3-(3-bromo-furan-2-yl)quinuclidin-3-ol | 154183-60-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 奎宁环
• 英文名称: 3-(3-bromo-furan-2-yl)quinuclidin-3-ol
• 英文别名: 3-(3-bromo-2-furyl)quinuclidin-3-ol；3-(3-Bromofuran-2-yl)-1-azabicyclo[2.2.2]octan-3-ol
• CAS: 154183-60-5
• 化学式: C₁₁H₁₄BrNO₂
• 分子量: 272.142
• InChiKey: RJFLSCKHMNKULS-UHFFFAOYSA-N

物化性质

• 沸点：
  223.9±10.0 °C(predicted)
• 密度：
  1.62±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  36.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(3-bromo-furan-2-yl)quinuclidin-3-ol 在 四(三苯基膦)钯 、 正丁基锂 、 甲酸 、 1,1,2,2-四氟-1,2-二溴乙烷 、 sodium carbonate 作用下， 反应 21.17h， 生成 3-(5-bromo-3-phenylfuran-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
• 作为产物：
  描述：

  3-溴呋喃 、 3-奎宁环酮 在 lithium diisopropyl amide 作用下， 生成 3-(3-bromo-furan-2-yl)quinuclidin-3-ol
  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

• Heteroaromatic quinuclidinenes, their use and preparation
  申请人：Pharmacia AB

  公开号：US05599937A1

  公开（公告）日：1997-02-04

  The invention relates to novel compounds of general formula (I), wherein R is a group of general formula (II) or (III), where X.sup.1 represents oxygen or sulphur and Y.sup.1 and Z.sup.1 both represent carbon, or X.sup.1 represents oxygen and one of Y.sup.1 and Z.sup.1 represents nitrogen and the other represents carbon, or X.sup.1 represents sulphur, Y.sup.1 represents nitrogen and Z.sup.1 represents carbon; one of X.sup.2, Y.sup.2 and Z.sup.2 represents oxygen or sulphur and the other two both represent carbon or one represents nitrogen and the other represents carbon, and the dotted line in formula (III) represents an optional additional carbon-carbon or carbon-nitrogen bond; A.sup.1, A.sup.2, A.sup.3 and A.sup.4 each represent carbon or, when one of X.sup.2, Y.sup.2 and Z.sup.2 represents oxygen or sulphur and the other two both represent carbon, one or two of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 may represent nitrogen and the others carbon; and R.sup.1 to R.sup.5 are as defined in the description. The compounds of formula (I) can be used for treating diseases related to muscarinic receptor function.

  该发明涉及通式(I)的新化合物，其中R是通式(II)或(III)的一个基团，其中X.sup.1代表氧或硫，Y.sup.1和Z.sup.1都代表碳，或者X.sup.1代表氧，其中Y.sup.1和Z.sup.1中的一个代表氮，另一个代表碳，或者X.sup.1代表硫，Y.sup.1代表氮，Z.sup.1代表碳；X.sup.2、Y.sup.2和Z.sup.2中的一个代表氧或硫，另外两个都代表碳，或者一个代表氮，另一个代表碳，而在通式(III)中的虚线代表可选的额外碳-碳或碳-氮键；A.sup.1、A.sup.2、A.sup.3和A.sup.4每个代表碳，或者当X.sup.2、Y.sup.2和Z.sup.2中的一个代表氧或硫，另外两个都代表碳时，A.sup.1、A.sup.2、A.sup.3和A.sup.4中的一个或两个可以代表氮，其他代表碳；而R.sup.1到R.sup.5如描述中所定义。通式(I)的化合物可用于治疗与肌胆碱受体功能相关的疾病。
• HETEROAROMATIC QUINUCLIDINENES, THEIR USE AND PREPARATION
  申请人：PHARMACIA AB

  公开号：EP0640082A1

  公开（公告）日：1995-03-01
• US5599937A
  申请人：——

  公开号：US5599937A

  公开（公告）日：1997-02-04
• [EN] HETEROAROMATIC QUINUCLIDINENES, THEIR USE AND PREPARATION<br/>[FR] QUINUCLIDINENES HETEROAROMATIQUES, LEUR UTILISATION ET LEUR PREPARATION
  申请人：KABI PHARMACIA AB

  公开号：WO1993023395A1

  公开（公告）日：1993-11-25

  (EN) The invention relates to novel compounds of general formula (I), wherein R is a group of general formula (II) or (III), where X1 represents oxygen or sulphur and Y1 and Z1 both represent carbon, or X1 represents oxygen and one of Y1 and Z1 represents nitrogen and the other represents carbon, or X1 represents sulphur, Y1 represents nitrogen and Z1 represents carbon; one of X2, Y2 and Z2 represents oxygen or sulphur and the other two both represent carbon or one represents nitrogen and the other represents carbon, and the dotted line in formula (III) represents an optional additional carbon-carbon or carbon-nitrogen bond; A1, A2, A3 and A4 each represent carbon or, when one of X2, Y2 and Z2 represents oxygen or sulphur and the other two both represent carbon, one or two of A1, A2, A3 and A4 may represent nitrogen and the others carbon; and R1 to R5 are as defined in the description. The compounds of formula (I) can be used for treating diseases related to muscarinic receptor function.(FR) L'invention concerne de nouveaux composés de la formule générale (I). Dans cette formule R est un groupe ayant la formule générale (II) ou (III), où X1 représente un oxygène ou un soufre et Y1 et Z1 représentent tous deux un carbone ou X1 représente un oxygène et un des éléments Y1 et Z1 représente un azote et l'autre représente un carbone, ou encore X1 représente un soufre, Y1 représente un azote et Z1 représente un carbone; un des éléments X2, Y2 et Z2 représente un oxygène ou un soufre et les deux autres représentent tous deux un carbone, ou un représente un azote et l'autre représente un carbone, et la ligne en pointillé de la formule (III) représente une liaison additionnelle facultative carbone-carbone ou carbone-azote; A1, A2, A3 et A4 représentent chacun un carbone, ou lorsqu'un des éléments X2, Y2 et Z2 représente un oxygène ou un soufre et les deux autres représentent tous deux un carbone, un ou deux des éléments A1, A2, A3 et A4 peuvent représenter un azote et les autres un carbone; et R1 à R5 sont comme définis dans la description. Les composés de la formule (I) peuvent être utilisés pour traiter des maladies liées au mauvais fonctionnement des récepteurs muscariniques.
• 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.