RU2484826C1 - Diuretic agent - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a diuretic of the aquaretic group that is 4-nitro-phenyl-O-D-glucopyranoside. The agent may be used both to treat greater and lesser circulation congestions caused by cardiac failure, and to intensify water release thereby helping to reduce oedemas. The diuretic agent has high and low saluretic activity unlike the existing diuretics and expands the range of products of synthetic origin possessing diuretic activity.

EFFECT: agent is applicable for treating a number of cardiovascular diseases accompanied by excessive hydration and developing oedema syndrome.

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Description

The invention relates to pharmacology, in particular to a medicinal product having the diuretic effect of a group of watercolourists, and can be used to treat nephritis, pyelonephrotic, cystitis, hypertension, symptomatic hypertension, diseases accompanied by the development of edematous syndrome, since this substance enhances the secretion of water by the body , thereby contributing to the reduction of edema.

Currently, there is a particularly acute need for the development of diuretics with high diuretic activity and low toxicity. Of particular interest is the creation of a drug that is diuretic and does not affect the excretion of sodium, potassium, and magnesium ions by the kidneys.

A diuretic agent is known, namely ethacrylic acid, which is used as a selective sodium-potassium chlorotransporter antagonist (NKCC).

The disadvantage of ethacrylic acid is its high toxicity, as well as the lack of diuretic effects in animals, for example, in rats (Brukhanov V.M., Zverev Y.F. Side effects of modern diuretics: Metabolic and toxic-allergic aspects - Novosibirsk .: CERIS, 2003 . - 224 p.).

The closest to the achieved result is a drug with a diuretic effect, namely furosemide.

The disadvantage of furosemide is primarily saluretic activity. Like all loop diuretics, furosemide inhibits reabsorption in the renal tubules of sodium, potassium, and chloride. In addition, furosemide causes metabolic disorders such as hypokalemia, hypochloremic alkalosis, hyperglycemia, hyperuricemia (Zverev Y.F., Bruchanov V.M. Pharmacology and clinical use of the extrarenal action of diuretics - M .: Medical book, 2000. - 256 p.) .

The technical result of the proposed drug is to expand the arsenal of drugs with diuretic activity of synthetic origin.

The technical result is achieved by the use of 4-nitro-phenyl-O-D-glucopyranoside as a means having a diuretic effect.

Description of the invention

The inventive tool is a 4-nitro-phenyl-O-O-glucopyranoside of the following formula:

The glycoside was obtained using acetobromoglucose in aqueous acetone. The structure was proved by NMR. The acyl protection was removed with sodium methylate. Preparative yield: 10.3%.

The inventive tool is prepared as follows: To 0.0012 mol (20% excess with respect to p-nitrophenol) of acetobromoglucose dissolved in 5 ml of acetone. Then add 0.001 mol of p-nitrophenol and an equimolar amount of 1.1 N. Maon. Leave the reaction mass for 24 hours at room temperature. Then acetone is distilled off under vacuum. The extraction is carried out with CHCl ₃ (3 × 20 ml), washed with 20 ml of 1.1 N. alkalis. The chloroform solution is dried over calcium chloride. After which chloroform is distilled off. The oily residue is crystallized from ethyl alcohol. Crystals of 4-nitrophenyl-2,3,4,6-tetra-O-β-acetyl-D-glucopyranoside are filtered off.

To a suspension containing 2 g of 4-nitrophenyl-2,3,4,6-tetra-D-β-acetyl-D-glucopyranoside in 5 ml of absolute methanol, add 0.5 ml of 2 N. solution of sodium methylate, the mixture is shaken until the precipitate is completely dissolved, then left at 5 (for 18 hours. After 15-20 minutes, evolution is observed. The solvent is distilled off, the residue is recrystallized from methanol. Yield: 16%.

NMR spectra of the claimed funds:

¹ H NMR spectrum (D ₂ O), δ, ppm: 3.42-3.70 (5Н, m, Н-2 ', Н-3', Н-4 ', Н-5', Н-6'b ); 3.84 (1H, d, H-6'a, J = 12.0 Hz); 5.1 (1H, m, H-1 '); 7.13 (2H, d, J = 8.1 Hz, H-2, H-6); 8.14 (2H, d, H-3, H-5, J = 8.4 Hz).

¹³ C NMR spectrum, (D ₂ O), δ, ppm: 60.4 (CH ₂ , C6 '); 69.3 (CH, C-4 '); 72.7 (CH, C-2 '); 75.5 (CH, C-5 '), 76.2 (CH, C-3'); 99.4 (CH, C-1 '); 116.4 (2 × CH, C-2, C-6); 126.0 (2 × CH, C-3, C-5); 142.42 (s, s-4); 161.7 (C, C-1).

¹ H, ¹³ C NMR spectra were recorded on a Brucker Avante-300 Fourier spectrometer (300 MHz) from Bruker (Germany), the internal standard was HMDS, and deuterated acetone was used as a solvent. Melting points were determined on a Boetius microheating table from Boetius (Germany).

The resulting tool is characterized by the following properties:

white crystals. Soluble in water, alcohol, chloroform.

The pharmacological effect of the claimed drug was checked by biological studies. The activity of the agent was evaluated on 12 laboratory female rats weighing 200-220 grams. At the beginning of the experiment, baseline diuresis parameters were determined, as well as the sodium and potassium content in the urine of experimental animals. The concentration of ions in the urine was determined by flame photometry using an FPA-2-01 analyzer (Russia). The test substances were administered to rats intragastrically for seven days at a dose of 54 μmol / kg. The volume of urine excreted was measured daily in experimental animals. The results of experimental studies were processed statistically using the Mann-Whitney test. The difference of the compared means was considered reliable if the confidence indicator (P) was less than 0.05.

The table provides a comparative description of the diuretic activity of 4-nitro-phenyl-O-D-glucopyranoside. Diuretic activity of 4-nitro-phenyl-O-D-glucopyranoside at a dose of 54 μmol / kg.

As can be seen from table 1, the introduction of the compounds according to the invention increased daily diuresis by 1.5 or more times compared with the control. Excretion of sodium and potassium ions under the influence of the compounds according to the invention decreased significantly starting from the 3rd day of the experiment.

Thus, the claimed agent has a pronounced diuretic activity and is applicable for the treatment of congestion in the large and small circle of blood circulation caused by heart failure, nephritis, cirrhosis with symptoms of portal hypertension, hypertension, symptomatic hypertension, glaucoma and other diseases accompanied by the development of edema syndrome .

Table 1. Diuretic Test substance administration day Kidney Function Daily diuresis Sodium excretion Potassium excretion The control 2.42 ± 0.33 29.71 ± 9.66 451.41 ± 45.27 1 day 3.93 ± 0.53 * 33.33 ± 10.44 618.33 ± 69.25 P <0.05 P <0.05 2 day 4.38 ± 0.54 * P <0.01 ---- ---- 3 day 4.34 ± 0.55 * 9.49 ± 1.59 321.67 ± 41.14 * P <0.01 P <0.05 P <0.05 4 day 4.44 ± 0.51 * P <0.01 ---- ---- 5 day 3.84 ± 0.71 9.19 ± 2.00 * 315.53 ± 49.54 * P <0.05 P <0.05 6 day 3.76 ± 0.70 ---- ---- 7 day 5.17 ± 0.68 * 7.96 ± 0.83 398.99 ± 33.68 P <0.01 P <0.05 Note. Asterisk - the difference is significant compared with the control.

Claims (1)

The use of 4-nitro-phenyl-OD-glucopyranoside formula

as a diuretic.