N-<6-<(4-amino-6,7-dimethoxyquinazolin-2-yl)methylamino>hexyl>-2-hydroxymethyl-N-methylbenzamide | 788141-76-4

• 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-<(4-amino-6,7-dimethoxyquinazolin-2-yl)methylamino>hexyl>-2-hydroxymethyl-N-methylbenzamide
• 英文别名: N-[6-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-methylamino]hexyl]-2-(hydroxymethyl)-N-methylbenzamide
• CAS: 788141-76-4
• 化学式: C₂₆H₃₅N₅O₄
• 分子量: 481.595
• InChiKey: DCUOVBCCCVDADB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  35
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-<6-<(4-amino-6,7-dimethoxyquinazolin-2-yl)methylamino>hexyl>-2-hydroxymethyl-N-methylbenzamide 在 氯化亚砜 作用下， 以 乙醇 、 氯仿 为溶剂， 反应 4.0h， 生成 N-[6-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-methylamino]hexyl]-2-[(dimethylamino)methyl]-N-methylbenzamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Activity of Prazosin-Related Antagonists. Role of the Piperazine and Furan Units of Prazosin on the Selectivity for α₁-Adrenoreceptor Subtypes

  摘要：

  Prazosin-related quinazolines 4-20 were synthesized, and their biological profiles at alpha(1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO cells expressing human cloned alpha(1)-adrenoreceptor subtypes. The replacement of piperazine and furan units of prazosin (1) by 1,6-hexanediamine and phenyl moieties, respectively, affording 3-20, markedly affected both affinity and selectivity for alpha(1D)-adrenoreceptor subtypes in functional experiments. Cystazosin (3), bearing a cystamine moiety, was a selective alpha(1D)-adrenoreceptor antagonist being 1 order of magnitude more potent at alpha(1D)-adrenoreceptors (pA(2), 8.54 +/- 0.02) than at the alpha(1A)- (pA(2), 7.53 +/- 0.01) and alpha(1B)-subtypes (pA(2), 7.49 +/- 0.01). The insertion of substituents on the furan ring of 3, as in compounds 4 and 5, did not improve the selectivity profile. The simultaneous replacement of both piperazine and furan rings of 1 gave 8 which resulted in a potent, selective alpha(1B)-adrenoreceptor antagonist (85- and 15-fold more potent than at alpha(1A)- and alpha(1D)-subtypes, respectively). The insertion of substituents on the benzene ring of 8 affected, according to the type and the position of the substituent, affinity and selectivity for alpha(1)-adrenoreceptors. Consequently, the insertion of appropriate substituents in the phenyl ring of 8 may represent the basis of designing new selective Ligands for a1-adrenoreceptor subtypes. Interestingly, the finding that polyamines 11, 16, and 20, bearing a 1,6-hexanediamine moiety, retained high affinity for alpha(1)-adrenoreceptor subtypes suggests that the substituent did not give rise to negative interactions with the receptor. Finally, binding assays performed with selected quinazolines (2, 3, and 14) produced affinity results, which were not in agreement with the selectivity profiles obtained from functional experiments. This rather surprising and unexpected finding may be explained by considering neutral and negative antagonism.

  DOI：

  10.1021/jm9810654
• 作为产物：
  描述：

  2-甲酰基苯甲酰氯 在 sodium tetrahydroborate 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 27.0h， 生成 N-<6-<(4-amino-6,7-dimethoxyquinazolin-2-yl)methylamino>hexyl>-2-hydroxymethyl-N-methylbenzamide
  参考文献：
  名称：

  Design, Synthesis, and Biological Activity of Prazosin-Related Antagonists. Role of the Piperazine and Furan Units of Prazosin on the Selectivity for α₁-Adrenoreceptor Subtypes

