倍他米松 | 378-44-9

• 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: 倍他米松
• 中文别名: 16b-甲基-11b,17a,21-三羟基-9a-孕甾-1,4-二烯-3,20-二酮；Beta-美松；甲醇中倍他米松
• 英文名称: betamethasone
• 英文别名: dexamethasone；(8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one
• CAS: 378-44-9
• 化学式: C₂₂H₂₉FO₅
• 分子量: 392.468
• InChiKey: UREBDLICKHMUKA-DVTGEIKXSA-N

物化性质

• 熔点：
  235-237°C
• 比旋光度：
  D +108° (acetone)
• 沸点：
  568.2±50.0 °C(Predicted)
• 密度：
  1.1283 (estimate)
• 溶解度：
  几乎不溶于水，微溶于无水乙醇，极微溶于二氯甲烷。
• LogP：
  2.01 at 25℃
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from ethyl acetate
• 气味：
  ODORLESS
• 水溶性：
  -3.77
• 稳定性/保质期：
  HYGROSCOPIC. /SODIUM PHOSPHATE/
• 旋光度：
  Specific optical rotation: +63.5 deg @ 24 °C/D (dioxane)
• 碰撞截面：
  186.7 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)：
  1.9
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  94.8
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

倍他米松的代谢产生6种代谢物。代谢过程包括6β-羟基化、11β-羟基氧化以及C-20羰基团的还原随后侧链的移除。

The metabolism of betamethasone yields 6 metabolites. The metabolic processes include 6β hydroxylation, 11β-hydroxyl oxidation, and reduction of the C-20 carbonyl group followed by removal of the side chain.

来源:DrugBank

代谢

所有生物活性的肾上腺皮质类固醇及其合成同类物在4,5位置有一个双键，在C 3位有一个酮基团。一般来说，类固醇激素的代谢涉及连续添加氧或氢原子，然后进行共轭反应形成水溶性衍生物。4,5双键的还原在肝脏和肝脏外部位发生，产生无活性化合物。随后，C 3位的酮基团还原为3-羟基衍生物，形成四氢可的松，这一过程仅发生在肝脏中。这些A环还原的类固醇大多数通过3-羟基团与硫酸或葡萄糖醛酸通过在肝脏中进行的酶促反应共轭，在肾脏中也有一部分。产生的硫酸酯和葡萄糖苷酸形成水溶性衍生物，是尿液中主要排泄的形式。在人类中，胆汁或粪便的排泄在数量上并不重要。/肾上腺皮质类固醇/

All of the biologically active adrenocortical steroids and their synthetic congeners have a double bond in the 4,5 position and a ketone group at C 3. As a general rule, the metabolism of steroid hormones involves sequential additions of oxygen or hydrogen atoms, followed by conjugation to form water-soluble derivatives. Reduction of the 4,5 double bond occurs at both hepatic and extrahepatic sites, yielding inactive compounds. Subsequent reduction of the 3-ketone substituent to the 3-hydroxyl derivative, forming tetrahydrocortisol, occurs only in the liver. Most of these A ring-reduced steroids are conjugated through the 3-hydroxyl group with sulfate or glucuronide by enzymatic reactions that take place in the liver and, to a lesser extent, in the kidney. The resultant sulfate esters and glucuronides form water-soluble derivatives and are the predominant forms excreted in the urine. Neither biliary nor fecal excretion is of quantitative importance in human beings. /Adrenocortical Steroids/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概述：由于只有大量使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，因此短期使用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，尽可能使用最弱效的药物在最小面积的皮肤上还是谨慎的做法。特别是要确保婴儿的皮肤不直接接触到已用药的区域。只有低效皮质类固醇应该用在乳头或乳晕上，因为婴儿可能会直接从皮肤上摄取药物；应避免在乳头上使用外用倍他米松。倍他米松软膏在治疗哺乳期乳头疼痛方面似乎没有比羊毛脂更优。应该只用可溶于水的乳膏或凝胶产品涂抹乳房，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被用在乳房或乳头区域，哺乳前应彻底擦除。 对哺乳婴儿的影响：将一种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）涂在母亲的乳头上，导致她2个月大的哺乳婴儿出现QT间期延长、库欣综合症外貌、严重高血压、生长减缓和电解质异常。这位母亲从出生时开始因乳头疼痛而使用该乳膏。 一位正在哺乳（具体程度未说明）的新生儿母亲，因天疱疮接受口服泼尼松龙25毫克/天的治疗，两周内剂量增至60毫克/天。她还每天服用西替利嗪10毫克，并每天两次在病变处使用0.1%的外用倍他米松。由于治疗效果不佳，将倍他米松改为0.05%的克洛贝塔索丙酸酯软膏。她在整个治疗期间继续哺乳，她的婴儿在8周龄及以后发育正常。 对哺乳和母乳的影响：在一项随机双盲试验中，将羊毛脂与一种多功能乳头膏进行比较，该膏剂含有0.05%的倍他米松、1%的莫匹罗星和2%的咪康唑，用于哺乳期前两周的乳头疼痛。两种治疗方法在减少乳头疼痛、乳头愈合时间、哺乳持续时间、哺乳专一率、乳腺炎和乳头症状、副作用或母亲对治疗的满意度方面同样有效。

