1,3-bis(4-methoxyphenyl)-2-(4-N-piperidinylbutyl)-propane-1,3-dione | 263717-73-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: 1,3-bis(4-methoxyphenyl)-2-(4-N-piperidinylbutyl)-propane-1,3-dione
• 英文别名: 1,3-Bis(4-methoxyphenyl)-2-(4-piperidin-1-ylbutyl)propane-1,3-dione；1,3-bis(4-methoxyphenyl)-2-(4-piperidin-1-ylbutyl)propane-1,3-dione
• CAS: 263717-73-3
• 化学式: C₂₆H₃₃NO₄
• 分子量: 423.552
• InChiKey: PSSOIOSSCAGPDB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  31
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1,3-bis(4-methoxyphenyl)-2-(4-N-piperidinylbutyl)-propane-1,3-dione 在 三氯化铝 、 乙硫醇 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.5h， 生成 4-(4-N-piperidinylbutyl)-3,5-di-(4-hydroxyphenyl)-1-phenylpyrazole hydrochloride
  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：

  6-溴-1-(4-甲氧基苯基)己烷-1-酮 在 四甲基乙二胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 1,3-bis(4-methoxyphenyl)-2-(4-N-piperidinylbutyl)-propane-1,3-dione
  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

• WO2007/98090
  申请人：——

  公开号：——

  公开（公告）日：——
• [EN] TREATMENT OF HYPERPROLIFERATIVE DISEASES WITH N-OXIDES OF ESTROGEN RECEPTOR MODULATORS<br/>[FR] TRAITMENT DE MALADIES HYPERPROLIFÉRATIVES AVEC DES N-OXIDES DE MODULATEURS DU RÉCEPTEUR D'OETROGÈNE
  申请人：NOVACEA INC

  公开号：WO2007098090A2

  公开（公告）日：2007-08-30

  [EN] The invention relates to N-oxides of tamoxifen analogs having activity for treating hyperproliferative disorders. Pharmaceutical compositions comprising therapeutically effective amount of an N-oxide of an estrogen receptor modulator, or a pharmaceutically acceptable salt or prodrug thereof, are disclosed. Further, the invention relates to methods of using the compounds, alone or in combination with one or more other active agents or treatments, to treat hyperproliferative disorders.
  [FR] L'invention concerne des N-oxides d'analogues de tamoxifène présentant une activité destinée à traiter des troubles hyperprolifératifs. L'invention concerne également des compositions pharmaceutiques contenant une quantité efficace sur le plan thérapeutique de N-oxyde d'un modulateur du récepteur d'oetrogène, ou un sel ou un promédicament de celui-ci acceptable sur le plan pharmaceutique. L'invention concerne enfin des procédés utilisant ces composés, seul ou en combinaison avec un ou plusieurs autres agents ou traitements actifs, en vue de traiter des troubles hyperprolifératifs.
• 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.