Substituted indoles, antiviral active component, synthesis and application method

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

 

The present invention relates to a new antiviral active component of the pharmaceutical composition, antiviral drug, method of prevention and treatment of viral diseases, especially caused by hepatitis C (HCV).

Viral infection can cause many diseases, which poses a serious threat to the health and life of mankind. Over the last 20 years found at least 30 new infectious diseases: AIDS, viral hepatitis, acute and chronic diarrhoea, haemorrhagic fevers (Ebola, Venezuelan, Brazilian, rift valley) [(a) Lednicky J.A., Rayner J.O. Uncommon respiratory pathogens. Curr. Opin. Pulm. Med. 2006, 12(3), 235-239. b) Hayden F.G.Respiratory viral threats. Curr. Opin. Infect. Dis. 2006, 79(2), 169-178]. In particular, special concern is the possibility of human infection with the so-called "bird flu" [a) Liu J.P. Avian influenza-a pandemic waiting to happen? J. Environ. Immunol. Infect. 2006, 39(1), 4-10. b) Henter J.I.; Chow C.B.; Leung C.W, Lau Y.L. Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet. 2006 367(9513), 870-873. Review]. According to statistics 60-65 % of epidemic infections are of viral etiology. Because of the complexity of interactions in the triad "virus - host organism - drug" most modern antiviral drugs during therapy are the side effects and form a resistant viral strains [R. Jain, N.M. Clark, Diaz-Linares M., Grim S.A. Limitations of curent antiretroviral agents and opportunities for development. Curr. Pharm. Des. 2006, 12(9), 1065-1074]. Currently, the number of antiviral drugs that can be used in clinical practice, is extremely limited - only 43 low molecular weight substances [http://integrity.prous.com/integrity]that not meets the needs of the prevention and treatment of viral diseases. In addition, there are a significant number of viral infections that cause disease, for which treatment does not currently exist chemotherapeutic agents. This applies, for example, diseases caused by papilloma viruses, adenoviruses, herpes 6, smallpox, syndrome SARS, haemorrhagic fevers, West Nile fever, avian influenza, etc. [De Clercq E. Recent highlights in the development of new antiviral drugs. Curr Opin Environ. 2005, 8(5), 552-560].

Thus, great importance is the creation of new antiviral drugs, especially with a new mechanism of antiviral action, high activity and low toxicity.

Published international application WO 2009039246 A2 and WO 2009039248 A2, which describes the new antiviral active ingredients, representing Climatol I and its analogs, for example, benzimidazole II, intended for the prevention and treatment of viral diseases caused by viruses of hepatitis C (HCV). µm

However, many of substituted indoles having activity against HCV, up to this time were not known.

Search highly effective antiviral drugs currently still is one of the main directions of development of new pharmacological agents for the treatment of a wide and diverse range of viral infections.

Below are definitions of terms used in the description of this invention.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Azaheterocycle can have one or more cyclic substituents" of the system. "Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance is synthetic or other (biotechnology, plant, animal, microbial or other origin, possessing pharmacological activity and which is the active beginning of the pharmaceutical composition used for the production and manufacture of the medicinal product (tools).

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or several what about the "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNC(=S)-, RkaRk+1aNSO2where Rkaand Rk+1aindependently from each other represent "amino substituents, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7 membered heterocyclyl or heterocyclyl. Preferred alkyl which groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation, methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Amino group" means RkaRk+1aN - group, substituted or unsubstituted "Deputy amino group" Rkaand Rk+1awhose value is defined in this section, for example, amino (H2N-), methylamino, diethylamino, pyrrolidine, morpholine, benzylamine or phenethylamine.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, predominantly from 6 to 10 carbon atoms.

Aryl can contain one or more "cyclic system substituents"which may be the same Il is different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle. "Hydrate" means the MES, in which water is a molecule or molecules of solvent.

"Deputy" means a chemical moiety that is attached to scaffold (fragment), for example, Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system.

"Deputy amino group" means the Deputy attached to the amino group. Deputy amino group represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonylmethyl, alcoxycarboxylates, g is teraelectronvolts. "Substituted amino group" means RkaRk+1aN - group, in which Rkaand Rk+1arepresent substituents of the amino group, the value of which is determined in this section.

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other fabricated forms intended for restoring, correcting or modifying physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Optionally substituted radical" means a radical without substituents or with one or more substituents.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms.

"Therapeutic cocktail" is simultaneously SKOLKOVO initiative combination of two or more drugs with different mechanisms of pharmacological action and aimed at different biological target involved in the pathogenesis of the disease.

