8-Methoxy-3-(4-methoxyphenyl)-3a-methyl-4,5-dihydrobenzo[g]indazole | 943539-31-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: 8-Methoxy-3-(4-methoxyphenyl)-3a-methyl-4,5-dihydrobenzo[g]indazole
• CAS: 943539-31-9
• 化学式: C₂₀H₂₀N₂O₂
• 分子量: 320.391
• InChiKey: PAWMOIHJUGCBMO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  43.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-Methoxy-3-(4-methoxyphenyl)-3a-methyl-4,5-dihydrobenzo[g]indazole 、 乙酰氯 在 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 生成 1-[(3S,3aS)-8-methoxy-3-(4-methoxyphenyl)-3a-methyl-4,5-dihydro-3H-benzo[g]indazol-2-yl]ethanone 、
  参考文献：
  名称：

  Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability

  摘要：

  Necroptosis is a regulated caspase-independent cell death pathway with morphological features resembling passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of 3,3a,4,5-tetrahydro-2H-benz[g]indazoles (referred to as the Nec-3 series) displaying potent activity in cellular assays. However, evaluation of the tricyclic necroptosis inhibitor's stability in mouse liver microsomes indicated that they were rapidly degraded. A structure-activity relationship (SAR) study of this compound series revealed that increased liver microsomal stability could be accomplished by modification of the pendent phenyl ring and by introduction of a hydrophilic substituent (i.e., alpha-hydroxyl) to the acetamide at the 2-position of the tricyclic ring without significantly compromising necroptosis inhibitory activity. Further increases in microsomal stability could be achieved by utilizing the 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro-[1]benzothiopyrano[4,3-c]pyrazoles. However, in this case necroptosis inhibitory activity was not maintained. Overall, these results provide a strategy for generating potent and metabolically stable tricyclic necrostatin analogs (e.g., 33, LDN-193191) potentially suitable for in vivo studies. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.06.098
• 作为产物：
  描述：

  7-甲氧基-1-萘满酮 在 hydrazine hydrate 、 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 8-Methoxy-3-(4-methoxyphenyl)-3a-methyl-4,5-dihydrobenzo[g]indazole
  参考文献：
  名称：

  Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability

  摘要：

  Necroptosis is a regulated caspase-independent cell death pathway with morphological features resembling passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of 3,3a,4,5-tetrahydro-2H-benz[g]indazoles (referred to as the Nec-3 series) displaying potent activity in cellular assays. However, evaluation of the tricyclic necroptosis inhibitor's stability in mouse liver microsomes indicated that they were rapidly degraded. A structure-activity relationship (SAR) study of this compound series revealed that increased liver microsomal stability could be accomplished by modification of the pendent phenyl ring and by introduction of a hydrophilic substituent (i.e., alpha-hydroxyl) to the acetamide at the 2-position of the tricyclic ring without significantly compromising necroptosis inhibitory activity. Further increases in microsomal stability could be achieved by utilizing the 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro-[1]benzothiopyrano[4,3-c]pyrazoles. However, in this case necroptosis inhibitory activity was not maintained. Overall, these results provide a strategy for generating potent and metabolically stable tricyclic necrostatin analogs (e.g., 33, LDN-193191) potentially suitable for in vivo studies. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.06.098

文献信息

• Compounds, Screens, and Methods of Treatment
  申请人：Yuan Junying

  公开号：US20100190836A1

  公开（公告）日：2010-07-29

  The present invention features compounds, pharmaceutical compositions, and methods for treating trauma, ischemia, stroke, degenerative diseases associated with cellular necrosis, and other conditions. Screening assays for identifying compounds useful for treating these conditions are also described.

  本发明涉及化合物、药物组合物和治疗创伤、缺血、中风、与细胞坏死相关的退行性疾病以及其他疾病的方法。还描述了用于识别治疗这些疾病的化合物的筛选测定方法。
• TRICYCLIC NECROSTATIN COMPOUNDS
  申请人：Yuan Junying

  公开号：US20130158024A1

  公开（公告）日：2013-06-20

  The present invention features compounds, pharmaceutical compositions, and methods for treating trauma, ischemia, stroke, degenerative diseases associated with cellular necrosis, and other conditions. Screening assays for identifying compounds useful for treating these conditions are also described.

  本发明涉及化合物、制药组合物和治疗创伤、缺血、中风、与细胞坏死相关的退行性疾病以及其他疾病的方法。还描述了用于鉴定治疗这些疾病的化合物的筛选测定。
• US8324262B2
  申请人：——

  公开号：US8324262B2

  公开（公告）日：2012-12-04
• [EN] COMPOUNDS, SCREENS, AND METHODS OF TREATMENT<br/>[FR] COMPOSES, ESSAIS ET METHODES DE TRAITEMENT
  申请人：HARVARD COLLEGE

  公开号：WO2007075772A2

  公开（公告）日：2007-07-05

  [EN] The present invention features compounds, pharmaceutical compositions, and methods for treating trauma, ischemia, stroke, degenerative diseases associated with cellular necrosis, and other conditions. Screening assays for identifying compounds useful for treating these conditions are also described.
  [FR] La présente invention concerne des composés, des compositions pharmaceutiques et des méthodes destinés au traitement d'un trauma, d'une ischémie, d'un accident vasculaire cérébral, de maladies dégénératives associées à une nécrose cellulaire, et d'autres troubles. L'invention concerne également des essais biologiques destinés à l'identification de composés utiles pour le traitement de ces troubles.
• Optimization of tricyclic Nec-3 necroptosis inhibitors for in vitro liver microsomal stability
  作者：Sungwoon Choi、Heather Keys、Richard J. Staples、Junying Yuan、Alexei Degterev、Gregory D. Cuny

  DOI：10.1016/j.bmcl.2012.06.098

  日期：2012.9

  Necroptosis is a regulated caspase-independent cell death pathway with morphological features resembling passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of 3,3a,4,5-tetrahydro-2H-benz[g]indazoles (referred to as the Nec-3 series) displaying potent activity in cellular assays. However, evaluation of the tricyclic necroptosis inhibitor's stability in mouse liver microsomes indicated that they were rapidly degraded. A structure-activity relationship (SAR) study of this compound series revealed that increased liver microsomal stability could be accomplished by modification of the pendent phenyl ring and by introduction of a hydrophilic substituent (i.e., alpha-hydroxyl) to the acetamide at the 2-position of the tricyclic ring without significantly compromising necroptosis inhibitory activity. Further increases in microsomal stability could be achieved by utilizing the 5,5-dioxo-3-phenyl-2,3,3a,4-tetrahydro-[1]benzothiopyrano[4,3-c]pyrazoles. However, in this case necroptosis inhibitory activity was not maintained. Overall, these results provide a strategy for generating potent and metabolically stable tricyclic necrostatin analogs (e.g., 33, LDN-193191) potentially suitable for in vivo studies. (C) 2012 Elsevier Ltd. All rights reserved.