Inhibitor atherosclerotic thickening of the inner lining of blood vessels

 

(57) Abstract:

The invention relates to the use of the following compounds as an inhibitor of proliferation of smooth muscle cells of the aorta, the migration medium smooth muscle cells of the aorta in its intima (inner lining) or the adhesion of blood cells and endothermy. The proposed connection previously known are:

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9 tab., 13 Il.

The invention relates to an inhibitor of atherosclerotic thickening of the inner lining of blood vessels, which is a derivative of pyridine, with a strong inhibitory effect on HMG-CoA reductase, as well as a strong inhibitory action on the proliferation of smooth muscle cells of the inner lining of the aorta (I-SMC) occurring in the process of atherosclerotic thickening of the inner lining of blood vessels, in relation to the migration of cells of smooth muscles of the middle layer of the aorta (M-SMC) and in respect of the adhesion of blood cells (such as lymphocytes, leukocytes and macrophages) to endothelially cells.

It is believed that the thickening of the inner lining of the coronary arteries is one of the main causes of myocardial infarction and angina. It is assumed that atherosclerotic thickening untimeliness by cytokines and lipid accumulation and further develops under influence of migration M-SMC from the middle layer in the inner lining of blood vessels, proliferation of smooth muscle cells in the inner membrane and increase of extracellular material from the pathological and proliferative activation or modulation of smooth muscle cells. This activation of cells stimulated by risk factors such as hyperlipemia. It was reported that inhibitors of HMG-CoA reductase inhibit atherosclerotic thickening of the inner lining of blood vessels as a result of significant reduction of serum cholesterol in animal models (Biochim Biophis Acta 960, 294-302 (1988)), but clinical trials have not confirmed the effectiveness of this action.

As a more effective inhibitor of atherosclerotic thickening of the inner lining of blood vessels, you need a drug that can have a direct impact on such atherosclerotic disease. In the literature reported the inhibitory effect on smooth muscle cells is a medicine that counteracts the platelet growth factor (PDGF), or drug that counteracts the fibroblast growth factor (FGF) (Lif. Science 28, 1641-1646, (1981); J. Pharm Exp. Ther 248, 1167-1174) (1989)), the inhibitory effect of calcium antagonists on the migration of smooth muscle cells under the influence of PDGF thrombosis. cll Biol., 112, 335-344 (1981)), about the inhibitory effect of the inhibitor of the synthesis of thromboxane re of Atanov after RTSA (Atherosclerosis 18, 661-665, (1990)). However, all these effects of drugs directed against platelets or stimulating factors, such as cytokines, there is no drug that would have a direct impact on pathological smooth muscle cells affected by atherosclerosis.

Factor in the migration of smooth muscle cells, secreted from these cells, provides a stronger stimulatory effect on migration than PDGF, it is considered that it is closely associated with the emergence and progression of atherosclerosis (Atherosclerosis, 72, 213-226, (1991)), but found no drugs that would suppress such migration of smooth muscle cells. In addition, the proliferative state of the I-SMC, which cannot be suppressed by prostaglandin I2(Atherosclerosis 73, 67-69 (1988)), is considered an important indicator of atherosclerosis. However, there is no drug that inhibited the proliferative state.

It was reported that inhibitors of HMG-CoA reductase have inhibitory effect on the proliferation of fibroblasts, smooth muscle cells and limpets. . Immunopharmac, 11, 863-869 (1069)). However, this inhibitory effect is not very satisfactory, so there is a need in the remedy, which would be more effective and more selective in relation to the target cells, in particular I-MG, macrophages and monocytes.

The invention provides an inhibitor of atherosclerotic thickening of the inner lining of blood vessels, which includes an effective amount of the compounds of formula (I):

,

in which ring X is phenyl, substituted phenyl or 5 - or 6-membered heterocyclic aryl;

R1and R2independently of one another represent hydrogen, C1-C8-alkyl, C3-C7-cycloalkyl, C1-C3-alkoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, R20R21N- (where R20and R21independently from each other represent hydrogen or C1-C3-alkyl), trifluoromethyl, triptoreline, deformedarse, fluorine, chlorine, bromine, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilane, hydroxymethyl or -- O/CH2/COR22(where R22is hydrogen or C1-C3-alkyl, and l is a number equal to 1, 2 or 3); or R1and R2together form-CH=the od C1-C8-alkyl, C2-C6alkenyl, C3-C7-cycloalkyl, C5-C7-cycloalkenyl or

,

where R7is hydrogen, C1-C8-alkyl, C1-C8-alkoxy, C1-C3-alkylthio, chlorine, bromine, fluorine, chloromethyl, trichloromethyl, trifluoromethyl, triptoreline, trichlormethane, deformedarse, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-tert-butylsilane or hydroxymethyl; or C1-C3-alkyl, substituted by one group

,

(where R7has the above values), and optionally one or two C1-C3-alkilani;

Y IS-CH2-, -CH2CH2-, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -C(CH3)=CH - or-CH=C(CH3)-;

Z IS-O-CH W-CH2-COP12,

,

(where O is-C(O)-, -C(OR13)2or-CH(OH)-,

W IS-C(O) =C(OR13)2or-C(R11) (OH)=,

R11is hydrogen or C1-C3-alkyl,

R12is hydrogen, R14(where R14represents alkyl chemically or physiologically hydrolyzable part of a complex Olkiluoto ether other23R24R25(where R23, R24and R25is hydrogen or C1-C4-alkyl), sodium, potassium or 1/2 calcium),

each R13independently -(CH2)3-,

R15and R16independently from each other represent a hydrogen atom or a C1-C3-alkyl, or R15and R16together form -(CH2)2or (CH2)3-.

