替勃龙 | 5630-53-5

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 避孕药
• 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: 替勃龙
• 中文别名: 17-羟基-7alpha-甲基-19-去甲孕甾-5(10)-烯-20-炔-3-酮；甲异炔诺龙；甲基异炔诺酮；甲基异炔酮
• 英文名称: tibolone
• 英文别名: (7R,8R,9S,13S,14S,17R)-17-ethynyl-17-hydroxy-7,13-dimethyl-1,2,4,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
• CAS: 5630-53-5
• 化学式: C₂₁H₂₈O₂
• mdl: MFCD00864178
• 分子量: 312.452
• InChiKey: WZDGZWOAQTVYBX-XOINTXKNSA-N

物化性质

• 熔点：
  169 °C
• 沸点：
  447.4±45.0 °C(Predicted)
• 密度：
  1.13±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶15mg/mL，澄清
• 稳定性/保质期：
  在常温常压下保持稳定

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.761
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

Tibolone 主要在肝脏中代谢。细胞色素P450同工酶系统参与Tibolone的轻度羟基化。Tibolone迅速转化为三种主要代谢物：3α-和3β-羟基-Tibolone具有雌激素作用，以及Δ(4)-异构体，具有孕激素和雄激素作用。3-羟基代谢物在循环中存在，主要是它们的无效硫酸化形式。

Tibolone is metabolized mainly in the liver. The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form.

来源:DrugBank

毒理性

• 肝毒性

在大规模的前瞻性研究中，替勃龙与一过性血清转氨酶水平低发生率相关，高于正常上限3倍的发生率为0.9%，而安慰剂组为0.2%，但没有报道出现临床明显的急性肝损伤。在欧洲，替勃龙已经临床使用，有零星报告显示在开始使用后6到12个月出现临床明显的肝损伤，并与肝细胞模式的血清酶升高和黄疸相关。报告的病例是自限性的，在停药后2到6个月内解决。没有免疫过敏特征，也没有自身抗体。

In large scale prospective studies, tibolone has been associated with a low rate of transient serum aminotransferase levels, being greater than 3 times the upper limit of normal in 0.9% of tibolone versus 0.2% of placebo recipients, but instances of clinically apparent acute liver injury were not reported. In Europe, where tibolone has been in clinical use, there have been isolated reports of clinically apparent liver injury arising 6 to 12 months after starting and associated with a hepatocellular pattern of serum enzyme elevations and jaundice. Reported cases were self-limited and resolved within 2 to 6 months of stopping. Immunoallergic features were not present nor were autoantibodies.

来源:LiverTox

毒理性

• 蛋白质结合

提博龙96%与血浆蛋白结合，最可能是白蛋白。

Tibolone is 96% bound to plasma proteins, most likely albumin.

来源:DrugBank

吸收、分配和排泄

• 吸收

替勃龙在口服给药后广泛且迅速被吸收。母药经过广泛代谢，大于80%的放射性剂量以代谢物的形式从体内排出，这表明替勃酮的血浆浓度非常低。代谢物的血浆浓度在30分钟内出现，在1-1.5小时内达到峰值。2,7 氢氧代谢物的血浆浓度高于Δ4-异构体。食物似乎对此药的吸收没有影响。

Tibolone is extensively and rapidly absorbed after oral administration. The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1.5 hours.2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug.

来源:DrugBank

吸收、分配和排泄

• 消除途径

以硫酸盐代谢物的形式通过尿液和粪便排出。大约40%的药物以代谢物的形式通过尿液排出。替勃龙的消除主要途径是通过粪便：大约60%的药物以代谢物的形式通过粪便排出。

Excreted in the urine and feces in the form of sulfated metabolites. About 40% of the drug is excreted as metabolites in urine. The predominant route of elimination of tibolone is via the feces: about 60% of the drug is excreted as metabolites in feces.

来源:DrugBank

吸收、分配和排泄

• 清除

地诺孕素（tibolone）的消除并不依赖于肾功能。

Elimination of tibolone is not dependent renal function.

来源:DrugBank

安全信息

• 危险品标志：
  N
• 安全说明：
  S22,S24/25,S61
• 危险类别码：
  R51/53
• RTECS号：
  RC8964020
• 危险品运输编号：
  UN 3077 9/PG 3
• 储存条件：
  请将药物存放在避光、阴凉干燥的地方，并密封保存。

SDS

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Section I.Chemical Product and Company Identification
Chemical Name Tibolone
Portland OR
Synonym 17α-Hydroxy-7α-methyl-19-norpregn-5(10)-en-20-yn-
3-one
Chemical Formula C21H28O2
CAS Number 5630-53-5

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Section II. Composition and Information on Ingredients
Toxicology Data
Chemical Name CAS Number Percent (%) TLV/PEL
Tibolone 5630-53-5 Min. 98.0 (GC) Not available. Not available.

