Mmp-2 and/or mmp-9 inhibitor

FIELD: chemistry.

SUBSTANCE: invention provides to a high degree a safe pharmaceutical drug which is effective for diseases caused by MMP-2 and/or MMP-9. The pharmaceutical drug contains, as an active ingredient, at least one member selected from a group which consists of thiazole derivatives of formula (1): where R1 is a phenyl group which can have 1-3 lower alkoxy groups as substitutes in the phenyl ring, and R2 is a pyridyl group which can have 1-3 carboxyl groups as substitutes in the pyridine ring, or salts thereof.

EFFECT: high activity and use when treating diseases such as fibrosis and pulmonary emphysema.

4 cl, 4 ex, 2 tbl

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to an inhibitor of matrix metalloprotease (hereinafter designated as "MMP")2 and/or MMP-9.

The LEVEL of TECHNOLOGY

Matrix metalloprotease is a collective term for the extracellular enzymes that destroy the matrix, which contains in its active site zinc ion (II). The metabolism of the extracellular matrix is mainly controlled by the balance between MMP and tissue inhibitor of metalloprotease (TIMP), specifically in relation to DFID.

MMP consists of ten or more kinds of enzymes, such as collagenase (MMP-1 and MMP-8), stromelysin (MMP-3), gelatinase (MMP-2 and MMP-9) and so on, and DFID are produced in many cell types.

It is known that among the MMD group gelatinase (MMP-2 and MMP-9) not only has relativeclause activity, but also digests collagen type IV, fibronectin, vitronectin, etc.

However, highly safe pharmaceutical drugs that inhibit MMP-2 and/or MMP-9 and are effective as a therapeutic treatment of diseases caused by such DFID, has not yet been developed.

It is known that derivatives of thiazole represented by the formula (1):

where R1represents a phenyl group which may have the t 1 to 3 alkoxygroup as the substituents at the phenyl ring, and R2represents pyridyloxy group which may have from 1 to 3 carboxyl groups as substituents in the pyridine ring, or salts of compounds have inhibitory activity against the production of superoxide (O2-), production of cytokine and adhesion of cells, in addition to beneficial effects on chronic obstructive pulmonary disease (for example, naturgewalt examination of Japanese patent publication No. H5-51318, naturgewalt examination of Japanese patent publication No. N10-152437, naturgewalt examination of Japanese patent publication No. 2003-104890 etc).

However, it is unknown at this time that the thiazole derivatives represented by the above formula (1)or their salts have an inhibitory effect on MMP-2 and/or MMP-9, which is completely different from the pharmacological actions listed above.

Description of the INVENTION

The PROBLEM addressed by the INVENTION

The present invention is the provision of a highly safe drug that is effective for diseases caused by MMP-2 and/or MMP-9.

TOOLS FOR PROBLEM SOLVING

The present applicants have conducted extensive research to achieve the above tasks and found that derivatives of thiazole, which are described in the above paten the different publications as having inhibitory activity against the production of O 2-, inhibitory action on the production of cytokine, adhesion inhibitory action and activity in the treatment of chronic obstructive pulmonary disease, also have a MMP-2 and/or MMP-9 inhibitory action, which could not assume specialist in the field of technology, on the basis of pharmacological actions listed above. The present invention is achieved on the basis of such information.

The present invention provides an inhibitor of MMP-2 and/or MMP-9 in accordance with the following items from 1 to 4.

Paragraph 1. Inhibitor of MMP-2 and/or MMP-9, comprising as active ingredient at least one compound selected from the group consisting of thiazole derivatives represented by the formula (1):

where R1represents a phenyl group which may have 1 to 3 lower alkoxygroup as the substituents at the phenyl ring and R2represents pyridyloxy group which may have from 1 to 3 carboxyl groups as substituents in the pyridine ring, and their salts.

Paragraph 2. Inhibitor of MMP-2 and/or MMP-9 according to claim 1, where the derivative of thiazole is a 6-[2-(3,4-dioxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid or its salt.

Item 3. Inhibitor of MMP-2 and/or MMP-9 according to claim 1 or 2 to use the Oia in the treatment of fibrosis.

