Co-crystals and their uses

Abstract

The present application relates to N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide (Compound I) fumaric acid co-crystals, and an X-ray amorphous complex of Compound (I) and fumaric acid. The present application also provides a method for preparing the same; a pharmaceutical composition comprising the same; and the use of the pharmaceutical composition in treating, preventing, inhibiting, alleviating, or eradicating the pathology and / or symptoms of diseases caused by kinetoplastid parasites, such as leishmaniasis, human African trypanosomiasis, and Chagas disease.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to PCT / CN2018 / 109415, filed on October 9, 2018, which is incorporated by reference in its entirety. Technical Field

[0003] The present invention is directed to solid forms of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide and methods for preparing the same; pharmaceutical compositions comprising the same; and methods of treatment using the pharmaceutical compositions. Background Art

[0004] N-(4-Fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide (Compound I) is a selective inhibitor of the kinetoplastid proteasome with activity against leishmaniasis, Chagas disease, and sleeping sickness. Diseases caused by infection with kinetoplastid parasites (Leishmania spp., Trypanosoma cruzi, and Trypanosoma brucei spp.) each affect 20 million people worldwide and cause more than 50,000 deaths each year (Khare et al., Nature (2016) 537:229-233).

[0005]

[0006] Compound I is described in WO 2015 / 095477 as a compound in free form. Summary of the invention

[0007] The present invention provides a solid form of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide.

[0008] Various enumerated embodiments of the present invention are described herein. The features specified in each embodiment can be combined with other specified features to provide further embodiments of the present invention.

[0009] Example 1. A co-crystal comprising N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide and an aliphatic C 2-8 Dicarboxylic acid.

[0010] Embodiment 2A. The co-crystal of Embodiment 1, wherein the C 2-8 The dicarboxylic acid is a C4 dicarboxylic acid. In one embodiment, the C4 dicarboxylic acid is fumaric acid, succinic acid, tartaric acid or maleic acid.

[0011] Embodiment 2B. The co-crystal of Embodiment 1, comprising N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide and fumaric acid.

[0012] Embodiment 3A. The co-crystal of Embodiment 2B, wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 2:(0.5-2.5). In one embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 2:(0.8-1.2) or 1:(0.8-1.2).

[0013] Embodiment 3C. The co-crystal of Embodiment 2B, wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is about 1:1; for example, 1:(0.7-1.3); preferably 1:(0.8-1.2), and more preferably 1:(0.9-1.1). In one embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 1:(0.8-1.2). In another embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 1:1.

[0014] Embodiment 3D. The co-crystal of Embodiment 2B, wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is about 2:1; for example, 2:(0.7-1.3); preferably 2:(0.8-1.2), and more preferably 2:(0.9-1.1). In one embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 2:(0.8-1.2). In another embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 2:1.

[0015] Embodiment 4. The co-crystal of Embodiment 2B, when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature, has an X-ray powder diffraction pattern comprising three or more 2θ peaks selected from about 9.4°, 11.0°, 14.2° and 25.8° (2θ); preferably at 9.4°±0.2°, 11.0°±0.2°, 14.2°±0.2° and 25.8°±0.2° (2θ).

[0016] Embodiment 5. The co-crystal of Embodiment 2B, wherein the co-crystal has an X-ray powder diffraction pattern comprising 2θ peaks at about 9.4°, 14.2° and 25.8° (2θ); preferably at 9.4°±0.2°, 14.2°±0.2° and 25.8°±0.2° (2θ), when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature.

[0017] Embodiment 6. The co-crystal of Embodiment 2B, characterized by one or more of the following: (a) when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature, substantially Figure 1 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 2 and (c) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 3 Thermogravimetric analysis (TGA) graph shown.

[0018] Embodiment 7. The co-crystal of Embodiment 2B, when measured at room temperature with CuKα radiation at a wavelength of 0.15 nm, has an X-ray powder diffraction pattern comprising three or more 2θ peaks selected from about 13.4°, 15.7°, 23.9° and 24.7° (2θ); preferably at 13.4°±0.2°, 15.7°±0.2°, 23.9°±0.2° and 24.7°±0.2° (2θ).

[0019] Embodiment 8. The co-crystal of Embodiment 2B, wherein the co-crystal has an X-ray powder diffraction pattern comprising 2θ peaks at about 15.7°, 23.9° and 24.7° (2θ); preferably at 15.7°±0.2°, 23.9°±0.2° and 24.7°±0.2° (2θ), when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature.

[0020] Embodiment 9. The co-crystal of Embodiment 2B, characterized by one or more of the following: (a) when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature, substantially Figure 4 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 5 and (c) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 6 Thermogravimetric analysis (TGA) graph shown.

[0021] Embodiment 10. The co-crystal of Embodiment 2B, wherein the co-crystal has an X-ray powder diffraction pattern comprising three or more 2θ peaks selected from about 9.8°, 11.3°, 14.8°, 24.6°, 25.0°, 26.5° and 27.6° (2θ); preferably at 9.8°±0.2°, 11.3°±0.2°, 14.8°±0.2°, 24.6°±0.2°, 25.0°±0.2°, 26.5°±0.2° and 27.6°±0.2° (2θ), when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature.

[0022] Embodiment 11. The co-crystal of Embodiment 2B, wherein the co-crystal has an X-ray powder diffraction pattern comprising 2θ peaks at about 9.8°, 14.8° and 27.6° (2θ); preferably at 9.8°±0.2°, 14.8°±0.2° and 27.6°±0.2° (2θ), when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature.

[0023] Embodiment 12. The co-crystal of Embodiment 2B, characterized by one or more of the following: (a) when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature, substantially Figure 7 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 8 and (c) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig. 9 Thermogravimetric analysis (TGA) graph shown.

[0024] Embodiment 13. The co-crystal of Embodiment 2B, wherein the co-crystal has an X-ray powder diffraction pattern comprising three or more 2θ peaks selected from about 3.8°, 13.5°, 17.2° and 26.6° (2θ), when measured at room temperature with CuKα radiation at a wavelength of 0.15 nm; preferably at 3.8°±0.2°, 13.5°±0.2°, 17.2°±0.2° and 26.6°±0.2° (2θ).

[0025] Embodiment 14. The co-crystal of Embodiment 2B, wherein the co-crystal has an X-ray powder diffraction pattern comprising 2θ peaks at about 3.8°, 13.5° and 17.2° (2θ); preferably at 3.8°±0.2°, 13.5°±0.2° and 17.2°±0.2° (2θ), when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature.

