RU2790479C1 - Application of 9-aroyl-8-hydroxy-6-(2-hydroxyalkyl)-2-imino-1-thia-3,6-diazaspiro[4,4]non-8-en-4,7-diones as agents, with antimicrobial activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the use of 9-aroyl-8-hydroxy-6-(2-hydroxyalkyl)-2-imino-1-thia-3,6-diazaspiro[4,4]non-8-en-4,7-diones of the total formulas

,

where R¹=Н, R²=Н, Ar=4-СН₃С₆Н₄; R¹=Me, R²=Н, Ar=Ph; R¹=Н, R²=Ph, Ar=4-BrC₆H₄, as antimicrobial agents.

EFFECT: new compounds that can be used in pharmacology as having antimicrobial activity.

1 cl, 1 tbl, 4 ex

Description

The invention relates to the field of organic chemistry, namely the use of individual compounds of the class 1-thia-3,6-diazaspiro[4,4]non-8-ene-4,7-diones as agents with antimicrobial activity, which can be used as initial products for the synthesis of new heterocyclic systems and in pharmacology.

Claimed compounds 9-aroyl-8-hydroxy-6-(2-hydroxyalkyl)-2-imino-1-thia-3,6-diazaspiro[4,4]non-8-ene-4,7-diones and their method synthesis known from the prior art. The claimed compounds are products of the interaction of 8-aroyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,6,7-triones with substituted thioureas (Facile regiodivergent synthesis of spiro pyrrole- substituted pseudothiohydantoins and thiohydantoins via reaction of [e]-fused 1H-pyrrole-2,3-diones with thiourea Kobelev A.I., Tretyakov N.A., Stepanova E.E., Dmitriev M.V., Rubin M., Maslivets A.N. Beilstein JOC, 2019, 15, 2864 2871. doi: 10.3762/bjoc.15.280), formed as follows:

The antimicrobial activity of 9-aroyl-8-hydroxy-6-(2-hydroxyalkyl)-2-imino-1-thia-3,6-diazaspiro[4,4]non-8-ene-4,7-diones has not been previously reported. researched.

The objective of the invention is to find new compounds with antimicrobial activity, and to expand the arsenal of means of influencing a living organism.

The problem is solved in that the compounds 9-aroyl-8-hydroxy-6-(2-hydroxyalkyl)-2-imino-1-thia-3,6-diazaspiro[4,4]non-8-en-4,7 -diones exhibit high antimicrobial activity at a concentration of 250-1000 µg/ml.

The claimed compounds are synthesized by reacting 8-aroyl-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,6,7-triones with substituted thioureas in a solvent medium, followed by isolation of target products , according to the following scheme:

The process is carried out at room temperature (20-25°C), and anhydrous ethyl acetate is used as a solvent.

The invention is illustrated by the following examples.

Example 1 8-Hydroxy-6-(2-hydroxyethyl)-2-imino-9-(4-methylbenzoyl)-1-thia-3,6-diazaspiro[4.4]non-8-ene-4.7 -dione (6a).

1.04 mmol thiourea, stirred at room temperature, after 12 h the precipitate was filtered off. Yield 75%, m.p. 196-198°C (ethyl acetate).

Compound (6a) C ₁₆ H ₁₅ N ₃ O ₅ S.

Found, %: С 53.56; H 3.84; N 11.31

Calculated, %: С 53.18; H 4.18; N 11.63.

Compound (6a) is a light yellow crystalline substance, readily soluble in DMSO and DMF, sparingly soluble in less polar organic solvents, and insoluble in water and alkanes. Stable when stored under normal conditions,

In the IR spectrum of compound (6a), recorded as a paste in vaseline oil, there are bands of stretching vibrations of NH groups in the form of a broad peak at 3573 cm ^-1 , alcohol group OH in the form of a broad peak at 3502 cm ^-1 , enol group OH in the form a broad band at 3139 cm ^-1 , two lactam carbonyl groups at 1759 cm ^-1 and 1709 cm ^-1 respectively, and an aroyl carbonyl group at 1614 cm ^-1 .

In the ^1H NMR spectrum of compound (6a), recorded in a solution in DMSO-d ₆ , in addition to the signals of the aromatic ring protons, there is a singlet of the methyl group of the aroyl fragment at 2.37 ppm, a group of 4 methylene protons of the ethoxy substituent at 3.07-3, 15 ppm (m, 1 H), 3.31-3.38 ppm (m, 1H), 3.47-3.62 ppm, (m, 2H), respectively, the broadened singlet of the proton of the OH ethoxy group at 3.89 ppm. and proton singlets of two NH groups of the thiazole fragment at 9.14 ppm. and 9.37 p.m.

Example 2 9-Benzoyl-8-hydroxy-6-(2-hydroxypropyl)-2-imino-1-thia-3,6-diazaspiro[4,4]non-8-en-4,7-dione (6b ).

0.761 mmol thiourea, stirred at room temperature, after 12 h the precipitate was filtered off. Yield 74%, m.p. 239-241°C (ethyl acetate).

Compound (66) C ₁₆ H ₁₅ N ₃ O ₅ S.

Found., %: С 53.50; H 3.89; N 11.37

Calculated, %: С 53.18; H 4.18; N 11.63.

