Antagonists of metbotropic glutamate receptor 5 (mglur5) and methods of prevention and treatment of gastroesophageal reflux (options)

FIELD: medicine; veterinary.

SUBSTANCE: antagonists of metabotropic glutamate receptor 5 (MGLUR5) are suggested to inhibit the transit relaxation of the inferior esophageal sphincter, as well as the corresponding method of treatment and/or prevention of related disorders. Particularly, such disorders include gastroesophageal reflux, gastroesophageal reflux disease, regurgitation, pulmonary disease, hypoplasia of organism, and asthma. The following antagonists of metabotropic glutamate receptor 5 are preferable: 2-methyl-6-(fenyl-etynyl) pyridine, hydrochloride 2- methyl-6-(fenyl-etynyl) pyridine, 3-[3-(5- fluoropyridine -2-il)-1,2,4-oxadiazol-5-il]-5-(metoxymethyl) benzonitrile, 3-fluor-5-[3-(5- fluoropyridine -2-il)-1,2,4- oxadiazol-5-il] benzonitrile.

EFFECT: compounds inhibited the pressure of inferior esophageal sphincter decreased by infusion pomp, in dogs.

26 cl, 4 tbl, 3 ex

 

The technical field to which the invention relates.

This invention relates to the use of antagonists of metabotropic glutamate receptor 5 (mGluR5) to suppress transient (transient) relaxation of the lower esophageal sphincter. Another aspect of the invention is directed to the use of antagonists of metabotropic glutamate receptor 5 for the treatment of gastroesophageal reflux disease and for the treatment of regurgitation.

The level of technology

Metabotropic glutamate receptors (mGluR) are G-protein-coupled receptors that are involved in the regulation and activity of many synapses in the Central nervous system (CNS). Identified eight subtypes of metabotropic glutamate receptors, and they are divided into three groups based on the similarity of sequences. Group I consists of mGluR1 and mGluR5. These receptors activate phospholipase C and increase neuronal excitability. Group II, consisting of mGluR2 and mGluR3, and group III, consisting of mGluR4, mGluR6, mGluR7 and mGluR8, is able to inhibit the activity of adenylylcyclase and reduce synaptic transmission. Some receptors also exist in different isoforms generated by alternative splicing (see Chen C-Y, et al., Journal of discrimination, 538. 3, s-786, (2002); Pin J-P et al, European Journal of Pharmacology, 375, s-294, (1999); Brauner-Osbome H. et al., Journa of Medicinal Chemistry, 43, s-2645, (2000); Schoepp D.D, D.E. Jane Monn J.A. Neuropharmacology, 38, s-1476, (1999)).

The lower esophageal sphincter (Les) is subject to periodic relaxation. As a result, the liquid from the stomach to enter the esophagus, as a mechanical barrier in such periods is temporarily absent, the event is further denoted by the term "reflux".

Gastroesophageal reflux disease (GERD) is the most common disease of the upper section of the gastrointestinal tract. Modern pharmacotherapy aimed at reducing the secretion of gastric acid or neutralization of acid in the esophagus. Believed that the main mechanism causing reflux depends on gipotonichnaya the lower esophageal sphincter. However, for example, article Holloway and Dent (see Gastroenterol. Clin. N. Amer., 19, C-535, (1990)), it is shown that the majority of reflux episodes occur during transient relaxation of the lower esophageal sphincter (TLESRs), i.e. relaxation, not initiated by swallowing. It has been shown that patients with GERD the secretion of gastric acid is usually within normal limits.

According to Blackshaw L.A. et al. (see the presentation at the conference Neurogastroenterology and mobility (Neurogastroenterology &Motility), Madison, Wisconsin, November 14, 2001), metabotropic glutamate receptor group II and group III, i.e. mGluR2, mGluR3, mGluR4, mGluR6, mGluR7 and mGluR8, can in order to participate in the selective inhibitory modulation of peripheral mechanosensory endings.

