METHODS OF TREATMENT WITH A 2,4,5-TRISUBSTITUTED 1,2,4-TRIAZOLONE

• US 20190307728A1
• Filed: 03/28/2019
• Published: 10/10/2019
• Est. Priority Date: 04/10/2018
• Status: Abandoned Application

• Current Assignee: Bayer Pharma AG (Bayer AG), The Broad Institute, Inc.
• Original Assignee: Bayer Pharma AG (Bayer AG), The Broad Institute, Inc.
• Inventors: Janzer, Andreas, Ferrara, Steven James
• Application Number:
  US16/367,708
• Publication Number:
  US 20190307728A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia

Abstract

The present invention provides a method of treating a mutant IDH cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of Compound (I):

and the use of said compound for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders bearing an IDH mutation, as a sole agent or in combination with other active ingredients.

Claims

1. A method of treating a mutant IDH cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of Compound (I), which N-(2-chloro-6-fluorophenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-5-fluoro-2-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}benzamide

2. The method of claim 1 where the mutant IDH cancer is characterized by a mutation in an IDH gene or in an IDH protein.

3. The method of claim 1 further comprising detecting DHO.

4. The method of claim 3 further comprising detecting the presence of a mutant IDH gene or protein.

5. The method of claim 4, wherein the IDH mutant is characterized by a mutation in an IDH-1 gene or in an IDH-1 protein.

6. The method of claim 5, wherein the IDH-1 mutation is an amino acid substitution selected from the group G27D, R132C, R132G, R132H, R132L and R132S.

7. The method of claim 4, wherein the the IDH mutant is characterized by a mutation in an IDH-2 gene or in an IDH-2 protein.

8. The method of claim 7, wherein the IDH-2 mutation is an amino acid substitution selected from the group R140L, R140W, R140Q, R172G and R172K.

9. The method of claim 1, wherein a combination of a mutant IDH inhibitor and Compound (I) is administered.

10. The method of claim 1, wherein the cancer is selected from the group consisting of acute myeloid leukemia, brain cancer, breast cancer, colorectal carcinoma, gastric cancer, gliosarcoma, head &

neck cancer, hepatocellular carcinoma, leukemia, lung cancer, lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, and sarcoma.

11. The method of claim 10, wherein the lymphoma is selected from the group AIDS-related lymphoma, chronic lymphocytic lymphoma (CLL), non-Hodgkin'"'"'s lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma;

anaplastic large cell lymphoma, B-cell lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell lymphoma, Hodgkin'"'"'s disease, mantle cell lymphoma (MCL), lymphoma of the central nervous system, small lymphocytic lymphoma and chronic lymphocytic lymphoma.

12. The method of claim 10, wherein the leukemia is selected from the group acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, bisphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, large granular lymphocytic leukemia, plasma cell leukemia, and also myelodysplastic syndrome, which can develop into an acute myeloid leukemia.