Claims for Patent: 11,192,895

Summary for Patent: 11,192,895

Title:	Crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-n-{4-[(4-methylpiperazin- -1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide and its mono hydrochloride salt
Abstract:	Novel crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin- -1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide free base and 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin- -1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride, pharmaceutical compositions thereof and methods of their preparation and use are disclosed herein.
Inventor(s):	Murray; Christopher K. (Lexington, MA), Rozamus; Leonard W. (Andover, MA), Chaber; John J. (Westford, MA), Sharma; Pradeep K. (Westford, MA)
Assignee:	ARIAD PHARMACEUTICALS, INC. (Cambridge, MA)
Application Number:	17/318,677
Patent Claims:	1. A method for treating chronic phase chronic myeloid leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one crystalline form of ponatinib hydrochloride characterized by: a) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 5.9, 7.1, 10.0, 12.5, 13.6, 14.1, 15.0, 16.4, 17.7, 18.6, 19.3, 20.4, 21.8, 22.3, 23.8, 24.9, 26.1, 27.0, 28.4, 30.3, 31.7, and 35.1; b) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 3.1, 6.5, 12.4, 13.8, 15.4, 16.2, 17.4, 18.0, 20.4, 23.2, 24.4, 26.1, and 26.9; c) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 3.1, 6.5, 12.4, 13.8, 17.4, 18.0, 20.6, 22.0, 23.0, 25.5, 26.5, 27.4, 28.4, and 29.0; d) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 8.2, 10.1, 10.9, 14.9, 16.0, 16.3, 16.8, 17.7, 18.7, 20.2, 22.9, 24.0, 25.6, 26.7, and 28.5; e) an x-ray powder diffraction pattern substantially as shown in FIG. 41 labelled HC11+HC14 (GRP1.1); f) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 7.9, 8.7, 9.7, 11.4, 15.6, 16.5, and 25.8; g) an x-ray powder diffraction pattern substantially as shown in FIG. 41 labelled HC15b (VDS28.2); h) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 8.0, 10.2, 10.9, 11.8, 14.1, 15.4, 16.3, 19.9, 22.3, 23.7, 25.0, and 28.2; i) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 6.1, 7.0, 13.3, 16.4, 20.7, 22.2, 23.9, 25.5, and 29.1; or j) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 6.1, 7.4, 13.5, 17.4, 18.5, 20.7, 23.9, and 28.3. 2. The method according to claim 1, wherein the subject is resistant or intolerant to at least one prior tyrosine-kinase inhibitor. 3. The method according to claim 2, wherein the subject is resistant or intolerant to at least two prior tyrosine-kinase inhibitors. 4. The method according to claim 1, wherein the leukemia results from a mutation in the Bcr-Abl kinase domain. 5. The method according to claim 1, wherein the pharmaceutical composition comprises crystalline Form A of ponatinib hydrochloride. 6. The method according to claim 1, wherein the pharmaceutical composition consists essentially of crystalline Form A of ponatinib hydrochloride. 7. A method for treating acute phase chronic myeloid leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising at least one crystalline form of ponatinib hydrochloride characterized by: a) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 5.9, 7.1, 10.0, 12.5, 13.6, 14.1, 15.0, 16.4, 17.7, 18.6, 19.3, 20.4, 21.8, 22.3, 23.8, 24.9, 26.1, 27.0, 28.4, 30.3, 31.7, and 35.1; b) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 3.1, 6.5, 12.4, 13.8, 15.4, 16.2, 17.4, 18.0, 20.4, 23.2, 24.4, 26.1, and 26.9; c) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 3.1, 6.5, 12.4, 13.8, 17.4, 18.0, 20.6, 22.0, 23.0, 25.5, 26.5, 27.4, 28.4, and 29.0; d) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 8.2, 10.1, 10.9, 14.9, 16.0, 16.3, 16.8, 17.7, 18.7, 20.2, 22.9, 24.0, 25.6, 26.7, and 28.5; e) an x-ray powder diffraction pattern substantially as shown in FIG. 41 labelled HC11+HC14 (GRP1.1); f) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 7.9, 8.7, 9.7, 11.4, 15.6, 16.5, and 25.8; g) an x-ray powder diffraction pattern substantially as shown in FIG. 41 labelled HC15b (VDS28.2); h) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 8.0, 10.2, 10.9, 11.8, 14.1, 15.4, 16.3, 19.9, 22.3, 23.7, 25.0, and 28.2; i) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 6.1, 7.0, 13.3, 16.4, 20.7, 22.2, 23.9, 25.5, and 29.1; or j) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 6.1, 7.4, 13.5, 17.4, 18.5, 20.7, 23.9, and 28.3. 8. The method according to claim 7, wherein the subject is resistant or intolerant to at least one prior tyrosine-kinase inhibitor. 9. The method according to claim 8, wherein the subject is resistant or intolerant to at least two prior tyrosine-kinase inhibitors. 