Acid-additive nitrate salts of compounds and pharmaceutical composition

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

 

The present invention relates to compounds or pharmaceutical compositions based on them for General use, which are used for the treatment of pathologies of the respiratory system with or without infectious etiopathogeny basics, including chronic lung disease (chronic obstructive pulmonary disease (HSLS)), such as asthma, bronchitis, emphysema, pulmonary embolism, with reduced side effects compared to drugs currently used to treat these pathologies.

From prior art it is known that the treatment of these pathologies main products are used salbutamol, salmeterol, etc. See, for example, the book "Textbook of Therapeutics - Drugs and Disease Management - 6thEdition 1996", page 685. These medicines are effective but have the disadvantage of causing side effects, in particular in relation to cardiovascular diseases. These drugs should be administered with caution to patients suffering from cardio-vascular disorders.

Other products used in these pathologies, or coadjuvante other drugs are, for example, Ambroxol and Bromhexine, the introduction of which is also accompanied by the presence of side effects in the gastrointestinal system, such the AK burning and stomach sensitivity.

Felt the need to have available compounds and pharmaceutical compositions based on them, is effective in the treatment of respiratory system pathologies in combination with reduced side effects in the cardiovascular system and/or gastrointestinal system.

The applicant has unexpectedly and surprisingly found specific compounds and compositions on their basis, solving the above technical problem.

The object of the present invention are the nitrate salts of the compounds or pharmaceutical compositions used for the treatment of respiratory system pathologies, including chronic lung disease (chronic obstructive pulmonary disease (HSLS)), such as asthma, bronchitis, emphysema, thrombosis, infectious lung diseases, and the above-mentioned compounds are characterized in that they contain at least one reactive group capable of forming salts with nitric acid, and the above-mentioned compounds are selected from the following:

- salbutamol having the formula (I)

- cetirizine having the formula (II)

- loratadine having the formula (III)

- terfenadine, having the formula (IV)

- emedastine, having the formula (V)

- ketotifen having the formula (VI)

- nedocromil, having the formula (VII)

- Ambroxol, having the formula (VIII)

- dextromethorphan having the formula (X)

- dextrorphan having the formula (XI)

- isoniazid having the formula (XIII)

- erythromycin having formula (XIV)

- pyrazinamide, having the formula (XVI)

The preferred compounds are salbutamol, also known as albuterol, cetirizine, emedastine, Ambroxol.

Nitrate salts according to the present invention can be obtained also when using the above-mentioned compounds which contain one or more groups-ONO2covalently attached to the molecule via one of the following bivalent linking bridges:

- YO, where Y represents C1-C20alkylene, linear, or branched, or substituted or unsubstituted cycloalkyl from 5-7 carbon atoms;

- Y1chosen from:

where n3 denotes an integer from 0 to 3, and n3' means a is e a number from 1 to 3;

where n3 and n3' have the above meanings;

where nf' is an integer from 1 to 6:

where R1f=H, CH3and nf' is the same as above.

These compounds containing the group-ONO2covalently associated with the molecule via one of the above bivalent linking bridges, receive, as described in patent application WO 95/30641 on behalf of the applicant, given here as a reference.

In the compositions according to the present invention can also be used one or more isomers, including optical isomers) of the above compounds, if any.

Examples of isomers are CIS-, TRANS-, optical isomers (d and L or racemic, the enantiomers. Basically one isomeric form has a higher activity compared with the other, for example, D shape compared to the L form, or Vice versa.

Salts according to the present invention contain at least one mole of nitrate ions/ mol predecessor. Preferably the ratio between the moles of nitrate ions and moles predecessor is equal to one; salt with a higher molar ratio can be obtained when the molecule has the other basic amino groups, capable of forming an ionic bond with the nitrate anion.

Of the salts of the present invention can be obtained corresponding pharmaceutical compositions in accordance with known methods in the art using conventional fillers; see, for example, the book "Remington's Pharmaceutical Sciences 15a Ed.".

Precursor salts corresponding to the above classes can be obtained according to the methods described in the Merck Index 14a Ed., shown here as a reference.