[0026] Embodiment 15. The co-crystal of Embodiment 2B, characterized by one or more of the following: (a) when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature, substantially Fig.10 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig.11and (c) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig.12 Thermogravimetric analysis (TGA) graph shown.

[0027] Embodiment 16. The co-crystals of Embodiments 1, 2A, 2B, 3A-3D, and 4-15, which are in substantially pure form.

[0028] Embodiment 17. A composition comprising the co-crystal as described in any one of the above embodiments.

[0029] Embodiment 18. The composition of embodiment 17, comprising at least 90% by weight of the co-crystal based on the weight of the composition.

[0030] Embodiment 19. A composition consisting essentially of the co-crystal of any of Embodiments 1, 2A, 2B, 3A-3D, and 4-16.

[0031] Embodiment 20. A pharmaceutical composition comprising the co-crystal of any one of Embodiments 1, 2A, 2B, 3A-3D, and 4-16, and a pharmaceutically acceptable carrier.

[0032] Embodiment 21. A combination comprising a co-crystal as described in any one of Embodiments 1, 2A, 2B, 3A-3D and 4-16, and one or more therapeutically active agents.

[0033] Embodiment 22. The co-crystal of any one of Embodiments 1, 2A, 2B, 3A-3D and 4-16, and optionally in combination with a second agent, for use in treating a disorder or disease selected from leishmaniasis, Chagas disease and human African trypanosomiasis.

[0034] Embodiment 23. Use of the co-crystal of any one of Embodiments 1, 2A, 2B, 3A-3D and 4-16, optionally in combination with a second agent, for treating leishmaniasis, Chagas disease or human African trypanosomiasis.

[0035] Embodiment 23A. Use of a co-crystal as described in any of Embodiments 1, 2A, 2B, 3A-3D and 4-16, optionally in combination with a second agent, in the manufacture of a medicament for treating a disorder or disease selected from leishmaniasis, Chagas disease and human African trypanosomiasis.

[0036] Embodiment 24. A co-crystal for use in treating a disorder or disease as described in Embodiment 22, or the use as described in Embodiment 23 or 23A; wherein the second agent is selected from: (a) antimoni gluconate, meglumine antimoniate, amphotericin, miltefosine and paromomycin or a combination thereof for treating visceral leishmaniasis or cutaneous leishmaniasis; (b) benznidazole, nifurtimox and amphotericin or a combination thereof for treating Chagas disease; and (c) pentamidine, suramin, melarsoprol, eflornithine and nifurtimox or a combination thereof for treating human African trypanosomiasis.

[0037] Embodiment 25A. A co-crystal for use in treating a disorder or disease as described in Embodiment 24, or the use as described in Embodiment 24; wherein the disease is visceral leishmaniasis or cutaneous leishmaniasis.

[0038] Embodiment 25B. A co-crystal for use in treating a disorder or disease as described in Embodiment 25A, or the use as described in Embodiment 25A; wherein the second agent is selected from antimony gluconate, meglumine antimoniate, amphotericin, miltefosine and paromomycin, or a combination thereof.

[0039] Embodiment 25C. A co-crystal for use in treating a disorder or disease as described in Embodiment 24, or the use as described in Embodiment 24; wherein the disease is Chagas disease.

[0040] Embodiment 25D. A co-crystal for use in treating a disorder or disease as described in Embodiment 25C, or the use as described in Embodiment 25C; wherein the second agent is selected from benznidazole, nifurtimox and amphotericin, or a combination thereof.

[0041] Embodiment 25E. A co-crystal for use in treating a disorder or disease as described in Embodiment 24, or the use as described in Embodiment 24; wherein the disease is human African trypanosomiasis.

[0042] Embodiment 25F. A co-crystal for use in treating a disorder or disease as described in Embodiment 25E, or the use as described in Embodiment 25E; wherein the second agent is pentamidine, suramin, melarsoprol, eflornithine and nifurtimox, or a combination thereof.

[0043] Embodiment 26. A method for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and / or symptoms of a disease caused by a parasite, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising the co-crystal of any one of Embodiments 1, 2A, 2B, 3A-3D, and 4-16, at least one pharmaceutically acceptable carrier, and optionally in combination with a second agent, wherein the disease is selected from leishmaniasis, human African trypanosomiasis, and Chagas disease.

[0044] Embodiment 27. The method of embodiment 26, wherein the pharmaceutical composition is administered at a dose ranging from about 10 mg to about 500 mg.

[0045] Embodiment 28. The method of embodiment 26, wherein the pharmaceutical composition is administered at a dose ranging from about 10 mg to about 400 mg.

[0046] Embodiment 29. The method of embodiment 26, wherein the pharmaceutical composition is administered at a dose ranging from about 50 mg to about 250 mg.

[0047] Embodiment 30. The method of embodiment 26, wherein the pharmaceutical composition is administered at a dose ranging from about 50 mg to about 150 mg.

[0048] Embodiment 31. The method of embodiment 26, wherein the pharmaceutical composition is administered at a dose ranging from about 100 mg to about 150 mg.

[0049] Embodiment 32. The method of any one of embodiments 26-31, wherein the pharmaceutical composition is administered once or twice daily.

[0050] Embodiment 33. The method of any one of embodiments 26-32, wherein the pharmaceutical composition is administered orally.

[0051] Embodiment 34. A kit comprising (i) a pharmaceutical composition comprising the co-crystal of any one of Embodiments 1, 2A, 2B, 3A-3D and 4-16, at least one pharmaceutically acceptable carrier, and optionally in combination with a second agent; and (ii) instructions for administration.

[0052] Embodiment 35. A method for preparing the co-crystals of any of Embodiments 1, 2A, 2B, 3A-3D and 4-16, the method comprising contacting (1) fumaric acid, optionally in a first solvent, with (2) N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide, optionally in a second solvent, under suitable conditions to form N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide fumaric acid co-crystals.

[0053] Embodiment 36. The method of embodiment 35, comprising (1) adding fumaric acid to a first solvent to form a fumaric acid solution; (2) adding N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to a second solvent to form a N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide solution; and (3) in a suitable Under the conditions, the fumaric acid solution is contacted with the N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide solution, and the reaction mixture is optionally heated between 40°C and 70°C, between 40°C and 60°C, or between 45°C and 55°C to form N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide fumaric acid co-crystals.

[0054] Example 37. A method as described in Example 36, comprising adding the N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide solution to the fumaric acid solution under suitable conditions, and optionally heating the reaction mixture between 45°C and 55°C to form the N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide fumaric acid co-crystal. In one embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is about 1:1 (“Compound 1 fumaric acid cocrystal (1:1)”).

