The method of obtaining n-(-hydroxyethyl)-4,6 - dimethylpyrimidine-2

 

(57) Abstract:

Usage: in the medical industry. The inventive method of obtaining N-( b-hydroxyethyl)-4,6-dimethyl-dihydropyrimidine-2. Reagent 1: urea. Reagent: ethanolamine in excess heated at 110-125°C for 6.5 1.5 h with bubbling in the reaction mass of nitrogen formed during ethanolgasoline isolated and treated with acetylacetone and hydrochloric acid in the environment isopropanol, the resulting crystalline product is isolated in the form of hydrochloride or base by treatment of a chloroform solution of the hydrochloride of the alkaline reagent. 3 C.p. f-crystals.

The invention relates to chemistry and technology of heterocyclic compounds, pyrimidine series, namely 4,6-dimethyl-N-( -oxyethyl)-2-oxo-1,2-dihydropyrimidine, which is called ksimedon recommended for use in medicine as a burn-drug immune action [1]

A known method of producing Ximena [2] consisting in the conversion of the hydrochloride of 2-hydroxy-4,6-dimethylpyrimidine sodium salt of 2-hydroxy-4,6-dimethylpyrimidine, when heated, which ethylenchlorhydrine received ksimedon. The main disadvantage of this method was the low quality of the CNS of the product was 134,5-135,5aboutC. in Accordance with the requirements of the temporary monograph (VFS) melting point of Ximena must be within 138-142aboutC. To improve the quality of Ximena developed an improved version of this method formed the basis of regulation [3] adopted for the prototype. The process of the prototype is carried out in three stages (figure 1).

Circuit 1

CO(NH2)

_____ +

+ +

In the first stage, urea is treated with acetylacetone in the environment isopropanol (isopropyl alcohol) in the presence of hydrochloric acid at the boiling point. After cooling, the mixture is filtered precipitated hydrochloride of 2-hydroxy-4,5-dimethylpyrimidine (I), washed with IPA and dried. Exit I-78% In the second stage I treated with an aqueous solution of sodium hydroxide at 105aboutC, poured into molds, cooled, transferred manually hardened mass of sodium salt of 2-hydroxy-4,6-dimethylpyrimidine (II) on a vacuum funnel, press from the mother liquor and dried under vacuum at 80-90aboutWith to a moisture content of not more than 0.5% Output II 85% I.

At the third stage heated to the boiling solution ethylenchlorhydrine in absolute methanol dosed II at 50-55aboutC for 6 h, after which give exposure at the boil for 20 hours Massa crystals technical Ximena red-brown color is filtered off, washed with acetone, dried, and crystallized from isopropyl alcohol. Get ksimedon red, containing 4-8% of impurities (mainly 2-hydroxy-4,6-dimethylpyrimidin). The output of Ximena on II 51% Norm ksimedon white get missing chloroform solution crystallized from isopropyl alcohol of Ximena through a column Packed with 2.5 M. D. aluminum oxide and 0.1 M. D. activated charcoal. Of the purified solution is distilled 80% taken chloroform, add to the residue acetone, ksimedon filtered off, washed and dried. The output of pharmacopoeial Ximena in terms of urea or acetylacetone 20,0%

Disadvantages of the process of the prototype are: low yield of the target product; the use of highly toxic substances (ethylenchlorhydrine and methanol) and deficient aluminum oxide; a multi-stage process; the complexity of the process and the presence of a large number of manual operations; high consumption of raw materials.

The aim of the invention is to increase the output of Ximena, simplification of the production technology, reducing consumption of raw materials.

The objective is achieved by heating urea with excess ethanolamine at 110-125aboutWith over a 6.5-1.5 h, respectively, with bubbling nitrogen are ethanolgasoline, no highlighting or outlining vasica crystalline hydrochloride 4,6-dimethyl-N-oxyethyl)-2-oxo-1,2-dihydropyrimidin (hydrochloride Ximena) from the mother liquor and process it with an alkaline reagent in an aqueous medium or aqueous chloroform, followed by separation of Ximena.

