Bromodomain inhibitor
Described herein is the bromodomain inhibitor 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, including crystalline forms, amorphous forms, solvates, and hydrates thereof, as well as pharmaceutical compositions that include this bromodomain inhibitor. In some embodiments, the pharmaceutical composition comprises 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one that has been processed by micronization or spray dried dispersion. In some embodiments, the pharmaceutical composition further comprises at least one polymer. In some embodiments, the pharmaceutical composition comprises a solid polymer matrix comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one and at least one polymer. Pharmaceutical compositions comprising 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one are useful for the treatment of cancer or neoplastic disease.
1. A pharmaceutical composition comprising a spray dried dispersion or a micronized form of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one exhibiting XRPD reflection peaks at 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6 and 24.5 2-theta (2θ).
2. The pharmaceutical composition of claim 1 , wherein the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is prepared by a process comprising (a) spray drying, or (b) micronizing by a rapid expansion of supercritical CO 2 solution (RESS).
3. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises at least one solid matrix polymer.
4. The pharmaceutical composition of claim 3 , wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is from about 1:1 to about 1:9.
5. The pharmaceutical composition of claim 3 , wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, or about 1:9.
6. The pharmaceutical composition of claim 3 , wherein the solid matrix polymer is polyvinylpyrrolidone.
7. The pharmaceutical composition of claim 3 , wherein the solid matrix polymer is a cellulose derivative.
8. The pharmaceutical composition of claim 7 , wherein the cellulose derivative is selected from the group consisting of hydroxypropylmethycellulose, hydroxypropylmethy-cellulose phthalate, hydroxypropylmethylcellulose acetate stearate, and hydroxypropyl-methylcellulose acetate succinate.
9. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition is prepared by a process comprising (a) spray drying, or (b) micronizing by RESS.
10. The pharmaceutical composition of claim 3 , comprising:
a solid polymer matrix comprising (a) the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, and (b) a polymer selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, or hydroxypropylmethylcellulose-acetate-succinate;
wherein said solid polymer matrix is a spray dried dispersion.
11. The pharmaceutical composition of claim 10 , wherein the polymer is hydroxypropyl methylcellulose present in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:3.
12. The pharmaceutical composition of claim 10 , wherein the polymer is hydroxypropyl methylcellulose present in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:1.
13. The pharmaceutical composition of claim 10 , wherein the polymer is polyvinylpyrrolidone in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:3.
14. The pharmaceutical composition of claim 10 , wherein the polymer is polyvinylpyrrolidone in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:1.
15. The pharmaceutical composition of claim 10 , wherein the polymer is hydroxypropylmethylcellulose-acetate-succinate present in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:3.
16. The pharmaceutical composition of claim 10 , wherein the polymer is hydroxypropylmethylcellulose-acetate-succinate present in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:1.
17. A pharmaceutical composition comprising a spray dried dispersion or a micronized form of amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one.
18. The pharmaceutical composition of claim 17 , wherein the 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one is prepared by a process comprising (a) spray drying, or (b) micronizing by a rapid expansion of supercritical CO 2 solution (RESS).
19. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition comprises at least one solid matrix polymer.
20. The pharmaceutical composition of claim 19 , wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is from about 1:1 to about 1:9.
21. The pharmaceutical composition of claim 19 , wherein the ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one to solid matrix polymer is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, or about 1:9.
22. The pharmaceutical composition of claim 19 , wherein the solid matrix polymer is polyvinylpyrrolidone.
23. The pharmaceutical composition of claim 19 , wherein the solid matrix polymer is a cellulose derivative.
24. The pharmaceutical composition of claim 23 , wherein the cellulose derivative is selected from the group consisting of hydroxypropylmethycellulose, hydroxypropylmethy-cellulose phthalate, hydroxypropylmethylcellulose acetate stearate, and hydroxypropyl-methylcellulose acetate succinate.
25. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition is prepared by a process comprising (a) spray drying, or (b) micronizing by RESS.
26. The pharmaceutical composition of claim 19 , comprising:
a solid polymer matrix comprising (a) amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, and (b) a polymer selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, or hydroxypropylmethylcellulose-acetate-succinate;
wherein said solid polymer matrix is a spray dried dispersion.
27. The pharmaceutical composition of claim 26 , wherein the polymer is hydroxypropyl methylcellulose present in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:3.
28. The pharmaceutical composition of claim 26 , wherein the polymer is hydroxypropyl methylcellulose present in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:1.
29. The pharmaceutical composition of claim 26 , wherein the polymer is polyvinylpyrrolidone in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:3.
30. The pharmaceutical composition of claim 26 , wherein the polymer is polyvinylpyrrolidone in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:1.
31. The pharmaceutical composition of claim 26 , wherein the polymer is hydroxypropylmethylcellulose-acetate-succinate present in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:3.
32. The pharmaceutical composition of claim 26 , wherein the polymer is hydroxypropylmethylcellulose-acetate-succinate present in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:1.