Pharmaceutical composition containing pyrazine derivative and method for using pyrazine derivative in combination

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical combination and to its use for treating an infection caused by influenza virus. The declared composition contains a pyrazine derivative of formula wherein R1 and R2 are identical or different, and each represents a hydrogen atom or a halogen atom; and R3 represent a hydrogen atom or a protective group for amino group or its salt, and, and a neuraminidase inhibitor. The neuraminidase inhibitor is specified in oseltamivir, zanamivir, peramivir or CS-8958.

EFFECT: invention provides preparing the combination which shows strong antiviral activity, smaller side effects and applicable for treating influenza.

12 cl, 8 tbl, 4 ex

 

TECHNICAL AREA

This invention relates to a pharmaceutical composition containing the derivative pyrazine or its salt, and one or more of the inhibitors of neuraminidase, which is applicable for treatment (e.g., treatment or prevention of viral diseases. In addition, this invention relates to a method of using the derived pyrazine or its salt and inhibitor(s) of the neuraminidase in combination for treatment (e.g., therapy or prevention) of influenza.

BACKGROUND of INVENTION

Infection caused by the influenza virus (hereinafter called the flu)is often fatal disease. In recent years there have been such viruses like the avian flu, which have a strong pathogenicity in humans. There is the threat of an avian flu pandemic.

However, medicines for the flu, much less than the antimicrobial agents or the like. For example, amantadine and oseltamivir, used at the present time, have problems such as resistance to them.

The method of application of anti-influenza virus in combination were discussed with the aim of reducing drug resistance of influenza virus, enhance therapeutic effects and/or reduce side effects, etc. But the number of drugs used in combination, Ogre is ichino, and they do not always give satisfactory effect.

For example, the neuraminidase inhibitors known as drugs that have an effect on the influenza virus. Neuraminidase, which is a prominent glycoprotein found on the surface of the influenza virus that are required for infection by influenza virus cells of the larynx or bronchi and proliferation has spread to neighboring ones of the cells. Inhibition of neuraminidase can suppress the spread of this flu virus to neighboring cells. For example, the neuraminidase inhibitor oseltamivir is converted in vivo to its active form, GS-4071, which exhibits antiviral activity so that it inhibits the neuraminidase of influenza virus (non-patent document 1). Oseltamivir and zanamivir are commercially available as neuraminidase inhibitors. These drugs are still being developed and studied.

On the other hand, it is known derived pyrazine possessing antiviral activity (patent document 1). It is derived pyrazine, as is well known, exhibits antiviral effect on the intracellular ribosyltransferase so that suppresses viral RNA polymerase (patent document 2).

However, until now, were not aware of any pharmaceutical composition comprising an inhibitor of neuraminidase and production is the top priority of pyrazine, either way the use of neuraminidase inhibitors and derived pyrazine in combination.

PATENT DOCUMENT 1: Description WO00/10569

PATENT DOCUMENT 2: Description WO03/015798

Non-PATENT DOCUMENT 1: Japanese Journal of Clinical Medicine, 2003, vol. 61, p. 1975-1979

Description of the INVENTION

There was a need for pharmaceutical compositions, which has strong antiviral activity, fewer side effects and is applicable for treatment (e.g., therapy or prevention) of influenza, and in the treatment of influenza.

Resolving PROBLEMS

This invention was made through the discovery that a pharmaceutical composition containing the derivative pyrazine represented by the following General formula [1] or its salt, and one or more of neuraminidase inhibitors:

where R1and R2are the same or different, and each represents a hydrogen atom or a halogen atom; and R3represents a hydrogen atom or a protective group for amino group,

possesses strong activity against influenza virus and is applicable for treatment of influenza, and that the method of using these compounds in combination is effective as a treatment for influenza.

Advantages of the INVENTION

The pharmaceutical composition containing the derivative pyrazine or with the l and one or more of the neuraminidase inhibitors, has sinergeticheskoj strong activity against influenza virus and is applicable for treatment (e.g., therapy or prevention) of influenza. The method of using these compounds in combination is effective as a treatment (e.g., therapy or prevention) of influenza.

The BEST WAY of carrying out the INVENTION

Hereinafter the invention will be described in detail.

