Bromophenyl substituted thiazolyl dihydropyrimidines

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or tautomer thereof

or enantiomer or physiologically acceptable salt, where R1 is o-bromo, R2 is n-fluoro, R3 is C1-C4 alkyl, R6 is thiazolyl-2-yl, X is methylene and Z is morpholinyl. The invention also relates to methods of producing (versions) compounds of formula (I) and (Ia). The compound of formula (I) or (Ia) is used to prepare a pharmaceutical composition for treating or preventing HBV infections and HBV-induced diseases such as hepatitis B.

EFFECT: bromophenyl substituted thiazolyl dihydropyrimidines for HBV infection control.

20 cl, 7 tbl, 14 ex

 

The SCOPE TO WHICH the INVENTION RELATES

The present invention relates to a new bromo-phenyl substituted thiazolidinedione, the method of its production and use as pharmaceuticals, particularly for the treatment and prevention of hepatitis C. the Present invention also relates to compositions containing dihydropyrimidin, another antiviral agent and, when appropriate, immunomodulator, and medicinal product containing the composition, especially for the treatment and prevention of HBV infections, such as hepatitis C.

PREREQUISITES TO the CREATION of INVENTIONS

Hepatitis b virus belongs to the family of hepadna viruses. It can cause acute and/or persistent, or progressive chronic disease. Many other clinical manifestations in the pathological condition is also caused by the hepatitis b virus, in particular chronic liver inflammation, cirrhosis and hepato-cellular carcinoma. In addition, co-infection with hepatitis Delta may have an adverse effect on the progression of the disease.

Interferon and lamivudine are traditional medicines approved for use in the treatment of chronic hepatitis. However, interferon has only moderate activity, but has adverse pobo the major reaction. Although lamivudine has good activity, it quickly develops resistance during treatment and often relapse after stopping treatment. The value of the IC50lamivudine (3-TC) is 300 nm (Science, 299 (2003), 893-896).

In U.S. patent No. 7074784 describes 6-aminoalkylphosphonic and its use as a medicine, in particular for the treatment and prevention of hepatitis C.

In Example 12 of U.S. patent No. 7074784 describes that R1represents o-chloro, R2represents the p-chloro, R6represents 3,5-debtor-pyridine-2-l, X represents-CH2and Z represents morpholinyl. This compound can inhibit the growth of hepatitis b virus in cell cultivation. The value of the IC50is 2 nm (tested by the inventors).

Main replacement in Example 12 is to replace the bis-chlorine in R1(o-bromine) and R2(p-fluoro)that results in the IC50Compounds 9, part 7 nm (described in Example 9 of the patent). And when major change substituents on the R1(o-chloro) and R2(p-fluoro), also get the approximate value of the IC50(IC50=2-4 nm in Example 5).

Specifies that the value of the IC50does not increase with the change of basic substituents R1and R2(see Table 1).

In the patent With The And No. 7074784 B2 also describes example, in which debtor radical substituted on the thiazole-2-yl (described in Example 45 this patent). This derivative has the same value IC50(2 nm) (see Table 1).

Table 1
Example 2 of U.S. patent No. 7074784 B2
ExampleR1R2R3R6IC50(nm)
12ClClCH32 (protestera-Vano by the authors)
9BrFCH37
5ClFCH32-4
45ClCl CH32

DETAILED description of the INVENTION

The inventors have unexpectedly discovered that a derivative with activity 10 times higher and the value of the IC50less than 1 nm can be obtained by replacing the thiazole-2-yl and change the main substituents on R1=o-bromo and R2=p-fluoro. This is unexpected given US 7074784 (see Table 2).

Table 2
Some Examples of the present invention
Example/Conn.R1R2R3R6IC50(NM)
6(a)BrFCH30,3
5(b)BrFCH2CH3 0,2

The present invention relates to the compound of formula (I) and its tautomer (Ia),

where R1is an o-bromo, R2represents the p-fluoro, R3represents a C1-C4alkyl, R6represents thiazol-2-yl, X is a methylene, and Z is morpholinyl.

Preferably, R1compounds of the present invention of formula (I) and (Ia) is an o-bromo, R2represents the p-fluoro, R3represents methyl or ethyl, R6represents thiazol-2-yl, X is a methylene, and Z is morpholinyl.

The present invention also relates to the enantiomer of the compound described in this application, and mixtures thereof. The racemate can be separated by using a known method and, basically, it is a homogeneous compound in a mixture of stereoisomeric forms.

Compounds of the present invention include isomers of the formula (I) and (Ia) and their mixture.

The compound of the present invention can also be in the form of a salt, preferably a physiologically acceptable salt.

Physiologically acceptable salt may be a salt of an inorganic acid or salt of organic acid. Preferably, a salt of an inorganic acid such as chloride, bromide, phosphate, or sulfate, and p, or carboxylate, or sulfonate, for example, acetate, maleate, fumarate, malate, citrate, tartrate, lactate, benzoate or methanesulfonate, aconsultant, bansilalpet, toluensulfonate or naphthalenedisulfonate, etc.

Physiologically acceptable salt may also be a metal salt or ammonium salt of the compounds of the present invention. In a preferred example, sodium salt, potassium salt, magnesium salt or calcium salt, and ammonium salt formed with ammonia or organic amines, such as ethylamine, diethylamine or triethylamine, diethanolamine or triethanolamine, dicyclohexylamine, dimethylaminoethanol alcohol, arginine, lysine, Ethylenediamine or 2-phenethylamine, etc.

The compound (I) of the present invention can be obtained in the following ways:

[A] first, the benzaldehyde of the formula (II) interacts with β-ketefian formula (III) with or without added alkali or acid, and, when appropriate, in the presence of an inert organic solvent with getting benzylidene the compounds of formula (IV):

,,,

where R1, R2, R3X and Z are defined in this application, and then benzylidene compound interacts with amidino formula (V) or its salt (such as Hydra is chloride or acetate) with or without added alkali or acid and, when appropriate, in the presence of an inert organic solvent:

where R6defined in this application; or

[B] β-ketoester formula (III) reacts with benzaldehyde of the formula (II) and amidino formula (V) or its salt (such as hydrochloride or acetate) with or without added alkali or acid and, where appropriate, in the presence of an inert organic solvent at a single stage; or

[C] when X in the formula (I) represents a methylene compound of the formula (VI) interacts with morpholine of the formula (VII) with or without added alkali and, when appropriate, in the presence of an inert organic solvent,

,

where R1, R2, R3and R6defined in this application, and Y represents a nucleophilic Deputy, such as chlorine, bromine, iodine, methylsulphonyl or toluensulfonyl; or

[D] the benzaldehyde of the formula (II) reacts with the compound of the formula (X) and amidino formula (V) with or without added alkali and, when appropriate, in an inert organic solvent,

where R3X and Z are defined in this application.

The compound of formula (VI) can be obtained, for example, put the m interaction of the compounds of formula (VIII)

where R1, R2, R3and R6defined in this application, with brainwashin reagent, such as N-bromosuccinimide, preferably in an inert organic solution, to obtain the compounds of formula (IX):

and interaction of the compounds with nucleophilic Deputy, directly or after further transformation of compounds in accordance with the conventional method described in the literature, with morpholine of the formula (VII).

