Derivatives of imidazole as inhibitors of phosphodiesterase vii

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention proposes applying derivatives of benzopyranoimidazole and benzothiopyranoimidazole as inhibitors of activity of phosphodiesterase VII, new derivatives of benzopyranoimidazole of the general formula (I)

with radical values given in the invention claim that elicit the above said activity and a pharmaceutical preparation based on thereof. Claimed derivatives elicit specific inhibition of rolipram-insensitive cAMP-phosphodiesterase (phosphodiesterase VII) in combination with good tolerance that allows their applying in asthma treatment. Indicated compounds show activity with respect to inhibition of tumor necrosis factor (TNF) producing that allows their applying for treatment of some autoimmune diseases.

EFFECT: valuable medicinal and biochemical properties of compounds.

3 cl, 2 tbl, 9 ex

 

The invention relates to compounds of formula I

in which

R1represents H, A, benzyl, indan-5-yl, 1,2,3,4-tetrahydronaphthalen-5-yl, dibenzothiophen-2-yl or phenyl, which is unsubstituted or mono-, di - or triamese Hal, A, A-CO-NH, benzyloxy, alkoxy, COOH or cooa,

R2represents H or A,

X represents O or S,

Hal represents F, Cl, Br or I,

And is an alkyl having from 1 to 6 atoms,

and their physiologically acceptable salt and/or solvate as inhibitors of phosphodiesterase VII.

The invention further relates to the use of compounds of formula I to obtain a pharmaceutical preparation for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, rejection of transplants, cachexia, tumor growth or metastasis of tumors, sepsis, memory disorders, atherosclerosis and AIDS.

Benzopyranones described, for example, M. Trkovnik and others in the Org. Prep. Proced. Int. (1987), 19(6), 450-5 or V.L. Savel'ev and others in Khim. - Farm. Zh. (1983), 17(6), 697-700. Derivatives benzopyranones OPI is Ana, for example, V.L. Savel'ev and others in Khim. Geterotsikl. Soedin. (1980), (4), 479-83.

The invention was based on the goal to discover new compounds with valuable properties, in particular those that can be used to obtain pharmaceutical preparations.

It was found that the compounds of formula I and their salts have very valuable pharmacological properties in combination with good tolerability.

In particular, they show specific inhibition "rolipram-insensitive camp phosphodiesterase (PDE VII).

Biological activity of the compounds of formula I can be determined by methods such as those described, for example, M.A. Giembycz and others in Br. J. Pharmacol. (1996), 118, 1945-1958. The affinity of compounds to camp phosphodiesterase (PDE VII) determine, by measuring their values IC50(the concentration of inhibitor required to achieve 50% inhibition of enzymatic activity).

The determination is done using homogenised cells neuroplasty SK-N-SH instead of T-lymphocytes, a CI-930 was used for inhibition of PDE VII. The last is a selective inhibitor of PDE VII (J.A. Bristol and others, J. Med. Chem. 1984, 27 (9), 1099-1101).

The compounds of formula I can be used for the treatment of asthmatic disorders.

Anti-asthma effect can be determined, for example, similarly to the method of T. Olson, Acta allergologica 26, 438-447 (1971).

Because of camp inhibits cell osteoclast and stimulates cells osteal the ASTA (S. Kasugai, etc., M 681 and K. Miyamoto, M 682, in Abstracts of the American Society for Bone and Mineral Research 18th Annual Meeting, 1996), the compounds of formula I can be used for the treatment of osteoporosis.

Connections are additionally exhibit an antagonistic effect on the production of TNFα (factor tumor necrosis) and thus suitable for the treatment of inflammatory and allergic disorders, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, reaction of transplants, cachexia and sepsis. Anti-inflammatory effect of the compounds of the formula I, and their effectiveness in the treatment of, for example, autoimmune diseases such as multiple sclerosis or rheumatoid arthritis, can be defined by analogy with the methods of N. Sommer et al., Nature Medicine I, 244-248 (1995) or L. Sekut, etc., Clin. Exp. Iimnunol. 100, 126-132 (1995).

The compounds can be used to treat cachexia. Anticoincidence action you can check on TNF-dependent models of cachexia (P. Costelli, etc., J. Clin. Invest. 95, 2367 ff (1995); J.M. Argiles, etc., Med. Res. Rev. 17, 477 ff (1997)).

