UA81111C2 - Use of a microglia inhibitor for the production of a pharmaceutical agent that inhibits immune reactions mediated by interleukin 12 (il 12) and interferon-? (variants) - Google Patents

Abstract

The invention relates to the use of a microglia inhibitor for the production of a pharmaceutical agent that inhibits immune reactions that are mediated by interleukin 12 (IL 12) and interferon-?.

Description

Description of the invention

The present invention relates to the use of a microglia inhibitor for the preparation of a medicinal product that inhibits 2 interleukin 12 (1-12) and uU-interferon-mediated immune reactions, and its use for the treatment of T-cell-mediated immunological diseases and non-T-cell-mediated inflammatory reactions.

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 is caused by an imbalance of soluble immune factors, for example, cytokines Moztapp and Soytapp, App. Kew.

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

Misgorios. Chem., 4, 1996, pp. 532-562; Romie and Soytap, Tgepdz RIagptasoi. 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 characterized by the expression of certain surface antigens (СО4 and СОВ), namely, СО4-positive T-cells (T-helper cells) and СОв-positive T-cells ( cytotoxic T cells).

Spra cells, in turn, can be divided into T-helper cells type 1 (TA1) and T-helper cells type 2 (TA2). high school

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-versus-graft reaction, graft-versus-host reaction).

Regarding interleukin 12, it is known that it plays the most important role in regulating the response of Tp1 cells. "-

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

And so on. Todau, 17, 1996, pp. 138-146; Sage|shu and others, Appy. Chem. Ittipoi., 16, 1998, pp. 495-521). It is IRMu that is an effective mediator of the action carried out by 1-12. Excess production of "γ-interferon" can be responsible, for example, for the occurrence of autoimmune diseases associated with MNS Ii (from the English "tai|og pPiviosotrayriyu s sotrieh", the main histocompatibility complex). In addition, there is also quite a lot of clear information about the pathological role that y-interferon plays in allergic diseases, as well as in sarcoidosis and psoriasis

IA. Viyach, Adu. Ittipoi., 62, 1996, pp. 61-130; Vavzpat et al., U. Ittipoiii., 130, 1983, pp. 1492-1494; Ni and others, Ittypoiodu, 98, 1999, pp. 379-385; O.R. Zeegu, Agpiyiv Kev., 2, 2000, pp. 437-440). In addition, 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" ("gay dose gezropze") during antibody therapy, for example after administration

OKTZ during allotransplantation) (Kyt et al., Ipyesi Ittyp., 69, 2001, pp. 7544-7549; Agai et al., 9U. HetsKkos. Vioi. 69, 2001, pp. 921-927; Nyiidgep et al., Agiigyiv Kev., Z, 2001, pp. 41-47, Agpai et al., At. .. Kevgrig. (ee) SeiI. Moi. Vioi., 22, 2000, pp. 708-713; Sgoptapp et al., U Ittipoi., 164, 2000, pp. 4197-4203; Mygaye et al., it. 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) |NauaKama et al., u. Kerhod. Ittipoi., td 47, 2000, pp. 121-138; Vapiev and others, At. IN). Kerhod. Ittypo)., 39, 1998, pp. 376-380). -l 20 Along with interleukin 12 and IRMUu, 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, I apsei, 351, 1998, p. 603; Sopep et al., Gapseyi, 351, 1998, p. 17311), but also in numerous other immune-mediated diseases. o Corticosteroids are often used for the treatment of II-12-mediated diseases and to alleviate the acute symptoms of such diseases, the side effects that appear during their use, and especially 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 a long period 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 regeneration of nerve cells. Activation of microglia can be caused by various stimuli, such as, for example, AB-peptide |B-amyloid, Yu.M. Agazio and SM. Soitap, 65 Vgaiip Kez. 569, 1992, pp. 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, 19984.

Compounds that inhibit the activation of microglia after AB-peptide stimulation are described in MO applications 01/51473,

OE 10134775.8 and OE 10135050.3). It is also known from these applications that benzimidazoles, which inhibit the activation of microglia, are used to treat neuroinflammatory diseases, such as AIDS dementia, amyotrophic lateral sclerosis, Creutefeld-Jakob disease, Down's disease, diffuse Lewy body disease, Huntington's disease, leukodystrophy, multiple sclerosis , Parkinson's disease, Pick's disease, disease

Alzheimer's disease, apoplexy, temporal lobe epilepsy and various tumors.

The basis of this invention was the task of offering a means that would be suitable for the treatment of 7/0 immunological diseases, the occurrence of which is due to the increased production of cytokines, such as, for example, I-12, IEMu, and TMEA, without affecting other factors in the immune system , which would make it possible to reduce side effects and, accordingly, avoid them.

According to the invention, it was found that inhibitors of microglia unexpectedly inhibit the production of 1! -12 and

IEMs induce the production of interleukin 10 (1-10) and therefore can be used for the preparation of 75 medicinal products intended for the treatment of monocyte-, macrophage- or

T cells, primarily Tp1 cells, of immunological disease, as well as non-mediated

T cells of pathophysiological inflammatory reactions.

As mentioned above, T-lymphocytes can be divided according to the expression of their surface antigens into

Sra-positive T-cells (T-helper cells) and CO8-positive T-cells (cytotoxic T-cells), and expressing 2nd COa4 T-helper cells (T-cells), in turn, can be divided into T cells - type 1 helpers (TR) and

Helper T-cells type 2 (TN2), which, in particular, differ among themselves in their ability to prevent the development of tolerance. Cytokines II-12 and IRMU play an important role in the induction and maintenance of differentiation

TA1 cells. Differentiated TN1 cells secrete IEM, interleukin 2, and TMEA/B. These cytokines in turn activate macrophages and CO8-positive cytotoxic T-cells. Ge

The present invention relates primarily to the use of microglia inhibitors for the preparation of a drug (5) intended to interrupt the production of 1-12, respectively, IEM in cells of monocytic origin, respectively, T-cells and MK-cells. Such inhibitors of microglia due to their ability to interrupt production

I--12th TMEA in monocytes/macrophages/dendrites and the production of IRM in T-cells and MK-cells, as well as enhance the induction of the production of II/-10 are suitable for the treatment of various diseases caused by the increased production of cytokines, such as TMRA and -B, IEMU, 1I--2 and 1-12, for example inflammatory diseases, "- not based on neuroinflammation, autoimmune diseases, allergic and infectious diseases caused by inflammation toxins, pharmacologically provoked inflammatory reactions, as well as pathophysiologically relevant (87 inflammatory reactions of currently undiscovered genesis."--

Chronic inflammatory bowel diseases can be cited as an example of inflammatory and autoimmune diseases

Zo (Crohn's disease, ulcerative colitis), arthritis, allergic contact eczema, psoriasis, pemphigus, asthma, multiple sclerosis, diabetes, insulin-dependent diabetes type I, rheumatoid arthritis, lupus and other collagenoses, Graves' disease, Hashimoto's goiter, reaction " graft versus host" and graft rejection.

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), damage to organs after reperfusion. An example of pharmacologically induced inflammation with pathophysiological relevance is the response to the first dose " ("igwi dose gezropze") after introducing into the body T-cell antibodies, such as OKTZ.

