Synthesis and investigation of the physicochemical properties of 2-(5-((theophylline-7'-yl)methyl)-4-phenyl-4H-1,2,4-triazole-3-ylthio)-acetic acid salts

Introduction. In last decades considerable interest to the search of biologically active compounds in series of azole derivatives is indicated. This is mainly connected with the successful use of several drugs with heterocyclic system in the structure. Analysis of the pharmacological properties of heterocyclic nitrogen–containing compounds of the known groups let us to suggest, that the triazole substituent is an important pharmacophore fragment, responsible for the availability of diverse physiological activity. In addition, it causes a little toxicity. Considerable attention belongs to synthesis and research of the biological activity of 1,2,4-triazoles derivatives. The great importance also has research of the influence of heterocyclic fragments of different nature in combination in one molecule on the activity of the synthesized compounds. Like different synthons in the structure of 1,2,4-triazoles in various kinds of biological activity of the reaction products with an aim of new and highly efficient low-toxicity compounds reception. The aim of work was to study synthesis and properties of substances among salts of 2-(5-((theophylline-7'-yl)methyle)-4-phenyle-4Н-1,2,4-triazole-3-ylthio)acetate acid. Materials and methods of the research. In the process as a starting material for reception of new series of compounds theophylline has been chosen. It is important to note, that by the diversity and strength of pharmacological effects, which appears, this structure takes its rightful place among heterocyclic compounds. Through the series of the successive stages 4-phenyle-5-(1',3'-dimethylxantine-7'-yl)methyle-1,2,4-triazole-3-thiol was obtained from the theophylline. Research of the physico-chemical properties of the received compounds conducted according to methods, described in the State Pharmacopoeia of Ukraine. open capillary method, elemental analysis (Elementar Vario L cube (CHNS)). 1H NMR spectra of compounds were recorded with a spectrometer “Mercury 400” (solvent - DMSO-d6 or DMSO-d6 + CCl4, the internal standard - tetramethylsilane). Chromatography-mass spectral researches were performed on the instrument Agilent 1100 Series LC/MSD System, method of ionization - chemical ionization at the atmospheric pressure (APCI). Propyl ester of the theophylline-7-acetic acid. To the 0,055 mol of sodium hydrogencarbonate in 150 ml of DMF adds 0,05 mole of the theophylline and heated with stirring 5 - 10 minutes. To the reaction compound adds 0,055 mole of the monochloracetate acid propyl ester and boil with constant stirring 5 - 6 hours. After cooling to the reaction mixture with stirring, adds an equal volume of water. The precipitate dissolves, then falles again. Ester precipitate is filtered, washed with water, then with a small amount of methanol and dried. White crystalline solid, insoluble in water, soluble in organic solvents (alcohols, dioxane, DMF, DMSO). For the analysis is purified from 1-propanol. Yield 82%. Hydrazide of the theophylline -7-acetic acid. To the heated 0,03 mole solution of the propyl ester theophylline -7- acetic acid in 200 ml of ethanol adds 0.3 mole of hydrazine hydrate. Reactionary compound leave at room temperature for 12 hours. Hydrazide precipitate is filtered, washed with water, acetone and dried. Output 79%. White, amorphous substance, insoluble in water, acetone, soluble in alcohols, dioxane, soluble in DMF, DMSO. Crystallized from a mixture DMF-water (1:1). Tm. = 210-211 ºC. 2-(2-(theophylline-7'-yl)acetyl)-N-phenylhydrazinecarbothioamide. 0,05 mol of phenylisothiocyanate, 130 ml of dioxane and 90 ml of water heated up to boiling for 1 hour, cooled, add 100 ml of water, the precipitate is filtered, washed with water, 2-propanol and crystallized from a mixture water- dioxane, dimethylformamide. Output - 71 %. Tm . = 262-265 ºC. 7-((5-mercapto-4-phenyl-4H-1,2,4-triazoles-3-yl)methyl)theophylline. 