2-<3-<(benzyloxycarbonyl)amino>-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl>-N-<2-<(tert-butyldimethylsilyl)oxy>-3,3,3-trifluoro-1-isopropylpropyl>acetamide | 147269-02-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 2-<3-<(benzyloxycarbonyl)amino>-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl>-N-<2-<(tert-butyldimethylsilyl)oxy>-3,3,3-trifluoro-1-isopropylpropyl>acetamide
• 英文别名: 2-<3-<(benzyloxycarbonyl)amino>-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl>-N-<2-<(tert-butyldimethylsilyl)oxy>-3,3,3-trifluoro-1-isopropyl>acetamide；2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide；benzyl N-[1-[2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]amino]-2-oxoethyl]-2-oxo-6-phenylpyridin-3-yl]carbamate
• CAS: 147269-02-1
• 化学式: C₃₃H₄₂F₃N₃O₅Si
• 分子量: 645.794
• InChiKey: QMQZFMROSNDCFQ-UHFFFAOYSA-N

物化性质

• 沸点：
  709.6±60.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.36
• 重原子数：
  45
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  97
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-<3-<(benzyloxycarbonyl)amino>-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl>-N-<2-<(tert-butyldimethylsilyl)oxy>-3,3,3-trifluoro-1-isopropylpropyl>acetamide 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 生成 methyl N-[1-[2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]amino]-2-oxoethyl]-2-oxo-6-phenylpyridin-3-yl]carbamate
  参考文献：
  名称：

  人白细胞弹性蛋白酶的非肽抑制剂。3.一系列口服活性的3-氨基-6-苯基吡啶-2-一三氟甲基酮的设计，合成，X射线晶体学分析和结构-活性关系。

  摘要：

  报道了一系列人类白细胞弹性蛋白酶（HLE）的非肽抑制剂。这些基于三氟甲基酮的抑制剂含有3-氨基-6-苯基吡啶酮基团作为中心模板。描述了在基于仓鼠的HLE诱导的肺损伤模型中，这些抑制剂中N-3取代基的变化对体外效能，物理特性和口服活性的影响。在此位置上对体外效能影响很小的各种取代基支持以下观点：分子的该区域不会与酶强烈相互作用。这种一般性的一个例外是13k，它被（4-乙酰氨基苯基）磺酰基取代。该化合物的K（i）为0.7 nM，在体外是该系列中最有效的抑制剂。相反，发现N-3取代基的变化对口服给药后的活性具有显着影响。当以2.5 mg / kg的口服剂量给药时，包括母体胺7，甲酰胺2u，苄基磺酰胺13e和苄基磺酰胺13f在内的几种类似物显示出显着的活性。通过体外SAR结果和13d与猪胰弹性蛋白酶（PPE）（一种密切相关的酶）之间的复合物的X射线晶体学分析，获得了基于模型的设计概念的支持。

  DOI：

  10.1021/jm00046a016
• 作为产物：
  描述：

  邻氯苯乙酮 在 palladium on activated charcoal 二苯基磷酸 、 氢溴酸 、 氢气 、 sodium methylate 、 sodium hydride 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 溶剂黄146 为溶剂， 25.0~100.0 ℃ 、340.0 kPa 条件下， 反应 6.0h， 生成 2-<3-<(benzyloxycarbonyl)amino>-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl>-N-<2-<(tert-butyldimethylsilyl)oxy>-3,3,3-trifluoro-1-isopropylpropyl>acetamide
  参考文献：
  名称：

  Nonpeptidic Inhibitors of Human Leukocyte Elastase. 2. Design, Synthesis, and in vitro Activity of a Series of 3-Amino-6-aryl-2-oxopyridyl Trifluoromethyl Ketones

  摘要：

  A series of potent nonpeptidic inhibitors of the enzyme human leukocyte elastase (HLE) is reported. These inhibitors contain a 3-amino-2-pyridone ring as a central template in which the pyridone carbonyl and 3-position NH group are thought to form important hydrogen bonding interactions with the Val-216 residue of HLE. Substitution of the 6-position of the pyridone ring by various alkyl and aryl groups was found to afford increases in the in vitro potency of these inhibitors. A 6-position phenyl group, compound 10f, was found to result in a large increase in binding affinity, which was not obtained when the phenyl group was placed in either the 4- or 5-position of the molecule. Compound 10f was found to have good selectivity for HLE over other proteolytic enzymes, with the exception of bovine pancreatic chymotrypsin (BPC). Substitution of the 6-phenyl group in these molecules was found to decrease binding affinity for BPC without adversely affecting affinity for HLE.