Disclosure of inventions

The objective of the invention is to define a new way of suppressing transient relaxation of the lower esophageal sphincter (TLESRs) for thereby preventing reflux. More specifically, the invention aims to search for new and improved ways of treating gastroesophageal reflux disease (GERD), as well as new and improved ways of treating regurgitation.

Unexpectedly it was found that antagonists of metabotropic glutamate receptor 5 (mGluR5) effective for suppressing transient relaxation of the lower esophageal sphincter (TLESRs), and thus, for treatment of gastroesophageal reflux disease (GERD).

As a consequence, this invention is directed to the use of an antagonist of metabotropic glutamate receptor 5 for the preparation of a medicine for suppressing transient relaxation of the lower esophageal sphincter (TLESRs).

The next aspect of the invention is the use of an antagonist of metabotropic glutamate receptor 5 for the preparation of drugs for prevention of reflux.

Another aspect of the invention is the use of an antagonist of metabotropic glutamate receptor 5 for the preparation of drugs for the treatment of gastroesophageal Ref is uksnow disease (GERD).

Effective prevention of regurgitation may be an important way of prevention and treatment of pulmonary disease caused by aspiration crygiving the contents of the stomach, and correction of insufficient development of the body. Thus, another aspect of the invention is the use of an antagonist of metabotropic glutamate receptor 5 for the preparation of drugs for the treatment of regurgitation.

Another aspect of the invention is the use of an antagonist of metabotropic glutamate receptor 5 for the preparation of drugs for treatment or prevention of lung disease.

Another aspect of the invention is the use of an antagonist of metabotropic glutamate receptor 5 for the preparation of medicines for the correction of insufficient development of the organism.

Another aspect of the invention is the use of an antagonist of metabotropic glutamate receptor 5 for the preparation of drugs for treatment or prevention of asthma, such as asthma, associated with reflux.

Another aspect of the invention is the use of an antagonist of metabotropic glutamate receptor 5 for the preparation of drugs for treatment or prevention of chronic laryngitis.

Following the top aspect the invention is a method of suppressing transient relaxation of the lower esophageal sphincter (TLESRs), in which the pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5 is administered to a subject in need of such suppression.

Another aspect of the invention is a method of prevention of reflux, whereby a pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5 is administered to a subject in need of such prevention.

Another aspect of the invention is a method of treatment of gastroesophageal reflux disease (GERD), whereby a pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5 is administered to a subject in need of this treatment.

Another aspect of the invention is a method for the treatment of regurgitation, whereby a pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5 is administered to a subject in need of this treatment.

Another aspect of the invention is a method for the treatment of asthma, such as asthma, associated with reflux, whereby a pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5 is administered to a subject in need of this treatment.

Another is the range of the invention is a method for the treatment of chronic laryngitis, according to which the pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5 is administered to a subject in need of this treatment.

Another aspect of the invention is a method for the treatment or suppression of pulmonary diseases, whereby a pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5 is administered to a subject in need of this treatment.

Another aspect of the invention is a method for correcting the insufficient development of the body, whereby a pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5 is administered to a subject in need of this treatment.

In the context of this invention, the term "antagonist" should be understood as including full antagonists, inverse agonists, competitive antagonists or competitive antagonists and partial antagonists, the term "partial antagonist" means a compound capable of partially, but not completely inactivate metabotropic glutamate receptor 5.

The expression "TLESR", transient relaxation of the lower esophageal sphincter, define in this context, according to Mittal R.K., Holloway, R.H., Penagini R., Blackshaw LA., Dent J., Provisional races is lublinie the lower esophageal sphincter (Transient lower esophageal sphincter relaxation) (see Gastroenterology, 109, s-610, (1995)).

The term "reflux" is defined as reflux of fluid from the stomach into the esophagus, because in such periods is temporarily absent a mechanical barrier.

The expression "GERD", gastroesophageal reflux disease, defined according to article van Heerwarden M.A., A.J.P.M. Smout, the Diagnosis of reflux disease (Diagnosis of reflux disease), (see Bailliere′s Clin. Gastroenterol., 14, s-774, (2000)).