To obtain the compounds of formula according to the present invention (I), where X represents a methylene, and Z is morpholinyl, CHLOROACETATE formula (XI) interacts with morpholine (VII) to give the β-keto of the carboxylate of the formula (III),

where R3defined in this application.

In as the starting material is commercially available 2-bromo-4-fluoro-benzaldehyde (II).

As an initial matter, β-ketocarbofuran (III) are well known or can be obtained by known methods published in the literature [e.g., D. Borrmann, "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen", in "Methods der organischen Chemie" (Houben-Weyl), vol. VII/4, 230 ff (1968); Y. Oikawa, K. Sugano und O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].

The compound (V) is well known and can be obtained in accordance with the descriptions WO-A-99/54326 and WO-A-99/54329.

M is Holin (VII) is commercially available.

Compounds (VIII) and (X) can be obtained in accordance with the stages of the [A] or [B], described in WO-A-99/54326.

All inert organic solvents suitable for use in the stages A, B, C, and D. the Inert organic solvent is preferably an alcohol, such as methanol, ethanol and isopropyl alcohol, simple ester, such as dioxane, diethyl ether, tetrahydrofuran, onomatology ether of ethylene glycol, dimethyl ether of ethylene glycol, carboxylic acid, such as acetic acid, dimethylformamide, dimethylsulfoxide, acetonitrile, pyridine or HEXAMETHYL-triamide, phosphoric acid.

The reaction temperature can be changed within a fairly wide range. Typically, the temperature ranges from 20°C to 150°C. Preferably, the temperature equal to the boiling temperature of the selected solvent.

The reaction can be conducted at atmospheric pressure or under high pressure. Usually the reaction is carried out at atmospheric pressure.

The reaction may be carried out with acid or alkali, or without them. It is preferable to conduct this reaction in the presence of weak acids, such as acetic acid, formic acid or the like.

One way of implementing the present invention relates to compositions containing A) at least one of the above dihydropyrimidines and (B) at least one of the others who protivovirusnyh funds other than A).

A particular variant of the present invention relates to compositions containing A) above desirability, B) inhibitor of HBV polymerase and, where appropriate, (C) an immunomodulator.

Preferably, immunomodulator C) is selected, for example, from any of the interferons, such as α-interferon, β-interferon and γ-interferon, mainly α-2a-interferon α-2b-interferon, interleukin, such as interleukin-2 polypeptide, such as thymosin-α-1 and Timokhina, derived imidazoquinolines, such as levamisole, immunoglobulin and therapeutic vaccines.

Thus, the present invention also relates to compositions for the treatment and prevention of HBV infection and its use for the treatment of diseases induced by HBV.

Using combinations of the present invention provides important advantages for the treatment of diseases induced by HBV, compared with monotherapy individual compounds, namely, first of all, synergistic antiviral activity and good tolerability of the combination of the present invention, expressed in Tox-50 (range of toxicity, which survives 50% of the cells).

Substances called HBV polymerase inhibitors for the purposes of the present invention are those that endogenous polymerase-analysis of the published Ph. A. Furman et al. inntimicrobial Agents and Chemotherapy Vol. 36 (No. 12), 2688 (1992) and described later in this application, lead to inhibition of the DNA double helix formation HBV) so as to bring the maximum to 50% of the activity from the original values.

HBV polymerase inhibitors B for use in the present invention are substances described in the experiment with endogenous polymerase, published in Antimicrobial Agents and Chemotherapy” Vol.36 (No.12), 2688 (1992) the author of the Ph. A. Furman, and substances described below for inhibiting the formation of HBV DNA double helix, resulting in the maximum to 50% of the value of the activity, from the original values.

HBV virions of cultural supernatants include nucleoside 5'-triphosphates in plus-circuit HBV DNA in vitro. Using agarose gel electrophoresis, the incorporation of [α-32P]-deoxynucleoside 5'-triphosphate into viral 3.2 thousand, inorg. The DNA product is observed in the presence and absence of substances potentially any abscopal properties in respect of the HBV polymerase. HBV virions obtained from the supernatant of cell culture HepG2.2.15 cells by means of precipitation with polyethylene glycol and concentrate. One part by volume of clarified cell culture supernatant is mixed with 1/4 volume of an aqueous solution containing 50% by weight of polyethylene glycol 8000 and 0.6 M sodium chloride. Virions are precipitated by centrifugation at 2500×g/15 minutes. Sediment resuspended 2 m the buffer, containing 0.05 M Tris-HCl (pH 7.5) and deleteroute against the same buffer containing 100 mm potassium chloride. Samples can be frozen at -80°C. Each reaction mixture (100 μl) contains at least 105 HBV virions; 50 mm Tris-HCl (pH 7.5); 300 mm KCl; 50 mm of magnesium chloride; 0,1% Nonident®P-40 (non-ionic detergent from Boehringer Mannheim); 10 μm dATP, 10 μm dGTP, 10 μm dTTP; 10 mccu [32P]dCTP (3000 Kiu/mmol; final concentration of 33 nm and 1 μm in a strong inhibitor polymerase in his triphosphorylated form. Samples incubated at 37°C for one hour and then the reaction stopped by the addition of 50 mm EDTA. 10% weight/volume solution of SDS (containing 10 g of SDS in 90 ml water) is added to a final concentration of 1% by volume (based on total volume), and add proteinase K to a final concentration of 1 mg/ml After incubation at 37°C for one hour, the samples extracted with the same volume of a mixture of phenol/chloroform/isoamyl alcohol (25:24:1 by volume), and the DNA precipitated from the aqueous phase by ethanol. Precipitate DNA resuspended in 10 μl of buffer for gel (solution of 10.8 g Tris, 5.5 g boric acid, and 0.75 g EDTA in 1 liter of water (=TBE buffer)and separated using agarose gel electrophoresis. Gel or dry, or nucleic acids in it are transferred using the method of southern blotting to a membrane. The number of labeled formed double-stranded DNA C is the defined relative to the negative control (= reaction endo-floor without substance or inactive control substance). Inhibitor of HBV polymerase is present, if there is a maximum of 50% of the activity of the negative control.

Preferred HBV polymerase inhibitors B) include, for example, 3TC=lamivudine=4-amino-1-[(2R-CIS)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl-]-pyrimidine-2(1H)-he, cf. EP-B 382 526 (=U.S. Patent No. 5047407) and WO 91/11186 (=U.S. Patent No. 5204466); Adefovir dipivoxil = 9-{2-[[bis[(pivaloyloxy)-methoxy]-phosphinyl]- methoxy]-ethyl}-a-dynein, cf. EP-B 481 214 (=U.S. Patent nos. 5663159 and 5792756), U.S. Patent nos. 4724233 and 4808716; BMS 200475=[1S-(1-α,3-α,4-β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylene-cyclopentyl]-6H-purine-6-he, cf. EP-B 481 754 (=U.S. Patent nos. 5206244 and 5340816), WO 98/09964 and 99/41275; ABC=(-)-(1S-CIS)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl]-2-cyclopenten-1-methanol, cf. EP-B 349 242 (=U.S. Patent No. 5049671) and EP-B 434 450 (=U.S. Patent No. 5034394); FTC=(2R-CIS)-4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-pyrimidine-2(1H)-he, cf. WO 92/14743 (=U.S. Patent№№. 5204466, 5210085, 5539116, 5700937, 5728575, 5814639, 5827727, 5852027, 5892025, 5914331, 5914400) and WO 92/18517; β-L-FDDC =5-(6-amino-2-fluoro-9H-purine-9-yl)-tetrahydro-2-furanmethanol, cf. WO 94/27616 (=U.S. Patent nos. 5627160, 5561120, 5631239 and 5830881); L-FMAU=1-(2-deoxy-2-fluoro-β-L-arabinofuranosyl)-5-methyl-pyrimidine-2,4(1H,3H)-dione, cf. WO 99/05157, WO 99/05158 and U.S. Patent No. 5753789.

