达比加群

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 中文名称: 达比加群
• 中文别名: N-[[2-[[[4-(氨基亚氨基甲基)苯基]氨基]甲基]-1-甲基-1H-苯并[D]咪唑-5-基]羰基]-N-吡啶-2-基-BETA-丙氨酸
• 英文名称: dabigatran
• 英文别名: BIBR 953；[14C]-Dabigatran；3-[[2-[[4-[amino(azaniumylidene)methyl]anilino]methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate
• 化学式: C₂₅H₂₅N₇O₃
• 分子量: 471.519
• InChiKey: YBSJFWOBGCMAKL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  150
• 氢给体数：
  4
• 氢受体数：
  7

ADMET

代谢

口服给药后，达比加群酯转化为达比加群。通过酯酶催化的水解，将达比加群酯分解为活性成分达比加群是主要的代谢反应。达比加群不是CYP450酶的底物、抑制剂或诱导剂。达比加群会形成药理活性的酰基葡萄糖苷酸共轭物。存在四种位置异构体，1-O、2-O、3-O和4-O-酰基葡萄糖苷酸，每种在血浆中的总量都不到10%。

After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.

来源:Hazardous Substances Data Bank (HSDB)

代谢

达比加群（BIBR 953 ZW，β-丙氨酸，N-((2-(((4-(氨基亚胺基甲基)苯基)氨基)甲基)-1-甲基-1H-苯并咪唑-5-基)羰基)-N-2-吡啶基）是直接凝血酶抑制剂，对其药代动力学和代谢进行了研究，研究对象为10名健康男性，他们接受了200毫克(14)C-达比加群乙酯（BIBR 1048 MS，达比加群的口服前药）或5毫克(14)C-达比加群的静脉输注。在一周内测量了血浆、尿液和粪便中的放射性。通过高效液相色谱在线放射性检测分析代谢物模式，并通过质谱阐明代谢物结构。达比加群乙酯迅速转化为达比加群，大约1.5小时后达到血浆达比加群浓度的峰值……主要代谢反应是酯酶介导的达比加群乙酯水解为达比加群。口服给药后，I相代谢物在尿液中的剂量占比小于或等于0.6%，在粪便中占5.8%；静脉给药后，在尿液和粪便中分别小于或等于1.5%和0.2%。口服和静脉给药后，达比加群酰葡萄糖苷酸在尿液中的剂量分别占0.4%和4%。体外实验证实，达比加群乙酯主要被酯酶代谢，细胞色素P450不起重要作用。这些发现表明，口服给药达比加群乙酯后，可以迅速达到达比加群的药理活性浓度，并且达比加群与细胞色素P450代谢的药物之间发生临床相关相互作用的潜力较低。

The pharmacokinetics and metabolism of the direct thrombin inhibitor dabigatran (BIBR 953 ZW, beta-alanine, N-((2-(((4-(aminoiminomethyl)phenyl)amino)methyl)-1-methyl-1H-benzimidazol-5-yl)carbonyl)-N-2-pyridinyl) were studied in 10 healthy males, who received 200 mg of (14)C-dabigatran etexilate (BIBR 1048 MS, the oral prodrug of dabigatran) or an i.v. infusion of 5 mg of (14)C-dabigatran. Radioactivity was measured in plasma, urine, and feces over 1 week. The metabolite pattern was analyzed by high-performance liquid chromatography with on-line radioactivity detection, and metabolite structures were elucidated by mass spectrometry. Dabigatran etexilate was rapidly converted to dabigatran, with peak plasma dabigatran concentrations being attained after approximately 1.5 hr ...The predominant metabolic reaction was esterase-mediated hydrolysis of dabigatran etexilate to dabigatran. Phase I metabolites accounted for <or=0.6% of the dose in urine and 5.8% of the dose in feces following p.o. administration and <or=1.5 and 0.2%, respectively, following i.v. administration. Dabigatran acylglucuronides accounted for 0.4 and 4% of the dose in urine after p.o. and i.v. dosing, respectively. In vitro experiments confirmed that dabigatran etexilate is metabolized primarily by esterases and that cytochrome P450 plays no relevant role. These findings suggest that pharmacologically active concentrations of dabigatran are readily achieved after p.o. administration of dabigatran etexilate and that the potential for clinically relevant interactions between dabigatran and drugs metabolized by cytochrome P450 is low.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