0,01 mol of compound 2 -(2-(theophylline)acetyl)-N-phenylhydrazyncarbothio-amide, 0,01 mol of sodium hydroxide and 50 ml of water heated up to boiling during 2 hours, cooled and added to the filtrate 2 ml of concentrated hydrochloric acid. Output - 84%. Tm. > 270 º C. 2-((5-((theophylline-7'-yl)methyle)-4-phenyle-4Н-1,2,4-triazole-3-il)thio)acetate acid. In a round, heat-resistant flack heated 0,01 mol of 7-((5-mercapto-4-phenyl-4H-1 ,2,4-triazoles-3-yl) methyl)theophylline, 0,02 mol NaOH and 0,01 mol monochloracetate acid. Heated up to boiling for 1 h. Cooled. Neutralized by acetic acid. Output - 71%. Tm. = 227-230 º C. Salts of 2-(5-((theophylline-7'-il)methyle)-4-phenyle-4Н-1,2,4-triazole-3-il-tiо)acetate acid. A compound: 0.01 mole of acetic acid, 35 ml of ethanol and 0.01 mol of corresponding base (monoethanolammonium, dyethylammonium, dyetanolammonium, monoetanolammonium, threebutylammonium, morpholine, piperidine, piperazine) heated for 1 hour in a water bath, the solvent is evaporated. Getting white crystalline substances soluble in water, soluble in diethyl ether and chloroform. For analysis compounds recrystallized from ethanol. Potassium, sodium salts of 2-(5-((theophylline-7'-il)methyle)-4-phenyle -4Н-1,2,4-triazole -3-iltio)acetate acid. A compound - 0.01 mole of acetic acid and 0.01 mole of potassium or sodium hydroxide in 30 ml of water evaporated in a water bath. The dry residuum crystallized from ethanol. Getting white crystalline substances, difficulty soluble in organic solvents. For analysis compounds recrystallized from water. Magnesium , calcium, zinc , copper (II) and iron (II ) salts of 2-(5-((teophylline-7'-yl)methyle)-4-phenyle-4Н-1,2,4-triazole-3-iltio)acetate acid. A compound of 0.02 mole acetic acid, 25 ml of water and accordingly 0.01 mol of magnesium oxide , calcium carbonate , zinc sulfate, copper ( II) sulfate or iron ( II) chloride is heated till the dissolution of precipitate , filtered , the filtrate evaporated. Received white, light blue , brown crystals with sharp melting points, little soluble in water, hardly soluble in organic solvents. For the analysis, compounds recrystallized from water. Ammonium salt of 2-(5-((teophylline-7'-yl)methyle)-4-phenyle-4Н-1,2,4-triazole-3-iltio)acetate acid. A solution of 0.01 mole acetic acid in 30 ml of 25% ammonia solution evaporated. Received a white crystalline solid, easily soluble in water, difficult soluble in ethanol. For the analysis compound recrystallized from the compound - dioxane: water (3:1). Results and their discussion. As starting material we used 7 - ((5-mercapto-4-phenyl-4H-1 ,2,4-triazoles-3-yl) methyl) theophylline, received from 2 - (2 - (theophylline) acetyl)-N phenylhydrazyncarbotioamide, which was obtained from the previously described hydrazide theophylline-7-acetic acid as a result of interaction with phenylizotiocyanate. By interaction of the resulting thiol with monochloracetate acid in an aqueous solution of double lye number received the corresponding carboxylic acid. Research has shown, that the reaction proceeds quantitatively In the 1Н NMR - spectra of the resulting acid was observed number of signals. In a strong part of magnetic field available the protons of -СН2-groups, which resonate as singlets at 3.90 m.p and 5.75 m.p The signals of СН3 groups protons also appears as intense singlet in the 3.30 - 3.36 m.p region. Proton of the methyne group is characterized by a signal at 8.36 m.p. Signals of the phenyl radical protons in 1Н NMR- spectra form two one - proton doublets (at 7.70 m.p. and at 7.48 m.p. ) and three one – proton triplets (at 6.83 - 7.17 m.p. ) . Broadening proton signal of aromatic COOH groups fixed at 12.0 m.p. IR- spectra of the received acid characterized by deformation and valence fluctuations of synthesized compounds basic fragments: plane deformation of C-H fluctuations in 1225 - 950 cm-1 area ( weak intensity band 1175-1125 сm-1 , 1110-1070 сm-1, 1070-1000 1 сm-1), out – plane deformation of C-H fluctuations in the 1000-650 сm-1 area ( strong intensity band 770 - 730 сm-1, , 710 - 690 сm-1 ). Available bands of the carboxyl group valence fluctuations - 1760 сm-1. C = N in a 1660-1480 сm-1 cycle . Theophylline fragment: 3060 - 3010(νс-н), 1000 - 960 сm-1 (C- H deformation fluctuations), 875 - 775 сm-1 (C- H deformation fluctuations) , 1580 - 1520 сm-1 ( ring fluctation) . Also, available bands of NH- groups fluctuations within 1650 - 1620 сm-1 (νas) and 1345 - 1310 сm-1 (νs).Conclusions Installed the optimal conditions of salts receptio

