Novel compounds and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

 

The technical field to which the invention relates.

The present invention relates to new derivatives of indochinensis, methods for their preparation and their pharmaceutical use. In particular, the invention relates to novim derived indochinensis and their use in treating viral infections.

The level of technology

As is well known, the viruses are the etiological cause of many, sometimes life-threatening, diseases of both man and animals. For example, herpes viruses, such as herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), cytomegalovirus (CMV), a virus Epstein-Barr (EBV), varicella zoster virus (VZC) and human herpes virus-6 (HHV 6) is associated with many common viral diseases.

Cytomegalovirus infection human (CPSC) is an infection that exists throughout life, which leads to morbidity and mortality. Pathology associated with CMVC include microcephaly, hepatosplenomegaly, jaundice, encephalitis, infections of the newborn or fetus in the uterus, and infection carriers with immune disorders.

For some reason an increasing number of persons with risk CMVC infection, and currently 80% of adults in the United States are infected CMVC. A particularly susceptible group are those who have a weakened immune system, t is such as patients with AIDS, have CMVC can cause retinitis, gastritis and pneumonitis. Also, CMVC-induced pneumonia or hepatitis are common and serious complications of bone marrow transplantation.

European patent EP 0238459 relates to substituted indulgencies having the General formula

where R1represented by hydrogen or one or more, preferably from 1 to 4 same or different substituents in positions 1-4 and/or 7-10 selected from a halogen, preferably Br, lower alkyl/CNS group having not more than 4 carbon atoms, triptorelin group, trichlorethylene group; X is a group -(CH2)n-R2where R2presents nitrogen-containing basic residue, such as NH2, Other4or NR5R6where R4, R5and R6independently are lower alkyl or cycloalkyl, and n is an integer from 1 to 4, and R3represented by hydrogen, lower alkyl/cycloalkyl group having not more than 4 carbon atoms, and physiologically acceptable products add compounds with acids and halogen adducts with iodine, monochloride iodine or monobromide iodine.

However, it is clear that there is still an urgent need for new drugs with anti-virus efficiency, h is particularly against herpes virus, such as CPSC, and the present invention is the provision of compounds, by fulfilling this need.

Disclosure of inventions

In accordance with the first aspect of the invention provides a compound of formula (I)

where

R1selected from H, F, Cl, Br, CF3C1-C6alkoxy and HE;

R2selected from N and C1-C6alkyl;

n is 1-12;

m is 0 or 1; and

Y is selected from CH2, NR3, (NR3R4)+X-, O and S;

R3and R4independently selected from N and C1-C4alkyl; and

X-selected from pharmaceutically acceptable anions.

In accordance with another aspect provides a method of obtaining the compounds of formula (I), by reaction of compounds of formula (II)

with the compound of the formula (III)

where

R1, R2, Y, m, and n are defined here above in accordance with formula (I); and

L is removed by the group;

in the solvent or solvent mixture.

In accordance with another aspect of the invention provides a pharmaceutical composition comprising a compound of formula I in Association with at least one pharmaceutically suitable excipient.

In accordance with one aspect and the gaining of the pharmaceutical composition is an antiviral compound, suitable for the treatment of viral infections. Further aspects of the invention, as well as their implementation, are defined in the claims.

The implementation of the invention

In one embodiment of the present invention R1in the formula (I) is selected from H, F, Cl, Br, CF3The co3or HE.

Further, in one embodiment of the invention, R2in the formula (I) selected from N and C1-C4of alkyl, for example, from N and C1-C3the alkyl, or such as N and CH3.

The counterion X-in the formula (I) may be any suitable pharmaceutically suitable anion, such as Cl-, VG-, methanesulfonate, toluensulfonate, acetate, citrate and maleate.

The index n in formula (I) may be selected from any value between 1 and 12, such as 2-10, or 4-10, for example, 4-8; or 1-6, for example 1-3.

The compound of formula (II)used for the preparation of compounds of the invention may be obtained as described in EP 0238459, as well as U.S. patent 4,990,510, which is incorporated herein by reference.

The compound of formula (III), namely L(CH2)n(Y)m(CH2)nL, can be synthesized by methods well known to experts in the art or can be obtained from the suppliers of chemicals.

Remove the group L of formula (III) may be selected from, for example, CL, Br, methansulfonate, toluensulfonate, although specialists in this is blasti technology clear what you can find other deleted group.

Apply a solvent system, where the reactants are soluble in the selected reaction conditions, and where it facilitates the reaction, giving the desired product. As an example, can be selected one or more polar aprotic or proton solvents such as acetonitrile, THF, methanol, ethanol, isopropanol, ethyl acetate and methyl acetate. Specialists in the art knows how to choose a solvent system, and suitable reaction conditions.

