Pharmaceutical composition, containing derivatives of glutarimides, and their application for treatment of eosinophilic diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics. A medication represents derivatives of glutarimides of the general formula (I) or their pharmaceutically acceptable salts. The invention also relates to pharmaceutical compositions and a method of treatment.

EFFECT: ensured by the application of non-toxic derivatives of the said glutarimides for the treatment of eosinophilic diseases, mainly of an allergic origin.

16 cl, 12 tbl, 7 ex

 

The invention relates to the use of biologically active compounds derived glutarimide or their pharmaceutically acceptable salts as remedies for the treatment of eosinophilic diseases.

The LEVEL of TECHNOLOGY

Eosinophils - cells of innate immunity. They are produced in the bone marrow and circulate mainly in the blood. The main effector function of eosinophils is the immediate release of cytoplasmic granules in response to activation by different stimuli. Cytoplasmic granules contain inflammatory mediators: cytokines, chemokines, lipid - and neurotransmitters, growth factors and cationic proteins. Cationic proteins of eosinophils include class 4: large basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP) and eosinophils-dependent neurotoxin (EDN). Together, these proteins have cytotoxic activity, both in relation to infectious microorganisms, and in relation to the host tissues, causing eosinophilic inflammation [Hogan SP, Rosenberg HF, Moqbel R, et al. Eosinophils: biological properties and role in health and disease // Clin Exp Allergy. 2008; 38(5): 709-50].

Normally, the number of eosinophils in the blood is 0,02-0,3-109/l, or 0.5-5% of all leukocytes. The increase in the number of blood eosinophils, compared with norm - eosinophilia.

The gipereozinofiliya, or big eosinophilia, call comprising�Oia, when the content of eosinophils in the blood is 15% or more, usually with the increase in the total number of leukocytes [Hoffman R, Benz Jr. EJ, Shattil SJ, et al., eds. Hematology: Basic Principles and Practice. 4th ed. Philadelphia, Pa: Churchill Livingston; 2005:768].

The increase in the number of eosinophils in the blood and tissues is accompanied by different etiology and pathogenesis of the disease. Among them: parasitic infestations, a wide range of allergic conditions, including asthma, rhinitis, nasal polyps, eosinophilic colitis, eosinophilic syndromes and atopic dermatitis, rheumatic diseases (rheumatoid arthritis, diffuse eosinophilic fasciitis, syndrome Cerca-Strauss, polyarteritis nodosa), and pathology of unknown etiology (eosinophilic esophagitis, eosinophilic gastroenteritis) [Blanchard C, Rothenberg ME. Biology of the eosinophi // Adv Immunol. 2009; 101: 81-121].

Among allergic diseases, the most important from a medical point of view is considered a bronchial asthma, a chronic inflammatory disease of the Airways characterized by episodic obstruction of airflow, airway inflammation and increased bronchial reactivity to non-specific allergens.

There is plenty of evidence that eosinophils are a key component of the allergic response in asthma. Excreted fat cells IL-3, IL-5 contribute to the accumulation of eosinophils in �eggie, subsequent activation of these cells with the release of LTC4, eosinophil cationic protein, the main core of the protein, neurotoxin, eosinophil peroxidase (EPO), transforming growth factors, free radicals [Blanchard C, Rothenberg ME. Biology of the eosinophil // Adv Immunol. 2009; 101: 81-121].

Revealed a direct correlation between the activity of the inflammatory process in bronchial asthma and content of eosinophil cationic protein in serum [Bjornsson Ε., Janson C, Hakansson L. et al. Serum eosinophil cationic protein in relation to bronchial asthma in young Swedish population. Allergy 1994; Vol. 49: 400-407]. In bronchial lavage fluid in patients with bronchial asthma revealed an increase in the number of eosinophils. On the surface of eosinophils are discapline receptors for IgE, in this regard, the eosinophils can be activated directly procynosuchidae allergens. On the surface of eosinophils identified as the receptors for IL-2, IL-3, IL-5, GM-CSF, PAF, prostaglandins. Through these receptors, these cytokines and lipid mediators are able to induce the activation of eosinophils and release of their mediators (LTC4, PAF) and cytokines (IL-3, IL-4, IL-5, IL-8, GM-CSF, TGFβ). Due to eosinophil proteins destruction of the airway epithelium contributes to the development of bronchial hyperresponsiveness, decreased barrier function of the mucous membranes of the respiratory tract.

Great attention is now paid to the possible role of eosinophils in the restoration and tissue remodeling, as discovered a clear link between eosinophilia in the tissues and certain fibrotic diseases (endomyocardial fibrosis of the liver in patients hypereosinophilia syndrome, nodular sclerosing variant of Hodgkin's disease, fibrosis beneath the basal membrane in bronchial asthma) [Noguchi Η. et al. Tissue eosinophilia and eosinophil degranulation in syndromes associated with fibrosis // Am. J. Pathol. 1992, Vol. 140. P. 521-528].

Eosinophils as the source of several fibrogenic and growth factors, including transforming factor-β (TGF-β), fibroblast growth factor (FGF)-2, endothelial growth factor vascular (VEGF), matrix metalloproteinase (MMP)-9, IL-1β, IL-13 and IL-17. Clinical trials of anti-IL-5 antibody also confirmed the role of eosinophils in the events associated with the deposition of certain matrix proteins in the reticular basal membrane [Kay AB, Phipps S, Robinson DS. A role for eosinophils in airway remodeling in asthma // Trends Immunol. 2004, Vol. 25, P. 477-82].

Currently the most common method of treatment of asthma is the use of corticosteroids (budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate) by inhalation. However, corticosteroid function by inducing General immunosuppression, and have an adverse side effects, �knitted their long term use, including high blood pressure, osteoporosis and the development of cataracts [Barnes PJ. New drugs for asthma // Semin Respir Crit Care Med. 2012; 33(6): 685-94]. Corticosteroidi must be taken every day and therefore the compliance of the patient is another problem for the successful application of the medicines. In addition, there are patients who are not susceptible to the use of corticosteroids, which requires the use of alternative therapies. Selective targeting to target eosinophils, can overcome the adverse effects of the use of General immunosuppressive funds pleiotropic actions.

