7-bromo-2-hydroxyxanthone | 134369-95-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 7-bromo-2-hydroxyxanthone
• 英文别名: 2-(4-Methoxyphenyl)-1-phenyl-2,3-dihydropyridin-4-one；2-bromo-7-hydroxyxanthen-9-one
• CAS: 134369-95-2
• 化学式: C₁₃H₇BrO₃
• 分子量: 291.101
• InChiKey: URTCJAGAAPBEKT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  7-bromo-2-hydroxyxanthone 在 四(三苯基膦)钯 、 二氧化碳 、 caesium carbonate 、 二乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.67h， 生成 (S)-2'-(neopentyloxy)-7'-(pyridin-2-yl)-5H-spiro[oxazole-4,9'-xanthen]-2-amine
  参考文献：
  名称：

  Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

  摘要：

  The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A beta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A beta reduction in a rat pharmacodynamic model (78% A beta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

  DOI：

  10.1021/jm501266w
• 作为产物：
  描述：

  7-Bromo-4a-methoxy-xanthene-2,9-dione 以 乙二醇二甲醚 为溶剂， 反应 0.17h， 以10%的产率得到7-bromo-2-hydroxyxanthone
  参考文献：
  名称：

  The synthesis of xanthones, xanthenediones, and spirobenzofurans: Their antibacterial and antifungal activity

  摘要：

  Exposure of the phenol, (5-bromo-2-hydroxyphenyl)(2,4,5-trimethoxyphenyl)methanone 18 to ceric ammonium nitrate (CAN) resulted in the formation of 7-bromo-3,4a-dimethoxy-2H-xanthene-2,9( 4aH)-dione 19 and 5-bromo-2',5'-dimethoxy-3H-spiro[benzofuran-2,1'-cyclohexa[2,5]diene]-3,4'-dione 20. The brominated spirobenzofuran 20 was then subjected to Suzuki-Miyaura reactions to give six derivatives 22a-f. These compounds, related diones and xanthones displayed mostly noteworthy antimicrobial activity, particularly towards the yeasts Cryptococcus neoformans and Candida albicans. Diones 15 and 30 displayed significant activity (7.8 mu g/mL) against C. albicans and C. neoformans, respectively. Furthermore, dione 10 displayed the most significant activity (3.6 mu g/mL) against both yeasts. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.088

文献信息

• Patel G N; Trivedi K N, Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1991, vol. 30, # 4, p. 437 - 439
  作者：Patel G N、Trivedi K N

  DOI：——

  日期：——
• Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
  作者：Oleg Epstein、Marian C. Bryan、Alan C. Cheng、Katayoun Derakhchan、Thomas A. Dineen、Dean Hickman、Zihao Hua、Jason B. Human、Charles Kreiman、Isaac E. Marx、Matthew M. Weiss、Robert C. Wahl、Paul H. Wen、Douglas A. Whittington、Stephen Wood、Xiao Mei Zheng、Robert T. Fremeau、Ryan D. White、Vinod F. Patel

  DOI：10.1021/jm501266w

  日期：2014.12.11

  The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A beta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A beta reduction in a rat pharmacodynamic model (78% A beta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.
• The synthesis of xanthones, xanthenediones, and spirobenzofurans: Their antibacterial and antifungal activity
  作者：Justin J. Omolo、Myron M. Johnson、Sandy F. van Vuuren、Charles B. de Koning

  DOI：10.1016/j.bmcl.2011.09.088

  日期：2011.12

  Exposure of the phenol, (5-bromo-2-hydroxyphenyl)(2,4,5-trimethoxyphenyl)methanone 18 to ceric ammonium nitrate (CAN) resulted in the formation of 7-bromo-3,4a-dimethoxy-2H-xanthene-2,9( 4aH)-dione 19 and 5-bromo-2',5'-dimethoxy-3H-spiro[benzofuran-2,1'-cyclohexa[2,5]diene]-3,4'-dione 20. The brominated spirobenzofuran 20 was then subjected to Suzuki-Miyaura reactions to give six derivatives 22a-f. These compounds, related diones and xanthones displayed mostly noteworthy antimicrobial activity, particularly towards the yeasts Cryptococcus neoformans and Candida albicans. Diones 15 and 30 displayed significant activity (7.8 mu g/mL) against C. albicans and C. neoformans, respectively. Furthermore, dione 10 displayed the most significant activity (3.6 mu g/mL) against both yeasts. (C) 2011 Elsevier Ltd. All rights reserved.