In this description, unless otherwise specified, the halogen atom means fluorine atoms, chlorine, bromine and iodine; acyl group means, for example, formyl group, a linear or branched C2-12alkanoyloxy group (for example, acetyl, propionyl, butyryl, isovaleryl and pivaloyl), aryl-C1-6-alkylcarboxylic group (for example, benzylcarbamoyl), cyclic hydrocarbon carbonyl group (for example, benzoyloxy and naftolin), heterocyclic carbonyl group (for example, nicotinoyl, tenolol, pyrrolidinecarbonyl and furolo), succinimido group, glutaryl group, Malolo group, palolo group, and linear or branched α-aminoalcohol group (which may be protected at the N-end), derived from amino acids (examples of amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, g utmin, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, Proline and hydroxyproline); allyloxycarbonyl group means, for example, linear or branched C2-12-allyloxycarbonyl group, such as methoxycarbonyl, etoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, 2-ethylhexyloxymethyl, tert-butoxycarbonyl and tert-pentyloxybenzoyl; aracelikarsaalyna group means, for example, aryl-C1-6-allyloxycarbonyl group, such as benzyloxycarbonyl and ventilatsiooniga group; aryloxyalkyl group means, for example, vinyloxycarbonyl group; kalkilya group means, for example, aryl-C1-6is an alkyl group such as benzyl, diphenylmethylene, triticina, penicilina and naphthylethylene; alkoxyalkyl group means, for example, With1-6-alkyloxy-C1-6is an alkyl group, such as methoxymethyl and 1-ethoxyethyl; aracelikarsaalyna group means, for example, aryl-C1-6-alkyloxy-C1-6is an alkyl group, such as benzoyloxymethyl and penetrometer; aristocrata means, for example, phenylthiourea; alkylsulfonyl group means, for example, With1-6-alkylsulfonyl group, such as methylsulphonyl, ethylsulfonyl and propylsulfonyl; arylsulfonyl group means, in the example, benzosulfimide, toluensulfonyl and naphthalenesulfonyl group; dialkylaminoalkyl group means, for example, N,N-dimethylaminomethylene and N,N-Diethylaminoethanol group; aralkylamines group means, for example, benzylidene and naphthylethylene group; nitrogen-containing heterocyclic alkylidene group means, for example, 3-hydroxy-4-pyridylmethylene group; cycloalkylcarbonyl group means, for example, cyclopentadienyl and cyclohexylidene group; diarylphosphino group means, for example, diphenylphosphoryl group; dialkylphosphinate group means, for example, dibenzoylresorcinol group; oxygen-containing heterocyclic alkyl group means, for example, 5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethylene group; and a substituted silyl group means, for example, trimethylsilyloxy, triethylsilanol and tributylstannyl group.

The term "protective group for the amino group" includes all groups possible as a normal group protecting the amino group. Their examples include groups described in W. Greene et al., Protective Groups in Organic Synthesis, 3rded., p. 494-653, 1999, John Wiley & Sons, Inc. Their specific examples include an acyl group, allyloxycarbonyl group, aracelikarsaalyna group, aryloxyalkyl group, aracelio group, alkoxyalkyl the ing group, kalkylarksmall group, killigrew, alkylsulfonyl group, arylsulfonyl group, dialkylaminoalkyl group, aralkylamines group, nitrogen-containing heterocyclic alkylidene group, cycloalkylcarbonyl group, diarylphosphino group, dialkylphosphorous group, oxygen-containing heterocyclic alkyl group and a substituted silyl group.

Examples of salts of compounds of General formula [1]are applicable in this invention may include commonly known salts of hydroxyl groups.

Their examples may include: salts of alkali metals such as sodium and potassium; salts of alkaline earth metals such as calcium and magnesium; ammonium salts and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-fenamin and N,N'-dibenziletilendiaminom.

Preferable examples of salts include pharmacologically acceptable salts. The preferred salt is sodium.

Desirable examples of the compounds of General formula [1]used in this invention include the following compounds:

The compound represented the General formula [1], where R1is a hydrogen atom, R2is a fluorine atom and R3is the atom of the m hydrogen.

