RS71304A - Microlia inhibitors for iterrupting immune reactions inducted by interleukin 12 and ifn$(g) - Google Patents

Abstract

The invention relates to the use of microglia inhibitors for producing medicaments that inhibit the monocyte, macrophage and T cell- induced immune reactions, and to their use for treating T cell-induced immunological diseases and inflammatory reactions that are not T-cell induced.

Description

Inhibitors of microglia to interrupt immune-mediated reactions

interleukin-12 and IFNy

The invention relates to the use of a microglia inhibitor to obtain a drug that inhibits interleukin 12 (IL 12) and interferon y-mediated immune reactions, and its use in the treatment of T-cell-mediated immune diseases and non-T-cell-mediated inflammatory reactions.

The immune system includes numerous cells and tissue complexes, which mainly communicate with each other through soluble factors. It is known that many immune diseases are caused by an imbalance of immunofactors, such as cytokines (Mosmann, and Coffman., Ann. Rev. Immunol. 7: 145 - 173 (1989 Street and Mosmann, FASEB J. 5:171 - 177 (1991); Lucey et al., Clin. Microbiol. Rev. 4: 532 - 562

(1996); Powrie and Coffman, Trends Pharmacol. Sci. 14:164 - 168

(1993); Singh et al., Immunolog. Res., 20: 164 - 168 (1999)). For example, there are many indications of the role of interferon gamma and interleukin 12 in the pathogenesis of autoimmune diseases. Special mention should be made of diseases that are characterized by a T-cell-mediated inflammatory reaction, such as multiple sclerosis, diabetes, chronic inflammatory bowel diseases (Inflammatory Bowel Diseases). Phagocytic cells produce the cytokine interleukin 12 (IL 12), such as macrophages/monocytes, dendrites, B-cells, and other antigen-presenting cells (APCs) and affect both the function of natural killer cells (NK-cells) and those of T-lymphocytes. IL 12 can stimulate the production of Interferon gamma (IFNy) in both cell types. T — lymphocytes can be roughly divided into two categories that are characterized by specific surface antigens (CD4 and CD8): CD4 - positive T - cells (helper-T- cells) and CD8 - positive T - cells (cytotoxic T - cells). CD4 cells can be further divided into T helper cells 1 (Th 1) and T helper cells 2 (Th2). Special Thl-mediated immune responses are associated with the pathogenesis of numerous immunodiseases, especially autoimmune diseases, such as type 1 insulin-dependent diabetes mellitus (IDDM), multiple sclerosis, allergic contact dermatitis, psoriasis, rheumatoid arthritis, chronic inflammatory bowel diseases ("Inflammatory Bowel diseases" - Morbus Crohn, Colitis ulcerosa), lupus - diseases and other collagenoses, as well as acute rejection reactions in allotransplantation ("Host - versus - Graft"-allograft rejection, "Graft — versus - host Disease").

Interleukin 12 is known to play a critical role in the regulation of the Th1 response. In these cells, interleukin 12 induces the production of mainly IL-2, IFNγ, TNFa and TNFf3 (Mosmann and Sad, Immunol. Today 17: 138-146 (1996); Gately et al. Annu. Rev. Immunol. 16: 495-521

(1998)). Especially IFNγ is a potent mediator of the effect of IL-12. Hyperproduction of interferon gamma can, for example, be responsible for MHC II (Major Histocompatibility Complex) associated autoimmune diseases. Additionally, there is ample evidence regarding the pathological role of interferon gamma in allergic diseases as well as sarcoidosis and psoriasis. (1999); Seery JP., Arthritis Res., 2: 437-440 (2000)). In addition, IL-12 and IL-12/IL-18 induced by IFNy from NK cells are important participants in the pathomechanism of inflammatory reactions that are not mediated by T cells (for example, "Toxic Shock Syndrome", endotoxinemia, sepsis and septic shock, ARDS, "first dose response" in antibody therapy, for example OKT3 - given in allotransplantation) (Kum et al., Infect. Immun. 69: 7544 - 7549 (2001); Arad et al., J Leukoc. Biol. 69_: 921 - 927 (2001); Hultgren et al., Arthritis Res. 3: 41 - 47 (2001); Arndt et al., Am..1. Respir.Cell. Moli.Biol. 22: 708-713 (2000); Grohmann et al., J. Immunol. 164; 4197 - 4203 (2000); Muraille et al., Int. Immunol. In:1403 - 1410 (1999)). IL-12 also plays a role in currently unclear pathomechanisms (eg eclampsia) (Hayakawa et al., J. Reprod. Immunol. 47: 121-138 (2000); Daniel et al., Am. J. Reprod. Immunol. 39: 376-380 (1998)).

In addition to interleukins and IFNy, other cytokines are also attributed a role in the pathogenesis of immune diseases and systemic inflammatory reactions, such as TNFa. TNFa has a significant pathological role in infectious diseases (such as sepsis, "toxic shock syndrome" (Tracey et al., Nature 330: 662-664 (1987); Basger et al., Circ. Shock, 27: 51-61

(1989); Hinshaw et al., Circ. Shock, 30: 279 - 292 (1990); Wage A., Lancet, 351: 603 (1998); Cohen et al., Lancet, 351: 1731 (1998) ), but also numerous other immune-mediated diseases.

Corticosteroids are often used for the treatment of diseases mediated by IL-12 and for the suppression of acute syndromes of these diseases, whose side effects during long-term use often lead to discontinuation of treatment.

Activation of microglia is a central step in the inflammatory process of almost all degenerative diseases of the central nervous system. Microglia can remain in an activated state for long periods of time by producing and secreting various inflammatory factors, for example, reactive oxygen/nitrogen intermediates, proteases, cytokines, complement factors, and neurotoxins. This again causes neuronal dysfunction and degeneration. Activation of microglia can be initiated by various stimulators, such as A(3 - peptide (|3 - Amyloid, Araujo, D.M. and Cotman, C.M., Brain Res. 569: 141 - 145

(1992)), prion - protein, cytokine or other cell fragments (Combs, C. K. et al., J. Neurosci. 19: 928 - 939 (1999); Wood, P. L., Neuroinflammation: Mechanisms and Management, Humana Press

(1998).

Compounds, which suppress the activation of microglia after stimulation with Aβ peptide, are described in WO 01/51473, DE-Aktenceichen 101 34 775.8 and DE Aktenceichen 101 35 0.50.3 From this it is also known that benzimidazoles, which suppress the activation of microglia, are used for the treatment of neuroinflammatory diseases, such as AIDS - dementia. amyotrophic lateral sclerosis, Creutzfeld - Jacobs disease, Down's syndrome, diffuse Lewy body disease, Huntington's disease, leukocephalopathy, multiple sclerosis, Parkinson's disease, Pick's disease, Alzheimer's disease, stroke, temporary Lob - epilepsy and tumors.

At the heart of the invention is the problem of making available an agent that is suitable for the treatment of immune diseases, whereby immune diseases are caused by increased production of cytokines, such as IL 12, IFNy and TNFa, without affecting other factors of the immune system, thereby reducing or preventing side effects.

It has now been found that microglial inhibitors surprisingly inhibit the production of IL 12 and IFNy and induce the production of interleukin 10 (IL 10) and therefore find application in drug production for the treatment of some myocyte, macrophage or T-cell mediated immune diseases as well as non-T-cell mediated pathophysiological inflammatory reactions.

As explained above, T-lymphocytes can, after the expression of their surface antigens, be divided into CD4-positive T-cells (T-helper cells) and CD8-positive T-cells (cytotoxic T-cells), and CD4-helper-T-cells (Th-cells) again into T-helper-cells 1 (Thl) and T-helper-cells 2 (Th2) which, among other things, differ in their ability to prevent tolerance. The cytokines IL 12 and IFNγ play an important role in the induction and maintenance of TH 1 cell differentiation. Differentiated Th 1 cells secrete IFNy, interleukin 2 and TNFa/(3. These cytokines activate macrophages and cytotoxic CD 8 positive T-cells.

