CO-CRYSTALS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME Russian patent published in 2018 - IPC C07D401/14 A61K31/506 A61P35/00 

FIELD: chemistry.

SUBSTANCE: invention relates to a novel co-crystal containing a compound of formula (I) and adipic acid as a co-crystal former with a molar ratio of the compound of formula I to adipic acid from about 2 to 1. Co-crystal has the properties of a DNA-dependent protein kinase inhibitor (DNA-PK) and has improved bioavailability. Co-crystal can be used in the treatment of cancer. Compound of formula (I) corresponds to the following structure:

,

where each of R¹ and R² independently represents hydrogen or deuterium. Co-crystal has reflection peaks in the X-ray powder diffraction pattern at approximately 6.46+/-0.2, 7.91+/-0.2, 11.92+/-0.2, 12.26+/-0.2, 12.99+/-0.2, 14.19+/-0.2, 18.68+/-0.2 and 19.07+/-0.2 °2-theta and DSC peak on its DSC thermogram at about 195 °C and about 245 °C. Invention also relates to versions of a method of producing a co-crystal. Method includes grinding, heating, co-sublimation, co-melting or contacting compound (I) with adipic acid under crystallisation conditions in order to form a co-crystal in the solid phase. Alternatively, the method includes preliminary preparation of a co-crystal, as a nucleant, and the addition and mixing of the obtained co-crystal nucleant into a suspension of compound (I) and adipic acid. Invention also relates to a pharmaceutical composition comprising an effective amount of a co-crystal, as well as to a method for potentiating a therapeutic regimen for treatment and to a method for treating a cancer disease mediated by DNA-PK activity. Each method involves administering an effective amount of a co-crystal or pharmaceutical composition. In treatment, additional anticancer therapy may be used, which comprises the administration of an additional anticancer agent or radiation therapy, or both. As an additional anticancer agent, an agent selected from a DNA damaging agent such as etoposide, doxorubicin, daunorubicin, epirubicin or bleomycin can be used. Combination of a co-crystal with an additional agent exhibits synergism. Administration of the primary and secondary agent is preferably carried out fairly close in time.

EFFECT: co-crystals and pharmaceutical compositions containing same are disclosed.

19 cl, 31 dwg, 21 tbl, 14 ex