3-(4-fluorophenyl)-4-(pyridin-4-yl)isoxazol-5-amine | 262364-88-5

• 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: 3-(4-fluorophenyl)-4-(pyridin-4-yl)isoxazol-5-amine
• 英文别名: 5-amino-3-(4-fluorophenyl)-4-(4-pyridyl)isoxazole；3-(4-Fluorophenyl)-4-pyridin-4-yl-1,2-oxazol-5-amine
• CAS: 262364-88-5
• 化学式: C₁₄H₁₀FN₃O
• 分子量: 255.251
• InChiKey: ZWIRUUBLMWVMKS-UHFFFAOYSA-N

物化性质

• 熔点：
  192 °C(Solv: dichloromethane (75-09-2))
• 沸点：
  408.1±45.0 °C(Predicted)
• 密度：
  1.304±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  64.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(4-fluorophenyl)-4-(pyridin-4-yl)isoxazol-5-amine 在 溶剂黄146 、 sodium nitrite 作用下， 以 水 为溶剂， 生成 3-(4-fluorophenyl)-4-(4-pyridyl)isoxazole
  参考文献：
  名称：

  Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept

  摘要：

  Inhibitors of p38 mitogen-activated protein (MAP) kinase, which are closely involved in the production of inflammatory cytokines, are considered promising curative drugs for chronic inflammatory disorders. However, there is also a growing concern regarding its systemic side effects. To reduce the occurrence of side effects, we have identified a novel p38 MAP kinase inhibitor that shows properties of an antedrug, which imparts its effect solely on the inflammatory site and is metabolically inactivated right after. We have designed isoxazole derivatives through the addition of a fresh interacting fourth site to the structure of the prototypical p38 MAP kinase inhibitor that harbors three point interactive sites. The derivative 26d (AKP-001) shows excellent p38 MAP kinase inhibitory activity and a high selectivity for various kinases. Its rapid metabolism has been confirmed in rats. Moreover, 26d has been shown to be effective in animal models of inflammatory bowel disease.

  DOI：

  10.1016/j.bmc.2014.05.045
• 作为产物：
  描述：

  syn-4-氟苯甲醛肟 在 N-氯代丁二酰亚胺 、 sodium 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 3-(4-fluorophenyl)-4-(pyridin-4-yl)isoxazol-5-amine
  参考文献：
  名称：

  Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept

  摘要：

  Inhibitors of p38 mitogen-activated protein (MAP) kinase, which are closely involved in the production of inflammatory cytokines, are considered promising curative drugs for chronic inflammatory disorders. However, there is also a growing concern regarding its systemic side effects. To reduce the occurrence of side effects, we have identified a novel p38 MAP kinase inhibitor that shows properties of an antedrug, which imparts its effect solely on the inflammatory site and is metabolically inactivated right after. We have designed isoxazole derivatives through the addition of a fresh interacting fourth site to the structure of the prototypical p38 MAP kinase inhibitor that harbors three point interactive sites. The derivative 26d (AKP-001) shows excellent p38 MAP kinase inhibitory activity and a high selectivity for various kinases. Its rapid metabolism has been confirmed in rats. Moreover, 26d has been shown to be effective in animal models of inflammatory bowel disease.

  DOI：

  10.1016/j.bmc.2014.05.045

文献信息

• Synthesis and Biological Testing of N-Aminoimidazole-Based p38α MAP Kinase Inhibitors
  作者：Claudia Bracht、Dominik R. J. Hauser、Verena Schattel、Wolfgang Albrecht、Stefan A. Laufer