Inhibitors PDF VII can also inhibit the growth of tumor cells and, thus, suitable for the treatment of tumors (about the inhibitors of PDE VII cm D. Marko and others, Cell Biochem. Biophys. 28, 75 ff (1998)).

They additionally can be used for therapy of sepsis and for the treatment of memory disorders, atheroscle the oz, atopic dermatitis and AIDS and for the treatment of diseases dependent on T cells (L. Li et al. Science, 1999, 283, 848-851).

The invention further relates to the use of inhibitors of phosphodiesterase VII to obtain pharmaceutical drugs to control allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, rejection of transplants, cachexia, tumor growth or metastasis of tumors, sepsis, memory disorders, atherosclerosis and AIDS.

The compounds of formula I can be used as active pharmaceutical ingredients for the inhibition of PDE VII in human and veterinary medicine.

And represents alkyl having 1-6 C atoms, and has 1, 2, 3, 4, 5 or 6 C atoms, and preferably represents methyl, ethyl or propyl, are also preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and n-pentyl, neopentyl, isopentyl or hexyl. And is cycloalkyl, such as, for example, cyclohexyl.

Alkoxy is preferably a methoxy, ethoxy, propoxy or butoxy.

Hal represents before occhialino F or Cl.

A-CO-NH represents preferably acetamido.

The basis of the formula I can be transferred using the acid into the corresponding acid salt additive, for example, by reaction of equivalent amounts of base and acid in an inert solvent, such as ethanol, followed by evaporation. Particularly suitable for this reaction acids are those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalogen acid, such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic mono - or politonalnye carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, Pavlova acid, diethyloxalate acid, malonic acid, succinea acid, Pimenova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultancy acid, ethicality acid, 2-hidroxi alsultanova acid, benzolsulfonat acid, p-toluensulfonate acid, naphtalene - or di sulphonic acid and louisanna acid. Salts with physiologically unacceptable acids, for example the picrate, can be used for identifying and/or purifying compounds of formula I.

The invention further relates to pharmaceutical preparations comprising at least one inhibitor of phosphodiesterase VII of the formula I and/or one of its physiologically acceptable salt and/or solvate to control allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, rejection of transplants, cachexia, tumor growth or metastasis of tumors, sepsis, memory disorders, atherosclerosis and AIDS.

Typically, the substance is administered in doses from about 1 to 500 mg, in particular from 5 to 100 mg per unit dosage. Daily dose is preferably from 0.02 to 10 mg/kg of body weight. The specific dose for each individual patient, however, depends on various factors, such as the effectiveness of specific applied compound, the age, body weight, General health, sex,diet, time and schedule of admission, level of discharge, pharmaceutical combination and complexity of the particular disorder to which the applied therapy. It is preferable to oral administration.

Pharmaceutical drugs can be used as pharmaceuticals in human and veterinary medicine. Suitable substances-carriers are organic or inorganic substances suitable for enteral (e.g., oral), parenteral administration or topical application and do not reacts with the new compounds, for example water, vegetable oils, benzyl alcohols, alkalophile, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. For oral administration is used, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, suspensions or drops, for rectal use - suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions and implants, for topical application are ointments, creams and powders. The new compounds can also be liofilizirovanny, and received lyophilizate can be applied, for example, to obtain products for injection. These preparations can be sterilized and/or enable e is Scipioni, such as lubricants, preservatives, stabilizers and/or humectants, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavorings and/or some other active ingredients, for example one or more vitamins.

The invention applies in particular to compounds of the formula I listed in the following examples, as well as their physiologically acceptable salts and/or solvate as inhibitors PDE VII and the use of them to obtain a pharmaceutical preparation for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, rejection of transplants, cachexia, tumor growth or metastasis of tumors, sepsis, memory disorders, atherosclerosis and AIDS.

