伯氨喹 | 90-34-6

• 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
• 中文名称: 伯氨喹
• 中文别名: 伯喹；N-(6-甲氧基喹啉-8-基)戊-1,4-二胺
• 英文名称: Primaquine
• 英文别名: 4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine
• CAS: 90-34-6
• 化学式: C₁₅H₂₁N₃O
• mdl: MFCD00598906
• 分子量: 259.351
• InChiKey: INDBQLZJXZLFIT-UHFFFAOYSA-N

物化性质

• 熔点：
  25°C
• 沸点：
  bp0.2 175-179°
• 密度：
  1.0313 (rough estimate)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Viscous liquid
• 蒸汽压力：
  9.9X10-6 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Primaquine phosphate tablets should be stored in well-closed, light-resistant containers at a temperature less than 40 °C, preferably between 15-30 °C.
• 解离常数：
  pKa1 = 2.9 (aromatic amine); pKa2 = 4.2 (secondary amine); pKa3 = 9.9 (primary amine) (est)
• 保留指数：
  2315;2314

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  60.2
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

伯氨喹的主要代谢物是羧基伯氨喹，这种代谢物的血浆浓度远高于未改变的伯氨喹。

The principal metabolite of primaquine is carboxyprimaquine, and plasma concentrations of the metabolite greatly exceed those of unchanged primaquine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

尚不清楚/羧基伯氨喹/是否具有抗疟疾活性。

It is not known whether /carboxyprimaquine/ has antimalarial activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

伯氨喹迅速被代谢...已经识别出三种氧化代谢物...分别是8-(3-羧基-1-甲基丙氨基)-6-甲氧基喹啉、5-羟基伯氨喹和5-羟基-6-去甲基伯氨喹。羧基衍生物是人类血浆中主要的代谢物。单次剂量后，它在血浆中的浓度是伯氨喹的10倍以上；这种无毒代谢物也被消除得更慢，并且随着多次剂量而积累...这3种代谢物...的抗疟疾活性明显低于伯氨喹。然而，除了羧基衍生物外，它们通过体外形成高铁血红蛋白的溶血活性大于母化合物。

Primaquine is rapidly metabolized ... Three identified oxidative metabolites ... are 8-(3-carboxyl-1-methylpropylamino)-6-methoxyquinoline, 5-hydroxy primaquine, and 5-hydroxy-6-desmethylprimaquine. The carboxyl derivative is the major metabolite found in human plasma. After a single dose it reaches concentrations in plasma more than 10 times those of primaquine; this nontoxic metabolite also is eliminated more slowly and accumulates with multiple doses ... The 3 metabolites ... appear to have appreciably less antimalarial activity than does primaquine. However, except for the carboxyl derivative, their hemolytic activity, as assessed by formation of methemoglobin in vitro, is greater than that of the parent compound.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

