Dioxoanthracene sulphonate derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound having formula (I): wherein each of the groups R1, R2, R3 are independently H or C1-4 alkyl group or C2-4 acyl group; each of the groups R4 and R5 are independently H or the group of formula -SO3R6, wherein R6 is H or the C1-4 alkyl group or the C2-4 acyl group; provided at least one of the groups R4 and R5 is a group having formula -SO3R6, or a pharmaceutically acceptable salt thereof. The invention also refers to a method for preparing the specified compounds of formula (I) and a pharmaceutical composition possessing activity in the inhibition of IL-1 anti-inflammatory cytokines based on these compounds.

EFFECT: there are produced new compounds and pharmaceutical composition on their basis which can find application in medicine for treating an inflammatory or autoimmune condition.

17 cl, 4 dwg, 4 ex

 

The technical field to which the invention relates.

The present invention relates to certain derivatives of dioxoanthracene sulfonate, method of their production and the use of compounds as a medicine, in particular, in the treatment of conditions affected by proinflammatory cytokines groups IL-1, more specifically, inflammatory and autoimmune diseases, such as arthritis.

The level of technology

Known application of Reina, 4,5-dihydroxy-9,10-dioxo-2-intracisternally acid, and its deacetylating derived diacerein, in some pharmaceutical formulations. In particular, it is known the use of Reina and diacerein for the treatment of arthritis, more specifically, osteoarthritis and rheumatoid arthritis, for example as described in US 4,244,968, GB 1578452, EP 544880 B1, EP 636602 B1 and US 6,610,750, and psoriasis and related conditions, as described in EP 1248608 B1. It was also described the use of Reina and diacerein for the treatment of various conditions, including inflammatory diseases, autoimmune diseases, vascular diseases, pain as a drug, diabetic nephrosis.

It is believed that cytokines IL-1 (α, β) and TNF-α play a key role as mediators in inflammatory processes and the processes of destruction of cartilage. Also consider that IL-1 and TNF-α are involved in the mediation of biological response reactions to endotoxin and other infectious stimuli. An extensive overview of proinflammatory and anti-inflammatory cytokines was made Sagginario, doctor of medicine and Old, doctor of Sciences (C.A.Dinarello, MD et L.L.Moldawer, PhD) in the textbook for clinicians "Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis" ("Proinflammatory and Antiinflammatory Cytokines in Rheumatoid Arthritis", 2000, Amgen Inc.). The cytokines IL-1 and TNF-α are involved in the mechanism of a number of inflammatory and autoimmune conditions such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, psoriasis, Paget's disease, osteoporosis, inflammatory pelvic disease, including ulcerative colitis and Crohn's disease, endometriosis, granulomatous's granulomatosis, neurological dysfunction, such as Alzheimer's and Parkinson's disease, myeloma, myeloid leukemia, bone metastasis, diabetic nephrosis, chronic heart disease, arthrosclerosis, asthma.

It is known that diacerein and its active metabolite failure to comply inhibit the synthesis and activity of Pro-inflammatory catabolic cytokines groups of interleukin-1 (IL-1), in particular IL-1β. It was shown that the failure to comply and diacerein inhibit the expression of IL-6, IL-8 and other cytokines, such as necrosis factor tissue (TNF-α). In particular, inhibition Reina and diacerein inflammatory cytokines IL-1 and TNF-α have been described in WO 02/058681, WO 01/051044, the authors Imortal-Pelletier and colleagues (J.Martel-Pelletieret al. Journal of Rheumatology, 1998, 25 (4), 753-762) and Adoni with colleagues (.Douni et al. Arthritis, Res Ther, 2004, 6: R65-R72 Include).

In the chondrocytes of patients suffering from these diseases, there is a high level of expression of TNF-α and IL-1 compared with chondrocytes healthy people, and it is believed that this specific mechanism of action Reina as an inhibitor of IL-1 explains, at least partially, the effectiveness of Reina and diacerein in the treatment of certain arthritic conditions such as rheumatoid arthritis, osteoarthritis and psoriatic arthritis.

However, it was shown that the metabolite aloe-emodin present in diacerein, has a clastogenic effect in the cells of the colon and kidneys. So, genotoxicity aloe-emodina in the study using comet analysis reports, for example, Cooller with colleagues (S..Müller et al., Mutation Research 371, (1996), 165-173).