Item 4. Inhibitor of MMP-2 and/or MMP-9 according to claim 1 or 2 for use in the treatment of pulmonary emphysema.

Derivatives of thiazole represented by the formula (1) of the present invention, are well-known compound that can be obtained, for example, by the method described in naturhaushalt examination of Japanese patent publication No. H5-51318.

Specific examples of the groups represented in the formula (1)represent respectively the following.

Examples of phenyl groups which may have 1 to 3 lower alkoxygroup as the substituents at the phenyl ring include phenyl groups which may have from 1 to 3 alkoxygroup with a normal chain or branched structure, having from 1 to 6 carbon atoms as substituents in the phenyl ring, such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyloxide, 3 ethoxy-4-methoxyphenyl, 4-hexyloxyphenyl, 3,4-acid, 3,4-dioxyphenyl, 2,3-acid, 2,6-acid, 3-propoxy-4-methoxyphenyl, 3,5-acid, 3,4-dipentylester, 3,4,5-trimethoxyphenyl, 3-methoxy-4-ethoxyphenyl and the like.

Examples peredelnyh groups which may have from 1 to 3 carboxyl groups as substituents in the pyridine ring include pyrid is l, 2-carboxypropyl, 3-carboxypropyl, 4-carboxyphenyl, 2,3-dicarboximide, 3,4-dicarboximide, 2,4-dicarboxylicacid, 3,5-dicarboxylicacid, 3,6-dicarboximide, 2,6-dicarboxylicacid, 2,4,6-tricarboxylate and the like.

Among the derivatives of thiazole represented by the formula (1) of the present invention, compounds which have a group of basic character, easily interact with conventional pharmacologically acceptable acid with formation of salts. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, Hydrobromic acid and the like; and organic acids such as acetic acid, p-toluensulfonate acid, econsultancy acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, succinic acid, benzoic acid and the like.

Among the derivatives of thiazole represented by the formula (1) of the present invention, compounds which have acid groups, easily interact with pharmaceutically acceptable compound of a basic nature of the formation of salt. Examples of such compounds are the main character include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, hydrocarb the NAT potassium and the like.

Derivatives of thiazole of the present invention have optical isomers.

Compounds represented by formula (1), usually used in the form of conventional pharmaceutical preparation. Such a pharmaceutical preparation can be prepared using commonly used diluents or excipients such as fillers, diluents, binders, humectants, disintegrators, surfactants, lubricants and the like.

The pharmaceutical preparation may take various forms depending on the goals of treatment. Typical examples of such forms include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), inhalations and the like.

For the preparation of a pharmaceutical preparation in the form of tablets, you can use different types of media that are well known in the art. Examples of such carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like; binders such as water, ethanol, propanol, simple syrup, glucose solutions, solutions of starch solutions, gelatin, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polivi iparralde and the like; disintegrant, such as dry starch, sodium alginate, agar powder, powder of laminaran, sodium bicarbonate, calcium carbonate, complex polyoxyethylenesorbitan esters of fatty acids, sodium lauryl sulfate, monoglyceride of stearic acid, starch, lactose and the like; disintegration inhibitors such as sucrose, stearin, cacao butter, gidrirovannoe oil and the like; absorption promoters such as the base of the Quaternary ammonium, sodium lauryl sulfate and the like; humectants such as glycerin, starch and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal oxide silicon and the like; and lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol and the like. Tablets can be advanced, if necessary, covered with a conventional covering materials for the production of, for example, coated sugar pellets coated with gelatin tablets, tablets, enteric coated, film-coated tablets and two-layer or multilayer tablets.

For the preparation of a pharmaceutical preparation in the form of pills, you can use different types of media that are well known in the art. Examples of carriers include excipients such as glucose, lactose, starch, cacao butter, hiderow the TES vegetable oil, kaolin, talc and the like; binders such as powdered gum Arabic, powdered tragakant, gelatin, ethanol and the like; and disintegrators such as laminaran, agar and the like.

For the preparation of a pharmaceutical preparation in the form of a suppository, you can use different types of media that are well known in the art. Examples of carriers include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohol, gelatin, semisynthetic glycerides, and the like.

Capsules can be manufactured in accordance with a known manner, by mixing the compounds of the usual active ingredient with various types of media shown in the example above, and filling the mixture into hard gelatin capsules, elastic capsules, etc.