Compounds of the invention useful as antiviral agents, and thus, in accordance with one aspect of the invention provides antiviral pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically suitable excipient.

In one embodiment of the invention the pharmaceutical composition is for treatment of a virus selected from herpes viruses, such as herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), cytomegalovirus (CMV), a virus Epstein-Barr (EBV), varicella zoster virus (VZC) and human herpes virus-6 (HHV 6).

In one embodiment of the invention, the virus is human cytomegalovirus.

Pharmaceutically suitable excipients may be, for example, solvents, adjuvants, carriers or diluents, is as well known to experts in the art and described, for example, in Remington: The Science and Practice of Pharmacy, 21th ed., Mack Printing Company, Easton, Pennsylvania (2005). Further, it is clear that the pharmaceutical composition of the invention, in addition to the compound of formula (I), can be used in conjunction with other compatible drugs such as another antiviral drug in the treatment of many drugs.

Further, the invention is illustrated by examples, which, however, shall not be construed as limiting the invention, the scope of which is defined by the claims. Note that the numbering of each one of the two systems of the rings is the same as in the General formula substituted indochinensis in the European patent EP 0238459.

Examples

Obtaining compounds of the invention

NMR spectra were recorded in DMSO-d6solutions at room temperature, applying a signal from DMSO-d6(lH:δ=2,50 ppm,13C:δ=39.5 C) as internal standard spectrometer Broker DPX300 (300 MHz). The values of δ are given in h/million Solvents were analytical grade and were used received from the provider.

Example 1

Synthesis alkilinity dimers

General procedure (scale 10 mmol)

220V (formula II, R1=H, R2=CH3or their derivatives), dihaloalkanes and acetonitrile was heated (in a flask under reflux or at 70°C) for 15 hours. Formed solid OTDELA and filtering, washed with acetonitrile and dried.

1a) R1=N, R2=CH3n=3, m=0, 3 X-=Br-,

Yield: 70%;1H-NMR δ: 8.34 (d, 1H), 7.94 (m, 2H). 7.77 (m, 2H), 7.43 (t, 1H), 4.93 (br. s, 2H), 3.86 (br. s, 2H), 3.54 (br. s, 2H), 3.27 (s, 6H), 2.39 (s, 6H), 1.77 (br. s, 2H), 1.28 (br. s, 2H).

1b) Rl=H, R2=CH3n=5, m=0, X-=Br-

Yield: 49%;1H-NMR δ; 8.35 (d, 1H), 8.00 (s, 1H), 7.92 (d, 1H), 7.80 (m, 2H), 7.45 (t, 1H), 4.9: (t, 2H), 3.85 (t, 2H), 3.49 (m, 2H), 3.24 (s, 6H), 2.48 (s. 3H), 2.45 (s, 3H), 1.69 (m, 2H). 1.17 (s,6H).

1c) R1=9-Br, R2=CH3n=3, m=0, X-=Br-

Yield: 73%;1H-NMR δ: 8.39 (s, 1H), 8.08-7.81 (m, 3H), 7.73 (s, 1H), 5.16 (br. s, 2H), 3.69 (br. s, 2H), 3.43 (br. s, 2H), 3.25 (s, 6H), 2.39 (s, 3H), 2.37 (s, 3H), 1.88 (br. s, 2H), 1.32 (br. s, 2H).

1d) R1=9-Cl, R2=H, n=3, m=0, X-=Br-

13C-NMR, DMSO-d6δ:21.6 (t), 25.2 (t), 35.3 (t), 50.8 (q), 59.0 (t), 63.3 (t). 112.6 (d), 120.4 (s), 121.6 (d), 126.1 (s), 126.8 (d), 127.5 (d), 129.3 (d), 129,8 (d), 131.1 (d), 138,6 (s), 139.0 (s), 139.8 (s), 142.0 (s), 144.9 (s).

1e) R1=H, R2=H, n=1, m=1, Y=CH2X-=VG-

13C-NMR, DMSO-d6δ:17-0 (t), 35.0 (t), 50.9 (q), 59.9 (t), 60.5 (t), 110.8 (d), 119.0 (s), 121.7 (d), 122.4 (d), 126.5 (d), 127.5 (d), 129.2 (d)*, 131.5 (d), 138.9 (s), 139.5 (s), 139.7 (s), 143.5 (s), 144.7 (s).

* 1 signal for the two hydrocarbons.

1f) R1=H, R2=H, n=3, m=0, X-=VG-

13C-NMR, DMSO-d6δ:21.7 (t), 25.4 (t), 35.0 (t), 50.8 (q), 59.2(t), 63.2 (t), 110.7 (d), 119.1 (s), 121.8 (d), 122.5 (d), 126.6 (d), 127.4 (d), 129.2 (d), 129.3 (d), 131.6 (d), 139.0 (s), 139.6 (s), 139.8 (s), 143.6 (s), 144.8 (s).

