9-acetamido-9H-fluorene-2-carboxylic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: 9-acetamido-9H-fluorene-2-carboxylic acid
• 英文别名: 9-acetylamino-fluorene-2-carboxylic acid；(+/-)-9-Acetamino-fluoren-carbonsaeure-(2)；9-Acetylamino-fluoren-2-carbonsaeure
• 化学式: C₁₆H₁₃NO₃
• 分子量: 267.284
• InChiKey: ZSTCTVFWTJWEQB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  盐酸胍 、 9-acetamido-9H-fluorene-2-carboxylic acid 在 N,N'-羰基二咪唑 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 5.0h， 以160 mg的产率得到9-(acetylamino)-N-(diaminomethylene)-9H-fluorene-2-carboxamide
  参考文献：
  名称：

  Synthesis and structure–activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists. Part 2

  摘要：

  We previously reported that the novel dual 5-HT₂B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT₂B and 5-HT₇ receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT₇), Tyr (Y370:5-HT₂B, Y374:5-HT₇) and aromatic residue (W131:5-HT2B, F158:5-HT₇). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT₂B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT₂A, 5-HT₂C, α₁, D₂ and M₁ receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.

  DOI：

  10.1016/j.bmc.2014.05.027
• 作为产物：
  描述：

  9-芴酮-2-羧酸 在 硫酸 、 palladium 10% on activated carbon 、 氢气 、 羟胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 111.5h， 生成 9-acetamido-9H-fluorene-2-carboxylic acid
  参考文献：
  名称：

  Synthesis and structure–activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists. Part 2

  摘要：

  We previously reported that the novel dual 5-HT₂B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT₂B and 5-HT₇ receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT₇), Tyr (Y370:5-HT₂B, Y374:5-HT₇) and aromatic residue (W131:5-HT2B, F158:5-HT₇). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT₂B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT₂A, 5-HT₂C, α₁, D₂ and M₁ receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.

  DOI：

  10.1016/j.bmc.2014.05.027

文献信息

• The Resolution of 9,2-Substituted Fluorenes¹
  作者：Francis Earl Ray、Elizabeth Kreiser

  DOI：10.1021/ja01204a042

  日期：1947.12
• Synthesis and structure–activity relationships of new carbonyl guanidine derivatives as novel dual 5-HT2B and 5-HT7 receptor antagonists. Part 2
  作者：Ayako Moritomo、Hiroyoshi Yamada、Toshihiro Watanabe、Hirotsune Itahana、Yuji Koga、Shinobu Akuzawa、Minoru Okada

  DOI：10.1016/j.bmc.2014.05.027

  日期：2014.8

  We previously reported that the novel dual 5-HT₂B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT₂B and 5-HT₇ receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT₇), Tyr (Y370:5-HT₂B, Y374:5-HT₇) and aromatic residue (W131:5-HT2B, F158:5-HT₇). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT₂B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT₂A, 5-HT₂C, α₁, D₂ and M₁ receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.