甲基(8S,9R,10S,11S,13S,14S,16R,17S)-9-氟-11-羟基-17-(2-羟基乙酰基)-10,13-二甲基-3-氧代-7,8,11,12,14,15,16,17-八氢-6H-环戊二烯并[a]菲-16-羧酸酯 | 152596-59-3

• 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
• 中文名称: 甲基(8S,9R,10S,11S,13S,14S,16R,17S)-9-氟-11-羟基-17-(2-羟基乙酰基)-10,13-二甲基-3-氧代-7,8,11,12,14,15,16,17-八氢-6H-环戊二烯并[a]菲-16-羧酸酯
• 英文名称: methyl 9α-fluoro-11β,21-dihydroxy-3,20-dioxo-pregna-1,4-diene-16α-carboxylate
• 英文别名: methyl 9α-fluoro-11β,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylate；Methyl 9alpha-fluoro-11beta,21-dihydroxy-3,20-dioxo-1,4-pregnadiene-16alpha-carboxylate；methyl (8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-7,8,11,12,14,15,16,17-octahydro-6H-cyclopenta[a]phenanthrene-16-carboxylate
• CAS: 152596-59-3
• 化学式: C₂₃H₂₉FO₆
• 分子量: 420.478
• InChiKey: KXYYKWWWSUCLLN-DWOUKENQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  甲基(8S,9R,10S,11S,13S,14S,16R,17S)-9-氟-11-羟基-17-(2-羟基乙酰基)-10,13-二甲基-3-氧代-7,8,11,12,14,15,16,17-八氢-6H-环戊二烯并[a]菲-16-羧酸酯 在 三乙胺 、 lithium chloride 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 methyl 21-desoxy-21-chloro-9α-fluoro-11β-hydroxy-3,20-dioxo-1,4-pregnadien-16α-carboxylate
  参考文献：
  名称：

  New steroidal anti-inflammatory antedrugs: methyl 21-desoxy-21-chloro-11β,17α-dihydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylate, methyl 21-desoxy-21-chloro-11β-hydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylate, and their 9α-fluoro derivatives⋆

  摘要：

  To a series of 21-desoxy-21-chloro-corticosteroids, a metabolically labile methoxycarbonyl group at C-16 has been incorporated The approach is to synthesize locally active compounds that are hydrolyzed to inactive and readily excretable acid metabolites upon entry into the systemic circulation. Novel antedrugs were evaluated for anti-inflammatory activity and their adverse effects in an acute and semichronic croton oil-induced ear edema bioassay. Binding affinity to glucocorticoid receptors and induction of L-tyrosine-2-oxoglutarate aminotransferase were studied in hepatoma tissue culture cells. After a single topical application in the croton oil-induced ear edema bioassay, treatment with all the compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID50 values (nmol/year resulting in a 50% reduction of edema) were calculated: 540, 618, 454, and 346 nmol for prednisolone (P), methyl 21-desoxy-21-chloro-11 beta,17 alpha-dihydroxy-3,20-dioxo-1,4-pregnadien-16 alpha-carboxylate (PClCM), methyl 21-desoxy-21-chloro-11 beta, 17 alpha-dihydroxy-9 alpha-fluoro-3,20-dioxo-1,4-pregnadien-16 alpha-carboxylate (FPClCM), and methyl 21-desoxy-21-chloro-9 alpha-fluoro-11 beta-hydroxy-3,20-dioxo-1,4-pregnadien-16 alpha-carboxylate (FDPClCM), respectively. Results of the 5-day rat croton oil ear edema bioassay indicated that, in contrast with the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. The binding affinities for cytosolic hepatoma tissue culture glucocorticoid receptors were 33, 201, 471, 5304, and 3765 nM for P, PClCM, FPClCM, methyl 21-desoxy-21-chloro-11 beta-hydroxy-3,20-dioxo-1,4-pregnadien-16 alpha-carboxylate (DPClCM), and FDPClCM, respectively. Collectively, results of these investigations suggest that modifications of P, which included replacement of 21-hydroxyl group with chlorine and addition of 16-methoxycarbonyl group with or without 17-hydroxyl moiety, retained the topical anti-inflammatory activity of the parent compound P without significant adverse systemic effects. (C) 2000 Elsevier Science Inc. All rights reserved.

  DOI：

  10.1016/s0039-128x(99)00103-8
• 作为产物：
  描述：

  16α-cyano-9α-fluoro-11β-hydroxy-21-acetoxy-3,20-dioxo-1,4-pregnadiene 在 盐酸 、 potassium carbonate 作用下， 以 甲醇 、 水 为溶剂， 反应 3.25h， 生成 甲基(8S,9R,10S,11S,13S,14S,16R,17S)-9-氟-11-羟基-17-(2-羟基乙酰基)-10,13-二甲基-3-氧代-7,8,11,12,14,15,16,17-八氢-6H-环戊二烯并[a]菲-16-羧酸酯
  参考文献：
  名称：

