6-(2-aminophenyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione | 433971-83-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 6-(2-aminophenyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione
• 英文别名: 6-(2-aminophenyl)-1,3-dimethyl-5-phenylpyrrolo[3,4-d]pyrimidine-2,4-dione
• CAS: 433971-83-6
• 化学式: C₂₀H₁₈N₄O₂
• mdl: MFCD03445141
• 分子量: 346.389
• InChiKey: ZZSSERPNGCHJDT-UHFFFAOYSA-N

物化性质

• 熔点：
  >310 °C(Solv: dimethyl sulfoxide (67-68-5))
• 沸点：
  590.6±60.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  71.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-(2-aminophenyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 在 对甲苯磺酸 、 三乙胺 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 1.58h， 生成 7,9-dimethyl-6-(5-methylfuran-2-yl)-5-(methylsulfonyl)-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
• 作为产物：
  描述：

  1,3,4-三甲基尿嘧啶 在 水 、 溴 、 zinc(II) chloride 作用下， 以 四氯化碳 、 乙醇 、 二氯甲烷 、 氯苯 为溶剂， 反应 4.17h， 生成 6-(2-aminophenyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-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-QUINOXALINEDIONE INHIBITORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR PROTEIN AND USES THEREFOR
  申请人：Verkman Alan S.

  公开号：US20120208822A1

  公开（公告）日：2012-08-16

  Provided herein are 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. The compounds, and compositions comprising the compounds, described herein are useful for treating diseases, disorders, and sequelae of diseases, disorders, and conditions that are associated with aberrantly increased CFTR activity, for example, polycystic kidney disease. The compounds may be used for inhibiting expansion or preventing formation of cysts in persons who have polycystic kidney disease.

  本文提供了嘧啶并吡咯并喹啉二酮（PPQ）化合物和包含这些化合物的组合物，它们抑制囊性纤维化跨膜传导调节因子（CFTR）介导的离子传输，并且可用于治疗与异常增加的CFTR氯离子通道活性相关的疾病和疾病。本文所述的化合物和包含这些化合物的组合物可用于治疗与异常增加的CFTR活性相关的疾病、疾病和病情后遗症，例如多囊肾病。这些化合物可用于抑制多囊肾病患者的囊肿扩张或预防囊肿的形成。
• 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：US09062073B2

  公开（公告）日：2015-06-23

  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并噁嗪二酮（BPO）化合物和嘧啶基吡咯并喹啉二酮（PPQ）化合物，以及包含这些化合物的组合物，它们能够抑制囊性纤维化跨膜传导调节器（CFTR）介导的离子传输，并且适用于治疗与异常增加的CFTR氯通道活性相关的疾病和障碍，例如多囊肾病和分泌性腹泻。所述的化合物和组合物可以用于抑制多囊肾病患者的囊肿扩张或预防囊肿的形成。
• 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。
• Pyrimido-pyrrolo-quinoxalinedione inhibitors of cystic fibrosis transmembrane conductance regulator protein and uses therefor
  申请人：Verkman Alan S.

  公开号：US08609661B2

  公开（公告）日：2013-12-17

  Provided herein are 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. The compounds, and compositions comprising the compounds, described herein are useful for treating diseases, disorders, and sequelae of diseases, disorders, and conditions that are associated with aberrantly increased CFTR activity, for example, polycystic kidney disease. The compounds may be used for inhibiting expansion or preventing formation of cysts in persons who have polycystic kidney disease.

  本文提供了嘧啶基-吡咯基-喹喔啉二酮（PPQ）化合物和含有这些化合物的组合物，这些化合物能够抑制囊性纤维化跨膜传导调节因子（CFTR）介导的离子转运，并且适用于治疗与CFTR氯离子通道活性异常增加相关的疾病和障碍。本文所描述的化合物和含有这些化合物的组合物适用于治疗与CFTR活性异常增加相关的疾病、障碍和疾病、障碍和病况的后遗症，例如多囊肾病。这些化合物可以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。
• Nanomolar Potency Pyrimido-pyrrolo-quinoxalinedione CFTR Inhibitor Reduces Cyst Size in a Polycystic Kidney Disease Model
  作者：Lukmanee Tradtrantip、N. D. Sonawane、Wan Namkung、A. S. Verkman

  DOI：10.1021/jm9009873

  日期：2009.10.22

  Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride, channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of similar to 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347. analogues established structure-activity relationships. The most potent compound, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido[4',5'-3,4]pyrrolo[ 1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC50 similar to 90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch-clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state. PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal-kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date.