(R)-(4-Fluoro-phenyl)-[(4aR,5S)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-methanol | 614761-17-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (R)-(4-Fluoro-phenyl)-[(4aR,5S)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-methanol
• 英文别名: (R)-[(4aR,5S)-1-(4-fluorophenyl)-4a-methyl-1H,4H,4aH,5H,6H,7H,8H-cyclohexa[f]indazol-5-yl](4-fluorophenyl)methanol；(R)-[(4aR,5S)-1-(4-fluorophenyl)-4a-methyl-5,6,7,8-tetrahydro-4H-benzo[f]indazol-5-yl]-(4-fluorophenyl)methanol
• CAS: 614761-17-0
• 化学式: C₂₅H₂₄F₂N₂O
• 分子量: 406.475
• InChiKey: LMWKGVHGBOZNCF-VJTSUQJLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  38
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-(4-Fluoro-phenyl)-[(4aR,5S)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-methanol 在 N-甲基吲哚酮 、 四丙基高钌酸铵 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 3.75h， 生成 (S)-1-(4-Fluoro-phenyl)-1-[(4aR,5S)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-ethanol
  参考文献：
  名称：

  Novel N-Arylpyrazolo[3,2-c]-Based Ligands for the Glucocorticoid Receptor:  Receptor Binding and in Vivo Activity

  摘要：

  A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC50 1.9 nM and 2.8 PM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED50 = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.

  DOI：

  10.1021/jm030585i
• 作为产物：
  描述：

  对溴氟苯 、 (4aR)-1-(4-fluorophenyl)-4a-methyl-4,4a,5,6,7,8-hyxahydro-1H-benzo[f]indazole-5-carbaldehyde 在 叔丁基锂 作用下， 以 乙醚 、 正戊烷 、 四氢呋喃 为溶剂， 反应 1.08h， 以55%的产率得到(R)-(4-Fluoro-phenyl)-[(4aR,5S)-1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazol-5-yl]-methanol
  参考文献：
  名称：

  Novel N-Arylpyrazolo[3,2-c]-Based Ligands for the Glucocorticoid Receptor:  Receptor Binding and in Vivo Activity

  摘要：

  A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC50 1.9 nM and 2.8 PM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED50 = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.

  DOI：

  10.1021/jm030585i

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。
• 1H-BENZO(F)INDAZOL-5-YL DERIVATIVES AS SELECTIVE GLUCOCORTICOID RECEPTOR MODULATORS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP1496892B1

  公开（公告）日：2011-01-26
• 1H-benzo[F]indazol-5-YL derivatives as selective glucocorticoid receptor modulators
  申请人：Ali Amjad

  公开号：US20080076795A1

  公开（公告）日：2008-03-27

  The present invention encompasses compounds of Formula I: or pharmaceutically acceptable salts or hydrates thereof, which are useful as selective glucocorticoid receptor ligands for treating a variety of autoimmune and inflammatory diseases or conditions. Pharmaceutical compositions and methods of use are also included.
• HEXAHYDROCYCLOPENTYL[F]INDAZOLE PYRIDYL ETHANOLS AND DERIVATIVES THEREOF AS SELECTIVE GLUCOCORTICOID RECEPTOR MODULATORS
  申请人：Mitchell Helen J.

  公开号：US20120214846A1

  公开（公告）日：2012-08-23

  The present invention encompasses compounds of Formula (I): or pharmaceutically acceptable salts or hydrates thereof, which are useful as selective glucocorticoid receptor ligands for treating a variety of autoimmune and inflammatory diseases or conditions. Pharmaceutical compositions and methods of use are also included.
• US7282591B2
  申请人：——

  公开号：US7282591B2

  公开（公告）日：2007-10-16