氨柔比星 | 110267-81-7

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 苯类化合物 - 并四苯
• 中文名称: 氨柔比星
• 英文名称: d-7α-[(2-deoxy-β-D-erythro-pentapyranosyl)oxy]-9α-amino-9β-acetyl-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione
• 英文别名: [14C]-Amrubicin；Amrubicin；(+)-9-amino-4-demethoxy-9-deoxy-7-O-(2-deoxy-β-D-erythro-pentopyranosyl)daunomycinone；(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythropentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxynaphthacene-5,12-dione；(7S,9S)-9-acetyl-9-amino-7-[(2S,4S,5R)-4,5-dihydroxyoxan-2-yl]oxy-6,11-dihydroxy-8,10-dihydro-7H-tetracene-5,12-dione
• CAS: 110267-81-7
• 化学式: C₂₅H₂₅NO₉
• 分子量: 483.475
• InChiKey: VJZITPJGSQKZMX-XDPRQOKASA-N

物化性质

• 熔点：
  172-1740C
• 比旋光度：
  D20 +119° (c = 0.02 in CHCl3)
• 沸点：
  717.8±60.0 °C(Predicted)
• 密度：
  1.60±0.1 g/cm3(Predicted)
• 溶解度：
  >16.45mg/mL，溶于 DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  35
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  177
• 氢给体数：
  5
• 氢受体数：
  10

ADMET

代谢

在大鼠和狗中，主要的代谢物（氨柔比星醇）是通过细胞质羰基还原酶在C-13羰基团还原的产物。参与氨柔比星和氨柔比星醇代谢的其他酶包括烟酸腺嘌呤二核苷酸磷酸，还原形式（NADPH）-P450还原酶和烟酸腺嘌呤二核苷酸[磷酸]（NAD[P]H）-醌氧化还原酶。在一项研究中，体内和体外共检测到12种额外的代谢物。在给药后立即到给药后1小时观察到活性代谢物氨柔比星醇的血浆峰浓度。这些包括四种苷元代谢物，两种氨柔比星醇葡萄糖苷酸，脱氨氨柔比星，以及五种高度极性的未知代谢物。体外细胞生长抑制活性的次要代谢物明显低于氨柔比星醇。氨柔比星及其代谢物的排泄主要是肝胆。在大鼠中证明了肠肝循环。

The primary metabolite (amrubicinol) in rats and dogs is a product of reduction by cytoplasmic carbonyl reductase at the C-13 carbonyl group. Other enzymes participating in the metabolism of amrubicin and amrubicinol were nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)–P450 reductase and nicotinamide adenine dinucleotide [phosphate] (NAD[P]H)-quinone oxidoreductase. Twelve additional metabolites were detected in vivo and in vitro in one study. Peak plasma concentrations of the active metabolite amrubicinol were observed from immediately after dosing to 1 hour after dosing. These included four aglycone metabolites, two amrubicinol glucuronides, deaminated amrubicin, and five highly polar unknown metabolites. In vitro cell growth inhibitory activity of the minor metabolites was substantially lower than that of amrubicinol. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats.

来源:DrugBank

毒理性

• 蛋白质结合

对肝功能受损患者和肝功能正常患者的血浆蛋白结合率进行了研究。在肝功能受损的患者中，血浆蛋白结合率为91.3-97.1%，而在肝功能正常的患者中，血浆蛋白结合率为82.0-85.3%。

A study was performed on the plasma protein binding of amrubicin in both patients with hepatic impairment and those with normal liver function. In those with liver impairment, the plasma protein binding was found to be 91.3–97.1% and in those with normal hepatic function, 82.0–85.3%.

来源:DrugBank

吸收、分配和排泄

• 吸收

活性代谢物_amrubicinol_的峰血浆浓度在给予amrubicin后立即观察到，并在给药后1小时达到。与amrubicin的血浆浓度相比，amrubicinol的血浆浓度较低。血浆中amrubicinol的AUC（曲线下面积）大约是amrubicin血浆AUC的十分之一。与血浆相比，红细胞（RBCs）中amrubicinol的浓度更高。与血浆相比，红细胞中amrubicinol的AUCs高出2.5倍至57.9倍。因为amrubicinol比amrubicin更多地分布到红细胞中，所以红细胞中amrubicinol和amrubicin的浓度非常相似。红细胞中amrubicinol的AUC大约是amrubicin红细胞AUC的两倍低。在一项研究中，经过连续每日给药amrubicin后，观察到血浆和红细胞中amrubicinol的积累。在第3天，amrubicinol的血浆AUC比第1天的值高出1.2倍至6倍；红细胞AUC比第1天的值高出1.2倍至1.7倍。在连续5天每日给药后，血浆和红细胞的amrubicinol AUC比第1天的值高出1.2倍至2.0倍。

