4-(3-hydroxy-5-fluorophenyl)-4-methylthio-3,4,5,6-tetrahydro-2H-pyran | 139368-13-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 4-(3-hydroxy-5-fluorophenyl)-4-methylthio-3,4,5,6-tetrahydro-2H-pyran
• 英文别名: 4-(5-fluoro-3-hydroxyphenyl)-4-methylthiotetrahydropyran；3-Fluoro-5-[4-(methylsulfanyl)oxan-4-yl]phenol；3-fluoro-5-(4-methylsulfanyloxan-4-yl)phenol
• CAS: 139368-13-1
• 化学式: C₁₂H₁₅FO₂S
• 分子量: 242.314
• InChiKey: QCMUFYAKUCKNEC-UHFFFAOYSA-N

物化性质

• 沸点：
  394.3±42.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  16
• 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：
  54.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(3-hydroxy-5-fluorophenyl)-4-methylthio-3,4,5,6-tetrahydro-2H-pyran 在 间氯过氧苯甲酸 作用下， 以 氯仿 为溶剂， 以81%的产率得到苯酚,3-氟-5-[四氢-4-(甲磺酰)-2H-吡喃-4-基]-
  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：

  甲硫醇 、 4-<3-fluoro-5-(benzyloxy)phenyl>-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran 在 三氟化硼 、 三氟乙酸 作用下， 以 乙醚 为溶剂， 生成 4-(3-hydroxy-5-fluorophenyl)-4-methylthio-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

• Pyran derivatives and their use as inhibitors of 5-lipoxygenase
  申请人：Imperial Chemical Industries PLC

  公开号：US05254581A1

  公开（公告）日：1993-10-19

  The invention concerns a cyclic ether derivative of the formula I ##STR1## wherein Ar.sup.1 is optionally substituted phenyl, naphthyl or a 9- or 10-membered bicyclic heterocyclic moiety; A.sup.1 is a direct link to X.sup.1 or (1-3C)alkylene; X.sup.1 is oxy, thio, sulphinyl, sulphonyl or imino; Ar.sup.2 is optionally substituted phenylene or pyridylene; R.sup.1 includes hydrogen, (1-4C)alkyl, (1-4C)alkcxycarbonyl and (1-4C)alkylthio; and R.sup.2 and R.sup.3 together form a group of the formula --A.sup.2 --X.sup.2 --A.sup.3 -- which, together with the carbon atom to which A.sup.2 and A.sup.3 are attached, defines a ring having 5 to 7 ring atoms, wherein each of A.sup.2 and A.sup.3 is (1-3C)alkylene and X.sup.2 is oxy, thio, sulphinyl or sulphonyl; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.

  该发明涉及公式I的环醚衍生物，其中Ar.sup.1是可选取代的苯基、萘基或9-或10-成员的双环杂环基；A.sup.1是直接连接到X.sup.1或(1-3C)烷基的链；X.sup.1是氧、硫、亚硫酰基、砜基或亚砜基；Ar.sup.2是可选取代的苯基或吡啶基；R.sup.1包括氢、(1-4C)烷基、(1-4C)烷基羰基和(1-4C)烷基硫基；而R.sup.2和R.sup.3一起形成一个具有5到7个环原子的环的基团，该环由A.sup.2和A.sup.3连接到的碳原子以及A.sup.2和A.sup.3定义，其中每个A.sup.2和A.sup.3是(1-3C)烷基，X.sup.2是氧、硫、亚硫酰基或砜基；或其药用可接受盐。该发明的化合物是5-脂氧合酶的抑制剂。
• 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。
• Cyclic ether derivatives
  申请人：ZENECA LIMITED

  公开号：EP0462830A2

  公开（公告）日：1991-12-27

  The invention concerns a cyclic ether derivative of the formula I wherein Ar1 is optionally substituted phenyl, naphthyl or a 9- or 10-membered bicyclic heterocyclic moiety ; A1 is a direct link to X1 or (1-3C)alkylene; X1 is oxy, thio, sulphinyl, sulphonyl or imino; Ar2 is optionally substituted phenylene or pyridylene ; R1 includes hydrogen, (1-4C)alkyl, (1-4C)alkoxycarbonyl and (1-4C)alkylthio; and R2 and R3 together form a group of the formula -A2-X2-A3- which, together with the carbon atom to which A2 and A3 are attached, defines a ring having 5 to 7 ring atoms, wherein each of A2 and A3 is (1-3C)alkylene and X2 is oxy, thio, sulphinyl or sulphonyl ; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.

  本发明涉及一种式 I 的环醚衍生物 其中 Ar1 是任选取代的苯基、萘基或 9 或 10 元双环杂环分子； A1 是与 X1 或（1-3C）亚烷基的直接连接； X1 是氧基、硫代、亚砜基、磺酰基或亚氨基； Ar2 是任选取代的亚苯基或亚吡啶； R1 包括氢、(1-4C)烷基、(1-4C)烷氧羰基和(1-4C)烷硫基；以及 R2 和 R3 共同形成一个式-A2-X2-A3-的基团，该基团与 A2 和 A3 所连接的碳原子一起定义一个具有 5 至 7 个环原子的环，其中 A2 和 A3 各为 (1-3C)烷基，X2 为氧基、硫基、亚砜基或磺酰基；或其药学上可接受的盐。 本发明的化合物是 5-脂氧合酶的抑制剂。
• IMIDAZOLES AS LIPOXYGENASE INHIBITORS
  申请人：PFIZER INC.

  公开号：EP0703913B1

  公开（公告）日：1997-06-11
• IMIDAZOLE LIPOXYGENASE INHIBITORS
  申请人：PFIZER INC.

  公开号：EP0703913A1

  公开（公告）日：1996-04-03