Substance possessing antioxidant, geroprotecting and anti-ischemic activity and method for its preparing

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutically acceptable salts of 2,4,6-trimethyl-2-hydroxypyridine with lower dicarboxylic acids of the general formulae (1-a-d): possessing an antioxidant activity wherein X means a simple bond (compound 1a), oxalate, C8H11NO x C2H2O4; X means -CH2 (compound 1b), malonate, C8H11NO x C3H4O4; X means -CH2-CH2 (compound 1c), succinate, C8H11NO x C4H6O4); X means the group -CH2CH(OH) (compound 1d), malate, C8H11NO x C4H6O5. Also, invention relates to a pharmaceutical composition of salt of the formula (1c) possessing geroprotecting and anti-ischemic activities, and to a method for preparing these salts.

EFFECT: improved preparing method, valuable medicinal properties of substances and pharmaceutical composition.

3 cl, 5 tbl, 6 ex

 

The invention relates to medicine, namely to new biologically active compounds, particularly salts of 2,4,6-trimethyl-3-hydroxypyridine with lower dicarboxylic acids (compounds of General formula 1 compounds a-g)with antioxidant, geroprotective and anti-ischemic effect. Connection "a-g" exhibit antioxidant activity in the process of lipid peroxidation, which is characteristic of all derivatives of 3-oksipiridina. This property suggests that connection, "g", as their counterparts, emoxipin (hydrochloride of 2-methyl-6-ethyl-3-hydroxypyridine) and Mexidol (succinate 2-methyl-6-ethyl-3-hydroxypyridine), can be used as therapeutic agents in ophthalmology, namely when subconjunctivally and intraocular hemorrhages in all departments and tissues of the eyes, angioretinopathia of various etiologies, including diabetes, chorioretinal dystrophy, thrombosis Central retinal vein and its branches, complicated myopia, degenerative keratitis, to protect and treatment of the cornea and the retina when exposed to high efficiency light, after operations with retinal detachment. In addition, the presence of connection "in" explicit anti-ischemic action suggests the possibility of application in cardiology for the treatment of coronary heart disease and atherosclerosis is.

Connectivity has also been active inhibitor-induced lipid peroxidation, sensitised "aging pigment" - lipofuscinosis granules isolated from the eyes of older people. This suggests that this compound capable of neutralizing the toxic activity lipofuscin granules that accumulate in old age, i.e. to show geroprotective action. From this we can assume that the connection is "in" can be used to inactivate the toxic effects of lipofuscin. Lipofuscin, as it is now generally accepted, is a major factor leading to the development of senile macular degeneration of retina. Senile macular retinal degeneration is the most common eye diseases developing in people over the age of 60 years. According to statistics, the disease of the retina, leading to complete blindness, affects almost 30% of Americans over the age of 65 years and the percentage of cases increases rapidly with age.

It is known tool antioxidant protection environments and tissues of the eye, which is a biorastvorimy polymer with hydrophilic plasticizing additive and contains as a drug emoxipin and pyridoxine hydrochloride (EN 2070010, 1993).

Known biologically AK is active food Supplement "glutamine", with including geroprotective effect, which as the active substance contains a salt of 2-(2,6-dimethyl-3,5-dietoksikarbonil-1,4-dihydropyridines-4-carboxamido) glutaric acid (RU 95116403, 1995).

Know the use of Pikalevo salt of N-(3-chloro-1,4-naphtohinone)-2-glutamic acid as a substance exhibiting including anti-ischemic activity.

The closest analogue to the invention is succinate 2-methyl-6-ethyl-3-hydroxypyridine (Mexidol) (Medmaravis, "Drugs", part II, 1993, M.: Medicine, s)with antioxidant and lipoic effect, which is obtained by heating an alcoholic solution of 2-methyl-6-ethyl-3-hydroxypyridine with succinic acid for 1 h (A.S. USSR 509047, 1973).

The objective of the invention is the development and creation of new substances, derivatives of 3-hydroxypyridine series, exhibiting antioxidant, geroprotective and anti-ischemic properties and do not show irritation of the eye tissue.

