3-(4-fluorophenyl)-1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-amine | 277746-65-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(4-fluorophenyl)-1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-amine
• 英文别名: 5-amino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole；5-amino-3-(4-fluorophenyl)-1-methyl-4-(pyridin-4-yl)pyrazole；5-(4-fluorophenyl)-2-methyl-4-pyridin-4-ylpyrazol-3-amine
• CAS: 277746-65-3
• 化学式: C₁₅H₁₃FN₄
• 分子量: 268.293
• InChiKey: HLPHXHPEFAORDT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 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：
  56.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(4-fluorophenyl)-1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-amine 、 苯乙酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 以35%的产率得到5-(4-fluorophenyl)-2-methyl-3-phenylacetylamino-4-(4-pyridyl)pyrazole
  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：

  2,5-二氧代吡咯烷-1-基4-氟苯甲酸 在 potassium carbonate 、 三氯氧磷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 26.5h， 生成 3-(4-fluorophenyl)-1-methyl-4-(pyridin-4-yl)-1H-pyrazol-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。
• Aminopyrazole derivatives
  申请人：Teikoku Hormone Mfg. Co., Ltd.

  公开号：US06511997B1

  公开（公告）日：2003-01-28

  Aminopyrazole derivatives represented by formula (I), or salts thereof, wherein X1 and X2 are each a hydrogen atom or a halogen atom, or X1 and X2 may be united together to form a lower alkylenedioxy group, Q is a pyridyl group or a quinolyl group, R1 is a hydrogen atom, a substituted or unsubstituted lower alkyl or aryl group, R2 is a hydrogen atom, a lower alkyl group, or an aralkyl group, and R3 represents a hydrogen atom, an organic sulfonyl group, or —C(═Y)—R4 in which R4 is a hydrogen atom or an organic residue and Y is an oxygen or sulfur atom, provided that, when R3 is a hydrogen atom, R1 is a group other than a hydrogen atom and R2 is a hydrogen atom. These amimopyrazole derivatives or their salts have excellent p38MAP kinase inhibiting activities and are hence useful in the prevention or treatment of diseases associated with tumor necrosis sis factor &agr;, interleukin 1, interleukin 6 or cyclooxygenase II.

  Aminopyrazole衍生物的化学式(I)或其盐，其中X1和X2分别为氢原子或卤素原子，或X1和X2可以结合在一起形成较低的烷二氧基基团，Q为吡啶基团或喹啉基团，R1为氢原子、取代或未取代的较低烷基或芳基，R2为氢原子、较低烷基或芳基，R3代表氢原子、有机磺酰基团，或—C(═Y)—R4，其中R4为氢原子或有机残基，Y为氧原子或硫原子，前提是当R3为氢原子时，R1是除氢原子以外的基团，且R2为氢原子。这些氨基吡唑衍生物或其盐具有优异的p38MAP激酶抑制活性，因此在预防或治疗与肿瘤坏死因子&agr;、白细胞介素1、白细胞介素6或环氧合酶II相关的疾病中非常有用。
• AMINOPYRAZOLE DERIVATIVES
  申请人：TEIKOKU HORMONE MFG. CO., LTD.

  公开号：EP1142890A1

  公开（公告）日：2001-10-10

  Aminopyrazole derivatives represented by formula (I), or salts thereof, wherein X1 and X2 are each a hydrogen atom or a halogen atom, or X1 and X2 may be united together to form a lower alkylenedioxy group, Q is a pyridyl group or a quinolyl group, R1 is a hydrogen atom, a substituted or unsubstituted lower alkyl or aryl group, R2 is a hydrogen atom, a lower alkyl group, or an aralkyl group, and R3 represents a hydrogen atom, an organic sulfonyl group, or -C(=Y)-R4 in which R4 is a hydrogen atom or an organic residue and Y is an oxygen or sulfur atom, provided that, when R3 is a hydrogen atom, R1 is a group other than a hydrogen atom and R2 is a hydrogen atom. These aminopyrazole derivatives or their salts have excellent p38MAP kinase inhibiting activities and are hence useful in the prevention or treatment of diseases associated with tumor necrosis factor α, interleukin 1, interleukin 6 or cyclooxygenase II.

  由式(I)代表的氨基吡唑衍生物或其盐，其中X1和X2各自为氢原子或卤原子，或X1和X2可结合在一起形成低级亚烷基二氧基，Q为吡啶基或喹啉基，R1为氢原子、取代或未取代的低级烷基或芳基、R2 是氢原子、低级烷基或芳烷基，R3 代表氢原子、有机磺酰基或-C(=Y)-R4，其中 R4 是氢原子或有机残基，Y 是氧原子或硫原子，但当 R3 是氢原子时，R1 是氢原子以外的基团，R2 是氢原子。这些氨基吡唑衍生物或其盐类具有优异的 p38MAP 激酶抑制活性，因此可用于预防或治疗与肿瘤坏死因子 α、白细胞介素 1、白细胞介素 6 或环氧合酶 II 有关的疾病。
• US6511997B1
  申请人：——

  公开号：US6511997B1

  公开（公告）日：2003-01-28
• 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.