SK10002002A3 - 1,2-Diaryl benzimidazoles for treating illnesses associated with a microglia activation - Google Patents

Abstract

The invention relates to 1,2-diaryl benzimidazoles of general formula (I) and to the use of benzimidazole derivatives for producing medicaments utilized for the treatment and prophylaxis of illnesses that are associated with a microglia activation.

Description

The invention relates to novel benzimidazole derivatives and to the use of benzimidazole derivatives. for the preparation of medicaments for the therapy and prophylaxis of diseases associated with the activation of microglia.

BACKGROUND OF THE INVENTION

Almost all degenerative diseases of the central nervous system are associated with chronic inflammation. The central step of the inflammatory process is the activation of mononuclear phagocytic cells, microglia. It occurs, for example, in Alzheimer's disease by senile plaques, in Kreuzfeld-Jacob disease by prion protein and in ischemic attack by dead cells. Microglia may remain in the activated state for a long period of time during which they produce and secrete various inflammatory factors, such as reactive oxygen or nitrogen intermediates, proteases, cytokines, complement factors and neurotoxins, and these in turn cause neuronal dysfunction and degeneration.

Non-steroidal anti-inflammatory agents (COX II inhibitors) have been described to date for the possible therapy of nerve inflammation (McGeer, PL, Roger, Neurology 42, 447-449 (1992), Rogers, J. Kirby, LC, Hempleman, S.R. Berry, DL, McGeer, PL, Kaszniak, AW, Zalinski, J., Cofield, M., Mansukhani, L., Wilson, P., Kogan, F., Neurology 43, 1609-1611 (1993). Andersen, K., Launer, LJ, Ott, A., Hoes, AW, Breteler, MMB, Hofman, A., Neurology 45, 1441-1445 (1995); Breitner, JCS, Gau, BA, Welsh, KA, Plassman, BL, McDonald, WM, Helms, MJ, Anthony, JC: Neurology 44: 227-232 (1994); The Canadian Study of Health and Aging, Neurology 44, 2073-2079 (1994)), cytokine modulators (McGeer, PL, McGeer, EG: Brain Research Rev. 21, 195-218 (1995); McGeer, E.G., McGeer, PL: CNS Drugs 7, 214-228 (1997); Barone, FC and Feuerstein, GZ: J. Cerebral Blood Flow and Metabolism 19: 819-834 (1999)) and complement cascade inhibitors (Chen, S., Frederickson, RCA and Brund en, K. R., Neurobiol., Aging (1996); McGeer, E. G., McGeer, P.L .: Drugs 55, 739-746 (1998)). These agents inhibit the synthesis or effect of individual inflammatory factors. However, there is a need for compounds that inhibit the earlier stages of the inflammatory process, thereby avoiding the emergence or effect of many inflammatory factors.

SUMMARY OF THE INVENTION

This problem has been solved by the preparation of the benzimidazole derivatives of the formula I, their tautomeric or isomeric forms or salts.

where

R ¹ is a monocyclic or bicyclic C 6-12 -aryl group or a monocyclic or bicyclic 5-10-membered heteroaryl group having 1-4 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein the aryl or heteroaryl group may be independently substituted with up to three of the following substituents:

fluorine atom, chlorine atom, bromine atom, iodine atom, C (NH) NH ₂ , C (NH) NHR ⁴ , C (NH) NR ⁴ R ⁴ , C (NR ⁴ ) NH ₂ , C ( NR ⁴ ) NHR ⁴ , C (NR ⁴ ) NR ⁴ R ⁴ ', 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 ', XCN, XCOCH, XCOOR ⁴ , group

XCONH ₂ , XCONR ⁴ R ⁴ , XCONHR ⁴ ,

XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO ₂ R ⁴ , SO ₂ NH _{2 /} SO ₂ NHR ⁴ , SO ₂ NR ⁴ R ⁴ , NO ₂ , XNH _2, groups XNHR ^4, XNR ⁴ group R ^4, a group of ⁴ XNHSO2R, "XN (SO 2 R ⁴⁾ SO 2 R ⁴ 'SO 2 R ⁴ XNR group ^4, group ⁴ XNHCOR, XNHCOOR group ^4, group XNHCONHR ^4, tetrahydro-2,5 -dioxopyrol-1-yl, 2,5-dihydro-2,5-dioxopyrrol-1-yl, 2,7-dihydro-2,7-dioxoisoindol-1-yl, or R 1 with two substituents on R ¹ , when in the ortho-position to each other, may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl,

R ² is a mono- or bicyclic C _S -i ₀ -aryl group or a mono- or bicyclic 5-10-membered heteroaryl having 1-4 heteroatoms selected from the group comprising nitrogen, sulfur or oxygen, wherein said aryl or heteroaryl group may be be independently substituted with up to three of the following substituents:

fluorine atom, chlorine atom, bromine atom, iodine atom, XOH group, XOR ⁴ group, XOCOR ⁴ group,

XOCONHR ⁴ , XOCOOR ⁴ , XCOR ⁴ , XC (NOH) R ⁴ , XC (NOR ⁴ ) R ⁴ , XC (NO (COR ⁴ )) R ⁴ , XCOOH, XCOOR ⁴ , XCONH ₂ , group

XCONHR ⁴ , XCONR ⁴ R ⁴ , XCONHOH,

XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO ₂ R ⁴ , SO ₂ NH ₂ , SO ₂ NHR ⁴ , SO ₂ NR ⁴ R ⁴ , NO ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , by a group

X NHS ₂ R ^4, XN (SO 2 R ⁴⁾ SO 2 R ^4, a group XNR ⁴ SO ₂ R ^4, tetrahydro-2,5-dioxopyrrole-l-yl, 2,5-dihydro-2,5-dioxopyrrole-l -yl, 2,7-dihydro-2,7-dioxoisoindol-1-yl, or R ⁴ , wherein the two substituents on R ² , when in the ortho position, may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl,

R ³ is one or two substituents, which independently of one another may be:

hydrogen, fluorine, chlorine, bromine, iodine, XOH, XOR ⁴ , XOCOR ⁴ , XOCONHR ⁴ , XOCOOR ⁴ , XCOR ⁴ , XC (NOH) R ⁴ , XC ( NO ⁴ ) R ⁴ , group

XC (NO (COR ⁴ )) R ⁴ ', -; ,.

XCN, XCOOH, XCOOR ⁴ , XCONH2, XCONHR ⁴ , XCONR ⁴ R ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SO2NH2 SO2NHR ⁴ , SO2NR ⁴ R ⁴ ', NO ₂ , XNH ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , XNHSO ₂ R ⁴ , XNR ⁴ SO2R ⁴ ', XN (SO2R ⁴ ) (SO ₂ R ⁴ '), XNHCOR ⁴ , XNHCOOR ⁴ , XNHCONHR ⁴ , tetrahydro-2,5-dioxopyrol-1-yl, 2,5-dihydro-2,5-dioxopyrol-1-yl, 2,7 -dihydro-2,7-dioxoisoindol-1-yl, or R ⁴ , wherein the two R ³ substituents, when in the ortho position, may be joined together to form a methanediylbisoxy group, ethane-1,2- diylbisoxy, propane-1,3-diyl or butane-1,4-diyl,

R ⁴ and R ^4, independently of one another are C ₄ -perfluóralkylová group, a Ci-6-alkyl, _C2-S alkenyl, C ₂ _ _p -alkynyl, C 3-7 -cycloalkyl, (C 3 alkyl C _1-3 -cycloalkyl, C 1-3 -alkyl-C ₆ . _{A 10-} aryl group, a C _1-3 -alkyl-substituted 5-10-membered heteroaryl group having 1-4 nitrogen, sulfur or oxygen atoms, a C _8-10 -aryl group, or a 5-10-membered heteroaryl group having 1-4 nitrogen, sulfur or O, wherein the aryl and heteroaryl groups may be substituted with one or two substituents from the group comprising of F, Cl, Br, CH _3, radical C2H5 / group N0 _2, OCH _3, OC ₂ H ₅ , CF ₃ , or C _{2 - 5} , or may also carry fused methanediylbisoxy or ethane-1,2-diyl-bisoxy, and furthermore, in the 5-membered cycloalkyl ring, one member of the ring may be nitrogen or oxygen and 6 - a member or ¹ i

The 7-membered cycloalkyl ring may be one or two ring members nitrogen and / or oxygen, wherein the ring nitrogen atoms may be optionally substituted with a C 1-3 -alkyl or a C _1-3 -alkanoyl group,

R ⁵ and R ^5, independently of one another are Ci-g-alkyl & al, C 2-6 alkenyl or C 2-6 alkynyl, wherein the carbon atom can be exchanged for ^one of O, S, SO, S02, NH, N-C _1-3 -alkyl or

N-Ci-3 alkanoyl,

_C3 -7 cycloalkyl-C0-3 ^{_ -} alkyl, in which the five membered cycloalkyl ring, which may be one member of the ring is N or O and, six or seven membered cycloalkyl ring, which may be one or two ring members is nitrogen and / or oxygen, the carbon . the ring nitrogen may be optionally substituted with a C 1-3 -alkyl group or a C 1-3 -alkanoyl group,

C6-io aryl, ^_ or a 5-10-membered heteroaryl with 1-4 heteroatoms from the group ATPM N, S and O, wherein the said alkyl, alkenyl and alkynyl may be substituted with one of said cycloalkyl, aryl or heteroaryl groups,

OH, O-C 1-3 -alkyl groups, NH-C 1-3 -alkoanoyl groups, all of the above alkyl and cycloalkyl groups being substituted by up to two substituents selected from the group consisting of CF ₃ , C ₂ F ₅ , NH ₂ groups, NH-C 1-6 -alkyl groups, N (C 1-3 -alkyl) ₂ groups, groups

N (C 1-3 -alkyl) (C 1-3 -alkanoyl), COOH, CONH ₂ , COO-C 1-3 -alkyl, and all the above-mentioned aryl and heteroaryl groups may be substituted with one or two substituents selected from the group consisting of which consists of a fluorine atom, a chlorine atom, a bromine atom, a CH ₃ group, a C ₂ H ₅ group, an NO ₂ group, an OCH 3 group, an OC ₂ H 5 group, a CF 3 group and a C ₂ F 3 group; ethane-1,2-diylbenzyloxy; ',.

or R ⁵ and R ⁵ together with the nitrogen atom form a 5-7 membered heterocycle containing a further oxygen, nitrogen or sulfur and optionally substituted Ci-4-alkyl, C _1-4 alkoxy-Co-2 ^_ alkyl, C 1-4 -alkoxycarbonyl, aminocarbonyl or phenyl,

A is C 10 alkanediyl, _{C2-IO-alkenediyl}

C ₂ _ ₁ o-alkynediyl group, a (Co-5-alkanediyl-C ₃ -7-cycloalkanediyl-Co-5 ^- alkanediyl) wherein the five membered cycloalkyl ring may be one member of the ring is N or O and, six or seven membered cycloalkyl ring, the one or two ring members may be nitrogen and / or oxygen, wherein the ring nitrogen atoms may be optionally substituted by a C 1-3 -alkyl group or a C 1-3 -alkanoyl group, wherein in the above-mentioned aliphatic chains one or two carbon atoms may be substituted with an oxygen atom, an NH group, an N-C 1-3 -alkyl group or an N-C 1-3 -alkanoyl group, and the alkyl or cycloalkyl groups may be substituted with up to two substituents from the group consisting of = O, OH, groups O-C 1-3 -alkyl, NH ₂ groups, NH-C 1-3 -alkyl groups, NH-C 1-3 -alkanoyl groups, N (C 1-3 -alkyl) 2 groups, and groups

N (C 1-3 -alkyl) (C 1-3 -alkanoyl),

B is COOH, COOR ⁵ , CONH ₂ , CONHNH ₂ , CONHR ⁵ , CONR ⁵ R ⁵ , CONHOH, CONHOR ⁵ , SO 3 H, SO ₂ NH ₂ , SO ₂ NHR ⁵ ,

SO ₂ NR ⁵ R ⁵ ', PO ³ H', PO (OH) (OR ⁵ ), PO (OR ⁵ ) (OR ⁵ ), PO (OH) (NHR ⁵ ), PO (NHR ³ ) ( NHR ^5), and terrazolylová group, each of which is attached to each carbon atom of A, or an array of YAB is N (SO ₂ R ⁴⁾ (SO 2 R ⁴⁾ or the group NHSO 2 R ^4, 1,

X is a bond, CH ₂ , (CH ₂ ) ₂ , CH (CH ₃ ), (CH ₂ ) 3, CH (CH ₂ CH 3), CH (CH 3) CH ₂ , CH ₂ CH ( CH ₃ ),

Y is O, NH, NR ⁴ , NCOR ⁴ , NSO ₂ R ⁴ , provided that when Y is NH, NR ⁴ , NCOR ^4, or NSO ₂ R ⁴ , and

(a) R ² contains a nitrogen-containing saturated heterocycle which is not substituted on the imine nitrogen atom by a hydrogen atom, a methyl group, an ethyl group, a propyl group or an isopropyl group, or

b) in the group XNHR ⁴ or XNR ⁴ R ⁴ , optionally present in the substituent R ² , R ⁴ and / or R ⁴ does not mean a C 1-4 alkyl group that simultaneously, B is not a COOH group, a SO ₃ H group, a PO group ₃ H ₂ or tetrazolyl, and R ¹ and R ² are independently C _5-6 -heteroaryl or phenyl, where these are independently unsubstituted, once substituted by C ₆ -alkyl, C 4-perf fluoroalkyl group, a group O-C _1-5 -alkyl, O-C 1-4 -fluoroalkyl, COOH,

COO-C 1-6 -alkyl, CO-C 1-6 -alkyl, CONH ₂ , CONHR ⁴ , NO 2, NH 2, NHCOR ⁴ , NHSO ² R ⁴ or one or two halogen atoms from fluorine, atom chlorine, bromine and iodine, and the following compounds are excluded:

[(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] acetic acid methyl ester, 5 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] pentanoic acid methyl ester, 4- [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] -butanoic acid, 5 - [[1- (4-nitrophenyl) -2-phenyl-1H-benzimidazo-b] methyl ester 6 - [[1- (4-nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 5 - [[1- (4-aminophenyl) -yl] oxy] pentanoic acid methyl ester 2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid, 5 - [[1- [4 - [[(4-chlorophenyl) sulfonyl] amino] phenyl] -2-phenyl-1H-benzimidazole methyl ester 6-yl] oxy] pentanoic acid, methyl 5 - [[1- [4 - [(acetyl) amino] phenyl] -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] pentanoic acid, methyl ester of 5- [ [1- (3-Nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid 6 - [[1- (3-nitrophenyl) -2-phenyl-1H-benzimidazol-6-methyl ester] 5 - [[1- (3-aminophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid methyl ester 5 - [[1- [3- [[(4- chlorophenyl) sulfonyl] amino] phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid 5 - [[1- [3 - [(acetyl) amino] phenyl] -2-phenyl-1H-methyl ester benzimidazol-6-yl] oxy] pentanoic acid.

Physiologically acceptable salts can be formed with inorganic and organic acids such as oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p acid. -toluenesulfonic acid or methanesulfonic acid.

Inorganic and organic bases which form physiologically acceptable salts, such as, for example, alkali hydroxides such as sodium or potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N, are suitable for the preparation of salts of acid groups. -methylglucamine or tris (hydroxymethyl) methylamine.

The term "aryl" refers in particular to an optionally substituted phenyl, biphenyl, naphthyl, indane or fluorenyl group.

The heteroaryl group consists of 5-10 basic backbone atoms and may contain 1-4 heteroatoms. The heteroatoms are an oxygen atom (O), a nitrogen atom (N) and a sulfur atom (S). Examples of monocyclic heteroaryl groups are pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, furazanyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazines. Examples of bicyclic heteroaryl groups are thienoimidazolyl, indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, imidazopyridinyl, purinyl, quinolyl, isoquinolyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl, quinazinyl; , naphthyridinyl and pteridinyl. When aryl or heteroaryl groups are part of the substituent R ¹ , the bond to the nitrogen atom in the benzimidazole proceeds via a carbon atom.

The alkyl groups may be unbranched or branched. Examples are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl, n -hexyl, sec-hexyl, heptyl, octyl, or nonyl.

Preferred as perfluorinated alkyl groups are CF ₃ and C2F 5, and alkanoyl groups are preferably formyl, acetyl or propionyl.

Alkenyl groups may be unbranched or branched. By way of example, the following may be mentioned: vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl or 3-methyl -2-propenyl.

The alkynyl groups may be unbranched or branched. Examples which may be mentioned are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl or 2-butynyl.

Cycloalkyl groups mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A saturated heterocycle responsively a cycloalkyl group with one or more heteroatoms may be, for example, piperidine, pyrrolidine, tetrahydrofuran, morpholine, piperazine, hexahydroazepine or 2,6-dimethylmorpholine, N-phenylpiperazine, methoxymethylpyrrolidine, wherein the ring can be adjacent to a carbon atom, via optionally present nitrogen atoms in the ring.

Examples of alkanes, alkenes, and alkynes for A are the following groups:

an unbranched or branched alkylene group containing 1-8 carbon atoms such as methylene, ethylene, propylene, butylene, pentylene, etc., 1-methylethylene, 1-ethylethylene, 1-methylpropylene, 2-methylene a group, 1-methylbutylene, 2-methylbutylene, 1-ethylbutylene, 2-ethylbutylene, 1-methylpentylene, 2-methylpentylene, ¹³ -methylpentylene, and so on.

Unbranched or branched alkenylene and alkynylene groups containing 2-8 carbon atoms are alkenylene groups, respectively. alkynylene groups with double and triple bonds at all possible positions, as well as with methyl or ethyl substituents at all possible positions. In these groups, with, and may, one or two atoms, carbon may be replaced by an oxygen atom, an NH group, a group ^; N-C _1-3 -alkyl or N-C 1-3 -alkanoyl, wherein the exchanged group is separated by at least two carbon atoms from Y.

If the two residues are in the ortho-position, they can form a common ring with the adjacent aroma. Compounds in which nitrogen, oxygen or sulfur atoms bind to olefinic or acetylenic multiple bonds, or in which several nitrogen, oxygen, sulfur or halogen atoms are bonded to the same aliphatic carbon atom, or in which nitrogen, oxygen or sulfur atoms together they are excluded unless these linkages are explicitly defined, for example, in the functional groups or heteroaromatics enumerated in the claims.

Preferred are benzimidazoles wherein

R ¹ is a monocyclic or bicyclic C 5-12 -aryl group or a monocyclic or bicyclic 5-10-membered heteroaryl group with 1-2 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein said aryl or heteroaryl group may be independently substituted with up to three of the following substituents:

fluorine atom, chlorine atom, bromine atom, XOH group, XOR ⁴ group, XOCOR ⁴ group,

XOCONHR ⁴ , XOCOOR ⁴ , XCOR ⁴ , XCN, XCOOH,

XCOOR ⁴ , XCONH ₂ , XCONR ⁴ R ⁴ , XCONHR ⁴ ,

XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , NO ₂ , XNHR 1, XNR ⁴ R ⁴ , or

R ⁴ , wherein the two substituents on R ¹ , when in orthocoke, may be joined together to form together methanedivicisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1, 4-diyl.

Also preferred are benzimidazoles in which

R ² is a monocyclic or bicyclic C _5-10 -aryl group or a mono- or bicyclic 5-10-membered heteroaryl group with 1-2 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, said aryl or heteroaryl group may be independently substituted with up to three of the following substituents:

a fluorine atom, a chlorine atom, a bromine atom,

XOCONHR ⁴ XOH, XOR ⁴ , XOCOR ⁴ , XOCOOR ⁴ , group group XCOR ⁴ , XC (NOH) R ⁴ , XC (NOR ⁴ ) R ⁴ ', group XC (NO (COR ⁴ )) R ⁴ ', group XCOOH, XCOOR ⁴ , XCONH- _; , group XCONHR ⁴ , XCONR ⁴ R ⁴ ', XCOMHOH, XCONHOR ⁴ ,

XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO ² R ⁴ ,

SO ₂ NH ₂ , SO ₂ NHR ⁴ , SO ₂ NR ⁴ R ⁴ , NO ₂ , XNHR ⁴ , XNR ⁴ R ⁴ ,

X NHS ₂ R ^4, XN (SO 2 R ⁴⁾ SO 2 R ^4, a group XNR ⁴ SO ₂ R ^4, or a group R ^4, where two substituents on R ^2, where they are in the ortho position, can be linked such that, together they form methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl.

Also preferred are the benzimidazoles of formula I wherein

R ³ is one or two substituents, which independently of one another may be:

hydrogen, fluorine, chlorine, bromine, XOH, XOR ⁴ , XOCOR ⁴ , XOCONHR ⁴ , XOCOOR ⁴ , XCOR ⁴ , XC (NOH) R ⁴ , XC (NOR ⁴ ) R ⁴ group

XC (NO (COR ⁴⁾⁾ R ⁴ ', a group XCN group, XSR ⁴ group, XSOR ^4, group XSO2R ^4, a group SO 2 NH _2, group 5 O ₂ NHR', SO ₂ NR ⁴ R ⁴ group, NO ₂ group, XNH ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , XNHSO ² R ⁴ , XNR ⁴ SO ² R ⁴ , XN (SO ² R ⁴ ) SO ² R ⁴ , XNHCOR ⁴ , XNHCOOR ⁴ , XNHCONHR ⁴ , or R ⁴ wherein: two R ³ substituents, when in ortho position to each other, may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1, 3-diyl or butane-1,4-diyl group.

Also preferred are the benzimidazoles of formula I wherein

R ⁴ and R ^4, independently of one another are CF3, C2F5, Ci-4-alkyl, C 2-4 ^_ alkenyl, C 2-4 alkynyl, C _3-6 -cycloalkyl, (C ₃ - _{alkyl-C3-s-cycloalkyl),} phenyl. or a 5-6-membered heteroaryl group having 1-2 nitrogen, sulfur or oxygen atoms, wherein the phenyl group and the heteroaryl group may be substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, CH ₃ group, radical C2H5, OCH _3, OC ₂ H _5, CF _3, or the group of C2F5, and on the 5-membered cycloalkyl ring, which may be one member of the ring nitrogen or oxygen atom and the 6-membered cycloalkyl ring, one or two ring members it may be a nitrogen and / or oxygen atom (s), wherein the ring nitrogen atoms may be optionally substituted with a C 1-3 -alkyl group. or a C _1-3 -alkanoyl group.

Also preferred are the benzimidazoles of formula I wherein

R ⁵ and R ⁵ independently of one another are a C 1-8 -alkyl group, wherein a carbon atom may be replaced by an oxygen atom, an NH group, an N-C _1-3 -alkyl group or an N-C 1-3 -alkanoyl group,

_{C3-T-cycloalkyl-Co-3} -alkyl, wherein the five-membered cycloalkyl ring may be a single ring member · N or O, and six or seven membered cycloalkyl ring may be one or two ring members N and / or O, wherein the ring nitrogen atoms may be optionally substituted by Ci-3 alkyl or C ₁ _ ₃ -alkanoyl, wherein said Ci-6-alkyl may be substituted by one of the mentioned cycloalkyl or a 5-6 membered a heteroaromatic with 1- 2 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, all of the above-mentioned alkyl and cycloalkyl groups being substituted by up to two substituents selected from the group consisting of CF ₃ , OH, OC _1-3 alkyl , and the aforementioned heteroaryl group may be substituted with one or two substituents selected from s that consists of a fluorine atom, a chlorine atom, a CF ₃ group, a CH ₃ group, a C ₂ H ₅ group, an OCH ₃ group, an OC ₂ H _{5 group} , or R ⁵ and R ⁵ together with the nitrogen atom form 5-7- heterocvklus membered, optionally containing a further oxygen, nitrogen or sulfur and may be substituted with Ci_4-alkyl, Ci-4-alkoxy-C 0-2 ^- alkyl, Ci-4-alkoxy-carbonyl, aminocarbonyl or phenyl.

Also preferred are the benzimidazoles of formula I wherein

A is C 10 alkanediyl, _{C2-IO-alkenediyl, C2--ic} · alkynediyl group, (CO-5-alkanediyl-C ₃ -7 ~ cycloalkanediyl-Co-5 alkanediyl), wherein the the five-membered cycloalkyl ring may be one nitrogen or oxygen member of the ring and the six-membered or seven-membered cycloalkyl ring may be nitrogen and / or oxygen, wherein the ring nitrogen atoms may be optionally substituted with a C _1-3 alkyl or C 1-6 alkyl group _3- alkanoyl, wherein in the above-mentioned aliphatic chains one or two carbon atoms may be exchanged for an oxygen atom, an NH group, an N-C 1-3 -alkyl group or an N-C 1-3 -alkanoyl group.

Also preferred are the benzimidazoles of formula I wherein

B is COOH, COOR ³ , CONH ₂ , CONHR ⁵ , CONR ⁵ R ⁵ , CONHOH, CONHOR ⁵ , or a tetrazolyl group, each of which is bound to a carbon atom in Group A.

Particularly preferred are compounds wherein B is COOR ⁵ , CONH ₂ , CONHR ⁵ , or CONR ⁵ R ⁵ .

Also preferred are the benzimidazoles of formula I wherein

X is a bond or a methylene group.

Also preferred are the benzimidazoles of formula (I) wherein

Y is an oxygen atom.

Preferably in particular, R ¹ and R ² independently represent phenyl or a 5-6 membered heteroaryl having 1-2 heteroatoms such as N, O or S, which may be substituted by F, Cl, Br, cyano, C 1-4 -alkyl, C _1-4 -alkoxy, methylenedioxy, C _1-4 -alkylthio, NO ₂ , CF 3, NH ₂ , NH (C _1-3 -alkyl), or N (C 1 -C ₄ -alkyl) -3-alkyl) ₂ .

Particularly preferred values for R ³ are hydrogen, fluorine, chlorine, OH, C 1-4 -alkoxy, C 1-4 -alkyl, NO ₂ , NH ₂ , NH-C _1-4 -alkanoyl, NH-SO ₂ -benzyl or NH-SO ₂ -phenyl, wherein the phenyl radical may be substituted by a fluorine atom, a chlorine atom, a bromine atom, a C 1-4 -alkyl group, a C 1-4 -alkoxy group, a CF ₃ group, or an acetylamino group .

The following benzimidazoles are particularly preferred:

[(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] acetic acid isopropyl ester, 3 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] propanoic acid methyl ester, 2- [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] propanoic acid, 4 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] butanoic acid isopropyl ester, 5 - [( 1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] pentanoic acid, 6 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester, 6 - [(1-isopropyl ester) , 2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanoic acid,

6 - [(1,2-diphenyl-IH-benzimidazol-6-y1) oxy] hexanamide,

N-methoxy-6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanamide,

N- (phenylmethoxy) -6 - [(1,2-diphenyl-IH-benzimidazole · 6-y1) oxy] hexanamide,

N-hydroxy-6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide, 7 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] heptanoic acid methyl ester, 6 - [[1- (3-Nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[2-phenyl-1- [3- (trifluoromethyl) phenyl] methyl ester isopropyl ester 6 - [[2-Phenyl-1- [3- (trifluoromethyl) phenyl] ΙΗ -benzoimidazol-6-yl] oxy] hexanoic acid, methyl ester, 6 - [[2-phenyl-1- [3- (trifluoromethyl) phenyl]] - [1H-benzimidazol-6-yl] oxy] hexanoic acid [1- (3-Cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (3-cyanophenyl) -2-phenyl-1H-benzimidazole-6-isopropyl ester] 6 - [[1- (3-cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (4-cyanophenyl) - 2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (4-cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, 6- methyl ester [f 1- (3-Chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (3-chlorophenyl) isopropyl ester] yl) 2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (4-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 6 - [[1- (4-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester 6 - [[1- (3-methylphenyl) -2-phenyl-1H-methyl ester] 6 - [[1- (3-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, methyl 6 - [[1- (3-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoate, methyl ester 4-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (4-methylphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] ^-1- isopropyl ester 6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, methyl ester 6 - [[1- (3,5- dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (3,5-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] isopropyl ester hexanoic acid, 6 - [[1- (3-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[1- (4-methoxy) methyl ester phenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[1- (3,4-dimethoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] methyl ester hexanoic acid, 6 - [[1- [3,4 '- (methylenedioxy) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[1- [3,4- (methylenedioxy) Phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] methyl ester 6 - [[2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[2-phenyl-1 - ( 3,4,5-trimethoxyphenyl) 1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- [4- (Λ7, N-dimethylamino) phenyl] -2-phenyl-1H-benzimidazole-6, methyl ester 6 - [[1- [4- (Ν, Ν-dimethylamino) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6-isopropyl ester [[1-phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[2- (3-chlorophenyl) -1-phenyl-1H-benzimidazo] methyl ester -δ-yl] oxy] hexane, iso 6 - [[2- (3-chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid propyl ester, 6 - [[2- (4-chlorophenyl) -1-phenyl-1H-methyl] -ethyl ester benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[2- (4-chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, 6 - [[2- (4 6-Methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[2- (4-methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester 6 - [[1-phenyl-2- (4-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 6 - [(1,2-diphenyl-5-nitro-1H-benzimidazole) methyl ester 6 - [(5 - [(4 - [(4-nitro-1 H -benzoimidazol-6-yl) oxy] hexanoic acid, 6 - [(1,2-diphenyl-5-nitro-1H-benzimidazol-6-yl) oxy] hexanoate] Bromophenyl) sulfonyl] amino] 1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] 1,2-diphenyl-1H-benzimidazole methyl ester 6-yl] oxy] hexanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] 1,2-diphenyl-1H-isopropyl ester 6 - [[1,2-diphenyl-5 - [[(3-methylphenyl) sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid, isopropyl ester, benzimidazol-6-yl] oxy] hexanoic acid, isopropyl ester 6 - [[1,2-diphenyl-5 - [[(4-methylphenyl) sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1,2-diphenyl- 5 - [[(4-methoxyphenyl) sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1,2-diphenyl-5 - [[[(4-trifluoromethyl) isopropyl ester] .) phenyl] sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[5 - [[[4- (acetylamino) phenyl] sulfonyl] amino] -1,2-diphenyl- 6-[[5 - [[bis (3-chlorophenyl) sulfonyl] amino] -1,2-diphenyl-6-benzimidazol-6-yl] oxy]-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester 6 - [[1,2-Diphenyl-5 - [(propylsulfonyl) amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid, isopropyl 6 - [[5 - [(benzylsulfonyl) amino] isopropyl ester 2- [2 - [(1,2-di] -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester phenyl-1H-benzimidazol-6-yl) oxy] ethoxy] acetic acid, 3- [2 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] ethoxy] propanoic acid methyl ester, 6- [ethyl ester] [1- (3-Nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[4-acetyl-1- (4-methylphenyl) -2-phenyl] benzimidazole-6-methyl ester 6 - [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester, 6 - [[2-phenyl-1 - [] - yl] oxy] hexanoic acid methyl ester 4- (thiomethyl) phenyl] -1H-benzimidazol-5-yl] oxy] hexanoic acid, 6- [, [2-phenyl-1- [4- (thiomethyl) phenyl] -1H-benzyl] imidazole-6-methyl ester 6 - [[2-phenyl-1- (3-thienyl) -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester, 6 - [[2-phenyl-1 - ( 3-thienyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid, 4 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] butanoic acid methyl ester,

N- (phenylmethoxy) -6 - [[2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanamide,

N, N-dimethyl-6 - [(1,2-diphenyl-6-benzimidazol-6-yl) oxy] hexanamide,

N-isopropyl-6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanamide,

6 - [(1,2-Diphenyl-ΙΗ-benzimidazol-6-yl) oxy] -1-pyrrolidin-1-ylhexan-1-one methyl 5 - [[5 - [[(4-chlorophenyl) sulfonyl] methyl ester amino] 1,2-diphenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] 1- (4-methylphenyl) -2- phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazole methyl ester 6-yl] oxy] hexanoic acid, 6 - [[4- (acetyloxy) -1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[methyl ester] 4-hydroxy-1- (4-methylphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[4-hydroxy-1- (4-methylphenyl) -2-phenyl-1H] 6 - [[7-methyl-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[2-methylbenzimidazol-6-yl] oxy] hexanoate phenyl-1- (3-pyridyl) -1H-benzimidazol-5-yl] oxy] hexanoic acid, 6 - [[2-phenyl-1- (3-pyridyl) -1H-benzimidazol-6-yl] oxymethyl ester Hexanoic acid, 6 - [[2-phen yl-1- (4-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6- [[2- (4-fluorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] methyl ester hexanoic acid, 6 - [[2- (4-methoxyphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxyl] hexanoic acid methyl ester, 6 - [[2- (4-bromophenyl) -1-phenyl- 6 - [[2- [4- (Trifluoromethyl) phenyl] -1-phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid, methyl 6 - [[methyl] -1H-benzimidazol-6-yl] oxy] hexanoate 1-phenyl-2- (benzothien-2-yl) -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1-phenyl-2- (benzothien-2-yl) -1H-benzimidazole- 6-yl] oxy] hexanoic acid, 6 - [[5-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, 6 - [[5-hydroxy 6 - [[5-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole] -1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester 6-yl] oxy] hexanoic acid, 6 - [[5-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester Met oxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1-, methyl ester,

- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6- [[5 - [[(4-chlorophenyl) sulfonyl] amino] 2- (4-fluorophenyl) methyl ester -1- (4-methoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] 1- (4-methoxyphenyl) -2-methyl ester - (4-methoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid, 4 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] methyl ester 24

1- (4-Methoxyphenyl) -2-phenyl-)-benzimidazol-6-yl] oxy] butanoic acid 5 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] 1- (4-methoxyphenyl) methyl ester 2-Phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid, 5 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] 1,2-diphenyl-1H-benzimidazol-6-yl methyl ester ] oxy] pentanoic acid, 6 - [[5 - [[(4- (trifluoromethyl) phenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] methyl ester hexanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] methylamino] -1- (4-methoxyphenyl) -2-phenyl-benz-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6- [[1- (indan-5-yl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (indan-5-yl) -2-phenyl-ΙΗ-] benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (3-fluorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[2- ( 4-nitrophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1-phenyl-2- (3-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester .

N 2 - (cyclopropylmethoxy) -6 - [(1,2-diphenyl-1 H -benzoimidazol-6-yl) oxy] hexanamide,

N-isobutoxy-6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide,

N- (cyclopropylmethoxy) -6- [2-phenyl-1- (3,4,5-trimeroxyfenyl) -lH-benzimidazol-6-yl) oxy] hexanamide,

N 2 -isobutoxy-6- [2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanamide,

N- (2-methoxyethyl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide,

N- (3-methoxypropyl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide,

N-isobutyl-6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide, 6 - [(1,2-diphenyl-6-benzimidazol-6-yl) oxy] -1- morpholin-l-yl-hexan-1-one,

N, N-di- (2-methoxyethyl) -6 - [(1,2-diphenyl-ΙΗ benzimidazo1-6-yl) oxy] hexanamide,

N-isopentyl-6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide,

N- (pyrid-2-yl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide,

N- (pyrid-3-yl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide,

N-isopropyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide,

N, N-dimethyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-ΙΗ benzimidazo1-6-yl] oxy] hexanamide,

N, N-diethyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide,

N-isobutyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide;

N-cyclopropyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide,

AJ-cyclobutyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide,

N-tert-butyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide; 4-Dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] 1- (2-methoxymethyl) pyrrolidin-1-ylhexan-1-one,

N- (3-imidazol-1-ylpropyl) -6 - [[1- (3,4-dimethylphenyl) -2-phenyl-6-benzimidazol-6-yl] oxy] hexanamide,

N- (2-pyridin-2-yl-ethyl) -6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide,

N- (3-methoxypropyl) -6 - [[1- (indan-5-yl) -2-phenyl-1H-benzimidazol-6-yl] oxy] heptanamide, 6 - [[1- (4-methylphenyl) phenyl] methyl ester 2- (3-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[1- (4-methylphenyl) -2- (4-pyridyl) -1H-benzimidazole-6- methyl ester] yl] oxy] hexanoic acid 6 - [[1- (4-methylphenyl) -2- (2-thienyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester Methylphenyl) -2- (3-thienyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[2- (3-indolyl) -1- (4-methylphenyl) -1H-benzimidazole] methyl ester 6-yl] oxy] hexanoic acid, 6 - [[1- (4-methylphenyl) -2- (2-furyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, methyl 6 - [[1- 6 - [[1- (4-Methylphenyl) -2- (5-methyl-2-thienyl) -2- (3-furyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 1 H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[[[1- (4-methylphenyl) -2- (3-methyl-2-thienyl) -1H-benzimidazol-6-yl] oxy] methyl ester ] hexanoic acid.

The benzimidazole derivatives of the invention inhibit the activation of microglia, and therefore may be used to prepare a medicament for the treatment or prophylaxis of diseases associated with microglia. Microglia are understood herein as brain macrophages.

This effect is surprising since the use of benzimidazole derivatives only for the treatment of thromboses and arteriosclerosis has been described so far (EP 0531883, WO 95/07263, EP 0104727;

WO 97/12613), cystitis (WO 97/33873) and diseases associated with β-amyloid peptide (US 5,552,426) and enhanced Ca-channel activation (EP 520200); the effect on microglia has not been known to date.

