N4-(7-氯喹啉-4-基)-N1-乙基-1,4-戊二胺 | 1476-52-4

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: N4-(7-氯喹啉-4-基)-N1-乙基-1,4-戊二胺
• 中文别名: 去乙基氯喹；羟基氯喹EP杂质D-d5二盐酸
• 英文名称: desethylchloroquine
• 英文别名: monodesethyl chloroquine；monodesethyl-chloroquine；monodesethylchloroquine；rac-desethylchloroquine；Monodesethylchloroquin；4-N-(7-chloroquinolin-4-yl)-1-N-ethylpentane-1,4-diamine
• CAS: 1476-52-4
• 化学式: C₁₆H₂₂ClN₃
• mdl: MFCD00871808
• 分子量: 291.824
• InChiKey: MCYUUUTUAAGOOT-UHFFFAOYSA-N

物化性质

• 熔点：
  94-97?C
• 沸点：
  173-175 °C(Press: 0.05 Torr)
• 密度：
  1.138±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少量）、二氯甲烷（少量）、乙酸乙酯（少量）
• 物理描述：
  Solid
• 保留指数：
  2575

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.437
• 拓扑面积：
  37
• 氢给体数：
  2
• 氢受体数：
  3

安全信息

• WGK Germany：
  3
• 海关编码：
  2933499090
• 储存条件：
  -20°C freezer

制备方法与用途

生物活性

Desethyl氯喹是氯喹的主要去乙基代谢产物。氯喹是一种自噬和Toll样受体（TLRs）的抑制剂，并且具有抗疟原虫活性。

体外研究

• P. falciparum

体内研究

对野生型小鼠和亨廷顿舞蹈病（Q175/Q175）小鼠进行腹腔注射氯喹。使用LC-MS/MS检测血、脑组织和肌肉中的氯喹及其代谢物的水平。4至24小时内，脑组织中氯喹浓度较低但更稳定（5-15μM），相比之下，血液或肌肉中的浓度较高且不稳定。注射后的24小时内，在肌肉和血液中的活性代谢产物Desethyl氯喹水平逐渐下降，而脑部Desethyl氯喹水平较低并略有上升。

反应信息

• 作为反应物：
  描述：

  N4-(7-氯喹啉-4-基)-N1-乙基-1,4-戊二胺 在 盐酸 、 ammonium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 4.0h， 生成 N-(2-carboxyethyl)desethylchloroquine
  参考文献：
  名称：

  灵敏的放射免疫测定和酶联免疫吸附测定，用于同时测定生物体液中的氯喹及其代谢物。

  摘要：

  描述了同时测定生物样品中氯喹及其两种主要代谢物（单去甲基氯喹和双去乙基氯喹）的两种新方法，即放射免疫测定 (RIA) 和酶联免疫吸附测定 (ELISA)。抗血清是在用 N-(2-羧乙基) 去乙基氯喹：蛋白质偶联物免疫的兔子身上产生的。除氯喹外，该抗血清还以良好的亲和力识别两种主要代谢物，单去乙基氯喹和双去乙基氯喹（分别为 70% 和 40% 的交叉反应）。阿莫地喹交叉反应为 4.5%；与单去乙基氨地喹、双去乙基氨地喹和其他抗疟药的交叉反应小于1%。两种系统都不需要提取步骤或样品制备。灵敏度限值分别为 0。70 nM（3 pg 硫酸氯喹在 10 µL 血浆样品中测量）用于 RIA，10 nM（22 pg 硫酸氯喹在 5 µL 血浆样品中测量）用于 ELISA。在 14-410 nM (6-180 ng/mL) 范围内，RIA 和 ELISA 的测定间变异系数分别小于 10% 和小于 16%。两种方法的结果具有良好的相关性

  DOI：

  10.1002/jps.2600790107
• 作为产物：
  描述：

  氯喹 在 recombinant human CYP₂C₈ 还原型辅酶II(NADPH)四钠盐 作用下， 以 phosphate buffer 为溶剂， 生成 N4-(7-氯喹啉-4-基)-N1-乙基-1,4-戊二胺
  参考文献：
  名称：

  Identification of human cytochrome P 450 s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data

  摘要：

  Objective. Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P-450 (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data.Methods. In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P-450 (rCYP), were used to determine the intrinsic clearance (CLint) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs.Results and discussion. CLint determined in RLM and HLM showed low (r(2)=0.50) but significant (P<0.01) correlation. The CLint values were scaled to predict in vivo hepatic clearance (CLH) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low (n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CLH predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (>70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (<30% liver blood flow; chloroquine, dapsone, diethylcarbamazine, pentamidine, primaquine, pyrantel, pyrimethamine, tinidazole) and intermediate clearance drugs (artemisinin, artesunate, quinine). With the exception of artemisinin, which is a high clearance drug in vivo, all other compounds were classified using in vitro data in agreement with in vivo observations. We identified hepatic CYP enzymes responsible for metabolism of some compounds (praziquantel-1A2, 2C19, 3A4; primaquine-1A2, 3A4; chloroquine-2C8, 2D6, 3A4; artesunate-2A6; pyrantel-2D6). For the other compounds, we confirmed the role of previously reported CYPs for their metabolism and identified other CYPs involved which had not been reported before.Conclusion. Our results show that it is possible to make in vitro-in vivo predictions of high, intermediate and low CLint drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.