Processing hydrochloride Ximena in the aquatic environment carried out with sodium hydroxide, sodium carbonate, sodium bicarbonate until a pH of not more than 9,0 (preferably pH 8.0) followed by distillation of water, extraction of the dry residue with chloroform, and the allocation of Ximena from chloroform-known trick.

Processing hydrochloride Ximena in water chloroform spend sodium carbonate, sodium bicarbonate, aqueous ammonia at a ratio of 1 M. D. hydrochloride Ximena: 0,4 about.D. water: about 12.D. chloroform, followed by separation of the chloroform extract and the release of his Ximena known trick.

The chemistry of the process can be represented by scheme 2.

Scheme 2

CO(NH2)2NH2CONHCH2CH2OH

< / BR>
P R I m e R 1. Obtaining hydrochloride Ximena.

Mix and 65.7 g of 97.5% ethanolamine (64,0 g or 1.05 mole in terms of 100% substance) and 60.0 g (1 mol) of urea was heated to 115aboutC and at this temperature, and the bubbling of the nitrogen was incubated for 4.5 hours, the Mixture is cooled and the temperature does not exceed 80aboutTo the reaction mass is poured 350 ml of isopropyl alcohol and 105,8 g 94,5% technical acetylacetone (100 g or 1.0 mol in terms of 100% substance). To the resulting solution shall provide the reaction mass at boiling (82-84about(C) for 2.5 h, then cooled to 10-15aboutC, the precipitated crystals of the hydrochloride Ximena filtered and washed twice with 70 ml of isopropyl alcohol, dried at 90aboutC. the Yield of the hydrochloride Ximena are 159,4 g (77,9% in terms of urea or acetylacetone). Mass fraction of the main substances to 99.6% (potentiometric titration).

The melting point of 232aboutC (with decomp.), IR-spectrum UV spectrum and Rfthe product is identical to the hydrochloride Ximena received counter synthesis of Ximena prototype and hydrochloric acid in the environment isopropanol.

Getting Ximena. The obtained hydrochloride Ximena (159,4 g) is dissolved with stirring and the temperature of 40-50aboutWith 200 ml of 1.25 m D.) water and at this temperature, dispense a 40% solution of sodium hydroxide to pH 8.0 (consumption of sodium hydroxide, about 31.5 g). From padmalochan solution distilled water under vacuum. To the dry residue add 1275 ml (about 8.d) chloroform, the mixture was stirred at 45-50aboutC for one hour, cooled to 20-25aboutWith that filter out the sodium chloride. From a chloroform solution Ximena excess distilled chloroform to volume of VAT residue 400-450 ml, add 640 ml of acetone with stirring, give in Cetona, dried at 80-90aboutWith in 2-3 hours Get 131,2 g (78,1%) Ximena with tPL= 141,0-141,8aboutC, M. D. basic substance 99.3% of the remaining indicators meet the requirements of the VFS.

P R I m e R s 2-9. Show the effect of synthesis conditions of ethanolgasoline (molar ratio of ethanolamine and urea, temperature and reaction time, the bubbling of nitrogen on yield and quality of the hydrochloride of Ximena and Ximena. The order of conducting the process described in example 1.

P R I m e R 10. The process emitting from the reaction mass ethanolgasoline. Mix and 65.7 g (1.05 m 100%) 97.5% of ethanolamine and 60 g (1 m) of urea while sparging the reaction mixture with nitrogen heated for 4.5 hours at 115aboutC, cooled to 80aboutTo add 95 ml of isopropanol, heated to boiling, cooled to 15-20aboutC and maintained under stirring for 1.5 hours the Precipitated crystals of ethanolgasoline filtered off, washed with 2 times 50 ml of fresh isopropanol and dried.

Get to 68.8 g (66,1%) ethanolgasoline with tPL=84-88aboutC.

Obtaining hydrochloride Ximena. of 68.8 g (0.66 m) ethanolgasoline dissolved in 230 ml of isopropyl alcohol and add 70 g (66,15 g in terms of 100% substance; 0.66 m) 94,5% technical acetylated h at boiling of the reaction mixture (82-84aboutC), then cooled for 1.5 h to 10-15aboutWith drop crystals of the hydrochloride Ximena. The suspension is stirred 0.5 h, hydrochloride Ximena filtered and washed twice with 45 ml of isopropyl alcohol, dried on the filter 0.5 h and dried at 90aboutC.

