3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}dihydropyrimidine-2,4(1H,3H)-dione | 1073656-56-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: 3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}dihydropyrimidine-2,4(1H,3H)-dione
• CAS: 1073656-56-0
• 化学式: C₂HF₃O₂*C₁₈H₁₈FN₅O₃
• 分子量: 485.395
• InChiKey: XRYJBPRNNUMCSS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.94
• 重原子数：
  34.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  144.49
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  2,3-吡啶二甲酸二甲酯 在 盐酸 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 platinum on carbon 、 氨 、 氢气 、 溴 、 碘 、 magnesium 、 三乙胺 、 potassium hydroxide 、 sodium hydroxide 、 肼 作用下， 以 甲醇 、 乙醚 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， -78.0~100.0 ℃ 、413.7 kPa 条件下， 反应 27.67h， 生成 3-{2-fluoro-5-[(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)methyl]phenyl}dihydropyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer

  摘要：

  PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K-i value of < 1 nM and an EC50 value of 1 nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ). (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.06.021