N'-[(2S,3S)-2-Hydroxy-4-phenyl-3-(2,2,2-trifluoro-acetylamino)-butyl]-N'-(4-thiazol-5-yl-benzyl)-hydrazinecarboxylic acid tert-butyl ester | 198904-45-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N'-[(2S,3S)-2-Hydroxy-4-phenyl-3-(2,2,2-trifluoro-acetylamino)-butyl]-N'-(4-thiazol-5-yl-benzyl)-hydrazinecarboxylic acid tert-butyl ester
• 英文别名: 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane；tert-butyl N-[[(2S,3S)-2-hydroxy-4-phenyl-3-[(2,2,2-trifluoroacetyl)amino]butyl]-[[4-(1,3-thiazol-5-yl)phenyl]methyl]amino]carbamate
• CAS: 198904-45-9
• 化学式: C₂₇H₃₁F₃N₄O₄S
• 分子量: 564.629
• InChiKey: CSPWQNVBBHOUNJ-VXKWHMMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  132
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N'-[(2S,3S)-2-Hydroxy-4-phenyl-3-(2,2,2-trifluoro-acetylamino)-butyl]-N'-(4-thiazol-5-yl-benzyl)-hydrazinecarboxylic acid tert-butyl ester 在 甲酸 、 potassium carbonate 、 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 甲醇 为溶剂， 反应 12.5h， 生成 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane
  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
• 作为产物：
  描述：

  4-(thiazol-5-yl)benzaldehyde 在 sodium hydroxide 、 sodium cyanoborohydride 、 对甲苯磺酸 作用下， 以 乙醇 、 异丙醇 为溶剂， 反应 60.5h， 生成 N'-[(2S,3S)-2-Hydroxy-4-phenyl-3-(2,2,2-trifluoro-acetylamino)-butyl]-N'-(4-thiazol-5-yl-benzyl)-hydrazinecarboxylic acid tert-butyl ester
  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

• Antivirally active heterocyclic azahexane derivatives
  申请人：Novartis Finance Corporation

  公开号：US05849911A1

  公开（公告）日：1998-12-15

  There are described compounds of formula I*, ##STR1## wherein R.sub.1 is lower alkoxycarbonyl, R.sub.2 is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl, R.sub.3 is phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals, or C.sub.4 -C.sub.8 cycloalkyl, R.sub.4 is phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl that is bonded by way of a ring carbon atom, has from 5 to 8 ring atoms, contains from 1 to 4 hetero atoms selected from nitrogen, oxygen, sulfur, sulfinyl (--SO--) and sulfonyl (--SO.sub.2 --) and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl, R.sub.5, independently of R.sub.2, has one of the meanings mentioned for R.sub.2, and R.sub.6, independently of R.sub.1, is lower alkoxycarbonyl, or salts thereof, provided that at least one salt-forming group is present. The compounds are inhibitors of retroviral aspartate protease and can be used, for example, in the treatment of AIDS. They exhibit outstanding pharmacodynamic properties.

  描述了化合物的公式I*，其中R.sub.1是较低的烷氧羰基，R.sub.2是次级或三级较低的烷基或较低的烷基硫代烷基，R.sub.3是未取代或取代有一个或多个较低的烷氧基的苯基，或C.sub.4-C.sub.8环烷基，R.sub.4是取代在4位的苯基或环己基，其通过环碳原子与不饱和杂环基相结合，该不饱和杂环基具有5至8个环原子，包含1至4个从氮、氧、硫、亚砜（-SO-）和磺酰（-SO.sub.2-）中选择的杂原子，并且未取代或取代有较低的烷基或苯基-较低的烷基，R.sub.5与R.sub.2独立，具有R.sub.2提到的意义之一，R.sub.6与R.sub.1独立，是较低的烷氧羰基或其盐，前提是至少存在一个盐形成基团。这些化合物是逆转录病毒天冬氨酸蛋白酶的抑制剂，例如可用于艾滋病的治疗。它们具有出色的药效学特性。
• Combinations of HIV protease inhibitors with reverse transcriptase
  申请人：Novartis Finance Corporation

  公开号：US06166004A1

  公开（公告）日：2000-12-26

  There are described compounds of formula I*, ##STR1## wherein R.sub.1 is lower alkoxycarbonyl, R.sub.2 is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl, R.sub.3 is phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals, or C.sub.4 -C.sub.8 cycloalkyl, R.sub.4 is phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl that is bonded by way of a ring carbon atom, has from 5 to 8 ring atoms, contains from 1 to 4 hetero atoms selected from nitrogen, oxygen, sulfur, sulfinyl (--SO--) and sulfonyl (--SO.sub.2 --) and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl, R.sub.5, independently of R.sub.2, has one of the meanings mentioned for R.sub.2, and R.sub.6, independently of R.sub.1, is lower alkoxycarbonyl, or salts thereof, provided that at least one salt-forming group is present. The compounds are inhibitors of retroviral aspartate protease and can be used, for example, in the treatment of AIDS. They exhibit outstanding pharmacodynamic properties.

  描述了化合物I*的公式，其中R.sub.1是较低的烷氧羰基，R.sub.2是次级或三级较低的烷基或较低的烷基硫基烷基，R.sub.3是苯基，未取代或取代了一个或多个较低的烷氧基，或C.sub.4-C.sub.8环烷基，R.sub.4是苯基或环己基，每个取代在4位的不饱和杂环基，通过环碳原子连接，具有5至8个环原子，包含1至4个从氮、氧、硫、亚砜（-SO-）和磺酰（-SO.sub.2 -）中选择的杂原子，并且未取代或取代了较低的烷基或苯基较低的烷基，R.sub.5与R.sub.2独立，具有R.sub.2提到的含义之一，R.sub.6与R.sub.1独立，是较低的烷氧羰基或其盐，至少存在一个盐形成基团。这些化合物是反转录病毒天冬氨酸蛋白酶的抑制剂，例如可用于治疗艾滋病。它们具有优异的药效学性质。
• ANTIVIRALLY ACTIVE HETEROCYCLIC AZAHEXANE DERIVATIVES
  申请人：Novartis AG

  公开号：EP0900210B1

  公开（公告）日：2005-02-09
• US5849911A
  申请人：——

  公开号：US5849911A

  公开（公告）日：1998-12-15
• US6110946A
  申请人：——

  公开号：US6110946A

  公开（公告）日：2000-08-29