1-phenyl-2-heteroarylsubstituted derivatives of benzimidazol, their application for production of medicinal products, and pharmaceuticals containing these derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzimidazol of the general formula I R1 designates phenyl group which unessentially contains up to three substitutors independently chosen of the group including F, Cl, Br, J, R4; R2 designates monocyclic or bicyclic 5-10-terms heteroaryl group which contains 1-2 heteroatoms, chosen of N, S and O; R3 designates H; R4 designatesC1-6alkyl; A designates C2-6 alkylene group; B designates group COOH, CONH2, CONHR5 or CONR5R5, in each case attached to atom of carbon of group A; R5 and R5 ' independently designate the residue chosen from group includingC1-6 alkyl where one C-atom can be replaced by O, and(C0-3 alkandiil-C3-7 cycloalkyl); and to their pharmaceutically acceptable salts, except for following compounds: 6 [[1-phenyl-2 (pyridine-4-il)-1H-benzimidazol-6-il] oxi] hexanic acid and 6 [[1-phenyl-2 (benzothien-2-il)-1H-benzimidazol-6-il] oxi] hexanic acid. The invention relates also to pharmaceuticals and to application of compounds of general formula I.

EFFECT: new biologically active compounds possess inhibiting effect on activation of microglia.

10 cl, 34 ex

 

The present invention relates to new derivatives of benzimidazole, method of their production and to their use for obtaining a drug intended for the treatment and prevention of diseases associated with activation of microglia, and to ensure mediated T-cell immunological diseases, and to pharmaceutical preparations containing these novel derivatives of benzimidazole.

The immune system comprises a large number of different cells and complex tissue structures, which interact primarily through soluble factors. It is known that the emergence of many immunological diseases caused by an imbalance of soluble factors of the immune system such as cytokines (Mosmann and Coffman, Ann. Rev.Immunol, 7, 1989, cc.145-173; Street and Mosmann, FASEB J., 5, 1991, cc.171-177; Lucey and others, Clin. Environ. Rev., 4, 1996, cc.532-562; Powrie and Coffman, Trends Pharmacol. Sci., 14, 1993, cc.164-168; Singh and others, Immunolog. Res., 20, 1999, cc.164-168). For example, there is plenty of evidence about the role γ-interferon and interleukin 12 play in the pathogenesis of autoimmune diseases. Particularly in this respect, it should be called a disease characterized mediated by T-cells (T-lymphocytes) inflammatory response, such as multiple sclerosis, diabetes, chronic inflammatory bowel disease. Interleukin 12 (IL-12), which is the one the m of the representatives of cytokines, produced by phagocytes, such as macrophages/monocytes, dendrites, b-cells and other antigen-presenting cells (APC), and affects both the function of natural killer cells (NK-cells), and the function of T-lymphocytes. IL-12 can stimulate the production of γ-interferon (IFNγ) in both cell types listed. T-lymphocytes can in first approximation be divided into two categories, which are characterized by the expression of certain surface antigens (CD4 and CD8), namely, CD4-positive T-cells (T cells-helper) and CD8-positive T-cells (cytotoxic T cells). CD4-cells in turn can be divided into T cells-helper type 1 (Th1) and T-cell helper type 2 (Th2). It is mediated by Th1-cells of the immune responses associated with the pathogenesis of many immune, especially autoimmune diseases such as insulin dependent diabetes mellitus type I (IDDM), multiple sclerosis, allergic contact eczema, psoriasis, rheumatoid arthritis, chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis), lupus disease and other collagenoses, as well as acute rejection reactions by allotransplantation (the reaction of the host against the graft, graft-versus-host).

Against interleukin 12 it is known that it plays an important rol is in the regulation of the response of Th1 cells. Interleukin 12 induces in these cells producing mainly IL-2, IFNγ, TNFα and TNFβ (Mosmann and Sad, Immunol Today 17, 1996, cc.138-146; Gately and others, Annu. Rev. Immunol, 16, 1998, cc.495-521). It IFNγ is an effective mediator provided by IL-12. Excessive production of γ-interferon may respond, for example, for the occurrence of autoimmune diseases associated with MHC II ("major histocompatibility complex, major histocompatibility complex). In addition, there is also quite a large number of explicit evidence regarding the pathological role γ-interferon plays in allergic diseases, as well as with sarcoidosis and psoriasis (A.Billiau, Adv.Immunol, 62, 1996, cc.61-130; Basham and others, J.Immunol., 130, 1983, cc.1492-1494; Hu and others, Immunology, 98, 1999, cc.379-385; J.P.Seery, Arthritis Res., 2, 2000, cc.437-440). In addition, interleukin 12, and induced interleukin 12/interleukin 18 γ-interferon from NK cells play an important role in pathomechanism not mediated T-cell inflammatory responses (such as toxic shock syndrome, endotoxemia, sepsis, septic shock, acute respiratory distress syndrome (ARDS), "response to the introduction of the first dose (first dose response") when treatment with antibodies, for example after the introduction ACT if allotransplantation) (Kum and others, Infect Immun., 69, 2001, cc.7544-7549; Arad and others, J. Leukoc. Biol. 69, 2001, cc.921-927; Hultgren and others, Arthritis Res., 3, 2001, cc.41-47, Arndt and others, Am. J.Respir. Cell. Ml. Biol., 22, 2000, cc.708-713; Grohmann and others, J.Immunol., 164, 2000, cc.4197-4203; Muraille, etc., Int. Immunol., 11, 1999, cc.1403-1410). IL-12 also plays a role in inflammation, which are based on not identified in the present pathomechanism (e.g. eclampsia) (Hayakawa and others, J.Reprod. Immunol., 47, 2000, cc.121-138; Daniel and others, Am. J.Reprod. Immunol., 39, 1998, cc.376-380).

Along with interleukin 12 and IFNγ a role in the pathogenesis of immune diseases and systemic inflammatory reactions attributed and other cytokines, such as TNFα (αtumor necrosis factor). TNFα plays an important pathological role in infectious diseases such as sepsis, toxic shock syndrome (Tracey and others, Nature, 330, 1987, cc.662-664; Basger and others, Circ. Shock, 27, 1989, cc.51-61; Hinshaw and others, Circ. Shock, 30, 1990, cc.279-292; A. Waage, Lancet, 351, 1998, s; Cohen and others, Lancet, 351, 1998, s)), but also in numerous other immunopositive diseases.

To ensure mediated IL-12 diseases and to alleviate acute symptoms of such diseases is often used corticosteroids, manifested in the application which side effects and primarily with long-term therapy are often the reason for discontinuation of treatment.

A key phase of the inflammatory process of almost all degenerative diseases of the Central nervous system is the activation of glial macrophages or microglia. Glial macrophages in ECENA long period of time can be in an activated state, they produce and secrete a variety of inflammatory factors, such as reactive oxygen/nitrogen intermediates, proteases, cytokines, complement factors and neurotoxins. These factors in turn lead to dysfunction and degeneration of nerve cells. Activation of microglia can cause various incentives, such as Aβ-Petit (β-amyloid, D.M.Araujo and ..Cotman, Brain Res. 569, 1992, cc.141-145 (1992)), prion protein, cytokines or cell fragments (..Combs and others, J.Neurosci. 19, 1999, cc.928-939, P.L.Wood, Neuroinflammation: Mechanisms and Management, published by Humana Press, 1998).

The benzimidazole, which inhibit the activation of microglia after stimulation Andβ-peptide, as described in the application WO 01/51473. From this application it is also known that the benzimidazole, which inhibit the activation of microglia, are used to treat neuropeptidergic diseases, such as AIDS dementia, amyotrophic lateral sclerosis, a disease of Creutzfeldt-Jakob disease, down's syndrome, diffuse disease Taurus Levi, Huntington's disease, leukodystrophies, multiple sclerosis, Parkinson's disease, diseases of the Peak, Alzheimer's disease, apoplexy, temporal lobe epilepsy and a variety of tumors.

In EP 0104727 A1 describes benzimidazole derivatives, which are not substituted in position 1 and in position 2 containing alkyl group. Substituents in the benzene ring of these is produced in the water are in particular, pyridyloxyacetic, peridically balance, pyridylacetate and pyridyloxyacetic the rest.

In the application WO 01/21634 A1 described later derivatives of benzimidazole, which in position 1 have elendilmir, and in position 2 contain, in particular, substituted phenyl or heteroaryl residue and which anilinophenol the benzene ring can be substituted, in particular, at least one substituted alkoxylated, alkylaminocarbonyl, alkylsulphonyl balance or alkylsulfonyl balance. In this application States that these compounds may as active ingredients of drugs to be used in a number of different indications.

In the patent US 5552426 described substituted benzimidazole, which in position 1 have, in particular, phenyl or nattily residue, and at position 2 contain, in particular, phenyl or heterocyclic residue. Annulirovano benzene ring such benzimidazole preferably substituted alkoxy - or aminoalkoxide. As described in the mentioned patent information such compounds are effective for diseases, which are based on related β-amyloid peptide neurotoxicity.

In the application WO 97/12613 A1 describes various suppress the inflammatory process and the pre is atstuma development of arteriosclerosis means. As an example, possessing similar properties of active substances in this application are listed derivative of benzimidazole that position 1 is substituted, in particular phenyl or substituted phenyl residue, and at position 2 substituted by alkoxylation. Substituents in the benzene ring such biologically active compounds can serve, in particular, alkyl residues, nitrostat, halogen atoms, alkoxylate, aminoacetate, ester residues, amide residues, alcantarillado and alcantarillado.

In the application EP 0520200 A2 describes benzimidazole derivatives, which in position 1 have substituted aryl residues, and in position 2 contain one - or disubstituted or unsubstituted amino group. The benzene ring of the benzimidazole skeleton may be substituted by halogen, trifluoromethyl and/or cyano. Such compounds intended for the treatment of diseases associated with increased activation of CA-channels.

In the application WO 97/33873 A1 also describes benzimidazole derivatives used for the treatment of cystitis. These compounds may contain in position 1, in particular, phenyl, raftiline and unsaturated heterocyclic residues. In position 2 such derivatives can be replaced by alkoxylation, generalkonsulaten, naphthylacetate, geterotsiklicheskikh is whether unsaturated geterotsiklicheskikh. Benzene ring skeleton of these derivatives may be substituted nitroethane, alkanolamine residues aminooctane, alkyl residues, alkoxystyrene, cycloalkenyl residues, heterocyclic residues, unsaturated heterocyclic residues, halogen atoms, alkylthiomethyl, hydroxyacetanilide residues hydroxyethylaminomethyl, aminoalkylindole residues aminoalkoxide, hydroxyalkyl residues, geterotsiklicheskikh, aminoalkylindole residues or triptoreline remains.

In the application EP 0531883 A1 describes a condensed 5-membered heterocycles such as substituted derivatives of benzimidazole, while such compounds according to their description in position 1 is preferably substituted substituted alkyl residue, and at position 2 substituted, for example, O-elendilmir, S-elendilmir, NH-elendilmir, N(alkyl)elendilmir, SO-elendilmir or SO2-alcantarilla balance. Described in this application connections is expected to have antidromically activity.

One of the possible described in the literature approaches for the treatment of inflammatory diseases of the nervous system is currently in use nonsteroidal suppress the inflammatory process inhibitors (inhibitors MOR II) (P.LMcGeer, Roger, Neurology, 42, 1992, cc.447-449; J.Rogers, L.C.Kirby, S.R.Hempleman, D.L.Berry, P.L. McGeer, A.W.Kaszniak, J.Zalinski, M.Cofield, L.Mansukhani, P.Wilson, F.Kogan, Neurology, 43, 1993, cc.1609-1611; .Andersen, L.J.Launer, A.Ott, A.W.Hoes, M.M.B.Breteler, A.Hofman, Neurology, 45, 1995, cc.1441-1445; J.C.S.Breitner, B.A.Gau, K.A.Welsh, B.L.Plassman, W.M.McDonald, M.J.Helms, J.C.Anthony, Neurology 44, 1994, cc.227-232; The Canadian Study of Health and Aging, Neurology, 44, 1994, cc.2073-2079), modulators of cytokines (P.L.McGeer, E.G.McGeer, Brain Res. Rev.21, 1995, cc.195-218; E.G.McGeer, P.L.McGeer, CNS Drugs, 7, 1997, cc.214-228; F.C.Barone and G.Z.Feuerstein, J.Cerebral Blood Flow and Metabolism, 19, 1999, cc.819-834) and inhibitors of pathway activation of complement (S.Chen., R.C.A.Frederickson and K.R.Brunden, Neurobiol. Aging, 1996; E.G.McGeer, P.L.McGeer, Drugs, 55, 1998, cc.739-746).