The invention also relates to the use of the benzimidazole of the formula II

where

R ¹ is a mono- or bicyclic C ₅ -i ₂ -aryl group or a mono- or bicyclic 5-10-membered heteroaryl group with 1-4 heteroatoms selected from the group consisting of N, S or O, where the specified aryl or the heteroaryl group may be independently substituted with up to three of the following substituents:

a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C (NH) NH _{2 group} , a C (NH) NHR ⁴ group, a C (NH) NR ⁴ R ⁴ group, a C (NR ⁴ ) NK 2 group, a C group (NR ⁴ ) NHR ⁴ ', C (NR ⁴ ) NR ⁴ R ⁴ ', XOH, XOR ⁴ , XOCOR ⁴ , XOCONHR ⁴ , XOCOOR ⁴ , XCORp XC (NOH) R ⁴ , XC (NOR ⁴ ) R ⁴ , XC (NO (COR ⁴ )) R ⁴ , XCN, XCOOH, XCOOR ⁴ , XCONH 2, XCONR ⁴ R ", XCONHR ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SO2NH ² , SO2NHR ⁴ , SO2NRR ⁴ , NO ₂ , XNH ₂ ,

XNHR ^4, XNR ⁴ group R ^4, a group XNHSO2R ^4, XN (SO 2 R ⁴⁾ (SO 2 R ⁴⁾ SO 2 R ⁴ XNR group ^4, group ⁴ XNHCOR, XNHCOOR group ^4, group XNHCONHR ^4, tetrahydro-2, 5-dioxo- pyrrol-1-yl, 2,5-dihydro-2,5-dioxopyrrol-1-yl, 2,7-dihydro-2,7-dioxoisoindol-1-yl, or R ⁴ ,

While the two substituents on R ¹ , when in ortho position to each other, may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4- a diyl group,

R ² is a mono- or bicyclic C6-io ^- an aryl group or a mono or bicyclic 5-10-membered heteroaryl having 1-4 heteroatoms selected from the group consisting of N, S or O, wherein said aryl or heteroaryl groups may be independently substituted with up to three of the following substituents:

fluorine atom, chlorine atom, bromine atom, iodine atom, C (NH) NH ₂ , C (NH) NHR ⁴ , C (NH) NR ⁴ R ⁴ , C (NR ⁴ ) NH 2, C (NR) ⁴ ) NHR ⁴ , C (NR ⁴ ) NR ⁴ R ⁴ , 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 , XCN, XCOOH, XCOOR ⁴ , XCONH2, XCONR ⁴ R ⁴ , XCONHR ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ^4, a group XSR ^4, group XSOR ^4, group XSO ₂ R ^4, a group SO2NH2, group SO2NHR ^4, a group SO 2 NR ⁴ R ^4, a group _NO2, XNH _2, groups XNHR ^4, group XNR ⁴ R ^4, a group XNHSO2R ⁴ , XN (SO 2 R ⁴⁾ (SO 2 R ⁴⁾ SO 2 R ⁴ XNR group ^4, group ⁴ XNHCOR, XNHCOOR group ^4, group XNHCONHR ^4, tetrahydro-2,5-dioxo-pyrrol-l-yl, 2,5-dihydro- -2,5-dioxopyrrol-1-yl, 2,7-dihydro-2, 7-dioxoisoindol-1-yl, or R ⁴ , wherein the two substituents on R ² , when in the ortho position, may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane- 1,3-diyl or butane-1,4-diyl,

R ³ is one or two substituents, which independently of one another may be:

hydrogen, fluorine, chlorine, bromine, iodine, 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 ', XCN, XCOOH, XCOOR ⁴ , XCONH2, XCONHR ⁴ , XCONR ⁴ R ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SO2NH ² , SO2NHR ⁴ , SO2NR ⁴ R ⁴ , NO2, XNH 2, XNHR ⁴ , XNR ⁴ R ⁴ , XNHSO2R ⁴ , XNR ⁴ SO ₂ R ⁴ , XN (SO ₂ R ⁴ ) (SO ₂ R ⁴ ), XNHCOR ⁴ , XNHCOOR ⁴ , XNHCONHR ⁴ , tetrahydro-2,5-dioxopyrol-1-yl, 2,5-dihydro-2, 5-dioxo-pyrrol-1-yl, 2,7-dihydro-2,7-dioxoisoindol-1-yl, or R ⁴ , wherein the two R ³ substituents, when in ortho position to each other, may be together linked together to form meta iylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl,

R ⁴ and R ^4, independently of one another are C and perfluoro-fluoroalkyl group, a Ci-g-alkyl, _C2 _6-alkenyl, C ₂ -6-alkynyl, C3-7-cycloalkyl, (Ci_3- alkyl, C3 _{7-cycloalkyl),} C 3 -C ₆ alkyl -i ₀ -aryl, C ₃ -alkylsubstituovaná 5-I0-membered heteroaryl with 1-4 N, s or O, C6-io ^- aryl or 5-10-membered heteroaryl having 1-4 nitrogen, sulfur or oxygen atoms, wherein the C 8-10 aryl and heteroaryl groups may be substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, a CH ₃ group, a C ₂ H ₅ group, a NO ₂ group, an OCH ₃ group, an OC ₂ H ₅ group, a CF 3 group, or a C ₂ F _{5 group} , or they may also carry an enriched methanediylbisoxy group or ethane-1,2-diyl in a five membered cycloalkyl ring, one ring member may be a nitrogen atom or an oxygen atom, and in a six or seven membered cycloalkyl ring, one or two ring members may be nitrogen and / or oxygen, wherein the ring nitrogen atoms may be optionally substituted with a C _1-3 -alkyl or a C _1-3 -alkanoyl group,

R ⁵ and R ^5, independently of one another are H, CH-S-alkyl group, a C 2-6 alkenyl group, or ^_ a C 2-6 ^- alkynyl, wherein one carbon atom can be exchanged for O, S, SO, SO2, NH, N-C1-3-alkyl or N-C1-3-alkanoyl,

A C 3 -C 3 -cycloalkyl-C ^0-3 alkyl group wherein one of the five-membered cycloalkyl ring may be nitrogen or oxygen and the six-membered or seven-membered cycloalkyl ring may be nitrogen and / or oxygen, wherein the nitrogen atoms in the ring may be optionally substituted with a C _1-3 -alkyl group or a C 1-3 -alkoanoyl group,

A C 6-10 -aryl or 5-10-membered heteroaryl group having 1-4 heteroatoms selected from nitrogen, sulfur and oxygen, wherein said alkyl, alkenyl and alkynyl chains may be substituted with one of said cycloalkyl, aryl or heteroaryl groups, wherein all of the foregoing alkyl and cycloalkyl groups may be substituted with up to two substituents selected from the group consisting of CF ₃ , C ₂ F ₅ , OH, O-C _1-3 -alkyl, NH ₂ , NH -C 1-3 -alkyl, NH-C 1-3 -alkanoyl, N (C 1-3 -alkyl) 2, N (C 1-3 -alkyl) (C 1-3 -alkanoyl), COOH, CONH ₂ , COO-C 1-3 -alkyl, and all of the foregoing aryl and heteroaryl groups. may be substituted by one or two substituents selected from the group consisting of fluorine, chlorine, bromine, CH ₃ , C ₂ H ₅ , NO ₂ , OCH ₃ , OC ₂ H ₅ , CF ₃ and the C ₂ F ₅ groups, or may also carry a fused methanediylbisoxy or ethane-1,2-diyl-bisoxy group, or R ⁵ and R ⁵ together with the nitrogen atom form a 5-7 membered heterocycle which may contain an additional oxygen, nitrogen atom or S and may be substituted "C-4-alkyl, C1-4-alkoxy-Co-2 ^- alkyl, Ci_4-alkoxy-carbonyl, aminocarbonyl or phenyl,

A is C 10 alkanediyl, C ₂ ^_-IO alkenediyl, C 2 ^_ io alkynediyl group, (CO-p-alkanediyl-C 3-7 cycloalkanediyl-Co-5 alkanediyl), (CO-5 -alkándiylarylén-Co-5 alkanediyl), (CO-5-alkanediyl-heteroarylene-C ₀ -5 alkanediyl), wherein the aryl and heteroaryl groups can be substituted by one or two substituents from the group of F, Cl, Br , methyl, ethyl, NO ₂ , OCH ₃ , OC ₂ H ₅ , CF ₃ , C ₂ F ₅ , wherein in the five-membered cycloalkyl ring, one of the ring members may be nitrogen or oxygen and in the six-membered or seven-membered ring the cycloalkyl ring may be one or two ring members nitrogen and / or oxygen, the ring nitrogen atoms optionally being substituted by a C _1-3 -alkyl or a C _1-3 -alkanoyl group, wherein in the aliphatic chains mentioned above com herein, one or two carbon atoms may be exchanged for O, NH, NR ^4, skupinuNCOR ⁴ or an NSO2R ^4, and the alkyl and cycloalkyl groups can be substituted with up to two substituents from the group consisting of F, the group OH, OR ⁴ , OCOR ⁴ , = O, NH 2, NR ⁴ R ⁴ , NHCOR ⁴ , NHCOOR ⁴ , NHCONHR ⁴ , NHSO ₂ R ⁴ , SH and SR ⁴ ,

B is hydrogen, OH, OCOR ⁵ , OCONHR ⁵ , OCOOR ⁵ , COR ⁵ , C (NOH) R ⁵ ,

C (NOR ⁵ ) R ⁵ , C (NO (COR ⁵ )) R ⁵ , COOH, COOR ⁵ , CONH2, CONHNH2, CONHR ⁵ , CONR ⁵ R ⁵ , CONHOH, CONHOR ⁵ , SO 3 H, SO ₂ NH ₂ , SO ₂ NHR ⁵ , SO ₂ NR ⁵ R ⁵ , PO ³ H, PO (OH) (OR ³ ), PO (OR ⁵ ) (OR ⁵ ), PO ( OH) (NHR ^5), PO (NHR ⁵⁾ (NHR ^5), or tetrazolyl, each of which is linked to a carbon atom of A, or a whole group of YAB is N (SO ₂ R ⁴⁾ (SO 2 R ⁴ ) or NHSO2R ⁴

X is a bond, CH ₂ , (CH ₂ ) ₂ , ΟΗ (ΟΗ ₃ ), (CH ₂ ) ₃ , ΟΗ (ΟΗ ₂ ΟΗ ₃ ), ΟΗ (ΟΗ ₃ ) ΟΗ ₂ , ΟΗ ₂ ΟΗ (ΟΗ ₃ ),

Y is a bond, an oxygen atom, a sulfur atom, an SO group, a group

SO ₂ , NH group, NR ⁴ group, NCOR ⁴ group or NSO ₂ R ^{4 group} , for the preparation of a medicament for the treatment or prophylaxis of diseases associated with the activation of microglia.

In addition to the novel compounds of the formula I, the formula II also comprises the known compounds (EP 0 531 883, DE 4330959). The compounds according to the invention of the general formula II suppress the activation of microglia. This effect is new, even for the compounds already known.

Preferred is the use of compounds of formula II wherein • "1 · 1, ¹

R ¹ is a monocyclic or bicyclic aryl group or a monocyclic or bicyclic 5-10-membered heteroaryl group with 1-2 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein said aryl or heteroaryl group may be independently substituted with up to with the following three substituents:

fluorine atom, chlorine atom, bromine atom, XOH group, XOR ⁴ group, XOCOR ⁴ group,

XOCONHR ⁴ , XOCOOR ⁴ , XCOR ⁴ , XCN, XCOOH, XCOOR ⁴ , XCONH2, XCONR ⁴ R ⁴ ', XCONHR ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , NO 2, XNHR ⁴ , XNR ⁴ R ⁴ , or R ⁴ , wherein the two substituents on R ¹ , when in the ortho-position to each other, may be joined together to form a methanediylbisoxy group, ethane-1,2- diylbisoxy, propane-1,3-diyl or butane-1,4-diyl.

Also preferred is the use of compounds of formula II wherein

R ² is a mono- or bicyclic aryl group or a mono cyclic or bicyclic. A 5-10-membered heteroaryl group having 1-2 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein said aryl or heteroaryl group may be independently substituted with up to three of the following substituents:

fluorine, chlorine, bromine, 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 , XCN, XCOOH, XCOOR ⁴ , XCONH2, XCONR ⁴ R ⁴ , XCONHR ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SO2NH ² , SO2NHR ⁴ , SO2NR ⁴ R ⁴ , NO ₂ , XNH ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , XNHSO2R ⁴ , XN (SO2R ⁴ ) ( SO ² R ⁴ ), XNR ⁴ SO ² R ⁴ , XNHCOR ⁴ , XNHCOOR ⁴ , XNKCONHR ⁴ , or R ⁴ , wherein the two substituents on R ² , when in ortho position, may be joined together such that they form methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl

Or a butane-1,4-diyl group.

Also preferred is the use of compounds of formula II wherein

R ³ is one or two substituents independently of one another hydrogen, fluorine, chlorine, bromine, 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 ', XCN, XSR ⁴ , XSOR ⁴ , XSO ₂ R ⁴ , SO2NH ₂ , SO2NHR ^4, a group SO 2 NR ⁴ R ^4, a group N0 ₂ group, XNH _2, XNHR ⁴ group, the group XNR ⁴ R ^4, a group XNHS02R ^4, XNR ⁴ S02R group ^4, group

XN (SO ₂ R ⁴ ) (SO ₂ R ⁴ group XNHCOR ⁴ , group XNHCOOR ⁴ , group

XNHCONHR ⁴ or R ⁴ , wherein the two R ³ substituents, when in ortho position to each other, may be joined together to form methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane -1,4-diyl.

Also preferred is the use of compounds of formula II wherein

R ⁴ and R ^4, independently of one another are CF _3, C ₂ F _5, C 4 -alkyl, C _2-4 -alkenyl, C ₂ _ ₄ -alkynyl, _C3 6-cycloalkyl, group (C ₃ -alkyl-C 3-6 cy ¹ 'I' kloalkyi), ^1-C 3 alkylaryl, C ₃ -alkylheteroarylová group, a monocyclic aryl or a 5-6 membered heteroaryl group having 1-2 carbon nitrogen, sulfur or oxygen, wherein the aryl and heteroaryl groups may be substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, CH ₃ group, C ₂ H ₅ group, NO ₂ group, OCH ₃ group, OC ₂ H ₅ , CF ₃ , or C ₂ F ₅ , or may also carry a fused methanediylbisoxy or ethane-1,2-diyl-bisoxy group, wherein in the five-membered cyclo-35 alkyl ring one of the ring members may be nitrogen or oxygen and in the six membered cycloalkyl ring may be one or two lenm ring N and / or O, wherein ring nitrogen atoms can be optionally substituted by Ci-3-alkyl group or a C ₃ -alkanoyl.

Also preferred is the use of compounds of formula II wherein

R ⁵ and R ⁵ independently of one another are a C 1-8 -alkyl group, wherein a carbon atom may be replaced by an oxygen atom, an NH group, an N-C 1-3 -alkyl group or an N-C 1-3 -alkanoyl group, a C 3-7 group -cycloalkyl-C 0-3 -alkyl wherein one of the five-membered cycloalkyl ring may be nitrogen or oxygen, and the six-membered or seven-membered cycloalkyl ring may be one or two ring members of nitrogen and / or oxygen, wherein the ring nitrogen atoms may be be optionally substituted with a C 1-3 -alkyl group or a C 1-3 -alkanoyl group, wherein said C 1-8 -alkyl moiety may be substituted by one of said cycloalkyl groups or also by one of 5-6-membered heteroaromates having 1-2 heteroatoms selected from a group consisting of a nitrogen, sulfur or oxygen atom;

wherein all of the foregoing alkyl and cycloalkyl groups may be substituted with up to two substituents selected from the group consisting of CF 3, OH, OC ₃ -alkyl, and the above heteroaryl groups may be substituted with one or two substituents selected from the group consisting of: a group consisting of a fluorine atom, a chlorine atom, a CF 3 group, a CH ₃ group, a C ₂ H = group, an OCH ₃ group and an OC ₂ H _{5 group} , or R ⁵ and R ⁵ 'together with the nitrogen atom form 5-7- olefins heterocycle containing a further oxygen, nitrogen or sulfur and is optionally substituted C ₄ -alkyl, C ₄ -alkoxy-C _0-2 -alkyl, q-Cu-alkoxycarbonyl, aminocarbonyl or phenyl .

Equally preferred is the use of compounds of formula II wherein:

A is C ^_ also aikándiylová group, a C2-io ^_ alkenediyl group, a C2-io ~ alkynediyl group, (CO-5-alkanediyl-C 3-7 cycloalkanediyl-Co_5 alkanediyl) group, or (Co-5-alkándiyl- heteroarylene-Co-s-alkanediyl), where the optionally present in the heteroaryl group may to be substituted by one or two substituents from the group of F, Cl, Br, CH3, C2H5 group, N0 _2, OCH _3, OC ₂ H ₅ , CF 3 and c ₂ f ₅ , wherein in the five-membered cycloalkyl ring one member of the ring may be a nitrogen or oxygen atom and in the six-membered or seven-membered cycloalkyl ring one or two of the ring member may be a nitrogen and / or oxygen atom; the ring may be optionally substituted with a C _1-3 -alkyl group or a C 1-3 -alkanoyl group, wherein in the aliphatic chain one or two carbon atoms may be replaced by an oxygen atom, an NH group, for N-C _1-3 -alkyl, N-C 1-3 -alkanoyl, or NSO ₂ C 1-3 -alkyl, and the alkyl or cycloalkyl moieties may be substituted with up to two fluorine atoms or one of the substituents of the group consisting of OH groups, Ο-Οχ-3-alkyl groups, O-C 1-3 -alkanoyl groups, atom = O, NH ₂ groups, NH-C _1-3 alkyl groups, ¹ N (C 1-3 alkyl) 2 groups , NHCi-3-alkartoyl,. groups

N (Ci-3-alkyl) (Οχ-3-alkanoyl), of NHCOOC 3-alkyl group NHCONHC-3-alkyl group NHSO ₂ C ₃ -alkyl groups, and SH groups Science 3 -alkyl.

Also preferred is the use of compounds of formula II wherein

B is hydrogen, OH, OCOR ⁵ ,

OCONHR ⁵ , OCOOR ⁵ , COOH, COOR ⁵ ,

CONH ₂ , CONHR ⁵ , CONR ⁵ R ⁵ ', CONHOH, CONHOR ⁵ , or a tetrazolyl group, each of which binds to a carbon atom of Group A.

Also preferred is the use of compounds of formula II wherein

X is a bond or a CH ₂ group.

Also preferred is the use of compounds of formula II wherein

Y is a bond, an oxygen atom, a sulfur atom, an NH group, an NR ⁴ group, an NCOR ⁴ group, or an NSO ₂ R ^{4 group} .

Example 307 illustrates how inhibition of microglia activation can be measured. Activation of microglia can be achieved by various stimulators, such as β-peptide (β-amyloid; Araujo, DM and Cotman, CM, Brain Res. 569, 141-145 (1992)), prion protein, cytokines, or cellular Fragments (Combs, CK et al. J. Neurosci. 19, 928-939 (1999); Wood, PL Neuroinflammation: Mechanisms and Management, 1998, Humana Press). For example, the compound of Example 49, 6 [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, shows an inhibition IC 50 = 0.75 μΜ.

Stimulation of β-peptides corresponds to the pathophysiological situation in Alzheimer's disease. In this assay, during the stimulation of β-peptides, the compounds of the invention showed inhibition of microglia activation. Suppression of microglia activation by the compounds of the invention results in a strong reduction in the production and secretion of cytokines such as β and TNFα (as measured by ELISA and mRNA expression analysis) and reduced secretion of the reactive oxygen / nitrogen intermediate. At the same time, several inflammatory factors are also suppressed.

The in vivo efficacy of the compounds of the invention has been demonstrated in the MCAO rat model. This model simulates a stroke condition.

The compounds of the invention reduce microglia activation, which occurs in acute damage to the animal brain.

The invention also relates to the use of the compounds according to the invention of formula I and formula II for the preparation of a medicament for the treatment or prophylaxis of diseases associated with the activation of microglia. Examples of such diseases are dementia due to AIDS, amyotrophic lateral sclerosis, Creuzfeld-Jacob disease, Down's syndrome, dementia due to diffuse inclusion of Lewy bodies in the cerebral cortex, Huntington's disease, leukoencephalopathy, multiple sclerosis, Farkinson's disease, Farkinson's disease, Farkinson's disease, Farkinson's disease temporal lobe and tumors.

The invention further relates to pharmaceutical compositions comprising one or more compounds of the formula I according to the invention and one or more carriers. Pharmaceutical compositions respectively. the formulations of the invention are prepared in a conventional manner using conventional solid or liquid carriers or diluents and conventional pharmaceutical and technical ingredients, according to the desired application type, in suitable dosages. Preferred are preparations which can be administered orally, enterally or parenterally. Such dosage forms are, for example, tablets, coated tablets, dragees, pills, capsules, powder or depot forms such as suppositories. Suitable tablets may be prepared by combining the active ingredient with known adjuvants, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrating agents such as corn starch, ^1, 1, and alginic acid, binding agents such as starch "or gelatin; lubricants such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of several layers.

Similarly, dragees can be prepared. Cores prepared analogously to tablets are coated with conventional coatings, such as polyvinylpyrrolidone or shellac, acacia, talc, titanium oxide, or sugar. The inside of the dragee can also consist of several layers, the additives already mentioned for tablets being used. For example, capsules containing the active ingredients can be prepared by mixing the active ingredient with milk sugar or sorbitol and filling the gelatin capsules with the mixture.

The compounds of the invention may also be used in suitable solutions, such as saline, for infusion or injection.

Particularly suitable for parenteral administration are oily solutions, such as those in sesame oil, castor oil and cottonseed oil. Solubilizers such as benzyl benzoate or benzyl alcohol may be added to increase solubility.

The compounds of the invention may also be incorporated into the transdermal system and thus administered transdermally.

The dosage of the compounds according to the invention of formula I and formula II will be determined by the attending physician and depends inter alia on the compound to be administered, the route of administration, the disease to be treated and its severity. The daily dose of the compound does not exceed 1000 mg, preferably not more than 100 mg, and can be administered in a single dose or in 2 or more divided doses per day.

The compounds of formula I may exist as tautomers, stereoisomers or geometric isomers. The invention also relates to all possible isomers such as E- and Z-isomers, S- and R-enantiomers, diastereoisomers, racemates and mixtures thereof, including tautomeric compounds ¹ . '

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

The compounds of the invention may be prepared analogously to known procedures, for example as described in EP 531 883. If the preparation of the starting compounds is not described, the starting compounds are known and commercially available, or prepared analogously to the procedures described herein. The following describes the preparation of some precursors, intermediates and products.

DETAILED DESCRIPTION OF THE INVENTION

For example, the following methods are used to prepare the compounds of the invention:

General Regulation 1

Reduction of nitro groups, hydrogenation of olefinic double bonds and hydrogenolytic cleavage of benzyl ethers

The reduced compound is dissolved in ethyl acetate, tetrahydrofuran, methanol or ethanol or a solvent mixture and hydrogenated at atmospheric pressure to 2-5% (based on nitro compound) of palladium on carbon (10%). After the hydrogen uptake is complete, the catalyst is filtered off with suction, washed with ethyl acetate, methanol or ethanol and the filtrate is concentrated in vacuo. The crude product is generally used without further purification.

General Regulation

Reduction of nitro groups

Dissolve 9.2 g of ferrous sulphate in 30 ml of water and add 9 ml of ammonia solution. To this was added dropwise a solution of 3.6 mmol of the nitro compound in 100 ml of ethanol, and the suspension was stirred vigorously at 70 ° C for 1 hour. The mixture is allowed to settle, the solid is filtered off, the filtrate is concentrated to near dryness, water is added and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated in vacuo. The obtained amino compound is further processed in the crude state.

General Regulation

Cyclization to the benzimidazoles by reaction with orthoesters of the 1,2-diaminobenzene derivative mmol is dissolved in 25 ml of ethanol. To this solution was added dropwise 47 ml of 0.8M ethereal hydrogen chloride solution, the mixture was stirred for 30 minutes and then evaporated to dryness in vacuo. The evaporation residue is dissolved in 230 ml of methanol and 6 ml of trimethyl orthobenzoate or an equivalent amount of another orthoester is added. The mixture was heated at reflux for 2-8 hours, poured into saturated sodium bicarbonate solution, cooled, extracted three times with ethyl acetate, the combined extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by crystallization or silica gel column chromatography.

General Regulation

Cyclization to benzimidazoles with iminoester hydrochlorides

1.2 mmol of the 1,2-diaminobenzene derivative are dissolved in 5 ml of tetrahydrofuran, 1.5 mmol of benzimidate hydrochloride are added and the mixture is stirred for 15 hours. Saturated sodium bicarbonate solution was added, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed three times with 1 N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulfate, filtered through a fritted silica gel and the filtrate was evaporated to dryness. The product is crystallized from diisopropyl ether.

General Regulation

Cyclization to benzimidazoles via carboxylic acid anilides

The 4.7 mmol of the 1,2-diaminobenzene derivative is dissolved in 20 ml of dichloromethane, 14 mmol of triethylamine are added, 6 mmol of carboxylic acid chloride are added slowly, and the mixture is then stirred for 15 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, diluted with water and extracted twice with dichloromethane. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The remaining crude acid anilide was dissolved in a 9: 1 mixture of methanol and concentrated hydrochloric acid and refluxed for 1 hour. After cooling, the reaction mixture was slowly transferred to a saturated sodium bicarbonate solution, diluted with water and extracted three times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The evaporation residue is purified by crystallization or by silica gel column chromatography as necessary.

General Regulation

Cleavage of ethers with hydrobromic acid

A mixture of 5 g of aryl methyl ether and 160 ml of 48% aqueous hydrobromic acid is refluxed for 1-5 hours and, after cooling, the reaction mixture is filtered off. The residue was dissolved in ethyl acetate, extracted three times with saturated sodium bicarbonate solution, and, after drying over sodium sulfate, evaporated in vacuo. The evaporation residue is purified by crystallization or by silica gel column chromatography as necessary. :

General Regulation 7

Cleavage of ethers with boron tribromide

To a solution of aryl methyl ether (1.86 mmol) in dichloromethane (18 ml) was slowly added 7.4 mL of a 1M solution of boron tribromide in dichloromethane at -35 ° C. The mixture was allowed to stand for 12-15 hours at -30 ° C, then saturated sodium bicarbonate solution was added, extracted three times with dichloromethane, the combined extracts were dried over sodium sulfate and concentrated in vacuo. The evaporation residue is purified by silica gel column chromatography as necessary.

General Regulation

Alkylation of hydroxybenzimidazole derivatives and phenol derivatives by reaction with halides

To a solution of 1.85 mmol of the hydroxybenzimidazole derivative in 12 mL of N, N-dimethylformamide was added 1.85 mmol of cesium carbonate and 2.24 mmol of alkyl bromide or alkyl iodide. If alkyl bromide is used, 1.85 mmol of sodium iodide are optionally added. The mixture is stirred for 12-96 hours, then poured into water, extracted into ethyl acetate, the organic phase is washed four times with water, dried over sodium sulphate and concentrated in vacuo.

Alternatively to this aqueous treatment, dichloromethane may also be added to the reaction mixture, the precipitated salts may be removed by filtration, and the filtrate concentrated in vacuo.

Irrespective of the processing method, the residue is then purified by crystallization or silica gel column chromatography.

General Regulation

Saponification of alkyl esters of carboxylic acids

To a solution of carboxylic acid alkyl ester (0.77 mmol) in methanol (5 ml) and tetrahydrofuran (5 ml) was added 0.5 N aqueous lithium hydroxide or sodium hydroxide (5 ml). The mixture was stirred for 2-12 hours, then concentrated to dryness in vacuo, neutralized by the addition of aqueous hydrochloric acid, and extracted with ethyl acetate. After drying over sodium sulfate and evaporation of the solvent, the residue is purified by silica gel column chromatography as necessary.

General Regulation 10

Esterification of carboxylic acids

To a solution of 0.2 mmol of carboxylic acid in 1 ml of primary or secondary alcohol, two drops of concentrated sulfuric acid are added and the solution is stirred for 12 hours at 60 ° C. Saturated potassium bicarbonate solution was then added, the mixture was diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The evaporation residue is crystallized from diisopropyl ether.

General rule 11

Reduction of alkyl esters of carboxylic acids with lithium aluminum hydride

To a solution of the carboxylic acid ester (0.15 mmol) in tetrahydrofuran was added 0.09 mmol of lithium aluminum hydride. The reaction mixture was stirred for 1-48 hours, quenched with water, and extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. The evaporation residue is purified by crystallization or by silica gel column chromatography as necessary.

General Regulation 12 t ₍ '' 1

Wittig reaction of benzimidazolecarbaldehydes with (ω-carboxyalkyl) triphenylphosphonium bromides and esterification with methanol

To 2 mmol of (ω-carboxyalkyl) triphenylphosphonium bromide in 2.5 ml of dimethylsulfoxide and 2.5 ml of tetrahydrofuran was added 4 mmol of potassium tert-butoxide at 0 ° C and stirred at> 10 ° C for 30 minutes. A solution of aldehyde (0.67 mmol) in tetrahydrofuran (ml) was then added and the mixture was stirred at 0 ° C for 3 hours. Saturated ammonium chloride solution was added, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. The residue is dissolved in 15 ml of methanol, two drops of concentrated sulfuric acid are added and allowed to stand for 43-72 hours. After concentration in vacuo, the residue was purified by silica gel column chromatography.

General Regulation 13

Reaction of aminobenzimidazoles with alkyl- and arylsulfonic acid halides

To a solution of 47 pmol of the aminobenzimidazole derivative in 0.5 ml of dichloromethane was added 51 pmol of triethylamine and 51 pmol of alkyl or arylsulfonic acid halide and the reaction mixture was stirred

2-15 hours. Saturated sodium bicarbonate solution was added, extracted three times with dichloromethane, the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The evaporation residue is purified by crystallization or silica gel column chromatography.

General Regulation

Copper-mediated O- or N-arylation of benzimidazoles

I

5 mmol of the N-unsubstituted benzimidazole derivative or N-arylsubstituted hydroxybenzimidazole derivative are dissolved in 20 ml of dichloromethane. Add 10 mmol of arylboronic acid, 5 mmol of anhydrous copper acetate, 10 mmol of pyridine or triethylamine and about 2.5 g of molecular sieve (4) and stir for 48-72 hours while eliminating moisture. Silica gel is added, the mixture is dried in vacuo and the powder remaining is chromatographed on silica gel. If necessary, the regioisomeric N-arylated products are separated by HPLC.

General rule 15

Basic catalyzed N-substitution of benzimidazoles

To a solution of 5 mmol of the N-unsubstituted benzimidazolium derivative in 20 mL of dimethylacetamide was added 25 mmol of sodium hydride and 20 mmol of electron deficient aryl halide or heteroaryl halide, and the mixture was refluxed for 48-72 hours while precipitation of moisture. Silica gel was then added, evaporated to dryness in vacuo and the remaining powder chromatographed on silica gel. If necessary, the regioisomeric β-aryl products are separated by HPLC.

General Regulation

Cyclization to benzimidazoles by reaction with aldehydes

To a solution of 1 mmol of the 1,2-diaminobenzene derivative in 3 ml of nitrobenzene is added 1 mmol of aryl or heteroaryl aldehyde. The mixture was heated at 150 ° C for 2-6 hours and then allowed to cool. The residue was purified by silica gel column chromatography without further work-up.

General Regulation

Conversion of carboxylic acids to carboxamides with a solution of 0.25 mmol carboxylic acid ml

N, N -dimethylformamide was added with a secondary amine, 0.5 mmol

0.38 mmol of primary or triethylamine and 0.25 mmol of diphenylphosphoryl azide were allowed to stir for 2 days. The reaction mixture is quenched by the addition of water, extracted three times with ethyl acetate, the combined organic phases are washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography.

General Regulation

Conversion of carboxylic acid esters to carboxamides

To a solution of the amine (0.36 mmol) in toluene (3 mL) was added dropwise a 2M solution of trimethylaluminium in toluene (0.18 mL) dropwise while cooling in an ice bath. A solution of 0.33 mmol of carboxylic acid methyl ester in 3 mL of toluene is then added and stirred at 95 ° C for 2-8 hours. After cooling, water is added, extracted three times with ethyl acetate, the combined organic layers are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography.

Example 1

[(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] acetic acid isopropyl ester

The compound is prepared by reacting 1,2-diphenyl-c-hydroxy-1H-benzimidazole (Beniricori, T .; Sannicolo, F .: J. Heterocycl. Chem., 25, 1988, 1029-1033) with isopropyl bromoacetate according to the general procedure 8th

MP: 137-138 ° C.

Example 2 [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] ethan-1-ol,

The compound is prepared from [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] acetic acid methyl ester (DE 4330959) according to the general formula 11.

¹ H-NMR (d 6 -DMSO): δ (ppm): 3.72 t (J = 7.5 Hz, 2H); 4.02 t (J = 7.5Hz, 2H); 6.72 d (J = 2Hz, 1 H); 7.10 dd (J = 8.2 Hz, 1H); 7.38-7.68 m (10H); 7.76 d (J = 8Hz, 1 H).

Example 3

3 - [(1,2-Diphenyl-ΙΗ-benzimidazol-6-y1) oxy] propan-1-o1

According to general formula 8, 0.5 g of 1,2-diphenyl-6-hydroxy-1H-benzimidazole is reacted with 3- (bromopropoxy) tert -butyldimethylsilane. It is dissolved in silica gel after chromatography on silica gel

2.5 ml of methanol, add 0.4 ml of concentrated hydrochloric acid and stir for 2 hours at 20 ° C. The mixture was poured into a saturated aqueous sodium bicarbonate solution, extracted three times with ethyl acetate, the combined extracts were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo.

MP: Mp 191-193 ° C.

Example 4

3 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] propanoic acid

To 100 mg of 3 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] propan-1-ol in 2.5 ml of acetone at -15 ° C is added 0.15 ml of Jones reagent solution ( prepared from 0.27 g of chromium trioxide, 1 ml of water and 0.23 ml of concentrated sulfuric acid). After

After stirring at -15 ° C for 3.5 hours, the reaction is stopped by adding isopropanol. The reaction mixture was diluted with water, extracted three times with dichloromethane, the combined organic phases were dried over sodium sulfate and the solvent was evaporated in vacuo. The residue is purified by chromatography on silica gel.

¹ H-NMR (d ₆ -DMSO): δ (ppm): 2.60 t (J = 7.5 Hz, 2H); 4.15 t (J = 7.5Hz, 2H); 6.64 d (J = 2Hz, 1 H); 6.95 dd (J = 8.2 Hz, 1H); 7.30-7.61 m (10H); 7.69 d (J = 8Hz, 1 H).

Example 5

3-[(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] propanoic acid methyl ester mg of 3 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] propanic acid is dissolved in 0.5 ml of N, N-dimethylformamide and 41 mg of cesium carbonate and 10 μ a of methyl iodide are added to the solution. The mixture was stirred for 2 days, then diluted with dichloromethane, filtered off, the filtrate concentrated in vacuo and the residue subjected to silica gel chromatography.

MP: 120-121 C. C.

Example 6

2 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] propanoic acid methyl ester

Prepared by reaction of 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 2-bromopropanoic acid methyl ester according to General Regulation 8.

MP: 132-135 C. C.

Example 7

4 - [(1,2-Diphenyl-1H-benzimidazol-o-yl) oxy] butanoic acid isopropyl ester

Prepared by reaction of 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 4-bromobutanoic acid isopropyl ester according to General Regulation 8.

MP: 89-91 C. C.

'.1. ',' '».

Example 8

4 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] -butan-l-ol

Prepared from methyl 4 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] butanoate according to General Regulation 11.

MP: Mp 159-160 ° C.

Example 9 [4 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] but-1-yl] acetate

To a solution of 50 mg of 4 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] butan-1-ol in 1 ml of dichloromethane is added 0.34 ml of pyridine and 20 μΐ of acetyl chloride and the mixture is stirred for 15 hours . Saturated sodium bicarbonate solution was added, the mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography.

MP: 68 - 69 ’C.

Example 10 [4 - [(1,2-Diphenyl-ΙΗ-benzimidazol-6-yl) oxy] but-1-yl] pivalate

Prepared in analogy to Example 9 from 50 mg of 4 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] butan-1-ol, 0.34 ml of pyridine and 22 μΐ of trimethylacetic acid chloride.

MP: Mp 104-106 ° C.

Example 11

4 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] butyl-N-methylcarbamate

To a solution of 100 mg of 4 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] butan-1-ol in 4 ml of dichloromethane was added 0.1 ml of triethylamine and 20 mg of methyl isocyanate and the mixture was stirred for 15 hours . An additional 0.1 ml of triethylamine and 20 mg of methyl isocyanate are then added and the mixture is stirred for a further 20 hours. It is then concentrated in vacuo and the residue is purified by silica gel chromatography.

MP: 124

126 [deg.] C.

Example 12

5 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] pentanoic acid isopropyl ester 994

It is prepared by reacting 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 5-bromopentanoic acid isopropyl ester according to General Regulation 8.

MP: Mp 91-92 ° C.

Example 13

6 - [(1,2-Diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

It is prepared by reacting 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

¹ H-NMR (CDC1 _3): δ = 1, 44-1, 56 m (2H); 1.64-1.85 m (4H); 2.33 t (J = 7.5Hz, 2H); 3.66 s (3H); 3.93 t (J = 7.5Hz, 2H); 6.70 d (J = 2Hz, 1H); 6.96 dd (J = 8.2 Hz, 1H); 7.22-7.38 m (5H);

7.43-7.58 m (5H); 7.76 d (J = 8Hz, 1 H).

Example 14

6 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester Prepared by the reaction of 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to of General Regulation 8.

