Derivatives of [2r,3r (2'r,3'r,), 6r,7s,8s,9r,10r] -3-(2',3'- dihydroxyphenyl-2'-yl)-2,6,8,10,12-pentamethyl-4,13 - dioxabicyclo [8,2,1]-tridec-12-en-5-she, the method of production thereof, pharmaceutical tool

 

(57) Abstract:

Usage: as agents with the ability to have a positive impact on motility the gastrointestinal tract. The inventive product is [2R, 3R (2'R, 3'R), 6R, 7S, 8S, 9R, 10R] - 3(2', 3'-dihydroxy-Penta 2'-yl)-2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8,2,1] -tridec-12-EN-5-one-derivatives of the formula I described in the claims:

where R' is methyl or hydrogen, or their stable and physiologically joint salt accession acid. I get the introduction of [2R, 3R(2'R, 3'R), 6R, 7S, 8S, 9R, 10R]-3(2', 3'-dihydroxyphenyl-2' - yl)-2, 6, 8, 10, 12-pentamethyl-4,13-dioxabicyclo [8, 2, 1]-tridec-12-ene isopropyl radical with subsequent translation of I in salt or converting a salt of I into the free compound I. 3 S. and 1 C. p. F.-ly.

The invention relates to new N-substituted [2R, 3R (2'R, 3'R), 6R, 7S, 8S, 9R, 10R]-3-(2',3'-dihydroxyphenyl-2'-yl)-7-[(2,6-dideoxy-3-C-methyl-3-O- -L-RIBO-hexopyranosyl)-oxy] -9-[(3,4,6-trideoxy-3-amino-B-D-Xylo-hexopyranosyl)-oxy] -2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8,2,1] -tridec-12-EN-5-he-connections with metalinguistically properties, to their salts, the acid products of accession, as well as to pharmaceutical remedies containing these compounds and methods, as well as promezhutochnoe-derivative of erythromycin A.

As you know, the antibiotic erythrocytosis A along with antibiotic activity of different unwanted side effects associated with the activity of the gastrointestinal tract, namely a pronounced increase in the contraction of activity in the stomach and intestines, accompanied by cramps and sometimes sharp pains in the stomach and intestines, nausea, vomiting, and diarrhea.

It was made many attempts to convert erythromycin A in such a way as to obtain the derivative, in which the antibiotic activity is almost never shown, but remained motility the gastrointestinal tract. From European patent application N 0349100 known pharmaceutical preparations, containing as active substance gastroprokinetic character narrowed in the ring of erythromycin A-derived or its Quaternary salt can increase in cholinergic mechanism, motility stomach.

Therefore, the basis of the invention was used to develop new narrowed in the ring derivatives of erythromycin A, does not have antibiotic activity, but with the ability to have a positive impact on motility the gastrointestinal tract.

The invention relates to new [2R, 3R(2'R, 3'R) 6R, 7S, 8S, 9R, 10R]-3-(2', 3'-dihydroxyphenyl-2'-yl)-2,6,8,10,12-pentamethyl-4,13 - dioxabicyclo[8,2,1]-tridec-12-EN-5-he-derivative with the General formula

,

where

R1is methyl or hydrogen, and their stable and physiologically compatible salts, addition products of acids.

Most successful in this sense can be considered, in particular, the compound of formula I, where R1is methyl.

The compounds of formula 1 can be obtained in a known manner so that the [2R, 3R(2'R, 3'R)6R, 7S, 8S, 9R, 10R]-3-(2',3'-dihydroxyphenyl-2'-yl)-2,6,8,10,12-pentamethyl-4,13 - dioxabicyclo[8,2,1] -tridec-12-EN-5-on-derivatives - compounds of General formula

,

where

R1has the above value, enter the isopropyl radical or optionally received in connection with formula I, where R1- hydrogen is injected methyl-sake1and optionally available compounds of formula I carry in their stable salt-acid products of accession or, on the contrary, transfer of salt products join acid into the free compounds of formula I.

For the introduction of the isopropyl moiety of the compounds of formula II can be acellerate known manner. Preferably the alkylation is as reductive alkylation by reacting compounds of the formula II with acetate under reducing conditions. For example, the compounds of formula II can interact with the acetate in the presence of reductant type complex borhydride compounds, such as cyanoborohydride sodium, triacetoxyborohydride sodium or bergeret sodium. Optionally, you can perform the alkylation, in particular, such compounds with formula II, where R1is methyl, through interaction with isopropylmalate, in particular isopropylidene, isopropylmalate or ether of isopropylalcohol. Alkylation should be carried out in an inert organic solvent. For reductive alkylation, for example, as a solvent, you can use the excess acetone. The solvent can be used is luol or lower alcohols. The alkylation can be carried out in the temperature range from room temperature up to the boiling point of the solvent. When alkylation using isopropylpyrazole, such as isopropylated, such as isopropylated, it is advisable to work in the presence of a base such as a carbonate of an alkali metal or tertiary organic amine.

The resulting compound with the formula I, where R1means hydrogen, optionally subsequent to alkilirovanii by a known method into the corresponding N-methyl compound. The alkylation can be performed in a known manner by interacting with methylenchloride or reductive alkylation by reacting with formaldehyde under reducing conditions or, for example, carried out under conditions similar to carrying out the alkylation of compounds of formula II.

Of the compounds of formula I, where R1means methyl, can be split methyl radical, R1. Demethylation can be performed in a known manner by treating the compound with halogen, in particular iodine or bromine, in an inert solvent in the presence of a suitable base. As bases there may be used, for example, what about in weakly alkaline region mainly at pH 9 in order to avoid side reactions of hydrolysis.

Connection with formula I can be selected, using known methods, and clear. Salt attached acids can be converted in the usual manner into the free bases and their subsequent transformation to desire in a known manner into a pharmacologically compatible salt accession acids. To eliminate the adverse reactions of hydrolysis suitable for the formation of salts to use only an equivalent amount of acid.

As pharmacologically acceptable salts of the products of accession acid compounds with formula I can be used, for example, their salts with inorganic acids, such as coal, kaleidotrope acids, in particular hydrochloric acid, or with organic acids, for example lower aliphatic mono - or dicarboxylic acids such as maleic, fumaric, lactic, tartaric or acetic acid.

Starting compound of formula II is still not well described in the literature. In accordance with the invention the compounds of formula II are valuable intermediates for obtaining pharmacologically active compounds, for example compounds of formula I.

Compounds with formula II can the emer, erythromycin A by a known method, in particular according to the method described in the patent application Germany N 2154032 subjected to single or double demethylation by interacting with a halogen, preferably iodine, in an inert solvent in the presence of a suitable base. As the bases can be used, for example, hydroxide, alkali metal carbonates and alkali metal salts of weak carboxylic acids, such as, for example, acetates and propionate alkali metals. Preferably from 1 to 5 equivalents of halogen in terms of the amount subject to demethylation of erythromycin compounds. The number of bases is preferably chosen in such a way as to maintain the pH at 5 to 9, to eliminate the possibility of adverse reactions of hydrolysis or alcoholysis. As suitable solvents methanol, cyclic ethers, such as dioxane or tetrahydrofuran, dimethylformamide or mixtures of these solvents with water. Demethylation expediently carried out at temperatures from room temperature up to 50oC. the Reaction requires irradiation with light, for example light with wavelengths above 290 nm from a mercury lamp, low pressure, equipped with a filter of the data or demetilirovannogo product based mainly on the number of halogen. When using one equivalent of halogen preferably receive monodimensional product. The desire to obtain demetilirovannogo product can come from monodimensional product.

Mono - and demetilirovanny erythromycin A can also, using the known technique, by treatment with acid in a gentle manner be converted into the corresponding mono - or decamethylferrocene 8, 9-anhydroerythromycin-A-6,9-hemiketal with the General formula

,

where

R1is hydrogen or methyl. The formation of hemiketal can be done, for example, by treatment with glacial acetic or dilute mineral acid at temperatures from room temperature up to 50oC.

In the compounds of formula IV in a known manner it is possible to carry out the intramolecular transectorial by a narrowing of the 14-membered lactoovo ring in the erythromycin molecule, converting it to 12-membered lactoovo ring with obtaining the corresponding compounds of formula II. For this purpose the compounds of formula IV is to be heated by well-known methods in the lower alcohol in the presence of a base, for example, at temperatures from 40 to 70oC, preferably to the boiling temperature of the reaction mixture. As the OS is such as tertiary amines, in particular, lower alkylamines followed. This constriction ring configuration centers of chirality centers does not change.

New compounds with the formula I and their physiologically compatible salts accession acids possess interesting pharmacological properties, in particular the ability to affect motilin the gastrointestinal tract, stimulating its activity. Antibiotic action in them is absent, however, they are highly selective means of receptors motilin, while in effective doses, has agonistic respect motilin action, they practically do not show relevant affinity to other receptors of the gastrointestinal tract, such as, for example, epinephrine, acetylcholine, histamine, dopamine, or serotonin.

To provide a regular digestion of food, in a healthy condition together act autonomic nervous system and hormones of the gastrointestinal tract, which provide organized activities for reducing the gastrointestinal tract is not only a meal, but as they say "on an empty stomach." Motilin is a known peptide hormone of the gastrointestinal tract, as well as when eating.

The compounds of formula I exhibit physiological activity similar to that of motilin, acting as agonists for receptor motilin. Thus, the compounds of formula I exhibit a pronounced stimulating effect of gastro-intestinal region and the lower esophageal sphincter. In particular, they promote rapid gastric emptying, increasing for a long time calm tone of the sphincter. Because of its madelinemadeline activity of these substances can be used to treat painful conditions associated with impaired function of motilin in the gastrointestinal tract and/or reverse ejection of the food slurry from the stomach into the esophagus. Thus, the compounds of formula I, for example, paresis of the stomach of different origin, disorders of function of stomach emptying and gastroesophagal the reflux, dispersion, abnormalities of motility colon (enhanced peristalsis of the large intestine, reducing the code of criminal procedure), as well as post-operative disorders motility, for example, intestinal obstruction (ileus).

The compounds of formula I, having gastrointestinal activity can be tested in standard pharmacological experiments in vivo and in vitro.

Determination of binding spasmodolin measured in ritro into fractions of tissue homogenate antrum (caves mastoid) rabbit. The aim of the study was to determine the degree of displacement of motilin, labeled with radioactive iodine, from motilin-receptor communication test substance.

The study of receptor relationships conducted by one of the modifications of the method Bormann al. Regulatory Peptides, 15 (1986), 143-153). To obtain 125iodine-bulleted motilin was conducted iodination of motilin by a known method, for example by analogy with the method of Blooma al. (Scand. T. Gastroenterol, 11 (1976)47-52), by enzymatic method using lactoperoxidase.

For selection used in the test fraction homogena of tissue antrum rabbit mucosa selected portions of antrum was rasmalai and gamogenetically in 10-fold volume of cold homogenizing buffer (50 mmol Tris-HCl buffer, 250 mmol of sucrose, 25 mmol KCl, 10 mmol of Mg2Cl2, pH 7,4) adding inhibitors (1 mmol iodated, 1 µmol of pepstatin, 0.1 g/l bactrain) using a homogenizer for 15 s (1500 rpm). Then homogenized centrifuged for 15 min in the amount of 1000 g, the obtained residue is washed four times with buffer solution homogenized solution, then re-suspended in 0.9%-him way faction fabric, called "membrane preparations", used for testing.

To experience 200 μl of the membrane fraction (0.5 - 1 mg of protein) in 400 μl of buffer A (50 mmol Tris-HCl-buffer, and 1.5% BSA, 10 mmol MgCl2, pH 8) was diluted in 100 ál of iodized motilin in buffer solution B (10 mmol Tris-HCl buffer, 1% BSA, pH 8) (final concentration 50 pM) and incubated for 60 min at 30oC. the Reaction was stopped by adding 3.2 ml of cold buffer solution B, and then made the Department associated motilin from unbound, using the method of centrifugation (1000 g, 15 min). The residue formed after centrifugation in the form of husk was washed with buffer B, and then made counting in a gamma counter. The study of the degree of displacement was carried out by adding increasing amounts of the analyte in the incubation medium. As solutions of the investigated substances used aqueous solutions, obtained by appropriate dilution 60100-4molar aqueous stem solutions. Difficultly soluble in water analyte pre-dissolved in 60% ethanol, and these solutions were diluted so much water that the concentration of ethanol in the Concentratio corresponding analyte as IC50that caused 50% inhibition of specific communication iodized communication receptors motilin. From this was calculated the corresponding pIC50-is. At the specified method determined the size pIC50for substances of example 1, part 8,32.

