fluvastatin | 93957-54-1

• 物质功能分类: 原料药 - 循环系统用药 - 调节血脂药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: fluvastatin
• 英文别名: fluvastatin acid；Lescol；(E,3S,5R)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoic acid
• CAS: 93957-54-1；93957-55-2
• 化学式: C₂₄H₂₆FNO₄
• 分子量: 411.473
• InChiKey: FJLGEFLZQAZZCD-JUFISIKESA-N

物化性质

• 熔点：
  193.9-196.9 °C
• 沸点：
  681.8±55.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)
• 溶解度：
  水 25 mg/ml DMSO 100 mg/ml 乙醇 25 mg/ml
• 物理描述：
  Solid
• 蒸汽压力：
  1.91X10-16 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions. /Fluvastatin sodium hydrate/
• 分解：
  Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), hydrogen fluoride, sodium oxides. /Fluvastatin sodium hydrate/
• 解离常数：
  pKa = 4.5 (carboxy) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  82.7
• 氢给体数：
  3
• 氢受体数：
  5

ADMET

代谢

主要通过在吲哚环的5位和6位进行羟基化，分别转化为5-羟基氟伐他汀和6-羟基氟伐他汀。N-脱烷基化生成N-脱异丙基氟伐他汀，以及侧链的β-氧化也发生。主要由CYP2C9同种物系统（75%）代谢，其次为CYP3A4（约20%）和CYP2C8（约5%）。羟基化代谢物保留了一些药理活性，但以结合物（葡萄糖苷酸和硫酸盐）的形式存在于血液中，并通过胆汁迅速排入粪便。氟伐他汀的两个对映异构体以相似的方式代谢。氟伐他汀还通过UGT酶发生葡萄糖苷酸化。

Undergoes hepatic metabolism primarily via hydroxylation of the indole ring at the 5- and 6-positions to 5-hydroxy fluvastatin and 6-hydroxy fluvastatin, respectively. N-dealkylation to N-desisopropyl fluvastatin and beta-oxidation of the side chain also occurs. Metabolized primarily by the CYP2C9 isozyme system (75%), and to a lesser extent by CYP3A4 (~20%) and CYP2C8 (~5%). Hydroxylated metabolites retain some pharmcological activity, but are present as conjugates (glucuronides and sulfates) in the blood and are rapidly eliminated via bile into feces. Both enantiomers of fluvastatin are metabolized in a similar manner. Fluvastatin also undergoes glucuronidation via UGT enzymes.

来源:DrugBank

代谢

体外数据表明，氟伐他汀的代谢涉及多种细胞色素P450（CYP）同工酶。CYP2C9同工酶主要参与氟伐他汀的代谢（约75%），而CYP2C8和CYP3A4同工酶的参与程度则要低得多，即分别大约为5%和大约20%。

In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氟伐他汀在肝脏中被代谢，主要是通过吲哚环在5和6位置的羟基化。N-脱烷基化和侧链的β-氧化也有发生。羟基代谢物具有一些药理活性，但不会在血液中循环。氟伐他汀有两个对映异构体。氟伐他汀的两个对映异构体以相似的方式被代谢。

Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5 and 6 positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner.

来源:Hazardous Substances Data Bank (HSDB)

代谢

非诺伐他汀已知的人体代谢物包括N-去异丙基非诺伐他汀、6-羟基非诺伐他汀和5-羟基非诺伐他汀。

Fluvastatin has known human metabolites that include N-Deisopropyl-fluvastatin, 6-hydroxy-fluvastatin, and 5-hydroxy-fluvastatin.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

识别和使用：氟伐他汀是一种抗胆固醇药物和羟甲戊二酸辅酶A还原酶抑制剂。人类暴露和毒性：已经报道了氟伐他汀胶囊和其他同类药物导致的横纹肌溶解伴急性肾功能衰竭。在接受他汀类药物，包括氟伐他汀治疗的患者中，有罕见报告肝衰竭，包括致命和非致命的情况。如果在氟伐他汀治疗期间出现严重的肝损伤、临床症状和/或高胆红素血症或黄疸，请立即中断治疗。氟伐他汀胶囊禁用于可能怀孕或已经怀孕的妇女。在正常怀孕期间，血清胆固醇和甘油三酯水平会升高，胆固醇或胆固醇衍生物对胎儿发育至关重要。给孕妇使用氟伐他汀胶囊可能会对胎儿造成伤害。药物不良反应报告已经证实，与statin治疗相关的神经精神反应的发生。它们包括行为改变；认知和记忆障碍；睡眠障碍；和性功能障碍。动物研究：在0.3、15和30毫克/千克/天的剂量水平下对小鼠进行的致癌性研究显示，在30毫克/千克/天的雄性和雌性以及15毫克/千克/天的雌性中，食道鳞状细胞乳头状瘤的统计学显著增加。氟伐他汀在大鼠中以12毫克/千克/天的剂量和家兔中以10毫克/千克/天的剂量导致骨骼发育延迟。在以下研究中，无论是否进行代谢激活，都没有观察到突变性：使用突变株的微生物突变试验；在BALB/3T3细胞中的恶性转化试验；在大鼠原代肝细胞中的非计划DNA合成；在V79中国仓鼠细胞中的染色体畸变；HGPRT V79中国仓鼠细胞。此外，在大鼠或小鼠微核试验中没有观察到突变性。

