3-[2-(4-morpholinyl)ethyl]-1,2,4-benzotriazine 1-oxide hydrochloride | 763131-68-6

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 3-[2-(4-morpholinyl)ethyl]-1,2,4-benzotriazine 1-oxide hydrochloride
• 英文别名: 4-[2-(1-oxido-1,2,4-benzotriazin-1-ium-3-yl)ethyl]morpholine;hydrochloride
• CAS: 763131-68-6
• 化学式: C₁₃H₁₆N₄O₂*ClH
• 分子量: 296.757
• InChiKey: SJYHPWHETIAWBQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.56
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  63.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-[2-(4-morpholinyl)ethyl]-1,2,4-benzotriazine 1-oxide hydrochloride 在 双氧水 、 三氟乙酸酐 作用下， 以 二氯甲烷 为溶剂， 以14%的产率得到3-(2-Morpholin-4-ylethyl)-1-oxido-1,2,4-benzotriazin-4-ium 4-oxide
  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：

  吗啉 、 以 四氢呋喃 为溶剂， 反应 19.0h， 以80%的产率得到3-[2-(4-morpholinyl)ethyl]-1,2,4-benzotriazine 1-oxide hydrochloride
  参考文献：
  名称：

  Benzoazine mono-N-oxides and benzoazine 1,4 dioxides and compositions therefrom for the therapeutic use in cancer treatments

  摘要：

  本发明涉及一种协同组合物，包括一种或多种苯并噁唑-单-N-氧化物，以及一种或多种苯并噁唑1,4-二氧化物，用于癌症治疗。 该发明还提供了一系列新颖的1,2,4苯并噁唑-单-N-氧化物及相关类似物。这些可以用作增强现有抗癌药物的细胞毒性和癌症治疗的治疗剂。

  公开号：

  EP1468688A2

文献信息

• Benzoazine mono-N-oxides and benzoazine 1,4 dioxides and compositions therefrom for the therapeutic use in cancer treatments
  申请人：Auckland Uniservices Limited

  公开号：EP1468688A2

  公开（公告）日：2004-10-20

  The present invention relates to a synergetistic composition comprising one or more benzoazine-mono-N-oxides, and one or more benzoazine 1,4 dioxides for use in cancer therapy. The invention also provides a range of novel 1,2,4 benzoazine-mono-N-oxides and related analogues. These can be used as potentiators of the cytotoxicity of existing anticancer drugs and therapies for cancer treatment.

  本发明涉及一种协同组合物，包括一种或多种苯并噁唑-单-N-氧化物，以及一种或多种苯并噁唑1,4-二氧化物，用于癌症治疗。 该发明还提供了一系列新颖的1,2,4苯并噁唑-单-N-氧化物及相关类似物。这些可以用作增强现有抗癌药物的细胞毒性和癌症治疗的治疗剂。
• 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.