6-(4-fluoro-3-(1-methyl-1,8-diazaspiro[4.5]decane-8-carbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-one | 959839-48-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 6-(4-fluoro-3-(1-methyl-1,8-diazaspiro[4.5]decane-8-carbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-one
• 英文别名: 3-[[4-fluoro-3-(1-methyl-1,8-diazaspiro[4.5]decane-8-carbonyl)phenyl]methyl]-4,5-dimethyl-1H-pyridazin-6-one
• CAS: 959839-48-6
• 化学式: C₂₃H₂₉FN₄O₂
• 分子量: 412.507
• InChiKey: NMXVVLRLQGYEPG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-(4-fluoro-3-(1-methyl-1,8-diazaspiro[4.5]decane-8-carbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-one 、 三氟乙酸 以 水 、 乙腈 为溶剂， 生成 8-{5-[(4,5-Dimethyl-6-oxo-1,6-dihydropyridazin-2-ium-3-yl)methyl]-2-fluorobenzoyl}-1-methyl-8-aza-1-azoniaspiro[4.5]decane bis(trifluoroacetate)
  参考文献：
  名称：

  Pyridinone and Pyridazinone Derivatives as Inhibitors of Poly (Adp-Ribose) Polymerase (Parp)

  摘要：

  本发明涉及式I的化合物及其药用可接受的盐或互变异构体，这些化合物是多聚腺苷二磷酸核糖聚合酶（PARP）的抑制剂，因此可用于治疗癌症、炎症性疾病、再灌注损伤、缺血症状、中风、肾衰竭、心血管疾病、除心血管疾病外的血管疾病、糖尿病、神经退行性疾病、逆转录病毒感染、视网膜损伤、皮肤衰老和紫外线诱导的皮肤损伤，以及作为癌症治疗的化疗或放射敏感剂。

  公开号：

  US20090176765A1
• 作为产物：
  描述：

  聚合甲醛 、 6-(4-fluoro-3-(1,8-diazaspiro[4.5]decane-8-carbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-one 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 、 1,2-二氯乙烷 为溶剂， 反应 1.0h， 生成 6-(4-fluoro-3-(1-methyl-1,8-diazaspiro[4.5]decane-8-carbonyl)benzyl)-4,5-dimethylpyridazin-3(2H)-one
  参考文献：
  名称：

  Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells

  摘要：

  We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.11.087

文献信息

• PYRIDINONE AND PYRIDAZINONE DERIVATIVES AS INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)
  申请人：MSD Italia S.r.l.

  公开号：EP2029551B1

  公开（公告）日：2018-10-31
• Pyridinone and Pyridazinone Derivatives as Inhibitors of Poly (Adp-Ribose) Polymerase (Parp)
  申请人：Jones Philip

  公开号：US20090176765A1

  公开（公告）日：2009-07-09

  The present invention relates to compounds of formula I: and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of poly(ADP-ribose)polymerase (PARP) and thus useful for the treatment of cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitizers for cancer treatment.

  本发明涉及式I的化合物及其药用可接受的盐或互变异构体，这些化合物是多聚腺苷二磷酸核糖聚合酶（PARP）的抑制剂，因此可用于治疗癌症、炎症性疾病、再灌注损伤、缺血症状、中风、肾衰竭、心血管疾病、除心血管疾病外的血管疾病、糖尿病、神经退行性疾病、逆转录病毒感染、视网膜损伤、皮肤衰老和紫外线诱导的皮肤损伤，以及作为癌症治疗的化疗或放射敏感剂。
• Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP–ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells
  作者：Federica Ferrigno、Danila Branca、Olaf Kinzel、Samuele Lillini、Laura Llauger Bufi、Edith Monteagudo、Ester Muraglia、Michael Rowley、Carsten Schultz-Fademrecht、Carlo Toniatti、Caterina Torrisi、Philip Jones

  DOI：10.1016/j.bmcl.2009.11.087

  日期：2010.2

  We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination. (C) 2009 Elsevier Ltd. All rights reserved.