去乙基胺碘酮 | 83409-32-9

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 去乙基胺碘酮
• 中文别名: 2-丁基-3-苯并呋喃基-[4-(2-乙氨基乙氧基)-3,5-二碘苯基]甲酮
• 英文名称: desethylamiodarone
• 英文别名: (2-butylbenzofuran-3-yl)(4-(2-(ethylamino)ethoxy)-3,5-diiodophenyl)methanone；(2-butylbenzofuran-3-yl)(4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl)methanone；mono-N-desethylamiodarone；N-monodesethylamiodarone；mono-desethylamiodarone；(2-butyl-1-benzofuran-3-yl)-[4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl]methanone
• CAS: 83409-32-9
• 化学式: C₂₃H₂₅I₂NO₃
• 分子量: 617.265
• InChiKey: VXOKDLACQICQFA-UHFFFAOYSA-N

物化性质

• 熔点：
  176.8-177.7 °C(Solv: toluene (108-88-3))
• 沸点：
  630.3±55.0 °C(Predicted)
• 密度：
  1.638±0.06 g/cm3(Predicted)
• 碰撞截面：
  219.8 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)：
  6.7
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  51.5
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

N-去乙基安碘达隆是安碘达隆已知的人类代谢物。

N-Desethylamiodarone is a known human metabolite of amiodarone.

来源:NORMAN Suspect List Exchange

制备方法与用途

desethylamiodarone（N-去乙基胺碘酮）是抗心律失常药物胺碘酮的主要代谢产物，它具有抗心律失常的作用，并且还能诱导癌细胞凋亡。

反应信息

• 作为反应物：
  描述：

  去乙基胺碘酮 在 phosphate buffer 、 rabbit liver microsomes 、 还原型辅酶II(NADPH)四钠盐 作用下， 反应 2.0h， 生成 (+/-)-{4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl}[2-(3-hydroxybutyl)benzofuran-3-yl]methanone
  参考文献：
  名称：

  Metabolism of amiodarone (Part III): identification of rabbit cytochrome P450 isoforms involved in the hydroxylation of mono-N-desethylamiodarone

  摘要：

  1. Amiodarone (AMI) is a potent anti-arrhythmic drug and mono-N-desethylamiodarone (MDEA) is its only known metabolite. It was found recently that in rabbit liver microsomes MDEA was biotransformed to n-3-hydroxybutyl-MDEA (3OH-MDEA).2. In liver microsomes isolated from the untreated rabbit, the formation of 3OH-MDEA obeyed Michaelis-Menten enzyme kinetics with K-m = 6.39 +/- 1.07 muM and V-max = 0.56 +/- 0.21 nmol min(-1) mg(-1) protein.3. Furthermore, (1) among chemicals usually used as inhibitors of cytochrome P450, only midazolam (MDZ), cyclosporin A and ketoconazole inhibited the MDEA hydroxylase activity significantly (> 60% inhibition), (2) MDZ, a substrate of CYP3A, inhibited the 3OH-MDEA formation competitively (K-i = 10 +/- 5 muM), (3) the formation rates of 3OH-MDEA correlated positively with those of 1'OH-MDZ (r = 0.81; n = 6), and (4) MDEA hydroxylase activity of microsomes isolated from rabbit rifampicin induced cultured hepatocytes was 4-fold more active than the control.4. Since CYP3A6 is mainly induced by rifampicin in rabbit-cultured hepatocytes, the data suggest that this isoform is involved in the biotransformation of MDEA to 3OH-MDEA.5. Since alpha -naphthoflavone, cimetidine and quinidine also partially inhibited the MDEA hydroxylase activity, it is possible that other CYPs, such as 1A, 2C and 2D, may also be active in the metabolism of amiodarone.

  DOI：

  10.1080/00498250110046442
• 作为产物：
  描述：

  胺碘酮 生成 去乙基胺碘酮
  参考文献：
  名称：

  快速液相色谱法测定血浆，尿液和胆汁中的胺碘酮及其N-去乙基代谢产物

  摘要：

  建立了一种快速高效液相色谱测定法，用于测定血浆，尿液和胆汁中的胺碘酮（1）及其N-去乙基代谢产物（去乙基胺碘酮，2）。使用由甲醇：水：58％氢氧化铵（94：4：2）组成的流动相，以1.5 mL / min的流速进样，在C18反相柱和预柱上进行分析。在244nm下监测洗脱液。在这些条件下，1，2，和内标物的洗脱时间分别为5.5、4.6和6.8分钟。通过用含有内标的乙腈沉淀血浆蛋白，然后将等分试样的上清液直接注入色谱柱中，制备血浆样品（100微升）。通过用浓盐酸酸化样品，然后用六倍体积的2，2-二甲氧基丙烷萃取混合物，来制备用于注射的尿液和胆汁样品（100微升）。从血浆中回收1和2实际上已完成。尿液和胆汁的回​​收率分别为1的80-90％和2的60-65％。两种化合物在血浆中的敏感性极限为100 ng / mL。对于尿液和胆汁，检出限分别为1和5微克/ mL。在0.1-10.0微克/ mL的血