The invention relates in particular to the application of microglial inhibitors to obtain a drug for stopping the production of IL 12, i.e. IFNy, in cells of monocytic origin, i.e. T-cells and NK-cells. Based on their ability to stop the production of IL-12 and TNFa in monocytes/macrophages/dendrites and the production of IFNy in T-cells and NK-cells, microglia-inhibitors are suitable for the treatment of numerous diseases, which are caused by increased production of cytokines, such as TNFa, p\ IFNy, IL-2 and IL-12, as well as inflammatory diseases, which are not based on neuroinflammation, autoimmune diseases, allergic and autoimmune diseases. infectious diseases, toxin-induced diseases, pharmacologically induced inflammatory reactions as well as pathophysiologically relevant inflammatory reactions of unclear genesis.

Examples of inflammatory and autoimmune diseases are: chronic inflammatory bowel diseases (Inflammtorv Bowel Diseases, Chron's Diseases Ulcerative Celitis) arthritis, allergic contact eczema, psoriasis, pemphigus, asthma, multiple sclerosis, diabetes, insulin-type dependent diabetes mellitus, rheumatoid arthritis, lupus-diseases and other collagenoses, Grave's Disease, Hashimoto's Disease, "Graft-versus-host-Disease" and transplant rejections.

Examples of allergic, infectious, toxin-induced and ischemia-induced diseases are: sarcoidosis, asthma, hypersensitivity pneumonitis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, toxic liver failure, ARDS (acute respiratory distress syndrome), eclampsia, cachexia, acute viral infections (for example, mononucleosis, fulminant hepatitis), organ damage after reperfusion.

An example of pharmacologically induced inflammation with pathophysiological relevance is the "first dose response" after administration of anti-T-cell antibodies such as OKT3.

An example of systemic inflammatory reactions of currently unknown genesis is eclampsia.

According to the invention, suitable microglial inhibitors are compounds which, when stimulated with Aβ-peptide, suppress microglial activity by at least 20% and suppress cytokine activity by at least 30%. The biological properties of microglial inhibitors can be demonstrated according to methods known to those skilled in the art, for example with the assay method described below, and which is described in WO 01/51473.

Particularly suitable microglial inhibitors with the properties described above are benzimidazoles of formula I, their tautomeric and isomeric forms and salts.

In it are

R<1>aryl group or one five- or six-membered heteroaryl group with one or two heteroatoms, selected from the group consisting of N, S and O, wherein the aryl- or heteroaryl group can be independently substituted with up to three residues selected from the group consisting of

F, Cl, Br,

C(NH)NH2, C(NH)NFLR¥, C(NH)NJ?V', C(N/?<*>)NH2

C( NR4) NUR4',C(NH)NflV',

X- OU, X- OR4, X- OCOR4, X- OCONHR4, X- COR4,

X- C(NOH) R4,

X-CN,X-COOH,*-COO^,X-CONH2,X-CONR4R4, X-CONHR4,X-CONHOH

X-SR4, X-SOR4, X-S02R4

S02NH2, S02NH/?', S02N7? V

N02, X-NH2,X- NHR4, X- NR4R4, X- NR4S02R4\

x- m- iso2R4'

X- NHCOR4, X- NHCOOR4, X- NUCONHR4iR<4>,

wherein X is a bond, CH2 or (CH2)2 or CH(CH3)2, wherein the residues R4 and R4 are chosen according to the meanings listed below and

wherein two substituents on R<1>, if they are mutually ortho-positioned, can be interconnected so that together they form a methanediylbisoxy-, ethane-1,2-diylbisoxy-, propane-1,3-diyl- or butane-1,4-diyl group, or a residue selected from the group that includes C1-6-alkyl, (C0-3-alkenedyl-C3-7-cycloalkyl) and C3-6-alkenyl, in which The H-atom can thus be replaced by a heterocyclic residue, selected from the group that includes piperazine, morpholine, piperidine and pyrrolidine, so that a bond is built towards the first N-atom of the heterocyclic residue, while the mentioned alkyl-, cycloalkyl-, alkenyl residues and the heterocyclic residue can be substituted with up to two residues, selected from the group that includes Co-2-alkanediyl-Oi? . C0.2-alkanediyl-NUS02R<7>,C0.2-alkanediyl-N7?<7>SO2/?<7>', C0.2-alkanediyl-CO2H, C0-2-alkanediyl-CO/?<7>, C0.2-alkanediyl-CONH2C0.2-alkanediyl-CONHi?<7>,C0.2-alkanediyl-N/?<7>CON/?<7>/?<7>',

phenyl and one five- or six-membered heteroaryl moiety, wherein the heteroaryl moiety contains one or two heteroatoms selected from the group consisting of N, S and O, wherein further phenyl- and hetero-

the aryl moiety may be substituted with up to two residues selected from the group consisting of F, Cl, Br, C2H5, OH, OCH3, OC2H5, NO2, N(CH3)2, CF3, C2F5 and SO2NFI2 and/or may

to carry one annealed methanediylbisoxy- or ethane-1,2-diylbis-oxy group, whereby the piperazine residue can also be substituted on the second nitrogen atom with R<7>, COR<7> or SO2R, whereby RiR, independently of each other, can further be chosen according to the meanings listed below,

R-Z-R, one aryl group or one five- or six-membered heteroaryl group with up to two heteroatoms, selected from the group consisting of N, S and O, one benzothienyl group or indolyl group, wherein said aryl- or heteroaryl groups can be substituted with up to three residues independently of each other, selected from the group

which includes

F, Cl, Br,

C(NH)NH2, C(NH)NH^^, C(NH)N/?V', C(N/^)NH2

C(NR4)N11R4', C(N R4)NR4R4',

X- OH, X- OR4, X- OCOR4, X- OCONHR4, X- COR4,

X- C(NOH) R4,

X- CN, X- COOU, X- COOR4,X-CONH2,X- CONR4R4', X- CONHR4,X-CONHOH

X-SR4, X-SOR4, X-S02R4

S02NH2, S02NH/^, S02N/?V

N02, X- NH2, X- NHR4, X- NR4R4, X- NR4S02R4,

X- NHS02R4'

X- NHCOR4, X- NUCOOR4, X- NHCONUR4iR<4>,

where X is a bond, CFI2 or (CH2)2 or CH(CH3)2,

wherein the residues R<4> and R<4> are chosen from each other independently according to the meanings given further below and wherein two residues on R<1>, if they are positioned ortho to each other, can be interconnected in such a way that together they form a methanediylbisoxy-, ethane-1,2-diylbisoxy-, propane-1,3-diyl- or butane-1,4-diyl group,

ZNH, N/r , O, S, SO or so2, where Rima in the following

the stated meaning,

R 2 and R 2 , independently of each other, each residue selected from the group consisting of: Ci-4-perfluoroalkyl, Ci-6-alkyl, (Co-3-alkanediyl-C3-7-cycloalkyl), (Co-3-alkanediyl-heteroaryl), wherein the heteroaryl group is five- or six-membered, and contains two heteroatoms, selected from the group containing N, S and O, and wherein the aryl- and heteroaryl groups can each be substituted with up to two residues selected from the group consisting of F, Cl, Br, CH3, C2H5, OH, OCH3, OC2H5, NO2, N(CH3)2, CF3, C2F5 and SO2NH2 and/or may bear an annealed methanediylbisoxy- or ethane-1,2-diylbisoxy group, and further one ring member in a five-membered cycloalkyl ring may be ring-N- or ring-O-atoms and one or two ring members in one a six-membered or seven-membered ring can be ring-N- and/or ring-O-atoms, whereby the ring-N-atoms in the given ring can be substituted with Ci-3-alkyl or Ci-3-alkanoyl,

and RiR2 together with Z form a five- to seven-membered heterocyclic ring, if Z is an N-atom, wherein Zima continues to have the above meaning, wherein further heterocyclic

the ring contains a further N-, O- or S-atom and can optionally be substituted with a residue selected from the group consisting of C 1-4 alkyl, (C 0-3 -alkanediyl-C 1-3 - alkoxy), C 1-4 -alkanoyl, C 1-4 - alkoxycarbonyl, aminocarbonyl and aryl

R<3>mutually independent one or two residues selected from the group comprising

hydrogen,

F, Cl, Br,

OH,OR<4>, OCOR<4>OCONH/^,

COR<4>,

CN, COOH, COOR<4>, CONH2, CONHR<4>, CONHOH,

CONHOi^,

SR<4>, SOR<4>, S02R<4>,S02NH2, SO^UR<4>,S02N/? 4R4'

NO2, NH2, NH/?', NR<4>R<4>'