The implementation of the invention

One example of compounds with antagonistic affinity to metabotropic glutamate receptor 5 and consequently used in accordance with the invention, is the compound 2-methyl-6-(phenylethynyl)pyridine (often abbreviated name of MRER). MRER commercially available, for example, the company Tocris, or can be synthesized according to well known procedures, such as disclosed in the article .Sonogashira et al. (see Tetrahedron Lett., 50, 4467-4470, (1975)).

Another example of the compounds having antagonistic affinity to metabotropic glutamate receptor 5 and consequently used in accordance with the invention, is the compound 3-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]-5-(methoxymethyl)benzonitrile having the structural formula:

Another example of compounds with antagonistic affinity to metabotropic glutamate receptor 5 and the result used in accordance with the invention, is the compound 3-fluoro-5-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]benzonitrile having the structural formula:

The use of pharmaceutically acceptable salts antagonists of metabotropic glutamate receptor 5 is also in the scope of this invention. These salts, for example, are salts formed with mineral acids such as hydrochloric acid, salts of alkali metals such as sodium or potassium, or salts of alkaline earth metals such as calcium salt or magnesium.

Antagonists of metabotropic glutamate receptor 5, having an asymmetric carbon atom, are chiral compounds, and depending on the presence of asymmetric atoms antagonists of metabotropic glutamate receptor 5 can be in the form of mixtures of isomers, including racemates, or in the form of pure isomers, such as specific enantiomers. The use of optical isomers antagonists of metabotropic glutamate receptor 5 is also in the scope of the invention.

Pharmaceutical

For clinical application of antagonists of metabotropic glutamate receptor 5 in accordance with this invention in an acceptable manner is prepared in the form of pharmaceutical preparations for oral administration. In addition, qualified with ecialist in the field of preparation may include rectal, parenteral and any other path of administration. Thus, antagonists of metabotropic glutamate receptor 5 is made with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of solid, semi-solid or liquid diluent.

To obtain oral pharmaceutical preparations in accordance with the invention used in preparations antagonists of metabotropic glutamate receptor 5 is mixed with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as leavening agents and moving components such as magnesium stearate, calcium stearate, sodium fumarate and waxes based on polyethylene glycol. The mixture is then granularit or pressed into tablets.

Soft gelatin capsules may be prepared with capsules containing a mixture of active compound or compounds of the invention, vegetable oil, fat or other suitable media for soft gelatin capsules. Hard gelatin capsules can contain the active compound in combination with solid powdered ingredients such galactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amyl is pectin, derivatives of cellulose or gelatin.

Dosage forms for rectal application can be prepared (i) in the form of suppositories which contain the active substance(s)mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture in a vegetable oil, paraffin oil or other suitable media for gelatin rectal capsules; (iii) in the form of ready-made micro or (iv) in the form of a dry preparation for micro, which restores in a suitable solvent just before the introduction.

Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, for example solutions or suspensions containing the active compound and the remainder of the composition consisting of sugars or polyalcohols, xylytol and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickener. Liquid preparations for oral administration can also be prepared in the form of a dry powder, designed to restore a suitable solvent before use.

Preparations for parenteral administration can be prepared is a solution of the compound, corresponding to the invention, in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or tabularasa ingredients and can be divided into a uniform dose in the form of ampoules or vials. Solutions for parenteral administration can also be prepared in the form of a dry preparation, which restores a suitable solvent immediately before use.

In one aspect of the present invention, the antagonists of metabotropic glutamate receptor 5 you can enter once or twice a day depending on the severity of the patient.

The normal dose of antagonists of metabotropic glutamate receptor 5 is from 0.1 to 100 mg/kg of body weight of the subject being treated, but this will depend on a number of factors such as route of administration, age and body weight of the patient, and the severity of the patient's condition.

Biological assessment

Screening of compounds with respect TLESR

Use adult dogs breed Labrador Retriever both sexes, accustomed to stand in the dressing Pavlova. Form esophagostomy (artificial external esophageal fistula) from the mucosal membranes and skin, and give dogs fully recover before conducting experiments.

Measuring mobility

Briefly, after fasting in t is an increase of approximately 17 hours at the free supply of water through esophagostomy enter multi-line sleeve/system with side holes (Dentsleeve, Adelaide, South Australia) to measure pressure in the stomach, the lower esophageal sphincter (Les) and esophageal. The system loads the water, using manometric perfusion pump with low flexibility (Dentsleeve, Adelaide, South Australia). Air-filled tube is passed towards the oral cavity for measuring glotony, and the electrode of antimony monitorium pH 3 cm above the NTC. All signals reinforce and serves on a personal computer with a frequency of 10 Hz.

After conducting a baseline measurement in the absence of motor activity of the stomach during fasting/phase III OPS, in the vein of the front paw injected with placebo (0.9% NaCl) or test compound (intravenously 0.5 ml/kg). Ten minutes after intravenous injection in the stomach pour in culture medium (10% peptone, 5% D-glucose, 5% intralipid, pH 3.0) through the Central channel of the system at a rate of 100 ml/min to a final volume of 30 ml/kg Immediately after the introduction of food is blown into the air at a speed of 40 mg/min In an alternative model (model Barostat) for infusion of the nutrient medium followed by the introduction of air at a rate of 500 ml/min to achieve the intragastric pressure 10±1 mm Hg (R.S.). Then the pressure is maintained at this level throughout the experiment using an infusion pump for the further introduction of air or exhaust air from the stomach. The time of the experiment from the beginning of the infusion is fateley environment until the end of the introduction of air is 45 minutes The procedure was approved as a secure means to start TLESRs.

TLESRs is defined as the reduction in pressure of the lower esophageal sphincter (with reference to intragastric pressure) at a rate of >1 mm R.S./s. Relaxation should not be preceded by faringealny (pharyngeal) signal ≤2 sec before it starts, in this case, the relaxation are classified as caused by swallowing. The pressure difference between the NTC and the stomach should be less than 2 mm R.S., and duration of complete relaxation is longer than 1 sec.

EXAMPLES

Example 1

2-methyl-6-(phenylethynyl)pyridine (MRER) are obtained according to the procedure described in article .Sonogashira et al. (see Tetrahedron Lett., 50, 4467-4470, (1975)). After purification using column chromatography (SiO2) hydrochloride (hydrochloride of 2-methyl-6-(phenylethynyl)pyridine there is also on sale, for example, the company Tocris) receive maintenance HCl (g) in chilled on ice, a solution of the product in Et2O. Hydrochloride, MRER test for adult Labrador retrievers both sexes in accordance with the above test model.

Inhibition of the number of TLESRs is calculated relative to the preceding five control experiments for each dog and get results which are presented below in Tables 1.1 and 1.2.

Table 1.1
The standard model
ConnectionDose [µmol/kg]% Inhibition ± SEM(N)
MRER1,430±5 (4)
MRER4,357±8 (4)
MRER8,759±11 (3)
N = Number of tested dogs SEM = standard error

Table 1.2
The standard model
ConnectionDose [µmol/kg/h] infusion for 60 min% Inhibition ± SEM(N)
MRER432+13 (4)
MRER643±3 (2)
N = Number of tested dogs SEM = standard error

Primer 2

3-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]-5-(methoxymethyl)benzonitrile receive according to the procedure described in WO 02/068417. 3-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]-5-(methoxymethyl)benzonitrile test for adult Labrador retrievers both sexes in accordance with the above birotational model.

Table 2.1
Birotational model
ConnectionDose [µmol/kg/h] infusion for 55 min% Inhibition ± SEM(N)
3-[3-(5-herperidin-2-yl]-1,2,4-oxadiazol-5-yl]-5-(methoxymethyl)benzonitrile1,158±11 (4)
3-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]-5-(methoxymethyl)benzonitrile2,283±17 (2)
N = Number of tested dogs SEM = standard error

Example 3

3-fluoro-5-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]benzonitrile receive according to the procedure described in WO 01/12627. 3-fluoro-5-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]benzonitrile test for adult Labrador retrievers both sexes in accordance with the above birotational model.

