(S)-[2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol | 53230-10-7

• 物质功能分类: 原料药 - 抗寄生虫病药 - 抗疟药
• 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: (S)-[2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol
• CAS: 53230-10-7
• 化学式: C₁₇H₁₆F₆N₂O
• 分子量: 378.31
• InChiKey: XEEQGYMUWCZPDN-CVRLYYSRSA-N

物化性质

• 熔点：
  242-244°C
• 沸点：
  415.7±40.0 °C(Predicted)
• 密度：
  1.383±0.06 g/cm3(Predicted)
• 溶解度：
  In water, 6.212 mg/L at 25 °C (est)
• 蒸汽压力：
  3.74X10-9 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Mefloquine hydrochloride/
• 解离常数：
  pKa1 = 9.46 (amine); pKa2 = 13.79 (hydroxy) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 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：
  2
• 氢受体数：
  9

ADMET

代谢

生物转化：肝脏（部分）；主要代谢为羧酸代谢物。

Biotransformation: Hepatic (partial); metabolized primarily to the carboxylic acid metabolite.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved. Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only. 疟疾药物Mefloquine在肝脏中通过细胞色素P450系统广泛代谢。体外和体内研究强烈表明，CYP3A4是主要的参与同型物。在人类中已经识别出Mefloquine的两个代谢物。主要代谢物，2,8-双三氟甲基-4-喹啉羧酸，在恶性疟原虫中是无效的。在一项对健康志愿者的研究中，羧酸代谢物在单次口服剂量后2到4小时出现在血浆中。代谢物的最大血浆浓度，比Mefloquine高出约50%，在2周后达到。此后，主要代谢物和Mefloquine的血浆水平以相似的速度下降。主要代谢物的血浆浓度-时间曲线下面积（AUC）是母药的大约3到5倍。另一个代谢物，一种醇，仅以极少量存在。

Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo studies strongly suggested that CYP3A4 is the major isoform involved. Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴别人和使用：Mefloquine 是一种白色或略带黄色的结晶粉末，制成片剂。Mefloquine 是一种抗疟疾药，作用为血液裂殖体杀虫剂。它用于预防由恶性疟原虫或 P. vivax 引起的疟疾。人类暴露和毒性：Mefloquine 过量会产生与药物报告的副作用相似的症状。2 名患者服用了过量的 Mefloquine（在 5 天内达到 5250 毫克）后出现眩晕、幻觉、头晕、恶心、低血压、心动过速和癫痫发作。由于在治疗剂量下也可能发生癫痫，因此有癫痫病史的患者禁用 Mefloquine。Mefloquine 还与神经精神症状有关：焦虑、偏执、抑郁、幻觉和精神行为异常。这些症状在停用 Mefloquine 后可能还会持续很长时间。这些神经精神效应在过量服用和治疗剂量下均有报道。为了尽量减少这些不良影响，患有活动性抑郁症、近期抑郁症史、广泛性焦虑症、精神分裂症、精神分裂症或其他重大精神病的患者禁忌使用 Mefloquine 进行预防。还有证据表明，在 Mefloquine 治疗期间和最后一次服用 Mefloquine 后的 15 周内使用 halofantrine 会增加校正 QT 间期 (QTc) 潜在致命延长的风险。与酮康唑联合使用时，这种风险也可能增加。在使用 Mefloquine 单一疗法时，没有报道出现临床显著的 QTc 间期延长。几项针对孕妇的研究表明，在怀孕期间使用 Mefloquine 治疗或预防并未增加致畸效应或不良妊娠结果的风险。然而，世卫组织得出结论，在怀孕的前 12-14 周应谨慎使用 Mefloquine。动物研究：尽管对小鼠和大鼠进行了为期两年的研究并未发现肿瘤增加，但 Mefloquine 确实产生了毒性效应。在其中一项研究中，大鼠通过饮食中以 0、5、12.5 或 30 mg/kg/天的剂量服用 Mefloquine，持续 2 年。在高剂量组中，两个性别的体重增长显著下降，自发死亡的发生率增加。雄性出现睾丸体积减小和后肢麻痹，而雌性出现阴道出血增加、囊肿性卵巢和充满液体的扩张子宫。两个性别的肝酶和血尿素氮水平升高。研究结束时，两个性别的眼睛、肺、肾、生殖器官、骨骼肌、脾和淋巴结均出现病变。在中剂量和高剂量组中，出现了视网膜变性、晶状体混浊和/或视网膜水肿（严重程度在雌性中更大）。在中剂量组中，观察到生殖器官的轻微病变和胆管增生。雄性在附睾和前列腺出现病变；低剂量组的两个性别均观察到附睾上皮细胞空泡化、肺泡中泡沫状巨噬细胞和骨骼肌变性。研究了 Mefloquine 对神经系统效应的潜力，给 7 周大的雌性大鼠单次口服给药。使用标准功能观察法、自动开阔场测试、自动自发活动监测、横梁穿越任务和组织病理学来监测 Mefloquine 诱导的神经学效应。Mefloquine 诱导了与自发活动和运动功能损害相关的终点的剂量相关变化，并导致特定脑干核（gracilis 核）的变性。仅在老鼠的正常睡眠阶段观察到自发活动增加，这表明与 Mefloquine 诱导的睡眠障碍有关。还表明 Mefloquine 对小鼠、大鼠和家兔具有致畸性。在一项研究中，通过胃管给大鼠喂食 Mefloquine，剂量高达 100 mg/kg/天。在高剂量组中，大鼠生长速度较慢，消耗的食物比对照组少。胎儿体重减轻、顶臀长缩短、外部可见软组织和骨骼缺陷的发生率增加；高比例的出现圆顶颅骨，脑积水的高发生率；还观察到不完整骨化的顶骨、枕骨和颅骨。在类似的小鼠研究中，Mefloquine 以 100 和 200 mg/kg/天的剂量导致胎儿体重下降和腭裂高发生率。还表明 Mefloquine 对大鼠的雌性和雄性生育能力有影响。在以下测试中未发现 Mefloquine 具有诱变性：Ames 测试、波动测试、宿主（小鼠）介导分析、微核测试、点突变诱导、酵母处理和板测试。

