[S-(R*,R*)]-4-amino-3-hydroxy-6-methyl-N-[2-(4-morpholinyl)ethyl]heptanamide | 127106-64-3

• 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: [S-(R*,R*)]-4-amino-3-hydroxy-6-methyl-N-[2-(4-morpholinyl)ethyl]heptanamide
• 英文别名: (3S,4S)-4-amino-3-hydroxy-6-methyl-N-(2-morpholin-4-ylethyl)heptanamide
• CAS: 127106-64-3
• 化学式: C₁₄H₂₉N₃O₃
• 分子量: 287.403
• InChiKey: XPMNJSJXCUXCOA-STQMWFEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  20
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  87.8
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(4-morpholinylsulfonyl)-L-phenylalanyl-DL-2-(methoxycarbonyl)glycine methyl ester 、 [S-(R*,R*)]-4-amino-3-hydroxy-6-methyl-N-[2-(4-morpholinyl)ethyl]heptanamide 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 以60%的产率得到*,R^*)>-N--3-<<2-hydroxy-1-(2-methylpropyl)-4-<<2-(4-morpholinyl)ethyl>amino>-4-oxobutyl>amino>-3-oxo-DL-alanine methyl ester
  参考文献：
  名称：

  Renin inhibitors containing esters at the P2-position. Oral activity in a derivative of methyl aminomalonate

  摘要：

  A series of renin inhibitors containing ester side chains at the P2 subsite are potent inhibitors of primate renin. Derivatives containing the diol isostere (ACDMH) at P1-P1' were the most potent inhibitors. Moderate selectivity for renin was observed relative to the closely related aspartic proteinase cathepsin D. The prototype compound, 4 (PD 132002), inhibited pepsin only weakly. In both high-renin normotensive and high-renin renal hypertensive monkeys, 4 produced substantial reductions in blood pressure after oral administration of 30 mg/kg. The maximum drop in blood pressure observed (24 +/- mmHg) in the renal hypertensive monkey model was comparable to the drop produced by an intravenous infusion of saralasin at a maximally effective dose. Both the magnitude and duration of the oral antihypertensive effect of 4 is greater than that produced by enalkiren, CGP-38560, or CP-80794 by direct comparison in the same hypertensive monkey model. The malonate ester derivatives were prepared as ca. 65:35 mixtures of epimers. The kinetics of epimerization of 4 were investigated in detail, and it was shown to equilibrate rapidly at physiological pH (t1/2 < 2 min). Fractional crystallization was employed to obtain the individual diastereomers in > 98% purity, which were indistinguishable in terms of their activity in vitro or in vivo, presumably due to rapid epimerization under the testing conditions.

  DOI：

  10.1021/jm00111a002
• 作为产物：
  描述：

  {(S)-3-Methyl-1-[2-(2-morpholin-4-yl-ethylcarbamoyl)-1-(tetrahydro-pyran-2-yloxy)-ethyl]-butyl}-carbamic acid tert-butyl ester 在 盐酸 、 氨 作用下， 生成 [S-(R*,R*)]-4-amino-3-hydroxy-6-methyl-N-[2-(4-morpholinyl)ethyl]heptanamide
  参考文献：
  名称：

  Klutchko, Sylvester; O'Brien, Patrick; Hodges, John C., Synthetic Communications, 1989, vol. 19, # 13-14, p. 2573 - 2584

  摘要：

  DOI：

文献信息

• REPINE, JOSEPH T.;HIMMELSBACH, RICHARD J.;HODGES, JOHN C.;KALTENBRONN, JA+, J. MED. CHEM., 34,(1991) N, C. 1935-1943
  作者：REPINE, JOSEPH T.、HIMMELSBACH, RICHARD J.、HODGES, JOHN C.、KALTENBRONN, JA+

  DOI：——

  日期：——
• US4876343A
  申请人：——

  公开号：US4876343A

  公开（公告）日：1989-10-24
• US5061808A
  申请人：——

  公开号：US5061808A

  公开（公告）日：1991-10-29
• Renin inhibitors containing esters at the P2-position. Oral activity in a derivative of methyl aminomalonate
  作者：Joseph T. Repine、Richard J. Himmelsbach、John C. Hodges、James S. Kaltenbronn、Ila Sircar、Richard W. Skeean、Sean T. Brennan、Timothy R. Hurley、Elizabeth Lunney

  DOI：10.1021/jm00111a002

  日期：1991.7

  A series of renin inhibitors containing ester side chains at the P2 subsite are potent inhibitors of primate renin. Derivatives containing the diol isostere (ACDMH) at P1-P1' were the most potent inhibitors. Moderate selectivity for renin was observed relative to the closely related aspartic proteinase cathepsin D. The prototype compound, 4 (PD 132002), inhibited pepsin only weakly. In both high-renin normotensive and high-renin renal hypertensive monkeys, 4 produced substantial reductions in blood pressure after oral administration of 30 mg/kg. The maximum drop in blood pressure observed (24 +/- mmHg) in the renal hypertensive monkey model was comparable to the drop produced by an intravenous infusion of saralasin at a maximally effective dose. Both the magnitude and duration of the oral antihypertensive effect of 4 is greater than that produced by enalkiren, CGP-38560, or CP-80794 by direct comparison in the same hypertensive monkey model. The malonate ester derivatives were prepared as ca. 65:35 mixtures of epimers. The kinetics of epimerization of 4 were investigated in detail, and it was shown to equilibrate rapidly at physiological pH (t1/2 < 2 min). Fractional crystallization was employed to obtain the individual diastereomers in > 98% purity, which were indistinguishable in terms of their activity in vitro or in vivo, presumably due to rapid epimerization under the testing conditions.
• Klutchko, Sylvester; O'Brien, Patrick; Hodges, John C., Synthetic Communications, 1989, vol. 19, # 13-14, p. 2573 - 2584
  作者：Klutchko, Sylvester、O'Brien, Patrick、Hodges, John C.

  DOI：——

  日期：——