INHIBITORS OF INFLUENZA VIRUSES REPLICATION

• US 20160251353A1
• Filed: 05/10/2016
• Published: 09/01/2016
• Est. Priority Date: 11/13/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Nti-Addae, Kwame W., O'Neil, Simon Adam, Van Alsten, John Gregg, Macikenas, Dainius, Robertson, Sarah Marie, Tsai, Wanjung, Waldo, Michael, Mudunuri, Praveen, Shi, Yi, Ledeboer, Mark Willem, Jurkauskas, Valdas, Medek, Ales, Jones, Steven, Byrn, Randal, Asmal, Mohammed
• Granted Patent: US 9,771,361 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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. The polymorphic form of claim 1, wherein the polymorphic form is Form A of HCl salt of Compound (1).½

H₂O.

3. The polymorphic form of claim 2, wherein Form A of HCl salt of Compound (1).½

H₂O is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 10.5±

0.2, 5.2±

0.2, 7.4±

0.2, and 18.9±

0.2 in an X-ray powder diffraction pattern.

4. The polymorphic form of claim 3, wherein Form A of HCl salt of Compound (1).½

H₂O is further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 25.2±

0.2, 16.5±

0.2, 18.1±

0.2, and 23.0±

0.2 in an X-ray powder diffraction pattern.

5. The polymorphic form of any of claims 2-4, wherein Form A of HCl salt of Compound (1).½

H₂O is characterized by one or more peaks corresponding to 29.2±

0.3 ppm, 107.0±

0.3 ppm, 114.0±

0.3 ppm, and 150.7±

0.3 ppm in a C¹³ SSNMR spectrum.

6. The polymorphic form of claim 5, wherein Form A of HCl salt of Compound (1).½

H₂O is further characterized by one or more peaks corresponding to 22.1±

0.3 ppm, 24.6±

0.3 ppm, 47.7±

0.3 ppm, and 54.8±

0.3 ppm in a C¹³ SSNMR spectrum.

7. The polymorphic form of claim 1, wherein the polymorphic form is Form F of HCl salt of Compound (1).3H₂O.

8. The polymorphic form of claim 7, wherein Form F of HCl salt of Compound (1).3H₂O is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.1±

0.2, 11.9±

0.2, 19.2±

0.2, and 12.4±

0.2 in an X-ray powder diffraction pattern.

9. The polymorphic form of claim 8, wherein Form F of HCl salt of Compound (1).3H₂O is further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 16.4±

0.2, 21.8±

0.2, and 23.9±

0.2 in an X-ray powder diffraction pattern.

10. The polymorphic form of any of claims 7-9, wherein Form F of HCl salt of Compound (1).3H₂O is characterized by one or more peaks corresponding to 20.7±

0.3 ppm, 27.4±

0.3 ppm, 104.8±

0.3 ppm, 142.5±

0.3 ppm, and 178.6±

0.3 ppm in a C¹³ SSNMR spectrum.

11. The polymorphic form of claim 10, wherein Form F of HCl salt of Compound (1).3H₂O is further characterized by one or more peaks corresponding to 154.3±

0.3 ppm, 20.3±

0.3 ppm, 132.3±

0.3 ppm, and 21.1±

0.3 ppm in a C^u SSNMR spectrum.

12. The polymorphic form of claim 1, wherein the polymorphic form is Form D of HCl salt of Compound (1).

13. The polymorphic form of claim 12, wherein Form D of HCl salt of Compound (1) is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 5.8±

0.2, 19.5±

0.2, and 17.1±

0.2 in an X-ray powder diffraction pattern.

14. The polymorphic form of claim 13, wherein Form D of HCl salt of Compound (1) is further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 5.3±

0.2, 10.5±

0.2, and 15.9±

0.2 in an X-ray powder diffraction pattern.

15. The polymorphic form of any of claims 12-14, wherein Form D of HCl salt of Compound (1) is characterized by one or more peaks corresponding to 29.4±

0.3 ppm, 53.4±

0.3 ppm, 113.3±

0.3 ppm, 135.4±

0.3 ppm, and 177.8±

0.3 ppm in a C¹³ SSNMR spectrum.

16. The polymorphic form of claim 15, wherein Form D of HCl salt of Compound (1) is further characterized by one or more peaks corresponding to 22.9±

0.3 ppm, 23.9±

0.3 ppm, 26.0±

0.3 ppm, and 31.6±

0.3 ppm in a C¹³ SSNMR spectrum.