[0055] Example 38. A method as described in Example 36, comprising adding the fumaric acid solution to the N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide solution under suitable conditions, and optionally heating the reaction mixture between 45°C and 55°C to form the N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide fumaric acid co-crystal. In one embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is about 2:1 (“Compound 1 fumaric acid cocrystal (2:1)”).

[0056] Embodiment 39. The method of any one of claims 35-38, wherein the first solvent is isopropanol.

[0057] Embodiment 40. The method of any one of claims 35-38, wherein the second solvent is tetrahydrofuran.

[0058] Example 41. An X-ray amorphous complex of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide and fumaric acid; wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 2:(0.1-5); and optionally substantially free of crystalline form.

[0059] Embodiment 42. An X-ray amorphous complex as described in Embodiment 41, wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 1:(0.5-2.5); 1:(0.8-2.3), 1:(0.7-1.3), 1:(0.8-1.2), 1:(0.9-1.1), 1:1; 2:(0.1-1.2), 2:(0.5-1.1), 2:(0.1-0.5), 2:(0.7-1.3), 2:(0.8-1.2), 2:(0.9-1.1) or 2:1.

[0060] Embodiment 43. An X-ray amorphous complex as described in Embodiment 41, wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 1:(0.5-2.5), preferably 1:(0.8-2.3).

[0061] Embodiment 44. The X-ray amorphous composite of embodiment 41, wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 1:(0.7-1.3), preferably 1:(0.8-1.2), and more preferably 1:(0.9-1.1). In one embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 1:1.

[0062] Embodiment 45. An X-ray amorphous complex as described in Embodiment 41, wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 2:(0.1-1.2), preferably 2:(0.5-1.1) or 2:(0.1-0.5).

[0063] Embodiment 46. The X-ray amorphous composite of embodiment 41, wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 2:(0.7-1.3), preferably 2:(0.8-1.2), and more preferably 2:(0.9-1.1). In one embodiment, the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is 2:1. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 The XRPD pattern of Compound 1 fumaric acid cocrystal (1:1) Form A is shown.

[0065] Figure 2 The differential scanning calorimetry (DSC) curve of Compound 1 fumaric acid cocrystal (1:1) Form A is shown.

[0066] Figure 3 A thermogravimetric analysis (TGA) graph of Compound 1 fumaric acid cocrystal (1:1) Form A is shown.

[0067] Figure 4 The XRPD pattern of Compound 1 fumaric acid cocrystal (1:1) Form B is shown.

[0068] Figure 5 The DSC curve of Compound 1 fumaric acid cocrystal (1:1) Form B is shown.

[0069] Figure 6 A TGA pattern of Compound 1 fumaric acid cocrystal (1:1) Form B is shown.

[0070] Figure 7 The XRPD pattern of Compound 1 fumaric acid cocrystal (1:1) Form C is shown.

[0071] Figure 8 The DSC curve of Compound 1 fumaric acid cocrystal (1:1) Form C is shown.

[0072] Fig. 9 A TGA pattern of Compound 1 fumaric acid cocrystal (1:1) Form C is shown.

[0073] Fig.10 The XRPD pattern of Compound 1 fumaric acid cocrystal (2:1) is shown.

[0074] Fig.11 The DSC curve of Compound 1 fumaric acid cocrystal (2:1) is shown.

[0075] Fig.12 The TGA pattern of Compound 1 fumaric acid cocrystal (2:1) is shown.

[0076] Fig.13 The XRPD pattern of the X-ray amorphous complex of Compound 1 and fumaric acid (1:1) is shown.

[0077] Fig.14 The DSC curve of the X-ray amorphous complex of Compound I and fumaric acid (1:1) is shown.

[0078] Fig.15 The TGA pattern of the X-ray amorphous complex of Compound I and fumaric acid (1:1) is shown.

[0079] Fig.16 The XRPD pattern of the X-ray amorphous complex of Compound 1 and fumaric acid (2:1) is shown.

[0080] Fig.17The DSC curve of the X-ray amorphous complex of Compound I and fumaric acid (2:1) is shown.

[0081] Fig.18 Shown is the TGA pattern of the X-ray amorphous complex of Compound I and fumaric acid (2:1). DETAILED DESCRIPTION

[0082] In one aspect, the present invention provides N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide (Compound I) fumaric acid co-crystals, and methods of preparing the same; pharmaceutical compositions comprising the same, and methods of treatment using such compositions. Compared to the free form, the co-crystals of the present invention have one or more improved physicochemical properties selected from the following: dissolution rate, solubility, chemical stability, physical stability, hygroscopicity, melting point, morphology, flowability, bulk density, and compressibility. Therefore, a pharmaceutical composition comprising at least one co-crystal of the present invention can have improved pharmacokinetic and / or pharmacodynamic effects in animals (such as humans) compared to a pharmaceutical composition comprising the free form. As another result, a pharmaceutical composition comprising at least one co-crystal of the invention may have one or more improved drug product attributes selected from the group consisting of: oral dosage form size, compatibility with one or more desired pharmaceutically acceptable carriers, shelf life, and storage conditions, compared to the free form.

[0083] In another aspect, the present invention provides an X-ray amorphous complex of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide and fumaric acid; wherein the molar ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide to fumaric acid is about 1:1 or 2:1; and optionally is substantially free of crystalline forms.

[0084] definition

[0085] As used herein, the term "eutectic" refers to a single-phase crystalline material comprising two or more components in a specific stoichiometric ratio, wherein the arrangement in the crystal lattice is not based on ionic bonds (such as those formed with a salt) and at least two of the components are solid at room temperature.

[0086] As used herein, the term "aliphatic C 2-8"Dicarboxylic acid" refers to a linear or branched, saturated or unsaturated, substituted or unsubstituted dicarboxylic acid having from 2 to 8 carbon atoms, preferably from 4 to 6 carbon atoms, including but not limited to fumaric acid, succinic acid, maleic acid, and tartaric acid.

[0087] As used herein, the term "Compound I fumaric acid co-crystal (1:1)" refers to N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide (Compound I) fumaric acid co-crystals having a stoichiometric ratio of Compound I:fumaric acid of about 1:1; for example, 1:(0.7-1.3), 1:(0.8-1.2) or 1:(0.9-1.1) or 1:1.

