(2S,4S)-3-aza-4-(morpholinocarbonyl)-2-butyl-5-phenylpentanamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane | 130316-76-6

• 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: (2S,4S)-3-aza-4-(morpholinocarbonyl)-2-butyl-5-phenylpentanamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane
• 英文别名: (2S)-N-[(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6-methylheptan-2-yl]-2-[[(2S)-1-morpholin-4-yl-1-oxo-3-phenylpropan-2-yl]amino]hexanamide
• CAS: 130316-76-6
• 化学式: C₃₃H₅₅N₃O₅
• 分子量: 573.817
• InChiKey: TYOBVSWYHQVCEW-STVCLKQXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  41
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  111
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  L-苯丙氨酸叔丁酯盐酸盐 在 palladium on activated charcoal N-甲基吗啉 、 盐酸 、 氢气 、 sodium acetate 、 sodium cyanoborohydride 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 70.0h， 生成 (2S,4S)-3-aza-4-(morpholinocarbonyl)-2-butyl-5-phenylpentanamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane
  参考文献：
  名称：

  Nonpeptide renin inhibitors employing a novel 3-aza (or oxa)-2,4-dialkyl glutaric acid moiety as a P2/P3 amide bond replacement

  摘要：

  A new series of renin inhibitors has been developed. The inhibitors feature a novel replacement for the P2/P3 dipeptide moiety normally associated with renin inhibitors. The dipeptide replacement was a (2S,4S)-3-aza(or oxa)-2,4-di-alkylglutaric acid amide. Extensive structure-activity relationship studies determined that optimum potency was achieved when inhibitors employed a benzyl and butyl group at the C(4) and C(2) carbon position, respectively. In addition, maximum in vitro potency was obtained when the N-terminus was functionalized by incorporating a 4-(1,3-dioxabutyl)piperidine amide. SAR data suggested that the 1,3-dioxabutyl group (methoxymethyl ether) interacted by hydrogen bonding to groups in the S4 domain of renin. This hypothesis was strengthened when a 4-butylpiperidine amide was substituted and inhibitor potency decreased dramatically. Inhibitors employing this novel dipeptide mimic were prepared by coupling the glutaric acid amides with either the transition-state mimic (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (18) or the hydroxyethylene dipeptide isostere. The glutaric acid amides were prepared by two general procedures. The first procedure involved the reductive amination of alpha-amino acid esters with alpha-keto esters. The second procedure involved the displacement reaction of alpha-bromo esters or acids with alpha-amino acid amides.

  DOI：

  10.1021/jm00088a006

文献信息

• Synthesis of the Nonpeptide Renin Inhibitor A-68064 and the ACE Inhibitor Methyl Enalaprilat from (5S)-2,3,5,6-Tetrahydro-5-alkyl-N-(tert-butyloxycarbonyl-4H-1,4-oxazine-2-ones
  作者：William R. Baker、Stephen L. Condon

  DOI：10.1016/s0040-4039(00)91678-2

  日期：1992.3

  The nonpeptide renin inhibitor, A-68064, and the ACE inhibitor methyl enalaprilat were synthesized from (5S) 2,3,5,6-tetrahydro-5-benzyl(butyl)-N-(tert-butoxycarbonyl)-4H-1,4-oxazine-2-ones 7a and 7b, and (5S) 2,3,5,6-tetrahydro-5-methyl-N-(tert-butoxycarbonyl)-4H-1,4-oxazine-2-one 12, respectively.
• Nonpeptide renin inhibitors employing a novel 3-aza (or oxa)-2,4-dialkyl glutaric acid moiety as a P2/P3 amide bond replacement
  作者：William R. Baker、Anthony K. L. Fung、Hollis D. Kleinert、Herman H. Stein、Jacob J. Plattner、Yoek Lin Armiger、Stephen L. Condon、Jerome Cohen、David A. Egan

  DOI：10.1021/jm00088a006

  日期：1992.5

  A new series of renin inhibitors has been developed. The inhibitors feature a novel replacement for the P2/P3 dipeptide moiety normally associated with renin inhibitors. The dipeptide replacement was a (2S,4S)-3-aza(or oxa)-2,4-di-alkylglutaric acid amide. Extensive structure-activity relationship studies determined that optimum potency was achieved when inhibitors employed a benzyl and butyl group at the C(4) and C(2) carbon position, respectively. In addition, maximum in vitro potency was obtained when the N-terminus was functionalized by incorporating a 4-(1,3-dioxabutyl)piperidine amide. SAR data suggested that the 1,3-dioxabutyl group (methoxymethyl ether) interacted by hydrogen bonding to groups in the S4 domain of renin. This hypothesis was strengthened when a 4-butylpiperidine amide was substituted and inhibitor potency decreased dramatically. Inhibitors employing this novel dipeptide mimic were prepared by coupling the glutaric acid amides with either the transition-state mimic (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (18) or the hydroxyethylene dipeptide isostere. The glutaric acid amides were prepared by two general procedures. The first procedure involved the reductive amination of alpha-amino acid esters with alpha-keto esters. The second procedure involved the displacement reaction of alpha-bromo esters or acids with alpha-amino acid amides.