Синтез i дослідження фізико-хімічних властивостей солей 2-(5-((теофілін-7'-іл)метил)-4-феніл-4Н-1,2,4-тріазол-3-ілтіо)-ацетатної кислоти

Introduction. In last decades considerable interest to the search of  biologically active compounds in series of azole derivatives is indicated. This is mainly connected with the  successful use of several drugs with heterocyclic system in the structure. Analysis of the pharmacological properties of heterocyclic nitrogen–containing compounds of the known groups let us to suggest, that the triazole substituent is an important pharmacophore fragment, responsible for the availability of diverse physiological activity. In addition, it causes a little toxicity. Considerable attention  belongs to synthesis and research of the biological activity of 1,2,4-triazoles derivatives.The great importance also has research of the influence of heterocyclic fragments of different nature in combination in one molecule on the activity of the synthesized compounds. Like different synthons in the structure of 1,2,4-triazoles in various kinds of  biological activity of the reaction products with an aim of new and highly efficient low-toxicity compounds reception.The aim of work was to study synthesis and properties of substances among salts of 2-(5-((theophylline-7'-yl)methyle)-4-phenyle-4Н-1,2,4-triazole-3-ylthio)acetate acid.Materials and methods of the research. In the process as a starting material for reception of new series of compounds theophylline has been chosen. It is important to note, that by the diversity and strength of pharmacological effects, which appears, this structure takes its rightful place among heterocyclic compounds. Through the series of the successive stages 4-phenyle-5-(1',3'-dimethylxantine-7'-yl)methyle-1,2,4-triazole-3-thiol was obtained from the theophylline.Research of the physico-chemical properties of  the received  compounds  conducted according to methods, described in the State Pharmacopoeia of Ukraine. open capillary method, elemental analysis (Elementar Vario L cube (CHNS)). 1H  NMR spectra of compounds were recorded with a spectrometer “Mercury 400” (solvent - DMSO-d6 or DMSO-d6 + CCl4, the internal standard - tetramethylsilane). Chromatography-mass spectral researches were performed on the instrument Agilent 1100 Series LC/MSD System, method of ionization - chemical ionization at the atmospheric pressure (APCI).Propyl ester of the theophylline-7-acetic acid. To the 0,055 mol of  sodium hydrogencarbonate in 150 ml of DMF adds 0,05 mole of  the theophylline and heated with stirring 5 - 10 minutes. To the reaction compound adds 0,055 mole of the monochloracetate acid propyl ester and boil with constant stirring 5 - 6 hours. After cooling to the reaction mixture with stirring, adds an equal volume of water. The precipitate  dissolves, then falles again. Ester precipitate is  filtered, washed with water, then with a small amount of methanol and dried. White crystalline solid, insoluble in water, soluble in organic solvents (alcohols, dioxane, DMF, DMSO). For the analysis is purified  from 1-propanol. Yield 82%.Hydrazide of the theophylline -7-acetic acid. To the heated 0,03 mole solution  of the propyl ester theophylline -7- acetic acid in 200 ml of ethanol  adds 0.3 mole of hydrazine hydrate. Reactionary compound  leave at room temperature for 12 hours. Hydrazide precipitate is filtered, washed with water, acetone and dried. Output 79%. White, amorphous substance, insoluble in water, acetone, soluble in alcohols, dioxane, soluble in DMF, DMSO. Crystallized from a mixture DMF-water (1:1). Tm. = 210-211 ºC.2-(2-(theophylline-7'-yl)acetyl)-N-phenylhydrazinecarbothioamide.0,05 mol of phenylisothiocyanate, 130 ml of dioxane and 90 ml of water heated up to boiling  for 1 hour, cooled, add 100 ml of water, the precipitate is filtered, washed with water, 2-propanol and crystallized from a mixture water- dioxane, dimethylformamide. Output - 71 %. Tm . = 262-265 ºC.7-((5-mercapto-4-phenyl-4H-1,2,4-triazoles-3-yl)methyl)theophylline.  