Salt of the present invention receive one of the following methods.

If the predecessor, which is used to obtain salt, available as a free base or as the corresponding salt, which is soluble in an organic solvent, which preferably does not contain hydroxyl groups in the molecule, for example, acetonitrile, ethyl acetate, tetrahydrofuran, etc., salt is obtained by dissolving this substance or its salt in the above-mentioned solvent at a concentration of, preferably equal to or higher than 10% wt./about., and then add the required quantity of concentrated nitric acid, preferably diluted before adding in the same solvent primarily used for dissolving compounds, preferably cooling the mixture during and after the aforementioned add totemperature in the range of 20-0° With, removing the product by filtration and optional washing this solid is the same chilled solvent.

When the predecessor or its suitable salts are slightly soluble in the above solvent to the above-mentioned solvent is added gidroksilirovanii solvent to improve solubility. Examples of such gidrauxilirovannogo solvents are methyl alcohol, ethyl alcohol and water. The precipitation can be accelerated by dilution of a non-polar solvent after the addition of nitric acid.

When the precursor forms a salt with a hydrogen halide, can be obtained salt with nitric acid, by adding silver nitrate to a solution of the halide in the above-mentioned solvent. After filtering off the silver halide solution is concentrated and cooled to highlight the nitrate salt by precipitation.

When the original product is a salt precursor, where the anion is different from the chloride, it is preferable, however, to process an aqueous solution of the above salt with a saturated solution of carbonate or bicarbonate of sodium or potassium or a diluted solution of sodium hydroxide or potassium hydroxide, then extracted the aqueous phase with a suitable organic solvent (for example, halogenated solvents, esters, ethers), dehydrate and the ATEM to evaporate the organic solvent, dissolving the thus obtained residue in the above-mentioned solvents which do not contain hydroxyl groups, for example acetonitrile, or in mixtures of the above-mentioned solvent with gidroksilirovanii solvent and then follow the above described methods of producing.

Salts and compositions according to the present invention can be used for a General introduction, for example, they may be administered orally by the way, as expectorants; intramuscular, intravenous method and so on; or they can be used for local injection, for example, as sprays, or for local use. Mostly salt according to the present invention can be used for the same therapeutic applications as their predecessors.

Nitrate salts of the present invention have higher total emissions than their predecessors.

Input dose are the usual doses predecessors; however, since the products of the present invention show higher therapeutic efficacy compared to their predecessors, they can also be used in doses exceeding the dose predecessors, without causing side effects.

The products of the present invention can also be used as tokoliticheskoe funds (antispasmodic medium spans the Islands) for example, antispasmodic remedies for uterine muscles, antispasmodic remedies for intestinal muscles; as antihistamines (anti-allergic drugs), for example, to the eye; as a remedy against cough, as an antibacterial agent for infectious respiratory diseases. They can be General or local path, as described above, or also in the form of ophthalmic compositions, such as lotions for the eyes, etc.

The following examples are only meant to illustrate the invention and they do not restrict it.

Example 1

Receiving nitrate salt of Ambroxol.

The solution of Ambroxol (4 g, 20.6 mmol) receive, dissolving it in a mixture of acetonitrile (30 ml) and tetrahydrofuran (10 ml). At low temperature (4° (C) add nitric acid, dissolved in acetonitrile (3.5 ml taken from a solution obtained by adding acetonitrile to the 2.7 ml of 65% nitric acid and bringing acetonitrile to a final volume of 10 ml). After 30 minutes, slowly add ethyl ether (100 ml) at the same temperature (+4°). The formed precipitate is filtered off, washed with ethyl alcohol and dried under vacuum. Get a white amorphous crystalline substance according to the results of the elemental analysis corresponds to the nitrate salt of Ambroxol:

NNBr
Calculated35,40%4,34%at 9.53%36,23%
Detected35,37%or 4.31%to 9.57%36,26%

Example 2

Receiving nitrate salt of salbutamol

Since the solution of salbutamol (4 g, 16.7 mmol) in acetonitrile (30 ml) and tetrahydrofuran (10 ml) and using 4 ml of a solution of nitric acid in acetonitrile and the same procedure as in Example 1, receive amorphous solid, which according to the results of the elemental analysis corresponds to the nitrate salt of salbutamol:

NN
Calculated51,65%7,32%9,27%
Detected51,54%7,38%which 9.22%

PHARMACOLOGICAL TESTS

Example 3

The study of the acute toxicity of salts of the invention

Products introduced in the form of suspension of 2% carboxymethylcellulose groups of 10 mice each.

