methyl 5-(benzoyloxy)-2-(2-(benzyloxycarbonylamino)propan-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate | 518048-00-5

• 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-oxo-1,6-dihydropyrimidine-4-carboxylate
• 英文别名: Methyl 5-(benzoyloxy)-2-(1-{[(benzyloxy)carbonyl]amino}-1-methylethyl)-6-hydroxypyrimidine-4-carboxylate；methyl 5-benzoyloxy-6-oxo-2-[2-(phenylmethoxycarbonylamino)propan-2-yl]-1H-pyrimidine-4-carboxylate
• CAS: 518048-00-5
• 化学式: C₂₄H₂₃N₃O₇
• 分子量: 465.463
• InChiKey: VDFHFNRANGCJHM-UHFFFAOYSA-N

物化性质

• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  132
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 5-(benzoyloxy)-2-(2-(benzyloxycarbonylamino)propan-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 lithium hydride 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 60.0 ℃ 、101.33 kPa 条件下， 反应 29.25h， 生成 雷特格韦
  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：

  N-苄氧羰酰基-2-甲基丙氨酸 在 吡啶 、 盐酸羟胺 、 氯甲酸乙酯 、 三乙胺 、 三氟乙酸酐 、 potassium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 氯仿 、 水 、 异丙醇 为溶剂， 反应 62.0h， 生成 methyl 5-(benzoyloxy)-2-(2-(benzyloxycarbonylamino)propan-2-yl)-6-oxo-1,6-dihydropyrimidine-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

• N-Substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase
  申请人：Crescenzi Benedetta

  公开号：US20080275004A1

  公开（公告）日：2008-11-06

  N-substituted 5-hydroxypyrimidin-6-one-4-carboxamides of formula: are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R 1 , R 2 , R 3 and R 4 are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

  本文描述了式子中定义的具有N取代的5-羟基嘧啶-6-酮-4-羧酰胺的化合物，这些化合物是HIV整合酶的抑制剂和HIV复制的抑制剂，其中R1、R2、R3和R4在此处定义。这些化合物在预防和治疗HIV感染以及预防、延迟发病和治疗艾滋病方面非常有用。这些化合物可以作为化合物本身或药物可接受的盐的形式用于对抗HIV感染和艾滋病。这些化合物及其盐可以作为药物组成部分，与其他抗病毒药物、免疫调节剂、抗生素或疫苗可选地结合使用。还描述了预防、治疗或延迟艾滋病发病的方法以及预防或治疗HIV感染的方法。
• N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase
  申请人：Crescenzi Benedetta

  公开号：US20060258860A1

  公开（公告）日：2006-11-16

  N-substituted 5-hydroxypyrimidin-6-one-4-carboxamides of formula: are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R 1 , R 2 , R 3 and R 4 are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of ASS. The compounds-are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

  本文介绍了式子中R1、R2、R3和R4已定义的N-取代的5-羟基嘧啶-6-酮-4-羧酰胺类化合物，其作为HIV整合酶抑制剂和HIV复制抑制剂。这些化合物可用于预防和治疗HIV感染以及预防、延缓ASS的发病和治疗。这些化合物可作为化合物本身或作为药物可接受的盐用于对抗HIV感染和AIDS。这些化合物及其盐可作为药物组合物中的成分，可选地与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用。本文还介绍了预防、治疗或延缓AIDS以及预防或治疗HIV感染的方法。
• N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase
  申请人：Crescenzi Benedetta

  公开号：US20050025774A1

  公开（公告）日：2005-02-03

  N-substituted 5-hydroxypyrimidin-6-one-4-carboxamides of formula (I): are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R 1 , R 2 , R 3 and R 4 are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

  描述了式(I)的N-取代的5-羟基嘧啶-6-酮-4-羧酰胺化合物作为HIV整合酶抑制剂和HIV复制抑制剂，其中R1、R2、R3和R4在此定义。这些化合物在预防和治疗HIV感染以及预防、延迟AIDS发病和治疗中是有用的。这些化合物可作为化合物本身或药学上可接受的盐的形式用于对抗HIV感染和AIDS。这些化合物及其盐可作为制药组合物的成分，可选择与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用。还描述了预防、治疗或延迟AIDS发病的方法以及预防或治疗HIV感染的方法。
• AN IMPROVED PROCESS FOR THE PREPARATION OF RALTEGRAVIR
  申请人：Budidet Shankar Reddy

  公开号：US20170334838A1

  公开（公告）日：2017-11-23

  The present invention provides a process for the preparation of crystalline anhydrous compound of Formula (X), Further, the present invention relates to the use of compound of Formula (X) preparation of Raltegravir (I) or its pharmaceutically acceptable salt thereof.

  本发明提供了一种制备公式（X）的结晶无水化合物的过程。此外，本发明还涉及使用公式（X）的化合物制备Raltegravir（I）或其药学上可接受的盐。
• 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.