1-(3-pyridyl)azetidin-3-amine

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 1-(3-pyridyl)azetidin-3-amine
• 英文别名: 1-(pyridin-3-yl)azetidin-3-amine；1-(Pyridin-3-yl)azetidin-3-amine；1-pyridin-3-ylazetidin-3-amine
• 化学式: C₈H₁₁N₃
• 分子量: 149.195
• InChiKey: ACRMQJYLNHOEJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  42.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylic acid 、 1-(3-pyridyl)azetidin-3-amine 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 5-amino-3,4-dimethyl-N-(1-pyridin-3-ylazetidin-3-yl)thieno[2,3-c]pyridazine-6-carboxamide
  参考文献：
  名称：

  Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

  摘要：

  This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c] pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and Pgp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3 mg/kg. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.05.014
• 作为产物：
  描述：

  tert-butyl [1-(pyridin-3-yl)azetidin-3-yl]carbamate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 1-(3-pyridyl)azetidin-3-amine
  参考文献：
  名称：

  Challenges in the development of an M 4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides

  摘要：

  This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c] pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and Pgp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3 mg/kg. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.05.014

文献信息

• [EN] SUBSTITUTED THIENO[2,3-B]PYRIDINE-2-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4<br/>[FR] ANALOGUES DE THIÉNO[2,3-B]PYRIDINE-2-CARBOXAMIDE SUBSTITUÉS À UTILISER EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE DE L'ACÉTYLCHOLINE M4
  申请人：UNIV VANDERBILT

  公开号：WO2015027204A1

  公开（公告）日：2015-02-26

  In one aspect, the invention relates to substituted thieno[2,3-b]pyridine-2-carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，该发明涉及替代噻吩[2,3-b]吡啶-2-羧酰胺类似物，其衍生物和相关化合物，这些化合物可用作肌胆碱受体M4（mAChR M4）的正向别构调节剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与肌胆碱受体功能障碍相关的神经系统和精神疾病的方法。本摘要旨在作为在特定领域进行搜索的扫描工具，并不限制本发明。
• [EN] 5,7-DIHYDRO-PYRROLO-PYRIDINE DERIVATIVES FOR TREATING NEUROLOGICAL AND NEURODEGENERATIVE DISEASES<br/>[FR] DÉRIVÉS DE 5,7-DIHYDRO-PYRROLO-PYRIDINE POUR LE TRAITEMENT DE MALADIES NEUROLOGIQUES ET NEURODÉGÉNÉRATIVES
  申请人：PFIZER

  公开号：WO2018002760A1

  公开（公告）日：2018-01-04

  The present invention provides, in part, compounds of Formula (I): or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N- oxide, wherein: R1, R2, L, A, and E are as described herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, N-oxides, or salts, and their uses for treating M4-mediated (or M4- associated) disorders including, e.g., Alzheimer's Disease, schizophrenia (e.g., its cognitive and negative symptoms), pain, addiction, and a sleep disorder.

  本发明部分提供了Formula (I)的化合物：或其N-氧化物，或该化合物或N-氧化物的药用盐，其中：R1、R2、L、A和E如本文所述；用于制备的过程；用于制备的中间体；以及含有这种化合物、N-氧化物或盐的组合物，以及它们用于治疗M4介导的（或M4相关的）疾病，例如阿尔茨海默病、精神分裂症（例如其认知和消极症状）、疼痛、成瘾和睡眠障碍。
• [EN] SUBSTITUTED THIENO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4<br/>[FR] ANALOGUES DE THIÉNO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE SUBSTITUÉS UTILISÉS EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE DE L'ACÉTYLCHOLINE M4
  申请人：UNIV VANDERBILT

  公开号：WO2015027214A1

  公开（公告）日：2015-02-26

  In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6- carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在某个方面，该发明涉及替代的5-氨基噻吩[2,3-c]吡啶嗪-6-羧酰胺类似物，其衍生物以及相关化合物，这些化合物可用作肌胆碱受体M4的正向变构调节剂（mAChR M4）；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与肌胆碱受体功能障碍相关的神经和精神疾病的方法。本摘要旨在作为在特定领域进行搜索的扫描工具，并不旨在限制本发明。
• VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate
  作者：Darren W. Engers、Bruce J. Melancon、Allison R. Gregro、Jeanette L. Bertron、Sean R. Bollinger、Andrew S. Felts、Leah C. Konkol、Michael R. Wood、Katrina A. Bollinger、Vincent B. Luscombe、Alice L. Rodriguez、Carrie K. Jones、Michael Bubser、Samantha E. Yohn、Michael W. Wood、Nicholas J. Brandon、Mark E. Dugan、Colleen M. Niswender、P. Jeffrey Conn、Thomas M. Bridges、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2019.05.026

  日期：2019.7

  PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which

  这封信描述了M4 PAM临床前候选药物的进展，该发现导致了VU6005806 / AZN-00016130的发现。尽管噻吩并[2,3-c]哒嗪核心一直是关键的M4 PAM的一致特征，但以前尚未报道有关哒嗪环C3位上的替代官能团的工作。在这里，我们详细介绍了探索该区域的新化学方法和类似物，并迅速产生了VU6005806 / AZN-00016130，该产品被认为是公认的候选产品。虽然，β-氨基羧酰胺部分在更高的物种中限制了吸收（限制了其发展）（或需要广泛的药物科学制剂），但溶解度受到限制，VU6005806 / AZN-00016130代表了一种新型的高质量临床前体内探针。
• SUBSTITUTED THIENO[2,3-B]PYRIDINE-2-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4
  申请人：Vanderbilt University

  公开号：US20160200733A1

  公开（公告）日：2016-07-14

  In one aspect, the invention relates to substituted thieno[2,3-b]pyridine-2-carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M 4 (mAChR M 4 ); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本发明涉及替代噻吩[2,3-b]吡啶-2-羧酰胺类似物、其衍生物和相关化合物，其作为肌动蛋白乙酰胆碱受体M4（mAChR M4）的正向变构调节剂具有用途；制备这些化合物的合成方法；包含这些化合物的制药组合物；以及使用这些化合物和组合物治疗与肌动蛋白乙酰胆碱受体功能障碍相关的神经和精神障碍的方法。本摘要旨在作为搜索特定技术领域的扫描工具，不限制本发明。