UA81243C2 - 1-phenyl-2-heteroaryl-substituted benzimidazole derivatives, the use thereof for producing drugs, pharmaceutical preparation containing such derivatives - Google Patents

Abstract

The invention relates to the novel benzimidazole derivatives of formula (I), to the production and use thereof in the treatment and prophylaxis of diseases that are associated with microglial activation, and of T-cell mediated immunological diseases. The invention also relates to the pharmaceutical preparations that contain the novel benzimidazole derivatives.

Description

Description of the invention

The present invention relates to new benzimidazole derivatives, the method of their preparation and their use for the 2 preparation of medicinal products intended for the treatment and prevention of diseases associated with the activation of microglia and for the treatment of immunological diseases mediated by T cells, as well as pharmaceutical preparations containing these new benzimidazole derivs.

The immune system includes many different cells and complex tissue structures that interact with each other mainly with the help of soluble factors. It is known that the occurrence of many immunological diseases 70 is caused by an imbalance of soluble factors of immunity, for example, cytokines Moztapp and Soyitap, App. To whom

Ipttipoi., 7, 1989, pp. 145-173; Bzigeei and Moztapp, RABEV .., 5, 1991, pp. 171-177; I iseu and others, Si.

Misgorios. Keum., 4, 1996, pp. 532-562; Romlieu and SoPipap, Tgtepdz RNaptasoi. Zsi.,, 14, 1993, pp. 164-168; zZipoi, etc., Ittypoiod. Kez., 20, 1999, pp. 164-168). So, for example, there is a lot of information about the role that interferon and interleukin 12 play in the pathogenesis of autoimmune diseases. Especially in this regard, diseases characterized by an inflammatory reaction mediated by T-cells (T-lymphocytes), such as multiple sclerosis, diabetes, chronic inflammatory bowel diseases, should be mentioned. Interleukin 12 (1-12), which is one of the representatives of cytokines, is produced by phagocytes, such as macrophages/monocytes, dendrites, B cells and other antigen-presenting cells (APCs), and affects both the function of natural killer cells (NK- cells), and on the function of T-lymphocytes. II/-12 can stimulate the production of γ-interferon (IEMu) in cells of both indicated types. T-lymphocytes can be roughly divided into two categories, which are characterized by the expression of certain surface antigens (СО4 and СОВ), namely, into СО4-positive T-cells (T-helper cells) and СО8-positive T-cells ( cytotoxic T cells).

CD cells, in turn, can be divided into T-helper cells 1 (TA) and T-helper cells 2 (TI). It is immune responses mediated by Tp1 cells that are associated with the pathogenesis of numerous immune, primarily autoimmune, diseases, such as, for example, insulin-dependent diabetes mellitus type I (ISDM), multiple (o) sclerosis, allergic contact eczema, psoriasis, rheumatoid arthritis , chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis), lupus and other collagenoses, as well as acute rejection reactions during allotransplantation ("host-against-graft" reaction, "graft-against-host" reaction). and -. and and;. - and -shsh, ;. and

Regarding interleukin 12, it is known that it plays the most important role in regulating the response of TN1 cells. "AND

Interleukin 12 induces the production of mainly 1-2, IEMU, TMEA and TMEV in these cells | Moztapp and Zad, ch.

And so on. Todau, 17, 1996, pp. 138-146; Saige|u and others, Appy. Kew. Ittipoi., 16, 1998, pp. 495-521). It is IRMu that is an effective mediator of the action performed by I/-1. Excess production of γ-interferon can be responsible (87 3z5 for example, for the occurrence of autoimmune diseases associated with MHC I (from the English "ta|og Piziosotranriyu so sotrieh", the main complex of histosuminity). In addition, there is also a fairly large number of obvious information about the pathological role that y-interferon plays in allergic diseases, as well as in sarcoidosis and psoriasis (A. ViShats, Adm. IttipoiY., 62, 1996, p. 6b1-130; Vavzpat et al., 9. IttipoiY. " , interleukin 12 and interleukin 12/interleukin 18-induced γ-interferon from MK-cells play an important role in the pathomechanism of non-T-cell-mediated inflammatory reactions (such as, for example, toxic shock syndrome, endotoxinemia, sepsis, septic shock, acute respiratory distress syndrome (ARDS), "response to the introduction of the first dose" (Chigei dose gezropze") during therapy antibodies, for example, after the introduction of OKTZ during allotransplantation) (Kit et al., Iyiesi Ittyp., 69, 2001, p. 7544-7549; Agai and others. 9. IGeiKos. Vio 69, 2001, pp. 921-927; NyiOgep et al., Agiigyiz Kev., Z, 2001, pp. 41-47, (ee) Aga et al., At. U. Kegzrig. SeiYi My. Vioi., 22, 2000, pp. 708-713; Sgoptapp et al., U. Ittipoi., 164, 2000, - with pages 4197-4203; MygaiShe and others, Iyyi. Ittipoi., 11, 1999, pp. 1403-1410). 1-12 also plays a certain role in inflammations, the basis of which are pathomechanisms that have not been discovered at the moment (for example, in eclampsia) |Nauakauma et al., U. Kergod. Ittipoi., 47, 2000, pp. 121-138; Oapiev and others, At. U. Kergod. Ittypo)., 39, 1998, pp. 376-380)1. 50 Along with interleukin 12 and IEM, a certain role in the pathogenesis of immune diseases and systemic inflammatory reactions is attributed to other cytokines, such as, for example, TMEA (tumor necrosis factor A). TMEA plays an important pathological role in infectious diseases (such as sepsis, Ptgaseu's toxic shock syndrome, etc.,

Maishghte, 330, 1987, pp. 662-664; Vazdeg and others, Sigse. ZposK, 27, 1989, pp. 51-61; Nipepyam/ etc., Sigs. ZPposK,

Z0, 1990, pp. 279-292; A. Muaade, Iapsei, 351, 1998, p. 603; Sopep et al., Iapsei, 351, 1998, p. 17311), but also in numerous other immune-mediated diseases. o Corticosteroids are often used to treat II-12 mediated diseases and to alleviate the acute symptoms of such diseases, the side effects that appear during their use, and above all with long-term therapy, are often the reason for stopping the course of treatment.

The key phase of the inflammatory process in almost all degenerative diseases of the central nervous system is the activation of glial macrophages, or microglia. Glial macrophages can remain in an activated state for long periods of time, in which they produce and secrete various inflammatory factors, such as reactive oxygen/nitrogen-containing intermediates, proteases, cytokines, complement factors, and neurotoxins. Such factors, in turn, will lead to dysfunction and degeneration of nerve cells. Activation of microglia can be caused by various stimuli, such as, for example, AB-peptide (B-amyloid, (O.M. Agazio and SM. Soitap, 65 Vgaiip Kevz. 569, 1992, p. 141-145 (1992))), prion protein, cytokines or cell fragments |S.K. Sotrz and others, U. Meygovzsi. 19, 1999, pp. 928-939, R.Yi. Language, Meigoiipshattatsop: Mespapiztv apa Mapadetepi, ed

Nytapa Rgezz, 1998).

Benzimidazoles, which inhibit the activation of microglia after AB-peptide stimulation, are described (in the application UUO 01/51473). It is also known from this application that benzimidazoles, which inhibit the activation of microglia, are used

For the treatment of neuroinflammatory diseases, such as AIDS dementia, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, Down's disease, diffuse Lewy body disease, Huntington's disease, leukodystrophy, multiple sclerosis, Parkinson's disease, Pick's disease, Alzheimer's disease, apoplexy, temporal lobe epilepsy and various tumors

IU ER 0104727 JSC described derivatives of benzimidazole, which are not substituted in position 1, but in position 2 contain /o alkyl group. Substituents in the benzene ring of these derivatives are, in particular, pyridyloxy residues, pyridylalkyl residues, pyridylalkyloxy residues and pyridyloxyalkanediyl residues.

GU applications MUO 01/21634 At| benzimidazole derivatives are also described, which in position 1 contain an alkanediylamido group, and in position 2 contain, in particular, a substituted phenyl or heteroaryl residue and which in the annelated benzene ring can be substituted, in particular, by at least one substituted /5 hydroxy residue, alkylamino residue, alkylsulfonyl residue or alkylsulfoxide remainder In the specified application, it is noted that these compounds can be used as an active ingredient in medicines for many different indications.

In patent 5 5552426) substituted benzimidazoles are described, which in position 1 contain, in particular, a phenyl or naphthyl residue, and in position 2 contain, in particular, a phenyl or heterocyclic residue. The ringed benzene ring of such benzimidazoles is preferably substituted with an alkoxy- or amino-alkyl residue. According to the information provided in the specified patent, similar compounds are effective in diseases based on B-amyloid peptide-related neurotoxicity.

In application MO 97/12613 AT) various means are described that inhibit the inflammatory process and prevent the development of arteriosclerosis. As an example of active substances that have similar properties, this application specifies derivatives of benzimidazole, which in position 1 are substituted, in particular, by a phenyl or substituted phenyl residue, and in position 2 are substituted by an alkoxy residue. Substituents in the benzene ring in such biologically active compounds i) can serve, in particular, as alkyl residues, nitro residues, halogen atoms, alkoxy residues, amino residues, ester residues, amide residues, alkandyl alkoxy residues and alkandylamino residues.

IU applications ER 0520200 A? described benzimidazole derivatives, which in position 1 contain substituted aryl c zo residues, and in position 2 contain mono- or disubstituted or unsubstituted amino groups. The benzene ring of the benzimidazole skeleton can be replaced by halogen, trifluoromethyl and/or cyano group. Such compounds are intended for the treatment of diseases associated with increased activation of Ca channels. with

GU application of UMO 97/33873 A1| benzimidazole derivatives used to treat cystitis are also described. These compounds can contain in position 1, in particular, phenyl, naphthyl and unsaturated heterocyclic (7 zv) RESIDUES. In position 2, such derivatives can be substituted with an alkoxy residue, a phenylalkyloxy residue, with a naphthylalkyloxy residue, a heterocyclyloxy residue or an unsaturated heterocyclyloxy residue.

The benzene ring of the skeleton of these derivatives can be substituted by nitro residues, alkanoyl residues, amino residues, alkyl residues, alkoxy residues, cycloalkyl residues, heterocyclic residues, unsaturated heterocyclic residues, halogen atoms, alkylthio residues, "hydroxyalkylideneyl residues, "hydroxyalkylideneylamino residues, aminoalkylideneyl residues, aminoyl residues hydroxyalkyl residues, heterocyclyloxy residues, aminoalkylidenyl residues or trifluoromethyl residues. ;" GU application EP 0531883 AT | describes condensed 5-membered heterocycles, for example, substituted benzimidazole derivatives, while such compounds, according to their general description, are preferably substituted in position 1 with a substituted alkyl residue, and in position 2 are substituted, for example, with O-alkanedyl, 5 - alkandyl,

Go! MH-alkanedyl, M(alkyl)alkanedyl, 5O-alkanedyl or 5O»-alkanedyl residue. The compounds described in this application are expected to have antithrombotic activity. - One of the possible approaches to the therapy of inflammatory diseases of the nervous system described in the literature currently consists in the use of non-steroidal inhibitors that suppress the inflammatory process (COX I inhibitors)

IRS MsOeeg, Codeg, Meygoiodu, 42, 1992, pp. 447-449; 9). Codegv, I.S. Kigru, 5.K. Netrieetap, O.I. Vegtu, pi R.G. MSOEEG, AMU. Kazagpiak, 9. 2aiipeKi, M. Soiyed4, Y. Mapzikpapi, R. MMUyvop, ER. Kodap, Meyigoiodu, 43, 1993, 4) pp. 1609-1611; K. Apaegzep, I.). Hashpeg, A. OK, A.MU. Noez, M.M.V. Vge(eieg, A. Noitap, Mepygoiodu, 45, 1995, p.1441-1445; .S.5. Vgeipeg, V.A. Sa, K.A. Mueizp, V.I. Riazztap, M.M. MesBropaida , M.). Neytv, 9.0.