磷酸伯氨喹用于治疗由恶性疟原虫引起的疟疾。伯氨喹是一种橙红色的无味结晶粉末，具有苦味，它在水中溶解，而在酒精、氯仿和醚中实际上不溶。为了消除恶性疟原虫、间日疟原虫和卵形疟原虫的一级和二级红细胞外期，以及仅限于疟疾疟原虫的一级红细胞外期形式，伯氨喹必须与4-氨基喹啉的全剂量一起给药。人类暴露：主要风险和靶器官：靶器官包括心血管系统、血液系统和消化系统。葡萄糖-6-磷酸脱氢酶（G6PD）缺乏的人在急性、剂量依赖性高铁血红蛋白血症和溶血性贫血中发生；还可能出现白细胞减少症或粒细胞缺乏症。治疗剂量下的不良反应通常是轻微的。临床效果总结：毒性表现包括心血管障碍，尤其是室性心律失常、腹部绞痛、呕吐、上腹部疼痛、头痛、混乱、发绀、高铁血红蛋白血症、白细胞增多或白细胞减少和贫血。对伯氨喹过敏的人可能会出现粒细胞减少症、急性溶血性贫血和急性溶血。禁忌症：在以下情况下给予伯氨喹时，应考虑风险与收益的平衡：在系统性疾病的急性发病患者中，表现为倾向粒细胞减少症（例如，患有类风湿性关节炎或红斑狼疮的患者）。能够抑制骨髓中的粒细胞元素（抗肿瘤药物、秋水仙碱、金盐、青霉胺、非那西丁、喹吖因）。对伯氨喹有既往特异质反应的人、有蚕豆病或急性溶血性贫血病史的人。有G6PD缺乏或NADH高铁血红蛋白还原酶缺乏的人；如果发生溶血，应立即停止使用伯氨喹。进入途径：口服：口服吸收是中毒的唯一常见原因。吸收方式：伯氨喹从胃肠道被迅速吸收。血浆浓度在摄入后1到3小时内达到峰值，但在24小时后几乎检测不到。据报道，相同剂量的伯氨喹在个体间的峰值血浆浓度存在显著差异。分布方式：伯氨喹广泛分布到人体组织中。大约75%的伯氨喹在血浆中与蛋白质结合，红细胞中的浓度很高。伯氨喹可以穿过胎盘，但尚不清楚是否在母乳中存在显著量。生物学半衰期：伯氨喹在健康成人的血浆消除半衰期为3.7到9.6小时。代谢：伯氨喹不受广泛的首次通过代谢的影响。然而，它很容易在肝脏代谢为三种代谢物：8-(3-羧基-1-甲基-丙基氨基)-6-甲氧基-喹啉、5-羟基伯氨喹和5-羟基-6-去甲基伯氨喹。羧基衍生物是血浆中的主要代谢物；在重复给药时积累，此时血浆浓度远高于未改变的伯氨喹。这些代谢物的抗疟疾活性明显低于伯氨喹，但它们产生高铁血红蛋白的活性，在体外评估时，大于母体化合物。消除方式：只有3.6%的伯氨喹剂量以未改变的药物形式被排泄。主要代谢物是羧基伯氨喹。作用方式：毒动力学：伯氨喹可能导致溶血和高铁血红蛋白血症。某些种族群体，特别是来自地中海盆地的群体，对这些影响更为敏感，G6PD缺乏的人对伯氨喹敏感。G6PD缺乏是遗传获得的；存在大量变体，其中缺乏的程度不同。因此，个体对伯氨喹的敏感性不同。G6PD是一种酶，通过维持还原型谷胱甘肽的细胞内储存，保护红细胞免受某些药物和化学品的直接氧化作用。在G6PD缺乏的人中，血红蛋白的氧化导致在细胞内沉淀，产生特征性的包涵体，称为海因茨小体；血红蛋白的进一步氧化还会导致高铁血红蛋白血症。自由基的生成增加，这也导致细胞损伤。这些效应最终导致溶血。药动力学：伯氨喹抗疟疾活性的确切机制尚未确定，但药物似乎能与疟原虫DNA结合并干扰其功能。人类数据：成人：磷酸伯氨喹的毒性是剂量依赖性的；每周给药（与氯喹联合）比每日给药的毒性小。即使在使用氯喹与伯氨喹联合预防疟疾的每周低剂量中，一些G6PD缺乏的人也可能出现严重的血液学反应。这主要发生在有家族或个人蚕豆病史的患者中。高铁血红蛋白血症在NADH高铁血红蛋白还原酶缺乏的人中更为常见。大约10%的G6PD缺乏的黑人人口在每日剂量水平为15毫克（基础）及以上时因血管