  DOI：10.1002/cmdc.201000114

  日期：——

  The p38 mitogen‐activated protein (MAP) kinase α plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro‐inflammatory cytokines. To date, diverse p38α inhibitors are in phase II clinical trials for numerous cytokine‐dependent diseases. 2‐Sulfanylimidazole derivatives offer

  p38促分裂原活化蛋白（MAP）激酶α在调节细胞反应（例如分化，增殖，凋亡和炎症）中起着核心作用。抑制p38会导致促炎性细胞因子的合成减少。迄今为止，针对多种细胞因子依赖性疾病的各种p38α抑制剂正在II期临床试验中。2-磺基氨基咪唑衍生物比原型抑制剂SB 203580具有优势，包括更少的细胞色素P450相互作用和更好的动力学性能。这项研究的目的是开发新型的1,2,4,5-四取代的吡啶并咪唑在咪唑N1位置带有酰基残基，该残基可以与激酶的疏水区II（HR II）或糖袋（SP）相互作用，从而提高二者的选择性。和活动。N-氨基咪唑核心。氨基功能的酰化用于优化，并产生有效的p38αMAPK抑制剂。
• Substituted isoxazole derivatives and their use in pharmaceutics
  申请人：Laufer Stefan

  公开号：US20060128759A1

  公开（公告）日：2006-06-15

  The invention relates to substituted isoxazole derivatives of formula (I), wherein the radicals R 1 , R 2 and R 3 have the meanings as cited in the description. The inventive compounds comprise an immunomodulatory action and/or an action that inhibits the release of cytokines and are thus suited for treating diseases associated with a disorder of the immune system, particularly immunologically mediated inflammatory diseases

  本发明涉及式(I)的取代异噁唑衍生物，其中基团R1、R2和R3的含义如描述中所述。本发明化合物具有免疫调节作用和/或抑制细胞因子释放作用，因此适用于治疗与免疫系统紊乱有关的疾病，特别是免疫介导的炎症性疾病。
• SUBSTITUIERTE ISOXAZOLDERIVATE UND IHRE VERWENDUNG IN DER PHARMAZIE
  申请人：MERCKLE GMBH

  公开号：EP1530468A1

  公开（公告）日：2005-05-18
• [DE] SUBSTITUIERTE ISOXAZOLDERIVATE UND IHRE VERWENDUNG IN DER PHARMAZIE<br/>[EN] SUBSTITUTED ISOXAZOLE DERIVATIVES AND THEIR USE IN PHARMACEUTICS<br/>[FR] DERIVES D'ISOXAZOLE SUBSTITUES ET LEUR UTILISATION EN PHARMACIE
  申请人：MERCKLE GMBH

  公开号：WO2004017968A1

  公开（公告）日：2004-03-04

  Die Erfindung betrifft substituierte Isoxazolderivate der Formel (I) worin die Reste R1, R2 und R3 die in der Beschreibung angegebene Bedeutung besitzen. Die erfindungsgemässen Verbindungen besitzen eine immunmodulierende und/oder die Cytokinfreisetzung hemmende Wirkung und sind daher geeignet zur Behandlung von Erkrankungen, die mit einer Störung des Immunsystems im Zusammenhang stehen, insbesondere immunologisch vermittelte entzündliche Erkrankungen.
• Design and synthesis of 5-[(2-chloro-6-fluorophenyl)acetylamino]-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (AKP-001), a novel inhibitor of p38 MAP kinase with reduced side effects based on the antedrug concept
  作者：Koichi Hasumi、Shuichiro Sato、Takahisa Saito、Jun-ya Kato、Kazuhiko Shirota、Jun Sato、Hiroyuki Suzuki、Shuji Ohta

  DOI：10.1016/j.bmc.2014.05.045

  日期：2014.8

  Inhibitors of p38 mitogen-activated protein (MAP) kinase, which are closely involved in the production of inflammatory cytokines, are considered promising curative drugs for chronic inflammatory disorders. However, there is also a growing concern regarding its systemic side effects. To reduce the occurrence of side effects, we have identified a novel p38 MAP kinase inhibitor that shows properties of an antedrug, which imparts its effect solely on the inflammatory site and is metabolically inactivated right after. We have designed isoxazole derivatives through the addition of a fresh interacting fourth site to the structure of the prototypical p38 MAP kinase inhibitor that harbors three point interactive sites. The derivative 26d (AKP-001) shows excellent p38 MAP kinase inhibitory activity and a high selectivity for various kinases. Its rapid metabolism has been confirmed in rats. Moreover, 26d has been shown to be effective in animal models of inflammatory bowel disease.