比索洛尔 | 66722-44-9

• 物质功能分类: 原料药 - 循环系统用药 - 抗心律失常药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 比索洛尔
• 中文别名: 1-[4-[[2-(1-甲基乙氧基)乙氧基]甲基]苯氧基]-3-[(1-甲基乙基)氨基]-2-丙醇
• 英文名称: bisoprolol
• 英文别名: 1-(4-{[2-(1-methylethoxy)ethoxy]methyl}phenoxy)-3-[(1-methylethyl)amino]propan-2-ol；1-(propan-2-ylamino)-3-[4-(2-(propan-2-yloxy)ethoxymethyl)phenoxy]propan-2-ol；1-{4-[(2-isopropoxyethoxy)methyl]phenoxy}-3-(isopropylamino)propan-2-ol；(±)-bisoprolol；BIS；1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy]propan-2-ol
• CAS: 66722-44-9
• 化学式: C₁₈H₃₁NO₄
• 分子量: 325.448
• InChiKey: VHYCDWMUTMEGQY-UHFFFAOYSA-N

物化性质

• 熔点：
  100 °C
• 沸点：
  445.0±45.0 °C(Predicted)
• 密度：
  1.033±0.06 g/cm3(Predicted)
• 溶解度：
  氯仿（微溶）、甲醇（微溶）
• 物理描述：
  Solid
• 蒸汽压力：
  9.54X10-9 mm Hg at 25 °C (est)
• 水溶性：
  -3.7
• 稳定性/保质期：
  Stable under recommended storage conditions.
• 解离常数：
  pKa1 = 9.27 (secondary amine); pKa2 = 14.09 (alcohol)
• 碰撞截面：
  192.2 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2321.3;2336.3

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  23
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  60
• 氢给体数：
  2
• 氢受体数：
  5

ADMET

代谢

大约50%的单剂量比索洛尔通过酶CYP3A4主要代谢为无活性代谢物。

About 50% of a single bisoprolol dose is metabolized mainly by the enzyme CYP3A4 to inactive metabolites.

来源:DrugBank

代谢

... 在人类中，已知的代谢物是不稳定的或者没有已知的药理活性。 ... 福马酸比索洛尔不会被细胞色素P450 II D6（脱布里司喹羟化酶）代谢。

... In humans, the known metabolites are labile or have no known pharmacologic activity. ... Bisoprolol fumarate is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).

来源:Hazardous Substances Data Bank (HSDB)

代谢

在对四名日本男性健康志愿者单次口服20毫克消旋比索洛尔后，评估了比索洛尔对映体的血浆浓度和尿液排泄。在所有受试者中，(S)-(-)-比索洛尔的AUC(无限大)和消除半衰期略大于(R)-(+)-比索洛尔。尽管差异很小，(R)-(+)-比索洛尔的代谢清除率显著(P < 0.05)大于(S)-(-)-比索洛尔（S/R比率：0.79+/-0.03）。相比之下，在人体血浆中没有发现比索洛尔的体外蛋白结合具有对映选择性。使用重组人细胞色素P450（CYP）同种型的体外代谢研究表明，两种比索洛尔对映体的氧化都被这两种同种型CYP2D6和CYP3A4催化。CYP2D6对比索洛尔进行立体选择性代谢（R > S），而CYP3A4对比索洛尔的代谢则不是立体选择性的。由于肾小管分泌导致的平均清除率的S/R比值为0.68，这表明肾小管分泌具有中等程度的立体选择性。这些发现总体上表明，(S)-(-)-比索洛尔和(R)-(+)-比索洛尔在药代动力学上的小差异主要是由于CYP2D6的固有代谢清除率和肾小管分泌的立体选择性所致。

The plasma concentrations and urinary excretions of bisoprolol enantiomers in four Japanese male healthy volunteers after a single oral administration of 20 mg of racemic bisoprolol were evaluated. The AUC(infinity) and elimination half-life of (S)-(-)-bisoprolol were slightly larger than those of (R)-(+)-bisoprolol in all subjects. The metabolic clearance of (R)-(+)-bisoprolol was significantly (P < 0.05) larger than that of (S)-(-)-bisoprolol (S/R ratio: 0.79+/-0.03), although the difference was small. In contrast, no stereoselective in vitro protein binding of bisoprolol in human plasma was found. An in vitro metabolic study using recombinant human cytochrome P450 (CYP) isoforms indicated that oxidation of both bisoprolol enantiomers was catalyzed by the two isoforms, CYP2D6 and CYP3A4. CYP2D6 metabolized bisoprolol stereoselectively (R > S), whereas the metabolism of bisoprolol by CYP3A4 was not stereoselective. The S/R ratio of the mean clearance due to renal tubular secretion was 0.68, indicating a moderate degree of stereoselective renal tubular secretion. These findings taken together suggest that the small differences in the pharmacokinetics between (S)-(-)- and (R)-(+)-bisoprolol are mainly due to the stereoselectivity in the intrinsic metabolic clearance by CYP2D6 and renal tubular secretion.

来源:Hazardous Substances Data Bank (HSDB)

代谢

双普罗尔-(14)C的药代动力学特性在Wistar大鼠、比格犬和食蟹猴中进行了研究。...双普罗尔的代谢在这三种动物以及人类中进行了研究。主要代谢物是O-脱烷基化和随后氧化成相应羧酸的产品。

The pharmacokinetic properties of bisoprolol-(14)C were studied in Wistar rats, beagle dogs, and Cynomolgus monkeys. ... The metabolism of bisoprolol was studied in the same three animal species and in humans. The major metabolites are the products of O-dealkylation and subsequent oxidation to the corresponding carboxylic acids. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别与用途：比索洛尔是一种β-肾上腺素能阻断剂，有时以药物名Zebeta出现，用于治疗高血压。它可能单独使用或与其他抗高血压药物联合使用。人类暴露和毒性：过量使用β-阻滞剂最常见的体征包括心动过缓、低血压、充血性心力衰竭、支气管痉挛和低血糖。已有至少两例报告，从普萘洛尔切换到比索洛尔后心律控制恶化。一位老年人在医院因误服高于规定剂量的比索洛尔富马酸盐后死于无法控制的心动过缓。然而，确定患者细胞色素P2D6存在突变，这影响了药物的代谢。动物研究：在大鼠中，以体重为基础的比索洛尔富马酸盐最大推荐人类剂量（MRHD）的125倍时发生胎儿毒性，而在375倍MRHD时发生母体毒性。在兔中，比索洛尔富马酸盐在剂量高达12.5 mg/kg/天（基于体重为MRHD的31倍）时并未表现出致畸性，但增加了早期吸收。比索洛尔富马酸盐的致突变潜力在微生物致突变性（Ames）试验、中国仓鼠V79细胞的点突变和染色体畸变分析、非计划DNA合成试验、小鼠的微核试验和 rats的细胞遗传学分析中进行了评估。在这些体外和体内试验中没有发现致突变潜力。对小鼠和大鼠进行了长期研究，通过饲料口服比索洛尔富马酸盐。在小鼠剂量高达250 mg/kg/天或大鼠剂量高达123 mg/kg/天的情况下，没有发现致癌潜力。

IDENTIFICATION AND USE: Bisoprolol is a beta-Adrenergic blocking agent, sometimes under the drug name Zebeta, which is indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents. HUMAN EXPOSURE AND TOXICITY: The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. There have been at least two reported cases where a switch from propranolol to bisoprolol resulted in worsening of arrhythmia control. An elderly person died of uncontrolled bradycardia in a hospital after being mistakenly given a higher-than-prescribed dose of bisoprolol fumarate. However, it was determined that the patient had a mutation within cytochrome P2D6, which influences metabolism of the drug. ANIMAL STUDIES: Fetotoxicity in rats occurred at 125 times the maximum recommended human dose (MRHD) of bisoprolol fumarate on a body-weight-basis, and maternal toxicity occurred at 375 times the MRHD. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day (31 times the MRHD based on body-weight), but increased early resorptions. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays. Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice and rats. No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 123 mg/kg/day.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

