4-[4-(4-氯苯基)-4-羟基-1-哌啶基]-2,2-二苯基丁酰胺 | 66164-06-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4-[4-(4-氯苯基)-4-羟基-1-哌啶基]-2,2-二苯基丁酰胺
• 英文名称: 4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide
• 英文别名: N-Didesmethyl Loperamide；4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,2-diphenylbutanamide
• CAS: 66164-06-5
• 化学式: C₂₇H₂₉ClN₂O₂
• 分子量: 448.992
• InChiKey: PXJHDOGGBLQFRX-UHFFFAOYSA-N

物化性质

• 熔点：
  210-212?C
• 沸点：
  677.8±55.0 °C(Predicted)
• 密度：
  1.229±0.06 g/cm3(Predicted)
• 溶解度：
  乙腈（微溶）、氯仿（微溶）、甲醇
• 碰撞截面：
  211.9 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  66.6
• 氢给体数：
  2
• 氢受体数：
  3

安全信息

• 海关编码：
  2933399090

反应信息

• 作为反应物：
  描述：

  4-[4-(4-氯苯基)-4-羟基-1-哌啶基]-2,2-二苯基丁酰胺 在 硫酸 作用下， 以 水 为溶剂， 反应 48.0h， 生成 4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanoic acid
  参考文献：
  名称：

  A Facile Synthesis for Novel Loperamide Analogs as Potential μ Opioid Receptor Agonists

  摘要：

  本文介绍了一种新型洛哌丁胺类似物的简便合成方法，该类似物可作为潜在的μ阿片受体。化合物 5 含有两个 4-苯基哌啶支架，其合成过程得到了优化，并且该化合物的合成收率极高。我们还介绍了合成化合物 6 和 7 的温和高效的方法。

  DOI：

  10.3390/molecules171214288
• 作为产物：
  描述：

  4-(4-氯苯基)-4-羟基哌啶 在 N,N-二异丙基乙胺 、 potassium hydroxide 作用下， 以 乙腈 、 叔丁醇 为溶剂， 反应 75.0h， 生成 4-[4-(4-氯苯基)-4-羟基-1-哌啶基]-2,2-二苯基丁酰胺
  参考文献：
  名称：

  A Facile Synthesis for Novel Loperamide Analogs as Potential μ Opioid Receptor Agonists

  摘要：

  本文介绍了一种新型洛哌丁胺类似物的简便合成方法，该类似物可作为潜在的μ阿片受体。化合物 5 含有两个 4-苯基哌啶支架，其合成过程得到了优化，并且该化合物的合成收率极高。我们还介绍了合成化合物 6 和 7 的温和高效的方法。

  DOI：

  10.3390/molecules171214288

文献信息

• RADIOTRACERS FOR IMAGING P-GLYCOPROTEIN FUNCTION
  申请人：Pike Victor W.

  公开号：US20090274624A1

  公开（公告）日：2009-11-05

  P-glycoprotein transporter (P-gp) acts as a pump at the blood-brain barrier to exclude a wide range of xenobiotics (e.g., toxins, drugs, etc.) from the brain and is also expressed in a tumor in response to exposure to established or prospective chemotherapeutics (a phenomenon known as multidrug resistance). This invention concerns the preparation and use of radiotracers for imaging P-gp function in vitro and in vivo. Radiotracers of the present invention are avid substrates for P-gp and have structures based on N-Desmethyl-loperamide.

