利伐沙班 | 366789-02-8

• 物质功能分类: 原料药 - 血液系统用药 - 抗凝血药及抗血小板药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 中文名称: 利伐沙班
• 中文别名: 5-氯-N-[[(5S)-2-氧代-3-[4-(3-氧代-4-吗啉基)苯基]-5-恶唑基]甲基]-2-噻吩甲酰胺；5-氯-N-(((5S)-2-氧代-3-(4-(3-氧代吗啉-4-基)苯基)-1,3-恶唑啉-5-基)甲基)噻吩-2-甲酰胺；利伐沙班中间体；立伐沙班；5-氯-氮-(5S)-2-氧-3-[4-(3-氧-4-吗啉基)苯基]-1,3-唑烷-5-基-2-噻吩羧酰胺
• 英文名称: Rivaroxaban
• 英文别名: 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide；Xarelto；5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide；5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl]thiophene-2-carboxamide；(S)-5-chloro-N-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide；(5-chloro-N-(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-ylmethyl)thiophene-2-carboxamide；5-chloro-N-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide；(S)-rivaroxaban；Riva；RXB；5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide
• CAS: 366789-02-8
• 化学式: C₁₉H₁₈ClN₃O₅S
• 分子量: 435.888
• InChiKey: KGFYHTZWPPHNLQ-AWEZNQCLSA-N

物化性质

• 熔点：
  228-229°C
• 沸点：
  732.6±60.0 °C(Predicted)
• 密度：
  1.460±0.06 g/cm3(Predicted)
• 溶解度：
  不溶于水；不溶于乙醇；温和加热下 DMSO 中≥13.9 mg/mL
• 颜色/状态：
  White to yellowish powder
• 气味：
  Odorless
• 蒸汽压力：
  6.66X10-16 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable if stored as directed; avoid strong oxidizing agents
• 分解：
  Dangerous products of decomposition: thermal ecomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides.

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

大约三分之二的剂量会被代谢。它通过CYP3A4、CYP3A5、CYP2J2和CYP独立机制进行代谢。

Approximately two-thirds of the dose is metabolized. It is metabolized by CYP3A4, CYP3A5, CYP2J2 and CYP-independant mechanisms

来源:DrugBank

代谢

Rivaroxaban 经由细胞色素 P-450（CYP）同工酶 3A4/5 和 2J2 的氧化降解以及水解；代谢物随后通过肾脏和粪便/胆汁途径排出。在血浆中未发现主要的循环代谢物。

Rivaroxaban undergoes oxidative degradation by cytochrome P-450 (CYP) isoenzymes 3A4/5 and 2J2 and hydrolysis; metabolites are subsequently eliminated through renal and fecal/biliary routes. No major circulating metabolites have been identified in plasma.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

慢性治疗与利伐沙班与1.5%至3%的患者中度ALT升高(大于正常上限的3倍)相关，总体发生率略低于低分子肝素，与华法林相似。在利伐沙班上市前的大型临床试验中，出现了几例ALT升高伴黄疸的情况，但未提供详细信息，不清楚肝损伤在临床上是否明显。这些病例显然是轻微和自限性的，停止治疗后就完全解决了。自从获得许可和更广泛的使用以来，利伐沙班已与许多急性肝损伤伴黄疸的实例有关。这些病例的临床特征差异很大。大多数病例在开始服用利伐沙班后1到8周内出现黄疸、疲劳和血清酶升高的肝细胞模式。在一些个体中，发现了胆汁淤积或混合模式。免疫过敏特征和自身免疫标志物不典型，但至少有一例出现皮疹和发热，提示DRESS综合征。已经报道了一例归因于利伐沙班的急性肝坏死和死亡，但严重心力衰竭导致的缺血性肝炎是急性肝衰竭的更可能原因。所有其他报道的利伐沙班诱导的肝损伤在停用利伐沙班后恢复，通常非常迅速，在2到4周内。在大型医疗数据库中，急性肝损伤的住院率约为1/2200例，但这些数据库中的所有病例是否代表利伐沙班引起的肝损伤尚不确定。