Output 107,15 g (79,2%) acetylacetone), tPL=232aboutC (with decomp.). M. D. basic substance according to the potentiometric titration 99.7% of the IR spectrum is identical to the IR spectrum of the hydrochloride Ximena obtained from Ximena obtained from Ximena the method prototype. Next hydrochloride Ximena use in the synthesis of Ximena without purification.

Getting Ximena. 107,15 g of the hydrochloride of Ximena dissolved under stirring at a temperature of 40-50aboutWith 135 ml of water, dispense a 40% solution of sodium hydroxide to pH 8.0 (approximately 21,0 g 100% NaOH), distilled water under vacuum. To the dry residue add 860 ml of chloroform, stirred for 1 h at 45-50aboutC, cooled to 20-25aboutWith that filter out the sodium chloride. From the filtrate distilled chloroform to volume of VAT residue 270-320 ml, add 430 ml of acetone, allowed to stand for 1 h at 15-20aboutC. Ksimedon filtered off, washed with 100 ml of acetone, dried at 80-90aboutWith in 2-3 hours Get 69,1 g (78.5 per cent) COP the pits VFS.

P R I m e R s 11-21. Obtaining hydrochloride Ximena is carried out as in example 1.

The selection of Ximena of the hydrochloride of Ximena alkaline reagents sodium hydroxide, sodium carbonate and sodium bicarbonate at different pH values padmalochan aqueous solution is carried out as in example 1.

The sodium hydroxide in the alkalization hydrochloride Ximena used as in example 1 in the form of a 40% aqueous solution, and sodium carbonate and sodium bicarbonate in solid form.

P R I m e R 22. The selection of Ximena of the hydrochloride of Ximena sodium carbonate in aqueous chloroform.

To a suspension 20,45 g (0.1 m) of the hydrochloride of Ximena (example 1) in 245 ml (about 12. D. ) chloroform add to 8.2 ml (0.4 M. D.) water and sprinkled 5.8 g (0.55 m) of sodium carbonate. Give exposure at 45aboutC for 1.5 h with vigorous stirring. Separate the chloroform by decantation from inorganic salts, then in a separating funnel the aqueous layer was separated. The resulting solution Ximena in chloroform is distilled off 190 ml of chloroform, VAT residue added 82 ml (about 4.D.) of acetone. Stirred for 1.5 h at 15aboutWith sucked ksimedon, washed with 15 ml of acetone and dried.

Output Ximena of 12.6 g P> P R I m e R s 23-29. The process is conducted as in example 22 with the change quantities of sodium carbonate, water and chloroform.

P R I m e R 30. The selection of Ximena of the hydrochloride of Ximena with sodium bicarbonate in aqueous chloroform.

To a suspension 20,45 g (0.1 m) of the hydrochloride of Ximena (example 1) in 245 ml (about 12. D. ) chloroform add to 8.2 ml (0.4 to about.D.) water and a 9.25 g (0,11 m) of sodium bicarbonate, stirred for 1.5 h at 45aboutTo separate the chloroform from a mixture of salt and water is distilled off from it ml chloroform, VAT residue added 82 ml (about 4. D.) acetone. Stirred for 1.5 h at 15aboutWith sucked ksimedon, washed with 15 ml of acetone and dried. The output of Ximena of 12.9 g (76,8% ), tPL= 139,5 - -140,4aboutC, M. D. basic substance 99.4% of the remaining parameters correspond to VFS.

P R I m e R 31. The selection of Ximena of the hydrochloride of Ximena sodium hydroxide in aqueous chloroform.

