BIOCONJUGATES OF LUPANE-SERIES TRITERPENIC ACIDS WITH "TROLOX" ACID HYDRAZIDE, PRODUCTION METHOD AND USE AS IMMUNOTROPIC AND ANTI-INFLAMMATORY SUBSTANCES Russian patent published in 2012 - IPC C07J53/00 C07J63/00 A61P29/00 A61P37/00 

FIELD: chemistry.

SUBSTANCE: invention relates to bioorganic chemistry and medicine and specifically to novel biologically active lupane-series triterpenoid derivatives (betulin, betulinic acid, betulonic acid), more specifically 6-hydroxy-N'-[3-oxolup-20(29)-en-28-oyl]-2,5,7,8-tetramethyl-3,4-dihydro- 2H-chromene-2-carbohydrazide (1) and 6-hydroxy-N'-[3β-hydroxylup-20(29)-en-28-oyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carbohydrazide (2) which exhibits anti-inflammatory activity. Compounds 1 and 2 are hybrid molecules composed of fragments of betulonic acid (3) or betulinic acid (4) and 6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxylic acid (Trolox acid) (5) bound by a hydrazide bridge. The compounds are obtained by reacting Trolox acid with a hydrazine monohydrate in pure tetrahydrofuran in the presence of CDI and condensation of a hydrazide derivative (9) with acid chlorides of betulonic acid and betulinic acid (7) and (8), obtained immediately before the reaction through the action of oxalyl chloride on acids (7) and (8). The condensation reaction is carried out in pure CH₂Cl₂ while boiling for 12 hours using N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) (preferably in two-fold molar excess) as a condensation agent with molar ratio of hydrazide 9 to acid chloride 7 or 8 equal to 8-1.1:1.0. Reaction products 1 or 2 are separated by column chromatography on silica gel. Output of hybrid compounds is equal to 65%. In vitro tests of hybrid molecules 1 and 2 and betulinic acid (4) on their effect on production of nitrogen oxide and activity of macrophagal arginase in macrophages, activated by lipopolysaccharides showed that betulinic acid suppressed both production of nitrogen oxide (characteristic M1) and activity of arginase (characteristic M2). Hybrid molecules 1 and 2, unlike betulinic acid, had selective action on macrophages (enabled to obtain macrophages with phenotype M2 while maintaining production of such anti-inflammatory cytokines as IL-10 and TGF-B). Compounds 1 and 2 also exhibited immunoregulating activity since they suppressed Th1-type immune response.

EFFECT: use of such compounds is efficient in different autoimmunie diseases.

3 cl, 6 ex, 2 tbl