1 H-NMR (CDCl 3): δ (ppm): 1.22 d (J = 7.5 Hz, 6H); 1.43-1.56 m (2 H); 1.62-1.87 m (4H); 2.30 t (J = 7.5Hz, 2H); 3.93 t (J = 7.5 Hz,

2H); 5.01 sp (J = 7.5Hz, 1H); 6.69 d (J = 2Hz, 1 H); 6.96 dd (J = 8,

Hz, 1H); 7.25-7.38 m (5H); 7.43-7.55 d (J = 8Hz, 1H).

Example 15

6 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid

Prepared by reaction of methyl 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoate according to the general formula

9 ¹ H-NMR (d 6 -DMSO): δ (ppm): 1.35-1.49 m (2H); 1.50-1.63 m (2H); 1.65-1.77 m (2H); 2.23 t (J = 7.5Hz, 2H); 3.92 t (J = 7.5Hz, 2H); 6.62 d (J = 2Hz, 1 H); 6.95 dd (J = 10.2 Hz, 1H); 7.30-7.62 m (10H), 7.68 d (J = 10 Hz, 1H).

Example 16

6 - [(1,2-Diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexane-l-ol

Prepared by reaction of methyl 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoate according to General Regulation 11.

H-NMR (CDC1 _3): δ (ppm): 1.35 to 1.85 m (8 H); 3.67 t (J = 7.5Hz, 2H); 3.98 t (J = 7.5Hz, 2H); 6.70 d (J = 2Hz, 1H); 6.98 dd (J = 8.2 Hz, 1H); 7.24-7.38 m (5H); 7.45-7.58 m (5H); 7.75 d (J = 8Hz, 1H).

Example 17

6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanamide

a) 6 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] hexanenitrile

It is prepared by reacting 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 6-bromohexanenitrile according to the general formula 8.

MP: 108-112 C. C.

- [(1,2-Diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide

To a solution of 50 mg of 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanenitrile in 1 ml of methanol is added 18 mg of potassium carbonate and 40 μΐ of a 30% hydrogen peroxide solution and stirred for 24 hours. While stirring, ice-cold sodium thiosulphate solution is added and extracted three times with ethyl acetate. After drying over sodium sulfate and evaporation in vacuo, the residue is chromatographed on silica gel.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1,48-1,60 m (2H); 1,65-1,87 m (4H); 2; 25 t (J = 7.5Hz, 2H); 3,94 t (J = 7.5Hz, 2H); 5,30-5,53 br (2H); 6, 68 d (J = 2Hz, 1 H); 6, 95dd (J = 8.2Hz, 1H); 7.23-7.38 m (5H); 7.42 " -7.58 m (5H); 7.75 d (J = 8 Hz, 1H).

Example 18

N-Methoxy-6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanamide

100 mg of 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid are dissolved in 2 ml of tetrahydrofuran, 39 mg of carbonyldiimidazole are added, the mixture is stirred at 20 ° C for 30 minutes and then is refluxed for 30 minutes. 21 mg of O-methylhydroxylamine hydrochloride are then added at 20 ° C and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid and saturated potassium bicarbonate solution. After drying over sodium sulfate and evaporation in vacuo, the residue is chromatographed on silica gel.

MP: Mp 144-145 ° C.

Example 19

N- (Phenylmethoxy) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide

Example 20

Prepared by reacting 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid with O-benzylhydroxylamine hydrochloride according to the procedure described in Example 18.

MP: 144 ° C.

N-Hydroxy-6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide mg N- (phenylmethoxy) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) The oxy] hexanamide is dissolved in 4 ml of ethanol, 15 mg of palladium on carbon (10%) are added and the mixture is stirred under a hydrogen atmosphere for 3 hours. After separation of the catalyst, the solvent is removed in vacuo and the residue is crystallized from diethyl ether.

MP: 83 - 85 ’C.

Example 21

7 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] heptanoic acid methyl ester

Prepared by reaction of 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 7-bromoheptanoic acid methyl ester according to General Regulation 8.

MP: 77-80 C. C.

Example 22

7 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] heptanoic acid

Prepared by reaction of methyl 7 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] heptanoate according to the general formula

9th

MP: Mp 142-145 ° C.

Example 23

7 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] heptanoic acid isopropyl ester

Prepared by reacting 7 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] heptanoic acid with isopropanol according to general formula 10.

MP: 98-100 C. C. ·

Example 24

6 - [[1- (3-Nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reacting 6-hydroxy-1- (3-nitrophenyl) -2-phenyl-1H-benzimidazole (DE 4330959) with 6-bromohexanoic acid isopropyl ester according to general rule 8.

MP: Mp 111-113 ° C.

Example 25

6 - [[2-Phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) (5-Methoxy-2-nitrophenyl) [(3-trifluoromethyl) phenyl] amine

A mixture of 2 g of 3-fluoro-4-nitroanisole and 16 ml of 3- (trifluoromethyl) aniline is stirred for 72 hours at 140 ° C, then diluted with ethyl acetate, washed ten times with 4 N aqueous hydrochloric acid and once with saturated sodium chloride solution. It is dried over sodium sulphate, concentrated in vacuo and the residue is chromatographed on silica gel.

¹ H-NMR (CDC1 _3): δ (ppm): 3.78 s (3H); 6.42 dd (J = 8.2 Hz, 1H); 6.60 d (J = 2Hz, 1 H); 7.45-7.60 m (4H); 8.22 d (J = 8Hz, 1H); 9.78 with br (1H).

b) 6-Methoxy-2-phenyl-1 - [(3-trifluoromethyl) phenyl] -1H-benzimidazole

Prepare by hydrogenation of (5-methoxy-2-nitrophenyl) [(3-trifluoromethyl) phenyl] amine according to general formula 1 and subsequent cyclization with triethyl orthobenzoate according to general formula 3.

'M.p. Mp 135-137 ° C.

c) 6-Hydroxy-2-phenyl-1 - [(3-trifluoromethyl) phenyl] -1H-benzimidazole

Prepared from 6-methoxy-2-phenyl-1 - [(3-trifluoromethyl) phenyl] -4-benzimidazole according to general formula 6.

1 H-NMR (d ₆ -DMSO): δ (ppm): 6.56 d (J = 2 Hz, 1H); 6.82 dd (J = 8.2 Hz, 1H); 7.32-7.50 m (5H); 7.60 d (J = 8Hz, 1H); 7.70-7.95 m (4H); 9.48 with br (1H).

6 - [[2-Phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared by the reaction of 6-hydroxy-2-phenyl-1 - [(3-trifluoromethyl) phenyl] -4-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: 106-108 ° C.

Example 26

6 - [[2-Phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reacting 6-hydroxy-2-phenyl-1 - [(3-trifluoromethyl) phenyl] -4-benzimidazole with 6-bromohexanoic acid isopropyl ester according to the general formula 8.

MP: Mp 113-115 ° C.

Example 27

6 - [[2-; phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepared from 6 - [[2-phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: 156-158 C. C.

Example 28

6 - [[2-Phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] 57 oxy] hexan-1-ol

Obtained from 6 - [[2-phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 11.

MP: Mp 143-145 ° C.

Example 29

6 - [[1- (3-Cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (5-Methoxy-2-nitrophenyl) aminobenzonitrile

A mixture of 2 g of 3-fluoro-4-nitroanisole and 15 ml of 3-aminobenzonitrile is stirred at 140 ° C for 65 hours. The reaction mixture was then diluted with ethyl acetate, washed three times with water and once with saturated sodium chloride solution. After drying over sodium sulfate, it is concentrated in vacuo and the residue is chromatographed on silica gel.

MP: 157-158 C. C.

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

It is prepared by hydrogenation of 3- (5-methoxy-2-nitrophenyl) aminobenzonitrile according to general formula 1 and subsequent cyclization with triethylorthobenzoate according to general formula 3. In cyclization, unlike the general formula, tetrahydrofuran is used as solvent.

MP: Mp 185-191 ° C (dec.).

c) 6-Hydroxy-1- (3-cyanophenyl) -2-phenyl-1H-benzimidazole

Prepared from 6-methoxy-1- (3-cyanophenyl) -2-phenyl-1H-benzimidazole according to the general formula 7.

MP: 216-218 C. C.

6 - [[1- (3-Cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6-hydroxy-1- (3-cyanophenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to the general formula 8.

MP: 115-118 C. C. '

Example 30

6 - [[1- (3-Cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Prepared by reaction of 6-hydroxy-1- (3-cyanophenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to General Regulation 8.

MP: 101 - 102 ’C.

Example 31

acid

6 - [[1- (3-cyanophenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanoic acid

Prepared from 6 - [[1- (3-cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: 99-101 C. C.

Example 32 '

6 - [[1- (4-Cyanophenyl) -2-phenyl-1H-benzimidyl] -methyl ester. zol-6-yl] oxy] hexanoic acid

a) 4- (5-Methoxy-2-nitrophenyl) aminobenzonitrile

A mixture of 2 g of 3-fluoro-4-nitroanisole and 15 ml of 4-aminobenzonitrile was stirred at 140 ° C for 22 hours. Then the reaction mixture was diluted with ethyl acetate, washed three times with 2 N aqueous hydrochloric acid, three times with water and once with saturated sodium chloride solution. After drying over sodium sulfate, the solvent is evaporated in vacuo and the residue is chromatographed on silica gel.

¹ H-NMR (CDCl ₃ ): δ (ppm): 3.70 s (3H); 6.38 dd (J = 8.2 Hz, 1H); 6.68 d (J = 2Hz, 1 H); 7.27 d (J = 8Hz, 2H); 7.54. d (J = 8Hz, 2H); 8.08 d (J = 8Hz, 1H); 9.60 with br (1H).

b) 6-Methoxy-1- (4-cyanophenyl) -2-phenyl-1H-benzimidazole

It is obtained by hydrogenation of 4- (5-methoxy-2-nitrophenyl) aminobenzonitrile according to general formula 1 and subsequent cyclization with triethyl orthobenzoate according to general formula 3.

I'm starting to drofurán. difference from prescription used as solvent tetrahy- 'Ή NMR (CDCl3): δ (ppm): 3.82 s (3H); 6.72 d (J = 2 Hz, 1H); 7.00 dd (J = 8.2 Hz, 1H) ; 7.30-7.49 m (7H); 7.78 d (J = 8 Hz, 1H); 7.81 d (J = 8 Hz, 2H).

c) 6-Hydroxy-1- (4-cyanophenyl) -2-phenyl-1H-benzimidazole

Prepared from 6-methoxy-1- (4-cyanophenyl) -2-phenyl-1H-benzimidazole according to general formula 7.

MP: Mp 266-268 ° C.

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

It is prepared by reacting 6-hydroxy-1- (4-cyanophenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to the general formula 8.

MP: 145-148 C. C.

Example 33

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

Prepared by reacting 6-hydroxy-1- (4-cyanophenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to the general formula 8 '.

MP: 102-103 ’C.

Example 34

6 - [[1- (3-Chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 1- (3-Chlorophenyl) -6-methoxy-2-phenyl-1H-benzimidazole

Prepared by reduction of (3-chlorophenyl) - (5-methoxy-2-nitrophenyl) -amine (Belton, McClnerney, Proc. R. Ir. Acad. Sect. B, 69, 21,27 (1970)) according to general formula 2 followed by cyclisation with triethyl orthobenzoate according to general rule 3.

MP: Mp 140-143 ° C.

b) 1- (3-Chlorophenyl) -6-hydroxy-2-phenyl-1H-benzimidazole

Prepared from 6-methoxy-1- (3-chlorophenyl) -2-phenyl-1H-benzimidazole according to general formula 6.

MP: 210-214 ’C.

6 - [[1- (3-Chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Is prepared by reaction of ¹ of 1- (3-phenyl čh'ľórf) '- 6-hydroxy-2- ^J phenyl-lH-benzimidazole sodium salt with methyl 6-bromo-hexanoic the general procedure eighth

MP: 101 - 105 ’C.

Example 35

6 - [[1- (3-Chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reacting 1- (3-chlorophenyl) -6-hydroxy-2-phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to General Regulation 8.

MP: Mp 107-112 ° C.

Example 36

6 - [[1- (3-Chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Obtained from 6 - [[1- (3-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

1 H-NMR (d ₆ -DMSO): δ (ppm): 1.36-1.78 m (6H); 2.24 t (J = 7.5Hz, 2H); 3.96 t (J = 7.5Hz, 2H); 6.68 d (J = 2Hz, 1 H); 6.97 dd (J = 8.2 Hz, 1H); 7.32-7.65 m (9H); 7.69 d (J = 8Hz, 1 H).

Example 37

6 - [[1- (3-Chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexan-1-ol

Obtained from 6 - [[1- (3-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 11.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.38-1.88 m (8H); 3.67 t (J = 7.5 Hz,

2H); 3.96 t (J = 7.5Hz, 2H); 6.70 d (J = 2Hz, 1H); 6.97 dd (J = 8,

Hz, 1H); 7.18 ddd (J = 8,2,2 Hz, 1H); 7.25-7.55 m < -1 >(8H); 7.76 d (J = 8 Hz, 1H).

Example 38

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

a) 1- (4-Chlorophenyl) -6-methoxy-2-phenyl-1H-benzimidazole

It is prepared by reduction of (4-chlorophenyl) - (5-methoxy-2-nitro-phenyl) amino (Kottenhahn et al., J. Org. Chem. 28, 3114, 3118 (1963)) according to general formula 2 followed by cyclization with triethyl orthobenzoate according to General Regulation 3.

¹ H-NMR (CDCl ₃ ): δ (ppm): 3.82 s (3H); 6.67 d (J = 2Hz, 1 H);

6.97 dd (J = 8.2 Hz, 1H); 7.22-7.40 m (5H); 7.46-7, 55 m (4H);

7.77 d (J = 8Hz, 1 H).

b) 1- (4-Chlorophenyl) -6-hydroxy-2-phenyl-1H-benzimidazole

Prepared from 1- (4-chlorophenyl) -6-methoxy-2-phenyl-1H-benzimidazole according to general formula 6.

1 H-NMR (d ₆ -DMSO): δ (ppm): 6.60 d (J = 2 Hz, 1H); 6.87 dd (J = 8.2 Hz, 1H); 7.40-7.56 m (7H); 7.64 d (J = 8Hz, 1H); 7.70 d (J = 8Hz, 2H); 9.50 with br (1H).

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

Prepared by the reaction of 1- (4-chlorophenyl) -6-hydroxy-2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: Mp 100-104 ° C.

Example 39

Isopropyl 6 - [[1- (4-chlorophenyl) -2-phenyl-lH-benzimidazole "" ¹ | dazol-6-yl] oxy] hexane. ''''

It is prepared by reacting 1- (4-chlorophenyl) -6-hydroxy-2-phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to General Regulation 8.

MP: Mp 83-88 ° C.

Example 40

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

Obtained from 6 - [[1- (4-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

¹ H-NMR (d ₆ -DMSO): δ (ppm): 1.35-1.78 m (6H); 2.25 t (J = 7.5Hz, 2H); 3.94 t (J = 7.5Hz, 2H); 6.68 d (J = 2Hz, 1 H); 6.95 dd (J = 8.2 Hz, 1H); 7.33-7.54 m (7H); 7.63 d (J = 8Hz, 2H);

7.69 d (J = 8Hz, 1 H).

Example 41

6 - [[1- (4-Chloro-phenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexan-l-ol

Obtained from 6 - [[1- (4-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 11.

MP: 115-120 ° C.

Example 42

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

a) 5-Chloro-2-nitrophenyl-o-tolylamine

To a solution of 10 g of 1-chloro-3,4-dinitrobenzene in 50 ml of ethanol is added 81 ml of o-toluidine and heated at reflux for 72 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 2 N aqueous hydrochloric acid. The organic phase is washed three more times with 2 N aqueous hydrochloric acid, dried over sodium sulphate and evaporated in vacuo. The residue was purified by silica gel chromatography.

^X H-NMR (CDCl 3): δ (ppm): 2.28 s (3H); 6.70 dd (J = 10.2 Hz)

1H); 6.80 d (J = 2Hz, 1 H); 7.22-7.40 m (4H); 8.18 d (J = 10Hz,

1H); 9.40 with br (1H).

b) 5-Methoxy-2-nitrophenyl-o-tolylamine

To a solution of 1 g of sodium in 20 ml of methanol was added 1 g of 5-chloro-2-nitrophenyl-o-tolylamine and the mixture was refluxed for 72 hours. It is then cooled to 0 ° C and the crystalline product is filtered off with suction.

^X H-NMR (CDC1 _3): δ (ppm): 2.30 s (3H); 3.72 s (3H); 6.19 d (J = 2Hz, 1 H); 6.32 dd (J = 10.2 Hz, 1H); 7.20-7.40 m (4H); 8.20 d (J = 10Hz, 1H); 9.62 with br (1H).

c) 6-Methoxy-1- (2-methylphenyl) -2-phenyl-1H-benzimidazole

It is prepared from 5-methoxy-2-nitrophenyl-o-tolylamine according to general formula 1 and subsequent cyclization with triethyl orthobenzoate according to general formula 3.

^{@ 1} H-NMR (CDCl3): .delta. (Ppm): 1.93 s (3H); 3.78 s (3H); 6.42 d (J = 2Hz, 1 H); 6.97 dd (J = 8.2 Hz, 1H); 7.22-7.48 m (7H); 7.57 dd (J = 8.1 Hz, 2H); 7.78 d (J = 8Hz, 1 H).

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

6-Methoxy-1- (2-methylphenyl) -2-phenyl-1H-benzimidazole was reacted according to general formula 6. The crude product was reacted with methyl 6-bromohexanoate according to general formula 8.

¹ H-NMR (CDCl 3): δ (ppm): ¹¹ 1.93 s' (3H ); 2.34 t (J = 7 (J = 7.5Hz, 2H); 6.42 d (J = 2 7.22-7.48 m (7H); 7,56 dd

1.43-1.58 m (2 H);

1.5 Hz, 2H); 3.168 Hz, 1H); 6.96 dd (J = 8, 1.5 Hz, 2H);

1H).

1.62-1.84 m (4H); s (3H); 3.90 t (J = 8.2 Hz, 1H);

7.76 d (J = 8Hz,

Example 43

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

Prepared from 6 - [[1- (2-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: 198-200 ’C.

Example 44

6 - [[1- (3-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 5-Chloro-2-nitrophenyl-m-tolylamine

To a solution of 1-chloro-3,4-dinitrobenzene (50 g) in ethanol (250 ml) was added m-toluidine (81 ml) and the solution was allowed to stand for 72 hours. The reaction mixture was then filtered and the crystalline solid was washed with cold ethanol and 2 N aqueous hydrochloric acid. The product was purified by silica gel chromatography.

¹ H-NMR (CDCl ₃ ): δ (ppm): 2.40 s (3H); 6.72 dd (J = 10.2 Hz, 1H); 7.04-7.13 m (3H); 7.14 d (J = 2 Hz, 1H); 7.32 t (J = 10Hz, 1H); 8.18 d (J = 10 Hz, 1H); 9.52 with br (1H).

b) 5-Methoxy-2-nitrophenyl-m-tolylamine

To a solution of 9 g of sodium in 670 ml of methanol was added 39 g of 5-chloro-2-nitrophenyl-m-tolylamine, and the mixture was heated under reflux for 72 hours. It is then cooled to 0 ° C and the crystalline product is filtered off with suction.

^X H-NMR (CDCl 3): δ (ppm): 2.40 s (3H); 3.73 s (3H); 6.33 dd (J = 10.2 Hz, 1H); 6.58 d (J = 2 Hz, 1H); 7.03-7.15 m (3H); 7.31 t (J = 10 Hz, 1H); 8.19 d (J = 10 Hz, 1H); 9.72 with br (1H).

c) 6-Methoxy-1- (3-methylphenyl) -2-phenyl-1H-benzimidazole

It is prepared from 5-methoxy-2-nitrophenyl-m-tolylamine according to general formula 1 and subsequent cyclization with triethyl orthobenzoate according to general regulation 3.

H-NMR (CDC1 _3): δ (ppm): 2.42 s (3H); 3.81 s (3H); 6.69 d (J = 2Hz, 1 H); 7.03 dd (J = 8.2 Hz, 1H); 7.10-7.18 m (2H);

7.30-7.48 m (5H); 7.62 dd (J = 8.1 Hz, 2H); 7.89 d (J = 8Hz, 1 H).

d) 6-Hydroxy-1- (3-methylphenyl) -2-phenyl-1H-benzimidazole

Prepared from 6-methoxy-1- (3-methylphenyl) -2-phenyl-1H-benzimidazole according to general formula 6.

¹ H-NMR (d 6 -DMSO):? δ (ppm): 2.34 s (3H); 6.52 d (J = 2Hz, 1 H); 6.80 dd (J = 8.2 Hz, 1H); 7.15 d (J = 8Hz, 1H); 7.28 with br (1H); 7.32-7.55 m (7H); 7.59 d (J = 8Hz, 1H); 9.37 with br (1H).

6 - [[1- (3-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6-hydroxy-1- (3-methylphenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to general formula 8.

¹ H-NMR (CDCl 3): δ (ppm): 1.44-1.58 m (2H); 1.64-1.85 m (4H); 2.35 t (J = 7.5Hz, 2H); 2.40 s (3H); 3.68 s (3H); 3,95 t

(J = 7.5Hz, 2H); 6,70 d (J = 2Hz, 1 H); 6.96 dd (J = 8.2 Hz, 1H); 7.10 d (J = 8Hz, 1H); 7 / 16 p br (2H); 7.25-7.43 m (4H); 7,55 dd (J = 8.1 Hz, 2H); 7.77 D (J = 8 Hz, 1H).

Example 45

6 - [[1- (3-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by the reaction of 6-hydroxy-1- (3-methylphenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to General Regulation 8.

^X H-NMR (CDCl 3): δ (ppm): 1.22 d (J = 8 Hz, (2H, _CH2), from 1.64 to 1, 84 m (4H, _CH2), 2.30 t ( J = 7, (3H); 3.95 t (J = 7.5 Hz, 2H); 5.00 sp (J = 8 (J = 2 Hz, 1H); 6.96 dd (J = 8, 2 Hz, 1H), 7.10

6H); 1,44-1,56 m

Hz, 2H); 2,41 s

Hz, 1H); 6.68 d d (J = 8Hz, 1H);

7.14 with br (1H); 7.25-7.41 m (4H); 7.54 dd (J = 8.1 Hz, 2H);

7.75 d (J = 8Hz, 1H).

Example 46

6 - [[1- (3-Methylphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yloxy] hexanoic acid

Prepared from 6 - [[1- (3-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

^X H-NMR (d-DMSO): δ (ppm): 1.38 to 1.80 m (6 H); 2.23 t (J = 7.5Hz, 2H); 3.84-3.93 m (2H); 6.60 d (J = 2Hz, 1 H); 6.8 d br (J = 8Hz, 1H); 7.15 d (J = 8Hz, 2H); 7.20-7.32 m (4H); 7.42-7.50 m (2 H); 7.59 d (J = 8Hz, 1H); 7.77 d (J = 8Hz, 1 H).

Example 47

6 - [[1- (3-methylphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexan-l-ol

Prepared from 6 - [[1- (3-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to General Regulation 11.

^X H-NMR (CDC1 _3): δ (ppm): 1, 40-1, 85 m (8H); 2.40 s (3H);

3.68 t (J = 7.5Hz, 2H); 3.96 t (J = 7.5Hz, 2H); 6.69 d (J = 1.5 Hz, 1H); 6.96 dd (J = 8, 1.5 Hz, 1H); 7.10 d (J = 8Hz, 1H); 7.13 with br (1H); 7.25-7.42 m (5H); 7.54 dd (J = 8.1 Hz, 2H); 7.76 d (J = 5Hz, 1H). '' ·. '

Example 48

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

a) 5-Chloro-2-nitrophenyl-p-tolylamine

Prepared in an analogous manner to 5-chloro-2-nitrophenyl-m-tolylamine from 1-chloro-3,4-dinitrobenzene and p-toluidine and purified by crystallization for 68.

¹ H-NMR (CDCl 3): δ (ppm): 2.40 s (3H); 6.70 dd (J = 10.2 Hz, 1H); 7.08 d (J = 2Hz, 1 H); 7.16 d (J = 10Hz, 2H); 7.28 d (J = 10Hz, 2H); 8.18 d (J = 10Hz, 1H); 9.50 with br (1H).

(b) 5-Methoxy-2-nitrophenyl-p-tolylamine;

Prepared in an analogous manner to 5-methoxy-2-nitrophenyl-m-tolylamine from 5-chloro-2-nitrophenyl-p-tolylamine and sodium methanolate.

1 H-NMR (CDCl 3): δ (ppm): 2.39 s (3H); 3.72 s (3H); 6.31 dd (J = 10.2 Hz, 1H); 6.50 d (J = 2Hz, 1 H); 7.19 d (J = 10, 2H); 7.25 d (J = 10Hz, 2H); 8.19 d (J = 10Hz, 1H); 9.70 with br (1H).

c) 6-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole

It is prepared from 5-methoxy-2-nitrophenyl-p-tolylamine according to general formula 1 and subsequent cyclization with triethyl orthobenzoate according to general formula 3.

¹ H-NMR (CDCl 3): δ (ppm): 2.49 s (3H); 3.80 s (3H); 6.69 d (J = 2Hz, 1 H); 6.97 dd (J = 8.2 Hz, 1H); 7.20 d br (J = 8Hz, 2H); 7.25-7.36 m (5H); 7.53 dd (J = 8.1 Hz, 2H); 7.76 d (J = 8Hz, 1 H).

d) 6-Hydroxy-1- (4-methylphenyl) -2-phenyl-ΙΗ-benzimidazole

Prepared from 6-methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole according to the general formula 6. '.

¹ H-NMR (d 6 -DMSO): δ (ppm): 2.40 s (3H); 6.50 d (J = 2Hz, 1 H); 6.80 dd (J = 8.2 Hz, 1H); 7.28 d (J = 8Hz, 2H); 7.32-7.43 m (5H); 7.46-7.52 m (2H); 7.56 d (J = 8Hz, 1H); 9.28 with br (1H).

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

Prepared from 6-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benz69-imidazole and methyl 6-bromohexanoate according to General Regulation 8.

^X H-NMR (CDC1 _3): δ (ppm): 1, 44 to 1.58 m (2H); 1.62-1.86 m (4H); 2.34 t (J = 7.5Hz, 2H); 2.48 s (3H); 3.68 s (3H); 3.94 t (J = 7.5Hz, 2H); 6.69 d (J = 2Hz, 1 H); 6.96 dd (J = 8.2 Hz, 1H); 7.19 d (J = 8Hz, 2H); 7.28-7.38 m (5H); 7.55 dd (J = 8.1 Hz, 2H); 7.75 d (J = 8Hz, 1H).

Example 49

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

It is prepared by reacting 6-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to the general formula 8.

^X H-NMR (CDCl 3): δ (ppm): 1.22 d (J = 7.5 Hz, 6H); 1.44-1.56 m (2 H); 1.62-1.85 m (4H); 2.30 t (J = 7.5Hz, 2H); 2.47 s (3H);

3.93 t (J = 7.5Hz, 2H); 5.01 sp (J = 7.5Hz, 1H); 6.68 d (J = 2 Hz)

1H); 6.96 dd (J = 8.2 Hz, 1H); 7.20 d (J = 8Hz, 2H); 7.26-7.36 m (5H); 7.55 dd (J = 8.1 Hz, 2H); 7.75 d (J = 8Hz, 1H).

Example 50

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

Obtained from methyl 6 - [[1- (4-methylphenyl) -2- £ ^{L-phenyl-lH-benzimidazol-6-yl]} oxy] hexanoic acid according to the general procedure ninth

MP: 186-190 C. C.

Example 51

6 - [[1- (4-methylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexan-l-ol

¹ obtained from methyl 6 - [[1- (4-methylphenyl) -2-phenyl-fe70 H-benzimidazol-6-yl] oxy] hexanoic acid according to the general procedure eleventh

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.38-1.80 m (8H); 2.47 s (3H); 3.65 t (J = 7.5Hz, 2H); 3.93 t (J = 7.5Hz, 2H); 6.68 d (J = 2Hz, 1 H); 6.97 dd (J = 8.2 Hz, 1H); 7,18 d. (J = 8Hz, 2H); 7.24-7, 37 m (5H); 7/54 dd (J = 8.1 Hz, 2H); 7.75 d (J = 8Hz, 1H).

Example 52

6 - [[1- (3,4-Dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (3,4-Dimethylphenyl) amino-4-nitrophenol

A mixture of 3 g of 3-fluoro-4-nitrophenol and 6.9 g of 3,4-dimethylaniline is stirred for 2 hours at 150 ° C. After cooling, the reaction mixture was dissolved in dichloromethane and extracted six times with 1 N aqueous hydrochloric acid. The organic phase is discarded and the combined aqueous phases are extracted three times with chloroform. The combined extracts were dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on silica gel.

1 H-NMR (CDCl ₃ / d ₆ -DMSO): δ (ppm): 2.18 s (6H); 6.13 dd (J = 8,

Hz, 1H); 6.36 d (J = 2Hz, 1 H); 6.90-7.00 m (2H); 7.09 d (J = 8Hz, 1H); 7.93 d (J = 8Hz, 1H); 9.50 with br (1H); 10.19 with br (1H).

b) 6- [3- (3,4-Dimethyl-phenyl) amino-4-nitrophenyl] oxyhexanoic acid methyl ester

It is prepared by reacting 3- (3,4-dimethylphenyl) amino-4-nitrophenol with methyl 6-bromohexanoate according to general formula 8.

^X H-NMR (CDCl 3): δ (ppm): 1.38 to 1.52 m (2H); 1.59-1.80 m (4H); 2.30 s (6H); 2.33 t (J = 7.5Hz, 2H); 3.68 s (3H); 3.87 (J = 7.5Hz, 2H); 6.28 dd (J = 8.2 Hz, 1H); 6.48 d (J = 2Hz, 1 H)

7.04 d (J = 8Hz, 1H); 7.06 with br (1H); 7.18 d (J = 8Hz, 1H); 8.17 d (J = 8Hz, 1H); 9.71 with br (1H).

6 - [[1- (3,4-Dimethylphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Obtained from methyl 6- [3- (3,4-dimethylphenyl) amino-4-nitrophenyl] oxyhexanoate according to general formula 1, followed by cyclization with triethyl orthobenzoate according to general formula 3.

¹ H-NMR (CDC1 _3): δ (ppm): 1, 44 to 1.56 m (2H); 1.62-1, 84 m (4H); 2.30 s (3H); 2.33 t (J = 7.5Hz, 2H); 2.34 s (3H); 3.68 s (3H); 3.93 t (J = 7.5Hz, 2H); 6.67 d (J = 2Hz, 1 H); 6.94 dd (J = 8.2 Hz, 1H); 7.03 dd (J = 8, 1.5 Hz, 1H); 7.09 with br (1H); 7.22-7.35 m (4H); 7.57 dd (J = 8, 1.5 Hz, 2H); 7.76 d (J = 8Hz, 1 H).

Example 53

6 - [[1- (3,4-Dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepared from methyl 6 - [[1- (3,4-dimethylphenyl) 2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid according to the general formula 9.

MP: Mp 158-161 ° C.

Example 54 (

'· I. i t

6 - [[1- (3,5-Dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (3,5-Dimethylphenyl) amino-4-nitrophenol

A mixture of 5.4 g of 3-fluoro-4-nitrophenol and 4.3 ml of 3,5-dimethyianiline was stirred at 120 ° C for 6 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and water, and the organic layer was extracted three times with 1 N aqueous hydrochloric acid. The combined aqueous phases are extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, concentrated in vacuo and the residue is crystallized.

1 H-NMR (d 6 -DMSO): δ (ppm): 2.30 s (6H); 6.28 dd (J = 8.2 Hz, 1H); 6.49 d (J = 2Hz, 1 H); 6.52 d (J = 2Hz, 1 H); 6.90 with br (1H); 6.98 with br (2H); 8.04 d (J = 8Hz, 1H); 9.51 with br (1H).

b) 6- [3- (3,5-Dimethylphenyl) amino-4-nitrophenyl] oxyhexanoic acid methyl ester

Prepared by the reaction of 3- (3,5-dimethylphenyl) amino-4-nitrophenol with methyl 6-bromohexanoate according to General Regulation 8.

^X H NMR (CDC1 _3): δ (ppm): 1, 40 -1.52 m (2H); 1.60 to 1.8 10 m (4H); 2.30 T (J = 7.5 Hz, 2 H); 2.32 with (6H); 3.68 s (3H) ; 3 , 88 t (J = 7, 5 Hz, 2H); 6.30 dd (J = 8, 2 Hz, 1H) ; 6.52 d (J = 2 Hz, 1H); 6, 88 with br i 1H); 6.81 with br (2H) T 8, 17 d (J = 8Hz, 1H); 9, 69 s br (1H).

6- [. [3- (3,5-dimethylphenyl) amino-4-nitro-phenyl] oxy] hexanoic acid

Prepare from 6- [3- (3,5-dimethylphenyl) amino-4-nitrophenyl] oxy-hexanoic acid methyl ester according to general formula 1, followed by cyclization with triethyl orthobenzoate according to general formula 3.

MP: Mp 124-126 ° C.

Example 55

6 - [[1- (3,5-Dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Obtained from 6 - [[3- (3,5-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: Mp 162-164 ° C.

Example 56

6 - [[1- (3,5-Dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reacting 6 - [[3- (3,5-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid with isopropanol according to the general formula 10.

MP: 98-101 C. C.

Example 57

6 - [[1- (3-Methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (3-methoxyphenyl) amino-4-nitrophenol

A mixture of 4 g of 3-fluoro-4-nitrophenol and 9.4 g of m-anisidine was stirred at 150 ° C for 2.5 hours. After cooling, the reaction mixture was dissolved in dichloromethane and extracted three times with 1 N aqueous hydrochloric acid. The organic phase is dried over sodium sulphate, concentrated in vacuo and the residue chromatographed on silica gel.

^X H-NMR (CDC1 _3): δ (ppm): 3.83 s (3H); 6.30 dd (J = 10.2 Hz, 1H); 6.57 d (J = 2Hz, 1 H); 6.70-6.84 m (2H); 6.89 d br (J = 10Hz, 1H); 7.32 t (J = 10Hz, 1 H); 8.19 d (J = 10Hz, 1H); 9.68 with br (1H); 9.69 with br.

b) 6- [3- (3-Methoxyphenyl) amino-4-nitro-phenyl] methyl ester. phenyl] oxyhexánovej

Prepared by the reaction of 3- (3-methoxyphenyl) amino-4-nitrophenol with methyl 6-bromohexanoate according to General Regulation 8.

^X H-NMR (CDCl 3): δ (ppm): 1, 2 · 42 to 1.58 m, 34 t (J = 7.5 Hz>2H); 3.68 '(3H);

(J = 7.5Hz, 2H); 6.32 dd (J = 10.2 Hz, 1H)

6.68-6.84 m (2H); 6.90 d br (J = 8Hz, 1H): 2H); 1.60-1.93 m (4H)

3.80 s 6. 59 d

7.32 t (J = 8Hz, 1 H) (3H); 4.03 (J = 2Hz, 1 H)

8.19 d (J = 10Hz, 1H); 9.70 with br (1H).

6 - [[1- (3-Methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared from 6- [3- (3-methoxyphenyl) amino-4-nitrophenyl] oxyhexanoic acid methyl ester according to general formula 1, followed by cyclization with triethyl orthobenzoate according to general formula 3.

³ Η- NMR : dci ₃ ) δ (ppm): 1.44-1.58 m (2 H ); 1.62-1.86 m (4H); 2.34 T (J = 7, 5 Hz, 2H); 3.68 s (3H); 3 78 s (3 H); 3,95 t (J = 7, 5 i Hz, 2H ); 6. 71 d (J = 1.5 Hz, 1H); 6, 83 dd (J = 1.5, 1.5 Hz, 1H); 6. , 90 dd (J = 8 (1.5 Hz, 1H); 6, 94 dd (J = 8, 1.5Hz, 1H); 7.01 dd (J = 8, 1.5 Hz, 1H); 7.27-7.36 m (3H) ; 7.40 t (J = 8, 1 H); 7.56 dd (J = 8, 2 Hz, 2H); 7.74 d (J = 8Hz, 1H). Ex .ad 58

acid

6 - [[1- (3-methoxyphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanoic acid

Prepared from methyl 6 - [[1- (3-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoate according to General Regulation 9.

MP: Mp 149-152 ° C.

Example 59 ' ^{1 1} ' I ' ¹ , ¹ '

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

a) 3- (4-Methoxyphenyl) amino-4-nitrophenol

A mixture of 3-fluoro-4-nitrophenol (0.16 g) and p-anisidine (0.37 g) was stirred at 150 ° C for 1.5 hours. After cooling, the reaction mixture was dissolved in dichloromethane, extracted twice with 1 N aqueous hydrochloric acid and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated in vacuo.

¹ H-NMR (CDCl ₃ / d ₆ -DMSO): δ (ppm): 3.57 s (3H); 6.06 dd (J = 10.2 Hz, 1H); 6.18 d (J = 2Hz, 1 H); 6.77 d (J = 10Hz, 2H); 7.03 d (J = 10Hz, 2H); 7.89 d (J = 10Hz, 1H); 9.40 with br (1H); 9.80 with br.

b) 6- [3- (4-Methoxyphenyl) amino-4-nitro-phenyl] oxyhexanoic acid methyl ester

It is prepared by reacting 3- (4-methoxyphenyl) amino-4-nitrophenol with methyl β-bromohexanoate according to General Regulation 8.

