Acid addition salts, hydrates and polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide and formulations comprising these forms
View Patent ↗The present invention relates to new salt forms of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide, in particular the mesylate, hydrochloride, tartrate, phosphate and hemi fumarate salt thereof; to crystalline forms of such salts; to polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide; to hydrates and polymorphs of the new salt forms mentioned above; to the use of the new salt forms mentioned above for the manufacture of a medicament for the treatment of a disorder mediated by Hsp90; to a method for treating a disorder mediated by Hsp90 using the new salt forms; to formulations comprising such salt forms, in particular aqueous solutions suitable for intravenous administration; and to amber glass containers being filled with such formulations.
1. A salt which is 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate or a hydrate thereof.
2. A crystalline form of the salt according to claim 1 .
3. The crystalline form according to claim 2 , which is 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate anhydrate.
4. Crystalline form I of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate anhydrate according to claim 3 .
5. The crystalline form according to claim 4 , which shows an X-ray diffraction diagram of the type shown in FIG. 7 , in which the relative peak intensities of each peak do not deviate by more than 10% from the relative peak intensities in the diagram shown in FIG. 7 .
6. The crystalline form according to claim 2 , which is a hydrate of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate.
7. Hydrate form H A of the salt according to claim 1 .
8. The hydrate form according to claim 7 which shows an X-ray diffraction diagram of the type shown in FIG. 8 , in which the relative peak intensities of each peak do not deviate by more than 10% from the relative peak intensities in the diagram shown in FIG. 8 .
9. Hydrate form H B of the salt according to claim 1 .
10. The hydrate form according to claim 9 which shows an X-ray diffraction diagram of the type shown in FIG. 9 , in which the relative peak intensities of each peak do not deviate by more than 10% from the relative peak intensities in the diagram shown in FIG. 9 .
11. A formulation comprising 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate according to claim 1 .
12. The formulation according to claim 11 , which is an aqueous solution comprising 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate being free of any other salts.
13. The formulation according to claim 12 having a pH between 3.2 and 5.2 pH.
14. A formulation comprising of an isotonic aqueous solution of the mesylate salt of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide according to claims 6 and 5% w/w of glucose.
15. A formulation comprising of an isotonic aqueous solution of the mesylate salt of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide according to claim 1 and 5% w/w of mannitol.
16. The formulation according to claim 12 comprising between around 4.8 and 5.2 mg/ml of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide mesylate.
17. An amber glass container being filled with a formulation according to claim 11 .