道诺霉素 | 20830-81-3

• 物质功能分类: 原料药 - 抗肿瘤药 - 抗生素类抗肿瘤药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 中文名称: 道诺霉素
• 中文别名: 红保霉素；柔红霉素；红比霉素；红卫霉素；柔毛霉素；正定霉素
• 英文名称: DNR
• 英文别名: daunorubicin；daunomycin；(7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
• CAS: 20830-81-3
• 化学式: C₂₇H₂₉NO₁₀
• 分子量: 527.528
• InChiKey: STQGQHZAVUOBTE-VGBVRHCVSA-N

物化性质

• 熔点：
  155 °C
• 沸点：
  608.13°C (rough estimate)
• 密度：
  1.3522 (rough estimate)
• 溶解度：
  DMSO 中≥83.33 mg/mL
• 物理描述：
  Anthracycline antibiotic. An anticancer agent.
• 颜色/状态：
  Reddish needles
• 蒸汽压力：
  9.4X10-15 mm Hg at 25 °C
• 稳定性/保质期：
  Following reconstitution as directed, daunorubicin hydrochloride solutions are stable for 24 hours at room temperature or 48 hours when refrigerated at 2-8 °C. The reconstituted solution should be protected from sunlight. Daunorubicin hydrochloride is unstable in solutions with a pH greater than 8; decomposition is indicated by a color change from red to blue-purple.
• 解离常数：
  pKa = 7.85
• 碰撞截面：
  222.9 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)：
  1.8
• 重原子数：
  38
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  186
• 氢给体数：
  5
• 氢受体数：
  11

ADMET

代谢

盐酸柔红霉素在肝脏和其他组织中广泛代谢，主要由细胞质醛酮还原酶进行，产生柔红霉素醇，这是主要代谢物，具有抗肿瘤活性。大约40%的药物在血浆中以柔红霉素醇的形式存在，在给予非包封柔红霉素30分钟内，60%在4小时后。

Daunorubicin hydrochloride is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of nonencapsulated daunorubicin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

柔红霉素醇仅在给予脂质体柔红霉素柠檬酸盐静脉注射后，在血浆中以低浓度被检测到。在接受静脉注射40毫克/平方米剂量的脂质体柔红霉素的艾滋病相关卡波西肉瘤患者中，柔红霉素醇的曲线下面积（AUC）仅占总柔红霉素AUC的2%。通过还原裂解糖苷键的额外代谢产生苷元，这些苷元几乎没有或没有细胞毒性，并且通过微体酶发生去甲基化和与硫酸盐和葡萄糖醛酸结合。

Daunorubicinol has been detected only in low concentrations in the plasma following iv administration of daunorubicin citrate liposomal injection. In patients with AIDS-associated Kaposi's sarcoma receiving iv administration of liposomal daunorubicin doses of 40 mg/sq m, the AUC of daunorubicinol represented only 2% of the total daunorubicin AUC. Additional metabolism by reductive cleavage of the glycosidic bond produces aglycones, which have little or no cytotoxic activity and are demethylated and conjugated with sulfate and glucuronide by microsomal enzymes.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在人体尿液中发现的代谢物包括：道诺霉素醇、道诺霉素醇苷元、去甲基脱氧道诺霉素醇苷元、去甲基脱氧鲁比霉素醇苷元-4-O-硫酸盐、去甲基氧道诺霉素醇苷元-4-O-葡萄糖苷酸和脱氧道诺霉素醇苷元葡萄糖苷酸。

Metabolites identified in human urine are daunorubicinol, daunorubicinol aglycone, desmethyldeoxydaunorubicinol aglycone, desmethyldeoxyrubicinol aglycone-4-o-sulfate, desmethyloxydaunorubicinol aglycone-4-o-glucuronide, and deoxydaunorubicinol aglycone glucuronide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

广泛代谢，最初转化为活性醇代谢物；进一步通过肝微粒体代谢为非活性的苷元和脱甲基的葡萄糖醛酸和硫酸结合物。

Extensively metabolized, initially to active alcohol metabolites; further metabolized by liver microsomes to inactive aglycones and demethylated glucuronide and sulfate conjugates.

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏 消除途径：给予剂量的盐酸多柔比星有25%以活性形式通过尿液排泄，估计有40%通过胆汁排泄。 半衰期：18.5小时

Hepatic Route of Elimination: Twenty-five percent of an administered dose of daunorubicin hydrochloride is eliminated in an active form by urinary excretion and an estimated 40% by biliary excretion. Half Life: 18.5 hours

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

柔红霉素具有抗有丝分裂和细胞毒活性，通过多种提出的机制作用：柔红霉素通过与碱基对之间的插入形成DNA复合物，并且通过稳定DNA-拓扑异构酶II复合物来抑制拓扑异构酶II的活性，阻止拓扑异构酶II催化的连接-再连接反应中的再连接部分。

Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Daunorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

