(4R,5S,6S,7R)-hexahydro-5,6-bis(2-methoxyethoxymethoxy)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one | 153181-25-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂卓
• 英文名称: (4R,5S,6S,7R)-hexahydro-5,6-bis(2-methoxyethoxymethoxy)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one
• 英文别名: (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(2-methoxyethoxymethoxy)-1,3-diazepan-2-one
• CAS: 153181-25-0
• 化学式: C₂₇H₃₈N₂O₇
• 分子量: 502.608
• InChiKey: YQOKUWNKUGSUIZ-XPGKHFPBSA-N

物化性质

• 沸点：
  652.3±55.0 °C(Predicted)
• 密度：
  1.17±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  36
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  96.5
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (4R,5S,6S,7R)-hexahydro-5,6-bis(2-methoxyethoxymethoxy)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one 在 吡啶 、 氢氧化钾 、 草酰氯 、 sodium hydride 作用下， 以 乙二醇 、 苯 为溶剂， 反应 72.0h， 生成 3-[[(4R,5S,6S,7R)-4,7-dibenzyl-3-[[3-(1H-imidazol-2-ylcarbamoyl)phenyl]methyl]-5,6-bis(2-methoxyethoxymethoxy)-2-oxo-1,3-diazepan-1-yl]methyl]-N-(1H-imidazol-2-yl)benzamide
  参考文献：
  名称：

  Cyclic Urea Amides:  HIV-1 Protease Inhibitors with Low Nanomolar Potency against both Wild Type and Protease Inhibitor Resistant Mutants of HIV

  摘要：

  Cyclic urea amides, a novel series of HIV-1 protease (HIV PR) inhibitors, have increased activity against drug-resistant mutants of the HIV PR. The design strategy for these inhibitors is based on the hypotheses that (i) the hydrogen-bonding interactions between the inhibitor and the protease backbone will remain constant for wild-type and mutant enzymes and (ii) inhibitors which are capable of forming many nonbonded interactions, distributed throughout the active site, will experience a lower percent change in binding energy as a result of mutation in the target enzyme than those that form fewer interactions by partial occupation of the active site. The cyclic urea amide, SD146, forms 14 hydrogen bonds and 191 van der Waals contacts to HIV PR. SD146 is a very potent antiviral agent (IC90 = 5.1 nM) against wild-type HIV and maintains the same or improved level of high potency against a range of mutant strains of HIV with resistance to a wide variety of HIV protease inhibitors.

  DOI：

  10.1021/jm960586t
• 作为产物：
  描述：

  N-Cbz-D-苯丙氨醛 在 palladium on activated charcoal [VCl3(thf)3] 、 氢气 、 N,N-二异丙基乙胺 、 锌 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 (4R,5S,6S,7R)-hexahydro-5,6-bis(2-methoxyethoxymethoxy)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one
  参考文献：
  名称：

  环状HIV蛋白酶抑制剂：合成，构象分析，P2 / P2'的结构活性关系和环状脲的分子识别。

  摘要：

  HIV-1蛋白酶（HIV-1PR）与拟肽抑制剂的复合物的高分辨率X射线结构揭示了结构水分子的存在，该结构水分子氢键合到酶的可移动侧翼和过渡过渡带两侧的两个羰基上态的抑制剂。利用C2对称二醇抑制剂的结构活性关系，计算机辅助药物设计工具和第一原理，我们设计并合成了新型的环状脲，其结合了该结构水并将侧链残基预先组织为最佳结合构象。构象分析表明对伪双轴苄基和伪二季基羟基取代基的偏爱和对RSSR立体化学的对映体偏爱。HIV-1PR和一种环状尿素DMP323的配合物的X射线和溶液NMR结构证实了结构水的置换。另外，结合的和“未结合的”（小分子X射线）配体具有相似的构象。提出了高度的预组织，互补性和水置换的熵增益，以解释这些小分子对酶的高度亲和力。小尺寸可能有助于在动物中观察到良好的口服生物利用度。基于结构优化的侧链填充酶的S2和S2'口袋产生了DMP323，该药物已在I期临床试验中进行了研究，但发现其

  DOI：

  10.1021/jm9602571

文献信息

• Cyclic HIV Protease Inhibitors:  Design and Synthesis of Orally Bioavailable, Pyrazole P2/P2‘ Cyclic Ureas with Improved Potency
  作者：Qi Han、Chong-Hwan Chang、Renhua Li、Yu Ru、Prabhakar K. Jadhav、Patrick Y. S. Lam

  DOI：10.1021/jm9704199

  日期：1998.6.1

  Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by introducing bidentate hydrogen-bonding oxime and pyrazole groups at the meta-position of the phenyl ring on the P2/P2' substituents of cyclic ureas. Nonsymmetrical cyclic ureas incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2' show potent protease inhibition and antiviral activities

