Hexasubstituted para-aminophenols with arylamide groups in 2,6 positions with respect to hydroxyl

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexasubstituted para-aminophenols: where R=C6H5, C6H4Cl, C6H4Br, C6H4CH3, with arylamide groups in 2,6 positions with respect to hydroxyl, which demonstrate antibacterial activity.

EFFECT: hexasubstituted para-aminophenols with arylamide groups in 2,6 positions with respect to hydroxyl, possessing high bactericidal and bacteriostatic activity.

1 tbl, 4 ex

 

The invention relates to organic chemistry, in particular to the synthesis of new aromatic hexosamine para-aminophenols, possess antibacterial properties, which can be used in pharmacology to create new drugs.

It is known that para-aminophenol is a connection, which is of great practical interest, because its derivatives are the basis of common pharmaceutical medicines (paracetamol, tylenol, Panadol), used as antipyretics and analgesics /Danilov, E. A. introduction to the chemistry and technology of chemical and pharmaceutical products [Text] / E. A. Danilov, M. K., Isaikin / Ivanovo: Ed. by G. P. Shaposhnikov, 2002. - 284 S./.

At the same time, the presence of amide groups in the ortho-position relative to the hydroxyl attached to substances other pharmacological properties. It is known that salicylic acid derivatives are used as antipyretic, anti-inflammatory agents and drugs that reduce the adhesiveness of their erythrocytes /Mashkovsky M. D. Medicines. Manual pharmacology for physicians [Text] / M. D. Mashkovsky. - M.: Medicine, 1985. - 620 S./.

Known to produce para-aminophenols recovery of para-nitrosophenol a suitable reducing agent /Weigand K. Methods of experiment in organic chemistry [Text] 2 t So 2 / K. Weigand. ), Izdat. Jn. lit. 1952. - S. 241/.

The disadvantages of aminophenols is their poor solubility and difficulty of excretion of the products of their metabolism, so they are toxic to the liver and kidneys, and cause a violation of the cardiovascular system, nervous system / Harmful substances in the environment. Oxygenated organic compounds. Part II: reference encyclopedia, Ed. by C. And Filova, B. A. Ivin, Y. I. of Musicala. - SPb.: ANO NGO Professional, 2004. -S. 148/.

Para-aminophenols, at the same time containing a benzene ring two arylamine groups in ortho-positions relative to the hydroxyl group, so far not known.

The authors first obtained hexosamine para-aminophenols with arylamine groups in the 2,6-positions relative to the hydroxyl, which were isolated and identified.

Hexosamine para-nitrosophenol with arylamine groups in the 2,6-positions relative to the hydroxyl obtained by the reaction of cyclocondensation /Tovbis M. C. Synthesis of nitrosophenol condensation of isonitroso-β-diketones with ketones [Text] / M. C. Tovbis [and other] // Izv. higher education institutions. Chemistry and chem. technology. - 2005. - T. 48, No. 8. - S. 117-118/ were subjected to restore hydrazinehydrate on palladium catalyst to produce new connections.

The resulting recovery exasan is on para-aminophenols simultaneously contain both aminophenolic fragment:

and double the fragment molecules amides of salicylic acid:

The introduction of amide groups attached to the molecule para-aminophenols advanced properties salicylamide, i.e. significantly modifies the properties of the original aminophenols. The obtained substituted para-aminophenols with arylamine groups in the 2,6-positions relative to the hydroxyl showed high antibacterial activity against E. coli (Escherichia coli, strain ADS 25822 sensitive to antibiotics), S. aureus MSSA (Staphylococcus aureus, strain 209 R sensitive Staphylococcus aureus) and Staphylococcus aureus MRSA (Methicillin-resistant Staphylococcus).

The invention solves the problem of obtaining new para-aminophenols, at the same time containing a benzene ring two arylamine groups in ortho-positions relative to the hydroxyl group.

The technical result consists in obtaining new para-aminophenols, at the same time containing a benzene ring two arylamine groups in ortho-positions relative to the hydroxyl group, which due to the presence of arylamine groups have antibacterial properties.

This technical result is achieved by the fact that hexosamine nitrosophenol obtained by cyclocondensation reaction of isonitroso-β-dicarbonyl compounds with amadamiaamoremio acid, subjected to restore hydrazinehydrate in an alcohol solution of a palladium catalyst to obtain hexosamine of aminophenols.

The authors first obtained hexosamine para-aminophenols with arylamine groups in the 2,6-positions relative to the hydroxyl, which are isolated and identified, the General formula

2,6-Bis (phenylcarbamoyl)-3,5-dimethyl-4-aminophenol

The white crystalline substance with MP.=280°C, soluble in organic solvents, slightly soluble in water. In NMR1H spectrum (DMSO-d6) observed signals metal groups of the benzene ring with him. shift 2,08 M. D., the signals of the protons of the amino group with him. shift 4.39 M. D., the signal of the proton of the hydroxyl group with him. shift 8.12 M. D., the signals of the protons of the phenyl rings in the field 7.08-7.75 M. D., in the area of 10.11 memorial plaques are present, the signals of the protons of the two amino groups.