使用多柔比星联合其他药物进行化疗与一定比例患者的血清酶水平升高有关，具体取决于使用的剂量和其他药物。多柔比星治疗期间ALT升高通常是无症状和短暂的，可能会在没有调整剂量的情况下解决。在许多情况下，由于接触其他可能具有肝毒性的药物，很难将肝功能测试异常归因于多柔比星。目前还没有确切的证据表明多柔比星治疗与急性、临床上明显的特发性肝损伤和黄疸有关。然而，高剂量的多柔比星与其他抗肿瘤药物联合使用时，已与静脉闭塞性疾病（肝窦阻塞综合征）的病例有关，典型表现为输注后10至30天内出现右上象限疼痛，随后是体重增加、腹水和肝功能测试异常。已有因肝衰竭导致的死亡病例，但大多数患者在发病后1到3个月内恢复。

Chemotherapy with daunorubicin in combination with other agents is associated with serum enzyme elevations in a proportion of patients depending upon the dose and other agents used. ALT elevations during daunorubicin therapy are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to daunorubicin, because of the exposure to other potentially hepatotoxic agents. There have been no convincing instances of acute, clinically apparent idiosyncratic liver injury with jaundice associated with daunorubicin therapy. However, high doses of daunorubicin given in combination with other antineoplastic agents have been linked to cases of sinusoidal obstruction syndrome, typically presenting with right upper quadrant pain 10 to 30 days after the infusion, followed by weight gain, ascites and liver test abnormalities. Fatalities due to hepatic failure have occurred, but most patients recover within 1 to 3 months of onset.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：道诺霉素

Compound:daunorubicin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

道诺霉素在以44 mg/m2剂量给予脂质体制剂90分钟静脉滴注后，达到峰浓度（cmax）为24.8 μg/mL，达峰时间（tmax）为2小时。

Daunorubicin was found to have a tmax of 2 h and a cmax of 24.8 μg/mL after a 90 min infusion of the liposomal formulation at a dose of 44 mg/m2.

来源:DrugBank

吸收、分配和排泄

• 消除途径

多柔比星通过肝脏消除。40%的多柔比星通过胆汁排出，而25%以活性形式（多柔比星或多柔比星醇）通过尿液排出。在脂质体配方中，只有9%的活性分子通过尿液排出。

Daunorubicin is eliminated hepatically. 40% of daunorubicin is excreted in the bile while 25% is excreted in an active form (daunorubicin or daunorubicinol) in the urine. In the liposomal formulation, only 9% of active molecules are excreted in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

用脂质体配方报告的道诺霉素稳态分布容积为1.91 L/m²。脂质体配方的平均分布容积报告为6.6 L。

Daunorubicin has a steady-state volume of distribution of 1.91 L/m² reported with the liposomal formulation. The average volume of distribution reported for the liposomal formulation is 6.6 L.

来源:DrugBank

吸收、分配和排泄

• 清除

多柔比星（Daunorubicin）的清除率为每平方米每小时68.4毫升，这一数据是通过使用脂质体制剂确定的。

Daunorubicin has a clearance of 68.4 mL/h/m² determined using the liposomal formulation.

来源:DrugBank

吸收、分配和排泄

注意：脂质体封装可以显著影响药物相对于未封装药物的功能特性。此外，不同的脂质体药物产品在脂质体的化学组成和物理形态上可能彼此不同。这些差异可能会显著影响脂质体药物产品的功能特性。

Note: Liposomal encapsulation can substantially affect a drug's functional properties relative to those of the unencapsulated drug. In addition, different liposomal drug products may vary from one another in the chemical composition and physical form of the liposomes. Such differences can substantially affect the functional properties of liposomal drug products.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1(b)
• 危险类别码：
  R3249
• 危险品运输编号：
  UN 3249
• 包装等级：
  III
• 危险类别：
  6.1(b)

制备方法与用途

柔红霉素

柔红霉素是一种临床一线抗癌药物，属于第一代蒽环类抗肿瘤抗生素。它还有多种别名，如正定霉素、红比霉素、红保霉素等，并被广泛应用于肿瘤的治疗。其主要作用机制是干扰细胞的核酸合成过程，能够直接与DNA结合，阻碍DNA和依赖DNA的RNA合成反应，对RNA的影响尤为显著，并且可以针对嘌呤核苷进行选择性作用。虽然柔红霉素在抗瘤谱上不如阿霉素广泛，但在对抗实体瘤方面也不如后者。

在人类肝脏中存在一种名为羰基还原酶1的酶，能将柔红霉素转化为新的醇代谢物——柔红霉素醇。这一转化过程不仅降低了柔红霉素的抗肿瘤活性，还会引起心脏毒性，造成心肌细胞损伤，从而限制了其临床应用。若能找到抑制羰基还原酶1的化合物，则有望提高柔红霉素等蒽环类抗癌药物的效果，并减少毒副作用。

动物实验显示，柔红霉素对小鼠L1210白血病有延长生命的作用，并且可以治疗氨基甲叶酸、6-巯基嘌呤及5-氟尿嘧啶耐药的细胞株。此外，它还能够治疗吉田肉瘤大鼠，并对环磷酰胺、三乙烯硫代磷酰胺、6-巯基嘌呤、5-氯尿嘧啶、丝裂霉素C及色霉素A3耐药的细胞株表现出一定疗效。

