2,3,9,9a-tetrahydro-1H-benzo<1,7>naphthyridin-7(8H)-one | 105400-83-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 2,3,9,9a-tetrahydro-1H-benzo<1,7>naphthyridin-7(8H)-one
• 英文别名: 1,2,3,8,9,9a-hexahydro-7H-benzo[de]-1,7-naphthyridin-7-one；2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-10-one
• CAS: 105400-83-7
• 化学式: C₁₁H₁₂N₂O
• 分子量: 188.229
• InChiKey: STFMKRBMUMYLTM-UHFFFAOYSA-N

物化性质

• 沸点：
  455.6±45.0 °C(Predicted)
• 密度：
  1.202±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  41.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2,3,9,9a-tetrahydro-1H-benzo<1,7>naphthyridin-7(8H)-one 在 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium iodide 、 lithium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 20.0h， 生成 N-[2-[4-(4-methoxyphenyl)piperazin-1-yl]-2-oxoethyl]-2-(10-oxo-2,11-diazatricyclo[7.3.1.05,13]trideca-5(13),6,8-trien-2-yl)acetamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors

  摘要：

  A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

  DOI：

  10.1021/jm301825t
• 作为产物：
  描述：

  4,6,7,8-四氢-1H,3H-喹啉-2,5-二酮 在 sodium azide 、 甲烷磺酸 作用下， 以 二氯甲烷 为溶剂， 生成 2,3,9,9a-tetrahydro-1H-benzo<1,7>naphthyridin-7(8H)-one 、 3a,4,5,6-tetrahydro-1H-benzo<1,6>naphthyridin-2(3H)-one
  参考文献：
  名称：

  一类哒嗪酮类化合物及其制备方法和用途

  摘要：

  本发明涉及一类如下通式I表示的哒嗪酮类化合物、其制备方法及其在制备预防或治疗与核糖多聚ADP‑核糖聚合酶（PARP）相关的疾病的药物中的用途。

  公开号：

  CN103833756B

文献信息

• Synthesis of the marine alkaloids aaptamine and demethyloxyaaptamine and of the parent structure didemethoxyaaptamine
  作者：Jeffrey C. Pelletier、Michael P. Cava

  DOI：10.1021/jo00380a024

  日期：1987.2
• Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)
  作者：Caterina Torrisi、Monica Bisbocci、Raffaele Ingenito、Jesus M. Ontoria、Michael Rowley、Carsten Schultz-Fademrecht、Carlo Toniatti、Philip Jones

  DOI：10.1016/j.bmcl.2009.12.002

  日期：2010.1

  A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported, subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties. (C) 2009 Elsevier Ltd. All rights reserved.
• WO2008/1134
  申请人：——

  公开号：——

  公开（公告）日：——
• [EN] 1,2,3,8,9,9A-HEXAHYDRO-7H-BENZO(DE)-1,7-NAPHTHYRIDIN-7-ONE DERIVATIVES AS INHIBITORS OF POLY(ADP-RIBOSE) POLYMERASE (PARP)<br/>[FR] DÉRIVÉS DE 1,2,3,8,9,9A-HEXAHYDRO-7H-BENZO(DE)-1,7-NAPHTHYRIDIN-7-ONE EN TANT QU'INHIBITEURS DE LA POLY(ADP-RIBOSE) POLYMÉRASE (PARP)
  申请人：ANGELETTI P IST RICHERCHE BIO

  公开号：WO2008001134A1

  公开（公告）日：2008-01-03

  [EN] 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, ischemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes, neurodegenerative diseases, retroviral infection, retinal damage or skin senescence and UV-induced skin damage, and as chemo-or radiosensitizers for cancer treatment.
  [FR] La présente invention concerne des composés de formule (I) ; et des sels pharmaceutiquement acceptables ou leurs tautomères qui sont des inhibiteurs de la poly (ADP-ribose) polymérase (PARP) et sont donc utiles pour le traitement du cancer, des maladies inflammatoires, des lésions de reperfusion, des états ischémiques, des AVC, de l'insuffisance rénale, des maladies cardiovasculaires, des maladies vasculaires autres que les maladies cardiovasculaires, du diabète, des maladies neurodégénératives, des infections à rétrovirus, des lésions rétiniennes ou de la sénescence cutanée et des lésions cutanées induites par UV, et en tant que chimio- ou radiosensibilisants pour le traitement du cancer.
• Design, Synthesis, and Biological Evaluation of a Series of Benzo[<i>de</i>][1,7]naphthyridin-7(8<i>H</i>)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors
  作者：Na Ye、Chuan-Huizi Chen、TianTian Chen、Zilan Song、Jin-Xue He、Xia-Juan Huan、Shan-Shan Song、Qiufeng Liu、Yi Chen、Jian Ding、Yechun Xu、Ze-Hong Miao、Ao Zhang

  DOI：10.1021/jm301825t

  日期：2013.4.11

  A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.