5,7-dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine | 214707-02-5

• 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: 5,7-dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine
• 英文别名: [1,2,4]Triazolo[1,5-a]pyrimidine, 5,7-dichloro-6-(2,4,6-trifluorophenyl)-
• CAS: 214707-02-5
• 化学式: C₁₁H₃Cl₂F₃N₄
• 分子量: 319.073
• InChiKey: FRUHHVIOSKAPJF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  43.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5,7-dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine 在 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 西维布林
  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 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 mineral oil 为溶剂， 反应 20.34h， 生成 5,7-dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine
  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

• 5-arylpyrimidines as anticancer agents
  申请人：Zhang Nan

  公开号：US20050075357A1

  公开（公告）日：2005-04-07

  This invention relates to certain 5-arylpyrimidine compounds or a pharmaceutically acceptable salt thereof, and compositions containing said compounds or a pharmaceutically acceptable salt thereof, wherein said compounds are anti-cancer agents useful for the treatment of cancer in mammals. This invention further relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal and further provides a method for the treatment or prevention of cancerous tumors that express multiple drug resistance (MDR) or are resistant because of MDR, in a mammal in need thereof which method comprises administering to said mammal an effective amount of said compounds or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal in need thereof by promotion of microtubule polymerization which comprises administering to said mammal an effective amount of said compounds and pharmaceutically acceptable salts thereof.

  这项发明涉及某些5-芳基嘧啶化合物或其药用盐，以及含有所述化合物或其药用盐的组合物，其中所述化合物是抗癌剂，可用于治疗哺乳动物的癌症。该发明还涉及一种治疗或抑制哺乳动物体内癌细胞和相关疾病生长的方法，并进一步提供了一种治疗或预防表达多药耐药性（MDR）或因MDR耐药的癌症肿瘤的方法，该方法包括向所述哺乳动物体内施用所述化合物或其药用盐的有效量。更具体地，本发明涉及通过促进微管聚合来治疗或抑制哺乳动物体内癌细胞和相关疾病的方法，该方法包括向所述哺乳动物体内施用所述化合物及其药用盐的有效量。
• Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines
  作者：Killian Oukoloff、Jane Kovalevich、Anne-Sophie Cornec、Yuemang Yao、Zachary A. Owyang、Michael James、John Q. Trojanowski、Virginia M.-Y. Lee、Amos B. Smith、Kurt R. Brunden、Carlo Ballatore

  DOI：10.1016/j.bmcl.2018.05.010

  日期：2018.7

  The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that

  [1,2,4]三唑并[1,5-a]嘧啶包括一类有前途的非天然存在的微管（MT）活性化合物。先前的研究表明，不同的三唑并嘧啶取代可产生促进MT稳定或破坏MT完整性的分子。这些差异在三唑并嘧啶的治疗应用中可能具有重要的意义，并表明不同的类似物可能在同一位点内表现出不同的结合模式，或者可能在其他结合位点与微管蛋白/ MT相互作用。为了帮助识别这些可能性，设计了一系列可光活化的三唑并嘧啶同源物，并在细胞测定中进行了评估，目的是鉴定用于光亲和标记实验的候选探针。这些研究导致鉴定出在三唑并嘧啶杂环的7位的胺取代基中掺入重氮基环的不同衍生物，从而导致促进MT稳定或破坏MT完整性的分子。这些可光活化的候选探针有望研究MT活性三唑并嘧啶的作用方式。
• [EN] DEUTERATED TRIAZOLOPYRIMIDINES<br/>[FR] TRIAZOLOPYRIMIDINES DEUTÉRÉS
  申请人：UNIV PENNSYLVANIA

  公开号：WO2020227491A1

  公开（公告）日：2020-11-12

  The present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1-R6 are defined herein. Also provided are compositions comprising a compound described herein and a pharmaceutically effective excipient, methods of stabilizing microtubules in a patient comprising administering to the patient a microtubule-stabilizing amount of a compound described herein, methods of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein, and methods of treating a neurodegenerative disease in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein.