IDENTIFICATION: Primaquine phosphate is used to treat malaria caused by Plasmodium virax. Primaquine is an orange-red, odorless crystalline powder which has a bitter taste It is soluble in water and it is practically insoluble in alcohol, chloroform and ether. For elimination of primary and secondary exoerythrocytic stages of Plasmodium vivax, Plasmodium malariae and Plasmodium ovale and the primary exoerythrocytic forms only of Plasmodium falciparum. Primaquine must always be given in conjunction with full doses of a 4-aminoquinoline. HUMAN EXPOSURE: Main risks and target organs: Target organs are: cardiovascular, hematological system, and gastrointestinal. Acute, dose-dependent methemoglobinemia and hemolytic anemia occurs in persons with a deficiency of glucose-6-phosphate dehydrogenase (G6PD); leucopenia or agranulocytosis may also occur. Adverse effects with therapeutic doses are usually mild. Summary of clinical effects: Toxic manifestations include cardiovascular disturbances, especially ventricular dysrhythmias, abdominal cramps, vomiting, burning epigastric distress, headache, confusion, cyanosis, methemoglobinemia, leucocytosis or leucopenia, and anemia. Granulocytopenia, acute hemolytic anemia and acute hemolysis may occur in individuals who are hypersensitive to primaquine. Contraindications: The balance of risk and benefit should be considered when primaquine is administered under the following conditions: in acutely ill patients suffering from systemic disease characterized by a tendency to granulocytopenia (for example, patients with arthritis or lupus erythematosus). Agents capable of depressing the myeloid elements of the bone marrow (antineoplastic agents, colchicine, gold salts, penicillamine, phenylbutazone, quinacrine). Individuals who have shown previous idiosyncratic reaction to primaquine, individuals with a history of favism or acute haemolytic anaemia. Individuals with G6PD deficiency or NADH methemoglobin reductase deficiency; primaquine should be discontinued immediately if hemolysis occurs. Routes of entry: Oral: Oral absorption is the only common cause of intoxication. Absorption by route of exposure: Primaquine is readily absorbed from the gastrointestinal tract. The plasma concentration peaks within 1 to 3 hr after ingestion but is negligibly low after 24 hr Considerable inter-individual variation in peak plasma concentrations of primaquine has been reported with the same dose of the drug. Distribution by route of exposure: Primaquine is extensively distributed into body tissues. About 75% of primaquine in plasma is bound to proteins and high concentrations occur in erythrocytes. Primaquine crosses the placenta but it is uncertain whether significant amounts occur in breast milk. Biological half-life by route of exposure: Primaquine has a plasma elimination half-life of 3.7 to 9.6 hr in healthy adults. Metabolism: Primaquine is not subject to extensive first pass metabolism. However, it is readily metabolized in the liver to three metabolites: 8-(3-carboxyl-1-methyl-propylamino)-6-methoxy-quinoline, 5-hydroxy primaquine and 5-hydroxy-6-desmethyl-primaquine. The carboxyl derivative is the major metabolite found in plasma; it accumulates during repeated administration, when the plasma concentration greatly exceeds that of unchanged primaquine. These metabolites have appreciably less antimalarial activity than primaquine but their haemolytic activity, as assessed by formation of methemoglobin in vitro, is greater than that of the parent compound. Elimination by route of exposure: Only 3.6% of the dose of primaquine is excreted as unchanged drug. The principal metabolite is carboxyprimaquine. Mode of action: Toxicodynamics: Primaquine may cause hemolysis and methemoglobinemia. Certain ethnic groups, especially those arising in the Mediterranean basin, are more susceptible to these effects and primaquine sensitivity occurs in persons with G6PD deficiency. G6PD deficiency is genetically acquired; there are a large number of variants in which the extent of the deficiency differs. The sensitivity of individuals to primaquine therefore varies. G6PD is an enzyme which protects the erythrocyte from the direct oxidative effects of some drugs and chemicals by maintaining intracellular stores of reduced glutathione. In people who are G6PD deficient, oxidation of hemoglobin leads to precipitation within the cell, producing characteristic inclusions called Heinz bodies; increased oxidation of hemoglobin also produces methemoglobinemia. There is an increase in the generation of free radicals which also contribute to cellular damage. These effects ultimately cause hemolysis. Pharmacodynamics: The exact mechanism of anti-malarial activity of primaquine has not been determined, but the drug appears to bind to plasmodial DNA and interfere with its function. Human data: Adults: The toxicity of primaquine phosphate is dose-dependent; weekly administration (in combination with chloroquine) is less toxic than daily administration. Serious hematologic reactions may occur in some people with a G6PD deficiency even at the low weekly doses of primaquine used in combination with chloroquine for the prophylaxis of malaria. This occurs primarily in patients with a family or personal history of favism. Methemoglobinemia is more common in individuals with nicotinamide adenine dinucleotide methemoglobin reductase deficiency. About 10% of the black population with G6PD deficiency develop anaemia due to intravascular