(1S,3R,6S)-(Z)-9-[(tri-n-butylstannyl)methylene]-7-azatricyclo[4.3.1.0^3,7]decane-2β-carboxylic acid methyl ester | 275355-51-6

• 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,3R,6S)-(Z)-9-[(tri-n-butylstannyl)methylene]-7-azatricyclo[4.3.1.0^3,7]decane-2β-carboxylic acid methyl ester
• CAS: 275355-51-6
• 化学式: C₂₄H₄₃NO₂Sn
• 分子量: 496.321
• InChiKey: NSYUQFNTTIMOJU-ZJHZWMAASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.96
• 重原子数：
  28
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  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 tris(dibenzylideneacetone)dipalladium (0) 吡啶 、 4-二甲氨基吡啶 、 copper(l) iodide 、 lithium aluminium tetrahydride 、 三(邻甲基苯基)磷 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.25h， 生成 (1S,3S,6R,10S)-(Z)-10-(acetoxymethyl)-9-(3-chlorobenzylidene)-7-azatricyclo[4.3.1.0^3,7]decane
  参考文献：
  名称：

  Further Studies on Conformationally Constrained Tricyclic Tropane Analogues and Their Uptake Inhibition at Monoamine Transporter Sites:  Synthesis of (Z)-9-(Substituted arylmethylene)-7-azatricyclo[4.3.1.0^3,7]decanes as a Novel Class of Serotonin Transporter Inhibitors

  摘要：

  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.

  DOI：

  10.1021/jm0105373
• 作为产物：
  描述：

  三正丁基氢锡 、 N-propargylnoranhydroecgonine methyl ester 在 偶氮二异丁腈 作用下， 以 苯 为溶剂， 生成 (1S,3R,6S)-(Z)-9-[(tri-n-butylstannyl)methylene]-7-azatricyclo[4.3.1.0^3,7]decane-2β-carboxylic acid methyl ester 、 (1S,3R,6S)-(Z)-9-[(tri-n-butylstannyl)methylene]-7-azatricyclo[4.3.1.0^3,7]decane-2β-carboxylic acid methyl ester
  参考文献：
  名称：

  Tropane analogs

  摘要：

  本发明提供了化合物，特别是新颖的曲梨酮类似物，能够作为单胺再摄取抑制剂。在优选实施方式中，这些组合物是选择性的血清素和/或去甲肾上腺素再摄取抑制剂。本文还提供了包括新颖的曲梨酮类似物和药用可接受载体的药物组合物，以及治疗需要抑制单胺再摄取的疾病的方法。如本文所述的创新组合物还可用于医学治疗和诊断。

  公开号：

  US06982271B1

文献信息

• Synthesis and pharmacological evaluation of ( Z )-9-(Heteroarylmethylene)-7-azatricyclo[4.3.1.0 3,7 ]decanes: thiophene analogues as potent norepinephrine transporter inhibitors
  作者：Jia Zhou、Thomas Kläß、Ao Zhang、Kenneth M Johnson、Cheng Z Wang、Yanping Ye、Alan P Kozikowski

  DOI：10.1016/s0960-894x(03)00786-8

  日期：2003.10

  at norepinephrine transporters (NET), we have introduced both five- and six-membered heteroaromatic moieties such as substituted pyridyl, pyrazinyl, pyrimidyl, thiazolyl, and mono- or disubstituted thienyl groups into conformationally constrained, tricyclic tropane analogues. A number of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes were synthesized, and their abilities to block dopamine

