sodium 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylate | 1451998-17-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: sodium 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylate
• 英文别名: Sodium 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylate；sodium;5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylate
• CAS: 1451998-17-6
• 化学式: C₉H₈N₃O₂S*Na
• 分子量: 245.237
• InChiKey: XQDLJMQRVUGQTN-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -2.74
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  120
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  sodium 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylate 、 邻溴苄胺 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-N-[(2-bromophenyl)methyl]-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxamide
  参考文献：
  名称：

  Optimization of M 4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology

  摘要：

  This letter describes the further chemical optimization of the 5-amino-thieno(2,3-c]pyridazine series (VU0467154/VU0467485) of M-4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.04.043
• 作为产物：
  描述：

  3-chloro-5,6-dimethylpyridazine-4-carbonitrile 、 巯基乙酸甲酯 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 0.5h， 以78%的产率得到sodium 5-amino-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxylate
  参考文献：
  名称：

  VU0467485 / AZ13713945的发现：被评估为治疗精神分裂症的临床前候选药物的M4 PAM。

  摘要：

  在这里，我们报告一系列有效的，选择性的和口服生物利用毒蕈碱乙酰胆碱受体4（M4）变构调节剂（PAMs）中的结构活性关系。在精神分裂症的临床前模型中，化合物6c（VU0467485）具有跨物种的强大体外M4 PAM效能和体内功效。结合有吸引力的DMPK谱和合适的预测人PK，将6c（VU0467485）评估为临床前开发候选药物。

  DOI：

  10.1021/acsmedchemlett.6b00461

文献信息

• [EN] SUBSTITUTED 5-AMINOTHIENO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4<br/>[FR] ANALOGUES DE 5-AMINOTHIÉNO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE SUBSTITUÉS EN TANT QUE MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR MUSCARINIQUE DE L'ACÉTYLCHOLINE M4
  申请人：UNIV VANDERBILT

  公开号：WO2013126856A1

  公开（公告）日：2013-08-29

  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.

  在一个方面，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）的正向变构调节剂；制备这些化合物的合成方法；包括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，并不意味着对本发明的限制。
• Discovery of VU0467485/AZ13713945: An M₄ PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia
  作者：Michael R. Wood、Meredith J. Noetzel、Bruce J. Melancon、Michael S. Poslusney、Kellie D. Nance、Miguel A. Hurtado、Vincent B. Luscombe、Rebecca L. Weiner、Alice L. Rodriguez、Atin Lamsal、Sichen Chang、Michael Bubser、Anna L. Blobaum、Darren W. Engers、Colleen M. Niswender、Carrie K. Jones、Nicholas J. Brandon、Michael W. Wood、Mark E. Duggan、P. Jeffrey Conn、Thomas M. Bridges、Craig W. Lindsley

  DOI：10.1021/acsmedchemlett.6b00461

  日期：2017.2.9

  Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted

  在这里，我们报告一系列有效的，选择性的和口服生物利用毒蕈碱乙酰胆碱受体4（M4）变构调节剂（PAMs）中的结构活性关系。在精神分裂症的临床前模型中，化合物6c（VU0467485）具有跨物种的强大体外M4 PAM效能和体内功效。结合有吸引力的DMPK谱和合适的预测人PK，将6c（VU0467485）评估为临床前开发候选药物。
• SUBSTITUTED 5-AMINOTHIENO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4
  申请人：VANDERBILT UNIVERSITY

  公开号：US20150018309A1

  公开（公告）日：2015-01-15

  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 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.

  本发明涉及取代的5-氨基噻吩[2,3-c]吡嗪-6-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；制备该化合物的合成方法；包括该化合物的药物组合物；以及使用该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。本摘要旨在作为特定领域搜索的扫描工具，不限制本发明。
• Selective Activation of M₄ Muscarinic Acetylcholine Receptors Reverses MK-801-Induced Behavioral Impairments and Enhances Associative Learning in Rodents
  作者：Michael Bubser、Thomas M. Bridges、Ditte Dencker、Robert W. Gould、Michael Grannan、Meredith J. Noetzel、Atin Lamsal、Colleen M. Niswender、J. Scott Daniels、Michael S. Poslusney、Bruce J. Melancon、James C. Tarr、Frank W. Byers、Jürgen Wess、Mark E. Duggan、John Dunlop、Michael W. Wood、Nicholas J. Brandon、Michael R. Wood、Craig W. Lindsley、P. Jeffrey Conn、Carrie K. Jones

  DOI：10.1021/cn500128b

  日期：2014.10.15

  Positive allosteric modulators (PAMs) of the M-4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M-4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-D-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M-1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M-4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M-4 PAMs, enabling a more extensive characterization of M-4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M-4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M-4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M-4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.
• US9493481B2
  申请人：——

  公开号：US9493481B2

  公开（公告）日：2016-11-15