6-chloro-2-(2-chlorobenzyl)-1,2,3,4-tetrahydroisoquinoline | 1552304-53-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 6-chloro-2-(2-chlorobenzyl)-1,2,3,4-tetrahydroisoquinoline
• 英文别名: 6-chloro-2-[(2-chlorophenyl)methyl]-3,4-dihydro-1H-isoquinoline
• CAS: 1552304-53-6
• 化学式: C₁₆H₁₅Cl₂N
• 分子量: 292.208
• InChiKey: IYMGHWBPKNMOQR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  3.2
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  6-氯-1,2,3,4-四氢异喹啉 、 邻氯氯苄 以 乙腈 为溶剂， 以40%的产率得到6-chloro-2-(2-chlorobenzyl)-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  Designing analogs of ticlopidine, a wall teichoic acid inhibitor, to avoid formation of its oxidative metabolites

  摘要：

  The thienopyridine antiplatelet agent, ticlopidine and its analog, clopidogrel, have been shown to potentiate the action of beta-lactam antibiotics, reversing the methicillin-resistance phenotype of methicillin- resistant Staphylococcus aureus (MRSA), in vitro. Interestingly, these thienopyridines inhibit the action of TarO, the first enzyme in the synthesis of wall teichoic acid, an important cell wall polymer in Gram-positive bacteria. In the human body, both ticlopidine and clopidogrel undergo a rapid P450-dependent oxidation into their respective antiplatelet-active metabolites, resulting in very low plasma concentrations of intact drug. Herein, a series of analogs of ticlopidine and clopidogrel that would avoid oxidative metabolism were designed, prepared and evaluated as inhibitors of TarO. Specifically, we replaced the P450-labile thiophene ring of ticlopidine and clopidogrel to a more stable phenyl group to generate 2-(2-chlorobenzyl)-1,2,3,4-tetrahydro-isoquinoline) (6) and (2-chloro-phenyl)-(3,4-dihydro-1H-isoquinolin- 2-yl)-acetic acid methyl ester (22), respectively. The latter molecules displayed inhibitory activity against TarO and formed the basis of a library of analogs. Most synthesized compounds exhibited comparable efficacy to ticlopidine and clopidogrel. So far, it was introduction of a trifluoromethyl group to compound 6, to generate 2-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-isoquinoline (13) that exhibited enhanced activity against TarO. Compound 13 represents a novel stable inhibitor of TarO with synergistic impact on b-lactam antibiotics against MRSA and low potential for P-450 metabolism. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.12.069

文献信息

• NOVEL ANTIBACTERIAL COMBINATION THERAPY
  申请人：Brown Eric D.

  公开号：US20140088069A1

  公开（公告）日：2014-03-27

  An antibacterial composition is provided including a combination of a β-lactam antibiotic that has a binding affinity for bacterial penicillin-binding protein 2; and a non-antibiotic compound which may be a thienopyridine or a non-thienopyridine compound. A method of treatment using the composition is also provided.
• Designing analogs of ticlopidine, a wall teichoic acid inhibitor, to avoid formation of its oxidative metabolites
  作者：Maya A. Farha、Kalinka Koteva、Robert T. Gale、Edward W. Sewell、Gerard D. Wright、Eric D. Brown

  DOI：10.1016/j.bmcl.2013.12.069

  日期：2014.2

  The thienopyridine antiplatelet agent, ticlopidine and its analog, clopidogrel, have been shown to potentiate the action of beta-lactam antibiotics, reversing the methicillin-resistance phenotype of methicillin- resistant Staphylococcus aureus (MRSA), in vitro. Interestingly, these thienopyridines inhibit the action of TarO, the first enzyme in the synthesis of wall teichoic acid, an important cell wall polymer in Gram-positive bacteria. In the human body, both ticlopidine and clopidogrel undergo a rapid P450-dependent oxidation into their respective antiplatelet-active metabolites, resulting in very low plasma concentrations of intact drug. Herein, a series of analogs of ticlopidine and clopidogrel that would avoid oxidative metabolism were designed, prepared and evaluated as inhibitors of TarO. Specifically, we replaced the P450-labile thiophene ring of ticlopidine and clopidogrel to a more stable phenyl group to generate 2-(2-chlorobenzyl)-1,2,3,4-tetrahydro-isoquinoline) (6) and (2-chloro-phenyl)-(3,4-dihydro-1H-isoquinolin- 2-yl)-acetic acid methyl ester (22), respectively. The latter molecules displayed inhibitory activity against TarO and formed the basis of a library of analogs. Most synthesized compounds exhibited comparable efficacy to ticlopidine and clopidogrel. So far, it was introduction of a trifluoromethyl group to compound 6, to generate 2-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-isoquinoline (13) that exhibited enhanced activity against TarO. Compound 13 represents a novel stable inhibitor of TarO with synergistic impact on b-lactam antibiotics against MRSA and low potential for P-450 metabolism. (C) 2013 Elsevier Ltd. All rights reserved.