8-carbamoyl-3-propargylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one | 1161825-73-5

• 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: 8-carbamoyl-3-propargylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one
• 英文别名: 4-Oxo-3-prop-2-ynylimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide
• CAS: 1161825-73-5
• 化学式: C₈H₆N₆O₂
• 分子量: 218.175
• InChiKey: JHGYHIRPZKSABQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-carbamoyl-3-propargylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one 在 tetraphosphorus decasulfide 、 六甲基二硅氧烷 作用下， 以 二氯甲烷 为溶剂， 以84 %的产率得到3-(propargyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4-oxo-8-thiocarboxamide
  参考文献：
  名称：

  发现具有克服肿瘤耐药性潜力的新型咪唑四嗪酮

  摘要：

  我们描述了临床使用的抗肿瘤药物替莫唑胺的一系列新型类似物的设计、有机合成和表征（包括 X 射线晶体学），以及它们的生物学评价。这项工作发现了一系列新的抗癌咪唑四嗪，它们有可能克服肿瘤对替莫唑胺的耐药性。合理设计的化合物包含炔丙基烷基化部分和噻唑环作为甲酰胺的等排替代物，易于合成（克级），表现出明确的固态结构，并增强对人类肿瘤细胞系的生长抑制活性，包括表达 MGMT 和 MMR 缺陷的细胞系，具有赋予肿瘤抗性的分子特征。细胞增殖数据通过克隆细胞存活测定得到证实，并进行DNA流式细胞术分析以确定新类似物对细胞周期进展的影响。详细的核磁共振氢谱研究表明，新试剂在溶液中稳定，并证实了其作用机制。炔丙基和噻唑取代基显着提高了效力和理化、药物代谢和渗透性特性，表明应优先考虑噻唑进行进一步的临床前评估。

  DOI：

  10.1016/j.ejmech.2023.115507
• 作为产物：
  描述：

  tert-butyl ((8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)methyl)carbamate 在 盐酸 、 sodium hydride 作用下， 以 水 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 0.33h， 生成 8-carbamoyl-3-propargylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one
  参考文献：
  名称：

  [EN] IMIDAZOTETRAZINE COMPOUNDS AND TREATMENT OF TMZ-RESISTANT CANCERS
  [FR] COMPOSÉS D'IMIDAZOTÉTRAZINE ET TRAITEMENT DE CANCERS RÉSISTANTS AU TMZ

  摘要：

  Imidazotetrazines were designed to evade resistance byO6-methylguanine DNA methyltransferase (MGMT) while retaining suitable hydrolytic stability, allowing for effective prodrug activation and biodistribution. One compound, called TABZ, exhibits activity against cancer cells irrespective of MGMT expression and MMR status. TABZ has comparable blood-brain barrier penetrance and comparable hematological toxicity relative to TMZ, while also matching its maximum tolerated dose (MTD) in mice when dosed once-per-day over five days. The activity of TABZ is independent of the two principal mechanisms suppressing the effectiveness of TMZ, making it a promising new candidate for the treatment of GBM, especially those that are TMZ resistant.

  公开号：

  WO2023150569A1

文献信息

• Antitumor imidazo[5,1-d]-1,2,3,5-tetrazines: compounds modified at the 3-position overcome resistance in human glioblastoma cell lines
  作者：David Cousin、Jihong Zhang、Marc G. Hummersone、Charles S. Matthews、Mark Frigerio、Tracey D. Bradshaw、Malcolm F. G. Stevens

  DOI：10.1039/c6md00384b

  日期：——

  Synthetic routes to 3-substituted imidazo[5,1-d]-1,2,3,5-tetrazines structurally related to temozolomide were explored. Interaction of 4-diazoimidazole-5-carboxamide with an isocyanate afforded high product yields when the isocyanate was available in acceptable purity. Alternatively, alkylation of the nor-temozolomide anion afforded high yields of new imidazotetrazines. Several compounds, evaluated

  探索了与替莫唑胺结构相关的3-取代的咪唑并[5,1- d ] -1,2,3,5-四嗪的合成途径。当以可接受的纯度获得异氰酸酯时，4-重氮咪唑-5-羧酰胺与异氰酸酯的相互作用提供了高产物收率。可选地，正-替唑啉酰亚胺阴离子的烷基化提供了高产率的新的咪唑并四嗪。针对含有匹配的MGMT±胶质瘤细胞系的一组化合物评估的几种化合物，无论MGMT的状态如何，均表现出相同的抑制活性。N3-炔丙基-咪唑并四嗪（10m）被优先作为替莫唑胺的替代品，后者能够绕过耐药机制。在Taq聚合酶测定法10m像替莫唑胺及其开环对应物MTIC一样，在三个和五个鸟嘌呤残基簇上的烷基化DNA；在哌啶裂解试验中检测到鸟嘌呤N-7位的共价修饰。化合物10m没有交联DNA，但是通过γ-H2AX检测证明诱导了双链断裂。炔丙基取代的咪唑三嗪（13g）显示出与10m相当的活性，表明新的咪唑四嗪的双环核开环可能是活性所必需的。
• [EN] 3-SUBSTITUTED-8-SUBSTITUTED-3H IMIDAZO[5,1-D][1,2,3,5-TETRAZIN-4-ONE COMPOUNDS AND THEIR USE<br/>[FR] COMPOSÉS 3H-IMIDAZO[5,1-D][1,2,3,5-TÉTRAZIN-4-ONE 3-SUBSTITUÉS-8-SUBSTITUÉS ET LEUR UTILISATION
  申请人：PHARMINOX LTD

  公开号：WO2010149968A1

  公开（公告）日：2010-12-29

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to 3-substituted-8-substituted-3H-imidazo[5,1-d][1,2,3,5]tetrazin-4-one compounds of the following formula, wherein -A and -B are as defined herein (collectively referred to herein as 38TM compounds): (1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit cell proliferation, and in the treatment of proliferative disorders such as cancer, etc., and methods of preparing such compounds.

