7,9-dimethyl-6-(4,5-dimethylfuran-2-yl)-11-phenyl-5,6-dihydropyrimido[4',5':3,4]pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione | 1314872-79-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 7,9-dimethyl-6-(4,5-dimethylfuran-2-yl)-11-phenyl-5,6-dihydropyrimido[4',5':3,4]pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione
• 英文别名: 9-(4,5-Dimethylfuran-2-yl)-12,14-dimethyl-17-phenyl-1,8,12,14-tetrazatetracyclo[8.7.0.02,7.011,16]heptadeca-2,4,6,10,16-pentaene-13,15-dione
• CAS: 1314872-79-1
• 化学式: C₂₇H₂₄N₄O₃
• 分子量: 452.513
• InChiKey: BVOYIPGLBAGFQD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  34
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  70.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1,3,4-三甲基尿嘧啶 在 水 、 溴 、 对甲苯磺酸 、 zinc(II) chloride 作用下， 以 四氯化碳 、 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 、 氯苯 为溶剂， 反应 4.17h， 生成 7,9-dimethyl-6-(4,5-dimethylfuran-2-yl)-11-phenyl-5,6-dihydropyrimido[4',5':3,4]pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione
  参考文献：
  名称：

  Potent, Metabolically Stable Benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR Inhibitors for Polycystic Kidney Disease

  摘要：

  We previously reported the discovery of pyrimido-pyrrolo-quinoxalinedione (PPQ) inhibitors of the cystic fibrosis transmentbrane conductance regulator (CFTR) chlordoide channel and showed their efficacy in an organ culture model of polycystic kidney disease (PKD) (J. Med. Chem. 2009, 52, 6447-6455). Here, we report related benzopyrimido-pyrrolo-oxazinedione (BPO) CFTR inhibitors. To establish structure activity relationships and select lead compound(s) with improved potency, metabolic stability, and aqueous solubility compared to the most potent prior compound 8 (PPQ:102, IC50 similar to 90 nM), we synthesized 16 PPQanalogues and 11 BPO analogues. The analogues were efficiently synthesized in 5-6 steps and 11-61% overall yield. Modification of 8 by bromine substitution at the 5-position of the furan ring, replacement of the secondary amine with an ether bridge, and carboxylation, gave 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 42 (BPO-27), which fully inhibited CFTR with IC50 similar to 8 nM and, compared to 8, had >10-fold greater metabolic stability and much greater polarity/aqueous solubility. In an embryonic kidney culture model of PKD, 42 prevented cyst growth with IC50 similar to 100 nM. Benzopyrimido-pyrrolo-oxazinediones such as 42 are potential development candidates for antisecretory therapy of PKD.

  DOI：

  10.1021/jm200505e

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.
• Potent, Metabolically Stable Benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR Inhibitors for Polycystic Kidney Disease
  作者：David S. Snyder、Lukmanee Tradtrantip、Chenjuan Yao、Mark J. Kurth、A. S. Verkman

  DOI：10.1021/jm200505e

  日期：2011.8.11

  We previously reported the discovery of pyrimido-pyrrolo-quinoxalinedione (PPQ) inhibitors of the cystic fibrosis transmentbrane conductance regulator (CFTR) chlordoide channel and showed their efficacy in an organ culture model of polycystic kidney disease (PKD) (J. Med. Chem. 2009, 52, 6447-6455). Here, we report related benzopyrimido-pyrrolo-oxazinedione (BPO) CFTR inhibitors. To establish structure activity relationships and select lead compound(s) with improved potency, metabolic stability, and aqueous solubility compared to the most potent prior compound 8 (PPQ:102, IC50 similar to 90 nM), we synthesized 16 PPQanalogues and 11 BPO analogues. The analogues were efficiently synthesized in 5-6 steps and 11-61% overall yield. Modification of 8 by bromine substitution at the 5-position of the furan ring, replacement of the secondary amine with an ether bridge, and carboxylation, gave 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 42 (BPO-27), which fully inhibited CFTR with IC50 similar to 8 nM and, compared to 8, had >10-fold greater metabolic stability and much greater polarity/aqueous solubility. In an embryonic kidney culture model of PKD, 42 prevented cyst growth with IC50 similar to 100 nM. Benzopyrimido-pyrrolo-oxazinediones such as 42 are potential development candidates for antisecretory therapy of PKD.