Crystalline salts 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 and methods of using the same

Patent metadata

Field	Value
Publication number	US-2016200671-A1
Application number	US-201514974813-A
Country	US
Kind code	A1
Filing date	Dec 18, 2015
Priority date	May 12, 2011
Publication date	Jul 14, 2016
Grant date	—

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

1 - 39 . (canceled)

40 . 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; the crystalline salt has a crystal-like internal structural arrangement; and wherein the crystalline salt has a total impurity content of less than about 10% peak area as measured by HPLC.

41 . The crystalline salt of claim 40 , wherein the crystalline salt has a total impurity content of less than about 4% peak area as measured by HPLC.

42 . The crystalline salt of claim 40 , wherein the crystalline salt is mono hydrochloride.

43 . The crystalline salt of claim 42 , wherein the crystalline salt has a β-isomer content after storage for about 75 days at about 40° C. and RH of 75% of not more than about 10% peak area greater that the β-isomer at about 0 days, as measured by HPLC.

44 . The crystalline salt of claim 40 , wherein the crystalline salt is mono mesylate.

45 . The crystalline salt of claim 44 , wherein the crystalline salt has a β-isomer content after storage for about 75 days at about 40° C. and RH of 75% of not more than about 10% peak area greater that the β-isomer at about 0 days, as measured by HPLC.

46 . The crystalline salt of claim 40 , wherein the crystalline salt is mono sulfate.

47 . The crystalline salt of claim 46 , wherein the crystalline salt has a β-isomer content after storage for about 75 days at about 40° C. and RH of 75% of not more than about 10% peak area greater that the β-isomer at about 0 days, as measured by HPLC.

48 . 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 the crystalline salt has less than about 8% peak area of amorphous salt present.

49 . The crystalline salt of claim 48 , wherein the crystalline salt has less than about 5% peak area of amorphous salt present.

50 . The crystalline salt of claim 48 , wherein the crystalline salt has less than about 3% peak area of amorphous salt present.

51 . The crystalline salt of claim 48 , wherein the crystalline salt is mono hydrochloride.

52 . The crystalline salt of claim 51 , wherein the crystalline salt has a β-isomer content after storage for about 75 days at about 40° C. and RH of 75% of not more than about 10% peak area greater that the β-isomer at about 0 days, as measured by HPLC.

53 . The crystalline salt of claim 48 , wherein the crystalline salt is mono mesylate.

54 . The crystalline salt of claim 53 , wherein the crystalline salt has a β-isomer content after storage for about 75 days at about 40° C. and RH of 75% of not more than about 10% peak area greater that the β-isomer at about 0 days, as measured by HPLC.

55 . The crystalline salt of claim 48 , wherein the crystalline salt is mono sulfate.

56 . The crystalline salt of claim 55 , wherein the crystalline salt has a β-isomer content after storage for about 75 days at about 40° C. and RH of 75% of not more than about 10% peak area greater that the β-isomer at about 0 days, as measured by HPLC.

57 . A method for treating a gram positive bacterial infection selected from Streptococcus pyogenes and Clostridium difficile , comprising administering to a subject a therapeutically effective amount 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 or a pharmaceutically effective salt thereof.

58 . The method of claim 64 , wherein the salt is mono hydrochloride.

59 . The method of claim 64 , wherein the salt is mono mesylate.

60 . The method of claim 64 , wherein the salt is mono sulfate.

Assignees

• Warner Chilcott Co Llc
• Paratek Pharm Innc

Inventors

• Coulter Catherine
• Johnston Sean M
• Seyedi Farzaneh

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P17/10

  Anti-acne agents · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• C07C2603/46

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

• C07C309/04

  containing only one sulfo group · CPC title