苯乙酰腈,3-[(二乙氧基氧膦基)甲基]- | 140151-14-0

• 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: 苯乙酰腈,3-[(二乙氧基氧膦基)甲基]-
• 英文名称: diethyl <<3-(cyanomethyl)phenyl>methyl>phosphonate
• 英文别名: Diethyl[[3-(cyanomethyl)phenyl]methyl]phosphonate；2-[3-(diethoxyphosphorylmethyl)phenyl]acetonitrile
• CAS: 140151-14-0
• 化学式: C₁₃H₁₈NO₃P
• 分子量: 267.265
• InChiKey: ORBCHQTVHLKERL-UHFFFAOYSA-N

物化性质

• 沸点：
  411.7±33.0 °C(Predicted)
• 密度：
  1.138±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  18
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  59.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  苯乙酰腈,3-[(二乙氧基氧膦基)甲基]- 在 sodium tetrahydroborate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 ethyl <2-<3-<(diethoxyphosphinyl)methyl>phenyl>ethyl>carbamate
  参考文献：
  名称：

  N-甲基-D-天冬氨酸激动剂和竞争性拮抗剂药效团模型的产生。设计和合成膦酰基烷基取代的四氢异喹啉作为新型拮抗剂。

  摘要：

  描述了一系列四氢异喹啉羧酸在谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型上的制备和结合亲和力，以及对NMDA激动剂和拮抗剂的分子模型分析。使用公开的NMDA配体，在激动剂药效团模型的产生中采用了活性类似物作图方法。尽管可以将已知的竞争性拮抗剂（例如CPP（1））叠加到激动剂模型上，但要克服它们与相同受体位点结合的假设，可以使用独立的建模方法来得出单独的药效团模型。竞争性拮抗剂模型的开发涉及一种逐步方法，其中包括定义PO3H2受体相互作用的优选几何形状，多重构象搜索，以及确定体积和电子公差。对该模型进行了详细描述，与观察到的强效NMDA拮抗剂的亲和力一致，并为已知拮抗剂AP5，AP6和AP7的亲和力观察到的周期性提供了解释。比较了激动剂和拮抗剂模型的特征，并提出了关于这两类化合物的受体相互作用性质的假说。本文报道的药效基团模型与可容纳激动剂和拮抗剂配体的NMDA受体上的单个识别位点一致

  DOI：

  10.1021/jm00086a004
• 作为产物：
  描述：

  diethyl 3-(bromomethyl)benzylphosphonate 在 sodium iodide 作用下， 以 水 、 丙酮 为溶剂， 反应 0.5h， 生成 苯乙酰腈,3-[(二乙氧基氧膦基)甲基]-
  参考文献：
  名称：

  Exploration of N-phosphonoalkyl-, N-phosphonoalkenyl-, and N-(phosphonoalkyl)phenyl-spaced .alpha.-amino acids as competitive N-methyl-D-aspartic acid antagonists

  摘要：

  A series of N-substituted alpha-amino acids containing terminal phosphonic acid groups has been synthesized as potential N-methyl-D-aspartate (NMDA) receptor antagonists. NMDA receptor affinity was determined by displacement of a known ligand ([H-3]CPP) from crude rat brain synaptic membranes; an antagonist action was demonstrated by the inhibition of glutamate-induced accumulation of [Ca-45(2+)] in cultured rat cortical neurons. Receptor affinity was significantly correlated with antagonist activity (Figure 1). Moderate affinity (IC50 = 1-2-mu-M) was retained for analogues (31 and 32, Table 1; and 59 and 66, Table II) with reduced flexibility in their phosphonate side chains and is consistent with entropy playing a role in determining receptor affinity. Modeling studies suggest a folded conformation that brings the distal phosphonic acid group into close proximity with the alpha-carboxylate is required for binding. Each of the active analogues possess entropy-limiting features (double bonds, phenyl rings) in their side chains that allows the superposition of their key NH2, alpha-COOH, and distal PO3H2 groups with those of known competitive antagonists. Affinity decreased for analogues with alpha-carbon substitution, presumably because the alpha-substituent inhibits the folding of these structures into a bioactive conformation and occupies receptor-excluded volume. A complete description of the NMDA antagonist pharmacophore model is provided in a companion paper. 1

  DOI：

  10.1021/jm00086a005

文献信息

• Substituted carboxytetrahydroisoquinolines and derivatives thereof having pharmaceutical activity
  申请人：WARNER-LAMBERT COMPANY

  公开号：EP0421436A3

  公开（公告）日：1992-03-11

  The invention includes a novel series of substituted aryl or heteroaryl fused 2- or 6-carboxy piperidines and derivatives thereof which are useful in the treatment of cerebrovascular disorders, epilepsy, Huntington's disease, or as anesthetics particularly in surgical processes where a finite risk of cerebrovascular damage exists. Processes for making the compounds, novel intermediates useful in the processes, methods for using, and compositions containing the compounds are also included.

