5-chloro-6-(2,3,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine | 849550-78-3

• 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: 5-chloro-6-(2,3,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine
• 英文别名: 5-chloro-6-(2,3,6-trifluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine
• CAS: 849550-78-3
• 化学式: C₁₄H₈ClF₆N₅
• 分子量: 395.694
• InChiKey: OYOGQNDXMWICRO-YFKPBYRVSA-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：

  5-chloro-6-(2,3,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine 、 3-二甲氨基-1-丙醇 在 sodium hydride 作用下， 以 二甲基亚砜 为溶剂， 反应 4.0h， 以10%的产率得到5-chloro-6-{3-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-[(1S)-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：

  (S)-1,1,1-三氟异丙胺盐酸盐 、 5,7-dichloro-6-(2,3,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 13.0h， 以85%的产率得到5-chloro-6-(2,3,6-trifluorophenyl)-N-[(1S)-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

文献信息

• [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。
• 6-[(Substituted)phenyl]triazolopyrimidines as anticancer agents
  申请人：Zhang Nan

  公开号：US20050090508A1

  公开（公告）日：2005-04-28

  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]三唑嘧啶化合物或其药学上可接受的盐，以及含有该化合物或其药学上可接受的盐的组合物，其中该化合物是对哺乳动物癌症治疗有用的抗癌剂。本发明还涉及一种用于治疗或抑制哺乳动物中癌细胞肿瘤的生长和相关疾病的方法，并进一步提供了一种用于治疗或预防因多药耐药（MDR）而表达多重药物抗性的癌性肿瘤的方法，该方法包括向所述哺乳动物中需要的部位注射所述化合物或其药学上可接受的盐的有效量。本发明还涉及一种通过促进微管聚合来治疗或抑制哺乳动物中癌细胞肿瘤的生长和相关疾病的方法，该方法包括向所述哺乳动物中注射所述化合物及其药学上可接受的盐的有效量。
• 6- [(SUBSTITUTED)PHENYL] TRIAZOLOPYRIMIDINES AS ANTICANCER AGENTS
  申请人：Wyeth Holdings Corporation

  公开号：EP1680425A1

  公开（公告）日：2006-07-19
• US7507739B2
  申请人：——

  公开号：US7507739B2

  公开（公告）日：2009-03-24
• 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.