米帕林 | 83-89-6

• 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: 米帕林
• 中文别名: 阿的平；甲氯苯氯喹；疟涤平
• 英文名称: quinacrine
• 英文别名: mepacrine；4-N-(6-chloro-2-methoxyacridin-9-yl)-1-N,1-N-diethylpentane-1,4-diamine
• CAS: 83-89-6
• 化学式: C₂₃H₃₀ClN₃O
• mdl: MFCD00242796
• 分子量: 399.964
• InChiKey: GPKJTRJOBQGKQK-UHFFFAOYSA-N

物化性质

• 熔点：
  247-250 °C
• 沸点：
  557.1±50.0 °C(Predicted)
• 密度：
  1.0989 (rough estimate)
• 溶解度：
  甲醇（微溶）、水（微溶）
• 物理描述：
  Solid
• 颜色/状态：
  Bright yellow crystals
• 蒸汽压力：
  1.8X10-10 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Sensitive to light. /Quinacrine hydrochloride/
• 解离常数：
  pKa1 = 9.4; pKa2 = 10.7 (amines) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  37.4
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

少量未改变的药物被人类和其他动物消除（L型；显然D型被完全代谢）。已经发现了几种代谢物，但它们的结构存在一些争议。

Small amt of unchanged drug is eliminated (l-form; apparently d-form is metabolized completely) by man and other animals. Several metabolites have been found in small amt, but there is some disagreement as to their structure.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Mepacrine yields 6-chloro-9-(4-ethylamino-1-methylbutyl amino)-2-methoxyacridine in rabbits 美帕曲林在大鼠体内产生6-氯-9-(4-乙胺基-1-甲基丁基氨基)-2-甲氧基吖啶

Mepacrine yields 6-chloro-9-(4-ethylamino-1-methylbutyl amino)-2-methoxyacridine in rabbits

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

美帕拉明据报道可以导致血清酶水平升高，但此类变化的频率尚不清楚，通常在1到6周后出现，表现为多种酶水平升高，并在停药后1到2个月内恢复正常。大多数患者没有症状，肝酶升高可以在剂量调整或有时无需调整剂量的情况下解决。临床上明显的美帕拉明引起的肝损伤也有报道，但损伤的临床特征尚未明确界定。由于美帕拉明会导致皮肤变黄，因此黄疸不是一个可靠的发现，大多数关于美帕拉明引起的肝损伤的报告中并没有包括胆红素升高。尽管如此，有几例急性肝衰竭和死亡归因于美帕拉明治疗，尽管这些报告通常是在甲型、乙型和丙型肝炎检测可用之前，并且往往缺乏组织学证据。美帕拉明还与再生障碍性贫血的病例以及与史蒂文斯-约翰逊综合征相似的超敏反应和剥脱性皮炎有关，这些状况可能与严重的肝损伤有关。

Mepacrine has been reported to cause elevations in serum enzymes, but the frequency of such changes is unknown, arising after 1 to 6 weeks with a mixed pattern of enzyme elevations and resolving within 1 to 2 months of stopping. Most patients are asymptomatic and liver enzyme elevations can resolve with, and sometimes without dose modification. Clinically apparent liver injury from mepacrine has also been reported, but the clinical features of the injury have not been well defined. Because mepacrine causes a yellowing of the skin, jaundice is not a reliable finding and most reports of liver injury from mepacrine have not included bilirubin elevations. Nevertheless, several instances of acute liver failure and death have been attributed to mepacrine therapy, although the reports usually predated the availability of tests for hepatitis A, B and C and often lacked histological documentation. Mepacrine has also been implicated in cases of aplastic anemia and in hypersensitivity reactions with exfoliative dermatitis, suggestive of Stevens Johnson syndrome, conditions that can be associated with liver injury that may be severe.

来源:LiverTox

毒理性

• 相互作用

患者在接受奎纳克林和皮质类固醇的同时出现了惊厥性发作。/奎纳克林盐酸盐/

Convulsive seizures have occurred in patients receiving quinacrine and corticosteroids concomitantly. /Quinacrine hydrochloride/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

同时使用伯氨喹与喹吖因可能会抑制伯氨喹的代谢，或者将其从组织结合位点置换出来，从而增加伯氨喹的血清浓度和潜在毒性。

Concurrent use /of primaquine/ with quinacrine may inhibit the metabolism of primaquine or may displace if from tissue-binding sites, thereby increasing serum concentrations and potential toxicity of primaquine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

乙醛脱氢酶可能被喹吖因抑制，导致饮酒后乙醛积累，并可能产生类似“双硫仑”反应...

