Prodrugs of nucleoside phosphonates
AssigneeKatholieke Universiteit Leuven
InventorsGraciela Andrei, Steven De Jonghe, Elisabetta Groaz, Piet Herdewijn, Min Luo, Dominique Schols, Robert Snoeck
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Abstract
The present invention relates to novel phosphonoamidate prodrugs. 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 as the herpes simplex virus 1, herpes simplex virus 2, human cytomegalovirus, varicella zoster virus, vaccinia virus and adenovirus.
Claims12
A compound of formula Ia:
- wherein
- B is a natural or modified nucleobase
- R1 has the general formula II
- wherein
- R3 is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, C3-C8-cycloalkyl, C3-C8-cycloalkyl-alkyl, aryl(C1-C6)alkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl C1-C10 alkyl, halo C1-C10 alkyl, and alkoxyalkyl;
- R4 is X—COOR5;
- wherein X is aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or C3-C8-cycloalkyl, and wherein said aryl, heteroaryl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8-cycloalkyl optionally contains one or more functions, atoms or radicals independently selected from the group consisting of halogen, halo-alkyl, cyano, C1-C7 alkoxy;
- and
- wherein R5 is selected from the group consisting of aryl, heteroaryl, C1-C10 alkyl, C3-C8-cycloalkyl, C3-C8cycloalkyl-alkyl, aryl(C1-C6)alkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl C1-C10 alkyl, halo C1-C10 alkyl, and alkoxyalkyl;
- and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.
A compound selected from the group consisting of Diamyl {(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-aspartate;
- Diamyl {(5R)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-aspartate;
- Diamyl {(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-aspartate;
- diamyl {(5R)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-aspartate;
- Amyl ((5S)-5-((6-amino-9H-purin-9-yl)methyl)-2-oxido-1,4,2-dioxaphosphinan-2-yl)-L-phenylalaninate;
- Amyl ((5S)-5-((6-amino-9H-purin-9-yl)methyl)-2-oxido-1,4,2-dioxaphosphinan-2-yl)-L-methioninate;
- Amyl ((5S)-5-((6-amino-9H-purin-9-yl)methyl)-2-oxido-1,4,2-dioxaphosphinan-2-yl)-L-alaninate;
- Diamyl {(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-glutamate;
- Amyl {(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-valinate;
- Amyl {(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-leucinate;
- Amyl {(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-isoleucinate;
- diamyl 2,2′-((((((S)-1-(6-amino-9H-purin-9-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(2S,2′S)-bis(3-methylbutanoate);
- amyl {(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl}-L-phenylalaninate;
- diamyl ((5S)-5-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)-2-oxido-1,4,2-dioxaphosphinan-2-yl)-L-glutamate;
- amyl ((5S)-5-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)-2-oxido-1,4,2-dioxaphosphinan-2-yl)-L-valinate;
- amyl ((5S)-5-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)-2-oxido-1,4,2-dioxaphosphinan-2-yl)-L leucinate;
- amyl ((5S)-5-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)-2-oxido-1,4,2-dioxaphosphinan-2-yl)-L-isoleucinate;
- and diamyl ((5S)-5-((4-amino-2-oxopyrimidin-1(2H)-yl)methyl)-2-oxido-1,4,2-dioxaphosphinan-2-yl)-D-aspartate.
Dependencies are inferred from the claim text.