NHS02R<4>, NR4S02R4\NHS02/?6,NR<4>S02R<6>,

NHCO/?',NHCOO/?', NHCONH/?' iR<4>

wherein the residues R<4>, R4 and R<6> may be selected as further below independently of each other,

A group selected from the group consisting of C1-10-alkanediyl, C2-

10-alkenediyl, C2-10-alkyndiyl and (C0-3-alkanediyl-C3.10-cyclo-alkanediyl-Co-3-alkanediyl) wherein in a five-membered cycloalkyl ring one member of the ring may be ring-N-or ring-O-atoms and one or two members of the ring in one six-membered or seven-membered ring may be ring-N- and/or ring-O-atoms wherein ring-N-atoms in the given

may be substituted with C1-3-alkyl or C1-3-alkanoyl,

wherein in the above aliphatic chains one carbon atom may be replaced by O, NH, N-Ci_3-alkyl, or alkanoyl wherein the alkyl- or cycloalkyl groups may be optionally substituted by a residue selected from the group consisting of -O, OH, OC,.3-alkyl, NH2, NH-d_3-alkyl, NH-Cj.3-alkanoyl, N(C,.3-alkyl)2i N(C1.3-alkyl)(C1.3-alka-

noil),

A substrate selected from the group consisting of COOH,COOR<5>,

CONH2, CONHNH2, CONHft5,CONR<5>R<5>',CONHOH, CONH07?<5>i

tetrazolyl,

always bound to the C-atom of group A

where the residues R<5> and i?5 are mutually independently chosen

nor according to the meanings given below

A Y group selected from the group consisting of O, NH, NR<4>, NCOR<4>

NS02R<4> and NS02R<6>

wherein R<4> and R<6> have the following meanings, where in the preceding residues, the residues R<4>, R<4>, R<5>, Rs and R<6> have the following meanings; in them: R<4> and R4 independently of each other are always a residue selected from the group, which includes CF3, C2F2, C1_4-alkyl, C2.4-alkenyl, C2.3-alkynyl,

and (Co-3-alkanediyl-C3.7-cycloalkyl), whereby in a five-membered cycloalkyl ring one member of the ring may be ring-N- or ring-O-atoms and one or two members of the ring in one six-membered or seven-membered ring may be ring-N- and/or ring-O-atoms, whereby the ring-N-atoms in the given

may be substituted with C1-alkyl or C1-3-alkanoyl,

R<5> and R5 are independently each residue selected from the group consisting of CF3, C2F5, C1-4-alkyl, C2-4-alkenyl, C2-3-alkynyl and (C0-3-alkanediyl-C3-7-cycloalkyl),

wherein in a five-membered cycloalkyl ring one member of the ring can be ring-N- or ring-O-atoms and one or two members of the ring in one six-membered or seven-membered ring can be ring-N- and/or ring-O-atoms, whereby

ring-N-atoms in a given case can be substituted with C1-3-alkyl or C1-3-alkanoyl, as well as (C0-3-alkanediyl-aryl)

and (Ci-3-alkendiyl-heteroaryl), wherein the heteroaryl group is five- or six-membered and contains one or two heteroatoms, selected from the group consisting of N, S and O, wherein all the aforementioned alkyl- and cycloalkyl substituents can be substituted with up to two residues selected from the group consisting of CF3, C2F5, OH, O-Ci.3-alkyl, NH2, NH-C,_3-alkyl, NII-C,.3-alkanoyl,

N(C,_3-alkyl)2, N(C,.3-alkyl)(C,.3-alkanoyl), COOH, CONH2, COO-Ci-3-alkyl and all the aforementioned aryl- and heteroaryl groups with up to two residues selected from the group, which includes F, Cl, Br, CH3, C2H5, OH, OCH3, OC2H5, N02, N(CH3)2, CF2, C2F5 and SO2NH2, and/or they can carry one annealed methanediylbisoxy- or ethane-1,2-diylbisoxy group, or R<5> and R5 together with the N-atom of the amide form a five- to seven-membered, saturated or unsaturated heterocyclic ring which can contain a further N- or O- or S-atom and which can be substituted with Ci_4-alkyl, (Co-2-alkanediyl-Ci_4- alkoxy), C1-4-Alkoxycarbonyl, aminocarbonyl or aryl,

R<6> residue selected from the group consisting of (Co-3-alkanediyl-aryl)

and (Co-3-alkanediyl-heteroaryl), wherein the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group consisting of N, S, and O, and wherein the aryl and heteroaryl groups may be substituted with up to two residues selected from the group consisting of F, Cl, Br, CH3, C2H5, OH, OCH3, OC2H5, N02, N(CH3)2, CF2, C2F5i SO2NH2, and/or can carry one annealed methanediylbisoxy- or ethane-1,2-diylbisoxy group,

R<7> and R<7> are mutually independent R<4> and R6.

Suitable benzimidazoles are those in which the substituent B-A-Y is attached to the 6-position of the benzimidazole.

The proposed invention also includes physiologically tolerable salts and esters of the aforementioned compounds, especially acid salts of nitrogen bases of benzimidazole derivatives according to the invention, further salts of carboxylic acids of derivatives according to the invention with bases as well as esters of carboxylic acid derivatives as well as carboxylic acids, derived from carboxylic acid derivatives, as well as from amides of carboxylic acids.

Benzimidazole derivatives can have one chiral center or more chiral centers, so the compounds can appear in several isomeric forms. Compounds of formula I can also be found as tautomers, stereoisomers or geometric isomers. The invention includes all possible isomers, such as E- and Z-isomers, S- and R-enantiomers, diastereomers, racemates and mixtures of these including tautomeric compounds. All these isomeric compounds are - if not explicitly mentioned - an integral part of the proposed invention. Mixtures of isomers can be separated into enantiomers or E/Z isomers by conventional methods, such as crystallization, chromatography or salt formation.

Heteroaryl groups contained in benzimidazole compounds are built from five or six skeletal forms and may contain one or two heteroatoms. Heteroatoms are oxygen (O), nitrogen (N) and sulfur (S). Examples of heteroaryl groups are pyrrole, thienyl, furanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolylpyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. When heteroaryl groups are part of R<1> or R<2>, the group is attached via the C-atom to the corresponding N-atom of the benzimidazole skeleton, i.e. to the substituent Z.

As aryl residues, the phenyl residue comes into consideration, but also the naphthyl residue. Aryl- and heteroaryl substituents can be arbitrarily attached to the benzimidazole backbone or to another group, for example 1- or 2-naphthyl, or 2-, 3- or 4-pyridinyl.

Alkyl groups can be straight or branched. Examples of alkyl groups are methyl, ethyl, rc-propyl, zzo-propyl, "-butyl, sec-b\ xt\\, tert-b\\ t\\, n-pentyl, se/r-pentyl, tert-pentyl, rceo-pentyl, "-hexyl, se/r-hexyl, heptyl, octyl, nonyl, decyl. The higher homologues also include both linear and branched alkyl groups, meaning especially 2-ethylhexyl for octyl and 3-propylhexyl for nonyl.

Perfluorinated alkyls are primarily CF3 and C2F5.

Alkenyl groups can be straight-chain or branched. For example, vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-bitenyl, 1-methyl-1-propenyl, 2-methyl-2-popenyl and 3-methyl-2-propenyl are alkenyl radicals according to the invention.

Alkynyl groups can be straight-chain or branched. Examples are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl and 2-butynyl

By cycloalkyl groups, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl (corresponds to C3_7-cycloalkyl) are always primarily understood.

As a saturated heterocyclic ring, i.e. as a cycloalkyl with one or more heteroatoms, examples are given: piperidine, pyrrolidine, tetrahydrofuran, morpholine, piperazine, hexahydroazepine, as well as 2,6-Dimethyl-morpholine, N-Phenyl-piperazine, Methoxymethyl-pyrrolidine, whereby the bond can be formed with the C-atom adjacent to the ring through the existing N-atoms of the ring.

In the description of the invention, the mentioned alkanediyl-, alkenedyl-, alkyndiyl- and cycloalkanediyl-residues have the same meaning as alkylene, alkenylene, alkynylene and cycloalkylene. If the number of C-atoms contained in the general formula of alkanediyl radicals is specified and if the value 0 is given as the lower limit of the range of these numbers, such an alkanediyl radical does not exist in that case.

