Prodrugs of 2,4-pyrimidinediamine compounds and their uses
The present disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds, salts and hydrates of the prodrugs, compositions comprising the prodrugs, intermediates and methods for synthesizing the prodrugs and methods of using the prodrugs in a variety of applications.
1. An oral dosage formulation comprising a hydrate of the prodrug salt:
or a pharmaceutically-acceptable carrier, excipient, and/or diluent; wherein:
M is Na;
the prodrug salt hydrate present in the oral dosage formulation is substantially crystalline prodrug salt hydrate; and
the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 17.2±0.1° in response to radiation of wavelength 1.54059 Å.
2. The oral dosage formulation of claim 1 , the formulation comprising from about 50 mg to about 400 mg of the crystalline prodrug salt hydrate.
3. The oral dosage formulation of claim 2 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 11.8±0.1°.
4. The oral dosage formulation of claim 2 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 21.8±0.1°.
5. The oral dosage formulation of claim 2 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 3.4±0.1°.
6. The oral dosage formulation of claim 2 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 12.3±0.1°.
7. The oral dosage formulation of claim 2 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 13.2±0.1°.
8. The oral dosage formulation of claim 2 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 3.4°±0.1°, 11.8°±0.1°, 12.3°±0.1°, 13.2°±0.1°,and 21.8±0.1°.
9. The oral dosage formulation of claim 8 , wherein the hydrate is:
10. The oral dosage formulation of claim 9 , wherein the formulation is in the form of a tablet.
11. The oral dosage formulation of claim 2 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 3.4°±0.1°, 6.6°±0.1°, 9.9°±0.1°, 13.2°±0.1°, 19.7°±0.1°, 21.2±0.1°, and 21.8±0.1°.
12. The oral dosage formulation of claim 1 , wherein the hydrate of the prodrug salt has the formula:
wherein x is from about 1 to about 15.
13. The oral dosage formulation of claim 1 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 11.8±0.1°.
14. The oral dosage formulation of claim 1 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 21.8±0.1°.
15. The oral dosage formulation of claim 1 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 3.4±0.1°.
16. The oral dosage formulation of claim 1 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 12.3±0.1°.
17. The oral dosage formulation of claim 1 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 13.2±0.1°.
18. The oral dosage formulation of claim 1 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 3.4°±0.1°, 11.8°±0.1°, 12.3°±0.1°, 13.2°±0.1°,and 21.8±0.1°.
19. The oral dosage formulation of claim 18 , wherein the hydrate is:
20. The oral dosage formulation of claim 19 , wherein the formulation is in the form of a tablet.
21. The oral dosage formulation of claim 1 , wherein the powder X-ray diffraction data of the crystalline prodrug salt hydrate comprises a characteristic peak at a two theta value of 3.4°±0.1°, 6.6°±0.1°, 9.9°±0.1°, 13.2°±0.1°, 19.7°±0.1°, 21.2±0.1°, and 21 . 8 ± 0 . 1 °.
22. The oral dosage formulation of claim 1 , wherein the hydrate is:
23. The oral dosage formulation of claim 22 , wherein the formulation is in the form of a tablet.