(6-bromo-2-memoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (6-bromo-2-memoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
• 英文别名: 6-bromo-α-[2-(dimethylamino)ethyl]-2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol；(1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol；(1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol
• 化学式: C₃₂H₃₁BrN₂O₂
• 分子量: 555.514
• InChiKey: QUIJNHUBAXPXFS-BHYZAODMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  45.6
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

CYP3A4是在体外代谢Bedaquiline和形成N-单去甲基代谢物（M2）的主要CYP同工酶，M2在抗分枝杆菌效力方面比Bedaquiline低4到6倍。根据临床前研究，Bedaquiline主要通过粪便消除。在临床研究中，未改变Bedaquiline的尿排泄量小于剂量的0.001%，这表明未改变药物的肾清除是不重要的。达到Cmax后，Bedaquiline浓度呈三重指数下降。Bedaquiline和N-单去甲基代谢物（M2）的平均终末消除半衰期大约为5.5个月。这个长的终末消除阶段可能反映了Bedaquiline和M2从外周组织的缓慢释放。

CYP3A4 was the major CYP isoenzyme involved in vitro in the metabolism of bedaquiline and the formation of the N-monodesmethyl metabolite (M2), which is 4 to 6-times less active in terms of antimycobacterial potency. Based on preclinical studies, bedaquiline is mainly eliminated in feces. The urinary excretion of unchanged bedaquiline was < 0.001% of the dose in clinical studies, indicating that renal clearance of unchanged drug is insignificant. After reaching Cmax, bedaquiline concentrations decline tri-exponentially. The mean terminal elimination half-life of bedaquiline and the N-monodesmethyl metabolite (M2) is approximately 5.5 months. This long terminal elimination phase likely reflects slow release of bedaquiline and M2 from peripheral tissues.

来源:Hazardous Substances Data Bank (HSDB)

代谢

单次给药后，主要代谢物M2的平均AUC0-24小时在小白鼠中比bedaquiline的AUC0-24小时高2到7倍，在大鼠和狗中通常相似，大约低2倍。

After a single dose the mean AUC0-24 hr of the major metabolite M2 was 2 to 7-fold higher than AUC0-24 hr of bedaquiline in mice and was generally similar to 2-fold lower in rats and dogs.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Bedaquiline是一种最近批准用于治疗多药耐药结核病的药物。在临床实践中已经注意到Bedaquiline对心脏和肝脏的不良药物反应。当前研究采用代谢组学方法研究了人肝细胞中Bedaquiline的代谢。确认了Bedaquiline通过CYP3A4的N-去甲基化是Bedaquiline代谢的主要途径。除了CYP3A4外，我们还发现CYP2C8和CYP2C19也参与了Bedaquiline的N-去甲基化。CYP2C8、CYP2C19和CYP3A4在Bedaquiline N-去甲基化中的Km值分别为13.1、21.3和8.5微摩尔。我们还确定了一种产生醛中间体的Bedaquiline新颖代谢途径。总之，这项研究扩展了我们对Bedaquiline代谢的了解，可以用来预测和预防与Bedaquiline相关的药物-药物相互作用和不良药物反应。

Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic drug reactions to bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via CYP3A4 was confirmed as the major pathway in bedaquiline metabolism. In addition to CYP3A4, we found that both CYP2C8 and CYP2C19 contributed to bedaquiline N-demethylation. The Km values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 uM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug-drug interactions and adverse drug reactions associated with bedaquiline.

来源:Hazardous Substances Data Bank (HSDB)

代谢

没有在体内发生手性转化。在小鼠、大鼠、狗、猴子和人体中，(14)C-贝达喹啉的体外代谢主要是通过第一阶段反应，最重要的途径是N-脱甲基生成M2，然后是第二次N-脱甲基生成M3，氧化和环氧化。根据动物体内的放射性分析和LC-MS/MS，M2是所有临床前物种中的主要循环代谢物。尚未在人体中进行放射性标记贝达喹啉的质量平衡研究。因此，不能排除人体中可能形成在动物物种中不形成的额外未检测到的代谢物。在重复给予贝达喹啉的大鼠和狗中，M2的AUC0-24小时血浆水平通常与贝达喹啉相似，但在MDR-TB的人类受试者中，M2的水平比贝达喹啉低3.5到4.5倍。除了M2和M3，还在人类血浆中检测到了M2的羟基衍生物（M20）和M2的二氢二醇衍生物（M11）。这两种代谢物在大鼠和狗中以类似的相对浓度也被发现。