Eclampsia can be called an example of systemic inflammatory reactions of currently unknown genesis. According to the invention, suitable compounds for use as microglial inhibitors are compounds that inhibit the activity of microglia upon AB-peptide stimulation by at least 20905, and the activity of cytokines is inhibited by at least 3095. The biological properties of microglial inhibitors can be investigated by methods known to specialists, for example, considered and described below |in UUO 01/51473) research methods. -oUu 70 Among the microglia inhibitors most suitable for use in the purposes envisaged by the invention with the properties described above are benzimidazoles of the following formula I, their tautomers and isomers, as well as salts -

F) name) 60 b5

I M o - - 8 (I) 15 v-A- M 20 () s 25 (8) "- 30 "- "- "- 35 g)

In this formula, the substituents have the following meanings:-

B represents an aryl group or a five- or six-membered heteroaryl group with one or two c heteroatoms selected from the group consisting of M, 5 and O, wherein said aryl or heteroaryl group "c" may contain up to three residues as substituents, regardless one from the other selected from the group that includes EC, SI, in C(MNMNo, C(MNHMNEIA, C(MNIMeLV, C(Me MH, C(MVOMNe?, cS(Me MeV, xX-OH, xX-OovV, Xx -osov, x-osOoMmNne t, x-sov, XxX-C(MOoNV, x-SM, X-COOH, Xx-soov, x-COoMN", X-SOMA" B, X-SOMNel, X-COoMnON, o хХ-887, Х-8ОВ7, Х-50287, 502МНо, 80О2МНА?, 802МВ7В', MO», Х-МНо, Х-МНА", х-МВ"В7, хХ-МНВЗОВУ, and хХ-ме750287, Х-МНСОВ . below, - and the two substituents at K", if they are in the ortho-position relative to each other, in each - 20 cases can be connected to each other in such a way that they jointly form methanediylbisoxygr upu, an ethane-1,2-dilbisoxy group, a propane-1,3-membered group or a butane-1,4-membered group, or means a residue selected from the group consisting of C1-4alkyl, (Sosalkanediyl-C3/7cycloalkyl ) and C3.valkenyl, where one H-atom can be replaced by a heterocyclic residue selected from the group that includes piperazine, morpholine, piperidine and pyrrolidine, with the formation of a bond with the first M-atom of the heterocyclic residue, while alkyl, cycloalkyl, alkenyl residues and a heterocyclic residue can contain up to two residues as substituents,

HF) selected from the group that includes C o»alkanedyl-OnH, Sogoalkanedyl-OB 7, Co oalkanedyl-MN", Sogoalkanedyl-MNE 7, kU Sooalkanedyl-MA "B 7, Sogoalkanedil-MNSOV, Sogoalkanedyl-MV SOV 7, Sogalkandil -MZZO»V,

Co oalkanedyl-MA "5027, Sogoalkanedyl-SOZN, Sooalkanedyl-SOV, Sooalkanedyl-SOMN", 6o0 Co oalkanedyl-SOMNA 7, Sogoalkanedyl-SOMA "B 7, phenyl and a five- or six-membered heteroaryl residue containing one or two heteroatoms selected from the group that includes M, 5 and O, and phenyl and heteroaryl residues can contain as substituents up to two residues selected from the group that includes PE, SI, Bg, CH3, CoHv, OH,

Osn», OSOHn, MO», MSH(CH»)», CEz, Sobv and ZO2MH», and/or may also carry an annelated methanediylbisoxy or ethane-1,2-dilbisoxy group, and a piperazine residue near the second nitrogen atom may also be replaced by group 65 B", group SOC" or group 50287, where B" and B" can have values independently selected from the following,

B2 means a -7-C2 group, an aryl group, a five- or six-membered heteroaryl group with one or two heteroatoms selected from the group consisting of M, C, and O, a benzothienyl group, or an indolyl group, wherein the aryl or heteroaryl group is indicated may contain as substituents up to three residues, independently of each other, selected from the group that includes Е, СИ, Вг, С(МНИМНо, С(МН)МНеЯ, сС(МНуМелв, С(Ме МН», СИМ Мне т, с( iMv MeV, xX-OnN, xX-ov?, xX-osSOovV?, X-OoSsOoMNA?, xX-SOv", X-C(MON, xX-SM, X-COOH, xX-SOOVU,

Kh-SOMN,, Kh-SOMAM, Kh-SOMNA", Kh-SOMNON, Kh-58", Kh-5OV", Kh-8028", 502MNo, 502MNA", 802MAIV", MO»

Х-МН", ХА-МНЕ?, Хх-МВ"В х-MmnIO»v, Хх-Ме780287, Х-МНСОВУ, Х-ЧНСООВ, Х--НСОМНе and 27, where X is a bond, CH », (СНо)» or СН(СН»У)», and residues Bl and 87 have values that are chosen independently of each other from the following, and two residues at K?, if they are in the ortho position relative to each other , can be connected to each other in such a way that they together form a methanediylbisoxy group, an ethane-1,2-diylbisoxy group, a propane-1,3-diyl group or a butane-1,4-diyl group, 7 means МН, MK, О , 5, 50 or 505, where KE? has the following values,

IN? and in independently of each other denote a residue selected from the group comprising

C1..perfluoroalkyl, C. alkyl, (Co zalkanediyl-C3 7cycloalkyl), (Co zalkanediylaryl) and (Co zalkanediylheteroaryl), while the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group, which includes M, 5 and O, aryl and heteroaryl groups in each case can contain as substituents up to two residues selected from the group that includes КЕ, СИ, Бг, СН5, СОН5, ОН, ОСНУ3, ОСОН, МО», MШ (CNaz)», CEz, Co» and 5OOMN», and/or may also carry an annelated methanedilbisoxy or ethane-1,2-dilbisoxy group, and in a five-membered cycloalkyl ring, one ring member may 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 ring M- and/or ring O-atoms, and ring M-atoms may optionally be replaced by C.4.alkyl c or C. zalkanoyl, or o

B2 ate together with 7, when it represents an M-atom, form a five-seven-membered heterocyclic ring which may contain one more M-, O- or 5-atom and may optionally be substituted by a residue selected from the group consisting of С. alkanoyl, C. .alkoxycarbonyl, aminocarbonyl and aryl,

BZ means one or two residues independently selected from the group consisting of hydrogen, E, SI, --

In on, ov, osSoV?, osSOoMNv", Sov", SM, СООН, Сон, СОМНо, СОМНЕ", СОМ, СОМНОН, «-

SOMNOK". А", BOR", 5028", 502МНо, БО2МНА", 502МАА, МО", МНо, МНА", МАТ", МНВОо В", MAI8Оо А", o. mno», Me"50289, МНСОВ?, МНСООВ", МНСОМНЕ and 7, where the residues K", K7 and 9 have values that are chosen independently from each other among the following, --

A represents a group selected from the group consisting of C4oralcandil. C»ochoalkenedyl, C»oalkenedyl and so (Sozalkandiyl-Cz y7cycloalkanediyl-Co zalkanedyl) 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 rings members can be ring M- and/or ring O-atoms, respectively, and ring M-atoms may optionally be replaced by C 4 alkyl or Si. zalkanoyl, while in the aliphatic chains specified above, one C atom can be replaced by 0, МН, М-С. alkyl or M-Sisalkanoyl and 7-C alkyl or cycloalkyl groups may optionally be substituted with a residue selected from the group consisting of -O, OH, O-C. Zalkil, MN", MN-S. Zalkil, MN-S. alkanoyl, M(C. alkyl)" and M(C. alkylu(C 4. alkanoyl), ;" B means attached in each case to the C-atom of group A a residue selected from the group that includes