Another preferred implementation of the present invention relates to compositions containing A) above dihydropyrimidine formula (I) and (Ia); and (B) lamivu the N.

Other preferred means B virus against HBV include, for example, phenylpropanamide the following formula:

where R1and R2each independently represent C1-4alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms containing carbon and/or oxygen; R3-R12each independently represent hydrogen, halogen, C1-4alkyl, optionally substituted C1-4alkoxy, nitro, cyano or trifluoromethyl; and R13represents hydrogen, C1-4alkyl, C1-7acyl or aralkyl and X represents a halogen or optionally substituted C1-4alkyl.

Phenyl propanamide and methods for their preparation are described in WO 98/33501 and referred to in this application for publication. AT-61 represents a connection

Preferred immunomodulators C) include, for example, any interferons, such as α-, β - and γ-interferons, in particular, also α-2a and α-2b-interferon, interleukins, such as interleukin-2 polypeptide, such as activin-α-1 and Timokhina, derivatives imidazoquinolines, such as Levamisole®the antibodies and therapeutic vaccines.

Another preferred implementation of the present invention relates to the combination of the m (A) above dihydropyrimidines (I) and (Ia), B) lamivudine and, where appropriate, C) interferon.

Description tests

The antiviral effect of the compounds of the present invention to hepatitis b virus investigate ways based on the methods described by M. A. Sells et al.,Proc. Natl. Acad. Sci., 84, 1005-1009 (1987) and B. E. Korba et al.,Antiviral Research19, 55-70 (1992).

Antiviral tests carried out in 96-well microtiter plates. The first vertical row of the tablet contains only growth medium and HepG2.2.15 cells. He serves as a virus control.

Royal solutions of the test compounds (50 mm) of the original dissolved in DMSO, and further diluted to prepare in the growth environment HepG2.2.15. Compounds in accordance with the invention usually dig a pipette in the tested concentration of 100 µm (1-I tested concentration) in each case in the second vertical test a number of microtiter tablet and subsequently diluted in two steps 210 times in growth medium plus 2% of the mass. fetal calf serum (volume 25 μl).

Each hole microtiter tablet thus contains 225 μl of the suspension of HepG2.2.15 cells (5×104 cells/ml) in growth medium plus 2% of the mass. fetal calf serum. The test mixture was incubated at 37°C and 5% CO2 (vol/about.) within 4 days.

Then the supernatant is sucked off and discarded, and the wells are placed 225 ál of freshly prepared growth with the food. Compounds of the present invention each add again in the form of 10-fold concentrated solution in a volume of 25 µl. The mixture is incubated for another 4 days.

Before collecting supernatants to determine the antiviral action of HepG2.2.15 cells were examined under a light microscope or by using biochemical methods of identification (for example, dye Alamar Blue or dye Trypanosoma blue) cytotoxic changes.

Supernatant and/or the cells are then harvested and draw with the help of vacuum in 96-well dot-blot chamber, covered with a nylon membrane (in accordance with the information of the manufacturer).

Determination of cytotoxicity

Cytotoxic or cytostatic changes induced by substance in HepG2.2.15 cells, detect, for example, under a light microscope as changes in the morphology of the cells. Such changes, induced by the substance in HepG2.2.15 cells compared with untreated cells, visible, such as cytolysis, vacuolization or change the morphology of the cells. 50% cytotoxicity (Tox.-50) means that 50% of the cells exhibit morphology, comparable with the corresponding cell control.

The portability of some compounds in accordance with the present invention additional testing on other cells-hosts such as HeLa cells, primary cells perifericos the th human blood or transformed cell lines, such as cell H-9.

When the concentrations of the compounds of the present invention >10 μm cytotoxic changes are not detected.

Determination of the antiviral action

After transfer of supernatants or lysed cells on nylon membrane blot apparatus (see above), intra - or extracellular supernatant HepG2.2.15 cells are denatured (1.5 M NaCl/0,5N NaOH), neutralized (3 M NaCl/0,5M Tris HCl, pH 7.5) and washed (2×SSC). Then the DNA is dried on the membrane by incubation of the filters at 120°C for 2-4 hours.

Hybridization of DNA

Detection of viral DNA from the treated HepG2.2.15 cells on nylon filters usually carried out using non-radioactive labeled with digoxigenin hepatitis b-specific DNA probes, each of which Machen digoxigenin, purified and used for hybridization in accordance with the information of the manufacturer.

Pre-hybridization and hybridization is carried out in 5×SSC, 1×blocking reagent, 0.1% of the mass. N-lauroylsarcosine, 0,02% of the mass. SDS and 100 μg DNA ROE herring. Pre-hybridization was performed at 60°C for 30 minutes and specific hybridization is carried out with the use of 20 to 40 ng/ml digoxigenin, denatured HBV-specific DNA (14 hours, 60°C). Then the filters are washed.

Detection of HBV DNA using digoxigenin antibodies

Immunological detection of DNA labeled with digoxigenin, carried out in accordance with information manufacturer:

Filters were washed and pre were hybridisable in blocking reagent (according to information supplied by the manufacturer). Then, hybridization was performed with anti-DIG antibody coupled with alkaline phosphatase for 30 minutes. After the stage of washing was added to the substrate of alkaline phosphatase, CSPD, incubated with the filters for 5 minutes, then Packed in plastic film and incubated at 37°C for 15 minutes. The chemiluminescence signals hepatitis b-specific DNA visualized, exposing the filters to x-ray film (shutter speed depends on signal strength: 10 minutes to 2 hours).

The half maximal inhibitory concentration (IC50the 50% inhibitory concentration) was defined as the concentration at which intra - and extracellular HBV-specific band was decreased under the action of the compounds according to the invention by 50% compared with untreated sample.

Unexpected is the fact that the compound of the present invention demonstrates effective antiviral effect with IC50less than 1 nm. Therefore, the connection of the present invention is suitable for use in the treatment of diseases caused by viruses, especially acute and chronic persistent HBV infections. Chronic viral disease caused by HBV can worsen the clinical manifestations and chronic hepatitis b viral infection can cause cirrhosis and/or liver cell carcinoma in many cases.

Areas of testimony that may be mentioned of the compounds of the present invention, are, for example: treatment of acute and chronic viral infections that can cause infectious hepatitis, such as infection with hepatitis C. the Compounds of the present invention are particularly suitable for the treatment of chronic infections of hepatitis b and treatment of acute and chronic hepatitis b viral infections.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable carriers, contain one or more compounds (I) or (Ia), or a combination according to the invention or which consist of one or more active ingredients (I) or (Ia) or a combination of the present invention.

It is assumed that the active ingredients (I) and (Ia) are present in the abovementioned pharmaceutical preparations in a concentration of from about 0.1 to 99.5 wt. -%, preferably from about 0.5 to 95% of the mass. the whole mixture.

