N-(3,5-dichloro-pyridin-4-yl)-3,4-dimethoxy-benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3,5-dichloro-pyridin-4-yl)-3,4-dimethoxy-benzamide
• 英文别名: N-(3,5-dichloropyridin-4-yl)-3,4-dimethoxybenzamide；N-(3,5-dichloro-4-pyridyl)-3,4-dimethoxybenzamide
• 化学式: C₁₄H₁₂Cl₂N₂O₃
• 分子量: 327.167
• InChiKey: WFWCXZPAPUKWOC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  60.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-(二乙氧基甲基)-1,2-二甲氧基苯 在 sodium chlorite 、 sodium dihydrogenphosphate 、 对甲苯磺酸一水合物 作用下， 以 四氢呋喃 、 水 为溶剂， 生成 N-(3,5-dichloro-pyridin-4-yl)-3,4-dimethoxy-benzamide
  参考文献：
  名称：

  [EN] PROCESS FOR PREPARATION OF ROFLUMILAST
  [FR] PROCÉDÉ DE PRÉPARATION DE ROFLUMILAST

  摘要：

  本发明提供了制备具有化学式(VIc)的N-取代苯甲酰胺的新工艺。在某些实施例中，本发明提供了一种制备罗氟米拉斯特和其他药用活性物质的工艺。此外，还提供了包括罗氟米拉斯特合成中间体在内的新化合物。

  公开号：

  WO2013131484A1

文献信息

• PROCESS FOR PREPARATION OF ROFLUMILAST
  申请人：SCINOPHARM (CHANGSHU) PHARMACEUTICALS, LTD.

  公开号：US20150025246A1

  公开（公告）日：2015-01-22

  The present invention provides novel processes for the preparation of N-substituted benzamides having the formula (VIc). In some embodiments, the invention provides a process for preparation of roflumilast and other pharmaceutically active species. Novel compounds, including intermediates for the synthesis of roflumilast, are also provided.

  本发明提供了制备具有公式（VIc）的N-取代苯甲酰胺的新型方法。在某些实施例中，本发明提供了一种制备罗氟米拉斯特和其他药物活性物种的方法。还提供了新型化合物，包括合成罗氟米拉斯特的中间体。
• [EN] PREPARATION METHOD OF ROFLUMILAST<br/>[FR] PROCÉDÉ DE PREPARATION DE ROFLUMILAST
  申请人：SCINOPHARM CHANGSHU PHARMACEUTICAL LTD

  公开号：WO2013131255A1

  公开（公告）日：2013-09-12

  The present invention provides novel processes for the preparation of N-substituted benzamides having the formula VIc: (formula) In some embodiments, the invention provides a process for preparation of roflumilast and other pharmaceutically active species. Novel compounds, including intermediates for the synthesis of roflumilast, are also provided.

  本发明提供了制备具有VIc式的N-取代苯甲酰胺的新工艺：（公式）。在某些实施例中，本发明提供了制备罗氟米拉斯特和其他药物活性物种的工艺。还提供了新的化合物，包括合成罗氟米拉斯特的中间体。
• To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?
  作者：Yang Zheng、Susanne Schroeder、Georgi K. Kanev、Sanaa S. Botros、Samia William、Abdel-Nasser A. Sabra、Louis Maes、Guy Caljon、Carmen Gil、Ana Martinez、Irene G. Salado、Koen Augustyns、Ewald Edink、Maarten Sijm、Erik de Heuvel、Iwan J. P. de Esch、Tiffany van der Meer、Marco Siderius、Geert Jan Sterk、David Brown、Rob Leurs

  DOI：10.3390/ijms24076817

  日期：——

  Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.

  血吸虫病是一种被忽视的热带疾病，发病率很高。最近，曼氏血吸虫磷酸二酯酶 SmPDE4A 被认为是一个潜在的新药靶点。为了支持 SmPDE4A 靶向药物的发现，我们克隆、分离并生化鉴定了 SmPDE4A 的全长结构域和催化结构域。具有酶活性的催化结构域以 apo 形式（PDB 代码：6FG5）以及 cAMP 和 AMP 结合态（PDB 代码：6EZU）结晶。与寄生虫 PDE 相比，SmPDE4A 催化域更像人类 PDE4，因为它缺少寄生虫 PDE 特异性 P 袋。纯化的 SmPDE4A 蛋白（全长和催化结构域）被用于分析内部的 PDE 抑制剂库（PDE4NPD 工具箱）。这一筛选确定了四氢酞嗪酮类和苯甲酰胺类为潜在的命中物。PDE抑制剂NPD-0001是活性最强的四氢酞嗪酮类化合物，而已获批准的人类PDE4抑制剂罗氟司特和吡氟司特则是最强的苯甲酰胺类化合物。随后，又制备了 83 种苯甲酰胺类似物，但最初发现的化合物的抑制效力并没有提高。最后，NPD-0001 和罗氟司特在体外抗曼森尼试验中进行了评估。遗憾的是，这两种 SmPDE4A 抑制剂都不能有效杀死蠕虫，而且在高微摩尔浓度下只能微弱地影响产卵。因此，这些SmPDE4A抑制剂的结果强烈表明，SmPDE4A并不是抗血吸虫病治疗的合适靶点。
• Discovery and Early Clinical Development of 2-{6-[2-(3,5-Dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-<i>N</i>-propylacetamide (LEO 29102), a Soft-Drug Inhibitor of Phosphodiesterase 4 for Topical Treatment of Atopic Dermatitis
  作者：Jakob Felding、Morten D. Sørensen、Tina D. Poulsen、Jens Larsen、Christina Andersson、Pia Refer、Karen Engell、Lotte G. Ladefoged、Thorsten Thormann、Anne Marie Vinggaard、Pontus Hegardt、Anders Søhoel、Simon Feldbæk Nielsen

  DOI：10.1021/jm500378a

  日期：2014.7.24

  Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the dinic for PDE4 inhibitors, primarily due to PDE4 mediated side effects. Here we describe our approach to circumvent this issue by applying a soft-drug concept in the design of a topically acting PDE4 inhibitor for treatment of dermatological diseases. We used a fast follower approach, starting from piclamilast. In particular, simultaneous introduction of 2'-alkoxy substituents and changing an amide to a keto linker proved to be beneficial when designing potential soft-drug candidates. This effort culminated in identification of LEO 29102 (20), a potent, selective, and soft-drug PDE4 inhibitor with properties suitable for patient-friendly formulations giving efficient drug delivery to the skin. Compound 20 has reached phase 2 and demonstrated clinically relevant efficacy in the treatment of atopic dermatitis.
• Selective Type IV Phosphodiesterase Inhibitors as Antiasthmatic Agents. The Syntheses and Biological Activities of 3-(Cyclopentyloxy)-4-methoxybenzamides and Analogs
  作者：Michael J. Ashton、David C. Cook、Garry Fenton、Jan-Anders Karlsson、Malcolm N. Palfreyman、David Raeburn、Andrew J. Ratcliffe、John E. Souness、Suga Thurairatnam、Nigel Vicker

  DOI：10.1021/jm00037a021

  日期：1994.5

  The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibition of the cytosolic PDE IV from pig aorta have been investigated. As a result, some highly potent and selective PDE IV inhibitors have been identified. The most potent compounds have been further evaluated for their inhibitory potencies against PDE IV obtained from and superoxide O-2(-) generation from guinea pig eosinophils in vitro. Selected compounds have also been examined for their activities in inhibiting histamine-induced bronchospasm in anaesthetized guinea pigs. 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.