Acute toxicity of salt was estimated oral introduction of single doses of the compounds to groups of 10 rats each, increasing the dose to 100 mg/kg

The animals were monitoring those is giving 14 days noting the deaths and the appearance of toxic symptoms.

At a dose of 100 mg/kg was not marked signs of toxicity.

Example 4

Study of the effects of salbutamol and salbutamol nitrate in experimental bronchostenosis in Guinea pigs.

Animals were prepared according to the method described by Del Soldato et al., J.Pharmacol. Methods, 5, 279, 1981 for studies of cardiorespiratory activity. Each group consisted of eight animals. The animal was injected intravenously with 0.1 ml of physiological solution of capsaicin (1 µg/kg). Within the overall amount of time 15 minutes, starting 5 minutes before injection of capsaicin to 10 minutes after, each group was administered intravenous infusion of salbutamol (0.3 nmole/min) or the corresponding nitrate salt (0.3 nmole/min) or thinner.

The change of the respiratory air volume before and after injection of capsaicin was measured by an apparatus Konzett, modified as described in the above link Del Soldato, coupled with the printing system.

Heart rate was determined by electrocardiographic equipment according to standard methods. The results are presented in Table I. the Average heart rate after the introduction of the solvent was 188±7 beats per minute. Responses were expressed as percent relative to control.

As shown the in Table I, nitrate salts of salbutamol as effective in the inhibition of bronchostenosis caused by capsaicin, as salbutamol, but more tolerant of salt (do not cause tachycardia) compared with salbutamol.

Table I
ProcessingBronchostenosisTachycardia
Solvent100100
Salbutamol·NGOC097
Salbutamol0116

Example 5.

Receiving nitrate salt of cetirizine.

Salt is produced by adding to a solution of cetirizine (2 g, 5,14 mmol) in a mixture of solvents, obtained from acetonitrile (10 ml) and tetrahydrofuran (5 ml), 1.23 ml of a solution of nitric acid in acetonitrile as described in Example 1. Receive an amorphous solid, which according to the results of the elemental analysis corresponds to the nitrate salt of cetirizine:

Example 6

Receiving nitrate salts loratidine

Salt is produced by adding to a solution of loratidine (1 g, 2,61 mmol) in a mixture of solvents, obtained from acetonitrile (7 ml) and tetrahydrofuran (3 ml), 0.63 ml of a solution of nitric acid in acetonitrile as described in Example 1. Receive an amorphous solid, which according to the results of the elemental analysis corresponds to the nitrate salt of loratidine:

NNC1
Calculated55,81%5,79%9,29%7,84%
Detected55,84%of 5.75%which 9.22%7,83%
NNC1
Calculated59,26%5,42%9,42%of 7.95%
Detected59,24%5,38%9,42%7,93%

Example 7

Receiving nitrate salts terfenadine

Salt is produced by adding to a solution of terfenadine (1.5 g, 3.18 mmol) in a mixture of solvents, obtained from acetonitrile (15 ml) and tetrahydrofuran (5 ml), 0,76 ml solution of nitric acid in acetonitrile as described in Example 1. Receive an amorphous solid, which according to the results of the elemental analysis corresponds to the nitrate salts terfenadine:

NN
Calculated71,88%to $ 7.91% 5,23%
Detected71,90%7,88%5,24%

Example 8

Receiving nitrate salt of emedastine

Salt is produced by adding to a solution of emedastine (2 g vs. 5.47 mmol) in a mixture of solvents, obtained from acetonitrile (10 ml) and tetrahydrofuran (7 ml), 0.7 ml of a solution of nitric acid in acetonitrile as described in Example 1. Receive an amorphous solid, which according to the results of the elemental analysis corresponds to the nitrate salt of emedastine:

