MULTICOMPONENT CRYSTALLINE SYSTEM COMPRISING NILOTINIB AND SELECTED CO-CRYSTAL FORMERS Russian patent published in 2018 - IPC C07D401/14 C07C65/03 C07C65/10 C07C57/145 C07C57/15 C07C309/35 C07D213/82 A61K31/506 A61P35/00 A61P35/02 

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline material in one crystalline phase, which is a multicomponent co-crystal of (a) nilotinib hydrochloride and (b) a component selected from fumaric acid, maleic acid, succinic acid, gentisic acid, methyl ester of gallic acid and isonicotinamide, or (a) nilotinib, nilotinib hydrochloride or a mixture of nilotinib and nilotinib hydrochloride and (b) a component selected from 1,5-naphthalenedisulfonic acid. Each co-crystalline compound is characterised by X-ray diffraction analysis. Crystalline material in which component (a) is nilotinib monohydrochloride, and component (b) is fumaric acid, characterised by a powder X-ray diffraction pattern including characteristic peaks expressed in values d (Ǻ): 13.6, 7.1, 5.68, 4.84, 4.67, 4.57, 3.87, 3.69, 3.39, 3.36, 3.31 and 3.16 (±0.1 at 2θ). Crystalline material in which component (a) is nilotinib monohydrochloride, and component (b) is maleic acid, characterised by a powder X-ray diffraction pattern including the following characteristic peaks, expressed in values d (Ǻ) (±0.1 at 2θ): a) 17.2, 15.8, 10.8, 9.1, 7.3, 5.89, 3.66 and 3,60, or b) 16.6, 15.7, 13.0, 10.7, 9.2, 8.7, 7.3, 6.0, 5.83, 5.39, 5.22, 3.92, 3.65, 3.53, 3.51, 3.44 and 3.40, or c) 10.8, 9.2, 3.93 and 3,66. Crystalline material in which component (a) is nilotinib monohydrochloride, and component (b) is succinic acid, characterised by a powder X-ray diffraction pattern including characteristic peaks expressed in values d (Ǻ): 21.1, 3.56, 3.45 and 3.36 or 10.3, 4.58, 3.52 and 3.35 (±0.1 at 2θ). Crystalline material in which component (a) is nilotinib monohydrochloride, and component (b) is gentisic acid, characterised by a powder X-ray diffraction pattern including characteristic peaks expressed in values d (Ǻ) (±0.1 at 2θ): A) 16.2, 10.1, 3.45, 3.33 and 3.31, which is designated as form A of the co-crystal of nilotinib hydrochloride and gentisic acid; or B) 16.1, 10.1, 7.3, 6.0, 5.60, 3.58, 3.42, 3.31, 3.28 and 3.25, which is designated as form B of the co-crystal of nilotinib hydrochloride and gentisic acid; or C) 10.1, 7.7, 5.93, 5.02, 3.60 and 3.55, which is designated as form C of the cocrystal of nilotinib hydrochloride and gentisic acid; or D) 16.3, 10.2, 6.1, 5.68, 3.62, 3.58, 3.46, 3.35, 3.32 and 3.29, which is designated as form D of the co-crystal of nilotinib hydrochloride and gentisic acid; or E) 16.2, 15.8, 9.9, 3.41 and 3.29, which is designated as form E of the co-crystal of nilotinib hydrochloride and gentisic acid. Crystalline material in which component (a) is nilotinib monohydrochloride, and component (b) is isonicotinamide, in which the molar ratio of component (a) to component (b) ranges from about 2: 1 to about 1: 1, is characterised by a powder X-ray diffraction pattern including characteristic peaks expressed in values d (Ǻ) (±0.1 at 2θ): 13.6, 12.4, 6.2, 3.65, 3.54, 3.48 and 3.38, and is designated as co-crystal of nilotinib hydrochloride and isonicotinamide. Crystalline material in which component (a) is nilotinib monohydrochloride, and component (b) is a gallic acid methyl ester in which the molar ratio of component (a) to component (b) ranges from about 2: 1 to about 1: 1, characterised by a powder X-ray diffraction pattern, including characteristic peaks, expressed in values d (Ǻ) (±0,1 at 2θ): 17.2, 15.0, 12.3, 11.5, 8.0, 6.8, 5.66, 5.51 and 3.46, and is designated as co-crystal of nilotinib hydrochloride and gallic acid methyl ester. Crystalline material, in which component (b) is 1,5-naphthalenedisulfonic acid, is characterised by a powder X-ray diffraction pattern including characteristic peaks expressed in values d (Ǻ) (±0,1 at 2θ): a) 10.0, 9.4, 9.2, 7.7, 5.95, 4.83, 4.69, 3.53, 3.50 and 3.35, which is designated as form 1 of the co-crystal nilotinib and naphthalene disulfonic acid; b) 18.4, 9.9, 8.3, 7.8, 6.1, 5.86, 4.85, 4.63, 4.42, 4.29, 4.10, 3.87 and 3.68, which is designated as form 2 of the co-crystal nilotinib and naphthalene disulfonic acid; c) 16.6, 5.78, 3.52, 3.46 and 3.40, which is designated as form 3 of the co-crystal nilotinib and naphthalene disulfonic acid; d) 12.0, 7.9, 6.8, 6.6, 5.50, 5.20, 4.74, 4.63, 3.76, 3.68 and 3,48, which is designated as form 4 of the co-crystal nilotinib and naphthalene disulfonic acid; e) 12.0, 7.9, 7.7, 6.8, 6.0, 5.17, 4.72, 4.65, 3.72 and 3.51, which is designated as form 5 of nilotinib naphthalenedisulfonate; f) 12.0, 6.8, 5.20, 3.76 and 3.69, which is designated as form 6 of nilotinib naphthalenedisulfonate.

EFFECT: resulting co-crystalline compounds can be used to treat a pathological condition for which tyrosine kinase inhibition is beneficial, for example, for treating chronic myelogenous leukemia (CML), preferably for treating drug-resistant chronic myelogenous leukemia (CML).

19 cl, 18 dwg, 24 tbl, 27 ex