Derivative hinzelin or benzodiazepina.beloe acids and their salts

 

(57) Abstract:

Usage: in the pharmaceutical industry. The inventive derivative hinzelin or benzodiazepina.beloe acid f-ly I, where R is hydrogen, halogen, lower alkyl, or lower alkoxygroup, And group C O, or S C, B-group-CH2-CH2- -CHR, where R1hydrogen, lower alkyl, or hydroxyl, X is oxygen or the group NH, Y is the group of f-crystals II, where R2lower alkyl, q is 2 or 3 and their salts have activity antimuskarinovoe act occurs. Reagent 1: connection f-crystals III. Reagent 2: connection f-ly IV, where Q1and Q2otsepleniya group. Reaction conditions 20 to 100°C. in the environment aprotic solvent, in the presence of an acid acceptor. I II III IV 2 C. p. F.-ly, 1 table.

The invention relates to new nitrogen-containing heterocyclic compounds, in particular to derive hinzelin or benzodiazepina.beloe acid formula

(I) where R is hydrogen, halogen, lower alkyl or lower alkoxygroup;

And group O or S;

In group-CH2-CH2or R1where R1means hydrogen, lower alkyl or hydroxyl;

X is oxygen or the group NH

The Y group of formula )qwhere R2means lower alkyl, q is 2 or 3, and Solti antimuskarinovoe act occurs activity and therefore can be used to treat diseases of the gastrointestinal tract and the respiratory tract.

The compounds of formula (I) can be obtained with known methods, for example, by reacting compounds of General formula

(II) where R, B, X and Y have the above significance, with a compound of the formula

Q1--Q2(III) where Q1and Q2identical or different and mean tsepliaeva group, for example, halogen atom, unsubstituted or substituted by halogen lower alkoxygroup, imidazolyl, unsubstituted or substituted fenoxaprop, preferably chloride, ethoxypropan, fenoxaprop, trichlormethiazide or imidazolyl.

The reaction can be performed in the environment aprotic solvent, such as tetrahydrofuran, methylenechloride, chloroform, acetone, acetonitrile, in the absence or presence of an acid acceptor, such as triethylamine, pyridine, sodium carbonate or potassium, at 20-100aboutC, preferably at room temperature.

Get the target product can be transferred to another target product of the formula (I) by known methods.

The new compounds of formula (I) are particularly suitable for the prevention or treatment of diseases in kotoryu, malfunctions intestinal regularity and obstructive spastic phenomena in the respiratory tract, and they have no side effect on the heart rate.

The following experiments show that the proposed compounds are accordingly useful properties.

Pharmacology. Antimuskarinovoe act occurs activity and selectivity.

Antimuskarinovoe act occurs the activity and selectivity were determined by in vitro experiments on the binding of receptors on the two types of tissue containing muscarinic receptors M1and M2, namely the cerebral cortex and heart, and functional experiments on isolated intestine and left presence Guinea pigs.

Experiments in vitro binding receptors.

Muscarinic M1activity was determined by analysis of displacement 3N-pirenzepine from homogenized cortex conducted in the following way.

For the experiment used the cerebral cortex of male rats CD COOBBS weighing 220-250, the Process of homogenization was carried out in the apparatus Potter Melhem in the environment sodium-magnesium buffer EPES with rn,4 (100 mmol NaCl, 10 mmol magnesium chloride and 20 mmol HEPES) filtering the suspension of the monitoring experience with 0.5 nmol3N-pirenzepine marking muscarinic receptors in the cerebral cortex. 1 ml of a homogeneous mass incubated at 30aboutC for 45 min in the presence of the marker ligand and cold ligand in different quantities, and under these conditions was reached equilibrium, as in the corresponding parallel experiments. The incubation was finished by centrifugation (12,000 rpm for 3 min) at room temperature in an Eppendorf centrifuge. To remove free radioactivity centrifugal washed twice with 1.5 ml of saline solution. Cut off the ends of the tubes containing centrifugal, was added 200 μl of tissue solubilizer and left to stand over night. Then added 4 ml Scintilla fluid (a mixture of damilola and toluene in a volume ratio of 1:10) and measured the radioactivity.