In addition, the lack of Reina and diacerein is their poor solubility in aqueous solutions, complicating the preparation of pharmaceutical dosage forms, of which a therapeutic tool becomes bioavailable. More specifically, poor solubility Reina and diacerein is a particular problem in the preparation of compositions for parenteral administration.

It is known that diacerein and its active metabolite failure to comply can cause a laxative effect in patients with long the treatment. It is believed that this laxative effect can be attributed, at least partly, on account of very poor solubility Reina and diacerein.

Currently, there is a need to provide other compounds for the treatment or therapy of the States that are affected by or involving proinflammatory cytokines groups IL-1, more specifically, inflammatory and autoimmune diseases, including arthritic disease.

It would be preferable to provide alternative compounds having activity to inhibit proinflammatory cytokines groups IL-1, which allows to eliminate some of the disadvantages Reina or diacerein.

It would also be preferable to provide a compound which has a high activity to inhibit proinflammatory cytokines groups of IL-1.

Disclosure of inventions

In the present work presents new pharmaceutical compounds of the formula

in which each group R1, R2, R3independently is H or C1-4alkyl group or a C2-4acyl group;

each of the groups R4and R5independently is H or a group of the formula-SO3R6where R6is H or C1-4alkyl group or a C2-4acyl group;

provided that at least one of the groups R 4and R5is a group of the formula-SO3R6.

According to a specific embodiment of the present invention features a compound of formula (I), in which groups R1, R2, R3and R4are H, and R5is-SO3R6(formula (III)).

The inventors unexpectedly found that the compounds of formula (I) can inhibit the production of proinflammatory cytokines groups of IL-1. It was also shown that the compounds of formula (I), where R4and/or R5is-SO3H also have the preferred properties of solubility.

One aspect of the present invention proposes a method of obtaining compounds of formula (I), which includes the handling of sulfuric acid corresponding compounds of formula (II):

in which each group R1, R2and R3independently are h

According to one aspect of the present invention features a pharmaceutical composition comprising a compound of formula (I), in combination with suitable pharmaceutically acceptable excipients.

According to other aspects of the present invention relates to the compound of formula (I), for use as drugs in the treatment of humans or animals, to the compound of formula I, to treat conditions that involve or are affected by cytokines of the group IL-1, more specifically, for the treatment of inflammatory or autoimmune diseases, to the use of compounds of formula (I), for preparing a medicinal product for treating conditions that involve or are affected by cytokines of the group IL-1, more specifically, for the treatment of inflammatory or autoimmune diseases, and treatment of conditions that involve or are affected by cytokines of the group IL-1, including the introduction to the patient a therapeutically effective amount of the compounds of formula (I).

Other objects and advantages of the present invention will become apparent from the claims and the following detailed description, examples and accompanying drawings.

Brief description of drawings

In figures 1(a), 1(b) and 1(C) shows1H-NMR spectrum of the compound of the present invention;

The figure 2 shows the mass spectrometric analysis of the same compounds of the present invention;

The figure 3 shows a bar chart reflecting the effects of the compounds of the present invention on the inhibition of production of IL-1β cytokine in human chondrocytes; and

The figure 4 shows a bar graph showing the dose-dependent inhibition of production of IL-1β cytokines in chondrocytes of human connection really to the invention.

The implementation of the invention

The present invention provides a compound of formula (I):

in which each group R1, R2, R3independently is H or C1-4alkyl group or a C2-4acyl group;

each of the groups R4and R5independently is H or a group of the formula-SO3R6where R6is H or C1-4alkyl group or a C2-4acyl group;

provided that at least one of the groups R4and R5is a group of the formula-SO3R6.

According to one embodiments of the invention R1and R2independently selected from H, C1-4alkyl group or a C2-4acyl group; R3is N, and R4and R5can be N or-SO3H, provided that at least one of the groups R4and R5is a group of the formula-SO3H. In the preferred embodiment, both groups R1and R2are either H or acetyl groups, both groups R3and R4are H, and R5is-SO3H.

According to one embodiments of the present invention R1, R2, R3are H, and R4and R5independently are H or-SO3H, provided that at least one of the groups R4and R5is-SO3H.

According to predpochtitelno embodiment of the present invention features a compound of formula (III) (6 sulfo-4,5-dihydroxy-9,10-dioxo-2-astratenkova acid):

The compound of the present invention may be in the form of pharmaceutically acceptable salts. More specifically, examines the salts of sodium, potassium or ammonium.

