(4S)-4-((1R)-1-(hydroxyamino)-2-(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)ethyl)-2,2-dimethyl-[1,3]dioxolane

• 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: (4S)-4-((1R)-1-(hydroxyamino)-2-(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)ethyl)-2,2-dimethyl-[1,3]dioxolane
• 英文别名: N-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonylethyl]hydroxylamine
• 化学式: C₂₀H₂₂F₃NO₇S
• 分子量: 477.458
• InChiKey: BAXIIXZCCUBQIC-ZWKOTPCHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  2,2,2-三氟乙基甲酸酯 、 (4S)-4-((1R)-1-(hydroxyamino)-2-(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)ethyl)-2,2-dimethyl-[1,3]dioxolane 以 various solvent(s) 为溶剂， 反应 20.0h， 生成 (1R)-N-[1-((4S)-2,2-dimethyl[1,3]dioxolan-4-yl)-2-(4-(4-trifluorometyhoxyphenoxy)phenylsulfonyl)ethyl]-N-hydroxyformamide
  参考文献：
  名称：

  Phenoxyphenyl Sulfone N-Formylhydroxylamines (Retrohydroxamates) as Potent, Selective, Orally Bioavailable Matrix Metalloproteinase Inhibitors

  摘要：

  A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.

  DOI：

  10.1021/jm0103920
• 作为产物：
  描述：

  (4S)-2,2-dimethyl-4-((E/Z)-2-(4-(4-trifluoromethoxyphenoxy)phenylsulfonyl)ethenyl)-[1,3]dioxolane 在 羟胺 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 以69%的产率得到(4S)-4-((1S)-1-(hydroxyamino)-2-((4-(4'-(trifluoromethoxy)phenoxy)phenyl)sulfonyl)ethyl)-2,2-dimethyl-1,3-dioxolane
  参考文献：
  名称：

  Phenoxyphenyl Sulfone N-Formylhydroxylamines (Retrohydroxamates) as Potent, Selective, Orally Bioavailable Matrix Metalloproteinase Inhibitors

  摘要：

  A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.

  DOI：

  10.1021/jm0103920

文献信息

• The Development of a Large-Scale Synthesis of Matrix Metalloproteinase Inhibitor, ABT-518
  作者：Sou-Jen Chang、Dilinie Fernando、Michael Fickes、Ashok K. Gupta、David R. Hill、Todd McDermott、Shyamal Parekh、Zhenping Tian、Steven J. Wittenberger

  DOI：10.1021/op025525l

  日期：2002.5.1

  A process for the preparation of matrix metalloproteinase inhibitor ABT-518 has been developed. Significant improvements have been made to the first generation synthesis and are described here. The new process is very robust and efficient; multikilogram quantities of the title compound have been synthesized for clinical trials. ABT-518 was prepared by this six-step synthetic sequence in 51% overall yield with >99% ee.
• REVERSE HYDROXAMATE INHIBITORS OF MATRIX METALLOPROTEINASES
  申请人：ABBOTT LABORATORIES

  公开号：EP1147101B1

  公开（公告）日：2002-11-20