苯甲酸,4-[[[(4-氯苯基)磺酰]氨基]羰基]-,1,1-二甲基乙基酯 | 105080-62-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 苯甲酸,4-[[[(4-氯苯基)磺酰]氨基]羰基]-,1,1-二甲基乙基酯
• 英文名称: tert-butyl-4-<<<(4-chlorophenyl)sulfonyl>amino>carbonyl>benzoate
• 英文别名: 1,1-Dimethylethyl 4-[(4-chlorophenyl)sulfonylaminocarbonyl]benzoate；tert-butyl 4-[(4-chlorophenyl)sulfonylcarbamoyl]benzoate
• CAS: 105080-62-4
• 化学式: C₁₈H₁₈ClNO₅S
• 分子量: 395.864
• InChiKey: ZHOGHVKKTOPFMY-UHFFFAOYSA-N

物化性质

• 密度：
  1.324±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  97.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  苯甲酸,4-[[[(4-氯苯基)磺酰]氨基]羰基]-,1,1-二甲基乙基酯 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 、 三氟乙酸 作用下， 以 四氢呋喃 为溶剂， 反应 4.5h， 生成
  参考文献：
  名称：

  Inhibition of human leukocyte elastase (HLE) by N-substituted peptidyl trifluoromethyl ketones

  摘要：

  A series of tripeptides possessing trifluoromethyl or aryl ketone residues at P1 were prepared and evaluated both in vitro and in vivo as potential inhibitors of human leukocyte elastase (HLE). Tripeptides containing non naturally occurring N-substituted glycine residues at the P2-position have been demonstrated to be potent in vitro inhibitors of HLE, with IC50 values in the submicromolar range. Sterically demanding substituents on the P2-nitrogen have no detrimental effect on in vitro potency. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing trifluoromethyl functionality. Deletion of the amino acid at the P3-subsite region affords inactive compounds. Valine is the preferred residue at the P1-position, whereas the corresponding glycine, alanine, alpha,alpha-dimethylglycine, or phenylalanine analogues are all inactive. The compounds described herein all confer a high degree of in vitro specificity when tested against representative cysteine, aspartyl, metallo, and other serine proteases. One of the most potent in vitro inhibitors is (3RS)-N-[4-[[[(4-chlorophenyl)sulfonyl]amino]carbonyl]phenyl]oxomethyl]-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]amide (20i; BI-RA-260) (IC50 = 0.084-mu-M). Compound 20i was also tested in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 20i, 5 min prior to HLE challenge, effectively inhibited hemorrhage in a dose-dependent manner with an ED50 of 4.8-mu-g. The inhibitor 20i, 20-mu-g administered it. 24, 48, and 72 h prior to HLE challenge, exhibits significant inhibition against hemorrhage at all time points (97%, 64% and 49%, respectively). In a 21-day chronic model of emphysema in hamsters, 200-mu-g of HLE administered it. caused an elastase-induced emphysema in the lungs which can be quantitated histologically utilizing image analysis. In this assay, 20i significantly inhibited pulmonary lesions associated with septal destruction and increased alveolar spaces, when dosed at 20-mu-g it. 5 min prior to challenge with HLE.

  DOI：

  10.1021/jm00082a005
• 作为产物：
  描述：

  对苯二甲酸二叔丁酯 在 4-二甲氨基吡啶 、 氢氧化钾 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 叔丁醇 为溶剂， 生成 苯甲酸,4-[[[(4-氯苯基)磺酰]氨基]羰基]-,1,1-二甲基乙基酯
  参考文献：
  名称：

  Inhibition of human leukocyte elastase (HLE) by N-substituted peptidyl trifluoromethyl ketones

  摘要：

  A series of tripeptides possessing trifluoromethyl or aryl ketone residues at P1 were prepared and evaluated both in vitro and in vivo as potential inhibitors of human leukocyte elastase (HLE). Tripeptides containing non naturally occurring N-substituted glycine residues at the P2-position have been demonstrated to be potent in vitro inhibitors of HLE, with IC50 values in the submicromolar range. Sterically demanding substituents on the P2-nitrogen have no detrimental effect on in vitro potency. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing trifluoromethyl functionality. Deletion of the amino acid at the P3-subsite region affords inactive compounds. Valine is the preferred residue at the P1-position, whereas the corresponding glycine, alanine, alpha,alpha-dimethylglycine, or phenylalanine analogues are all inactive. The compounds described herein all confer a high degree of in vitro specificity when tested against representative cysteine, aspartyl, metallo, and other serine proteases. One of the most potent in vitro inhibitors is (3RS)-N-[4-[[[(4-chlorophenyl)sulfonyl]amino]carbonyl]phenyl]oxomethyl]-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]amide (20i; BI-RA-260) (IC50 = 0.084-mu-M). Compound 20i was also tested in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 20i, 5 min prior to HLE challenge, effectively inhibited hemorrhage in a dose-dependent manner with an ED50 of 4.8-mu-g. The inhibitor 20i, 20-mu-g administered it. 24, 48, and 72 h prior to HLE challenge, exhibits significant inhibition against hemorrhage at all time points (97%, 64% and 49%, respectively). In a 21-day chronic model of emphysema in hamsters, 200-mu-g of HLE administered it. caused an elastase-induced emphysema in the lungs which can be quantitated histologically utilizing image analysis. In this assay, 20i significantly inhibited pulmonary lesions associated with septal destruction and increased alveolar spaces, when dosed at 20-mu-g it. 5 min prior to challenge with HLE.