Examples:

1-Phenyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-Benzyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-Cyclohexyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-Cyclopentyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-Butyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-Isopropyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-Propyl-[1]benzopyrano[3,4-d]is midazol-4-(1H)-he,

1-Ethyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-Methyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

[1]Benzopyrano[3,4-d]imidazole-4-(1H)-he,

2-Methyl-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-Phenyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-Benzyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-Cyclohexyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-Cyclopentyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-Butyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-Isopropyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-Propyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-Ethyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-Methyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

[1]Benzothiophene[3,4-d]imidazole-4-(1H)-he,

2-Methyl-[1]benzothiophene[3,4-d]imidazole-4-(1H)-he,

1-(2-Course-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(4-Were)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(4-Forefeel)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(2,4-Dimetilfenil) [1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(3-Course)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(2,4-Dichlorophenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(2,5-Dichlorophenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(4-Acetamidophenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(2-Forefeel)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(3-Forefeel)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(2-Benzyloxyphenyl)-[1]benzopyrano[3,4-d]them dasol-4-(1H)-he,

1-(2,6-Dimetilfenil) [1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(Indan-5-yl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(2-Methoxyphenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(2,3-Dimetilfenil) [1]benzopyrano[3,4-d]imidazole-(1H)-4-he,

1-(2,3-Dichlorophenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(3-Chloro-4-were)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(2,5-Dimetilfenil) [1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(4-Course)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(1,2,3,4-Tetrahydronaphthalen-5-yl)-[1]benzopyrano-[3,4-d]imidazole-4-(1H)-he,

1-(Dibenzothiophen-2-yl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(3-Methoxyphenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

1-(4-Carboxy-2-were)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he,

The following examples relate to farmatsevticheskii drugs:

Example: Capsules

A solution of 100 g of the inhibitor phoshodiesterase VII of the formula I and 5 g of hydrogenphosphate disodium in 3 l of double-distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, making capsules for injection, lyophilizers and aseptically sealed. Each capsule for injection contains 5 mg of active ingredient.

Example: Suppositories

A mixture of 20 g of inhibitor phoshodiesterase VII of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allow to cool. Each suppository contains 20 the g of the active ingredient.

Example: Solution

The solution obtained from 1 g of inhibitor phoshodiesterase VII of the formula I, 9,38 g NaH2PO4·2H2O, 28,48 g NaH2PO4·12H2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. pH set to 6.8, and the solution is brought to 1 l and sterilized by irradiation. The solution can be applied in the form of eye drops.

Example D: Ointment

500 mg of inhibitor phoshodiesterase VII of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of the inhibitor phoshodiesterase VII of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in the usual way to obtain the tablets such that each tablet contained 10 mg of the active ingredient.

Example F: coated Tablets

Tablets are pressed analogously to Example E, and then cover in the usual way by a coating consisting of sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules

2 kg of the inhibitor phoshodiesterase VII of the formula I are making hard gelatin capsules in the usual way, so that each capsule contained 20 mg of the active ingredient.

Example N: Ampoules

A solution of 1 kg of the inhibitor phoshodiesterase VII of the formula I in 60 l of double-distilled water is brought into ampoules, lyophilizer when aseptic the ski conditions and aseptically sealed. Each ampoule contains 10 mg of inhibitor phoshodiesterase VII.

Example I: Spray for inhalation

14 g of inhibitor phoshodiesterase VII of the formula I are dissolved in 10 l of isotonic NaCl solution and the solution is metered into commercially available spray containers with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (about 0.1 ml) corresponds to a dose of about 0.14 mg

Physico-chemical constants of new compounds of formula I

Retention time Rf[min] and MW[M+H+]spectral data were obtained by gas chromatography-mass spectral analysis of compounds using the measuring system manufactured by Hewlett-Packard, HP series 1100, under the following conditions:

The ionization source: electrospective (positive mode);

Scan: 100-1000 m/z;

Pulse voltage: 60 V;

Gas temperature: 300°C;

Setting detector diode array (DAD): 220 nm.

The volumetric rate: 2.4 ml/min Used fragments of lower volumetric rate depending on DAD for the mass spectrum of 0.75 ml/ min

Column: Chromolith SpeedROD RP-18e 50-4,6

Solvent: LiChrosolv-Qualitat Merck KgaA

Solvent A: H2(0.01% of TFA)

Solvent B: CAN (0,008% TFA)

Gradient:

20% 100%: 0 min - 2,8 min

100%: 2,8 min-3,3 min

100% In 20% In: 3.3V min - 4 min

1-(2-chlorophenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /23-e connection, preveden the e in the description under the heading "Examples", Rf[min] 1,708 MW[M+H+] 297;

1-(4-were)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /24-th connection, see the description under the heading "Examples", Rf[min] 1,745 MW[M+H+] 277;