The invention achieves new compounds, pharmaceutically acceptable salts of 2,4,6-trimethyl-3-hydroxypyridine with lower dicarboxylic acids, of General formula 1a-g with antioxidant activity:

when X is equal to the simple relation (compound Ia, oxalate,9H11NO·C2H2About4);

when X is equal to CH2(compound IB, malonate,9H11NO·C3H4O4);

when X is equal to CH2CH2(compound IB, succinate, C9H11NO·C4H6O4);

when X is equal to the group of CH2CH(OH),

connection 1 g, malate,9H11NO·C4H6O5)

In addition, pharmaceutically acceptable salt of formula 1B has also geroprotective and anti-ischemic activity.

The objective of the invention is also solved by a method of obtaining salts of 2,4,6-trimethyl-3-hydroxypyridine with antioxidant, geroprotective and anti-ischemic activities, which includes the interaction equimolecular quantities of 2,4,6-trimethyl-3-hydroxypyridine with a dicarboxylic acid in a solution of lower alcohol boiling with subsequent treatment of the reaction mixture with an organic solvent and, if necessary, the shutter speed for 2-5 h at 10-15°C.

Example 1. Obtaining organic salts of 2,4,6-trimethyl-3-oksipiridina

A) Obtaining oxalate 2,4,6-trimethyl-3-oksipiridina (Ia).

In a flask with a magnetic stirrer and reflux condenser load 0.8 g (0.00583 mol) of 2,4,6-trimethyl-3-oksipiridina, 0.525 g (mol) of anhydrous oxalic acid and 10 ml of methanol. When operating the stirrer, the reaction mixture is heated to boiling and boiled for 0.5 hour. Then stop heating, the solvent is distilled off in a vacuum, added to the reaction mass 5 ml of acetone, pound for 5-10 min with a glass rod. The resulting crystalline precipitate was separated by filtration, washed on the filter with acetone, dried in vacuum. Obtain 1.1 g (83% of theory) of the salt. So pl. 140-142°C. Found, %: 53.4, N 5.9. Calculated, %: 52.9, N 5.8. NMR1H Bruker WM-400 (400 MHz) (DMSO-d6): of 2.20 (3H, s, CH3); of 2.34 (3H, s, CH3); is 2.37 (3H, s, CH3); 7,05 ppm (1H, s, CH).

B). Getting malonate 2,4,6-trimethyl-3-oksipiridina (IB).

In a flask with a magnetic stirrer and reflux condenser load 0.8 g (0.00583 mol) of 2,4,6-trimethyl-3-oksipiridina, 0.607 g (0.00583 mol) of malonic acid and 10 ml of ethanol. When operating the stirrer, the reaction mixture is heated to boiling and boiled for 0.5 hour. Then stop heating, the solvent is distilled off in a vacuum, added to the reaction mass 5 ml of acetone, incubated 3 hours at 10-15°C. the precipitate pound, separated by filtration, washed on the filter with acetone, dried in vacuum. Obtain 1.2 g (85.3% of theory) of the salt. So pl. 118-120°C. Found, %: 55.0, N 6.5. Calculated, %: 54.8, N. 6.3. NMR1H Bruker WM-400 (400 MHz) (DMSO-d6): of 2.16 (3H, s, CH3); is 2.30 (3H, s, CH3); of 2.33 (3H, s, CH32); 6,93 ppm (1H, s, CH).

C) Obtaining succinate 2,4,6-trimethyl-3-oksipiridina (Ie).

In a flask with a magnetic stirrer and reflux condenser load 3.4 g (0.025 mol) of 2,4,6-trimethyl-3-oksipiridina, 2.93 g (0.025 mol) of succinic acid and 50 ml of isopropanol. When operating the stirrer, the reaction mixture is heated to boiling and boiled for 0.5 hour. Then the heating is stopped and gradually add to the reaction mass 30 ml of acetone, incubated 3 hours at 10-15°C. the Formed precipitate was separated by filtration, washed on the filter with acetone, dried in vacuum. Obtain 5.6 g (88.5% of theory) of the salt. So pl. 128-129°C. Found, %: 56.5, N. 6.9. Calculated, %: 56.5, N 6.7. NMR1H (DMSO-d6): 2.12 (3H, s, CH3), 2.26 (3H, s, CH3), 2.31 (3H, s, CH3), 2.42 (4H, s, CH3), 6.79 (1H, s, CH-PY), 10.57 (USS, COOH).

