4-[4-(4-hydroxytetrahydropyranyl)]-2-pyridylmethanol | 155819-70-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 4-[4-(4-hydroxytetrahydropyranyl)]-2-pyridylmethanol
• 英文别名: 2-Pyridinemethanol, 4-(tetrahydro-4-hydroxy-2H-pyran-4-yl)-；4-[2-(hydroxymethyl)pyridin-4-yl]oxan-4-ol
• CAS: 155819-70-8
• 化学式: C₁₁H₁₅NO₃
• 分子量: 209.245
• InChiKey: XCANHZPJTNNWPS-UHFFFAOYSA-N

物化性质

• 沸点：
  412.2±40.0 °C(Predicted)
• 密度：
  1.274±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  62.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(呋喃-3-基)-3-氰基-6-萘酚 、 4-[4-(4-hydroxytetrahydropyranyl)]-2-pyridylmethanol 在 偶氮二甲酸二叔丁酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以63%的产率得到2-cyano-4-(3-furyl)-7-({4-[4-(4-hydroxytetrahydropyranyl)]-2-pyridyl}methoxy)naphthalene
  参考文献：
  名称：

  Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors:  Synthesis, Biological Profile, and Pharmacokinetics of L-739,010

  摘要：

  Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicycle derivatives were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1] octanyl)]-2-pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC(50)s of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 mu g/kg/min, respectively, iv infusion). In addition, 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and >85% inhibition in early and late phases, respectively at 2.5 mu g/kg/min, iv infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in R-L and 76% in the decrease of C-dyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based on its overall biological profile, compound 3g has been selected for preclinical animal toxicity studies.

  DOI：

  10.1021/jm970046b
• 作为产物：
  描述：

  4-溴吡啶-2-羧酸 在 咪唑 、 lithium aluminium tetrahydride 、 正丁基锂 、 四丁基氟化铵 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 4.42h， 生成 4-[4-(4-hydroxytetrahydropyranyl)]-2-pyridylmethanol
  参考文献：
  名称：

  Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors:  Synthesis, Biological Profile, and Pharmacokinetics of L-739,010

  摘要：

  Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicycle derivatives were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1] octanyl)]-2-pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC(50)s of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 mu g/kg/min, respectively, iv infusion). In addition, 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and >85% inhibition in early and late phases, respectively at 2.5 mu g/kg/min, iv infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in R-L and 76% in the decrease of C-dyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based on its overall biological profile, compound 3g has been selected for preclinical animal toxicity studies.

  DOI：

  10.1021/jm970046b

文献信息

• Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors:  Synthesis, Biological Profile, and Pharmacokinetics of L-739,010
  作者：Pierre Hamel、Denis Riendeau、Christine Brideau、Chi-Chung Chan、Sylvie Desmarais、Daniel Delorme、Daniel Dubé、Yves Ducharme、Diane Ethier、Erich Grimm、Jean-Pierre Falgueyret、Jocelyne Guay、Tom R. Jones、Elizabeth Kwong、Malia McAuliffe,、Cyril S. McFarlane、Hanna Piechuta、Marie Roumi、Philip Tagari、Robert N. Young、Yves Girard

  DOI：10.1021/jm970046b

  日期：1997.8.1

  Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicycle derivatives were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1] octanyl)]-2-pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC(50)s of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 mu g/kg/min, respectively, iv infusion). In addition, 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and >85% inhibition in early and late phases, respectively at 2.5 mu g/kg/min, iv infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in R-L and 76% in the decrease of C-dyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based on its overall biological profile, compound 3g has been selected for preclinical animal toxicity studies.