  DOI：

  10.1002/jps.2600740418

文献信息

• Identification of Novel Substrates for Human Cytochrome P450 2J2
  作者：Caroline A. Lee、David Neul、Andrea Clouser-Roche、Deepak Dalvie、Michael R. Wester、Ying Jiang、J. P. Jones、Sascha Freiwald、Michael Zientek、Rheem A. Totah

  DOI：10.1124/dmd.109.030270

  日期：2010.2

  Several antihistamine drugs including terfenadine, ebastine, and astemizole have been identified as substrates for CYP2J2. The overall importance of this enzyme in drug metabolism has not been fully explored. In this study, 139 marketed therapeutic agents and compounds were screened as potential CYP2J2 substrates. Eight novel substrates were identified that vary in size and overall topology from relatively rigid structures (amiodarone) to larger complex structures (cyclosporine). The substrates displayed in vitro intrinsic clearance values ranging from 0.06 to 3.98 μl/min/pmol CYP2J2. Substrates identified for CYP2J2 are also metabolized by CYP3A4. Extracted ion chromatograms of metabolites observed for albendazole, amiodarone, astemizole, thioridazine, mesoridazine, and danazol showed marked differences in the regioselectivity of CYP2J2 and CYP3A4. CYP3A4 commonly metabolized compounds at multiple sites, whereas CYP2J2 metabolism was more restrictive and limited, in general, to a single site for large compounds. Although the CYP2J2 active site can accommodate large substrates, it may be more narrow than CYP3A4, limiting metabolism to moieties that can extend closer toward the active heme iron. For albendazole, CYP2J2 forms a unique metabolite compared with CYP3A4. Albendazole and amiodarone were evaluated in various in vitro systems including recombinant CYP2J2 and CYP3A4, pooled human liver microsomes (HLM), and human intestinal microsomes (HIM). The Michaelis-Menten-derived intrinsic clearance of N -desethyl amiodarone was 4.6 greater in HLM than in HIM and 17-fold greater in recombinant CYP3A4 than in recombinant CYP2J2. The resulting data suggest that CYP2J2 may be an unrecognized participant in first-pass metabolism, but its contribution is minor relative to that of CYP3A4.

  几种抗组胺药物，包括特非那定、依巴斯丁和阿斯特米唑，已被确定为CYP2J2的底物。然而，该酶在药物代谢中的整体重要性尚未完全探讨。在这项研究中，筛选了139种市场上销售的治疗药物和化合物作为潜在的CYP2J2底物。鉴定出8种新型底物，它们在大小和整体拓扑结构上有所不同，从相对刚性的结构（氨碘索）到较大的复杂结构（环孢素）。这些底物在体外表现出内源性清除率值范围为0.06到3.98 μl/min/pmol CYP2J2。为CYP2J2鉴定的底物也被CYP3A4代谢。对醚氟烯、氨碘索、阿斯特米唑、噻吩噻嗪、美索噻嗪和达那唑的代谢物提取离子色谱图显示CYP2J2和CYP3A4的区域选择性存在显著差异。CYP3A4通常在多个位点代谢化合物，而CYP2J2的代谢则更为限制，通常仅限于大化合物的单个位点。尽管CYP2J2的活性位点可以容纳较大的底物，但可能比CYP3A4更窄，从而限制了代谢的分子延伸至活性血红素铁的距离。对于醚氟烯，CYP2J2形成一种与CYP3A4不同的独特代谢物。醚氟烯和氨碘索在各种体外系统中进行了评估，包括重组CYP2J2和CYP3A4、 pooled人肝微粒体（HLM）和人肠道微粒体（HIM）。N-去乙基氨碘索的迈克利斯-门腾推导内源性清除率在HLM中比在HIM中高出4.6倍，在重组CYP3A4中比在重组CYP2J2中高出17倍。结果数据表明，CYP2J2可能是首过代谢中未被识别的参与者，但与CYP3A4相比，其贡献相对较小。
• Quantification of Electrochemically Generated Iodine-Containing Metabolites Using Inductively Coupled Plasma Mass Spectrometry
  作者：Wiebke Lohmann、Björn Meermann、Ines Möller、Andy Scheffer、Uwe Karst

