[4-(3-Chloro-phenyl)-[1,3,2]dioxaphosphinan-2-yl]-diisopropyl-amine | 872354-90-0

• 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: [4-(3-Chloro-phenyl)-[1,3,2]dioxaphosphinan-2-yl]-diisopropyl-amine
• 英文别名: 4-(3-chlorophenyl)-N,N-di(propan-2-yl)-1,3,2-dioxaphosphinan-2-amine
• CAS: 872354-90-0
• 化学式: C₁₅H₂₃ClNO₂P
• 分子量: 315.78
• InChiKey: YSCLWEFNTAILRO-UHFFFAOYSA-N

物化性质

• 熔点：
  44-46 °C
• 沸点：
  318.9±41.0 °C(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  21.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  [4-(3-Chloro-phenyl)-[1,3,2]dioxaphosphinan-2-yl]-diisopropyl-amine 在 叔丁基过氧化氢 、 5-甲硫基四氮唑 作用下， 以 正庚烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 4-amino-1-{2-[4-(3-chloro-phenyl)-2-oxo-2λ⁵-[1,3,2]dioxaphosphinan-2-yloxymethyl]-[1,3]oxathiolan-5-yl}-1H-pyrimidin-2-one
  参考文献：
  名称：

  LIVER TARGETING OF HEPATITIS-B ANTIVIRAL LAMIVUDINE USING THE HEPDIRECT™ PRODRUG TECHNOLOGY

  摘要：

  A new class of phosphate and phosphonate prodrugs, called HepDirect (TM) prodrugs, has been developed to deliver drugs to the liver while simultaneously diminishing drug exposure to extra-hepatic tissues. The technology combines liver-selective cleavage and kinase bypass with high plasma and tissue stability to achieve increased drug levels in the liver. Lamivudine (LMV), a nucleoside analogue, is a currently approved treatment for hepatitis B infection, but shows modest efficacy and significant drug resistance due to inefficient phosphorylation. LMV is inadequately phosphorylated to the corresponding nucleoside triphosphate in rat and human hepatocytes. A HepDirect prodrug of LMV monophosphate generated 34-fold higher levels of the triphosphate in rat hepatocytes and 320-fold higher triphosphate levels in the liver of treated rats relative to LMV.

  DOI：

  10.1081/ncn-200059781
• 作为产物：
  描述：

  ethyl 3-(3-chlorophenyl)-3-hydroxypropanoate 在 lithium aluminium tetrahydride 、 三乙胺 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 生成 [4-(3-Chloro-phenyl)-[1,3,2]dioxaphosphinan-2-yl]-diisopropyl-amine
  参考文献：
  名称：

  一系列细胞色素 P4503A 激活的前药（HepDirect 前药）的设计、合成和表征，可用于将基于磷（上）酸盐的药物靶向肝脏§

  摘要：

  描述了一类新的磷酸盐和膦酸盐前药，称为 HepDirect 前药，它结合了快速肝脏裂解的特性与高血浆和组织稳定性，以实现肝脏中药物水平的增加。前药是取代的环状 1,3-丙酸酯，设计用于经历由主要在肝脏中表达的细胞色素 P(450) (CYP) 催化的氧化裂解反应。本文报道了在 C4 上含有芳基取代基的前药系列的发现及其用于将基于核苷的药物递送至肝脏的用途。阿糖腺苷、拉米夫定 (3TC) 和阿糖胞苷的 5'-单磷酸酯前药以及膦酸阿德福韦在暴露于肝脏匀浆后显示出裂解，并在血液和其他组织中表现出良好的稳定性。前药裂解需要在顺式构型中存在芳基，但相对独立于 C4 的核苷和绝对立体化学。机理研究表明，前药裂解通过初始 CYP3A 催化氧化为中间体开环一元酸，随后通过 β-消除反应转化为磷酸（on）酸酯和芳基乙烯基酮。在原代大鼠肝细胞和正常大鼠中比较 3TC 和相应的 HepDirect 前药的研究表

  DOI：

  10.1021/ja031818y

文献信息

• Novel 2'-C-methyl nucleoside derivatives
  申请人：Reddy Raja K.

