3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide
• 英文别名: SN29751；3-ethyl-6-(3-morpholin-4-ylpropoxy)-1-oxido-1,2,4-benzotriazin-4-ium 4-oxide
• 化学式: C₁₆H₂₂N₄O₄
• 分子量: 334.375
• InChiKey: QVUPZRCWEOZDTE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  80.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide 以 aq. phosphate buffer 为溶剂， 以35%的产率得到3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1-oxide
  参考文献：
  名称：

  水溶液中苯并三嗪1,4-二-N-氧化物低氧激活的前药SN30000的光降解。

  摘要：

  SN30000是一种苯并三嗪二氧化氮，对肿瘤中的耐辐射缺氧细胞有选择性毒性。考虑到某些芳香族N-氧化物的光化学反应复杂，我们评估了SN30000溶液的光降解潜力。最初的研究表明，在正常的实验室照明条件下，氧气对氧气的敏感性会大大降低。光降解动力学显示比尔定律预测的形式具有明显的浓度依赖性，其量子产率为0.016。光产物可以合理地认为是由恶唑烷中间体产生的。主要的稳定产物（化合物6；在UV或可见光下，SN30000损失约50％）的特征在于分子内的氧转移至SN30000的吗啉侧链。该机制与从类似物（SN29751）形成相应的吗啉N-氧化物的缺乏相一致，在该类似物中不能形成所提出的六元环过渡态。在缺氧或需氧条件下，Cmpd 6对培养的人类肿瘤细胞的细胞毒性比SN30000小，并且以高于最大耐受剂量的剂量（750μmol/ kg）腹膜内给予NIH-III裸鼠无毒SN30000本身。总之，SN300

  DOI：

  10.1002/jps.24099
• 作为产物：
  描述：

  4-(3-羟丙基)吗啉 在 三氟过氧乙酸 、 sodium hydride 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 5.5h， 生成 3-ethyl-6-[3-(4-morpholinyl)propoxy]-1,2,4-benzotriazine 1,4-dioxide
  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

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。
• Hypoxia-Selective 3-Alkyl 1,2,4-Benzotriazine 1,4-Dioxides: The Influence of Hydrogen Bond Donors on Extravascular Transport and Antitumor Activity
  作者：Michael P. Hay、Karin Pchalek、Frederik B. Pruijn、Kevin O. Hicks、Bronwyn G. Siim、Robert F. Anderson、Sujata S. Shinde、Victoria Phillips、William A. Denny、William R. Wilson

  DOI：10.1021/jm701037w

  日期：2007.12.27

  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.
• US7816521B2
  申请人：——

  公开号：US7816521B2

  公开（公告）日：2010-10-19