Known used for the treatment of immunological diseases compounds, such as steroids, often affect several factors in the immune system and as a result cause numerous side effects. On this basis the basis of the present invention was based on the task to offer substances which due to their activity against microglial would have the ability to inhibit the activity of cytokines, without causing serious toxic side effects.

This problem is solved using the proposed in the invention of new benzimidazole derivatives according to claim 1 claims, as well as through the application of the proposed invention is a derivative of benzimidazole for obtaining a medicinal product intended for the Prerow the project for the production of IL-12 and IFNγ in cells of monocytic origin, respectively T-cells and NK-cells.

Inhibitors of microglia due to their ability to interrupt the production of IL-12 and TNFα in monocytes/macrophages/the dendrites and the production of IFNγ in T-cells and NK-cells suitable for the treatment of various diseases, due to an increased biogas produced cytokines, such as TNFα and -β, IFNγ, IL-2 and IL-12, such as inflammatory diseases, not based on neurospine, autoimmune diseases, allergic and infectious diseases caused by toxins, inflammation, pharmacologically triggered inflammation reactions and pathophysiologically relevant inflammatory reactions not detected in the present Genesis.

In accordance with this invention offers benzimidazole derivatives of the following General structural formula I

in which R1denotes a phenyl group which optionally contains up to three substituents, independently from each other selected from the group comprising F, Cl, Br, J, OH, OR4, OCOR4, SR4, SOR4, SO2R4, R4, NH2, Other4and NR4R4'or two adjacent substituent at R1together form a group-O-CH2-O-, -O-CH2-CH2-O - or-CH2-CH2-CH2-,

R2denotes a monocyclic or bicyclic 5-to 10-membered heteroaryl group which contains 1-2 heteroatoms selected from N, S and O and which is optionally contain up to two substituents, independently from each other selected from the group comprising F, Cl, Br, J, HE, OR4, OCOR4, COR4, SR4, SOR4, SO2R4and R4or two adjacent substituent at R2together form a group-O-CH2-O-, -O-CH2-CH2-O - or-CH2-CH2-CH2-,

R3denotes H, HE, or O-C1-6alkyl,

R4and R4'independently of one another denote With1-4perfluoroalkyl or1-6alkyl,

And indicates With2-6alkylenes group, which is optionally substituted by =O, HE, O-C1-3the alkyl, NH2, NH-C1-3the alkyl, NH-C1-3alkanoyl, N(C1-3by alkyl)2or N(C1-3alkyl)(C1-3alkanoyl),

In refers to a group COOH, CONH2, CONHNH2, CONHR5or CONR5R5'in each case attached to the carbon atom of group a,

R5and R5'independently of one another denote a residue selected from the group comprising From1-6alkyl, C2-6alkenyl,2-6quinil, where one C-atom may be replaced by O, S, SO, SO2, NH, N-C1-3alkyl or N-C1-3alkanoyl, (C0-3alcander-C3-7cyclea the keel), where in the five-membered cycloalkene ring one ring member may be a ring N-atom or O ring atom, and in six or semikina cycloalkyl ring one or two ring members can be respectively an annular N - and/or O ring atoms, this ring N-atoms optionally can be substituted With1-3the alkyl or C1-3alkanoyl, and also includes (C0-3alkadienes) and (C0-3lendergeorgia), where the heteroaryl group is five - or six-membered and contains one or two heteroatoms selected from the group comprising N, S and O, all of the above alkyl and cycloalkyl residues optionally may contain up to two substituents selected from the group including CF3C2F5HE, O-C1-3alkyl, NH2, NH-C1-3alkyl, NH-C1-3alkanoyl, N(C1-3alkyl)2N(C1-3alkyl)(C1-3alkanoyl), COOH, CONH2and COO-C1-3alkyl, and above all phenyl and heteroaryl groups optionally can contain up to two substituents selected from the group comprising F, Cl, Br, CH3With2H5HE co3OS2H5, NO2N(CH3)2, CF3C2F5and SO2NH2or

R5and R5'together with the N atom form a five-semiline heterocyclic the prioritization of the ring, which may contain one N-, O - or S-atom, and which may be substituted With1-4the alkyl, (C0-2alcander-C1-4alkoxygroup)1-4alkoxycarbonyl, aminocarbonyl or phenyl,

as well as their optical or geometric isomers or tautomers or pharmaceutically acceptable salts, with the exception of the following compounds:

6-[[1-phenyl-2-(pyridin-4-yl)-1H-benzimidazole-6-yl]oxy]hexanoic acid and

6-[[1-phenyl-2-(bestien-2-yl)-1H-benzimidazole-6-yl]oxy]hexanoic acid.

Preferred are compounds in which R1denotes a phenyl group which optionally contains up to two substituents, independently from each other selected from the group comprising F, Cl, HE, OR4, OCOR4, SR4and R4or two adjacent substituent at R1form a group-O-CH2-O - or-CH2-CH2-CH2-.

Preferred derivatives of benzimidazole, in which R2denotes a monocyclic 5-6-membered heteroaryl group which contains 1-2 heteroatoms selected from the group comprising N, S and O and which is optionally contain up to two substituents, independently from each other selected from F, Cl, OR4, OCOR4, SR4, SOR4, SO2R4and R4or two adjacent substituent at R2form a group-O-CH2-O - or-CH -CH2-CH2-.

Preferred further benzimidazole derivatives, in which R3denotes N.

Among preferred are derivatives of benzimidazole, in which R4and R4'independently of one another denote With1-2perfluoroalkyl or1-4alkyl.

Preferred derivatives of benzimidazole, in which R5and R5'independently of one another denote With1-6alkyl, where one carbon atom may be replaced by O, S, SO or SO2With3-5cycloalkyl-C0-3alkylen, where a 5-membered cycloalkyl ring one ring member can be an N-atom or O-atom, while the ring nitrogen atom optionally substituted C1-3the alkyl or C1-3alkanoyl or0-2alkylen-(5-6-membered heteroaryl with 1-2 heteroatoms of N, S and O), while all of the aforementioned alkyl and cycloalkyl residues may be substituted by a group of CF3, group IT, group NH2, NH-C1-3the alkyl, NH-C1-3alkanoyl, N(C1-3by alkyl)2N(C1-3alkyl)(C1-3alkanoyl), a group COOH or CONH group2and all the above-mentioned heteroaryl groups may be substituted by one or two substituents selected from the group comprising F, Cl, CH3With2H5The co3OS2H5, CF3and C2F5or R5The R 5'together with the nitrogen atom form a 5-7-membered heterocycle, which may contain one oxygen atom, nitrogen or sulfur and may be substituted With1-4the alkyl or C1-4alkoxy-C0-2the alkyl.

Preferred further derivatives of benzimidazole, in which a denotes unbranched3-6alkylen.

Preferred derivatives of benzimidazole, which refers to a group COOH or CONH2in each case attached to the carbon atom of group A.

Particularly preferred are the following specific benzimidazole:

6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

4-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid,

6-[[1-(4-were)-2-(4-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

5-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

4-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid,

5-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

4-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid,

6-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

5-[[1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

6-[[1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

5-[[1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

5-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

4-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid,

6-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

N-(3-methoxypropyl)-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]-1-morpholine-1-elexan-1-he,

N-methyl-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

N,N-dimethyl-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

N-cyclopropyl-6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

N-methyl-6-[[1-(4-were-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

6-[[1-(4-were)-2-phenyl-1H-benzimidazole-6-yl]oxy]-1-(thiazolidin-3-yl)hexane-1-he,

N-(2-methoxyethyl)-5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanone,

N,N-dimethyl-5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanone,

5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-the l]oxy] pentanone and

6-[[1-(4-were)-2-(2-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid.

In the scope of the present invention also includes a physiologically compatible salts of the above compounds, especially salts are acidic proposed in the invention derivatives of benzimidazole, when they are presented in the form of nitrogenous bases and basic salts proposed in the invention is derived, when they are presented in the form of carboxylic acids.

Proposed in the invention derivatives of benzimidazole can have one or more asymmetric centers and therefore, such compounds can exist in several isomeric forms. The compounds of formula I can also be presented in the form of the tautomers, stereoisomers and geometric isomers. In the scope of the invention in accordance with this also includes all possible isomers, such as E - and Z-isomers, S - and R-enantiomers, diastereomers, racemates and mixtures thereof, including tautomeric compounds. All such isomeric compounds, even if in each case it is not specifically mentioned, are an integral part of the present invention.

The mixture of isomers is possible by conventional methods such as crystallization, chromatography or salt formation, divided into enantiomers, respectively, E/Z-isomers.

Contained in the proposed invention benzimida the Aulnay connections heteroaryl groups consist of 5-10 skeletal atoms and may contain 1 or 2 heteroatoms. Such heteroatoms are oxygen (O), nitrogen (N) and sulfur (S).

As examples of monocyclic heteroaryl groups can be called pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyridazinyl.

Examples of bicyclic heteroaryl groups are indolyl, isoindolyl, benzothiophene, benzofuran, benzimidazole, indazole, hinely, ethanolic, phthalazine, hintline, cinnoline, honokalani and naphthyridine. When the heteroaryl group may form part of a substituent R1the connection with the N atom of the benzimidazole through a carbon atom.

Heteroaryl residues can be in any way attached to the benzimidazole skeleton or to another group, such as 2-, 3 - or 4-pyridinyl, in the form of a 2 - or 3-tanila or 1 imidazolyl.

Alkyl groups can be straight or branched chain. As examples of such alkyl groups can be called methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl, n-hexyl and second-hexyl.

Perforated alkyl residues are preferably CF3and C2F5.

Under cycloalkyl groups in each case are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohe the mud.

As examples of saturated heterocyclic rings, respectively, as examples of cycloalkyl with one or more heteroatoms can be called piperidine, pyrrolidine, tetrahydrofuran, morpholine, piperazine, hexahydroazepin, and 2,6-dimethylmorpholine, N-phenylpiperazine, 2-methoxypyridine, piperidine-4-carbonamide, thiomorpholine, thiazolidine, the connection may be through a present under certain conditions, the ring N-atoms.

Examples of unbranched or branched, containing up to six C-atoms alkylene as values Deputy And are ethylene, propylene, butylene, pentile, hexylen, and 1-mutilation, 1-ethylethylene, 1-methylpropyl, 2-methylpropyl, 1-methylbutyl, 2-methylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl and similar compounds.

Maybe dunamase, preferably odnosnie, group IT, group NH2, NH-C1-3the alkyl or NH-C1-3alkanoyl.

For the formation of physiologically compatible acid salts proposed in the invention derivatives of benzimidazole, when they are presented in the form of nitrogenous bases, suitable inorganic and organic acids, such as oxalic acid, lactic acid, citric acid, fumaric acid, acetic to the slot, maleic acid, tartaric acid, phosphoric acid, hydrochloric acid, Hydrobromic acid, sulfuric acid, n-toluensulfonate acid and methanesulfonamide acid.

If proposed in the invention the compounds of acid groups, especially groups of carboxylic acids, can also form salts with inorganic or organic bases, which are known for their use for the formation of physiologically compatible salts and as an example, the hydroxides of alkali metals, especially sodium hydroxide and potassium hydroxide, hydroxides of alkaline earth metals such as calcium hydroxide, and ammonia and amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and Tris(hydroxymethyl)methylamine.

