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 compositions 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 solid form of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one.
2 . The pharmaceutical composition of claim 1 , comprising crystalline 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one designated crystalline Form A.
3 . The pharmaceutical composition of claim 2 , wherein crystalline Form A of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one exhibits XRPD reflection peaks at 7.8, 9.0, 15.7, 18.0, 21.1, 22.0, 23.6 and 24.5 2-theta (2θ).
4 . The pharmaceutical composition of claim 1 , comprising amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one.
5 . 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).
6 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises at least one solid matrix polymer.
7 . The pharmaceutical composition of claim 6 , 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.
8 . The pharmaceutical composition of claim 6 , 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.
9 . The pharmaceutical composition of claim 6 , wherein the solid matrix polymer is polyvinylpyrrolidone or a polyvinylpyrrolidone derivative.
10 . The pharmaceutical composition of claim 6 , wherein the solid matrix polymer is a cellulose derivative.
11 . The pharmaceutical composition of claim 10 , wherein the cellulose derivative is selected from the group consisting of hydroxypropylmethycellulose, hydroxypropylmethy-cellulose phthalate, hydroxypropylmethylcellulose acetate stearate, and hydroxypropylmethylcellulose acetate succinate.
12 . The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is prepared by a process comprising (a) spray drying, or (b) micronizing by RESS.
13 . The pharmaceutical composition of claim 6 , comprising:
a solid polymer matrix comprising (a) amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, and (b) a polymer selected from polyvinylpyrrolidone or hydroxypropyl methylcellulose;
wherein said solid polymer matrix is a spray dried dispersion.
14 . The pharmaceutical composition of claim 13 , 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.
15 . The pharmaceutical composition of claim 14 , 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.
16 . The pharmaceutical composition of claim 13 , wherein the polymer is polyvinylpyrrolidone in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:3.
17 . The pharmaceutical composition of claim 13 , wherein the polymer is polyvinylpyrrolidone in a ratio of 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one:polymer of about 1:1.
18 . A method for treating cancer or other neoplastic disease in a subject in need of such treatment comprising administering to the subject the pharmaceutical composition of claim 1 .
19 . A method for treating cancer or other neoplastic disease in a subject in need of such treatment comprising administering to the subject the pharmaceutical composition of claim 6 .
20 . The method of claim 19 , wherein the pharmaceutical composition comprises:
a solid polymer matrix comprising (a) amorphous 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, and (b) a polymer selected from polyvinylpyrrolidone or hydroxypropyl methylcellulose;
wherein said solid polymer matrix is a spray dried dispersion.