Experiments were performed three or four times, and nonspecific relationship was defined as associated or contained within centrifugal radioactivity when the incubation medium contained 1 µm atropine sulphate. Nonspecific relationship averaged less than 30% of the Value ofD(dissociation constant) was determined by analysis of nonlinear regression in a known manner.

Muscarinic M2activity was determined for an muscarinic M1activity.

Functional in vitro experiments

Experience in the intestine of the Guinea pig.

The section length of 2 cm of the end of the intestine was prepared by a known method, it is suspended in a solution of Tyrode and reduced graded amounts of betangel (limits concentrations of 0.3-10 Microm, EC501.5 Microm). The reaction was registered as a result of isotopically. Values FORbwas calculated according to Arunachala and Schild.

Experience on the left presence Guinea pigs.

Tissue in the 32aboutWith filed in the solution of Even (humidity 131.6 mmol of sodium chloride, 5.6 mmol potassium chloride, of 2.16 mmol of calcium chloride, 24,9 mmol of sodium bicarbonate, 1,03 mmol of dinatriumfosfaatti, 11 mmol glucose and 13 mmol sucrose) and excited by pulses in the form of a square wave with a duration of 2 MS and a frequency of 3 Hz, lying on 100% above the threshold voltage, supplied through platinum electrodes. Inotropic activity was determined isometrically. Used increasing number of betanal (1-30 Microm) for excitation of a negative inotropic effect. Values FORbwere evaluated by the above method.

The results of the experiments are shown in the table.

See connection table 1-25 belong to kategorija-2(H)-2-oxo-3-chinesesynchronous acid (compound 1).

A solution of 30.4 g (N-(aminobenzyl)-endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-alkarbala and 12,74 g of triethylamine in 0.5 l of methylene chloride for 2.5 h drops added to a cooled to 3-6aboutWith the solution 22,86 g trichlorochloroform in 240 ml of the same solvent. The resulting solution continued to stir at room temperature for one hour, then add water, and the organic layer removed. The aqueous layer was treated with 10% sodium hydroxide solution and extracted with methylene chloride. After drying and removal of solvent by evaporation obtain the target product, which crystallized from ethanol. Output: 30,3 g of the indicated compound as hydrochloride. Melting point >260aboutC; the melting point of the free base 175-177aboutC.

Analysis of C17H21N3O3HCl:

Calculated WITH 58,03; N 6,30; N 11,94

Found, C 59,28; H 6,36; N 11,68.

MS: 316 m/e [M+H]+< / BR>
Similarly receive the following connections:

A complex of endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-6-methyl-2(H)-2-oxo-3-chinesesynchronous acid (compound 2).

Citrate; melting point 158-160aboutC.

Analysis of C18H23N3O3C6H8O7[3.2.1]Oct-3-silt ether 1,4-dihydro-6-methoxy-2(H)-2-oxo-3-khinazolinov - howl acid (compound 3).

Hydrochloride; melting point >260aboutC.

Analysis of C18H23N3O4HCl:

Calculated C 56,61; H 6,33; H 11,00;

Found, C 56,19; H 6,35; N 10,90.

A complex of endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt ester of 6-chloro-1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid (compound 4).

Hydrochloride; melting point >260aboutC.

Analysis17H20ClN3O3HCl:

Calculated C 52,86; H 5,48; N 10,88;

Found, C 52,88; H 5,50; N Is 10.68.

N-(endo-8-methyl-8-azabicyclo[3.2.1] Oct-3-yl)-1,4-dihydro-2(H)-2-oxo-3-hinoto - linecarboxylic (compound 5).

Hydrochloride; melting point >260aboutC.

Analysis of C17H22N4O4HCl:

Calculated C 58,19; H is 6.61; N 15,97;

Found, C 57,83; H 6,64; N 15,81.

Complex endo-9-methyl-9-azabicyclo[3.3.1]non-3-silt ether 1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid (compound 6).

Hydrochloride; melting point 220-222aboutC.

Analysis18H23N3O3HCl:

Calculated With 59,09; H is 6.61; N 11,49;

Found, C 58,74; H Of 6.65; N 11,41.

A complex of endo-8-methyl-8-azabicyclo[3.2.1] Oct-3-silt ester of 7-chloro-1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid (compound 7).


Found, C 51,55; H Vs. 5.47; N 10,66.

A complex of endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-6-fluoro-2(H)-oxo-3-chinesesynchronous acid (compound 8).

Hydrochloride; melting point >260aboutC.

Analysis of C17H20FN3O3HCl:

Calculated C 55,21; H 5,72; N 11,36;

Found, C 54,96; H 5,79; N 11,24.

A complex of endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-4-methyl-2(H)-2-oxo-2-chinesesynchronous acid (compound 9).

Hydrochloride; melting point >260aboutC.

Analysis of C18H23N3O3HCl:

Calculated C 59,09; H is 6.61; N 11,49;

Found, C 58,73; H Of 6.65; N 11,38.

A complex of endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-7-fluoro-2(H)-2-oxo-3-chinesesynchronous acid (compound 10).

Hydrochloride; melting point >260aboutC.

Analysis of C17H20FN3O3HCl:

Calculated C 55,21; H 5,72; N 11,36;

Found, C 54,76; H 5,79; N 11,29.

A complex of endo-8-methyl-8-azabicyclo[3.2.1] Oct-3-silt ester 5-chloro-1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid (compound 11).

Hydrochloride; melting point >260aboutC.

Analysis of C17H20ClN3 is sabillo[3.2.1]Oct-3-silt ether 1,4-dihydro-5-Mtel-2(H)-2-oxo-3-chinesesynchronous acid (compound 12).

Hydrochloride; melting point > 260aboutC.

Analysis of C18H23N3O3HCl:

Calculated C 59,09; H is 6.61; N 11,49;

Found, C 58,53; H 6,67; N 11,38.

A complex of endo-8-isopropyl-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-2(H)-2-oxo-3-khinazolinov acid (compound 13).

Hydrochloride; melting point 265-266aboutC.

Analysis of C19H25N3O3HCl:

Calculated C 60,07; H 6,90; N 11,06;

Found, C 59,90; H 6,97; N 10,98.

A complex of endo-8-methyl-8-azabicyclo[3.2.1] Oct-3-silt ether 2,3,4,5-tetrahydro-2-oxo-1(N)-1,3-benzodiazepine-3-Carbo - new acid (compound 14).

The melting point of 144-145aboutC.

Analysis of C18H23N3O3:

Calculated C 65,63; H? 7.04 baby mortality; N 12,76;

Found, C 65,33; H To 7.09; N 12,67.

A complex of endo-8-ethyl-8-azabicyclo[3.2.1] Oct-3-silt ether 1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid (compound 15).

Hydrochloride; melting point >260aboutC.

Analysis of C18H23N3O3HCl:

Calculated C 59,09; H is 6.61; N 11,49;

Found, C 58,88; H 6,64; N 11,34.

P R I m m e R 2. Methobromide complex endo-8-methyl-8-azabicyclo[3.2.1] Oct-3-ILO - new ether 1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous the draw-2(H)-2-oxo-3-khinazolinov - howl acid in 15 ml of acetone at 0aboutWith drops added to a mixture of 15 ml of acetone and 15 ml of 2 M solution of bromide in the simple diethyl ether. The reaction vessel is closed and left to stand at room temperature for 20 hours the Crude product obtained by evaporation of the solvent, after which he crystallized from ethanol. Yield: 0.3 g of the target product. Melting point >260aboutC.

Analysis of C18H24BrN3O3:

Calculated C 53,69; H of 5.89; N 10,24; Br 19,47;

Found, C 52,44; H By 5.87; N 10,14; Br 19,00.

Similarly receive the following connections:

Methobromide complex endo-8-isopropyl-8-azabicyclo[3.2.1] Oct-3-silt ether 1,4-dihydro-2(H)-2-oxo-3-hinazolinam new acid (compound 17).

The melting point 259-261aboutC.

