(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol | 655237-16-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol
• 英文别名: (2S,3R,4R,5S,6R)-2-(5-(azulen-2-ylmethyl)-2-hydroxyphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol；(1S)-1,5-anhydro-1-C-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol；YM-543 free acid；(2S,3R,4R,5S,6R)-2-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
• CAS: 655237-16-4
• 化学式: C₂₃H₂₄O₆
• 分子量: 396.44
• InChiKey: AGJJCLBOHJQGFA-ZQGJOIPISA-N

物化性质

• 沸点：
  625.3±55.0 °C(Predicted)
• 密度：
  1.400±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  110
• 氢给体数：
  5
• 氢受体数：
  6

制备方法与用途

YM543游离碱是一种有效的口服活性钠葡萄糖协同转运蛋白（SGLT）2抑制剂，能够降低血糖水平，并且适用于糖尿病研究[1][2]。

反应信息

• 作为反应物：
  描述：

  (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol 在 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 生成 sodium 4-(azulen-2-ylmethyl)-2-β-D-glucopyranosylphenolate
  参考文献：
  名称：

  EP1908757

  摘要：

  公开号：
• 作为产物：
  描述：

  (1S)-1,5-anhydro-2,3,4,6-tetra-O-acetyl-1-(2-acetoxy-5-{[1-(methoxycarbonyl)azulen-2-yl]methyl}phenyl)-D-glucitol 在 sodium hydroxide 、 盐酸 作用下， 以 甲醇 、 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 5.67h， 以53%的产率得到(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol
  参考文献：
  名称：

  Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: Discovery of YM543

  摘要：

  Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.03.067

文献信息

• Azulene derivatives and salts thereof
  申请人：Tomiyama Hiroshi

  公开号：US20050124555A1

  公开（公告）日：2005-06-09

  The present invention provides an azulene derivative and a salt thereof, wherein an azulene ring is bonded to a benzene ring directly or via a lower alkylene which may be substituted with a halogen atom and the benzene ring is directly bonded to the glucose residue, and it is usable as a Na + -glucose cotransporter inhibitor, especially for a therapeutic and/or preventive agent for diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as diabetes-related diseases such as insulin-resistant diseases and obesity.

  本发明提供了一种吲哚蓝衍生物及其盐，其中吲哚蓝环直接或通过可被取代为卤原子的较低烷基与苯环结合，苯环直接与葡萄糖残基结合，可用作Na+-葡萄糖共转运蛋白抑制剂，特别用于治疗和/或预防糖尿病，如胰岛素依赖型糖尿病（1型糖尿病）和胰岛素非依赖型糖尿病（2型糖尿病），以及糖尿病相关疾病，如胰岛素抵抗性疾病和肥胖症。
• THERAPEUTIC USES OF SGLT2 INHIBITORS
  申请人：Seed Brian

  公开号：US20110077212A1

  公开（公告）日：2011-03-31

  Provided are methods of using one or more SGLT2 inhibitors, independently or in combination, for treating edema or reducing fluid retention. The invention also provides methods of using one or more SGLT2 inhibitors for the preparation of a medicament for treating edema or fluid retention. Methods are also provided for treating diabetes with an amount of one or more SGLT2 inhibitors and one or more PPAR-gamma agonists.

  提供了使用一种或多种SGLT2抑制剂的方法，独立使用或结合使用，用于治疗水肿或减少液体潴留。本发明还提供了使用一种或多种SGLT2抑制剂制备治疗水肿或液体潴留药物的方法。还提供了使用一种或多种SGLT2抑制剂和一种或多种PPAR-γ激动剂治疗糖尿病的方法。
• Process for Production of Azulene Derivatives and Intermediates for the Synthesis of the Same
  申请人：Tomiyama Hiroshi

  公开号：US20070293690A1

  公开（公告）日：2007-12-20

  A process for producing an azulene derivative useful as a Na + -glucose cotransporter inhibitor, which is high in yield, is simple in operation, is low in cost, is suited for environmental protection, and is advantageous industrially, the process being characterized by reducing and deprotecting at least one compound selected from penta-acyl compounds and tetra-acyl compounds or salts thereof to obtain a C-glycoside compound; and a useful intermediate for synthesis of such an azulene derivative, obtained in the course of the above process.

  生产一种用作Na+-葡萄糖共转运体抑制剂的蓝莓衍生物的方法，其产量高，操作简单，成本低，适用于环保，具有工业优势，该方法的特点是将至少选自五酰基化合物和四酰基化合物或其盐的化合物还原和去保护，以获得C-糖苷化合物；以及在上述过程中获得的用于合成这种蓝莓衍生物的有用中间体。
• Choline Salt Crystal of Azulene Compound
  申请人：Imamura Masakazu

  公开号：US20090182039A1

  公开（公告）日：2009-07-16

  A choline salt crystal of (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol which shows an endothermic peak at 194 to 198° C. as measured by differential scanning calorimetry (DSC analysis) and shows main peaks at about 2θ (°) 5.58, 14.72, 16.80, 17.82, 21.02, and 22.46 as measured by X-ray powder diffraction. Thus, a crystal of an azulene compound can be produced which is in a single crystal form, has a constant quality, can be produced with good reproducibility, can be provided stably as a crystal of an drug substance for use in the preparation of a pharmaceutical and is excellent in storage stability.

  一种胆碱盐晶体，化学式为(1S)-1,5-去水-1-[5-(偏二氢芴-2-甲基)-2-羟基苯基]-D-葡萄糖醇，通过差示扫描量热法（DSC分析）在194到198°C之间显示出一个吸热峰，在X射线粉末衍射测量中显示主要峰位于2θ（°）5.58、14.72、16.80、17.82、21.02和22.46左右。因此，可以制备出一种单晶形式的偏二氢芴化合物晶体，具有恒定的质量，可以具有良好的再现性，可以稳定地提供作为药物物质的晶体用于制备制药品，且具有优异的储存稳定性。
• AZULENE DERIVATIVES AND SALTS THEREOF
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：EP1553094A1

  公开（公告）日：2005-07-13

  The present invention provides an azulene derivative and a salt thereof, wherein an azulene ring is bonded to a benzene ring directly or via a lower alkylene which may be substituted with a halogen atom and the benzene ring is directly bonded to the glucose residue, and it is usable as a Na+-glucose cotransporter inhibitor, especially for a therapeutic and/or preventive agent for diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as diabetes-related diseases such as insulin-resistant diseases and obesity.

  本发明提供了一种偶氮烯衍生物及其盐，其中偶氮烯环直接或通过可被卤原子取代的低级亚烷基与苯环键合，苯环直接与葡萄糖残基键合、可用作 Na+-葡萄糖共转运体抑制剂，特别是用于治疗和/或预防糖尿病，如胰岛素依赖型糖尿病（1 型糖尿病）和胰岛素非依赖型糖尿病（2 型糖尿病），以及与糖尿病相关的疾病，如胰岛素抵抗性疾病和肥胖症。