Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use
Compound of Formula A and pharmaceutically acceptable salts thereof and crystalline Forms I and II of Compound of Formula A! Also, methods for the preparation of such compounds, pharmaceutical compositions comprising such compounds, and methods for their uses.
1. N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide,
and/or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition, comprising at least one pharmaceutically acceptable carrier and N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide,
and/or a pharmaceutically acceptable salt thereof.
3. Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
4. Form I N-(2-(dimethylamino) ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide substantially free of the amorphous form N-(2-(dimethylamino) ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide and also substantially free of Form II N-(2-(dimethylamino) ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
5. A method of preparing Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide, comprising:
(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide with at least one dissolution organic solvent, then heating the mixture to reflux to obtain a solution;
(2) cooling the solution to ambient temperature; and
(3) isolating Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
6. The method of claim 5 , wherein the at least one dissolution organic solvent is chosen from alcohols and aprotic solvents.
7. The method of claim 6 , wherein the alcohols are chosen from methanol, ethanol, and isopropanol.
8. The method of claim 6 , wherein the aprotic solvents are chosen from acetone, acetonitrile, ethyl acetate, toluene, dichloromethane, and N,N-dimethylformamide.
9. A method of preparing Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide, comprising:
(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide with at least one dissolution solvent, then heating the mixture to reflux to obtain a first solution;
(2) adding at least one anti-dissolution organic solvent to the first solution at refluxing temperature to obtain a second solution;
(3) leaving the second solution to cool at ambient temperature; and
(4) isolating Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
10. The method of claim 9 , wherein the at least one dissolution solvent is chosen from methanol, ethanol, acetone, acetonitrile, and N,N-dimethylformamide.
11. The method of claim 9 , wherein the at least one anti-dissolution solvent is chosen from water, heptane, hexane, and ethyl acetate.
12. The method of claim 9 , wherein the volume ratio of the at least one dissolution solvent to the at least one anti-dissolution solvent ranges from 1:3 to 5:1.
13. A pharmaceutical composition, comprising at least one pharmaceutically acceptable carrier and Form I N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
14. Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
15. Form II N-(2-(dimethylamino) ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide substantially free of the amorphous form N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide and also substantially free of Form I N-(2-(dimethylamino) ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
16. A method of preparing Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide, comprising:
(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide with at least one dissolution solvent, and heating the mixture to reflux to obtain a first solution;
(2) adding at least one anti-dissolution solvent to the first solution at reflux temperature to obtain a second solution;
(3) cooling the second solution to 0-5° C. at a cooling rate of 1-40° C./minute; and
(4) isolating Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
17. The method of claim 16 , wherein the at least one dissolution solvent is chosen from alcohols and aprotic solvents.
18. The method of claim 17 , wherein the alcohols are chosen from methanol, and ethanol.
19. The method of claim 17 , wherein the aprotic solvents are chosen from acetone, acetonitrile, ethyl acetate, toluene, dichloromethane, and N,N-dimethylformamide.
20. A method of preparing Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide, comprising:
(1) mixing N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide with at least one dissolution solvent, and heating the mixture to reflux to obtain a solution;
(2) cooling the solution, then seeding said cooled solution with Form II;
(3) cooling said seeded solution to ambient temperature, and
(4) isolating Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.
21. The method of claim 20 , wherein the solution in (2) is slowly cooled to 45-55° C.
22. The method of claim 20 , wherein the seeded solution is slowly cooled to ambient temperature.
23. The method of claim 20 , wherein the at least one dissolution solvent is chosen from alcohols and aprotic solvents.
24. The method of claim 23 , wherein the alcohols are chosen from methanol and ethanol.
25. The method of claim 23 , wherein the aprotic solvents are chosen from acetone, acetonitrile, ethyl acetate, toluene, dichloromethane, and N,N-dimethylformamide.
26. A pharmaceutical composition, comprising at least one pharmaceutically acceptable carrier and Form II N-(2-(dimethylamino)ethyl)-1-(3-((4-((2-methyl-1H-indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.