^X H-NMR (CDC1 _3): δ (Ppm): 1.38-1.50 m (2H); 1.60-1.80 m (4H); 2 33 t (J = 7.5Hz, 2H) ; 3 67 b (3H ); 3,8 5 t (J = 7.5Hz, 2H); 3 88 s (3H); 6.29 dd ( J 10, 1.5 Hz, 1H); 6.30 d (J = 1.5Hz, 1H); 6. 98 d (J = 10Hz, 2H); 7.20 d (J = 10 Hz, 2H); 8.18 d (J = 10 Hz) 1H ); 9.63 with br (1H).

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

Prepared from methyl 6- [3- (4-methoxyphenyl) amino-4-nitrophenyl] oxyhexanoate according to general formula 1 a, followed by cyclisation with triethyl orthobenzoate according to general formula 3.

MP: 98-102 ’C.

I,

Example 60

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

Prepare from 6 - [[1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: 160-165 C. C.

Example 61

6 - [[1- (3,4-Dimethoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (3,4-dimethoxyphenyl) amino-4-nitrophenol

A mixture of 3 g of 3-fluoro-4-nitrophenol and 8.8 g of 3,4-dimethoxyaniline was stirred at 150 ° C for 2 hours. After cooling, the reaction mixture was dissolved in dichloromethane and extracted twice with 1 N aqueous hydrochloric acid. The aqueous phase is extracted twice with chloroform and the combined chloroform extracts are dried over sodium sulphate and concentrated in vacuo.

^X H-NMR (d-DMSO): δ (ppm): 3.75 s (3H); 3.78 s (3H); 6.25 dd (J = 10.2 Hz, 1H); 6.35 d (J = 2Hz, 1 H); 6.88 dd (J = 8, 1.5 Hz, 1H); 6.98 dd (J = 1.5 Hz, 1H); 7.05 d (J = 8Hz, 1H); 8.04 d (J = 10Hz, 1H); 9.52 with br (1H); 10,72 with br.

b) 6- [3- (3,4-Dimethoxyphenyl) amino-4-nitro-phenyl] oxyhexanoic acid methyl ester

It is prepared by reacting 3- (3,4-dimethoxyphenyl) amino-4-nitrophenol with methyl 6-bromohexanoate according to General Regulation 8.

^X H-NMR (CDC1 _3): δ (ppm) ': 1.40 to 1.52 m (2H); 1.60-1.80 m (4H); 2.32 t (J = 7.5Hz, 2H); 3.68 s (3H); 3.85 t (J = 7.5Hz, 2H);

3.88 s (3H); 3.93 s (3H); 6.29 dd (J = 10, 1.5 Hz, 1H); 6.33 d (J = 1.5 Hz, 1H); 6.80 d (J = 1.5 Hz, 1H); 6.87 dd (J = 10, 1.5 Hz,

1H); 6.92 d (J = 10Hz, 1H); 8.18 d (J = 10Hz, 1H); 9.68 sbr (1H).

6 - [[1- (3,4-Dimethoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared from 6- [3- (3,4-dimethoxyphenyl) amino-4-nitrophenyl] oxyhexanoic acid methyl ester according to general formula 1 and subsequent cyclization with triethyl orthobenzoate according to general formula 3.

MP: Mp 116-118 ° C.

Example 62

acid

6 - [[1- (3,4-dimethoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexane

Prepared from methyl 6 - [[1- (3,4-dimethoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoate according to General Regulation 9.

MP: Mp 158-161 ° C.

Example 63

6 - [[1- [3,4- (methylenedioxy) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (3,4-Methylenedioxyphenyl) amino-4-nitrophenol

A mixture of 0.86 g of 3-fluoro-4-nitrophenol and 2.25 g of 3,4-methylenedioxyaniline was stirred at 120 ° C for 5 hours. The crude reaction mixture was subjected to silica gel chromatography.

¹ H-NMR (d ₆ -DMSO): δ (ppm): 6.02 s (2H); 6.25 dd (J = 10.2Hz, 1H); 6, 33 d (J = 2 Hz) 1H); 6.72 dd ( J = 8, 1.5 Hz, 1H); 6, 87 d (J = 5 Hz, 1H); 7.05 d (J = 10Hz, 1 H) ); 8.18 d (J = TO. Hz, 1H); 9, 52 s br 1 : ih).

b) 6- [3- (3,4-methylenedioxyphenyl) amino-4-nitrophenyl] oxyhexanoic acid methyl ester

Prepared by the reaction of 3- (3,4-methylenedioxyphenyl) amino-4-nitrophenol with methyl 6-bromohexanoate according to General Regulation 8.

MP: 108

111 ’C.

6 - [[1- (3,4-methylenedioxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared from methyl 6- [3- (3,4-methylenedioxyphenyl) amino-4-nitrophenyl] oxyhexanoate according to general formula 1 followed by cyclisation with triethyl ortho-benzoate according to general formula 3.

¹ H-NMR (CDCl ₃ ) 2.35 t (J = 7.5 Hz, 6.10 s (2H); 6.65 δ (ppm): 1.43-1.55

2H); 3.68 s (3H);

d (J = 1.5Hz, 1H);

(J = 10Hz, 1 H); 6.93 dd (J = 10, 1.5 Hz)

7.52-7.62 m (2H); 7.72 d (J = 10Hz, 1 H).

m (2H); 1.65-1.82 m 3.95 t (J = 7.5 Hz,

6.72-6.83 m (2H); 1H); 7.29-7.38 m (4H);

2H); 6.90 d (3H);

Example 64

6 [[1- [3,4- (methylenedioxy) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepared from 6 - [[1- (3,4-methylenedioxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: 130 [deg.] C.

Example 65

6 - [[2-Phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (3,4,5-trimethoxyphenyl) amino-4-nitrophenol

A mixture of 3.7 g of 3-fluoro-4-nitrophenol and 4.76 g of 3,4,5-trimethoxyaniline is stirred for 10 hours at 100 ° C. After cooling, the mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases are extracted three times with 1 N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulphate and evaporated as much as possible in vacuo. The product was digested with diisopropyl ether.

9 ¹ H-NMR (d 6 -DMSO): δ (ppm): 3.70 s (3H); 3.80 s (6H); 6.28 dd (J = 10.2 Hz, 1H); 6.53 d (J = 2Hz, 1 H); 6.70 s (2H); 8.05 d (J = 10Hz, 1H); 9.50 with br (1H); 10.71 with br.

b) 6- [4-Nitro-3 - [(3,4,5-trimethoxyphenyl) amino] phenyl] oxyhexanoic acid methyl ester

It is prepared by reacting 4-nitro-3 - [(3,4,5-trimethoxyphenyl) amino] -phenol with methyl 6-bromohexanoate according to General Regulation 8.

^¾ H NMR (CDC1 _3): δ (ppm): 1, 40 to 1.53 m (2H); 1.60-1.82 m (4H); 2.32 T (J = 7.5 Hz, 2 H); 3.67 s (3H ); 3.85 s (6H); 3,88 t (J = 7, 5 Hz, 2H); 3.90 s (3H); 6. 30 dd ( J = 10, 1.5 Hz, 1H); 6,50 d (J = 5 Hz, 1H); 6.52 s (2H); 8,18 d (J = 10Hz, 1 H); 9 68 s br (1H).

6 - [[2-Phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Obtained from 6- [4-nitro-3 - [(3,4,5-trimethoxyphenyl) amino] phenyl] oxy-hexanoic acid methyl ester according to general formula 1 and subsequent cyclization with triethyl orthobenzoate according to general formula 3.

MP: Mp 128-130 ° C.

Example 66

6 - [[2-Phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepared from methyl 6 - [[2-phenyl-1- (3,4,5-trimethoxyphenyl) -4-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: Mp 198-201 ° C. '

Example 67

6 - [[2-Phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reaction of an acid

6 - [[2-phenyl-1- (3,4,5-trimethoxy-phenyl) -ΙΗ-benzimidazol-6-yl] oxy] hexane with isopropanol according to the general formula 10.

MP: Mp 98-101 ° C.

Example 68

6 - [[1- [4- (N, N-dimethylamino) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) N, N-Dimethyl-N '- (5-chloro-2-nitrophenyl) benzene-1,4-diamine

Prepared in analogy to 5-chloro-2-nitrophenyl-m-tolylamine from 1-chloro-3,4-dinitrobenzene and N, N-dimethyl-p-phenylenediamine.

¹ H-NMR (CDCl ₃ ): δ (ppm): 3.01 s (6H); 6.63 dd (J = 10.2 Hz)

IH); 6.80 d br (J = 10Hz, 2H); 6.97 d (J = 2 Hz, 1H); 7.14 d (J = 10Hz, 2H); 8.14 d (J = 10Hz, 1H); 9.42 with br (1H).

b) N, N-Dimethyl-N- (5-methoxy-2-nitrophenyl) benzene-1,4-diamine

24.9 g of N, N-dimethyl-N '- (5-chloro-2-nitrophenyl) benzene-1,4-diamine is added to a solution of 8 g of sodium in 200 ml of methanol and the mixture is heated at autoclave for 9 hours at 120 [deg.] C. After cooling, the crystalline product is filtered off with suction.

^X H-NMR (CDCl 3): δ (ppm): 3.00 s (6H); 3.70 s (3H); 6.25 dd (J = 10.2 Hz, 1H); 6.34 d (J = 2 Hz, 1H); 6.78 d (J = 10Hz, 2H); 7.14 d (J = 10Hz, 2H); 8.16 d (J = 10Hz, 1H); 9.67 with br (1H).

c) 6-Methoxy-1- [4- (N, N-dimethylamino) phenyl] -2-phenyl-1H-benzimidazole

Prepared from N, N-dimethyl-N '- (5-methoxy-2-nitrophenyl) benzene-1,4-diamine according to general formula 1, followed by reaction of the crude diamine with trimethyl orthobenzoate according to general regulation 3, followed by refluxing with 6 N aqueous hydrochloric acid for 1 hour. After alkalization of the reaction mixture with aqueous sodium hydroxide, the mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and concentrated in vacuo.

^{1 H-L-NMR} (CDC1 _3): δ (ppm): 3.04 s (6H); 3.80 s (3H); 6.68 d (J = 2Hz, 1 H); 6.78 d (J = 10Hz, 2H); 6.95 dd (J = 10.2 Hz, 1H);

7.17 d (J = 10Hz, 2H); 7.25-7.33 m (3H); 7.56-7.64 m (2H); 7.74 d (J = 10Hz, 1 H).

d) 6-Hydroxy-1- [4- (Z, Z, N-dimethylamino) phenyl] -2-phenyl-1H-benzimidazole

Prepared from 6-methoxy-1- [4- (AZ, N-dimethylamino) phenyl] -2-phenyl-1H-benzimidazole according to the general formula 6.

¹ H-NMR (d ₆ -DMSO): δ (ppm): 2.98 s (6H); 6.48 d (J = 2Hz, 1 H); 6.78 dd (J = 10.2 Hz, 1H); 6.83 d (J = 10Hz, 2H); 7.17 d (J = 10Hz, 2H); 7.30-7.38 m (3H); 7.50-7.57 m (3H); 9.32 with br (1H).

6 - [[1- [4- (Z, N-Dimethylamino) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6-hydroxy-1- [4- (N, N -dimerylamino) phenyl] -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to general formula 8.

1 H-NMR (CDCl 3): δ (ppm): 1.43-1.57 m (2H); 1,64-1,85 m (4H); 2.33 t (J = 7.5Hz, 2H); 3.05 s (6H); 3.67 s (3H); 3.93 t (J = 7.5Hz, 2H); 6.65 d (J = 2Hz, 1 H); 6.76 d (J = 10 Hz, 2H);

6.93 dd (J = 10.2 Hz, 1 H); 7.14 d (J = 10Hz, 2H); 7.23-7.27 m (3H); 7.62 dd (J = 10, 1.5 Hz, 2H); 7.74 d (J = 10Hz, 1K).

Example 69

6 - [[1- [4- (AZ, N-Dimethylamino) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepared from methyl 6 - [[1- [4- (N, N-dimethylamino) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid according to the general formula 9.

MP: Mp 210-213 ° C.

Example 70

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

a) 5-chloro-2-nitrophenyl-4-biphenylamine

Prepared in analogy to 5-chloro-2-nitrophenyl-m-tolylamine from 1-chloro-3,4-dinitrobenzene and 4-biphenylamine. The product was purified by silica gel chromatography.

H-NMR (CDC1 _3): δ (ppm): 6.76 d (J = 10, 2 Hz, 1 H); 7.26 d (J = 2Hz, 1 H); 7.35 d (J = 8Hz, 1H); 7.32-7.52 m (4H); 7.60-7.72 m (4H); 8.19 d (J = 10Hz, 1H); 9.60 with br (1H).

b) 5-Methoxy-2-nitrophenyl-4-biphenylamine

Prepared in analogy to 5-methoxy-2-nitrophenyl-m-tolylamine by reacting 5-chloro-2-nitrophenyl-4-biphenylamine with sodium methoxide.

MP: Mp 150-154 ° C.

c) 1- (4-Biphenyl) -6-methoxy-2-phenyl-1H-benzimidazole

It is prepared from 5-methoxy-2-nitrophenyl-4-biphenylamine according to general formula 1 and subsequent cyclization with triethyl orthobenzoate according to general regulation 3.

MP: Mp 140-144 ° C.

d) 1- (4-Biphenyl) -6-hydroxy-2-phenyl-1H-benzimidazole

Prepared from 1- (4-biphenyl) -6-methoxy-2-phenyl-1H-benzimidazole according to the general formula 6.

MP: 312 ’C.

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

It is prepared by reacting 1- (4-biphenyl) -6-hydroxy-2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: 106-108 ° C.

Example 71

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

Prepared from 6 - [[1- (4-biphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

¹ H-NMR (d 6 -DMSO): δ (ppm): 1.35-1.78 m (6H); 2.20 t (J = 7.5Hz, 2H); 3.96 m (2H); 6.72 d (J = 2Hz, 1 H); 6.97 dd (J = 10.2 Hz, 1H); 7.32-7.58 m (10H); 7.69 d (J = 10Hz, 1H); 7.80 d (J = 8Hz, 2H); 7.89 d (J = 10Hz, 2H).

Example 72

6 - [[1- (2-Naphthyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (2-Naphthylamino) -4-nitrophenol

A mixture of 3 g of 3-fluoro-4-nitrophenol and 8.2 g of 2-naphthylamine is stirred at 180 ° C for 8 hours. The crude mixture was dissolved in chloroform and washed with 2 N aqueous hydrochloric acid. The organic phase is dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel.

1 H-NMR (d ₆ -DMSO): δ (ppm): 6.02 s (2H); 6.25 dd (J = 10.2 Hz, 1H); 6.33 d (J = 2Hz, 1 H); 6.72 dd (J = 8, 1.5 Hz, 1H); 6.87 d (J = 1.5 Hz, 1H); 7.05 d (J = 10Hz, 1H); 8.18 d (J = 10Hz, 1H);

9.52 with br (1H).

b) 6- [3- (2-Naphthyl) amino-4-nitrophenyl] oxy-hexanoic acid methyl ester

It is prepared by reacting 3- (2-naphthylamino) -4-nitrophenol with 6-bromohexanoic acid methyl ester as described in General Regulation 8.

¹ H-NMR (CDC1 _3): δ (ppm): 1.35 to 1.49 m (2H); 1.60-1, 80 m (4H); 2 30 t (J = 7.5Hz, 2H); 3.64 s (3H); 3.84 t (J = 7.5Hz, 2H); 6, 35 dd (J = 10.2 Hz, 1H); 6.62 d (J = 2Hz, 1 H); 7.43 dd (J = 10, 2 Hz, 1H ); 7.58-7.57 m (2H); 7.75 d (J = 2Hz, 1 H); 7.78-7, 90 m (2H); 7 91 d (J = 10Hz, 1 H); 8.21 d (J = 10Hz, 1H); 9.92 with br (1H).

6 - [[1- (2-Naphthyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared from methyl 6- [3- (2-naphthyl) amino-4-nitrophenyl] oxyhexanoate according to general formula 1, followed by cyclisation with triethyl orthobenzoate according to general formula 3.

MP: Mp 111-114 ° C.

Example 73

6 - [[1- (2-Naphthyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid

MP: 170-175 C. C.

Prepared from 6 - [[1- (2-naphthyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester as described in General Regulation 9.

Example 74

6 - [[1- (2-Fluorenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 3- (2-Fluoro-phenylamino) -4-nitrophenol

A mixture of 2.17 g of 3-fluoro-4-nitrophenol and 5 g of 2-aminofluorene was stirred at 140 ° C for 9 hours. The crude reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with 1 N aqueous hydrochloric acid. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed 3x with 2 N aqueous hydrochloric acid and once with saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel.

^X H- NMR (d ₆ -DMSO) δ (ppm) 3 96 s (2 H); 6.30 dd (J = 10, 2 Hz, 1H); 6 52 d (J = 2 Hz) (1H); 7.28- -7.45 m (3 H); 7,57 with br (1H); 7.60 D (J = 8Hz, 1H); 7.92 d (J = 8 Hz, 1H); 7.98 d (J = 8 Hz, 1H); 8.10 D (J = 10Hz, 1 H); 9.70 s (1H); : 10.80 with br (1H). b) methyl of acid 6-1 [3- (2-Fluoro-phenylamino) -4-nit rof e-

nyl] oxyhexane. It is prepared by reacting 3- (2-fluorenylamino) -4-nitrophenol with methyl 6-bromohexanoate according to General Regulation 8.

I ¹ H-NMR (CDC1 _3): δ (ppm): 1, 38-1, 50 m (2H); 1.58-1.80 m (4H); 2.30 t (J = 7.5Hz, 2H); 3.65 s (3H); 3.84 t (J = 7.5Hz, 2H); 3.95 s (2H); 6.31 dd (J = 10.2 Hz, 1H); 6.53 d (J = 2Hz, 1 H); 7.33 t (J = 8Hz, 2H); 7.42 t (J = 8Hz, 1H); 7.47 s (1H); 7.58 d (J = 8Hz, 1H); 7.80 d (J = 8Hz, 1H); 7.83 d (J = 8Hz, 1H); 8.21 d (J = 10Hz, 1H); 9.87 with br (1H).

6 - [[1- (2-Fluorenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared from methyl 6- [3- (2-fluorenylamino) -. 4-nitrophenyl] oxyhexane according to general formula 1, followed by cyclization with triethyl orthobenzoate according to general regulation 3.

MP: Mp 125-128 ° C.

Example 75

6 - [[1-Phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) Ethyl (3-trifluoromethyl) benzimidate hydrochloride

A solution of 9.7 mL of 3- (trifluoromethyl) benzonitrile in 12 mL of ethanol was saturated with hydrogen chloride gas while cooling in an ice bath. After 72 hours, the precipitated product is filtered off with suction and washed with diethyl ether.

MP: Mp 131-133 ° C (dec.).

b) 5-Methoxy-2-nitrophenyldiphenylamine

A solution of 2 g of 3-fluoro-4-nitroanisole in 16 ml of aniline was stirred at 140 ° C for 24 hours. After cooling, the reaction mixture was diluted with ethyl acetate and extracted with 2 N aqueous hydrochloric acid. The organic phase is dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel.

¹ H-NMR (CDC1 _3): δ (ppm): 3.72 s (3H); 6.36 dd (J = 10.2 Hz)

1H); 6.57 d (J = 2Hz, 1 H); 7.22-7.33 m (3H); 7.44 dd (J = 8.8 Hz,

2H); 8.18 d (J = 10Hz, 1H); 9.78 with br (1H).

c) 4-Methoxy-N ² -phenyl-o-phenylenediamine

Prepared from 5-methoxy-2-nitrophenyldiphenylamine according to General Regulation 1.

¹ H-NMR (CDCl 3): δ (ppm): 3.42 s br (2H); 3.72 s (3H); 5.33 with br (1H); 6.56 dd (J = 10.2 Hz, 1H); 6.76 d (J = 10Hz, 1H); 6.79 d (J = 2 Hz, 1H); 6.82-6.90 m (3H); 7.25 dd (J = 8.2 Hz, 2H).

d) 6-Methoxy-1-phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazole

Prepared by reaction of 4-methoxy-N ^2- phenyl-o-phenylenediamine with ethyl (3-trifluoromethyl) benzimidate hydrochloride according to general formula 4.

MP: 138-140 ° C.

e) 6-Hydroxy-1-phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazole

Prepare from 6-methoxy-1-phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazole according to the general formula 7.

¹ H-NMR (d 6 -DMSO): δ (ppm): 6.60 d (J = 2 Hz, 1H); 6.99 dd (J = 10.2 Hz >1H); 7.50-7.89 m (10H).

6 - [[1-Phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared by the reaction of 6-hydroxy-1-phenyl-2- [3- (trifluoromethyl) phenyl] -4-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: Mp 68-70 ° C.

Example 76

6 - [[1-Phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Prepared by reaction of 6-hydroxy-1-phenyl-2- [3- (trifluoromethyl) phenyl] -4-benzimidazole with 6-bromohexanoic acid isopropyl ester according to general formula 8.

MP: 96-98 ° C.

Example 77

acid

6 - [[1-phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazin-6-yl] oxy] hexane

From methyl 6 - [[1-phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid according to the general formula 9.

1 H-NMR (d ₆ -DMSO): δ (ppm): 1.38-1.80 m (6H); 2.27 t (J = 7.5Hz, 2H); 3.98 t (J = 7.5Hz, 2H); 6.70 d (J = 2 Hz, 1H); 7.02 dd (J = 10.2 Hz, 1H); 7.58-7.88 m (9H); 7.77 d (J = 10Hz, 1H); 11.94 with br (1H).

Example 78

6 - [[1-Phenyl-2- [3- (trifluoromethyl) phenyl] -4-benzimidazol-6-yl] oxy] hexan-1-ol

Prepared from 6 - [[1-phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 11.

^X H-NMR (CDC1 ₃ ): δ (ppm): 1.38-1.68 m ( 6H); 1.75-1.87 m (2H); 3, 60- -3.72 m (2H); 3.94 t (J = 7.5 Hz, 2H) ; 6.69 d (J = 2Hz, 1 H); 6, 99 dd (J = 10,2) Hz, 1H); 7.25-7.35 m (2H ); 7.4 dd (J = 8.8 Hz, 1H); 7,50-7,61 m (4H); 7.68 d br (J = 8 Hz) 1H); 7.78 d (J = 10Hz,

1H); 7.83 with br (1H).

Example 79

6 - [[2- (3-Chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 2- (3-Chlorophenyl) -6-methoxy-1-phenyl-1H-benzimidazole

It is prepared by reacting 4-methoxy-N ^2- phenyl-o-phenylenediamine with ethyl 3-chlorobenzimidate hydrochloride (which is prepared according to

DeWolfe and Augustine, J. Org. Chem. 30, 699) according to General Regulation 4.

MP: Mp 149-151 ° C.

b) 2- (3-Chlorophenyl) -6-hydroxy-1-phenyl-1H-benzimidazole

Prepared from 2- (3-chlorophenyl) -6-methoxy-1-phenyl-1H-benzimidazole according to the general formula 7.

MP: Mp 199-202 ° C.

6 - [[2- (3-Chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared by reacting 2- (3-chlorophenyl) -6-hydroxy-1-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: Mp 69-72 ° C.

Example 80

6 - [[2- (3-Chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Prepared by reacting 2- (3-chlorophenyl) -6-hydroxy-1-phenyl-1H-benzimidazole with 6-bromo-hexanoic acid isopropyl ester according to General Regulation 8.

MP: 98-100 ° C.

Example 81

6 - [[2- (3-Chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Obtained from 6 - [[2- (3-chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: Mp 137-140 ° C.

Example 82

6 - [[2- (3-Chloro-phenyl) -l-phenyl-lH-benzimidazol-6-yl] oxy] hexan-l-ol

Obtained from 6 - [[2- (3-chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 11.

^X H-NMR (CDC1 _3): δ (ppm): 1.40 to 1.70 m (6 H); 1.75-1.86 m (2H); 3.67 t (J = 7.5Hz, 2H); 3.93 t (J = 7.5, 2H); 6.69 d (J = 2Hz, 1 H); 6.99 dd (J = 10.2 Hz, 1H); 7.20 dd (J = 8.8 Hz, 1H);

7.26-7.38 m (4H); 7.47-7.58 m (3H); 7.60 dd (J = 2.2 Hz, 1H);

7.76 d (J = 10Hz, 1H).

Example 83

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

a) Ethyl 4-chlorobenzimidate hydrochloride 4-chlorobenzonitrile g is suspended in 12 ml of ethanol and diethyl ether is added until dissolution. The solution was saturated with hydrogen chloride gas while cooling in an ice bath. After 72 hours, the precipitated product is filtered off with suction and washed with diethyl ether.

MP: Mp 173-174 ° C (dec.).

a) 2- (4-Chlorophenyl) -6-methoxy-1-phenyl-1H-benzimidazole

Prepared by reacting 4-methoxy-N ² -phenyl-o-phenylenediamine with ethyl 4-chlorobenzimidate hydrochloride according to the general formula.

MP: 162-164 C. C.

b) 2- (4-Chlorophenyl) -6-hydroxy-1-phenyl-1H-benzimidazole

Prepared from 2- (4-chlorophenyl) -6-methoxy-1-phenyl-1H-benzimidazole according to the general formula 7.

MP: 246-250 C. C.

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

It is prepared by reacting 2- (4-chlorophenyl) -6-hydroxy-1-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: Mp 86-87 ° C.

Example 84

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

It is prepared by reacting 2- (4-chlorophenyl) -6-hydroxy-1-phenyl-1H-benzimidazole with isopropyl ester of β-bromohexanoic acid according to the general rule 8.

MP: Mp 124-126 ° C.

Example 85

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

Obtained from 6 - [[2- (4-chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

¹ H-NMR (d ₆ -DMSO): δ (ppm): 1.35-1.48 m (2H); 1.50-1.62 m (2H); 1.64-1.77 m (2H); 2.23 t (J = 7.5Hz, 2H); 3.91 t (J = 7.5Hz, 2H); 6.64 d (J = 2Hz, 1 H); 6.96 dd (J = 10.2 Hz, 1H); 7.38-, 50 m (6H); 7.52-7.65 m (3H); 7.70 d (J = 10Hz, 1H).

Example 86

6 - [[2- (4-Chlorophenyl) -1-phenyl-lH-benzimidazol-6-yl] oxy] hexan-l-ol

Obtained from 6 - [[2- (4-chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 11.

1 H-NMR (CDCl ₃ ): δ (ppm): 1.38-1, 68 m (6H); 1.74-1.85 m (2H); 3.67 t br (J = 7.5Hz, 2H); 3.94 t (J = 7.5Hz, 2H); 6.68 dd (J = 2Hz, 1H); 6.98 dd (J = 10.2 Hz, 1H); 7.22-7.35 m (5H);

7.47 d (J = 8Hz, 2H); 7.49-7.59 m (2H); 7.73 d (J = 10Hz, 1 H).

Example 87

6 - [[2- (3-Methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

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

It is prepared by reacting 4-methoxy-W ^2- phenyl-o-phenylenediamine with ethyl 3-methylbenzimidate hydrochloride (prepared according to: DeWolfe and Augustine, J. Org. Chem. 30, 699) according to the general formula.

MP: Mp 156-158 ° C.

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

Prepared from 6-methoxy-2- (3-methylphenyl) -1-phenyl-1H-benzimidazole according to the general formula 7.

¹ H-NMR (d ₆ -DMSO): δ (ppm): 2.23 s (3H); 6.52 d (J = 2Hz, 1 H); 6.80 dd (J = 10.2 Hz, 1H); 7.18 with br (3H); 7.35-7.52 m (3H); 7.50-7.63 m (4H); 9.28 with br (1H).

6 - [[2- (3-Methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6-hydroxy-2- (3-methylphenyl) -1-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to general formula 8.

MP: Mp 82-84 ° C.

Example 88

6 - [[2- (3-Methylphenyl) -1-phenyl-1H-benzoimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by the reaction of 6-hydroxy-2- (3-methylphenyl) -1-phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to General Regulation 8.

^X H-NMR (CDC1 _3): δ (ppm): 1,22'd (J = 7.5 Hz, 6H); 1.38-1.56 m (2 H); 1.62-1.85 m (4H); 2.30 t (J = 7.5Hz, 2H); 2.30 s (3H);

3.93 t (J = 7.5Hz, 2H); 5.00 sp (J = 7.5Hz, 1H); 6.68 d (J = 2Hz, 1H); 6.95 dd (J = 10.2 Hz, 1H); 7.13 with br (3H); 7.31 dd (J = 8.2 Hz, 2H); 7.42-7.57 m (4H); 7.76 d (J = 10Hz, JH).

Example 89

6 - [[2- (3-Methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Obtained from 6 - [[2- (3-methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

^X H-NMR (d-DMSO): δ (ppm): 1, 35 to 1.49 m (2H); 1.50-1.63 m (2H); 1.64-1.78 m (2H); 2.22 t (J = 7.5Hz, 2H); 2.24 s (3H); 3.92 t (J = 7.5Hz, 2H); 6.62 d (J = 2Hz, 1 H); 6.95 dd (J = 10.2 Hz, 1H); 7.18 with br (3H); 7.37-7.42 m (3H); 7.51-7.65 m (3H); 7.67 d (J = 10Hz, 1H); 11.90 with br (1H).

Example 90

6 - [[2- (3-Methylphenyl) -1-phenyl-lH-benzimidazol-6-yl] oxy] hexan-l-ol

Obtained from 6 - [[2- (3-methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MP: Mp 92-94 ° C.

Example 91

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

a) 6-Methoxy-2- (4-methylphenyl) -1-phenyl-1H-benzimidazole

Is it prepared by reaction of 4-methoxy-W ^? phenyl-o-phenylenediamine with ethyl 4-methylbenzimidate hydrochloride (prepared according to DeWolfe and Augustine, J. Org. Chem. 30, 699) according to the general regulation.

MP: Mp 150-152 ° C.

b) 6-Hydroxy-2- (4-methylphenyl) -1-phenyl-1H-benzimidazole

Prepared from 6-methoxy-2- (4-methylphenyl) -1-phenyl-1H-benzimidazole according to the general formula 7.

MP: 257-264 ° C.

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

It is prepared by reacting 6-hydroxy-2- (4-methylphenyl) -1-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to general formula 8.

MP: Mp 99-102 ° C.

Example 92

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

It is prepared by reacting 6-hydroxy-2- (4-methylphenyl) -1-phenyl-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to the general formula 8.

MP: Mp 107-109 ° C.

Example 93

6 - [[2- (4-Methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] 95 hexanoic acid

Prepared from 6 - [[2- (4-methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

^X H-NMR (d-DMSO): δ (ppm): 1.33 to 1.49 m (2H); 1.50-1.62 m (2H); 1.64-1.77 m (2H); 2.22 t (J = 7.5Hz, 2H); 2.30 s (3H);

3.90 t (J = 7.5Hz, 2H); 6.62 d (J = 2Hz, 1 H); 6.94 dd (J = 10.2 Hz, 1H); 7.15 d (J = 8Hz, 2H); 7.36 d (J = 8Hz, 2H); 7.40 dd (J = 8, 1.5 Hz, 2H); 7.52-7.62 m (3H); 7.68 d (J = 10Hz, 1H). '

Example 94

6 - [[2- (4-methylphenyl) -l-phenyl-lH-benzimidazol-6-yl] oxy] hexan-l-ol

Prepared from methyl 6 - [[2- (4-methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to General Regulation 11.

MP: Mp 150-152 ° C.

Example 95

6 - [[1-Phenyl-2- (4-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 6-Methoxy-1-phenyl-2- (4-pyridyl) -1H-benzimidazole

To a solution of 0.4 g of ^4-methoxy-2 .V-phenyl-phenylenediamine of in 8 ml of N, N-dimethylformamide was added 0.7 g of ethyl 2-ethoxy-l, 2-dihydroquinoline-l-carboxylate 0 , 34 g of isonicotinic acid. The mixture was stirred at 10 ° C for 16 hours, diluted with water after cooling, and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. After chromatography on silica gel, the amide obtained is refluxed with 5 ml of 6 N aqueous hydrochloric acid for 3 hours. After cooling, the mixture was stirred with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo.

^X H-NMR (CDC1 _3): δ (ppm): 3.80 s (3H); 6.65 d (J = 2Hz, 1 H);

7.02 dd (J = 10.2 Hz, 1H); 7.32-7.38 m (2H); 7.42 dd. (J = 8,

1.5 Hz, 2H); 7.54-7.62 m (3H); 7.79 d (J = 10Hz, 1H); 8.53 d br (J = 6Hz, 2H).

b) 6-Hydroxy-1-phenyl-2- (4-pyridyl) -1H-benzimidazole

Prepared from 6-methoxy-1-phenyl-2- (4-pyridyl) -1H-benzimidazole according to general formula 7.

^X H-NMR (CD 3 OD): δ (ppm): 6.52 d (J = 2 Hz, 1 H); 6.82 dd (J = 10.2 Hz, 1H); 7.28-7.33 m (2H); 7.39 dd (J = 8, 1.5 Hz, 2H);

7.49-7.57 m (4H); 8.40 d br (J = 6Hz, 2H).

6 - [[1-Phenyl-2- (4-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared from 6-hydroxy-1-phenyl-2- (4-pyridyl) -1H-benzimidazole according to the general formula 8.

MP: Mp 100-103 ° C.

Example 96

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

Obtained from 6 - [[1-phenyl-2- (4-pyridinyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula

9th

MP: 160-162 C. C.

Example 97

Acid methyl ester

6 - [(1,2-Diphenyl-5-nitro-1H-benzimidazol-6-yl) oxy] hexane

a) 1,2-Diphenyl-6-hydroxy-5-nitro-1H-benzimidazole

b) 1,2-Diphenyl-6-hydroxy-7-nitro-1H-benzimidazole

c) 1,2-Diphenyl-6-hydroxy-5,7-dinitro-1H-benzimidazole

To a solution of 5 g of 1,2-diphenyl-6-hydroxy-1H-benzimidazole in 45 ml of acetic acid at 10-15 ° C is added dropwise a solution of 1.67 g of potassium nitrite in 15 ml of water. The mixture was stirred in an ice bath for 2 hours and at 20 ° C for 2 hours, concentrated in vacuo and the product purified by silica gel chromatography.

a) ^X H-NMR (CDC1 _3): δ (ppm): 6.83 s (1H); 7.25-7, 44 m (5H); 7.52-7.60 m (5H); 8.66 s (1H); 10.78 s (1 H).

b) ^X H-NMR (d ₆ -DMSO): δ (ppm): 7.05 d (J = 10 Hz, 1H); 7.30-7.53 m (10H); 7.82 d (J = 10Hz, 1H); 10.83 s (1 H).

c) ^X H-NMR (d-DMSO): δ (ppm): from 7.32 to 7, 58 m (10 H); 8.67 s (1H).

6 - [(1,2-Diphenyl-5-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

Prepared by reaction of 1,2-diphenyl-6-hydroxy-5-nitro-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: 123 ’C.

Example 98

6 - [(1,2-Diphenyl-5-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester

Prepared by the reaction of 1,2-diphenyl-6-hydroxy-5-nitro-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to the general formula 8.

MP: 115-117 C. C.

Example 99

6 - [(1,2-Diphenyl-7-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

Prepared by reaction of 1,2-diphenyl-6-hydroxy-7-nitro-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: 110-112 C. C.

Example 100

6 - [(1,2-Diphenyl-7-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester

It is prepared by the reaction of 1,2-diphenyl-6-hydroxy-7-nitro-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to general formula 8.

MP: 88 ’C.

Example 101

6 - [(7-Amino-1,2-diphenyl-1H-benzimidazol-β-yl) oxy] hexanoic acid methyl ester

340 mg of 6 - [(1,2-diphenyl-7-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester was hydrogenated in ethanol on Raneynikli in an autoclave at 50 ° C at atmospheric pressure. After the hydrogen uptake is complete, the catalyst is filtered off and the filtrate is concentrated in vacuo.

MP: 113-115 C. C.

Example 102

6 - [(7-Amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester

Prepared from 6 - [(1,2-diphenyl-7-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester analogously to Example 101.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.22 d (J = 7.5 Hz, 6H); 1.43-1, 88 m (6H); 2.30 t (J = 7.5Hz, 2H); 4.04 t (J = 7.5Hz, 2H); 5.00 sp (J = 7.5Hz, 1H); 6.97 d (J = 7.5Hz, 1H); 7.20 _{I '7.33} m (4 H); 7.42-7.53 m (7H).

Example 103

6 - [(5,7-Dinitro-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

It is prepared by reacting 5,7-dinitro-1,2-diphenyl-6-hydroxy-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to general formula 8.

MP: 88-91 C. C.

Example 104

6 - [(5,7-Dinitro-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester

It is prepared by the reaction of 5,7-dinitro-1,2-diphenyl-6-hydroxy-1H-benzimidazole with 6-bromohexanoic acid isopropyl ester according to general formula 8.

MP: 92 - 93 ’C.

Example 105

6 - [[5- (Acetylamino) -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 5-Fluoro-2,4-dinitrophenol

A solution of 0.41 g of 1,3-difluoro-4,6-dinitrobenzene in 8 ml of 0.5 N aqueous sodium hydroxide solution was refluxed for 2 hours. After

After cooling, the reaction mixture is diluted with water and extracted three times with diethyl ether. The aqueous phase is acidified with 1 N hydrochloric acid and then extracted with diethyl ether. The organic phase is dried over sodium sulphate and concentrated in vacuo.

