4'-azidouridine 5'-O-[phenyl(ethyloxy-L-cyclopentylglycinyl)] phosphate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4'-azidouridine 5'-O-[phenyl(ethyloxy-L-cyclopentylglycinyl)] phosphate
• 英文别名: ethyl N-[{1-((2R,3S,4R,5R)-5-azido-tetrahydro-3,4-dihydro-5-(hydroxymethyl)furan-2-yl)pyrimidine-2,4(1H,3H)-dione} (phenoxy)-phosphoryl]-cylopentylglycinate；1-{[(2R,3S,4R,5R)-2-Azido-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-cyclopentanecarboxylic acid ethyl ester；ethyl 1-[[[(2R,3S,4R,5R)-2-azido-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]cyclopentane-1-carboxylate
• 化学式: C₂₃H₂₉N₆O₁₀P
• 分子量: 580.491
• InChiKey: YRUOJALSRCTUBC-JAKNXHAOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  40
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  187
• 氢给体数：
  4
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  2',3'-O,O-cyclopentylidene-4'-azidouridine 在 甲酸 、 叔丁基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 21.25h， 生成 4'-azidouridine 5'-O-[phenyl(ethyloxy-L-cyclopentylglycinyl)] phosphate
  参考文献：
  名称：

  Application of the Phosphoramidate ProTide Approach to 4‘-Azidouridine Confers Sub-micromolar Potency versus Hepatitis C Virus on an Inactive Nucleoside

  摘要：

  We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.

  DOI：

  10.1021/jm0613370

文献信息

• Antiviral phosphoramidates
  申请人：Klumpp Klaus

  公开号：US20070042988A1

  公开（公告）日：2007-02-22

  The invention provides novel nucleoside compounds of formula I wherein R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 8a , R 9 and R 10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,

  该发明提供了一种新颖的核苷类化合物，其化学式为I，其中R1、R2a、R2b、R3、R4、R5、R6、R8a、R9和R10如本文所定义，这些化合物对治疗由丙型肝炎病毒（HCV）介导的疾病是有用的。该发明还提供了使用化合物I的方法进行治疗或预防HCV介导的疾病，以及包含这些化合物的药物组合物。
• ANTIVIRAL PHOSPHORAMIDATES OF 4'-SUBSTITUTED PRONUCLEOTIDES
  申请人：F.HOFFMANN-LA ROCHE AG

  公开号：EP1928475A2

  公开（公告）日：2008-06-11
• ANTIVIRAL PHOSPHORAMIDATES OF 4'-C-AZIDO-SUBSTITUTED PRONUCLEOTIDES
  申请人：Riboscience LLC

  公开号：EP1928475B1

  公开（公告）日：2018-05-23
• US7608599B2
  申请人：——

  公开号：US7608599B2

  公开（公告）日：2009-10-27
• [EN] ANTIVIRAL PHOSPHORAMIDATES<br/>[FR] PHOSPHORAMIDATES ANTIVIRAUX
  申请人：HOFFMANN LA ROCHE

  公开号：WO2007020193A2

  公开（公告）日：2007-02-22

  [EN] The invention provides novel nucleoside compounds of formula I wherein R¹, R^2a, R^2b, R³, R⁴, R⁵, R⁶, R^8a, R⁹ and R¹⁰ are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds. Formula (I)
  [FR] L'invention concerne des nouveaux composés nucléosides de formule (I) dans laquelle R¹, R^2a, R^2b, R³, R⁴, R⁵, R⁶, R^8a, R⁹ et R¹⁰ ont la signification indiquée dans la description, qui sont utilisés pour le traitement de maladies à médiation assurée par le virus de l'hépatite C (VHC). L'invention concerne en outre des méthodes de traitement ou de prophylaxie de maladies à médiation assurée par le VHC à l'aide des composés de formule (I) et des compositions pharmaceutiques comprenant lesdits composés.