Derivatives of 1-benzylaminopurine-2-(1-methyl-2-phenylethylamine)- ethanol-1 in the form of mixtures of isomers or racemate or pharmaceutically acceptable salt, manifesting bronchospasmolytic activity

 

(57) Abstract:

Usage: in medicine, as they have bronchospasmolytic activity. Essence: the proposed new derivatives II-benzylaminopurine-2-/I-methyl-2-phenylethylamine/ -ethanol of the formula

3-[nCH3OPHCH2NH] 4-OH-PhHC (OH)CH2NHCH(CH3) CH2PhR1R2,

where R1and R2every OCH3or together form a chain O-CH2O - in the form of a mixture Izmerov, or racemate, or pharmaceutically acceptable salt. table 2.

The invention relates to new compounds with therapeutic activity.

Derivatives of 1-benzylaminopurine-2-(1-methyl-2-phenyl-ethylamino)-ethanol-1 in the form of mixtures of isomers, or racemate, or pharmaceutically-acceptable salts, manifesting bronchospasmolytic activity.

In particular, the compounds of this invention are bronchospasmolytic activity and effective in the treatment of reversible pulmonary diseases of various origins, in particular, asthmatic conditions. These compounds, if they possess the appropriate stereochemical configuration shown in inhalation therapeutic effect of increased deletelines the spine.

It is desirable to find such a bronchospasmolytic agent, who had a longer duration than the drugs available on the market.

The duration of action will give patients adequate protection during the night and early morning hours, when asthma is usually escalates. Bronchodilating agents, currently used for inhalation therapy (fenoterol, salbutamol, terbutaline and bitolterol) typically have a duration of only about 4-6 hours, and thus do not create effective protection during the night when taken before bedtime. Bitolterol described by the authors Kass I. and T. S. Mingo b Chest 1980 78. "283." Anew longacting bronchodilatoz with reduced chronotopic effect. U.S. patent 4072760 describes compounds structurally similar to those described in this application, but only with a short validity period. Attempts to get bronchospasmolytic active connections with long time steps are described in the literature, for example, formoterol, salmeterol. The problem, however, was to find bronchospasmolytic active compound, which would be clinically suitable duration for at least 12 h after inhalation aerosol micronized drug. the treatment involved only a small amount. In this case, the risk of such systemic side effects like palpitations and tremor is reduced to the limit.

Found that the new compounds of formula (X)

and their pharmaceutically acceptable salts, where

R1and R2each represents och3or together form a chain-och2O - highly efficient and have a long bronchospasmolytic activity, especially when the local application in the lungs, for example, after inhalation aerosol form compounds.

Pharmacologically acceptable salts of this invention are in particular salts with acids. They can be obtained by the reaction of compounds capable of forming such salts with suitable pharmacologically acceptable organic or inorganic acid. Examples of suitable organic acids are acetic, fumaric, citric, tartaric, maleic, and benzoic acid. Examples of suitable inorganic acids are hydrochloric, Hydrobromic, chamois and phosphoric acid.

The compounds of this invention also exhibit a low degree of side effects. As pharmaceutical activity, and the duration of action of new compounds su is anolamine circuit and the asymmetric carbon atom in the Deputy under nitrogen. So the optimal pharmacological effect is achieved only when the R configuration at the benzyl position and the duration of action is optimal for S group configuration, which is the Deputy under nitrogen.

A particularly preferred compound according to this invention is a racemic mixture of (R,S + S,R isomers and racemic mixture (R,R + S,S isomers) 1[(4-Hydroxy)-3-(n-methoxybenzylamine)-phenyl] 2-[(1-methyl-2- (3,4-methylenedioxyphenyl)ethyl)amino]ethanol.

Most preferred is the isomer 1-(R-(4-hydroxy)-3-(n-methoxybenzylamine)phenyl-2-[(1-(S)-methyl - 2-(3,4-methylenedioxyphenyl)ethyl)amino]ethanol.

The compounds of formula (X) obtained at the interface between the oxide 4-benzyloxy-3-nitrostyrene formula V

(V) with the compound of the formula VI

(VI) in which R1and R2have the meanings given above, or

with the formation of the compounds of formula VII

in which R1, R2have the meanings given above, then the connection VII hydronaut, receiving, either directly or through the connection of the formula VIII

the compound of formula IX

HNH R1where R1, R2defined above, after which the compound of formula lX is subjected to reaction with SUB>, R2such as defined above, either in the form of a pure isomer or a mixture of varying amounts of stereoisomers, as described below.

