N-ethyl-2-{2-[(4aS,5R)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide | 1021537-64-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-ethyl-2-{2-[(4aS,5R)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide
• 英文别名: 2-(2-((4aS,5R)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl)ethyl)-N-ethylbenzamide；2-[2-[(4aS,5R)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-6,7-dihydro-4H-cyclopenta[f]indazol-5-yl]ethyl]-N-ethylbenzamide
• CAS: 1021537-64-3
• 化学式: C₂₈H₃₀FN₃O₂
• 分子量: 459.564
• InChiKey: VFKWDQUKNZHRGJ-NSOVKSMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  67.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-ethyl-2-{2-[(4aS,5R)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide 在 CYP₃A₄ bioreactor 作用下， 以4.3 mg的产率得到N-ethyl-2-{2-[(4aR,5R)-1-(4-fluorophenyl)-4,5-dihydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide
  参考文献：
  名称：

  Discovery of selective glucocorticoid receptor modulator MK-5932

  摘要：

  A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.10.054
• 作为产物：
  描述：

  (4aS,5R)-5-ethynyl-1-(4-fluorophenyl)-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-ol 在 copper(l) iodide 、 四(三苯基膦)钯 、 palladium 10% on activated carbon 、 水 、 氢气 、 二异丙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 N-ethyl-2-{2-[(4aS,5R)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide
  参考文献：
  名称：

  Discovery of selective glucocorticoid receptor modulator MK-5932

  摘要：

  A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.10.054

文献信息

• 2-[1-PHENYL-5-HYDROXY OR METHOXY-4ALPHA-METHYL-HEXAHYDROCYCLOPENTA [f]INDAZOLE-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS
  申请人：Bungard Christopher J.

  公开号：US20100311709A1

  公开（公告）日：2010-12-09

  The present invention is directed to 2-[ 1 -phenyl-5-hydroxy or methoxy-4alpha-methyl-hexahydrocyclopenta[f]indazol-5-yl]ethyl phenyl derivatives of formula I (I) as glucocorticoid receptor ligands useful for treating a variety of autoimmune and inflammatory diseases or conditions. Pharmaceutical compositions and methods of use are also included.

  本发明涉及公式I（I）的2-[1-苯基-5-羟基或甲氧基-4α-甲基-六氢环戊[f]吲唑-5-基]乙基苯基衍生物，作为糖皮质激素受体配体，用于治疗各种自身免疫和炎症性疾病或症状。还包括制药组合物和使用方法。
• WO2008/51532
  申请人：——

  公开号：——

  公开（公告）日：——
• 2-[1-PHENYL-5-HYDROXY-4ALPHA-METHYL-HEXAHYDROCYCLOPENTA[F]INDAZOL-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2091922B1

  公开（公告）日：2011-12-21
• 2-[1-PHENYL-5-HYDROXY OR METHOXY-4ALPHA-METHYL-HEXAHYDROCLOPENTA[F]INDAZOL-5-YL]ETHYL PHENYL DERIVATIVES AS GLUCOCORTICOID RECEPTOR LIGANDS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2097385B1

  公开（公告）日：2012-08-01
• US8119681B2
  申请人：——

  公开号：US8119681B2

  公开（公告）日：2012-02-21