达比加群长期治疗与轻至中度ALT升高（超过正常上限的3倍）相关，发生在1.5%至3%的患者中，总体发生率略低于低分子量肝素，与华法林相似。尽管尚未发表因达比加群导致临床明显肝损伤的病例报告，但在达比加群的大规模、上市前临床试验中确实出现了几例伴有黄疸的ALT升高病例。这些病例病情轻微且自限性，停药后完全恢复。然而，并非总能确定肝损伤的其他原因，与达比加群治疗的关系仍不明确。这些病例的临床特征没有描述。在一项大型临床试验中，这些无法解释的肝损伤伴胆红素升高的大约发生在2000名治疗患者中的1名。在随后的一个病例报告中，肝损伤伴黄疸和血清酶升高的混合模式在开始使用达比加群后4周内出现，并在停药后迅速解决。没有出现免疫过敏和自身免疫特征。世界卫生组织和美国食品药品监督管理局的监测数据库收到了多份关于肝损伤的自发报告，其中一些是致命的，但事件的关联性尚未明确界定。因此，由于达比加群导致的临床明显肝损伤伴黄疸是罕见的，通常轻微且自限性。 可能性评分：D（可能是临床明显肝损伤的罕见原因）。 达比加群之所以被严格审查其肝毒性的证据，一个原因是首个口服直接凝血酶抑制剂，即在临床试验中开发和评估的希美加群（ximelagatran），后来被发现与罕见但可能严重的肝损伤病例相关，通常在治疗1至6个月后出现，表现为肝细胞模式的血清酶升高，并可能发展为严重和致命的病程。由于对肝毒性的担忧，希美加群在美国未获得使用批准。在发现几例服用希美加群的患者出现临床明显肝损伤后，它也被撤出了欧洲市场。后来发现，服用希美加群期间血清ALT升高的风险与HLA-DRB1*07和DQA1*-02有关。

Chronic therapy with dabigatran 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 heparin and similar to the rates with warfarin. While case reports of clinically apparent liver injury due to dabigatran have not been published, several instances of ALT elevations with jaundice occurred during the large, prelicensure clinical trials of dabigatran. These cases were mild and self-limited, resolving completely once therapy was stopped. However, other causes of liver injury could not always be identified and the relationship of the injury to dabigatran therapy remains unclear. The clinical features of these cases were not described. In one large clinical trial, these unexplained cases of liver injury with bilirubin elevations occurred in approximately 1 in 2000 patients treated. In a subsequent case report, liver injury with jaundice and a mixed pattern of serum enzyme elevations arose within 4 weeks of starting dabigatran and resolved rapidly with its discontinuation. Immunoallergic and autoimmune features were not present. There have been multiple spontaneous reports of liver injury, some of which were fatal, made to WHO and FDA surveillance databases, but the relatedness of the episodes has not been clearly defined. Thus, clinically apparent liver injury with jaundice due to dabigatran occurs but is rare and typically mild and self-limited. Likelihood score: D (possible rare cause of clinically apparent liver injury). One reason why dabigatran was subjected to close scrutiny for evidence of hepatotoxicity was that the initial oral, direct thrombin inhibitor developed and evaluated in clinical trials was ximelagatran (zye" mel a gat' ran), which subsequently was found to be associated with rare but potentially severe cases of liver injury, typically arising after 1 to 6 months of treatment with a hepatocellular pattern of serum enzyme elevations and potentially severe and fatal course. Ximelagatran did not receive approval for use in the United States because of concerns about hepatotoxicity. After several further cases of clinically apparent hepatic injury were found in patients taking ximelagatran, it was also withdrawn from use in Europe. Risk of serum ALT elevations during ximelagatran therapy were later shown to be linked to HLA-DRB1*07 and DQA1*-02.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概要：在成人中，少于7%的达比加群以达比加群乙磺酸盐的前药形式口服吸收；达比加群本身口服不吸收。来自2个个体的初步数据显示，达比加群很少排入母乳中，不太可能影响哺乳的婴儿。如果母亲需要使用达比加群，这不是停止哺乳的理由。由于数据有限，监测早产儿或新生儿是否有出血迹象。 ◉ 对哺乳婴儿的影响：将达比加群加入新生儿和早产儿血液样本中，浓度与服用220毫克达比加群乙磺酸盐后母乳中的浓度相同，结果显示对凝血没有影响。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:In adults, less than 7% of dabigatran is absorbed orally in its prodrug form of dabigatran etexilate mesylate; dabigatran itself is not absorbed orally. Preliminary data from 2 individuals indicate that dabigatran is poorly excreted into breastmilk and unlikely to affect the breastfed infant. If dabigatran 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:Samples of newborn and preterm infant blood spiked with of dabigatran in the concentrations found in breastmilk after a 220 mg dose of dabigatran etexilate indicate that no effect on coagulation would occur. ◉ 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

联合使用CYP3A4同工酶底物（阿托伐他汀）和达比加群酯对这两种药物的药代动力学没有临床相关影响。此外，联合使用CYP2C9底物（双氯芬酸）和达比加群酯对这两种药物的药代动力学也没有临床相关影响。

The concomitant use of a CYP3A4 isoenzyme substrate (atorvastatin) and dabigatran did not have clinically relevant effects on the pharmacokinetics of either drug. Also, the concomitant use of a CYP2C9 substrate (diclofenac) and dabigatran did not have clinically relevant effects on the pharmacokinetics of either drug.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

