3-[2-(4-Benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid | 207737-35-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羟基酸及其衍生物
• 英文名称: 3-[2-(4-Benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid
• 英文别名: 3-hydroxy-4-methyl-3-[2-(4-phenylmethoxyphenyl)ethyl]pentanoic acid
• CAS: 207737-35-7
• 化学式: C₂₁H₂₆O₄
• 分子量: 342.435
• InChiKey: STRJNZMKVUCZKT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-[2-(4-Benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid 在 palladium on activated charcoal sodium hydroxide 、 R(+)-alpha-甲基苄胺 、 氢气 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 4.0h， 生成 (R)-4-hydroxy-6-[2-(4-hydroxy-phenyl)ethyl]-6-isopropyl-5,6-dihydro-pyran-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
• 作为产物：
  描述：

  3-[4-(苄氧基)苯基]丙酸 在 吡啶 、 lithium hydroxide 、 正丁基锂 、 氯化亚砜 、 二异丙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 39.0h， 生成 3-[2-(4-Benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid
  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
• 作为试剂：
  描述：

  3-[2-(4-Benzyloxy-phenyl)ethyl]-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester 、 氢氧化锂 在 3-[2-(4-Benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid 、 水 、 乙醚 作用下， 以 甲醇 、 水 为溶剂， 反应 5.0h， 以to give the title compound (mp 97°-98° C.)的产率得到3-[2-(4-Benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid
  参考文献：
  名称：

  Dihydropyrones with improved antiviral activity

  摘要：

  本发明涉及通过在3和/或6位置巧妙放置某些极性取代基而改善6,6-二取代-5,6-二氢吡喃-2-酮的抗病毒活性。增强细胞活性的相同取代基还进一步减少细胞毒性，从而增强这些药物作为抗病毒药物的理想特性。

  公开号：

  US05834506A1

文献信息

• DIHYDROPYRONES WITH IMPROVED ANTIVIRAL ACTIVITY
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP0935597A2

  公开（公告）日：1999-08-18
• US6046355A
  申请人：——

  公开号：US6046355A

  公开（公告）日：2000-04-04
• [EN] DIHYDROPYRONES WITH IMPROVED ANTIVIRAL ACTIVITY<br/>[FR] DIHYDROPYRONES A ACTIVITE ANTIVIRALE AMELIOREE
  申请人：——

  公开号：WO1998019997A2

  公开（公告）日：1998-05-14

  [EN] This invention pertains to improved antiviral activity of 6,6-disubstituted-5,6-dihydropyran-2-ones caused by judicious placement of certain polar substituents at the 3 and/or 6 positions. The same substituents which enhance the cellular activity also diminish cytotoxicity further enhancing the desirable properties of these agents as antivirals.
  [FR] La présente invention concerne une amélioration de l'activité antivirale de 5,6-dihydropyran-2-ones disubstitués en 6,6 obtenue grâce à une disposition judicieuse de substituants en positions 3 et/ou 6. Ces mêmes substituants qui renforcent l'activité cellulaire diminuent également la cytotoxicité, ce qui renforce encore plus les propriétés souhaitables de ces agents comme antiviraux.
• [EN] PROCESS FOR THE PREPARATION OF SUBSTITUTED 5,6-DIHYDRO-2H-PYRAN-2-ONES<br/>[FR] ELABORATION DE 5,6-DIHYDRO-2H-PYRAN-2-ONES SUBSTITUES
  申请人：WARNER-LAMBERT COMPANY

  公开号：WO1999014210A1

  公开（公告）日：1999-03-25

  (EN) An improved process for the preparation of substitued 5,6-dihydro-2H-pyran-2-ones is described where a hydroxy acid chloride is converted in ten steps to the desired product, as well as valuable intermediates used in the process.(FR) La présente invention concerne un perfectionnement de l'élaboration de 5,6-dihydro-2h-pyran-2-ones substitués. En l'occurrence, on obtient le produit attendu par une conversion, en dix opérations, d'un chlorure d'acide hydroxylé. L'invention concerne également des intermédiaires intéressants pour le procédé.
• 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.