No chiral conversion of bedaquiline occurred in vivo after administration of bedaquiline to mice, rats, dogs, monkeys and humans. In hepatocytes and subcellular fractions from preclinical species and humans, the in vitro metabolism of (14)C-bedaquiline was via Phase I reactions and the most important pathway was N-demethylation to M2, which was followed by a second N-demethylation to M3, oxidation and epoxidation. M2 was the major circulating metabolite in all preclinical species as determined by radioactivity profiling and LC-MS/MS in the animals. No mass balance study with radiolabelled bedaquiline has been conducted in humans. It can therefore not be excluded that additional undetected metabolites may be formed in humans that are not formed in the animal species. M2-AUC0-24 hr plasma levels were generally comparable to 2-fold lower than those of bedaquiline in rats and dogs upon repeated administration of bedaquiline, and 3.5- to 4.5-fold lower in human subjects with MDR-TB. In addition to M2 and M3, a hydroxylated derivative of M2 (M20) and a dihydrodiol derivative of M2 (M11), were detected in human plasma. These two metabolites were also found in rats and dogs at similar relative concentrations.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

8%至12%的使用包括bedaquiline在内的多种药物治疗方案的患者的肝功能检测出现异常。这些异常通常无症状，严重程度为轻至中度，持续时间有限。在许多情况下，很难确定哪种抗结核药物导致了这些异常，但建议在bedaquiline治疗期间每月监测肝功能检测。已经报道了使用bedaquiline治疗时出现的临床明显的肝损伤，但这些病例的临床特征、病程和结果尚未描述。至少有三例终末期肝病死亡的患者在使用bedaquiline，但对肝衰竭归因于bedaquiline的说法存在争议。多药耐药结核病的治疗具有挑战性，应在有结核病治疗专长的医生的指导下进行。

Liver test abnormalities occur in 8% to 12% of patients treated with multiple drug regimens that include bedaquiline. These abnormalities are usually asymptomatic, mild-to-moderate in severity and self-limited in duration. In many instances, it is difficult to determine which of the antituberculosis medications accounts for the abnormalities, but monitoring of liver tests at monthly intervals is recommended during bedaquiline therapy. Clinically apparent liver injury has been reported with bedaquiline therapy, but the clinical features, course and outcome of these cases has not been described. At least three deaths from end stage liver disease have been described in patients taking bedaquiline, but the attribution of the hepatic failure to bedaquiline has been questioned. The management of multidrug resistant tuberculosis is challenging and should be under the direction of physicians with expertise in tuberculosis therapy.

来源:LiverTox

毒理性

• 相互作用

药物相互作用（增加QT间期延长的风险）。与其他延长QT间期的药物（例如，氯法齐明、氟喹诺酮类、大环内酯类）同时使用可能会导致QT间期的累加或协同效应。

Pharmacologic interaction (increased risk of QT interval prolongation). Concomitant use with other drugs that prolong the QT interval (e.g., clofazimine, fluoroquinolones, macrolides) may result in additive or synergistic effects on the QT interval.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

贝达喹啉主要通过细胞色素P-450（CYP）同工酶3A4进行代谢。与强效CYP3A4抑制剂（例如，酮康唑）同时使用贝达喹啉可能会增加贝达喹啉的浓度-时间曲线下面积（AUC），并增加与药物相关的不良反应风险。应避免长时间（超过14天）同时使用贝达喹啉和强效CYP3A4抑制剂系统药物，除非同时使用的益处大于风险。接受此类联合治疗的患者应监测与贝达喹啉相关的不良反应。与强效CYP3A4诱导剂（包括利福霉素类药物，例如利福平、利福喷丁、利福布汀）同时使用贝达喹啉可能会减少贝达喹啉的AUC，并降低药物的疗效。应避免与利福霉素类药物或其他强效CYP3A4诱导剂同时使用贝达喹啉。

