氯喹 | 54-05-7

• 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
• 中文名称: 氯喹
• 中文别名: 氯喹盐基4-(4-二乙氨基-1-甲基丁氨基)-7-氯喹啉；氯喹盐基；4-(4-二乙氨基-1-甲基丁氨基)-7-氯喹啉
• 英文名称: Chloroquine
• 英文别名: chloroquinine；4-N-(7-chloroquinolin-4-yl)-1-N,1-N-diethylpentane-1,4-diamine
• CAS: 54-05-7
• 化学式: C₁₈H₂₆ClN₃
• mdl: MFCD00024009
• 分子量: 319.878
• InChiKey: WHTVZRBIWZFKQO-UHFFFAOYSA-N

物化性质

• 熔点：
  87°
• 沸点：
  475.41°C (rough estimate)
• 密度：
  1.0500 (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：
  WHITE TO SLIGHTLY YELLOW, CRYSTALLINE POWDER
• 气味：
  ODORLESS
• 味道：
  Bitter taste
• 蒸汽压力：
  5.0X10-9 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable to heat in solutions of pH 4.0 to 6.5 /Chloroquine Diphosphate/
• 解离常数：
  pKa = 10.1
• 碰撞截面：
  176.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2600;2610;2630;2637;2660;2578.2;2590;2660;2642.7

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  28.2
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

氯喹主要通过CYP2C8和CYP3A4去烷基化成N-脱乙基氯喹。它在较小程度上通过CYP3A5、CYP2D6去烷基化，而通过CYP1A1去烷基化的程度更小。N-脱乙基氯喹可以进一步去烷基化成N-双脱乙基氯喹，后者还可以进一步去烷基化成7-氯-4-氨基喹啉。

Chloroquine is N-dealkylated primarily by CYP2C8 and CYP3A4 to N-desethylchloroquine. It is N-dealkylated to a lesser extent by CYP3A5, CYP2D6, and to an ever lesser extent by CYP1A1. N-desethylchloroquine can be further N-dealkylated to N-bidesethylchloroquine, which is further N-dealkylated to 7-chloro-4-aminoquinoline.

来源:DrugBank

代谢

氯喹部分代谢；主要代谢物是去乙基氯喹。去乙基氯喹也具有抗疟疾活性，但活性略低于氯喹。双去乙基氯喹，是一种羧酸衍生物，以及其他几个未识别的小量代谢物也被形成。

Chloroquine is partially metabolized; the major metabolite is desethylchloroquine. Desethylchloroquine also has antiplasmodial activity, but is slightly less active than chloroquine. Bisdesethylchloroquine, which is a carboxylic acid derivative, and several other unidentified metabolites are also formed in small amounts.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏（部分），转化为活性去乙基化代谢物。主要代谢物是去乙基氯喹。

Hepatic (partially), to active de-ethylated metabolites. Principal metabolite is desethylchloroquine

来源:Hazardous Substances Data Bank (HSDB)

代谢

完全从胃肠道吸收。氯喹部分代谢；主要代谢物是去乙基氯喹。去乙基氯喹也具有抗疟疾活性，但活性略低于氯喹。双去乙基氯喹是一种羧酸衍生物，还有少量其他未识别的代谢物形成（A625）。 消除途径：氯喹的排泄相当缓慢，但可以通过酸化尿液来增加。 半衰期：1-2个月

Completely absorbed from gastrointestinal tract. Chloroquine is partially metabolized; the major metabolite is desethylchloroquine. Desethylchloroquine also has antiplasmodial activity, but is slightly less active than chloroquine. Bisdesethylchloroquine, which is a carboxylic acid derivative, and several other unidentified metabolites are also formed in small amounts (A625). Route of Elimination: Excretion of chloroquine is quite slow, but is increased by acidification of the urine. Half Life: 1-2 months

