3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1S,2R)-(2-methoxyethyl)cyclopropyl]pyridine | 1222137-91-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环丁烷
• 英文名称: 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1S,2R)-(2-methoxyethyl)cyclopropyl]pyridine
• 英文别名: tert-butyl (2S)-2-[[5-[(1S,2R)-2-(2-methoxyethyl)cyclopropyl]pyridin-3-yl]oxymethyl]azetidine-1-carboxylate
• CAS: 1222137-91-8
• 化学式: C₂₀H₃₀N₂O₄
• 分子量: 362.469
• InChiKey: RXEBSGCVWBLIJV-ZVZYQTTQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  60.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1S,2R)-(2-methoxyethyl)cyclopropyl]pyridine 在 三氟乙酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 3.0h， 以55%的产率得到3-[(2(S)-azetidinyl)methoxy]-5-[(1S,2R)-(2-methoxyethyl)cyclopropyl]pyridine
  参考文献：
  名称：

  NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF

  摘要：

  该发明涉及吡啶基烟碱乙酰胆碱受体配体，包含有效量吡啶基烟碱乙酰胆碱受体配体的组合物，以及治疗或预防某种疾病的方法，如抑郁症和尼古丁依赖症，包括向需要的动物施用有效量吡啶基烟碱乙酰胆碱受体配体。

  公开号：

  US20130184313A1
• 作为产物：
  描述：

  3-苯甲氧基-5-溴吡啶 在 4-二甲氨基吡啶 、 platinum(IV) oxide 、 sodium tetrahydroborate 、 正丁基锂 、 草酰氯 、 三丁基膦 、 苯基脲 、 palladium 10% on activated carbon 、 水 、 氢气 、 palladium diacetate 、 sodium hydride 、 potassium carbonate 、 二甲基亚砜 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 27.59h， 生成 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[(1S,2R)-(2-methoxyethyl)cyclopropyl]pyridine
  参考文献：
  名称：

  Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile

  摘要：

  Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing alpha 4 beta 2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at alpha 4 beta 2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other alpha 4 beta 2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.

  DOI：

  10.1021/jm201157c

文献信息

• [EN] NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF<br/>[FR] LIGANDS DES RÉCEPTEURS CHOLINERGIQUES NICOTINIQUES ET LEURS UTILISATIONS
  申请人：PSYCHOGENICS INC

  公开号：WO2010045212A3

  公开（公告）日：2010-07-29
• US8445684B2
  申请人：——

  公开号：US8445684B2

  公开（公告）日：2013-05-21
• NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS AND THE USES THEREOF
  申请人：Chandrasekhar Jayaraman

  公开号：US20130184313A1

  公开（公告）日：2013-07-18

  The invention relates to pyridinyl nicotinic acetylcholine receptor ligands, compositions comprising an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand and methods to treat or prevent a condition, such as depression and nicotine dependence, comprising administering to an animal in need thereof an effective amount of a pyridinyl nicotinic acetylcholine receptor ligand.

  该发明涉及吡啶基烟碱乙酰胆碱受体配体，包含有效量吡啶基烟碱乙酰胆碱受体配体的组合物，以及治疗或预防某种疾病的方法，如抑郁症和尼古丁依赖症，包括向需要的动物施用有效量吡啶基烟碱乙酰胆碱受体配体。
• Chemistry and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile
  作者：Hankun Zhang、Werner Tückmantel、J. Brek Eaton、Po-wai Yuen、Li-Fang Yu、Krishna Mohan Bajjuri、Allison Fedolak、Daguang Wang、Afshin Ghavami、Barbara Caldarone、Neil E. Paterson、David A. Lowe、Daniela Brunner、Ronald J. Lukas、Alan P. Kozikowski

  DOI：10.1021/jm201157c

  日期：2012.1.26

  Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing alpha 4 beta 2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at alpha 4 beta 2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other alpha 4 beta 2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression.