ethyl (3SR,4aSR,8aSR)-6-oxo-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate | 128073-42-7

• 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,4aSR,8aSR)-6-oxo-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,4aS,8aS)-6-oxo-1,3,4,4a,5,7,8,8a-octahydroisoquinoline-2,3-dicarboxylate
• CAS: 128073-42-7；134388-86-6；134388-92-4；134389-01-8；134389-03-0；134389-04-1
• 化学式: C₁₄H₂₁NO₅
• 分子量: 283.324
• InChiKey: HAEQCUWBOVQMOJ-FOGDFJRCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• 海关编码：
  2933499090

反应信息

• 作为反应物：
  描述：

  ethyl (3SR,4aSR,8aSR)-6-oxo-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 在 palladium on activated charcoal 盐酸 、 氢气 、 sodium hydride 、 三正丁基叠氮化锡 作用下， 以 乙醇 为溶剂， 25.0~100.0 ℃ 、413.69 kPa 条件下， 反应 2.5h， 生成 (3SR,4aRS,8aSR)-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：

  6-Oxo-3,4,5,6,7,8-hexahydro-1H-isoquinoline-2,3-dicarboxylic acid 2-methyl ester 在 氨 、 lithium 、 sodium hydride 、 碳酸氢钠 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 52.75h， 生成 ethyl (3SR,4aSR,8aSR)-6-oxo-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-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

• Structure−Activity Studies of 6-(Tetrazolylalkyl)-Substituted Decahydroisoquinoline-3-carboxylic Acid AMPA Receptor Antagonists. 1. Effects of Stereochemistry, Chain Length, and Chain Substitution
  作者：Paul L. Ornstein、M. Brian Arnold、Nancy K. Allen、Thomas Bleisch、Peter S. Borromeo、Charles W. Lugar、J. David Leander、David Lodge、Darryle D. Schoepp

  DOI：10.1021/jm950912p

  日期：1996.1.1

  subsequent publication look at the AMPA antagonist aspects of this SAR. Herein we report the effects of varying stereochemistry around the hydroisoquinoline ring; of tetrahydro-versus decahydroisoquinoline; of having the carboxylic acid at C-1 versus C-3; of varying the length of the carbon chain connecting a tetrazole to the bicyclic nucleus; and of holding the connecting chain constant at two atoms

  制备了一系列6-取代的十氢异喹啉-3-羧酸作为兴奋性氨基酸（EAA）受体拮抗剂。这些化合物是配体门控离子通道（离子型）的N-甲基-D-天冬氨酸（NMDA）和2-氨基-3-（5-甲基-3-羟基异恶唑-4-基）丙酸（AMPA）亚类的拮抗剂。 EAA受体。（3S，4aR，6R，8aR）-6-（2-（1H-四唑-5-基）乙基）-1,2,3,4,4a，5,6,7,8,8,8a-十氢异喹啉-3 -羧酸（9）是有效的，选择性的和内在活性的AMPA拮抗剂。该系列的其他类似物，包括（3S，4aR，6S，8aR）-6-（（（1H-四唑-5-基）甲基）-1,2,3,4,4a，5,6,7,8， 8a-十氢异喹啉-3-羧酸（32）和（3S，4aR，6S，8aR）-6-（膦酰基甲基）-1,2,3,4,4a，5,6,7,8,8,8a-十氢异喹啉- 3-ca rboxylic acid（61）是有效的，选择性的和内吸性的