Derivatives of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylindoles, pharmaceutically acceptable salts thereof, having antiviral activity and method of producing said compounds

FIELD: chemistry.

SUBSTANCE: invention relates to an agent which has antiviral activity towards influenza A virus, which is a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl (or cycloheptyl)-3-alkoxycarbonylindoles of general formula (I) , where X denotes - H; n=1, 2; R3 denotes C1-C5alkyl; Alk denotes C1-C6alkyl; R1 and R2 are independently selected from C1-C4-alkyl, mainly CH3, or its pharmaceutically acceptable salts.

EFFECT: obtaining an agent which has antiviral activity towards influenza A virus.

2 dwg, 2 tbl, 3 ex

 

The invention relates to a new group of derivatives of 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl, as well as their pharmaceutically acceptable salts, possessing antiviral activity. These compounds can be used to obtain drugs for the prevention and treatment of viral diseases.

Known antiviral compounds and drugs based on them, as a rule, possess antiviral activity only against certain viruses. Therefore, the search for and creation of new compounds with antiviral activity, and create preparations on their basis are essential.

The mechanism of action of modern antiviral drugs by blocking a step in the reproduction of viruses in the cells of the infected person (person), which includes the step of attaching the virus to the cell and penetration inside her, embedding nucleic acid of the virus into the genome of the host cell, synthesis of DNA and RNA synthesis and Assembly of native proteins of the virus. Most of the available antiviral drugs is a nucleoside analogues. They are effective, however, after applying a number of patients possible rebound phenomenon, leading to exacerbation of disease. In addition, for a number of compounds with the anti-Christ. overuses activity is characterized by the development of resistance to them.

Currently, for the treatment of influenza is widely used in medical preparations having as active ingredients compounds of the group amantadine (amantadine and rimantadine) (EN 2214997). However, these drugs have side effects on the Central nervous system. An important direction in the search for new antiviral agents is the search for biologically active compounds on the basis of which can be created medicines, which would have a new mechanism of action. It can be a means to modulate (stimulate or inhibit) the immune response of the body. This tool is Arbidol (EN 2033156 and EN 2033157) represents 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole. Arbidol is able to stimulate various functions of the immune system and, as shown, has a preventive and therapeutic effect in viral infections. This Arbidol practically non-toxic and well tolerated by the healthy and the sick with the flu people. However, Arbidol insufficient to certain strains of viruses, such as influenza viruses a and B.

There are a number of other patent publications EP 1731506 A1, JP-63-188665 and CN 1482118)related to derivative 5-hydroxyindole-3-carboxylates having antiviral activity. Closest to the compounds of this image is to be placed are 5-hydroxyindole-3-carboxylates and their use as pharmaceuticals for the treatment and prevention of viral infections, such as hepatitis b and HIV infection, as described in EP 1731506 A1.

However, none of these publications is not received and are not disclosed compounds of the present invention, and their use as pharmaceuticals for treating or preventing viral infections, such as influenza a or b, as well as avian influenza.

The task of the invention was to find new indole derivatives having immunostimulatory activity simultaneously with high antiviral activity against specific viruses, such as influenza viruses a and b, as well as avian influenza.

According to the present invention offers derivatives of 1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonyl-4-diaminophenyl-5-hydroxyindole corresponding to General formula (I):

where X means hydrogen, chlorine, iodine, n=1 or 2

R3- C1-C3alkyl,

Alk means C1-C6alkyl group,

R1, R2independently selected from C1-C4-alkyl, mainly methyl, or R1R2together with the nitrogen atom (thegroup NR1R2) means a group corresponding to the formula

,,,,.

The invention also is refers to pharmaceutically acceptable salts of these compounds of General formula I. Salts can be obtained by conventional methods, for example by treatment of compounds of formula (I) with appropriate acids.

To pharmaceutically acceptable salts include, first of all, hydrochloride, mesylates, oxalates, etc.

The preferred compound is 5-hydroxy-4-dimethylamino-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl (compound A) and its hydrochloride.

The synthesis of the compounds is carried out according to scheme 1:

In this scheme, R1, R2, R3, X, Alk, n have the above values.