Determination of the influence of the substances on the rate of gastric emptying in experiments in vivo.

The gastric emptying rate was determined on the dogs breed "hound", which before the experiment was carried out an operation to overlay fistula implantation of a duodenal channel. After 15 min after duodenal insertion of the analyte hungry adult dogs were injected through the fistula 285 g semi-rigid high-calorie food. Content oboronyayuschihsya of the stomach were taken every 15 min through duodenalnyh channel. Of the selected amounts of stomach contents was calculated that the length of time during which there was 50% gastric emptying. This temporary period and was considered as a measure of gastric emptying.

In this test the compound of example 1 was found pronounced stimulating effect on the rate of gastric emptying in a dose 0.46 mcmol/kg. the Time required for 50% gastric emptying, of the composition is decreased to 27 minutes

Determination of the effect of substances on the tone of the rest of the sphincter in experiments in vivo.

The determination was carried out by trained adult dogs breed "hound" on an empty stomach, which until the beginning of the experiment was introduced fistula and inserted duodenalnyh channel. The pressure on the lower end of the sphincter was measured using perponderance system catheter with a side opening, which was connected to the pressure receiver and recorder. The catheter fistula of esophagus was introduced into the stomach, and then slowly manually withdrawn from it (duct manometry). With the passage of the catheter with a side opening through a zone of high pressure at the lower end of the sphincter was recorded peak. This peak was determined pressure in millimeters of mercury.

Thus, first as reference values were determined main (basal) pressure of the sphincter of the esophagus. Then the test substance was administered inside the duodenum and after 15 min was measured pressure on the lower esophageal sphincter. The intervals between measurements was 2 min, duration of measurements was 46 minutes was Calculated pressure increase after the introduction of the analyte in comparison stose 0,251 mcmol per kg of the substance from example 1 was more than doubled. This effect persisted throughout the course of the test, i.e. 45 minutes

Due to their activity in the gastrointestinal tract compounds with the formula I used in gastroenterology as medicines for large mammals, especially for humans, for the prevention and treatment of dysfunction of motilin in the gastro-intestinal activity.

Take the dose should be administered on an individual basis and may vary based on the status of the patient, or application of medication. For example, parenteral administered drugs may contain less of the active substance than oral. Mainly, however, for the treatment of large mammals, in particular humans, use of the dosage form with a content of active substance of from 5 to 200 mg in a single dose.

The compounds of formula I used as a drug, taken together with conventional pharmaceutical auxiliary substances in galenically forms, such as tablets, capsules, suppositories or solutions. These Galenika compounds may be obtained by known methods using conventional solid carriers, such as lactose, starch, talc, or liquid diluents, narimatsu, such as table.tablename tools, stimulants dissolution, or preserving drugs.

The following examples are intended more to illustrate the subject invention, however, the list of examples of the essence of the present invention is not limited to.

Example 1. [2R, 3R(2'R, 3'R), 6R, 7S, 8S, 9S, 10R]-3-(2',3'-dihydroxyphenyl-2'-yl)-7-[(2,6-dideoxy-3-C-methyl-3-O-methyl-L-RIBO-ekspiresii)-oxy] -9-[(3,4,6-trideoxy-3-(N-methyl-N - isopropylamino)-B-D-ksilopiranozil)-oxy] -2,6,8,10,12-pentamethyl - 4,13-dioxabicyclo[8,2,1]-tridec-12-EN-5-he (connection with formula I, where R1- methyl).

A. Obtaining N-desmethylsertraline A.

20 g of erythromycin A (27, 2 mmole) and 11.2 g (136,2 mmole) of sodium acetate was dissolved in 200 ml of a mixture of methanol and water (852). The solution was heated to 47oC, after which was added 6.9 g (136,2 mmole) of iodine. By adding a dilute solution (water) of sodium hydroxide maintained pH at 8 to 9. After 3 h the reaction mixture for further processing was poured into a mixture of 1 l of water and 20 ml of ammonium hydroxide. Carried out the extraction of the reaction mixture using ethyl ester acetic acid, and the organic extract was washed with water containing ammonium hydroxide, and end with a solution of ammonium hydroxide, taken in the ratio of 50:3. The melting point of 143 - 148oC.