IDENTIFICATION AND USE: Mefloquine is a white or slightly yellow crystalline powder that is formulated into tablets. Mefloquine is an antimalarial agent which acts as a blood schizonticide. It is used for the prevention and treatment of malaria caused by strains of Plasmodium falciparum or P. vivax. HUMAN EXPOSURE AND TOXICITY: Overdosage of mefloquine produces manifestations that are similar to the adverse reactions reported with the drug. Vertigo, hallucinations, dizziness, nausea, hypotension, tachycardia, and seizures occurred in 2 patients who ingested an overdosage of mefloquine (up to 5250 mg over 5 days). Since seizures may also occur at therapeutic doses, mefloquine is contraindicated in patients with a history of seizures. Mefloquine has also been associated with neuropsychiatric manifestations: anxiety, paranoia, depression, hallucinations and psychotic behavior. These manifestations may continue long after mefloquine has been discontinued. These neuropsychiatric effects have been reported both after overdose and at therapeutic doses. To minimize the chance of these adverse effects, use of mefloquine for prophylaxis is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders. There is also evidence that the use of halofantrine during mefloqune therapy and within 15 weeks of the last dose of mefloquine increases the risk of a potential fatal prolongation of the corrected QT interval (QTc). This risk may also be increased following co-administration with ketoconazole. Clinically significant QTc interval prolongation has not been reported with mefloquine monotherapy. Several studies in pregnant women have shown no increase in the risk of teratogenic effects or adverse pregnancy outcomes following mefloquine treatment or prophylaxis during pregnancy. The WHO concluded however, that treatment with mefloquine should be undertaken cautiously during the first 12-14 weeks of gestation. ANIMAL STUDIES: While two year studies in mice and rats failed to show an increase in tumors, mefloquine did produce toxic effects. In one such study, rats were administered mefloquine in the diet at 0, 5, 12.5 or 30 mg/kg/day for 2 years. In the high dose group the weight gain of both sexes was significantly depressed and the incidence of spontaneous death was increased. Males had decreased testicle size and paralysis of hind limbs, while females showed increased vaginal hemorrhage, cystic ovaries and distended uteri filled with fluid. Elevated liver enzymes and blood urea nitrogen levels occurred for both sexes. At study completion, both sexes showed lesions in eye, lung, kidney, reproductive organs, skeletal muscle, spleen and lymph node. Retinal degeneration, opacity of the lens and/or retinal edema occurred at both the mid and high dose group. (Severity was greater in females). Mild lesions of reproductive organs and bile duct hyperplasia were seen in the mid dose group. Males had lesions in the epididymis and prostate; epithelial vacuolization of epididymis, foamy macrophages in lungs and skeletal muscle degeneration were observed in both sexes of the low dose group. The potential for mefloquine to cause neurological effects were investigated in 7-week-old female rats given a single oral dose of the drug. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. Mefloquine was also shown to be teratogenic in mice, rats and rabbits. In one study, rats were administered mefloquine at doses up to 100 mg/kg/day by intragastric intubation. In the high dose group, rats grew slower and consumed less feed than controls. Fetuses had reduced body weight, reduced crown-rump length, increased incidence of externally visible soft tissue and skeletal defects; domes craniums occurred at a high rate, high incidence of hydrocephalus; malformed interparietals, incompletely ossified supra occipitals, and incompletely ossified skull bones were also observed. In a similar study in the mouse, mefloquine at doses of 100 and 200 mg/kg/day resulted in decreased body weight and a high incidence of cleft palate in fetuses. Mefloquine was also shown to impair fertility in both male and female rats. Mefloquine was not found to be mutagenic in the following tests: Ames Test, Fluctuation Test, Host (Mouse) Mediated Assay, Micronucleus Test, Induction of Point Mutations, Yeast Treat and Plate Test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

慢性治疗使用氯喹与无症状、短暂血清酶升高有关，多达18%的患者会出现这种情况。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

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：非常小量的甲氟喹会在母乳中排出；药物的数量不足以对婴儿造成伤害，也不足以保护儿童免受疟疾的侵害。母乳喂养的婴儿应接受推荐的甲氟喹剂量。 ◉ 对哺乳婴儿的影响：截至修订日期，未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，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Very small amounts of mefloquine are excreted in breastmilk; the amount of drug is not sufficient to harm the infant nor is the quantity sufficient to protect the child from malaria. Breastfeeding infants should receive the recommended dosages of mefloquine. ◉ 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

如果与β受体阻滞剂、钙通道阻滞剂、胺碘酮、匹莫齐特、地高辛或抗抑郁药同时使用，美氟奎可能会增加心律失常的风险；与氯喹和奎宁同时使用，也可能会增加惊厥的风险。当与氨苄西林、四环素和甲氧氯普胺同时使用时，美氟奎的浓度会增加。应谨慎观察与酒精的相互作用。

There is a possible increase in the risk of arrhythmias if mefloquine is given together with beta blockers, calcium channel blockers, amiodarone, pimozide, digoxin or antidepressants; there is also a possible increase in the risk of convulsions with chloroquine and quinine. Mefloquine concentrations are increased when given with ampicillin, tetracycline and metoclopramide. Caution should be observed with alcohol.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与其他相关抗疟化合物（例如：奎宁、奎尼丁和氯喹）联合给药时，可能会产生心电图异常并增加惊厥的风险。如果这些药物用于严重疟疾的初始治疗，应在最后一剂药物后至少推迟12小时给予本药。单独使用本药时未发现临床上显著的QTc间期延长。

