Inhibitors of influenza viruses replication

• US 9,771,361 B2
• Filed: 05/10/2016
• Issued: 09/26/2017
• Est. Priority Date: 11/13/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Nti-Addae, Kwame W., Waldo, Michael, O'Neil, Simon Adam, Van Alsten, John Gregg, Macikenas, Dainius, Mudunuri, Praveen, Shi, Yi, Ledeboer, Mark Willem, Jurkauskas, Valdas, Medek, Ales, Jones, Steven, Byrn, Randal, Asmal, Mohammed, Robertson, Sarah Marie, Tsai, Wanjung
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US15/150,459
• Publication Number:
  US 20160251353A1
• Time in Patent Office: 504 Days
• Field of Search: 544328, 514256
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 309/30 of six-membered aromatic rings substituted by alkyl groups
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Polymorphic forms of Compound (1) or a pharmaceutically acceptable salt thereof, wherein Compound (1) is represented by the following structural formula:

are Form A of HCl salt of Compound (1).½H₂O, Form F of HCl salt of Compound (1).3H₂O, Form D of HCl salt of Compound (1), Form A of Compound (1), and Form A of tosylate salt of Compound (1). Such polymorphic forms are employed for treating influenza, inhibiting the replication of influenza viruses, or reducing the amount of influenza viruses in a biological sample or in a subject.

Claims

1. A polymorphic form of Compound (1) or a pharmaceutically acceptable salt thereof, wherein Compound (1) is represented by the following structural formula:

2. A pharmaceutical composition comprising a polymorphic form of Compound (1) according to claim 1 and at least one pharmaceutically acceptable carrier or excipient.

3. A method of reducing the amount of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample or the subject an effective amount of a polymorphic form of Compound (1) according to claim 1.

4. A method of inhibiting the replication of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample or subject an effective amount of a polymorphic form of Compound (1) according to claim 1.

5. A method of treating influenza in a subject, comprising administering to the subject a therapeutically effective amount of a polymorphic form of Compound (1) according to claim 1.

6. The method of claim 5, further comprising co-administering one or more additional therapeutic agents to the subject.

7. A method of preparing a polymorphic form of Compound (1) according to claim 1 comprising:

mixing HCl with Compound (1) in a solvent system comprising water and one or more organic solvents, wherein the solvent system has a water activity of 0.05-0.85.

8. A dosage regimen comprising administering to a subject a polymorphic form of Compound (1) or a pharmaceutically acceptable salt thereof according to claim 1 in a dosage amount of 100 mg to 1,600 mg, wherein the dosage amount is administered once, twice or three times per day.

26. The method of claim 7, wherein the solvent system comprises one or more organic solvents selected from chlorobenzene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, formamide, hexane, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran (THF), tetralin, tolune, 1,1,2-trichloroethene and xylene, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, ethyl acetate, ethyl ether, ethyl formate, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, or any combination thereof.

27. The method of claim 26, wherein the solvent system comprises one or more organic solvents selected from chlorobenzene, cyclohexane, 1,2-dichloroethane, dichloromethane, 1,2-dimethoxyethane, formamide, hexane, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, nitromethane, tetralin, xylene, toluene, 1,1,2-trichloroethane, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, 2-methy-1-propanol, pentane, 1-propanol, 1-pentanol, 2-propanol, propyl acetate, tetrahydrofuran, methyl tetrahydrofuran, or any combination thereof.

28. The method of claim 26, wherein solvent system comprises one or more organic solvents selected from 2-ethoxyethanol, ethyleneglycol, methanol, 2-methoxyethanol, 1-butanol, 2-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, ethanol, 1-pentanol, 1-propanol, 2-propanol, methylbutyl ketone, acetone, methylethyl ketone, methylisobutyl ketone, butyl acetate, isobutyl acetate, isopropyl acetate, methyl acetate, ethyl acetate, propyl acetate, pyridine, toluene, xylene, or any combination thereof.

29. The method of claim 26, wherein solvent system comprises one or more organic solvents selected from acetone, n-propanol, isopropanol, iso-butylacetate, acetic acid, or any combination thereof.

30. The method of claim 29, wherein the solvent system comprises one or more organic solvents selected from acetone or isopropanol.

