(4R)-4-[(3S,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-二羟基-10,13-二甲基-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基]戊酸 | 78919-26-3

• 物质功能分类: 生物 - 细胞培养 - 添加剂
• 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: (4R)-4-[(3S,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-二羟基-10,13-二甲基-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基]戊酸
• 中文别名: 3&Beta-熊去氧胆酸；3Β-熊去氧胆酸
• 英文名称: 3β,7β-dihydroxy-5β-cholan-24-oic acid
• 英文别名: 3β,7β-dihydroxycholanic acid；3β-ursodeoxycholic acid；ursodeoxycholic acid；iso-ursodeoxycholic acid；iso-UDCA；Isoursodeoxycholic acid；(4R)-4-[(3S,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
• CAS: 78919-26-3
• 化学式: C₂₄H₄₀O₄
• 分子量: 392.579
• InChiKey: RUDATBOHQWOJDD-DNMBCGTGSA-N

物化性质

• 熔点：
  184 - 186°C
• 沸点：
  547.1±25.0 °C(Predicted)
• 密度：
  1.128±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO（微溶）、甲醇（微溶、超声处理）、水（微溶、加热）
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  4

ADMET

代谢

我们的去氧胆酸是否已知人类代谢物包括3,6,7-三羟基胆烷-24-酸和4-(7-羟基-10,13-二甲基-3-氧代-1,2,4,5,6,7,8,9,11,12,14,15,16,17-四十四氢环戊二烯[a]菲-17-基)戊酸。

Isoursodeoxycholic acid has known human metabolites that include 3,6,7-Trihydroxycholan-24-oic acid and 4-(7-Hydroxy-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl)pentanoic acid.