B. Obtaining N-des-methyl-8,9-anhydroerythromycin-A-6,9-hemiketal (connection with formula IV, R1-methyl).

21 g obtained in accordance with the product was dissolved in 110 ml of glacial acetic acid and the resulting solution was stirred for 1 h at room temperature. Then the reaction mixture for the purpose of processing under ice cooling was added dropwise into 400 ml of concentrated solution of ammonium hydroxide. The reaction mixture was extracted with ethyl ester of acetic acid, the organic extract was washed with water and the solvent drove away. Formed as the residual crude product is recrystallized first from ether and then from methanol. Received 14 g of pure product with so pl. 145oC.

C. Receipt of [2R,3R(2'R,3'R),6R,7S,8S,9R,10R]-3-(2',3'-dihydroxyphenyl - 2'-yl)-7-[(2,6-dideoxy-3-C-methyl-3-O-methyl-L-RIBO-ekspiresii)-oxy] 9-[(3,4,6-trideoxy-3-methylamino-B-D-Xylo - hexopyranosyl)-oxy] -2,6,8,10,12-pentamethyl-4,13-dioxabicyclo-[8,2,1] - tridec-12-EN-5-on (compound of formula II, where R1-methyl).

9.4 g (a 13.4 mmole) of the product obtained by p. B., boiled with 1.9 grams (to 13.4 mmole) of potassium carbonate in methanol for 2.5 h before phlegmy. Order Asisa after removal of the solvent the crude product was precrystallization from isopropanol. Received of 7.1 g of pure product with so pl. 199 - 200oC optical rotation ()2D0: -31,6o(c = 1, methanol).

, Obtaining specified in the connection header.

2 g (2.8 mmol) of the product obtained in accordance with p. In, was dissolved in methanol and by adding diluted hydrochloric acid solution was set to pH 4. To the solution was added 2 g of molecular sieves (aluminosilicate calcium, the diameter of pores ), an excess of acetone and 0.4 g (6.4 mmole) of nutritionrelated. The reaction mixture was stirred for 12 hours To process the molecular sieve was filtered, the filtrate was agglomerated, was diluted with water and was extracted with ethyl ester of acetic acid. Formed after separation of the extract ethyl ester of acetic acid as a residue the crude product was purified by chromatography on a column through kieselgel (eluent - ethyl ester acetic acid: methanol 95:5). Received 1.4 g specified in the title compound with a melting point of 130 -134oC optical rotation ()2D0: -32,8.

Example 2. [2R, 3R(2'R, 3'R), 6R,7S,8S,9R,10R]-3-(2',3'-dihydroxyphenyl - 2'-yl)-7-[(2,6-dideoxy-3-C-methyl-3-O-methyl-L-RIBO-ekspiresii)-oxy] -9-[(3,4,6-trideoxy-3-(N-methyl-N - isopropanolic I, R1-methyl).

A. Obtaining N-desmethylsertraline A.

5 g of erythromycin A and 4.7 g of sodium acetate (3H2O) was dissolved in 200 ml of a mixture consisting of methanol and water 8 : 2. To the solution was added 1.75 g of iodine, after which the reaction mixture at room temperature for 20 min was irradiated with a sun lamp. Then half of the solvent evaporated, and the remaining reaction mixture was poured into a mixture of 140 ml of water and 10 ml of ammonia. The reaction mixture was extracted three times, using each time with 20 ml methyl-1-butyl ether. The ether extract was separated and the ether is partially evaporated. Then, place the crystallization of the reaction product, which was further recrystallize from acetone. Received 2 g of N-desmethylsertraline A.

B. To obtain the N-desmethyl-8,9-anhydroerythromycin-A-6,9-hemiketal (connection with formula IV, R1-methyl) 2 g obtained in accordance with the product treated according to the method described in example 1 b was Obtained 2.3 g of hemiketal as an amorphous product.

C. To obtain [2R,3R(2'R,3'R),6R,7S,8S,9R,10R]-3-(2',3'-dihydroxyphenyl-2'-yl)-7-[(2,6 - dideoxy-3-C-methyl-3-O-methyl-L-RIBO-ekspiresii)-oxy]-9-[(3,4,6 - trideoxy-3-methylamino-B-D-Xylo-hexopyranosyl)-oxy] -2,6,8,10,12-Penta - medacta processed in accordance with the method of example 1 Century The resulting crude product was recrystallized from ethyl acetate. Was obtained 1.3 g of pure product with so pl. 199 - 202oC.

