N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di[(4-bromobenzyl)oxy]-3,4-dihydroxyhexanediamide | 214139-74-9

• 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
• 英文名称: N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di[(4-bromobenzyl)oxy]-3,4-dihydroxyhexanediamide
• 英文别名: (2R,3R,4R,5R)-2,5-bis[(4-bromophenyl)methoxy]-3,4-dihydroxy-N,N'-bis[(1S)-2-methyl-1-(methylcarbamoyl)propyl]hexanediamide；(2R,3R,4R,5R)-2,5-bis[(4-bromophenyl)methoxy]-3,4-dihydroxy-N,N'-bis[(2S)-3-methyl-1-(methylamino)-1-oxobutan-2-yl]hexanediamide
• CAS: 214139-74-9
• 化学式: C₃₂H₄₄Br₂N₄O₈
• 分子量: 772.531
• InChiKey: FFUDEABEDNGPMU-BQXGFVACSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  46
• 可旋转键数：
  17
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  175
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di[(4-bromobenzyl)oxy]-3,4-dihydroxyhexanediamide 在 四(三苯基膦)钯 、 sodium azide 、 氯化铵 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.71h， 生成 N1,N6-bis[(1S)-2-methyl-1-(methylcarbamoyl)propyl](2R,3R,4R,5R)-2,5-bis[4-(5-tetrazolyl)benzyloxy]-3,4-dihydroxyhexanediamide
  参考文献：
  名称：

  从有机卤化物快速微波辅助制备芳基和乙烯基腈及相应的四唑

  摘要：

  使用钯催化的反应，以微波辐射为能源，可以从相应的溴化物中以很高的收率制备芳基和乙烯基腈。此外，快速加热成功地用于通过环加成反应将这些腈转化为芳基和乙烯基四唑。可以在溶液中和在固体载体上完成一锅法将卤代芳基直接转化为芳基四唑。所有反应都在几分钟之内完成，而不是像以前用标准热加热技术所报道的那样在数小时或数天内完成。通过微波促进溴前体的氰化反应和随后的环加成反应，在一个锅中制备了一种非常有效的HIV-1蛋白酶抑制剂（K（i）= 0. 56 nM），该抑制剂包含两个四唑杂环作为羧基生物等位线。

  DOI：

  10.1021/jo0009954
• 作为产物：
  描述：

  4-bromobenzyl 2,2,2-trichloroacetimidate 在 三氟甲磺酸 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 为溶剂， 反应 50.0h， 生成 N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di[(4-bromobenzyl)oxy]-3,4-dihydroxyhexanediamide
  参考文献：
  名称：

  Design and Fast Synthesis of C-Terminal Duplicated Potent C₂-Symmetric P1/P1‘-Modified HIV-1 Protease Inhibitors

  摘要：

  tin analysis of the X-ray structure of a complex of HIV-1 protease with a linear C-2-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K-i values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K-i values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.

  DOI：

  10.1021/jm9910371

文献信息

• Antiviral protease inhibitors
  申请人：MEDIVIR AB

  公开号：EP1647545A1

  公开（公告）日：2006-04-19

  Compounds of the formula I: wherein: A' and A" are independently the same or different group of the formula II: wherein: R' is H, CH3, C(CH3)2, -ORa, -N(Ra)2, -N(Ra)ORa or -DP R''' is H or CH3; Ra is H, C1-C3 alkyl; D is a bond, alkylene, -C(=O)-, -S(O)- or -S(O)2- ; P is an optionally substituted, mono or bicyclic carbo- or heterocycle; R" is H, any of the sidechains found in the natural amino acids, carboxacetamide, or a group (CH2)nDP; M is a bond or -C(=O)N(R''')-; Q is absent, a bond, -CH(OH)- or -CH2-; or R" together with Q , M and R' define an optionally substituted 5 or 6 membered carbo- or heterocyclic ring which is optionally fused with a further 5 or 6 membered carbo- or heterocyclic ring; with the proviso that R' is -ORa, -N(Ra)2, -N(Ra)ORa or -DP, if M is a bond and Q is absent; X is H, OH, OCH3; Y is H, OH, OCH3, but X and Y are not both H; Z' and Z" are independently -(CH2)mP where P is as defined above; n and m are independently 0,1 or 2; and pharmaceutically acceptable salts and prodrugs thereof have utility as aspartyl protease inhibitors of HIV. They can be prepared in a facile two step synthesis from novel 2,5-di-O-benzyl-L-mannaro-1,4:6,3-dilactone intermediates.