Apipyopu, Metsygoiodu 44, 1994, pp. 227-232; Te Sapadiap Bishau oi Neayi apa Adipo, Meyigoiodu, 44, 1994, pp. 2073-2079), cytokine modulators (R.Y. Msoseeg, E.b. Mesoseeg, Vgaiip Kev. Chem. 21, 1995, p.195-218 ;

E.b. Msobeeg, R.G. MsbSeeg, CM5 Ogydv, 7, 1997, pp. 214-228; B.S. Vagope and 0.7. Recegvivip, U. Segebga! Viosa

F) Riom/ apa Megiaroiizt, 19, 1999, p. 819-8341 and inhibitors of the pathway of complement activation |Z. Specialist, K.S.A. ka Egedegiskhop and K.K. Vgypaep, Meiygobio!. Adipo, 1996; E.b. Messeeg, R.I. MesSeeg, Ogydv, 55, 1998, p. 739-746).

Known compounds that are used for the therapy of immunological diseases, such as, for example, steroids, because they often affect several factors in the immune system and, as a result, cause numerous side effects.

Based on this, this invention was based on the task of offering substances that, thanks to their activity in relation to microglia, would have the ability to inhibit the activity of cytokines without causing serious toxic side effects.

This task is solved with the help of new benzimidazole derivatives proposed in the invention in accordance with 65 7.1 of the claims of the invention, as well as due to the use of the benzimidazole derivative proposed in the invention to obtain a medicinal product intended for interrupting the production of 1/-12 and IRMG in cells of monocyte origin, respectively T - cells and MK cells.

Microglial inhibitors due to their ability to interrupt the production of 11-12 and TMERA in monocytes/macrophages/dendrites and the production of IPM in T cells and MK cells are suitable for the treatment of various diseases caused by increased production of cytokines, such as TMRA and -B, IRMH, 1-2 th

I/-12, for example, inflammatory diseases not based on neuroinflammation, autoimmune diseases, allergic and infectious diseases caused by inflammatory toxins, pharmacologically provoked inflammatory reactions, as well as pathophysiologically relevant inflammatory reactions of currently unknown genesis.

Accordingly, the invention offers benzimidazole derivatives of the following general structural formula:

V-A-O s what -4 o () so « s «- d) - s . and?

What about which of B! means a phenyl group which optionally contains up to three substituents independently selected from the group consisting of E, SI, Vg, U, OH, OK", OSOK, 527, ZOV, 50287, B", МНо, МНЕ " and ME!V", or name) two adjacent substitutes for KE! jointly form the group -О-СН»-О-, -ОО-СНо-СНо-О-or -СНо-СНо-СНо-, и» 20 V? means a monocyclic or bicyclic 5-10-membered heteroaryl group which contains 1-2 heteroatoms selected from M, 5 and O, and which optionally contains up to two substituents, independently of each other, selected from the group consisting of Е, СИ, Вг, ), ОН, ОВУ, OSОВ", СОВ", 587, ЗОВ, 50287 and В", or two adjacent substituents at 2 together form the group -О-СН»-О-, -«0-СНо -СНо-О- or -СНО-СНо-СНе-,

EZ means H, OH or O-C. Valkil, 29 4:ri : : :

Kik" independently of each other mean C..perfluoroalkyl or C. alkyl, (F) A means a C. alkylene group, which is optionally substituted by -O, OH, 0O-C 4 alkyl, MH", MN-C. alkyl, g MH-C..alkanoyl, M(C..alkyl)" or M(C.alkyl(C..alkanoyl),

B means the group СООН, СОМН»о, СОМНМН», СОМНЕ? or COM", in each case attached to the boron atom of Carbon group A,

BZ and Y independently of each other represent a residue selected from the group consisting of C/alkyl,

C, dalkenyl, Co valkynyl, where one C-atom can be replaced by 0, 5, 50, 505, MH, M-Sisalkyl or

М-С4.alkanoyl, (Sozalkandiyl-C3 7cycloalkyl) where in a five-membered cycloalkyl ring one ring member can be a ring M-atom or a ring O-atom, and in a six- or seven-membered cycloalkyl ring 65 one or two ring members can be, respectively, a ring M- and/or ring O-atoms, while ring M-atoms may optionally be replaced by C 4 alkyl or C isalkanoyl, and also includes

(Co-alkanediylphenyl) and (Co-alkanediylheteroaryl), where the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group consisting of M, io, while all of the above alkyl and cycloalkyl residues may optionally contain up to two substituents selected from the group consisting of CE with, SoEv, OH, О-С..alkyl, МНо, МН-С. zalkyl, MN-S.. zalkanoyl,

M(C..alkyl)", M(C.alkyl)x/C-alkanoyl) COOH, SOMNo and COO-C.alkyl, and all the above-mentioned phenyl and heteroaryl groups may optionally contain up to two substituents selected from the group , which includes BC, SI,

Вг, СН,., Сон», ОН, Осн», ОСН», МО», M(СН»З)», Сг, Согв and ЗО2МН», or

Bo and 2" together with the M-atom form a five-seven-membered heterocyclic ring, which may contain one more M-, 70 O- or 5-atom and which may be substituted by C..alkyl, (Co-alkanediyl-C.4-4-alkoxy group) , S. lalkoxycarbonyl, aminocarbonyl or phenyl, as well as their optical or geometric isomers or tautomers or their pharmaceutically acceptable salts, with the exception of the following compounds: 6-(1-phenyl-2-(pyridin-4-yl)-1H-benzimidazol- b-yl|oxy|hexanoic acid and 6-(1-phenyl-2-(benzothien-2-yl)-1nH-benzimidazol-b-yl|oxy)hexanoic acid.

Preferred are compounds in which B represents a phenyl group, which optionally contains up to two substituents independently selected from the group consisting of EK, SI, OH, OB, oSOK, 5827 and B, or two adjacent substituents at B " form the group -О-СН»-О- or -СНо-СНо-СНео-.

Also preferred are benzimidazole derivatives, in which EC? means a monocyclic 5-6-ene heteroaryl group which contains 1-2 heteroatoms selected from the group consisting of M, 5 and O, and which optionally contains up to two substituents independently selected from E, CI, ОВ", OSOV", 887, ZOV, 50287 and В", or two adjacent substituents at В? form the group -"О-СН»-О- or СНИ-СНо-СНе»-.

Derivatives of benzimidazole are also preferred, in which Z stands for N. sch

Benzimidazole derivatives, in which Bl and B independently of each other, are among the preferred ones

C. operfluoroalkyl or C. dalalkyl. and)

Derivatives of benzimidazole are also preferred, in which the 25th VU independently of each other mean C. alkyl, where one carbon atom can be replaced by O, 5, ZO or 50", Cz 5vcycloalkyl-Soalkylene, where in the 5-ene cycloalkyl ring one the ring member can be an M-atom or an O-atom, while the ring nitrogen atom (9 is optionally substituted with C4alkyl or C4alkanoyl, or So»alkylene-(5-b6-ene heteroaryl with 1-2" heteroatoms with numbers M, C and 0), while all the above-mentioned alkyl and cycloalkyl residues can be replaced by a CEz group, an OH group, a MH group, MH-C alkyl, MH-C alkanoyl, M(C.4 alkyl)". with

M(Ci-alkyl)(C..alkanoyl), COOH group or COMH group", and all the above heteroaryl groups can "- be substituted by one or two substituents selected from the group consisting of PE, SI, CH3, CeH5, OSH3 , OSoNv, SEz | CoEv, or B ii KU together with the nitrogen atom form a 5-7-ene heterocycle, which may contain one more atom of oxygen, nitrogen or sulfur and may be substituted by C-alkyl or C-alkyl.

Also preferred are benzimidazole derivatives in which A is an unbranched C3 valkylene.

Also preferred are benzimidazole derivatives, in which B means the COOH or СОМН 5 group, in each case "attached to the carbon atom of the A group.

Particularly preferred are the following specific benzimidazoles: 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid, "» 5-(1-( 4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|Ioxy|Ipentanoic acid, " 4-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazole- b-yl|ioxy)butyric acid, 6-(1-(4-methylphenyl)-2-(4-pyridinyl)-1H-benzimidazole-b-yl|oxy|hexanoic acid, 6-(1-(4-methylphenyl) )-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid, so 5-((1--4-methyl phenyl )-2-(3-thienyl)-1H-benzimidazole-b -yl|oxy|pentanoic acid, - 4-(1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|ioxy|butyric acid, 5-(1-phenyl-2- (3-thienyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid, and 4-(1-phenyl-2-(3-thienyl)U-1H-benzimidazol-b-yl|ioxy|butyric acid, their 20 6-(1-phenyl-2-(3-thienyl)-IN-benzimidazol-b-yl|oxy)hexanoic acid, 6-(1-(4-fluorophenyl)-2-(3-thienyl)-1H- benzimidazole-b-yl|oxy|hexanoic acid, c» 5-(1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole-b-yl|!oxy|ipene tannic acid, 6-(1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|)hexanoic acid, 5-(1-(4-fluorophenyl)-2-( 3Z-pyridinyl)-1H-benzimidazol-b-yl|oxy|)pentanoic acid, 59 5-C1-phenyl-2-(Z-pyridinyl)-1H-benzimidazol-b-yl|!oxy|Ipentanoic acid,

HF) 4-(1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy)butyric acid, 6-(1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-b -yl|oxy|hexanoic acid, where M-(3-methoxypropyl)-6-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy|hexanamide, 6 -(1--4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|-1-morpholin-1-ylhexan-1-one, 6o M-methyl-6-(1 -(4-methylphenyl)-2-(3-pyridinyl)-IN-benzimidazol-b-yl|oxy|hexanamide,

M,M-dimethyl-6-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanamide, 6-(1-(4-methylphenyl)-2 -(Z-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanamide,

M-cyclopropyl-6-|(1-(4-methylphenyl)-2-(3-thienyl)-1IN-benzimidazol-b-yl|oxy|hexanamide,

M-methyl-6-((1-(4-methylphenyl-2-(3-thienyl)-1IN-benzimidazol-b-yl|oxy|hexanamide, because 6-(1-(4-methylphenyl)-2-phenyl -1H-benzimidazol-b-yl|oxy|-1-(thiazolidin-3-yl)hexan-1-one,

M-(2-methoxyethyl)-5-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanamide,

M,M-dimethyl-5-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanamide, 5-(1-(4-methylphenyl)-2 -(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanamide and 6-(1-(4-methylphenyl)-2-(2-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid .

The scope of this invention also includes physiologically compatible salts of the above compounds, primarily acid salts of benzimidazole derivatives proposed in the invention, when they are presented in the form of nitrogenous bases, as well as basic salts of the derivatives proposed in the invention, when they are presented in the form of carboxylic acids.

The benzimidazole derivatives proposed in the invention 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 represented as tautomers, stereoisomers or geometric isomers. Accordingly, the scope of the invention also includes all possible isomers, such as E- and 2-isomers, 5- and K-enantiomers, diastereomers, racemates and their mixtures, including tautomeric compounds. All such isomeric compounds, even if not specifically indicated in each case, are part of the present invention.

Mixtures of isomers can be separated into enantiomers, respectively E/7-isomers, by conventional methods such as crystallization, chromatography or salt formation.

Heteroaryl groups contained in the benzimidazole compounds proposed in the invention consist of 5-10 skeletal atoms and may contain 1 or 2 heteroatoms. Such heteroatoms are oxygen (0), nitrogen (M) and sulfur (5).

Examples of monocyclic heteroaryl groups include pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrimidinyl and pyridazinyl.

Examples of a bicyclic heteroaryl group are indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, cinolinyl, quinoxalinyl. and naphthyridinyl. When the heteroaryl group forms part of the VC substituent, the bond with the M atom of benzimidazole Ha

It is carried out through a carbon atom.

Heteroaryl residues can be attached in any way to the benzimidazole skeleton or to another i9) group, for example in the form of 2-, 3- or 4-pyridinyl, in the form of 2- or 3-thienyl or in the form of 1-imidazolyl.

Alkyl groups can have a straight or branched chain. Examples of such alkyl groups include methyl, ethyl, "-propyl, isopropyl, n-butyl, sec-butyl, tert-butp, n-pentyl, sec-pentyl, tert-pentyl, "Z neopentyl, n-hexyl and sec - hexyl.