Currently undergoing clinical trials of drugs aimed at reducing eosinophilia by inhibition of the interaction of interleukin-5 receptor, IL-5Rα, located on the surface of eosinophils. Such drugs include humanized monoclonal antibody (MAB) against IL-5 and competitive inhibitors of IL-5Rα.

Among neutralizing IL-5 monoclonal antibodies the most effective it is possible to call SB 240563 (mepolizumab, Glaxo Smith Kline). According to [Nair R, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. NEJM. 2009; 360: 985-93] therapy mepolizumab prednisolon-dependent asthmatics have reduced eosinophilia in the blood and sputum, and, most importantly, improved the condition of patients, by reducing the number �of pistov of exacerbation and the dose of prednisolone. In another study, the use of anti-IL-5 antibodies (mepolizumab) patients with corticosteroid-insensitive asthma has also led to a reduction in the frequency of episodes of exacerbations and improved health questionnaire AQLQ. Besides the influence on asthma in this test were additionally registered therapeutic effect in respect of polypoid rinosinusopatii [Haldar Ρ, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. NEJM. 2009; 360: 973-84].

In independent testing on adult patients with polypous rinosinusopatia mepolizumab significantly reduced the content of ECP and soluble forms of IL-5Rα in the blood, and the concentration of IL-5Rα, IL-6 and IL-1b in the nose, which correlated with relief of the disease on the common scale of polyps (total polip score) [Gevaert Ρ, Van Bruaene Ν, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011; 128(5): 989-995].

The use of anti-IL-5 antibody is not limited to bronchial asthma and polypous rinosinusopatia. This therapy is effective in the other eosinophiles-oposredovannyh diseases. For example, patients with hypereosinophilia syndrome therapy mepolizumab decreased eosinophilia of the blood and allowed to reduce the dose of prednisone [Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. NEJM. 2008; 358(12): 1215-28]. In patients with eosinophilic esophagitis on the background of therapy� anti-IL-5 antibodies was observed clinical improvement, associated with reduction of dysphagia was observed 6-fold reduction in the level of eosinophils in the blood and in some patients was reduced hyperplasia of esophageal epithelium [Stein ML, Collins ΜΗ, Villanueva JM, et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy CLin Immunol. 2006; 118(6): 1312-9]. In a clinical trial of the drug in children have shown that patients in the blood that no more than 20 eosinophils in the same field of view of the microscope, had improved on indicators: redness, fragility, furrows and vertical lines of the esophagus [Assa'ad AH, Gupta SK, Collins MH, et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology. 2011; 141(5): 1593-604].

Also mepolizumab successfully used in the treatment of eosinophilic vasculitis [Kahn JE, Grandpeix-Guyodo C, Marroun I, et al. Sustained response to mepolizumab in refractory Churg-Strauss syndrome. J Allergy Clin Immunol. 2010; 125: 267-70]. Monthly introduction mepolizumab 28-year-old woman has reduced the level of eosinophils in the blood to normal levels, prevented the formation of corticosteroid asthma and according to radiographs improved the state of the lung parenchyma [Kim S, Marigowda G, Oren Ε, Israel Ε, Wechsler Μ. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol. 2010; 125: 1336-43]. When conducting clinical trials in patients with eosinophilic vasculitis and marked eosinophilia therapy mepolizumab allowed to reduce the dose of corticosteroids. Was also reduced eosino�Elijah, but after the termination of the study repeated exacerbations [Oldhoff JM, Darsow U, Werfel T, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005; 60(5): 693-6].

According to [Amini-Vaughan ZJ, Martinez-Moczygemba M, Huston DP. Therapeutic strategies for harnessing human eosinophils in allergic inflammation, hypereosinophilic disorders, and cancer // Curr Allergy Asthma Rep. 2012, Vol. 12, No. 5. P. 402-412] mepolizumab is in the second stage of clinical trials for the treatment of asthma, eosinophilic esophagitis adults, eosinophilic esophagitis children, eosinophilic vasculitis and polypoid of rinosinusopatii and in the third stage of clinical trials as a treatment hypereosinophilic syndrome, eosinophilic esophagitis children, asthma, rhinovirus-induced and chronic obstructive bronchitis. Another drug, reslizumab (Cephalon), which also humanized monoclonality antibodies SCH 55700 to IL-5 passes the second stage of clinical trials as a therapy hypereosinophilia syndrome and endemicity, and the third stage - in the treatment of asthma and eosinophilic esophagitis children. All this allows to conclude that the electoral therapy aimed at reducing eosinophilia - a promising direction in the treatment of diseases mediated by this type of cells (bronchial asthma, allergic rhinitis, polyposis; rinosinusopatii, eosinophilic esophagitis, eosinophilic vasculitis, ISU�eosinophiles syndrome).

However, therapy using Mat entails several drawbacks. Monoclonal antibodies are expensive therapeutic drugs which must be taken within one month or two months. An important factor is the issue of non-compliance of the requirements of the patients, which arises from the multiple visits to the doctor for injectable medicines. In addition, variation in allotype between the patient and therapeutic antibody can lead to the fact that the monoclonal antibody therapy will eventually become ineffective. High dose mate and the possibility of the formation of immune complexes can also reduce the effectiveness of passive immunization.

Other methods for providing a therapeutic agent against pathological conditions characterized by eosinophilia, described in WO 97/45448 and WO 03/040164. In the application WO 97/45448 proposed the use of "modified and variant forms of IL5 molecules able to antagonize the activity of IL5" to improve, mitigate or otherwise reduce aberrant effects caused by native and mutant forms of IL5. It is reported that antagonizers action is the result of variant forms of IL5, communicating with nishatganj chain IL5R, but not with high-affinity receptors. In doing so, the options con�uriroot with IL5 for binding to its receptors, without affecting the physiological action of IL5.

