RU2416404C1 - Medication possessing diuretic activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is medication, which has diuretic activity. Medication represents 4-chloro-2-((5-iodinefurane)methylamino)-5-sulphamylbenzoic acid (formula

1), has diuretic activity of saluretic group and can be applied for treatment of stagnant phenomena in greater and lesser blood circulation, conditioned by impaired cardiac function.

EFFECT: substance initially increases release of sodium ions from organism and secondly enhances water excretion, thus favouring edema reduction; compound is more active than furosemide by 80%.

1 tbl

Description

The invention relates to pharmacology, in particular to a drug having a diuretic effect of a group of saluretics, and can be used to treat stagnation in the large and small circle of blood circulation caused by heart failure, nephritis, liver cirrhosis with symptoms of portal hypertension, hypertension, symptomatic hypertension , glaucoma and other diseases accompanied by the development of edematous syndrome, since this substance primarily increases the release of sodium ions from the body and toricity enhances the release of water, thereby facilitating the reduction of edema.

Currently, there is a particularly acute need for the development of a more active inhibitor of the cation-chlorine transporter (NKCC), which selectively blocks the NKCC transporter and has high diuretic activity and at the same time low toxicity. Of particular interest is the creation of a drug that has a higher diuretic and saluretic activity than existing diuretics.

A diuretic agent is known, namely ethacrylic acid, which is used as a selective NKCC antagonist.

The disadvantage of ethacrylic acid is its high toxicity, as well as the lack of diuretic action in animals, for example in rats. In addition, ethacrylic acid does not have an injectable dosage form (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 the ability to cause metabolic disorders such as hypokalemia, hypochloremic alkalosis, hyperglycemia, hyperuricemia (Zverev Y.F., Brukhanov 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 fact that 4-chloro-2- (2-furylmethylamine) -5-sulfamylbenzoic acid is used as a diuretic.

Description of the invention

The inventive tool is 4-chloro-2 - ((5-iodofuran) methylamino) -5-sulfamylbenzoic acid of the following formula:

The tool has the characteristic of a chemical structure in which there is an iodine atom instead of hydrogen in the second position of the furan cycle, which is completely different from other sulfamoylanthranilic acid derivatives of the traditionally known selective inhibitors of the NKCC transporter.

The inventive tool is prepared as follows: 0.33 g (1 mmol) of 4-chloro-2- (2-furylmethylamine) -5-sulfamylbenzoic acid is kept in a solution of 0.508 g of I ₂ (2 mmol) in 5 ml of dimethyl sulfaxide for 7 days at room temperature. Plant the reaction product with water, treat with sodium sulfite and filter. 0.4 g of 4-chloro-2 - ((5-iodofuran) methylamino) -5-sulfamylbenzoic acid will be obtained (87% yield).

NMR spectra of the claimed funds:

¹ H NMR (300 MHz, DMSO): δ = 4.59 (s, 1H), 6.33 (s, 1H), 6.62 (s, 1H), 7.04 (s, 1H), 7.34 (s, 2H), 8.38 (s , 1H), 8.61 (s, 1H).

¹³ C NMR (75 MHz, DMSO): δ = 91; 108; 110; 112; 123; 128; 133; 136; 152; 156; 168.

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: crystalline powder with T _PL = 177-178 ° C, with a slight yellowish tint, insoluble in water, chloroform, ether; sparingly soluble in alcohol; soluble in dimethylformamide, dimethyl sulfaxide and acetone.

The pharmacological effect of the claimed drug was checked by biological studies. The activity of the agent was studied in experiments on 24 white male Wistar rats weighing 200-220 g. The value of diuresis and excretion of sodium and potassium ions was determined during the day after the administration of the test substances. The concentration of ions in the urine was determined by flame photometry using a PAJ-3 analyzer (USSR). The studied drugs were administered once subcutaneously in equimolar doses (7 and 5 mg / kg), a dose of 15 micromol / kg in 1 ml of a 0.9% sodium chloride solution. As a control, 1 ml of 0.9% sodium chloride solution was subcutaneously administered to rats. Statistical processing of the obtained results was carried out using Student's criterion. Differences between the compared values were considered significant at P <0.001-0.05. The table shows the comparative characteristics of the diuretic activity of 4-chloro-2 - ((5-iodofuran) methylamino) -5-sulfamylbenzoic acid with furosemide. As can be seen from the table, the introduction of furosemide increased daily diuresis by 3.2 times, the introduction of the compounds according to the invention by 5.7 times compared with the control. The excretion of sodium ions under the influence of furosemide increased 6.1 times, under the influence of the compounds according to the invention 11.7 times compared with the control. The excretion of potassium ions increased 1.9 times compared with the control under the influence of furosemide and 3.3 times compared with the control under the influence of the compounds according to the invention. Thus, comparative studies showed that the compound according to the invention has a greater diuretic and saluretic activity compared to the prototype 1.8 times (80% more active than the prototype).

Thus, the claimed agent has a high diuretic and saluretic activity and is applicable for the treatment of congestion in the large and small circle of blood circulation caused by heart failure, nephritis, liver cirrhosis with symptoms of portal hypertension, hypertension, symptomatic hypertension, glaucoma and other diseases accompanied by the development edematous syndrome, so this substance primarily increases the excretion of sodium ions from the body and secondarily enhances the excretion of water, contributing to m the most reducing edema.

Diuretic Test substances Diuresis, ml / day Excretion of sodium ions, μmol / day Excretion of potassium ions, μmol / day Control 1 ml fiziol. solution Substance administration Control 1 ml fiziol. solution Substance administration Control 1 ml fiziol. solution Substance administration Furosemide 6.29 ± 1.0 20.16 ± 1.5 * P <0.001 166.08 ± 23.12 1015.4 ± 60.2 * P <0.001 448.57 ± 83.1 848.74 ± 34.0 * P <0.001 4-chloro-2 - ((5-iodofuran) methylamino) -5-sulfamylbenzoic acid 4.35 ± 0.6 24.66 ± 1.68 * P <0.001 108.7 ± 27.5 1270.5 ± 71.4 * P <0.001 327.65 ± 26.4 1081.0 ± 54.2 * P <0.001 Note. Asterisk - the difference is significant compared with the control.

Claims (1)

The use of 4-chloro-2 - ((5-iodofuran) methylamino) -5-sulfamylbenzoic acid of the formula

,
as a diuretic.