苏式-甲氟喹盐酸盐 | 58737-31-8

• 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
• 中文名称: 苏式-甲氟喹盐酸盐
• 英文名称: (+)-threo-mefloquine
• 英文别名: mefloquine；(S)-[2,8-bis(trifluoromethyl)quinolin-4-yl]-[(2S)-piperidin-2-yl]methanol
• CAS: 58737-31-8；51744-85-5；53230-10-7
• 化学式: C₁₇H₁₆F₆N₂O
• 分子量: 378.317
• InChiKey: XEEQGYMUWCZPDN-WFASDCNBSA-N

物化性质

• 沸点：
  415.7±40.0 °C(Predicted)
• 密度：
  1.383±0.06 g/cm3(Predicted)
• 熔点：
  174-176 °C
• 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. 美氟奎在肝脏中被细胞色素P450系统广泛代谢。体外和体内研究强烈表明CYP3A4是主要的同种型。在人体中已经识别出两种美氟奎的代谢物。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，比美氟奎高出约50%，在2周后达到。此后，主要代谢物和美氟奎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）是母药物的3到5倍。另一种代谢物，一种醇，只存在于极少量。

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性粉末，被制成片剂。Mefloquine 是一种抗疟疾药物，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 菌株引起的疟疾。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天内最多达5250毫克）后，出现了眩晕、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 还与神经精神表现有关：焦虑、偏执、抑郁、幻觉和精神行为异常。这些症状在停用 Mefloquine 后很长时间内可能仍然持续。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效应的风险，患有活动性抑郁、近期抑郁史、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 ketoconazole 联合使用也可能增加这种风险。然而，尚未有报道称 Mefloquine 单一疗法会导致临床显著的 QTc 间期延长。几项对孕妇的研究表明，在怀孕期间使用 Mefloquine 治疗或预防不会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，在妊娠的前12-14周应谨慎使用 Mefloquine。动物研究：尽管对小鼠和大鼠进行的两年研究没有显示肿瘤增加，但 Mefloquine 确实产生了毒性效应。在一项研究中，大鼠在饮食中分别给予0、5、12.5或30毫克/千克/天的 Mefloquine，持续2年。在高剂量组中，两性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瘫痪，而雌性出现阴道出血增加、囊性卵巢和充满液体的扩张子宫。两性的肝酶和血尿素氮水平升高。在研究结束时，两性在眼、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，视网膜变性、晶状体混浊和/或视网膜水肿发生（严重程度在雌性中更高）。在中剂量组中观察到生殖器官的轻度病变和胆管增生。雄性在附睾和前列腺出现病变；在低剂量组的两性中观察到附睾上皮细胞的空泡化和肺泡状巨噬细胞以及骨骼肌变性。研究了 Mefloquine 引起神经效应的潜力，7周大的雌性大鼠单次口服给药。使用标准功能观察测试、自动开放领域测试、自动自发活动监测、梁跨越任务和组织病理学来监测 Mefloquine 诱导的神经效应。Mefloquine 诱导了与自发活动和运动功能障碍相关的终点的剂量相关变化，并导致特定脑干核（gracilis 核）的退化。仅在老鼠的正常睡眠阶段观察到自发性运动活动增加，这表明与 Mefloquine 诱导的睡眠障碍有关。Mefloquine 还在小鼠、大鼠和家兔中显示出致畸性。在一项研究中，通过胃管给药的方式给予大鼠最高100毫克/千克/天的 Mefloquine。在高剂量组中，大鼠的生长速度较慢，饲料消耗量较对照组少。胎儿体重减轻，顶臀长减少，外部可见软组织和骨骼缺陷的发生率增加；圆顶颅骨的发生率很高，脑积水的发生率很高；还观察到不完全骨化的顶骨、枕骨和颅骨。在类似的小鼠研究中，Mefloquine 在100和200毫克/千克/天的剂量下导致胎儿体重下降和腭裂高发生率。Mefloquine 还显示出对大鼠的雌雄两性都有生育能力的影响。在以下测试中未发现 Mefloquine 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

