2-amino-4-(2-phosphonomethylphenyl)butyric acid | 95306-99-3

• 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: 2-amino-4-(2-phosphonomethylphenyl)butyric acid
• 英文别名: 4-[2-phosphonomethylphenyl]-2-aminobutanoic acid；2-amino-4-[2-(phosphonomethyl)phenyl]butanoic acid
• CAS: 95306-99-3
• 化学式: C₁₁H₁₆NO₅P
• 分子量: 273.226
• InChiKey: CEKBDCFPGSKRFK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  121
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(2-溴乙基)-2-(溴甲基)苯 在 盐酸 、 碳酸二乙酯 作用下， 反应 33.0h， 生成 2-amino-4-(2-phosphonomethylphenyl)butyric acid
  参考文献：
  名称：

  Structural modification of bioactive compounds. II. Syntheses of aminophosphonoic acids.

  摘要：

  为了开发对神经递质具有选择性阻断作用的拮抗剂，合成了几种氨基膦酸，包括2-氨基-5-膦酸戊酸（IVb）、2-氨基-4-（2-膦甲基苯基）丁酸（VIII）、2-（2-氨基-2-羧基）乙基苯膦酸（XIc）和N-苄基脯氨酸-4-膦酸（XIX）。化合物IVb、VIII和XIc是通过相应的卤化物（分别为V、Xa和XIa）与二乙基乙酰胺基丙二酸钠（VI）反应制备的。化合物XIX是通过乙基N-苄基-N-苯硫甲基甘氨酸酯（XV）与二乙基乙烯基膦酸酯（XVI）的1, 3-偶极环加成反应合成的。

  DOI：

  10.1248/cpb.32.3918

文献信息

• Exploration of phenyl-spaced 2-amino-(5-9)-phosphonoalkanoic acids as competitive N-methyl-D-aspartic acid antagonists
  作者：Christopher F. Bigge、James T. Drummond、Graham Johnson、Thomas Malone、Albert W. Probert、Frank W. Marcoux、Linda L. Coughenour、Laura J. Brahce

  DOI：10.1021/jm00127a030

  日期：1989.7

  To investigate the preferred spatial relationship of the distal phosphonic acid to the alpha-amino acid group of the established competitive N-methyl-D-aspartic acid (NMDA) antagonists APH (1) and APV (2), we have prepared a series of ortho-, meta-, and para-substituted (phosphonoalkyl)phenylglycine and -phenylalanine derivatives. With use of a [3H]CPP receptor binding assay, significant binding activity

  为了研究末端膦酸与已建立的竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂APH（1）和APV（2）的α-氨基酸之间的优选空间关系，我们制备了一系列邻，间和对位取代的（膦酰基烷基）苯基甘氨酸和-苯丙氨酸衍生物。使用[3H] CPP受体结合测定法，观察到显着的结合活性关键取决于取代位置和烷基间隔基团的长度。4-（膦酰基甲基）-苯基甘氨酸（6，PD 129635）和3-（膦酰基甲基）苯丙氨酸（15，PD 130527）这两种化合物显示出与APH相当的受体结合亲和力。像APH一样，这些化合物也可有效拮抗NMDA给药的后球在小鼠中的惊厥作用和致死作用。还提供了将这些化合物与最近公开的有关NMDA拮抗剂18（NPC 451）的结合功效直接进行比较的数据。对显示出良好的受体结合亲和力和体内拮抗剂活性的结构进行初步比较表明，NMDA受体更喜欢“折叠”构象而不是“延伸”构象。
• 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.

  本发明涉及通过拮抗特定兴奋性氨基酸神经递质受体实现作用的新型、强效的抗惊厥剂、镇痛剂和认知增强剂。特别地，本发明涉及具有一般式的ω-[2-磷酸烷基)苯基]-2-氨基烷酸：##STR1##其中R.sub.1和R.sub.2相同或不同，选自氢、低级烷基、卤素、--CH.dbd.CH--CH.dbd.CH.dbd.、氨基、硝基、三氟甲基或氰基的群；n和m＝0、1、2或3；以及其药学上可接受的盐和衍生物。具体优选化合物的例子包括：4-[2-磷酸甲基苯基]-2-氨基丁酸、乙酰氨基-2-羧乙酸-3-[2-(2-二乙基磷酸乙基)苯基]-2-羧乙酯、3-[2-磷酸甲基苯基]-2-氨基丙酸、乙酰氨基-3-羧乙酸-3-[2-(3-溴丙基)苯基]-2-羧乙酯、乙酰氨基-2-羧乙酸-3-[2-(3-二乙基磷酸丙基)苯基]-2-羧乙酯、乙酰氨基-2-羧丙酸-3-[2-(3-磷酸丙基)苯基]-2-氨基丙酸、乙酰氨基-2-羧乙酸-5-[2-(二乙基磷酸甲基)苯基]-2-羧乙酯和5-[2-磷酸甲基苯基]-2-氨基戊酸。
• Phenyl glycines for use in reducing neurotoxic injury
  申请人：G.D. Searle & Co.