来源:NORMAN Suspect List Exchange

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用的总结：熊去氧胆酸（Ursodiol）天然存在于人乳中。由于外源性给药后母乳中熊去氧胆酸（ursodeoxycholic acid）的水平较低，婴儿摄入的量很小，预计不会对哺乳婴儿造成任何不良影响。无需特别注意事项。 对哺乳婴儿的影响：一名哺乳的婴儿（哺乳程度未说明）在母亲每天服用750至1000毫克熊去氧胆酸治疗期间，前6个月正常发育。 七位孕妇在分娩前后每天服用14毫克/公斤的熊去氧胆酸。她们报告在产后早期哺乳期间她们的婴儿没有不良反应。 一名患有原发性胆汁性肝硬化，接受口服熊去氧胆酸250毫克，每日三次的母亲，据报道正常哺乳她的婴儿，尽管哺乳的程度和持续时间没有说明。 一名患有原发性胆汁性硬化的妇女在产后3周出现严重瘙痒和血清胆酸升高。开始服用熊去氧胆酸，剂量为每天500毫克（7.5毫克/公斤），在接下来的8周内增加到每天1500毫克（25毫克/公斤）。她的哺乳婴儿（哺乳程度未说明）的心理运动发展正常，婴儿没有观察到明显的副作用。 对安卡拉土耳其一家医院的孕妇病历进行回顾性审查，发现8名患者在产后服用了13-15毫克/公斤的熊去氧胆酸。其中“大多数”患者哺乳了她们的婴儿（哺乳程度未说明）。没有报告婴儿的副作用。 一名妇女正在哺乳她8天大的早产儿，每天大约10次，每次大约15分钟。婴儿在34周妊娠时通过剖宫产出生，体重为3600克。她被诊断患有胆汁淤积，1型糖尿病和甲状腺功能减退症。她接受了熊去氧胆酸500毫克/日，胰岛素levemir和aspart，以及左甲状腺素治疗。她还服用了头孢呋辛，氟比洛芬，以及由对乙酰氨基酚、丙酸倍他米松和咖啡因组成的止痛药组合。母亲总共服用了12天的熊去氧胆酸，头孢呋辛和止痛药组合服用了10天，氟比洛芬服用了15天。在熊去氧胆酸治疗期间没有注意到不良反应。 二十名哺乳母亲因胆汁淤积每天服用500至1500毫克或13至15毫克/公斤的熊去氧胆酸，根据病情而定。熊去氧胆酸在产后3天停止使用。根据早期新生儿期的标准临床检查，没有观察到任何新生儿明显的副作用，并且在常规1年的儿科随访中也没有观察到新生儿发展的恶化。 对哺乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Ursodiol is naturally present in human milk. Because of the low levels of ursodiol (ursodeoxycholic acid) in breastmilk after exogenous administration, amounts ingested by the infant are small and are not expected to cause any adverse effects in breastfed infants. No special precautions are required. ◉ Effects in Breastfed Infants:One breastfed (extent not stated) infant developed normally over the first 6 months of life during maternal ursodiol therapy of 750 to 1000 mg daily. Seven women who were taking ursodiol 14 mg/kg daily near term and postpartum. They reported no adverse reactions in their breastfed infants during the early postpartum period. A mother receiving oral ursodiol 250 mg 3 times daily for primary biliary cirrhosis reportedly breastfed her infant normally, although the extent and duration of breastfeeding was not stated. A woman with primary biliary cirrhosis developed severe pruritus and elevated serum bile acids 3 weeks postpartum. Ursodiol was started at a dose of 500 mg (7.5 mg/kg) daily, increasing to 1500 mg (25 mg/kg) daily over the next 8 weeks. Psychomotor development of her breastfed (extent not stated) infant was normal, and no apparent side effects were observed in the infant. A retrospective review of the medical records of pregnant patients at a hospital in Ankara, Turkey who had a diagnosis of primary biliary cirrhosis found 8 patients who took ursodiol postpartum in doses of 13–15 mg/kg daily. “Most” of the patients breastfed their infants (extent not stated). No infant side effects were reported. A woman was breastfeeding her 8-day-old preterm infant 10 times daily for about 15 minutes each time. The infant was born by cesarean section at 34 weeks of gestation with a weight of 3600 grams. She was diagnosed with cholestasis, type 1 diabetes, and hypothyroidism. She was treated with ursodiol 500 mg daily, insulin levemir and aspart, and levothyroxine. She was also taking cefuroxime, flurbiprofen, a combination of acetaminophen, propyphenazone, and caffeine. The mother took the ursodiol for a total of 12 days, cefuroxime and the analgesic combination for 10 days and flurbiprofen for 15 days. No adverse effects were noticed during the period of ursodiol treatment. Twenty nursing mothers were taking ursodiol for cholestasis in daily dosages of 500 to 1500 mg or 13 to 15 mg/kg, depending on the condition. Ursodiol was discontinued 3 days postpartum. No apparent side effects were observed in any newborn infant based on standard clinical examination during early postnatal period, and no deterioration in postnatal development was observed during routine 1-year follow-up on routine pediatric examinations. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

制备方法与用途

生物活性方面，3β-熊去氧胆酸（异熊去氧胆酸）是一种胆汁酸。研究显示，通过口服给药，它表现出良好的耐受性，并且能够有效吸收。在肠和肝酶的作用下，3β-熊去氧胆酸可以转化为UDCA。

反应信息

• 作为反应物：
  描述：

  氨基磺酸 、 (4R)-4-[(3S,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-二羟基-10,13-二甲基-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基]戊酸 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 0.5h， 以93.7%的产率得到ursodeoxycholic acid di-ammonium 3,7-disulfate
  参考文献：
  名称：

  [EN] PROCESS FOR PREPARING URSODEOXYCHOLIC ACID DI-SODIUM 3,7-DISULFATE
  [FR] PROCEDE DE PREPARATION D'ACIDE URSODEOXYCHOLIQUE, 3,7-DISULFATE DI-SODIQUE

  摘要：

  制备双钠3,7-二硫酸鱼胆酸的过程包括：a）将鱼胆酸与磺酸反应，得到双铵3,7-二硫酸鱼胆酸；b）用有机钠碱或无机钠碱处理双铵3,7-二硫酸鱼胆酸，然后用无机酸处理反应混合物，直到pH在3.0至4.5之间，得到溶解的双钠3,7-二硫酸鱼胆酸；c）通过稀释有机溶剂，去除存在的盐（通过过滤），然后沉淀双钠3,7-二硫酸鱼胆酸。

