1-[4-(2-N-piperidinyl-ethoxy)phenyl]butan-1-one | 331831-81-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[4-(2-N-piperidinyl-ethoxy)phenyl]butan-1-one
• 英文别名: 1-[4-(2-Piperidin-1-ylethoxy)phenyl]butan-1-one
• CAS: 331831-81-3
• 化学式: C₁₇H₂₅NO₂
• 分子量: 275.391
• InChiKey: GWAFZETWFKVTHK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-[4-(2-N-piperidinyl-ethoxy)phenyl]butan-1-one 在 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 生成 4,4'-(4-ethyl-3-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-1H-pyrazole-1,5-diyl)diphenol
  参考文献：
  名称：

  Triarylpyrazoles with basic side chains

  摘要：

  Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERT alpha. subtype in terms of binding affinity and agonist potency (Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Sun, J.; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ER alpha) with 20-fold higher affinity than to ERP. In cell-based transcription assays, pyrazole 5 was an antagonist on both ER alpha and ER beta, and it was also more potent on ER alpha. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ER alpha -raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene. (CV) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00226-1
• 作为产物：
  描述：

  N-羟乙基哌啶 、 4-羟基苯丁酮 在 偶氮二甲酸二异丙酯 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 以35%的产率得到1-[4-(2-N-piperidinyl-ethoxy)phenyl]butan-1-one
  参考文献：
  名称：

  Triarylpyrazoles with basic side chains

  摘要：

  Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERT alpha. subtype in terms of binding affinity and agonist potency (Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Sun, J.; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ER alpha) with 20-fold higher affinity than to ERP. In cell-based transcription assays, pyrazole 5 was an antagonist on both ER alpha and ER beta, and it was also more potent on ER alpha. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ER alpha -raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene. (CV) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00226-1

文献信息

• [EN] NOVEL FUNCTIONALIZED N,N-DIALKYLAMINO PHENYL ETHERS AND THEIR METHOD OF USE<br/>[FR] NOUVEAUX ÉTHERS DE N,N-DIALKYLAMINO-PHÉNYLE FONCTIONNALISÉS ET LEUR PROCÉDÉ D'UTILISATION
  申请人：TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION

  公开号：WO2017205451A1

  公开（公告）日：2017-11-30

  Pharmaceutical compositions of the invention comprise functionalized N,N-dialkylamino phenyl ethers derivatives having a disease-modifying action in the treatment of diseases associated with lysosomal storage dysfunction that include Gaucher's disease, and any disease or condition involving lysosomal storage dysfunction.

  本发明的药物组合物包括具有疾病修饰作用的N,N-二烷基氨基苯醚衍生物，用于治疗与溶酶体贮积功能障碍相关的疾病，包括高雪氏病，以及涉及溶酶体贮积功能障碍的任何疾病或病况。
• US7314937B2
  申请人：——

  公开号：US7314937B2

  公开（公告）日：2008-01-01
• Triarylpyrazoles with basic side chains
  作者：Shaun R Stauffer、Ying R Huang、Zachary D Aron、Christopher J Coletta、Jun Sun、Benita S Katzenellenbogen、John A Katzenellenbogen

  DOI：10.1016/s0968-0896(00)00226-1

  日期：2001.1

  Recently, we developed a novel triaryl-substituted pyrazole ligand system that has high affinity for the estrogen receptor (ER) (Fink, B. E.; Mortenson, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205). Subsequent work has shown that some analogues in this series are very selective for the ERT alpha. subtype in terms of binding affinity and agonist potency (Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Sun, J.; Katzenellenbogen, J. A. J. Med. Chem. 2000, submitted). We now investigate how this pyrazole ER agonist system might be converted into an antagonist or a selective estrogen receptor modifier (SERM) by incorporating a basic or polar side chain like those typically found in antiestrogens and known to be essential determinants of their mixed agonist/antagonist character. We selected an N-piperidinyl-ethyl chain as a first attempt, and introduced it at the four possible sites of substitution on the pyrazole core structure to determine the orientation that the pyrazole might adopt in the ER ligand binding pocket. Of these four, the C(5) piperidinyl-ethoxy-substituted pyrazole 5 had by far the highest affinity. Also, it bound to the ER subtype alpha (ER alpha) with 20-fold higher affinity than to ERP. In cell-based transcription assays, pyrazole 5 was an antagonist on both ER alpha and ER beta, and it was also more potent on ER alpha. Based on structure-binding affinity relationships and on molecular modeling studies of these pyrazoles in a crystal structure of the ER alpha -raloxifene complex, we propose that pyrazoles having a basic substituent on the C(5) phenyl group adopt a binding mode that is different from that of the pyrazole agonists that lack this group. The most favorable orientation appears to be one which places the N(1) phenol in the A-ring binding pocket so that the basic side chain can adopt an orientation similar to that of the basic side chain of raloxifene. (CV) 2000 Elsevier Science Ltd. All rights reserved.