3-[3-(4-butoxyphenyl)furan-2-yl]quinuclidin-2-ene

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 3-[3-(4-butoxyphenyl)furan-2-yl]quinuclidin-2-ene
• 英文别名: 3-[3-(4-Butoxyphenyl)furan-2-yl]-1-azabicyclo[2.2.2]oct-2-ene
• 化学式: C₂₁H₂₅NO₂
• 分子量: 323.435
• InChiKey: FPGYVSKEOKZERL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  25.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3-奎宁环酮 在 正丁基锂 、 甲酸 、 硼酸三异丙酯 、 Pd(PPh₃ 、 sodium carbonate 、 lithium diisopropyl amide 作用下， 反应 14.0h， 生成 3-[3-(4-butoxyphenyl)furan-2-yl]quinuclidin-2-ene
  参考文献：
  名称：

  Antimuscarinic 3-(2-Furanyl)quinuclidin-2-ene Derivatives:  Synthesis and Structure−Activity Relationships

  摘要：

  A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[H-3]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (K-i 300 nM), it is much higher for the 6-methyl (49; K-i = 12 nM), 5-ethyl (52; K-i = 7.4 nM), 5-bromo (33; K-i = 6.4 nM), and 3-phenyl (49; K-i = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (K-i = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta-and para-substituted analogues of 49 was synthesized and tested. derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.

  DOI：

  10.1021/jm970346t

文献信息

• Antimuscarinic 3-(2-Furanyl)quinuclidin-2-ene Derivatives:  Synthesis and Structure−Activity Relationships
  作者：Gary Johansson、Staffan Sundquist、Gunnar Nordvall、Björn M. Nilsson、Magnus Brisander、Lisbeth Nilvebrant、Uli Hacksell

  DOI：10.1021/jm970346t

  日期：1997.11.1

  A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[H-3]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (K-i 300 nM), it is much higher for the 6-methyl (49; K-i = 12 nM), 5-ethyl (52; K-i = 7.4 nM), 5-bromo (33; K-i = 6.4 nM), and 3-phenyl (49; K-i = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (K-i = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta-and para-substituted analogues of 49 was synthesized and tested. derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.