COOH, SOOC5, SOMN»o, SOMNMN», SOMN?, SOMASK5, SOMNON, SOMNOCBZ and tetrazolyl, wherein the residues Kb and U have values independently selected from the following, and (o) XM is a group selected from group, which includes О, МН, MAЕ", МСОВ", МО» and МО», where Б" and 2? have the following values, while the residues Б", 7, 25, 25 and В, which occur in the given above the residues, have the following meanings: -oUu 70 B and 7 independently of each other mean a residue selected from the group that includes CE z, Сов, а С, dalkyl, Со dalkenyl, Со zalkynyl and (Со-alkanediyl-Сз / 7cycloalkyl), while in a five-membered cycloalkyl 7" 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 ring M- and/or ring O, respectively -atoms, and ring M-atoms may optionally be replaced by C 4 alkyl or 25 C) alkanoyl,

HF) VZ and VU independently of each other mean a residue selected from the group that includes C 4 alkyl, 7 C, dalkenyl, Co valkynyl, where one C atom can be replaced by 0, 5, 50, 505, МН, M-Sizalkil or

M-Co zalkanoyl, (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, and the ring M-atoms may optionally be substituted with C 4 alkyl or C 4 isalkanoyl, and also includes (Co zalkanediylaryl) and (Co zalkanediylheteroaryl), where the heteroaryl group is five - or six-membered and contains one or two heteroatoms selected from the group that includes M, 5 and O, while all the above-mentioned alkyl and 65 cycloalkyl residues may contain as substituents up to two residues selected from the group that includes Ce3, CoEv,

ON, O-S)u zalkil, MN", MN-S. Zalkil, MN-S. zalkanoyl, M(S. zalkyl)", M(C4 zalkyl)u(S.- zalkanoyl), COOH, SOMN" and

SOO-S. alkyl, and all of the above aryl and heteroaryl groups can contain as substituents up to two residues selected from the group that includes РЕ, СИ, ВК, СН», СоН5, ОН, OSНУ, OSоН, MO», M(СН»)» СЕз, СОЕ» and 5О»МН», and/or may also carry an annelated methanediylbisoxy- or ethane-1,2-diylbisoxy group, or

B5 and VU together with the amide M-atom of the B substituent form a five-seven-membered, saturated or unsaturated heterocyclic ring, which may contain one more M-, O- or Z-atom and may be substituted with C 4.dalkyl, (Soalkanediyl-C. ..an alkoxy group), Si. by alkyloxycarbonyl, aminocarbonyl or aryl, 25 means a residue selected from the group consisting of (C ozalkanediaryl) and (Co zalkanediylheteroaryl), wherein the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group consisting of М, 5 and О, while the specified aryl and heteroaryl groups can contain as substituents up to two residues selected from the group that includes ЕК, СИ, Вг, СН», СОН, ОН, ОСН», ОСОН5, МО», MЩ( СН3», СЕз, Сов | and 5О»МН», and/or may also carry an annelated methanediylbisoxy- or ethane-1,2-diylbisoxy group, and

B ate independently of each other mean B" or P,

Those benzimidazole derivatives in which the B-A-X substituent is attached at position 6 of benzimidazole are preferred.

The scope of this invention also includes physiologically compatible salts, as well as esters of the above compounds, primarily acid salts of the above-described benzimidazole derivatives, when they are presented in the form of nitrogenous bases, basic salts of these derivatives, when they are presented in the form of carboxylic acids, as well as esters of these derivatives, when they are represented in the form of carboxylic acids, and esters of carboxylic acids, which are derivatives of such derivatives represented in the form of carboxylic acids, for example amides of carboxylic acids.

The benzimidazole derivatives described above can have one or more chiral centers, and therefore such compounds can exist in several isomeric forms. Compounds of the formula | 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 they are not specifically mentioned in each case, are part of the present invention. Mixtures of isomers can be separated into enantiomers by conventional methods, such as crystallization, chromatography or salt formation, respectively

E/2-isomers.

Heteroaryl groups, which are contained in benzimidazole compounds, consist of five or six skeletal atoms and may contain one or two heteroatoms. Such heteroatoms are oxygen (0), nitrogen (M) and sulfur (5). Examples of heteroaryl groups are pyrrolyl, thienyl, and furanyl. imidazolyl, thiazolyl, isothiazolyl, «- oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrazinyl and pyridazinyl. When heteroaryl groups are the structural element of the substituent ЕК" or К?, such a group is attached via a C-atom to the Y" of the corresponding M-atom of the benzimidazole skeleton, according to the substituent 7. "-

As aryl residues, mainly a phenyl residue is used, but also a naphthyl residue. 3o Aryl and heteroaryl residues can be attached in any way to the benzimidazole skeleton or to another group, for example in the form of 1- or 2-naphthyl or in the form of 2-, 3- or 4-pyridinyl.

Alkyl groups can have a straight or branched chain. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl, n-hexyl, sec- hexyl, heptyl, octyl, nonyl and decyl. Each of their higher homologues also contains both linear and branched alkyl groups, that is, for example, octyl can contain o)c 2-ethylhexyl, and nonyl can contain 3-propyl hexyl. "» Perfluorinated alkyl residues are mainly CE" and CoEv. "Alkenyl groups can have a straight or branched chain. Examples of alkenyl residues in the context of this invention include vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl and 3-methyl-2- propenyl co Alkynyl groups can have a straight or branched chain. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

Cycloalkyl groups in each case mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl (corresponds to C3-7cycloalkyl). -oUu 70 As examples of a saturated heterocyclic ring, respectively, as examples of cycloalkyl with one or several heteroatoms, we can name piperidine, pyrrolidine, tetrahydrofuran, morpholine, piperazine, hexahydroazepine, and -6y also 2,6-dimethylmorpholine, M-phenylpiperazine and methoxymethylpyrrolidine, while connection with adjacent to the ring

The C-atom can be carried out through ring M-atoms present under certain conditions.

Alkanedyl, alkenedyl, alkyndyl, and cycloalkandyl residues that occur in the description of this 99 invention are identical to alkylene, alkenylene, alkynylene, and cycloalkylene residues, respectively. If in

HF) general formulas of alkandyl residues indicate the number of C atoms contained in them, and as the lower limit value of this number, the value 0 is indicated, then in this particular case there is no such alkandyl o residue.

An example of alkanes, alkenes and alkynes as the value of the substituent A is alkandyl with a straight or branched 60 chain containing up to eight C atoms, in particular methanediyl, ethanedyl, propanediyl, butanediyl, pentanediyl, hexanedyl, as well as 1-methylethanediyl, 1-ethylethanediyl, 1-methylpropanediyl, 2-methylpropanediyl, 1-methylbutanediyl, 2-methylbutanediyl, 1-ethylbutanediyl, 2-ethylbutanediyl, 1-methylpentanediyl, 2-methylpentanediyl, 3-methylpentanediyl and similar compounds.

Unbranched or branched alkendiyl and alkyndyl residues containing from two to eight C-atoms are alkendiyl groups, respectively, alkyndyl groups with double and triple bonds in all possible positions, as well as with all possible metal or ethyl substitutions. In each of these residues, one or two C atoms can be replaced by О, МН, МС. Zalkil or M-S. alkanoyl, while the substituted group is separated from the substituent B by at least two C atoms.