The compound of General formula [1]used in this invention, is obtained by using a combination of methods known in themselves experts in this field, and can be obtained, for example, in the production method, described in patent document 1.

Examples of neuraminidase inhibitor used in this invention include yourself compounds or their metabolites in vivo, has an overwhelming effect on neuraminidase, such as oseltamivir, zanamivir, peramivir, CS8958 and prunet (FRUNET). Preferred oseltamivir and zanamivir. More preferred oseltamivir.

Route of administration of the pharmaceutical compositions of this invention are not specifically limited, and can be administered intravenously, orally, intramuscularly, subcutaneously, by inhalation, by injection or other routes of administration. In addition, the derived pyrazine, we present the General formula [1]or its salt can be entered with a neuraminidase inhibitor simultaneously or in a specific order.

The pharmaceutical composition of the present invention is applicable for treatment (e.g., therapy or prophylaxis) of influenza.

The pharmaceutical composition of the present invention enables treatment (e.g., therapy or prophylaxis) more severe cases of influenza. In addition, the individual used drugs are silhoutette against influenza virus, even when they are used in a reduced amount. Therefore, their corresponding side effects may be reduced.

When using the pharmaceutical composition of the present invention, it can be generally mixed with pharmaceutical excipients used in the manufacture of medicines, such as an adjuvant, a carrier and diluent. Such drugs can be administered orally or parenterally in the form, such as tablet, capsule, powder, syrup, granule, pill, suspension, emulsion, solution, powder preparation, suppository, eye drops, nose drops, ear drops, band-AIDS, ointment or medication for injection, in the usual way. In addition, the route of administration, dose and frequency of injection can be selected in accordance with the age, body weight and symptoms of the patient. You can enter adult oral or parenteral (e.g., by injection, intravenous and rectal) in the form of one or more fractional doses at a dosage of from 0.01 to 1000 mg/kg per day.

EXAMPLES

Then, the invention will be described with reference to the examples of trials. However, they are not intended to limit the present invention.

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide (hereinafter referred to as T-705) was selected as a test compound. GS-4071 to the th is active in vivo form of oseltamivir, and zanamivir have been selected as neuraminidase inhibitors. In this context, GS-4071 used in these tests was obtained by extraction of Tamiflu (Tamiflu; industrially produced medicinal product), followed by hydrolysis according to the conventional method.

The test example 1

T-705 is selected as the test compounds. GS-4071 was selected as neuraminidase inhibitors.

(1) cell Culture MDCK

Cells of the kidney of the dog Madin-Darby (Madin-Darby Canine Kidney; hereinafter referred to as MDCK), cultured under conditions at 37°C in an atmosphere with 5% carbon dioxide environment Needle MEM, supplemented with 10% fetal bovine serum in the culture solution was separated using ethylenediaminetetraacetic acid, trypsin and suspended in the same medium, which is described above. The obtained cell suspension that contained 2×104cells in 100 μl were seeded, in turn, to the wells of 96-well plates. Cells were cultured over night in the conditions at 37°C in an atmosphere with 5% carbon dioxide to obtain a monolayer of MDCK cells.

(2) Infection with influenza virus and add medicines

Environment for testing was a medium obtained by adding the processed L-1 tosylamide-2-phenylethylenediamine (TFHC; TPCK) trypsin at a concentration of 3 μg/ml in the medium Needle MEM, containing the Yu 1% bovine serum albumin, with the addition of 60 μg/ml kanamycin and four to the normal concentration of vitamins.

The MDCK cells, obtained in section (1), washed with medium Needle MEME after removal of the supernatant liquid of the culture. Then to each well was added the following: 100 μl of eagle medium MEM containing bovine serum albumin and vitamins in a dual concentration in relation to the environment for testing; 50 μl of a solution with influenza a PR/8 (H1N1)), increased to 4.0×103PFU/ml medium Needle MEM containing processed TFHC trypsin in a fourfold concentration environment for testing; and 50 μl of eagle medium MEM containing T-705 or GS-4071 quadrupled compared to the target concentration (target concentration of T-705 (µg/ml): 0,0156; 0,0313; 0,0625; 0,125; 0,25; 0,5; 1; 2 and 4; and the target concentration of GS-4071 (µg/ml): 0,00313; 0,00625; 0,0125; 0,025; 0,05; 0,1; 0,2; 0,4 and 0.8) or containing T-705/GS-4071 (in a weight concentration ratio of 5:1) mixture in a fourfold compared to the target concentration.