In the application WO 03/040164 the proposed composition for vaccination aimed at the endogenous formation of antibodies to IL-5, IL-13 and eotaxin, i.e. the key factors in the maturation, activation, localization and viability of eosinophils. The composition comprises a virus-like particle and at least one associated protein or peptide of IL-5, IL-13 or human eotaxin. According to the invention, this composition is applicable for the receipt of vaccines used for the treatment of allergic diseases with an eosinophilic component and as a pharmaceutical vaccine for the prevention or treatment of allergic diseases with an eosinophilic component.

In the application No. 8501176 proposed the use of antibodies that bind IL-5R. These antibodies include a section specifically binding to the receptor IL-5 (IL-5R) and the Fc-fragment. Invented method reduces the number of eosinophils in the blood, bone marrow, gastrointestinal tract (e.g., esophagus, stomach, small intestine and colon) or in the lungs and reducing the clinical manifestations of asthma and chronic obstructive bronchitis of the lungs in humans ().

The article Yong Sup Lee et al., Studies on the site-selective N-acyliminium ion cyclazation: synthesis of (±) - glochidine and (±) - glochidicine. Heterocycles. Vol 37. No. 1. 1994, discloses the receipt of succinimide of histamine, a fusion dihydrochloride gist�ina and succinic anhydride by heating the initial reactants to 200-230°C for 40 minutes.

In a publication of the international application WO 2007/007054 disclosed derivatives of suktinimida and glutarimides of the General formula (I), having the effect of inhibiting DNA methylation in cells, in particular tumor cells. Disclosed in this publication, compounds obtained by reaction of a combination of amine derivatives compounds containing a hydrocarbon chain, with the corresponding anhydride or acid or ether, followed, if necessary, the closure ring, optionally in the presence of base.

The described methods of synthesis of imido glutaric acid, consist in heating a dicarboxylic acid or its derivative such as the anhydride, diester, etc. with the primary amine or the amide (thermal cyclization) [Weigand - Hilgetag. Methods of experiment in organic chemistry. Edited by Professor Η.N. Suvorov. M., Chemistry, 1968, p. 446], cyclization of monoamines corresponding dicarboxylic acids using vodootnimajushchih funds as a reagent that activates the carboxyl group, such as acetic anhydride [Shimotori et al, Asymmetric synthesis of δ-lactones with lipase catalyst. Flavour and Fragrance Journal, 2007, V. 22, No. 6, P. 531-539], acetyl chloride [Ito et al,; Chemoselective Hydrogenation of Imides Catalyzed by CpRu(PN) complexes and ecological feasibility study and Its Application to the Asymmetric Synthesis of Paroxetine. // Journal of the American Chemical Society, 2007, V. 129, No. 2, P. 290-291], carbonyldiimidazole [Polniaszek, et al; Stereoselective nucleophilic additions to the carbon-nitrogen double bond. 3. Chiral acyliminium ions. / Journal of Organic Chemistry, 1990, V. 55, No. 1, p. 215-223], glutaric or succinic anhydrides [Ainhoa Ardeo et al, A practical approach to the fused β-carboline system. Asymmetric synthesis of indolo[2,3-α]indolizidinones via a diastereoselective intramolecular α-amidoalkylation reaction. /Tetrahedron Letters, 2003, 44, 8445-8448].

In the international publication of patentee application WO 2007/000246 described method of synthesis of glutarimides by alkylation of the piperidine-2,6-dione and pyrrolidine-2,5-dione corresponding halogen derivatives in DMF, with the earmarking of substituted imido by the method of preparative chromatography that is not applicable for the synthesis of macroscopic quantities.

Thus, the aim of the present invention is the use of non-toxic derivatives of glutarimide, effective for the treatment of eosinophilic diseases, mainly allergic nature such as bronchial asthma, allergic rhinitis, polyposis; rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis.

Summary of the INVENTION

The present invention relates to the use of derivatives of glutarimide of the General formula (I):

in which R1and R'1independently represent hydrogen or C1-C6alkyl, e.g., methyl;

R2is a

optional

substituted C1-C6the alkyl, for example,for the treatment of eosinophilic diseases, mainly allergic nature such as bronchial asthma, allergic rhinitis, polyposis; rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis.

The authors found that the derivatives of glutarimide inhibit eosinophilia in various models of inflammation in all of the evaluated biological fluids (blood, bronchoalveolar lavage (BAL)) and tissues. In particular, on the model of Sephadex-induced lung inflammation in rats derivatives glutarimide reduced eosinophils in BAL, on the model of ovalbumin-induced asthma in Guinea pigs derivatives glutarimide reduced eosinophilia in BAL and blood.

Thus, the present invention relates to a therapeutic method for the treatment of eosinophilic diseases, mainly allergic nature, preferably of bronchial asthma, allergic rhinitis, polyposis; rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, uh�sinofile vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis, comprising administering to the patient an effective amount of derivatives of glutarimide of the General formula (I) or its pharmaceutically acceptable salt.

The present invention also relates to a drug for the treatment of eosinophilic diseases, mainly allergic nature, preferably of bronchial asthma, allergic rhinitis, polyposis; rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis, representing a derivative of glutarimides of the General formula (I) or its pharmaceutically acceptable salt.

Another object of the present invention is a pharmaceutical composition for the treatment of eosinophilic diseases, mainly allergic nature,preferably of bronchial asthma, allergic rhinitis, polyposis; rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis, comprising an effective amount�tvo derivatives of glutarimide of the General formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

Used in the present invention compounds can be obtained by the method comprising heating the source monoamino dicarboxylic acids with vodootnimajushchih agent in the environment of an organic solvent or in the environment of the vodootnimajushchih agent optionally with the addition of sodium acetate. As vodootnimajushchih agents in this way can be used anhydrides of dicarboxylic acids, anhydrides of organic acids and carbonyldiimidazole.

