Crystalline forms of a pi3k inhibitor and uses of same
Patent Information
- Application Number
- HK62026125321
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-08-15
- Filing Date
- 2026-06-25
- Publication Date
- 2026-09-18
- Estimated Expiration
- 2044-08-13
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Abstract
Description
Abstract This article discloses the crystalline forms, formulations, and uses of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) α isoform (PI3Kα) inhibitors.
Claims
WHAT IS CLAIMED IS:
1. A crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.
2. The crystalline form of claim 1, wherein the (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a pharmaceutically acceptable solvate.
3. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form 1 characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 18.3 ± 0.2 degrees 26.
4. The crystalline form of claim 3, wherein the XRPD pattern has a peak at 15.8 ± 0.2 degrees 29.
5. The crystalline form of any one of claims 3-4, wherein the XRPD pattern has a peak at 6.4 ± 0.2 degrees 20.
6. The crystalline form of any one of claims 3-5, wherein the XRPD pattern has a peak at 22.3 ± 0.2 degrees 20.
7. The crystalline form of any one of claims 3-6, wherein the XRPD pattern has a peak at 20.8 ± 0.2 degrees 20.
8. The crystalline form of any one of claims 3-7, wherein the XRPD pattern has a peak at 19.3 ± 0.2 degrees 20.
9. The crystalline form of any one of claims 3-8, wherein the XRPD pattern has a peak at 24.0 ± 0.2 degrees 20.
10. The crystalline form of any one of claims 3-9, wherein the XRPD pattern has a peak at 26.9 ± 0.2 degrees 20.
11. The crystalline form of any one of claims 3-10, wherein the XRPD pattern has a peak at 14.6 ± 0.2 degrees 20.
12. The crystalline form of any one of claims 3-11, wherein the XRPD pattern has a peak at 31.3 ± 0.2 degrees 20.
13. The crystalline form of any one of claims 3-12, wherein the XRPD pattern has a peak at 28.3 ± 0.2 degrees 20.
14. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form 1, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.4, 15.8, and 18.3.
15. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form 1, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.4, 14.6, 15.8, 18.3, 19.3, 20.8, 22.3, 24.0, 26.9, 28.3, 29.2 and 31.3.
16. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form 1, characterized by an XRPD pattern substantially the same as that shown in FIG. 4.
17. The crystalline form of any one of claims 1-16, wherein the crystalline form is Form 1 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 112.5 °C.
18. The crystalline form of any one of claims 1-17, wherein the crystalline form is Form 1 having a TGA curve characterized by a weight loss of about 17.6% at about 245 °C.
19. The crystalline form of any one of claims 1-18, wherein the crystalline form is Form 1 having a TGA curve that is substantially the same as that shown in FIG. 28.
20. The crystalline form of any one of claims 1-19, wherein the crystalline form is Form 1 prepared by a method comprising:(a) dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in isopropanol to form a solution;(b) adding water to the solution to form a mixture;(c) reducing the temperature of the mixture then maintaining the temperature for a first period of time;(d) increasing the temperature of the mixture then maintaining the temperature for a second period of time;(e) reducing the temperature of the mixture then maintaining the temperature for a third period of time; and(f) isolating Form 1 from the mixture.
21. The crystalline form of any one of claims 1-4, wherein the crystalline form is Form 1 prepared by a method comprising:(a) dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in methanol to form a solution;(b) adding water to the solution to form a first mixture;(c) adding (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture;(d) agitating the second mixture;(e) adding water to the second mixture to form a third mixture;(f) agitating the third mixture; and(g) isolating Form 1 from the third mixture.
22. The crystalline form of claim 21 , wherein isolating Form 1 from the third mixture comprises:(i) filtering the third mixture to provide a solid;(ii) rinsing the solid with methanol and water; and(iii) drying the solid to provide Form 1.
23. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form1 * characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.3 ± 0.2 degrees 26.
24. The crystalline form of claim 23, wherein the XRPD pattern has a peak at 15.8 ± 0.2 degrees 20.
25. The crystalline form of any one of claims 23-24, wherein the XRPD pattern has a peak at 20.8 ± 0.2 degrees 26.
26. The crystalline form of any one of claims 23-25, wherein the XRPD pattern has a peak at 15.9 ± 0.2 degrees 26.
27. The crystalline form of any one of claims 23-26, wherein the XRPD pattern has a peak at 19.8 ± 0.2 degrees 26.
28. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form2 characterized by an X-ray powder diffraction (XRPD) pattern having peaks (± 0.2 degrees 26) at 6.2, 15.2, 15.3, 20.9, 21.9, 22.0, 21.0, 18.7, 18.7, and 26.9.
29. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form3 characterized by an X-ray powder diffraction (XRPD) pattern having peaks (± 0.2 degrees 26) at 4.0, 4.9, 25.8, 21.4, 9.1, 19.2, 6.9, 15.7, 16.8, and 9.9.
30. The crystalline form of any one of claims 1 -2, wherein the crystalline form is Form 4 characterized by an X-ray powder diffraction (XRPD) pattern having peaks (± 0.2 degrees 20) at 6.3, 20.9, 15.5, 24.1, 21.5, 27.7, 15.8, 14.9, 20.5, and 26.9.
31. A pharmaceutical composition comprising the crystalline form of any one of claims 1-30 and a pharmaceutically acceptable carrier.
32. The pharmaceutical composition of claim 31, wherein the composition is in the form of a tablet.
33. The pharmaceutical composition of any one of claims 31-32, wherein the composition comprises microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate, or any combination thereof.
34. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of any one of claims 1-30, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition of any one of claims 31-33.
35. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of the crystalline form of any one of claims 1-30, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition of any one of claims 31-33.
36. A method of treating a PI3Ka-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Ka-associated cancer a therapeutically effective amount of the crystalline form of any one of claims 1-30 or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition of any one of claims 31-33.
37. A method for modulating PI3Ka in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of the crystalline form of any one of claims 1-30, or a pharmaceutically acceptable salt and / or solvate thereof.