1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(iodomethyl)-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone | 162882-87-3

• 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: 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(iodomethyl)-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone
• CAS: 162882-87-3
• 化学式: C₂₂H₃₅IO₂
• 分子量: 458.423
• InChiKey: CMSHWTRVHPHRJX-HMWSDPSDSA-N

物化性质

• 沸点：
  498.891±10.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.346±0.06 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(iodomethyl)-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone 在 palladium on activated charcoal 氢气 、 sodium acetate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 18.0h， 以51%的产率得到加奈索酮
  参考文献：
  名称：

  Synthesis and in Vitro Activity of 3β-Substituted-3α-hydroxypregnan-20-ones:  Allosteric Modulators of the GABA_A Receptor

  摘要：

  Two naturally occurring metabolites of progesterone, 3 alpha-hydroxy-5 alpha- and 5 beta-pregnan-20-one (1 and 2), are potent allosteric modulators of the GABA(A) receptor. Their therapeutic potential as anxiolytics, anticonvulsants, and sedative/hypnotics is limited by rapid metabolism. To avoid these shortcomings, a series of 3 beta-substituted derivatives of 1 and 2 was prepared. Small lipophilic groups generally maintain potency in both the 5 alpha- and 5 beta-series as determined by inhibition of [S-35]TBPS binding. In the 5 alpha-series, 3 beta-ethyl, -propyl, -trifluoromethyl and -(benzyloxy)methyl, as well as substituents of the form 3 beta-XCH(2), where X is Cl, Br, or I or contains unsaturation, show limited efficacy in inhibiting [S-35]TBPS binding. In the 5 beta-series, the unsubstituted parent 2 is a two-component inhibitor, whereas all of the 3 beta-substituted derivatives of 2 inhibit TBPS via a single class of binding sites. In addition, all of the 3-substituted 5 beta-sterols tested are full inhibitors of [S-35]TBPS binding. Electrophysiological measurements using alpha 1 beta 2 gamma 2L receptors expressed in oocytes show that 3 beta-methyl- and 3 beta-(azidomethyl)-3 alpha-hydroxy-5 alpha-pregnan-20-one (6 and 22, respectively) are potent full efficacy modulators and that 3 alpha-hydroxy-3 beta-(trifluoromethyl)-5 alpha-pregnan-20-one (24) is a low-efficacy modulator, confirming the results obtained from [S-35]TBPS binding. These results indicate that modification of the 3 beta-position in 1 and 2 maintains activity at the neuroactive steroid site on the GABA(A) receptor. In animal studies, compound 6 (CCD 1042) is an orally active anticonvulsant, while the naturally occurring progesterone metabolites I and 2 are inactive when administered orally, suggesting that 3 beta-substitution slows metabolism of the S-hydroxyl, resulting in orally bioavailable steroid modulators of the GABA(A) receptor.

  DOI：

  10.1021/jm960021x
• 作为产物：
  描述：

  氢化黄体酮 在 sodium hydride 、 溶剂黄146 、 sodium iodide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 9.5h， 生成 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(iodomethyl)-10,13-dimethyl-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethanone
  参考文献：
  名称：

  Synthesis and in Vitro Activity of 3β-Substituted-3α-hydroxypregnan-20-ones:  Allosteric Modulators of the GABA_A Receptor

  摘要：

  Two naturally occurring metabolites of progesterone, 3 alpha-hydroxy-5 alpha- and 5 beta-pregnan-20-one (1 and 2), are potent allosteric modulators of the GABA(A) receptor. Their therapeutic potential as anxiolytics, anticonvulsants, and sedative/hypnotics is limited by rapid metabolism. To avoid these shortcomings, a series of 3 beta-substituted derivatives of 1 and 2 was prepared. Small lipophilic groups generally maintain potency in both the 5 alpha- and 5 beta-series as determined by inhibition of [S-35]TBPS binding. In the 5 alpha-series, 3 beta-ethyl, -propyl, -trifluoromethyl and -(benzyloxy)methyl, as well as substituents of the form 3 beta-XCH(2), where X is Cl, Br, or I or contains unsaturation, show limited efficacy in inhibiting [S-35]TBPS binding. In the 5 beta-series, the unsubstituted parent 2 is a two-component inhibitor, whereas all of the 3 beta-substituted derivatives of 2 inhibit TBPS via a single class of binding sites. In addition, all of the 3-substituted 5 beta-sterols tested are full inhibitors of [S-35]TBPS binding. Electrophysiological measurements using alpha 1 beta 2 gamma 2L receptors expressed in oocytes show that 3 beta-methyl- and 3 beta-(azidomethyl)-3 alpha-hydroxy-5 alpha-pregnan-20-one (6 and 22, respectively) are potent full efficacy modulators and that 3 alpha-hydroxy-3 beta-(trifluoromethyl)-5 alpha-pregnan-20-one (24) is a low-efficacy modulator, confirming the results obtained from [S-35]TBPS binding. These results indicate that modification of the 3 beta-position in 1 and 2 maintains activity at the neuroactive steroid site on the GABA(A) receptor. In animal studies, compound 6 (CCD 1042) is an orally active anticonvulsant, while the naturally occurring progesterone metabolites I and 2 are inactive when administered orally, suggesting that 3 beta-substitution slows metabolism of the S-hydroxyl, resulting in orally bioavailable steroid modulators of the GABA(A) receptor.