When two residues are in the ortho position, they can form a common ring with adjacent aromatic groups. At the same time, the scope of the invention excludes compounds in which either M-, O- or 5-atoms are connected with ethylene or acetylene multiple bonds, or several M-, O-, C-atoms or halogen atoms are connected with by the same aliphatic carbon atom, or M-, O- or 5-atoms are directly connected to each other, if such connections are not specifically indicated, for example, in the functional 7/o groups specified in the formula of the invention or in heteroaromatic groups.

Physiologically compatible acid salts of the benzimidazole derivatives described above, when they are presented in the form of nitrogenous bases, can be formed with inorganic and organic acids, such as, for example, oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid 7/5 Acid and methanesulfonic acid.

If the benzimidazole derivatives 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, alkaline earth metal hydroxides such as calcium hydroxide, and ammonia and amines such as ethanolamine, diethanolamine, triethanolamine, M-methylglucamine and tris(hydroxymethyl)methylamine.

All lower monoatomic, diatomic and triatomic alcohols are suitable for the formation of esters, primarily methanol, ethanol, isopropanol and tert-butapol, as well as ethylene glycol and glycerin.

The most preferred are benzimidazoles of the general formula I, in which the following residues and groups independently of each other have the following values: с

IN! means a phenyl group which may contain as substituents up to two residues, independently of each other, selected from the group consisting of E, SI, Bg, C(MH)MH 5", CI(IMNIMNE?, C(MH)IMAV, C( Me)MN»o, С(MeМНе, о сС(Mv MeV, ОН, ОВ, осо", OSOMNE", Сов, С(МОНВ, СМ, СООН, СоОвК", СОМНо, СОМ,

SOMNE?, SOMNON, 587, 8ОБ7, 80287, 802МНо, 50оМНЕ", 8ОоМв'В?, MO", МНо, МН, MAV,

MNSOMNKYA | Kl, where the residues BK" and B" have values that are chosen independently of each other from - given below, while the two substituents at K", if they are in the ortho-position to each other "- can be connected between themselves in such a way that they together form a methanediylbisoxy group, an ethane-1,2-diylbisoxy group, a propane-1,3-diyl group or a butane-1,4-diyl group,

IN? means a mono- or bicyclic sloaryl group or a mono- or bicyclic 5-10-membered heteroaryl 7 with 5 group with 1-2 heteroatoms selected from the group consisting of M, 5 and O, while the specified aryl or c heteroaryl group may contain up to three substituents independently selected from the group consisting of E, SI, Vg, HON, XO", ЧооСОоВ ХооСОоМнНе", хХОоСОоОоВ", хХЧсОовВ, Hemmone, chemokzv", хХЭ(MO(СОк В, хХСоонН, ХхсоОвВ), KhsOMNo, KhSOMNA", KhSOMA" V", KhSOMNON, KhSOMNOV", KhxSOZv, " hv", ХО, Х50287, 502МНо, З0О2МНА", 502, MO", ХМНА", ХМ", ХМНЗО»ВХ, ХМ(30287) 508 . propane-1,3-diyl or butane-1,4-diyl, "BZ means a residue selected from the group consisting of hydrogen, PE, SI, Bg, CH z, SoN, SEz, SoEv, OH, Ov,

МНЗО, В и МНСОВ", where K" and RE? have the following meanings, about 175 A means S. oralkandiil, So zoralkendiil, So. zoalkanedyl or (Co alkanediyl-C3 7cycloalkanediyl-Co alkanediyl), where in the 5-membered cycloalkyl ring one ring member can be an M atom or an O atom, and in the 6- or 7-membered cycloalkyl ring one or two ring members can be M- and/or O-atoms, and - ring nitrogen atoms can optionally be replaced by C..alkyl or C.alkanoyl, while in the aliphatic chains indicated 5p above, one carbon atom or two carbon atoms can -ut) be replaced by О, МН, - М-С..alkyl or М-С. alkanoyl, and B means in each case attached to the C atom of group A a residue selected from the group consisting of

СООН, СООВ5, СОМН», СОМНЕЗ and СОМ», where the residues 2 and КУ have values chosen independently of each other from those indicated below, and 5B Y means 0, while the residues B", 7, 25, 25 and B, which occur in the above residues have the following

Ф, values: ko VL B have the same values as indicated for them above,

VZ and VU independently of each other mean a residue selected from the group that includes C 4.valyl, 600 C, dalkenyl, Co valkynyl, where the C atom can be replaced by 0, 5, ZO, 505, MH, M-C ..alkyl or M-S. zalkanoyl, (Co-alkanediyl-C3.cycloalkyl), 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 ring M, respectively - and/or ring O-atoms, and ring M-atoms may optionally be substituted by C ..alkyl or C.alkanoyl, and also includes (Sosalkanedylphenyl) and (Sosalkanediylheteroaryl), where the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group consisting of M, 5 and O, while all of the above alkyl and cycloalkyl residues may be replaced by a residue selected from the group consisting of CE z, CoEv, OH, O-Su alkyl , MN",

MN-S. Zalkil, MN-S. zalkanoyl, M(S. zalkyl)", (S. zalkiluS. zalkanoyl), COOH, SOMN" and SOO-S. alkyl, and all of the above-mentioned phenyl and heteroaryl groups may contain as substituents up to two residues selected from the group that includes P, SI, Bi, CH3, SoHn, OH, OSN», OSONh, MO», ShCH»), CEz, Sogv and ZO»MN», labo can also carry an annelated methanediylbisoxy- or ethane-1,2-diylbisoxy group, or

BZ and KU together with the amide M-atom of the substituent B form a five-seven-membered, saturated or unsaturated heterocyclic ring, which may contain one more M-, O- or Z-atom and may be substituted with C 4.dalkyl, (Sogalkandiyl-C. .alkoxy group), Si. alkyloxycarbonyl, aminocarbonyl, or phenyl, and 25 represents a phenyl group or a heteroaryl group that is five- or six-membered and contains one or two heteroatoms selected from the group consisting of M, 5, and O, wherein said phenyl and heteroaryl groups may contain as substituents up to two residues selected from the group that includes ЕК, СИ, Вг, СН з, СеН5, ОН, ОСН», ОСОНвБ,

MO», M(CHnaz)», SEz, Sobv and 5OOMN», or may also carry an annelated methanediylbisoxy- or ethane-1,2-dilbisoxy group.

Mostly BEZ means hydrogen. The U-A group in one of the preferred embodiments of the invention is represented by a valkyleneoxy group, which is attached to the benzimidazole skeleton through an O atom.

The present invention also relates to pharmaceuticals containing one or more compounds of the general formula I, 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, capsules, powders, pastes, ointments, lotions, liquid preparations, such as syrups, gels, liquid preparations for injections, for example for intraperitoneal, intravenous, or internal ulcerative or transdermal injections, and other dosage forms. The list of other medicinal forms also includes depot forms, in particular implanted forms of application, as well as suppositories. At the same time, benzimidazole derivatives, depending on their type, are released into the body gradually or in full in a short period of time from such separate dosage forms. --

Capsules, pills, tablets, dragees and liquid preparations or other known dosage forms for oral administration can be used as pharmaceutical preparations for oral use. In this case, medicinal products can be prepared in the form of preparations that either release the active "-- substances in a short period of time and secrete them into the body, or have a prolonged effect, which 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, (ee) for example, substances for regulating the rheological properties of the medicinal product, 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, flavorings and other substances.

