1-{4-[3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-benzyl}-4-phenyl-piperazine | 1383717-86-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-{4-[3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-benzyl}-4-phenyl-piperazine
• 英文别名: 1-[[4-[3-[2,4-Bis(phenylmethoxy)-5-propan-2-ylphenyl]triazol-4-yl]phenyl]methyl]-4-phenylpiperazine；1-[[4-[3-[2,4-bis(phenylmethoxy)-5-propan-2-ylphenyl]triazol-4-yl]phenyl]methyl]-4-phenylpiperazine
• CAS: 1383717-86-9
• 化学式: C₄₂H₄₃N₅O₂
• 分子量: 649.836
• InChiKey: ROPDESBYZAWHGR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.5
• 重原子数：
  49
• 可旋转键数：
  12
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  55.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-{4-[3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-benzyl}-4-phenyl-piperazine 在 三氯化硼 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以157 mg的产率得到4-(5-{p-[(4-phenyl-1-piperazinyl)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-1,3-cumenediol
  参考文献：
  名称：

  Synthesis and Evaluation of New Hsp90 Inhibitors Based on a 1,4,5-Trisubstituted 1,2,3-Triazole Scaffold

  摘要：

  Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate.

  DOI：

  10.1021/jm401536b
• 作为产物：
  描述：

  2,4-bis(benzyloxy)-5-isopropylaniline 在 亚硝酸特丁酯 、 chloro(pentamethylcyclopentadienyl)ruthenium(II) tetramer 、 叠氮基三甲基硅烷 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 37.5h， 生成 1-{4-[3-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-3H-[1,2,3]triazol-4-yl]-benzyl}-4-phenyl-piperazine
  参考文献：
  名称：

  Synthesis and Evaluation of New Hsp90 Inhibitors Based on a 1,4,5-Trisubstituted 1,2,3-Triazole Scaffold

  摘要：

  Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate.

  DOI：

  10.1021/jm401536b

文献信息

• [EN] ARYL TRIAZOLE COMPOUNDS WITH ANTITUMOURAL ACTIVITY<br/>[FR] COMPOSÉS ARYL TRIAZOLE AYANT UNE ACTIVITÉ ANTI-TUMORALE
  申请人：SIGMA TAU RES SWITZERLAND SA

  公开号：WO2012084602A1

  公开（公告）日：2012-06-28

  The present invention relates to aryl triazole derivatives of Formula I having antitumoural activity through, as one possible biological target, the molecular chaperone heat shock protein 90 (Hsp90) inhibition. The invention includes the use of such compounds in medicine, in relation to cancer disease as well as other diseases where an inhibition of Hsp90 is responsive, and the pharmaceutical composition containing such compounds.

  本发明涉及具有抗肿瘤活性的Formula I的芳基三唑衍生物，作为一个可能的生物靶标，通过分子伴侣热休克蛋白90（Hsp90）的抑制作用。该发明包括在医学上使用这些化合物，涉及癌症疾病以及其他需要抑制Hsp90的疾病，以及含有这些化合物的药物组合物。
• ARYL TRIAZOLE COMPOUNDS WITH ANTITUMOURAL ACTIVITY
  申请人：Giannini Giuseppe

  公开号：US20140329812A1

  公开（公告）日：2014-11-06

  The present invention relates to aryl triazole derivatives of Formula I having antitumoural activity through, as one possible biological target, the molecular chaperone heat shock protein 90 (Hsp90) inhibition. The invention includes the use of such compounds in medicine, in relation to cancer disease as well as other diseases where an inhibition of Hsp90 is responsive, and the pharmaceutical composition containing such compounds.

  本发明涉及公式I的芳基三唑衍生物，通过作为可能的生物靶点之一，分子伴侣热休克蛋白90（Hsp90）抑制具有抗肿瘤活性。本发明包括将这些化合物用于医学，与癌症疾病以及其他需要抑制Hsp90的疾病有关，并且包含这些化合物的制药组合物。
• US9302998B2
  申请人：——

  公开号：US9302998B2

  公开（公告）日：2016-04-05
• Synthesis and Evaluation of New Hsp90 Inhibitors Based on a 1,4,5-Trisubstituted 1,2,3-Triazole Scaffold
  作者：Maurizio Taddei、Serena Ferrini、Luca Giannotti、Massimo Corsi、Fabrizio Manetti、Giuseppe Giannini、Loredana Vesci、Ferdinando M. Milazzo、Domenico Alloatti、Mario B. Guglielmi、Massimo Castorina、Maria L. Cervoni、Marcella Barbarino、Rosanna Foderà、Valeria Carollo、Claudio Pisano、Silvia Armaroli、Walter Cabri

  DOI：10.1021/jm401536b

  日期：2014.3.27

  Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate.