{(1S,2S,3R,6S)-9-[1-(4-Bromo-3-chloro-phenyl)-meth-(Z)-ylidene]-7-aza-tricyclo[4.3.1.0^3,7]dec-2-yl}-methanol | 1027247-02-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚里西啶
• 英文名称: {(1S,2S,3R,6S)-9-[1-(4-Bromo-3-chloro-phenyl)-meth-(Z)-ylidene]-7-aza-tricyclo[4.3.1.0^3,7]dec-2-yl}-methanol
• 英文别名: [(1S,2S,3R,6S,9Z)-9-[(4-bromo-3-chlorophenyl)methylidene]-7-azatricyclo[4.3.1.03,7]decan-2-yl]methanol
• CAS: 1027247-02-4
• 化学式: C₁₇H₁₉BrClNO
• 分子量: 368.701
• InChiKey: QLRJYDXMGVHKNZ-IHKUXFPDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  苯甲酰氯 、 {(1S,2S,3R,6S)-9-[1-(4-Bromo-3-chloro-phenyl)-meth-(Z)-ylidene]-7-aza-tricyclo[4.3.1.0^3,7]dec-2-yl}-methanol 在 吡啶 、 4-二甲氨基吡啶 作用下， 反应 2.0h， 生成 (1S,3S,6R,10S)-(Z)-10-(benzoyloxymethyl)-9-(4-bromo-3-chlorobenzylidene)-7-azatricyclo[4.3.1.0^3,7]decane
  参考文献：
  名称：

  构象约束的三环环烷的芳基类似物作为有效的和选择性的去甲肾上腺素再摄取抑制剂：合成和评估其在单胺转运蛋白位点的摄取抑制作用。

  摘要：

  合成了一系列新型的构象约束的三环环烷衍生物，其中含有联芳基部分（Z）-9-（联芳基亚甲基）-7-氮杂三环[4.3.1.0（3,7）]癸烷，并评估了其抑制重吸收的能力。多巴胺（DA），5-羟色胺（5-HT）和去甲肾上腺素（NE）通过DA，5-HT和NE转运蛋白进行转运。大多数在C-10处含有甲氧羰基取代基的化合物在NET上显示中等至高抑制活性，但在DAT和SERT上显示较低的活性。在这些新化合物中，鉴定出一些有效的，NET选择配体。对甲氧基衍生物11a具有39nM的K（i）值，用于在NET处的吸收抑制，并且在SERT（100倍）和DAT（20倍）上具有中等至高选择性。化合物11f表现出显着的效能（K（i）= 9。NET的选择性（7 nM），选择性比SERT和DAT高25倍。含有噻吩环作为苯环Ar（1）的生物等位替代物的类似物23对NET表现出高活性（K（i）= 10.3 nM），并且在SER

  DOI：

  10.1021/jm020596w
• 作为产物：
  描述：

  (1S,3R,6S)-(Z)-9-[(tri-n-butylstannyl)methylene]-7-azatricyclo[4.3.1.0^3,7]decane-2β-carboxylic acid methyl ester 在 copper(l) iodide 、 lithium aluminium tetrahydride 、 tris(dibenzylideneacetone)dipalladium (0) 、 三苯胂 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.33h， 生成 {(1S,2S,3R,6S)-9-[1-(4-Bromo-3-chloro-phenyl)-meth-(Z)-ylidene]-7-aza-tricyclo[4.3.1.0^3,7]dec-2-yl}-methanol
  参考文献：
  名称：

  构象约束的三环环烷的芳基类似物作为有效的和选择性的去甲肾上腺素再摄取抑制剂：合成和评估其在单胺转运蛋白位点的摄取抑制作用。

  摘要：

  合成了一系列新型的构象约束的三环环烷衍生物，其中含有联芳基部分（Z）-9-（联芳基亚甲基）-7-氮杂三环[4.3.1.0（3,7）]癸烷，并评估了其抑制重吸收的能力。多巴胺（DA），5-羟色胺（5-HT）和去甲肾上腺素（NE）通过DA，5-HT和NE转运蛋白进行转运。大多数在C-10处含有甲氧羰基取代基的化合物在NET上显示中等至高抑制活性，但在DAT和SERT上显示较低的活性。在这些新化合物中，鉴定出一些有效的，NET选择配体。对甲氧基衍生物11a具有39nM的K（i）值，用于在NET处的吸收抑制，并且在SERT（100倍）和DAT（20倍）上具有中等至高选择性。化合物11f表现出显着的效能（K（i）= 9。NET的选择性（7 nM），选择性比SERT和DAT高25倍。含有噻吩环作为苯环Ar（1）的生物等位替代物的类似物23对NET表现出高活性（K（i）= 10.3 nM），并且在SER

  DOI：

  10.1021/jm020596w

文献信息

• Further Studies on Conformationally Constrained Tricyclic Tropane Analogues and Their Uptake Inhibition at Monoamine Transporter Sites:  Synthesis of (<i>Z</i>)-9-(Substituted arylmethylene)-7-azatricyclo[4.3.1.0^3,7]decanes as a Novel Class of Serotonin Transporter Inhibitors
  作者：Ao Zhang、Guochun Zhou、Alexander Hoepping、Jayanta Mukhopadhyaya、Kenneth M. Johnson、Mei Zhang、Alan P. Kozikowski

  DOI：10.1021/jm0105373

  日期：2002.4.1

  A novel series of conformationally constrained tricyclic tropane analogues, (Z)-9-(substituted arylmethylene)-7-azatricyclo [4.3.1.0(3,7)] decanes, were prepared, and their abilities to inhibit high-affinity uptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes) were evaluated. First, a systematic screening of a variety of different substituents on the phenyl ring indicated that the substitution pattern plays an important role in the monoamine transporter activity. Most compounds in this series possessed a very low activity at the DA transporter (DAT) but a good to excellent affinity for the 5-HT transporter (SERT). In the case of para-substituted phenyl analogues, the electronic character of the substituent did not affect uptake inhibition as dramatically as observed in some benztropine analogues. Among these compounds, the 4-bromophenyl and 4-isopropylphenyl analogues 8d and 8j exhibited the highest potency at the SERT with a K-i value of 10 nM. In the 3,4-disubstituted phenyl series, even more potent and highly selective compounds were discovered. Compound So has a K-i value of 2.3 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 2360, and a NET/SERT uptake ratio of 200. Compound 8p exhibited a Ki value of 1.8 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 1740, and a NET/SERT uptake ratio of 151. These compounds are 3-4-fold more potent than the antidepressant medication fluoxetine, and the selectivities for SERT over DAT and NET are also better than those of fluoxetine. Second, a variety of functional modifications on the ester moiety were investigated. Substitution by other esters or amides as well as alkenes did not increase potency, while most of the acetates or benzoates (16-21, 23, and 24) and the ketone 28 exhibited significantly improved activity. A good hydrogen-bonding ability of the substituent is believed to be required for high activity. The most potent and selective ligand is compound 23, which displayed a K-i value of 0.06 nM and has essentially no activity at the DAT or NET. The present results have important implications for drug addiction as well as a number of psychiatric diseases.
• Biaryl Analogues of Conformationally Constrained Tricyclic Tropanes as Potent and Selective Norepinephrine Reuptake Inhibitors:  Synthesis and Evaluation of Their Uptake Inhibition at Monoamine Transporter Sites
  作者：Jia Zhou、Ao Zhang、Thomas Kläss、Kenneth M. Johnson、Cheng Z. Wang、Yan Ping Ye、Alan P. Kozikowski

  DOI：10.1021/jm020596w

  日期：2003.5.1

  A series of novel conformationally constrained tricyclic tropane derivatives containing a biaryl moiety, (Z)-9-(biarylylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes, were synthesized and evaluated for their ability to inhibit reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) by the DA, 5-HT, and NE transporters. Most of the compounds containing a methoxycarbonyl substituent at C-10

  合成了一系列新型的构象约束的三环环烷衍生物，其中含有联芳基部分（Z）-9-（联芳基亚甲基）-7-氮杂三环[4.3.1.0（3,7）]癸烷，并评估了其抑制重吸收的能力。多巴胺（DA），5-羟色胺（5-HT）和去甲肾上腺素（NE）通过DA，5-HT和NE转运蛋白进行转运。大多数在C-10处含有甲氧羰基取代基的化合物在NET上显示中等至高抑制活性，但在DAT和SERT上显示较低的活性。在这些新化合物中，鉴定出一些有效的，NET选择配体。对甲氧基衍生物11a具有39nM的K（i）值，用于在NET处的吸收抑制，并且在SERT（100倍）和DAT（20倍）上具有中等至高选择性。化合物11f表现出显着的效能（K（i）= 9。NET的选择性（7 nM），选择性比SERT和DAT高25倍。含有噻吩环作为苯环Ar（1）的生物等位替代物的类似物23对NET表现出高活性（K（i）= 10.3 nM），并且在SER