Analysis20H28BrN3O3:

Calculated C 54,79; H 6,44; N 9,59;

Found, C 54,22; H 6,46; N 9,43.

Cyclopropylboronic complex endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt - th ether 1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid (compound 18).

The melting point 257-258aboutC.

Analysis21H28BrN3O3:

Calculated C 56,00; H 6,27; N WAS 9.33;

Found, C 55,48; N 6,28; N 9,17.

Methobromide complex endo-8-ethyl-8-the P> The melting point 250-252aboutC.

Analysis of C19H26BrN3O3:

Calculated C 53,78; H 6,18; N 9,90;

Found, C 53,19; H 6,22; N 9,63.

Ethobromide complex endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-2(H)-2-oxo-3-khinazolinov - howl acid (compound 20).

Melting point >260aboutC.

Analysis of C19H26BrN3O3:

Calculated C 53,78; H 6,18; N 9,90;

Found, C 53,73; H 6,23; N 9,76.

P R I m e R 3. A complex of endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-4-hydroxy-2(H)-2-oxo-3-hinazolina - oil acid (compound 21).

A solution of 3.45 g of the hydrochloride of compound endo-8-methyl-8-azabicyclo[3.2.1] Oct-3-ILO - new ether 1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid in 100 ml of water by addition of saturated sodium carbonate adjusted to pH 7. The gradual addition of 0.1 N sulfuric acid keeping the reaction mixture at pH 7, in the lower part of the reaction vessel slowly add a solution of 3.1 g of potassium permanganate in 100 ml of water. As soon as using thin-layer chromatography installed the disappearance of the parent compound, add 81 ml of potassium permanganate solution. Then the reaction mixture was filtered, treated with the STATCOM, which crystallize of ethyl acetate. Yield: 1.55 g of the target product.

The melting point 178-180aboutC.

Analysis of C17H21N3O4:

Calculated C 61,62; H to 6.39; N 12,68;

Found, C 61,47; H 6,48; N 12,65.

Similarly receive the following connections:

A complex of endo-8-methyl-8-azabicyclo[3.2.1] Oct-3-silt ether 1,4-dihydro-7-fluoro-4-hydroxy-2(H)-2-oxo-3-hinzelin carboxylic acid (compound 22).

The melting point of 169-170aboutC.

Analysis of C17H20FN3O4:

Calculated C 58,45; H 5,77; N A 12.03;

Found, C 58,03; H Of 5.81; N 11,84.

N-(Endo-8-methyl-8-azabicyclo[3.2.1] Oct-3-yl)-1,4-dihydro-4-hydroxy - 2(H)-2-oxo-3-chineselearnonline (compound 23).

The melting point of 150-152aboutC.

Analysis of C17H22N4O3:

Calculated C 61,80; H of 6.71; N 16,96;

Found, C 61,45; H 6,77; N Of 16.84.

P R I m e R 4. A complex of endo-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid (compound 24).

A solution of 0.4 g of the hydrochloride of compound endo-8-benzyl-8-azabicyclo[3.2.1] Oct-3-ILO - new ether 1,4-dihydro-2(H)-2-oxo-3-chinesesynchronous acid in 10 ml of ethanol is subjected to hydrogenation at room temp which are square-0.25 g of the desired product as hydrochloride.

Melting point >260aboutC.

Analysis of C16H19N3O3HCl:

Calculated C 56,89; N 5,97; N TO 12.44;

Found, C 55,81; H 6,04; N 12,24.

P R I m e R 5. A complex of endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-silt ether 1,4-dihydro-2(H)-2-thioxo-3-khinazolinov - howl acid (compound 25).

A solution of 2.0 g of N-(2-aminobenzyl)endo-8-methyl-8-azabicyclo[3.2.1]Oct-3-ylcarbamate and 1.2 ml of triethylamine in 30 ml of methylene chloride while stirring and at ambient temperature drops added to a solution of 0.6 ml of thiophosgene in 10 ml of the same solvent. Within 10 min appears solid. Continue to stir for a further one hour and then the solid allocate filtering. This solid is suspended in 5 ml of 1,2-dichlorobenzene, and the suspension is heated to 160-170aboutC for 15 minutes After cooling, the solid is titrated with the same solvent with subsequent filtering. As a result of crystallization in acetonitrile obtain 0.28 g of the desired product as hydrochloride. The melting point 224-225aboutC (with decomp.).

