N-(4-methoxyphenyl)-N-(1,1,1-trifluoro-2-propyl)-4-methoxybenzamide | 117730-47-9

• 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: N-(4-methoxyphenyl)-N-(1,1,1-trifluoro-2-propyl)-4-methoxybenzamide
• 英文别名: N-(4-Methoxyphenyl)-N-(1,1,1-trifluor-2-propyl)-4-methoxybenzamid；4-methoxy-N-(4-methoxyphenyl)-N-(1,1,1-trifluoropropan-2-yl)benzamide
• CAS: 117730-47-9
• 化学式: C₁₈H₁₈F₃NO₃
• 分子量: 353.341
• InChiKey: RWYXXQZPQNACJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  25.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  38.77
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  N-(4-methoxyphenyl)-N-(1,1,1-trifluoro-2-propyl)-4-methoxybenzamide 在 劳森试剂 、 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 8.0h， 生成 4-hydroxy-N-(4-hydroxyphenyl)-N-(1,1,1-trifluoropropan-2-yl)benzenecarbothioamide
  参考文献：
  名称：

  Acyclic amides as estrogen receptor ligands: Synthesis, binding, activity and receptor interaction

  摘要：

  We have prepared a series of bisphenolic amides that mimic bibenzyl and homobibenzyl motifs commonly found as substructures in ligands for the estrogen receptor (ER). Representative members were prepared from three classes: N-phenyl benzamides, N-phenyl acetamides, and N-benzyl benzamides; in some cases the corresponding thiocarboxamides and sulfonamides were also prepared. Of these three classes, the N-phenyl benzamides had the highest affinity for ER, the N-phenyl acetamides had lower, and the N-benzyl benzamides were prone to fragmentation via a quinone methide intermediate. In the N-phenyl benzamide series, the highest affinity analogues had bulky N-substituents; a CF3 group, in particular, conferred high affinity. The thiocarboxamides bound better than the corresponding carboxamides and these bound better than the corresponding sulfonamides. Binding affinity comparisons suggest that the p-hydroxy group on the benzoate ring, which contributes most to the binding, is playing the role of the phenolic hydroxyl of estradiol. Computational studies and NMR and X-ray crystallographic analysis indicate that the two anilide systems studied have a strong preference for the s-cis or exo amide conformation, which places the two aromatic rings in a syn orientation. We used this structural template. together with the X-ray structure of the ER ligand binding domain, to elaborate an additional hydrogen bonding site on a benzamide system that elevated receptor binding further. When assayed on the individual ER subtypes, ER alpha and ER beta, these compounds show modest binding affinity preference for ER alpha. In a reporter gene transfection assay of transcriptional activity, the amides generally have full to nearly full agonist character on ERa, but have moderate to full antagonist character on ER beta. One high affinity carboxamide is 500-fold more potent as an agonist on ER alpha than on ER beta. This work illustrates that ER ligands having simple amide core structures can be readily prepared, but that high affinity binding requires an appropriate distribution of bulk, polarity, and functionality. The strong conformational preference of the core anilide function in all of these ligands defines a rather rigid geometry for further structural and functional expansion of these series. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00075-4
• 作为产物：
  描述：

  甲氧苯胺 在 吡啶 、 lithium aluminium tetrahydride 、 硫酸 、 potassium carbonate 作用下， 以 乙醚 、 甲苯 、 苯 为溶剂， 反应 16.0h， 生成 N-(4-methoxyphenyl)-N-(1,1,1-trifluoro-2-propyl)-4-methoxybenzamide
  参考文献：
  名称：

  Acyclic amides as estrogen receptor ligands: Synthesis, binding, activity and receptor interaction

  摘要：

  We have prepared a series of bisphenolic amides that mimic bibenzyl and homobibenzyl motifs commonly found as substructures in ligands for the estrogen receptor (ER). Representative members were prepared from three classes: N-phenyl benzamides, N-phenyl acetamides, and N-benzyl benzamides; in some cases the corresponding thiocarboxamides and sulfonamides were also prepared. Of these three classes, the N-phenyl benzamides had the highest affinity for ER, the N-phenyl acetamides had lower, and the N-benzyl benzamides were prone to fragmentation via a quinone methide intermediate. In the N-phenyl benzamide series, the highest affinity analogues had bulky N-substituents; a CF3 group, in particular, conferred high affinity. The thiocarboxamides bound better than the corresponding carboxamides and these bound better than the corresponding sulfonamides. Binding affinity comparisons suggest that the p-hydroxy group on the benzoate ring, which contributes most to the binding, is playing the role of the phenolic hydroxyl of estradiol. Computational studies and NMR and X-ray crystallographic analysis indicate that the two anilide systems studied have a strong preference for the s-cis or exo amide conformation, which places the two aromatic rings in a syn orientation. We used this structural template. together with the X-ray structure of the ER ligand binding domain, to elaborate an additional hydrogen bonding site on a benzamide system that elevated receptor binding further. When assayed on the individual ER subtypes, ER alpha and ER beta, these compounds show modest binding affinity preference for ER alpha. In a reporter gene transfection assay of transcriptional activity, the amides generally have full to nearly full agonist character on ERa, but have moderate to full antagonist character on ER beta. One high affinity carboxamide is 500-fold more potent as an agonist on ER alpha than on ER beta. This work illustrates that ER ligands having simple amide core structures can be readily prepared, but that high affinity binding requires an appropriate distribution of bulk, polarity, and functionality. The strong conformational preference of the core anilide function in all of these ligands defines a rather rigid geometry for further structural and functional expansion of these series. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00075-4

文献信息

• N-(4-Hydroxyphenyl)-N-(1,1,1-trifluor-2-propyl)-4-hydroxybenzamid: Synthese und pharmakologische Bewertung eines neues Antiestrogens
  作者：Rolf W. Hartmann、Hans-Dieter Vom Orde、Alexander Heindl、Helmut Schönenberger

  DOI：10.1002/ardp.19883210814

  日期：——

  Die Synthese von N‐(4‐Hydroxyphenyl)‐N‐(1,1,1‐trifluor‐2‐propyl)‐4‐hydroxybenzamid (1) wird beschrieben. Die Verbindung zeigt eine relative Bindungsaffinität zum Estrogenrezeptor (ER) von 2.4. Im Uterusgewichtstest an der juvenilen NMRI‐Maus erweist sich 1 als starkes Antiestrogen. Schwache estrogene Nebenwirkungen werden nur in hohen Dosen festgestellt. Weder am hormonabhängigen, transplantablen MXT‐Mammatumor

  描述了 N-(4-羟基苯基)-N-(1,1,1-三氟-2-丙基)-4-羟基苯甲酰胺 (1) 的合成。该化合物对雌激素受体 (ER) 的相对结合亲和力为 2.4。在对幼年 NMRI 小鼠进行的子宫重量测试中，1 证明是一种强抗雌激素。弱雌激素副作用仅在高剂量下才会出现。BD2F1 小鼠的激素依赖性、可移植 MXT 乳腺肿瘤和激素依赖性 9,10-二甲基-1,2-苯并蒽 (DMBA) 诱导的 SD 大鼠乳腺癌均未显示出显着的抗肿瘤作用。
• HARTMANN, ROLF W.;ORDE, HANS-DIETER VOM;HEINDL, ALEXANDER;SCHONENBERGER, +, ARCH. PHARM., 321,(1988) N 8, C. 497-501
  作者：HARTMANN, ROLF W.、ORDE, HANS-DIETER VOM、HEINDL, ALEXANDER、SCHONENBERGER, +

  DOI：——

  日期：——