Bedaquiline is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A4. Concomitant use of bedaquiline with potent inhibitors of CYP3A4 (e.g., ketoconazole) may increase the area under the concentration-time curve (AUC) of bedaquiline and increase the risk of adverse effects associated with the drug. Concomitant use of bedaquiline and systemic drugs that are potent inhibitors of CYP3A4 for a duration longer than 14 consecutive days should be avoided, unless the benefits of concomitant use outweigh the risks. Patients receiving such concomitant therapy should be monitored for bedaquiline-related adverse effects. Concomitant use of bedaquiline with potent inducers of CYP3A4, including rifamycins (e.g., rifampin, rifapentine, rifabutin), may reduce the AUC of bedaquiline and decrease the therapeutic effects of the drug. Concomitant use of bedaquiline with rifamycins or other potent inducers of CYP3A4 should be avoided.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

因为bedaquiline和氟喹诺酮类药物的联合使用可能会增加QT间期延长的风险，所以在联合治疗期间应密切监测心电图。

Because concomitant use of bedaquiline and fluoroquinolones may increase the risk of QT interval prolongation, ECGs should be monitored closely during concomitant therapy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

因为bedaquiline（贝达喹啉）和macrolides（大环内酯类抗生素）的联合使用可能会增加QT间期延长的风险，所以在联合治疗期间应密切监测心电图。

Because concomitant use of bedaquiline and macrolides may increase the risk of QT interval prolongation, ECGs should be monitored closely during concomitant therapy.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Bedaquiline 是一种用于治疗肺多药耐药结核分枝杆菌感染的新药，与其他药物联合使用。本研究的目的是开发一个群体药代动力学（PK）模型，以描述健康受试者和药物敏感或耐多药结核病患者在一期和二期研究中Bedaquiline的浓度-时间数据。总共使用了来自480个受试者的5,222个PK观察数据，采用非线性混合效应建模方法。PK模型用具有双重零级输入（以捕捉吸收期间观察到的双重峰）和长末端半衰期（t1/2）的四室处置模型来描述。该模型包括了对表观清除率（CL/F）、表观中央分布容积（Vc/F）、第一次输入的剂量比例和生物利用度（F）的受试者间变异性。Bedaquiline广泛分布，稳态时表观容积大于10,000升，清除率低。长末端t1/2可能是由于从组织室重新分布。最终的协变量模型充分描述了数据，并且具有良好的模拟特性。CL/F在黑人受试者中比其他种族的受试者高出52.0%，而Vc/F在女性中比男性低15.7%，尽管它们对Bedaquiline暴露的影响被认为临床上不相关。研究之间在F和CL/F上观察到了小的差异。未解释的残留变异性为20.6%，长期二期研究中更高（27.7%）。

Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Bedaquiline在大鼠中会分布到乳汁中；目前尚不清楚该药物是否也会分布到人类乳汁中。

Bedaquiline is distributed into milk in rats; it is not known whether the drug is distributed into human milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

bedaquiline的血浆蛋白结合率大于99.9%。中央室的分布容积估计大约为164升。

The plasma protein binding of bedaquiline is > 99.9%. The volume of distribution in the central compartment is estimated to be approximately 164 L.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服给药后，贝达喹啉的最大血浆浓度（Cmax）通常在给药后约5小时达到。Cmax和血浆浓度-时间曲线下的面积（AUC）与健康志愿者研究的最高剂量（700毫克单次剂量和每日一次400毫克多次剂量）成比例增加。与空腹条件下的给药相比，与含有大约22克脂肪（总共558千卡路里）的标准餐一起服用贝达喹啉，相对生物利用度增加了约2倍。因此，为了提高贝达喹啉的口服生物利用度，应与食物一起服用。

