N¹-[6-(2-methoxyethoxy)-1-oxido-1,2,4-benzotriazin-3-yl]-N²,N²-dimethyl-1,2-ethanediamine

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N¹-[6-(2-methoxyethoxy)-1-oxido-1,2,4-benzotriazin-3-yl]-N²,N²-dimethyl-1,2-ethanediamine
• 英文别名: N1-[6-(2-methoxyethoxy)-1-oxido-1,2,4-benzotriazin-3-yl]-N2,N2-dimethyl-1,2-ethanediamine；N-[6-(2-methoxyethoxy)-1-oxido-1,2,4-benzotriazin-1-ium-3-yl]-N',N'-dimethylethane-1,2-diamine
• 化学式: C₁₄H₂₁N₅O₃
• 分子量: 307.352
• InChiKey: LPPNOAMIILOVFZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  85
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N¹-[6-(2-methoxyethoxy)-1-oxido-1,2,4-benzotriazin-3-yl]-N²,N²-dimethyl-1,2-ethanediamine 在 双氧水 、 三氟乙酸 、 三氟乙酸酐 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 6.25h， 以50%的产率得到N¹-[6-(2-methoxyethoxy)-1,4-dioxido-1,2,4-benzotriazin-3-yl]-N²,N²-dimethyl-1,2-ethanediamine
  参考文献：
  名称：

  [EN] NOVEL 1,2,4-BENZOTRIAZINE-1,4-DIOXIDES
  [FR] 1,2,4-BENZOTRIAZINE-1,4-DIOXYDES

  摘要：

  本发明提供了一种简化的特征集，可用于选择对人类肿瘤异种移植物中的缺氧细胞具有治疗活性的1,2,4-苯并三氮唑-1,4-二氧化物（TPZ类似物），并进一步提供了一种新型的1,2,4-苯并三氮唑-1,4-二氧化物（TPZ类似物），预测其对肿瘤的体内活性，以及它们的制备和用作缺氧选择性细胞毒药物和放射增敏剂用于癌症治疗，单独或与放射线和/或其他抗癌药物结合使用。

  公开号：

  WO2005082867A1
• 作为产物：
  描述：

  N¹-(6-fluoro-1-oxido-1,2,4-benzotriazin-3-yl)-N²,N²-dimethyl-1,2-ethanediamine 、 乙二醇甲醚 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 以93%的产率得到N¹-[6-(2-methoxyethoxy)-1-oxido-1,2,4-benzotriazin-3-yl]-N²,N²-dimethyl-1,2-ethanediamine
  参考文献：
  名称：

  [EN] NOVEL 1,2,4-BENZOTRIAZINE-1,4-DIOXIDES
  [FR] 1,2,4-BENZOTRIAZINE-1,4-DIOXYDES

  摘要：

  本发明提供了一种简化的特征集，可用于选择对人类肿瘤异种移植物中的缺氧细胞具有治疗活性的1,2,4-苯并三氮唑-1,4-二氧化物（TPZ类似物），并进一步提供了一种新型的1,2,4-苯并三氮唑-1,4-二氧化物（TPZ类似物），预测其对肿瘤的体内活性，以及它们的制备和用作缺氧选择性细胞毒药物和放射增敏剂用于癌症治疗，单独或与放射线和/或其他抗癌药物结合使用。

  公开号：

  WO2005082867A1

文献信息

• [EN] NOVEL 1,2,4-BENZOTRIAZINE-1,4-DIOXIDES<br/>[FR] 1,2,4-BENZOTRIAZINE-1,4-DIOXYDES
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2005082867A1

  公开（公告）日：2005-09-09

  The present invention provides a simplified set of characteristics that can be used to select 1,2,4 benzotriazine 1,4 dioxide compounds (TPZ analogues) with therapeutic activity against hypoxic cells in human tumour xenografts, and to further provide a novel class of 1,2,4-benzotriazine-1,4-dioxides (TPZ analogues) with predicted in vivo activity against tumours, to their preparation, and to their use as hypoxia-selective cytotoxic drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明提供了一种简化的特征集，可用于选择对人类肿瘤异种移植物中的缺氧细胞具有治疗活性的1,2,4-苯并三氮唑-1,4-二氧化物（TPZ类似物），并进一步提供了一种新型的1,2,4-苯并三氮唑-1,4-二氧化物（TPZ类似物），预测其对肿瘤的体内活性，以及它们的制备和用作缺氧选择性细胞毒药物和放射增敏剂用于癌症治疗，单独或与放射线和/或其他抗癌药物结合使用。
• Novel 1,2,4-benzotriazine-1,4-dioxides
  申请人：Denny Alexander William