  本发明一般涉及治疗化合物领域，更具体地涉及以下公式的3-取代-8-取代-3H-咪唑[5,1-d][1,2,3,5]四唑-4-酮化合物，其中-A和-B如本文所定义（统称为38TM化合物）：（1）。本发明还涉及包含这种化合物的药物组合物，以及利用这种化合物和组合物在体外和体内抑制细胞增殖，治疗增生性疾病如癌症等的用途，以及制备这种化合物的方法。
• [EN] THERAPEUTIC COMPOUNDS<br/>[FR] COMPOSÉS THÉRAPEUTIQUES
  申请人：UNIV NOTTINGHAM

  公开号：WO2020240199A1

  公开（公告）日：2020-12-03

  The invention provides a product which is a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof: (I) wherein: X is selected from: hydrogen; a methyl group which is optionally substituted, wherein any substituent groups present are independently selected from hydroxyl, halo and NR'2, where each R' is independently selected from hydrogen and methyl; and an ethyl group which is either unsubstituted or is substituted with from one to five F substituent groups; Y is selected from: hydrogen; a methyl group which is optionally substituted, wherein any substituent groups present are independently selected from hydroxyl, halo and NR'2, where each R' is independently selected from hydrogen and methyl; and an ethyl group which is either unsubstituted or is substituted with from one to five F substituent groups; RA is hydrogen, or is a C1-2 alkyl group which is optionally substituted, wherein any substituent groups present are independently selected from hydroxyl, halo and NR'2, where each R' is independently selected from hydrogen and methyl.

  该发明提供了一种化合物产品，其化学式为(I)，或其药学上可接受的盐、水合物或溶剂化合物：(I)其中：X选自：氢；一个甲基基团，可选择地被取代，其中任何存在的取代基独立地选自羟基、卤素和NR'2，其中每个R'独立地选自氢和甲基；和一个乙基基团，要么未取代，要么被从一个到五个F取代基团取代；Y选自：氢；一个甲基基团，可选择地被取代，其中任何存在的取代基独立地选自羟基、卤素和NR'2，其中每个R'独立地选自氢和甲基；和一个乙基基团，要么未取代，要么被从一个到五个F取代基团取代；RA为氢，或是一个可选择地被取代的C1-2烷基基团，其中任何存在的取代基独立地选自羟基、卤素和NR'2，其中每个R'独立地选自氢和甲基。
• [EN] METHODS AND INTERMEDIATES FOR THE SYNTHESIS OF 4-OXO-3,4-DIHYDRO-IMIDAZO[5,1-D][1,2,3,5]TETRAZINES<br/>[FR] PROCÉDÉS ET INTERMÉDIAIRES POUR EFFECTUER LA SYNTHÈSE DE 4-OXO-3,4-DIHYDRO-IMIDAZO[5,1-D][1,2,3,5]TÉTRAZINES
  申请人：PHARMINOX LTD

  公开号：WO2011107726A1

  公开（公告）日：2011-09-09

  The present invention provides a compound of general formula (II), or a salt or solvate thereof wherein A is independently -A1, -A2, -A3, -A4, -A5, -A6, or -A7, wherein: -A1 is independently C5-12heteroaryl, and is optionally substituted; -A2 is independently thioamido or substituted thioamido; -A3 is independently imidamido, substituted imidamido, N-hydroxyimidamido, or substituted N-hydroxyimidamido; -A4 is independently hydroxamic acid or hydroxamate; -A5 is independently carboxamide or substituted carboxamide; -A6 is independently aliphatic C2-6alkenyl, and is optionally substituted; and -A7 is independently carboxy or C1-4alkyl-carboxylate; and its use in the synthesis of temozolomide and analogues thereof.

  本发明提供了通式（II）的化合物，或其盐或溶剂化合物，其中A独立地为-A1、-A2、-A3、-A4、-A5、-A6或-A7，其中：-A1独立地为C5-12杂环芳基，并且可以被取代；-A2独立地为硫代酰胺或取代硫代酰胺；-A3独立地为咪唑酰胺、取代咪唑酰胺、N-羟基咪唑酰胺或取代N-羟基咪唑酰胺；-A4独立地为羟肟酸或羟肟酸酯；-A5独立地为羧酰胺或取代羧酰胺；-A6独立地为脂肪族C2-6烯基，并且可以被取代；-A7独立地为羧基或C1-4烷基羧酸酯；以及其在替莫唑胺及其类似物的合成中的用途。
• Synthesis and growth-inhibitory activities of imidazo[5,1-<i>d</i>]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position
  作者：David Cousin、Marc G. Hummersone、Tracey D. Bradshaw、Jihong Zhang、Christopher J. Moody、Magdalena B. Foreiter、Helen S. Summers、William Lewis、Richard T. Wheelhouse、Malcolm F. G. Stevens

  DOI：10.1039/c7md00554g

  日期：——

  The synthesis and biological evaluation of imidazotetrazines substituted at N-3 is described.

  对N-3位取代的咪唑四氮唑类化合物的合成和生物评价进行了描述。