NN
Calculated55,87%7,44%19,15%
Detected55,84%7,43%MT 19 : 18%

Example 9

Receiving nitrate salt of dextromethorphan

Salt is produced by adding silver nitrate (0.96 g, of 5.68 mmol) to a solution of the hydrobromide of dextromethorphan (2 g, of 5.68 mmol) in acetonitrile (20 ml). The solution was stirred at room temperature for 30 minutes. Filtration removes sediment hydrobromide silver. To the clear solution was added ethyl ether (110 ml). Formed precipitate, which is filtered, washed with ethyl ether and dried under vacuum. The obtained solid substance according to item is on analysis corresponds to the nitrate salt of dextromethorphan:

NN
Calculated64,65%7,83%12,56%
Detected64,68%the 7.85%12,54%

Example 10

Receiving nitrate salt ketotifen

Salt is produced by adding to the solution ketotifen (1 g, 3.23 mmol) in a mixture of solvents, obtained from acetonitrile (10 ml) and tetrahydrofuran (5 ml), to 0.78 ml of a solution of nitric acid in acetonitrile as described in Example 1. The obtained solid substance according to the elemental analysis corresponds to the nitrate salt ketotifen:

NNS
Calculated61,27%of 5.40%11,28%8,61%
Detected61,24%5,43%11,27%at 8.60%

Example 11

Receiving nitrate salts, nedocromil

Salt is produced by adding to a solution of nedocromil (1 g, 2.69 mmol) in a mixture of solvents, obtained from acetonitrile (7 ml) and tetrahydrofuran (5 ml)of 0.64 ml of a solution of nitric acid in acetonitrile as described in Example 1. The obtained solid substance according to lamentoso analysis corresponds to the nitrate salt of nedocromil:

NN
Calculated52,54%4,17%9,67%
Detected52,56%4,19%9,63%

Example 12

Receiving nitrate salt of dextrorphan

Salt is produced by adding silver nitrate (0.50 g, 2.96 mmol) to a solution of the hydrobromide of dextrorphan (1 g, 2.96 mmol) in acetonitrile (17 ml). Then the solution was stirred at room temperature for 30 minutes. Filtration removes sediment hydrobromide silver. To the clear solution was added ethyl ether (100 ml). Formed precipitate, which is filtered, washed with ethyl ether and dried under vacuum. The obtained solid substance according to the elemental analysis corresponds to the nitrate salt of dextrorphan:

NN
Calculated63,73%7,54%13,11%
Detected63,71%at 7.55%13,10%

PHARMACOLOGICAL STUDIES

Example 13

Antihistaminic activity of nitrate of cetirizine hydrochloride cetirizine in Guinea pigs - study is the experimental bronchostenosis.

Animals prepared according to the method Del Soldato et al., J.Pharmacol. Methods, 5, 279, 1981 for studies of cardiorespiratory activity. Animals were injected intravenously with 0.1 ml of physiological solution with histamine (2 mg/kg). Formed three groups, each group consisted of 8 animals. Intravenously injected nitrate cetirizine, cetirizine hydrochloride, or only the solvent dose 77 mcmole/ug.

The change of the respiratory air volume before and after injection of capsaicin was measured by an apparatus Konzett, modified as in the above link Del Soldato, coupled with the printing system.

Below in Table II reaction of animals for each treated group expressed as a percentage with respect to control.

As shown in Table II, the nitrate of cetirizine has improved antihistaminic activity compared with cetirizine hydrochloride.

Table II
ProcessingBronchostenosis (%)
Solvent100
Nitrate cetirizine0
Hydrochloride cetirizine40

Example 14

Antitussive activity hydrochloride dextromethorphan, nitrate dextromethorphan, hydrochloride of dextrorphan and nitrate dextr is Hana, studied on Guinea pigs

Guinea pigs (weight: 430±20) was treated as described Ugada et al. Al. Arzneim. Forsch./ Drug Res.43, 550, 1993.