The pharmaceutical preparations mentioned above, can also contain other active pharmaceutical ingredients in addition to the compounds (I) and (Ia).

The ratio between the amounts of components A, B and, where appropriate, C in the compositions of the present invention can vary within wide limits, preferably this ratio is from 5 d is 500 mg A/10-1000 mg B, in particular from 10 to 200 mg A/20 to 400 mg B.

Component C, which is also used where appropriate, may be used in quantities of, preferably, from 1 to 10 million, in particular from 2 to 7 million IU (international units), approximately three times per week over a period of time up to one year.

It is assumed that the compounds or compositions of the present invention are present in the abovementioned pharmaceutical preparations mainly in a concentration of from about 0.1 to 99.5, preferably about 0.5 to 95% of the mass. the whole mixture.

The pharmaceutical preparations mentioned above, can be obtained in the usual way using known methods, for example, by mixing the active ingredient (ingredient) with the carrier (s).

Basically, appeared to be preferred as humans and in veterinary medicine, to introduce the active ingredient(s) in total amounts of about 0.5 to about 500, preferably from 1 to 100 mg/kg of body weight every 24 hours, where appropriate, in the form of a number of single doses, to achieve the desired results. A single dose contains the active ingredient(s), preferably in amounts from about 1 to about 80, in particular from 1 to 30 mg/kg of body weight. However, it may be necessary to deviate from the above-mentioned dosages, in particular, depending the spine from the species and body weight of the individual, which carry out the treatment, the nature and severity of the disease, type of drug and route of administration of the medicinal product, and the time or interval at which occurs the introduction.

Therefore, the present invention additionally relates to compounds and compositions as described above for disease control.

The present invention additionally relates to medicines containing at least one of the compounds or compositions described above, and, where appropriate, one or more other active pharmaceutical ingredients.

The present invention additionally relates to the use of compounds and compositions as described above, to obtain a medicine for the treatment and prevention of the above diseases, preferably of viral diseases, in particular hepatitis C.

Percentages in the following examples relate in each case to the weight, unless otherwise indicated. The ratio of solvents in mixtures of the solvents in each case based on the volume.

EXAMPLES

A. Obtaining intermediates

The intermediate connection 1

Ethyl 4-(2-bromo-4-forfinal)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidin - 5-carboxylic ester

A mixture of 10.0 g (to 49.3 mmol) of 2-bromo-4-forventelige, 6.4 g (493 mmol) ethylacetoacetate, 8,1 g (to 49.3 mmol) 2-amidino-thiazolecarboxamide and 4.8 g (58,5 mmol) of sodium acetate was dissolved or suspended in 400 ml of ethanol and then boiled and delegirovali for 16 hours. The resulting solution was cooled to room temperature and filtered. The residue was washed with water to remove inorganic salts. Received the product 10.8 g (51.6 per cent). Melting point: 163-165°C.

Intermediate compound 2

Methyl 4-(2-bromo-4-forfinal)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidin - 5-carboxylic ester

Intermediate compound 2 was synthesized from methylacetoacetate in a manner analogous to the method for intermediate 1. Yield: 53% (melting point: 155-157°C).

Intermediate compound 3

Ethyl 6-methyl bromide-4-(2-bromo-4-forfinal)-2-(thiazol-2-yl)-1,4-dihydropyrimidin - 5-carboxylic ester

5.0 g (to 11.8 mmol) intermediate compound 1 was added to 100 ml four-chloride carbon and heated to 50°C in an atmosphere of gaseous argon to obtain a transparent solution. At this temperature of 2.33 g (13,0 mmol) of N-bromosuccinimide was added to the solution and stirred at this temperature for 10 minutes. The resulting solution was then immediately cooled and filtered at room temperature and reduced pressure for concentration. The purity of the obtained product are above 90% according to the results testrow the deposits using HPLC, and this product was used as starting material in the next stage. Rf=0,69 (the ratio of petroleum ether to ethyl acetate is 8:2).

Intermediate compound 4

Methyl 6-methyl bromide-4-(2-bromo-4-forfinal)-2-(thiazol-2-yl)-1,4-dihydropyrimidin-5-carboxylic ester

Intermediate compound 4 was synthesized from intermediate compound 2 in a manner analogous to the way to obtain the intermediate compound 3. Rf=0,69 (the ratio of petroleum ether to ethyl acetate is 8:2).

C. for the Examples

Example 5

Ethyl 4-(2-bromo-4-forfinal)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidin-5-carboxylic ester (b)

2.0 g of the intermediate compound 3 was added to 15 ml of methanol to obtain a solution. The solution was mixed with 5-fold volume of the research and was stirred for 30 minutes at room temperature. The resulting solution then was diluted with water and extracted with ethyl acetate. Output: 1,7, melting point: 161-163°C. Rf=0.45 in (the ratio of petroleum ether to ethyl acetate is 8:2)

Example 6

Methyl 4-(2-bromo-4-forfinal)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidin-5-carboxylic ester (a)

The compound of example 6 was synthesized from intermediate compound 4 in a manner analogous to the method of producing soedineniyami 5. Melting point: 173-175°C. Rf=0,43 (the ratio of petroleum ether to ethyl acetate is 8:2).

The enantiomers obtained in Example 5 and Example 6, were separated on a chiral column (Daicel Chiralpak AS-H, mobile phase:n-hexane/ethanol=99/1).

Active compounds against HBV in these two examples are enantiomers, with relatively long retention time.

Data concerning the activity of the compounds of the present invention, are listed below:

No. of example/connection-eIC50(NM)
5(b)0,2
(-)-50,1
6(a)0,3
(-)-60,2

Treatment of HepG2.2.15 cells, producing hepatitis b virus by compounds of the present invention, can lead to a reduction in intra - and/or extracellular viral DNA.

Example 7

Stage 1: Obtain methyl 4-(4-morpholinyl)-3-oxobutanoate

To a mixture of methyl-4-chloroacetoacetate (1.0 g, only 6.64 mmol) in dichloromethane (10 ml) was added morpholine (1.27 g, 14.6 mmol). The reaction mixture was stirred pikantnoi temperature for 2 hours, then added water and the mixture is then neutralize 2N hydrochloric acid to pH 7.0. The organic phase was separated and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo, then the residue was purified column chromatography on silica gel using a mixture of 10:1 (vol./about.) petroleum ether/ethyl acetate as eluent to obtain methyl-4-(4-morpholinyl)-3-oxobutanoate as a colourless liquid (0,48 g, 36%). The product was characterized by the following spectroscopic data: MS (ESI, positive ion) m/z: 202,1 [M+l];1H-NMR (400 MHz, Dl3): δ 2,52 (t, J=2,4 Hz, 4H), to 3.38 (s, 2H), 3,50 (s, 2H), 3,69 (t, J=2,4 Hz, 4H), 3,76 (s, 3H).