Such a connection may have at least one or two asymmetric carbon atom and, therefore, at least two or more optical isomers. Thus, the compound of formula (I) include all optical isomers and their mixtures.

In addition, among the compounds, which are derived fragment of a carboxylic acid (-CO2R12) substituent Z of the compounds of formula (I) of the invention has a value other than-CO2R12compounds that possess the ability to turn into a carboxylic acid (the compound in which the fragment-COR12represents-CO2H) under the action of physiological hydrolysis after absorption are considered equivalent to the compounds of the invention.

Compounds of the invention can be a potent inhibitor of adhesion of blood cells (such as monocytes, macrophages) to endothelial cells and may inhibit the initial stage of atherosclerotic thickening of the inner lining of blood vessels. In addition, they spleak smooth muscle (SMC-CM), which may contain factor migration of smooth muscle cells system stimulation derived movement. In addition, the connection according to the invention inhibits the uptake of 3H-thymidine by the cells of the smooth muscles and, thus, inhibits DNA replication, which results in effective suppression of cell proliferation. These impacts are stronger in relation to the I-SMC than in respect of the M-SMC. It follows from the above that the compounds of the invention inhibit the proliferation of smooth muscle cells in the inner membrane of the aorta, which is the most important stage of atherosclerotic thickening of the inner lining of blood vessels. The basis of the invention lies in the discovery that the compounds according to the invention have an inhibitory effect against atherosclerotic thickening of the inner lining of blood vessels.

Compounds of the invention, i.e. mevalonate formula (I) can be obtained by carrying out the following reactions (see Fig. 1-4).

In formulas reactions R1, R2, R3, R12, R14ring and X have the meanings indicated above for formula (I), and R17is1-C4-lower alkyl, such as methyl, ethyl, n-propyl, isopropyl or n-bedstvie methods, described not in the examined patent publication Japan N 279866 (1989), corresponding to European patent N 304063 and U.S. patent N 5011930, C 07 D 215/00), in unexamined patent publication Japan N 275878 (1990), corresponding to European patent N 339358 and U.S. patent N 5024999) and in unexamined patent publication Japan N 7290 (1991), corresponding to European patent N 367235 and U.S. patent N 5026698, A 61 K 31/435).

Stage A represents the recovery of ester to the primary alcohol, which can be done using a variety of metal hydrides, preferably hydride diisobutylaluminum, in a solvent such as tetrahydrofuran, toluene or methylene chloride, at a temperature of from -20oC to 20oC, preferably from -10oC to 10oC.

Stage B is the oxidation of the primary alcohol to the aldehyde, which can be done using different oxidants. A preferred such method, at which the reaction is carried out using chloramine pyridinium in methylene chloride at 0 - 25oC, and method, according to which the reaction (oxidation reaction Swarna) is carried out using oxalicacid, dimethyl sulfoxide and tretinoin compounds of sulfur trioxide and pyridine.

Stage C represents the synthesis of a derivative of 3-ethoxy-1-hydroxy-2-propene, which can be obtained as a result of interaction of the compound (V) with a compound of lithium, formed by pre-treatment of CIS-1-ethoxy-2-(tri-n-butylstannyl)ethylene-butyllithium in tetrahydrofuran. As the reaction temperature preference is given to low temperature in the range from -60oC to -78oC.

Stage D represents the synthesis of anal by acid hydrolysis. When using an acid catalyst, which preferably is paratoluenesulfonyl, hydrochloric acid or sulphuric acid, this reaction can be conducted in a solvent mixture consisting of water and tetrahydrofuran or ethanol, with 10 - 25oC.

The derived 3-ethoxy-1-hydroxy-2-propene obtained in stage C can be used without purification in stage D, producing only delete simultaneously formed of Tetra-n-butyanova.

Stage E is the reaction accession enamel (III) and a complex ester of acetoacetic acid. This reaction is preferably carried out using sodium hydride and n-utillity used as the base in tetrahydrofuran at the same time the et reaction, where ketocarboxylic ester of the acid (II) is restored by using different reducing agents.

In accordance with the reaction of the carbonyl group is restored using sodium borohydride, cyanoborohydride sodium, zinc borohydride, dissimilarly, DIBORANE, tributylamine, pyridine-Baranovka complex, dicyclohexylurea, axillary, 9-borabicyclo (3.3.1) nonane, diisocyanatobutane or three-second-butylbromide lithium, resulting in a gain corresponding ester dihydroxycinnamic acid (I-1).

This reaction can be carried out in a solvent selected from a hydrocarbon, halogenated hydrocarbon, C1-C4-alcohol, simple ester and mixtures of these solvents, at a temperature of from -100oC to 50oC, preferably from -78oC to 30oC.

Otherwise, you can use trialkylborane, such as tri-n-butylboron or triethylborane and borohydride sodium, at a low temperature, as described in the journal "J. Amer. Chem. Soc", 105, 593 (1983).

In addition, as described in "Tetrahedron Letters 28, 155 (1987), can preferably get erythropoda with more strong derbaran or autoxidation.

