4-[(3,4-dichlorobenzyl)oxy]-3-fluorobenzaldehyde | 1202577-51-2

• 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-[(3,4-dichlorobenzyl)oxy]-3-fluorobenzaldehyde
• 英文别名: (40A) 4-(3,4-Dichlorobenzyloxy)-3-fluorobenzaldehyde；4-(3,4-Dichlorobenzyloxy)-3-fluorobenzaldehyde；4-[(3,4-dichlorophenyl)methoxy]-3-fluorobenzaldehyde
• CAS: 1202577-51-2
• 化学式: C₁₄H₉Cl₂FO₂
• 分子量: 299.129
• InChiKey: OHCUKVNBYVULRY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  19
• 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：
  3

反应信息

• 作为反应物：
  描述：

  4-[(3,4-dichlorobenzyl)oxy]-3-fluorobenzaldehyde 在 水 、 sodium hydroxide 、 silver(l) oxide 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 乙醇 、 甲苯 为溶剂， 反应 7.5h， 生成 3-{4-[(3,4-dichlorobenzyl)oxy]-3-fluorophenyl}-3-ethoxypropanoic acid
  参考文献：
  名称：

  CARBOXYLIC ACID COMPOUND

  摘要：

  寻找具有优异活性和安全性的治疗剂和/或预防剂，用于糖尿病或类似疾病。以下通用式（I）所代表的化合物，或其药理学上可接受的盐。在该式中，X代表 ═C(R5)- 或 ═N—；Y代表 —O— 或 —NH—；L代表键或可替代的C1-C3烷基链；M代表可替代的C3-C10环烷基，可替代的C6-C10芳基，或可替代的杂环基；R1代表C1-C6烷基，C3-C10环烷基，C1-C6卤代烷基，C2-C6烯基，C2-C6炔基，C1-C6脂肪酰基，C1-C6烷氧基C1-C6烷基，或C6-C10芳基；而R2、R3、R4和R5可以相同也可以不同，每个代表氢原子，卤原子，C1-C3烷基，C1-C3卤代烷基，C1-C3烷氧基，或硝基。在这种情况下，R1和R2的烷基基团可以结合在一起形成含有一个氧原子的5-至6-成员杂环环。

  公开号：

  US20110053974A1
• 作为产物：
  描述：

  4-[(3,4-Dichlorophenyl)methoxy]-3-fluorobenzonitrile 在 二异丁基氢化铝 作用下， 以 正己烷 、 甲苯 为溶剂， 反应 1.0h， 生成 4-[(3,4-dichlorobenzyl)oxy]-3-fluorobenzaldehyde
  参考文献：
  名称：

  Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P₅) Agonist for the Potential Treatment of Neurodegenerative Disorders

  摘要：

  S1P(5) is one of S receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood brain barrier, where it maintains barrier integrity in in vitro models (j Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P(5) modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris et al., 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, et al., AAIC 2014). Herein we describe the development of a series of selective S1P(5) agonists that led to the identification of compound 29, which is highly selective for S1P(5) and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P(5) biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P(1). and S1P(3) function in rats. In addition, we found that 29 improves blood brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P(5) agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood brain barrier such as Alzheimer's disease or multiple sclerosis.

  DOI：

  10.1021/acs.jmedchem.5b00928

文献信息

• Carboxylic acid compound
  申请人：Daiichi Sankyo Company, Limited

  公开号：US08222281B2

  公开（公告）日：2012-07-17

  To find a therapeutic agent and/or a preventive agent for diabetes mellitus or the like having excellent activity and safety. A compound represented by the following general formula (I), or a pharmacologically acceptable salt thereof. In the formula, X represents ═C(R5)- or ═N—; Y represents —O— or —NH—; L represents a bond or a substitutable C1-C3 alkylene group; M represents a substitutable C3-C10 cycloalkyl group, a substitutable C6-C10 aryl group, or a substitutable heterocyclic group; R1 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 aliphatic acyl group, a C1-C6 alkoxy C1-C6 alkyl group, or a C6-C10 aryl group; and R2, R3, R4, and R5 may be the same or different and each represent a hydrogen atom, a halogen atom, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, or a nitro group. In this connection, the alkyl group moieties of R1 and R2 may be bonded to each other to form a 5- to 6-membered heterocyclic ring containing one oxygen atom.

