EP1539741A1 - 2-thio-substituted imidazole derivatives and their use in pharmaceutics - Google Patents

Abstract

The invention relates to 2-thio-substituted imidazole derivatives of formula (I), wherein the radicals R1, R2, R3 and m have the meanings as cited in the description. The inventive compounds comprise an immunomodulatory action and/or an action that inhibits the release of cytokines and are thus suited for treating diseases associated with a disorder of the immune system.

Description

2-Thio-substituted imidazole derivatives and their use in pharmacy

The present invention relates to 2-thio-substituted imidazole derivatives with immunomodulating and cytokine release-inhibiting activity, pharmaceutical compositions containing these compounds and their use in pharmacy.

Pharmacologically active imidazole compounds with anti-inflammatory activity are already known. Among other things, compounds with 4,5-di (hetero) aryl imidazole elements were investigated in more detail and various pharmaceutical effects thereof were described. Compounds are also known which have a substitution at the 2-position. US Pat. No. 4,585,771 discloses 4,5-diphenylimidazole derivatives which are substituted at the 2-position with a pyrrolyl, indolyl, imidazolyl or thiazolyl radical and have an anti-inflammatory and anti-allergic activity. US Pat. Nos. 4,528,298 and 4,402,960 describe 4,5-di (hetero) arylimidazole derivatives which are at the 2-position via a thio, sulfinyl or sulfonyl group. a phenyl, pyridyl, N-oxypyridyl, pyrimidyl, thiazolyl or thienyl radical, and have anti-inflammatory and anti-allergic activity. US Patents 4,461, 770, 4,528,298 and 4,584,310 (EP 004 648 A) describe 4- (5-aryl) -5- (4-heteroaryl) imidazole derivatives which are at the 2-position via a thio, sulfinyl or Are substituted sulfonyl group with a substituted or unsubstituted aliphatic hydrocarbon, and inter alia have an anti-inflammatory effect. Imidazole compounds with an immunomodulating effect and inhibiting the cytokine release are described in WO 02/066458, WO 02/076951 and DE 102 22 103. Further imidazole compounds with an anti-inflammatory effect are described in WO 96/03387, EP 005 545 (US 4,440,776; 4,355,039; 4,269,847), EP 236 628 (US 4,686,231), DE 35 04 678, US 4,190,666, US 4,402,960 and US 4,585,771. EP 372 445 (US 5,318,984; US 5,166,214) and US 5,364,875 describe imidazole compounds with antihypercholesterolemic activity.

WO 00/17192 (DE 198 42 833) relates to 4-heteroaryl-5-phenylimidazole derivatives which are substituted at the 2-position with a phenylalkylthio group. These connections genes act as anti-inflammatory agents and inhibitors of cytokine release. WO 99/03837 and WO 93/14081 describe 2-substituted imidazoles which inhibit the synthesis of a number of inflammatory cytokines. In the 2-position, the compounds described in WO 93/14081 have a phosphorus-containing substituent or an aryl or heteroaryl substituent which is bonded via a sulfur atom. WO 91/10662 and WO 91/13876 describe imidazole derivatives which inhibit the acyl coenzymes A: cholesterol-0-acyltransferase and the binding of thromboxane TxA ₂ . WO 95/00501 describes imidazole derivatives which are useful as cyclooxygenase inhibitors.

J. Med. Chem. 1996, 39, 3927-37 describes compounds with 5-lipoxygenase and cyclooxygenase inhibiting activity, where 2- (4-methylsulfinylphenyl) -4- (4 ~ fluorophenyl-5- (pyrid-4-yl ) -imidazole also has a cytokine inhibitory effect.

Further 2-thio-substituted imidazole derivatives are described in JP 01-040 467, SU 1 415 725, Acta Chim. 1969, 61, 69-77, J. Prakt. Chem. 1972, 314, 785-792 and DE 101 14 775, Indian J. Chem., Sect. B, 1983, 22B (3), 268-269, Bioorganic & Medical Chem. Lett., Vol 5, No. 2, 177-180, 1995, Phosphorus Sulfur 1988, 35 (1-2), 83-88, Arch. Biochem. Biophys. Vol. 297, 258-264, 1992, J. Med. Chem. 1995, 38, 1067-1083, Helv. Chim. Acta 82, 1999, 290-296, Helv. Chim. Acta 81, 1998, 1585-1595.

Despite the numerous known compounds, there is therefore still a need for compounds having an anti-inflammatory effect which inhibit cytokine release.

The object of the invention is to provide such connections.

Surprisingly, it has now been found that certain 2-substituted imidazole derivatives have a high immunomodulating activity and / or cytokine release-inhibiting activity.

The present invention therefore relates to the 2-thio-substituted imidazole derivatives of the formula I.

wherein

R ^{1 represents} CrC ₆ alkyl, C ₃ -C ₇ cycloalkyl or aryl, which is optionally substituted by a halogen atom, CrCe alkyl or halogen -C ¹ -C ₆ alkyl;

R ^{2 is} selected from

a) Aryl -CC ₄ -alkyl, where the aryl radical can have one, two or three substituents which are selected independently of one another from CrC ₆ -alkyl, -C-C ₆ -alkoxy, halogen, CrC ₆ - alkylsulfanyl, CrC ₆ -Alkylsulfinyl, C-ι-C ₆ alkylsulfonyl and hydroxy-, and

b) CrC ₆ alkyl, which is optionally substituted by CN or halogen;

R ° is selected under

a) NR ⁴ R ¹⁰ ;

b) NR ⁷ COR ¹⁰ ; c) NR ⁷ COOR ¹⁰ ;

d) NR ⁷ CONR ⁷ R ¹⁰ ;

e) NR ⁷ CONR ⁷ COR ¹⁰ ;

f) OR ¹⁰ ;

g) S (0) _m R ¹⁰ ;

h) halogen;

i) OH;

j) N ₃

k) NH ₂

I) SH;

where R ^{3 is} not OH, halogen, CrC ₆ alkylthio or -CC ₆ alkoxy when R ^{2 is} phenyl-C C ₄ -alkyl and the phenyl radical is a CrC ₆ -alkylsulfanyl-, Ci-Cβ-alkylsulfinyl- or has CrC ₆ alkylsulfonyl substituents;

R ^{4 represents} H or a physiologically removable group,

R ⁵ and R ⁶ , which may be the same or different, for H, halogen, OH, d- C ₆ alkoxy, CrCe alkyl, halogen C ₆ alkyl, -C ₆ alkyl sulfanyl, NH ₂ , dC ₆ - alkylamino or di-CrC ₆ -alkylamino;

R ^{7 represents} R ⁴ , CrCe alkyl or benzyl;

R ^{10 has} one of the following meanings: a) A - B

f) d-Cβ-alkyl which is substituted with 2 or 3 phenyl groups;

g) trifluoromethyl (in particular if R ^{3 is} the radicals b) to f))

A for straight-chain or branched dC ₆ alkylene, C ₂ -C ₆ alkenylene or C ₃ -

Alkynylene;

B is selected under

a) H

f) Od-Ce alkyl; g) NR ¹¹ R ¹² ; h) OH; i) halogen; j) d-Ce alkylsulfanyl

R ¹¹ and R ¹² , which may be the same or different, represent H, CrCe alkyl or phenyl;

Hy represents a 3- to 10-membered non-aromatic mono-, bi- or tricyclic carbocycle which can optionally be fused with a benzene ring;

Ar represents a 5- or 6-membered aromatic heterocycle which has 1, 2 or 3 heteroatoms, which are independently selected from 0, S and N and which can optionally be fused with a benzene ring;

Het represents a 5- or 6-membered non-aromatic heterocycle which has 1, 2 or 3 heteroatoms which are selected independently of one another from O, S and N, which can optionally be fused with a benzene ring or which can also be bicyclic or can be tricyclically bridged;

m represents 0.1 or 2; n represents 1, 2, 3, 4 or 5; and the tautomers, optical isomers and physiologically acceptable salts thereof.

If the compounds according to the invention have centers of asymmetry, racemates and optical isomers (enantiomers, diastereomers) are included. The following tautomeric equilibrium can be present in the compounds according to the invention:

The invention encompasses both tautomeric forms.

The invention also encompasses the physiologically tolerated salts of the compounds of the formula I. In the present case, these are in particular acid addition salts. For acid addition salts, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or organic acids such as tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, mandelic acid, ascorbic acid, gluconic acid and the like are used.

The term “alkyl” (also in connection with other groups such as phenylalkyl, alkylsulfonyl, alkoxy etc.) encompasses straight-chain and branched alkyl groups with 1 to 6 or 1 to 4 carbon atoms, such as methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, sec-butyl, n-pentyl, isoamyi, neopentyl and n-hexyl The same applies to "CrC ₆ - alkylene".

The term "carbocycle" includes saturated or unsaturated, non-aromatic, monocyclic, bicyclic and tricyclic hydrocarbons. The hydrocarbons can be fused with one or two benzene rings. Monocyclic hydrocarbons are C ₃ -C ₆ cycloalkyl, such as cyclopropyl, cyclopentyl, cyclohexyl. Examples of bi- and tricyclic hydrocarbons and benzo-fused carbocycles are indanyl, decalinyl, tetralinyl, fluorenyl, dihydroanthracenyl, dibenzosubane renyl, norbomyl or adamantyl. Examples of substituted carbocycles are methylcyclopropyl or methylcyclohexyl. Unsubstituted radicals are preferred.

The term "aryl" encompasses aromatic ring systems such as phenyl or naphthyl.

The term "halogen" stands for a fluorine, chlorine, bromine or iodine atom, in particular a fluorine or chlorine atom.

The term “halogen-CrC ₆ -alkyl” encompasses straight-chain and branched alkyl groups with 1 to 6 and in particular 1 to 4 carbon atoms, which are mono- or poly-halogenated. Preferably 1, 2, 3, 4 or 5 halogen atoms are present. Preferred halogen atoms are F and Cl. Examples of halogen -CC ₆ -alkyl are -CH ₂ CI, -CH ₂ CH ₂ CI, -CH ₂ CCI ₃ , -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ and -CF ₂ CF ₃ . CF ₃ is preferred.

A physiologically cleavable group is a group that can be cleaved enzymatically or chemically from the rest of the molecule under physiological conditions. Examples are -COR ¹⁴ , -C0 ₂ R ¹⁴ , -CONH ₂ , -CONHR ¹⁴ , -CHR ¹⁶ -OR ¹⁴ , -CHR ¹⁶ -0- COR ¹⁴ , -COC (R ¹⁶ ) ₂ -OH, -COR ¹⁵ , SO ₂ R ¹⁵ and -S0 ₂ R ¹⁴ , wherein R ^{14 is} dC ₆ alkyl or CF ₃ , R ^{15 is} phenyl or tolyl (in particular p-tolyl) and R16 is H or d-Ce-alkyl.

The aromatic, 5- or 6-membered heterocycle is in particular unsubstituted (R ⁵ , R ⁶ = H) or substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, thiazolyl, imidazolyl, oxazolyl, isothiazolyl, pyrazolyl, isoxazolyl, triazolyl or pyrimidyl. Preferred substituents are one or two groups which are selected independently of one another from halogen, in particular Cl or CC ₆ alkyl. The substituent or substituents are bonded to a carbon atom or nitrogen atom of the aromatic radical. Unsubstituted radicals are preferred. Examples of substituted radicals are chlorothienyl, especially 5-

Chlorothien-2-yl, chlorofuryl, especially 5-chloro-fur-2-yl, examples of fused residues are benzofuranyl, benzothiazolyl and benzothiophene. The non-aromatic 5- or 6-membered heterocycle can be saturated or unsaturated. It is preferably unsubstituted or substituted tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, N-ethylpyrrolidinyl, piperazinyl or morpholinyl, it being possible for the heterocycle to be bonded or substituted via an N-hetero atom or ring carbon atom. Preferred substituents are one or two radicals which are selected independently of one another from halogen, in particular Cl, or d-Cβ-alkyl. Unsubstituted radicals are preferred.

stands for substituted or unsubstituted cyclopropyl, cyclobutyl, cycloheptyl and especially cyclopentyl and cyclohexyl. R ⁵ and R ⁶ are preferably and independently of one another H, halogen or CrCe-alkyl.

Examples of substituted cycloalkyl groups are methylcyclopropyl or methylcyclohexyl. Unsubstituted radicals are preferred.

Phenyl-d-d-alkyl means in particular benzyl, 1-phenylethyl or 2-phenylethyl.

R ¹ preferably represents a phenyl radical and in particular a halogen, CF ₃ - or CrCβ-alkyl-substituted phenyl radical, a fluorine-substituted phenyl radical being particularly preferred. The substituent is preferably in the 3- and in particular in the 4-position. Examples of substituted phenyl radicals are 4-fluorophenyl, 2,4-difluorophenyl, 3-trifluoromethyl, 3-tolyl or 3-chlorophenyl.

R ² preferably represents a benzyl, C ₃ -C ₆ cycloalkyl, C4-C ₇ methylcycloalkyl or d-Cβ-alkyl radical, it being possible for the phenyl group of the benzyl radical to be substituted as indicated above. Preferred substituents of the phenyl group of the benzyl radical are CrC ₆ -alkylsulfanyl, d-Cβ-alkylsulfinyl and dC ₆ -alkylsulfonyl. Examples of R ² are CH ₃₎ CH ₃ CH ₂ , (CH ₃ ) ₂ CH, CH ₂ CN, CH ₂ CF ₃ , CF ₃ and cyclopropyl.

R ³ preferably represents the rest of the formula

wherein R ⁴ , R ⁵ and R ⁶ and A have the meanings given above. R ⁵ and R ⁶ are preferably H, methyl, methoxy or chlorine. If the phenyl ring of this group is substituted, the radicals R ⁵ and R ^{6 are} preferably in the 3- and / or 4-position.

