(R)-9-{2-[O,O'-bis(isopropoxycarbonyloxymethyl)thiophosphonomethoxy]propyl}adenine | 1173789-34-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (R)-9-{2-[O,O'-bis(isopropoxycarbonyloxymethyl)thiophosphonomethoxy]propyl}adenine
• 英文别名: (R)-9-[2-(thiophosphonomethoxy)propyl]adenine bis-isopropyloxycarbonyloxymethyl ester；[[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphinothioyl]oxymethyl propan-2-yl carbonate
• CAS: 1173789-34-8
• 化学式: C₁₉H₃₀N₅O₉PS
• 分子量: 535.515
• InChiKey: FLBNNVMXDHQGSP-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  35
• 可旋转键数：
  17
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  201
• 氢给体数：
  1
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  (R)-9-{2-[O,O'-bis(isopropoxycarbonyloxymethyl)thiophosphonomethoxy]propyl}adenine 在 水 作用下， 以30%的产率得到(R)-9-{2-[O-mono(isopropoxycarbonyloxymethyl)thiophosphonomethoxy]propyl}adenine
  参考文献：
  名称：

  Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study

  摘要：

  9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl] adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12,13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA Sand S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.02.039
• 作为产物：
  描述：

  替诺福韦二乙酯 在 N-甲基吡咯烷酮 、 三甲基氯硅烷 、 2,4-二(甲硫基)-1,3,2,4-二噻二磷杂丁环-2,4-二硫 、 sodium bromide 作用下， 以 苯 为溶剂， 反应 20.5h， 生成 (R)-9-{2-[O,O'-bis(isopropoxycarbonyloxymethyl)thiophosphonomethoxy]propyl}adenine
  参考文献：
  名称：

  Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study

  摘要：

  9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl] adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12,13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA Sand S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.02.039

文献信息

• NOVEL NUCLEOTIDE ANALOGUES AS PRECUSOR MOLECULES FOR ANTIVIRALS
  申请人：Canard Bruno

  公开号：US20100099869A1

  公开（公告）日：2010-04-22

  This invention relates to a purine or pyrimidine phosphonate compound of formula (I) or pharmaceutically acceptable salt thereof; wherein B, X, and R 1 -R 3 are as defined in classes and subclasses herein. These compounds may be used as antiviral precursors. The invention also relates to therapeutic compositions of these compounds and their use for the preparation of a medication for testing and/or preventing a viral infection in a patient. The invention also provides methods for making these compounds. In particular, the invention provides an H-phosphinate precursor intermediate of formula (II) wherein B is a purine or pyrimidine base as defined herein and R 1 is selected from the group comprising a hydrogen atom, and a methyl, ethyl, hydroxymethyl, hydroxyethyl and C 1-6 haloalkyl group.

  本发明涉及一种嘌呤或嘧啶磷酸酯化合物(I)或其药学上可接受的盐；其中B、X和R1-R3的定义如本文中的类和子类所述。这些化合物可以用作抗病毒前体。本发明还涉及这些化合物的治疗组合物及其用于制备用于测试和/或预防患者病毒感染的药物。本发明还提供制备这些化合物的方法。特别是，本发明提供了一种公式(II)的H-磷酸酯前体中间体，其中B是如本文所述的嘌呤或嘧啶碱基，R1选自包括氢原子，甲基，乙基，羟甲基，羟乙基和C1-6卤代烷基的群体。
• WO2008/56264
  申请人：——

  公开号：——

  公开（公告）日：——
• US8884011B2
  申请人：——

  公开号：US8884011B2

  公开（公告）日：2014-11-11
• [EN] NOVEL NUCLEOTIDE ANALOGUES AS PERCURSOR MOLECULES FOR ANTIVIRALS<br/>[FR] ANALOGUES DE NUCLÉOTIDES INNOVANTS EN TANT QUE MOLÉCULES PRÉCURSEURS D'ANTIVIRAUX
  申请人：CT NAT DE RECH SCIENT CNRS

  公开号：WO2008056264A2

  公开（公告）日：2008-05-15

  [EN] This invention relates to a purine or pyrimidine phosphonate compound of formula (I) or pharmaceutically acceptable salt thereof; wherein B, X, and R¹-R³ are as defined in classes and subclasses herein. These compounds may be used as antiviral precursors. The invention also relates to therapeutic compositions of these compounds and their use for the preparation of a medication for treating and/or preventing a viral infection in a patient. The invention also provides methods for making these compounds. In particular, the invention provides an H- phosphinate precursor intermediate of formula (II) wherein B is a purine or pyrimidine base as defined herein and R¹ is selected from the group comprising a hydrogen atom, and a methyl, ethyl, hydroxymethyl, hydroxyethyl and C_1-6haloalkyl group.
  [FR] La présente invention concerne un composé de phosphonate de purine ou de pyrimidine de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci ; dans laquelle B, X et R¹-R³ sont tels que définis dans les présentes classes et sous-classes. Ces composés peuvent être utilisés en tant que précurseurs d'antiviraux. L'invention concerne également des compositions thérapeutiques de ces composés et leur utilisation pour la préparation d'un médicament destiné au traitement et/ou à la prévention d'une infection virale chez un patient. L'invention concerne également des procédés de fabrication de ces composés. En particulier, L'invention concerne un intermédiaire précurseur de H-phosphinate de formule (II) dans laquelle B est une base purique ou pyrimidique telle que définie ici et R¹ est choisi dans le groupe comprenant un atome d'hydrogène et un groupe méthyle, éthyle, hydroxyméthyle, hydroxyéthyle et haloalkyle en C_1-6.
• Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study
  作者：Loïc Roux、Stéphane Priet、Nadine Payrot、Clément Weck、Maëlenn Fournier、Fabien Zoulim、Jan Balzarini、Bruno Canard、Karine Alvarez

  DOI：10.1016/j.ejmech.2013.02.039

  日期：2013.5

  9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl] adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12,13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA Sand S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12. (C) 2013 Elsevier Masson SAS. All rights reserved.