6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]-2-pyridylmethanol | 155933-93-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧杂环己烷
• 英文名称: 6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]-2-pyridylmethanol
• 英文别名: (1S,3S,5R)-3-[6-(hydroxymethyl)pyridin-2-yl]-6,8-dioxabicyclo[3.2.1]octan-3-ol
• CAS: 155933-93-0
• 化学式: C₁₂H₁₅NO₄
• 分子量: 237.255
• InChiKey: OWJWUQUGHXRUMO-WCQGTBRESA-N

物化性质

• 沸点：
  458.7±40.0 °C(predicted)
• 密度：
  1.381±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  71.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]-2-pyridylmethanol 、 1-benzyl-4-(furan-3-yl)-7-hydroxy-2-quinolinone 在 偶氮二甲酸二苄酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 生成
  参考文献：
  名称：

  喹啉作为有效的5-脂氧合酶抑制剂：L-746,530的合成和生物学特征。

  摘要：

  白三烯生物合成抑制剂作为哮喘和炎性疾病的新治疗剂具有潜力。已经合成了一系列新颖的取代的2-氰基喹啉，并就它们通过5-脂氧合酶抑制白三烯形成的能力评估了结构活性关系。[1S，5R] -2-氰基-4-（3-呋喃基）-7-¿3-氟-5- [3-（3α-羟基-6,8-二氧杂双环[3.2.1]-辛基）]苯氧基甲基喹啉（L-746,530）3代表一类独特的抑制剂，其体外和体内效价与萘类似物（L-739,010）2相当或更高。

  DOI：

  10.1016/s0960-894x(98)00201-7
• 作为产物：
  描述：

  1,6-anhydro-2,4-dideoxy-β-D-glycero-hexopyranos-3-ulose 在 正丁基锂 、 trans-dichlorobis(triphenylphosphine)palladium(II) 、 二异丁基氢化铝 、 三乙胺 作用下， 以 四氢呋喃 、 甲苯 为溶剂， -78.0~75.0 ℃ 、101.33 kPa 条件下， 反应 49.5h， 生成 6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]-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.
• Quinolines as potent 5-lipoxygenase inhibitors: Synthesis and biological profile of L-746,530
  作者：Daniel Dubé、Marc Blouin、Christine Brideau、Chi-Chung Chan、Sylvie Desmarais、Diane Ethier、Jean-Pierre Falgueyret、Richard W. Friesen、Mario Girard、Yves Girard、Jocelyne Guay、Denis Riendeau、Philip Tagari、Robert N. Young

  DOI：10.1016/s0960-894x(98)00201-7

  日期：1998.5

  Leukotriene biosynthesis inhibitors have potential as new therapeutic agents for asthma and inflammatory diseases. A series of novel substituted 2-cyanoquinolines have been synthesized and the structure activity relationships were evaluated with respect to their ability to inhibit the formation of leukotrienes via the 5-lipoxygenase enzyme. [1S,5R]-2-Cyano-4-(3-furyl)-7-¿3-fluoro-5-[3-(3 alpha-hydroxy-6

  白三烯生物合成抑制剂作为哮喘和炎性疾病的新治疗剂具有潜力。已经合成了一系列新颖的取代的2-氰基喹啉，并就它们通过5-脂氧合酶抑制白三烯形成的能力评估了结构活性关系。[1S，5R] -2-氰基-4-（3-呋喃基）-7-¿3-氟-5- [3-（3α-羟基-6,8-二氧杂双环[3.2.1]-辛基）]苯氧基甲基喹啉（L-746,530）3代表一类独特的抑制剂，其体外和体内效价与萘类似物（L-739,010）2相当或更高。