3-(正丁氨基)-1-(1,3-二氯-6-(三氟甲基)菲-9-基)-1-丙醇 | 69756-48-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 中文名称: 3-(正丁氨基)-1-(1,3-二氯-6-(三氟甲基)菲-9-基)-1-丙醇
• 中文别名: 1,3-二氯-6-三氟甲基-9-菲基-3-(N-丁基)氨基丙醇
• 英文名称: desbutylhalofantrine
• 英文别名: N-debutylhalofantrine；3-(butylamino)-1-[1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl]propan-1-ol
• CAS: 69756-48-5
• 化学式: C₂₂H₂₂Cl₂F₃NO
• 分子量: 444.324
• InChiKey: FYHCHSNOXWVJJT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  32.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  卤方特瑞 生成 3-(正丁氨基)-1-(1,3-二氯-6-(三氟甲基)菲-9-基)-1-丙醇
  参考文献：
  名称：

  配对离子液相色谱法分析全血中的苯二胺乙醇抗疟疾。

  摘要：

  建立了灵敏而高效的高效液相色谱（HPLC）分析方法，用于测定候选抗疟药（+/-）-（1,3-二氯-6-三氟甲基-9-菲基）-3-二-（n全血中的正丁基）氨基丙醇盐酸盐。反相配对离子（月桂基硫酸盐）系统通过紫外检测（254 nm）实现了从干扰成分中分离抗疟和内标物，其灵敏度极限为10 ng / mL。检查色谱变量（平衡浓度，pH和柱温），以确定其对临床分析中测定特性（保留，效率和相对响应）的影响。从2中分离出抗疟药。使用30％乙酸乙酯的己烷溶液过夜萃取，然后酸/碱分配顺序除去主要干扰物，提取0 mL全血。抗疟药的总回收率为84％，CV为5.0％，内标的回收率为81％（CV = 3.6％）。通过实验室内和实验室间样品的分析验证了该测定法。该测定法用于分析从30岁健康男性男性中采集的全血样品，该男性已接受了14.1 mg / kg的单次口服剂量。还证明了抗疟药在-17摄氏度下在全血中长达4个月的稳定性以及在样本提取物中长达34

  DOI：

  10.1002/jps.2600740413

文献信息

• Halofantrine Metabolism in Microsomes in Man: Major Role of CYP 3A4 and CYP 3A5
  作者：B Baune、J P Flinois、V Furlan、F Gimenez、A M Taburet、L Becquemont、R Farinotti

  DOI：10.1211/0022357991772628

  日期：2010.2.18

  We have clarified the contribution of the different enzymes involved in the N-debutylation of halofantrine in liver microsomes in man. The effect of ketoconazole and cytochrome P450 (CYP) 3A substrates on halofantrine metabolism has also been studied.

  The antimalarial drug halofantrine is metabolized into one major metabolite, N-debutylhalofantrine. In microsomes from nine livers from man, N-debutylation of halofantrine was highly variable with apparent Michaelis-Menten constant Vmax and Km values of 215 ± 172 pmol min−1 mg−1 and 48 ± 26/μmol L−1, respectively, (mean ± standard deviation). Formation of N-debutylhalofantrine was cytochrome P450 (CYP)-mediated. Studies using selective inhibitors of individual CYPs revealed the role of CYP 3As in the formation of N-debutylhalofantrine. α-Naphthoflavone, a CYP 3A activator, increased metabolite formation. In microsomes from 12 livers from man the rate of N-debutylation of halofantrine correlated strongly with CYP 3A4 relative levels (P = 0.002) and less strongly, but significantly, with CYP 2C8 levels (P = 0.025). To characterize CYP-mediated metabolism of halofantrine further, incubations were performed with yeast microsomes expressing specific CYP 3A4, CYP 3A5, CYP 2D6, CYP 2C8 and CYP 2C19 from man. The rate of formation of N-debutylhalofantrine was six- and twelvefold with CYP 3A4 than with CYP 3A5 and CYP 2C8, respectively. CYP 2D6 and CYP 2C19 did not mediate the N-debutylation of halofantrine, but, because in-vivo CYP 2C8 is present at lower concentrations than CYP 3A in the liver in man, the involvement of CYP 3As would be predominant. Diltiazem, erythromycin, nifedipine and cyclosporin (CYP 3A substrates) inhibited halofantrine metabolism. Similarly, ketoconazole inhibited, non-competitively, formation of N-debutylhalofantrine with an inhibition constant, Ki, of 0–05 μM. The theoretical percentage inhibition of halofantrine metabolism in-vivo by ketoconazole was estimated to be 99%.