Analysis of C17H21N3O2S HCl:

Calculated C 55,50; H 6,03; N 11,42; S 8,72;

Found, C 55,47; H Equal To 6.05; N 11,34; S 8,64.

1. Derivatives chinsali the th alkoxygroup;

And the group With O or C= S;

In group-CH2-CH2- or-CHR1where R1hydrogen, lower alkyl and hydroxyl;

X is oxygen or the group NH;

Y is a group of the formula

where R2lower alkyl;

q is 2 or 3,

and their salts.

2. Derivative hinzelin or benzodiazepina.beloe acid of General formula

< / BR>
where R is hydrogen, halogen, lower alkyl or lower alkoxygroup;

And group C=O or C=S;

In group-CH2-CH2- or-CHR1where R1hydrogen, lower alkyl or hydroxyl;

X is oxygen or the group NH;

The Y group of the formula

where R2lower alkyl;

q is 2 or 3,

and their physiologically tolerated salts, antimuskarinovoe act occurs with activity.

 

Same patents:

The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

-CH=CH-CH=N (a-5) or

-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

-Alk - Z1- C(=X) - Z2- R7(b-3), or

-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

The invention relates to the first new derivatives of 1,2,5-thiadiazolo[3,4-h] quinoline General formula 1

NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

The invention relates to dentistry and can be used in prosthetic dentistry and orthodontics with increased pharyngeal reflex in a patient

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

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

14 cl, 36 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, cardiology.

SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.

EFFECT: higher efficiency of application.

12 cl, 2 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with medicinal preparations designed as solution and indicated for therapeutic needs. Eye drops contain ciprofloxacin hydrochloride monohydrate being equivalent to 0.3% free foundation, a buffer system that keeps pH within 3.5-5.5 interval, as a conserving agent - benzalconium chloride and a s a stabilizer - the salt of disodium ethylenediamine tetraacetic acid, moreover, their range of osmolality values correspond to 150-450 mM/kg H2O. Eye drops should be obtained by preparing buffer system in which mannitol should be dissolved followed by the salt of disodium ethylenediamine tetraacetic acid, benzalconium chloride, ciprofloxacin hydrochloride. Then one should perform the control for the quality of obtained solution to be then filtered by applying sterilizing elements and packed. This innovation provides treatment of eyes at creating the pressure in an eye and at certain desired osmolality.

EFFECT: higher efficiency of therapy.

4 cl, 1 ex

Endoparasitic agent // 2250779

FIELD: medicine.

SUBSTANCE: invention relates to endoparasitic agent containing cyclic depsipeptide of general formula 1 and piperazine of formula 2 .

EFFECT: endoparasitic agent with synergetic agent.

6 cl, 7 ex, 7 tbl

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

EFFECT: improved method for preparing and treatment, valuable medicinal properties of compounds.

13 cl, 88 ex

FIELD: medicine.

SUBSTANCE: at performing curative endoscopy one should apply pneumoapplication of granulated sorbent - diovine at the quantity of 0.2 g, the pressure being 15 atm. at the distance of 1.5 cm against the defect onto the surface of bleeding rupture of gastric mucosa. Diovine's coarse-grained structure enables to keep the integrity of mucous-bicarbonate barrier due to providing normal vapor exchange and moisture medium in the defect. Moreover, diovine's antimicrobial action helps to suppress gram-positive and gram-negative microflora that enables to shorten terms for defects healing and decrease the frequency of repeated hemorrhages.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a medicinal formulation consisting of a core and the stomach-dissolving envelope. The core comprises trimetazidine dihydrochloride as an active component, and starch, mannitol, povidone, magnesium stearate, croscarmelose and microcrystalline cellulose as accessory substances. The envelope comprises hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, magnesium stearate and acid red as a dye. Also, invention describes a method for making the trimetazidine medicinal formulation. Trimetazidine tablets show high mechanical strength in the low pressing strength (3.5-5 kH). The composition of the medicinal formulation provides releasing 80% of trimetazidine for 30 min.