◉ Summary of Use during Lactation: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. Only the lower potency corticosteroids should be used on the nipple or areola where the infant could directly ingest the drugs from the skin; topical betamethasone should be avoided on the nipple. Betamethasone ointment appears to have no advantage over lanolin for treating sore nipples during breastfeeding. 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. A woman who was nursing (extent not stated) her newborn infant was treated for pemphigus with oral prednisolone 25 mg daily, with the dosage increased over 2 weeks to 60 mg daily. She was also taking cetirizine 10 mg daily and topical betamethasone 0.1% twice daily to the lesions. Because of a poor response, the betamethasone was changed to clobetasol propionate ointment 0.05%. She continued breastfeeding throughout treatment and her infant was developing normally at 8 weeks of age and beyond. ◉ Effects on Lactation and Breastmilk:In a randomized, double-bind trial, lanolin was compared to an all-purpose nipple ointment containing betamethasone 0.05%, mupirocin 1%, and miconazole 2% for painful nipples while nursing in the first 2 weeks postpartum. The two treatments were equally effective in reducing nipple pain, nipple healing time, breastfeeding duration, breastfeeding exclusivity rate, mastitis and nipple symptoms, side effects or maternal satisfaction with treatment.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：倍他米松在哺乳期间并未经过充分研究。由于倍他米松的效力强和低蛋白结合，有利于其进入乳汁，因此最好避免使用，转而选择作用时间更短、研究更充分的替代品。在早产儿出生前3到9天使用倍他米松可能会降低部分妇女的产后泌乳量。局部注射，例如用于腱炎的，不会预期对哺乳婴儿产生任何不良影响，但可能会偶尔导致暂时性的乳汁供应减少。参见倍他米松，外用。 对哺乳婴儿的影响：任何皮质类固醇都没有报告产生影响。 对泌乳和母乳的影响：一位母亲肩部注射5.7毫克倍他米松储库用于治疗滑囊炎，对乳汁供应没有影响。然而，据报道，中到大剂量储库型皮质类固醇关节注射可导致暂时性的泌乳减少。 在20世纪70年代的一项双盲研究中，将早产劳动的孕妇随机分配到接受6毫克短效倍他米松磷酸盐加6毫克长效倍他米松醋酸或含有6毫克可的松醋酸的对照治疗。后来在试验中，由于反应不完全，剂量加倍。共有560名妇女接受了倍他米松，582名接受了可的松。出院时泌乳的妇女百分比没有差异（分别为32%和30.5%）；然而，与当今许多医院的比率相比，这些百分比非常低。 一项对46名在34周前分娩的妇女的研究发现，如果在分娩前3到9天给予倍他米松（两次肌注11.4毫克倍他米松，间隔24小时），会导致哺乳II期延迟和分娩后10天内平均乳汁量减少。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。 一项对87名孕妇的研究发现，孕期给予倍他米松（如上所述）会导致孕期过早刺激乳糖分泌。尽管增加在统计学上是有意义的，但临床意义似乎很小。