IDENTIFICATION AND USE: Fluvastatin is anticholesteremic agent and hydroxymethylglutaryl-CoA reductase inhibitor. HUMAN EXPOSURE AND TOXICITY: Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with fluvastatin capsules and other drugs in this class. There have been rare reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin, promptly interrupt therapy. Fluvastatin capsules are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin capsules may cause fetal harm when administered to pregnant women. Adverse drug reaction reports have demonstrated the occurrence of neuropsychiatric reactions associated with statin treatment. They include behavioral alterations; cognitive and memory impairments; sleep disturbance; and sexual dysfunction. ANIMAL STUDIES: The carcinogenicity study conducted in mice at dose levels of 0.3, 15 and 30 mg/kg/day revealed, as in rats, a statistically significant increase in forestomach squamous cell papillomas in males and females at 30 mg/kg/day and in females at 15 mg/kg/day. Fluvastatin produced delays in skeletal development in rats at doses of 12 mg/kg/day and in rabbits at doses of 10 mg/kg/day. No evidence of mutagenicity was observed in vitro, with or without metabolic activation, in the following studies: microbial mutagen tests using mutant strains of Salmonella typhimurium or Escherichia coli; malignant transformation assay in BALB/3T3 cells; unscheduled DNA synthesis in rat primary hepatocytes; chromosomal aberrations in V79 Chinese Hamster cells; HGPRT V79 Chinese Hamster cells. In addition, there was no evidence of mutagenicity in vivo in either a rat or mouse micronucleus test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

氟伐他汀治疗与1%至5%的患者出现轻度、无症状且通常是暂时的血清转氨酶升高有关，但在超过3倍ULN的水平上大约为1%。在大规模前瞻性监测研究的总结分析中，ALT升高超过正常范围的患者高达5%；氟伐他汀治疗组的ALT水平超过正常上限3倍（ULN）的发生率为1.1%，而安慰剂接受者为0.3%。这些升高更常见于较高剂量的氟伐他汀。大多数这些升高是自限性的，不需要调整剂量。氟伐他汀是最常与血清转氨酶升高和症状性肝损伤最高发生率相关的他汀类药物，然而，明显的、临床上可见的氟伐他汀引起的肝损伤仍然非常罕见，估计在使用10,000人年中的发生率为1.7例。在报告的少数病例中，临床损伤的发病时间在1到4个月之内，损伤模式通常是胆汁淤积性或混合型。皮疹、发热和嗜酸性粒细胞增多不常见。至少有一例具有自身免疫特征的病例已被描述。大多数病例在发病后几个月内解决。罕见的急性肝衰竭和死亡病例被归因于氟伐他汀。

Fluvastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations in 1% to 5% of patients but in levels above 3 times ULN is approximately 1%. In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in up to 5% of patients; ALT levels of above 3 times the upper limit of normal (ULN) occurred in 1.1% of fluvastatin treated versus 0.3% of placebo recipients. These elevations were more common with higher doses of fluvastatin. Most of these elevations were self-limited and did not require dose modification. Fluvastatin is the statin most commonly associated with serum aminotransferase elevations and the highest rates of symptomatic liver injury, yet frank, clinically apparent hepatic injury from fluvastatin is still quite rare estimated to occur in 1.7 per 10,000 person years of use. In the few cases that have been reported, the onset of clinical injury has been within 1 to 4 months, the pattern of injury is typically cholestatic or mixed. Rash, fever and eosinophilia are uncommon. At least one case with features of autoimmunity has been described. Most cases resolve within a few months of onset. Rare cases of acute liver failure and death have been attributed to fluvastatin.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概述：目前没有关于在母乳喂养期间使用氟伐他汀的相关已发布信息。由于担心会干扰婴儿的脂质代谢，共识认为在母乳喂养期间不应使用氟伐他汀。然而，也有人认为对于家族性高胆固醇血症的同型纯合子儿童，从1岁开始就使用他汀类药物，他汀类药物的口服生物利用度较低，对哺乳婴儿的风险很低，尤其是罗苏伐他汀和阿伐他汀。[1] 在有更多数据可用之前，可能更倾向于使用其他药物，特别是在哺乳新生儿或早产儿时。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关已发布信息。