Source monoamide dicarboxylic acids as well as methods for their preparation are disclosed in the published international application WO 1999/001103.

DETAILED description of the INVENTION

Preferable used in the present invention the compounds are compounds of the General formula (I),

in which R1and R'1independently represent hydrogen or methyl;

R2is a

The most preferred compounds of the present invention are compounds presented in table 1.

As pharmaceutically acceptable salts of the compounds of the present invention can be used additive salts of organic acids (e.g., formate, acetate, maleate, tartrate, metasolv�at, benzolsulfonat, toluensulfonate, etc.), additive salts of inorganic acids (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), salts with amino acids (e.g., salt, aspartic acid salt, glutamic acid etc.), preferably one and acetates.

Derivatives glutarimides of the General formula (I) have therapeutic activity against eosinophilic diseases.

In particular, the compounds of the present invention can be used for treating of bronchial asthma, allergic rhinitis, polyposis; rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis and fibrosis.

Compounds of the present invention is administered in an effective amount that provides a desired therapeutic result.

Compounds of the General formula (I) can be administered orally, topically, parenterally, intranasally, by inhalation or rectally in the form of standard dosage forms containing non-toxic pharmaceutically acceptable carriers.

Used in the present description, the term "parenteral administration" means subcutaneous, intravenous, intramuscular injection or infusion.

Connected�I of the present invention can be administered to a patient in doses constituting from 0.1 to 30 mg/kg of body weight per day, preferably in doses from 0.25 to 10 mg/kg once or more a day.

It should be noted that the specific dose for each particular patient will depend on many factors, including the activity of the compounds used, the age, body weight, sex, General health and diet of the patient, the time and method of administration the medicinal product, its rate of elimination from the body, specifically used a combination of drugs and the severity of the disease in the individual being treated.

Pharmaceutical compositions of the present invention contain a compound of the General formula (I) in an amount effective to achieve the desired result, and may be introduced in the form of standard dosage forms (for example, in solid, semisolid or liquid forms), containing compounds of the present invention as an active ingredient in admixture with a carrier or excipient suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal and intrarectal administration. The active ingredient may be included in a composition together with commonly used non-toxic pharmaceutically acceptable carriers suitable for the manufacture of solutions, tablets, pills, capsules�l, dragees, suppositories, emulsions, suspensions, ointments, gels and any other dosage forms.

As fillers can be used various substances, such as sugars, for example glucose, lactose or sucrose, mannitol or sorbitol, cellulose derivatives and/or calcium phosphates, for example tricalcium phosphate or acid phosphate of calcium. The binder component can be used, such substances as starch paste, for example, corn, wheat, rice, potato starch, gelatin, tragakant, methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose and/or polyvinylpyrrolidone. If necessary, can be used disintegrating agents, such as the aforementioned starches and carboxymethylcel, transversely crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.

Can be used optional additives, such as agents that regulate the fluidity and lubricating agents such as silica, talc, stearic acid and its salts, such as magnesium stearate or calcium stearate, and/or propylene glycol.

The dragee core is usually covered with a layer resistant to gastric juice. For this purpose one can use concentrated solutions of sugars, which may not necessarily contain the Aravis�ical gum, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, and suitable organic solvents or mixtures thereof.

As additives can also be used stabilizers, thickeners, dyes and fragrances.

As ointment bases may be used hydrocarbon ointment bases such as white and yellow vaseline (Vaselinum album, Vaselinum flavum), vaseline oil (Oleum Vaselini), white ointment and liquid (Unguentum album, Unguentum flavum), and as an additive to give a more solid consistency, such as paraffin wax and beeswax; absorptive ointment bases such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (Unguentum leniens); ointment bases, washed with water, such as hydrophilic ointment (Unguentum hydrophylum); water-soluble ointment bases such as polyethylene glycol ointment (Unguentum Glycolis Polyaethyleni), bentonite foundations and others.

As a basis for gels can be used methyl cellulose, sodium salt of carboxymethyl cellulose, oxypropylation, polyethylene glycol, polyethylene oxide or carbopol.

As a basis for suppositories can be used bases are not soluble in water, such as cocoa butter; bases which are soluble in water or miscible with water, such as gelatin and glycerol or polyethylenoxide; combined the basics of soap and glycerin.

When ready�attachment a standard dosage form amount of active ingredient, used in combination with the carrier, can vary depending on the recipient undergoing treatment, the specific method of administration of the drug.

For example, when using the compounds of the present invention in the form of solutions for injection, the content of active agent in amounts up to 5% by weight. Suitable diluents can be used 0.9% sodium chloride solution, distilled water, novocaine solution for injection, ringer's solution, glucose solution, specific additives to dissolve. When introduced into the body of the compounds of the present invention in the form of tablets and suppositories reaches 200 mg standard dosage form.

Dosage forms of the present invention are prepared by standard techniques, such as, for example, the processes of mixing, granulating, forming pellets, the dissolution and lyophilization.

It should be noted that compounds of the present invention revealed no negative side effects and no contraindications. Thus in the study of the toxicity of the compounds of the present invention at a dose of 1500 mg/kg, oral, have not registered the death of experimental animals.

Detailed description compounds of the present invention, pharmacological research asset�spine presented in the following examples intended to illustrate preferred embodiments of the invention, and not limiting its scope.

EXPERIMENTAL PART

Examples of synthesis of derivatives of glutarimide of the General formula (I)

Means and methods

The individuality of the obtained compounds test method TCX on the plates "Kieselgel 60 F254" (company "Merck", Germany) in the solvent system: chloroform-methanol 9:1(1), chloroform-methanol(1:1) (2).

Chromatograms and electrophoregram proyavlayut chloro-tetramethylbenzidine reagent and reagent Pauli.