Stage 2: Obtaining methyl-2-(2-bromo-4-formanilide)-4-morpholino-3-oxobutanoate

To a solution of 2-bromo-4-forventelige (3.12 g, to 15.4 mmol) and methyl-4-(4-morpholinyl)-3-oxobutanoate (3,09 g of 15.4 mmol) in isopropanol (20 ml) was added piperidine (0.1 ml) and glacial acetic acid (0,13 ml). The reaction mixture was stirred at room temperature overnight, then the mixture was concentrated in vacuo and the residue was purified column chromatography on silica gel using a mixture of 10:1 (vol./about.) dichloromethane/ethyl acetate as eluent to give the desired compound as a yellow solid (3,32 g, 56%). The product used on the next stud and as a mixture of CIS/TRANS isomers. The product was characterized by the following spectroscopic data: MS (ESI, positive ion) m/z: 387,0 [M+2];1H-NMR (400 MHz, Dl3): δ 2,52-2,60 (m, 4H), 3,69-and 3.72 (m, 4H), of 3.77 (s, 3H), 4,10 (s, 2H), 7,17 and 7.36 (m, 3H), charged 8.52 (s, 0,6N), of 8.90 (s, 0,4N).

Stage 3: Obtaining methyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin-5-carboxylate (Conn. a)

To a solution of methyl 2-(2-bromo-4-formanilide)-4-morpholino-3-oxobutanoate (of 0.77 g, 2.0 mmol) in isopropanol (10 ml) were added hydrochloride thiazole-5-carboxyamide (0.32 g, 2 mmol)and sodium acetate (0.20 g, 2.4 mmol). The reaction mixture is boiled under reflux for 8 hours and concentrated, then the residue was dissolved in dichloromethane (30 ml), the organic phase is washed with an aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 4:1 (vol./about.) petroleum ether/ethyl acetate as eluent to obtain specified in the title compound as a yellow solid (0.45 g, 45%). The product was characterized by the following data: melting point 173-175°C; MS (ESI, positive ion) m/z: 496,0 [M+2];1H-NMR (400 MHz, DMSO): δ 3,30 (s, 3H), 3,40 (s, 4H), 3,90 (s, 4H), to 4.52-4,74 (m, J=16 Hz, 2H), 6,02 (s, 1H), 7,27-of 7.60 (m, 3H), 8,08 (d, J=2,8 Hz, 1H), they were 8.22 (s, 1H),9,98 (s, user. s, 1H).

Example 8

Stage 1: Getting ethyl-4-morpholino-3-oxobutanoate

To a solution of ethyl-4-chloroacetoacetate (1,09 g, only 6.64 mmol) in dichloromethane (10 ml) was added morpholine (1.27 g, 14.6 mmol). The mixture was stirred at room temperature for 2 hours, then added water (20 ml) and the mixture neutralize 2 N hydrochloric acid to PH 7.0. The organic phase was separated and dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 10:1 (vol./about.) petroleum ether/ethyl acetate as eluent to obtain specified in the title compound as a colourless liquid (0.4 g, 30%). The product was characterized by the following spectroscopic data: MS (ESI, positive ion) m/z: 216,1 [M+1];1H-NMR (400 MHz, CDCl3): δ of 1.29 (t, J=7.2 Hz, 3H), of 2.51(q, J=2,4 Hz, 4H), of 3.28 (s, 2H), 3,50 (s, 2H), of 3.73 (t, J=2,4 Hz, 4H), 4,19 (t, J=7.2 Hz, 2H).

Stage 2: Getting ethyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin-5-carboxylate (Conn. in)

To a solution of 2-bromo-4-forventelige (0.40 g, 2.0 mmol) in isopropanol (10 ml), was added ethyl ethyl-4-morpholino-3-oxobutanoate (of 0.43 g, 2 mmol), hydrochloride enous is l-5-carboxamidine (0.32 g, 2 mmol) and sodium acetate (0.20 g, 2.4 mmol). Then the reaction mixture is boiled under reflux for 8 hours and then concentrated in vacuo, the residue was dissolved in dichloromethane (30 ml). The organic phase was washed with an aqueous solution of sodium chloride (20 ml×2), dried over anhydrous sodium sulfate, filtered, and then concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 4:1 (vol./about.) petroleum ether/ethyl acetate as eluent to obtain specified in the title compound as a yellow solid (0,57 g, 56%). The product was characterized by the following data: melting point 161-163°C; MS (ESI, positive ion) m/z: 510,0 [M+2];1H-NMR (400 MHz, DMSO): δ 1,08 (t, J=7.2 Hz, 3H), 3,40 (s, 4H), 3,90 (s, 4H), was 4.02 (kb, J=7.2 Hz, 2H), 4,50-4.72 in (m, J=16 Hz, 2H), 6,02 (s, 1H), 7,27-of 7.60 (m, 3H), of 8.06 (d, J=2,8 Hz, 1H), 8,12 (s, 1H), 10.30 a.m. (with user. s, 1H).

Example 9

Stage 1: getting ethyl-3-amino-4-morpholino-2-enoate

To a solution of ethyl-4-morpholino-3-oxobutanoate (8,56 g, 40 mmol) in ethanol (30 ml) was added an aqueous solution of NH3(50 ml, 25%). The reaction mixture was stirred at 25°C for 1 hour after which formed a white precipitate. White precipitate was filtered, combined, washed with 10 ml of water, and then dried at room temperature for 24 hours from the receipt of the specified reception in the e compound as a white solid (7,1 g, 83%). The product was characterized by the following spectroscopic data: MS (ESI, positive ion) m/z: 215,1 [M+1];1H-NMR (400 MHz, Dl3): δ of 1.29 (t, J=7.2 Hz, 3H), 2,50 (kb, J=2,4 Hz, 4H), 3,10 (s, 2H), of 3.73 (t, J=2,4 Hz, 4H), 4,19 (t, J=7.2 Hz, 2H), 4,74 (s, 1H), to 8.62 (s, 2H).

Stage 2: Getting ethyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin-5-carboxylate (Conn. in)

To a solution of 2-bromo-4-forventelige (0.40 g, 2.0 mmol) in isopropanol (10 ml), was added 3-amino-4-morpholino-2-ENOAT (of 0.43 g, 2 mmol), the hydrochloride thiazole-5-carboxyamide (0.32 g, 2 mmol) and sodium acetate (0.20 g, 2.4 mmol). The reaction mixture is boiled under reflux for 8 hours and then concentrated in vacuo, then the residue was dissolved in dichloromethane (30 ml). The organic phase was washed with an aqueous solution of sodium chloride (20 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified column chromatography on silica gel using a mixture of 4:1 (vol./about.) petroleum ether/ethyl acetate as eluent to obtain specified in the title compound as a yellow solid (0,57 g, 56%). The product was characterized by the following data: melting point 161-163°C; MS (ESI, positive ion) m/z: 510,0 [M+2];1H-NMR (400 MHz, DMSO): δ 1,08 (t, J=7.2 Hz, 3H), 3,40 (s,4H), are 3.90 (s, 4H), was 4.02 (q, J=7.2 Hz, 2H), 4,50-4.72 in (m, J=16 Hz, 2H), 6,02 (s, 1H), 7,27-of 7.60 (m, 3H), of 8.06 (d, J=2,8 Hz, 1H), 8,12 (s, 1H), 10.30 a.m. (with, of user. S., 1H).

m/z: 387,0 [M+2];1H-NMR (400 MHz, Dl3): δ 2,52-2,60 (m, 4H), 3,69-and 3.72 (m, 4H), of 3.77 (s, 3H), 4,10 (s, 2H), 7,17 and 7.36 (m, 3H), charged 8.52 (s, 0,6N), of 8.90 (s, 0,4N).

