(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-1-piperidinepropanoic acid

• 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: (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-1-piperidinepropanoic acid
• 英文别名: 4-(3-hydroxyphenyl)-3(R),4(R)-dimethyl-2'(SR)-(phenylmethyl)-1-piperidinepropanoic acid；2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanoic acid
• 化学式: C₂₃H₂₉NO₃
• 分子量: 367.488
• InChiKey: KSBSLJKYJXTATP-MDGGQCKNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  60.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-1-piperidinepropanoic acid 在 盐酸 、 1-羟基苯并三唑一水物 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 78.0h， 生成 爱维莫潘
  参考文献：
  名称：

  Discovery of a Potent, Peripherally Selective trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonist for the Treatment of Gastrointestinal Motility Disorders

  摘要：

  Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (K-i = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (>200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.

  DOI：

  10.1021/jm00041a003
• 作为产物：
  描述：

  乙基2-苄基丙烯酸酯 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 242.0h， 生成 (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-1-piperidinepropanoic acid
  参考文献：
  名称：

  Discovery of a Potent, Peripherally Selective trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonist for the Treatment of Gastrointestinal Motility Disorders

  摘要：

  Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (K-i = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (>200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.

  DOI：

  10.1021/jm00041a003

文献信息

• SUBSTITUTED PIPERIDINYLPROPANOIC ACID COMPOUNDS AND METHODS OF THEIR USE
  申请人：Dolle Roland E.

  公开号：US20100311782A1

  公开（公告）日：2010-12-09

  Novel 3,4-disubstituted-4-(3-carbamoylphenyl)-piperidinylpropanoic acid compounds and their salts, including pharmaceutically acceptable salts, pharmaceutical compositions and methods of their use are disclosed. The novel compounds are useful, inter alia, as antagonists of opioid receptors.

  3,4-二取代-4-(3-羧基苯基)-哌啶基丙酸化合物及其盐，包括药用可接受的盐、药物组合物及其用途方法被披露。这些新颖化合物可用作阿片受体拮抗剂等。
• Piperidine derivatives
  申请人：ELI LILLY AND COMPANY

  公开号：EP0506478A1

  公开（公告）日：1992-09-30

  3,4,4-trisubstitutedpiperidinyl-alkyl-carboxylates and intermediates for their preparation are provided. These piperidine-N-alkylcarboxylates are useful as peripheral opioid antagonists.

  提供了 3,4,4-三取代哌啶-N-烷基羧酸盐及其制备中间体。这些哌啶-N-烷基羧酸盐可用作外周阿片拮抗剂。
• Synthesis of <i>trans</i>-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonists:  Application of the <i>Cis</i>-Thermal Elimination of Carbonates to Alkaloid Synthesis
  作者：John A. Werner、Louis R. Cerbone、Scott A. Frank、Jeffrey A. Ward、Parviz Labib、Roger W. Tharp-Taylor、C. W. Ryan

  DOI：10.1021/jo951403y

  日期：1996.1.1

  Improved syntheses of two trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists from 1,3-dimethyl-4-piperidinone are described. The 1,3 dimethyl-4-arylpiperidinol 23 was selectively dehydrated in a two step process to the 1,3-dimethyl-4-aryl-1,2,3,6-tetrahydropyrodome 26 by the cis-thermal elimination of the corresponding alkyl carbonate derivative at 190 degrees C. In the presence of a basic nitrogen, the success of the elimination was found to be critically dependent upon the nature of the carbonate alkyl group, with Et, i-Bu, and i-Pr being preferred (90% yield). Alkylation of the metalloenamine, formed by deprotonation of 26 with n-BuLi, proceeded regio- and stereospecifically to give the trans-3,4-dimethyl-4-aryl-1,2,3,4-tetrahydrpyridine 27, which was converted in three steps to the common intermediate, (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)-piperidine. LY255582, a centrally-active opioid antagonist, and LY246736-dihydrate, a peripherally-active opioid antagonist, were prepared from 1,3-dimethyl-4-piperidinone in 11.8% yield (8 steps) and 6.2% yield (12 steps), respectively.
• US5250542A
  申请人：——

  公开号：US5250542A

  公开（公告）日：1993-10-05
• Discovery of a Potent, Peripherally Selective trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonist for the Treatment of Gastrointestinal Motility Disorders
  作者：Dennis M. Zimmerman、Jaswant S. Gidda、Buddy E. Cantrell、Darryle D. Schoepp、Bryan G. Johnson、J. David Leander

  DOI：10.1021/jm00041a003

  日期：1994.7

  Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (K-i = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (>200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.