LC MC-system for analysis of multicomponent mixtures Shimadzu Analytical HPLC SCLlOAvp, the mass spectrometer ΡΕ SCIEX API 165(150) (Canada). Conditions: column Waters ACQUITY UPLC VEINS C18 1.7 um 2.1×50mm, gradient elution in the system: water with 0.1% HCOOH - acetonitrile with 0.1% HCOOH.

Analytical reversed-phase HPLC was carried out on the device: chromatograph Shimadzu HPLC in the conditions: column Luna C18 (2) 100A 250 x 4.6 mm (ser. 599779-23), gradient elution in the system of phosphate buffer solution pH 3.0: methanol (condition A); column Merk. LiChroCART 250×4 mm, 5 µm. LiChrospher 100RP-8E 5 μm. C8. Serial number 1.50837.0001, gradient elution in the system acetate-ammonium buffer solution pH 7,5:acetonitrile (B); gradient elution in a buffer system with 1-hexylsilane sodium 0,0025 M pH 3: acetonitrile (B); column Symmetry C18 150×4.6 mm, gradient elution in the system buffer solution with 1-hex�sulfonate sodium 0,0025 M pH 3: acetonitrile (conditions C).

1H-NMR spectra recorded on the instrument Bruker DPX-400 (Germany).

Mass high resolution spectra get on time-of-flight mass spectrometer by the method of matrix laser desorption ionization using as a matrix of 2,5-dihydroxybenzoic acid, on the device Ultraflex ("Bruker", Germany).

Example 1

1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (compound 1)

In flat-bottomed flask (250 ml) was charged with 60 ml of Ν,Ν'-dimethylformamide and 20 g of 2-(imidazol-4-yl)-ethanamide pentandiol-1,5 acid. Under vigorous stirring was added 17.3 g (1.2 EQ.) carbonyldiimidazole. The reaction mass is heated with stirring to 90°C for 2 hours, monitoring the reaction by NMR method (sample, 0.5 ml, diluted with ethyl ether, the precipitate was dissolved in DMSO (d6). In the absence of the original 2-(imidazol-4-yl)-ethanamide pentandiol-1,5 acid in the reaction mass, it is cooled and poured into three times the volume of methyl tert-butyl ether (180 ml). Leave under stirring for 1 hour, the precipitate was filtered off, washed with 60 ml of methyl tert-butyl ether, dried. Output technical 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione 12.4 g (67%).

In a flat-bottomed flask of 100 ml load 12 g technical 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione and 36 ml of isopropanol. The mixture was heated until complete dissolution of the precipitate, then� add 1.2 g of activated carbon and maintained at boiling for hours. The still hot solution is quickly filtered over a pre-heated ceramic filter. The filter cake was washed with 6 ml of hot isopropanol. Hot mother liquor is cooled to room temperature and left overnight under stirring for crystallization. The precipitated crystals was filtered, washed with 6 ml of cold isopropanol and dried. The yield of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione recrystallization is 10.1 g (84%). Rf of 0.43 (1). The product was analyzed by LC MS, individual peak retention time of 1.57 min, [M+H]=208. HPLC under conditions a: individual peak retention time of 15.5 min. the NMR Spectrum1H (400,13 MHz, DMSO-d6d, M. D., J/Hz): 1,81 (pent. 2H, CH2CH2CH2, J=6,5 Hz); 2,58 (m, 6H, CH2C, CH2CH2CH2); 3,82 (m, 2H, CH2N, J=7,8 Hz); was 6.77 (ush.s, 1H, CCH); 7,49 (s, 1H, NCHN); 11,81 (ush.s, 1H, NH)

Similar to the above methods, the following compounds shown in table 2:

Obtain hydrochloride of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione (hydrochloride of compound 1)

Dispersed 2.5 g of 1-(2-(1H-imidazol-4-yl)ethyl)piperidine-2,6-dione in 20 ml of acetonitrile, is added to 0.36 ml (1 EQ.) hydrochloric acid. The precipitate was filtered off, dried to constant weight. HPLC mustache�oveh A: individual peak, retention time of 14.5 min. the NMR Spectrum1H (400,13 MHz, DMSO-d6d, M. D., J/Hz): 1,80 (pent. 2H, CH2CH2CH2, J=6,5 Hz); of 2.57 (m, 6H, CH2C, CH2CH2CH2); Of 3.80 (t, 2H, CH2N, J=7,8 Hz); 6,78(ush.s, 1H, CCH); and 7.5 (s, 1H, NCHN); 11,85 (ush.s, 2H, NH+HCl).

Example 3

The tablets, coated tablets, 2 mg, 10 mg and 100 mg

The composition of one coated tablet.

Tests for biological activity

Means and methods

Morphological study of histological preparations were carried out using light optical microscope Leica DM LS (Leica Microsystemc, Germany). Micromorphometric study was performed using the ocular micrometer of the microscope Leica DM LS. Photomicrography was carried out using a digital camera Leica DC 320 (Leica Microsystemc, Germany).

Mathematical processing of the results was performed with analysis of variance using Statistica 6.0. For data analysis descriptive statistics were used: the data were checked for normality of distribution using the Shapiro-Wilk test. Because the data belong to a normal distribution, and intergroup differences were analyzed by parametric methods using student's criterion. The differences were considered significant at p<0,05.

Example 4

Evaluation of the effectiveness of compounds of the General formula (I) in the model� asthma in Guinea pigs

Induction of asthma in Guinea pigs was performed by standard methods [Ricciardolo FL, Nijkamp F, De Rose V, Folkerts G. The guinea pig as an animal model for asthma // Current Drug Targets. 2008 Jun; 9(6): 452-65]. Animals immunized once by intraperitoneal injection of 0.5 ml of a solution containing 100 μg/ml ovalbumin (Sigma) and 100 mg/ml of hydrocity aluminum. Intact animals were intraperitoneally injected with saline in a volume of 0.5 ml.

