diisopropyl ({1-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate | 441785-41-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: diisopropyl ({1-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate
• 英文别名: 9-[[1-[Di(propan-2-yloxy)phosphorylmethoxy]cyclopropyl]methyl]-6-methylpurin-2-amine
• CAS: 441785-41-7
• 化学式: C₁₇H₂₈N₅O₄P
• 分子量: 397.414
• InChiKey: DHJJMKFTVYRUSG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  diisopropyl ({1-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate 在 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以53%的产率得到({1-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid
  参考文献：
  名称：

  A Novel Class of Phosphonate Nucleosides. 9-[(1-Phosphonomethoxycyclopropyl)methyl]guanine as a Potent and Selective Anti-HBV Agent

  摘要：

  9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine (PMCG, 1), representative of a novel class of phosphonate nucleosides, blocks HBV replication with excellent potency (EC50 = 0.5 muM) in a primary culture of HepG2 2.2.15 cells. It exhibits no significant cytotoxicity in several human cell lines up to 1.0 mM. It does not inhibit replication of human immunodeficiency virus (HIV-1) or herpes simplex virus (HSV-1) at 30 muM. Many purine base analogues of 1 also exhibit inhibitory activity against HBV, but at 30 muM, pyrimidine analogues do not. 1 is 4 times more potent than 9- [2-(phosphonomethoxy)ethyl] adenine (PMEA), which was used as a positive control (EC50 = 2.0 muM). The characteristic cyclopropyl moiety at the 2'-position of 1 was prepared by titanium-mediated Kulinkovich cyclopropanation. 1 was modified to give the orally available drug candidate, PMCDG Dipivoxil (2). Compound 2 exhibited excellent efficacy when administered at 5 mg per kg per day in a study with woodchucks infected with woodchuck hepatitis B virus (WHBV). Drug candidate 2 has successfully completed phase I clinical trials and is currently undergoing phase II clinical studies for evaluation of efficacy.

  DOI：

  10.1021/jm0305265
• 作为产物：
  描述：

  [[[1-[[(甲基磺酰基)氧基]甲基]环丙基]氧基]甲基]膦酸二异丙酯 在 sodium hydride 、 zinc dibromide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 diisopropyl ({1-[(2-amino-6-methyl-9H-purin-9-yl)methyl]cyclopropyl}oxy)methylphosphonate
  参考文献：
  名称：

  [EN] NUCLEOSIDE PHOSPHONATE DERIVATIVES USEFUL IN THE TREATMENT OF HIV INFECTIONS
  [FR] DERIVES DE NUCLEOSIDE PHOSPHONATE UTILES DANS LE TRAITEMENT D'INFECTIONS VIH

  摘要：

  本发明涉及通过给予由式(I)表示的核苷酸膦酸衍生物来治疗HIV感染的方法。

  公开号：

  WO2005079812A1

文献信息

• [EN] NUCLEOSIDE PHOSPHONATE DERIVATIVES USEFUL IN THE TREATMENT OF HIV INFECTIONS<br/>[FR] DERIVES DE NUCLEOSIDE PHOSPHONATE UTILES DANS LE TRAITEMENT D'INFECTIONS VIH
  申请人：ANADYS PHARMACEUTICALS INC

  公开号：WO2005079812A1

  公开（公告）日：2005-09-01

  The present invention relates to a method of treating HIV infections by administering a nucleoside phosphonate derivative represented by formula (I).

  本发明涉及通过给予由式(I)表示的核苷酸膦酸衍生物来治疗HIV感染的方法。
• PROCESS FOR PREPARING DIISOPROPYL((1-(HYDROXYMETHYL)-CYCLOPROPYL)OXY)METHYLPHOSPHONATE
  申请人：YOON Suk-Kyoon

  公开号：US20100305364A1

  公开（公告）日：2010-12-02

  The present invention relates to a new process for preparing diisopropyl [1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate (2), which is a key intermediate for synthesizing an antiviral (particularly, against hepatitis B virus) nucleoside analogue. The present invention also relates to new intermediates, and a process for preparing the antiviral nucleoside analogue from the compound (2) prepared according to the present invention.

  本发明涉及一种制备二异丙基[1-(羟甲基)-环丙基]氧基}甲基膦酸二异丙酯（2）的新工艺，该化合物是合成抗病毒（特别是对乙型肝炎病毒）核苷类似物的关键中间体。本发明还涉及新的中间体，以及从根据本发明制备的化合物（2）制备抗病毒核苷类似物的工艺。
• Process for preparing diisopropyl((1-(hydroxymethyl)-cyclopropyl)oxy)methylphosphonate
  申请人：Yoon Suk-Kyoon

  公开号：US20090187019A1

  公开（公告）日：2009-07-23

  The present invention relates to a new process for preparing diisopropyl [1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate (2), which is a key intermediate for synthesizing an antiviral (particularly, against hepatitis B virus) nucleoside analogue. The present invention also relates to new intermediates, and a process for preparing the antiviral nucleoside analogue from the compound (2) prepared according to the present invention.

  本发明涉及一种制备二异丙基[1-(羟甲基)-环丙基]氧基}甲基膦酸二酯（2）的新工艺，该化合物是合成抗病毒（特别是对乙型肝炎病毒）核苷类似物的关键中间体。本发明还涉及新的中间体和从根据本发明制备的化合物（2）制备抗病毒核苷类似物的工艺。
• US7795463B2
  申请人：——

  公开号：US7795463B2

  公开（公告）日：2010-09-14
• A Novel Class of Phosphonate Nucleosides. 9-[(1-Phosphonomethoxycyclopropyl)methyl]guanine as a Potent and Selective Anti-HBV Agent
  作者：Jong-Ryoo Choi、Dong-Gyu Cho、Kee Y. Roh、Jae-Taeg Hwang、Sinbyoung Ahn、Hyun S. Jang、Woo-Young Cho、Kyong W. Kim、Young-Gyo Cho、Jeongmin Kim、Yong-Zu Kim

  DOI：10.1021/jm0305265

  日期：2004.5.1

  9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine (PMCG, 1), representative of a novel class of phosphonate nucleosides, blocks HBV replication with excellent potency (EC50 = 0.5 muM) in a primary culture of HepG2 2.2.15 cells. It exhibits no significant cytotoxicity in several human cell lines up to 1.0 mM. It does not inhibit replication of human immunodeficiency virus (HIV-1) or herpes simplex virus (HSV-1) at 30 muM. Many purine base analogues of 1 also exhibit inhibitory activity against HBV, but at 30 muM, pyrimidine analogues do not. 1 is 4 times more potent than 9- [2-(phosphonomethoxy)ethyl] adenine (PMEA), which was used as a positive control (EC50 = 2.0 muM). The characteristic cyclopropyl moiety at the 2'-position of 1 was prepared by titanium-mediated Kulinkovich cyclopropanation. 1 was modified to give the orally available drug candidate, PMCDG Dipivoxil (2). Compound 2 exhibited excellent efficacy when administered at 5 mg per kg per day in a study with woodchucks infected with woodchuck hepatitis B virus (WHBV). Drug candidate 2 has successfully completed phase I clinical trials and is currently undergoing phase II clinical studies for evaluation of efficacy.