ethyl <3--2-oxopropyl>(cyclohexylmethyl)phosphinate | 133457-84-8

• 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: ethyl <3--2-oxopropyl>(cyclohexylmethyl)phosphinate
• 英文别名: ethyl 3-(N-tert.-butoxycarbonylamino)-2-oxo-propyl(cyclohexylmethyl)phosphinate；ethyl-3-(N-tert-butoxycarbonylamino)-2-oxopropyl(cyclohexylmethyl)phosphinate；tert-butyl N-[3-[cyclohexylmethyl(ethoxy)phosphoryl]-2-oxopropyl]carbamate
• CAS: 133457-84-8
• 化学式: C₁₇H₃₂NO₅P
• 分子量: 361.419
• InChiKey: SSLKAXPLEJUNKN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.88
• 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：

  ethyl <3--2-oxopropyl>(cyclohexylmethyl)phosphinate 在 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以55%的产率得到(3-amino-2-oxopropyl)(cyclohexylmethyl)phosphinic acid hydrobromide
  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：

  P-(cyclohexylmethyl)phosphinic acid ethyl ester 在 sodium hydride 、 lithium diisopropyl amide 作用下， 反应 28.25h， 生成 ethyl <3--2-oxopropyl>(cyclohexylmethyl)phosphinate
  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

• P-subsituted propane-phosphinic acid compounds
  申请人：Ciba-Geigy Corporation

  公开号：US05190934A1

  公开（公告）日：1993-03-02

  Compounds of the formula I ##STR1## wherein either R.sub.1 is halogen, R.sub.1 ' is halogen or hydrogen and R.sub.2 and R.sub.2 ' denote hydrogen or R.sub.1 and R.sub.1 ' represent hydrogen, R.sub.2 is an aliphatic or aromatic radical and R.sub.2 ' is hydroxy or R.sub.2 and R.sub.2 ' together represent oxo, and wherein R denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbon atoms or, if R.sub.1 and R.sub.1 ' denote hydrogen, R.sub.2 represents an aromatic radical and R.sub.2 ' is hydroxy, R represents methyl, and their salts are useful as nootropics, antidepressants and/or anxiolytics. The can be manufacture by replacing any group R.sub.5 by hydrogen and/or converting any group Z.sub.0 into amino in a compound of formula II ##STR2## in which R, R.sub.1, R.sub.1 ', R.sub.2 and R.sub.2 ' have their previous significances, Z represents a protected or latent amino group Z.sub.0 and R.sub.4 denotes hydrogen or a hyddroxy-protective group R.sub.5, and wherein amino as a constituent of R and/or hydroxy R.sub.2 ' or oxo R.sub.2 +R.sub.2 ' may be present in a temporarily protected form.

  式I的化合物##STR1##中，R.sub.1为卤素，R.sub.1'为卤素或氢，R.sub.2和R.sub.2'表示氢或R.sub.1和R.sub.1'代表氢，R.sub.2为脂肪族或芳香基团，R.sub.2'为羟基或R.sub.2和R.sub.2'一起表示羰基，其中R表示具有2个或更多碳原子的脂肪族、环脂肪族、环脂肪族-脂肪族或芳基脂肪族基团，或者如果R.sub.1和R.sub.1'表示氢，则R.sub.2表示芳香基团，R.sub.2'为羟基，R表示甲基，它们的盐可用作脑功能增强剂、抗抑郁剂和/或抗焦虑剂。可以通过将任何基团R.sub.5替换为氢和/或将任何基团Z.sub.0转化为氨基来制备，其中R、R.sub.1、R.sub.1'、R.sub.2和R.sub.2'具有其先前的含义，Z表示受保护或潜在的氨基团Z.sub.0，R.sub.4表示氢或羟基保护基团R.sub.5，氨基作为R的组分和/或羟基R.sub.2'或羰基R.sub.2+R.sub.2'可能以暂时受保护的形式存在于式II的化合物中##STR2##。
• P-substituted propane-phosphinic acid compounds
  申请人：CIBA-GEIGY AG

  公开号：EP0402312A2

  公开（公告）日：1990-12-12

  Compounds of the formula I wherein either R₁ is halogen, R₁′ is halogen or hydrogen and R₂ and R₂′ denote hydrogen or R₁ and R₁′ represent hydrogen, R₂ is an aliphatic or aromatic radical and R₂′ is hydroxy or R₂ and R₂′ together represent oxo, and wherein R denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbon atoms or, if R₁ and R₁′ denote hydrogen, R₂ represents an aromatic radical and R₂′ is hydroxy, R represents methyl, and their salts are useful as nootropics, antidepressants and/or anxiolytics. The can be manufacture by replacing any group R₅ by hydrogen and/or converting any group Z₀ into amino in a compound of formula II in which R, R₁, R₁′, R₂ and R₂′ have their previous significances, Z represents a protected or latent amino group Z₀ and R₄ denotes hydrogen or a hydroxy-protective group R₅, and wherein amino as a constituent of R and/or hydroxy R₂′ or oxo R₂ + R₂′ may be present in a temporarily protected form.

  式 I 的化合物 其中 R₁ 是卤素，R₁′ 是卤素或氢，R₂ 和 R₂′ 表示氢或 R₁ 和 R₁′ 表示氢、R₂ 是脂肪族或芳香族基，且 R₂′ 是羟基，或 R₂ 和 R₂′ 共同代表氧代，其中 R 表示脂肪族、如果 R₁ 和 R₁′ 表示氢、R₂ 表示芳香族基且 R₂′ 是羟基，则 R 表示甲基。在式 II 的化合物中，可以通过将任何基团 R₅ 替换为氢和/或将任何基团 Z₀ 转换为氨基来制造该化合物。 其中，R、R₁、R₁′、R₂和 R₂′ 具有它们以前的意义，Z 表示受保护或潜在的氨基 Z₀，R₄ 表示氢或羟基保护基团 R₅、其中氨基作为 R 和/或羟基 R₂′ 或氧代 R₂ + R₂′ 的组成成分，可以暂时受保护的形式存在。
• US5190934A
  申请人：——

  公开号：US5190934A

  公开（公告）日：1993-03-02
• Phosphinic Acid Analogs of GABA. 2. Selective, Orally Active GABAB Antagonists
  作者：Wolfgang Froestl、Stuart J. Mickel、Georg von Sprecher、Peter J. Diel、Roger G. Hall、Ludwig Maier、Dietrich Strub、Vito Melillo、Peter A. Baumann

  DOI：10.1021/jm00017a016

  日期：1995.8

  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.