◉ Summary of Use during Lactation:Betamethasone has not been well studied during breastfeeding. Systemic betamethasone is best avoided in favor of one of the shorter-acting and better studied alternatives because of its potency and low protein binding which would favor its passage into milk. Use of betamethasone 3 to 9 days prior to delivery of a preterm infant might decrease postpartum milk production in some women. 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 Betamethasone, Topical. ◉ Effects in Breastfed Infants:None reported with any corticosteroid. ◉ Effects on Lactation and Breastmilk:A 5.7 mg dose of depot betamethasone injected into the shoulder for bursitis had no effect in the milk supply in one mother. However, medium to large doses of depot corticosteroids injected into joints have been reported to cause temporary reduction of lactation. A double-blind study in the 1970s randomized pregnant women in preterm labor to either 6 mg of short-acting betamethasone phosphate plus 6 mg long-acting betamethasone acetate or a control treatment containing 6 mg cortisone acetate. Later in the trial, the doses were doubled because of an incomplete response. A total of 560 women received betamethasone and 582 received cortisone. No difference was seen in the percentage of women lactating at hospital discharge (32% and 30.5%, respectively); however, these percentages are very low compared to the rates in many hospitals today. A study of 46 women who delivered an infant before 34 weeks of gestation found that a course of 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. 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.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

皮质醇/倍他米松/的高血糖作用可能会抵消氯丙嗪的低血糖效果...

Hyperglycemic action of cortisone /betamethasone/ may offset hypoglycemic effect of chlorpropamide...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

糖皮质激素诱导的肝酶可能增加一种对肝脏有毒的扑热息痛代谢物的形成，从而在使用慢性或高剂量扑热息痛治疗时增加肝毒性的风险。/糖皮质激素/

Induction of hepatic enzymes by corticosteroids may increase the formation of a hepatotoxic acetaminophen metabolite, thereby increasing the risk of hepatotoxicity, when they are used concurrently with chronic or high-dose acetaminophen therapy. /Corticosteroid/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

胃肠道溃疡或出血的风险可能会在使用这些物质（酒精或非甾体抗炎药（NSAIDs））与糖皮质激素同时使用时增加；然而，在治疗关节炎时，同时使用NSAIDs可能会提供额外的治疗益处，并允许减少糖皮质激素的剂量。/皮质类固醇/

Risk of gastrointestinal ulceration or hemorrhage may be increased when these substances /alcohol or nonsteroidal anti-inflammatory drugs (NSAIDs)/ are used concurrently with glucocorticoids; however, concurrent use of NSAIDs in the treatment of arthritis may provide additive therapeutic benefit and permit glucocorticoids dosage reduction. /Corticosteroids/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

任何局部皮质类固醇，包括倍他米松的吸收和效力取决于运送皮质类固醇的载体。例如，0.05%的倍他米松二丙酸酯软膏被归类为高效局部皮质类固醇，而0.05%的倍他米松二丙酸酯乳膏或乳液被认为是中等效力的。局部皮质类固醇的效力可以通过几种结构上的修改来决定。例如，含有卤素或含有酯的皮质类固醇由于增强了亲脂性而更有效。因此，含有倍他米松二丙酸酯和倍他米松戊酸酯的局部产品之间存在明显差异。倍他米松二丙酸酯含有2个酯，增强了其效力，而倍他米松戊酸酯只有一个酯，效力较低。值得注意的是，使用封闭敷料与局部皮质类固醇显著增加了吸收，从而增加了不良反应的风险。

The absorption and potency of any topical corticosteroid including betamethasone depends on the vehicle in which the steroid is delivered. For example, betamethasone dipropionate 0.05% ointment is classified as a highly potent topical steroid, while betamethasone dipropionate 0.05% cream or lotion is considered to be moderately potent. There are several structural modifications that can determine the potency of a topical corticosteroid. For example, corticosteroids containing a halogen at specific carbons, or that contain esters are more potent due to enhanced lipophilicity. As such, there is a marked difference between topical products containing betamethasone dipropionate vs. betamethasone valerate. Betamethasone dipropionate contains 2 esters which enhances its potency, while betamethasone valerate has only one ester and is less potent. It should be noted that the use of occlusive dressings with topical steroids significantly increases the absorption, increasing the risk for adverse effects.