比索洛尔治疗与血清转氨酶水平轻至中度升高的低发生率有关，这些升高通常无症状、短暂，即使在继续治疗的情况下也会解决。目前还没有记录在案的因比索洛尔导致临床明显的急性肝损伤的病例。因此，如果比索洛尔导致肝毒性，这种情况也必须非常罕见。最常用的β受体阻滞剂与罕见的临床明显肝损伤有关，通常在开始后的2到12周内发病，表现为肝细胞模式的肝酶升高，停药后迅速恢复，并且很少有过敏反应（皮疹、发热、嗜酸性粒细胞增多）或自身抗体形成的证据。

Bisoprolol therapy has been associated with a low rate of mild-to-moderate elevations of serum aminotransferase levels which are usually asymptomatic and transient and resolve even with continuation of therapy. There have been no well documented cases of clinically apparent, acute liver injury attributable to bisoprolol. Thus, hepatotoxicity due to bisoprolol must be very rare, if it occurs at all. Most commonly used beta-blockers have been linked to rare instances of clinically apparent liver injury, typically with onset within 2 to 12 weeks, a hepatocellular pattern of liver enzyme elevations, rapid recovery upon withdrawal, and little evidence of hypersensitivity (rash, fever, eosinophilia) or autoantibody formation.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：比索洛尔

Compound:bisoprolol

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

比索洛尔在胃肠道的吸收良好。比索洛尔的曲线下面积(AUC)为642.87 g·hr/mL，由于首过效应最小，其生物利用度约为90%。食物摄入不影响吸收。比索洛尔的血浆峰浓度在2-4小时内达到，并且在给药5天内达到稳态浓度。在一项药代动力学研究中，比索洛尔的平均峰浓度为52微克/升。在稳态浓度下，比索洛尔的Cmax为64±21 ng/ml，每日剂量为10毫克。

Bisoprolol is well absorbed in the gastrointestinal tract. The AUC is 642.87 g.hr/mL and bioavailability of bisoprolol is about 90% due to the minimal first pass effects. Absorption is unaffected by food intake. Peak plasma concentrations of bisoprolol are attained within 2-4 hours and steady-state concentrations are achieved within 5 days of administration. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 micrograms/L. Cmax at steady state concentrations of bisoprolol is 64±21 ng/ml administered at 10 mg daily.

来源:DrugBank

吸收、分配和排泄

• 消除途径

比索洛尔通过肾脏和肝脏途径等量消除。大约50%的口服剂量以原形在尿液中排泄，其余剂量以无活性的比索洛尔代谢物形式排泄。摄入剂量的不到2%被发现排泄在粪便中。

Bisoprolol is eliminated equally by both renal and hepatic pathways. About 50% of an oral dose is excreted unchanged in the urine with the remainder of the dose excreted as inactive bisoprolol metabolites. Under 2% of the ingested dose is found to be excreted in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

双丙洛尔的分布体积为3.5 L/kg。在心力衰竭患者中，平均分布体积发现为230 L/kg，这与健康患者的分布体积相似。已知双丙洛尔可以穿过胎盘。

The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution was found to be 230 L/kg in heart failure patients, which was similar to the volume of distribution in healthy patients. Bisoprolol is known to cross the placenta.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康患者中，总体清除率确定为14.2升/小时。在肾功能损害的患者中，清除率降低到7.8升/小时。肝功能不全也降低了比索洛尔的清除率。

Total body clearance in healthy patients was determined to be 14.2 L/h. In patients with renal impairment, clearance was reduced to 7.8 L/h. Hepatic dysfunction also reduced the clearance of bisoprolol.