适应症

柔红霉素主要用于治疗急性白血病（包括慢性转为急性的骨髓性白血病）、对常用抗肿瘤药物耐药的急性淋巴细胞或粒细胞白血病，以及小儿急性淋巴细胞白血病缓解率可达60%，但缓解期短，需与其他药物联合使用。

此外，柔红霉素还可以用于治疗淋巴肉瘤、神经母细胞瘤、骨骼肌瘤及绒癌等疾病。

化学性质

柔红霉素是一种红色结晶性或无定形粉末。熔点在188-190℃（分解），易溶于水和甲醇，而不溶于乙醚、丙酮、氯仿或苯。

用途

柔红霉素属于抗癌抗菌素及抗肿瘤药物。

生产方法

我国从河北省正定县土壤中分离出的天蓝淡红色放线菌正定变种（Str. Coeruleorubidus var. Zhengding) 发酵液中提取得到。在发酵过程中产生柔红霉素A和B两种组分，其中A是有效成分，约占30%左右；而B组分毒性比A大近100倍。采用氯仿等溶剂萃取后，通过精炼去除B组分。

类别与毒性 性质

• 类别：有毒物品
• 毒性分级：高毒
• 急性毒性
  • 大鼠经口LD50：336毫克/公斤；
  • 小鼠经口LD50：205毫克/公斤。

可燃性危险特性

明火、受热或遇氧化剂可燃；燃烧时排放氮氧化物，产生刺激烟雾。

储运特性

• 应存放在通风低温干燥的库房内；
• 轻装轻卸，并与氧化剂和酸类分开存放。

灭火方法

使用雾状水、泡沫、砂土或二氧化碳灭火器以及1211灭火剂。

反应信息

• 作为反应物：
  描述：

  道诺霉素 在 potassium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 2.0h， 以99%的产率得到柔红酮
  参考文献：
  名称：

  Bipiperidine conjugates as soluble sugar surrogates in DNA-intercalating antiproliferative polyketides

  摘要：

  1,4'-双哌啶-1'-氨基甲酸酯残基在多柔比星和查特鲁辛中被评估为糖替代物，产生了水溶性衍生物和前药，其抗增殖活性显著提高。

  DOI：

  10.1039/c6cc00890a
• 作为产物：
  描述：

  N-[4-(daunorubicin-N-carbonyloxymethyl)phenyl] O-β-D-glucopyranosyl carbamate 在 bovine liver β-galactosidase 、 水 作用下， 生成 道诺霉素
  参考文献：
  名称：

  Novel anthracycline-spacer-β-glucuronide, -β-glucoside, and -β-galactoside prodrugs for application in selective chemotherapy

  摘要：

  A series of anthracycline prodrugs containing an immolative spacer was synthesized for application in selective chemotherapy. The prodrugs having the general structure anthracycline-spacer-beta-glycoside were designed to be activated by beta-glucuronidase or beta-galactosidase. Prodrugs with -chloro, bromo or -n-hexyl substituents on the spacer were synthesized as well as prodrugs containing a -beta-glucuronyl, -beta-glucosyl or -beta-galactosyl carbamate specifier. The key step in the synthesis of all prodrugs is the highly beta-diastereoselective addition reaction of the anomeric hydroxyl of a glycosyl donor to a spacer isocyanate resulting in the respective beta-glycosyl carbamate pro-moieties. The resulting protected pro-moieties were coupled to an anthracycline. Prodrugs were evaluated with respect to activation rate by the appropriate enzyme and additionally, their IC50 values were determined. Optimal prodrugs in this study were at least 100- to 200-fold less toxic than their corresponding drug in vitro and were activated to the parent drug in a half-life time of approximately 2 h. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00095-4
• 作为试剂：
  描述：

  、 、 柔红霉素 盐酸盐 、 三乙胺 、 acetone diethyl ether 在 道诺霉素 作用下， 以 二甲基亚砜 为溶剂， 反应 1.0h， 生成 道诺霉素
  参考文献：
  名称：

  Synthetic polymeric drugs

  摘要：

  一种聚合物药物，包括惰性合成聚合物载体，通过氨基酸或肽间隔物与生物活性分子、靶向基团和可选的交联结合，包括：(a) 5.0至99.7摩尔％的单位，来自N-(2-羟基丙基)甲基丙烯酰胺，(b) 0.2至20.0摩尔％的单位，来自N-甲基丙烯酰化肽，肽基团与生物活性基团结合，(c) 0.1至94.8摩尔％的单位，来自N-甲基丙烯酰胺、N-甲基丙烯酸或N-甲基丙烯酰化氨基酸或肽，与能够与细胞表面特定受体相互作用的决定因子结合，(d) 可选地，0至5摩尔％的单位，来自N-甲基丙烯酰化肽，肽基团与类似肽基团连接的另一个聚合物链相似，(e) 可选地，作为生物测定标签，0至2摩尔％的单位，来自N-甲基丙烯酰化酪氨酰胺。

  公开号：

  US05037883A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。
• [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。