42-(2-四唑基)雷帕霉素 | 221877-56-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 中文名称: 42-(2-四唑基)雷帕霉素
• 英文名称: 42-(2-tetrazolyl)-rapamycin
• 英文别名: 42-(2-Tetrazolyl)rapamycin；(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-12-[(2R)-1-[(1S,3R,4S)-3-methoxy-4-(tetrazol-2-yl)cyclohexyl]propan-2-yl]-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
• CAS: 221877-56-1
• 化学式: C₅₂H₇₉N₅O₁₂
• 分子量: 966.226
• InChiKey: IURNHYDSJVLLPN-JUKNQOCSSA-N

物化性质

• 溶解度：
  二甲基亚砜：≥130 mg/ml（134.55mM）

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  69
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  219
• 氢给体数：
  2
• 氢受体数：
  15

安全信息

• 储存条件：
  -20°C，密闭保存，置于干燥处

制备方法与用途

生物活性药物42-(2-四唑基)雷帕霉素是一种来自US 20080171763 A1专利、在实例1中描述的雷帕霉素类似物前体化合物。雷帕霉素是一种特异性mTOR抑制剂。

反应信息

• 作为产物：
  描述：

  雷帕霉素 在 2,6-二甲基吡啶 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 醋酸异丙酯 为溶剂， 反应 18.58h， 生成 42-(2-四唑基)雷帕霉素
  参考文献：
  名称：

  Rapamycin analogs with reduced systemic exposure

  摘要：

  The synthesis and biological activities of rapamycin (1) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.06.106

文献信息

• One pot synthesis of tetrazole derivatives of sirolimus
  申请人：Dhaon Madhup K.

  公开号：US20080167335A1

  公开（公告）日：2008-07-10

  A single-step, one-pot process to obtain zotarolimus and other rapamycin derivatives on large scale is presented, which improves currently available synthesis schemes. In one embodiment, dried rapamycin is dissolved in isopropylacetate (IPAc). The solution is cooled, and 2,6-Lutidine is added, followed slowly adding triflic anhydride at −30° C. Salts are then removed by filtration. Tetrazole, followed by a tert-base diisopropylethylamine (DIEA) is added to the triflate solution. After incubation at room temperature, the product is concentrated and purified by a silica gel column using THF/heptane as eluant. The fractions containing the product are collected, concentrated, and purified again using an acetone/heptane column. The product containing fractions are concentrated. The product is dissolved in t-BME and precipitated with heptane. The solids are dissolved in acetone, treated with butylated-hydroxy toluene (BHT), and the solution concentrated. The process is repeated twice with acetone to remove solvents. At least one stabilizing agent is added, such as BHT at 0.5% before drying.

  提供了一种单步、一锅法的方法来大规模获得左旋西罗莫司和其他雷帕霉素衍生物，该方法改进了目前可用的合成方案。在一种实施例中，干燥的雷帕霉素溶解在丙酮酸异丙酯（IPAc）中。溶液冷却后，加入2,6-二甲基吡啶，随后缓慢加入三氟甲磺酸酐，在-30°C下进行。通过过滤去除盐。向三氟甲磺酸酯溶液中加入四唑，随后加入一种叔基二异丙基乙基胺（DIEA）的叔碱。在室温下孵育后，产品被浓缩并通过硅胶柱使用THF/庚烷作为洗脱剂进行纯化。收集含有产品的分数，浓缩并再次使用丙酮/庚烷柱进行纯化。含有产品的分数被浓缩。将产品溶解在t-BME中，用庚烷沉淀。将固体溶解在丙酮中，加入叔丁基羟基甲苯（BHT），并浓缩溶液。使用丙酮重复两次此过程以去除溶剂。在干燥之前添加至少一种稳定剂，例如0.5%的BHT。
• MEDICAL DEVICES CONTAINING RAPAMYCIN ANALOGS
  申请人：Abbott Laboratories

  公开号：US20160220739A1

  公开（公告）日：2016-08-04

  A medical device comprises a supporting structure capable of containing or supporting a pharmaceutically acceptable carrier or excipient, which carrier or excipient may contain one or more therapeutic agents or substances, with the carrier preferably including a coating on the surface thereof, and the coating containing the therapeutic substances, such as, for example, drugs. Supporting structures for the medical devices that are suitable for use in this invention include, but are not limited to, coronary stents, peripheral stents, catheters, arterio-venous grafts, by-pass grafts, and drug delivery balloons used in the vasculature. Drugs that are suitable for use in this invention include, but are not limited to drugs of Formula (I). The drugs of Formula (I) can be used in combination with another drug including those selected from anti-proliferative agents, anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents, cytotoxic drugs, agents that inhibit cytokine or chemokine binding, cell de-differentiation inhibitors, anti-lipaedemic agents, matrix metalloproteinase inhibitors, cytostatic drugs, or combinations of these drugs.