EFFECT: improved and valuable properties of formulation.

3 cl, 1 tbl, 1 ex

FIELD: medicine, neurology, pharmacy.

SUBSTANCE: invention proposes using levetiracetam and the corresponding levetiracetam-base pharmaceutical composition used in treatment of bipolar disorders, mania and migraine. Also, invention relates to a pharmaceutical composition based on levetiracetam and at least one inhibitor of GABA type A neuronal receptors that is used in treatment of epilepsy, alcohol withdrawal syndrome, tremor, bipolar disorders, obsessive-compulsive disorder, panic state, depression, headache, pain, ischemia and head trauma, to corresponding methods for treatment, to a method for selective enhancing the therapeutic effect of inhibitors of GABA type A neuronal receptors, to a method for treatment of patient with inhibitor of GABA type A neuronal receptors involving the combined administration of indicated inhibitor of GABA type A neuronal receptors with levetiracetam. Invention shows the possibility for using levetiracetam for treatment of chronic and neuropathic pain in lower doses as compared with doses causing secondary effects, and shows its property to enhance activity of inhibitor of GABA type A neuronal receptors.

EFFECT: improved and valuable medicinal properties of agent.

18 cl, 18 tbl, 7 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with compounds of formula IV , or their acidoadditive salts, methods of their obtaining and application while applying medicinal preparation for treating osseous diseases associated with increased calcium loss or resorption or when the stimulation of osteogenesis and fixation of bone calcium are required.

EFFECT: higher efficiency.

6 cl, 190 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds with formula I where R1, R2, R3 and Y together with a formula I residue, are compounds, chosen from a group given in the formula of invention, or to their pharmaceutically used and split esters, or to their acid-additive salts, which promote release of parathyroid hormone.

EFFECT: compounds can be used for making medicinal agents, with antagonistic properties towards calcium sensitive parathyroid gland receptor for treating diseases mediated by effect of parathyroid hormone.

7 cl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing dihydroquinazolines of formula (I), which are used to prepare medicinal agents. In formula

Ar denotes phenyl, possibly substituted with a C1-C4alkoxy group, R1 and R2 are selected from hydrogen, C1-C4alkoxy group and trifluoromethyl, R3 is selected from C1-C4 alkoxy group and trifluoromethyl, R4 denotes hydrogen or C1-C4alkyl, R5 denotes hydrogen or C1-C4alkyl, each of R6 R7 and R8 denotes hydrogen or halogen. The method involves hydrolysis of an ester of a compound of formula (II) in which Ar, R1, R2, R3, R4, R5, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, with a base or acid, where the compound of formula (II) obtained from reaction of a compound

of formula (III), is used, in which R1, R2, R3, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, in the presence of a base, with a compound of formula (IV) in which Ar, R4 and R5 are as described above. The method simplifies extraction of products.

EFFECT: invention also relates to novel intermediate compounds and a method of obtaining said compounds.

11 cl, 5 dwg, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing dihydroquinazolines of formula (I), which are used to prepare medicinal agents. In formula

Ar denotes phenyl, possibly substituted with a C1-C4alkoxy group, R1 and R2 are selected from hydrogen, C1-C4alkoxy group and trifluoromethyl, R3 is selected from C1-C4 alkoxy group and trifluoromethyl, R4 denotes hydrogen or C1-C4alkyl, R5 denotes hydrogen or C1-C4alkyl, each of R6 R7 and R8 denotes hydrogen or halogen. The method involves hydrolysis of an ester of a compound of formula (II) in which Ar, R1, R2, R3, R4, R5, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, with a base or acid, where the compound of formula (II) obtained from reaction of a compound

of formula (III), is used, in which R1, R2, R3, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, in the presence of a base, with a compound of formula (IV) in which Ar, R4 and R5 are as described above. The method simplifies extraction of products.

EFFECT: invention also relates to novel intermediate compounds and a method of obtaining said compounds.

11 cl, 5 dwg, 24 ex

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