2-(5-Bromo-pyrimidin-2-yl)-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one | 374927-46-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2-(5-Bromo-pyrimidin-2-yl)-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one
• 英文别名: 2-(5-bromopyrimidin-2-yl)-3-(2,3-dihydro-1-benzofuran-5-yl)-3,4-dihydro-1H-pyrrolo[3,4-b]quinolin-9-one
• CAS: 374927-46-5
• 化学式: C₂₃H₁₇BrN₄O₂
• 分子量: 461.318
• InChiKey: HZZQRGYYLYWJER-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  67.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(5-Bromo-pyrimidin-2-yl)-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one 、 3-吡啶硼酸 在 1,1'-双(二苯基膦)二茂铁 、 palladium diacetate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 30.0h， 以23%的产率得到3-(2,3-Dihydro-benzofuran-5-yl)-2-(5-pyridin-3-yl-pyrimidin-2-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one
  参考文献：
  名称：

  Pyrroloquinolone PDE5 Inhibitors with Improved Pharmaceutical Profiles for Clinical Studies on Erectile Dysfunction

  摘要：

  We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-111 were selected as development candidates for MED and other indications.

  DOI：

  10.1021/jm0401098
• 作为产物：
  描述：

  1,2,3,4-tetrahydro-3-(2,3-dihydrobenzofuran-5-yl)-9H-pyrrolo-[3,4-b]quinolin-9-one, hydrochloride salt 、 5-溴-2-氯嘧啶 在 potassium fluoride 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 以41%的产率得到2-(5-Bromo-pyrimidin-2-yl)-3-(2,3-dihydro-benzofuran-5-yl)-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one
  参考文献：
  名称：

  Pyrroloquinolone PDE5 Inhibitors with Improved Pharmaceutical Profiles for Clinical Studies on Erectile Dysfunction

  摘要：

  We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-111 were selected as development candidates for MED and other indications.

  DOI：

  10.1021/jm0401098

文献信息

• Pyrroloquinolone PDE5 Inhibitors with Improved Pharmaceutical Profiles for Clinical Studies on Erectile Dysfunction
  作者：Weiqin Jiang、Jihua Guan、Mark J. Macielag、Suying Zhang、Yuhong Qiu、Patricia Kraft、Sheela Bhattacharjee、T. Matthew John、Donna Haynes-Johnson、Scott Lundeen、Zhihua Sui

  DOI：10.1021/jm0401098

  日期：2005.3.1

  We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-111 were selected as development candidates for MED and other indications.