Compounds and methods for treating influenza
View Patent ↗This invention is directed to methods for treating and preventing influenza infection by inhibiting influenza virus HA maturation processes employing compounds of formula I. It is also directed to combinations for treating and preventing influenza infection comprising compounds of formula I and other agents.
1. A method of treating viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I
wherein one of R 1 , R 2 , R 3 is OH or OC(═O)Q, where Q is R 7 , OR 7 , or NHR 7 ; R 7 is lower alkyl, aryl, or heteroaryl and is optionally substituted; R 4 , R 5 , and the remainder of R 1 , R 2 , and R 3 , are H; and R 6 is NO 2 and R 9 is H, and
wherein the viral infection is caused by an influenza virus, and
wherein the compound of formula I is administered orally at a therapeutically effective amount suitable for blocking the maturation of viral hemagglutinin at a stage preceding resistance to endoglycosidase-H digestion in the patient.
2. The method of claim 1 , wherein R 1 is OH or OC(═O)Q, where Q is R 7 , OR 7 , or NHR 7 ; R 7 is lower alkyl, aryl, or heteroaryl and is optionally substituted; R 4 , R 5 , and R 2 , and R 3 , are H; and R 6 is NO 2 and R 9 is H.
3. The method of claim 1 , wherein the viral infection is caused by a virus selected from H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, and H10N7.
4. The method of claim 1 , wherein the compound of formula I is administered in combination with a neuraminidase inhibitor.
5. The method of claim 1 , wherein the compound of formula I is administered in combination with a vaccine.
6. The method of claim 1 , wherein the compound of formula I is administered in combination with an immunostimulant.
7. The method of claim 1 , wherein the compound of formula I is administered in combination with an adamantine analogue.
8. The method of claim 1 , wherein the compound of formula I is administered in combination with a recombinant sialidase fusion protein.
9. The method of claim 1 , wherein the compound of formula I is administered in combination with an antisense oligonucleotide.
10. The method of claim 4 , wherein the combination is administered in a substantially simultaneous manner.
11. The method of claim 4 , wherein the combination is administered in a sequential manner.
12. A combination comprising (a) a compound of formula I as claimed in claim 1 , and (b) a neuraminidase inhibitor, when used in a combination therapy, for treatment of a viral infection.
13. The combination of claim 12 , wherein the neuraminidase inhibitor is selected from the group consisting of Oseltamivir, Zanamivir, Permivir, RWJ-270201, DANA, and CS-8958.
14. A combination comprising (a) a compound of formula I as claimed in claim 1 , and (b) a vaccine, when used in a combination therapy, for treatment of a viral infection.
15. The combination of claim 14 , further comprising an immunostimulant.
16. A combination comprising (a) a compound of formula I as claimed in claim 1 , and (b) an adamantine analogue, when used in a combination therapy, for treatment and prevention of a viral infection.
17. The combination of claim 16 , wherein the adamantine analogue is selected from the group consisting of Amantadine and Rimantadine.
18. A combination comprising (a) a compound of formula I as claimed in claim 1 , and (b) an immunostimulant, when used in a combination therapy, for treatment of a viral infection.
19. The combination of claim 18 , wherein the immunostimulant is Polyoxidonium.
20. A combination comprising (a) a compound of formula I as claimed in claim 1 , and (b) a PEGylated interferon, when used in a combination therapy, for treatment of a viral infection.
21. A combination comprising (a) a compound of formula I as claimed in claim 1 , and (b) a recombinant sialidase fusion protein, when used in a combination therapy, for treatment of a viral infection.
22. The combination of claim 21 , wherein the recombinant sialidase fusion protein is Fludase®.
23. A combination comprising (a) a compound of formula I as claimed in claim 1 , and (b) an antisense oligonucleotide, when used in a combination therapy, for treatment of a viral infection.
24. The combination of claim 21 , wherein the antisense oligonucleotide comprises Neugene® antisense phosphorodiamidate morpholino oligomers.
25. The method of claim 12 , wherein the combination is administered in a sequential manner.
26. The method of claim 12 , wherein the combination is administered in a substantially simultaneous manner.
27. A method of disrupting or preventing the production of infectious viral particles in a human or other mammal, comprising administering to said human or other mammal a therapeutically effective amount of a compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt or ester thereof.
28. The method of claim 1 , wherein the compound of formula I is selected from a compound represented by a formula:
29. A pharmaceutical composition comprising
i) an amount of a compound of formula I as claimed in claim 1 , or of a salt or ester thereof, effective for the treatment or prevention of influenza infection; and
ii) a pharmaceutically acceptable carrier.
30. The pharmaceutical composition of claim 29 , further comprising an amount of another antiviral agent sufficient to provide a synergistic effect with the compound of formula I.
31. The pharmaceutical composition of claim 29 , further comprising an amount of a vaccine sufficient to provide a synergistic antiviral protective effect with the compound of formula I.
32. A method of treating influenza-like illness in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of formula I as defined in claim 1 ; or a pharmaceutically acceptable salt or ester thereof.
33. The method of claim 32 , wherein one of R 1 , R 2 , R 3 is OH or OC(═O)Q, where Q is R 7 , OR 7 , or NHR 7 ; R 7 is lower alkyl, aryl, or heteroaryl and is optionally substituted; R4, R5, and the remainder of R 1 , R 2 , and R 3 , are H; and either R 6 is NO 2 and R 9 is H, or R 6 is H and R 9 is SO 2 R 12 where R 12 is lower alkyl, aryl, or heteroaryl and is optionally substituted.
34. A pharmaceutical composition comprising
i) an amount of a compound of formula I as claimed in claim 32 , or of a salt or ester thereof, effective for the treatment or prevention of influenza-like illness; and
ii) a pharmaceutically acceptable carrier.
35. The method of claim 1 , wherein said compound of formula I is administered at a dose selected from 100 mg to 600 mg.
36. The method of claim 1 , wherein said compound of formula I is administered at a dose selected from the group consisting of: 300 mg and 600 mg.
37. The method of claim 1 , wherein said compound of formula I is administered twice daily at a dose selected from the group consisting of: 300 mg and 600 mg.
38. The method of claim 1 , wherein said compound of formula I is administered twice daily at a dose selected of 300 mg.
39. The method of claim 38 , wherein said compound is not administered for more than five days.
40. The method of claim 1 , wherein said compound of formula I is nitazoxanide and wherein the nitazoxanide is administered twice daily.
41. The method of claim 40 , wherein the nitazoxanide is administered as a modified release bi-layer tablet.
42. The method of claim 1 , wherein the subject is a human.
43. The method of claim 1 , wherein the compound of formula I is administered as a mono-therapy.
44. The method of claim 43 , wherein the compound of formula I is nitazoxanide or a pharmaceutically acceptable salt thereof.
45. The method of claim 1 , wherein the compound of formula I is nitazoxanide or a pharmaceutically acceptable salt thereof.
46. The method of claim 1 , wherein said compound of formula I is administered twice daily at a dose selected of 600 mg.