曲安西龙 | 124-94-7

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 肾上腺皮质激素类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 曲安西龙
• 中文别名: 9a-氟-11b,16a,17a,21-四羟基-1,4-孕烯-3,20-二酮；曲安奈德；氟羟泼尼松龙
• 英文名称: triamcinolone
• 英文别名: (8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one
• CAS: 124-94-7
• 化学式: C₂₁H₂₇FO₆
• 分子量: 394.44
• InChiKey: GFNANZIMVAIWHM-OBYCQNJPSA-N

物化性质

• 熔点：
  262-263 °C(lit.)
• 比旋光度：
  69 º (c=2, DMF)
• 沸点：
  587.5±50.0 °C(Predicted)
• 密度：
  1.1703 (estimate)
• 溶解度：
  在DMF中的溶解度为20mg/mL
• 物理描述：
  Solid
• 颜色/状态：
  Crystals
• 蒸汽压力：
  7.20X10-15 mm Hg at 25 °C
• 稳定性/保质期：

  Commercially available oral and parenteral preparations of triamcinolone should be stored at a temperature less than 40 °C, preferably between 15-30 °C; freezing of the sterile suspensions should be avoided. Exposure of sterile suspensions of the drug to freezing temperatures can result in irreversible clumping or agglomeration (granular appearance); such suspensions should not be used. Triamcinolone tablets should be stored in well-closed containers. Triamcinolone acetonide sterile suspension should be protected from light. Triamcinolone acetonide oral inhaler should be stored at controlled room temperature (20-25 °C). Because the contents of the oral inhaler are under pressure, the aerosol container should not be punctured, used or stored near heat or an open flame, exposed to temperatures greater than 49 °C, or placed into a fire or incinerator for disposal.

• 旋光度：
  SPECIFIC OPTICAL ROTATION: +75 DEG @ 25 °C/D (ACETONE); MAX ABSORPTION: 238 NM (E= 15,800)
• 碰撞截面：
  186.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  115
• 氢给体数：
  4
• 氢受体数：
  7

ADMET

代谢

曲安奈德的主要代谢物是6-β-羟基-曲安奈德。关于曲安奈德的代谢数据并不容易获得。

The major metabolite of triamcinolone is 6-beta-hydroxy-triamcinolone. Data regarding the metabolism of triamcinolone is not readily available.

来源:DrugBank

代谢

肝脏将其转化为3种较少活性的代谢物，分别是6-β-羟基曲安奈德醋酸酯、21-羧基曲安奈德醋酸酯和21-羧基-6-β-羟基曲安奈德醋酸酯。/醋酸曲安奈德/

Hepatic to 3 less active metabolites, 6-beta-hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide, and 21-carboxy-6-beta-hydroxytriamcinolone acetonide. /Triamcinolone acetonide/

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏的。 半衰期：88分钟

Hepatic. Half Life: 88 minutes

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

皮质类固醇的抗炎作用被认为涉及脂皮质素，这是一种磷脂酶A2抑制蛋白，通过抑制花生四烯酸，控制前列腺素和白三烯的生物合成。首先，然而，这些糖皮质激素与糖皮质激素受体结合，这些受体转移到细胞核内并与DNA（GRE）结合，从而正向和负向改变基因表达。由于皮质类固醇减少了淋巴系统的功能，降低了免疫球蛋白和补体的浓度，促发了淋巴细胞减少，以及干扰抗原-抗体结合，因此免疫系统被抑制。