Perfluorinated alkyl residues are mainly CE" and CoEv. M

Cycloalkyl groups in each case mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

As examples of a saturated heterocyclic ring, respectively, as examples of cycloalkyl with one or several heteroatoms, piperidine, pyrrolidine, tetrahydrofuran, morpholine, piperazine, hexahydroazepine, as well as 2,6-dimethylmorpholine, M-phenylpiperazine, 2-methoxymethylpyrrolidine, piperidine-4- carbonamide, thiomorpholine and thiazolidine, while the connection can be carried out through ring M-atoms present under certain conditions.

Examples of unbranched or branched alkylene containing up to six C-atoms as the value of "A" are ethylene, propylene, butylene, pentylene, hexylene, as well as 1-methylethylene, 1-ethylethylene, 1-methylpropylene, 2-methylpropylene, 1- methylbutylene, 2-methylbutylene, 1-ethylbutylene, 2-ethylbutylene, 8c 1-methylpentylene, 2-methylpentylene, 3-methylpentylene and similar compounds. ц A can be disubstituted, preferably monosubstituted, by the group OH, the group МН», МН-С. zalkylom or "» MN-S. zalkanoyl.

For the formation of physiologically compatible acid salts of the benzimidazole derivatives proposed in the invention, when they are presented in the form of nitrogenous bases, inorganic and organic acids are suitable, such as, for example, oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, - p-toluenesulfonic acid and methanesulfonic acid. If the compounds proposed in the invention contain acidic groups, primarily carboxylic acid groups,

It is also possible to form salts with inorganic or organic bases, which are known for their use in the formation of physiologically compatible salts and as an example of which we can name hydroxides of alkali metals, primarily sodium hydroxide and potassium hydroxide, hydroxides of alkaline earth metals, such as calcium hydroxide, and also ammonia and amines such as ethanolamine, diethanolamine, triethanolamine, M-methylglucamine and tris(hydroxymethyl)methylamine.

Compounds of the formula | inhibit the activation of microglia and the production of interleukin 12 (1-12) and y-interferon (IEMUu). Accordingly, the invention also relates to the use of a compound of formula I, as well as its optical or o-geometric isomers or its tautomers or a physiologically acceptable salt for the preparation of a medicinal product intended for the treatment or prevention of a disease associated with the activation of microglia, primarily caused by overproduction AND! -12 and IRMG of the disease, and to induce the production of interleukin 10 (P--10). 60 In one of the preferred options, the compounds proposed in the invention are used for the treatment of T-cell-mediated, in particular TN-1 cell-mediated, immunological disease and non-T-cell-mediated inflammatory reactions. The compounds proposed in the invention are used primarily for the preparation of a medicinal product designed to interrupt the production of 1-12 and IRMG in cells of monocyte origin, respectively, T-cells and MK-cells. The compounds 65 proposed in the invention, due to their ability to interrupt the production of 1-12 and TMEA in monocytes/macrophages and the production of IRMG in T cells, are suitable for the treatment of various diseases caused by increased production of cytokines, such as TMEA and -B, IEMG, 1-2 and

I/-12, such as inflammatory diseases not based on neuroinflammation, autoimmune diseases, allergic and infectious diseases caused by toxins of inflammation, pharmacologically provoked

Inflammatory reactions, as well as pathophysiologically relevant inflammatory reactions of currently unknown genesis.

Examples of inflammatory and autoimmune diseases include chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis), arthritis, allergic contact eczema, psoriasis, pemphigus, asthma, multiple sclerosis, diabetes, insulin-dependent type I diabetes, rheumatoid arthritis, lupus, and others. collagenosis, Graves' disease, Hashimoto's goiter, graft-versus-host reaction, and graft rejection. 70 Examples of allergic, infectious, toxin-induced, and ischemia-induced diseases are sarcoidosis, asthma, hypersensitivity pneumonitis, sepsis, septic shock, endotoxin-bacterial-toxic shock, toxic shock syndrome, toxic liver failure, ARDS (acute respiratory distress syndrome), eclampsia, cachexia, acute viral infections (for example, infectious mononucleosis, fulminant hepatitis), organ damage after reperfusion.

An example of pharmacologically induced inflammation with pathophysiological relevance is the "response to the introduction of the first dose" ("igvi dose gezropse") after the introduction into the body of T-cell antibodies, such as OKTZ.

Eclampsia can be called an example of systemic inflammatory reactions of currently unknown genesis.

The list of neuroinflammatory diseases associated with the activation of microglia includes, for example,

AIDS dementia, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Down's disease, diffuse Lewy body disease, Huntington's disease, leukodystrophy, multiple sclerosis, Parkinson's disease,

Pica, Alzheimer's disease, apoplexy, temporal lobe epilepsy and various tumors. Accordingly, the invention also relates to the use of benzimidazole derivatives proposed therein for the treatment of these diseases, as well as for their prevention.

According to the invention, effective microglial inhibitors include compounds that inhibit the activity of microglial cells when stimulated by AB-peptide by at least 20905, and the activity of cytokines is inhibited by at least 3090.

The biological properties of microglia inhibitors can be studied by methods known to specialists in this field, i) for example, the research methods discussed below and (described in UUO 01/51473).

Example 29 describes a method by which inhibition of microglial activation can be assessed. At the same time, various stimuli can be used to activate microglia, for example AB-peptide (B-amyloid, (O.M. zo Agazio and S.M. Soitap, Vgayp Kev. 569, 1992, pp. 141-145 (1992)) ), prion protein, cytokines or cell fragments |S.K. Sotrv and others, U. Meiygovssi. 19, 1999, pp. 928-939, R... MUood, Meigoiish Shattatsop: Mespapiztv « apa Mapadetepi, ed. Nytapa Rgezz, 1998). with

Stimulation with AB peptide corresponds to the pathophysiological situation in Alzheimer's disease. In this study, upon stimulation with AB peptide, the compounds proposed in the invention show an inhibitory effect on the activation of microglia. The inhibitory effect of the compounds proposed in the invention on the activation of microglia is manifested in a significant decrease in the production and secretion of cytokines, for example, interleukin 18 (11-18) and

tumor necrosis factor A (TMEA) (according to the results of solid-phase enzyme-linked immunosorbent assay (ELISA) and analysis of MRNYC expression), and in the reduced secretion of reactive oxygen-/nitrogen-containing intermediates. Accordingly, simultaneous inhibition of several inflammatory factors is ensured. "

The effectiveness of the compounds proposed in the invention was determined using the MSAO model in rats. stv) c A similar model allows simulating a condition that corresponds to apoplexy. The compounds proposed in the invention. reduce the activation of microglia, which occurs with acute pathological changes in the brain of animals. and?" The inhibitory effect on the production of cytokines is evaluated, for example, by determining the amount of TMEA and interleukin 12 in lipopolysaccharide (LPS)-stimulated TNR-1 cells. The compounds proposed in the invention inhibit the production of TMRA and interleukin 12 in lipopolysaccharide (LPS)-stimulated TNR-1 cells.

Go! To determine the effect that the compounds proposed in the invention have on the activation of T cells, the secretion of IEM, for example, is studied. The compounds proposed in the invention inhibit the production of IEM in peripheral blood mononuclear cells. The present invention also relates to pharmaceuticals containing one or more of the compounds of the general formula I proposed in the present invention, as well as one or more carriers. Such pharmaceuticals proposed in the invention, respectively, compositions are obtained depending on the intended route of their introduction into the body in the required dosage according to known methods using conventional solid or liquid carriers or diluents, as well as conventional pharmaceutical and technological auxiliary substances. Preferred compositions are presented in the form of a dosage form suitable for oral, enteral or parenteral, for example intraperitoneal, intravenous, intramuscular or transdermal administration. Examples of such dosage forms are tablets, film-coated tablets, dragees, pills, (F, capsules, powders, pastes, ointments, lotions, liquid preparations such as syrups, gels, liquid preparations for injections, such as for intraperitoneal, intravenous , intramuscular or transdermal injections, and other dosage forms. The list of other dosage forms also includes depot forms, in particular, implanted forms for use, as well as suppositories. At the same time, from such individual dosage forms, the invention offers derivatives depending on their Tina are released into the body gradually or in full in a short period of time.

Capsules, pills, tablets, dragees and liquid preparations or other known dosage forms for oral administration can be used as pharmaceutical preparations for oral administration. In this case, medicinal products can be prepared in the form of preparations that either release active b5 substances in a short period of time and secrete them into the body, or have a prolonged effect that ensures a longer, slower entry of the active substance into the body. The composition of such single-dose dosage forms together with at least one benzimidazole derivative may include one or more pharmaceutically acceptable carriers, for example, substances for regulating the rheological properties of the drug, surface-active substances, hydrotropic solubilizers, microcapsules, microparticles, granules, diluents, binders , such as

Starch, sugar, sorbitol and gelatin, as well as fillers such as silicic acid and talc, lubricants, dyes, flavors and other substances.

Suitable tablets can be prepared, for example, by mixing the active substance with known excipients, such as inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as carboxypolymethylene, carboxymethylcellulose, acetylcellulose phthalate or polyvinyl acetate. Tablets can also have a multilayer structure.

Accordingly, it is also possible to obtain dragees by coating the cores made in the same way as tablets from materials commonly used as dragee shells, such as, for example, polyvinylpyrrolidone or /5 shellac, gum arabic, talc, titanium oxide or sugar. At the same time, the shell of the dragee can also have a multi-layered structure, for the preparation of which you can use the auxiliary substances specified above for tablets.

Capsules containing active substances can be made, for example, by mixing the active substance with an inert carrier, such as lactose or sorbitol, and packaging the resulting mixture into gelatin capsules.

The benzimidazole derivatives proposed in the invention can also be used in pharmaceutical form in the form of a solution that is intended for oral administration and which, together with the biologically active benzimidazole derivative, contains as ingredients a pharmaceutically acceptable oil and/or a pharmaceutically acceptable lipophilic surfactant and/or a pharmaceutically acceptable a hydrophilic surfactant and/or a pharmaceutically acceptable solvent that is miscible with water.

To increase the bioavailability of the active substances proposed in the invention, such compounds can also be used in the form of clathrates with a cyclodextrin framework. For this, the compounds proposed in the invention are subjected to interaction with A-, B- or G-cyclodextrin or its derivatives. (8)

The use of pastes, ointments, lotions and liquid preparations intended for external use presupposes the presence of such properties in them that ensure the entry of the compounds proposed in the invention into the body in sufficient quantity. The composition of similar dosage forms includes auxiliary substances, for example, substances for regulating the rheological properties of drugs, surface-active substances, preservatives, hydrotropic solubilizers, diluents, substances for improving the permeability of benzimidazole derivatives proposed in the invention through the skin, dyes, flavorings and protective skin care products such as conditioners and moisturizers. The medicinal product, together with the compounds proposed in the invention, may also contain other active substances 1963, p. 918 et seq.; N. M. Sleivsp-I ipdepulaid, NiyevioPye Pyaig RNnapta?gie so pa apdgeplepde Sebie(e, RIagt. Ipa., 2, 1961, p. 72 et seq.; Og. N.R. Rivedieg, Gehikop deg NijevioPe Tig

Rpagta?giev, KozteiiikK pa apdgepgepade Sebieie, vid-vo Sapiog AS, Ashepaopl/myty., 19711.

The compounds proposed in the invention can also be used in the form of appropriate solutions, for example in the form of a physiological saline solution, as solutions for infusion or injection. For parenteral administration, the active substances can be present in a dissolved or suspended form in a physiologically compatible diluent form. Oil solutions, for example solutions in sesame oil, are suitable as such diluents. oil, castor oil and cottonseed oil. Hydrotropic solubilizers can be added to increase solubility, and? such as, for example, benzyl benzoate or benzyl alcohol.

