(5S)-5-(4,4-difluoro-3-oxobutyl)-3-(2,5-difluorophenyl)-N,N-dimethyl-5-phenyl-2H-pyrrole-1-carboxamide | 686321-45-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯啉
• 英文名称: (5S)-5-(4,4-difluoro-3-oxobutyl)-3-(2,5-difluorophenyl)-N,N-dimethyl-5-phenyl-2H-pyrrole-1-carboxamide
• CAS: 686321-45-9
• 化学式: C₂₃H₂₂F₄N₂O₂
• 分子量: 434.433
• InChiKey: XFWOKFHSCJSZLT-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (5S)-5-(4,4-difluoro-3-oxobutyl)-3-(2,5-difluorophenyl)-N,N-dimethyl-5-phenyl-2H-pyrrole-1-carboxamide 在 palladium on activated charcoal 1,4-环己二烯 、 TEA 、 四氯化钛 、 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 、 1,2-二氯乙烷 为溶剂， 生成 (S)-2-((R)-3-amino-4,4-difluorobutyl)-4-(2,5-difluorophenyl)-N,N-dimethyl-2-phenyl-2H-pyrrole-1(5H)-carboxamide
  参考文献：
  名称：

  Kinesin spindle protein (KSP) inhibitors. Part V: Discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein

  摘要：

  Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.006
• 作为产物：
  描述：

  N-benzylidenephenylglycine methyl ester 在 四(三苯基膦)钯 咪唑 、 盐酸 、 sodium hydroxide 、 sodium tetrahydroborate 、 lithium aluminium tetrahydride 、 TEA 、 四丁基硫酸氢铵 、 sodium hexamethyldisilazane 、 sodium hydride 、 sodium carbonate 、 戴斯-马丁氧化剂 、 臭氧 、 lithium chloride 、 nickel dichloride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 (5S)-5-(4,4-difluoro-3-oxobutyl)-3-(2,5-difluorophenyl)-N,N-dimethyl-5-phenyl-2H-pyrrole-1-carboxamide
  参考文献：
  名称：

  Kinesin spindle protein (KSP) inhibitors. Part V: Discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein

  摘要：

  Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.006

文献信息

• US7235580B2
  申请人：——

  公开号：US7235580B2

  公开（公告）日：2007-06-26
• Kinesin spindle protein (KSP) inhibitors. Part V: Discovery of 2-propylamino-2,4-diaryl-2,5-dihydropyrroles as potent, water-soluble KSP inhibitors, and modulation of their basicity by β-fluorination to overcome cellular efflux by P-glycoprotein
  作者：Christopher D. Cox、Michael J. Breslin、David B. Whitman、Paul J. Coleman、Robert M. Garbaccio、Mark E. Fraley、Matthew M. Zrada、Carolyn A. Buser、Eileen S. Walsh、Kelly Hamilton、Robert B. Lobell、Weikang Tao、Marc T. Abrams、Vicki J. South、Hans E. Huber、Nancy E. Kohl、George D. Hartman

  DOI：10.1016/j.bmcl.2007.03.006

  日期：2007.5

  Installation of a C2-aminopropyl side chain to the 2,4-diaryl-2,5-dihydropyrrole series of kinesin spindle protein (KSP) inhibitors results in potent, water soluble compounds, but the aminopropyl group induces susceptibility to cellular efflux by P-glycoprotein (Pgp). We show that by carefully modulating the basicity of the amino group by beta-fluorination, this series of inhibitors maintains potency against KSP and has greatly improved efficacy in a Pgp-overexpressing cell line. The discovery that cellular efflux by Pgp can be overcome by carefully modulating the basicity of an amine may be of general use to medicinal chemists attempting to transform leading compounds into cancer cell- or CNS-penetrant drugs. (c) 2007 Elsevier Ltd. All rights reserved.