17α-Butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid | 80473-94-5

• 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: 17α-Butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid
• 英文别名: (6S,8S,9R,10S,11S,13S,14S,16R,17R)-17-butanoyloxy-6,9-difluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-17-carbothioic S-acid
• CAS: 80473-94-5
• 化学式: C₂₅H₃₂F₂O₅S
• 分子量: 482.589
• InChiKey: YTOYSNNRIZRHHV-CENSZEJFSA-N

物化性质

• 沸点：
  573.5±50.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  81.7
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  17α-Butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid 在 碳酸氢钠 、 sodium iodide 作用下， 以 N,N-二甲基乙酰胺 、 丙酮 为溶剂， 反应 2.0h， 生成 S-iodomethyl 17α-(butyryloxy)-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate
  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：

  6,9-二氟-11,17-二羟基-16-甲基-3-氧代雄甾-1,4-二烯-17-羧酸 在 硫化氢 、 二乙胺 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 5.75h， 生成 17α-Butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-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

文献信息

• 17&bgr;-2-oxo-tetrahydrofuranyl)-carbothioic acid ester, -carboxylic acid ester and -carboxylic acid amide androstane derivatives
  申请人：Glaxo Wellcome Inc.

  公开号：US06197761B1

  公开（公告）日：2001-03-06

  Compounds of the androstane series are described having general formula and solvates thereof, in which R1 represents O, S or NH; R2 individually represents OC(═O)C1-6 alkyl; R3 individually represents hydrogen, methyl (which may be in either the &agr; or &bgr; configuration) or methylene; or R2 and R3 together represent where R6 and R7 are the same or different and each represents hydrogen or C1-6 alkyl; R4 and R5 are the same or different and each represents hydrogen or halogen and represents a single or a double bond. These compounds and their solvates have use in medicine as anti-inflammatory or anti-allergic agents.

  本发明涉及一般式及其溶剂化物的雄甾烷系化合物，其中R1代表O、S或NH；R2分别代表OC(═O)C1-6烷基；R3分别代表氢、甲基（可以是α或β构型）或亚甲基；或者R2和R3一起代表其中R6和R7相同或不同，分别代表氢或C1-6烷基；R4和R5相同或不同，分别代表氢或卤素，表示单键或双键。这些化合物及其溶剂化物在医学上可用作抗炎或抗过敏剂。
• [EN] LACTONE DERIVATIVES OF 17.BETA.-CARBOXY, CARBOTHIO AND AMIDE ANDROSTANE DERIVATIVES<br/>[FR] DERIVES DE LACTONE DE DERIVES DE 17-BETA-CARBOXY, CARBOTHIO ET AMIDE ANDROSTANE
  申请人：GLAXO GROUP LIMITED

  公开号：WO1997024365A1

  公开（公告）日：1997-07-10

  (EN) Compounds of the androstane series are described having general formula (I) and solvates thereof, in which R1 represents O, S or NH; R2 individually represents OC(=O)C1-6 alkyl; R3 individually represents hydrogen, methyl (which may be in either the $g(a) or $g(b) configuration) or methylene; or R2 and R3 together represent (a) wherein R6 and R7 are the same or different and each represents hydrogen or C1-6 alkyl; R4 and R5 are the same or different and each represents hydrogen or halogen; and (b) represents a single or a double bond. Compounds of formula (I) and their solvates have use in medicine as anti-inflammatory or anti-allergic agents.(FR) Composés de la série androstane possédant la formule générale suivante (I) ainsi que leurs solvates, dans laquelle R1 représente O, S ou NH; R2 individuellement représente OC(=O)C1-6 alkyle; R3 individuellement représente hydrogène, méthyle (pouvant être dans la configuration $g(a) ou $g(b)) ou méthylène; ou R2 et R3 ensemble représentent (a) dans laquelle R6 et R7 sont semblables ou différents et chacun représente hydrogène ou C1-6 alkyle; R4 et R5 sont semblables ou différents et chacun représente hydrogène ou halogène; et (b) représente une liaison simple ou double. Composés représentés par la formule (I) et leurs solvates utilisables médicalement en tant qu'agents anti-inflammatoires ou anti-allergiques.

  (中文翻译) 描述了具有通式（I）及其溶剂化物的雄甾烷系化合物，其中R1代表O，S或NH; R2分别代表OC（= O）C1-6烷基; R3分别代表氢，甲基（可以处于$a或$b构型中）或亚甲基; 或R2和R3一起代表（a）其中R6和R7相同或不同，分别代表氢或C1-6烷基; R4和R5相同或不同，分别代表氢或卤素; 和（b）代表单键或双键。具有通式（I）及其溶剂化物的化合物在医学上用作抗炎或抗过敏剂。
• LACTONE DERIVATIVES OF 17.BETA.-CARBOXY, CARBOTHIO AND AMIDE ANDROSTANE DERIVATIVES
  申请人：GLAXO GROUP LIMITED

  公开号：EP0876392A1

  公开（公告）日：1998-11-11
• PROCESS FOR THE ESTERIFICATION OF A CARBOTHIOIC ACID
  申请人：Hovione Inter AG

  公开号：EP1802647B1

  公开（公告）日：2010-09-29
• Process for the Esterification of a Carbothioic Acid
  申请人：Sobral Luis

  公开号：US20070287846A1

  公开（公告）日：2007-12-13

  A process for preparing compounds of formula [II] by esterification of the C-17 hydroxyl group of 6α,9α-difluoro-11α,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid, the compound of formula [I] comprises treating compound [I] with a slight excess of an acyl chloride of general formula R—COCl, where R represents —CH2CH3, —CH2CH2CH3 or —CH(CH3)2, in an inert solvent, in the presence of a tertiary amine. Preferably the process is carried out using pyridine in the presence of acetone at a temperature of from 5° C. to −20° C.