RTI-5989-239 | 1192142-11-2

• 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: RTI-5989-239
• 英文别名: tert-butyl (3R)-3-{[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]carbamoyl}-7-methoxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate；tert-Butyl (3R)-3-{[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]carbamoyl}-7-methoxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate；tert-butyl (3R)-3-[[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]carbamoyl]-7-methoxy-3-methyl-1,4-dihydroisoquinoline-2-carboxylate
• CAS: 1192142-11-2
• 化学式: C₃₅H₅₁N₃O₅
• 分子量: 593.807
• InChiKey: RGJGHKZMCLPTEM-YYQSLOINSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  43
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  91.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  RTI-5989-239 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 以250 mg的产率得到(3R)-7-methoxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide
  参考文献：
  名称：

  Synthesis and In Vitro Opioid Receptor Functional Antagonism of Methyl-Substituted Analogues of (3R)-7-Hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic)

  摘要：

  In previous structure-activity relationship (SAR) studies, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic, 3) was identified as the first potent and selective kappa-opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present study, we report the synthesis of analogues 8a-p of 3 and present their in vitro opioid receptor functional antagonism using a [S-35]GTP gamma S binding assay. Compounds 8a-p are analogues of 3 containing one, two, or three methyl groups connected to the JDTic structure at five different positions. All the analogues with one and two added methyl groups with the exception of 8k had subnanomolar K-e values at the kappa receptor. The three most potent analogues were the monomethylated (3 R)-7-hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide (8e) with K-e values of 0.03 nM at the kappa receptor and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with K-e = 0.037 nM at the kappa receptor. All three compounds were selective for the kappa receptor relative to the mu and delta receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.

  DOI：

  10.1021/jm900756t
• 作为产物：
  描述：

  (3R)-2-(tert-butoxycarbonyl)-7-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 、 3-[1-(2S-amino-3-methylbutyl)-3R,4R-dimethyl-4-piperidinyl]phenol 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以68%的产率得到RTI-5989-239
  参考文献：
  名称：

  KAPPA OPIOID RECEPTOR LIGANDS

  摘要：

  κ阿片受体拮抗剂提供了在κ阿片受体的功能结合测定中产生显著改善的结果，并且这些拮抗剂在治疗通过结合κ阿片受体得到缓解的疾病状态中的使用，例如海洛因或可卡因成瘾。

  公开号：

  US20090264462A1

文献信息

• KAPPA OPIOID RECEPTOR LIGANDS
  申请人：Carroll Frank Ivy

  公开号：US20090264462A1

  公开（公告）日：2009-10-22

  Kappa opioid receptor antagonists are provided that yield significant improvements in functional binding assays to kappa opioid receptors, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions.

  κ阿片受体拮抗剂提供了在κ阿片受体的功能结合测定中产生显著改善的结果，并且这些拮抗剂在治疗通过结合κ阿片受体得到缓解的疾病状态中的使用，例如海洛因或可卡因成瘾。
• Kappa opioid receptor ligands
  申请人：Research Triangle Institute

  公开号：US08048895B2

  公开（公告）日：2011-11-01

  Kappa opioid receptor antagonists are provided that yield significant improvements in functional binding assays to kappa opioid receptors, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions.

  提供了Kappa阿片受体拮抗剂，可以在功能性结合测定中显著改善对Kappa阿片受体的结合，并且可以将这些拮抗剂用于治疗因结合Kappa阿片受体而改善的疾病状态，如海洛因或可卡因成瘾。
• Synthesis and In Vitro Opioid Receptor Functional Antagonism of Methyl-Substituted Analogues of (3<i>R</i>)-7-Hydroxy-<i>N</i>-[(1<i>S</i>)-1-{[(3<i>R</i>,4<i>R</i>)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic)
  作者：Juan Pablo Cueva、Tingwei Bill Cai、S. Wayne Mascarella、James B. Thomas、Hernán A. Navarro、F. Ivy Carroll

  DOI：10.1021/jm900756t

  日期：2009.12.10

  In previous structure-activity relationship (SAR) studies, (3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic, 3) was identified as the first potent and selective kappa-opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present study, we report the synthesis of analogues 8a-p of 3 and present their in vitro opioid receptor functional antagonism using a [S-35]GTP gamma S binding assay. Compounds 8a-p are analogues of 3 containing one, two, or three methyl groups connected to the JDTic structure at five different positions. All the analogues with one and two added methyl groups with the exception of 8k had subnanomolar K-e values at the kappa receptor. The three most potent analogues were the monomethylated (3 R)-7-hydroxy-N-[(1S,2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3, 4-tetrahydroisoquinoline-3-carboxamide (8e) with K-e values of 0.03 nM at the kappa receptor and (3R)-7-hydroxy-N-[(1S)-1-[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with K-e = 0.037 nM at the kappa receptor. All three compounds were selective for the kappa receptor relative to the mu and delta receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.