6,7-dimethoxy-2-cis-perhydro-1-quinoxalinyl-4-quinazolinamine

• 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: 6,7-dimethoxy-2-cis-perhydro-1-quinoxalinyl-4-quinazolinamine
• 英文别名: cis-6,7-dimethoxy-2-[octahydroquinoxalin-1(2H)-yl]quinazolin-4-amine；2-[(4aS,8aR)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinoxalin-1-yl]-6,7-dimethoxyquinazolin-4-amine
• 化学式: C₁₈H₂₅N₅O₂
• 分子量: 343.429
• InChiKey: ISQDTGONOPZFAB-GXTWGEPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  85.5
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-甲氧基苯乙酰氯 、 6,7-dimethoxy-2-cis-perhydro-1-quinoxalinyl-4-quinazolinamine 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 1-[4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-cis-perhydro-1-quinoxalinyl]-2-(4-methoxyphenyl)-1-ethanone
  参考文献：
  名称：

  Searching for cyclazosin analogues as α1B-adrenoceptor antagonists

  摘要：

  A series of quinazoline derivatives, 2-20, structurally related to the racemic alpha(1)-adrenoceptor antagonist cyclazosin (1), were synthesized and evaluated for their functional antagonism at alpha(1)- and alpha(2)-adrenoceptors and for their binding affinity at human cloned alpha(1a)-, alpha(1b)- and alpha(1d)-adrenoceptor subtypes. They displayed, like 1, preferential antagonism and selectivity for alpha(1) versus alpha(2)-adrenoceptors. Compounds 10, 13, and 18 showed high potency at alpha(1)-adrenoceptors similar to that of 1 (pK(B) values 8.47-8.89 versus 8.67), whereas 13 and 15 were endowed with the highest alpha(1)-adrenoceptor selectivity, only 3- to 4-fold lower than that of 1. In binding experiments, all of the compounds displayed an affinity practically similar to that found for 1, with the exception of 19 and 20 that were definitely less potent. The s-triazine analogue 18 was the most potent of the series with pK(i) values of 10.15 (alpha(1a)), 10.22 (alpha(1b)) and 10.40 (alpha(1d)), resulting 77-fold more potent than 1 at alpha(1a)-adrenoceptors. In addition, the majority of compounds, like prototype 1, showed the same trend of preferential affinity for alpha(1d)- and alpha(1b)-adrenoceptors that alpha(1a)-subtype. In conclusion, we identified compounds 2-5, 10, 12 and 13, bearing either an aliphatic- or an arylalkyl- or aryloxyalkyl-acyl function, with an interesting subtype-selectivity profile, which makes them suitable candidates for their resolution as enantiomers structurally related to (+)-cyclazosin.

  DOI：

  10.1016/s0014-827x(02)00025-3
• 作为产物：
  描述：

  benzyl (4aR,8aS)-4-(4-amino-6,7-dimethoxyquinazolin-2-yl)octahydroquinoxaline-1(2H)-carboxylate hydrochloride 在 palladium on activated charcoal 环己烯 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 6.0h， 生成 6,7-dimethoxy-2-cis-perhydro-1-quinoxalinyl-4-quinazolinamine
  参考文献：
  名称：

  Synthesis and α1-adrenoceptor antagonist activity of derivatives and isosters of the furan portion of (+)-cyclazosin

  摘要：

  alpha(1)-Adrenoceptor selective antagonists are crucial in investigating the role and biological functions of alpha(1)-adrenoceptor subtypes. We synthesized and studied the alpha(1)-adrenoceptor blocking properties of new molecules structurally related to the alpha(1B)-adrenoceptor selective antagonist (+)-cyclazosin, in an attempt to improve its receptor selectivity. In particular, we investigated the importance of substituents introduced at position 5 of the 2-furan moiety of (+)-cyclazosin and its replacement with classical isosteric rings. The 5-methylfuryl derivative (+)-3, [(+)-metcyclazosin], improved the pharmacological properties of the progenitor, displaying a competitive antagonism and an 11 fold increased selectivity for alpha(1B) over alpha(1A), while maintaining a similar selectivity for the alpha(1B)-adrenoceptor relative to the alpha(1D)-adrenoceptor. Compound (+)-3 may represent a useful tool for alpha(1B)-adrenoceptor characterization in functional studies. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.01.028

文献信息

• Doxazosin-Related α₁-Adrenoceptor Antagonists With Prostate Antitumor Activity
  作者：Dario Giardinà、Daniele Martarelli、Gianni Sagratini、Piero Angeli、Dario Ballinari、Ugo Gulini、Carlo Melchiorre、Elena Poggesi、Pierluigi Pompei

  DOI：10.1021/jm8016046

  日期：2009.8.13

  Doxazosin analogues 1-3 and 1 a were synthesized and investigated at alpha(1)-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying anti proliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.
• Synthesis and α1-adrenoceptor antagonist activity of derivatives and isosters of the furan portion of (+)-cyclazosin
  作者：Gianni Sagratini、Piero Angeli、Michela Buccioni、Ugo Gulini、Gabriella Marucci、Carlo Melchiorre、Amedeo Leonardi、Elena Poggesi、Dario Giardinà

  DOI：10.1016/j.bmc.2007.01.028

  日期：2007.3

  alpha(1)-Adrenoceptor selective antagonists are crucial in investigating the role and biological functions of alpha(1)-adrenoceptor subtypes. We synthesized and studied the alpha(1)-adrenoceptor blocking properties of new molecules structurally related to the alpha(1B)-adrenoceptor selective antagonist (+)-cyclazosin, in an attempt to improve its receptor selectivity. In particular, we investigated the importance of substituents introduced at position 5 of the 2-furan moiety of (+)-cyclazosin and its replacement with classical isosteric rings. The 5-methylfuryl derivative (+)-3, [(+)-metcyclazosin], improved the pharmacological properties of the progenitor, displaying a competitive antagonism and an 11 fold increased selectivity for alpha(1B) over alpha(1A), while maintaining a similar selectivity for the alpha(1B)-adrenoceptor relative to the alpha(1D)-adrenoceptor. Compound (+)-3 may represent a useful tool for alpha(1B)-adrenoceptor characterization in functional studies. (c) 2007 Elsevier Ltd. All rights reserved.
• Searching for cyclazosin analogues as α1B-adrenoceptor antagonists
  作者：Dario Giardinà、O Polimanti、G Sagratini、P Angeli、U Gulini、G Marucci、C Melchiorre、E Poggesi、A Leonardi

  DOI：10.1016/s0014-827x(02)00025-3

  日期：2003.7

  A series of quinazoline derivatives, 2-20, structurally related to the racemic alpha(1)-adrenoceptor antagonist cyclazosin (1), were synthesized and evaluated for their functional antagonism at alpha(1)- and alpha(2)-adrenoceptors and for their binding affinity at human cloned alpha(1a)-, alpha(1b)- and alpha(1d)-adrenoceptor subtypes. They displayed, like 1, preferential antagonism and selectivity for alpha(1) versus alpha(2)-adrenoceptors. Compounds 10, 13, and 18 showed high potency at alpha(1)-adrenoceptors similar to that of 1 (pK(B) values 8.47-8.89 versus 8.67), whereas 13 and 15 were endowed with the highest alpha(1)-adrenoceptor selectivity, only 3- to 4-fold lower than that of 1. In binding experiments, all of the compounds displayed an affinity practically similar to that found for 1, with the exception of 19 and 20 that were definitely less potent. The s-triazine analogue 18 was the most potent of the series with pK(i) values of 10.15 (alpha(1a)), 10.22 (alpha(1b)) and 10.40 (alpha(1d)), resulting 77-fold more potent than 1 at alpha(1a)-adrenoceptors. In addition, the majority of compounds, like prototype 1, showed the same trend of preferential affinity for alpha(1d)- and alpha(1b)-adrenoceptors that alpha(1a)-subtype. In conclusion, we identified compounds 2-5, 10, 12 and 13, bearing either an aliphatic- or an arylalkyl- or aryloxyalkyl-acyl function, with an interesting subtype-selectivity profile, which makes them suitable candidates for their resolution as enantiomers structurally related to (+)-cyclazosin.