CO-CRYSTALS OF 5-AMINO-2-OXOTHIAZOLO[4,5-D]PYRIMIDIN-3(2H)-YL-5-HYDROXYMETHYL TETRAHYDROFURAN-3-YL ACETATE AND METHODS FOR PREPARING AND USING THE SAME

• US 20160176899A1
• Filed: 12/21/2015
• Published: 06/23/2016
• Est. Priority Date: 12/23/2014
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Schwitter, Urs, Bliss, Fritz, Tixeront, Florence, Kammerer, Michael
• Granted Patent: US 9,676,793 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 55/08 Malonic acid
• CPC Class Codes: C07C 55/12 Glutaric acid
• CPC Class Codes: C07C 55/14 Adipic acid
• CPC Class Codes: C07C 57/15 Fumaric acid
• CPC Class Codes: C07C 59/06 Glycolic acid
• CPC Class Codes: C07C 59/185 Saturated compounds having only one carboxyl group and containing keto groups
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Co-crystals of Formula I compounds and their pharmaceutical compositions are novel therapeutics for the treatment of diseases, such as human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection and cancer. The co-crystal are more stable to oxidation and aqueous degradation, have a better pharmacokinetic profile and superior biological activity than the corresponding tosylate salt form of Formula I compound.

Claims

1. A co-crystal comprising at least two components:

(A) A compound according to Formula I or a pharmaceutically acceptable stereoisomer, or tautomer thereof; and

2. The co-crystal according to claim 1, wherein the co-crystal former is selected from the group consisting of fumaric acid, malonic acid, glutaric acid, adipic acid and glycolic acid.

3. The co-crystal according to claim 2, wherein the co-crystal former is glutaric acid.

4. The co-crystal according to claim 1, wherein the co-crystal comprises the compound of Formula I and malonic acid.

5. The co-crystal according to claim 1, wherein the co-crystal comprises the compound of Formula I and fumaric acid.

6. The co-crystal according to claim 1, wherein the co-crystal comprises the compound of Formula I and glutaric acid.

7. The co-crystal according to claim 1, wherein the co-crystal comprises the compound of Formula I and adipic acid.

8. The co-crystal according to claim 1, wherein the co-crystal comprises the compound of Formula I and 2-aminobenzoic acid.

9. The co-crystal according to claim 1, wherein the co-crystal comprises the compound of Formula I and α

-ketoglutaric acid

10. The co-crystal according to claim 1, wherein the compound of Formula I and co-crystal former are present in the co-crystal in a ratio of 1:

1, 1;

2, or 2;

1.

11. The co-crystal according to claim 6, wherein the gluraic acid co-crystal has X-ray powder diffraction peaks at a diffraction angle of 20 of 5.9, 8.1, 11.3, 11.9, 12.4, 15.7, 17.8, 18.3, 18.9, 20.6, 20.8, 21.6, 22.4, 24.2, 24.6, 25.4, 25.6, 26.5, and 28.6.

14. A method for treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of the co-crystal according to claim 1, wherein the co-crystal further comprises (A) a compound according to Formula I or a pharmaceutically acceptable stereoisomer or tautomer thereof;

15. The method according to claim 14, wherein the disease or condition is selected from cancer, inflammation, or Hepatitis B infection.

16. The method according to claim 15, wherein the disease or condition is the Hepatitis B infection.

17. The method according to claim 14, wherein the co-crystal of claim 1 is administered in combination with a therapeutically effective amount of a second therapeutic agent selected from the group consisting of antibiotics, antiemetic agents, anti-inflammatory agents, antiviral agents, anticancer agents, immunomodulatory agents, α

-interferon, β

-interferon, pegylated α

-interferon, pegylated β

-interferon, ribavirin, alkylating agents, hormones, cytokines, polymerase inhibitors, and toll receptor-like modulators.

18. The method according to claim 18, wherein the co-crystal of claim 1 is administered in combination with a therapeutically effective amount of α

-interferon, β

-interferon, pegylated α

-interferon, or pegylated β

-interferon.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a co-crystal comprising at least two components:

(A) a compound according to Formula I or a pharmaceutically acceptable stereoisomer or tautomer thereof;

13. The pharmaceutical composition according to claim 12, wherein the co-crystal former is glutaric acid.

19. A method for synthesizing a co-crystal comprising:

(i) combining a solution of a co-crystal former with a solution of a compound according to Formula I

20. The method according to claim 19, wherein the solution of the co-crystal former and the solution of the compound of Formula I are obtained using an organic solvent, water, or a mixture of water and an organic solvent.

21. The method according to claim 20, wherein organic solvent is selected from methanol, ethanol, propanol, isopropanol, isopropyl acetate, hexane, heptane, toluene, acetone, acetonitrile, dioxane, THF, ethyl acetate, or combinations thereof.