Compositions and methods for treating myelofibrosis

• US 10,391,094 B2
• Filed: 05/06/2013
• Issued: 08/27/2019
• Est. Priority Date: 11/07/2010
• Status: Active Grant

• Current Assignee: Impact Biomedicines, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: Impact Biomedicines, Inc. (Bristol-Myers Squibb Company)
• Inventors: Jayan, Arvind, Cacace, Janice
• Primary Examiner(s): Haghighatian, Mina
• Assistant Examiner(s): Chui, Mei Ping
• Application Number:
  US13/888,096
• Publication Number:
  US 20130243853A1
• Time in Patent Office: 2,304 Days
• Field of Search: 424452
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid

Abstract

Provided herein are compositions and methods for treating myelofibrosis in a subject. The methods comprise administering to the subject an effective amount of compound which is which is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutical salt thereof or a hydrate thereof.

Claims

1. A capsule comprising a formulation comprising (i) a compound that is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate,

wherein:

the weight ratio of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide to microcrystalline cellulose in the formulation is about 1;

1.5 to about 1;

9, and

sodium stearyl fumarate is about 1% by weight of the formulation.

2. The capsule unit of claim 1, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

3. The capsule of claim 1, wherein the to formulation comprises about 117 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

4. The capsule of claim 1, wherein the formulation comprises about 235 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate, about 357 mg of silicified microcrystalline cellulose, and about 6 mg of sodium stearyl fumarate.

5. The capsule of claim 1, wherein the capsule is a hard gelatin capsule.

9. The capsule or claim 3, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

12. The capsule of claim 1, wherein the weight ratio or N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide to microcrystalline cellulose in the formulation is about 1:

1.5 to about 1;

2.

13. The capsule of claim 12, wherein the formulation comprises about 117 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

14. The capsule of claim 12, wherein the formulation comprises about 235 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

15. The capsule of claim 12, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

16. The capsule of claim 15, wherein the formulation comprises about 117 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

17. The capsule of claim 15, wherein the formulation comprises about 235 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

18. The capsule of claim 4, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

6. A method of treating myelofibrosis in a subject comprising administering a capsule comprising a formulation comprising (i) a compound that is N-tert-butyl-3-[(5-methyl-2-{[4(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate,

wherein:

the weight ratio of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide to microcrystalline cellulose in the formulation is about 1;

1.5 to about 1;

9, and

sodium stearyl fumarate is about 1% by weight of the formulation.

7. A method of preparing a capsule comprising a formulation, wherein the method comprises blending a microcrystalline cellulose and sodium stearyl fumarate with a compound that is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate,

wherein:

the weight ratio of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide to microcrystalline cellulose in the formulation is about 1;

1.5 to about 1;

9, and

sodium stearyl fumarate is about 1% by weight of the formulation.

11. The method of claim 7, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

8. An article of manufacture comprising:

(a) a capsule comprising a formulation comprising (i) a compound that is N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate,

wherein;

the weight ratio of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide to microcrystalline cellulose in the formulation is about 1;

1.5 to about 1;

9, and

sodium stearyl fumarate is about 1% by weight of the formulation; and

(b) a package insert or a label indicating that the formulation is useful for treating myelofibrosis in a subject.

10. The article of manufacture of claim 8, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

19. The article of manufacture of claim 8, wherein the formulation comprises about 117 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

20. The article of manufacture of claim 19, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

21. The article of manufacture of claim 8, wherein the weight ratio of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide to microcrystalline cellulose in the formulation is about 1:

1.5 to about 1;

2.

22. The article of manufacture of claim 21, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.

23. The article or manufacture of claim 22, wherein the formulation comprises about 117 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino)}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

24. The article of manufacture of claim 8, wherein the formulation comprises about 235 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

25. The article of manufacture of claim 22, wherein the formulation comprises about 235 mg of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.

26. The article of manufacture of claim 24, wherein the microcrystalline cellulose is silicified microcrystalline cellulose.