After adding the drug, the cells were cultured in conditions at 35°C for 2 days with content in the atmosphere of 5% carbon dioxide.

(3) study of the uptake of neutral red

Cytopathic effect (the centre e)observed in the proliferation of influenza virus were evaluated by the methods described in J. Virol. Methods, 2002, vol. 106, p. 71-79 and Proc. Natl. Acad. Sci., 1998, vol. 95, p. 8874-8849.

p> After completion of cultivation in each well was added 0,033% solution of neutral red, diluted phosphate buffer, Dulbecco, not containing calcium/magnesium in the amount of 100 µl. The plate was left to stand at 35°C in the conditions of 5% carbon dioxide in the atmosphere. After two hours the solution from the wells was removed by aspiration. After two washing 100 μl of phosphate buffer, Dulbecco, not containing calcium/magnesium, to each well was added 100 μl of a mixed solution of buffer (pH 4.2; consisting of 0.1 mol/l sodium citrate, and 0.1 mol/l hydrochloric acid and ethanol in the ratio 1:1 by volume. The plate was left to stand at room temperature, protected from light. Thirty minutes later they measured the absorbance (540 nm) using a reading device for microtiter plate reader (BIO-RAD Model 550). Uninfected controls were obtained by adding instead of a solution with influenza virus in 50 µl medium Needle MEM containing processed TFHC trypsin in a fourfold concentration in relation to the environment for testing and subjected to the same procedures as the procedures for the test group, with subsequent absorption measurement. As for the control wells without sowing MDCK cells were subjected to the same procedures as for uninfected controls, with subsequent absorption measurement. Used eight holes on each is oncentration. Used the average value, and a numeric value obtained by subtracting the uptake in the control of values, measurement values for subsequent calculations of absorption. The value obtained by subtracting the absorption infected controls from the value of uninfected controls, was used as the value of total suppression of proliferation of the virus. The degree of suppression of proliferation of the virus in each test was calculated by the following formula:

The degree of suppression of proliferation of the virus = [(Absorption if one drug or combination of drugs) - (Absorption in infected control)]/[(Absorption uninfected control) - (Absorption in infected control)]

Analysis of effects combination

The concentrations of the individual drugs and the two drugs used in combination, the ratio of drugs in combination, and the degree of suppression of proliferation of the virus, using the release of SAS 8.2 (SAS Institute Japan Ltd.) according to the method of the average effect Chou et al. Of the methods presented in Advanced Enzyme Regulation, 1984, vol. 22, p. 27-55, used the equation for drugs, mechanisms of action are completely independent of one another (not mutually exclusive drugs) to calculate the values of CI. The combined effects were determined on the OS is ove values of CI at 50% inhibition of proliferation of the virus in accordance with the description in the article Taira et al. [Acta Medica Okayama., 2006, vol. 60, p. 25-34), where CI≤0,8 represents the synergies of 0.8<CI<1,2 represents additivity, and 1.2 ≤ is antagonism.

The degree of suppression of proliferation of the virus T-705, used separately, GS-4071 used separately, and the combination of these drugs is presented in Table 1. The results of the analysis using these values, presented in Table 2.

/tr>
Table 1
Use one
T-705
Use one
GS-4071
The combined use
T-705 and GS-4071
Conc.
(ág/ml)
Degree
suppression
Conc.
(ág/ml)
Degree
suppression
Conc.
(ág/ml)
Degree
suppression
0,01560,0190,003130,0190,018730,040
0,03130,0670,006250,11 0,037550,21
0,06250,097of 0.01250,140,0750,41
0,1250,270,0250,250,150,59
0,250,430,050,290,30,73
0,50,600,10,420,60,96
10,850,20,611,20,88
20,930,40,732,40,95
41,00,80,844,80,94

Table 2
The ratio of drug
in combination
(T-705: GS-4071)
The value of CI at 50% inhibition
5:10,66

With the combined use of T-705 and GS-4071 (active form of oseltamivir in vivo) showed stronger Energeticheskie suppressive effects on the proliferation of the virus than reflected in the use of one drug.

The test example 2

T-705 was selected as the test compounds. Zanamivir was selected as an inhibitor of neuraminidase. The test was performed in the same manner as in the method described in test example 1.

The degree of suppression of proliferation of the virus T-705, used separately, zanamivir, applied separately, and the combination of these drugs is presented in Table 3. The results of the analysis using these values, presented in Table 4.

0,89
Table 3
Use one
T-705
Use one
of zanamivir
The combined use
T-705 and zanamivir
Conc.
(ág/ml)
Degree
suppression
Conc.
(ág/ml)
Degree
suppression
Conc.
(ág/ml)
Degree
suppression
0,06250,0620,00310,0620,018750,10
0,1250,170,006250,120,03750,23
0,250,34of 0.01250,230,0750,38
0,50,640,0250,280,150,69
10,770,050,490,30,87
20,10,600,60,94
0,20,67
0,40,75

Table 4
The ratio of drug
in combination
(T-705:zanamivir)
The value of CI at 50% inhibition
5:10,38

With the combined use of T-705 and zanamivir showed stronger Energeticheskie suppressive effects on the proliferation of the virus than the effects that occur when one drug.

The test example 3

T-705 was selected as the test compounds. GS-4071 was selected as neuraminidase inhibitors. The test was performed in the same manner as in the method described in test example 1, using as influenza a / Victoria/3/75 (H3N2).

The degree is davleniya proliferation of the virus T-705, used separately, GS-4071 used separately, and the combination of these drugs is presented in Table 5. The results of the analysis using these values, presented in Table 6.

Table 5
Use one
T-705
Use one
GS-4071
The combined use
T-705 and GS-4071
Conc.
(ág/ml)
Degree
suppression
Conc.
(ág/ml)
Degree
suppression
Conc.
(ág/ml)
Degree
suppression
0,1250,0260,0031250,0860,018750,15
0,250,090,006250,140,03750,37
0,50,42of 0.01250,44 0,0750,72
10,760,0250,540,150,92
20,860,050,680,31,03
40,940,10,80
0,20,88

Table 6
The ratio of drug
in combination
The value of CI at 50% inhibition
5:10,36

With the combined use of T-705 and GS-4071 (active form of oseltamivir in vivo) showed stronger Energeticheskie suppressive effects on the proliferation of the virus than reflected in the use of one drug.

the example test 4

T-705 was selected as the test compounds. Zanamivir was selected as an inhibitor of neuraminidase. The test was performed in the same manner as in the method described in test example 3.

The degree of suppression of proliferation of the virus T-705, used separately, zanamivir, applied separately, and the combination of these drugs is presented in Table 7. The results of the analysis using these values, presented in Table 8.

Table 7
Use one
T-705
Use one
of zanamivir
The combined use
T-705 and zanamivir
Conc.
(ág/ml)
Degree
suppression
Conc.
(ág/ml)
Degree
suppression
Conc.
(ág/ml)
Degree
suppression
0,1250,026of 0.01250,0740,01875to 0.032
0,25 0,0920,0250,140,03750,12
0,50,420,050,270,0750,27
10,760,10,400,150,70
20,860,20,600,30,87
40,940,40,710,60,94
0,80,81

Table 8
The ratio of drug
in combination
The value of CI at 50% inhibition
5:1 0,25

With the combined use of T-705 and zanamivir showed stronger Energeticheskie suppressive effects on the proliferation of the virus than reflected in the use of one drug.

As can be seen from the results, when combined application of the derived pyrazine General formula [1] or its salt and different neuraminidase inhibitors appears Energeticheskaya activity against influenza virus, and it is effective for the treatment (e.g., therapy or prophylaxis) of influenza.

The POSSIBILITY of APPLICATION IN INDUSTRY

The pharmaceutical composition containing the derivative pyrazine or its salt, and one or more of the neuraminidase inhibitors, has high sinergeticheskoj activity against influenza virus and is applicable for treatment (e.g., therapy or prophylaxis) of influenza. The method of using these compounds in combination is effective as a treatment (e.g., therapy or prophylaxis) of influenza.

