1,2,4-苯并噻嗪-3-胺,7-甲氧基-,1-氧化物 | 27238-35-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: 1,2,4-苯并噻嗪-3-胺,7-甲氧基-,1-氧化物
• 英文名称: 7-methoxy-1,2,4-benzotriazin-3-amine 1-oxide
• 英文别名: 7-methoxy-3-aminobenzo-as-triazine 1-oxide；7-methoxy-1-oxy-benzo[e][1,2,4]triazin-3-ylamine；7-Methoxy-1-oxy-benzo[e][1,2,4]triazin-3-ylamin；7-methoxy-1-oxido-1,2,4-benzotriazin-1-ium-3-amine
• CAS: 27238-35-3
• 化学式: C₈H₈N₄O₂
• mdl: MFCD00151618
• 分子量: 192.177
• InChiKey: VUYQZWURLBMUHP-UHFFFAOYSA-N

物化性质

• 熔点：
  258-259 °C (decomp)
• 沸点：
  458.6±37.0 °C(Predicted)
• 密度：
  1.54±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.125
• 拓扑面积：
  86.5
• 氢给体数：
  1
• 氢受体数：
  5

安全信息

• 海关编码：
  2933699090

反应信息

• 作为反应物：
  描述：

  1,2,4-苯并噻嗪-3-胺,7-甲氧基-,1-氧化物 在 copper(l) iodide 、 四(三苯基膦)钯 亚硝酸特丁酯 、 碘 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 2.33h， 生成 3-ethyl-7-methoxy-1,2,4-benzotriazine 1-oxide
  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
• 作为产物：
  描述：

  4-甲氧基-2-硝基乙酰苯胺 在 盐酸 作用下， 以 乙醚 、 水 为溶剂， 反应 7.0h， 生成 1,2,4-苯并噻嗪-3-胺,7-甲氧基-,1-氧化物
  参考文献：
  名称：

  Discovery and Optimization of Benzotriazine Di-N-Oxides Targeting Replicating and Nonreplicating Mycobacterium tuberculosis

  摘要：

  Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 mu g/mL against H37Rv and a cytotoxicity (CC50) against Vero cells of 25 mu g/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.

  DOI：

  10.1021/jm300123s

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。
• Synthesis, hypoxia-selective cytotoxicity of new 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives
  作者：Qing Xia、Ling Zhang、Jun Zhang、Rong Sheng、Bo Yang、Qiaojun He、Yongzhou Hu

  DOI：10.1016/j.ejmech.2011.01.007

  日期：2011.3

  We reported the synthesis, hypoxic cytotoxic activities and selectivities of 18 new 3-(alkoxymethylamino)-1,2,4-benzotriazine 1,4-dioxides. The synthesized compounds were screened in vitro against 5 cell lines: K562, SMMC-7721, A549, PC-3 and KB in hypoxia and in normoxia. Some of them showed higher or similar cytotoxic activity when compared to tirapazamine. Physico-chemical study showed the positive

  我们报道了18种新的3-（烷氧基甲基氨基）-1，2，4-苯并三嗪1，4-二氧化物的合成，低氧的细胞毒性活性和选择性。在缺氧和常氧条件下，针对5种细胞系（K562，SMMC-7721，A549，PC-3和KB）进行体外筛选。与替拉帕明相比，其中一些表现出更高或相似的细胞毒活性。理化研究表明，低氧活性与亲脂性在一定范围内呈正相关。对有效衍生物4b，4l和4m的初步机理研究表明，这些化合物的细胞毒性活性可能是通过诱导细胞凋亡来介导的。
• Structure−Activity Relationships of 1,2,4-Benzotriazine 1,4-Dioxides as Hypoxia-Selective Analogues of Tirapazamine
  作者：Michael P. Hay、Swarna A. Gamage、Mary S. Kovacs、Frederik B. Pruijn、Robert F. Anderson、Adam V. Patterson、William R. Wilson、J. Martin Brown、William A. Denny

  DOI：10.1021/jm020367+

  日期：2003.1.1

  well with that derived by the clonogenic endpoint. Most substituents, except 5- and 8-dimethylamino and 8-diethylamino, gave analogues less soluble than TPZ. E(1) values ranged from -240 mV through -670 mV (with TPZ having a value of -456 mV) and correlated well with the electronic parameter sigma for substituents at the 5-, 6-, 7-, and 8-positions. Aerobic cytotoxic potency showed a strong positive correlation