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

氯喹是一种白色或略带黄色的无味结晶性粉末，具有苦味。它几乎不溶于水，溶于氯仿、醚和稀酸。氯喹二磷酸盐是一种白色、苦味、结晶性粉末。氯喹硫酸盐也是一种白色、无味、苦味、结晶性粉末。羟氯喹是一种无色液体。 用途：适应症包括： - 疟疾：氯喹是预防和治疗由间日疟原虫、卵形疟原虫、疟原虫和敏感的恶性疟原虫引起的疟疾的首选药物。 - 阿米巴病：氯喹用于治疗肠道外阿米巴病（通常与阿米巴杀菌剂联合使用）。 - 盘状红斑狼疮和类风湿性关节炎（急性和慢性）的治疗。 - 氯喹还可用于治疗以下少见病症：阿米巴肝脓肿、迟发性皮肤卟啉病、日光性荨麻疹、慢性皮肤血管炎。 人类接触：主要风险和靶器官： - 氯喹的主要毒性作用与其对心脏的类似奎尼丁（膜稳定）作用有关。 - 其他急性效应包括呼吸抑制和严重的胃肠刺激。 临床表现总结： - 氯喹中毒的临床表现通常在摄入后一至三小时内迅速出现，包括： - 心脏异常：心跳停止、休克、传导障碍、室性心律失常。 - 神经系统症状：嗜睡、昏迷，有时伴有抽搐。 - 视觉障碍：不常见。 - 呼吸系统症状：呼吸暂停。 - 消化系统症状：严重的胃肠刺激；恶心、呕吐、痉挛、腹泻。 - 儿童对毒性作用特别敏感。 - 氯喹中毒的特征性症状包括：头晕、恶心、呕吐、腹泻、头痛、嗜睡、视力模糊、复视、失明、抽搐、昏迷、低血压、心源性休克、心跳停止和呼吸受损。 - 心电图（ECG）可能出现T波降低、QRS增宽、室性心动过速和心室颤动。 - 严重中毒时伴有低钾血症。 禁忌症： - 肝脏和肾脏功能受损、血液病、胃肠疾病、葡萄糖-6-磷酸脱氢酶（G-6-PD）缺乏、严重神经系统疾病、视网膜或视野改变。 - 氯喹不应与金盐或非那西丁联合使用。 进入途径： - 口服：口服吸收是中毒最常见的原因。 - 注射：注射给药后中毒罕见。 - 一例报告了一名42岁男性在静脉注射250毫克氯喹后死亡。 暴露途径的吸收： - 从胃肠道几乎完全吸收。 - 片剂的生物利用度为89%。 - 血浆浓度峰值在摄入后1.5至3小时达到。 暴露途径的分布： - 蛋白质结合：50%至65%。 - 氯喹在肾脏、肝脏、肺和脾脏中积累高浓度，并在含有黑色素的细胞（眼睛和皮肤）中强烈结合。 - 红细胞浓度是血浆浓度的五至十倍。 - 在肠壁中浓度非常低。 - 氯喹可通过胎盘。 暴露途径的生物半衰期： - 血浆终末半衰期为平均278小时或70至120小时。 - 儿童的血浆消除半衰期较短：75至136小时。 代谢： - 氯喹通过肝脏机制进行代谢。 - 主要活性代谢物是去乙基氯喹。 - 去乙基氯喹的血浆半衰期与氯喹相似。 暴露途径的消除： - 氯喹消除非常缓慢。在用310毫克治疗14天后的77天内，约55%通过尿液排出，19%通过粪便排出。 - 肾脏：尿液中约70%为未改变的氯喹，23%为去乙基氯喹。 - 氯喹可通过母乳排出。 毒动力学： - 氯喹的心脏毒性与其类似奎尼丁（膜稳定）作用有关。 - 氯喹具有负性肌力作用，抑制自发性舒张期去极化，减慢传导，延长有效不应期并提高电阈值。 - 这导致收缩力下降、传导能力受损、兴奋性降低，但可能出现异常刺激重入机制。 - 低钾血症：急性中毒时可能出现急性低钾血症。这可能与细胞膜渗透性直接作用于细胞内钾的转运有关。 - 神经系统症状：急性过量时的神经系统症状可能与中枢神经系统的直接毒性作用或由于循环衰竭或呼吸不足导致的脑缺血有关。 - 抗炎作用的机制尚不清楚。 毒性： - 人类数据：