  DOI：

  10.1021/jm960021x

文献信息

• [EN] ANDROSTANE AND PREGNANE SERIES FOR ALLOSTERIC MODULATION OF GABA RECEPTOR<br/>[FR] SERIES DE L'ANDROSTANE ET DE LA PREGNANE PRODUISANT UNE MODULATION ALLOSTERIQUE DU RECEPTEUR DU GABA
  申请人：COCENSYS, INC.

  公开号：WO1996016076A1

  公开（公告）日：1996-05-30

  (EN) Methods, compositions, and compounds for modulating the GABAA receptor-chloride ionophore complex to alleviate stress, anxiety, seizures, mood disorders, PMS and PND and to induce anesthesia.(FR) Procédés, compositions et composés servant à moduler le complexe ionophore de chlorure et récepteur du GABAA, permettant ainsi d'atténuer le stress, l'anxiété, les crise d'épilepsie, les troubles de l'humeur, la dépression post natale et le syndrome prémenstruel, et de provoquer l'anesthésie.

  (中文) 用于调节GABAA受体-氯离子复合物以缓解压力、焦虑、癫痫、情绪障碍、PMS和PND并诱导麻醉的方法、组合物和化合物。
• Complex Metabolism of the Novel Neurosteroid, Ganaxolone, in Humans. A Unique Challenge for MIST Assessment
  作者：William L. Fitch、Steven Smith、Michael Saporito、Gregory Busse、Mingbao Zhang、Julie Ren、Michael E Fitzsimmons、Ping Yi、Stephen English、Adam Carter、Thomas A. Baillie

  DOI：10.1124/dmd.122.001218

  日期：——

  pharmacokinetics, metabolism, and excretion of [14C]-ganaxolone (GNX) were characterized in healthy male subjects (n = 8) following a single 300-mg (150 μCi) oral dose. GNX exhibited a short half-life of 4 hours in plasma, whereas total radioactivity had a half-life of 413 hours indicating extensive metabolism to long-lived metabolites. Identification of the major GNX circulating metabolites required extensive

  [ 14 C]-加奈索酮 (GNX)的人体药代动力学、代谢和排泄在健康男性受试者 ( n = 8)中进行了表征，单次口服剂量为 300 毫克 (150 μ Ci)。GNX 在血浆中表现出 4 小时的短半衰期，而总放射性的半衰期为 413 小时，表明广泛代谢为长寿命代谢物。主要 GNX 循环代谢物的鉴定需要液相色谱-串联质谱分析的广泛分离和纯化，以及体外研究、核磁共振光谱和合成化学支持。这表明 GNX 代谢的主要途径涉及 16 α的羟基化-羟基位置，20-酮的立体选择性还原得到相应的 20α-羟基甾醇，3α-羟基硫酸化。后一反应产生不稳定的叔硫酸盐，它消除了 H 2 SO 4的元素以在 A 环中引入双键。这些途径的组合，连同将 3 β-甲基取代基氧化成羧酸和在 20 α处硫酸化位置，导致血浆中的主要循环代谢物，称为 M2 和 M17。这些研究导致对不少于 59 种 GNX 代谢物的完整或部分
• METHODS AND COMPOSITIONS FOR INDUCING SLEEP
  申请人：Purdue Pharma Ltd.

  公开号：EP0701444B1

  公开（公告）日：2010-04-07
• ANDROSTANE AND PREGNANE SERIES FOR ALLOSTERIC MODULATION OF GABA RECEPTOR
  申请人：COCENSYS, INC.

  公开号：EP0808325A1

  公开（公告）日：1997-11-26
• EP0808325A4
  申请人：——

  公开号：EP0808325A4

  公开（公告）日：1997-12-17