4-Acetyl-4-(3-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran | 179420-72-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 4-Acetyl-4-(3-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran
• 英文别名: 1-[4-(3-Fluoro-5-hydroxyphenyl)oxan-4-yl]ethanone
• CAS: 179420-72-5
• 化学式: C₁₃H₁₅FO₃
• 分子量: 238.259
• InChiKey: YEATUYGBRMGLAA-UHFFFAOYSA-N

物化性质

• 沸点：
  393.7±42.0 °C(Predicted)
• 密度：
  1.228±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  4

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-Acetyl-4-(3-fluoro-5-hydroxyphenyl)-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 4-Acetyl-4-[-5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-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
• 作为产物：
  描述：

  1-(苄氧基)-3-溴-5-氟苯 在 palladium on activated charcoal lithium aluminium tetrahydride 、 四丙基高钌酸铵 、 15-冠醚-5 、 3 A molecular sieve 、 氢气 、 sodium hydride 、 N-甲基吗啉氧化物 、 lithium chloride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醚 、 乙醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.08h， 生成 4-Acetyl-4-(3-fluoro-5-hydroxyphenyl)-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

• [EN] 5-LIPOXYGENASE INHIBITORS<br/>[FR] INHIBITEURS DE LA LIPOXYGENASE-5
  申请人：PFIZER INC.

  公开号：WO1996011911A1

  公开（公告）日：1996-04-25

  (EN) Novel compounds having the ability to inhibit 5-lipoxygenase enzyme and having formula (I) and the pharmaceutically acceptable salts thereof, wherein Ar1 is a heterocyclic moiety which is selected from imidazolyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, indolyl, indazolyl and benzimidazolyl, which is bonded to X1 through a ring nitrogen atom, and which may be optionally substituted with one or two substituents selected from halo, hydroxy, cyano, amino, C1-4 alkyl and the like; X1 is a direct bond or C1-4 alkylene; Ar2 is phenylene optionally substituted with halo, hydroxy, cyano, amino and the like; X2 is -A-X- or -X-A- wherein A is a direct bond or C1-4 alkylene and X is oxy, thio, sulfinyl or sulfonyl; Ar3 is phenylene, pyridylene, thienylene, furylene, oxazolylene or thiazolylene optionally substituted with one or two substituents selected from halo, hydroxy, cyano, amino, C1-4 alkyl and the like; R1 and R2 are each C1-4 alkyl, or together they form a group of formula -D1-Z-D2- which together with the carbon atom to which it is attached defines a ring having 3 to 8 atoms, wherein D1 and D2 are C1-4 alkylene and Z is a direct bond or oxy, thio, sulfinyl, sulfonyl, or vinylene, and D1 and D2 may be substituted by C1-3 alkyl; and Y is CONR3R4, CN, C(R3)=N-OR4, COOR3, COR3 or CSNR3R4, wherein R3 and R4 are each H or C1-4 alkyl. These compounds are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals and as the active ingredient in pharmaceutical compositions for treating such conditions.(FR) L'invention concerne des composés nouveaux capables d'inhiber l'enzyme lipoxygenase-5 et ayant la formule (I), ainsi que leurs sels pharmaceutiquement acceptables. Dans la formule, Ar1 est une fraction hétérocyclique sélectionnée parmi imidazolyle, pyrrolyle, pyrazolyle, 1,2,3-triazolyle, 1,2,4-triazolyle, indolyle, indazolyle et benzimidazolyle, liés à X1 par un atome cyclique d'azote et le cas échéant substitués par un ou deux substituants sélectionnés parmi halo, hydroxy, cyano, amino, alkyle C1-4 et similaires; X1 est une liaison directe ou alcylène C1-4; Ar2 désigne phénylène le cas échéant substitué par halo, hydroxy, cyano, amino et similaires; X2 désigne -A-X- ou -X-A-, où A désigne une liaison directe ou alcylène C1-4 et X désigne oxy, thio, sulfinyle ou sulfonyle; Ar3 désigne phénylène, pyridylène, thiénylène, furylène, oxyzolylène ou thiazolylène le cas échéant substitués par un ou deux substituants sélectionnés parmi halo, hydroxy, cyano, amino alkyle C1-4 et similaires; R1 et R2 désignent chacun alkyle C1-4, ou forment ensemble un groupe ayant la formule -D1-Z-D2- qui définit avec l'atome de carbone auquel il est lié un composé cyclique ayant 3 à 8 atomes et dans lequel D1 et D2 désignent alcylène C1-4 et Z désigne une liaison directe ou oxy, thio, sulfinyle, sulfonyle ou vinylène, et D1 et D2 peuvent être substitués par alkyle C1-3; et Y désigne CONR3R4, CN, C(R3)=N-OR4, COOR3, COR3 ou CSNR3R4, où R3 et R4 désignent tous les deux H ou alkyle C1-4. Ces composés sont utiles pour traiter ou soulager des maladies inflammatoires, des allergies et des maladies cardio-vasculaires chez des mammifères et comme principes actifs de compositions pharmaceutiques de traitement de ces maladies.

  这是一种具有抑制5-脂氧合酶酶活性的新型化合物，其化学式为（I）及其药学上可接受的盐。其中，Ar1是通过环氮原子与X1连接的杂环基团，可选用的杂环基团包括咪唑基、吡咯基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吲哚基、吲唑基和苯并咪唑基，可以选择地取代为卤素、羟基、氰基、氨基、C1-4烷基等一或两个取代基；X1是直接键或C1-4烷基；Ar2是苯基，可选用的取代基包括卤素、羟基、氰基、氨基等；X2是-A-X-或-X-A-，其中A是直接键或C1-4烷基，X是氧、硫、亚硫酰基或磺酰基；Ar3是苯基、吡啶基、噻吩基、呋喃基、噻唑基，可以选择地取代为卤素、羟基、氰基、氨基、C1-4烷基等一或两个取代基；R1和R2分别是C1-4烷基，或者它们一起形成一个公式为-D1-Z-D2-的基团，该基团与所连接的碳原子共同定义具有3-8个原子的环，其中D1和D2是C1-4烷基，Z是直接键、氧、硫、亚硫酰基、磺酰基或乙烯基，D1和D2可以被C1-3烷基取代；Y是CONR3R4、CN、C（R3）=N-OR4、COOR3、COR3或CSNR3R4，其中R3和R4分别是氢或C1-4烷基。这些化合物在哺乳动物的炎症性疾病、过敏和心血管疾病的治疗或缓解中有用，并可作为治疗这些疾病的药物组合物的活性成分。
• 5-LIPOXYGENASE INHIBITORS
  申请人：PFIZER INC.

  公开号：EP0787127A1

  公开（公告）日：1997-08-06
• US5883106A
  申请人：——

  公开号：US5883106A

  公开（公告）日：1999-03-16
• US6063928A
  申请人：——

  公开号：US6063928A

  公开（公告）日：2000-05-16
• 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.