The compounds of formula I inhibit the activation of microglia and production of interleukin 12 (IL-12) and γ-interferon (IFNγ). In accordance with this invention also relates to use of compounds of formula I, as well as its optical or geometric isomers or tautomers or physiologically acceptable salts for obtaining a medicinal product intended for the treatment or prophylaxis is associated with activation of microglia disease, primarily caused by an excess biogas produced IL-12 and IFNγ diseases, and for range of complete the AI production of interleukin 10 (IL-10).

In one of the preferred options proposed in the invention compounds are used to treat mediated by T-cells, in particular mediated by Th cells-1, immunological diseases and not mediated T-cell inflammatory responses. Proposed in the invention compounds are used primarily for medicinal products intended to interrupt the production of IL-12 and IFNγ in cells of monocytic origin, respectively T-cells and NK-cells. Proposed in the invention compounds because of their ability to interrupt the production of IL-12 and TNFα in monocytes/macrophages and the production of IFNγ in T-cells suitable for the treatment of various diseases, due to an increased biogas produced cytokines, such as TNFα and -β, IFNγ, IL-2 and IL-12, such as inflammatory diseases, not based on neurospine, autoimmune diseases, allergic and infectious diseases caused by toxins, inflammation, pharmacologically triggered inflammation and pathophysiologically relevant inflammatory reactions not detected in the present Genesis.

As an example, inflammatory and autoimmune diseases may be considered a chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis), rtrim, allergic contact eczema, psoriasis, pemphigus, asthma, multiple sclerosis, diabetes, insulin dependent diabetes mellitus type I, rheumatoid arthritis, lupus disease and other collagenoses, graves ' disease, goiter Hashimoto, graft-versus-host and graft rejection.

Examples of allergic, infectious, caused by toxins and ischemia-induced diseases include sarcoidosis, asthma, hypersensitive pneumonitis, sepsis, septic shock, endotoxin bacterial toxic shock, toxic shock syndrome, toxic liver failure, ARDS (acute respiratory distress syndrome), eclampsia, cachexia, acute viral infections (eg, infectious mononucleosis, fulminant hepatitis), organ damage after reperfusion.

Examples of pharmacologically triggered inflammation with pathophysiological relevance is "the response to the introduction of the first dose (first dose response") after introduction into the body of T-cell antibodies such as OCT.

As an example of systemic inflammatory reactions not detected in the present Genesis can be called eclampsia.

Among neuropeptidergic diseases associated with activation of microglia, include, for example, AIDS dementia, amyotrophic lateral sclerosis, a disease of Creutzfeldt-Jakob disease, disease Dau is a, the disease is diffuse Taurus Levi, Huntington's disease, leukodystrophy, multiple sclerosis, Parkinson's disease, a disease of the Peak, Alzheimer's disease, apoplexy, temporal lobe epilepsy, and various tumors. In accordance with this invention also relates to the use of the proposed therein benzimidazole derivatives for the treatment of these diseases and their prevention.

According to the invention to effective inhibitors of microglia are compounds that inhibit the activity of microglia during stimulation Andβa peptide of at least 20%, and the activity of cytokines inhibit at least 30%. Biological properties of inhibitors of microglia can explore well-known specialists in the field of methods, such as discussed below and described in WO 01/51473 research methods.

In example 29 described method, in accordance with which to evaluate the inhibition of microglial activation. For activation of microglia can use a variety of incentives, such Asβ-Petit (β-amyloid, D.M.Araujo and ..Cotman, Brain Res. 569, 1992, cc.141-145 (1992)), prion protein, cytokines or cell fragments (..Combs and others, J.Neurosci. 19, 1999, cc.928-939, P.L.Wood, Neuroinflammation: Mechanisms and Management, published by Humana Press, 1998).

Stimulation with Aβ-peptide corresponds to the pathophysiological situation in Alzheimer's disease. In this issledovaniia stimulation using Aβ -peptide proposed in the invention compounds exhibit inhibitory effect on the activation of microglia. The inhibitory action proposed in the invention compounds on the activation of microglia is manifested in a significant reduction in the production and secretion of cytokines, such as interleukin 1β (Il-1β) and α-tumor necrosis factor (TNFα) (according to the results of enzyme-linked immunosorbent assay (ELISA) analysis of mRNA expression), and reduced secretion of reactive oxygen/nitrogen intermediates. In accordance with this ensures the simultaneous inhibition of several inflammatory factors.

The effectiveness of the proposed in the invention compounds in vivo was determined using MCAO model in rats. This model allows to simulate the state of the apoplexy. Proposed in the invention compounds reduce microglial activation occurring in acute pathological changes in the brain of animals.

Inhibitory effect on the production of cytokines evaluated, for example, determining the amount of TNFα and interleukin 12 in stimulated with lipopolysaccharide (LPS) cells TNR-1. Proposed in the invention compounds inhibit the production of TNFα and interleukin 12 in stimulated with lipopolysaccharide (LPS) cells TNR-1.

To define which of influence, which is proposed in the invention compounds have on the activation of T cells, investigate, for example, the secretion of IFNγ. Proposed in the invention compounds inhibit the production of IFNγ peripheral mononuclear blood cells.

The present invention further relates to pharmaceutical means containing one or more proposed in the invention compounds of General formula I, and one or more carriers. Such proposed invention pharmaceuticals, accordingly, the compositions receive depending on the intended path of their introduction into the body in the required dosage by known methods using conventional solid or liquid carriers or diluents and the conventional pharmaceutical and technological auxiliaries. Preferred compositions are presented in the form of a dosage form suitable for oral, enteral or parenteral, such as intraperitoneal, intravenous, intramuscular or transcutaneous administration. Examples of such dosage forms are tablets, film tablets, coated tablets, pills, capsules, powders, pastes, ointments, lotions, liquid preparations such as syrups, gels, liquid preparations for injections, for example, intraperitoneal, intravenous, intramuscular, or percutaneous injection, and other drugs is a war form. Other dosage forms include depot-forms, in particular implantable applications, as well as suppositories. Of such separate dosage forms proposed in the invention of derivatives depending on their type, are released into the body gradually or all numbers in a short period of time.

For oral administration as pharmaceutical preparations may be capsules, pills, tablets, pills and liquid medications or other known pharmaceutical forms for oral administration. In this case, medicines can be prepared in the form of drugs, either for a short period of time release active substances and excrete them in the body, or have a prolonged action, providing more long, slow intake of the active substance in the body. The composition of such single dosage form together with at least one benzimidazole derivative may contain one or more pharmaceutically acceptable carriers, for example substances to regulate the rheological properties of drugs, surfactants, girotropnye soljubilizatory, microcapsules, microparticles, granules, diluents, binders, such as starch, sugar, sorbitol and the same is Athyn, as well as fillers such as silicic acid and talc, lubricants, colorants, flavorings and other substances.

Appropriate tablets can be produced, for example, by mixing the active substance with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, lubricating agents such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also have a multilayer structure.

Accordingly, you can also get dragee coating produced analogously to the tablets kernel coatings are usually applied as a shell bean materials, such as polyvinylpyrrolidone or shellac, gum Arabic, talc, titanium dioxide or sugar. When the shell drops may also have a multilayer structure, for which you can use excipients listed above for tablets.

Containing active substances of the capsule can be produced, for example, by mixing the active substance with an inert carrier such as lactose or sorbitol, and rasfasovyvanie mixture gelatino the e capsules.

Proposed in the invention benzimidazole derivatives can also be used in the dosage form in the form of a solution, which is intended for oral administration and which, along with biologically active derivative of benzimidazole contains as ingredients pharmaceutically acceptable oil and/or pharmaceutically acceptable lipophilic surfactant, and/or pharmaceutically acceptable hydrophilic surfactant, and/or pharmaceutically acceptable mixing with the water solvent.

To improve the bioavailability of the proposed to the invention of active substances such compounds can also be used in the form of clathrates with cyclodextrines frame. To this end proposed in the invention compounds are subjected to interaction with α-, βor γ-cyclodextrin or its derivatives.

The use of pastes, ointments, lotions and designed for outdoor use liquid preparations suggests that they have such properties that ensure delivery of the proposed invention compounds in the body in sufficient quantities. The composition of such dosage forms include auxiliary substances, for example substances to regulate the rheological properties of drugs, surfactants, preservatives, who idroterapia soljubilizatory, thinners, substances for improving the permeability of the proposed invention derivatives of benzimidazole through the skin, colors, flavors and protective equipment for the skin, such as air conditioners and regulators humidity. In medicine, together with the proposed invention compounds may also contain other active substances (Ullmanns Enzyklopädie der technischen Chemie, 1953, v.4, cc.1-39; J.Pharm. Sci., 52, 1963, cc.918 and forth; .V.Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete, Pharm. Ind., 2, 1961, cc.72 and forth; Dr. H.P.Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Izd-vo Cantor AG, Aulendorf/Württ., 1971).

Proposed in the invention compounds can also be applied in the form of appropriate solutions, such as physiological saline, solutions for infusion or injection. For parenteral administration the active substances can be present in dissolved or suspended in a physiologically compatible diluent. As such diluents suitable primarily oil solutions, for example, solutions in sesame oil, castor oil and cottonseed oil. To improve the solubility can be added girotropnye soljubilizatory, such as benzyl benzoate or benzyl alcohol.

To prepare drugs for injection can be used by any carrier liquid in which the proposed invention compounds are present in dissolved or emulsified form. The composition of such liquid preparations often include substances for regulating the viscosity, surfactants, preservatives, girotropnye soljubilizatory, thinners and other additives, which give the solution isotonicity. Together with benzimidazole derivatives in the composition of such drugs in the body can enter other active ingredients.

Proposed in the invention compounds can also be embedded in the corresponding material receiving transdermal system and thereby to introduce them into the body transdermally. In this case, derivatives of benzimidazole injected into the body, for example subcutaneously, in the form of a depot injection or drug-implant. Such drugs can be given such properties, which provide a slow release of the active substance. This purpose can be used well-known solutions such as dissolving or provided with a membrane depo-forms. As inert materials implants may also contain, for example, biodegradable polymers or synthetic silicones, for example silicone rubber. For percutaneous introduction benzimidazole derivatives can then be sealed, for example, in the patch.

Assign the patient a dose proposed in the invention compounds of General formula I is determined by the treating physician and depends among other things on oncrete introduced into the body connection from the way of introduction, from being treated with disease and its severity. Daily dose of the active substance does not exceed 1000 mg, preferably not more than 100 mg, and can be designed for a single injection per day as a single dose or divided into several smaller doses based on two or more doses per day.

The benzimidazole of the formula I can be obtained in various ways known from literature methods.

As possible methods of obtaining the proposed in the invention compounds, along with other worth mentioning discussed below.

1. Recovery substituted in ortho-position to the leaving group, preferably halogen-substituted) nitrobenzene derivatives (a) arylamine (C) At different reaction conditions, for example by heating the reagents in the absence or in the presence of acceptable inert solvent, in particular alkyl benzenes, you can get N-aryl-2-nitrobenzol (C). The solvent can also be used as the reactant amine when used in excess. The reaction is carried out without or in the presence of bases (e.g. potassium carbonate, sodium hydride). The reactions can also use other auxiliary substances, such as copper salts. Examples regarding the reactions performed in accordance with the considered you the e methodology can be found in numerous devoted to this theme works for example D.Jerchel, H.Fischer, M.Graft, Ann. Chem., 575, 1952, s.162; CAS, 53 (2138); R. A. Abramovitch, Can. J. Chem., 38, 1960, s.

SCHEME 1

Thus obtained N-arylnitrenes derivatives (C) different methods can be used to translate in 1,2-disubstituted benzimidazole (E) according to the following scheme:

SCHEME 2

The nitrogroup (C) is preferably recovered by hydrogenation in polar solvents, such as acetic acid, lower alcohols or esters of acetic acid, with the addition of catalysts, such as Raney Nickel or palladium on charcoal, or by chemical recovery, for example tin in hydrochloric acid, SnCl2(F.D.Bellamy, Tet. Lett., 1984] or Fe in acetic acid (D.C.Owslly, J.J.Bloomfield, Synthesis, 118, 1977, p.150).