  公开号：

  WO2004092193A1
• 作为产物：
  描述：

  熊去氧胆酸钠盐 在 1,4-dihydronicotinamide adenine dinucleotide 、 DL-dithiothreitol 、 β-烟酰胺腺嘌呤二核苷酸 作用下， 以 乙醇 、 水 、 乙酸乙酯 为溶剂， 反应 70.0h， 生成 (4R)-4-[(3S,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-二羟基-10,13-二甲基-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊并[a]菲-17-基]戊酸
  参考文献：
  名称：

  Enzymic .alpha./.beta. inversion of C-3 hydroxyl of bile acids and study of the effects of organic solvents on reaction rates

  摘要：

  DOI：

  10.1021/jo00236a018

文献信息

• [EN] NOVEL DRUG DELIVERY CONJUGATED MOIETY FOR ORAL ADMINISTRATION OF DRUG UNSUITABLE FOR ORAL ADMINISTRATION AND PREPARATION METHOD THEREOF<br/>[FR] NOUVELLE FRACTION CONJUGUÉE D'ADMINISTRATION DE MÉDICAMENT POUR L'ADMINISTRATION PAR VOIE ORALE D'UN MÉDICAMENT NE CONVENANT PAS À L'ADMINISTRATION PAR VOIE ORALE ET SON PROCÉDÉ DE PRÉPARATION
  申请人：ST PHARM CO LTD

  公开号：WO2017014332A1

  公开（公告）日：2017-01-26

  The present invention provides a novel drug delivery conjugated moiety for oral administration of a drug that is not suitable for oral administration or a pharmaceutically acceptable salt thereof. When the drug delivery conjugated moiety of the present invention or a pharmaceutically acceptable salt thereof is combined with a drug, which is not suitable for oral administration, and is administered orally, it exhibits an excellent absorption rate without decreasing the biological activities of the drug. Moreover, the drug delivery conjugated moiety of the present invention or a pharmaceutically acceptable salt thereof can be easily prepared in a few steps, which is very advantageous in terms of mass production.

  本发明提供了一种新型的药物给药共轭基团，用于口服给药一种不适合口服给药的药物或其药用可接受的盐。当本发明的药物给药共轭基团或其药用可接受的盐与一种不适合口服给药的药物结合并口服给药时，它具有出色的吸收率，不会降低药物的生物活性。此外，本发明的药物给药共轭基团或其药用可接受的盐可以在几个步骤内轻松制备，这在大规模生产方面非常有优势。
• SOLUBLE STEROIDAL PEPTIDES FOR NUCLEIC ACID DELIVERY
  申请人：Mahato I. Ram

  公开号：US20050032722A1

  公开（公告）日：2005-02-10

  Amphiphilic lipopeptide compositions for gene delivery are disclosed. An illustrative amphiphilic lipopeptide composition includes a human protamine 2 peptide conjugated to a hydrophobic moiety. Illustrative hydrophobic moieties include sterols, bile acids, and fatty acids. The amphiphilic lipopeptide composition is mixed with a nucleic acid such that the nucleic acid binds to the peptide portion of the lipopeptide. This mixture is placed in contact with mammalian cells to effect transfection of the cells with the nucleic acid. A method of making such amphiphilic lipopeptides is also described.

