methyl (chloro(4-chlorophenoxy)phosphoryl)glycinate | 940280-53-5

• 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: methyl (chloro(4-chlorophenoxy)phosphoryl)glycinate
• CAS: 940280-53-5
• 化学式: C₉H₁₀Cl₂NO₄P
• 分子量: 298.062
• InChiKey: LNXKYOMLSWNVRY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.83
• 重原子数：
  17.0
• 可旋转键数：
  5.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  64.63
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  N'-[9-[(2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]purin-6-yl]-N'-methylmethanesulfonohydrazide 、 methyl (chloro(4-chlorophenoxy)phosphoryl)glycinate 在 N-甲基咪唑 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 生成 methyl 2-[[(4-chlorophenoxy)-[[(2R,3R,4R,5R)-3,4-dihydroxy-5-[6-[methanesulfonamido(methyl)amino]purin-9-yl]-4-methyloxolan-2-yl]methoxy]phosphoryl]amino]acetate
  参考文献：
  名称：

  6-Hydrazinopurine 2′-methyl ribonucleosides and their 5′-monophosphate prodrugs as potent hepatitis C virus inhibitors

  摘要：

  A series of 6-hydrazinopurine 2 '-methyl ribonucleosides was synthesized and tested for its inhibitory activity against the hepatitis C virus (HCV). The lack of antiviral activity of these nucleosides was associated with a poor affinity for adenosine kinase, which prompted us to synthesize several of their 5 '-monophosphate prodrugs. Some of these prodrugs exhibited more than 1000-fold improvement in anti-HCV activity when compared to their parent nucleosides (EC50 of 24 mu M vs 92 mu M for the parent). (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.02.029
• 作为产物：
  描述：

  甘氨酸甲酯盐酸盐 、 4-氯苯基二氯磷酸酯 在 TEA 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 methyl (chloro(4-chlorophenoxy)phosphoryl)glycinate
  参考文献：
  名称：

  6-Hydrazinopurine 2′-methyl ribonucleosides and their 5′-monophosphate prodrugs as potent hepatitis C virus inhibitors

  摘要：

  A series of 6-hydrazinopurine 2 '-methyl ribonucleosides was synthesized and tested for its inhibitory activity against the hepatitis C virus (HCV). The lack of antiviral activity of these nucleosides was associated with a poor affinity for adenosine kinase, which prompted us to synthesize several of their 5 '-monophosphate prodrugs. Some of these prodrugs exhibited more than 1000-fold improvement in anti-HCV activity when compared to their parent nucleosides (EC50 of 24 mu M vs 92 mu M for the parent). (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.02.029

文献信息

• 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.