"Pharmaceutical composition" means a composition comprising an active component and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible with stomach fillers, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and the mixture vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, aginova acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal injection of the active principle, one or in combination with other active early, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt" means in relation to detox cnie organic and inorganic salts of acids and bases, claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like (for a Detailed description of the properties of such salts are described in Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, g is droxia lithium calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The subject of this invention is a new antiviral active component that represents a substituted indole of General formula 1 and its pharmaceutically acceptable salts

where: R1 represents a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, etoxycarbonyl, nitro GRU is PU;

R2 represents a hydrogen atom;

R3 represents N-mono - or N,N-disubstituted 1-methylene-piperidine-3-carboxamide General formula 1A or N-mono - or N,N-disubstituted 1-methylene-piperidine-4-carboxamide General formula 1b;

R4 represents a hydrogen atom, optionally substituted C1-C3alkyl, a group-CH2-R12, where R12 represents a hydrogen atom or optionally substituted by halogen or C1-C4the alkyl phenyl;

or

R2, R3 and R4 together with the atoms to which they are linked, form two substituted annelated with pyrrole ring and with each other six or six - and semichronic cycle with the formation of azaheterocycle General formula 1.2;

or

R2 and R3 together with the carbon atoms to which they are linked, form a substituted six-membered saturated, and annelirovannymi with pyrrole ring cycle with the formation of 2,3,4,9-tetrahydro-1H-carbazole General formula 1.1 in which R1 represents methyl, etoxycarbonyl, nitro group; R4 represents a hydrogen atom, methyl,2-C3alkyl, substituted N-benzylamino; R7 and R8 represent hydrogen atoms or R7 and R8 together with the carbon atom to which they are attached, form the group C=O;

R5 and R6 are not necessarily identical, represent a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6C is cloacal;

or R5 and R6 together with the nitrogen atom to which they are bound, form an optionally substituted 5 - or 6-membered azaheterocyclic containing one or two nitrogen atom, possibly condensed with benzene ring, or form a groupwhere R11 represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl;

R9 represents azaheterocyclic containing at least one nitrogen atom, unsubstituted of formamid, or phenyl, substituted ethoxycarbonyl or nitro group;

R10 represents a hydrogen atom, optionally substituted C1-C3alkyl; substituted acetyl, where the substituents are selected from 5-6-membered nitrogen-containing heterocyclyl or 5-6-membered nitrogen-containing, heteroaryl-group;

n=1 or 2;

the dotted line with its accompanying solid linerepresents a single or double bond.

Preferred is an antiviral active component that represents a substituted amide 1-[(1H-indol-2-yl)methyl]piperidine-4-carboxylic acid of General formula 1.3.1 or substituted amide 1-[(1H-indol-2-yl)methyl]piperidine-3-carboxylic acid of General formula 1.3.2 and their pharmaceutically acceptable salts.

where R4, R5 and R6 have the above value.

More preferred is an antiviral active component, represents a substituted amide 1-[(1H-indol-2-yl)methyl]piperidine-4-carboxylic acid of General formula 1.3.1.1 and its pharmaceutically acceptable salt

where R11 represents a C1-C3alkyl; R12 represents a hydrogen atom or optionally substituted by halogen or C1-C3the alkyl phenyl.

More preferred is an antiviral active component, which has antiviral activity against HCV, representing a substituted indole of General formula 1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 or its pharmaceutically acceptable salt.

The subject of this invention is also a pharmaceutical composition having antiviral activity, containing a pharmaceutically effective amount of the antiviral active component representing at least one substituted indole of General formula 1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 or its pharmaceutically acceptable salt.

More preferred is a pharmaceutical composition having antiviral activity against hepatitis C virus (HCV), containing as an active ingredient, at least one substituted indole of General formula 1,1.1,1.2,1.3,1.3.1,1.3.1.1,1.3.2.1 or its pharmaceutically acceptable salt.

Pharmaceutical compositions can include pharmaceutical is Ki acceptable excipients. Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. The pharmaceutical composition along with substituted indoles of General formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 or its pharmaceutically acceptable salt according to the present invention may include other active ingredients, provided that they do not cause unwanted effects, such as allergic reactions.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed with other components for the production of different forms, however, they can contain conventional pharmaceutical carriers; for example, oral formulations such as tablets, gelatin capsules, pills, solutions or suspensions); forms for injection (such as solutions or suspensions for injection or dry powder for injection, which requires only the addition of water for injection before use); local forms such as ointments or solutions).

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including: oral forms are used binders is, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

The object of the present invention is also a method of obtaining a pharmaceutical composition.

This goal is achieved by the mixing of at least one antiviral active component that represents a substituted indole of General formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 or its pharmaceutically acceptable salt with an inert filler and/or diluent.

The subject of this invention is also a drug intended for the treatment of viral diseases, incorporating new antiviral component representing at least one substituted indole of General formula 1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 or its pharmaceutically acceptable salt, or a new pharmaceutical composition containing this active ingredient, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.

According to this invention the preferred drug is a drug, prednaznachennoe for the treatment of diseases, caused by viruses, HCV, incorporating new antiviral component representing at least one substituted indole of General formula 1,1.1,1.2,1.3,1.3.1,1.3.1.1,1.3.2.1 or its pharmaceutically acceptable salt, or a new pharmaceutical composition containing this active ingredient, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing.

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of the pharmaceutical composition or drug containing antiviral active component of General formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1, patients can be corrected depending on: therapeutic efficiency and bio-availability of active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg, preferably 50~300 mg. Therefore, during the preparation of the pharmaceutical composition of the medicinal product according to the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10~500 mg active on the Ala General formula 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1, preferably 50~300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

The object of the present invention is also a therapeutic cocktail for the prevention and treatment of viral diseases, including diseases caused by hepatitis C, including a new active ingredient or new pharmaceutical composition comprising at least one substituted indole of General formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 or its pharmaceutically acceptable salt.

