(3R,10S,13S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydrospiro[cyclopenta[a]phenanthrene-3,2'-oxirane] | 148256-46-6

• 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: (3R,10S,13S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydrospiro[cyclopenta[a]phenanthrene-3,2'-oxirane]
• 英文别名: 3(R)-20,20-ethylenedioxy-5α-pregnane-3-spiro-2'-oxirane；20,20-(ethylenedioxy)-(3R)-spiro[oxirane-2',5α-pregnane]；(3R,5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)spiro[1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3,2'-oxirane]
• CAS: 148256-46-6
• 化学式: C₂₄H₃₈O₃
• 分子量: 374.564
• InChiKey: BGWBEWADQXHORU-IKIYHMGGSA-N

物化性质

• 沸点：
  460.8±20.0 °C(Predicted)
• 密度：
  1.12±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  27
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  31
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3R,10S,13S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydrospiro[cyclopenta[a]phenanthrene-3,2'-oxirane] 在 盐酸 、 四丁基氟化铵 作用下， 以 丙酮 、 苯 为溶剂， 反应 0.5h， 生成 3β-fluoromethyl-3α-hydroxy-5α-pregnan-20-one
  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：

  (3β)-17-(2-methyl-1,3-dioxolan-2-yl)-androstan-3-ol 在 sodium hydride 、 戴斯-马丁氧化剂 作用下， 以 二氯甲烷 、 二甲基亚砜 、 mineral oil 为溶剂， 反应 7.0h， 生成 (3R,10S,13S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydrospiro[cyclopenta[a]phenanthrene-3,2'-oxirane]
  参考文献：
  名称：

  雄甾酮衍生物抑制17β-羟基类固醇脱氢酶类型3的A和D环结构修饰：化学合成与结构-活性关系。

  摘要：

  通过使用3β17β-羟基类固醇脱氢酶（17β-HSD3）抑制剂来减少肿瘤内雄激素的生物合成是治疗前列腺癌的策略。雄甾酮（ADT）衍生物1（RM-532-105）对17β-HSD3具有强抑制活性，但有待改进。在这里，我们描述了两个系列类似物的化学合成和表征，以解决A和D环修饰对17β-HSD3抑制活性，雄激素作用和代谢稳定性的影响。通过在C16 / C17上添加不同的基团（D环多样化）或用正雄烷或雌激素骨架取代ADT骨架（A环多样化）来生成结构活性关系。与铅化合物1相比，D环衍生物的抑制剂作用更弱 而甾体骨架（A环）的变化导致鉴定出有前途的新型雌激素衍生物。最后用有效的17β-HSD3抑制剂23、27、31和33（IC50分别为0.10、0.02、0.13和0.17μM）达到终点，该抑制剂不刺激LAPC-4细胞增殖，并且在小鼠中的血浆浓度高于铅。化合物1。

  DOI：

  10.1021/acs.jmedchem.9b00624

文献信息

• Use of neurosteroids to treat neuropathic pain
  申请人：Whiting Roger

  公开号：US20060009432A1

  公开（公告）日：2006-01-12

  Ganaxolone (3α-hydroxy-3β-methyl-5β-pregnan-20-one) and 3α-hydroxy-3β-methyl-5β-pregnan-20-one and their physiologically cleavable esters are useful for treating neuropathic pain. Compositions comprising a pharmaceutically acceptable excipient and an appropriate compound, along with methods for preparing the compositions are disclosed. Also disclosed are articles of manufacture wherein the composition is combine with labeling instructions for treating neuropathic pain.

  Ganaxolone（3α-羟基-3β-甲基-5β-孕酮-20-酮）和3α-羟基-3β-甲基-5β-孕酮-20-酮及其生理可分解的酯类对治疗神经病性疼痛有用。包含药用可接受的赋形剂和适当化合物的组合物以及制备该组合物的方法被披露。还披露了制造物品，其中该组合物与治疗神经病性疼痛的标签说明结合。
• Anaesthetic steroids of the androstance and pregnane series
  申请人：Glaxo Laboratories Limited

  公开号：US03953429A1

  公开（公告）日：1976-04-27

  Steroids of the androstane and pregnane series possessing a 2.alpha.-hydrogen or halogen or an alkyl group; a 3.alpha.-hydroxy or acyloxy group, a 3.beta.-hydrogen or alkyl group; an 11.beta.-hydrogen or hydroxy group or an epoxy group linked also to the 9-position; an 11.alpha.-hydrogen or alkyl or allyl group; or an 11-oxo group; a 16 hydrogen or halogen or a methyl or dimethyl group; a 20-oxo or ethylenedioxy group; and a 20-methyl or alkoxy group. The compounds may be unsaturated at the 1(2), 8(9) or 9(11) positions. The compounds possess anaesthetic properties.