10. The method according to claim 7, wherein the leukemia results from a mutation in the Bcr-Abl kinase domain. 11. The method according to claim 7, wherein the pharmaceutical composition comprises crystalline Form A of ponatinib hydrochloride. 12. The method according to claim 7, wherein the pharmaceutical composition consists essentially of crystalline Form A of ponatinib hydrochloride. 13. A method for treating blast phase chronic myeloid leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising at least one crystalline form of ponatinib hydrochloride characterized by: a) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 5.9, 7.1, 10.0, 12.5, 13.6, 14.1, 15.0, 16.4, 17.7, 18.6, 19.3, 20.4, 21.8, 22.3, 23.8, 24.9, 26.1, 27.0, 28.4, 30.3, 31.7, and 35.1; b) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 3.1, 6.5, 12.4, 13.8, 15.4, 16.2, 17.4, 18.0, 20.4, 23.2, 24.4, 26.1, and 26.9; c) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 3.1, 6.5, 12.4, 13.8, 17.4, 18.0, 20.6, 22.0, 23.0, 25.5, 26.5, 27.4, 28.4, and 29.0; d) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 8.2, 10.1, 10.9, 14.9, 16.0, 16.3, 16.8, 17.7, 18.7, 20.2, 22.9, 24.0, 25.6, 26.7, and 28.5; e) an x-ray powder diffraction pattern substantially as shown in FIG. 41 labelled HC11+HC14 (GRP1.1); f) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 7.9, 8.7, 9.7, 11.4, 15.6, 16.5, and 25.8; g) an x-ray powder diffraction pattern substantially as shown in FIG. 41 labelled HC15b (VDS28.2); h) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 8.0, 10.2, 10.9, 11.8, 14.1, 15.4, 16.3, 19.9, 22.3, 23.7, 25.0, and 28.2; i) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 6.1, 7.0, 13.3, 16.4, 20.7, 22.2, 23.9, 25.5, and 29.1; or j) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 6.1, 7.4, 13.5, 17.4, 18.5, 20.7, 23.9, and 28.3. 14. The method according to claim 13, wherein the subject is resistant or intolerant to at least one prior tyrosine-kinase inhibitor. 15. The method according to claim 14, wherein the subject is resistant or intolerant to at least two prior tyrosine-kinase inhibitors. 16. The method according to claim 13, wherein the leukemia results from a mutation in the Bcr-Abl kinase domain. 17. The method according to claim 13, wherein the pharmaceutical composition comprises crystalline Form A of ponatinib hydrochloride. 18. The method according to claim 13, wherein the pharmaceutical composition consists essentially of crystalline Form A of ponatinib hydrochloride. 19. A method for treating Philadelphia chromosome positive acute lymphoblastic leukemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising at least one crystalline form of ponatinib hydrochloride characterized by: a) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 5.9, 7.1, 10.0, 12.5, 13.6, 14.1, 15.0, 16.4, 17.7, 18.6, 19.3, 20.4, 21.8, 22.3, 23.8, 24.9, 26.1, 27.0, 28.4, 30.3, 31.7, and 35.1; b) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 3.1, 6.5, 12.4, 13.8, 15.4, 16.2, 17.4, 18.0, 20.4, 23.2, 24.4, 26.1, and 26.9; c) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 3.1, 6.5, 12.4, 13.8, 17.4, 18.0, 20.6, 22.0, 23.0, 25.5, 26.5, 27.4, 28.4, and 29.0; d) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 8.2, 10.1, 10.9, 14.9, 16.0, 16.3, 16.8, 17.7, 18.7, 20.2, 22.9, 24.0, 25.6, 26.7, and 28.5; e) an x-ray powder diffraction pattern substantially as shown in FIG. 41 labelled HC11+HC14 (GRP1.1); f) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 7.9, 8.7, 9.7, 11.4, 15.6, 16.5, and 25.8; g) an x-ray powder diffraction pattern substantially as shown in FIG. 41 labelled HC15b (VDS28.2); h) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 8.0, 10.2, 10.9, 11.8, 14.1, 15.4, 16.3, 19.9, 22.3, 23.7, 25.0, and 28.2; i) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 6.1, 7.0, 13.3, 16.4, 20.7, 22.2, 23.9, 25.5, and 29.1; or j) an x-ray powder diffraction pattern comprising at least three 2.theta. values (.+-.0.3) chosen from 6.1, 7.4, 13.5, 17.4, 18.5, 20.7, 23.9, and 28.3. 20. The method according to claim 19, wherein the subject is resistant or intolerant to at least one prior tyrosine-kinase inhibitor. 21. The method according to claim 20, wherein the subject is resistant or intolerant to at least two prior tyrosine-kinase inhibitors. 22. The method according to claim 19, wherein the leukemia results from a mutation in the Bcr-Abl kinase domain. 23. The method according to claim 19, wherein the pharmaceutical composition comprises crystalline Form A of ponatinib hydrochloride. 24. The method according to claim 19, wherein the pharmaceutical composition consists essentially of crystalline Form A of ponatinib hydrochloride.