G 1.3 g product obtained above was loaded in a mixture of 26 ml of acetone and 0.1 ml of acetic acid. To the reaction mixture portions were added 0.6 g of nutritionalcolorado in nitrogen atmosphere and stirred the reaction mixture for 4 h at room temperature. Then two-thirds of the solvent evaporated, and the residue was diluted with 40 ml ethyl acetate. With vigorous stirring, was added 65 ml of a saturated solution of acid sodium carbonate. From the resulting clear solution was separated organic phase and the aqueous phase is again washed with 20 ml of ethyl acetate. The combined organic phases are washed with 13 ml of water and dried over sodium sulfate. The solvent is evaporated, the residue was dissolved in 20 ml of toluene, whereupon the latter is also evaporated. The resulting crude product was purified by filtration through a column of alumina (25 g Al2O3stage activity II/III) using ethyl acetate as eluent. Then was added n-hexane until the turbidity of the mixture. Crystallization of the product produced in the cold. The resulting crystals were filtered off under reduced pressure preobrazovaniya in acetate 1 g (1.3 mmole) specified in the title compound was dissolved in methanol, and the solution was diluted to 0.08 ml (1.3 mmole) of acetic acid. The solvent is then drove away under reduced pressure, and the resulting acetate is indicated in the title compound was dried. So pl. acetate 145 - 150oC, optical rotation ()2D0:30,8o(c = 1, methanol).

Example 3. Received the tablets of the following composition per 1 tablet:

[2R, 3R(2'R, 3'R), 6R, 7S,8S,9R,10R]-3-(2',3'-dihydroxyphenyl-2'-yl)-7-[(2,6-dideoxy-3-C-methyl-3-O-methyl-L-RIBO-ekspiresii)-oxy] -9-[(3,4,6 - trideoxy-3-(N-methyl-N-isopropylamino)-B-D-Xylo-hexopyranosyl)-oxy] - 2,6,8,10,12-pentamethyl-4,13-dioxabicyclo[8,2,1] -tridec-12-EN-5-he (connection with formula I, where R1-methyl) - 20 mg

Maize starch - 135 mg

Milk sugar - 60 mg

Gelatin (10% solution) 6 mg

The active ingredient, maize starch and lactose zagadyvali a 10% solution of gelatin. The resulting paste was rasmalai, distributed on the leaves and dried at 45C. The dried granulate was passed through a crusher and mixed in a mixer with the following auxiliary substances, mg:

Talc - 5

Magnesium stearate - 5

Maize starch - 9,

then squeezed through the press tablets of 240 mg

1. Derivatives of [2R, 3R (2'R, 3'R), 6R, 7
< / BR>
where R1is methyl or hydrogen, or their stable and physiologically compatible salts accession acid.

2. Derivatives under item 1 of General formula I, where R1is methyl.

3. Pharmaceutical stimulant action of the gastrointestinal tract, comprising the active substance and the usual pharmaceutical carriers, characterized in that the active substance it contains a join I on p. 1, where R1is methyl or hydrogen, as well as their stable and physiologically compatible salts accession acid in an effective amount.

4. The method of obtaining derivatives of [2R, 3R, (2'R, 3'R), 6R, 7S, 8S, 9R, 10R] -3-(2,3-dihydroxyphenyl-2-yl)-2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8,2,1]-tridec-12-EN-5-it General formula

< / BR>
where R1is methyl or hydrogen, or their stable and physiologically acceptable salts accession acids, characterized in that the derivatives of [2R, 3R (2'R, 3'R), 6R, 7S, 8S, 9R, 10R]-3-(2', 3'- dihydroxyphenyl-2-yl)-2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8,2,1]-tridec-12-EN-5-it General formula

< / BR>
where R' has the above value, enter the remaining isopropyl, optionally available compounds of formula I translate in their stable salt accession acids or salts joining Ki is

 

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< / BR>
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FIELD: medicine.

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EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg

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EFFECT: higher efficiency of therapy.

1 ex, 2 tbl

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