The method of obtaining quinoline-carboxylic acid or its pharmaceutically acceptable salts and connection
(57) Abstract:Usage: as preparations possessing antibacterial activity. The inventive method of obtaining quinoline-carboxylic acid f-crystals(I) where the radicals R1-R6have the respective meanings interaction quinoline derivative f-crystals II, where R are the corresponding values derived from piperazine f-crystals III. The structure of the compounds f-l I,II,III . 2 C. 48 h. p. F.-ly. The invention relates to a new method of obtaining derivatives of 1-(possibly halo-substituted)-ethyl-7-(3,4,5-substituted piperazine)-6,8-debtor-4-oxo-1,4-dihydroxy - nolin-3-carboxylic acid of General formula
(I) and their pharmaceutically acceptable salts.In the General formula (I)
R1and R3hydrogen or C1-4-alkyl,
R4, R5and R6each hydrogen or halogen.It is known that the group of 7-(3, 4, 5-substituted piperazine)-quinoline-3-carboxylic acid derivatives of General formula (I) exhibits a high antibacterial activity [Antimicrob Agents Chemother. 1987, , 854; Drugs of Fur. 1986, , 578; 25-th Intersci Conf. Antimicrob Agents Chemother, 1985, 567; 26-th Intersci Conf. Antimicrob Agents Chemother. 1986, Abstr, 430-431]
Connection groups can be obtained by Pb 401/04, application Japan N 60-142980, N 61-85381 and N 61-65882).According to the present invention, a new method of obtaining derivatives of quinoline-3-carboxylic acid of General formula (I), where R1and R3hydrogen or C1-4-alkyl, R2C1-4-alkyl; R4, R5and R6each hydrogen or halogen, and pharmaceutically acceptable salts involves the reaction of compounds of General formula
(II) where R is halogen, aliphatic, acyloxy-group containing from 2 to 6 carbon atoms, or aromatic acyloxy-group containing from 7 to 11 carbon atoms; R4, R5and R6have the above significance, with an amine of General formula
RNH (III) where R1, R2and R3have the above significance, or its salt and the hydrolysis of the thus obtained compounds of General formula
(IV) where R, R1-R6such as described above, after or without isolation and, if desired, converting the thus obtained compounds of General formula (I) in its salt or its release from its salts.The advantage of the method according to the present invention is that it simplifies obtaining the compounds of General formula (I), provides a very high yield at low reaction time. The boron deposition is of the invention is a boron derivative of General formula (IV) is transformed into the desired quinoline-3-carboxylic acid of General formula (I) without their prior allocation.Boron-derivative of General formula (II) can be reacted with an amine of General formula (III), optionally in the presence of an inert organic solvent and agent for binding the acid.As the organic solvent preferably used acid amide (for example, dimethyl-formamide, dimethyl-ndimethylacetamide), ketone (e.g. acetone, methyl-ethyl-ketone), an ether (e.g. dioxane, tetrahydrofuran, diethyl ether), esters (e.g. ethyl acetate, methyl acetate, ethylpropane), a sulfoxide (e.g., dimethylsulfoxide), alcohol (e.g. methanol, ethanol, 1-decanol, butanol), and halogenated nitrile (e.g. acetonitrile) organic solvent (e.g. chloroform, dichloromethane).As agent for binding the acid can be used organic or inorganic base. From the group of organic bases include trialkyl-amines (e.g. triethylamine; tributylamine), cyclic amines (e.g. pyridine, 1,5-diazabicyclo(5.4.0)-undec-5-ene, 1,5-diazabicyclo(4.3.0) non-5-ene, 1,4-diazabicyclo(2.2.2) octane), as well as inorganic bases can be used hydroxides or carbonates of alkali or alkaline earth metals. So, as is the atrium, calcium hydroxide, etc. or an excess of amine of General formula (III).Boron-derivative of General formula (II) and the amine of General formula (III) reacting at a temperature of from 10 to 200aboutWith depending on the used solvent. The reaction time may vary from 0.1 to 10 hours reaction Time also depends on temperature. If the reaction is carried out at a higher temperature, the reaction time can be shortened. These conditions are preferred, but can also be used and other conditions.Compounds of General formula (IV) can be hydrolyzed to the desired quinoline-3-carboxylic acids of General formula (I) after or without isolation, in an acidic or basic environment. Compounds of General formula (IV) may optionally be deposited from the reaction mixture, for example, cooling, and can be separated, e.g. by filtration or centrifugation.Basic hydrolysis can be carried out preferably by heating, using a hydroxide of alkali or alkaline-earth metal in the form of its aqueous solution. It is preferable to use an aqueous solution of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, calcium hydroxide. At the stage of hydrolysis, however, can also is with the use of aqueous mineral acid. The hydrolysis of compounds of General formula (IV) is preferably carried out by heating these compounds with an aqueous solution of HCl, HBr, H2SO4and H3PO4. The hydrolysis can also be carried out using an organic acid (e.g. acetic, propionic, and others).The hydrolysis of compounds of General formula (IV) can be carried out in aqueous medium in the presence of an organic solvent, able to mix with water. For this purpose can be used, for example, alcohols (e.g. methanol, ethanol), a ketone (e.g. acetone), ether (e.g. dioxane), acid amide (e.g. dimethylformamide), a sulfoxide (e.g., dimethyl sulfoxide or pyridine.Thus obtained quinoline-3-carboxylic acid of General formula (I) can be selected by bringing the pH to a suitable value, and separating the precipitated crystals, for example by filtration or centrifugation, or by lyophilization of aqueous reaction mixture.Compounds of General formula (I) can be converted into their pharmaceutically acceptable salts by a known method. Thus, preferably, these salts can be formed by adding an acid, for example by reaction with hydrogen halide, sulfonic acids, sulfuric kaleolani, maleate, fumarate, benzoate, and other Compounds of General formula (I) also form salts with ions of alkali, alkaline earth and other metals. Respectively can be obtained salts of sodium, potassium, magnesium, silver, copper, etc.Compounds of General formula (I) and their pharmaceutically acceptable salts can be converted into hydrates (for example, hemihydrate, trihydrate and so on) known methods.A further aspect of the present invention is to provide new compounds of General formula (IV), where R, R1-R6above.Starting materials of General formula (II) can be prepared by reaction of 1-ethyl-6,7,8-Cryptor-4-oxo-1,4-dihydrothieno - Lin-3-carboxylic acid (patent UK N 2.057.440) with a derivative of boron, for example with a compound of General formula (V)
B (V) where R is hydrogen or an aliphatic, acyloxy-group containing from 2 to 6 carbon atoms, or aromatic acyloxy-group containing from 7 to 11 carbon atoms, or perborate in aqueous or organic medium.Details of the present invention described in the examples without limiting the scope of protection of these examples.P R I m e R 1. 31,9 g (1-ethyl-6,7,8-tri-fluoro-1,4-dihydro-4-hydroxy-quinoline-3-carbox - Silat- , )-deferror 3% (wt. or about.) an aqueous solution of sodium hydroxide and carry out the hydrolysis by heating for 2 hours, the Reaction mixture is filtered, the pH adjusted to 7 of 96% acetic acid.The crystalline reaction mixture is cooled overnight and the precipitated crystals are filtered, washed with water and dried. You get a 29.9 g of 7-(3,5-dimethyl-piperazine derivatives)-1-ethyl-6,8-debtor-1,4-dihydro-4-oxo-quinoline-3-carbon - howl acid.So pl. 232-234aboutC.Analysis by the formula C18H21F2N3O3:
calculated C=59,17, H=5,80, N=11,49
found, C=59,05, H=5,91, N=OF 11.45
P R I m m e R 2. In example 1 to 31.9 g (1-ethyl-6,7,8-Cryptor-1,4-dihydro-4-oxo - quinoline-3-carboxylate-,)deferror react with 50.1 g of 2-methyl-piperazine in 150 ml of dimethyl sulfoxide. You get 30,6 g of 1-ethyl-6,8-debtor-1,4-dihydro-4-oxo-7-(3-methyl-piperazine derivatives)quinoline - 3-carboxylic acid.So pl. 238-240aboutC.Analysis by the formula C17H19F2N3O3:
calculated C=58,11, H=the 5.45, N=11,96
found, C=58,01, H=5,55, N=12,07
P R I m e R 3. In example 1 and 39.9 g (1-ethyl-6,7,8-Cryptor-1,4-dihydro-4-oxo - quinoline-3-carboxylate-,) -bis(acetato-)-boron react with 50.1 g of 2-methyl-piperazine in 150 ml of dimethyl sulfoxide. This perfectly-239aboutC.Analysis by the formula C17H19F2N3O3:
calculated C=58,11, H=the 5.45, N=11,96
found, C=57,97, H=of 5.53, N=11,90
P R I m e R 4. In example 1 of 42.7 g (1-ethyl-6,7,8-Cryptor-1,4-dihydro-4-oxo - quinoline-3-carboxylate-, ) -bis-(propionato-)-boron react with 50.1 g of 2-methylpiperazine. You get to 28.7 g of 1-ethyl-6,8-debtor-1,4-dihydro-4-oxo-7- (3-methyl-piperazine derivatives)quinoline-3-carboxylic acid.So pl. 237-239aboutC.Analysis by the formula C17H19F2N3O3:
calculated C=58,11, H=the 5.45, N=11,96
found, C=57,99, H=5,52, N=12,10
P R I m e R 5. To a solution of 3.99 g (0.01 mol) of 1-ethyl-6,7,8-Cryptor-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03that 04(bis)ACE tat-0)-boron in 40 ml of chloroform added 3.0 g (0.03 mol) of 2-methyl-piperazine and the solution stirred at room temperature for 1.5 h Chloroform distilled off in vacuum and the oily residue, retinoid, yellowish, add 40 ml of 4% NaOH and the mixture is heated under stirring for 1 h the resulting solution is filtered, cooled to room temperature and bring the solution pH to 6.5-7 96% acetic acid (1.5 ml). After cooling roll crystalline precipitate, which is washed with water (5 ml), ethanol (5 McIlroy acid. Melting point 241-242aboutC.Analysis calculated for C17H19F2N3O3:
calculated, C=58,11, H=the 5.45, N=11,96
found, C=58,02, H=5,54, N=11,94
P R I m e R 6. To a solution of 3.99 g (0.01 mol) of 1-ethyl-6,7,8-Cryptor-1,4-dihydro-4-oxo-hee - nolin-3-carboxylate-03that 04bis(acetate-0)-boron in 20 ml of dimethyl-sulfoxide add 3.0 g (0.03 mol) of 2-methyl-piperazine. The solution is stirred at room temperature for 10 minutes, then add 20 ml of 8% aqueous NaOH and the mixture is heated at 80aboutC for 1 h the resulting solution is filtered, cooled to room temperature and adjusted pH to 6.5-7 with 96% acetic acid. After cooling, the precipitated crystals filtered, washed with water (5 ml), then methanol (5 ml) and dried. So get 3,19 g (91%) of 1-ethyl-6,8-debtor-1,4-dihydro-4-oxo-7-(3-methylpiperazin)-quinoline - 3-carboxylic acid. Melting point 241-242aboutC.Analysis for C17H19F2N3O3:
calculated, C=58,11, H=the 5.45, N=11,96
found, C=57,98, H=5,50, N=12,00
P R I m e R 7 (comparative). The mixture 2,71 g (0.01 mol) of 1-ethyl-6,7,8-Cryptor-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and 3.0 g (0.03 mol) of 2-methyl-piperazine in 100 ml of chloroform is stirred at room. the Nov get the original 1-ethyl-6,7,8-Cryptor-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with a yield of 90%
P R I m e R 8 (comparative). A solution of 2.0 g (2-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-03that 04) -bis (ACET-0)-boron and 1.3 g of piperazine in 20 ml of DMSO is stirred at room temperature for 3 hours the reaction Products were investigated by TLC. Did not find any product other than the original. After hydrolysis with exit 94% of newly allocate the original 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline- -3-carboxylic acid. Melting point 272aboutC.Analysis for C12H9ClFNO3:
calculated, C=53,45 H=3,36 N=5,19 Cl=13,14
found, C=53,41 H=3,43 N=5,18 Cl=13,31.P R I m e R 9. To a mixture of 4.2 g of 1-(2-foradil)-6,7,8-Cryptor-1,4-dihydro-4-oxo-hin - Olin-3-carboxylate - 03that 04bis-(ACET-0)-boron and 35 ml of chloroform added 3.4 g of 2-methyl-piperazine and the mixture is stirred at room temperature for 3 hours the Solvent is removed in vacuo and to the precipitate add 4% aqueous NaOH solution (40 ml) and the mixture is stirred for 1 h the resulting solution is acidified to pH= 6.5 96% acetic acid. The crystals are collected, washed with cold methanol and dried. So get a 3.06 g (84,6%) 1-(0-foradil)-7-(3-methylpiperidino formula C17H13N3O3F3:
calculated, C=55,28, H=4,91, N=11,37
found, C=55,20, H=4,94, N=11,40
P R I m e R 10 (comparative). The mixture 2,82 g (0.01 mol) 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoindole-3-carbon - OIC acid and 2.58 g (0.03 mol) of piperazine in 100 ml of chloroform is stirred at room temperature for 8 hours Liquid thin layer chromatography shows no other product other than the original products. After this initial 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoindole-3-carboxylic acid get back with the release of 92%
P R I m e R 11 (comparative). A solution of 4.1 g (0.01 mol) (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-1-exogenesis-3-carbox-Silat-) -bis (ACET-)-Bora and 1.3 g (0.015 mol) of piperazine in 20 ml of DMSO, stirred at room temperature for 8 hThe reaction mixture was subjected to TLC. In addition to the original products, no other was not found.After hydrolysis get 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-Hino - Lin-3-carboxylic acid with a yield of 91% of T. pl. 241 to 243aboutC.Analysis of formula: C13H9ClFNO3:
Calculated, C=55,43; H=3,22; N=4,9; Cl=12,59; F=6,74.Found, C=54,81, H=3,03; N=4,67; Cl=12,67, F=6,97
P R I m e R 12. To 3,99 g (0,0 sid added 3.0 g (of 0.003 mol) of 2-methylpiperazine. The solution was stirred at room temperature for 10 minutes, add a mixture of 10 ml of water and 5.4 ml of HCl and the reaction mixture is heated at 100aboutC for 30 minutes the Mixture is filtered, the filtrate is neutralized to 4.0 ml of 25% (wt./about) ammonia solution. After cooling, the precipitated crystals are filtered, washed with water (5 ml), methanol (5 ml) and dried. So get to 3.16 g (90%) of 1-ethyl-6,8-debtor-1,4-dihydro-4-oxo-7-(3-Meile - perinchery) -3-carboxylic acid.Analysis of C17H19F2N3O3:
calculated, C=58,11, H=the 5.45, N=11,96
found, C=58,05, H=5,50, N=11,91
P R I m e p 13. To a solution of 3.99 g (0.01 mol) (1-ethyl-6,7,8-Cryptor-1,4-dihydro-4-oxoindole-3-carboxylate-) -bis-(Aceto-)boron in 40 ml of chloroform added 3.0 g (0.03 mol) of 2-methylpiperazine and the solution stirred at room temperature for 1.5 hours, the Chloroform is distilled off in vacuum and the remaining yellowish oily resin handle N. hexane (20 ml). The resulting crystalline material was separated, washed N. hexane (5 ml). So get 4,55 g (95%) of intermediate chelate, 1-ethyl-6,8-debtor-7-(3-methylpiperazin)-1,4-dihydro-4-oxoindole - 3-carboxylate-, )-bis-(Aceto-)-Bora.T. sq. > 280aboutC.Intermediate chelate (4,55 g) hydrolyzing within 1.5 hours The resulting solution is filtered, cooled to room temperature and bring the solution pH to 6.5-7 96% acetic acid (1.5 ml). The mixture was kept overnight in the refrigerator, then the crystals are selected, washed with water (5 ml) and then ethanol (5 ml) and dried.Thereby obtaining 3.1 g (88%) of 1-ethyl-6,8-debtor-1,4-dihydro-4-oxo-7-(3-IU - teleperson)-quinoline-3-carboxylic acid. So pl. 242-243aboutC.Analysis for C17H19F2N2O3< / BR>calculated, C=58,11, H=the 5.45, N=11,96
found, C=58,05, H=5,52, N=11,95
P R I m e R 14. To a mixture of 4.2 g of [1-(2-foradil)-6,7,8-Cryptor-1,4-dihydro-4-oxigeno - Lin-3-carboxylate-,] -bis-(Aceto-)-Bora and 35 ml of chloroform added 3.4 g of 2-methylpiperazine and the mixture is stirred at room temperature for 3 hours the Solvent is removed in vacuo and to the residue is added 40 ml of 4% (wt./about) aqueous solution of NaOH, and the mixture is stirred for one hour. The resulting solution is acidified to pH=6.5 96% (wt/V) acetic acid.The crystals are collected, washed with cold methanol and dried.So get a 3.06 g (84,6%) 1-(2-foradil)-quinoline-3-carboxylic acid. So pl. 238-240aboutC.Analysis for C17H18N3O3F3:
calculated, C=55,2 the crystals I
< / BR>where R1and R3hydrogen or C1-C4alkyl;
R4, R5and R6hydrogen or halogen,
or its pharmaceutically acceptable salts by the interaction of the quinoline derivative with piperazine derivatives, characterized in that as a derivative of quinoline is used as a compound of General formula II
< / BR>where R is halogen, aliphatic C2-C6-alloctype or aromatic7-C11-alloctype;
R4, R5, R6have the specified values,
as a derivative of piperazine compound of General formula III
< / BR>where R1R3have the specified values,
or its salt, the process is carried out at a temperature from room temperature to 100oIn the environment of an organic solvent with subsequent hydrolysis of the thus obtained compounds of General formula IV
< / BR>where R, R1R3have the specified values,
and produce the target product in free form or in salt form.2. The method according to p. 1, characterized in that the reaction of compounds of General formula II with the amine of General formula III is carried out in the presence of an organic solvent, preferably audica fact, as the organic solvent used sulfoxide.4. The method according to p. 1, characterized in that the reaction of the compounds of General formulas II and III is carried out in the presence of an agent that binds acid.5. The method according to p. 4, wherein the agent that binds acid, using amine or an excess of the compounds of General formula IV.6. The method according to p. 1, characterized in that the hydrolysis is carried out in an acidic environment.7. The method according to p. 6, characterized in that the reaction is carried out using organic or inorganic acid, preferably hydrochloric, sulfuric or acetic acid.8. The method according to p. 1, characterized in that the hydrolysis is carried out in an alkaline medium.9. The method according to p. 8, characterized in that to create an alkaline environment using a hydroxide of alkali or alkaline earth metal or organic base, preferably an aqueous solution of triethylamine.10. The compound of General formula
< / BR>where R1and R3hydrogen or C1-C4alkyl;
R4, R5and R6hydrogen or halogen.
(I) where R is hydrogen, halogen, lower alkyl or lower alkoxygroup;
And group O or S;
In group-CH2-CH2or СНR1where R1means hydrogen, lower alkyl or hydroxyl;
X is oxygen or the group NH
The Y group of the formula)qwhere R2means lower alkyl, q is 2 or 3, and their salts, in particular physiologically tolerable salts, which possess pharmacological activity, in particular activity antimuskarinovoe act occurs, and therefore can be used to treat diseases of the gastrointestinal tract and respiratory tract
(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=N (a-5) or
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;
Y is O or NH;
Z1or Z2each independently NH or a direct link X-O
each Аlk independently - C1-C6alcander
NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity
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
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
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:
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
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.
