methyl 11-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1,5-dioxa-8-azaspiro[5.5]undecane-8-carboxylate | 1007595-41-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: methyl 11-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1,5-dioxa-8-azaspiro[5.5]undecane-8-carboxylate
• 英文别名: methyl 11-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1,5-dioxa-8-azaspiro[4.5]undecane-8-carboxylate
• CAS: 1007595-41-6
• 化学式: C₁₆H₂₁Cl₂N₃O₅
• 分子量: 406.266
• InChiKey: UIXLNUJSXUQEAE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.33
• 重原子数：
  26.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  92.89
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  methyl 11-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1,5-dioxa-8-azaspiro[5.5]undecane-8-carboxylate 在 N,N-二异丙基乙胺 、 barium(II) hydroxide 作用下， 以 N-甲基吡咯烷酮 、 乙醇 、 水 为溶剂， 反应 2.0h， 生成 methyl 2-[11-[(3,4-dichloro-5-methyl-1H-pyrrole-2-carbonyl)amino]-1,5-dioxa-8-azaspiro[5.5]undecan-8-yl]thiazole-5-carboxylate
  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：

  11-ethyl 8-methyl 1,5-dioxa-8-azaspiro[5.5]undecane-8,11-dicarboxylate 在 N-甲基吗啉 、 sodium azide 、 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 barium(II) hydroxide 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 、 丙酮 、 甲苯 为溶剂， 反应 78.5h， 生成 methyl 11-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1,5-dioxa-8-azaspiro[5.5]undecane-8-carboxylate
  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