[0088] As used herein, the term "Compound I fumaric acid co-crystal (2:1)" refers to N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide (Compound I) fumaric acid co-crystals having a stoichiometric ratio of Compound I:fumaric acid of about 2:1; for example, 2:(0.7-1.3), 2:(0.8-1.2), 2:(0.9-1.1) or 2:1.

[0089] As used herein, the terms "Form A," "Form B," "Form C," etc., used to characterize specific co-crystal embodiments are merely identifiers that should be interpreted in light of the characterization information presented herein; and should not be considered limiting with respect to any other substances having similar or identical physical and chemical characteristics.

[0090] As used herein, the term "amorphous" refers to a solid form of molecules, atoms, and / or ions that are not crystalline. Amorphous solids do not display a defined X-ray diffraction pattern.

[0091] As used herein, the term "amorphous Compound I fumaric acid (1:1)" refers to an X-ray amorphous complex of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide (Compound I) and fumaric acid, wherein the X-ray amorphous complex has a stoichiometric ratio of Compound I:fumaric acid of about 1:1 (e.g., 1:(0.7-1.3), 1:(0.8-1.2), 1:(0.9-1.1) or 1:1); and wherein the complex may comprise co-crystals, salts, and solid dispersions.

[0092] As used herein, the term "amorphous Compound I fumaric acid (2:1)" refers to an X-ray amorphous complex of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide (Compound I) and fumaric acid, wherein the X-ray amorphous complex has a stoichiometric ratio of Compound I:fumaric acid of about 2:1 (e.g., 2:(0.7-1.3), 2:(0.8-1.2), 2:(0.9-1.1) or 2:1); and wherein the complex may comprise co-crystals, salts, and solid dispersions.

[0093] As used herein, with respect to the co-crystals of the present invention, the term "substantially pure" means a co-crystal form having a purity of greater than 80% by weight (including greater than 85, 90, 95, 96, 97, 98, and 99% by weight, and also including equal to about 100% by weight) of the co-crystal based on the weight of the composition. The remaining material comprises one or more other co-crystal forms, reaction impurities, and / or processing impurities resulting from their preparation. For example, co-crystal Form A can be considered substantially pure because it has a purity of greater than 90% by weight as measured by means known and generally accepted in the art, wherein the remaining less than 10% by weight of the material comprises other co-crystal forms, reaction impurities, and / or processing impurities. The presence of reaction impurities and / or processing impurities can be determined by analytical techniques known in the art (e.g., chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy).

[0094] As used herein, the term "room temperature" (RT) refers to a temperature in the range of 20°C to 30°C as measured under standard conditions. Typically, standard conditions may also additionally refer to measurements at 20%-50% relative humidity. In one embodiment, "room temperature" refers to a temperature of about 22°C-25°C.

[0095] As used herein, the term "about" means within a range of statistically significant values. Such ranges may be within an order of magnitude of the indicated value or range, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1%. Sometimes, such ranges may be within the experimental error range, which is a typical value for a standard method used to measure and / or determine a given value or range.

[0096] As used herein, the term "endothermic peak" refers to a melting peak in a differential scanning calorimetry (DSC) thermogram.

[0097] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0098] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom or disorder, or a disease, or a significant decrease in the baseline activity of a biological activity or process.

[0099] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviation or amelioration of the disease or disorder (i.e., slowing or arresting the progression of the disease or at least one clinical symptom thereof); or alleviation or amelioration of at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient.

[0100] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0101] As used herein, the term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or an improvement in symptoms, relief of a condition, slowing or delaying disease progression, or prevention of a disease, etc.). In non-limiting embodiments, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and / or ameliorate a condition, disorder or disease caused by the proliferation of kinetoplastid parasites; or (2) reduce or inhibit the proliferation of kinetoplastid parasites.

[0102] As used herein, the term "subject" refers to primates (e.g., humans (male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice). In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0103] As used herein, the terms "a", "an", "the" and similar terms used in the context of the invention (especially in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0104] Aspects of the Invention

[0105] In one aspect, the present invention provides Compound 1 fumaric acid co-crystals. In one embodiment, the present invention provides Compound 1 fumaric acid co-crystals (1:1) Form A, Form B or Form C; or Compound 1 fumaric acid co-crystals (2:1). In another embodiment, the present invention provides substantially pure Compound 1 fumaric acid co-crystals (1:1) Form A, Form B or Form C; or substantially pure Compound 1 fumaric acid co-crystals (2:1). In yet another embodiment, the present invention provides a composition consisting essentially of Compound 1 fumaric acid co-crystals (1:1) Form A, Form B or Form C; or a composition consisting essentially of Compound 1 fumaric acid co-crystals (2:1).

[0106] The co-crystals of the invention may be characterized as having "substantially as shown in Figure (e.g., Figure 1 )” as shown in the X-ray powder diffraction pattern, differential scanning calorimetry (DSC) thermogram, or thermogravimetric analysis (TGA) pattern. Those skilled in the art will understand that due to variability between devices and between samples (e.g., concentration, purity, crystallinity, orientation, preparation, etc.) and other factors known to those skilled in the art, some variability in peak position and relative intensity may occur, but still relate to the same solid form. Those skilled in the art will also understand that variability in relative peak intensity may occur within an acceptable experimental error. For example, the diffraction angles (2θ) in the XRPD pattern are collected with a variance of about ±0.3° (2θ), preferably about ±0.2° (2θ), more preferably about ±0.1° (2θ), and even more preferably ±0.05° (2θ). TGA measurements are collected with a variance of about ±0.3%, preferably about ±0.2%, more preferably about ±0.1%. Melting point determination based on DSC with a variability of ±3°C, preferably ±2°C, more preferably ±1°C.

[0107] Preferably, the crystalline form has substantially pure phase homogeneity, as indicated by less than 10%, preferably less than 5%, and more preferably less than 2% of the total peak area in the experimentally measured XRPD pattern being caused by additional peaks not present in the simulated XRPD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity, which has less than 1% of the total peak area in the experimentally measured XRPD pattern being caused by additional peaks not present in the simulated XRPD pattern.

[0108] In another aspect, the present invention provides an X-ray amorphous complex of Compound I and fumaric acid; wherein the molar ratio of Compound I is about 1:1 or 2:1; and optionally, substantially free of crystalline forms. In one embodiment, the present invention provides a substantially pure X-ray amorphous complex of Compound I and fumaric acid as described herein. In yet another embodiment, the present invention provides a composition consisting essentially of an X-ray amorphous complex of Compound I and fumaric acid, wherein the molar ratio of Compound I and fumaric acid is about 1:1 or 2:1.

