ethyl 1-(5-chloro-2-methoxybenzyl)-3-(4-methyl-2-pivalamidothiazol-5-yl)-1H-pyrazole-5-carboxylate | 1402464-42-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 1-(5-chloro-2-methoxybenzyl)-3-(4-methyl-2-pivalamidothiazol-5-yl)-1H-pyrazole-5-carboxylate
• 英文别名: Ethyl 2-[(5-chloro-2-methoxyphenyl)methyl]-5-[2-(2,2-dimethylpropanoylamino)-4-methyl-1,3-thiazol-5-yl]pyrazole-3-carboxylate
• CAS: 1402464-42-9
• 化学式: C₂₃H₂₇ClN₄O₄S
• 分子量: 491.011
• InChiKey: KWQTVJDRDDUOTR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 1-(5-chloro-2-methoxybenzyl)-3-(4-methyl-2-pivalamidothiazol-5-yl)-1H-pyrazole-5-carboxylate 、 C.I.酸性橙108 以 乙醇 为溶剂， 反应 0.5h， 以33%的产率得到2-[(5-chloro-2-methoxyphenyl)methyl]-5-[2-(2,2-dimethylpropanoylamino)-4-methyl-1,3-thiazol-5-yl]-N-(2-hydroxyethyl)pyrazole-3-carboxamide
  参考文献：
  名称：

  Pyrazolylthiazole as ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Correctors with Improved Hydrophilicity Compared to Bithiazoles

  摘要：

  Deletion of phenylalanine residue 508 (Delta F508) in the cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR) is a major cause of CF. Small molecule "correctors" of defective A Delta 508-CFTR cellular processing hold promise for CF therapy. We previously identified and characterized bithiazole CF corrector 1 and s-cis-locked bithiazole 2. Herein, we report the regiodivergent synthesis of N gamma and N beta isomers of thiazole-tethered pyrazoles with improved hydrophilicity compared to bithiazoles. We synthesized a focused library of 54 pyrazolylthiazoles 3, which included examples of both regioisomers 4 and 5. The thiazole-tethered pyrazoles allowed incorporation of property-modulating functionality on the pyrazole ring (ester, acid, and amide) while retaining Delta F508-CFTR corrector activity (EC50) of under 1 mu M. The most active pyrazolylthiazole (14h) has an experimentally determined log P of 4.1, which is 1.2 log units lower than bithiazole CF corrector 1.

  DOI：

  10.1021/jm100235h
• 作为产物：
  描述：

  ethyl 3-(4-methyl-2-pivalamidothiazol-5-yl)-1H-pyrazole-5-carboxylate 、 2-(溴甲基)-4-氯-1-甲氧基苯 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 24.0h， 以0.37 g的产率得到ethyl 1-(5-chloro-2-methoxybenzyl)-3-(4-methyl-2-pivalamidothiazol-5-yl)-1H-pyrazole-5-carboxylate
  参考文献：
  名称：

  Pyrazolylthiazole as ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Correctors with Improved Hydrophilicity Compared to Bithiazoles

  摘要：

  Deletion of phenylalanine residue 508 (Delta F508) in the cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR) is a major cause of CF. Small molecule "correctors" of defective A Delta 508-CFTR cellular processing hold promise for CF therapy. We previously identified and characterized bithiazole CF corrector 1 and s-cis-locked bithiazole 2. Herein, we report the regiodivergent synthesis of N gamma and N beta isomers of thiazole-tethered pyrazoles with improved hydrophilicity compared to bithiazoles. We synthesized a focused library of 54 pyrazolylthiazoles 3, which included examples of both regioisomers 4 and 5. The thiazole-tethered pyrazoles allowed incorporation of property-modulating functionality on the pyrazole ring (ester, acid, and amide) while retaining Delta F508-CFTR corrector activity (EC50) of under 1 mu M. The most active pyrazolylthiazole (14h) has an experimentally determined log P of 4.1, which is 1.2 log units lower than bithiazole CF corrector 1.

  DOI：

  10.1021/jm100235h