methyl 1-(4-fluorobenzyl)-3-[(3-hydroxypyrrolidin-1-yl)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate | 879398-89-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: methyl 1-(4-fluorobenzyl)-3-[(3-hydroxypyrrolidin-1-yl)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate
• 英文别名: 1h-Pyrrolo[2,3-c]pyridine-5-carboxylic acid,1-[(4-fluorophenyl)methyl]-3-[(3-hydroxy-1-pyrrolidinyl)methyl]-,methyl ester；methyl 1-[(4-fluorophenyl)methyl]-3-[(3-hydroxypyrrolidin-1-yl)methyl]pyrrolo[2,3-c]pyridine-5-carboxylate
• CAS: 879398-89-7
• 化学式: C₂₁H₂₂FN₃O₃
• 分子量: 383.422
• InChiKey: JPSNNFUPKQRDNQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  67.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 1-(4-fluorobenzyl)-3-[(3-hydroxypyrrolidin-1-yl)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate 、 N-甲基羟胺盐酸盐 在 sodium methylate 作用下， 以 甲醇 为溶剂， 以35%的产率得到1-(4-fluorobenzyl)-N-hydroxy-3-[(3-hydroxypyrrolidin-1-yl)methyl]-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide
  参考文献：
  名称：

  Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK

  摘要：

  HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the beta-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.10.022
• 作为产物：
  描述：

  3-羟基吡咯烷 、 methyl 3-[(dimethylamino)methyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate 在 氯甲酸乙酯 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 以88%的产率得到methyl 1-(4-fluorobenzyl)-3-[(3-hydroxypyrrolidin-1-yl)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate
  参考文献：
  名称：

  Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK

  摘要：

  HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the beta-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.10.022

文献信息

• Inhibitors of the Hiv Integrase Enzyme
  申请人：Dress Ruprecht Klaus

  公开号：US20070232644A1

  公开（公告）日：2007-10-04

  The present invention relates to compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, pharmaceutical compositions comprising compounds of formula (I), and their methods of use in treating HIV-infected mammals.

  本发明涉及公式(I)的化合物，或其药学上可接受的盐或溶剂，包括公式(I)的化合物的制药组合物，以及它们在治疗感染HIV的哺乳动物中的使用方法。