The antiinflammatory actions of corticosteroids are thought to involve lipocortins, phospholipase A2 inhibitory proteins which, through inhibition of arachidonic acid, control the biosynthesis of prostaglandins and leukotrienes. Firstly, however, these glucocorticoids bind to the glucocorticoid receptors which translocate into the nucleus and bind DNA (GRE) and change genetic expression both positively and negatively. The immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：外用曲安奈德在母乳喂养期间尚未进行研究。由于只有大量应用最强效的皮质类固醇才可能在母亲体内产生系统性影响，因此短期外用皮质类固醇不太可能通过进入母乳而对哺乳婴儿构成风险。然而，最好还是使用最弱效的药物，并且尽可能在最小的皮肤区域上使用。特别是要确保婴儿的皮肤不直接接触到已经涂抹药物的皮肤区域。曲安奈德可以应用于乳房或乳头区域，但在哺乳前应彻底擦除。只有水溶性乳膏或凝胶产品可以应用于乳房，因为软膏可能会使婴儿通过舔舐接触到高水平的矿物石蜡。如果外用皮质类固醇应用于乳房或乳头区域，在哺乳前应彻底擦除。 ◉ 对哺乳婴儿的影响：将具有相对较高盐皮质激素活性的外用皮质类固醇（异氟泼尼松醋酸酯）应用于母亲的乳头，导致她的2个月大哺乳婴儿出现QT间期延长、库欣综合征外观、严重高血压、生长减缓和电解质异常。这位母亲从婴儿出生起就因为乳头疼痛而使用该乳膏。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。正常的泌乳需要足够的内源性肾上腺皮质激素水平。

◉ Summary of Use during Lactation:Topical triamcinolone has not been studied during breastfeeding. Since only extensive application of the most potent corticosteroids may cause systemic effects in the mother, it is unlikely that short-term application of topical corticosteroids would pose a risk to the breastfed infant by passage into breastmilk. However, it would be prudent to use the least potent drug on the smallest area of skin possible. It is particularly important to ensure that the infant's skin does not come into direct contact with the areas of skin that have been treated. Triamcinolone can be applied to the breast or nipple area, but should be wiped off thoroughly prior to nursing. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking. Any topical corticosteroid should be wiped off thoroughly prior to nursing if it is being applied to the breast or nipple area. ◉ Effects in Breastfed Infants:Topical application of a corticosteroid with relatively high mineralocorticoid activity (isofluprednone acetate) to the mother's nipples resulted in prolonged QT interval, cushingoid appearance, severe hypertension, decreased growth and electrolyte abnormalities in her 2-month-old breastfed infant. The mother had used the cream since birth for painful nipples. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date. Adequate endogenous adrenocorticoid levels are necessary for normal lactation.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概述：因为没有关于口服或注射曲安奈德在哺乳期间使用的可用信息，可能更倾向于使用另一种药物，特别是在哺乳新生儿或早产儿时。然而，将曲安奈德作为鼻喷剂或局部注射（例如用于肌腱炎）不会预期对哺乳婴儿产生任何不良反应。专家意见认为，在哺乳期间使用吸入和口服皮质类固醇是可以接受的。局部注射，例如用于肌腱炎，不会预期对哺乳婴儿产生任何不良反应，但偶尔可能导致暂时性的乳汁供应减少。另请参见曲安奈德，局部外用。 对哺乳婴儿的影响：任何皮质类固醇均未报告有影响。 对泌乳和母乳的影响：一位母亲正在哺乳她14个月大的婴儿，每天3到7次。她在肩部注射了5.7毫克倍他米松磷酸钠和醋酸混合物，用于滑囊炎，对泌乳没有影响。四周后，她继续在胸颈椎区域感到疼痛，并被诊断为神经敏感化。她在颈椎和胸椎硬脊膜外以及小面关节处注射了80到120毫克的曲安奈德二醋酸酯。三天后，她注意到乳汁供应减少和喷乳反射减弱，这种情况在接下来的5天内持续恶化。她开始使用频繁抽吸的吸奶器和多潘立酮作为催乳剂。她的乳汁在几天内逐渐增加，在注射后的21天停止多潘立酮时恢复正常。那时，她的血清催乳素水平升高。母亲乳汁供应的减少可能是由于皮质类固醇注射。 一项对46位在34周前分娩妇女的研究发现，如果在分娩前3到9天给予另一种皮质类固醇（倍他米松，2次肌肉注射，每次11.4毫克，间隔24小时）会导致第二阶段泌乳延迟和产后10天内的平均乳汁量减少。如果婴儿在母亲接受皮质类固醇后不到3天或多于10天分娩，乳汁量不会受到影响。等效剂量的曲安奈德可能会有相同的效果。 一项对87位孕妇的研究发现，在怀孕期间给予上述剂量的倍他米松会导致在怀孕期间过早刺激乳糖分泌。尽管增加在统计学上是有意义的，但临床重要性似乎很小。等效剂量的曲安奈德可能会有相同的效果。 一位产后7个月的哺乳母亲在手背第一间隔区注射了40毫克曲安奈德，并加注了2毫升1%利多卡因，用于德奎尔万腱鞘炎。注射24小时后，患者报告通过吸奶器测量，哺乳量减少了90%。她继续泵吸乳房，并开始服用葫芦巴以刺激泌乳。在1周内，她的乳汁供应增加了50%，在注射后1个月，她能够满足婴儿的哺乳需求。 一位患有特发性肉芽肿性乳腺炎的妇女在受影响的乳房红斑区域注射了40毫克曲安奈德醋酸酯。她的左乳产量减少。她原本能够用电动吸奶器从那一侧挤出60毫升，注射后只能挤出10毫升。受影响的乳房的乳汁供应在2周内恢复。未受影响的右侧乳房的产量没有减少。