Concomitant administration of mefloquine and other related antimalarial compounds (e.g., quinine, quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of convulsions. If these drugs are to be used in the initial treatment of severe malaria, mefloquine administration should be delayed at least 12 hours after the last dose. Clinically significant QTc prolongation has not been found with mefloquine alone.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

甲氟喹在胃肠道中被较好地吸收，但达到峰值血浆浓度所需的时间在个体间有显著差异。甲氟喹经历肠肝循环。大约98%与血浆蛋白结合，并在全身广泛分布。甲氟喹的药代动力学可能会因疟疾感染而改变，吸收减少，清除加速。甲氟喹在小量分泌在母乳中。它有一个长达约21天的消除半衰期，在疟疾中缩短到大约14天，可能是由于肠肝循环中断。甲氟喹在肝脏中代谢，并主要在胆汁和粪便中排泄。给药后，甲氟喹的药代动力学显示出手性选择性，与SR对映体相比，SR对映体的峰值血浆浓度和曲线下面积值更高，分布体积和总清除率更低。

Mefloquine is reasonably well absorbed from the gastrointestinal tract but there is marked interindividual variation in the time required to achieve peak plasma concentrations. ... Mefloquine undergoes enterohepatic recycling. It is approximately 98% bound to plasma proteins and is widely distributed throughout the body. The pharmacokinetics of mefloquine may be altered by malaria infection with reduced absorption and accelerated clearance. ... Mefloquine is excreted in small amounts in breast milk. It has a long elimination half-life of around 21 days, which is shortened in malaria to about 14 days, possibly because of interrupted enterohepatic cycling. Mefloquine is metabolized in the liver and excreted mainly in the bile and feces. Its pharmacokinetics show enantioselectivity after administration of the racemic mixture, with higher peak plasma concentrations and area under the curve values, and lower volume of distribution and total clearance of the SR enantiomer than its RS antipode.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

片剂与口服溶液的生物利用度比较超过85%。食物的存在显著提高了吸收的速度和程度，使生物利用度增加了大约40%。单次口服甲氟喹后，血浆浓度在6-24小时（中位数，大约17小时）达到峰值。最大血浆浓度（以ug/L为单位）大致相当于剂量（以毫克为单位），例如，单次1000毫克剂量产生的最大浓度约为1000ug/L。在每周一次250毫克的剂量下，7-10周后达到1000-2000ug/L的最大稳态血浆浓度。

The bioavailability of the tablet formulation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. Plasma concentrations peak 6-24 hours (median, about 17 hours) after a single oral dose of mefloquine. Maximum plasma concentrations in ug/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000 ug/L). At a dose of 250 mg once weekly, maximum steady state plasma concentrations of 1000-2000 ug/L are reached after 7-10 weeks.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

分布到血液、尿液、脑脊液和组织中；在红细胞中浓缩...

Distributed to blood, urine, CSF, and tissues; concentrated in erythrocytes...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在健康的成年人中，表观分布容积大约为20升/千克，这表明药物在组织中广泛分布。甲氟喹可能以红细胞与血浆浓度比值约2的比例在感染的红细胞中积累。蛋白质结合率约为98%。为了达到95%的预防效果，所需的甲氟喹血药浓度为620纳克/毫升。

In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes at an erythrocyte-to-plasma concentration ratio of about 2. Protein binding is about 98%. Mefloquine blood concentrations of 620 ng/mL are considered necessary to achieve 95% prophylactic efficacy.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• Allosteric inhibitors of thymidylate synthase
  申请人：UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INCORPORATED

  公开号：US10420761B2

  公开（公告）日：2019-09-24

  The current invention is directed to a class of compounds that inhibit the function of Thymidylate synthase. Thymidylate synthase inhibition was noted to result in inhibition of tumor cell grow and killing of tumor cells. Thymidylate synthase inhibition is, thus, useful for treatment of various types of cancers, including but not limited to, acute lymphoblatic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia, large cell immunoblastic lymphoma, plasmacytoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, brain cancer, lung cancer, central nervous system (CNS) cancer, melanoma, renal cancer, prostate cancer, colon cancer, ovarian cancer and breast cancer. The compounds disclosed herein can be used alone or in combination with other cancer treatment regimens (e.g., radiation therapy and/or other chemotherapeutic agents that are administered to a subject having a tumor, cancer or neoplasia).

