diethyl 2-acetamido-2-(2-(2-bromoethyl)benzyl)malonate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: diethyl 2-acetamido-2-(2-(2-bromoethyl)benzyl)malonate
• 英文别名: ethyl 3-[2-(2-bromoethyl)phenyl]-2-acetamido-2-carboethoxypropanoate；diethyl 2-acetamido-2-[[2-(2-bromoethyl)phenyl]methyl]propanedioate
• 化学式: C₁₈H₂₄BrNO₅
• 分子量: 414.296
• InChiKey: QSCWWIUZBJNDOQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  25
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  81.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  diethyl 2-acetamido-2-(2-(2-bromoethyl)benzyl)malonate 在 氢溴酸 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (RS)-2-amino-3-(2-(2-carboxyethyl)phenyl)propionic acid
  参考文献：
  名称：

  A New Phenylalanine Derivative Acts as an Antagonist at the AMPA Receptor GluA2 and Introduces Partial Domain Closure: Synthesis, Resolution, Pharmacology, and Crystal Structure

  摘要：

  In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (RS)-3h, showed micromolar affinity for GluA1(o). and GluA2(R)(o) receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (RS)-3h competitively antagonized GluA2(Q)(i) receptors. The X-ray structure of the active enantiomer (S)-3h in complex with GluA2-S1S2J showed a domain closure around 8 degrees. Even though the nitro and the carboxyethyl groups of (S)-3h were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (S)-3h induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands.

  DOI：

  10.1021/jm200862h
• 作为产物：
  描述：

  异色满 在 氢溴酸 、 sodium hydride 作用下， 以 溶剂黄146 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 34.5h， 生成 diethyl 2-acetamido-2-(2-(2-bromoethyl)benzyl)malonate
  参考文献：
  名称：

  A New Phenylalanine Derivative Acts as an Antagonist at the AMPA Receptor GluA2 and Introduces Partial Domain Closure: Synthesis, Resolution, Pharmacology, and Crystal Structure

  摘要：

  In order to map out molecular determinants for competitive blockade of AMPA receptor subtypes, a series of 2-carboxyethylphenylalanine derivatives has been synthesized and pharmacologically characterized in vitro. One compound in this series, (RS)-3h, showed micromolar affinity for GluA1(o). and GluA2(R)(o) receptors with an approximately 4-fold preference for GluA1/2 vs GluA3/4. In TEVC electrophysiological experiments (RS)-3h competitively antagonized GluA2(Q)(i) receptors. The X-ray structure of the active enantiomer (S)-3h in complex with GluA2-S1S2J showed a domain closure around 8 degrees. Even though the nitro and the carboxyethyl groups of (S)-3h were both anchored to Tyr702 through a water H-bond network, these interactions only induced weak subtype selectivity. In spite of the fact that (S)-3h induced a domain closure close to that observed for partial agonists, it did not produce agonist responses at GluA2 receptors under nondesensitizing conditions. 2-Carboxyethylphenylalanine derivatives provide a new synthetic scaffold for the introduction of substituents that could lead to AMPA receptor subtype-selective ligands.

  DOI：

  10.1021/jm200862h

文献信息

• Antagonists of specific excitatory amino acid neurotransmitter receptors
  申请人：Nova Pharmaceutical Corporation

  公开号：US04657899A1

  公开（公告）日：1987-04-14

  The invention pertains to novel, potent anticonvulsants, analgesics and cognition enhancers achieving their action through the antagonism of specific excitatory amino acid neurotransmitter receptors. In particular, the invention is directed to .omega.-[2-phosphonoalkyleneyl)phenyl]-2-aminoalkanoic acids having general formula: ##STR1## Wherein R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of hydrogen, lower alkyl, halogen, --CH.dbd.CH--CH.dbd.CH.dbd., amino, nitro, trifluoromethyl or cyano; n and m=0, 1, 2, or 3; and the pharmaceutically acceptable salts and derivatives thereof. Examples of specific preferred compounds of general formula are selected from the group consisting of: 4-[2-phosphonomethylphenyl]-2-aminobutanoic acid, ethyl 3-[2-(2-diethylphosphonoethyl)phenyl]-2-acetamido-2-carboethoxypropanoate, 3-[2-(2-phosphonomethyl)phenyl]-2-aminopropanoic acid, ethyl 3-[2-(3-bromopropyl)phenyl]-2-acetamido-3-carboethoxypropanoate, ethyl 3-[2-(3-diethylphosphonopropyl)phenyl]-2-acetamido-2-carboethoxypropanoate , ethyl 3-[2-(3-phosphonopropyl)-phenyl]-2-aminopropanoic acid, ethyl 5-[2-(diethylphosphonomethyl)-phenyl]-2-acetamido-2-carboethoxypentanoate, and 5-[2-phosphonomethylphenyl]-2-aminopentanoic acid.

