6-methoxy-N-[3-(4-morpholinyl)propyl]-1,2,4-benzotriazin-3-amine 1-oxide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 6-methoxy-N-[3-(4-morpholinyl)propyl]-1,2,4-benzotriazin-3-amine 1-oxide
• 英文别名: 6-methoxy-N-(3-morpholin-4-ylpropyl)-1-oxido-1,2,4-benzotriazin-1-ium-3-amine
• 化学式: C₁₅H₂₁N₅O₃
• 分子量: 319.363
• InChiKey: XSPUPYUKCMUXRE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 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：

  6-methoxy-N-[3-(4-morpholinyl)propyl]-1,2,4-benzotriazin-3-amine 1-oxide 在 双氧水 、 三氟乙酸 、 三氟乙酸酐 作用下， 以 二氯甲烷 为溶剂， 以6%的产率得到6-methoxy-N-(3-morpholin-4-ylpropyl)-1,4-dioxido-1,2,4-benzotriazine-1,4-diium-3-amine
  参考文献：
  名称：

  Pharmacokinetic/Pharmacodynamic Model-Guided Identification of Hypoxia-Selective 1,2,4-Benzotriazine 1,4-Dioxides with Antitumor Activity: The Role of Extravascular Transport

  摘要：

  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.

  DOI：

  10.1021/jm070670g
• 作为产物：
  描述：

  N-(3-氨丙基)吗啉 、 3-chloro-6-methoxy-1,2,4-benzotriazine 1-oxide 在 三乙胺 作用下， 以 乙二醇二甲醚 为溶剂， 反应 8.0h， 以96%的产率得到6-methoxy-N-[3-(4-morpholinyl)propyl]-1,2,4-benzotriazin-3-amine 1-oxide
  参考文献：
  名称：

  Pharmacokinetic/Pharmacodynamic Model-Guided Identification of Hypoxia-Selective 1,2,4-Benzotriazine 1,4-Dioxides with Antitumor Activity: The Role of Extravascular Transport

  摘要：

  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.

  DOI：

  10.1021/jm070670g

文献信息

• 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.