2R,4S,2'S-itraconazole | 154003-18-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 2R,4S,2'S-itraconazole
• 英文别名: (2R,4S,2'R)-Itraconazole；Itraconazole, (R)-(+)-；2-[(2S)-butan-2-yl]-4-[4-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one
• CAS: 154003-18-6
• 化学式: C₃₅H₃₈Cl₂N₈O₄
• 分子量: 705.644
• InChiKey: VHVPQPYKVGDNFY-TUJWMRSMSA-N

物化性质

• 颜色/状态：
  Solid
• 熔点：
  166.2 °C
• 溶解度：
  Practically insoluble in water and dilute acidic solutions
• 蒸汽压力：
  2.6X10-20 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 3.7

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  49
• 可旋转键数：
  11
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  9

ADMET

代谢

伊曲康唑主要通过细胞色素P450 3A4同工酶系统（CYP3A4）代谢，形成包括羟基伊曲康唑在内的多个代谢物，羟基伊曲康唑是主要的代谢物。一项药代动力学研究结果表明，伊曲康唑在多次给药后可能会经历饱和代谢。

Itraconazole is metabolized predominantly by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing.

来源:Hazardous Substances Data Bank (HSDB)

代谢

伊曲康唑（ITZ）在体外代谢为三种抑制性代谢物：羟基伊曲康唑（OH-ITZ）、酮基伊曲康唑（keto-ITZ）和N-脱烷基伊曲康唑（ND-ITZ）。本研究的目的是确定这些代谢物对ITZ引起的药物-药物相互作用的贡献。六名健康志愿者口服100毫克ITZ，连续7天，并在研究的第一天和第七天进行药代动力学分析。使用这些数据预测ITZ及其代谢物对CYP3A4的抑制程度。所有志愿者的血浆样本中均检测到ITZ、OH-ITZ、keto-ITZ和ND-ITZ。使用ITZ、OH-ITZ、keto-ITZ和ND-ITZ的平均游离稳态浓度（C(ss,ave,u)）和肝脏微粒体抑制常数预测了CYP3A4底物的肝脏固有清除率降低了3.9倍。考虑到ITZ的循环代谢物，与仅考虑ITZ暴露相比，显著改进了CYP3A4抑制的体外到体内的外推。

Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：目前没有关于哺乳期间使用伊曲康唑的临床信息。然而，有限的数据表明，母体使用伊曲康唑在乳汁中的水平低于推荐用于治疗婴儿的5毫克/千克每日剂量。在更多数据出现之前，可能更倾向于使用其他药物，特别是在哺乳新生儿或早产儿时。如果哺乳期间使用伊曲康唑，应考虑监测婴儿的肝酶，尤其是在长期治疗期间。 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the clinical use of itraconazole during breastfeeding. However, limited data indicate that maternal itraconazole produces levels in milk that are less than the 5 mg/kg daily doses that have been recommended to treat infants. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. If itraconazole is used during breastfeeding, monitoring of the infant’s liver enzymes should be considered, especially with long courses of therapy. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

IA类抗心律失常药物奎尼丁和III类抗心律失常药物多非利特已知会延长QT间期。同时给予奎尼丁或多非利特与伊曲康唑可能会增加奎尼丁或多非利特的血浆浓度，这可能导致严重的心血管事件。因此，伊曲康唑与奎尼丁或多非利特的联合使用是禁忌的。IA类抗心律失常药物双异丙吡胺在高血浆浓度下有可能增加QT间期。当伊曲康唑和双异丙吡胺同时给药时需谨慎。地高辛与伊曲康唑的联合使用已导致地高辛血浆浓度的增加。

The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Co-administration of quinidine or dofetilide with itraconazole may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and quinidine or dofetilide is contraindicated. The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when itraconazole and disopyramide are administered concomitantly. Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当伊曲康唑与苯妥英同时给药时，报告了伊曲康唑血浆浓度降低。卡马西平、苯巴比妥和苯妥英都是CYP3A4的诱导剂。尽管尚未研究卡马西平和苯巴比妥的相互作用，但预期伊曲康唑与这些药物的同时给药会导致伊曲康唑的血浆浓度降低。

Reduced plasma concentrations of itraconazole were reported when itraconazole was administered concomitantly with phenytoin. Carbamazepine, phenobarbital and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of itraconazole and these drugs would be expected to result in decreased plasma concentrations of itraconazole.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

药物相互作用研究表明，当唑类抗真菌药物（包括伊曲康唑和羟基伊曲康唑）与利福布汀或利福平同时给药时，这些药物及其代谢物的血浆浓度显著降低。体内数据显示，利福布汀部分由CYP3A4代谢。伊曲康唑可能抑制利福布汀的代谢。

Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Itraconazole may inhibit the metabolism of rifabutin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

伊曲康唑可能抑制白消安、多西他赛和长春碱类药物的代谢。

Itraconazole may inhibit the metabolism of busulfan, docetaxel and vinca alkaloids.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