To a suspension 20,45 g (0.1 m) of the hydrochloride of Ximena (example 1) in 245 ml (about 12.D.) chloroform added under stirring a solution of 4.0 g (0.1 m) sodium hydroxide in 3 ml of water. Stirred for 1 h at 45aboutTo separate the chloroform solution Ximena from the aqueous phase and solid sodium chloride. From a chloroform solution ximera ksimedon, washed with 15 ml of acetone, dried at 80-90aboutWith 2 hours Yield 3.4 g (50%), tPL=132,2-138,4, M. D. basic substance to 98.6%

P R I m e R s 32-33. The process is conducted as described in example 31, but using different amounts of sodium hydroxide.

P R I m e R 34. The selection of Ximena of the hydrochloride of Ximena water ammonia in the environment of chloroform.

To a suspension 20,45 g (0.1 m) of the hydrochloride of Ximena (example 1) in 245 ml (about 12. D. ) chloroform type of 8.9 ml (0.4 to about.d) to 25.4%-aqueous ammonia (1.2 m), stirred for 1 h at 45aboutTo separate the chloroform solution Ximena of water and ammonium chloride. Added 10.4 g of anhydrous sodium sulfate, stirred for 3 h, the drying agent is filtered off. From a chloroform solution Ximena distilled 210 ml of chloroform, added 82 ml (about 4.D.) acetone, cooled to 15-20aboutTo give a shutter speed of 1.5 h, ksimedon filtered off and dried. The yield of 13.1 g (77,9%).

to 1.0 g (6.1%) Ximena contained in chloroforming-the acetone mother liquor, the remaining losses are due to the high solubility of Ximena in the aqueous phase.

P R I m e R 35 carried out analogously to example 34 without drying plaforming solution Ximena before allocation of a target product.

Presented prioria.

We use the same reagents (urea, acetylacetone, hydrochloric acid).

The use of the reaction of formation of pyrimidine cycle of ureides component of acetylacetone and hydrochloric acid at the boiling point.

The selection of Ximena from a chloroform solution by planting acetone.

Distinctive features of the present invention.

In the prototype, the use of urea as ureides component, warming her with acetylacetone and hydrochloric acid in isopropanol. This forms a hydrochloride of 2-hydroxy-4,6-dimethylpyrimidin.

In the present invention urea is heated with an excess of ethanolamine and formed ethanolgasoline (emitting or directly as reaction mass) is used as ureides component in the reaction with acetylacetone and hydrochloric acid in the environment of isopropanol at the boiling point. This forms a hydrochloride Ximena. In the further selection process Ximena of its hydrochloride, in addition to the final stage of the selection Ximena from a chloroform solution, is different from the prototype. The fundamental difference methods can be seen when comparing figures 1 and 2.

Put the percent mass of nitrogen provides high quality formed with ethanolgasoline and the absence of impurities therein urea, allowing further the process of obtaining hydrochloride Ximena and Ximena without allocation ethanolgasoline (examples 1-9).

In the absence of an excess of ethanolamine (examples 3, 4) in the reaction mass contains unreacted urea, which when reacted with acetylacetone forms a mixture of the hydrochloride of 2-hydroxy-4,6-dimethylpyrimidine (scheme 1), and this mixture during the alkalization of the forms of the free base 2-hydroxy-4,6-dimethylpyrimidin, removal of which requires the use of a column with alumina. A small excess ethanolamine does not form insoluble in the reaction medium of impurities in obtaining hydrochloride Ximena and is removed by filtration and washed with ISO-propanol hydrochloride Ximena.

Temperature and process time is determined by the kinetics of the ammonia.

Use as ureides component directly ethanolgasoline isolated from the reaction mixture during the synthesis of etilenmocevina (example 10) leads to the complication of the General scheme of the process and waste of raw materials (urea, ethanolamine, isopropanol).

The selection of Ximena by alkalinization of the aqueous solution of the hydrochloride Ximena to a pH of not higher than 9,0 (predpochtite reformage solution known technique provides the maximum yield and quality of Ximena (examples 1 and 11-21). At pH below 8.0 for not achieved the fullness of neutralization (pH of an aqueous solution of Ximena 8,2), and at pH 9.5 and above the selected ksimedon does not meet the requirements of VFS by the mass fraction of the main substances and impurities, the melting temperature and color. The appearance of impurities and related to the presence of yellow color at pH of 9.5 is due to the property of Ximena, as proven by heating Ximena in water at rn,5; ksimedon reacts samarangense.

