3,17β-Bis[(3-pyridinylcarbonyl)oxy]-estra-1,3,5(10)-triene | 4248-62-8

• 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
• 英文名称: 3,17β-Bis[(3-pyridinylcarbonyl)oxy]-estra-1,3,5(10)-triene
• 英文别名: 3,17β-bis<(3-pyridinylcarbonyl)oxy>estra-1,3,5(10)-triene；estra-1,3,5(10)-triene-3,17β-diyl dinicotinate；estradiol 3,17β-dinicotinate ester；3,17β-Bis[(3-pyridinylcarbonyl)oxy]estra-1,3,5(10)-triene；estradiol 3,17β-dinicotinate；Estradiol-dinicate；[(8R,9S,13S,14S,17S)-13-methyl-3-(pyridine-3-carbonyloxy)-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] pyridine-3-carboxylate
• CAS: 4248-62-8
• 化学式: C₃₀H₃₀N₂O₄
• 分子量: 482.579
• InChiKey: OMYYNMAXTHDLFS-KACYJRNJSA-N

物化性质

• 熔点：
  183.5-185 °C(Solv: ethyl acetate (141-78-6); hexane (110-54-3))
• 沸点：
  630.3±55.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  78.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3,17β-Bis[(3-pyridinylcarbonyl)oxy]-estra-1,3,5(10)-triene 在 potassium hydrogencarbonate 作用下， 以 甲醇 、 水 为溶剂， 以94%的产率得到3-hydroxy-17β-<(3-pyridinylcarbonyl)oxy>estra-1,3,5(10)-triene
  参考文献：
  名称：

  通过生物膜改善递送。32.各种雌二醇衍生物的脑靶向递送系统的合成和生物学活性。

  摘要：

  在平衡吡啶鎓盐氧化还原互变中基于二氢吡啶的脑靶向递送系统被合成为雌二醇，3-苯甲酸雌二醇和乙炔雌二醇。最初的生物学评估表明，虽然通过血清LH抑制测量到，所合成的所有四种化合物都发挥着中枢的雌激素活性，但只有基于17-取代的雌二醇和乙炔雌二醇的递送系统显示出延长的作用（大于12天）。乙炔雌二醇的17-（1-甲基-1,4-二氢烟酸酯）在各种测定中的行为与前述雌二醇类似物相似。在大鼠中进行的组织分布研究表明，施用乙炔雌二醇衍生物可导致中枢神经系统（CNS）中较高的相应吡啶鎓盐持续水平，而氧化代谢产物的血液水平迅速下降。持续的大脑水平与乙炔雌二醇的延长释放有关。到处理后24小时，通过HPLC在血液中未发现乙炔雌二醇，而在CNS中检测到超过20 ng / g的组织水平。这种增强的中央递送提供了剂量和时间依赖性的LH抑制，这表明与相应的雌二醇衍生物相比，其效力增加了三至五倍。HPLC在血液中未发现乙炔

  DOI：

  10.1021/jm00396a038
• 作为产物：
  描述：

  烟酸 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 生成 3,17β-Bis[(3-pyridinylcarbonyl)oxy]-estra-1,3,5(10)-triene
  参考文献：
  名称：

  Synthesis of pyridine-carboxylate derivatives of hydroxysteroids for liquid chromatography–electrospray ionization-mass spectrometry

  摘要：

  Synthesis and liquid chromatography-electrospray ionization-mass spectrometric (LC-ESI-MS) behaviors of the picolinoyl, 6-methylpicolinoyl, nicotinoyl, 2-methoxynicotinoyl and isonicotinoyl derivatives of the hydroxysteroids estrone, estradiol, 3 beta-hydroxyandrost-5en-17-one (dehydroepiandrosterone) and testosterone in positive mode were investigated. Each steroid was converted to the corresponding pyridine-carboxylate derivative by the acyl chloride method or the mixed anhydride method using the corresponding free acids and 2-methyl-6-nitrobenzoic anhydride; in each case, the latter method principally gave a better yield. The pyridine-carboxylate derivative of each steroid exhibited a clear single peak in liquid chromatography with a reversed phase column and CH3CN-0.1% CH3COOH as a mobile phase. The positive-ESI-mass spectra of the picolinoyl, 6-methylpicolinoyl and 2-methoxynicotinoyl derivatives showed a predominance of [M+H](+), whereas [M+H+CH3CN](+) was observed with high intensity in the nicotinoyl and isonicotinoyl derivatives. Even in the case of estradiol, with its two hydroxyl groups, a single charged ion of [M+H](+) or [M+H+CH3CN](+) was observed in the positive-ESI-mass spectrum of each derivative. The results revealed that picolinoyl derivatization is a simple and versatile method suitable for the sensitive and specific determination of hydroxysteroids by LC-ESI-MS (selected reaction monitoring). (c) 2006 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2006.10.005

文献信息

• Pharmaceutical formulations for parenteral use
  申请人：University of Florida

  公开号：US04983586A1

  公开（公告）日：1991-01-08

  Aqueous parenteral solutions of drugs which are insoluble or only sparingly soluble in water and/or which are unstable in water, combined with hydroxypropyl-.beta.-cyclodextrin, provide a means for alleviating problems associated with drug precipitation at the injection site and/or in the lungs or other organs following parenteral administration.

  将不溶或在水中仅微溶或在水中不稳定的药物与羟丙基-β-环糊精结合，提供了一种缓解与药物在注射部位沉淀以及/或在注射后在肺部或其他器官中沉淀相关问题的方法。
• Redox systems for brain-targeted drug delivery
  申请人：University of Florida

  公开号：US05017566A1

  公开（公告）日：1991-05-21

  Inclusion complexes of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .beta.- and .gamma.-cyclodextrin with the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal forms of dihydropyridine.revreaction.pyridinium salt redox systems for brain-targeted drug delivery provide a means for stabilizing the redox systems, particularly against oxidation. The redox inclusion complexes also provide a means for decreasing initial drug concentrations in the lungs after administration of the systems, leading to decreased toxicity. In selected instances, complexation results in substantially improved water solubility of the redox systems as well.