  一种医疗器械包括一个支撑结构，该支撑结构能够容纳或支撑一种药学上可接受的载体或赋形剂，该载体或赋形剂可以含有一个或多个治疗剂或物质，其中载体最好在其表面包含一层涂层，该涂层含有治疗物质，例如药物。适用于本发明的医疗器械的支撑结构包括但不限于冠状动脉支架、外周支架、导管、动静脉移植物、旁路移植物和用于血管系统的药物输送球。适用于本发明的药物包括但不限于公式（I）中的药物。公式（I）中的药物可以与另一种药物结合使用，包括从抗增殖剂、抗血小板剂、抗炎剂、抗血栓剂、细胞毒性药物、抑制细胞因子或趋化因子结合的药物、细胞去分化抑制剂、降脂药、基质金属蛋白酶抑制剂、细胞周期停滞药或这些药物的组合中选择的药物。
• CASCADE SYSTEM
  申请人：Li Yao-En

  公开号：US20080287675A1

  公开（公告）日：2008-11-20

  A method of purifying an active pharmaceutical ingredient sufficient for administration into a human subject can include: obtaining a reaction product composition having the active pharmaceutical ingredient and impurities, wherein said active pharmaceutical ingredient is rapamycin or a rapamycin analog; introducing the reaction product composition into a first column of a chromatography system; directing a first portion of a first elutant from the first column to waste, said first portion having more impurity than active pharmaceutical ingredient; directing a second portion of the first elutant from the first column into a second column, said second portion having more active pharmaceutical ingredient than impurity; collecting factions of a second elutant from the second column that include the active pharmaceutical ingredient; and concentrating the said collected fractions to obtain a purity of the active pharmaceutical ingredient greater than 98% and with less than or about 0.95% being first and second major impurities.

  一种用于纯化足以用于人体的活性药物成分的方法，包括：获取含有所述活性药物成分和杂质的反应产物组成物，其中所述活性药物成分为雷帕霉素或雷帕霉素类似物；将反应产物组成物引入色谱系统的第一柱；将第一柱的第一洗脱剂的第一部分排放到废物中，所述第一部分中的杂质比活性药物成分更多；将第一柱的第一洗脱剂的第二部分引导到第二柱中，所述第二部分中的活性药物成分比杂质更多；收集第二柱的第二洗脱剂的分数，其中包括活性药物成分；浓缩所述收集的分数以获得纯度大于98％的活性药物成分，其中第一和第二主要杂质少于或约为0.95％。
• METHODS OF MANUFACTURING CRYSTALLING FORMS OF RAPAMYCIN ANALOGS
  申请人：Viswanath Shekhar

  公开号：US20110009618A1

  公开（公告）日：2011-01-13

  A process for preparing a crystalline rapamycin analog includes: combining the rapamycin analog with an organic medium to form a mixture; incubating the mixture until the rapamycin analog crystallizes; and recovering the crystalline rapamycin analog. The organic medium can be a solvent, and the process can include causing the rapamycin analog to dissolve into the solvent, and incubating the solvent until the rapamycin analog crystallizes. The following can also be performed: forming a slurry of crystalline rapamycin analog; stirring the rapamycin analog mixture until the rapamycin analog crystallizes; saturating the rapamycin analog solution; forming a supersaturated rapamycin analog solution; combining an antisolvent with the rapamycin analog and the solvent to form a biphasic mixture, and incubating the biphasic mixture to cause a liquid-liquid phase split.

  一种制备结晶雷帕霉素类似物的方法包括：将雷帕霉素类似物与有机介质混合以形成混合物；孵育混合物直到雷帕霉素类似物结晶；并回收结晶的雷帕霉素类似物。有机介质可以是溶剂，该过程可以包括使雷帕霉素类似物溶解到溶剂中，并孵育溶剂直到雷帕霉素类似物结晶。还可以进行以下步骤：形成结晶雷帕霉素类似物的悬浮液；搅拌雷帕霉素类似物混合物直到雷帕霉素类似物结晶；饱和雷帕霉素类似物溶液；形成超饱和雷帕霉素类似物溶液；将抗溶剂与雷帕霉素类似物和溶剂混合以形成两相混合物，并孵育两相混合物以引起液液相分离。
• Medical Devices Containing Rapamycin Analogs
  申请人：Mollison Karl W.

  公开号：US20080175884A1

  公开（公告）日：2008-07-24

  A medical device comprises a supporting structure capable of containing or supporting a pharmaceutically acceptable carrier or excipient, which carrier or excipient may contain one or more therapeutic agents or substances, with the carrier preferably including a coating on the surface thereof, and the coating containing the therapeutic substances, such as, for example, drugs. Supporting structures for the medical devices that are suitable for use in this invention include, but are not limited to, coronary stents, peripheral stents, catheters, arterio-venous grafts, by-pass grafts, and drug delivery balloons used in the vasculature. Drugs that are suitable for use in this invention include, but are not limited to drugs of Formula (I). The drugs of Formula (I) can be used in combination with another drug including those selected from anti-proliferative agents, anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents, cytotoxic drugs, agents that inhibit cytokine or chemokine binding, cell de-differentiation inhibitors, anti-lipaedemic agents, matrix metalloproteinase inhibitors, cytostatic drugs, or combinations of these drugs.