◉ Summary of Use during Lactation:Because no information is available on the use of oral or injectable triamcinolone during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. However, use of triamcinolone as a nasal spray or local injections, such as for tendinitis, would not be expected to cause any adverse effects in breastfed infants. Expert opinion considers inhaled and oral corticosteroids acceptable to use during breastfeeding. Local injections, such as for tendinitis, would not be expected to cause any adverse effects in breastfed infants, but might occasionally cause temporary loss of milk supply. See also Triamcinolone, Topical. ◉ Effects in Breastfed Infants:None reported with any corticosteroid. ◉ Effects on Lactation and Breastmilk:A mother was nursing her 14-month-old 3 to 7 times daily. She had 5.7 mg of betamethasone sodium phosphate and acetate mixture injected into her shoulder for bursitis with no effect on lactation. Four weeks later, she continued to have pain in her thoracic cervical regions and was diagnosed with neural sensitization. She had 80 to 120 mg of triamcinolone diacetate injected into her cervical and thoracic spine epidurally and into the facets. Three days later, she noticed a decrease in milk supply and a reduced ejection reflex which continued to worsen over the next 5 days. She began using a breast pump with frequent pumping and domperidone as a galactogogue. Her milk slowly increased over several days and was normal by 21 days after the injection when she stopped domperidone. At that time, her serum prolactin levels were elevated. The decrease in the mother's milk supply was possibly caused by the corticosteroid injections. A dose of depot methylprednisolone injected into the wrist has also been reported to cause temporary cessation of lactation. A study of 46 women who delivered an infant before 34 weeks of gestation found that a course of another corticosteroid (betamethasone, 2 intramuscular injections of 11.4 mg of betamethasone 24 hours apart) given between 3 and 9 days before delivery resulted in delayed lactogenesis II and lower average milk volumes during the 10 days after delivery. Milk volume was not affected if the infant was delivered less than 3 days or more than 10 days after the mother received the corticosteroid. An equivalent dosage regimen of triamcinolone might have the same effect. A study of 87 pregnant women found that betamethasone given as above during pregnancy caused a premature stimulation of lactose secretion during pregnancy. Although the increase was statistically significant, the clinical importance appears to be minimal. An equivalent dosage regimen of triamcinolone might have the same effect. A nursing mother who was 7 months postpartum had triamcinolone 40 mg injected into the first dorsal compartment of the wrist along with 2 mL of 1% lidocaine for de Quervain tenosynovitis. Twenty-four hours after the injection, the patient reported a 90% decrease in lactation as measured by breast pumping before and after the injection. She continued to pump her breasts and began taking fenugreek to stimulate lactation. Within 1 week, her milk supply increased by 50% and by 1 month after the injection, she was able to meet her infants breastfeeding needs. A woman with idiopathic granulomatous mastitis received an injection of 40 mg of triamcinolone acetonide into erythematous areas of the affected breast. Her milk production decreased from the injected left breast. She had originally been able to express 60 mL on that side with an electric breast pump, and after the injection she was only able to express 10 mL. Her milk supply on the affected side recovered over the course of 2 weeks. Production on the unaffected right breast did not decrease.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 暴露途径