31. The method of claim 7, wherein the solvent system has a water activity value of from 0.4 to 0.6.

32. The method of claim 7, wherein the mixing is performed at a temperature in a range from 5°

C. to 75°

C.

33. The method of claim 7, wherein the HCl is introduced as an aqueous solution having 30 wt % to 40 wt % HCl by weight of the aqueous solution.

34. The dosage regimen of claim 8, wherein the dosage amount is 300 mg to 1,600 mg.

35. The dosage regimen of claim 34, wherein the dosage amount is 600 mg to 1,200 mg.

36. The dosage regimen of claim 35, wherein the dosage is administered once per day.

37. The dosage regimen of claim 36, wherein the dosage amount is 600 mg or 800 mg.

38. The dosage regimen of claim 34, wherein the dosage amount is 300 mg to 900 mg.

39. The dosage regimen of claim 38, wherein the dosage is administered twice per day.

40. The dosage regimen of claim 39, wherein the dosage amount is 400 mg or 600 mg.

41. The dosage regimen of claim 8, wherein the polymorphic form of Compound (1) or a pharmaceutically acceptable salt thereof is administered for duration of treatment of 1 day to an entire flu season.

42. The dosage regimen of claim 41, wherein the treatment duration is 3 days to 14 days.

43. The dosage regimen of claim 42, wherein the treatment duration is 3 days, 4 days, or 5 days.

44. The dosage regimen of claim 8, wherein a loading dosage amount of 600 mg to 1,600 mg is administered to the subject on day 1 and a dosage amount of 400 mg to 1,200 mg is administered to the subject for the rest of the treatment duration.

45. The dosage regimen of claim 44, wherein a loading dosage amount of 900 mg to 1,600 mg is administered to the subject on day 1 and a dosage amount of 400 mg to 1,200 mg is administered to the subject for the rest of the treatment duration.

46. The dosage regimen of claim 45, wherein a loading dosage amount of 900 mg or 1,200 mg is administered to the subject on day 1 and a dosage amount of 600 mg to 800 mg is administered to the subject for the rest of the treatment duration.

47. The dosage regimen of claim 46, wherein a loading dosage amount of 900 mg is administered to the subject on day 1 and a dosage amount of 600 mg is administered once a day to the subject for the rest of the treatment duration.

48. The dosage regimen of claim 46, wherein a loading dosage amount of 1,200 mg is administered to the subject on day 1 and a dosage amount of 600 mg is administered once a day to the subject for the rest of the treatment duration.

9. A crystalline HCl salt of Compound (1).½

H₂O, wherein Compound (1) is represented by the following structural formula;

10. A pharmaceutical composition comprising a crystalline HCl salt of Compound (1).½

H₂O according to claim 9 and at least one pharmaceutically acceptable carrier or excipient.

11. A method of reducing the amount of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample or the subject an effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 9.

12. A method of inhibiting the replication of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample or subject an effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 9.

13. A method of treating influenza in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 9.

14. The method of claim 13, further comprising co-administering one or more additional therapeutic agents to the subject.

15. A crystalline HCl salt of Compound (1).½

H₂O, wherein Compound (1) is represented by the following structural formula;

16. A pharmaceutical composition comprising a crystalline HCl salt of Compound (1).½

H₂O according to claim 15 and at least one pharmaceutically acceptable carrier or excipient.

17. A method of reducing the amount of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample or the subject an effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 15.

18. A method of inhibiting the replication of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample or subject an effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 15.

19. A method of treating influenza in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 15.

20. The method of claim 19, further comprising co-administering one or more additional therapeutic agents to the subject.

25. A method of treating influenza in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 15.

21. A crystalline HCl salt of Compound (1).½

H₂O, wherein Compound (1) is represented by the following structural formula;

22. A pharmaceutical composition comprising a crystalline HCl salt of Compound (1).½

H₂O according to claim 21 and at least one pharmaceutically acceptable carrier or excipient.

23. A method of reducing the amount of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample or the subject an effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 21.

24. A method of inhibiting the replication of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample or subject an effective amount of a crystalline HCl salt of Compound (1).½

H₂O according to claim 21.