G) Receiving malate 2,4,6-trimethyl-3-oksipiridina (g).

In a flask with a magnetic stirrer and reflux condenser load 0.8 g (0.00583 mol) of 2,4,6-trimethyl-3-oksipiridina, 0.782 g (0.00583 mol) of malic acid and 10 ml of methanol. When operating the stirrer, the reaction mixture is heated to boiling and boiled for 0.5 hour. Then the solvent is removed in vacuum. The oily residue is washed twice with acetone under stirring, the solvent is removed by decantation. The resulting mass is vacuum and incubated for cha is and at a residual pressure of 0.5 mm Hg, then left for crystallization at 48-72 hours Receive a white solid connection with TPL-75°C. the Yield 1.12 g (70.8% of theoretical). Found, %: 53.5, N 6.4. Calculated: 53.1. N 6.3. NMR1H Bruker WM-400 (400 MHz) (DMSO-d6): 2,12 (3H, s, CH3); and 2.26 (3H, s, CH3); is 2.30 (3H, s, CH3); the 3.11 (2H, s, CH3); to 2.41 (1H, doublet duplicates. J2HAHB=15.7 Hz; J3HACH=5.4 Hz, CHAHB); of 2.58 (1H, doublet duplicates. J2HAHB=15.7 Hz; J3HACH=7,4 Hz, CHAHB); to 4.2 ppm (1H, doublet duplicates. J3CHHA=5,4 Hz; J3CHHB=7,4 (1H, s, CH-PY).

Example 2. Geroprotective effect of compound 1 on the example of inhibition of photoinduced lipofuscinosis granules person peroxidation of liposomes.

Liposomes were prepared from methanolic solution of cardiolipin (initial concentration 5 mg/ml) by evaporation of methanol and solubilization of cardiolipin in phosphate buffer. A mixture containing a suspension of liposomes and lipofuscin granules isolated from tissue of the retinal pigment epithelium of the human eye, was subjected to irradiation of an intense blue light with constant stirring. After 20, 40, 60 and 90 min were determined concentration of products of lipid peroxidation (TBA-active products). Experienced sample contained either 2 mm solution of compound "b"or 2 mm solution of Mexidol. The results of the EC is periment are shown in table 1.

Table 1

The inhibitory activity of the compounds (in comparison with Mexidol) - induced lipofuscin photoperoxidation cardiolipin
The exposure time, minThe concentration of TBA-active products, nmol/mg lipidInhibition, %
ControlConnection "in"MexidolConnection "in"Mexidol
01,831.831,8300
203,02,422,84205
403,52,533,5280
60to 4.522,854,5400
905,383,285,0407

The results suggest a protective effect of the compounds in relation to the phototoxic action of senile pigment - lipofuscin granules of the human eye. Mexidol in these conditions practically had no inhibitory effect.

Example 3. Antioxidant effect is soedineniya 1-induced ascorbate the peroxidation of photoreceptor cells of the eye of a pig.

The outer segments of the photoreceptor cells were obtained from retinas of the pig according to standard methods, using the methods of differential centrifugation in density gradient of sucrose. A mixture containing sodium phosphate buffer (pH 7.3), 108segments/ml outer segments of photoreceptor cells, 0.5 mm ascorbic acid and 17 mm of compound 1B, incubated in the dark with constant stirring for 15 and 30 minutes. Then the process was stopped 15% trichloroacetic acid and determined the concentration of TBA-active products. Served as control samples without added compounds. The results obtained are presented in table 2A.

Table 2A

The inhibitory activity of the compounds "in" on escortinbrisbane the peroxidation outer segments of photoreceptor cells.
Reaction time, minThe concentration of TBA-active products, regards. unitsInhibition, %
controlConnection "in"
011-
154,372,7049,6
30? 7.04 baby mortality5,0932,3

Comparison of the Academy of Sciences of Occidental compounds "a", "b", "C" and "d" are shown in table 2B. In these experiments compared the speed escortinbrisbane peroxidation outer segments of photoreceptor cells of the eye of the pig, as measured by the accumulation of TBA-active products, in the presence of different salts of the compounds I.

