5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihydrobenzo[b]furan | 142873-41-4

• 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: 5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihydrobenzo[b]furan
• 英文别名: 5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidino)methyl-2,3-dihydrobenzofuran；Lipid peroxidation inhibitor 1；2,4,6,7-tetramethyl-2-[(4-phenylpiperidin-1-yl)methyl]-3H-1-benzofuran-5-amine
• CAS: 142873-41-4
• 化学式: C₂₄H₃₂N₂O
• 分子量: 364.531
• InChiKey: OFJJFTDZPRQPBY-UHFFFAOYSA-N

物化性质

• 沸点：
  520.4±50.0 °C(Predicted)
• 密度：
  1.090±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  38.5
• 氢给体数：
  1
• 氢受体数：
  3

制备方法与用途

生物活性

Lipid peroxidation inhibitor 1 是一种脂质过氧化 (lipid peroxidation) 抑制剂，其 IC50 值为 0.07 μM。

靶点

• IC50: 0.07 μM (lipid peroxidation)

体外研究

在所合成的化合物中，Lipid peroxidation inhibitor 1（26n）表现出显著抑制脂质过氧化的效果，其 IC50 值为 0.07 μM。

体内研究

基本分子 8a 和 27 在对抗 (甲基苯丙胺) MAP 引起的肠管高运动性方面表现出了显著效果。除了这些化合物外，在位置 2 的甲基旁边有一个相邻的苯基似乎是必不可少的（比较化合物 26m、o、p 与 Lipid peroxidation inhibitor 1（26n）、q、r）。在这些化合物中，具有位置 2 苯基哌啶基团的 Lipid peroxidation inhibitor 1 被发现是最有效的。

反应信息

• 作为反应物：
  描述：

  5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihydrobenzo[b]furan 生成 (R)-(-)-5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihydrobenzo [b]furan dihydrochloride
  参考文献：
  名称：

  5-Aminocoumarans:  Dual Inhibitors of Lipid Peroxidation and Dopamine Release with Protective Effects against Central Nervous System Trauma and Ischemia

  摘要：

  A series of 2,3-dihydro-5-benzofuranamines (5-aminocoumarans) were developed for the treatment of traumatic and ischemic central. nervous system (CNS) injury. Compounds within this class were extremely effective inhibitors of lipid peroxidation in vitro and antagonized excitatory behavior coupled with peroxidative injury induced by spinal intrathecal injection of FeCl2 (mouse-FeCl2-it assay) in vivo. Selected compounds were tested for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mouse brain. Among the compounds synthesized, compound 26n (2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)meth]-5-benzofuranamine) exhibited potent effects in these assays (inhibition of lipid peroxidation, IC50 = 0.07 mu M; mouse-FeCl2-it assay, ID50 = 10.4 mg/kg, po; MAP-induced hypermotility, 98% inhibition, 10 mg/kg, ip). The S-(+)-form of compound 26n dihydrochloride (TAK-218), which has 30 times more potent antagonistic activity on MAP-induced hypermotility than the R-(-)-form, improved more significantly the survival rate in the cerebral ischemia model (rat, 1-3 mg/kg, ip) during the period of 1-14 days after ischemia and decreased functional disorders in the traumatic brain injury model (rat, 0.1-1 mg/kg, ip) 3-14 days after injury. These results imply a role for dopamine in deterioration of CNS function after ischemic and traumatic injury. TAK-218 is a promising compound for the treatment of stroke and CNS trauma and is now under clinical investigation.

  DOI：

  10.1021/jm960411j
• 作为产物：
  描述：

  N-(4-hydroxy-2,3,6-trimethylphenyl)-formamide 在 盐酸 、 溴 、 sodium acetate 、 potassium carbonate 、 三乙胺 、 N,N-二乙基苯胺 作用下， 以 甲醇 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.17h， 生成 5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihydrobenzo[b]furan
  参考文献：
  名称：

  5-Aminocoumarans:  Dual Inhibitors of Lipid Peroxidation and Dopamine Release with Protective Effects against Central Nervous System Trauma and Ischemia

  摘要：

  A series of 2,3-dihydro-5-benzofuranamines (5-aminocoumarans) were developed for the treatment of traumatic and ischemic central. nervous system (CNS) injury. Compounds within this class were extremely effective inhibitors of lipid peroxidation in vitro and antagonized excitatory behavior coupled with peroxidative injury induced by spinal intrathecal injection of FeCl2 (mouse-FeCl2-it assay) in vivo. Selected compounds were tested for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mouse brain. Among the compounds synthesized, compound 26n (2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)meth]-5-benzofuranamine) exhibited potent effects in these assays (inhibition of lipid peroxidation, IC50 = 0.07 mu M; mouse-FeCl2-it assay, ID50 = 10.4 mg/kg, po; MAP-induced hypermotility, 98% inhibition, 10 mg/kg, ip). The S-(+)-form of compound 26n dihydrochloride (TAK-218), which has 30 times more potent antagonistic activity on MAP-induced hypermotility than the R-(-)-form, improved more significantly the survival rate in the cerebral ischemia model (rat, 1-3 mg/kg, ip) during the period of 1-14 days after ischemia and decreased functional disorders in the traumatic brain injury model (rat, 0.1-1 mg/kg, ip) 3-14 days after injury. These results imply a role for dopamine in deterioration of CNS function after ischemic and traumatic injury. TAK-218 is a promising compound for the treatment of stroke and CNS trauma and is now under clinical investigation.