1-(2.4-dimetilfenil) [1]benzopyrano[3,4-d]imidazole-4-(1H)-he /26-th connection, see the description under the heading "Examples", Rf[min] 1,952, MW[M+H+] 291;

1-(4-acetamidophenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /30-th connection, see the description under the heading "Examples", Rf[min] 1,215 MW[M+H+] 320;

1-(3-forfinal)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /32-th connection, see the description under the heading "Examples", Rf[min] 1,647 MW[M+H+] 281;

1-(2-benzyloxyphenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /33rd connection, refer to the description under the heading "Examples", Rf[min] 2,079 MW[M+H+] 369;

1-(2-methoxyphenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /36-th connection, see the description under the heading "Examples", Rf[min] 1,641, MW[M+H+] 293;

1-(1,2,3,4-tetrahydronaphthalen-5-yl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /42nd connection, see the description under the heading "Examples", Rf[min] 2,141, MW[M+H+] 317;

1-(3-methoxyphenyl)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /44-th connection, see the description under the heading "Examples", Rf[Inn] 1,708 MW[M+H+] 293;

1-(4-carboxy-2-were)-[1]benzopyrano[3,4-d]imidazole-4-(1H)-he /45-th connection, see the description under the heading "Examples of the, Rf[min] of 1.321, MW[M+H+] 321;

Pharmacological test 1

Compounds described in claim 1 of the formula of the invention were evaluated for pharmacological activity against inhibition phosphodiesterase VII.

The studies were conducted according to the method described M.A.Giembycz and others in Br. J. Phamacol. (1996), 118,1945-1958.

Presents data below illustrate the structure of the tested compounds is their IC50and the page and the sequence number of the connection represented in the description under the heading "Examples".

Presented in table IC50(concentration of test compound in mol/liter, providing 50%inhibition phosphodiesterase VII) were obtained for compounds of General formula I

P./No.R1R2XIC50[mol/l]
5/1phenylNabout6,20E-07
6/12phenylNS7,E-08

As can be seen from the data presented above, the compounds are inhibitors of phosphodiesterase VII.

Pharmacological test 2

Compounds described in claim 2, were researchers who were on pharmacological activity against inhibition phosphodiesterase VII.

The studies were conducted according to the method described M.A.Giembycz and others in Br. J. Phamacol. (1996), 118, 1945-1958.

Presents data below illustrate the structure of the tested compounds is their IC50and the page and the sequence number of the connection represented in the description under the heading "Examples".

Presented in table IC50(concentration of test compound in mol/liter, providing 50%inhibition phosphodiesterase VII) were obtained for compounds of General formula I

P./No.R1R2XIC50[mol/l]
6/332-benzyloxyphenylNO7,E-07
6/454-carboxy-2-wereNO5,E-06
6/232-chlorophenylNO6,E-08
6/362-methoxyphenylNO1,10E-06
6/262,4-dimetilfenilNO1,90E-07
6/244-wereNO6,40E-08
6/0 4-acetamidophenylNO3,80E-07
6/443-methoxyphenylNO4,10E-06
6/323-forfinalNO6,10E-07
6/421,2,3,4-tetrahydronaphthalen-5-ylNO3,the ' 60S-06

As can be seen from the data presented above, the compounds are inhibitors of phosphodiesterase VII.

1. The use of 1-phenyl-[1]benzopyrano[3,4]imidazole-4-(1H)-it, 1-phenyl-[1]benzothiophene[3,4]imidazole-4-(1H)-she and/or their pharmacologically acceptable salt or solvate as an inhibitor of phosphodiesterase VII.

2. Imidazole derivatives of the formula I

in which R1represents a 1,2,3,4-tetrahydronaphthalen-5-yl or phenyl, which is mono-, di - or triamese Hal, A, A-CO-NH, benzyloxy, alkoxy, COOH or cooa;

R2represents H, X represents Oh, Hal represents F, Cl, Br or I, And represents alkyl having from 1 to 6 atoms,

and their physiologically acceptable salt and/or solvate.

3. Pharmaceutical preparation containing at least one inhibitor of phosphodiesterase VII, characterized in claim 1 or representation is shining a compound of formula I according to claim 2, and/or its physiologically acceptable salt and/or solvate.