  式 I 的化合物： 其中 A'和 A "分别为式 II 中相同或不同的基团： 其中 R' 是 H、CH3、C(CH3)2、-ORa、-N(Ra)2、-N(Ra)ORa 或 -DP R''' 是 H 或 CH3；Ra 是 H、C1-C3 烷基； D 是键、亚烷基、-C(=O)-、-S(O)- 或 -S(O)2- ； P 是任选取代的单环或双环碳环或杂环； R" 是 H、天然氨基酸中的任何侧链、羧乙酰胺或基团 (CH2)nDP； M 是键或-C(=O)N(R''')-； Q 不存在、是键、-CH(OH)- 或 -CH2-； 或 R "与 Q、M 和 R'一起定义了一个任选取代的 5 或 6 位碳环或杂环，该环任选与另一个 5 或 6 位碳环或杂环融合； 但条件是，如果 M 是键且 Q 不存在，R'是-ORa、-N(Ra)2、-N(Ra)ORa 或-DP； X 是 H、OH、OCH3； Y 是 H、OH、OCH3，但 X 和 Y 并非都是 H； Z' 和 Z" 独立地为-(CH2)mP，其中 P 如上定义； n 和 m 独立地为 0、1 或 2； 及其药学上可接受的盐和原药可用作 HIV 的天冬氨酰蛋白酶抑制剂。它们可以从新颖的 2,5- 二-O-苄基-L-甘露-1,4:6,3-二内酯中间体通过简单的两步合成制备。
• P1/P1′ modified HIV protease inhibitors as tools in two new sensitive surface plasmon resonance biosensor screening assays
  作者：Mathias Alterman、Hans Sjöbom、Pär Säfsten、Per-Olof Markgren、U.Helena Danielson、Markku Hämäläinen、Stefan Löfås、Johan Hultén、Björn Classon、Bertil Samuelsson、Anders Hallberg

  DOI：10.1016/s0928-0987(01)00109-9

  日期：2001.5

  The commonly used HIV-1 protease assays rely on measurements of the effect of inhibitions on the hydrolysis rate of synthetic peptides. Recently an assay based on surface plasmon resonance (SPR) was introduced. We have taken advantage of the fact that the SPR signal is proportional to the mass of the analyte interacting with the immobilised molecule and developed two new improved efficient competition assay methods. Thus. high molecular weight binders were used as amplifiers of the surface plasmon resonance signal. Linkers were attached by a Heck reaction to the para-positions of the P1/P1' benzyloxy groups of a linear C-2-symmetric C-terminal duplicated inhibitor to enable (a) biotin labelling or (b) direct immobilisation of the inhibitor to the biosensor surface matrix. The interaction properties of a series of 17 structurally diverse inhibitors was assessed and compared to previously reported data. The most sensitive assay was obtained by immobilising the enzyme and amplifying the signal with an antibody, giving a detection range between 0.1 nM and 10 muM Immobilisation of the inhibitor resulted in a stable and durable surface but a narrower detection range (1-100 nM). The two competition assays are anticipated to be very suitable for fast screening of potential HIV inhibitors. (C) 2001 Elsevier Science B.V. All rights reserved.
• ANTIVIRAL PROTEASE INHIBITORS
  申请人：MEDIVIR AB

  公开号：EP1005493B1

  公开（公告）日：2005-11-02
• US6291687B1
  申请人：——

  公开号：US6291687B1

  公开（公告）日：2001-09-18
• US6489364B2
  申请人：——

  公开号：US6489364B2

  公开（公告）日：2002-12-03