4(S)-amino-α(S)-butyl-N-<4(S)-<(butylamino)carbonyl>-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl>-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetamide | 138571-23-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4(S)-amino-α(S)-butyl-N-<4(S)-<(butylamino)carbonyl>-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl>-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetamide
• 英文别名: (2S,4S,5S)-5-[[(2S)-2-[(4S)-4-amino-3-oxo-4,5-dihydro-1H-2-benzazepin-2-yl]hexanoyl]amino]-N-butyl-6-cyclohexyl-4-hydroxy-2-propan-2-ylhexanamide
• CAS: 138571-23-0
• 化学式: C₃₅H₅₈N₄O₄
• 分子量: 598.87
• InChiKey: ATPBQJUSFYKOML-XDIGFQIYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  43
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  125
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 4(S)-amino-α(S)-butyl-N-<4(S)-<(butylamino)carbonyl>-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl>-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetamide 以 二氯甲烷 为溶剂， 反应 1.0h， 以100%的产率得到4(S)-(acetylamino)-α(S)-butyl-N-<4(S)-<(butylamino)carbonyl>-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl>-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetamide
  参考文献：
  名称：

  Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors

  摘要：

  The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleucinamide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)-[butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.

  DOI：

  10.1021/jm00083a006
• 作为产物：
  描述：

  (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl hexanoic acid n-butyl amide 在 1-羟基苯并三唑 、 一水合肼 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 4(S)-amino-α(S)-butyl-N-<4(S)-<(butylamino)carbonyl>-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl>-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetamide
  参考文献：
  名称：

  Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors

  摘要：

  The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleucinamide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)-[butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.

  DOI：

  10.1021/jm00083a006

文献信息

• Synthesis and use of 3-amino-4-phenyl-2-piperidones and 4-amino-2-benzazepin-3-ones as conformationally restricted phenylalanine isosteres in renin inhibitors
  作者：S. E. De Laszlo、B. L. Bush、J. J. Doyle、W. J. Greenlee、D. G. Hangauer、T. A. Halgren、R. J. Lynch、T. W. Schorn、P. K. S. Siegl

  DOI：10.1021/jm00083a006

  日期：1992.3

  The design of P2-P3 conformational restrictions in renin inhibitors by the use of a renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N-[4(S)-[(butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-L-norleucinamide (32). The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselectivity and also to act as a leaving group in an intramolecular cyclization to the piperidone. The most potent inhibitor, 3(S)-(acetylamino)-alpha(S)-butyl-N-[4(S)-[butylamino)carbonyl]-1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32. Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies. Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.