ethyl N-[chloro(4-chlorophenoxy)phosphoryl]-L-alaninate | 840506-39-0

• 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 N-[chloro(4-chlorophenoxy)phosphoryl]-L-alaninate
• 英文别名: 4-chlorophenyl(ethoxy-L-alaninyl)phosphochloridate；ethyl N-[chloro(4-chlorophenoxy)phosphoryl]-1-alaninate；4-chlorophenyl-(ethoxy-L-alaninyl)-phosphorochloridate；4-chlorophenyl 2-ethoxyalaninyl phosphorochloridate；ethyl (2S)-2-[[chloro-(4-chlorophenoxy)phosphoryl]amino]propanoate
• CAS: 840506-39-0
• 化学式: C₁₁H₁₄Cl₂NO₄P
• 分子量: 326.116
• InChiKey: PEYQUDAZUXFFHR-LQABBHMDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  L-丙氨酸乙酯盐酸盐 、 4-氯苯基二氯磷酸酯 以 二氯甲烷 为溶剂， 生成 ethyl N-[chloro(4-chlorophenoxy)phosphoryl]-L-alaninate
  参考文献：
  名称：

  发现用于治疗丙型肝炎病毒的 β-d-2'-Deoxy-2'-α-fluoro-2'-β-C-甲基尿苷核苷酸前药 (PSI-7977)

  摘要：

  丙型肝炎病毒 (HCV) 是一个全球性的健康问题，需要新的方法来有效治疗这种疾病。HCV NS5B 聚合酶已被证明是开发 HCV 疗法的可行靶标。β- d -2'-Deoxy-2'-α-fluoro-2'-β- C-甲基核苷是 HCV NS5B 聚合酶的选择性抑制剂，并已在临床上显示出有效的活性。制备了 β- d -2'-deoxy-2'-α-fluoro-2'-β- C-甲基尿苷核苷的 5'-磷酸衍生物的氨基磷酸酯前药，并在 HCV 亚基因组复制子测定中显示出显着的效力（< 1 μM）并产生高水平的三磷酸盐6当体内给药时，在原代肝细胞和大鼠、狗和猴子的肝脏中。使非对映体混合物14的单一非对映体51结晶，确定X射线结构，将氨基磷酸酯立体化学建立为S p ，从而首次将氨基磷酸酯前药的立体化学与生物活性相关联。51（PSI-7977）被选为临床开发候选者。

  DOI：

  10.1021/jm100863x

文献信息

• [EN] CARBA-NUCLEOSIDE ANALOGS FOR ANTIVIRAL TREATMENT<br/>[FR] ANALOGUES DE CARBA-NUCLÉOSIDE POUR UN TRAITEMENT ANTIVIRAL
  申请人：GILEAD SCIENCES INC

  公开号：WO2009132123A1

  公开（公告）日：2009-10-29

  Provided are imidazol [1,5-f] [1,2.4]triazinyl, imidazol [1,2,4]triazinyl, and [1,2,4] triazolo [4,3-f] [1,2,4] triazinyl nucleosides of formula I nucleoside phosphates and prodrugs thereof. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections. Wherein X1 or X2 is indepently C-R10 or N and wherein at least one of X1 or X2 is N.

  提供的是式I核苷酸磷酸酯和其前药，包括咪唑[1,5-f][1,2.4]三唑基、咪唑[1,2,4]三唑基和[1,2,4]三唑[4,3-f][1,2,4]三唑基。所提供的化合物、组合物和方法对于治疗黄病毒科病毒感染，特别是丙型肝炎感染，具有益处。其中X1或X2独立地为C-R10或N，且至少其中之一为N。
• [EN] CARBA-NUCLEOSIDE ANALOGS FOR ANTIVIRAL TREATMENT<br/>[FR] ANALOGUES DE CARBA-NUCLÉOSIDE POUR TRAITEMENT ANTIVIRAL
  申请人：GILEAD SCIENCES INC

  公开号：WO2010093608A1

  公开（公告）日：2010-08-19

  Provided are thieno[3,4-d]pyrimidin-7-yI and furo[3,4-d]pyrimidin-7-yl ribosides, riboside phosphates and prodrugs thereof as well as intermediates and methods of preparation. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections.

  提供了噻吩[3,4-d]嘧啶-7-基和呋喃[3,4-d]嘧啶-7-基核糖苷、核糖苷磷酸盐及其前药，以及其中间体和制备方法。所提供的化合物、组合物和方法对于治疗黄病毒科病毒感染是有用的。
• 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。
• Nucleoside aryl phosphoramidates for the treatment of RNA-dependent RNA viral infection
  申请人：Merck Sharp & Dohme Corp.

  公开号：US07879815B2

  公开（公告）日：2011-02-01

  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衍生物，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病毒复制的抑制剂前体，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聚合酶抑制剂前体，作为HCV复制抑制剂前体，和/或用于治疗丙型肝炎感染。该发明还描述了包含这种核苷酸芳基磷酰胺衍生物的药物组合物，单独或与其他针对RNA依赖性RNA病毒感染，特别是HCV感染的活性剂结合使用。本发明还揭示了使用这些核苷酸芳基磷酰胺衍生物抑制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。