  为了进一步探索某些对烷的结构活性关系（SAR），并深入了解去甲肾上腺素转运蛋白（NET）的高活性和选择性所需要的结构特征，我们引入了五元和六元杂芳族部分，例如取代的吡啶基，吡嗪基，嘧啶基，噻唑基和单或二取代的噻吩基成构象约束的三环托烷类似物。合成了许多（Z）-9-（杂芳基亚甲基）-7-氮杂三环[4.3.1.0（3,7）]癸烷，并评估了它们各自转运蛋白阻断多巴胺，5-羟色胺和去甲肾上腺素再摄取的能力。发现五元或六元含氮芳族化合物太碱性，无法显示出较高的NET活性，
• Novel Conformationally Constrained Tropane Analogues by 6-<i>e</i><i>ndo-trig</i> Radical Cyclization and Stille Coupling − Switch of Activity toward the Serotonin and/or Norepinephrine Transporter
  作者：Alexander Hoepping、Kenneth M. Johnson、Clifford George、Judith Flippen-Anderson、Alan P. Kozikowski

  DOI：10.1021/jm0001121

  日期：2000.5.1

  tricyclic tropane analogues has been synthesized by making use of radical cyclization technology in combination with the Stille coupling reaction. As hybrids between tropanes and quinuclidines, these tropaquinuclidines represent a significant structural departure from many of the other classes of tropane ligands synthesized to date. This structure class is characterized by the boat conformation of the

  利用自由基环化技术与Stille偶联反应相结合，合成了一类新型的三环环烷类似物。作为托烷和奎宁环烷之间的杂化物，这些托烷奎核苷与迄今合成的许多其他类别的托烷配体具有明显的结构偏离。该结构类别的特征是托烷环的船形和附加桥的取向（以及氮孤对的取向）以及芳族部分的不寻常位置。测试了所有化合物在相同条件下抑制单胺再摄取的能力。与可卡因相比，该系列药物抑制多巴胺再摄取的能力通常会下降，但仅针对一种化合物。（1S，3R，6S）-（Z）-9-（噻吩基亚甲基）-7-氮杂三环[4.3.1.0（3，7）]癸烷-2β-羧酸甲酯（5h）在多巴胺转运蛋白（DAT）上具有合理的活性（K（ i）= 268 nM）和去甲肾上腺素转运蛋白（NET）的活性良好（K（i）= 26 nM）。这些配体中的一些对NET，5-羟色胺转运蛋白（SERT）或NET / SERT表现出的效能和选择性令人震惊，特别是考虑到该系列芳香环从其通常
• 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
• Discovery of novel conformationally constrained tropane-based biaryl and arylacetylene ligands as potent and selective norepinephrine transporter inhibitors and potential antidepressants
  作者：Jia Zhou、Thomas Kläß、Kenneth M. Johnson、Kelly M. Giberson、Alan P. Kozikowski

  DOI：10.1016/j.bmcl.2005.03.083

  日期：2005.5

  To further explore the structure-activity relationships of conformationally constrained tropanes, a number of new biaryl and arylacetylene analogs were designed and synthesized. Some of these compounds such as 3a-b, 3d, 3f-h, 5b, and 7g were found to be highly potent and selective or mixed norepinephrine transporter (NET) inhibitors with K-i values of 0.8-9.4 nM. Moreover, all of these compounds display weak to extremely weak muscarinic receptor binding affinity, indicating that as potential antidepressants, they may overcome certain side effects that are of concern with other antidepressants, which are thought to be mediated by their anticholinergic properties. (c) 2005 Elsevier Ltd. All rights reserved.
• Thiophene derivatives: a new series of potent norepinephrine and serotonin reuptake inhibitors
  作者：Ao Zhang、Guochun Zhou、Suo-Bao Rong、Kenneth M. Johnson、Mei Zhang、Alan P. Kozikowski

  DOI：10.1016/s0960-894x(02)00103-8

  日期：2002.4

  A series of (1S,3S,6R,10S)-(Z)-9-(thienylmethylene- or substituted thienylmethylene)-7-azatricyclo[4.3.1.0(3.7)]decanes was prepared and evaluated for the ability to block dopamine, serotonin, and norepinephrine reuptake by their respective transporters. Compound 5b is a NET-selective inhibitor, 5c is a mixed NET- and SERT-selective inhibitor, while 11 is a SERT-selective inhibitor. (C) 2002 Elsevier Science Ltd. All rights reserved.