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
SUBSTANCE: invention relates to derivatives with anticancer activity of formulae:
, , , , ,
R2', R3', R4', R5' and R6' are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9; Y is selected from O and S; X is selected from F, Cl and Br; R8 and R9 are selected from (CH2)nCH3; R2, R3, R4 and R5 are selected from H, Y(CH2)nCH3, X and (CH2)nNR8R9, or R3 and R4 together form -Y(CH2)nY-; R1 and R1' are selected from H, Li+, Na+, K+, N+R8R9R10R11 or benzyl, where R10 and R11 are selected from H, (CH2)nYH, (CH2)nN(CnH2n+1)(CmH2m+1) or (CH2)nCH3, where n and m are integers from 0 to 4, q is an integer from 1 to 4.
EFFECT: obtaining novel compounds with anticancer activity.
37 cl, 3 dwg, 10 ex, 2 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new quinolone derivatives of general formula (1) or a pharmaceutically acceptable salts thereof, wherein R1 represents a hydrogen atom, a lower alkyl group, cyclo C3-8 alkyl, a lower alkyl group or a lower alkoxy, a lower alkyl group; R2 represents a hydrogen, a lower alkyl group or a halogen-substituted lower alkyl group; R3 represents a phenyl group, a difurylglyoxal group, a thienyl group or pyridyl group with each group of the above is optionally substituted by one or two groups specified in a group consisting of the following (1) to (16) in an aromatic or heterocyclic ring, presented by the above R3: (1) lower alkyl groups, (2) lower alkoxy groups, (3) halogen-substituted lower alkoxy groups; (4) a phenoxy group, (5) lower alkylthio groups, (6) a hydroxy group, (7) hydroxy lower alkyl groups, (8) halogen atoms, (9) lower alkanoyl groups, (10) lower alkoxycarbonyl groups, (11) amino groups optionally substituted by one or two lower alkyl groups, (12) carbamoyl groups optionally substituted by one or two lower alkyl groups, (13) cyclo C3-8 alkyl lower alkoxy groups, (14) pyrrolidinyl carbonyl groups, (15) morpholinyl carbonyl groups and (16) a carboxyl group; R1 represents a halogen atom; R5 represents a hydrogen atom or a halogen atom; R6 represents a hydrogen atom; and R7 represents any of the above groups (1) to (15): (1) a hydroxyl group, (2) a halogen atom, (3) a lower alkoxy group, (4) a halogen-substituted lower alkoxy group, (5) a hydroxy lower alkoxy group, (6) a lower alkoxy lower alkoxy group, (7) an amino group optionally substituted by one or two members specified in a group consisting of lower alkyl groups, lower alkoxy lower alkyl groups and cyclo C3-8 alkyl groups, (8) an amino lower alkoxy group optionally substituted in an amino group by one or two members specified in a group consisting of lower alkyl groups, lower alkanoyl group, lower alkyl sulphonyl groups and carbamoyl groups optionally substituted by one or two lower alkyl groups, (9) a cyclo C3-8 alkoxy group, (10) a cyclo C3-8 alkyl lower alkoxy group, (11) a tetrahydrofuryl lower alkoxy group, (12) a lower alkylthio group, (13) a heterocyclic group specified in a group consisting of morpholinyl groups, pyrrolidinyl groups, difurylglyoxal groups, thienyl groups and benzothienyl groups, (14) a phenyl lower alkoxy lower alkoxy group and (15) a pyrrolidinyl carbonyl group. Also, the invention refers to a pharmaceutical composition, and a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method of treating or preventing the above diseases, to a method of preparing the compound of formula (1).
EFFECT: there are prepared new quinolone derivatives effective for treating and/or preventing the neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.
11 cl, 1 tbl, 104 ex