2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid | 292616-27-4

• 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
• 英文别名: 2-(pyrrolidin-1-ylmethyl)-1,3-oxazole-4-carboxylic acid
• CAS: 292616-27-4
• 化学式: C₉H₁₂N₂O₃
• 分子量: 196.206
• InChiKey: IVSFBKFNMKSNJO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  66.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid 在 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 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 sodium hydroxide 、 N-溴代丁二酰亚胺(NBS) 、 potassium carbonate 、 过氧化苯甲酰 作用下， 以 1,4-二氧六环 、 四氯化碳 、 水 、 乙腈 为溶剂， 反应 6.5h， 生成 2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid
  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

• (Indazol-4-YL) Hexahydropyrrolopyrrolones and Methods of Use
  申请人：AbbVie Inc.

  公开号：US20160264582A1

  公开（公告）日：2016-09-15

  Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein G Ar , L 1 , Z 1 and Z 2 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by voltage-gated sodium channels, e.g., Na v 1.7 and/or Na v 1.8. Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

  式（I）的化合物及其药用可接受的盐、酯、酰胺或放射标记形式，其中G、Ar、L1、Z1和Z2如规范中所定义，可用于治疗由电压门控钠通道如Na v 1.7和/或Na v 1.8预防或改善的病症或紊乱。公开了制备这些化合物的方法。还公开了式（I）化合物的药物组合物，以及使用这些化合物和组合物的方法。
• [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。
• (INDAZOL-4-YL)HEXAHYDROPYRROLOPYRROLONES AND METHOD OF USE
  申请人：AbbVie Inc.

  公开号：EP3268366A1

  公开（公告）日：2018-01-17
• US9682985B2
  申请人：——

  公开号：US9682985B2

  公开（公告）日：2017-06-20
• [EN] (INDAZOL-4-YL)HEXAHYDROPYRROLOPYRROLONES AND METHOD OF USE<br/>[FR] (INDAZOL-4-YL)HEXAHYDROPYRROLOPYRROLONES ET LEUR MÉTHODE D'UTILISATION
  申请人：ABBVIE INC

  公开号：WO2016149169A1

  公开（公告）日：2016-09-22

  Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein GAr, L1, Z1and Z2are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by voltage-gated sodium channels, e.g., Nayl.7 and/or Nayl.8. Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions for the treatment of pain.