(5alpha,10alpha,17beta)-5,10-环氧-17-羟基-17-(1-丙炔-1-基)-雌甾-9(11)-烯-3-酮环1,2-乙二基缩醛 | 84371-57-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧杂环己烷
• 中文名称: (5alpha,10alpha,17beta)-5,10-环氧-17-羟基-17-(1-丙炔-1-基)-雌甾-9(11)-烯-3-酮环1,2-乙二基缩醛
• 中文别名: 1-苄基-1,7-二氮杂螺[4.4]壬烷半草酸盐
• 英文名称: (5'R,8'S,10'R,13'S,14'S,17'S)-13'-methyl-17'-(prop-1-yn-1-yl)-1',2',7',8',12',13',14',15',16',17'-decahydro-4'H,6'H-spiro[[1,3]dioxolane-2,3'-[5,10]epoxycyclopenta[a]phenanthren]-17'-ol
• 英文别名: (5R,8S,10R,13S,14S,17S)-13-methyl-17-(prop-1-yn-1-yl)-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[5,10-epoxycyclopenta[a]phenanthrene-3,2'-[1,3]dioxolan]-17-ol；3,3-<1,2-ethylenedioxybis(oxy)>-17α-(1-propynyl)-estra-9(11)-en-5α,10α-epoxy-17β-ol；5α,10α-epoxy-17α-ethynyl-17β-hydroxy-3,3-(ethane-1,2-diyldioxy)-estra-9(11)-en；5α,10α-epoxy-3,3-ethylenedioxy-17β-hydroxy-17α-(1-propynyl)-9(11)-estrene；(5'R,10'R,13'S,17'S)-13'-methyl-17'-prop-1-ynyl-1',2',7',8',12',13',14',15',16',17'-decahydro-6'H-spiro[1,3-dioxolane-2,3'-[5,10]epoxycyclopenta[a]phenanthren]-17'-ol；3,3-ethylenedioxy-5,10-epoxy-17α-(1-propynyl)-17β-hydroxy-9(11)-estrene；(5alpha,10alpha,17beta)-5,10-Epoxy-17-hydroxy-17-(1-propyn-1-yl)-estr-9(11)-en-3-one cyclic 1,2-ethanediyl acetal；(1'R,5'S,6'S,9'S,10'S,13'R)-5'-methyl-6'-prop-1-ynylspiro[1,3-dioxolane-2,15'-18-oxapentacyclo[11.4.1.01,13.02,10.05,9]octadec-2-ene]-6'-ol
• CAS: 84371-57-3
• 化学式: C₂₃H₃₀O₄
• 分子量: 370.489
• InChiKey: NRUIWWWJNIPUBD-XZJZWBLTSA-N

物化性质

• 熔点：
  122-125°C
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  27
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  51.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (5alpha,10alpha,17beta)-5,10-环氧-17-羟基-17-(1-丙炔-1-基)-雌甾-9(11)-烯-3-酮环1,2-乙二基缩醛 在 sodium hydride 、 对甲苯磺酸 、 copper(l) chloride 作用下， 以 四氢呋喃 为溶剂， 生成 [4-[(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-11-yl]phenyl] trifluoromethanesulfonate
  参考文献：
  名称：

  Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist

  摘要：

  Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-diabetic activities. For glucocorticoid receptor (GR) program, we sought an unexplored, synthetically accessible phosphorus-containing steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. One compound 4a, with high oral bioavailability (59%) in rat, exhibited functional antagonism of GR in oral glucose tolerance test (OGTT). Thus this series of compounds might be potentially useful for the treatment of type II diabetes.

  DOI：

  10.1016/j.bmcl.2006.10.003
• 作为产物：
  描述：

  3-缩酮 在 双氧水 、 六氟丙酮 作用下， 以 四氢呋喃 、 aq. phosphate buffer 、 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 为溶剂， 反应 2.17h， 生成 (5alpha,10alpha,17beta)-5,10-环氧-17-羟基-17-(1-丙炔-1-基)-雌甾-9(11)-烯-3-酮环1,2-乙二基缩醛
  参考文献：
  名称：

  发现强效和选择性的类固醇糖皮质激素受体拮抗剂（ORIC-101）

  摘要：

  糖皮质激素受体（GR）已与多种癌症类型的治疗耐药性相关。临床前数据表明，该核受体的拮抗剂可以增强抗癌治疗的活性。第一代GR拮抗剂米非司酮目前正在各种肿瘤学环境中进行临床评估。米非司酮的基于结构的修饰导致发现了ORIC-101（28），这是一种高效的甾体GR拮抗剂，具有降低的雄激素受体（AR）激动活性，适合雄激素受体阳性肿瘤给药，并且对CYP2C8和CYP2C9的抑制作用得到改善最大限度地减少药物相互作用的可能性。与米非司酮不同，28可以与容易被CYP2C8代谢的化疗药物（如紫杉醇）共用。此外，在GR + OVCAR5卵巢癌异种移植模型中，有28种药物通过增强对化疗的反应表现出体内抗肿瘤活性。正在对28种药物的安全性和治疗潜力进行临床评估。

  DOI：

  10.1021/acs.jmedchem.8b00743

文献信息

• 11-PHOSPHOROUS STEROID DERIVATIVES USEFUL AS PROGESTERONE RECEPTOR MODULATORS
  申请人：Fiordeliso J. James

  公开号：US20070232570A1

  公开（公告）日：2007-10-04

  The present invention is directed to novel 11-phosphorous steroid derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by a progesterone or glucocorticoid receptor.

