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Prodrugs of fluorinated acyclic nucleoside phosphonates

A cycloalkyl compound technology, applied in the field of new aminophosphonate prodrugs, can solve the problems of impenetrability and hindering antiviral activity

Inactive Publication Date: 2018-06-08
KATHOLIEKE UNIV LEUVEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Phosphonates are negatively charged at physiological pH, and thus cannot penetrate lipid-rich cell membranes, which hinders their antiviral activity

Method used

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  • Prodrugs of fluorinated acyclic nucleoside phosphonates
  • Prodrugs of fluorinated acyclic nucleoside phosphonates
  • Prodrugs of fluorinated acyclic nucleoside phosphonates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Example 1: (S)-1-{3-fluoro-2-[(diethylphosphoryl)methoxy]propyl}-N 3 Synthesis of -(Benzyloxymethyl)thymine (6a)

[0160]

[0161] A solution of DIAD (0.32 mL, 1.64 mmol) in anhydrous THF (1 mL) was added dropwise to compound 4a at room temperature 1 (200mg, 0.82mmol), compound 5 (240mg, 0.98mmol) and Ph 3 P (430mg, 1.64mmol) in a mixture of anhydrous THF (5mL). The reaction mixture was stirred for 12 hours, then it was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient DCM / MeOH, 80:1, v / v; DCM / MeOH, 50:1, v / v) to give 6a (310 mg, 80%) as a colorless oil . 1 H NMR (300MHz, CDCl 3 ): δ7.39-7.25(m,5H,ArH),7.14-7.12(m,1H,H-6),5.50(s,2H,OCH 2 N),4.73-4.33(m,4H,CH 2 -Ar,H-3'),4.17-3.92(m,7H,H-1',H-2',2x CH 2 CH 3 ),3.84-3.66(m,2H,PCH 2 ), 1.93 (d, J=1.2Hz, 3H, CH 3 -5),1.34-1.28(m,6H,2xCH 2 CH 3 ); 13 C NMR (75MHz, CDCl 3 ): δ163.8(C-4), 151.8(C-2), 140.5(C-6), 138.1(Ar-C), 128.3(Ar-C), 127.7(Ar...

Embodiment 2

[0162] Example 2: Synthesis of (R)-1-{3-fluoro-2-[(diethylphosphoryl)methoxy]propyl}-N3-(benzyloxymethyl)thymine (6b)

[0163]

[0164] According to the procedure used for the preparation of 6a, from compound 4b 1 (300mg, 1.23mmol), Compound 5 (360mg, 1.47mmol), Ph 3 A solution of P (640 mg, 2.46 mmol) and DIAD (0.48 mL, 2.46 mmol) in anhydrous THF (8 mL) initially gave compound 6b (460 mg, 70%) as a colorless oil. The crude residue was purified by silica gel column chromatography (gradient DCM / MeOH, 80:1, v / v; DCM / MeOH, 50:1, v / v). 1 H NMR (300MHz, CDCl 3 ): δ7.39-7.25(m,5H,ArH),7.13(t,J=1.3Hz,1H,H-6),5.50(s,2H,OCH 2 N),4.73-4.33(m,4H,CH 2 -Ar,H-3'),4.17-3.91(m,7H,H-1',H-2',2x CH 2 CH 3 ),3.84-3.66(m,2H,PCH 2 ), 1.93 (d, J=1.1Hz, 3H, CH 3 -5),1.34-1.28(m,6H,2xCH 2 CH 3 ); 13 C NMR (75MHz, CDCl 3 ): δ163.8(C-4), 151.8(C-2), 140.5(C-6), 138.0(Ar-C), 128.3(Ar-C), 127.7(Ar-C), 109.7(C- 5), 82.3(d, 1 J C,F =173.5Hz, C-3'), 78.6(dd, 2 J C,F =18.5Hz, 3 J C,P =9...

Embodiment 3

[0165] Example 3: (S)-1-{3-fluoro-2-[(diethylphosphoryl)methoxy]propyl}thymine (7a)

[0166]

[0167] A suspension of compound 6a (240 mg, 0.51 mmol) and Pd / C on charcoal (10% w / w, 120 mg) in EtOH (10 mL) was purged with nitrogen and then hydrogen, then allowed to stir under an atmosphere of hydrogen. After 24 hours, the mixture was filtered through a pad of celite, and the filtrate was evaporated under reduced pressure to give the crude product. Then, the residue was redissolved in MeOH (10 mL) and Et 3 N (1 mL), and the solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting crude residue was purified by silica gel column chromatography (gradient DCM / MeOH, 30:1, v / v; DCM / MeOH, 20:1, v / v) to give a colorless oil Form 7a (160 mg, 90%). 1 H NMR (300MHz, CDCl 3 ): δ9.63(s,1H,NHCO),7.16(t,J=1.3Hz,1H,H-6),4.72-4.33(m,2H,H-3'),4.17-3.90(m,7H ,H-1',H-2',2x CH 2 CH 3 ),3.83-3.63(m,2H,PCH 2 ), 1.89...

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Abstract

The present invention relates to novel phosphonoamidate prodrugs of acyclic nucleoside phosphonates with a 3-fluoro-2-(phosphonomethoxy)propyl side chain. The invention also relates to the use of these novel phosphonate-modified nucleosides to treat or prevent viral infections and their use to manufacture a medicine to treat or prevent viral infections, particularly infections with viruses such asthe hepatitis B virus, the human immunodeficiency virus, the human cytomegalovirus and the varicella zoster virus.

Description

technical field [0001] The present invention relates to novel phosphonoamidate prodrugs of acyclic nucleoside phosphonates having a 3-fluoro-2-(phosphonomethoxy)propyl side chain. The present invention also relates to the use of these novel phosphonate-modified nucleosides for the treatment or prevention of viral infections and their use in the manufacture of medicaments for the treatment or prevention of viral infections, especially those produced by viruses such as hepatitis B virus, human immunodeficiency virus, Infection with human cytomegalovirus and varicella-zoster virus. Background technique [0002] Acyclic nucleoside phosphonate (ANP) is an important class of antiviral drugs. Their main structural features are: (1) the aliphatic side chain in place of the cyclic sugar moiety and (2) the presence of a phosphonate group attached to the acyclic nucleoside moiety. [0003] The phosphonomethoxy functional group (P-C-O) present in ANP can be considered an isostere of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6512A61K31/685C07F9/6561
CPCC07F9/65616C07F9/6512A61K45/06A61K31/675A61P35/00A61P31/12Y02A50/30A61K2300/00
Inventor 格拉谢拉·安德烈史蒂文·德·容格伊丽莎白·格洛阿扎皮特·赫德维金罗敏多米尼克·斯科尔斯罗伯特·斯诺克
Owner KATHOLIEKE UNIV LEUVEN
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