[1-[(4-tert-butylphenyl)methyl]-4-piperidinyl]methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate | 1444006-50-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: [1-[(4-tert-butylphenyl)methyl]-4-piperidinyl]methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate
• 英文别名: [1-[(4-tert-butylphenyl)methyl]piperidin-4-yl]methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate
• CAS: 1444006-50-1
• 化学式: C₂₉H₃₆N₂O₃
• 分子量: 460.616
• InChiKey: LBTADUZYQQBKOV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  43.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [1-[(4-tert-butylphenyl)methyl]-4-piperidinyl]methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate 在 盐酸 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 [1-[(4-tert-butylphenyl)methyl]-4-piperidinyl]methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate hydrochloride
  参考文献：
  名称：

  Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist

  摘要：

  5-HT4 receptor antagonists have been suggested to have clinical potential in treatment of atrial fibrillation, diarrhea-prone irritable bowel syndrome and urinary incontinence. Recently, the use of 5-HT4 antagonists has been suggested to have a therapeutic benefit in heart failure. Affinity for the hERG potassium ion channel and increased risk for prolonged QT intervals and arrhythmias has been observed for several 5-HT4 ligands. Serotonin may also have beneficial effects in the central nervous system (CNS) through stimulation of the 5-HT4 receptor, and reduced distribution of 5-HT4 antagonists to the CNS may therefore be an advantage. Replacing the amide and N-butyl side chain of the 5-HT4 receptor antagonist SB207266 with an ester and a benzyl dimethyl acetic acid group led to compound 9; a hydrophilic 5-HT4 antagonist with excellent receptor binding and low affinity for the hERG potassium ion channel. To increase oral bioavailability of carboxylic acid 9, two different prodrug approaches were applied. The tertbutyl prodrug 11 did not improve bioavailability, and LC-MS analysis revealed unmetabolized prodrug in the systemic circulation. The medoxomil ester prodrug 10 showed complete conversion and sufficient bioavailability of 9 to advance into further preclinical testing for treatment of heart failure. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.060
• 作为产物：
  描述：

  1-苄基-4-哌啶甲醇 在 正丁基锂 、 palladium on activated charcoal 、 氢气 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 溶剂黄146 、 丙酮 为溶剂， 20.0 ℃ 、500.01 kPa 条件下， 反应 84.08h， 生成 [1-[(4-tert-butylphenyl)methyl]-4-piperidinyl]methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate
  参考文献：
  名称：

  Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist

  摘要：

  5-HT4 receptor antagonists have been suggested to have clinical potential in treatment of atrial fibrillation, diarrhea-prone irritable bowel syndrome and urinary incontinence. Recently, the use of 5-HT4 antagonists has been suggested to have a therapeutic benefit in heart failure. Affinity for the hERG potassium ion channel and increased risk for prolonged QT intervals and arrhythmias has been observed for several 5-HT4 ligands. Serotonin may also have beneficial effects in the central nervous system (CNS) through stimulation of the 5-HT4 receptor, and reduced distribution of 5-HT4 antagonists to the CNS may therefore be an advantage. Replacing the amide and N-butyl side chain of the 5-HT4 receptor antagonist SB207266 with an ester and a benzyl dimethyl acetic acid group led to compound 9; a hydrophilic 5-HT4 antagonist with excellent receptor binding and low affinity for the hERG potassium ion channel. To increase oral bioavailability of carboxylic acid 9, two different prodrug approaches were applied. The tertbutyl prodrug 11 did not improve bioavailability, and LC-MS analysis revealed unmetabolized prodrug in the systemic circulation. The medoxomil ester prodrug 10 showed complete conversion and sufficient bioavailability of 9 to advance into further preclinical testing for treatment of heart failure. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.060

文献信息

• Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist
  作者：Bjarne Brudeli、Lise Román Moltzau、Cam H.T. Nguyen、Kjetil Wessel Andressen、Nils Olav Nilsen、Finn Olav Levy、Jo Klaveness

  DOI：10.1016/j.ejmech.2013.03.060

  日期：2013.6

  5-HT4 receptor antagonists have been suggested to have clinical potential in treatment of atrial fibrillation, diarrhea-prone irritable bowel syndrome and urinary incontinence. Recently, the use of 5-HT4 antagonists has been suggested to have a therapeutic benefit in heart failure. Affinity for the hERG potassium ion channel and increased risk for prolonged QT intervals and arrhythmias has been observed for several 5-HT4 ligands. Serotonin may also have beneficial effects in the central nervous system (CNS) through stimulation of the 5-HT4 receptor, and reduced distribution of 5-HT4 antagonists to the CNS may therefore be an advantage. Replacing the amide and N-butyl side chain of the 5-HT4 receptor antagonist SB207266 with an ester and a benzyl dimethyl acetic acid group led to compound 9; a hydrophilic 5-HT4 antagonist with excellent receptor binding and low affinity for the hERG potassium ion channel. To increase oral bioavailability of carboxylic acid 9, two different prodrug approaches were applied. The tertbutyl prodrug 11 did not improve bioavailability, and LC-MS analysis revealed unmetabolized prodrug in the systemic circulation. The medoxomil ester prodrug 10 showed complete conversion and sufficient bioavailability of 9 to advance into further preclinical testing for treatment of heart failure. (C) 2013 Elsevier Masson SAS. All rights reserved.