N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide
• 化学式: C₂₀H₂₃FN₆O
• 分子量: 382.441
• InChiKey: ZKLAQRFKZCJHJW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  74.6
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,4-二氟苯甲酰氯 在 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基乙酰胺 为溶剂， 反应 2.75h， 生成 N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide
  参考文献：
  名称：

  Discovery of a Novel Class of Survival Motor Neuron 2 Splicing Modifiers for the Treatment of Spinal Muscular Atrophy

  摘要：

  Spinal muscular atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, resulting in low levels of functional SMN protein. We have reported recently the identification of small molecules (coumarins, iso-coumarins and pyrido-pyrimidinones) that modify the alternative splicing of SMN2, a paralogous gene to SMN1, restoring the survival motor neuron (SMN) protein level in mouse models of SMA. Herein, we report our efforts to identify a novel chemotype as one strategy to potentially circumvent safety concerns from earlier derivatives such as in vitro phototoxicity and in vitro mutagenicity associated with compounds 1 and 2 or the in vivo retinal findings observed in a long-term chronic tox study with 3 at high exposures only. Optimized representative compounds modify the alternative splicing of SMN2, increase the production of full length SMN2 mRNA, and therefore levels of full length SMN protein upon oral administration in two mouse models of SMA.

  DOI：

  10.1021/acs.jmedchem.7b00406

文献信息

• COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY
  申请人：HOFFMANN-LA ROCHE INC.

  公开号：US20160145270A1

  公开（公告）日：2016-05-26

  The present invention provides compounds of formula (I) wherein A, B, X, Y, R1 and R2 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.

  本发明提供了式（I）化合物，其中A、B、X、Y、R1和R2如本文所述，以及其药学上可接受的盐。此外，本发明涉及制备式（I）化合物，包括它们的药物组合物以及它们作为药物的用途。
• [EN] COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY<br/>[FR] COMPOSÉS POUR LE TRAITEMENT D'UNE AMYOTROPHIE SPINALE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2014209841A3

  公开（公告）日：2015-10-29
• Discovery of a Novel Class of Survival Motor Neuron 2 Splicing Modifiers for the Treatment of Spinal Muscular Atrophy
  作者：Emmanuel Pinard、Luke Green、Michael Reutlinger、Marla Weetall、Nikolai A. Naryshkin、John Baird、Karen S. Chen、Sergey V. Paushkin、Friedrich Metzger、Hasane Ratni

  DOI：10.1021/acs.jmedchem.7b00406

  日期：2017.5.25

  Spinal muscular atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, resulting in low levels of functional SMN protein. We have reported recently the identification of small molecules (coumarins, iso-coumarins and pyrido-pyrimidinones) that modify the alternative splicing of SMN2, a paralogous gene to SMN1, restoring the survival motor neuron (SMN) protein level in mouse models of SMA. Herein, we report our efforts to identify a novel chemotype as one strategy to potentially circumvent safety concerns from earlier derivatives such as in vitro phototoxicity and in vitro mutagenicity associated with compounds 1 and 2 or the in vivo retinal findings observed in a long-term chronic tox study with 3 at high exposures only. Optimized representative compounds modify the alternative splicing of SMN2, increase the production of full length SMN2 mRNA, and therefore levels of full length SMN protein upon oral administration in two mouse models of SMA.