On 29, 30 and 31 day experiment was conducted provocation hyperreactivity of the respiratory tract by inhalation injection of ovalbumin in increasing concentrations of 0.1, 0.3 and 0.5 mg/ml in 1, 2 and 3 day of provocation, respectively. Inhalation was performed for 5 minutes or until overt signs of asphyxia (falling sideways). On the 32nd day, the animals were injected a resolving dose of ovalbumin 1 mg/ml for 5 minutes with the assessment of bronchospastic reactions.

Tested compound was administered to animals intragastrically daily once a day for 6 or 10 days, ending 2 days before the introduction of the resolving dose of antigen.

Assessment of bronchospastic reactions were carried out by changing the frequency and depth of respiratory movements, as well as on the basis of this asphyxia, as the animal fall to the side. Spirogram was recorded by means of equipment for laboratory research ADInstruments, Australia) using a basic registration�yuusha station PowerLab 8sp. and programs LabCart. For the registration of a used air flow meter for laboratory animals and the spirograph with built-in amplifier (ADInstruments).

24 hours after the introduction of the resolving dose of ovalbumin in animals were collected bronchoalveolar lavage (BAL) and blood from the cavities of the heart. Taking BAL was performed under General anesthesia by washing the lungs with 5 ml warmed to 37°C saline via the trachea using a syringe dispenser.

In bronchoalveolar fluid flush with the camera Goryaeva counted the absolute number of cellular elements in 1 mm flush (cytosis). Then BAL was centrifuged at 200 g for 10 minutes. From the sediment cells were prepared smears, which later were fixed in methanol and stained by Romanovsky-Giemsa for counting andpulmonary cytograms.

Blood was analyzed for hemocytometer to determine leucoformula.

The study included 3 of the experiment, was performed in the first evaluation of the effect of the compounds No. 1-6 on the cellular composition of BAL, in the second and third evaluation of the effect of compounds No. 1 and No. 2 on the cellular composition of BAL cellular composition of blood and the severity of bronchoconstriction.

A 10-fold introduction of compounds No. 1-6 Guinea pigs at a dose of 14 mg/kg reduced increased on the background of the development of pathology number of cellular components in BAL from 17.3×109 CL/l to 2.5 to 6.3×109cells/l (table 4). Mainly of a compound reduced the number of eosinophils in the control group, the number of eosinophils in BAL made 7.05×109CL/l in the groups receiving treatment - 0,60-to 1.61×109TC/l, i.e. at 91-77% less.

The introduction of the investigated compounds at lower doses (0,045, 0.14 and 1.4 mg/kg) and in two modes (10-and 6-fold) showed that the compounds reduce eosinophilia in BAL in a wide range of doses (0,045-14 mg/kg) and different treatment regimens (table 5). In addition, in all tested doses of the investigated compounds decreased the number of lymphocytes and in some doses, the number of monocytes in BAL, indicating the suppression of local inflammatory reactions in the lung.

The investigated compounds decreased eosinophilia of the blood. In the control group the number of blood eosinophils in 6-8 times higher than the indicator of intact animals. The introduction of the investigated compounds allowed to keep it at the level of intact animals (table 6).

Determining the severity of bronchospasm in Guinea pigs in response to inhalation of them provocative dose of ovalbumin has allowed to establish that the model of bronchial asthma investigational compounds not only reduce eosinophilia, but also to�Inocencia manifestations of the disease. In particular, if in the control group, receiving placebo, 8 5 animals had pronounced bronchospasm with acute and subacute phase, in groups of animals treated with the studied compounds, these animals were absent or their number did not exceed 2 PCs. In turn, the number of animals with normal depth and rate of breathing (bronchospasm without) increased with 0-1 units in the control group to 4-7 PCs in the groups receiving treatment (table 7).

The results provide convincing evidence that in experimental models of eosinophilia, in particular bronchial asthma, etc., of the investigated compounds inhibit eosinophilia and reduce clinical manifestations of the disease.

Example 5

Evaluation of the effectiveness of compounds of the General formula (I) on the model of Sephadex-induced eosinophilic lung inflammation in rats

The model of Sephadex-induced eosinophilic lung inflammation in rats implemented by standard methods [Evaldsson C, Ryden I, Uppugunduri S. Isomaltitol exacerbates neutrophilia but reduces eosinophilia: new insights into the sephadex model of lung inflammation // Int Arch Allergy Immunol. 2011; 154(4): 286-94]. Rats-males of Wistar line once inhaled injected Sephadex G-200 (Pharmacia, Sweden) at a dose of 5 mg/kg of the tested compound(0,06, 0,18, 0,54, 1,8, 5,4 and 18 mg/kg) was administered to animals intragastrically four times: 24 and 1 h before, and also� 24 and 45 h after injection of Sephadex. The reference drug budesonide was administered according to the same scheme by inhalation in a dose of 0.5 mg/kg 48 h after inhalation of Sephadex was collected bronchoalveolar lavage. The lavage was evaluated by the total number of leukocytes and leukocyte was determined formula. The number of rats in the group - 7-10 PCs.

The BAL analysis showed that a single inhalation introduction of Sephadex G-200 to rats causes a marked influx of leukocytes into the lung. The number of all cell types was increased in the control group compared with intact, however, the maximum increase was noted in respect of eosinophils (table 8-9).

Intragastric administration of the compounds of the General formula (I) to rats reduced the level of eosinophils in BAL several times. The claimed compounds are active in a wide range of tested doses.