Suitable tablets can be made, for example, by mixing the active substance with known auxiliary substances, for example with inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as such as starch or gelatin, lubricants such as carboxypolymethylene, carboxymethylcellulose, acetylcellulose phthalate or polyvinyl acetate. Tablets can also have a multilayer structure. Similarly, it is also possible to obtain dragees by coating cores made in the same way as tablets - coatings of materials commonly used as dragee shells, such as, for example, polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. At the same time, the shell of the dragee can also have a multi-layer structure, for the preparation of which you can use the auxiliary substances specified above for tablets. -oUu 70 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. "6 Active substances can also be used in a dosage form in the form of a solution that is intended for oral administration and which, together with a biologically active benzimidazole derivative, contains as ingredients a pharmaceutically acceptable oil and/or a pharmaceutically acceptable lipophilic surfactant or a pharmaceutically acceptable hydrophilic surfactant substance and/or a pharmaceutically acceptable solvent that is miscible with water.

To increase the bioavailability of active substances, such compounds can also be used in the form of clathrates with a cyclodextrin framework. For this purpose, these compounds are subjected to interaction with A-, B- or y-cyclodextrin or its derivatives. 60 The use of pastes, ointments, lotions and liquid preparations intended for external use assumes that they have such properties that ensure the entry of biologically active compounds into the body in sufficient quantity. The composition of such dosage forms includes auxiliary substances, for example, substances for regulating the rheological properties of drugs, surface-active substances, preservatives, hydrotropic solubilizers, diluents, substances to improve the permeability of active substances through the skin, dyes, flavorings, and protective agents for the skin, such as air conditioners and humidity controllers.

Along with the biologically active compounds used in accordance with the invention, the medicinal product may also contain other active substances |

Rpagt. zsi., 52, 1963, p. 918 et seq.; N.M.

Sebriee(e, RIapt. pa, 2, 1961, p. 72 et seq.; Og. N.R. Rigedieg, Iehikop deg Niizviyoye ho RNagta?iv,

Kozpteiiik ipa apdgepgepde Sebieie, vid-vo Sapiog AS, AshShepaopl/miy., 19711.

The compounds that are used according to 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, active substances can be present in a dissolved or suspended form in a physiologically compatible diluent. Oil solutions, 7/0, for example, solutions in sesame oil, castor oil, and cottonseed oil, are suitable as such diluents. Hydrotropic solubilizers, such as benzyl benzoate or benzyl alcohol, can be added to increase solubility.

Any liquid carrier in which the compounds used according to the invention are present in dissolved or emulsified form can be used to prepare the drug for injection. The composition of such liquid preparations often also includes substances for regulating viscosity, surfactants, preservatives, hydrotropic solubilizers, diluents, and other additives that make the solution isotonic. Along with benzimidazole derivatives, other active substances can be introduced into the body as part of such drugs.

The compounds that are used according to 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 properties can be given to such drugs, which 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 synthetic silicones, such as silicone rubber. For transdermal administration, benzimidazole derivatives can be further immersed, for example, in a patch.

The dose of the compounds used according to the invention, which is prescribed to the patient, is determined by the attending physician i) and depends, in particular, on the specific compound that is introduced into the body, on the route of administration, on the disease to be treated, and on its severity. The daily dose of the active substance does not exceed 1000mg, preferably does not exceed 10Omg, 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.

Study of biological properties -

Example 1: Activation of macrophages "-

TNR-1 cells activated by lipopolysaccharide (LPS) were used to study the biological properties of the compounds on macrophages/monocytes. For this purpose, cells were seeded in ERMI medium (VRMI medium (7 1640-1095 FTS) in the amount of 2.5x105 cells per ml of medium. Then the tested compounds were added to the cells at a concentration of 5 μM and pre-incubated for 30 h. The cells were stimulated for overnight at 372C using LPS at a concentration of 1mg/ml. After that, the medium was collected and the content of TMEA in it was quantified. In this experiment, the decrease in the amount of TMEA as a result of the treatment of cells with the tested compounds " was at least 30905.

Example 2: Inhibitory effect on the production of TMRA and 1-12 in TNR-1 cells. The inhibitory effect on the production of -c cytokines can be investigated, for example, by determining the amount of TMEA and interleukin 12 in TNR-1 cells stimulated with lipopolysaccharide (LPS). ," For this, TNR-1 cells (obtained from the American Collection of Type Cultures (Ategisap Toure Siyshge

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

Me Tesppoiodiev), supplemented with 1095 FTS (Ishe Tesppoiodiev, cat. Mo10270-106), were sown on 9b-well flat-bottom culture plates (TRP company, product Mo9296) (in the amount of 100 μl per well). Then, the tested compounds 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 379C with lipopolysaccharide -sh 20 (Zidt company, cat. Mo 2630, from E. soy serotype 0111.84), which was used in the amount of 0.1 μg/ml. After that, the medium was collected and the content of TMREA in it was quantitatively assessed, corresponding to interleukin 12. The content of TMEA was determined using a commercially available kit for determining TMEA of the company SIZ Bio Ipiegpaiopai! (product

Mo62TMEREV). The content of interleukin 12 was determined using the OKISEM technology (developed by ISEM

Ipsegpayopa!, Ips., Geisersburg, st. Maryland). The calculated value of IC 5o corresponds to the concentration of 22 of the tested substance, which is necessary to inhibit the level of TMEA production, respectively interleukin 12 by 5095

F! from the maximum level of their production.

According to the results of this experiment, it was established that the IC 50 value when using the tested compounds is less than 1O0μM.

The inhibitory effect of the tested compounds on the production of II/-12 and TMEA can also be investigated by a similar method using peripheral leukocytes and comparable stimuli.

Example 3: Inhibitory effect on the production of IEM by peripheral blood mononuclear cells

The effect of the tested compounds on the activation of T cells can be studied, for example, by analyzing the secretion of IEM.

Human whole blood was used for the isolation of peripheral mononuclear blood cells (for blood sampling, the 5-Mopometse "Sovadoshayop 9 MS/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 ( firm

Ogeipeg, cat. Мо227290) were previously introduced with 15 ml of Nivioradce-1077 (Zidt company, cat. МоН8880) and centrifuged for 30 minutes at 10009. After that, 15 ml of whole blood was added and centrifuged for 10 minutes at 100049. Then the upper layer of plasma was removed using a pipette, and located under with it, a layer of cells (peripheral blood mononuclear cells) was transferred into 15-milliliter test tubes (Rysop company) and washed several times with 1 Oml of Hanks' balanced salt solution (without Ma? and Sa?), cat. Mo14175-53. At the end, the cell debris was resuspended in the culture medium KRMI 1640, supplemented with 25 mM Nerez (2-M-hydroxyethylpiperazine-M-2-hydroxypropanesulfonic acid, I Me Tesppoiodiev company, cat. Mo52400-041), 1095 FTS (I Ye Tesppoiodiez company, cat. Mo10270-106) and 0.495 of a solution of penicillin and streptomycin (Ge 70 Tesppoiodiev company, cat. Mo15140-106) (1x1 cells/ml). 100 μl of the cell suspension was distributed on 96-well flat-bottom culture plates (TPP company, product Mo9296) and stimulated with phytohemagglutinin, which was used at a concentration of 5 μg/ml. Next, the tested compounds were added in different concentrations and pre-incubated for 30 minutes. Cells were stimulated for 48 hours. After that, the medium was collected and its IEM content was quantified. The content of IEM was determined using the OKISEM technology (developed by the company 75 |SEM Ipiegpaiopai!, Ips., Geisersburg, Maryland). The calculated value of IC 5o corresponds to the concentration of the tested substance that is necessary to inhibit the level of IEM production by 5095 from the maximum level of its production.