This reaction can be carried out using a mixture of solvents, including1-C4alcohol and tetrahydrofuran, at temperatures from -80oC to -50oC, preferably from -72oC to -68oC.

Stage G is the hydrolysis of ester, and the reaction can be carried out using equimolar amount of base, preferably potassium hydroxide or sodium hydroxide, in a solvent mixture comprising water and methanol or ethanol, with 10 - 25oC.

Obtained at this stage the free acid can interact with an acceptable base with formation of salts.

Stage H is the dehydration of the free hydroxy acid (I-2) with the formation of mevalonate, and this reaction can be carried out as a result of heating under reflux in benzene or toluene while removing the formed water, or by adding appropriate desiccant, such as molecular sieve.

Otherwise, this reaction can be carried out using lactonase substances, such as carbodiimide, preferably water-soluble carbodiimide, such as N-cyclohexyl-N'-[2'-(methylmorpholin)ethyl]="ptx2">

Stage J is the hydrogenation of a double bond connecting mevalonate part with the heterocyclic ring, which can be carried out using catalytic amounts of palladium charcoal or erodirovannogo coal in a solvent such as methanol, ethanol, tetrahydrofuran or acetonitrile, at 0 - 50oC, preferably 10 to 25oC.

Stage K is the reaction of receipt , -unsaturated ketone in the selective oxidation of ester dihydroxycinnamic acid, which can be carried out using activated manganese dioxide in a solvent such as simple ethyl ether, tetrahydrofuran, benzene or toluene, at 20 - 80oC, preferably 40 to 80oC.

Otherwise, the compound of formula (I-6) can be synthesized from aldehyde of formula (V) with the help of combination reaction of the Wadsworth - Emmons (J. Amer. Chem. Soc, 107, 3731, (1985)).

In addition, this compound can be synthesized from anala formula (III) (Tetrahedron Letters, 26, 2951, (1985)). The compound of the formula (I-7) can also be obtained by adding the double anion of ester zetoxydi acid, producing this operation is the same as in stage E, the aldehyde (VIII), cinesiology the ketocarboxylic ester of the acid (IX), and subsequent recovery of carboxylic groups as well as on stage F.

The compounds listed in the table. 1 to 4, including the compounds described in the examples that follow are merely specific examples of compounds according to the invention. Used in these formulas Deputy-Y-Z are listed in the table. 1, and the other substituents are presented in table. 2-4.

In the following definitions of the substituents of different symbols denote the following substituents, namely, n is normal, i is ISO, sec-secondary, tert - tertiary, c is cyclo, Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl, Pent - pentyl, Hex - hexyl and Ph is phenyl.

In addition, similarly you can get a pharmacologically acceptable salt, such as potassium salts or salts poluchilcia, esters such as methyl ester, complex n-propyl esters, complex isopropyl esters, complex cyclopropylamine esters, complex n-butyl esters, complex isobutyl esters, complex, sec-butyl esters, complex tert-butyl esters, complex n-peptinovoye esters, complex isopentylamine esters or complex n-hexyl esters, ammonium salts, salts of trimethylamine, salt diethylamine, salt, piperazine salt of the research, salt of piperidine is bladud not only a high inhibitory effect on the biosynthesis of cholesterol in the case when HMG-CoA reductase acts as an enzyme, limiting the speed of growth, but the inhibiting effect against migration M-MC, proliferation 1-SMC and adhesion of blood cells to endothelially cells, as shown by the test results below. Thus, the compounds according to the invention are useful therapeutic agents against hyperlipemia, hyperlipoproteinemia and atherosclerosis.

Of these compounds can be manufactured in various acceptable compositions depending on the method of introduction. Compounds according to the invention can be administered in the form of free acids or in the form physiologically hydrolyzable and acceptable esters or lactones or in the form of pharmaceutically acceptable salts.

The pharmaceutical composition according to the invention is preferably administered orally in the form of the compounds according to the invention or in the form of powders, granules, tablets and capsules, the resulting mixture of compounds according to the invention with a pharmaceutically acceptable carrier, including a binder such as hydroxypropylcellulose, syrup, Arabian gum, gelatin, sorbitol, tragant, polyvinylpyrrolidone or carboxymethylcellulose-calcium complex, this filler, as the vine, such lubricant as magnesium stearate, talc, polyethylene glycol or silica, and a disintegrator such as potato starch.

However, the pharmaceutical composition according to the invention is not limited to orally administered and is suitable for parenteral administration. For example, it may be in the form of a suppository made with an oil base, such as cocoa butter, polyethylene glycol, lanolin or triglyceride of fatty acids, transdermal therapeutic framework made of liquid paraffin, white vaseline, higher alcohol, makroglou ointment, hydrophilic ointment or hydrogel core material, as well as in the form of a composition for injection manufactured using one or more materials selected from a group comprising polyethylene glycol hydrogel core material, distilled water, distilled water for injection, and a filler such as lactose or corn starch, either in the form of a composition intended for administration through mucous membranes, such as the mucous membrane of the eyes and mucous membranes of the mouth.

In addition, the compounds according to the invention can be connected with the basic ion exchange resin capable of what I the dose of a compound of formula I is 0.05 - 500 mg, preferably 0.5 to 50 mg for an adult. Its introduction is one to three times a day. This dose, no doubt, may vary depending on the age, weight and condition of the patient.

