(1α,5α,6α)-(3-aza-bicyclo[3.1.0]hex-6-yl)-acetic acid ethyl ester | 1251668-97-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (1α,5α,6α)-(3-aza-bicyclo[3.1.0]hex-6-yl)-acetic acid ethyl ester
• 英文别名: (2-(1α,5α,6α)-3-azabicyclo[3.1.0]hexan-6-yl)acetic acid ethyl ester；ethyl (1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-ylacetate
• CAS: 1251668-97-9
• 化学式: C₉H₁₅NO₂
• 分子量: 169.224
• InChiKey: GGOXACSGIVGNKF-WHUPJOBBSA-N

物化性质

• 沸点：
  230.8±13.0 °C(Predicted)
• 密度：
  1.073±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  12.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  38.33
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (1α,5α,6α)-(3-aza-bicyclo[3.1.0]hex-6-yl)-acetic acid ethyl ester 在 碳酸氢钠 、 三乙胺 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 19.0h， 生成 ethyl 2-[(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetate
  参考文献：
  名称：

  Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose

  摘要：

  Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.

  DOI：

  10.1021/acs.jmedchem.0c00944
• 作为产物：
  描述：

  [(1R,5S,6r)-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl]methyl methanesulfonate 在 硫酸 、 10% palladium hydroxide on charcoal 、 氢气 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 80.0 ℃ 、344.75 kPa 条件下， 反应 48.0h， 生成 (1α,5α,6α)-(3-aza-bicyclo[3.1.0]hex-6-yl)-acetic acid ethyl ester
  参考文献：
  名称：

  Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose

  摘要：

  Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.

  DOI：

  10.1021/acs.jmedchem.0c00944

文献信息

• SUBSTITUTED 3-AZABICYCLO[3.1.0]HEXANES AS KETOHEXOKINASE INHIBITORS
  申请人：Pfizer Inc.

  公开号：US20170183328A1

  公开（公告）日：2017-06-29

  Provided herein are substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

  本文提供了替代3-氮杂双环[3.1.0]己烷作为酮己糖激酶抑制剂，制备该类化合物的方法，以及包括向需要的哺乳动物施用该类化合物的方法。
• PYRAZOLO[1,5-a]PYRIMIDINE COMPOUND
  申请人：Eisai R&D Management Co., Ltd.

  公开号：US20180057499A1

  公开（公告）日：2018-03-01

  The compounds represented by formulas (I) to (XVIII) or pharmaceutically acceptable salts thereof.

  由化学式（I）到（XVIII）表示的化合物或其药用盐。
• 6-(3-AZA-BICYCLO[3.1.0]HEX-3-YL)-2-PHENYL-PYRIMIDINES
  申请人：Caroff Eva

  公开号：US20120028989A1

  公开（公告）日：2012-02-02

  The present invention relates to 6-(3-aza-bicyclo[3.1.0]hex-3-yl)-2-phenyl-pyrimidine derivatives and their use as P2Y 12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals.

  本发明涉及6-(3-aza-bicyclo[3.1.0]hex-3-yl)-2-苯基-嘧啶衍生物及其作为P2Y12受体拮抗剂在治疗和/或预防外周血管、内脏、肝脏和肾脏血管、心血管和脑血管疾病或与血小板聚集有关的病症，包括在人类和其他哺乳动物中的血栓形成的使用。
• Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors
  申请人：Pfizer Inc.

  公开号：US10174007B2

  公开（公告）日：2019-01-08

  Provided herein are substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

  本文提供了作为酮六磷酸酶抑制剂的取代 3-氮杂双环[3.1.0]己烷、制造所述化合物的工艺，以及将所述化合物施用给需要的哺乳动物的方法。
• 6-(3-AZA-BICYCLO[3.1.0]HEX-3-YL)-2-PHENYL-PYRIMIDINES AS ADP RECEPTOR ANTAGONISTS
  申请人：Actelion Pharmaceuticals Ltd.

  公开号：EP2417128B1

  公开（公告）日：2016-03-02