  DOI：

  10.1007/s00228-003-0636-9

文献信息

• Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas
  作者：Kekeli Ekoue-Kovi、Kimberly Yearick、Daniel P. Iwaniuk、Jayakumar K. Natarajan、John Alumasa、Angel C. de Dios、Paul D. Roepe、Christian Wolf

  DOI：10.1016/j.bmc.2008.11.009

  日期：2009.1

  We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3–8 and 11–26, ureas 19–22, thioureas 23–26, and amides 27–54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance indices

  我们报告了 50 多种 7-氯-4-氨基喹啉衍生的磺酰胺3 – 8和11 – 26、尿素19 – 22、硫脲23 – 26和酰胺27 – 54的合成和体外抗疟活性。许多为本研究制备的 CQ 类似物显示出亚微摩尔级抗疟活性，而 HB3（对氯喹敏感）和 Dd2（恶性疟原虫的氯喹抗性菌株）) 和低电阻指数在大多数情况下获得。侧链长度的系统变化和氟化脂肪族和芳香族末端的引入揭示了克服 CQ 抗性的有希望的线索。特别是，磺酰胺3具有短侧链和末端丹磺酰部分，结合了高抗疟原虫效力和低抗性指数，对 HB3 和 Dd2 寄生虫的IC 50 s 分别为 17.5 和 22.7 nM。
• A Convenient, Short Synthesis of Desethylchloroquine [7-Chloro-4-(4’-ethylamino-1’-methyl-butylamino)quinoline]
  作者：Aslam M. Ansari、J. Cymerman Craig

  DOI：10.1055/s-1995-3886

  日期：1995.2

  A short, efficient 2-step synthesis of desethylchloroquine is achieved by generating an internal amide ion from the secondary nitrogen in chloroquine, followed by in situ reaction with 2,2,2-trichloroethyl chloroformate giving rapid elimination of ethylene. The carbamate thus produced easily undergoes deprotection to the target compound at room temperature.

  一种简短、高效的两步合成去乙基氯喹的方法是通过从氯喹的二级氮生成内酰胺离子，然后与2,2,2-三氯乙基氯甲酸酯发生原位反应，迅速消除乙烯。由此生成的氨基甲酸酯在室温下容易脱保护形成目标化合物。
• Metabolites of Chloroquine:Some Observations on Desethylchloroquine andN‐Acetyldesethylchloroquine
  作者：Aslam M. Ansari、J. Cymerman Craig

  DOI：10.1002/jps.2600830722

  日期：1994.7

  The major metabolite of chloroquine, (+)-desethylchloroquine, produced by stereoselective N-dealkylation of the drug, was obtained in 81.5% enantiomeric purity by resolution of racemic desethylchloroquine using an atropisomeric resolving agent and was shown by circular dichroism to have the absolute (S)-configuration. The minor metabolite N-acetyldesethylchloroquine was prepared in both the racemic

  氯喹的主要代谢物 (+)-去乙基氯喹是通过药物的立体选择性 N-脱烷基化产生的，通过使用阻转异构拆分剂拆分外消旋去乙基氯喹以 81.5% 的对映体纯度获得，并通过圆二色性显示具有绝对 ( S)-配置。次要代谢物 N-乙酰去乙基氯喹以外消旋和 (S)-(+)-形式制备。
• Nanoporous Gold Catalyst for the Oxidative N‐Dealkylation of Drug Molecules: A Method for Synthesis of N‐Dealkylated Metabolites
  作者：Ali Alipour Najmi、Elchin Jafariyeh‐Yazdi、Mojgan Hadian、Jos Hermans、Rainer Bischoff、Jun Yue、Alexander Dömling、Arne Wittstock、Hjalmar P. Permentier

  DOI：10.1002/cmdc.202200040

  日期：2022.6.3

  Facilitating drug discovery: We describe a novel method for the selective catalytic N-dealkylation of drug molecules on a nanoporous gold (NPG) catalyst producing valuable N-dealkylated metabolites and intermediates. Various examples examined in this study showed that aerobic catalytic N-dealkylation of drug molecules on NPG has a broad scope, supporting N-deethylation, N-deisopropylation and N-demethylation

  促进药物发现：我们描述了一种在纳米多孔金 (NPG) 催化剂上选择性催化 N-脱烷基化药物分子的新方法，可产生有价值的 N-脱烷基代谢物和中间体。本研究中检查的各种示例表明，药物分子在 NPG 上的有氧催化 N-脱烷基化具有广泛的范围，支持 N-去乙基化、N-去异丙基化和 N-去甲基化，将 3° 胺转化为 2° 胺或 2° 胺至 1° 胺。
• Ophthalmic pharmaceutical compositions and methods for treating ocular inflammation
  申请人：——

  公开号：US20030216431A1

  公开（公告）日：2003-11-20

  The present invention relates to novel ophthalmic pharmaceutical compositions comprising an inflammation-treating amount of a 4-aminoquinoline compound, derivative, isomers, or chemical salts, and methods for using these compositions for the treatment of ocular inflammatory conditions by topical administration directly to the eye.

  本发明涉及新型眼科制剂，包括一种4-氨基喹啉化合物、衍生物、异构体或化学盐的消炎治疗剂量，并且涉及使用这些制剂通过直接眼部局部给药治疗眼部炎症状况的方法。

表征谱图