Example 2

Synthesis of dimer ester

General procedure (scale 10 mmol)

To-220 (or the th derivative), dihaloalkanes and acetonitrile was heated to the reaction flask under reflux for 20 hours. The resulting solid was isolated by filtration, washed with acetonitrile and dried.

2A) R1=H, R2=CH3n=2, Y=O, m=1, X-=VG-

Yield: 58%;1H-NMR δ: 8.22 (d, 1H), to 7.84 (s, 1H), 7,72 (m, 2H), 7.59 (s. 1H), 7.47 (d, 1H), 7.38 (t, 1H), 7.08 (d, 1H), 4.85 (t, 2H), 4.09 (br. s, 2H), 3.93 (m, 4H), 3.29 (s, 6N), 2.35 (s, 3H), 2.26 (s, 3H), 2.24 (s. 3H).

2b) R1=9-Br, R2=CH3n=2,Y=O, m=1, X-=Br-

Yield: 91%;1H-NMR δ: 8.02 (d, 1H), 7.77-7.66 (m, 3H), 7.49 (s, 1H), 7.45 (d, 2H), 7.07 (d, 2H), 4.78 (t, 2H), 4.11 (br. s, 2H), 3.95-3.90 (m, 4H), 3.27 (s, 6H), 2.31 (s, 3H), 2.26 (s, 3H), 2.18 (s, 3H).

Biological analysis

Analyses of antiviral activity against human cytomegalovirus, as described below, was performed with a connection in accordance with the invention, namely compound 1A of Example 1. The control connection, indicated At-220 is 2,3-dimethyl-6-(N,N-dimethylaminoethyl)-6N-indolo(2,3-b)cinoxacin described in European patent EP 0238459.

Analysis of inhibitory effects against viral infections.

In order to assess whether targeting structural viral proteins as effective as targeting viral transcription was performed in a modified analysis on the plates, where one of new antiviral agents was compared with the known antiviral agents which inhibit transcri the tion CMVC [GCV (Cymevene, Roche) and PFA (Foscavir, AstraZeneca)] or infection [IVIg (IVIG CP, Biotest Pharma), as antibodies].

At 0 dpi (day post-infection) experiment was also added anti-virus agents and TU/E, thus showing how agents inhibit infection. The results of these experiments were obtained when comparing the number of infected cells in the treated wells with positive controls, by counting the inhibition of infection due analyzed agents. The experiments were repeated with the strain CMVC AD-169 and with the clinical isolate, respectively, primarily with the same results.

The inhibiting effect of the analyzed substances shown in table 1, in the form of % inhibition of infection. These data are the result of tests on the tablets using a strain AD-169 and TV of the human lung fibroblasts infected with CMVC.

Table 1
The inhibiting effect of the analyzed substances in the form of % inhibition of infection
SubstanceInhibitory effects, %
1A100
IVIG (control)100
To-220 (control 20
Leflunomide (control)25-50
Foscavir (control)20-50
Ganciclovir (control)20-30

The analysis results show that the compounds of the invention have an excellent inhibitory effect against viral infections.

Analysis of the inhibition of Assembly and exit CMVC

Infected fibroblasts of the human lung (HL cells) were treated with antiviral agent-220 and other control substances, as shown in table 2, with the compound of the invention 1A in order to assess the effect of compounds of the invention against CMVC infection, Assembly and exit.

Antiviral agents were added to 3 or day 5 after infection (dpi) in these experiments, and left in culture for up to 7 dpi. Next, the supernatant and the damaged cells was transferred into a new cell culture overnight, and then stained for the expression of IE. The results show how substances inhibit viral Assembly and release. More specifically, at 3 dpi the most viral caspid gathered in the nucleus, whereas at 5 dpi in the main they have gained the membrane in the cytoplasm, and some began to form secondary shell.

In the tables the figure 2 shows the inhibitory effect of antiviral substances, using the modified system analysis on tablets. Some substances showed 100% inhibition of the expression of IE on the measurement results of staining IE, and the results of electron microscopy were observed formation cuspid in the nuclei of the majority of treated cells. The compound of the invention, designated 1A, showed very good results coincide with the results obtained with ganciclovir.

