[4-[(Tetrahydro-2H-pyran2-yl)oxy]-1-butynyl]-phosphonic acid, diethyl ester | 148665-72-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: [4-[(Tetrahydro-2H-pyran2-yl)oxy]-1-butynyl]-phosphonic acid, diethyl ester
• 英文别名: 2-(4-diethoxyphosphorylbut-3-ynoxy)oxane
• CAS: 148665-72-9
• 化学式: C₁₃H₂₃O₅P
• 分子量: 290.296
• InChiKey: HQPWGSFDRMJVJA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  54
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [4-[(Tetrahydro-2H-pyran2-yl)oxy]-1-butynyl]-phosphonic acid, diethyl ester 在 对甲苯磺酸 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 4-(diethoxyphosphinyl)-3-butynyl methanesulfonate
  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
• 作为产物：
  描述：

  2-(3-丁炔氧基)四水-2H-吡喃 、 氯磷酸二乙酯 在 正丁基锂 作用下， 生成 [4-[(Tetrahydro-2H-pyran2-yl)oxy]-1-butynyl]-phosphonic acid, diethyl ester
  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

• 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。
• 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