  羟丙基、羟乙基、葡萄糖基、麦芽糖基和麦芽三糖基衍生物与β-和γ-环糊精的包含复合物，与还原的、可生物氧化的、能穿透血脑屏障的、脂质形式的二氢吡啶.反应.pyridinium盐氧化还原系统形成脑靶向药物输送的一种手段，用于稳定氧化还原系统，特别是对抗氧化作用。氧化还原包含复合物还提供了一种减少系统给药后肺部初始药物浓度的手段，从而降低毒性。在某些情况下，复合作用显著提高了氧化还原系统的水溶性。
• Improved Delivery through Biological Membranes XXXI: Solubilization and Stabilization of an Estradiol Chemical Delivery System by Modified β‐Cyclodextrins
  作者：Marcus E. Brewster、Kerry S. Estes、Thorsteinn Loftsson、Robert Perchalski、Hartmut Derendorf、Gotelind Mullersman、Nicholas Bodor

  DOI：10.1002/jps.2600771118

  日期：1988.11

  A dihydropyridine in equilibrium pyridinium salt chemical delivery system (CDS) for estradiol (E2CDS) was complexed with various modified beta-cyclodextrins including hydroxyethyl-beta-cyclodextrin (HECD), hydroxypropyl-beta-cyclodextrin (HPCD), and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DMCD). Complex formation with all of these cyclodextrins resulted in dramatic increases in the water solubility

  将雌二醇（E2CDS）的平衡吡啶鎓盐化学递送系统（CDS）中的二氢吡啶与各种改性的β-环糊精（包括羟乙基-β-环糊精（HECD），羟丙基-β-环糊精（HPCD）和庚烷）复合（2,6 -二-O-甲基）-β-环糊精（DMCD）。与所有这些环糊精的复合物形成导致E2CDS的水溶性急剧增加。对E2CDS和HPCD的复合物（E2CDS-CD）的研究表明，包封的雌激素比未处理的CDS稳定大约四倍，与之相比，室温下未复合的药物的降解半衰期估计为4年，而1.2年温度。E2CDS和HPCD的络合也稳定了含铁氰化钾溶液中的二氢烟酸酯。该配方在将氧化的雌二醇前体（E2Q +）输送至大脑时，相当于在二甲基亚砜中的E2CDS等效，并且也产生了相似的生物学反应。其中包括减少cast割雌性大鼠的黄体生成素（LH）分泌和体重增加率。
• Brain-specific drug delivery
  申请人：University of Florida

  公开号：US05187158A1

  公开（公告）日：1993-02-16

  The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are: (a) compounds of the formula [D-DHC] (I) wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine .revreaction. pyridinium salt redox carrier, with the proviso that when [DHC] is ##STR1## wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH.sub.2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH.sub.2 or OH functional group to the carbonyl function of [DHC], then [D] must be other than a sympathetic stimulant, steroid sex hormone or long chain alkanol; and (b) non-toxic pharmaceutically acceptable salts of compounds of formula (I) wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine .revreaction. pyridinium salt redox carrier. The corresponding ionic pyridinium salt type drug/carrier entities [D-QC].sup.+ X.sup.- are also disclosed.

  这些化合物适用于针对特定部位/持续释放中枢作用药物物种到达大脑，其中包括：（a）式[D-DHC]（I）的化合物，其中[D]是中枢作用药物物种，[DHC]是一种二氢吡啶的还原、可生物氧化、穿越血脑屏障的脂质形式.revreaction.吡啶盐氧化还原载体，但当[DHC]为##STR1##其中R为较低的烷基或苄基，[D]是含有单个NH.sub.2或OH官能团的药物物种，当存在单个OH官能团时，该官能团为一次级或二次级OH官能团，该药物物种直接通过所述NH.sub.2或OH官能团与[DHC]的羰基功能相连结，那么[D]必须是除了交感神经兴奋剂、类固醇性激素或长链烷醇之外的其他药物物种；以及（b）公认为无毒的药物可接受盐，其中[D]是中枢作用药物物种，[DHC]是一种二氢吡啶的还原、可生物氧化、穿越血脑屏障的脂质形式.revreaction.吡啶盐氧化还原载体的化合物的式（I）。还公开了相应的离子吡啶盐型药物/载体实体[D-QC].sup.+ X.sup.-。
• Improvements in redox systems for brain-targeted drug delivery
  申请人：University of Florida

  公开号：US05002935A1

  公开（公告）日：1991-03-26

  Inclusion complexes of hydroxypropyl-.beta.-cyclodextrin with the reduced biooxidizable, blood-brain barrier penetrating, lipoidal forms of dihydropyridine.revreaction.pyridinium salt redox systems for brain-targeted drug delivery provide a means for stabilizing the redox systems, particularly against oxidation. The reodox inclusion complexes also provide a means for decreasing initial drug concentrations in the lungs after administration of the systems, leading to decreased toxicity. In selected instances, complexation results in substantially improved water solubility of the redox systems as well.

  羟丙基-β-环糊精与可还原、可氧化的穿过血脑屏障的脂质型二氢吡啶盐氧化还原系统形成的包合物，可用于脑靶向药物传递，提供了一种稳定氧化还原系统的手段，特别是对抗氧化反应。包合物还可用于降低系统给药后肺部初始药物浓度，从而降低毒性。在某些情况下，包合物也可显著提高氧化还原系统的水溶性。