  DOI：

  10.1021/jm00046a015

文献信息

• Heterocyclic amides
  申请人：Zeneca Limited

  公开号：US05521179A1

  公开（公告）日：1996-05-28

  The present invention relates to certain novel heterocyclic amides which are 1-pyridylacetamide compounds of formula I, set out herein, 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 heterocyclic amides, processes for preparing the heterocyclic amides, pharmaceutical compositions containing such heterocyclic amides and methods for their use.

  本发明涉及某些新颖的杂环酰胺，它们是式I所示的1-吡啶乙酰胺化合物，这些化合物是人类白细胞弹性蛋白酶（HLE）的抑制剂，也被称为人类中性粒细胞弹性蛋白酶（HNE），使它们在需要这种抑制作用时非常有用，例如用作药理学、诊断和相关研究工具以及治疗哺乳动物中HLE相关疾病。该发明还包括在合成这些杂环酰胺过程中有用的中间体，制备这些杂环酰胺的方法，含有这些杂环酰胺的药物组合物以及它们的使用方法。
• Nonpeptidic Inhibitors of Human Leukocyte Elastase. 3. Design, Synthesis, X-ray Crystallographic Analysis, and Structure-Activity Relationships for a Series of Orally Active 3-Amino-6-phenyl-2-pyridinyl Trifluoromethyl Ketones
  作者：Peter R. Bernstein、Don Andisik、Prudence K. Bradley、Craig B. Bryant、Christopher Ceccarelli、James R. Damewood、Roger Earley、Philip D. Edwards、Scott Feeney

  DOI：10.1021/jm00046a016

  日期：1994.9

  enzyme. One exception to this generality is 13k, which is substituted with a (4-acetamidophenyl)sulfonyl group. This compound has a K(i) of 0.7 nM and is, in vitro, the most potent inhibitor in the series. In contrast, variation of the N-3 substituent was found to have a dramatic effect on activity after oral administration. Several analogs, including the parent amine, 7, formamide, 2u, benzyl sulfamide

  报道了一系列人类白细胞弹性蛋白酶（HLE）的非肽抑制剂。这些基于三氟甲基酮的抑制剂含有3-氨基-6-苯基吡啶酮基团作为中心模板。描述了在基于仓鼠的HLE诱导的肺损伤模型中，这些抑制剂中N-3取代基的变化对体外效能，物理特性和口服活性的影响。在此位置上对体外效能影响很小的各种取代基支持以下观点：分子的该区域不会与酶强烈相互作用。这种一般性的一个例外是13k，它被（4-乙酰氨基苯基）磺酰基取代。该化合物的K（i）为0.7 nM，在体外是该系列中最有效的抑制剂。相反，发现N-3取代基的变化对口服给药后的活性具有显着影响。当以2.5 mg / kg的口服剂量给药时，包括母体胺7，甲酰胺2u，苄基磺酰胺13e和苄基磺酰胺13f在内的几种类似物显示出显着的活性。通过体外SAR结果和13d与猪胰弹性蛋白酶（PPE）（一种密切相关的酶）之间的复合物的X射线晶体学分析，获得了基于模型的设计概念的支持。
• Nonpeptidic Inhibitors of Human Leukocyte Elastase. 2. Design, Synthesis, and in vitro Activity of a Series of 3-Amino-6-aryl-2-oxopyridyl Trifluoromethyl Ketones
  作者：James R. Damewood、Philip D. Edwards、Scott Feeney、Bruce C. Gomes、Gary B. Steelman、Paul A. Tuthill、Joseph C. Williams、Peter Warner、Sheila A. Woolson

  DOI：10.1021/jm00046a015

  日期：1994.9

  A series of potent nonpeptidic inhibitors of the enzyme human leukocyte elastase (HLE) is reported. These inhibitors contain a 3-amino-2-pyridone ring as a central template in which the pyridone carbonyl and 3-position NH group are thought to form important hydrogen bonding interactions with the Val-216 residue of HLE. Substitution of the 6-position of the pyridone ring by various alkyl and aryl groups was found to afford increases in the in vitro potency of these inhibitors. A 6-position phenyl group, compound 10f, was found to result in a large increase in binding affinity, which was not obtained when the phenyl group was placed in either the 4- or 5-position of the molecule. Compound 10f was found to have good selectivity for HLE over other proteolytic enzymes, with the exception of bovine pancreatic chymotrypsin (BPC). Substitution of the 6-phenyl group in these molecules was found to decrease binding affinity for BPC without adversely affecting affinity for HLE.