Agent having diuretic and anti-inflammatory action

FIELD: biotechnology.

SUBSTANCE: agent is proposed which has diuretic and anti-inflammatory action. It is shown that the sodium salt of 4-carboxyphenyl-O-β-D-glucopyranoside increased the daily diuresis 2 times or more, at that the excretion of sodium and potassium ions is reduced compared to the control; its anti-inflammatory activity is slightly higher than that of nimesulide. Due to the combination of the diuretic effect with anti-inflammatory and antimicrobial activities the agent can be used for the treatment of nephritis, pyelonephritis, cystitis of stagnant phenomena in the systemic and pulmonary circulation due to heart failure.

EFFECT: increased water excretion thus contributing to reduction of swelling.

2 tbl

 

The invention relates to pharmacology, namely a drug with diuretic and anti-inflammatory action and can be used to treat nephritis, pyelonephritis, cystitis, hypertension, diseases, accompanied by the development of edema syndrome, as this substance increases the excretion of water.

Currently, there is a need to develop diuretics, high diuretic and anti-inflammatory activities. This is due to the need for a comprehensive impact on the pathological process in the treatment of diseases of the urinary system, where, along with the diuretic effect requires anti-inflammatory and antimicrobial activity. Of particular interest is the creation of medicines, which has diuretic activity and does not affect the allocation of kidneys ions of sodium, potassium, magnesium.

It is known tool that has diuretic and anti-inflammatory activities such as furosemide, which is used as a selective antagonist of sodium-potassium-glastransporter (Zverev AF, Bryukhanov V.M. Pharmacology and clinical use extrarenal action of diuretics. - M: Medical book, 2000. - 256 S.).

Lack of furosemide is high calibre the practical activity, what in the exchange application causes severe violations of water-salt metabolism in the body in the form of hypokalemia (Bryukhanov V.M., Zverev AF Side effects of modern diuretics: Metabolic and toksikoallergicheskie aspects. - Novosibirsk.: CARES, 2003. - 224 S.).

The closest in the achieved results are the means possessing diuretic and anti-inflammatory actions, namely drug charges, containing in its composition the leaves of bearberry, cranberry, simalube, rhizomes of bergenia tolstolistnogo and other

The main disadvantages of funds of plant origin are inconvenient to use extemporally dosage forms (there is a necessity to prepare daily dosage form), limited term storage of charges, and made from them infusions and decoctions, complex dosing regimen (Kurkin V.A. fundamentals of herbal medicine. - Etching, 2009 - 963 S.).

Object of the invention is the expansion of the means of possessing diuretic and anti-inflammatory effect of synthetic origin.

The problem is solved in that use 4-carboxyphenyl-O-β-D-glucopyranoside sodium salt as a means possessing diuretic and anti-inflammatory actions.

The invention is as follows.

Declare sidstodisable a 4-carboxyphenyl-O-β-D-glucopyranoside sodium salt of the following formula:

The proposed tool was prepared as follows:

Obtaining methyl ester 4-carboxyphenyl-2,3,4,6-tetraacetyl-O-β-D-glucopyranoside:

To a solution of 3.9 g (10 mmol) of β-pentaacetate glucose and 1.52 g (15 mmol) of methyl-4-hydroxybenzoate in 40 ml of dry chloroform pour in a solution of 0.7 ml of triethylamine in 5 ml of dry chloroform. The reaction mass to survive 30 minutes under stirring. Then, under the nitrogen atmosphere contribute to 3.3 ml epirate of boron TRIFLUORIDE. The reaction mass is stirred at room temperature for 12 hours. The chloroform was washed with saturated sodium bicarbonate solution until cessation of gas evolution, water (1×50 ml), 5% sodium hydroxide solution (2×50 ml), water (1×50 ml). Then the chloroform layer is dried with magnesium sulfate. The solvent is distilled off, the oily residue is crystallized from ethanol. Obtain 3.2 g (yield: 66%) of white crystals with a melting point of 156°C.

An NMR spectrum1H (CDCl3), δ, ppm; 2.04, 2.05, 2.07, 2.08 (4×3H, s, och3'); 3.91 (m, H-5' COCH3); 4.14-4.31 (2H, m, H-6'a, H-6'b); 5.13-5.31 (4H, m, H-1', H-2', H-3', H-4'); 7.00 (2H, d, J=9.0 Hz, H-2, H-6); 7.99 (2H, d, H-3, H-5, J=8.7 Hz).

An NMR spectrum13C (CDCl3), δ, ppm; 20.5 (4×CH3, COCH3'); 52.0 (CH3, COCH3), 61.8 (CH2, C6'); 68.0 (CH, C-4'); 70.9 (CH, C-2'); 72.1(CH, C-5'); 72.4 (CH, C-3'); 98.1 (CH, C-1); 116.1 (2×CH, C-2, C-6); 125.0 (C, C-4); 131.5 (2×CH, C-3, C-5); 60.1(C, S-1); 166.3, 169.3, 170.1,170.4 (4×C, COCH3').

Obtaining methyl ester 4-carboxyphenyl-O-β-D-glucopyranoside:

To a suspension of 1.2 g of methyl ester 4-carboxyphenyl-2,3,4,6-tetraacetyl-O-β-D-glucopyranoside in 12 ml of methanol pour in 2 ml of 5% solution of sodium methylate in methanol. The reaction mass is intensively stirred until dissolved and leave at room temperature for 10 hours. Obtain 1.11 g (yield: 93%) of white crystals with a melting point of 170°C.