Table 2
The inhibiting effect of anti-viral compounds
SubstanceInhibition of 3 dpi (%)Inhibition of 5 PDI (%)
1A95-10085-95
To-220 (control)65-8565-80
Leflunomide (control)65-8080-90
Foscavir (control)85-10065-85
Ganciclovir (control)10080-95

The mechanism of action

Not communicating with any theory of the mechanism dei is the major compounds of the invention, it is noted that the analysis of the compounds of the invention 1A showed a clear inhibition of the expression of IE. Further, the electron microscopy data showed damage to the Assembly of the virus. Indeed, an analysis technique to obtain images used for identification and counting of stable intermediate particles CMVC showed damage to the binding of the coated proteins and viral cuspidal. Taken together, these data demonstrate the high potential for the application of compounds of the invention for antiviral therapy. Also, when using the compounds of the invention in combination with at least one other antiviral agent, such as for the treatment of many drugs, it is expected Energeticheskiy effect, and the risk of acquired drug resistance may be reduced or eliminated.

Toxicity

Compounds of the invention do not show any toxicity in the analysis by staining propidium-iodide cell cultures infected and uninfected fibroblasts of the human lung. The concentration of compounds 1A, 10 times more than used in the experiment did not show toxicity in the range 0-7 dpi. The concentration of the compounds used in viral experiments, was at the micromolar level. Cellular toxicity-220 was shown for concentrations above 100 ám.

<> Materials and methods

Cell culture

The fibroblasts of the human lung, HL-cells (MRC-5)used in these experiments were incubated at 37°C and 5% CO2in a solution of MEM with the environment Earl and L-glutamine (GIBCO), to which was added 10% fetal calf serum (ETS) and 1% penicillin and streptomycin (PeSt).

In early experiments, HL-cells kept in bottles for cell culture Falcon 175 cm2. To remove the cells from the flask for cell culture by transferring them into 48-well plates (Becton Dickinson) for infection and incubation with anti-viral agents used trypsin and EDTA.

Cells were incubated until then, until they reached 50% confluence under the same conditions as above, and used up to passage 26.

Infection of cells CMVC

HL cells infected CMVC, viral strain TV 40/E (endothelial adapted clinical isolate (UR1814), kindly provided by Professor G. Jahn) and viral strain AD-169, respectively, at a multiplicity of infection (MO) of 0.02, and incubated for up to 3 or 5 days after infection (dpi) at 37°C and 5% CO2in the same medium as above. Some cells (for experiment 0 PDI) were simultaneously subjected to anti-virus agents (see above). Negative controls were left uninfected.

Treatment of cells with inhibitors and antiviral agents

Existing environment (in experiments 3 and 5 dpi) were replaced and added new environment, with inhibitors and antiviral agents at various concentrations. However, this was done simultaneously with infection at 0 dpi experiment and left for incubation up to 1 dpi. The medium containing IVIg, incubated for one hour with the virus on ice before adding to the cells.

The modified analysis on tablets

In experiments 3 and 5 dpi supernatant from MRC-5 cells was transferred into a non-infected cells to evaluate the amount of excreted virus. The remaining cells were added to a new environment and destroyed the glass beads by shaking the microplate on IKA-Vibrax-VXR with shaking at 300 minute for 10 minutes. Next, cellular detritus carried in uninfected cells to estimate the number of infectious intracellular viral particles.

After infection with viral particles of new cells for about one hour, the medium was changed, purifying from the cellular detritus.

In experiments 0 dpi cells were immediately fixed in 1 dpi (in accordance with the procedure explained below).

Immunofluorescent staining of cells

New HL cells (3 and 5 days of the experiment) were fixed the next day by paraformaldehyde (PFA) for 15 minutes at room temperature (RT). In order to do the b cell permeable, used with 0.3% Triton X in Phosphate-saline buffer solution (FBI) for a 15 minute incubation at RT, followed by blocking background blocker of the background from DAKO for 20 minutes at RT, sufficient for covering the inner surface. After that, all microplates were incubated with primary antibodies (mouse)diluted 1:100, against pretannage antigen (IEA, Antigene) for 45 minutes at 8°C. Next, cells were incubated with the secondary antibody, rabbit and mouse FITZ (Daco Cytomation)diluted 1:100 for 45 minutes at 8°C, and were simultaneously stained with DAPI (Sigma)diluted to 1:250. DAPI is a chemical substance, a dye cell nuclei.

Positive and negative controls for both types of cells were treated, respectively, as described above.

Immunofluorescent microscopic analysis

Cells were analyzed by fluorescence microscopy using a Nikon Eclipse TE 2000-u, the Number of cells expressing the IEA, in two different parts of the wells was determined with the naked eye and compared with the total number of cells (indicated by DAPI), in the same parts. These values were used to assess the percentage of infected cells in each well, which was calculated the amount of inhibition caused by different substances. This method of counting infected cells in two parts link and apply to the entire well was selected because what is the total number of cells in the well is not possible to calculate manually.

