4-hydroxyisoquinoline-3-carboxylic acid | 22080-18-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 4-hydroxyisoquinoline-3-carboxylic acid
• CAS: 22080-18-8
• 化学式: C₁₀H₇NO₃
• mdl: MFCD18253791
• 分子量: 189.17
• InChiKey: SDANCITUOADILO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  70.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6α-naltrexamine dihydrochloride 、 4-hydroxyisoquinoline-3-carboxylic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 甲醇 为溶剂， 反应 0.25h， 以60%的产率得到17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(4-hydroxyisoquinoline-3-carboxamido)morphinan
  参考文献：
  名称：

  Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

  摘要：

  A series of 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3 '-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1 '- and/or 4 '-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6 '- and/or 7 '-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6 '-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2015.02.055
• 作为产物：
  描述：

  1-氯-4-羟基异喹啉-3-羧酸甲酯 在 palladium 10% on activated carbon 、 氢气 、 sodium acetate 、 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 48.0h， 生成 4-hydroxyisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  Structure activity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function

  摘要：

  17-Cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3'-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1'- or 4'-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQanalogues retained low efficacy at the MOR compared to NAQin the S-35-GTP[gamma S] binding assays while electron-withdrawing groups at 1'-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1'- or 4'-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.07.043

文献信息

• Reactions of boroxazolidones with aromatic aldehydes
  作者：G.H.L. Nefkens、B. Zwanenburg

  DOI：10.1016/s0040-4020(01)91449-8

  日期：1985.1

  Boroxazolidones 1 derived from glycine and phenylalanine react with aromatic aldehydes to form the corresponding imines. The product 3 from 1a with o-carboxybenzaldehyde is converted into 4-hydroxyisoquinoline-3-carboxylic acid 6 by dimethyl sulfate, followed by t-BuOK, and aqueous acid.

  衍生自甘氨酸和苯丙氨酸的硼恶唑烷酮1与芳族醛反应形成相应的亚胺。由1a得到的具有邻-羧基苯甲醛的产物3通过硫酸二甲酯，随后用t-BuOK和酸水溶液转化为4-羟基异喹啉-3-羧酸6。
• 一种甲状腺激素受体β激动剂化合物及其制备方法和应用
  申请人：中国科学院广州生物医药与健康研究院

  公开号：CN115838354A

  公开（公告）日：2023-03-24

  本发明提供了一种甲状腺激素受体β(TRβ)激动剂化合物及其制备方法和应用。所述化合物以及所述化合物在药学上可接受的盐、酯、酰胺或氨基甲酸酯、以及异构体、外消旋体、前体药物、共结晶复合物或溶剂合物等均可作为甲状腺激素受体β激动剂使用，且制备得到甲状腺激素受体β激动剂对野生型和突变型的甲状腺激素受体β具有很好的激活作用，对甲状腺激素受体α(TRα)和脯氨酰羟化酶(PHD2)靶点具有较弱的作用或基本无作用，选择性较好。因此，所述化合物可用在预防或治疗甲状腺激素受体β介导的相关疾病中。
• Structure activity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues as potent opioid receptor ligands: Preliminary results on the role of electronic characteristics for affinity and function
  作者：Yunyun Yuan、Orgil Elbegdorj、Irina O. Beletskaya、Dana E. Selley、Yan Zhang

  DOI：10.1016/j.bmcl.2013.07.043

  日期：2013.9

  17-Cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 alpha-(isoquinoline-3'-carboxamido)morphinan (NAQ) was previously designed following the 'message-address' concept and was identified as a potent and highly selective mu opioid receptor (MOR) ligand based on its pharmacological profile. We here report the preliminary structure activity relationship (SAR) studies of this novel lead compound. For the new ligands synthesized as NAQ analogues, their binding assay results showed that a longer spacer and a saturated ring system of the side chain were unfavorable for their MOR selectivity over the kappa and delta opioid receptors. In contrast, substitutions with different electronic properties at either 1'- or 4'-position of the isoquinoline ring of the side chain were generally acceptable for reasonable MOR selectivity. The majority of NAQanalogues retained low efficacy at the MOR compared to NAQin the S-35-GTP[gamma S] binding assays while electron-withdrawing groups at 1'-position of the isoquinoline ring induced higher MOR stimulation than electron-donating groups did. In summary, the electronic characteristics of substituents at 1'- or 4'-position of the isoquinoline ring in NAQ seem to be critical and need to be further tuned up to achieve higher MOR selectivity and lower MOR stimulation. Published by Elsevier Ltd.
• NEFKENS, G. H. L.;ZWANENBURG, B., TETRAHEDRON, 1985, 41, N 24, 6063-6066
  作者：NEFKENS, G. H. L.、ZWANENBURG, B.

  DOI：——

  日期：——
• US6093730A
  申请人：——

  公开号：US6093730A

  公开（公告）日：2000-07-25