From diamines (D) their interaction with derivatives of carboxylic acids, such as orthoepy, aminoether, acid anhydrides, aldehydes, or with the free carboxylic acids by acid catalysis or without him and/or in the presence or in the absence of a dehydrating means you can get benzimidazole (E). As an example, you can call receiving 1,2-diphenylimidazole of benzoic acid and N-phenyl-o-phenylenediamine using triphenylphosphine and anhydride triftormetilfullerenov acid (J.B.Hendrickson, M.S.Hussoin, J.Org. Chem., 52, 1987, s).

In using the implement of aromatic aldehydes as the solvent used, for example, nitrobenzene in order to ensure the possibility of oxidation of the initially formed benzimidazolone in situ. Cyclization to the benzimidazole is also possible in the case when aromatic aldehydes in the form of bisulfite adducts are subjected to interaction with diamines (D).

2. Another method of obtaining benzimidazole (E) described in Topps and F.Sannicolo in J.Heterocyclic Chem. 25, 1988, s, which allows you to implement a variety of circuits both aryl substituents and substitution in the benzene ring of the benzimidazole. For the person skilled in the art it is obvious that such deputies shall be compatible with the used at various stages in the sequence of synthesis reagents and reaction conditions. If necessary, the substituents can be modified. In the resulting product in this case is always present functional hydroxy-group, located in the 6 position of the benzimidazole (see structural formula (F)

3. In conclusion it should be mentioned that in some cases there is the possibility of a direct N-arilirovaniya pre-benzimidazole obtained, for example, by the method described in M.J.Sansone, M.S.Kwiatek US 4933397, or by the method described in D.M.T.Chan, K.L.Monaco, R.-P.Wang, M.P.Winters in Tet. Lett. 39, 1998, s, or ..Combs, S.Saubern, M.Rafalski, P.Y.S.Lam, Tet. Lett. 40, 1999, s.

<> For the person skilled in the art it is obvious that the substituents R must be compatible with the used at various stages in the sequence of synthesis reagents and reaction conditions. Under certain conditions, the substituents can be modified.

If the structural element In-And-O (formula I) in protected or unprotected form because they are incompatible with the reaction conditions prevailing in the process of synthesis of the corresponding benzimidazole, or otherwise associated with the process of its synthesis reasons, embed only upon completion of the synthesis of benzimidazole, depending on the audience of the substituents R3in the benzene ring of the benzimidazole there are various approaches to embedding structural element In-And-O (formula I), in this case, as is obvious to experts in this field, it is necessary to consider the compatibility of methods used with aryl substituents and specific residues whose value is R3.

The following are some possible methods of building structural element In-A-O.

The oxygen may be in free form (for example, R indicates HE's in the formula (A)) or in protected form, for example in the form of Olkiluoto ether (see, for example, B.D.Jerchel, H.Fischer, M.Graft, Ann. Chem., 575, 1952, s.162), initially present as a substituent in the process of synthesis of benzimidazole. Hydra is xinnuo group can be freed up by off Olkiluoto ether, for example, by treating it with concentrated Hydrobromic acid, under certain conditions, using hydrotropic of solubilization, such as halogenated hydrocarbons, or tribromide boron in an inert solvent, such as dichloromethane. Hydroxyl functional group by known methods of interaction with the optional containing end group (formula I) or its predecessor alkylhalogenide to turn in the ethers, and the interaction with alkylating agents is preferably carried out at a temperature in the range from 0 to 120°in polar solvents, such as dimethylformamide, dimethyl sulfoxide, ethers such as tetrahydrofuran, or a lower ketone, such as acetone or methyl ethyl ketone, with the addition of bases, such as hydrides of alkali and alkaline earth metals, preferably, however, sodium hydride, or with the addition of carbonates alkali metals such as potassium carbonate or cesium. In addition, the reaction can be carried out in a two-phase system with interfacial catalysis by dissolving the reagents in acceptable inert organic solvent, for example in halogenating, preferably, however, in dichloromethane. The other phase is a solid alkali metal hydroxide, preferably sodium hydroxide or potassium, and the and as a concentrated aqueous solution of the corresponding hydroxide. As phase transfer catalysts are used, for example, Quaternary ammonium salt. The reaction under interfacial catalysis preferably at room temperature.

For example, in one possible method, the compound of formula A (where R is a HE) is dissolved in dimethylformamide and adding cesium carbonate is subjected to interaction with the methyl ether 6-Bromhexine acid at a temperature in the range from 0 to 50°C. to Cleave ester by acid or baseòate hydrolysis can methods known in the art, for example in the presence of cosòate catalysts, such as carbonates or hydroxides of alkali or alkaline earth metals in water or in an aqueous solution of alcohol. As alcohols are aliphatic alcohols, such as methanol, ethanol, butanol and other, preferably, however, the methanol. In addition, it is possible to use aqueous solutions ethers, such as tetrahydrofuran. As an example, carbonates and hydroxides of alkali metals can be called lithium, sodium and potassium salts. Preferred while lithium and sodium salts. For use as carbonates and hydroxides of alkaline earth metals are suitable, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction is usually conducted in the range of those which of peratur -10 to 70° With, preferably, however, at 25°C. ester can, however, be broken and in acidic conditions, such as aqueous hydrochloric acid, optionally using hydrotropes a solubilizer, for example a lower alcohol, preferably methanol.

From present alkylating agent or formed in subsequent nitrile by hydrolysis to form a carboxyl functional group. Alkylating agents can also contain functional groups such as hydroxyl functional group, in free or protected form, which after conversion into leaving groups, such as, for example, tosylate, mesilate, bromide or iodide, can be replaced, for example, an amino group or alkyl group. Alkylating agents may contain such functional groups such as halogen atoms or optionally protected amino group, which in this case can be subjected to further modification.

Depending on the desired circuit, the substituents R3may initially be present in used in the synthesis of structural fragments or as necessary, embed, respectively, are present acceptable predecessors at the appropriate point in the synthesis process of the corresponding connection.

Derivatives of formula I in the form freedoms what's acids or their predecessors in the form of esters can be different, known from the literature methods to translate in the amide derivatives of formula I.

Derivatives of formula I in the form of free acids can also use appropriate amounts of the corresponding inorganic bases by neutralization to translate in salt. So, for example, by dissolving the corresponding acids in water containing the stoichiometric amount of base, after evaporation of the water or after adding miscible with water solvent, such as alcohol or acetone, it is possible to obtain a solid salt.

Salts with amines can be obtained by traditional methods. With this purpose, the corresponding acid is dissolved in an appropriate solvent, such as ethanol, acetone, diethyl ether or benzene and to this solution add from one to five equivalents of the corresponding amine. The resultant salt usually precipitates in solid form or as usual emit after evaporation of the solvent.

Clathrates with α-, βor γ-cyclodextrin get similar to the method described in WO 87/05294. It is preferable to use β-cyclodextrin. Liposomes receive according to the method described in the journal "Pharmazie in unserer Zeit", 11, 1982, p.98.

Below is the example described getting some compounds, the precursors, intermediates and final products. If after the corresponding description of the reception of those or other source compounds is not considered, it is assumed that these initial compounds are either known and commercially available compounds, or get similar to that shown in the present description methods.

The proposed invention in connection receive, for example, by the following methods.

General method 1: restore the nitro group

The recovered compound was dissolved in ethyl acetate, tetrahydrofuran, methanol or ethanol, or in mixtures of these solvents and hydronaut at normal pressure in the presence of 2-5% (in terms of nitrosoaniline) palladium on coal (10%). Upon completion of the process of absorption of hydrogen, the mixture is subjected to vacuum filtration, the residue is washed with ethyl acetate, methanol or ethanol and the filtrate concentrated in vacuo. The obtained crude product is typically used without additional purification in subsequent reactions.

General method 2: simple removal of the ether with Hydrobromic acid

5 g kilmacanoge ether is mixed with 160 ml of 48%aqueous HBr and within 1-5 h refluxed. After cooling, the mixture is filtered. The residue is dissolved in ethyl acetate and shaken out three times with a saturated solution of sodium bicarbonate. After drying over sodium sulfate concentrated in vacuo. The residue is optionally purified by crystallization or column chromium is ografia on silica gel.

General method 3: alkylation hydroxybenzimidazole derivatives and phenol derivatives by alkylhalogenide

A solution of 1.85 mmole hydroxybenzimidazole derived in 12 ml of N,N-dimethylformamide is mixed with 1,85-mmol of cesium carbonate and the 2,24 mmol of allylbromide or alkylated. When using allylbromide optional type of 1.85 mmole of sodium iodide. The mixture is stirred for 12-96 h, then poured into water, dissolved in ethyl acetate, the organic phase is washed four times with water, dried over sodium sulfate and concentrated in vacuo. Alternative such water processing of the reaction mixture can be mixed with dichloromethane, separated by filtration, dropped in salt precipitate and concentrate the filtrate in vacuo. Regardless of the selected method of processing the residue purified by crystallization or column chromatography on silica gel.

General method 4: saponification alilovic esters of carboxylic acids

0.77 mmole Olkiluoto ether carboxylic acid is dissolved in 5 ml methanol and 5 ml of tetrahydrofuran and mixed with 5 ml of 0.5 N. aqueous solution of lithium hydroxide or sodium. After stirring for 2-12 h the mixture is almost dry concentrated in vacuo, neutralized by adding aqueous hydrochloric acid and extracted with ethyl acetate. Next, dried over sodium sulfate and contentresult vacuum. The residue is optionally purified column chromatography on silica gel.

General method 5: cyclization to the benzimidazole with aldehydes

1 mmol of 1,2-diaminobenzene derived dissolved in 3 ml of nitrobenzene. To this solution is added 1 mmol of aryl-, respectively wateroriented. Next heated to 150°With, maintaining at this temperature for 2-6 h, and then the mixture is allowed to cool. The residue without further processing directly purified column chromatography on silica gel.

General method 6: translation of esters of carboxylic acids into amides of carboxylic acids

of 0.36 mmole amine dissolved in 3 ml of toluene and cooled in an ice bath mix of 0.18 ml added dropwise 2-molar solution of trimethylaluminum in toluene. Then mixed with a solution of 0.33 mmol methyl ester carboxylic acid in 3 ml of toluene and stirred for 2-8 h at 95°C. processing after cooling, add water, extracted three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is purified column chromatography on silica gel.

Example 1

6-[[1-(4-Were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

a) 3-(4-Were)amino-4-NITROPHENOL

to 5.4 g of 3-fluoro-4-NITROPHENOL was mixed with 4.8 ml of 4-methylaniline and was stirred for 6 h at 120°C. After cooling, was dissolved in ethyl acetate and water and was extracted three times 1 N. aqueous hydrochloric acid. The combined aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuum and led the rest.

MS (EI): 244 (molecular ion peak).

b) Methyl ester of 6-[3-(4-were)amino-4-nitrophenyl]oxohexanoate acid

The specified connection was obtained by interaction of 3-(4-were)amino-4-NITROPHENOL with methyl ether 6-Bromhexine acid according to General method 3.

MS (EI): 372 (molecular ion peak).

C) Methyl ester 6-[[4-amino-3-((4-(were)amino)phenyl]oxy]hexanoic acid

The specified connection was obtained from methyl ester of 6-[3-(4-were)amino-4-nitrophenyl]oxohexanoate acid in accordance with the General method 1.

MS (EI): 342 (molecular ion peak).

d) Methyl ester 6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained by interaction of methyl ester 6-[[4-amino-3-((4-(were)amino)phenyl]oxy]hexanoic acid with 3-pyridylcarbinol in accordance with the General method 5.