Under this scheme 1 the method is as follows:

When interacting alkylcarboxylic ether of the formula

R3COCH2COOAlk,

preferably acetoacetic ester, cyclohexylamino or cycloheptylamine in the presence of catalytic amount of acid, for example hydrochloric acid, in an environment of a solvent, for example benzene or toluene, receive appropriate alkilany ether β-cyclohexyl (or cycloheptyl) amino-alkenilovyh acid mainly With1-C6alkilany ether β-cyclohexyl (or cycloheptyl)aminocrotonic acid of formula (II)

When interacting ether of the formula (II) with benzoquinone get 5-hydroxy-2-alkyl - 1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl forms the crystals (III)

Then the compound of formula (III) is subjected to aminomethylpropanol corresponding bis-aminomethane General formula:

CH2(N(R1R2)2)2

under the reaction conditions, manniche to obtain the corresponding 5-hydroxy-4-aminomethyl-2-alkyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl formula 1A:

The values of the radicals R1, R2, R3, X, Alk, n all structural formulas such as described above.

When galoidirovaniya the compounds of formula (III) are obtained the corresponding 5-hydroxy-6-halogen-2-alkyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl formula (IV)

The compound (IV) then aminomethylated corresponding compound of General formula

CH2(N(R1R2)2)2

under the reaction conditions, manniche, to obtain the corresponding 5-hydroxy-6-halogen-4-aminomethyl-2-alkyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl formula 1B

The values of the radicals R1, R2, R3, X n such as described above.

To obtain the compounds of formula 1A or 1B, where the group NR1R2means a group corresponding to the formula

,,, ,,

it is preferable to use as aminometilirovannogo agent corresponding cyclic secondary amine and formaldehyde. Upon receipt of compounds 1A, where each of R1and R2mean, for example, methyl, can also be used as aminometilirovannogo agent is formaldehyde and the corresponding dialkylamino.

The resulting products are isolated in free form or in the form of pharmaceutically acceptable salts.

Proposed according to the present invention compounds are active against different strains of influenza virus. While there are differences in the effectiveness of the proposed connections and analog - Arbidol against different strains. The proposed compounds are also effective against other viruses and thus are not nucleoside analogues. This suggests that the compounds of the present invention will join the list of connections with "soft", not affecting the metabolic processes in the cells mechanism of action. Furthermore, the method of obtaining compounds simpler and involves fewer stages than getting known analogues. Therefore, the method of obtaining the proposed connection is more profitable.

The method of obtaining the proposed compounds does not require the use of unpleasant and poisonous, and the output connections, such as thiophenol.

The examples below illustrate in more detail the present invention.

The way to obtain 5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl (A).

Scheme of synthesis of 2.

Example 1. Ethyl ester of β-cyclohexyl aminocrotonic acid(II).

To 13 g (0.1 mol) of acetoacetic ester in 20 ml of toluene added 11.9 g (0.12 mol) of cyclohexylamine and 1 drop of concentrated HC1. Leave at room temperature for a day. Then distilled water released from the nozzle Dean-stark. The toluene evaporated in vacuo, the residue is distilled. BP. 130-134°C /1 mm1,514. Output (II) of 18.5 g (87%).

Example 2. 5-hydroxy-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl(III).

To a solution of 2.1 g (0.01 mol) (II) in 10 ml of glacial acetic acid while stirring add 1.08 g (0.01 mol) of 1,4-benzoquinone. The reaction mixture is left at room temperature for a day. The formed precipitate is filtered off, washed with cold acetic acid and dried. Output (III) 0.6 g (20%), TPL 237°C (from acetic acid).

Found, %: C 71,14; H 7,87; N 4,78. C18H23NO3. Calculated C 71,74; H Of 7.69; N 4,65.

Example 3. 5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl (A).

A mixture of 1.2 g (0,004 mol) (III), 0.9 ml of bis(dimethylamino)methane in 10 ml of dioxane is boiled for 4 casabona distillation dioxane in vacuo add 5 ml of alcohol, cooled, the precipitate filtered off. Yield 1.0 g (69,7%), TPL 141-142°C (from alcohol).

