tert-butyl (1R)-2-{4-[(acetylamino)methyl]anilino}-1-methylethyl-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]carbamate | 402508-93-4

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: tert-butyl (1R)-2-{4-[(acetylamino)methyl]anilino}-1-methylethyl-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]carbamate
• 英文别名: tert-butyl N-[(2R)-1-[4-(acetamidomethyl)anilino]propan-2-yl]-N-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(3-chlorophenyl)ethyl]carbamate
• CAS: 402508-93-4
• 化学式: C₃₁H₄₈ClN₃O₄Si
• 分子量: 590.278
• InChiKey: UELFQEJLOUMTJL-DFHRPNOPSA-N

物化性质

• 沸点：
  679.2±55.0 °C(Predicted)
• 密度：
  1.096±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.78
• 重原子数：
  40
• 可旋转键数：
  14
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  79.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl (1R)-2-{4-[(acetylamino)methyl]anilino}-1-methylethyl-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]carbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.0h， 生成 N-[[4-[[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]amino]phenyl]methyl]acetamide
  参考文献：
  名称：

  Synthesis and Evaluation of Potent and Selective β₃ Adrenergic Receptor Agonists Containing Acylsulfonamide, Sulfonylsulfonamide, and Sulfonylurea Carboxylic Acid Isosteres

  摘要：

  Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3) beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.

  DOI：

  10.1021/jm0101500
• 作为产物：
  描述：

  (R)-(-)-methyl 2-(3-chlorophenyl)-2-hydroxyacetate 在 咪唑 、 三乙酰氧基硼氢化钠 、 二异丁基氢化铝 、 溶剂黄146 作用下， 以 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 11.75h， 生成 tert-butyl (1R)-2-{4-[(acetylamino)methyl]anilino}-1-methylethyl-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]carbamate
  参考文献：
  名称：

  Synthesis and Evaluation of Potent and Selective β₃ Adrenergic Receptor Agonists Containing Acylsulfonamide, Sulfonylsulfonamide, and Sulfonylurea Carboxylic Acid Isosteres

  摘要：

  Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3) beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.

  DOI：

  10.1021/jm0101500

文献信息

• Synthesis and Evaluation of Potent and Selective β₃ Adrenergic Receptor Agonists Containing Acylsulfonamide, Sulfonylsulfonamide, and Sulfonylurea Carboxylic Acid Isosteres
  作者：David E. Uehling、Kelly H. Donaldson、David N. Deaton、Clifton E. Hyman、Elizabeth E. Sugg、David G. Barrett、Robert G. Hughes、Barbara Reitter、Kim K. Adkison、Mary E. Lancaster、Frank Lee、Robert Hart、Mark A. Paulik、Bryan W. Sherman、Timothy True、Conrad Cowan

  DOI：10.1021/jm0101500

  日期：2002.1.1

  Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3) beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.