丙酸倍氯米松 | 5534-09-8

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 肾上腺皮质激素类药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 丙酸倍氯米松
• 中文别名: 倍氯米松丙酸酯；倍氯米松二丙酸盐；倍氯米松双丙酸酯；氯地米松；倍氯美松双丙酸酯；二丙酸培氯松；二丙酸氯地米松；必酮碟；安得新；丙酸倍美松；倍氯米松二丙酸酯
• 英文名称: beclomethasone 17,21-dipropionate
• 英文别名: Beclomethasone dipropionate；[2-[(8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-propanoyloxy-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] propanoate
• CAS: 5534-09-8
• 化学式: C₂₈H₃₇ClO₇
• 分子量: 521.051
• InChiKey: KUVIULQEHSCUHY-XYWKZLDCSA-N

物化性质

• 熔点：
  117-120 C
• 比旋光度：
  D +98.0° (c = 1.0 in dioxane)
• 沸点：
  613.3°C (rough estimate)
• 密度：
  1.0766 (rough estimate)
• 溶解度：
  氯仿（微溶）、二恶烷（微溶、超声）、甲醇（微溶、加热）
• 最大波长(λmax)：
  238nm(EtOH)(lit.)
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  7

ADMET

代谢

在吸收过程中，倍氯米松双丙酸酯通过酯酶CYP3A介导的快速和广泛的水解，形成倍氯米松-17-单丙酸酯（17-BMP）、倍氯米松-21-单丙酸酯（21-BMP）和倍氯米松（BOH）。17-BMP是主要的活性代谢物，具有最强的抗炎活性。大约95%通过口腔吸入的总倍氯米松双丙酸酯在肺部发生系统前转化，形成17-BMP。

During absorption, beclomethasone dipropionate is undergoes rapid and extensive hydrolysis mediated by esterases CYP3A to form beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP), and beclomethasone (BOH). 17-BMP is the major active metabolite with the most potent anti-inflammatory activity. About 95% of the total beclomethasone dipropionate administered via oral inhalation undergoes presystemic conversion to form 17-BMP in the lung.

来源:DrugBank

毒理性

• 蛋白质结合

根据体外研究的结果，主要活性代谢物倍氯米松-17-单丙酸（17-BMP）的蛋白结合率在1000至5000 pg/mL的浓度范围内为94-96%。

Based on the findings of _in vitro_ studies, the protein binding of the main active metabolite, beclomethasone-17-monopropionate (17-BMP), was 94-96% over the concentration range of 1000 to 5000 pg/mL.

来源:DrugBank

吸收、分配和排泄

• 吸收

在吸入320微克倍氯米松双丙酸盐（BDP）后，其Cmax（最高血药浓度）为88皮克/毫升，在给药后0.5小时达到。主要且活性较高的代谢物，倍氯米松-17-单丙酸盐（17-BMP）的平均Cmax为1419皮克/毫升，在给药后0.7小时达到。在另一项药代动力学研究中，BDP和17-BMP的AUC（药时曲线下面积）分别为6660和6185皮克*小时/毫升。BDP的Cmax为35356皮克/毫升，17-BMP的Cmax为2633皮克/毫升，达到这些浓度的一半时间（Tmax）中位数为0.2小时。在同一研究中，口服和鼻内给药后17-BMP的AUC分别为10158和3660皮克*小时/毫升。口服和鼻内给药后17-BMP的Cmax分别为703和310皮克/毫升，Tmax为4小时。口服和鼻内给药后17-BMP的总生物利用度分别为41%和44%。

Following oral inhalation of 320 mcg of beclomethasone dipropionate (BDP), the Cmax was 88 pg/mL and it was reached after 0.5 at post-administration. The mean Cmax of the major and most active metabolite, beclomethasone-17-monopropionate (17-BMP), was 1419 pg/mL at 0.7 hour post-dosing. In another pharmacokinetic study, the AUC of BDP and 17-BMP were 6660 and 6185 pgxh/mL, respectively. The Cmax was 35356 pg/mL for BDP and 2633 pg/mL for 17-BMP, and and the median time to reach these concentrations (Tmax) was 0.2 hours. In the same study, the AUC of 17-BMP following oral and intranasal administration were 10158 and 3660 pgxh/mL, respectively. The Cmax of 17-BMP following oral and intranasal administration were 703 and 310 pg/mL, respectively, and the Tmax was 4 hours. The total bioavailability of 17-BMP following oral and intranasal administration were 41% and 44%, respectively.

