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
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.
1. A co-crystal comprising at least two components:
(A) A compound according to Formula I or a pharmaceutically acceptable stereoisomer, or taut omer thereof;
and
(B) a co-crystal former selected from the group consisting of fumaric acid, malonic acid glutaric acid, adipic acid, glycolic acid, 2-aminobenzoic acid and α-ketoglutaric acid.
2. The co-crystal according to claim 1 , wherein the co-crystal comprises the compound of Formula I and glycolic acid.
3. The co-crystal according to claim 1 , wherein the co-crystal comprises the compound of Formula I and malonic acid.
4. The co-crystal according to claim 1 , wherein the co-crystal comprises the compound of Formula I and fumaric acid.
5. The co-crystal according to claim 1 , wherein the co-crystal comprises the compound of Formula I and glutaric acid.
6. The co-crystal according to claim 1 , wherein the co-crystal comprises the compound of Formula I and adipic acid.
7. The co-crystal according to claim 1 , wherein the co-crystal comprises the compound of Formula I and 2-aminobenzoic acid.
8. The co-crystal according to claim 1 , wherein the co-crystal comprises the compound of Formula I and α-ketoglutaric acid.
9. 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.
10. The co-crystal according to claim 5 , wherein the glutaric acid co-crystal has X-ray powder diffraction peaks at a diffraction angle of 2θ 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.
11. An anhydrous pharmaceutical composition comprising a pharmaceutically acceptable carrier and a co-crystal comprising at least two components:
(A) A compound according to Formula I or a pharmaceutically acceptable stereoisomer, or taut omer thereof;
and
(B) a co-crystal former selected from the group consisting of fumaric acid, malonic acid glutaric acid, adipic acid, glycolic acid, 2-aminobenzoic acid and α-ketoglutaric acid.
12. The pharmaceutical composition according to claim 11 , wherein the co-crystal former is glutaric acid.
13. 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 disease or condition is selected from mammary, colon, bladder, liver, lung, prostate, stomach and pancreas carcinomas or Hepatitis B infection.
14. The method according to claim 13 , wherein the disease or condition is Hepatitis B infection.
15. The method according to claim 13 , wherein the co-crystal is administered in combination with a therapeutically effective amount of a second therapeutic agent selected from the group of 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.
16. The method according to claim 15 , wherein the co-crystal is administered in combination with a therapeutically effective amount of α-interferon, β-interferon, pegylated α-interferon, or pegylated β-interferon.
17. 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
or a pharmaceutically acceptable steroisomer or tautomer thereof to obtain a co-crystallization mixture; or
(ii) combining a suspension of a co-crystal former with a suspension of a compound according to Formula I
or a pharmaceutically acceptable steroisomer or tautomer thereof to obtain a co-crystallization mixture; and
(iii) supersaturating the co-crystallization mixture to initiate formation of co-crystals.
18. The method according to claim 17 , 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.
19. The method according to claim 18 , wherein the organic solvent is selected from methanol, ethanol, propanol, isopropanol, isopropyl acetate, hexane, heptane, toluene, acetone, acetonitrile, dioxane, tetrahydrofuran (THF), ethyl acetate, or combinations thereof.