17. The polymorphic form of claim 1, wherein the polymorphic form is Form A of Compound (1).

18. The polymorphic form of claim 17, wherein Form A of Compound (1) is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 15.5±

0.2, 18.9±

0.2, and 22.0±

0.2 in an X-ray powder diffraction pattern.

19. The polymorphic form of claim 18, wherein Form A of Compound (1) is further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 11.8±

0.2, 16.9±

0.2, 25.5±

0.2, and 9.1±

0.2 in an X-ray powder diffraction pattern.

20. The polymorphic form of any of claims 17-19, wherein Form A of Compound (1) is characterized by one or more peaks corresponding to 21.0±

0.3 ppm, 28.5±

0.3 ppm, 50.4±

0.3 ppm, 120.8±

0.3 ppm, 138.5±

0.3 ppm, and 176.2±

0.3 ppm in a C¹³ SSNMR spectrum.

21. The polymorphic form of claim 20, wherein Form A of Compound (1) is further characterized by one or more peaks corresponding to 30.1±

0.3 ppm, 25.9±

0.3 ppm, 22.8±

0.3 ppm, and 25.0±

0.3 ppm in a C¹³ SSNMR spectrum.

22. The polymorphic form of claim 1, wherein the polymorphic form is Form A of tosylate salt of Compound (1).

23. The polymorphic form of claim 22, wherein Form A of tosylate salt of Compound (1) is characterized by one or more peaks corresponding to 2-theta values measured in degrees of 7.2±

0.2, 9.3±

0.2, 13.7±

0.2, 14.3±

0.2, 14.7±

0.2, 16.9±

0.2, 18.7±

0.2, 26.3±

0.2, and 26.9±

0.2 in an X-ray powder diffraction pattern.

24. The polymorphic form of claim 23, wherein Form A of tosylate salt of Compound (1) is further characterized by one or more peaks corresponding to 2-theta values measured in degrees of 6.0±

0.2, 28.0±

0.2, and 27.5±

0.2 in an X-ray powder diffraction pattern.

25. A pharmaceutical composition comprising a polymorphic form according to claim 1 and at least one pharmaceutically acceptable carrier or excipient.

26. The pharmaceutical composition of claim 25, wherein the polymorphic form is Form A of HCl salt of Compound (1).½

H₂O.

27. The pharmaceutical composition of claim 25, wherein the polymorphic form is Form F of HCl salt of Compound (1).3H₂O.

28. The pharmaceutical composition of claim 25, wherein the polymorphic form is Form D of HCl salt of Compound (1).

29. The pharmaceutical composition of claim 25, wherein the polymorphic form is Form A of Compound (1).

30. The pharmaceutical composition of claim 25, wherein the polymorphic form is Form A of tosylate salt of Compound (1).

31. A method of reducing the amount of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample an effective amount of a polymorphic form of Compound (1) according to any one of claims 1-24.

32. A method of inhibiting the replication of influenza viruses in a biological in vitro sample or in a subject, comprising administering to the sample an effective amount of a polymorphic form of Compound (1) according to any one of claims 1-24.

33. A method of treating influenza in a subject, comprising administering to the subject a therapeutically effective amount of a polymorph form of Compound (1) according to any one of claims 1-24.

34. The method of any one of claims 31-33, further comprising co-administering one or more additional therapeutic agents to the subject.

35. The method of claim 34, wherein the additional therapeutic agents include an anti-virus drug.

36. The method of claim 35, wherein the anti-virus drug is a neuraminidase inhibitor.

37. The method of claim 36, wherein the neuraminidase inhibitor is oseltamivir or zanamivir.

38. The method of claim 35, wherein the anti-virus drug is a polymerase inhibitor.

39. The method of claim 38, wherein the polymerase inhibitor is flavipiravir.

40. The method of any one of claims 31-39, wherein the influenza viruses are influenza A viruses.

67. A dosage regimen comprising administering to a subject a polymorphic form of Compound (1) or a pharmaceutically acceptable salt thereof according to any one of claims 1-24 in a dosage amount of 100 mg to 1,600 mg, wherein the dosage amount is administered once, twice or three times per day.