 

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6 cl, 5 tbl, 19 ex

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5 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with the ways for body purification and detoxication with the help of products of plant origin. The method includes preliminary period at additional survey for the presence of parasites followed by body purification due to curative starvation: during the first day a patient should apply nocturnal purifying enema, next morning - saline purgative preparation, then during the second and next day of starvation it is prescribed the intake of not less than 1-1.5 l water at daily application of purifying enemas for the whole period of starvation, and restorative period at applying juice-fruit-vegetable diet. Moreover, at the background of starvation, one should perform hepatic purification and that of gastro-intestinal tract along with body disinfection and withdrawal of parasites: at 7 p.m. during the 1st d of starvation a patient should apply 150 mg decaris, daily since the 1st d to the 7th d of starvation it is necessary to use decoctions of cholagogue, diuretic and antiparasitic herbal species. Since the 4th d of starvation one should add the intake of garlic decoction based upon milk, on the 3d, 5th, 7th d of starvation it is necessary to fulfill hepatic tubing at 7 p.m. after the intake of natural apple juice at 4 p.m., moreover, on the 3d d of starvation tubing should be conducted after the intake of vegetable oil in lemon juice, 4 times, on the 5th d - after the intake of cholagogue species, 4 times, on the 7th d - after the intake of purgative species with sorbitol. During the 1st d of starvation end one should perform parasitic disinfection due to the intake of acid milk whey to one's empty stomach, in 30-40 min -herring without bread, in 2 h - a glass of warm, sweet milk and application of purifying enema in 6-8 h. The method provides simultaneous restoration of affected body metabolism, hepatic purification and that of gastro-intestinal tract followed by withdrawal of parasites.

EFFECT: higher efficiency of body healing.

6cl, 2 ex, 1 tbl

FIELD: medicine, microbiology.

SUBSTANCE: method involves applying hydrogen sulfide mineral water from the health resort "Ust-Kachka" with the total mineralization 76 g/dm3. Invention promotes to enhancing sensitivity of microorganisms to antibacterial preparations that, in turn, promotes to reducing doe of the latter and prophylaxis of iatrogenic complications associated with carrying out antibacterial therapy. Invention can be used for enhancing sensitivity of microorganisms to antibacterial preparations.

EFFECT: valuable properties of agent.

3 tbl, 3 ex

FIELD: medicine, biochemistry.

SUBSTANCE: invention proposes applying CDP-choline (cytidinediphosphocholine) or its salt as a prophylactic agent for treatment of cerebral ischemia and a method for such prophylactic treatment. Invention found new and unknown early mechanism of action of CDP-choline or its salt: inhibition of activation of caspase cascade being the effectiveness of this effect is high in prophylactic intake of drug.

EFFECT: valuable medicinal properties of agent.

6 cl, 5 dwg, 4 ex

FIELD: medicine, surgery.

SUBSTANCE: method involves administration of verapamil solution in the amount 20-30 mg by intraperitoneal route by spraying method on visceral and parietal peritoneum on the final stage of operation. Invention promotes to reducing frequency in formation and relapse of post-operative adhesions. Invention can be used for prophylaxis of post-operative adhesions.

EFFECT: improved method for prophylaxis.

2 ex

FIELD: medicine, obstetrics.

SUBSTANCE: at the first stage of pregravidic training one should introduce leukinferon per 10000 IU intramuscularly every other day 10 times, at the second stage it is necessary to perform 3 seances of discrete plasmapheresis. The present innovation enables to decrease the frequency in developing gestosis and the risk for abortion due to normalized activity of female immune system, that in its turn, enables to stop virusemia and virusuria, prevent fetoplacental failure and intrauterine fetal infectioning.

EFFECT: higher efficiency of training.

3 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of glucopyranosyloxybenzylbenzene represented by the formula (I): wherein R1 represents hydrogen atom or hydroxy(lower)alkyl; R2 represents lower alkyl group, lower alkoxy-group and lower alkylthio-group being each group is substituted optionally with hydroxy- or (lower)alkoxy-group, or to its pharmaceutically acceptable salts. Also, invention relates to pharmaceutical composition eliciting hypoglycemic activity and to a method for treatment and prophylaxis of hyperglycemia-associated diseases, such as diabetes mellitus, obesity and others, and to their intermediate compounds. Invention provides preparing new derivatives of glucopyranosyloxybenzylbenzene that elicit the excellent inhibitory activity with respect to human SGLT2.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 2 ex

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