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：非常少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。哺乳期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，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: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

如果将伯氨喹与β受体阻滞剂、钙通道阻滞剂、胺碘酮、匹莫齐特、地高辛或抗抑郁药一起使用，可能会增加心律失常的风险；与氯喹和奎宁一起使用，也可能会增加抽搐的风险。当与氨苄西林、四环素和甲氧氯普胺一起使用时，伯氨喹的浓度会增加。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，甲氟喹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，甲氟喹的给药应至少在最后一剂后的12小时延迟。单独使用甲氟喹并未发现临床意义上的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%。单次口服剂量后，血浆浓度在6-24小时（中位数约为17小时）达到峰值。以微克/升为单位的最大血浆浓度大致等同于毫克剂量（例如，单次1000毫克剂量产生的最大浓度约为1000微克/升）。在每周一次250毫克的剂量下，7-10周后达到1000-2000微克/升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，表观分布容积约为20 L/kg，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约为2的比例在寄生的红细胞中积聚。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 ng/mL。

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)

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  4-溴-2,8-二(三氟甲基)喹啉	(2,8-bis-trifluoromethyl)-4-bromoquinoline	35853-45-3	C11H4BrF6N	344.054

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	(S)-tert-butyl 2-((R)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carboxylate	1309854-88-3	C22H24F6N2O3	478.435

反应信息

• 作为反应物：
  描述：

  苏式-甲氟喹盐酸盐 在 sodium tetrahydroborate 、 cerium(III) chloride 、 戴斯-马丁氧化剂 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 (S)-tert-butyl 2-((R)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carboxylate
  参考文献：
  名称：

  使用高对映选择性催化硼烷基烯异构化的所有四种甲喹喹立体异构体的简明合成和抗疟活性

  摘要：

  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。

  DOI：

  10.1002/anie.201303931
• 作为产物：
  描述：

  4-溴-2,8-二(三氟甲基)喹啉 在 正丁基锂 、 Crabtree's catalyst 、 (R,Rp)-1-(2-(diphenylphosphano)ferrocenyl)-1-(2-diphenylphosphanophenyl)-N,N-dimethylmethanamine 、 氢气 、 palladium diacetate 、 N,N-二甲基苯胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， -78.0~130.0 ℃ 、101.33 kPa 条件下， 反应 62.0h， 生成 苏式-甲氟喹盐酸盐
  参考文献：
  名称：

  使用高对映选择性催化硼烷基烯异构化的所有四种甲喹喹立体异构体的简明合成和抗疟活性

  摘要：

  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。

  DOI：

  10.1002/anie.201303931

文献信息

• [EN] ASYMMETRIC ALPHA FUNCTIONALIZATION AND ALPHA, ALPHA BISFUNCTIONALIZATION OF ALDEHYDES AND KETONES<br/>[FR] FONCTIONNALISATION EN ALPHA ET DOUBLE FONCTIONNALISATION EN ALPHA, ALPHA ASYMÉTRIQUES D'ALDÉHYDES ET DE CÉTONES
  申请人：UNIV DUKE

  公开号：WO2009131657A1

  公开（公告）日：2009-10-29

  The present invention relates, generally, to asymmetric α-functionalization and to asymmetric α,α-bisfunctionalization of ketones and aldehydes and, in particular, to chiral auxiliaries suitable for use in effecting such functionalizations and to methods of using same.

