7-azaindoles, their using as inhibitors of phosphodiesterase 4 and method for their preparing

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes new 7-azaindoles of the general formula (I): wherein n = 1 or 2; R1 means mono- or multi-unsaturated, linear or branched (C2-C10)-alkenyl, linear or branched, unsubstituted (C1-C10)-alkyl that can be monosubstituted with (C1-C6)-alkoxy-group, naphthyl, pyridinyl, (C3-C6)-cycloalkyl, phenyl that, in turn, can be substituted with (C1-C6)-alkyl, halogen atom, (C1-C6)-alkoxy-group or hydroxy-group, or radical of the formula: ; R2 and R3 are similar or different being only one of them can mean hydrogen atom and mean (C1-C5)-alkyl possibly substituted with -O-(C1-C6)-alkyl or pyridyl, phenyl possibly substituted twice with -F, -Cl, -Br, -O-(C1-C3)-alkyl or monosubstituted with -COOH or -COO-(C1-C3)-alkyl, pyridyl possibly twice substituted with -Cl, -Br, or group of formulae: or , or R2 and R3 in common with N-atom mean: or under condition that if n = 1 then they don't mean simultaneously: R1 - (C1-C6)-alkyl; R2 - hydrogen atom (H) or (C1-C6)-alkyl, and R3 or wherein R and R' mean independently -Cl or -Br. These compounds possess inhibitory activity with respect to activity of phosphodiesterase 4. Also, invention relates to a medicinal agent comprising these compounds, methods for its preparing and using these compounds for preparing medicinal agents.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and drug.

17 cl, 6 tbl, 40 ex

 

The invention relates to substituted 7-azaindole General formula 1,

the method of production thereof, pharmaceutical compositions containing these compounds, and pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 4, as biologically active substances for the treatment of diseases that depend on inhibit the activity of phosphodiesterase 4 responsible for immune cells (e.g. macrophages and lymphocytes) by compounds according to the invention.

Activation of receptors in the membrane of the cell by means of the transmitter leads to activation of the system "repeat signal" ("second messenger"-Systems). The adenylate cyclase synthesizes from AMP (adenosine-3,5-monophosphate) and GMP (guanosine-3,5-monophosphate) active cyclic AMP (cAMP) or cyclic GMP (cGMP). They cite, for example, smooth muscle cells to relax or inflamed cells to suppression of the release or synthesis of the mediator. The destruction of "repeat signal" cAMP and cGMP occurs through phosphodiesterase (PDE). Thus far, there are 11 families of enzymes PDE (PDE 1-11), which differ in their specificity towards the substrate (cAMP, cGMP or both) and dependence on other substrates (for example, calmoduline). These isoenzymes have different functions in the body and are expressed differently in separate VI is Ah cells (Beavo JA, Conti M and Heaslip RJ. Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 1994, 46: 399-405; Hall IP. Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. clin. Pharmacol. 1993, 35: 1-7). By suppressing different types of PDE isoenzymes this leads to the accumulation of cAMP or cGMP within cells that can be used for medicinal purposes (Torphy TJ, Livi GP, Christensen SB. Novel Phosphodiesterase Inhibitors for therapy of Asthma, Drug News and Perspectives 1993, 6: 203-214).

In cells responsible for allergic inflammation (lymphocytes, mast cells, eosinophilic granulocytes, macrophages), is the predominant enzyme PDE type 4 (Torphy, T. J and Undem, B. J. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991, 46: 512-523). Suppression of PDE 4 by means of suitable inhibitors are still seen as an important approach to the treatment of many diseases caused by allergies (Schudt Ch, Dent G, Rabe K Phosphodiesterase Inhibitors, Academic Press, London, 1996).

An important property of inhibitors of phosphodiesterase 4 is a suppression of the release of tumor necrosis factor a (TNFa) from vospalennnah cells. TNFa is a well-known proinflammatory cytokine that affects a large number of biological processes. TNFa is released, for example, activated macrophages, activated T-lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. This in itself promotes activation of neutrophils, eosinophils, FIB is oblastof and endothelial cells, consequently released various mediators, destroying tissue. In monocytes, macrophages and T-lymphocytes TNFa causes increased production of the following proinflammatory cytokines, such as GM-CSF (factor, colony stimulating granulocyte macrophages) or interleukin-8. Due to its causes inflammation and catabolic actions TNFa plays a major role in many diseases, such as airway inflammation, joint inflammation, endotoxic shock, tissue rejection, AIDS, and numerous other immunological diseases. Thus, for the treatment of diseases associated with TNFa, also suitable inhibition of phosphodiesterase 4.

Chronic obstructive pulmonary disease (COPD) are widely distributed among the population and also have great economic value. Thus, diseases caused by COPD, approximately 10-15% of all costs associated with diseases in developed countries, and are the cause of about 25% of deaths in the United States (Norman P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11(7), 431-437, 1998), however, most of the deceased patients was 55 years (D. Nolte: Chronische Bronchitis - eine Volkskrankheit multifaktorieller Genese. Atemw.-Lungenkrkh. 20 (5), 260-267, 1994). Who estimates that COPD over the next 20 years will be on the third place among all causes of death.

Under the clinical picture of chronic obstructive ill the deposits in the lungs (COPD) understand various patterns of illness chronic bronchitis with symptoms of cough and sputum, as well as progressive and irreversible deterioration of lung function (especially exhalation). The disease is accompanied by seizures and is often complicated by bacterial infections (Rennard, S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S-241S, 1998). In the course of the disease pulmonary function has been steadily shrinking, light is becoming more emphysematous, and shortness of breath patients is obvious. This disease is clearly harms the quality of life of patients (shortness of breath, lack of stamina) and significantly reduces the life expectancy. The main risk factor in addition to environmental factors is Smoking (Kummer F.: Asthma and COPD. Atemw.-Lungenkrkh. 20 (5), 299-302, 1994; Rennard, S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S-241S, 1998), and so men get sick much more often than women. However, due to changing living habits and growth in the number of smokers this picture in the future will change.

Modern therapy is directed only to alleviate symptoms, without interfering with the reasons for the development of the disease. The use of long-acting beta2-agonists (e.g. salmeterol on the list), possibly in combination with muscarinic antagonists (eg, ipratropium), improves lung function by increasing the bronchi and is widely used (Norman P: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431-437, 1998). Bo is favoured role in the attacks of COPD play a bacterial infection, who should be treated with antibiotics (Wilson R.: The role of infection in COPD, Chest, 113 (4) Suppl., 242S-248S, 1998; Grossman, R. F.: The value of antibiotics and the outcomes of antibiotic therapy in exacerbations of COPD. Chest, 113 (4) Suppl., 249S-255S, 1998). The treatment of this disease is still unsatisfactory, especially from the point of view of permanent impairment of lung function. New treatment guidelines, attacking inflammatory mediators, proteases or molecules clutch can be very promising (Barnes P.J.: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415-423, 1998).

Regardless bacterial infections complicating disease, bronchitis are chronic inflammation, which is dominated by neutrophilic granulocytes. For the observed structural changes in the Airways (emphysema), among others, are responsible mediators and enzymes released by neutrophils. The suppression of activity of neutrophilic granulocytes, therefore, is a rational basis to prevent the development of COPD (worsening parameters of lung function) or to slow it down. An important stimulus for the activation of granulocytes is a proinflammatory cytokine TNFa (tumor necrosis factor). So, it is known that TNFa stimulates the formation of oxygen radicals by neutrophils (Jersmann, H.P.A.; Rathjen, D.A. and A. Ferrante: Enhancement of LPS-induced neutrophil oxygen radical production by TNa, Infection and Immunity, 4, 1744-1747, 1998). Inhibitors of PDE 4 can very effectively suppress the release of TNFa from a large number of cells and thereby suppress the activity of neutrophilic granulocytes. Nonspecific PDE inhibitor pentoxifylline able to inhibit both the formation of oxygen radicals and phagocytose the ability of neutrophils (Wenisch, C.; Zedtwitz-Liebenstein, K.; Parschalk, and B. Graninger W.: Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability assessed by flow cytometry, Clin. Drug Invest., 13(2): 99-104, 1997).

Already known various inhibitors of PDE 4. Mainly when it comes to xanthine derivatives, analogs of rolipram or derivatives of nitecapone (review in: Karisson J-A, Aldos D. Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997, 7: 989-1003). None of these compounds is still not been brought to clinical use. It was definitely established that known inhibitors of PDE 4 also have a variety of side effects as nausea and vomiting, which still could not be eliminated sufficiently. There is therefore a need in the discovery of new inhibitors of PDE 4 with the best therapeutic spectrum of action.

The use of 7-azaindole for new biologically active substances for various purposes of the definitions so far described only in relatively small cases.

In Japanese patent JP 10120681 (Fujisaa Pharmaceutical Co., LTD.) the stated 5 - and 7-azaindole General formula

and R1denotes hydrogen or a lower alkyl group, R2may denote hydrogen, halogen, short alkyl groups, cycloalkyl group, alkylcarboxylic group or alcoholnye group, R3means alcoholnye group, protected carboxyl group, a cyano or substituted carbamoyl group. L indicates the lowest Allenby bridge. Q denotes a substituted aromatic or heterocyclic compounds. And1and2mean: one is N and the other is CH. These compounds differ from the compounds according to the invention particularly in relation to substituents R2and R3partially - R1and2. The described connections claimed as inhibitors of phosphodiesterase (PDE 5)specific to cGMP. As applications are called various cardiovascular diseases, bronchitis, asthma, rhinitis, and impotence, diabetic complications and glaucoma.

L.N. Yakhontov, S.S. Liberman, D.M. Krasnokutskaya et al., Khim.-Farm. Zh. 8 (11), 1974, 5-9, described the synthesis of various 3-aminoalkyl-4-azaindole and 3-aminoalkyl-7-azaindole. 3-(2-amino-ethyl)-7-azaindole described depression or antidepressant effect. 3-aminomethyl-7-azaindole installed effect of blood pressure lowering.

A.J. Verbiscar, J. Med. Chem. 15 (2), 1972, 149-52, describes with the Association of the formula:

with antimalarial action.

In the patent GB 1141949 (Sterling Drug Inc.) described the synthesis of various 2-(imidazolin-2-yl)-alkyl-7-azaindole or 3-(imidazolin-2-yl)-alkyl-7-azaindole from the appropriate 2 - or 3-cianelli-7-azaindole and for these compounds is shown used as a vasoconstrictor funds.

Still the effect of 7-azaindole as inhibitors of PDE 4 completely unknown.

The invention relates to substituted 7-azaindole General formula 1:

where

n can be equal to 1 or 2, and

R1means

-C1-C10-alkyl, unbranched or branched,

if necessary, one or multiply substituted by the groups-OH, -SH, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, -NH-C6-C14-aryl, -N(C6-C14-aryl)2, -N(C1-C6-alkyl)(C6-C14-aryl),

-NO2, -CN, -F, -Cl, -Br, -I, -O-C1-C6-alkyl, -O-C6-C14-aryl, -S-C1-C6-alkyl, -S-C6-C14-aryl, -SO3H, -SO2-C1-C6-alkyl, -SO2-C6-C14-aryl, -OSO2-C1-C6-alkyl, -OSO2-C6-C14-aryl, -COOH, -(CO)-C1-C5-alkyl, mono-, bi - or tricyclic saturated or mono - or multiply unsaturated, carbazic the AMI 3-14 members in the ring, with mono-, bi - or tricyclic saturated or mono - or multiply unsaturated heterocycles with 5-15 members in the ring and 1-6 heteroatoms, preferably N, O and S,

and C1-C6-aryl groups and the carbocyclic and heterocyclic substituents, for its part, if necessary, one or multiple can be substituted for R4,

-C2-C10alkenyl, single or multiply unsaturated, unbranched or branched, if necessary, one or multiply substituted by the groups-OH, -SH, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, -NH-C6-C14-aryl, -N(C6-C14-aryl)2, -N(C1-C6-alkyl)(C6-C14aryl), -NO2, -CN, -F, -Cl, -Br, -I, -O-C1-C6-alkyl, -O-C6-C14-aryl, -S-C1-C6-alkyl, -S-C6-C14-aryl, -SO3H, -SO2-C1-C6-alkyl, -SO2-C6-C14-aryl, -OSO2-C1-C6-alkyl, -OSO2-C6-C14-aryl, -COOH, -(CO) -C1-C5-alkyl, mono-, bi - or tricyclic saturated or mono - or multiply unsaturated carbocycle with 3-14 members in the ring, mono-, bi - or tricyclic saturated or mono - or multiply unsaturated heterocycles with 5-15 members in the ring and 1-6 heteroatoms, preferably N, O and S,

the rich C 6-C14-aryl groups and the carbocyclic and heterocyclic substituents, for its part, if necessary, one or multiple can be substituted for R4.

R2and R3may be the same or different, and only one of them may be hydrogen. Further, R2and R3can mark

-C1-C5-alkyl, if necessary, one - or multi-substituted groups: -OH, -SH, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, -NO2, -CN, -F, -Cl, -Br, -I, -O-C1-C6-alkyl, -S-C1-C6-alkyl, -phenyl, -pyridyl, -phenyl, if necessary, one or multiply substituted by the groups-OH, -SH, -NH2, -NH-C1-C3-alkyl, -N(C1-C3-alkyl)2, -NO2, -CN, -COOH, -COO-C1-C3-alkyl, -F, -Cl, -Br, -O-C1-C3-alkyl, -S-C1-C3-alkyl, -pyridyl, if necessary, one - or multi-substituted groups-NO2, -CN, -COOH, -COO-C1-C3-alkyl, -Cl, -Br, -O-C1-C3-alkyl, -S-C1-C3-alkyl, and

Together the group-NR2R3can refer to:

R4means

-H, -OH, -SH, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, -NH-C6-C14-aryl, -N(C6-C 14-aryl)2, -N(C1-C6-alkyl)(C6-C14aryl), -NHCO-C1-C6-alkyl, -NO2, -CN, -COOH, -COO-C1-C6-alkyl, -(CO)-C1-C6-alkyl, -(CS)-C1-C6-alkyl, -F, -Cl, -Br, -I, -O-C1-C6-alkyl, -O-C6-C14-aryl, -S-C1-C6-alkyl, -S-C6-C14-aryl, -SO-C1-C6-alkyl, -SO2-C1-C6-alkyl.

7-azaindole formula 1 according to the invention, the remainder R1preferably is C1-C10-alkyl residue. Such alkyl residue may be linear, branched or cyclic and is preferably linear. Especially preferred alkyl residues with 1 to 6, more preferred alkyl residues with 1 to 4 carbon atoms. In the following a preferred form of execution of R1stands With2-C10especially With2-C6and most preferably-C2-C4is an alkyl residue. Alkanniny residue may be single or multiple, for example, double or triple unsaturated. If alkenylphenol balance it may be unbranched, branched or cyclic hydrocarbon residue. Especially preferred are the remains of R1in which alkyl or alkanniny the residue of one or repeatedly, for example, twice, three times, caterer the IDT or fivefold substituted. Particularly preferred remainder R1replaced With1-alkyl (e.g. methyl) balance. From the above-mentioned substituents for alkyl or alkenylphenol group balance R1particularly preferred substituents are-OH, -F, -Cl, -Br, -I, -C1-C4-alkoxygroup. Hereinafter, preferred substituents which, if necessary, available the alkyl residue contains 1 to 4 carbon atoms and, if necessary, available aryl residue containing 6 to 10 carbon atoms. From carbocycles preferred is a phenyl residue, in particular substituted phenyl residue, preferably substituted by-F, -Cl, -Br, -I, -C1-C6-alkoxy - or hydroxy-group. Of heterocycles such preferred, which are characterized by at least one heteroatom selected from the group N, O or S. Particularly preferred in heterocycles is peredelnyj balance and isoxazolines balance, especially 3,5-dimethylisoxazole balance. An example of a condensed carbocyclic substituents is nattily the rest.

