1-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)-((dimethylaminoethoxycarbonyl)amino)-3-methylbutane | 130317-39-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 1-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)-((dimethylaminoethoxycarbonyl)amino)-3-methylbutane
• 英文别名: tert-butyl (4S,5S)-4-(cyclohexylmethyl)-5-[(2S)-2-[2-(dimethylamino)ethoxycarbonylamino]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
• CAS: 130317-39-4
• 化学式: C₂₇H₅₁N₃O₅
• 分子量: 497.719
• InChiKey: QTGWOERMEMZFDJ-VABKMULXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  35
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  80.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)-((dimethylaminoethoxycarbonyl)amino)-3-methylbutane 在 溶剂黄146 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 66.5h， 生成 {(1S,3S,4S)-4-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-phenyl-propionylamino)-3-(1H-imidazol-4-yl)-propionylamino]-5-cyclohexyl-3-hydroxy-1-isopropyl-pentyl}-carbamic acid 2-dimethylamino-ethyl ester
  参考文献：
  名称：

  C-Terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties

  摘要：

  We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.

  DOI：

  10.1021/jm00088a007
• 作为产物：
  描述：

  N,N-二甲基乙醇胺 、 2-(S)-((3-(tert-butyloxycarbonyl)-2,2-dimethyl-4(S)-(cyclohexylmethyl)-5(S)-oxazolidinyl)methyl)-3-methylbutanoic acid 在 二苯基膦叠氮化物 、 三乙胺 作用下， 生成 1-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)-((dimethylaminoethoxycarbonyl)amino)-3-methylbutane
  参考文献：
  名称：

  C-Terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties

  摘要：

  We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.

  DOI：

  10.1021/jm00088a007

文献信息

• Non-peptide renin inhibitors
  申请人：ABBOTT LABORATORIES

  公开号：EP0364804A1

  公开（公告）日：1990-04-25

  A renin inhibiting compound of the formula: wherein A is a substituent; R1 is hydrogen, loweralkyl, substituted loweralkyl or loweralkenyl; X is CH2, CHOH, C(O), O, S, S(O), S02, NH, N(O) or -P(O)O-; R3 is loweralkyl, loweralkenyl or substituted loweralkyl; and T is mimic of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof.

  式中的肾素抑制化合物： 其中 A 是取代基；R1 是氢、低级烷基、取代的低级烷基或低级烯基；X 是 CH2、CHOH、C(O)、O、S、S(O)、S02、NH、N(O)或-P(O)O-；R3 是低级烷基、低级烯基或取代的低级烷基；T 是血管紧张素原的 Leu-Val 裂解位点的模拟物；或其药学上可接受的盐、酯或原药。
• US5268374A
  申请人：——

  公开号：US5268374A

  公开（公告）日：1993-12-07
• C-Terminal modifications of nonpeptide renin inhibitors: improved oral bioavailability via modification of physicochemical properties
  作者：Steven A. Boyd、Anthony K. L. Fung、William R. Baker、Robert A. Mantei、Yoek Lin Armiger、Herman H. Stein、Jerome Cohen、David A. Egan、Jennifer L. Barlow

  DOI：10.1021/jm00088a007

  日期：1992.5

  We describe the development of a series of soluble, potent, and bioavailable nonpeptide renin inhibitors. These inhibitors derived from a series of novel nonpeptide renin inhibitors which were recently identified in our laboratories, by alteration of the nature of the C-terminus (P2') of the molecules. Introduction of basic substituents into modified hydroxyethylene dipeptide isosteres gave inhibitors with improved solubility as well as improved potency against human plasma renin. In addition, these modifications produced inhibitors which displayed markedly improved intraduodenal bioavailability in both the ferret and cynomolgus monkey. We also present data which demonstrate excellent efficacy in the monkey for A-74273 (65), with an intraduodenal bioavailability of 16 +/- 4% in the monkey, compared to 1.7 +/- 0.5% for the dipeptide renin inhibitor enalkiren (A-64662, 75). A-74273 is an example of a nonpeptide inhibitor which possesses a good balance of the desirable properties of potency, solubility, and lipophilicity and which is well absorbed into the intestine.