(2R)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid | 668455-62-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (2R)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid
• 英文别名: (2R)-2-{3-[[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy}butyric acid；Butanoic acid,2-[3-[[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-,(2R)-；(2R)-2-[3-[[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)indol-1-yl]methyl]phenoxy]butanoic acid
• CAS: 668455-62-7
• 化学式: C₂₈H₂₃ClF₃NO₅
• 分子量: 545.943
• InChiKey: QTNLJMSTDKBAOB-XMMPIXPASA-N

物化性质

• 熔点：
  172-173 °C
• 沸点：
  650.5±55.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.6
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  77.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 在 sodium hydroxide 作用下， 以 异丙醇 为溶剂， 生成
  参考文献：
  名称：

  WO2006/99077

  摘要：

  公开号：
• 作为产物：
  描述：

  ethyl (2R)-2-{3-[[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy}butyrate 在 sodium hydroxide 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 以99%的产率得到
  参考文献：
  名称：

  [EN] INDOLES HAVING ANTI-DIABETIC ACTIVITY
  [FR] INDOLES A ACTIVITE ANTIDIABETIQUE

  摘要：

  印度戊酸取代的吲哚类化合物或芳基氧烷酸取代的吲哚类化合物是PPAR-γ的激动剂或部分激动剂，对于治疗和控制与2型糖尿病相关的症状性高血糖、以及常伴有2型糖尿病的血脂异常、高血脂、高胆固醇、高甘油三酯和肥胖等方面具有用处。

  公开号：

  WO2004020408A1

文献信息

• Practical, Highly Convergent, Asymmetric Synthesis of a Selective PPARγ Modulator
  作者：Peter E. Maligres、Guy R. Humphrey、Jean-François Marcoux、Michael C. Hillier、Dalian Zhao、Shane Krska、Edward J. J. Grabowski

  DOI：10.1021/op8002882

  日期：2009.5.15

  arylation reaction between 2-nitro-4-trifluoromethoxyaniline and isopropenyl acetate and subsequent reductive cyclization. The α-aryloxybutanoic acid was prepared via an asymmetric hydrogenation of the corresponding α-aryloxy-α,β-unsaturated acid. Tetrabutylammonium iodide-catalyzed coupling of the two fragments and ester hydrolysis completed the convergent synthesis. The described convergent synthesis was

  描述了一种实用的，高度收敛的，选择性PPARγ调节剂1的不对称合成。该抑制剂包含两个关键成分，即6-三氟甲氧基-3-酰基（6）和（R）-α-芳氧基丁酸衍生物（10）。开发了两种方法来克服在6-取代的吲哚的制备中遇到的区域选择性问题。第一个涉及碘代芳基烯胺的分子内Heck反应。第二个涉及2-硝基-4-三氟甲氧基苯胺和乙酸异丙烯酯之间的催化Meerwein芳基化反应的应用和随后的还原环化。通过相应的α-芳氧基-α，β-不饱和酸的不对称氢化制备α-芳氧基丁酸。四丁基碘化铵催化的两个片段偶联和酯水解完成了聚合合成。所描述的收敛合成用于制备> 3kg的药物物质1，其总收率为50％，且ee> 99.5％。
• Indoles having anti-diabetic activity
  申请人：Acton III J. John

  公开号：US20050277685A1

  公开（公告）日：2005-12-15

  Indoles having aryloxyalkanoic acid substituents or arylalkanoic acid substituents are agonists or partial agonists of PPAR gamma and are useful in the treatment and control of hyperglycemia that is symptomatic of type II diabetes, as well as dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity that are often associated with type 2 diabetes.

  具有芳氧基烷酸取代基或芳基烷酸取代基的吲哚类化合物是PPARγ激动剂或部分激动剂，可用于治疗和控制II型糖尿病的症状性高血糖，以及常与II型糖尿病相关的失调脂质代谢、高脂血症、高胆固醇血症、高甘油三酯血症和肥胖症。
• Novel Crystalline Forms of Antidiabetic Compounds
  申请人：Zhao Dalian

  公开号：US20080221198A1

  公开（公告）日：2008-09-11

  Novel crystalline forms of two indole compounds connected to phenoxyalkylcarboxylic acid groups are selective PPAR gamma partial agonists that are useful in the treatment of type 2 diabetes, hyperglycemia, obesity, dyslipidemia, and the metabolic syndrome. The novel crystal forms include a crystalline free acid dihydrate and crystalline free acid anhydrate of one compound and several crystalline forms of the free acid and the sodium salt of the second compound. The invention also relates to pharmaceutical compositions comprising these novel crystal forms, processes to prepare the crystal forms and their pharmaceutical compositions, and uses of the crystal forms in the treatment of type 2 diabetes and other PPAR gamma modulated diseases.

  两种吲哚化合物与苯氧烷基羧酸基团相连的新晶体形式是选择性PPARγ部分激动剂，可用于治疗2型糖尿病、高血糖、肥胖症、血脂异常和代谢综合征。新晶体形式包括一种化合物的结晶自由酸二水合物和结晶自由酸无水物，以及第二种化合物的自由酸和钠盐的几种晶体形式。本发明还涉及包含这些新晶体形式的制药组合物、制备晶体形式及其制药组合物的工艺，并将晶体形式用于治疗2型糖尿病和其他PPARγ调节疾病。
• Discovery of a Peroxisome Proliferator Activated Receptor γ (PPARγ) Modulator with Balanced PPARα Activity for the Treatment of Type 2 Diabetes and Dyslipidemia
  作者：Weiguo Liu、Kun Liu、Harold B. Wood、Margaret E. McCann、Thomas W. Doebber、Ching H. Chang、Taro E. Akiyama、Monica Einstein、Joel P. Berger、Peter T. Meinke

  DOI：10.1021/jm900367w

  日期：2009.7.23

  A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPAR gamma modulator with additional moderate intrinsic PPAR alpha agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-(2R)-butanoic acid (12d) was identified as such an agent which demonstrated potent efficacy in lowering both glucose and lipids in multiple animal models with significantly attenuated side effects such as fluid retention and heart weight gain associated with PPAR gamma full agonists, The moderate PPAR alpha activity of 12d not only contributed to the agent's ability to manage lipid profiles but also appears to have potentiated its PPAR gamma efficacy in lowering glucose levels in preclinical diabetic animal models.
• INDOLES HAVING ANTI-DIABETIC ACTIVITY
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP1537078B1

  公开（公告）日：2010-04-14