ethyl ((R)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate | 912809-27-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl ((R)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate
• 英文别名: ethyl (((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl) (phenoxy)phosphoryl)-L-alaninate；9-(R)-[5-(R)-[[(S)-1-[(ethoxycarbonyl)ethyl]amino]phenoxyphosphonyl]methoxy-3-fluoro-2,5-dihydrofuran-2-yl]-9H-adenine；L-Alanine, N-((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydro-2-furanyl)oxy)methyl)phenoxyphosphinyl)-, ethyl ester；ethyl (2S)-2-[[[(2R,5R)-5-(6-aminopurin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl]oxymethyl-phenoxyphosphoryl]amino]propanoate
• CAS: 912809-27-9
• 化学式: C₂₁H₂₄FN₆O₆P
• 分子量: 506.43
• InChiKey: OCJRRXHWPBXZSU-BJBBEUPESA-N

物化性质

• 沸点：
  699.7±65.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  153
• 氢给体数：
  2
• 氢受体数：
  12

制备方法与用途

罗瓦福韦依塔芬酰胺（GS-9131）是腺苷核苷酸类似物GS-9148的前药，是一种口服活性核苷逆转录酶抑制剂(NRTI)。研究显示，罗瓦福韦依塔芬酰胺对多种NRTI突变体具有有效活性，并表现出显著的抗HIV-1活性。

反应信息

• 作为产物：
  描述：

  ((2R,3R,4S,5R)-3-(benzoyloxy)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methyl benzoate 在 吡啶 、 N-甲基咪唑 、 ammonium hydroxide 、 sodium hypochlorite 、 Jones reagent 、 偶氮二甲酸二异丙酯 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 silica gel 、 一溴化碘 、 potassium carbonate 、 溶剂黄146 、 三苯基膦 作用下， 以 甲醇 、 二氯甲烷 、 水 、 丙酮 、 乙腈 为溶剂， 反应 26.5h， 生成 ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate 、 ethyl ((R)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate
  参考文献：
  名称：

  CYCLOPENTENE-OXYMETHYLENE PHOSPHONAMIDATES AND RELATED COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS

  摘要：

  Substituted cyclopentene-oxymethylene phosphonamidates and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV- K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer, are disclosed herein.

  公开号：

  WO2024107859A1

文献信息

• [EN] SALTS OF HIV INHIBITOR COMPOUNDS<br/>[FR] SELS DE COMPOSÉS INHIBITEURS DU VIH
  申请人：GILEAD SCIENCES INC

  公开号：WO2010005986A1

  公开（公告）日：2010-01-14

  The invention is related to salts of anti-viral compounds, compositions containing such salts, and therapeutic methods that include the administration of such salts, as well as to processes and intermediates useful for preparing such salts.

  这项发明涉及抗病毒化合物的盐、含有这种盐的组合物，以及包括给予这种盐的治疗方法，还涉及用于制备这种盐的过程和中间体。
• 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。
• Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148
  作者：Richard L. Mackman、Adrian S. Ray、Hon C. Hui、Lijun Zhang、Gabriel Birkus、Constantine G. Boojamra、Manoj C. Desai、Janet L. Douglas、Ying Gao、Deborah Grant、Genevieve Laflamme、Kuei-Ying Lin、David Y. Markevitch、Ruchika Mishra、Martin McDermott、Rowchanak Pakdaman、Oleg V. Petrakovsky、Jennifer E. Vela、Tomas Cihlar

  DOI：10.1016/j.bmc.2010.03.041

  日期：2010.5

  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.
• THERAPEUTIC COMPOSITIONS FOR TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS
  申请人：Gilead Sciences, Inc.

  公开号：US20180085387A1

  公开（公告）日：2018-03-29

  Pharmaceutical formulations suitable for treating viral infections such as HIV are provided, in particular solid oral dosage forms including the compounds of Formula I, Formula II, Formula III, Formula IV, or pharmaceutically acceptable salts or solvates thereof, and one or more excipients.
• 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).