1. Pharmaceutical combination for the treatment of infections caused by influenza virus containing the derived pyrazine, General formula, or its salt
,
where R1and R2are the same or different, and each represents a hydrogen atom or a halogen atom; and R3represents a hydrogen atom, and one or more of inhibi the Directors neuraminidase, where the neuraminidase inhibitor is oseltamivir, zanamivir, peramivir or CS-8958.

2. The pharmaceutical combination according to claim 1, where R1represents a hydrogen atom, R2represents a fluorine atom, and R3represents a hydrogen atom.

3. The pharmaceutical combination according to claim 1 or 2, where the neuraminidase inhibitor is oseltamivir.

4. The pharmaceutical combination according to claim 1 or 2, where the neuraminidase inhibitor zanamivir is.

5. The pharmaceutical combination according to claim 1 or 2, where the neuraminidase inhibitor is peramivir.

6. The pharmaceutical combination according to claim 1 or 2, where the neuraminidase inhibitor is CS-8958.

7. Applying a combination of the derived pyrazine following General formula or its salt
[Formula 2]
,
where R1and R2are the same or different, and each represents a hydrogen atom or a halogen atom; and R3represents a hydrogen atom and one or more neuraminidase inhibitors, where the neuraminidase inhibitor is oseltamivir, zanamivir, peramivir or CS-8958, for the treatment of infections caused by influenza virus.

8. The use according to claim 7, where R1represents a hydrogen atom, R2represents a fluorine atom, and R3represents a hydrogen atom.

9. The use according to claim 7 or 8, wherein the neuraminidase inhibitor is osellame the er.

10. The use according to claim 7 or 8, wherein the neuraminidase inhibitor zanamivir is.

11. The use according to claim 7 or 8, wherein the neuraminidase inhibitor is peramivir.

12. The use according to claim 7 or 8, wherein the neuraminidase inhibitor is CS-8958.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

, where A denotes CH or N; R1 is selected from a group consisting of: cycloalkyl which is unsubstituted or substituted with hydroxy, lower hydroxyalkyl or lower alkoxy, 1-hydroxy-2-indanyl, lower hydroxyalkyl, lower hydroxy haloalkyl, lower hydroxy alkoxyalkyl, CH2-CR9R10-cycloalkyl and -CR11R12- COOR13; R9 denotes hydrogen or lower alkyl; R10 denotes hydrogen, hydroxy or lower alkoxy; R11 and R12 independently denote hydrogen or lower alkyl; R13 denotes lower alkyl; R2 denotes hydrogen; or R1 and R2 together with the nitrogen atom with which they are bonded form a morpholinyl ring; R15 is selected from a group consisting of lower alkoxyalkyl, cycloalkyl and furanyl, substituted with halogen; R17 is selected from a group consisting of hydrogen, lower alkyl and lower haloalkyl; R4 and R8 independently denote hydrogen or halogen; R5 and R7 are independently selected from a group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower haloalkyl, lower haloalkoxy and cyano; R6 is selected from a group consisting of hydrogen, lower alkoxy, halogen, lower haloalkyl, lower haloalkoxy and cyano; and pharmaceutically acceptable salts thereof. The invention also relates to use of said compounds to produce medicinal agents for treating and/or preventing diseases which can be cured by HDL-cholesterol raising agents and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be useful in treating diseases which can be treated with HDL-cholesterol raising agents are obtained and described.

36 cl, 164 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a coformulated drug exhibiting antituberculous action and representing a solid dosage form which contains as an active principle a formulation of rifampicin, isoniazid, pyrazinamide, and a zinc-containing compound, and pharmaceutically acceptable excipients. The zinc-containing compound is zinc salt, preferentially zinc sulphate.

EFFECT: pharmaceutical composition under the invention is characterised by high efficacy and provides synergetic antimycobacterial activity when using the formulation of rifampicin, isoniasid, pyrazinamide and zinc sulphate as an antituberculous drug as compared with a formulation of standard antituberculous drugs.