The use of water-chloroform environment while highlighting Ximena of the hydrochloride of Ximena (examples 22-35) allows to significantly simplify the technological process of Ximena, as this prevents Stripping of the water to dryness. The process of distillation of water to dryness difficult in technological design, requires heating and vacuum.

When using water-chloroform environment requirements are reduced pH environment, because there is no heating of the aqueous phase. At the same time, the use of such hard alkaline reagents as sodium hydroxide impractical (examples 31-33) due to the passage adverse reactions with chloroform.

The use of chloroform due to the fact that this solvent only, sufficient is the action scene with water.

The quantity of chloroform should be not less than about 12. D. to exclude a significant loss of Ximena with water, in which it dissolves very well (requires 0,8 about.D. water dissolving 1 m e Ximena).

Due to the high solubility in water, the optimum quantity of it in the process should be 0,4 M. D. 1 M. D. hydrochloride Ximena.

In M. D. waters less than 0.4 reduced output Ximena due to the fact that it is impossible to achieve dissolution hydrochloride Ximena and partly heterogeneous process to perform up to the end fails and the output of Ximena reduced (example 24). Increase the amount of water more than about 4.D. also leads to lower output Ximena, but due to the loss of Ximena with water after separation from the chloroform layer (examples 25, 26).

The use of aqueous ammonia requires additional drying of the chloroform solution Ximena, but this gives the same output as with the technique of neutralization of the hydrochloride Ximena in the water without chloroform with subsequent distillation of water (examples 34, 35).

Despite the use of a significant amount of chloroform, it is quite economical as before okonchatelnogo) Argonauts and can be reused in subsequent operations of the process.

From the examples above, a process diagram and explanations you can make the following conclusions.

Technology for Ximena the proposed method is much simpler than the prototype.

In the best case scenario, the proposed method output Ximena per urea or acetylacetone is 54.8% and prototype based on the same components 20%

In the process of the proposed method significantly reduces the consumption of raw materials.

1. The METHOD of OBTAINING N-( -HYDROXYETHYL)-4,6-DIMETHYLPYRIMIDINE-2 using urea, acetylacetone, hydrochloric acid, isopropanol with the formation of the pyrimidine cycle boiling with subsequent processing of muriate pyrimidine derivative in an aqueous solution of the base with the receipt of pyrimidine bases and the selection of the target product from a chloroform solution by partial evaporation of the chloroform and planting acetone, characterized in that the urea is heated with an excess of ethanolamine at a temperature of 110-125oWith over a 6.5-1.5 h with bubbling in the reaction mass of nitrogen formed during ethanolgasoline optionally isolated from the reaction mixture and treated with acetylacetone and zolpidemability-2, which is separated from the mother liquor, is treated with an alkaline reagent in an aqueous medium or aqueous chloroform to obtain the corresponding solution of the base, remove the water and get a chloroform solution, which is partially evaporated.

2. The method according to p. 1, characterized in that the processing in the aquatic environment as the alkaline reagent is used sodium hydroxide, sodium carbonate, sodium bicarbonate, and the treatment is carried out to a pH not exceeding 9, followed by distillation of water, extraction of the dry residue with chloroform to obtain a chloroform solution.

3. The method according to p. 1, characterized in that the alkaline processing solution lead to a pH of 8.

4. The method according to p. 1, characterized in that the processing in aqueous chloroform as the alkaline reagent is used sodium carbonate, sodium bicarbonate, aqueous ammonia at a ratio of 1 wt.D. the hydrochloride of N-( b-hydroxyethyl)-4,6-dimethylpyrimidine-2: 0, 4 vol.D. water: about 12.D. the chloroform.