Chronic therapy with rivaroxaban is associated with moderate ALT elevations (greater than 3 times the upper limit of normal) in 1.5% to 3% of patients, an overall rate which is slightly lower than with low molecular weight heparins and similar to the rates with warfarin. During the large, prelicensure clinical trials of rivaroxaban, several instances of ALT elevations with jaundice occurred, but few details were provided and it was not clear whether the liver injury was clinically apparent. The cases were evidently mild and self-limited, resolving completely once therapy was stopped. Since its licensure and more wide scale use, rivaroxaban has been linked to many instances of acute liver injury with jaundice. The clinical features of these cases varied widely. Most cases had an onset within 1 to 8 weeks of starting rivaroxaban and presented with jaundice, fatigue and a hepatocellular pattern of serum enzyme elevations. In some individuals, a cholestatic or mixed pattern was found. Immunoallergic features and autoimmune markers were atypical but at least one case occurred with skin rash and fever suggestive of DRESS syndrome. One case of acute hepatic necrosis and death attributed to rivaroxaban has been reported, but ischemic hepatitis due to severe heart failure was a more likely cause of the acute liver failure. All other reported cases of rivaroxaban induced liver injury recovered upon stopping rivaroxaban, usually quite promptly, within 2 to 4 weeks. In large health care databases, hospitalization for acute liver injury arises in approximately 1 in 2,200 cases, but whether all cases in these databases represent liver injury from rivaroxaban is uncertain.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：多个病例报告一致表明，母亲每天服用15至30毫克的利伐沙班，在乳汁中产生的水平远低于婴儿抗凝所需剂量。如果母亲需要服用利伐沙班，这不是停止哺乳的理由。由于数据有限，监测早产或新生儿是否有出血迹象。 ◉ 对哺乳婴儿的影响：一名38岁患有抗磷脂综合征的女性，在产后第5天开始每天服用15毫克（0.19毫克/千克）的利伐沙班，用于预防深静脉血栓形成。她部分哺乳她的婴儿（至少50%）。在1个月和3个月的检查中没有发现婴儿有明显的出血迹象，18个月时发育正常。 ◉ 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。

◉ Summary of Use during Lactation:Several case reports consistently indicate that maternal doses of rivaroxaban of 15 to 30 mg daily produce low levels in milk that are considerably below doses required for anticoagulation in infants. If rivaroxaban is required by the mother, it is not a reason to discontinue breastfeeding. Because data are limited, monitor preterm or newborn infants for signs of bleeding. ◉ Effects in Breastfed Infants:A 38-year-old woman with antiphospholipid syndrome began rivaroxaban 15 mg (0.19 mg/kg) daily at 5 days postpartum for prophylaxis of deep vein thrombosis. She partially breast-fed her infant (at least 50%). No apparent evidence of bleeding was noted in the infant at 1- and 3-month check-ups and development was normal at 18 months of age. ◉ 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

接受全剂量Xarelto治疗的同时服用被分类为联合P-gp和弱或中等CYP3A4抑制剂的药物（例如，胺碘酮、地尔硫卓、维拉帕米、奎尼丁、兰诺拉嗪、多非利特、非洛地平、红霉素和阿奇霉素）的肾损害患者，与正常肾功能且未使用抑制剂的患者相比，可能会有暴露量的增加，因为rivaroxaban消除的两种途径都受到影响。只有在潜在的益处证明潜在风险合理时，才应在CrCl为15至50 mL/min且同时接受联合P-gp和弱或中等CYP3A4抑制剂治疗的患者中使用Xarelto。

Patients with renal impairment receiving full dose Xarelto in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected. Xarelto should be used in patients with CrCl 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

单独给予依诺肝素和拜瑞妥的剂量共同作用可产生抗因子Xa活性的叠加效应。华法林和拜瑞妥的单次剂量共同使用可产生对因子Xa抑制和PT的叠加效应。在疗效试验中，已确定同时使用阿司匹林是重大出血事件的独立风险因素。已知非甾体抗炎药（NSAIDs）会增加出血风险，当与拜瑞妥同时使用时，出血风险可能会增加。与拜瑞妥联合使用的血小板聚集抑制剂氯吡格雷在一些受试者中增加了出血时间。除非益处大于风险，否则应避免将拜瑞妥与其他抗凝药物同时使用，因为会增加出血风险。如果患者同时接受阿司匹林、其他血小板聚集抑制剂或NSAIDs治疗，应立即评估任何出血迹象或症状。

Single doses of enoxaparin and Xarelto given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and Xarelto resulted in an additive effect on factor Xa inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with Xarelto. Coadministration of the platelet aggregation inhibitor clopidogrel and Xarelto resulted in an increase in bleeding time for some subjects. Avoid concurrent use of Xarelto with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