According to the results of this experiment, it was established that when the cells were treated with the tested substances at a concentration equal to 10 μM, the amount of IEMU decreased by at least 3095.

The inhibitory effect of the tested compounds on the production of IEM in can also be investigated by a similar method using specific activators of T cells, for example, monoclonal antibodies to SOYUZ. school

Substance 1:

Isopropyl ether of 6-(1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-b-yl|ioxy|hexanoic acid "--

Substance 2: "- 6-(1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-b-yl|oxy)hexanoic acid

Example 4: Induction of production of 1-10 by peripheral blood mononuclear cells "-

The ability of the tested compounds to induce the production of I/-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). (uh)

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. MoHn8880) were pre-introduced into 50-milliliter GEOSO5ER tubes (Ogeipeg company, cat. Mo227290) and centrifuged for 30 seconds at 2509, 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 8004 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 (Raisop) and then washed three times in the culture medium ME KRMI 1640 ( Zegotead company,

MoeO1415) (centrifugation in cycles of 1 Ohv. at 2509 and room temperature). At the end, the cell debris was resuspended in MI E KRMI 1640 culture medium (Zegotea company, Moe01415), supplemented with 1096 FTS (Ibe Tesppoiodiyev company, cat. Mo16000-044, with low endotoxin content, inactivated by heating for an hour at 56,922) and a solution of penicillin and streptomycin at a concentration of 5Omkg/ml (Me - Tesppoodiev company, cat. Mo15140-106), and after counting the cells using trypan blue staining, their -sh 20 concentration was adjusted to 3x105 cells per ml. Next, 100 μl of the cell suspension was distributed on 96-well flat-bottomed culture tablets (Sovziag company, product Mo3599). After that, 100 μl of a triple concentration stimulation solution (with LPS/ml of LPS from E. soya serotype 0127: B8, Zidt company, cat. MoY-4516, respectively, ZOOmkg/ml of phytohemagglutinin RNA- Y, firm Viospgot KO, cat. MoM5030). After that, the tested compounds were added in different concentrations in the form of their solution of triple concentration (10O0μl per well). Cells were stimulated at 372С and 596 СО" for 24 hours. Then they collected

HF) cell culture supernatant and the content of II -10 in it was quantified.

The concentration of II/-10 was determined using a commercially available kit for EP IZA-analysis of the company Viobotsgse Ipiegpayopa! (Nitap 1-10, cat. MoKNSO101С). The calculated value of EC 50 corresponds to the concentration of the tested substance, which is necessary to increase the level of secretion of II -10 by 5095 from the maximum 60 degree of increase in their secretion.

According to the results of this experiment, it was established that the tested compounds increase production

And--10 peripheral blood mononuclear cells.

Example 5: Inhibitory effect on the production of TMRA and 1Y-12HO by peripheral blood mononuclear cells

The inhibitory effect of the tested compounds on the production of TMREA and 1/-12 HO p70 can be investigated, for example, by determining the amount of TMEA and 1-12 HO p70 in lipopolysaccharide (LPS) and G-interferon (IEM y) stimulated

peripheral blood mononuclear cells.

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 pre-introduced into 50-milliliter test tubes GEOSO5ER (Ogeipeg company, cat. Mo227290) and by centrifugation for 30 minutes at 2509, it was 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 7/o was discarded, and the layer of cells (lymphocytes and monocytes) located below it was transferred to 50-milliliter centrifuge tubes (Raisop) and then washed three times in the culture medium ME KRMI 1640 (Zegotead firm,

MoeO1415) (centrifugation in cycles of 1 Ohv. at 2509 and room temperature). At the end, the cell debris was resuspended in the MI E KRMI 1640 culture medium (Zegotea company, Moe01415), supplemented with 1096 FTS (Ibe Tesppoiodiev company, cat. Mo16000-044, with a low endotoxin content, inactivated by heating 7/5 for Lhd. at 56 22 ) and a solution of penicillin and streptomycin at a concentration of 5 Ωkg/ml (She

Tesppoodiez, cat. Mo15140-106), and after counting the cells using trypan blue staining, their concentration was adjusted to 3x109 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, 100 μl of a solution for stimulation of triple concentration was added to the cells on the plates (with LPS/ml of LPS from the E. soy serotype 0127: B8, Zidta company, cat. ItikKip, company Voengipdeg IpdeINEit). After that, the tested compounds were added in different concentrations in the form of their solution of triple concentration (100 μl per well). Cells were stimulated at 372С and 595 СО" for 24 hours. Then the cell culture supernatant was collected and with the help of commercially available kits for EI IZA-analysis of ViozZoshgse Ipiegpayopa! (TME-A

EAUBIA, cat. MOKAS 1752) and KO Bzuvietv (OtsapiiKkipetm H5 1-12, cat. MON 120) determined the concentration in it of SM 29 TMRA and 1-12HO p70. at

The calculated value of IC 5o corresponds to the concentration of the tested substance that is necessary to inhibit the production level of TMRA, respectively interleukin 12 HO p70 by 5095 from the maximum level of their production.

According to the results of this experiment, it was established that the tested compounds inhibit the production of TMEA and 07 11 -12HO p70 by peripheral blood mononuclear cells. "-- -

Substance Inhibition of secretion 1--12HO after |Inhibition of secretion of TMRA after stimulation Induction of secretion II -10 after - зв ШЙ ssh she B so

Substance 1: h

Isopropyl ether 6-(1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-b-yl|ioxy|hexanoic acid C c Substance 2: i » 6-(1-(4-methylphenyl)-2-phenyl -1H-benzimidazole-b-yl|oxy|)hexanoic acid.

Claims (1)

Formula of the invention (ee) - 1. Application of a microglia inhibitor to obtain a drug that exhibits inhibitory activity in relation to the production of interleukin 12 (II -12) and G-interferon (IEMG). - 2. Application according to claim 1 for the treatment of diseases caused by immune reactions mediated by sho 20 interleukin 12 (1-12) and G-interferon (IRMG) immune reactions. C. Application according to claim 1 for the treatment of diseases caused by inflammatory reactions, not -Z mediated by T cells. 4. Application according to claim 1 for the treatment of autoimmune diseases, inflammatory diseases not based on neuroinflammation, allergic and infectious diseases. 5. Application according to claim 4 for the treatment of chronic inflammatory bowel diseases, for example, Crohn's disease or ulcerative colitis, arthritis, allergic contact eczema, psoriasis, pemphigus, asthma, diabetes, insulin-dependent diabetes mellitus type !, rheumatoid arthritis, lupus diseases and other collagenoses ) syndrome), eclampsia, cachexia, acute viral infections, organ damage after reperfusion, "responses to the introduction of the first dose" ("igei dose gezropve") after the introduction of T-cell antibodies into the body. 6. Use of benzimidazole of formula I, its tautomer or isomer or salt b5 EE WHAT) their B-A-Z - in which B is an aryl group or a five- or six-membered heteroaryl group with one or two 70 tetraatoms selected from the group consisting of M, 5 and O, while aryl or heteroaryl is indicated the group can contain as substituents up to three residues, independently of each other, selected from the group that includes EC, SI, Vg, C(MN)MNo, C(MNIMNeg, C(MNIMvO B, C(MvMNo, C(MVOMNe), C (Me MVV, xX-oH, X-Ov, Xx-osovU, xX-OoSsOoMNe g, Xx-sov, Xx-C(MOon in, X-SM, X-COOH, X-SoOv, X-SOMN", X -SOMv in X-SOMNe, X-COoMnON, /5 xX-887, X-8OV7, X-50287, 502МНо, 80О2МНА?, 802МВ7В', MO», X-МНо, X-МНА", х-МВ"В7 . have values independently selected from the following, wherein the two substituents at K", when in the ortho position relative to each other, in each case may be joined together so that they together form methanediyl an isoxy group, an ethane-1,2-diylbisoxy group, a propane-1,3-diyl group or a butane-1,4-diyl group, or means a residue selected from the group consisting of C 1-4 alkyl, (Sozalkanediyl-C 3 /7 cycloalkyl) and C3.valkenyl, wherein one H atom may be replaced by a heterocyclic residue selected from the group consisting of piperazine, morpholine, piperidine, and pyrrolidine, forming a bond with the first M atom of the heterocyclic residue, wherein alkyl, cycloalkyl , alkenyl residues and a heterocyclic residue can contain as substituents up to two residues selected from the group that includes C o»alkanedyl-OnH, Coalkanediyl-OVK 7, Coalkanediyl-MN», Coalkanediyl-MNE 7, d) Coalkanediyl-MA" B 7, Sogoalkanedil-MNSOV, Sogoalkanedil-MV SOV 7, Sogoalkanedil-MNZO»V, Co oalkanedil-MA "30287, Co oalkanedil-СО2Н, Co oalkanedyl-SOV, Co oalkanedyl-SOMN", Co oalkanedil-SOMNA 7, Sogoalkanedil- SOMA B 7, phenyl and a five- or six-membered heteroaryl radical which "-- contains one or two heteroatoms selected from the group consisting of M, C and O, and the phenyl and heteroaryl residues can contain as substituents up to two residues selected from the group that includes PE, SI, Bg, CH», СОН5, ОН, - Osn», ОСОН, MO», M(CH3)» CEz, CoEv and 502МН", and/or may also carry an annelated methanediylbisoxy or: ethane-1,2-dilbisoxy group, and the piperazine residue near the second nitrogen atom may also be substituted by group B", group SOV" or group 5027, where B" and B" can have values that are chosen independently of each other and from the following, with B? means a -72-K2 group, an aryl group, a five- or six-membered heteroaryl group with one or two heteroatoms selected from the group consisting of M, C, and O, a benzothienyl group, or an indolyl group, wherein said aryl or heteroaryl group may contain as substituents up to three residues, independently of each other, selected from the group that includes E, SI, Vg, SIMNIUMNo, C(MH)IMNeYa, C(MNMVV, C(Me)MH»o, C(IMAMNA, Z to cS(Mv MeV, X-OH, xX-Oov?, x-oSOovV, X-OoSsOoMNe?, xX-SOV", xX-C(MON), XxX-SM, X-COOH, xX-SOOVU, c x- somMn,, х-соМмАв7, Х-SOMNE", Х-SOMNON, х-587, Хх-Ов, Х-502587, 502МНо, VOMNEL, 502МВ"В, MO", ;» Х-МН»о, Хх-MNA ?, Xx-M"V Xx-MNZO»vV, Xx-Me780287, X-MNSOV, X-ChNSOOVU, X-ChMNSOMNE and B", where X is a bond, CH», (CHNo)» or CH( CH»U)», and the residues Bl and 27 have values that are chosen independently of each other from the following, and the two residues at K?7, if they are in the ortho-position to each other (ee), can be from connected to each other in such a way that they are common form a methanediylbisoxy group, - an ethane-1,2-diylbisoxy group, a propane-1,3-diyl group or a butan-1,4-diyl group, 7 means MH, MK2, O, 8, 50 or 505, where K7 has the following value, - In? in? independently of each other mean a residue selected from the group consisting of -C 70 C. perfluoroalkyl, C. alkyl, (Co zalkanediyl-C3 cycloalkyl), (Co zalkanediylaryl) and (Co zalkanediylheteroaryl), while the heteroaryl group is p' seven- or six-membered and contains one or two heteroatoms selected from the group consisting of M, 5 and O, aryl and heteroaryl groups in each case may contain as substituents up to two residues selected from the group consisting of P, CI, Bg, CH5, CoH5, OH, OSNUz, OSON5, MO», MSH(CHaz)», SEz, Со» and ря 5ООМН», and/or may also carry an annelated methanedilbisoxy or ethane-1,2-dilbisoxy group and in p In a three-membered cycloalkyl ring, one ring member can be a ring M-atom or a ring HF) O-atom, and in a six- or seven-membered cycloalkyl ring, one or two ring members can be 7 ring M- and/or ring O-atoms, and ring M-atoms can optionally be replaced by C.-.alkyl or C.alkanoyl, or B? and K? together with 7, when it is an M-atom, form a five-seven-membered heterocyclic ring, which may contain one more M-, O- or 5Z-atom and may optionally be substituted by a residue selected from the group consisting of includes C 4 alkyl, (Sozalkandiyl-C- zalkoxy group), C..allkanoyl, C. Alkoxycarbonyl, aminocarbonyl and aryl, EZ means one or two residues, independently of each other, selected from the group consisting of hydrogen, E, Si, B, OH, OVK", OSOV", OSOMNEV", SOV", CM, COOH . », Me"50289, МНСОВ?, МНСООВ", МНСОМНЕ and 7, where the residues K", K7 and 9 have values independently selected from each other below, A means a group selected from the group which includes C 4oralcandyl, C»ochoalkenedyl, C» oalkenedyl and (Sosalkanediyl-C3 y7cycloalkanediyl-Co zalkanediyl) 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 ring M- and/or ring O-atoms, respectively, and ring M-atoms can optionally be replaced by C4.alkyl or C.alkanoyl, while in the above-mentioned aliphatic in their chains, one C atom can be replaced by O, MH, M-C, alkyl, or M-C. alkanoyl and alkyl or cycloalkyl groups may optionally be substituted with a residue selected from the group consisting of 7/0. 59, ON, O-S.. zalkil, MN", MN-S. Zalkil, MN-S. alkanoyl, M(C..-alkyl)" and M(C.