◉ Summary of Use during Lactation:No relevant published information exists on the use of fluvastatin during breastfeeding. Because of a concern with disruption of infant lipid metabolism, the consensus is that fluvastatin should not be used during breastfeeding. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and risks to the breastfed infant are low, especially with rosuvastatin and pravastatin.[1] Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ 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

肌病病例，包括横纹肌溶解症，已经报告了与秋水仙碱联合使用氟伐他汀的情况，在开具氟伐他汀与秋水仙碱联合处方的时应谨慎。

Cases of myopathy, including rhabdomyolysis, have been reported with fluvastatin coadministered with colchicine, and caution should be exercised when prescribing fluvastatin with colchicine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在使用香豆素类抗凝剂的同时服用其他HMG-CoA还原酶抑制剂的患者中，已经报道了出血和/或凝血酶原时间增加的情况。因此，当开始使用氟伐他汀钠或更改氟伐他汀钠剂量时，接受华法林型抗凝剂治疗的患者应密切监测其凝血酶原时间。

Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when fluvastatin sodium is initiated or the dosage of fluvastatin sodium is changed.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

迅速且几乎完全吸收（> 90%），但经历广泛的首过代谢。当给予10毫克剂量时，生物利用度为24%（范围9-50%）。与空腹条件下给药的即释胶囊相比，缓释片的平均相对生物利用度为29%（范围：9%至66%）。口服氟伐他汀后，在不到一小时的时间内达到峰值浓度（Tmax）。服用高脂肪餐后，缓释片的吸收会延迟（Tmax = 6小时），并且生物利用度会增加约50%。然而，高脂肪餐后氟伐他汀钠缓释片达到的最大浓度低于单次剂量或每日两次剂量的40毫克氟伐他汀胶囊后的峰值浓度。

Rapidly and almost completely absorbed (> 90%), but undergoes extensive first pass metabolism. Bioavailability is 24% (range 9-50%) when a 10 mg dose is given. The mean relative bioavailability of the extended-release tablet is 29% (range: 9% to 66%) compared to an immediate-release capsule administered under fasting conditions. When given orally, fluvastatin reaches peak concentrations (Tmax) in less than one hour. Taking the extended release tablet with a high-fat meal will delay absorption (Tmax = 6 hours) and increase bioavailability by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule.

来源:DrugBank

吸收、分配和排泄

• 消除途径

当口服给药时，氟伐他汀主要在粪便中以代谢物形式排泄（约90%），不到2%以未改变药物的形态存在。大约5%在尿液中回收。

When orally administered, fluvastatin is primarily excreted in the faces ( ~90%) as metabolites, with less than 2% present as unchanged drug. Approximately 5% was recovered in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

0.35升/千克

0.35 L/kg

来源:DrugBank

吸收、分配和排泄

• 清除

0.8 升/小时/千克 107 ± 38.1 升/小时 [高胆固醇血症患者单次剂量20毫克] 87.8 ± 45 升/小时 [高胆固醇血症患者每日两次20毫克] 108 ± 44.7 升/小时 [高胆固醇血症患者单次剂量40毫克] 64.2 ± 21.1 升/小时 [高胆固醇血症患者每日两次40毫克]

0.8 L/h/kg 107 ± 38.1 L/h [Hypercholesterolemia patients receiving a single dose of 20 mg] 87.8 ± 45 L/h [Hypercholesterolemia patients receiving 20 mg twice daily] 108 ± 44.7 L/h [Hypercholesterolemia patients receiving 40 mg single] 64.2 ± 21.1 L/h [Hypercholesterolemia patients receiving 40 mg twice daily]

来源:DrugBank

吸收、分配和排泄

基于动物数据，氟伐他汀在母乳中的比例约为2:1（母乳：血浆）。

/MILK/ Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma).

