vinblastine sulfate | 865-21-4

• 物质功能分类: 原料药 - 抗肿瘤药 - 天然来源类抗肿瘤药
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 长春花生物碱
• 英文名称: vinblastine sulfate
• 英文别名: vinblastine sulfuric acid salt；Vinblastine sulphate；methyl (1S,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(13S,15S,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-11-aza-1-azoniatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-10-hydroxy-5-methoxy-8-methyl-8-aza-16-azoniapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate;sulfate
• CAS: 865-21-4；143-67-9
• 化学式: C₄₆H₅₈N₄O₉*H₂O₄S
• 分子量: 909.067
• InChiKey: KDQAABAKXDWYSZ-JKDPCDLQSA-N

物化性质

• 熔点：
  267 °C (dec.)(lit.)
• 比旋光度：
  -21.7 º (c=2, CH3OH 21 ºC)
• 溶解度：
  在水中的溶解度10 mg/mL
• 物理描述：
  Vinblastine sulfate appears as an anticancer drug. White to slightly yellow crystalline powder. (NTP, 1992)

计算性质

• 辛醇/水分配系数(LogP)：
  3.34
• 重原子数：
  64
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  237
• 氢给体数：
  5
• 氢受体数：
  16

ADMET

毒理性

• 致癌物分类

国际癌症研究机构致癌剂：硫酸长春碱

IARC Carcinogenic Agent:Vinblastine sulfate

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构（IARC）致癌物分类：第3组：对其对人类的致癌性无法分类

IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans

来源:International Agency for Research on Cancer (IARC)

毒理性

• 致癌物分类

国际癌症研究机构专著：第26卷：(1981年)一些抗癌和免疫抑制剂

IARC Monographs:Volume 26: (1981) Some Antineoplastic and Immunosuppressive Agents

来源:International Agency for Research on Cancer (IARC)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间的用药概述：大多数资料认为，在母体抗肿瘤药物治疗期间，母乳喂养是禁忌的。由于长春碱类药物的半衰期较长，因此在长春碱治疗结束后恢复母乳喂养可能是不切实际的。化疗可能会不利地影响母乳的正常微生物组和化学成分。在孕期接受化疗的女性更可能难以哺乳她们的婴儿。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：一名在孕中期被诊断为霍奇金淋巴瘤的女性在孕晚期接受了3轮化疗，并在产后4周恢复化疗。在重新开始化疗后的16周内，收集了她在化疗前后15至30分钟的乳汁样本。治疗方案包括每2周一次，2小时内给予多柔比星40毫克，博来霉素16单位，长春碱9.6毫克和达卡巴嗪600毫克。将该患者的乳汁微生物群和代谢概况与8名未接受化疗的健康女性进行了比较。患者的乳汁微生物群与健康女性明显不同，其中不动杆菌属、黄色单胞菌科和窄食单胞菌属增加，而双歧杆菌属和真杆菌属减少。在接受治疗的女性乳汁中的许多化学成分也发现了显著差异，尤其是DHA和肌醇的减少。 通过对在一个中心在孕中期或孕晚期接受癌症化疗的74名女性进行电话随访研究，以确定她们产后是否成功进行母乳喂养。只有34%的女性能够完全母乳喂养她们的婴儿，而66%的女性报告遇到了母乳喂养困难。这与其他22位在孕期被诊断但未接受化疗的母亲91%的母乳喂养成功率形成了对比。其他具有统计学意义的相关性包括：1. 有哺乳困难的母亲平均接受了5.5个周期的化疗，而没有困难的母亲平均接受了3.8个周期；2. 有哺乳困难的母亲平均在孕早期3.4周就开始了她们的第一个化疗周期。在接受了含有长春新碱方案的6名女性中，有5名遇到了哺乳困难。

◉ Summary of Use during Lactation:Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It is probably impractical to resume breastfeeding after vinblastine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:A woman diagnosed with Hodgkin's lymphoma during the second trimester of pregnancy received 3 rounds of chemotherapy during the third trimester of pregnancy and resumed chemotherapy 4 weeks postpartum. Milk samples were collected 15 to 30 minutes before and after chemotherapy for 16 weeks after restarting. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg and dacarbazine 600 mg, all given over a 2-hour period every 2 weeks. The microbial population and metabolic profile of her milk were compared to those of 8 healthy women who were not receiving chemotherapy. The breastmilk microbial population in the patient was markedly different from that of the healthy women, with increases in Acinetobacter sp., Xanthomonadacae and Stenotrophomonas sp. and decreases in Bifidobacterium sp. and Eubacterium sp. Marked differences were also found among numerous chemical components in the breastmilk of the treated woman, most notably DHA and inositol were decreased. A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 6 women who received a vincristine-containing regimen, 5 had breastfeeding difficulties.

