4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)-oxy)-1-methyl-6-morpholinopyrimidin-2(1H)-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)-oxy)-1-methyl-6-morpholinopyrimidin-2(1H)-one
• 英文别名: 4-[4-[3-(Trifluoromethyl)-4-chlorophenoxy]-3,5-difluorobenzyloxy]-6-morpholino-1-methylpyrimidine-2(1H)-one；4-[[4-[4-chloro-3-(trifluoromethyl)phenoxy]-3,5-difluorophenyl]methoxy]-1-methyl-6-morpholin-4-ylpyrimidin-2-one
• 化学式: C₂₃H₁₉ClF₅N₃O₄
• 分子量: 531.867
• InChiKey: AWWXPCCSNMKHGY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  63.6
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-氯-5-羟基三氟甲苯 在 sodium tetrahydroborate 、 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 4-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)-oxy)-1-methyl-6-morpholinopyrimidin-2(1H)-one
  参考文献：
  名称：

  Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A₂ (Lp-PLA₂) Inhibitors as a Potential Therapy for Diabetic Macular Edema

  摘要：

  Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA(2) inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA(2) in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA(2) inhibitors for prevention and/or treatment of DME.

  DOI：

  10.1021/acs.jmedchem.5b01930

文献信息

• PYRIMIDONE COMPOUNDS USED AS LP-PLA2 INHIBITORS AND PHARMACEUTICAL COMPOSITIONS THEREOF
  申请人：Shanghai Institute Of Materia Medica Chinese Academy of Sciences

  公开号：EP3239135A1

  公开（公告）日：2017-11-01

  The present invention relates to pyrimidone compounds used as Lp-PLA2 inhibitors and pharmaceutical compositions thereof. The structure of the pyrimidone compounds is represented by general formula (I), wherein R1, R2, R3, X, Ar, Y and n are defined as in the specification and claims. The compounds of general formula (I) in the present invention, stereoisomers and pharmaceutically acceptable salts thereof can be used as Lp-PLA2 inhibitors for preventing, treating and/or ameliorating diseases associated with the activity of Lp-PLA2 enzyme.

  本发明涉及用作 Lp-PLA2 抑制剂的嘧啶酮化合物及其药物组合物。嘧啶酮化合物的结构由通式（I）表示，其中 R1、R2、R3、X、Ar、Y 和 n 的定义如说明书和权利要求书中所述。本发明中通式(I)化合物、其立体异构体和药学上可接受的盐可用作 Lp-PLA2 抑制剂，用于预防、治疗和/或改善与 Lp-PLA2 酶活性有关的疾病。
• Pyrimidone compounds used as Lp-PLA2 inhibitors and pharmaceutical compositions thereof
  申请人：Shanghai Institute of Materia Medica, Chinese Academy of Sciences

  公开号：US10280146B2

  公开（公告）日：2019-05-07

  The present invention relates to pyrimidone compounds used as Lp-PLA2 inhibitors and pharmaceutical compositions thereof. The structure of the pyrimidone compounds is represented by general formula (I), wherein R1, R2, R3, X, Ar, Y and n are defined as in the specification and claims. The compounds of general formula (I) in the present invention, stereoisomers and pharmaceutically acceptable salts thereof can be used as Lp-PLA2 inhibitors for preventing, treating and/or ameliorating diseases associated with the activity of Lp-PLA2 enzyme.

  本发明涉及用作 Lp-PLA2 抑制剂的嘧啶酮化合物及其药物组合物。嘧啶酮化合物的结构由通式（I）表示，其中 R1、R2、R3、X、Ar、Y 和 n 的定义如说明书和权利要求书中所述。本发明中通式(I)化合物、其立体异构体和药学上可接受的盐可用作 Lp-PLA2 抑制剂，用于预防、治疗和/或改善与 Lp-PLA2 酶活性有关的疾病。
• [EN] PYRIMIDONE COMPOUNDS USED AS LP-PLA2 INHIBITORS AND PHARMACEUTICAL COMPOSITIONS THEREOF<br/>[FR] COMPOSÉS PYRIMIDONE UTILISÉS COMME INHIBITEURS DE LA LP-PLA2 ET COMPOSITIONS PHARMACEUTIQUES ASSOCIÉES<br/>[ZH] 用作Lp-PLA2抑制剂的嘧啶酮类化合物及其药物组合物
  申请人：SHAGNHAI INST OF MATERIA MEDICA CHINESE ACADEMY OF SCIENCES

  公开号：WO2016101927A1

  公开（公告）日：2016-06-30

  本发明涉及用作Lp-PLA2抑制剂的嘧啶酮类化合物及其药物组合物，所述嘧啶酮类化合物的结构如通式I所示，R1、R2、R3、X、Ar、Y、n的定义如说明书和权利要求书所示。本发明的通式I化合物其立体异构体或其药学上可以接受的盐，可用作Lp-PLA2抑制剂，预防和/或治疗和/或改善与Lp-PLA2酶活性有关的疾病。
• Pyrimidone Compounds Used as Lp-PLA2 Inhibitors and Pharmaceutical Compositions Thereof
  申请人：Shanghai Institute of Materia Medica, Chinese Academy of Sciences

  公开号：US20180009766A1

  公开（公告）日：2018-01-11

  The present invention relates to pyrimidone compounds used as Lp-PLA 2 inhibitors and pharmaceutical compositions thereof. The structure of the pyrimidone compounds is represented by general formula (I), wherein R 1 , R 2 , R 3 , X, Ar, Y and n are defined as in the specification and claims. The compounds of general formula (I) in the present invention, stereoisomers and pharmaceutically acceptable salts thereof can be used as Lp-PLA 2 inhibitors for preventing, treating and/or ameliorating diseases associated with the activity of Lp-PLA 2 enzyme.
• Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A₂ (Lp-PLA₂) Inhibitors as a Potential Therapy for Diabetic Macular Edema
  作者：Xinde Chen、Kai Wang、Wenwei Xu、Quanxin Ma、Minli Chen、Lili Du、Mingguang Mo、Yiping Wang、Jianhua Shen

  DOI：10.1021/acs.jmedchem.5b01930

  日期：2016.3.24

  Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA(2) inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA(2) in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA(2) inhibitors for prevention and/or treatment of DME.