As alkanes, alkenes and alkynes are listed, for example: straight-chain or branched alkanediyl with one to eight carbon atoms, for example methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, further 1-methylethanediyl, 1-ethylethanediyl, 1-methylpropanediyl, 2-methylpropanediyl, 1-methylbutanediyl, 2-methylbutanediyl, 1-ethylbutanediyl, 2-ethylbutanediyl, 1-methylpentanediyl, 2-methylpentanediyl, 3-methylpentanediyl and analogous compounds.

Straight-chain or branched alkenedyl and alkenedyl with two to eight C-atoms are alkenedyl groups, i.e. alkenedyl groups with double and triple bonds in all possible positions as well as with all possible methyl- and ethyl-substitutions. In these residues, one or two C-atoms can always be replaced by O, NH, N-Ci-3-alkyl or N-Ci-3-alkanoyl, whereby the substituted group, with at least two C-atoms, is separated from Y.

If two residues are ortho-positioned, they can form a common ring with neighboring aromatics. Compounds in which N-, O- or S-atoms are attached to olefinic or acetylenic multiple bonds, or in which several N-, O-, S- or halogen atoms are attached to the same aliphatic C-atom or in which N-; O- or S-atoms directly bonded to each other are excluded, as long as such bonds are not explicitly defined, as in the requirement for functional groups or heteroaromatics.

Physiologically tolerable acid salts of the nitrogen bases of the benzimidazole derivatives according to the invention can be obtained with organic and inorganic acids, for example oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, sonic acid, hydrobromic acid, sulfuric acid, p-toluene sulfonic acid acids, methanesulfonic acid.

For obtaining salts of acid groups, especially groups of carboxylic acids, inorganic or organic bases are also suitable, which are known for obtaining physiologically tolerable salts, such as, for example, alkaline hydroxides, especially sodium and potassium hydroxide, alkaline earth hydroxides, such as calcium hydroxide, further ammonia, as well as amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and tris-(hydroxymethyl)methylamine.

All lower monovalent, divalent and trivalent alcohols are suitable for obtaining the ester, especially methanol, ctanol, zso-propanol and/er/-butane! as well as ethylene glycol and glycerin.

Particularly suitable are benzimidazoles of the general formula I, in which, in the following, the residues and groups independently of each other have the following meanings: R<1>phenyl group, which can be, independently of each other, sup substituted with up to two residues selected from the group consisting of:

F, Cl, Br,

C(NH)NH2, C(NH)NH/?', C(NH)N/?V, C(N/?')NH2

C(NR4)NHR4',C(NR4)NR4R4',

OH,OR<4>, OCOR<4>,OCONFLff',COR<4>,

CNOUR<4>,

CN, COOII,COOR<4>,CONH2,CONR<4>R<4>',

CONHR4, CONHOH

SR<4>, SOR<4>, S02R<4>

S02NH2, S02NHjR', S02NR<4>R<4>'

N02, NH2, NHR<4>, NR V, NHCONHR<4> and

R<4>

wherein the residues R<4> and R<4> are chosen from each other independently according to the meanings given further below and wherein two substituents on R<1> can be connected to each other in such a way that together they form a methanediylbisoxy-, ethane-1,2-diylbisoxy-, propane-1,3-diyl- or butane-1,4-diyl group, if they are mutually ortho-positioned

R<2> mono- or bicyclic C6.10-aryl group or mono or bicyclic 5-10-membered heteroaryl group with 1-2 heteroatoms selected from the group of N, S or 0, wherein said aryl- or heteroaryl group can be substituted independently of each other with up to three of the following substituents:

F, Cl, Br,

XOH, XOR<4>, XOCOR<4>, XOCONHR<4>, XOCOOR<4>,

XCOR<4>, XC(NOH)R<4>, XC(NOR<4>)R<4>,XC(NO(COR<4>))R<4>XCOOH, XCOOR<4>, XCONH2, XCONR<4>R<4>, XCONHR<4>

XCONHOH, XCONHOR<4>, XCOSR<4>

XSR<4>, XSOR<4>, X-S02R<4>, S02NH2, S02NHR<4>, S02NR<4>R<4>N02, XNHR<4>, XNR<4>R<4>, XNR<4>(S02R<4>)S02R<4>, XNR<4>S02R<4>i

R<4>,

where two residues on /?<2> if mutually ortho-positioned can be so interconnected that together they form a methanediylbisoxy-, ethane-1,2-diylbisoxy-, propane-1,3-diyl- or butane-1,4-diyl group,

R<3>A residue selected from the group consisting of hydrogen, F, Cl, Br,

CH3, C2H5, CF3, C2F5, OH, OR<4>, NHS02/?6 and NHCOZ?<*>,

wherein R<4> and R<6> have the meanings further specified below,

ACi.10-alkanediyl, C2-10-alkenediyl, C2.10-alkendiyl, (Co-5-alkanediyl-C3-7cycloalkanediyl-C0-5-alkanediyl), whereby in a five-membered cycloalkyl ring one member of the ring can be ring-N-or ring-O- atoms one or two members of the ring in one six-membered or seven-membered cycloalkyl ring can be ring-N- and/or ring-O-atoms, whereby ring-N-atoms in a given case can be substituted with C1-3-alkyl or C1-3-alkanoyl,

whereby in the above-mentioned aliphatic chains one or two carbon atoms can be replaced by O, NH, NCi-3-alkyl, NCi-3-alkanoyl

A base selected from the group consisting of COOH, COOR<5>, CONH2, CONHR<5> and CONR<5>R<5>', always attached to C-atom groups

Oh,

wherein the residues R<5> and R<5> can be chosen independently of each other according to the meanings given further below,

YO

where the preceding residues R4, R4, R<5>, R5 and R6 have the following meanings; in them mean:

R4 and R4same as above

R5 and R5' are mutually independent always one residue, selected from the group that includes Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, whereby one carbon atom can be replaced by O, S, SO, SO2, NH, N-Ci_3alkyl or N-C,.3-alkanoyl, further (Co-3-alkanediyl-C3.7-cycloalkyl), whereby in the five-membered cycloalkyl-ring one a ring member can be a ring-N or a ring-O-atom and in a six-membered or seven-membered cycloalkyl ring one or two members of the ring can each be ring-N- and/or ring-O-atoms, whereby the ring-N-atoms in a given case can be substituted with Ci_3-alkyl or C].3-alkanoyl, as well as (Co-3-alkanediyl-phenyl) and (C0.3-alkanediyl-heteroaryl), whereby is a five-or heteroaryl group six-membered and contains one or two heteroatoms, selected from the group consisting of N, S and O, wherein all the aforementioned alkyl- and cycloalkyl residues can be substituted with a residue selected from the group consisting of CF3, C2F5, OH, O-C,.3-alkyl, NFI2, NH-C,.3-alkyl, NHC-,.3-alkanoyl, N(C,.3-alkyl)2,N(Ci-3-alkyl)(Ci.3-alkanoyl)JCOOH, CONH2i COO-Ci_3-alkyl and all of the aforementioned phenyl- and heteroaryl groups with up to two residues selected from the group consisting of F, Cl, Br, CH3, C2H5, OH, OCH3, OC2H5, N02, N(CH3)2,

CF3, C2F5i SO2NH2i/or can carry an annelated methanediylbisoxy- or ethane-1,2-diylbisoxy group, or RiR together with the N-atom of the amide form a five- to seven-membered, saturated or unsaturated heterocyclic ring which can contain another N- or S- or O-atom and which can be substituted with Ci.4-alkyl, (Co-2-alkanediyl-C 1-4 -Alkoxy), C 1-4-Alkoxycarbonyl, aminocarbonyl, or phenyl

R<6>phenyl- or heteroaryl, wherein the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group consisting of N, S, and O, and wherein the phenyl- and heteroaryl groups may be substituted with up to two residues selected from the group consisting of, F, C1, Br, CH3, C2H5, OH, OCH3, OC2H5, N02, N(CH3)2, CF3, C2F5i S02NH2i/or can also

bear an annealed methanediylbisoxy- or ethane-1,2-diylbisoxy group.

R3 is preferably hydrogen.

The Y-A-group is represented in a favorable form by one C1-8-alkylenoxy group, connected to the benzimidazole skeleton via an O-atom.