9 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to animal breeding and veterinary science. There are declared an antiviral agent for animals, animal feedstuff, and a method for murrain treatment and prevention in animals. The antiviral agent and feedstuff contain 3-oxo-3,4-dihydro-2-pyrazinecarboxamide or its salt. The method for murrain prevention and treatment includes prescription of 3-oxo-3,4-dihydro-2-pyrazinecarboxamide or its salts.

EFFECT: group of inventions is effective for murrain prevention and treatment in pig and sheep family animals.

10 cl, 5 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds selected from a group comprising piperazine compounds of formula I: , where X is -CH2- or a bond; n equals 1; R1 is alkyl; cycloakyl; hydroxyethyl; benzo[1,3]dioxolyl; phenyl, which can be mono-substituted with a halide, alkyl, alkoxy, -CF3 or alkylcarbonyl; or phenyl which is di- or tri-substituted with substitutes independently selected from alkyl and halide; pyridyl which can be mono-substituted with a halide, alkyl or -CF3; furanyl which can be mono-substituted with methyl, hydroxymethyl or bromine, or furanyl which is disubstituted with an alkyl; thienyl which can be mono-substituted with methyl or chromium; pyrimidinyl; isoquinolinyl; benzhydryl; imidazolyl optionally mono-substituted with an alkyl; or thiazolyl; or X is -C(=O)- and R1 is hydrogen; R2 is indolyl, imidazolyl optionally mono-substituted with alkyl; phenyl which can be mono-substituted with a halide, alkyl, hydroxy or cyano, or phenyl which is disubstituted with a halide; pyridyl; benzothienyl; thiazolyl or thienyl; R3 is indolyl, pyridyl which can be mono-substituted with alkoxy, alkoxyalkoxy, NR31R32, morpholine, piperadine, oxopiperidinyl, oxopyrrolidinyl, pyridyl or phenyl; or phenyl which is mono-substituted with phenyl, pyridyl, alkyl, alkoxy, dialkylamino, morpholine, N-benzyl-N-alkylamino, (dialkylamino)alkoxy, phenylalkoxy or tetrahydroisoquinolinyl; or R3 denotes the group: , where Z is phenyl or pyridyl; R31 is 2-C1-C5alkoxyethyl, phenyl, pyridyl, phenylalkyl, hydroxyalkylcarbonyl, alkylcarbonyl, cycloalkylcarbonyl or phenylcarbonyl; R32 is hydrogen or methyl; R35 is alkyl, alkylcarbonyl, phenyl, pyridyl or pyrimidinyl; and R4 is phenyl-CH=CH-, where the phenyl can be mono-, di- or tri-substituted with substitutes independently selected from halide, alkyl, alkoxy and -CF3; or phenyl-CH2-CH2, where the phenyl is disubstituted with -CF3; and to optically pure enantiomers thereof, mixtures of enantiomers, such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and mesoforms, such as salts of such compounds. The invention also relates to a pharmaceutical composition, as well as to use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds with antimalarial activity.

8 cl, 138 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of 3-cyanonaphthalene-1-carboxylic acid and perhydroxyalkylmethylpiperazine of formula

, where R1 means C1-C4alkyl, R2 and R3 mean halogen, R4 is selected from the group consisting of 2-furanyl, 3-furanyl, 2-thiophen, 3-thiophen, phenyl, benzyl, 2-benzofuranyl, etc., R5 is selected from the group consisting of hydrogen and R6, R6 means a subgroup of general formula

which are antagonists of tachykinin receptors. Also, there are described pharmaceutical compositions containing such compounds, and methods for making such compounds and intermediate products for making the compounds according to said methods.

EFFECT: preparation of new compounds.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or a pharmaceutically acceptable salt thereof, in which R1 denotes hydrogen or C1-6alkyl; R2 denotes isooxazolyl group, substituted with C1-6alkyl; RB denotes -CF3, -CHF2, -CH2F, or C1-6alkyl. The invention also relates to pharmaceutical compositions for treating cancer which contain the disclosed compounds.

EFFECT: obtaining novel compounds and a pharmaceutical compositions based on said compounds, which can be used in medicine for treating cancerous diseases.

15 cl, 77 dwg, 10 tbl, 13 ex

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