  公开号：US20050182252A1

  公开（公告）日：2005-08-18

  Compounds of Formula I, stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof, their preparation, and their uses for the treatment of hepatitis C viral infection are described:

  化合物I的配方、立体异构体以及其药用可接受的盐或前药，它们的制备以及它们用于治疗丙型肝炎病毒感染的用途被描述：
• [EN] RADIO-AND CHEMO-PROTECTIVE COMPOUNDS<br/>[FR] COMPOSÉS RADIOPROTECTEURS ET CHIMIOPROTECTEURS
  申请人：TONIX PHARMACEUTICALS INC

  公开号：WO2021226559A8

  公开（公告）日：2021-12-09
• RADIO-AND CHEMO-PROTECTIVE COMPOUNDS
  申请人：TONIX PHARMACEUTICALS, INC.

  公开号：US20210388011A1

  公开（公告）日：2021-12-16

  The present disclosure relates to prodrugs, double prodrugs, derivatives and analogues of 3-(methylamino)-2-((methylamino)methyl)propane-1-thiol. Their use as radio- and chemo-protectors is also described.
• Design, Synthesis, and Characterization of a Series of Cytochrome P₄₅₀ 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver^§
  作者：Mark D. Erion、K. Raja Reddy、Serge H. Boyer、Michael C. Matelich、Jorge Gomez-Galeno、Robert H. Lemus、Bheemarao G. Ugarkar、Timothy J. Colby、Jürgen Schanzer、Paul D. van Poelje

  DOI：10.1021/ja031818y

  日期：2004.4.28

  A new class of phosphate and phosphonate prodrugs, called HepDirect prodrugs, is described that combines properties of rapid liver cleavage with high plasma and tissue stability to achieve increased drug levels in the liver. The prodrugs are substituted cyclic 1,3-propanyl esters designed to undergo an oxidative cleavage reaction catalyzed by a cytochrome P(450) (CYP) expressed predominantly in the

  描述了一类新的磷酸盐和膦酸盐前药，称为 HepDirect 前药，它结合了快速肝脏裂解的特性与高血浆和组织稳定性，以实现肝脏中药物水平的增加。前药是取代的环状 1,3-丙酸酯，设计用于经历由主要在肝脏中表达的细胞色素 P(450) (CYP) 催化的氧化裂解反应。本文报道了在 C4 上含有芳基取代基的前药系列的发现及其用于将基于核苷的药物递送至肝脏的用途。阿糖腺苷、拉米夫定 (3TC) 和阿糖胞苷的 5'-单磷酸酯前药以及膦酸阿德福韦在暴露于肝脏匀浆后显示出裂解，并在血液和其他组织中表现出良好的稳定性。前药裂解需要在顺式构型中存在芳基，但相对独立于 C4 的核苷和绝对立体化学。机理研究表明，前药裂解通过初始 CYP3A 催化氧化为中间体开环一元酸，随后通过 β-消除反应转化为磷酸（on）酸酯和芳基乙烯基酮。在原代大鼠肝细胞和正常大鼠中比较 3TC 和相应的 HepDirect 前药的研究表
• LIVER TARGETING OF HEPATITIS-B ANTIVIRAL LAMIVUDINE USING THE HEPDIRECT™ PRODRUG TECHNOLOGY
  作者：K. Raja Reddy、Timothy J. Colby、James M. Fujitaki、Paul D. van Poelje、Mark D. Erion

  DOI：10.1081/ncn-200059781

  日期：2005.4.1

  A new class of phosphate and phosphonate prodrugs, called HepDirect (TM) prodrugs, has been developed to deliver drugs to the liver while simultaneously diminishing drug exposure to extra-hepatic tissues. The technology combines liver-selective cleavage and kinase bypass with high plasma and tissue stability to achieve increased drug levels in the liver. Lamivudine (LMV), a nucleoside analogue, is a currently approved treatment for hepatitis B infection, but shows modest efficacy and significant drug resistance due to inefficient phosphorylation. LMV is inadequately phosphorylated to the corresponding nucleoside triphosphate in rat and human hepatocytes. A HepDirect prodrug of LMV monophosphate generated 34-fold higher levels of the triphosphate in rat hepatocytes and 320-fold higher triphosphate levels in the liver of treated rats relative to LMV.