2-[2,3']Bipyridinyl-6'-yl-1-(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline | 374633-56-4

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 2-[2,3']Bipyridinyl-6'-yl-1-(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline
• 英文别名: 2-[2,3']bipyridinyl-6'-yl-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline；2-[2,3'']Bipyridinyl-6''-yl-1-(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline；1-(2,3-dihydro-1-benzofuran-5-yl)-2-(5-pyridin-2-ylpyridin-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole
• CAS: 374633-56-4
• 化学式: C₂₉H₂₄N₄O
• 分子量: 444.536
• InChiKey: WBTKLEFBLWJDCP-UHFFFAOYSA-N

物化性质

• 沸点：
  702.9±60.0 °C(Predicted)
• 密度：
  1.307±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  54
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-[2,3']Bipyridinyl-6'-yl-1-(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline 在 potassium tert-butylate 、 氧气 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 以11%的产率得到2-[2,3']Bipyridinyl-6'-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
• 作为产物：
  描述：

  2,3-二氢苯并呋喃-5-甲醛 在 tris-(dibenzylideneacetone)dipalladium(0) 、 四(三苯基膦)钯 、 1,3-双(二苯基膦)丙烷 、 三氟乙酸 、 sodium t-butanolate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 70.0h， 生成 2-[2,3']Bipyridinyl-6'-yl-1-(2,3-dihydro-benzofuran-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline
  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：——

  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。
• beta-carboline derivatives useful as inhibitors of phosphodiesterase
  申请人：——

  公开号：US20020010189A1

  公开（公告）日：2002-01-24

  The present invention relates to novel &bgr;-carboline derivatives of the general formula 1 wherein all the variables are as described within the specification, useful as phosphodiesterase inhibitors. The present invention further relates to use of the described derivatives for the treatment of diseases and conditions related to PDE, for example male erectile dysfunction.

  本发明涉及一种新颖的β-咔啉衍生物，其通式如下，其中所有变量如规范中所述，用作磷酸二酯酶抑制剂。本发明还涉及所述衍生物用于治疗与PDE相关的疾病和病况，例如男性勃起功能障碍。
• Beta-carboline derivatives useful as inhibitors of phosphodiesterase
  申请人：——

  公开号：US20030166641A1

  公开（公告）日：2003-09-04

  The present invention relates to novel &bgr;-carboline derivatives of the general formula 1 wherein all the variables are as described within the specification, useful as phosphodiesterase inhibitors. The present invention further relates to use of the described derivatives for the treatment of diseases and conditions related to PDE, for example male erectile dysfunction.

  本发明涉及新颖的β-咔啉衍生物，其通式为1，其中所有变量如规范中所述，可用作磷酸二酯酶抑制剂。本发明还涉及所述衍生物用于治疗与PDE相关的疾病和病状，例如男性勃起功能障碍。
• Benzo[4,5]thieno[2,3-c]pyridine and Benzo[4,5]furo[2,3-c]pyridine Derivatives Useful as Inhibitors of Phosphodiesterase
  申请人：Sui Zhihua

  公开号：US06864253B2

  公开（公告）日：2005-03-08

  The present invention relates to novel β-carboline derivatives of the general formula wherein all the variables are as described within the specification, useful as phosphodiesterase inhibitors. The present invention further relates to use of the described derivatives for the treatment of diseases and conditions related to PDE, for example male erectile dysfunction.

  本发明涉及新的β-咔唑啉衍生物，其一般式如下： 其中，所有变量均如规范中所述，可用作磷酸二酯酶抑制剂。本发明还涉及所述衍生物用于治疗与PDE相关的疾病和病情，例如男性勃起功能障碍。
• &bgr;-carboline derivatives useful as inhibitors of phosphodiesterase
  申请人：Ortho-McNeil Pharmaceutical, Inc.

  公开号：US06492358B2

  公开（公告）日：2002-12-10

  The present invention relates to novel &bgr;-carboline derivatives of the general formula wherein all the variables are as described within the specification, useful as phosphodiesterase inhibitors. The present invention further relates to use of the described derivatives for the treatment of diseases and conditions related to PDE, for example male erectile dysfunction.

  本发明涉及一种新的&bgr;-咔啉衍生物，其通式中的所有变量均如规范中所述，可用作磷酸二酯酶抑制剂。本发明还涉及所述衍生物用于治疗与PDE相关的疾病和病症，例如男性勃起功能障碍。