[(8R,9S,13S,14S,17S)-3-羟基-13-甲基-6,7,8,9,11,12,14,15,16,17-十氢环戊烯并[a]菲-17-基]1-甲基-4H-吡啶-3-羧酸酯 | 103562-82-9

• 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: [(8R,9S,13S,14S,17S)-3-羟基-13-甲基-6,7,8,9,11,12,14,15,16,17-十氢环戊烯并[a]菲-17-基]1-甲基-4H-吡啶-3-羧酸酯
• 中文别名: 化合物 T27287
• 英文名称: 3-hydroxy-17β-<<(1-methyl-1,4-dihydropyridin-3-yl)-carbonyl>-oxy>estra-1,3,5(10)-triene
• 英文别名: 3-hydroxy-17β-<<(1-methyl-1,4-dihydropyridin-3-yl)carbonyl>oxy>estra-1,3,5(10)-triene；estra-1,3,5(10)-triene-3,17β-diol-17-(1,4-dihydro-1-methylpyridine-3-carboxylate)；estredox；17β-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy]estra-1,3,5(10)-trien-3-ol；3-hydroxy-17β-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}estra-1,3,5(10)-triene；Estra-1,3,5(10)-triene-3,17-diol (17beta)-, 17-(1,4-dihydro-1-methyl-3-pyridinecarboxylate)；[(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] 1-methyl-4H-pyridine-3-carboxylate
• CAS: 103562-82-9
• 化学式: C₂₅H₃₁NO₃
• 分子量: 393.526
• InChiKey: KTMLJZFJHDUEAU-BZDYCCQFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  4

制备方法与用途

E2-CDS（ Estradiol 17-Dihydrotrigonelline）是一种基于氧化还原反应的雌二醇(E2)化学输送系统，能够实现持续且具有大脑选择性的雌二醇输送。

反应信息

• 作为反应物：
  描述：

  [(8R,9S,13S,14S,17S)-3-羟基-13-甲基-6,7,8,9,11,12,14,15,16,17-十氢环戊烯并[a]菲-17-基]1-甲基-4H-吡啶-3-羧酸酯 生成 [(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] 1-methylpyridin-1-ium-3-carboxylate
  参考文献：
  名称：

  ANDERSON, WESLEY R.;SIMPKINS, JAMES W.;BREWSTER, MARCUS E.;BODOR, NICHOLA+, ENDOCRINE RES., 14,(1988) N 2-3, C. 131-148

  摘要：

  DOI：
• 作为产物：
  描述：

  雌二醇 在 sodium dithionite 、 potassium hydrogencarbonate 作用下， 以 甲醇 、 叔丁醇 为溶剂， 生成 [(8R,9S,13S,14S,17S)-3-羟基-13-甲基-6,7,8,9,11,12,14,15,16,17-十氢环戊烯并[a]菲-17-基]1-甲基-4H-吡啶-3-羧酸酯
  参考文献：
  名称：

  通过生物膜改善递送。XXXL：通过修饰的β-环糊精增溶和稳定雌二醇化学递送系统。

  摘要：

  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。

  DOI：

  10.1002/jps.2600771118

文献信息

• Improved delivery through biological membranes. 32. Synthesis and biological activity of brain-targeted delivery systems for various estradiol derivatives
  作者：Marcus E. Brewster、Kerry S. Estes、Nicholas Bodor

  DOI：10.1021/jm00396a038

  日期：1988.1

  Brain-targeted delivery systems based on the dihydropyridine in equilibrium pyridinium salt redox interconversion were synthesized for estradiol, estradiol 3-benzoate, and ethynylestradiol. Initial biological evaluation indicated that while all four compounds synthesized exerted central estrogenic activity as measured by serum LH suppression, only the delivery systems based on the 17-substituted estradiol

  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
• Determination of estredox, a compound with sustained estradiol function, and its impurity profile by HPLC
  作者：Patthy、Seres、Toth-Sarudy、Hazai、Pallagi、Simay, Antal、Bodor

  DOI：10.1691/ph.2008.7321

  日期：——

  The HPLC methods described here for the assay and purity test of Estredox (E2CDS), a molecule with a redox-based, brain-targeted chemical delivery system for estradiol, allow reliable conclusions to be made on the potency and purity of API and E2CDS/HPCD complex samples. Extensive work was done to isolate and characterize the major, potential contaminants, and ensure the required stability of solutions of E2CDS, an inherently labile compound by design. Both the sample solvent and the eluent were thoroughly tested to avoid unwanted changes in sample solutions during analyses. The 12 minute isocratic assay method at 220 or 360 nm is simple, well-founded, highly precise and accurate. Purity profiling of E2CDS raised several problems in detection, stability and accuracy, owing to the fact that the pattern of the UV spectra and the stability of the compound and those of the potential contaminants often differed greatly. As a result of meticulous analysis of the UV spectra and the factors influencing the behaviour, in solution, of the compounds concerned, the 20 minute gradient method developed for the purity test, at 220 nm, of E2CDS and E2CDS/HPCD complex samples has proved to be a reliable means of adequately resolving 15–20 peaks of known and unknown compounds, and establishing the purity of various E2CDS samples. Sample impurity can be expressed as area % at 220nm, and/or as approximate w/w % (if needed), since the relative response factors, at 220 nm, of the 6 major, potential contaminants have also been determined.

