(3R,4S)-4-hydroxy-3-[(pyridine-4-carbonyl)amino]azepane-1-carboxylic acid tert-butyl ester | 602277-74-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (3R,4S)-4-hydroxy-3-[(pyridine-4-carbonyl)amino]azepane-1-carboxylic acid tert-butyl ester
• 英文别名: (3R,4S)-4-Hydroxy-3-[ (pyridine-4-carbonyl)-amino]-azepane-1-carboxylic Acid tert-Butyl Ester；(3R,4S)-4-Hydroxy-3-[(pyridine-4-carbonyl)-amino]-azepane-1-carboxylic Acid tert-Butyl Ester；tert-butyl (3R,4S)-4-hydroxy-3-(pyridine-4-carbonylamino)azepane-1-carboxylate
• CAS: 602277-74-7
• 化学式: C₁₇H₂₅N₃O₄
• 分子量: 335.403
• InChiKey: NICJXCVTVHYXLO-KGLIPLIRSA-N

物化性质

• 沸点：
  554.5±50.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  91.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3R,4S)-4-hydroxy-3-[(pyridine-4-carbonyl)amino]azepane-1-carboxylic acid tert-butyl ester 在 吡啶 作用下， 以 二甲基亚砜 为溶剂， 反应 72.0h， 生成 (3R,4R)-4-cyano-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
• 作为产物：
  描述：

  异烟酸 、 (3R,4S)-3-Amino-4-hydroxy-azepane-1-carboxylic acid tert-butyl ester 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以98%的产率得到(3R,4S)-4-hydroxy-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

文献信息

• Novel azepane derivatives
  申请人：——

  公开号：US20030181716A1

  公开（公告）日：2003-09-25

  This invention provides novel azepane derivatives or pharmaceutically acceptable salts thereof, according to the general formula (I) 1 wherein the symbols are defined in the specification, as well as processes for their manufacture. The compounds according to this invention possess anti-cell proliferation activity and show an increased plasma-stability.

  该发明提供了新型的环庚烷衍生物或其药用盐，其通式如下（I）其中符号在说明书中有定义，并提供了它们的制备方法。根据该发明的化合物具有抗细胞增殖活性，并显示出增强的血浆稳定性。
• Azepane derivatives
  申请人：Friebe Walter-Gunar

  公开号：US06887864B2

  公开（公告）日：2005-05-03

  This invention provides novel azepane derivatives or pharmaceutically acceptable salts thereof, according to the general formula (I) wherein the symbols are defined in the specification, as well as processes for their manufacture. The compounds according to this invention possess anti-cell proliferation activity and show an increased plasma-stability.

  本发明提供了新型的氮杂七元环衍生物或其药学上可接受的盐，其符合一般式(I)中所定义的符号如说明书所示，以及它们的制备过程。根据本发明的化合物具有抗细胞增殖活性并显示出增加的血浆稳定性。
• US6887864B2
  申请人：——

  公开号：US6887864B2

  公开（公告）日：2005-05-03
• Structure-Based Optimization of Novel Azepane Derivatives as PKB Inhibitors
  作者：Christine B. Breitenlechner、Thomas Wegge、Laurent Berillon、Klaus Graul、Klaus Marzenell、Walter-Gunar Friebe、Ulrike Thomas、Ralf Schumacher、Robert Huber、Richard A. Engh、Birgit Masjost

  DOI：10.1021/jm0310479

  日期：2004.3.1

  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.