ethyl (3-chloro-2(R)-hydroxypropyl)benzylphosphinate | 139668-40-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl (3-chloro-2(R)-hydroxypropyl)benzylphosphinate
• 英文别名: (2R)-3-chloro-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester；(2R)-1-[benzyl(ethoxy)phosphoryl]-3-chloropropan-2-ol
• CAS: 139668-40-9
• 化学式: C₁₂H₁₈ClO₃P
• 分子量: 276.7
• InChiKey: BEUJIYDGMCASAZ-WHUIICBVSA-N

物化性质

• 沸点：
  401.0±55.0 °C(Predicted)
• 密度：
  1.213±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl (3-chloro-2(R)-hydroxypropyl)benzylphosphinate 在 氨 作用下， 以 乙醇 为溶剂， 反应 4.0h， 生成 ethyl (3-amino-2(S)-hydroxypropyl)benzylphosphinate
  参考文献：
  名称：

  Phosphinic Acid Analogs of GABA. 2. Selective, Orally Active GABAB Antagonists

  摘要：

  In 1987, 25 years after the synthesis of the potent and selective GABA(B) agonist baclofen (1), Kerr et al.(5) described the first GABA(B) antagonist phaclofen 2. However, phaclofen and structurally similar derivatives 3-5 did not cross the blood-brain barrier and hence were inactive in vivo as central nervous system agents. As a consequence, the therapeutic potential of GABA(B) antagonists remained unclear. In exploring GABA and baclofen derivatives by replacing the carboxylic acid residue with various phosphinic acid groups, we discovered more potent and water soluble GABA(B) antagonists. Electrophysiological experiments in vivo demonstrated that some of the new compounds were capable of penetrating the blood-brain barrier after oral administration. Neurotransmitter release experiments showed that they interacted with several presynaptic GABA(B) receptor subtypes, enhancing the release of GABA, glutamate, aspartate, and somatostatin. The new GABA(B) antagonists interacted also with postsynaptic GABA(B) receptors, as they blocked late inhibitory postsynaptic potentials. They facilitated the induction of long-term potentiation in vitro and in, vivo, suggesting potential cognition enhancing effects. Fifteen compounds were investigated in Various memory and learning paradigms in rodents. Although several compounds were found to be active, only 10 reversed the age-related deficits of old rats in a multiple-trial one-way active avoidance test after chronic treatment. The cognition facilitating effects of 10 were confirmed in learning experiments in Rhesus monkeys. The novel GABA(B) antagonists showed also protective effects in various animal models of absence epilepsy.

  DOI：

  10.1021/jm00017a016
• 作为产物：
  描述：

  Benzyl-((R)-3-chloro-2-trimethylsilanyloxy-propyl)-phosphinic acid ethyl ester 在 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 24.0h， 生成 ethyl (3-chloro-2(R)-hydroxypropyl)benzylphosphinate
  参考文献：
  名称：

  Phosphinic Acid Analogs of GABA. 2. Selective, Orally Active GABAB Antagonists

  摘要：

  In 1987, 25 years after the synthesis of the potent and selective GABA(B) agonist baclofen (1), Kerr et al.(5) described the first GABA(B) antagonist phaclofen 2. However, phaclofen and structurally similar derivatives 3-5 did not cross the blood-brain barrier and hence were inactive in vivo as central nervous system agents. As a consequence, the therapeutic potential of GABA(B) antagonists remained unclear. In exploring GABA and baclofen derivatives by replacing the carboxylic acid residue with various phosphinic acid groups, we discovered more potent and water soluble GABA(B) antagonists. Electrophysiological experiments in vivo demonstrated that some of the new compounds were capable of penetrating the blood-brain barrier after oral administration. Neurotransmitter release experiments showed that they interacted with several presynaptic GABA(B) receptor subtypes, enhancing the release of GABA, glutamate, aspartate, and somatostatin. The new GABA(B) antagonists interacted also with postsynaptic GABA(B) receptors, as they blocked late inhibitory postsynaptic potentials. They facilitated the induction of long-term potentiation in vitro and in, vivo, suggesting potential cognition enhancing effects. Fifteen compounds were investigated in Various memory and learning paradigms in rodents. Although several compounds were found to be active, only 10 reversed the age-related deficits of old rats in a multiple-trial one-way active avoidance test after chronic treatment. The cognition facilitating effects of 10 were confirmed in learning experiments in Rhesus monkeys. The novel GABA(B) antagonists showed also protective effects in various animal models of absence epilepsy.