A common method of obtaining

+

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Method A.

This method is used to obtain the pure stereoisomers and epimeres that differ in configuration only at the benzyl position. (R1, R2and R6as indicated above).

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Method IN

This method is used to produce racemates and mixtures of racemates

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HN

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Getting the initial connection.

Amines VI.

Method C.

Obtaining pure enantiomers.

Replaced with the appropriate 1-phenyl-2-propanone was subjected to reaction with R - or S-methyl-benzyl-amine, followed by reduction imine using Raney Nickel to obtain respectively a pure R,R - or S,S-amine. R1and R2have the meanings given above.

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Method D.

Obtaining racemic amines VI.

Substituted appropriately benzaldehyde were subjected to interaction with nitroalkanes with subsequent restoration of obtaining amine.

R1, R2and R3have obtained by the method, described in I. Med.Chem. 1749 (1974) Kaiso etc.

P R I m e R 1 (get method).

1-(R)-(4-Hydroxy-3-(methoxybenzyl)phenyl)-2-((1-(S)-methyl - 2-(3,4-methylenedioxyphenyl)ethylamino-ethanol (X) 1-(4-(benzyloxy-3-nitrophenyl)-2-(N-methylbenzyl-1-methyl-2-(3,4 - methylenedioxyphenyl) ethylamino-ethanol (VII) (R,S,S, S,S,S-isomers).

of 23.9 g (88 mmol) oxide 4-benzyloxy-3-nitrostyrene (V) and 24.9 g (88 mmol) of (S, S)-N-1-phenethyl-1-(1,3-benzodioxol-5-yl)-2-propanamine (VI) was stirred at 150aboutC in nitrogen atmosphere for 15 hours the Crude product is dissolved in ethyl acetate, add conc. HCl, and the solvent evaporated, obtaining the crude hydrochloride in the form of solids. Recrystallization from ethyl acetate gives 17.3 g S,S,S - and R,S,S-isomers (85:15).

Concentration of the mother liquor gives 29 g of the crude R,S,S - and S,S, S-isomers (70: 30). Flash chromatography of the concentrated Queen cells (petroleum ether-ethyl acetate to 2.5:1, silica network of 21.3 g of the isomeric mixture of 70:30. Pure R,S,S - and S,S,S-isomers, respectively, were obtained using chromatography using MeCN/silica gel or repeated flash chromatography.

NMR (R,S,S-isomer, CDCl3)

the 7.85 (d, 1H), 7,54-6,33 (m, 15 NM), by 5.87 (m, 2H), 5,23 (s, 2H), 4,58 (DD, 1H), 4,08 (square 1H), 3,06-of 2.54 (m, 4H), 2,09 (DD. 1H)(m, 1H), 2,84-2,39 (m, 4H), of 1.44 (d, 3H), of 1.01 (d, 3H).

Accordingly received R,R,R - and S,Q,R-isomers. 1-(4-benzyloxy-3-AMINOPHENYL)-2-(N-methylbenzyl-1-methyl-2-(3,4 - methylenedioxyphenyl)ethylamino-ethanol (VIII)

(R,S,S, S,S,S-isomers).

10.8 g (20 mmol) of the corresponding nitro compounds (ratio of isomers 70:30) was dissolved in 250 ml of methanol. Add 23 g (100 mmol) SnCl22N2On and heat the solution to 60aboutC. for 50 min servings add 400 mg of NaBH4. After 40 min of additional stirring at 60aboutWith the solution concentrated to 150 ml and then add 350 ml of 0.5 norms. aqueous NaOH and then with 200 ml of diethyl ether. Extraction of the aqueous phase with ether, drying and evaporation give 7.9 g of the oily product. Chromatography (MeCN) silicon dioxide gives 4.5 g of pure R,S,S-isomer and 1.5 g of S,S,S-isomer.

NMR (R,S,S-isomer, l3)

7,46-6,33 (m, N), by 5.87 (d, 2H), 5,09 (s, 2H), 4,54 (DD, 1H), 4,08 (kV, 1H), 3,05-2,02 (m, 5H), of 1.50 (d, 3H), of 0.97 (d, 3H), (S,S,S-isomer).

