CRYSTAL SALTS OF B-RAF-KINASE INHIBITOR Russian patent published in 2023 - IPC C07D471/04 

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline salts of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide, a RAF kinase inhibitor useful in the treatment of cancer and other conditions. The invention relates to a method for obtaining a crystalline monosuccinate salt N-(3-(5-((1-ethylpiperidin-4-yl) (methyl) amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide having a powder X-ray diffraction pattern containing at least five of the following peaks, in units of 2θ: 15.4° ± 0.5°; 16.1° ± 0.5°; 17.2° ± 0.5°; 19.1° ± 0.5°; 19.8° ± 0.5°; 20.0° ± 0.5°; 20.2° ± 0.5°; 20.5° ± 0.5°; 21.5° ± 0.5°; and 21.8° ± 0.5°, including the interaction of N-(3-(5-((1-ethylpiperidin-4-yl) (methyl) amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridine-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide with one equivalent of succinic acid in a solvent, where the solvent is selected from C_1-4 alcohol or aqueous C_1-4 alcohol, or from ethyl acetate, where the method includes: heating and stirring N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridine-1-yl)-2,4-difluorophenyl) propane-1-sulfonamide with one equivalent of succinic acid in solvent at 30–100°C for 5 min to 4 h with the formation of a suspension, cooling and stirring the suspension to 0–25°C for 5 min to 24 h, filtering the crystalline salt from the suspension, and drying the crystalline salt under reduced pressure at 50°C to give a crystalline salt.

EFFECT: method for obtaining a crystalline monosuccinate salt of N-(3-(5-((1-ethylpiperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide useful in the treatment of cancer and other diseases associated with RAF kinase activity, which is soluble, stable and non-hygroscopic.

2 cl, 50 dwg, 18 tbl