  DOI：

  10.1021/jm00017a016

文献信息

• Certain N-substituted-amino-alkane phosphinic acid derivatives having
  申请人：Ciba-Geigy Corporation

  公开号：US05229379A1

  公开（公告）日：1993-07-20

  Compounds having GABA.sub.B -antagonistic properties, for example those of formula I ##STR1## wherein one of the radicals R.sub.1, R.sub.2 and R.sub.3 is hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, another is hydrogen or, in the case of R.sub.1 or R.sub.2, hydroxy or, in the case of R.sub.1, halogen or, in the case of R.sub.2 together with R.sub.2 ', oxo, and the remaining radical is hydrogen, R.sub.1 ' is hydrogen or halogen, R.sub.2 ' is hydrogen, hydroxy or, together with R.sub.2, is oxo, R.sub.4 and R.sub.5 are hydrogen or R.sub.4 is an araliphatic or heteroarylaliphatic radical and R.sub.5 is hydrogen or an aliphatic radical, and R is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, heteroarylaliphatic or aromatic radical having at least 2 carbon atoms or, when R.sub.1 is hydrogen or hydroxy, R.sub.2 is an aromatic radical and R.sub.1 ', R.sub.2 ' and R.sub.3 are hydrogen, R is methyl, and their pharmaceutically acceptable salts, can be used as active ingredients in medicaments for the treatment of epilepsies of the "petit mal" type. The invention relates also to novel compounds of formula I and processes for the preparation thereof.

  具有GABA.sub.B-拮抗性质的化合物，例如具有以下式I的化合物##STR1##其中R.sub.1、R.sub.2和R.sub.3中的一个是氢或脂肪族、环脂族、芳基脂肪族或芳香族基团，另一个是氢或在R.sub.1或R.sub.2的情况下是羟基或在R.sub.1的情况下是卤素或在R.sub.2与R.sub.2'一起是氧代基，其余基团是氢，R.sub.1'是氢或卤素，R.sub.2'是氢、羟基或与R.sub.2一起是氧代基，R.sub.4和R.sub.5是氢或R.sub.4是芳基脂肪族或杂环芳基脂肪族基团，R.sub.5是氢或脂肪族基团，R是至少有2个碳原子的脂肪族、环脂族、环脂族-脂肪族、芳基脂肪族、杂环芳基脂肪族或芳香族基团，当R.sub.1是氢或羟基时，R.sub.2是芳香族基团，且R.sub.1'、R.sub.2'和R.sub.3是氢时，R是甲基，以及它们的药学上可接受的盐，可用作治疗“小发作”型癫痫的药物中的活性成分。该发明还涉及具有式I的新化合物以及其制备方法。
• N-substituted aminoalkanephosphinic acid derivatives, compositions
  申请人：Ciba-Geigy Corporation

  公开号：US05545631A1

  公开（公告）日：1996-08-13

  Compounds having GABA.sub.B -antagonistic properties, for example those of formula I ##STR1## wherein one of the radicals R.sub.1, R.sub.2 and R.sub.3 is hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, another is hydrogen or, in the case of R.sub.1 or R.sub.2, hydroxy or, in the case of R.sub.1, halogen or, in the case of R.sub.2 together with R.sub.2 ', oxo, and the remaining radical is hydrogen, R.sub.1 ' is hydrogen or halogen, R.sub.2 ' is hydrogen, hydroxy or, together with R.sub.2, is oxo, R.sub.4 and R.sub.5 are hydrogen or R.sub.4 is an araliphatic or heteroarylaliphatic radical and R.sub.5 is hydrogen or an aliphatic radical, and R is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, heteroarylaliphatic or aromatic radical having at least 2 carbon atoms or, when R.sub.1 is hydrogen or hydroxy, R.sub.2 is an aromatic radical and R.sub.1 ', R.sub.2 ' and R.sub.3 are hydrogen. R is methyl, and their pharmaceutically acceptable salts, can be used as active ingredients in medicaments for the treatment of epilepsies of the "petit mal" type. The invention relates also to novel compounds of formula I and processes for the preparation thereof.