Any liquid carrier in which

The compounds proposed in the invention are present in dissolved or emulsified form. The composition of such liquid preparations often includes substances for regulating viscosity, surface-active substances, preservatives, hydrotropic solubilizers, diluents and other additives that make the solution isotonic. - Along with benzimidazole derivatives in the composition of such drugs, other active substances can be introduced into the body. The compounds proposed in the invention can also be immersed in a suitable material to obtain a transdermal system and thereby introduce them into the body through the skin. In this case, benzimidazole derivatives are injected into the body, for example, subcutaneously, in the form of a depot injection or an implant preparation. Similar 4) drugs can be given such properties that ensure a slow release of the active substance. For this, known solutions can be used, for example, depot forms that dissolve or are equipped with a membrane. As inert materials, implants can also contain, for example, biodegradable polymers or two binthetic silicones, for example, organosilicon rubber. For transdermal administration, benzimidazole derivatives can also be immersed, for example, in a patch.

F) The dose of the compounds of the general formula I proposed in the invention, which is prescribed to the patient, is determined by the attending physician and depends, in particular, on the specific compound that is introduced into the body, on the route of administration, on the disease that is being treated, and on its severity. The daily dose of the active substance does not exceed 1000 mg, preferably does not exceed 100 mg, and can be calculated for a single administration per day in the form of a single dose or divided into several smaller doses at the rate of two or more doses per day.

Benzimidazoles of the formula | can be obtained in various ways by methods known from the relevant literature.

As possible methods of obtaining the compounds proposed in the invention, together with others, the considered bb5 below should be mentioned. 1. Restoration of groups substituted in the ortho position by groups that are removed (mainly halogen-substituted)

of nitrobenzene derivatives (A) with arylamines (B) under different reaction conditions, for example, by heating the reagents in the absence or presence of an acceptable inert solvent, in particular alkylbenzenes, it is possible to obtain M-aryl-2-nitrobenzenes (C). The amine used as a reagent can also serve as a solvent when it is used in excess. Reactions are carried out without or in the presence of bases (for example, potassium carbonate, sodium hydride). Other excipients, such as copper salts, can also be used in the reactions.

Examples of conducting reactions according to the methodology discussed above can be found in numerous works devoted to this topic, (for example, in YuO. Degspei, N. Rizspeg, M. Sgai, App. Spet., 575, 1952, p. 162; in SAB5, 53 (2138); in K.-A. then SCHEME 1 mo, mo,

E I NMearyl 0-3 e -NH MH aryl (A) (c) (c)

X stands for the group being removed

KE means substitutes) or N

M-arylnitroaniline derivatives (C) obtained in this way can be converted into He 1,2-disubstituted benzimidazoles (E) by various methods: o

SCHEME 2

Recovery - A derivative of aromatic so

Mo. we, - sol 2 lation of carbon chain or aldehyde -X shi i -X --Y.Yal o zoryu d U --Ag "Her

Thai tsinii sch aryl grill aryl - (c) (B) (E)

The nitro group (C) is preferably reduced by hydrogenation in polar solvents such as acetic acid, lower alcohols or acetic acid esters, with the addition of catalysts such as Raney nickel or palladium on carbon, or by chemical reduction, such as tin in hydrochloric acid, ZpSI about (B.O. VeiMatu, Tei.

And e(i., 1984) or Re in acetic acid (0.S. Omu/zPu, 99. Viootiyiia, Zupipevziv, 118, 1977, p. 150). "

Benzimidazoles can be obtained from diamines (0) by their interaction with derivatives of carboxylic acids, such as orthoethers, iminoethers, acid anhydrides, aldehydes, or with free carboxylic acids with or without acid catalysis and/or in the presence or absence of dehydrating agents (IS). As an example of this, we can cite the preparation of 1,2-diphenylbenzimidazole from benzoic acid and M-phenyl-o-phenylenediamine with the use of triphenylphosphine oxide and trifluoromethanesulfonic acid anhydride (Y.V. Nepagiskvop, M.5.

Nygzzgoip, 9. Ogd. Spet., 52, 1987, p. 4137).

When using aromatic aldehydes, nitrobenzene is used as a solvent, for example, in order to ensure the possibility of oxidation of benzimidazoline, which is initially formed by oxidation. Cyclization to - benzimidazoles is also possible when aromatic aldehydes in the form of bisulfite adducts are reacted with diamines (0). and 2. Another method of obtaining benzimidazoles (E) (described in T. Vepipsog and E. Zappisoo in U. Nei (egosusiis Speth. "" 20 25, 1988, p. 1029), which allows to implement the most diverse schemes of substitution with both aryl substituents , as well as substitution in the benzene ring of benzimidazole. It is obvious to a specialist in this field that such substituents must be compatible with the reagents and reaction conditions used at various stages in the synthesis sequence. If necessary, the substituents can be modified as follows. In the resulting product, in this case, always a functional hydroxy group is present, which is in position 6 of benzimidazole 29 (see structural formula E):

F) (5 names) 60 M

NARO) b5 Ag and

Z. In the end, it should be mentioned that in some cases there is a possibility of direct M-arylation of previously obtained benzimidazoles, for example, according to the method described in M.). Zapzope, M.5. Km/iaYiek in O5 4933397, or by the method described in O.M.T. Spap, K.Yi. Maupaso, K.-R. MUapd, M. R. M/ipiege in Theia. Gay. 39, 1998, p. 2933, or in A.R. Sotr", 5. Zatsbrep, M. KagiaizKi, R.U.5. And at, Thei. And hey. 40, 1999, p. 1623).

For a specialist in this field, it is obvious that the K substituents must be compatible with the reagents and reaction conditions used at various stages in the synthesis sequence. Under certain conditions, the substitutes can be modified in the following.

If the structural element B-A-O (formula I) is in a protected or unprotected form due to incompatibility with the reaction conditions that prevail in the synthesis of the corresponding benzimidazole, or in connection with other reasons connected with the process of its synthesis, embed only after the synthesis of benzimidazole is completed, then, depending on the presence of KZ substituents in the benzene ring of benzimidazole, different approaches are possible for embedding the structural element B-A-O (formula I), while, as is obvious to specialists in this field, it is necessary /5 to take into account the compatibility of the used methods with aryl substituents and specific residues, the meaning of which is the short term.

Some possible methods of embedding the B-A-O structural element are considered below.

Oxygen can be in free form (for example, K means OH in formula (A)) or in a protected form, for example, in the form of an alkyl ether | see, for example, V.O. Uegspei, N. Rivspeg, M. Sgai, App. Spet., 575, 1952, p. 162), to initially be present as a substitute in the synthesis of benzimidazole. The hydroxyl group can be released by cleavage of the alkyl ether, for example by treatment with concentrated hydrobromic acid, under certain conditions with hydrotropic solubilizers such as halogenated hydrocarbons, or with boron tribromide in inert solvents such as dichloromethane. The hydroxyl functional group can be converted into ethers by known methods by interaction with alkyl halides, which do not necessarily contain the so-called end group B (formula I!) or its precursor, while the interaction with alkylating agents is preferably carried out at a temperature in the range from O to 120920 in polar i) solvents such as dimethylformamide, dimethylsulfoxide, ethers such as tetrahydrofuran, or in lower ketones such as acetone or methyl ethyl ketone, with the addition of bases such as alkali and alkaline earth metal hydrides, preferably, however, sodium hydride , or with the addition of alkali metal carbonates, such as potassium or cesium carbonate. In addition, the reaction can be carried out in a two-phase system with interphase catalysis, while dissolving the reagents in an acceptable inert organic solvent, for example in M haloalkanes, preferably, however, in dichloromethane. Another phase is a solid alkali metal hydroxide, preferably sodium or potassium hydroxide, or a concentrated aqueous solution of the corresponding hydroxide. For example, quaternary ammonium salts are used as interphase catalysts. Reactions during interphase catalysis --

Зз5 is preferably carried out at room temperature. with

So, for example, in one of the possible methods, the compound of the formula A (where K means OH) is dissolved in dimethylformamide and, with the addition of cesium carbonate, is subjected to interaction with the methyl ether of b-bromohexanoic acid at a temperature in the range from 0 to 502. Split the complex ether by acid or Basic hydrolysis is possible by methods known to specialists, for example in the presence of basic catalysts, such as carbonates or hydroxides of alkali or alkaline earth metals in water or in an aqueous solution of alcohol. Aliphatic alcohols such as methanol, ethanol, butanol and others are used, preferably, however, methanol. In addition, you can also use aqueous solutions of simple ethers, such as tetrahydrofuran. Examples of carbonates and hydroxides of alkali metals include lithium, sodium, and potassium salts. Lithium and sodium salts are preferred. Calcium carbonate, calcium hydroxide, and barium carbonate are suitable for use as carbonates and hydroxides of alkaline earth metals. The reaction is usually carried out in the temperature range (o) from -10 to 702C, preferably, however, at 2593. The ester can, however, also be split in acidic conditions, for example in aqueous hydrochloric acid, optionally with the help of a hydrotropic solubilizer, for example, a lower alcohol, preferably methanol. Namely) A functional carboxyl group can be formed from the nitrile present in the alkylating agent or the resulting nitrile by hydrolysis 1" 50. Alkylating agents can also contain functional groups, such as, for example, a functional hydroxyl group, in a free or protected form, which after conversion to leaving groups such as tosylate, mesylate, bromide or iodide, can be replaced, for example, by an amino group or alkyl groups. Alkylating agents can also contain such functional groups as, for example, halogen atoms or optionally protected amino groups, which in this case can be subjected to further modification.

Gee! Depending on the desired substitution scheme, KZ substituents may initially be present in the structural fragments used in the synthesis process or they may be incorporated as necessary, respectively formed from acceptable precursors present at the appropriate moment in the synthesis process of the corresponding compound.

Derivatives of formulas I! in the form of free acids or their precursors in the form of esters can be converted into amide derivative formulas by various methods known from the literature.

Derivatives of formula I in the form of free acids can also be converted into salts with the use of acceptable amounts of appropriate inorganic bases upon neutralization. So, for example, when the corresponding acids are dissolved in water containing stoichiometric amounts of the base, after evaporation of the water or after the addition of a solvent that is miscible with water, such as alcohol or acetone, a solid salt can be obtained. 65 Salts with amines can be obtained by traditional methods. To do this, the corresponding acid is dissolved in an acceptable solvent, for example, in ethanol, acetone, diethyl ether or benzene, and one to five equivalents of the corresponding amine are added to this solution. The salt that is formed during this usually precipitates in a solid form or it is isolated in the usual way after the solvent has evaporated.

Clathrates with A-, B- or uU-cyclodextrin are obtained similarly to the method described in UMO 87/05294.

It is preferable to use B-cyclodextrin. Liposomes are obtained according to the method (described in the magazine "Rpapta?ie ip opzegeg 2eiy, 11, 1982, p. 98).

The preparation of some precursor compounds, intermediates, and final products is described below as an example.

If in the following description the preparation of certain starting compounds is not considered, then it is understood that such starting compounds are either known and commercially available compounds, or they are obtained similarly to the methods presented in this description.

The compounds proposed in the invention are obtained, for example, by the following methods.

General technique 1: Reduction of nitro groups

The reduced compound is dissolved in ethyl acetate, tetrahydrofuran, methanol or ethanol or in a mixture of these solvents and hydrogenated at normal pressure in the presence of 2-595 (calculated per nitro compound) 7/5 palladium on carbon (1095). After completion of the water absorption process, the mixture is subjected to vacuum filtration, the residue is washed with ethyl acetate, methanol or ethanol and the filtrate is concentrated in a vacuum. The resulting raw product is usually used in the next reaction without additional purification.

General technique 2: Cleavage of a simple ether using hydrobromic acid 5 g of aryl methyl ether is mixed with 1 b0 ml of 4895 aqueous NHg and for 1-5 hours. boil under reflux. After cooling, the mixture is filtered. The residue is dissolved in ethyl acetate and extracted three times with a saturated solution of sodium bicarbonate. After drying over sodium sulfate, concentrate in vacuo.

If necessary, the residue is purified by crystallization or column chromatography on silica gel.

General method 3: Alkylation of hydroxybenzimidazole derivatives and phenolic derivatives with alkyl halides

A solution of 1.8 mmol of hydroxybenzimidazole derivative in 12 ml of M,M-dimethylformamide is mixed with 1.865 mmol of cesium carbonate and 2.24 mmol of alkyl bromide or alkyl iodide. When using alkyl bromide, it is optional to add 1.85 mmol of sodium iodide. The mixture is stirred for 12-96 hours, after which it is poured into water, dissolved in ethyl acetate, the organic phase is washed four times with water, dried over sodium sulfate and concentrated in a vacuum. As an alternative to such an aqueous treatment, the reaction mixture can be mixed with dichloromethane, the precipitated salts can be separated by filtration, and the filtrate can be concentrated in a vacuum.

