9α-fluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid | 160283-12-5

• 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: 9α-fluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid
• 英文别名: (8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid；(11β,16α,17α)-9-fluoro-11,17-dihydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothioic S-acid；(8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-17-carbothioic S-acid
• CAS: 160283-12-5
• 化学式: C₂₁H₂₇FO₄S
• 分子量: 394.507
• InChiKey: IKUUMGMKUCTRGD-AFKBWYBQSA-N

物化性质

• 沸点：
  548.3±50.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  75.6
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  9α-fluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid 在 二乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.75h， 生成 9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(propionyloxy)androsta-1,4-diene-17β-carbothioic acid
  参考文献：
  名称：

  Synthesis and Structure-Activity Relationships in a Series of Antiinflammatory Corticosteroid Analogs, Halomethyl Androstane-17.beta.-carbothioates and -17.beta.-carboselenoates

  摘要：

  The preparation and topical antiinflammatory potencies of a series of halomethyl 17 alpha-(acyloxy)11 beta-hydroxy-3 -oxoandrosta-1,4-diene-17 beta-carbothioates, carrying combinations of 6 alpha-fluoro, 9 alpha-fluoro, 16-methyl, and 16-methylene substituents, are described. Key synthetic stages were the preparation of carbothioic acids and their reaction with dihalomethanes. The carbothioic acids were formed from 17 beta-carboxylic acids by initial reaction with dimethylthiocarbamoyl chloride followed by aminolysis of the resulting rearranged mixed anhydride with diethylamine, or by carboxyl activation with 1,1'-carbonyldiimidazole (CDI) or 2-fluoro-N-methylpyridinium tosylate (FMPT) and reaction with hydrogen sulfide, the choice of reagent being governed by the 17 alpha-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandrostane-17 beta-carboselenoat analogues. Antiinflammatory potencies were measured in humans using the vasoconstriction assay and in rats and mice by a modification the Tonelli croton oil ear assay. Best activities were shown by fluoromethyl and chloromethyl carbothioates with a 17 alpha-propionyloxy group. S-Fluoromethyl 6(alpha,9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-3-oxo-17 alpha-(propionyloxy)androsta-1,4-diene-17 beta-carbothioate (fluticasone propionate, FP) was selected for clinical study as it showed high topical antiinflammatory activity but caused little hypothalamic-pituitary-adrenal suppression after topical or oral administration to rodents.

  DOI：

  10.1021/jm00048a008
• 作为产物：
  描述：

  地塞米松 在 过碘酸 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.5h， 生成 9α-fluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid
  参考文献：
  名称：

  [EN] GLUCOCORTICOID RECEPTOR AGONIST AND IMMUNOCONJUGATES THEREOF
  [FR] AGONISTE DU RÉCEPTEUR DES GLUCOCORTICOÏDES ET IMMUNOCONJUGUÉS DE CELUI-CI

  摘要：

  本文提供了糖皮质激素受体激动剂免疫结合物、糖皮质激素受体激动剂、包括相同成分的药物组合物，以及使用它们的方法。

  公开号：

  WO2021161263A1

文献信息

• [EN] NOVEL GLUCOCORTICOID RECEPTOR AGONISTS<br/>[FR] NOUVEAUX AGONISTES DU RÉCEPTEUR DES GLUCOCORTICOÏDES
  申请人：PFIZER LTD

  公开号：WO2010136940A1

  公开（公告）日：2010-12-02

  This invention relates to novel glucocorticoid receptor agonists of formula (I) and to processes and intermediates for their preparation. The present invention also relates to pharmaceutical compositions containing these compounds, to their combination with one or more other therapeutic agents, as well as to their use for the treatment of a number of inflammatory and allergic diseases, disorders and conditions.

  本发明涉及一种新型的化学式（I）的糖皮质激素受体激动剂，以及用于它们的制备的过程和中间体。本发明还涉及含有这些化合物的药物组合物，以及它们与一个或多个其他治疗剂的联合使用，以及它们用于治疗多种炎症和过敏性疾病、紊乱和症状。
• Novel Glucocorticoid Receptor Agonists
  申请人：Glossop Paul Alan

  公开号：US20100303758A1

  公开（公告）日：2010-12-02

  This invention relates to novel glucocorticoid receptor agonists of formula (I): and to processes and intermediates for their preparation. The present invention also relates to pharmaceutical compositions containing these compounds, to their combination with one or more other therapeutic agents, as well as to their use for the treatment of a number of inflammatory and allergic diseases, disorders and conditions.

  本发明涉及一种新的糖皮质激素受体激动剂，其化学式为（I）：以及其制备过程和中间体。本发明还涉及含有这些化合物的药物组合物，以及它们与一个或多个其他治疗剂的组合，以及它们用于治疗多种炎症和过敏性疾病，失调和状况。
• Anti-TNF Thioester Glucocorticoid Antibody–Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model
  作者：Christopher C. Marvin、Adrian D. Hobson、Michael J. McPherson、Martin E. Hayes、Meena V. Patel、Diana L. Schmidt、Tongmei Li、John T. Randolph、Agnieszka K. Bischoff、Julia Fitzgibbons、Lu Wang、Lu Wang、Axel Hernandez、Ying Jia、Christian A. Goess、Shaughn H. Bryant、Suzanne L. Mathieu、Jianwen Xu

  DOI：10.1021/acs.jmedchem.4c00598

  日期：2024.6.13

  thioester-containing glucocorticoid receptor modulator (GRM) payload and the corresponding antibody–drug conjugate (ADC). Payload 6 was designed for rapid hepatic inactivation to minimize systemic exposure of nonconjugated GRM. Mouse PK indicated that 6 is cleared 10-fold more rapidly than a first-generation GRM payload, resulting in 10-fold lower exposure and 3-fold decrease in Cmax. The anti-mTNF conjugate ADC5

  我们描述了含硫酯的糖皮质激素受体调节剂（GRM）有效负载和相应的抗体药物偶联物（ADC）的发现。有效负载6设计用于快速肝灭活，以尽量减少非结合 GRM 的全身暴露。小鼠 PK 表明6 的清除速度比第一代 GRM 有效负载快 10 倍，导致暴露量降低 10 倍，Cmax 降低 3 倍。抗 mTNF 偶联物ADC5在剂量高达（含 100 mg/kg）时完全抑制小鼠接触性超敏反应中的炎症，对皮质酮（全身 GRM 效应的生物标志物）影响极小。 P1NP 的同时抑制表明可能被递送至参与骨重塑的细胞，这可能是 TNF 靶向或旁观者有效负载效应的结果。此外，在胶原蛋白诱导的关节炎小鼠模型中，连续 21 天服用 10 mg/kg 剂量后， ADC5完全抑制了炎症。抗 hTNF 缀合物的特性适合液体制剂，并且可以实现皮下给药。
• US4335121A
  申请人：——

  公开号：US4335121A

  公开（公告）日：1982-06-15
• US4578221A
  申请人：——

  公开号：US4578221A

  公开（公告）日：1986-03-25