4-hydroxy-6-phenyl-6-phenethyl-5,6-dihydro-pyran-2-one | 169602-01-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃
• 英文名称: 4-hydroxy-6-phenyl-6-phenethyl-5,6-dihydro-pyran-2-one
• 英文别名: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one；4-hydroxy-2-phenyl-2-(2-phenylethyl)-3H-pyran-6-one
• CAS: 169602-01-1
• 化学式: C₁₉H₁₈O₃
• 分子量: 294.35
• InChiKey: JYKPRQNMODBPRE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-hydroxy-6-phenyl-6-phenethyl-5,6-dihydro-pyran-2-one 在 sodium cyanoborohydride 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 甲苯 为溶剂， 生成 5,6-Dihydro-4-hydroxy-6-phenyl-3,6-bis(2-phenylethyl)-2H-pyran-2-one
  参考文献：
  名称：

  5,6-dihydropyrone derivatives as protease inhibitors and antiviral agents

  摘要：

  本发明涉及新颖的5,6-二氢吡咯衍生物及相关结构，这些衍生物能有效抑制HIV天冬氨酸蛋白酶，从而阻断HIV的感染性。5,6-二氢吡咯衍生物在开发用于治疗细菌和病毒感染及疾病（包括艾滋病）的治疗方法中是有用的。本发明还涉及多功能化5,6-二氢吡咯及其相关结构的合成方法。

  公开号：

  US05840751A1
• 作为产物：
  描述：

  ω-苄基苯乙酮 、 乙酰乙酸甲酯 在 sodium hydroxide 、 正丁基锂 、 sodium hydride 作用下， 生成 4-hydroxy-6-phenyl-6-phenethyl-5,6-dihydro-pyran-2-one
  参考文献：
  名称：

  4-羟基-5,6-二氢吡喃酮。2.有效的HIV蛋白酶的非肽抑制剂。

  摘要：

  4-羟基-5,6-二氢吡喃酮模板被用作柔性支架，从该支架可构建有效的HIV蛋白酶活性位点抑制剂。使用类似的结合模式在HIV蛋白酶的活性位点中模拟了二氢吡喃酮1c（5,6-二氢-4-羟基-6-苯基-3-[（2-苯基乙基）硫代] -2H-吡喃-2-酮）发现为先前报道的4-羟基苯并吡喃-2-酮。我们的模型导致我们追求6，6-二取代的二氢吡喃酮的合成，目的是填充S1和S2，从而提高未填充S2的母体二氢吡喃酮1c的效力。为此，我们在二氢吡喃酮的6-位连接了各种疏水和亲水侧链，以模拟天然和非天然氨基酸，已知它们是P2和P2'的有效底物。将母体二氢吡喃酮1c（IC50 = 2100 nM）制成化合物，其效力提高了100倍以上[18c，IC50 = 5 nM，5-（3,6-dihydro-4-hydroxy-6-oxo-2-苯基-5- [2-苯基乙基）硫代] -2H-吡喃-2-基）戊酸和12c，IC50 =

  DOI：

  10.1021/jm970615f

文献信息

• 4-Hydroxy-5,6-Dihydro-2H-pyran-2-ones. 3. Bicyclic and hetero-aromatic ring systems as 3-position scaffolds to bind to S1′ and S2′ of the HIV-1 protease enzyme
  作者：Edmund L. Ellsworth、John Domagala、J.V.N. Vara Prasad、Susan Hagen、Donna Ferguson、Tod Holler、Donald Hupe、Neil Graham、Caroline Nouhan、Peter J. Tummino、Greg Zeikus、Elizabeth A. Lunney

  DOI：10.1016/s0960-894x(99)00332-7

  日期：1999.7

  5,6-Dihydro-2H-pyran-2-ones are potent inhibitors of HIV-1 protease, which bind to the S-1, S-2, S-1', and S-2' pockets and have a unique binding mode with the catalytic aspartyl groups and the flap region of the enzyme. Efforts to explore 3-position heterocyclic scaffolds that bind to the S-1' and S-2' pockets have provided a number of selected analogs that display high HIV-1 protease inhibitory activity, (C) 1999 Elsevier Science Ltd. All rights reserved.
• Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor
  作者：J.V.N. Vara Prasad、Frederick E. Boyer、John M. Domagala、Edmund L. Ellsworth、Christopher Gajda、Harriet W. Hamilton、Susan E. Hagen、Larry J. Markoski、Bruce A. Steinbaugh、Bradley D. Tait、Christine Humblet、Elizabeth A. Lunney、Alexander Pavlovsky、John R. Rubin、Donna Ferguson、Neil Graham、Tod Holler、Donald Hupe、Carolyn Nouhan、Peter J. Tummino、A. Urumov、Eric Zeikus、Greg Zeikus、Stephen J. Gracheck、James M. Saunders、Steven VanderRoest、Joanne Brodfuehrer、K. Iyer、M. Sinz、Sergei V. Gulnik、John W. Erickson

  DOI：10.1016/s0968-0896(99)00215-1

  日期：1999.12

  With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.
• Nonpeptidic HIV protease inhibitors: 6-alkyl-5, 6-dihydropyran-2-ones possessing achiral 3-(4-amino/carboxamide-2-t-butyl, 5-methylphenyl thio) moiety: Antiviral activities and pharmacokinetic properties
  作者：J.V.N. Vara Prasad、Fred E. Boyer、John M. Domagala、Edmund L. Ellsworth、Christopher Gajda、Susan E. Hagen、Larry J. Markoski、Bradley D. Tait、Elizabeth A. Lunney、Peter J. Tummino、Donna Ferguson、Tod Holler、Donald Hupe、Carolyn Nouhan、Stephen J. Gracheck、Steven VanderRoest、James Saunders、Krishna Iyer、Michael Sinz、Joanne Brodfuehrer

  DOI：10.1016/s0960-894x(99)00237-1

  日期：1999.6

  Dihydropyran-2-ones possessing amino and carboxamide functionalities on 3-SPh (2-tert-butyl, 5-methyl) ring were synthesized and evaluated for their antiviral activities. Both the enantiomers of inhibitor 15 were synthesized. The in vitro resistance profile, inhibitory activities against cytochrome P450 isozymes and pharmacokinetic properties of inhibitor 15S will be discussed.
• Synthesis of 5,6-Dihydro-4-hydroxy-2- pyrones as HIV-1 Protease Inhibitors:  The Profound Effect of Polarity on Antiviral Activity
  作者：Susan E. Hagen、J. V. N. Vara Prasad、Frederick E. Boyer、John M. Domagala、Edmund L. Ellsworth、Christopher Gajda、Harriet W. Hamilton、Larry J. Markoski、Bruce A. Steinbaugh、Bradley D. Tait、Elizabeth A. Lunney、Peter J. Tummino、Donna Ferguson、Donald Hupe、Carolyn Nouhan、Stephen J. Gracheck、James M. Saunders、Steven VanderRoest

  DOI：10.1021/jm970522y

  日期：1997.11.1
• 5,6-DIHYDROPYRONE DERIVATIVES AS PROTEASE INHIBITORS AND ANTIVIRAL AGENTS
  申请人：PARKE DAVIS & COMPANY

  公开号：EP0729463B1

  公开（公告）日：2002-05-22