¹ H-NMR (CDCl ₃ ): δ (ppm): 7.10 d (J = 12 Hz, 1H); 9.03 d (J = 8 Hz, 1 H) ^1; 11.10. s (1 H).

b) 2,4-Dinitro-5-hydroxydiphenylamine

To a suspension of 50 mg of 5-fluoro-2,4-dinitrophenol in 0.5 ml of ethanol is added 100 μΐ of aniline, the mixture is stirred for 30 minutes and then left to stand for 15 hours. The solid is filtered off with suction, washed with 1 N aqueous hydrochloric acid and dried under vacuum.

¹ H-NMR (CDCl 3): δ (ppm): 6.58 s (1H); 7.31 d (J = 10Hz, 2H); 7.39 dd (J = 10, 10 Hz, 1H); 7.51 dd (J = 10, 10 Hz, 2H); 9.20 s (1H); 9.90 with br (1H); 10.97 with br (1H).

c) (2,4-Dinitro-5-phenylamino) phenylacetate

To a solution of 275 mg of 2,4-dinitro-5-hydroxydiphenylamine in 1 ml of pyridine was added 0.11 ml of acetic anhydride, the mixture was stirred in an ice bath for 30 minutes and then at 20 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed three times with glacial 1N aqueous hydrochloric acid, once with saturated potassium bicarbonate solution and once with saturated sodium chloride solution. After drying over sodium sulfate, the solvent was evaporated in vacuo.

@ ¹ H-NMR (CDCl3): .delta. (Ppm): 2.34 s (3H); 6.80 s (1 H); 7.32 d (J = 10Hz, 2H); 7.40 dd (J = 10, 10 Hz, 1H); 7.52 dd (J = 10, 10 Hz, 2H); 9.21 s (1H); 9.95 with br (1H).

d) (1,2-Diphenyl-6-hydroxy-1H-benzimidazol-5-yl) acetamide

It is prepared from (2,4-dinitro-5-phenylamino) phenylacetate according to general formula 1 and subsequent reaction with trimethyl orthobenzoate according to general formula 3.

101 ¹ H-NMR (CDCl ₃ ): δ (ppm): 2.26 s (3H); 6.88 s (1H);

7.22-7.36 m (5H); 7.42-7.53 m (5H); 7.61 s (1H); 8.43 with br (1H).

6 - [[5- (Acetylamino) -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared by reaction of (1,2-diphenyl-6-hydroxy-1H-benzimidazol-5-yl) acetamide with methyl 6-bromohexanoate according to general procedure 8.

MP: Mp 128-130 ° C.

Example 106

6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester

Prepared from 6 - [(1,2-diphenyl-5-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester according to General Regulation 1.

^X H-NMR (CDCl 3): δ (ppm): 1.23 d (J = 7.5 Hz, 6H); 1.47-1.90 m (6H); 2.32 t (J = 7.5Hz, 2H); 3.95 t (J = 7.5Hz, 2H); 5.02 sp (J = 7.5Hz, 1H); 6.60 s (1 H); 7.20 s (1H); 7.22-7.33 m (5H); 7.43-7.58 m (5Η):

Example 107

6 - [[5 - [[(4-Bromophenyl) sulfonyl] amino] -1,2-diphenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Prepared by reaction of 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with 4-bromobenzenesulphonic acid chloride according to General Regulation 13.

MP: Mp 173-175 ° C.

Example 108

6 - [(5-amino-1,2-diphenyl-1H-benzimidazole) methyl ester 102

6-yl) oxy] hexanoic acid

Prepared from methyl 6 - [(1,2-diphenyl-5-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester according to the general formula

First

^X H-NMR (CDC1 _3): δ. (ppm): 1.48-1.88 m (6H); 2.36 t (J = 7.5 Hz, 2H, = _CH2 CO); 3.67 s (3H); 3.94 t (J = 7.5Hz, 2H);

6.60 s (1 H); 7.21 s (1H); 7.22-7.35 m (5H); 7.43-7.59 m (5Hi.

Example 109

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared by reaction of 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester with 4-chlorobenzenesulfonic acid chloride according to General Regulation 13.

MP: Mp 157-159 ° C.

Example 110

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reacting 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with 4-chlorobenzenesulfonic acid chloride according to General Regulation 13.

MP: Mp 158-159 ° C.

Example 111

6 - [[5 - [[(4-Chlorophenyl) sulfonyl] amino] -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepared by reaction of 6 - [[5 - [[(4-chlorophenyl) -sulfonyl] amino] -1,2-diphenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

103

MP: 201-203 ’C.

Example 112

6 - [[1,2-Diphenyl-5 - [[(3-methylphenyl) -sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Prepared by reaction of 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with 3-methylbenzenesulphonic acid chloride according to the general formula 13.

MP: 149 - '151 C. · '

Example 113 '

6 - [[1,2-Diphenyl-5 - [[(4-methylphenyl) -sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reacting 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with 4-methylbenzenesulfonic acid chloride according to the general formula 13.

MP: 139-141 C. C.

Example 114

6 - [[1,2-Diphenyl-5 - [[(4-methoxyphenyl) -sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reacting 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with 4-methoxybenzenesulfonic acid chloride according to the general formula 13.

^X H-NMR (CDC1 _3): δ (ppm): 1.25 d (J = 7.5 Hz, 6H); 1.35-1.45 m (2H); 1.59-1.73 m (4H); 2.30 t (J = 7.5Hz, 2H); 3.72 t (J = 7.5 Hz,

2H); 3.80 s (3H); 5.02 sp (J = 7.5Hz, 1H); 6.50 s (lH); 6.85 d (J = 10Hz, 2H); 6.99 s (1H); 7.25-7.35 m (5H); 7.45-7.52 m (5H);

7.74 d (J = 10Hz, 2H); 7.99 s (1 H).

Example 115

104

6 - [[1,2-Diphenyl-5 - [[[(4-trifluoromethyl) phenyl] sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Prepared by reaction of 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with 4-trifluoromethylbenzenesulphonic acid chloride according to General Regulation 13.

MP: Mp 170-171 ° C.

Example 116

6 - [[5 - [[[4- (acetylamino) phenyl] sulfonyl] amino] -1,2-diphenyl-benz-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Prepared by reaction of 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with 4-acetylaminobenzenesulphonic acid chloride according to General Regulation 13.

MP: .100-102 ° C.

Example 117

6 - [[5 - [[Bis (3-chlorophenyl) sulfonyl] amino] -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester. It is prepared by reacting 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with 3-chlorobenzenesulfonic acid chloride according to General Regulation 13.

MP: Mp 163-167 ° C.

Example 118

6 - [[1,2-Diphenyl-5 - [(propylsulfonyl) amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by the reaction of 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with propanesulphonic acid chloride according to General Regulation 13.

105

MP: Mp 126-128 ° C.

Example 119

6 - [[5 - [(Benzylsulfonyl) amino] -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

It is prepared by reacting 6 - [(5-amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid isopropyl ester with benzene methanesulfonic acid chloride according to General Regulation 13.

Mp 137-138 ^° C

Example 120

4 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] methylbenzoic acid methyl ester

Prepared by reaction of 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 4- (bromomethyl) berizoic acid methyl ester of General Regulation 8.

MP: Mp 180-184 ° C.

Example 121

4 - [(1,2-Diphenyl-ΙΗ-benzimidazol-6-yl) oxy] methylbenzoic acid

Prepared from 4 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] methylbenzoic acid methyl ester according to the procedure in General Regulation 9.

¹ H-NMR (d 6 -DMSO): δ (ppm): 5.12 s (2H); 6.76 d (J = 2Hz, 1H); 7.04 dd (J = 10.2 Hz, 1H); 7.30-7.63 m (12H); 7.70 d (J = 10Hz,

1H); 7.89 d (J = 8Hz, 2H).

Example 122

4 - [[1- (3-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] methylbenzoic acid methyl ester

106

It is prepared by reacting 6-hydroxy-1- (3-methylphenyl) -2-phenyl-1H-benzimidazole with 4- (bromomethyl) benzoate methyl ester according to the general formula 8.

MP: 138-142 C. C.

Example 123. .

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

It is prepared by reacting 6-hydroxy-1- (4-methylphenyl) -2-phenyl-ΙΗ-benzimidazole with 4- (bromomethyl) benzoate methyl ester according to the general formula 8.

MP: Mp 145-148 ° C.

Example 124

2- [2 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] ethoxy] acetic acid tert-butyl ester

To a suspension of 0.2 g of [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] ethan-1-ol in 1.7 ml of toluene and 0.7 ml of tetrahydrofuran is added 0.1 ml of tert- butyl bromoacetate, 13 mg tetrabutylammonium hydrogensulfate and 1.45 ml 32% sodium hydroxide solution and the mixture was stirred for 48 hours. An additional 0.1 ml of tert-butyl bromoacetate and 13 mg of tetrabutylammonium hydrogen sulfate are then added and the mixture is placed in an ultrasonic bath for 48 hours. Finally, it is diluted with water and extracted three times with toluene. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel.

¹ H-NMR (CDC1 _3):? (Ppm): 1.43 (9H); 3.91 t (J = 6Hz, 2H);

4.10 s (2H); 4.17 t (J = 6 Hz, 2H); 6.75 d (J = 2Hz, 1 H); 7.00 dd (J = 10.2 Hz, 1H); 7.24-7.36 m (5H); 7.45-7.56 m (5H); 7.76 d (J = 10Hz, 1 H).

107

Example 125

2- [2 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) -2- [2 - [(1,2-diphenyl-enyl-benzimidazol-6-yl) oxy] ethoxy] acetic acid mg of tert-butyl ester -yl) oxy] ethoxy] acetic acid is dissolved in 0.5 ml of trifluoroacetic acid and the solution is allowed to stir for 48 hours. It is then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried. over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel.

MP: 134-136 C. C.

Example 126

2- [2 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] ethoxy] acetic acid methyl ester mg of 2- [2 - [(1,2-diphenyl-1H-benzimidazol-6-yl) (oxy) ethoxy] acetic acid is dissolved in 0.4 ml of N, N-dimethylformamide and 29 mg of cesium carbonate and 50 µl of methyl iodide are added, the mixture is stirred for 20 hours, concentrated in vacuo and chromatographed on silica gel.

^X H-NMR (CDC1 _3): δ (ppm): 3.73 s (3H); 3.93 t (J = 6Hz, 2H); 4.18 t (J = 6Hz, 2H); 4.25 s (2H); 6.73 d (J = 2Hz, 1 H); 7.00'dd (J = 10.2Hz, 1H); 7.25-7.42 m (5H); 7.46-7.58 m < -1 >(5H); 7.77 d (J = 10Hz, 1 H).

Example 127

3- [2 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] ethoxy] propanoic acid tert-butyl ester

To a suspension of 0.2 g of [(1,2-diphenyl-1H-benzimidgzol-6-yl) oxy] ethan-1-ol in 1.7 ml of toluene and 0.7 ml of tetrahydrofuran is added 60 μΐ of tert-butyl ester of acrylic acid, 13 mg of tetrabutyl108 ammonium hydrogensulfate and 1.45 ml of 32% sodium hydroxide solution and the mixture was stirred for 48 hours. An additional 60 μΐ of acrylic tert-butyl ester and 13 mg of tetrabutylammonium hydrogen sulfate are then added and the mixture is placed in an ultrasonic bath for 48 hours. Finally, it is diluted with water and extracted three times with toluene. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel.

^X H-NMR (CDC1; ): δ (ppm) : 1, 45 sec (9H) ; 2.52 t (J = 8 Hz, 2H); 3.73- -3.84 m (4H); 4,10 t (J = 6 Hz, 2H); 6.72 d (J = 2Hz, 1H); 6, 99 dd (J = 10, 2 Hz, 1H); 7.22 -7,38m (5H); 7.45-7.57 m (5H);

7.75 d (J = 10Hz, 1 H).

Example 128

3- [2 - [(1,2-Diphenyl-ΙΗ-benzimidazol-6-yl) oxy] ethoxy] propanoic acid 3- [2 - [(1,2-diphenyl-1H-benzimidazol-6) -teriate] -yl) oxy] ethoxy] propanoic acid was dissolved in 0.5 ml of trifluoroacetic acid and stirred for 15 hours. It is then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel.

^X H-NMR (d ₆ -DMSO): δ (ppm): 2.26 t (J = 8 Hz, 2H); 3.60-3.70 m (4H); 3.98-4.06 m (2H); 6.65 d (J = 2Hz, 1 H); 6.94 dd (J = 10.2 Hz, 1H); 7.30-7.62 m (10H); 7.68 d (J = 10Hz, 1 H).

Example 129

3- [2 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] ethoxy] propanoic acid methyl ester mg of 3- [2 - [(1,2-diphenyl-1H-benzimidazol-6-yl) (oxy) ethoxy] propanoic acid is dissolved in 0.4 ml of N, N-dimethylformamide and 28 mg of cesium carbonate and 50 μΐ of methyl iodide are added and the mixture

109 was stirred for 30 hours. Water was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel.

MP: Mp 91-93 ° C. '

Example 130 3- [3 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] propoxy] propanoic acid tert-butyl ester

0.2 g of 3 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] propan-1-ol is suspended in 1.7 ml of toluene and 0.7 ml of tetrahydrofuran. To this suspension was added 60 μΐ of acrylic acid tert-butyl ester, 13 mg of tetrabutylammonium hydrogen sulfate and 1.47 ml of a 3.2% sodium hydroxide solution, and the mixture was stirred for 48 hours. An additional 60 μΐ of t-butyl acrylate and 13 mg of tetrabutylammonium hydrogen sulfate are then added and the mixture is placed in an ultrasonic bath for 48 hours. Finally, the reaction mixture is diluted with water and extracted three times with toluene. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel.

MP: Mp 95-98 ° C.

Example 131

(E / Z) -5- (1,2-Diphenyl-1H-benzimidazol-6-yl) pent-4-enoic acid methyl ester

a) 1,2-Diphenyl-6-methyl-1H-benzimidazole

5.1 g of 5-methyl-2-nitrodiphenylamine are hydrogenated in 55 ml of ethanol according to general formula 1 and the crude product is reacted with trimethyl orthobenzoate according to general formula 3.

110

MP: Mp 134-136 ° C.

b) 1,2-Diphenyl-1H-benzimidazole-6-carbaldehyde

To a suspension of 1 g of 1,2-diphenyl-6-methyl-1H-benzimidazole in 31 ml of 40% sulfuric acid is added 13.5 g of cerium ammonium nitrate. The mixture was stirred at 80 ° C for 2.5 hours, cooled to 20 ° C, and added cautiously to saturated aqueous sodium bicarbonate while stirring. The mixture is extracted three times with ethyl acetate, the combined extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent is evaporated to dryness in vacuo. The residue is chromatographed on silica gel.

1 H-NMR (CDCl ₃ ): δ (ppm): 7, 30-7.42 m (5H); 7.50-7.66 m (5H); 7.81 d (J = 2 Hz, 1H); 7.89 dd (J = 8.2 Hz, 1H); 8.00 d (J = 8Hz, 1H); 10.05 s (1H).

(E / Z) -5- (1,2-Diphenyl-1H-benzimidazol-6-yl) pent-4-enoic acid methyl ester

It is prepared by reacting 1,2-diphenyl-1H-benzimidazole-6-carbaldehyde with 3-carboxypropyltriphenylphosphonium bromide according to the general formula 12.

1 H-NMR (CDCl 3): δ (ppm): 2.40-2.71 m (4H); 3.68 s (3H);

3.66 s (3H); 5.56-5.64 m (1H); 6.12-6.22 m (1H); 6.50 d (J = 18 Hz, 1H); 6.58 d br (J = 12 Hz, 1H); 7.12 s br (1H); 7.15 s br (1H); 7.25-7, 40 m (6H); 7.45-7.62 m (5H); 7.80 d (J = 8Hz, 1H); 7.83 d (J = 8Hz, 1H).

Example 132

(E) -5- (1,2-Diphenyl-1H-benzimidazol-6-yl) pent-4-enoic acid

Prepared from (E / Z) -5- (1,2-diphenyl-1H-benzimidazol-6-yl) pent-4-enoic acid methyl ester according to the general formula

9th

111 ^X H-NMR (CD ₃ OD): δ (ppm): 2.26 to 2.43 m (4 H); 6.10-6.21 m (1H); 6.45 d (J = 18Hz, 1H); 7.08 s (1H); 7.22-7.52 m (11H); 7.59 d (J = 8Hz, 1H).

Example 133

5- (1,2-Diphenyl-1H-benzimidazol-6-yl) pentanoic acid methyl ester

Prepared from (E / Z) -5- (1,2-diphenyl-1H-benzimidazol-6-yl) pent-4-enoic acid methyl ester according to the general formula

First

^X H-NMR (CDCl 3): δ (ppm): 1.63 to 1.72 m (4 H); 2.30-2.39 m (2H); 2.68-2.77 m (2H); 3.65 s (3H); 7.04 with br (1H); 7.17 dd (J = 8.2 Hz, 1H); 7.25-7.38 m (5H); 7.45-7.60 m (5H); 7.79 d (J = 8Hz, 1 H).

Example 134

5- (1,2-Diphenyl-1H-benzimidazol-6-yl) pentanoic acid

Prepared from methyl 5- (1,2-diphenyl-1H-benzimidazol-6-yl) pentanoate according to General Regulation 9.

MP: 192-193 C. C.

Example 135

(E / Z) -6- (1,2-Diphenyl-1H-benzimidazol-6-yl) hex-5-enoic acid methyl ester

Obtained from 1,2-diphenyl-1H-benzimidazole-6-carbaldehyde and 4-carboxybutyltriphenylphosphonium bromide according to the general formula 12.

^X H-NMR (CDCl 3): δ (ppm): 1.72 to 1.88 m · (2 H); 2.20-2.42 m (4H); 3.65 s (3H, _CH3); 3.67 s (3H, _CH3); 5.57-5.68 m (1H); 6.10-6.20 m (lH); 6.48 d (J = 18Hz, 1H); 6.56 d br (J = 12Hz, 1H); 7.12 with br (1H); 7.16 with br (1H); 7.25-7.38 m (6H); 7.45-7.60 m (5H); 7,80 d

112 (J = 8Hz, 1 H); 7.84 d (J = 8Hz, 1 H).

Example 136

(E / Z) -6- (1,2-Diphenyl-1H-benzimidazol-6-yl) hex-5-enoic acid

Prepared from (E / Z) -6- (1,2-diphenyl-1H-benzimidazol-6-yl) -hex-5-enoic acid methyl ester according to the general formula 9.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.74-1.89 m (2H); 2.22-2.43 m (4H); 5.58-5.68 m (lH); 6.10-6.22 m (1H); 6.47 d (J = 18Hz, 1H); 6.55 d br (J = 12Hz, 1H); 7.11 s (1H); 7.14 s (1H); 7.25-7.40 m (6H);

7.48-7.59 m (5H); 7.80 d (J = 8Hz, 1H); 7.85 d (J = 8Hz, 1 H).

Example 137

6- (1,2-Diphenyl-1H-benzimidazol-6-yl) hexanoic acid methyl ester i

Prepared from (E / Z) -6- (1,2-diphenyl-1H-benzimidazol-6-yl) hex-5-enoic acid methyl ester according to General Regulation 1.

^X H-NMR (CDCl 3): δ (ppm): 1.32 to 1, 43 m (2H); 1.62-1.74 m (4H); 2.31 t (J = 7.5Hz, 2H); 2.72 t (J = 7.5 Hz, 2H); 3.56 s (3H); 7.02 with br (1H); 7.18 dd (J = 8.2 Hz, 1H); 7.27-7.38 m (5H); 7.45-7, 60m (5H); 7.80 d (J = 8Hz, 1H).

Example 138

6- (1,2-Diphenyl-1H-benzimidazol-6-yl) hexanoic acid

Prepared from 6- (1,2-diphenyl-1H-benzimidazol-6-yl) hexanoic acid methyl ester according to general formula 9.

¹ H- -NMR (CDCl 3): δ (ppm): 1.30-1.45 m (2H); 1,54-1,74 m (4H); 2.32 T (J = 7.5Hz, 2H) ; 2.70 t (J = 7.5 Hz, 2H) ; 7,0 2 s b r (1H); 7.20  dd (J = 8.2Hz, 1H); 7.25-7.38 m (5H); 7.42-7.60 m (5H); 7.81 D (J = 8Hz, 1 H).

Example 139

113

(E / Z) -7- (1,2-Diphenyl-1H-benzimidazol-6-yl) hept-6-enoic acid methyl ester

It is prepared by reacting 1,2-diphenyl-1H-benzimidazole-6-carbaldehyde with 5-carboxybutyltriphenylphosphonium bromide according to the general formula 12.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.43-1.55 m - (2H); 1.58-1.72 m (2H); 2.18-2.38 m (4H); 3.65 s (3H, _CH3); 3.66 s (3H, _CH3); 5.58-5.68 m (lH); 6.12-6.22 m (1H); 6.45 d (J = 18Hz, 1H); 6.54 d br (J = 12Hz, 1H); 7.12 with br (1H); 7.14 s br (ΊΗ); 7.26-7.40 m (6H); 7.4 8-7.60 m (5H); 7.80 d (J = 8Hz, 1H); 7.83 d (J = 8Hz, 1H).

Example 140

(E / Z) -7- (1,2-Diphenyl-1H-benzimidazol-6-yl) hept-6-enoic acid

Prepared from (E / Z) -7- (1,2-diphenyl-1H-benzimidazol-6-yl) hept-6-enoic acid methyl ester according to the general regulation

9th

¹ H-NMR (d ₆ -DMSO): δ (ppm): 1.40-1.60 m (4H); 2.14-2.28 m (4H); 6.18-6.30 m (1H); 6.50 d (J = 18Hz, 1H); 7.07 with br (1H); 7.12 with br (1H); 7.32-7.64 m (11H); 7.70 d (J = 8Hz, 1H); 7.78 d (J = 8Hz, 1H); 12.00 with br (1H).

Example 141

7- (1,2-Diphenyl-1H-benzimidazol-6-yl) heptanoic acid methyl ester i

Prepared from (E / Z) -7- (1,2-diphenyl-1H-benzimidazol-6-yl) hept-6-enoic acid methyl ester according to the general regulation

First

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.30-1.42 2.30 t (J = 7.5 Hz, 2H); 2.68 t (J = 7,

7.02 with br (1H); 7.18 dd (J = 8.2 Hz)

7.45-7.58 m (5H); 7.79 d (J = 8Hz, 1 H).

m (4H); 1.55-1.70 m 5 Hz, 2H); 3,56 s

1H); 7.28-7.35 m (4H); (3H);

(5H);

114

Example 142

7- (1,2-Diphenyl-1H-benzimidazol-6-yl) heptanoic acid

It is prepared from 7- (1,2-diphenyl-1H-benzimidazol-6-yl) heptanoic acid methyl ester according to the general formula 9.

T. t. 99-103 ° C.

Example 143

N- (1,2-Diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide.

Example 144

N- (phenylsulfonyl) -N- (1,2-diphenyl-ΙΗ-benzoimidazol-5-y1) -benzenesulfonamide

a) 5-Amino-1,2-diphenyl-1H-benzimidazole

It is prepared by reacting 2,4-diaminodiphenylamine with trimethyl orthobenzoate according to general rule 3.

^X H-NMR (CDC1 _3): δ (ppm): 6.70 dd (J = 7.5, 2 Hz, 1 H); 7.06 d (J = 7.5Hz, 1H); 7.18 d (J = 2Hz, 1 H); 7.28-7.60 m (10H).

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted with benzenesulfonyl chloride according to general formula 13.

143: m.p. Mp 196-205 ° C.

144 ^X H-NMR (CDC1 _3): δ (ppm): 6.94 dd (J = 7.5, 2 Hz, 1 H);

7.20 d (J = 2Hz, 1H); 7.26-8.04 m (21H).

Example 145

3-Chloro- N - (1,2-diphenyl-ΙΗ-benzimidazol-5-yl) benzenesulfonamide

Example 146

N - [(3-Chlorophenyl) sulfonyl] -N- (1,2-diphenyl-ΙΗ-benzimidazol-5-yl) 115 (3-chlorobenzene) sulfonamide

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted with 3-chlorobenzenesulfonyl chloride according to the general formula 13.

145: m.p. 160-162 C. C.

144: ¹ H-NMR (CDCl ₃ ): δ (ppm): 6.93 dd (J = 7.5, 2 Hz, 1H);

7.25 d (J = 2Hz, 1 H); 7.28-7.57 m (13H); 7.66 d br (2H); 7.90 d br (2H); 8.00 d br (2H).

Example 147 i

4-Chloro-N- (1,2-diphenyl-lH-benzoimidazol-5-yl) -benzenesulfonamide

5-Amino-1,2-diphenyl-1H-berisimidazole is reacted with

4-chlorobenzenesulfonyl chloride according to the general formula 13.

¹ H-NMR (CDCl 3): δ (ppm): 6.86 s br (1H); 7.11 d (J = 7.5, 2 Hz, 1H); 7.17 d (J = 2Hz, s); 7.25-7.55 m (12H); 7.70 d (J = 10Hz, 2H).

Example 148

4-Bromo-N- (1,2-diphenyl-lH-benzoimidazol-5-yl) -benzenesulfonamide

Example 149

N - [(4-Bromophenylsulfonyl) -N- (1,2-diphenyl-1H-benzimidazol-5-yl)] - 4-bromobenzenesulfonamide

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted with 4-bromobenzenesulfonyl chloride according to general formula 13.

148: m.p. 135-139 C. C.

149: 1 H-NMR (CDCl ₃ ): δ (ppm): 6.90 dd (J = 7.5, 2 Hz, 1H); 7.23 d (J = 2Hz, 1 H); 7,28-7 _? 43 m (11H); 7.72 d (J = 10Hz, 2H); 7.86 d '(J = 10Hz, 2H).

Example 150

116

4- (Trifluoromethyl) -N- (1,2-diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide

Example 151

N- (1,2-diphenyl-1H-benzimidazol-5-yl) -N - [(3-trifluoromethyl) phenylsulfonyl] - (3-trifluoromethyl) benzenesulfonamide

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted with (3-trifluoromethyl) benzenesulfonyl chloride according to the general formula 13.

150: m.p. Mp 116-121 ° C.

151: m.p. Mp 238-241 ° C.

Example 152

3-Methyl-N- (1,2-diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide

Example 153

N- (1,2-diphenyl-lH-benzoimidazol-5-yl) -N- (3-methylphenyl sulfonyl) -3-methyl-benzenesulfonamide

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted with

3-methylbenzenesulfonyl chloride according to the general formula 13.

152: m.p. Mp 192-195 ° C.

153: m.p. 173-176 C. C.

Example 154

4-Methyl-N- (1,2-diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide

Example 155

N- (1,2-difeny1-1H-benzoimidazol-5-yl) -N- (4-methyl-phenylsulfonyl) -4-methyl-benzenesulfonamide

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted

117 with 4-methylbenzenesulfonyl chloride according to general formula 13.

154: H-NMR (CDC1 _3): δ '(ppm): 2.38 s (3H); 6.77 with br (1H);

7.14-7.55 m (14H); 7.66 d (J = 10Hz, 2H).

155: m.p. Mp 234-236 ° C.

Example 156

4-Methoxy-N- (1,2-diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide

Example 157

N- (1,2-Diphenyl-1H-benzimidazol-5-yl) -N- (4-methoxyphenylsulfonyl) -4-methoxybenzenesulfonamide

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted with 4-methoxybenzenesulfonyl chloride according to general formula 13.

156: 1 H-NMR (CDCl ₃ ): δ (ppm): 3.82 s (3H); 6.78 with br (1H,

H-4); 6.88 d (J = 7.5Hz, 1H); 7.14 d (J = 1.5 Hz, 1H); 7.28-7.55 m (12H); 7.72 d (J = 8Hz, 2H).

157: ¹ H-NMR (CDCl ₃ ): δ (ppm): 3.90 s (6H); 6.93 dd (J = 7.5, 2 Hz, 1H); 7.00 d (J = 10Hz, 4H); 7.06 d (J = 2Hz, 1 H);

7.30-7.58 m (11H); 7.93 d (J = 10Hz, 4.H).

Example 158

N- (1,2-diphenyl-1H-benzimidazol-5-yl) propanesulfonamide; ·.

I ·,,

Example 159

N- (1,2-diphenyl-1H-benzimidazol-5-yl) -N- (propylsulfonyl) propanesulfonamide

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted with propanesulfonyl chloride according to general formula 13.

158: ¹ H-NMR (CDCl ₃ / d ₆ -DMSO): δ (ppm): 0.80 t (J = 7.5 Hz, 3H);

118

1.65 m (2H); 2.82 m (2H); 6.95 d (J = 7.5Hz, 1H); 7.08 dd (J = 7.5, 2 Hz, 1H); 7.10-7.40 m (10H); 7.61 d (J = 2Hz, 1 H); 9.05 with br (1H, NH).

159: ¹ H-NMR (CDCl ₃ ): δ (ppm): 1.08 t (J = 7.5 Hz, 3H); 1.12 t (J = 7.5Hz, 3H); 2.00 m (4H); 3.60 m (4H); 7.25-7.63 m (13H).

Example 160

N- (1,2-diphenyl-1H-benzimidazol-5-yl) -benzenemethanesulfonamide

5-Amino-1,2-diphenyl-1H-benzimidazole is reacted with benzenemethanesulfonyl chloride according to general formula 13.

MP: 185-188 C. C.

I

Example 161

6 - [[1,2-Diphenyl-1H-benzimidazol-5-yl] amino] hexanoic acid methyl ester

Example 162

6- [N- (1,2-Diphenyl-1H-benzimidazol-5-yl) -Z7 - [(5-methoxycarbonyl) pentyl] amino] hexanoic acid methyl ester

To a solution of 285 mg of 5-amino-1,2-diphenyl-1H-benzimidazole in 5 mL of methanol was added 207 mg of 6-bromohexanoic acid methyl ester, 138 mg of potassium carbonate and 150 mg of iodide. solution, and the mixture is stirred, t ^r ± days at 20 ° C. Water is then added, extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel.

16i: m.p. 109-113 C. C.

162: ¹ H-NMR (CDCl ₃ ): δ (ppm): 1.30-1.43 m (4H); 1.53-1.73 m (8H); 2.32 t (J = 7.5Hz, 4H); 3.30 t (J = 7.5Hz, 4H); 3.68 s (6H); 6.75 dd (J = 10.2 Hz, 1H); 7.10 d (J = 10Hz, 1H); 7.14 d (J = 2Hz, 1 H); 7.23-7.35 m (5H); 7.42-7.58 m (5H).

119

Example 163

6 - [[1,2-Diphenyl-1H-benzimidazol-5-yl] amino] hexanoic acid

Prepared from methyl 6 - [[1,2-diphenyl-1H-benzimidazol-5-yl] amino] hexanoate according to General Regulation 9.

¹ H-NMR (d 6 -DMSO): δ (ppm): 1.35-1.50 m (2H); 1.50-1.68 m (4H); 2.23 t (J = 7.5Hz, 2H); 3.05 t (J = 7.5Hz, 2H); 6.67 dd (J = 10.2 Hz, 1H); 6.80 d (J = 2Hz, 1 H); 6.92 d (J = 10Hz, 1H);

7.30-7.40 m (4H); 7.45-7.62 m (6H).

Example 164

6 - [[2-Phenyl-1- [4- (phenylmethoxy) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) (5-Hydroxy-2-nitrophenyl) [4- (phenylmethoxy) phenyl] amine

A mixture of 1 g of 3-fluoro-4-nitrophenol and 3.8 g of 4-benzyloxyaniline was stirred at 150 ° C for 6.5 hours. The reaction mixture was then diluted with dichloromethane. After extraction twice with 1 N aqueous hydrochloric acid and washing with water, it is extracted twice with 2 N aqueous sodium hydroxide solution. Ethyl acetate and 1N aqueous hydrochloric acid were added to the basic aqueous phase. After phase separation, the organic phase is washed several times with 1N aqueous hydrochloric acid and saturated sodium chloride solution. After drying over sodium sulfate and. by evaporating the solvent in vacuo, the residue is chromatographed on silica gel.

1 H, ¹ H-NMR (d ₆ -DMSO): δ (ppm): 5.14 s (2H); 6.23 m (2H); 7.10 d (J = 8Hz, 2H); 7.26 d (J = 8Hz, 2H); 7.32-7.52 m (5H); 8.03 d (J = 8Hz, 1H); 9.52 s (1H); 10.71 s (1 H).

b) 6 - [[4-Nitro-3 - [[4- (phenylmethoxy) phenyl] amino] phenyl] oxy] hexanoic acid methyl ester

Prepared by reaction of (5-hydroxy-2-nitrophenyl) [4- (phenylmethoxy) phenyl] amine with methyl 6-bromohexanoate according to

120 of the General Regulation 8.

^X H-NMR (CDC1 _3): δ (ppm): 1.37 to 1.50 m (2H); 1.59-1.80 m (4H); 2.33 t (J = 7.5 Hz, 2H); 3.67 s (3H); 3.83 t (J = 7.5Hz, 2H); 5.12 s (2H); 6.24-6.33 m (2H); 7.04 d (J = 8Hz, 2H); 7.21 d (J = 8Hz, 2H); 7.32-7.50 m (5H); 8.17 d (J = 8Hz, 1H); 9.66 s (1H). '

6 - [[2-Phenyl-1- [4- (phenylmethoxy) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared by reduction of 6 - [[4-nitro-3 - [[4- (phenylmethoxy) phenyl] amino] phenyl] oxy] hexanoic acid methyl ester according to General 2 and subsequent cyclization with trimethyl orthobenzoate according to General 3.

^Χ Η ' -NMR '(CDCl 3): δ (ppm): 1.43-1.58 m (2H); 1,65-1,86 m (4H); 2.35 T (J = 7.5Hz, 2H); 3.67 s (3H); 3.94 t (J = 7.5 Hz) 2H); 5.14 with (2H); 6.64 d (J = 2Hz, 1 H); 6.95 dd (J = 8.2 Hz) 1H); 7.11 D (J = 8Hz, 2H); 7.18-7.61 m (12H); 7.74 d (J = 8Hz, 1H).

Example 165

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

Prepared from 6 - [[2-phenyl-1- [4- (phenylmethoxy) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9. , ^X H-NMR (d-DMSO): δ (ppm): 1.36 to 1.62 m (4 H); 1.65-1.78 m (2H); 2.22 t (J = 7.5Hz, 2H); 3.92 t (J = 7.5Hz, 2H); 5.18 s (2H); 6.59 d (J = 2Hz, 1 H); 6.92 dd (J = 8.2 Hz, 1H); 7.20 d (J = 8 Hz,

2H); 7.30-7.54 m (12H); 7.66 d (J = 8Hz, 1H).

Example 166

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

121

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

First

^X H-NMR (d-DMSO): δ (ppm):

(J = 7.5Hz, 2H); 3.92 t (J = 7.5 Hz)

6.91 dd (J = 8.2 Hz, 1H); 6.94 d (J = 2H); 7.36 m (3 H); 7.52 m (2 H); 7.63 according to the general regulation

1.37-1.79 m (6H); 2,22 t

2H); 6.60 d (J = 2Hz, 1 H);

1.2 Hz, 2H); 7.20 d (J = 8Hz, d (J = 8Hz, 1H).

Example 167

6 - [[2-Phenyl-1- [3- (phenylmethoxy) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) (5-Hydroxy-2-nitrophenyl) [3- (phenylmethoxy) phenyl] amine

A mixture of 1 g of 3-fluoro-4-nitrophenol and 3.81 g of 3-benzyloxyaniline was stirred at 150 ° C for 22 hours. The mixture was diluted with a small amount of dichloromethane and chromatographed directly on silica gel.

^X H-NMR (CDC1 _3): δ (ppm): 5.10 s (2H); 5.82 with br (1H); 6.27 dd (J = 8.2 Hz, 1H); 6.48 d (J = 2Hz, 1 H); 6.86 m (3 H); 7.28-7.48 m (5H); 8.15 d (J = 8Hz, 1H); 9.52 with br (1H); 10.71 s (1 H).

b) 6 - [[4-Nitro-3 - [[3- (phenylmethoxy) phenyl] amino] phenyl] oxy] hexanoic acid methyl ester

Prepared by reaction of (5-hydroxy-2-nitrophenyl) [3- (phenylmethoxy) phenyl] amine with methyl 6-bromohexanoate according to General Regulation 8.

^X H-NMR (CDCl3) δ (ppm): 1.40-1.53 m (2H); 1,61-1,82 m ( 4H); 2 34 t (J = 7.5 Hz) 2H); 3.67 s (3H); 3.88 t (J = 7.5Hz, 2H); 5.10 with (2H); 6, 33 dd (J = 8.2 Hz, 1H); 6.58 d (J = 2 Hz) 1H); 6. 83-6.96 m (3 H); 7.28-7.49 m (5H); 8.17 d (J = 8Hz, 1 H); 9 74 p

br.

122

6 - [[2-Phenyl-1- [3- (phenylmethoxy) -phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reduction of 6 - [[4-nitro-3 - [[3- (phenylmethoxy) phenyl] amino] phenyl] oxy] hexanoic acid methyl ester according to general formula 2 and subsequent cyclization with trimethyl orthobenzoate according to general formula 3:

1 H-NMR (CDCl 3): δ (ppm): 1.45-1.60 m (2H); 1.66-1.88 m (4H); 2.35 t (J = 7.5 Hz) 2H); 3.68 s (3H); 3.93 t (J = 7.5Hz, 2H); 5.02 s (2H); 6,69 d (J = 2Hz, 1 H); 6.90 m (2H); 6.97 dd (J = 8, 2 Hz, 1H); 7,11 ddd (J = 8.2,2Hz, 1H); 7.28-7.46 m (9H); 7.78 d

(J = 8Hz, 1 H).