Regardless of the selected processing method, the residue is purified by crystallization or column chromatography on silica gel. Ha

General technique 4: Saponification of alkyl ethers of carboxylic acids 0.77 mmol of alkyl ether of carboxylic acids is dissolved in Bml of methanol and 5 ml of tetrahydrofuran and mixed with 5 ml of 0.5N. of an aqueous solution of hydroxide (37 lithium or sodium. After stirring for 2-12 hours, the mixture is concentrated to almost dryness in a vacuum, He) neutralized by adding aqueous hydrochloric acid and extracted with ethyl acetate. It is then dried over sodium sulfate and concentrated in vacuo. If necessary, the residue is purified by column chromatography on silica gel.

General technique 5: Cyclization to benzimidazoles with the help of aldehydes. One mole of 1,2-diaminobenzene derivative is dissolved in three ml of nitrobenzene. To this solution, 1 mmol of aryl, respectively "heteroarylaldehyde" is added. Then it is heated to 15023, kept at this temperature for 2 hours, and then the mixture is allowed to cool. The residue without further processing is directly purified by column chromatography on silica gel. "» General method 6: Conversion of esters of carboxylic acids into amides of carboxylic acids

0.2 mmol of amine is dissolved in 3 ml of toluene and, upon cooling in an ice bath, is mixed with 0.18 ml of a 2-Molar solution of trimethylaluminum in toluene, which is added dropwise. Then it is mixed with a solution of (oo) 0.33 mmol of carboxylic acid methyl ether in 3 ml of toluene and stirred for 2-8 hours. at 95260. For - processing, after cooling, water is added, 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. ko The residue is purified by column chromatography on silica gel. 50 Example 1 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid siu a) 3-(4-methylphenyl)amino-4-nitrophenol 5.4 g of 3-fluoro-4-nitrophenol was mixed with 4.8 ml of 4-methylaniline and stirred for two hours. at 120 26.

After cooling, it was dissolved in ethyl acetate and water and extracted three times with 1N. aqueous hydrochloric acid. The combined aqueous phases were extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and the residue crystallized.

M5 (EI): 244 (molecular ion peak). eat) b) Methyl ether of 6-I3-4-methylphenyl)amino-4-nitrophenyl|oxyhexanoic acid

The indicated compound was obtained by the interaction of 3-(4-methylphenyl)amino-4-nitrophenol with methyl ester 60 of 6-bromohexanoic acid according to the general method 3.

M5 (EI): 372 (molecular ion peak). c) Methyl ether of 6-((4-amino-3-((4-methylphenyl)amino)phenyl|oxy)hexanoic acid

The indicated compound was obtained from the methyl ether of 56-I(3-(4-methylphenyl)amino-4-nitrophenyl|oxyhexanoic acid according to the general method 1. 65 M (EI): 342 (molecular ion peak). d) Methyl ether of 6- (1-(4-Methylphenyl)-2-(3Z-pyridinyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid

This compound was obtained by the interaction of 6-(4-amino-3-((4-methylphenyl)amino)phenyl|oxy)hexanoic acid methyl ether with 3-pyridylcarbaldehyde according to the general method 5.

M5 (EI): 429 (molecular ion peak). e) 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy|hexanoic acid

The indicated compound was obtained from the methyl ester of 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid according to general method 4. 70 M5 (EI): 415 (molecular ion peak).

Example 2 5-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid a) Methyl ether 5-I3--4-methylphenyl)amino-4- nitrophenyl|oxypentanoic acid

This compound was obtained by the interaction of 3-(4-methylphenyl)amino-4-nitrophenol with methyl ester of 5-bromopentanoic acid according to the general method 3.

M5 (EI): 358 (molecular ion peak). b) Methyl ether of 5-((4-amino-3-«((4-methylphenyl)amino)phenyl|oxy|pentanoic acid

The specified compound was obtained from the methyl ester of 5-I3-4-methylphenyl)amino-4-nitrophenyl|oxypentanoic acid according to the general method 1.

M5 (EI): 328 (molecular ion peak). c) Methyl ether of 5-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy|Ipentanoic acid)

The specified compound was obtained by the interaction of 5-(4-amino-3-((4-methylphenyl)amino)phenyl|oxy|pentanoic acid methyl ether with 3-pyridylcarbaldehyde according to the general method 5.

M5 (EI): 415 (molecular ion peak). d) 5-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazole-b-yloxy|pentanoic acid and)

The specified compound was obtained from the methyl ester of 5-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid according to the general method 4. c zo M5 (EI): 401 (molecular ion peak).

Example C « 4-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy)butyric acid c a) 4-(3-(4-methylphenyl)amino) methyl ester -4-nitrophenyl|oxy)butyric acid

The specified compound was obtained by the interaction of 3-(4-methylphenyl)amino-4-nitrophenol with methyl ether (787 4-bromobutyric acid according to the general method 3.

M5 (EI): 344 (molecular ion peak). b) Methyl ether of 4-((4-amino-3-((4-methylphenyl)amino)phenyl|oxy|butyric acid)

The indicated compound was obtained from the methyl ester of 4-I3-(4-methylphenyl)amino-4-nitrophenyl|oxybutyric acid according to general method 1.

M5 (EI): 314 (molecular ion peak). c c) Methyl ether of 4-((1-(4-methylphenyl)-2-(3Z-pyridinyl)-1H-benzimidazol-b-yl|oxy)butyric acid. The specified compound was obtained by the interaction of methyl ether and?» 4- (4-amino-3-((4-methylphenyl)amino)phenyl)oxy|butyric acid with 3-pyridylcarbaldehyde according to general method 5.

M5 (EI): 401 (molecular ion peak).

Go! d) 4-C1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazole-b-yloxy|butyric acid

The specified compound was obtained from the methyl ether of 4-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazole-b-yl|oxybutyric acid according to the general method 4.

M5 (EI): 387 (molecular ion peak). Example 4 4) 6-(1-(4-methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid a) Methyl ether 6-(1-(4-methylphenyl) -2-(4-pyridinyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid

The specified compound was obtained by the interaction of the methyl ether of 8-C4-amino-3-(4-methylphenyl)amino)phenyl|oxy|hexanoic acid with 4-pyridylcarbaldehyde according to the general method 5.

F) M5 (EI): 429 (molecular ion peak). ka b) 6-(1-(4-methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid

The indicated compound was obtained from the methyl ester of 6-(1-(4-methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid according to general method 4.

M5 (EI): 415 (molecular ion peak).

Example 5 6-(1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid 65 a) Methyl ether 6-I((1-(4-methylphenyl) -2-(3-thienyl)-IN-benzimidazol-b-yl|oxy)hexanoic acid

This compound was obtained by the interaction of methyl ether

6-(4-amino-3-((4-methylphenyl)amino)phenyl|oxy)hexanoic acid with 3-thienylcarbaldehyde according to general method 5.

M5 (EI): 434 (molecular ion peak). b) 6-(1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|ioxy|)hexanoic acid

This compound was obtained from its methyl ester 6-(1-(4-methylphenyl)-2-(3-thienyl)-1H-beumidazol-b-yl|oxy|hexanoic acid according to the general method 4.

M5 (EI): 420 (molecular ion peak). 70 Example 6 5-(1--4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|Ioxy|pentanoic acid a) Methyl ether 5-I((1-(4-methylphenyl) -2-(3-thienyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid

This compound was obtained by the interaction of 5-(4-amino-3-((4-methylphenyl)amino)phenyl|oxy|pentanoic acid methyl ether with 3-thienylcarbaldehyde according to the general method 5.

M5 (EI): 420 (molecular ion peak). b) 5-((1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|ioxy|pentanoic acid

The specified compound was obtained from 5-(1-4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid methyl ester according to general method 4.

M5 (EI): 406 (molecular ion peak).

Example 7 4-(1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|Ioxy|Butyric acid a) Methyl ether 4-((1-(4-methylphenyl)-2 -(3-thienyl)-1H-benzimidazole-b-yloxy|butyric acid

The specified compound was obtained by the interaction of 4-(4-amino-3-((4-methylphenyl)-amino)phenyl|oxybutyric acid methyl ether with 3-thiophenecarbaldehyde according to i) of general method 5.

M5 (EI): 406 (molecular ion peak). b) 4-(1-(4-metalphenyl)-2-(3-thienyl)-1H-benzimidazol-6-yl|ioxy|butyric acid c zo This compound was obtained by the interaction of methyl ether 4-(1-(4- methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy|butyric acid according to general method 4. -

M5 (EI): 392 (molecular ion peak). with

Example 8 5-(1-phenyl-2-(3-thienyl)-IN-benzimidazol-b-yl|oxy|pentanoic acid -- a) 4-methoxy-M2-phenyl-o-phenylenediamine c

The specified compound was obtained from (5-methoxy-2-nitrophenyl)phenylamine (Kobeppapitp et al., U. Ogd. Spet., 28; 1963; p. 3114-3118; Vapipogre, Sooreg, U). Spent wasps B, 1968, p. 605) according to the general method 1. "H-NMR (SOSIv): 5 (in parts/million)-3.42 in (broad) (2H); 3.72 8 (ZH); 5 .33 v (wide) (1H); 6.56 aa « (9-10, 2Hz, 1n); 6.76 a (U-10Hz, 1); 6.79 a (0-2HzC, 1); 6 .82-6.90 t (ZH); 7.25 aa (9-8, 8Hz, 2H). b) b-methoxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole - c The specified compound was obtained by the interaction of 4-methoxy-N?-phenyl-o-phenylenediamine with thiophene-3-carbaldehyde "" according to the general method 5. " M5 (EI): 306 (molecular ion peak). c) b-hydroxy-1-phenyl -2-(3-thienyl)-NAIN-benzimidazole

The specified compound was obtained from b-methoxy-1-phenyl-2-(3-thienyl)-LH-benzimidazole according to the general procedure of 2. - M5 (EI): 292 (molecular ion peak). d) Methyl ether of 5-((1-phenyl-2-(33-thienyl)-1H-benzimidazole-b-yl|ioxy|pentanoic acid) de This compound was obtained by the interaction of b-hydroxy-1-phenyl-2-(3- thienyl)-1H-benzimidazole with its methyl ester of 5-bromopentanoic acid according to the general method 3.

M5 (EI): 406 (molecular ion peak).

Fe» d) 5-C1-phenyl-2-(3-thienyl)-1H-benzimidazole-b-yloxy|pentanoic acid

The indicated compound was obtained from the methyl ester of 5-(1-phenyl-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid according to the general method 4. 29 M5 (EI): 392 (molecular ion peak) ).

GF! Example 9 4-(1-phenyl-2-(3-thienyl)-1H-benzimidazol-b-yl|ioxy|butyric acid o a) Methyl ether 4-((/1-phenyl-2-(3-thienyl) U-1H-benzimidazole-b-yl|oxy|butyric acid

The specified compound was obtained by the interaction of b-hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole with methyl 60 ether of 4-bromobutyric acid according to the general method 3.

M5 (EI): 392 (molecular ion peak). b) 4-I1-phenyl-2-(3-thienyl)-1H-benzimidazol-6-yl|ioxy|butyric acid

The indicated compound was obtained from 4-((1-phenyl-2-(3-thienyl)-IN-benzimidazol-b-yl|oxy|butyric acid methyl ester) according to the general method 4. bo M5 (EI): 378 (molecular peak ion).

Example 10

6-(C1-phenyl-2-(3-thienyl)-1N-benzimidazol-b-yl|oxy)hexanoic acid a) Methyl ether 6-((1-phenyl-2-(3-thienyl)-IN-benzimidazole) -b-yl|oxy)hexanoic acid

The specified compound was obtained by the interaction of b-hydroxy-1-phenyl-2-(3-thienyl)-1H-benzimidazole with methyl ester of b-bromohexanoic acid according to general method 3.

