Crystalline salts of (4S,4AS,5AR,12AS)-4-dimethylamino-3,10,12,12A-tetrahydroxy-7-[methoxy(methyl)amino)-methyl] acid amide and methods of using the same

Patent metadata

Field	Value
Publication number	US-9255068-B2
Application number	US-201213471275-A
Country	US
Kind code	B2
Filing date	May 14, 2012
Priority date	May 12, 2011
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

Abstract

A crystalline mono hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide is disclosed having improved stability. In addition, a crystalline mono mesylate salt and crystalline mono sulfate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide are also disclosed having improved stability. A pharmaceutical composition containing the crystalline salts and methods of treating inflammatory skin disorders and bacterial infections comprising administering the crystalline salts are also disclosed.

First claim

What is claimed is:

1. A crystalline salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide, wherein the salt is selected from a group consisting of mono hydrochloride, mono mesylate and mono sulfate, and wherein the crystalline salt has a crystal-like internal structural arrangement.

2. The crystalline salt of claim 1 , wherein the salt is substantially pure.

3. The crystalline salt of claim 1 , wherein the salt is mono hydrochloride.

4. The crystalline salt of claim 3 , having an XRPD pattern substantially as illustrated in FIG. 1 after synthesis of the crystalline salt.

5. The crystalline salt of claim 3 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 13.4, about 20.5 and about 23.3, as measured by XRPD.

6. The crystalline salt of claim 3 , having a DSC curve substantially as illustrated in FIG. 2 after synthesis of the crystalline salt.

7. The crystalline salt of claim 3 , having a TGA curve substantially as illustrated in FIG. 3 after synthesis of the crystalline salt.

8. The crystalline salt of claim 3 , wherein the salt has a β-isomer content at 0 days of about 0.1% peak area to about 7.0% peak area, as measured by HPLC.

9. The crystalline salt of claim 1 , wherein the salt is mono mesylate.

10. The crystalline salt of claim 9 , having an XRPD pattern substantially as illustrated in FIG. 4 after synthesis of the crystalline salt.

11. The crystalline salt of claim 9 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 9, about 15 and about 23.8, as measured by XRPD.

12. The crystalline salt of claim 9 , having a DSC curve substantially as illustrated in FIG. 5 after synthesis of the crystalline salt.

13. The crystalline salt of claim 9 , having a TGA curve substantially as illustrated in FIG. 6 after synthesis of the crystalline salt.

14. The crystalline salt of claim 9 , wherein the salt has a β-isomer content at 0 days of about 2.0% peak area to about 10.0% peak area, as measured by HPLC.

15. The crystalline salt of claim 1 , wherein the salt is mono sulfate.

16. The crystalline salt of claim 15 , having an XRPD pattern substantially as illustrated in FIG. 7 after synthesis of the crystalline salt.

17. The crystalline salt of claim 15 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 15, about 17.8 and about 23.5, as measured by XRPD.

18. The crystalline salt of claim 15 , having a DSC curve substantially as illustrated in FIG. 8 after synthesis of the crystalline salt.

19. The crystalline salt of claim 15 , having a TGA curve substantially as illustrated in FIG. 9 after synthesis of the crystalline salt.

20. The crystalline salt of claim 15 , wherein the salt has a β-isomer content at 0 days of about 3.0% peak area to about 26.0% peak area, as measured by HPLC.

21. A pharmaceutical composition comprising the crystalline salt of claim 1 and a pharmaceutically acceptable excipient.

22. The pharmaceutical composition of claim 21 , wherein the salt is mono hydrochloride.

23. The pharmaceutical composition of claim 21 , wherein the salt is mono mesylate.

24. The pharmaceutical composition of claim 21 , wherein the salt is mono sulfate.

25. A method for treating acne comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1 .

26. The method of claim 25 , wherein the salt is mono hydrochloride.

27. The method of claim 25 , wherein the salt is mono mesylate.

28. The method of claim 25 , wherein the salt is mono sulfate.

29. A method for treating rosacea comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1 .

30. The method of claim 29 , wherein the salt is mono hydrochloride.

31. The method of claim 29 , wherein the salt is mono mesylate.

32. The method of claim 29 , wherein the salt is mono sulfate.

33. A method for treating a gram positive bacterial infection, wherein the gram positive bacteria is selected from the group consisting of Propionibacterium acnes, Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes , and Clostridium difficile , comprising administering to a subject a therapeutically effective amount of the crystalline salt of claim 1 .

34. The method of claim 33 , wherein the salt is mono hydrochloride.

35. The method of claim 33 , wherein the salt is mono mesylate.

36. The method of claim 33 , wherein the salt is mono sulfate.

37. A crystalline salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide, wherein the salt is selected from a group consisting of mono hydrochloride, mono mesylate and mono sulfate, and wherein the crystalline salt is substantially free of an amorphous salt.

38. The crystalline salt of claim 37 , wherein the salt is substantially pure.

39. The crystalline salt of claim 37 , wherein the salt is mono hydrochloride.

40. The crystalline salt of claim 39 , having an XRPD pattern substantially as illustrated in FIG. 1 after synthesis of the crystalline salt.

41. The crystalline salt of claim 39 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 13.4, about 20.5 and about 23.3, as measured by XRPD.

42. The crystalline salt of claim 39 , having a DSC curve substantially as illustrated in FIG. 2 after synthesis of the crystalline salt.

43. The crystalline salt of claim 39 , having a TGA curve substantially as illustrated in FIG. 3 after synthesis of the crystalline salt.

44. The crystalline salt of claim 39 , wherein the salt has a β-isomer content at 0 days of about 0.1% peak area to about 7.0% peak area, as measured by HPLC.

45. The crystalline salt of claim 37 , wherein the salt is mono mesylate.

46. The crystalline salt of claim 45 , having an XRPD pattern substantially as illustrated in FIG. 4 after synthesis of the crystalline salt.

47. The crystalline salt of claim 45 , having at least three characteristic peaks at diffraction angle 2-theta degrees appearing at about 48, about 15 and about 23.8, as measured by XRPD.

48. The crystalline salt of claim 45 , having a DSC curve substantially as illustrated in FIG. 5 after synthesis of the crystalline salt.

49. The crystalline salt of claim 45 , having a TGA curve substantially as illustrated in FIG. 6 after synthesis of the crystalline salt.

50. The crystalline salt of claim 45 , wherein the salt has a β-isomer content at 0 days of about 2.0% peak area to about 10.0% peak area, as measured by HPLC.

51. The crystalline salt of claim 37 , wherein the salt is mono sulfate.

52. The crystalline salt of claim 51 ,

Assignees

• Coulter Catherine
• Johnston Sean M
• Seyedi Farzaneh
• Warner Chilcott Co Llc
• Paratek Pharm Innc

Inventors

• Coulter Catherine
• Johnston Sean M
• Seyedi Farzaneh

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P17/10

  Anti-acne agents · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07C2603/46

  1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines · CPC title