Therapeutic cocktails for the prevention and treatment of hepatitis C along with drugs in this invention may include: inhibitors of inosine-5-monophosphate dehydrogenase, such as Ribavirin (allowed) and Ribamidil;

inhibitors of the NS3 protease of hepatitis C, for example, Telaprevir, Ciluprevir and SCH-503034; inhibitors of RNA polymerase NS5B, for example, XTL-2125; alpha-glucosidase inhibitors, such as aminoplast Celgosivir; and agonists of TLR receptors, hepatoprotectors, cyclosporine, various proteins (e.g., interferons), antibodies, vaccines, etc.

The subject of this invention is also a method for the prevention and treatment of viral diseases of animals and people the th.

In accordance with this invention a method for the prevention and treatment of viral diseases of animals and people, including those caused by hepatitis C, is the introduction of warm-blooded animals or humans of new drugs, new pharmaceutical compositions or new therapeutic cocktail containing an effective quantity of new antiviral active component of General formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 or its pharmaceutically acceptable salt.

The subject of this invention is also a previously unknown 2-(8-isopropyl-1,2,3A,4,5,6-hexahydro-3H-pyrazino[3,2,1-Jk]carbazole-3-yl)ndimethylacetamide and its hydrochloride of the formula 1.2(1)·Hcl

The subject of this invention are previously unknown substituted amides of 1-[(1H-indol-2-yl)methyl]piperidine-4-carboxylic acid of General formula 1.3.1 and substituted amides of 1-[(1H-indol-2-yl)methyl]piperidine-3-carboxylic acid of General formula 1.3.2 and their pharmaceutically acceptable salts.

where R4, R5 and R6 have the above value.

The subject of this invention are previously unknown substituted amides of 1-[(1H-indol-2-yl)methyl]piperidine-4-carboxylic acid of General formula 1.3.1.1 and substituted amides of 1-[(1H-indol-2-yl)methyl]piperidine-3-carboxylic acid of General formula 1.3.2.1 and the x pharmaceutically acceptable salt.

where R11 represents a C1-C3alkyl; R12 represents a hydrogen atom or optionally substituted by halogen or C1-C3the alkyl phenyl.

Preferred substituted inorganic salts are {1-[1-(4-Chlorobenzyl)-1H-indole-2-ylmethyl]-piperidine-4-yl}-(4-propylpiperazine-1-yl)-methanone 1.3.1.1(13), {1-[1-(4-Chlorobenzyl)-1H-indole-2-ylmethyl]-piperidine-3-yl}-(4-propylpiperazine-1-yl)-methanone 1.3.2.1(13) [1-(1-methyl-1H-indole-2-ylmethyl)-piperidine-4-yl]-(4-propylpiperazine-1-yl)-methanone 1.3.1.1 (14), [1-(1-methyl-1H-indole-2-ylmethyl)-piperidine-3-yl]-(4-propylpiperazine-1-yl)-methanone 1.3.2.1(14) and their hydrochloride.

The subject of this invention is also a method of obtaining substituted amides of 1-(1H-indol-2-ylmethyl)-piperidine-carboxylic acid of General formula 1.3.1, 1.3.2 and their pharmaceutically acceptable salts, which lies in the interaction of substituted 1-(1H-indol-2-ylmethyl)-piperidine-carboxylic acids of General formula 2.1, 2.2 with amines 3. Optimal results were achieved when carrying out the reaction in the presence of 1,1'-carbonyldiimidazole. Pharmaceutically acceptable salts of amides 1.3.1, 1.3.2 get when interacting reason 1.3.1, 1.3.2 with the corresponding acids in the environment of a suitable organic solvent.

where R4, R5 and R6 have the above value.

The subject of this invention is also a method of obtaining a hydrochloride of 2-(8-isopropyl-1,2,3A,4,5,6-hexahydro-3H-pyrazino[3,2,1-Jk]carbazole-3-yl)ndimethylacetamide formula 1.2(1)·Hcl by hydrogenation of 9-[2-(dibenzylamino)ethyl]-6-isopropyl-3,4-dihydro-2H-carbazole-1(9H)-she's in the presence of 10% Pd/C, followed by alkylation of the resulting 2-(8-isopropyl-1,2,3A,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazole chloracetamide and converting the received base hydrochloride according to the following scheme:

The following are specific examples which illustrate, but not limit the scope of the present invention.

Example 1. Determination of the antiviral activity of the compounds of General formula 1 in respect of hepatitis C.

Determination of the antiviral activity of the compounds of General formula 1,1.1,1 .2, 1.3, 1.3.1, 1.3.1.1, in relation to HCV was performed on the cell culture Huh7. Used immune in vitro ELISA test on short-antigen of HCV virus. With this test measured the efficiency of inhibition of the test compounds production of the antigen (and hence replication of the virus in cells infected with JFH-1. Used in this experiment, cultures of Huh7 cells capable of being infected by HCV virus, to support the full cycle of viral replication.

Re ominantly virus JFH-1 HCV, used in the experiment was obtained by transfection of Huh7 cells RNA JFH-1, obtained by in vitro transcription. DNA JFH-1 (NCBI, catalogue number AW [Wakita, T. and other Production of Infectious Hepatitis C Virus in Tissue Culture from a Cloned Viral Genome. Nature Medicine 2005, 11:791-796]), used as DNA templates for transcription, was synthesized chemically.

The Huh7 cells were seeded in 96-well card (3,0×103cells per well) in the medium of Huh-7 (50 µl per well). For each test compound prepared 9 solutions in the medium of Huh-7 in the concentration range of 0.09 to 200 μm. 4 hours later after vysielanie cells, the original solution was removed by aspiration, and then to each well was added 50 μl of a solution of test compound and 50 μl of drug JFH-1 HCV. Thus, the final concentration of the tested compounds were in the range of 0.045-100 μm. If necessary, the stage of infection was performed 24 hours after the addition of test compounds. After incubation for 16 hours a viral medium was removed by aspiration, and the cultures were added to test compounds in source concentrations to a final volume of 200 μl. Cells and test compounds were additionally incubated for 4 days at 37°C in an atmosphere of air containing 5% carbon dioxide CO2. After removal of the nutrient medium of the cells was the fixed 250 μl of a mixture of acetone-methanol (1:1) for 1 minute, thrice washed with phosphate buffer (PBS buffer and then they were blocked with a 10% solution of FBS-PBS (150 μl/LUN) for 1 hour at room temperature. Each well three times washed with a solution of PBS, incubated with mouse monoclonal antibodies to core-HCV antigen (Affinity BioReagents, catalogue number MA 1-080), dissolved in buffer FBS-PBS (100 μl/LUN solution prepared from the original concentrate, diluted in the ratio 1:500 in 10% FBS - PBS)for 2 hours at 37°C. Each well was washed three times with a solution of PBS, incubated with antibodies specific to mouse immunoglobulins conjugated with horseradish peroxidase (HRP, 100 μl/LUN solution prepared from the original concentrate diluted in a ratio of 1:2500 in 10% FBS - PBS) for 1 hour at 37°C. Washed each well three times with PBS solution, and then was treated with 100 μl/LUN OPD solution (prepared by dissolving 1 tablet of OPD in 12 ml citratestates buffer with the addition of 5 μl of 30% H2O2) for 30 minutes in the dark at room temperature. The reaction was stopped by adding to each well 100 μl of 2N H2SO4after that he measured the absorbance at a wavelength of 490 nm. The value of the IC50representing the concentration of test compound at which the replication of the virus is reduced by half, was determined for each test compound using software which we Xlfit method, described in [Wakita, T. and others (2005). Production of Infectious Hepatitis With Virus in Tissue Culture from a Cloned Viral Genome. Nature Medicine; 11: 791-796].

The table presents the value of the IC50substituted indoles of General formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, reflecting their ability to inhibit hepatitis C.

Substituted indoles of General formulas 1, 1.1, 1.2, 1.3, 1.3.1, 1.3.1.1, 1.3.2.1 possess high activity against HCV (table). As a rule, they are more active than the known preparations I and II [WO 2009039246 A2, WO 2009039248 A2]. So, for example, compounds 1.3.1.1(2) and 1.3.1.1(13) have the IC50= 0,3 µm, and connection 1.1(8), 1.3.1(2) 1.3.1.1 and(7) have the IC50= 0,4 µm.

Example 2. Hydrochloride of 2-(8-isopropyl-1,2,3A,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazole-3-yl)-ndimethylacetamide 1.2(1)·Hcl. A solution of 8.45 g (18.8 mmol) of 9-[2-(dibenzylamino)ethyl]-6-isopropyl-3,4-dihydro-2H-carbazole-1(9H)-she. in 80 ml of methanol hydronaut in the autoclave with 0.5 g 10 % Pd/C at 30 psi for 24 h at 70°C. the Solution is filtered through celite and evaporated the vacuum. The remainder of the formed 2-(8-isopropyl-1,2,3A,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazole boil with 1.93 g (20.6 mmol) of chloracetamide and 3.88 g2CO3in 50 ml of acetonitrile for 12 hours, the Solvent is distilled off in vacuum, the residue is treated with water and extracted with CH2CL2. The extract is dried over Na2SO4, evaporated and recrystallized from alcohol. Obtain 3.27 g (56 %) of 2-(8-isopropyl-1,2,3A,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazole-3-yl)-ndimethylacetamide 1.2(1). LCMS (M+H)+312.1H NMR (CDCl3, 400 MHz) δ 7.34 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.10 (DD, J1= 8.4 Hz, J2= 1.2 Hz, 1H), 7.02 (ush. s, 1H), 5.50 (ush. s, 1H), 4.18 (DD, J1= 11.6 Hz, J2= 3.6 Hz, 1H),3.84 (dt, J1= 11.6 Hz, J2= 4.8 Hz, 1H), 3.59 (m, 1H), 3.53 (d, J1= 12.8 Hz, 1H), 3.23 (DD, J1= 12.4 Hz, J2= 4.8 Hz, 1H), 3.06 (m, 3H), 2.82 (DD, J1= 11.6 Hz, J2= 6.4 Hz, 1H), 2.70 (m, 1H), 2.22 (m, 2H), 1.86 (m, 1H), 1.53 (m, 1H), 1.32 (d, J1= 6.8 Hz, 6H). Hydrochloride of 2-(8-isopropyl-1,2,3A,4,5,6-hexahydro-3H-pyrazino[3,2,1-jk]carbazole-3-yl)-ndimethylacetamide 1.2(1)·Hcl planted by adding 5%excess 3N solution of Hcl in dioxane to a solution of the base 1.2(1) in CH2Cl2.1H NMR (DMSO-d6, 400 MHz) δ at 10.89 (ush. s, 1H), 8.16 (ush. s, 1H), 7.75 (ush. s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.77 (ush. m, 1H), 4.46 (d, J = 6.4 Hz, 1H), 4.25 (ush. m, 1H), 3.95 (ush. m, 4H), 2.97 (t, J = 6.8 Hz, 1H), 2.73 (ush. d, J = 15.6 Hz, 1H), 2.58 (ush. m, 1H), 2.35 (ush. m, 1H), 2.20 (ush. m, 1H), 1.78 (ush. m, 2H), 1.24 (d, J = 6.8 Hz, 6H).