Table 2B

Comparison of the inhibitory effect of compounds of "a", "b", "C", "g" escortinbrisbane the peroxidation of the outer segments of the photo-receptor cells.
Compound I concentration in mmThe rate of accumulation of TBA-active products within 30 min of reaction, nmol/mgInhibition, %
Control, 0 mm0,77-
Connection "a", 44 mm0100
Connection "b", 44 mm0,2370
Connectivity", 43 mm0,0593,5
Connection "g", 43 mm0,187

The results indicate that all salts of the compounds I are pronounced antioxidant activity against the dark peroxidation photoreceptor cells of the eye.

Example 4. Determination of antiradical activity of compound 1B in comparison with Mexidol.

7.

Measuring the intensity of chemiluminescence (CHL) was performed on the installation SNK-7 designed and manufactured in chemical physics Russian Academy of Sciences of the USSR. As the light receiver used a photomultiplier tube PMT-38. The steady state concentration of radicals in the oxidation of cumene was provided by the initiator azo-bis-isobutyronitrile.

To enhance the glow of the PI used the activator Eu chelate (tretinoin triptorelin europium with 1,10-penetralia), which allowed measurements at low speeds initiating radicals (W1=10-8·10-9mol/L.S) and, consequently, small supplements of the drug. A portion of the samples was dissolved in a suitable solvent (chlorobenzene or acetonitrile), and then a small amount of the prepared solution (0.1-0.25 ml) was injected into the reaction mixture (5-6 ml), placed in a thermostatted reaction vessel holdem-install, and register the change in light intensity. The results are shown in table 3.

Table 3

Antiradical activity R-auxiproizvodnykh nitrogenous heterocycles relatively peroxy radicals ethylbenzene
ConnectionK7×10-4l/mol ×
Mexidol4,5
Compound IB9,5

Comparative evaluation of antiradical activity of compounds 1 and Mexidol has shown that first manifests in two times higher antiradical activity.

Example 5. The study of the influence of connection "in" on the sizes of the areas of ischemic necrosis in acute myocardial ischemia.

Experiments put on nonlinear albino male rats weighing 250-300 g, anesthetized with atenalol sodium (40 mg/kg intraperitoneally). In animals, translated into controlled breath, simulated myocardial infarction by ligation of the descending branch of the left coronary artery at the level of the lower edge of the atrial appendage.

The size of the zone of necrosis and ischemia was determined 4 hours after occlusion of a coronary artery differential display method, the principle of which is based on the separate quantification of Evans blue (indicator of ischemia) and red formazan (indicator necrosis).

Table 4

Anti-ischemic activity of the compounds in comparison with other derivatives of 3-oksipiridina (4 hours after occlusion of a coronary artery in rats).

Conditions of experienceDose, mg/kgThe number of animalsRel is the solution of the necrosis to the total mass of the myocardium (%) The ratio of the area of necrosis of the ischemic area (%)
Control-1722±2.068±4.3
Connection 11674±2.311±3.3
The emoxipin2689±2.432±4.6
Mexidol2688±1.446±5.6
Nicorandil12810±1.642±5.4

It is seen that the connection "b" shows a significantly higher anti-ischemic activity compared to other 3-oxypyridine.

Example 6. Research local irritant compounds "in" on the eye tissue.

Experimental studies were performed on six rabbits. All animals once produced instillation of a 1% solution of compound 1 in the right eye and 1% solution of emoxipin in the left eye. After 1 minute after instillation of the drops was performed inspection of the anterior segment of the eye by the method of the focal light with a magnifying glass in D. The results showed that:

On the right eyes of animals reaction of the conjunctiva of the eyelids and the eyeball cornea is not found.

On the left eyes of 4 animals nablyudalas is marked conjunctival injection eyeball and hyperemia of the conjunctiva of the lower eyelid, the other two animals had moderate conjunctival injection eye.

The results thus show that the claimed compound I possesses antioxidant, geroprotective and anti-ischemic activity and do not show local irritating action on the tissues of the eye.