7,43 and 6.25 (m, N), to 5.85 (d, 2H), of 5.05 (s, 2H), to 4.38 (DD, 1H), 4,08 (kV, 1H), 3,11 (m, 1H), 2,81-of 2.36 (m, 4H), of 1.41 (d, 3H), of 0.95 (d, 3H).

Monohydrochloride R, S, S-isomer was obtained by the reaction of 0.58 ml acetylchloride and 180 ml of methanol, followed by adding a base (4.5 g) and evaporation. After washing desteno, turned out using chromatography using MeCN/silica gel or repeated flash chromatography.

NMR (R,S,S-isomer, CDCl3)

the 7.85 (d, 1H), 7,54-6,33 (m, 15 NM), by 5.87 (m, 2H), 5,23 (s, 2H), 4,58 (DD, 1H), 4,08 (square 1H), 3,06-of 2.54 (m, 4H), 2,09 (DD. 1H), 1,50 (d, 3H), of 0.96 (d, 1H).

(S,S,S-isomer)

7,79 (d, 1H), 7,47-6,28 (m, 15 NM), of 5.89 (DD, 2H), 5,23(s, 2H), and 4.40 (DD, 1H), 4,08 (kV, 1H), 3,18 (m, 1H), 2,84-2,39 (m, 4H), of 1.44 (d, 3H), of 1.01 (d, 3H).

Accordingly received R,R,R - and S,Q,R-isomers. 1-(4-benzyloxy-3-AMINOPHENYL)-2-(N-methylbenzyl-1-methyl-2-(3,4 - methylenedioxyphenyl)ethylamino-ethanol (VIII)

(R,S,S, S,S,S-isomers).

10.8 g (20 mmol) of the corresponding nitro compounds (ratio of isomers 70:30) was dissolved in 250 ml of methanol. Add 23 g (100 mmol) SnCl22N2On and heat the solution to 60aboutC. for 50 min servings add 400 mg of NaBH4. After 40 min of additional stirring at 60aboutWith the solution concentrated to 150 ml and then add 350 ml of 0.5 norms. aqueous NaOH and then with 200 ml of diethyl ether. Extraction of the aqueous phase with ether, drying and evaporation give 7.9 g of the oily product. Chromatography (MeCN) silicon dioxide gives 4.5 g of pure R,S,S-isomer and 1.5 g of S,S,S-isomer.

NMR (R,S,S-isomer, l3)

7,46-6,33 (m, N), by 5.87 (d, 2H), 5,09 (s, 2H), 4,54 (DD, is in, 1H), 3,11 (m, 1H), 2,81-of 2.36 (m, 4H), of 1.41 (d, 3H), of 0.95 (d, 3H). Monohydrochloride R,S,S-isomer was obtained by the reaction of 0.58 ml acetylchloride and 180 ml of methanol, followed by adding a base (4.5 g) and evaporation. After washing with diethyl ether there was obtained 4.3 g of monohydrochloride in the form of a salt. S,R,R - and R,R,R-isomers were obtained accordingly.

(R)-1-(3-amino-4-hydroxyphenyl)-2-[(S)-1-methyl-2-(3,4 - methylenedioxyphenyl)ethylamino]ethanol (IX).

4.3 g (8 mmol) of the previous compound (R,S,S-isomer) is dissolved in the form of a hydrochloride in 75 ml Meon, add 0.3 g 100 Pd/C and hydronaut mixture at a pressure of 40 psi for 5 hours the Methanol solution is filtered and use it at the next stage, S,S,S - and R,RR-isomer (IX) are obtained similarly.

1-(R)-(4-hydroxy-3-(n-methoxybenzyl - Mino)phenyl)-2-[(1(S)-methyl-2- (3,4-methylenedioxyphenyl)ethyl)amino]ethanol (X). 2 ml (16 mmol) of n-anisaldehyde added to the previously obtained methanol solution of R,S,S-isomer (IX). After 30 minutes of boiling add 30 mg PtO2and hydronaut mixture under a pressure of 50 pounds per square inch to 1.5 hours Yield crude product (90% purity) is 2.3, Chromatography (CHCl3) silicon dioxide base and adding to the base of the H2SO4/EtOH gives 1.2 g of pure (X), 2,89 is 2.44 (m, DMSO), 0,99 (d, 3H), Similarly get S,S, S,R - and R,R-isomers (X).

NMR (S,S-isomer).