  P-糖蛋白转运体（P-gp）在血脑屏障处作为泵，排除大范围的异物（例如毒素、药物等）进入大脑，并且在肿瘤中响应已建立或预期化疗药物的暴露而表达（这种现象称为多药耐药）。本发明涉及制备和使用放射示踪剂来在体外和体内成像P-gp功能。本发明的放射示踪剂是P-gp的亲和底物，并且基于N-去甲基-洛哌丁的结构。
• Radiotracers for imaging P-glycoprotein function
  申请人：National Institutes of Health Represented by the Secretary of the Department of Health and Human Services, National Institutes of Health

  公开号：US07989630B2

  公开（公告）日：2011-08-02

  P-glycoprotein transporter (P-gp) acts as a pump at the blood-brain barrier to exclude a wide range of xenobiotics (e.g., toxins, drugs, etc.) from the brain and is also expressed in a tumor in response to exposure to established or prospective chemotherapeutics (a phenomenon known as multidrug resistance). This invention concerns the preparation and use of radiotracers for imaging P-gp function in vitro and in vivo. Radiotracers of the present invention are avid substrates for P-gp and have structures based on N-Desmethyl-loperamide.

  P-糖蛋白转运体（P-gp）在血脑屏障上起泵的作用，排除各种异物（如毒素、药物等）进入大脑，并且在肿瘤中表达，以应对已知或可能的化疗药物（这种现象称为多药耐药）。本发明涉及制备和使用放射示踪剂来体外和体内成像P-gp功能。本发明的放射示踪剂是P-gp的亲和底物，并且基于N-去甲基-洛哌丁的结构。
• Overcoming chloroquine resistance in malaria: Design, synthesis and structure–activity relationships of novel chemoreversal agents
  作者：Aicha Boudhar、Xiao Wei Ng、Chiew Yee Loh、Wan Ni Chia、Zhi Ming Tan、Francois Nosten、Brian W. Dymock、Kevin S.W. Tan

  DOI：10.1016/j.ejmech.2016.04.058

  日期：2016.8

  Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies. (C) 2016 Elsevier Masson SAS. All rights reserved.
• A high-yield route to synthesize the P-glycoprotein radioligand [ C]N-desmethyl-loperamide and its parent radioligand [ C]loperamide
  作者：Min Wang、Mingzhang Gao、Qi-Huang Zheng

  DOI：10.1016/j.bmcl.2013.08.024

  日期：2013.10

  N-Desmethyl-loperamide and loperamide were synthesized from a, a-diphenyl-c-butyrolactone and 4-(4-chlorophenyl)-4-hydroxypiperidine in five and four steps with 8% and 16% overall yield, respectively. The amide precursor was synthesized from 4-bromo-2,2-diphenylbutyronitrile and 4-(4-chlorophenyl)-4-hydroxypiperidine in 2 steps with 21-57% overall yield. [C-11] N-Desmethyl-loperamide and [C-11] loperamide were prepared from their corresponding amide precursor and N-desmethyl-loperamide with [C-11] CH3OTf through N-[C-11] methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 20-30% and 10-15% radiochemical yields, respectively, based on [C-11] CO2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/lmol specific activity at EOB. (C) 2013 Elsevier Ltd. All rights reserved.
• Synthesis and Evaluation of [<i>N-</i>methyl-¹¹C]<i>N</i>-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function
  作者：Neva Lazarova、Sami S. Zoghbi、Jinsoo Hong、Nicholas Seneca、Ed Tuan、Robert L. Gladding、Jeih-San Liow、Andrew Taku、Robert B. Innis、Victor W. Pike

  DOI：10.1021/jm800510m

  日期：2008.10.9

  [C-11]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-C-11]N-desmethyl-loperamide ([C-11]dLop; [C-11]3) precludes quantification. We considered that [C-11]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [C-11]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [C-11]iodomethane to give [C-11]3. After administration of [C-11]3 to wild-type mice, brain radioactivity uptake was very low. In P-gp (mdr-la(-/-)) knockout mice, brain uptake of radioactivity at 30 min increased about 3.5-fold by PET measures, and over 7-fold by ex vivo measures. In knockout mice, brain radioactivity was predominantly (90%) unchanged radiotracer. In monkey PET experiments, brain radioactivity uptake was also very low but after P-gp blockade increased more than 7-fold. [C-11]3 is an effective new radiotracer for imaging brain P-gp function and, in favor of future successful quantification, appears free of extensive brain-penetrant radiometabolites.