M5 (EI): 420 (molecular ion peak). b) 6-C1-phenyl-2-(3Z-thienyl)-1H-benzimidazol-b-yl|oxy|)hexanoic acid

The indicated compound was obtained from the methyl ester of 6-(1-phenyl-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy|)hexanoic acid according to the general method 4. 70 M5 (EI): 406 (peak molecular ion).

Example 11 6-(1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|ioxy|)hexanoic acid a) (b-chloro-2-nitrophenyl)-(4-fluorophenyl) )amine

A solution of 1-chloro-3,4-dinitrobenzene in 250 ml of ethanol was mixed with 500 ml of 4-fluoroaniline and stirred for 7/5 hours. at 602C. After concentration to half the volume, the mixture was distributed between water and dichloromethane. After washing the organic phase, with aqueous hydrochloric acid, it was dried over sodium sulfate, filtered and concentrated. After chromatography of the residue on silica gel, 62.33 g of (5-chloro-2-nitrophenyl)-(4-fluorophenyl)amine was obtained. "H-NMR (SOSIv): 5-6.71 da (9-9, 2Hz, 1H); 6.97 a (9-2Hz, yin); 7.13 aa (9-9, 9Hz, 2H); 7.22 aa (9-9, 6Gu, 2H); 8.154 20-10Gu, 1H); 9.45 z (ext.) (1H). b) (5-methoxy-2-nitrofensch)-(4-fluorophenyl) )amine

36.44 g of (5-chloro-2-nitrophenyl)-(4-fluorophenyl)amine was added to a solution of b,bg sodium in 450 ml of methanol and the reaction mixture was added for 1 h. boiled under reflux. After stirring for the next ZOh. at 6°C, the reaction mixture was cooled and the crystalline product was separated by SM vacuum filtration. In this way, Za4g (5-methoxy-2-nitrophenyl)-(4-fluorophenyl)amine was obtained. o 7"H-NMR (SOSIv): 5-3.72 v (ZN); 6.44 da (9-9, 2Hz, 1n); 6.48 a (9-2Hz, 1); 7.13 aa (9-9, 9Hz, 2H); 7.27 ad (9, 6Hz, 2H); 8.20 a (9-9HzC, 1H); 9.65 z (width) (1H). c) "- (4-fluorophenyl)-4-methoxybenzene-1,2-diamine 33.5 g (0.128 ml) of (5-methoxy-2-nitrophenyl)-(4-fluorophenyl)amine was subjected to chemical transformation according to to the general method 1. The crude product without purification was used in the next reaction. ""H-NMR (SOSI"): 5 (ppm)-3.70 z (ZN); 6.49 a (width) (9-9Hz, 1H); 6.68 a (9U -2Hz, 1H); 6.78-6.97 t (5H). d) b-methoxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole with 7.48 g thiophene-3 -aldehyde was stirred for two hours in boml of a 4090 solution of Manzo with 15 g of 2-(4-fluorophenyl)-4-methoxybenzene-1,2-diamine in 10 ml of ethanol and boiled for 4 hours. and so were then stirred overnight. The mixture was then partitioned between water and ethyl acetate and the organic phase was washed with water. After drying over sodium sulfate and concentrating the filtrate, 18.1 g of crude b-methoxy-1-(4-fluorophenyl)-2-(3- thienyl)-1H-benzimidazole. dl 154-15850. "e) 6-hydroxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole 2 s 18g (55.5 mmol) b-methoxy- 1-(4-Fluorophenyl)-2-(3-thienyl)-1H-benzimidazole was subjected to a chemical transformation similar to the general method 2. As a result, 12.65 g (4 mmoles) of crude t b-hydroxy-1-(4-fluorophenyl) were obtained )-2-(3-thienyl)-1H-benzimidazole. idl 212-21896. e) Met 6-(C(1-(4-fluorophenyl)-2-(3-thienyl)-IN-benzimidazol-b-yl|oxy)hexanoic acid clay ester

Ho) The specified compound was obtained by the interaction of b-hydroxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole with methyl ester of b-bromohexanoic acid according to the general method 3. - Fig. 131-1345C. 6-(1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid

The specified compound was obtained from the methyl ester of 6-(1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid according to the general method 4. se»ill 170-17596 .

Example 12 5-(1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|!oxy|Ipentanoic acid a) Methyl ether 5-I((1-(4-fluorophenyl- 2-(3-thienyl)-1H-benzimidazole-b-yl|oxy|pentanoic acid

The specified compound was obtained by the interaction of b-hydroxy-1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole with o methyl ester of 5-bromopentanoic acid according to the general method 3. ime) Ill 90.5-92.590. b) 5-((1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazole-b-yloxy|pentanoic acid 60 This compound was obtained from the methyl ether of 5-(1-(4-fluorophenyl-2 -(3-thienyl)-1nH-benzimidazole-b-yl|oxy|pentanoic acid according to general method 4.

Ill 184-18926.

Example 13 6-(1-(4-fluorophenyl)-2-(33-pyridinyl)-IN-benzimidazol-b-yl|oxy)hexanoic acid 65 a) b-methoxy-1-(4-fluorophenyl)-2- (3-pyridinyl)-1H-benzimidazole

The specified compound was obtained by the interaction of M-(4-fluorophenyl)-4-methoxybenzene-1,2-diamine with pyridine-3-carbaldehyde similarly to example 11g.

Ill 132.5-13426. b) b-hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole

The indicated compound was obtained from b-methoxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole according to the general method 2. c) Methyl ether 6-((1-(4-fluorophenyl)-2 -(Z-pyridinyl)-IN-benzimidazol-b-yl|oxy)hexanoic acid

The indicated compound was obtained by the interaction of b-hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-IN-benzimidazole with methyl ester of b-bromohexanoic acid according to the general method 3. 70 ul. 105.5-111.596. d) 6-C1-(4-fluorophenyl)-2-(3Z-pyridinyl)-1H-benzimidazol-b-yl|ioxy|hexanoic acid

The specified compound was obtained from the methyl ester of 6-(1-(4-fluorophenyl)-2-(33-pyridinyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid according to the general method 4. 15 Ill 127.5-12996 ,

Example 14 5-(1-(4-fluorophenyl)-2-(33-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid a) Methyl ether 5-((1-(4-fluorophenyl)-2 -(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid

The indicated compound was obtained by the interaction of b-hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-IN-benzimidazole with 20 methyl ester of 5-bromopentanoic acid according to general method 3.

Il 52-5596. b) 5-C(1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole-b-yloxy|pentanoic acid

The specified compound was obtained from 5-(1-(4-fluorophenyl)-2-(33-pyridinyl)-1H-benzimidazol-b-yl|oxy|)pentanoic acid methyl ester according to General EM 25 method 4.

Ill 181.5-18396. at

Example 15 5-C1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-b-yl|oxy|pentanoic acid a) 6-methoxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole co 30 This compound was obtained by the interaction of 4-methoxy-M2-phenyl-o-phenylenediamine with pyridine-3-carbaldehyde according to the general method 5.

M5 (EI): 301 (molecular ion peak). c b) b-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole "-

The specified compound was obtained from b-methoxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole according to the general

From method 2. co "H-NMR (05-DMSO): 5 (ppm)-6b.52 a (9U-2GHz, 1); 6.81 aa (9-8, 2Hz, 1); 7.34-7.48 t (ZN); 7.53-7.68 t (4H); 7.80 (davd, 9-8, 2, 1Hz, 1H); 8.53 aa (9-2, 1Hz, 1H); 8.67 a (9-1HzC, 1H); 9.42 (c, 1H). c) Methyl ether 5-|((1-phenyl-2-(3-pyridinyl)-1H-benzimidazole -b-yl|ioxy|pentanoic acid «

The indicated compound was obtained by the interaction of b-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with methyl 7-ester of 5-bromopentanoic acid according to the general method 3. s M5 (EI): 401 (molecular ion peak). with d) 5-C1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-b-yl|Ioxy|pentanoic acid

The indicated compound was obtained from the methyl ester of 5-(1-phenyl-2-(3-pyridinyl)-1H-benzimidazole-b-yloxy|pentanoic acid according to the general method 4. so that TNA-NMR (CO3O0): 5 (in part ./million)-1.72-1.88 t (4H); 2.30 u (y-8Hz, 2H); 3.98 u (9-8Hz, 2H); 6.72 a (o-2Hz, tn); 7.03 aa (9-8, 2Hz, 1H); 7.40-7.48 t (ZN); 7.55-7.65 t (ZN); 7.70 (a, U-8Hz , 1H); 7.92 aza (0-8, - 2, 1Hz, 1H); 8.53 aa (9-8, 2Hz, 1Hn); 8.70 da (9-2, 1Hzc, 1H). g ) Example 16 4-(1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy)butyric acid - a) Methyl ether 4-(C(1-phenyl-2-(3-pyridinyl) )-1H-benzimidazole-b-yl|oxy|butyric acid c» This compound was obtained by the interaction of b-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with the methyl ester of 4-bromobutyric acid according to the general method 3.

M5 (EI): 387 (molecular ion peak). b) 4-11-phenyl-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy)butyric acid

The specified compound was obtained from methyl ether (F) 4-((1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|butyric acid) according to general method 4.

GI M5 (EI): 373 (molecular ion peak).

Example 17 in 6-(1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy|)hexanoic acid a) Methyl ether 6-(C(1-phenyl-2-(3-pyridinyl) )-IN-benzimidazole-b-yl|oxy)hexanoic acid

The specified compound was obtained by the interaction of b-hydroxy-1-phenyl-2-(3-pyridinyl)-1H-benzimidazole with methyl ester of b-bromohexanoic acid according to general method 3.

M5 (EI): 415 (molecular ion peak). 65 b) 6-((1-Phetyl-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid) This compound was obtained from the methyl ether of 6-C1-phenyl-2-(3-pyridinyl) -1H-benzimidazole-b-yl|oxy|hexanoic acid according to general method 4.

M5 (EI): 401 (molecular ion peak).

Example 18

M-(3-methoxypropyl)-6-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy|hexanamide

This compound was obtained by the interaction of 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid methyl ether with 3-methoxypropylamine according to the general method 6.

M5 (EI): 486 (molecular ion peak). 70 Example 19 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|-1-morpholin-1-ylhexan-1-one

This compound was obtained by the interaction of 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazole-b-yl|!oxy|hexanoic acid methyl ether with morpholine according to the general method 6.

M5 (EI): 442 (molecular ion peak).

Example 20

M-methyl-6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanamide

The specified compound was obtained by the interaction of 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid methyl ester with hydrochloride

M-methylamine according to the general method 6.

M5 (EI): 428 (molecular ion peak).

Example 21

N,M-dimethyl-6-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanamide)

The specified compound was obtained by the interaction of the methyl ester of 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid with dimethylamine hydrochloride according to the general method 6. (8)

M5 (EI): 442 (molecular ion peak).

Example 22 6-(1--4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy|hexanamide c zo This compound was obtained by the interaction of methyl ether 6-(1-(4-methylphenyl) -2-(Z-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid with ammonium chloride according to the general method 6. c

M5 (EI): 414 (molecular ion peak).

Example 23 --

M-cyclopropyl-6-|(1-(4-methylphenyl)-2-(-3-thienyl)-1H-benzimidazol-b-yl|oxy|)hexanamide co

This compound was obtained by the interaction of 6-(1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid methyl ester with cyclopropylamine according to the general method 6.

M5 (EI): 459 (molecular ion peak). "

Example 24 with M-methyl-6-(1-(4-methylphenyl)-2-(-3-thienyl)-1IN-benzimidazol-b-yl|oxy|hexanamide. The specified compound was obtained by the interaction of methyl ether and -(1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid with M-methylamine hydrochloride according to general method 6.

M5 (EI): 433 (molecular ion peak).

Go! Example 25

M-(2-Methoxyethyl)-5-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanamide - This compound was obtained by the interaction of methyl ether with 5-(1 -(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid with 0/0 2-methoxyethylamine according to the general method 6. ve M5 (EI): 458 (peak molecular 4) Example 26

N,M-dimethyl-5-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy|Ipentanamide)

This compound was obtained by the interaction of 5-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazole-b-yl|ioxy|pentanoic acid methyl ether) (example 5bv) with dimethylamine according to general method 6.