Examples 10-12

Compound: methyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl) -2-(thiazol-2-yl)-1,4-dihydropyrimidin-5-carboxylate (Conn. a)

Compound: ethyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin-5-carboxylate (Conn. in)

Example 10

The active ingredients of example 10 represents a connection (Conn. : (methyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin-e-5-carboxylate) and the inhibitor of HBV polymerase (adefovir dipivoxil). The composition of example 10 is as shown in the table below.

IngredientsContent (%)Weight (g)
Connection (Conn. a)7,515,0
Adefovir dipivoxil2,55,0
Microcrystalline cellulose50,0 100,0
Pregelatinized starch32,064,0
Polyvidone K303,06,0
Purified waterenoughQS
Polyvinylpolypyrrolidone (first Addendum)2,55,0
Polyvinylpolypyrrolidone (second Addendum)2,04,0
Magnesium stearate0,51,0
Only100,0200,0

The technique of example 10

1) Of polyvidone K30 were prepared 10% aqueous solution of polyvidone K30.

2) a Mixture of microcrystalline cellulose, pregelatinized starch, polyvinylpolypyrrolidone (first Addendum), connection (Conn. a) and adefovir dipivoxil was mixed into a homogeneous mixture at high speed wet granulator. To the mixture was added a binder and granulation process was continued for approximately 5 minotauromachy granules are conveyed to the third which has been created size using a 1-mm sieve.

3) the Granules were dried in a drying oven or in a fluidized bed.

4) the Dried granules were brought to the desired size using a 1-mm sieve.

5) To the granules after adjusting the amount added to the second part of polyvinylpolypyrrolidone. The mixture was stirred for 5 minutes.

6) To the mixture obtained in stage 5, was added magnesium stearate. The mixture was stirred for 5 minutes.

7) From the mixture obtained in stage 6, received tablets.

Example 11

The active ingredients of example 11 represents a connection (Conn. in):(ethyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin e-5-carboxylate) and lamivudine. The composition of example 11 is as shown in the table below.

IngredientsContent (%)Weight (g)
Connection (Conn. in)5,020,0
Lamivudine15,060,0
Microcrystalline cellulose48,0192,0
Lactose24,096,0
Hydra is nsiproperties 3,0to 12.0
Purified waterenoughenough
Croscarmellose sodium (first Addendum)2,510,0
Croscarmellose sodium (second Addendum)2,08,0
Magnesium stearate0,52,0
Only100400,00

The technique of example 11

1) From hydroxypropylmethylcellulose received 8% aqueous solution of hydroxypropylmethylcellulose.

2) a Mixture of microcrystalline cellulose, lactose, croscarmellose sodium (first Addendum), connection (Conn. in) and lamivudine was stirred into a homogeneous mixture at high speed wet granulator. To the mixture was added a binder, and the granulation process was continued for approximately 5 minutes. The resulting granules are brought up to the desired size using a 1-mm sieve.

3) the Granules were dried in a drying oven or in a fluidized bed.

4) the Dried granules are conveyed to the third which has been created size using a 1-mm sieve.

5) To the granules after adjusting the size of the added second part of croscarmellose sodium. The mixture was stirred for 5 minutes.

6) To the mixture obtained in stage 5, was added magnesium stearate. The mixture was stirred for 5 minutes.

7) From the mixture obtained in stage 6, received tablets.

8) Simple tablets covered Opadry II.

Example 12

The active ingredients of example 12 represents a connection (Conn. in): (ethyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin e-5-carboxylate) and at-61. The composition of example 12 is as shown in the table below.

IngredientsContent (%)Weight (g)
Connection (Conn. in)7,515,0
At-612,55,0
Microcrystalline cellulose50,0100,0
Lactose32,064,0
The hypromellose3,06,0
The eyes of the military water enoughenough
Croscarmellose sodium (first2,55,0
add)
Croscarmellose sodium (second2,04,0
add)
Magnesium stearate0,51,0
Only100200,00

The technique of example 12

1) From hydroxypropylmethylcellulose received 8% aqueous solution of hydroxypropylmethylcellulose.

2) a Mixture of microcrystalline cellulose, lactose, croscarmellose sodium (first Addendum), connection (Conn. C) and at-61 was stirred into a homogeneous mixture at high speed wet granulator. To the mixture was added a binder, and the granulation process was continued for approximately 5 minutes. The resulting granules are brought up to the desired size using a 1-mm sieve.

3) the Granules were dried in a drying oven or in pseudo is eigendom layer.

4) the Dried granules were brought to the desired size using a 1-mm sieve.

5) To the granules after adjusting the size of the added second part of croscarmellose sodium. The mixture was stirred for 5 minutes.

6) To the mixture obtained in stage 5, was added magnesium stearate. The mixture was stirred for 5 minutes.

7) From the mixture obtained in stage 6, received tablets.

8) Simple tablets covered Opadry II.

Examples 13-14

Example 13

The active ingredient of example 13 is a connection (Conn. a) methyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin-5-carboxylate)having the following structure:

The composition of example 13 is the same as presented in the table below.

IngredientsContent (%)Weight (g)
Connection (Conn. a)15,030,0
Microcrystalline cellulose28,056,0
Lactose55,0110,0
Carboximetilkrahmal sodium1,5 3,0
Magnesium stearate0,51,0
Only100,0200,0

The technique of example 13

The mixture of compounds (Conn. a), microcrystalline cellulose, lactose and sodium carboxymethyl amylum screened and stirred for 10 minutes. To the mixture was added magnesium stearate and the mixture was stirred for 5 minutes to obtain mixed powder. Shell capsules were filled with the mixed powder, and then sealed with receipt capsules.

Example 14

The active ingredient of this example is

connection (Conn. in) (ethyl-4-(2-bromo-4-forfinal)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidin-5-carboxylate)having the following structure:

The composition of example 14 is as shown in the table below.

IngredientsContent (%)Weight (g)
Connection (Conn. b).10,030,0
Microcrystalline cellulose43,0Pregelatinization starch43,0129,0
Polyvinylpolypyrrolidone3,510,5
Magnesium stearate0,51,5
Only100,0300,0

The technique of example 2

The mixture of compounds (Conn. in), microcrystalline cellulose, pregelatinized starch and polyvinylpolypyrrolidone screened and stirred for 10 minutes. To the mixture was added magnesium stearate, and the mixture was stirred homogeneous mixture for 5 minutes to obtain mixed powder. From the mixed powder was obtained tablets.

INDUSTRIAL APPLICABILITY

The examples described in this application show that the compounds described in this invention demonstrate effective antiviral effect with IC50less than 1 nm. Therefore, these compounds can be used to treat diseases induced by viruses, mainly acute and chronic persistent HBV infections in accordance with the methods of the present invention or by any method known special the students in this field.

1. The compound of formula (I) or its tautomer (Ia):

or an enantiomer or its physiologically acceptable salt, where
R1is an o-bromo, R2represents the p-fluoro, R3represents a C1-C4alkyl, R6represents thiazolyl-2-yl, X is a methylene, and Z is morpholinyl.

2. The compound according to claim 1 or its enantiomer or a physiologically acceptable salt, where R1is an o-bromo, R2represents the p-fluoro, R3represents methyl or ethyl, R6represents thiazolyl-2-yl, X is a methylene, and Z is morpholinyl.

3. Connection with one of the following structures or its enantiomer, tautomer or a physiologically acceptable salt:or

4. Connection with one of the following structures or Lavoisier, tautomer or a physiologically acceptable salt:
or

5. The compound according to any one of claims 1 to 4, or its enantiomer or a physiologically acceptable salt, where salt is a salt of an inorganic acid or salt of organic acid.

