戊柔比星 | 56124-62-0

• 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: 戊柔比星
• 英文名称: valrubicin
• 英文别名: N-(trifluoroacetyl)adriamycin 14-valerate；N-trifluoroacetyldoxorubicin-14-valerate；Valstar；(2S-cis)-2-[1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-[[4 2,3,6-trideoxy-3-(trifluoroacetyl)-amino-α-L-lyxo-hexopyranosyl]oxyl]-2-naphthacenyl]-2-oxoethyl pentanoate；N-trifluoroacetyladriamycin-14-valerate；[2-oxo-2-[(2S,4S)-2,5,12-trihydroxy-4-[(2R,4S,5S,6S)-5-hydroxy-6-methyl-4-[(2,2,2-trifluoroacetyl)amino]oxan-2-yl]oxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]ethyl] pentanoate
• CAS: 56124-62-0
• 化学式: C₃₄H₃₆F₃NO₁₃
• 分子量: 723.654
• InChiKey: ZOCKGBMQLCSHFP-KQRAQHLDSA-N

物化性质

• 熔点：
  116-117 °C
• 沸点：
  135-136 C
• 密度：
  1.3473 (estimate)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）
• 颜色/状态：
  Orange or orange-red powder

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  51
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  215
• 氢给体数：
  5
• 氢受体数：
  16

ADMET

代谢

曲贝替丁被代谢为两个主要代谢物：N-三氟乙酰阿霉素和N-三氟乙酰阿霉素醇。

Valrubicin is metabolized to two primary metabolites: N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol.

来源:DrugBank

代谢

在膀胱内灌注valrubicin后，在2小时的保留期间，药物转化为其主要代谢物，N-三氟乙酰阿霉素和N-三氟乙酰阿霉素醇的量是最小的。2小时保留期后排出灌注液，药物几乎完全排出。大约98.6%的膀胱内给药剂量以原形药物形式从尿液中排出；N-三氟乙酰阿霉素和总蒽环类药物分别占给药剂量的0.4%和99.0%。

Following intravesical instillation of valrubicin, conversion of the drug to its major metabolites, N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol, is minimal during the 2 hr retention period. Voiding of the instillate after the 2-hour retention period results in almost complete excretion of the drug. About 98.6% of an intravesical dose of the drug is excreted in the urine unchanged; N-trifluoroacetyladriamycin and total anthracyclines account for 0.4 and 99.0%, respectively, of an administered dose.

来源:Hazardous Substances Data Bank (HSDB)

代谢

主要代谢物是N-三氟乙酰阿霉素和N-三氟乙酰阿霉素醇，它们已在血液中进行了测量。

Major metabolites are N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol, which have been measured in blood.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在体内研究中，钙通道阻断剂维拉帕米增强了瓦鲁比星对人类膀胱肿瘤细胞耐药株的活性。

In an in vivo study, the activity of valrubicin against a resistant line of human bladder tumor cells was enhanced by the calcium-channel blocking agent verapamil.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支持性措施：保持呼吸道通畅，必要时辅助呼吸。如果出现昏迷、癫痫、低血压和心律不齐，应予以治疗。使用甲氧氯普胺治疗恶心和呕吐，使用静脉晶体液治疗由胃肠炎引起的液体流失。对于骨髓抑制，应在有经验的血液学家或肿瘤学家的帮助下进行治疗。/抗肿瘤药物/

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

对瓦鲁比辛过量没有已知的解药。

There is no known antidotes to valrubicin over dose.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

Decontamination: Prehospital: 如果有条件，给予活性炭。如果预计在给予活性炭前会有超过60分钟的延迟，考虑使用吐根糖浆诱导呕吐，如果在接触后几分钟内可以给药且没有禁忌症的情况下。Hospital: 给予活性炭。在小剂量摄入后，如果可以迅速给予活性炭，则不需要胃排空。/抗肿瘤药物/

Decontamination: Prehospital: Administer activated charcoal, if available. If a delay of more than 60 minutes is expected before charcoal can be given, consider using ipecac to induce vomiting. If it can be administered within a few minutes of exposure and there are no contraindications. Hospital: Administer activated charcoal. Gastric emptying is not necessary after a small ingestion if activated charcoal can be given promptly. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 医疗监测

/抗癌药物的预防措施：/目前没有可用于常规监测人员接触危险药物证据的方法。检测诱变剂或染色体损伤的测试并非针对特定药物，且仅在控制性研究中具有价值。对尿液中存在危险药物的化学分析，在需要检测职业暴露的灵敏度水平上，仅限于少数药物，且尚未在商业上可用。/抗癌药物/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