F) M5 (EI): 428 (molecular ion peak). ka Example 27 5-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazole-b-yl|ioxy|pentanamide vo This compound was obtained by the interaction of methyl ether 5-((1--4-methylphenyl )-2-(3-pyridinyl)-1H-benzimidazol-b-yl)|oxy|pentanoic acid with ammonium chloride according to general method 6.

M5 (EI): 400 (molecular ion peak).

Example 28 65 6-(1-(4-methylphenyl)-2-(2-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid a) Methyl ether 6-I((1-(4-methylphenyl) -2-(2-thienyl)-IN-benzimidazol-b-yl|oxy)hexanoic acid

The specified compound was obtained by the interaction of 6-(4-amino-3-((4-methylphenyl)amino)phenyl|oxy)hexanoic acid methyl ether with 2-thienylcarbaldehyde according to general method 5.

M5 (EI): 434 (molecular ion peak). b) 6-(1-(4-methylphenyl)-2-(2-thienyl)-1H-benzimidazol-b-yl|ioxy|)hexanoic acid

The specified compound was obtained from the methyl ester of 6-(1-(4-methylphenyl)-2-(2-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid according to the general method 4. 70 M5 (EI): 420 (molecular ion peak).

Example 29: Inhibition of microglia activation

To obtain AB-peptide-activated microglia, rat primary microglia cells (glial macrophages) were incubated with synthetic AB-peptide.

To simulate AB-peptide deposits, synthetic AB-peptide was dried on a 9b-well plate for 7/5 Growing of tissue cultures. For this purpose, the peptide mother solution with its concentration of 2 mg/ml HO was diluted with HO in a ratio of 1:50. To cover 9b-well tablets, ZOmcl of this diluted peptide solution was used per well. It was left overnight to dry at room temperature.

Primary rat microglial cells were isolated from mixed cultures of glial cells obtained from the 2nd brain of RZ rats. To obtain mixed cultures of glial cells, the brain was isolated from 3-day rats and the meninges were removed. Separation of cells into individual cells was carried out by treatment with trypsin (0.2596 trypsin solution, 15 min. at 372). After separating the tissue fragments that did not decompose, using a nylon mesh with a cell size of 40 μm, the selected cells were separated by centrifugation (800 rpm for 1 hour). Cellular debris was resuspended in culture medium and transferred into 100-milliliter dishes for growing tissue cultures (1 brain per dish). Cells were cultured at 372 and 596 CO" for 5-7 days in OMEM medium (Igla medium modified by the method of

Dulbecco's, with glutamine), supplemented with penicillin (50 units/ml), streptomycin (4 µg/ml) and 1006.95 fetal calf serum (FCS). During this incubation, an adhesive cell cover was formed, which consisted mainly of astrocytes. Glial macrophages that proliferated on this cover in the form of non- or weakly adherent cells were collected by incubation on a shaker (420 rpm for 1 hour).

To activate microglia with AB-peptide, glial macrophages were seeded on AB-peptide-coated tablets for the cultivation of tissue cultures in the amount of 2.5x107 cells per well and incubated at 372C and 5956 СО" for 7 days. SM in OMEM medium (with glutamine), supplemented with penicillin (50 units/ml), streptomycin (4 Омkg/ml) and 10о6.90 "-

FCS. On the 5th day, one of the compounds proposed in the invention was added in different concentrations (0.1, 0.3, 1.3 and 1µM). with

To quantitatively assess the reactivity of microglia on the 7th day of cultivation, metabolic activity was determined by the degree of Mte recovery

13-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(sulfophenyl)-2H-tetrazolium, Owen's reagent, .A. "

Vaihor and others, Viosogd. 5 Med. Spent And ek. 1, 1991, p. 6111). Data on the degree of inhibition were expressed as a percentage relative to the control treated only with DMSO. The results of this experiment indicate that the compounds proposed in the invention inhibit the activation of microglia. Example 30: Cerebral infarction in rats (MSAO model) The activity of the compounds proposed in the invention was studied by simulating cerebral ischemia (apoplexy) in animals, i.e. using the so-called MSAO model (from the English "regtapepi tiaae segerga! apegu ossiviop", permanent occlusion of the middle cerebral artery). When using such a model, unilateral blockage of the middle cerebral artery (MSA) initiates a cerebral infarction caused by insufficient (o) supply of the corresponding area or part of the brain with oxygen and nutrients. Such an insufficient supply of oxygen and nutrients leads to pronounced cell death, as well as to the subsequent intensive activation of microglia. However, such activation of microglia reaches its maximum extent after only a few days and can persist for several weeks. The compounds proposed in the invention were administered intraperitoneally 1-6 days after middle cerebral artery occlusion to investigate their effectiveness in inhibiting the activation of microglia. On the 7th day, the animals were perfused and killed. The degree of activation of microglia was determined by a modified immunohistochemical method. For this purpose, slices of the fixed brain obtained with the Mibgayut microtome were incubated with antibodies that recognize the SKZ receptor for complement, respectively, the MHC II complex on activated microglia. Primary antibody binding was quantified using an enzyme-linked immunosorbent assay (ELISA) detection system. In this experiment, treatment with the compounds proposed in the invention led to a decrease in the activation of microglia in the infarcted hemisphere of the brain. име) Example 31: Inhibitory effect on the production of TMRA and 1I-12 in TNR-1 cells

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

To this end, TNR-1 cells (obtained from the American Type Culture Collection (Ategisap Toure Siyige

Sotrapu, Rockville, st. Maryland)) in the amount of 2.5x109 cells per ml of ERMI 1640 medium (firm

She Tesppoiodiev) supplemented with 1095 FTS (Ishe Tesppoodiez, cat. Mo10270-106), were sown on 9b-well flat-bottomed culture plates (TRR company, product Mo9296) (in the amount of 100 μl per well). Then, the compounds proposed in the invention were added to the cells in various concentrations and pre-incubated for 30 minutes.

The tested substances were previously diluted in the incubation medium. The tested substances were added in the form of their double-concentration solution (in the amount of 1000 μl per well). Cells were stimulated overnight at 372 with lipopolysaccharide (Zidt company, cat. MoI 2630, from E. Soyii serotype 0111.84), which was used in the amount

Oh, 1μg/ml. After that, the medium was collected and the content of TMREA in it was quantitatively assessed, respectively interleukin 12. The content of TMERA was determined using a commercially available kit for determining TMREA of the company SIZ Bio ipiegpayopa! (product of Mob2TMEREV). The content of interleukin 12 was determined using the "OKISEM" technology (developed by ISEM Ipiegpaiiopai, Ips., Gaisersburg, Maryland). The calculated ISvo value corresponds to the concentration of the tested substance that is necessary to inhibit the production level of TMREA, respectively, interleukin 12 by 5095 from the maximum level of their production. 70 According to the results of this experiment, it was established that the compounds proposed in the invention inhibit the production of TMRA and interleukin 12 in lipopolysaccharide (LPS)-stimulated TNR-1 cells.

Example 32: Inhibitory effect on the production of IEM by peripheral blood mononuclear cells

The effect of the compounds proposed in the invention on the activation of T cells can be studied, for example, by analyzing the secretion of IEMU.

To isolate peripheral mononuclear blood cells, human whole blood was used (for blood sampling, the 5-Mopomece "Sovadoshayop 9 MC/1Oti" system with sodium citrate, Zageiedyu company was used. Blood cells were enriched by centrifugation with a density gradient. For this purpose, GEOSO5ER test tubes (company

Ogeipeg, cat. Мо227290) 15 ml of Nivioradce-1077 (Zidt company, cat. МоН8880) were previously introduced and centrifuged for 30 minutes at 10009. After that, 15 ml of whole blood was added and centrifuged for 1 hour. at 10009. Then the upper layer of plasma was removed with the help of a pipette, and the layer of cells located below it (peripheral blood mononuclear cells) was transferred to 15-milliliter test tubes (Rysop company) and washed several times with 1 Oml of Hanks' balanced salt solution (without Ma? and Ca ?", cat. Mo14175-53). At the end, the cellular debris was resuspended in the culture medium KRMI 1640, supplemented with 25 mM Nerez (2-M-hydroxyethylpiperazine-M'-2-hydroxypropanesulfonic acid, I.e. Tespoiodiez, cat. Mo52400-041). CSE 1095 FTS (She Tesppoiodiev firm, cat. Mo10270-106) and 0.495 penicillin and streptomycin solution (I Ge o

Tesppoiodieev, cat. Mo15140-106) (1x10 Ucells/ml). 100 μl of the cell suspension was distributed on 9b-well flat-bottomed culture plates (TPP company, product Mo9296) and stimulated with antibodies to SOYUZ, which were used at a concentration of 2.5 μg/ml. Then the compounds proposed in the invention were added in different concentrations and pre-incubated for 30 minutes. Cells were stimulated for 24 hours. After that, the medium was collected and the IEM content in it was quantified. The content of IEM was determined with the help of the E "OKISEM" technology (developed by the company ISEM Ipiegpaiopai, Ips., Geisersburg, Maryland). The calculated value of ISvo corresponds to the concentration of the tested substance, which is necessary to inhibit the level of production of IEM in 5090 s from the maximum level of its production. "--

According to the results of this experiment, it was established that the compounds proposed in the invention inhibit

On the production of IRM by peripheral blood mononuclear cells. co

Example 33: Inhibitory effect on the production of TMRA and 1(-12HO by peripheral blood mononuclear cells

The inhibitory effect of the compounds proposed in the invention on the production of TMRA and 11-12 HO p70 can be studied, for example, by determining the amount of TMEA and 11-12 HO p7/0 in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS) and y-interferon (IEM) . - c For the isolation of peripheral blood mononuclear cells, human whole blood was used (for blood sampling, the 5-Mopomece "Soadshayop 9 MS/Oti" system with sodium citrate, a company from Zagviveai|. :c» Lymphocytes and monocytes were enriched by centrifugation with a density gradient. for this purpose, 15 ml of Nizioradce-1077 (Zidt company,

Executioner. MoNe880) and by centrifugation for 30 seconds at 2509 were pushed down through the frit, which is in the test tubes. After that, 20 ml of whole blood was added and centrifuged for 15 minutes. at 8009 and room temperature. After centrifugation, the supernatant (plasma and platelets) was removed using a pipette and discarded, and the layer of cells (lymphocytes and monocytes) located below it was transferred to a 50-milliliter centrifuge

HF tubes (Raisop company) and then washed three times in culture medium ME KRMI 1640 (Zegotead company,

MoeO1415) (centrifugation in cycles of 1 Ohv. at 2509 and room temperature). At the end, the cellular debris was resuspended in the MI E KRMI 1640 culture medium (Zegotea company, Moes1415), supplemented with SO 1096 FTS (Ibe Tesppoiodiev company, cat. Mo16000-044, with a low endotoxin content, inactivated by heating for an hour at 56 22) and a solution of penicillin and streptomycin at a concentration of 5 Ωkg/ml (the company Me

Tesppoodiev, cat. Mo15140-106), and after counting cells using trypan blue staining

The concentration was adjusted to 3x10b cells per ml. Then, 10 μl of the cell suspension was distributed on 96-well flat-bottomed culture tablets (Sovziag company, product Mo3599). After that, to the cells that are located

F) on tablets, 100 μl of a solution for stimulation of triple concentration was added (Z LPS/ml LPS from serotin E. ko soii 0127:88, company Zidta, cat. MoY -4516, and ZOng/ml GRM IB, ItyKip, company Voengipdeg IpdeINeit ). After that, the compounds proposed in the invention were added in different concentrations in the form of their solution of triple concentration (OOmcl per well). Cells were stimulated at 372С and 595 СО" for 24 hours. Then, the supernatant liquid of the cell culture was collected and with the help of commercially available kits for EGISA analysis of the companies ViozZoigse Ipiegpaiopai (TME-A EAFZIA, cat. 11-12 NO p70. The calculated value of IC 5o corresponds to the concentration of the tested substance that is necessary to inhibit the level of production of TMEA, respectively interleukin 12 HO p70 by 5095 of 65 of the maximum level of their production.