An NMR spectrum1H (D2O), δ, ppm; 3.49-3.80 (6N, m, H-2', H-3', H-4', H-5', H-6'b, H-6'a); 3.77 (3H, s, COCH3); 5.1 (1H, m, H-1); 7.05 (2H, d, J=8.7 Hz, H-3, H-5); 8.36 (2H, d, H-2, H-6, J=8.7 Hz).

An NMR spectrum,13C (D2O), δ, ppm; 52.3 (CH3, COCH3); 60.2 (CH2, C6'); 69.1 (CH, C-4'); 72.6 (CH, C-2'); 75.4(CH, C-5'), 76,0 (CH, C-3'); 99.2(CH, C-1); 115.8 (2×CH, C-2, C-6); 123.7 (C, C-4); 131.4 (2×CH, C-3, C-5); 160.3 (C, C-1); 169.3 (CO, COCH3).

Obtaining the sodium salt of 4-carboxyphenyl-O-β-D-glucopyranoside:

To 1.07 g (3.3 mmol) of methyl ester 4-carboxyphenyl-O-β-D-glucopyranoside, dissolved in 20 ml of water, add 0.1 to 3 g (3.3 mmol) of sodium hydroxide. The reaction mass is left under stirring at room temperature for 24 hours. Then the water is distilled off to dryness. The resulting residue is dried in a desiccator. Obtain 0.9 g of white crystals (yield: 84%) with a melting point of over 300°C.

JV is KTR NMR 1H (D2O), δ, ppm; 3.42-3.80 (6N, m, H-2', H-3', H-4', H-5', H-6'b, H-6'a); 5.1 (1H, m, H-1); 7.02 (2H, d, J=8.4 Hz, H-3, H-5); 7.74 (2H, d, H-2, H-6,7=8.4 Hz).

An NMR spectrum13C (D2O), δ, ppm; 60.3 (CH2, C6'); 69.2 (CH, C-4'); 72.7 (CH, C-2'); 75.3 (CH, C-5'), 75,9 (CH, C-3'); 99.5 (CH, C-1); 115.5 (2×CH, C-2, C-6); 131.4 (2×CH+C, C-3, C-5+C-4); 158.5 (C, C-1); 174.8 (CO, COCH3).

The NMR spectra of1H,13C were recorded on FTIR spectrometer Bruker Avante-300 (300 MHz) of the company Which (Germany) internal standard HMDS. The melting point was determined on microsegregation table Boetius company Boetius (Germany).

The resulting tool is characterized by the following properties: white crystals. Soluble in water, slightly in alcohol.

Pharmacological action the proposed drug tested by biological research. Activity funds were estimated at 12 laboratory rats-females weighing 200-220 grams.

Example 1

In the beginning of the experiment were determined baseline urine output, as well as the content of sodium and potassium in the urine of experimental animals. The concentration of ions in the urine were determined by flame photometry on the analyzer the FCA-2-01 (Russia). The analyte was injected to rats intragastrically for seven days at a dose of 54 µmol/kg

Daily in experimental animals was measured volume of allocated urine and excretion of ions once in 48 hours.

Table 1 provides a comparative summary of ieraticheskoy and diuretic activity 4-carboxyphenyl-O-β-D-glucopyranoside sodium salt at a dose of 54 µmol/kg

Table 1
The day of introduction of the analyte of interestEsigns of kidney function
Daily diuresisThe excretion of sodiumExcretion of potassium
Control6,38±1,1615,88±6,15328,81±62,14
1 day9,17±1,3is 3.08±0,46* P<0,01269,65±24
day 29,41±1,6
3 dayof 10.75±1,65* P<0,056,0±0,5* P<0,01283,45±35,2
day 410,02±1,8
5 day12,5±2,0* P<0,057,73±1,13* P<0,01308±39,2
day 612,9°±2,36* P&t; 0,05
day 711,1±1,8* P<0,056,38±0,92* P<0,01258,2±26,5
Note. The asterisk is a difference significantly compared to control.

As can be seen from table 1, the introduction of the compounds according to the invention increased daily diuresis 2 or more times compared with the control. Excretion of sodium and potassium ions was decreased compared to control.

Thus, the applied tool has a pronounced diuretic activity and can be used to treat nephritis, pyelonephritis, cystitis and other diseases associated with development of edema syndrome.

Example 2

Acute exudative inflammation induced subplanetary the introduction of 0.1 ml of 1%aqueous solution carragenin. Measurement of the volume of the right hind limb was performed using plethysmometer before the introduction and after 60, 120 and 240 minutes after injection Logistica. Based on the data the average increase of the limbs of animals, obtained from three parallel measurements used to calculate the degree of anti-inflammatory activity. The substance has a pronounced anti-inflammatory activity, if the result exceeded 30%. In the operation of the comparator drug was used nimesulide. The experimental results were processed by the statistical method using student's criterion. The difference compared averages were considered significant if the confidence value (P) was less than 0.05.

Anti-inflammatory activity of 4-carboxyphenyl-O-β-D-glucopyranoside sodium salt at a dose of 54 µmol/kg are presented in table 2.

Table 2
Watch
124
Anti-inflammatory
Naya activity, %
Anti-inflammatory
Naya activity, %
Anti-inflammatory activity, %
4-carboxyphenyl-O-β-D-
glucopyranoside sodium salt
42,865,564,2
Nimesulide40,8147,2761,19

As can be seen from table 2, the compound according to the invention has a pronounced anti-inflammatory activity, which is slightly above the drug is even nimesulide.

Thus, the technical result of the invention is the expansion of the means of possessing diuretic and anti-inflammatory action.

The use of 4-carboxyphenyl-O-β-D-glucopyranoside sodium salt of the formula

as a means possessing diuretic and anti-inflammatory actions.



 

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