2-amino-9-((1S,3R,4R,7R)-7-hydroxy-1-(hydroxymethyl)-4-methyl-2,5-dioxabicyclo[2.2.1]heptan-3-yl)-1H-purin-6(9H)-one | 1608455-82-8

• 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: 2-amino-9-((1S,3R,4R,7R)-7-hydroxy-1-(hydroxymethyl)-4-methyl-2,5-dioxabicyclo[2.2.1]heptan-3-yl)-1H-purin-6(9H)-one
• 英文别名: 2-amino-9-[(1S,3R,4R,7R)-7-hydroxy-1-(hydroxymethyl)-4-methyl-2,5-dioxabicyclo[2.2.1]heptan-3-yl]-1H-purin-6-one
• CAS: 1608455-82-8
• 化学式: C₁₂H₁₅N₅O₅
• 分子量: 309.282
• InChiKey: MIGBPNZAOXEJDS-SPFNVWMYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.4
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  144
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  ((1R,3R,4R,7R)-3-(2-amino-6-oxo-1H-purin-9(6H)-yl)-7-(benzyloxy)-4-methyl-2,5-dioxabicyclo[2.2.1]heptan-1-yl)methyl methanesulfonate 在 palladium 10% on activated carbon 、 氨 、 甲酸铵 作用下， 以 四氢呋喃 、 甲醇 、 二甲基亚砜 为溶剂， 反应 27.0h， 生成 2-amino-9-((1S,3R,4R,7R)-7-hydroxy-1-(hydroxymethyl)-4-methyl-2,5-dioxabicyclo[2.2.1]heptan-3-yl)-1H-purin-6(9H)-one
  参考文献：
  名称：

  Synthesis of 2′-O,4′-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase

  摘要：

  The synthesis of 2'-O,4'-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2'-C-methyl or 5'C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive hydrates prior to alkylation. The 2'-C-methyl- and 5'-C-methyl-modified bicyclic guanosines were evaluated, along with the known uracil-, cytosine-, adenine-, guanine-LNA and guanine-ENA nucleosides, as potential antiviral agents and found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay. Examination of the corresponding nucleoside triphosphates, however, against the purified HCV NS5B polymerase indicated that LNA-G and 2'-C-methyl-LNA-G are potent inhibitors of both 1b wild type and S282T mutant enzymes in vitro. Activity was further demonstrated for the LNA-G-triphosphate against HCV NS5B polymerase genotypes 1a, 2a, 3a and 4a. A phosphorylation by-pass prodrug strategy may be required to promote anti-HCV activity in the replicon assay. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.04.050

文献信息

• 2′,4′-bridged nucleosides for HCV infection
  申请人：IDENIX PHARMACEUTICALS LLC

  公开号：US10723754B2

  公开（公告）日：2020-07-28

  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. In certain embodiments, the compounds are 2′,4′-bridged nucleosides which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the 2′,4′-bridged nucleosides are of Formula 3001: or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, where PD, B, W, X, RA, RB, RC and RD 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。在某些实施方案中，公开了核苷衍生物的化合物和组合物，可单独使用或与其他抗病毒药物联合使用。在某些实施方案中，这些化合物是2′,4′桥接核苷，在治疗人类HCV感染等方面具有显著的疗效和生物利用度。在某些实施方案中，2′，4′桥核苷为式3001： 或其药学上可接受的盐、溶液、立体异构体、同分异构体或多晶型，其中 PD、B、W、X、RA、RB、RC 和 RD 如本文所述。
• [EN] 2',4'-BRIDGED NUCLEOSIDES FOR HCV INFECTION<br/>[FR] NUCLÉOSIDES 2', 4'-PONTÉS POUR L'INFECTION PAR LE VHC
  申请人：IDENIX PHARMACEUTICALS INC

  公开号：WO2014066239A1

  公开（公告）日：2014-05-01

  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 are 2',4'-bridged nucleosides which display remarkable efficacy and bioavailability for the treatment of, for example, HCV infection in a human. In certain embodiments, the 2',4'-bridged nucleosides are of Formula 3001:(I) (3001); or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, where PD, B, W, X, RA, RB, RC and RD are as described herein.
• Synthesis of 2′-O,4′-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase
  作者：Christopher Chapron、Rebecca Glen、Massimiliano La Colla、Benjamin A. Mayes、Joseph F. McCarville、Stephen Moore、Adel Moussa、Ruhul Sarkar、Maria Seifer、Ilaria Serra、Alistair Stewart

  DOI：10.1016/j.bmcl.2014.04.050

  日期：2014.6

  The synthesis of 2'-O,4'-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2'-C-methyl or 5'C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive hydrates prior to alkylation. The 2'-C-methyl- and 5'-C-methyl-modified bicyclic guanosines were evaluated, along with the known uracil-, cytosine-, adenine-, guanine-LNA and guanine-ENA nucleosides, as potential antiviral agents and found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay. Examination of the corresponding nucleoside triphosphates, however, against the purified HCV NS5B polymerase indicated that LNA-G and 2'-C-methyl-LNA-G are potent inhibitors of both 1b wild type and S282T mutant enzymes in vitro. Activity was further demonstrated for the LNA-G-triphosphate against HCV NS5B polymerase genotypes 1a, 2a, 3a and 4a. A phosphorylation by-pass prodrug strategy may be required to promote anti-HCV activity in the replicon assay. (C) 2014 Elsevier Ltd. All rights reserved.