tert-butyl [(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]carbonyl}-2-methylpentyl]carbamate | 1016162-91-6

• 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: tert-butyl [(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]carbonyl}-2-methylpentyl]carbamate
• CAS: 1016162-91-6
• 化学式: C₂₅H₄₀N₂O₄
• 分子量: 432.604
• InChiKey: YQLFSWZAPVPZCY-VNAHJIIRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.76
• 重原子数：
  31.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  67.87
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  tert-butyl [(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]carbonyl}-2-methylpentyl]carbamate 在 硼烷四氢呋喃络合物 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 生成
  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：

  BOC-L-异亮氨酸 、 (3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidine 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 2.0h， 以680 mg的产率得到tert-butyl [(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]carbonyl}-2-methylpentyl]carbamate
  参考文献：
  名称：

  [EN] KAPPA OPIOID RECEPTOR BINDING LIGANDS
  [FR] LIGANDS DE LIAISON DE RÉCEPTEUR OPIOÏDE KAPPA

  摘要：

  Kappa阿片受体拮抗剂提供了在kappa阿片受体功能结合测定中获得显著改善的结果，并且这些拮抗剂在治疗通过kappa阿片受体结合而得到改善的疾病状态中的使用，例如海洛因或可卡因成瘾。

  公开号：

  WO2011090473A1

文献信息

• Synthesis and In Vitro Opioid Receptor Functional Antagonism of Analogues of the Selective Kappa Opioid Receptor Antagonist (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：Tingwei Bill Cai、Zhou Zou、James B. Thomas、Larry Brieaddy、Hernán A. Navarro、F. Ivy Carroll

  DOI：10.1021/jm701344b

  日期：2008.3.1

  In previous structure-activity relationship (SAR) studies, we identified (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, 1) as the first potent and selective K opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [S-35]GTP gamma S binding assay. The results from the studies better define the pharmacophore for this class of K opioid receptor antagonist and has identified new potent and selective kappa antagonist. (3R)-7-Hydroxy-N-[(1 S, 2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4tetrahydroisoquinoline-3-carboxamide (3) with a K-e value of 0.03 nM at the kappa receptor and 100- and 793-fold selectivity relative to the mu and delta receptors was the most potent and selective kappa opioid receptor antagonist identified.