(3R,4R)-4-[4-(2-fluoro-3-methoxy-6-methoxymethoxybenzoyl)benzyloxy]-3-[(pyridine-4-carbonyl)amino]azepane-1-carboxylic acid tert-butyl ester | 677323-89-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (3R,4R)-4-[4-(2-fluoro-3-methoxy-6-methoxymethoxybenzoyl)benzyloxy]-3-[(pyridine-4-carbonyl)amino]azepane-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (3R,4R)-4-[[4-[2-fluoro-3-methoxy-6-(methoxymethoxy)benzoyl]phenyl]methoxy]-3-(pyridine-4-carbonylamino)azepane-1-carboxylate
• CAS: 677323-89-6
• 化学式: C₃₄H₄₀FN₃O₈
• 分子量: 637.705
• InChiKey: NSFRXXVRJVLBPD-CLJLJLNGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.16
• 重原子数：
  46.0
• 可旋转键数：
  11.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  125.52
• 氢给体数：
  1.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  (3R,4R)-4-[4-(2-fluoro-3-methoxy-6-methoxymethoxybenzoyl)benzyloxy]-3-[(pyridine-4-carbonyl)amino]azepane-1-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 15.0h， 以40 mg的产率得到(3R,4R)-N-{4-[4-(2-fluoro-6-hydroxy-3-methoxybenzoyl)benzyloxy]azepan-3-yl}isonicotinamide dihydrochloride
  参考文献：
  名称：

  Structure-Based Optimization of Novel Azepane Derivatives as PKB Inhibitors

  摘要：

  Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)aminol-azepan4-yl ester (1) (IC50 (PKB-alpha.) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-{(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepan-3-yl}-isonicotinamide (4), (3R,4R)-N-{4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3-yl}-isonicotinamide (5), N-{(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl}-azepan-3-yl)-isonicotinamide (6), N-{(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan-3-yl}-isonicotinamide (7), and N-{(3R,4S)-4-(4-{trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl] -vinyl}-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1)Compound 4 was found to be plasma stable and highly active (IC50 (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.

  DOI：

  10.1021/jm0310479
• 作为产物：
  描述：

  4-[(2-fluoro-3-methoxy-6-methoxymethoxyphenyl)-(1,1,1-triisopropylsilanyloxy)methyl]benzoic acid methyl ester 在 四氯化碳 、 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 四丁基氟化铵 、 N,N'-二环己基碳二亚胺 、 三苯基膦 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 66.0h， 生成 (3R,4R)-4-[4-(2-fluoro-3-methoxy-6-methoxymethoxybenzoyl)benzyloxy]-3-[(pyridine-4-carbonyl)amino]azepane-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Structure-Based Optimization of Novel Azepane Derivatives as PKB Inhibitors

  摘要：

  Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)aminol-azepan4-yl ester (1) (IC50 (PKB-alpha.) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-{(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepan-3-yl}-isonicotinamide (4), (3R,4R)-N-{4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3-yl}-isonicotinamide (5), N-{(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl}-azepan-3-yl)-isonicotinamide (6), N-{(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan-3-yl}-isonicotinamide (7), and N-{(3R,4S)-4-(4-{trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl] -vinyl}-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1)Compound 4 was found to be plasma stable and highly active (IC50 (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.

  DOI：

  10.1021/jm0310479