经膀胱内给药800毫克valrubicin并在膀胱内保留2小时后，对于膀胱原位癌（CIS）患者……药物仅有极少量被吸收进入血浆；valrubicin的代谢物也已在血浆中检测到。在膀胱内每周一次给予200至900毫克valrubicin的膀胱原位癌或Ta、T1或T2期膀胱癌患者中，第一次、第三次和第六次给药后6小时内，检测到valrubicin及其代谢物的低血浆浓度……。

Following intravesical administration of 800 mg valrubicin and retention in the bladder for a period of 2-hours in patients with carcinoma in situ (CIS) of the bladder ... minimal amounts of the drug are absorbed into the plasma; metabolites of valrubicin also have been detected in plasma. Following intravesical administration of 200 to 900 mg valrubicin once weekly in patients with CIS of the bladder or stage Ta, T1, or T2 bladder cancer low plasma concentrations of valrubicin and its metabolites, ... were detected within 6 hours after administration of the first, third and sixth doses of the drug.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：几乎完全通过排空灌入物。

Elimination: Almost entirely by voiding the instillate.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

长春瑞滨（Valrubicin）通过膀胱内给药后能轻易渗透进入膀胱细胞壁。任何系统性吸收的程度取决于膀胱壁的状况。血清浓度通常非常低（纳克量级），即使在广泛的经尿道切除术后，尽管曾有一个案例报告，在给一个膀胱穿孔的患者给药后，其浓度与静脉给药后达到的浓度相似。

Valrubicin penetrates easily into the bladder cell wall after intravesical administration. The degree of any systemic absorption depends on the condition of the bladder wall. Serum concentration usually are very low (nanogram quantities), even after extensive transurethral resection, although a case has been reported in which concentrations after administration to a patient with a perforated bladder were similar to those achieved after intravenous administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚不清楚长春瑞滨是否分布在人乳中。

It is not known whether valrubicin is distributed in breast milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... Valrubicin比多柔比星更迅速地进入体外细胞。当将Valrubicin通过膀胱内给药给膀胱癌患者时，药物的细胞毒浓度渗透到了膀胱的浅层肌肉。...

... Valrubicin entered individual cells more rapidly than doxorubicin in vitro. When valrubicin was administered intravesically to patients with bladder cancer, cytotoxic concentrations of the drug penetrated the superficial muscle layer of the bladder. ...

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S37/39
• 危险类别码：
  R36/37/38
• 海关编码：
  2941906000
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P201,P202,P264,P270,P280,P301+P312+P330,P308+P313,P405,P501
• 危险品运输编号：
  2811
• 危险性描述：
  H302,H340,H350,H360
• 储存条件：
  2-8℃

制备方法与用途

生物活性

Valrubicin 是一种化疗药物，用于治疗膀胱癌。它可抑制 TPA- 和 PDBu- 诱导的 PKC 活化，对应的 IC50 值分别为 0.85 μM 和 1.25 μM。

靶点

Target	Value
TPA-activated PKC (Cell-free assay)	0.85 μM
PDBu-activated PKC (Cell-free assay)	1.25 μM

体外研究

Valrubicin（AD 32）是一种化疗剂，能够抑制 TPA- 和 PDBu 诱导的 PKC 活化，IC50 值分别为 0.85 μM 和 1.25 μM。此外，Valrubicin 还能竞争性地与肿瘤促进剂结合于 PKC 的结合位点，并阻止其与磷脂以及 PKC 结合。研究显示，Valrubicin 对鳞状细胞癌（SCC）细胞系集落形成具有细胞毒性作用，对于 UMSCC5 细胞的 IC50 和 IC90 值分别为 8.24 ± 1.60 μM 和 14.81 ± 2.82 μM；对于 UMSCC5/CDDP‡ 细胞为 15.90 ± 0.90 μM、29.84 ± 0.84 μM；对于 UMSCC10b 细胞分别为 10.50 ± 2.39 μM 和 19.00 ± 3.91 μM。此外，Valrubicin 与辐射联用可增强细胞毒性。