IDENTIFICATION: Chloroquine is a white or slightly yellow, odorless crystalline powder with a bitter taste. Very slightly soluble in water, soluble in chloroform, ether and dilute acids. Chloroquine diphosphate is a white, bitter, crystalline powder. Chloroquine sulfate is a white, odorless, bitter, crystalline powder. Hydroxychloride chloroquine is a colorless liquid. Uses: Indications: Malaria: Chloroquine is the drug of choice for the prophylaxis and treatment of malaria caused by Plasmodium vivax. P. ovale, P. malariae and sensitive P. falciparum. Amebiasis: Chloroquine is used for the treatment of extraintestinal amebiasis (usually in combination with amebicides). Treatment of discoid lupus erythematosis and rheumatoid arthritis (acute and chronic). Chloroquine may be used for the treatment of these conditions. Other less common indications are: amebic liver abscess, porphyria cutanea tarda, solar urticaria, chronic cutaneous vasculitis. HUMAN EXPOSURE: Main risks and target organs: The main toxic effects of chloroquine are related to its quinidine-like (membrane stabilizing) actions on the heart. Other acute effects are respiratory depression and severe gastro-intestinal irritation. Summary of clinical effects: Toxic manifestations appear rapidly within one to three hours after ingestion and include: Cardiac disturbances: circulatory arrest, shock, conduction disturbances, ventricular arrhythmias. Neurological symptoms: drowsiness, coma and sometimes convulsions. Visual disturbances not uncommon. Respiratory symptoms: apnea. Gastrointestinal symptoms: severe gastrointestinal irritation; nausea, vomiting, cramps, diarrhea. Children are specially sensitive to toxic effects. Dizziness, nausea, vomiting, diarrhea, headache, drowsiness, blurred vision, diplopia, blindness, convulsions, coma, hypotension, cardiogenic shock, cardiac arrest and impaired respiration are the characteristic features of chloroquine poisoning. Electrocardiography (ECG) may show decrease of T wave, widening of QRS, ventricular tachycardia and fibrillation. Hypokalemia is associated with severe poisoning. Contraindications: Hepatic and renal function impairment, blood disorders, gastrointestinal illnesses, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, severe neurological disorders, retinal or visual field changes. Chloroquine should not be used in association with gold salts or phenylbutazone. Routes of entry: Oral: Oral absorption is the most frequent cause of intoxication. Parenteral: Intoxication after parenteral administration is rare. A fatal outcome reported was after 250 mg IV chloroquine in a 42-year-old man. Absorption by route of exposure: Readily and almost completely absorbed from the gastrointestinal tract. Bioavailability is 89% for tablets. Peak plasma concentration is reached 1.5 to 3 hours after ingestion. Distribution by route of exposure: Protein binding: 5O to 65%. Chloroquine accumulates in high concentrations in kidney, liver, lung and spleen, and is strongly bound in melanin-containing cells (eye and skin). Red cell concentration is five to ten times the plasma concentration. Very low concentrations are found in the intestinal wall. Crosses the placenta. Biological half-life by route of exposure: Plasma terminal half-life is mean 278 hours or 70 to 120 hours. Shorter plasma elimination half-lives have been reported in children: 75 to 136 hours. Metabolism: Chloroquine undergoes metabolism by hepatic mechanisms. The main active metabolite is desethylchloroquine. Plasma half-life of desethylchloroquine is similar to chloroquine. Elimination by route of exposure: Chloroquine is eliminated very slowly. About 55% is excreted in urine and 19% in feces within 77 days following therapy with 310 mg for 14 days. Kidney: in urine about 70% is unchanged chloroquine and 23% is desethylchloroquine. It is excreted in breast milk. Toxicodynamics: The cardiotoxicity of chloroquine is related to it quinidine-like (membrane/stabilizing) effects. Chloroquine has a negative inotropic action, inhibits spontaneous diastolic depolarization, slows conduction, lengthens the effective refractory period and raises the electrical threshold. This results in depression of contractility, impairment of conductivity, decrease of excitability, but with possible abnormal stimulus re-entry mechanism. Hypokalemia: Acute hypokalemia may occur in acute poisoning. It is probably related to intracellular transport of potassium by a direct effect on cellular membrane permeability. Neurological symptoms: Neurological symptoms in acute overdose may be related to a direct toxic effect on CNS or to cerebral ischemia due to circulatory failure or respiratory insufficiency. The mechanism of the anti-inflammatory effect is not known. Toxicity: Human data: Chloroquine has a low margin of safety; the therapeutic, toxic and lethal doses are very close. Fatalities have been reported in children after chloroquine overdoses. Interactions: Chloroquine toxicity may be increased by all drugs with quinidine-like effects. Combination with hepatotoxic or dermatitis-causing medication should be avoided, as well as with heparin (risk of hemorrhage) and penicillamine. Eye: Keratopathy and retinopathy may occur when large doses of chloroquine are used for long periods. Changes occurring in the cornea are usually completely reversible on discontinuing treatment; changes in the retina, pigmentary degeneration of the retina, loss of vision, scotomas, optic nerve atrophy, field defects and blindness are irreversible. Retinopathy is considered to occur when the total cumulative dose ingested exceeds 100 g. Blurring of vision, diplopia may occur with short-term chloroquine therapy and are reversible. ANIMAL/PLANT STUDIES: The following progression of ECG changes was observed in dogs with experimental overdosage: severe tachycardia preceded by loss of voltage and widening of QRS, followed by sinus bradycardia, ventricular tachycardia, ventricular fibrillation and finally asystole.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

