methyl (+/-)-cis-2-(chloromethyl)-1-phenylcyclopropanecarboxylate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl (+/-)-cis-2-(chloromethyl)-1-phenylcyclopropanecarboxylate
• 英文别名: methyl (1RS,2SR)-2-(chloromethyl)-1-phenylcyclopropanecarboxylate；methyl (1R,2S)-2-(chloromethyl)-1-phenylcyclopropane-1-carboxylate
• 化学式: C₁₂H₁₃ClO₂
• 分子量: 224.687
• InChiKey: KKLUMGJFWLFMOO-PWSUYJOCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  methyl (+/-)-cis-2-(chloromethyl)-1-phenylcyclopropanecarboxylate 在 sodium amide 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 12.0h， 生成 (Z)-1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethylcyclopropane
  参考文献：
  名称：

  一种药物中间体及其制备和应用

  摘要：

  本发设计了一种药物中间体III，其结构式如下所示：及其利用此中间体III应用。

  公开号：

  CN112759542B
• 作为产物：
  描述：

  (1S,5R)-1-苯基-3-氧杂双环[3.1.0]己-2-酮 在 盐酸 、 氯化亚砜 、 zinc(II) chloride 作用下， 以 苯 为溶剂， 反应 5.0h， 生成 methyl (+/-)-cis-2-(chloromethyl)-1-phenylcyclopropanecarboxylate
  参考文献：
  名称：

  Synthesis and pharmacological evaluation of potent and enantioselective σ1 and σ2 ligands

  摘要：

  In a previous study we found that substitutions of the (+)-cis-N-normetazocine nucleus of (+)-MPCB with 1-adamantanamine provide the compound (+/-)-10 with high affinity and selectivity for sigma receptors. Starting with this result we have synthesized a new series of eight 1-phenyl-2-cyclopropylmethylamines structurally related to (+/-)-10, and binding affinities, with respect to sigma(1), sigma(2), opioid and dopaminergic D-2 receptors, have been reported. All compounds showed a negligible opioid and dopaminergic affinity and high selectivity for sigma receptors. Modifications on the amino moiety and methylcarboxyester group of 10 provide compounds with different sigma(1), and sigma(2) binding affinity and selectivity. Moreover, we have also synthesized the respective enantiomers of componds (+/-)-10 and (+/-)-18 in order to evaluate the enantioselectivity for sigma(1) and sigma(2) receptors. The binding data showed that carboxymethylester on the cyclopropane ring was more critical for enantioselectivity than the hydroxymethylenic group. In fact, the (-)-10 enantionter showed a preference for sigma(1) whereas (+)-10 showed a preference for sigma(2), (C) 2001 Elsevier Science S.A. All rights reserved.

  DOI：

  10.1016/s0014-827x(01)01039-4

文献信息

• Non-peptide ligands for opioid receptors. Design of .kappa.-specific agonists
  作者：G. Ronsisvalle、L. Pasquinucci、M. S. Pappalardo、F. Vittorio、G. Fronza、C. Romagnoli、E. Pistacchio、S. Spampinato、S. Ferri

  DOI：10.1021/jm00065a009

  日期：1993.6

  A series of phenyl carboxy esters 5a-d derived from N-(cyclopropylmethyl)normetazocine was synthesized and evaluated for its selectivity at mu, kappa, and delta opioid receptors. Compound 5a, although 43 times less potent than the reference compound U50488, was specific for kappa receptors, having no detectable affinity for either mu or delta receptors. Greater binding affinity was seen with the diastereoisomer having the 1'R,2'S stereochemistry in the cyclopropyl ring of the nitrogen substituent, which was only 12 times less active than U50488. Antinociceptive activity in the mouse tail flick was only slightly lower than that of U50488 (ED50 = 7.66 vs 4.52 mg/kg). Naloxone fully prevented antinociception induced by (1'R,2'S)-5a at the doses of 2.0 mg/kg. Compound (1'R,2'S)-5a is one of the most kappa-selective non-peptide compounds reported to date. The implications of these results in terms of requirements for kappa ligands are discussed.
• Substituted 1-phenyl-2-cyclopropylmethylamines with high affinity and selectivity for sigma sites
  作者：Giuseppe Ronsisvalle、Agostino Marrazzo、Orazio Prezzavento、Lorella Pasquinucci、Barbara Falcucci、Rosanna Di Toro、Santi Spampinato

