methyl 5-(benzoyloxy)-2-(2-(benzyloxycarbonylamino)propan-2-yl)-6-methoxypyrimidine-4-carboxylate | 857664-99-4

• 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: methyl 5-(benzoyloxy)-2-(2-(benzyloxycarbonylamino)propan-2-yl)-6-methoxypyrimidine-4-carboxylate
• 英文别名: Methyl 5-benzoyloxy-6-methoxy-2-[2-(phenylmethoxycarbonylamino)propan-2-yl]pyrimidine-4-carboxylate
• CAS: 857664-99-4
• 化学式: C₂₅H₂₅N₃O₇
• 分子量: 479.489
• InChiKey: ACBICMOODWSLML-UHFFFAOYSA-N

物化性质

• 沸点：
  670.0±55.0 °C(Predicted)
• 密度：
  1.270±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  126
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl 5-(benzoyloxy)-2-(2-(benzyloxycarbonylamino)propan-2-yl)-6-methoxypyrimidine-4-carboxylate 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 28.25h， 生成 2-(2-(2-(diethylamino)-2-oxoacetamido)propan-2-yl)-4-(4-fluorobenzylcarbamoyl)-6-methoxypyrimidin-5-yl benzoate
  参考文献：
  名称：

  Hydroxyl may not be indispensable for raltegravir: Design, synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors

  摘要：

  A series of raltegravir derivatives 20-42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC50 values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.02.015
• 作为产物：
  描述：

  methyl 2-(2(((benzyloxy)carbonyl)amino)propan-2-yl)-5,6-dihydroxy-1,6-dihydropyrimidine-4-carboxylate 在 吡啶 、 lithium hydride 作用下， 以 1,4-二氧六环 为溶剂， 反应 14.0h， 生成 methyl 5-(benzoyloxy)-2-(2-(benzyloxycarbonylamino)propan-2-yl)-6-methoxypyrimidine-4-carboxylate
  参考文献：
  名称：

  Hydroxyl may not be indispensable for raltegravir: Design, synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors

  摘要：

  A series of raltegravir derivatives 20-42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC50 values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.02.015

文献信息

• Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection
  作者：Vincenzo Summa、Alessia Petrocchi、Fabio Bonelli、Benedetta Crescenzi、Monica Donghi、Marco Ferrara、Fabrizio Fiore、Cristina Gardelli、Odalys Gonzalez Paz、Daria J. Hazuda、Philip Jones、Olaf Kinzel、Ralph Laufer、Edith Monteagudo、Ester Muraglia、Emanuela Nizi、Federica Orvieto、Paola Pace、Giovanna Pescatore、Rita Scarpelli、Kara Stillmock、Marc V. Witmer、Michael Rowley

  DOI：10.1021/jm800245z

  日期：2008.9.25

  Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
• Hydroxypyrimidinone derivatives having inhibitory activity against hiv integrase
  申请人：Mikamiyama Hidenori

  公开号：US20070149556A1

  公开（公告）日：2007-06-28

  Compounds of Formula (1), pharmaceuticals containing the same, especially anti-HIV agents having anti viral activity, especially inhibitory activity against HIV integrase, wherein X represents either one of the following groups: (wherein, C ring is nitrogen-containing aromatic heterocyclic ring in which at least one atom in atoms neighboring the atom bound to the pyrimidine ring is unsubstituted nitrogen atom; R 10 is hydrogen or lower alkyl; D ring is aryl or heteroaryl) Z 1 and Z 3 each is independently a single bond, O, S, S (═O) or SO 2 ; Z 2 is a single bond, lower alkylene or lower alkenylene; Ar is optionally substituted aryl or optionally substituted heteroaryl; R 1 is lower alkyl, substituted lower alkyl or the like; R 2 is a hydrogen atom or optionally substituted lower alkyl; or R 1 and R 2 may form, together with an adjacent atom, an optionally substituted heterocyclic ring, a pharmaceutically acceptable salt or a solvate thereof.
• Hydroxypyrimidinone derivatives having inhibitory activity against HIV integrase
  申请人：Mikamiyama Hidenori

  公开号：US20100204237A1

  公开（公告）日：2010-08-12

  Compounds of Formula (1), pharmaceuticals containing the same, especially anti-HIV agents having anti viral activity, especially inhibitory activity against HIV integrase, wherein X represents either one of the following groups: (wherein, C ring is nitrogen-containing aromatic heterocyclic ring in which at least one atom in atoms neighboring the atom bound to the pyrimidine ring is unsubstituted nitrogen atom; R 10 is hydrogen or lower alkyl; D ring is aryl or heteroaryl) Z 1 and Z 3 each is independently a single bond, O, S, S(═O) or SO 2 ; Z 2 is a single bond, lower alkylene or lower alkenylene; Ar is optionally substituted aryl or optionally substituted heteroaryl; R 1 is lower alkyl, substituted lower alkyl or the like; R 2 is a hydrogen atom or optionally substituted lower alkyl; or R 1 and R 2 may form, together with an adjacent atom, an optionally substituted heterocyclic ring, a pharmaceutically acceptable salt or a solvate thereof.
• US7745453B2
  申请人：——

  公开号：US7745453B2

  公开（公告）日：2010-06-29
• Hydroxyl may not be indispensable for raltegravir: Design, synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors
  作者：Ziwen Wang、Mingxiao Wang、Xue Yao、Yue Li、Wentao Qiao、Yunqi Geng、Yuxiu Liu、Qingmin Wang

  DOI：10.1016/j.ejmech.2012.02.015

  日期：2012.4

  A series of raltegravir derivatives 20-42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC50 values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors. (C) 2012 Elsevier Masson SAS. All rights reserved.