[0109] Pharmaceutical compositions, dosage forms and administration

[0110] In yet another aspect, the present invention provides a pharmaceutical composition comprising Compound I fumaric acid cocrystals and / or amorphous Compound I fumaric acid, and a pharmaceutically acceptable carrier.

[0111] In one embodiment, the present invention provides a pharmaceutical composition comprising at least one of Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1); and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier can be easily selected by a person of ordinary skill in the art according to the desired mode of administration. Exemplary examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal and rectal modes of administration.

[0112] The composition of the present invention can take any suitable pharmaceutical form that can be recognized by those skilled in the art. Suitable pharmaceutical forms include solid, semisolid, liquid or lyophilized preparations, such as tablets, powders, capsules, suppositories, suspensions, liposomes and aerosols. In one embodiment, the present invention provides a pharmaceutical composition comprising Compound 1 fumaric acid cocrystal (1: 1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2: 1), amorphous Compound 1 fumaric acid (1: 1), or amorphous Compound 1 fumaric acid (2: 1); for oral or parenteral administration.

[0113] The pharmaceutical compositions of the present invention can be used for subjects of about 50-70 kg in a unit dosage form of about 1-1000 mg of active ingredient (or about 1-600 mg; or about 1-400 mg; or about 1-300 mg; or about 1-150 mg; or about 1-50 mg of active ingredient). The therapeutically effective dose of such compositions depends on the species, weight, age, and individual condition, disorder, or disease being treated or its severity. A physician, clinician, or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of a disorder or disease.

[0114] The above dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and preparations thereof. The compositions of the invention can be administered in vitro in the form of a solution (e.g., an aqueous solution), and in vivo enterally, parenterally, advantageously intravenously, for example, as a suspension or in an aqueous solution. In vitro doses can be administered in about 10 -3 Molar concentration and 10 -9 The molar concentration range is between .

[0115] The present invention further provides a therapeutic regimen for treating, preventing, inhibiting, alleviating, or eradicating the symptoms and / or symptoms of a disease caused by a kinetoplastid parasite. In one embodiment, the present invention provides a method for treating a disease caused by a kinetoplastid parasite, the method comprising administering to a subject in need thereof a composition comprising a fumaric acid cocrystal (1:1) Form A, Form B or Form C of Compound I, a fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound I fumaric acid (2:1) at a dosage ranging from about 10 mg to about 400 mg; about 30 mg to about 300 mg; about 100 mg to about 300 mg; or about 100 mg to about 150 mg. In some embodiments, the composition is administered at a dosage of about 10 mg, about 30 mg, about 50 mg, about 100 mg, about 150 mg, about 300 mg, about 400 mg, or about 600 mg. Such dosages may be for oral administration; and may be for daily administration (eg, once or twice daily administration).

[0116] The pharmaceutical composition of the present invention can be administered simultaneously with one or more other therapeutic agents or before or after the therapeutic agent. The composition of the present invention can be administered separately with other agents by the same or different administration routes, or administered together in the same pharmaceutical composition. The therapeutic agent is, for example, a chemical compound, a peptide, an antibody, an antibody fragment, or a nucleic acid, which has therapeutic activity or enhances therapeutic activity when the therapeutic agent is administered to a patient in combination with the compound of the present invention.

[0117] In one embodiment, the present invention provides a product for use in therapy, comprising Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1); and at least one other therapeutic agent (as a combined preparation for simultaneous, separate or sequential use). Products provided as combination preparations include compositions comprising Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1), and one or more other therapeutic agents together in the same pharmaceutical composition; or Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1) and one or more other therapeutic agents in separate form (e.g., in the form of a kit). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

[0118] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1). In one embodiment, the kit comprises a device (e.g., a container, a separate bottle, or a separate foil packet) for separately retaining the compositions. An example of such a kit is a blister pack, such as a typical package for tablets, capsules, and the like.

[0119] The kits of the invention can be used for administering different dosage forms (e.g., oral and parenteral), for administering the separate compositions at different dosage intervals or for titrating the separate compositions relative to each other. To aid compliance, the kits of the invention typically include instructions for administration.

[0120] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. In addition, the compound of the present invention and the other therapeutic agent may be combined to form a combination therapy in the following manner: (i) before the combination product is issued to the physician (e.g., in the case of a kit comprising the compound of the present invention and the other therapeutic agent); (ii) shortly before administration, by the physician himself (or under the guidance of the physician); (iii) by the patient himself, for example, during the sequential administration of the compound of the present invention and the other therapeutic agent.

[0121] Therefore, the present invention provides a composition comprising Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1) for treating a disease or condition caused by the growth and proliferation of kinetoplastid parasites, wherein the drug is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease or condition caused by the growth and proliferation of kinetoplastid parasites, wherein the drug is administered together with Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1).

[0122] The present invention also provides the use of a composition comprising Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1) for treating a disease or condition caused by the growth and proliferation of kinetoplastid parasites, wherein the patient has previously (e.g., 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease or condition caused by the growth and proliferation of kinetoplastid parasites, wherein the patient has previously (e.g., within 24 hours) been treated with Compound 1 fumaric acid cocrystal (1:1) Form A, Form B or Form C, Compound 1 fumaric acid cocrystal (2:1), amorphous Compound 1 fumaric acid (1:1), or amorphous Compound 1 fumaric acid (2:1).

[0123] In one embodiment, the other therapeutic agent is selected from antimony gluconate, meglumine antimoniate, amphotericin, miltefosine and paromomycin, or a combination thereof, for the treatment of leishmaniasis. In another embodiment, the other therapeutic agent is selected from benznidazole, nifurtimox and amphotericin, or a combination thereof, for the treatment of Chagas disease. In yet another, the other therapeutic agent is selected from pentamidine, suramin, melarsoprol, eflornithine and nifurtimox, or a combination thereof, for the treatment of human African trypanosomiasis. When the drug combination of the present invention is administered in combination with other therapies, the dosage of the co-administered compound will of course vary according to the type of combined drug used, the specific drug used, the condition treated, etc.

[0124] Examples

[0125] The following examples are illustrative only and do not limit the scope of the invention otherwise claimed. The purity of the reagents was analytical reagent grade or HPLC grade.