hemolysis at daily dose levels of 15 mg (base) and higher. Some darker-skinned Mediterranean populations are more sensitive than blacks. Teratogenicity: No reports are available to associate primaquine with congenital defects. Interactions: Primaquine should not be administered concurrently with any other drug that is likely to induce hemolysis or bone marrow depression (see section 4.3) as this may increase the risk of toxicity. Concurrent use of primaquine with bone marrow depressants may increase the risk of leukopenia. If concurrent use is essential, close observation for myelotoxicity should be considered. The toxicity of primaquine appears to be potentiated by antimalarial agents that are structurally similar (for example, quinacrine). Primaquine should not be administered to patients who have received quinacrine within the previous 3 months. Although primaquine inhibits the elimination of drugs which undergo oxidative metabolism (for example, antipyrine), therapeutic doses have no effect on paracetamol metabolism. The combination of chloroquine and primaquine with dapsone may prevent hemolysis in G6PD deficient subjects. The antimalarial effects of quinacrine and primaquine in various test organisms are synergistic with many antibiotics. After administration of primaquine, the metabolism of antipyrine (calculated from 0 to 24 h) to its 3 main metabolites, 3 hydroxymethyl-antipyrine, 4 hydroxy-antipyrine and norantipyrine, is significantly reduced. There is no selective effect on a particular metabolic pathway. Main adverse effects: Gastrointestinal tract: Dose-related gastrointestinal symptoms include anorexia, nausea, vomiting, epigastric distress, and abdominal cramps. Hematological system: Acute hemolytic anemia occurs most frequently in G6P Ddeficient individuals. It is usually self-limiting but in severe cases blood transfusion may be necessary. Methemoglobinemia, agranulocytosis, granulocytopenia and leucopenia are also reported. Methemoglobinemia can be severe in people who are nicotinamide dinucleotide (NADH) methemoglobin reductase deficient. Cardiovascular system: Hypertension and arrhythmias have been reported. Other: Headache, interference with visual accommodation and pruritus have been reported with primaquine. Adverse CNS effects, including depression and confusion, can also occur. Clinical effects: Acute poisoning: Ingestion: Toxic manifestations such as methemoglobinemia and cyanosis occur in most subjects; adverse gastrointestinal effects occur at higher doses. These doses also cause severe hematologic reactions such as leucopenia, anemia and intravascular hemolysis. Chronic poisoning: Ingestion: The adverse effects associated with chronic administration are similar to those which occur in acute poisoning. Course, prognosis, cause of death: Course: Commonly, symptoms of overdoses are nausea, abdominal pain, sometimes vomiting and jaundice. Hemolytic anemia may occur in G6PD deficiency but is usually self-limiting. Prognosis: If patient survives for 48 h recovery is likely. Death: Cardio-circulatory arrest may occur within 1 to 2 h of ingestion due to ventricular dysrhythmia or asystole. Hypotension is common and may progress rapidly to cardiogenic shock with increased central venous pressure. Hypertension and cardiac arrhythmias have been reported on rare occasions. Systematic description of clinical effects Cardiovascular: Based on its anti-arrhythmic activity in mice, primaquine is predicted to have quinidine like cardiotoxicity. Hypertension and cardiac arrhythmias have been reported on rare occasions. Respiratory: Respiratory arrest secondary to circulatory arrest or severe shock may occur within 1 to 2 hr following overdose. Neurological: CNS: In severe cases, headache, mental depression and confusion occur, especially in persons with prior exposure to chloroquine. Gastrointestinal: Abdominal cramps and epigastric distress have been reported. Hepatic: Hepatic function is unaffected. Dermatological: Pruritus and urticaria. Eye, ear, nose, throat: local effects: Diplopia; visual disturbances; blurred vision; irreversible changes to the cornea and retina; optic neuritis. Hematological: Toxic doses of primaquine induce marked bone marrow depression, methemoglobinemia, agranulocytosis and hemolytic anemia. Hemolytic anemia is commonest in persons with G6PD deficiency. The effects are more pronounced in the B-type G6PD deficiency (the Mediterranean type) than in the A-type (the type mainly present among black American and African populations) Immunological: Primaquine may also cause immunosuppression Metabolic: Fluid and electrolyte disturbances: Hypokalemia is common in severe intoxication. Others: Hypo- or hyperthermia and hypo- or hyperglycemia have been reported. Special risks: Pregnancy: Primaquine should be withheld from women with G6PD deficiency who are pregnant. If prophylaxis or treatment is essential, the possible benefits should outweigh the potential risks. Transplacental transfer of primaquine to a fetus with G6PD deficiency may result in life-threatening anemia and methemoglobinemia in utero. Breast-feeding: It is not known whether primaquine is excreted in breast milk. However, problems in man have not been documented. Enzyme deficiency: Primaquine should be used with caution in patients with G6PD deficiency who are receiving other drugs likely to induce hemolysis, (for example, nitrites, sulfonamides). /Primaquine phosphate/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

