4(S)-butyl-4(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetic acid | 138571-21-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: 4(S)-butyl-4(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetic acid
• 英文别名: (2S)-2-[(4S)-4-(1,3-dioxoisoindol-2-yl)-3-oxo-4,5-dihydro-1H-2-benzazepin-2-yl]hexanoic acid
• CAS: 138571-21-8
• 化学式: C₂₄H₂₄N₂O₅
• 分子量: 420.465
• InChiKey: ZIGLWKQFHLXUNO-PMACEKPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  95
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4(S)-butyl-4(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetic acid 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
• 作为产物：
  描述：

  4(S)-butyl-3-<2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl>-5-oxazolidinone 在 三氟甲磺酸 作用下， 以 二氯甲烷 为溶剂， 以96%的产率得到4(S)-butyl-4(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetic acid
  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

• Variation of the Net Charge, Lipophilicity, and Side Chain Flexibility in Dmt¹-DALDA: Effect on Opioid Activity and Biodistribution
  作者：Alexandre Novoa、Sylvia Van Dorpe、Evelien Wynendaele、Mariana Spetea、Nathalie Bracke、Sofie Stalmans、Cecilia Betti、Nga N. Chung、Carole Lemieux、Johannes Zuegg、Matthew A. Cooper、Dirk Tourwé、Bart De Spiegeleer、Peter W. Schiller、Steven Ballet

  DOI：10.1021/jm3008079

  日期：2012.11.26

  The influence of the side chain charges of the second and fourth amino acid residues in the peptidic mu opioid lead agonist Dmt-D-Arg-Phe-Lys-NH2. ([Dmt(1)-DALDA) was examined. Additionally, to increase the overall lipophilicity of [Dmt(1)]-DALDA and to investigate the Phe(3) side chain flexibility, the final amide bond was N-methylated and Phe(3) was replaced by a constrained aminobenzazepine analogue. The in vitro receptor binding and activity of the peptides, as well as their in vivo transport (brain in- and efflux and tissue biodistribution) and antinociceptive properties after peripheral administration (ip and sc) in mice were determined. The structural modifications result in significant shifts of receptor binding, activity, and transport, properties. Strikingly, while [Dmt(1)]-DALDA and its N-methyl analogue, Dmt-D-Arg-Phe-NMeLys-NH2, showed a long-lasting antinociceptive effect (>7 h), the peptides with D-Cit(2) generate potent antinociception more rapidly (maximal effect at 1h postinjection) but also lose their analgesic activity faster when compared to [Dmt(1)]-DALDA. and [Dmit(1),NMeLys(4)]-DALDA.
• 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.