Furthermore, the invention relates to pharmaceutical agents containing one or more compounds according to the invention of the general formula I as well as one or more carrier substances. Pharmaceutical agents or compositions of the invention are produced in a known manner with usual solid or liquid carriers or solvents and usual pharmaceutical and technical auxiliary substances corresponding to the desired method of application with suitable dosage. Suitable preparations exist in dosage forms suitable for oral, enteral or parenteral administration, for example. p. (interperitoneal), i.v. (intravenous), i. m. (intramuscular) or percutaneous. Such administration forms are for example tablets, film-coated tablets, dragees, pills, capsules, powders, creams, ointments, lotions, liquids such as syrups, gels, injectable liquids, for example zai. p., i. v., i. m., or percutaneous injections and so on. Furthermore, depot forms are suitable as implantable preparations, as well as suppositories. In addition, individual preparations of derivatives according to the invention are released into the body, but according to their type, gradually or in total amount in a short time.

For oral use, capsules, pills, tablets, dragees and liquids or other known forms of administration can be used as pharmaceutical preparations. In that case, drugs can be formulated in such a way that they release the active substance in a short time and deliver it to the body, or they can have a depot effect, so that a longer-lasting light flow of the active substance into the body is achieved. Dose units may contain, in addition to at least one benzimidazole derivative, one or more pharmaceutically acceptable carriers, for example substances for establishing the rheology of the drug, surfactants, dissolution agents, microcapsules, microparticles, granules, diluents, binders, such as starch, sugar, sorbitol, and gelatin, further fillers such as silicic acid and talc, lubricants, dyes, fragrances and other substances.

Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, for example with inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binding agents such as starch and li gelate, sliding agents such as carboxypolymethylene, carboxymethylcellulose, acetate phthalate-cellulose or polyvinylacetate. Tablets can also consist of several layers.

Dragees can be suitably produced by coating cores obtained analogously to tablets with the usual agents used for dragee coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. At the same time, the dragee membrane can consist of several layers, whereby the auxiliary substances mentioned above can be applied to the tablets.

Capsules containing the active substance can for example be produced by mixing the active substance with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.

The benzimidazole derivatives according to the invention can also be formulated in the form of a solution, which is intended for oral administration and which, in addition to the active benzimidazole derivative, contains as components some pharmaceutical acceptable oil and/or pharmaceutical acceptable lipophiles, surface-active substances and/or some pharmaceutical acceptable hydrophilic, surface-active substances and/or pharmaceutical acceptable water-miscible solvent.

In order to achieve better bioavailability of the active substance according to the invention, the compounds can also be formulated as cyclodextrin clathrates. Therefore, the compounds react with α-, β- or γ-cyclodextrins or their derivatives.

If creams, ointments, lotions and externally applicable liquids are to be applied, these must be composed in such a way that the compounds according to the invention are delivered to the body in sufficient quantity. These administration forms contain auxiliary substances, for example, substances for establishing the rheology of the drug, surfactants, preservatives, dissolution agents, diluents, substances for increasing the permeability of benzimidazole derivatives according to the invention through the skin, dyes, fragrances and skin protection agents, such as conditioners and moisture regulators. Along with the compounds according to the invention, other active substances can also be contained in the drug [Ullmanns Enzyklopadia der technischen Chemie, Band 4 (1953), Seiten 1 — 39; J. Pharm. Sci., 52,918 ff. (1963); H. v. Czetsch-Lindemwald, Hilfsstoffe fur Pharmacie und angrencende Gebiete; Pharm. Ind., 2, 72 ff (1961); Dr. H. P. Fiedler,

Lexikon der Hilfsstoffe fur Pharmacie, Kosmetik und angrencende

Gebiete, Cantor AG, Aulendorf AVurtt, 1971].

The substances can also be used in suitable solutions, for example in a physiological saline solution, as an infusion or injection solution. For parenteral application, the active substance may be dissolved or suspended in a physiologically acceptable diluent. Particularly suitable diluents are oil solutions, such as solutions in sesame oil, castor oil, and cottonseed oil. To increase solubility, solubilizing agents such as benzyl benzoate or benzyl alcohol can be added.

Any liquid carrier in which the compounds according to the invention are dissolved or emulsified can be used for the formulation of the injectable preparation. These liquids often contain substances for regulating viscosity, surface-active substances, preservatives, dissolution agents, diluents and other additional substances with which the solution is made isotonic. Along with benzimidazole derivatives, other active substances can be given.

It is also possible to incorporate the substances according to the invention into a transdermal system and thus apply them transdermally. For this, benzimidazole derivatives are administered in the form of a depot injection or an implant preparation, for example subcutaneously. Preparations of this type can be formulated in such a way as to enable prolonged release of the active substance. For this, known techniques can be used, for example soluble or membrane-based depots. Implants can contain as inert materials, for example, biodegradable polymers or synthetic silicones, for example silicone rubber. The benzimidazole derivatives can further be administered percutaneously, for example by being incorporated into a patch.

The dosage of substances according to the invention of the general formula I is determined by the treating physician and depends, among other things, on the substance that is given, the route of administration, the disease that is being treated and the severity of the disease. The daily dose is not more than 1000 mg, preferably not more than 100 mg, and the dose may be given as a single dose or divided into two or more single doses.

Examination of biological properties

Example1

Activation of microglia

LPS-activated THP-1 cells were used to test substances on macrophages/monocytes. For this, 2.5 x 106 cells/ml are dispersed in RPMI medium (RPMI 1640 + 10%FCS). Compounds according to the invention were added thereto at a concentration of 5 µM and preincubated for 30 minutes. Stimulation of cells followed overnight at 37°C with 1 µg/ml LPS. Then the medium was removed and the amount of TNFα was determined quantitatively. Treatment of cells with substances according to the invention led to a reduction of TNFα-amount of at least 30%.

Example 2

Inhibition of TNFα and IL 12 production in THP-1 cells

Inhibition of cytokine production is shown for example by measuring TNFα and interleukin 12 in THP-1 cells stimulated with liposaccharide (LPS).

For this, 2.5 x 10<6>THP-1 cells (American Type Culture Company, Rockville, Md)/ml RPMI 1640 Medium (Life technologies) 10% FCS (Life Technologies, Cat. Nr. 10270-106) are spread in a 96-well flat bottom cell culture plate (TPP; Product Nr. 9296) (100 uL/well). The compounds according to the invention are added in different concentrations and pre-incubated for 30 min. Pre-dilution of the test substances is performed in the incubation medium. Addition of the test substance follows as a double concentrated solution of the substance (100 uJ/well). Stimulation of cells follows overnight at 37°C with 0.ug/ml LPS (Sigma L2630, from E. Coli Serotwp 0111. B4). Then the medium is washed and the amount of TNFa, ie interleukin 12, is quantitatively determined. To measure TNFa, a commercially available TNFa kit from CIS bio international (Product No. 62TNFPEB) was used. The amount of interleukin 12 was determined using ORIGEN Technologie (IGEN International, Inc. Gaithersburg, Marwland). The calculated IC5 value corresponds to the concentration of the test substance that is required to achieve a 50% inhibition of the maximum production of TNFa or interleukin 12.

The substances show in this test setup an IC50 below 10 µM. With the help of similar methods, the inhibition of IL 12 and TNFa with substances can be presented, also with the use of peripheral blood leukocytes and comparable stimulators.

Example 3

Inhibition of fNFy production by peripheral blood mononuclear cells

For example, measurement of INFy secretion can be used to represent the effect of substances on T-cell activation.

For the isolation of peripheral mononuclear cells, human pure blood is used

(blood collection via Na-citrate S-Monovettcn "Coagulation")

NC/lOml/Sarstedt"). Enrichment of blood cells was performed by density gradient centrifugation: therefore, 15 ml of Hostoraque 1077 Sigma, Cat. Nr.H8880) were placed in LEUCOSEP tubes (Greiner, Cat. Nr.227290) and centrifuged for 30 seconds at 1000 g. Then 15 ml of pure blood was added and centrifuged for 10 min at 1000 g. The upper layer of plasma is pipetted off and the underlying cell layer (mononuclear cells) is poured into a 15 ml test tube (Falcon) and then washed several times with 10 ml of FIBSS balanced solution (without Mg<+> and Ca<+>), Finally, the cell pellet is resuspended in the culture medium RPMI 1640 +25 mM (Life Technologie Cat. Nr. 52400-041, 10% FCS (Life Technologie Cat. Nr. 10270-106), 0.4% penicillin-streptomycin solution (Life Techologie, Cat. Nr. 15140-106) (1 x IO<6>cell/ml). Per 100ul of the cell suspension solution is dispensed into a 96-well flat bottom cell culture plate (TPP, Product No. 9296) and stimulated with 5 µg/ml of phytohemagglutinin. The substances according to the invention are added to it in different concentrations and pre-incubated for 30 minutes. Stimulation of the cells follows during a time period of 48 hours. Then the medium is washed and INFy is quantitatively determined. fNFy was determined with the help of ORIGEN Technologie (IGEN International, Inc. Gaithersburg, Marwland). The calculated IC50 value corresponds to the concentration of the test substance that is required to achieve 50%> inhibition of maximal production FNFy. Treatment of cells with test substances led to a reduction of INFy-quantity of at least 30%. With the help of similar methods, the inhibition of fNFy with substances can be presented, also with the use of specific T-cell activators such as monoclonal anti-CD3-antibodies.

