N-{4-[2-(4-fluorophenyl)-2-hydroxyliminoacetyl]pyridin-2-yl}acetamide | 452056-82-5

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N-{4-[2-(4-fluorophenyl)-2-hydroxyliminoacetyl]pyridin-2-yl}acetamide
• 英文别名: N-{4-[2-(4-fluorophenyl)-2-hydroxyiminoacetyl]pyridin-2-yl}acetamide；N-[4-[2-(4-fluorophenyl)-2-hydroxyiminoacetyl]pyridin-2-yl]acetamide
• CAS: 452056-82-5
• 化学式: C₁₅H₁₂FN₃O₃
• 分子量: 301.277
• InChiKey: WLOZERWZRKTXMB-UHFFFAOYSA-N

物化性质

• 熔点：
  162.5 °C
• 沸点：
  560.4±50.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.24
• 重原子数：
  22.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  91.65
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  N-{4-[2-(4-fluorophenyl)-2-hydroxyliminoacetyl]pyridin-2-yl}acetamide 在 盐酸 、 2,2,4,4-四甲基-1,3-环丁烷二硫酮 、 potassium carbonate 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 42.0h， 生成 4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-amine
  参考文献：
  名称：

  Identification of Regioisomers in a Series of N-Substituted Pyridin-4-yl Imidazole Derivatives by Regiospecific Synthesis, GC/MS, and ¹H NMR

  摘要：

  The regiospecific synthesis of 2a (Scheme 3), a novel and potent pyridinyl imidazole inhibitor of p38 MAP (mitogen-activated protein) kinase, and the regioselective preparation of its regioisomer 2b (Scheme 4) are described. Chromatographic and spectroscopic data are presented, which in this class of compounds allow the unambiguous identification of regioisomers prepared by a nonregiospecific synthetic strategy. Biological data demonstrating the importance of the correct regiochemistry for inhibition of p38 are given.

  DOI：

  10.1021/jo026619w
• 作为产物：
  描述：

  对氟苯乙腈 在 4-二甲氨基吡啶 、 氢溴酸 、 sodium methylate 、 N,N'-羰基二咪唑 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 41.75h， 生成 N-{4-[2-(4-fluorophenyl)-2-hydroxyliminoacetyl]pyridin-2-yl}acetamide
  参考文献：
  名称：

  Tetrasubstituted Imidazole Inhibitors of Cytokine Release:  Probing Substituents in the N-1 Position

  摘要：

  We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-activated protein kinase p38 (p38 IC50 = 0.218 muM) as well as the release of the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha. (TNFalpha) from human whole blood after stimulation with LPS. Furthermore, compound 9b exhibited reduced cytochrome P450 interaction in comparison with SB203580. This result is particularly important, since cytochrome P450 interaction is observed for some p38 inhibitors and in turn can potentially cause drug-drug interaction or lead to other hepatic changes such as P450 enzyme induction.

  DOI：

  10.1021/jm0496584

文献信息

• Novel Substituted Pyridinyl Imidazoles as Potent Anticytokine Agents with Low Activity against Hepatic Cytochrome P450 Enzymes
  作者：Stefan A. Laufer、Gerd K. Wagner、Dunja A. Kotschenreuther、W. Albrecht

  DOI：10.1021/jm030766k

  日期：2003.7.1

  been linked to the liver toxicity observed for model p38 inhibitors, was very efficiently reduced through introduction of a tetramethylpiperidine substituent at the 1 position of the imidazole nucleus. Combination of both structural features provided 14c (p38: 0.34 microM, inhibition of CYP1A2 0%, 2C9 2.6%, 2C19 7.6% at 10 microM), which was selected for further development.

  制备了一系列p38 MAP（有丝分裂原活化蛋白）激酶的多取代吡啶-4-基咪唑抑制剂，作为小分子抗细胞因子药物和候选药物，用于治疗慢性炎性疾病。评估了吡啶基和咪唑部分的取代基对选择性抑制p38的贡献，而没有伴随的细胞色素P450相互作用。将1-苯基乙基（7e，p38：IC（50）0.38 microM）或乙酰基取代基放置在几个2-氨基吡啶咪唑的环外氮原子上导致鉴定出有效的p38抑制剂，该抑制剂超过了起始铅ML 3375（p38：IC （50）0.63 microM）效能。初步的模型研究将7e的增强生物活性与其1-苯基乙基氨基侧链和靠近p38接头区域的疏水口袋之间的新型相互作用相关。该系列中最活跃的p38抑制剂在功能性PBMC（外周血单个核细胞）和全血测定中保持了其功效。此外，与在模型p38抑制剂中观察到的肝毒性有关的细胞色素P450相互作用，通过在咪唑核的1位上引入四甲基哌啶取代基而非常有效
• Tri- and tetrasubstituted imidazoles as p38α mitogen-activated protein kinase inhibitors
  作者：Stefan Laufer、Dominik Hauser、Thomas Stegmiller、Claudia Bracht、Kathrin Ruff、Verena Schattel、Wolfgang Albrecht、Pierre Koch

  DOI：10.1016/j.bmcl.2010.09.012

  日期：2010.11

  The synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles as potent p38 alpha mitogen-activated protein kinase inhibitors is described. The trisubstituted imidazole series was found to be more potent than the tetrasubstituted imidazole series. Many of these compounds show low-nanomolar activities in the isolated p38 alpha MAP kinase inhibition assay. The structure-activity relationships between these two series are different and not comparable. (C) 2010 Elsevier Ltd. All rights reserved.
• Discovery of <i>N</i>-{4-[5-(4-Fluorophenyl)-3-methyl-2-methylsulfanyl-3<i>H</i>-imidazol-4-yl]-pyridin-2-yl}-acetamide (CBS-3595), a Dual p38α MAPK/PDE-4 Inhibitor with Activity against TNFα-Related Diseases
  作者：Wolfgang Albrecht、Anke Unger、Silke M. Bauer、Stefan A. Laufer

  DOI：10.1021/acs.jmedchem.6b01647

  日期：2017.7.13

  The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38 alpha MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38 alpha MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.