(+/-)-{4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl}[2-(3-hydroxybutyl)benzofuran-3-yl]methanone | 334542-32-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (+/-)-{4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl}[2-(3-hydroxybutyl)benzofuran-3-yl]methanone
• 英文别名: n-3-hydroxybutyl-N-desethylamiodarone；n-3'-hydroxybutyl-mono-N-desethylamiodarone；3'-hydroxy-N-monodesethylamiodarone；3'-Hydroxydesethylamiodarone；[4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl]-[2-(3-hydroxybutyl)-1-benzofuran-3-yl]methanone
• CAS: 334542-32-4
• 化学式: C₂₃H₂₅I₂NO₄
• 分子量: 633.265
• InChiKey: HUCFRTSKJVTUPE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  30
• 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：
  71.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (+/-)-[2-(3-{[(tert-butyl)diphenylsilyl]oxy}butyl)benzofuran-3-yl](4-hydroxy-3,5-diiodophenyl)methanone 在 1-氯乙基氯甲酸酯 、 氢氟酸 、 potassium carbonate 作用下， 以 水 、 1,2-二氯乙烷 、 甲苯 、 乙腈 为溶剂， 反应 24.0h， 生成 (+/-)-{4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl}[2-(3-hydroxybutyl)benzofuran-3-yl]methanone
  参考文献：
  名称：

  摘要：

  The metabolism of the potent antiarrythmic drug amiodarone (AMI 1) has yet not been fully investigated. Recently, in vitro experiments revealed that in rabbit-liver microsomes, AMI (1) and its main metabolite MDEA (2) were biotransformed to the hydroxylated derivatives T-OH-AMI (3) and 3'-OH-MDEA (4). respectively. To establish the chemical structure of 3 and 4, we developed a total synthesis of these two metabolites of AMI (1). H-1- and C-13-NMR Signal assignment from HSQC and HMBC 2D NMR data of synthesized 4 showed that the proposed structure of metabolite 4 is correct. Even the structure of 3 was found to be correct by comparing its HPLC/MS-MS/MS with the data described earlier.

  DOI：

  10.1002/1522-2675(200209)85:9<2990::aid-hlca2990>3.0.co;2-r

文献信息

• Metabolism of amiodarone (Part III): identification of rabbit cytochrome P450 isoforms involved in the hydroxylation of mono-<i>N</i>-desethylamiodarone
  作者：P. Kozlik、H. R. Ha、B. Stieger、L. Bigler、F. Follath

  DOI：10.1080/00498250110046442

  日期：2001.1

  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.