The compounds of formula (I) can be obtained according to the method of the present invention, which includes the processing of concentrated sulfuric acid compounds of the formula (II).

in which R1, R2and R3are H, to obtain the corresponding compound of formula (I), in the form of sulfonic acids. In the next step, the desired C1-4alkyl group or a C2-4the acyl group can be selectively replace using traditional methods. For example, reaction with C2-4acyl-halide, or corresponding acyl-anhydride to give the desired C2-4acyloxy group, reaction with alcohol C1-4for the formation of the corresponding ether, or, for example, reaction with diazomethane (CH2N2for the introduction of C1alkyl groups or C2-4alkyl-halide to introduce the corresponding C2-4alkyl groups. Depending on the desired substitution, if necessary, may be introduced known protective groups and derived using traditional methods.

Alternative sulfuric acid may be replaced prosernat acid.

Reaction with sulfuric acid Ave is doctitle carried out at a temperature from 60 to 120°C, preferably about 100°C.

The reaction time of acid can vary depending on, for example, from the reaction temperature used acid, the desired product (for example, di - or monotomidae the acid) and the like. As a General guidance on the reaction time, it is possible to consider a time from 1 hour to 48 hours, for example about 24 hours. The course of the reaction can preferably be tracked, for example, by HPLC, and stopping the reaction after the reaction to give the desired substituted product: di - or monosulfonated.

The product can be isolated in the form of a corresponding salt, for example, by adding a suitable metal halide (e.g., NaCl), or substance that forms the corresponding alkali metal (for example, NaOH, KOH or NH3). Consider salts include any pharmaceutically acceptable salt, e.g. sodium salt, potassium or ammonium.

Thus obtained compound of formula (I) can be cleaned using any suitable conventional purification method such as, for example, preparative HPLC or separation of liquid phases.

The compounds of formula (I) according to the present invention are active in the inhibition of Pro-inflammatory cytokines groups of IL-1.

In the course of research on human chondrocytes in vitro unexpectedly, it was shown that the connection is of formula (I) have a more pronounced activity to inhibit interleukin -1 (IL-1β) in comparison with Reina.

Preferably, the compounds of formula (I) can afford to avoid metabolite aloe-emodina present in diacerein.

In light of their activity in the inhibition of Pro-inflammatory cytokines groups IL-1, compounds of the present invention are considered for use in the treatment of conditions characterized by extremely high or increased level of IL-1.

Conditions that can be treated by the compounds of the present invention include inflammatory and autoimmune diseases. In a number of States that may be mentioned include rheumatoid arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, psoriasis, arthrosclerosis, Paget's disease, chronic heart disease, inflammatory pelvic disease, including ulcerative colitis and Crohn's disease, endometriosis, granulomatous's granulomatosis, neurological dysfunction, such as Alzheimer's and Parkinson's disease, myeloma, myeloid leukemia, bone metastasis, diabetic nephrosis, emphysema, and asthma.

One aspect of the present invention relates to a method for treating conditions characterized by elevated levels of IL-1 compared with healthy individuals, which includes an introduction to the patient an effective amount of the compounds of the present invention or its pharmaceutically acceptable salt. Such is Otaniemi preferably are inflammatory or autoimmune disease. More specifically state that are intended to treat, include inflammation of the joints, such as osteoarthritis or rheumatoid arthritis. It should also be mentioned psoriatic arthritis and psoriasis.

It is likely that the compounds of the present invention will be applicable in clinics for the treatment of many inflammatory and autoimmune diseases, as described above, due to their superior physical properties compared to Reina.

One aspect of the invention features a pharmaceutical composition comprising a compound of formula (I), in combination with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of the present invention can be designed for use in human or veterinary medicine.

The pharmaceutical composition of the present invention may have a composition suitable for administration by any method, including, for example, oral, intramuscular, intravenous, subcutaneous, rectal, outdoor, percutaneous, intranasal, intra-articular, sublingual and intraperitoneal route of administration.

Compositions for oral administration can include, for example, tablets, hard or soft gelatin capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules for recovery, syrups or emulsi is.

The compositions for parenteral administration can be in any suitable pharmaceutical form, for example, in the form of a sterile aqueous buffer solution or suspension for injection, sterile solution or suspension for injection in any other non-toxic acceptable for injecting the solvent or diluent, or in dried form, intended for recovery at the point of use.

The compositions of the present invention can be also presented in the form of compositions for external use, for example, in the form of a cream, gel, ointment or emulsion in water or an oil medium.

It is expected that the compounds of formula (I) according to the present invention will have a better solubility in water compared to Reina or diacerein, thanks to the presence of sulphonate groups. For example, it was shown that the compounds of formula (I) according to the present invention, in which the group R1, R2, R3are H, and the group R4and R5independently of one another are H or SO3H or both are SO3H, have particularly good solubility in aqueous solution. For example, the compound of formula (III) has a solubility in water of 1.2 mg/ml, whereas failure to comply and diacerein practically insoluble in water.

The good solubility of the compounds of the present invention p is positioned preferably these compounds parenterally, that is, by injection or infusion, more specifically, by intra-articular, intramuscular, intravenous or subcutaneous injection or infusion.

The pharmaceutical compositions can be prepared according to known methods using known pharmaceutical excipients and/or additives.

Discusses any conventional pharmaceutically acceptable excipients, for example diluting agents; binding agents; surfactants; lubricants; suspendresume agents; emulsifying agents; buffering agents that prevent clumping; water or oil carriers; substances for improving raspadaemosti tablets; preservatives; flavorings; sweeteners; dyes, in accordance with the selected method of administration.

Suitable dosage regimen will vary among others depending on such factors as therapeutic, the severity of the condition with regard to a patient who receives treatment. The usual daily dose can range from about 0.05 mg to about 150 mg per kg of body weight of the patient per day. As a rule, the daily dose is from about 10 mg to 500 mg per day, but can be considered a dose in the range from about 10 mg to about 250 mg per day. The amount of active ingredient in the same dosage form will depend on erecycling above factors, and on the selected method of administration, and will usually be in the range from 1 mg to 500 mg of the active ingredient in dosage form.

Below the invention will be illustrated in the following non-limiting examples.

EXAMPLES

Example 1

Getting 6-sulfo-4,5-dihydroxy-9,10-dioxo-2-intracisternally acid

Failure to comply (1 g), obtained by deacetylation of pure diacerein with a purity of more than 99%, was dissolved in concentrated sulfuric acid (100 ml). The solution was heated at 100°C with stirring for 24 hours. The course of the reaction was monitored in real time using HPLC until completion of the reaction. Then the reaction mixture is cooled and added to it 2 liters of water with stirring. The resulting solution was kept overnight at 4°C. Unreacted in the formation of salt material Reina was removed by centrifugation.

6 sulfo-4,5-dihydroxy-9,10-dioxo-2-astratenkova acid was precipitated as sodium salt by adding 110 g of sodium chloride. The resulting suspension was cooled at 4°C for one hour, then spent centrifugation to separate the solid product was dried under vacuum. Received 2,32 g of the product.

Secretion of salts:

The above product was added to water (115 ml) under stirring at 4°C for 30 minutes. Then spent zentrifugenbau the suspension and the supernatant liquid with residual salt was decanted from the sediment. This operation was repeated seven times until a constant conductivity (about 330 s/cm), which is measured using an instrument for measuring the electrical conductivity (radiometer CDM 206). Then the precipitate after centrifugation was dried under vacuum, having received 480 mg of product with a purity of 95.6% of according to the analysis by HPLC.

Example 2

Characterization

1H-NMR analysis:

Registration1H-NMR spectrum of the product obtained in example 1 were carried out in dimethyl sulfoxide (DMSO) on a Brucker spectrometer (Bruker®) at 400 MHz. The obtained spectra are shown in figures 1(a) and 1(C)shows the coincidence with the product 6-sulfo-4,5-dihydroxy-9,10-dioxo-2-intracisternally acid.

Range1H-NMR indicates the presence of four aromatic protons, two in metaprogram and two in the ortho-position, which confirms the fact that the substitution sulfopropyl ring, which was previously only one hydroxyl substituent. Chemical shift (shifts) in comparison with the calculated chemical shifts on the basis of discrete increments show that the substitution sulfopropyl occurred in the ortho-position.