  这里描述的 HPLC 方法用于 Estredox (E2CDS) 的测定和纯度测试，E2CDS 是一种具有基于氧化还原的脑靶向雌二醇化学输送系统的分子，可以对 API 和 E2CDS/ 的效力和纯度得出可靠的结论。 HPCD 复杂样品。我们进行了大量工作来分离和表征主要的潜在污染物，并确保 E2CDS（一种本质上不稳定的化合物）溶液所需的稳定性。样品溶剂和洗脱液都经过彻底测试，以避免分析过程中样品溶液发生不必要的变化。 220 或 360 nm 的 12 分钟等度测定方法简单、有依据、高度精确和准确。 E2CDS 的纯度分析在检测、稳定性和准确性方面提出了一些问题，因为紫外光谱的模式以及化合物和潜在污染物的稳定性通常差异很大。通过对 UV 光谱和影响相关化合物在溶液中行为的因素进行仔细分析，为 E2CDS 和 E2CDS/HPCD 复合样品的纯度测试开发的 20 分钟梯度方法（在 220 nm 处）已证明成为充分分离已知和未知化合物的 15-20 个峰并确定各种 E2CDS 样品纯度的可靠方法。样品杂质可以表示为 220 nm 处的面积百分比和/或近似 w/w %（如果需要），因为 6 种主要潜在污染物在 220 nm 处的相对响应因子也已确定。
• Use of estrogen-dihydropyridine compounds for weight control
  申请人：UNIVERSITY OF FLORIDA

  公开号：EP0220844A2

  公开（公告）日：1987-05-06

  The invention provides the use of a compound of the formula [E-DHC] (I) or a non-toxic pharmaceutically acceptable salt thereof, wherein [E] is an estrogen and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine#pyridinium salt redox carrier in the preparation of a medicament for controlling mammalian body weight. Novel compositions for weight control comprising a compound of formula (I) or its salt are also disclosed. A preferred compound for use herein is an estradiol derivative, namely, 17β-[(1-methy)-1,4-dihydro-3-pyridiny))carbony)oxy]estra-1,3.5(10)-trien-3-ol.

  本发明提供了一种式[E-DHC] (I)化合物的用途。 [E-DHC] (I) 或其无毒的药学上可接受的盐，其中[E]是一种雌激素，[DHC]是二氢吡啶#吡啶鎓盐氧化还原载体的还原型、可生物氧化、可透过血脑屏障的脂质形式，用于制备控制哺乳动物体重的药物。还公开了包含式（I）化合物或其盐的用于控制体重的新型组合物。这里使用的一种优选化合物是雌二醇衍生物，即17β-[(1-甲基)-1,4-二氢-3-吡啶))羰基)氧基]雌甾-1,3.5(10)-三烯-3-醇。
• Method for treating male sexual dysfunction
  申请人：UNIVERSITY OF FLORIDA

  公开号：EP0256668A2

  公开（公告）日：1988-02-24

  The invention provides the use of a compound of the formula or a non-toxic pharmaceutically acceptable salt thereof, wherein [E] is an estrogen and [DHC] is the reduced, biooxidizable, blood-brain barrier-penetrating, lipoidal form of a dihydropyridine pyridinium salt redox carrier in the preparation of a medicament for treating male sexual dysfunction. Compositions for use in the subject method are also disclosed. A preferred compound for use in the method and compositions is an estradiol derivative, namely, 17β-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy]estra-1,3,5(1O)-trien-3-ol.

  本发明提供了式化合物或其无毒药学上可接受的盐在制备治疗男性性功能障碍的药物中的用途，其中[E]是雌激素，[DHC]是二氢吡啶吡啶盐氧化还原载体的还原型、生物可氧化型、血脑屏障穿透型、脂质型。 还公开了用于所述方法的组合物。 用于所述方法和组合物的优选化合物是雌二醇衍生物，即17β-[(1-甲基-1,4-二氢-3-吡啶基)羰基氧基]雌甾-1,3,5(1O)-三烯-3-醇。
• Pharmaceutical formulations for parenteral use
  申请人：UNIVERSITY OF FLORIDA

  公开号：EP0335545A2

  公开（公告）日：1989-10-04

  Aqueous parenteral solutions of drugs which are insoluble or only sparingly'soluble in water and/or which are unstable in water, combined with a hydroxypropyl,hydroxyethyl, glucosyl, maltosyl or maltotriosyl derivative of 3-or γ-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.

  不溶于水或只能少量溶于水和/或在水中不稳定的药物的肠外水溶液与 3-或 γ-环糊精的羟丙基、羟乙基、葡糖基、麦芽糖基或麦芽三糖基衍生物结合使用，可以缓解肠外给药后药物在注射部位和/或肺部或其他器官沉淀的问题。