Below is a more detailed description of the invention with reference to examples demonstrating the inhibitory activity of the compounds according to the invention in relation to atherosclerotic thickening of the inner lining of blood vessels. Compound to compound (compound I-3) and comparative compounds (pravastatin described in the publication of unexamined Japan patent N 185275/1982 or in the European patent N 65835, and simvastatin described in the publication of unexamined Japan patent N 122373/1984 or in the European patent N 33536) have the chemical structure shown in Fig. 5.

Reference example

(E) - TRANS-6-/2'-[4"-/4"'/forfinal/-1",3"-dimethyl-6"- /1"'-methylethyl/pyrazolo/3,4-b/pyridine-5"-yl] ethynyl/4-hydroxy - 3,4,5,6-tetrahydro-2H-Piran-2-on (compound I-3b-1)

This compound was obtained using as a starting material methyl-2-cyclopropyl-5-ethyl-3-/4'-forfinal/-6-methylthieno/2,3-b/ pyridine-3-yl-carbanilate (compound IIIb-1) in the implementation stages A - H.

Compound VIIb-2

Methyl-6-cyclopropyl-1,3-dimethyl-4-/4'-forfinal/pyrazolo-3,4 - pyridine-5-yl-carboxylate

Compound VIIc-1

Methyl-6-cyclopropyl-3-ethyl-4-/4'-forfinal/-2-methylthieno-2,3 - pyridine-5-yl-carboxylate.

Test connection 1 (I/3a-1)

(E)-TRANS-6-/2'[2"-cyclopropyl-4"/4"'-forfinal/quinoline-3"- yl]ethynyl/-4-hydroxy-3,4,5,6-tetrahydro-2H-Piran-2-he

Test connection 2 (I-3b-2)

(E)-TRANS-6-/2'[6"-cyclopropyl/1", 3"-dimethyl-4"-/4"'- forfinal/pyrazolo[3,4-b] pyridine-5"-yl] ethynyl/-4-hydroxy-3,4,5,6 - tetrahydro-2H-Piran-2-he

Test connection 3(I-3c-1)

(E)-TRANS-6-(2'-/2"-cyclopropyl-5"-ethyl-3"-/4"'-forfinal/- 6"-methylthieno[2,3-b] pyridine-3"-yl]ethynyl/-4-hydroxy-3,4,5,6 - tetrahydro-2H-Piran-2-he

Stage A

4-/4'-forfinal/-5-hydroxymethyl-1,3-dimethyl-6-/1'-methylethyl/- pyrazolo[3,4-b]pyridine /connection VI-b-1/

5.0 g (of 0.014 mol) of the compound VIIb-1 was dissolved in dry toluene, producing this operation in a nitrogen atmosphere, and cooled to 0oC in an ice bath. To this solution was added dropwise 35 ml of toluene containing 16 wt. % hydride diisobutylaluminum, after which this mixture is re the complete disappearance of compound VIIb-1 to the end of the reaction to this mixture was added at 0oC a saturated solution of ammonium chloride. To the reaction mixture was added a simple ethyl ether, after which the separated organic layer. To gilotinirovaniya substance was added an aqueous solution of sodium hydroxide with a view to its dissolution, after which the resulting solution was extracted with ethyl simple ether. Extract simple ethyl ester was collected, dried over anhydrous magnesium sulfate and filtered, and the solvent drove with the formation of 3.9 g of the target product is yellowish in color.

Yield: 88%, melting point: 174 - 175oC.

In a similar manner there were obtained the compounds shown in Fig. 7.

Stage B

[4-/4'-forfinal/-1,3-dimethyl-6-/1'-methylenedi/pyrazolo[3,4-b] pyridine-5-yl]carboxaldehyde (compound Vb-1)

4,2 (19 mmol) Harrogate pyridinium, 0,69 g of anhydrous sodium acetate and 3.8 g (12 mmol) of compound VIb-1 suspended in 50 ml of dry dichloromethane at room temperature. The reaction solution was stirred for one hour, after which was added 100 ml of a simple ethyl ether and thoroughly mixed. The reaction mixture was filtered under vacuum through a layer perica, after which the filtrate is evaporated until dry under reduced movement which it was obtained 2.9 g of the target product is yellowish in color.

Yield: 78%, melting point: 144-146oC.

In a similar manner there were obtained the compounds shown in Fig. 8.

Stage C and D

(E)-3-[4'-/4"-forfinal/-1', 3'-dimethyl-6'-/1 '-methylethyl/- pyrazolo[3,4-b]pyridine-5'-yl]Propionaldehyde (compound III-1)

Stage C

1.45 g (40 mmol) of CIS-1-ethoxy-2-(tri-n-butylstannyl) ethylene was dissolved in 50 ml of dry tetrahydrofuran, and then the resulting solution was cooled to -78oC in a stream of nitrogen. To this solution was added dropwise 26 ml (40 mmol) of a solution of 15 wt.% n-utility in n-hexane. This mixture was stirred for 20 minutes Then a solution containing 2.5 g (8 mmol) of the compound Vb-1, dissolved in 20 ml of dry tetrahydrofuran was added dropwise to the above mixture. The reaction mixture was stirred for one hour at a temperature of -78oC, and then for the end of the reaction was added 26 ml of a saturated solution of ammonium chloride. The organic layer was extracted with simple diethyl ether, the ether extract was washed with a saturated aqueous solution of chloride, kept at reduced pressure, and the residue was subjected to liquid separation between n-hexane and acetonitrile, after which the acetonitrile layer was distilled under reduced pressure to what I D

Compound IVb-1, obtained in stage C, was dissolved in 70 ml of tetrahydrofuran and to this solution was added 20 ml of water and 3 g of paratoluenesulfonyl. This mixture was stirred for 2 h at room temperature. The reaction solution is carefully neutralized with an aqueous solution of sodium hydroxide, and then was extracted several times simple diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After that, the solvent is kept at reduced pressure. The residue was purified by chromatography on columns of silica gel, eluent: a mixture of ethyl acetate and n-hexane = 1/9 (volume ratio), the result of which was obtained target product yellow.

