Hydrogen sulfate salt
The present invention relates to Compound 1 hydrogen sulfate salt and solvates, crystalline forms and amorphous forms thereof, and to processes for their preparation.
1. A method for reversing, alleviating or inhibiting the progress of a cancer associated with overactivation of MEK in a mammal in need thereof, the method comprising administering to said mammal a therapeutically effective amount of a crystalline hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide, wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide has an X-ray powder diffraction pattern with specific peaks at about 2-theta equal to 24.59°, 20.97°, 27.65°, 12.24°, and 17.02°.
2. The method according to claim 1 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide has an X-ray powder diffraction pattern with specific peaks at about 2-theta equal to 24.59°, 20.97°, 23.99°, 27.65°, 12.24°, 23.49°, 24.30°, 17.02°, 25.91° and 22.50°.
3. The method according to claim 1 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide has a powder X-ray diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 1 .
4. The method according to claim 1 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide has an X-ray powder diffraction pattern with specific peaks at about 2-theta equal to 24.59°, 20.97°, 27.65°, 12.24°, 23.49°, 23.99°, 17.02° and 25.91°.
5. The method according to claim 1 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide is administered orally.
6. The method according to claim 5 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide is formulated as a tablet, lozenge, hard or soft capsule, emulsion, dispersible powder or granule, syrup, elixir, oily suspension, or aqueous suspension.
7. The method according to claim 6 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide is formulated as a tablet or hard or soft capsule.
8. The method according to claim 1 , wherein said cancer is selected from the group consisting of brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, esophageal, testicular, gynecological, bone, melanoma, leukemia, myeloma, stomach, colon, anal, and thyroid cancer.
9. The method according to claim 8 , wherein said cancer is a lung cancer.
10. The method according to claim 9 , wherein said lung cancer is a non small cell lung cancer.
11. The method according to claim 8 , wherein said cancer is a melanoma.
12. The method according to claim 11 , wherein said melanoma is an intraocular melanoma.
13. The method according to claim 8 , wherein said cancer is a thyroid cancer.
14. A crystalline hydrogen sulfate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide, prepared by the process comprising: (i) reacting a slurry of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide in butanone with at least a stoichiometric amount of sulfuric acid and water; and (ii) recovering the salt from the resultant solution, wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide has an X-ray powder diffraction pattern with specific peaks at about 2-theta equal to 24.59°, 20.97°, 27.65°, 12.24°, and 17.02°.
15. The crystalline hydrogen sulfate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide according to claim 14 , wherein the amount of water added in step (i) is an amount necessary to ensure that the salt is formed.
16. The crystalline hydrogen sulfate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide according to claim 15 , wherein the amount of water is present in an amount of less than 20% v/v of the total liquid present.
17. The crystalline hydrogen sulfate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide according to claim 16 , wherein the amount of water is present in an amount from 13-17% v/v of the total liquid present.
18. The crystalline hydrogen sulfate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide according to claim 15 , wherein step (i) is carried out at a temperature of from 40-80° C.
19. The crystalline hydrogen sulfate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide according to claim 14 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide has an X-ray powder diffraction pattern with specific peaks at about 2-theta equal to 24.59°, 20.97°, 23.99°, 27.65°, 12.24°, 23.49°, 24.30°, 17.02°, 25.91° and 22.50°.
20. The crystalline hydrogen sulfate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide according to claim 14 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide has a powder X-ray diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 1 .
21. The crystalline hydrogen sulfate salt of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)amide according to claim 14 , wherein said hydrogen sulfate salt of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide has an X-ray powder diffraction pattern with specific peaks at about 2-theta equal to 24.59°, 20.97°, 27.65°, 12.24°, 23.49°, 23.99°, 17.02° and 25.91°.