In the preparation of a pharmaceutical preparation in the form of injection, it is preferable that the solutions, emulsions and suspensions are sterilized and are prepared in isotonic with blood. In the preparation of pharmaceutical preparations in the forms you can use any diluents commonly used in the field of engineering. Examples of such diluents include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearoyl alcohol, polysilicone isostearyl alcohols, complex polyoxide isorbitancia esters of fatty acids and the like. In this case, the pharmaceutical preparations can contain salt, glucose or glycerin in an amount sufficient for making the resulting preparations isotonic. In addition, you can optionally add to the drugs conventional solubilizing agents, buffers, soothing agents, etc.

In addition, colorants, preservatives, corrigentov, flavorings, sweeteners, etc. and other additional drugs can be added to pharmaceuticals when necessary.

Inhalation preparations can be prepared in accordance with the known method. Specifically inhaled medicines can be prepared by obtaining a connection of the active ingredient in powder form or in liquid form, adding the resulting powder or liquid for inhalation propellant and/or media, and filling the mixture into a suitable inhalation container. When the connection of the active ingredient is in powder form, used conventional mechanical powder inhaler. When the connection of the active ingredient is in a liquid form, you can use this inhaler as a spray. As inhalation propellants, it is possible to apply the known pharmaceutical forms for inhalation. Examples of this include fluorocarbons such as Flon 11,Flon 12, the Flon 21, Flon 22, Flon 113, Flon 114, Flon 123, Flon s, Flon 134a, Flon 227, Flon S, 1,1,1,2-Tetrafluoroethane, etc.; hydrocarbons such as propane, isobutane, n-butane and so on; ethers, such as simple diethyl ether and so on; and compressed gases, such as gaseous nitrogen, gaseous carbon dioxide, etc.

Commonly used surfactants, oils, simple flavoring agents, cyclodextrin or its derivatives, etc. if you want, additionally you can respectively add to inhalation drug of the present invention. Examples of such surfactants include oleic acid, lecithin, diethylenglycol, tetrahydrofurfurylamine, etiloleat, isopropylmyristate, glyceryltrinitrate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetylpyridinium, sorbitan trioleate (trade name: span 85), sorbitan monooleate (trade name: span 80), sorbitan monolaurate (trade name: span 20), polyoxyethylenated gidrirovannoe castor oil (trade name: HCO-60), polyoxyethylenated (20) sorbitan monolaurate (trade name: tween 20), polyoxyethylenated (20) sorbitan monooleate (trade name: tween 80), lecithin, derived from natural the of sources (trade name: epicure), alaipayuthey (2) a simple ether (trade name: Bria 92), simple steadilyincreasing (2) ether (trade name: Beria 72), simple lowerpriority (4) ether (trade name: Beria 30), simple alaipayuthey (2) ether (trade name: genapol 0-020), a block copolymer of oxyethylene and oxypropylene (brand name: synperonic) etc. are Examples of oils include corn oil, olive oil, cottonseed oil, sunflower oil etc.

When the connection is active ingredient of the present invention in liquid form, the connection of the active ingredient can, for example, be dissolved in the carrier in liquid form. Examples of such carriers in liquid form include water, a solution of salt in water, organic solvents, etc. Among the holders of preferred is water. When dissolved to the solution can respectively add surfactants such as polyethylene glycol having a molecular weight of from 200 to 5000, polyoxyethylene (20) sorbitan monooleate etc.; sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.

When the connection is active ingredient of the present invention in powder form, the sputtering can be performed in accordance with the known method. For example, the preferred means is aetsa, the connection of the active ingredient is sprayed with lactose, starch, etc. and mix with the formation of a uniformly mixed powder.

The number of connections active ingredient contained in therapeutic preparations of the present invention is not limited and can be installed in a wide range. Usually, it is preferable that the composition of the preparation contains from about 1 to 70% by weight of compounds of the active ingredient.

Methods of administration of therapeutic drugs of the present invention is not specifically limited and can be entered depending on the forms of drugs, age, sex and other conditions of the patient, painful conditions of the patient, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injection drugs injected alone or in combination with reinfusion, such as glucose, amino acid and so on; and, if necessary, injectable drugs administered separately intramuscularly, intracutaneously, subcutaneously or administered intraperitoneally. Suppositories administered intrarectally. Inhaled medicines are inhaled into the oral cavity.

The dosage of therapeutic drug of the present invention, respectively, are selected in accordance with use, age, gender and drugimmediately patient, painful conditions of the patient, and the like, but typically, the dosage is from about 0.2 to 200 mg/kg of body weight per day, usually on the basis of the connection of the active ingredient.

The EFFECT of the INVENTION

The present invention offers a highly safe pharmaceutical drug that is effective in the treatment of diseases caused by MMP-2 and/or MMP-9.

Inhibitor of MMP-2 and/or MMP-9 of the present invention selectively inhibits MMP-2 and/or MMP-9. More specifically, the inhibitor of MMP-2 and/or MMP-9 of the present invention inhibits the expression of MMP-2 and/or MMP-9. Examples of effective reading inhibitor of MMP-2 and/or MMP-9 of the present invention include RAs and bone diseases, such as rheumatoid arthritis, arthritis, arthrosis, bone disease, osteoporosis, bone damage, osteoarthritis, bone disorder of metabolism, etc.; inflammation, such as Crohn's disease, ocular inflammation, inflammatory bowel disease, anaphylaxis, irritable bowel syndrome, bacterial infection, periodontal disease, inflammation, ulcer, ulcerative colitis, inflammation of the mucous membrane, pneumonia, abdominal inflammation, cystitis, etc.; cancers, such as lymphoma, gastric tumor, a cancerous pleural leakage of liquid, a cancerous ascites, solid carcinoma, mesland the mA bone metastases, tumor of the digestive tract, esophageal cancer, glioma, renal cancer cells, astrocytoma, prostate cancer, multiple myeloma, metastasis, tumor of the head and neck, sarcoma, breast cancer, brain tumor, lung tumor, nebulosity lung cancer, cancer of the eye, swelling of the ovary, glioblastoma, pancreatic cancer, etc.; blood diseases and endocrine diseases such as diabetes mellitus type 2, non-insulin-dependent diabetes mellitus, hyperphosphatemia, myelodysplastic syndrome, diabetes, leukemia, etc.; cardiovascular diseases such as congestive heart failure, hypertension, atherosclerosis, acute coronary artery syndrome, vascularization disorder, restenosis, heart attack, cardiovascular disorders, cardiopathy, heart failure, aortic aneurysm, diabetic nephropathy, ischemic cerebrovascular and myocardial vessels of the brain, etc.; ocular and neurological disorders such as age-related macular degeneration, corneal injury, corneal ulcer, infectious diseases in the eye area feels dry eyes, eye disease, neurological disease, neurodegenerative disease, multiple sclerosis, diabetic retinopathy, retinal m is molecular degeneration, Parigi, disease of the lacrimal gland, etc.; infectious diseases, such as HIV infection, infection Clostridium botulinum, oral infection, bacterial infection of the respiratory tract, infection of Plasmodium falciparum, the infection Clostridium tetani, septic fever, septic shock, etc.; respiratory diseases such as asthma, a disease of the respiratory system, pulmonary emphysema, etc.; skin diseases such as atopic dermatitis, Kaposi's sarcoma, psoriasis, acne, rosacea, skin burns, skin disease, scar tissue, chronic ulcer of the skin and so on; and other diseases such as Alzheimer's disease, proteinuria, epilepsy, a disease of the "graft versus host", the damage caused by chemotherapy, kidney disease, fibrosis, wound healing, diabetic complications, poisoning toxin, endotoxic shock, brain damage, lung damage, anemia, pain, etc.

Inhibitor of MMP-2 and/or MMP-9 of the present invention exhibits a significant, high therapeutic efficacy especially pulmonary fibrosis and emphysema.

The BEST WAY of carrying out the INVENTION

The following are examples of drugs and test examples. Below "Connection a" refers to 6-[2-(3,4-dioxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid.

1 Example drug
Connection150 g
Avicel (trade mark received Asahi Kasei Corporation)40 g
Corn starch30 g
Magnesium stearate2 g
The hypromellose10 g
Polyethylene glycol 60003 g
Castor oil40 g
Ethanol40 g

Connection And, Avicel, corn starch and magnesium stearate were mixed and crushed. The resulting mixture was formed into tablets using a pestle (R 10 mm) for sugar coating. The obtained tablets were covered with a film coating agent containing hypromellose, polyethylene glycol 6000, castor oil and ethanol. It was obtained film-coated tablets.

150 g
2 Example drug
Connection
Citric acid1.0 g
Lactose33,5 g
The dicalcium phosphate70,0
Pluronic F-6830.0 g
Sodium lauryl sulfate15.0 g
Polyvinylpyrrolidone15.0 g
Polyethylene glycol (Carbowax 1500)4.5 g
Polyethylene glycol (Carbowax 6000)45,0 g
Corn starch30.0 g
Dry sodium stearate3.0 g
Dry magnesium stearate3.0 g
Ethanolas needed

Connection And citric acid, lactose, dicalcium phosphate, pluronic F-68 and sodium lauryl sulfate were mixed together.

The resulting mixture was sieved through sieve No. 60. The sifted mixture was subjected to wet granulation with an alcohol solution containing p is livingparrillas, carbowax 1500 and carbowax 6000. If you have added alcohol to the resulting powder wet granulation, which is then turned into like a paste mass. Subsequently received similar pasta weight was added corn starch and, in addition, the blending operation was performed until, until it forms a homogeneous particles. The resulting mixture particles were sieved through sieve No. 10, was placed in a tray and dried in a drying oven at 100°C for 12 to 14 hours. The dried particles were sieved through sieve No. 16. Then, to the obtained sieved particles were added dry sodium lauryl sulfate and dry magnesium stearate and mixed together. Then the resulting mixture was subjected to extrusion in the core tablets having the desired shape, using a device for forming tablets.

The resulting core tablets were coated with glaze and then they were sprayed talc to prevent moisture absorption. On the surface of the resulting core tablets was applied primer coating. Then was coated with a glaze on ground floor enough times to get tablets for internal use. To make the resulting coated tablets are completely spherical and smooth, they are additionally applied and the primer coat and smooth coat. Then put the painted coating so that the surface tablet had the desired colour. Coated tablets were dried and then polished in order to obtain tablets having a uniform outer glow.

3 Example drug
Connection5 g
Polyethylene glycol (molecular weight: 4000)0.3 g
Sodium chloride0.9 g
Polyoxyethylene sorbitan monooleate0.4 g
Metabisulphite sodium0.1 g
Methylparaben0.18 g
Propylparaben0.02 g
Distilled water for injection10.0 ml

Listed above parabens, sodium metabisulfite and sodium chloride were dissolved in about half volume of the above-mentioned distilled water at 80°C under stirring. The resulting solution was cooled to 40°C. Then RA is tarali in solution the compound And, then the polyethylene glycol and polyoxyethylene sorbitan monooleate. To the resulting solution were added the other half of the volume of distilled water for injection so as to establish a solution with a final volume. Thus obtained solution was sterilized by exposing sterilizing filtration using an appropriate filter paper. Thereby received injectable drug.

Test example(the rabbit model with induced Lactasoy damage easy)

Test procedures

Rabbits were divided into three groups (n = 10 animals/group). Two hundred IU/kg porcine pancreatic elastase (RRE) was administered intratrahealno in the lungs of animals group "Solvent" and "Connection". Animals in group "Simulation" intratrahealno were administered the same volume of saline instead of re. Rabbits were subjected to anatomy through 28 days after administration of RRE. Lung tissue of each rabbit were fixed in formalin for making this histological sections. Two hours until the introduction of RRA rabbits orally injected with a solvent (0.5% tragakant) or compound a (10 mg/kg) in the "Solvent" and "Compound a", respectively; the next day oral administration of a solvent or connection And continued once a day 5 days a week until the end of the experiment.

GIS is ideological cuts immunohistochemically were stained with the appropriate antibodies against MMP-2 or MMP-9. Then under the microscope assessed the level of expression of MMP-2 and MMP-9 were expressed as a quantitative indicator. Also watched the degree fibrocycstic changes in the subepithelial region of the respiratory tract and the degree of alveolar destruction.

TEST RESULT

Table 1 summarizes the expression of MMP in the lungs of animals in the respective groups. Group "Solvent" had significantly higher quantity, the expression of MMP-2 and MMP-9 (both values represent p<0.01) compared with the quantitative indicators of the group "Simulation". In addition we also observed a thickened subepithelial layer of the respiratory tract and fibrations changes in the lungs in the "Solvent". In contrast, quantitative expression of MMP-2 and MMP-9 in the group "Compound a were significantly lower than the quantity in the "Solvent" (MMP-2: p<0.05 and MMP-9: p<0,01). Further thickening subepithelial layer of the respiratory tract in fibrocycstic changes have been weakened, and alveolar destruction was significantly suppressed. Table 2 shows the average longitudinal partitions (linear segment), the typical option of increasing alveolar volume. On the basis described above results demonstrated that closedeye And significantly inhibits the expression of MMP-2 and MMP-9.

Table 1
A quantitative measure of the expression of MMP estimated using pathological samples
GroupNumberThe quantitative index (Average ± standard deviation)
MMP-2MMP-9
Group "Simulation"100,58±0,040,73±0,06
Group "Solvent"102,02±0,18**2,40±0,03**
Group "Compound a"101,49±0,12#1,81±0,03##

Differences between groups "Simulation" and "Solvent" and between groups "Solvent" and "Connection And" analyzed several comparative tests. In table 1 **: p<0,01 compared with the group "Simulation", #: p<0,05 in comparison with a group of "Solvent" and ##: p<0,01 compared with the group of Races is foretell".

Table 2
The average alveolar linear segment
GroupExamplesThe average alveolar linear segment (average ± standard deviation)
Group "Simulation"1048,7±1,0 µm
Group "Solvent"10104,5±6,2 µm **
Group "Compound a"1072,8±2,6 μm ##

Comparison of the linear segment between groups "Simulation" and "Solvent" and between groups "Solvent" and "Connection And" carried out through a series of comparative tests. In table 2, * * : p<0,01 compared with the group "Simulation", ##: p<0,01 compared with "Solvent".

Discussion regarding the link between fibrosis and the expression of MMP

The fibrosis that occurs in various tissues, is a dangerous disease with a poor prognosis. The main histological characteristics ablauts the damage to endothelial and epithelial cells; inflammation involving the infiltration of neutrophils, macrophages and lymphocytes; the proliferation of fibroblasts and excessive synthesis and deposition of extracellular matrix components (ECM)such as collagen. Specifically believe that excessive synthesis and deposition of ECM is caused by an imbalance between MMP, enzymes, selectively destroying the ESM, and TIMP (tissue inhibitor of metalloprotease), a substance that regulates the activity of the ECM in vivo. However, the details of this mechanism remain unclear. On the other hand reported that the levels of expression of MMP (specifically MMP-2 and/or MMP-9) increase in lung tissue and bronchoalveolar lavagno fluid from patients with pulmonary fibrosis, and similar results are also reported for animal models of pulmonary fibrosis. Other reports show that in the case of animal models of pulmonary fibrosis induced by bleomycin and asbestos, the introduction of MMP inhibitors, such as batimastat or GM6001 inhibited the increased activity of MMP and the number of leukocytes infiltrated in bronchoalveolar lavagno liquid; as a result of pulmonary fibrosis was suppressed in histological and biochemical aspects. These results illustrate that the increase in the enzyme activity of MMP or quantitative indication of the expression induces fibrations changes in the tissues. On on the basis of such evidence likely, that suppression of MMP activity in the tissues results in the inhibition of fibrosis tissue.

Taken together clearly shows that the compound that inhibits the expression of MMP may inhibit tissue fibrosis. From the point of view of the above results illustrate that compound a inhibits the expression of both MMP-2 and MMP-9 in lung tissue, in addition suppresses alveolar destruction and fibrations changes in the subepithelial region of the respiratory tract, it is clear that the compounds represented by formula 1 of the present invention, or their salts are largely effective as a therapeutic drug against fibrosis, particularly pulmonary fibrosis and/or pulmonary emphysema.