Quantity: 2.2 g (yield: 79%), melting point: 133-134oC.

In a similar manner there were obtained the compounds shown in Fig. 9.

Stage E

Ethyl-/E/-7-[4'-/4"forfinal/-1', 3'-dimethyl-6-'-/1 ' - methylethyl/-pyrazolo[3,4-b]pyridine-5-yl]-5 - hydroxy-3-oxalate-6-ENOAT (compound IIb-1)

1,25 g of 60% sodium hydride was washed dried petroleum ether, dried in a stream of nitrogen and then suspended in 200 ml of dry tetrahydrofuran. The resulting suspension cooling the mixture was stirred for 15 minutes Then thereto was added dropwise 20 ml (30 mmol) of a solution of 15 wt.% n-utility in n-hexane and stirred the mixture for 30 minutes in Addition, this mixture was added dropwise a solution containing 2.1 G (6.1 mmole) of compound IIIb-1, dissolved in dry tetrahydrofuran, and stirred for one hour. To the reaction mixture were added 10 ml of a saturated aqueous solution of ammonium chloride at a temperature of -15oC, after which it was extracted three times simple diethyl ether. The ether solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then evaporated until dry under reduced pressure. The residue was purified by chromatography on columns of silica gel (eluent: a mixture of ethyl acetate and chloroform = 1/9 (volume ratio).

The result was obtained 2.5 g (yield: 89%) of the target product in white. Melting point: 95 - 98oC.

In a similar manner there were obtained the compounds shown in Fig. 10.

Stage F

Ethyl-(E)-7-[4'-/4"-forfinal/-1',3'-dimethyl-6'-/1 '-methylethyl)- pyrazolo[3,4-b]pyridyl-5'-yl-3,5-dihydroxylated-6-ENOAT (compound I-1b-1)

2,32 g (4,96 mmole) of compound IIb-1 was dissolved in 20 ml of ethanol, performing AG (20 mmol) of sodium borohydride and stirred the mixture for one hour. To this mixture was added 10% aqueous hydrochloric acid solution, which allowed to make a thorough neutralization of the mixture. This mixture was extracted three times simple ethyl ether. The ether solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then evaporated until dry under reduced pressure. The residual oil was purified by chromatography on columns of silica gel (eluent: a mixture of ethanol and chloroform = 3/97 (volume ratio), which allowed to obtain the pure target product as a colorless viscous oil.

Quantity: 1,81 g (yield: 78%).

Spectrum NMR (6 ppm, CDCl3): of 1.28 (t, J = 8 Hz, 3H), 1,32 (D. , J = 8 Hz, 6H), 1,4 - 1,8 (m, 1H), 1,92 (C., 3H), 2,2 - 2,6 (m, 3H), of 2.9 to 3.8 (m, 2H), 3,42 (7 septet, J=8 Hz, 1H), 4,06 (C., 3H), of 4.1 to 4.6 (m, 4H), 5,1 - 5,5 (m, 1H), from 6.4 to 6.7 (m, 1H), 6,9 - to 7.3 (m, 4H).

In a similar manner there were obtained the following compounds shown in Fig. 11.

Stage G

Sodium salt of (E)-7- [4"-forfinal/-1', 3'-dimethyl-6'-1"- methylethyl/pyrazolo [3,4-b] pyridine-5'-yl/-3,5-dihydroxylated-6-gnoevoi acid (compound I-5b-1)

200 mg (0.43 mmole) of compound I-1b-1 was dissolved in 2 ml of ethanol and to the resulting solution was added dropwise to 0.85 ml of 0.5 odnogo hours. Then under reduced pressure drove ethanol and was added to the residue, 2 ml of water. The resulting mixture was extracted with ethyl simple ether. The water layer was dried by freezing, which allowed us to obtain 180 mg (91%) of a hygroscopic yellow powder.

Melting point: 258 - 264oC (decomposition).

In a similar manner there were obtained the compounds shown in Fig. 12.

(E)-7-[4'/4"-forfinal/-1', 3'-dimethyl-6'-/1 '-methylethyl/- pyrazolo[3,4-b] pyridine-5'-yl/-3,5-dihydroxylated-6-anoia acid (compound I-2b-1)

0.25 g (of 0.53 mmole) of compound I-1b-1 was dissolved in 3 ml of ethanol and to the resulting solution was added dropwise 1,06 ml of 0.5 N. aqueous sodium hydroxide solution. Ethanol drove under reduced pressure and to the residue was added 3 ml of distilled water. After that, the mixture was extracted with ethyl simple ether. The aqueous layer was carefully neutralized with 1% hydrochloric acid and then was extracted with ethyl simple ether. The ether layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure with the formation of the target product.

