(R)-5-chloro-6-(2,4,6-trifluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine | 388060-93-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (R)-5-chloro-6-(2,4,6-trifluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
• 英文别名: 5-chloro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine；5-chloro-6-(2,4,6-trifluorophenyl)-N-[(2R)-1,1,1-trifluoropropan-2-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
• CAS: 388060-93-3
• 化学式: C₁₄H₈ClF₆N₅
• 分子量: 395.694
• InChiKey: MGSIJDCPNJZOHF-RXMQYKEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (R)-5-chloro-6-(2,4,6-trifluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine 、 3-(甲胺基)-1-丙醇 在 sodium hydride 作用下， 以 二甲基亚砜 为溶剂， 反应 4.0h， 以51%的产率得到5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1R)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine
  参考文献：
  名称：

  Synthesis and SAR of [1,2,4]Triazolo[1,5-a]pyrimidines, a Class of Anticancer Agents with a Unique Mechanism of Tubulin Inhibition

  摘要：

  The synthesis and SAR of a series of triazolopyrimidines as anticancer agents are described. Treatment of 5-chloro-6-(trifluorophenyl)-N-fluoroalkyl [1,2,4]triazolo[1,5-a]pyrimidin-7-amine with an alcohol, a thiol, or an alkylamine provided the corresponding final compounds. A clear SAR requirement has been established for optimal activity. A (1S)-2,2,2-trifluoro-1-methylethylamino group or an achiral 2,2,2-trifluoroethylamino group is required at the 5-position to achieve high potency. On the phenyl ring, both fluoro atoms, at the positions ortho to the triazolopyrimidine core, are needed for optimal activity. At the position para to the triazolopyrimidine core, on the phenyl ring, the best activity is achieved with an oxygen linkage followed by a three-methylene unit, and an alkylamino or a hydroxy group. The mechanism of action for this series of triazolopyrimidines was shown to be unique in that they promoted tubulin polymerization in vitro, but did not bind competitively with paclitaxel.(1) Instead, they inhibit the binding of vincas to tubulin. Selected compounds were studied further, and it was shown that these compounds were able to overcome resistance attributed to several multidrug resistance transporter proteins. Lead compounds were shown to inhibit tumor growth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orally or intravenously.

  DOI：

  10.1021/jm060717i
• 作为产物：
  描述：

  1-溴-2,4,6-三氟苯 在 三正丁胺 、 sodium hydride 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 20.34h， 生成 (R)-5-chloro-6-(2,4,6-trifluorophenyl)-N-(1,1,1-trifluoropropan-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
  参考文献：
  名称：

  评估微管靶向 1,2,4-三唑并[1,5-a]嘧啶的构效关系确定了神经退行性 Tauopathies 的新候选者

  摘要：

  对 tau 和 Aβ 斑块转基因小鼠模型的研究表明，脑渗透性微管 (MT) 稳定化合物，包括 1,2,4-三唑[1,5- a]嘧啶，有望成为阿尔茨海默病和相关神经退行性 tau 蛋白病的候选治疗方法。三唑并嘧啶已作为抗癌剂进行了研究。然而，这些化合物的抗有丝分裂活性并不总是与细胞中 MTs 的稳定性相关。事实上，我们实验室以前的研究确定了在 C6 上连接的片段在确定三唑并嘧啶是否促进 MT 稳定或相反地破坏细胞中的 MT 完整性方面的关键作用。为了进一步阐明构效关系 (SAR) 并确定神经退行性疾病的潜在改善 MT 稳定候选物，设计、合成和评估了一套全面的 68 种三唑并嘧啶同系物，这些同系物在 C6 和/或 C7 处具有结构修饰。

  DOI：

  10.1021/acs.jmedchem.0c01605

文献信息

• Substituted-triazolopyrimidines as anticancer agents
  申请人：American Home Products Corporation

  公开号：US20020068744A1

  公开（公告）日：2002-06-06

  The invention provides a method of treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof which comprises administering to said mammal an effective amount of a substituted triazolopyrimidine derivative or a pharmaceutically acceptable salt thereof and further provides a method of treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof by interacting with tubulin and microtubules and promoting microtubule polymerization which comprises administering to said mammal an effective amount of a substituted triazolopyrimidine derivative or a pharmaceutically acceptable salt thereof.

  该发明提供了一种治疗或抑制哺乳动物体内癌症肿瘤细胞及相关疾病的方法，包括向该哺乳动物体内施用有效量的取代三唑吡啶衍生物或其药学上可接受的盐，并进一步提供了一种通过与微管蛋白和微管相互作用并促进微管聚合的方法，治疗或抑制哺乳动物体内癌症肿瘤细胞及相关疾病，包括向该哺乳动物体内施用有效量的取代三唑吡啶衍生物或其药学上可接受的盐。
• SUBSTITUTED-TRIAZOLOPYRIMIDINES AS ANTICANCER AGENTS
  申请人：Wyeth

  公开号：EP1307200A2

  公开（公告）日：2003-05-07
• US7329663B2
  申请人：——

  公开号：US7329663B2

  公开（公告）日：2008-02-12
• [EN] SUBSTITUTED-TRIAZOLOPYRIMIDINES AS ANTICANCER AGENTS<br/>[FR] TRIAZOLOPYRIMIDINES SUBSTITUES COMME AGENTS ANTICANCEREUX
  申请人：AMERICAN HOME PROD

  公开号：WO2002002563A2

  公开（公告）日：2002-01-10

  The invention provides a method of treating of inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof which comprises administering to said mammal an effective amount of a substituted triazolopyrimidine derivative or a pharmaceutically acceptable salt thereof and further provides a method of treating or inhibiting the growth of cancerous tumour cells and associated diseases in a mammal in need thereof by interacting with tubulin and microtubules and promoting microtubule polymerization which comprises administering to said mammal an effective amount of a substituted triazolopyrimidine derivative or a pharmaceutically acceptable salt thereof.
• Synthesis and SAR of [1,2,4]Triazolo[1,5-<i>a</i>]pyrimidines, a Class of Anticancer Agents with a Unique Mechanism of Tubulin Inhibition
  作者：Nan Zhang、Semiramis Ayral-Kaloustian、Thai Nguyen、Jay Afragola、Richard Hernandez、Judy Lucas、James Gibbons、Carl Beyer

  DOI：10.1021/jm060717i

  日期：2007.1.1

  The synthesis and SAR of a series of triazolopyrimidines as anticancer agents are described. Treatment of 5-chloro-6-(trifluorophenyl)-N-fluoroalkyl [1,2,4]triazolo[1,5-a]pyrimidin-7-amine with an alcohol, a thiol, or an alkylamine provided the corresponding final compounds. A clear SAR requirement has been established for optimal activity. A (1S)-2,2,2-trifluoro-1-methylethylamino group or an achiral 2,2,2-trifluoroethylamino group is required at the 5-position to achieve high potency. On the phenyl ring, both fluoro atoms, at the positions ortho to the triazolopyrimidine core, are needed for optimal activity. At the position para to the triazolopyrimidine core, on the phenyl ring, the best activity is achieved with an oxygen linkage followed by a three-methylene unit, and an alkylamino or a hydroxy group. The mechanism of action for this series of triazolopyrimidines was shown to be unique in that they promoted tubulin polymerization in vitro, but did not bind competitively with paclitaxel.(1) Instead, they inhibit the binding of vincas to tubulin. Selected compounds were studied further, and it was shown that these compounds were able to overcome resistance attributed to several multidrug resistance transporter proteins. Lead compounds were shown to inhibit tumor growth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orally or intravenously.