  寻找具有优异活性和安全性的治疗糖尿病或类似疾病的药物或预防药物。该化合物由以下通式(I)表示，或其药理学上可接受的盐。在该式中，X代表═C（R5）-或═N—; Y代表—O—或—NH—; L代表键或可替换的C1-C3烷基; M代表可替换的C3-C10环烷基，可替换的C6-C10芳基或可替换的杂环基; R1代表C1-C6烷基，C3-C10环烷基，C1-C6卤代烷基，C2-C6烯基，C2-C6炔基，C1-C6脂肪酰基，C1-C6烷氧基C1-C6烷基或C6-C10芳基; R2、R3、R4和R5可以相同也可以不同，每个代表氢原子，卤原子，C1-C3烷基，C1-C3卤代烷基，C1-C3烷氧基或硝基。在此连接中，R1和R2的烷基基团可以结合在一起形成含有一个氧原子的5-至6-成员杂环环。
• Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558
  作者：Rieko Takano、Masao Yoshida、Masahiro Inoue、Takeshi Honda、Ryutaro Nakashima、Koji Matsumoto、Tatsuya Yano、Tsuneaki Ogata、Nobuaki Watanabe、Masakazu Hirouchi、Takako Kimura、Narihiro Toda

  DOI：10.1016/j.bmc.2015.07.028

  日期：2015.9

  GPR40 agonists stimulate insulin secretion only under the presence of high glucose concentration. Based on this mechanism, GPR40 agonists are believed to be promising novel insulin secretagogues with low risk of hypoglycemia. The optimizations of 3-aryl-3-ethoxypropanoic acids were performed to improve in vitro activity. We discovered compound 29r (DS-1558), (3S)-3-ethoxy-3-(4-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, which was confirmed to have an enhancing effect on glucose-dependent insulin secretion after intravenous glucose injection in SD rats. (C) 2015 Elsevier Ltd. All rights reserved.
• US8222281B2
  申请人：——

  公开号：US8222281B2

  公开（公告）日：2012-07-17
• CARBOXYLIC ACID COMPOUND
  申请人：TODA Narihiro

  公开号：US20110053974A1

  公开（公告）日：2011-03-03

  To find a therapeutic agent and/or a preventive agent for diabetes mellitus or the like having excellent activity and safety. A compound represented by the following general formula (I), or a pharmacologically acceptable salt thereof. In the formula, X represents ═C(R5)- or ═N—; Y represents —O— or —NH—; L represents a bond or a substitutable C1-C3 alkylene group; M represents a substitutable C3-C10 cycloalkyl group, a substitutable C6-C10 aryl group, or a substitutable heterocyclic group; R 1 represents a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 aliphatic acyl group, a C1-C6 alkoxy C1-C6 alkyl group, or a C6-C10 aryl group; and R 2 , R 3 , R 4 , and R 5 may be the same or different and each represent a hydrogen atom, a halogen atom, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, or a nitro group. In this connection, the alkyl group moieties of R 1 and R 2 may be bonded to each other to form a 5- to 6-membered heterocyclic ring containing one oxygen atom.

  寻找具有优异活性和安全性的治疗剂和/或预防剂，用于糖尿病或类似疾病。以下通用式（I）所代表的化合物，或其药理学上可接受的盐。在该式中，X代表 ═C(R5)- 或 ═N—；Y代表 —O— 或 —NH—；L代表键或可替代的C1-C3烷基链；M代表可替代的C3-C10环烷基，可替代的C6-C10芳基，或可替代的杂环基；R1代表C1-C6烷基，C3-C10环烷基，C1-C6卤代烷基，C2-C6烯基，C2-C6炔基，C1-C6脂肪酰基，C1-C6烷氧基C1-C6烷基，或C6-C10芳基；而R2、R3、R4和R5可以相同也可以不同，每个代表氢原子，卤原子，C1-C3烷基，C1-C3卤代烷基，C1-C3烷氧基，或硝基。在这种情况下，R1和R2的烷基基团可以结合在一起形成含有一个氧原子的5-至6-成员杂环环。
• Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P₅) Agonist for the Potential Treatment of Neurodegenerative Disorders
  作者：Adrian D. Hobson、Christopher M. Harris、Elizabeth L. van der Kam、Sean C. Turner、Ayome Abibi、Ana L. Aguirre、Peter Bousquet、Tegest Kebede、Donald B. Konopacki、Gary Gintant、Youngjae Kim、Kelly Larson、John W. Maull、Nigel S. Moore、Dan Shi、Anurupa Shrestha、Xiubo Tang、Peng Zhang、Kathy K. Sarris

  DOI：10.1021/acs.jmedchem.5b00928

  日期：2015.12.10

  S1P(5) is one of S receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood brain barrier, where it maintains barrier integrity in in vitro models (j Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P(5) modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris et al., 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, et al., AAIC 2014). Herein we describe the development of a series of selective S1P(5) agonists that led to the identification of compound 29, which is highly selective for S1P(5) and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P(5) biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P(1). and S1P(3) function in rats. In addition, we found that 29 improves blood brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P(5) agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood brain barrier such as Alzheimer's disease or multiple sclerosis.