N-<3-(4-morpholinyl)propyl>-(2S,4'S,5'S)-2-<<3-(tert-butyloxycarbonyl)-2,2-dimethyl-4-(cyclohexylmethyl)-5-oxazolidinyl>methyl>-3-methylbutanamide | 130316-92-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: N-<3-(4-morpholinyl)propyl>-(2S,4'S,5'S)-2-<<3-(tert-butyloxycarbonyl)-2,2-dimethyl-4-(cyclohexylmethyl)-5-oxazolidinyl>methyl>-3-methylbutanamide
• 英文别名: 3-(4-Morpholinyl)propyl 2(S)-((3-(tert-butyloxycarbonyl)-2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)-oxazolidinyl)methyl)-3-methylbutanamide；tert-butyl (4S,5S)-4-(cyclohexylmethyl)-2,2-dimethyl-5-[(2S)-3-methyl-2-(3-morpholin-4-ylpropylcarbamoyl)butyl]-1,3-oxazolidine-3-carboxylate
• CAS: 130316-92-6
• 化学式: C₃₀H₅₅N₃O₅
• 分子量: 537.784
• InChiKey: PHBVAHVEQPTPDE-GSDHBNRESA-N

物化性质

• 沸点：
  651.8±55.0 °C(Predicted)
• 密度：
  1.032±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  3.0
• 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：

  N-<3-(4-morpholinyl)propyl>-(2S,4'S,5'S)-2-<<3-(tert-butyloxycarbonyl)-2,2-dimethyl-4-(cyclohexylmethyl)-5-oxazolidinyl>methyl>-3-methylbutanamide 在 N-甲基吗啉 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 46.0h， 生成 A-74273
  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-(3-氨丙基)吗啉 、 2-(S)-((3-(tert-butyloxycarbonyl)-2,2-dimethyl-4(S)-(cyclohexylmethyl)-5(S)-oxazolidinyl)methyl)-3-methylbutanoic acid 在 N-甲基吗啉 、 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， 生成 N-<3-(4-morpholinyl)propyl>-(2S,4'S,5'S)-2-<<3-(tert-butyloxycarbonyl)-2,2-dimethyl-4-(cyclohexylmethyl)-5-oxazolidinyl>methyl>-3-methylbutanamide
  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：EP0437508A1

  公开（公告）日：1991-07-24
• US5182266A
  申请人：——

  公开号：US5182266A

  公开（公告）日：1993-01-26
• US5268374A
  申请人：——

  公开号：US5268374A

  公开（公告）日：1993-12-07
• [EN] NON-PEPTIDE RENIN INHIBITORS
  申请人：——

  公开号：WO1990003971A1

  公开（公告）日：1990-04-19

  [FR] L'invention concerne un composé d'inhibition de la rénine ayant la formule (I), dans laquelle A est un substituant; R1 représente hydrogène, alkyl inférieur, alkyl inférieur substitué ou alkényl inférieur; X représente CH2, CHOH, C(O), O, S, S(O), SO2, NH, N(O) ou -P(O)O-; R3 représente un alkyl inférieur, un alkényl inférieur ou un alkyl inférieur substitué; et T est une mimique du site de clivage Leu-Val de l'angiotensinogène; ou un sel, un ester ou un promédicament pharmaceutiquement acceptable de celui-ci.
  [EN] A renin inhibiting compound of formula (I), wherein A is a substituent; R1? is hydrogen, loweralkyl, substituted loweralkyl or loweralkenyl; X is CH2?, CHOH, C(O), O, S, S(O), SO2?, 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.
• 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.