1. The compound of formula (I)

where R1selected from H, F, Cl, Br, CF3C1-C6alkoxy and HE;
R2selected from H and C1-C6alkyl;
n is 1-5;
m is 0 or 1; and
Y is selected from CH2, NR3, (NR3R4)+X-, O and S;
R3and R4independently selected from H and C1-C4alkyl; and
X-selected from pharmaceutically acceptable anions.

2. The compound according to claim 1, where R1selected from H, F, Cl, Br, CF3The co3HE.

3. The compound according to claim 1, where R2selected from H and co3.

4. The compound according to claim 2, where R2selected from N and CH3.

5. The compound according to claim 1, where X-selected from CL-, VG-, methansulfonate, toluensulfonate, acetate, citrate and maleate.

6. The compound according to any one of claims 1 to 5, where m is equal to 0.

7. The compound according to any one of claims 1 to 5, where m is equal to 1.

8. The connection according to claim 7, where Y is O.

9. The compound according to any one of claims 1 to 5, where n is 1-3.

10. The connection according to claim 6, where n is 1-3.

11. The connection according to claim 7, where n is 1-3.

12. The connection of claim 8, where n is 1-3.

13. The compound according to claim 1, where
R1=H, R2=CH3n=3, m=0, X-=VG;
R1-H, R2=CH3n=3, m=0, X-=VG;
R1=9-Br, R2=CH3n=3, m=0, X-=Br;
R1 =9-Cl, R2=H, n=3, m=0, X-=Br;
R1=H, R2=H, n=1, m=1, Y=CH2X-=Br;
R1=H, R2=N, n=3, m=0, X-=Br;
R1=H, R2=CH3n=2, m=1, Y=O, X-=Br or
R1=9-Br, R2=CH3n=2, m=1, Y=O, X-=Br;

14. The method of obtaining the compounds according to claims 1-13, by reaction of compounds of formula (II)

with the compound of the formula (III)

where R1, R2, Y, m, and n are defined according to any one of claims 1 to 13; and
L is removed by the group; in a solvent or solvent mixture.

15. The method according to 14, where the deleted group selected from CL, Br, methansulfonate and toluensulfonate.

16. The compound according to any one of claims 1 to 13 for use as antiviral pharmaceuticals.

17. Antiviral pharmaceutical composition comprising a compound according to any one of claims 1 to 13, and a pharmaceutically acceptable filler.

18. The pharmaceutical composition according to 17, for use as anti-herpes drugs.

19. The pharmaceutical composition according p, where the herpes virus is human cytomegalovirus.



 

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10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of general formula , where R is an optional ortho- or meta-substitute selected from halogen and (C1-4)alkyloxy; R1 is halogen or CF3; R2 is H, (C1-4)alkyloxy or halogen; R3 is H or (CH2)n-NR5R6; R4 is H or (C1-6)alkyl, optionally substituted COOR7 or NR8R9; R5 and R6 independently denote H, (C3-8)cycloalkyl, quinuclidin-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted mono-substituted with CF3, (C3-8)cycloalkyl, (C6)aryl, a 5- or 6-member heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14 or NR13SO2(C1-4)alkyl; or R5 and R6 together with a nitrogen atom to which they are bonded form a 4-8-member saturated heterocyclic ring which also contains 1 heteroatom selected from O, SO2 and NR15, where the ring is optionally mono-substituted or di-substituted with oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17 or CONR18R19; R7 is H or (C1-4)alkyl; R8 and R9 independently denote H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or R8 and R9 together with a nitrogen atom with which they are bonded form a 4-8-member saturated heterocyclic ring which also contains one heteroatom which is O; R11 and R12 independently denote H or (C1-4)alkyl; R13 and R14 independently denote H or (C1-4)alkyl; R15 is H, (C1-4)alkyl (optionally mono-substituted OH, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20; R16 and R17 denote (C1-4)alkyl; or R16 and R17 together with a nitrogen atom with which they are bonded from a 4-8-member saturated heterocyclic ring; R18 and R19 denote H; R20 is (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and n equals 0 or 1; or its pharmaceutically acceptable salt. The invention also relates to use of formula I compounds to prepare a medicinal agent and to a pharmaceutical composition based on formula I compound.

EFFECT: novel derivatives have catepsin S and K inhibitory activity.

9 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of photoactivation of a photocatalyst by irradiating a composition containing the said catalyst. The method of using a photolatent catalyst (a) in which a composition containing said catalyst is irradiated before subsequent treatment is characterised by that, the photolatent catalyst is: (a1) a compound selected from a group consisting of a photolatent acid, an aromatic iodonium salt or oxime-based photolatent acid; (a2) a photolatent base compound. Also described is a substrate on which a coating made from the composition is deposited in accordance with the above described method. Also described is a method of using photolatent catalyst (a), in which a composition containing said catalyst is irradiated before subsequent treatment, characterised by that subsequent treatment is preparation of foam material and the composition contains polyol and isocyanate components and photolatent base (a2) as photolatent catalyst.