氯喹对疟原虫的杀灭作用机制尚不完全清楚。与其他喹啉衍生物一样，人们认为它抑制了血红素聚合酶的活性。这导致自由血红素的积累，对寄生虫来说是有毒的。在红细胞内，疟原虫必须降解血红蛋白以获取必需氨基酸，这些氨基酸是寄生虫构建自身蛋白质和进行能量代谢所必需的。消化过程在寄生虫细胞的液泡中进行。 在这个过程中，寄生虫产生有毒且可溶的血红素分子。血红素部分由一个名为Fe(II)-原卟啉IX（FP）的卟啉环组成。为了避免被这种分子破坏，寄生虫将血红素生物结晶形成赫默佐因，这是一种无毒分子。赫默佐因作为不溶性晶体在消化液泡中积累。 氯喹通过简单扩散进入红细胞，占据寄生虫细胞和消化液泡。随后，由于消化液泡呈酸性（pH 4.7），氯喹质子化（变为CQ2+），因此无法通过扩散离开。氯喹封盖赫默佐因分子，阻止血红素的进一步生物结晶，从而导致血红素的积累。氯喹与血红素（或FP）结合形成所谓的FP-氯喹复合物；这个复合物对细胞极具毒性，并破坏膜功能。有毒FP-氯喹和FP的作用导致细胞裂解，最终导致寄生虫细胞的自我消化。实质上，寄生虫细胞沉溺于自己的代谢产物中。

The mechanism of plasmodicidal action of chloroquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. nside red blood cells, the malarial parasite must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasite cell. During this process, the parasite produces the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a non-toxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals. Chloroquine enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-Chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. In essence, the parasite cell drowns in its own metabolic products.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

尽管氯喹已经使用超过50年，但它很少与血清转氨酶升高或临床上明显的急性肝损伤有关联。在急性卟啉病和迟发型卟啉病患者中，氯喹可能触发急性发作，伴随发热和血清转氨酶升高，有时可能导致黄疸。羟氯喹不会引起这种反应，并且在卟啉病中似乎具有部分有益效果。在氯喹用于预防和管理COVID-19的临床试验中，没有报告肝毒性事件，而且在氯喹治疗期间血清酶升高的发生率较低，与接受安慰剂或标准治疗的患者的发生率相似。

Despite use for more than 50 years, chloroquine has rarely been linked to serum aminotransferase elevations or to clinically apparent acute liver injury. In patients with acute porphyria and porphyria cutanea tarda, chloroquine can trigger an acute attack with fever and serum aminotransferase elevations, sometimes resulting in jaundice. Hydroxychloroquine does not cause this reaction and appears to have partial beneficial effects in porphyria. In clinical trials of chloroquine for COVID-19 prevention and treatment, there were no reports of hepatotoxicity, and rates of serum enzyme elevations during chloroquine treatment were low and similar to those in patients receiving placebo or standard of care.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：氯喹

Compound:chloroquine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

氯喹口服溶液的生物利用度为52-102%，口服片的生物利用度为67-114%。静脉注射氯喹的Cmax达到650-1300µg/L，口服氯喹的Cmax达到65-128µg/L，Tmax为0.5小时。

Chloroquine oral solution has a bioavailability of 52-102% and oral tablets have a bioavailability of 67-114%. Intravenous chloroquine reaches a Cmax of 650-1300µg/L and oral chloroquine reaches a Cmax of 65-128µg/L with a Tmax of 0.5h.

来源:DrugBank

吸收、分配和排泄

• 消除途径

氯喹主要在尿液中排泄。50%的剂量以未改变的氯喹形式在尿液中回收，10%的剂量以脱乙基氯喹的形式在尿液中回收。

Chloroquine is predominantly eliminated in the urine. 50% of a dose is recovered in the urine as unchanged chloroquine, with 10% of the dose recovered in the urine as desethylchloroquine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

氯喹的分布容积为200-800L/kg。

The volume of distribution of chloroquine is 200-800L/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

氯喹的总血浆清除率为0.35-1L/小时/公斤。

Chloroquine has a total plasma clearance of 0.35-1L/h/kg.

