1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one | 374927-07-8

• 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: 1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one
• 英文别名: 3-(1,3-benzodioxol-5-yl)-2-(5-bromopyrimidin-2-yl)-3,4-dihydro-1H-pyrrolo[3,4-b]quinolin-9-one
• CAS: 374927-07-8
• 化学式: C₂₂H₁₅BrN₄O₃
• 分子量: 463.29
• InChiKey: MSNMTBLMABIHNJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  76.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one 、 4-三正丁基锡基吡啶 在 catalyst 、 四(三苯基膦)钯 Brine 、 水 、 Sodium sulfate-III 、 silica gel 、 乙腈 作用下， 以 N,N-二甲基甲酰胺 、 乙酸乙酯 为溶剂， 反应 16.0h， 以actonitrile=1:10, v/v) yielded the product as a white solid的产率得到1,2,3,4-Tetrahydro-2-[5-(4-pyridinyl)-pyrimidin-2-yl]-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one
  参考文献：
  名称：

  Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors

  摘要：

  本发明涉及式(I)或(II)的新型吡咯吡啶酮衍生物，以及含有该化合物的药物组合物及其用于治疗性功能障碍的用途。

  公开号：

  US20040044021A1
• 作为产物：
  描述：

  1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-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40%的产率得到1,2,3,4-tetrahydro-2-(5-bromopyrimidin-2-yl)-3-(3,4-methylenedioxyphenyl)-9H-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

• SUBSTITUTED PYRROLOPYRIDINONE DERIVATIVES USEFUL AS PHOSPHODIESTERASE INHIBITORS
  申请人：Ortho-McNeil Pharmaceutical, Inc.

  公开号：EP1296981B1

  公开（公告）日：2004-10-06
• US6635638B2
  申请人：——

  公开号：US6635638B2

  公开（公告）日：2003-10-21
• US6818646B2
  申请人：——

  公开号：US6818646B2

  公开（公告）日：2004-11-16
• Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors
  申请人：——

  公开号：US20020010183A1

  公开（公告）日：2002-01-24

  The invention relates to novel pyrrolopyridinone derivatives of the formula (I) or (II): 1 pharmaceutical compositions containing the compounds and their use for the treatment of sexual dysfunction.

  这项发明涉及公式(I)或(II)的新型吡咯吡啶酮衍生物： 1 含有这些化合物的药物组合物及其用于治疗性功能障碍的用途。
• 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.