口服给药后快速吸收

Rapid absorption following oral administration

来源:Toxin and Toxin Target Database (T3DB)

吸收、分配和排泄

• 吸收

16毫克的曲安奈德口服剂量可达到5.23±0.84纳克/毫升的Cmax，Tmax为2.24±0.78小时，AUC为36.0±6.2纳克*小时/毫升。2毫克曲安奈德醋酸酯静脉注射的AUC为57.7纳克*小时/毫升。800微克吸入用曲安奈德醋酸酯的生物利用度为25%，其中10.4%来自肺部吸收，其余部分归因于沉积在口腔黏膜和其他潜在因素。吸入用曲安奈德醋酸酯的剂量可达到0.92纳克/毫升的Cmax，Tmax为1.74小时，AUC为5.12纳克*小时/毫升。通过肺部途径实际吸收的吸入剂量部分可达到0.55纳克/毫升的Cmax，Tmax为0.66小时，AUC为2.15纳克*小时/毫升。16毫克曲安奈德二醋酸酯的口服剂量可达到5.33±1.55纳克/毫升的Cmax，Tmax为1.86±0.47小时，AUC为32.7±9.9纳克*小时/毫升。

A 16mg oral dose of triamcinolone reaches a Cmax of 5.23±0.84ng/mL with a Tmax of 2.24±0.78h and an AUC of 36.0±6.2ng\*h/mL. A 2mg intravenous dose of triamcinolone acetonide has an AUC of 57.7ng\*h/mL. The bioavailability of 800µg of inhaled triamcinolone acetonide is 25%, with 10.4% coming from pulmonary absorption and the rest being accounted for by deposition on the oral mucosa and other underlying factors. An inhaled dose of triamcinolone acetonide reaches a Cmax of 0.92ng/mL with a Tmax of 1.74h and an AUC of 5.12ng\*h/mL. The fraction of an inhaled dose that is actually absorbed via the pulmonary route reaches a Cmax of 0.55ng/mL with a Tmax of 0.66h and an AUC of 2.15ng\*h/mL. A 16mg oral dose of triamcinolone diacetate reaches a Cmax of 5.33±1.55ng/mL with a Tmax of 1.86±0.47h and an AUC of 32.7±9.9ng\*h/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约20%的曲安奈德剂量以未改变的药物形式在尿液中回收，25%以6-β-羟基-曲安奈德形式回收，还有5%以未识别的代谢物形式回收。

Approximately 20% of a dose of triamcinolone is recovered in the urine as the unchanged drug, 25% is recovered as 6-beta-hydroxy-triamcinolone, and 5% is recovered as unidentified metabolites.

来源:DrugBank

吸收、分配和排泄

• 分布容积

曲安奈德的表观分布容积为115.2±10L。曲安奈德醋酸酯的平均表观分布容积为1.96L/kg。曲安奈德二醋酸酯的表观分布容积为119.7±33.14L。

The apparent volume of distribution of triamcinolone is 115.2±10L. The mean apparent volume of distribution of triamcinolone acetonide is 1.96L/kg. The apparent volume of distribution of triamcinolone diacetate is 119.7±33.14L.

来源:DrugBank

吸收、分配和排泄

• 清除

曲安奈德的清除率为28.6±5.6L/h。曲安奈德醋酸酯的平均总清除率为0.57L/h。曲安奈德二醋酸的清除率为34.4±10.6L/h。

The clearance of triamcinolone is 28.6±5.6L/h. The mean total body clearance of triamcinolone acetonide is 0.57L/h. The clearance of triamcinolone diacetate is 34.4±10.6L/h.

