2,2,2-三氟乙酸 1-(2,4-二甲基苯基)-2-[(3-甲氧基苯基)亚甲基]酰肼 | 1146963-51-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 2,2,2-三氟乙酸 1-(2,4-二甲基苯基)-2-[(3-甲氧基苯基)亚甲基]酰肼
• 中文别名: 2,2,2-三氟乙酸1-(2,4-二甲基苯基)-2-[(3-甲氧基苯基)亚甲基]酰肼
• 英文名称: (E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-(3-methoxybenzylidene)-acetohydrazide
• 英文别名: N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N-[(E)-(3-methoxyphenyl)methylideneamino]acetamide
• CAS: 1146963-51-0；1807913-16-1
• 化学式: C₁₈H₁₇F₃N₂O₂
• 分子量: 350.34
• InChiKey: HYMZAYGFKNNHDN-SSDVNMTOSA-N

物化性质

• 沸点：
  412.8±55.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO:68.0(最大浓度 mg/mL);194.1(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  41.9
• 氢给体数：
  0
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  -20℃

制备方法与用途

生物活性

J-147 是一种特别有效的、具有口服活性的神经保护剂，能够增强认知能力。它可透过血脑屏障 (BBB)，并抑制单胺氧化酶 B (MAO B) 和多巴胺转运体 (dopamine transporter)，EC50 分别为 1.88 μM 和 0.649 μM。J-147 在阿尔茨海默氏症 (AD) 的研究中显示出潜力。

靶点

• MAO B
• 多巴胺转运体

体外研究

J-147 以剂量依赖性方式促进 HT22 细胞和原代细胞的生存，EC50 值范围为 0.06-0.115 μM。

体内研究

给予 J-147 (在饮食中添加至浓度为 200 ppm；连续 6 个月) 可显著增强老年小鼠的记忆力和树突棘数量。J-147 在单次口服剂量 20 mg/kg 下的半衰期分别为血浆中的 1.5 小时和脑部的 2.5 小时。

实验数据

• 动物模型：24 只 24 月龄 C57Bl/6 雄性小鼠；使用 8 月龄小鼠作为对照
• 剂量：200 ppm
• 给药方式：通过添加 200ppm J-147 的饮食连续给予 6 个月
• 结果：年轻和老年动物均能识别移动了较大距离（135 度）的对象。然而，当对象仅移动较小的距离（45 度）时，年老小鼠的识别指数 (RI) 显著降低。J-147 的治疗逆转了这一效应。

反应信息

• 作为反应物：
  描述：

  2,2,2-三氟乙酸 1-(2,4-二甲基苯基)-2-[(3-甲氧基苯基)亚甲基]酰肼 在 碘环己烷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 以63%的产率得到(E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-(3-hydroxybenzylidene)acetohydrazide
  参考文献：
  名称：

  Metabolism of a potent neuroprotective hydrazide

  摘要：

  Using a drug discovery scheme for Alzheimer's disease (AD) that is based upon multiple pathologies of old age, we identified a potent compound with efficacy in rodent memory and AD animal models. Since this compound, J147, is a phenyl hydrazide, there was concern that it can be metabolized to aromatic amines/hydrazines that are potentially carcinogenic. To explore this possibility, we examined the metabolites of J147 in human and mouse microsomes and mouse plasma. It is shown that J147 is not metabolized to aromatic amines or hydrazines, that the scaffold is exceptionally stable, and that the oxidative metabolites are also neuroprotective. It is concluded that the major metabolites of J147 may contribute to its biological activity in animals. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.03.020
• 作为产物：
  描述：

  2,4-二甲基苯肼盐酸盐 在 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 2,2,2-三氟乙酸 1-(2,4-二甲基苯基)-2-[(3-甲氧基苯基)亚甲基]酰肼
  参考文献：
  名称：

  Metabolism of a potent neuroprotective hydrazide

  摘要：

  Using a drug discovery scheme for Alzheimer's disease (AD) that is based upon multiple pathologies of old age, we identified a potent compound with efficacy in rodent memory and AD animal models. Since this compound, J147, is a phenyl hydrazide, there was concern that it can be metabolized to aromatic amines/hydrazines that are potentially carcinogenic. To explore this possibility, we examined the metabolites of J147 in human and mouse microsomes and mouse plasma. It is shown that J147 is not metabolized to aromatic amines or hydrazines, that the scaffold is exceptionally stable, and that the oxidative metabolites are also neuroprotective. It is concluded that the major metabolites of J147 may contribute to its biological activity in animals. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.03.020

文献信息

• Dicyanovinyl-substituted J147 analogue inhibits oligomerization and fibrillation of β-amyloid peptides and protects neuronal cells from β-amyloid-induced cytotoxicity
  作者：Kyoungdo Kim、Kwang-su Park、Mi Kyoung Kim、Hyunah Choo、Youhoon Chong

  DOI：10.1039/c5ob01463h

  日期：——

  AJ147 derivative3jinhibits Aβ₄₂oligomerization and fibrillization, disassembles the preformed Aβ₄₂fibrils and prevents Aβ₄₂induced neurotoxicity.