2,6-Bis [(4-chlorophenyl)carbarnoyl]-3,5-dimethyl-4-aminophenol

The white crystalline substance with MP.=275°C, soluble in organic solvents, slightly soluble in water. In NMR1H spectrum (DMSO-d6) observed signals metal groups of the benzene ring with him. shift 2,04 M. D., the signals of the protons of the amino group with him. shift 4.36 M. D., the signal of the proton of the hydroxyl group with him. shift 8.23 M. D., the signals of the protons of the phenyl rings in the field 7.37-7.5 M. D., in the field 10.27 memorial plaques are present, the signals of the protons of the two amino groups.

2,6-Bis [(4-bromophenyl)carbarnoyl]-3,5-dimethyl-4-aminophenol

The white crystalline substance with MP.=240°C, soluble in organic solvents, slightly soluble in water. In NMR1H spectrum (DMSO-d6) observed the signals of methyl groups of the benzene ring with him. shift 2,04 M. D., the signals of the protons of the amino group with him. shift 4.36 M. D., the signal of the proton of the hydroxyl group with him. shift 8.25 M. D., the signals of the protons of the phenyl rings in the field 7.50-7.69 M. D., in the field 10.29 memorial plaques are present, the signals of the protons of the two amino groups.

2,6-Bis [(4-were)carbarnoyl]-3,5-dimethyl-4-aminophenol

The white crystalline substance with MP.=240°C, soluble in organic solvents, slightly soluble in water. In NMR1H spectrum (DMSO-d6) observed the signals of methyl groups of the benzene ring with him. shift 2,07 M. D., the signals of the protons of methyl groups are in the para position relative to the amino groups are in the area of 2.27 M. D., the signals of the protons of the amino group with him. shift 4.37 M. D., the signal of the proton of the hydroxyl group with him. shift 8.32 M. D., the signals of the protons of the phenyl rings in the sphere 7.12-7.63 M. D., in the field of 10.00 memorial plaques are present, the signals of the protons of the two amino groups.

Getting hexosamine para-aminophenols with arylamine groups in the 2,6 - positions for which the compared to the hydroxyl carry out the following method.

In ethanol dissolve 2,6-bis (arylcarbamoyl)-3,5-dimethyl-4-nitrosophenol. Then add the catalyst, palladium on charcoal, stirred for 30 minutes. After this time poured dropwise hydrazinehydrate (3-6-fold molar excess relative to nitrosophenol). The start of the reaction you will notice if you start to stand out gas bubbles. After all of hydrazine hydrate added another 30 minutes to mix and control the availability of the source nitrosophenol using thin-layer chromatography on Sorbfil plates brand PTSH-AF-(Russia). When the original connection is fully reacted, filtered off the catalyst on the filter, SCHOTT, and the filtrate is evaporated in the evaporator Cup. The final product is precipitated in the form of white crystals. Output 21-53%.

Example 1

The method of obtaining 2,6-bis (phenylcarbamoyl)-3,5-dimethyl-4-aminophenol

In ethanol dissolving 0.14 g (0.0003 mol) of 2,6-bis (phenylcarbamoyl)-3,5-dimethyl-4-nitrosophenol. Then add 0.042 g of palladium on charcoal, stirred for 30 minutes. After this time poured dropwise 0.098 g (0.0019 mol) of hydrazine hydrate is added. After all of hydrazine hydrate added another 30 minutes to mix and control the availability of the source nitrosophenol using thin-layer chromatography on Sorbfil plates brand PTSH-AF-(Russia). is when the original connection is fully reacted, filtered off the catalyst on the filter, SCHOTT, and the filtrate is evaporated in the evaporator Cup. The final product is precipitated in the form of white crystals. The output of 21.6%.

Example 2

The method of obtaining 2,6-bis [(4-chlorophenyl)carbarnoyl]-3,5-dimethyl-4-aminophenol

Analogously to example 1. In ethanol dissolve 0.1 g (0.0002 mol) of 2,6-bis (4-chlorpheniramol)-3,5-dimethyl-4-nitrosophenol. Then add 0.03 g of palladium on charcoal, stirred for 30 minutes. After this time poured dropwise 0.06 g (0.0012 mol) of hydrazine hydrate is added. Yield 38%.

Example 3

The method of obtaining 2,6-bis [(4-bromophenyl)carbarnoyl]-3,5-dimethyl-4-aminophenol

Analogously to example 1. In ethanol dissolve 0.1 g (0.00017 mol) of 2,6-bis (4-brompheniramine)-3,5-dimethyl-4-nitrosophenol. Then add 0.03 g of palladium on charcoal, stirred for 30 minutes. After this time poured dropwise 0.05 g (0.001 mol) of hydrazine hydrate is added. Yield 53%.

Example 4

The method of obtaining 2,6-bis [(4-were)carbarnoyl]-3,5-dimethyl-4-aminophenol

Analogously to example 1. In ethanol dissolve 0.062 g (0.00013 mol) of 2,6-bis (4-methylphenylcarbinol)-3,5-dimethyl-4-nitrosophenol. Then add 0.018 g of palladium on charcoal, stirred for 30 minutes. After this time poured dropwise 0.04 g (0.0008 mol) of hydrazine hydrate is added. Yield 31%.