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Section III. Hazards Identification
Acute Health Effects No specific information is available in our data base regarding the toxic effects of this material for humans. However,
exposure to any chemical should be kept to a minimum. Skin and eye contact may result in irritation. May be harmful if
inhaled or ingested. Always follow safe industrial hygiene practices and wear proper protective equipment when handling
this compound.
Chronic Health Effects CARCINOGENIC EFFECTS : Not available.
MUTAGENIC EFFECTS : Not available.
TERATOGENIC EFFECTS : Not available.
DEVELOPMENTAL TOXICITY: Not available.
Repeated or prolonged exposure to this compound is not known to aggravate existing medical conditions.

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Section IV. First Aid Measures
Eye Contact Check for and remove any contact lenses. In case of contact, immediately flush eyes with plenty of water for at least 15
minutes. Get medical attention.
Skin Contact In case of contact, immediately flush skin with plenty of water. Remove contaminated clothing and shoes. Wash clothing
before reuse. Thoroughly clean shoes before reuse. Get medical attention.
If the victim is not breathing, perform mouth-to-mouth resuscitation. Loosen tight clothing such as a collar, tie, belt or
Inhalation
waistband. If breathing is difficult, oxygen can be administered. Seek medical attention if respiration problems do not
improve.
Ingestion INDUCE VOMITING by sticking finger in throat. Lower the head so that the vomit will not reenter the mouth and throat.
Loosen tight clothing such as a collar, tie, belt or waistband. If the victim is not breathing, perform mouth-to-mouth
resuscitation. Examine the lips and mouth to ascertain whether the tissues are damaged, a possible indication that the toxic
material was ingested; the absence of such signs, however, is not conclusive.

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Section V. Fire and Explosion Data
Not available.
May be combustible at high temperature. Auto-Ignition
Flammability
Flash Points Flammable Limits Not available.
Not available.
These products are toxic carbon oxides (CO, CO2).
Combustion Products
Fire Hazards
Not available.
Risks of explosion of the product in presence of mechanical impact: Not available.
Explosion Hazards
Risks of explosion of the product in presence of static discharge: Not available.
Fire Fighting Media
SMALL FIRE: Use DRY chemical powder.
LARGE FIRE: Use water spray, fog or foam. DO NOT use water jet.
and Instructions
Consult with local fire authorities before attempting large scale fire-fighting operations.
Continued on Next Page
Tibolone

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Section VI. Accidental Release Measures
Spill Cleanup Use a shovel to put the material into a convenient waste disposal container. Finish cleaning the spill by rinsing any
contaminated surfaces with copious amounts of water. Consult federal, state, and/or local authorities for assistance on
Instructions
disposal.

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Section VII. Handling and Storage
Handling and Storage Keep away from heat. Mechanical exhaust required. When not in use, tightly seal the container and store in a dry, cool
place. Avoid excessive heat and light. Do not breathe dust.
Information
Always store away from incompatible compounds such as oxidizing agents.

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Section VIII. Exposure Controls/Personal Protection
Use process enclosures, local exhaust ventilation, or other engineering controls to keep airborne levels below recommended
Engineering Controls
exposure limits. If user operations generate dust, fume or mist, use ventilation to keep exposure to airborne contaminants
below the exposure limit.
Splash goggles. Lab coat. Dust respirator. Boots. Gloves. Suggested protective clothing might not be sufficient; consult a
Personal Protection
specialist BEFORE handling this product. Be sure to use a MSHA/NIOSH approved respirator or equivalent.
Exposure Limits Not available.

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Section IX. Physical and Chemical Properties
Solid. (Crystal, powder. White - almost Solubility
Physical state @ 20°C Not available.
white.)
Not available.
Specific Gravity
Molecular Weight 312.45 Partition Coefficient Not available.
Boiling Point
Not available. Vapor Pressure Not applicable.
Melting Point 169°C (336.2°F) Vapor Density Not available.
Refractive Index Not available. Volatility Not available.
Critical Temperature Not available. Odor Not available.
Not available. Not available.
Viscosity Taste

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Section X. Stability and Reactivity Data

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This material is stable if stored under proper conditions. (See Section VII for instructions)
Stability
Conditions of Instability Avoid excessive heat and light.
Incompatibilities
Reactive with oxidizing agents.