  具有GABA.sub.B-拮抗作用的化合物，例如式I的化合物##STR1## 其中R.sub.1，R.sub.2和R.sub.3中的一个是氢或脂肪族，环脂肪族，芳基脂肪族或芳香族基，另一个是氢或，在R.sub.1或R.sub.2的情况下，羟基或，在R.sub.1的情况下，卤素或，在R.sub.2与R.sub.2'的情况下，是氧代，其余基团是氢，R.sub.1'是氢或卤素，R.sub.2'是氢，羟基或与R.sub.2一起是氧代，R.sub.4和R.sub.5是氢或R.sub.4是芳基脂肪族或杂环芳基脂肪族基，R.sub.5是氢或脂肪族基，R是至少具有2个碳原子的脂肪族，环脂肪族，环脂肪族-脂肪族，芳基脂肪族，杂环芳基脂肪族或芳香族基，当R.sub.1为氢或羟基时，R.sub.2是芳基基团，R.sub.1'，R.sub.2'和R.sub.3为氢。其中R为甲基，以及它们的药学上可接受的盐，可用作治疗“小发作”型癫痫的药物的活性成分。本发明还涉及式I的新化合物及其制备方法。
• Neue Aminoalkanphosphinsäuren und ihre Salze
  申请人：CIBA-GEIGY AG

  公开号：EP0543780A2

  公开（公告）日：1993-05-26

  Verbindungen der Formel I worin R Butyl, R1 Wasserstoff, R2 3,4-Dichlorbenzyl, 1-(4-Chlorphenyl)ethyl- oder 1-(3,4-Dichlor)phenethyl und R3 Wasserstoff bedeutet oder R Diethoxymethyl, R1 Wasserstoff und R2 2,6- oder 3,5-Dichlorbenzyl, Pyrid-3-ylmethyl, 1-(4-Methoxyphenyl)ethyl, 1-(4-Chlor-3-jod-phenyl)ethyl oder 1-(3-Chlor-4-jod-phenyl)ethyl oder R1 Hydroxy und R2 3,4-Dichlorbenzyl, 1-(3-Chlor-4-jod-phenyl)ethyl, 1-(4-Chlor-3-jod-phenyl)ethyl oder 1-(3,4-Dichlorphenyl)ethyl und R3 Wasserstoff bedeutet oder R Cyclohexylmethyl, R1 Wasserstoff und R2 3,5-Dichlorbenzyl, Chinolin-4-ylmethyl, 1-(3-Chlorphenyl)-ethyl, oder 1-(3,4,5-Trimethoxyphenyl)ethyl oder R1 Hydroxy und R2 3,4-Dimethylbenzyl, 3,4-Methylendioxybenzyl, 1-(3-Chlorphenyl)ethyl, 1-(3,4-Dichlorphenyl)ethyl, 1-(3-Chlor-4-jod-phenyl)ethyl, 1-(4-Chlor-3-jod-phenyl)ethyl, 1-(2,4-Dimethoxyphenyl)ethyl, 1-(2,5-Dimethoxyphenyl)ethyl, 1-(2,6-Dimethoxyphenyl)ethyl, 1-(3,4-Dimethoxyphenyl)ethyl, 1-(3,4-Methylendioxyphenyl)ethyl, 1-(3,5-Dimethoxyphenyl)ethyl, 1-(3,4,5-Trimethoxy)phenethyl,3-Phenylprop-2-yl, 2-(3,4-Dichlorphenyl)propyl 2-(3,4-Dichlorphenyl)propyl, 3-(3,4-Dichlorphenyl)prop-2-yl oder 3-Phenyl-3-hydroxy -prop-2-yl und R3 Wasserstoff bedeutet oder R Cyclohexylmethyl, R1 Wasserstoff, R2 4-Chlorbenzyl und R3 Methyl bedeutet oder R Cylohex-3-enylmethyl, R1 (S)-Hydroxy, R2 1(S)-(3,4-Dichlorphenyl)ethyl und R3 Wasserstoff bedeutet oder R Benzyl, R1 Hydroxy, R2 a-Cyclopropyl-3,4-dichlor-benzyl, 3,4,5-Trimethoxybenzyl, 1-(3,5-Dimethoxyphenyl)ethyl, 1-(3,4-Dichlorphenyl)ethyl, 2-(3,4-Dichlorphenyl)ethyl, 1-(3-Chlor-4-jod- phenyl)ethyl, 1-(3,4-Dichlorphenyl)-2-hydroxy-ethyl, 2-(3,4-Dichlorphenyl)-2-hydroxy-ethyl, 1-(2,4-Dimethoxyphenyl)ethyl, 1-(2,5-Dimethoxyphenyl)ethyl, 1-(2,6-Dimethoxyphenyl)ethyl, 1-(3,4-Dimethoxyphenyl)ethyl, 1-(3,4-Methylendioxyphenyl)ethyl, 1-(3,4,5-Trimethoxyphenyl)ethyl, 3-Phenylprop-2-yl, 3-Phenyl-3-hydroxy-prop -2-yl, 1-, 2- oder 3-(3,4-Dichlorphenyl)propyl, 3-(3,4-Dichlorphenyl)prop-2-yl, 3-(3,4-Dichlorphenyl)-3-hydroxy-prop-2-yl oder 4-(3,4-Dichlorphenyl)butyl und R3 Wasserstoff bedeutet, oder R 4-Chlorbenzyl, 4-Methylbenzyl, 4-Methoxybenzyl oder Cyclohex-3-enmethyl bedeutet und R1' R2 und R3 Wasserstoff darstellen, und ihre Salze besitzen GABAB-antagonistische Eigenschaften und können zur Behandlung von auf GABAB-Antagonisten ansprechenden Erkrankungen verwendet werden.

