ethyl (3SR,4aRS,6RS,8aRS)-6-(cyanomethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate | 128073-44-9

• 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 (3SR,4aRS,6RS,8aRS)-6-(cyanomethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
• 英文别名: 3-O-ethyl 2-O-methyl (3S,4aR,6R,8aR)-6-(cyanomethyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2,3-dicarboxylate
• CAS: 128073-44-9；143267-64-5；143267-65-6；143267-77-0；143267-84-9；143267-85-0
• 化学式: C₁₆H₂₄N₂O₄
• 分子量: 308.378
• InChiKey: UNNVTGQYXVKNAX-FQUUOJAGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  79.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl (3SR,4aRS,6RS,8aRS)-6-(cyanomethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 在 盐酸 、 三正丁基叠氮化锡 作用下， 生成 (3S,4aR,6R,8aR)-6-(1H-Tetrazol-5-ylmethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  6-Substituted decahydroisoquinoline-3-carboxylic acids as potent and selective conformationally constrained NMDA receptor antagonists

  摘要：

  We have prepared a series of 6-substituted decahydroisoquinoline-3-carboxylic acids, and structurally similar analogs, as potential N-methyl-D-aspartate receptor antagonists. There is a large body of evidence to support the use of such compounds as cerebroprotective agents in a variety of acute and chronic neurodegenerative disorders, where some component of glutamate-mediated excitotoxicity may exist. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical wedge preparation (versus NMDA, AMPA, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced lethality in mice. We synthesized many of the possible diastereomers of the decahydroisoquinoline nucleus in order to examine the spatial and steric requirements for affinity at the NMDA receptor and activity as NMDA antagonists. From our structure-activity relationship we identified two potent and selective NMDA receptor antagonists, the phosphonate- and tetrazole-substituted amino acids 31a and 32a, respectively, that show good activity in animals following systemic administration. For example, 31a and 32a selectively displaced [H-3]CGS19755 binding with IC50s of 55 +/- 14 and 856 +/- 136 nM, respectively, and selectively antagonized responses due to NMDA in a cortical wedge preparation with IC50s of 0.15 +/- 0.01 and 1.39 +/- 0.29-mu-M, respectively. And compounds 31a and 32a blocked NMDA-induced lethality in mice with minimum effective doses of 1.25 and 2.5 mg/kg (intraperitoneal), respectively. These novel amino acids are among some of the most potent NMDA antagonists described thus far, and are excellent candidates for development as neuroprotective agents for a number of CNS disorders.

  DOI：

  10.1021/jm00097a012
• 作为产物：
  描述：

  Ethyl (3SR,4aRS,6RS,8aRS)-6-(hydroxymethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 在 吡啶 、 溴 、 三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 2.75h， 生成 ethyl (3SR,4aRS,6RS,8aRS)-6-(cyanomethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
  参考文献：
  名称：

  Stereoselective Synthesis of 6-Substituted Decahydroisoquinoline-3-carboxylates: Intermediates for the Preparation of Conformationally Constrained Acidic Amino Acids

  摘要：

  In this article we describe the stereoselective preparation of two 6-(hydroxymethyl) substituted decahydroisoquinoline-3-carboxylates, which are useful in the synthesis of a number of excitatory amino acid antagonists, e.g., (-)-1a (LY235959), (-)-2a (LY202157) and (-)-3a(LY293558). For example, the known ketone 4 was converted to either the (3SR,4aRS,6SR,8aRS)-alcohol 18 or the (3SR,4aRS,6RS,8aRS)-alcohol 21, the former via a stereoselective hydroboration reaction, the latter via a stereoselective enol ether hydrolysis followed by reduction. These C-6 epimeric alcohols were easily converted to a number of useful intermediates, e.g., aldehydes, bromides and iodides. If we used resolved ketone 4, then these intermediates could be obtained in optically active form. In either racemic or non-racemic form, these intermediates provided access to a number of diastereomerically pure amino acids that were difficult to obtain by earlier routes.

  DOI：

  10.1021/jo00104a051

文献信息

• 6-Substituted decahydroisoquinoline-3-carboxylic acids as potent and selective conformationally constrained NMDA receptor antagonists
  作者：Paul L. Ornstein、Darryle D. Schoepp、M. Brian Arnold、Nancy K. Augenstein、David Lodge、John D. Millar、John Chambers、Jack Campbell、Jonathan W. Paschal

  DOI：10.1021/jm00097a012

  日期：1992.9

  We have prepared a series of 6-substituted decahydroisoquinoline-3-carboxylic acids, and structurally similar analogs, as potential N-methyl-D-aspartate receptor antagonists. There is a large body of evidence to support the use of such compounds as cerebroprotective agents in a variety of acute and chronic neurodegenerative disorders, where some component of glutamate-mediated excitotoxicity may exist. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical wedge preparation (versus NMDA, AMPA, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced lethality in mice. We synthesized many of the possible diastereomers of the decahydroisoquinoline nucleus in order to examine the spatial and steric requirements for affinity at the NMDA receptor and activity as NMDA antagonists. From our structure-activity relationship we identified two potent and selective NMDA receptor antagonists, the phosphonate- and tetrazole-substituted amino acids 31a and 32a, respectively, that show good activity in animals following systemic administration. For example, 31a and 32a selectively displaced [H-3]CGS19755 binding with IC50s of 55 +/- 14 and 856 +/- 136 nM, respectively, and selectively antagonized responses due to NMDA in a cortical wedge preparation with IC50s of 0.15 +/- 0.01 and 1.39 +/- 0.29-mu-M, respectively. And compounds 31a and 32a blocked NMDA-induced lethality in mice with minimum effective doses of 1.25 and 2.5 mg/kg (intraperitoneal), respectively. These novel amino acids are among some of the most potent NMDA antagonists described thus far, and are excellent candidates for development as neuroprotective agents for a number of CNS disorders.
• Stereoselective Synthesis of 6-Substituted Decahydroisoquinoline-3-carboxylates: Intermediates for the Preparation of Conformationally Constrained Acidic Amino Acids
  作者：Paul L. Ornstein、Nancy K. Augenstein、M. Brian Arnold

  DOI：10.1021/jo00104a051

  日期：1994.12

  In this article we describe the stereoselective preparation of two 6-(hydroxymethyl) substituted decahydroisoquinoline-3-carboxylates, which are useful in the synthesis of a number of excitatory amino acid antagonists, e.g., (-)-1a (LY235959), (-)-2a (LY202157) and (-)-3a(LY293558). For example, the known ketone 4 was converted to either the (3SR,4aRS,6SR,8aRS)-alcohol 18 or the (3SR,4aRS,6RS,8aRS)-alcohol 21, the former via a stereoselective hydroboration reaction, the latter via a stereoselective enol ether hydrolysis followed by reduction. These C-6 epimeric alcohols were easily converted to a number of useful intermediates, e.g., aldehydes, bromides and iodides. If we used resolved ketone 4, then these intermediates could be obtained in optically active form. In either racemic or non-racemic form, these intermediates provided access to a number of diastereomerically pure amino acids that were difficult to obtain by earlier routes.