Mass spectrometric analysis:

Mass spectrometric analysis of the product in example 1 was performed on the spectrometer Agilent 1100 LC-MS, ionization at atmospheric pressure and electrotactile the eating of negative ions. The obtained spectrum is shown in figure 2, has a peak at 364, and it coincides with the product 6-sulfo-4,5-dihydroxy-9,10-dioxo-2-intracisternally acid of formula (III).

Example 3

Obtaining the sodium salt of 6-sulfo-4,5-dihydroxy-9,10-dioxo-2-intracisternally acid

Failure to comply (1 g), obtained by deacetylation of pure diacerein with a purity of more than 99%, was dissolved in concentrated sulfuric acid (100 ml). The solution was heated at 100°C with stirring for 24 hours. The course of the reaction was monitored in real time using HPLC until completion of the reaction. Then the reaction mixture is cooled and added to it 2 liters of water with stirring. The resulting solution was kept overnight at 4°C. Unreacted in the formation of salt material Reina was removed by centrifugation. The PH of the supernatant is brought to 7.0 by adding 1 M NaOH. Then the product 6-sulfo-4,5-dihydroxy-9,10-dioxo-2-astratenkova acid in the form of its sodium salt was separated from the solution and purified by the method of preparative HPLC using obraniakowi chromatography on a silica column With 18 and using a mixture of methanol/water/H3PO4as eluent. Was allocated 1 g of the product, and characterized as a sodium salt of 6-sulfo-4,5-dihydroxy-9,10-dioxo-2-intracisternally acid using the methods of NMR and mass spectrometric analysis is as described in example 2.

Example 4

The study of inhibition of IL-1β in human chondrocytes in vitro

Studied the potency of the compound from example 1 and activity Reina on inhibition stimulated by lipopolysaccharide (LPS) production of IL-1β cytokine-controlname a normal patient and a patient suffering from osteoarthritis (OA).

Materials and methods:

Human cartilage was obtained during orthopedic surgery total hip joint arthroplasty as the result of traumatic fractures in normal patients or in patients with OA. Patients with OA were selected on the following criteria (1) bilateral OA, (2) diagnosis of moderate OA (grade I-III, Kellgren-Lawrence), confirmed by fluoroscopic examination and examination in the subject of pathology.

From cartilage samples obtained from four patients with OA and nine normal patients, preparing a suspension of isolated chondrocytes. The samples were obtained and maintained under aseptic conditions. The cartilage was cut into small fragments and incubated with 1 mg/ml clostridial collagenase in carbonate-bicarbonate buffer for 48 hours at 37°C. After separation of the cartilaginous framework of the chondrocytes were centrifuged at 1500 rpm for five minutes. For experience were used isolated chondrocytes suspended in culture medium (medium Needle, modify the new method of Dulbecco, with the addition of 10% of the stem cell factor). Cell viability was assessed by the method of exclusion Trypanosoma blue.

The chondrocytes were stimulated to produce IL-1β bacterial endotoxin (LPS) in vitro as follows:

Aliquot of sample 1×106cells/ml in culture medium were placed in 15-ml Falcon tubes and stood with shaking on a rotary shaker (100 rpm).

The chondrocytes were cultured for 48 hours in the presence of mucopolysaccharides (10 μg/ml) with 20 mg/ml Reina or increasing concentrations (1, 5, 10, 20 and 30 μg/ml) test compound (compound of example 1). The samples with the addition of a solution Reina was subjected to sonication for five minutes to minimize solubility problems associated with the hydrophobic nature of Reina. This was not a problem with solutions of the test compounds due to its good solubility.

Investigated the production of IL-1β by chondrocytes in culture medium for cultures grown from different samples using the kit enzyme-linked immunosorbent assay ELISA.

Figure 3 shows the results obtained when exposed to Reina and compounds from example 1 on the production of IL-1β LPS-stimulated normal chondrocytes and chondrocytes of patients with OA in the study using ELISA method. Figure 4 shows dozozawisim the th inhibition of production of IL-1β in normal chondrocytes when exposed to the compounds (compound of example 1). The results presented in figure 3, show that the compound of the present invention exhibits a significantly higher IL-1β - inhibitory activity compared to Reina. The results in figure 4 show that the compound according to the invention shows a marked inhibition of production of IL-1β, and the maximal level of inhibition achieved at a concentration of from 10 to 20 mg/ml

1. The compound having the formula (I):

in which each group R1, R2, R3independently is H or C1-4alkyl group or a C2-4acyl group;
each of the groups R4and R5independently is H or a group of the formula-SO3R6where R6is N or C1-4alkyl group or a C2-4acyl group;
provided that at least one of the groups R4and R5is a group having the formula-SO3R6,
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R1, R2independently are N or C1-4alkyl group or a C3-4acyl group, R3and R4are H, and R5is-SO3N.

