methyl 9α-fluoro-11β,17α,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16α-carboxylate | 191999-13-0

• 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: methyl 9α-fluoro-11β,17α,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16α-carboxylate
• 英文别名: methyl (8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-16-carboxylate
• CAS: 191999-13-0
• 化学式: C₂₃H₂₉FO₇
• 分子量: 436.477
• InChiKey: MTXPTQKSKYSPNG-VRRZBTPDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  31
• 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：
  121
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 9α-fluoro-11β,17α,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16α-carboxylate 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,17α-dihydroxy-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：

  21-乙酰氧基-9-氟-11-羟基孕甾-1,4,16-三烯-3,20-酮 在 盐酸 、 溶剂黄146 、 三乙胺 、 lithium bromide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 methyl 9α-fluoro-11β,17α,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16α-carboxylate
  参考文献：
  名称：

  新的甾体抗炎抗药：Methyl 3,20-dioxo-9α-fluoro-11β,17α,21-trihydroxy-1,4-pregnadiene-16α-carboxylate 和methyl 21-acetyloxy-3,20-dioxo-11β,17α -dihydroxy-9α-fluoro-1,4-pregnadiene-16α-carboxylate

  摘要：

  已经集中努力增加用于局部和/或局部应用的强效抗炎类固醇的局部与全身活性比率。本研究中采用的方法基于“抗药性”的概念，定义为局部活性化合物，在应用部位发挥作用，但迅速进行可预测的生物转化，转化为无活性代谢物，进入全身后很容易排出体外。循环。在不断努力合成没有全身性糖皮质激素活性的强效抗炎类固醇，9 α-氟-甲基 11 β, 17 α, 21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 α-carboxylate (FP16CM) 及其 21-乙酸酯衍生物 (FP16CMAc) 已被合成和筛选。在急性巴豆油诱导的耳水肿生物测定中评估了新型抗炎症药物的抗炎活性、5 天巴豆油模型中的不良全身效应、受体结合以及伴随的 L-酪氨酸-2-酮戊二酸氨基转移酶 (EC 2.6.1.5)（ TAT) 培养的 HTC 细胞中的酶诱导。在巴豆油诱导的耳水肿生物测定中单次局部

  DOI：

  10.1016/s0039-128x(97)00020-2

文献信息

• Synthesis and pharmacological evaluations of new steroidal anti-inflammatory antedrugs: 9α-Fluoro-11β,17α,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16α-carboxylate (FP16CM) and its derivatives
  作者：Kwan-Kyun Park、Dong-Hoon Ko、Zhengqing You、Ann S. Heiman、Henry Joung Lee

  DOI：10.1016/j.steroids.2005.08.005

  日期：2006.1

  potent anti-inflammatory steroids without systemic adverse effects, methyl 9alpha-fluoro-11beta,17alpha,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16alpha-ca rboxylate (FP16CM) and its 16-alkoxycarbonyl derivatives (FP16CE, FP16CP and FP16CB) were synthesized based on the antedrug concept. The steroids were evaluated for their pharmacological activities and adverse systemic effects. All steroidal antedrugs

  在继续努力开发有效的抗炎类固醇而没有全身性不良反应的过程中，甲基9alpha-fluoro-11beta，17alpha，21-三羟基-3,20-二氧代-孕烷-1,4-二烯-16alpha-卡巴基氧基化物（FP16CM）和根据前药概念合成了其16-烷氧羰基衍生物（FP16CE，FP16CP和FP16CB）。对类固醇的药理活性和不利的全身作用进行了评估。所有类固醇前药都显示出对肝细胞溶胶中糖皮质激素受体的结合亲和力和对RAW 264.7巨噬细胞中脂多糖（LPS）诱导的一氧化氮（NO）产生的抑制作用。这些化合物还可以抑制巴豆油诱导的耳部水肿，并且在治疗5天后没有显示出全身性作用，例如胸腺萎缩和皮质酮水平的抑制。在那些经过测试的化合物中，FP16CM在受体结合，NO抑制和耳水肿方面表现出最高的活性，这些活性与泼尼松龙相当。血浆中的水解研究表明FP16CB迅速水解，半衰期（T1 / 2）为3.2分钟，其他化合物的半衰期为16
• New steroidal anti-inflammatory antedrugs: Methyl 3,20-dioxo-9α-fluoro-11β,17α,21-trihydroxy-1,4-pregnadiene-16α-carboxylate and methyl 21-acetyloxy-3,20-dioxo-11β,17α-dihydroxy-9α-fluoro-1,4-pregnadiene-16α-carboxylate
  作者：Ann S. Heiman、Dong-Hoon Ko、Chen Meiqin、J.Lee Henry

  DOI：10.1016/s0039-128x(97)00020-2

  日期：1997.6

  indicated that, in contrast to the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. Relative binding potencies for cytosolic HTC glucocorticoid receptors were 1.0, 20.1, 5.4, and 2.5 for HC, P, FP16CM, and FP16CMAc, respectively. As predicted by the antedrug concept, FP16CM and FP16CMAc were very weak agonists for

  已经集中努力增加用于局部和/或局部应用的强效抗炎类固醇的局部与全身活性比率。本研究中采用的方法基于“抗药性”的概念，定义为局部活性化合物，在应用部位发挥作用，但迅速进行可预测的生物转化，转化为无活性代谢物，进入全身后很容易排出体外。循环。在不断努力合成没有全身性糖皮质激素活性的强效抗炎类固醇，9 α-氟-甲基 11 β, 17 α, 21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 α-carboxylate (FP16CM) 及其 21-乙酸酯衍生物 (FP16CMAc) 已被合成和筛选。在急性巴豆油诱导的耳水肿生物测定中评估了新型抗炎症药物的抗炎活性、5 天巴豆油模型中的不良全身效应、受体结合以及伴随的 L-酪氨酸-2-酮戊二酸氨基转移酶 (EC 2.6.1.5)（ TAT) 培养的 HTC 细胞中的酶诱导。在巴豆油诱导的耳水肿生物测定中单次局部
• 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.