5-amino-3-(4-fluoro-3-methyl)-4-(4-pyrimidinyl)isoxazole | 897647-50-6

• 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: 5-amino-3-(4-fluoro-3-methyl)-4-(4-pyrimidinyl)isoxazole
• 英文别名: 5-Amino-3-(3-methyl-4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole；3-(4-Fluoro-3-methylphenyl)-4-pyrimidin-4-yl-1,2-oxazol-5-amine
• CAS: 897647-50-6
• 化学式: C₁₄H₁₁FN₄O
• 分子量: 270.266
• InChiKey: FMIHLXKLEAJSNU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  77.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-amino-3-(4-fluoro-3-methyl)-4-(4-pyrimidinyl)isoxazole 、 邻甲基苯乙酸 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以82%的产率得到3-(4-fluoro-3-methylphenyl)-5-[(2-methylphenyl)acetylamino]-4-(4-pyrimidinyl)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：

  4-甲基嘧啶 在 sodium methylate 、 hydroxylamine-O-sulfonic acid 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 5-amino-3-(4-fluoro-3-methyl)-4-(4-pyrimidinyl)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

文献信息

• Pyrimidinylisoxazole Derivatives
  申请人：Hasumi Koichi

  公开号：US20080114003A1

  公开（公告）日：2008-05-15

  The invention discloses isoxazole derivatives represented by a formula, in which R 1 stands for hydrogen, lower alkyl, amino, halogen, lower alkoxy and the like, R 2 stands for substituted or unsubstituted aryl and the like, R 3 stands for hydrogen or lower alkyl, R 4 stands for substituted or unsubstituted phenyl and the like, and Y stands for —CH 2 —, —CO—, —CH(CH 3 )—, —O—, —NH— and the like, or pharmaceutically acceptable salts thereof, which have excellent p38MAPkinase inhibitory action.

  本发明揭示了由式子表示的异唑啉衍生物，其中R1代表氢、低碳基、氨基、卤素、低烷氧基等；R2代表取代或未取代的芳基等；R3代表氢或低碳基；R4代表取代或未取代的苯基等；Y代表—CH2—、—CO—、—CH(CH3)—、—O—、—NH—等，或其药学上可接受的盐，具有出色的p38MAPkinase抑制作用。
• PYRIMIDINYLISOXAZOL DERIVATIVE
  申请人：ASKA Pharmaceutical Co., Ltd.

  公开号：EP1832584A1

  公开（公告）日：2007-09-12

  The invention discloses isoxazole derivatives represented by a formula, in which R1 stands for hydrogen, lower alkyl, amino, halogen, lower alkoxy and the like, R2 stands for substituted or unsubstituted aryl and the like, R3 stands for hydrogen or lower alkyl, R4 stands for substituted or unsubstituted phenyl and the like, and Y stands for -CH2, -CO-, -CH(CH3)-, -O-, -NH- and the like, or pharmaceutically acceptable salts thereof, which have excellent p38MAPkinase inhibitory action.

  本发明公开了由式表示的异噁唑衍生物，其中 R1 代表氢、低级烷基、氨基、卤素、低级烷氧基等，R2 代表取代或未取代的芳基等，R3 代表氢或低级烷基，R4 代表取代或未取代的苯基等，Y 代表-CH2、-CO-、-CH(CH3)-、-O-、-NH-等，或其药学上可接受的盐，它们具有优异的 p38MAPkinase 抑制作用。
• PYRIMIDINYLISOXAZOLE DERIVATIVE
  申请人：ASKA Pharmaceutical Co., Ltd.

  公开号：EP1832584B1

  公开（公告）日：2011-12-21
• US7939536B2
  申请人：——

  公开号：US7939536B2

  公开（公告）日：2011-05-10
• 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.