1-isopropyl-3-methyl-2,4-dioxo-6-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid | 925688-15-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-isopropyl-3-methyl-2,4-dioxo-6-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
• 英文别名: 3-Methyl-2,4-dioxo-1-propan-2-yl-6-[[2-(trifluoromethyl)phenyl]methyl]thieno[2,3-d]pyrimidine-5-carboxylic acid
• CAS: 925688-15-9
• 化学式: C₁₉H₁₇F₃N₂O₄S
• 分子量: 426.416
• InChiKey: YFMLPKMJMIQICS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-isopropyl-3-methyl-2,4-dioxo-6-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid 在 草酰氯 、 sodium carbonate 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 3.5h， 生成 N,N,3-trimethyl-2,4-dioxo-1-(propan-2-yl)-6-{[2-(trifluoromethyl)phenyl]methyl}-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-5-carboxamide
  参考文献：
  名称：

  Optimization of Monocarboxylate Transporter 1 Blockers through Analysis and Modulation of Atropisomer Interconversion Properties

  摘要：

  We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.

  DOI：

  10.1021/jm060995h
• 作为产物：
  描述：

  6-氯-3-甲基尿嘧啶 在 三乙基硅烷 、 sodium hydroxide 、 三氟乙酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 为溶剂， 反应 3.0h， 生成 1-isopropyl-3-methyl-2,4-dioxo-6-[2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylic acid
  参考文献：
  名称：

  Optimization of Monocarboxylate Transporter 1 Blockers through Analysis and Modulation of Atropisomer Interconversion Properties

  摘要：

  We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.

  DOI：

  10.1021/jm060995h

文献信息

• Optimization of Monocarboxylate Transporter 1 Blockers through Analysis and Modulation of Atropisomer Interconversion Properties
  作者：Simon D. Guile、John R. Bantick、Martin E. Cooper、David K. Donald、Christine Eyssade、Anthony H. Ingall、Richard J. Lewis、Barrie P. Martin、Rukhsana T. Mohammed、Timothy J. Potter、Rachel H. Reynolds、Stephen A. St-Gallay、Andrew D. Wright

  DOI：10.1021/jm060995h

  日期：2007.1.1

  We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.