1-[[[[(3S,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-基]氧基]羰基]氧基]-2,5-吡咯烷二酮 | 253265-98-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃类
• 中文名称: 1-[[[[(3S,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-基]氧基]羰基]氧基]-2,5-吡咯烷二酮
• 中文别名: 地瑞那韦杂质
• 英文名称: Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester (3S,3aR,6aS)-(hexahydro-furo[2,3-b]furan-3-yl) ester
• 英文别名: BIS THF HNS Derivative 1；[(3aR,4S,6aS)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] (2,5-dioxopyrrolidin-1-yl) carbonate
• CAS: 253265-98-4
• 化学式: C₁₁H₁₃NO₇
• 分子量: 271.227
• InChiKey: VCFNCYVHQSHFRH-XSSZXYGBSA-N

物化性质

• 沸点：
  391.8±52.0 °C(Predicted)
• 密度：
  1.51±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  91.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-[[[[(3S,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-基]氧基]羰基]氧基]-2,5-吡咯烷二酮 、 4-氨基-N-[(2R, 3S)-3-氨基-2-羟基-4-苯丁基]-N-异丁基苯磺酰胺 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 darunavir
  参考文献：
  名称：

  Discovery and Selection of TMC114, a Next Generation HIV-1 Protease Inhibitor

  摘要：

  The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2 ' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC 114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.

  DOI：

  10.1021/jm049560p
• 作为产物：
  描述：

  六氢呋喃并[2,3-b]呋喃-3-醇 在 potassium carbonate 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成 1-[[[[(3S,3aR,6aS)-六氢呋喃并[2,3-b]呋喃-3-基]氧基]羰基]氧基]-2,5-吡咯烷二酮
  参考文献：
  名称：

  Discovery and Selection of TMC114, a Next Generation HIV-1 Protease Inhibitor

  摘要：

  The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2 ' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC 114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.

  DOI：

  10.1021/jm049560p

文献信息

• Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation
  作者：Arun K. Ghosh、Heather L. Osswald、Kristof Glauninger、Johnson Agniswamy、Yuan-Fang Wang、Hironori Hayashi、Manabu Aoki、Irene T. Weber、Hiroaki Mitsuya

  DOI：10.1021/acs.jmedchem.6b00639

  日期：2016.7.28

  A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF

  已经设计、合成和评估了一系列具有亲脂性金刚烷基 P1 配体的强效 HIV-1 蛋白酶抑制剂。我们利用 Sharpless 不对称环氧化作为关键步骤开发了金刚烷衍生的羟乙胺等排体的对映体选择性合成。检测了结合 P1-金刚烷基甲基和 P2 配体的各种抑制剂，例如 3-( R )-THF、3-( S )-THF、双-THF 和 THF-THP。S1' 口袋也用苯基和苯甲基配体进行了探测。具有异丁基 P1' 配体和双 THF P2 配体的抑制剂15d被证明是该系列中最有效的。与抑制剂2相比，抑制剂15d的 cLogP 值有所提高与苯甲基 P1-配体。15d、15h和15i与 HIV-1 蛋白酶复合物的 X 射线结构研究揭示了抑制剂-蛋白质相互作用的分子洞察力。
• [EN] CARBAMATES AS HIV PROTEASE INHIBITORS<br/>[FR] CARBAMATES INHIBITEURS DE PROTEASE DU VIH
  申请人：UNIV ILLINOIS

  公开号：WO2003078438A1

  公开（公告）日：2003-09-25

  Compounds useful for inhibiting HIV protease are disclosed. Methods of making the compounds, and their use as thereapeutic agents, for example, in treating wild-type HIV and of multidrug-resistant strains of HIV, also are disclosed.

  本发明揭示了用于抑制HIV蛋白酶的化合物。本发明还揭示了制备这些化合物的方法以及它们作为治疗剂的用途，例如用于治疗野生型HIV和多药耐药株的HIV。
• HIV protease inhibitors
  申请人：Ghosh K. Arun

  公开号：US20070082883A1

  公开（公告）日：2007-04-12

  Compounds useful for inhibiting HIV protease are disclosed. Methods of making the compounds, and their use as therapeutic agents, for example, in treating wild-type HIV and of multidrug-resistant strains of HIV, also are disclosed.

  本发明公开了用于抑制HIV蛋白酶的化合物，公开了制备这些化合物的方法以及这些化合物作为治疗剂的用途，例如用于治疗野生型HIV和多药耐药株的HIV。
• PROCESS FOR THE PREPARATION OF (3R,3AS,6AR)-HEXAHYDROFURO [2,3-B] FURAN-3-YL (1S,2R)-3-[[(4-AMINOPHENYL) SULFONYL] (ISOBUTYL) AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE
  申请人：Wigerinck Piet Tom Bert Paul

  公开号：US20110160468A1

  公开（公告）日：2011-06-30

  The present invention relates to a process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate as well as novel intermediates for use in said process. (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate is particularly useful as an HIV protease inhibitor.

  本发明涉及一种制备（3R,3aS,6aR）-六氢呋喃[2,3-b]呋喃-3-基（1S,2R）-3-[[(4-氨基苯基)磺酰](异丁基)氨基]-1-苄基-2-羟基丙基氨基甲酸酯的方法，以及用于该方法的新型中间体。 （3R,3aS,6aR）-六氢呋喃[2,3-b]呋喃-3-基（1S,2R）-3-[[(4-氨基苯基)磺酰](异丁基)氨基]-1-苄基-2-羟基丙基氨基甲酸酯特别适用于作为HIV蛋白酶抑制剂。
• Method and compositions for treating HIV infections
  申请人：Purdue Research Foundation

  公开号：EP2491785A1

  公开（公告）日：2012-08-29

  Described herein are compounds and compositions that are useful in the treatment of AIDS, and AIDS-related diseases. In addition, compounds are described herein that are both a protease dimerization and a protease inhibitor.

  本文描述了可用于治疗艾滋病和艾滋病相关疾病的化合物和组合物。此外，本文还描述了既是蛋白酶二聚体又是蛋白酶抑制剂的化合物。