Peak plasma concentrations of the active metabolite _amrubicinol_ were observed from immediately after administration of amrubicin to 1h after administration. Plasma concentrations of amrubicinol were low compared with amrubicin plasma concentrations. The plasma amrubicinol AUC (area under the curve) was approximately 10-fold lower than the amrubicin plasma AUC. Concentrations of amrubicinol were higher in RBCs as compared with plasma. Amrubicinol AUCs ranged from 2.5-fold to 57.9-fold higher in red blood cells (RBCs) compared to plasma. Because amrubicinol distributes itself into RBCs more than amrubicin, the concentrations of amrubicinol and amrubicin in RBCs were quite similar. The AUC of amrubicinol in RBCs was approximately twofold lower than the amrubicin RBC AUC. In one study, after repeated daily amrubicin administration, amrubicinol accumulation was observed in plasma and RBCs. On day 3, the amrubicinol plasma AUC was 1.2-fold to 6-fold higher than day 1 values; the RBC AUC was 1.2-fold to 1.7-fold higher than day 1 values. After 5 consecutive daily doses, plasma and RBC amrubicinol AUCs were 1.2-fold to 2.0-fold higher than day 1 values.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在一项研究中，摄入安罗ubicin后，安罗ubicin和安罗ubicinol的尿排泄量占给药剂量的2.7%至19.6%。排泄的安罗ubicinol量大约是排泄的安罗ubicin的10倍。安罗ubicin及其代谢物的排泄主要是通过肝胆系统。在大鼠中已经证明了肠肝循环。

In one study, urinary excretion of amrubicin and amrubicinol after ingestion of amrubicin accounted for 2.7% to 19.6% of the administered dose. The amount of excreted amrubicinol was approximately 10-fold greater than excreted amrubicin. Excretion of amrubicin and its metabolites is primarily hepatobiliary. Enterohepatic recycling was demonstrated in rats.

来源:DrugBank

吸收、分配和排泄

• 分布容积

适中的分布容积（总身体水分的1.4倍）。

Moderate volume of distribution (1.4 times total body water).

来源:DrugBank

吸收、分配和排泄

• 清除

癌症患者中安柔比星的血浆药代动力学特征是总清除率低（总肝血流量的22%）。

The plasma pharmacokinetics of amrubicin in cancer patients are characterized by low total clearance (22% of total liver blood flow).

来源:DrugBank

制备方法与用途

氨柔比星是一种合成的蒽环类抗生素，它能够抑制DNA拓扑异构酶II的作用。

反应信息

• 作为反应物：
  描述：

  、 氨柔比星 以 甲醇 、 乙醇 为溶剂， 反应 6.0h， 生成
  参考文献：
  名称：

  [EN] MODIFIED ANTHRACYCLINE COMPOUNDS AND THEIR THERAPEUTIC USE
  [FR] COMPOSÉS D'ANTHRACYCLINE MODIFIÉS ET LEUR UTILISATION THÉRAPEUTIQUE

  摘要：

  本公开涉及一般用于治疗癌症的化合物。在某些方面，本公开提供经化学修饰的蒽环类化合物，其具有一个或多个包含亲水性部分的基团。在某些方面，本公开提供包括这种修饰的阿霉素化合物和蛋白质（如白蛋白或白蛋白类似物）的组合物。此外，本公开提供这些化合物和组合物的各种用途。

  公开号：

  WO2018175622A1
• 作为产物：
  描述：

  氨柔比星中间体2 在 吡啶 、 sodium hydroxide 、 三氯化铝 、 1,3-二溴-5,5-二甲基海因 、 硫酸 、 silver trifluoromethanesulfonate 、 sodium hydride 、 potassium carbonate 、 对甲苯磺酸 、 1,1,3,3-四甲基脲 、 sodium chloride 、 锌 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 、 甲苯 、 苯 为溶剂， 反应 58.82h， 生成 氨柔比星
  参考文献：
  名称：

  Stereospecific total synthesis of 9-aminoanthracyclines: (+)-9-amino-9-deoxydaunomycin and related compounds

  摘要：

  DOI：

  10.1021/jo00229a010

文献信息

• [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。
• [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] 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] PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS<br/>[FR] DÉRIVÉS DE PYRROLOTRIAZINONE EN TANT QU'INHIBITEURS DES PI3K
  申请人：ALMIRALL SA

  公开号：WO2014060432A1

  公开（公告）日：2014-04-24

  New pyrrolotriazinone derivatives having the chemical structure of formula (I), are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks)

  新的吡咯三唑酮衍生物具有化学结构式（I），公开；以及它们的制备方法，包括它们的药物组合物和它们作为磷脂酰肌醇3-激酶（PI3Ks）抑制剂在治疗中的应用。