  公开号：US20070197534A1

  公开（公告）日：2007-08-23

  The present invention provides a simplified set of characteristics that can be used to select 1,2,4 benzotriazine 1,4 dioxide compounds (TPZ analogues) with therapeutic activity against hypoxic cells in human tumour xenografts, and to further provide a novel class of 1,2,4-benzotriazine-1,4-dioxides (TPZ analogues) with predicted in vivo activity against tumours, to their preparation, and to their use as hypoxia-selective cytotoxic drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明提供了一组简化的特征，可用于选择对人类肿瘤异种移植物中的低氧细胞具有治疗活性的1,2,4-苯并三氮唑-1,4-二氧化物化合物（TPZ类似物），并进一步提供一种新型的1,2,4-苯并三氮唑-1,4-二氧化物（TPZ类似物），预测其对肿瘤的体内活性，以及它们的制备和作为低氧选择性细胞毒性药物和放射增敏剂用于癌症治疗，单独或与放射线和/或其他抗癌药物联合使用。
• 1,2,4-benzotriazine-1,4-dioxides
  申请人：Auckland Uniservices Limited

  公开号：US07816521B2

  公开（公告）日：2010-10-19

  The compound 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide and pharmacologically acceptable salts thereof. A method of treating cancer in a subject is also described in which 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide or a pharmacologically acceptable salt thereof is administered to tumor cells in a hypoxic environment. Also described is a method of radiosensitising in a subject tumor cells of solid tumors in hypoxic conditions by administering to the subject a pharmaceutical composition containing 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide or a pharmacologically acceptable salt thereof in an amount sufficient to produce radiosensitivity in the tumor cells, and subjecting the tumor cells to radiation. A pharmaceutical composition is additionally provided containing a therapeutically effective amount of 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser.

  本文描述了化合物3-乙基-6-[3-(4-吗啡啶基)丙氧基]-1,2,4-苯并三氮唑1,4-二氧化物及其药学上可接受的盐。还描述了一种治疗受体癌症的方法，其中3-乙基-6-[3-(4-吗啡啶基)丙氧基]-1,2,4-苯并三氮唑1,4-二氧化物或其药学上可接受的盐被用于在低氧环境下治疗肿瘤细胞。此外，还提供了一种方法，通过向患者注射含有3-乙基-6-[3-(4-吗啡啶基)丙氧基]-1,2,4-苯并三氮唑1,4-二氧化物或其药学上可接受的盐的药物组合物，以在低氧条件下使实体瘤中的肿瘤细胞放射敏感性，然后将肿瘤细胞暴露于放射线。此外，还提供了一种药物组合物，其中包含治疗有效量的3-乙基-6-[3-(4-吗啡啶基)丙氧基]-1,2,4-苯并三氮唑1,4-二氧化物或其药学上可接受的盐和药学上可接受的赋形剂、辅料、载体、缓冲剂或稳定剂。
• US7816521B2
  申请人：——

  公开号：US7816521B2

  公开（公告）日：2010-10-19
• Pharmacokinetic/Pharmacodynamic Model-Guided Identification of Hypoxia-Selective 1,2,4-Benzotriazine 1,4-Dioxides with Antitumor Activity: The Role of Extravascular Transport
  作者：Michael P. Hay、Kevin O. Hicks、Frederik B. Pruijn、Karin Pchalek、Bronwyn G. Siim、William R. Wilson、William A. Denny

  DOI：10.1021/jm070670g

  日期：2007.12.13

  Pharmacokinetic/pharmacodynamic (PK/PD) modeling has shown the antitumor activity of tirapazamine (TPZ), a bioreductive hypoxia-selective cytotoxin, to be limited by poor penetration through hypoxic tumor tissue. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ to improve activity against hypoxic cells by increasing extravascular transport. The 6 substituents modified lipophilicity and rates of hypoxic metabolism. 3-Alkylamino substituents increased aqueous solubility and also influenced lipophilicity and hypoxic metabolism. PK/PD model-guided screening was used to select six BTOs for evaluation against hypoxic cells in HT29 human tumor xenografts. All six BTOs were active in vivo, and two provided greater hypoxic cell killing than TPZ because of improved transport and/or plasma PK. This PK/PD model considers two causes of therapeutic failure (limited tumor penetration and poor plasma pharmacokinetics) often not addressed early in drug development and provides a general strategy for selecting candidates for in vivo evaluation during lead optimization.