3-[2-(2-hydroxyethoxy)ethyl]amino-1,2,4-benzotriazine 1-oxide | 637032-98-5

• 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-[2-(2-hydroxyethoxy)ethyl]amino-1,2,4-benzotriazine 1-oxide
• 英文别名: 3-{[2-(2-Hydroxyethoxy)ethyl]amino}-1,2,4-benzotriazine 1-oxide；2-[2-[(1-oxido-1,2,4-benzotriazin-1-ium-3-yl)amino]ethoxy]ethanol
• CAS: 637032-98-5
• 化学式: C₁₁H₁₄N₄O₃
• 分子量: 250.257
• InChiKey: CODLEEAAONSXIU-UHFFFAOYSA-N

物化性质

• 熔点：
  131-131.5 °C(Solv: dichloromethane (75-09-2); ethyl acetate (141-78-6))
• 沸点：
  500.6±56.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  92.7
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-[2-(2-hydroxyethoxy)ethyl]amino-1,2,4-benzotriazine 1-oxide 在 吡啶 、 碳酸氢钠 、 sodium iodide 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 3-[2-(2-iodoethoxy)ethyl]amino-1,2,4-benzotriazine 1,4-dioxide
  参考文献：
  名称：

  推定的电子亲和性放射增敏剂和缺氧组织标志物：C3-氨基取代的苯并三嗪二氧化物（BTDOs）的合成和体外初步生物学表征

  摘要：

  介绍 1,2,4-苯并三嗪-1,4-二氧化物（BTDO）的氧化还原特性使其成为潜在的固体人类癌症中低氧细胞的放射增敏剂。尽管雷帕拉明（TPZ）在有效剂量下具有毒性，但它是经过临床测试最多的BTDO放射增敏剂。迄今为止，尚未开发出BTDO作为组织缺氧的诊断标记。 假设 具有适当报告群体的TPZ类似物可作为潜在的放射增敏剂和缺氧选择性诊断剂。 实验与结果 在C 3位置取代3-氯-1,2,4-苯并三嗪-1-氧化物，得到3-（2-羟基乙氧基乙基）-氨基-1,2,4-苯并三嗪-1-氧化物，将其氧化为3 -（2-羟基乙氧基乙基）-氨基-1,2,4-苯并三嗪-1,4-二氧化物（HO-EOE-TPZ）或转化为3-（2-甲苯磺酰氧基乙氧基乙基）-氨基-1,2,4-苯并三嗪- 1,4-二氧化物（Tos-EOE-TPZ）。Tos-EOE-TPZ用于合成3-（2-叠氮基乙氧基乙基）-氨基-1,2,4-苯并三嗪-1

  DOI：

  10.1016/j.ejmech.2019.01.009
• 作为产物：
  描述：

  3-氨基-1,2,4-苯并噻嗪-1-n-氧化物 在 三氟乙酸 、 sodium nitrite 作用下， 以 二氯甲烷 为溶剂， 反应 2.2h， 生成 3-[2-(2-hydroxyethoxy)ethyl]amino-1,2,4-benzotriazine 1-oxide
  参考文献：
  名称：

  推定的电子亲和性放射增敏剂和缺氧组织标志物：C3-氨基取代的苯并三嗪二氧化物（BTDOs）的合成和体外初步生物学表征

  摘要：

  介绍 1,2,4-苯并三嗪-1,4-二氧化物（BTDO）的氧化还原特性使其成为潜在的固体人类癌症中低氧细胞的放射增敏剂。尽管雷帕拉明（TPZ）在有效剂量下具有毒性，但它是经过临床测试最多的BTDO放射增敏剂。迄今为止，尚未开发出BTDO作为组织缺氧的诊断标记。 假设 具有适当报告群体的TPZ类似物可作为潜在的放射增敏剂和缺氧选择性诊断剂。 实验与结果 在C 3位置取代3-氯-1,2,4-苯并三嗪-1-氧化物，得到3-（2-羟基乙氧基乙基）-氨基-1,2,4-苯并三嗪-1-氧化物，将其氧化为3 -（2-羟基乙氧基乙基）-氨基-1,2,4-苯并三嗪-1,4-二氧化物（HO-EOE-TPZ）或转化为3-（2-甲苯磺酰氧基乙氧基乙基）-氨基-1,2,4-苯并三嗪- 1,4-二氧化物（Tos-EOE-TPZ）。Tos-EOE-TPZ用于合成3-（2-叠氮基乙氧基乙基）-氨基-1,2,4-苯并三嗪-1

  DOI：

  10.1016/j.ejmech.2019.01.009

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。
• [EN] DNA-TARGETED BENZOTRIAZINE 1,4-DIOXIDES AND THEIR USE IN CANCER THERAPY<br/>[FR] 1,4-DIOXIDES DE BENZOTRIAZINE CIBLEES SUR ADN ET LEUR UTILISATION DANS LE TRAITEMENT DU CANCER
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2004026846A1