7,31-6.42 per (m, 10H), 5,98 (s, 2H), 4.53-in (d, 1H), 4.26 deaths (s, 2H), 3,74 (s, 3H), 3,1 (m, 1H), 2,90 at 2.45 (m, DMSO), of 1.02 (d, 3H).

P R I m m e R 2 (get method).

Getting the racemate (R, S + S,R-isomers) 1-(4-hydroxy-3-(n-methoxybenzylamine)phenyl-2-[(1-phenyl-2-(3,4 - methylenedioxyphenyl)ethyl)amino]ethanol, 1-(4-benzyloxy-3-nitrophenyl-2-[(1-methyl-2-(3,4-methylenedioxyphenyl)] ethyl)amino-ethanol. (VIII) a mixture of different R,R, R,S, S,S - and S,R-isomer).

1.4 g (5 mmol) oxide (R/S)-1-(3,4-methylenedioxyphenyl)-2-aminopropane (VI) is heated under reflux in 10 ml of methanol for 20 hours After evaporation of methanol, the crude mixture of isomers is dissolved in diethyl ether and R,S - and S,R-isomer is crystallized, gaining 0.4 g of the racemate (R,R - and S, S-isomers are removed).

NMR (l3)

of 7.8 (d, 1H), 7,5-6,5 (m, 10H) and 5.9 (s, 2H), and 5.2 (s, 2H), 4,6 (DD, 1H), 3,0-2,5 (m, 5H), 1,2 (d, 3H).

The racemate hydronaut (Pd/C in EtOH) to give the corresponding aminophenol (IX), which is then injected into the reaction with n-anisaldehyde, as already described, with the receipt of the racemate (R,S - and S,R-isomer) previously described compounds (X) R, R - and S, S-isomers are obtained from previously remote isomeric mixture of products (VII).

P R I m e R 3. 1-(4-Hydroxy-3-benzylamino-phenyl-2-(1-methyl-2-(3,4 - methylenedioxyphenyl)-ethylamino)ethanol (X) (mixture of R,S- + S R,S + R,R-isomers). From 2.4 g of nitro compounds VII, 0.7 g of Pd/C, 1.1 g of benzaldehyde and 40 mg PtO2there was obtained 1.2 g of the hydrochloride.

NMR (DMSO-d62as the solvent, and standard).

the 7.4-6.4 (m, 11N), 6,01 (s, 2H), 5,90 (d, 1H), 5,35 (s, 1H), 4.72 in (m, 1H), 4,35 (s, 2H), 3,37 (s, 3H), of 3.1 and 2.9 (m, 4H), 1,10 (d, 3H).

P R I m e R 4. 1-(4-Hydroxy-3-n-methoxybenzylamine-phenyl)-2-(1-methyl-2-(3,4 - acid)-ethylamino)-ethanol (X) (mixture of R,S + S,S). Of the 5.2 g of nitro compounds VII, 0.5 g Pd/C, 3.0 g of n-methoxybenzaldehyde and 50 mg PtO2there was obtained 1.0 product as hydrochloride.

NMR (as indicated is hydroxy-3-n-methoxybenzylamine-phenyl)-2-(1,1-dimethyl-2- (3,4-methylenedioxyphenyl)ethylamino)ethanol (X) (R/S racemate).

From 5 g of nitro compounds VII, 0.3 g Pd/C, to 4.9 ml of n-methoxybenzaldehyde and 30 mg PtO2there was obtained 3.1 g of the product as hydrochloride.

NMR (as above).

of 7.3 (d, 2H), 6,9-6.4 (m, 8H), 6,0 (s, 2H), to 5.93 (m, 1H), 5,24 (s, 1H), 4,73 (d, 1H), 4,25 (s, 2H), 3,70 (s, 3H), 3,37 (s, 2H), 2,89 (m, 5H), 1,10 (s, 3H).

P R I m e R 6. 1-(4-Hydroxy-3-methoxybenzylamine-phenyl)-2-(1-methyl-2-(n - methoxyphenyl)-ethylamino-ethanol (X) (mixture of R,S + S,S).

Out of 7.7 g of the nitro compounds (VII), 0.3 g of Pd/C, 6.5 g of n-methoxybenzaldehyde and 30 mg PtO2there was obtained 0.6 g of product in the form of sulphate.

NMR (see above).