Example 3. Amides of 1-(1H-indol-2-ylmethyl)piperidine-carboxylic acids of General formula 1.3.1, 1.3.2 (General method). To a suspension of 10 mmol of acid 6 in 45 ml of dry acetonitrile is added 1.95 g (12 mmol) of 1,1'-carbonyldiimidazole. The mixture is stirred for three hours at 70°C (control over education imidazoline carried out by TLC), cooled to room temperature, added 12 mmol of the appropriate piperazine and stirred at 70°C for 12 hours (monitoring by LCMS). After the reaction mixture was poured into water, the precipitated precipitate is filtered off, washed several times with water and dried in vacuum. Get amides 1.3.1, 1.3.2.

Dihydrochloride amides 1.3.1, 1.3.2 is produced by adding 5% of the excess 3 N model HC1 in dioxane to a solution of amides in ether (5 g in 500 ml).

1-Methyl-2-({4-[(4-propylpiperazine-1-yl)carbonyl]piperidine-1-yl}methyl)-1H-indole 1.3.1.1(14). The output of 28%. LCMS (M+H)+383.1H NMR (DMSO-d6400 MHz) δ 11.29 (ush. s, 1H), 10.80 (ush. s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1 H), 7.23 (m, 1H), 7.09 (m, 1H), 6.80 (s, 1H), 4.55 (ush. s, 2H), 4.39 (ush. m, 1H), 4.11 (ush. m, 1H), 3.85 (s, 3H), 3.59 (ush. m, 1H), 3.51 (ush. m, 2H), 3.43 (ush. m, 2H), 3.12 (m, 1H), 2.98 (ush. m, 5H), 2.86 (ush. m, 2H), 2.73 (s, 3H), 1.96 (ush. m, 2H), 1.82 (ush. m, 2H), 1.72 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

1-Methyl-2-({4-[(4-methylpiperazin-1-yl)carbonyl]piperidine-1-yl}methyl)-1H-indole 1.3.1.1(15). Yield 56%. LCMS (M+H)+355.1H NMR (DMSO-d6, 400 MHz) δ 11.41 (USS, 1H),10.93 (USS, 1H),7.60 (d, J = 7.6 Hz, 1H), 7.51 (d, J = Hz, 1 is), 7.23(m, 1H), 7.08 (m, 1H), 6.81 (s, 1H), 4.54 (ush. s, 2H), 4.40 (ush. m, 1H), 4.12 (ush. m, 1H), 3.85 (s, 3H), 3.50 (ush. m, 5H), 3.00 (ush. m, 4H), 2.87 (ush. m, 2H), 2.73 (s, 3H), 1.98 (ush. m, 2H), 1.82 (ush. m, 2H).

1-Methyl-2-({3-[(4-methylpiperazin-1-yl)carbonyl]piperidine-1-yl}methyl)-1H-indol the dihydrochloride 1.3.2.1(1). Yield 46%. LCMS (M+H)+355.1H NMR (DMSO-d6, 400 MHz) δ 11.28 (USS, 1H), 11.14 (USS, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.22 (m, 1H), 7.07 (m, 1H), 6.83 (ush. m, 1H), 4.57 (ush. s, 2H), 4.37 (ush. m, 1H), 4.07 (ush. m, 1H), 3.87 (s, 3H), 3.55 (ush. m, 1H), 3.42 (ush. m, 4H), 3.14 (ush. m, 2H), 3.02 (ush. m, 3H), 2.89 (ush. m, 1H), 2.72 (ush. m, 3H), 1.98 (ush. m, 1 H), 1.86 (ush. m, 2H), 1.44 (ush. m, 1H).

1-Methyl-2-({3-[(4-propylpiperazine-1-yl)carbonyl]piperidine-1-yl}methyl)-1H-indol the dihydrochloride 1.3.2.1(2). Yield 47%. LCMS (M+H)+383.1H NMR (DMSO-d6400 MHz) δ 11.19 (ush. m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.22 (m, 1H), 7.07 (m, 1H), 6.83 (ush. m, 1H), 4.56 (ush. s, 2H), 4.37 (m, 1H), 4.05 (m, 1H), 3.87 (s, 3H), 3.61 (m, 1H), 3.44 (ush. m, 5H), 3.14 (ush. m, 2H), 2.98 (ush. m, 4H), 2.86 (ush. m, 1H), 1.98 (ush. m, 1H), 1.86 (ush. m, 2H), 1.70 (ush. m, 2H), 1.44 (ush. m, 1H), 0.89 (ush. m, 3H).

