Inhibitors of influenza viruses replication

Patent metadata

Field	Value
Publication number	US-10273233-B2
Application number	US-201715807984-A
Country	US
Kind code	B2
Filing date	Nov 9, 2017
Priority date	May 13, 2015
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

Abstract

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

include Hydrate 2 of Compound (1), Hydrate 3 of Compound (1), Form A of Compound (1), Form B of Compound (1), Form C of Compound (1), Form D of Compound (1), and amorphous Compound (1). Such polymorphic forms are useful for treating influenza, inhibiting the replication of influenza viruses, or reducing the amount of influenza viruses in a biological sample or in a subject.

First claim

What is claimed is:

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

and wherein the polymorphic form is selected from the group consisting of: Hydrate 2 of Compound (1) and Hydrate 3 of Compound (1), wherein Hydrate 2 of Compound (1) is characterized by one or more peaks corresponding to 2-theta values, measured in degrees, of 6.9±0.2, 7.9±0.2, 13.8±0.2, 15.9±0.2, 20.9±0.2, and 23.4±0.2 in an X-ray powder diffraction pattern and wherein Hydrate 3 of Compound (1) is characterized by one or more peaks corresponding to 2-theta values, measured in degrees, of 7.0±0.2, 18.6±0.2, 20.8±0.2, 23.3±0.2, and 26.0±0.2 in an X-ray powder diffraction pattern.

2. The polymorphic form of claim 1 , wherein the polymorphic form is Hydrate 2 of Compound (1), and wherein Hydrate 2 of Compound (1) is further characterized by one or more peaks corresponding to 2-theta values, measured in degrees, of 17.1±0.2, 18.6±0.2, 22.1±0.2 and 29.2±0.2 in an X-ray powder diffraction pattern.

3. The polymorphic form of claim 1 , wherein the polymorphic form is Hydrate 2 of Compound (1), and wherein Hydrate 2 of Compound (1) is further characterized by a 13 C SSNMR spectrum of 178.5 ppm, 137.2 ppm, 126.8 ppm, 107.0 ppm, and 35.3 ppm.

4. The polymorphic form of claim 1 , wherein the polymorphic form is Hydrate 3 of Compound (1), and wherein Hydrate 3 of Compound (1) is further characterized by one or more peaks corresponding to 2-theta values, measured in degrees, of 8.9±0.2, 16.6±0.2, and 28.9±0.2 in an X-ray powder diffraction pattern.

5. The polymorphic form of claim 1 , wherein the polymorphic form is Hydrate 3 of Compound (1), and wherein Hydrate 3 of Compound (1) is further characterized by a 13 C SSNMR spectrum of 178.8 ppm, 136.7 ppm, 107.8 ppm, 34.9 ppm, and 26.3 ppm.

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

7. 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 subject an effective amount of a polymorphic form of Compound (1) according to claim 1 .

8. 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 .

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

10. The method of claim 7 , further comprising co-administering one or more additional therapeutic agents to the sample or subject.

11. The method of claim 10 , wherein the additional therapeutic agents include an anti-virus drug.

12. The method of claim 11 , wherein the anti-virus drug is a neuraminidase inhibitor or a polymerase inhibitor.

13. The method of claim 12 , wherein the neuraminidase inhibitor is oseltamivir or zanamivir.

14. The method of claim 12 , wherein the polymerase inhibitor is flavipiravir.

15. The method of claim 9 , wherein the influenza infection is an influenza A virus infection.

16. A method of preparing Hydrate 2 of Compound (1), wherein Compound (1) is represented by the following structural formula:

and Hydrate 2 of Compound (1) is characterized by one or more peaks corresponding to 2-theta values, measured in degrees, of 6.9±0.2, 7.9±0.2, 13.8±0.2, 15.9±0.2, 20.9±0.2, and 23.4±0.2 in an X-ray powder diffraction pattern, comprising:
mixing Hydrate 1 of Compound (1) with a solvent system comprising water to generate a mixture; and
removing at least some of the solvent system from the mixture to generate Hydrate 2 of Compound (1).

17. The method of claim 16 , wherein the solvent system further comprises 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, methyl tetrahydrofuran, tetralin, tolune, 1,1,2-trichloroethene, 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.

18. The method of claim 16 , wherein the solvent system further comprises 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, t-butylmethylether, 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.

19. The method of claim 16 , wherein the solvent system further comprises 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.

20. The method of claim 16 , wherein the solvent system further comprises acetone, n-propanol, isopropanol, iso-butylacetate, acetic acid, or any combination thereof.

21. The method of claim 16 , wherein the solvent system includes water and acetone, or water and isopropanol.

22. The method of claim 16 , wherein the solvent system further comprises sodium chloride, dextrose, glycerine, or a surfactant.

23. The method of claim 16 , wherein the mixing is performed at a temperature in a range from 20° C. to less than 40° C.

24. The method of any claim 16 , further comprising applying a vacuum to the mixture to remove the solvent system.

25. A method of preparing Hydrate 3 of Compound (1), wherein Compound 1 is represented by the following structural formula:

and wherein Hydrate 3 of Compound (1) is characterized by one or more peaks corresponding to 2-theta values, measured in degrees, of 7.0±0.2, 18.6±0.2, 20.8±0.2, 23.3±0.2, and 26.0±0.2 in an X-ray powder diffraction pattern, comprising:
mixing Hydrate 1 of Compound (1) or amorphous Compound (1) with a solvent system comprising water to generate a mixture;
heating the mixture; and
removing at least some of the solvent system to generate Hydrate 3 of Compound (1).

Assignees

• Vertex Pharma

Inventors

• Farmer Luc J
• Boyd Michael John
• Shannon Dean
• Waldo Michael
• Nti-Addae Kwame W
• Zhang Yuegang

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4965

  Non-condensed pyrazines · CPC title