体内研究

在恒河猴的体内实验中，注射 Valrubicin（剂量为 3 mg、6 mg 或 9 mg）可在第 3 周显著减少肿瘤生长。使用非细胞毒性的辐射（150 cGy、250 cGy 或 350 cGy）与 Valrubicin（6 mg）联用，可在恒河猴体内引起显著的肿瘤缩小。Valrubicin（浓度为 0.1 μg/μL）可显著减少 TPA 挑战下活检样本中的浸润中性粒细胞数量，并减轻慢性炎症反应。此外，在急性模型中，Valrubicin 还能降低炎性细胞因子的表达水平。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  N-三氟乙酰基阿霉素	N-trifluoroacetyl doxorubicin	26295-56-7	C29H28F3NO12	639.536
  ——	adriamycin 14-valerate	80287-44-1	C32H37NO12	627.645
  (8S,10S)-10-[(3-氨基-2,3,6-三脱氧-alpha-L-吡喃来苏己糖基)氧基]-8-(2-溴-1,1-二甲氧基乙基)-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-并四苯醌	14-bromo-13-dimethylketal-daunorubicin	106401-68-7	C29H34BrNO11	652.493

反应信息

• 作为反应物：
  描述：

  戊柔比星 在 三氟乙酸酐 作用下， 以 吡啶 、 乙醚 为溶剂， 反应 1.5h， 以85%的产率得到9,10-anhydro-N-(trifluoroacetyl)adriamycin 14-valerate
  参考文献：
  名称：

  Adriamycin analogs. Preparation and biological evaluation of some N-perfluoroacyl analogs of daunorubicin, adriamycin, and N-(trifluoroacetyl)adriamycin 14-valerate and their 9,10-anhydro derivatives

  摘要：

  The experimental and clinical antitumor activity, as well as the low toxicity, of N-(trifluoroacetyl)adriamycin 14-valerate (AD 32), a non-DNA binding anthracycline analogue, has led us to prepare and evaluate several N-perfluoroacyl analogues of daunorubicin, adriamycin, and N-(trifluoroacetyl)adriamycin 14-valerate. Target compounds were prepared by reaction of the appropriate perfluoroacyl anhydride with daunorubicin in chloroform-ether, with adriamycin in cold pyridine, and with adriamycin 14-valerate in ethyl acetate. In connection with this work, it was found that reaction of perfluoroacyl anhydrides with N-acylated or N-unsubstituted anthracyclines in pyridine at room temperature afforded with ease and in good yield the corresponding 9,10-anhydro-N-acylated derivatives. A number of products showed good to highly significant antitumor activity in vivo against the murine P388 leukemia system. However, the lack of in vivo antitumor activity of the pentafluoropropionyl and heptafluorobutyryl analogues of N-(trifluoroacetyl)adriamycin 14-valerate is noteworthy. The results continue to show that non-DNA binding anthracycline analogues can exhibit in vivo antitumor activity. Loss of the anthracycline 9-carbinol function by dehydration leads to reduction of biological activity as compared to the parent compound.

  DOI：

  10.1021/jm00344a019
• 作为产物：
  描述：

  柔红霉素 盐酸盐 在 氢溴酸 、 溴 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 10.0h， 生成 戊柔比星
  参考文献：
  名称：

  一种戊柔比星合成方法

  摘要：

  本发明公开了一种戊柔比星合成方法，盐酸柔红霉素在原甲酸三乙酯对其羰基进行保护下，进行溴代反应，反应液经过浓缩处理，直接进入脱保护反应，脱保护反应结束后，即以盐析的方式将溴化物中间体结晶出来，结晶出来的溴化物中间体先与正戊酸钾反应，再与三氟醋酸酐反应成酰胺制得戊柔比星。本发明反应条件温和，反应时间较短，易于操作控制，适合大规模工业生产。

  公开号：

  CN108484689B

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] 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。
• Anti-angiogenic compounds
  申请人：Bradshaw W. Curt

  公开号：US20060205670A1

  公开（公告）日：2006-09-14

  The present invention provides AA targeting compounds which comprise AA targeting agent-linker conjugates which are linked to a combining site of an antibody. Various uses of the compounds are provided, including methods to treat disorders connected to abnormal angiogenesis.

  本发明提供了包括与抗体的结合位点连接的AA靶向剂-连接剂共轭物的AA靶向化合物。提供了化合物的各种用途，包括治疗与异常血管生成相关的疾病的方法。
• [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。
• BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas Operations, Inc.

  公开号：US20190300521A1

  公开（公告）日：2019-10-03

  The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为SMARCA2或BRM（靶蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合Von Hippel-Lindau E3泛素连接酶的配体，另一端结合靶蛋白的双功能化合物，使得靶蛋白与泛素连接酶靠近以实现靶蛋白的降解（和抑制）。本公开展示了与靶蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由靶蛋白聚集或积累导致的疾病或紊乱。