N-{(1S,2S)-1-苯甲基-3-[1-(联苯基-4-基甲基)-2-{(2S)-2-[(甲酯基)氨基]-3-甲基丁酰}肼基]-2-羟基丙基}-N~2~-(甲酯基)-3-甲基-L-缬氨酸酰胺 | 191594-61-3

• 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
• 中文名称: N-{(1S,2S)-1-苯甲基-3-[1-(联苯基-4-基甲基)-2-{(2S)-2-[(甲酯基)氨基]-3-甲基丁酰}肼基]-2-羟基丙基}-N~2~-(甲酯基)-3-甲基-L-缬氨酸酰胺
• 英文名称: methyl N-[(2S)-1-[2-[(2S,3S)-2-hydroxy-3-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoyl]amino]-4-phenylbutyl]-2-[(4-phenylphenyl)methyl]hydrazinyl]-3-methyl-1-oxobutan-2-yl]carbamate
• CAS: 191594-61-3
• 化学式: C₃₈H₅₁N₅O₇
• 分子量: 689.852
• InChiKey: DXYWQVONJOEGHT-ZWDYZTTJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  50
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  158
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  对苯基苯甲醛 在 palladium on activated charcoal N-甲基吗啉 、 盐酸 、 氢气 、 potassium carbonate 、 1-羟基苯并三唑 、 O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 异丙醇 为溶剂， 反应 45.75h， 生成 N-{(1S,2S)-1-苯甲基-3-[1-(联苯基-4-基甲基)-2-{(2S)-2-[(甲酯基)氨基]-3-甲基丁酰}肼基]-2-羟基丙基}-N~2~-(甲酯基)-3-甲基-L-缬氨酸酰胺
  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

• [EN] AZAHEXANE DERIVATIVES AS SUBSTRATE ISOSTERS OF RETROVIRAL ASPARATE PROTEASES<br/>[FR] DERIVES D'AZAHEXANE UTILES COMME ISOSTERES SUBSTRATS D'ASPARTATES PROTEASES RETROVIRALES
  申请人：NOVARTIS AG

  公开号：WO1997019055A1

  公开（公告）日：1997-05-29

  (EN) The invention relates to compounds of formula (I): wherein R1 and R10 are each independently of the other lower alkoxycarbonyl; either R2, R3 and R4 are each independently of the other C1-C4alkyl and R7, R8 and R9 are each selected from hydrogen and C1-C4alkyl, with not more than 2 of the radicals being hydrogen; or R7, R8 and R9 are each independently of the other C1-C4alkyl and R2, R3 and R4 are each selected from hydrogen and C1-C4alkyl, with 1 or 2 of the radicals being hydrogen; R5 is phenyl or cyclohexyl; and R6 is phenyl or cyanophenyl; or salts thereof; those compounds are inhibitors of retroviral aspartate proteases and are effective, for example, against HIV.(FR) L'invention concerne des composés de la formule (I) ou des sels de ceux-ci. Dans cette formule, R1 et R10 représentent chacun indépendamment alcoxycarbonyle inférieur, soit R2, R3 et R4 représentent chacun indépendamment alkyle C1-C4, et R7, R8 et R9 représentent chacun hydrogène ou alkyle C1-C4, deux de ces radicaux au maximum représentant hydrogène, soit R7, R8 et R9 représentent chacun indépendamment alkyle C1-C4 et R2, R3 et R4 représentent chacun hydrogène ou alkyle C1-C4, 1 ou 2 de ces radicaux représentant hydrogène, R5 représente phényle ou cyclohexyle, et R6 représente phényle ou cyanophényle. Ces composés sont des inhibiteurs des aspartates protéases rétrovirales et ils sont efficace, par exemple, contre le VIH.

  本发明涉及式(I)的化合物，其中R1和R10各自独立地为低级烷氧羰基；要么R2、R3和R4各自独立地为C1-C4烷基，而R7、R8和R9分别选择自氢和C1-C4烷基，其中不超过2个基团为氢；要么R7、R8和R9各自独立地为C1-C4烷基，而R2、R3和R4分别选择自氢和C1-C4烷基，其中1或2个基团为氢；R5为苯基或环己基；R6为苯基或氰基苯基；或其盐。这些化合物是反转录病毒天冬氨酸蛋白酶的抑制剂，并且对HIV等病毒有效。
• AZAHEXANE DERIVATIVES AS SUBSTRATE ISOSTERS OF RETROVIRAL ASPARATE PROTEASES
  申请人：Novartis AG

  公开号：EP0876336B1

  公开（公告）日：2002-06-05
• US6225345B1
  申请人：——

  公开号：US6225345B1

  公开（公告）日：2001-05-01
• 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.