N1-((1S,3S,4S)-1-benzyl-3-{[bis(benzyloxy)phosphoryl]oxy}-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N2-{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide | 875435-73-7

• 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: N1-((1S,3S,4S)-1-benzyl-3-{[bis(benzyloxy)phosphoryl]oxy}-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N2-{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide
• 英文别名: 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-bis(phenylmethoxy)phosphoryloxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate
• CAS: 875435-73-7
• 化学式: C₅₁H₆₁N₆O₈PS₂
• 分子量: 981.186
• InChiKey: KVVMBIQOHMFHST-UDRSJHJCSA-N

物化性质

• 沸点：
  1077.9±65.0 °C(Predicted)
• 密度：
  1.254±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  9
• 重原子数：
  68
• 可旋转键数：
  26
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  227
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  N1-((1S,3S,4S)-1-benzyl-3-{[bis(benzyloxy)phosphoryl]oxy}-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N2-{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide 在 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以24%的产率得到1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenyl-3-phosphonooxyhexan-2-yl]carbamate
  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：

  在 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 以6.2 g的产率得到N1-((1S,3S,4S)-1-benzyl-3-{[bis(benzyloxy)phosphoryl]oxy}-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N2-{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide
  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：DeGoey A. David

  公开号：US20070270383A1

  公开（公告）日：2007-11-22

  A compound of the formula is disclosed as a prodrug of an HIV protease inhibitor. Methods and compositions for inhibiting HIV protease activity and treating HIV infection are also disclosed.

  公开了一种化合物，其化学式为，作为HIV蛋白酶抑制剂的前药。还公开了用于抑制HIV蛋白酶活性和治疗HIV感染的方法和组合物。
• PRODRUGS OF HIV PROTEASE INHIBITORS
  申请人：DeGoey David A.

  公开号：US20100286032A1

  公开（公告）日：2010-11-11

  A compound of the formula is disclosed as a prodrug of an HIV protease inhibitor. Methods and compositions for inhibiting HIV protease activity and treating HIV infection are also disclosed.

  本发明揭示了一种化合物的公式作为HIV蛋白酶抑制剂的前药。本发明还揭示了抑制HIV蛋白酶活性和治疗HIV感染的方法和组合物。
• [EN] PRODRUGS OF HIV PROTEASE INHIBITORS<br/>[FR] PROMEDICAMENTS D'INHIBITEURS DE PROTEASE DE VIH
  申请人：ABBOTT LAB

  公开号：WO2006014282A3

  公开（公告）日：2006-05-11
• US7718633B2
  申请人：——

  公开号：US7718633B2

  公开（公告）日：2010-05-18
• US8426388B2
  申请人：——

  公开号：US8426388B2

  公开（公告）日：2013-04-23