  公开号：EP0313002A2

  公开（公告）日：1989-04-26

  A class of phenyl glycine compounds is described for treatment to reduce neurotoxic injury associated with anoxia or ischemia which typically follows stroke, cardiac arrest or perinatal asphyxia. The treatment includes administration of a phenyl glycine compound alone or in a composition in an amount effective as an antagonist to inhibit excitotoxic actions at major neuronal excitatory amino acid receptor sites.

  描述了一类苯基甘氨酸化合物，用于治疗减少与缺氧或缺血有关的神经毒性损伤，缺氧或缺血通常发生在中风、心脏骤停或围产期窒息之后。治疗方法包括单独施用或在组合物中施用苯基甘氨酸化合物，施用量应能有效抑制主要神经元兴奋性氨基酸受体部位的兴奋毒性作用。
• Phosphono-hydroisoquinoline compounds useful in reducing neurotoxic injury
  申请人：G.D. Searle & Co.

  公开号：EP0364996A2

  公开（公告）日：1990-04-25

  A class of phosphono-hydroisoquinoline compounds is described for treatment to reduce neurotoxic injury associated with anoxia or ischemia which typically follows stroke, cardiac arrest or perinatal asphyxia. The treatment includes administration of a phosphono-hydroisoquinoline compound alone or in a composition in an amount effective as an antagonist to inhibit excitotoxic actions at major neuronal excitatory amino acid receptor sites. Compounds of most interest are those of Formula 1: wherein each of R' through R4 is hydrido, wherein each of Z1 and Z2 is hydroxyl, wherein W is a single bond connecting the phosphorus atom with the aromatic ring and wherein the A ring is aromatic. Also disclosed are two classes of intermediate compounds having a fully unsaturated A ring, which intermediate compounds are useful in methods to make product compounds of Formula I.

  描述了一类膦酰基氢化异喹啉化合物，用于治疗减少与缺氧或缺血相关的神经毒性损伤，缺氧或缺血通常发生在中风、心脏骤停或围产期窒息之后。治疗方法包括单独施用或在组合物中施用膦酰基氢化异喹啉化合物，施用量应能有效地作为拮抗剂抑制主要神经元兴奋性氨基酸受体部位的兴奋毒性作用。最令人感兴趣的化合物是式 1： 其中，R'到 R4 中的每一个都是氢基，Z1 和 Z2 中的每一个都是羟基，W 是连接磷原子和芳香环的单键，A 环是芳香环。还公开了两类具有完全不饱和 A 环的中间体化合物，这些中间体化合物在制造式 I 产品化合物的方法中是有用的。
• Imidazo[1,2-a]pyridinylalkyl compounds for treatment of neurotoxic injury
  申请人：G.D. Searle & Co.

  公开号：EP0436831A2

  公开（公告）日：1991-07-17

  A class of imidazo[1,2-a]pyridinylalkyl compounds is described for treatment to reduce neurotoxic injury associated with anoxia or ischemia which typically follows stroke, cardiac arrest or perinatal asphyxia. The treatment includes administration of a compound of this class alone or in a composition in an amount effective as an antagonist to inhibit excitotoxic actions at major neuronal excitatory amino acid receptor sites. Compounds of most interest are those of the formula: wherein each of R22, R23 and R24 is independently selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; wherein each of Ym and Yn is a spacer group independently selected methylene and ethylene radicals which may be unsubstituted and from methylene radicals which may be substituted with a group selected from halo, hydroxy and oxo; wherein each of m and n is a number independently selected from zero to two, inclusive; wherein each X and T is one or more groups independently selected from hydrido, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl and alkanoyl; or a pharmaceutically-acceptable salt thereof.

  描述了一类咪唑并[1,2-a]吡啶烷基化合物，用于治疗减少与缺氧或缺血相关的神经毒性损伤，这种损伤通常发生在中风、心脏骤停或围产期窒息之后。治疗方法包括单独施用或在组合物中施用该类化合物，施用量为有效的拮抗剂，以抑制主要神经元兴奋性氨基酸受体部位的兴奋毒性作用。最令人感兴趣的化合物是式中的化合物： 其中 R22、R23 和 R24 各自独立地选自肼、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基和环庚基；其中 Ym 和 Yn 各自是一个间隔基团，该间隔基团独立地选自可能未被取代的亚甲基和亚乙基，以及可能被选自卤代、羟基和氧代的基团取代的亚甲基；其中每个 m 和 n 是独立选自 0 至 2（包括 2）的数字；其中每个 X 和 T 是一个或多个独立选自氢基、烷基、环烷基、卤基、卤代烷基、羟基、羟基烷基、烷氧基、烷氧基烷基和烷酰基的基团；或其药学上可接受的盐。