  本发明涉及新颖的11-磷酸类固醇衍生物，含有它们的药物组合物以及它们在治疗受孕激素或糖皮质激素受体调节的疾病和症状中的应用。
• [EN] GLUCOCORTICOID RECEPTOR LIGANDS FOR THE TREATMENT OF METABOLIC DISORDERS<br/>[FR] LIGANDS DE RECEPTEURS GLUCOCORTICOIDES POUR LE TRAITEMENT DE TROUBLES METABOLIQUES
  申请人：ABBOTT LAB

  公开号：WO2004000869A1

  公开（公告）日：2003-12-31

  This invention relates to novel compounds that are liver selective glucocorticoid receptor antagonists, to methods of preparing such compounds, and to methods for using such compounds in the regulation of metabolism, especially lowering serum glucose levels, insulin levels, or lipid levels, and/or decreasing body weight.

  这项发明涉及一种新型化合物，它们是肝选择性糖皮质激素受体拮抗剂，涉及制备这种化合物的方法，以及利用这种化合物在调节新陈代谢方面的方法，特别是降低血清葡萄糖水平、胰岛素水平或脂质水平，和/或减少体重。
• 17-PHOSPHOROUS STEROID DERIVATIVES USEFUL AS PROGESTERONE RECEPTOR MODULATORS
  申请人：Jiang Weiqin

  公开号：US20070207982A1

  公开（公告）日：2007-09-06

  The present invention is directed to novel 17-phosphorous steroid derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by a progesterone or glucocorticoid receptor.

  本发明涉及新颖的17-磷类固醇衍生物，含有它们的药物组合物以及它们在治疗受孕激素或糖皮质激素受体调节的疾病和症状中的用途。
• [EN] INHIBITORS OF GLUCOCORTICOID RECEPTOR<br/>[FR] INHIBITEURS DE RÉCEPTEURS GLUCOCORTICOÏDES
  申请人：ORIC PHARMACEUTICALS INC

  公开号：WO2017112904A1

  公开（公告）日：2017-06-29

  The present invention relates generally to compositions and methods for treating cancer and hypercortisolism. Provided herein are substituted steroidal derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of glucocorticoid receptors. Furthermore, the subject compounds and compositions are useful for the treatment of cancer and hypercortisolism.

  本发明一般涉及治疗癌症和高皮质醇血症的组合物和方法。本文提供了替代类固醇衍生物化合物和包含该化合物的药物组合物。所述化合物和组合物对于抑制糖皮质激素受体是有用的。此外，所述化合物和组合物对于治疗癌症和高皮质醇血症是有用的。
• Synthesis and evaluation of [11C]RU40555, a selective glucocorticoid receptor antagonist
  作者：Takahiro Matsuya、Hiroyuki Takamatsu、Yoshihiro Murakami、Akihiro Noda、Kazuhiko Osoda、Rikiya Ichise、Yuji Awaga、Shintaro Nishimura

  DOI：10.1002/jlcr.958

  日期：2005.8

  We demonstrated the synthesis of carbon-11 labeled 17-α-hydroxy-11-β-/4-/[methyl]-[1-methylethyl]-aminophenyl/-17α-[prop-1-ynyl]esta-4-9-diene-3-one (RU40555), a selective glucocorticoid receptor (GR) antagonist, and examined the in vivo profile of [11C]RU40555. [11C]RU40555 was synthesized by direct N-methylation with [11C]CH3OTf at 60°C for 5 min and an injectable solution of [11C]RU40555 was obtained in 31 min at the end of bombardment. The decay-corrected radiochemical yield was 19%, the specific radioactivity was 57.5±14.0 GBq/µmol, and the radiochemical purity was more than 99% as determined by HPLC. In rat experiments, the effects of adrenalectomy (ADX) on brain accumulation of [11C]RU40555 were examined. ADX significantly decreased plasma corticosterone levels, and significantly increased brain accumulation of [11C]RU40555. We succeeded in developing a rapid automated synthesis method for [11C]RU40555, a GR antagonist, and showed [11C]RU40555 had a potential as a PET tracer for mapping GR. Copyright © 2005 John Wiley & Sons, Ltd.

  我们展示了碳-11标记的17-α-羟基-11-β-/4-/[甲基]-[1-甲基乙基]-氨基苯基/-17α-[丙-1-炔基]酯-4-9-二烯-3-酮（RU40555）这一特定糖皮质激素受体（GR）拮抗剂的合成，并检查了[11C]RU40555的体内特性。[11C]RU40555通过在60°C下用[11C]CH3OTf直接进行N-甲基化合成，合成时间为5分钟，并在轰击结束后31分钟获得可注射的[11C]RU40555溶液。经衰变校正后的放射化学产率为19%，比放射活度为57.5±14.0 GBq/µmol，放射化学纯度通过高效液相色谱法（HPLC）测定超过99%。在大鼠实验中，我们研究了肾上腺切除术（ADX）对[11C]RU40555在脑中的积累的影响。ADX显著降低了血浆皮质酮水平，并显著增加了[11C]RU40555在脑中的积累。我们成功开发了一种快速的自动合成方法来合成GR拮抗剂[11C]RU40555，并显示[11C]RU40555作为PET示踪剂用于映射GR具有潜力。版权所有 © 2005 John Wiley & Sons, Ltd.