来源:DrugBank

吸收、分配和排泄

• 消除途径

无论给药途径如何，倍氯米松双丙酸盐及其代谢物主要在粪便中排出，药物及其代谢物在尿液中的排出量不到10%。

Regardless of the route of administration, beclomethasone dipropionate and its metabolites are predominantly excreted in the feces, with less than 10% of the drug and its metabolites being excreted in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉给药后，倍他米松二丙酸酯的稳态分布容积为20升，其活性代谢物，17-单丙酸倍他米松的稳态分布容积为424升。

Following intravenous administration, the steady-state volume of distribution was 20 L for beclomethasone dipropionate and 424 L for the active metabolite, beclomethasone-17-monopropionate.

来源:DrugBank

吸收、分配和排泄

• 清除

静脉给药后，倍他米松二丙酸酯和17-BMP的清除率分别为150 L/h和120 L/h。

Following intravenous administration, the clearance of beclomethasone dipropionate and 17-BMP were 150 L/h and 120 L/h, respectively.

来源:DrugBank

安全信息

• 危险品标志：
  T
• 安全说明：
  S36/37/39,S45,S53
• 危险类别码：
  R60,R61
• WGK Germany：
  3
• 海关编码：
  2937290090
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  TU3805000

制备方法与用途

丙酸倍氯米松气雾剂

丙酸倍氯米松气雾剂（二丙酸氯倍他米松气雾剂）是目前常用的治疗哮喘的激素类药物。它具有抗炎和抗过敏的作用，有助于扩张支气管、解除痉挛，缓解哮喘症状，并降低发作频率。尽管药物在体内起效需要2至3天，喷后不能迅速缓解病人的呼吸困难，因此对急性哮喘发作无效。

药理学特性

丙酸倍氯米松是人工合成的第一代糖皮质激素，是一种受体亲和力较低的前体药物。95%的丙酸倍氯米松吸入后在肺内迅速被酶水解为活性代谢物17-单丙酸倍氯米松（17-BMP），最终水解为无活性的倍氯米松。BDP水溶性较低，导致其在支气管黏膜的黏液层溶解缓慢，限制了其肺部吸收过程。BDP和BMP口服绝对生物利用度分别为13%和26%，首过消除约为70%。

药理作用及作用机制

丙酸倍氯米松是一种强效糖皮质激素类药物，其抗炎作用较地塞米松、曲安奈德、氟轻松、曲安西龙更强。它还具有抗过敏、止痒和抗细胞有丝分裂的作用。脂溶性较强，对皮肤的渗透作用较好，涂于患处30分钟后即生效，并维持时间较长。外用主要通过毛囊皮脂腺和表皮吸收，可收缩局部微血管并发挥强效的抗炎作用，不会引起因肾上腺皮质功能紊乱而产生的副作用。

药代动力学 气雾剂

丙酸倍氯米松气雾剂亲脂性较强，易渗透，约吸入量的25%到达肺部。

乳膏

本品可经皮肤吸收，尤其在皮肤破损处吸收更快。大面积使用于皮肤破损或长期用封包性敷料时可能因吸收引起全身反应。本品亲脂性强，易渗透，涂于患处30分钟后即生效。软膏剂的T1/2约为3小时，钠潴留及糖原沉着作用很弱，无雄性、雌性或蛋白同化激素样的作用，对体温和尿液也无明显影响。

适应症 丙酸倍氯米松

用于治疗湿疹、过敏性皮炎、神经性皮炎、扁平苔藓、盘状红斑狼疮、掌跖脓疱病、接触性皮炎、局限性银屑病和皮肤瘙痒症等。丙酸倍氯米松气雾剂适用于慢性或过敏性哮喘及过敏性鼻炎。