[0126] abbreviation

[0127] XRPD X-ray powder diffraction

[0128] DSC Differential Scanning Calorimetry

[0129] TGA Thermogravimetric Analysis

[0130] DVS Dynamic Vapor Sorption

[0131] RT Room temperature

[0132] RH Relative humidity

[0133] THF Tetrahydrofuran

[0134] UPLC Ultra-Performance Liquid Chromatography

[0135] FaSSIF fasting state simulated intestinal fluid

[0136] FeSSIF fed state simulated intestinal fluid

[0137] DVS Dynamic Vapor Sorption (DVS)

[0138] Instrumental method

[0139]

[0140]

[0141] Example 1

[0142] Preparation of Compound I Fumaric Acid Cocrystal (1:1) Form A

[0143] At 55°C, ethyl acetate (1 mL) was added to Compound I (50 mg) and stirred at 500 rpm for 2 hr, to which fumaric acid (1 equivalent, 13.1 mg) was added. The reaction mixture was stirred at 55°C for 5 hr, cooled to RT over a period of 4 hr, and stirred for an additional 12 hr. The resulting solid was filtered and stirred at 55°C under vacuum for 6 hr to give Compound I fumaric acid cocrystal (1:1) Form A ("Form A").

[0144] Form A is characterized by one or more of the following parameters: (a) having substantially the same peaks as listed in Table 1 when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature. Figure 1 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 2 The differential scanning calorimetry (DSC) thermogram shown; and when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 3Thermogravimetric analysis (TGA) pattern shown. In one embodiment, Form A is characterized by an X-ray powder diffraction pattern comprising three or more 2θ peaks selected from about 9.4°, 11.0°, 14.2°, and 25.8°. Form A has a melting point (by DSC) onset at 225.4°C and a melting enthalpy of 127 J / g.

[0145] Table 1

[0146]

[0147]

[0148] Example 2A

[0149] Preparation of Compound I Fumaric Acid Cocrystal (1:1) Form B by Seeding Form A

[0150] At 55 ° C, ethyl acetate (60 mL) was added to compound I (3 g) and stirred at 500 r.pm for 2 hours, to which fumaric acid (1 equivalent, 796 mg) was added. The reaction mixture was stirred at 55 ° C for 6 hours, to which a small amount of Form A (20 mg) prepared in Example 1 was added. The reaction mixture seeded with Form A was stirred at 55 ° C for 16 hours, cooled to RT over a period of 2 hours, and stirred for 8 hours. The resulting solid was filtered, washed with ethyl acetate (5 mL) and dried under vacuum at 55 ° C for 12 hours to give Compound I fumaric acid cocrystal (1: 1) Form B ("Form B").

[0151] Example 2B

[0152] Preparation of Compound I Fumaric Acid Cocrystal (1:1) Form B Seed Crystals

[0153] At RT, THF (200mL) is added to compound I (20g, 45.1mmol, 1 equivalent) to form compound I / THF suspension. At RT, fumaric acid (5.8g, 49.6mmol, 1.1 equivalent) is added to isopropanol (160mL) and the resulting fumaric acid solution is added to compound I / THF suspension over a 1hr period. The reaction mixture is stirred at RT for 20hr, filtered, and the filter cake is washed with isopropanol (40mL). The collected solid is dried at 50°C under vacuum for 20hr, and balanced at 50°C for 30hr in ethyl acetate (100mL). Filter the solid and dry 16h at 50°C under vacuum to give form B, which is used as fumaric acid seed.

[0154] Example 2C

[0155] Preparation of Compound I Fumaric Acid Cocrystal (1:1) Form B by Form B Seeding

[0156] Fumaric acid (6.0 g, 51.9 mmol, 1.15 equivalents) was added to isopropanol (130 mL). The resulting solution was heated to 52 ° C and filtered to obtain a clear fumaric acid solution. The fumaric acid solution was maintained at 50 ° C, to which a small amount of Form B (10 mg) prepared in Example 2B was added to give a fumaric acid solution seeded with Form B.

[0157] At RT, compound I (20g, 45.1mmol, 1 equivalent) is added to THF (500mL); and the resulting suspension is heated to 55°C to obtain a clear solution, which is then filtered. The filtrate is partially concentrated under vacuum, and the remaining compound (287g) is added dropwise to a fumaric acid solution seeded with Form B at 50°C over 1 hour. The reaction mixture is kept at 50°C for 2hr, then cooled to RT over 5-7hr, and then concentrated at 50°C under vacuum. Isopropanol (200mL*3) is added to the concentrate to further remove residual THF. The resulting suspension is cooled to RT over 2-4hr, filtered and washed with pre-cooled isopropanol (40mL). The solid is dried at 60°C under vacuum for 16hr to give Form B as an off-white solid. 1 HNMR(400MHz,DMSO-d6)δppm 2.40(s,3H),6.64(s,2H),7.41-7.45(m,1H),7.82(br d,J=0.73Hz,1H),7.87-8.00(m,1H),8.59(dd,J=4.65,1.10Hz,1H),8.79(dd,J=6.6 6,2.75Hz,1H),9.14(d,J=2.45Hz,1H),9.75(d,J=2.32Hz,1H),10.35-10.44(m,1H); 13 C NMR(101MHz,DMSO-d6)δppm 13.24,14.25,19.78,117.34,117.56,118.34,118.45,122.84,122.86,124.02,124.18,124.70,124.78,132.79,134.42,135.44,13 5.47,136.76,139.16,139.67,143.45,147.86,151.16,154.70,155.46,156.78,157.18,157.98,161.42,162.38,162.44,166.42; m / z = 444.9 (M + H + ).

[0158] Form B is characterized by one or more of the following parameters: (a) having substantially the same peaks as listed in Table 2 when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature. Figure 4 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 5 The differential scanning calorimetry (DSC) thermogram shown; and when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 6 Thermogravimetric analysis (TGA) pattern shown. In one embodiment, Form B is characterized by an X-ray powder diffraction pattern comprising three or more 2θ peaks selected from about 13.4°, 15.7°, 23.9°, and 24.7°.

[0159] Form B has a melting point onset at 227.3°C (by DSC) and a 0.5% weight loss at 180°C (by TGA). Form B is non-hygroscopic and absorbs 0.3% water at 90% RH at 25°C (by DVS). Form B shows comparable stability and solubility to the free form hydrate in aqueous media (24 h).

[0160] Table 2

[0161]

[0162]

[0163] Example 3

[0164] Preparation of Compound I Fumaric Acid Cocrystal (1:1) Form C

[0165] Form B (500 mg) was equilibrated in acetone (6 mL) at 50° C. for 72 hr. The solid was filtered at RT and dried under vacuum at 40° C. for 18 h to give Compound I fumaric acid cocrystal (1:1) Form C (“Form C”).

