1,8-dioxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid | 1015770-89-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧烷类
• 英文名称: 1,8-dioxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid
• CAS: 1015770-89-4
• 化学式: C₈H₁₁NO₄
• 分子量: 185.18
• InChiKey: WRSZOAVGXHWMNN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  68.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1,8-dioxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid 在 盐酸 、 草酰氯 、 铁粉 、 sodium hydride 、 溶剂黄146 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 异丙醇 、 mineral oil 为溶剂， 反应 22.0h， 生成 3-[7-chloro-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl]-1,8-dioxa-2-azaspiro[4.5]dec-2-ene hydrochloride
  参考文献：
  名称：

  Design and Optimization of Benzimidazole-Containing Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists

  摘要：

  Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that is thermo-responsive to cool to cold temperatures (8-28 degrees C) and also may be activated by chemical agonists such as menthol and Antagonism of TRPM8 activation is currently under investigation for the treatment of painful conditions related to cold, such as cold allodynia and cold hyperalgesia The design, synthesis, and optimization of a class of selective TRPM8 antagonists based on a benzimidazole scaffold is described, leading to the identification of compounds that exhibited potent antagonism of TRPM8 in cell-based functional assays for human, rat, and canine TRPM8 channels Numerous compounds in the series demonstrated excellent in vivo activity in the TRPM8-selective "wet-dog shakes" (WDS) pharmacodynamic model and in the rat chronic constriction injury (CCI)-induced model of neuropathic pain Taken together the present results suggest that the in vivo antagonism of TRPM8 constitutes a viable new strategy for treating a variety of disorders associated with cold hypersensitivity, including certain types of neuropathic pain

  DOI：

  10.1021/jm101075v
• 作为产物：
  描述：

  ethyl 1,8-dioxa-2-azaspiro[4.5]dec-2-ene-3-carboxylate 在 甲醇 、 lithium hydroxide monohydrate 、 水 、 盐酸 作用下， 反应 2.5h， 生成 1,8-dioxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid
  参考文献：
  名称：

  [EN] HETEROCYCLIC BENZIMIDAZOLES AS TRPM8 MODULATORS
  [FR] BENZIMIDAZOLES HÉTÉROCYCLIQUES EN TANT QUE MODULATEURS DE TRPM8

  摘要：

  揭示了用于治疗各种疾病、综合症、症状和疾病的化合物、组合物和方法，包括疼痛。这些化合物由以下式（I）表示：其中W1、W2、W3、R1、R1a、R2、R2a、R3、V、Q和X在此处定义。

  公开号：

  WO2010045166A1

文献信息

• [EN] HETEROCYCLIC BENZIMIDAZOLES AS TRPM8 MODULATORS<br/>[FR] BENZIMIDAZOLES HÉTÉROCYCLIQUES EN TANT QUE MODULATEURS DE TRPM8
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2010045166A1

  公开（公告）日：2010-04-22

  Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula (I) as follows: wherein W1, W2, W3, R1, R1a, R2, R2a, R3, V, Q, and X are defined herein.

  揭示了用于治疗各种疾病、综合症、症状和疾病的化合物、组合物和方法，包括疼痛。这些化合物由以下式（I）表示：其中W1、W2、W3、R1、R1a、R2、R2a、R3、V、Q和X在此处定义。
• HETEROCYCLIC BENZIMIDAZOLES AS TRPM8 MODULATORS
  申请人：Player Mark R.

  公开号：US20100093788A1

  公开（公告）日：2010-04-15

  Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: wherein W 1 , W 2 , W 3 , R 1 , R 1a , R 2 , R 2a , R 3 , V, Q, and X are defined herein.

  本发明涉及一种用于治疗各种疾病、综合症、病况和疾患，包括疼痛的化合物、组合物和方法。这些化合物由以下公式I表示：其中W1、W2、W3、R1、R1a、R2、R2a、R3、V、Q和X在此被定义。
• Heterocyclic benzimidazoles as TRPM8 modulators
  申请人：Janssen Pharmaceutica N.V.

  公开号：US08232409B2

  公开（公告）日：2012-07-31

  Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: wherein W1, W2, W3, R1, R1a, R2, R2a, R3, V, Q, and X are defined herein.

  本发明涉及化合物、组合物和方法，用于治疗各种疾病、综合症、状况和疾患，包括疼痛。这些化合物由以下式子I所表示：其中，W1、W2、W3、R1、R1a、R2、R2a、R3、V、Q和X在此定义。
• US8232409B2
  申请人：——

  公开号：US8232409B2

  公开（公告）日：2012-07-31
• Design and Optimization of Benzimidazole-Containing Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists
  作者：Daniel J. Parks、William H. Parsons、Raymond W. Colburn、Sanath K. Meegalla、Shelley K. Ballentine、Carl R. Illig、Ning Qin、Yi Liu、Tasha L. Hutchinson、Mary Lou Lubin、Dennis J. Stone、Judith F. Baker、Craig R. Schneider、Jianya Ma、Bruce P. Damiano、Christopher M. Flores、Mark R. Player

  DOI：10.1021/jm101075v

  日期：2011.1.13

  Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that is thermo-responsive to cool to cold temperatures (8-28 degrees C) and also may be activated by chemical agonists such as menthol and Antagonism of TRPM8 activation is currently under investigation for the treatment of painful conditions related to cold, such as cold allodynia and cold hyperalgesia The design, synthesis, and optimization of a class of selective TRPM8 antagonists based on a benzimidazole scaffold is described, leading to the identification of compounds that exhibited potent antagonism of TRPM8 in cell-based functional assays for human, rat, and canine TRPM8 channels Numerous compounds in the series demonstrated excellent in vivo activity in the TRPM8-selective "wet-dog shakes" (WDS) pharmacodynamic model and in the rat chronic constriction injury (CCI)-induced model of neuropathic pain Taken together the present results suggest that the in vivo antagonism of TRPM8 constitutes a viable new strategy for treating a variety of disorders associated with cold hypersensitivity, including certain types of neuropathic pain