  本公开提供了式（I）的化合物或其药学上可接受的盐或立体异构体，其中R1-R6在此处定义。还提供了包括本文描述的化合物和药学有效赋形剂的组合物，稳定微管的方法包括向患者施用本文描述的化合物的微管稳定剂量，治疗患者癌症的方法包括向患者施用本文描述的化合物的治疗有效量，以及治疗患者神经退行性疾病的方法包括向患者施用本文描述的化合物的治疗有效量。
• [EN] 6-[(SUBSTITUTED)PHENYL]TRIAZOLOPYRIMIDINES AS ANTICANCER AGENTS<br/>[FR] 6-[(SUBSTITUTEES)PHENYL]TRIAZOLOPYRIMIDINES UTILISEES EN TANT QU'AGENT ANTICANCEREUX
  申请人：WYETH CORP

  公开号：WO2005030775A1

  公开（公告）日：2005-04-07

  This invention relates to certain 6-[(substituted)phenyl]triazolopyrimidine compounds or pharmaceutically acceptable salts thereof, and compositions containing said compounds or pharmaceutically acceptable salts thereof, wherein said compounds are anti-cancer agents useful for the treatment of cancer in mammals. This invention further relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal and further provides a method for the treatment or prevention of cancerous tumors that express multiple drug resistance (MDR) or are resistant because of MDR, in a mammal in need thereof which method comprises administering to said mammal an effective amount of said compounds or pharmaceutically acceptable salts thereof. The present invention relates to a method of treating or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal in need thereof by promotion of microtubule polymerization which comprises administering to said mammal an effective amount of said compounds and pharmaceutically acceptable salts thereof.

  本发明涉及某些6-[(取代)苯基]三唑吡咯嗪化合物或其药用盐，以及含有所述化合物或其药用盐的组合物，其中所述化合物是对哺乳动物中的癌症具有治疗作用的抗癌剂。本发明还涉及一种治疗或抑制哺乳动物中癌症肿瘤细胞及相关疾病生长的方法，并进一步提供了一种治疗或预防表达多药耐药性（MDR）或因MDR而具有耐药性的癌症肿瘤的方法，该方法包括向该哺乳动物施用所述化合物或其药用盐的有效量。本发明涉及一种通过促进微管聚合来治疗或抑制哺乳动物中癌症肿瘤细胞及相关疾病生长的方法，该方法包括向该哺乳动物施用所述化合物及其药用盐的有效量。
• [DE] 7-ALKINYLAMINO-TRIAZOLOPYRIMIDINE, VERFAHREN ZU IHRER HERSTELLUNG UND IHRE VERWENDUNG ZUR BEKÄMPFUNG VON SCHADPILZEN SOWIE SIE ENTHALTENDE MITTEL<br/>[EN] 7-ALKINYLAMINO-TRIAZOLOPYRIMIDINES, METHODS FOR THE PRODUCTION AND USE THEREOF TO COMBAT HARMFUL FUNGI AND AGENTS CONTAINING SAID COMPOUNDS<br/>[FR] 7-ALKINYLAMINO-TRIAZOLOPYRIMIDINES, LEURS PROCEDES DE PRODUCTION ET LEUR UTILISATION POUR LUTTER CONTRE LES CHAMPIGNONS NUISIBLES ET LES PRODUITS LES CONTENANT
  申请人：BASF AG

  公开号：WO2004087706A1

  公开（公告）日：2004-10-14

  7-Alkinylamino-Triazolopyrimidine der Formel (I), in der die Substituenten folgende Bedeutung haben: L Halogen, Alkyl, Halogenalkyl, Alkoxy, Amino, NHR, NR2, Cyano, S(O)nA1 oder C(O)A2, R Alkyl oder Alkylcarbonyl; A1 Wasserstoff, Hydroxy, Alkyl, Alkylamino oder Dialkylamino n 0, 1 oder 2; A2 Alkenyl, Alkoxy, Halogenalkoxy oder eine der bei A1 genannten Gruppen; m 1, 2, 3, 4 oder 5, wobei mindestens eine Gruppe L in ortho-Stellung zu der Bindung mit dem Triazolopyrimidin­Gerüst vorliegt; X Halogen, Cyano, Alkyl, Halogenalkyl oder Alkoxy; R1 Wasserstoff oder Alkyl; R2 Alkinyl, welches unsubstituiert oder gemäss der Beschreibung substituiert sein kann; Verfahren zur Herstellung dieser Verbindungen, sie enthaltende Mittel sowie ihre Verwendung zur Bekämpfung von pflanzenpathogenen Schadpilzen.

  化合物(I)是7-炔基氨基三唑嘧啶，其中取代基具有以下含义：L为卤素、烷基、卤代烷基、烷氧基、氨基、NHR、NR2、氰基、S(O)nA1或C(O)A2；R为烷基或烷基羰基；A1为氢、羟基、烷基、烷基氨基或二烷基氨基；n为0、1或2；A2为烯基、烷氧基、卤代烷氧基或A1中提到的任一基团；m为1、2、3、4或5，其中至少一个L基团位于与三唑嘧啶骨架的连接处的邻位；X为卤素、氰基、烷基、卤代烷基或烷氧基；R1为氢或烷基；R2为炔基，可以是未取代的或按描述取代的；本发明还涉及制备这些化合物的方法、含有这些化合物的制剂以及它们用于对抗植物病原真菌的用途。