6-[2-(4-aminophenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one | 249728-37-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 6-[2-(4-aminophenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one
• 英文别名: 2-[2-(4-aminophenyl)ethyl]-4-hydroxy-2-propan-2-yl-3H-pyran-6-one
• CAS: 249728-37-8
• 化学式: C₁₆H₂₁NO₃
• 分子量: 275.348
• InChiKey: LWSUWZWPUKKPKY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  72.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-[2-(4-aminophenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one 、 toluene-4-thiosulfonic acid S-(2-tert-butyl-4-dimethylsulfamoyloxy-5-methyl-phenyl) ester 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 Dimethyl-sulfamic acid 4-{6-[2-(4-amino-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-5-tert-butyl-2-methyl-phenyl ester
  参考文献：
  名称：

  Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety

  摘要：

  Dihydropyran-Zones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S-3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(99)00360-1
• 作为产物：
  描述：

  (E)-4-methyl-1-(p-nitrophenyl)-1-penten-3-one 在 Pd-BaSO₄ 盐酸 、 正丁基锂 、 氢气 、 sodium hydride 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 55.0 ℃ 、351.63 kPa 条件下， 反应 102.57h， 生成 6-[2-(4-aminophenyl)ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one
  参考文献：
  名称：

  Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor

  摘要：

  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.

  DOI：

  10.1016/s0968-0896(99)00215-1

文献信息

• 5,6-Dihydropyran-2-ones Possessing Various Sulfonyl Functionalities:  Potent Nonpeptidic Inhibitors of HIV Protease
  作者：Frederick E. Boyer、J. V. N. Vara Prasad、John M. Domagala、Edmund L. Ellsworth、Christopher Gajda、Susan E. Hagen、Larry J. Markoski、Bradley D. Tait、Elizabeth A. Lunney、Alexander Palovsky、Donna Ferguson、Neil Graham、Tod Holler、Donald Hupe、Carolyn Nouhan、Peter J. Tummino、A. Urumov、Eric Zeikus、Greg Zeikus、Stephen J. Gracheck、James M. Sanders、Steven VanderRoest、Joanne Brodfuehrer、Krishna Iyer、Michael Sinz、Sergei V. Gulnik、John W. Erickson

  DOI：10.1021/jm990281p

  日期：2000.3.1

  On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S-3' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S3' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1, In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.
• 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
• US6380400B1
  申请人：——

  公开号：US6380400B1

  公开（公告）日：2002-04-30
• [EN] METHODS OF MAKING DIHYDROPYRONE HIV PROTEASE INHIBITORS<br/>[FR] PROCEDES DE PREPARATION D'INHIBITEURS DIHYDROPYRONE DE PROTEASE DE VIH
  申请人：WARNER LAMBERT CO

  公开号：WO2000015625A2

  公开（公告）日：2000-03-23

  The present invention relates to methods of making dihydropyrone HIV protease inhibitors.