METHOD FOR PREPARING WATER-SOLUBLE LYOPHILIZED SALT FORM BIS(2-THIO-4,6-DIOXO-1,2,3,4,5,6-HEXAHYDROPYRIMIDIN-5-YL)-(4-NITROPHENYL)METHANE Russian patent published in 2018 - IPC C07D239/68 A61K9/19 A61J1/20 A61J1/10 A61J1/22 A61P31/20 

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a novel water-soluble lyophilized salt form bis(2-thio-4,6-dioxo-1,2,3,4,5,6-hexahydropyrimidin-5-yl)-(4-nitrophenyl)methane of formula 2a, which has hepatoprotective activity and is intended for the liver treatment, in particular hepatitis. Method for preparing a water-soluble lyophilized salt form bis(2-thio-4,6-dioxo-1,2,3,4,5,6-hexahydropyrimidin-5-yl)-(4-nitrophenyl)methane of formula 2a

comprises: preparing a solution of bis(2-thio-4,6-dioxo-1,2,3,4,5,6-hexahydropyrimidin-5-yl)-(4-nitrophenyl)methane, preparing a solution of tris-hydroxymethylammonium, combining the resultant solutions to form a solution of tris-hydroxymethylammonium salt of formula 2a, followed by lyophilization of the resultant saline. Salt solution 2a used for lyophilization usually contains from 1.5 to 5 wt.% of bis(2-thio-4,6-dioxo-1,2,3,4,5,6-hexahydropyrimidin-5-yl)-(4-nitrophenyl)methane. Solution of tris-oxy methyl ammonium salt of bis(2-thio-4,6-dioxo-1,2,3,4,5,6-hexahydropyrimidin-5-yl)-(4-nitrophenyl)methane used for lyophilization has a concentration from 2.5 to 8.2 wt.% and pH from 6.9 to 7.2. Lyophilization is carried out at a pressure of 0.3–0.5 bar for 15–16 hours, followed by drying for 2–4 hours at a pressure of 0.05 mbar. Resultant lyophilized water-soluble salt form is generally used in a pharmaceutical composition suitable for parenteral administration, in a therapeutically or prophylactically effective amount as a single dose. Typically, a lyophilized water-soluble salt form is used to prepare a medicament packaged in a vessel suitable for parenteral administration. Vessel is a multi-dose vial, ampoule, pre-filled syringe, flexible perfusion bag. For treating or preventing hepatitis, the compound of formula 2a is also administered by infusion, perfusion or injection or orally, for example as a suspension in an aqueous medium.

EFFECT: resultant lyophilized water-soluble salt form has increased storage stability and reduced toxicity while maintaining high hepatoprotective activity.

13 cl, 5 tbl