1. Inhibitor of MMP-2 and/or MMP-9, comprising as active ingredient at least one compound selected from the group consisting of thiazole derivatives represented by the formula (1)

where R1represents a phenyl group which may have 1 to 3 lower alkoxygroup as the substituents at the phenyl ring, and R2represents pyridyloxy group which may have from 1 to 3 carboxyl groups as substituents in the pyridine ring, and their salts.

2. Inhibitor of MMP-2 and/or MMP-9 according to claim 1, g is th derivative of thiazole is a 6-[2-(3,4-dioxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid or its salt.

3. Inhibitor of MMP-2 and/or MMP-9 according to claim 1 or 2 for use in the treatment of fibrosis.

4. Inhibitor of MMP-2 and/or MMP-9 according to claim 1 or 2 for use in the treatment of pulmonary emphysema.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

EFFECT: compounds can be used as anti-cancer agents, particularly as agents for treating solid tumours.

8 cl, 217 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , wherein R2 means methyl, Y means carbon or nitrogen, and R1, R3 and R4 have the value specified in the patent claim. Also, the invention refers to a pharmaceutical composition for the use as a pharmaceutical drug having activity of a phosphatidylinositol-3-kinase inhibitor, to the use of the compounds of formula I for preparing the pharmaceutical drug for treating a disease mediated by phosphatidylinositol 3-kinase and to a method for preparing the compounds of formula I .

EFFECT: preparing the compounds of formula I possessing activity of the phosphatidylinositol-3-kinase inhibitor.

10 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I), wherein A represents a pyrrole group or a pyrazole group, and X represents a carbon atom or a nitrogen atom; R1 represents a carboxy group; R2 independently represents a group specified in a substitute group α; R3 independently represents phenyl(C1-C6alkyl)group substituted by, phenyl(C1-C6alkyl)group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α); m is equal to 0, 1, 2 or 3, n is equal to 0 or 1; each of R4, R5, R6 and R7 independently represents a hydrogen atom, C1-C6alkyl group or a halogen atom; B represents a substituted naphthyl group (wherein the substitute(s) represents (represent) 1-4 groups independently specified in the substitute group α), or the group represented by formula (II), wherein B1, B2 and α are those as specified in the patent claim. Also, the invention refers to a pharmaceutical composition possessing lipolysis inhibiting activity, to the use of the compounds of formula (I) in preparing a drug preparation for treating hyperlipidemia, dislipidemia, abnormal lipid metabolism, arteriosclerosis or type II diabetes mellitus and to a method of treating or preventing the mentioned diseases.

EFFECT: preparing the compounds of formula (I) possessing lipolysis inhibiting activity.

36 cl, 1 dwg, 1 tbl, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1) and pharmaceutically acceptable salts thereof, which exhibit inhibitory activity on phospholipase A2 enzyme and therefore have prostaglandin and/or leucotriene production suppressing action. In formula X is a halogen atom, cyano group, C1-C3 alkyl group, which can be substituted with halogen atoms, C1-C3 alkoxy group or hydroxy group, C2-C4 alkenyl group, C1-C3 alkoxy group or hydroxy group; Y is a hydrogen atom or C1-C3 alkyl group; Z is C1-C3 alkyl group; G is selected from formulae and , where in formulae (G2) and (G5) R4 is a hydrogen atom or C1-C6 alkyl group which can be substituted with halogen atoms; D is -NR10C(O)-, -C(O)NR10-, -S(O)2NR10- or -N(R11)-; R10 is a hydrogen atom; R11 is a hydrogen atom or C1-C3 alkyl group; A is a single bond, C1-C6 alkylene, which can be substituted with a phenyl group, or C2-C4 alkenylene; Q is a phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, optionally substituted with a benzene ring; R5, R6 and R7 all or independently denote a hydrogen atom, a halogen atom, C1-C6 alkyl group which can be substituted with halogen atoms, C1-C6 alkoxy group which can be substituted with halogen atoms, phenyloxy group, phenyl group or a 5-6-member aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, where said phenyl group and 5-6-member aromatic heterocyclic group can be substituted with a C1-C3 alkyl group which can be substituted with halogen atoms or a C1-C3 alkoxy group. The invention also relates to specific compounds, a medicinal agent, a pharmaceutical composition, a phospholipase A2 enzyme activity inhibitor and a treatment method.