  这项发明涉及一种新颖的一系列取代芳基或杂环芳基融合的2-或6-羧基哌啶及其衍生物，这些化合物在治疗脑血管疾病、癫痫、亨廷顿病或作为麻醉剂特别是在存在有限脑血管损伤风险的手术过程中是有用的。制备这些化合物的方法、在制备过程中有用的新颖中间体、使用方法以及含有这些化合物的组合物也包括在内。
• N-substituted .alpha.-amino acids and derivatives thereof having
  申请人：Warner-Lambert Company

  公开号：US05179085A1

  公开（公告）日：1993-01-12

  N-substituted .alpha.-amino acids and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful in selectively blocking the N-methyl-D-aspartate (NMDA) excitatory amino acid receptors in mammals and also are useful in treating cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus and cerebral trauma as well as for treating schizophrenia, epilepsy, neurodegenerative disorders, Alzheimer's disease or Huntington's disease and also additionally useful as anesthetics in surgical procedures where a finite risk of cerebrovascular damage exists.

  本文介绍了N-取代的α-氨基酸及其衍生物，以及制备方法和药物组成物，这些物质在哺乳动物中选择性地阻断N-甲基-D-天门冬氨酸（NMDA）兴奋性氨基酸受体方面有用，也可用于治疗脑血管疾病，如由栓塞性或出血性中风引起的脑缺血或脑梗死、脑血管痉挛、低血糖、心脏停跳、持续性癫痫状态和脑外伤，以及治疗精神分裂症、癫痫、神经退行性疾病、阿尔茨海默病或亨廷顿病，并且还可作为麻醉剂用于存在有限脑血管损伤风险的外科手术中。
• US5179085A
  申请人：——

  公开号：US5179085A

  公开（公告）日：1993-01-12
• Exploration of N-phosphonoalkyl-, N-phosphonoalkenyl-, and N-(phosphonoalkyl)phenyl-spaced .alpha.-amino acids as competitive N-methyl-D-aspartic acid antagonists
  作者：Christopher F. Bigge、Graham Johnson、Daniel F. Ortwine、James T. Drummond、Daniel M. Retz、Laura J. Brahce、Linda L. Coughenour、Frank W. Marcoux、Albert W. Probert

  DOI：10.1021/jm00086a005

  日期：1992.4

  A series of N-substituted alpha-amino acids containing terminal phosphonic acid groups has been synthesized as potential N-methyl-D-aspartate (NMDA) receptor antagonists. NMDA receptor affinity was determined by displacement of a known ligand ([H-3]CPP) from crude rat brain synaptic membranes; an antagonist action was demonstrated by the inhibition of glutamate-induced accumulation of [Ca-45(2+)] in cultured rat cortical neurons. Receptor affinity was significantly correlated with antagonist activity (Figure 1). Moderate affinity (IC50 = 1-2-mu-M) was retained for analogues (31 and 32, Table 1; and 59 and 66, Table II) with reduced flexibility in their phosphonate side chains and is consistent with entropy playing a role in determining receptor affinity. Modeling studies suggest a folded conformation that brings the distal phosphonic acid group into close proximity with the alpha-carboxylate is required for binding. Each of the active analogues possess entropy-limiting features (double bonds, phenyl rings) in their side chains that allows the superposition of their key NH2, alpha-COOH, and distal PO3H2 groups with those of known competitive antagonists. Affinity decreased for analogues with alpha-carbon substitution, presumably because the alpha-substituent inhibits the folding of these structures into a bioactive conformation and occupies receptor-excluded volume. A complete description of the NMDA antagonist pharmacophore model is provided in a companion paper. 1
• Generation of N-methyl-D-aspartate agonist and competitive antagonist pharmacophore models. Design and synthesis of phosphonoalkyl-substituted tetrahydroisoquinolines as novel antagonists
  作者：Daniel F. Ortwine、Thomas C. Malone、Christopher F. Bigge、James T. Drummond、Christine Humblet、Graham Johnson、Garry W. Pinter

  DOI：10.1021/jm00086a004

  日期：1992.4

  The preparation and binding affinity of a series of tetrahydroisoquinoline carboxylic acids at the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is described, together with a molecular modeling analysis of NMDA agonists and antagonists. Using published NMDA ligands, the active analogue mapping approach was employed in the generation of an agonist pharmacophore model. Although known

  描述了一系列四氢异喹啉羧酸在谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型上的制备和结合亲和力，以及对NMDA激动剂和拮抗剂的分子模型分析。使用公开的NMDA配体，在激动剂药效团模型的产生中采用了活性类似物作图方法。尽管可以将已知的竞争性拮抗剂（例如CPP（1））叠加到激动剂模型上，但要克服它们与相同受体位点结合的假设，可以使用独立的建模方法来得出单独的药效团模型。竞争性拮抗剂模型的开发涉及一种逐步方法，其中包括定义PO3H2受体相互作用的优选几何形状，多重构象搜索，以及确定体积和电子公差。对该模型进行了详细描述，与观察到的强效NMDA拮抗剂的亲和力一致，并为已知拮抗剂AP5，AP6和AP7的亲和力观察到的周期性提供了解释。比较了激动剂和拮抗剂模型的特征，并提出了关于这两类化合物的受体相互作用性质的假说。本文报道的药效基团模型与可容纳激动剂和拮抗剂配体的NMDA受体上的单个识别位点一致