用途

系强效外用糖皮质激素类药，具有抗炎、抗过敏和止痒等作用，能抑制支气管渗出物、消除支气管粘膜肿胀并解除支气管痉挛。可用于治疗各种炎症皮肤病。

类别与毒性

类别: 有毒物品
毒性分级: 中毒
急性毒性: 口服-大鼠 LD50: >3750 毫克/公斤; 口服-小鼠 LD50: >5000 毫克/公斤

危险特性 可燃性危险特性

易燃；燃烧产生有毒氯化物烟雾。

储运特性

库房应通风、低温干燥，与食品原料分开存放。

灭火剂

干粉、泡沫、砂土、二氧化碳及雾状水。

反应信息

• 作为反应物：
  描述：

  丙酸倍氯米松 在 potassium hydrogencarbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 120.0h， 生成 (8S,9R,10S,11S,13S,14S,16S,17R)-9-Chloro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid
  参考文献：
  名称：

  Efficient Interfacially Driven Vehiculization of Corticosteroids by Pulmonary Surfactant

  摘要：

  Pulmonary surfactant is a crucial system to stabilize the respiratory air liquid interface. Furthermore, pulmonary surfactant has been proposed as an effective method for targeting drugs to the lungs. However, few studies have examined in detail the mechanisms of incorporation of drugs into surfactant, the impact of the presence of drugs on pulmonary surfactant performance at the interface under physiologically meaningful conditions, or the ability of pulmonary surfactant to use the air liquid interface to vehiculise drugs to long distances. This study focuses on the ability of pulmonary surfactant to interfacially vehiculize corticosteroids such as beclomethasone dipropionate (BDP) or Budesonide (BUD) as model drugs. The main objectives have been to (a) characterize the incorporation of corticosteroids into natural and synthetic surfactants,. (b) evaluate whether the presence of corticosteroids affects surfactant functionality, and (c) determine whether surfactant preparations enable the efficient spreading and distribution of BDP and BUD along the air liquid interface. We have compared the performance of a purified surfactant from porcine lungs and two clinical surfactants: Poractant alfa, a natural surfactant of animal origin extensively used to treat premature babies, and CHF5633, a new synthetic surfactant preparation currently under clinical trials. Both, natural and clinical surfactants spontaneously incorporated corticosteroids up to at least 10% by mass with respect to phospholipid content. The presence of the drugs did not interfere with their ability.to efficiently adsorb into air liquid interfaces and form surface active films able to reach and sustain very low surface tensions (<2 mN/m) under compression expansion cycling mimicking breathing dynamics. Furthermore, the combination of clinical surfactant with corticosteroids efficiently promoted the active diffusion of the drug to long distances along the air liquid interface. This effect could not be mimicked by vehiculisation of corticosteroids in liposomes or in micellar emulsions similar to the formulations currently in use to deliver anti-inflammatory corticosteroids through inhalation.

  DOI：

  10.1021/acs.langmuir.7b01177
• 作为产物：
  描述：

  9β, 11β-epoxy-17α,21-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate 生成 丙酸倍氯米松
  参考文献：
  名称：

  Novel 9.alpha.-fluoro- or chloro-corticosteroid esters and a process for

  摘要：

  9.alpha.-氟和氯皮质类固醇的新酯化合物的公式为##STR1##其中Y是氯或OR.sub.1，R.sub.1和R.sub.2代表2-6个碳原子的酰基或苯甲酰基，其中R.sub.1和R.sub.2可以在同一分子中相同或不同，R.sub.3是甲基或氟在α-或β-取向中，X是氯或氟，C.sub.1 C.sub.2键可以饱和或不饱和，特别是公式##STR2##中的化合物，其中Y和R.sub.2具有上述给定的意义，通过将相应的9.beta.,11.beta.-环氧化合物与氟化氢或氯化氢反应制备而成。

  公开号：

  US05026693A1

文献信息

• [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。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• [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。
• IRAK DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20190192668A1

  公开（公告）日：2019-06-27

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。