Example '168

6 - [[2-Phenyl-1- [3- (phenylmethoxy) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid

Obtained from 6 - [[2-phenyl-1- [3- (phenylmethoxy) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to Regulation 9.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.49-1.62 m (2H); 1.67-1.88 m (4H); 2.39 t (J = 7.5Hz, 2H); 3.93 t (J = 7.5Hz, 2H); 5.03 s (2H);

6.68 d (J = 2Hz, 1 H); 6.91 m (3 H); 6.98 dd (J = 8.2 Hz, 1H); 7.12 ddd (J = 8.2,2Hz, 1H); 7.29-7.47 m (8H); 7.57 d (J = 8Hz, 1H); 7.81 d (J = 8Hz, 1 H).

Example 169 ...., ¹

6 - [[1- (3-Hydroxyphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid

Prepared from 6 [[2-phenyl-1- [3- (phenylmethoxy) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid according to the general formula

First

H-NMR (d ₆ -DMSO): δ (ppm):

(J = 7.5Hz, 2H); 3.94 t (J = 7.5 Hz)

1.39-1.80 m 2H); 6.57 d (6H); 2.23 t (J = 2Hz, 1 H);

123

6.74 dd (J = 2.2 Hz, 1H); 6.84 dd (J = 8.2 Hz, 1H); 6.94 m (2 H);

7.38 m (4H); 7.53 m (2 H); 7.66 d (J = 8Hz, 1H).

Example 170

6 - [[1- (3-Hydroxyphenyl) -2-phenyl-1H-benzimidazole methyl ester]

zo1-6-y1] oxy] hexanoic acid

Prepared from 6 - [[2-phenyl-1- [3- (phenylmethoxy) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to General Regulation 1.

¹ H-NMR (d ₆ -DMSO): δ (ppm): 1.38-1.80 m (6H); 2.32 t (J = 7.5Hz, 2H); 3.59 s (3H); 3.94 t (J = 7.5Hz, 2H); 6,66 d

(J = 2 Hz, 1H); 6.74 dd (J = 2, 2 Hz, 1H); 6.83 dd (J = 8.2 Hz, 1H); 6, 93 dd (J = 8, 2 Hz, 2H); 7.38 m (4H); 7.54 m (2 H); 7,67 d (J = 8 Hz, 1H).

Example 171

6 - [[1- (3-Nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid ethyl ester

It is prepared by reacting 6-hydroxy-1- (3-nitrophenyl) -2-phenylbenzimidazole (DE 4330959) with 6-bromohexanoic acid ethyl ester according to general regulation 8.

MP: Mp 104-106 ° C.

Example 172 6 - [[4-Bromo-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

a) 4-Bromo-6-methoxy-2-phenyl-1H-benzimidazole

To 36.6 g of 4-amino-3-bromo-5-nitroanisole (J. Chem. Soc. 1966, 1769) in 750 ml of ethanol is added 19.8 g of iron powder and 126 ml of acetic acid. The mixture was stirred at 55 ° C for 2.5 hours, then 350 mL of dichloromethane was added and basified with

124

N sodium hydroxide. After filtration through celite, the filtrate was washed with water and saturated sodium chloride solution and the solvent was evaporated. The crude phenylenediamine thus obtained is reacted with trimethyl orthobenzoate according to general formula 3.

MP: Mp 203-205 ° C.

b) 4-Bromo-6-methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole

A mixture of 2.5 g of 4-bromo-6-methoxy-2-phenyl-1H-benzimidazole, 2.24 g of 4- (methylbenzene) boronic acid, 1.5 g of copper (II) acetate and about 3 g of molecular sieve in 35 ml of pyridine is stirred at 100 ° C for 7 hours. After addition of dichloromethane and celite, the mixture was concentrated and chromatographed on silica gel with hexane-ethyl acetate.

MP: 209-210 ´C

c) 4-Bromo-6-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole

A mixture of 1.2 g of 4-bromo-6-methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole, 6 ml of acetic acid and 6 ml of aqueous hydrobromic acid (62%) is heated to boiling for 5 hours. ,5 hours. Water is then added and the precipitate formed is filtered off with suction and partitioned between ethyl acetate and 2N sodium hydroxide. After washing the organic phase with water, the solvent is evaporated.

MP: Mp 136-137 ° C.

'. ₍ i I.,

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

Prepared by reaction of 4-bromo-6-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

MP: 136 ’C.

Example 173

125

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

A mixture of 0.5 g of 4-bromo-6-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole, 0.37 ml of (α-ethoxyvinyl) tributyltin and 140 mg of dichlorobis (triphenylphosphine) palladium in 10 ml of toluene was stirred at 100 ° C for 18 hours. After cooling, the mixture was stirred with 2 N aqueous hydrochloric acid for 0.25 hours. After phase separation, the organic phase is washed with water and concentrated. The residue is chromatographed on silica gel with hexane-ethyl acetate.

MP: Mp 114-115 ° C.

Example 174

6 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

a) 5-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole

16.8 g of 5-methoxy-2-phenyl-1H-benzimidazole (Bull. Sci. Fac. Chim. Ind. Bologna 11, 42 (1953)) is reacted with 20.4 g of 4- (methylbenzene) boronic acid according to of the General Regulation 14.

^X H-NMR (CDC1 _3): δ (ppm): 2.45 s (3H); 3.91 s (3H); 6.90 dd (J = 8.2 Hz, 1H); 7.12 d (J = 8Hz, 1H); 7.18 d (J = 8Hz, 2H);

7.25-7.38 m (6H); 7.57 m (2 H).

In addition, 6-methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole is also obtained.

b) 5-Hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole

Prepared from 5-methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole according to general formula 6.

MP: 270 ° C.

6 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

126

Prepared by reaction of 5-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to General Regulation 8.

¹ H-NMR (CDC1 _3): δ (ppm): 1, 48-1, 92 m (6H); 2.38 t (J = 7.5Hz, 2H); 2.46 s (3H); 3.69 s (3H); 4.06.t (J = 7.5Hz, 2H); 6.89 dd (J = 8.2 Hz, 1H); 7.11 d (J = 8Hz, 1H); 7.18 d (J = 8 Hz, 2H); 7.24-7.37 m (6H); 7.57 m (2 H).

Example 175

6 - [[1- (4-Methylphenyl) -2-phenyl-ΙΗ-benzimidazol-5-yl] oxy] hexanoic acid

Obtained from 6 - [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

¹ H-NMR (d 6 -DMSO): δ (ppm): 1.41-1.67 m (4H); 1.70-1.83 m (2H); 2.26 t (J = 7.5Hz, 2H); 2.43 s (3H); 4.05 t (J = 7.5Hz, 2H); 6.90 dd (J = 8.2 Hz, 1H); 7.04 d (J = 8Hz, 1H); 7.23-7.40 m (8H); 7.52 m (2 H); 11.92 with br (1H).

Example 176

6 - [[2-Phenyl-1- [4- (thiomethyl) phenyl] -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

(a) 6 - [[2-Phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 4,84 g of 2-phenyl-5-hydroxy-1H-benzimidazole (Izv. Akad. USSR Ser. Chim. 8, 1888 (1990)) with 6-bromohexanoic acid methyl ester according to general formula 8.

¹ H-NMR (CDCl 3): δ (ppm): 1.43-1.58 m (2H); 1.64-1.87 m (4H); 2.37 t (J = 7.5Hz, 2H); 3.69 s (3H); 3.94 t (J = 7.5Hz, 2H); 6.87 dd (J = 8.2 Hz, 1H); 7.02 s br; 7.40-7.57 m (4H); 8,05 m

127 (2Η).

6 - [[2-Phenyl-1- [4- (thiomethyl) phenyl] -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

Prepared by reaction of methyl 6 - [[2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid with 4- (thiomethylbenzene) boronic acid according to the general formula 14.

^X H-NMR (CDC1 _3): δ (ppm): 1.48 to 1.61 m (2H); 1.66-1.92 m (4H); 2.36 t (J = 7.5Hz, 2H); 2.54 s (3H); 3.68 s (3H); 4.05 t (J = 7.5Hz, 2H); 6.90 dd (J = 8.2 Hz, 1H); 7.11 d (J = 8Hz, 1H);

7.22 d (J = 8Hz, 2H); 7.27-7.49 m (6H); 7.57 m (2 H).

Example 177

6 - [[2-Phenyl-1 - [(4-thiomethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared by reaction of methyl 6 - [[2-phenyl] -1H-benzimidazol-5-yl] oxy] hexanoic acid with 4- (thiomethylbenzene) boronic acid according to the general formula 14.

^X H-NMR (CDCl 3): δ (ppm): 1.45 to 1.57 m (2H); 1.62-1.86 m (4H); 2.44 t (J = 7.5 Hz, 2H); 2.56 s (3H); 3.66 s (3H); 3.93 t (J = 7.5Hz, 2H); 6.66 d (J = 2Hz, 1 H); 6.96 dd (J = 8.2 Hz, 1H);

7.18-7.39 m (7H); 7.54 m (2 H); 7.73 d (J = 8Hz, 1 H).

Example 178

6 - [[2-Phenyl-1- (3-thienyl) -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6 - [[2-phenyl] -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester with thiophene-3-boronic acid according to the general formula 14.

^X H-NMR (CDCl 3): δ (ppm): 1, 48-1, 62 m (2H); 1.66-1.92 m (4H); 2.47 t (J = 7.5Hz, 2H); 3.68 s (3H); 4.04 t (J = 7.5Hz, 2H);

6.93 dd (J = 8.2 Hz, 1H); 6.98 dd (J = 5.1 Hz, 1H); 7,18 d

128 (J = 8Hz, 1 H); 7.28 dd (J = 3.1 Hz, 1H); 7.30-7.40 m (4H); 7.46 dd (J = 5.3 Hz, 1H); 7.60 m (2 H).

Example 179

6 - [[2-Phenyl-1- (3-thienyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester '

Prepared by reaction of 6 - [[2-phenyl] -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester with thiophene-3-boronic acid according to the general formula 14.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.45-1, 58 m (2H); 1.64-1.87 m (4H); 2.35 t (J = 7.5Hz, 2H); 3.67 s (3H); 3.97 t (J = 7.5Hz, 2H);

6,74 d (J = 2 Hz, 1H); 6,95 dd (J = 8, 2 Hz, 1H); 7.01 dd (J = 5) 1 Hz, 1H); 7.29 dd ( J = 3.1 Hz, 1H); 7.30 to 7 , 38 m (4H) ; 7.47 dd (J = 5.3 Hz, 1H); 7.58 m (2H); 7 73d (J = 8Hz, 1H).

Example 180

4- [3 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenoxy] buranoic acid methyl ester

a) 6- (3-Methoxyphenoxy) -1- (4-methylphenyl) -2-phenyl-1H-benzimidazole

Prepared from 6-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole and 3-methoxybenzeneboronic acid according to General Regulation 14.

MP: 120 - 122 C. C.

b) 3 - [[1- (4-Methylphenyl) -2-phenyl-6-benzimidazol-6-yl] oxy] phenol

Prepared from 6- (3-methoxyphenoxy) -1- (4-methylphenyl) -2-phenyl-1H-benzimidazole according to general formula 6 with addition of 10 mol% hexadecyltributylphosphonium bromide.

MP: Mp 252-253 ° C.

129

4- [3 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenoxy] butanoic acid methyl ester

It is prepared by reacting 3 - [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenol with 4-bromobutyric acid methyl ester according to General Regulation 8.

and ^X H-NMR (CDC1 _3): δ (ppm): 2.00 to 2.13 m (2H); 2.43 s (3H); 2.50 t (J = 7.5Hz, 2H); 3.67 s (3H); 3.93 t (J = 7.5Hz, 2H); 6.44-6.62 m (3H); 6.95 d (J = 2 Hz, 1H); 7.06 dd (J = 8.2 Hz, 1H); 7.12-7.22 m (3H); 7.25-7.39 m (5H); 7.59 m (2 H); 7.87 d (J = 8Hz, 1H).

Example 181

4- [4 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenoxy] butanoic acid methyl ester

a) 6- (4-Methoxyphenoxy) -1- (4-methylphenyl) -2-phenyl-1H-benzimidazole

Obtained from 6-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole and 4-methoxybenzeneboronic acid according to the general formula 14.

H-NMR (CDC1 _3): δ (ppm): 2.44 s (3H); 3.79 s (3H); 6.82-6.98 m (5H); 7.01 dd (J = 8.2 Hz, 1H); 7.17 d (J = 8Hz, 2H); 7.25-7.41 m (5H); 7.57 m (2H); 7.82 d (J = 8Hz, 1H).

b) 4 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenol

Prepared from 6- (3-methoxyphenoxy) -1-. (4-methylphenyl) -2-phenyl-1H-benzimidazole according to general formula 6 with the addition of 10 mol% hexadecyltributylphosphonium bromide.

H-NMR (de-DMSO): δ (ppm): 2.38 s (3H); 6. 61 d (J = 2 Hz, IH); 6.74 d (J = 8 Hz, 2H); 6.86 d (J = 8 Hz, 2H); 6, 91- • 7.01 m (2H); 7.22-7.41 m (6H); 7.49 m (2 H); 7.75 d (J = 8Hz, 1H); 9.32 with (IH).

130

4- [4 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenoxy] butanoic acid methyl ester

Prepared by the reaction of 4- [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenol with 4-bromobutyric acid methyl ester according to General Regulation 8.

^X H-NMR (CDC1 _3): δ (ppm): 2.03 to 2.16 m (2H); 2.42 s (3H); 2.53 t (J = 7.5Hz, 2H); 3.59 s (3H); 3.97 t (J = 7.5Hz, 2H); 6.78-6.94 m (5H); 6.99 dd (J = 8.2 Hz, 1H); 7.16 d (J = 8Hz, 2H); 7.24-7.38 m (5H); 7.57 m (2H); 7.79 d (J = 8Hz, 1 H).

Example 182

4 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenoxy] acetic acid methyl ester

It is prepared by reacting 4 - [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] phenol with methyl bromoacetate according to the general formula 8.

^X H-NMR (CDCl 3): δ (ppm): 2.43 s (3H); 3.82 s (3H); 4.61 s (2H); 6.78-6.96 m (5H); 7.00 dd (J = 8.2 Hz, 1H); 7.14 d (J = 8Hz, 2H); 7.23-7.38 m (5H); 7.56 m (2 H); 7.80 d (J = 8Hz, 1H).

Example 183

4 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) -oxy] butanoic acid methyl ester

Obtained from 1,2-diphenyl-6-hydroxy-1H-benzimidazole and methyl 4-bromobutyrate according to General Regulation 8.

MP: Mp 107-110 ° C.

Example 184

6 [[2-Phenyl-1- (3-pyridyl) -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

131

Prepared by reaction of 6 - [[2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester with pyridine-3-boronic acid according to the general formula 14.

MS (EI): 415 (molecular ion).

Example 185.

6 - [[2-Phenyl-1- (3-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6 - [[2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester with pyridine-3-boronic acid according to general formula 14.

MS (EI): 415 (molecular ion).

Example 186

6 - [[2-Phenyl-1- (2-pyridyl) -1H-benzimidazol-5-yl] oxy] hexanoic acid

It is prepared by reacting 6 - [[2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester with 2-fluoropyridine according to the general formula 15.

MS (EI): 401 (molecular ion).

Example 187

6 - [[2-Phenyl-1- (2-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepared by reaction of 6 - [[2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester with 2-fluoropyridine according to general procedure 15.

MS (EI): 401 (molecular ion).

Example 188

132

6- [• [2-Phenyl-1- (4-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6 - [[2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester with pyridine-4-boronic acid according to the general formula 14.

MS (EI): 415 (molecular ion).

Example 189

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

It is prepared by reacting 6 - [[4-amino-3- (phenylamino) phenyl] oxy] hexanoic acid methyl ester with 4-fluorobenzoyl chloride according to general formula 5.

MS (EI): 432 (molecular ion).

Example 190

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

Prepared by reaction of 6 - [[4-amino-3- (phenylamino) phenyl] oxy] hexanoic acid methyl ester with 4-methoxybenzoyl chloride according to general formula 5.

MS (EI): 444 (molecular ion).

Example 191

6 - [[2- (3-Fluorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6 - [[4-amino-3- (phenylamino) phenyl] oxy] hexanoic acid methyl ester with 3-fluorobenzoyl chloride according to general formula 5.

MS (EI): 432 (molecular ion).

133

Example 192

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

Prepared by reaction of methyl 6 - [[4-amino-3- (phenylamino) phenyl] oxy] hexanoic acid with 4-bromobenzoyl chloride according to general formula 5.

MS (EI): 492/494 (molecular ions).

Example 193

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

It is prepared by reacting 6 - [[4-amino-3- (phenylamino) phenyl] oxy] hexanoic acid methyl ester with 4- (trifluoromethyl) benzoylphiloride according to general procedure 5.

MS (EI): 482 (molecular ion).

Example 194

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

Obtained from 6 - [[2- (4-fluorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester according to the general formula 9.

MS (EI): 418 (molecular ion).

Example 195

6 - [[1-Phenyl-2- (benzothien-2-yl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is prepared by reacting 6 - [[4-amino-3- (phenylamino) phenyl] oxy] hexanoic acid methyl ester with benzothiophene-2-carboxylic acid chloride according to general formula 5.

134

MP: Mp 129-130 ° C.

Example 196

6 - [[1-Phenyl-2- (benzothien-2-yl) -1H-benzimidazol-6-yl] oxy] hexanoic acid

It shall be prepared in accordance with General Regulation 9.

MP: 340 ° C (dec.).

Example 197

6 - [[5-Hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

Example 198

6 - [[6-hydroxy-1- (4-methylphenyl) -2-phenyl-ΙΗ-benzimidazol-5-yl] oxy] hexanoic acid isopropyl ester

4,5-Dimethoxy-1,2-dinitrobenzene is hydrogenated according to general formula 1 to a diamino compound which is cyclized as a crude product of general formula 3 with trimethyl orthobenzoate to give 5,6-dimethoxy-2-phenyl-1H-benzimidazole ( mp 131-133 ° C). This benzimidazole derivative was reacted with 4-methylphenylboronic acid according to general formula 14 to give 5,6-dimethoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole (m.p. 145-148 ° C). This was cleaved with hydrobromic acid according to general formula 6 to give 5,6-dihydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole @ 1 H-NMR of hydrobromide (ds-DMSO): .delta. s (3H); 6.68 s (1H); 7.22 s (1H); 7.40-7.62 m (10H)) which is then alkylated according to general formula 8 with isopropyl 6-bromohexanoate. There was thus obtained 6 - [[5-hydroxy-1- (4-methylphenyl) -2-phenyl-4-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester,

mp 137-139 ° C, and 6 - [[6-hydroxy-1- (4-methylphenyl) -2-phenyl-ΙΗ-benzimidazol-5-yl] oxy] hexanoic acid isopropyl ester,

mp Mp 177-178 ° C.

Example 199

6 - [[5-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepare in accordance with General Regulation 9.

MP: 245-248 ’C.

Example 200

6 - [[6-hydroxy-1- (4-methylphenyl) -2-phenyl-4-benzimidazol-5-yl] oxy] hexanoic acid

It shall be prepared in accordance with General Regulation 9.

MP: 182-184 C. C.

Example 201

6 - [[5-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester

6 - [[5-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester is methylated with methyl iodide according to General Regulation 8.

MP: 89-91 C. C. /

Example 202

6 - [[5-Methoxy-1- (4-methylphenyl) -2-phenyl-4-benzimidazol-6-yl] oxy] hexanoic acid

It shall be prepared in accordance with General Regulation 9.

MP: Mp 184-186 ° C.

136

Example 203

6 - [[5-Hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Example 204

6 - [[6-Hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

Esters are prepared analogously to the corresponding isopropyl esters by alkylation of 5,6-dihydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazole with 6-bromohexanoic acid methyl ester according to general formula 8. The 6 - [[5- hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexane, ¹ H-NMR (CDCl ₃ ): δ (ppm): 1.45-1.58 m (2H ); 1.65-1.90 m (4H); 2.37 t (J = 7.5Hz, 2H); 2.48 s (3H); 3.68 s (3H); 3.98 t (J = 7.5Hz, 2H); 5.68 s br (lH, OH); 6.62 s (1H); 7.18 d (J = 8Hz, 2H);

7.22-7.38 m (5H); 7.40 s (lH); 7.53 dd (J = 8.1 Hz, 2H), and 6 - [[6-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester,

mp 141-143 C. C.

Example 205

6 - [[5-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester mg 6 - [[5-methoxy-1- (4-methylphenyl)] Dissolve -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid in 2 mL of methanol, add 1 drop of concentrated sulfuric acid and stir for 2 hours. Saturated potassium bicarbonate solution was added, the mixture was diluted with water, extracted with ethyl acetate, the extracts dried over sodium sulfate and concentrated in vacuo. The evaporation residue is crystallized from diisopropyl ether.

MP: 81 ’C.

137

Example 206

6 - [[6-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester

6 - [[6-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid is methylated with methyl iodide according to General Regulation 8.

MP: 108-110 C. C.

Example 207

6 - [[6-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid

Prepare in accordance with General Regulation 9.

MP: 182-184 C. C.

Example 208

6 - [(5-amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

a) 3 - [(3,4-Dimethylphenyl) amino] -4,6-dinitrophenol

To a suspension of 4 g of 4,6-dinitro-3-fluorophenol (J. Org. Chem. 1991, 5958) in 100 ml of ethanol is added 6.6 g of 3,4-dimethylaniline and the mixture is allowed to stir for 7 days at 40 °. C. After cooling, the reaction mixture is filtered off with suction and the residue is recrystallized from ethanol.

¹ H-NMR (CDC1 _3): δ (ppm): 2.20 s (6H); 6.43 s (1H); 6.90-7.0 m (2H); 7.14 d (J = 8Hz, 1H); 9.08 s (1H); 9.70 with br (1H); 10.2-10.6 (1 H).

b) 6 - [[3 - [(3,4-Dimethylphenyl) amino] -4,6-dinitrophenyl] oxy] hexanoic acid methyl ester

5.0 g of 3 - [(3,4-dimethylphenyl) amino] -4,6-dinitrophenol is O-alkylated with methyl 6-bromohexanoate at 70 ° C

138 analogously to that described in General Regulation 8.

^X H-NMR (CDC1 _3): δ (ppm): 1.45 to 1.88 m (6 H); 2.30 s (6H); 2.33 t (J = 7.5Hz, 2H); 3.68 s (3H); 3.88 t (J = 7.5Hz, 2H); 6.45 s (1H); 7.00-7.08 m (2H); 7.25 d (J = 8Hz, 1H); 9.03 s (1H); 9.89 with br (1H).

c) 6 - [(5-Amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

2.45 g of 6 - [[3 - [(3,4-dimethylphenyl) amino] -4,6-dinitrophenyl] oxy] hexanoic acid methyl ester was hydrogenated in methanol according to general formula 1 and 500 mg of the crude product was treated with benzimidate hydrochloride. according to General Regulation 4, except that the crude product is not washed with aqueous hydrochloric acid after removal into the solvent.

@ 1 H-NMR (CDCl3): .delta. (Ppm): 1.48-1.58 m (2H); 1.62-1.78 m (2H); 1.78-1, 90m (2H); 2.30 s (3H); 2.38 s (3H); 2.38 t (J = 7.5Hz, 2H); 3.67 s (3H); 3.93 t (J = 7.5Hz, 2H); 6.56 s (1H); 6.98-7.08 m (2H); 7.18 s (1H); 7.20-7.32 m (4H); 7.52 dd (J = 8.2 Hz, 2H).

Example 209

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

6 - [(5-Amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester is reacted with 4-chlorobenzenesulfonic acid chloride according to the general formula 13.

MP: Mp 186-191 ° C.

Example 210

6 - [(5-Amino-2- (4-fluorophenyl) -1- (4-methoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

Prepared in an analogous manner to methyl acid ester

139

6 - [(5-amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexane.

MS (EI): 477 (molecular ion).

Example 211

6 - [(5-amino-1- (4-methoxyphenyl) -2- (4-methoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

Prepared in analogy to 6 - [(5-amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester.

MS (EI): 489 (molecular ion).

Example 212 '

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -2- (4-fluorophenyl) -1- (4-methoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

6 - [(5-amino-2- (4-fluorophenyl) -1- (4-methoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to the general procedure of Regulation 13.

MP: Mp 180-182 ° C.

Example 213

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2- (4-methoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

6 - [(5-Amino-1- (4-methoxyphenyl) -2- (4-methoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to the general formula 13 .

MP: Mp 169-171 ° C.

140

Example 214

4 - [(5-amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] butanoic acid methyl ester

Prepared in analogy to 6 - [(5-amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester.

¹ H-NMR (CDCl 3): δ (ppm): 2.17 tt (J = 8.8 Hz, 2H); 2.52 t (J = 8 Hz, 2H); 3.68 s (3H); 90 s (3H); 3.98 t (J = 7.5 Hz, 2H); 6.54 s (1H); 7.0 d (J = 12 Hz, 2H); 7.18-7.35 m (6H), 7.50-7.58 m (2H).

Example -215

4 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] butanoic acid methyl ester

4 - [(5-amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] buranoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to the general formula 13.

MS (EI): 605 (molecular ion).

Example 216

5 - [(5-amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] pentanoic acid methyl ester

Prepared in an analogous manner to methyl 6 - [(5-amino-1- (3,4-dimerylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoate.

¹ H-NMR (CDCl 3): δ (ppm): 1.78-1, 89 m (4H); 2.32 t (J = 8 Hz,

2H); 3.68 s (3H); 3.88 s (3H); 3.92 t (J = 7.5Hz, 2H); 6.53 s (1H); 7.0 d (J = 12Hz, 2H); 7.18-7.36 m (6H); 7, 48-7.58 m (2K).

Example 217

141

5 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid methyl ester

5 - [(5-amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] pentanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to the general formula 13.

MS (EI): 619 (molecular ion).

Example 218

6 - [(5-amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester

Prepared in an analogous manner as 6 - [(5-amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester.

MP: 129-131 C. C.

Example 219

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

6 - [(5-Amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to the general formula 13.

MP: Mp 168-170 ° C.

Example 220

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-4-benzimidazol-6-yl] oxy] hexanoic acid

Prepare in accordance with General Regulation 9.

MP: 181-182 C. C.

142

Example 221

Acid methyl ester

6 - [(5-amino-l- (4-methylphenyl) -2-phenyl-lH-benzimidazol-6-yl) oxy] hexanoic acid

Prepared in an analogous manner ^; as 6 - [(5-amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester.

MP: 105-107 ° C.

Example 222

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

6 - [(5-amino-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to the general formula 13.

MP: Mp 189-191 ° C.

Example 223

6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

It shall be prepared in accordance with General Regulation 9.

MP: 102 - 105 C. C.

Example 224

5 - [(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] pentanoic acid methyl ester

Prepared in analogy to 6 - [(5-amino-1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester.

143 ^X H-NMR (CDCl 3): δ (ppm): 1.82 to 1.95 m (4 H); 2.39 t (J = 8Hz, 2H); 3.69 s (3H); 3.92-4.00 m (2H); 6.60 s (1 H); 7.26-7.34 m (6H); 7.43-7.58 m (5H).

Example 225

5 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1,2-diphenyl-ΙΗ-benzimidazol-6-yl] oxy] pentanoic acid methyl ester

5 - [(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl) oxy] pentanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to the general formula 13.

MP: 157-161 ° C.

Example 226

5 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1,2-diphenyl-6-benzimidazol-6-yl] oxy] pentanoic acid

Prepare in accordance with General Regulation 9.

MP: Mp 236-242 ° C.

Example 227

6 - [[5 - [[(4-Fluorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

6 - [(5-Amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester was reacted with 4-fluorobenzenesulfonic acid chloride according to the general formula 13.

MS (EI): 617 (molecular ion).

Example 228

6 - [[5 - [[(4- (Trifluoromethyl) phenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

144

6 - [(5-amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester was reacted with 4- (trifluoromethyl) benzenesulfonic acid chloride according to the general formula 13.

MS (EI): 668 (molecular ion).

Example 229

6 - [[5 - [[(4- (trifluoromethyl) phenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

It shall be prepared in accordance with General Regulation 9.

MP: Mp 190-192 ° C.

Example 230

6 - [[5 [[(4-chlorophenyl) sulfonyl] methylamino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

To a solution of 100 mg of 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-16-yl] oxy] hexanoic acid methyl ester in 3 ml of tetrahydrofuran was added at 0 ° C to 10 mg of sodium hydride. After stirring for 30 minutes, 50 µL of methyl iodide is added dropwise and stirred for an additional 60 minutes at 0 ° C. The mixture is quenched with ammonium chloride solution, extracted 3x with ethyl acetate, the organic phases are washed with water, dried over sodium sulphate, evaporated in vacuo and the residue chromatographed on silica gel.

MP: 178-180 ° C.

Example 231

[[(4-chlorophenyl) sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] amino] acetic acid methyl ester

To a suspension of 100 mg of 4-chloro-N- (1,2-diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide in 0.5 ml of Ν, Ν-dimethylformamide is added 8 mg of sodium hydride at 145 and stirred for 30 minutes at temperature 20 ° C. 50 mg of methyl bromoacetate is added, the mixture is stirred for 15 hours, quenched with leader and extracted 3 times with ethyl acetate. After drying over sodium sulfate, it is concentrated in vacuo and the residue is chromatographed on silica gel.

¹ H-NMR (CDCl 3): δ (ppm): 3.70 s (3H); 4.52 s (2H); 7.20 d (J = 8Hz, 1H); 7.26-7.58 m (14H); 7.70 d (J = 10Hz, 2H).

Example 232

[[(4-chlorophenyl) sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] amino] acetic acid

I

It shall be prepared in accordance with General Regulation 9.

MP: 248 ° C.

Example 233

4 - [[(4-Chlorophenyl) sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] amino] butanoic acid methyl ester

100 mg of 4-chloro-N- (1,2-diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide are suspended in 0.5 ml of ΛΖ, ΛΖ-dimethylformamide. 6 mg of sodium hydride was added to the suspension, and the mixture was stirred at 20 ° C for 30 minutes. 56 mg of 4-bromobutyric acid methyl ester is then added, the mixture is stirred for 15 hours, quenched with water and extracted three times with ethyl acetate. After drying over sodium sulfate, the combined extracts are concentrated in vacuo and the residue digested with diisopropyl ether.

MP: 54 - 58

Example 234

4 - [[(4-Chlorophenyl) sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] amino] butanoic acid

Obtained according to general regulation 9.

146

MP: 249-254 C. C.

Example 235

5 - [[(4-Chloro-phenyl) -sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] -amino] -pentanoic acid methyl ester

100 mg of 4-chloro-N- (1,2-diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide are suspended in 0.5 ml of N, N-dimethylformamide, 8 mg of sodium hydride are added to the suspension and stirred for 30 minutes. minutes at 20 ° C. 60 mg of 5-bromopentanoic acid methyl ester was added and the mixture was stirred for 15 hours, then quenched with water and extracted three times with ethyl acetate. The extracts are dried over sodium sulfate, concentrated in vacuo and the residue is chromatographed on silica gel.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.46-1.54 m (2H); 1.62-1.78 m (2H); 2.30 t (J = 8Hz, 2H); 3.62 s (3H); 3.62 t (J = 8Hz, 2H);

7.12-7.53 m (17H).

Example 236

5 - [[(4-Chlorophenyl) sulfonyl] [1,2-diphenyl-4-benzimidazol-5-yl] amino] pentanoic acid

Obtained according to General Regulation 9.

MP: 123-127 ’C.

Example-237

6 - [[(4-Chlorophenyl) sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] amino] hexanoic acid methyl ester

Prepared by reaction of 6 - [[1,2-diphenyl-1H-benzimidazol-5-yl] amino] hexanoic acid methyl ester with acid chloride

4-chloro-benzenesulfonic acid according to General Regulation 13.

MS (EI): 588 (molecular ion).

147

Example 238

7 - [[(4-Chloro-phenyl) -sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] -amino] -heptanoic acid methyl ester

100 mg of 4-chloro-N- (1,2-diphenyl-1H-benzimidazol-5-yl) benzenesulfonamide are suspended in 0.5 ml of N, N-dimethylformamide, 8 mg of sodium hydride are added to the suspension and stirred for 30 minutes at 20 ° C. 70 mg of 7-bromoheptanoic acid methyl ester was added and the mixture was stirred for 15 hours, then quenched with water and extracted three times with ethyl acetate. The extracts are dried over sodium sulfate, concentrated in vacuo and the residue subjected to silica gel chromatography.

'H-NMR (CDC1 _3): δ (ppm): 1.26 to 1, 64 m (8H); 2.27 t (J = 8Hz, 2H); 3.60 t (J = 8Hz, 2H); 3.68 s (3H); 7.12 dd (J = 10.2 Hz, 1H); 7.22 d (J = 10Hz, 1H); 7.30-7.61 m (15H).

Example 239

7 - [[(4-Chlorophenyl) sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] amino] heptanoic acid

Obtained according to general regulation 9.

MP: Mp 172-178 ° C.

Example 240 (1,2-Diphenyl-1H-benzimidazol-5-yl) -4-fluorobenzenesulfonamide

Prepared by reacting 5-amino-1,2-diphenyl-1H-benzimidazole with 4-fluorobenzenesulfonic acid chloride according to general procedure 13.

MP: Mp 209-214 ° C.

Example 241

6 - [[(4-Fluorophenyl) sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] amino] hexanoic acid methyl ester

148

150 mg of N- (1,2-diphenyl-1H-benzimidazol-5-yl) -4-fluorobenzenesulfonamide are suspended in 0.5 ml of Ν, Ν-dimethylformamide, 12 mg of sodium hydride are added to the suspension and stirred for 30 minutes at temperature 20 ° C. 98 mg of 6-bromohexanoic acid methyl ester was added and the mixture was stirred for 15 hours, then quenched with water and extracted three times with ethyl acetate. The extracts were dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on silica gel.

MP: 128-134 C. C.

Example 242

6 - [[(4-Fluorophenyl) sulfonyl] [1,2-diphenyl-4-benzimidazol-5-yl] amino] hexanoic acid

A podium of General Regulation 9 is obtained.

MP: 200-210 C. C.

Example 243

6 - [[[4- (Trifluoromethyl) phenyl] sulfonyl] [1,2-diphenyl-1H-benzimidazol-5-yl] amino] hexanoic acid methyl ester

150 mg of 4- (trifluoromethyl) -N- (1,2-diphenyl-1H-benzimidazol-5-yl) -benzenesulfonamide are suspended in 0.5 ml of Ν, Ν-dimethylformamide, 11 mg of sodium hydride are added to the suspension and stirred at 30 ° C for 30 minutes. 88 mg of 6-bromohexanoic acid methyl ester is added and the mixture is stirred for 15 hours, then quenched with water and extracted three times with ethyl acetate. The extracts were dried over sodium sulfate, the solvent was evaporated in vacuo and the residue digested with diisopropyl ether.

MP: 159-161 ’C.

Example 244

6 - [[[4- (Trifluoromethyl) phenyl] sulfonyl] - [1,2-diphenyl-1H-benzimidazol-5-yl] amino] hexanoic acid

149

Obtained according to general regulation 9.

MP: Mp 224-230 ° C.

Example 245

4-Chloro-N- [1- (4-methoxyphenyl) -2-phenyl-lH-benzoimidazol-5-y1] benzenesulfonamide

a) (2,4-Dinitrophenyl) (4-methoxyphenyl) amine

A mixture of 1.43 g of 4- (2,4-dinitroaniline) phenol, 500 mg of potassium carbonate, 0.32 ml of methyl iodide and 5 ml of N, N-dimethylformamide was allowed to stir for 2 days at 20 ° C. The mixture was poured into water, extracted three times with ethyl acetate, dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on silica gel.

MP: Mp 117-127 ° C.

b) 5-Amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazole (2,4-Dinitrophenyl) (4-methoxyphenyl) amine is hydrogenated according to general formula 1 and the crude product is cyclized with trimethylorthobenzoate to the benzimidazole derivative according to general regulation 3.

^X H-NMR (CDC1 _3): δ (ppm): 3.88 s (3H); 6.70 dd (J = 12.2 Hz)

1H); 6.95-7.06 m (4H); 7.18-7.38 m (7H); 7.53-7.65 m (2 H).

c) 4-Chloro-N- [1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-5-yl] -benzenesulfonamide

It is prepared by reacting 5-amino-1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazole with 4-chlorobenzenesulfonic acid chloride according to the general formula 13.

MP: Mp 238-240 ° C.

Example 246

150

6 - [[(4-Chloro-phenyl) -sulfonyl] - [1- (4-methoxy-phenyl) -2-phenyl-1H-benzoimidazol-5-yl] -amino] -hexanoic acid methyl ester

To a suspension of 75 mg of 4-chloro-N- [1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-5-yl] benzenesulfonamide in 0.5 ml of N, N-dimethylformamide was added 6 mg of sodium hydride and stirred at 30 ° C for 30 minutes. After addition of 44 mg of ^1- methyl-6-bromohexanoate, the mixture was stirred for 15 hours, quenched with water and extracted three times with ethyl acetate. The extracts were dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on silica gel.

MS (EI): 617 (molecular ion).

Example 247

6 - [[(4-Chlorophenyl) sulfonyl] - [1- (4-methoxyphenyl) -2-phenyl-ΙΗ-benzimidazol-5-yl] amino] hexanoic acid

Prepare in accordance with General Regulation 9.

MP: 205 - 208 C. C.