  AJ147衍生物3j抑制Aβ42寡聚体化和纤维化，解体预先形成的Aβ42纤维，并防止Aβ42诱导的神经毒性。
• 베타 아밀로이드의 올리고화 및 섬유화 저해능과 함께 신경세포 보호능력을 갖는 신규 알츠하이머병 치료제
  申请人：Konkuk University Industrial Cooperation Corp 건국대학교 산학협력단(220040157648) BRN ▼206-82-07325

  公开号：KR20170017173A

  公开（公告）日：2017-02-15

  본 발명은 베타 아밀로이드의 올리고화 및 섬유화 저해능과 함께 신경세포 보호능력을 갖는 신규 알츠하이머병 치료제 개발에 관한 것으로 본 발명의 화합물은 알쯔하이머병 치료효과를 유지한 채 기존의 커큐민의 특이적 활성인 올리고머 및 섬유형 아밀로이드베타의 직접적 저해능력을 회복시킴으로써 새로운 저해제로 사용될 수 있다.

  This invention relates to the development of a novel Alzheimer's disease treatment with the ability to inhibit the oligomerization and fibrillation of beta-amyloid, while also possessing neuroprotective capabilities. The compound of this invention can be used as a new inhibitor by restoring the specific activity of curcumin, while maintaining the therapeutic effect on Alzheimer's disease, directly inhibiting the oligomeric and fibrillar forms of beta-amyloid.
• The structure of the anti-aging agent J147 used for treating Alzheimer's disease
  作者：Guy J. Clarkson、M. Ángeles Farrán、Rosa M. Claramunt、Ibon Alkorta、José Elguero

  DOI：10.1107/s205322961900144x

  日期：2019.3.1

  The molecular structure of the anti-aging agent J147 [systematic name: (E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N′-(3-methoxybenzylidene)acetohydrazide], C₁₈H₁₇F₃N₂O₂, has been determined at 150 K. The crystal structure corresponds to the minimum-energy conformation in the gas phase calculated by density functional theory (DFT). 15 other conformations have been calculated and compared with the minimum, denoted 1111. NMR spectroscopic data have been obtained and compared with those from Gauge Independent Atomic Orbital (GIAO) calculations. DFT calculations allow the reduction of the 16 possible rotamers to the four most stable (i.e. 1111, 1112, 1121 and 1222); in addition, the calculated barriers connecting these minima are low enough to permit their interconversion. Comparison of the NMR spectroscopic results, both experimental and calculated, point to the 1121 isomer being present in chloroform solution.

  在 150 K 下测定了抗衰老剂 J147 [系统名称：(E)-N-(2,4-二甲基苯基)-2,2,2-三氟-N′-(3-甲氧基亚苄基)乙酰肼]（C18H17F3N2O2）的分子结构。该晶体结构与密度泛函理论（DFT）计算的气相最小能构象一致。还计算出了其他 15 种构象，并与最小构象进行了比较。我们获得了核磁共振光谱数据，并将其与量规独立原子轨道 (GIAO) 计算结果进行了比较。通过 DFT 计算，可以将 16 种可能的旋转体还原为四种最稳定的旋转体（即 1111、1112、1121 和 1222）；此外，连接这些最小值的计算壁垒足够低，允许它们相互转换。核磁共振光谱的实验结果和计算结果都表明，1121 异构体存在于氯仿溶液中。
• 一种广谱神经保护活性苯基酰肼化合物的工业化制备方法
  申请人：陈开云

  公开号：CN112279780A

  公开（公告）日：2021-01-29

  本发明提供一种广谱神经保护活性苯基酰肼化合物的工业化制备方法，该方法采用两步合成技术、大孔树脂纯化技术、重结晶技术、超临界CO2流体干燥技术和全自动控制技术相结合，在多者的协同作用下进行合成与纯化，利用该组合技术生产产品，具有工艺线路短、生产成本低、产品纯度高、产品收率高、质量稳定、环境污染小的特点，适宜工业化生产。
• 2,2,2-trifluoroacetic acid 1-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide polymorphs and method of making the same
  申请人：Abrexa Pharmaceuticals, Inc.

  公开号：US10968167B2

  公开（公告）日：2021-04-06

  Crystalline polymorph forms of neurotrophic agent 2,2,2-trifluoroacetic acid 1-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide (J147), and process for producing the crystalline polymorphic form are provided.

  提供了神经营养剂 2,2,2-三氟乙酸 1-(2,4-二甲基苯基)-2-[(3-甲氧基苯基)亚甲基]酰肼（J147）的结晶多晶型和生产结晶多晶型的工艺。