8-(4-fluoro-3-{[(2R)-2-phenylpiperazin-1-yl]carbonyl}benzyl),-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one | 1073657-18-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 8-(4-fluoro-3-{[(2R)-2-phenylpiperazin-1-yl]carbonyl}benzyl),-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
• 英文别名: 8-[[4-fluoro-3-[(2R)-2-phenylpiperazine-1-carbonyl]phenyl]methyl]-2,3,4,6-tetrahydro-1H-pyrido[2,3-d]pyridazin-5-one
• CAS: 1073657-18-7
• 化学式: C₂₅H₂₆FN₅O₂
• 分子量: 447.512
• InChiKey: VYBRSTDIXMSCGM-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  85.8
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  8-(3-溴-4-氟苄基)吡啶并[3,2-d]哒嗪-5-(6H)-酮 在 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 、 氢气 、 1-羟基苯并三唑 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 20.0~100.0 ℃ 、413.7 kPa 条件下， 反应 38.0h， 生成 8-(4-fluoro-3-{[(2R)-2-phenylpiperazin-1-yl]carbonyl}benzyl),-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one
  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

文献信息

• INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE
  申请人：Gandhi Virajkumar B.

  公开号：US20080269234A1

  公开（公告）日：2008-10-30

  Inhibitors of poly(ADP-ribose)polymerase, ways to make them and methods of treating patients using them are disclosed.

  本发明公开了聚(ADP-核糖)聚合酶的抑制剂，制备它们的方法以及使用它们治疗患者的方法。
• US8466150B2
  申请人：——

  公开号：US8466150B2

  公开（公告）日：2013-06-18
• US9283222B2
  申请人：——

  公开号：US9283222B2

  公开（公告）日：2016-03-15
• Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer
  作者：Gui-Dong Zhu、Jianchun Gong、Viraj B. Gandhi、Xuesong Liu、Yan Shi、Eric F. Johnson、Cherrie K. Donawho、Paul A Ellis、Jennifer J. Bouska、Donald J. Osterling、Amanda M. Olson、Chang Park、Yan Luo、Alexander Shoemaker、Vincent L. Giranda、Thomas D. Penning

  DOI：10.1016/j.bmc.2012.06.021

  日期：2012.8

  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.