  本发明一般涉及不对称α-官能化和不对称α,α-双官能化的酮和醛，特别涉及适用于实现这种官能化的手性辅助剂以及使用相同的方法。
• Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine
  作者：Nina Schützenmeister、Michael Müller、Uwe M. Reinscheid、Christian Griesinger、Andrei Leonov

  DOI：10.1002/chem.201303403

  日期：2013.12.16

  an important anti‐malaria drug that is applied as a racemate of the erythro form. However, the (−)‐isomer induces psychosis, while the (+)‐enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations

  在这里，我们报告了甲氟喹的所有四个立体异构体的合成。Mefloquine（Lariam）是一种重要的抗疟疾药物，被用作赤型外消旋体。但是，（-）-对映体会引起精神病，而（+）-对映体不会产生这种不良副作用。有六种合成方法，其中五种导致错误的对映异构体，而这些合成方法的作者并未指出他们合成了错误的化合物。同时，物理化学研究正确地分配了绝对构型，并且考虑到这些结果的最后对映选择性合成提供了正确的绝对构型。由于各种合成方法都无法在以前的合成中提供正确的立体异构体，
• Methods and compositions for treating diseases associated with pathogenic proteins
  申请人：Chiang K. Peter

  公开号：US20070179123A1

  公开（公告）日：2007-08-02

  Methods and compositions are provided comprising a therapeutically effective amount of a compound of formula I wherein R 1-4 , W, X, Y and Z are as defined in the specification, for inhibiting and treating diseases and disorders associated with pathogenic proteins causing neurodegenerative diseases and amyloid diseases, such as protease resistant prion proteins (PrP Sc ) and those associated with transmissible spongiform encephalopathies (TSEs), Alzheimer's Disease, amyloidosis, and the like.

  提供了一种方法和组合物，包括公式I中化合物的治疗有效量，其中R1-4，W，X，Y和Z如规范中所定义，用于抑制和治疗与致病蛋白质相关的疾病和障碍，这些致病蛋白质导致神经退行性疾病和淀粉样疾病，如蛋白酶抵抗性朊病毒蛋白（PrPSc）和与可传播性海绵状脑病（TSEs），阿尔茨海默病，淀粉样变性等相关的蛋白质。
• Synthesis and antitubercular activity of new mefloquine-oxazolidine derivatives
  作者：Raoni S.B. Gonçalves、Carlos R. Kaiser、Maria C.S. Lourenço、Marcus V.N. de Souza、James L. Wardell、Solange M.S.V. Wardell、Adilson D. da Silva

  DOI：10.1016/j.ejmech.2010.09.024

  日期：2010.12

  In this work, we report the synthesis and the antitubercular evaluation of 16 new mefloquine derivatives, formed from reactions between mefloquine and benzaldehydes, with the activity expressed as the minimum inhibitory concentration (MIC) in μM. The compounds were non-cytotoxic and exhibited an important activity (12.6 μM). The appreciable activity of these compounds can be considered an important

  在这项工作中，我们报告了由甲氧喹与苯甲醛之间的反应形成的16种新型甲氧喹衍生物的合成和抗结核性评估，其活性表示为以μM为单位的最小抑制浓度（MIC）。这些化合物无细胞毒性，并显示出重要的活性（12.6μM）。这些化合物的明显活性可以被认为是合理设计抗结核化合物新药的重要发现。
• Crystalline forms of (+)- and (-) erythro-mefloquine hydrochloride
  申请人：Sinden Walter Kenneth

  公开号：US20070078161A1

  公开（公告）日：2007-04-05

  (+)- or (−)-erythro-Mefloquine hydrochloride can exist in four crystalline forms A, B, C and D, whereby form A is the most stable form. Form A can be directly produced in morphological forms like thick columns, cuboids, cubes and cube-like forms, which can be easily handled during processing and formulation. (+)- or (−)-eroryth-Mefloquine hydrochloride also forms solvates with acetone, methyl ethyl ketone and tetrahydrofuran.

  (＋)-或（－）-赤型甲氟喹盐酸盐可以以四种晶型A、B、C和D存在，其中A型是最稳定的晶型。A型可以直接形成厚柱形、长方体形、立方体形或类似立方体的形态，这些形态在加工和制剂过程中易于处理。（＋)-或(－)-赤型甲氟喹盐酸盐还可以与丙酮、甲乙酮和四氢呋喃形成溶剂化物。