3. The compound according to claim 1, having the formula (III):

4. The compound according to any one of claims 1 to 3 for use as a drug, the way the CSOs to inhibit the production of proinflammatory cytokines groups of IL-1.

5. The compound according to any one of claims 1 to 3 for treating conditions that are affected by or involving proinflammatory cytokines groups of IL-1.

6. The compound according to any one of claims 1 to 3 for use as a drug for the treatment of inflammatory or autoimmune condition.

7. The compound according to any one of claims 1 to 3 for the treatment of a condition selected from among the following: rheumatoid arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, psoriasis, arthrosclerosis, Paget's disease, chronic heart disease, inflammatory pelvic disease, including ulcerative colitis and Crohn's disease, endometriosis, granulomatous's granulomatosis, neurological dysfunction, such as Alzheimer's and Parkinson's disease, myeloma, myeloid leukemia, bone metastasis, diabetic nephrosis, emphysema, and asthma.

8. The connection according to claim 7, wherein the condition is selected from among the following: osteoarthritis, rheumatoid arthritis, psoriatic arthritis and psoriasis.

9. Pharmaceutical composition having activity in the inhibition of Pro-inflammatory cytokines groups IL-1, comprising the compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt in an effective amount as an active ingredient, and pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9, the call is connected with the fact, the composition is intended for parenteral administration.

11. The pharmaceutical composition according to claim 9, characterized in that the composition is intended for oral administration.

12. The pharmaceutical composition according to claim 9, characterized in that the composition is intended for external use.

13. Method of treatment of a condition in which or on which the influence of proinflammatory cytokines groups IL-1, which is the introduction to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.

14. Method of treating inflammatory or autoimmune diseases, which is the introduction to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 3, or its pharmaceutically acceptable salt.

15. Method according to item 13, wherein the disease is selected from among the following: osteoarthritis, rheumatoid arthritis, psoriatic arthritis and psoriasis.

16. The use of compounds according to any one of claims 1 to 3 for the preparation of medicines for treating conditions that are affected by or involving proinflammatory cytokines groups of IL-1.

17. Method of preparing compounds having the formula (I):

in which each group R1, R2, R3independently is H or C1-4alkiline the group or C 2-4acyl group;
each of the groups R4and R5independently is H or a group of the formula-SO3R6where R6is N or C1-4alkyl group or a C2-4acyl group;
provided that at least one of the groups R4and R5is a group of the formula-SO3R6,
or its pharmaceutically acceptable salt,
includes treatment with concentrated sulfuric acid compounds having the formula (II)

in which R1, R2, R3are N.



 

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3 cl, 7 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is an antimicrobial, anti-inflammatory and analgesic agent of a benzamidine derivative of empirical formula (C13H11N3O2), namely N-4-nitrophenylbenzamidine (I) as an active substance. It is shown that N-4-nitrophenylbenzamidine is low-toxic; it possess antimicrobial (on Gram-positive and Gram-negative bacteria), anti-inflammatory and analgesic activity.

EFFECT: these properties make it possible to suggest that N-4-nitrophenylbenzamidine may be used in medicine, as an ingredient of the drug preparation for specified application.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention discloses a product of modification of sulphanilic acid, and specifically n-(1,5-dihydro-3-methyl-8-R1-8-R2-9-hydroxy-[1,3]dioxepino[5,6-c]pyridinyl-6-azo)phenylsulphonic acid and salt forms thereof of general formula I: , where R1, R2 are selected from a group comprising: a hydrogen atom, methyl, a linear or branched alkyl or R1 and R2 together form a spirocycloalkyl group. Compounds of formula (I) have antibacterial activity, are more efficient with respect to both gram-negative bacteria Proteus vulgaris, Pseudomonas aeroginosa and gram-positive bacteria Staphylococcus aureus, and can be used in medicine and veterinary.

EFFECT: improved properties.