Example 6

Evaluation of the effectiveness of compounds of the General formula (I) on the model of the leukotriene-induced eosinophilic lung inflammation in Guinea pigs

Model leukotriene-induced eosinophilic lung inflammation in Guinea pigs implemented by standard methods [Underwood DC1, Osborn RR, Newsholme SJ, Torphy TJ, Hay DW. Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: modulation by the LTD4 receptor antagonist, pranlukast, or aninterleukin-5 monoclonal antibody // Am J Respir Crit Care Med. 1996 Oct; 154(4 Pt 1): 850-7.]. Male Guinea pigs (250-300g) in two-chamber plethysmograph (Emka Technologies, France) for 1 minute inhalerbuy solution leukotriene D4 (LTD4, Cayman Chemical, USA) at a concentration of 10 μg/ml (flow rate of 250 ml/min). The investigated compound was administered to animals intragastrically four times: 24 and 1 h before and 24 and 45 h after inhalation of LTD4. The reference drug montelukast (0.8 mg/kg) was administered intragastrically once 1 hour before inhalation of LTD4. 48 h after inhalation of LTD4 were collected bronchoalveolar lavage. The lavage was evaluated by the total number of leukocytes and leukocyte was determined formula. The number of Guinea pigs in the group - 8 PCs.

The BAL analysis showed that a single inhaled administration of leukotriene D4 Guinea pigs causes a marked influx of neutrophils, eosinophils and monocytes/macrophages in the lung. The most pronounced increase in the number of cells (25-fold) was observed in eosinophils (table 10).

Intragastric administration of a compound Guinea pigs reduced the eosinophils in BAL in 2.1-3.4 times. The compound effect in a wide dose range (0.14-14 mg/kg). Comparative analysis of the efficiency of the investigated compounds and montelukast showed that the severity of the action of the studied compound is not inferior to the leukotriene antagonist Retz�of Perov.

Example 7

Evaluation of the effectiveness of compounds of the General formula (I) on the model of allergic rhinitis in Guinea pigs

The model of allergic rhinitis implemented by standard methods [Vishnu N. Thakare, Μ.Μ. Osama, Suresh R. Naik. Therapeutic potential of curcumin in experimentally induced allergic rhinitis in guinea pigs // Int Immunopharmacol. 2013 Sep; 17(1): 18-25].

Guinea pigs (250-300 g) were immunized 4x (at 0, 7, 14 and 21 days) by intraperitoneal injection of a mixture of ovalbumin (100 μg/mumps) and aluminum hydroxide (5 mg/pig), diluted and suspended in a physiological solution. On the 28th day of the study, a solution of ovalbumin (60 mg/ml), the animals were injected intranasally with 20 μl in each nostril. At 35 days, the animals were injected a solution of OVA (200 μg/ml, 25 μl) intradermally, pre-wybrew the area of skin on the back. Evidence of sensitization was the formation of edema and redness at the injection site. On the 42nd day of the study conducted intranasal administration of OVA solution (60 mg/ml, 20 μl/nostril). To control the formation of allergic inflammation group was formed monomaniacally animals at 0, 7, 14 and 21 days pigs received aluminum hydroxide solution (5 mg/pig), 28 th and 35 th day - saline, on 42nd OVA (60 mg/ml, 20 μl/nostril).

Tested compound (14 mg/kg) enter�and animals intragastrically multiple of 3: 48, 24 and 1 h before the last intranasal OVA. The reference drug dexamethasone was administered intragastrically once for 3 hours until the last intranasal OVA.

Within 2 h after the last administration of OVA evaluated the clinical manifestations of rhinitis: counting the number of sneezes, petting his nose. 24 hours after the last administration of ovalbumin was collected nasal flushing. In nasal flushing was evaluated by the total number of leukocytes and leukocyte was determined formula. The number of Guinea pigs in the group - 8 PCs.

Analysis of nasal washings showed that allergic rhinitis is accompanied by a marked influx of leukocytes in the nasal cavity. The maximum increase was noted in the number of eosinophils (table 11).

Three-time intragastric administration of the compounds of the General formula (I) Guinea pigs reduced the eosinophils in nasal flush to the level of monomaniacally animals. According to the severity of the action of the investigated compounds are not inferior to dexamethasone.

Notes:

* - the difference from the intact group by t-student test at p<0,05

& - difference from control group by t-student test at p<0,05

Account of clinical manifestations of allergic rhinitis within 2 hours after the last intranasal� the introduction of OVA animals showed a marked increase in experimental animals the number of sneezes and petting and nose, which indicates the correctness of the implemented model of allergic rhinitis. Therapy with compounds of the General formula (I) reduced the clinical manifestations of rhinitis to the level monomaniacally animals. The reference drug dexamethasone had a similar effect (table 12).

The obtained results give grounds to conclude that in experimental models of eosinophilia, in particular, the Sephadex-induced eosinophilic lung inflammation in rats, leukotriene-induced eosinophilic lung inflammation in Guinea pigs with allergic rhinitis and asthma in Guinea pigs, etc., the compounds of the General formula (I) significantly reduce the eosinophilia.

1. A medicament for the treatment of eosinophilic diseases, representing a compound of General formula (I):

in which R1and R'1independently represent hydrogen or C1-C6alkyl;
R2is a
optional
substituted C1-C6the alkyl,
or its pharmaceutically acceptable salt.

2. Medicament according to claim 1, where R1and R'1independently represent hydrogen or methyl, and
R2is a

3. Medicament according to claim 1, where with�the Association of the General formula (I) or its pharmaceutically acceptable salt is selected from the group consisting of the following compounds:

4. Medicament according to claim 1, wherein the eosinophilic diseases are bronchial asthma, allergic rhinitis, polyp of rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis.

5. Pharmaceutical composition for the treatment of eosinophilic diseases, comprising an effective amount of the compounds of the General formula (I):

in which R1and R'1independently represent hydrogen or C1-C6alkyl;
R2is a
optional
substituted C1-C6the alkyl,
or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

6. Pharmaceutical composition according to claim 5, where R1and R'1independently represent hydrogen or methyl, and
R2is a

7. Pharmaceutical composition according to claim 5, where the compound of the General formula (I) or its pharmaceutically acceptable salt selected from the group consisting of the following compounds:

8. Pharmaceutical composition according to claim 5, where eosinophilic diseases are bronchial asthma, allergic rhinitis, polyp of rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis.