[0166] Form C is characterized by one or more of the following parameters: (a) having substantially the same peaks as listed in Table 3 when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature. Figure 7 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Figure 8 The differential scanning calorimetry (DSC) thermogram shown; and when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig. 9Thermogravimetric analysis (TGA) pattern shown. In one embodiment, Form C is characterized by an X-ray powder diffraction pattern comprising three or more 2θ peaks selected from about 9.8°, 11.3°, 14.8°, 24.6°, 25.0°, 26.5°, and 27.6°.

[0167] Form C has a melting point onset at 219.2°C (by DSC) and a 1.3% weight loss at 180°C (by TGA). Form C is slightly hygroscopic, reversibly absorbing approximately 0.6% water at 90% RH (by DVS).

[0168] Table 3

[0169]

[0170]

[0171] Example 4

[0172] Preparation of Compound I Fumaric Acid Cocrystal (2:1) by Form B Seeding

[0173] At RT, Compound I (22.5 g, 50.7 mmol, 1 eq) was added to THF (450 mL); and the resulting suspension was heated to 55° C. to obtain a clear solution, which was then filtered. The filtrate was partially concentrated under vacuum to give a residue (202.5 g) containing Compound I and THF.

[0174] Fumaric acid (6.5g, 55.8mmol, 1.1 equivalents) is added in isopropanol (225mL). The resulting solution is heated to 52°C, filtered to obtain a clear fumaric acid solution, and added dropwise to the residue comprising Compound I and THF. After half of the fumaric acid solution is added to the residue comprising Compound I and THF over a 1hr period, a small amount of Form B (11.3mg) prepared in Example 2B is added to the remaining fumaric acid solution. The remaining fumaric acid solution is added to the reaction mixture over a 2hr period.

[0175] The reaction mixture was kept at 50 ° C for 2 hr, then cooled to RT over 5-7 hr, and then concentrated under vacuum at 50 ° C. Isopropanol (225 mL * 2) was added to the concentrate to further remove residual THF. The resulting suspension was cooled to RT over 2-4 hr, filtered and washed with pre-cooled isopropanol (45 mL). The solid was dried at 60 ° C under vacuum for 16 hr to give a fumaric acid co-crystal of Compound I (2: 1) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δppm 2.41(s,3H),6.63(s,1H),7.43-7.46(m,1H),7.85(dd,J=7.70,0.73Hz,1H),7.91-7.99(m,1H),8.61(dd,J=4.65, 0.98Hz,1H),8.80(dd,J=6.66,2.75Hz,1H),9.15(d,J=2.45Hz,1H),9.76(d,J=2.32Hz,1H),10.35-10.48(m,1H); 13 C NMR(101MHz,DMSO-d6)δppm 13.26,14.28,19.77,117.38,117.61,118.37,118.48,122.87,124.05,124.22,124.74,124.82,132.83,134.49,135.45,135.48 MS m / z=444.9(M+H + ).

[0176] The fumaric acid cocrystal of Compound 1 (2:1) is characterized by one or more of the following parameters: (a) having substantially the same peaks as listed in Table 4 when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature. Fig.10 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig.11 and (c) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig.12 Thermogravimetric analysis (TGA) graph shown. In one embodiment, Compound I fumaric acid cocrystal (2:1) is characterized by an X-ray powder diffraction pattern comprising three or more 2θ peaks selected from about 3.8°, 13.5°, 17.2°, and 26.6°.

[0177] Compound 1 fumaric acid cocrystal (2:1) has a melting point onset at 206.4°C (by DSC), and a 1.3% weight loss (by TGA) up to 180°C. Compound 1 fumaric acid cocrystal (2:1) is non-hygroscopic and absorbs only 0.12% (by DVS) at 90% RH at 25°C.

[0178] Table 4

[0179]

[0180]

[0181] Example 5

[0182] Preparation of amorphous compound I fumaric acid (1:1)

[0183] Will Compound I fumaric acid cocrystal (1:1) Form B seed (100 mg) (prepared according to the procedure in Example 2B) was dissolved in 1,4-dioxane (30 mL). The resulting suspension was filtered and the filtrate was frozen using an acetone dry ice bath. The frozen filtrate was freeze-dried at -20°C for 3 days to provide amorphous Compound I fumaric acid (1:1).

[0184] Amorphous Compound I fumaric acid (1:1) is characterized by one or more of the following parameters: (a) a substantially uniform crystalline structure showing no well-defined peaks when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature; Fig.13 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig.14 and (c) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig.15 Thermogravimetric analysis (TGA) graph shown.

[0185] Example 6

[0186] Preparation of amorphous compound I fumaric acid (2:1)

[0187] Will Compound I fumaric acid cocrystal (2:1) (100 mg) (prepared according to the procedure in Example 4 ) was dissolved in 1,4-dioxane (15 mL). The resulting suspension was filtered and the filtrate was frozen using an acetone dry ice bath. The frozen filtrate was freeze-dried at -20°C for 3 days to provide amorphous Compound I fumaric acid (2:1).

[0188] Amorphous Compound I fumaric acid (2:1) is characterized by one or more of the following parameters: (a) a substantially uniform crystalline structure showing no well-defined peaks when measured with CuKα radiation at a wavelength of 0.15 nm at room temperature; Fig.16 X-ray powder diffraction pattern shown; (b) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig.17 and (c) when heated from 30°C to 300°C at a rate of 10K / min, substantially as Fig.18Thermogravimetric analysis (TGA) graph shown.

[0189] Example 7

[0190] Stability of Compound I Solid Form

[0191] Compound I, Compound I fumaric acid cocrystal and amorphous Compound I fumaric acid samples (10 mg) were placed in open vials in 50°C / 75% RH and 80°C / 75% RH chambers for one week. The same amount of samples were placed in sealed vials in 50°C and 80°C chambers for 1 week. The samples were exposed to a 100k Lux lamp at 25°C for 12 h.

[0192] The solids were checked by XRPD for physical stability and UPLC for chemical stability. The color of the samples was evaluated by visual inspection. Table 5 compares the stability of Compound I and its various solid forms.

[0193] At initial purity, the free form of compound I is a hydrate, which becomes a dihydrate when stored at 92% RH and after DVS testing. After degradation at 160°C, the hydrate of the free form is converted into an amorphous form. The free form hydrate is chemically stable in volume for one week at 50°C, 50°C / 75&RH, 80°C and 80°C / 75% RH, but it is noted that the form has changed. After exposure to 75% RH humidity at these two temperatures, a dihydrate is obtained. At 50°C / 75% RH, a mixture of free form hydrates and a mixture of anhydrous modifiers are observed. The free form is stable after exposure to a 1200kLuxh lamp for 12hr.