R ³ also preferably represents

a) NR ⁴ R ¹⁰ , where R ^{10 is} cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl or cycloheptyl;

b) NR ⁴ R ¹⁰ , where R ¹⁰ is d-Ce-alkyl, in particular methyl, ethyl or isopropyl, or 3,3-diphenylpropyl or 1,3-diphenylprop-2-yl;

c) NR ⁴ R ¹⁰ , where R ^{10 is} A - B and B is OH, CC ₆ -alkoxy, NR ¹¹ R ¹² or phenyl;

d) NR ⁷ COR ¹⁰ - where R ^{10 is} A - B and B is phenyl;

e) NR ⁷ COOR ¹⁰ , where R ^{10 is} dC ₆ alkyl.

A is preferably dC ₂ alkylene and especially ethylidene.

m is preferably 0.

A particularly preferred embodiment is the compounds of the formula I in which R ^{1 is} 4-fluorophenyl, R ^{2 is} CrC ₆ alkyl or benzyl, where the phenyl group of the benzyl radical can be substituted as indicated above; R ³ for the rest of the formula

is where R ⁴ , R ⁵ , R ⁶ and A have the meanings given above and m is 0.

A further preferred embodiment are compounds of the formula I in which R ^{2 is} CrCe-alkyl, in particular methyl, and R ^{1 is} halophenyl or halogen-CrC ₆ -alkylphenyl, in particular 4-fluorophenyl, 2,4-difluorophenyl, 4-trifluoromethylphenyl or 3-trifluoromethylphenyl. R ³ then preferably has the following meanings:

a) halogen, in particular F or Cl;

b) OH or O -CC ₆ alkyl, especially methoxy and isopropoxy,

c) phenylamino;

d) phenyl group by phenyl or naphthyl-dd-alkylamino 1 or 2 halo gene, in particular F or Cl, CrC ₆ alkoxy or CrC ₆ alkyl may be substituted. The amino group can additionally be substituted by CrC ₆ alkyl. Examples of such radicals are benzylamino, 4-methoxybenzylamino, 4-methylbenzylamino, 4-chlorobenzylamino, 3,4-dichlorobenzylamino, 2-

Phenylethylamino, 1-phenylethylamino, 1-naphth-1-yl-amino 1-naphth-2-ylamino; 1-phenylprop-3-yl-amino, 3-phenylpropylamino, 1- (4-isobutylphenyl) ethylamino;

wherein A for CrC ₂ alkylene, R ⁵ and R ⁶ for H and

stand for thienyl, furyl, 2-, 3- or 4-pyridyl, thiazolyl, oxazolyl, benzothiophenyl or benzofuranyl, where the heterocyclic radicals can be substituted by halogen, in particular F or Cl, or dC ₆ -alkyl.

f)

wherein A, R ⁵ , R ⁶ and

have the meanings given under e).

g) NH-d-Ce alkyl which is substituted by 2 or 3 phenyl groups, e.g. B. 3,3-diphenylpropylamino, 1,3-diphenylprop-2-ylamino;

H)

wherein A for C ₁ -C ₂ alkylene, R 5 ^ü and i R _D 6 for H and

represent tetrahydrofuranyl, tetrahydropyranyl, pyrrolidine, N-methyl- or N-ethylpyrrolidine; i)

wherein R ⁵ , R ^δ and

have the meanings mentioned under h);

j) -NH-COOR ¹⁰ , wherein R ^{10 is} C ₃ -C ₆ cycloalkyl;

k) -NH-CO-NHR ^1ß , wherein R ^{10 is} C ₃ -C ₆ cycloalkyl;

I) -NH-COR ¹⁰ , wherein R ^{10 is} C ₃ -C ₆ cycloalkyl-CrC ₄ alkyl, e.g. B. cyclopentylmethyl, cyclohexylmethyl;

m) NH-CONH CO phenyl;

n) -AC ₃ -C ₆ cycloalkyl, in which A represents dC ₂ alkylene, e.g. B. cyclopentylmethylamino, cyclohexylmethylamino.

The compounds according to the invention can be prepared in a corresponding manner by the processes described in the prior art mentioned at the outset, in particular WO 00/17192. Production according to the following two-stage process has proven to be particularly expedient. In the first step, a substituted imidazole-2-thione of the general formula II is first prepared. This is then implemented in the second step such that the 2-thio-substituted imidazole derivatives of the formula I are obtained by introducing the desired substituent R ² .

1) Preparation of imidazole-2-thione 5

Process A or B is used to prepare imidazole-2-thiones with R ³ = H, halogen (Br, Cl, F), O-alkyl or S-alkyl. Process A is exemplified using compounds in which R ^{1 is} 4-fluorophenyl and R ^{3 is} H, process B is in compounds where R ^{1 is} 4-fluorophenyl and R ^{3 is} Cl, (25a), F (25b) or O-

L0 alkyl (25c, 25d) stand (the numbers in brackets refer to the numbers of the examples). 2-Thio-substituted-imidazole derivatives with R ³ = NR ⁴ R ¹⁰ are not produced from corresponding imidazole-2-thions with R ³ = NR ⁴ R ¹⁰ but according to method C in a different way. 2-Thio-substituted-imidazole derivatives with R ³ = O-alkyl or S-alkyl can be prepared either by process C or by process B.

15 will be asked.

Procedure A

0 The synthesis of the substituted imidazole-2-thiones with R ³ = H takes place starting from ethyl isonicotinate and 4-fluorophenylacetonitrile according to the course of the reaction in Scheme 1.

The starting materials are seen in a condensation reaction with the help of metallic sodium in an alcohol, e.g. B. ethanol, converted to 2-cyano-2- (4-fluorophenyl) -1- (4-pyridyl) -ethanone (purple). The cyano group is then removed by hydrolysis, e.g. B. with hydrobromic acid, and decarboxylation, so that 2- (4-fluorophenyl) -1- (4-pyridyl) ethanone (IVa) is formed. In the next step, the IVa is converted into the oxime (Va) by treatment with ammonium chloride / sodium acetate in an alcoholic solvent, such as methanol. This is converted into the tosylate (via) by reaction with p-toluenesulfochloride in pyridine. The Thion Compound (IIIa) is obtained from the tosylate by treatment with sodium ethylate and reaction of the azirene intermediate formed with potassium thiocyanate.

Scheme 1:

Svntheseweq of the inventive thione by method A

Procedure B:

Those compounds according to the invention in which the pyridine radical has a halogen, O-alkyl or S-alkyl substituent are prepared in accordance with Scheme 2 via corresponding 2-halopyridyl-substituted imidazolthiones (process B). The preparation of these imidazolthiones is illustrated using the example of the 2-fluoro-substituted pyridine compounds (R ³ = 2-F) with R ¹ = p-fluorophenyl. Imidazole thiols which carry alkyl and cycloalkyl radicals in position 4 (R ¹ = CC ₄ alkyl, C ₃ -C ₇ cycloalkyl) are prepared in an analogous manner, starting from the correspondingly substituted 2-fluoro-γ-picoline ketones won. Scheme 2:

(VIIIb)

γ-picoline (R ³ = H), as well as those with halogen- (R ³ = F, Cl, Br, I), methoxy- (R ³ = OCH ₃ ), and methylthio- (24, R ³ = SCH ₃ ) Substituted γ-picolines are excluded from moisture in suitable solvents, such as hydrocarbons, ethers and their mixtures (e.g. hexane, tetrahydrofuran, ethylene glycol dimethyl ether), lithiated with lithium diisopropylamide (LDA) in the γ-methyl group and then with suitable ones Carboxylic acid derivatives (R ¹ -COOR, R ¹ -CONR ₂ , R ¹ -CN) condensed. The amides of N, 0-dimethyl-hydroxylamine (R ¹ -CONCH ₃ (OCH ₃ ), 20) are particularly suitable. The γ-picolyl ketones (IVb) formed are mixed with nitrous acid esters and bases, e.g. B. amyl nitrite / sodium methylate or nitrosated with alkali nitrite and acid in the γ-picolyl position. The reaction of the γ-picolyl ketone dissolved in glacial acetic acid with aqueous sodium nitrite solution has proven to be particularly advantageous. The nitrosoketones convert completely into the tautomeric oxime ketones (VI Ib). The oxime ketones are in alcoholic solution in the presence of hydrogen and mineral acids, e.g. B. HCl, reduced by palladium on activated carbon in the ammonium salts of the amine ketones (VIIIb) (23b).

Alternatively, other oxime ketones in alcoholic solution in the presence of mineral acids, e.g. B. H ₂ Sθ4, can be reduced with zinc dust to the corresponding ammonium ketones (23f).

These ammonium ketone compounds are obtained by the action of alkali lithiocyanates, e.g. B. potassium rhodanide in dry dimethylformamide (DMF) when heated under reflux the imidazolthiones of the general formula Mb, with R ³ = F, Cl, Br, O-alkyl, or S-alkyl as yellow-colored solids (24b).

The compounds according to the invention in which the pyridine residue has an ether (R ³ = OR ⁰ ), thioether (R ³ = SR ¹⁰ ) or amino substituent (R ³ = NR ⁴ R ¹⁰ ) are prepared in accordance with Scheme 4 or Scheme 5 on corresponding 2-halopyridyl-substituted imidazolthiones (process C below).

2) Preparation of the 2-thio-imidazole compound

The imidazolthione compounds of the general formula II obtained according to process A or B are converted into the compounds of the formula I according to the invention by substitution of the sulfur atom in the 2-position. The substitutions, as shown by way of example for some compounds in Scheme 3, are carried out in a known manner by a nucleophilic substitution reaction. The compound Ila or Ilb is reacted with R ² -X in an inert polar solvent, such as an alcohol. X stands for an easily exchangeable group, such as shark, in particular Cl, Br, I, methylsulfonyl, tosyl, etc. Suitable processes are known to the person skilled in the art and are described, for example, in WO 00/17192, EP 0 372 445 and US 4,440,776. The compounds R ² -X are known or can by known methods, such as. B. are described in WO 00/17192. Scheme 3:

3. Substitution of the sulfur by alkyl and arylalkyl halides or alcohol sulfonates.

3.1.

3.2.

Procedure C:

The compounds according to the invention in which R ^{3 represents} an amino substituent (R ³ = NR ⁴ R ¹⁰ ) are prepared starting from the 2-thioimidazoles with 4 (5) - (2-halopyridin-4-yl) substitution , The process (process C) is illustrated in Scheme 4 using the example of 2-benzylamino (R ³ = NH-CH ₂ Ph) with R ¹ = p-fluorophenyl (25f).

The starting compounds (lb) can be prepared by the processes described above. Scheme 4:

4.1. 4- (2-aminopyridin-yl) substituted 2-thioimidazoles

4.2. 4- (2-aryloxypyridin-4yl) substituted 2-thioimidazoles

4.3. 4- (2-arylthio-pyridine-4yl) substituted 2-thioimidazoles

4.4. 4- (2-arylsulfonyl-pyridin ^ yl) substituted 2-thioimidazoles

The reaction is advantageously carried out in the particular amine which is preferably used in an amount of 5 to 20 molar equivalents per molar equivalent of the compound (Ib). The reaction temperature is generally in the range from 100 to 200 ° C. If desired, an inert solvent such as dioxane, dimethylformamide, diethylacetamide, tetraethylurea, methylpyrrolidone, etc. and corresponding additives such as alkali metal carbonates or monovalent copper halides, for neutralizing released acid equivalents or for catalysing the halogen output can also be used.

The compounds according to the invention in which R3 is an alkoxy substituent or alkylthio substituent (R ³ = 0-dC ₆ -alkyl, Sd-Ce-alkyl) can not only by process B (starting from appropriately substituted picolines), but also can also be prepared by process C starting from the 4 (5) - (2-halopyridin-4-yl) - substituted 2-thioimidazoles.

Procedure D:

The compounds according to the invention in which R ^{3 represents} an alkoxy substituent (R ³ = 0-CrC ₆ -alkyl) can be prepared not only by process B or C, but also by process D starting from 4 (5) - (2 -Halogenopyridin-4-yl) -substituted 2-

Thioimidazoles can be produced. The procedure is based on the example of 2- Isopropyloxy-pyridine compounds (R ³ = OCH (CH ₃ ) ₂ ) with R ¹ = p-fluorophenyl explained in Scheme 5.

The starting compounds (lb) can be prepared by the processes described above.

Scheme 5:

4- (2-alkoxy-pyridine-4yl) substituted 2-thioimidazoles

The reaction is expediently carried out in the alcohol, which is preferably used in an amount of 5 to 20 molar equivalents per molar equivalent of the compound (Ib), in the case of lower alcohols also up to 100 times in the presence of a strong acid such as HCl or trifluoroacetic acid, methanesulfonic acid, etc. .. The reaction temperature is generally in the boiling range of the lower alcohols, with higher alcohols in the range of 100 to 200 ° C. It has proven beneficial to use alcohol, e.g. B. to saturate with gaseous HCI or to saturate during the reaction.

The exchange of fluorine for alkoxy in position 2 of the pyridyl substituent can alternatively be carried out at an earlier intermediate synthesis stage, for example at the oxime ketone or amine ketone stage. In these cases, the implementations are carried out under conditions comparable to those of the level 1b (22c) just described. Procedure E, F and G:

The compounds according to the invention in which R ^{3 stands} for an amido substituent (R ³ = NR ⁷ COR ¹⁰ ) are, on the one hand, starting from the 2-thioimidazoles with 4 (5) - (2-halopyridin-4-yl) substitution manufactured. The process (process E) is explained using the example of 2-benzoylamido (R ³ = NH-COPh) with R ¹ = p-fluorophenyl in Scheme 6.1. Secondly, further amido-substituents can be obtained after hydrolysis of the amides to the amine-substituted (R ³ = NR ⁷ H, NHR ¹⁰ ) 2-thioimidazoles and their renewed acylation or derivatization to amides, ureas and urethanes (method F). This is explained in Scheme 6.2. Third, 2-aminopyridine precursor compounds from 4 (5) - (2-halopyridin-4-yl) compounds can be taken via the detour of 4 (5) - (2-azidopyridin-4-yl) - Compounds are obtained (method G). In this variant, the halogen is nucleophilically substituted by alkali azide and then the azide group is converted to the amino group by reduction methods, see Scheme 6.3.

