1-(2-Methylpropyl)-1H-Imidazo[4,5-C](1,5]Naphthyridin-4-Amine Ethanesulfonate and 1-(2-Methylpropyl)-1H-Imidazo[4,5-C](1,5]Naphthyridin-4-Amine Methanesulfonate

• US 20080188513A1
• Filed: 12/28/2005
• Published: 08/07/2008
• Est. Priority Date: 12/30/2004
• Status: Abandoned Application

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Skwierczynski, Raymond D., Brostrom, Myles L., Tran, Tai T., Jacobson, Joel R.
• Application Number:
  US11/813,005
• Publication Number:
  US 20080188513A1
• Time in Patent Office: Days
• US Class Current: 514/293
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/14 Ortho-condensed systems

Abstract

This invention provides methanesulfonate and ethanesulfonate salts of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine, pharmaceutical compositions containing the salts, methods of making, and methods of use.

Claims

1. A salt selected from the group consisting of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate and 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate, or a solvate or hydrate thereof.

2. The salt of claim 1, wherein the salt is 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate, or a solvate or hydrate thereof.

3. The salt of claim 1, wherein the salt is 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate, or a solvate or hydrate thereof.

4. The salt of claim 1 in dissolved form.

5. The salt of claim 1 in solid form.

6. The salt of claim 5 in crystalline form.

7. The salt of claim 5 in amorphous form.

8. The salt of claim 5 in solvated form.

9. The salt of claim 5 in hydrate form.

10. The salt of claim 9, in the form of a monohydrate.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the salt of any preceding claim.

12. The pharmaceutical composition of claim 11 wherein the pharmaceutically acceptable carrier comprises water.

13. A method of treating a neoplastic disease in an animal, the method comprising administering a therapeutically effective amount of a salt of any one of claims 1 through 10, or a pharmaceutical composition of claim 11 or claim 12 to the animal.

14. A method of treating a viral disease in an animal, the method comprising administering a therapeutically effective amount of a salt of any one of claims 1 through 10, or a pharmaceutical composition of claim 11 or claim 12 to the animal.

15. A method of inducing cytokine biosynthesis in an animal, the method comprising administering an effective amount of a salt of any one of claims 1 through 10, or a pharmaceutical composition of claim 11 or claim 12 to the animal.

16. The method of claim 13, wherein the neoplastic disease is located in the cervix.

17. The method of claim 14, wherein the viral disease comprises human papilloma virus located in the cervix.

25. The salt of claim 3 in crystalline form and having an X-ray powder diffraction pattern with peaks at 8.51 degrees two-theta, 14.12 degrees two-theta, 16.80 degrees two-theta, 17.88 degrees two-theta, 21.43 degrees two-theta, 23.24 degrees two-theta, and 29.16 degrees two-theta, wherein each of these values is ±

0.15 degree two-theta.

26. The salt of claim 25 having an X-ray powder diffraction pattern with peaks at 7.15 degrees two-theta, 8.51 degrees two-theta, 14.12 degrees two-theta, 16.80 degrees two-theta, 17.88 degrees two-theta, 18.49 degrees two-theta, 18.88 degrees two-theta, 21.04 degrees two-theta, 21.43 degrees two-theta, 23.24 degrees two-theta, 25.40 degrees two-theta, 27.92 degrees two-theta, 28.77 degrees two-theta, and 29.16 degrees two-theta, wherein each of these values is ±

0.15 degree two-theta.