MS (EI): 429 (molecular ion peak).

d) 6-[[1-(4-Methylphen is)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained from methyl ester 6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid in accordance with the General method 4.

MS (EI): 415 (molecular ion peak).

Example 2

5-[[1-(4-Were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid

a) Methyl ester 5-[3-(4-were)amino-4-nitrophenyl]oxopentanoic acid

The specified connection was obtained by interaction of 3-(4-were)amino-4-NITROPHENOL with methyl ester of 5-bromopentanoate acid according to General method 3.

MS (EI): 358 (molecular ion peak).

b) Methyl ester 5-[[4-amino-3-((4-(were)amino)phenyl]oxy]pentanol acid

The specified connection was obtained from methyl ester 5-[3-(4-were)amino-4-nitrophenyl]oxopentanoic acid in accordance with the General method 1.

MS (EI): 328 (molecular ion peak).

C) Methyl ester 5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid

The specified connection was obtained by interaction of methyl ester 5-[[4-amino-3-((4-(were)amino)phenyl]oxy]pentanol acid with 3-pyridylcarbinol in accordance with the General method 5.

MS (EI): 415 (molecular ion peak).

g) 5-[[1-(4-Were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid

The specified connection was obtained from methyl ester 5-[[1-(4-m is terphenyl)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid in accordance with the General method 4.

MS (EI): 401 (molecular ion peak).

Example 3

4-[[1-(4-Were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid

a) Methyl ester of 4-[3-(4-were)amino-4-nitrophenyl]hydroxybutyric acid

The specified connection was obtained by interaction of 3-(4-were)amino-4-NITROPHENOL with methyl ether 4-pamakani acid according to General method 3.

MS (EI): 344 (molecular ion peak).

b) Methyl ester of 4-[[4-amino-3-((4-(were)amino)phenyl]oxy]butyric acid

The specified connection was obtained from methyl ester 4-[3-(4-were)amino-4-nitrophenyl]hydroxybutyric acid in accordance with the General method 1.

MS (EI): 314 (molecular ion peak).

C) Methyl ester of 4-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy] butyric acid

The specified connection was obtained by interaction of methyl ester 4-[[4-amino-3-((4-(were)amino)phenyl]oxy]butyric acid with 3-pyridylcarbinol in accordance with the General method 5.

MS (EI): 401 (molecular ion peak).

g) 4-[[1-(4-Were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid

The specified connection was obtained from methyl ester 4-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid in accordance with the General method 4.

MS (EI): 387 (molecular ion peak).

Example 4

6-[[1-(4-Were)-2-(4-pyridine is l)-1H-benzimidazole-6-yl]oxy]hexanoic acid

a) Methyl ester 6-[[1-(4-were)-2-(4-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained by interaction of methyl ester 6-[[4-amino-3-((4-(were)amino)phenyl]oxy]hexanoic acid (4-pyridylcarbonyl in accordance with the General method 5.

MS (EI): 429 (molecular ion peak).

b) 6-[[1-(4-Were)-2-(4-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained from methyl ester 6-[[1-(4-were)-2-(4-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid in accordance with the General method 4.

MS (EI): 415 (molecular ion peak).

Example 5

6-[[1-(4-Were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

a) Methyl ester 6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl] oxy] hexanoic acid

The specified connection was obtained by interaction of methyl ester 6-[[4-amino-3-((4-(were)amino)phenyl]oxy]hexanoic acid with 3-taylormadeadidas in accordance with the General method 5.

MS (EI): 434 (molecular ion peak).

b) 6-[[1-(4-Were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained from methyl ester 6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid in accordance with the General method 4.

MS (EI): 420 (molecular ion peak).

Example 6

-[[1-(4-Were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid

a) Methyl ester 5-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentanol acid

The specified connection was obtained by interaction of methyl ester 5-[[4-amino-3-((4-(were)amino)phenyl]oxy]pentanol acid with 3-taylormadeadidas in accordance with the General method 5.

MS (EI): 420 (molecular ion peak).

b) 5-[[1-(4-Were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid

The specified connection was obtained from methyl ester 5-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentanol acid in accordance with the General method 4.

MS (EI): 406 (molecular ion peak).

Example 7

4-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid

a) Methyl ester of 4-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid

The specified connection was obtained by interaction of methyl ester 4-[[4-amino-3-((4-(were)amino)phenyl]oxy]butyric acid with 3-thiophenecarbaldehyde in accordance with the General method 5.

MS (EI):406 (molecular ion peak).

b) 4-[[1-(4-Were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy] butyric acid

The specified connection was obtained by interaction of the methyl ester 4-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid in accordance with the General method 4.

MS (EI): 392 (molecular ion peak).

Example 8

5-[[1-Fe the Il-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid

a) 4-Methoxy-N2-phenyl-o-phenylenediamine

The specified connection was obtained from (5-methoxy-2-nitrophenyl)phenylamine [Kottenhahn, and others, J.Org. Chem., 28; 1963; cc.3114-3118; Banthorpe, Cooper, J.Chem. Soc. B, 1968, s] in accordance with the General method 1.

1H-NMR (CDCl3): δ (part./million)=3,42 s (broad) (2H); 3.72 points s (3H); 5,33 s (broad) (1H); 6,56 dd (J=10, 2 Hz, 1H); 6,76 d (J=10 Hz, 1H); 6,79 d (J=2 Hz, 1H); 6,82-6,90 m (3H); 7,25 dd (J=8, 8 Hz, 2H).

b) 6-Methoxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole

The specified connection was obtained by interaction of 4-methoxy-N2-phenyl-o-phenylenediamine with thiophene-3-carbaldehyde according to General method 5.

MS (EI): 306 (molecular ion peak).

b) 6-Hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole

The specified connection was obtained from 6-methoxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole in accordance with the General method 2.

MS (EI): 292 (molecular ion peak).

d) Methyl ester 5-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentanol acid

The specified connection was obtained by interaction of 6-hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole with methyl ester of 5-bromopentanoate acid according to General method 3.

MS (EI): 406 (molecular ion peak).

e) 5-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid

The specified connection was obtained from methyl ester 5-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentanol acid in accordance with the tvii with the General method 4.

MS (EI): 392 (molecular ion peak).

Example 9

4-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid

a) Methyl ester of 4-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid

The specified connection was obtained by interaction of 6-hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole with methyl ether 4-pamakani acid according to General method 3.

MS (EI): 392 (molecular ion peak).

b) 4-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid

The specified connection was obtained from methyl ester 4-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid in accordance with the General method 4.

MS (EI): 378 (molecular ion peak).

Example 10

6-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

a) Methyl ester 6-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained by interaction of 6-hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole with methyl ether 6-Bromhexine acid according to General method 3.

MS (EI): 420 (molecular ion peak).

b) 6-[[1-Phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained from methyl ester 6-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid in accordance with the General method 4.

MS (EI): 406 (molecular ion peak).

Example 11

6-[[1-(4-Forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

a) (5-Chloro-2-nitrophenyl)-(4-forfinal)Amin

50 g of 1-chloro-3,4-dinitrobenzene in 250 ml of ethanol was mixed with 50 ml of 4-foronline and was stirred for 35 h at 60°C. After concentration to half the volume of the mixture was distributed between water and dichloromethane. After washing the organic phase 1 N. aqueous hydrochloric acid was dried over sodium sulfate, filtered and concentrated. After chromatography of the residue on silica gel received 62,33 g (5-chloro-2-nitrophenyl)-(4-forfinal)amine.

1H-NMR (CDCl3): δ=of 6.71 dd (J=9, 2 Hz, 1H); 6,97 d (J=2 Hz, 1H); 7,13 dd (J=9, 9 Hz, 2H); 7,22 dd (J=9, 6 Hz, 2H); 8,15 d (J=10 Hz, 1H); 9,45 s (lat.) (1H).

b) (5-Methoxy-2-nitrophenyl)-(4-forfinal)Amin

To a solution of 6.6 g of sodium in 450 ml of methanol was added 36,44 g (5-chloro-2-nitrophenyl)-(4-forfinal)amine and the reaction mixture for 16 h boiled under reflux. After stirring for 30 h at 60°the reaction mixture was cooled and the crystalline product was separated by vacuum filtration. In this way received 34 g of (5-methoxy-2-nitrophenyl)-(4-forfinal)amine.

1H-NMR (CDCl3): δ=3,72 s (3H); 6,44 dd (J=9, 2 Hz, 1H); 6.48 in d (J=2 Hz, 1H); 7,13 dd (J=9, 9 Hz, 2H); 7,27 dd (9, 6 Hz, 2H); 8,20 d (J=9 Hz, 1H); 9,65 s (lat.) (1H).

in) N2-(4-Forfinal)-4-methoxybenzo-1,2-diamine

33,5 g (0,128 ml) (5-methoxy-2-nitrophenyl)-(4-Fortini is)amine was subjected to chemical conversion in accordance with the General method 1. The crude product is used without purification in subsequent reactions.

1H-NMR (CDCl3): δ (part./million)=3,70 s (3H); of 6.49 d (W) (J=9 Hz, 1H); 6,68 d (J=2 Hz, 1H); 6,78-6,97 m (5H).

g) 6-Methoxy-1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole

of 7.48 g of thiophene-3-aldehyde in two hours was stirred in 65 ml of 40%aqueous solution of NaHSO3. After adding 15 g of N2-(4-forfinal)-4-methoxybenzo-1,2-diamine in 50 ml of ethanol and the mixture was boiled for 4 h and then was stirred overnight. Next, the mixture was distributed between water and ethyl acetate and the organic phase is washed with water. After drying over sodium sulfate and concentration of the filtrate got to 18.1 g of crude 6-methoxy-1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole.

tPL154-158°C.

d) 6-hydroxy-1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole

18 g (of 55.5 mmole) 6-methoxy-1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole was subjected to chemical conversion similar to the General method 2. The result was 12,65 g (40 mmol) of crude 6-hydroxy-1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole.

tPL212-218°C.

e) Methyl ester 6-[[1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained by interaction of 6-hydroxy-1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole with methyl ether 6-Bromhexine acid according to General method 3.

tPL131-134#x000B0; C.

g) 6-[[1-(4-Forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained from methyl ester 6-[[1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid in accordance with the General method 4.

tPL170-175°C.

Example 12

5-[[1-(4-Forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid

a) Methyl ester 5-[[1-(4-forfinal-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentanol acid

The specified connection was obtained by interaction of 6-hydroxy-1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole with methyl ester of 5-bromopentanoate acid according to General method 3.

tPL90,5-92,5°C.

b) 5-[[1-(4-Forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid

The specified connection was obtained from methyl ester 5-[[1-(4-forfinal-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentanol acid in accordance with the General method 4.

tPL184-189°C.

Example 13

6-[[1-(4-Forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

a) 6-Methoxy-1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole

The specified connection was obtained by interaction of N2-(4-forfinal)-4-methoxybenzo-1,2-diamine and pyridine-3-carbaldehyde as in example 11,

tPL132,5-134°C.

b) 6-Hydroxy-1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole

The criminal code of the above compound was obtained from 6-methoxy-1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole in accordance with the General method 2.

tPL238-241°C.

C) Methyl ester 6-[[1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained by interaction of 6-hydroxy-1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole with methyl ether 6-Bromhexine acid according to General method 3.

tPL105,5-111,5°C.

g) 6-[[1-(4-Forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained from methyl ester 6-[[1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid in accordance with the General method 4.

tPLof 127.5-129°C.

Example 14

5-[[1-(4-Forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid

a) Methyl ester 5-[[1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid

The specified connection was obtained by interaction of 6-hydroxy-1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole with methyl ester of 5-bromopentanoate acid according to General method 3.

tPL52-55°C.

b) 5-[[1-(4-Forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid

The specified connection was obtained from methyl ester 5-[[1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid in accordance with the General method 4.

tPL181,5-183°C.

