2,4-pyrimidinediamine compounds and their uses
View Patent ↗The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.
1. A method of inhibiting IgG-induced or IgE-induced degranulation of a cell, comprising contacting a cell capable of undergoing degranulation with an amount of N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine or a salt, and/or N-oxide thereof, effective to inhibit IgG-induced or IgE-induced degranulation of the cell.
2. The method of claim 1 in which the cell is a human mast, basophil cell, neutrophil or eosinophil cell.
3. A method of inhibiting IgG-induced or IgE-induced mast or basophil cell degranulation in an animal, comprising administering to the animal an amount of N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine or a salt, and/or N-oxide thereof, effective to inhibit IgG-induced or IgE-induced mast or basophil cell degranulation.
4. The method of claim 3 in which the animal is a human.
5. The method of claim 4 in which the human is suffering from a disease selected from an allergic disease, a low grade scarring disease, a disease associated with tissue destruction and a disease associated with tissue inflammation.
6. The method of claim 5 in which the allergic disease is selected from the group consisting of conjunctivitis, rhinitis, asthma, atopic dermatitis and a food allergy.
7. The method of claim 6 in which the allergic disease is asthma.
8. The method of claim 5 in which the low grade scarring disease is selected from the group consisting of scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction.
9. The method of claim 8 in which the low grade scarring disease is pulmonary fibrosis.
10. The method of claim 5 in which the disease associated with tissue destruction is selected from the group consisting of chronic obstructive pulmonary disease, cardiobronchitis and post myocardial infarction.
11. The method of claim 10 in which the disease associated with tissue destruction is chronic obstructive pulmonary disease.
12. The method of claim 5 in which the disease associated with tissue inflammation is selected from the group consisting of irritable bowel syndrome, spastic colon and inflammatory colon disease.
13. A method of inhibiting a Syk kinase, comprising contacting a Syk kinase with an effective amount of N4-[2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine or a salt, and/or N-oxide thereof.
14. The method of claim 13 which is practiced in vitro with an isolated or recombinant Syk kinase.
15. The method of claim 13 which is practiced in vitro with a cell or cell population that expresses an endogenous or recombinant Syk kinase.
16. The method of claim 13 which is practiced in vivo.
17. A method of inhibiting a Syk kinase in an animal, comprising the step of administering to the animal an amount of N4-[(2,2-difluoro-4H-benzo [1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine or a salt, and/or N-oxide thereof, effective to inhibit a Syk kinase.
18. The method of claim 17 in which the animal is a human.