Table 3.1
Birotational model
ConnectionDose [µmol/kg/h] infusion for 60 min% Inhibition ± SEM(N)
3-fluoro-5-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]-benzonitrile170±4 (3)
N = Number of tested dogs SEM = standard error

The results presented in privedennyh examples support the assumption that antagonists of metabotropic glutamate receptor 5 effective for the inhibition of transient relaxation of the lower esophageal sphincter and, thus, for the treatment of GERD.

1. The use of an antagonist of metabotropic glutamate receptor 5, or its pharmaceutically acceptable salt or optical isomer as an active ingredient of a medicinal product for the prevention and/or treatment of disorders and/or diseases associated with transient relaxation of the lower esophageal sphincter.

2. The use according to claim 1, in which the specified drug is used for prophylaxis and/or treatment of gastroesophageal reflux disease.

3. The use according to claim 1, in which the specified drug is used for prophylaxis and/or treatment of gastroesophageal reflux.

4. The use according to claim 1, in which the specified drug is used for prophylaxis and/or treatment of regurgitation.

5. The use according to claim 1, in which the specified drug is used for prophylaxis and/or treatment of asthma associated with gastroesophageal reflux.

6. The use according to claim 1, in which the specified drug is used for prophylaxis and/or treatment of chronic laryngitis associated with gastroesophageal reflux is.

7. The use according to claim 1, in which the specified drug is used for prophylaxis and/or treatment of pulmonary diseases associated with gastroesophageal reflux.

8. The use according to claim 1, in which the specified drug is used for prophylaxis and/or treatment of insufficient development of the organism associated with gastroesophageal reflux.

9. The use according to any one of claims 1-8 antagonist of metabotropic glutamate receptor 5, a 2-methyl-6-(phenylethynyl)-pyridine.

10. The use according to any one of claims 1-8 antagonist of metabotropic glutamate receptor 5, a hydrochloride of 2-methyl-6-(phenylethynyl)pyridine.

11. The use according to any one of claims 1-8 antagonist of metabotropic glutamate receptor, representing 3-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]-5-(methoxymethyl)benzonitrile.

12. The use according to any one of claims 1-8 antagonist of metabotropic glutamate receptor represents 3-fluoro-5-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]benzonitrile.

13. The use according to any one of claims 1-8 antagonist of metabotropic glutamate receptor 5 in a daily dose of from 0.1 to 100 mg/kg of body weight of the subject undergoing treatment.

14. The method of prevention and/or treatment of disorders and/or diseases associated with transient relaxation of the lower pisew the underwater sphincter, wherein the subject in need of such prevention and/or treatment administered pharmaceutically and pharmacologically effective amount of an antagonist of metabotropic glutamate receptor 5, or its pharmaceutically acceptable salt or optical isomer.

15. The method according to 14, in which the specified condition is gastroesophageal reflux disease.

16. The method according to 14, in which the specified violation is gastroesophageal reflux.

17. The method according to 14, in which the specified violation is regurgitation.

18. The method according to 14, in which the specified pulmonary disease is a disease associated with gastroesophageal reflux.

19. The method according to 14, in which the violation and/or a disease associated with insufficient development of the organism, caused by gastroesophageal reflux.

20. The method according to 14, in which the specified condition is asthma associated with gastroesophageal reflux.

21. The method according to 14, in which the specified condition is chronic laryngitis associated with gastroesophageal reflux.

22. The method according to any of PP-21, characterized in that the antagonist of metabotropic glutamate receptor 5 is a 2-methyl-6-(phenylethynyl)pyridine.

23. The method according to any of PP-21, characterized in that the antagonist of metabotropic glutamate what about the receptor 5 is a hydrochloride of 2-methyl-6-(phenylethynyl)pyridine.

24. The method according to any of PP-21, characterized in that the antagonist of metabotropic glutamate receptor 5 is a 3-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]-5-(methoxymethyl)benzonitrile.

