methyl 5-(benzoyloxy)-2-{1-[(benzyloxy)carbonyl]piperidin-2-yl}-6-hydroxypyrimidine-4-carboxylate | 917238-91-6

• 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-{1-[(benzyloxy)carbonyl]piperidin-2-yl}-6-hydroxypyrimidine-4-carboxylate
• 英文别名: methyl 5-benzoyloxy-6-oxo-2-(1-phenylmethoxycarbonylpiperidin-2-yl)-1H-pyrimidine-4-carboxylate
• CAS: 917238-91-6
• 化学式: C₂₆H₂₅N₃O₇
• 分子量: 491.5
• InChiKey: FTSUZHGHDOFVKX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 5-(benzoyloxy)-2-{1-[(benzyloxy)carbonyl]piperidin-2-yl}-6-hydroxypyrimidine-4-carboxylate 在 palladium on activated charcoal 氢气 、 caesium carbonate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 7.0h， 生成 Methyl 5-(benzoyloxy)-1-methyl-6-oxo-2-piperidin-2-yl-1,6-dihydropyrimidine-4-carboxylate
  参考文献：
  名称：

  4,5-Dihydroxypyrimidine Carboxamides and N-Alkyl-5-hydroxypyrimidinone Carboxamides Are Potent, Selective HIV Integrase Inhibitors with Good Pharmacokinetic Profiles in Preclinical Species

  摘要：

  The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.

  DOI：

  10.1021/jm060854f
• 作为产物：
  描述：

  benzyl 2-[(Z)-amino(hydroxyimino)methyl]piperidine-1-carboxylate 在 吡啶 作用下， 以 氯仿 为溶剂， 生成 methyl 5-(benzoyloxy)-2-{1-[(benzyloxy)carbonyl]piperidin-2-yl}-6-hydroxypyrimidine-4-carboxylate
  参考文献：
  名称：

  4,5-Dihydroxypyrimidine Carboxamides and N-Alkyl-5-hydroxypyrimidinone Carboxamides Are Potent, Selective HIV Integrase Inhibitors with Good Pharmacokinetic Profiles in Preclinical Species

  摘要：

  The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.

  DOI：

  10.1021/jm060854f

文献信息

• Discovery and Synthesis of HIV Integrase Inhibitors:  Development of Potent and Orally Bioavailable N-Methyl Pyrimidones
  作者：Cristina Gardelli、Emanuela Nizi、Ester Muraglia、Benedetta Crescenzi、Marco Ferrara、Federica Orvieto、Paola Pace、Giovanna Pescatore、Marco Poma、Maria del Rosario Rico Ferreira、Rita Scarpelli、Carl F. Homnick、Norihiro Ikemoto、Anna Alfieri、Maria Verdirame、Fabio Bonelli、Odalys Gonzalez Paz、Marina Taliani、Edith Monteagudo、Silvia Pesci、Ralph Laufer、Peter Felock、Kara A. Stillmock、Daria Hazuda、Michael Rowley、Vincenzo Summa

  DOI：10.1021/jm0704705

  日期：2007.10.1

  reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable

  人类1型免疫缺陷病毒（HIV-1）编码三种对于病毒复制必不可少的酶：逆转录酶，蛋白酶和整合酶。后者负责将病毒基因组整合到人类基因组中，因此代表了对AIDS进行化学疗法干预的诱人靶标。基于这种机制的药物尚未获得批准。在我们的实验室中发现苄基-二羟基嘧啶-羧酰胺是一类新型的，代谢稳定的药物，对HIV整合酶链转移步骤具有有效的抑制作用。进一步的努力导致了基于结构相关的N-Me嘧啶酮骨架的非常有效的化合物。该系列中最有趣的化合物之一是2-N-Me-吗啉代衍生物27a，其显示在血清存在下细胞中的CIC95为65 nM。该化合物在三种临床前物种中均具有良好的药代动力学特性，并且在几种抗筛选试验中未显示任何责任。
• Dihydroxy-pyrimidine and N-methylpyrimidone HIV-integrase inhibitors: Improving cell based activity by the quaternarization of a chiral center
  作者：Emanuela Nizi、Maria Vittoria Orsale、Benedetta Crescenzi、Giovanna Pescatore、Ester Muraglia、Anna Alfieri、Cristina Gardelli、Stéphane A.H. Spieser、Vincenzo Summa

  DOI：10.1016/j.bmcl.2009.06.091

  日期：2009.8

  In the context of HIV-integrase, dihydroxypyrimidine and N-methyl pyrimidone inhibitors the cellular activity of this class of compounds has been optimized by the introduction of a simple methyl substituent in the alpha-position of the C-2 side chains. Enhanced passive membrane permeability has been identified as the key factor driving the observed cell-based activity improvement. The rat PK profile of the alpha-methyl derivative 26a was also improved over its des-methyl exact analog. (C) 2009 Elsevier Ltd. All rights reserved.
• 4,5-Dihydroxypyrimidine Carboxamides and <i>N</i>-Alkyl-5-hydroxypyrimidinone Carboxamides Are Potent, Selective HIV Integrase Inhibitors with Good Pharmacokinetic Profiles in Preclinical Species
  作者：Vincenzo Summa、Alessia Petrocchi、Victor G. Matassa、Cristina Gardelli、Ester Muraglia、Michael Rowley、Odalys Gonzalez Paz、Ralph Laufer、Edith Monteagudo、Paola Pace

  DOI：10.1021/jm060854f

  日期：2006.11.1

  The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.