使用利福平7天后，随后单次给予达比加群，导致达比加群血药浓度-时间曲线下面积（AUC）和峰浓度分别下降66%和67%。在停用利福平7天内，达比加群的暴露量接近不与利福平同时使用时的预期水平。应避免同时使用。

Administration of rifampin for 7 days followed by a single dose of dabigatran resulted in decreases of 66 and 67% in dabigatran area under the plasma concentration-time curve (AUC) and peak plasma concentration, respectively. Within 7 days of rifampin discontinuance, dabigatran exposure approached levels expected without concurrent use of rifampin. Concomitant use should be avoided.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

达比加群与P-糖蛋白抑制剂的联合使用可能会增加达比加群的全系统暴露。尽管临床数据和药代动力学研究表明，达比加群与某些P-糖蛋白抑制剂（例如，胺碘酮、克拉霉素、酮康唑、奎尼丁、维拉帕米）的联合使用并不需要调整剂量，但制造商表示，这些结果不应推广到所有P-糖蛋白抑制剂。

Concomitant use of dabigatran with P-glycoprotein inhibitors may increase systemic exposure to dabigatran. While clinical data and pharmacokinetic studies indicate that concomitant use of dabigatran with certain P-glycoprotein inhibitors (i.e., amiodarone, clarithromycin, ketoconazole, quinidine, verapamil) does not necessitate dosage adjustments, the manufacturer states that these results should not be extrapolated to all P-glycoprotein inhibitors.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

达比加群酯口服给药后，达比加群的绝对生物利用度大约为3%到7%。达比加群酯是外排转运蛋白P-gp的底物。在健康志愿者中口服给予达比加群酯后，空腹状态下的Cmax出现在给药后1小时。与高脂肪餐同服达比加群会使Cmax的时间延迟大约2小时，但对达比加群的生物利用度没有影响；达比加群可以在有或没有食物的情况下给药。

The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3 to 7%. Dabigatran etexilate is a substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilate in healthy volunteers, Cmax occurs at 1 hour post-administration in the fasted state. Coadministration of Dabigatran with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran; Dabigatran may be administered with or without food.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

达比加群酯的口服生物利用度在没有胶囊壳的情况下服用颗粒时，比完整胶囊配方增加了75%。因此，在给药前不应压碎、咀嚼或打开达比加群胶囊。

The oral bioavailability of dabigatran etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation. Dabigatran capsules should therefore not be broken, chewed, or opened before administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

达比加群大约有35%与人类血浆蛋白结合。以总放射性测量的达比加群在红细胞与血浆中的分配比小于0.3。

Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

达比加群的地域分布量为50至70升。在单次剂量为10至400毫克时，达比加群的药代动力学呈剂量比例。每天两次给药时，达比加群的积累因子大约为二。

The volume of distribution of dabigatran is 50 to 70 L. Dabigatran pharmacokinetics are dose proportional after single doses of 10 to 400 mg. Given twice daily, dabigatran's accumulation factor is approximately two.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  达比加群 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 、 potassium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 5.25h， 生成
  参考文献：
  名称：

  多取代4-甲氨基苯甲脒的酯衍生物及其制备方 法和用途

  摘要：

  本发明提供具有通式(Ⅰ)结构的一类新的多取代4‑甲氨基苯甲脒的酯衍生物，式中A1、A2、A3、A4同说明书中的定义，或其医药上可接受的盐。该类化合物具有抗凝血作用，可用于制备预防和治疗血栓栓塞性疾病的药物。

  公开号：

  CN103524559B
• 作为产物：
  描述：

  3-[[[2-[[(4-氰基苯基)氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基]吡啶-2-基氨基]丙酸乙酯 在 盐酸 、 potassium carbonate 、 sodium hydroxide 作用下， 以 乙醇 、 水 、 丙酮 为溶剂， 反应 34.0h， 生成 达比加群
  参考文献：
  名称：

  达比加群酯的一种中间体及其制备方法

  摘要：

  本发明公开了达比加群酯的一种新的中间体形式，即式V‑A所示的3‑[[[2‑[[[4‑[[乙氧基]亚胺甲基]苯基]氨基]甲基]‑1‑甲基‑1H‑苯并咪唑‑5‑基]羰基](吡啶‑2‑基)氨基]丙酸乙酯的盐，该类盐纯度和稳定性良好，可长期贮存和作为工艺中间体或起始原料使用，而且在制备后续中间体及达比加群酯时，反应操作简便，产品纯度高，有利于工业化应用。

  公开号：

  CN104177337B

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] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2017046658A1

  公开（公告）日：2017-03-23

  Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

  Amernita毒素的衍生物的化学式（I），其中，化学式（a）中的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、X、L、m、n和Q在此处被定义。这些衍生物的制备。这些衍生物在靶向治疗癌症、自身免疫性疾病和传染病中的治疗用途。
• [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。