  替拉帕明（TPZ，1,2,4-苯并三嗪-3-胺1,4-二氧化物）是一种生物还原性低氧细胞毒素，目前在II / III期临床试验中结合放疗和基于顺铂的化学疗法。作为开发具有改善的溶解度/效能和治疗指数的TPZ类似物的程序的一部分，我们合成了34 1,2,4-苯并三嗪-3-胺1,4-二氧化物（BTO），以检查其结构活性关系（SAR）。环取代。系统地改变了5、6、7和8位上取代基的电子，疏水和空间参数，并确定了类似物的水溶性和单电子还原电位[E（1）] 。对于每种化合物，我们通过克隆形成存活率确定了有氧和低氧条件下小鼠SCCVII肿瘤细胞的体外杀伤作用，并确定了它们的相对低氧毒性（RHT；相对于TPZ）和低氧细胞毒性比（HCR）。使用96孔SRB增殖测定法独立评估了化合物的子集，其数据与克隆形成终点所得出的数据具有良好的相关性。除5-和8-二甲基氨基和8-二乙基氨基外，大多数取代基的溶解度均低于TPZ。E（1）值的范围是-240
• Radical properties governing the hypoxia-selective cytotoxicity of antitumor 3-amino-1,2,4-benzotriazine 1,4-dioxides
  作者：Robert F. Anderson、Sujata S. Shinde、Michael P. Hay、Swarna A. Gamage、William A. Denny

  DOI：10.1039/b502586a

  日期：——

  following the one-electron reduction of tirapazamine and its elimination of water from the initial reduction intermediate, and have suggested that this species is a cytotoxin. In this paper we have used pulse radiolysis to measure the one-electron reduction potentials of the benzotriazinyl radicals E(B*,H(+)/B) of 30 analogues of tirapazamine as well as the one-electron reduction potentials of their two-electron

  揭示抗癌药物替拉帕明（3-氨基-1,2,4-苯并三嗪1,4-二氧化物）引起缺氧选择性细胞毒性的自由基机制，被视为开发临床上有用的针对化学疗法的生物还原药物的方法。和耐辐射的缺氧肿瘤细胞。我们以前的研究指出，单电子还原替拉帕明并从初始的还原中间体中除去水后，会形成一个活性的苯并三嗪基自由基，并表明该物种是一种细胞毒素。在本文中，我们使用脉冲辐解法测量了替拉帕明的30个类似物的苯并三嗪基自由基E（B *，H（+）/ B）的单电子还原电势以及它们的两个电子还原的代谢物，苯并三嗪1氧化物E（B / B *-）。发现主要通过苯并三嗪1的单电子还原电位来追踪单电子还原的1,3-二氧化苯并三嗪1,4-二氧化物被氧反氧化的氧化还原依赖性，自由基的质子性和除水反应。 ，4-二氧化物E（A / A *-）。对已发表的SCCVII鼠肿瘤细胞系需氧和低氧克隆性细胞毒性数据进行多元回归分析，并在此研究中测量其物理化
• Heterocyclic N-oxides. Part VI. Synthesis and nuclear magnetic resonance spectra of 3-aminobenzo-1,2,4-triazines and their mono- and di-N-oxides
  作者：J. C. Mason、G. Tennant

  DOI：10.1039/j29700000911

  日期：——

  A series of 3-aminobenzo-1,2,4-triazine derivatives has been synthesised and their oxidation with hydrogen peroxide in acetic acid studied. The position of the N-oxide group(s) in the products has been established by analysis of n.m.r. spectra. It is shown that oxidation of 3-aminobenzo-1,2,4-triazines at room temperature leads almost exclusively to the 2-oxide whereas prolonged oxidation at 50° yields

  已经合成了一系列的3-氨基苯并-1,2,4-三嗪衍生物，并研究了它们在乙酸中用过氧化氢的氧化作用。通过核磁共振光谱分析，已经确定了产物中N-氧化物基团的位置。结果表明，在室温下3-氨基苯并-1,2,4-三嗪的氧化几乎只导致生成2-氧化物，而在50°下长时间氧化会生成1,4-二-N-氧化物。