7,28 (d, 2H), 7,14-6,36 (m, 11N), 5,12 (s, 1H), to 4.52 (m, 1H), 4,22 (s, 2H), and 3.72 (2D, 6N), 3,4-2,5 (m,incl. DMSO), and 1.0 (d, 3H).

P R I m e R 7. 1-(4-Hydroxy-3-methoxybenzylamine-phenyl)-2-(1-methyl-2-phenyl - ethylamino)-ethanol (X).

From 2.5 g of the nitro compounds (VII) was obtained 260 mg of the product in the form of sulphate.

NMR (see above).

the 7.4-6.4 (m, N), 5,16 (s, 1H), 4,59 (s, 1H), 4,22 (s, 2H), 3,70 (s, 3H), 3,2-2,5 (m, incl DMSO), and 1.00 (DD, 3H).

To illustrate the activity of the compounds of the invention are described below pharmacological studies and their results.

Pharmacological evaluation.

I. Duration bronhorasshiratego actions examined in living morshchinki. The compounds of examples 1 and 2, salmeterol and terbutaline was administered via inhalation or injection into the trachea, after which the animals were exposed vitaminnogo fog over different periods of time.

A. Inhalation.

Guinea pigs were placed in plastic boxes and the compound was given at continuous spray flow of drugs within 15 minutes

b. The infusion into the trachea.

Animals slightly anaesthetize inhalation Afrana. Test connection pour with a thin cannula in place bifurcation of the trachea. Control animals injected with saline.

C. Procedure provocation.

After the introduction of one of the above methods animals were placed in transparent plastic boxes and were exposed to aerosol histamine. This mist is generated in the spray of a solution containing 0.5 to 1.0 x 10-3mol/l of histamine in 3% glycerol. This concentration caused breathing problems, which have appeared in control animals within 2-3 minutes This phase is usually determined by observation, and sometimes also with the help of a blind experience" or were recorded using a tonometer (see O. A. T. Olsson in Acta Allergologica 26 438 1971).

the animal to resist this Histaminum spasm. Once installed respiratory disorders Guinea pigs were removed from histamines environment because the same animals were forced to undergo the action of histamine not only after 30 minutes and after 3, 6 and 9 h after drug administration.

In some cases, instead of histamine used metafolin, to eliminate the possibility of the antihistaminic effect of the test drug.

C. The Results.

The agonist-receptor, salmeterol and terbutaline, both are used in inhalation therapy, so they were selected for this study as a comparative compounds in the evaluation of new-agonists according to the invention, for the duration of their bronchodilatory action.

Usually, the initial effect of the new compounds according to example 1 and 2 is about the same as the terbutalina, but about 10 times less than that of salmeterol on the list. The duration of exposure, calculated on the basis of the equipotential level, however, proved to be more of the compounds of this invention and salmeterol on the list compared to terbutalina. In comparison with salmeterol duration of action of new compounds appeared to be somewhat longer.

Soedinenii)ethyl)amino] ataneli or in the form of a racemic mixture, or in the form of one of the isomers.

Put connections provide equal protection from histamines provocation (6-7 min after 30 min after administration of the test compounds. Degree of protection after 6 h after drug administration characterizes the duration of the bronchospasmolytic activity.

II. The study bronchospasmolytic and cardio-stimulating effect on shot Guinea pigs. The purpose of this study was to compare the agonist-receptor according to the invention with terbutalina and salmeterol on the list for their ability to suppress respiratory spasm in anesthetized Guinea pigs after injection or inhalation. Additionally, we evaluated the inuence of the tested compounds on the heart rate.

Methods.

A. Intravenous administration.

In this study, was used Guinea pigs of both sexes. Anesthesia was performed by intravenous pentobarbital. The trachea kanyoro and do artificial lung ventilation at constant volume breathing. Intratracheal pressure (ETC) is measured by the pressure sensor. Raising ETC above ground level pressure, indicating respiratory spasm, called westoby to follow cardio-stimulating effect of the tested drugs, arterial blood pressure is recorded using a pressure sensor. The pulse is transmitted to the tachograph recording heart rate. Compound studied inheritability for 3 min before the infusion of histamine, and the percentage reduction ETC was taken as a measure bronchospasmolytic activity.

Effects on cardiac function was assessed after cumulative injection, one injection was performed when the previous ensured a constant level.

century Introduction inhalation.

