3-(1-cyclopropyl-1,2,3,4-tetrahydro-1-naphthalenyl)-N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-2-oxopropanamide | 872835-05-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 3-(1-cyclopropyl-1,2,3,4-tetrahydro-1-naphthalenyl)-N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-2-oxopropanamide
• 英文别名: 3-(1-cyclopropyl-3,4-dihydro-2H-naphthalen-1-yl)-N-(4-methyl-1-oxo-2,3-benzoxazin-6-yl)-2-oxopropanamide
• CAS: 872835-05-7
• 化学式: C₂₅H₂₄N₂O₄
• 分子量: 416.477
• InChiKey: KZLXOBMJIUJZKB-UHFFFAOYSA-N

物化性质

• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  84.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(1-cyclopropyl-1,2,3,4-tetrahydro-1-naphthalenyl)-N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-2-oxopropanamide 、 (三氟甲基)三甲基硅烷 在 cesium fluoride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 2-[(1-cyclopropyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-3,3,3-trifluoro-2-hydroxy-N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)propionamide
  参考文献：
  名称：

  Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series

  摘要：

  The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay ( representing transrepression effects) over an MMTV GR agonist assay ( representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.

  DOI：

  10.1021/jm060302x
• 作为产物：
  描述：

  2-(1-Cyclopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-furan-2-yl-ethanone 在 氯化亚砜 、 臭氧 作用下， 以 甲醇 、 N,N-二甲基乙酰胺 为溶剂， 生成 3-(1-cyclopropyl-1,2,3,4-tetrahydro-1-naphthalenyl)-N-(4-methyl-1-oxo-1H-2,3-benzoxazin-6-yl)-2-oxopropanamide
  参考文献：
  名称：

  Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series

  摘要：

  The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay ( representing transrepression effects) over an MMTV GR agonist assay ( representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.

  DOI：

  10.1021/jm060302x

文献信息

• [EN] SUBSTITUTED OXAZINES AS GLUCOCORTICOID RECEPTOR MODULATORS<br/>[FR] OXAZINES SUBSTITUEES UTILISEES COMME MODULATEURS DU RECEPTEUR GLUCOCORTICOIDE
  申请人：GLAXO GROUP LTD

  公开号：WO2006000401A1

  公开（公告）日：2006-01-05

  The present invention is directed to compounds of formula (I), wherein R1 represents a C3-6cycloalkyl group; or a physiologically functional derivative thereof, pharmaceutical compositions comprising the compounds, the use of the compounds for the manufacture of medicaments particularly for the treatment of inflammatory and/or allergic conditions, processes for the preparation of the compounds, and chemical intermediates in the processes for the manufacture of the compounds.

  本发明涉及以下式（I）化合物，其中R1代表C3-6环烷基基团；或其生理功能衍生物，包括该化合物的药物组合物，该化合物用于制造特别用于治疗炎症和/或过敏症的药物，该化合物的制备方法，以及用于制造该化合物的过程中的化学中间体。
• Dissociated Nonsteroidal Glucocorticoid Receptor Modulators; Discovery of the Agonist Trigger in a Tetrahydronaphthalene−Benzoxazine Series
  作者：Mike Barker、Margaret Clackers、Royston Copley、Derek A. Demaine、Davina Humphreys、Graham G. A. Inglis、Michael J. Johnston、Haydn T. Jones、Michael V. Haase、David House、Richard Loiseau、Lesley Nisbet、Francois Pacquet、Philip A. Skone、Stephen E. Shanahan、Dan Tape、Victoria M. Vinader、Melanie Washington、Iain Uings、Richard Upton、Iain M. McLay、Simon J. F. Macdonald

  DOI：10.1021/jm060302x

  日期：2006.7.1

  The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism. These compounds are efficacy selective in an NFkB GR agonist assay ( representing transrepression effects) over an MMTV GR agonist assay ( representing transactivation effects). 52 and 60 have NFkB pIC(50) = 8.92 (105%) and 8.69 (92%) and MMTV pEC(50) = 8.20 (47%) and 7.75 (39%), respectively. The impact of the trigger substituent on agonism is modeled within GR and discussed. 36, 52, and 60 have anti-inflammatory activity in a mouse model of inflammation after topical dosing with 52 and 60, having an effect similar to that of dexamethasone. The original lead was discovered by a manual agreement docking method, and automation of this method is also described.