In this pharmacological experiment were formed 5 groups of 8 animals each. One group was not treated, and it was the control group.

Each animal was placed in a cylindrical glass container having at least one tube passing through each of the two round flat surfaces. The above pipe was intended respectively for input and output of the aerosol. Facing the tube was connected with the printing system.

The aerosol was obtained from a solution of 7.5 wt.% citric acid in water.

Vibrations of air inside the glass container were recorded before and after a bout of coughing caused by aerosol. After an hour intraperitoneally injected hydrochloride, dextromethorphan, nitrate dextromethorphan, hydrochloride of dextrorphan and nitrate of dextrorphan in physiological solution dose 110 micromol/kg 30 minutes after injection, animals were treated with aerosol. Then recorded the number of coughing spells for 10 minutes. In the following Table III presents the average results obtained for each treated group compared to the control group, which is taken as 100%.

Table III
ProcessingCoughing

(%)
Solvent100
Nitrate dextromethorphan0
Hydrochloride dextromethorphan30
Nitrate of dextrorphan0
Hydrochloride of dextrorphan40

As shown in the Table, the nitrates of dextromethorphan and dextrorphan are more effective antitussive agents than the corresponding hydrochloride.

Example 15

Mucolytic activity of nitrate of Ambroxol hydrochloride and Ambroxol in mice

Mucolytic activity in male mice was evaluated according to the method Engler and Zselenyi, J.Pharm. Methods 11, 151, 1984. Using this method, determine the amount of phenol red in tracheal secretions. Animals previously injected intraperitoneally a dose of 500 mg/kg of the dye, dissolved in a physiological solution. 3 groups of mice (weighing 18±2 g) in 10 animals each were treated intraperitoneally dye. One group was the control group. Each of the two treated groups 10 minutes before the above-mentioned injection was given by intraperitoneal injection 264 micromole/kg nitrate Ambroxol or Ambroxol hydrochloride, respectively. After 30 minutes iny the functions phenol red dogs were killed. The trachea was freed from surrounding tissues were cut and washed for 30 minutes in 3 ml of saline. Then added 0.1 ml of 1 M sodium hydroxide to the physiological solution. Wash was centrifuged for 15 minutes at 3000 rpm spectrophotometric analysis was Performed on the supernatant to determine the concentration of phenol red in physiological solution. Mucolytic activity was defined as the % change of the optical density of the sample compared with the control group, assumed as 100%. In Table IV summarizes the results obtained.

Table IV
ProcessingMucolytic activity (%)
Solvent100
Nitrate Ambroxol0
Hydrochloride Ambroxol30

The Table shows that the mucolytic activity of nitrate Ambroxol higher than the corresponding hydrochloride.

Example 16

Receiving nitrate salt of metronidazole

Salt is produced by adding to a solution of metronidazole (1 g, 5.84 mmol) in a mixture of solvents, obtained from acetonitrile (8 ml) and tetrahydrofuran (5 ml), 1,40 ml solution of nitric acid in acetonitrile as described in Example 1. The floor is built solid according to the elemental analysis corresponds to the nitrate salt of metronidazole:

NN
Calculated30,77%4,30%24,03%
Detected30,74% /4,28%24,00%

Example 17

Receiving nitrate salt isoniazid

Salt is produced by adding to a solution of polymer (2 g, 14.58 mmol) in a mixture of solvents, obtained from acetonitrile (20 ml) and tetrahydrofuran (10 ml), 3,50 ml solution of nitric acid in acetonitrile as described in Example 1. The obtained solid substance according to the elemental analysis corresponds to the nitrate salt of isoniazid:

NN
Calculatedto 36.00%was 4.02%27,99%
Detected35,97%4,00%28,01%

Example 18

Receiving nitrate salt of erythromycin

Salt is produced by adding to a solution of erythromycin (2 g, 2.72 mmol) in a mixture of solvents, obtained from acetonitrile (23 ml) and tetrahydrofuran (17 ml)of 0.65 ml of a solution of nitric acid in acetonitrile as described in Example 1. . obtained solid substance according to the elemental analysis corresponds to the nitrate is Oh salt of erythromycin:

