phenyl [5-(R)-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-(R)-yloxymethyl]phosphonic acid | 1234081-00-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: phenyl [5-(R)-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-(R)-yloxymethyl]phosphonic acid
• 英文别名: [(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-phenoxyphosphinic acid
• CAS: 1234081-00-5
• 化学式: C₁₆H₁₅FN₅O₅P
• 分子量: 407.298
• InChiKey: WXTVLKRDSWMOIL-BLLLJJGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  135
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  L(-)-乳酸乙酯 、 phenyl [5-(R)-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-(R)-yloxymethyl]phosphonic acid 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以19%的产率得到ethyl (2S)-2-[[(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-phenoxyphosphoryl]oxypropanoate
  参考文献：
  名称：

  Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

  摘要：

  GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] 4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver 4 and its active phosphorylated metabolite 15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug 5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3 mg/kg) in Beagle dogs, high levels (>9.0 mu M) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.03.041
• 作为产物：
  描述：

  在 ammonium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 5.0h， 以240 mg的产率得到phenyl [5-(R)-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-(R)-yloxymethyl]phosphonic acid
  参考文献：
  名称：

  Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

  摘要：

  GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] 4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver 4 and its active phosphorylated metabolite 15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug 5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3 mg/kg) in Beagle dogs, high levels (>9.0 mu M) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.03.041

文献信息

• Processes and intermediates for preparing anti-HIV agents
  申请人：Gilead Sciences, Inc.

  公开号：US10196419B2

  公开（公告）日：2019-02-05

  The invention provides synthetic processes and synthetic intermediates that can be used to prepare compounds having useful anti-HIV properties.

  本发明提供了可用于制备具有有用的抗艾滋病毒特性的化合物的合成工艺和合成中间体。
• Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate
  申请人：Gilead Sciences, Inc.

  公开号：US10851125B2

  公开（公告）日：2020-12-01

  The present invention relates to novel forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate, pharmaceutical formulations, and therapeutic uses thereof in treating viral infections (e.g., an HIV infection).

  本发明涉及新型((S)-((((2R,5R)-5-(6-氨基-9H-嘌呤-9-基)-4-氟-2,5-二氢呋喃-2-基)氧基)甲基)(苯氧基)磷酰)-L-丙氨酸乙酯、药物制剂及其在治疗病毒感染（如艾滋病毒感染）中的治疗用途。
• PROCESSES AND INTERMEDIATES FOR PREPARING ANTI-HIV AGENTS
  申请人：Gilead Sciences, Inc.

  公开号：EP2710019B1

  公开（公告）日：2017-05-03
• CRYSTALLINE FORMS OF ETHYL ((S)-((((2R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-4-FLUORO-2,5-DIHYDROFURAN-2-YL)OXY)METHYL)(PHENOXY)PHOSPHORYL)-L-ALANINATE
  申请人：Gilead Sciences, Inc.

  公开号：US20190040092A1

  公开（公告）日：2019-02-07

  The present invention relates to novel forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate, pharmaceutical formulations, and therapeutic uses thereof in treating viral infections (e.g., an HIV infection).
• US8987437B2
  申请人：——

  公开号：US8987437B2

  公开（公告）日：2015-03-24