(S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide | 105108-62-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide
• 英文别名: (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro 1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide；(2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)pyrrolidine-2-carboxamide
• CAS: 105108-62-1
• 化学式: C₂₄H₃₄F₃N₃O₅
• 分子量: 501.546
• InChiKey: MUOJCULIFHYGLN-IQNGYNMSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide 在 二氯乙酸 、 二甲基亚砜 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲苯 为溶剂， 反应 18.0h， 以87%的产率得到(S)-1-[(S)-2-(4-Methoxy-benzoylamino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid (3,3,3-trifluoro-1-isopropyl-2-oxo-propyl)-amide
  参考文献：
  名称：

  Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase

  摘要：

  Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protectin against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 mu g/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.

  DOI：

  10.1021/jm960819g
• 作为产物：
  描述：

  对甲氧基苯甲酰氯 、 (S)-1-((S)-2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-1-isopropyl-propyl)-amide 在 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以87%的产率得到(S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoro-1-hydroxyethyl)propyl]pyrrolidine-2-carboxamide
  参考文献：
  名称：

  Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase

  摘要：

  Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protectin against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 mu g/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.

  DOI：

  10.1021/jm960819g

文献信息

• [EN] DIASTEREOMERIC PURE TRIFLUOROMETHYL KETONE PEPTIDE DERIVATIVES AS INHIBITORS OF HUMAN LEUKOCYTE ELASTASE<br/>[FR] DERIVES DIASTEREOMERES PURS DE PEPTIDES DE CETONES TRIFLUOROMETHYLIQUES INHIBITEURS DE L'ELASTASE LEUCOCYTAIRE HUMAINE
  申请人：ZENECA LIMITED

  公开号：WO1995021855A1

  公开（公告）日：1995-08-17

  (EN) The present invention relates to crystalline forms of the compound (S)-1-[(S)-2-(4-methoxybenzamido)-3-methylbutyryl]-N-[(S)-2-methyl-1-(trifluoroacetyl)propyl]pyrrolidine-2-carboxamide (I) and crystalline solvates thereof 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 phrmaceutical compositions containing the crystalline forms and solvates, processes for preparing the crystalline forms and solvates and intermediates useful in the synthesis of the crystalline forms and solvates.(FR) L'invention porte sur des formes cristallines du composé [(S)-1-[(S)-2-(4-méthoxybenzamido)-3-méthylbutyryl]-N-[(S)-2-méthyl-1-(trifluoroacétyl)propyl]pyrrolidine-2-carboxamide] et ses solvates cristallins inhibiteurs de l'élastase leucocytaire humaine (HLE), également dite élastase neutrophile humaine (HNE), utiles chaque fois qu'une telle inhibition est requise, par exemple comme outils de recherche en matière de pharmacologie, de diagnostic ou d'études associées et dans le traitement d'affections de mammifères où l'HLE intervient. L'invention porte également sur des compositions pharmaceutiques en contenant les formes cristallines et les solvates, leurs procédés de préparation, et sur les intermédiaires de synthèse de formes cristallines et de solvates.

  本发明涉及化合物(S)-1-[(S)-2-(4-甲氧基苯甲酰胺)-3-甲基丁酰基]-N-[(S)-2-甲基-1-(三氟乙酰基)丙基]吡咯烷-2-羧酰胺(I)的晶体形式及其晶体溶剂化物，它们是人类白细胞弹性蛋白酶(HLE)，也称为人类中性粒细胞弹性蛋白酶(HNE)的抑制剂，因此在需要这种抑制剂的情况下，如在药理学、诊断学和相关研究中的研究工具以及治疗哺乳动物患有HLE相关疾病中都非常有用。本发明还包括含有晶体形式和晶体溶剂化物的药物组合物，制备晶体形式和晶体溶剂化物的方法以及在合成晶体形式和晶体溶剂化物中有用的中间体。
• Diastereomeric pure trifluoromethyl ketone peptide derivatives as
  申请人：Zeneca Limited

  公开号：US05739157A1

  公开（公告）日：1998-04-14

  The present invention relates to pyrrolidine derivatives, and more particularly to the compound (S)-1-\x9b(S)-2-(4-methoxybenzamido)-3-methylbutyryl!-N-\x9b(S)-2-methyl-1-(trif luoroacetyl)propyl!pyrrolidine-2-carboxamide, shown by formula I, and solvates thereof. The present invention also provides pharmaceutical compositions, intermediates and methods of preparation of the compound. The compound of formula I is an inhibitor of human neutrophil elastase and is useful in the treatment of diseases in which the enzyme is implicated, such as, for example, emphysema and acute respiratory distress syndrome (ARDS).

  本发明涉及吡咯烷衍生物，更具体地涉及化合物(S)-1-\x9b(S)-2-(4-甲氧基苯甲酰胺)-3-甲基丁酰基!-N-\x9b(S)-2-甲基-1-(三氟乙酰基)丙基!吡咯烷-2-羧酰胺（化学式I），以及其溶剂化物。本发明还提供了该化合物的药物组合物、中间体和制备方法。化合物I是人类中性粒细胞弹性蛋白酶的抑制剂，对于该酶参与的疾病的治疗非常有用，例如肺气肿和急性呼吸窘迫综合征（ARDS）。
• US06037363
  申请人：——

  公开号：——

  公开（公告）日：——
• DIASTEREOMERIC PURE TRIFLUOROMETHYL KETONE PEPTIDE DERIVATIVES AS INHIBITORS OF HUMAN LEUKOCYTE ELASTASE
  申请人：ZENECA LIMITED

  公开号：EP0743953A1

  公开（公告）日：1996-11-27
• US6037363A
  申请人：——

  公开号：US6037363A

  公开（公告）日：2000-03-14