1-(4-Chlorobenzyl)-2-({3-[(4-methylpiperazin-1-yl)carbonyl]piperidine-1-yl}methyl)-1H-indol the dihydrochloride 1.3.2.1(12). Yield 79 %. LCMS (M+N)+465, 467.1H NMR (DMSO-d6, 400 MHz) δ 11.07 (ush. m, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.17 (m, 1H), 7.09 (m, 1H), 6.98 (ush. m, 1H), 6.93 (d, J = 8.0 Hz, 2H), 5.69 (ush. s, 2H), 4.50 (ush. s, 2H), 4.38 (ush. m, 1H), 4.07 (ush. m, 1H), 3.49 (ush. m, 5H), 3.16 (ush. m, 2H), 3.00 (ush. m, 3H), 2.89 (ush. m, 1H), 2.74 (ush. m, 3H), 1.95 (is. m, 1H), 1.86 (ush. m, 2H), 1.43 (ush. m, 1H).

1-(4-Chlorobenzyl)-2-({3-[(4-propylpiperazine-1-yl)carbonyl]piperidine-1-yl}methyl)-1H-indol the dihydrochloride 1.3.2.1(13). Yield 78 %. LCMS (M+H)+493,495.1H NMR (DMSO-d6, 400 MHz) δ 11.12 (ush. m, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.17 (m, 1H), 7.09 (m, 1H), 6.99 (ush. m, 1H), 6.93 (d, J = 8.0 Hz, 2H), 5.69 (ush. s, 2H), 4.51 (ush. s, 2H), 4.37 (ush. m, 1H), 4.06 (ush. m, 1H), 3.59 (m, 1H), 3.41 (ush. m, 5H), 3.14 (ush. m, 2H), 2.98 (ush. m, 4H), 2.85 (ush. m, 1H), 1.96 (ush. m, 1H), 1.86 (ush. m, 2H), 1.70 (ush. m, 2H), 1.43 (ush. m, 1H), 0.90 (ush. m, 3H).

1-Methyl-2-({3-[(4-propylpiperazine-1-yl)carbonyl]piperidine-1-yl}methyl)-1H-indol the dihydrochloride 1.3.2.1(14). Yield 47%. LCMS (M+H)+383.1H NMR (DMSO-d6. 400 MHz) δ 11.19 (ush. m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.22 (m, 1H), 7.07 (m, 1H), 6.83 (ush. m, 1H), 4.56 (ush. s, 2H), 4.37 (m, 1H), 4.05 (m, 1H), 3.87 (s, 3H), 3.61 (m, 1H), 3.44 (ush. m, 5H), 3.14 (ush. m, 2H), 2.98 (ush. m, 4H), 2.86 (ush. m, 1H), 1.98 (ush. m, 1H), 1.86 (ush. m, 2H), 1.70 (ush. m, 2H), 1.44 (ush. m, 1H), 0.89 (ush. m, 3H).

Example 4. Obtaining medicines in tablet form. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of the dihydrochloride [1-(1-methyl-1H-indole-2-ylmethyl)-piperidine-4-yl]-(4-propyl-piperazine-1-yl)-methanone 1.3.1.1(14). The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each.

Example 5. Getting medicines from the estva in the form of capsules. Thoroughly mix the dihydrochloride [1-(1-methyl-1H-indole-2-ylmethyl)-piperidine-4-yl]-(4-propylpiperazine-1-yl)-methanone 1.3.1.1(14) with lactose powder in a 2:1 ratio. The obtained powder mixture is Packed 300 mg in gelatin capsules of suitable size.

Example 6. Obtaining medicines in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg dihydrochloride [1-(1-methyl-1H-indole-2-ylmethyl)-piperidine-4-yl]-(4-propylpiperazine-1-yl)-methanone 1.3.1.1(14) with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed.

1. Antiviral component active against hepatitis C virus (HCV), which represents a substituted indole of General formula 1 and its pharmaceutically acceptable salt

where R1 represents a hydrogen atom, optionally substituted C1-C4alkyl, C6cycloalkyl, phenyl, etoxycarbonyl, the nitro-group;
R2 represents a hydrogen atom;
R3 represents N-mono - or N,N-disubstituted 1-methylene-piperidine-3-carboxamide General formula 1A or N-mono - or N,N-disubstituted 1-methylene-piperidine-4-carboxamide General formula 1b;
R4 provide the focus of a hydrogen atom, optionally substituted C2-C3alkyl, a group-CH2-R12, where R12 represents a hydrogen atom or optionally substituted with halogen or1-C4the alkyl phenyl;
or
R2, R3 and R4 together with the atoms to which they are linked, form a substituted azaheterocycle General formula 1.2;
or
R2 and R3 together with the carbon atoms to which they are linked, form a substituted 2,3,4,9-tetrahydro-1H-carbazole General formula 1.1,

in which R1 represents methyl, etoxycarbonyl, the nitro-group; R4 represents a hydrogen atom, methyl,2-C3alkyl, substituted N-benzylamino;
R7 and R8 represent hydrogen atoms or R7 and R8 together with the carbon atom to which they are attached, form the group C=O;
R5 and R6 are not necessarily identical, represent a hydrogen atom, optionally substituted C1-C3alkyl or C3-C6cycloalkyl;
or R5 and R6 together with the nitrogen atom to which they are bound, form an optionally substituted 5 - or 6-membered azaheterocyclic containing one or two nitrogen atom, possibly condensed with benzene ring, or form a group
,
where R11 represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl;
R9 represents azaheterocyclic containing at least the one nitrogen atom, unsubstituted of formamide or phenyl, substituted ethoxycarbonyl or nitro-group;
R10 represents a hydrogen atom, optionally substituted C1-C3alkyl; substituted acetyl, where the substituents are selected from 5-6-membered nitrogen-containing heterocyclyl or 5-6-membered nitrogen-containing heteroepitaxy;
n=1 or 2;
the dotted line with its accompanying solid linerepresents a single or double bond.