伊曲康唑静脉给药后的药代动力学以及从口服溶液中的绝对口服生物利用度在6名健康男性志愿者中进行了一项随机交叉研究。观察到的伊曲康唑的绝对口服生物利用度为55%。

The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

伊曲康唑的口服生物利用度在服用胶囊时与一顿完整的餐食一起服用时达到最大。对伊曲康唑的药代动力学进行了研究，研究对象为6名健康的男性志愿者，采用交叉设计，单次给予100毫克剂量的伊曲康唑作为聚乙二醇胶囊，并与一顿完整的餐食一起或不一起服用。同样的6名志愿者还以交叉设计的方式，在一顿完整的餐食后服用了50毫克或200毫克的剂量。在这项研究中，只测量了伊曲康唑的血浆浓度。伊曲康唑的相关药代动力学参数如下表所示。

The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100 mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table /provided/.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

稳定状态浓度在口服剂量每日50毫克至400毫克后15天内达到。下表中给出的值是在一项药代动力学研究中，27名健康男性志愿者连续15天每日两次服用200毫克伊曲康唑胶囊（随完整餐食）时的稳态数据[表#7580]。

Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200 mg itraconazole capsules b.i.d. (with a full meal) for 15 days [Table#7580]

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

三十名健康男性在空腹条件下单次服用了200毫克伊曲康唑胶囊，分为三种情况：1）仅用水；2）用水，并在之前三天内每天两次服用150毫克雷尼替丁；3）用可乐，并在之前三天内每天两次服用150毫克雷尼替丁。当伊曲康唑胶囊在雷尼替丁预处理后服用时，伊曲康唑的吸收程度比单独服用伊曲康唑胶囊时要小，AUC0-24（药时曲线下面积）和Cmax（最大血药浓度）分别下降了39% +/- 37%和42% +/- 39%。当伊曲康唑胶囊在雷尼替丁预处理后与可乐一起服用时，伊曲康唑的吸收与单独服用伊曲康唑胶囊时相当。

Thirty healthy men received single 200 mg doses of itraconazole capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When itraconazole capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when itraconazole capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% +/- 37% and 42% +/- 39%, respectively. When itraconazole capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  1-(2,4-二氯l苯基)-2-(1H-1,2,4-噻唑-1-基)-乙酮 在 甲烷磺酸 、 三乙胺 、 lithium hydroxide 作用下， 以 N-甲基吡咯烷酮 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 62.0h， 生成 2R,4S,2'S-itraconazole
  参考文献：
  名称：

  一种光学纯伊曲康唑关键中间体及合成方法 以及由该中间体合成光学纯伊曲康唑的方法

  摘要：

  本发明公布了一种光学纯伊曲康唑关键中间体及合成方法以及由该中间体合成光学纯伊曲康唑的方法。本发明方法利用1‑(2,4‑二氯苯)‑2‑(1‑亚甲基‑1,2,4三氮唑)‑1‑酮制备了光学纯伊曲康唑关键中间体，再将光学纯伊曲康唑关键中间体制备光学纯伊曲康唑。本方法原料易得，不仅能够降低生产成本，还能够得到高纯度产品，并且，通过控制关键中间体化合物Ⅶ的光学纯，可有效控制目标产物伊曲康唑的光学纯，具有工业化价值。

  公开号：

  CN104774195B

文献信息

• [EN] BENZAMIDE OR BENZAMINE COMPOUNDS USEFUL AS ANTICANCER AGENTS FOR THE TREATMENT OF HUMAN CANCERS<br/>[FR] COMPOSÉS BENZAMIDE OU BENZAMINE À UTILISER EN TANT QU'ANTICANCÉREUX POUR LE TRAITEMENT DE CANCERS HUMAINS
  申请人：UNIV TEXAS

  公开号：WO2017007634A1

  公开（公告）日：2017-01-12

  The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not affect normally dividing cells.

  所描述的发明提供了用于治疗对胆固醇生物合成抑制作出反应的肿瘤的小分子抗癌化合物。这些化合物选择性地抑制肿瘤来源的癌细胞中的胆固醇生物合成途径，但不影响正常分裂的细胞。
• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] 2,4-DIAMINOQUINAZOLINES FOR SPINAL MUSCULAR ATROPHY<br/>[FR] 2,4-DIAMINOQUINAZOLINES UTILES POUR LE TRAITEMENT D'UNE ATROPHIE MUSCULAIRE SPINALE
  申请人：DECODE CHEMISTRY INC

  公开号：WO2005123724A1

  公开（公告）日：2005-12-29

  2,4-Diaminoquinazolines of formulae I-IV and VI (I, II, III, IV and VI) are useful for treating spinal muscular atrophy (SMA).

  2,4-二氨基喹唑啉的化学式I-IV和VI（I，II，III，IV和VI）可用于治疗脊髓性肌萎缩症（SMA）。
• Integrase inhibitors
  申请人：Cai R. Zhenhong

  公开号：US20080058315A1

  公开（公告）日：2008-03-06

  Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

  三环化合物，其受保护的中间体，以及用于抑制HIV整合酶的方法被披露。
• PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY
  申请人：Rewcastle Gordon William

  公开号：US20110009405A1

  公开（公告）日：2011-01-13

  Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

  本文提供了式I的嘧啶基和1,3,5-三嗪基苯并咪唑化合物，以及它们的药物组合物、制备方法，以及作为抗癌治疗药物或药剂的用途，可以单独使用，也可以与放疗和/或其他抗癌药物联合使用。