Quantity: 0.21 g (yield 90%).

Range of pulse NMR (DMCO - d6) ppm: 1,29 (D., J = 7 Hz, 6H), 1,83 (the singlet, 1H).

Stage H

(E)-TRANS-6-/2'-[4"-/4"'-forfinal/-1", 3"-dimethyl-6"-1"'- methylethyl/pyrazolo[3,4 - b)pyridine-5"-yl/ethynyl/-4-hydroxy-3,4,5,6 - tetrahydro-2H-Piran-2-he-(compound I-3b-1)

130 mg (0,29 mmole) of compound I-2b-1 was dissolved in 6 ml dichloromethane and the resulting solution was added 125 mg (0,29 mmole) of N-cyclohexyl-N'-/2"-methylmorpholine/ carbodiimide-paratoluolsulfonata. The resulting mixture was stirred at room temperature for 2 h, and then at reduced pressure drove the solvent until dry. The residual oil was purified by thin-layer chromatography on silica gel (eluent: a mixture of hexane and ethyl acetate = 9/1 (volume ratio), which allowed to obtain the pure target product as a colorless viscous oil.

Number: 47 mg (yield: 39%).

Range of pulse NMR (CDCl3) ppm: 1,33 (D., J = 6.8 Hz, 6H), 1,4 - 1,5 (m, 1H), 1.6 to 1.7 (m, 2H), 1.93 and (C., 3H), 2,5 - 2,6 (m , 1H), 2,68 (double doublet, J = 18 Hz, J = 5 Hz, 1H), 3,39 (7 septet, J = 6,8 Hz, 1H), 1,07 (C., 8H), 4,1 - 4,2 (m, 1H), 5,1 - 5,2 (m, 1H), 5,31 (double doublet, J = 16 Hz, J = 6 Hz, 1H), 6,61 (double doublet, J = 16 Hz, J = 1.5 Hz, 1H), 7,1 - 7,3 (m, 4H).

In a similar manner there were obtained the following compounds shown in Fig. 13.

Example 1. Inhibit the s compounds according to the invention in relation to migration M-SMC was determined using the following methods.

Sections of the middle layer of the thoracic aorta of male rats "Spragne Dawley was cultured in medium Needle, modified, Dulbecco (DME) containing 10% fetal serum cows (FBS), at 37 oC in an atmosphere consisting of 95% air and 5% carbon dioxide for 3 or 4 weeks. Smooth muscle cells the middle layer of the aorta grown from sections of the middle layer of the artery, was inoculable by dividing the density of cells in a ratio of 1:2 to obtain a stable subcultures. After three or four inoculation United cells were treated with trypsin and suspended in the above medium at a density of cells equal to 500000 cells / ml For the suspension of cells was added a test compound dissolved in dimethyl sulfoxide (DMCO), resulting in a final concentration DMCO-0.2%, after which a suspension of cells pre-incubated at temperature 37oC for 30 minutes To obtain a control sample was added to one DMCO in the same concentration. In the lower compartment of the chamber Boyden divided nitrocellulose membrane, which was administered 10 mg/ml of platelet growth factor (PDGF) or DME environment, representing 10% of the DME environment, standardized by smooth muscle cells (SMC-CM), the resulting 48-Chay was introduced 1 ml of suspended cells and produced incubation at a temperature of 37oC for 4 h in culture conditions. To obtain a blank sample in the lower compartment was introduced Wednesday DME without the factor of migration. After 4-hour incubation was removed, the cells adhered to the upper side of the nitrocellulose membrane, and the cells transferred to the underside of the membrane were fixed and stained with Diff Quik". The number of transferred cells was counted in 10 fields with the help of light microscope at 400 x field of view under high magnification.

The results were presented as average number of cells in the three cells obtained in each case, and the magnitude of inhibition (%) was calculated according to the following formula:

Inhibition (%) - {100 - (T-B) (C-B) 100}

where

B is the number of cells in a single sample, C is the number of cells in the control sample, T is the number of cells in the sample containing the test compound.

The results are shown in table. 5. Compounds according to the invention showed a strong inhibitory effect against migration M-SMC compared with the comparative compound.

Example 2. Inhibitory activity against proliferation of smooth muscle cells of the inner lining and the middle layer of the aorta (1-SMC and SMC)

Inhibitory effect of the is and the DME, containing 10% serum fetal cow and antibiotic sections of the middle layer of the aorta obtained from healthy Japanese white rabbit, and the sections affected area of the inner lining of the aorta isolated from the middle layer taken from Japanese white rabbit atherosclerotic, were cultured as described in example 1. After two - and three-inoculation United cells were treated with trypsin and suspended in the above environment, so that the density of cells at 20,000 cells/ml and Then made the planting of 10,000 cells, which were cultured in a Cup with 24 cells. After incubation for 6 h in the above medium was replaced with 0.5 ml of control medium or medium containing the test compound. At this time, counted the number of cells initially attached to the Cup, which was adopted for the initial number of cells (I). To the medium was added to the test compound, as described in example 1. To obtain a control sample was injected one DMCO, so that the final concentration was 0.2%. Replacement environment produced every 2 days, and during the first, second, third, fifth and seventh day, cells were treated with trypsin and suspended in isotonic solution then was determined by Chi the ex cells, obtained in each case, and the magnitude of inhibition (%) the process of increasing the number of cells from the second to the fifth day was calculated in accordance with the following formula:

Inhibition (%) = 100 = {(T5/T2/ /C5/C2/ 100}

where

T2and T5the number of cells respectively in the second and the fifth day in a medium containing the test compound, C2and C5the number of cells respectively in the second and the fifth day in the control environment.