药物相互作用研究和临床研究的人群药代动力学分析表明，与P-gp和强效CYP3A4诱导剂（例如，利福平、苯妥英）联合使用Xarelto，可导致利伐沙班暴露量降低多达50%。类似地，对药效动力学效应的降低也观察到了。这些利伐沙班暴露量的降低可能会减少疗效。避免将Xarelto与P-gp和强效CYP3A4诱导剂（例如，卡马西平、苯妥英、利福平、圣约翰草）联合使用。

Results from drug interaction studies and population PK analyses from clinical studies indicate coadministration of Xarelto with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin) decreased rivaroxaban exposure by up to 50%. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy. Avoid concomitant use of Xarelto with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

口服给药后，利伐沙班迅速吸收，2-4小时内达到血浆峰值浓度。10毫克剂量的生物利用度超过80%。然而，如果空腹状态下服用15-20毫克剂量，生物利用度会较低，因此应随餐服用。

Following oral administration, rivaroxaban is rapidly absorbed and reaches peak plasma concentration in 2-4 hours. Bioavailability of the 10 mg dose is >80%. However, the 15-20 mg dose have a lower bioavailability if taken in the fasted state and consequently should be taken with food.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约三分之二的利伐沙班通过尿液排出（通过活跃的肾小管分泌，其中大约36%为未改变的药物，30%为不活跃的代谢物）。剩余的三分之一给药剂量通过粪便排出，其中7%为未改变的药物形式，21%为不活跃的代谢物。

Approximately two-thirds of rivaroxaban is excreted into urine (via active tubular secretion in which approximately 36% as unchanged drug and 30% as inactive metabolism). The remaining third of the administered dose is excreted via feces in which 7% is in the form of unchanged drug and 21% as inactive metabolites.

来源:DrugBank

吸收、分配和排泄

• 分布容积

稳态分布容积 Vd 为 50 升

The steady state Vd is 50 L

来源:DrugBank

吸收、分配和排泄

• 清除

系统清除率大约为10升/小时，因此将利伐沙班视为清除率低的药物。肾清除率约为3-4升/小时。

Systemic clearance is approximately 10 L/h, so rivaroxaban is considered a drug with low clearance. Renal clearance is ~3-4 L/h.

来源:DrugBank

吸收、分配和排泄

经口服给药后，大约三分之一的吸收剂量以原形药物的形式在尿液中排泄，其余三分之二作为非活性代谢物在尿液和粪便中排泄。在一项一期研究中，给予(14)C-利伐沙班剂量后，66%的放射性剂量在尿液中回收（36%为原形药物），28%在粪便中回收（7%为原形药物）。原形药物主要通过活性管分泌进入尿液，其次通过肾小球滤过（大约5:1的比例）。利伐沙班是外排转运蛋白P-gp和ABCG2（也简称为Bcrp）的底物。利伐沙班对内流转运蛋白的亲和力尚不清楚。

Following oral administration, approximately one-third of the absorbed dose is excreted unchanged in the urine, with the remaining two-thirds excreted as inactive metabolites in both the urine and feces. In a Phase 1 study, following the administration of a (14)C-rivaroxaban dose, 66% of the radioactive dose was recovered in urine (36% as unchanged drug) and 28% was recovered in feces (7% as unchanged drug). Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban's affinity for influx transporter proteins is unknown.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  Refrigerator

制备方法与用途

概述

利伐沙班是一种新型口服抗凝药物，适用于非瓣膜性房颤（排除风湿性心脏瓣膜病导致的房颤及心脏瓣膜置换术后出现的房颤）成年患者，旨在降低脑卒中和全身性栓塞的风险。

药物作用

利伐沙班高度选择性和竞争性地抑制游离和结合的Xa因子以及凝血酶原活性。它以剂量依赖方式延长活化部分凝血活酶时间和凝血酶原时间。与磺达肝素钠/肝素相比，利伐沙班无需抗凝血酶III参与，可直接拮抗游离和结合的Xa因子，减少凝血酶的激活，从而延长凝血时间。这种药物不仅阻止新形成的血栓，还能破坏已有的血栓。在进行全髋关节或膝关节置换手术时，腿部静脉血液逆流至心脏易形成血栓，利伐沙班可防止这类血栓的生成与进展。

应用

新型抗凝药最初用于骨科手术后的预防血栓，包括全髋关节和膝关节置换术。研究显示其效果并不亚于低分子肝素。如今，它们已广泛应用于治疗下肢静脉血栓和肺栓塞，并在急性肺栓塞的诊断与治疗指南中被推荐作为替代传统抗凝疗法的选择。

