2-{7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide

• 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: 2-{7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide
• 英文别名: 2-(7-bromo-4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-N-methylacetamide；2-{7-Bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide；2-[7-bromo-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]-N-methylacetamide
• 化学式: C₂₀H₁₈BrN₃O₅
• 分子量: 460.284
• InChiKey: POJKNBHEJAUGMR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  97
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-{7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide 在 ChiralPak OJ 作用下， 以 甲醇 为溶剂， 40.0 ℃ 、15.0 MPa 条件下， 以40.7%的产率得到2-{(3R)-7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide
  参考文献：
  名称：

  BENZOXAZINONE AMIDES AS MINERALOCORTICOID RECEPTOR MODULATORS

  摘要：

  本文披露了具有化学式(I)的苯并噁唑酮酰胺衍生物，或其药用盐，这些衍生物作为矿物皮质激素受体调节剂，可能减少内皮氧化应激，从而改善血管功能，以及它们潜在治疗用途的方法，含有它们的药物组合物，以及制备这些化合物的方法。

  公开号：

  US20150376170A1
• 作为产物：
  描述：

  2-硝基-5-溴苯酚 在 铁粉 、 potassium carbonate 、 溶剂黄146 、 1-丙基磷酸酐 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 水 、 乙酸乙酯 为溶剂， 反应 26.0h， 生成 2-{7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide
  参考文献：
  名称：

  Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection

  摘要：

  The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.

  DOI：

  10.1021/acs.jmedchem.8b01523

文献信息

• BENZOXAZINONE AMIDES AS MINERALOCORTICOID RECEPTOR MODULATORS
  申请人：ASTRAZENECA AB

  公开号：US20150376170A1

  公开（公告）日：2015-12-31

  Disclosed are certain derivatives of benzoxazinone amides of formula (I), or pharmaceutically acceptable salts thereof, that act as mineralocorticoid (MR) receptor modulators that may reduce oxidative stress in endothelium and hence improve vascular function, to methods for their potential therapeutic use, to pharmaceutical compositions containing them and to processes for preparing such compounds.

  本文披露了具有化学式(I)的苯并噁唑酮酰胺衍生物，或其药用盐，这些衍生物作为矿物皮质激素受体调节剂，可能减少内皮氧化应激，从而改善血管功能，以及它们潜在治疗用途的方法，含有它们的药物组合物，以及制备这些化合物的方法。
• Benzoxazinone amides as mineralocorticoid receptor modulators
  申请人：AstraZeneca AB

  公开号：US09394291B2

  公开（公告）日：2016-07-19

  Disclosed are certain derivatives of benzoxazinone amides of formula (I), or pharmaceutically acceptable salts thereof, that act as mineralocorticoid (MR) receptor modulators that may reduce oxidative stress in endothelium and hence improve vascular function, to methods for their potential therapeutic use, to pharmaceutical compositions containing them and to processes for preparing such compounds.

  本发明涉及一些苯并噁唑酮酰胺衍生物或其药学上可接受的盐，其作为矿物质皮质激素受体调节剂，可以减少内皮氧化应激，从而改善血管功能，以及它们的潜在治疗用途的方法，含有它们的制药组合物和制备这些化合物的过程。
• US9394291B2
  申请人：——

  公开号：US9394291B2

  公开（公告）日：2016-07-19
• [EN] BENZOXAZINONE AMIDES AS MINERALOCORTICOID RECEPTOR MODULATORS<br/>[FR] AMIDES DE BENZOXAZINONE COMME MODULATEURS DU RÉCEPTEUR DES MINÉRALCORTICOÏDES
  申请人：ASTRAZENECA AB

  公开号：WO2016001631A1

  公开（公告）日：2016-01-07

  Disclosed arecertain derivatives of benzoxazinone amidesof formula (I),or pharmaceutically acceptable salts thereof, (Formula (I)) that act as mineralocorticoid (MR) receptor modulatorsthat may reduce oxidative stress in endothelium and hence improve vascular function, to methods for their potential therapeutic use, to pharmaceutical compositions containing them and to processes for preparing such compounds.
• Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection
  作者：Kenneth L. Granberg、Zhong-Qing Yuan、Bo Lindmark、Karl Edman、Johan Kajanus、Anders Hogner、Marcus Malmgren、Gavin O’Mahony、Anneli Nordqvist、Jan Lindberg、Stefan Tångefjord、Michael Kossenjans、Christian Löfberg、Jonas Brånalt、Dongmei Liu、Nidhal Selmi、Grigorios Nikitidis、Peter Nordberg、Ahlke Hayen、Anna Aagaard、Eva Hansson、Majlis Hermansson、Ida Ivarsson、Rasmus Jansson-Löfmark、Ulla Karlsson、Ulrika Johansson、Lena William-Olsson、Judith Hartleib-Geschwindner、Krister Bamberg

  DOI：10.1021/acs.jmedchem.8b01523

  日期：2019.2.14

  The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators (S)-1 and (S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na+/K+ ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of (S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na+/K+ ratio in vivo.