methyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxaline carboxylate | 212117-87-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: methyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxaline carboxylate
• 英文别名: methyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carboxylate；Methyl 5,5,8,8-tetramethyl-6,7-dihydroquinoxaline-2-carboxylate
• CAS: 212117-87-8
• 化学式: C₁₄H₂₀N₂O₂
• 分子量: 248.325
• InChiKey: UXNZSFKWZUMJAT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  52.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxaline carboxylate 在 草酰氯 、 二异丁基氢化铝 、 二甲基亚砜 、 copper(ll) bromide 作用下， 以 乙醚 、 二氯甲烷 、 氯仿 、 乙酸乙酯 、 甲苯 为溶剂， 反应 10.0h， 生成 2-bromo-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxalinyl)-1-ethanone
  参考文献：
  名称：

  5,6,7,8-四氢-5,5,8,8-四甲基-2-喹喔啉衍生物与视黄酸受体α激动活性的合成及其构效关系。

  摘要：

  在我们对视黄酸受体（RAR）激动剂的研究过程中，我们设计并合成了一系列喹喔啉衍生物。其中之一是4- [5-（5,6,7,8-四氢-5,5,8，8-四甲基-2-喹喔啉基）-1H-2-吡咯基]苯甲酸（3a），具有2,5-二取代的吡咯部分，对RARalpha受体表现出选择性，并在HL-60细胞上表现出很强的细胞分化活性。

  DOI：

  10.1021/jm990063w
• 作为产物：
  描述：

  2,2,5,5-四甲基己烷二酸 在 chromium(VI) oxide 、 sodium hydroxide 、 硫酸 、 sodium 、 溶剂黄146 作用下， 以 甲醇 、 xylene 为溶剂， 反应 75.0h， 生成 methyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxaline carboxylate
  参考文献：
  名称：

  5,6,7,8-四氢-5,5,8,8-四甲基-2-喹喔啉衍生物与视黄酸受体α激动活性的合成及其构效关系。

  摘要：

  在我们对视黄酸受体（RAR）激动剂的研究过程中，我们设计并合成了一系列喹喔啉衍生物。其中之一是4- [5-（5,6,7,8-四氢-5,5,8，8-四甲基-2-喹喔啉基）-1H-2-吡咯基]苯甲酸（3a），具有2,5-二取代的吡咯部分，对RARalpha受体表现出选择性，并在HL-60细胞上表现出很强的细胞分化活性。

  DOI：

  10.1021/jm990063w

文献信息

• Synthesis and Structure−Activity Relationships of 2-Pyrazinylcarboxamido- benzoates and β-Ionylideneacetamidobenzoates with Retinoidal Activity
  作者：Paul Jones、Gérald B. Villeneuve、Chengpei Fei、Josie DeMarte、Allison J. Haggarty、Khin Than Nwe、Deborah A. Martin、Anne-Marie Lebuis、Joshua M. Finkelstein、Barbara J. Gour-Salin、Tak Hang Chan、Brian R. Leyland-Jones

  DOI：10.1021/jm9801354

  日期：1998.7.1

  The structure-activity relationships of two series of novel retinoids (2-pyrazinylcarboxamidobenzoates and beta-ionylideneacetamidobenzoates) have been investigated by evaluating their ability to induce differentiation in both human promyelocytic leukemia (HL60) cells and mouse embryonal carcinoma (P19) cells. The most active compound (ED50 = 8.3 x 10(-9) M) of the 2-pyrazinylcarboxamidobenzoates is 4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylquinoxalyl)-carboxamido]benzoic acid (9u), while the most active analogue of the beta-ionylideneacetamidobenzoates is 4-[3-methyl-5-(2',6',6'-trimethyl-1'-cyclohexen-1'-yl)-(2E,4E)-pentadienamido]benzoic acid (10a, ED50 = 3.2 x 10(-8) M). Our studies identify an absolute requirement for the carboxylic acid moiety on the aromatic ring to be para relative to the amide linkage for activity. Benzoate substitutions in the ortho position relative to the terminal carboxylate (9d,k,r) are well-tolerated; however, a methoxy substituent meta relative to the terminal carboxylate gives rise to only weakly active analogues (9x). Conformational studies (NMR, X-ray crystallography) of the 2-pyrazinylcarboxamidobenzoates indicate that the preferred conformation exhibits a trans-amide bond and an internal hydrogen bond between the quinoxaline N1 and HN amide which locks the torsional angle between C2 and CO in the s-trans conformation. N-Methylation (9y) results in loss of activity. Studies indicate that there is now a cis-amide bond present which redirects the carboxylate toward the pharmacophoric gem-dimethyl groups. The distance between the gem-dimethyl group and the terminal carboxylate appears to be too short to activate the retinoid receptor. N-Methylation in the beta-ionylideneacetamidobenzoate series (10c) also results in the formation of a cis-amide bond and loss of activity.
• WO2020183173A5
  申请人：——

  公开号：WO2020183173A5

  公开（公告）日：2023-02-14
• SYNTHETIC RETINOIDS FOR USE IN RAR ACTIVATION
  申请人：University Of Durham

  公开号：EP3937923A2

  公开（公告）日：2022-01-19
• SYNTHETIC RETINOIDS FOR USE IN RAR ACTIVATION
  申请人：UNIVERSITY OF DURHAM

  公开号：US20220144783A1

  公开（公告）日：2022-05-12

  The present invention relates to compounds of formula I: in which A 1 -A 7 and R 1 to R 5 are defined herein, for use in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). The invention also relates to pharmaceutical compounds comprising such compounds, and related methods of treatment. In an aspect, the invention relates to a method of screening compounds for therapeutic potential in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). Aspects of the invention relate to novel compounds of formula I in which at least one of A 1 to A 3 is or at least one of A 4 is CR 12 or A 5 is CR 13 in which R 12 /R 13 is halogen.
• [EN] SYNTHETIC RETINOIDS FOR USE IN RAR ACTIVATION<br/>[FR] RÉTINOÏDES SYNTHÉTIQUES DESTINÉS À ÊTRE UTILISÉS DANS L'ACTIVATION DE RAR
  申请人：UNIV DURHAM

  公开号：WO2020183173A2

  公开（公告）日：2020-09-17

  The present invention relates to compounds of formula I: in which A1-A7 and R1 to R5 are defined herein, for use in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). The invention also relates to pharmaceutical compounds comprising such compounds, and related methods of treatment. In an aspect, the invention relates to a method of screening compounds for therapeutic potential in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR). Aspects of the invention relate to novel compounds of formula I in which at least one of A1 to A3 is N or at least one of A4 is CR12 or A5 is CR13 in which R12/R13 is halogen.