来源:DrugBank

吸收、分配和排泄

• 消除途径

皮质类固醇主要通过尿液排出。

Corticosteroids are eliminated predominantly in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

在一项包括育龄印度女性的研究中，单次肌内注射倍他米松磷酸钠后的分布体积为94,584±23,539毫升。

In a study that included Indian women of reproductive age, the volume of distribution following a single intramuscular dose of betamethasone phosphate was 94,584±23,539 mL(s).

来源:DrugBank

吸收、分配和排泄

• 清除

在一项包含育龄印度女性的研究中，单次肌内注射磷酸倍他米松后的CL/F为6,466 ± 805 mL/小时。

In a study that included Indian women of reproductive age, the CL/F following a single intramuscular dose of betamethasone phosphate was 6,466 ± 805 mL/hour.

来源:DrugBank

吸收、分配和排泄

糖皮质激素...从局部给药部位全身吸收，例如关节腔、结膜囊、皮肤和呼吸道。当给药时间延长、给药部位被遮盖敷料覆盖，或者当大面积皮肤受到影响时，吸收可能足以引起系统效应，包括抑制下丘脑垂体肾上腺轴。/肾上腺皮质激素/

Glucocorticoids ... absorbed systemically from sites of local administration, such as synovial spaces, the conjunctival sac, skin, and respiratory tract. When administration is prolonged, when the site of application is covered with an occlusive dressing, or when large areas of skin are involved, the absorption may be sufficient to cause systemic effects, including suppression of the HPA axis. /Adrenocorticalsteroids/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn,Xi
• 安全说明：
  S22,S36
• 危险类别码：
  R40
• WGK Germany：
  2
• 海关编码：
  2937229000
• 危险品运输编号：
  HAZARD
• RTECS号：
  TU4000000

制备方法与用途

激素类药物：倍他米松

倍他米松介绍

倍他米松又称培他美松、贝皮质醇、贝氟美松、培氟美松，属于肾上腺皮质激素类药物。它是地塞米松的同分异构体，作用与泼尼松龙和地塞米松相同。该药物具有抗炎、抗风湿、抗过敏和抑制免疫等多种药理作用。

倍他米松的抗炎作用显著强于其他几种常见肾上腺皮质激素（如地塞米松、曲安西龙、氢化可的松）。它可以减轻和防止组织对炎症的反应，减少局部非感染性炎症引起的发热、发红及肿胀。根据研究，0.3毫克倍他米松的抗炎效果与地塞米松0.75毫克、泼尼松5毫克或可的松25毫克相当。

临床应用

倍他米松用于治疗多种疾病和症状，包括活动性风湿病、类风湿性关节炎、红斑狼疮、严重支气管哮喘、严重皮炎、急性白血病、过敏性皮炎、湿疹、神经性皮炎、脂溢性皮炎及瘙痒症等。此外，在某些感染的综合治疗中也有应用。

禁忌症

倍他米松禁用于有严重精神病史、活动性十二指肠或胃溃疡、新近进行过胃肠吻合手术、较重骨质疏松、明显糖尿病、严重高血压，以及病毒、细菌、霉菌感染未能控制的情况下（如脓疱病、体癣、股癣等）。