According to the results of this experiment, it was established that the compounds proposed in the invention inhibit the production of TMRA and 11-12 HO p70 by peripheral blood mononuclear cells.

Example 34: Induction of production of 1-10 by peripheral blood mononuclear cells

The ability of the compounds proposed in the invention to induce the production of 1-10 can be investigated, for example, by determining the amount of I/-10 in peripheral blood mononuclear cells stimulated by phytohemagglutinin (FGA) or lipopolysaccharide (LPS).

For isolation of peripheral blood mononuclear cells, human whole blood was used (for blood sampling, the 5-Mopomece "Soadshayop 9 MS/Oti" system with sodium citrate, a company from Zagviveai|.

Lymphocytes and monocytes were enriched by density gradient centrifugation. For this purpose, 15 ml of Nizioradtse-1077 (Zidt company, cat. MoNe880) was previously introduced into 50-milliliter 70 test tubes GEOSO5ER (Ogeipeg company, cat. Mo227290) and pushed down through the frit located in the test tubes by centrifugation for 30 seconds at 2509. After that, 20 ml of whole blood was added and centrifuged for 15 minutes. at 8009 and room temperature. After centrifugation, the supernatant liquid (plasma and platelets) was removed using a pipette and discarded, and the layer of cells located below it (lymphocytes and monocytes) was transferred to 50-milliliter centrifuge tubes (Rysop company) and then washed three times in the culture medium ME KRMI 1640 (company Zegothead,

MoeO1415) (centrifugation in cycles of 1 Ohv. at 2509 and room temperature). At the end, the cell debris was resuspended in the culture medium MI E KRMI 1640 (Zegotea company, Moe01415), supplemented with 1096 FTS (Ibe Tesppoiodiev company, cat. Mo16000-044, with a low endotoxin content, inactivated by heating for an hour at 56 22) and a solution penicillin and streptomycin at a concentration of 5 Ωkg/ml (Me Tesppoiodiez company, cat. Mo15140-106), and after counting the cells using trypan blue staining, their concentration was adjusted to 3x1O cells per ml. Then 10 μl of the cell suspension was distributed on 96-well flat-bottomed culture tablets (Sozvziag company, product Mo3599). After that, 100 μl of a triple concentration stimulation solution (with LPS/ml LPS from E. soy serotype 0127:88, bidta company, cat. Mo! -4516, respectively ZOOmkg/ml phytohemagglutinin RNA- Y, firm Viospgot KO, si cat. MoM5030). After that, the compounds proposed in the invention were added in different concentrations in the form of their triple concentration solution (10 Ωcl per well). Cells were stimulated at 372С and 596 СО" for 24 hours.

Then the cell culture supernatant was collected and its content was quantified 1-10. The concentration of 1-10 was determined using a commercially available kit for EI IZA-analysis of ViozZoigse Ipiegpaiopa! (For example

I--10, cat. MOKNSO101C). The calculated EC 50 value corresponds to the concentration of the tested substance that is necessary to increase the level of secretion 1-10 by 5095 from the maximum degree of increase in their secretion. "

According to the results of this experiment, it was established that the compounds proposed in the invention increase the production of II-10 by peripheral blood mononuclear cells. with "- with

Claims (12)

The formula of the invention of 1. Derivatives of benzimidazole of the general formula dk M ;() « Z | 5-2 - s y M 0 V-A-O uh E! B means a phenyl group which optionally contains up to three substituents, independently of each other, selected from the group consisting of E, SI, Bg, y, OH, OK", Oso, 587, OK, 50287, B", MNo , MNE" and ME", or - two adjacent substitutes for KE! jointly form the group -О-СН»-О-, -ОО-СНо-СНо-О- or -СНо-СНо-СНе-, т В? means a monocyclic or bicyclic 5-10-membered heteroaryl group which contains 1-2 heteroatoms selected from M, 5 and O, and which optionally contains up to two substituents independently selected from the group consisting of E , СИ, Вг, у), ОН, ОВ", ОСОБ", СОВ", 587, 8087, 50287 and В", or two adjacent substitutes at В? c jointly form the group -О-СН»-О-, -О-СНо-СНо-О- or -СНО-СНо-СНе-, ЕЗ means H, ОН or О-С. alkyl, BB" independently of each other mean C. aperfluoroalkyl or C. alkyl, A means Co alkylene group, which is optionally substituted -O, OH, 0О-C 4 alkyl, МН", МН-С. alkyl, МН- C. zalkanoyl, M(C.4.alkyl)»o or M(C. zalkylu/C4 zalkanoyl), o B means the group СОН, СОМН»о, СОМНМН», СОМНЕ? or СОМ?" in each case attached to the carbon atom of group A, Bo and B" independently of each other mean a residue selected from the group consisting of C 4-alkyl, 60 C, dalkenyl, Co-valkynyl, where one C-atom may be replaced on 0, 5, 50, 505, MN, M-Sizalkyl or M-C..alkanoyl, (Co zalkanediyl-C3 7cycloalkyl), where in a five-membered cycloalkyl ring one ring member can be a ring M-atom or a ring O-atom, and in a six- or seven-membered cycloalkyl ring one or two ring members can be respectively, ring M- and/or ring O-atoms, while ring M-atoms may optionally be replaced by C 4 alkyl or C isalkanoyl, and also includes b2 (Cosalkanediylphenyl) and (Cosalkanediylheteroaryl), where the heteroaryl group is p' seven- or six-membered and contains one or two heteroatoms selected from the group consisting of M, Zi, while all of the above alkyl and cycloalkyl residues may optionally contain up to two substituents selected from the group consisting of CE z, CoEv, OH , O-S.. zalkil, MN", MN-S. Zalkil, MN-S. alkanoyl, M(Ci-alkyl)", M(Ci-alkyl)uCi-alkanoyl), COOH, SOMN" and COO-C.alkyl, and all of the above phenyl and heteroaryl groups may optionally contain up to two substituents selected from of the group that includes BE, SI, Vg, CH,., Son", OH, Osn", OSN", MO", M(CH»Z)", Cg, Sogv and ZO2MN", or Vo together with the M atom form a five-seven-membered heterocyclic ring, which may contain one more M-, O-, or 5-atom and which may be substituted by C..alkyl, (Co alkanediyl-Ci.alkoxy group), C..alkoxycarbonyl, 70 aminocarbonyl or phenyl, and also their optical or geometric isomers or tautomers or their pharmaceutically acceptable salts, with the exception of the following compounds: 6-(1-phenyl-2-(pyridin-4-yl)-1H-benzimidazol-b-yl|oxy)hexanoic acid, 6 -(1-phenyl-2-(benzothien-2-yl)-1H-benzimidazol-b-yl|oxy|hexanoic acid. 2. Benzimidazoles according to claim 1, which differ in that B" means a phenyl group, which optionally contains up to two substituents, independently of each other, selected from the group that includes PE, SI, OH, OK 4 ОоСОв, 587 and in , or two adjacent substituents at KE" form the group -О-СН»-О- or -СНо-СНо-СН»о-. 3. Benzimidazoles according to claim 1 or 2, which differ in that K? means a monocyclic 5-6-linked heteroaryl group which contains 1-2 heteroatoms selected from the group consisting of M, C and O, and which optionally contains up to two substituents independently selected from E, CI, OB, OSOB", 587, OK, 5058 and VC", or two adjacent substitutes at B? form the group -О-СН»-О- or СНо-СНо-СН»о-. 4. Benzimidazoles according to any of claims 1-3, which differ in that VZ stands for H. 5. Benzimidazoles according to any of claims 1-4, which differ in that Vl ate? independently of each other, Ha means Su operfluoroalkyl or C. dalalkyl. 6. Benzimidazoles according to any one of claims 1-5, which differ in that 5 V independently of each other o mean Sivalkyl, where one carbon atom can be replaced by 0, 5, 5O or 50,, C3.5cycloalkyl-Co alkylene, where in a 5-ene cycloalkyl ring, one ring member can be an M atom or an O atom, while the ring nitrogen atom is optionally replaced by C .. alkyl or Ci alkanoyl, or "9 Coalkylene- (5-6-lene heteroaryl with 1-2 heteroatoms from the number of M, C and 0), while all the above-mentioned alkyl and cycloalkyl residues can be replaced by the CEz group, the OH group, the МН», МН-С group. Zalkylom, Z MN-S. alkanoyl, M(C4 alkyl), M(C4 alkyl)/C4 alkanoyl), a COOH group or a COMH group, and all of the above heteroaryl groups may be substituted with one or two substituents selected from the group consisting of E . lalalkyl or 00C daloxy-Co 2alkyl. 7. Benzimidazoles according to any of claims 1-6, which differ in that A means an unbranched C3 valkylene. 8. Benzimidazoles according to any of claims 1-5, 7, which differ in that B means the COOH group or the "СОМН" group, in each case attached to the carbon atom of the A group. 9. The compound according to claim 1, selected from the group that is 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid, part 5 -((1--4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid, » 4-(1-(4-methylphenyl)-2-(3-pyridinyl) )-1H-benzimidazol-b-yl|oxy)butyric acid, 6-(1-(4-methylphenyl)-2-(4-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid, 6-( 1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid, (ee) 5-(1-(4-methylphenyl)-2-(3-thienyl) -1H-benzimidazol-b-yl|Ioxy)pentanoic acid, - 4-(1-(4-methylphenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|Ioxy|butyric acid, 5-C1 -phenyl-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy)pentanoic acid, i.e.) 4-(1-phenyl-2-(3-thienyl)-1H-benzimidazol-b-yl|Ioxy |butyric acid, iz 20 6-(1-phenyl-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid, 6-(1-(4-fluorophenyl)-2-(3- thienyl)-1H-benzimidazol-b-yl|oxy|hexanoic acid, c» 5-(1-(4-fluorophenyl)-2-(3-thienyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid y, 6-(1-(4-fluorophenyl)-2-(3Z-pyridinyl)-1H-benzimidazol-b-yl|oxy)hexanoic acid, 5-(1-(4-fluorophenyl)-2-(3Z- pyridinyl)-1H-benzimidazol-b-yl|Ioxy)pentanoic acid, 22 5-(1-phenyl-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanoic acid, Ge! 4-(1-phenyl-2-(Z-pyridinyl)-1H-benzimidazol-b-yl|Ioxy|butyric acid, 6-(1-phenyl-2-(Z-pyridinyl)-1H-benzimidazol-b-yl) |ioxy|hexanoic acid, where M-(3-methoxypropyl)-6-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|ioxy|hexanamide, 6-( 1--4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|-1-morpholin-1-ylhexan-1-one, 60 M-methyl-6-(1-( 4-methylphenyl)-2-(3-pyridinyl)-IN-benzimidazol-b-yl|oxy|hexanamide, M,M-dimethyl-6-((1-(4-methylphenyl)-2-(3-pyridinyl) -1H-benzimidazol-b-yl|oxy|hexanamide, 6-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|hexanamide, M-cyclopropyl-6- |(1-(4-methylphenyl)-2-(3-thienyl)-1IN-benzimidazol-b-yl|oxy|hexanamide, M-methyl-6-((1-(4-methylphenyl-2-(3- thienyl)-1H-benzimidazol-b-yl|oxy|hexanamide, 65 M-(2-methoxyethyl)-5-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl |oxy|pentanamide, M,M-dimethyl-5-((1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanamide, 5-(1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-b-yl|oxy|pentanamide, 6-(1-(4-methylphenyl)-2-(2-thienyl)- 1H-benzimidazole-b-yl|oxy)hexanoic acid. 10. Use of the compound according to any one of claims 1-9 for the preparation of a medicinal product intended for the treatment or prevention of diseases associated with the activation of microglia. 11. Application according to claim 10 for the treatment or prevention of inflammatory, allergic, infectious or autoimmune diseases. 12. A pharmaceutical agent, which is characterized by the fact that it contains one or more compounds according to any of claims 1-9 and one or more carriers and/or excipients. 0. and and and and. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2008, M 21, 25.12.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s schi 6) so « s «- d) - with . and? (ее) - име) щ» сю» Ф) име) 60 b5