适应症

利伐沙班已被批准用于髋关节或膝关节置换手术成年患者以预防静脉血栓形成（VTE），以及治疗成人深静脉血栓形成（DVT），降低急性DVT后复发和肺栓塞（PE）的风险。此外，它还被推荐用于非瓣膜性房颤成年患者的卒中和全身性栓塞风险降低。

抗血栓药物

利伐沙班与达比加群酯是目前最前沿的抗血栓药物。与传统抗凝药肝素不同的是，它们不需要依赖抗凝血酶Ⅲ即可直接拮抗游离和结合的Xa因子。这两种新型口服抗凝药物在抗凝治疗及潜在致命性血栓预防方面取得了重大进展，在心血管类药物发展史上具有里程碑意义。

利伐沙班

利伐沙班由德国拜耳医药与美国强生公司联合研发，于2008年10月获加拿大和欧盟批准上市，商品名为Xarelto。它作为全球首个口服直接Xa因子抑制剂，在选择性、竞争性和剂量依赖性上表现优异，有效延长活化部分凝血活酶时间和凝血酶原时间，并降低出血风险。

达比加群酯

达比加群酯由德国勃林格殷格翰公司开发，2008年4月在德国和英国上市，商品名为Pradaxa。作为继华法林之后50年来首个上市的新型抗凝血药物，它具有多种独特特点。

用途

利伐沙班用于择期髋关节或膝关节置换手术成年患者，以预防静脉血栓形成（VTE）。

反应信息

• 作为反应物：
  描述：

  利伐沙班 在 盐酸 、 溶剂黄146 作用下， 以 水 为溶剂， 反应 5.0h， 以92.2%的产率得到利伐沙班杂质18
  参考文献：
  名称：

  一种利伐沙班相关物质二胺的合成方法

  摘要：

  一种利伐沙班相关物质二胺，能作为研究，并控制利伐沙班的对照品，且制备方法简便，原料易得。其结构式为：分子式：C25H24CL2N4O4S2，分子量为610.5。本发明的利伐沙班相关物质二胺，能作为监控利伐沙班杂质的对照品。本发明的利伐沙班相关物质二胺的合成方法，操作简单，具有很好的实用性，能够产生较好经济效益和社会效益。

  公开号：

  CN104844588B
• 作为产物：
  描述：

  5-chloro-N-[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolin-5-yl]methyl-N'-benzyl-2-thiophene carboxamide 以54.3的产率得到利伐沙班
  参考文献：
  名称：

  [EN] PROCESSES FOR THE PREPARATION OF 5-CHLORO-N-({(5S)-2-OXO-3-[4-(3-OXO-4-MORPHOLINYL)PHENYL]-1,3-OXAZOLIDIN-5-YL}METHYL)-2-THIOPHENE-CARBOXAMIDE AND INTERMEDIATES THEREOF
  [FR] PROCÉDÉS DE PRÉPARATION DE 5-CHLORO-N-( {(5S)-2-OXO-3-[4-(3-OXO-4-MORPHOLINYL)PHÉNYL]-1,3-OXAZOLIDIN-5-YL MÉTHYL)-2-THIOPHÈNE-CARBOXAMIDE ET DE SES INTERMÉDIAIRES

  摘要：

  本发明涉及制备噁唑烷酮衍生物的过程。更具体地，本发明提供了制备5-氯-N-({(5S)-2-氧代-3-[4-(3-氧代-4-吗啡基)苯基]-1,3-噁唑烷-5-基甲基}-2-噻吩羧酰胺及其中间体的过程。其中L是离去基，如卤素原子（F、Cl、Br、I）或-OSO2R，其中R = C'-4烷基直链或支链，取代或未取代芳基，取代或未取代芳基烷基；使用适当的试剂反应，以提供式（II）的化合物。反应步骤通过将式（IV）的化合物与胺源反应来完成，胺源可以溶解在水或醇等溶剂中，例如氢氧化铵。

  公开号：

  WO2013105100A1

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] BRUTON'S TYROSINE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE LA TYROSINE KINASE DE BRUTON
  申请人：PFIZER

  公开号：WO2014068527A1

  公开（公告）日：2014-05-08

  Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (BTK). Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the BTK inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions. (Formula I)

  本文披露了一种与Bruton's酪氨酸激酶（BTK）形成共价键的化合物。公开了制备这些化合物的方法。还披露了包括这些化合物的药物组合物。公开了使用BTK抑制剂的方法，单独或与其他治疗剂联合治疗自身免疫疾病或症状、异源免疫疾病或症状、癌症，包括淋巴瘤，以及炎症性疾病或症状的方法。 (化学式I)
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。