 

Same patents:

The invention relates to an improved method of producing chlorinol containing o-hydroxyphenyl group, of General formula I-III I

< / BR>
where Ia 4-CL; 2-o-HOC6H6; R = 6-CH3< / BR>
IB 4-CL; 2-o-HOC6H4; R = 6-CF3< / BR>
IB 4-Cl; 2-o-HOC6H4; R = 6-C6H5< / BR>
Iك 4-Cl; 2-o-HOC6H4; R = 5-CN

Ia 4-Cl; 2-o-HOC6H4; R = 5-COOC2H5< / BR>
Ie 4-Cl; 2-o-HOC6H4; R = 5-C6H5< / BR>
If 4-Cl; 2-o-HOC6H4; R = H

Z 4-Cl; 6-o-HOC6H4; R = H

AI 2-Cl; 4-o-HOC6H4; R = H

IC 2-Cl; 4-o-HOC6H4; R = 6-C6H5< / BR>
IIa R = H

IIb R = 4' -OC3H7< / BR>
IIb R = 5' -Br

G R = 5' -NO2< / BR>
D R = 3' , 5' -Cl2< / BR>
IIIa R = H is used as intermediate products in the synthesis of universal stabilizers for polyethylene, i.e

The invention relates to new biologically active compound derived isonicotinic acid of General formula I,

with antimycobacterial and immunotropic activity, which can find application in medicine

The invention relates to experimental medicine, namely to Oncology and can be used to enhance the antitumor effect of radiation therapy

The invention relates to medicine, namely to therapy, and the use of exametazime as an immunostimulating agent in the treatment of bronchopulmonary diseases

The invention relates to medicine, in particular to drugs, and can be used as a means of preventing thrombosis in various pathological conditions

The invention relates to chemical-pharmaceutical industry, namely to new biologically active compounds on the basis of which can be created medicines that possess immunostimulating action

The invention relates to allpresan replacement pyrimidines, in particular 2-amino - and 2-substituted amino-4-substituted-5-hydroxypyrene-dyn, which may be substituted in the 6 position, pharmaceutical compositions containing these compounds as active ingredients and methods of treatment using these compounds

The invention relates to medicine, in particular to the treatment of viral infections, and is intended for the treatment of viral hepatitis B

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical neuroleptics according to titration scheme and tricyclic antidepressants. Neuroleptics are applied according to titration scheme in the morning and tricyclic antidepressants are introduced as intravenous drop-by-drop infusion in the evening in combination with per os application of atypic neuroleptic risperidon. After having given 12-14 intravenous infusions, strategic supporting risperidon psychopharmacotherapy in combination with tricyclic antidepressants during 4-6 months.

EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

FIELD: medicine.

SUBSTANCE: method involves applying eradicative anti-helicobacterial therapy comprising Omeprazol administration at a dose of 20 mg twice a day and Ximedone at a dose of 500 mg twice a day in 12 days long course.

EFFECT: enhanced effectiveness of eradication; reduced adverse side effects risk.

FIELD: organic chemistry, medicine, pharmacy, pharmacotherapy.

SUBSTANCE: method involves administration in mammal the effective dose of 6-hydroxy-8-[4[4-(2-pyrimidinyl)piperazinyl]butyl]-8-azaspiro[4,5]-7,9-dione or its pharmaceutically acceptable salt of acid addition or its hydrate. Method expands arsenal of medicinal agents used for suppression of fear sensation.

EFFECT: valuable properties of agent.

3 tbl, 6 dwg, 4 ex

FIELD: medicine, narcology.

SUBSTANCE: invention relates to hepatoprotective and anti-encephalopathic agent used for reducing alcoholic intoxication. Invention comprises components based on succinic, fumaric, glutamic acids and, additionally, at least one vitamin of B group. Agent can comprise additionally vegetable extracts or their mixture, L-carnitine, glycine, L-arginine, taurine and/or their mixture, methylsulfonylmethane, dihydroquercitin, dimethylsulfoxide or their mixture, nicotinamide or nicotinic acid or their mixture, energy source and sweetening agent. Also, invention proposes a method for reducing alcoholic intoxication, prophylaxis and removing withdrawal syndrome, liver protection, among them, in non-alcoholic intoxication and protection against encephalopathy. Invention provides described effects without qualifying medical control.

EFFECT: valuable medicinal properties of agent.

16 cl, 3 tbl

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

Up!