N3-cyclopropyl-N4'-(cyclopropylmethyl)-5-fluoro-6-methyl-3,4'-biphenyldicarboxamide | 515135-07-6

• 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: N3-cyclopropyl-N4'-(cyclopropylmethyl)-5-fluoro-6-methyl-3,4'-biphenyldicarboxamide
• 英文别名: N3-cyclopropyl-N4'-(cyclopropylmethyl)-5-fluoro-6-methyl-1,1'-biphenyl-3,4'-dicarboxamide；N-cyclopropyl-3-[4-(cyclopropylmethylcarbamoyl)phenyl]-5-fluoro-4-methylbenzamide
• CAS: 515135-07-6
• 化学式: C₂₂H₂₃FN₂O₂
• 分子量: 366.435
• InChiKey: UXGTUHTUFCYCPT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  58.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3 -bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide 、 N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide 在 四(三苯基膦)钯 、 碳酸氢钠 作用下， 以 水 、 异丙醇 为溶剂， 反应 18.0h， 以60%的产率得到N3-cyclopropyl-N4'-(cyclopropylmethyl)-5-fluoro-6-methyl-3,4'-biphenyldicarboxamide
  参考文献：
  名称：

  p38α Mitogen-Activated Protein Kinase Inhibitors: Optimization of a Series of Biphenylamides to Give a Molecule Suitable for Clinical Progression

  摘要：

  p38 alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNF alpha and IL-1 beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38 alpha/beta inhibitors using crystal structures of our inhibitors bound to p38 alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.

  DOI：

  10.1021/jm9004779
• 作为试剂：
  描述：

  3 -bromo-N-cyclopropyl-5-fluoro-4-methylbenzamide 、 N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide 、 disodium;carbonate 在 四(三苯基膦)钯 silica 、 乙酸乙酯 、 环己烷 、 N3-cyclopropyl-N4'-(cyclopropylmethyl)-5-fluoro-6-methyl-3,4'-biphenyldicarboxamide 、 2H 作用下， 以 乙二醇二甲醚 为溶剂， 反应 16.0h， 以cyclohexane (2:) then 100% ethyl acetate to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-5-fluoro-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide (34 mg, 62%) NMR: δH [2H6]-DMSO 8.66, (1H, t), 8.53, (1H, d), 7.97, (2H, d), 7.63, (1H, d), 7.60, (1H, s), 7.49, (2H, d), 3.18, (2H, t), 2.85, (1H, m), 2.17, (2H, d), 1.05, (1H, m), 0.69, (2H, m), 0.57, (2H, m), 0.44, (2H, m), 0.25, (2H, m)的产率得到N3-cyclopropyl-N4'-(cyclopropylmethyl)-5-fluoro-6-methyl-3,4'-biphenyldicarboxamide
  参考文献：
  名称：

  5'-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors

  摘要：

  化学式为(I)的化合物：其中当m为0至4时，R1从C1-6烷基，C3-7环烷基，C2-6烯基，—SO2NR4R5，—CONR4R5和—COOR4中选择；当m为2至4时，R1还可从C1-6烷氧基，羟基，NR4R5，—NR4SO2R5，—NR4SOR5，—NR4COR5和—NR4CONR4R5中选择；R2从氢，C1-6烷基和—（CH2）n-C3-7环烷基中选择；R3为—CO—NH—（CH2）p-R6基团；U从甲基和卤素中选择；W从甲基和氯中选择；V和Y各自独立地从氢，甲基和卤素中选择；m从0、1、2、3和4中选择，其中所得碳链的每个碳原子可以选择性地被一个或两个从C1-6烷基中独立选择的基团取代；n从0、1、2和3中选择；p和r独立地从0、1和2中选择；s从0、1和2中选择；或其药学上可接受的盐或溶剂，以及它们作为药物的用途，特别是作为p38激酶抑制剂。

  公开号：

  US20040267012A1

文献信息

• [EN] 5'-CARBAMOYL-1,1-BIPHENYL-4-CARBOXAMIDE DERIVATIVES AND THEIR USE AS P38 KINASE INHIBITORS<br/>[FR] DERIVES DE 5'-CARBAMOYL-1,1-BIPHENYL-4-CARBOXAMIDE ET LEUR UTILISATION COMME INHIBITEURS DE LA KINASE P38
  申请人：GLAXO GROUP LTD

  公开号：WO2003032972A1

  公开（公告）日：2003-04-24

  Compounds of formula (I): wherein when m is 0 to 4 R1 is selected from C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl, -SO2NR4R5, -CONR4R5 and -COOR4; and when m is 2 to 4 R1 is additionally selected from C1-6alkoxy, hydroxy, NR4R5, -NR4SO2R5, -NR4SOR5, -NR4COR5, and -NR4CONR4R5; R2 is selected from hydrogen, C1-6alkyl and -(CH2)n-C3-7cycloalkyl; R3 is the group -CO-NH-(CH2)p-R6; U is selected from methyl and halogen; W is selected from methyl and chlorine; V and Y are each selected independently from hydrogen, methyl and halogen; m is selected from 0, 1, 2, 3 and 4 wherein each carbon atom of the resulting carbon chain may be optionally substituted with one or two groups selected independently from C1-6alkyl; n is selected from 0, 1, 2 and 3; p and r are independently selected from 0, 1 and 2; s is selected from 0, 1 and 2; or pharmaceutically acceptable salts or solvates thereof, and their use as pharmaceuticals, particularly as p38 kinase inhibitors.