  式 I 的化合物 其中 R 是丁基，R1 是氢，R2 是 3,4-二氯苄基、1-(4-氯苯基)乙基或 1-(3,4-二氯)苯乙基，R3 是氢，或 R 是二乙氧基甲基，R1 是氢，R2 是 2、6-或 3,5-二氯苄基、吡啶-3-基甲基、1-(4-甲氧基苯基)乙基、1-(4-氯-3-碘苯基)乙基或 1-(3-氯-4-碘苯基)乙基，或 R1 是羟基，R2 是 3、4-二氯苄基、1-(3-氯-4-碘苯基)乙基、1-(4-氯-3-碘苯基)乙基或 1-(3,4-二氯苯基)乙基且 R3 为氢或 R 为环己基甲基，R1 为氢且 R2 为 3,5-二氯苄基、喹啉-4-基甲基、1-(3-氯苯基)乙基或 1-(3,4、5-三甲氧基苯基)乙基，或 R1 是羟基，R2 是 3,4-二甲基苄基、3,4-亚甲二氧基苄基、1-(3-氯苯基)乙基、1-(3,4-二氯苯基)乙基、1-(3-氯-4-碘苯基)乙基、1-(4-氯-3-碘苯基)乙基、1-(2,4-二甲氧基苯基)乙基、1-(2,5-二甲氧基苯基)乙基、1-(2,6-二甲氧基苯基)乙基、1-(3、1-(2,5-二甲氧基苯基)乙基、1-(2,6-二甲氧基苯基)乙基、1-(3,4-二甲氧基苯基)乙基、1-(4-二甲氧基苯基)乙基、1-(3,4,5-三甲氧基苯基)乙基、3-苯基丙-2-基、2-(3、2-(3,4-二氯苯基)丙基、3-(3,4-二氯苯基)丙-2-基或 3-苯基-3-羟基-丙-2-基，R3 为氢或 R 为环己基甲基、R1 是氢，R2 是 4-氯苄基，R3 是甲基，或 R 是环己-3-烯基甲基，R1 是 (S)-羟基，R2 是 1(S)-(3,4-二氯苯基)乙基，R3 是氢，或 R 是苄基，R1 是羟基，R2 是 a-环丙基-3,4-二氯苄基、3,4,5-三甲氧基苄基、1-(3,5-二甲氧基苯基)乙基、1-(3、(3,4-二氯苯基)乙基、2-(3,4-二氯苯基)乙基、1-(3-氯-4-碘苯基)乙基、1-(3,4-二氯苯基)-2-羟基乙基、2-(3、1-(2,4-二甲氧基苯基)乙基、1-(2,5-二甲氧基苯基)乙基、1-(2,6-二甲氧基苯基)乙基、1-(3,4-二甲氧基苯基)乙基、1-(3、1-(3,4,5-三甲氧基苯基)乙基、3-苯基丙-2-基、3-苯基-3-羟基丙-2-基、1-、2-或 3-(3,4-二氯苯基)丙基、3-(3,4-二氯苯基)丙-2-基、3-(3,4-二氯苯基)-3-羟基丙-2-基或 4-(3,4-二氯苯基)丁基，且 R3 为氢、或 R 是 4-氯苄基、4-甲基苄基、4-甲氧基苄基或环己-3-烯甲基，R1' R2 和 R3 是氢，它们的盐具有 GABAB 拮抗特性，可用于治疗 GABAB 拮抗剂反应性疾病。
• US5229379A
  申请人：——

  公开号：US5229379A

  公开（公告）日：1993-07-20
• US5376684A
  申请人：——

  公开号：US5376684A

  公开（公告）日：1994-12-27