2-[(3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)-amino]-3-methoxy-1-piperidyl]thiazole-5-carboxylic acid

• 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-[(3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)-amino]-3-methoxy-1-piperidyl]thiazole-5-carboxylic acid
• 英文别名: 2-((3S,4R)-4-([(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino)-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid；2-[(3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylic acid
• 化学式: C₁₆H₁₈Cl₂N₄O₄S
• 分子量: 433.315
• InChiKey: VJLIVOQJQIHFHR-BDAKNGLRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  136
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-[(3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)-amino]-3-methoxy-1-piperidyl]thiazole-5-carboxylic acid 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以47%的产率得到2-[(3S,4R)-4-[(3,4-Dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-3-hydroxy-1-piperidyl]thiazole-5-carboxylic acid
  参考文献：
  名称：

  Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)

  摘要：

  AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

  DOI：

  10.1021/jm500462x
• 作为产物：
  描述：

  ethyl (-)-cis-4-amino-3-methoxy-1-piperidinecarboxylate 在 N-甲基吗啉 、 碘代三甲硅烷 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 3.83h， 生成 2-[(3S,4R)-4-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)-amino]-3-methoxy-1-piperidyl]thiazole-5-carboxylic acid
  参考文献：
  名称：

  Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)

  摘要：

  AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

  DOI：

  10.1021/jm500462x

文献信息

• [EN] ANTIBACTERIAL PIPERIDINE DERIVATIVES<br/>[FR] COMPOSÉS ANTIBACTÉRIENS DÉRIVÉS DE PIPÉRIDINE
  申请人：ASTRAZENECA AB

  公开号：WO2006087543A1

  公开（公告）日：2006-08-24

  (EN) Compounds of formula (I) and their pharmaceutically acceptable salts are described: Formula (I). Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.(FR) La présente invention décrit des composés de formule (I) ainsi que leurs sels de qualité pharmaceutique : Formule (I). La présente invention décrit en outre des procédés de synthèse desdits composés, des préparations pharmaceutiques les contenant, leur emploi en tant que médicaments et leur emploi dans le traitement d'infections bactériennes.

  公式（I）的化合物及其药用盐被描述：公式（I）。还描述了它们的制备方法、含有它们的药物组成物、作为药物的用途以及在治疗细菌感染中的用途。
• ANTIBACTERIAL PIPERDINE DERIVATIVES
  申请人：Basarab Gregory

  公开号：US20100179150A1

  公开（公告）日：2010-07-15

  Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.

  描述了化学式（I）的化合物及其药学上可接受的盐。描述了制备它们的过程，含有它们的药物组合物，它们作为药物的用途以及它们在治疗细菌感染中的用途。
• CHEMICAL COMPOUNDS
  申请人：AstraZeneca, Intellectual Property

  公开号：US20130150366A1

  公开（公告）日：2013-06-13

  Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use in the treatment of bacterial infections are also described.

  本文描述了化学式(I)的化合物及其药学上可接受的盐。还描述了制备它们的过程、含有它们的制药组合物，以及它们在治疗细菌感染方面的用途。
• ANTIBACTERIAL PIPERIDINE DERIVATIVES
  申请人：AstraZeneca AB

  公开号：EP1853586A1

  公开（公告）日：2007-11-14
• US8399489B2
  申请人：——

  公开号：US8399489B2

  公开（公告）日：2013-03-19