Particularly preferably, R1denotes a group containing a cyclic hydrocarbon residue, such as, for example, cyclopropylmethyl-linear hydrocarbon, such as n-hexyl-, linear hydrocarbon, substituted CNS a rest, as the example 2-methoxyethyl-branched hydrocarbon residue, such as, for example, isobutyl-, unsaturated hydrocarbon residue, such as, for example, 2-methylpropan-3-yl-or a hydrocarbon residue containing an aromatic group, which, if necessary, can be substituted, as, for example, 4-terbisil-, 3-methoxybenzyl-, 4-methoxybenzyl-, 4-chlorbenzyl-, 4-methylbenzyl-, 3-hydroxybenzyl - or 4-hydroxybenzyl, a group containing heteroaromatic hydrocarbon residue, such as, for example, 4-pyridylmethyl - or 3,5-dimethylisoxazol-4-methyl-, or a group containing a condensed aromatic hydrocarbon, as, for example, 1-naphthylmethyl. The substituents at the nitrogen atom, R2andR3in the preferred form of execution may constitute, if necessary, replaced With1-C5especially With1-C3and particularly preferably1(respectively methyl) alkyl residue.

One of the residues R2or/and R3preferably denotes a residue comprising heteroaromatic hydrocarbon, as, for example, 4-pyridylmethyl-and heteroaromatic hydrocarbon may be substituted preferably by halogen, such as, for example, 3,5-dichloro-4-pyridyl-. In the following a preferred form of execution for residues R2or/and R3we are talking about morpholinoethoxy. Further, before actualname are the remains of R 2and R3including aromatic hydrocarbons, preferably substituted, in particular by halogen or carboxypropyl, as, for example, 2,6-dichlorophenyl-, 4-carboxyphenyl-, 4-ethoxycarbonylphenyl-, 3,4-acid-. Further, as R2and R3preferably denote methoxyethyl-. In the following a preferred form of execution of R2or R3denotes the rest:

or together the group-NR2R3:

Further, the invention relates to a physiologically compatible salts of the compounds according to formula 1.

Physiologically compatible salt get in the usual way by neutralization with inorganic bases or organic acids or by neutralization of the acids with inorganic or organic bases. As inorganic acids mean, for example, hydrochloric acid, sulfuric acid, phosphoric acid or Hydrobromic acid, organic acids such as carboxylic, sulfo or sulfonic acids, as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinea acid, Aleynikova acid, benzoic acid, 2-phenoxybenzoic the I acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, albanova acid, nicotinic acid, isonicotinamide acid, oxalic acid, amino acids, methansulfonate, econsultation, 2-hydroxyethanesulfonic, ethane-1,2-disulfonate, benzosulfimide, 4-methylbenzenesulfonate or naphthalene-2-acid. As inorganic bases mean, for example, sodium hydroxide, potassium hydroxide, ammonia, and organic bases (amines, but preferably tertiary amines, as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline, isoquinoline, a-picoline, beta-picoline, g-picoline, heraldin or pyrimidine.

Further, the physiologically compatible salts of the compounds according to the formula 1 could be obtained due to the fact that derivative having a tertiary amino group, are translated into the corresponding Quaternary ammonium salt in a known manner using quaternaire funds. Under quaternization means mean, for example, alkylhalogenide as methyliodide, ethylbromide and n-propylchloride and arylalkylamine as benzylchloride or 2-fenilatilamin.

Further, the invention relates to compounds of formula 1 containing asymmet is practical a carbon atom, D-form, L-form and D, L-mixtures and, in the case of several asymmetric carbon atoms - diastereomeric forms. The compounds of formula 1 which contain asymmetric carbon atoms and, as a rule, formed as racemates, can be separated into the optically active isomers in a known manner, for example, optically active acid. It is also possible from the outset to use optically active starting material, and in this case, the quality of the final product is obtained the corresponding optically active or diastereomeric connection.

For compounds according to the invention were found pharmacologically important properties that can be used therapeutically.

Compounds according to the invention are inhibitors of TNFa release.

Therefore, the compounds may be used to suppress the release of TNFa.

Thus, an object of the present invention are compounds according to formula 1 and their salts, and pharmaceutical compositions containing these compounds or their salts that may be used for the treatment of diseases which require inhibition of TNFa. These diseases include, for example, inflammation of the joints, including arthritis and rheumatoid arthritis, and other arthritic diseases, such as rheumatoid spondylosis and osteoarthritis. The trail is overall use is the treatment of patients that's sick osteoporosis, sepsis, septic shock, gram negative sepsis, toxic shock syndrome, syndrome of asthma, asthma or other chronic lung diseases, diseases of bone resorption or reactions, transplant rejection, or other autoimmune diseases such as lupus erythematosus, multiple sclerosis, glomerulonephritis, uveitis, insulin-dependent diabetes mellitus, and chronic demyelination.

In addition, the compounds according to the invention can also be used to treat infections such as viral infections and parasitic infections, for example malaria, leishmaniasis, dengue, caused by infection, infectious myalgia, AIDS and cachexia.

Compounds according to the invention are inhibitors of phosphodiesterase 4.

Therefore, the compounds according to the invention can be used to inhibit phosphodiesterase 4.

Thus, an object of this invention are compounds according to formula 1 and their salts, and pharmaceutical preparations containing these compounds or their salts that may be used for the treatment of diseases which require inhibition of phosphodiesterase 4.

Thus, the compounds according to the invention can be used as bronchodilators for asthma prevention. Further, the connection fo the mules 1 are inhibitors of accumulation of eosinophils and their activity. Consequently, the compounds according to the invention can also be used for diseases in which the role of the eosinophils. These diseases include, for example, inflammatory diseases of the respiratory tract as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic anghit, inflammation, which contribute eosinophils, as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary eosinophilic infiltration), urticaria, ulcerative colitis, Crohn's disease, and proliferative skin diseases, like psoriasis or keratosis.

The object of this invention is the ability of the compounds according to the formula 1 and their salts to inhibit both the release of TNFa in vitro, and induced by LPS (lipopolysaccharides) pulmonary neutrophil infiltration in rats in vivo. The combination of these detected pharmacologically important properties substantiates the fact that the compounds according to the formula 1 and their salts, and pharmaceutical preparations containing these compounds or their salts, can be used therapeutically for the treatment of chronic obstructive pulmonary disease.

Further, the compounds according to the invention possess neuroprotective properties and may be used for the treatment of diseases that require a neuroprotective d the op perate. Such diseases are, for example, senile dementia (Alzheimer's disease), memory loss, Parkinson's disease, depression, stroke and intermittent claudication.

Another possibility of use of the compounds according to the invention is the prevention and treatment of diseases of the prostate, such as benign prostatic hyperplasia, pollakiuriya, nocturia (Nocturie), and treatment of incontinence, colic, caused by urinary stones and male and female sexual dysfunctions.

In conclusion, the compounds according to the invention can also be used to inhibit the occurrence of drug dependence with repeated use of analgesics, such as morphine, and to reduce the development of tolerance with repeated reception of these analgesics.

To obtain drugs along with the usual excipients, carriers and additives used effective dose of the compounds according to the invention or their salts.

The dosage of the biologically active substances may vary depending on route of administration, age, weight of the patient, type and severity of the disease being treated, and like factors.

Daily dose can be administered as a single dose taken once or divided into 2 or more daily doses and is, as ravelo, 0.001 to 100 mg

Under the forms of introduction mean oral, parenteral, intravenous, subcutaneous, local, inhalation and intranasal compositions.

For application using conventional herbal preparative form as tablets, pills, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrups, juices or drops.

Solid dosage forms may contain inert ingredients and carriers, as, for example, calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guaran, magnesium stearate or aluminum stearate, methylcellulose, talc, highly dispersed silicic acid, silicone oil, high molecular weight fatty acid (as stearic acid), gelatine, agar-agar or vegetable or animal fats and oils, solid high-molecular polymers (such as polyethylene glycol); oral preparative forms may contain, if desired, additional gives taste substances and/or sweeteners.

Liquid formulations can be sterilized and/or, if necessary, to contain auxiliary substances, such as preservatives, stabilizers, wetting means, penetration tools, emulsifiers, spray tools, agents, dissolution, salts, sugars or sugar alcohols for the regulation of the Oia osmotic pressure or buffer and/or viscosity regulators.

Such additives are, for example, tartrate or citrate buffer, ethanol, complexing agents (such as Ethylenediamine-tetraoxane acid and its non-toxic salts). To adjust the viscosity using high molecular weight polymers, such as liquid polyethylene oxide, microcrystalline cellulose, carboxymethylcellulose, polyvinylpyrrolidone, dextran or gelatin. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular weight fatty acid (as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers such as polyethylene glycol.

Oily suspensions for parenteral or local application can be of vegetable, synthetic or semi-synthetic oils, such as, for example, liquid esters of fatty acids, if necessary, with 8 to 22 C-atoms in chain fatty acids such as palmitic, lauric, tridecanol, margaric, stearic, arachnid, myristic, beganovic, pentadecanol, linoleic, elaidic, brassicicola, erucic or oleic acids, which etherification one - to trivalent alcohols with 1 to 6 C-atoms, such as methanol, ethanol, propanol, butanol, pentanol or isomery, glycol or glycerin. Such fatty acid esters are, for example, commercially available miglioli, isopropylmyristate, isopropyl, isopropylene, ether of polyethylene glycol (PEG) and 6-capric acid, esters of capryl/capric acid and saturated fatty alcohols, polyoxyethyleneglycol, etiloleat, wax-like esters of fatty acids, artificial fat filling sacral glands, isopropyl ether acids of coconut oil, alerby ester of oleic acid, decroly ester of oleic acid, ethyl ester of lactic acid, dibutyl phthalate, diisopropyl ether, adipic acid, Paleologue esters of fatty acids and others. Also suitable silicone oils of different viscosity or fatty alcohols, as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or alerby alcohol, fatty acids, such as oleic acid. Next, you can apply vegetable oil such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil.

Under the solvent, gelling and agent dissolving mean water or miscible with water solvents. Suitable are, for example, alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polietileno the Oli, phthalates, adipate, propylene glycol, glycerol, di - or tripropyleneglycol, waxes, marcelosalim, cellosolve, ester, morpholine, dioxane, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, and so on

As the foaming agent can be applied ethers of cellulose, which can dissolve or swell in water and in organic solvents, such as, for example, hypromellose, methylcellulose, ethylcellulose or soluble chromalife quite possible mixed form between the gel and the film. Here, above all, suitable for use ionic macromolecule, such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, amylopectinosis sodium, alginic acid or propilenglikolstearat in the form of sodium salt, gum Arabic, xanthan gum, guaran or carrageen.

As a further auxiliary means for preparative ready-made forms can be entered: glycerin, paraffins different viscosities, triethanolamine, collagen, allantoin, eventially acid. Also for preparative ready-made forms you may need the use of surfactants, emulsifiers or wetting agents, such as sodium lauryl sulphate, sulphates, ethers of fatty alcohols, di-Na N-lauryl-B2; -iminodipropylamine, polyoxyethylene castor oil or sorbitan-monooleate, sorbitan-monostearate, Polysorbate (e.g., Tween), cetyl alcohol, lecithin, glycerylmonostearate, polyoxyethylenated, alkylphenolate ethers of polyglycols, cetyltrimethylammonium chloride or salt of monoethanolamine and ether mono/dialkylphosphites acid and phosphoric acid. Also, if necessary, for desired compositions preparative forms may require stabilizers, as montmorillonite or colloidal silicic acid to stabilize emulsions, or active substances to prevent decomposition, as antioxidants, such as tocopherol or butylhydroxyanisole, or preservatives, as an ester of p-hydroxybenzoic acid.

Preparations for parenteral administration can be in a separate dosage unit forms, such as ampoules or vials. Mainly use solutions of biologically active substances, preferably aqueous solutions, and, above all, isotonic solutions, and suspensions. These injection mold can be used in the form of a finished product or prepared just before use by mixing the active compounds, for example, freeze-dried, if necessary, with other solid media with the desired solvent or with spendierhosen agent.

Intranasal preparations can be in the form of aqueous or oily solutions or in the form of aqueous or oil suspensions. They can also be in the form of liofilizatow which before use are mixed with a suitable solvent or suspenders agent.

Receiving, filling and plugging of drugs occurs in the conventional antimicrobial and aseptic conditions.

Further, the invention relates to a method of preparing compounds according to the invention.

According to the invention obtain compounds of General formula 1 with the earlier values of R1, R2, R3and n=1,

the fact that 7-azaindole-3-carboxylic acid of formula 2 with the same value of R1

per se known manner by acid chlorides of the acids, preferably with thionyl chloride or acid chloride oxalic acid, primarily transferred in a similar anhydrides 7-azaindole-3-carboxylic acids of the formula 3.

Of the selected anhydrides 7-azaindole-3-carboxylic acids of formula 3 and then by reaction with a primary or secondary amine are obtained compounds according to the invention of General formula 1 with the earlier values of R1, R2, R3and n=1. The reaction prefers the equipment takes place in the presence of an auxiliary base. As auxiliary bases can be used an excess of amine used in the reaction as a reactant, a tertiary amine, preferably pyridine or triethylamine, and inorganic bases, preferably the hydroxides of alkali metals or hydrides of alkali metals.

According to the invention compounds of General formula 1 with the earlier values of R1, R2, R3and n=2 receive

the fact that 7-azaindole formula 4 with the same value of R1

per se known manner by acylation with acid chloride oxalic acid primarily transferred in a similar anhydrides 7-azaindole-3-yl - Glyoxylic acid of formula 5.

Of the selected anhydrides 7-azaindole-3-yl - Glyoxylic acid of formula 5 and then by reaction with a primary or secondary amine get a connection according to the invention of General formula 1 with the earlier values of R1, R2, R3and n=2. The reaction preferably takes place in the presence of an auxiliary base. As auxiliary bases can be used an excess of amine used in the interaction as a reagent, a tertiary amine, preferably n is ridin or triethylamine, as well as inorganic bases, preferably the hydroxides of alkali metals or hydrides of alkali metals.

Examples

Variant of the method of obtaining the compounds according to the invention of formula 1, where n=1:

Example 1. Amide N-(4-pyridylmethyl)-1-cyclopropylmethyl-7-azaindole-3-carboxylic acid

of 1.87 g of 1-cyclopropylmethyl-7-azaindole-3-carboxylic acid (8.6 mmol) is suspended in 15 ml of dichloromethane. When cooling water is added to 1.8 ml of the acid chloride oxalic acid a (17.4 mmol). The reaction mixture is stirred for 8 hours. This leads to crystallization of the acid chloride of 1-cyclopropylmethyl-7-azaindole-3-carboxylic acid. It is isolated and dissolved in 18 ml of tetrahydrofuran (THF).

to 1.14 g of sodium hydride (60%) are suspended in 21 ml of THF. Under stirring at a temperature of about 10°With added dropwise a solution of 0.93 g of 4-aminomethylpyridine (8.6 mmol) in 21 ml of THF. After approximately 15 minutes to the reaction mixture was added dropwise the previously obtained solution of the acid chloride of 1-cyclopropylmethyl-7-azaindole-3-carboxylic acid. Then the whole mixture is refluxed for 3 hours. After cooling, to the reaction mixture was added 36 ml of ethyl ether, acetic acid and 36 ml of water. The phases are separated and the organic phase is washed with water. The solvent is distilled off and the residue is recrystallized from ethanol.

Yield: 1.3 g (50% of theory).

Melting point: 187-189°C.

When using this method of obtaining can be obtained a large number of other compounds of formula 1, where n=1, examples of which are listed below:

ExampleR1-NR2R3nThe melting temperature, [°]
1Cyclopropylmethyl-4 pyridylmethylamine-1187-189 ethanol
2Isobutyl-3,5-dichloro-4-pyridylamino-1168-170 ethanol
3n-hexyl-3,5-dichloro-4-pyridylamino-1136-137 methanol
4Cyclopropylmethyl-3,5-dichloro-4-pyridylamino-1186-187 ethanol
54-terbisil-4 pyridylmethylamine-1189-191 ethanol
64-terbisil-3,5-dichloro-4-pyridylamino-1232-233 ethanol
74-methoxybenzyl-3,5-dichloro-4-pyridylamino-1193-195 ethanol
8 4-chlorbenzyl-4 pyridylamino-1192-194 methanol
94-terbisil-Morpholino-1182-184 ethanol
102-methylpropan-3-yl-2,6-dichlorophenylamino-1171-174 ethanol
114-pyridylmethyl-3,5-dichloro-4-pyridylamino-1190-192 methanol

Variant of the method of obtaining the compounds according to the invention of formula 1, where n=2:

Example 12. Amide N-(3,5-dichloropyridine-4-yl)-[1-(3-methoxybenzyl)-7-azaindole-3-yl]Glyoxylic acid.

3.57 g of 1-(3-methoxybenzyl)-7-azaindole (15 mmol) is dissolved in 50 ml of tert. butyl methyl ether. When 0°under stirring was added dropwise a solution of 1.54 ml of acid chloride oxalic acid (18 mmol) in 10 ml of tert. butyl methyl ether. After that, the mixture is boiled for 2 hours under reflux. The solvent is then distilled off under vacuum. The resulting acid chloride of 1-(3-methoxybenzyl)-7-azaindole-3-illikkalam acid obtained as a solid residue, which was suspended in 50 ml of tetrahydrofuran (THF).

To a suspension of 2 g of sodium hydride in 20 ml of THF at -5°With added dropwise a solution of 2.4 g of 4-amino-3,5-dichloropyridine (15 mmol) in 30 ml THF. Under stirring the mixture for 1 hour given out to the t at 20° C. and Then at a temperature of approximately 0°With previously obtained was added dropwise a suspension of the acid chloride of 1-(3-methoxybenzyl)-7-azaindole-3-illikkalam acid. In conclusion, the reaction mixture is boiled for 4 hours under reflux. The solvent is distilled under vacuum. The residue is mixed with 50 ml ethyl ester of acetic acid and 50 ml of water. The phases are separated. The organic phase is washed with water. The solvent is distilled under vacuum. The precipitate is recrystallized from isopropanol.

Yield: 3.5 g (51,5% of theory).

Melting point: 165-167°C.

When using this method of obtaining can be obtained a large number of other compounds of formula 1, where n=2, examples of which are listed below:

ExampleR1-NR2R3nThe melting temperature, [°]
123-methoxybenzyl-3,5-dichloro-4-pyridylamino-2165-167 isopropanol
134-terbisil-4 pyridylamino-·HCl2275-278 decomposition of DMF
144-terbisil-3,5-dichloro-4-pyridylamino-2201-202 ethanol
15 4-chlorbenzyl-4 pyridylamino-·HCl2280-283 decomposition of DMF
164-chlorbenzyl-3,5-dichloro-4-pyridylamino-2205-207 ethanol
174-methoxybenzyl-3,5-dichloro-4-pyridylamino-2165-167 ethanol
184-chlorbenzyl-2,6-dichlorophenylamino-2166-168 ethanol
194-terbisil-4-carboxy-phenylamino-2279-282 isopropanol
204-terbisil-4 ethoxy-carbonitrile-2209-211 ethanol
214-terbisil-3,4-dimethoxyaniline-2173-176 ethanol
224-methylbenzyl-3,5-dichloro-4-pyridylamino-2176-178 ethanol
234-hydroxybenzyl-3,5-dichloro-4-pyridylamino-2140-142 ethanol
243-hydroxybenzyl-3,5-dichloro-4-pyridylamino-2241-244 ethanol
25Cyclopropylmethyl- 3,5-dichloro-4-pyridylamino-2215-218 ethanol
26n-hexyl3,5-dichloro-4-pyridylamino-2165-167 ethanol
27Isobutyl-3,5-dichloro-4-pyridylamino-2152-154 methanol
282-methyl-propene-3-yl-3,5-dichloro-4-pyridylamino-2114-116 methanol
292-methoxyethyl-3,5-dichloro-4-pyridylamino-2166-168 methanol
301-naphthylmethyl-3,5-dichloro-4-pyridylamino-2181-183 ethanol
314-pyridylmethyl-3,5-dichloro-4-pyridylamino-2199-201 ethanol
323,5-dichloro-4-pyridylamino-2196-198 ethanol
334-terbisil--N(C2H4-OCH3)2263-66 methanol
344-terbisil-2184-185 ethanol
354-terbisil- 2188-191 ethanol
364-terbisil-2179-181 methanol
374-terbisil-2297-300 decomposition of DMF
384-terbisil-2310-313 DMF)
394-terbisil-2160-162 acetone
404-terbisil-2312-315 decomposition of DMF

Compounds according to the invention are powerful inhibitors of phosphodiesterase 4 and TNFa release. Their therapeutic potential is confirmed in vivo, e.g., by suppressing asthmatic reactions late phase (eosinophilia), and through the influence of vascular permeability induced by allergen in actively sensitized rats Brown-Norway.

The inhibition of phosphodiesterase

The activity of PDE 4 determined at the preparation of enzymes from human polymorphonuclear lymphocytes (PMNL), the activity of PDE 2, 3, and 5 with PDE from human platelets. The human will hinder the blood stabilized against coagulation by citrate. By centrifugation at 700g for 20 minutes at room temperature, platelet-rich plasma in the supernatant is separated from erythrocytes and leukocytes. Platelets via ultrasound subjected to lysis and used in the analysis of PDE 3 and PDE 5. For determining the activity of PDE 2 clear cytosolic fraction of platelets using anion-exchange column by a gradient of NaCl and get peak PDE 2 for analysis. PMNL to determine PDE 4 emit through follow-dextran sedimentation and subsequent gradient centrifugation with what she calls with picola (Ficoll-Paque). After twice washing the cells still contained erythrocytes subjected to lysis by adding 10 ml of hypotonic buffer (155 mm NH4Cl, 10 mm NaHCO3, 0.1 mm EDTA, pH=7,4) for 6 minutes at 4°C. still intact PMNL 2 more times washed with PBS and subjected to lysis by means of ultrasound. The supernatant after centrifugation time at 4°at 48000g contains the cytosolic fraction PDE 4 and is used to define the PDE 4.

The activity of phosphodiesterase identify with some modifications according to the method of Thompson and others (Thompson, W.J.; Appleman, M.M., Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme. Adv. Cycl. Nucl. Res. 1979, 10, 69-92).

The reaction mixture containing 50 mm Tris-HCl (pH of 7.4), 5 mm MgCl2inhibitors vary in the s concentrations, the enzymes, subjected to dissection, and other components required to meet the individual isoenzymes (see below). By adding a substrate of 0.5 μm [3H]cAMP or [3H]-cGMP (about 6000 CMP/test) start the reaction. The final volume is 100 ml of Test substance used as a mother solutions in DMSO. The concentration of DMSO in the reaction mixture is 1% vol./about. At this concentration of DMSO has no effect on the activity of PDE. After starting the reaction by addition of substrate samples incubated for 30 minutes at 37°C. By heating the test tubes for 2 minutes at 110aboutWith the reaction to stop. Samples on following 10 minutes leave on ice. After adding 30 μl of 5'-nucleotidase (1 mg/ml of the suspension of snake venom of Crotalus adamanteus) followed by incubation for 10 minutes at 37°C. the Process in the samples stop on ice, as needed add 400 μl of a mixture of Dowex-water-ethanol (1+1+1), mix well and again incubated 15 minutes on ice. The reaction vessel centrifuged for 20 minutes at 3000g. 200 ál aliquots of the supernatant liquid is transferred directly into scintillation vessel. After adding 3 ml of scintillator measure samples in a beta scintillation counter.

For determining the activity of PDE 4, 3 and 2 as a substrate of the IC is result [ 3H]-cAMP for determining the activity of PDE 5 use [3H]-cGMP. Nonspecific enzyme activity, as needed, to determine the presence of 100 μm Rolipram for PDE 4 and in the presence of 100 μm IBMX for determination of PDE 3 and 5 and subtracted from the test values. The initial mixture for incubation analyzed PDE 3 contain 10 μm Rolipram, in order to suppress possible contamination by PDE 4. PDE 2 testing through analysis of SPA company Amersham. The analysis is performed in the presence of activator PDE 2 (5 μm cGMP).

For compounds according to the invention on inhibition of phosphodiesterase 4, it was determined the value of the IC50in the region 10-9up to 10-5M. the Selectivity for PDE types 2, 3 and 5 had the factor 100-10000.

Results suppression of PDE 4 for the selected examples are summarized in the following table:

ExampleSuppression of PDE 4 IC50[µmol/l]
10,710
21,400
120,005
130,058
140,004
150,031
160,002
170,008
180,031
220,002
23 0,001
240,003
250,004
260,021
270,002
280,003
320,113
370,987

Suppression of TNFa release from cells of nasal polyps

The sequence of experience is essentially the method described by Campbell A.M. and Bousquet J. (Anti-allergic activity of H1-blockers. Int. Arch. Allergy Immunol., 1993, 101, 308-310). The source material consisted of nasal polyps (OP-material) patients subjected to surgical treatment.

The fabric was washed in RPMI 1640 and then were treated with protease (2.0 mg/ml), collagenase (1.5 mg/ml), hyaluronidase (0.75 mg/ml) and DNA-zoé (0.05 mg/ml) after 2 h at 37°C (1 g of tissue in 4 ml of RPMI 1640 with enzyme). The obtained cells, a mixture of epithelial cells, monocytes, macrophages, lymphocytes, fibroblasts and granulocytes filtered through repeated centrifugation washed with nutrient solution, passively sensibiliser adding human IgE and cell suspension is used at a concentration of 2 million cells/ml in RPMI 1640 (adding antibiotics, 10% fetal calf serum, 2 mm glutamine and 25 mm Hepes). This suspension is distributed in the 6-hole tablet for cell cultures (1 ml per well). Cells tentative is but incubated with test substances at different final concentrations of 30 minutes and then stimulated by addition of anti-IgE (7.2 µg/ml) for the release of TNFa. The maximum release occurs in a nutrient medium in approximately 18 hours. During this period, the cells are incubated at 37°C and 5% CO2. Culture medium (supernatant) are obtained by centrifugation (5 min, 4000 rpm) and stored at -70°until the determination of cytokines. Determination of TNF occurs in the supernatant with the so-called sandwich structures ELISAs (Grundmaterial Pharmingen), which can be detected concentration of the cytokine in the field from 30-1000 PG/ml.

Cells that were not stimulated with anti-IgE, barely produce TNFa-stimulated cells, in contrast, produce large amounts of TNFa that, for example, can be reduced by inhibitors of PDE 4 depending on the dose. The percentage of suppression (the release of TNFa cells stimulated by anti-IgE, =100%) examinees substances at various concentrations calculated IC50(concentration of 50%inhibition).

For compounds according to the invention was determined value IC50in the region 10-7up to 10-5M

Results suppression of TNFa release for the selected examples are summarized in the following table:

ExampleSuppression of TNFa release
ConcentrationThe hearth is of
140.3 µmol/l92
161.0 µmol/l90
171.0 µmol/l91
271.0 µmol/l91

Inhibition of late-phase eosinophilia after 48 h after inhalation analbuminemia call in actively sensitized rats Brown-Norway.

Suppression of pulmonary eosinophilic infiltration using the substances according to the invention have actively sensitized against ovalbumin (OVA) male rats individuals Brown-Norway (200-250 g). Sensitization occurs via subcutaneous injection of a suspension of 10 ág OVA together with 20 mg of aluminum hydroxide as an adjuvant in 0.5 ml of physiological saline, for animal 1, 14 and 21 days. Additionally, animals were injected through the same periods of time the vaccine Bordetella pertussis dilution for animal 0.25 ml intraperitoneally. On the 28th day of the experiment in open Plexiglas boxes 1 liter individually placed animals in which the head and nose are covered with special devices (Expositionsgerdt). Animals exposed to aerosol of 1,0%ovalbumine suspension (allergic challenge). Ovalbumin aerosol is formed by spray (Bird micro nebulizer, Palm Spring CA, USA), operating by means of compressed air (0.2 MPa). The exposure time is 1 hour, and control animals are sprayed by the spray of a 0.9%aqueous common salt solution during 1 hour.

After 48 hours Allergology call leads to massive introduction of eosinophilic granulocytes in the lungs of animals. To this period, the animals were injected to cordozo drugs of ethylurethane (1.5 g/kg body weight intraperitoneally) and were performed bronchoalveolar lavage (BAL) with C ml of balance Hanks solution. The total number of cells and a number of eosinophilic granulocytes wash liquid after BAL then determined using an automatic device differentiation of cells (Bayer Diagnostics Technicon H1E). For each animal counting eosinophils (EOS) in BAL in million/animal: EOS/μl·regenerated BAL (BAL-Recovery) (ml)=EOS/animal.

In each test, there are 2 control group (spraying physiological common salt solution and spraying the solution of ovalbumin).

The percentage inhibition of eosinophils in the group of the treated substances, calculated according to the following formula:

{((OVAC-SC)-(OVAD-SC))/(OVAC-SC)}·100%=% suppression(SC=control group treated indifferent basis of drug and 0.9%sodium chloride solution; OVAC=control group treated with indifference the tonew drug and 1%suspension of ovalbumin; OVAD=test group, the treated active material and treated with a 1%suspension of ovalbumin).

The test substance is applied intraperitoneally or orally in the form of a suspension in 10% polyethylene glycol 300 and 0.5%5-hydroxyethyl cellulose, 2 hours before entering the allergen. The control group treated according to the form of application of the test substance indifferent basis of the medicinal product.

Compounds according to the invention inhibit the late-phase eosinophilia after intraperitoneal administration of 10 mg/kg 30-100% and after oral administration of 30 mg/kg at 30-75%.

Thus, the compounds according to the invention is particularly suitable for the production of medicines for the treatment of diseases associated with the activity of eosinophils.

Results suppression of eosinophilia for the selected examples are summarized in the following table:

ExampleSuppression of eosinophilia
Dose/introductionInhibition [%]
1410 mg/kg intraperitoneally62
10 mg/kg oral59
1610 mg/kg intraperitoneally100
10 mg/kg oral70
1710 mg/kg intraperitoneally75
10 mg/kg oral32
2710 mg/kg intraperitoneally50
10 mg/kg oral70

Suppression of pulmonary neutrophilia induced by lipopolysaccharides (LPS), Lewis rats.

Suppression of pulmonary neutrophilic infiltration through the substances according to the invention have on the male animals Lewis rats (200-250 g). On the day of experiment in open Plexiglas boxes 1 liter individually placed animals in which the head and nose are covered with special devices. Animals exposed to aerosol of lipopolysaccharide suspension (100 μg LPS/ml of 0.1% solution of hydroxylamine) in PBS (LPS provocation). Aerosol LPS/hydroxylamine is formed by spray (Bird micro nebulizer, Palm Springs CA, USA), operating by means of compressed air (0.2 MPa). The exposure time is 40 minutes, and control animals are sprayed by the spray of 0.1%solution of hydroxylamine in PBS for 40 minutes.

After 6 hours of LPS provocation leads to maximum mass introduction of neutrophilic granulocytes into the lungs of animals. To this period the animals injected cordozo drugs of ethylurethane (1.5 g/kg body weight inside Rusina) and performed bronchoalveolar lavage (BAL) with C ml of balance Hanks solution. The total number of cells and a number of neutrophilic granulocytes wash liquid BAL then determined using an automatic device differentiation of cells (Bayer Diagnostics Technicon H1E). For each animal count neutrophils (NEUTRO) in BAL in million/animal: NEUTRO/ál·regenerated BAL (ml)=NEUTRO/animal.

In each test, there are 2 control group (spraying of 0.1%solution of hydroxylamine in PBS and spraying 100 µg LPS/ml 0.1%solution of hydroxylamine in PBS).

The percentage inhibition of neutrophils in the experimental group, the treated substances, calculated according to the following formula:

{((LPSC-SC)-(LPSD-SC))/(LPSC-SC)}·100%=% suppression

(SC=control group treated indifferent basis of drug and 0.1%solution of hydroxylamine; LPSC=control group treated indifferent basis of drug and LPS (100 μg/ml of 0.1% solution of hydroxylamine); LPSD = test group treated with active substance and treated LPS (100 μg/ml of 0.1% solution of hydroxylamine).

The test substance used orally in the form of a suspension in 10% polyethylene glycol 300 and 0.5%5-hydroxyethyl cellulose, 2 hours before LPS provocation. The control group treated according to the form of application of the test substance indifferent basis of drug is.