Example 248

2,2-Dimethyl-6 - [(1,2-diphenyl-6-benzimidazol-6-yl) oxy] hexanamide

(a) 2,2-Dimethyl-6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanenitrile;

Prepared by the reaction of 1,2-diphenyl-6-hydroxy-1 _; H-benzimidazole with 6-bromo-1,1-dimethylhexanenitrile according to the general formula 8.

MP: 115-118 ° C.

b) 2,2-Dimethyl-6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide

500 mg of 2,2-dimethyl-6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanenitrile was heated under reflux for 2 hours with 5 ml of 80% sulfuric acid. After cooling, the reaction mixture was poured carefully into ice water, adjusted to pH 8 by addition of sodium hydroxide, and extracted three times with ethyl acetate. The extracts were dried over sodium sulfate, concentrated in vacuo and the residue chromatographed on silica gel.

MP: 115-118 C. C. ·

Example 249

8- [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] octanoic acid methyl ester

Prepared by the reaction of 1,2-diphenyl-6-hydroxy-1H-benzimidazole with 8-bromooctanoic acid methyl ester according to general procedure 8.

MP: Mp 92-95 ° C.

Example 250

8 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] octanoic acid

Prepare in accordance with General Regulation 9.

MP: Mp 136-140 ° C.

Example 251

6 - [[1- (Indan-5-yl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester. ·

Prepared in an analogous manner to methyl 6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester.

MP: Mp 81-85 ° C.

Example 252

6 - [[1- (Indan-5-yl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] 152 hexanoic acid

It shall be prepared in accordance with General Regulation 9.

MP: 176-180 C. C.

Example 253

7 - [[1- (Indan-5-yl) -2-phenyl-1H-benzimidazol-6-yl] oxy] heptanoic acid methyl ester

Prepared in analogy to 6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester.

MP: 92 - 98 ’C.

153

Example 254

acid

7 - [[1- (indan-5-yl) -2-phenyl-lH-benzimidazol-6-yl] oxy] -heptanoic

Prepare according to the general formula 9. '

MP: 175-178 ° C.

Example 255

6 - [[1- (3-Fluorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepared in an analogous manner to methyl 6 - [[1- (3,4-dimethylphenyl) -2-phenyl-4-benzimidazol-6-yl] oxy] hexanoic acid methyl ester.

MP: Mp 104-106 ° C.

Example 256

6 - [[1- (3-Fluorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid

Prepare in accordance with General Regulation 9.

MP: Mp 149-151 ° C.

Example 257. I i ¹ I

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

a) 6-Methoxy-2- (4-nitrophenyl) -1-phenyl-1H-benzimidazole

200 mg of 4-methoxy-W ^2- phenyl-o-phenylenediamine is dissolved in 5 ml of Ν, ΛΖ-dimethylformamide, 346 mg of EEDQ and 234 mg of 4-nitrobenzoic acid are added and stirred at 100 ° C for 5 hours. After cooling, the mixture is quenched with water, the precipitate is filtered off with suction and purified

154 was chromatographed on a silica gel column. It is then taken up in 6N hydrochloric acid and heated under reflux for 2 hours. After cooling, it is added dropwise to a saturated solution of potassium bicarbonate. The precipitate formed is filtered off with suction and dried.

MP: Mp 189-191 ° C.

b) 6-Hydroxy-2- (4-nitrophenyl) -1-phenyl-1H-benzimidazole

Prepare in accordance with General Regulation 6.

^X H-NMR (d-DMSO): δ (ppm): 6.56 d (J = 2 Hz, 1 H); 6.87. dd (J = 10.2 Hz, 1H); 7.46 dd (J = 10.2 Hz, 2H); 7.53-7.70 m (4H);

7.75 d (J = 10Hz, 2H); 8.20 d (J = 10Hz, 2H); 9.55 with br (1H).

c) 6 - [[2- (4-Nitrophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

Prepare in accordance with General Regulation 8.

^X H-NMR (CDC1 _3): δ (ppm): 1, 45 to 1.55 m (2H); 1.62-1.84 m (4H); 2.33 t (J = 8Hz, 2H); 3.68 s (3H); 3.95 t (J = 8Hz, 2H); 6.67 d (J = 2Hz, 1 H); 7.00 dd (J = 10.2 Hz, 1H); 7.28-7.38 m (2H); 7.52-7.60 m (3H); 7.71 d (J = 10Hz, 2H); 7.77 d (J = 10Hz, 1H); 8.13 d (J = 10Hz, 2H).

Example 258

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

Prepare in accordance with General Regulation 9.

MP: 181-186 ° C.

Example 259

6 - [[1-Phenyl-2- (3-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

155

Prepared in analogy to 6 - [[1-phenyl-2- (4-pyridyl) -4-benzimidazol-6-yl] oxy] hexanoic acid methyl ester.

MP: Mp 159-160 ° C.

Example 260

N- (Cyclopropylmethoxy) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide

It shall be prepared in accordance with General Regulation 18.

MS (EI): 469 (molecular ion).

Example 261

N -isobutoxy-6 - [(1,2-diphenyl-6-benzimidazol-6-yl) oxy] hexanamide

It shall be prepared in accordance with General Regulation 18.

MS (EI): 471 (molecular ion).

Example 262

N- (Phenylmethoxy) -6 - [(2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanamide

To a solution of 17 mg of carbonyldiimidazole in 1 ml of tetrahydrofuran is added a solution of 50 mg of 6 - [(2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanoic acid in 1 ml. tetrahydrofuran and the mixture is stirred for 30 minutes at 20 ° C and then for 30 minutes at reflux. 16 mg of O-benzylhydroxylamine hydrochloride are added at 20 ° C and the mixture is stirred for 20 hours. Ethyl acetate was then added and the mixture was extracted with 2 N hydrochloric acid and saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography.

MP: Mp 145-148 ° C.

Example 263

156

N- (Cyclopropylmethoxy) -6 - [(2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanamide

Prepared in analogy to N- (phenylmethoxy) -6 - [(2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanamide.

MS (EI): 559 (molecular ion).

Example 264

N-Isobutoxy-6 - [(2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanamide

Prepared in analogy to N- (phenylmethoxy) -6 - [(2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanamide.

^Χ Η-ΝΜΡ (CDCl ₃ ): δ (ppm): 0.94 d (J = 8 Hz, 6H); 1.48-2.03 (7H); 2.05-2.18 m (2H); 3.60-3.72 m (2H); 3.76 s (6H)

3.90-4.00 m (2H); 3.96 s (3H); 6.50 s (2H); 6.72 d (J = 2 Hz, 1H); 6.95 dd (J = 10.2 Hz, 1H); 7.28-7.38 m (3H); 7.55-7.62 m (2H) 7.74 d (J = 10 Hz, 1H); 8.20 with br (1H).

Example 265

N-Isopropyl-6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide

It shall be prepared in accordance with General Regulation 17.

MP: 107-112 C. C.

Example 266

N, N-Dimethyl-6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanamide

It shall be prepared in accordance with General Regulation 17.

MP: Mp 83-88 ° C.

Example 267

157

6 - ((1,2-diphenyl-lH-benzimidazol-6-yl) oxy] -1-pyrrolidin-1-y1-hexan-l-one

Prepare in accordance with General Regulation 17.

MP: Mp 84-88 ° C.

Example 268

N- (2-methoxyethyl) -6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide

It shall be prepared in accordance with General Regulation 17.

MP: 63, -68 ° C.

Example 269

N- (3-Methoxypropyl) -6 - ((1,2-diphenyl-6-benzimidazol-6-yl) oxy] hexanamide

Prepare in accordance with General Regulation 18.

T, i. 84-91 ° C.

Example 270

N-Isobutyl-6 - [(1,2-difeny1-lH-benzimidazol-6-yl) oxy] hexanamide

Prepare in accordance with General Regulation 17.

H-NMR (CDC1 _third): δ (ppm): 0,90 d (J = 8Hz, 6H); . 1,44-1,57 m (2H); 1.65-1.85 m (2H); 2.20 T (J = 8 Hz, 2H); 3.08 T (J = 8Hz, 2H); 3.94 t (J = 8Hz, 2H); 6.68 D (J = 2 Hz, 1H); 6, 96 dd (J = 10,2 Hz, 1H); 7.25-7.38 m (5H); 7 45 -7.58 m (5H); 7.75 D (J = 10Hz,

Example 271

N - [(2,2-Dimethylamino) ethyl] -N-methyl-6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide

Prepare in accordance with General Regulation 17.

158 ¹ H-NMR (CDCl 3) (major rotamer signals): δ (ppm):

1.44-1.57 m (2H); 1.64-1.84 m (4H); 2.30 s (6H); 2.34 t (J = 8 Hz,

2H); 2.47 t (J = 8 Hz, 2H) / 3.00 s (3H); 3.50 t (J = 8Hz, 2H);

3.94 t (J = 8Hz, 2H); 6.69 d (J = 2Hz, 1 H); 6.96 dd (J = 10.2 Hz)

1H); 7.25-7.36 m (5H); 7.45-7.56 m (5H); 7.73 d (J = 10Hz, 1 H).

Example 272

N- (Methoxyethyl) -N-methyl-6 - ((1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide

It shall be prepared in accordance with General Regulation 17.

1 H-NMR (CDCl 3) (major rotamer signals): δ (ppm): 1.43-1.58 m (2H); 1.63-1.84 m (4H); 2.33 t (J = 8Hz, 2H); 3.07 s (3H); 3.32 s (3H); 3.47-3.58 m (4H); 3.95 t (J = 8Hz, 2H); 6.70 d (J = 2Hz, 1H); 6.96 dd (J = 10.2 Hz, 1H); 7.25-7.35 m (5H);

7.45-7.55 m (5H); 7.75 d (J = 10Hz, 1 H).

Example 273

6 - [(1,2-Diphenyl-ΙΗ-benzimidazol-6-yl) oxy] -1-morpholin-yl-hexan-1-one The

It shall be prepared in accordance with General Regulation 17.

¹ H-NMR (CDCl 3): δ (ppm): 1.47-1.59 m (2H); 1.63-1.88 m (4H); 2.34 t (J = 8Hz, 2H); 3.42-3, 49 m (2H); 3.57-3.70 m (6H); 3.94 t (J = 8Hz, 2H); 6.68 d (J = 8Hz, 1H); 6.96 dd (J = 10.2 Hz, 1H); 7.23-7.38 m (5H); 7.45-7.56 m (5H); 7.75 d (J = 10Hz, 1 H).

159

Example 274

Ν, Ν-Di (2-methoxyethyl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide

Prepare in accordance with General Regulation 18.

MP: 88-98 C. C.

Example 275

N-Isopentyl-6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanamide

Prepare in accordance with General Regulation 18.

MP: 127-129 ° C.

Example 276

N- (Pyrid-2-yl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide

Prepare in accordance with General Regulation 18.

MP: 120-124 C. C.

Example 277

N- (Pyrid-3-yl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide

Prepare in accordance with General Regulation 18.

MP: 154 [deg.] C.

Example 278

6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] -1-piperidin-1-y1-hexan-l-one

Prepare in accordance with General Regulation 18.

160

MP: Mp 93-98 ° C.

Example 279 [6 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] -1-hexanoyl] piperidine-4-carboxamide

Prepare in accordance with General Regulation 17.

MP: Mp 177-178 ° C.

Example 280

[[6 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) -oxy] -1-hexanoyl] methylamino] acetic acid ethyl ester

It shall be prepared in accordance with General Regulation 17.

^X H-NMR (CDCl 3) (signals of the main rotamer): δ (ppm): 1.23 t (J = 8 Hz, 3H); 1.45-1.88 m (6H); 2.40 t (J = 8Hz, 2H); 3.08 s (3H); 3.93 t (J = 8Hz, 2H); 4.12 s (2H); 4.18 q (J = 8Hz, 2H); 6.70 d (J = 2Hz, 1H); 6.97 dd (J = 10.2 Hz, 1H); 7.23-7.35 m (5H);

7.45- 7.58 m (5H); 7.75 d (J = 10Hz, 1H).

Example 281

4 - [[6 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] -1-hexanoyl]] piperazine-1-carboxylic acid ethyl ester

It shall be prepared in accordance with General Regulation 17.

¹ H-NMR (CDCl 3): δ (ppm): 1.27 t (J = 8 Hz, 3H); 1.45-1.60 m (2H); 1.63-1.88 m (4H); 2.36 t (J = 8Hz, 2H); 3.40-3.53 m (6H); 3.56-3.64 m (2H); 3.93 t (J = 8Hz, 2H); 4.15 g (J = 8Hz, 2H); 6.69 d (J = 2Hz, 1 H); 6.96 dd (J = 10.2 Hz, 1H); 7.23-7.38 m (5H);

7.45-7.56 m (5H); 7.76 d (J = 10Hz, 1 H).

Example 282

N-Isopropyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide

161

It shall be prepared in accordance with General Regulation 18.

MS (EI): 469 (molecular ion).

Example 283

N, N-Dimethyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

It shall be prepared in accordance with General Regulation 18.

MS (EI): 455 (molecular ion).

Example 284,

N, N-diethyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

Prepare in accordance with General Regulation 18.

MS (EI): 483 (molecular ion).

Example 285

N-Isobutyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

Prepare in accordance with General Regulation 18.

¹ H-NMR (CDCl ₃ ): δ (ppm): 0.90 d (J = 8 Hz, 6H); 1.44-1.55 m (2H); 1.58-1.83 m (5H); 2.20 t (J = 8Hz, 2H); 2.30 s (3H); 2.35 s (3H); 3.09 t (J = 8Hz, 2H); 3.94 t (J = 8 Hz, 2H); 6.63 d (J = 2Hz, 1 H); 6.94 dd (J = 10.2 Hz, 1H); 7.02 dd (J = 10.2 Hz, 1H); 7.10 d (J = 2Hz, 1 H); 7.22-7.35 m (4H); 7.56 dd (J = 8.2 Hz, 2H); 7.73 d (J = 10Hz, 1 H).

Example 286

N-Cyclopropyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

162

Prepare in accordance with General Regulation 18.

MS (EI): 467 (molecular ion).

Example 287

N-cyclobutyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

It shall be prepared in accordance with General Regulation 18.

^X H-NMR (CDCl3): δ (ppm): 1.42-1.55 m (2H); 1,60-1,88 m (8H); 2.15 T (J = 8 Hz, 2H); 2.28-2.40 m (2H); 2.30 s (3H); 2,35 s (3H); 3, 93 T (J = 8 Hz, 2H); 4.40 quintet (J = 8 Hz, 2H); 5,55 with br (1H); 6, 63 D (J = 2 Hz, 1H) ; 6.92 dd (J = 10,2) Hz, 1H); 7.03 dd (J = 10,

Hz, 1H); 7.08 d (J = 2Hz, 1 H); 7.20-7.36 m (4H); 7.57 dd (J = 8.2 Hz, 2H); 7.72 d (J = 10Hz, 1 H).

Example 288

N-tert-butyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide

Prepare in accordance with General Regulation 18.

¹ H-NMR (CDC1 _3): δ (ppm): 1.32 (9H); 1.42-1.55 m (2H); 1.62-1.82 m (4H); 2.10 t (J = 8Hz, 2H); 2.30 s (3H); 2.36 s (3H); 3.92 t (J = 8Hz, 2H); 5.23 with br (1H); 6.66 d (J = 2Hz, 1 H); 6.93 dd (J = 10.2 Hz, 1H); 7.02 dd (J = 10.2 Hz, 1H); 7.09 with br (1H); 7.22-7.36 m (4H); 7.56 dd (J = 8.2 Hz, 2H); 7.73 d

I, (J = 10 Hz, 1H).

Example 289 (R) -6 - [[1- (3,4-Dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] -1- (2-methoxymethyl) pyrrolidin-1-yl-hexane- l-one

It shall be prepared in accordance with General Regulation 18.

MS (EI): 467 (molecular ion).

163

Example 290

N- (3-imidazol-l-yl-propyl) -6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

Prepared according to general procedure ^{18; H-NMR} (CDC1 _3): δ (ppm): 1.42 to 1.53 m (2H); 1.62-2.02 m (6H); 2.17 t (J = 8Hz, 2H); 2.27 s (3H); 2.34 s (3H); 3.24 q (J = 8Hz,

2H); 3.92 t (J = 8Hz, 2H); 3.96 t (J = 8Hz, 2H); 5.68 with br (1H);

6.63 d (J = 2Hz, 1 H); 6.88-6.95 m (2 H); 7.00 dd (J = 10.2 Hz, 1H);

7.04-7.10 m (2H); 7.20-7.36 m (4H); 7.5.0 with br (1H); 7.53 dd (J = 8.2 Hz, 2H); 7.72 d (J = 10Hz, 1 H).

Example 291

N- (2-Pyrid-2-yl-ethyl) -6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide

Prepare in accordance with General Regulation 18.

^X H-NMR (CDCl 3): δ (Ppm): 1,38-1,52 i m (2H); 1.62-1.82 m (4H); 2.15 t (J = 8Hz, 2H); 2,30 s (3 H); 2.35 with (3H) ; 2.96 t (J = 8Hz, 2H); 3.66 q (J = 8Hz, 2H); 3 90 t (J = 8 Hz , 2H) ; 6.48 with br (1H); 6, 65 d (J = 2Hz, 1 H); 6,92 dd (J = 10,2 Hz , 1H) ; 7.00 dd (J = 10, 2 Hz, (1H); 7.06-7.38 m (7H); 7.53-7.62 m (3H); 7.72 d (J = 10Hz,

1H); 8.50 d br (J = 6Hz, 1H).

Example 292

N, N-Dimethyl-6 - [[2- (4-nitrophenyl) -l-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

Prepare in accordance with General Regulation 18.

¹ H-NMR (CDCl 3): δ (ppm): 1.46-1, 58 m (2H); 1.64-1.88 m (4H); 2.32 t (J = 8Hz, -2H); 2.93 s (3H); 3.00 s (3H); 3.96 t (J = 8Hz, 2H); 6.65 d (J = 2Hz, 1 H); 7.00 dd (J = 10.2 Hz, 1H); 7.28-7.36 m (2H); 7.53-7.61 m (3H); 7.70 d (J = 10Hz, 2H); 7.76 d (J = 8Hz,

164

1Η); 8.13 d (J = 8Hz, 2H).

Example 293

N-Isopropyl-6 - [[2- (4-nitrophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide

It shall be prepared in accordance with General Regulation 18.

MP: 162-165 C. C.

Example 294

N-Isopentyl-6 - [[2- (4-nitrophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide

Prepare in accordance with General Regulation 18.

MP: 148-154 C. C.

Example 295

N- (3-methoxypropyl) -6 - [[2- (4-nitrophenyl) -1-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

Prepare a stage of General Regulation 18.

MP: 104-110 C. C.

Example 296

N- (3-methoxypropyl) -6 - [[1- (indan-5-yl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide

Prepare in accordance with General Regulation 18.

¹ H-NMR (CDCl ₃ ): δ (ppm): 1.43-1.56 m (2H); 1,62-1,85 m ( 6H); 2.10-2.23 m (4H); 2.95 t (J = 10Hz, 2H); 3.00 t (J = 10 Hz) 2H); 3.32 s (3H); 3,32- 3.40m - (2H); 3,48 t (J = 8 Hz, 2H); 3 93 t (J = 8Hz, 2H); 6.03 with br (1H); 6, 67d ( J = 2 Hz, 1 H); 6.93 dd (J = 10.2 Hz, 1H); 7.03 dd (J = 10.2 Hz) 1Ή); 7,12 N br ( 1H); 7.26-7.35 m (4H); 7 55 dd (J = 10Hz, 2H); 7 , 72 d (J = 8Hz, 1 H).

165

Example 297

6 - [[1- (4-Methylphenyl) -2- (3-pyridyl) -1H-benzyl] methyl ester

I. , imidazol-6-yl] oxy] hexane

It is obtained by reacting 6 - [[4-amino-3 - ((4-methylphenyl) amino) phenyl] oxy] hexanoic acid methyl ester with 3-pyridylcarbaldehyde according to general formula 16.

MS (EI): 429 (molecular ion).

Example 298

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

It is obtained by reacting 6 - [[4-amino-3 - ((4-methylphenyl) amino) phenyl] oxy] hexanoic acid methyl ester with 4-pyridylcarbaldehyde according to the general formula 16.

MS (EI): 429 (molecular ion).

Example 299

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

It is obtained by reacting 6 - [[4-amino-3 - ((4-methylphenyl) amino) phenyl] oxy] hexanoic acid methyl ester with 2-thienylcarbaldehyde according to the general formula 16.

MS (EI): 434 (molecular ion).

Example 300

6 - [[1- (4-Methylphenyl) -2- (3-thienyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is obtained by reacting 6 - [[4-amino-3 - ((4-methylphenyl) amino) phenyl] oxy] hexanoic acid methyl ester with 3-thienylcarbaldehyde according to the general formula 16.

166

MS (EI): 434 (molecular ion).

Example 301

6 - [[2- (3-Indolyl) -1- (4-methylphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is obtained by reacting 6 - [[4-amino-3 - ((4-methylphenyl) amino) phenyl] oxy] hexanoic acid methyl ester with 3-indolylcarbaldehyde according to general formula 16.

MS (EI): 467 (molecular ion).

Example 302

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

It is obtained by reacting 6 - [[4-amino-3 - ((4-methylphenyl) amino) phenyl] oxy] hexanoic acid methyl ester with 2-furylcarbaldehyde according to the general formula 16.

MS (EI): 418 (molecular ion).

Example 303

6 - [[1- (4-Methylphenyl) -2- (3-furyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester. This is obtained by reaction of methyl 6 - [[4-amino-3] ester. - ((4-methylphenyl) amino) phenyl] oxy] hexane with 3-furylcarbaldehyde according to general formula 16.

MS (EI): 418 (molecular ion).

Example 304

6 - [[1- (4-Methylphenyl) -2- (5-methyl-2-thienyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is obtained by reaction of 6 - [[4-amino-3 - ((4-me

167 5-methyl-2-thienylcarbaldehyde according to the general formula 16.

MS (EI): 448 (molecular ion).

Example 305

6 - [[1- (4-Methylphenyl) -2- (4-bromo-2-thienyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is obtained by reacting 6 - [[4-amino-3 - ((4-methylphenyl) amino) phenyl] oxy] hexanoic acid methyl ester with 4-bromo-2-thienylcarbaldehyde according to the general formula 16.

MS (EI): 512/514 (molecular ions).

Example 306

6 - [[1- (4-Methylphenyl) -2- (3-methyl-2-thienyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester

It is obtained by reacting 6 - [[4-amino-3 - ((4-methylphenyl) amino) phenyl] oxy] hexanoic acid methyl ester with 3-methyl-2-thienylcarbaldehyde according to the general formula 16.

MS (EI): 448 (molecular ion).

Example 307

Suppression of microglia activation

For in vitro preparation of β-activated microglia, primary rat microglia are incubated with synthetic β-peptide:

To simulate β-deposits, the synthetic β-peptide is dried in a 96-well. cultivation plate. To this end, the 2 mg / ml H ₂ O peptide stock solution is diluted 1:50 with water. When applied to a 96-well plate, 30 μΐ of this diluted peptide solution is pipetted into each well and allowed to dry overnight at room temperature.

168

Primary rat microglia are prepared from mixed glial cultures obtained from rat brain P3. In order to prepare these mixed cultures of glia, the 3 day old rats are harvested and the brain skins removed. Cell release was achieved by trypsinization (0.25% trypsin solution, 15 min, 37 ° C). After the uncleaved tissue fragments were separated by passing through a 40 µm nylon mesh, the isolated cells were centrifuged (800 rpm, 10 minutes). The cell pellet is suspended in culture medium and transferred to 100 ml culture flasks (1 brain / culture flask). Cells are cultured for 5-7 days in Dulbeccos' Modified Eagle Medium (DMEM, glutamine) containing medium containing penicillin (50 U / ml), streptomycin (40 µg / ml ·) and 10% (v / v) fetal calf serum (FOS) at 37 ° C and 5% CO ₂ . During this incubation, an adhesive cell coating is formed, mainly composed of astrocytes. Microglia proliferate there as non-adherent or only weakly adherent cells and are discarded after suspension (420 rpm, 1 hour).

To activate microglia by β-peptide, 2.5 x 10 ⁴ microgliels / well are plated in β-peptide coated culture plates and incubated for 7 days in DMEM (with glutamine) containing penicillin (50 U / ml), streptomycin (40 μς / πιΐ) and 10% (v / v) fetal calf serum (FCS) at 37 ° C and 5% CO ₂ . On the fifth day, the compound of the invention is added at various concentrations (0.1, 0.3, 1, 3 and 10 μΜ).

To quantify the microglia reactivity on day ¹ cul inactivation of the metabolic activity measured by reduction of MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (sulfophenyl) -2H-tetrazolium) , Owen's Reagent, Baltrop, JA et al., Bioorg. & Med. Chem. Lett. 1, 6111 (1991)). Percent inhibition refers to a control that was treated exclusively with DMSO. The compounds of the invention inhibit the activation of microglia.

Example 308

Stroke in rats (MCAO-model)

169

The compounds of the invention are tested in an animal model of cerebral ischemia (stroke), the MCAO model (permanent middle cerebral artery occlusion), for an in vivo inhibitory effect. Unilateral occlusion of the middle cerebral artery (MCA) induces a cerebral infarction, which is due to an insufficient supply of oxygen and nutrients to the corresponding brain area. As a result, there is a significant cell death along with subsequent activation of the microglia. However, this activation will reach its maximum at the earliest days and may last for several weeks. For testing, the compounds of the invention are administered intraperitoneally 1-6 days after occlusion. On day 7, animals are perfused and sacrificed. The extent of microglia activation is measured using a modified immunohistochemical method. To this end, the fixed brain vibratoma sections are incubated with antibodies that recognize the CR3 complement receptor and the respiratory system. MHCI1 complex on activated microglia. Quantitation of the primary antibody binding is performed using an enzyme-linked detection system. The addition of the compounds of the invention results in a significant reduction in microglia activation in the hemispheres affected by cerebral infarction. This reduction shall be at least 20%.

Example 309

Activation of macrophages

LPS-activated THP-1 cells are used in the macrophage / monocyte compound assay. To this end, 2.5 x ^{10 6} cells / ml RPMI medium (RPMI 1640 + 10% FCS) are seeded. The compounds of the invention are added at a concentration of 5 μΜ and preincubated for 30 minutes. The cells are stimulated overnight at 37 ° C with 1 μς / πιΐ LPS. The medium is then discarded and the amount of TNFα is quantitated. Treatment of cells with the compounds of the invention results in at least a 30% reduction in the amount of TNFα.

Claims (21)