[0194] The free form hydrate is hygroscopic (8.9% water uptake by DVS at 25°C) and the form change is most likely to be a dihydrate. A dihydrate was also obtained after storing the free form hydrate at 92% RH for 24 hr. After grinding, compression and wet granulation with water and ethanol, the free form hydrate was converted to a different hydrate or hydrate mixture.

[0195] In contrast, Form B and Compound I fumaric acid cocrystal (2:1) are non-hygroscopic and retain the same form with 0.3% and 0.12% moisture uptake, respectively, at 90% RH (by DVS). Milling, compression, and wet granulation do not alter the crystalline form of Form B.

[0196] Table 5

[0197]

[0198]

[0199]

[0200] *ND (not determined); DP (degradation product); CL (color)

[0201] Example 8

[0202] Solubility of Compound 1 Solid Form

[0203] Compound I, Compound I fumaric acid cocrystals, and amorphous Compound I fumaric acid samples (2 mg) in various media (1 mL) were mixed in glass vials to make slurries. Each sample was equilibrated at 25° C. for 24 hours and then centrifuged at 13400 rpm for 3 min using a 0.2 μm membrane to separate the solid from the liquid. The liquid was used to measure solubility by UPLC.

[0204] Table 6 provides the solubility data of Compound I and its various solid forms at 25°C after 24 hours of equilibrium, with the final pH of the samples shown in parentheses. Compared with the solubility of the free form, Form B has significantly better solubility in biological fluids such as SGF, FaSSIF, and FeSSIF. Compared with the solubility of the free form, the solubility of Compound I fumaric acid cocrystal (2:1) in FeSSIF is significantly better.

[0205] Table 6

[0206]

[0207]

[0208] *ND(Not Determined)

[0209] By fully describing the present invention, it will be appreciated by those skilled in the art that the present invention can be carried out in various modifications without departing from the scope of the present invention or any embodiment thereof. For all purposes, all publications, patents, and patent applications cited herein are hereby incorporated by reference.

Claims

1. A co-crystal of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide and fumaric acid, wherein the co-crystal is characterized by an X-ray powder diffraction pattern comprising the following 2θ peaks, measured with CuKα radiation at a wavelength of 0.15 nm at room temperature: 24.7°±0.2°, 23.9°±0.2°, 20.2°±0.2°, 16.1°±0.2°, 16.0°±0.2°, 13.4°±0.2° and 9.8°±0.2° (2θ).

2. The co-crystal of claim 1, wherein the stoichiometric ratio of N-(4-fluoro-3-(6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)phenyl)-2,4-dimethyloxazole-5-carboxamide and fumaric acid is 1:

1.

3. The co-crystal of claim 1 or 2, wherein the co-crystal is characterized by an X-ray powder diffraction pattern comprising the following 2θ peaks: 24.7°±0.2°, 23.9°±0.2°, 22.8°±0.2°, 22.7°±0.2°, 20.4°±0.2°, 20.2°±0.2°, 18.1°±0.2°, 16.6°±0.2°, 16.1°±0.2°, 16.0°±0.2°, 13.4°±0.2°, 12.0±0.2°, 9.8°±0.2°, and 9.0°±0.2° (2θ), measured with CuKα radiation at a wavelength of 0.15 nm at room temperature.

4. The co-crystal of claim 1 or 2, wherein the co-crystal is characterized by having an X-ray powder diffraction pattern as shown in Figure 4, measured using CuKα radiation at a wavelength of 0.15 nm at room temperature.

5. The co-crystal of claim 1 or 2, wherein the co-crystal is characterized by having a differential scanning calorimetry (DSC) thermogram as shown in Figure 5 when heated from 30°C to 300°C at a rate of 10K / min.

6. The co-crystal of claim 3, wherein the co-crystal is characterized by having a differential scanning calorimetry (DSC) thermogram as shown in Figure 5 when heated from 30°C to 300°C at a rate of 10K / min.

7. The co-crystal of claim 4, wherein the co-crystal is characterized by having a differential scanning calorimetry (DSC) thermogram as shown in Figure 5 when heated from 30°C to 300°C at a rate of 10K / min.

8. The co-crystal of claim 1 or 2, wherein the co-crystal is characterized by a thermogravimetric analysis (TGA) graph as shown in Figure 6 when heated from 30°C to 300°C at a rate of 10K / min.

9. The co-crystal of claim 3, wherein the co-crystal is characterized by a thermogravimetric analysis (TGA) graph as shown in FIG. 6 when heated from 30°C to 300°C at a rate of 10 K / min.

10. The co-crystal of claim 4, wherein the co-crystal is characterized by a thermogravimetric analysis (TGA) graph as shown in FIG. 6 when heated from 30°C to 300°C at a rate of 10 K / min.

11. The co-crystal of claim 1 , wherein the co-crystal B is characterized by: (a) an X-ray powder diffraction pattern as shown in FIG. 4 , measured using CuKα radiation at a wavelength of 0.15 nm; (b) a differential scanning calorimetry (DSC) thermogram as shown in FIG. 5 , when heated from 30° C. to 300° C. at a rate of 10 K / min; and (c) a thermogravimetric analysis (TGA) graph as shown in FIG. 6 , when heated from 30° C. to 300° C. at a rate of 10 K / min.

12. A composition comprising the co-crystal of any one of claims 1-11.

13. The composition of claim 12, comprising at least 90% by weight of the co-crystal based on the weight of the composition.

14. The composition of claim 12, comprising at least 80% by weight of the co-crystal based on the weight of the composition.

15. A pharmaceutical composition comprising the co-crystal according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

16. A combination comprising the co-crystal of any one of claims 1 to 11 and one or more therapeutically active agents.

17. Use of the co-crystal of any one of claims 1 to 11, optionally in combination with a second agent, in the preparation of a medicament for treating a disorder or disease selected from leishmaniasis, Chagas disease and human African trypanosomiasis.

18. The use of claim 17, wherein the second agent is selected from: (a) antimoni gluconate, meglumine antimoniate, amphotericin, miltefosine and paromomycin, or a combination thereof, for the treatment of visceral leishmaniasis or cutaneous leishmaniasis; (b) benznidazole, nifurtimox and amphotericin, or a combination thereof, for the treatment of Chagas disease; and (c) pentamidine, suramin, melarsoprol, eflornithine and nifurtimox, or a combination thereof, for the treatment of human African trypanosomiasis.

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