Comparative evaluation of antioxidant, antiradical geroprotective and anti-ischemic properties of the compound and is widely used in clinical practice, drugs of Mexidol and emoxipin demonstrates the greater effectiveness and lower toxicity of the proposed product, and also about the prospects of its application in ophthalmology and cardiology practice, and other areas of medicine.

1. Pharmaceutically acceptable salts of 2,4,6-trimethyl-3-hydroxypyridine with lower dicarboxylic acids, of General formula 1A-g with antioxidant activity,

when X is equal to the simple relation (compound 1A, oxalate, C8H11NO·C2H2O4) when X is equal to CH2(compound 1B, malonate, C8H11NO·C3H4O4); when X is equal to CH2CH2(compound 1B, succinate,8H11NO·C4H6O4); when X is equal to the group of CH2CH(OH), (compound 1G, malate, C8H1 NO·C4H6O5).

2. Pharmaceutically acceptable salt of formula 1B as described in claim 1, having a geroprotective and anti-ischemic activity.

3. The method of obtaining salt according to claim 1, namely, that interact equimolecular quantities of 2,4,6-trimethyl-3-hydroxypyridine with a dicarboxylic acid in a solution of lower alcohol boiling with subsequent treatment of the reaction mixture with an organic solvent and, if necessary, the shutter speed for 2-5 h at 10-15°C.



 

Same patents:

FIELD: new 2,4,6-trimethyl-3-oxypyridine nitrosuccinate and method for production thereof.

SUBSTANCE: claimed compound is useful in medicine as future antiishemic agent with vasodilatation effect and has potent protective action in barotraumatic damages and ballistic wounds due to inhibition of secondary necrosis creation and progress. Compound of present invention is obtained by nitration of malic acid with mixture of sulfuric and nitric acids, separation of nitrohydroxymalic acid and treatment thereof with 2,4,6-trimethyl-3-oxypyridine in alcohol media with subsequent isolation of target product.

EFFECT: new antiishemic agent.

2 cl, 1 ex

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< / BR>
where R1and R2each independently of one another, denote hydrogen, fluorine, chlorine, bromine, iodine

The invention relates to the chemistry of oxypyridine and relates to new biologically active compounds in this series, namely succinate 3-(N,N-dimethylcarbamoyl)-2-ethyl-6-methylpyridine of formula I:

< / BR>
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6 cl, 3 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

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SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for treatment of diseases, associated with alterations of blood extracellular DNA, such as generalized infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. Method includes administering of blood extracellular DNA destroying agent into blood. As such agent DNAase is used, in particular in doses providing alteration of electrophoretic profile of blood extracellular DNA, detectable by pulse gel electrophoresis. DNAase may be administrated in doses and regimes providing exceeded levels of blood plasma DNA-hydrolytic activity, namely 150 Kuntz/l of plasma, during 12 h/day in total.

EFFECT: effective method for treatment of abovementioned diseases without side effects.

4 cl, 14 tbl, 15 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: claimed method includes blending of active base and auxiliary ingredients to form tablet corn, representing composition of sugar powder, monocrystalline cellulose, vinylpyrrolidone and calcium stearate; humidifying of obtained mixture; drying of obtained granules; dry granulation through granulator with standardized holes; pelletization of standardized granules to produce tablet corn; and coating. Mixture is humidified with 5-7 % starch mucilage in starch mucilage/humidifying mixture mass ratio of 1:25-30, wherein mixture is blending with starch mucilage for homogeneous distribution wet in whole mass.

EFFECT: tablets with increased hardness and enhanced pharmacological activity.

2 cl, 2 ex

FIELD: experimental medicine.

SUBSTANCE: in rabbits one should induce hepatic ischemia due to occlusion of hepato-duodenal ligament for 30 min. Moreover, reamberin should be introduced at the dosage of 35 ml/kg during the whole period of occlusion, and at the dosage of 5 ml/kg for 10 min after removing the above-mentioned occlusion. The method provides preventing the death of experimental animals in case of ischemic exposure being harmful for this type of animals.

EFFECT: higher efficiency of protection.

2 tbl

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