-alkyl C alkanoyl!l), B means attached in each case to the C-atom of group A a residue selected from the group that includes COOH, COOK5, SOMN" о, СОМНМН», СОМНЕ?, СОМАЗК5, СОМНОН, СОМНОКБЗ and tetrazolyl, wherein the residues Kb and U are independently selected from the following, and XM is a group selected from the group consisting of O, MH, MAE ", МСОВ", МО» and М8О»В5, where В and КЗ have the following values, while the residues В", 7, В", В? and Кб, which occur in the above residues, have the following values: Вl and B' independently of each other mean a residue selected from the group that includes CE with, CoEv, C. dalalkyl, Co. dalkenyl, Co. alkynyl and (Co. alkanediyl-C3.7cycloalkyl), while 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 may be respectively ring M- and/or ring O-atoms, and ring M-atoms may optionally be substituted by C 4 alkyl or C) alkanoyl, BZ and VU independently of each other mean a residue selected from the group, which includes C 4 alkyl, c 29 C, valkenyl, sovalkynyl, where one C atom can be replaced by 0, 5, 50, 50", MH, M-C alkyl or Ge) M-C..alkanoyl, (Co zalcandil-C3 7Ucycloalkyl), 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, and "- ring M-atoms may optionally be substituted by C 4 alkyl or C isalkanoyl, and also includes (Co-alkanediylaryl) and (Cosalkanedylheteroaryl), where the heteroaryl group is five- or six-membered and contains -- one or two heteroatoms selected from the group that includes M, 5 and O, while all of the above alkyl and "- cycloalkyl residues may contain as substituents up to two residues selected from the group, which includes SE»z, SoEBv, ON, O-S.u zalkil, MN», MN-S. Zalkil, MN-S. zalkanoyl, M(C. alkyl)", M(C4 alkyl)/Si zalkanoyl) СООН, СОМНо and ж- СОО-Sisalkyl, and all the above aryl and heteroaryl groups can contain as substituents up to two CO residues selected from the group that includes P, SI, Vg, CH 5 , CoH 5 , OH, OSNUz, OSON 5 , MO», MSH(CHnaz)», CEz, Co» and 5O»MH», and/or may also carry an annelated methanediylbisoxy- or ethane-1 ,2-diylbisoxy group, or B5 and VU, together with the amide M-atom of the B substituent, form a five-seven-membered, saturated or unsaturated heterocyclic ring, which may contain one more M-, O- or Z-atom and may be substituted with C 4.dalalkyl , " "Co-halcanediyl-C 1 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or six-membered and contains one or two heteroatoms selected from the group that "" includes M, 5 and O, while the indicated aryl and heteroaryl groups may contain as substituents up to two residues selected and from the group that includes P, SI, Vg, CH 5 , CoH 5 , OH, OSNUz, OSON5, MO», MSH(CHnaz)», CEz, Co» and 435 ЗО2МН», and/or may also carry an annelated methanediylbisoxy- or ethane-1,2-diylbisoxy group, and (ee) В В" independently of each other mean КВ" or Э, for obtaining a medicinal product intended for the treatment of a disease according to any of claims 1-5. 7. The use of benzimidazole according to claim 6, which differs in that B! means a phenyl group, which may contain as substituents up to two residues, independently of each other: 20 selected from the group consisting of E, SI, Vg, C(IMH)MH 5", SIMNIMNEA", C(MH)IMe"B7 . 7 SOMNe?, SOMNON, 587, 5ОВ7, 50287, 502МНо, 80оМНВ", 80О2МВ'В7, МО", МН, МН", MeV, МН!SOMNK I | Kk, where the residues В" and 27 have values that are chosen independently from each other from the following two Below, while the two substituents at 2", if they are in the ortho position relative to each other, can be connected to each other in such a way that they together form a methanediylbisoxy group, F) ethane-1,2 -diylbisoxy group, propane-1,3-diyl group or butan-1,4-diyl group, where B is a mono- or bicyclic sevoaryl group or a mono- or bicyclic 5-10-membered heteroaryl group with 1-2 heteroatoms , selected from the group that includes M, 5 and O, while the specified aryl or heteroaryl group may contain up to three substituents independently selected from the group consisting of E, SI, Vg, HON, XO", XOOSOV, XOoSOoMNeE", XoSOoOv", xXsOov, HemMmoOshe, xHemMmovzv-, XO(MO(SOK Ya), XCOOH, ХСООвВ", ХСОМНо, ХСОМнеЕ?, ХСОМv"В", ХСОМНОН, ХСОМНОВ, хоСоЗ5в, хв", ХО, Х50287, 502МНо, З0О2МНА", 502, МО", ХМНА", ХМ", ХМНЗО»ВХ, ХМ(30287) 508, xMme7507 and 27, and the two substituents at c, if they are in the ortho position relative to each other, because they can be connected to each other in such a way that they jointly form a methanediylbisoxy group, ethane-1,2-dilbisoxy group, propane-1,3-dil or butane-1,4-diyl, Kz means a residue selected from the group consisting of hydrogen, PE, SI, Hg, CH z, CoNv, CEz, CoEv , ON, Ov, MNZO, K 5 | MNSORU, where B" and KZ have the values indicated below, A means C. oralcanediyl, Co-oalkenediyl, Co"oalkyndyl or (Co-5alkanediyl-C3-7cycloalkanediyl-Co-alkanediyl), where in the 5-ene cycloalkyl ring one ring member can be M -atom or O-atom, and in a 6- or 7-ene cycloalkyl ring, one or two ring members can be M- and/or O-atoms, and the ring nitrogen atoms can optionally be replaced by C..alkyl or C . alkanoyl, while in the aliphatic chains indicated above, one carbon atom or two carbon atoms can be replaced by О, МН, 70... M-S. Zalkil or M-S. alkanoyl, B means in each case attached to the C atom of group A a residue selected from the group consisting of СООН, СООВ5, СОМН», СОМНЕЗ and СОМ», where the residues 2 and КУ have values selected independently of each other from the specified below, and Y means 0, while the residues В", 7, В", В? VU independently of each other means a residue selected from the group consisting of C 4 alkyl, C valkenyl, Co valkynyl, where the C atom can be replaced by 0, 5, 50, 505, MH, M-C 4 alkyl or M-C.alkanoyl, (Co-alkanediyl-C3.cycloalkyl), 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 ring M- and/or ring O-atoms, respectively, and ring M-atoms may optionally be replaced by C..alkyl or C.alkano and also includes (Sosalkanedylphenyl) and (Sosalkanediylheteroaryl), where the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group consisting of M, 5 and O, while all of the above alkyl and cycloalkyl o) residues can be replaced by a residue selected from the group that includes CE with, CoEv, OH, O-C. Zalkil, MN", MN-S. Zalkil, MN-S. zalkanoyl, M(S. zalkyl)", (S. zalkiluS. zalkanoyl), COOH, SOMN" and SOO-S. alkyl, and all of the above-mentioned phenyl and heteroaryl groups can contain as substituents up to two residues selected from the group, "-- zr which includes E, СИ, Vg, СНУз, СОН, ОН, ОСН»з, ОСОНв, МО", Ш( CH»z)», CEz, CoEv and 5О»МН», and/or can also carry an annelated methanediylbisoxy or ethane-1,2-diylbisoxy group, or «- Vo and VU together with the amide M-atom of the substituent B form p' seven-membered, saturated or unsaturated "- heterocyclic ring, which may contain one more M-, O- or Z-atom and may be substituted by C 4.alkyl, (Sohalcandiyl-C 4 lalkoxy group), Si. lkoxycarbonyl, aminocarbonyl or phenyl, and - 25 means a phenyl group or a heteroaryl group that is five- or six-membered and contains one or two o heteroatoms selected from the group consisting of M, 5 and O, while phenyl and heteroaryl are indicated groups may contain as substituents up to two residues selected from the group consisting of EC, SI, Vg, CHz, SeNv, OH, OSN»z, OSONv, MO», M(CHnaz)», SEz, Sobv and 5OOMN». , or may also carry an annelated methanediylbisoxy or ethane-1,2-dilbisoxy group. 8. The use of benzimidazole according to item b or 7, which differs in that VZ means hydrogen, and U-A means - with C, a valkyleneoxy group. ;" Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 20, 10.12.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. (ee) - - - 50 - Ф) name) 60 b5