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

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.

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.