N-<(octylamino)thiocarbonyl>-5,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: N-<(octylamino)thiocarbonyl>-5,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline
• 英文别名: 5,6-dihydroxy-N-octyl-3,4-dihydroisoquinoline-2(1H)-carbothioamide；5,6-dihydroxy-N-octyl-3,4-dihydro-1H-isoquinoline-2-carbothioamide
• 化学式: C₁₈H₂₈N₂O₂S
• 分子量: 336.499
• InChiKey: HRFHZRGFBNAFJK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  87.8
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride 在 氢溴酸 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 N-<(octylamino)thiocarbonyl>-5,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  The Discovery of Capsazepine, the First Competitive Antagonist of the Sensory Neuron Excitants Capsaicin and Resiniferatoxin

  摘要：

  Capsaicin and resiniferatoxin are natural products which act specifically on a subset of primary afferent sensory neurons to open a novel cation-selective ion channel in the plasma membrane. These sensory neurons are involved in nociception, and so, these agents are targets for the design of a novel class of analgesics. Although synthetic agonists at the capsaicin receptor have been described previously, competitive antagonists at this receptor would be interesting and novel pharmacological agents. Structure-activity relationships for capsaicin agonists have previously been rationalized, by ourselves and others, by dividing the capsaicin molecule into three regions-the A (aromatic ring)-, B (amide bond)-, and C (hydrophobic side chain)-regions. In this study, the effects on biological activity of conformational constraint of the A-region with respect to the B-region are discussed. Conformational constraint was achieved by the introduction of saturated ring systems of different sizes. The resulting compounds provided agonists of comparable potency to unconstrained analogues as well as a moderately potent antagonist, capsazepine. This compound is the first competitive antagonist of capsaicin and resiniferatoxin to be described and is active in various systems, in vitro and in vivo. It has recently attracted considerable interest as a tool for dissecting the mechanisms by which capsaicin analogues evoke their effects. NMR spectroscopy and X-ray crystallography experiments, as well as molecular modeling techniques, were used to study the conformational behavior of a representative constrained agonist and antagonist. The conformation of the saturated ring contraint in the two cases was found to differ markedly, dramatically affecting the relative disposition of the A-ring and B-region pharmacophores. In agonist structures, the A- and B-regions were virtually coplanar in contrast to those in the antagonist, in which they were approximately orthogonal. A rationale for agonist and antagonist activity at the capsaicin receptor is proposed, based on the consideration of these conformational differences.

  DOI：

  10.1021/jm00039a006

文献信息

• Bronchorelaxing compounds
  申请人：Skogvall Staffan

  公开号：US20050165004A1

  公开（公告）日：2005-07-28

  A compound of the general formula (I) including its pharmaceutically acceptable acid addition salts wherein A is CHR 9 , wherein R 9 is H, C 1 -C 6 alkyl; n is 1-3; B is CHR 10 , wherein R 10 is H, C 1 -C 6 alkyl; m is 1 or 2; D is O or S or optionally NR 16 , wherein R 16 is H, C 1 -C 6 alkyl or C 2 -C 6 acyl; E is CR 11 R 12 or NR 13 , wherein R 11 and R 12 are, independent of each other, H or C 1 -C 6 alkyl, R 13 is H or C 1 -C 6 alkyl; F is C 1 -C 18 alkyl which may be mono- or di-unsaturated and/or substituted, is useful in treating and preventing pulmonary disease characterized by bronchoconstriction. Also disclosed are pharmaceutical compositions comprising the compound and methods for their manufacture.

  通用式（I）的化合物及其药学上可接受的酸盐包括其中 其中A为CHR 9 ，其中R 9 为H，C 1 -C 6 烷基；n为1-3；B为CHR 10 ，其中R 10 为H，C 1 -C 6 烷基；m为1或2；D为O或S或可选地为NR 16 ，其中R 16 为H，C 1 -C 6 烷基或C 2 -C 6 酰基；E为CR 11 R 12 或NR 13 ，其中R 11 和R 12 独立地为H或C 1 -C 6 烷基，R 13 为H或C 1 -C 6 烷基；F为C 1 -C 18 烷基，可以是单烯或双烯和/或取代的，用于治疗和预防以支气管痉挛为特征的肺部疾病。还公开了包含该化合物的药物组合物及其制备方法。
• [EN] BRONCHORELAXING COMPOUNDS<br/>[FR] COMPOSES BRONCHO-RELACHANTS
  申请人：RESPIRATORIUS AB

