甲基{(1S,4S,5S,10S)-4-苯甲基-1,10-二-叔-丁基-7-[4-(2-叔-丁基-2H-四唑-5-基)苯甲基]-5-羟基-2,9,12-三羰基-13-氧杂-3,7,8,11-四氮杂十四碳-1-基}氨基甲酸酯(non-preferredname) | 198904-20-0

• 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
• 中文名称: 甲基{(1S,4S,5S,10S)-4-苯甲基-1,10-二-叔-丁基-7-[4-(2-叔-丁基-2H-四唑-5-基)苯甲基]-5-羟基-2,9,12-三羰基-13-氧杂-3,7,8,11-四氮杂十四碳-1-基}氨基甲酸酯(non-preferredname)
• 英文名称: 2,5,6,10,13-Pentaazatetradecanedioic acid, 3,12-bis(1,1-dimethylethyl)-6-((4-(2-(1,1-dimethylethyl)-2H-tetrazol-5-yl)phenyl)methyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-, dimethyl ester, (3S,8S,9S,12S)-
• 英文别名: methyl N-[(2S)-1-[2-[[4-(2-tert-butyltetrazol-5-yl)phenyl]methyl]-2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-4-phenylbutyl]hydrazinyl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate
• CAS: 198904-20-0
• 化学式: C₃₈H₅₇N₉O₇
• 分子量: 751.927
• InChiKey: RXWRDDXNHGYOJF-VZNYXHRGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  54
• 可旋转键数：
  19
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  202
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  methyl (S)-(1-hydrazinyl-3,3-dimethyl-1-oxobutan-2-yl)carbamate 在 N-甲基吗啉 、 盐酸 、 甲烷磺酸 、 potassium tetraborate 、 sodium cyanoborohydride 、 O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 异丙醇 、 甲苯 为溶剂， 反应 80.17h， 生成 甲基{(1S,4S,5S,10S)-4-苯甲基-1,10-二-叔-丁基-7-[4-(2-叔-丁基-2H-四唑-5-基)苯甲基]-5-羟基-2,9,12-三羰基-13-氧杂-3,7,8,11-四氮杂十四碳-1-基}氨基甲酸酯(non-preferredname)
  参考文献：
  名称：

  New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors:  Candidates for Clinical Development

  摘要：

  On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,(8) azadipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) ororthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.

  DOI：

  10.1021/jm970873c

文献信息

• New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors:  Candidates for Clinical Development
  作者：Guido Bold、Alexander Fässler、Hans-Georg Capraro、Robert Cozens、Thomas Klimkait、Janis Lazdins、Jürgen Mestan、Bernard Poncioni、Johannes Rösel、David Stover、Marina Tintelnot-Blomley、Figan Acemoglu、Werner Beck、Eugen Boss、Martin Eschbach、Thomas Hürlimann、Elvira Masso、Serge Roussel、Katharina Ucci-Stoll、Dominique Wyss、Marc Lang

  DOI：10.1021/jm970873c

  日期：1998.8.1

  On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,(8) azadipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) ororthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.