RU2003655C1 - 4- oxo -4- phenyl -2- (9- fluorenylenehydrazino) -2- butenoic acid methyl ester inhibiting growth of gram-positive microflora - Google Patents

Abstract

Usage: in medicine, as an inhibitory growth of gram-positive microflora SUMMARY OF THE INVENTION: product - 4-oxo-4-phenyl-2- (9-fluorenylene hydrazino) 2-butene acid methyl ester С Н С (0) (СООСН) -NM-N fluorenylene-9, BF C2DDod. yield 63%. mp 133-134 ° C. Reagent 1: 2,4-dioxo-4-phenylbutanoic acid methyl ester Reagent 2 of fluorenone-9 hydrazone. Reaction conditions: in a toluene fed at a temperature of 110 ° C. 1table

Description

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ABOUT

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ABOUT

The invention relates to new biologically active chemical compounds of the class of 4-aryl-4-oxo-2-butenoic acid esters, namely to 4-oxr-4-phenyl-2- (9-fluorenylene hydrazino) -2-butene methyl ester acids of the formula.

SOOSNz

Bcf

b

 NHN

The closest analogues in structure showing antimicrobial activity are methyl esters of 4-aryl- / 2-bromo-2,4-dioxobutanoic acids of the formula 4

,

R-O-C-SNVg-S-SOOCNe h / i,

OO

I

where R is SNCO, F.

It is an object of the invention to provide compounds with a more pronounced antimicrobial effect in the presence of 4-aryl-4-oxo-2-butenoic acid esters.

This goal is achieved by the synthesis of 4-oxo-4-phenyl-2- (9-fluorenileihydrazino) -2-butenoic acid methyl ester exhibiting antimicrobial activity.

The inventive compound is prepared by reacting 2,4-dioxo-4-phenylbutanoic acid methyl ester with an equimolecular amount of hydrazone fluorenone-9 in toluene at a temperature of 109-110 ° C for 2.5 hours, followed by isolation of the target product by known methods.

The reaction proceeds according to the scheme

: -sng-s-coax -v about hvT "

CH, COOCHj. / t

Example 1. 4-oxo-4-phenyl-2- (9-fluorenylenehydrazino} -2-butene acid methyl ester,

A solution of 5.00 g (0.0242 mol) of 2,4-dioxo-4-phenylbutanoic acid methyl ester and 4.70 g (0.0242 mol) of fluorenone-9 hydrazone in 30 ml of toluene was boiled at 110 ° C.

0

5

0

5

0

5

0

5

0

5

with a Dean-Stark nozzle 2.5 hours. After removal of the solvent, the precipitate was recrystallized from hexane. Yield 5.83 g (63%), mp. 133-4 ° C. Found,%: C 75.66; H 4.30; N 7.17

C24H18N203

Calculated,%: C 75.38; H 4.74; N, 7.33.

4-oxo-4-phenyl-2- (9-fluorenylenehydrazino) -2-butenoic acid methyl ester npeACTaeflnef is a yellow-orange substance, highly soluble in chloroform, benzene, acetone, ethanol, insoluble in water.

The IR spectrum of the obtained compound (UR-20, liquid paraffin) contains absorption bands of ester carbonyl (1730), ketone carbonyl (1610) and double bonds and (1560-1575).

In the PMR spectrum of the claimed substance there are proton signals (РЯ-2310, ГМДС, d, ppm): 3.90 (s, 3Н, СНзО), 6.15 (s. 1Н, СН), 7 49 (m. 13H, C6Hs + Ci2Ha); 13.39 (s. 1H.IMH).

The spectral characteristics of 4-oxo-4-phenyl-2- (9-fluorenylenhydhydrazino) -2-butenoic acid methyl ester are consistent with published data for 2-B-amino-4-aryl-4-oxo-2-butenoic acids 1.

4-oxo-4-phenyl-2- (9-fluorenylenehydrazino) -2-butenoic acid methyl ester, inhibiting the growth of gram-positive microflora.

Studies of the biological activity (toxicity and specific action) of the claimed compound were carried out on white mongrel mice weighing 18-20 tons and four strains of microorganisms: Staph.aureus 209-P, Staph, epiderm. 42a, Microc.lyteus 4698, Mocroc.variaus 9341.

The determination of the average lethal dose (Ldbo) was carried out according to method 2 by a single intraperitoneal administration followed by monitoring the behavior and death of animals within 7 days.The antimicrobial effect was revealed by the method of double serial dilutions in accordance with the methodology for studying the antimicrobial effect of drugs ( G.I. Pershin, J971). For the cultivation of bacteria, m sopeptone broth and agar (pH 7.2-7.4) were used. The initial dilution of microbial bodies was prepared according to the optical turbidity standard from daily agar culture. To determine the bacteriostatic effect (1), the microbial load corresponded to 2.5-105 microbial bodies in 1 ml of medium. Microbial suspension was added to prepared dilutions of the preparation in a nutrient medium. The results of the experiments were taken into account after 20 hours of incubation at 37 ° C. Bacteriostatic activity was evaluated by the minimum effective concentration. The maximum tested concentration of the compound was 1000.0 g / ml. The reference standard was phenyl salicylate 3, known in medical practice. An analogue in structure and action.

- methyl esters / J-bromo-aryloxy-

grape acid 1.

Studies performed (see table) showed that 4-oxo-4-phenyl-2- {9-fluorenylenehydrazino) -2-butenoic acid methyl ester exhibited a pronounced bacteriostatic effect on gram-positive microflora. Thus, the claimed compound inhibits the growth of Staphylococcus aureus at a concentration of 1.0 μg / ml, and the structural analogue at a concentration of 62.0 μg / ml, phenyl salicylate - 750.0 μg / ml, thus, the activity of the claimed compound 60 times or more. The same dependence is traced with respect to the effect of the compounds on the micrococcus culture, namely, the test compound inhibits the growth of micrococcus bacteria at a concentration of 0.5 μg / ml, and the standard phenyl

on the table.

salicylate concentration of 62.5, i.e. the activity of the former is 60 times higher.

4-oxo-4-phenyl-2- (9-fluorenylenehydrazino) -2-butenoic acid methyl ester is practically non-toxic, because its LDV with a single intraperitoneal administration exceeds 1000.0 mg / kg of animal body weight.

The research results presented5

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Due to the fact that 4-oxo-4-phenyl-2- (9-fluorenylenehydrazino} -2-butenoic acid methyl ester is practically non-toxic and has a pronounced inhibitory effect on gram-positive microflora in comparison with the structural analogue and reference, it may find application in practical medicine as an antiseptic.

(56) 1. Andreichikov, Yu.S. et al. ZhORKh, 1987, v. 23, no. 7, p. 1534-1543.

2. Pershin G.N. Methods of experimental chemotherapy. M. (1971.

3.Mashkovsky M.D. Medicines, M .; Medicine, t. 2.1986, p. 406.

4. The author's certificate of the USSR No. 650329, cl. C 07 C 69/63, 1977.

Study of the antimicrobial effect of 4-oxo-4-phenyl-2- / 9-fluorenylene hydrazino / -2-butenoic acid methyl ester.

Note - / - / means lack of information on PMD connection

on this strain of the microorganism.