不良反应

长期使用倍他米松常见的不良反应包括医源性库欣综合征面容和体态改变、体重增加、下肢浮肿、紫纹、易出血倾向、创口愈合不良、痤疮、月经紊乱、骨质疏松及骨折（如脊椎压缩性骨折、长骨病理性骨折）、肌无力、肌萎缩、低血钾综合征、胃肠道刺激（恶心、呕吐）、胰腺炎、消化性溃疡或穿孔等。

生物活性

倍他米松是一种糖皮质激素类固醇，具有显著的抗炎和免疫抑制特性。它对II型糖皮质激素受体具有特异亲合力，并存在于大多数脑区。

体内研究

在妊娠晚期胎羊中，倍他米松可直接收缩外围股动脉血管并减少脑血流量（CBF）。此外，在大鼠实验中发现，倍他米松能够减少NF-κB的活化及肿瘤坏死因子α和IL-1β水平上升，并诱导大脑中IL-10的表达。这些作用与疼痛阈值的变化有关。

倍他米松还能在神经损伤时注射部分减轻神经性痛觉过敏的发展，降低随后升高的脑促炎性细胞因子水平，同时促进抗炎细胞因子IL-10的表达。此外，在成年大鼠肺部中，倍他米松小幅增加胞苷酰转移酶（CT）的表达，并在神经损伤时注射部分减少了炎症性介质。

化学性质

倍他米松为白色结晶粉末，熔点231-234℃。醋酸倍他米松亦为白色结晶粉末，熔点205-208℃。它微溶于丙醇和乙醇，极难溶于氯仿或乙醚，并不溶于水。

用途

倍他米松主要用于抗炎及抗过敏治疗。适用于风湿性关节炎及各种皮肤病等临床病症。

生产方法

醋酸倍他米松通过甲醇-氯仿-水的混合物中以盐酸处理，可转换为倍他米松。

分类与毒性

倍他米松属于有毒物品，具有中毒级别，急性口服小鼠LD50大于4500毫克/公斤。该药物是可燃的，在燃烧时会产生有毒氟化物烟雾。

储运与灭火方法

储存和运输应通风、低温干燥。对于火灾使用干粉、泡沫、沙土、二氧化碳或雾状水作为灭火剂。

反应信息

• 作为反应物：
  描述：

  倍他米松 在 aluminum (III) chloride 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 水 为溶剂， 10.0~80.0 ℃ 、60.0 kPa 条件下， 反应 26.5h， 生成 倍他米松二丙酸酯
  参考文献：
  名称：

  一种倍他米松17α-丙酸酯的制备方法

  摘要：

  一种倍他米松17α‑丙酸酯的制备方法，采用倍他米松与原丙酸三乙酯反应，所述的反应在在四氢呋喃溶剂中进行且采用对甲苯磺酸作为催化剂，反应完成后，不经出料，直接在同一溶剂体系下，向体系中滴加三氯化铝溶液，滴加完毕后，保温反应，反应完毕后，经过后处理工艺得到倍他米松17α‑丙酸酯。本发明在解决倍他米松17α‑丙酸酯采用二氧六环或者二甲基甲酰胺或者其他溶剂等做反应溶剂的同时，还简化了制造流程、提高了收率和纯度。

  公开号：

  CN110003299A
• 作为产物：
  描述：

  在 盐酸 作用下， 以 乙酸乙酯 、 水 为溶剂， 反应 1.0h， 以45%的产率得到倍他米松
  参考文献：
  名称：

  倍他米松或地塞米松合成母液料的回收利用 方法

  摘要：

  本发明涉及一种倍他米松或地塞米松合成母液料的回收利用方法，包括步骤：从母料液提取式1所示化合物；将式1所示化合物进行20位羟基基团的保护反应，得到式2所示化合物；将式2所示化合物进行21位醛基的还原反应，得到式3所示化合物，继续进行氧化反应和水解反应，得到式4所示化合物，所述式4所示化合物即为倍他米松或地塞米松；上述回收利用方法可将倍他米松或地塞米松母液料转化成药用价值和经济效益高的倍他米松或地塞米松，具有巨大的经济效益。

  公开号：

  CN110845562B

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。
• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。
• [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] 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