1-[(2S,3S,5S)-2-[[2-(2,6-dimethylphenoxy)acetyl]amino]-5-[[(2S)-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanoyl]amino]-1,6-diphenylhexan-3-yl]oxyethyl dihydrogen phosphate | 875515-89-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 1-[(2S,3S,5S)-2-[[2-(2,6-dimethylphenoxy)acetyl]amino]-5-[[(2S)-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanoyl]amino]-1,6-diphenylhexan-3-yl]oxyethyl dihydrogen phosphate
• CAS: 875515-89-2
• 化学式: C₃₉H₅₃N₄O₉P
• 分子量: 752.845
• InChiKey: ZQVMJJPKEHLQBT-ZTYIYWNCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  53
• 可旋转键数：
  19
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  176
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  1-[(2S,3S,5S)-2-[[2-(2,6-dimethylphenoxy)acetyl]amino]-5-[[(2S)-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanoyl]amino]-1,6-diphenylhexan-3-yl]oxyethyl dihydrogen phosphate 在 sodium carbonate 作用下， 以0.066 g的产率得到disodium 1-[((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]-amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]ethylphosphate
  参考文献：
  名称：

  Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir

  摘要：

  We studied the synthesis, cleavage rates, and oral. administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of the parent drugs in vivo. However; oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the. solid prodrugs led to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited solubility.

  DOI：

  10.1021/jm900080g
• 作为产物：
  描述：

  (2S)-N-{(1S,3S,4S)-1-benzyl-4-{[(2,6-dimethylphenoxy)acetyl]amino}-3-[1-(ethylthio)ethoxy]-5-phenylpentyl}-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanamide 在 N-碘代丁二酰亚胺 、 磷酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 1-[(2S,3S,5S)-2-[[2-(2,6-dimethylphenoxy)acetyl]amino]-5-[[(2S)-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanoyl]amino]-1,6-diphenylhexan-3-yl]oxyethyl dihydrogen phosphate
  参考文献：
  名称：

  Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir

  摘要：

  We studied the synthesis, cleavage rates, and oral. administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of the parent drugs in vivo. However; oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the. solid prodrugs led to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited solubility.

  DOI：

  10.1021/jm900080g

文献信息

• PRODRUGS OF HIV PROTEASE INHIBITORS
  申请人：ABBOTT LABORATORIES

  公开号：EP1773850B1

  公开（公告）日：2013-01-30
• Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir
  作者：David A. DeGoey、David J. Grampovnik、William J. Flosi、Kennan C. Marsh、Xiu C. Wang、Larry L. Klein、Keith F. McDaniel、Yaya Liu、Michelle A. Long、Warren M. Kati、Akhteruzzaman Molla、Dale J. Kempf

  DOI：10.1021/jm900080g

  日期：2009.5.14

  We studied the synthesis, cleavage rates, and oral. administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of the parent drugs in vivo. However; oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the. solid prodrugs led to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited solubility.