Aldehyde dehydrogenase may be inhibited by quinacrine, resulting in acummulation of acetaldehyde after alcohol ingestion and possibly "disulfram-like" reaction...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

对于过量用药的处理：推荐的处理方法包括以下内容：通过洗胃来排空胃部……使用苯二氮卓类药物或超短效巴比妥类药物控制癫痫。通过输液和血管收缩药物治疗休克……支持呼吸。实施支持性措施，如保持呼吸道畅通、呼吸和血液循环。密切观察至少6小时那些已经度过急性期并且无症状的幸存患者。

For treatment of overdose: Recommended treatment consists of the following: Evacuating the stomach by gastric lavage ... Controlling seizures with benzodiazepines or ultrashort-acting barbiturates. Treating shock by administration of fluids and vasopressors ... Supporting respiration. Administer supportive measure such as maintaining an open airway, breathing and circulation. Closely observing for at least 6 hours those patients who have survived the acute phase and are asymptomatic.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

经口服给药后，从胃肠道迅速吸收。

Absorbed rapidly from the gastrointestinal tract following oral administration.

来源:DrugBank

吸收、分配和排泄

经口服给药后，从胃肠道迅速吸收。经胸膜内给药后也迅速吸收。

Rapidly absorbed from the gastrointestinal tract following oral administration. Also rapidly absorbed after intrapleural administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

广泛分布；在肝脏、脾脏、肺部和肾上腺中浓度较高。肝脏中的浓度可能比血浆中高20,000倍。也沉积在皮肤、指甲和头发中。脑脊液（CSF）中的浓度是相应血浆水平的1%至5%。在大脑、心脏、骨骼肌和母乳中发现的浓度最低。

Widely distributed; concentrates in the liver, spleen, lungs, and adrenal glands. Concentration in the liver may be 20,000 times that in the plasma. Also deposited in skin, fingernails, and hair. Cerebrospinal fluid (CSF) concentration are 1 to 5% of corresponding plasma level. Lowest concentrations are found in the brain, heart, skeletal muscles, and breast milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

每天有不到11%通过尿液排出；尿液酸化可增加尿液中喹吖因的排泄量，增幅达14%；喹吖因排泄缓慢，在停用喹吖因后2个月或更长时间内，尿液中仍有显著量的药物排出。少量药物也会通过胆汁、汗液和唾液排出。

Less than 11% eliminated in the urine daily; acidification of urine increases urinary excretion of quinacrine by up to 14%; excreted slowly, significant amounts being excreted in the urine for 2 months or more after discontinuation of quinacrine. Small amounts also excreted in bile, sweat, and saliva.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

奎纳克林可穿过胎盘，胎儿组织中的药物浓度与母体相似。

Quinacrine crosses the placenta and concentrations of drugs in fetal tissue are similar to maternal concentrations.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R36/37/38
• 储存条件：
  通风、低温、干燥

制备方法与用途

类别：有毒物品

• 毒性分级：中毒
• 急性毒性：
  • 口服（小鼠）LD50：1320毫克/公斤
  • 皮下（小鼠）LD50：239毫克/公斤

可燃性危险特性：

• 可燃，燃烧时会产生有毒的氮氧化物和氯化物烟雾。病人用药可能引起再生障碍贫血。

储运特性：

• 通风、低温、干燥保存

灭火剂：

• 干粉、泡沫、沙土、二氧化碳、雾状水

反应信息

• 作为反应物：
  描述：

  米帕林 在 水 、 双氧水 作用下， 生成 Chinacrin-N^w-oxyd
  参考文献：
  名称：

  Elslager,E.F. et al., Journal of medicinal and pharmaceutical chemistry, 1962, vol. 5, p. 1159 - 1176

  摘要：

  DOI：
• 作为产物：
  描述：

  6-chloro-2,9-dimethoxyacridine 在 盐酸 、 甲醇 、 溶剂黄146 作用下， 生成 米帕林
  参考文献：
  名称：

  Kitani, Nippon Kagaku Zasshi, 1954, vol. 75, p. 475,476

  摘要：

  DOI：

文献信息

• [EN] SUBSTITUTED BENZYLAMINE COMPOUNDS, THEIR USE IN MEDICINE, AND IN PARTICULAR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION<br/>[FR] COMPOSÉS DE BENZYLAMINE SUBSTITUÉS, LEUR UTILISATION EN MÉDECINE, EN PARTICULIER DANS LE TRAITEMENT D'UNE INFECTION PAR LE VIRUS DE L'HÉPATITE C (VHC)
  申请人：ASTEX THERAPEUTICS LTD