  These results indicate that both CYP 3A4 and CYP 3A5 metabolize halofantrine, with major involvement of CYP 3A4. In-vivo, the other CYPs have a minor role only. Moreover, strong inhibition, and consequently increased halofantrine cardiotoxicity, might occur with the association of ketoconazole or other CYP 3A4 substrates.

  我们已经澄清了参与人体肝微粒体中halofantrine N-脱丁基化的不同酶的贡献。此外，还研究了酮康唑和细胞色素P450（CYP）3A底物对halofantrine代谢的影响。抗疟药halofantrine代谢成一个主要代谢物N-脱丁基halofantrine。在九例人体肝脏微粒体中，halofantrine的N-脱丁基化变化很大，表观米氏常数Vmax和Km值分别为215±172 pmol min-1 mg-1和48±26/μmol L-1（平均±标准偏差）。N-脱丁基halofantrine的形成是通过细胞色素P450（CYP）介导的。使用选择性CYP抑制剂的研究揭示了CYP 3As在N-脱丁基halofantrine形成中的作用。CYP 3A激活剂α-萘氧化素增加了代谢物的形成。在12例人体肝脏微粒体中，halofantrine的N-脱丁基化速率与CYP 3A4相对水平强相关（P=0.002），与CYP 2C8水平相关性较弱但显著（P=0.025）。为进一步表征halofantrine的CYP介导代谢，使用表达人体特定CYP 3A4、CYP 3A5、CYP 2D6、CYP 2C8和CYP 2C19的酵母微粒体进行培养。N-脱丁基halofantrine的形成速率与CYP 3A4相比，CYP 3A5和CYP 2C8分别增加了6倍和12倍。CYP 2D6和CYP 2C19不介导halofantrine的N-脱丁基化，但由于人体肝脏中CYP 2C8的浓度低于CYP 3A，CYP 3As的参与将是主导的。地尔硫卓、红霉素、硝苯地平和环孢霉素（CYP 3A底物）抑制了halofantrine的代谢。同样，酮康唑以非竞争性方式抑制了N-脱丁基halofantrine的形成，抑制常数Ki为0-05 μM。据估计，酮康唑在体内对halofantrine代谢的理论百分比抑制率为99%。这些结果表明，CYP 3A4和CYP 3A5都代谢halofantrine，其中CYP 3A4的参与最为重要。在体内，其他CYP仅起辅助作用。此外，与酮康唑或其他CYP 3A4底物的联合使用可能导致强烈抑制，从而增加halofantrine的心脏毒性。
• Paired-Ion Liquid Chromatographic Method for the Analysis of a Phenanthrenemethanol Antimalarial in Whole Blood
  作者：J.W. Hines、P.D. Elkins、C.E. Cook、C.M. Sparacino

  DOI：10.1002/jps.2600740413

  日期：1985.4

  antimalarial (+/-)-(1,3-dichloro-6-trifluoromethyl-9-phenanthryl)-3-di-(n-butyl )aminopropanol hydrochloride in whole blood. A reversed-phase, paired-ion (lauryl sulfate) system achieved separation of the antimalarial and internal standard from interfering constituents with a sensitivity limit of 10 ng/mL by UV detection (254 nm). Chromatographic variables (counterion concentration, pH, and column temperature)

  建立了灵敏而高效的高效液相色谱（HPLC）分析方法，用于测定候选抗疟药（+/-）-（1,3-二氯-6-三氟甲基-9-菲基）-3-二-（n全血中的正丁基）氨基丙醇盐酸盐。反相配对离子（月桂基硫酸盐）系统通过紫外检测（254 nm）实现了从干扰成分中分离抗疟和内标物，其灵敏度极限为10 ng / mL。检查色谱变量（平衡浓度，pH和柱温），以确定其对临床分析中测定特性（保留，效率和相对响应）的影响。从2中分离出抗疟药。使用30％乙酸乙酯的己烷溶液过夜萃取，然后酸/碱分配顺序除去主要干扰物，提取0 mL全血。抗疟药的总回收率为84％，CV为5.0％，内标的回收率为81％（CV = 3.6％）。通过实验室内和实验室间样品的分析验证了该测定法。该测定法用于分析从30岁健康男性男性中采集的全血样品，该男性已接受了14.1 mg / kg的单次口服剂量。还证明了抗疟药在-17摄氏度下在全血中长达4个月的稳定性以及在样本提取物中长达34