NN
Calculated57,72%8,89%3,63%
Detected57,75%8,90%3,65%

Example 19

Receiving nitrate salt of acyclovir

Salt is produced by adding to a solution of ganciclovir (1 g, of 4.44 mmol) in a mixture of solvents, obtained from acetonitrile (10 ml) and tetrahydrofuran (10 ml)of 1.06 ml of a solution of nitric acid in acetonitrile as described in Example 1. The obtained solid substance according to the elemental analysis corresponds to the nitrate salt of acyclovir:

NN
Calculated33,33%4,19%29,17%
Detected33,30%4,20%29,18%

Example 20

Receiving nitrate salt pyrazinamide

Salt is produced by adding to a solution of pyrazinamide (1 g, 8.12 mmol) in a mixture of solvents, obtained from acetonitrile (10 ml) and tetrahydrofuran (10 ml)of 1.95 ml of a solution of nitric acid in acetonitrile as described in Example 1. The obtained solid substance according to the elemental analysis corresponds to the nitrate is Oli pyrazinamide:

NN
Calculated48,78%of 3.25%30,10%
Detected48,80%3,24%30,13%

Example 21

Synthesis of nitrate 2-(2-methyl-5-nitroimidazol-yl) ethyl ester 4-(nitroxy)butane acid.

A) Sintez-(2-methyl-5-nitroimidazol-yl)ethyl ester 4-bromoethanol acid.

To a solution of metronidazole (7.5 g, 43,82 mmol) in l3(75 ml) and DMF (93 ml) is added 4-brummelen acid (6,1 g, 36,51 mmol), DDC (8,3 g, 40,16 mmol). DMAP (0.4 g, 3.65 mol). After stirring the mixture for 24 hours at room temperature the organic phase is washed with water, dried with sodium sulfate and evaporated under reduced pressure.

The residue is purified by chromatography on silica gel, elwira a methylene chloride/ acetone (V/V 9/1)to give 2-(2-methyl-5-nitroimidazol-yl) ethyl ester 4-bromoethanol acid.

(6.5 g, 20.3 mmol). Yield 55%.

B) Synthesis of 2-(2-methyl-5-nitroimidazol-yl)ethyl ester 4-(nitroxy)butane acid.

To a solution of 2-(2-methyl-5-nitroimidazol-1 yl) ethyl ester 4-bromoethanol acid (6.4 g, 20,05 mmol) in anhydrous acetonitrile (170 ml) is added silver nitrate (5,11, 30,07 mmol). The mixture is heated at 40°C for 48 hours in the dark.

See the camping filter, and the filtrate is washed with water, dried with sodium sulfate and evaporated in vacuum. The residue is purified by chromatography on silica gel, awarua a methylene chloride/ acetone (V/V 9/1)to give 2-(2-methyl-5-nitroimidazol-yl) ethyl ester of 4-(nitroxy)butane acid (3,68 g, 12,17 moles) in the form of oil.

Yield 60%.

1H NMR (DMSO) ppm: 8,08 (1H, s); 4,55 (2H, t); 4,43 (2H, t); of 2.51 (3H, s); 2.40 a (2H, t); at 1.91 (2H, TT).

C) Synthesis of nitrate 2-(2-methyl-5-nitroimidazol-yl) ethyl ester 4-(nitroxy)butane acid.

To a solution of 2-(2-methyl-5-nitroimidazol-yl) ethyl ester 4-(nitroxy)butane acid (3,68 g, 12,17 mmol) in CH2Cl2(80 ml) is added HN3(13 mmol). After stirring for 1 hour at room temperature the solvent is evaporated at low temperature and the residue is dissolved in THF (75 ml), then add silver nitrate (2 g, 12,17 mmol). The mixture is stirred for 1 h at room temperature, the suspension is filtered and the precipitate washed with THF, dried, receiving nitrate 2-(2-methyl-5-nitroimidazol-yl) ethyl ester 4-(nitroxy)butane acid (4 g) as a solid. Output 90%.