0,01 mol of compound  2 -(2-(theophylline)acetyl)-N-phenylhydrazyncarbothio-amide, 0,01 mol of sodium hydroxide and 50 ml of water heated up to boiling  during 2 hours, cooled and added to the filtrate 2 ml of concentrated hydrochloric acid. Output - 84%. Tm. > 270 º C.2-((5-((theophylline-7'-yl)methyle)-4-phenyle-4Н-1,2,4-triazole-3-il)thio)acetate acid. In a round, heat-resistant flack heated 0,01 mol of 7-((5-mercapto-4-phenyl-4H-1 ,2,4-triazoles-3-yl) methyl)theophylline, 0,02 mol NaOH and 0,01 mol monochloracetate acid. Heated up to boiling for 1 h. Cooled. Neutralized by acetic acid. Output - 71%. Tm. = 227-230 º C.Salts of 2-(5-((theophylline-7'-il)methyle)-4-phenyle-4Н-1,2,4-triazole-3-il-tiо)acetate acid. A compound: 0.01 mole of acetic acid, 35 ml of ethanol and 0.01 mol of corresponding base (monoethanolammonium, dyethylammonium, dyetanolammonium, monoetanolammonium, threebutylammonium, morpholine, piperidine, piperazine) heated for 1 hour in a water bath, the solvent is evaporated. Getting  white crystalline substances soluble in water, soluble in diethyl ether and chloroform. For analysis compounds recrystallized  from ethanol.Potassium, sodium salts of 2-(5-((theophylline-7'-il)methyle)-4-phenyle -4Н-1,2,4-triazole -3-iltio)acetate acid. A compound  - 0.01 mole of acetic acid and 0.01 mole of potassium or sodium hydroxide in 30 ml of water evaporated in a water bath. The dry residuum crystallized from ethanol. Getting white crystalline substances, difficulty soluble in organic solvents. For analysis compounds recrystallized from water.Magnesium , calcium, zinc , copper (II) and iron (II ) salts of 2-(5-((teophylline-7'-yl)methyle)-4-phenyle-4Н-1,2,4-triazole-3-iltio)acetate acid. A compound of 0.02 mole  acetic acid, 25 ml of water and accordingly 0.01 mol of magnesium oxide , calcium carbonate , zinc sulfate, copper ( II) sulfate or iron ( II) chloride is heated till the dissolution of   precipitate , filtered , the filtrate evaporated. Received white, light blue , brown crystals with sharp melting points, little soluble in water, hardly soluble in organic solvents. For the analysis, compounds recrystallized from water.Ammonium salt  of 2-(5-((teophylline-7'-yl)methyle)-4-phenyle-4Н-1,2,4-triazole-3-iltio)acetate acid.  A solution of  0.01 mole  acetic acid in 30 ml of 25% ammonia solution  evaporated. Received a white crystalline solid, easily soluble in water, difficult soluble in ethanol. For the analysis  compound recrystallized from the compound - dioxane: water (3:1).                       Results and their discussion. As starting material we used 7 - ((5-mercapto-4-phenyl-4H-1 ,2,4-triazoles-3-yl) methyl) theophylline, received from 2 - (2 - (theophylline) acetyl)-N phenylhydrazyncarbotioamide, which was obtained from the previously described hydrazide theophylline-7-acetic acid as a result of interaction with phenylizotiocyanate.By interaction of the resulting thiol with monochloracetate acid in an aqueous solution of double lye number received the corresponding carboxylic acid. Research has shown, that the reaction proceeds quantitativelyIn the 1Н NMR - spectra of the resulting acid was observed number of signals. In a strong part of magnetic field available the protons of -СН2-groups, which resonate  as  singlets at 3.90 m.p and 5.75 m.p The signals of СН3 groups protons also appears as intense singlet in the 3.30 - 3.36 m.p region. Proton of the methyne group is characterized by a signal at 8.36 m.p. Signals of  the phenyl radical protons in 1Н NMR- spectra form two one - proton doublets (at 7.70 m.p. and at 7.48 m.p. ) and three one – proton triplets (at 6.83 - 7.17 m.p. ) .Broadening proton signal of aromatic COOH groups  fixed at 12.0 m.p.IR- spectra of the received acid characterized by deformation and valence fluctuations of synthesized compounds basic fragments: plane deformation of C-H fluctuations  in 1225 - 950 cm-1  area ( weak intensity band 1175-1125 сm-1 , 1110-1070  сm-1, 1070-1000 1 сm-1), out – plane deformation of C-H fluctuations in the 1000-650 сm-1  area  ( strong intensity band 770 - 730 сm-1,  , 710 - 690 сm-1 ).            Available bands of the carboxyl group valence fluctuations - 1760 сm-1. C = N in a 1660-1480 сm-1  cycle  . Theophylline fragment: 3060 - 3010(νс-н),  1000 - 960 сm-1   (C- H deformation fluctuations), 875 - 775 сm-1  (C- H deformation fluctuations) , 1580 - 1520 сm-1  ( ring fluctation) . Also, available bands of   NH- groups fluctuations within  1650 - 1620 сm-1  (νas)  and 1345 - 1310 сm-1 (νs).ConclusionsInstalled the optimal conditions of salts receptionИсследованы реакции получения солей 2-(5-((теофиллин-7'-ил)метил)-4-фенил-4Н-1,2,4-триазол-3-илтио)ацетатной кислоты. Изучены физико-химические свойства полученных соединений. Досліджено реакції отримання солей 2-(5-((теофілін-7'-іл)метил)-4-феніл-4Н-1,2,4-тріазол-3-ілтіо)ацетатної кислоти. Вивчено фізико-хімічні властивості отриманих сполук