  摘要：

  Prazosin-related quinazolines 4-20 were synthesized, and their biological profiles at alpha(1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO cells expressing human cloned alpha(1)-adrenoreceptor subtypes. The replacement of piperazine and furan units of prazosin (1) by 1,6-hexanediamine and phenyl moieties, respectively, affording 3-20, markedly affected both affinity and selectivity for alpha(1D)-adrenoreceptor subtypes in functional experiments. Cystazosin (3), bearing a cystamine moiety, was a selective alpha(1D)-adrenoreceptor antagonist being 1 order of magnitude more potent at alpha(1D)-adrenoreceptors (pA(2), 8.54 +/- 0.02) than at the alpha(1A)- (pA(2), 7.53 +/- 0.01) and alpha(1B)-subtypes (pA(2), 7.49 +/- 0.01). The insertion of substituents on the furan ring of 3, as in compounds 4 and 5, did not improve the selectivity profile. The simultaneous replacement of both piperazine and furan rings of 1 gave 8 which resulted in a potent, selective alpha(1B)-adrenoreceptor antagonist (85- and 15-fold more potent than at alpha(1A)- and alpha(1D)-subtypes, respectively). The insertion of substituents on the benzene ring of 8 affected, according to the type and the position of the substituent, affinity and selectivity for alpha(1)-adrenoreceptors. Consequently, the insertion of appropriate substituents in the phenyl ring of 8 may represent the basis of designing new selective Ligands for a1-adrenoreceptor subtypes. Interestingly, the finding that polyamines 11, 16, and 20, bearing a 1,6-hexanediamine moiety, retained high affinity for alpha(1)-adrenoreceptor subtypes suggests that the substituent did not give rise to negative interactions with the receptor. Finally, binding assays performed with selected quinazolines (2, 3, and 14) produced affinity results, which were not in agreement with the selectivity profiles obtained from functional experiments. This rather surprising and unexpected finding may be explained by considering neutral and negative antagonism.

  DOI：

  10.1021/jm9810654

文献信息

• Design, Synthesis, and Biological Activity of Prazosin-Related Antagonists. Role of the Piperazine and Furan Units of Prazosin on the Selectivity for α₁-Adrenoreceptor Subtypes
  作者：Maria L. Bolognesi、Roberta Budriesi、Alberto Chiarini、Elena Poggesi、Amedeo Leonardi、Carlo Melchiorre

  DOI：10.1021/jm9810654

  日期：1998.11.1

  Prazosin-related quinazolines 4-20 were synthesized, and their biological profiles at alpha(1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)) and by binding assays in CHO cells expressing human cloned alpha(1)-adrenoreceptor subtypes. The replacement of piperazine and furan units of prazosin (1) by 1,6-hexanediamine and phenyl moieties, respectively, affording 3-20, markedly affected both affinity and selectivity for alpha(1D)-adrenoreceptor subtypes in functional experiments. Cystazosin (3), bearing a cystamine moiety, was a selective alpha(1D)-adrenoreceptor antagonist being 1 order of magnitude more potent at alpha(1D)-adrenoreceptors (pA(2), 8.54 +/- 0.02) than at the alpha(1A)- (pA(2), 7.53 +/- 0.01) and alpha(1B)-subtypes (pA(2), 7.49 +/- 0.01). The insertion of substituents on the furan ring of 3, as in compounds 4 and 5, did not improve the selectivity profile. The simultaneous replacement of both piperazine and furan rings of 1 gave 8 which resulted in a potent, selective alpha(1B)-adrenoreceptor antagonist (85- and 15-fold more potent than at alpha(1A)- and alpha(1D)-subtypes, respectively). The insertion of substituents on the benzene ring of 8 affected, according to the type and the position of the substituent, affinity and selectivity for alpha(1)-adrenoreceptors. Consequently, the insertion of appropriate substituents in the phenyl ring of 8 may represent the basis of designing new selective Ligands for a1-adrenoreceptor subtypes. Interestingly, the finding that polyamines 11, 16, and 20, bearing a 1,6-hexanediamine moiety, retained high affinity for alpha(1)-adrenoreceptor subtypes suggests that the substituent did not give rise to negative interactions with the receptor. Finally, binding assays performed with selected quinazolines (2, 3, and 14) produced affinity results, which were not in agreement with the selectivity profiles obtained from functional experiments. This rather surprising and unexpected finding may be explained by considering neutral and negative antagonism.