  具有2α-氢或卤素或烷基；3α-羟基或酰氧基，3β-氢或烷基；11β-氢或羟基或与9-位点连接的环氧基；11α-氢或烷基或烯丙基；或11-酮基的雄甾烷和孕甾烷系列类固醇；16-氢或卤素或甲基或二甲基基团；20-酮或乙二氧基基团；和20-甲基或烷氧基团。这些化合物在1（2），8（9）或9（11）位置可能不饱和。这些化合物具有麻醉特性。
• [EN] GABA RECEPTOR MODULATORS
  申请人：COCENSYS, INC.

  公开号：WO1993003732A1

  公开（公告）日：1993-03-04

  (EN) Method, compositions, and compounds for modulating brain excitability to alleviate stress, anxiety, insomnia and seizure activity using certain steroid derivatives that act at a newly identified site on the gamma-aminobutyric acid receptor-chloride ionophore (GR) complex.(FR) L'invention se rapporte à un procédé, à des compositions et à des composés destinés à moduler l'excitabilité du cerveau, de façon à obtenir une amélioration du stress, de l'angoisse, de l'insomnie et des crises à l'aide de certains dérivés stéroïdes agissant sur un site nouvellement identifié sur le complexe (GR) récepteur d'acide gamma-aminobutyrique/ionophore au chlorure.

  (EN) 通过使用某些类固醇衍生物在新发现的γ-氨基丁酸受体-氯离子复合物上作用的位置，调节大脑兴奋性以缓解压力、焦虑、失眠和癫痫活动的方法、组合物和化合物。(FR) L'invention se rapporte à un procédé, à des compositions et à des composés destinés à moduler l'excitabilité du cerveau, de façon à obtenir une amélioration du stress, de l'angoisse, de l'insomnie et des crises à l'aide de certains dérivés stéroïdes agissant sur un site nouvellement identifié sur le complexe (GR) récepteur d'acide gamma-aminobutyrique/ionophore au chlorure.
• A- and D-Ring Structural Modifications of an Androsterone Derivative Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3: Chemical Synthesis and Structure–Activity Relationships
  作者：Francisco Cortés-Benítez、Jenny Roy、Martin Perreault、René Maltais、Donald Poirier

  DOI：10.1021/acs.jmedchem.9b00624

  日期：2019.8.8

  The androsterone (ADT) derivative 1 (RM-532-105) has shown strong inhibitory activity on 17β-HSD3, but needs to be improved. Herein, we describe the chemical synthesis and characterization of two series of analogues to address the impact of A- and D-ring modifications on 17β-HSD3 inhibitory activity, androgenic effect, and metabolic stability. Structure-activity relationships were generated by adding

  通过使用3β17β-羟基类固醇脱氢酶（17β-HSD3）抑制剂来减少肿瘤内雄激素的生物合成是治疗前列腺癌的策略。雄甾酮（ADT）衍生物1（RM-532-105）对17β-HSD3具有强抑制活性，但有待改进。在这里，我们描述了两个系列类似物的化学合成和表征，以解决A和D环修饰对17β-HSD3抑制活性，雄激素作用和代谢稳定性的影响。通过在C16 / C17上添加不同的基团（D环多样化）或用正雄烷或雌激素骨架取代ADT骨架（A环多样化）来生成结构活性关系。与铅化合物1相比，D环衍生物的抑制剂作用更弱 而甾体骨架（A环）的变化导致鉴定出有前途的新型雌激素衍生物。最后用有效的17β-HSD3抑制剂23、27、31和33（IC50分别为0.10、0.02、0.13和0.17μM）达到终点，该抑制剂不刺激LAPC-4细胞增殖，并且在小鼠中的血浆浓度高于铅。化合物1。
• Synthesis and <i>in Vitro</i> Activity of 3β-Substituted-3α-hydroxypregnan-20-ones:  Allosteric Modulators of the GABA_A Receptor
  作者：Derk J. Hogenkamp、S. Hasan Tahir、Jon E. Hawkinson、Ravi B. Upasani、Mian Alauddin、Catherine L. Kimbrough、Manuel Acosta-Burruel、E. R. Whittemore、R. M. Woodward、Nancy C. Lan、Kelvin W. Gee、Michael B. Bolger

  DOI：10.1021/jm960021x

  日期：1997.1.1

  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.