1 cl, 1 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to novel pyridyloxy derivatives or its pharmaceutically acceptable ester or a pharmaceutically acceptable salt of the mentioned derivatice or ester of general formula (I), wherein R represents a pyridyl group substituted by 1-3 groups independently specified in a group of substitutes A; the group of substitutes A represents a group comprising halogen atom, C1-C6 alkyl group and C1-C6 alkoxy group, and Me represents a methyl group. Also, the invention refers to specific compounds of formula (I), to a pharmaceutical composition and a receptor-γ activator/modulator on the basis of a compound of formula (I), to a method of treating and/or preventing a disease.

EFFECT: there are prepared novel pyridyloxy derivatives effective in treating the disease mediated by peroxisome proliferator activated receptor-γ (PPAR) γ.

37 cl, 2 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new lipid compound of general formula , wherein n=0; R1 and R2 are identical or different, and may be specified in a group of substitutes consisting of a hydrogen atom, a C1-C7alkyl group, a halogen atom and a C1-C7alkoxy group; X represents COR3 or CH2OR4, wherein R3 is specified in a group consisting of hydrogen, hydroxy, C1-C7alkoxy and amino; and R4 is specified in a group consisting of hydrogen, C1-C7alkyl or C1-C7acyl, Y represents C9-C21 alkene with one or more double bonds in E- or Z-configurations with the chain Y being unsubstituted and containing a double bond in the ω-3 position; provided R1 and R2 cannot simultaneously represent a hydrogen atom.

EFFECT: invention refers to pharmaceutical compositions containing the lipid compounds which are used for treating and/or preventing the conditions related to high NFkB functions, treating and/or preventing an inflammatory disease or a condition, lower plasma insulin and/or blood glucose levels, treating insulin resistance, treating and/or preventing peripheral tissue insulin resistance and/or diabetic condition, eg type 2 diabetes mellitus.

45 cl, 1 tbl, 1 dwg, 31 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: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and represents application of composition, including adapalene and benzoyl peroxide, in preparation of local medication, intended for application by patient who requires it to provide long-term treatment of acne vulgaris, where scheme of application of local medication includes application of therapeutically efficient quantity of composition for, at least, 9 months.

EFFECT: invention ensures achievement of stable positive effect in long-term treatment of acne with composition, including adapalene and benzoyl peroxide, as well as absence of side effects.

19 cl, 1 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to fizzy therapeutic form of ibuprofen, which includes (a) granule, which contains active ingredient, containing water-soluble ibuprofen salt and main filling agent, and (b) fizzy granule, which contains sour component and component, which forms carbon dioxide. Said fizzy therapeutic form is selected from fizzy tablet, having weight from 1000 to 1500 mg per 200 mg of ibuprofen, or drinkable granules, whose single dose has weight from 500 to 950 mg per 200 mg of ibuprofen.

EFFECT: claimed invention ensures obtaining fizzy therapeutic forms of ibuprofen with reduced relative weight per a single dose, pleasant taste and dissolving in water with formation of transparent solution.

13 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical composition for local application, which possesses antibacterial properties.

EFFECT: invention represents pharmaceutical stable semi-hard compositions for local application, which contain from 0.2 to 5 wt % of desfluoroquinolone compound, suitable for ointment or cream production.

24 cl, 5 ex, 15 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and cosmetology and represents a method for preparing an aqueous adapalene gel which involves the following stages: i) preparing a gel-forming composition A by mixing water and propylene glycol and adding a gel-forming agent after propylene glycol wherein the composition A additionally contains a preserving agent to be dissolved in propylene glycol at room temperature; ii) preparing an adapalene composition B by dispersing adapalene in water with a surfactant added; wherein the stages i) and ii) are concurrent, or any of the stages i) or ii) follow the other; iii) adding the adapalene composition B to the gel-forming composition A; iv) reducing pH by adding a neutralising agent to prepare gel with each stage conducted at room temperature.

EFFECT: invention provides improving the method for preparing the aqueous adapalene gel commercially.

15 cl, 2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is using water-soluble hybrid macromolecular compounds O-(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl-(1→6)-α-D-glucan and polyethylene glycol bis-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate as erythroprotective agents for phenylhydrazine poisoning. It is shown that the course intravenous introduction of the compounds has manifested erythroprotective action.

EFFECT: invention extends the range of agents applicable in integrated therapy of phenylhydrazine poisoning.

1 tbl, 3 ex

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