N,N,3-trimethyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑四嗪类
• 英文名称: N,N,3-trimethyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide
• 英文别名: N,N,3-trimethyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide
• 化学式: C₈H₁₀N₆O₂
• 分子量: 222.206
• InChiKey: ITCSSQHXIMMGKH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  83.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  替莫唑胺 在 氯化亚砜 、 硫酸 、 N,N-二甲基甲酰胺 、 sodium nitrite 作用下， 以 四氢呋喃 、 水 为溶剂， 生成 N,N,3-trimethyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide
  参考文献：
  名称：

  咪唑四嗪的可调稳定性导致胶质母细胞瘤的有效化合物。

  摘要：

  即使在个性化医学和免疫疗法的时代，替莫唑胺（TMZ），一种小分子DNA烷基化剂，仍然是胶质母细胞瘤（GBM）的护理标准。TMZ具有异常的作用方式，可通过体内水解自发转化为其活性成分。尽管TMZ已获得FDA批准长达20年之久，但对于肿瘤表达抗性酶MGMT并通过骨髓抑制引起全身毒性的患者，TMZ几乎没有益处。TMZ于1984年首次合成，但由于TMZ的化学敏感性，无法获得某些关键衍生物，这排除了对咪唑四嗪结构与生物活性之间联系的广泛探索。在这里，我们试图辨别咪唑并四嗪的水解稳定性和抗癌活性之间的关系，目的是确定前药激活的最佳时机，并通过增加血脑屏障的渗透性来开发具有增强功效的合适化合物。这项工作需要开发新的合成方法，以便在咪唑并四嗪的C8位上获得以前未开发的功能（例如脂族，酮，卤素和芳基）。通过合成和评估一系列具有一定范围水稳定性（0.5至40 h）的化合物，我们基于C8取代基的Hammett常

  DOI：

  10.1021/acschembio.8b00864

文献信息

• [EN] TEMOZOLOMIDE ANALOGS AND METHODS OF USE<br/>[FR] ANALOGUES DE TÉMOZOLOMIDE ET PROCÉDÉS D'UTILISATION
  申请人：ST JOHNS CANCER INST

  公开号：WO2022026756A1

  公开（公告）日：2022-02-03

  Disclosed herein are compounds and methods for treating cancer, such as glioblastomas.

  本文揭示了用于治疗癌症（如胶质母细胞瘤）的化合物和方法。
• [EN] IMIDAZOTETRAZINE COMPOUNDS<br/>[FR] COMPOSÉS D'IMIDAZOTÉTRAZINE
  申请人：UNIV ILLINOIS

  公开号：WO2020033880A1

  公开（公告）日：2020-02-13

  New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.

  新的合成方法提供了对咪唑四唑的C8位置以前未探索功能的访问。通过合成和评估一系列具有不同水稳定性（从0.5到40小时）的化合物，基于C8取代基的Hammett常数建立了咪唑四唑水解稳定性的预测模型。鉴定了具有活性的化合物，对一系列GBM细胞系具有活性，具有适当的水解和代谢稳定性，并且脑血清比例相对于TMZ显著升高，导致较低的血液毒性剖面和在GBM小鼠模型中优于TMZ的活性。
• Tetrazines
  申请人：MAY & BAKER LIMITED

  公开号：EP0252682A2

  公开（公告）日：1988-01-13

  Tetrazines of the formula: wherein R¹ represents cycloalkyl, optionally substituted alkyl, alkenyl or alkynyl, A¹ represents nitrogen or -CR³= wherein R³ represents hydrogen or a substituent, A² represents nitrogen or, when A¹ represents nitrogen, A² represents nitrogen or a group -CR³= as hereinbefore defined, Z¹ represents oxygen or sulphur, and R² represents a cyano or azidocarbonyl group or a group of the formula -COZ²R⁹, -CONHOR⁹, -CONHNR⁹R¹⁰, -CONHNHCOOR⁹, -CONHNHCONHR⁹ -COCR¹¹=N₂, -CONHR¹² or -CON=S(O)R¹³R¹⁴ wherein Z² is oxygen or sulphur and R⁹ and R¹⁰ each represents hydrogen, alkyl which may carry an optionally substituted phenyl substituent, or represents optionally substituted phenyl, R¹¹ represents hydrogen or alkyl, and R¹² represents optionally substituted alkyl and R¹³ and R¹⁴ each represent alkyl, and when R¹, R², or R³ represents or contains an acidic group, salts thereof are useful as pharmaceuticals; processes for their preparation and new intermediates are described.

  式中的四嗪： 其中 R¹ 代表环烷基、任选取代的烷基、烯基或炔基，A¹ 代表氮或-CR³= 其中 R³ 代表氢或取代基，A² 代表氮或当 A¹ 代表氮时、Z¹ 代表氧或硫，R² 代表氰基或叠氮羰基或式-COZ²R⁹、-CONHOR⁹、-CONHNR⁹R¹⁰、-CONHNHCOOR⁹、-CONHNHCONHR⁹ -COR¹=N₂的基团、-CONHR¹²或-CON=S(O)R¹³R¹⁴，其中 Z² 是氧或硫，R⁹和 R¹⁰ 各自代表氢、可带有任选取代的苯基取代基的烷基或代表任选取代的苯基、 R¹¹代表氢或烷基，R¹²代表任选取代的烷基，R¹³和R¹⁴各自代表烷基，当R¹、R²或R³代表或含有酸性基团时，其盐可用作药物；描述了其制备工艺和新的中间体。
• IMIDAZOTETRAZINE COMPOUNDS
  申请人：The Board of Trustees of the University of Illinois

  公开号：US20210002286A1

  公开（公告）日：2021-01-07

  New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.