25. The method according to any of PP-21, characterized in that the antagonist of metabotropic glutamate receptor 5 is a 3-fluoro-5-[3-(5-herperidin-2-yl)-1,2,4-oxadiazol-5-yl]benzonitrile.

26. The method according to any of PP-21, wherein the daily dose of the antagonist of metabotropic glutamate receptor 5 is injected in an amount of from 0.1 to 100 mg/kg of body weight of the subject undergoing treatment.



 

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41 cl, 12 sch, 35 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel hydrogenated azepino[4,3-b]indoles of the general formula (1): , their racemates, optical isomers, geometric isomers and their pharmaceutically acceptable salts and/or hydrates. In the general formula (1) a dotted line with accompanying unbroken line represents a simple or double bond; R1 and R2 represent independently of one another substitutes of amino-group chosen from hydrogen atom, possibly substituted (C1-C8)-alkyl possibly substituted with aryl, 5-6-membered azaheterocyclyl, (C1-C8)-alkoxycarbonyl, possibly substituted phenyl, possibly substituted carbonylamino- or thiocarbonylamino-group, substituted acyl, (C1-C8)-alkylsulfonyl, possibly substituted arylsulfonyl and wherein substitutes in indicated R1 and R2 are chosen independently from (C1-C8)-alkyl, halogen atoms, nitro-, carboxy-, alkoxy-group, aryl; Rin represents one or some similar or different substitutes of cyclic system chosen from hydrogen atom, (C1-C8)-alkyl, (C6-C10)-aryl, halogen atom, 5-6-membered azaheterocyclyl. Also, invention relates to methods for synthesis of these compounds, their using and pharmaceutical composition and libraries of compounds. Synthesized compounds possess neuroprotective, cognitive-stimulating and anti-histaminic properties and can be used in treatment of different neurological disorders, allergic and autoimmune diseases, for example, for memory improvement.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition, improved method of synthesis.

25 cl, 2 tbl, 12 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, medicine, cardiology.

SUBSTANCE: invention proposes using derivatives of fumaric acid chosen from group consisting of dialkylfumarates, monoalkylhydrofumarates, fumaric acid monoalkyl ester salts, fumaric acid monoamides, fumaric acid diamides, monoalkyl-monoamidofumarates, carbocyclic isomers of these compounds and their mixture for preparing a pharmaceutical preparation used in treatment of asthma and chronic pulmonary obstructive diseases, in particular, asthma caused by allergy, infections, analgesic drugs, labor conditions or physical strength, asthma mixed forms or asthma cardiale. Dimethylfumarate decreased enhanced proliferation of bronchi smooth muscle cells.

EFFECT: valuable medicinal properties of compounds.

12 cl, 4 dwg, 7 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the formula (I): and their salts, to methods for their preparing, compositions containing thereof and their using in medicine, in particular, for prophylaxis or treatment of clinical state wherein a selective agonist of β2-adrenoceptors is prescribed.

EFFECT: valuable medicinal properties of compound and compositions.

32 cl, 4 dwg, 82 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-pyrazinylphenylsulfonamides of the general formula (I) or their pharmaceutically acceptable salts or solvates wherein each R1, R2 and R3 represents independently hydrogen atom, halogen atom, cyano-group, -CF3, -OCF3, -O-(C1-C6)-alkyl or (C1-C6)-alkyl; R4 represents halogen atom, -CO2R12, (C1-C6)-alkoxy-, (C3-C6)-alkenyloxy- or (C3-C6)-alkynyloxy-group, -O-(C1-C6)-alkyl-X-(C1-C6)-alkyl, -O-(C1-C6)-alkyl-R11, -O-(C2-C6)-alkyl-X-R11 or -O-(C1-C6)-alkyl-R16; each R5 and R6 represents independently hydrogen atom, halogen atom, -CO2R12, -CONR14R15, (C1-C6)-alkyl substituted possibly with hydroxy-group, -NR14R15 or 1-3 fluorine atoms; (C1-C6)-alkyl-R11, -XCH(R11)-(C1-C6)-alkyl or -XCH(R16)-(C1-C6)-alkyl, -NR14R15, -N(R11)R11, X-(CH2)qNR14R15, (CH2)nNR14R15, -NHC(O)-(C1-C6)-alkyl substituted possibly with one or more hydroxy-group, (C3-C6)-alkynyl or (C3-C6)-alkenyl possibly branched and, possibly, substituted with 1-3 groups chosen from hydroxy-, cyano-group, halogen atom and =O. Proposed compounds can be used in treatment of chemokine-mediates diseases, for example, inflammatory diseases, such as asthma. Also, invention describes methods for synthesis of compounds of the formula (I), pharmaceutical composition based on thereof, method for preparing pharmaceutical composition and using compounds in producing a medicinal agent.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 212 ex