Procedure H:

This interesting variant also opens up access to alkylated amines from aldehyde and ketone precursors. If the conversion of the azide group into the amino group is carried out under hydrogenation conditions using a hydrogenation catalyst in the presence of these aldehydes and ketones, alkylated amines with R ³ = NHCH ₂ -B or NHCH (alkyl) -B are obtained (process H, scheme 6.4). The same result is obtained if the azide is cleaved to the phosphimide with a phosphine and these are reduced to the amines with complex hydrides after an aza-Wittig reaction with an aldehyde (or ketone) (method H, Scheme 6.5).

The starting compounds (lb) can be prepared by the processes described above. Scheme 6:

6.1: 4- (2-Amido-pyridine-4yl) -substituted 2-thioimidazoles

The reaction is expediently carried out in the particular amide which is preferably used in an amount of 5 to 20 equivalent moles per mole equivalent of the compound (Ib). The reaction temperature is generally in the range from 100 to 200 ° C. If desired, an inert solvent such as dioxane, dimethylformamide, diethylacetamide, tetraethylurea, methylpyrrolidone, etc. and corresponding additives such as alkali metal carbonates or monovalent copper halides, for neutralizing acid equivalents released or for catalysing the halogen outlet can also be used.

The 2-aminopyridine compounds can be obtained from 2-amidoacyl-pyridines by hydrolysis (6.2) or by azide substitution of the 2-fluorine compounds and subsequent reduction of the 2-azido-pyridines (6.3) z. B. by hydrogenation on palladium-activated carbon in alcoholic solvents. 6.2

(lb) (id) (le)

6.3

(lb) (li) (Ik)

6.4

(Id) (Id) 6.5

Further conversions of the amines (Ik, Id) obtained by derivatization are possible (process F). Reactions of the amines Id and Ik both with acid anhydrides and acid chlorides to form further amides, as well as reactions with chloroformic acid esters to urethanes, with isocyanates to ureas and with acyl isocyanates to acylureas are used. These derivative formations are explained in Scheme 7.

Scheme 7

Conversions of amines (Ik, Id) to amides, urethanes, and ureas

The compounds according to the invention have an immunomodulating effect in vitro and in vivo and inhibit the cytokine release. Cytokines are proteins like TNF-α and IL-ß, which play an important role in numerous inflammatory diseases. Due to their cytokine release-inhibiting action, the compounds according to the invention are suitable for the treatment of diseases which are connected with a disturbance of the immune system. They are suitable, for example, for the treatment of autoimmune diseases, cancer, rheumatoid arthritis, gout, septic shock, osteoporosis, neuropathic pain, HIV spread, HIV dementia, viral myocarditis, insulin-dependent diabetes, periodontal diseases, restenosis, alopecia, T- Cell depletion in HIV infections or AIDS, psoriasis, acute pancreatitis, rejection reactions in allogeneic transplants, allergic pneumonia, atherosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, Ictus, colitis uicerosa, Crohn's disease, inflammatory bowel disease Disease (IBD), ischemia, congestive heart failure, Lung fibrosis, hepatitis, glioblastoma, Guillain-Barre syndrome, systematic lupus erythematosus, adult respiratory distress syndrome (ARDS) and shortness of breath syndrome.

The compounds according to the invention can be administered either as individual therapeutic active substances or as mixtures with other therapeutic active substances. The compounds can be administered alone, but generally they are dosed and administered in the form of pharmaceutical agents, i. H. as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents. The compounds or agents can be administered orally or parenterally, preferably they are given in oral dosage forms.

The type of pharmaceutical agent or carrier or of the diluent depends on the desired form of administration. Oral agents can be present, for example, as tablets or capsules and can contain conventional excipients, such as binders (for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (for example lactose, sugar, corn starch) , Calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide), disintegrating agents (e.g. starch) or wetting agents (e.g. sodium lauryl sulfate). Liquid oral preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays and the like. They can also be in the form of dry powder, which is prepared for reconstitution with water or another suitable vehicle. Such liquid preparations can contain customary additives, for example suspending agents, flavoring agents, diluents or emulsifiers. Solutions or suspensions with conventional pharmaceutical carriers can be used for parenteral administration.

The compounds or compositions according to the invention can be administered to mammals (humans or animals) in a dose of about 0.5 mg to 100 mg per kg of body weight per day. They can be given in a single dose or in multiple doses. The spectrum of activity of the compounds as inhibitors of cytokine release was investigated using the test systems below (C. Donat and S. Laufer in Arch. Pharm. Pharm. Med. Chem. 333, Suppl. 1, 1-40, 2000). // 7-wϊ o test procedure with whole human blood

Samples from human potassium EDTA whole blood (400 μl each) are mixed with the test substance and preincubated for 15 min at 37 ° C. in a CO ₂ incubator (5% CO _2; 95% moisture-saturated air). The samples are then stimulated for 4 hours with 1 μg / ml LPS (E.coli 026: B6) at 37 ° C. in a CO ₂ incubator (5% CO _2; 95% moisture-saturated air). The reaction is stopped by placing the samples on ice, adding DPBS buffer and then centrifuging at 1000 * g for 15 min. The amount of IL-1ß and TNFα in the plasma supernatant is then determined by means of ELISA.

/ n- Yro test procedure with PBMCs

1) Mono-nuclear cells are made from 1: 3 diluted human potassium EDTA whole blood using density gradient centrifugation (Histopaque®-1,077)

(PBMCs) isolated. These are washed twice with DPBS buffer, resuspended in macrophage SFM medium and adjusted to a cell count of 1 * 10 ⁶ cells / ml.

The PBMCs suspension obtained (390 μl samples) is preincubated with the test substance for 15 min at 37 ° C. in a CO ₂ incubator (5% CO _2; 95% moisture-saturated air). The samples are then stimulated for 4 hours with 1 μl / ml LPS (E.coli 026: B6) at 37 ° C in a C0 ₂ incubator (5% C0 _2: 95% moisture-saturated air). The reaction is stopped by placing the samples on ice, adding DPBS buffer and then centrifuging at 15880 * g for 12 min. The amount of IL-1β and TNFα in the plasma supernatant is then determined by means of ELISA.

2) Kinase assay

Micro-titer plates were coated with 50 μl ATF2 solution (20 μg / ml) for one hour at 37 ° C. After washing three times with water, 50 μl of kinase mixture (50 mM tris-HCl 10 mM MgCfe, 10 mM β-glycerol phosphate, 10 μg / ml BSA, 1 mM DTT, 100 μM ATP, 100 μM Na ₃ V0 ₄ , 10 activated p38α) with or without inhibitor was added to the wells and incubated for 1 hour at 37 ° C. After washing three times, the plates were incubated with phosphorus ATF-2 antibody for one hour at 37 ° C. After washing again three times, goat anti-rabbit IgG labeled with alkaline phosphatase was added for one hour at 37 ° C. (in order to hold the antibody phosphorylated protein-substrate complex). After washing three times, the alkaline phosphatase substrate solution (3 mM 4-NPP, 50 mM NaHCO ₃ , 50 mM MgCl _2> 100 μl / well) was added at 37 ° C. for 1.5 hours. The formation of 4-nitrophenolate was measured at 405 nm using a microtiter plate reader. The ICso values were calculated.

The results of the in vitro tests are shown in Table 1 below.

Table 1: Test results

The following examples illustrate the invention without limiting it. example 1

a) 4- (4-Fluorophenyl) -5-pyridin-4-yl-1,3-dihydro-imidazol-2-thione

2- (4-fluorophenyl) -3-hydroxy-3-pyridin-4-yl-acrylonitrile (a1)

To a solution of metallic sodium (17.3 g; 0.7 mol) in absolute ethanol (250 mL) was added a mixture of ethyl isonicotinate (75.8 g; 0.5 mol) and 4-fluorophenylacetonitrile (67.6 g; 0.5 mol) was added dropwise. The reaction mixture was stirred at 100 ° C. for 15 minutes. It was then cooled in an ice bath and mixed with 600 mL distilled H ₂ 0. When acidified with concentrated HCl (90 mL), the hydrochloride of a1 precipitated as a yellow precipitate at pH 1. The precipitate was filtered off, washed with H ₂ 0 and dried in vacuo over P ₂ 0 ₅ . Mp 226 ° C

2- (4-fluorophenyl) -1-pyridin-4-yl-ethanone (a2)

A solution of a1 (40.6 g; 0.15 mol) in 48% hydrobromic acid (130 mL) was stirred under reflux for 19 h. The mixture was cooled in an ice bath, the precipitate which separated out (4-fluorophenylacetic acid) was filtered off and washed with H ₂ O. When the filtrate was neutralized with ammonia water (80 mL), a2 precipitated out as a dark green precipitate, which was filtered off, washed with H ₂ 0 and dried in vacuo over P ₂ O ₅ : light gray-beige powder. Mp 215 ° C

2- (4-fluorophenyl) -1-pyridin-4-yl-ethanone oxime (a3)

Sodium acetate (36.1 g; 0.44 mol) and hydroxylamine hydrochloride (22.0 g; 0.32 mol) were added to a suspension of a2 (21.5 g; 0.1 mol) in 50% methanol (350 mL) ) entered. The reaction mixture was stirred under reflux for 1 h. When the clear solution was cooled in an ice bath, a3 precipitated out as a beige precipitate, which was filtered off, washed with H ₂ 0 and dried in vacuo over P ₂ O5. Mp 155 ° C 2- (4-fluorophenyl) -1-pyridin-4-ylethanone, 0 - [(4-methylphenyl) su (fonyl] oxime (a4)

Under an argon atmosphere, a3 (10.1 g; 0.04 mol) was dissolved in absolute pyridine (50 mL). The solution was cooled to 6 ° C. and toluene sulfonic acid chloride (10.1 g; 0.05 mol) was added in portions. After the addition had ended, the reaction mixture was stirred at room temperature for 20 h. The mixture was then poured onto 500 ml of ice water. The precipitate (a4) was filtered off, washed cold with H ₂ 0 and dried in a drying cabinet at 50 ° C. Mp 201 ° C

4- (4-fluorophenyl) -5-pyridin-4-yl-1,3-dihydro-imidazol-2-thione (1 a).

A solution of a4 (10.0 g; 0.03 mol) in absolute ethanol (56 mL) was cooled to 5 ° C under an argon atmosphere and added dropwise with a freshly prepared solution of metallic sodium (0.75 g; 0.03 mol ) in absolute ethanol (30 mL). The reaction mixture was stirred at 5 ° C for 5 h. After addition of diethyl ether (500 mL), the mixture was stirred for a further 30 min. touched. The precipitate (TosOH) was filtered off and washed with diethyl ether (4 * 50 mL). The combined ethereal phase was extracted with 10% hydrochloric acid (3 * 90 mL). The aqueous extract was concentrated to a volume of approx. 40 mL and potassium thiocyanate (5.0 g; 0.05 mol) was added. The reaction mixture was stirred under reflux for 1 h. When neutralizing with 5% sodium hydrogen carbonate solution (270 mL), a5 precipitated out as a beige precipitate, which was filtered off, washed with H ₂ 0 and dried in a drying cabinet at 60 ° C. Yield 5.6 g (79%); Mp 382 ° C

¹ H NMR (DMSO-of ₆ ): δ (ppm) 7.1 (m, 2H, 4-F-Ph), 7.3 (m, 2H, 4-Pyr), 7.5 (m, 2H , 4-F-Ph), 8.5 (m, 2H, 4-Pyr), 12.7 (d, 2H, exchangeable, NH)

The following were obtained in a corresponding manner:

1b 3- (4-fluorophenyl) -5-pyridin-4-yl-1,3-dihydroimidazol-2-thione 1c 4- (4-chlorophenyl) -5-pyridin-4-yl-1,3-dihydroimidazol-2 -thione 1d 4- (4-bromophenyl) -5-pyridin-4-yl-1,3-dihydroimidazol-2-thione

1e 4-phenyl-5-pyridin-4-yl-1,3-dihydroimidazol-2-thione Example 2

1-chloromethyl-4-methylsulfanyl-benzene (2)

4-Methylsulfanylbenzyl alcohol (30.5 g; 0.2 mol) was dissolved in dichloromethane (180 mL). A solution of thionyl chloride (23.8 g; 0.2 mol) in dichloromethane (120 mL) was added dropwise to the template, which was kept under reflux. The reaction mixture was stirred under reflux for a further 2 h. The solution was cooled to room temperature, washed with H ₂ 0 (2 × 250 mL), dried over Na ₂ S0 ₄ and concentrated. The oily residue (6) was purified by column chromatography (Al ₂ 0 ₃ , CH ₂ CI ₂ ).

¹ H NMR (CDCI ₃ ): δ (ppm) 2.46 (s, 3H, CH3), 4.5 (s, 2H, CH ₂ ), 7.2-7.3 (q, 4H, 4- MeS- Ph)

Example 3

1-chloromethyl-4-methanesulfinyl-benzene (3)

A solution of 2 (17.3 g; 0.1 mol) in glacial acetic acid (150 mL) was cooled to 10 ° C. A solution of H ₂ 0 ₂ (35% solution; 13.1 g; 0.13 mol) in glacial acetic acid (50 ml) was added dropwise to the initial charge. The reaction mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice bath, ice (200 g) was added and the mixture was neutralized with ammonia water (290 ml). The aqueous phase was extracted with ethyl acetate (2 * 300 mL). The organic phase was washed with H ₂ 0 (2 * 300 mL), dried over Na ₂ S0 and concentrated. 3 was obtained from the oily residue by rubbing and cooling in crystalline form.

¹ H NMR (CDCI ₃ ): δ (ppm) 2.73 (s, 3H, CH ₃ ), 4.6 (s, 2H, CH ₂ ), 7.5 (d, 2H, 4-MeS (0 ) - Ph), 7.6 (d, 2H, 4-MeS (0) -Ph) Example 4

1-chloromethyl-4-methanesulfonyl-benzene (4)

M-Chloroperbenzoic acid (70%; 8.6 g; 0.04 mol) was added to a solution of 3 (3.0 g; 0.02 mol) in chloroform (50 mL). The reaction mixture was stirred under reflux for 4 h. The mixture was cooled to room temperature and filtered. The filtrate was washed with saturated NaHC0 ₃ solution (2 *) and dried over Na ₂ S0 ₄ . After concentration of the organic phase, 8 remained as a crystalline, white solid. Mp 102 ° C

¹ H-NMR (CDCl ₃ ): d (ppm) 3.07 (s, 3H, CH ₃ ), 4.6 (s, 2H, CH ₂ ), 7.6 (d, 2H, 4-MeS0 ₂ - Ph), 7.9 (d, 2H, 4-MeS0 ₂ -Ph)

Example 5

5-chlorosulfonyl-2-hydroxy-benzoic acid methyl ester (5a)

5a was prepared starting from methyl salicylic acid (10.0 g; 65.7 mmol) according to the method described in the synthesis of 5c.

¹ H NMR (CDCI3): δ (ppm) 4.05 (s, 3H, CH ₃ ), 7.18 (d, 1H, 8.9 Hz, C ³ -H), 8.09 (dd, 1H , 2.5 / 9.0 Hz, C ⁴ -H), 8.57 (d, 1H, 2.5 Hz, C ⁶ -H), 11.55 (s, 1H, exchangeable, phenol-OH)

5-chloro-3-chlorosulfonyl-2-hydroxy-benzoic acid methyl ester (5b)

5b was prepared starting from methyl 5-chlorosalicylic acid (16.0 g; 85.7 mmol) according to the method described in the synthesis of 5c.

¹ H NMR (CDCI ₃ ): δ (ppm) 4.06 (s, 3H, CH ₃ ), 8.11 (d, 1 H, 2.7 Hz, C ⁶ -H), 8.19 (d , 1 H, 2.7 Hz, C ⁴ -H), 12.09 (s, 1H, exchangeable, phenol-OH) 3-chlorosulfonyl-4-methoxy-benzoic acid ethyl ester (5c)

A solution of 4-methoxy-benzoic acid ethyl ester (15.7 g; 87.2 mmol) in CCI ₄ (60 mL) was cooled to -15 ° C and dropwise with chlorosulfonic acid (17.5 mL; 263 mmol) within 15 min. added, the temperature rising to -10 ° C. After the addition had ended, the reaction mixture was stirred at room temperature for 2 h and then heated to 50 ° C. until the starting material could no longer be detected by thin layer chromatography. The reaction mixture was added to a suspension of ice (50 g) in CCU (100 mL) with ice cooling and vigorous stirring. The mixture was stirred vigorously for 3 minutes. The organic phase was separated and the aqueous phase extracted with CH ₂ CI ₂ (3 * 100 mL). The combined organic extracts were washed with saturated NaCl solution (3 ×), dried over Na ₂ S0 ₄ and concentrated. When the oily, brown residue was triturated with diethyl ether, 5c was obtained as a crystalline, white solid.

¹ H-NMR (CDCI ₃ ): δ (ppm) 1.41 (t, 3H, 7.1 Hz, CH ₃ ), 4.14 (s, 3H, CH ₃ ), 4.42 (q, 2H, 7.1 Hz, CH ₂ ), 7.18 (d, 1 H, 8.8 Hz, C ⁵ -H), 8.37 (dd, 1 H, 2.1 / 8.8 Hz, C ⁶ - H), 8.63 (d, 1 H, 2.1 Hz, C ² -H)

Example e

2-hydroxy-5-mercapto-benzoic acid (6a)

6a was obtained starting from 6a (0.50 g; 2.0 mmol) by the method described in the synthesis of 7c without the alkylation with dimethyl sulfate.

¹ H-NMR (DMSO-dβ): δ (ppm) 5.39 (bs, 1H, exchangeable, carboxyl-OH), 6.90 (d, 1H, 8.7 Hz, C ³ -H), 7, 45 (dd, 1H, 2.5 / 8.6 Hz, C-H), 7.75 (d, 1H, 2.5 Hz, C ⁶ -H), phenol-OH not visible Example 7

2-hydroxy-5-methylsulfanyl-benzoic acid (7a)

7a was prepared from 5a (10.0 g; 40.0 mmol) according to the method described in the synthesis of 7c.

¹ H NMR (CDCI ₃ ): δ (ppm) 2.48 (s, 3H, CH ₃ ), 6.97 (d, 1H, 8.7 Hz, C ³ -H), 7.51 (dd, 1H, 2.5 / 8.7 Hz, C ⁴ -H), 6.97 (d, 1H, 8.7 Hz, C ³ -H), 7.87 (d, 1H, 2.4 Hz, C ⁶ -H), 10.26 (bs, 1 H, phenol-OH), CO _z H not visible

5-chloro-2-hydroxy-3-methylsulfanyl-benzoic acid (7b)

7b was prepared from 5b (13.0 g; 45.6 mmol) according to the method described in the synthesis of 7c.

¹ H NMR (DMSO-ds): δ (ppm) 2.47 (s, 3H, CH ₃ ), 7.33 (d, 1H, 2.4 Hz, C ⁶ -H), 7.52 (d , 1H, 2.4 Hz, C ⁴ -H), phenol-OH and C0 ₂ H not visible

4-methoxy-3-methylsulfanyl-benzoic acid (7c)

Triphenylphosphine (20.5 g; 78.2 mmol) was added in portions to a solution of 5c (5.1 g; 18.3 mmol) in toluene (50 mL). The reaction mixture was stirred for 4.5 h at room temperature. The precipitate (triphenylphosphine oxide) was filtered off and the yellow filtrate was extracted with 10% sodium hydroxide solution (4 ×). Dimethyl sulfate (2 mL) was added to the combined aqueous extract and the reaction mixture was stirred at room temperature for 2 h. The deposited precipitate was dissolved by heating to the reflux temperature. The clear solution was cooled and adjusted to pH 1 with 20% hydrochloric acid. The precipitate (7c) was filtered off, washed with H ₂ O and dried in vacuo over CaCl ₂ .

¹ H-NMR (CD ₃ OD): δ (ppm) 2.43 (s, 3H, S-CH3), 3.93 (s, 3H, O-CH ₃ ), 6.98 (d, 1 H, 8.4 Hz, C ⁵ -H), 7.79-7.86 (m, 2H, C ² - / C ⁶ -H) 4-hydroxy-3-methylsulfanyl-benzoic acid (7d)

A suspension of 7c (0.5 g; 2.5 mmol) in glacial acetic acid / hydrobromic acid 48% (1 + 1, 7 mL) was stirred under reflux for 6 h. The reaction mixture was cooled, added to H ₂ 0 (20 mL) and adjusted to pH 2 with 10% Na ₂ C0 ₃ solution. The aqueous solution was extracted with diethyl ether (4 * 20 mL). The combined organic extract was washed with saturated NaCl solution (2 ×), dried over Na ₂ S0 ₄ and concentrated. When left to stand at room temperature, the dirty brown, oily residue (7d) crystallized out. The crystals were stirred with H ₂ O, filtered off and dried.

¹ H NMR (CDCI ₃ ): δ (ppm) 2.38 (s, 3H, CH ₃ ), 7.05 (d, 1 H, 8.5 Hz, C ⁵ -H), 8.02 (dd , 1 H, 2.2 / 8.5 Hz, C ⁶ -H), 8.29 (d, 1H, 2.2 Hz, C ² -H), phenol-OH and C0 ₂ H not visible

Example 8

2-hydroxymethyl-4-methylsulfanylphenol (8a)

8a was prepared starting from 7a (1.5 g; 8.1 mmol) according to the method described in the synthesis of 8c.

¹ H-NMR (CDCI3): δ ppm) 2.42 (s, 3H, CH ₃ ), 4.79 (s, 2H, CH ₂ ), 6.81 (d, 1 H, 8.4 Hz, C ⁶ -H), 7.01 (d, 1H, 2.1 Hz, C ³ -H), 7.17 (dd, 1H, 2.3 / 8.4 Hz, C ³ -H), OH not visible

4-chloro-2-hydroxymethyl-6-methylsulfanylphenol (8b)

8b was prepared from 7b (2.2 g; 10.1 mmol) according to the method described in the synthesis of 8c.

¹ H-NMR (DMSO-cfe): δ (ppm) 2.38 (s, 3H, CH ₃ ), 4.52 (s, 2H, CH ₂ ), 5.3-5.5 (bs, 1H, replaceable, hydroxyl-OH), 7.03 (d, 1H, 2.6 Hz, C ⁵ -H), 7.11 (d, 2.4 Hz, C ³ -H), 9.02 (bs, 1H , exchangeable, phenol-OH) 4-hydroxymethyl-2-methylsulfanylphenol (8c)

A solution of 7d (1.37 g; 7.4 mmol) in abs. Tetrahydrofuran (THF; 15 mL) was added dropwise to a suspension of 95% LiAIH (0.55 g; 14 mmol) in absolute THF (10 mL) in a heated, three-necked flask (DHK) flushed with argon so that only moderate gas evolution occurred. After the addition had ended, the cooling was removed and the reaction mixture was stirred at room temperature for 30 min and at 55-65 ° C. for a further 21 h. Ice water was added to the reaction mixture while cooling with ice. The precipitate of Al (OH) ₃ was dissolved by adding 10% strength sulfuric acid and the aqueous acidic solution (pH 1) was extracted with diethyl ether (3 50 ml). The combined ethereal extract was extracted with 10% sodium hydroxide solution (2 25 ml). The combined sodium alkaline solution was neutralized with 20% hydrochloric acid. The precipitate (8c) was filtered off, washed with H ₂ O and dried. Another amount of 8c was obtained by extracting the neutral, aqueous solution with diethyl ether. The ethereal extract was washed with saturated NaCl solution, dried over Na ₂ S0 ₄ and concentrated: crystalline, white residue.

¹ H NMR (CDCI ₃ ): δ (ppm) 2.34 (s, 3H, CH ₃ ), 4.60 (s, 2H, CH ₂ ), 6.97 (d, 1 H, 8.3 Hz , C ⁶ -H), 7.24 (dd, 1 H, 2.0 / 8.4 Hz, C ⁵ -H), 7.50 (d, 1 H, 2.0 Hz, C ³ -H) , OH not visible

Example 9

2-hydroxy-5-methylsulfanyl-benzaldehyde (9a)

The title compound was obtained as a by-product in the synthesis of 8a.

¹ H NMR (CDCI3): δ (ppm) 2.48 (s, 3H, CH ₃ ), 6.96 (d, 1H, 9.8 Hz, C ³ -H), 7.48-7.54 (m, 2H, C ⁴ - / C ⁶ -H), 9.87 (s, 1H, exchangeable, OH), 10.91 (s, 1H, aldehyde-H) Example 10

4- (3-chloroethyl) benzenesulfonyl chloride (10a)

While cooling with ice, (2-chloroethyl) benzene (14.0 g; 0.1 mol) was added dropwise to chlorosulfonic acid (72 g) within 40 min. The brown solution was stirred at room temperature for 24 h, cooled in an ice bath and added to ice in portions, a viscous, non-filterable mass separating. The aqueous solution was extracted with ethyl acetate (3 ×). The combined organic extract was washed with 10% NaH-CO ₃ solution, dried over Na ₂ SO ₄ and concentrated. The oily residue was taken up in tert-butyl methyl ether / petroleum ether. The solution was rubbed with a glass rod and cooled. The white crystals were filtered off and dried. Another reaction product was obtained from the mother liquor. The crude product was used in the synthesis of 11a without further purification.

¹ H NMR (CDCI ₃ ): δ (ppm) 3.20 (t, 2H, 6.8 Hz, CH ₂ ), 3.79 (t, 2H, 6.8 Hz, CH ₂ ), 7.46 - 7.53 (m, 2H, phenyl), 7.97-8.04 (m, 2H, phenyl)

4- (3-chloropropyl) benzenesulfonyl chloride (1 Ob)

10b was prepared starting from (3-chloropropyl) benzene (15.5 g; 0.1 mol) according to the method described in the synthesis of 10a. The crude product was used in the synthesis of 11b without further purification.

MS: m / z (%) 253 (90, M ⁺ ), 217 (100, M ⁺ -Cl), 189 (35), 153 (97, M ⁺ -S0 ₂ CI), 125 (94), 119 ( 65, phenylpropylcarbenium ⁺ ), 91 (90), 77 (29, phenyl ⁺ )

Example 11

1 - (3-chloroethyl) -4-methylsulfanyl-benzene (11 a)

11a was prepared starting from 10a (12.0 g; 0.05 mol) according to the method described in the synthesis of 11b. ¹ H NMR (CDCI3): δ (ppm) 2.47 (s, 3H, CH ₃ ), 3.02 (t, 2H, 7.4 Hz, CH ₂ ), 3.68 (t, 2H, 7 , 5 Hz, CH ₂ ), 7.11-7.25 (m, 4H, phenyl)

1 - (3-chloropropyl) -4-methylsulfanyl-benzene (11 b)

At room temperature, a solution of 10b (12.7 g; 5.0 mmol) in diethyl ether (75 mL) was added to a suspension of LiAIH4 (2.9 g; 7.6 mmol) in diethyl ether (50 mL) within 2. Added dropwise for 5 h. After the addition had ended, the reaction mixture was stirred at room temperature and occasional addition of LiAIH ₄ until the starting material could no longer be detected by thin layer chromatography (2.5 h). Ice was introduced into the reaction mixture while cooling with ice and the aqueous phase was acidified with 10% hydrochloric acid (pH 1). The organic phase was separated and the aqueous phase extracted with diethyl ether (3 ×). The combined organic extract was washed with 10% sodium hydroxide solution (4 x 50 mL) until it was largely colorless. The combined sodium alkaline extract was mixed with dimethyl sulfate (9.0 g; 7.0 mmol) and stirred at room temperature for 16.5 h. The oily deposit was taken up in diethyl ether. The organic phase was separated and the aqueous phase extracted again with diethyl ether (2 ×). The combined organic extract was dried over Na ₂ S0 ₄ and concentrated. The brown, oily residue was distilled on a Kugelrohr (0.2 mbar, 250 ° C).

