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

Inventors: Christopher K. Murray (Lexington, MA); Leonard W. Rozamus (Andover, MA); John J. Chaber (Westford, MA); Pradeep K. Sharma (Westford, MA)

Assignee: ARIAD PHARMACEUTICALS, INC.

C07D487/04 C07B2200/13 H05K999/99

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Quick Facts

Patent No.: US 11,192,895
App. No.: 17/318,677
Granted: Dec 7, 2021
Kind: B2

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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.

Claims (64)

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 2θ 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 2θ 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 2θ 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 2θ 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 2θ 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 2θ 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 2θ 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 2θ 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: