4-(Chloromethyl)-5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazole | 1026882-11-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(Chloromethyl)-5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazole
• CAS: 1026882-11-0
• 化学式: C₁₂H₉ClF₃NO₂
• 分子量: 291.657
• InChiKey: DMHMYJOODZJZTR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  35.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(Chloromethyl)-5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazole 在 五氯化磷 、 sodium hydride 、 二异丁基氢化铝 、 potassium carbonate 、 calcium carbonate 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 60.0h， 生成 4-({3-[(E)-3-chloro-1-methyl-1-propenyl]phenoxy}methyl)-5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazole
  参考文献：
  名称：

  New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties

  摘要：

  Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPase may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC50 values. Elongated spacers between the azolidinedione moiety and the central aromatic portion of the molecule as well as hydrophobic groups at the vicinity of this aromatic region were very important to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhibitors with IC50 values in the range of 0.12-0.3 mu M. Several compounds normalized plasma glucose and insulin levels in the ob/ob and db/db diabetic mouse models.

  DOI：

  10.1021/jm990476x
• 作为产物：
  描述：

  对三氟甲氧基苯甲醛 在 盐酸 、 三氯氧磷 作用下， 以 氯仿 、 乙酸乙酯 为溶剂， 反应 5.5h， 生成 4-(Chloromethyl)-5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazole
  参考文献：
  名称：

  New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties

  摘要：

  Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPase may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC50 values. Elongated spacers between the azolidinedione moiety and the central aromatic portion of the molecule as well as hydrophobic groups at the vicinity of this aromatic region were very important to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhibitors with IC50 values in the range of 0.12-0.3 mu M. Several compounds normalized plasma glucose and insulin levels in the ob/ob and db/db diabetic mouse models.

  DOI：

  10.1021/jm990476x

文献信息

• Synthesis and Structure–Activity Relationships of Novel Zwitterionic Compounds as Peroxisome Proliferator Activated Receptor α/γ Dual Agonists with Improved Physicochemical Properties
  作者：Yoshihiro Shibata、Katsuji Kagechika、Mitsuhiro Yamaguchi、Kenji Yoshikawa、Kiyoshi Chiba、Hiromichi Takano、Chiyuki Akiyama、Mayumi Ono、Mina Nishi、Hideo Kubo、Yoshimasa Kobayashi、Hiroyuki Usui

  DOI：10.1248/cpb.c13-00513

  日期：——

  We describe herein the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound

  我们在本文中描述了新型两性离子化合物作为基于非噻唑烷二酮（TZD）的过氧化物酶体增殖物激活受体（PPAR）α/γ双激动剂的设计，合成和构效关系（SAR）。在以前的报告中，我们获得了在db / db小鼠中显示出有效PPARα/γ双重激动活性以及极大的降糖作用的化合物1。但是，该化合物具有致命问题，例如有效的细胞色素P450（CYP）3A4直接抑制活性。因此，我们进行了药物优化以改善它们，同时保持有效的PPAR激动活性。结果，通过将呋喃环改变为低亲脂性的1,3,4-恶二唑环得以解决。另外，
• Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist
  作者：Yan Shi、Jun Li、Lawrence J. Kennedy、Shiwei Tao、Andrés S. Hernández、Zhi Lai、Sean Chen、Henry Wong、Juliang Zhu、Ashok Trehan、Ngiap-Kie Lim、Huiping Zhang、Bang-Chi Chen、Kenneth T. Locke、Kevin M. O’Malley、Litao Zhang、Rai Ajit Srivastava、Bowman Miao、Daniel S. Meyers、Hossain Monshizadegan、Debra Search、Denise Grimm、Rongan Zhang、Thomas Harrity、Lori K. Kunselman、Michael Cap、Jodi Muckelbauer、Chiehying Chang、Stanley R. Krystek、Yi-Xin Li、Vinayak Hosagrahara、Lisa Zhang、Pathanjali Kadiyala、Carrie Xu、Michael A. Blanar、Robert Zahler、Ranjan Mukherjee、Peter T. W. Cheng、Joseph A. Tino

  DOI：10.1021/acsmedchemlett.6b00033

  日期：2016.6.9

  proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure–activity relationship

  BMS-711939（3）是一种有效的选择性过氧化物酶体增殖物激活受体（PPAR）α激动剂，对人PPARα的EC 50为4 nM，相对于人PPARγ（EC 50 = 4.5μM）和PPARδ的选择性> 1000倍（EC 50 > 100μM）在PPAR-GAL4反式激活检测中。化合物3在临床前研究中还显示出优异的体内功效和安全性，因此被选择用于进一步的临床前评估。描述了临床前动物模型中3的合成，结构-活性关系（SAR）研究和体内药理作用及其ADME谱。
• Antihyperglycemic activity of new 1,2,4-oxadiazolidine-3,5-diones
  作者：M Malamas

  DOI：10.1016/s0223-5234(00)01191-0

  日期：2001.1

  A series of 1,2,4-oxadiazolidine-3,5-diones was synthesized and evaluated as oral antihyperglycemic agents in the obese insulin resistant db/db and ob/ob mouse - the two models for Type 2 diabetes mellitus. The majority of the prepared methoxy- and ethoxy-linked oxazole 1,2,4-oxadiazolidine-3,5-diones normalized plasma glucose levels at the 100 mg kg(-1) oral dose in the db/db diabetic mouse model, and several amongst them reduced the glucose levels at the 20 mg kg(-1) oral dose. The most potent compounds in the db/db mouse model were also active in the ob/ob mouse model normalizing the plasma glucose levels at the 20 mg kg(-1) oral dose. The trifluoromethoxy analog 32 was the most active compound of the series, reducing significantly the plasma glucose levels at the 5 mg kg(-1) oral dose. Oxadiazole-tailed 1,2,4-oxadiazolidine-3,5-diones were also active in both the db/db and ob/ob diabetic mouse models normalizing plasma glucose levels at the 100 mg kg(-1) oral dose. (C) 2001 Editions scientifiques et medicales Elsevier SAS.
• New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties
  作者：Michael S. Malamas、Janet Sredy、Iwan Gunawan、Brenda Mihan、Diane R. Sawicki、Laura Seestaller、Donald Sullivan、Brenda R. Flam

  DOI：10.1021/jm990476x

  日期：2000.3.1

  Insulin resistance in the liver and peripheral tissues together with a pancreatic cell defect are the common causes of type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibiton of PTPase may be an effective method in the treatment of type 2 diabetes. A series of azolidinediones has been prepared as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Several compounds were potent inhibitors against the recombinant rat and human PTP1B enzymes with submicromolar IC50 values. Elongated spacers between the azolidinedione moiety and the central aromatic portion of the molecule as well as hydrophobic groups at the vicinity of this aromatic region were very important to the inhibitory activity. Oxadiazolidinediones 87 and 88 and the corresponding acetic acid analogues 119 and 120 were the best h-PTP1B inhibitors with IC50 values in the range of 0.12-0.3 mu M. Several compounds normalized plasma glucose and insulin levels in the ob/ob and db/db diabetic mouse models.