来源:Drugs and Lactation Database (LactMed)

安全信息

• 危险等级：
  6.1(a)
• 危险品运输编号：
  UN 1544
• 包装等级：
  II
• 危险类别：
  6.1(a)

制备方法与用途

性质

硫酸长春碱为白色或类白色的疏松状或无定形固体，具有引湿性，遇光或热易变黄。它在水中极易溶解，在甲醇或三氯甲烷中可溶解，在乙醇中的溶解度极微。

用途

硫酸长春碱（Vinblastine Sulfate）是一种国家基本药物，主要用于治疗霍奇金淋巴瘤及恶性淋巴瘤，也适用于绒毛膜上皮癌和乳腺癌的治疗。此外，它还用于支气管肺癌、软组织肉瘤、睾丸肿瘤、卵巢癌、消化道癌以及恶性黑色素瘤和神经母细胞瘤等疾病的治疗。它是目前国际上应用最广泛的天然植物抗癌药物之一。

药理作用

硫酸长春碱是一种从夹竹桃科植物长春花中提取的生物碱，属于细胞周期特异性抗肿瘤药，主要作用于G1、S及M期，并对M期有延缓作用。它可以干扰增殖细胞纺锤体的形成，使有丝分裂停滞在中期。在高剂量下，它能直接破坏染色体并使微管蛋白质结晶化，阻止微管蛋白质的装配。此外，它还具有一定的免疫抑制作用。

化学性质

硫酸长春碱是一种白色结晶粉末，可溶于甲醇、乙醇和DMSO等有机溶剂，来源于长春花。

用途

从植物长春花中分离出的一种天然生物碱，能与微管蛋白结合并抑制微管的形成，导致有丝分裂纺锤体的断裂和细胞周期M期肿瘤细胞的停滞。主要用于治疗霍奇金淋巴瘤、绒毛膜上皮癌，并对淋巴肉瘤、急性白血病和乳腺癌等有一定的疗效。

反应信息

• 作为反应物：
  描述：

  vinblastine sulfate 在 盐酸 、 1,1'-双(二苯基膦)二茂铁 、 硫酸 、 溶剂黄146 、 三乙胺 作用下， 以 N-甲基吡咯烷酮 、 水 、 异丙醇 、 乙腈 为溶剂， 反应 13.94h， 生成 12'-thiomethylvinblastine dihydrochloride
  参考文献：
  名称：

  Process Development, Impurity Control, and Production of a Novel Tubulin Inhibitor

  摘要：

  Process development and production of a novel tubulin inhibitor are described. The desired API was obtained through selective iodination of the 12' position of vinblastine and subsequent thiomethylation. Most of the impurities were identified, and process parameters were adjusted to control such impurities. The optimized process was scaled up under cGMP conditions to afford 230 g of the desired API.

  DOI：

  10.1021/op3002307

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。
• Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
  申请人：——

  公开号：US20020143182A1

  公开（公告）日：2002-10-03

  The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I): 1 wherein: (a) m is an integer 0 or 1; (b) R 12 is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue; (c) Ar 3 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (d) Ar 4 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (e) R 5 is hydrogen, hydroxy, alkyl or substituted alkyl; (f) - - - - - represents a bond present or absent; and (g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.

  该发明涉及某些对治疗癌症和其他疾病有用的杂环化合物，其具有以下式（I）： 1 其中： (a) m是整数0或1； (b) R12是烷基，取代烷基，环烷基，取代环烷基，杂环基，取代杂环基，杂芳基，取代杂芳基，芳基或取代芳基残基； (c) Ar3是芳基，取代芳基，杂芳基或取代杂芳基残基； (d) Ar4是芳基，取代芳基，杂芳基或取代杂芳基残基； (e) R5是氢，羟基，烷基或取代烷基； (f) - - - - - 代表存在或不存在的键；以及 (g) W、X、Y和Z独立或一起是C(O)、C(S)、S、O或NH；或其药学上可接受的盐。
• [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] 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。
• Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
  申请人：Xu Feng

  公开号：US20100120727A1

  公开（公告）日：2010-05-13

  In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.

  在一个方面，本发明提供了一种氟硝西汀类似物与抗炎药物的共价结合物的组合物。在另一个方面，本发明提供了一种氟硝西汀前药的组合物。在另一个方面，本发明提供了一种氟硝西汀或其衍生物水杨酸盐的组合物。在另一个方面，本发明提供了使用氟硝西汀类似物或氟硝西汀前药的共轭物或盐来治疗或预防癌症的方法。