Substance 1

6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid isopropyl ester

Substance 2

6-[[1-(4-Methylphenyl)-2-phenyl-1H-benzimazol-6-yl]oxy]hexanoic acid

Example 4

Induction of IL-10 production by peripheral blood mononuclear cells

Induction of IL-10 production is demonstrated for example by measuring IL-10 in phytohemagglutinin (PHA) or lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells.

To isolate preferred blood mononuclear cells, human pure blood is used (blood collection via Na-citrate S-Monovetten "Coagulation ) 9NC/10ml/Sarstedt"). Enrichment of lymphocytes and monocytes was performed using gradient density centrifugation: for this, 15 ml of Hostoraque-1077 Sigma, Cat. Nr.H8880) in a 50ml LEUCOSEP tube (Greiner, Cat. Nr.227290) and by centrifugation for 30 seconds at 250 g, pushed down through the frits in the tubes. Then 20 ml of pure blood is added and centrifuged for 15 min at 800 g at room temperature. After centrifugation, the layer above is pipetted off (plasma and platelets) and discarded, and the layer below (lymphocytes and monocytes) is transferred to a 50 ml centrifuge tube (Falcon) and then washed 3 times in the culture medium VLE PPMI 1640 (Seromed, No. FG1415) (Centrifugation each time for 10 min at 250 g, room temperature). Finally, the cell pellet is resuspended in the culture medium VLE RPMI 1640(/Seromed), No. FG1415), 10% FCS (Life Technologies Cat.Nr. 16000-044, Low endotoxin, heat-inactivated lh 56°C), 50 u.g/ml penicillin-streptomycin solution (Life Techologie, Cat. Nr. 15140-106) and after counting the cells with the help of trypan-blue staining set to 3x106 cells/ml. 100 ul of the cell suspension solution were distributed on a flat-bottom 96-well cell culture plate (Costar, Produkt Nr.3599). To this was added 100 u.1 of a 3 times more concentrated stimulating solution (3 u.g/ml LPS from E. coliSerotvp 0127:B8; Sigma, Cat. No. L-4516 and 300 ng/ml PHA-L Biochrom KG Cat. Nr. M 5030). The substances according to the invention were added in different concentrations as a 3 times more concentrated solution of the substance (100ul/well). Stimulation of cells takes place at 37°C and 5% C02 for 24 hours. Then the layer above the cell culture was removed and the concentration and IL-10 quantitatively determined. The concentration of IL-10 was determined using commercially available ELISA kits from the company BioSource International (Human IL-10, Cat. NO. KHC0101C). The calculated EC50 value corresponds to the concentration of the test substance required to increase IL-10 production by 50% of the maximum increase. The compounds of the invention increase IL-10 production by peripheral blood mononuclear cells.

Example 5

Inhibition of TNFα and IL-12 HD production by peripheral mononuclear cells

blood

Inhibition of TNFα and IL-12 HD p70-production is shown for example by measuring TNFα and IL-12 HD p70 in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS) and interferon gamma rNFγ. For the isolation of peripheral blood mononuclear cells, pure human blood was used (blood collection via Na-citrate S-Monovetten "Coagulation) 9NC/10ml/Sarstedt"). Enrichment of lymphocytes and monocytes was carried out by means of density gradient centrifugation: for this, 15 ml of Hostoraque 1077 Sigma, Cat. Nr.H8880) in LEUCOSEP tubes (Greiner, Cat. Nr.227290) and by centrifugation for 30 seconds at 250 g, pushed down through the frits in the tubes. Then 20 ml of pure blood is added and centrifuged for 15 min at 800 g at room temperature. After centrifugation, the layer above is pipetted off and discarded, and the layer below (lymphocytes and monocytes) is transferred to a 50 ml centrifuge tube (Falcon) and then washed 3 times in culture medium VLE PPMI 1640 (Seromed, No. FG1415) (Centrifugation each time for 10 min at 250g room temperature). Finally, the cell pellet is resuspended in the culture medium VLE RPMI 1640 /Seromed), No. FG1415), 10% FCS (Life Technologies Cat.Nr. 16000-044, Lovv endotoxin, heat-inactivated lh 56°C), 50 µg/ml penicillin-streptomycin solution (Life Techologie, Cat. Nr.15140-106) and after counting the cells with the help of trypan-blue staining set at 3x106 cells/ml. Each 100 u.l of the cell suspension solution is divided into a cell culture plate with 96 holes with a flat bottom (Costar, Produkt Nr.3599). To this was added 100 ul of a 3 times more concentrated stimulating solution (3 ug/ml LPS of E. coliSerotvp 0127:B8; Sigma, Cat. No. L-4516 and 30 ng/ml LNFy lb, Imukin, Boehringer Ingelheim). The substances according to the invention were added in different concentrations as a 3 times more concentrated solution of the substance (100ul/well). Cell stimulation takes place at 37°C and 5% CO2 for 24 hours. Then the layer above the cell culture was removed and the concentration of TNFα and IL-12 HD p70 was determined using commercially available ELISA kits from BioSource International (TNFa EASIA, Cat. Nr. KACI752) and R& D Systems (Quantikine™ HS IL-12, Cat. Nr. HS120).

The calculated IC50 value corresponds to the concentration of the test substance that is required to achieve a 50% inhibition of the maximum production of TNFa, ie interleukin 12 HD p70.

The compounds according to the invention inhibit the production of TNFα and interleukin 12 HD p70 by peripheral blood mononuclear cells.

Sipstanca 1

6-[[1-(4-methylphenyl)-2-phenyl-1H-benzimazol-6-yl]oxy]hexanoic acid isopropyl ester

Substance 2

6-[[ 1 -(4-Methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid

Claims (8)

