methyl 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)pyrimidine-4-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: methyl 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)pyrimidine-4-carboxylate
• 英文别名: 2-(4-(2-Trifluoromethylphenyl)piperidine-1-yl)-6-methylpyrimidine-4-carboxylic acid methyl ester；methyl 6-methyl-2-[4-[2-(trifluoromethyl)phenyl]piperidin-1-yl]pyrimidine-4-carboxylate
• 化学式: C₁₉H₂₀F₃N₃O₂
• 分子量: 379.382
• InChiKey: JTROMNJXIJLLPR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  55.3
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)pyrimidine-4-carboxylate 在 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 16.0h， 以91%的产率得到6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)pyrimidine-4-carboxylic acid
  参考文献：
  名称：

  Bicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

  摘要：

  Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AIVID) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant -vision loss associated with geographic atrophy of the macula. We previously disdosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocydopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).

  DOI：

  10.1021/acs.jmedchem.5b00423
• 作为产物：
  描述：

  邻溴三氟甲苯 在 盐酸 、 正丁基锂 、 氯化亚砜 、 palladium 10% on activated carbon 、 甲酸铵 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 25.09h， 生成 methyl 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)pyrimidine-4-carboxylate
  参考文献：
  名称：

  Bicyclic [3.3.0]-Octahydrocyclopenta[c]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease

  摘要：

  Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AIVID) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant -vision loss associated with geographic atrophy of the macula. We previously disdosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocydopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).

  DOI：

  10.1021/acs.jmedchem.5b00423

文献信息

• NON-RETINOID ANTAGONISTS FOR TREATMENT OF AGE-RELATED MACULAR DEGENERATION AND STARGARDT DISEASE
  申请人：Petrukhin Konstantin

  公开号：US20150126494A1

  公开（公告）日：2015-05-07

  A method for treating a disease characterized by excessive lipofuscin accumulation in the retina in mammals afflicted therewith, comprising administering to the mammal an effective amount of a non-retinoid antagonist compound or a pharmaceutically acceptable salt thereof.
• US9333202B2
  申请人：——

  公开号：US9333202B2

  公开（公告）日：2016-05-10
• Bicyclic [3.3.0]-Octahydrocyclopenta[<i>c</i>]pyrrolo Antagonists of Retinol Binding Protein 4: Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease
  作者：Christopher L. Cioffi、Boglarka Racz、Emily E. Freeman、Michael P. Conlon、Ping Chen、Douglas G. Stafford、Daniel M. C. Schwarz、Lei Zhu、Douglas B. Kitchen、Keith D. Barnes、Nicoleta Dobri、Enrique Michelotti、Charles L. Cywin、William H. Martin、Paul G. Pearson、Graham Johnson、Konstantin Petrukhin

  DOI：10.1021/acs.jmedchem.5b00423

  日期：2015.8.13

  Antagonists of retinol-binding protein 4 (RBP4) impede ocular uptake of serum all-trans retinol (1) and have been shown to reduce cytotoxic bisretinoid formation in the retinal pigment epithelium (RPE), which is associated with the pathogenesis of both dry age-related macular degeneration (AIVID) and Stargardt disease. Thus, these agents show promise as a potential pharmacotherapy by which to stem further neurodegeneration and concomitant -vision loss associated with geographic atrophy of the macula. We previously disdosed the discovery of a novel series of nonretinoid RBP4 antagonists, represented by bicyclic [3.3.0]-octahydrocydopenta[c]pyrrolo analogue 4. We describe herein the utilization of a pyrimidine-4-carboxylic acid fragment as a suitable isostere for the anthranilic acid appendage of 4, which led to the discovery of standout antagonist 33. Analogue 33 possesses exquisite in vitro RBP4 binding affinity and favorable drug-like characteristics and was found to reduce circulating plasma RBP4 levels in vivo in a robust manner (>90%).