来源:DrugBank

吸收、分配和排泄

氯喹在口服给药后从胃肠道迅速且几乎完全吸收，药物在1-2小时内达到血浆峰浓度。据报道，氯喹的血清浓度在个体间有相当大的差异。每日口服310毫克的氯喹，据报道可达到约0.125微克/毫升的血浆峰浓度。如果每周一次服用500毫克的氯喹，据报道药物的血浆峰浓度范围在0.15-0.25微克/毫升，而低谷浓度范围在0.02-0.04微克/毫升。一项研究的结果表明，氯喹可能表现出非线性剂量依赖性药代动力学。在这项研究中，单次口服500毫克氯喹的给药导致峰血清浓度为0.12微克/毫升，而单次口服1克药物的给药导致峰血清浓度为0.34微克/毫升。

Chloroquine is rapidly and almost completely absorbed from the GI tract following oral administration, and peak plasma concn of the drug are generally attained within 1-2 hr. Considerable interindividual variations in serum concn of chloroquine have been reported. Oral administration of 310 mg of chloroquine daily reportedly results in peak plasma concn of about 0.125 ug/mL. If 500 mg of chloroquine is administered once weekly, peak plasma concn of the drug reportedly range from 0.15-0.25 ug/mL and trough plasma concn reportedly range from 0.02-0.04 ug/mL. Results of one study indicate that chloroquine may exhibit nonlinear dose dependent pharmacokinetics. In this study, administration of a single 500 mg oral dose of chloroquine resulted in a peak serum concentration of 0.12 ug/mL, and administration of a single 1 g oral dose of the drug resulted in a peak serum concentration of 0.34 ug/mL.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933499090
• 危险性防范说明：
  P280,P305+P351+P338,P310
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  存储温度：0-10°C；应存放在惰性气体中，并避免与空气接触和加热。

制备方法与用途

根据您提供的信息，我将对氯喹及其相关药物进行一个总结：

1. 氯喹的化学性质：

• 外观：白色结晶性粉末。
• 熔点：193-195℃（磷酸盐）。
• 溶解度：易溶于水，不溶于乙醇、氯仿及乙醚。

2. 主要用途：

• 抗疟疾：主要用于控制疟疾病症的症状。
• 抗阿米巴病：可作为治疗阿米巴感染的药物使用。
• 自身免疫性疾病：对类风湿关节炎、红斑狼疮等有一定的疗效。

3. 制剂与规格：

• 磷酸氯喹注射液：80mg/2ml, 155mg/2ml, 200mg/5ml。
• 磷酸氯喹片剂：75mg, 0.25g。

4. 抗药性检测方法：

• 常用的实验室技术包括PCR扩增测序、突变特异性PCR检测等，用于研究间日疟原虫对氯喹的抗性。

5. 注意事项与相互作用：

• 心脏抑制：注射液不宜做肌注，儿童尤易引起。
• 与其他药物的相互作用：
  • 与保泰松、肝素或青霉胺合用可能增加毒性或出血风险。
  • 与伯氨喹合用可根治间日疟。
  • 与单胺氧化酶抑制剂、氟羟强的松龙等合用需谨慎。

6. 研究进展：

• 对于氯喹抗性的检测，分子生物学技术（如PCR扩增测序）成为研究焦点，有助于监测药物耐药情况及流行趋势。

总结

氯喹是一种多功能药物，在疟疾、阿米巴感染以及某些自身免疫性疾病的治疗中发挥重要作用。然而，其使用需谨慎，注意剂量和潜在的不良反应，并考虑与其他药物相互作用的风险。此外，随着抗药性的增加，分子生物学技术的应用越来越重要，以更准确地评估药物的效果及其耐药情况。

反应信息

• 作为反应物：
  描述：

  氯喹 在 bis(triphenylphosphine)nickel(II) chloride 二甲胺基甲硼烷 、 potassium carbonate 、 三苯基膦 作用下， 以 乙腈 为溶剂， 反应 16.0h， 以100%的产率得到N¹,N¹-diethyl-N⁴-(quinolin-4-yl)pentane-1,4-diamine
  参考文献：
  名称：