The results are shown in table.6. Compounds according to the invention showed strong inhibitory activity against proliferation as I-SMC and M-SMC compared with the comparative compound. In addition, the inhibitory activity with respect to the proliferation of I-SMC was higher efficiency than in relation to the proliferation of M-SMC.

Example 3. Inhibitory effect on absorption of 3H-trimedia cells of smooth muscles of the inner shell and the middle layer of the aorta (I-SMC and M-SMC)

The inhibitory activity of the compounds according to the invention in relation to the absorption of 3H-thymidine by the cells of the smooth muscles of the inner shell and the middle layer of the aorta were determined using the following methods.

M-SMC and SMC were obtained from sredinom what about atherosclerosis, as it was mentioned in example 2. After three or four inoculation United cells were treated with trypsin and suspended in the medium of DME containing 10% serum fetal cow and the antibiotic, so the density of cells was 40000 cells/ml 10000 cells were sown in a Cup with 48 cells. After culturing for 4 days above the medium was replaced with control medium or medium containing the test compound, similar to that used in example 2, then the cultivation was continued for 24 hours Then add 1 Ci (37 MBg) 3H-thymidine and continued culturing for 3 hours the Cells are washed three times with phosphate-saline buffer solution (PBS) and processed chilled 5% trichloroacetic acid (TCA). The insoluble fraction was washed chilled TCA and dissolved in 0.5 N. aqueous solution of potassium hydroxide. The 3H radioactivity was measured using liquid scintillation counter and the protein content was determined.

The results were calculated as the quantity of radioactivity at 1 mg protein and presented as average values for 3 cells. The magnitude of inhibition (%) was calculated according to the following formula:

Inhibition (%) = 100-T/C 100

Received resultat absorption of 3H-thymidine by the fraction of DNA in the cells of the smooth muscles of the inner shell and the middle layer of the aorta compared with the comparative compound.

Example 4. Inhibitory effect against the adhesion of leukemic cells (HL-60)

The inhibitory activity of the compounds according to the invention in respect of the adhesion of cells HL-60 was determined using the following methods. Cells HL-60 were cultured in medium RPMI 1640 containing 10% serum fetal cow and antibiotic, at a temperature of 37oC in an atmosphere consisting of 95% air and 5% carbon dioxide, after which these cells were sown in a Cup with 6 cells in 2 ml to each well at a density of cells equal to 1000000/ml Test compound, dissolved in DMCO, was added in such amount that the final concentration DMCO reached 0.2 percent, and continued incubation for 48 h as pre-treatment. Then 500000 cells were sown in a Cup with 24 cells, was added to 0.02 mm phorbol-myristate-acetate (TPA), dissolved in ethanol, in the amount of 1/250 (volume ratio) of culture medium and continued culturing for 12 hours Following this, cells were washed in phosphate-saline buffer solution, the cells adhered to the cell cups were removed by treatment with trypsin and suspended in isotonic, and then determined the number of cells using a counter of Coulter. A control test was performed with doporuceno during pre-processing, and the magnitude of inhibition (%) was calculated according to the following formula:

Inhibition (%) adhesion = 100 - T/C100

where

T is the number of cells in a medium containing the test compound,

C is the number of cells in the control environment.

The results are shown in table. 8. Compounds according to the invention showed a strong inhibitory effect against the adhesion of cells HL-60 under the action of TPA compared with the comparative compound.

Example 5. Inhibitory effect against the adhesion of macrophages

J 774 (774-MF)

The inhibitory activity of the compounds according to the invention in respect of the adhesion of cells J774-MF were determined using the following methods.

1000000 cells were sown in a Cup with 6 cells and cultured in 1 ml of medium DME containing 10% serum fetal cow and antibiotic, at a temperature of 37oC in an atmosphere consisting of 95% air and 5% carbon dioxide for 2 days. Then the cultivation was continued in the control medium containing 0.2% DMCO, or in a medium containing the test compound, which was pre-treatment. Then the cells were removed with a rubber scraper and suspended in the above environment. 200,000 cells were sown in a Cup with 24 cells and to the use of counter Coulter to determine the number of cells.

The results were represented as mean number of cells in three cells obtained in each case during the pre-treatment, and the magnitude of inhibition (%) adhesion was calculated in accordance with the following formula:

Inhibition (%) adhesion = 100 - T/C 100

where

T is the number of cells in a medium containing the test compound, C is the number of cells in the control environment.

The results are shown in table. 9. Compounds according to the invention showed a strong inhibitory effect against the adhesion of cells J774-MF.

Compounds according to the invention have an inhibitory effect on HMG-CoA reductase and inhibit atherosclerotic thickening of the inner lining of blood vessels, therefore they are useful preventive means for preventing occurrence of coronary heart disease such as angina, myocardial infarction, re-Utenos after PTCA, the reduction of cerebrovascular vessels after intracerebral hemorrhage and peripheral sclerotic Takayasu.

