(2R,3R,4R,5R)-2-(2-amino-6-ethoxy-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol | 1106011-12-4

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: (2R,3R,4R,5R)-2-(2-amino-6-ethoxy-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol
• 英文别名: 2-(2-amino-6-ethoxy-purin-9-yl)-5-hydroxymethyl-3-methyl-tetrahydrofuran-3,4-diol；2-(2-amino-6-ethoxy-purin-9-yl)-5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol；6-O-ethyl-2'-β-C-methylguanosine；2′-C-methyl-6-ethoxy-guanosine；(3R,4R,5R)-2-(2-amino-6-ethoxy-9H-purin-9-yl)-5-(hydroxymethyl)-3-methyltetrahydrofuran-3,4-diol；2-(2-amino-6-ethoxypurin-9-yl)-5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol；(2R,3R,4R,5R)-2-(2-amino-6-ethoxypurin-9-yl)-5-(hydroxymethyl)-3-methyloxolane-3,4-diol
• CAS: 1106011-12-4
• 化学式: C₁₃H₁₉N₅O₅
• 分子量: 325.324
• InChiKey: RDBMPIXNGFXEQI-VHQAPHLWSA-N

物化性质

• 沸点：
  684.5±65.0 °C(Predicted)
• 密度：
  1.74±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  149
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2R,3R,4R,5R)-2-(2-amino-6-ethoxy-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 (2S,2'S)-benzyl 2,2'-((((2R,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purin-9-yl)-3,4-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate
  参考文献：
  名称：

  Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

  摘要：

  We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2'-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both D and L., and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 mu M, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases.

  DOI：

  10.1021/jm2011673
• 作为产物：
  描述：

  2-氨基-6-氯嘌呤 在 三氟甲磺酸三甲基硅酯 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 5.0h， 生成 (2R,3R,4R,5R)-2-(2-amino-6-ethoxy-purin-9-yl)-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-3,4-diol
  参考文献：
  名称：

  Dual pro-drugs of 2′-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus

  摘要：

  We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate prodrug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.06.013

文献信息

• THIOPHOSPHATE NUCLEOSIDES FOR THE TREATMENT OF HCV
  申请人：IDENIX PHARMACEUTICALS, INC.

  公开号：US20140248242A1

  公开（公告）日：2014-09-04

  Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, the compounds are according to Formula 2001: where PD, Base, R A and R B are as provided herein. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

  本文提供了用于治疗黄病毒科感染，包括HCV感染的化合物、组合物和方法。在某些实施例中，所述化合物符合以下公式2001： 其中PD、Base、R A 和R B 如本文所述。在某些实施例中，披露了核苷类衍生物的化合物和组合物，可以单独或与其他抗病毒药物联合使用。
• 3',5'-CYCLIC PHOSPHATE PRODRUGS FOR HCV INFECTION
  申请人：Idenix Pharmaceuticals Inc.

  公开号：US20130315867A1

  公开（公告）日：2013-11-28

  Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

  本文提供了用于治疗黄病毒科感染，包括HCV感染的化合物、组合物和方法。在某些实施例中，披露了核苷类衍生物的化合物和组合物，可以单独或与其他抗病毒药物联合使用。
• DINUCLEOTIDE COMPOUNDS FOR HCV INFECTION
  申请人：IDENIX PHARMACEUTICALS, INC.

  公开号：US20140112886A1

  公开（公告）日：2014-04-24

  Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents. In certain embodiments, the compounds comprise two 2′-methyl nucleotides linked according to Formula I: N 1 -L-N 2 (I) or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, isomeric form, tautomeric form or polymorphic form thereof; wherein N 1 , L and N 2 are as described herein.

  本文提供了用于治疗黄病毒科感染，包括HCV感染的化合物、组合物和方法。在某些实施方式中，披露了核苷类衍生物的化合物和组合物，可以单独或与其他抗病毒药物联合给药。在某些实施方式中，所述化合物包括根据以下式I连接的两个2'-甲基核苷酸：N1-L-N2(I)或其药学上可接受的盐、酯、溶剂合物、立体异构体、同分异构体、互变异构体或其多形形式；其中N1、L和N2如本文所述。
• COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF VIRAL INFECTIONS
  申请人：SURLERAUX Dominique

  公开号：US20130064793A1

  公开（公告）日：2013-03-14

  Provided herein are compounds, compositions and methods for the treatment of liver disorders, including HCV infections. In one embodiment, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

  本文提供了用于治疗肝脏疾病，包括HCV感染的化合物、组合物和方法。在一种实施例中，披露了核苷衍生物的化合物和组合物，可以单独或与其他抗病毒药物联合使用。
• [EN] 2 '-C-METHYL NUCLEOSIDES CONTAINING A CYCLIC PHOSPHATE DIESTER OF 1, 3-PROPANEDIOL (2-OXO-[1, 3, 2]-DIOXAPHOSPHORINANE) AT POSITION 5'<br/>[FR] NUCLÉOSIDES 2'-C-MÉTHYL COMPRENANT UN DIESTER DE PHOSPHATE CYCLIQUE DE 1,3-PROPANEDIOL (2-OXO-[1,3,2]-DIOXAPHOSPHORINANE À LA POSITION 5'
  申请人：LIGAND PHARM INC

  公开号：WO2013106344A1

  公开（公告）日：2013-07-18

  2'-C-methyl nucleosides containing a 5'-monophosphate ester (a cyclic phosphate ester of 1,3-propanediol or 2-oxo-[1,3,2]-dioxaphos-phorinane) Compositions and methods relating to 2'-C-methyl nucleosides containing a 5'-monophosphate ester (a cyclic phosphate ester of 1,3-propanediol or 2-oxo-[1,3,2]-dioxaphosphorinane) are provided. In some embodiments, the novel compounds are useful to treat viral infections. In particular, 2'-C-methyl nucleoside 5'-monophosphate derivative compounds, stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof, their preparation, and their uses for the treatment of hepatitis C virus (HCV) are described. The compounds have the following formulas:

  提供了与2'-C-甲基核苷酸含有5'-单磷酸酯（1,3-丙二醇环状磷酸酯或2-氧-[1,3,2]-二氧杂磷杂环磷酸酯）相关的组合物和方法。在某些实施例中，这些新型化合物有助于治疗病毒感染。具体地，描述了2'-C-甲基核苷酸5'-单磷酸衍生物化合物、立体异构体及其药学上可接受的盐或前药的制备以及它们用于治疗丙型肝炎病毒（HCV）的用途。这些化合物具有以下公式：