¹ H-NMR (CDCI3): δ (ppm) 2.01-2.11 (m, 2H, CH ₂ ), 2.46 (s, 3H, CH ₃ ), 2.73 (t, 2H, 7, 1 Hz, CH ₂ ), 3.51 (t, 2H, 6.5 Hz, CH ₂ ), 7.09-7.25 (m, 4H, phenyl)

Example 12

1 - (2-chloroethyl) -4-methanesulfinyl-benzene (12a)

A 35% solution of H ₂ O ₂ (0.9 g; 9.3 mmol) was added to a solution of 11a (1.5 g; 8.0 mmol) in glacial acetic acid (20 mL) while cooling. After the addition had ended, the reaction mixture was stirred at room temperature for 2.5 h, diluted with ice water while cooling and adjusted to pH 8 with 25% strength ammonia water. The oily, white deposit was taken up with diethyl ether and the aqueous phase extracted with diethyl ether (3 x). The combined organic extract was dried over Na ₂ Sθ and concentrated.

¹ H-NMR (CDCI ₃ ): δ (ppm) 2.73 (s, 3H, CH ₃ ), 3.14 (t, 2H, 7.1 Hz, CH ₂ ), 3.76 (t, 2H, 7.1 Hz, CH ₂ ), 7.38-7.42 (m, 2H, phenyl), 7.60-7.64 (m, 2H, phenyl)

1 - (3-chloropropyl) -4-methanesulfinyl-benzene (12b)

12b was prepared from 11b (2.0 g; 10.0 mmol) using the method described in the synthesis of 12a. Mp: 46 ° C

General methods for the preparation of the compounds of the formula I:

Preparation of the 2-arylalkyl or alkylsulfanylimidazoles (General Method A)

A suspension of the respective imidazole-2-thione (1 equivalent), the respective base (1, 2 equivalents) and the respective arylalkyl or alkyl halide (1 equivalent) in ethanol / THF (8 + 2) was stirred under reflux until the imidazole-2-thione was no longer detectable by thin layer chromatography. The reaction mixture was cooled to room temperature and filtered. The mostly red-orange colored filtrate was concentrated and the residue was purified by column chromatography, recrystallization or stirring. In this way, compounds 13a-c, 14a-c and 17a-m were produced.

Preparation of 2-benzylsulfanylimidazoles with phenolic functionality in the radical R ² (general method B)

By adding 10% hydrochloric acid (10-15 drops), imidazole-2-thione 1a (1 equivalent) was dissolved in glacial acetic acid (5 ml). The respective benzyl alcohol (1 equivalent) was added to the pale yellow colored template and the reaction mixture was stirred at a suitable temperature (temperature / time) until 1a was no longer detectable by thin layer chromatography. In the case of the sulfoxides 18g-i, a 35% H ₂ 0 ₂ solution was added and the reaction mixture was stirred for a further 4 h at room temperature. temperature stirred. The reaction mixture was diluted with H ₂ 0 (5 mL) and adjusted to pH 8 with 25% ammonia water. The precipitate was filtered off and washed with water. The crude product was purified by column chromatography, recrystallization or stirring. The imidazol-2-ylsulfanylmethylphenols 18a-i were prepared in this way.

Preparation of N-substituted 2-aminopyridines (General Method C)

The respective 5- (2-halopyridin-4-yl) imidazole (1 equivalent) was suspended in the respective amine (approx. 10 equivalents) under argon. The reaction mixture was stirred at the respective temperature until the starting material was no longer detectable by thin layer chromatography. The reaction mixture was cooled to room temperature and taken up in 10% citric acid, which had previously been adjusted to pH 5 with 20% NaOH. The aqueous emulsion was extracted with ethyl acetate (3x). The combined organic extract was washed with 10% citric acid / pH 5 (1 x), 10% Na ₂ CO ₃ solution (2 x) and saturated NaCl solution (1 x), dried over Na ₂ S0 ₄ and concentrated. The oily residue was separated by column chromatography. The aminopyridines 25f-p, 26c-e and 27c-d were prepared in this way.

Example 13

3- [5- (4-fluorophenyl) -2- (4-methylsulfanyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridine (13a)

According to General Method A, the title compound was prepared starting from 1b (0.42 g; 1.5 mmol) and 2 (0.25 g; 1.4 mmol) after a reaction time of 4.5 hours and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / Et0H 9 + 1) obtained. Mp 163 ° C

| R (ATR) (attenuated total reflection) 1506, 1493, 1222 (CF), 837, 806 cm -1 ¹ H NMR (DMSO-d ₆ ): δ (ppm) 2.45 (s, 3H, CH ₃ ), 4.38 (s, 2H, CH ₂ ), 7.19-7.49 (m, 10H) , 3-Pyr, 4-F-Ph and 4-MeS-Ph), 7.78-7.82 (m, 1H, 3-Pyr), 8.45-8.47 (m, 1H, 3-Pyr ), 8.61 (s, 1H, 3-Pyr), 12.71 (bs, 1H, exchangeable, NH)

3- [5- (4-fluorophenyl) -2- (4-methanesulfinyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridine (13b).

According to general method A, the title compound was prepared starting from 1b (0.42 g; 1.5 mmol) and 3 (0.27 g; 1.5 mmol) after a reaction time of 8 hours and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 127 ° C

IR (ATR): 1506, 1222 (CF), 1027 (S = 0), 1013, 838, 811 cm ^"1

¹ H NMR (DMSO-c β): δ (ppm) 3.19 (s, 3H, CH ₃ ), 4.46 (s, 2H, CH ₂ ), 7.16-7.46 (m, 5H) , 3-Pyr and 4-F-Ph), 7.56-7.66 (m, 4H, 4-MeS (0) -Ph), 7.72-7.81 (m, 1H, 3-Pyr ), 8.41- 8.62 (m, 2H, 3-pyr), 12.77 (bs, 1H, exchangeable, NH)

3- [5- (4-fluorophenyl) -2- (4-methanesulfonylbenzylsulfanyl) -3H-imidazol-4-yl] pyridine (13c).

According to General Method A, the title compound was prepared from 1b (0.42 g; 1.5 mmol) and 4 (0.29 g; 1.43 mmol) and with the addition of Na ₂ CO ₃ (0.43 g; 4 , 1 mmol) after 6.5 hours of reaction and stirring with hot ethyl acetate. Mp 129 ° C

IR (ATR): 1506, 1296 (S02), 1222 (CF), 1145 (S02), 1089, 839, 812 cm ^-1

¹ H-NMR (DMSO-de): δ (ppm) 3.19 (s, 3H, CH ₃ ), 4.50 (s, 2H, CH ₂ ), 7.17-7.45 (m, 5H, 3- Pyr and 4-F-Ph), 7.64-7.90 (m, 5H, 3-Pyr and 4-MeSO ₂ -Ph), 8.43-8.61 (m, 2H, 3-Pyr), 12.78 (bs, 1 H, exchangeable, NH) Example 14

4- [5- (4-chlorophenyl) -2- (4-methylsulfanyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridine (14a)

According to General Method A, the title compound was prepared from 1c (0.26 g; 0.9 mmol) and 6 (0.15 g; 0.87 mmol) and with the addition of Na ₂ CO ₃ (two spatula tips) after 6, 5-hour reaction time and column chromatography separation (SiQ ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 236 ° C

IR (ATR): 1600, 1492, 1094, 1005, 968, 829, 684 (C-Cl), 561 cm ^'1

¹ H-NMR (DMSO-dβ): δ (ppm) 2.44 (s, 3H, CH ₃ ), 4.38 (s, 2H, CH ₂ ), 7.18-7.56 (m, 10H, 4-Pyr, 4-CI-Ph and 4-MeS-Ph), 8.45-8.55 (m, 2H, 4-Pyr), 12.86 (bs, 1H, exchangeable, NH)

4- [5- (4-chlorophenyl) -2- (4-methanesulfinyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridine (14b)

According to General Method A, the title compound was started from 1c (0.26 g; 0.9 mmol) and 3 (0.16 g; 0.85 mmol) and with the addition of a reaction time of 6.5 hours and column chromatography separation (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 224 ° C

IR (ATR): 1600, 1510, 1490, 1033 (S = 0), 1001, 967, 829, 677 cm ^"1 (C-Cl)

¹ H NMR (DMSO-d ₆ ): δ (ppm) 2.70 (s, 3H, CH ₃ ), 4.47 (s, 2H, CH ₂ ), 7.31-7.65 (m, 10H) , 4-Pyr, 4-CI-Ph and 4-MeS (0) -Ph), 8.44-8.54 (m, 2H, 4-Pyr), 12.87 (bs, 1H, exchangeable, NH) 4- [5- (4-chlorophenyl) -2- (4-methanesulfonylbenzylsulfanyl) -3H-imidazol-4-yl] pyridine (14c)

According to general method A, the title compound was prepared from 1c (0.26 g; 0.9 mmol) and 4 (0.18 g; 0.9 mmol) and with the addition of Na ₂ CO ₃ (two spatula tips) after 6, 5-hour reaction time and column chromatography separation (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 232 ° C

IR (ATR): 1603, 1490, 1300 (S02), 1141 (S02), 1086, 1002, 952, 829, 681 (C-Cl), 550 cm ^"1

¹ H NMR (DMSO-d ₆ ): δ (ppm) 3.19 (s, 3H, CH ₃ ), 4.52 (s, 2H, CH ₂ ), 7.32-7.58 (m, 6H , 4-Pyr and 4-CI-Ph), 7.67 (d, 2H, 8.2 Hz, 4-MeS0 ₂ -Ph), 7.88 (d, 2H, 8.3 Hz, 4-MeS0 ₂ - Ph), 8.45-8.55 (m, 2H, 4-pyr), 12.89 (bs, 1H, exchangeable, NH)

Example 15

4- [5- (4-bromophenyl) -2- (4-methylsulfanyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridine (15a)

According to general method A, the title compound was prepared starting from 1d (0.25 g; 0.75 mmol) and 2 (0.13 g; 0.72 mmol) after a reaction time of 5 hours and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained.

IR (ATR): 1600, 1517, 1490, 1089, 1069, 1003, 968, 826 cm ^"1

1H-NMR (DMSO-d ₆ ): δ (ppm) 2.43 (s, 3H, CH ₃ ), 4.36 (s, 2H, CH ₂ ), 7.16-7.87 (m, 10H, 4-Pyr, 4-Br-Ph and 4-MeS-Ph), 8.45-8.55 (m, 2H, 4-Pyr), 12.90 (bs, 1H, exchangeable, NH) 4- [5- (4-bromophenyl) -2- (4-methanesulfinylbenzylsulfanyl) -3H-imidazol-4-yl] pyridine (15b)

According to General Method A, the title compound was prepared from 1d (0.25 g; 0.75 mmol) and 3 (0.14 g; 0.72 mmol) after a reaction time of 10 hours and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 222 ° C

IR (ATR): 1604, 1487, 1035 (S = 0), 1010, 1000, 966, 822 cm ^"1

¹ H NMR (DMSO-d ₆ ): δ (ppm) 2.71 (s, 3H, CH ₃ ), 4.48 (s, 2H, CH ₂ ), 7.40-7.62 (m, 20H) , 4-Pyr, 4-Br-Ph and 4-MeS (0) -Ph), 8.49-8.57 (m, 2H, 4-Pyr), 12.90 (bs, 1H, exchangeable, NH)

4- [5- (4-bromophenyl) -2- (4-methanesulfonylbenzylsulfanyl) -3H-imidazol-4-yl] pyridine (15c)

According to General Method A, the title compound was prepared from 1d (0.25 g; 0.75 mmol) and 4 (0.15 g; 0.72 mmol) after a reaction time of 5 hours and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 226 ° C

IR (ATR): 1605, 1318, 1303 (S02), 1145 (S02), 1003, 967, 957, 827, 822 cm ^"1

¹ H NMR (DMSO-d ₆ ): δ (ppm) 3.18 (s, 3H, CH ₃ ), 4.50 (s, 2H, CH ₂ ), 7.33-7.89 (m, 10H) , 4-Pyr, 4-Br-Ph and 4-MeS0 ₂ -Ph), 8.45-8.54 (m, 2H, 4-Pyr), 12.91 (bs, 1 H, exchangeable, NH) Example 16

4- [2- (4-Methylsulfanyl-benzylsulfanyl) -5-phenyl-3H-imidazol-4-yl] pyridine (16a)

According to general method A, the title compound was prepared starting from 1e (0.38 g; 1.5 mmol) and 2 (0.25 g; 1.4 mmol) after a reaction time of 5.75 hours and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / Et0H 9 + 1) obtained. Mp 213 ° C

IR (ATR): 1601, 1491, 1417, 1094, 1004, 967, 828, 771, 700 cm ^"1

¹ H NMR (DMSO-d ₆ ): δ (ppm) 2.44 (s, 3H, CH ₃ ), 4.38 (s, 2H, CH ₂ ), 7.18-7.58 (m, 11 H, 4-Pyr, Ph and 4-MeS-Ph), 8.44-8.47 (m, 2H, 4-Pyr), 12.82 (bs, 1 H, exchangeable, NH)

