1-(4-(4-(((2R,4S)-2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethanone | 1056027-41-8

• 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-(4-(((2R,4S)-2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethanone
• 英文别名: FL-B-12；1-[4-[4-[[(2R,4S)-2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
• CAS: 1056027-41-8
• 化学式: C₂₃H₂₆F₂N₂O₄
• 分子量: 432.467
• InChiKey: VVAHJSXAXRVBPR-NZQKXSOJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  51.2
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-乙酰哌嗪 、 在 三叔丁基膦 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 反应 18.0h， 以56%的产率得到1-(4-(4-(((2R,4S)-2-(2,4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)ethanone
  参考文献：
  名称：

  Synthesis of novel ketoconazole derivatives as inhibitors of the human Pregnane X Receptor (PXR; NR1I2; also termed SXR, PAR)

  摘要：

  PXR, pregnane X receptor, in its activated state, is a validated target for controlling certain drug-drug interactions in humans. In this context, there is a paucity of inhibitors directed toward activated PXR. Using prior observations with ketoconazole as a PXR inhibitor, the target compound 3 was synthesized from (s)-glycidol with overall 56% yield. (+)-Glycidol was reacted with 4-bromophenol and potassium carbonate in DMF to yield the ring opened compound 6. This was then heated to reflux in benzene along with 2', 4'-difluoroacetophenone and catalytic amount of para-toluene sulfonic acid to yield 8. The resultant acetal 8 was then functionalized using Palladium chemistry to yield the target compound 3. The activity of the compound was compared with ketoconazole and UCL2158H. However, in contrast with ketoconazole (IC50 similar to 0.020 mu M; similar to 100% inhibition), 3 has negligible effects on inhibition of microsomal CYP450 (maximum similar to 20% inhibition) at concentrations > 40 mu M. In vitro, micromolar concentration of ketoconazole is toxic to passaged human cell lines, while 3 does not exhibit cytotoxicity up to concentrations similar to 100 mu M(viability > 85%). This is the first demonstration of a chemical analog of a PXR inhibitor that retains activity against activated PXR. Furthermore, in contrast with ketoconazole, 3 is less toxic in human cell lines and has negligible CYP450 activity. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.06.018

文献信息

• KETOCONAZOLE-DERIVATIVE ANTAGONIST OF HUMAN PREGNANE X RECEPTOR AND USES THEREOF
  申请人：Mani Sridhar

  公开号：US20110105522A1

  公开（公告）日：2011-05-05

  The application discloses ketoconazole derivatives that are antagonists of the human pregnane X receptor (PXR), methods of preparing the derivatives, uses of the derivatives with drug therapy, and methods of inhibiting tumor cell proliferation and multidrug resistance using inhibitors of PXR.
• US8669260B2
  申请人：——

  公开号：US8669260B2

  公开（公告）日：2014-03-11
• [EN] KETOCONAZOLE-DERIVATIVE ANTAGONISTS OF HUMAN PREGNANE X RECEPTOR AND USES THEREOF<br/>[FR] ANTAGONISTES DE DÉRIVÉS DE KÉTOCONAZOLE DU RÉCEPTEUR X DE PRÉGNANE HUMAIN ET LEURS UTILISATIONS
  申请人：EINSTEIN COLL MED

  公开号：WO2009110955A2

  公开（公告）日：2009-09-11

  The application discloses ketoconazole derivatives that are antagonists of the human pregnane X receptor (PXR), methods of preparing the derivatives, uses of the derivatives with drug therapy, and methods of inhibiting tumor cell proliferation and multidrug resistance using inhibitors of PXR.
• [EN] ADJUVANT OR NEOADJUVANT THERAPY FOR SENSITIZING CANCER STEM CELLS TO CHEMOTHERAPY<br/>[FR] TRAITEMENT ADJUVANT OU NÉOADJUVANT DE SENSIBILISATION DE CELLULES SOUCHES CANCÉREUSES À UNE CHIMIOTHÉRAPIE
  申请人：CENTRE NAT RECH SCIENT

  公开号：WO2016026933A1

  公开（公告）日：2016-02-25

  The invention relates to a compound for use for preventing cancer recurrences wherein said compound is selected from the group consisting of antagonists of PXR and inhibitors of PXR expression and/or activity; said cancer responds correctly to chemotherapy; and said compound acts specifically on cancerous stem cells by sensitizing them to chemotherapy.