  揭示了用于基因传递的两性脂肽组合物。一个示例的两性脂肽组合物包括将人类前白蛋白2肽与一个疏水基团结合。示例的疏水基团包括类固醇、胆汁酸和脂肪酸。将两性脂肽组合物与核酸混合，使核酸结合到脂肽的肽段上。将这种混合物与哺乳动物细胞接触，以实现细胞对核酸的转染。还描述了制备这种两性脂肽的方法。
• 一种3β-熊去氧胆酸的制备方法
  申请人：上海科骊科生物技术有限公司

  公开号：CN109912676B

  公开（公告）日：2021-08-27

  本发明公开了一种3β‑熊去氧胆酸的合成方法，采用熊去氧胆酸为原料，经过酯化，保护3、7位羟基，选择性脱除3位保护基，氧化3位羟基，然后还原为3β羟基，水解7位、24位保护基得到所述3β‑熊去氧胆酸。本发明合成方法新颖，成本较低，产率高，条件温和，操作简便，环境友好。
• BILE ACID OLIGOMER CONJUGATE FOR NOVEL VESICULAR TRANSPORT AND USE THEREOF
  申请人：MEDIPLEX CORP.

  公开号：US20150290335A1

  公开（公告）日：2015-10-15

  The present invention relates to a method for preparing an end site-specific macromolecule-bile acid oligomer conjugate, comprising conjugating a bile acid oligomer which is prepared by oligomerization of two or more bile acid monomers to the terminal site of a macromolecule; a method for body absorption of an end site-specific macromolecule-bile acid oligomer conjugate, comprising administering the macromolecule-bile acid oligomer conjugate prepared by the above method to a subject orally; an end site-specific macromolecule-bile acid oligomer conjugate wherein the bile acid oligomer is conjugated to the terminal site of macromolecule; a composition comprising the conjugate; an oral formulation for macromolecule comprising the conjugate, a solubilizer, an excipient, a disintegrant, a binder, and a lubricant; a pharmaceutical composition comprising a heparin-bile acid oligomer conjugate wherein the bile acid oligomer is conjugated to the terminal site of heparin; and a method for treating thrombosis using said composition.

  本发明涉及一种制备端点特异性大分子-胆酸寡聚体共轭物的方法，包括将由两个或更多胆酸单体寡聚而成的胆酸寡聚体共轭到大分子的末端位点；一种通过口服将上述方法制备的大分子-胆酸寡聚体共轭物给予受试者的端点特异性大分子-胆酸寡聚体共轭物的体内吸收方法；一种胆酸寡聚体共轭到大分子末端位点的端点特异性大分子-胆酸寡聚体共轭物；一种包括该共轭物的组合物；一种包括该共轭物、溶剂、赋形剂、崩解剂、粘合剂和润滑剂的大分子口服制剂；一种包括胶原酶-胆酸寡聚体共轭物的药物组合物，其中胆酸寡聚体共轭到肝素的末端位点；以及使用该组合物治疗血栓形成的方法。
• APJ Receptor Compounds
  申请人：ANCHOR THERAPEUTICS, INC.

  公开号：US20160159861A1

  公开（公告）日：2016-06-09

  The invention relates generally to compounds which are allosteric modulators (e.g., negative and positive allosteric modulators, allosteric agonists, and ago-allosteric modulators) of the G protein coupled receptor apelin, also known as the APJ receptor. The APJ receptor compounds are derived from the it intracellular loop and domain of the APJ receptor. The invention also relates to the use of these APJ receptor compounds and pharmaceutical compositions comprising the APJ receptor compounds in the treatment of diseases and conditions associated with APJ receptor modulation, such as cardiovascular diseases, (e.g., hypertension and heart failure, such as congestive heart failure), cancer, diabetes, stem cell trafficking, fluid homeostasis, cell proliferation, immune function, obesity, metastatic disease, and HIV infection.

  本发明涉及一般意义上的化合物，它们是G蛋白偶联受体apelin的变构调节剂（例如，负和正的变构调节剂，变构激动剂和激动-变构调节剂）。APJ受体化合物源自APJ受体的细胞内环和结构域。本发明还涉及使用这些APJ受体化合物和包含APJ受体化合物的药物组成物治疗与APJ受体调节相关的疾病和病况，例如心血管疾病（例如高血压和心力衰竭，如充血性心力衰竭）、癌症、糖尿病、干细胞移植、液体稳态、细胞增殖、免疫功能、肥胖症、转移性疾病和HIV感染。