Example 15

5-[[1-Phenyl-2-(3-pyridinyl)1H-benzimidazole-6-yl]oxy]pentane acid

a) 6-Methoxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole

The specified connection was obtained by interaction of 4-methoxy-N2-phenyl-o-phenylenediamine with pyridine-3-carbaldehyde according to General method 5.

MS (EI): 301 (molecular ion peak).

b) 6-Hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole

The specified connection was obtained from 6-methoxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole in accordance with the General method 2.

1H-NMR (D6-DMSO): δ (part./million)=6,52 d (J=2 Hz, 1H); for 6.81 dd (J=8, 2 Hz, 1H); 7,34-of 7.48 m (3H); 7,53-of 7.68 m (4H); 7,80 (ddd, J=8 and 2.1 Hz, 1H); 8,53 dd, J=2.1 Hz, 1H); 8,67 d (J=1 Hz, 1H); 9,42 (s, 1H).

C) Methyl ester 5-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid

The specified connection was obtained by interaction of 6-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with methyl ester of 5-bromopentanoate acid according to General method 3.

MS (EI): 401 (molecular ion peak).

g) 5-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid

The specified connection was obtained from methyl ester 5-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid in accordance with the General method 4.

1H-NMR (CD3OD): δ (part./million)=1,72-1,88 m (4H); 2,30 t (J=8 Hz, 2H); 3,98 t (J=8 Hz, 2H); 6,72 d (J=2 Hz, 1H); 7.03 is dd (J=8, 2 Hz, 1H); 7,40-of 7.48 m (3H); 7,55-7,65 m (3H); of 7.70 (d, J=8 Hz, 1H); 7,92 ddd, J=8, 2, 1 Hz, 1H); 8,53 dd (J=8, 2 Hz, 1H); 8,70 dd, J=2.1 Hz, 1H).

Example 16

p> 4-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid

a) Methyl ester of 4-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid

The specified connection was obtained by interaction of 6-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with methyl ether 4-pamakani acid according to General method 3.

MS (EI): 387 (molecular ion peak).

b) 4-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid

The specified connection was obtained from methyl ester 4-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid in accordance with the General method 4.

MS (EI): 373 (molecular ion peak).

Example 17

6-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

a) Methyl ester 6-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained by interaction of 6-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with methyl ether 6-Bromhexine acid according to General method 3.

MS (EI): 415 (molecular ion peak).

b) 6-[[1-Phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained from methyl ester 6-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid in accordance with the General method 4.

MS (EI): 401 (molecular ion peak).

Example 18

N-(3-IU the oksipropil)-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide

The specified connection was obtained by interaction of methyl ester 6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid with 3-methoxypropylamine in accordance with the General method 6.

MS (EI): 486 (molecular ion peak).

Example 19

6-[[1-(4-Were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]-1-morpholine-1-elexan-1-he

The specified connection was obtained by interaction of methyl ester 6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid with morpholine according to General method 6.

MS (EI): 442 (molecular ion peak).

Example 20

N-Methyl-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy] hexanamide

The specified connection was obtained by interaction of methyl ester 6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid hydrochloride N-methylamine according to the General method 6.

MS (EI): 428 (molecular ion peak).

Example 21

N,N-Dimethyl-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl] oxy] hexanamide

The specified connection was obtained by interaction of methyl ester 6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid with dimethylamine hydrochloride according to General method 6.

MS (EI): 442 (molecular ion peak).

Example 22

6-[[1-(4-Were)-2-(3-pyridinyl)-1H-benzimidazole-6-and the]oxy]hexanamide

The specified connection was obtained by interaction of methyl ester 6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid with ammonium chloride according to General method 6.

MS (EI): 414 (molecular ion peak).

Example 23

N-Cyclopropyl-6-[[1-(4-were)-2-(-3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanamide

The specified connection was obtained by interaction of methyl ester 6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid with cyclopropylamine in accordance with the General method 6.

MS (EI): 459 (molecular ion peak).

Example 24

N-Methyl-6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy] hexanamide

The specified connection was obtained by interaction of methyl ester 6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid hydrochloride N-methylamine according to the General method 6.

MS (EI): 433 (molecular ion peak).

Example 25

N-(2-Methoxyethyl)-5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanone

The specified connection was obtained by interaction of methyl ester 5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid with 2-methoxyethylamine in accordance with the General method 6.

MS (EI): 458 (molecular ion peak).

Example 26

N,N-Dimethyl-5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]on the si]pentanone

The specified connection was obtained by interaction of methyl ester 5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid (example V) with dimethylamine in accordance with the General method 6.

MS (EI): 428 (molecular ion peak).

Example 27

5-[[1-(4-Were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanone

The specified connection was obtained by interaction of methyl ester 5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanol acid with ammonium chloride according to General method 6.

MS (EI): 400 (molecular ion peak).

Example 28

6-[[1-(4-Were)-2-(2-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

a) Methyl ester 6-[[1-(4-were)-2-(2-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained by interaction of methyl ester 6-[[4-amino-3-((4-(were)amino)phenyl]oxy]hexanoic acid 2-taylormadeadidas in accordance with the General method 5.

MS (EI): 434 (molecular ion peak).

b) 6-[[1-(4-Were)-2-(2-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid

The specified connection was obtained from methyl ester 6-[[1-(4-were)-2-(2-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid in accordance with the General method 4.

MS (EI): 420 (molecular ion peak).

Example 29: inhibition of microglial activation

To receive the Deposit And activatedβ the peptide of microglia in vitro primary microglial cells (glial macrophages) rats were incubated with synthetic Andβ-peptide.

To simulate sediment Andβ-peptide And syntheticβ-peptide was dried in 96-hole tablet for growing tissue cultures. To this end the mother solution of the peptide with its concentration of 2 mg/ml of H2O was diluted with H2O in a ratio of 1:50. For coating 96-well plates used in 30 μl of this diluted solution of peptide per well and left overnight to dry at room temperature.

Primary microglial cells of rats were isolated from mixed glial cultures of cells derived from rat brain P3. To obtain mixed cultures of glial cells in 3-day-old rats were allocated the brain and the brain was removed shell. The division of cells into individual cells was carried out by treatment with trypsin (0,25%trypsin solution for 15 minutes at 37°). After separation of the decayed fragments of tissue through a nylon mesh with a cell size of 40 μm selected cells were separated by centrifugation (800 rpm for 10 min). Cellular debris resuspendable in culture medium and transferred into 100-ml cups for growing tissue cultures (1 brain per Cup). Cells were cultured at 37°C and 5% CO2within 5-7 d is she in DMEM (Wednesday Needle, modified by way of Dulbecco, with glutamine), supplemented with penicillin (50 u/ml), streptomycin (40 mg/ml) and 10% vol. fetal calf serum (FCS). During this incubation was formed adhesive cell cover, consisting mainly of astrocytes. Glial macrophages, which proliferated on the cover in the form of not - or subodhini cells were collected by incubation on a shaker (420 rpm for 1 h).

For activation of microglia Andβ-peptide glial macrophages were sown on covered Andβ-peptide tablets for growing tissue cultures in the amount of 2.5×104cells per well and incubated at 37°C and 5% CO2within 7 days in DMEM medium (with glutamine), supplemented with penicillin (50 u/ml), streptomycin (40 mg/ml) and 10% vol. TCF. On the 5th day added one proposed in the invention compounds at different concentrations of 0.1, 0.3, and 1.3 and 10 μm).

To quantify the reactivity of microglia on the 7th day of cultivation was determined by metabolic activity according to the degree of recovery of the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy)-2-(sulfophenyl)-2H-tetrazole, reagent Owen, J.A.Baltrop and others, Bioorg. & Med. Chem. Lett. 1, 1991, s]. Data on the degree of inhibition was expressed as percent relative to control treated with only DMSO. The results of this experience to the testimony of the t about what is proposed in the invention compounds inhibit the activation of microglia.

Example 30: the heart and brain in rats (MCAO-model)

The activity proposed in the invention compounds in vivo was investigated by modeling cerebral ischemia (apoplexy) in animals, i.e. using the so-called MAO-model (from the English. "permanent middle cerebral artery occlusion", permanent occlusion of the middle cerebral artery). When using such models unilateral occlusion of the middle cerebral artery (MCA) triggers a heart attack brain, caused by an insufficient supply of the relevant section or Department brain with oxygen and nutrients. This insufficient supply of oxygen and nutrients leads to pronounced cell death, and subsequent intensive activation of microglia. However, such activation of microglia reaches the maximum degree only after a few days and may persist for several weeks. Proposed in the invention compounds to study their effectiveness to inhibit the activation of microglia was injected intraperitoneally after 1-6 days after occlusion of the middle cerebral artery. On day 7, animals were subjected to perfusion and squashed. The degree of microglial activation was determined by a modified immunohistochemical method. Since this is the order obtained by microtome type Vibratom sections fixed brain were incubated with antibodies sensing receptor CR3 for the complement, respectively, the complex of MHC II on activated microglia. Binding of primary antibodies was quantitatively evaluated using a detector system for immunoassay analysis. In this experiment, the treatment proposed in the invention compounds led to the reduction of microglial activation in the damaged heart the brain.

Example 31: inhibitory effect on the production of TNFα and IL-12 in cells TNR-1

The inhibitory action proposed in the invention compounds on the production of cytokines can be investigated, for example, by determining the amount of TNFα and interleukin 12 in stimulated with lipopolysaccharide (LPS) cells TNR-1.

With this purpose, cells TNR-1 (obtained from the American type culture collection (American Type Culture Company, Raquel, PCs Maryland)) in an amount of 2.5×106cells per 1 ml of medium RPMI 1640 (firm Life Technologies), supplemented with 10% FCS (Life Technologies, cat. No. 10270-106), were sown in 96-well flat-bottomed culture plates (firm TRR, product # 9296) (100 μl per well). Next to the cells was added proposed in the invention compounds in various concentrations and pre-incubated for 30 minutes Test substance was pre-diluted in the incubation medium. The test substance was added in the form of their rest the RA dual concentration (100 µl per well). Cells were stimulated over night at 37°With lipopolysaccharide (firm Sigma, cat. No. L2630, from E. coli serotype 0111.B4), which is used in an amount of 0.1 μg/ml thereafter, the medium was collected and quantitatively evaluated the content of TNFα, respectively interleukin 12. The content of TNFα was determined using a commercially available kit for determination of TNFα company CIS bio international (product No. 62TNFPEB). The content of interleukin-12 were determined using technologies "ORIGEN" (developed by IGEN International, Inc. Gaithersburg, PCs Maryland). The calculated value IC50corresponds to the concentration of the test substance, which is necessary for inhibition of the level of production of TNFα, respectively interleukin 12 on 50% of the maximum level of production.

The results of this experiment it was found that proposed in the invention compounds inhibit the production of TNFα and interleukin 12 in stimulated with lipopolysaccharide (LPS) cells TNR-1.

Example 32: inhibitory effect on the production of IFNγ peripheral mononuclear blood cells

The impact of the proposed invention compounds on the activation of T cells can be examined, for example, the analysis of the secretion of IFNγ.

For isolation of peripheral mononuclear blood cells used human whole blood (l the I blood collection used the S-Monovette "Coagulation 9 NC/10 ml with sodium citrate, the firm Sarstedt). Blood cells were enriched by centrifugation with a density gradient. With this purpose in LEUCOSEP tubes (firm Greiner, cat. No. 227290) previously introduced into 15 ml of Histopaque-1077, Sigma, cat. No. n) and centrifuged for 30 s at 1000g. After this was added 15 ml of whole blood and centrifuged for 10 min at 1000g. Then the upper plasma layer was removed with a pipette, and located below the layer of cells (peripheral mononuclear blood cells) was transferred into a 15-ml tubes (firm Falcon) and washed several times with 10 ml of balanced salt solution Hanks (without Mg2+and CA2+, cat. No. 14175-53). In conclusion, cellular debris resuspendable in culture medium RPMI 1640, supplemented with 25 mm Hepes (2-N-hydroxyethylpiperazine-N'-2-hydroxypropanesulfonic acid, firm Life Technologies, cat. No. 52400-041), 10% FCS (firm Life Technologies, cat. No. 10270-106) and 0.4% solution of penicillin and streptomycin (firm Life Technologies, cat. No. 15140-106) (1×106cells/ml). 100 μl of cell suspension was distributed in 96-well flat-bottomed culture plates (firm TRR, product # 9296) and stimulated with antibodies to CD3, which are used in a concentration of 2.5 μg/ml was Then added proposed in the invention compounds in various concentrations and pre-incubated for 30 min the Cells were stimulated for 24 hours After this is th medium were collected and quantitatively evaluated the concentration of IFNγ . The content of IFNγ determined with the help of technology "ORIGEN" (developed by IGEN International, Inc. Gaithersburg, PCs Maryland). The calculated value IC50corresponds to the concentration of the test substance, which is necessary for inhibition level production of IFNγ 50% of the maximum level of its production.

