Claims for Patent: 10,414,773

Summary for Patent: 10,414,773

Title:	Forms of a PI3K delta selective inhibitor for use in pharmaceutical formulations
Abstract:	The present invention relates to solid state forms of a p-toluenesulfonic acid salt (PTSA) of the selective PI3K delta inhibitor (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrim- idin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (TGR-1202). The present invention also relates to methods of preparing the same, pharmaceutical compositions containing them, and methods of treating a PI3K kinase mediated disease or disorder, such as cancer, by administering the same.
Inventor(s):	Vakkalanka; Swaroop K. (La Chaux-de-Fonds, CH)
Assignee:	RHIZEN PHARMACEUTICALS SA (La Chaux-de-Fonds, CH)
Application Number:	15/950,606
Patent Claims:	1. A crystalline p-toluenesulfonic acid salt of the compound ##STR00004## wherein the crystalline salt exhibits an XRPD pattern having one or more peaks selected from 5.0, 10.1, 22.1, and 24.5.+-.0.2.degree. 2.THETA.. 2. The salt of claim 1, wherein the salt exhibits an XRPD pattern substantially as shown in FIG. 2. 3. The salt of claim 1, wherein the salt has a d(0.5) of from about 1 to about 10 .mu.m. 4. The salt of claim 1, wherein the salt has a d(0.5) of from about 2 to about 5 .mu.m. 5. The salt of claim 1, wherein the salt has a d(0.9) of from about 5 to about 25 .mu.m. 6. The salt of claim 1, wherein the salt has a d(0.9) of from about 5 to about 15 .mu.m. 7. The salt of claim 1, wherein the salt has a d(0.1) of from about 0.5 to about 1.5 .mu.m. 8. The salt of claim 1, wherein the salt has a d(0.1) of from about 0.5 to about 1.0 .mu.m. 9. The salt of claim 1, wherein the salt is substantially free of other solid state forms of the p-toluenesulfonic acid salt. 10. The salt of claim 1, wherein the salt contains less than 5% of other solid state forms of the p-toluenesulfonic acid salt. 11. A pharmaceutical composition comprising a salt of claim 1 and a pharmaceutically acceptable excipient. 12. A method of inhibiting a catalytic activity of a PI3 .delta. kinase present in a cell, comprising contacting the cell with an effective amount of a salt of claim 1. 13. The method of claim 12, wherein the inhibition takes place in a subject suffering from a disease or disorder which is cancer, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, thrombosis, or cardiac disease. 14. A method for the treatment of a PI3K associated disease or disorder comprising the step of administering to a subject in need thereof an effective amount of a salt of claim 1. 15. The method of claim 14, further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal antiinflammatory agent, antihistamine, analgesic, or a mixture thereof. 16. The method of claim 14, wherein the PI3K associated disease, disorder or condition is an immune system-related disease, a disease or disorder involving inflammation, cancer or other proliferative disease, a hepatic disease or disorder, or a renal disease or disorder. 17. The method of claim 14, wherein the PI3K associated disease, disorder or condition is selected from inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis, asthma, Sjogren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's disease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder of the adrenal gland, systemic lupus erythematosus, polymyositis, dermatomyositis, ankylosing spondylitis, transplant rejection, skin graft rejection, arthritis, bone diseases associated with increased bone resorption; ileitis, Barrett's syndrome, adult respiratory distress syndrome, chronic obstructive airway disease; corneal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmitis, endophthalmitis; gingivitis, periodontitis; tuberculosis; leprosy; uremic complications, nephrosis; sclerodermatitis, psoriasis, chronic demyelinating diseases of the nervous system, AIDS-related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis viral or autoimmune encephalitis; autoimmune disorders, immune-complex vasculitis, systemic lupus and erythematodes; systemic lupus erythematosus (SLE); cardiomyopathy, ischemic heart disease hypercholesterolemia, atherosclerosis, preeclampsia; chronic liver failure, brain and spinal cord trauma, and cancer. 18. The method of claim 14, wherein the PI3K associated disease, disorder or condition is selected from hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome, promyelocytic leukemia; carcinoma of the bladder, carcinoma of the breast, carcinoma of the colon, carcinoma of the kidney, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladdercancer, ovarian cancer, pancreatic cancer, stomachcancer, cervical cancer, thyroidcancer, prostatecancer, skincancer, squamous cell carcinoma; tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma; tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. 19. The method of claim 14, wherein the PI3K associated disease, disorder or condition is selected from chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, chronic bronchitis, atopic dermatitis, multiple sclerosis, inflammatory bowel disease, allergic rhinitis, lupus erythematosus and ulcerative colitis. 20. The method of claim 14, wherein the PI3K associated disease, disorder or condition is selected from hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, chronic lymphocytic leukemia, hairy cell lymphoma and Burkett's lymphoma, hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome, promyelocytic leukemia or multiple myelomas which includes smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma. 21. The method of claim 14, wherein the PI3K associated disease, disorder or condition is selected from Chronic Lymphocytic Leukemia (CLL), Lymphoma Non-Hodgkin (NHL), Acute Myeloid Leukemia (AML), Multiple Myeloma (MM), Small Lymphocytic Lymphoma (SLL), Indolent Non-Hodgkin's Lymphoma (I-NHL), acute lymphocytic leukemia (ALL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). 22. A method for the treatment of a relapsed or refractory hematologic malignancy comprising the step of administering to a subject in need thereof an effective amount of a salt of claim 1. 23. The method of claim 22, wherein the malignancy is selected from non-Hodgkin's lymphoma, chronic lymphocytic leukemia, peripheral T-cell lymphoma, and Hodgkin's lymphoma. 24. A method for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, peripheral T-cell lymphoma, and Hodgkin's lymphoma comprising the step of administering to a subject in need thereof an effective amount of a salt of claim 1. 25. The salt of claim 1, wherein the salt exhibits a differential scanning calorimeter (DSC) pattern with a characteristic endothermic peak at about 146.degree. C. 26. The salt of claim 1, wherein the crystalline salt exhibits an XRPD pattern having two or more peaks selected from 5.0, 10.1, 22.1, and 24.5.+-.0.2.degree. 2.THETA.. 27. The salt of claim 1, wherein the crystalline salt exhibits an XRPD pattern having peaks at 5.0, 10.1, 22.1, and 24.5.+-.0.2.degree. 2.THETA.. 28. The salt of claim 1, wherein the ratio of p-toluenesulfonic acid to the compound ##STR00005## is about 1:1.