Found, %: C 70,25; N 8,32; N 7,72. C21H30N2O3. Calculated: C 70,35; N 8,44; N Of 7.82.

The hydrochloride is obtained by adding HCl in ether to a solution of the base in acetone, TPL 194-195°C (from ethanol with ether).

Found, %: C 63,93; N. Of 7.70; N 6,99. C21H31ClN2O3. Calculated With 63,87; N To $ 7.91; N 7,09.

Under similar conditions using the appropriate starting compounds get:

5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cycloheptyl-3-ethoxycarbonylethyl,

5-hydroxy-4-diethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl,

6-chloro-5-hydroxy-4-dimethylaminomethyl-2-ethyl-1-cyclohexyl-3-ethoxycarbonylethyl,

6-iodine-5-hydroxy-4-dimethylaminomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl.

When processing compounds corresponding acid salts were obtained in these compounds.

Using the appropriate parent compound (III), formaldehyde and cyclic secondary amine under the reaction conditions, manniche receive the following connections:

5-hydroxy-4-piperidinomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl and its hydrochloride

5-hydroxy-4-morpholinomethyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl and its hydrochloride

5-hydroxy-4-(N-methylpiperazine)methyl-2-ethyl-1-cyclohexyl-3-ethoxycarbonylethyl, his guide is chlorid and mesilate,

5-hydroxy-4-(N-benzylpiperazine)methyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl and its hydrochloride

5-hydroxy-4-(N-phenylpiperazine)methyl-2-methyl-1-cyclohexyl-3-ethoxycarbonylethyl, its oxalate and hydrochloride.

Salts of the compounds were obtained by treatment of the bases of the corresponding acid.

The identity of the products obtained is confirmed by chromatographic system

the benzene-alcohol 10:2 plates Silufol UV 254.

Was studied in vitro antiviral activity of these compounds was detected Antigrippin activity of these compounds against influenza viruses A.

Antiviral activity.

Study of the activity of a compound As influenza virus And enzyme-linked immunosorbent assay (ELISA) was performed according to the following scheme: on the monolayer of cells MDCK 96 hole panel made the analyzed compound (pre-dissolved in ethanol, then in a nutrient medium MEM). To viral control was added 100 μl of the same medium, and the cell control - 200 ál. The panels were incubated at 37°C in an atmosphere of 5% CO2within two hours.

When determining the effect of the antiviral drugs on the expression of viral antigens to the cells after their incubation with compound a was added to a ten-fold dilution of the virus with regard to drug cultivation(1:5, 1:50, 1:500 etc) in a volume of 100 μl of MEM medium. the Annelie incubated in an incubator in an atmosphere of 5% CO 2for 24 hours at 37°C.

The medium was removed, and the cells were fixed with 80% acetone in phosphate-buffered saline PBS for 15-20 minutes in a volume of 100 μl, and then well dried and washed with a solution of PBS. Then the cells were added to 100 ál of ELISA buffer (phosphate-saline buffer with 1% fetal serum and 0.05% TWEEN 20) and incubated at 37°C for 30 minutes After removal of the solution to the cells was added 100 μl of monoclonal antibody (MAB) to the internal proteins of M and NP of influenza a virus at a dilution of 1:1000 in ELISA buffer. After incubation with the antibody for 1 hour at 37°C and subsequent 2-fold the washing, the wells were made in 100 μl of rabbit IgG against mouse IgG labeled with horseradish peroxidase at a dilution of 1:5000 in ELISA buffer and incubated 1 hour at 37°C. After 3 times washing alloy peroxidase was revealed by adding to the wells, 100 μl of 0.05% solution of orthophenylphenol (OFD) 0,003% citrate buffer pH 5.0, containing 0,003% H2O2(abstractly buffer). Panel withstood 15-30 minutes in the dark until a yellow colour, the reaction was stopped by adding to each well 50 µl 1H H2SO4. Next, we measured the optical density (OD) on automatic spectrophotometer at a wavelength of 492 nm. As control was used wells, uninfected by the virus.