EFFECT: provision for solidification of the system.

13 cl, 10 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of formulae pharmaceutically acceptable salts or stereoisomers thereof, where R1 = -OR5, -NH-SO2R6; R2 = hydrogen; R3 = C1-6-alkyl; R4 = isoquinolinyl, possibly substituted; n equals 4 or 5; R5 = hydrogen; R6 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: novel compounds have hepatitis C virus replication inhibitory action and can be used in medicine.

6 cl, 32 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes a compound of general formula where A1 is selected from the following formula R1c denotes a hydrogen atom, a lower alkenyl group or a -Q3-A3(R1d)R1e group; A3 denotes a methane or lower alkyl group; Q3 denotes a single bond; R1d and R1e independently denote a hydrogen atom, hydroxyl group, lower alkyl group or hydroxyl-containing lower alkyl group, or together form a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1 denotes a lower alkenyl group or a lower alkynyl group; R2 denotes a phenyl, pyridyl or thienyl group, which can contain a -Q4-A4(R1g)R1h group; A4 denotes a nitrogen atom, a lower alkyl group optionally substituted with a hydroxy-lower alkyl group, or a methane group optionally substituted with a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q denotes a single bond or a lower alkylene group in which one or two or more methylene groups constituting the lower alkylene group can be independently substituted with an oxygen atom; R1g and R1h independently denote a hydrogen atom, a lower alkyl group or a lower alkylsulphonyl group; R5 and R6 independently denote a hydrogen atom, a lower alkyl group or a hydroxyl-containing lower alkyl group, or a pharmaceutically acceptable salt thereof. The invention also describes a pharmaceutical composition based on compounds of formula I, having anti-cancer activity, an anticancer agent, a codrug, as well as an exposure sensitising agent containing the pharmaceutical composition.

EFFECT: novel compounds are obtained and described, having excellent Well-kinase inhibitory action and can therefore be used in medicine, especially when treating different malignant tumours.

13 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel macrocyclic compounds of general formulae (I-c) (I-d), pharmaceutically acceptable salt or stereoisomer thereof, where R1 = -OR11 or -NH-SO2R12; R2 = hydrogen and R3 =C1-6-alkyl; n = 3-6; W is a radical of formula , where R5 = phenyl, possibly substituted with C1-6alkyl or alkoxy; thiazolyl, possibly substituted with C1-6alkyl; or pyridyl; R11 denotes hydrogen; R12 = C3-7-cycloalkyl, and a pharmaceutical composition containing said compounds.

EFFECT: said compounds are hepatitis C virus inhibitors and can be used in medicine.

3 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antiviral active components - substituted indoles of general formula 1 and pharmaceutically acceptable salts thereof, which can be used to treat and/or prevent viral diseases caused by hepatitis C virus (HCV). In general formula , R1 denotes a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, ethoxycarbonyl, nitro group; R2 denotes a hydrogen atom; R3 denotes N-mono- or N,N-disubstituted 1-methylene-piperidine-3-carboxamide of general formula 1a or N-mono- or N,N-disubstituted 1-methylene-piperdine-4-carboxamide of general formula 1b; R4 denotes a hydrogen atom, optionally substituted C2-C3alkyl, a -CH2-R12 group, where R12 denotes a hydrogen atom or phenyl which is optionally substituted with halogen or C1-C4alkyl; or R2, R3, and R4 together with atoms with which they are bonded form a substituted azaheterocycle of general formula 1.2; or R2 and R3 together with carbon atoms with which they are bonded form a substituted 2,3,4,9-tetrahydro-1H-carbazole of general formula 1.1, in which R1 denotes methyl, ethoxycarbonyl, nitro group; R4 denotes a hydrogen atom, methyl, C2-C3alkyl substituted with N-benzylamine; R7 and R8 denote hydrogen atoms or R7 and R8 together with a carbon atom with which they are bonded form a C=O group; R5 and R6, which are optionally identical, denote a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6cycloalkyl; or R5 and R6 together with a nitrogen atom with which they are bonded form an optionally substituted 5- or 6-member azaheterocyclyl containing one or two nitrogen atoms, etc.

EFFECT: improved properties of compounds.