  公开号：WO2005070887A1

  公开（公告）日：2005-08-04

  A compound of the general formula (I) including its pharmaceutically acceptable acid addition salts formula (I) wherein A is CHR9, wherein R9 is H, C1-C6 alkyl;n is 1-3; B is CHR10, wherein R10 is H, C1-C6 alkyl; m is 1 or 2; D is O or S; E is CR11R12 or NR13, wherein R11 and R12 are, independent of each other, H or C1-C6 alkyl, R13 is H or C1-C6 alkyl; F is C1-C18 alkyl or R4-R7 cycloalkyl, which may be mono- or di-unsaturated and/or substituted, is useful in treating and preventing pulmonary disease characterized by bronchoconstriction; also disclosed is a pharmaceutical composition comprising the compound of formula (I), a pharmaceutical carrier and, optionally, an anti-asthmatic, a method for its manufacture, and a method for treating or preventing such disease.

  通式（I）的化合物及其药学上可接受的酸加合盐，其中A为CHR9，其中R9为H，C1-C6烷基；n为1-3；B为CHR10，其中R10为H，C1-C6烷基；m为1或2；D为O或S；E为CR11R12或NR13，其中R11和R12独立地为H或C1-C6烷基，R13为H或C1-C6烷基；F为C1-C18烷基或R4-R7环烷基，可以是单烯或双烯和/或取代的，用于治疗和预防以支气管收缩为特征的肺部疾病；还公开了包含通式（I）的药物组合物、药物载体和可选的抗哮喘药、其制造方法以及治疗或预防该疾病的方法。
• BRONCHORELAXING COMPOUNDS
  申请人：RESPIRATORIUS AB

  公开号：EP1708999A1

  公开（公告）日：2006-10-11
• The Discovery of Capsazepine, the First Competitive Antagonist of the Sensory Neuron Excitants Capsaicin and Resiniferatoxin
  作者：Christopher S. J. Walpole、Stuart Bevan、Guenter Bovermann、Johann J. Boelsterli、Robin Breckenridge、John W. Davies、Glyn A. Hughes、Iain James、Lukas Oberer、Janet Winter、Roger Wrigglesworth

  DOI：10.1021/jm00039a006

  日期：1994.6.1

  Capsaicin and resiniferatoxin are natural products which act specifically on a subset of primary afferent sensory neurons to open a novel cation-selective ion channel in the plasma membrane. These sensory neurons are involved in nociception, and so, these agents are targets for the design of a novel class of analgesics. Although synthetic agonists at the capsaicin receptor have been described previously, competitive antagonists at this receptor would be interesting and novel pharmacological agents. Structure-activity relationships for capsaicin agonists have previously been rationalized, by ourselves and others, by dividing the capsaicin molecule into three regions-the A (aromatic ring)-, B (amide bond)-, and C (hydrophobic side chain)-regions. In this study, the effects on biological activity of conformational constraint of the A-region with respect to the B-region are discussed. Conformational constraint was achieved by the introduction of saturated ring systems of different sizes. The resulting compounds provided agonists of comparable potency to unconstrained analogues as well as a moderately potent antagonist, capsazepine. This compound is the first competitive antagonist of capsaicin and resiniferatoxin to be described and is active in various systems, in vitro and in vivo. It has recently attracted considerable interest as a tool for dissecting the mechanisms by which capsaicin analogues evoke their effects. NMR spectroscopy and X-ray crystallography experiments, as well as molecular modeling techniques, were used to study the conformational behavior of a representative constrained agonist and antagonist. The conformation of the saturated ring contraint in the two cases was found to differ markedly, dramatically affecting the relative disposition of the A-ring and B-region pharmacophores. In agonist structures, the A- and B-regions were virtually coplanar in contrast to those in the antagonist, in which they were approximately orthogonal. A rationale for agonist and antagonist activity at the capsaicin receptor is proposed, based on the consideration of these conformational differences.