What is claimed is: 1. A compound of the formula (I) EMI2.0 wherein: EMI3.0 [0000] EMI2.0 [0005] EMI2.0 [0005] R ¹ is a mono- or bicyclic C 6 ^_ i2 aryl group, or a mono- or bicyclic 5-10-membered heteroaryl having 1-4 heteroatoms selected from the group comprising nitrogen, sulfur or oxygen, wherein said ^aryl; or the heteroaryl group may be independently substituted with up to three of the following substituents: fluorine atom, chlorine atom, bromine atom, iodine atom, C (NH) NH ₂ , C (NH) NHR ⁴ , C (NH) NR ⁴ R ⁴ , C (NR ⁴ ) NH ₂ , C ( NR ⁴ ) NHR ⁴ ', C (NR ⁴ ) NR ⁴ R ⁴ , 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 ', XCN, XCOOH, XCOOR ⁴ , XCONH ₂ , XCONR ⁴ R ⁴ , XCONHR ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SC> 2NH ₂ , SO ₂ NHR ⁴ , SO ₂ NR ⁴ R ⁴ , NO 2, XNH ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , 171 X NHS group ₂ R ^4, XN (SO 2 R ⁴⁾ SO 2 R ^4, a group XNR ⁴ SO ₂ R ^4, group ⁴ XNHCOR, XNHCOOR group ^4, group XNHCONHR ^4, tetrahydro-2,5-dioxopyrrole-l-yl, 2 , 5-dihydro-2,5-dioxopyrrol-1-yl, 2,7-dihydro-2,7-dioxoisoindol-1-yl, or R ⁴ , wherein the two substituents on R ¹ are ortho to one another -position ¹ , may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl, R ² is a monocyclic or bicyclic C 8-10 -aryl group or a monocyclic or bicyclic 5-10-membered heteroaryl group with 1-4 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein the aryl or heteroaryl group may be independently substituted with up to three of the following substituents: fluorine, chlorine, bromine, iodine, XOH, XOR ⁴ , XOCOR ⁴ , XOCONHR ⁴ , XOCOOR ⁴ , XCOR, XC (NOH) R ⁴ , XC (NOR ⁴ ) R ⁴ ', XC (NO (COR ⁴ )) R' ^: ', XCOOH, XCOOR ⁴ , XCONH ₂ , XCONHR ⁴ , XCONR ⁴ R ⁴ ', XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ', XSOR ⁴ , XSO2R ⁴ , SO ₂ NH ₂ , SO-NHR ⁴ , SO ₂ NR ⁴ R ⁴ , NO ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , X NHS ₂ R ^4, XN (SO 2 R ⁴⁾ SO 2 R ^4, a group XNR ⁴ SO ₂ R ^4, tetrahydro-2,5-dioxopyrrole-l-yl, 2,5-dihydro-2,5-dioxopyrrole-l-yl, a 2,7-dihydro-2,7-dioxoisoindol-1-yl group, or an R ⁴ group, 172 wherein the two substituents on R ^2, where they are in the ortho position, can be linked so that they together form methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl, butane-1,4- a diyl group, R ³ is one or two substituents, which independently of one another may be: hydrogen, fluorine, chlorine, bromine, iodine, 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 ', XCN, XCOOH, XCOOR ⁴ , XCONH2, XCONHR ⁴ , XCONR ⁴ R ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SO2NH ² , SO2NHR ⁴ , SO2NR ⁴ R ⁴ , NO ₂ , XNH ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , XNHSO ₂ R ⁴ , XNR ⁴ SO ₂ R ⁴ ', XN (SO ₂ R ⁴ ) (SO ₂ R ⁴ '), XNHCOR ⁴ , XNHCOOR ⁴ , XNHCONHR ⁴ , tetrahydro-2,5-dioxopyrol-1-yl, 2,5 -dihydro-2,5-dioxopyrrol-1-yl, 2,7-dihydro-2,7-dioxo-isoindol-1-yl, or R ⁴ , wherein the two substituents R ³ when they are in each other ortho-position, they can be joined together so that they form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl, R ⁴ and R ^4, independently of one another are C ₄ -perfluóralkylová group, a Ci-g-alkyl, _C2 _6-alkenyl, C ₂ _ ₆ -alkynyl, C 3-7 -cycloalkyl, (C 3 alkyl), C ₃ -7-cycloalkyl, Ci-3-alkyl-C _6-10 -aryl, C 3 -alkyl-monosubstituted sub173 5-10-membered heteroaryl with 1-4 N, s or O , C _6-10 -aryl, or a 5-10 membered heteroaryl group having 1-4 nitrogen, sulfur or oxygen atoms, wherein the aryl and heteroaryl groups may be substituted by one or two substituents from the group consisting of a fluorine atom, a chlorine atom, an atom Br, CH3, C2H5 group, a group N0 _2, OCH _3, OC ₂ H _5, CF _3, or C ₂ F ₅ or else can carry a fused methanediylbisoxy or ethane-1,2-diyl bisoxyskupinu, and further, in the 5-membered cycloalkyl ring, one member of the ring may be a nitrogen or oxygen atom and in the 6-membered member the singly or 7-membered cycloalkyl ring may be one or two ring members nitrogen and / or oxygen, wherein the ring nitrogen atoms may be optionally substituted by a C _1-3 -alkyl or a C 1-3 -alkanoyl group, R ⁵ and R ^5, independently of one another are Ci-g-alkyl, _C2 -6 -alkenyl or C ₂ _g-alkynyl, wherein one carbon atom can be exchanged for O, S, SO, S0 ₂ , NH, N-C 1-3 -alkyl or N-C 1-3 -alkanoyl, A C ^3-7 cycloalkyl-C ^0-3 -alkyl group wherein one of the five-membered cycloalkyl ring may be nitrogen or oxygen and the six-membered or seven-membered cycloalkyl ring may be nitrogen and / or oxygen, with nitrogen atoms in the ring may be optionally substituted with a C _1-3 -alkyl group or a C _1-3 -alkanoyl group, C6-io ^- aryl or 5-10-membered heteroaryl with 1-4 heteroatoms from the group N, S and O, wherein the said alkyl, alkenyl and alkynyl may be substituted with one of said cycloalkyl, aryl or heteroaryl groups, 174 wherein all of the aforementioned alkyl and cycloalkyl groups may be substituted with up to two substituents selected from the group consisting of CF ₃ , C ₂ F ₅ , OH, O-C 1-3 -alkyl, NH ₂ , NH -C _1-3 alkyl, NH-C 1-3 alkanoyl, N (C _1-3 alkyl) ₂ , N (C _1-3 alkyl) (C 1-3 alkanoyl) groups. COOH, CONH ₂ , COO-C _1-3 -alkyl, and all of the aforementioned aryl and heteroaryl groups may be substituted by one or two substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a CH ₃ group, C ₂ H ₅ , NO ₂ , OCH ₃ , OC ₂ H ₅ , CF ₃ and C ₂ F ₅ , or may also carry fused methanediylbisoxy or ethane-1,2-diyl-bisoxy, or R ⁵ and R ⁵ together with the nitrogen atom form a 5-7-membered heterocycle which may contain an additional oxygen, nitrogen or sulfur atom and may be substituted by a C 1-4 -alkyl group, a C 1-4 -alkoxy-Co- _2- alkyl group, C N-alkoxycarbonyl, aminocarbonyl or phenyl, A is C ic-aikándiylová group, a _C2-IO ~ alkenediyl group, a _{C2-IO-alkynediyl} group, (CO-5-alkanediyl-C ₃ -7-cycloalkanediyl-Co-5 alkanediyl) wherein the five membered the cycloalkyl ring may be one nitrogen or oxygen member of the ring, and the six- or seven-membered cycloalkyl ring may be one or two ring members nitrogen and / or oxygen, wherein the ring nitrogen atoms may optionally be substituted with a C _1-3 alkyl or C _1-3 alkyl alkanoyl, wherein in the aforementioned aliphatic chains, one or two carbon atoms may be replaced by an oxygen atom, an NH group, an NC group> ₃ -alkyl or an N-C _1-3 -alkanoyl group, and the alkyl or cycloalkyl groups may be substituted by up to two substituents from the group consisting of = O, OH, O-C _1-3 -alkyl, NH ₂ , NH-C _1-3 -alkyl, NH-C 1-3 -alkanoyl, N (C 1-6 -alkyl) _3- alkyl) ₂ , and groups 175 N (C 1-3 -alkyl) (C _1-3 -alkanoyl), B is COOH, COOR ⁵ , CONH ₂ , CONHNH ₂ , CONHR ⁰ , CONR ⁵ R ⁵ , CONHOH, CONHOR ⁵ , SO 3 H, SO ₂ NH ₂ , SO ₂ NHR ⁵ , SO ₂ NR ⁵ R ⁵ ', PO 3 H, PO (OH) (OR ⁵ ), PO (OR ⁵ ) (OR ⁵ ), PO (OH) (NHR ⁵ ), PO (NHR ⁵ ) ( NHR ^5), or tetrazolyl, each of which is attached to each carbon atom of A, or an array of YAB is N (SO ₂ R ⁴⁾ (SO 2 R ⁴⁾ or the group NHSO 2 R ^4, X is a bond, CH ₂ , (CH ₂ ) ₂ , CH (CH ₃ ), (CH ₂ ) ₃ , CH (CH ₂ CH ₃ ), CH (CH ₃ ) CH ₂ , CH ₂ CH (CH _3), Y is O, NH, NR ⁴ , NCOR ⁴ , NSO ₂ R ⁴ , provided that when Y is NH, NR ⁴ , NCOR ^4, or NSO ₂ R ⁴ , and (a) R ² contains a nitrogen-containing saturated heterocycle which is not substituted on the imine nitrogen atom by a hydrogen atom, a methyl group, an ethyl group, a propyl group or an isopropyl group, or b) in the group XNHR ⁴ or XNR ⁴ R ⁴ , optionally present in the substituent R ² , R ⁴ and / or R ⁴ does not mean that C 1-4 alkyl is not simultaneously B is COOH, SO ₃ H, PO ₃ H ₂ or tetrazolyl and R ¹ and R ² independently of one another C 5-6 -heteroaryl or phenyl when these are independently 176 unsubstituted, once substituted by Ci-6-alkyl, Ci-4-perf fluoroalkyl group, O-C ₆ -alkyl, O-Ci-4-perfluoroalkyl, COOH, COO-C 1-6 -alkyl, CO-C 1-6 -alkyl, CONH ₂ , CONHR ⁴ , NO 2, NH 2, NHCOR ⁴ , NHSO ² R ⁴ or one or two halogen atoms from fluorine, atom chlorine, bromine and iodine, and the following compounds are excluded: acetic acid, (1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] methyl 5 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] pentanoic acid, methyl ester of 4- [ (1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] butanoic acid, 5 - [[1- (4-nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid methyl ester, methyl ester 6 - [[1- (4-nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 5 - [[1- (4-aminophenyl) -2-phenyl-1H-benzimidazole methyl ester] 6-yl] oxy] pentanoic acid, 5 - [[1- [4 - [[(4-chlorophenyl) sulfonyl] amino] phenyl] -2-phenyl-benz-benzimidazol-6-yl] oxy] pentanoic acid methyl ester 5 - [[1- [4 - [(Acetyl) amino] phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid methyl ester 5 - [[1- (3- nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid, 6 - [[1- (3-nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, methyl ester 5 - [[1- (3-aminophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid methyl ester 5 - [[1- [3 - [[ 5 - [[1- [3 - [(acetyl) amino] phenyl] - (4-chlorophenyl) sulfonyl] amino] phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid methyl ester 2-phenyl-lH-benzimidazol-6-yl] oxy] pentanoic acid. i ₍ Benzimidazoles according to claim 1, characterized in that: R ¹ is a mono- or bicyclic C 6 and ₂ -aryl or a mono- or bicyclic 5-10-membered heteroaryl having 1-2 heteroatoms selected from the group contain a nitrogen, sulfur or oxygen, wherein said aryl or "heteroaryl may be independently substituted with up to three of the following substituents: fluorine, chlorine, bromine, XOH, XOR ⁴ , XOCOR ⁴ , XOCONHR ⁴ , XOCOOR ⁴ , XCOR ⁴ , XCN, XCOOH, XCOOR ⁴ , XCONH 2, XCONR ⁴ R ⁴ , XCONHR ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , NO 2, XNHR ⁴ , XNR ⁴ R ⁴ , or R ⁴ , wherein the two substituents on R ¹ are each other. ortho-position, they can be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl. Benzimidazoles according to claim 1 or 2, characterized in that R ² is a monocyclic or bicyclic C 8-10 -aryl group or a monocyclic or bicyclic 5-10-membered heteroaryl group having 1-2 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein the a178 yl or heteroaryl group may be independently substituted with up to three of the following substituents: fluorine, chlorine, bromine, 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 , XCONH ₂ , XCONHR ⁴ , XCONR ⁴ R ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ^4, "a group · XSO2R ^4, the group SO 2 NH _2, SO ₂ NHR ^4, SO ₂ NR ⁴ R ^4, a group N0 ₂ groups XNHR ^4, group XNR ⁴ R ^4, group X NHS ₂ R ^4, XN (SO 2 R ⁴⁾ sO 2 R ^4, a group XNR ⁴ sO ₂ R ^4, or a group R ^4, where two substituents on R ^2, where they are in the ortho position, can be linked so that they together form methanediylbisoxy, ethane-1,2- diyibisoxy, propane-1,3-diyl or butane-1,4-diyl. 4. Benzimidazoles according to one of claims 1-3, characterized in that R ³ is one or two substituents, which independently of one another may be: hydrogen, fluorine, chlorine, bromine, XOH, XOR ⁴ , XOCOR ⁴ , XOCONHR ⁴ , XOCOOR ⁴ , XCOR ⁴ , XC (NOH) R ⁴ , XC (NOR ⁴ ) R ⁴ , group XC (NO (COR ⁴ )) R ⁴ ', 179 XCN group, XSR ⁴ group, XSOR ⁴ group, XSO ₂ R ⁴ group, SO2NH ₂ group, SO2NHR ⁴ group, SO2NR ⁴ R ⁴ group, NO ₂ group, XNH ₂ group, XNHR ⁴ group, XNR ⁴ R ⁴ group X NHS ₂ R ⁴ group, XNR ⁴ SO 2 R ^4, XN (SO 2 R ⁴⁾ SO ₂ R ⁴ group, XNHCOR ⁴ group XNHCOOR ⁴ group, XNHCONHR ^4, or R ^4, where two substituents R ^3, where they are in the ortho position, may be joined together to form a methanediylbisoxy group, ethane-1,2-diylbisoxy group, propane-1,3-diyl group or butane-1,4-diyl group. 5. Benzimidazoles according to one. of claims 1-4, characterized in that R ⁴ and R ^4, independently of one another are CF3, C2F5, Ci-4-alkyl, C 2-4 ^_ alkenyl, C 2-4 alkynyl group, a _C3 _6-cycloalkyl, (C ₃ -C 3 alkyl phenyl or 5-6-membered heteroaryl having 1-2 nitrogen, sulfur or oxygen atoms, wherein the phenyl and heteroaryl groups may be substituted by one or two substituents from the group consisting of a fluorine atom, an atom Cl, Br, CH _3, C ₂ H _5, OCH 3, OC ₂ H _5, CF _3, or the group of C2F5, and on the 5-membered cycloalkyl ring, which may be one member of the ring nitrogen or oxygen atom and in the 6-membered cycloalkyl ring, one or two ring members may be nitrogen and / or oxygen, wherein the ring nitrogen atoms may be optionally substituted with a C 1-3 -alkyl or a C 1-3 -alkanoyl group. Benzimidazoles according to one of claims 1-5, characterized in that 180 R ⁵ and R ⁵ independently of one another are C 1-6 -alkyl, wherein the carbon atom may be replaced by an oxygen atom, NH, N-C 1-3 -alkyl or N-C _1-3 -alkanoyl, ^_ C 3-7 cycloalkyl-C 3 ^- alkyl group, wherein the five-membered cycloalkyl ring may be one member of the ring is N or O and, six or seven membered cycloalkyl ring may be one or two ring members N and / or O, wherein the nitrogen in the ring may be optionally substituted with a C _1-3 -alkyl group or a C _1-3 -alkanoyl group, wherein said C 1-6 -alkyl moiety may be substituted with one of the aforementioned cycloalkyls or a 5-6-membered heteroaromate with 1-2 heteroatoms selected nitrogen, sulfur or oxygen, all of the foregoing alkyl and cycloalkyl groups being substituted by up to two substituents selected from the group consisting of CF ₃ , OH, O-C _1-3 -alkyl, and previously said heteroaryl groups may be substituted with one or two substituents selected from the group consisting of: consisting of a fluorine atom, a chlorine atom, a CF ₃ group, a CH ₃ group, a C2 H5 group, an OCH ₃ group, an OC ₂ H- group, or R ⁵ and R ⁵ together with the nitrogen atom form a 5-7-membered heterocycle which it may contain an additional oxygen, nitrogen or sulfur atom and may be substituted with a C 1-4 -alkyl group, a C _1-4 -alkoxy-C 0-2 -alkyl group, a C _1-4 -alkoxycarbonyl group, an aminocarbonyl group or a phenyl group. Benzimidazoles according to one of Claims 1-6, characterized in that A is C 10 alkanediyl, C 2 ^_ io alkenediyl group, a C2-io ~ alkynediyl group, a group (C _{0 5-alkándiyi-C3} 7-cycloalkyl-Co-alkanediyl 5 alkanediyl), wherein the the five membered cycloalkyl ring may be one The ring member is nitrogen or oxygen, and in the 6 or 7 membered cycloalkyl ring, one or two ring members may be a nitrogen and / or oxygen atom, wherein the ring nitrogen atoms may be optionally substituted by a C 1-3 alkyl or C 1-3 alkanoyl group, wherein in the aforementioned aliphatic chains one or two carbon atoms may be replaced by an oxygen atom, an NH group, an N-C 1-3 -alkyl group or an N-C _1-3 -alkanoyl group. 8. Benzimidazoles by one from claims 1-7, characterized by and by that B is COOH, group COOR ⁵ , group ΟΟΝΗ ₂ , group CONHR ⁵ , group CONR ⁵ R ⁵ ', group CONHOH group CONHOR ⁵ , or tetrazolyl, each of which is bonded to a carbon atom in group A. 9. Benzimidazoles by one from claims 1-8. marked group of drugs. is that X is a or methylene 10. Benzimidazoles by one from claims 1 - 9, characterized by and wherein Y is atom oxygen. 11. Compounds: [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] acetic acid isopropyl ester, 3 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] propanoic acid methyl ester 2 4 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] butanoic acid, isopropyl ester, 5 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] propanoate (1,2-diphenyl-lH-benzimidazol-6182 -yl) oxy] pentanoic acid, 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanoic acid methyl ester, 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) isopropyl ester ) oxy] hexanoic acid, 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide, N-methoxy-6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide, N- (phenylmethoxy) -6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide, 7 - [(1,2-Diphenyl-1H-benzimidazol-6-yl) oxy] heptanoic acid methyl ester, N-hydroxy-6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide, isopropyl ester 6 - [[1- (3-nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[2-phenyl-1- [3- (trifluoromethyl) phenyl] phenyl] -, methyl ester 6 - [[2-Phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid, methyl ester, 6 - [[2-phenyl-1- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoate [1- (3-cyanophenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (3-Cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, 6 - [[1- (3-Cyanophenyl) -2-phenyl-1H- benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (4-cyanophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[1- (4 cyanophenyl) -2-phenyl-H- 183 Benzimidazol-6-yl] oxy] hexanoic acid, 6- [• [1- (3-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[1] isopropyl ester 6 - [[1- (4-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] - (3-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 6 - [[1- (4-chlorophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (3-methylphenyl) -2-phenyl] -, methyl ester 6 - [[1- (3-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (3-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester 6 - [[1- (4-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] -1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester oxy] hexanoic acid 6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 6 - [[1- (3,5-dimethylphenyl)] 2-phenyl-H -benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (3,5-Dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, 6 - [[1- (3-methoxyphenyl) -2-methyl ester] 6 - [[1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 6-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 6 - [[1- (3,4-dimethoxyphenyl) -2-phenyl 184 6H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- [3,4- (methylenedioxy) phenyl] -2-phenyl-6-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[1- [3,4- (methylenedioxy) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[2-phenyl-1- (3,4, 5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[2-phenyl-1- (3,4,5-trimethoxyphenyl) -4-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, 6 - [[1- [4- (N, N, N-dimethylamino) phenyl] -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- [4- (N, N-dimethylamino) phenyl] -2-phenyl-1H benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1-phenyl-2- [3- (trifluoromethyl) phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, 6- methyl ester 6 - [[2- (3-Chloro-phenyl) -1-phenyl-1H-benzimidazol-6-yl] -hexanoic acid, isopropyl ester -yl] oxy] hexane, me 6 - [[2- (4-chlorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid ethyl ester, 6 - [[2- (4-chlorophenyl) -1-phenyl-1-isopropyl ester] 6 - [[2- (4-methylphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[2- (4-methylphenyl) -1-phenyl] -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester (4-methylphenyl) -1-phenyl-H 185 Benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1-phenyl-2- (4-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [(1,2-methyl) methyl ester 6 - [(1,2-Diphenyl-5-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid, isopropyl ester 6-diphenyl-5-nitro-1H-benzimidazol-6-yl) oxy] hexanoic acid 6 - [[5 - [[(4-chlorophenyl)] - [[5 - [[(4-bromophenyl) sulfonyl] amino] -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester sulfonyl] amino] -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1,2-diphenyl-1H-isopropyl ester 6 - [[1,2-diphenyl-5 - [[(3-methylphenyl) sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid, isopropyl ester, benzimidazol-6-yl] oxy] hexanoic acid, isopropyl ester 6 - [[1,2-diphenyl-5 - [[(4-methylphenyl) sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1,2-diphenyl-5] isopropyl ester 6 - [[1,2-dife] - [[(4-methoxyphenyl) sulfonyl] amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester phenyl-5 - ([[(4-trifluoromethyl) phenyl] sulfonyl] amino] -lH-benzimidazol-6-yl] oxy] hexanoic acid, • the ^J L isopropyl 6 - [[5 - [[[4- ( acetylamino) phenyl] sulfonyl] amino] -1,2-diphenyl-6-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[5 - [[bis (3-chlorophenyl) sulfonyl] amino] amino] -1-isopropyl ester, 2-Diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1,2-Diphenyl-5 - [(propylsulfonyl) amino] -1H-benzimidazol-6-yl] oxy] hexanoic acid isopropyl ester, Isopropyl ester 6 - [[5 - [(benzylsulfonyl) amino] -1,2186 diphenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 2- [2 - [(1,2-diphenyl-1H-benzimidazole-) methyl ester 6-yl) oxy] ethoxy] acetic acid, 3- [2 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] ethoxy] propenoic acid methyl ester, 6 - [[1- ( 3-nitrophenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[4-acetyl-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] methyl ester 6 - [[1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester 6] 6 - [[2-phenyl-1- [4- (thiomethyl) phenyl] - [[2-phenyl-1- [4- (thiomethyl) phenyl] -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester - 1H-benzimidazol-6-yl] oxy] hexane, i 6 - [[2-phenyl-1- (3-thienyl) -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester, 6 - [[2-phenyl-1- (3-thienyl) -1H- benzimidazol-6-yl] oxy] hexanoic acid, 4 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] butanoic acid methyl ester, N- (phenylmethoxy) -6 - [[2-phenyl-l- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl] oxy] hexanamide, N, N-dimethyl-6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide, N-isopropyl-6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide, 6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] -1-pyrrolidin-1-yl187 hexan-1-one, 5 - [[5 - [[(4-chlorophenyl) sulfonyl] methyl ester amino] -1,2-diphenyl-4-benzimidazol-6-yl] oxy] pentanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methylphenyl) -, methyl ester 2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-methyl ester Benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[4- (acetyloxy) -1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6- [[4-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[4-hydroxy-1- (4-methylphenyl) -2-phenyl] 1 H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[7-methyl-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester. 12. Compounds: 6 - [[2-phenyl-1- (3-pyridyl) -1H-benzimidazol-5-yl] oxy] hexanoic acid methyl ester, 6 - [[2-phenyl-1- (3-pyridyl) -1H- benzimidazol-6-yl] oxy] hexanoic acid 6 - [[2-phenyl-1- (4-pyridyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 6-Fluorophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoate, 6 - [[2- (4-methoxyphenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexane methyl ester 6 - [[2- (4-bromophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 188 6 - [[2- [4- (Trifluoromethyl) phenyl] -1-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[1-phenyl-2- (benzothien-2) methyl ester -yl) -1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1-phenyl-2- (benzothien-2-yl) -4-benzimidazol-6-yl] oxy] hexanoic acid, isopropyl ester 6 - [[5-hydroxy-1- (4-methylphenyl) -2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[5-hydroxy-1- (4-methylphenyl) - 2-Phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[5-Methoxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] isopropyl ester hexanoic acid, 6 - [[5-hydroxy-1- (4-methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[5-methoxy-1- (4-methylphenyl) -1-methyl ester] 6-Methylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoate, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (3,4-dimethylphenyl) -, methyl ester 2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -2- (4-fluorophenyl) -1- (4-methoxyphenyl) methyl ester ) -lH-benzimidazol-6 -yl] oxy] hexanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2- (4-methoxyphenyl) -1H-benzimidazol-6-yl methyl ester ] oxy] hexanoic acid, 4 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] butanoic acid methyl ester, methyl ester 5 - [[5 - [[(4-chlorophenyl) sulfonyl] amino] -1- (4-methoxyphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid, 5 - [[5] methyl ester - [[(4-chlorophenyl) sulfonyl] amino] 189 -1,2-diphenyl-1H-benzimidazol-6-yl] oxy] pentanoic acid, 6 - [[5 - [[(4- (trifluoromethyl) phenyl) sulfonyl] amino] -1- (4-methoxyphenyl) methyl ester 2-phenyl-ΙΗ-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[5 - [[(4-chlorophenyl) sulfonyl] methylamino] -1- (4-methoxyphenyl) -2- phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (indan-5-yl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6- [ [1- (Indan-5-yl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[1- (3-fluorophenyl) -2-phenyl-1H-benzimidazol-6] methyl ester 6 - [[2- (4-nitrophenyl) -1-phenyl-1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6 - [[1-phenyl-2- (methyl) -oxy] hexanoic acid, methyl ester 3-pyridinyl) -lH-benzimidazol-6-yl] oxy] hexanoic acid, N- (cyclopropylmethoxy) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide, N-isobutoxy-6 - [(1,2-diphenyl-ΙΗ-benzimidazol-6-yl) oxy] hexanamide, N- (cyclopropylmethoxy) -6- [2-phenyl-1- (3,4,5-trimethoxyphenyl) -1H-benzimidazol-6-yl) oxy] hexanamide, N-isobutoxy-6- [2-phenyl-l- (3,4,5-trimethoxy-phenyl) -lH-benzimidazol-6-yl) oxy] hexanamide, N- (2-methoxyethyl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide, N- (3-methoxypropyl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide, 190 N-isobutyl-6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanamide, 6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] -1-morpholin-l-yl-hexan-l-one, N, N-di- (2-methoxyethyl) -6 - [(1,2-diphenyl-1H-benzimidazol-6-yl) oxy] hexanamide, N-isopentyl-6 - [(1,2-diphenyl-lH-benzimidazol-6-yl) oxy] hexanamide, N- (pyrid-2-yl) -6 - [(1,2-diphenyl-6-benzimidazol-6-yl) oxy] hexanamide, N- (pyrid-3-yl) -6 - [(1,2-diphenyl-6-benzimidazol-6-yl) oxy] hexanamide, N-isopropyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide, N, N-dimethyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide, N, N-diethyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide, N-isobutyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide, N-cyclopropyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide, N-cyclobutyl-6 - [[1- (3,4-Dimethyl-phenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide, N-tert-butyl-6 - [[1- (3,4-dimethylphenyl) -2-phenyl-1H-benzimidazol-6-yl] oxy] hexanamide, (R) -6 - [[1- (3,4) dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] 1- (2-methoxymethyl) pyrrolidin-l-yl-hexan-l-one, 191 N- (3-imidazol-1-yl-propyl) -6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide, N- (2-pyridin-2-yl-ethyl) -6 - [[1- (3,4-dimethylphenyl) -2-phenyl-lH-benzimidazol-6-yl] oxy] hexanamide, N- (3-methoxypropyl) -6 - [[1- (indan-5-yl) -2-phenyl-1H-benzimidazol-6-yl] oxy] heptanamide, 6 - [[1- (4-methyl-4-methyl-propyl) -amide] Methylphenyl) -2- (3-pyridyl) -4-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (4-methylphenyl) -2- (4-pyridyl) -4-benzimidazole] methyl ester 6-yl] oxy] hexanoic acid, 6 - [[1- (4-methylphenyl) -2- (2-thienyl) -4-benzimidazol-6-yl] oxy] hexanoic acid methyl ester 6 - [[2- (3-Indolyl) -1- (4-methylphenyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester (4-methylphenyl) -2- (3-thienyl) -1H-benzimidazol-6-yl] -1H 6-1 '- [1- (4-methylphenyl) -2- (2-furyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid methyl ester, 6- [benzimidazol-6-yl] oxy] hexanoic acid methyl ester [1- (4-Methylphenyl) -2- (3-furyl) -1H-benzimidazol-6-yl] oxy] hexanoic acid 6 - [[1- (4-methylphenyl) -2- (5-methyl- 2-Thienyl) -4-benzimidazol-6-yl] oxy] hexanoic acid, 6 - [[1- (4-methylphenyl) -2- (3-methyl-2-thienyl) -ΙΗ-benzimidazol-6-yl] methyl ester ] oxy] hexanoic acid. Use of a compound according to any one of claims 1-12 for the preparation of a medicament for the treatment or prophylaxis of diseases associated with microglia activation. 14. A pharmaceutical composition 192 comprising one or more compounds according to one of claims 1-12 and one or more carriers. Use of a benzimidazole of formula II wherein R ¹ is a mono- or bicyclic Cs_i ₂ -aryl group or a mono- 'or bicyclic 5-10-membered heteroaryl having 1-4 heteroatoms selected from the group consisting of N, S or O, wherein said aryl or heteroaryl. the group may be independently substituted with up to three of the following substituents: fluorine atom, chlorine atom, bromine atom, iodine atom, C (NH) NH ₂ , C (NH) NHR ⁴ , C (NH) NR ⁴ R ⁴ , C (NR ⁴ ) NH 2, C (NR) ⁴ ) NHR ⁴ , C (NR ⁴ ) NR ⁴ R ⁴ , 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 , XCN, XCOOH, XCOOR ⁴ , XCONH 2, XCONR ⁴ R ⁴ , XCONHR ", XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SO ₂ NH ₂ , SO ₂ NHR ⁴ , SO ₂ NR ⁴ R ⁴ ', NO 2, XNH ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , XNHSO ₂ R ⁴ , XN (SO ₂ R ⁴ ) (SO ₂ R), XNR ⁴ SO ₂ R ⁴ ', XNHCOR ⁴ , XNHCOOR ⁴ , XNHCONHR ⁴ , tetrahydro-2,5-dioxo-pyrrol-1-yl, 2,5-dihydro-2,5-dioxopyrrol-1-yl, 2,7-dihyd r-2,7-dioxoisoindol-1-yl, or R ⁴ , wherein the two substituents on R ¹ , when in ortho position with each other, 193 may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl, R ² is a mono- or bicyclic C ₆ _ ₁₀ -aryl group or a mono- or bicyclic 5-10-membered heteroaryl having 1-4 heteroatoms selected from the group consisting of N, S or O, where the specified aryl or heteroaryl group may be independently substituted with up to three of the following substituents: fluorine atom, chlorine atom, bromine atom, iodine atom, C (NH) NH ₂ , C (NH) NHR ⁴ , C (NH) NR ⁴ R ⁴ , C (NR ⁴ ) NH 2, C (NR) ⁴ ) NHR ⁴ , C (NR ⁴ ) NR ⁴ R ⁴ , 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 , XCN, XCOOH, XCOOR ⁴ , XCONH2, XCONR ⁴ R ⁴ , XCONHR *, XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SO2NH ₂ , SO ₂ NHR ⁴ , SO2NR ⁴ R ⁴ , NO 2, XNH ₂ , XNHR ⁴ , XNR ⁴ R ⁴ , XNHSO2R ⁴ , XN (SO ² R ⁴ ) (SO ² R ⁴ ), XNR ⁴ SO ² R ⁴ , XNHCOR ⁴ , XNHCOOR ⁴ , XNHCONHR ⁴ , tetrahydro-2,5-dioxo-pyrrol-1-yl, 2,5- dihydro-2,5-dioxopyrrol-1-yl, 2,7-dihydro-2,7- dioxoisoindol-1-yl or R ⁴ , wherein the two substituents on R ² , when they are in the ortho-position to each other, may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propan-1 , 3-diyl or butane-1,4-diyl, R ³ is one or two substituents, which independently of one another may be: hydrogen, fluorine, chlorine, bromine, iodine, XOH, XOR ⁴ , XOCOR ⁴ , XOCONHR ⁴ , 194 XOCOOR ⁴ , XCOR ⁴ , XC (NOH) R ⁴ , XC (NOR ⁴ ) R ⁴ , XC (NO (COR ⁴ )) R ⁴ , XCN, XCOOH, XCOOR ⁴ , XCONH2 , XCONHR ⁴ , XCONR ⁴ R ⁴ ', XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , XSOR ⁴ , XSO2R ⁴ , SO2NH2, SO2NHR ⁴ , SO2NR ⁴ R ⁴ , NO2 group, XNH2 group, XNHR ⁴ group, XNR ⁴ R ^4, a group XNHSO2R ^4, · a group XNR ⁴ SO 2 R ^4, XN (SO 2 R ⁴⁾ (SO ₂ R ⁴⁾ group, XNHCOR ⁴ group XNHCOOR ⁴ group, XNHCONHR ^4, tetrahydro-2,5-dioxopyrrol-1-yl, 2,5-dihydro-2,5-dioxo-pyrrol-1-yl, 2,7-dihydro-2,7-dioxoisoindol-1-yl, or a group R ⁴ , wherein the two substituents R ³ , when in the ortho position, can be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1, A 4-diyl group, R ⁴ and R ^4, independently of one another are C ₄ -perfluóralkylová group, a Ci-6-alkyl, C _{2 to 6} -alkenyl, C _{2nd 6-al} alkinyl group, 03-7-cykloalkyiová group, a (C ₃ -alkyl-C ₃ -7-cycloalkyl), C ₃ -C ₆ -alkyl-aryl-IO, C 5-10 alkyl-substituted-3 a-membered heteroaryl group having 1-4 nitrogen, sulfur or oxygen atoms, a C 8-10 aryl group or a 5-10-membered heteroaryl group having 1-4 nitrogen, sulfur or oxygen atoms, wherein the C _6-10 aryl and heteroaryl groups they may be substituted by one or two substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, CH ₃ group, C ₂ H ₅ group, NO ₂ group, OCH ₃ group, OC ₂ H ₅ group, CF ₃ group, or C ₂ F ₅ , or may also carry fused methanediylbisoxy or ethane-1,2-diylbisoxy wherein one of the five-membered cycloalkyl ring may be nitrogen or oxygen and the six-membered or seven-membered cycloalkyl ring may be one or two ring members nitrogen and / or at oxygen atom, wherein the ring nitrogen atoms may be optionally substituted with a C _1-3 -alkyl group or a C 1-3 -alkanoyl group, R ⁵ and R ^5, independently of one another are H, Ci_6-alkyl, C2-6 ^_ alkenyl or C 2-6 alkynyl, wherein the carbon atom can be exchanged for O, S, SO, S0 ₂ group, NH, N-C 1-3 -alkyl or N-C 1-3 -alkanoyl, C 3-7 -cycloalkyl-C 0-6 -alkyl, wherein one of the five-membered cycloalkyl ring may be nitrogen or oxygen, and the six-membered or seven-membered cycloalkyl ring may be nitrogen and / or oxygen, with nitrogen atoms in the ring, they may be optionally substituted by a C 1-3 -alkyl group or a C _1-3 -alkanoyl group, A C 6-10 aryl group or a 5-10 membered heteroaryl group having 1-4 heteroatoms from the group consisting of nitrogen, sulfur and oxygen, wherein said alkyl, alkenyl and alkynyl chains may be substituted once with said cycloalkyl, aryl or heteroaralkyl groups wherein all of the aforementioned alkyl and cycloalkyl groups may be substituted by up to two substituents selected from the group consisting of CF ₃ , C2F 5, OH, O-C 1-3 -alkyl, NH ₂ , NH-C 1 - 3-alkyl, NH-C 1-3 -alkanoyl, N (C 1-3 -alkyl) ₂ , N (C 1-3 -alkyl) (C 1-3 -alkanoyl), COOH, CONH ₂ , COO -C 3 alkyl, and all of the previously mentioned aryl and heteroaryl groups optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, CK3, C2H5 group, a group N0 _2, Item OCH ₃ pins, 00 ₂ Η ₅ groups, C _1-3 groups and C ₂ F ₅ groups, or may also carry a fused methanediylbisoxy or ethane-1,2-diyl-bisoxy group, or R ⁵ and R ⁵ together with the nitrogen atom form a 5- A 7-membered heterocycle which may contain an additional oxygen, nitrogen or nitrogen atom 196 sulfur and may be substituted with a C 1-4 -alkyl group, a C 1-4 -alkoxy-C 0-2 -alkyl group, a C _1-4 -alkoxycarbonyl group, an aminocarbonyl group or a phenyl group, A is C 10 alkanediyl, C ₂ -i ₀ -alkéndiylová group, a C ₂ -i ₀ -alkíndiylová group, a group. (C ₀ -5 alkanediyl-C ₃ -7-cycloalkanediyl-Co-5 alkanediyl) group _(the C-5-alkándiylarylén-Co-5 alkanediyl) group, (C ₀ _ ₅ -alkanediyl-heteroarylene-Co -5-alkanediyl) wherein the aryl and heteroaryl groups may be substituted by one or two substituents from the group fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, NO ₂ group, OCH ₃ group, OC ₂ H ₅ group, CF ₃ , C ₂ F ₅ , wherein in the five-membered cycloalkyl ring one member of the ring may be a nitrogen or oxygen atom and in the six-membered or seven-membered cycloalkyl ring one or two of the ring member may be a nitrogen and / or oxygen atom; be optionally substituted with a C _1-3 -alkyl group or a C 1-3 -alkanoyl group, wherein in the above-mentioned aliphatic chains one or two carbon atoms may be replaced by an oxygen atom, an NH group, an NR ⁴ group, an NCOR group ⁴ or NSO ² R ⁴ , and the alkyl or cycloalkyl groups may be substituted by up to two substituents from the group consisting of a fluorine atom, an OH group, an OR ⁴ group, an OCOR ⁴ group, an = O atom, an NH 2 group, an NR ⁴ R ⁴ 'group. , NHCOR ⁴ , NHCOOR ⁴ , NHCONHR ⁴ , NHSO ₂ R ⁴ , SH and SR ⁴ , B is hydrogen, OH, OCOR ⁵ , OCONHR ⁵ , OC00R ⁵ , COR ⁵ , C (NOH) R ⁵ , C (NOR ⁵ ) R ⁵ ', C (NO (COR ⁵ )) R ⁵ , COOH, COOR ⁵ , CONH2, CONHNH 2, CONHR ⁵ , CONR ⁵ R ⁵ , CONHOH, CONHOR ⁵ , SO 3 H, SO ₂ NH ₂ , SO ₂ NHR ⁵ , a group SO 2 NR ⁵ R ⁵ group, PO3H, PO (OH) (OR ^5), PO (OR ⁵⁾ (OR ⁵ '), PO (OH) (NHR ^5), PO (NHR ⁵⁾ (NHR ⁵ ), or a tetrazolyl group, 197 each of which is attached to each carbon atom of A, or- whole group of YAB is N (SO ₂ R ⁴⁾ (SO 2 R ⁴⁾ or the group NHSO 2 R ^4, X is a bond, CH ₂ , (CH ₂ ) ₂ , CH (CH ₃ ), (CH ₂ ) ₃ , CH (CH ₂ CH ₃ ), CH (CH ₃ ) CH ₂ , CH ₂ CH (CH _3), Y is a bond, oxygen, sulfur, SO, SO ₂ , NH, NR ⁴ , NCOR ^4, or NSO ₂ R ⁴ , for the preparation of a medicament for the treatment or prophylaxis of diseases associated with the activation of microglia. Use according to claim 15, wherein in formula II R ¹ is a monocyclic or bicyclic aryl group or a monocyclic or bicyclic 5-10 membered heteroaryl group with 1-2 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, wherein said aryl or heteroaryl group may be independently substituted with up to with the following three substituents: fluorine, chlorine, bromine, XOH, XOR ⁴ , XOCOR ⁴ , XOCONHR ⁴ , XOCOOR ⁴ , XCOR ⁴ , XCN, XCOOH, XCOOR ⁴ , XCONH 2, XCONR ⁴ R ⁴ · XCONHR ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , NO 2, XNHR ⁴ , XNR ⁴ R ⁴ , or R ⁴ , with two substituents on R ¹ when they are in each other ortho-position, they can be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl. 198 Use according to claim 15 or 16, wherein in formula II R ² is a mono- or bicyclic aryl or mono- or bicyclic 5-10-membered heteroaryl having 1-2 heteroatoms selected from the group consisting of N, S or O, wherein said aryl or heteroaryl group may be independently substituted with up to with the following three substituents: fluorine atom, chlorine atom, bromine atom, XOH group, XOR ⁴ group, XOCOR ⁴ group, XOCONHR ⁴ group, XOCOOR ⁴ group, XCOR ⁴ group, XC (NOH) R ⁴ group, XC (NOR ⁴ ) R ⁴ group, XC (NO (COR ⁴ )) R ⁴ , XCN, XCOOH, XCOOR ⁴ , XCONH ₂ , XCONR ⁴ R ⁴ , XCONHR ⁴ , XCONHOH, XCONHOR ⁴ , XCOSR ⁴ , XSR ⁴ , group XSOR ^4, group XSO2R ^4, the group SO 2 NH _2, 'SO ₂ NHR ^4, a group SO 2 NR ⁴ R ^4, N02, group XNH _2, groups XNHR ^4, group XNR ⁴ R ^4, group X NHS ₂ R ^4, XN (SO ₂ R ⁴ ) (SO ₂ R ⁴ ), XNR ⁴ SO ₂ R ⁴ , XNHCOR ⁴ , XNHCOOR ⁴ , XNHCONHR ⁴ , or R ⁴ , wherein the two substituents on R ² , when in ortho position to each other, may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl. Use according to one of claims 15 - 17, wherein in formula II R ³ is one or two substituents independently of one another: hydrogen atom, fluorine atom, chlorine atom, bromine atom, 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 ', XCN, XSR ⁴ , XSOR ⁴ , 199 XSO ₂ R ⁴ , SO2NH ₂ , SO2NHR ⁴ , SO2NR ⁴ R ⁴ , NO 2, XNH 2, XNHR ⁴ , XNR ⁴ R ⁴ , XNHSO2R ⁴ , XNR ⁴ SO2R ⁴ ', XN ( SO ₂ R ⁴ ) (SO ₂ R ⁴ '), XNHCOR ⁴ , XNHCOOR ⁴ , XNHCONHR ⁴ or R ⁴ , wherein the two R ³ substituents, when in the ortho position, may be joined together to form together methanediylbisoxy, ethane-1,2-diylbisoxy, propane-1,3-diyl or butane-1,4-diyl. Use of a stage according to one of claims 15-18, wherein in formula II R ⁴ and R ^4, independently of one another are CF 3, C ₂ F _5, C-4-alkyl groups, "C ₂ -4-aIkenylová group, a _C2 -4 alkynyl group, C 3-6 cycloalkyl, (C 1-3 -alkyl-C 3-8 -cycloalkyl), C 1-3 -alkylaryl, C 1-3 -alkyl heteroaryl, monocyclic aryl or 5-6-membered heteroaryl having 1-2 nitrogen, sulfur or oxygen atoms, wherein the aryl and heteroaryl groups may be substituted by one or two substituents selected from the group consisting of fluorine, chlorine, bromine, CH ₃ , C ₂ H ₅ , NO ₂ , OCH ₃ , OC ₂ H ₅ , CF ₃ , or C ₂ F ₅ , or may also carry fused methanediylbisoxy or ethane-1,2-diylbisoxy wherein one of the five-membered cycloalkyl ring may be nitrogen or oxygen and one or two of the six-membered cycloalkyl ring nitrogen atom ring members and / or an oxygen atom, wherein the ring nitrogen atoms may be optionally substituted with a C 1-3 -alkyl group or a C 1-3 -alkanoyl group. Use according to one of claims 15-19, wherein in the general formula II R ⁵ and R ⁵ independently of one another are C 1-6 -alkyl, wherein a carbon atom may be replaced by an oxygen atom, an NH group, an N-C 1-3 -alkyl group or an N-C 1-3 -alkanoyl group, 200 a C _{3 -7-cycloalkyl-Co-3-alkyl,} wherein the five-membered cycloalkyl ring may be one member of the ring is N or O and, six or seven membered cycloalkyl ring may be one or two ring members N and / or O, wherein the ring nitrogen atoms may be optionally substituted by a C _1-3 -alkyl or a C _1-3 -alkanoyl group, wherein said C 1-6 -alkyl moiety may be substituted by one of said cycloalkyl groups or also by one of the 5-6-membered heteroaromates having 1- 2 heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, all of the above alkyl and cycloalkyl groups being substituted by up to two substituents selected from the group consisting of CF ₃ , OH, O-C _1-3 -alkyl, and the above-mentioned heteroaryl groups may be substituted by one or two substituents from the group consisting of a fluorine atom, a chlorine atom, a CF ₃ group, a CH ₃ group, a C ₂ H ₅ group, an OCH ₃ group and an OC ₂ H _{5 group} , or R ⁵ and R ⁵ together with the nitrogen atom form 5- 7-membered heterocycle containing a further oxygen, nitrogen or sulfur and is optionally substituted C 4 -alkyl, C <i-alkoxy-Co-2 ^- alkyl, Ci_4-alkoxy-carbonyl, aminocarbonyl, or phenyl group. Use according to one of claims 15 - 20, wherein in the general formula II A is C-io-alkanediyl, _C2-IO ^- alkenediyl group, a C ₂ -i ₀ -alkíndiylová group, a group (C ₀ _5-alkanediyl-C ₃ -7-cycloalkanediyl-Co-s-alkanediyl) group, or ( Co-5-alkanediyl-heteroarylene-Co-5-alkanediyl),. wherein the optionally present heteroaryl group may be substituted by one or two substituents selected from fluorine, chlorine, bromine, CH ₃ , C ₂ H 5, NO ₂ , OCH ₃ , OC ₂ H ₅ , CF ₃ and category C ₂ F ₅ , 201 wherein in the five-membered cycloalkyl ring one member of the ring may be nitrogen or oxygen and in the six-membered or seven-membered cycloalkyl ring one or two member of the ring may be nitrogen and / or oxygen, wherein the nitrogen atoms in the ring may be optionally substituted by C _1-3 alkyl or a C 1-3 -alkanoyl group, wherein in the aliphatic chain one or two carbon atoms may be replaced by an oxygen atom, an NH group, an NC-3-alkyl group, an N-C 1-3 -alkanoyl group, or an NSO ₂ C 1-3 group -alkyl, and alkyl or cycloalkyl moieties may be substituted with up to two fluorine atoms or one of the substituents selected from the group consisting of OH, O-C 1-3 -alkyl, O-C 1-3 -alkanoyl, atom = 0 , NH ₂ , NH-C 1-3 -alkyl, N (C 1-3 -alkyl) ₂ , NHC _1-3 -alkanoyl, N (C 1-3 -alkyl) (C 1-3 -alkanoyl), NHCOOC1-3-alkyl groups, NHCONHC1-3-alkyl groups, NHSO groups 2C _1-3 alkyl, SH groups and SC _1-3 alkyl groups. Use according to any one of claims 15-21, wherein in formula II B is hydrogen, OH, OCOR ⁵ , OCONHR ⁵ , OCOOR ⁵ , COOH, COOR ⁵ , CONH ₂ , CONHR ⁵ , CONR ⁵ R ⁵ , CONHOH, CONHOR ⁵ , or tetrazolyl each of which is bonded to the carbon atom of the group A. Use according to one of claims 15-22, wherein in formula II X is a bond or a CH ₂ group. Use according to one of claims 15 - 23, wherein in formula II Y is a bond, O, S, NH, NR ^4, NCOR ⁴ group, or a group NSO2R ^fourth