EFFECT: improved method.

21 cl, 56 tbl, 561 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention relates to methods of synthesis and to intermediate products of compounds of formula (XVII) and salts thereof.

EFFECT: preparing the hepatitis C virus protease inhibitor.

32 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , wherein R2 means methyl, Y means carbon or nitrogen, and R1, R3 and R4 have the value specified in the patent claim. Also, the invention refers to a pharmaceutical composition for the use as a pharmaceutical drug having activity of a phosphatidylinositol-3-kinase inhibitor, to the use of the compounds of formula I for preparing the pharmaceutical drug for treating a disease mediated by phosphatidylinositol 3-kinase and to a method for preparing the compounds of formula I .

EFFECT: preparing the compounds of formula I possessing activity of the phosphatidylinositol-3-kinase inhibitor.

10 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indole compounds of formula:

wherein A means 5-member heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms specified in N, O and S, R1 means R5 -X-B-X'-, R2 means -(CR8 R9 )p-Y-R7, R3 means hydrogen, C1-C6-alkyl or -(CH2)q-C3-C6-cycloalkyl, R4 means C3-C6-cycloalkyl (the other radical values are presented in cl.1 of the patent claim), their pharmaceutically acceptable salts or isomers which may be used for preventing or treating cell necrosis and necrosis-related diseases.

EFFECT: preparing the compounds to be used for preventing or treating cell necrosis and necrosis-related diseases.

34 cl, 2 tbl, 263 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented nitrogen-containing heterocyclic compounds presented by the following formula wherein the radical values are specified in the description. These compounds or their pharmaceutically acceptable salts possess strong EP1 activity if introduced in a human or an animal; they are used as an effective component of a pharmaceutical agent, e.g. for preventing and/or treating overactive bladder.

EFFECT: compounds are used as an effective component of the pharmaceutical agent for preventing and/or treating the symptoms including frequent urination, heavy urination demand accompanied by fear of involuntary urination, and urinary incontinence.

24 cl, 145 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (aza)indole derivatives of formula

wherein the values T, X1-X3, R1, Q, Y, J are presented in clause 1 of the patent claim.

EFFECT: compounds possess xanthine oxidase inhibitory action that enables using it in a pharmaceutical composition for treating a disease specified in a group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal diseases associated with hyperuricemia and nephrolithiasis.

19 cl, 62 tbl, 332 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 7-substituted indoles of formula I:

or their pharmaceutically acceptable salts wherein the values A1, B1, C1, D1, E1, F1, G1, L are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit activity of anti-apoptotic protein Mc1-1 that enables using them in pharmaceutical compositions.

5 cl, 7 dwg, 2 tbl, 609 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or pharmaceutically acceptable salts thereof: where: each of R1, R2, R3, R4 is independently selected from a group consisting of a hydrogen atom, a halogen atom, an aryl, a C5-6 heteroaryl having 1-3 heteroatoms in the ring which are selected from O, S and N, -OR5, -NR5R6, and -NR5COR6, where said aryl or C5-6 heteroaryl, having 1-3 heteroatoms in the ring selected from O, S and N, is unsubstituted or additionally substituted with one or more groups selected from a group consisting of alkyl, alkoxyl and halogen, each of R5 and R6 is independently selected from a group consisting of a hydrogen atom or an alkyl, where said alkyl is unsubstituted or additionally substituted with one or more groups selected from a group consisting of an aryl, haloaryl, hydroxyl and alkoxyl. The invention also relates to a pharmaceutical composition which inhibits protein kinase and contains a compound of formula I, a method of producing the compound of formula I, use of said compounds to produce a medicinal agent for treating disorders associated with protein kinase, and a method of modulating catalytic activity of protein kinase.

EFFECT: improved method.

10 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I:

or pharmaceutically acceptable salts thereof, wherein the values R1, R3, and R4 are specified in cl. one of the patent claim.

EFFECT: compounds inhibit the HCV replication that makes them applicable for preparing a pharmaceutical composition and a drug preparation for HCV infection.

16 cl, 3 tbl, 10 dwg, 30 ex

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