  公开（公告）日：2004-04-01

  The present invention relates to DNA-targeted 1,2,4-benzotriazine- 1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明涉及以DNA为靶标的1,2,4-苯并三氮唑-1,4-二氧化物及相关类似物，其制备方法，以及它们作为针对缺氧选择性药物和放射增敏剂在癌症治疗中的应用，无论是单独使用还是与放射线和/或其他抗癌药物结合使用。
• [EN] BIOREDUCTIVELY-ACTIVATED COMPOUNDS, THEIR PRODRUGS, RADIOPHARMACEUTICALS, THE COMPOSITIONS, AND THEIR APPLICATIONS IN MULTIMODAL THERANOSTIC MANAGEMENT OF HYPOXIA DISEASES INCLUDING CANCER<br/>[FR] COMPOSÉS ACTIVÉS PAR BIORÉDUCTION, LEURS PROMÉDICAMENTS, PRODUITS RADIOPHARMACEUTIQUES, LES COMPOSITIONS ET LEURS APPLICATIONS DANS LA GESTION THÉRANOSTIQUE MULTIMODALE DE L'HYPOXIE, DONT LE CANCER
  申请人：UNIV ALBERTA

  公开号：WO2019056098A1

  公开（公告）日：2019-03-28

  Described herein are bioreductively- activated compounds, their prodrugs, radiopharmaceuticals, the compositions, and their application in multimodal theranostic management of hypoxia diseases including cancer.

  本文描述了生物还原激活化合物，它们的前药，放射性药物，以及这些组合物在多模式治疗和诊断管理低氧病（包括癌症）中的应用。
• Dna-targeted benzotriazine 1,4-dioxides and their use in cancer therapy
  申请人：Brown Martin J.

  公开号：US20070191372A1

  公开（公告）日：2007-08-16

  The present invention relates to DNA-targeted 1,2,4-benzotriazine-1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明涉及以DNA为靶点的1,2,4-苯并三氮唑-1,4-二氧化物及其相关类似物，其制备方法以及它们作为低氧选择性药物和放射增敏剂在癌症治疗中的使用，可以单独使用或与放射线和/或其他抗癌药物结合使用。
• DNA-Targeted 1,2,4-Benzotriazine 1,4-Dioxides:  Potent Analogues of the Hypoxia-Selective Cytotoxin Tirapazamine
  作者：Michael P. Hay、Frederik B. Pruijn、Swarna A. Gamage、H. D. Sarath Liyanage、Mary S. Kovacs、Adam V. Patterson、William R. Wilson、J. Martin Brown、William A. Denny

  DOI：10.1021/jm030399c

  日期：2004.1.1

  Tirapazamine (TPZ, 1,2,4-benzotriazin-3-amine 1,4-dioxide) is a bioreductive hypoxia-selective cytotoxin, currently in phase II/III clinical trials in combination with radiotherapy and with cisplatin-based chemotherapy. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ where a DNA-targeting chromophore is attached at the 3-position via a flexible linker. DNA binding affinity was modified through variation of the chromophore or the pK(a) of the linker chain. The association constants (K-DNA) for calf thymus DNA ranged from 1 x 10(2) to 5.6 x 10(5) M-1 (ionic strength of 0.01 M). DNA binding affinity was dependent on the presence of a positive charge, either in the linker chain or in the chromophore, and (for a series of 4-acridine carboxamide chromophore analogues) correlated strongly with linker chain pKa. The efficacy of these BTOs in killing aerobic and hypoxic mouse SCCVII tumor cells in vitro was determined by clonogenic survival. Cytotoxicity was measured as the concentration required to reduce plating efficiency to 10% of controls (C-10), and the hypoxic cytotoxicity ratio (HCR) for each BTO was calculated as C-10(aerobic)/C-10(hypoxic). BTOs bearing a positive charge showed increased hypoxic cytotoxicity (1.5-56-fold) compared to TPZ and mostly modest HCRs (8-51), but some excellent (> 167 and 400) values. There was a strong correlation between K-DNA and hypoxic cytotoxicity but no correlation between K-DNA and HCR. Cytotoxicity in HT-29 human colon carcinoma cells, determined using IC50 assays, showed similar relationships with a correlation between KDNA and hypoxic cytotoxicity but no correlation between KDNA and HCR. In this cell line, a higher proportion of compounds (7 of 11) had HCRs greater than or equal to that of TPZ. The data confirm that DNA targeting is a useful concept for increasing potency while maintaining hypoxic selectivity and provide a direction for the further development of DNA-targeted analogues of TPZ.