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• WGK Germany：
  3
• 危险类别：
  3
• 安全说明：
  S23,S26,S37
• 危险类别码：
  R36/37/38,R42/43
• 包装等级：
  III
• 危险品运输编号：
  UN 3272 3/PG 3

制备方法与用途

降胆固醇药物：氟伐他汀 氟伐他汀简介

氟伐他汀（fluvastatin）是第一个全化学合成的降胆固醇药物，属于羟甲戊二酰辅酶A (HMG-CoA) 还原酶抑制剂。它通过将HMG-CoA转化为3-甲基-3, 5-二羟戊酸来发挥作用。

与洛伐他汀、新伐他汀和普伐他汀等已上市的天然或半合成HMG-CoA还原酶抑制剂相比，氟伐他汀具有结构相对简单、作用选择性高及不良反应发生率低的优点。因此，它是一种优秀的降血脂药。

药代动力学 吸收

健康志愿者空腹服用氟伐汀钠后，吸收迅速且完全（98%）。餐后服用会减慢其吸收速度。在服20 mg或40 mg氟伐汀钠胶囊1小时后，血浆峰浓度分别约为140 ng/mL和365 ng/mL。

分布

表观分布容积(Vz/f) 为330 L。超过98%的循环药物与血浆蛋白结合，且这种结合不受血药浓度的影响。

代谢

氟伐他汀主要通过β氧化、吲哚环5、6位的羟化和1位异丙基的丢失途径进行体内代谢。在人肝微粒体中，它主要被细胞色素P450同功酶CYP2C9亚族代谢。

药物相互作用

1. 消胆胺能增强氟伐他汀降胆固醇效能。
2. 与西咪替丁、雷尼替丁或奥美拉唑同用，可使本品血浓度升高，清除率下降。
3. 与利福平同用则降低本品血药浓度，增加清除率。
4. 与地高辛合用，可使地高辛血浓度升高。

作用和用途

氟伐他汀为人工合成品，化学结构类似普伐他汀。它通过抑制HMG-CoA还原酶和其他途径降胆固醇，在用药后4周达到最大疗效，继续用药疗效稳定。

适应症

用于动物脂肪和胆固醇饮食所致的高胆固醇血症（Ⅱa和Ⅱb）的治疗。

合成路线

氟伐他汀的活性成分为氟伐他汀钠。其合成路线如下：

参考资料：李玉龙, 刘菊. 氟伐他汀钠的合成工艺研究[J], 药物资讯, 20XX, X(X): XX-XX。

注意事项

1. 尽管氟伐他汀仅小部分药物经CYP3A4代谢，但应慎用。
2. 监测病人使用本品时出现的肌肉痛、触痛及突然衰弱，并注意不适和发热症状。如发现肌酐磷酸激酶（CPK）水平升高或肌痛即停止给药。
3. 在活动型肝炎、重症肝炎、孕妇、哺乳期妇女中禁用。与树脂类药物合用时，需间隔4小时避免降低生物利用度。
4. 给药前曾用过利福平的患者，将降低氟伐他汀的生物利用度50%。
5. 肝功能不正常者禁用。给药前或期间必须进行肝功测定。
6. 消胆胺可加强本品的药理活性。
7. 西咪替丁、雷尼替丁、奥美拉唑使本品Gmax 和AUC显著升高，血浆清除率下降。
8. 氟伐他汀与利福平同时使用则降低血药浓度，清除率升高。
9. 本品使地高辛Gmax升高，给药时应注意监护。

反应信息

• 作为反应物：
  描述：

  fluvastatin 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以2.18 g的产率得到氟伐他汀内酯
  参考文献：
  名称：

  多取代吲哚类他汀内酯脱水化合物及其用途

  摘要：

  发明属于药物化学领域，提供了一种化合物，其结构式如下描述：、或、或，这类化合物经测试具有抑制HMG‑coA还原酶活性的效果，可作为新一代的潜在HMG‑coA还原酶抑制剂。

  公开号：

  CN104327057B
• 作为产物：
  描述：

  fluvastatin sodium 在 盐酸 作用下， 以 二氯甲烷 、 水 为溶剂， 生成 fluvastatin
  参考文献：
  名称：

  多取代吲哚类他汀内酯脱水化合物及其用途

  摘要：

  发明属于药物化学领域，提供了一种化合物，其结构式如下描述：、或、或，这类化合物经测试具有抑制HMG‑coA还原酶活性的效果，可作为新一代的潜在HMG‑coA还原酶抑制剂。

  公开号：

  CN104327057B

文献信息

• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015054038A1

  公开（公告）日：2015-04-16

  This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

  这项发明涉及一类新型化合物，它们是半胱氨酸蛋白酶抑制剂，包括但不限于对卡特普辛K、L、S和B的抑制剂。这些化合物可用于治疗需要抑制骨吸收的疾病，如骨质疏松症。
• [EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
  申请人：AMGEN INC

  公开号：WO2013123444A1

  公开（公告）日：2013-08-22

  The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的磺酰基化合物。此外，本发明涉及使用这些化合物或其药学上可接受的盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药学上可接受的盐的药物组合物。
• 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。