БИОКОНЪЮГАТЫ ТРИТЕРПЕНОВЫХ КИСЛОТ ЛУПАНОВОГО РЯДА С ГИДРАЗИДОМ КИСЛОТЫ "ТРОЛОКС", СПОСОБ ПОЛУЧЕНИЯ И ПРИМЕНЕНИЕ В КАЧЕСТВЕ ИММУНОТРОПНЫХ И ПРОТИВОВОСПАЛИТЕЛЬНЫХ ВЕЩЕСТВ
UCHREZHDENIE ROSSIJSKOJ AKADEMII NAUK INSTITUT NEFTEKHIMII I KATALIZA RAN
发明人:
SPIVAK ANNA JULEVNA,Спивак Анна Юльевна (RU),KHALITOVA REZEDA RAFISOVNA,Халитова Резеда Рафисовна (RU),SHAKUROVA EHLVIRA RIFOVNA,Шакурова Эльвира Рифовна (RU),ODINOKOV VIKTOR NIKOLAEVICH,Одиноков Викт
申请号：
RU2010139776/04
公开号：
RU0002464273C2
申请日:
2010.09.27
申请国别(地区):
RU
年份:
2012
代理人:
摘要：
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 cytoki
