2-[3-(4-Methoxybenzyl)-2,4,8-trioxo-1,2,3,4,7,8-hexahydropyrido-[3,4-d]pyrimidin-7-yl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide | 159780-52-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 2-[3-(4-Methoxybenzyl)-2,4,8-trioxo-1,2,3,4,7,8-hexahydropyrido-[3,4-d]pyrimidin-7-yl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide
• 英文别名: N-[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]-2-[3-[(4-methoxyphenyl)methyl]-2,4,8-trioxo-1H-pyrido[3,4-d]pyrimidin-7-yl]acetamide
• CAS: 159780-52-6
• 化学式: C₂₉H₃₉F₃N₄O₆Si
• 分子量: 624.733
• InChiKey: CEUXSBIRPGKYEN-UHFFFAOYSA-N

物化性质

• 密度：
  1.269±0.10 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.0
• 重原子数：
  43
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-[3-(4-Methoxybenzyl)-2,4,8-trioxo-1,2,3,4,7,8-hexahydropyrido-[3,4-d]pyrimidin-7-yl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 2-[3-(4-Methoxybenzyl)-2,4,8-trioxo-1,2,3,4,7,8-hexahydropyrido-[3,4-d]pyrimidin-7-yl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide
  参考文献：
  名称：

  Nonpeptidic Inhibitors of Human Neutrophil Elastase. 7. Design, Synthesis, and in Vitro Activity of a Series of Pyridopyrimidine Trifluoromethyl Ketones

  摘要：

  Using molecular modeling and the information derived from X-ray crystal structures of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) complexed to peptidic ligands, we have developed a new series of nonpeptidic inhibitors of HNE, the pyridopyrimidine trifluoromethyl ketones (TFMKs). These bicyclic inhibitors were designed to extend the concept of the related pyridone trifluoromethyl ketones by incorporating a rigidly positioned carbonyl group to participate in a hydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a scaffold to vector substituents toward the S-5-S-4 subsites of the enzyme's extended binding pocket. Furthermore, the heteroatoms of the pyrimidine ring generally increase the aqueous solubility of the pyridopyrimidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and several inhibitors from this class of compounds possessed aqueous solubilities of > 0.1 mg/mL and K-i values of less than or equal to 10 nM.

  DOI：

  10.1021/jm950684z
• 作为产物：
  描述：

  2-(3-benzyloxycarbonylamino-4-carboxy-2-oxo-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 2-[3-(4-Methoxybenzyl)-2,4,8-trioxo-1,2,3,4,7,8-hexahydropyrido-[3,4-d]pyrimidin-7-yl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide
  参考文献：
  名称：

  Nonpeptidic Inhibitors of Human Neutrophil Elastase. 7. Design, Synthesis, and in Vitro Activity of a Series of Pyridopyrimidine Trifluoromethyl Ketones

  摘要：

  Using molecular modeling and the information derived from X-ray crystal structures of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) complexed to peptidic ligands, we have developed a new series of nonpeptidic inhibitors of HNE, the pyridopyrimidine trifluoromethyl ketones (TFMKs). These bicyclic inhibitors were designed to extend the concept of the related pyridone trifluoromethyl ketones by incorporating a rigidly positioned carbonyl group to participate in a hydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a scaffold to vector substituents toward the S-5-S-4 subsites of the enzyme's extended binding pocket. Furthermore, the heteroatoms of the pyrimidine ring generally increase the aqueous solubility of the pyridopyrimidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and several inhibitors from this class of compounds possessed aqueous solubilities of > 0.1 mg/mL and K-i values of less than or equal to 10 nM.

  DOI：

  10.1021/jm950684z

文献信息

• Heterocyclic amides
  申请人：Zeneca Limited

  公开号：US05532366A1

  公开（公告）日：1996-07-02

  The present invention relates to certain novel amide derivatives which are pyrido[3,4-d]pyrimidin-7-ylacetamides which are inhibitors of human leukocyte elastase (HLE), also known as human neutrophil elastase (HNE), making them useful whenever such inhibition is desired, such as for research tools in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which HLE is implicated. The invention also includes intermediates useful in the synthesis of these amide derivatives, processes for preparing the amide derivatives, pharmaceutical compositions containing such amide derivatives and methods for their use.

  本发明涉及一种新型酰胺衍生物，即吡啶并[3,4-d]嘧啶-7-基乙酰胺，它们是人类白细胞弹性酶（HLE），也称为人类中性粒细胞弹性酶（HNE）的抑制剂，使它们在需要抑制此类酶时具有用途，例如用于药理学、诊断和相关研究工具以及治疗哺乳动物中HLE所涉及的疾病。该发明还包括在合成这些酰胺衍生物过程中有用的中间体，制备酰胺衍生物的方法，含有此类酰胺衍生物的药物组合物以及它们的使用方法。
• Nonpeptidic Inhibitors of Human Neutrophil Elastase. 7. Design, Synthesis, and <i>in Vitro</i> Activity of a Series of Pyridopyrimidine Trifluoromethyl Ketones
  作者：Philip D. Edwards、Donald W. Andisik、Anne M. Strimpler、Bruce Gomes、Paul A. Tuthill

  DOI：10.1021/jm950684z

  日期：1996.1.1

  Using molecular modeling and the information derived from X-ray crystal structures of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) complexed to peptidic ligands, we have developed a new series of nonpeptidic inhibitors of HNE, the pyridopyrimidine trifluoromethyl ketones (TFMKs). These bicyclic inhibitors were designed to extend the concept of the related pyridone trifluoromethyl ketones by incorporating a rigidly positioned carbonyl group to participate in a hydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a scaffold to vector substituents toward the S-5-S-4 subsites of the enzyme's extended binding pocket. Furthermore, the heteroatoms of the pyrimidine ring generally increase the aqueous solubility of the pyridopyrimidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and several inhibitors from this class of compounds possessed aqueous solubilities of > 0.1 mg/mL and K-i values of less than or equal to 10 nM.