4-[[3-[4-(2-hydroxyethyl)-1,4-diazepane-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one | 763111-57-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 4-[[3-[4-(2-hydroxyethyl)-1,4-diazepane-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
• 英文别名: 4-[(3-{[4-(2-Hydroxyethyl)-1,4-diazepan-1-yl]carbonyl}phenyl)methyl]-1,2-dihydrophthalazin-1-one
• CAS: 763111-57-5
• 化学式: C₂₃H₂₆N₄O₃
• 分子量: 406.484
• InChiKey: SKIAOPZHWKLNDO-UHFFFAOYSA-N

物化性质

• 密度：
  1.30±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  85.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-[(3,4-二氢-4-氧代-1-酞嗪基)甲基]-苯甲酸 、 2-(1,4-二叠氮烷-1-基)乙酮 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 16.0h， 生成 4-[[3-[4-(2-hydroxyethyl)-1,4-diazepane-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
  参考文献：
  名称：

  4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1

  摘要：

  Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.

  DOI：

  10.1021/jm8001263

文献信息

• 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2<i>H</i>-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1
  作者：Keith A. Menear、Claire Adcock、Robert Boulter、Xiao-ling Cockcroft、Louise Copsey、Aaron Cranston、Krystyna J. Dillon、Jan Drzewiecki、Sheila Garman、Sylvie Gomez、Hashim Javaid、Frank Kerrigan、Charlotte Knights、Alan Lau、Vincent M. Loh、Ian T. W. Matthews、Stephen Moore、Mark J. O’Connor、Graeme C. M. Smith、Niall M. B. Martin

  DOI：10.1021/jm8001263

  日期：2008.10.23

  Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.