  DOI：10.1021/ac801878k

  日期：2008.12.15

  For the risk assessment of drug candidates, the identification and quantification of their metabolites is required. The majority of analytical techniques is based on calibration standards for quantification of the metabolites. As these often are not readily available, the use of inductively coupled plasma mass spectrometry (ICPMS) is an attractive alternative for drugs containing heteroatoms. In this work, the online coupling of electrochemistry (EC), liquid chromatography (LC), and ICPMS is presented. The antiarrhythmic agent amiodarone, which contains two iodine atoms, is oxidized in an electrochemical flow-through cell under N-dealkylation and deiodination. The metabolites that are generated at different EC potentials are identified by electrospray ionization (ESI) mass spectrometry, compared to those from rat liver microsomal incubations and quantified by ICPMS. Phase-optimized LC, a recent approach for high-performance isocratic separations, is used to avoid the ICPMS calibration problems known to occur with gradient separations. The potential of the complementary use of ESI-MS and ICPMS for the qualitative and quantitative analysis of drug metabolites becomes apparent in this work.

  为了对候选药物进行风险评估，需要鉴定和量化其代谢产物。大多数分析技术都是基于校准标准来量化代谢产物的。由于这些标准通常不易获得，因此对于含有杂原子的药物，使用电感耦合等离子体质谱（ICPMS）是一个有吸引力的替代方案。在这项工作中，我们介绍了电化学（EC）、液相色谱（LC）和ICPMS的在线耦合。抗心律失常药物胺碘酮含有两个碘原子，在N-脱烷基化和脱碘化的电化学流通池中氧化。通过电喷雾电离（ESI）质谱法鉴定在不同EC电位下产生的代谢产物，并与大鼠肝微粒体孵育产生的代谢产物进行比较，通过ICPMS进行量化。相位优化的LC是一种最近用于高效等度分离的方法，用于避免已知在梯度分离中出现的ICPMS校准问题。在这项工作中，ESI-MS和ICPMS互补用于药物代谢产物的定性和定量分析的潜力变得显而易见。
• FMO3 inhibitors for treating pain
  申请人：Akron Molecules GmbH

  公开号：EP2674161A1

  公开（公告）日：2013-12-18

  The present invention relates to new therapies to treat pain and related diseases, as well as pharmaceutical compounds for use in said therapies.

  本发明涉及治疗疼痛和相关疾病的新疗法，以及用于上述疗法的药物化合物。
• PARENTERAL DOSAGE FORM OF AMIODARONE
  申请人：Sun Pharmaceutical Industries Ltd

  公开号：EP3000461A1

  公开（公告）日：2016-03-30

  The present invention relates to a stable, sterile, ready to administer parenteral dosage form of amiodarone or its pharmaceutically acceptable salt. Particularly, the present invention provides a stable, sterile, ready to administer parenteral dosage form of amiodarone comprising an aqueous solution comprising amiodarone or its pharmaceutically acceptable salt, an acid, and a polyol, wherein the pH of the solution is in the range of about 2.0 to 4.0, wherein the solution is filled in a plastic container and wherein the solution is free of a solubilizer.

  本发明涉及一种稳定、无菌、可随时给药的胺碘酮或其药学上可接受的盐的肠外剂型。特别是，本发明提供了一种稳定、无菌、可随时给药的胺碘酮肠外剂型，该剂型包括一种水溶液，该水溶液由胺碘酮或其药学上可接受的盐、一种酸和一种多元醇组成，其中溶液的 pH 值在约 2.0 至 4.0 之间，溶液灌装在塑料容器中，溶液中不含增溶剂。
• DESETHYLAMIODARONE FOR USE IN CANCER TREATMENT
  申请人：Pécsi Tudományegyetem

  公开号：EP3173081A1

  公开（公告）日：2017-05-31

  The invention relates to a compound selected from the group consisting of desethylamiodarone and pharmaceutically acceptable salts, hydrates and solvates thereof, as well as pharmaceutical composition comprising the compound together with a pharmaceutically acceptable excipient, vehicle or carrier, for use in the treatment of a proliferative disorder.

  本发明涉及一种选自去乙基胺碘酮及其药学上可接受的盐、水合物和溶液组成的组的化合物，以及包含该化合物和药学上可接受的赋形剂、载体或载体的药物组合物，用于治疗增殖性疾病。