Compound (6b) is a light yellow crystalline substance, readily soluble in DMSO and DMF, sparingly soluble in less polar organic solvents, and insoluble in water and alkanes. Stable when stored under normal conditions,

In the IR spectrum of compound (6b), recorded as a paste in vaseline oil, there are bands of stretching vibrations of the alcohol group OH in the form of a broad peak at 3544 cm ^-1 , the enol group OH in the form of a wide band at 3155 cm ^-1 , two lactam carbonyl groups at 1.763 cm ^-1 and 1712 cm ^-1 respectively, and an aroyl carbonyl group at 1.615 cm ^-1 .

In the ^1H NMR spectrum of compound (6b), recorded in a solution in DMSO-d ₆ , in addition to signals from the protons of the aromatic ring, there is a doublet of the methyl group of the hydroxypropyl fragment at 1.05 ppm, two doublets of the methylene group of the hydroxypropyl substituent at 2.86 ppm . and 3.23 ppm, a multiplet of the methine group of the hydroxypropyl substituent at 4.07-4.15 ppm, a broadened singlet of the proton of the OH hydroxypropyl group at 4.47 ppm. and proton singlets of two NH groups of the thiazole fragment at 9.09 ppm. and 9.33 p.m.

Example 3 9-(4-Bromobenzoyl)-8-hydroxy-6-(2-hydroxyethyl)-3-phenyl-2-(phenylimino)-1-thia-3,6-diazaspiro[4,4]non-8 -en-4,7-dione (6c).

0.491 mmol N,N-diphenylthiourea, stirred at room temperature, after 12 h the precipitate was filtered off. Yield 86%, m.p. 180-182°C (ethyl acetate).

Compound (6c) C ₂₇ H ₂₀ BrN ₃ O ₅ S.

Found, %: С 56.43; H 3.19; N 6.87

Calculated, %: С 56.06; H 3.49; N 7.26.

Compound (6c) is a light yellow crystalline substance, readily soluble in DMSO and DMF, sparingly soluble in less polar organic solvents, and insoluble in water and alkanes. Stable under normal storage conditions.

In the IR spectrum of compound (6c), recorded as a paste in vaseline oil, there are bands of stretching vibrations of the alcohol group OH in the form of a broad peak at 3501 cm ^-1 , the enol group OH in the form of a wide band at 3059 cm ^-1 , two lactam carbonyl groups at 1722 cm ^-1 and 1716 cm ^-1 respectively, the imino group C=N at 1651 cm ^-1 and the aroyl carbonyl group at 1634 cm ^-1 .

In the ^1H NMR spectrum of compound (6c), recorded in a solution in DMSO-d ₆ , in addition to the signals of the aromatic ring protons, there is a group of 4 methylene protons of the ethoxy substituent at 3.52-3.60 ppm. (m, 2H), 3.62-3.71 ppm (m, 2H), respectively, and the broadened singlet of the proton of the OH ethoxy group at 6.05 ppm.

Example 4. Pharmacological study of compounds (6a-c) for the presence of antimicrobial activity.

For research, the generally accepted method of two-fold serial dilutions in a liquid nutrient medium by the micromethod was used [Guidelines for the experimental (preclinical) study of new pharmacological substances - M.: I-vo Medicine, 2005]. Initial dilutions of microorganisms in physiological saline were prepared from daily agar culture according to the optical turbidity standard (OCO) for 5 ME using a densitometer. After a series of dilutions, the final concentration of cells in the experiment was 2.5×10 ⁵ cells/ml.

The antimicrobial properties of the chemical were studied on 3 collection opportunistic strains of microorganisms: Staphylococcus aureus (strain 906), Escherichia coli (strain 1257), Candida albicans (RKPGY 1353/1277), obtained at the Scientific Center for Expertise of Medicinal Products Ministry of Health and Social Development of Russia. The fact of inhibition (inhibition of growth) of microbial cells in the dilutions of preparations was noted after 20 hours of thermostating at 37°C. The final results were recorded 7 days after inoculation on RPA agar slant. The maximum tested concentration of the compounds corresponded to 1000.0 μg/ml. Antimicrobial (inhibitory, bactericidal) activity was evaluated by the minimum effective concentration.

Analysis of the obtained data showed;

• compound 6a has an inhibitory effect on the culture of C. albicans at a concentration of 500.0 µg/ml, death occurs from a concentration of 1000.0 µg/ml;

• Compound 6b has an inhibitory effect on cultures of S. aureus at a concentration of 1000.0 µg/ml and C. albicans at a concentration of 500.0 µg/ml;

•; compound 6c has antimicrobial activity against S. aureus culture; inhibitory effect at a concentration of 1000.0 µg/ml;

Proposed Substances c) have pharmacological activity, namely antimicrobial activity, and can be used in pharmacology as potential drugs.

Claims (4)

Application of 9-aroyl-8-hydroxy-6-(2-hydroxyalkyl)-2-imino-1-thia-3,6-diazaspiro[4,4]non-8-en-4,7-diones of the general formula

, where R ¹ =H, R ² =H, Ar=4-CH ₃ C ₆ H ₄ (a); R ¹ =Me, R ² =H, Ar=Ph (b); R ¹ \u003d H, R ² \u003d Ph, Ar \u003d 4-BrC ₆ H ₄ (c), as agents with antimicrobial activity.