2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid methyl ester | 221323-67-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid methyl ester
• 英文别名: methyl 2-(pyrrolidin-1-ylmethyl)-1,3-oxazole-4-carboxylate
• CAS: 221323-67-7
• 化学式: C₁₀H₁₄N₂O₃
• 分子量: 210.233
• InChiKey: HPRCDTCZLUPVTP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  15
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  55.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid methyl ester 在 sodium hydroxide 、 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 6.5h， 生成 2-Pyrrolidin-1-ylmethyl-oxazole-4-carbonyl chloride
  参考文献：
  名称：

  Discovery of Further Pyrrolidine trans-Lactams as Inhibitors of Human Neutrophil Elastase (HNE) with Potential as Development Candidates and the Crystal Structure of HNE Complexed with an Inhibitor (GW475151)

  摘要：

  Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with I while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.

  DOI：

  10.1021/jm020881f
• 作为产物：
  描述：

  2-甲基恶唑-4-甲酸甲酯 在 N-溴代丁二酰亚胺(NBS) 、 potassium carbonate 、 过氧化苯甲酰 作用下， 以 四氯化碳 、 乙腈 为溶剂， 反应 1.5h， 生成 2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid methyl ester
  参考文献：
  名称：

  Discovery of Further Pyrrolidine trans-Lactams as Inhibitors of Human Neutrophil Elastase (HNE) with Potential as Development Candidates and the Crystal Structure of HNE Complexed with an Inhibitor (GW475151)

  摘要：

  Described herein is a modern approach to the rapid preparation and evaluation of compounds as potential back-up drug candidates. GW311616A, 1, a derivative of pyrrolidine trans-lactams, has previously been described as a potent, orally active inhibitor of human neutrophil elastase (HNE) for the treatment of respiratory disease. These properties made it a suitable candidate for development. Described here is the discovery of three further derivatives of pyrrolidine trans-lactams, which fulfill the criteria required for back-up candidates 28, 29, and 32. These include increased activity in inhibiting HNE in human whole blood (HWB) and comparable pharmacokinetic properties, in particular clearance, in two species. To provide a rapid assessment of clearance, cassette dosing in dog was used. Modern array techniques, including the synthesis of mixtures, were used to synthesize compounds rapidly. Having selected three potential compounds as back-up candidates, they were prepared as single enantiomers and profiled in in vitro and in vivo assays and evaluated pharmacokinetically in rat and dog. These compounds are highly potent and selective HNE inhibitors, with a prolonged pharmacodynamic action. Pharmacokinetically, these compounds are comparable with I while they are more potent in HWB. Compound 28, however, has a higher clearance. One of these compounds, 32, was cocrystallized with HNE, and features of this structure are described and compared with the cocrystal structure of 1 in porcine pancreatic elastase.

  DOI：

  10.1021/jm020881f

文献信息

• [EN] PROCESS FOR PREPARING OXAZOLE DERIVATIVES<br/>[FR] PROCEDE DE PREPARATION DE DERIVES D'OXAZOLE
  申请人：GLAXO GROUP LTD

  公开号：WO2000053589A1

  公开（公告）日：2000-09-14

  A process for the preparation of a compound of formula (I) or a salt thereof or a carboxylic acid ester derivative thereof, wherein L represents a leaving group, which comprises (a) treating a compound of formula (II) wherein R represents COOH or a salt thereof or a derivative thereof and L and L1 represent leaving groups with a base such that L1 is eliminated and the oxazole ring is formed; and (b) if necessary converting the R moiety to COOH or a salt thereof or a carboxylic acid ester derivative thereof. A further aspect of this invention is the preparation of the potassium salt of a pyrrolidinyl derivative of compound of formula (I) and coupling of the said salt to an amine.

  一种制备式（I）化合物或其盐或羧酸酯衍生物的过程，其中L代表离去基团，包括（a）用碱处理式（II）化合物，其中R代表COOH或其盐或衍生物，L和L1代表离去基团，使L1被消除并形成噁唑环；以及（b）必要时将R基团转化为COOH或其盐或羧酸酯衍生物。本发明的另一方面是制备式（I）化合物的吡咯烷基衍生物的钾盐，并将该盐与胺偶联。
• PYRROLOPYRROLONE DERIVATIVES AS INHIBITORS OF NEUTROPHIL ELASTASE
  申请人：GLAXO GROUP LIMITED

  公开号：EP1003748A2

  公开（公告）日：2000-05-31
• [EN] PYRROLOPYRROLONE DERIVATIVES AS INHIBITORS OF NEUTROPHIL ELASTASE<br/>[FR] DERIVES DE PYRROLOPYRROLONE EN TANT QU'INHIBITEURS DE NEUTROPHILE ELASTASE
  申请人：——

  公开号：WO1999012933A2

  公开（公告）日：1999-03-18

  [EN] There are provided according to the invention compounds of formula (I) wherein R<1>, R<2> and R<3> are as defined in the specification. Compounds of formula (I) are useful, inter alia, in the treatment of inflammatory disorders of the respiratory tract.
  [FR] L'invention concerne des composés représentés par la formule (I) dans laquelle R<1>, R<2> et R<3> sont tels qu'ils sont définis dans le descriptif. Ces composés sont utiles notamment pour traiter des maladies inflammatoires des voies respiratoires.