CRYSTALLINE FORMS OF THE TLR7/TLR8 INHIBITOR Russian patent published in 2023 - IPC C07D471/04 A61K31/437 A61P37/00 

FIELD: crystalline form of the compound.

SUBSTANCE: invention relates to a method for obtaining a crystalline form of the compound ( S ) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide, comprising the steps: a) suspension of the amorphous free form (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6 ,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide in a solvent mixture containing acetone, ethanol, methanol , isopropanol, isobutanol, tetrahydrofuran or acetonitrile and at least 2% by weight of water, to form a mixture in suspension, b) heating the mixture in suspension until dissolved to form a solution, c) cooling the solution to -10° C. to form a slurry, d) filtering the slurry to collect the crystalline form, wherein the compound is a hemiheptahydrate, the crystalline form is in free form and is characterized by one of the following: (i) an X-ray powder diffraction pattern containing characteristic peaks expressed as 2θ , at a value of °2θ , which is 6.6± 0.2, value °2θ , which is 16.0± 0.2 and a value of °2θ , which is 17.3± 0.2 measured at a temperature of approximately 25°Cand at an X-ray wavelength,λ , which is 1.5418 ; (ii) an X-ray powder diffraction pattern containing four or more values of 2θ , selected from the group consisting of values °2θ , constituting 6.6±0.2°, 7.1±0.2°, 10.6±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 17.3±0.2°, 23.5±0.2°, 26.5±0.2° and 27.3±0.2° measured at a temperature of approximately 25°Cand at an X-ray wavelength, λ , which is 1.5418Å; and (iii) an X-ray powder diffraction pattern containing five or more values of 2θ , selected from the group consisting of values °2θ , constituting 6.6±0.2°, 7.1±0.2°, 10.6±0.2°, 13.2±0.2°, 14.3±0.2°, 16.0±0.2°, 17.3±0.2°, 23.5±0.2°, 26.5±0.2° and 27.3±0.2, measured at a temperature of approximately 25°C and at an X-ray wavelength,λ , which is 1.5418Å .The new method for obtaining a crystalline form (S) -N- (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide, which is applicable in treatment of various autoimmune disease states associated with the activity of an endosomal Toll-like receptor selected from TLR7 and TLR8. The solid form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of ease of formulation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability.

EFFECT: new method for obtaining a crystalline form has been developed.

3 cl, 6 dwg, 2 tbl, 2 ex