The percentage inhibition of viral reproduction connection As determined by the formula: percentage of inhibition = 100-(OD of experience OP cell control/OD virus control in the absence of compound - OP cell control)×100. For one point of experience used three holes of the panel. The concentration of the drug or compound that reduces the value of OD at 50%, took over the minimum inhibitory concentration (MIC50).

Table 1
Minimum inhibitory concentration (MIC50and the potency of the compound As compared to the reference virus A/New Caledonia/20/99 (H1N1) in experiments in vitro
ConnectionSolventMICK50µg/mlActivity at 10 μg/ml %
ArbidolAlcohol6,0to 89.5
ConnectionAlcoholof 5.496,5

To determine the effectiveness of compounds And on the model of influenza pneumonia in mice.

Experiments were performed on 60 white mice weighing 12-15, Animals were infected intranasally under light ether anesthesia influenza virus A/Aichi/2/69 (H3N2) (10 LD50). Tested the e compounds were administered per os at a dose of 60 or 15 mg/kg/day. The treatment was performed according to the following scheme: for 24 hours and 1 hour before infection, then 2 times a day (at 8 am and 8 PM) for 5 days. Chemotherapeutic activity of Arbidol and connections And on the model of influenza pneumonia mice was evaluated by two criteria: a measure of protection against lethal viral infection and the increase in the average life span of the treated animals compared with the control group. The average lifespan of mice was calculated by the formula:where f is the number of mice dead at day d (surviving mouse included in f, d = 16), n is the number of mice in the group.

Table 2
The effectiveness of the compounds As compared with Arbidol on the model of influenza infection in mice (virus A/Aichi/2/69).
Connection
of
SurvivalMortality, %Reduction of mortality, %The average lifespan, days
Arbidol, 60 mg/kg/day6/10405010,8
Arbidol, 15 mg/kg/day3/1070207,3
Connection And 15 mg/kg/day5/8405011,5
Virus control (10 LD50)1/10907,2

Thus, the results obtained indicate virousspecificakih activity of the claimed compounds. Connection And in vitro experiments were slightly more Arbidol (table 1).

In animal experiments, the compound a was more active Arbidol. So the effectiveness of the compound And the dose of 15 mg/kg/day in the treatment of influenza pneumonia mice was equal to the effectiveness of Arbidol in a dose 4 times higher (60 mg/kg/day). At the dose of 15 mg/kg/day Arbidol was almost not active (table 2).

The tool, which has antiviral activity against influenza a and representing a derivative of 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylmethyl General formula (I)

where X is hydrogen, n=1 or 2
R3- C1-C5 Alk means C1-C6alkyl group,
R1, R2independently selected from C1-C4-alkyl, mainly methyl, or its pharmaceutically acceptable salt.



 

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9 cl, 2 dwg, 15 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new 3-amino-1-arylpropylindoles of formula I: or to its pharmaceutically acceptable salts, where: p is equal to 1 or 2; Ar means: indolyl, 2,3-dihydroindolyl, indazolyl, benzimidazolyl, benzofuranyl, and each can be substituted; R1 means: phenyl, naphthyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isoxazolyl, pyrazolyl, quinolinyl, aryl-C1-6alkyl where each can be substituted; C3-6cycloalkyl; branched C1-6alkyl; R2 and R3 each independently stands for: H, C1-6alkyl; OH-C1-6alkyl; benzyl; or R2 and R3 together with nitrogen atom whereto attached can form optionally substituted tetra-heptamerous ring, optionally with additional heteroatom chosen from N, O; Ra means H, C1-6alkyl; Rb means H, C1-6alkyl; OH; Rc and Rd each independently means H, C1-6alkyl; Or one of R2 and R3 together with one of Ra and Rb and atoms whereto attached can form penta- or hexamerous ring, optionally with additional heteroatom chosen from O, N; or one of R2 and R3 together with one of Rc and Rd together with atoms whereto attached, can form tetra-hexamerous ring, optinally with additional heteroatom chosen from O, N; Rc means H, C1-6alkyl; provided when p =1, Ra, Rb, Rc and Rd mean H, Ar means indole-1-yl and R1 means C6H5, then R2 and R3 do not mean CH3 and do not form hexamerous ring, and when Ar means indole-3-yl, p =1, Ra, Rb, Rc and Rd means H and R1 means C6H5-, 3-OCH3C6H5- then R2 and R3 do not mean simultaneously H, and when p =1, Ra, Rb, Rc and Rd mean H, Ar means indolyl and R1 means thienyl, pyridinyl, quinolinyl, then one of R2 and R3 means H, and another means C1-6alkyl where possible substitutes are presented in cl.1 of.

