METHOD FOR PRODUCING AMINO ACID ANALOGUES OF THE ANTITUMOUR ANTIBIOTIC REBECCAMYCIN Russian patent published in 2021 - IPC C07H19/23 A61P35/00 

FIELD: medicine.

SUBSTANCE: invention relates to a method for producing amino acid analogues of the antitumour antibiotic rebeccamycin – derivatives of N13-methylindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione by the formulas [II] and [III], containing a methyl group by the N13-atom of heterocyclic nitrogen, carbohydrate residues of five- or six-membered sugars by the N12-atom of heterocyclic nitrogen, and, independently, residues of S- or R-amino acids by the N6-atom of heterocyclic nitrogen. In the formulas [II] and [III], respectively, G equals , R=Ac for compounds by the formula [II] and R=H for compounds by the formula [III]; n=3, 4; Q is the side chain of an amino acid selected from -H, -CH₃ (2S and 2R), -CH(CH₃)₂ (2S or 2R), -CH₂-OH (2S or 2R), -CH(OH)-CH₃(2S or 2R), -CH₂-S₆H ₅ (2S or 2R), -CH ₂-p-C ₆H₄OH (2S), -(CH₂)₂ -S-CH₃ (2S or 2R), -(CH₂)₂-SOCH₃ (2S or 2R) -(CH₂)₂-COOH (2S), -(CH₂)₃-C(=NH)-NH(-NO₂) (2S), -(CH₂)₄-NH-CO-O-CH₂-C₆H₅(2S), -CH₂-Ind (2S or 2R, Ind is the side chain of tryptophan). The method consists in the fact that the corresponding per-O-acetylated N12-β-D-ribopyranoside of indolo[2,3-a]furano[3,4-c]carbazole-5,7-dione, or per-O-acetylated N12-β-D-glucopyranoside of indolo[2,3-a]furano[3,4-c]carbazole-5,7-dione, or per-O-acetylated N12-β-D-galactopyranoside of indolo[2,3-a]furano[3,4-c]carbazole-5,7-dione by the formula [I] is boiled in dry pyridine with an amino acid in the presence of 3 moles of pyridine hydrochloride for 7 to 12 hours, controlling the course of the reaction according to the TLC data on silufol; for the directed course of the reaction in the proposed conditions, protection is only required for nitrogen-containing fragments of the side chain Q of arginine (NO₂/Arg) and lysine (Cbz/Lys), at the end of the reaction, pyridine is evaporated, the residue is crystallised with water, then the formed N6-amino acid derivatives by the formula [II] are isolated using the methods for extraction and liquid chromatography on silica gel: per-O-acetylated N12-β-D-ribopyranosides, or N12-β-D-glucopyranosides, or N12-β-D-galactopyranosides of indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione. The carbohydrate residue is deacetylated by the impact of anhydrous potassium carbonate in methanol on acetylglycoside by the formula [II], the end of the reaction is registered by the TLC data on silufol, then water is added until the residue is dissolved, a cation exchanger (H⁺) is introduced into the solution until a pH of 5, the reaction mixture is washed from the resin with water and evaporated to dryness; liquid chromatography on silica gel is used to isolate N6-amino acid derivatives by the formula [III]: N12-β-D-ribopyranosides, or N12-β-D-glucopyranosides, or N12-β-D-galactopyranosides of indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione.

EFFECT: production of amino acid analogues of the antitumour antibiotic rebeccamycin.

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