2. Antiviral active component according to claim 1, which represents a substituted amide 1-[(1H-indol-2-yl)methyl]piperidine-4-carboxylic acid of General formula 1.3.1 or substituted amide 1-[(1H-indol-2-yl)methyl]piperidine-3-carboxylic acid of General formula 1.3.2, and its pharmaceutically acceptable salt,

where R4, R5 and R6 have the above value.

3. Antiviral active component according to claim 1, which represents a substituted amide 1-[(1H-indol-2-yl)methyl]piperidine-4-carboxylic acid of General formula 1.3.1.1, and its pharmaceutically acceptable salt,

where R11 and R12 have the above values.

4. Antiviral active component according to claim 1, which represents a 2-(8-isopropyl-1,2,3A,4,5,6-hexahydro-3H-pyrazino[3,2,1-Jk]carbazole-3-yl)ndimethylacetamide and its hydrochloride of the formula 1.2(1)·Hcl

5. Pharmaceutical composition having antiviral activity against hepatitis C virus (HCV), containing a pharmaceutically effective amount of the active ingredient according to any one of claims 1 to 4.

6. A method of obtaining a pharmaceutical composition according to claim 5 mixing at least one antiviral active component according to any one of claims 1 to 4 with an inert filler and/or diluent.

7. The drug is in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, for the prevention and treatment of viral diseases caused by viruses of hepatitis C (HCV), comprising an active component according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 in an effective amount.

8. Method for the prevention and treatment of viral diseases caused by viruses of hepatitis C (HCV), the introduction of the active component according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 5, or a medicinal product according to claim 7 in an effective amount.

9. A compound selected from the group represents a substituted amide 1-[(1H-indol-2-yl)methyl]piperidine-carboxylic acid of General formula 1.3.2 or [1-(1-methyl-1H-indole-2-ylmethyl)-piperidine-4-yl]-(4-propylpiperazine-1-yl)-methanon 1.3.1.1(14), and its pharmaceutically acceptable salt,

where R4, R5 and R6 are you EUcasino value.

10. The connection according to claim 9, represents a substituted amide 1-[(1H-indol-2-yl)methyl]piperidine-carboxylic acid of General formula 1.3.2.1, and its pharmaceutically acceptable salt,

where R11 represents a C1-C3alkyl; R12 represents a hydrogen atom or optionally substituted by halogen or C1-C3the alkyl phenyl.

11. The compound of claim 10 selected from {1-[1-(4-Chlorobenzyl)-1H-indole-2-ylmethyl]-piperidine-3-yl}-(4-propylpiperazine-1-yl)-methanone 1.3.2.1(13) or [1-(1-methyl-1H-indole-2-ylmethyl)-piperidine-3-yl]-(4-propylpiperazine-1-yl)-methanone 1.3.2.1(14), and its hydrochloride.



 

Same patents:

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: described is a method of producing 5,6-dihydro-4H-benzo[f]pyrrolo[ 1,2-α][1,4]diazepin-6-one 1, involving moulding a pyrrolodiazepine frame as a result of reduction of nitro-groups of N-(2,5-dioxoalkyl)-2-nitrobenzamides 4, in acetic acid in the presence of iron while carrying out the reaction until boiling and holding for 60 minutes at room temperature.

EFFECT: simultaneous formation of a pyrrole and a diazepine ring, and high output of end products owing to change in the sequence and conditions of the reaction.

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formulae Ia, Ic, Ig, Ik and pharmaceutically acceptable salts thereof, having activity towards cannabinoid 1 receptor. In formulae

, ,

, ,

R2 is selected from halogen, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, pyridinyl-N-oxide and phenyl; where the said pyrimidinyl, pyridinyl, pyridinyl-N-oxide, pyrazinyl and phenyl are optionally substituted with an amino group; R3 is selected from hydrogen, methylsulphonyl, methlsulphoxide and dimethylaminocarbonyl; R4 is selected from hydrogen, cyano, nitro, carbamimidoyl, tetrazolyl, aminosulphonyl, aminocarbonyl, methylsulphonylamino and methylsulphonyl; R6 is selected from hydrogen, hydroxyethylaminomethyl and methylsulphonylaminomethyl. The invention also relates to a pharmaceutical composition, methods of treating and preventing diseases mediated by the cannabinoid 1 receptor, and use of said compounds in preparing a medicinal agent used to treat such diseases.

EFFECT: improved properties of the derivatives.