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: invention proposes a composition that prevents dryness in mouth and voice "breaking" and maintains tonus of vocal chords comprising the following components, weight %: (a) Piper cubeba extract, 0.5-2; (b) Glycyrrhiza glabra extract, 0.5-2; (c) Acorus calamus extract, 0.01-0.1; (d) Alpinia galanga extract, 0.01-0.1; (e) Zingiber officinale extract, 0.01-0.1, and (f) pharmaceutically acceptable additives, the balance. Method for preparing the composition involves the following steps: (a) preparing necessary parts of medicinal plants; (b) drying vegetable material from step (a) in shade; (c) milling dried vegetable material from step (b) for preparing small powder; (d) extraction of milled vegetable material from step (c) with aqueous-alcoholic solution at temperature 25-350C for 4-7 days for preparing aqueous-alcoholic extract; (e) concentrating the extract from step (d) under reduced pressure and temperature 40-600C for preparing the concentrated extract; (f) lyophilization of the concentrated extract from step (e) for complete removal of solvent residue and preparing the necessary vegetable extract, and (g) addition of vegetable extract from step (f) to prescription in common with suitable pharmaceutically acceptable additives for preparing the necessary composition. The composition is used in bronchitis and allergic throat diseases. Invention provides realization of indicated designations.

EFFECT: valuable medicinal properties of composition.

35 cl, 2 tbl, 5 ex

FIELD: otolaryngology.

SUBSTANCE: endoscopy-controlled tissue of adenoid vegetation is pretreated with 0.01% miramistin solution, after which 8-10 mL of 0.1% levamisol are introduced into adenoid crypts.

EFFECT: enhanced treatment efficiency due to optimal amounts and concentrations of drugs as well as methods for administration thereof.

2 ex

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: invention relates to a method for treatment of chronic hyperplastic laryngitis. Method involves using the immunoglobulin preparation "Immunovenin" for intravenous administration that is administrated by drop route as a single dose 25.0 ml at the rate 10-20 drops/min. Method provides reducing treatment period, diminishing complications as candidiasis and amounts of relapses based on enhancing formation of antibodies, especially of G class, and retaining high phagocytic activity of neutrophiles.

EFFECT: improved method of treatment.

1 tbl, 1 ex

FIELD: otolaryngology.

SUBSTANCE: in order to treat tonsillitis, ml of 1% solution of emoxipine is introduced into lacunas of palatine tonsils, after which the latter are exposed to helium-neon laser radiation with wavelength 0.63 μm, maximum output power 10-20 mW, light spot diameter 2-3 mm, and power flow density 35-60 W/cm2, distal end of monofiber beamguide being introduced into lacuna cavity. Single dose ranges from 3.0 to 5.5 J/cm. Radiation exposition time is 2 min per 1 lacuna and full course consists of 5-7 procedures.

EFFECT: accelerated accumulation of required concentration of emoxipine in tissues of palatine tonsils so enhancing treatment efficiency.

2 tbl

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: method involves administration in patient 1% emoxipine solution in the volume 1 ml to lateral and posterior sections of mouth-pharynx after its preliminary application anesthesia with 2% lidocaine solution by submucosa injection. The treatment course is 5-10 procedures with break for 1 day. Method provides the stable clinical effect of treatment based on rapid accumulation of the required concentration of the medicinal preparation both in pharynx mucosa and in blood. Invention can be used in treatment of chronic pharyngitis.