  DOI：

  10.1021/jm960411j

文献信息

• Crystalline salts of optically active aminocoumaran derivatives, their
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US05552552A1

  公开（公告）日：1996-09-03

  A crystalline salt of an enantiomer of 5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihdrobenzo [b]furan which is stable and improved in solubility in water, is useful for an excellent lipidperoxide formation inhibitor.

  一种手性异构体的晶体盐，化学名为5-氨基-2,4,6,7-四甲基-2-(4-苯基哌啶甲基)-2,3-二氢苯并[b]呋喃，其稳定性和水溶性得到改善，可用作出色的脂质过氧化物形成抑制剂。
• PHENYLAZOLE COMPOUNDS, PRODUCTION PROCESS AND ANTIOXIDANTS
  申请人：Umeda Nobuhiro

  公开号：US20090306055A1

  公开（公告）日：2009-12-10

  The present invention is directed to compounds represented by the formula (1): B-D-Z (1), wherein B represent the following formula (B-1), A represents an optionally substituted imidazole or pyrazole group; E represents the following formula (1a): X represents an oxygen atom, the formula: SOu, or the formula: N—R 9 ; Y represents a carbon atom or a nitrogen atom; D represents an oxygen atom, a sulfur atom or the formula (1a); Z represents (a chroman-2-yl group, a chroman-4-yl group, a 2,3-dihydrobenzofuran-2-yl group, a 2,3-dihydrobenzofuran-3-yl group, etc.) which is substituted with NHR 10 or OR 11 )] or pharmaceutically acceptable salts thereof, and to antioxidants, therapeutic agents for kidney diseases or cerebrovascular disorder, and retinal oxidative damage inhibitors, which include the compounds as the active ingredient.

  本发明涉及由式(1)表示的化合物：B-D-Z(1)，其中B代表以下式(B-1)，A代表可选取代的咪唑或吡唑基团；E代表以下式(1a)：X代表氧原子，式：SOu，或式：N—R9；Y代表碳原子或氮原子；D代表氧原子、硫原子或式(1a)；Z代表（一个被NHR10或OR11取代的2-色基基团、4-色基基团、2,3-二氢苯并呋喃-2-基基团、2,3-二氢苯并呋喃-3-基基团等）或其药学上可接受的盐，以及将该化合物作为活性成分的抗氧化剂、肾脏疾病或脑血管疾病的治疗剂和视网膜氧化损伤抑制剂。
• Aminocoumaran derivatives, their production and use
  申请人：TAKEDA CHEMICAL INDUSTRIES, LTD.

  公开号：EP0483772A1

  公开（公告）日：1992-05-06

  A novel aminocoumaran derivatives of the general formula (I): wherein R¹ and R² are a hydrogen atom, an acyl group, an alkoxycarbonyl group, an aliphatic group or aromatic group; R³, R⁴ and R⁵ are an optionally acylated hydroxyl, optionally substituted amino group, alkoxy group or aliphatic group, or two of R³, R⁴ and R⁵ may be linked together to form a carbocyclic group; R⁶ and R⁷ are an aliphatic group and at least one of them has a methylene group at the α-position; R⁸ and R⁹ are a hydrogen atom or an aliphatic group or aromatic group, or a salt thereof is useful for medicines for preventing and treating various diseases such as arterial sclerosis, hepatopathy, cerebrovascular diseases and the like.

  通式 (I) 的新型氨基香豆素衍生物： 其中 R¹ 和 R² 是氢原子、酰基、烷氧羰基、脂肪族基团或芳香族基团；R³、R⁴ 和 R⁵ 是任选酰化的羟基、任选取代的氨基、烷氧基或脂肪族基团，或者两个 R³、R⁴ 和 R⁵ 可以连接在一起形成碳环基团；R⁶ 和 R⁷ 是脂肪族基团，且其中至少一个在 α 位上有亚甲基； R⁸ 和 R⁹ 是氢原子或脂肪族基团或芳香族基团，或其盐可用于预防和治疗动脉硬化、肝病、脑血管疾病等各种疾病的药物。
• Crystalline salts of optically active aminocoumaran derivatives, their production and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP0601547A1

  公开（公告）日：1994-06-15

  A crystalline salt of an enantiomer of 5-amino-2,4,6,7-tetramethyl-2-(4-phenylpiperidinomethyl)-2,3-dihydrobenzo[b]furan which is stable and improved in solubility in water, is useful for an excellent lipidperoxide formation inhibitor.

  5-氨基-2,4,6,7-四甲基-2-（4-苯基哌啶甲基）-2,3-二氢苯并[b]呋喃对映体的结晶盐在水中的稳定性和溶解度都有所提高，是一种非常有用的过氧化脂质形成抑制剂。
• QUINONE COMPOUND, ITS PRODUCTION AND USE
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP0846109A1

  公开（公告）日：1998-06-10