6. The compound according to claim 5 or its enantiomer or a physiologically acceptable salt, where salt reorgan the standard acid is a salt of hydrochloric acid, salt, Hydrobromic acid salt, phosphoric acid or a salt of sulphuric acid.

7. The compound according to any one of claims 1 to 4, or its enantiomer or a physiologically acceptable salt, where the salt of the organic acid is a carboxylate or sulfonate.

8. The connection according to claim 7 or its enantiomer or a physiologically acceptable salt, where the carboxylate is an acetate, maleate, fumarate, malate, citrate, tartrate, lactate, or benzoate.

9. The connection according to claim 7 or its enantiomer or a physiologically acceptable salt, where the sulfonate is a methanesulfonate, aconsultant, bansilalpet, toluensulfonate or naphthalenedisulfonate.

10. A method of obtaining a compound according to claim 1, where the said method is characterized by:
(a) the interaction of benzaldehyde of the formula (II) with β-ketefian formula (III) with the formation of benzylidene the compounds of formula (IV):
and
(b) interaction benzylidene the compounds of formula (IV) with amidino formula (V):
or its salt
where R1is an o-bromo, R2represents the p-fluoro, R3represents a C1-C4alkyl, R6represents thiazolyl-2-yl, X is a methylene, and Z is morpholinyl.

11. A method of obtaining a compound according to claim 1, where the specified method Hara is marked by the interaction of the compounds of formula (III) with aldehyde (II) and amidine (V) or its salt at one stage;

where R1is an o-bromo, R2represents the p-fluoro, R3represents a C1-C4alkyl, R6represents thiazolyl-2-yl, X is a methylene, and Z is morpholinyl.

12. A method of obtaining a compound according to claim 1, where X of formula (I) represents a methylene, and where this method is characterized by the interaction of the compounds of formula (VI) with morpholine (VII) or its salt:

where Y represents a nucleophilic Deputy, and R1is an o-bromo, R2represents the p-fluoro, R3represents a C1-C4alkyl, and R6represents thiazolyl-2-yl.

13. A method of obtaining a compound according to claim 1, characterized by the stage of interaction of the compounds of formula (II) with an aldehyde of formula (X) and amidino formula (V) or its salt:

where R1is an o-bromo, R2represents the p-fluoro, R3represents a C1-C4alkyl, R6represents thiazolyl-2-yl, X is a methylene, and Z is morpholinyl.

14. Pharmaceutical composition for the treatment and prevention of HBV infections, and diseases induced by HBV containing the following active ingredients:
A) less the th least one compound according to any one of claims 1 to 9; and,
B) at least one tool against HBV, other than component A.

15. The pharmaceutical composition according to 14, in which the component is an inhibitor of polymerase HBV, lamivudine or phenylpropanamide compound of the following formula:

or its salt, where
each of R1and R2independently represents a C1-4alkyl or together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms containing carbon and/or oxygen; and
each of R3-R12independently represents hydrogen, halogen, C1-C4-alkyl, optionally substituted C1-C4-alkoxy, nitro, cyano or trifluoromethyl.

16. The pharmaceutical composition according to item 15, where the component is phenylpropanamide compound, which has the following structure:

17. The use of compounds according to any one of claims 1 to 9 to obtain drugs for treatment and prophylaxis of viral diseases, hepatitis b or disease caused by hepatitis C.

18. The use of a composition according to any one of p-16 to obtain drugs for treatment and prophylaxis of viral diseases, hepatitis b or disease caused by hepatitis C.

19. Use PP-18, where the drug is a tool is a tool for the treatment and prevention of diseases, caused by hepatitis b is selected from hepatitis, cirrhosis or hepato-cellular carcinoma.

20. Antiviral pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9, or at least one composition according to any one of p-16 and a pharmaceutically acceptable carrier.



 

Same patents:

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 refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutics. The method involves introducing a liposome-containing drug preparation. The liposome-containing drug preparation contains a dispersion of unilamellar liposomes prepared of a suspension of multilamellar liposomes of phospholipid group similar in composition with human cell membrane phospholipids. Linear size of the unilamellar liposomes are specified in view of the conformity to linear size of influenza virions.

EFFECT: method and drug preparation provide virus inhibitory action in consistently changing antigenic structure of various influenza virus strains and eliminate hepatotoxic action by immediate effect on lipid membrane of influenza virus.

17 cl, 2 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: vaccine contains an active substance and a target additive. As the active substance, the vaccine contains a mixture of an avirulent purified antigen material of La Sota strain of ND virus. of fam. Paramyxoviridae, subfam. Paramyxovirinae, gen. Avulavirus, serotype 1, of an arivulent purified antigen material of H-52 strain of IB virus, fam. Coronaviridae, gen. Coronavirus, serotype Massachusetts, of an arivulent purified antigen material of BISS No. 113 strain of EDS-76 of fam. Adenoviridae, gen. Aviadenovirus, serotype 3, collection of FGU VGNKI BISS No. 113 DEP, of an arivulent purified antigen material of K-58 strain or BG strain of IBD virus, of fam. Birnaviridae, gen. Avibirnavirus, collection of FGU VGNKI K-58 No.122-DEP or BG 102 DEP respectively, or of an avirulent purified antigen material of 1133 strain of RTV virus, fam. Reoviridae, gen. Orthoreovirus, collection of FGU VGNKI 1133 - DEP taken in proportions 0.5:2.0:0.5:1:1 respectively and in the amounts to provide protective immunogenic activity of each antigen in a body after a target preparation has been introduced. As the target additive, the vaccine contains the oil adjuvant Montanide ISA- 70 VG.

EFFECT: invention provides induction in vaccinated poultry of high antibody level to ND, IB, EDS-76, IBD and RTV agents in 28 days after application of the vaccine which appears to remain unchanged for 12 days and transovarially transmitted to offsprings.

8 cl, 6 tbl, 10 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly pharmaceutical industry. The method is characterised by the fact that: - viscosity of 1% sodium alginate in water makes 9-26 mPa·s, and concentration of calcium in colour sugar solution is 0 mg/l to 120 mg/l. - viscosity of 1% sodium alginate in water makes 26-90 mPa·s, and concentration of calcium in colour sugar solution is 0 mg/l to 80 mg/l. - viscosity of 1% sodium alginate in water makes 90-250 mPa·s, and concentration of calcium in colour sugar solution is 0 mg/l to 60 mg/l.

EFFECT: improved antiviral agent technologies (versions) with using a complex of remantadin and sodium alginate.

3 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the compound of formula I and its prodrug that is represented by 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1N-pyrazole-5-yl)ureide)methyl)-4-fluorophenoxy)-1N-indazole-1-yl)ethyl dihydrogen phosphate, and to their pharmaceutically acceptable salts and pharmaceutical compositions based on them. The mentioned compounds are kinase inactivators. The objects of the invention also include the ways of production of the formula I compound, intermediate comppounds for its production and means of treatment of the mammal's condition that is mediated by kinases. In particular, the mentioned compounds can be used in the course of treatment of inflammatory diseases, autoimmune diseases, destructive diseases of bones, proliferative diseases, virulent diseases or neurodegenerative diseases.