Compound was sprayed, and received the "fog" was administered to the animals through a mask or tracheal cannula. The inhalation was continued for 15 min for each concentration of the test compounds. Bronchodilator effect on heart rate was calculated as the percentage reduction, ETC.

Effect on heart rate was determined after a cumulative increase in the concentration of the spray solution. The measurements were performed at a constant level and used three different concentrations.

C. The Results.

A. Inhalation exposure.

Three used agonist-receptor compound according to example 2, salmeterol and terbutaline show salmeterol was the most active, and its action is about 10 times stronger than the other two drugs by injection, and about 5 times during inhalation. Injection of 5x10-10mol/kg of salmeterol on the list of 5x10-9mol/kg of the compound according to example 2 and 1x10-8mol/kg of terbutalina gives about 50% reduction, ETC.

C. Effects on heart.

Effect on heart rate depends on the dose and appears to be primarily dependent on the direct activity of the test compounds, and not the result of changes in blood pressure. It was possible to demonstrate the effect on heart rate not only after intravenous injection, but also after inhalation. When injected salmeterol and terbutaline increase heart rate to a greater extent than the compounds of this invention and a dose of 1x10-7mol/kg of salmeterol on the list and terbutalina increases it by about 30 beats per min.

To achieve such an increase in the frequency of heartbeats in the case of using the compounds of the present invention, the dose had to be at least 10 times more. Inhalation 5x10-4mol/l of salmeterol on the list increases heart rate by 15 beats per minutes the same increase was obtained by 5x10-3mol/l in the case of the compounds of this invented what and heart equally to compounds according to example 2 and salmeterol on the list when injecting drugs. However, this ratio is different inhalation. In this case, the connection according to example 2 exhibits a lower degree of influence on the heart than salmeterol.

The compounds of this invention are thus active for a longer time than, for example, terbutaline.

In addition, they are less at heart than salmeterol.

The best way of carrying out the invention known to date is the use of compounds 1-(R)-(4-hydroxy)-3-(n-methoxybenzylamine)phenyl-2-[(1-methyl-1(S)- 3,4-(methylenedioxyphenyl)ethyl)amino]ethanol.

Derivatives of 1-benzylaminopurine-2-(1-methyl-2-phenylethylamine)-ethanol-1, General formula

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where R1and R2every OCH3or together form a chain O-CH2O-,

in the form of mixtures of isomers or racemate or pharmaceutically acceptable salt, manifesting bronchospasmolytic activity.

 

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FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: method involves applying fractal introduction of 0.2 mg/kg MT calypsol and 0.4 mcg/kg MT fentanyl every 10 min during operation. Additional local spinal cord root irrigation with 2% lidocaine solution at maximum traumatic operation moment.

EFFECT: enhanced effectiveness of treatment; preserved spontaneous patient respiration.

1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

FIELD: obstetrics and gynecology.

SUBSTANCE: over a 2-5 day period, 2.0 ml of Ginipral is administered once a day intravenously in a drop-by-drop manner followed by intravenously drop-by-drop administered 30-40 min later 2.0 ml of Instenone and, in the evening, 1 dragee Instenone orally. Afterwards, Instenone and Ginipral are administered orally: the former in dose of 1 dragee thrice a day with meal and the latter in dose of 1 pellet four times a day after meal until symptoms of the risk of prevention of pregnancy disappear.

EFFECT: prolonged pregnancy and prevented premature birth, which favors reduced irritation, normalized tonus, contractive activity of uterus, and improved psychic and emotional state of women.

2 ex

Antioxidants // 2454394

FIELD: chemistry.

SUBSTANCE: present invention relates to use of compounds of formula Ia, Ib or Ic or cosmetically acceptable salts thereof as antioxidants, for preparing cosmetic compositions and for controlling pigmentation, particularly for clearing areas on the skin, to certain specific compounds of formula Ia, Ib or Ic or cosmetically acceptable salts thereof, a method of producing compounds of formula Ia, Ib or Ic, a cosmetic composition based on compounds of formula Ia, Ib or Ic and preparation method thereof or . In formulae la, lb or Ic, each of R2-R6 and R9-R13 is independently selected from H, OH, straight or branched C1-C20-alkoxy groups, straight or branched C1-C20-alkyl groups.

EFFECT: obtaining compounds used as antioxidants.

14 cl, 9 ex, 3 tbl, 1 dwg

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