来源:DrugBank

吸收、分配和排泄

比格犬接受了一种名为比索洛尔（bisoprolol）的β1选择性肾上腺素能受体拮抗剂的治疗，持续30天，每天的剂量如下：口服：30毫克/千克；结膜：0.5%溶液（约0.04毫克/千克）和5%溶液（约0.4毫克/千克）。在治疗后的第1天、第16天、第30天以及随访期间的第29天（即第59天）测定了血浆和各种眼组织中的药物浓度。血浆中和大多数眼组织中的比索洛尔浓度在口服治疗后比结膜治疗后要高得多。在虹膜（+睫状体）和视网膜（+脉络膜）中观察到最高的组织浓度，口服给药后的组织/血浆浓度比在100到150之间，而结膜滴注（5%溶液）后的比值在1000到3000之间。在血浆中没有观察到药物的累积，这与它的血浆半衰期4到5小时相符合。与此相反，虹膜和视网膜中的浓度从第1天到第16天和第30天增加了3到8倍，这些组织中比索洛尔的半衰期估计在3到5天之间。

Beagles were treated with bisoprolol, a beta 1-selective adrenoceptor antagonist, for 30 days with the following daily doses: oral: 30 mg/kg; conjunctival: 0.5% solution (approx. 0.04 mg/kg) and 5% solution (approx. 0.4 mg/kg). Drug concentrations were determined in plasma and various eye tissues on days 1, 16, and 30, and on day 59, i.e. on day 29 of the follow-up period. Bisoprolol concentrations in plasma and most eye tissues were considerably higher after oral than after conjunctival treatment. The highest tissue concentrations were observed in the iris (+ciliary body) and retina (+choroid) with tissue/plasma concentration ratios between 100 and 150 after oral and 1000 to 3000 after conjunctival instillation (5% solution). In plasma no accumulation of the drug was observed which is in accordance with its plasma half-life of 4 to 5 hr. In contrast to this, concentrations in the iris and retina increased from day 1 to day 16 and 30 by 3 to 8 times and the half-life of bisoprolol in these tissues was estimated to be between 3 to 5 days.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xi
• 危险类别码：
  R22,R36/37/38
• WGK Germany：
  1
• 海关编码：
  2922509090
• 安全说明：
  S26,S36
• 储存条件：
  可燃，燃烧会产生有毒的氮氧化物气体。

制备方法与用途

心血管药物：比索洛尔 一、概述

比索洛尔由德国默克制药于1978年研制成功，商品名称包括康可、博苏、圣诺德、康心等。它是一种高度选择性β1肾上腺素受体阻滞剂，并且具有亲水性和亲脂性的特性。比索洛尔是治疗高血压、心绞痛、心律失常及心衰等心血管疾病的首选药物之一。

二、药代动力学

比索洛尔口服吸收率高达88%，血浆清除半衰期为10～12小时，一次服药后作用可持续24小时。它几乎完全通过胃肠道被吸收（＞90%），由于肝脏首过效应小（＜10%），生物利用度约为90%。比索洛尔的血浆蛋白结合率为30%，分布容积为3.5升/公斤，总清除率约为15升/小时。

三、药理作用

比索洛尔是一种高度选择性β1肾上腺素受体阻滞剂，并且具有亲水性和亲脂性的特性。它对心脏的抑制作用强于血管平滑肌，可以有效降低心率和心肌收缩力，从而达到治疗高血压、冠心病（心绞痛）的目的。

四、适应症

比索洛尔适用于治疗高血压、冠心病（心绞痛），伴有左心室收缩功能减退的慢性稳定性心力衰竭。使用时需遵医嘱接受ACE抑制剂、利尿剂和选择性使用强心甙类药物治疗。

五、禁忌症

比索洛尔禁用于急性心力衰竭或处于心力衰竭失代偿期需用正性肌力药物治疗的患者，心源性休克者，二度或三度房室传导阻滞（未安装心脏起搏器）者，病窦综合征、窦房阻滞及有症状的心动过缓者，有症状的低血压，严重支气管哮喘或严重慢性阻塞性肺部疾病患者等。

六、药物过量

比索洛尔常见的药物过量反应包括心动过缓、低血压、支气管哮喘和急性心功能不全。对于单次高剂量的敏感性个体差异很大，心力衰竭患者可能非常敏感。通常需要及时停药并给予支持性的对症治疗。

七、毒性

比索洛尔属于有毒物品，具有中毒危险性，并且其急性毒性静脉注射小鼠LD50为164毫克/公斤。它可燃，燃烧时产生有毒氮氧化物气体。应储存在库房通风低温干燥处，灭火剂可用水、干粉、泡沫或砂土。

八、用途

用于治疗心脑血管疾病。

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-[[2-(1-甲基乙氧基)乙氧基]甲基]苯氧基]甲基]环氧乙烷	2-((4-((2-isopropoxyethoxy)methyl)phenoxy)methyl)oxirane	66722-57-4	C15H22O4	266.337
  ——	5-[[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]methyl]-3-(1-methylethyl)-2-oxazolidinone	87844-84-6	C19H29NO5	351.443
  4-异丙氧基乙氧基甲基酚	4-((2-isopropoxyethoxy)methyl)phenol	177034-57-0	C12H18O3	210.273

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  S-(-)-比索洛尔	(S)-bisoprolol	99103-03-4	C18H31NO4	325.448
  ——	EZ-[3-[4-(2-Isopropoxyethoxy-methyl)phenoxy]allyl]isopropylamine	——	C18H29NO3	307.433

反应信息

• 作为反应物：
  描述：

  比索洛尔 在 四溴化碳 、 potassium carbonate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三苯基膦 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氯化碳 、 二氯甲烷 、 乙腈 为溶剂， 反应 42.0h， 生成 EZ-[3-[4-(2-Isopropoxyethoxy-methyl)phenoxy]allyl]isopropylamine
  参考文献：
  名称：

  一种比索洛尔重要杂质的合成方法

  摘要：

  本发明是一种比索洛尔欧洲药典EP杂质E的合成方法，(1)游离的比索洛尔API作为起始原料，用对甲氧基苄氯保护氨基，得到中间体1；(2)中间体1用三苯基膦、四溴化碳将羟基溴化，得到中间体2；(3)中间体2用碱将溴消去生成双键，得到中间体3；(4)中间体3用氧化剂脱对甲氧基苄基保护，得到目标产物比索洛尔EP杂质E；本发明路线设计合理，反应条件温和，操作简单，成本低廉，收率高；本发明制备得到的富马酸比索洛尔杂质，为富马酸比索洛尔的质量控制、安全性和有效性的评价提供了重要依据，具有十分重要的意义。

  公开号：

  CN114369032A
• 作为产物：
  描述：

  富马酸比索洛尔 在 水 、 sodium hydroxide 作用下， 以 甲基叔丁基醚 为溶剂， 生成 比索洛尔
  参考文献：
  名称：

  [EN] MANUFACTURE OF BISOPROLOL AND INTERMEDIATES THEREFOR
  [FR] FABRICATION DE BISOPROLOL ET SES INTERMÉDIAIRES

  摘要：

  制备比索洛尔的过程包括将噁唑烷酮磺酸酯与4-羟基苯甲醛反应，形成噁唑烷酮苯甲醛，从噁唑烷酮苯甲醛形成噁唑烷酮苄醇，然后将噁唑烷酮苄醇与异丙基氧乙醇反应，形成比索洛尔。噁唑烷酮磺酸酯和噁唑烷酮苯甲醛是新颖的中间体。

  公开号：

  WO2010061366A1

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。
• 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。
• [EN] SULFOXIMINE SUBSTITUTED PYRROLOTRIAZINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] PYRROLOTRIAZINES À SUBSTITUTION SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2015091156A1

  公开（公告）日：2015-06-25

  This invention relates to novel sulfoximine substituted pyrrolotriazine derivatives of formula wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1 a or MNK1 b) 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 (MNK1 a or MNK1 b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的噻氧亚胺取代吡咯三嗪衍生物，其化学式中Ar、R1和R2的定义如描述和权利要求中所定义，并且它们作为MNK1（MNK1 a或MNK1 b）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（MNK1 a或MNK1 b）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 UNE SULFOXIMINE DESTINÉES À DES COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2015169677A1

  公开（公告）日：2015-11-12

  The application relates to novel sulfoximine substituted quinazoline derivatives of formula (I) wherein Ar, R1, R2 and R3 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.

  该申请涉及式(I)的新型磺酰胺取代喹唑啉衍生物，其中Ar、R1、R2和R3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，含有相同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。