4- [2- (4-methanesulfinyl-benzylsulfanyl) -5-phenyl-3H-imidazol-4-yl] pyridine (16b)

According to general method A, the title compound was prepared from 1e (0.38 g; 1.5 mmol) and 3 (0.27 g; 1.43 mmol) after a reaction time of 5.5 hours and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 189 ° C

IR (ATR): 1603, 1494, 1051 (S = 0), 1003, 833, 701 cm ^"1

¹ H-NMR (DMSO-de): δ (ppm) 2.71 (s, 3H, CH ₃ ), 4.48 (s, 2H, CH ₂ ), 7.32-7.52 (m, 7H, 4-Pyr and Ph), 7.57-7.67 (m, 4H, 4-MeS (0) -Ph), 8.45-8.54 (m, 2H, 4-Pyr), 12.84 (bs, 1 H, interchangeable, NH)

4- [2- (4-methanesulfonyl-benzylsulfanyl) -5-phenyl-3H-imidazol-4-yl] pyridine (16c)

According to general method A, the title compound was prepared starting from 1e (0.38 g; 1.5 mmol) and 4 (0.29 g; 1.43 mmol) after a reaction time of 4.25 hours and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 247 ° C IR (ATR): 1602, 1298 (S02), 1145 (S02), 1006, 953, 827, 775, 701 cm ^"1

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 3.21 (s, 3H, CH), 4.54 (s, 2H, CH ₂ ), 7.31-7.58 (m, 7H, 4-Pyr and Ph), 7.70 (d, 2H, 8.3 Hz, 4-MeS0 ₂ -Ph), 7.91 (d, 2H, 8.3 Hz, 4-MeS0 ₂ -Ph), 8 , 45-8.59 (m, 2H, 4-pyr), 12.87 (bs, 1 H, exchangeable, NH)

Example 17

4- {5- (4-fluorophenyl) -2- [2- (4-methanesulfinylphenyl) ethylsulfanyl] -1H-imidazol- 4-yl} pyridine (17a)

According to General Method A, the title compound was prepared from 1a (0.25 g; 0.9 mmol) and 12a (0.22 g; 1.1 mmol) and with the addition of Na ₂ CO ₃ (1 spatula tip) and a catalytic one Amount of Nal obtained after a reaction time of 50 hours and purification by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1). Mp 177 ° C

IR (ATR): 1221 (CF), 1032 cm ^"1 (S = 0)

¹ H-NMR (DMSO-de): δ (ppm) 2.71 (s, 3H, CH ₃ ), 3.06-3.13 (m, 2H, CH ₂ ), 3.42-3.49 ( m, 2H, CH ₂ ), 7.25-7.65 (m, 10H, 4-Pyr, 4-F-Ph and 4-MeS (0) -Ph), 8.40-8.58 (m, 2H, 4-Pyr), 12.80 (bs, 1 H, exchangeable, NH)

4- {5- (4-Fuorphenyl) -2- [2- (4-methanesulfinylphenyl) propylsulfanyl] -1H-imidazol-4-yl} pyridine (17b)

According to General Method A, the title compound was prepared from 1a (0.25 g; 0.9 mmol) and 12b (0.22 g; 1.0 mmol) and with the addition of Na ₂ CO ₃ (1 spatula tip) and a catalytic one Amount of Nal obtained after a reaction time of 40 hours and purification by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1). Mp 142 ° C

IR (ATR): 1222 (CF), 1043 cm ^"1 (S = 0) ¹ H NMR (DMSO-d ₆ ): δ (ppm) 1.95-2.09 (m, 2H, CH ₂ ), 2.71 (s, 3H, CH ₃ ), 2.82 (t, 2H) , 7.4 Hz, CH ₂ ), 3.15 (t, 2H, 7.0 Hz, CH ₂ ), 7.25-7.62 (m, 10H, 4-Pyr, 4-F-Ph and 4 - MeS (O) -Ph), 8.46-8.49 (m, 2H, 4-Pyr), 12.86 (bs, 1H, exchangeable, NH)

4- [2-Benzylsulfanyl-5- (4-f luorphenyl) -1 H -imidazol-4-yl] pyridine (17c)

According to General Method A, the title compound was obtained starting from 1a (0.28 g; 1.0 mmol) and 1-chloromethylbenzene (0.13 g; 1.0 mmol) after a reaction time of 6 hours and stirring with MeOH. Mp 223 ° C

IR (ATR): 1233 cm - ^" 1 ¹ (CF)

¹ H NMR (DMSO-d ₆ ): δ (ppm) 4.41 (s, 2H, CH ₂ ), 7.23-7.51 (m, 11H, 4-Pyr, 4-F-Ph and Bz ), 8.44-8.47 (m, 2H, 4-pyr), 12.82 (bs, 1H, exchangeable, NH)

4- [5- (4-fluorophenyl) -2-phenethylsulfanyl-1 H -imidazol-4-yl3 "pyridm (17d)

According to General Method A, the title compound was started from 1a (0.5 g; 1.9 mmol) and 2-chloroethylbenzene (0.28 g; 2.0 mmol) and with the addition of Na ₂ CO ₃ (1 spatula tip) and obtained a catalytic amount of Nal after a reaction time of 70 hours and stirring with EtOH. Mp 257 ° C

IR (ATR): 1223 cm ^"1 (CF)

¹ H-NMR (DMSO-de): δ (ppm) 2.99 (t, 2H, 7.4 Hz, CH ₂ ), 3.40 (t, 2H, 7.5 Hz, CH ₂ ), 7, 17-7.53 (m, 11H, 4-Pyr, 4-F-Ph and Bz), 8.44-8.46 (m, 2H, 4-Pyr), NH not visible

4- [5- (4-fluorophenyl) -2- (3-phenyl-propylsulfanyl) -1 H -imidazol-4-yl] pyridine (17e)

According to general method A, the title compound was started from 1a (0.5 g; 1.9 mmol) and 3-chloropropylbenzene (0.31 g; 2.0 mmol) and with the addition of Na ₂ CO ₃ (1 spatula tip) and obtained a catalytic amount of Nal after a reaction time of 70 hours and stirring with EtOH. Mp 183 ° C IR (ATR): 1226 cm ^"1 (CF)

¹ H NMR (DMSO-d ₆ ): δ (ppm) 1.90-2.04 (m, 2H, CH ₂ ), 2.72 (t, 2H, 7.4 Hz, CH ₂ ). 3.12 (t, 2H, 7.0 Hz, CH ₂ ), 7.18-7.51 (m, 11 H, 4-Pyr, 4-F-Ph and Bz), 8.37-8.44 (m, 2H, 4- Pyr), 12.82 (bs, 1H, exchangeable, NH)

[5- (4-fluorophenyl) -4-pyridin-4-yl-1 H -imidazol-2-ylsulfanyl] acetonitrile (17f)

According to General Method A, the title compound was obtained starting from 1a (1.1 g; 4.0 mmol) and chloroacetonitrile (0.30; 4.0 mmol) after a reaction time of 18 hours and purification by column chromatography (Si0 ₂ 60, ethyl acetate) , Mp 219 ° C

IR (ATR): 2243 (CN), 1226 cm ^"1 (CF)

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.32 (s, 2H, CH ₂ ), 7.34-7.57 (m, 6H, 4-Pyr and 4-F-Ph), 8.50-8.52 (m, 2H, 4-Pyr), 13.20 (bs, 1H, interchangeable, NH)

4- [5- (4-fluorophenyl) -2- (naphthalen-1-ylmethylsulfanyl) -1H-imidazol-4-yl] pyridine (17g)

According to general method A, the title compound was prepared starting from 1a (0.28 g; 1.0 mmol) and 1-chloromethylnaphthol (0.18 g; 1.0 mmol) after a reaction time of 6.5 hours and purification by column chromatography (Si0 ₂ 60, ethyl acetate). Mp 364 ° C

IR (ATR): 1225 cm ^"1 (CF)

¹ H NMR (DMSO-d ₆ ): δ (ppm) 4.90 (s, 2H, CH ₂ ), 7.25-7.62 (m, 10H, 4-Pyr, 4-F-Ph and naphthyl ), 7.80-7.98 (m, 2H, naphthyl), 8.20-8.23 (m, 1H, naphthyl), 8.48-8.52 (m, 2H, 4-pyr), 12, (bs, 1 H, exchangeable, NH) 4- [2-Cyclohexylmethylsulfanyl-5- (4-fluorophenyl) -1 H-imidazol-4-yl] -pyπ'din (17h)

According to general method A, the title compound was started from 1a (0.25 g; 0.9 mmol) and 1-chloromethylcyclohexane (0.18 g; 1.0 mmol) and with the addition of Na ₂ CO ₃ (1 spatula tip) and obtained a catalytic amount of Nal after a reaction time of 47 hours and stirring with EtOH. Mp 235 ° C

IR (ATR): 2922, 2852 (c-Hex), 1222 cm ^"1 (CF)

¹ H NMR (DMSO-de): δ (ppm) 0.95-1.23 (m, 5H, cyc / o-hex), 1.51-1.85 (m, 6H, cyc / o-hex) ), 3.06 (d, 2H, 6.7 Hz, CH ₂ ), 7.22-7.51 (m, 6H, 4-Pyr and 4-F-Ph), 8.43-8.45 ( m, 2H, 4-Pyr), 12.76 (bs, 1H, exchangeable, NH)

4- [5- (4-fluorophenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridine (17i)

According to general method A, the title compound was obtained starting from 1a (0.41 g; 1.5 mmol) and methyl iodide (0.27 g; 1.9 mmol) after a reaction time of 8 hours and stirring with EtOH. Mp 263 ° C

IR (ATR): 1226 cm ^"1 (CF)

H-NMR (DMSO-d ₆ ): δ (ppm) 2.61 (s, 3H, CH ₃ ), 7.22-7.51 (m, 6H, 4-Pyr and 4-F-Ph), 8 , 42-8.45 (m, 2H, 4-pyr), NH not visible

4- [5- (4-fluorophenyl) -2- (2-methylsulfanyl-benzylsulfanyl) -1 H-imidazol-4-yl] pyridine (17j)

According to General Method A, the title compound, starting from 1a (0.28 g; 1.0 mmol) and 1-chloromethyl! -2-methylsu! Fanylbenzene (0.17 g; 1.0 mmol), became 5.5 hours longer Reaction time and column chromatography purification (Si0 ₂ 60, ethyl acetate) obtained. Mp 223 ° C

IR (ATR): 1228 cm ^"1 (CF) ¹ H-NMR (CD ₃ OD): δ (ppm) 2.51 (s, 3H, CH ₃ ), 4.44 (s, 2H, CH ₂ ), 7.13-7.48 (m, 10H, 4-Pyr, 4-F-Ph and 2-MeS-Ph), 8.43-8.46 (m, 2H, 4-Pyr)

4- [5- (4-Fluoφhenyl) -2- (2-methanesulfinyl-benzylsulfanyl) -1H-imidazol-4-yl] pyridine (17k)

According to General Method A, the title compound was prepared from 1a (0.28 g; 1.0 mmol) and 1-chloromethyl-2-methanesulfinylbenzene (0.18 g; 1.0 mmol) after a reaction time of 4 hours and recrystallization from methanol / Get ethyl acetate (1 + 1). Mp 205 ° C

IR (KBr): 1213 (CF), 1033 cm ^"1 (S = 0)

¹ H NMR (CD ₃ OD): δ (ppm) 2.87 (s, 3H, CH ₃ ), 4.50 (d, 1H, 13.6 Hz, CH ₂ ), 4.62 (d, 1H) , 13.6 Hz, CH ₂ ), 7.24-7.33 (m, 2H, 4-F-Ph), 7.47-7.62 (m, 5H, 4-F-Ph, C ⁴ - / C ⁵ - / C ⁶ -H 2-MeS (O) -Ph), 7.95 (d, 1 H, 7.2 Hz, C ³ -H 2-MeS (0) -Ph), 7.99 -8.03 (m, 2H, 4-pyr), 8.55- 8.58 (m, 2H, 4-pyr)

4- [5- (4-fluorophenyl) -2- (3-methylsulfanyl-benzylsulfanyl) -1H-imidazol-4-yl] pyridine (171)

According to General Method A, the title compound was prepared from 1a (1.1 g; 4.1 mmol) and 1-chloromethyl-3-methylsulfanylbenzene (0.7 g; 4.1 mmol) after a reaction time of 11 hours and recrystallization from EtOH receive. Mp 218 ° C

IR (KBr): 1225 cm ^"1 (CF)

¹ H NMR (DMSO-d ₆ ): δ (ppm) 2.40 (s, 3H, CH ₃ ), 4.46 (s, 2H, CH ₂ ), 7.16-7.43 (m, 6H , 4-F-Ph and 3-MeS-Ph), 7.56-7.63 (m, 2H, 4-F-Ph), 7.90-7.93 (m, 2H, 4-Pyr), 8.66-8.69 (m, 2H, 4-pyr), NH not visible 4- [5- (4-Fluoιphenyl) -2- (3-methanesulfinyl-benzylsulfanyl) -1H-imidazol-4-yl] pyridine (17m)

A 35% solution of HO ₂ (0.13 mL; 1.3 mmol) was added dropwise to a suspension of 171 (0.50 g; 1.2 mmol) in glacial acetic acid (7 mL). The reaction mixture was stirred for 20.5 h at room temperature, diluted with H ₂ 0 (5 mL), adjusted to pH 9 with 25% ammonia water and extracted with ethyl acetate (3 ×). The combined organic extract was washed with saturated NaCl solution (3 ×) and dried over Na ₂ S0 ₄ . The oily crude product obtained after removal of the solvent was triturated with diethyl ether / ethyl acetate (1 + 1) and the semi-solid residue was purified by column chromatography (RP-18, MeOH). Mp 171 ° C

IR (KBr): 1228 (CF), 1019 cm ^"1 (S = 0)