Синтез і дослідження властивостей 3-тіосульфонілпохідних 4-(2-метоксифеніл)-5-алкіл(арил)-1,2,4-тріазолу

Introduction. 1,2,4-Triazoles derivatives are known to a number of scientists thanks to the valuable properties that appear in the antimicrobial, antifungal, analgesic, anticancer, antiviral, antituberculosis, anti-inflammatory, anticonvulsant and antidepressant activities and effects on the central nervous system. Thus, 5-thiosulfonyl 1,2,4-triazole derivatives are a sufficiently light known class of compounds.Analysis of literature showed the perspective for pharmacology impact of the 1,2,4-triazolе fragment and sulfonic group combination within a single molecule.The aim of the study was the synthesis and properties of substances among 1,2,4-triazoles 3-thiosulfonyl derivatives.The 4-(2-methoxyphenyl)-5-methyl-1,2,4-triazole-3-thiol and 4-(2-methoxyphenyl)-5-phenyl-1,2,4-triazole-3-thiol were used as starting materials, which were synthesized by known methods, namely, nucleophilic substitution reactions (esterification, hydrazinolysis), nucleophilic addition and intramolecular cyclization.Investigations of reaction with sulfochlorides (4-toluensulfochloride, benzensulfochloride, 3-nitrobenzensulfochloride, 2-naphtholsulfohloride, butane-1-sulfochloride and other) were conducted before the studies to determine the optimal conditions for subsequent work. Materials and methods of the researchResearches of the compounds’ physical-chemical properties we conducted according to methods, described in the State Pharmacopoeia of Ukraine. The melting point defined by the open capillary method on the ITM (M) instrument. The structure of the compounds is confirmed by elemental analysis instrument Elementar Vario L cube (CHNS), IR spectra (4000-400 cm-1) have been removed on  the ALPHA-T (KBr, CHCl3/HPLC) module  by Bruker ALPHA FT-IR spectrometer. 1H NMR spectra of compounds have been recorded by means of “Mercury 400” (solvent - DMSO-d6 or DMSO-d6 + CCl4 spectrometer, the internal standard - tetramethylsilane). Chromatography-mass spectral researches have been conducted on the Agilent 1100 Series LC/MSD System instrument, the ionization method - chemical ionization at atmospheric pressure (APCI).Investigation of antimicrobial and antifungal action has been performed by disco-diffusion method on Mueller-Hinton medium using the following test strains of microorganisms: gram-positive cocci (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212), gram-negative bacillus (Enterobacter aerugenes, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922), facultative anaerobic gram-negative bacillus (Klebsiella pneumonia 12) and fungi (Candida albicans ATCC 885-653).ConclusionsIt was determined, that the best option of  the alkylation reactions passing of 4- (2-metoxyphenyl)-5-R-1,2,4-triazoles-3-thiol sulfochloride is a reception of the intermediate potassium salt output compound, with it’s next dissolving it in water and gradual addition of appropriate  sulfochloride in acetone to a solution.Microbiological screening results showed that the synthesized compounds do not show antibacterial and antifungal activity relatively the number of test-strains of microorganisms.  Исследованы реакции получения 3-тиосульфонилпроизводных 4-(2-метоксифенил)-5-метил-1,2,4-триазола и 4-(2-метоксифенил)-5-фенил-1,2,4-триазола. Изучены физико-химические свойства и антимикробная активность синтезированных соединений.Дослідили реакції отримання 3-тіосульфонілпохідних 4-(2-метоксифеніл)-5-метил-1,2,4-тріазолу та 4-(2-метоксифеніл)-5-феніл-1,2,4-тріазолу. Вивчили фізико-хімічні властивості й антимікробну активність синтезованих сполук