The thesis is devoted to the development of a strategy for directed search of anti-inflammatory agents using the in silico, in vitro and in vivo methodology, within which a number of unknowns substituted pyrrolo(pyrido)[1,2-a]triazolo(triazino)[c]quinazolines were synthesized. At same time, the influence of several factors on the course of tandem heterocyclization, physicochemical properties, anti-inflammatory, anti-radicaland LOX-inhibitory activity of the synthesized compounds were established. The interaction features of 2-(3-R-1H-1,2,4-triazol-5-yl)- and 2-(6-R-2,5-dihydro-5-oxo-1,2,4-triazine-3-yl)anilines with ketocarboxylic acids (4-oxopentanoic, 4-oxo-4-phenylbutanoic, 2-oxopentanedioic, 3-oxoheptandioic, 5-oxohexanoic acids) were investigated. The developed optimal conditions were used for the preparative synthesis of the above. Also the methods of forming unknown 2-R1-4a-methyl-(phenyl-)-5,6-dihydropyrrolo[1,2-a][1,2,4]triazolo[1,5-c]quinazoline-7(4aH)-ones, 3-R1-5a-methyl-(phenyl-)-6,7-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-2,8(5aH)-diones, 2-R1-4a-methyl-4a,5,6,7-tetrahydro-8H-pyrido[1,2-a]-[1,2,4]triazolo[1,5-c]quinazoline-8-ones, 3-R1-5a-methyl-5a,6,7,8-tetrahydro-2H,9H-pyrido[1,2-a][1,2,4]triazino[2,3-c]quinazoline-2,9-diones, 2-R1-7-oxo-6,7-dihydropyrrolo[1,2-a][1,2,4]triazolo[1,5-c]quinazoline-4a(5H)- and 3-R1-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)-carboxylic (propanoic) acids have been proposed. The structural modification of the carboxyl groupin pyrrolo[1,2-a][1,2,4]triazolo-(triazino-)[c]quinazoline-carboxylic (propanoic) acids was the aimofimproving the pharmacokinetic and pharmaco-technological characteristics. Inthiscase, methods for the synthesis of estersandamides of 2,8-dioxo-3-R1-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)-carboxylic (propanoic) acids were developed. The Tandem heterocyclization of 2-(6-R1-2,5-dihydro-5-oxo-1,2,4-triazin-3-yl)anilines with diethyl 4-oxoheptanedioate provedtobe a more efficient method of ester synthesis. It was shown, that 3-R1-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino¬[2,3-c]quinazoline-5a(6H)-carboxylic acid seas ilyform water-solubles alts with inorganic an dorganic bases. During the studies 106 compounds (90 for the first time) were synthesized for which a comprehensive study of physicochemical properties was performed using a set of methods (IR, 1H, 13C, NMR spectroscopy, chromato-mass and massspectrometry, X-ray diffraction analysis), which allowed to establish the directions oft heheterocyclization reaction and the peculiarities of their structure. It was found, that among pyrrolo-(pyrido-)[1,2-a][1,2,4]triazolo-([1,2,4]triazino-)-[c]quinazolines high anti-inflammatory activity was characteristic for substituted of 2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-carboxylic acids, which in the model of carrageen an and formaline demaexceed the reference drug «Diclofenac», and prognostic values of affinity and visualization of the secom pounds in active centers of biotargets have become a the oretical platform for studying the probable mechanism of their action, namely inhibition of DFPG and LOG by invitro methods. It was shown, that mentioned getarylcarboxylic acids in most cases were characterized by high LOG-inhibitory and antiradical activity, which could beconsidered as one of the possible anti-inflammatory mechanisms. For the first time, the in vivo screening results of the synthesized compound sall owed to establish qualitative (SAR), quantitative (QSAR) «structure-activity» relationships and to create pharmacophoremodels as an effective direction of optimization and further prediction of anti-inflammatory activity among pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolines. It is shown, that the «critical» pharma cophore fragments that cause the manifestation of anti-inflammatory activity, in addition to the heterocycle itself, include the Oxygen atom in the second position, the carboxyl and ethylcarboxyl group sin the 5ath position. Additional factors that contribute to the manifestations of anti-inflammatory activity were the presence of a methyl group or 4-fluorophenyl fragment in the third position and fluor ineatom sin the 11th and 12th positions. The developed strategy of NSAID search amongpyrrolo-(pyrido-)[1,2-a]triazolo-(triazino-)[c]quinazolines and products of their modification allowed to reveal a promising active pharmaceutical ingredient with high anti-inflammatory activity, namely 3-(3-methyl-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)-yl)-propanoic acid, which is virtually on-toxic (LD50>1500 mg/kg) compared to diclofenac sodium, exceeds it in efficacy and therapeutic index and is recommended for fur the rin-depth pharmacological studies.