Detected
Elemental analysis:
With%N%N%
Calculated32,884,1419,17
32,834,1619,15

1. Acid-additive nitrate salts of the compounds selected from the following:

salbutamol having the formula (I)

cetirizine having the formula (II)

loratadine having the formula (III)

terfenadine, having the formula (IV)

emedastine having the formula (V)

ketotifen having the formula (VI)

nedocromil having the formula (VII)

Ambroxol having the formula (VIII)

dextromethorphan having the formula (X)

dextrorphan having the formula (XI)

isoniazid, having the formula (XIII)

erythromycin having formula (XIV)

pyrazinamide having the formula (XVI)

2. Pharmaceutical composition for proceduretesting means for the treatment of pathologies of the respiratory system, containing salt according to claim 1 or nitrate salt

metronidazole formula (XII)

or ganciclovir of formula (XV)

3. Pharmaceutical composition to obtain drugs for the treatment of pathologies of the respiratory system according to claim 2, containing nitrate salts metronidazole or acyclovir.

4. Pharmaceutical composition for obtaining medicines according to claim 2, having antiallergic, preferably suitable for ophthalmic applications.

5. Pharmaceutical composition for obtaining medicines according to claim 4, containing a nitrate salt of cetirizine and has anti-allergic effect.

6. Pharmaceutical composition for obtaining medicines according to claim 2 for the treatment of asthma, containing nitrate salt of cetirizine.



 

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2 cl, 6 ex

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28 cl, 11 ex

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The invention relates to a derivative of (2R, 3S, 4S, 5R, 6R, 10R,11R)-2,4,6,8,10-pentamethyl-11-acetyl-12,13-dioxabicyclo[8.2.1] tridec-8-EN-1-it General formula (I), where R1denotes hydrogen or methyl and R2denotes hydrogen or (NISS
The invention relates to the field of medicine

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

The invention relates to derivatives of 1-arylsulfonyl, arylcarbamoyl or aristoteleion General formula I where L is selected from the group consisting of Co, CS and SO2; R1and R2independently selected from the group consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6), provided that when L - SO2, R1and R2at the same time do not represent hydrogen; R3independently represents 1 to 3 groups consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6); X is chosen from (CH2)nor Y(CH2)n-1where Y Is O or S, and n = 1, 2, 3

The invention relates to new coumadinhydrochloride acids, in which the system of pyridone condensed in the 3,4-, 6,7 - and 7,8-positions coumarin system, the General formula I

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where R1R2= NHCH=C(CO2R6)CO., R3= NO2or NH2, R4= R5= H, R6= H or C2H5; R1R2= NHCH=C(CO2R6)CO., R3= R4= H, R5= F, R6= H or C2H5; R1R2= CO(CO2R6) = СНNH, R3= R4= R5= H, R6= H or C2H5; R1R2= R3R4= NHCH= C(CO2R6)CO., R5= H, R6= H or C2H5; R1= H or HE, R2= R5= N, R3R4= -NHCH=C(CO2R6)CO., R6= H or C2H5; R1= HE, R2= R3= N, R4R5= -CO(CO2R6) = СНNH, R6= H or C2H5; R1= R5= N, R2- CH3or CF3, R3R4= CO(CO2R6)C = CHNH, R6= H or C2H5and their pharmaceutically acceptable salts

The invention relates to new substituted dihydropyrimidines, methods for their preparation, pharmaceutical compositions containing them and their use as pharmaceuticals, in particular for the prevention or treatment of disorders characterized by excessive expansion of vessels, in particular migraine

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts

The invention relates to a new diisobutylaluminum connection, which has an excellent activity, which increases potassium exchange by opening potassium channels and therapeutic agents for the treatment of hypertension, angina pectoris and asthma, which contain diazabicyclo connection as the active agent

The invention relates to pharmaceutical compounds, their preparation and use

The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions

The invention relates to chemical compounds with valuable properties, in particular derivatives of 2,3-dihydropyrano[2,3-b] pyridine of General formula

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(I) where a lower alkylene;

R is a hydrogen atom or a group

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or their salts

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine
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