68. The dosage regimen of claim 67, wherein the dosage amount is 300 mg to 1,600 mg.

69. The dosage regimen of claim 68, wherein the dosage amount is 600 mg to 1,200 mg.

70. The dosage regimen of claim 69, wherein the dosage is administered once per day.

71. The dosage regimen of claim 70, wherein the dosage amount is 600 mg or 800 mg.

72. The dosage regimen of claim 68, wherein the dosage amount is 300 mg to 900 mg.

73. The dosage regimen of claim 72, wherein the dosage is administered twice per day.

74. The dosage regimen of claim 68, wherein the dosage amount is 400 mg or 600 mg.

75. The dosage regimen of any one of claims 67-74, 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.

76. The dosage regimen of claim 75, wherein the treatment duration is 3 days to 14 days.

77. The dosage regimen of claim 76, wherein the treatment duration is 3 days, 4 days, or 5 days.

78. The dosage regimen of any one of claims 67-77, 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.

79. The dosage regimen of claim 78, 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.

80. The dosage regimen of claim 79, 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.

81. The dosage regimen of claim 80, 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.

82. The dosage regimen of claim 80, 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.

41. A method of preparing Form A of HCl salt of Compound (1).½

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

42. The method of claim 41, wherein the solvent system comprises one or more organic solvents selected from chlorobenzene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimentylacetamide, 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.

43. The method of claim 42, 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.

44. The method of claim 42, 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.

45. The method of claim 42, wherein solvent system comprises one or more organic solvents selected from acetone, n-propanol, isopropanol, iso-butylacetate, acetic acid, or any combination thereof.

46. The method of claim 42, wherein the solvent system comprises one or more organic solvents selected from acetone or isopropanol.

47. The method of any one of claims 41-46, wherein the solvent system has a water activity value of from 0.4 to 0.6.

48. The method of any one of claims 41-47, wherein the mixing is performed at a temperature in a range from 5°

C. to 75°

C.

49. The method of any one of claims 41-48, wherein the HCl is introduced as an aqueous solution having 30 wt % to 40 wt % HCl by weight of the aqueous solution.

50. A method of preparing Form F of HCl salt of Compound (1).3H₂O, wherein Compound 1 is represented by the following structural formula:

51. The method of claim 50, wherein the solvent system further comprises one or more organic solvents selected from chlorobenzene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimentylacetamide, 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.

52. The method of claim 51, wherein the solvent system further 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, or methyl tetrahydrofuran.

53. The method of claim 51, wherein the solvent system further 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.

54. The method of claim 51, wherein the solvent system further comprises one or more organic solvents selected from iso-propanol, acetone or any combination thereof.

55. A method of preparing Form D of HCl salt of Compound (1), wherein Compound (1) is represented by the following structural formula:

56. A method of preparing Form A of Compound (1), wherein Compound (1) is represented by the following structural formula:

57. The method of claim 56, wherein the stirring step is performed at a temperature in a range of 18°

C. to 90°

C.

58. The method of either of claim 56 or 57, wherein the solvent system comprises 5 wt % to 15 wt % of water by weight of the solvent system.

59. The method of any one of claims 56-58, further comprising:

(b) stirring amorphous form of Compound (1) in nitromethane to form crystalline seed of Form A of Compound (1); and

(c) adding the crystalline seed of Form A of Compound (1) to the resulting mixture of the mixing step (a).

60. The method of any one of claims 56-59, wherein the stirring step (a) is performed at a refluxing temperature of the solvent system.

61. The method of any of claims 56-58, further comprising:

(b) stirring the amorphous form of Compound (1) in nitromethane to form crystalline seed of Form A of Compound (1); and

(c) cooling the resulting mixture of the mixing step (a) to a temperature in a range of 18°

C. to 60°

C.; and

(d) adding the crystalline seed of Form A of Compound (1) to the resulting mixture step (c).

62. The method of claim 61, further comprising adding water, prior to the addition of crystalline seed of Form A of Compound (1), to the resulting mixture that has gone through the refluxing step in an amount sufficient to impart the resulting solvent system with 15 wt % to 25 wt % of water after the addition of water.

63. The method of claim 61, further comprising adding water to the mixture that includes crystalline seed of Form A of Compound (1) in an amount sufficient to impart the resulting solvent system with 35 wt % to 45 wt % of water after the addition of water.

64. The method of claim 61, further comprising cooling the mixture that includes crystalline seed of Form A of Compound (1), after the addition of water, to a temperature of 0°

C. to 10°

C.

65. A method of preparing Form A of tosylate salt of Compound (1), wherein Compound (1) is represented by the following structural formula:

66. A 2-methyl tetrahyrdrofuran solvate of Compound (1), wherein Compound (1) is represented by the following structural formula: