(2,8-bis-trifluoromethyl-quinolin-4-yl)-piperidin-2-yl-methanol; hydrochloride | 51744-83-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (2,8-bis-trifluoromethyl-quinolin-4-yl)-piperidin-2-yl-methanol; hydrochloride
• 英文别名: (+)RS mefloquine hydrochloride；11R,12S-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol hydrochloride；(+)-mefloquine hydrochloride；(-)-erythro-mefloquine hydrochloride；(R)-[2,8-bis(trifluoromethyl)quinolin-4-yl][(2S)-piperidin-2-yl]methanol hydrochloride；(+)-(11R,2'S)-α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol hydrochloride；(11R,12S)-(-)-erythro-mefloquine hydrochloride；(-)-(11R,12S)-mefloquine hydrochloride；(-)-anti-mefloquine hydrochloride；(R)-(2,8-bis(trifluoromethyl)quinolin-4-yl)((S)-piperidin-2-yl)methanol hydrochloride；(R)-[2,8-bis(trifluoromethyl)quinolin-4-yl]-[(2S)-piperidin-2-yl]methanol;hydrochloride
• CAS: 51744-83-3
• 化学式: C₁₇H₁₆F₆N₂O*ClH
• mdl: MFCD00797519
• 分子量: 414.778
• InChiKey: WESWYMRNZNDGBX-SBKWZQTDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.11
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  45.2
• 氢给体数：
  3
• 氢受体数：
  9

ADMET

毒理性

• 肝毒性

慢性使用氯喹与多达18%的患者无症状、暂时性血清酶水平升高有关。这些升高通常是轻微的，并且在不调整剂量的情况下会自行解决。尽管氯喹被广泛使用，但它很少与临床上明显的急性肝损伤有关，而且关于此类损伤的临床特征的报告太少。急性肝细胞损伤以及胆汁淤积性肝炎的案例已与使用氯喹有关。过敏表现（皮疹、发热、嗜酸性粒细胞增多）和自身抗体的形成是罕见的。

Chronic therapy with mefloquine is associated with asymptomatic, transient serum enzyme elevations in up to 18% of patients. These elevations are usually mild and resolve without dose modifications. Despite widespread use, mefloquine has rarely been linked to clinically apparent acute liver injury and too few reports are available to characterize the clinical features of such injury. Instances of acute hepatocellular injury as well as cholestatic hepatitis have been linked to use of mefloquine. Allergic manifestations (rash, fever, eosinophilia) and autoantibody formation are rare.

来源:LiverTox

反应信息

• 作为反应物：
  描述：

  四氢呋喃 、 (2,8-bis-trifluoromethyl-quinolin-4-yl)-piperidin-2-yl-methanol; hydrochloride 反应 120.0h， 生成 (+)-(11R,2'S)-α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol hydrochloride tetrahydrofuran solvate
  参考文献：
  名称：

  [EN] CRYSTALLINE FORMS OF (+)- AND (-)-ERYTHRO-MEFLOQUINE HYDROCHLORIDE
  [FR] FORMES CRISTALLINES D'HYDROCHLORURE D'ERYTHRO-MEFLOQUINE (+) ET (-)

  摘要：

  (+)或(-)-麦氟林盐酸盐可以存在四种结晶形式A、B、C和D，其中形式A是最稳定的形式。形式A可以直接以厚柱、长方体、立方体和类立方体形式产生，这些形式在处理和配方过程中易于处理。(+)或(-)-麦氟林盐酸盐还与丙酮、甲乙酮和四氢呋喃形成溶剂合物。

  公开号：

  WO2005058872A1
• 作为产物：
  描述：

  (-)-erythro-mefloquine 在 盐酸 作用下， 以 乙醚 为溶剂， 反应 0.5h， 以18 mg的产率得到(2,8-bis-trifluoromethyl-quinolin-4-yl)-piperidin-2-yl-methanol; hydrochloride
  参考文献：
  名称：

  通过手性N-氨基环氨基甲酸酯Hy不对称合成抗疟药（+）-盐酸甲氟喹

  摘要：

  盐酸甲氟喹是一种重要的抗疟药。目前以消旋形式生产和管理。然而，关于两种对映异构体的生物活性的迹象表明（+）-形式的优越性。描述了盐酸甲氟喹的（+）-对映异构体的不对称全合成。所利用的关键的不对称转化是衍生自N-氨基环状氨基甲酸酯（ACC）手性助剂的手性α-氯-N-氨基环状氨基甲酸酯的新型不对称Darzens反应。

  DOI：

  10.1021/ol2010193

文献信息

• Concise Synthesis and Antimalarial Activity of All Four Mefloquine Stereoisomers Using a Highly Enantioselective Catalytic Borylative Alkene Isomerization
  作者：Jinyue Ding、Dennis G. Hall

  DOI：10.1002/anie.201303931

  日期：2013.7.29

  isomerization/aldehyde allylboration method for the stereoselective synthesis of the antimalarial drug mefloquine was optimized, thus leading to an efficient synthesis of all four mefloquine stereoisomers and analogues (see scheme). The absolute configuration of these potent compounds was determined for the first time by using chemical synthesis.