After oral administration bedaquiline maximum plasma concentrations (Cmax) are typically achieved at approximately 5 hours post-dose. Cmax and the area under the plasma concentration-time curve (AUC) increased proportionally up to the highest doses studied in healthy volunteers (700 mg single-dose and once daily 400 multiple doses). Administration of bedaquiline with a standard meal containing approximately 22 grams of fat (558 total Kcal) increased the relative bioavailability by about 2-fold compared to administration under fasted conditions. Therefore, bedaquiline should be taken with food to enhance its oral bioavailability.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  (6-bromo-2-memoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol 在 sodium hydroxide 作用下， 以 2-甲基四氢呋喃 为溶剂， 反应 4.0h， 以91%的产率得到3-苄基-6-溴-2-甲氧基喹啉
  参考文献：
  名称：

  制备贝达喹啉中间体的方法以及使用该中间体制备贝达喹啉的方法

  摘要：

  本发明涉及制备贝达喹啉中间体的方法以及使用该中间体制备贝达喹啉的方法。具体地，本发明涉及一种制备3‑苄基‑6‑溴‑2‑甲氧基喹啉的方法，其包括在2‑甲基四氢呋喃溶剂中与碱反应，并且涉及一种通过使用由所述方法制备的3‑苄基‑6‑溴‑2‑甲氧基喹啉来制备1‑(6‑溴‑2‑甲氧基喹啉‑3‑基)‑4‑(二甲基氨基)‑2‑(萘‑1‑基)‑1‑苯基丁‑2‑醇的方法。

  公开号：

  CN114380742A
• 作为产物：
  描述：

  3-苄基-6-溴-2-氯喹啉 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 13.0h， 生成 (6-bromo-2-memoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol
  参考文献：
  名称：

  一种通过碱催化的Csp3Csp3键裂解将Bedaquiline的非活性立体异构体再循环到两个先前的中间体中的高效方法

  摘要：

  摘要贝达喹啉是一种具有两个手性中心的纯对映异构体，是一种抗肺多药结核的新药。当前的工业制备方法需要从四种异构体的混合物中分离出活性贝达奎林。显然，直接处置其他三种不希望的立体异构体将导致大量浪费并增加不必要的生产成本。在这里，我们开发了一种高效，简便且可扩展的方法来回收Bedaquiline的非活性立体异构体。所有这些非活性立体异构体都可以通过转化为Bedaquiline合成中的两个重要中间体而循环利用，这是通过苄基醇中间体的碱催化C sp3 C sp3键裂解实现的。并讨论了碱催化裂解反应的精确条件和机理。

  DOI：

  10.1016/j.cclet.2015.04.013

文献信息

• Practical Syntheses of (2S)-R207910 and (2R)-R207910
  作者：Srivari Chandrasekhar、G. S. Kiran Babu、Debendra K. Mohapatra

  DOI：10.1002/ejoc.201001720

  日期：2011.4

  Concise and practical syntheses of (2S)-R207910 (3a) and (2R)-R207910 (3b) have been achieved in high overall yield of 12 % in 10 steps for each isomer starting from a known intermediate following Sharpless asymmetric epoxidation, regioselective epoxide opening, modified allylzinc bromide addition as key reactions.

  (2S)-R207910 (3a) 和 (2R)-R207910 (3b) 在 Sharpless 不对称环氧化、区域选择性环氧化物之后，从已知中间体开始，每个异构体分 10 步以 12% 的高总产率实现了简洁实用的合成打开，改性烯丙基溴化锌加成作为关键反应。
• [EN] CHIRAL RESOLUTION OF BEDAQUILINE BY USING CYCLCIC PHOSPHORIC ACIDS<br/>[FR] RÉSOLUTION CHIRALE DE LA BÉDAQUILINE AU MOYEN D'ACIDES PHOSPHORIQUES CYCLIQUES
  申请人：ZENTIVA KS

  公开号：WO2016116073A1

  公开（公告）日：2016-07-28

  A method of performing isolation and purification of bedaquiline (la) from a mixture of stereoisomers of 6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-(l-naphthyl)-l- phenyl-butan-2-ol identified as I-rac, being a mixture of the stereoisomers of formulae la, lb, and II-rac, being a mixture of the stereoisomers of formulae Ila, lib, with any ratio of individual constituents of the mixture, wherein said mixture is dissolved together with derivatives of 1,3 -propanediol hydrogen phosphate of formula IV, wherein R1, R2, and R3 independently stand for hydrogen, a halogen, C1-C6 alkyl, aryl, naphthyl, phenyl and preferably a halogenated phenyl or phenyl substituted in any way, and the resulting salt is crystallized.

  从被鉴定为I-rac的6-溴-2-甲氧基喹啉-3-基)-4-二甲基氨基-2-(1-萘基)-1-苯基-丁-2-醇的立体异构体混合物中分离和纯化bedaquiline（la）的方法，该混合物是由公式la，lb的立体异构体混合物和II-rac的公式Ila，lib的立体异构体混合物组成，其中混合物的各个成分之间的比例可以任意，所述混合物与公式IV的1,3-丙二醇氢磷酸盐衍生物一起溶解，其中R1，R2和R3独立地代表氢，卤素，C1-C6烷基，芳基，萘基，苯基，最好是卤代苯基或以任何方式取代的苯基，并结晶得到所述盐。
• [EN] METHOD OF ISOLATION OF A MIXTURE OF ENANTIOMERS OF 1-(6-BROMO-2-METHOXYQUINOLIN-3-YL)-4-(DIMETHYLAMINO)-2-(NAPHTHALEN-1-YL)-1-PHENYLBUTAN-2-OL<br/>[FR] PROCÉDÉ D'ISOLEMENT D'UN MÉLANGE D'ÉNANTIOMÈRES DE 1-(6-BROMO-2-MÉTHOXYQUINOLÉIN-3-YL)-4-(DIMÉTHYLAMINO)-2-(NAPHTALÉN-1-YL)-1-PHÉNYLBUTAN-2-OL
  申请人：ZENTIVA KS

  公开号：WO2016116075A1

  公开（公告）日：2016-07-28

  A method of isolation of the E1 and E2 optical isomers, forming an enantiomeric mixture, from a mixture of four optical isomers E1, E2, E3, E4, wherein the enantiomeric mixture of E3 and E4 is first separated from the solution and subsequently the mixture of E1 and E2 is isolated in the form of a base in the mother liquors, wherein E1 is (1R,2S)-1-(6-bromo-2-memoxyqumolm-3-yl)-4-(dimethylamino)-2- (naphthalen-1-yl)-1-phenylbutan-2-ol, E2 is the (1S,2R)-enantiomer of the same compound, and E3 and E4 are the (1R,2R) and (1S,2S) enantiomers, respectively.

  一种从四个光学异构体E1、E2、E3、E4的混合物中分离出E1和E2光学异构体形成对映异构体混合物的方法，其中先从溶液中分离出E3和E4的对映异构体混合物，然后在母液中分离出E1和E2混合物的碱式形式，其中E1是(1R,2S)-1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲氨基)-2-(萘-1-基)-1-苯基丁-2-醇，E2是同一化合物的(1S,2R)-对映异构体，E3和E4分别是(1R,2R)和(1S,2S)的对映异构体。
• Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline**
  作者：Sarah Jane Mear、Tobias Lucas、Grace P. Ahlqvist、Juliana M. S. Robey、Jule‐Philipp Dietz、Pankaj V. Khairnar、Sanjay Maity、Corshai L. Williams、David R. Snead、Ryan C. Nelson、Till Opatz、Timothy F. Jamison

  DOI：10.1002/chem.202201311

  日期：2022.8.22

  treatment of multidrug-resistant tuberculosis. Improvements to the industrial synthesis are reported here that affords racemic bedaquiline in yields twice as high as those reported in patents, presenting an opportunity to dramatically improve the affordability of this drug. Close attention to reaction mechanism informed optimization of this synthesis by providing rationale for operational controls

  富马酸贝达喹啉是治疗耐多药结核病的关键药物。本文报道了对工业合成的改进，使外消旋贝达喹啉的产率是专利中报道的两倍，这为显着提高这种药物的可负担性提供了机会。密切关注反应机理，通过提供以令人惊讶的方式影响产率和非对映选择性的操作控制和反应参数的基本原理来优化该合成。
• WO2006/125769
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