Hydrates of polymorphs of 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)-2,3-dihydroimidazo[1,2-a]pyrazin-8-amine bis-mesylate as Syk inhibitors
Polymorphs of a bis-mesylate salt of a compound of Formula IA: are provided. Also provided are process for making the polymorphs and methods of use thereof.
1. A polymorphic form of a compound of Formula IA:
wherein the polymorphic form is a hydrate of Form XIX; and
wherein Form XIX is characterized by a powder X-ray diffraction pattern comprising characteristic peaks (°2θ) at 6.3°±0.2° 2θ and 26.3°±0.2° 2θ.
2. The polymorphic form of claim 1 , wherein the polymorphic form is further characterized by a powder X-ray diffraction pattern as shown in FIG. 9 A .
3. The polymorphic form of claim 1 , wherein the polymorphic form is further characterized by a differential scanning calorimetry (DSC) curve as shown in FIG. 9 B .
4. The polymorphic form of claim 1 , wherein the polymorphic form is further characterized by a thermogravimetric analysis (TGA) curve as shown in FIG. 9 C .
5. The polymorphic form of claim 1 , wherein the polymorphic form is further characterized by a dynamic vapor sorption (DVS) plot as shown in FIG. 9 D .
6. A dispersion comprising a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the polymorphic form of claim 1 .
7. An oral dosage form comprising a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the polymorphic form of claim 1 .
8. The oral dosage form of claim 7 , wherein the oral dosage form is a tablet.
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the polymorphic form of claim 1 .
10. The pharmaceutical composition of claim 9 , wherein the pharmaceutically acceptable carrier is hydroxypropyl methylcellulose (HMPC).
11. A method for inhibiting spleen tyrosine kinase (Syk) activity in a human in need thereof, wherein the method comprises administering to the human a therapeutically effective amount of the polymorphic form of claim 1 .
12. The method of claim 11 , wherein the human has a condition selected from the group consisting of an autoimmune disease, a cancer, and an inflammatory disease.
13. The method of claim 12 , wherein the autoimmune disease, cancer, or inflammatory disease is selected from the group consisting of acute graft-versus-host disease, an acute inflammatory reaction, acute lymphocytic leukemia, acute myeloid leukemia, Addison's disease, adult respiratory distress syndrome, Alzheimer's disease, asthma, atherosclerosis, an autoimmune hemolytic state, an autoimmune thrombocytopenic state, B-cell acute lymphoblastic leukemia, B-cell lymphoma, Burkitt lymphoma, chronic graft-versus-host disease, chronic idiopathic thrombocytopenic purpura, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, diabetes, follicular lymphoma, glomerulonephritis, Goodpasture's syndrome, hyperacute rejection of a transplanted organ, irritable bowel syndrome, lymphoplasmacytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, multiple sclerosis, myasthenia gravis, myelodysplastic syndrome, myeloproliferative disease, non-Hodgkin's lymphoma, Parkinson's disease, polycystic kidney disease, psoriasis, pulmonary hemorrhage, rheumatoid arthritis, scleroderma, septic shock, Sjogren's disease, small lymphocytic lymphoma, systemic lupus erythematosus, T-cell acute lymphoblastic leukemia, T-cell lymphoma, tissue graft rejection, ulcerative colitis, vasculitis, and Waldestrom's macroglobulinemia.
14. The method of claim 13 , wherein the acute inflammatory reaction is selected from the group consisting of appendicitis, cholocystitis, dermatitis, encephalitis, enteritis, gastritis, gingivitis, hepatitis, inflammatory bowel disease, inflammatory pelvic disease, meningitis, myocarditis, myositis, nephritis, osteomyelitis, pancreatitis, pneumonitis, skin sunburn, sinusitis, urethritis, and uveitis.
15. The method of claim 13 , wherein the B-cell lymphoma is diffuse large B-cell lymphoma.
16. The method of claim 13 , wherein the non-Hodgkin's lymphoma is indolent non-Hodgkin's lymphoma.
17. The method of claim 16 , wherein the indolent non-Hodgkin's lymphoma is refractory indolent non-Hodgkin's lymphoma.
18. The method of claim 13 , wherein the vasculitis is anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis.
19. The method of claim 13 , wherein the cancer is acute myeloid leukemia.