Синтез, хімічні та біологічні властивості моно- та біс-похідних спіро-2-оксіндол[3,3']піролу

Abstract

Дисертаційна робота присвячена синтезу нових біологічно активних речовин – похідних моно- та біс-спіро-2-оксіндол[3,3']піролу та виявленню серед них перспективних сполук, які можуть бути рекомендовані для подальших поглиблених фармакологічних досліджень. Реакцією 1,3-диполярного циклоприєднання азометинілідів, отриманих in situ із ізатинів та α-амінокислот з різноманітними диполярофілами на основі біс-малеїнімідів були синтезовані нові гексамети-лен(етилен, оксаліламін, м-фенілен)-N,N'-біс(спіроіндол-3,3'-піроло[3,4-с]пірол-2а', 5а'-дигідро-2,2',6'(1H,1'H,5'H)-тріони) та їх моноаналоги. Досліджено перебіг цієї реакції в залежності від співвідношення та природи реагентів, розчиннику та її механізм. Досліджено можливості нітрозування, алкілування та ацилування отриманих речовин. Структури синтезованих сполук підтверджено за допомогою ІЧ-, 1Н, 13С ЯМР-спектроскопії, хромато-мас-спектрометрії, елементного аналізу. Знайдено сполуки, які виявили виражену протимікробну, антиоксидантну, протизапальну активності та інгібуючи властивості стосовно рецептора фактора росту фібробластів (FGFR1) та є перспективними БАР.

Диссертация посвящена синтезу новых биологически активных веществ – производных моно- и бис-спиро-2-оксиндол[3,3']пиррола и поиску среди них перспективных соединений, которые могут быть рекомендованы для дальнейших углубленных фармакологических исследований. Реакцией 1,3-диполярного циклоприсоединения азометинилидов (полученных in situ из изатинов и α-амино-кислот) с разнообразными диполярофилами на основе бис-малеинимидов синтезированы новые гексаметилен(этилен, оксалиламин, м-фенилен)-N,N'-бис (спироиндол-3,3'-пирроло[3,4-с]пиррол-2а',5а'-дигидро-2,2',6'(1H,1'H,5'H)-трионы) и их моноаналоги. Исследован процесс протекания реакции в зависимости от соотношения и природы реагентов, растворителя и ее механизм. Проведено нитрозирование, алкилирование и ацилирование полученных веществ. Строение полученных соединений подтверждено с помощью ИК-, 1Н, 13С ЯМР-спектроскопии, хромато-масс-спектрометрии и элементным анализом. Найдено соединения с выраженной противомикробной, антиоксидантной, противовоспалительной активностью и ингибирующими свойствами относительно рецептора фактора роста фибробластов (FGFR1), которые являются перспективными БАВ.

