ethyl 6-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate | 134388-88-8

• 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 6-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
• 英文别名: ethyl 6-hydroxy-1,2,3,4-tetrahydro-2-methoxycarbonyl-3-isoquinolinecarboxylate；Ethyl 6-Hydroxy-2-methoxycarbonyltetrahydroisoquinoline-3-carboxylate；3-ethyl 2-methyl 6-hydroxy-3,4-dihydro-2,3(1H)-isoquinolinedicarboxylate；3-O-ethyl 2-O-methyl 6-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylate
• CAS: 134388-88-8
• 化学式: C₁₄H₁₇NO₅
• 分子量: 279.293
• InChiKey: FUIIRPDTBLOESH-UHFFFAOYSA-N

物化性质

• 沸点：
  432.4±45.0 °C(Predicted)
• 密度：
  1.284±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 6-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate 在 吡啶 、 盐酸 、 sodium tetrahydroborate 、 sodium periodate 、 四氧化锇 、 四(三苯基膦)钯 、 N,N-二异丙基乙胺 、 methyloxirane 、 lithium chloride 、 二溴三苯基膦 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 2.08h， 生成 (3SR)-6-(phosphonomethyI)-1,2,3,4-tetrahydroisoquinoline-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：

  1,2,3,4-四氢-6-羟基异喹啉-3-羧酸 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.33h， 生成 ethyl 6-hydroxy-2-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
  参考文献：
  名称：

  Syntheses of 6-oxodecahydroisoquinoline-3-carboxylates. Useful intermediates for the preparation of conformationally defined excitatory amino acid antagonists

  摘要：

  We have prepared three of the four possible diastereomers of ethyl 6-oxo-2-(methoxycarbonyl)decahydroisoquinoline-3-carboxylic acid (two cis- ring and one trans ring juncture ketones, 3a-c) by a convergent route from (+/-)-m-tyrosine. These ketones are useful intermediates for the preparation of conformationally constrained acidic amino acids as N-methyl-D-aspartic acid (NMDA) receptor antagonists, e.g., LY274614 and LY233536 (1 and 2, respectively). The cis ring juncture ketones were prepared selectively by hydrogenation of a key tetrahydroisoquinoline intermediate 7, while the corresponding trans ring juncture ketone was prepared selectively by consecutive dissolving metal reductions of the tetrahydroisoquinoline 8. One of the ketones, 3b, that possesses the optimal stereochemical array for NMDA antagonist activity, was resolved via the alpha-methylbenzylamine salts of the corresponding acid to allow for determination of the active optical isomer of these amino acids. The synthesis and resolution of the keto esters can easily be performed on a multigram scale.

  DOI：

  10.1021/jo00014a012

文献信息

• ORNSTEIN, PAUL L.
  作者：ORNSTEIN, PAUL L.

  DOI：——

  日期：——
• Decahydro isoquinoline derivatives, process for their preparation and use as medicines
  申请人：ELI LILLY AND COMPANY

  公开号：EP0383504B1

  公开（公告）日：1995-07-19
• Decahydro-isoquinoline derivatives
  申请人：ELI LILLY AND COMPANY

  公开号：EP0658545B1

  公开（公告）日：1999-09-29
• US4902695A
  申请人：——

  公开号：US4902695A

  公开（公告）日：1990-02-20
• 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.