  DOI：

  10.1021/jm00082a005

文献信息

• 1-alkyl-2-hydroxy-2-trifluoromethyl ethylamines
  申请人：Zeneca Inc.

  公开号：US05414132A1

  公开（公告）日：1995-05-09

  The invention concerns pharmaceutically useful trifluoromethyl ketone substituted di-, tri- and tetra-peptide derivatives of the formulae Ia, Ib, Ic set out hereinafter, and salts thereof, which are inhibitors of human leukocyte elastase. Also described herein are pharmaceutical compositions containing a peptide derivative and processes and intermediates for use in the manufacture of the peptide derivatives.

  本发明涉及以下公式Ia、Ib、Ic所示的具有药用三氟甲基酮取代的二肽、三肽和四肽衍生物及其盐，它们是人类白细胞弹性蛋白酶的抑制剂。本文还描述了含有肽衍生物的药物组合物，以及用于制造肽衍生物的过程和中间体。
• Aminoalcohol intermediates for peptide derivatives
  申请人：ICI Americas Inc.

  公开号：US05194588A1

  公开（公告）日：1993-03-16

  The invention concerns pharmaceutically useful trifluoromethyl ketone substituted di-, tri- and tetra-peptide derivatives of the formulae Ia, Ib, Ic set out hereinafter, and salts thereof, which are inhibitors of human leukocyte elastase. Also described herein are pharmaceutical compositions containing a peptide derivative and processes and intermediates for use in the manufacture of the peptide derivatives.

  本发明涉及一些药用三氟甲基酮取代的二肽、三肽和四肽衍生物，其化学式如下：Ia、Ib、Ic，并且包括它们的盐，这些衍生物是人类白细胞弹性蛋白酶的抑制剂。本文还描述了含有肽衍生物的药物组合物，以及用于制造肽衍生物的过程和中间体。
• Fluoro-amide derivatives
  申请人：ICI Americas Inc.

  公开号：US05270301A1

  公开（公告）日：1993-12-14

  The present invention relates to certain fluoro-amide derivatives, as described herein, which are human leukocyte elastase (HLE) inhibitors 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, including treatment of tissue degenerative diseases such as pulmonary emphysema. The invention also includes intermediates useful in the synthesis of these fluoro-amide derivatives, processes for preparing them, pharmaceutical compositions containing such peptide derivatives and methods for their use.

  本发明涉及某些氟酰胺衍生物，如所述，它们是人类白细胞弹性蛋白酶（HLE）抑制剂，使它们在需要该抑制剂的情况下有用，例如用作药理学、诊断和相关研究的研究工具，并用于治疗哺乳动物中存在HLE的疾病，包括治疗组织退行性疾病，如肺气肿。本发明还包括在合成这些氟酰胺衍生物过程中有用的中间体、制备它们的方法、包含这种肽衍生物的制药组合物以及它们的使用方法。
• Selected difluoro derivatives
  申请人：ICI Americas Inc.

  公开号：US04880780A1

  公开（公告）日：1989-11-14

  The invention discloses a series of difluoroketone, mono- di- and tri-peptide derivatives of formula Ia, Ib and Ic: ______________________________________ (Formula set out on pages following Examples) Ia (Formula set out on pages following Examples) Ib (Formula set out on pages following Examples) Ic ______________________________________ PAL and salts thereof where appropriate, and wherein the radicals are defined hereafter in the specification. The derivatives are useful in inhibiting the action of human leukocyte elastase. There are also disclosed methods and intermediates for the manufacture of, and pharmaceutical compositions comprising, the said derivatives.

  本发明揭示了一系列二氟酮，单肽，二肽和三肽衍生物，其化学式为Ia，Ib和Ic：______________________________________（公式在示例后的页面上）其中适当的还原剂为PAL及其盐，其中基团在本规范中定义。这些衍生物有用于抑制人类白细胞弹性蛋白酶作用的作用。还揭示了制造，中间体和制备所述衍生物的制药组合物的方法。
• Peptidic human leukocyte elastase (HLE) inhibitors
  申请人：ZENECA INC.

  公开号：EP0291234A2

  公开（公告）日：1988-11-17

  The invention provides a series of novel heterocyclic ketones of formula I (set out hereinafter) and pharmaceutically acceptable base-addition salts thereof, in which the values of R4, L, A, X and Q have the meanings defined in the following specification. The compounds of formula I are inhibitors of human leukocytic elastase. The invention also provides pharmaceutical compositions containing a compound of formula I, or a pharmaceutically acceptable base-addition salt thereof, and processes and intermediates for the manufacture of compounds of formula I.

  本发明提供了一系列新颖的式 I 杂环酮类化合物（如下所述）及其药学上可接受的碱加成盐，其中 R4、L、A、X 和 Q 的值具有以下说明书中定义的含义。式 I 的化合物是人白细胞弹性蛋白酶的抑制剂。本发明还提供了含有式 I 化合物或其药学上可接受的碱加成盐的药物组合物，以及制造式 I 化合物的工艺和中间体。