1. Application of a microglia-inhibitor to obtain a drug for treatment, monocytes, macrophages or T-cells mediated, immunoreaction. 2. Use according to claim 1 for the treatment of immunoreactions mediated by interleukin 12 (IL 12) and interferon y (INFy) 3. Use according to claim 1 for the treatment of inflammatory reactions that are not mediated by T-cells 4. Application according to requirements For the treatment of autoimmune diseases, inflammatory diseases that are not based on neuroinflammation, allergic and infectious diseases. 5. Use according to claim 4 for the treatment of chronic inflammatory bowel diseases, for example Inflammatory Bowel Diseases, Chron's Diseases, or Ulcerative Colitis, arthritis, allergic contact eczema, psoriasis, pemphigus, asthma, diabetes, type-1 insulin-dependent diabetes mellitus, rheumatoid arthritis, lupus diseases and other collagenoses, Graves' Diseases, Hashimoto's Diseases, "Graft-versus-host Disease" and transplantation rejection, sarcoidosis, asthma, hypersensitivity pneumonitis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, toxic liver failure, ARDS (acute respiratory distress syndrome), eclampsia, cachexia, acute viral infection, organ damage after reperfusion, "first dose response" after administration of anti-T-cell antibodies. 6. Application of a benzimidazole of formula 1, its tautomeric or isomeric forms or salts in which means R<1>aryl group or one five- or six-membered heteroaryl group with with one or two heteroatoms selected from the group consisting of N, S and O, wherein the aryl- or heteroaryl group may be independently substituted with up to three residues selected from the group consisting of F, Cl, Br, C(NH)NH2, C(NH)NHR<4>,C( NH) NR4R4,C(N7?')NH2C( NR4) N¥LR4', C( NH) NR4R4', X- OH, X- OR4, X- OCOR4, X- OCONHR4, X- COR4, X- C(NOU) R4, x- cn, at-cooh, x- coor4, x-conh2, x- conr4r4', x- conhr4,jt-conhoh x-sr4, x-sor4, x-s02r4 s02nh2, s02nh/?', s02n/?vn02, x- nr2, x- nhr4, x- nr4r4, x- nr4s02r4\ x- i<irso2r4' X- NHCOR4, X- NHCOOR4, X- NHCON¥lR4iR<4>, where is the X bond, CH2 or (CH2)2 or CH(CH3)2, whereby the residues R<4> and R<4> are chosen according to the meanings listed below and wherein the two substituents on R<1>, if they are mutually ortho-positioned, can be so interconnected that together they form a methanediylbisoxy-, ethane-1,2-diylbisoxy-, propane-1,3-diyl- or butane-1,4-diyl group, or a residue selected from the group that includes C1-6-alkyl, (C0-3-alkenedyl-C3-7-cycloalkyl) and C3-6-alkenyl, in which the H-atom can thus be replaced by a heterocyclic radical, selected from the group that includes piperazine, morpholine, piperidine and pyrrolidine, so that the bond is built towards the first N-atom of the heterocyclic radical, while the said alkyl-, cycloalkyl-, alkenyl radicals and heterocyclic radical can be substituted with up to two residues selected from the group consisting of C0-2-alkanediyl-O7? . C0-2-alkanediyl-N/?<7>SO2/?<7>', C0.2-alkanediyl-C02H, Co-2-alkanediyl-CO/?<7>, C0-2-alkanediyl-CONH2C0.2-alkanediyl-CONl-lR7, C0-2-alkanediyl-N/?7CONi?7/?7', phenyl and one five- or six-membered heteroaryl moiety, wherein the heteroaryl moiety contains one or two heteroatoms selected from the group consisting of N, S, and O, wherein further phenyl- the heteroaryl group can be substituted with up to two residues, selected from the group consisting of F, Cl, Br, C2H5, OH, OCH3, OC2H5, N02, N(CH3)2, CF3, C2F5i SO2NH2i/or it can carry one annealed methanediylbisoxy- or ethane-1,2-diylbis-oxy group, whereby the piperazine residue can also be on the second nitrogen atom substituted with R<7>, COR<7> or SO2R 7 , where R 7 and ■R 7 are mutually independent, may further be selected according to the following meanings, R-Z-R, one aryl group or one five- or six-membered hetero an aryl group with up to two heteroatoms, selected from the group consisting of N, S and O, one benzothienyl group or an indolyl group, wherein said aryl- or heteroaryl groups can be substituted with up to three residues independently of each other, chosen from the group it includes F, Cl, Br, C(NH)NH2, C(NH)NPLR*, C(NH)Ni?V', C(N/?')NH2C(NR4)NHR4',C(NR4)NR4R4', X- OH, X- OR4, X- OCOR4, AT-OCONHfl', X- COR4, X- C( NOH) R4, AT-CN,AT-COOH,X-COOR4,X-CONH2,X-CONR4R4',X-CONHR4,JVT-CONHOH X-SR4, X-SOR4, X-S02R4 S02NH2, S02NKR<4>, S02N/?V N02,X- NH2, X- NHR4, X- NR4R4', X- NR4S02R4\ X- NRS02R4' X-NHCO^,X-NHCOO^,X-NHCONHi?<¥>iR<4>, where X is the bond, CH2 or (CII2)2 or CH(CH3)2, wherein the residues R<4> and R<4> are chosen from each other independently according to the meanings given further below and wherein two residues of R<1>, if they are positioned ortho to each other, can be interconnected in such a way that together they form a methanediylbisoxy-, ethane-1,2-diylbisoxy-, propane-1,3-diyl- or butane-1,4-diyl group, Z NH, NR 2 , O, S, SO or SO 2 , wherein Rima in the following stated meaning, Rz \ R2 independently of each other each residue selected from the group which includes: Ci_4-perfluoroalkyl, Ci_6-alkyl, (Co-3-alkanediyl-C3-7-cycloalkyl), (Co-3-alkanediyl-heteroaryl), wherein the heteroaryl group is five- or six-membered, and contains two heteroatoms, selected from the group consisting of N, S, and O, and wherein the aryl and heteroaryl groups may each be substituted with one to two residues selected from the group consisting of F, Cl, Br, CH3, C2H5, OH, OCH3, OC2H5, N02, N(CH3)2, CF3, C2F5, and SO2NH2 and/or bear an annealed methanediylbisoxy- or ethane-1,2-diylbisoxy group, and one ring member in a five-membered cycloalkyl ring can be ring-N- or ring-O-atoms and one or two ring members in a six-membered or seven-membered ring can be ring-N- and/or ring-O-atoms, whereby the ring-N-atoms in a given range can be substituted with Ci_3-alkyl or C 1 -alkanoyl, and R 1 R 2 together with They form a five- to seven-membered heterocyclic ring, if Z is an N-atom, wherein Z continues as defined above, wherein the heterocyclic ring further contains a further N-, O-, or S-atom and may optionally be substituted with a residue selected from the group consisting of C1-4-alkyl, (C0-3-alkanediyl-C1-3- alkoxy), C1,4-alkanoyl, C1-4- alkoxycarbonyl, aminocarbonyl and arylR<3>mutually independently one or two residues selected from the group consisting of hydrogen, F, Cl, Br, OH,OR<4>, OCOR<4>OCONUR<4>,COR<4>,CN, COOH,COOR<4>,CONH2, CONHtf', CONHOH,CONFIO^,SR<4>, SOR<4>, S02R<4>,S02NH2, S02NHjR<*>,S02NR<4>R<4>'N02, NH2,NHR<4>,NflVNHS02R<4>, NR<4>S02R<4>', NHS02R<6>, NR<4>S02R<6>,NHCOfl', NHCOO/^, NHCONH/f^ iR<4>, where the residues are R<4> and R<6> may be selected as further below independently of each other, A group selected from the group consisting of C 0 -alkanediyl, C 2 - io-alkenediyl, C2_10-alkynediyl and (Co-3-alkanediyl-C3_io-cyclo-alkanediyl-Co-3-alkanediyl) whereby in a five-membered cycloalkyl ring one member of the ring can be ring-N-or ring-O-atoms and one or two members of the ring in one six-membered or seven-membered ring-N- and/or ring-O-atoms can be ring-N- and/or ring-O-atoms, whereby ring-N-atoms in the given ring can be substituted with C1-3-alkyl or C1-3-alkanoyl, wherein in the above aliphatic chains one carbon atom may be replaced by O, NH, N-Ci_3-alkyl, or alkanoyl wherein the alkyl- or cycloalkyl groups may be optionally substituted with a residue selected from the group consisting of =0, OH, OC,.3-alkyl, NH2, NH-C,.3-alkyl, NH-C,.3-alkanoyl, N(C,.3-alkyl)2i NCC3-alkylKC3-alkanoyl), A substrate selected from the group consisting of COOH,COOR<5>, CONH2, CONHNH2, CONHtf<5>,CONff V,CONHOH, CONHO/?