  化合物的式子(I)：其中当m为0到4时，R1从C1-6烷基、C3-7环烷基、C2-6烯基、-SO2NR4R5、-CONR4R5和-COOR4中选择；当m为2到4时，R1还从C1-6烷氧基、羟基、NR4R5、-NR4SO2R5、-NR4SOR5、-NR4COR5和-NR4CONR4R5中选择；R2从氢、C1-6烷基和-(CH2)n-C3-7环烷基中选择；R3是群- CO-NH-(CH2)p-R6; U从甲基和卤素中选择；W从甲基和氯中选择；V和Y各自独立地从氢、甲基和卤素中选择；m从0、1、2、3和4中选择，其中所得碳链的每个碳原子可以选择性地用一个或两个独立选择的C1-6烷基基团取代；n从0、1、2和3中选择；p和r独立地从0、1和2中选择；s从0、1和2中选择；或其药学上可接受的盐或溶剂，以及它们作为药物的用途，特别是作为p38激酶抑制剂。
• 5′-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
  申请人：Glaxo Group Limited

  公开号：US07208629B2

  公开（公告）日：2007-04-24

  Compounds of formula (I): wherein when m is 0 to 4 R1 is selected from C1–6alkyl, C3–7cycloalkyl, C2–6alkenyl, —SO2NR4R5, —CONR4R5 and —COOR4; and when m is 2 to 4 R1 is additionally selected from C1–6alkoxy, hydroxy, NR4R5, —NR4SO2R5, —NR4SOR5, —NR4COR5, and —NR4CONR4R5; R2 is selected from hydrogen, C1–6alkyl and —(CH2)n-C3–7cycloalkyl; R3 is the group —CO—NH—(CH2)p-R6; U is selected from methyl and halogen; W is selected from methyl and chlorine; V and Y are each selected independently from hydrogen, methyl and halogen; m is selected from 0, 1, 2, 3 and 4 wherein each carbon atom of the resulting carbon chain may be optionally substituted with one or two groups selected independently from C1–6alkyl; n is selected from 0, 1, 2 and 3; p and r are independently selected from 0, 1 and 2; s is selected from 0, 1 and 2; or pharmaceutically acceptable salts or solvates thereof, and their use as pharmaceuticals, particularly as p38 kinase inhibitors

  式（I）的化合物：其中当m为0至4时，R1从C1-6烷基，C3-7环烷基，C2-6烯基，—SO2NR4R5，—CONR4R5和—COOR4中选择；当m为2至4时，R1还从C1-6烷氧基，羟基，NR4R5，—NR4SO2R5，—NR4SOR5，—NR4COR5和—NR4CONR4R5中选择；R2从氢，C1-6烷基和—（CH2）n-C3-7环烷基中选择；R3为—CO—NH—（CH2）p-R6基团；U从甲基和卤素中选择；W从甲基和氯中选择；V和Y各自独立地从氢，甲基和卤素中选择；m从0、1、2、3和4中选择，其中所得碳链的每个碳原子可以选择性地用一个或两个从C1-6烷基中独立选择的基团替换；n从0、1、2和3中选择；p和r各自独立地从0、1和2中选择；s从0、1和2中选择；或其药学上可接受的盐或溶剂，以及它们作为药物的用途，特别是作为p38激酶抑制剂。
• 5'-CARBAMOYL-1,1-BIPHENYL-CARBOXAMIDE DERIVATIVES AND THEIR USE AS P38 KINASE INHIBITORS
  申请人：GLAXO GROUP LIMITED

  公开号：EP1435936A1

  公开（公告）日：2004-07-14
• US7208629B2
  申请人：——

  公开号：US7208629B2

  公开（公告）日：2007-04-24
• p38α Mitogen-Activated Protein Kinase Inhibitors: Optimization of a Series of Biphenylamides to Give a Molecule Suitable for Clinical Progression
  作者：Nicola M. Aston、Paul Bamborough、Jacqueline B. Buckton、Christopher D. Edwards、Duncan S. Holmes、Katherine L. Jones、Vipulkumar K. Patel、Penny A. Smee、Donald O. Somers、Giovanni Vitulli、Ann L. Walker

  DOI：10.1021/jm9004779

  日期：2009.10.22

  p38 alpha MAP kinase is a key anti-inflammatory target for rheumatoid arthritis, influencing biosynthesis of pro-inflammatory cytokines TNF alpha and IL-1 beta at a translational and transcriptional level. In this paper, we describe how we have optimized a series of novel p38 alpha/beta inhibitors using crystal structures of our inhibitors bound to p38 alpha, classical medicinal chemistry, and modeling of virtual libraries to derive a molecule suitable for progression into clinical development.