FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention relates to derivatives of 5-imino-13-deoxy-anthracycline of the formula:
wherein R1, R2 and R3 mean hydrogen atom (H), hydroxyl group (OH) or OCH3-group; R4 represents the following groups:
Invention proposes a pharmaceutical composition eliciting an anti-tumor activity and comprising at least one derivative of 5-imino-12-deoxy-anthracycline. Invention proposes a method for treatment of cancer, autoimmune diseases or immunodeficient disorders comprising administration of the effective dose of at least one derivative of 5-imino-13-deoxy-anthracycline. Also, invention proposes methods (variants) for preparing derivatives of 5-imino-13-deoxy-anthracycline. Method is carried out by reduction of anthracycline-13-tosylhydrazone with sodium cyanoborohydride in anhydrous methanol at pH about 7.0 or below in the presence of p-toluene sulfoacid by cautious boiling a solution with a back-flow condenser in nitrogen atmosphere at temperature about 75oC. Then the reaction mixture is cooled, treated with water and chloroform, dried and drying agent is filtered off. Filtrate is separated in column with silica gel washed out in gradient chloroform/methanol and product of 13-deoxyanthracycline is eluted with methanol. Then method involves the further purification of methanol eluate using the preparative HPLC and then potassium hydrocarbonate and di-tert.-butyl-dicarbonate are added to solution of purified 13-deoxy-anthracycline in mixture of methylene chloride and water. Prepared 3'-N-Boc-deoxy-anthracycline is isolated, dissolved in anhydrous methanol, the prepared solution is cooled and amination of 3'-N-Boc-13-deoxy-anthracycline is carried out by saturation with ammonium solution at temperature about 0-4o C. Solvent and ammonia are removed, residue is dissolved in anhydrous methanol, 3'-N-Boc-group is removed and the end product is isolated by the preparative HPLC and converted, if necessary, to 5-imino-13-deoxy-anthracycline hydrochloride. Method provides preparing derivatives of 5-imino-13-deoxy-anthracycline eliciting the reduced cardiotoxicity adverse effect.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
13 cl, 4 tbl, 12 dwg, 1 ex
