Ethyl 6S-(5-Bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4',5':3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylate | 1415390-49-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: Ethyl 6S-(5-Bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4',5':3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylate
• 英文别名: (S)-Ethyl 6-(5-bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4',5':3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylate；ethyl (9S)-9-(5-bromofuran-2-yl)-12,14-dimethyl-13,15-dioxo-17-phenyl-8-oxa-1,12,14-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-2(7),3,5,10,16-pentaene-4-carboxylate
• CAS: 1415390-49-6
• 化学式: C₂₈H₂₂BrN₃O₆
• 分子量: 576.403
• InChiKey: IQTUORHYHHBSMV-RUZDIDTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  38
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  94.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-(5-bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4',5':3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylic acid 在 盐酸 、 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 24.0h， 生成 Ethyl 6S-(5-Bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9,10-tetrahydro-6H-benzo[b]pyrimido[4',5':3,4]pyrrolo[1,2-d][1,4]oxazine-2-carboxylate
  参考文献：
  名称：

  Absolute Configuration and Biological Properties of Enantiomers of CFTR Inhibitor BPO-27

  摘要：

  We previously reported benzopyrimido-pyrrolo-oxazine-dione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27 (1), which contains a single chiral center, and determined their absolute configuration, activity, and metabolic stability. Following separation by chiral supercritical fluid chromatography, the R enantiomer, as determined by X-ray crystallography, inhibited CFTR chloride conductance with IC50 approximate to 4 nM, while S enantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with <5% metabolism in 4 h. Following bolus interperitoneal administration in mice, serum (R)-1 decayed with t(1/2) approximate to 1.6 h and gave sustained therapeutic concentrations in kidney.

  DOI：

  10.1021/ml400069k

文献信息

• PYRIMIDO-PYRROLO-OXAZINE-DIONE COMPOUND INHIBITORS OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR PROTEIN AND USES THEREFOR
  申请人：Verkman Alan S.

  公开号：US20140080821A1

  公开（公告）日：2014-03-20

  Provided herein are benzopyrimido-pyrrolo-oxazine-dione (BPO) compounds and pyrimido-pyrrolo-quinoxalinedione (PPQ) compounds, and compositions comprising these compounds, that inhibit cystic fibrosis transmembrane conductance regulator (CFTR) mediated ion transport and that are useful for treating diseases and disorders associated with aberrantly increased CFTR chloride channel activity, such as polycystic kidney disease and secretory diarrheas. The compounds and compositions comprising the compounds described herein may be used for inhibiting expansion or preventing formation of cysts in persons who have polycystic kidney disease.

  本文提供了苯并嘧啶基吡咯氧噻吩二酮（BPO）化合物和嘧啶基吡咯喹啉二酮（PPQ）化合物以及含有这些化合物的组合物，其抑制囊性纤维化跨膜传导调节因子（CFTR）介导的离子传输，并且可用于治疗与CFTR氯通道活性异常增加相关的疾病和障碍，例如多囊肾病和分泌性腹泻。本文所描述的化合物和组合物可用于抑制在患有多囊肾病的人中囊肿的扩张或预防囊肿的形成。
• US9062073B2
  申请人：——

  公开号：US9062073B2

  公开（公告）日：2015-06-23
• USRE48842E1
  申请人：——

  公开号：USRE48842E1

  公开（公告）日：2021-12-07
• [EN] PYRIMIDO-PYRROLO-OXAZINE-DIONE COMPOUND INHIBITORS OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR PROTEIN AND USES THEREFOR<br/>[FR] INHIBITEURS DE COMPOSÉS PYRIMIDO-PYRROLO-OXAZINE-DIONES DE LA PROTÉINE RÉGULATRICE DE LA CONDUCTANCE TRANSMEMBRANAIRE DE LA FIBROSE CYSTIQUE ET LEURS UTILISATIONS
  申请人：UNIV CALIFORNIA

  公开号：WO2012166658A1

  公开（公告）日：2012-12-06

  Provided herein are benzopyrimido-pyrrolo-oxazine-dione (BPO) compounds and pyrimido-pyrrolo-quinoxalinedione (PPQ) compounds, and compositions comprising these compounds, that inhibit cystic fibrosis transmembrane conductance regulator (CFTR) mediated ion transport and that are useful for treating diseases and disorders associated with aberrantly increased CFTR chloride channel activity, such as polycystic kidney disease and secretory diarrheas. The compounds and compositions comprising the compounds described herein may be used for inhibiting expansion or preventing formation of cysts in persons who have polycystic kidney disease.
• Absolute Configuration and Biological Properties of Enantiomers of CFTR Inhibitor BPO-27
  作者：David S. Snyder、Lukmanee Tradtrantip、Sailaja Battula、Chenjuan Yao、Puay-wah Phuan、James C. Fettinger、Mark J. Kurth、A. S. Verkman

  DOI：10.1021/ml400069k

  日期：2013.5.9

  We previously reported benzopyrimido-pyrrolo-oxazine-dione (BPO) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in a model of polycystic kidney disease. Here, we separated the enantiomers of lead compound BPO-27 (1), which contains a single chiral center, and determined their absolute configuration, activity, and metabolic stability. Following separation by chiral supercritical fluid chromatography, the R enantiomer, as determined by X-ray crystallography, inhibited CFTR chloride conductance with IC50 approximate to 4 nM, while S enantiomer was inactive. In vitro metabolic stability in hepatic microsomes showed both enantiomers as stable, with <5% metabolism in 4 h. Following bolus interperitoneal administration in mice, serum (R)-1 decayed with t(1/2) approximate to 1.6 h and gave sustained therapeutic concentrations in kidney.