1. The use of the compounds of formula I

< / BR>
in which ring X is

< / BR>
where R4ais hydrogen, C1- C6-alkyl, fluorine, chlorine or bromine;

5c is hydrogen or C1- C8-alkyl;

R1is hydrogen, fluorine, chlorine or bromine;

R3- C1- C7-alkyl or C3- C7-cycloalkyl;

Y IS-CH2CH2- or-CH=CH-;

Z IS-CH(OH)-CH2- CH(OH)-CH2-CO2R12,

where R12represents hydrogen, alkyl chemically or physiologically hydrolyzable fragment complex Olkiluoto ether, NH4, sodium, or potassium, 1/2 calcium,

or

< / BR>
as an inhibitor of proliferation of smooth muscle cells of the aorta, the median migration of smooth muscle cells of the aorta in its intima (inner lining) or the adhesion of blood cells to the endothelium.

2. Application under item 1, in which the specified connection is an inhibitor of proliferation of smooth muscle cells of the aorta.

3. Application under item 1, in which the specified compound is inhibitor of migration median smooth muscle cells of the aorta in its intima.

4. Application under item 1, in which the specified connection is an inhibitor of adhesion of blood cells to the endothelium.

5. The use according to any one of paragraphs.1 to 4, wherein the specified compound is a compound of formula Ia

< / BR>
6. The use according to any one of paragraphs.1 to 4, in which specified what Obedinenie is a compound of formula Ic

< / BR>
8. Application under item 5, wherein in the formula Ia, R1- fluorine, R3- cyclopropyl, Y is-CH=CH-.

9. Application under item 5, wherein in the formula Ib, R1- fluorine, R3- cyclopropyl, R1band R5bis methyl, Y is-CH=CH-.

10. Application under item 5, wherein in the formula IC R1- fluorine, R3- cyclopropyl, R1cis ethyl, R5cis methyl, Y is-CH=CH-.

11. Application under item 8, wherein in formula Ia, Z is-CH(OH)-CH2-CH(OH)-CH2-CO21/2 Ca.

 

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The invention relates to compounds of the formula

(I)

where R1represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl lower alkyl, cycloalkyl lower alkyl, lower alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono - or di-lower alkyl, amino lower alkyl, formyl, lower alkylsulphonyl, amino lower alkylsulphonyl, lower alkoxycarbonyl, mono - or di-aryl-substituted lower alkyl, arylcarbamoyl lower alkyl, aryloxy lower alkyl, or lower alkylene

< / BR>
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W represents hydrogen, halogen, hydroxy, lower alkoxy, aryl lower alkoxy, nitro, trifluoromethyl or

< / BR>
where R3represents hydrogen, lower alkyl or aryl lower alkyl, and R4represents lower alkyl or aryl lower alkyl; or alternatively the groupas a whole represents the

< / BR>
R5is hydrogen, lower alkyl, aryl or aryl lower alkyl; and

Z predepression

Eye ointment // 2082434
The invention relates to medicine, in particular to ophthalmology, and can be used in the treatment of traumatic keratitis, chemical burns, conjunctivitis, corneal, and especially when wound infection

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, cardiology, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I)

wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

41 cl, 1 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with preventing hemodynamic complications at restoring circulation in a prolongly ischemized limb, or due to premeditated tourniquet application during operative interference. For this purpose, 5-12 min before the onset of circulatory restoration it is necessary to start intravenous injection of antihistamine and glucocorticosteroid preparations, followed by drop-by-drop infusion of inhibitors of proteolytic enzymes which should be continued after tourniquet removal, as well. The method provides tourniquet shock and tourniquet shock-associated complications along with developing the chance for increasing the duration period of operation.

EFFECT: higher efficiency of prophylaxis.

3 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new pharmaceutical compositions comprising bicyclic compound of the formula (I): wherein A means -COOH or their functional derivative; X1 and X2 mean hydrogen or halogen atom; V1 and V2 mean carbon atoms; W1 and W2 mean groups and wherein R4 and R mean hydrogen atom, hydroxy-group; Z means carbon, oxygen, sulfur or nitrogen atom; R1 means saturated or unsaturated bivalent (C1-C10)-aliphatic hydrocarbon residue; R2 means saturated or unsaturated (C1-C10)-aliphatic hydrocarbon residue; R3 means hydrogen atom and glyceride. Also, invention relates to a method for stabilizing compositions and novel bicyclic compounds. Invention provides enhancing stability of pharmaceutical composition based on its dissolving in glyceride.

EFFECT: improved and valuable properties of compositions, improved stabilization of compositions.

42 cl, 8 tbl, 8 ex

FIELD: medicine, neurology, virology.

SUBSTANCE: invention relates to treatment of neurological diseases caused by herpes virus, such as Bell's paralysis, Hunt's disease, herpetic encephalitis accompanying with damage of cerebral nerves. Invention involves using 1,4-dihydropyridine blockers of calcium channels, such as felodipine, nifedipine, nimodipine, nisodipine being taken preferably in combination with herpes virus antagonist. Invention provides repairing damaged cerebral nerves by topical expanding arteriols and recovery of local microcirculation based on specific competitive interaction of definite groups of calcium blockers of 1,4-dihydropyridine type with vasoconstrictor endothelin.

EFFECT: enhanced effectiveness of treatment.

47 cl, 2 dwg, 1 ex

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