(+/-)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonic acid ester

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 6,7-苯并吗啡烷
• 英文名称: (+/-)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonic acid ester
• 英文别名: (+/-)-cyclazocine triflate；[(1R,9R,13R)-10-(cyclopropylmethyl)-1,13-dimethyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-4-yl] trifluoromethanesulfonate
• 化学式: C₁₉H₂₄F₃NO₃S
• 分子量: 403.466
• InChiKey: UBEXGYVVGBCJAB-JBBXEZCESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  55
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (+/-)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonic acid ester 在 吡啶 、 1,1'-双(二苯基膦)二茂铁 、 palladium diacetate 、 三乙胺 作用下， 以 二甲基亚砜 为溶剂， 反应 56.5h， 生成 (+/-)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-phenylpropyl)-2,6-methano-3-benzazocine-8-carboxamide
  参考文献：
  名称：

  Redefining the Structure−Activity Relationships of 2,6-Methano-3-benzazocines. 4. Opioid Receptor Binding Properties of 8-[N-(4‘-phenyl)-phenethyl)carboxamido] Analogues of Cyclazocine and Ethylketocycalzocine

  摘要：

  The synthesis and evaluation of a series of aryl-containing N-monosubstituted analogues of the lead compound 8-carboxamidocyclazocine were performed to probe a putative hydrophobic binding pocket of opioid receptors. High binding affinity to mu, kappa, and delta opioid receptors was observed for the 8-[N-(4'-phenyl)-phenethyl)carboxamido] analogue.

  DOI：

  10.1021/jm060278n
• 作为产物：
  描述：

  6-乙氧基-2,2,4-三甲基-1,2-二氢喹啉 在 吡啶 、 potassium hydrogencarbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (+/-)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yltrifluoromethanesulfonic acid ester
  参考文献：
  名称：

  8-Aminocyclazocine analogues: synthesis and structure–activity relationships

  摘要：

  Opioid binding affinities were assessed for a series of cyclazocine analogues where the prototypic S-OH substituent of cyclazocine was replaced by amino and substituted-amino groups. For mu and kappa opioid receptors, secondary amine derivatives having the (2R,6R,11R)-configuration had the highest affinity. Most targets were efficiently synthesized from the triflate of cyclazocine or its enantiomers using Pd-catalyzed amination procedures. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(99)00670-8

文献信息

• 2-Aminothiazole-Derived Opioids. Bioisosteric Replacement of Phenols
  作者：Ao Zhang、Wennan Xiong、James E. Hilbert、Emily K. DeVita、Jean M. Bidlack、John L. Neumeyer

  DOI：10.1021/jm049978n

  日期：2004.4.1

  A series of aminothiazole-derived morphinans, benzomorphans, and morphine were synthesized. Although their affinities were somewhat lower than their phenol prototypes, one compound (9a, ATPM) has been identified possessing high affinity and selectivity at the kappa receptor. Functional assays showed that 9a was a full kappa but partial mu agonist; the efficacy at kappa was significantly greater than at mu receptors. This novel compound may be valuable for the development of long-acting analgesics and drug abuse medication.
• Syntheses and Opioid Receptor Binding Affinities of 8-Amino-2,6-methano-3-benzazocines
  作者：Mark P. Wentland、Yingchun Ye、Christopher L. Cioffi、Rongliang Lou、Qun Zhou、Guoyou Xu、Wenhu Duan、Christoph M. Dehnhardt、Xufeng Sun、Dana J. Cohen、Jean M. Bidlack

  DOI：10.1021/jm020429w

  日期：2003.2.1

  8-Amino-2,6-methano-3-benzazocine derivatives have been made using Pd-catalyzed amination procedures, and their affinities for opioid receptors were assessed. The 8-amino group was hypothesized to be a replacement for the prototypic 8-OH substituent for 2,6-methano-3-benzazocines and related opiates. This OH group is generally required for binding yet is implicated in unfavorable pharmacokinetic characteristics such as low oral bioavailability and rapid clearance via O-glucuronidation. The core structures in which the 8-OH group was replaced were cyclazocine and its enantiomers, ethylketocyclazocine and its enantiomers, ketocyclazocine, and Mr2034. Many new analogues had high affinity for opioid receptors with several in the subnanomolar range. Highest affinity was seen in analogues with secondary 8-(hetero)arylamino appendages. Binding to opioid receptors was enantioselective with the (2R,6R,11R)-configuration preferred and high selectivity for mu and kappa over delta opioid receptors was observed within the series. Several derivatives were shown to have intrinsic opioid-receptor-mediated activity in [S-35]GTPgammaS assays.
• Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. 5. Opioid receptor binding properties of N-((4′-phenyl)-phenethyl) analogues of 8-CAC
  作者：Melissa A. VanAlstine、Mark P. Wentland、Dana J. Cohen、Jean M. Bidlack

  DOI：10.1016/j.bmcl.2007.09.082

  日期：2007.12

  A series of aryl-containing N-monosubstituted analogues of the lead compound 8-[N-((40-phenyl)-phenethyl)]-carboxamidocyclazocine were synthesized and evaluated to probe a putative hydrophobic binding pocket of opioid receptors. Very high binding affinity to the mu opioid receptor was achieved though the N-(2-(4'-methoxybiphenyl-4-yl)ethyl) analogue of 8-CAC. High binding affinity to mu and very high binding affinity to kappa opioid receptors was observed for the N-(3-bromophenethyl) analogue of 8-CAC. High binding a. nity to all three opioid receptors were observed for the N-(2-naphthylethyl) analogue of 8-CAC. (c) 2007 Elsevier Ltd. All rights reserved.
• Redefining the structure–activity relationships of 2,6-methano-3-benzazocines. Part 8. High affinity ligands for opioid receptors in the picomolar Ki range: Oxygenated N-(2-[1,1′-biphenyl]-4-ylethyl) analogues of 8-CAC
  作者：Mark P. Wentland、Sunjin Jo、Joseph M. Gargano、Melissa A. VanAlstine、Dana J. Cohen、Jean M. Bidlack

  DOI：10.1016/j.bmcl.2012.10.081

  日期：2012.12

  N-[2-(4'-methoxy[1,1'-biphenyl]-4-yl) ethyl]-8-CAC (1) is a high affinity (K-i = 0.084 nM) ligand for the mu opioid receptor and served as the lead compound for this study. Analogues of 1 were made in hopes of identifying an SAR within a series of oxygenated (distal) phenyl derivatives. A number of new analogues were made having single-digit pM affinity for the l receptor. The most potent was the 3',4'-methylenedioxy analogue 18 (K-i = 1.6 pM). (C) 2012 Elsevier Ltd. All rights reserved.
• 8-Carboxamidocyclazocine analogues
  作者：Mark P. Wentland、Rongliang Lou、Yingchun Ye、Dana J. Cohen、Gregory P. Richardson、Jean M. Bidlack

  DOI：10.1016/s0960-894x(01)00014-2

  日期：2001.3

  Unexpectedly high affinity for opioid receptors has been observed for a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group. For mu and kappa opioid receptors, the primary carboxamido derivative of cyclazocine ((+/-)-15) displayed high affinity (K-i=0.41 and 0.53 nM, respectively) nearly comparable to cyclazocine. A high enantiopreference ((2R,6R,11R)-) for binding was also observed. Compound (+/-)-15 also displayed potent antinociception activity in mice when administered icv. (C) 2001 Elsevier Science Ltd. All rights reserved.