidine for Therapy of Hepatitis C Virus Infection
  作者：Cristina Gardelli、Barbara Attenni、Monica Donghi、Malte Meppen、Barbara Pacini、Steven Harper、Annalise Di Marco、Fabrizio Fiore、Claudio Giuliano、Vincenzo Pucci、Ralph Laufer、Nadia Gennari、Isabella Marcucci、Joseph F. Leone、David B. Olsen、Malcolm MacCoss、Michael Rowley、Frank Narjes

  DOI：10.1021/jm900447q

  日期：2009.9.10

  The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.