4-[(3,5-Difluorobenzyl)oxy]benzaldehyde

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 4-[(3,5-Difluorobenzyl)oxy]benzaldehyde
• 英文别名: 4-[(3,5-difluorophenyl)methoxy]benzaldehyde
• 化学式: C₁₄H₁₀F₂O₂
• mdl: MFCD00278356
• 分子量: 248.229
• InChiKey: FPPHFHASSCUGJM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.071
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[(3,5-Difluorobenzyl)oxy]benzaldehyde 、 间氨基苯甲酸 在 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 甲苯 、 四氢呋喃 为溶剂， 反应 14.25h， 以74%的产率得到3-((4-((3,5-difluorobenzyl)oxy)benzyl)amino)benzoic acid
  参考文献：
  名称：

  2-苯基-4-羧基喹啉化学型的结构引导进化为 PPARα 选择性激动剂：眼血管疾病的新线索

  摘要：

  PPARα 的小分子激动剂为开发糖尿病视网膜病变和年龄相关性黄斑变性等眼血管疾病的非侵入性治疗提供了一条有前景的新途径。在此，我们报告了新鉴定的基于喹啉的 PPARα 激动剂 Y-0452 的初始结构-活性关系。初步计算研究得出这样的假设：Y-0452 喹啉系统的羧酸转座和解构将增强配体-蛋白质相互作用并更好地补充结合袋的性质。设计、合成并评估了 PPARα 激动作用的重点类似物子集。这项工作产生了两个关键观察结果：1) 与其他 PPARα 激动剂相反，贝特“头基”的掺入降低了 PPARα 选择性，反而提供了泛PPAR 激动剂；2) 计算模型揭示了 PPARα 中相对未开发的两亲性口袋，它提供了新的开发新型激动剂的机会。例如，化合物10表现 出比 Y-0452 (EC 50 = ∼50 µM)更有效的 PPARα 激动作用 ( EC 50  = ∼6 µM)，并且对 PPARα 的选择性比

  DOI：

  10.1016/j.bmcl.2018.03.010
• 作为产物：
  描述：

  对羟基苯甲醛 、 3,5-二氟溴苄 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.17h， 生成 4-[(3,5-Difluorobenzyl)oxy]benzaldehyde
  参考文献：
  名称：

  2-苯基-4-羧基喹啉化学型的结构引导进化为 PPARα 选择性激动剂：眼血管疾病的新线索

  摘要：

  PPARα 的小分子激动剂为开发糖尿病视网膜病变和年龄相关性黄斑变性等眼血管疾病的非侵入性治疗提供了一条有前景的新途径。在此，我们报告了新鉴定的基于喹啉的 PPARα 激动剂 Y-0452 的初始结构-活性关系。初步计算研究得出这样的假设：Y-0452 喹啉系统的羧酸转座和解构将增强配体-蛋白质相互作用并更好地补充结合袋的性质。设计、合成并评估了 PPARα 激动作用的重点类似物子集。这项工作产生了两个关键观察结果：1) 与其他 PPARα 激动剂相反，贝特“头基”的掺入降低了 PPARα 选择性，反而提供了泛PPAR 激动剂；2) 计算模型揭示了 PPARα 中相对未开发的两亲性口袋，它提供了新的开发新型激动剂的机会。例如，化合物10表现 出比 Y-0452 (EC 50 = ∼50 µM)更有效的 PPARα 激动作用 ( EC 50  = ∼6 µM)，并且对 PPARα 的选择性比

  DOI：

  10.1016/j.bmcl.2018.03.010

文献信息

• Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders
  作者：Xiaozheng Dou、Dinesh Nath、Henry Shin、Elmar Nurmemmedov、Philip C. Bourne、Jian-Xing Ma、Adam S. Duerfeldt

  DOI：10.1021/acs.jmedchem.9b01189

  日期：2020.3.26

  Peroxisome proliferator-activated receptor alpha (PPAR alpha) is expressed in retinal Muller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPAR alpha with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPAR alpha is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >2,700-fold selectivity for PPAR alpha over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.
• [EN] AMINO ACID DERIVATIVES AS INHIBITORS OF MAMMALIAN SODIUM CHANNELS<br/>[FR] DERIVES D'ACIDES AMINES EN TANT QU'INHIBITEURS DES CANAUX SODIQUES DE MAMMIFERES
  申请人：IONIX PHARMACEUTICALS LTD

  公开号：WO2004087125A1

  公开（公告）日：2004-10-14

  Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment or prevention of a condition selected from chronic and acute pain, tinnitus, bowel disorders, bladder dysfunctions and demyelinating diseases, Formula (I) wherein: - R1 is Cl-C6 alkyl, C6-C10 aryl, a 5- to 10- membered heteroaryl group, a 5- to 10- membered heterocyclyl group or a C3-C6 carbocyclyl group; each R2 is the same or different and represents Cl-C6 alkyl, halogen, Cl-C6 alkoxy, Cl-C6 alkythio, hydroxy, nitro, cyano, amino, (Cl-C6 alkyl)amino or di-( Cl-C6 alkyl)amino; - R3 represents hydrogen, Cl-C6 alkyl, or together with R4 represents a C2-C4 alkylene group; - R4 is hydrogen, Cl-C6 alkyl, C6-C10 aryl, C3-C6 carbocyclyl, a 5- to 10­membered heteroaryl group, a 5- to 10- membered heterocyclyl group, -( Cl-C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(C3-C6 carbocyclyl), -(C1-C6 alkyl)-(5-to 10- membered heteroaryl), - ( Cl-C6 alkyl)-(5- to 10- membered heterocyclyl) or, together with R3 represents a C2-C4 alkylene group; - R5 and R6 are the same or different and each represent hydrogen or a Cl-C6 alkyl group; - n is 0,1, 2, 3 or 4; X1 represents a direct bond or a methylene group; and X2 represents a -CH2-, -CO-, -SO- or -S(O)2- group, wherein: the alkyl and alkylene groups and moieties in the substituents R1 to R6 and X, are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from hydroxy, amino, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino and di(C1-C4 alkyl)amino substituents; and the aryl, heteroaryl, heterocyclyl and carbocyclyl groups and moieties in the substituents R1 and R4 are unsubstituted or are substituted by 1, 2 or 3 substituents which are the same or different and are selected from halogen, Cl-C6 alkyl, Cl-C6 alkoxy, Cl-C6 alkylthio, hydroxy, amino, Cl-C6 alkylamino, di-( Cl-C6 alkyl)amino, Cl-C6 haloalkyl, Cl-C6 haloalkoxy and Cl-C6 haloalkylthio substituents. provided that, when n is 1, 2, 3 or 4, R4 is other than hydrogen and when n is 0, X2 is -CH2- and R1 is an aryl or heteroaryl group, then either: (a) R, is a phenyl group which carries at least one -SCF3 substituent or is a thienyl group which carries at least one chloro substituent; (d) R1 is a phenyl group which carries at least one -CF3 substituent or at least two halogen substituents; or (e) R4 is benzyl or hydroxybenzyl and R1 is a phenyl group which carries a fluorine or -OCH3 substituent.