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Section XI. Toxicological Information
RTECS Number RC8964020
Eye Contact. Ingestion. Inhalation.
Routes of Exposure
Not available.
Toxicity Data
Chronic Toxic Effects CARCINOGENIC EFFECTS : Not available.
MUTAGENIC EFFECTS : Not available.
TERATOGENIC EFFECTS : Not available.
DEVELOPMENTAL TOXICITY: Not available.
Repeated or prolonged exposure to this compound is not known to aggravate existing medical conditions.
No specific information is available in our data base regarding the toxic effects of this material for humans. However,
Acute Toxic Effects
exposure to any chemical should be kept to a minimum. Skin and eye contact may result in irritation. May be harmful if
inhaled or ingested. Always follow safe industrial hygiene practices and wear proper protective equipment when handling this
compound.

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Section XII. Ecological Information
Ecotoxicity Not available.
Environmental Fate Not available.
Continued on Next Page
Tibolone

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Section XIII. Disposal Considerations
Waste Disposal Recycle to process, if possible. Consult your local regional authorities. You may be able to dissolve or mix material with a
combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber system. Observe all
federal, state and local regulations when disposing of the substance.

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Section XIV. Transport Information
DOT Classification Not a DOT controlled material (United States).
PIN Number Not applicable.
Proper Shipping Name Not applicable.
Packing Group (PG) Not applicable.
DOT Pictograms

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Section XV. Other Regulatory Information and Pictograms
TSCA Chemical Inventory This product is NOT on the EPA Toxic Substances Control Act (TSCA) inventory. The following notices are required by 40
CFR 720.36 (C) for those products not on the inventory list:
(EPA)
(i) These products are supplied solely for use in research and development by or under the supervision of a technically
qualified individual as defined in 40 CFR 720.0 et sec.
(ii) The health risks of these products have not been fully determined. Any information that is or becomes available will be
supplied on an MSDS sheet.
WHMIS Classification Not controlled under WHMIS (Canada).
(Canada)
EINECS Number (EEC) 227-069-1
EEC Risk Statements
Not available.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

背景

替勃龙是一种用于治疗女性更年期综合征并预防骨质疏松的药物。其主要成分是具有雄激素和同化激素特性的化合物。

作用与用途

• 作用：主要用于缓解妇女更年期症状，如热潮红、出汗等。
• 用途：能够有效预防因雌激素水平下降导致的骨密度流失，从而降低骨质疏松的风险。

生产工艺

替勃龙的合成涉及多个步骤，具体包括以下合成路线：

1. 中间体4的制备
   • 从化合物2出发，通过重铬酸吡啶盐氧化反应生成化合物4。
2. 乙炔化反应
   • 使用锂和乙炔进行还原性加成反应，得到化合物6。
3. 草酸缩合反应
   • 化合物6与草酸在乙醇溶液中发生缩合反应，最终制备出替勃龙。

合成步骤

1. 中间体4的合成：
   • 3,3-二甲氧基-7α-甲基雌甾-5(10)-烯-17-酮（化合物4）由3,3-二甲氧基-7α-甲基雌甾-5(10)-烯-17-醇经过重铬酸吡啶盐氧化得到。
2. 乙炔化反应：
   • 在氮气保护下，将锂还原剂与乙炔气体在高温条件下反应，得到3,3-二甲氧基-7α-甲基雌甾-5(10)-烯-17 β-羟-17 α-乙炔基（化合物6）。
3. 替勃龙的制备：
   • 最终通过草酸与化合物6在乙醇中的缩合反应，得到目标产物替勃龙。

整个合成过程中，需要严格控制温度、溶剂和试剂的比例，以确保高效且安全地完成各步反应。通过多次纯化步骤（如重结晶），最终可获得高纯度的替勃龙产品。该药物具有重要的临床应用价值，在缓解更年期症状和预防骨质疏松方面表现优异。

反应信息

• 作为反应物：
  描述：

  替勃龙 在 盐酸 作用下， 以 水 、 丙酮 为溶剂， 反应 4.0h， 生成 [7α,17α]-17-hydroxy-7-methyl-19-norpregn-4(5)-en-20-yn-3-one
  参考文献：
  名称：

  异胡波酮的晶体结构：替勃龙的主要降解产物†

  摘要：

  异丁烯酮经常被发现是一种杂质 替勃龙，由于某些不足，用于绝经后女性荷​​尔蒙重新定位的药物 替勃龙合成或在药物存储过程中降解的结果。应检测并定量以下药物的活性药物成分产品中异丁酮酮杂质的存在替勃龙在将其用于制造药物之前。X射线粉末衍射技术提供了在从化学合成到最终制剂的药物生产和储存的不同阶段，定量异丁酮含量的可能性。在一项涉及通过X射线粉末衍射定量分析异丁酮的研究过程中，作者使用最近开发的方法确定了标题化合物的结构（A. Gomez和S. Kycia，J. Appl。Crystallogr。2011 ，44，708-713）。该结构为单斜晶系，空间群为P 2 1（4），单位晶胞参数为a = 6.80704（7）Å，b = 20.73858（18）Å，c = 6.44900（6）Å，β = 76.4302（5）°，V = 884.980（15）一种3单位电池和两个分子（Ž = 2）。分子在a