Compounds according to the invention inhibit neutrophilia after oral administration of 1 mg/kg 40-90% and, therefore, especially suitable for the production of medicines for the treatment of diseases associated with the activity of neutrophils.

Results suppression of neutrophilia for the selected examples are summarized in the following table:

ExampleSuppression of neutrophilia
Dose/introductionInhibition [%]
141 mg/kg orally80
221 mg/kg orally64
271 mg/kg orally52

1. 7-Azaindole formula 1

where n denotes an integer of 1 or 2;

R1stands With2-C10alkenyl, single or multiply unsaturated, unbranched or branched; C1-C10-alkyl, unbranched or branched, unsubstituted or once substituted C1-C6-alkoxy, naphthyl, pyridinyl, C3-C6-cycloalkyl, phenyl, which in turn may be substituted C1-C6-alkyl, halogen, C1-C6-alkoxy or hydroxy or a radical

R2and R3may be the same or different, and only one of them can be hydrogen, and denote C1-C6-alkyl, unsubstituted or once substituted by a group-O-C1-C6-alkyl or pyridyl; phenyl, unsubstituted or twice substituted by-F, -Cl, -Br, -O-C1-C3the alkyl or once substituted by-COOH or-COO-C1-C3-alkyl; pyridyl, unsubstituted or twice substituted by-Cl, -Br, and

or together the group-NR2R3means

provided that, if n=1, at the same time does not mean

R1- C1-6-alkyl,

R2- N or C1-6-alkyl and

R3

and R, R' independently of one another denote Cl or Br,

as well as their physiologically compatible salts.

2. Compounds according to claim 1, which represents a physiologically compatible salts obtained by neutralization with inorganic bases or organic acids, or by neutralization of the acids with inorganic or organic bases, or by quaternization of tertiary amines to Quaternary ammonium salts.

3. The compounds of formula 1 according to claims 1 and 2, representing the connection is with the asymmetric carbon atom in the D-form, L-form or in the form of D, L-mixtures, or in the case of several asymmetric carbon atoms in diastereoisomeric forms.

4. The compound of formula 1 according to claims 1-3, where n=1, selected from the following compounds:

amide N-(4-pyridylmethyl)-1-cyclopropylmethyl-7-azaindole-3-carboxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-1-isobutyl-7-azaindole-3-carboxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-1-hexyl-7-azaindole-3-carboxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-1-cyclopropylmethyl-7-azaindole-3-carboxylic acid,

amide N-(4-pyridylmethyl)-1-(4-terbisil)-7-azaindole-3-carboxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-1-(4-terbisil)-7-azaindole-3-carboxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-1-(4-methoxybenzyl)-7-azaindole-3-carboxylic acid,

amide N-(4-pyridylmethyl)-1-(4-Chlorobenzyl)-7-azaindole-3-carboxylic acid,

morpholin 1-(4-terbisil)-7-azaindole-3-carboxylic acid,

amide N-(2,6-dichlorophenyl)-1-(2-methylpropan-3-yl)-7-azaindole-3-carboxylic acid and

amide N-(3,5-dichloropyridine-4-yl)-1-(4-pyridylmethyl)-7-azaindole-3-carboxylic acid.

5. The compound of formula 1 according to claims 1-3, where n=2, selected from the following compounds:

amide N-(3,5-dichloropyridine-4-yl)-[1-(3-methoxybenzyl)-7-azaindole-3-yl]Glyoxylic acid,

amide hydrochloride N-(4-pyridyl)-[1-(4-terbisil)-7-Aza ndol-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

amide hydrochloride N-(4-pyridyl)-[1-(4-Chlorobenzyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(4-Chlorobenzyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(4-methoxybenzyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(2,6-dichlorophenyl)-[1-(4-Chlorobenzyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(4-carboxyphenyl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(4-ethoxycarbonylphenyl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,4-acid)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(4-methylbenzyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(4-hydroxybenzyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(3-hydroxybenzyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-(1-cyclopropylmethyl-7-azaindole-3-yl)Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-(1-hexyl-7-azaindole-3-yl)Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-(1-isobutyl-7-azaindole-3-yl)Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(2-methylpropan-3-yl)-7-Aza ndol-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(2-methoxyethyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(1-naphthylmethyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(4-pyridylmethyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,5-dichloropyridine-4-yl)-[1-(3,5-dimethylisoxazol-4-yl-methyl)-7-azaindole-3-yl]Glyoxylic acid,

amide N,N-bis(2-methoxyethyl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

morpholin [1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

S,S-diocletianopolis[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

4-methylpiperazin 1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(6-methyluracil-5-yl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(3,6-dimethyluracil-5-yl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid,

amide N-(1,3,6-trimethylacetyl-5-yl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid and

amide N-(1,2,4-4H-triazole-3-yl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid.

6. The method of obtaining compounds of formula 1 according to claims 1-4, where n=1, characterized in that the 7-azaindole-3-carboxylic acid of the formula

where R1has specified in claim 1 values

through anhydrides cicloturista into the corresponding acid chlorides 7-azaindole-3-carboxylic acid and then by reaction with primary or secondary amines are converted into compounds according to the invention of formula 1, where R1R2and R3have specified in claim 1 values and n=1.

7. The method of obtaining compounds of formula 1 according to claim 6, characterized in that for the synthesis of acid chlorides 7-azaindole-3-carboxylic acid as the carboxylic acid anhydrides using thionyl chloride or acid chloride oxalic acid.

8. The method of obtaining compounds of formula 1 according to claim 6 or 7, characterized in that interact acid chlorides 7-azaindole-3-carboxylic acids with primary or secondary amines in the presence of an auxiliary base, preferably in the presence of excess amine used in the interaction as a reagent, a tertiary amine, for example pyridine or triethylamine, and inorganic bases, preferably hydroxides of alkali metals or hydrides of alkali metals.

9. The method of obtaining compounds of formula 1 according to claims 1-3 and 5, where n=2, characterized in that the 7-azaindole formula

where R1has specified in claim 1 values

by acid chloride oxalic acid transferred in a similar anhydrides 7-azaindole-3-yl-Glyoxylic acid, and then by reaction with primary or secondary amines are converted into the compounds of formula 1, where R1, R2and R3have specified in claim 1 values and n=2.

10. Pic is b obtain the compounds of formula 1 according to claim 9, characterized in that interact acid chlorides 7-azaindole-C-illikkalam acid with primary or secondary amines in the presence of an auxiliary base, preferably in the presence of excess amine used in the interaction as a reagent, a tertiary amine, for example pyridine or triethylamine, and inorganic bases, preferably hydroxides of alkali metals or hydrides of alkali metals.

11. The use of compounds of formula 1 according to claims 1 to 5 as a therapeutic biologically active substances to obtain drugs for the treatment of diseases in which therapeutically necessary suppression of the release of TNFα from inflamed cells.

12. The use of compounds of formula 1 according to claims 1 to 5 as a therapeutic biologically active substances to obtain drugs for the treatment of diseases in which therapeutically necessary suppression of phosphodiesterase 4.

13. The use of compounds of formula 1 according to claims 1 to 5 as a therapeutic biologically active substances to obtain drugs for the treatment of diseases that are associated with the action of eosinophils.

14. The use of compounds of formula 1 according to claims 1 to 5 as a therapeutic biologically active substances to obtain drugs for l the treatment of diseases, associated with the action of pulmonary neutrophils.