The results of this experiment it was found that proposed in the invention compounds inhibit the production of IFNγ peripheral mononuclear blood cells.

Example 33: inhibitory effect on the production of TNFα and IL-12 HD peripheral mononuclear blood cells

The inhibitory action proposed in the invention compounds on the production of TNFα and IL-12 HD R you can explore, for example, by determining the amount of TNFα and IL-12 HD R in stimulated with lipopolysaccharide (LPS) and γ-interferon (IFNγ) peripheral mononuclear blood cells.

For isolation of peripheral mononuclear blood cells used human whole blood (blood collection used the S-Monovette "Coagulation 9 NC/10 ml with sodium citrate, the company Sarstedt). Lymphocytes and monocytes were enriched by centrifugation with a density gradient. With this purpose, 50 ml LEUCOSEP tubes (firm Greiner, cat. No. 227290) previously introduced into 15 ml of Histopaque-1077, Sigma, cat. No. n) centrifugational for 30 s at 250g squeezed down through which the tubes Frit. After this was added 20 ml of whole blood and centrifuged for 15 min at 800g and room temperature. After centrifugation the supernatant (plasma and platelets) was removed with a pipette and discarded, and an underlying layer of cells (lymphocytes and monocytes) was transferred into a 50-ml centrifuge tubes (firm Falcon) and then washed three times in culture medium VLE RPMI 1640 (firm Seromed, No. FG1415) (centrifugation cycles for 10 min at 250g and room temperature). In conclusion, cellular debris resuspendable in culture medium VLE RPMI 1640 (firm Seromed, No. FG1415), supplemented with 10% FCS (firm Life Technologies, cat. No. 16000-044, low endotoxin, inactivated by heating for 1 h at 56° (C) and a solution of penicillin and streptomycin at a concentration of 50 μg/ml (firm Life Technologies, cat. No. 15140-106), and after counting the cells using staining Trifanova blue their concentration was brought to 3×106cells in 1 ml Then 100 ál of cell suspension was distributed in 96-well flat-bottomed culture plates (firm Costar, product No. 3599). After that on the tablets the cells were added 100 μl of a solution to stimulate the triple concentration (3 μg/ml LPS from E. coli serotype 0127:B8, the company Sigma, cat. No. L-4516, and 30 ng/ml IFNγ 1b, Imukin, firm Boehringer Ingelheim). After this was added proposed in the invention is soedineniya in various concentrations in solution triple concentration (100 µl per well). Cells were stimulated at 37°C and 5% CO2within 24 hours Then collected the supernatant of cell culture and using commercially available kits for ELISA analysis firms BioSource International (TNF-α EASIA, cat. No. KAC1752) and R & D Systems (QuantikineTMHS IL-12, cat. No HS 120) determined the concentration of TNFα and IL-12 HD R. The calculated value IC50corresponds to the concentration of the test substance, which is necessary for inhibition of the level of production of TNFα, respectively interleukin 12 HD R 50% of the maximum level of production.

The results of this experiment it was found that proposed in the invention compounds inhibit the production of TNFα and IL-12 HD R peripheral mononuclear blood cells.

Example 34: induction of production of IL-10 in peripheral mononuclear blood cells

The ability of the proposed invention compounds to induce the production of IL-10 might include, for example, measuring the amount of IL-10 in stimulated phytohemagglutinin (PHA) or lipopolysaccharide (LPS) peripheral mononuclear blood cells.

For isolation of peripheral mononuclear blood cells used human whole blood (blood collection used the S-Monovette "Coagulation 9 NC/10 ml with sodium citrate, the company Sarstedt). Lymphocytes and monocytes were enriched p is the centrifugation with a density gradient. With this purpose, 50 ml LEUCOSEP tubes (firm Greiner, cat. No. 227290) previously introduced into 15 ml of Histopaque-1077, Sigma, cat. No. n) and centrifugation for 30 s at 250g squeezed down through which the tubes Frit. After this was added 20 ml of whole blood and centrifuged for 15 min at 800g and room temperature. After centrifugation the supernatant (plasma and platelets) was removed with a pipette and discarded, and an underlying layer of cells (lymphocytes and monocytes) was transferred into a 50-ml centrifuge tubes (firm Falcon) and then washed three times in culture medium VLE RPMI 1640 (firm Seromed, No. FG1415) (centrifugation cycles for 10 min at 250g and room temperature). In conclusion, cellular debris resuspendable in culture medium VLE RPMI 1640 (firm Seromed, No. FG1415), supplemented with 10% FCS (firm Life Technologies, cat. No. 16000-044, low endotoxin, inactivated by heating for 1 h at 56° (C) and a solution of penicillin and streptomycin at a concentration of 50 μg/ml (firm Life Technologies, cat. No. 15140-106), and after counting the cells using staining Trifanova blue their concentration was brought to 3×106cells in 1 ml Then 100 ál of cell suspension was distributed in 96-well flat-bottomed culture plates (firm Costar, product No. 3599). Then to being on the Board is Ah cells were added 100 μl of a solution to stimulate the triple concentration (3 μg/ml LPS from E. coli serotype 0127:B8, the company Sigma, cat. No. L-4516, respectively, 300 μg/ml of phytohemagglutinin PHA-L, the company Biochrom KG, cat. No. m). After this was added proposed in the invention compounds in various concentrations in solution triple concentration (100 µl per well). Cells were stimulated at 37°C and 5% CO2within 24 hours Then collected the supernatant of cell culture and quantitatively evaluated the content of IL-10. The concentration of IL-10 were determined using commercially available ELISA kit-analysis firm BioSource International (Human IL-10, cat. No. KHC0101C). The calculated value of the EU50corresponds to the concentration of the test substance, which is necessary to enhance the secretion of IL-10 on 50% of the maximum extent of the increase in their secretion.

The results of this experiment it was found that proposed in the invention compounds increase the production of IL-10 in peripheral mononuclear blood cells.

1. Derivatives of benzimidazole of General formula I

R1denotes a phenyl group which optionally contains up to three substituents, independently from each other selected from the group comprising F, Cl, Br, J, R4,

R2denotes a monocyclic or bicyclic 5-to 10-membered heteroaryl group which contains 1-2 heteroatoms selected from N, S and O,

R3denotes H,

R4represents C1-6alkyl,

And indicates With2-6alkylenes group,

In refers to a group COOH, CONH2, CONHR5or CONR5R5'in each case attached to the carbon atom of group a,

R5and R5'independently of one another denote a residue selected from the group comprising C1-6alkyl, where one C-atom may be replaced by O, and (C0-3alcander-C3-7cycloalkyl),

as well as their pharmaceutically acceptable salt,

with the exception of the following compounds:

6-[[1-phenyl-2-(pyridin-4-yl)-1H-benzimidazole-6-yl]oxy]hexanoic acid and

6-[[1-phenyl-2-(bestien-2-yl)-1H-benzimidazole-6-yl]oxy]hexanoic acid.

2. The benzimidazole according to claim 1, wherein R1denotes a phenyl group which optionally contains up to two substituents, independently from each other selected from the group comprising F, Cl, and R4.

3. The benzimidazole according to claim 1, wherein R4stands With1-4alkyl.

4. The benzimidazole according to claim 1, wherein R5and R5'independently of one another denote C1-6alkyl, where one carbon atom may be replaced by O3-5cycloalkyl-C0-3alkylen.

5. The benzimidazole according to claim 1, characterized in that a denotes Neretva is undertaken With 3-6alkylen.

6. The benzimidazole according to claim 1, characterized In that refers to a group COOH or CONH group2in each case attached to the carbon atom of group A.

7. The benzimidazole according to claim 1, which represents the

6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

4-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid,

6-[[1-(4-were)-2-(4-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

5-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

4-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid,

5-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

4-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]butyric acid,

6-[[1-phenyl-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

6-[[1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

5-[[1-(4-forfinal)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

6-[[1-(4-forfinal)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

5-[[1-(4-forfinal)-2-(3-pyridinyl)-1H-benzo is imidazol-6-yl]oxy]pentane acid,

5-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentane acid,

4-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]butyric acid,

6-[[1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid,

N-(3-methoxypropyl)-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]-1-morpholine-1-elexan-1-he,

N-methyl-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

N,N-dimethyl-6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

6-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

N-cyclopropyl-6-[[1-(4-were)-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

N-methyl-6-[[1-(4-were-2-(3-thienyl)-1H-benzimidazole-6-yl]oxy]hexanamide,

N-(2-methoxyethyl)-5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanone,

N,N-dimethyl-5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanone,

5-[[1-(4-were)-2-(3-pyridinyl)-1H-benzimidazole-6-yl]oxy]pentanone,

6-[[1-(4-were)-2-(2-thienyl)-1H-benzimidazole-6-yl]oxy]hexanoic acid.

8. The use of compounds according to one of claims 1 to 7 for obtaining a medicinal product intended for the treatment or prevention of diseases is any, associated with microglial activation.

9. The use of claim 8 for the treatment or prevention of inflammatory, allergic, infectious or autoimmune diseases.

10. The pharmaceutical agents having inhibitory effect on the activation of microglia, characterized in that they contain one or more compounds according to one of claims 1 to 7 and one or more carriers and/or auxiliary substances.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) or their pharmaceutically acceptable salts wherein R1 and R2 are similar or different and chosen independently from group comprising aryl and heteroaryl. Each of them as a substitute comprises optionally from one to sic groups chosen from group comprising the following groups: (a) halogen atom; (b) -OCF3 or -OCHF2; (c) -CF3; (d) -CN; (e) alkyl; (f) R18-heteroaljyl; (k) hydroxyl; (l) alkoxyl comprising cyclopropylmethoxyl, and (s) trifluoroalkoxyl; R3 means hydrogen atom (H); R4, R5, R7 and R8 are similar or different and chosen independently from group comprising H, -OH, alkyl, heteroalkyl and

under condition that if Z and/or X means nitrogen atom (N) then all radicals R4, R5, R7 and R8 don't mean -OH; R6 means -C(O)R15; R9 and R10 mean H; R11 is chosen from group comprising H and alkyl; R12 is chosen from group comprising H and alkyl; R13 is chosen from group comprising alkyl and alkoxyl; R14 means H; R15 is chosen from group comprising -NR16R17, -OR16 and alkyl wherein R16 and R17 are similar or different and chosen independently from group comprising H and alkyl; R18 means a substitute chosen from group comprising lower alkyl, halogen alkyl, halogenalkyl, alkoxycarbonyl, dialkylamino-group and piperidinyl; X and Z are similar or different and chosen independently from carbon atom (C) and N. Proposed compounds possess properties of inhibitor of 17β-hydroxysteroid dehydrogenase of type 3. Also, invention describes a pharmaceutical composition based on compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical composition.

