INFLUENZA VIRUS REPLICATION INHIBITORS Russian patent published in 2019 - IPC C07D471/04 A61K31/506 A61K31/505 A61P31/16 A61P31/22 A61P31/12 

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline salt of HCl compound (1)⋅1/2H₂O (form A). Compound (1) is represented by the following structural formula:

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Crystalline salt of HCl compound (1)⋅1/2H₂O is characterized by peaks corresponding to 2-theta measured in degrees equal to 10.5±0.2, 5.2±0.2, 7.4±0.2 and 18.9±0.2 on a powder X-ray diffraction pattern, and additionally with peaks corresponding to 2-theta values measured in degrees equal to 25.2±0.2, 16.5±0.2, 18.1±0.2 and 23.0±0.2 on powder X-ray diffraction pattern. Crystalline form is also characterized by peaks corresponding to 29.2±0.3 ppm, 107.0±0.3 ppm, 114.0±0.3 ppm and 150.7±0.3 ppm in spectrum SSNMR on C¹³, and further characterized by peaks corresponding to 22.1±0.3 ppm, 24.6±0.3 ppm, 47.4±0.3 ppm and 54.8±0.3 ppm in spectrum SSNMR on C¹³. Crystalline form A is obtained by mixing HCl with compound (1) in a solvent system which includes water and one or more organic solvents, where the solvent system has water activity equal to 0.05–0.85, and where one or more organic solvents are selected from a group consisting of chlorobenzene, cyclohexane, 1,2-dichloroethane, dichloromethane, 1,2-dimethoxyethane, 1,4-dioxane, hexane, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, nitromethane, tetralin, toluene, 1,1,2-trichloroethane, xylene, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran and methyl tetrahydrofuran. Invention also relates to a method for reducing the amount of influenza virus in a biological sample in vitro or in an individual, as well as a method of treating influenza using crystalline form A salt or a pharmaceutical composition. Amount of administered dose in treatment ranges from 100 mg to 1600 mg. Dose is administered once a day, twice a day or three times a day.

EFFECT: crystalline salt can be used for treating influenza or for preparing a solid pharmaceutical composition for treating influenza.

31 cl, 13 dwg, 32 tbl, 13 ex