27. The salt of claim 26 having an X-ray powder diffraction pattern with peaks at 7.15 degrees two-theta, 7.55 degrees two-theta, 8.51 degrees two-theta, 11.83 degrees two-theta, 13.65 degrees two-theta, 14.12 degrees two-theta, 14.87 degrees two-theta, 16.80 degrees two-theta, 17.88 degrees two-theta, 18.49 degrees two-theta, 18.88 degrees two-theta, 19.92 degrees two-theta, 20.24 degrees two-theta, 21.04 degrees two-theta, 21.43 degrees two-theta, 22.24 degrees two-theta, 23.24 degrees two-theta, 24.64 degrees two-theta, 25.40 degrees two-theta, 25.71 degrees two-theta, 27.20 degrees two-theta, 27.92 degrees two-theta, 28.77 degrees two-theta, 29.16 degrees two-theta, 30.94 degrees two-theta, 31.29 degrees two-theta, 32.76 degrees two-theta, 33.56 degrees two-theta, 34.04 degrees two-theta, 34.88 degrees two-theta, and 35.40 degrees two-theta, wherein each of these values is ±

0.15 degree two-theta.

28. The salt of claim 3 having a unit cell with the following crystal interplanar spacings:

about 10.38 Angstroms, about 6.27 Angstroms, about 5.27 Angstroms, about 4.96 Angstroms, about 4.14 Angstroms, about 3.82 Angstroms, and about 3.06 Angstroms.

29. The salt of claim 3 characterized by:

having an X-ray powder diffraction pattern with peaks at 7.15 degrees two-theta, 8.51 degrees two-theta, 14.12 degrees two-theta, 16.80 degrees two-theta, 17.88 degrees two-theta, 18.49 degrees two-theta, 18.88 degrees two-theta, 21.04 degrees two-theta, 21.43 degrees two-theta, 23.24 degrees two-theta, 25.40 degrees two-theta, 27.92 degrees two-theta, 28.77 degrees two-theta, and 29.16 degrees two-theta, wherein each of these values is +0.15 degree two-theta; and

a weight loss of 4.5% to 5.5% over a temperature range of 60°

C. to 80°

C. as measured by thermogravimetric analysis.

18. A method for preparing 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate, the method comprising:

combining 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free base with ethanesulfonic acid and a carrier to form a mixture, wherein the carrier comprises an organic liquid and optionally water; and

allowing the components of the mixture to react under sufficient conditions to form 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate.

19. The method of claim 18 further comprising heating the free base, ethanesulfonic acid, and/or the carrier prior to combining them, and/or heating the mixture thereof.

20. The method of claim 18 or claim 19 further comprising forming a precipitate of the 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate in the mixture.

21. The method of claim 20 wherein forming a precipitate comprises cooling the mixture to form a precipitate.

22. The method of claim 21 wherein cooling occurs at a rate less than 2.0°

C. per minute.

23. The method of any one of claims 18 through 22 wherein the carrier comprises at least two moles of water per mole of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free base present.

24. The method of claim 20 further comprising:

optionally adding an additional organic liquid to the mixture comprising the precipitate;

separating at least a portion of the precipitate from at least a portion of the mixture;

washing the precipitate; and

at least partially drying the precipitate.

30. 1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate having an X-ray powder diffraction pattern substantially as depicted in FIG. 1.

31. A method for preparing 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate, the method comprising:

combining 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free base with methanesulfonic acid and a carrier to form a mixture, wherein the carrier comprises an organic liquid and optionally water; and

allowing the components of the mixture to react under sufficient conditions to form 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate.

32. The method of claim 31 further comprising heating the free base, methanesulfonic acid, and/or the carrier prior to combining them, and/or heating the mixture thereof.

33. The method of claim 31 or claim 32 further comprising forming a precipitate of the 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate in the mixture.

34. The method of claim 33 wherein forming a precipitate comprises cooling the mixture to form a precipitate.

35. The method of any one of claims 31 through 34 wherein the carrier comprises at least two moles of water per mole of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine free base present.

36. The method of claim 33 further comprising:

optionally adding an additional organic liquid to the mixture comprising the precipitate;

separating at least a portion of the precipitate from at least a portion of the mixture;

washing the precipitate; and

at least partially drying the precipitate.

37. A method of treating high risk cervical HPV infection by applying to the cervix a topical formulation comprising dissolved salt 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate or 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate.