atovaquone | 1263285-46-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: atovaquone
• 英文别名: 3-[4-(4-chlorophenyl)cyclohexyl]-4-hydroxynaphthalene-1,2-dione
• CAS: 1263285-46-6
• 化学式: C₂₂H₁₉ClO₃
• 分子量: 366.844
• InChiKey: BSJMWHQBCZFXBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

一些证据表明有限的新陈代谢（尽管没有确定代谢物）。

Some evidence suggests limited metabolism (although no metabolites have been identified).

来源:DrugBank

代谢

阿托喹酮在人体内不被显著代谢。它通过胆汁排泄，药物中有超过94%以原形在粪便中回收；尿液中仅出现微量。

Atovaquone is not significantly metabolized by human beings. It is excreted in bile and more than 94% of the drug is recovered unchanged in feces; only traces appear in the urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

阿托喹酮是一种抗原虫化合物，具有良好的体外稳定性，能抵抗代谢失活。以前未涉及放射性标记的人体研究没有解释剂量中相当大的一部分。在一项涉及四名健康男性志愿者的放射性标记研究中，检查了阿托喹酮在人体内可能的代谢情况。放射性物质几乎完全通过粪便排出。血浆、尿液和粪便中的所有放射性均可归因于阿托喹酮，没有代谢物的证据。放射性标记的阿托喹酮在手术后给一名带有内置胆管管的病人服用。胆汁中的放射性活性大约是血浆中的10到40倍，并且可以归因于阿托喹酮。阿托喹酮在人体内不显著代谢，但会逆着高浓度梯度进入胆汁排出。

Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radioactivity was eliminated almost exclusively via the feces. All radioactivity in plasma, urine, and feces was accounted for by atovaquone, with no evidence of metabolites. Radiolabelled atovaquone was administered to a patient with an indwelling biliary tube after surgery. Biliary radioactivity was approximately 10- to 40-fold higher than that in plasma and was accounted for by atovaquone. Atovaquone is not significantly metabolized in humans but is excreted into bile against a high concentration gradient.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

阿托伐醌在一小部分患者中（1%至6%）与血清转氨酶升高有关。也有罕见报道指出阿托伐醌会导致临床上明显的急性肝损伤。在一篇已发表的病例报告中（病例1），在开始治疗（以及停药几天后）25天后出现了损伤。血清酶升高的模式是胆汁淤积型。免疫过敏表现（发热、皮疹和嗜酸性粒细胞增多）并不显著，自身抗体也不存在。停药后2个月内肝损伤得到解决。因为使用了丙胍和阿托伐醌的联合用药，所以两种药物中的任何一种都可能是损伤的原因。阿托伐醌还与罕见情况下史蒂文斯-约翰逊综合征有关，这通常伴有轻度肝损伤或肝酶升高。

Atovaquone has been linked to serum aminotransferase elevations in a small proportion of patients (1% to 6%). There have also been rare reports of clinically apparent, acute liver injury due to atovaquone. In one published case report (Case 1), the onset of injury was 25 days after starting (and a few days after stopping) treatment. The pattern of serum enzyme elevations was cholestatic. Immunoallergic manifestations (fever, rash and eosinophilia) were not prominent and autoantibodies were not present. The liver injury resolved within 2 months of stopping the medication. Because a combination of proguanil and atovaquone was used, either agent could have been responsible for the injury. Atovaquone has also been linked to rare instances of Stevens Johnson syndrome, which is frequently accompanied by mild liver injury or liver enzyme elevations.

来源:LiverTox

毒理性

• 药物性肝损伤

阿托喹酮

Compound:atovaquone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

阿托喹的 生物利用度 低且多变，高度依赖于配方和饮食。与食物一起服用时，悬浮液的生物利用度增加两倍。与食物一起服用时，生物利用度大约为47%。不与食物一起服用时，生物利用度为23%。

The bioavailability of atovaquone is low and variable and is highly dependent on formulation and diet. Bioavailability of the suspension increases two-fold when administered with meals. When administered with food, bioavailability is approximately 47%. Without food, the bioavailability is 23%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

阿托喹酮的半衰期较长，这是由于假定的肠肝循环和最终的粪便排泄。阿托喹酮在尿液中的排泄很少或没有（小于0.6%）。

The half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. There was little or no excretion of atovaquone in the urine (less than 0.6%).

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.60 ± 0.17 升/千克

0.60 ± 0.17 L/kg

来源:DrugBank

吸收、分配和排泄

• 清除

10.4 ± 5.5 毫升/分钟 [接受静脉注射的HIV感染患者]

10.4 +/- 5.5 ml/min [HIV-infected patients receiving IV administration]

来源:DrugBank

吸收、分配和排泄

单次口服给药后，药物吸收缓慢、不稳定且变化无常；脂肪食物可使其增加2到3倍；750毫克以上剂量受限。超过99%的药物与血浆蛋白结合，因此其在脑脊液中的浓度不到血浆中浓度的1%。

Drug absorption after a single oral dose is slow, erratic and variable; increased by 2- to 3-fold by fatty food; and dose-limited above 750 mg. More than 99% of the drug is bound to plasma protein, so its concentration in cerebrospinal fluid is less than 1% of that in plasma.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  atovaquone 在 N-溴代丁二酰亚胺(NBS) 、 silver hexafluoroantimonate 、 C₁₂H₃₂B₁₀S₂ 作用下， 以 1,2-二氯乙烷 为溶剂， 以72 %的产率得到
  参考文献：
  名称：

  使用碳硼烷催化剂进行芳香卤化

  摘要：

  卤代芳烃一直是现代有机化学领域中的一类重要化学品，因为卤化物官能团提供了许多可能的转化。使用分子卤素和路易斯/布朗斯台德酸活化剂的经典亲电芳香族卤化仍然是一种有前途的合成工具；然而，它存在操作困难、选择性低和官能团耐受性有限的问题。我们在此介绍基于碳硼烷的路易斯碱催化剂，用于使用卤代琥珀酰亚胺进行芳族卤化。所开发的反应体系易于应用于药物分子的后期功能化和多卤代芳烃的高效合成。 β-碳硼烷支架最适合催化，并且通过装饰簇顶点进行可能的微调对于调节卤物种的电子性质以最大化催化性能非常重要。

  DOI：

  10.1016/j.chempr.2023.10.006
• 作为产物：
  描述：

  2-chloro-1,4-napthoquinone 生成 atovaquone
  参考文献：
  名称：

  Org. Process Res. Dev. 2014, 18, 618-625

  摘要：

  DOI：

文献信息

• [EN] NOVEL METHOD FOR PREPARATION OF ATOVAQUONE<br/>[FR] NOUVEAU PROCÉDÉ DE PRÉPARATION D'ATOVAQUONE
  申请人：LUPIN LTD

  公开号：WO2012153162A1

  公开（公告）日：2012-11-15

  Provided is a process of preparation of 2-[trans,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy- 1,4-naphthoquinone, i.e. Atovaquone [I] which is cost effective, green, and eco-friendly process, without separation of any diastereomers or geometric isomers of intermediates obtained during the reactions. Also provided is separation of 'cis' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent. A method for converting 2-[cis,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone to 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis/ Bronsted acid is also provided. A process for preparation of compound 2-(4-(4- chlorophenyl)- 1 -hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one [IV] comprising condensation of (1,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4- chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent. The invention also encompasses a highly efficient and atomeconomic process for synthesis of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone as well as a process for synthesis of 2-[cis-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone. Further provided is a process for isomerization of cis- Atovaquone i.e. 2-[cis-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4- naphthoquinone to tnms-Atovaquone i.e. 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3- hydroxy- 1,4-naphthoquinone in presence of Lewis acid.

  提供了一种制备2-[反式,-4-(4'-氯苯基)环己基]-3-羟基-1,4-萘醌，即阿托喹酮[I]的过程，这是一种具有成本效益、绿色、环保的过程，无需分离在反应过程中获得的中间体的对映异构体或几何异构体。还提供了通过在适当溶剂中选择性结晶来分离中间体VI、VII和VIII的'顺式'和'反式'异构体的方法。还提供了一种在路易斯/布朗斯特酸的存在的条件下将2-[顺式,-4-(4'-氯苯基)环己基]-3-羟基-1,4-萘醌转化为2-[反式-4-(4'-氯苯基)环己基]-3-羟基-1,4-萘醌的方法。还提供了一种制备化合物2-(4-(4-氯苯基)-1-羟基环己基)-3,4-二氢萘-1(2H)-酮[IV]的过程，包括(1,2-二氢萘-4-氧基)三甲基硅烷[II]与4-(4-氯苯基)环己酮[III]在有机溶剂中在路易斯酸的存在的条件下进行缩合。本发明还涵盖了高效且原子经济的合成化合物[III]即4-(4-氯苯基)环己酮的过程以及合成2-[顺式-4-(4'-氯苯基)环己基]-3-羟基-1,4-萘醌的过程。还提供了一种在路易斯酸的存在的条件下将顺式-阿托喹酮即2-[顺式-4-(4'-氯苯基)环己基]-3-羟基-1,4-萘醌异构化为反式-阿托喹酮即2-[反式-4-(4'-氯苯基)环己基]-3-羟基-1,4-萘醌的过程。
• [EN] IMPROVED SYNTHESIS OF 2-(4-(4-CHLOROPHENYL) CYCLOHEX-1-ENYL) -3, 4-DIHYDRONAPHTHALEN-1 (2H)-ONE; AN INTERMEDIATE FOR ATOVAQUONE<br/>[FR] SYNTHÈSE PERFECTIONNÉE DE 2-(4-(4-CHLOROPHÉNYL)CYCLOHEX-1-ÉNYL)-3,4-DIHYDRONAPHTALÈN-1(2H)-ONE ; INTERMÉDIAIRE POUR ATOVAQUONE
  申请人：LUPIN LTD

  公开号：WO2013014486A1

  公开（公告）日：2013-01-31

  A process for preparation of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- 1(2H)-one (V), key intermediate for synthesis of Atovaquone [I]. The process for preparation of compound(V) comprising of the steps of; i) Reaction of 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen- 1(2H)-one (IV) with trifluro acetic anhydride in presence of base in organic solvent to yield compound of formula (XIa) ii) Elimination of trifluoroacetyl functionality of compound (XIa) in organic solvent and in presence of organic base to give compound of formula (V). The invention also provides a Process for preparation of compound(XIa) comprising of the steps of; i) reaction of 2-(4-(4-chlorophenyl)-l-hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1(2H)-one (IV) with trifluro acetic anhydride in presence of organic base in organic solvent. A further process is provided for preparation of compound(V) from compound (XIa) comprising elimination reaction of trifluoroacetyl functionality compound (XIa) in organic solvent and in presence of organic base.

  一种用于制备2-(4-(4-氯苯基)环己-1-烯基)-3,4-二氢萘-1(2H)-酮(V)的方法，该化合物是合成阿托喹酮[I]的关键中间体。制备化合物(V)的过程包括以下步骤：i) 2-(4-(4-氯苯基)-1-羟基环己基)-3,4-二氢萘-1(2H)-酮(IV)与三氟乙酸酐在有机溶剂中，在碱的存在下反应，得到公式(XIa)的化合物；ii) 在有机溶剂中，并在有机碱的存在下，消除化合物(XIa)的三氟乙酰功能，得到公式(V)的化合物。本发明还提供了一种制备化合物(XIa)的方法，包括以下步骤：i) 2-(4-(4-氯苯基)-1-羟基环己基)-3,4-二氢萘-1(2H)-酮(IV)与三氟乙酸酐在有机溶剂中，在有机碱的存在下反应。还提供了另一种从化合物(XIa)制备化合物(V)的过程，包括在有机溶剂中，并在有机碱的存在下，消除化合物(XIa)的三氟乙酰功能的消除反应。
• CONJUGATES OF WATER SOLUBLE POLYMER-AMINO ACID OLIGOPEPTIDE-DRUG, PREPARATION METHOD AND USE THEREOF
  申请人：JENKEM TECHNOLOGY CO. LTD. TIANJIN BRANCH

  公开号：US20150359900A1

  公开（公告）日：2015-12-17

  A conjugate of water soluble polymer-amino acid oligopeptide-drug of Formula (I) below and a pharmaceutical composition comprising the conjugate are provided. In the conjugate, P is a water soluble polymer; X is a linking group, wherein the linking group links P and A 1 ; each of A 1 , A 2 and A 3 is independently same or different amino acid residue or amino acid analogue residue; each of D 1 and D 2 is independently same or different drug molecule residue; a is 0 or 1; b is an integer of 2-12; c is an integer of 0-7; d is 0 or 1. The conjugate could improve drug load capacity, water solubility, stability and activity of the drug.

  提供一种水溶性聚合物-氨基酸寡肽-药物的共轭物，其化学式（I）如下，并提供包含该共轭物的制药组合物。在该共轭物中，P是水溶性聚合物；X是一个连接基团，连接基团连接P和A1；A1、A2和A3中的每一个独立地是相同或不同的氨基酸残基或氨基酸类似物残基；D1和D2中的每一个独立地是相同或不同的药物分子残基；a为0或1；b是2-12的整数；c是0-7的整数；d为0或1。该共轭物能够提高药物的载荷能力、水溶性、稳定性和活性。
• [EN] A PROCESS FOR PREPARING ATOVAQUONE AND ASSOCIATE INTERMEDIATES<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ATOVAQUONE ET INTERMÉDIAIRES ASSOCIÉS
  申请人：CHEMAGIS LTD

  公开号：WO2010001379A1

  公开（公告）日：2010-01-07

  The invention provides novel intermediates of atovaquone and use thereof for the preparation of atovaquone

  该发明提供了阿托伐醌的新型中间体及其用于制备阿托伐醌的用途。
• 一种阿托伐醌的制备方法
  申请人：山东鲁抗舍里乐药业有限公司

  公开号：CN103570521A

  公开（公告）日：2014-02-12

  本发明公开了一种阿托伐醌(Atovaquone)的制备方法，属于药物合成领域。该方法通过α-萘酚与4-(4-氯苯基)环己醇在酸催化下缩合得到2-(4-(4-氯苯基)环己基)-1-萘酚(式Ⅴ)；式Ⅴ所示化合物经氧化，得到2-(4-(4-氯苯基)环己基)-1,4-萘醌(式Ⅳ)。式Ⅳ与溴发生加成反应，得到2,3-二溴-2-(4-(4-氯苯基)环己基)-1,4-萘醌(式Ⅲ)，然后脱去一分子的溴化氢，得到3-溴-2-(4-(4-氯苯基)环己基)-1,4-萘醌(式Ⅱ)，最后经水解反应获得阿托伐醌(式Ⅰ)。与现有技术相比，本发明的方法不仅工艺简单，制备过程中还避免了使用价格昂贵的硝酸银，同时提高了产率，减少了对环境的污染，具有很好的推广应用价值。