  本发明涉及一类抑制胸苷酸合成酶功能的化合物。据指出，抑制胸腺苷酸合成酶可抑制肿瘤细胞生长并杀死肿瘤细胞。因此，胸苷酸合成酶抑制剂可用于治疗各种类型的癌症，包括但不限于急性淋巴细胞白血病（ALL）、急性髓性白血病（AML）、急性早幼粒细胞白血病、慢性淋巴细胞白血病（CLL）、慢性髓性白血病（CML）、急性单核细胞白血病（AMOL）、毛细胞白血病、大细胞免疫母细胞淋巴瘤、浆细胞瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、白血病、脑癌、肺癌、中枢神经系统（CNS）癌、黑色素瘤、肾癌、前列腺癌、结肠癌、卵巢癌和乳腺癌。本文公开的化合物可单独使用，也可与其他癌症治疗方案（如对患有肿瘤、癌症或新生物的受试者施用的放射治疗和/或其他化疗药物）联合使用。
• Molecular adjuvants for enhanced cytosolic delivery of active agents
  申请人：Universiteit Gent

  公开号：US11033572B2

  公开（公告）日：2021-06-15

  The present invention relates to a method and compositions for optimized intracellular delivery of active agents, in particular nucleic acids, using a specific class of adjuvants. The method and compositions of the invention enhance cytosolic release of the agents and can be used for the treatment of various disorders.

  本发明涉及一种使用特定类别佐剂优化活性剂（尤其是核酸）细胞内递送的方法和组合物。本发明的方法和组合物能增强药剂的细胞释放，可用于治疗各种疾病。
• USE OF (+)MEFLOQUINE FOR THE TREATMENT OF MALARIA
  申请人：Cerebrus Pharmaceuticals Limited

  公开号：EP0966285A1

  公开（公告）日：1999-12-29
• NOVEL ALLOSTERIC INHIBITORS OF THYMIDYLATE SYNTHASE
  申请人：UNIVERSITY OF FLORIDA RESEARCH FOUNDATION INCORPORATED

  公开号：US20160067240A1

  公开（公告）日：2016-03-10

  The current invention is directed to a class of compounds that inhibit the function of Thymidylate synthase. Thymidylate synthase inhibition was noted to result in inhibition of tumor cell grow and killing of tumor cells. Thymidylate synthase inhibition is, thus, useful for treatment of various types of cancers, including but not limited to, acute lymphoblatic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), hairy cell leukemia, large cell immunoblastic lymphoma, plasmacytoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, brain cancer, lung cancer, central nervous system (CNS) cancer, melanoma, renal cancer, prostate cancer, colon cancer, ovarian cancer and breast cancer. The compounds disclosed herein can be used alone or in combination with other cancer treatment regimens (e.g., radiation therapy and/or other chemotherapeutic agents that are administered to a subject having a tumor, cancer or neoplasia).
• MOLECULAR ADJUVANTS FOR ENHANCED CYTOSOLIC DELIVERY OF ACTIVE AGENTS
  申请人：Universiteit Gent

  公开号：US20190328768A1

  公开（公告）日：2019-10-31

  The present invention relates to a method and compositions for optimized intracellular delivery of active agents, in particular nucleic acids, using a specific class of adjuvants. The method and compositions of the invention enhance cytosolic release of the agents and can be used for the treatment of various disorders.