<5>i tetrazolyl, always attached to the C-atom of group A where are they the residues R<5> and R5 are mutually independently selected according to the meanings given further below A Y group selected from the group consisting of O, NH, NR<4>, NCOR<4> NS02R<4> and NS02/?6 wherein R<4> and R<6> have the following meanings, where in the preceding residues, the residues R<4>, R4, R<5>, R5 and R<6> have the following meanings; in them are: /Ti/Tindependently of each other always a remainder, chosen from the group, which includes CF3, C2F2, C1-4-alkyl, C2-4-alkenyl, C2-3-alkynyl, and (Co-3-alkanediyl-C3.7-cycloalkyl), whereby in a five-membered cycloalkyl ring one member of the ring can be ring-N-or ring-O-atoms and one or two members of the ring in a six-membered or seven-membered ring can be ring-N- and/or ring-O-atoms, whereby the ring-N-atoms in the given ring can be substituted with Ci_3-alkyl or CV3-alka-noyl, R<5> and R<5> independently of each other each residue, selected from the group which includes CF3, C2F5, C1-C4-alkyl, C2-4-alkenyl, C2-3-alkynyl and (Co-3-alkanediyl-C3.7-cycloalkyl), whereby in a five-membered cycloalkyl ring one member of the ring can be ring-N- or ring-O-atoms and one or two members of the ring in a six-membered or seven-membered ring can be ring-N- and/or ring-O-atoms, whereby the ring-N-atoms in the given range can be substituted with C1.3-alkyl or C1-3-alkanoyl, as well as (C0-3-alkanediyl-aryl) and (Ci.3-alkendiyl-heteroaryl), wherein the heteroaryl group is five- or six-membered and contains one or two heteroatoms, selected from the group comprising N, S and O, whereby all the aforementioned alkyl- and cycloalkyl substituents can be substituted with up to two residues selected from the group comprising CF3, C2F5, OH, O-d.3-alkyl, NH2, NH-C^-alkyl, NH-C^-alkanoyl, N(C,_3-alkyl)2, N(C1.3-alkyl)(C,.3-alkanoyl), COOFI, CONH2, COO-Ci_3-alkyl and all of the aforementioned aryl- and heteroaryl groups with up to two residues selected from the group consisting of F, Cl, Br, CH3, C2H<5>, OH, OCH3, OC2H5, N02, N(CH3)2, CF2, C2F5 and SO2NH2, and/or they can carry one annealed methanediylbisoxy- or ethane-1,2-diylbisoxy group, or R<5> and R<5> together with the N-atom of the amide form a five- to seven-membered, saturated or unsaturated heterocyclic ring which can contain another N- or O- or S-atom and which can be substituted with Ci_4-alkyl, (C0-2-alkanediyl-C1-4-Alkoxy), C1-4-Alkoxycarbonyl, aminocarbonyl or aryl, R<6> residue selected from the group consisting of (Co-3-alkanediyl-aryl) and (Co-3-alkanediyl-heteroaryl), wherein the heteroaryl group is five- or six-membered and contains one or two heteroatoms selected from the group consisting of N, S, and O, and wherein the aryl and heteroaryl groups may be substituted with up to two residues selected from the group consisting of F, Cl, Br, CFF, C2FI5, OH, OCH3, OC2H5, N02, N(CH3)2, CF2, C2F5i SO2NH2, and/or can carry one annealed methanediylbisoxy- or ethane-1,2-diylbisoxy group, R<7>and R<7>are mutually independent R<4>and R<6>for the production of medicine for treatment a disease according to requirements 1-5. 7. Application of a benzimidazole according to claim 6 characterized in that is R<1>phenyl group, which can be, independently of each other, sup substituted with up to two residues, selected from the group consisting of: F, Cl, Br, C(NH)NH2, C(NH)NHrt', C(NH)Ntf<V>', C(Nfl')NH2C( NR4) NHR4\C(NR<4>JNR<4>R<4>',OH,OR<4>, OCOR<4>,OCONH/?',COR<4>,CNOUR<4>,CN, COOH,COOR<4>,CONH2,CONR<4>R<4>',CONH/?', CONHOHSR<4>, SOR<4>, S02R<4>S02NH2, S02miR<4>,S02NR<4>R<4>'N02, NH2, miR<4>, NR<4>R<4>, NHCONH/?* and R<4>, wherein the residues R<4> and R4 are chosen from each other independently according to the meanings further below and wherein the two substituents on R<1> can be connected to each other in such a way that together they form methanediylbisoxy-, ethane-1,2-diylbisoxy-, propane-1,3-diyl- or butane-1,4-diyl group, if they are mutually orthopositioned Rmono- or bicyclic Ce-io-aryl group or mono- or bicyclic 5- 10-membered heteroaryl group with 1-2 heteroatoms selected from the group of N, S or O, wherein said aryl- or heteroaryl group can be substituted independently of each other with up to three of the following substituents: F, Cl, Br, XOH, XOR<4>, XOCOR<4>, XOCONHR<4>, XOCOOR<4>, XCOR<4>, XC(NOH)R<4>, XC(NOR4)R4,XC(NO(COR4))R4 XCOOH, XCOOR<4>, XCONH2, XCONR<4>R<4>, XCONHR<4>XCONHOH, XCONHOR<4>, XCOSR<4>XSR<4>, XSOR<4>, X-S02R<4>, S02NH2. S02NFIR4, S02NR<4>R<4>N02, XNHR<4>, XNR<4>R<4>, XNR<4>(S02R<4>)S02R<4>, XNR<4>S02R<4>iR<4>, where the two residues of R<2>, if mutually ortho-positioned, may be so interconnected that together they form methanediylbisoxy-, ethane-1,2-diylbisoxy-, propane-1,3-diyl- or butane-1,4-diyl group, R<3>A residue selected from the group consisting of hydrogen, F, Cl, Br, CH3, C2H5, CF3, C2F5, OH, OR<4>, NHS02/?6 and NRCOR<4>, where R4\R6 further have the following meanings, ACi_10-alkanediyl, C2_10-alkenediyl, C2.10-alkanediyl, (C0-s-alk andiyl-C3-7cycloalkanediyl-C0-5-alkanediyl), whereby in a five-membered cycloalkyl ring one member of the ring can be ring-N-or ring-O-atoms and one or two members of the ring in a six-membered or seven-membered cycloalkyl ring can be ring-N- and/or ring-O-atoms, whereby the ring-N-atoms in a given case can be substituted with CV3-alkyl or Ci_3-alkanoyl, wherein in the above-mentioned aliphatic chains one or two carbon atoms can be replaced by O, NH, NCi_3-alkyl, NC,.3-alkanoyl A compound selected from the group consisting of COOH,COO/<T>,CO NH2, CONH/?<5>and CONR<V>, always attached to the C-atom of group A, wherein the residues R<5> and R5 can be chosen independently of each other according to the meanings given further below, YO where in the preceding residues the residues R<4>, R<4>', R<5>, R5 and R<6> have the following meanings; in them mean: R<4>and R4same as further above R5 and R5' are mutually independent always one residue selected from the group which include C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, wherein one carbon atom may be replaced by O, S, SO, SO2, NH, N-C,.3alkyl or N-C,.3-alkanoyl, further (Co-3-alkanediyl-C3-7-cycloalkyl), whereby in a five-membered cycloalkyl-ring one member of the ring can be a ring-N or a ring-O-atom and in a six-membered or seven-membered cycloalkyl ring one or two members of the ring can be each ring-N- and/or ring-O-atoms, whereby ring-N-atoms in a given case can be substituted with C1-3-alkyl or C1-3-alkanoyl, as well as (C0-3-alkanediyl-phenyl) and (Co-3-alkanediyl-heteroaryl), whereby the heteroaryl group is five- or six-membered and contains one or two heteroatoms, selected from the group comprising N, S and O, whereby all the previously mentioned alkyl- and cycloalkyl residues can be substituted with some residue selected from the group consisting of CF3, C2F5, OH, O-C,_3-alkyl, NH2, NH-C,_3-alkyl, NHC-,.3-alkanoyl, N(C,.3-alkyl)2,N(C,.3-alkyl)(C1.3-alkanoyl), COOH, CONH2i COO-CV3-alkyl and all of the aforementioned phenyl- and heteroaryl groups with up to two residues selected from the group consisting of F, Cl, Br, CH3, C2H5, OH, OCH3, OC2H5, N02, N(CH3)2, CF3, C2F5i SO2NH2i/or can carry an annelated methanediylbisoxy- or ethane-1,2-diylbisoxy group, or R5 and R5' together with the N-atom of the amide form a five- to seven-membered, saturated or unsaturated heterocyclic ring which can contain a further atom of N- or S- or O-atom and which can be substituted with C 1-4 -alkyl, (Co-2-alkanediyl-C 1-4 -alkyloxy), C 1-4 -alkoxycarbonyl, aminocarbonyl, or phenyl R<6>phenyl- or heteroaryl group, wherein the heteroaryl group is penta- or six-membered and contains one or two heteroatoms selected from the group consisting of N, S, and O, and wherein the phenyl- and heteroaryl groups may be substituted with up to two residues selected from the group consisting of, F, C1, Br, CH3, C2H5, OH, OCH3, OC2H5, N02, N(CH3)2, CF3, C2F5, and SO2NH2 and/or may also bear annealed methanediylbisoxy- or ethane-1,2-diylbisoxy group. 8. Use of a benzimidazole according to claim 6 or 7, characterized in that R3 is hydrogen and Y-ACi_6-alkylenoxy.