3-(5-bromothiophen-2-yl)-6-((4-methylpiperazin-1-yl)methyl)-1,4-dihydroindeno[1,2-c]pyrazole | 866849-77-6

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 3-(5-bromothiophen-2-yl)-6-((4-methylpiperazin-1-yl)methyl)-1,4-dihydroindeno[1,2-c]pyrazole
• 英文别名: 3-(5-Bromothiophen-2-yl)-6-[(4-methylpiperazin-1-yl)methyl]-2,4-dihydroindeno[1,2-c]pyrazole
• CAS: 866849-77-6
• 化学式: C₂₀H₂₁BrN₄S
• 分子量: 429.384
• InChiKey: FPNBMRDXYQLROV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  63.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(5-bromothiophen-2-yl)-6-((4-methylpiperazin-1-yl)methyl)-1,4-dihydroindeno[1,2-c]pyrazole 、 苯基炔丙基醚 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 三乙胺 、 三苯基膦 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以74%的产率得到6-[(4-Methylpiperazin-1-yl)methyl]-3-[5-(3-phenoxyprop-1-ynyl)thiophen-2-yl]-2,4-dihydroindeno[1,2-c]pyrazole
  参考文献：
  名称：

  1,4-Dihydroindeno[1,2-c]pyrazoles with Acetylenic Side Chains as Novel and Potent Multitargeted Receptor Tyrosine Kinase Inhibitors with Low Affinity for the hERG Ion Channel

  摘要：

  The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 mu M in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.

  DOI：

  10.1021/jm061223o
• 作为产物：
  描述：

  5-(hydroxymethyl)-1-indanone 在 sodium hydride 、 potassium carbonate 、 溶剂黄146 、 三乙胺 、 肼 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 苯 为溶剂， 生成 3-(5-bromothiophen-2-yl)-6-((4-methylpiperazin-1-yl)methyl)-1,4-dihydroindeno[1,2-c]pyrazole
  参考文献：
  名称：

  1,4-Dihydroindeno[1,2-c]pyrazoles with Acetylenic Side Chains as Novel and Potent Multitargeted Receptor Tyrosine Kinase Inhibitors with Low Affinity for the hERG Ion Channel

  摘要：

  The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 mu M in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.

  DOI：

  10.1021/jm061223o