  低价镍络合物催化的芳基卤化物的轻度和选择性还原

  摘要：

  在温和的条件下，在CH 3 CN中当量Me 2 NH·BH 3和K 2 CO 3或Cs 2 CO 3的存在下，用催化量的（PPh 3）2 NiCl 2 + PPh 3处理芳基氯化物导致减少到相应的乘积。使用这种试剂组合，也可以选择性地还原芳基溴化物和碘化物。

  DOI：

  10.1016/s0040-4039(01)01522-2
• 作为产物：
  描述：

  3-氯苯胺 在 4,4'-二甲氧基-2,2'-联吡啶 、 氧气 、 copper diacetate 、 palladium diacetate 、 三甲基乙酸 作用下， 以 甲苯 为溶剂， 生成 氯喹
  参考文献：
  名称：

  Pd/Cu协同催化有氧脱氢芳构化制备4-氨基喹啉衍生物

  摘要：

  4-氨基喹啉部分广泛存在于各种生物活性化合物和市售药物中，而该目标结构的制备很大程度上依赖于4-氯喹啉的胺化。在此，基于有氧脱氢芳构化策略开发了原子和步骤经济程序。与众所周知的钯催化环己酮与胺的脱氢芳构化不同，协同 Pd/Cu 催化对于 2,3-二氢喹啉-4(1 H )-one 类型的底物至关重要。在优化条件下，一系列芳香族/脂肪族胺和2,3-二氢喹啉-4(1H ) -酮偶联，以中等到高收率得到相应的4-氨基喹啉产物，并应用当前的方法还展示了上市药物的制备和后期多样化。

  DOI：

  10.1021/acs.joc.3c01400
• 作为试剂：
  描述：

  二甲基亚砜 、 hemin 在 氯喹 作用下， 反应 24.5h， 生成 β-hematin DMSO solvate
  参考文献：
  名称：

  在氯喹（一种 β-血红素生长速率抑制剂）存在下生长的 β-血红素 DMSO 溶剂化物的单晶 X 射线结构

  摘要：

  溶剂化 β-血红素的单晶是从含有抗疟药氯喹（一种已知的 β-血红素形成抑制剂）的 DMSO 溶液中生长出来的。此外，还进行了采用仿生脂质-水乳液条件的动力学研究，以进一步研究氯喹和奎尼丁对 β-血红素形成的影响。扫描电子显微镜显示，β-血红素 DMSO 溶剂化物晶体的外部形态与疟疾色素（血红素）的外部形态几乎没有区别，单晶 X 射线衍射证实了铁（III）原卟啉的 μ-丙酸配位二聚体的存在九。相邻二聚体的游离丙酸官能团与包含的 DMSO 分子形成氢键，而不是形成羧酸二聚体。观察到的指数动力学使用 Avrami 方程建模，Avrami 常数等于 1。在两种药物的低浓度下观察到的 β-血红素形成率降低可以通过假设药物吸附到最快的位点的机制来解释β-血红素的生长面。这种行为是使用朗缪尔等温线建模的。较高浓度的药物导致 β-血红素的最终产量降低，并且推测药物诱导的铁 (III) 原卟啉 IX 不可逆

  DOI：

  10.1021/ja308741e

文献信息

• [EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
  申请人：GALAPAGOS NV

  公开号：WO2017012647A1

  公开（公告）日：2017-01-26

  The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.

  本发明公开了根据式（I）的化合物，其中R1、R3、R4、R5、L1和Cy如本文所定义。本发明还提供了该发明的化合物、制备该化合物的方法、包括相同化合物的药物组合物以及它们在过敏或炎症症状、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨周转障碍的疾病、先天软骨畸形和/或与IL6和/或干扰素过度分泌相关的疾病中的使用。本发明还提供了通过给予该发明的化合物来预防和/或治疗上述疾病的方法。
• [EN] COMPOUNDS AS MODULATORS OF TIGIT SIGNALLING PATHWAY<br/>[FR] COMPOSÉS MODULATEURS DE LA VOIE DE SIGNALISATION DE TIGIT
  申请人：AURIGENE DISCOVERY TECH LTD

  公开号：WO2018047139A1

  公开（公告）日：2018-03-15

  The present invention relates to compound of formula (I) as therapeutic agents to modulate the TIGIT signalling pathway. The invention also encompasses the use of the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by TIGIT.

  本发明涉及一种化合物，其化学式为（I），作为调节TIGIT信号通路的治疗剂。该发明还涵盖了利用化合物（I）或其立体异构体或其药学上可接受的盐来治疗由TIGIT介导的疾病或紊乱。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• 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。

表征谱图