EFFECT: improved method of treatment.

2 tbl, 1 ex

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: method involves administration to a patient 1% solution of emoxipine in volume 5 ml in the treatment course 3-4 procedures in each other day by intralacunar route. Method provides the curative effect based on deeper penetration and rapid absorption of medicinal agent possessing with antioxidant effect by palatine tonsil surface of lacunas.

EFFECT: improved treatment method.

2 tbl, 1 ex

The invention relates to medicine, otolaryngology, and can be used for the treatment of acute stenozirutego of laryngotracheobronchitis in children
The invention relates to medicine

The invention relates to the field of medicine and for the preparation of Bresolin drops nasal 0.06% and 0.1% for the treatment of diseases of the nose and throat
The invention relates to medicine, in particular to therapy, and can be used for the treatment of angina

Indanol derivatives // 2323937

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): (where R1 and R2 may be identical or different, and each is a 1,3-substituted aryl with substituents from group α; R3 stands for any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N(Ra)Rb, -(CH2)m-CO-R5, -(CH2)m-R5, -CO-NH-CO-N(Ra)Rb, -CO-NH-SO2-N(Ra)Rb, -CO-NH-CO-(CH2)m-N(Ra)Rb, or -CO-NH2; R4 stands for a lower alkyl, cycloalkyl, cycloalkyl substituted with 1-3 substituent from group α, lower alkenyl, lower alkynyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl, lower alkoxyalkyl, lower aliphatic acyloxyalkyl or lower alkoxycarbonylalkyl; R5 stands for hydroxyl, -OR4 or -N(Ra)Rb; Rа and Rb may be identical or different, each of them stands for hydrogen, hydroxyl, lower alkoxy group, hydroxyl-substituted lower alkoxyl, hydroxyl-substituted lower alkoxyalkyl, lower alkoxy lower alkoxyalkyl, cyano lower alkyl, cyano lower alkoxyalkyl, carboxy lower alkyl, carboxy lower alkoxyalkyl, aliphatic lower alkoxycarbonyl lower alkoxyalkyl, carbamoyl lower alkyl group, carbamoyl lower alkoxyalkyl, lower aliphatic acylamino lower alkyl, lower aliphatic acylamino lower alkoxyalkyl, lower alkylsulphonylamino lower alkyl, lower alkylsulphanylamino lower alkoxyalkyl, (N-hydroxy-N-methylcarbamoyl) lower alkyl, (N-hydroxy-N-methylcarbamoyl) lower alkoxyalkyl, (N-lower alkoxy-N-methylcarbamoyl) lower alkyl, (N-lower alkoxy-14-methylcarbamoyl) lower alkoxyalkyl or R4, or both, including associated nitrogen, stand for nitrogen-containing heterocyclic group or nitrogen-containing 1-3 substituted heterocyclic group with substituents from group α; m is an integer from 1 to 6; А stands for carbonyl; В stands for straight bond; D stands for oxygen atom; Е stands for С14 alkylene; n is an integer from 1 to 3; and α group is a group of substituents, which consist of halogen atoms, lower alkyls, hydroxy lower alkyls, halogen lower alkyls, carboxy lower alkyls, lower alkoxyls, hydroxy lower alkoxyls, hydroxy lower alkoxyalkyls, lower alkoxycarbonyls, carboxyls, hydroxyls, lower aliphatic acyls, lower aliphatic acylamines, (N-hydroxy-N-methylcarbamoyl) lower alkyls, (N-lower alkoxy-N-methylcarbamoyl) lower alkyls, hydroxy lower aliphatic acylamines, amines, carbamoyls and cyano groups), or pharmacologically suitable salt thereof. Invention also relates to pharmaceutical composition and method for disease prevention and treatment.

EFFECT: preparation of novel biologically active compounds.

18 cl, 117 ex

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