EFFECT: compounds that can be used in the course of treatment of inflammatory diseases, autoimmune diseases, destructive diseases of bones, proliferative diseases, virulent diseases or neurodegenerative diseases.

15 cl, 8 tbl, 22 ex

FIELD: veterinary.

SUBSTANCE: composition for the induction of the animal's immune response to Blue Tongue Virus (BTV) contains immunogenically efficient number of at least one strain of doubly inactivated Blue Tongue Virus and a biologically acceptable adjuvant; doubly inactivated Blue Tongue Virus is inactivated for the first time by the inactivating agent in concentration of approximately 10 mM and is inactivated for the second time by the inactivating agent in concentration of approximately 5 mM; the inactivating agent represents the binary ethylene inline (BEI); the applied adjuvant is chosen from the group consisting of one or several aluminum hydrates, saponins, SL-CD, Carbopol and SP-oil; one or several doses of the composition is injected to strengthen the animal's immune response to Blue Tongue Virus or prevent or reduce at least one symptom associated with that illness or to prevent or alleviate the Blue Tongue Virus outbreak; in purpose of production of inactivated integral Blue Tongue Virus it is treated by the inactivating agent, the proportion of the inactivating agent to BTV counts to 1:10; hereafter the received mixture is homogenated and decanted, after that BTV is treated by the inactivating agent for the second time in proportion to BTV - 1:20, hereafter the attained mixture is repeatedly homogenated and decanted and then neutralized for the adjustment of the final pH up to approximately 7.2.

EFFECT: group on inventions is an efficient means of protecting cud-chewing animals from infection caused by Blue Tongue Virus.

32 cl, 16 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: The invention relates to pharmacology, in particular, to medication for preventing or treating herpes labialis or herpes genitalis. The homeopathic medication or biologically active additive with anti-viral effect or preventing or treating herpes labialis or herpes genitalis contains: Nisylen, Cepa, Euphrasia, Belladonna and Mericulis Solubilis, furthermore, the components are present with a certain dilution and amount. The combination of the said components is used for production of homeopathic medication or biologically active additive with anti-viral effect or preventing or treating herpes labialis or herpes genitalis.

EFFECT: production of medication which effectively treats herpes labialis or herpes genitalis.

14 cl, 1 ex

Acid complex // 2442578

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to a complex for the antimicrobial and / or anti-inflammatory action, which contains fulvic acid having a molecular weight not exceeding 20 kDa herewith fulvic acid derived from sugar. The complex can also contains aluminum, mercury, cadmium, chromium and lead in amounts which do not harm human body. The invention also relates to a method of producing the specified complex which comprises dissolving the carbohydrate to form of a solution and oxidation of this carbohydrate in the water vapor. The obtained product, containing acidic components is subjected to filtration to remove acidic components with a molecular mass greater than 20 kDa.

EFFECT: invention provides complexes of fulvic acid, which practically does not contain harmful elements such as aluminum, chromium, mercury, other, and can be safely used in the pharmaceutical industry.

26 cl, 2 dwg, 1 tbl, 4, ex

Antiviral compouds // 2441869

FIELD: pharmacology.

SUBSTANCE: invention refers to the new compounds or its pharmaceutically acceptable salts where the compound has formula I possessing the activity towards hepatitis C virus (HCV). In the compound of formula I, Each W1 and W2 means nitrogen, W3 is chosen out of group consisting of nitrogen and -CH-, and W4 is -CH-; A is phenyl and is not mandatory substituted, X is chosen out of group consisting out of bond, -O- and -S-, Z is chosen out of group consisting of -CH2- and -NH-; R22 is chosen out of group consisting of hydrogen, benzimidazole, indole and thiophene, where R22 is not mandatory substituted, Y is chosen out of group consisting of C(O)N(R15)- and -N(R15)C(O)-, where R15 in each case is chosen out of group consisting of hydrogen and C1-C6alkyl; R50 is -L1-A1 where L1 is chosen out of group consisting of bond and C1-C6alkylene, and A1 is chosen out of group consisting of phenyl, pyridyl, benzothiazolyl, thiadiazole, isothiazole and thiophene, where A1 is not mandatory replaced, each R10 and R35 means hydrogen; R17 is C1-C6alkyl; and each C3-C18carbocyclil and M3-M18heterocyclil in -LE-Q-LE-(C3-C18carbocyclil) and -LE-Q-LE-( M3-M18heterocyclil) is not mandatory independently substituted in each case.

EFFECT: enhanced cure of hepatitis C.

13 cl, 12 dwg, 459 ex

FIELD: pharmachology

SUBSTANCE: invention refers to the RSV-replication inhibitors with formula (I) Its additive salts and stereochemically isomeric forms where Q means hydroxy, C1-4alkyloxy, C1-4alkylcarbonylamino, C1-4alkyloxycarbonylamino, carboxyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl; each Alk is C1-6alkandiyl; R1 means heterocycle chosen out of pyridyl, pyrazynil, pirydazynil, pyrimidinyl and pyrrolyl; where each of stated heterocycles optionally can be substituted with 1, 2 or 3 substitutes, each of which is independently chosen out of group including hydroxyl, C1-6alkyl and hydroxyC1-6alkyl; R2 means hydrogen atom; R3 means hydrogen atom; R4 means Ar2; Ar2 means phenyl substituted with one or several substitutes i.e. 2, 3, 4 or 5 chosen out of halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, N(R5aR5b)-sulphonyl, R5b-O-C1-6-alkyl, Het, Het-C1-6alkyl, where Het means morhpolynyl, N(R5aR5b)- C1-6-alkyl, N(R5aR5b)-C(=O)-C1-6-alkyl; R5a means hydrogen atom; R5b means hydrogen atom, and also refers to pharmaceutical compositions containing compounds (I) and methods of production of compounds (I).

EFFECT: improved production of medicine.

8 cl, 4 ex, 1 tbl

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an immunodepressant based on a heterocyclic compound of formula

or to its pharmaceutically acceptable salt where X represents a nitrogen atom or CH, both or one of R1 or R2 represents a hydrogen atom, hydroxyl, a halogen atom, an amino group, C1-C6 alkoxy or C1-C6 alkyl: R3 represents a hydrogen atom, difluoromethyl, an amino group, methyl or hydroxymethyl; R4 or R5 represents a hydrogen atom or C1-C6 alkyl; R6 represents morpholino (optionally substituted by one or two C1-C6 alkyl groups), pyrrolidinyl (optionally substituted by hydroxy C1-C6 alkyl), piperidine (which is optionally substituted by an oxygen atom, hydroxyl, formyl or C1-C6 alkyl), piperazinyl (optionally substituted by one or two oxygen atoms, where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a groups consisting of formyl, C1-C6 hydroxyalkyl, C1-C6 alkoxycarbonyl, C1-C6 oxoalkyl, furoyl, benzoyl, methoxybenzoyl, benzylcarbonyl, dimethylcarbamoyl, diethylcarbamoyl, morpholinocarbonyl and methoxyacetyl) or 1,4-diazepano (optionally substituted by one oxygen atom where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a group consisting of formyl, C1-C6 oxoalkyl). Also, the invention refers to a heterocyclic compound of general formula

and to an anticancer drug based on the compound of formula (II).

EFFECT: there are produced new immunodepressant based on the compound of formula (I) and compound of formula (II) which can be used as anticancer drugs.

12 cl, 8 tbl, 60 ex

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