11 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I): or its pharmaceutically acceptable salt where Q is 2,6-pyrimidyl; where Q is optionally substituted by 1-5 substitutes JQ; Z is a link or NH; R1 is H; R2 is H; R3 is halogen or -(U)m-X where m is equal to 0; X is H or halogen; JQ is halogen, OCF3, -(Vn)-R", -(Vn)-CN or -(Vn)-(C1-4 halogenaliphatic group) where JQ is not H; V is C1-10aliphatic group where up to three methylene groups are substituted by GV where Gv is selected from -NH-, -NR-, -O-, -S-, -CO2-, -C(O)CO-, -C(O), -C(O)NH-, -C(O)NR-, -C(=N-CN)-, -NHCO-, -NRCO-, -NHSO2-, -NRSO2-, -NHC(O)NH-, -NRC(O)NH-, -NHC(O)NR-, -NRC(O)NR or -SO2-; and where V is optionally substituted by 1-6 substitutes JV; R" is H or an optionally substituted group selected from C1-6aliphatic group, C3-10cycloaliphatic group, C6-10aryl, 5-10-member heteroaryl or 5-10-member heterocyclyl; or two R" groups on the same substitute or various substitutes together with atom (s) whereto each group R" is attached, form optionally substituted 3-8-member heterocyclyl; where each optionally substituted R" group is independently and optionally substituted by 1-6 substitutes JR; R is an optionally substituted group selected from C1-6aliphatic group and C6-10aryl where each group R is independently and optionally substituted by 1-4 substitutes JR; each Jv and JR are independently selected from halogen, L, - (Ln)-R', - (Ln)-N(R')2, -(Ln)-OR', C1-4haloalkyl, -(Ln)-CN, - (Ln)-OH, -CO2R', -CO2H or -COR'; or two Jv, JR groups on the same substitute or various substitutes together with atom (s) whereto each group JV and JR is attached, form a 5-7-member saturated, unsaturated or partially saturated ring; R' is H or C1-6aliphatic group; L is C1-6aliphatic group where up to three methylene units are substituted by -C(O)-; each n is independently equal to 0 or 1. Besides, an invention refers to of a pharmaceutical composition for ROCK or JAK kinase inhibition on the basis of the given compounds, to a method of ROCK or JAK kinase activity inhibition, and also to application of the compounds of formula I, for preparing a drug where Q, Z, R1, R2 and R3 are those as described in cl. 1 of the patent claim, effective as protein kinase inhibitors, especially JAK and ROCK families kinase inhibitors.

EFFECT: there are prepared and described new compounds which can find the application in medicine.

42 cl, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of general formula (I) or pharmaceutically acceptable salts thereof, having JANUS: JAK2, JAK3 protein kinase, protein kinase A (PKA), serine/threonine protein kinase ROCK inhibiting properties. The compounds can be used to treat such diseases as allergy, asthma, atopic dermatitis and others. In structural formula (I): R1 denotes H; R2 denotes H; Z1 denotes C1-6aliphatic group or C5-7cycloaliphatic group, optionally substituted with 0-1 groups Jz; if the bond between Z1 and C is a double bond, then Z1 can also denote =O or =C(R)2; Z2 denotes H; or C1-10halogenalkyl, -(Vn)-CN, (Vn)-(heterocyclyl), where the heterocyclyl is a 6-member ring containing a nitrogen atom or two oxygen atoms as heteroatoms, -(Vn)-(phenyl) or -(Vn)-(C3-10cycloaliphatic group), optionally substituted with 0-1 groups Jz; or Z1 and Z2 together with the carbon atom with which they are bonded form a ring Q; Z3 denotes H or C1-6alkyl, optionally substituted with 0-1 groups Jz; or Z1, Z2 and Z3 together with the carbon atom with which they are bonded form a 6-8-member saturated bicyclic ring Q; where if the bond between Z1 and C is a triple bond, then Z2 and Z3 are absent; if the bond between Z1 and C is a double or triple bond, then Z3 is absent or Z2 and Z3 are absent; Q denotes a 3-8-member saturated or partially saturated monocyclic ring containing 0-2 heteroatoms selected from nitrogen, oxygen or sulphur, where said Q is optionally and independently condensed with Q1; where said Q is optionally substituted with 0-4 groups JQ, where said Q is optionally substituted with 0-4 groups JQ. Values of other radicals are given in the claim.

EFFECT: high efficiency of using the compositions.

