ethyl 3-<1-(methoxycarbonyl)-4-piperidyl>-3-oxopropanoate | 167414-69-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: ethyl 3-<1-(methoxycarbonyl)-4-piperidyl>-3-oxopropanoate
• 英文别名: ethyl 3-(1-methoxycarbonyl-4-piperidyl)-3-oxopropionate；ethyl 4-(1-methoxycarbonyl-4-piperidyl)-3-oxopropionate；Methyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate
• CAS: 167414-69-9
• 化学式: C₁₂H₁₉NO₅
• 分子量: 257.287
• InChiKey: OWWHZBTZTMZZJJ-UHFFFAOYSA-N

物化性质

• 沸点：
  354.9±32.0 °C(Predicted)
• 密度：
  1.172±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 3-<1-(methoxycarbonyl)-4-piperidyl>-3-oxopropanoate 在 盐酸 、 ammonium hydroxide 、 硫化氢 、 碘 、 potassium carbonate 作用下， 以 乙醇 为溶剂， 反应 34.0h， 生成 5-<1-(methoxycarbonyl)-4-piperidyl>isothiazol-3-ol
  参考文献：
  名称：

  部分GABAA受体激动剂。一系列4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇的非环状类似物的合成及体外药理作用。

  摘要：

  5-（4-哌啶基）异恶唑-3-醇（4-PIOL，10），4-氨基丁酸（GABA，1）和GABAA激动剂4,5,6,7-四氢异恶唑的结构类似物[5,4 -c] pyridin-3-ol（THIP，5）是低效的部分GABAA激动剂。从10种生物立体异构体衍生的许多化合物，包括5-（4-哌啶基）异噻唑-3-醇（11），3-（4-哌啶基）异噻唑-5-醇（12），5-（1,2,3合成了1,6-四氢吡啶-4-基）异噻唑-3-醇（13）和5-（1,2,3,6-四氢吡啶-4-基）异噻唑-3-醇（14） GABAA受体配体。尽管这些化合物均未显着影响GABAB受体的结合或GABA的吸收，但它们在低微摩尔范围内显示出对GABAA受体位点的亲和力。使用培养的大脑皮层神经元和全细胞膜片钳技术，这些化合物相对于完整GABAA激动剂的功效，测定了异胍卡因（8）（20 microM）。11的相对功效比10（IC50 =

  DOI：

  10.1021/jm00017a014
• 作为产物：
  描述：

  1-(甲氧基羰基)哌啶-4-羧酸 在 氯化亚砜 、 三乙胺 、 magnesium chloride 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.33h， 生成 ethyl 3-<1-(methoxycarbonyl)-4-piperidyl>-3-oxopropanoate
  参考文献：
  名称：

  Novel Class of Potent 4-Arylalkyl Substituted 3-Isoxazolol GABA_A Antagonists:  Synthesis, Pharmacology, and Molecular Modeling

  摘要：

  A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K-i = 9.1 muM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K-i = 0.074 muM and K-i = 0.049 muM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC50 = 0.37 muM and IC50 = 0.02 muM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC50 = 0.24 muM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED50 = 0.024 mumol/kg) and 7s (ED50 = 0.21 mumol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity.

  DOI：

  10.1021/jm020027o

文献信息

• A Novel Class of Potent 3-Isoxazolol GABA_A Antagonists:  Design, Synthesis, and Pharmacology
  作者：Bente Frølund、Lena Tagmose、Tommy Liljefors、Tine Bryan Stensbøl、Christine Engblom、Uffe Kristiansen、Povl Krogsgaard-Larsen

  DOI：10.1021/jm000371q

  日期：2000.12.1
• Novel Class of Potent 4-Arylalkyl Substituted 3-Isoxazolol GABA_A Antagonists:  Synthesis, Pharmacology, and Molecular Modeling
  作者：Bente Frølund、Anne T. Jørgensen、Lena Tagmose、Tine B. Stensbøl、Henrik T. Vestergaard、Christine Engblom、Uffe Kristiansen、Connie Sanchez、Povl Krogsgaard-Larsen、Tommy Liljefors

  DOI：10.1021/jm020027o

  日期：2002.6.1

  A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K-i = 9.1 muM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K-i = 0.074 muM and K-i = 0.049 muM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC50 = 0.37 muM and IC50 = 0.02 muM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC50 = 0.24 muM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED50 = 0.024 mumol/kg) and 7s (ED50 = 0.21 mumol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity.
• Partial GABAA Receptor Agonists. Synthesis and in Vitro Pharmacology of a Series of Nonannulated Analogs of 4,5,6,7-Tetrahydroisoxazolo[4,5-c]pyridin-3-ol
  作者：Bente Frolund、Uffe Kristiansen、Lotte Brehm、Annette B. Hansen、Povl Krogsgaard-Larsen、Erik Falch

  DOI：10.1021/jm00017a014

  日期：1995.8

  5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAA agonist. A number of compounds bioisosterically derived from 10, including 5-(4-piperidyl)isothiazol-3-ol (11), 3-(4-piperidyl)isoxazol-5-ol (12), 5-(1,2,3,6-tetrahydropyrid-4-yl)isoxazol-3-ol

  5-（4-哌啶基）异恶唑-3-醇（4-PIOL，10），4-氨基丁酸（GABA，1）和GABAA激动剂4,5,6,7-四氢异恶唑的结构类似物[5,4 -c] pyridin-3-ol（THIP，5）是低效的部分GABAA激动剂。从10种生物立体异构体衍生的许多化合物，包括5-（4-哌啶基）异噻唑-3-醇（11），3-（4-哌啶基）异噻唑-5-醇（12），5-（1,2,3合成了1,6-四氢吡啶-4-基）异噻唑-3-醇（13）和5-（1,2,3,6-四氢吡啶-4-基）异噻唑-3-醇（14） GABAA受体配体。尽管这些化合物均未显着影响GABAB受体的结合或GABA的吸收，但它们在低微摩尔范围内显示出对GABAA受体位点的亲和力。使用培养的大脑皮层神经元和全细胞膜片钳技术，这些化合物相对于完整GABAA激动剂的功效，测定了异胍卡因（8）（20 microM）。11的相对功效比10（IC50 =