ethyl (8-isobutyl-6-phenyl-1,2,4-triazolo<4,3-a>pyrazin-3-yl)acetate | 128972-12-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: ethyl (8-isobutyl-6-phenyl-1,2,4-triazolo<4,3-a>pyrazin-3-yl)acetate
• 英文别名: ethyl 8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-ylacetate；ethyl (8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)acetate；ethyl 2-[8-(2-methylpropyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]acetate
• CAS: 128972-12-3
• 化学式: C₁₉H₂₂N₄O₂
• 分子量: 338.409
• InChiKey: QJICYRWWIGGNEW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  69.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl (8-isobutyl-6-phenyl-1,2,4-triazolo<4,3-a>pyrazin-3-yl)acetate 在 sodium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 (2S)-2-[[(3S,4S)-5-cyclohexyl-3-hydroxy-4-[[2-[8-(2-methylpropyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]acetyl]amino]pentanoyl]amino]-4-methyl-N-(pyridin-2-ylmethyl)pentanamide
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives

  摘要：

  A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.

  DOI：

  10.1021/jm00171a005
• 作为产物：
  描述：

  N-<<(ethoxycarbonyl)methylene>carbonyl>-N'-(3-isobutyl-5-phenylpyrazin-2-yl)hydrazine 在 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 反应 2.5h， 以74%的产率得到ethyl (8-isobutyl-6-phenyl-1,2,4-triazolo<4,3-a>pyrazin-3-yl)acetate
  参考文献：
  名称：

  1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives

  摘要：

  A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.

  DOI：

  10.1021/jm00171a005

文献信息

• 5-(heterocyclylalkanoyl)amino-4-hydroxypentanamides
  申请人：Imperial Chemical Industries plc

  公开号：US05091425A1

  公开（公告）日：1992-02-25

  This invention concerns novel nitrogen derivatives of the formula I ##STR1## (and their pharmaceutically-acceptable salts), together with pharmaceutical compositions containing them. The nitrogen derivatives are inhibitors of the catalytic action of renin. The invention further concerns novel processes for the manufacture of said inhibitors.

  这项发明涉及公式I的新颖氮衍生物##STR1##（及其药用盐），以及含有它们的药物组合物。这些氮衍生物是肾素催化作用的抑制剂。该发明还涉及制造上述抑制剂的新型工艺。
• ROBERTS, DAVID A.;BRADBURY, ROBERT H.;BROWN, DAVID;FAULL, ALAN;GRIFFITHS,+, J. MED. CHEM., 33,(1990) N, C. 2326-2334
  作者：ROBERTS, DAVID A.、BRADBURY, ROBERT H.、BROWN, DAVID、FAULL, ALAN、GRIFFITHS,+

  DOI：——

  日期：——
• US5091425A
  申请人：——

  公开号：US5091425A

  公开（公告）日：1992-02-25
• 1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives
  作者：David A. Roberts、Robert H. Bradbury、David Brown、Alan Faull、David Griffiths、John S. Major、Alec A. Oldham、Robert J. Pearce、Arnold H. Ratcliffe

  DOI：10.1021/jm00171a005

  日期：1990.9

  A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.