((S)-2-hydroxy-3-{3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-(1S,3R,5R)-8-azabicyclo[3.2.1]oct-8-yl}propyl)methylcarbamic acid tert-butyl ester | 866933-61-1

• 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: ((S)-2-hydroxy-3-{3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-(1S,3R,5R)-8-azabicyclo[3.2.1]oct-8-yl}propyl)methylcarbamic acid tert-butyl ester
• CAS: 866933-61-1
• 化学式: C₂₉H₄₂N₄O₅
• 分子量: 526.676
• InChiKey: UIBIZGGAGXMEFK-KAOXLYBCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.54
• 重原子数：
  38.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  104.11
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  ((S)-2-hydroxy-3-{3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-(1S,3R,5R)-8-azabicyclo[3.2.1]oct-8-yl}propyl)methylcarbamic acid tert-butyl ester 、 甲基磺酰氯 在 三氟乙酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 二氯甲烷 为溶剂， 生成 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(S)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide
  参考文献：
  名称：

  Discovery, oral pharmacokinetics and in vivo efficacy of velusetrag, a highly selective 5-HT4 receptor agonist that has achieved proof-of-concept in patients with chronic idiopathic constipation

  摘要：

  Utilization of Theravance's multivalent approach to drug discovery towards 5-HT4 receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT4 receptor, selectivity over the 5-HT3 receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.08.051
• 作为产物：
  描述：

  1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-aza-bicyclo[3.2.1]oct-3-yl}amide 、 ((R)-3-chloro-2-hydroxy-propyl)-methyl-carbamic acid tert-butyl ester 在 N,N-二异丙基乙胺 作用下， 以 甲醇 为溶剂， 生成 ((S)-2-hydroxy-3-{3-[(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carbonyl)amino]-(1S,3R,5R)-8-azabicyclo[3.2.1]oct-8-yl}propyl)methylcarbamic acid tert-butyl ester
  参考文献：
  名称：

  Discovery, oral pharmacokinetics and in vivo efficacy of velusetrag, a highly selective 5-HT4 receptor agonist that has achieved proof-of-concept in patients with chronic idiopathic constipation

  摘要：

  Utilization of Theravance's multivalent approach to drug discovery towards 5-HT4 receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT4 receptor, selectivity over the 5-HT3 receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.08.051

文献信息

• Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
  申请人：Marquess Daniel

  公开号：US20050228014A1

  公开（公告）日：2005-10-13

  The invention provides novel quinolinone-carboxamide 5-HT 4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT 4 receptor activity, and processes and intermediates useful for preparing such compounds.

  这项发明提供了新型喹诺酮-羧酰胺5-HT4受体激动剂化合物。该发明还提供包含这些化合物的药物组合物，使用这些化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备这些化合物的过程和中间体。
• QUINOLINONE-CARBOXAMIDE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
  申请人：Marquess Daniel

  公开号：US20100285519A1

  公开（公告）日：2010-11-11

  The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds of Formula (I). The invention also provides pharmaceutical compositions comprising such compounds, the use such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds. Wherein; R 1 is hydrogen, halo, hydroxy, C 1-4 alkyl, or C 1-4 alkoxy; R 2 is C 3-4 alkyl, or C 3-6 cycloalkyl; R 3 is hydrogen or C 1-3 alkyl: R 4 is S(O) 2 R 6 or C(O)R 7 ; R 5 is hydrogen, C 1-3 alkyl, C 2-3 alkyl substituted with —OH or C 1-3 alkoxy, or —CH 2 -pyrydyl; R 6 is C 1-3 alkyl; or R 5 and R 6 taken together from C 3-4 alkylenyl; and R 7 is hydrogen, C 1-3 alkyl, or pyrydyl; or pharmaceutically-acceptable salt or solvate or stereoisomer thereof.

  该发明提供了公式（I）的新型喹啉酮-羧酰胺5-HT4受体激动剂化合物。该发明还提供了包括这些化合物的制药组合物，使用这些化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备这些化合物的过程和中间体。其中，R1为氢、卤素、羟基、C1-4烷基或C1-4烷氧基；R2为C3-4烷基或C3-6环烷基；R3为氢或C1-3烷基；R4为S（O）2R6或C（O）R7；R5为氢、C1-3烷基、C2-3烷基取代的-OH或C1-3烷氧基，或-CH2-吡啶基；R6为C1-3烷基；或R5和R6一起形成C3-4烷基亚乙基；R7为氢、C1-3烷基或吡啶基；或其药学上可接受的盐、溶剂或立体异构体。
• Quinolinone-carboxamide compounds as 5-HT4, receptor agonists
  申请人：Marquess Daniel

  公开号：US20080176895A1

  公开（公告）日：2008-07-24

  The invention provides novel quinolinone-carboxamide 5-HT 4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT 4 receptor activity, and processes and intermediates useful for preparing such compounds.

  这项发明提供了新型的喹诺酮-羧酰胺5-HT4受体激动剂化合物。该发明还提供了包括这种化合物的制药组合物，使用这种化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备这种化合物的过程和中间体。
• Quinolinone-carboxamide compounds as 5-HT, receptor agonists
  申请人：Marquess Daniel

  公开号：US20070270457A1

  公开（公告）日：2007-11-22

  The invention provides novel quinolinone-carboxamide 5-HT 4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT 4 receptor activity, and processes and intermediates useful for preparing such compounds.

  该发明提供了新型的喹诺酮-羧酰胺5-HT4受体激动剂化合物。该发明还提供了包含这些化合物的药物组合物，使用这些化合物治疗与5-HT4受体活性相关的疾病的方法，以及用于制备这些化合物的过程和中间体。
• Quinolinone-Carboxamide Compounds as 5-Ht4 Receptor Agonists
  申请人：Marquess Daniel

  公开号：US20070281970A1

  公开（公告）日：2007-12-06

  The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds of Formula (I). The invention also provides pharmaceutical compositions comprising such compounds, the use such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds. Wherein; R 1 is hydrogen, halo, hadroxy, C 1-4 alkyl, or C 1-4 alkoxy; R 2 is C 3-4 alkyl, or C 3-6 cycloakyl; R 3 is hydrogen or C 1-3 alkyl: R 4 is —S(O) 2 R 6 or —C(O)R 7 ; R 5 is hydrogen, C 1-3 alkyl, C 2-3 alkyl subtituted with —OH or C 1-3 alkoxy, or —CH 2 -pyrydyl; R 6 is C 1-3 alkyl; or R 5 and R 6 taken together from C 3-4 alkylenyl; and R 7 is hydrogen, C 1-3 alkyl, or pyrydyl; or pharmaceutically-acceptable salt or solvate or stereoisomer thereof.

  该发明提供了公式(I)的新型喹啉酮-羧酰胺5-HT4受体激动剂化合物。该发明还提供了包含这些化合物的药物组合物，使用这些化合物治疗与5-HT4受体活性相关的疾病，以及用于制备这些化合物的过程和中间体。其中，R1为氢，卤素，羟基，C1-4烷基或C1-4烷氧基；R2为C3-4烷基或C3-6环烷基；R3为氢或C1-3烷基；R4为—S(O)2R6或—C(O)R7；R5为氢，C1-3烷基，C2-3烷基取代的—OH或C1-3烷氧基，或—CH2-吡啶基；R6为C1-3烷基；或R5和R6一起形成C3-4烷基亚基；R7为氢，C1-3烷基或吡啶基；或其药学上可接受的盐或溶剂或立体异构体。