尽管使用了超过50年，伯氨喹并未与显著血清转氨酶升高或临床明显的急性肝损伤有关联。伯氨喹可能会在患有G6PD缺乏症的患者中引起溶血，这可能导致轻度黄疸。

Despite use for more than 50 years, primaquine has not been linked to significant serum aminotransferase elevations or to clinically apparent acute liver injury. Primaquine can cause hemolysis in patients with G6PD deficiency, which can result in mild jaundice.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：伯氨喹

Compound:primaquine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

迅速吸收；生物利用度大约为96%。

Rapidly absorbed; Bioavailability is approximately 96%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

伯氨喹从胃肠道吸收良好。口服给药后，药物在血浆中的峰值浓度通常在6小时内达到；24小时后血浆浓度通常可以忽略不计。据报道，相同剂量的伯氨喹在个体间峰值血浆浓度存在较大差异。

Primaquine is well absorbed from the GI tract. Following oral administration, peak plasma concentrations of the drug generally are attained within 6 hours; plasma concentrations generally are negligible after 24 hours. Considerable interindividual variation in peak plasma concentrations of primaquine have been reported with the same dose of the drug.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尽管关于伯氨喹在身体组织和液体中的分布的具体信息不可用，但药物在口服给药后似乎在体内广泛分布。伯氨喹在健康成年人中的表观分布容积约为150至250升。

Although specific information on the distribution of primaquine into body tissues and fluids is not available, the drug appears to be widely distributed in the body following oral administration. Primaquine has an apparent volume of distribution of about 150 to 250 L in healthy adults.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

广泛分布；在一项研究中，接受每日15毫克（碱基）治疗14天的患者的全血与血浆分布比率为0.93。

Extensively distributed; ... the whole-blood-to-plasma distribution ratio was 0.93 in one study of patients being treated with 15 mg (base) daily for 14 days.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933499090
• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  | 2-8°C |

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Primaquine
Synonyms: N-(6-Methoxyquinolin-8-yl)pentane-1,4-diamine

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Primaquine
CAS number: 90-34-6

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C15H21N3O
Molecular weight: 259.4

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

化学性质
这是一种粘性的液体，沸点在175-179℃（0.0266kPa）时会挥发，能溶解于醚中。其磷酸盐（C15H21N3O·2H3PO4，[63-45-6]）则表现为橙红色的结晶性粉末，熔点为197-198℃。这种物质不溶于氯仿或乙醚，但能溶解于水中，其水溶液呈酸性反应。无特殊气味，味道微苦。

用途
伯氨喹对间日疟原虫红外期及各型疟原虫配子体有较强的杀虫效果，是根治间日疟疾与阻断各型疟疾传播的有效药物。然而，它对红内期裂殖体的作用较弱，尤其是对于恶性和三日疟原虫的红内期裂殖体完全无效，因此不能用于控制症状。伯氨喹主要用于预防和控制间日疟与三日疟的复发及传播，以及防止恶性疟疾的传播。

反应信息

• 作为反应物：
  描述：

  伯氨喹 在 sodium dithionite 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 1-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-3-(3,3,3-trifluoro-2-hydroxypropyl)urea
  参考文献：
  名称：

  第二代伯氨喹脲和双脲作为潜在的抗分枝杆菌药。

  摘要：

  摘要在这里，我们描述了十二个新颖的化合物的设计和合成，这些化合物带有伯氨喹和通过尿素或双脲间隔基连接的羟基或卤代胺。尿素3a - f的制备开始于将伯氨喹啉转化为苯并三唑并2，然后在微波辐射下，通过4-（2-氨基乙基）苯酚或带有氟原子，环烷基或三氟甲基的氨基醇对后一种化合物进行氨解。导致双脲6a - f的四个步骤包括制备苯并三唑2和两个中间体氨基脲4和苯并三唑双脲5。用相同的氨基苯酚或氨基醇进行氨解后，得到标题化合物。抗分枝杆菌筛选检测到了三种抗海洋分枝杆菌和结核分枝杆菌的活性化合物，即3b，3f和6f，它们分别来自环丁基氨基醇或氨基酚。 图形概要

  DOI：

  10.1007/s11030-018-9899-z
• 作为产物：
  描述：

  8-[4-(2-ethoxycarbonylmethoxycarbonyl)amino-1-methylbutylamino]-6-methoxyquinoline 在 sodium hydroxide 作用下， 以 水 、 乙腈 为溶剂， 生成 伯氨喹
  参考文献：
  名称：