  DOI：

  10.1039/c2ce06504e
• 作为产物：
  描述：

  炔诺酮 在 吡啶 、 N-溴代丁二酰亚胺(NBS) 、 硫酸 、 乙酸酐 、 溶剂黄146 、 乙酰氯 作用下， 以 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 19.0h， 生成 替勃龙
  参考文献：
  名称：

  一种替勃龙的合成方法

  摘要：

  一种替勃龙的合成方法，具体包括以下步骤：1)炔化反应：酸性脱羧物(I)甲苯溶液，通入乙炔气至原料反应得炔诺酮(II)；2)酰化反应，步骤1)得到的炔诺酮(II)加入醋酐和缚酸剂，控制室温滴加乙酰氯，搅拌反应6小时至原料反应完全，得酰化物(III)；3)上脱溴反应，酰化物反应得4,6‑二烯醋酸炔诺酮(V)；4)甲基化反应，4,6‑二烯醋酸炔诺酮(V)，加入醚类溶剂，降温至‑10～30℃，滴加甲基化试剂，控制温度0～5℃搅拌反应至原料反应完全得7α‑甲基醋酸炔诺酮(VI)；5)转位反应，7α‑甲基醋酸炔诺酮(VI)反应得转位物(VII)湿品；6)水解反应，转位物(VII)反应得替勃龙。

  公开号：

  CN110981930B

文献信息

• 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。
• [EN] GLUCOCORTICOID RECEPTOR MODULATORS<br/>[FR] MODULATEURS DE RÉCEPTEURS DES GLUCOCORTICOÏDES
  申请人：ORIC PHARMACEUTICALS INC

  公开号：WO2018191283A1

  公开（公告）日：2018-10-18

  Described herein are glucocorticoid receptor modulators and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer and hypercortisolism.

  本文描述了糖皮质激素受体调节剂和包含该类化合物的药物组合物。这些化合物和组合物对于治疗癌症和高皮质醇症是有用的。
• Fused cyclic modulators of nuclear hormone receptor function
  申请人：——

  公开号：US20030114420A1

  公开（公告）日：2003-06-19

  Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.

  融合环化合物，使用这种化合物治疗与核激素受体相关疾病（如癌症和免疫紊乱）的方法，以及含有这种化合物的药物组合物。
• Benzoxazepinones and their use as squalene synthase inhibitors
  申请人：——

  公开号：US20030078251A1

  公开（公告）日：2003-04-24

  There is disclosed a compound represented by the formula [I]: 1 wherein R 1 is optionally substituted 1-carboxyethyl group, optionally substituted alkyl-sulfonyl group, optionally substituted (carboxy-cycloalkyl)-alkyl group, —X 1 —X 2 —Ar—X 3 —X 4 —COOH (wherein X 1 and X 4 are a bond or alkylene group, X 2 and X 3 are a bond, —O—, —S—, Ar is divalent aromatic group etc.), R 2 is alkyl group optionally substituted with alkanoyloxy group and/or hydroxy group, R 3 is alkyl group, and W is halogen atom, etc., or a salt thereof. The compound has the cholesterol lowering activity and the triglyceride lowering activity and is useful for preventing and/or treating hyperlipidemia.

  披露了一种由公式[I]表示的化合物： 1 其中R 1 是可选地取代的1-羧乙基，可选地取代的烷基亚磺酰基，可选地取代的(羧基环烷基)-烷基，—X 1 —X 2 —Ar—X 3 —X 4 —COOH(其中X 1 和X 4 是键或亚烷基，X 2 和X 3 是键，—O—，—S—，Ar是二价芳香族等)，R 2 是可选地由酰氧基和/或羟基取代的烷基，R 3 是烷基，W是卤素原子等，或其盐。该化合物具有降低胆固醇活性和降低甘油三酯活性，用于预防或治疗高脂血症。
• [EN] NOVEL COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS
  申请人：PFIZER LTD

  公开号：WO2009144632A1

  公开（公告）日：2009-12-03

  The present invention relates to a class of substituted purine compounds of formula (I), uses thereof, processes for the preparation thereof and compositions containing said compounds. These compounds have utility in a variety of therapeutic areas including sexual dysfunction.(I).

  本发明涉及一类取代嘌呤化合物的公式（I），其用途、制备过程以及包含所述化合物的组合物。这些化合物在包括性功能障碍在内的多种治疗领域具有用途。

表征谱图