The thesis is dedicated to the synthesis of the new biologically active compounds among mono- and bis-derivatives of spiro-2-oxindole-[3,3']-pyrrole and study of their pharmacological activity. New hexamethylene(ethylene, oxalyl amine, m-phenylene)-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-2a,5a'-dihydro-2,2',6'(1H,1'H,5'H)-triones) were synthesized via 1,3-dipolar cycloaddition of azomethinilides (obtained in situ from isatines and α-amino acids) with various dipolarophils based on bis-maleimides. New mono-derivatives of spiro-2-oxindole[3,3']pyrrole are interesting in pharmacological aspect because they contain in their structure two highly active pharmacophoric fragments: the core of spiroindole-3,3'-pyrrolo[3,4-c]pyrrole and maleimide residue. On the other hand, from the point of view of the study of biological properties, bis-derivatives are also of interest, which can be regarded as identical “twin drugs” – physiologically active compounds containing two identical pharmacophore groups covalently combined into one molecule. In order to optimize the method of synthesis of target compounds, the process of the reaction of three-component one-pot condensation of isatins, α-amino acids and N,N'-hexamethylene-bis-maleimide was studied depending on the ratio and nature of the reagents as well as the solvent and the mechanism of this interaction was analyzed. It is shown that the nature of the substituents in position 1 of isatin does not affect the process of this interaction. The structure of α-amino acids affects its flow. Thus, with the use of primary α-amino acids with aryl and benzyl radicals, the target compounds were formed with high yields in 30 - 60 minutes. With the use of primary α-amino acids with alkyl radicals and secondary L-proline and sarcosine, the reaction takes5 - 8 hours. An optimal solvent system for this reaction was selected: isopropanol mixed with water in a ratio (3:1). Compared to condensation in methanol-water (3:1) (which is widely used in the synthesis of such derivatives), the reaction time was shortened and the yields of the target products increased. The peculiarities of the three-component interaction between isatin, amino acids and N,N'-di(3-carboxypropenoyl)-1,2-ethylenediamine are investigated. It was found that in the course of this reaction additionally there is a closure of the imide cycle to form ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-2a,5a'-dihydro-2,2',6'-(1H,1'H,5'H)-triones. A counter-synthesis was carried out in which, instead of dipolarofil (N N'-di (3-carboxypropenoyl)-1,2-ethylenediamine), a product of its cyclization (N,N'-ethylene-bis-maleiminide was used. It is shown that the main path of this interaction involves cycling into the imide cycle at the stage of formation of the adduct. To confirm this, a blank experiment was conducted: the heating of N,N'-di(3-carboxypropenoyl)-1,2-ethylenediamine under the same conditions without the addition of isatin and amino acids. In order to expand the series of the new biologically active compounds, the possibilities of nitrosation, alkylation and acylation of the obtained substances were investigated. Thus, the nitrosation of hexamethylene-N,N'-bis(spiroindol-3,3'-pyrrolo [3,4-c]pyrrole-5'-benzyl-2a',5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione); ethylene-N,N'-bis (spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-methyl-2a',5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione); ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-isopropyl-2a',5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) and 1'-(m-phenylene-N-maleimido)-2a',5a'-dihydro-1'H-spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-methyl-2,2',6'(1H,1'H,5'H)-trione occurred at the NH-group of the pyrrole fragment in position 4'. Alkylation of ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-phenyl-2a',5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) occurred at the indole’s N-1 position. Acylation of 1'-(m-phenylene-N-maleimido)-2a',5a'-dihydro-1'H-spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-benzyl-2,2',6'(1H,1'H,5'H)-trione occurred on two positions: on the secondary amino group of the pyrrole and indole fragments. The structure of compounds synthesized was confirmed by IR-, 1H, 13C NMR-spectroscopy, mass-spectrometry and elemental analysis. Data on the biological activity of the synthesized mono- and bis-derivatives of spiro-2-oxindole-[3,3']-pyrrole were obtained. Pharmacological studies allowed to identify substances with a significant level of antimicrobial, antioxidant, anti-inflammatory activities and inhibiting properties relative to kinase FGFR1. Results allowed to select “leading substances” [(1'-( hexamethylene-N-maleimido)-2а',7а'-spiroindole-3,3'-pyrrolo[3,4-c]pyrrolizidine-2,2',7'(1H,1'H,5'H)-trione; hexamethylene-N,N'-bis(spiroindol-3,3'-pyrrolo[3,4-c]pyrrole-1-benzyl-5'-hydroxymethyl -2а',5а'-dihydro-2,2',6'(1H,1'H,5'H)-trione), 1'-(hexamethylene-N-maleimido)-5'-methyl-2a',5a'-dihydro-1'H-spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-2,2',6'(1H,1'H,5'H)-trione, ethylene-N,N'-bis(spiro-indole-3,3'-pyrrolo[3,4-c]pyrrole-2a',5a'-dihydro-2,2',6'(1H,1'H, 5'H)-trione), ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-methyl-2a',5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione), ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c] pyrrole-4'-nitroso-5'-methyl-2a',5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione)] that can be recommended for further pharmacological studies in order to create on their basis new drugs with the above types of pharmacological actions.