  该发明涉及新型、有效的抗癫痫药、镇痛药和认知增强剂，通过拮抗特定的兴奋性氨基酸神经递质受体来发挥作用。具体来说，该发明涉及具有一般化学式的.ω.-[2-磷酸烷基)苯基]-2-氨基烷酸：其中R.sub.1和R.sub.2相同或不同，选自氢、较低烷基、卤素、--CH.dbd.CH--CH.dbd.CH.dbd.、氨基、硝基、三氟甲基或氰基的群体；n和m=0、1、2或3；以及其药学上可接受的盐和衍生物。一般式的具体优选化合物示例选自以下群体：4-[2-磷酸甲基苯基]-2-氨基丁酸、乙基3-[2-(2-二乙基磷酸乙基)苯基]-2-乙酰氨基-2-羧乙酸乙酯、3-[2-(2-磷酸甲基)苯基]-2-氨基丙酸、乙基3-[2-(3-溴丙基)苯基]-2-乙酰氨基-3-羧乙酸乙酯、乙基3-[2-(3-二乙基磷酸丙基)苯基]-2-乙酰氨基-2-羧乙酸乙酯、乙基3-[2-(3-磷酸丙基)-苯基]-2-氨基丙酸、乙基5-[2-(二乙基磷酸甲基)-苯基]-2-乙酰氨基-2-羧乙氧基戊酸酯和5-[2-磷酸甲基苯基]-2-氨基戊酸。
• RZESZOTARSKI, WACLAW J.;HUDKINS, ROBERT L.;GUZEWSKA, MARIA E.
  作者：RZESZOTARSKI, WACLAW J.、HUDKINS, ROBERT L.、GUZEWSKA, MARIA E.

  DOI：——

  日期：——
• US4657899A
  申请人：——

  公开号：US4657899A

  公开（公告）日：1987-04-14
• US4761405A
  申请人：——

  公开号：US4761405A

  公开（公告）日：1988-08-02
• [EN] ANTAGONISTS OF SPECIFIC EXCITATORY AMINO ACID NEUROTRANSMITTER RECEPTORS
  申请人：RZESZOTARSKI, Janusz, Waclaw

  公开号：WO1987006131A1

  公开（公告）日：1987-10-22

  (EN) Novel, potent anticonvulsants, analgesics and cognition enhancers achieving their action through the antagonism of specific excitatory amino acid neurotransmitter receptors. In particular, the invention is directed to $g(v)-[2-(phosphonoalkylenyl)phenyl]-2-aminoalkanoic acids having general formula (I), wherein R1 and R2 are the same or different and are selected from the group consisting of hydrogen, lower alkyl, halogen, -CH=CH-CH=CH=, amino, nitro, trifluoromethyl or cyano; n and m = 0, 1, 2 or 3; and the pharmaceutically acceptable salts and derivatives thereof. Examples of specific preferred compounds of general formula are selected from the group consisting of: 4-[2-phosphonomethylphenyl]-2-aminobutanoic acid, ethyl 3-[2-(2-diethylphosphonoethyl)phenyl]-2-acetamido-2-carboethoxypropanoate, 3-[2-(phosphonomethyl)phenyl]-2-aminopropanoic acid, ethyl 3-[2-(3-bromopropyl)phenyl]-2-acetamido-3-carboethoxypropanoate, ethyl 3-[2-(3-diethylphosphonopropyl)phenyl]-2-acetamido-2-carboethoxypropanoate, ethyl 3-[2-(3-phosphonopropyl)-phenyl]-2-aminopropanoic acid, ethyl 5-[2-(diethylphosphonomethyl)-phenyl]-2- acetamido-2-carboethoxypentanoate, and 5-[2-phosphonomethylphenyl]-2-aminopentanoic acid.(FR) L'invention concerne de nouveaux anticonvulsants, analgésiques et agents d'amélioration de cognition puissants qui agissent par l'antagonisme de récepteurs neurotransmetteurs d'acides aminés d'excitation spécifiques. En particulier l'invention concerne les acides $g(v) de phosphonoalkylphényle d'aminoalcaloïques ayant la formule générale (I) où R1 et R2 sont les mêmes ou différents, et sont choisis dans le groupe composé d'hydrogène, alkyle inférieur, halogène, -CH=CH-CH=CH=, amino, nitro, trifluorométhyle ou cyano; n et m égalent 0, 1, 2 ou 3; et leurs sels et dérivés pharmaceutiquement acceptables. Des exemples de composés préférés spécifiques de formule générale sont choisis dans le groupe composé de 4-¨AD2-phosphonométhylphényle¨BD-2-acide aminobutanoïque, éthyle 3-¨AD2-(2-(2-diéthylphosphonéthyle)phényle¨BD-2-acétamido-2-carboéthoxypropanoate, 3-¨AD2-phosphonométhyle)phényle¨BD-2-acide aminopropanoïque, éthyle 3-¨AD2-(3-bromopropyle)phényle¨BD-2-acétamido-3-carboéthoxypropanoate, éthyle 3-¨AD2-(3-diéthylphosphonopropyle)phényle¨BD-2-acétamido-2-carboéthoxypropanoate, éthyle 3-¨AD2-(3-phosphonopropyl)-phényle¨BD-2-acide aminopropanoïque, éthyle 5-¨AD2-(diéthylphosphonométhyle)-phényle¨BD-2-acétamido-2-carboéthoxypentanoate, et 5-¨AD2-phosphonométhylphényle¨BD-2-acide aminopentanoïque.