Antiviral compounds, a process for their preparation, and their use for treating viral infections

1. A compound of formula I:

wherein

B is any natural nucleobase

R 1 has the general formula II

wherein

R 3 is selected from the group consisting of aryl, heteroaryl, C 1 -C 10 alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 cycloalkyl-alkyl, aryl(C 1 -C 6 )alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, hydroxyl C 1 -C 10 alkyl, halo C 1 -C 10 alkyl, and alkoxyalkyl;

R 4 is selected from the group consisting of aryl, heteroaryl, C 1 -C 10 alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 cycloalkyl-alkyl, aryl(C 1 -C 6 )alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, hydroxyl C 1 -C 10 alkyl, halo C 1 -C 10 alkyl, alkoxyalkyl, X—COOR 5 , X—O(C═O)—R 5 ;

wherein X is aryl, heteroaryl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, or C 3 -C 8 -cycloalkyl, and wherein said aryl, heteroaryl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 -cycloalkyl optionally contains one or more functions, atoms or radicals independently selected from the group consisting of halogen, halo-alkyl, cyano, C 1 -C 7 alkoxy; and

wherein R 5 is selected from the group consisting of aryl, heteroaryl, C 1 -C 10 alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 cycloalkyl-alkyl, aryl(C 1 -C 6 )alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, hydroxyl C 1 -C 10 alkyl, halo C 1 -C 10 alkyl, and alkoxyalkyl;

R 2 is O—Ar, wherein Ar is a fused bicyclic aryl moiety or a monocyclic aryl moiety, either of which aryl moieties is carbocyclic or heterocyclic and is phenyl optionally substituted with a halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;

or R 2 has the general formula II

wherein R 1 and R 2 can be identical or different;

or R 1 and R 2 have the general formula III

wherein R 1 and R 2 can be identical or different;

Z is O;

R is selected from the group consisting of H, aryl, heteroaryl, C 1 -C 10 alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 cycloalkyl-alkyl, aryl(C 1 -C 6 )alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, hydroxyl C 1 -C 10 alkyl, halo C 1 -C 10 alkyl, alkoxyalkyl;

and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.

2. The compound according to claim 1 , wherein B is selected from the group of adenine, thymine, cytosine and guanine.

3. The compound according to claim 1 , wherein R 2 is O-Ph.

4. The compound according to claim 1 , wherein R 3 is selected from C 1 -C 10 alkyl.

5. The compound according to claim 1 , wherein X is C 1 -C 10 alkyl and R 5 is C 1 -C 10 alkyl.

6. The compound according to claim 1 , wherein R 2 is O-Ph, and wherein R 1 is selected from the group consisting of

7. The compound according to claim 1 , wherein R 1 and R 2 are identical and are selected from the group consisting of:

8. A compound selected from the group consisting of:

1′α-(Adenin-9-yl)-2′-deoxy-3′-O-{[N,N′-bis(n-propyl-L-phenylalaninate)]methylphosphonobisamidate}-L-threose;

1′α-(Adenin-9-yl)-2′-deoxy-3′-O-{[N-(isopropyl-L-alaninate)](phenoxy)methylphosphonoamidate]}-L-threose;

1′α-(Adenin-9-yl)-2′-deoxy-3′-O-{[N-(diisoamyl-L-aspartate)](phenoxy)methylphosphonoamidate}-L-threose;

1′α-(Thymin-1-yl)-2′-deoxy-3′-O-[N,N′-bis(n-propyl-L-phenylalaninate)) methylphosphonobisamidate]-threose;

1′α-(Thymin-1-yl)-2′-deoxy-3′-O-{[N-(isopropyl-L-alaninate)](phenoxy)methylphosphonoamidate}-L-threose;

1′α-(Thymin-1-yl)-2′-deoxy-3′-{[N-(diisoamyl-L-aspartate)](phenoxy)methylphosphonoamidate}-L-threose;

1′α-(Cytosin-1-yl)-2′-deoxy-3′-O-{[N,N′-bis(n-propyl-L-alaninate)]methylphosphonobisamidate}-L-threose;

1′α-(Cytosin-1-yl)-2′-deoxy-3′-O-{[N-(isopropyl-L-alaninate)](phenoxy)methylphosphonoamidate}-L-threose;

1′α-(Guanin-9-yl)-2′-deoxy-3′-O-[N,N′-bis(n-propyl-L-phenylalaninate)]methylphosphonobisamidate]-threose;

1′α-(Guanin-9-yl)-2′-deoxy-3′-O-[N,N′-bis(n-propyl-L-alaninate)]methylphosphonobisamidate]-threose;

1′α-(Guanin-9-yl)-2′-deoxy-3′-O-{[N-(isopropyl-L-alaninate)](phenoxy)methylphosphonoamidate}-L-threose,

with respectively the following structural formula's:

9. A compound according to claim 1 for use as a medicine.

10. A compound according to claim 1 for use as a medicine for the treatment of a viral infection in an animal, mammal or human.

11. The compound according to claim 10 , wherein said viral infection is an infection of HBV, HIV, HCV, RSV, dengue virus, influenza virus, CMV, adenovirus, parainfluenza, rhinovirus, BK virus, and/or HSV.

12. A compound according to claim 1 for use as a medicine for the treatment of a proliferative disorder or a cancer in an animal, mammal or human.

13. A pharmaceutical composition comprising a therapeutic amount of a compound according to claim 1 and one or more pharmaceutically acceptable excipients.

14. The pharmaceutical composition according to claim 13 , further comprising one or more biologically active drugs being selected from the group consisting of antiviral drugs and/or anti-proliferative drugs.

15. A method of treatment of a viral infection in an animal, mammal or human, comprising the administration of a therapeutically effective amount of a compound according to claim 1 , optionally in combination with one or more pharmaceutically acceptable excipients.

16. A method of treatment of a proliferative disorder in an animal, mammal or human, comprising the administration of a therapeutically effective amount of a compound according to claim 1 , optionally in combination with one or more pharmaceutically acceptable excipients.

17. A process for preparing a compound according to claim 1 , including a step comprising reacting a corresponding nucleoside phosphonate, or a salt thereof, with an amino acid ester represented by the structural formula

or a salt thereof, and optionally a monocyclic or fused bicyclic aromatic or heteroaromatic hydroxy compound represented by the structural formula HO—Ar.

18. A compound according to claim 8 for use as a medicine.

19. A compound according to claim 8 for use as a medicine for the treatment of a viral infection in an animal, mammal or human.

20. A compound according to claim 8 for use as a medicine for the treatment of a proliferative disorder or a cancer in an animal, mammal or human.

21. A pharmaceutical composition comprising a therapeutic amount of a compound according to claim 8 and one or more pharmaceutically acceptable excipients.

22. The pharmaceutical composition according to claim 21 , further comprising one or more biologically active drugs being selected from the group consisting of antiviral drugs and/or anti-proliferative drugs.

23. A method of treatment of a viral infection in an animal, mammal or human, comprising the administration of a therapeutically effective amount of a compound according to claim 8 , optionally in combination with one or more pharmaceutically acceptable excipients.

24. A method of treatment of a proliferative disorder in an animal, mammal or human, comprising the administration of a therapeutically effective amount of a compound according to claim 8 , optionally in combination with one or more pharmaceutically acceptable excipients.