EFFECT: compounds express activity of double inhibition serotonin reuptake, possibility to use thereof in making a pharmaceutical composition and a medical product.

32 cl, 7 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to gynecology and concerns treatment of patients with sterility induced by anovulation at the background of chronic and acute inflammation of small pelvis organs. For this purpose mixture of the following composition is introduced paracervically: amoxicillin 1000 mg, clavulanic acid 200 mg, longidase 1500 U and Novocain in form of 0.5% solution - 8 ml. Preparation is introduced 1 time a day during 10 days. Additionally serotonin in dose 1.0 ml 2 times a day during 5 days is introduced.

EFFECT: method ensures normalisation of ovulation and menstrual cycle, increase of libido, elimination of premenstrual syndrome, algodismenoria, acne in short terms with possibility of treatment in the outpatient setting.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives of formula I: , where: Ra is H, C1-4alkyl; one of Ra, Rc, Rd and Re is C1-4alkyl; and the other three substitutes are H; or Rb, Rd, Re are all H; and R is a radical of formula (a): , where R1 is -(CH2)n-NR3R4, where each of R3 and R4 are independently H, C1-4alkyl; n is 0, 1, 2; R2 is H; halogen; or its pharmaceutically acceptable salt.

EFFECT: wider field of use of the compounds.

8 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indole-alanine derivatives of formula I: , where: R1 is phenyl, naphthyl, where phenyl is substituted with one or two halogen atoms, C1-6 alkyls, C1-6 alkoxy or phenyl C1-6 alkyls; and R2 is H, C1-6 alkyl; in free form, in hydrate form or in form of a pharmaceutically acceptable salt. Formula I compounds exhibit selective agonist activity towards S1P4 receptor, at least ten times more selective towards one or more of S1P1, S1P2, S1P3 or S1P5 receptors.

EFFECT: possibility of using derivatives in a pharmaceutical composition.

7 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives with formula I , where: Ra is H; C1-C4alkyl; one of Rb, Rc, Rd and Re is C1-C4alkyl, and the others are H; or Rb, Re, Rd and Re are all H; and R is a radical with formula (a), (b) and (c), presented in the claim.

EFFECT: compounds inhibit protein kinase C (PKC), which allows for their use in making a medicinal agent for treating or preventing diseases or disorders mediated by T lymphocytes and/or PKC, particularly during transplantation.

8 cl, 11 tbl, 47 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to experimental ophthalmology, and can be applied for suppression of positive regulation of short form of c-Maf transcription factor in processed with steroids or transforming growth factor β2 (TGF β2) cells of trabecular net. For this purpose introduced is antagonist c-Maf, also possessing inhibiting activity with respect to cyclin-dependent kinase cdk2, for instance purvalanol A.

EFFECT: invention explains mechanism and possible new approach to treatment of primary open-angle and steroid glaucoma.

4 cl, 1 tbl, 7 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

FIELD: medicine.

SUBSTANCE: invention covers new compounds of formula (I) where: one of groups R6, R7 and R8 meets formula (II) and groups X, Y1-Y4, R1-R14 and n possess the values specified in the patent claim, and also their pharmaceutically acceptable salts. Compounds I show activating effect with respect to PPARδ and/or PPARαreceptors.

EFFECT: applicability of compounds for treatment and prevention of the diseases modulated by PPARδ and PPARα agonists.

22 cl, 8 dwg, 1 tbl, 21 ex

FIELD: medicine, pharmacology, pharmacy, medicinal biochemistry.

SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.

EFFECT: valuable medicinal properties of composition.

71 cl, 2 tbl, 3 ex

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