  具有减少的副作用的新型氟化抗炎类固醇：9α-氟泼尼松龙-16-羧酸甲酯。

  摘要：

  为了检验以下假设，即甾类前药的9α-氟化会增强受体结合亲和力和局部抗炎活性，而不会同时增加不利的全身作用，因此，甲基11β，21-二羟基-3的氟化类似物10合成并评估了20-二氧-1,4-孕二烯-16α-羧酸盐（DP16CM，1）。在急性大鼠巴豆油诱导的耳部水肿生物测定中，发现10的效力是1的两倍。相对于1，这种局部效力的提高与10的结合亲和力增强相一致。[3H]置换的IC50值大鼠肝癌组织培养细胞中糖皮质激素受体的地塞米松分别为10、1和泼尼松龙的0.16、1.2和0.03 microM。继泼尼松龙的多个主题ID50应用后，1 在大鼠亚急性巴豆油诱导的耳水肿生物测定中，其新的氟化类似物10，仅泼尼松龙具有明显的不良作用，例如相对胸腺和肾上腺重量的减少，血浆皮质酮水平的增加和正常体重的增加。因此，尽管氟化1增强了其局部效力，但伴随的不良全身作用并未随之增加。表面上这种不利的全身作用的缺乏表

  DOI：

  10.1002/jps.2600830406

文献信息

• McLean, Hugh M.; Heiman, Ann S.; Lee, Henry J., Medicinal Chemistry Research, 2002, vol. 11, # 5, p. 255 - 277
  作者：McLean, Hugh M.、Heiman, Ann S.、Lee, Henry J.

  DOI：——

  日期：——
• Novel Fluorinated Antiinflammatory Steroid with Reduced Side Effects: Methyl 9α-Fluoroprednisolone-16-carboxylate
  作者：Hugh M. McLean、Ann S. Heiman、Henry J. Lee、Mounir A. Khalil

  DOI：10.1002/jps.2600830406

  日期：1994.4

  In an effort to test the hypothesis that 9 alpha-fluorination of a steroidal antedrug would enhance receptor binding affinity and local antiinflammatory activity, without concomitantly increasing adverse systemic effects, a fluorinated analog, 10, of methyl 11 beta, 21-dihydroxy- 3,20-dioxo-1,4-pregnadiene-16 alpha-carboxylate (DP16CM, 1) was synthesized and evaluated. In the acute rat croton oil-induced

  为了检验以下假设，即甾类前药的9α-氟化会增强受体结合亲和力和局部抗炎活性，而不会同时增加不利的全身作用，因此，甲基11β，21-二羟基-3的氟化类似物10合成并评估了20-二氧-1,4-孕二烯-16α-羧酸盐（DP16CM，1）。在急性大鼠巴豆油诱导的耳部水肿生物测定中，发现10的效力是1的两倍。相对于1，这种局部效力的提高与10的结合亲和力增强相一致。[3H]置换的IC50值大鼠肝癌组织培养细胞中糖皮质激素受体的地塞米松分别为10、1和泼尼松龙的0.16、1.2和0.03 microM。继泼尼松龙的多个主题ID50应用后，1 在大鼠亚急性巴豆油诱导的耳水肿生物测定中，其新的氟化类似物10，仅泼尼松龙具有明显的不良作用，例如相对胸腺和肾上腺重量的减少，血浆皮质酮水平的增加和正常体重的增加。因此，尽管氟化1增强了其局部效力，但伴随的不良全身作用并未随之增加。表面上这种不利的全身作用的缺乏表
• New steroidal anti-inflammatory antedrugs: methyl 21-desoxy-21-chloro-11β,17α-dihydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylate, methyl 21-desoxy-21-chloro-11β-hydroxy-3,20-dioxo-1,4-pregnadiene-16α-carboxylate, and their 9α-fluoro derivatives⋆
  作者：D Ko

  DOI：10.1016/s0039-128x(99)00103-8

  日期：2000.4

  To a series of 21-desoxy-21-chloro-corticosteroids, a metabolically labile methoxycarbonyl group at C-16 has been incorporated The approach is to synthesize locally active compounds that are hydrolyzed to inactive and readily excretable acid metabolites upon entry into the systemic circulation. Novel antedrugs were evaluated for anti-inflammatory activity and their adverse effects in an acute and semichronic croton oil-induced ear edema bioassay. Binding affinity to glucocorticoid receptors and induction of L-tyrosine-2-oxoglutarate aminotransferase were studied in hepatoma tissue culture cells. After a single topical application in the croton oil-induced ear edema bioassay, treatment with all the compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID50 values (nmol/year resulting in a 50% reduction of edema) were calculated: 540, 618, 454, and 346 nmol for prednisolone (P), methyl 21-desoxy-21-chloro-11 beta,17 alpha-dihydroxy-3,20-dioxo-1,4-pregnadien-16 alpha-carboxylate (PClCM), methyl 21-desoxy-21-chloro-11 beta, 17 alpha-dihydroxy-9 alpha-fluoro-3,20-dioxo-1,4-pregnadien-16 alpha-carboxylate (FPClCM), and methyl 21-desoxy-21-chloro-9 alpha-fluoro-11 beta-hydroxy-3,20-dioxo-1,4-pregnadien-16 alpha-carboxylate (FDPClCM), respectively. Results of the 5-day rat croton oil ear edema bioassay indicated that, in contrast with the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. The binding affinities for cytosolic hepatoma tissue culture glucocorticoid receptors were 33, 201, 471, 5304, and 3765 nM for P, PClCM, FPClCM, methyl 21-desoxy-21-chloro-11 beta-hydroxy-3,20-dioxo-1,4-pregnadien-16 alpha-carboxylate (DPClCM), and FDPClCM, respectively. Collectively, results of these investigations suggest that modifications of P, which included replacement of 21-hydroxyl group with chlorine and addition of 16-methoxycarbonyl group with or without 17-hydroxyl moiety, retained the topical anti-inflammatory activity of the parent compound P without significant adverse systemic effects. (C) 2000 Elsevier Science Inc. All rights reserved.