2,5,5-三甲基哌嗪-1-羧酸叔丁酯 | 308109-96-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 2,5,5-三甲基哌嗪-1-羧酸叔丁酯
• 英文名称: tert-butyl 2,5,5-trimethyl-1-piperazinecarboxylate
• 英文别名: Tert-butyl 2,5,5-trimethylpiperazine-1-carboxylate
• CAS: 308109-96-8
• 化学式: C₁₂H₂₄N₂O₂
• 分子量: 228.335
• InChiKey: RFKDQNITCIOVID-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.92
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2,5,5-三甲基哌嗪-1-羧酸叔丁酯 在 potassium carbonate 、 三氟乙酸 作用下， 以 乙腈 为溶剂， 反应 99.0h， 生成 N,N-Diethyl-4-[(3-methoxy-phenyl)-(2,2,5-trimethyl-piperazin-1-yl)-methyl]-benzamide
  参考文献：
  名称：

  New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability

  摘要：

  Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl( 1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC50 = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for delta receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for delta binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)- methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, mu/delta = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.

  DOI：

  10.1021/jm000228x
• 作为产物：
  描述：

  3,3,6-trimethyl-2,5-piperazinedione 在 lithium aluminium tetrahydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.0h， 生成 2,5,5-三甲基哌嗪-1-羧酸叔丁酯
  参考文献：
  名称：

  New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability

  摘要：

  Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl( 1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC50 = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for delta receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for delta binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)- methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, mu/delta = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.

  DOI：

  10.1021/jm000228x

文献信息

• SUBSTITUTED 6-(4-HYDROXY-PHENYL)-1H-PYRAZOLO[3,4-B]PYRIDINE DERIVATIVES AS KINASE INHIBITORS
  申请人：SANOFI

  公开号：US20150133432A1

  公开（公告）日：2015-05-14

  The present invention relates to pyrazolo[3,4-b]pyridine compounds of the formula I, in which R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as indicated below. The compounds of the formula I are kinase inhibitors, and are useful for the treatment of diseases associated with diabetes and diabetic complications, such as, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy, for example. The invention furthermore relates to the use of compounds of the formula I, in particular as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

  本发明涉及式I的吡唑并[3,4-b]吡啶化合物，其中R1、R2、R3、R4、R5和R6如下所示。式I的化合物是激酶抑制剂，用于治疗与糖尿病和糖尿病并发症相关的疾病，例如糖尿病肾病、糖尿病神经病和糖尿病视网膜病变。此外，本发明还涉及使用式I的化合物，特别是作为药物的活性成分以及包含它们的制药组合物。
• Substituted 6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine derivatives as kinase inhibitors
  申请人：SANOFI

  公开号：US09133181B2

  公开（公告）日：2015-09-15

  The present invention relates to pyrazolo[3,4-b]pyridine compounds of the formula I, in which R1, R2, R3, R4, R5 and R6 are defined as indicated below. The compounds of the formula I are kinase inhibitors, and are useful for the treatment of diseases associated with diabetes and diabetic complications, such as, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy, for example. The invention furthermore relates to the use of compounds of the formula I, in particular as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

  本发明涉及式I的吡唑并[3,4-b]吡啶化合物，其中R1、R2、R3、R4、R5和R6如下所示。式I的化合物是激酶抑制剂，可用于治疗与糖尿病和糖尿病并发症相关的疾病，例如糖尿病肾病、糖尿病神经病变和糖尿病视网膜病变。本发明还涉及使用式I的化合物，特别是作为制药活性成分以及包含它们的制药组合物。
• New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability
  作者：Niklas Plobeck、Daniel Delorme、Zhong-Yong Wei、Hua Yang、Fei Zhou、Peter Schwarz、Lars Gawell、Hélène Gagnon、Benjamin Pelcman、Ralf Schmidt、Shi Yi Yue、Christopher Walpole、William Brown、Edward Zhou、Maryse Labarre、Kemal Payza、Stephane St-Onge、Augustus Kamassah、Pierre-Emmanuel Morin、Denis Projean、Julie Ducharme、Edward Roberts

  DOI：10.1021/jm000228x

  日期：2000.10.1

  Nonpeptide delta opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl( 1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human delta receptor (IC50 = 11 nM, mu/delta = 740, kappa/delta > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for delta receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for delta binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)- methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, mu/delta = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.