2′-fluoro-6′-methylene carbocyclic nucleosides and methods of treating viral infections

Patent metadata

Field	Value
Publication number	US-9700560-B2
Application number	US-201314079412-A
Country	US
Kind code	B2
Filing date	Nov 13, 2013
Priority date	Nov 16, 2009
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

The present invention relates to 2′-Fluoro-6′-methylene carbocyclic nucleosides, pharmaceutical compositions containing these nucleosides and their use in the treatment or prophylaxis of a number of viral infections and secondary disease states and conditions thereof, especially including Hepatitis B virus (HBV) and secondary disease states and conditions thereof (cirrhosis and liver cancer), Hepatitis C virus (HCV), Herpes Simplex virus I and II (HSV-1 and HSV-2), cytomegalovirus (CMV), Varicella-Zoster Virus (VZV) and Epstein Barr virus (EBV) and secondary cancers which occur thereof (lymphoma, nasopharyngeal cancer, including drug resistant (especially including lamivudine and/or adefovir resistant) and other mutant forms of these viruses, especially HBV.

First claim

The invention claimed is:

1. A nucleoside compound according to the structure:

Where B is

Wherein R is H, CH 3 ,

X is H;
R a is H or a —C 1 -C 4 alkyl group;
R 1 and R 1a are each independently, H, an acyl group, a C 1 -C 20 alkyl or ether group, an amino acid residue (D or L), a phosphate, diphosphate, triphosphate, phosphodiester or phosphoramidate group or together R 1 and R 1a form a carbodiester or phosphodiester group with the oxygen atoms to which they are bonded;
R 2 is H, an acyl group, a C 1 -C 20 alkyl or ether group or an amino acid residue (D or L);
Or a pharmaceutically acceptable salt or enantiomer thereof.

2. The compound according to claim 1 , wherein R 1a is H.

3. The compound according to claim 1 wherein R 1 and R 2 are each independently H or a C 2 -C 20 acyl group.

4. The compound according claim 1 wherein R 1 , R 1a and R 2 are each H.

5. The compound according to claim 1 wherein B is

6. The compound according to claim 1 which is represented by the chemical structure:

7. The compound according to claim 6 wherein R 1 , R 1a and R 2 are each independently H or a C 2 -C 20 acyl group.

8. The compound according to claim 1 wherein R is H or F.

9. The compound according to claim 1 wherein R 1a is H and R 1 and R 2 are each independently H or a C 2 -C 20 acyl group.

10. The compound according to claim 1 wherein R 1 is an acyl group, a phosphate, phosphdiester or phosphoramidate group.

11. The compound according to claim 1 wherein R 1 together with the nucleoside to which it is attached forms a group according to the structure:

where each R 5 and R 6 is independently selected from H, a C 1 to C 20 linear, branched or cyclic alkyl group, alkoxyalkyl, aryloxyalkyl, aryl, alkoxy or alkoxycarbonyloxy group, each of which groups may be optionally substituted, with the proviso that at least one R 5 group is other than H, or the two R 5 groups together form a five- or six-membered heterocyclic group;
B′ is a group according to the structure

Where R 8 is sidechain of an amino acid; and
Each R″ is independently a C 1 to C 20 linear, branched or cyclic alkyl or a phenyl or heteroaryl group, each of which groups may be optionally substituted.

12. The compound according to claim 1 wherein R 1 , together with the nucleoside to which it is attached is a group according to the structure:

Where R 6 is a C 1 -C 20 alkyl or an optionally substituted phenyl group;
B′ is a group according to the structure

Where R 8 is a C 1 -C 3 linear or branch-chained alkyl group; and
R″ is a C 1 -C 20 linear, cyclic or branch-chained alkyl group or an optionally substituted phenyl group.

13. A compound according to claim 1 wherein R 2 and R 1a are each independently H or a C 2 -C 20 acyl group; and
R 1 is a

group;
Where R p1 is an optionally substituted C 1 -C 20 alkyl group; and
R P is H, nitro, cyano, methoxy, or a C 1 -C 3 alkyl group optionally substituted with from 1-3 halogen substituents.

14. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.

15. The pharmaceutical composition according to claim 14 comprising an effective amount of an additional antiviral agent.

16. A composition according to claim 14 further in combination with at least one anticancer agent.

17. A method of reducing the likelihood of a viral infection caused by a viral agent selected from the group consisting of Hepatitis B virus (HBV), Hepatitis C virus (HCV), Herpes Simplex 1 (HSV-1), Herpes Simplex 2 (HSV-2), cytomegalovirus (CMV), Varicella Zoster virus (VZV) and Epstein Barr virus (EBV) in a patient at risk for a viral infection comprising administering to said patient an effective amount of a composition according to claim 14 .

18. The compound

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18 which is

or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 18 which is

or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Georgia

Inventors

• Chu Chung K
• Wang Jianing

Classifications

• C07D473/18

  one oxygen and one nitrogen atom, e.g. guanine · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• A61K31/522

  having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title