3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine | 1562343-12-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine
• 英文别名: 3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)methyl]pyridazine
• CAS: 1562343-12-7
• 化学式: C₂₄H₃₁N₅O
• 分子量: 405.543
• InChiKey: QLACWJVHVUIAQK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.64
• 重原子数：
  30.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  75.72
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine 在 potassium carbonate 、 苯硫酚 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 0.25h， 以62%的产率得到5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol
  参考文献：
  名称：

  Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)

  摘要：

  Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

  DOI：

  10.1021/acs.jmedchem.8b01291
• 作为产物：
  描述：

  四甲基哌啶酮 在 2-双环己基膦-2',6'-二甲氧基联苯 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium tert-butylate 、 sodium carbonate 、 三乙胺 、 9-硼双环[3.3.1]壬烷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醚 、 二氯甲烷 、 水 为溶剂， 反应 39.58h， 生成 3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine
  参考文献：
  名称：

  Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)

  摘要：

  Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

  DOI：

  10.1021/acs.jmedchem.8b01291

文献信息

• [EN] 1,4-DISUBSTITUTED PYRIDAZINE ANALOGS AND METHODS FOR TREATING SMN-DEFICIENCY-RELATED CONDITIONS<br/>[FR] ANALOGUES DE PYRIDAZINE 1,4-DISUBSTITUÉE ET PROCÉDÉS DE TRAITEMENT DE TROUBLES LIÉS À UNE DÉFICIENCE EN SMN
  申请人：NOVARTIS AG

  公开号：WO2014028459A1

  公开（公告）日：2014-02-20

  The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

  本发明提供了一种公式(I)的化合物或其药用可接受的盐；一种制造本发明化合物的方法及其治疗用途。本发明进一步提供了一种药物活性剂的组合物和一种药物组合物。
• 1,4-DISUBSTITUTED PYRIDAZINE ANALOGS THERE OF AND METHODS FOR TREATING SMN-DEFICIENCY-RELATED CONDITIONS
  申请人：NOVARTIS AG

  公开号：US20170290828A1

  公开（公告）日：2017-10-12

  The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

  本发明提供了式I的化合物或其药学上可接受的盐；制备本发明化合物的方法以及其治疗用途。本发明还提供了具有药理活性剂的组合物和制药组合物。
• 1,4-disubstituted pyridazine analogs there of and methods for treating SMN-deficiency-related conditions
  申请人：Cheung Atwood Kim

  公开号：US08729263B2

  公开（公告）日：2014-05-20

  The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

  本发明提供了公式I的化合物或其药学上可接受的盐；一种制造该发明化合物的方法以及其治疗用途。本发明还提供了一种药理活性剂的组合和制药组合物。
• 1,4-disubstituted pyridazine analogs thereof and methods for treating SMN-deficiency-related conditions
  申请人：Novartis AG

  公开号：US11229648B2

  公开（公告）日：2022-01-25

  The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

  本发明提供了一种式 I 的化合物或其药学上可接受的盐； 一种制造本发明化合物的方法及其治疗用途。本发明还提供了一种药理活性剂组合和药物组合物。
• 1,4-DISUBSTITUTED PYRIDAZINE ANALOGS AND METHODS FOR TREATING SMN-DEFICIENCY-RELATED CONDITIONS
  申请人：Novartis AG

  公开号：EP2885288A1

  公开（公告）日：2015-06-24