  甲氟喹的优缺点：优化了用于抗疟药甲氟喹立体选择性合成的高对映选择性催化硼化异构化/醛烯丙基硼化方法，从而有效合成了所有四种甲氟喹立体异构体和类似物（参见方案）。这些强效化合物的绝对构型是通过化学合成首次确定的。
• The antimalarial drug mefloquine enhances TP53 premature termination codon readthrough by aminoglycoside G418
  作者：Michael W. Ferguson、Chloe A. N. Gerak、Christalle C. T. Chow、Ettore J. Rastelli、Kyle E. Elmore、Florian Stahl、Sara Hosseini-Farahabadi、Alireza Baradaran-Heravi、Don M. Coltart、Michel Roberge

  DOI：10.1371/journal.pone.0216423

  日期：——

  Small molecule phthalimide derivatives that can enhance the readthrough activity of G418 have also been described. To determine whether readthrough enhancers exist among drugs that are already approved for use in humans, we tested seven antimalarial drugs for readthrough of the common R213X TP53 nonsense mutation in HDQ-P1 breast cancer cells. Mefloquine induced no TP53 readthrough activity as a single

  无意义的突变约占癌症中TP53突变的10％。他们引入了一个过早的终止密码子，该密码子会导致功能受损的截短的p53蛋白。氨基糖苷G418可以诱导TP53提前终止密码子通读，从而增加全长蛋白的细胞水平。还已经描述了可以增强G418的通读活性的小分子邻苯二甲酰亚胺衍生物。为了确定在已经批准用于人类的药物中是否存在通读增强剂，我们测试了7种抗疟药对HDQ-P1乳腺癌细胞中常见的R213X TP53无意义突变进行通读。甲氟喹单剂不引起TP53的通读活性，但被G418强烈增强了通读。组成药物甲氟喹的两种对映体在HDQ-P1细胞以及SW900，NCI-H1688和HCC1937癌细胞中具有不同的TP53无意义突变，从而将通读增强到相似的水平。DNA损伤后，暴露于G418和甲氟喹会增加Ser15和P21转录水平的p53磷酸化，表明通过通读产生的p53具有功能。甲氟喹似乎没有通过溶溶同质作用来增强通透性，因
• Medicament with anti-parasitic activity
  申请人：ADCOCK INGRAM LIMITED

  公开号：EP0729757A1

  公开（公告）日：1996-09-04

  The invention provides the use of a riminophenazine in the manufacture of a medicament to treat parasitic infections. The riminophenazine may be used for the prophylactic treatments of maleria or for the therapeutic treatment of maleria. A known anti-maleria drug, e.g. chloroquine or mefloquine may be administered as well. The riminophenazine may be a compound of the general formula: wherein: R1 is selected from hydrogen atoms, halogen atoms, alkyl, alkoxy and trifluoromethyl radicals, R2 is selected from hydrogen or halogen atoms, R3 is selected from hydrogen atoms, alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, unsubstituted heterocyclic radicals, substituted heterocyclic radicals, unsubstituted heterocyclicalkyl and substituted heterocyclicalkyl radicals, R4 is selected from hydrogen atoms, halogen atoms, alkyl, alkoxyl and trifluoromethyl radicals; and n is 1, 2 or 3.

  本发明提供了使用利米诺吩嗪制造治疗寄生虫感染药物的方法。利米诺吩嗪可用于疟疾的预防性治疗或疟疾的治疗性治疗。也可使用已知的抗疟疾药物，如氯喹或甲氟喹。利米诺吩嗪可以是通式如下的化合物： 其中 R1 选自氢原子、卤素原子、烷基、烷氧基和三氟甲基、 R2 选自氢原子或卤素原子、 R3 选自氢原子、烷基、取代的烷基、环烷基、环烷基烷基、未取代的杂环基、取代的杂环基、未取代的杂环烷基和取代的杂环烷基、 R4 选自氢原子、卤素原子、烷基、烷氧基和三氟甲基基；以及 n 为 1、2 或 3。
• Potassium channel mediated delivery of agents through the blood-brain barrier
  申请人：Black L. Keith

  公开号：US20050089473A1

  公开（公告）日：2005-04-28

  This invention includes pharmaceutical compositions, methods and kits for the treatment or diagnosis of a malignant tumors, including brain tumors, and diseases or disorders characterized by abnormal brain tissue.

  本发明包括用于治疗或诊断恶性肿瘤（包括脑肿瘤）以及以脑组织异常为特征的疾病或紊乱的药物组合物、方法和试剂盒。
• A Stereospecific Synthesis and Unambiguous Assignment of the Absolute Configuration of (−)‐ <i>erythro</i> ‐Mefloquine Hydrochloride
  作者：Gang Zhou、Xian Liu、Xueying Liu、Huifang Nie、Shengyong Zhang、Weiping Chen

  DOI：10.1002/adsc.201300531

  日期：2013.12.16

  Abstract(−)‐erythro‐Mefloquine hydrochloride was synthesized stereospecifically from commercially available (S)‐(−)‐1‐Boc‐2‐piperidinecarboxylic acid in four steps without disturbing the chiral center, and the absolute configuration of (−)‐erythro‐mefloquine hydrochloride was unambiguously determined as (11R,12S). (11S,12R)‐(+)‐erythro‐Mefloquine hydrochloride was synthesized utilizing [(S,S)‐TsDpen]Ru(p‐cymene)Cl complexes‐catalyzed enantioselective transfer hydrogenation of pyridyl ketone 7 as the key step, and the sense of asymmetric induction of 2‐pyridyl ketone 7 is opposite to that of normal ketones in the transfer hydrogenation. Our results confirm the correctness of the determination of the absolute configuration by three physical chemistry methods, and, unbelievably, the erroneous assignments by all previous five asymmetric syntheses.magnified image