15. The use of compounds according to claims 1 to 5 as biologically active substances to obtain drugs for the treatment and/or prophylaxis of diseases which require inhibition of TNFαin particular inflammation of joints, arthritis, rheumatoid arthritis, arthritic diseases, rheumatoid spondylosis, osteoarthritis, osteoporosis, sepsis, septic shock, gram negative sepsis, toxic shock syndrome, syndrome of asthma, asthma, chronic pulmonary diseases, diseases of bone resorption, reactions, transplant rejection, autoimmune diseases, lupus erythematosus, multiple sclerosis, glomerulonephritis, uveitis, insulin dependent diabetes mellitus chronic demyelination, viral diseases, viral infections, parasitic infections, malaria, leishmaniasis, dengue, caused by infection, infectious myalgia, AIDS, cachexia, diseases that can be treated by inhibition of phosphodiesterase 4, asthma, diseases in which the role of the eosinophils: bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic angiitis, inflammation caused by eosinophils: eosinophilic fasciitis, eosinophilic pneumonia, PIE syndrome, urticaria, asonog the colitis, Crohn's disease, proliferative skin diseases, psoriasis, keratosis, chronic obstructive pulmonary diseases, diseases that can be treated with neuroprotective action: senile dementia, Alzheimer's disease, memory loss, Parkinson's disease, depression, stroke, intermittent claudication, diseases of the prostate: benign prostate hyperplasia, pollakiuria, nocturia, incontinence, abdominal cramps, colic, caused by urinary stones, male or female sexual dysfunction, as well as bronchodilators, for inhibiting the emergence of drug dependence and to reduce the development of tolerance.

16. Drug, possess inhibitory activity against phosphodiesterase 4 and containing one or more compounds according to claims 1-5, along with the usual physiologically acceptable carriers and/or diluents, or excipients.

17. The compound of formula 1 according to claim 1, which represents the amide N-(3,5-dichloropyridine-4-yl)-[1-(4-terbisil)-7-azaindole-3-yl]Glyoxylic acid.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

EFFECT: improved preparing method, valuable properties of compounds and compositions.

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

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

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new urea-substituted imidazoquinolines of the formula (1):

wherein R, R1, R2 and n have values given in the description, and to pharmaceutical preparations based on these compounds. Proposed compounds possess effect of immunomodulators initiating biosynthesis of different cytokines. Also, invention relates to methods for treatment of different states, among them viral diseases and neoplastic pathologies.

EFFECT: improved method for induction, valuable properties of compounds.

47 cl, 11 tbl, 142 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes derivatives of imidazo-3-ylamine of the general formula (I):

wherein X and Y mean CH or nitrogen atom (N) under condition that X and Y don't mean nitrogen atom (N) simultaneously; R1 means tert.-butyl, (CH2)nCN wherein n means 4, 5 or 6, phenyl substituted optionally with (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C4-C8)-cycloalkyl, 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra represents hydrogen atom, branched or linear (C1-C8)-alkyl, phenyl substituted optionally with halogen atom, (C1-C4)-alkoxy-group, CO(OR') wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl, PO(OR')2 wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl; R2 means hydrogen atom, CORb wherein Rb represents branched or linear (C1-C4)-alkyl; R3 means methyl, ethyl, tert.-butyl, (C3-C8)-cycloalkyl, phenyl monosubstituted optionally at position 3, 5 or 6 or optionally multisubstituted at position 4 and additionally at position 2 and/or 3, and/or 5, and/or 6 with halogen atom, hydroxyl group (OH), (C1-C4)-alkyl or (C1-C4)-alkoxy-group, naphthyl, optionally substituted (C1-C4)-alkoxy-group, di-(C1-C4)-alkylamino-group, pyrrole substituted optionally with (C1-C4)-alkyl, benzylsulfonyl, COOCH3, pyridyl substituted optionally with (C1-C4)-alkyl, OH, hydroxy-(C1-C4)-alkyl, furan substituted optionally with (C1-C4)-alkyl, nitro-group (-NO2), halogen-substituted phenyl, CH2COOCH3, COOH, thiophene substituted optionally with halogen atom, (C1-C4)-alkyl, (C1-C4)alkylsulfanyl, -NO2, phenoxy-group, thiophene, alkynylphenyl, unsubstituted anthracene or quinoline substituted optionally with halogen atom under condition that R3 doesn't means cyclohexyl-unsubstituted phenyl or phenyl monosubstituted with carboxylic acid amide at position 3 if R1 means tert.-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, monosubstituted phenyl, 2,6-dimethylphenyl or benzyl, and R2 means simultaneously hydrogen atom or -CO-(methyl) and under condition that R2 doesn't mean hydrogen atom if R1 means benzyl simultaneously and R3 means methyl or R1 means simultaneously CH2C(O)-tert.-butyl and R3 means unsubstituted phenyl, in forms of bases or pharmaceutically acceptable salts, and a method for their preparing and a medicinal agent based on thereof. Described compounds possess analgesic activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

7 cl, 2 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives if azaindole of the formula (I)

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: the present innovation deals with one of the components of complex therapy of purulent-inflammatory diseases of paranasal sinuses. For this purpose, it is necessary to conduct the puncture of paranasal sinus and its sanitation with physiological solution. Then one should introduce about 8-12%-ximedone solution into the sinus, the procedure should be repeated once daily till complete recovery. The innovation enables to decrease the acuity of inflammatory reaction, prevents the transition of inflammatory process into its chronic form and, also, enables to restore normal structure and function of paranasal sinuses mucosa.

EFFECT: higher efficiency of therapy.

4 dwg, 1 ex, 4 tbl

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: medicine, pulmonology.

SUBSTANCE: the present innovation deals with carrying out aeroionotherapy. Moreover, beforehand one should fulfill inhalations with atrovent at the dosage of 0.25 mg once daily through nebulizer , the size of sprayed particles ranged 3-5 mcm, power of aeroionotherapy corresponds to 90 bln ions for 20 min. The innovation enables to increase peak flowmetry value up to 95% and the values of bronchial permeability by 25.3%.

EFFECT: higher efficiency of therapy.

2 ex, 1 tbl

FIELD: medicine, pulmonology.

SUBSTANCE: the present innovation deals with carrying out aeroionotherapy. Moreover, beforehand one should fulfill inhalations with atrovent at the dosage of 0.25 mg once daily through nebulizer , the size of sprayed particles ranged 3-5 mcm, power of aeroionotherapy corresponds to 90 bln ions for 20 min. The innovation enables to increase peak flowmetry value up to 95% and the values of bronchial permeability by 25.3%.

EFFECT: higher efficiency of therapy.

2 ex, 1 tbl

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: under conditions of artificial pulmonary ventilation at positive pressure at the end of expiration one should set the level of positive pressure at the end of expiration being above against pre-chosen optimal one for 4-8 cm water column. About 10-15 min later one should introduce perfluorocarbon as aerosol with the help of nebulizer for 10-15 min. The innovation enables to introduce perfluorocarbons without depressurization of respiratory contour, decreases damaging impact upon pulmonary parenchyma and, also, reduce invasiveness of the method and decrease expenses of perfluorocarbons.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

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

SUBSTANCE: invention relates to novel derivatives of quinuclidine of the general formula (I):

wherein © represents phenyl ring, (C4-C9)-heteroaromatic group comprising one or some heteroatoms, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 represent hydrogen halogen atom, phenyl and others; n represents a whole number from 0 to 4; A represents group -CH=CR6-, -CR6=CH-, -CR6R7 and others; R6 and R7 represent hydrogen atom, alkyl and others; m represents a whole number from 0 to 8; p represents a whole number from 1 to 2; and a substitute in azoniabicyclic ring can be at position 2, 3 or 4 including all possible configurations of asymmetric carbon atoms; B represents the group of the formula i) or ii) wherein R10 represents hydrogen atom, hydroxyl group or methyl; each R8 and R9 represents: wherein R11 represents hydrogen, halogen atom, alkyl; Q represents a single bond, -CH2- and others; X represents pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess antagonistic activity with respect to muscarinic M3-receptors and can be used in medicine for treatment of diseases wherein muscarinic M3-receptors are implicated.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

36 cl, 164 ex

FIELD: medicine, gerontology.

SUBSTANCE: the present innovation deals with rehabilitation therapy of cerebrovascular diseases. One should introduce microcirculators and nootropic preparations to conduct training neuropsychological procedures. Moreover, microcirculatory and nootropic preparations should be introduced as intravenous infusions for 10 d, ten during 1 mo it is necessary to introduce tableted forms of the same preparations at simultaneous neuropsychological training directed to improving household skills valuable for a patient that deal with memorizing different names, important dates, names of medicinal preparations and location of domestic articles. On achieving a success the tasks should be complicated. Training should last for 30 min carried out thrice weekly: therapy course includes 12 trainings. The innovation widens the number of preparations for treating elderly and senile patients at discirculatory encephalopathy stage III and coarse cognitive deficiency.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl

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