  基于氨基甲酸酯的伯氨喹前药的方法：抗疟疾活性，化学稳定性和酶促活化

  摘要：

  合成了抗疟疾药物伯氨喹的O-烷基和O-芳基氨基甲酸酯衍生物，作为潜在的前药，可以防止非活性代谢产物羧基伯氨喹的氧化脱氨作用。既ø -烷基和ö -芳基氨基甲酸盐进行水解在碱性和pH为7.4的磷酸盐缓冲液为母药，与ö -芳基氨基甲酸盐是约 10 6 –10 10比其O-烷基对应物更具反应性。在人血浆Ø烷基氨基甲酸酯是稳定的，而与此相反的Ø芳基对应物迅速释放出相应的苯酚产物，而伯氨喹在较长的孵育时间内仅缓慢释放。人体血浆中O-芳基氨基甲酸酯的活化似乎由丁酰胆碱酯酶（BuChE）催化，该酶导致酶催化丝氨酸的氨基甲酰化，随后发生缓慢的酶再活化和母体药物释放。在大鼠肝匀浆中，大多数O-芳基和O-烷基氨基甲酸酯被激活，半衰期为9至15小时，而4-硝基苯基氨基甲酸酯的水解速度太快，无法确定准确的速率常数。使用由伯氏疟原虫，Balb C小鼠和斯蒂芬斯按蚊（Anopheles stephensi）蚊子。与对照

  DOI：

  10.1016/j.bmc.2011.11.059

文献信息

• Quinolone-based compounds, formulations, and uses thereof
  申请人：Manetsch Roman

  公开号：US10000452B1

  公开（公告）日：2018-06-19

  Provided herein are quinolone-based compounds that can be used for treatment and/or prevention of malaria and formulations thereof. Also provided herein are methods of treating and/or preventing malaria in a subject by administering a quinolone-based compound or formulation thereof provided herein.

  本文提供了基于喹诺酮的化合物，可用于治疗和/或预防疟疾及其配方。本文还提供了通过给予本文提供的基于喹诺酮的化合物或配方来治疗和/或预防受试者疟疾的方法。
• [EN] AZADECALIN DERIVATIVES AS INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION<br/>[FR] DÉRIVÉS D'AZADÉCALINE EN TANT QU'INHIBITEURS DE LA RÉPLICATION DU VIRUS DE L'IMMUNODÉFICIENCE HUMAINE
  申请人：VIIV HEALTHCARE UK (NO 5) LTD

  公开号：WO2018002848A1

  公开（公告）日：2018-01-04

  Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, azadecaline derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula (I). These compounds are useful for the treatment of HIV and AIDS.

  具有药物和生物影响特性的化合物，其药物组合物和使用方法已列出。具体来说，提供了具有独特抗病毒活性的阿扎德卡林衍生物，作为HIV成熟抑制剂，如化合物(I)的公式所代表的那样。这些化合物对于治疗HIV和艾滋病是有用的。
• Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
  申请人：D'Sidocky Neil R.

  公开号：US20080242694A1

  公开（公告）日：2008-10-02

  Provided herein are Heterocyclic Compounds having the following structure: wherein R 1 , R 2 , X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.

  本文提供具有以下结构的杂环化合物： 其中R1、R2、X、Y和Z如本文所定义，包含有效量杂环化合物的组合物，以及治疗或预防癌症、炎症性疾病、免疫疾病、代谢性疾病以及通过给予患者需要的有效量杂环化合物来抑制激酶途径治疗或预防的疾病的方法。
• [EN] HETEROCYCLIC AMIDES USEFUL AS PROTEIN MODULATORS<br/>[FR] AMIDES HÉTÉROCYCLIQUES UTILES EN TANT QUE MODULATEURS DE PROTÉINE
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2017175147A1

  公开（公告）日：2017-10-12

  Disclosed are compounds having the formula (I-N), wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof.

  揭示了具有化学式（I-N）的化合物，其中q、r、s、A、B、C、RA1、RA2、RB1、RB2、RC1、RC2、R3、R4、R5、R6、R14、R15、R16和R17如本文所定义，或其互变异构体，或其盐，特别是其药用可接受盐。
• [EN] MODULATORS OF STIMULATOR OF INTERFERON GENES (STING) USEFUL IN TREATING HIV<br/>[FR] MODULATEURS DE STIMULATEUR DES GÈNES (STING) D'INTERFÉRON UTILES DANS LE TRAITEMENT DU VIH
  申请人：GLAXOSMITHKLINE IP DEV LTD

  公开号：WO2019069269A1

  公开（公告）日：2019-04-11

  Disclosed are compounds having the formula: (I-N) wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof, along with combinations thereof, all of which are useful in HIV therapies.

  揭示了具有以下式的化合物：(I-N)其中q、r、s、A、B、C、RA1、RA2、RB1、RB2、RC1、RC2、R3、R4、R5、R6、R14、R15、R16和R17如本文所定义，或其互变异构体，或其盐，特别是其药用可接受盐，以及其组合物，所有这些在HIV疗法中是有用的。

表征谱图