  DOI：10.1016/s0968-0896(00)00072-9

  日期：2000.6

  A series of 1-phenyl-2-cyclopropylmethylamines structurally related to (+)- and (-)-MPCB were synthesized and their binding affinities for or, oz, opioid and dopamine (D-2) receptors were evaluated. Substitution of the cis-N-normetazocine with different aminic moieties provided compounds with high affinity and selectivity for sigma binding sites with respect to opioid and dopamine (D2) receptors. The observed increase in sigma(2) affinity as compared to the parent(+)-MPCB, supports the idea that the particular stereochemistry of (+)-cis-N-normetazocine affects sigma(1) selectivity but does not affect ol affinity. The (+/-)-cis isomers of methyl 2-[(1-adamantylamino)methyl]-1-phenylcyclopropane-1-carboxylate (18) displayed a higher affinity and selectivity for the ol and sigma(2) receptor subtypes compared to the (+/-)-trans 19. interestingly, the enantiomer (-)-cis 18 displayed a preference for ol receptor subtype whereas the (+)-cis 18 did for sigma(2). These results prompt us to synthesize compounds with modification of nitrogen and carboxyl groups. The compounds obtained showed high affinities and selectivity for sigma sites. Moreover, modifications of carboxyl groups provided compounds with the highest affinities in the series. In particular, compound 25 with reverse-type ester showed a K-i of 0.6 and 4.05 nM for sigma(1) and sigma(2) binding sites, respectively. (C) 2000 Elsevier Science Ltd. All rights reserved.
• Novel Sigma Receptor Ligands:  Synthesis and Biological Profile
  作者：Orazio Prezzavento、Agata Campisi、Simone Ronsisvalle、Giovanni Li Volti、Agostino Marrazzo、Vincenzo Bramanti、Giuseppe Cannavò、Luca Vanella、Alfredo Cagnotto、Tiziana Mennini、Riccardo Ientile、Giuseppe Ronsisvalle

  DOI：10.1021/jm0611197

  日期：2007.3.1

  The aim of the present study was to investigate the biological profile of new substituted 1-phenyl-2-cyclopropylmethylamines. High affinity for both sigma subtypes was achieved when 4-phenylpiperidin-4-ol (4a-e) and 4-benzylpiperidine moieties were present (5a-e). (1R,2S/1S,2R)-2-[4-Hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate (4b) showed high affinity for the sigma(1) sites (K-i = 1.5 nM) and the most favorable sigma(1)/sigma(2) selectivity (K-i(sigma(2))/K-i(sigma(1)) = 33.9). Binding affinity studies showed that 4b binding on N-methyl-d-aspartate (NMDA), dopaminergic (D-1, D-2, D-3), muscarinic, histaminergic H-1, adrenergic (alpha(1), alpha(2)), serotoninergic (5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT6), DA (DAT), and 5-HT (SERT) transporters was not significant. Interestingly, sigma ligands differently induced the expression of tissue transglutaminase (TG-2) in primary astroglial cell cultures. We suggest that 4b may act as a sigma(1)/sigma(2) agonist and that the sigma ligands may modulate TG-2 differently.
• Ronsisvalle; Prezzavento; Pasquinucci, Il Farmaco, 1997, vol. 52, # 6-7, p. 471 - 476
  作者：Ronsisvalle、Prezzavento、Pasquinucci、Pappalardo、Marrazzo、Vittorio、Carboni、Spampinato

  DOI：——

  日期：——
• Synthesis and pharmacological evaluation of potent and enantioselective σ1 and σ2 ligands
  作者：Agostino Marrazzo、Orazio Prezzavento、Lorella Pasquinucci、Franco Vittorio、Giuseppe Ronsisvalle

  DOI：10.1016/s0014-827x(01)01039-4

  日期：2001.4

  In a previous study we found that substitutions of the (+)-cis-N-normetazocine nucleus of (+)-MPCB with 1-adamantanamine provide the compound (+/-)-10 with high affinity and selectivity for sigma receptors. Starting with this result we have synthesized a new series of eight 1-phenyl-2-cyclopropylmethylamines structurally related to (+/-)-10, and binding affinities, with respect to sigma(1), sigma(2), opioid and dopaminergic D-2 receptors, have been reported. All compounds showed a negligible opioid and dopaminergic affinity and high selectivity for sigma receptors. Modifications on the amino moiety and methylcarboxyester group of 10 provide compounds with different sigma(1), and sigma(2) binding affinity and selectivity. Moreover, we have also synthesized the respective enantiomers of componds (+/-)-10 and (+/-)-18 in order to evaluate the enantioselectivity for sigma(1) and sigma(2) receptors. The binding data showed that carboxymethylester on the cyclopropane ring was more critical for enantioselectivity than the hydroxymethylenic group. In fact, the (-)-10 enantionter showed a preference for sigma(1) whereas (+)-10 showed a preference for sigma(2), (C) 2001 Elsevier Science S.A. All rights reserved.