4-(3-fluoro-5-hydroxyphenyl)-4-methylsulfinyl-3,4,5,6-tetrahydro-2H-pyran | 167758-68-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 4-(3-fluoro-5-hydroxyphenyl)-4-methylsulfinyl-3,4,5,6-tetrahydro-2H-pyran
• 英文别名: 4(3-Hydroxy-5-fluorophenyl)-4-methylsulfinyl-3,4,5,6-tetrahydro-2H-pyran；3-fluoro-5-(4-methylsulfinyloxan-4-yl)phenol
• CAS: 167758-68-1
• 化学式: C₁₂H₁₅FO₃S
• 分子量: 258.314
• InChiKey: QWIMIKTXZRIHTE-UHFFFAOYSA-N

物化性质

• 沸点：
  493.6±45.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  65.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(4-氯甲基苯基)-2-甲基-1H-咪唑 、 4-(3-fluoro-5-hydroxyphenyl)-4-methylsulfinyl-3,4,5,6-tetrahydro-2H-pyran 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 1-[4-[[3-Fluoro-5-(4-methylsulfinyloxan-4-yl)phenoxy]methyl]phenyl]-2-methylimidazole
  参考文献：
  名称：

  4-[5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6- tetrahydro-2H-pyran-4-carboxamide, an Orally Active Inhibitor of 5-Lipoxygenase with Improved Pharmacokinetic and Toxicology Characteristics

  摘要：

  Described herein are structure-activity relationships (SARs) of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1, CJ-12,918), an imidazole 5-lipoxygenase (5-LO) inhibitor. When I was tested in preclinical studies, cataract formation was observed in rats; however, this compound was metabolized extensively in vivo and showed low systemic exposure. To eliminate this side effect and enhance bioavailability, structural modification was focused on replacing the methoxy group of 1 by modulating lipophilicity (i.e., predicted log D at pH 7.4). The SARs led to the discovery of 4- [5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (10, CJ-13,454), which was less lipophilic by 1.2 log D units and showed in vivo potency (ED50 = 4-9 mg/kg) equipotent to 1. Enhanced metabolic stability resulted in fewer in vivo metabolites, as well as improved bioavailability and a better toxicological profile. Thus, 10 was found to be a more practical lead for an orally active 5-LO inhibitor.

  DOI：

  10.1021/jm0303554
• 作为产物：
  描述：

  4-<3-fluoro-5-(benzyloxy)phenyl>-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran 在 sodium periodate 、 三氟化硼 、 三氟乙酸 作用下， 以 甲醇 、 乙醚 为溶剂， 反应 4.0h， 生成 4-(3-fluoro-5-hydroxyphenyl)-4-methylsulfinyl-3,4,5,6-tetrahydro-2H-pyran
  参考文献：
  名称：

  4-[5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6- tetrahydro-2H-pyran-4-carboxamide, an Orally Active Inhibitor of 5-Lipoxygenase with Improved Pharmacokinetic and Toxicology Characteristics

  摘要：

  Described herein are structure-activity relationships (SARs) of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1, CJ-12,918), an imidazole 5-lipoxygenase (5-LO) inhibitor. When I was tested in preclinical studies, cataract formation was observed in rats; however, this compound was metabolized extensively in vivo and showed low systemic exposure. To eliminate this side effect and enhance bioavailability, structural modification was focused on replacing the methoxy group of 1 by modulating lipophilicity (i.e., predicted log D at pH 7.4). The SARs led to the discovery of 4- [5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (10, CJ-13,454), which was less lipophilic by 1.2 log D units and showed in vivo potency (ED50 = 4-9 mg/kg) equipotent to 1. Enhanced metabolic stability resulted in fewer in vivo metabolites, as well as improved bioavailability and a better toxicological profile. Thus, 10 was found to be a more practical lead for an orally active 5-LO inhibitor.

  DOI：

  10.1021/jm0303554

文献信息

• Imidazole lipoxygenase inhibitors
  申请人：Pfizer Inc.

  公开号：US05753682A1

  公开（公告）日：1998-05-19

  Certain novel imidazole derivatives having the ability to inhibit the lipoxygenase enzyme and having formula (I), wherein Y is hydrogen, C.sub.1 -C.sub.8 alkyl, halosubstituted C.sub.1 -C.sub.4 alkyl, phenyl, substituted phenyl, C.sub.7 -C.sub.14 phenylalkyl, C.sub.7 -C.sub.14 (substituted phenyl)alkyl, pyridyl, substituted pyridyl, C.sub.6 -C.sub.13 pyridylalkyl or C.sub.6 -C.sub.13 (substituted pyridyl)alkyl, wherein each substituent is independently halo, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halosubstituted C.sub.1 -C.sub.4 alkyl, halosubstituted C.sub.1 -C.sub.4 alkoxy, NR.sup.4 R.sup.5, CO.sub.2 R.sup.4 or CONR.sup.4 R.sup.5, wherein R.sup.4 and R.sup.5 are each, independently, hydrogen or C.sub.1 -C.sub.6 alkyl; Ar.sup.1 and Ar.sup.2 are each, independently, phenylene, mono-substituted phenylene or di-substituted phenylene, wherein the substituents are, independently, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halo-substituted C.sub.1 -C.sub.4 alkyl or halo-substituted C.sub.1 -C.sub.4 alkoxy; X and X.sup.1 are each, independently, O, S, SO or SO.sub.2 ; R' is hydrogen or C.sub.1 -C.sub.4 alkyl; and R.sup.2 and R.sup.3 are each, independently, methylene, ethylene or propylene. These compounds are useful for the treatment of disease states such as bronchial asthma, skin disorders and arthritis in mammals, and as the active ingredient in pharmaceutical compositions for treating such conditions.

  具有抑制脂氧酶酶活性能力的某些新型咪唑衍生物具有以下结构式（I），其中Y为氢、C.sub.1 -C.sub.8烷基、卤代C.sub.1 -C.sub.4烷基、苯基、取代苯基、C.sub.7 -C.sub.14苯基烷基、C.sub.7 -C.sub.14（取代苯基）烷基、吡啶基、取代吡啶基、C.sub.6 -C.sub.13吡啶基烷基或C.sub.6 -C.sub.13（取代吡啶基）烷基，其中每个取代基独立地为卤素、硝基、氰基、C.sub.1 -C.sub.4烷基、C.sub.1 -C.sub.4烷氧基、卤代C.sub.1 -C.sub.4烷基、卤代C.sub.1 -C.sub.4烷氧基、NR^4R^5、CO_2R^4或CONR^4R^5，其中R^4和R^5各自独立地为氢或C.sub.1 -C.sub.6烷基；Ar^1和Ar^2各自独立地为苯基、单取代苯基或双取代苯基，其中取代基各自独立地为卤素、C.sub.1 -C.sub.4烷基、C.sub.1 -C.sub.4烷氧基、卤代C.sub.1 -C.sub.4烷基或卤代C.sub.1 -C.sub.4烷氧基；X和X^1各自独立地为O、S、SO或SO_2；R'为氢或C.sub.1 -C.sub.4烷基；R^2和R^3各自独立地为亚甲基、乙烯基或丙烯基。这些化合物可用于治疗哺乳动物的疾病状态，如支气管哮喘、皮肤疾病和关节炎，并作为治疗这些疾病条件的药物组合物中的活性成分。
• IMIDAZOLES AS LIPOXYGENASE INHIBITORS
  申请人：PFIZER INC.

  公开号：EP0703913B1

  公开（公告）日：1997-06-11
• US5753682A
  申请人：——

  公开号：US5753682A

  公开（公告）日：1998-05-19
• 4-[5-Fluoro-3-[4-(2-methyl-1<i>H</i>-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6- tetrahydro-2<i>H</i>-pyran-4-carboxamide, an Orally Active Inhibitor of 5-Lipoxygenase with Improved Pharmacokinetic and Toxicology Characteristics
  作者：Takashi Mano、Yoshiyuki Okumura、Minoru Sakakibara、Takako Okumura、Tetsuya Tamura、Kimitaka Miyamoto、Rodney W. Stevens

  DOI：10.1021/jm0303554

  日期：2004.1.1

  Described herein are structure-activity relationships (SARs) of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1, CJ-12,918), an imidazole 5-lipoxygenase (5-LO) inhibitor. When I was tested in preclinical studies, cataract formation was observed in rats; however, this compound was metabolized extensively in vivo and showed low systemic exposure. To eliminate this side effect and enhance bioavailability, structural modification was focused on replacing the methoxy group of 1 by modulating lipophilicity (i.e., predicted log D at pH 7.4). The SARs led to the discovery of 4- [5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (10, CJ-13,454), which was less lipophilic by 1.2 log D units and showed in vivo potency (ED50 = 4-9 mg/kg) equipotent to 1. Enhanced metabolic stability resulted in fewer in vivo metabolites, as well as improved bioavailability and a better toxicological profile. Thus, 10 was found to be a more practical lead for an orally active 5-LO inhibitor.