16 cl, 23 tbl, 651 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines represented by the formula (I): wherein n means 2, 3 or 4; R1 means hydrogen atom or alkyl with 1-4 carbon atoms; R2 means pyridyl or thiazolyl that can be substituted with alkyl with 1-4 carbon atoms, halogen atom, amino-, dimethylamino-, acetylamino-, guanidino-, pyridylamino-group, thienyl, pyridyl, morpholinyl and thiazolyl substituted if necessary with alkyl with 1-4 carbon atoms or phenyl comprising if necessary up to three substitutes as halogen atom, alkyl with 1-4 carbon atoms or alkoxy-group with 1-4 carbon atoms, and to their salts, hydrates, salt hydrates and solvates, and also to substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridine of the formula (I) possessing properties of agonist of A1-adenosine receptors. Also, invention describes a medicinal agent possessing properties of agonist of A1-adenosine receptors. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal and pharmacological properties of compounds and drug.

7 cl, 3 tbl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method for treatment.

26 cl, 17 tbl, 221 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of nicotinamide of the general formula (I): wherein R1 is chosen from hydrogen atom, unsubstituted or substituted (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl, phenyl or heteroaryl; R2 is chosen from hydrogen atom, (C1-C6)-alkyl and group -(CH2)q-(C3-C7)-cycloalkyl, or -(CH2)mR1 and R2 in common with nitrogen atom to which they are bound form (four-six)-membered heterocyclic ring; R3 represents chlorine atom or methyl group; R4 represents group -NH-CO-R7 or -CO-NH-(CH2)q-R8; R7 is chosen from hydrogen atom, (C1-C6)-alkyl, group -(CH2)q-(C3-C7)-cycloalkyl and others; R8 is chosen from hydrogen atom, (C1-C6)-alkyl, (C3-C7)-cycloalkyl and others; each X and Y is chosen independently from hydrogen atom, methyl group and halogen atom; Z represents halogen atom; m is chosen from 0,1, 2, 3 and 4; n and q are chosen from 0, 1 and 2, and to pharmaceutically acceptable salts or their solvates. Indicated compounds possess inhibitory activity with respect to p38 kinase and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 127 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means lower alkyl, -(CH2)n-O-lower alkyl, -(C3-C6)-cycloalkyl or -(CH2)n-NR'2 wherein R' means hydrogen atom, lower alkyl or -(CH2)n-O-lower alkyl independently of one another for R'2; or R'2 in common with nitrogen atom can form pyrrolidine ring, and wherein n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition possessing antagonistic activity with respect to A2 receptors and containing one or some compounds of the general formula (I) and its pharmaceutically acceptable excipients. Invention provides synthesis of compound of the general formula (I) possessing antagonistic activity with respect to A2 receptors.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

11 cl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein radicals and symbols have values given in the invention claim. Compounds of the formula (I) possess properties of H3 receptors antagonist. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I). Also, invention relates to a method for treatment of disease of group comprising difficulty in nasal breath, obesity, somnolence, narcolepsy, attention deficiency with hyperactivity, Alzheimer's disease and schizophrenia that involves using compounds of the formula (I) and, optionally, in combination of H receptor antagonist.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

39 cl, 3 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2- pyrrolidine-2-yl-[1, 3, 4]oxadiazole with common formula I where R1 is aryl or heteroaryl, aryl here being phenyl unsubstituted or substituted with F, Cl, O-alkyl or phenyl, whereas heteroaryl is pyridinyl or thyenyl, R2 designates H, SO2R3 or COR4 where R3 and R4 independently designate C1-C10alkyl, C3-C10cycloalkyl, (C1-C6alkyl)-C3-C10cycloalkyl, aryl, (C1- C6alkyl)aryl, heterocyclyl, carboxylate residues with 3-10 C-atoms, dimethylamide or NR5R6, C1-C10alkyl at that being methyl, propyl, butyl, butenyl, isobutyl, amyl, pent-3-yl, hept-3-yl, hept-4-yl, 2,2-dimethylpropyl, CH2OCH3, CH2O(CH2)2OCH3 or CH(benzyl)MSO2C6H4CH3, C3-C10cycloalkyl is cyclopropyl, cyclobutyl, cycloamyl, adamantane-1-yl, 2-phenylcyclopropyl or 4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-3-on-1-yl, (C1-C6alkyl)-C3-C10cycloalkyl is CH2-cycloamyl, (CH2)2-cycloamyl or 7,7-dimethyl-1-methylbicyclo[2.2.1]heptane-2-on, aryl is phenyl, benzyl or naphthyl unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: phenyl, NO2, C1-C6alkyl, O-alkyl, CO2-alkyl, C(=O)C1-C6alkyl, CH2OC(=O)C6H5, F, Cl, Br, N(CH3)2, OCF3, CF3 or (C=O)CH3, (C1-C6alkyl)aryl is 3,4-dimethoxyphenyl-CH2, 4-chlorophenoxy-CH2, phenyl-CH=CH, benzyl-OCH2, phenyl-(CH2)2, 2-bromphenyl-CH2, 1-phenylpropyl, 2-chlorophenyl-CH=CH, 3-trifluorinemethylhenyl-CH=CH, phenoxy-CH2, phenoxy-(CH2)3 or phenoxy-CH(CH3), heterocyclyl is pyridinyl, isoxazole, thienyl, furanyl, triazole, benzoxadiazole, thiadiazole, pyrazole or isoquinoline unsubstituted, monosubstituted or polysubstituted with identical or different substitutes, namely: Cl, C1-C6alkyl, phenyl, in their turn unsubstituted or mono- or polysubstituted with identical or different substitutes, namely: Cl or C1-C6alkyl, CF3, carboxylate residues with 3-10 C-atoms are CH3OC(=O)CH2, CH3OC(=O)(CH2)3, CH3CH2OC(=O)CH2, CH3CH2OC(=O)(CH2)2, CH3C(=O)OCH2, CH3C(=O)OC(CH3)2 or CH3C(=O)OCH(C6H5), and R5 and R6 independently designate H or aryl, aryl at that being benzyl or phenyl respectively mono- or polysubstituted with identical or different substitutes, namely: F, C1, O-alkyl, CN, CF3. Invention also relates to method of obtaining, to medicament and to use of compounds with common formula I.

EFFECT: obtaining of new biologically active compounds and medicinal agents based on the above formulas.

9 cl, 248 ex, 2 tbl

Indanol derivatives // 2323937

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): (where R1 and R2 may be identical or different, and each is a 1,3-substituted aryl with substituents from group α; R3 stands for any of the following groups: -CO-R4, -CO-O-R4, -CO-NH-R4, -CO-CH2-N(Ra)Rb, -(CH2)m-CO-R5, -(CH2)m-R5, -CO-NH-CO-N(Ra)Rb, -CO-NH-SO2-N(Ra)Rb, -CO-NH-CO-(CH2)m-N(Ra)Rb, or -CO-NH2; R4 stands for a lower alkyl, cycloalkyl, cycloalkyl substituted with 1-3 substituent from group α, lower alkenyl, lower alkynyl, halogen-substituted lower alkyl, hydroxyl-substituted lower alkyl, lower alkoxyalkyl, lower aliphatic acyloxyalkyl or lower alkoxycarbonylalkyl; R5 stands for hydroxyl, -OR4 or -N(Ra)Rb; Rа and Rb may be identical or different, each of them stands for hydrogen, hydroxyl, lower alkoxy group, hydroxyl-substituted lower alkoxyl, hydroxyl-substituted lower alkoxyalkyl, lower alkoxy lower alkoxyalkyl, cyano lower alkyl, cyano lower alkoxyalkyl, carboxy lower alkyl, carboxy lower alkoxyalkyl, aliphatic lower alkoxycarbonyl lower alkoxyalkyl, carbamoyl lower alkyl group, carbamoyl lower alkoxyalkyl, lower aliphatic acylamino lower alkyl, lower aliphatic acylamino lower alkoxyalkyl, lower alkylsulphonylamino lower alkyl, lower alkylsulphanylamino lower alkoxyalkyl, (N-hydroxy-N-methylcarbamoyl) lower alkyl, (N-hydroxy-N-methylcarbamoyl) lower alkoxyalkyl, (N-lower alkoxy-N-methylcarbamoyl) lower alkyl, (N-lower alkoxy-14-methylcarbamoyl) lower alkoxyalkyl or R4, or both, including associated nitrogen, stand for nitrogen-containing heterocyclic group or nitrogen-containing 1-3 substituted heterocyclic group with substituents from group α; m is an integer from 1 to 6; А stands for carbonyl; В stands for straight bond; D stands for oxygen atom; Е stands for С14 alkylene; n is an integer from 1 to 3; and α group is a group of substituents, which consist of halogen atoms, lower alkyls, hydroxy lower alkyls, halogen lower alkyls, carboxy lower alkyls, lower alkoxyls, hydroxy lower alkoxyls, hydroxy lower alkoxyalkyls, lower alkoxycarbonyls, carboxyls, hydroxyls, lower aliphatic acyls, lower aliphatic acylamines, (N-hydroxy-N-methylcarbamoyl) lower alkyls, (N-lower alkoxy-N-methylcarbamoyl) lower alkyls, hydroxy lower aliphatic acylamines, amines, carbamoyls and cyano groups), or pharmacologically suitable salt thereof. Invention also relates to pharmaceutical composition and method for disease prevention and treatment.

EFFECT: preparation of novel biologically active compounds.

18 cl, 117 ex

FIELD: medicine, pharmacology.

SUBSTANCE: compound formula I is described, including the pharmaceutically acceptable salts, , where: Z presents ; Q is taken from the group that consists of: -W - presents , and the pharmaceutical composition, application of compound formula (I) for preparation of antiviral medicine.

EFFECT: proposed compounds can be helpful in treatment of HIV and AIDS.

70 cl, 2 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I) possessing inhibitory effect on production of interleukin-12 (IL-12) wherein R1 represents group of the formula , aryl or heteroaryl; each among R2 and R4 represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy group; R3 represents Rc, alkenyl, -ORc, -OC(O)Rc, -SRc, -NRcCORd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcSO2Rd, -CORc, -C(O)ORc or -C(O)NRcRd; R5 represents hydrogen atom (H); n = 0, 1, 2, 3, 4, 5 or 6; X represents oxygen atom (O) or -NRc; Y represents a covalent bond. -CH2, O or -NRc; Z represents nitrogen atom (N); one of values U and V represents N and another represents -CRc; W represents O, sulfur atom (S) or -S(O)2 wherein each radical among Ra and Rb represents independently H, (C1-C6)-alkyl, aryl or heteroaryl; each radical among Rc and Rd represents independently H, (C1-C6)-alkyl, phenyl, heteroaryl, cyclyl, heterocyclyl or (C1-C6)-alkylcarbonyl wherein term "aryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring; term "heteroaryl" relates to hydrocarbon cyclic system (monocyclic or bicyclic) comprising at least one aromatic ring that comprises at least one heteroatom, such as O, N or S as a part of cyclic system and wherein other atoms mean carbon; term "cyclyl" and "heterocyclyl" relate to partially or completely saturated monocyclic or bicyclic system comprising from 4 to 14 carbons in rings wherein heterocyclic ring comprises one or some heteroatoms (for example, O, N or S) as part of cyclic system and wherein other atoms mean carbon, and under condition that when X represents -NH, Y represents a covalent bond, n = 0, and R3 represents H or CH3 then R1 doesn't mean thiazolyl or pyrimidinyl. Also, invention relates to a pharmaceutical composition and a method for treatment of disorder associated with hyperproduction of interleukin-12.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

49 cl, 43 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to nonhygroscopic crystalline 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,2-dimethyl-1H-pyrrol-3-carboxamide maleate salt that possesses inhibitory effect on tyrosine kinase receptors. Also, invention relates to a pharmaceutical composition and to a method for treatment of cancer in mammals using such compositions.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

12 cl, 12 tbl, 17 dwg, 5 ex

FIELD: medicinal chemistry, pharmacy.

SUBSTANCE: invention relates to compounds and pharmaceutical compositions that act as antagonists of metabotropic glutamate receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

7 cl, 3 tbl, 11 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical agent.

6 cl, 67 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

22 cl, 3 tbl, 8 dwg, 6 ex

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