N-(6,7-methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamide | 500214-52-8

• 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: N-(6,7-methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamide
• 英文别名: N-butyl-N-([1,3]dioxolo[4,5-g]cinnolin-4-yl)-2-iodo-4,5-dimethoxybenzamide
• CAS: 500214-52-8
• 化学式: C₂₂H₂₂IN₃O₅
• 分子量: 535.338
• InChiKey: UXTKGVCFSGYSMK-UHFFFAOYSA-N

物化性质

• 沸点：
  594.4±50.0 °C(Predicted)
• 密度：
  1.582±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  83
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(6,7-methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamide 在 palladium diacetate 三(邻甲基苯基)磷 、 silver carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 以27%的产率得到12-Butyl-2,3-dimethoxy-12H-8,10-dioxa-5,6,12-triaza-cyclopenta[b]chrysen-13-one
  参考文献：
  名称：

  11H-Isoquino[4,3-c]cinnolin-12-ones novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity

  摘要：

  Recent studies have identified 2,3-dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)ethyl]-22H-isoquino[4,3-c]cinnolin-12-one (1a) as a novel topoisomerase 1-targeting agent with potent cytotoxic activity. The effect of varied substituents at the 11-position of 2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-ones on topoisomerase I-targeting activity and cytotoxicity was evaluated. Potent TOP1-targeting activity was observed when the 11-position was substituted with either a 2-(N,N-dimethylamino)ethyl, a 2-(N,N-diethylamino)ethyl, a n-butyl, or a 2-(pyrrolidin-1-yl)ethyl group. The addition of a beta-methyl group to la provided an analogue with dramatically reduced TOP1-targeting activity and cytotoxicity. Analogues of la wherein the 2(N,N-dimethylamino)ethyl group was replaced with a (2-tetrahydrofuranyl)methyl, a 2-(piperidin-1-yl)ethyl, or a 2-(4-methylpiperazin-1-yl)ethyl substituent exhibited decreased activity as TOP1-targeting agents. Replacement of the dimethoxy groups of la with hydrogen atoms resulted in an analogue with significantly decreased TOP1-targeting activity and cytotoxicity. Removal of both the vicinal dimethoxyl groups and the methylenedioxy moiety resulted in a complete loss of TOP1-targeting activity. The presence of a 9-nitro substituent in place of the 8,9-methylenedioxy group of la resulted in a decrease in relative TOP1-targeting activity and cytotoxicity. Compounds 1a and the 11-n-butyl analogue 1d were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line MDA-MB-435 was used in these assays. At dose levels that approached its maximum tolerated dose, la proved to be effective in inhibiting tumor growth in vivo when administered orally or by ip injection. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2003.10.061
• 作为产物：
  描述：

  6,7-methylenedioxy-4-cinnolone 在 五氯化磷 、 铜 、 三乙胺 、 三氯氧磷 作用下， 以 二氯甲烷 为溶剂， 反应 40.0h， 生成 N-(6,7-methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamide
  参考文献：
  名称：

  11H-Isoquino[4,3-c]cinnolin-12-ones novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity

  摘要：

  Recent studies have identified 2,3-dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)ethyl]-22H-isoquino[4,3-c]cinnolin-12-one (1a) as a novel topoisomerase 1-targeting agent with potent cytotoxic activity. The effect of varied substituents at the 11-position of 2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-ones on topoisomerase I-targeting activity and cytotoxicity was evaluated. Potent TOP1-targeting activity was observed when the 11-position was substituted with either a 2-(N,N-dimethylamino)ethyl, a 2-(N,N-diethylamino)ethyl, a n-butyl, or a 2-(pyrrolidin-1-yl)ethyl group. The addition of a beta-methyl group to la provided an analogue with dramatically reduced TOP1-targeting activity and cytotoxicity. Analogues of la wherein the 2(N,N-dimethylamino)ethyl group was replaced with a (2-tetrahydrofuranyl)methyl, a 2-(piperidin-1-yl)ethyl, or a 2-(4-methylpiperazin-1-yl)ethyl substituent exhibited decreased activity as TOP1-targeting agents. Replacement of the dimethoxy groups of la with hydrogen atoms resulted in an analogue with significantly decreased TOP1-targeting activity and cytotoxicity. Removal of both the vicinal dimethoxyl groups and the methylenedioxy moiety resulted in a complete loss of TOP1-targeting activity. The presence of a 9-nitro substituent in place of the 8,9-methylenedioxy group of la resulted in a decrease in relative TOP1-targeting activity and cytotoxicity. Compounds 1a and the 11-n-butyl analogue 1d were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line MDA-MB-435 was used in these assays. At dose levels that approached its maximum tolerated dose, la proved to be effective in inhibiting tumor growth in vivo when administered orally or by ip injection. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2003.10.061

文献信息

• Cytotoxic agents
  申请人：LaVoie J. Edmond

  公开号：US20050009825A1

  公开（公告）日：2005-01-13

  The invention provides compounds of the invention pharmaceutical compositions comprising a compound of the invention, processes for preparing compounds of the invention, intermediates useful for preparing compounds of the invention, and therapeutic methods for treating cancer and other topoisomerase mediated conditions.

  本发明提供了本发明的化合物、包含本发明化合物的制药组合物、制备本发明化合物的方法、制备本发明化合物有用的中间体以及治疗癌症和其他拓扑异构酶介导病症的治疗方法。
• CYTOTOXIC AGENTS
  申请人：LaVoie J. Edmond

  公开号：US20080090831A1

  公开（公告）日：2008-04-17

  The invention provides compounds of the invention pharmaceutical compositions comprising a compound of the invention, processes for preparing compounds of the invention, intermediates useful for preparing compounds of the invention, and therapeutic methods for treating cancer and other topoisomerase mediated conditions.

  该发明提供了化合物的发明，包括化合物的制药组合物，制备化合物的过程，用于制备化合物的中间体以及治疗癌症和其他拓扑异构酶介导疾病的治疗方法。
• Diaza- and triazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft, MDA-MB-435
  作者：Alexander L. Ruchelman、Sudhir K. Singh、Xiaohua Wu、Abhijit Ray、Jin-Ming Yang、Tsai-Kun Li、Angela Liu、Leroy F. Liu、Edmond J. LaVoie

  DOI：10.1016/s0960-894x(02)00737-0

  日期：2002.11

  Several 5,12-diazachrysen-6-ones and 5,6,11-triazachrysen-12-ones were synthesized with varied substituents at the 5- or 11-position, respectively. Each compound was evaluated for its potential to stabilize the cleavable complex formed with TOP I and DNA. Two analogues with very potent TOP1-targeting activity, 3a and 4a, exhibited cytotoxic activity with IC50 values at or below 2 nM against RPM18402. Compound 3a was active in vivo by either ip or po administration in the human tumor xenograft athymic nude mice model. (C) 2002 Elsevier Science Ltd. All rights reserved.
• US7319105B2
  申请人：——

  公开号：US7319105B2

  公开（公告）日：2008-01-15
• US7468366B2
  申请人：——

  公开号：US7468366B2

  公开（公告）日：2008-12-23