9. A method for the treatment of eosinophilic diseases, comprising administering to the patient an effective amount of compounds of the General formula (I):

in which R1and R'1independently represent hydrogen or C1-C6alkyl;
R2is a
optionally substituted C1-C6the alkyl,
or its pharmaceutically acceptable salt.

10. A method according to claim 9, where R1and R'1independently represent hydrogen or methyl, and
R2is a

11. A method according to claim 9, where the compound of the General formula (I) or its pharmaceutically acceptable salt selected from the group consisting of the following compounds:

12. A method according to claim 9, where the disease is bronchial asthma, allergic rhinitis, polyp Rinus�dosapati, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic esophagitis, eosinophilic gastroenteritis, or fibrosis.

13. Use of a compound of the General formula (I):

in which R1and R'1independently represent hydrogen or C1-C6alkyl;
R2is a
optional
substituted C1-C6the alkyl,
or its pharmaceutically acceptable salt to obtain drugs for the treatment of eosinophilic diseases.

14. The use according to claim 13, wherein R1and R'1independently represent hydrogen or methyl, and
R2is a

15. The use according to claim 13, wherein the compound of the General formula (I) or its pharmaceutically acceptable salt selected from the group consisting of the following compounds:

16. The use according to claim 13, wherein the disease is a asthma, allergic rhinitis, polyp of rinosinusopatii, eosinophilic colitis, eosinophilic syndrome, atopic dermatitis, syndrome Charge-Strauss, anaphylactic shock, angioedema, eosinophilic vasculitis, eosinophilic ESOP�git eosinophilic gastroenteritis or fibrosis.



 

Same patents:

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SUBSTANCE: invention relates to substituted glutarimides of the general formula (I): wherein X means group of the formula -(CH2)n-(CR8R9)p-Z-(CR8R)m wherein Z means sulfur (S) or oxygen (O) atom, SO- or SO2-group, residue -NR8 (optionally as N-oxide) or the group -CR8R9; m and p mean 0 or 1; n means 0, 1, 2 or 3, and m, n and p can't mean 0 simultaneously; R1 and R2 mean carboxyl, ester or acyl group and others; R3 means hydrogen atom, hydroxyl group and others; R4 means hydrogen atom, (C1-C3)-alkyl group, fluorine atom, trifluoromethyl group; R8 and R9 means hydrogen atom, benzyl, alkyl and others, and to their physiologically acceptable salts also. Compounds of the formula (I) possess immunomodulating effect and can be used in treatment of angiopathy and/or oncohematological diseases.

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< / BR>
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< / BR>
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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a tabletted oral dosage form containing desloratadine in an amount of 3 to 15%, processing additives and a pharmaceutically acceptable excipient. The processing additives consist of sodium croscarmellose, magnesium stearate and povidone. The excipient represents a mixture of lactose disaccharide and microcrystalline cellulose polysaccharide in ratio from 2:1 to 8:1. Lactose and microcrystalline cellulose have an average particle size from 30 to 200 mcm. Producing the table involves granulating desloratadine, lactose and microcrystalline cellulose.

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8 cl, 1 tbl, 1 ex

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16 cl, 7 dwg, 1 ex

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14 cl, 2 tbl, 5 dwg

FIELD: chemistry.

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EFFECT: crystalline form has the X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1,5418 E, with the crystalline peaks with a value 2-theta (in degrees) 12,9, 13,1, 18,0, 21,0, 22,5, 25,1, 25,3, 28,8, 29,1 and 30,4, and has melting point (beginning) 152,7°C.

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel derivatives of pyrazole pyridine of formula , as well as to its tautomers, geometrical isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, where G1 represents H; G2 represents -CHR1R2; R1 and R2 independently on each other are selected from H; C1C6-alkoxy-C1C6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or -CHR1R2 together form a ring, selected from an optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3 is selected from an optionally substituted C1C6-alkoxy -C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1C6-alkyl; G4 is selected from a substituted acyl-C1C6-alkyl, where acyl represents a group -CO-R and R stands for H or morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridine- or furanyl-C1C6-alkyl; morpholine- or piperidine-C1-C6-alkyl; G5 represents H; where the term "substituted" stands for the groups, substituted with 1 to 5 substituents, selected from the group, which includes a "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "acylamino", which stands for the group NRCOR", where R represents H and R" represents a C1-C6-alkyl, "phenyl", "fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6-alkoxycarbonyl", "halogen". The invention also relates to a pharmaceutical composition based on the formula (I) compound and particular compounds.

EFFECT: obtained are the novel derivatives of pyrasole pyridine, useful for the treatment and/or prevention of disorders or states, associated with NADPH-oxidase.

12 cl, 3 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a method for reducing extracellular matrix producing cells in lungs or suppressing an increase of the extracellular matrix producing cells in lungs, involving administering into an individual a composition containing (i) a carrier containing retinoid as a targeting agent, and (ii) a pro-drug specified in a group consisting of siRNA, RNA enzyme, anti-sense nucleic acid and DNA/RNA chimeric polynucleotide, which is targeted on HSP47, and vectors expressing said siRNA, RNA enzyme, anti-sense nucleic acid and/or DNA/RNA chimeric polynucleotide.

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8 cl, 6 dwg, 3 ex

FIELD: medicine, pharmaceutics.

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,

wherein A represents a group specified in furanyl, oxazolyl and thiazolyl, wherein two attachment points of the above group are found in 1,3-position; R1 represents phenyl, which is unsubstituted, mono- or disubstituted, wherein the substitutes are independently specified in a group consisting of halogen, methyl, methoxy group, trifluoromethyl, trifluormethoxy group and dimethylamino group; and R2 represents hydrogen, methyl, ethyl or cyclopropyl. Besides, the invention refers to a pharmaceutical composition containing the compound of formula (I), and to using the compound of formula (I) for preparing a therapeutic agent.

EFFECT: compounds of formula (I) possessing the agonist activity in relation to ALX receptor.

26 cl, 2 tbl, 36 ex

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