1-[2-(5-bromo-1-benzofuran-2-yl)ethyl]-2(R)-methylpyrrolidine | 460748-22-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: 1-[2-(5-bromo-1-benzofuran-2-yl)ethyl]-2(R)-methylpyrrolidine
• 英文别名: (R)-1-(2-(5-bromobenzofuran-2-yl)ethyl)-2-methylpyrrolidine；(2R)-1-[2-(5-bromo-1-benzofuran-2-yl)ethyl]-2-methylpyrrolidine
• CAS: 460748-22-5
• 化学式: C₁₅H₁₈BrNO
• 分子量: 308.218
• InChiKey: VTKKXXQRBFNDRN-LLVKDONJSA-N

物化性质

• 沸点：
  368.9±27.0 °C(Predicted)
• 密度：
  1.333±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  16.4
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-[2-(5-bromo-1-benzofuran-2-yl)ethyl]-2(R)-methylpyrrolidine 在 bis-triphenylphosphine-palladium(II) chloride potassium acetate 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 异丙醇 为溶剂， 反应 36.0h， 生成 A-698418
  参考文献：
  名称：

  Novel heterocyclic-substituted benzofuran histamine H3 receptor antagonists: In vitro properties, drug-likeness, and behavioral activity

  摘要：

  Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H-3 receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H-3 receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H-3 receptors (H-3, K-i = 13 nM) versus off-target receptors and channels (including the hERG K+ channel, K-i > 9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4) = 2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP450 inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9 h, 1.7 h in dog, 1.8 h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound. (c) 2007 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2007.02.010
• 作为产物：
  描述：

  4-溴-2-碘苯酚 、 3-丁炔-2-(R)-甲基吡咯烷 在 二异丙胺 palladium diacetate 、 copper(l) iodide 、 三苯基膦 作用下， 以 乙腈 为溶剂， 反应 84.0h， 以26%的产率得到1-[2-(5-bromo-1-benzofuran-2-yl)ethyl]-2(R)-methylpyrrolidine
  参考文献：
  名称：

  4-（2- [2-（2（R）-甲基吡咯烷-1-基）乙基]苯并呋喃-5-基）苄腈和相关的2-氨基乙基苯并呋喃H3受体拮抗剂有效地增强了认知和注意力。

  摘要：

  已发现基于2-氨基乙基苯并呋喃骨架的H（3）受体拮抗剂，在人和大鼠的H（3）受体中具有很强的体外作用力，K（i）值为0.1-5.8 nM。在动物模型中发现具有有效（0.01-1 mg / kg）认知和注意力增强特性的类似物。一种化合物，特别是4-（2- [2-（2（R）-甲基吡咯烷-1-基）乙基]苯并呋喃-5-基）苄腈（ABT-239），具有有效和选择性的H（3）受体拮抗作用以及跨物种优异的药代动力学和代谢特性，在两种行为模型中均具有完整的功效：大鼠幼崽以0.1 mg / kg的五次试验性避免回避获取模型和成年大鼠以0.01 mg / kg的社交认知记忆模型。此外，与基于中枢神经系统的副作用相比，该化合物不刺激运动活性，并且对诱导行为功效具有很高的选择性。该化合物及其类似物的效能和选择性支持H（3）受体拮抗剂治疗认知功能障碍的潜力。

  DOI：

  10.1021/jm040118g

文献信息

• Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H₃ Receptor Antagonists with Improved Potency
  作者：Minghua Sun、Chen Zhao、Gregory A. Gfesser、Christine Thiffault、Thomas R. Miller、Kennan Marsh、Jill Wetter、Michael Curtis、Ramin Faghih、Timothy A. Esbenshade、Arthur A. Hancock、Marlon Cowart

  DOI：10.1021/jm0504398

  日期：2005.10.1

  A new series of H3 receptor antagonists was discovered with nanomolar and subnanomolar affinities at human and rat H3 receptors. Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with greater in vitro potency. One compound in particular, [2-[2-(2-(R)-methylpyrrolidin-1-yl)ethyl]benzof

  发现了一系列新的H3受体拮抗剂，它们在人和大鼠H3受体上具有纳摩尔和亚纳摩尔亲和力。从较早的，在结构上更受限制的苯并呋喃系列开始，本系列化合物证明了增加的结构多样性和柔韧性以及更高的体外效能。一种化合物，尤其是[2- [2-（2-（R）-甲基吡咯烷-1-基）乙基]苯并呋喃-5-基]（5-硝基吡啶-2-基）酰胺（7h）效果最好。结合力（人K（i）为0.05 nM，大鼠K（i）为0.11 nM），与ABT-239（化合物5）相比，代表了9倍（人）和11倍（大鼠）的提高。 ，一种先前据报道具有出色的体外效价和体内功效的化合物。H3结合亲和力的合成，SAR，磷脂酶的体外测定，
• Novel amines as histamine-3 receptor ligands and their therapeutic applications
  申请人：——

  公开号：US20020169188A1

  公开（公告）日：2002-11-14

  Compounds of formula (I) 1 or a pharmaceutically acceptable salts or prodrug thereof which are useful for the modulation of the histamine-3 receptors in mammals and which are useful for the treatment of disorders ameliorated by histamine-3 receptor ligands.

  化合物的公式(I)1或其药用可接受的盐或前药，对哺乳动物的组胺-3受体进行调节是有用的，并且对组胺-3受体配体改善的疾病的治疗是有用的。
• Process for preparing amine-substituted benzofurans
  申请人：——

  公开号：US20040054185A1

  公开（公告）日：2004-03-18

  The present invention relates to processes for preparing amine substituted benzofurans, and more particularly 4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile, and salts thereof. Compounds prepared by the processes of the invention have demonstrated activity as histamine-3 receptor ligands.

  本发明涉及制备胺基取代苯并呋喃的方法，更具体地是4-(2-2-[(2R)-2-甲基-1-吡咯基]乙基}-1-苯并呋喃-5-基)苯甲腈及其盐。根据本发明的方法制备的化合物已经表现出作为组胺-3受体配体的活性。
• Amines as histamine-3 receptor ligands and their therapeutic applications
  申请人：Abbott Laboratories

  公开号：US07538138B2

  公开（公告）日：2009-05-26

  Compounds of formula (I) or a pharmaceutically acceptable salts or prodrug thereof which are useful for the modulation of the histamine-3 receptors in mammals and which are useful for the treatment of disorders ameliorated by histamine-3 receptor ligands.

  公式（I）的化合物或其药学上可接受的盐或前药，对哺乳动物组织中组胺-3受体的调节具有有用作用，并且对通过组胺-3受体配体改善的疾病的治疗具有有用作用。
• Structure–activity relationships of arylbenzofuran H3 receptor antagonists
  作者：Gregory A. Gfesser、Ramin Faghih、Youssef L. Bennani、Michael P. Curtis、Timothy A. Esbenshade、Arthur A. Hancock、Marlon D. Cowart

  DOI：10.1016/j.bmcl.2005.03.047

  日期：2005.5

  An SAR study of histamine H-3 receptor antagonists based on substituted (R)-2-methyl-1-[2-(5-phenyl-benzofuran-2-yl)ethyl] -pyrrolidines is presented. (c) 2005 Elsevier Ltd. All rights reserved.