35 cl, 5 dwg, 5 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel conformationally stable compounds of general formula (I), which imitate the secondary structure of reverse-configuration regions of biologically active peptides and proteins which are reverse-configuration mimetics. The compounds can be used to inhibit or treat disorders modulated by Wnt-signalling pathway, such as cancer, especially colorectal cancer. The invention also relates to a library containing the disclosed compound. In general formula (I), A denotes -(C=O)-, B denotes -(CHR4)-, D denotes -(C=O)-, E denotes -(ZR6)-, G denotes -(XR7)-, Z denotes CH, X denotes a nitrogen atom, W denotes -(C=O)NH-, R1 denotes benzyl; R2 denotes a heterocyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms; a substituted hetercyclylC1-6alkyl group, including a 9-member condensed bicyclic ring having 2-3 heteroatoms selected from nitrogen, oxygen or sulphur atoms, an the ring has 1-3 substitutes independently selected from a group comprising halogen, piperidinyl, morpholinyl, C2-6alkenyl, phenyl, hydroxyphenyl, C1-6alkoxycarbonyl, dialkylamino, hydroxypiperidinyl, C1-6alkyl, hydroxyC1-6alkylpiperazinyl, amino, piperidinyl carbonyl; heterocyclyl-C1-6alkyl group having a 9-member condensed bicyclic ring which has one or two nitrogen atoms; and other values given in the claim. R4 denotes a substituted benzyl, having a substitute selected from disodium phosphate, monosodium phosphate, phosphate; R6 denotes hydrogen; R7 denotes: C1-6alkyl; C1-6alkynyl; C2-6alkenyl; substituted benzyl, having one or more substitutes independently selected from halogen and C1-6alkyl.

EFFECT: high efficiency of the compounds.

8 cl, 34 dwg, 19 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing novel compounds of general formula , where NR1R2=NH2; NHAlk, where Alk=C1-C6, or cycloalkyl-C3-C6; NAlk2, where Alk=C1-C6, or cycloalkyl-C3-C6; N(CH2)n, where n=2, 3, 4, 5, 6; N(CH2CH2)2O; NHAr, where Ar=C6H5, C6H4R3, where R3=Alk(C1-C6), NO2, halide, which can be used as biologically active substances and intermediate products in synthesis of biologically active substances (anomalous nucleosides, nucleotides etc). Sodium salts of 5-NR1R2-tetrazolo[1,5-a]-1,3,5-triazin-7-ones are obtained via successive substitution of chlorine atoms in 2-NR1R2-4,6-dichloro-1,3,5-triazines with a hydroxy and azido group. The corresponding 2-NR1R2-4,6-dichloro-1,3,5-triazine reacts with aqueous sodium hydroxide solution followed by acidation and the obtained 4-NR1R2-6-chloro-(3H)-1,3,5-triazin-2-one is treated with sodium azide in an organic solvent such as acetone, acetonitrile, dimethylformamide or mixtures thereof.

EFFECT: obtaining sodium salts of 5-NR1R2-tetrazolo[1,5-a]-1,3,5-triazin-7-ones directly from 2-amino-4,6-dichloro-1,3,5-triazines without obtaining and use of bis- and mono-trinitromethyl-1,3,5-triazines.

1 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel derivatives of condensed pyrazole-, imidazole-, oxazole- and triazole pyrimidines, structural formulae of which are disclosed in the claims, as well as pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with cannabinoid receptor 1 (CB1) activity.

EFFECT: improved properties of compounds.

33 cl, 448 ex, 1 tbl

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel derivatives of quinolone or one pharmaceutically acceptable salts thereof, solvates thereof or solvates of salts thereof, having general formula I , in which R1 denotes fluorine, R3 denotes halogen, a hydroxy group or a C1-C4-alkoxy group, R4 denotes C1-C6-alkyl or C3-C8-cycloalkyl, where the alkyl can contain 1-3 substitutes, and the substitutes are independently selected from a group comprising halogen or trifluoromethyl, and where the cycloalkyl can contain 1-3 halogen atoms as substitutes, or R3 and R4 together with atoms to which they are bonded form a ring with a group of formula , in which * indicates a site for bonding with a carbon atom, and # indicates a site for bonding with a nitrogen atom, R7 and R8 independently denote halogen, trifluoromethyl, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, C1-C3-alkyl or C1-C3-alkoxy group, and R9 denotes hydrogen, halogen or C1-C3-alkyl, or R8 denotes a trifluoromethoxy group, and R7 and R9 denote hydrogen, R10 denotes a group of formula or , in which * indicates a site for bonding with a carbon atom, R2 is bonded in position 3 or 4 and denotes a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C3-C6-cycloalkylcarbonyl or optionally hydroxy-substituted C1-C6-alkylaminocarbonyl, where the alkyl is substituted with one substitute and the substitute is selected from a group comprising a hydroxy group, hydroxycarbonyl, aminocarbonyl, C1-C4-alkoxycarbonyl and 2-oxopyrrolidin-1-yl, R5 and R6 are independently bonded in positions 3, 4 or 5 and independently denote hydrogen, hydroxy group, methyl or ethyl, and Y denotes a methylene group or an oxygen atom. The invention also relates to methods of producing a compound of formula I, a medicinal agent based on the compound of formula I, use of the compound of formula I and a method of fighting viral infections.

EFFECT: novel substituted quinolone derivatives which are useful in treating viral diseases are obtained.

11 cl, 1 tbl, 69 ex

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