  通过在环状脲的P2 / P2'取代基上苯环的间位引入二齿氢键合肟和吡唑基，可以设计和合成高效HIV-1蛋白酶（HIVPR）抑制剂。包含3（1H）-吡唑基苄基作为P2和亲水性官能团作为P2'的非对称环状脲显示出强大的蛋白酶抑制作用和针对HIV的抗病毒活性，并具有良好的口服生物利用度。HIVPR.10A复合物的X射线结构证实，两个10A的吡唑环与HIVPR的Asp30 / 30'的侧链氧（C = O）和主链氮（NH）形成双齿氢键。
• Catalytic Carbonylation of Functionalized Diamines:  Application to the Core Structure of DMP 323 and DMP 450
  作者：Keisha-Gay Hylton、A. Denise Main、Lisa McElwee-White

  DOI：10.1021/jo026816v

  日期：2003.2.1

  W(CO)(6)-catalyzed carbonylation provides an alternative to phosgene or phosgene derivatives such as 1,1-carbonyldiimidazole (CDI) for the conversion of amines to ureas. As an illustration, the core structure of the HIV protease inhibitors DMP 323 and DMP 450 has been prepared by catalytic carbonylation of diamine intermediates from the original syntheses.
• Chem. Biol. 1996, 3, 301-314
  作者：

  DOI：——

  日期：——
• Cyclic HIV Protease Inhibitors:  Synthesis, Conformational Analysis, P2/P2‘ Structure−Activity Relationship, and Molecular Recognition of Cyclic Ureas
  作者：Patrick Y. S. Lam、Yu Ru、Prabhakar K. Jadhav、Paul E. Aldrich、George V. DeLucca、Charles J. Eyermann、Chong-Hwan Chang、George Emmett、Edward R. Holler、Wayne F. Daneker、Liangzhu Li、Pat N. Confalone、Robert J. McHugh、Qi Han、Renhua Li、Jay A. Markwalder、Steven P. Seitz、Thomas R. Sharpe、Lee T. Bacheler、Marlene M. Rayner、Ronald M. Klabe、Linyee Shum、Dean L. Winslow、David M. Kornhauser、David A. Jackson、Susan Erickson-Viitanen、C. Nicholas Hodge

  DOI：10.1021/jm9602571

  日期：1996.1.1

  X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first

  HIV-1蛋白酶（HIV-1PR）与拟肽抑制剂的复合物的高分辨率X射线结构揭示了结构水分子的存在，该结构水分子氢键合到酶的可移动侧翼和过渡过渡带两侧的两个羰基上态的抑制剂。利用C2对称二醇抑制剂的结构活性关系，计算机辅助药物设计工具和第一原理，我们设计并合成了新型的环状脲，其结合了该结构水并将侧链残基预先组织为最佳结合构象。构象分析表明对伪双轴苄基和伪二季基羟基取代基的偏爱和对RSSR立体化学的对映体偏爱。HIV-1PR和一种环状尿素DMP323的配合物的X射线和溶液NMR结构证实了结构水的置换。另外，结合的和“未结合的”（小分子X射线）配体具有相似的构象。提出了高度的预组织，互补性和水置换的熵增益，以解释这些小分子对酶的高度亲和力。小尺寸可能有助于在动物中观察到良好的口服生物利用度。基于结构优化的侧链填充酶的S2和S2'口袋产生了DMP323，该药物已在I期临床试验中进行了研究，但发现其
• Cyclic Urea Amides:  HIV-1 Protease Inhibitors with Low Nanomolar Potency against both Wild Type and Protease Inhibitor Resistant Mutants of HIV
  作者：Prabhakar K. Jadhav、Paul Ala、Francis J. Woerner、Chong-Hwan Chang、Sena S. Garber、Elizabeth D. Anton、Lee T. Bacheler

  DOI：10.1021/jm960586t

  日期：1997.1.1

  Cyclic urea amides, a novel series of HIV-1 protease (HIV PR) inhibitors, have increased activity against drug-resistant mutants of the HIV PR. The design strategy for these inhibitors is based on the hypotheses that (i) the hydrogen-bonding interactions between the inhibitor and the protease backbone will remain constant for wild-type and mutant enzymes and (ii) inhibitors which are capable of forming many nonbonded interactions, distributed throughout the active site, will experience a lower percent change in binding energy as a result of mutation in the target enzyme than those that form fewer interactions by partial occupation of the active site. The cyclic urea amide, SD146, forms 14 hydrogen bonds and 191 van der Waals contacts to HIV PR. SD146 is a very potent antiviral agent (IC90 = 5.1 nM) against wild-type HIV and maintains the same or improved level of high potency against a range of mutant strains of HIV with resistance to a wide variety of HIV protease inhibitors.