6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one | 749929-97-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one
• 英文别名: 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[l,3]dioxin-4-one；6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one；6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-1,3-dioxin-4-one
• CAS: 749929-97-3
• 化学式: C₁₅H₂₀O₄
• 分子量: 264.321
• InChiKey: YEORFXLRFIQXGI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one 在 bis-triphenylphosphine-palladium(II) chloride 、 palladium dihydroxide 、 copper(l) iodide dimethyl sulfide borane 、 氢气 、 potassium carbonate 、 二异丙胺 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 6-[2-(3-chloro-4-ethoxy-phenyl)-ethyl]-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one
  参考文献：
  名称：

  Allosteric Inhibitors of Hepatitis C Polymerase:  Discovery of Potent and Orally Bioavailable Carbon-Linked Dihydropyrones

  摘要：

  The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.

  DOI：

  10.1021/jm0704447
• 作为产物：
  描述：

  2,2,6-三甲基-4H-1,3-二英-4-酮 在 cesium fluoride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 为溶剂， 反应 0.5h， 生成 6-(2-cyclopentyl-2-hydroxy-but-3-ynyl)-2,2-dimethyl-[1,3]dioxin-4-one
  参考文献：
  名称：

  Allosteric Inhibitors of Hepatitis C Polymerase:  Discovery of Potent and Orally Bioavailable Carbon-Linked Dihydropyrones

  摘要：

  The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.

  DOI：

  10.1021/jm0704447

文献信息

• Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same
  申请人：Borchardt Allen

  公开号：US20050176701A1

  公开（公告）日：2005-08-11

  The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R 1 and R 2 , are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula 1, and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

  这项发明涉及公式1的化合物，以及其药学上可接受的盐、溶剂化合物、前药和代谢物，其中W、Z、R1和R2如本文所定义。该发明还涉及通过给哺乳动物施用公式1的化合物来治疗丙型肝炎病毒的方法，以及用于治疗这类疾病的含有公式1化合物的药物组合物。该发明还涉及制备公式1化合物的方法。
• [EN] INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME<br/>[FR] INHIBITEURS DE POLYMERASE D'ARN DEPENDANT D'ARN DU VIRUS DE L'HEPATITE C ET COMPOSITIONS ET TRAITEMENT UTILISANT CES INHIBITEURS
  申请人：PFIZER

  公开号：WO2006018725A1

  公开（公告）日：2006-02-23

  The present invention provides compounds of formula (4), and their pharmaceutically acceptable salts and solvates, which are useful as inhibitors of the Hepatitis C virus (HCV) polymerase enzyme and are also useful for the treatment of HCV infections in HCV-infected mammals. The present invention also provides pharmaceutical compositions comprising compounds of formula (4), their pharmaceutically acceptable salts and solvates. Furthermore, the present invention provides intermediate compounds and methods useful in the preparation of compounds of formula (4).

  本发明提供了公式（4）的化合物，以及它们的药学上可接受的盐和溶剂化合物，这些化合物可用作肝炎病毒（HCV）聚合酶酶的抑制剂，并且也可用于治疗HCV感染的HCV感染的哺乳动物。本发明还提供了包含公式（4）的化合物、其药学上可接受的盐和溶剂的药物组合物。此外，本发明提供了制备公式（4）化合物的中间体化合物和方法。
• Synthetic Route Optimization of PF-00868554, An HCV Polymerase Inhibitor in Clinical Evaluation
  作者：Hui Li、Sarah Johnson、Matt Drowns、John Tatlock、Angelica Linton、Javier Gonzalez、Robert Hoffman、Tanya Jewell、Leena Patel、Julie Blazel、Mingnam Tang

  DOI：10.1055/s-0029-1219352

  日期：2010.3

  This paper describes the optimization efforts to establish an enabling synthesis to provide multigram quantity of PF-00868554, an HCV polymerase inhibitor currently in phase II clinical evaluations.

  本文介绍了为提供多克级 PF-00868554 而进行的优化工作，PF-00868554 是一种 HCV 聚合酶抑制剂，目前正处于二期临床评估阶段。
• Development of a Synthetic Process towards a Hepatitis C Polymerase Inhibitor
  作者：David Camp、Chris F. Matthews、Sean T. Neville、Michael Rouns、Robert W. Scott、Yen Truong

  DOI：10.1021/op0600761

  日期：2006.7.1

  hepatitis C viral polymerase (HCVP) protein was executed via a racemic synthetic route coupled with chiral HPLC separation. Due to the achiral route and instability of key intermediates, the initial route was determined to be unsuitable for large-scale manufacture. An alternate route was developed utilizing a convergent Heck coupling, resolution of a carboxylic acid via diastereomeric salt formation, and

  2-（4- 2-[（2 R）-2-环戊基-5-（5,7-二甲基-[1,2,4]三唑并[1,5-a]嘧啶-2-基甲基）的合成以多千克规模描述了）-4-羟基-6-氧代-3,6-二氢-2H-吡喃-2-基]-乙基} -2-氟-苯基）-2-甲基-丙腈（1）。该抑制丙型肝炎病毒聚合酶（HCVP）蛋白的临床候选物的初步合成是通过外消旋合成途径与手性HPLC分离相结合进行的。由于关键中间体的非手性路线和不稳定性，确定了初始路线不适合大规模生产。利用会聚的Heck偶联，通过非对映异构体盐的形成来拆分羧酸以及对不期望的对映异构体进行有效的化学循环，开发了另一种途径。
• Pharmaceutical compositions and methods for their use
  申请人：Agouron Pharmaceuticals, Inc.

  公开号：US20040224960A1

  公开（公告）日：2004-11-11

  The present invention relates to pharmaceutical compositions and to methods for their use in decreasing cytochrome P450 (CYP450) enzyme activity. The present invention also relates to methods of increasing the bioavailability of a compound in a mammal. Additionally, the present invention relates to methods of decreasing the metabolism of certain compounds in a mammal that are metabolized by the cytochrome P450 enzyme. Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound metabolized by at least one cytochrome P450 enzyme and a cytochrome P450 enzyme-inhibiting amount of a compound of formula (I).

  本发明涉及制药组合物及其在降低细胞色素P450（CYP450）酶活性方面的使用方法。本发明还涉及一种在哺乳动物中增加化合物生物利用度的方法。此外，本发明还涉及一种在哺乳动物中降低细胞色素P450酶代谢某些化合物的方法。此外，本发明还涉及包含至少一种由至少一种细胞色素P450酶代谢的化合物和公式（I）化合物的细胞色素P450酶抑制量的制药组合物。