¹ H-NMR (CD ₃ OD): δ (ppm) 2.67 (s, 3H, CH ₃ ), 4.37 (s, 2H, CH ₂ ), 7.13-7.21 (m, 2H, 4- F-Ph), 7.37-7.58 (m, 8H, 4-Pyr, 4-F-Ph and 3-MeS (0) -Ph), 8.40-8.43 (m, 2H , 4-pyr)

Example 18

2- [5- (4-fluorophenyl) -4-pyridin-4-yl-1 H -imidazol-2-ylsulfanylmethyl] phenol (18a)

According to general method B (23 h, room temperature), the title compound was obtained starting from 1a (0.20 g; 0.7 mmol) and 2-hydroxymethylphenol (0.10 g; 0.8 mmol) after stirring with EtOH. Mp 200 ° C (decomposition)

IR (ATR): 1266 (OH bending), 1222 (C-F), 1005 (C-O)

¹ H NMR (DMSO-d ₆ ): δ (ppm) 4.37 (s, 2H, CH ₂ ), 6.70-6.85 (m, 2H, 2-HO-Ph), 7.05- 7.14 (m, 1H, 2-HO-Ph), 7.23-7.53 (m, 7H, 4-Pyr, 4-F-Ph and 2-HO-Ph), 8.46-8 , 49 (m, 2H, 4-Pyr), 9.95 (bs, 1H, exchangeable, OH), 12.81 (bs, 1H, exchangeable, NH)

3- [5- (4-fluorophenyl) -4-pyridin-4-yl-1 H -imidazol-2-ylsulfanylmethyl] phenol (18b) According to general method B (9 h, reflux), the title compound was purified from 1a (0.20 g; 0.7 mmol) and 3-hydroxymethylphenol (0.10 g; 0.8 mmol) after purification by column chromatography (Si0 ₂ 60 , CH ₂ CI / EtOH 9 + 1). Mp 230 ° C

IR (ATR): 1287 (OH bending), 1241 (CF), 1007 cm ^"1 (CO)

¹ H NMR (DMSO-de): δ (ppm) 4.34 (s, 2H, CH ₂ ), 6.65 (dd, 1H, 1, 4 / 8.0 Hz, 3-HO-Ph C ⁴ -H), 6.79-6.82 (m, 2H, 3-HO-Ph C ² - / C ⁶ -H), 7.07-7.15 (m, 1H, 3-HO-Ph C) ⁵ -H), 7.27-7.53 (m, 6H, 4-Pyr and 4-F-Ph), 9.45 (s, 1H, exchangeable, OH), 12.83 (bs, 1H, exchangeable , NH)

4- [5- (4-fluorophenyl) -4-pyridin-4-yl-1 H -imidazol-2-ylsulfanylmethyl] phenol (18c)

According to General Method B (14 h, room temperature), the title compound was purified from 1a (0.20 g; 0.7 mmol) and 4-hydroxymethylphenol (0.10 g; 0.8 mmol) after purification by column chromatography (Si0 ₂ 60 , CH ₂ CI ₂ / EtOH 9 + 1). Mp 250 ° C (decomposition)

IR (ATR): 1271 (OH bending), 1232 (CF), 1004 cm ^"1 (CO)

¹ H NMR (DMSO-de): δ (ppm) 4.32 (s, 2H, CH ₂ ), 6.69 (d, 2H, 7.5 Hz, 4-HO-Ph), 7.19 ( d, 2H, 7.9 Hz, 4-HO-Ph), 7.27-7.51 (m, 6H, 4-Pyr and 4-F-Ph), 8.43-8.53 (m, 2H , 4- pyr), 9.41 (s, 1H, exchangeable, OH), 12.79 (bs, 1H, exchangeable, NH)

2- [5- (4-fluorophenyl) -4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl] -4-methylsulfanylphenol (18d)

According to general method B (1 h, room temperature), the title compound was obtained from 1a (0.50 g; 2.9 mmol) and 8a (0.50 g; 2.9 mmol) after stirring with MeOH. Mp 243 ° C

IR (KBr): 1275 (OH bending), 1230 (CF), 1005 cm ^"1 (CO) ¹ H NMR (DMF-d ₇ ): δ (ppm) 2.36 (s, 3H, CH ₃ ), 4.46 (s, 2H, CH ₂ ), 6.90 (d, 1H, 8.4) Hz, 2-HO-Ph C ³ -H), 7.13 (dd, 1H, 2.3 / 8.3 Hz, 2-HO-Ph C ⁴ -H), 7.27-7.35 (m, 3H) , 4-F-Ph and 2-HO-Ph C ⁶ -H), 7.51-7.53 (m, 2H, 4-Pyr), 7.58-7.65 (m, 2H, 4-F -Ph), 8.52-8.55 (m, 2H, 4-pyr), 10.30-10.70 (bs, 1H, exchangeable, NH), OH not visible

4-chloro-2- [5- (4-fluQrphenyl) -4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl] -6-methylsulfanylphenol (18e)

According to general method B (1.5 h, 75 ° C.), the title compound was started from 1a (0.80 g; 3.0 mmol) and 8b (0.60 g; 3.0 mmol) after stirring with OH received. Mp 220 ° C (decomposition)

IR (KBr): 1259 (OH bending), 1225 (CF), 1007 cm ^"1 (CO)

¹ H NMR (DMSO-de): δ (ppm) 2.34 (s, 3H, CH ₃ ), 4.38 (s, 2H, CH ₂ ), 6.97 (d, 1H, 2.3 Hz) , 3-CI-Ph C ² -H), 7.17 (d, 1 H, 2.3 Hz, 3-CI-Ph C ⁴ -H), 7.23-7.51 (m, 6H, 4 -Pyr and 4- F-Ph), 8.48-8.50 (m, 2H, 4-Pyr), 12.74 (bs, 1H, exchangeable, NH), OH not visible

4- [5- (4-fluorophenyl) -4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl] -2-methylsulfanylphenol (18f)

According to general method B (2 h, room temperature), the title compound was obtained from 1a (0.20 g; 0.7 mmol) and 8c (0.14 g, 0.8 mmol) after stirring with MeOH. Mp 230 ° C (decomposition)

IR (KBr): 1227 (CF), 1019 cm ^"1 (CO)

¹ H NMR (CD ₃ OD): δ (ppm) 2.21 (s, 3H, CH ₃ ), 4.17 (s, 2H, CH ₂ ), 6.69 (d, 1H, 8.0 Hz) , 4-HO-Ph C ³ -H), 6.90-7.01 (m, 2H, 4-HO-Ph C ² - / C ⁶ -H), 7.12-7.21 (m, 2H , 4-F-Ph), 7.32-7.53 (m, 4H, 4-Pyr and 4-F-Ph), 8.39-8.43 (m, 2H, 4-Pyr) 2- [5- (4-fluorophenyl) -4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl] -4-methanesulfinyiphenol (18g)

According to General Method B (1 h, room temperature), the title compound was prepared from 1a (0.27 g; 1.0 mmol) and 8a (0.17 g; 1.0 mmol) with the addition of 35% H ₂ O. ₂ solution obtained after recrystallization from toluene / THF (1 + 1). Mp 216 ° C

IR (KBr): 1278 (OH bending), 1232 (CF), 1031 (S = 0), 1003 cm ^"1 (CO)

¹ H NMR (CD ₃ OD): δ (ppm) 2.60 (s, 3H, CH ₃ ), 4.33 (s, 2H, CH ₂ ), 6.96 (d, 1H, 8.2 Hz) , 2-HO-Ph C ³ -H), 7.11-7.21 (m, 2H, 4-F-Ph), 7.41-7.47 (m, 6H, 4-Pyr, 4-F -Ph and 2- HO-Ph C ⁴ - / C ⁶ -H), 8.39-8.42 (m, 2H, 4-Pyr)

4-chloro-2- [5- (4-fluorophenyl) -4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl] -6-methanesulfinyl-phenol (18h)

According to general method B (1.5 h, 75 ° C.), the title compound was started from 1a (0.27 g; 1.0 mmol) and 8b (0.21 g, 1.0 mmol) with the addition of 35% iger H ₂ θ ₂ solution obtained after purification by column chromatography (Si0 ₂ 60, acetone). Mp 175 ° C (decomposition)

IR (KBr): 1265 (OH bending), 1236 (CF), 1051 (S = 0), 1005 cm ^"1 (CO)

¹ H-NMR (CD ₃ OD): δ (ppm) 2.72 (s, 3H, CH ₃ ), 4.39 (s, 2H, CH ₂ ), 7.14-7.23 (m,

2H, 4-F-Ph), 7.39 (d, 1H, 2.6 Hz, 3-CI-Ph C ² -H), 7.42-7.49 (m, 6H, 4-Pyr, 4 -F-Ph and 3-CI-Ph C ⁴ -H), 8.43-8.46 (m, 2H, 4-pyr)

Example 19

4- [5- (4-fluorophenyl) -4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl] -2-methanesulfinylphenol (19) According to General Method B (2.5 h, room temperature), the title compound was prepared from 1a (0.20 g; 0.7 mmol) and 8c (0.14 g; 0.8 mmol) with the addition of 35% H ₂ 0 ₂ solution obtained after stirring with acetone. Mp 185 ° C (decomposition)

IR (KBr): 1296 (OH bending), 1230 (CF), 1062 (S = 0), 1013 cm ^"1 (CO)

¹ H NMR (CD ₃ OD): δ (ppm) 2.70 (s, 3H, CH ₃ ), 4.28 (s, 2H, CH ₂ ), 6.78 (d, 1 H, 8.3 Hz, 4-HO-Ph C ³ -H), 7.12-7.21 (m, 2H, 4-F-Ph), 7.28 (dd, 1H, 2.2 / 8.3 Hz, 4 -HO-Ph C ² -H), 7.39-7.46 (m, 5H, 4-Pyr, 4-F-Ph and 4-HO-Ph C ⁶ -H), 8.40 (m, 2H , 4-pyr)

Example 20

4-fluoro-N-methoxy-N-methyl-benzamide (20)

A suspension of 4-fluorobenzoic acid (20 g, 143 mmol) in thionyl chloride (130 g; 1.1 mol) was stirred under reflux for 6 h: vigorous gas evolution, clear solution after approx. 10 min, color deepening from yellow to orange. The excess thionyl chloride was removed by distillation (first normal pressure / 40 ° C, then membrane pump vacuum / 40 ° C). 4-Fluorobenzoic acid chloride was distilled off from the distillation residue in a membrane pump vacuum at 90 ° C over a short column. The reaction product crystallized when stored in the refrigerator (Π ²⁰ D 1.5315; F 9 ° C, yield 20 g / 89%). Freshly distilled triethylamine (29 mL) was added to a suspension of N, 0-dimethylhydroxylamine hydrochloride (9.0 g; 92 mmol) in CH ₂ Cl ₂ (75 mL). The reaction mixture was stirred at room temperature for 2 h and then cooled to -10 ° C. 4-Fluorobenzoic acid chloride (13.5 g; 85 mmol) was added dropwise with cooling for submission within 6 min. After the addition had ended, the cooling was removed and the reaction mixture was stirred at room temperature for 1.5 hours. The light brown suspension was added to H ₂ O (100 mL). The organic phase was separated and the aqueous phase extracted with diethyl ether (2 ×). The combined organic extract was washed with saturated NaCl solution, dried over NaSO ₄ and concentrated. The oily, brown residue crystallized on cooling and rubbing. The raw product was dried on the oil pump (triethylamine residues!) and implemented without further cleaning.

¹ H NMR (CDCI3): δ (ppm) 3.37 (s, 3H, NCH ₃ ), 3.54 (s, 3H, OCH ₃ ), 7.04-7.13 (m, 2H, 4- F-Ph), 7.71-7.78 (m, 2H, 4-F-Ph)

Example 21

2- (2-chloropyridin-4-yl) -1 - (4-fluorophenyl) ethanone (21a)

To a solution of diisopropylamine (15 mL, 106 mmol) in THF abs. Cooled to -85 ° C. (150 mL) was added dropwise in a heated and argon-flushed DHK n-BuLi (15% solution in n-hexane, 45 mL, 104 mmol): temperature rise to -50 ° C. After the addition had ended, the light yellow solution was stirred at -85 ° C. for 55 min. A solution of 2-chloro-4-methylpyridine (2-chloro-γ-picolin, 8.6 g; 68 mmol) in THF abs. (75 mL) added dropwise: temperature rise to -50 ° C, immediate purple color. After the addition had ended, the reaction mixture was stirred at -85 ° C. for 1 h and at this temperature within 3 min with a solution of 20 (12.4 g; 68 mmol) in THF abs. (75 mL) added: temperature rise to -60 ° C. The purple, mushy reaction mixture was stirred at -85 ° C for 1 h and then warmed to 0 ° C within 1 h. The mixture was added to saturated NaCl solution (300 ml), which was covered with an layer of ethyl acetate (300 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2 * 250 mL), with only a little brown, foamy precipitate of 1,3-bis- (2-chloropyridin-4-yl) -2- ( 4-fluorophenyl) propan-2-ol farewell. The combined organic extract was washed with saturated NaCl solution, dried over NaSO ₄ and concentrated. The oily residue was taken up in a little tert-butyl methyl ether and stored at 4 ° C. overnight. The crystals were filtered off and dried.

¹ H NMR (CDCI ₃ ): δ (ppm) 4.26 (s, 2H, CH ₂ ), 7.11-7.26 (m, 4H, C - / C ⁵ -H 2-CI-Pyr and 4-F-Ph), 7.99-8.06 (m, 2H, 4-F-Ph), 8.35 (dd, 1 H, 0.6 / 5.1 Hz, C ⁶ -H 2- CI-Pyr) 1 - (4-fluorophenyl) -2- (2-f luorpyι idin-4-yl) -ethanone (21 b)

21b was prepared starting from 2-fluoro-4-methyl-pyridine (13.9 g; 125 mmol) according to the method described in the synthesis of 21a.