For the first time obtained 2,6-bis (arylcarbamoyl)-35-dimethyl-4-aminophenol proved their structure by NMR spectroscopy and the detection of antibacterial activity studies of these substances in the laboratory of Microbiology. Assoc. B. M. of Zelmanovich ("Krasnoyarsk state medical University. Professor C. F. Voyno-Yasenetsky"). Determination of antibacterial activity was performed by serial dilution method on the test cultures: E. coli (Escherichia coli, strain ADS 25822 sensitive to antibiotics), S. aureus MSSA (Staphylococcus aureus, strain 209 P sensitive Staphylococcus aureus) and Staphylococcus aureus MRSA (Methicillin - resistant Staphylococcus). A twofold dilution of compounds in a volume of 1 ml was prepared in distilled water. In each tube with the dissolved aminophenol was made 0.1 ml of the suspension of the subjects of the test cultures prepared from 18-hour agar cultures by standard turbidity of 0.5 Mcfarland. The tubes were incubated at 37 degrees Celsius. The sowing was made in 24 hours by sector the bar in a Cup with mesopartner agar. Records of the results produced by the presence and nature of crop growth on a nutrient medium. Initial concentration of the studied persuading para-aminophenols was 5*10-4mol/L. the Data obtained in determining the activity presented in the table below:

SubstanceConcentration, mg/ml, (mol/l)Bacterial growth (+);
from OUTSTA growth (-)
E. coliS. aureus MSSAS. aureus MRSA
2,6-Bis (phenylcarbamoyl)-3,5-dimethyl-4-aminophenol (I)0.187, (5*10-4)(+)(-)(+)
0.093, (2,5*10-4)(+)(+)(+)
0.046, (1,2*10-4)(+)(+)(+)
2,6-Bis [(4-chlorophenyl)carbarnoyl]-3,5-dimethyl-4-aminophenol (II)0.222, (5*10-4)(-)(-)(-)
0.111, (2,5*10-4)(-)(-)(-)
0.055, (1,2*10-4)(+)(-)(+)
2,6-Bis [(4-bromophenyl)carbarnoyl]-3,5-dimethyl-4-aminophenol (III)0.266, (5*10-4)(-)(-)(-)
0.133, (2,5*10-4)(-)(-)(-)
0.066, (1,2*10-4)(+)(-)(+)
2,6-Bis [(4-were)carbarnoyl]-3,5-dimethyl-4-aminophenol (IV)0.202, (5*10-4)(-)(-)(-)
0.101, (2,5*10-4)(+)(-)(-)
0.05, (1,2*10-4)(+)(-)(+)

Thus, it was found that for the first time synthesized peremeshenie para-aminophenols have bacteriostatic action.

Compound I inhibits the growth of S. aureus MSSA at a concentration of 5*10-4mol/L.

Compound II is effective against E. coli at concentrations of 2.5*10-4mol/l - 5*10-4mol/l, also inhibits the growth of S. aureus MSSA at the end is Tralach 1,2*10 -4mol/l - 5*10-4mol/l and shows activity against S. aureus MRSA at concentrations of 2.5*10-4mol/l - 5*10-4mol/L.

Compound III effect on E. coli at concentrations of 2.5*10-4mol/l - 5*10-4mol/l for S. aureus MSSA has an effect at concentrations of 1.2*10-4mol/l - 5*10-4mol/l, and S. aureus MRSA at concentrations of 2.5*10-4mol/l - 5*10-4mol/L.

Compound IV active against E. Coli at a concentration of 5*10-4mol/l, inhibited the growth of S. aureus MSSA and S. aureus MRSA at concentrations similar to II and III compounds.

Hexosamine para-aminophenols with arylamine groups in the 2,6-positions relative to the hydroxyl General formula

where R=C6H5C6H4Cl,C6H4Br, C6H4CH3



 

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9 cl, 11 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to methods of treating cystitis of various origins. Increasing the clinical effectiveness and reducing a probability of recurrences are ensured by administering therapeutically active and gel preparations possessing a high adhesion to urothelium walls. The method involves instilling sodium alginate in the form of Colegel gel containing the therapeutically active preparations dioxidine, lidocaine, deoxyribonucleate, sodium hyaluronate in a therapeutically effective amount with the instillation procedure suggested to be performed according to the schedule specified depending on the cystitis origin. If observing chronic bacterial recurrent cystitis, the following schedule is presented: instillations of Colegel-ADL from the 1st to 10th therapeutic day daily, instillations of Colegel-DNK-L from the 11th to 20th therapeutic day every second day, 2-month instillation of Colegel-Hyal once a week. Treating radiation and interstitial cystitis requires the following therapeutic schedule: instillations of Colegel-ADL from the 1st to 20th day, while Colegel-DNK-L and Colegel-Hyal are instilled once twice a week from the 21st to 56th day alternated every second day. The presented therapeutic schedules using the given therapeutically active preparations enabling relieving pain, reducing a rate and a length of recurrent cystitis.

EFFECT: using these therapeutic schedules is high-efficient and safe.

1 ex

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