来源:DrugBank

吸收、分配和排泄

局部应用霜剂...含有...[(14)C]曲安奈德醋酸酯...在兔子上。...9%...的(14)C从封闭/磨损的皮肤被吸收，通过这种皮肤，经皮吸收将会最大化增强。/曲安奈德醋酸酯/

TOPICAL APPLICATIONS OF CREAM...CONTAINING...[(14)C]TRIAMCINOLONE ACETONIDE... IN RABBIT. ...9%...OF (14)C WERE ABSORBED FROM OCCLUDED/ABRADED SKIN, THROUGH WHICH PERCUTANEOUS ABSORPTION WOULD BE MAXIMALLY ENHANCED. /TRIAMCINOLONE ACETONIDE/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S22,S36
• 危险类别码：
  R40
• WGK Germany：
  3
• 海关编码：
  2937229000
• 危险品运输编号：
  OTH
• RTECS号：
  TU3850000

制备方法与用途

醋酸曲安西龙（Triamcinolone）概述

醋酸曲安西龙（Triamcinolone）是一种肾上腺皮质激素及促肾上腺皮质激素药物，其抗炎作用比氢化可的松和泼尼松更强，但水钠潴留作用较轻微。口服易吸收，适用于类风湿性关节炎、其他结缔组织疾病、支气管哮喘、过敏性皮炎、神经性皮炎、湿疹等。特别适合对皮质激素禁忌且伴有高血压或水肿的关节炎患者。

适应症

利用其强大的免疫抑制作用，醋酸曲安西龙用于治疗各种变态反应性炎症和自身免疫性疾病。其主要药理作用与醋酸泼尼松（强的松）相似，因此适用证也基本相同，主要包括：

1. 系统性红斑狼疮等结缔组织病。
2. 肾病综合征等免疫性肾脏疾病。
3. 特发性血小板减少性紫癜等免疫性疾病。
4. 醋酸泼尼松适用的其他疾病。

生物活性

Triamcinolone是一种糖皮质激素，可采用游离醇或酯化形式口服、肌肉注射、局部注射、吸入或外用。用于治疗多种以皮质类固醇表示的疾病。

目标	值
肾上腺素受体	()

用途

作为激素类药物使用。

反应信息

• 作为反应物：
  描述：

  曲安西龙 在 双氧水 、 potassium carbonate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 以45%的产率得到9α-fluoro-16α,17α,11β-trihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid
  参考文献：
  名称：

  抗炎的17β-硫代烷基-16α，17α-缩酮和-缩醛雄酮类：一类新的用于治疗哮喘的气道选择性类固醇。

  摘要：

  描述了新型的17β-硫代烷基-16α，17α-缩酮和-缩醛雄烷烃的合成和抗炎作用。这类新的类固醇是通过将相应的17个酸的2-硫代-1,2-二氢吡啶-1-基酯片段化为17-自由基制成的。使用多种亲二硫键捕获生成的自由基，得到在C-16和C-17处具有乙缩醛或缩酮功能的甾族D环，以及在C-17处具有硫键。该系列化合物与糖皮质激素受体高效结合，是功能性激动剂，通过在体外诱导大鼠肝细胞系中酪氨酸氨基转移酶活性的能力来衡量。当直接施用于呼吸道时，这些17β-硫代烷基雄烷酮可有效抑制Sephadex诱导的大鼠肺部炎症。与目前可获得的吸入式糖皮质激素相比，高的局部效力以及诱导全身性类糖皮质激素样副作用（大鼠胸腺退化）的低倾向使本发明化合物具有高度的气道选择性。本文所述的17β-硫代烷基-16α，17α-缩酮雄烷酮可用于治疗炎性疾病例如哮喘。

  DOI：

  10.1021/jm9604639
• 作为产物：
  描述：

  16β,21-diacetoxy-9-fluoro-11β,17-dihydroxy-pregna-1,4-diene-3,20-dione 在 氢氧化钾 作用下， 生成 曲安西龙
  参考文献：
  名称：

  ALKALINE REARRANGEMENT OF PHENYL GROUPS LINKED TO SILICON

  摘要：

  DOI：

  10.1021/ja01514a062

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] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• 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] ARYL ETHER-BASE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE KINASES DE TYPE ARYLÉTHER-BASE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2015038112A1

  公开（公告）日：2015-03-19

  The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.

  本公开涉及一般可抑制AAK1（适配器相关激酶1）的化合物，包括这些化合物的组合物，以及抑制AAK1的方法。

表征谱图