3-ethyl-7-fluoro-1,2,4-benzotriazine 1-oxide | 910105-70-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三嗪类
• 英文名称: 3-ethyl-7-fluoro-1,2,4-benzotriazine 1-oxide
• 英文别名: 3-Ethyl-7-fluoro-1-oxido-1,2,4-benzotriazin-1-ium
• CAS: 910105-70-3
• 化学式: C₉H₈FN₃O
• 分子量: 193.18
• InChiKey: OLEGPUVSXPEZKJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  51.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-ethyl-7-fluoro-1,2,4-benzotriazine 1-oxide 、 1,3-丙二醇 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以68%的产率得到3-[(3-ethyl-1-oxido-1,2,4-benzotriazin-7-yl)oxy]propanol
  参考文献：
  名称：

  Hypoxia-Selective 3-Alkyl 1,2,4-Benzotriazine 1,4-Dioxides: The Influence of Hydrogen Bond Donors on Extravascular Transport and Antitumor Activity

  摘要：

  Tirapazamine (TPZ) and related 1,2,4-benzotriazine 1,4 dioxides (BTOs) are selectively toxic under hypoxia, but their ability to kill hypoxic cells in tumors is generally limited by their poor extravascular transport. Here we show that removing hydrogen bond donors by replacing the 3-NH2 group of TPZ with simple alkyl groups increased their tissue diffusion coefficients as measured in multicellular layer cultures. This advantage was largely retained using solubilizing 3-alkylaminoalkyl substituents provided these were sufficiently lipophilic at pH 7.4. The high reduction potentials of such compounds resulted in rates of metabolism too high for optimal penetration into hypoxic tissue, but electron-donating 6- and 7-substituents moderated metabolism. Pharmacokinetic/pharmacodynamic model-guided screening was used to select BTOs with optimal extravascular transport and hypoxic cytotoxicity properties for evaluation against HT29 human tumor xenografts in combination with radiation. This identified four novel 3-alkyl BTOs providing greater clonogenic killing of hypoxic cells than TPZ at equivalent host toxicity, with the 6-morpholinopropyloxy-BTO 22 being 3-fold more active.

  DOI：

  10.1021/jm701037w
• 作为产物：
  描述：

  3-amino-7-fluoro-1,2,4-benzotriazine-1-oxide 在 四(三苯基膦)钯 三氟乙酸 、 sodium nitrite 、 三氯氧磷 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 4.33h， 生成 3-ethyl-7-fluoro-1,2,4-benzotriazine 1-oxide
  参考文献：
  名称：

  Stille Coupling Reactions in the Synthesis of Hypoxia-Selective 3-Alkyl-1,2,4-Benzotriazine 1,4-Dioxide Anticancer Agents

  摘要：

  The introduction of a 3-alkyl substituent is a key step in the synthesis of 1,2,4-benzotriazine 1,4-dioxide hypoxia-selective anticancer agents, such as SN29751. The Stille reaction of 3-chloro-1,2,4-benzotriazine 1-oxides ( BTOs) 5 was inhibited by the presence of electron donating substituents on the benzo ring, thus limiting the range of compounds available for SAR studies. The use of 3-iodo-BTOs 8 did not provide a significant improvement in the yields of 3-ethyl-BTOs 6. Microwave-assisted Stille coupling of chlorides 5 gave dramatically improved yields, which were consistently superior to those from the corresponding iodides 8. The application of microwave-assisted synthesis extended the range of substituted BTOs available for SAR studies and provided an efficient, scalable synthesis of the investigational anticancer agent, SN29751 ( 1).

  DOI：

  10.1021/jo060986g