12 cl, 1 tbl, 62 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): or to their pharmaceutically acceptable derivatives selected from a group consisting of pharmaceutically acceptable salts and esters; in which: R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R8c and R8d are such as presented in the patent claim 1. The invention also refers to compounds of formula (I), to a compounds selected from a group, to a pharmaceutical composition, to methods of treating, to a method of decreasing the plasma cholesterol level in a patient, to a method of modulating cholesterol metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal, to a method of modulating farnesoid X receptor activity, to a compound representing 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b]indole-5-isopropylcarboxamide, to a composition, to a method of reducing the risk of an onset or a recurrence, to a method of modulating triglyceride metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal, and also to a method of modulating bile acid metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal.

EFFECT: preparation of the new biologically active compounds showing possessing nuclear receptor activity.

73 cl, 76 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidine-2,6-diamines of general formula 1, their pharmaceutically acceptable salts and/or hydrates which have serotonin 5-HT6 receptor antagonist properties and can be used in treating or preventing development of various central nervous system diseases, whose pathogenesis is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases, cognitive and anxiety disorders and obesity. In general formula (I): R1, R2 and R4, which are optionally identical, independently denote C1-C3 alkyl; R3 and R4, which are optionally identical, denote: a hydrogen atom, optionally substituted C1-C3 alkyl or acetyl; R5 denotes a hydrogen atom or halogen atom.

EFFECT: high treatment efficiency.

13 cl, 12 dwg, 4 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt - monohydrate of monohydrochloride of 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide, having protein kinase inhibiting properties. The invention also relates to a method of obtaining said compound. The method involves the following steps: (a) merging 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethylphenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)benzamide in form of a free base and hydrochloric acid in methanol in a nitrogen atmosphere; (b) heating the reaction mixture to temperature in the range of approximately 42-50°C; (c) stirring the reaction mixture; (d) filtering the reaction mixture while maintaining temperature higher than 40°C to obtain a transparent solution; (e) cooling the transparent solution to approximately 30°C while stirring in a nitrogen atmosphere; (f) adding an inoculant to the solution; (g) cooling the solution containing the inoculant to approximately 23°C; (h) stirring the solution to obtain a suspension; (i) cooling the obtained suspension to approximately -10°C; (j) stirring the obtained suspension; (k) filtering solid substances, washing the solid substance with cold methanol; and (l) drying the solid substance at approximately 50-55°C and 10-20 torr to obtain the end product.

EFFECT: monohydrate of monohydrochloride of said compound has high solubility compared to a base and hydrochloride salt and has high bioavailability in vivo compared to said compounds.

4 cl, 17 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) (I), its N-oxide form, addition salt or stereochemically isomeric form, where m equals 0, 1, and m equals 0 denotes a direct bond; n equals 0, 1, 2 or 3, and n equals 0 denotes a direct bond; p equals; t equals 0 or 1, and t equals 0 denotes a direct bond; denotes -CR8=C<, and the dotted line denotes a bond, where R8 denotes hydrogen; R1 and R2 denotes hydrogen; R3 and R4 denote hydrogen; R5 denotes hydrogen; R6 and R7 each is independently selected from hydrogen or C1-6alkyl; Z denotes a radical selected from (a-1) (a-2) (a-4), where R10 and R11 are each independently selected from hydrogen, hydroxy, C1-6 alkylcarbonyl, C1-6 alkylcarbonyloxy C1-6 alkyl, C1-6 alkyloxycarbonyl, C1-6 alkylcarbonyloxy, hydroxy C1-6 alkyl. The invention also describes a pharmaceutical composition for treating cancer, based on the compound of formula I, as well as a method of preparing said composition and use of the compound of formula I, combination thereof with an anticancer agent and preparation method thereof.

EFFECT: improved properties of compounds.

14 cl, 6 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to RSV replication inhibitors of formula (I) or salts thereof or stereochemically isomeric forms, where R is a radical of formula (a) or (b) . Q is hydrogen or C1-6alkyl substituted with a heterocycle selected from oxazolidine, morpholinyl and hexahydrooxazepine. Alk denotes C1-6alkanediyl. X is O; -a1=a2-a3=a4 - is -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH- or -CH=CH-CH=N-; R1 is selected from optionally substituted pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and pyrrolyl. R2 is C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, Ar-C1-6alkyloxyC1-6alkyl, C3-7cycloalkyl, Ar-C1-6alkyl. R3 is cyano. Ar is phenyl o substituted phenyl. The invention also relates to pharmaceutical compositions containing compounds (I) and a method of producing compounds (I).

EFFECT: high efficiency of the compositions.

9 cl, 20 ex, 3 tbl

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

FIELD: chemistry.

SUBSTANCE: invention relates to a salt of succinate 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline. A novel salt of 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline is obtained and described, which can be used in treating central nervous system disorders.

EFFECT: high efficiency of using the compounds.

7 cl, 1 ex, 1 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention describes novel bicyclic derivatives of general formula (I)

(values of radicals are given in the description) and a pharmaceutical composition containing said derivatives, as well as use of said novel compounds to treat or inhibit symptomatic diseases where CEPT is involved, and a method of treating said diseases.

EFFECT: high efficiency of using compounds when treating diseases.

14 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a heterocycle, L1 and L2 are different linker groups, and Q is a 6-member heterocycle, and use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds of compositions.

EFFECT: high effectiveness of the compounds.

17 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

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