  公开号：WO2013064538A1

  公开（公告）日：2013-05-10

  The invention provides compounds of the formula (I): or a salt, N-oxide or tautomer thereof, wherein A is CH, CF or nitrogen; E is CH, CF or nitrogen; and R0 is hydrogen or C1-2 alkyl; R1a is selected from CONH2; CO2H; an optionally substituted acyclic C1-8 hydrocarbon group; and an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S; R2 is selected from hydrogen and a group R2a; R2a is selected from an optionally substituted acyclic d-8 hydrocarbon group; an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1 or 2 ring members are heteroatom ring members selected from O, N and S; and an optionally substituted bicyclic heterocyclic group of 9 or 10 ring members, of which 1 or 2 ring members are nitrogen atoms; wherein at least one of R1 and R2 is other than hydrogen; R3 is an optionally substituted 3- to 10-membered monocyclic or bicyclic carbocyclic or heterocyclic ring containing 0, 1, 2 or 3 heteroatom ring members selected from N, O and S; R4a is selected from halogen; cyano; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy-C1-4 alkyl; and C1-2 alkoxy-C1-4 alkyl; R5 is selected from hydrogen and a substituent R5a; and R5a is selected from C1-2 alkyl optionally substituted with one or more fluorine atoms; C1-3 alkoxy optionally substituted with one or more fluorine atoms; halogen; cyclopropyl; cyano; and amino, The compounds have activity against hepatitis C virus and can be used in the prevention or treatment of hepatitis C viral infections.

  该发明提供了以下式（I）的化合物，或其盐、N-氧化物或互变异构体，其中A为CH、CF或氮；E为CH、CF或氮；R0为氢或C1-2烷基；R1a选自CONH2；CO2H；一个可选择取代的非环状C1-8碳氢化合物基团；以及一个可选择取代的含有3至7个环成员的单环碳环或杂环基团，其中0、1、2、3或4个是从O、N和S中选择的杂原子环成员；R2选自氢和一个基团R2a；R2a选自一个可选择取代的非环状d-8碳氢化合物基团；一个可选择取代的含有3至7个环成员的单环碳环或杂环基团，其中0、1或2个环成员是从O、N和S中选择的杂原子环成员；以及一个可选择取代的含有9或10个环成员的双环杂环基团，其中1或2个环成员是氮原子；其中R1和R2中至少一个不是氢；R3选自一个可选择取代的含有0、1、2或3个从N、O和S中选择的杂原子环成员的3至10个成员的单环或双环碳环或杂环环；R4a选自卤素；氰基；C1-4烷基，可选择取代一个或多个氟原子；C1-4烷氧基，可选择取代一个或多个氟原子；羟基-C1-4烷基；和C1-2烷氧基-C1-4烷基；R5选自氢和一个取代基R5a；R5a选自C1-2烷基，可选择取代一个或多个氟原子；C1-3烷氧基，可选择取代一个或多个氟原子；卤素；环丙基；氰基；和氨基。这些化合物对丙型肝炎病毒具有活性，并可用于预防或治疗丙型肝炎病毒感染。
• [EN] FUSED PYRAZOLE DERIVATIVES AS JAK INHIBITORS<br/>[FR] DÉRIVÉS DE PYRAZOLE CONDENSÉS UTILISÉS EN TANT QU'INHIBITEURS DE JAK
  申请人：ALMIRALL SA

  公开号：WO2017220431A1

  公开（公告）日：2017-12-28

  Novel fused pyrazole derivatives of Formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).

  公开了式（I）的新型融合吡唑衍生物；以及它们的制备方法，包含它们的药物组合物以及它们作为Janus激酶（JAK）抑制剂在治疗中的用途。
• CYCLOPROPYLAMINES AS LSD1 INHIBITORS
  申请人：Incyte Corporation

  公开号：US20150225379A1

  公开（公告）日：2015-08-13

  The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

  本发明涉及环丙胺衍生物，这些衍生物是LSD1抑制剂，可用于治疗癌症等疾病。
• [EN] NOVEL SMALL MOLECULE INHIBITORS OF TEAD TRANSCRIPTION FACTORS<br/>[FR] NOUVEAUX INHIBITEURS À PETITES MOLÉCULES DE FACTEURS DE TRANSCRIPTION TEAD
  申请人：MASSACHUSETTS GEN HOSPITAL

  公开号：WO2020190774A1

  公开（公告）日：2020-09-24

  The present disclosure compounds, as well as their compositions and methods of use. The compounds inhibit the activity of the TEAD transcription factor, and are useful in the treatment of diseases related to the activity of TEAD transcription factor including, e.g., cancer and other diseases.

  本公开涉及化合物及其组合物和使用方法。这些化合物抑制TEAD转录因子的活性，并可用于治疗与TEAD转录因子活性相关的疾病，例如癌症和其他疾病。
• [EN] TRICYCLIC TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY<br/>[FR] COMPOSÉS TRIAZOLES TRICYCLIQUES MODULANT L'ACTIVITÉ HSP90
  申请人：SYNTA PHARMACEUTICALS CORP

  公开号：WO2009139916A1

  公开（公告）日：2009-11-19

  The present invention relates to substituted tricyclic triazole compounds and compositions comprising substituted tricyclic triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

  本发明涉及替代三环三唑化合物和包含替代三环三唑化合物的组合物。该发明还涉及在需要的受体中抑制Hsp90活性的方法，以及预防或治疗高增殖性疾病（如癌症）的方法，其中包括向受体施用本发明的化合物或包含这种化合物的组合物。