¹ H-NMR (CDCI ₃ ): δ (ppm) 4.32 (s, 2H, CH ₂ ), 6.85-6.86 (m, 1H, C ³ -H 2-F-Pyr), 7, 08- 7.19 (m, 3H, C ⁵ -H 2-F-Pyr and 4-F-Ph), 8.00-8.07 (m, 2H, 4-F-Ph), 8.18 ( d, 1H, 5.1 Hz, C ⁶ -H 2-F-Pyr)

2- (2-bromopyridin-4-yl) -1- (4-fluorophenyl) ethanone (21c)

21c was prepared from 2-bromo-4-methyl-pyridine (9.6 g; 56 mmol) according to the method described in the synthesis of 21a.

¹ H-NMR (CDCI ₃ ): δ (ppm) 4.35 (s, 2H, CH ₂ ), 7.17-7.37 (m, 3H, 2-Br-Pyr and 4-F-Ph), 7.50 (s, 1H, C ³ -H 2-Br-Pyr), 8.07-8.15 (m, 2H, 4-F-Ph), 8.42 (d, 1H, 5.1 Hz , C ⁶ -H 2- Br-Pyr)

Example 22

1 - (2-chloropyridin-4-yl) -2- (4-fluorophenyl) ethane-1,2-dione-1-oxime (22a)

A solution of 21a (3.0 g; 12 mmol) in glacial acetic acid (30 mL) was added dropwise with stirring and cooling in a water bath (approx. 10 ° C) within 2.5 min with a solution of NaN0 ₂ (0 , 85 g; 12.3 mmol) in H ₂ 0 (10 mL). After the addition had ended, the reaction mixture was stirred at room temperature for 0.5 h, supplemented with H ₂ 0 (60 ml) and stirred at room temperature for a further 3 h. The light beige precipitate was filtered off, washed with water and dried in vacuo over CaCl ₂ .

¹ H NMR (DMSO-de): δ (ppm) 7.34-7.52 (m, 4H, C ³ - / C ⁵ -H 2-CI-Pyr and 4-F-Ph), 7.93 - 8.00 (m, 2H, 4-F-Ph), 8.47 (d, 1 H, 5.2 Hz, C ⁶ -H 2-CI-Pyr), 12.71 (bs, 1H, exchangeable , OH) 1 - (2-fluoropyridin-4-yl) -2- (4-fluorophenyl) ethane-1,2-dione-1-oxime (22b)

22b was prepared from 21b (10.0 g; 43 mmol) using the method described in the synthesis of 22a.

¹ H-NMR (DMSO-de): δ (ppm) 7.19-7.20 (m, 1H, C ³ -H 2-F-Pyr), 7.35-7.47 (m, 3H, C ⁵ - H 2-F-Pyr and 4-F-Ph), 7.91-7.98 (m, 2H, 4-F-Ph), 8.29 (d, 1H, 5.3 Hz, C ⁶ -H 2-F- Pyr), 12.69 (s, 1H, exchangeable, OH)

1 - (4-fluorophenyl) -2- (2-isopropoxypyridin-4-yl) -ethane-1,2-dione-2-oxime (22c)

A solution of 22b (200 mg; 0.76 mmol) in HCl-saturated isopropanol (15 mL) was stirred under reflux for 2.5 h. The solution was concentrated and the yellowish-white residue was stirred with a little ethanol, filtered off and dried.

¹ H NMR (DMSO-de): δ (ppm) 1.24 (d, 6H, 6.2 Hz, 2 x CH ₃ ), 5.15-5.27 (m, 1H, methylene-H ), 6.54 (s, 1H, C ³ -H 2-iso-O-Pyr), 7.08 (dd, 1H, 1, 2 / 5.3 Hz, C ⁵ -H 2-iso-O- Pyr), 7.36-7.49 (m, 2H, 4-F-Ph), 7.88-7.97 (m, 2H, 4-F-Ph), 8.19 (d, 1 H, 5.4 Hz, C ⁶ -H 2- Iso-O-Pyr), 12.44 (bs, 1H, exchangeable, OH)

1 - (2-bromopyridin-4-yl) -2- (4-f luorphenyl) ethane-1,2-dione-1-oxime (22d)

22d was prepared from 21c (5.0 g; 17 mmol) using the method described in the synthesis of 22a.

¹ H NMR (DMSO-d ₆ ): δ (ppm) 7.40-7.48 (m, 3H, C ³ -H 2-Br-Pyr and 4-F-Ph), 7.65 (d, 1H, 0.8 Hz, C ⁵ -H 2-Br-Pyr), 7.93-8.01 (m, 2H, 4-F-Ph), 8.45 (d, 1H, 5.2 Hz, C ⁶ -H 2- Br-Pyr), 12.72 (bs, 1H, exchangeable, OH) Example 23

2-amino-2- (2-chloropyridin-4-yl) -1- (4-fluorophenyl) ethanone hydrochloride (23a)

22a (1.5 g; 5.4 mmol) was dissolved in methanol (15 mL) with gentle warming. The solution was cooled to room temperature, supplemented with hydrochloric acid methanol (20 mL) and transferred to a DHK. Pd-C 10% (150 mg) was entered in the template. The reaction vessel was evacuated on the oil pump and then charged with H via a gas inlet capillary (4 x). The suspension was shaken (240 strokes / min) at room temperature in a closed three-necked flask in an H ₂ atmosphere until the starting material was no longer detectable by thin layer chromatography (6 h). The suspension was filtered and the catalyst was washed with plenty of methanol. The combined filtrate was concentrated and the mustard-colored, solid amorphous residue was dried on an oil pump. The crude product was used in the next reaction step without further purification.

¹ H NMR (DMSO-d6): δ (ppm) 6.53 (bs, 1H, methine-H), 7.35-7.45 (m, 2H, 4-F-Ph), 7.59 ( dd, 1H, 1.5 / 5.2 Hz, C ⁵ -H 2-CI-Pyr), 7.85 (d, 1H, 0.9 Hz, C ³ -H 2-CI-Pyr), 8 , 17- 8.25 (m, 2H, 4-F-Ph), 8.49 (d, 1H, 4.9 Hz, C ⁶ -H 2-CI-Pyr), 9.33 (bs, 3H, interchangeable, NH ₃ ⁺ )

2-amino-2- (2-fluoropyridin-4-yl) -1- (4-fluorophenyl) ethanone hydrochloride (23b)

22b (5.0 g; 19 mmol) was dissolved in hydrochloric isopropanol (IsOH / HCl-saturated IsOH 1 +1, 60 mL) while warming gently. The yellowish solution was cooled to room temperature and transferred to a DHK (100 mL). Pd-C 10% (1.5 g) was added to the template. The reaction vessel was evacuated on the oil pump and then charged with H ₂ (4 ×) via a gas inlet capillary. At room temperature, the suspension was shaken in a sealed three-necked flask in an H ₂ atmosphere (240 strokes / min) until the starting material was no longer detectable by thin layer chromatography (6.5 h). The catalyst was filtered off. The filtration residue was washed with plenty of methanol (approx. 800 mL). The combined filtrates were concentrated and the solid amorphous residue on the oil pump dried. The crude product was used in the next reaction step without further purification.

¹ H-NMR (DMSO-de): δ (ppm) 6.58 (bs, 1H, methine-H), 7.33-7.41 (m, 2H, 4-F-Ph), 7.54 ( m, 2H, C ³ - / C ⁵ -H 2-F-Pyr), 8.14-8.25 (m, 2H, 4-F-Ph), 8.30 (d, 1 H, 5.5 Hz, C ⁶ -H 2-F-Pyr), 9.40 (bs, 3H, exchangeable, NH ₃ ⁺ )

2-amino-1- (4-fluorophenyl) -2- (2-isopropoxypyridin-4-yl) ethanone hydrochloride (23c)

23c was prepared from 22c (2.0 g; 7.6 mmol) using the method described in the synthesis of 23a.

¹ H-NMR (DMSO-de): δ (ppm) 1, 23 (d, 6H, 5.6 Hz, 2 x CH ₃ ), 5.09-5.22 (m, 1 H, meth- H CH (CH ₃ ) ₂ ), 6.38-6.41 (bs, 1H, methine-H CH-NH ₃ ⁺ ), 7.00-7.08 (m, 2H, 2-iso-O-pyr ), 7.33-7.46 (m, 2H, 4-F-Ph), 8.14-8.23 (m, 3H, 2-iso-O-Pyr and 4-F-Ph), 9, 21 (bs, 3H, interchangeable, NH ₃ ⁺ )

2-amino-1- (4-fluorophenyl) -2- (2-methoxypyridin-4-yl) ethanone hydrochloride (23d)

23d was formed by treating 22b (7.5 g; 29 mmol) under the conditions described in the synthesis of 23a.

¹ H-NMR (DMSO-de): δ (ppm) 3.83 (s, 3H, CH ₃ ), 6.44 (bs, 1H, methine-H), 7.13-7.16 (m, 2H , C ³ - / C ⁵ -H 2-MeO-Pyr), 7.34-7.46 (m, 2H, 4-F-Ph), 8.16-8.25 (m, 3H, C ⁶ - H 2- MeO-Pyr and 4-F-Ph), 9.29 (bs, 3H, exchangeable, NH ₃ ⁺ )

2-amino-1- (4-fluorophenyl) -2-pyridin-4-ylethanone hydrochloride (23e)

23e was formed by treating 22c (4.0 g; 12.4 mmol) under the conditions described in the synthesis of 23b. ¹ H NMR (DMSO-de): δ (ppm) 6.78 (bs, 1 H, methine-H), 7.32-7.38 (m, 2H, 4-F-Ph), 8.07 -8.13 (m, 2H, 4-Pyr), 8.17-8.27 (m, 2H, 4-F-Ph), 8.92-8.95 (m, 2H, 4-Pyr), 9.43 (bs, 3H, interchangeable, NH ₃ ⁺ )

2-amino-2- (2-bromopyridin-4-yl) -1 - (4-fluorophenyl) ethanone hydrochloride (23f)

A solution of 22d (1.8 g; 5.6 mmol) in absolute ethanol (30 mL) was cooled to -10 ° C and concentrated sulfuric acid (1.3 mL) was added. Zinc dust (1.1 g) was added in portions to the receiver while cooling. The reaction mixture was stirred at -10 ° C. for 30 min and then warmed to room temperature. The gray-green suspension was filtered and the white residue (ZnS0 ₄ ) washed with plenty of ethanol. The combined, yellow-colored filtrate was concentrated and the solid, yellowish residue was dried on an oil pump.

¹ H NMR (DMSO-de): δ (ppm) 6.39 (bs, 1H, methine-H), 7.35-7.44 (m, 2H, 4-F-Ph), 7.56 ( dd, 1 H, 1, 4 / 5.1 Hz, C ⁵ -H 2-Br-Pyr), 7.91 (s, 1H, C ³ -H2-Br-Pyr), 8.12-8.19 (m, 2H, 4-F-Ph), 8.46 (d, 1H, 5.1 Hz, C ⁶ -H2-Br-Pyr), 8.94 (bs, 3H, exchangeable, NH ₃ ⁺ )

Example 24

4- (2-chloropyridin-4-yl) -5- (4-fluorophenyl) -1,3-dihydro-imidazol-2-thione (24a)

23a (2.9 g; approx. 9.6 mmol) was dissolved in DMF absolute (75 mL) with gentle warming. Potassium rhodanide (1.9 g; 19.6 mmol) was added to the clear, orange-red solution: immediate cloudiness and lightening of the color. The reaction mixture was stirred under reflux for 1.5 hours. The suspension was cooled to room temperature and H ₂ 0-cooling dropwise with H ₂ 0 (about 140 mL). The yellow precipitate was filtered off, washed with H ₂ 0 and dried in vacuo over CaCl ₂ .

¹ H NMR (DMSO-de): δ (ppm) 7.12-7.52 (m, 6H, C ³ - / C ⁵ -H 2-CI-Pyr and 4-F-Ph), 8.27 (d, 1H, 5.2 Hz, C ⁶ -H 2-CI-Pyr), 12.82 (bs, 2H, exchangeable, 2 NH)

4- (4-fluorophenyl) -5- (2-fluoropyridin-4-yl) -1,3-dihydro-imidazol-2-thione (24b) 24b was prepared from 23b (6.1 g; 20 mmol) according to the method described in the synthesis of, 24a.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.12-7.16 (m, 2H, C ³ - / C ⁵ -H 2-F-Pyr), 7.28-7.27 ( m, 2H, 4-F-Ph), 7.46-7.55 (m, 2H, 4-F-Ph), 8.13 (d, 1 H, 5.1 Hz, C ⁶ -H 2- F-Pyr), 12.85 (bs, 2H, interchangeable, 2 x NH)

4- (4-fluorophenyl) -5- (2-isopropoxypyridin-4-yl) -1,3-dihydro-imidazol-2-thione (24c)

24c was prepared from 23c (2.5 g; 7.6 mmol) using the method described in the synthesis of 24a.

H-NMR (DMSO-de): δ (ppm) 1.24 (d, 6H, 6.2 Hz, 2 CH ₃ ), 5.10-5.19 (m, 1H, methine-H), 6, 69-6.76 (m, 2H, 2-iso-O-Pyr), 7.24-7.32 (m, 2H, 4-F-Ph), 7.42-7.49 (m, 2H, 4-F-Ph), 8.02 (d, 1H, 5.5 Hz, C ⁶ -H 2-iso-O-Pyr), 12.68 (bs, 2H, exchangeable, 2 NH)

4- (4-fluorophenyl) -5- (2-methoxypyridin-4-yl) -1,3 ~ dihydro-imidazol-2-thione (24d)

Potassium rhodanide (2 g; 20.6 mmol) was added to a solution of 23d (3.2 g; 10.8 mmol) in 10% hydrochloric acid (50 mL). The reaction mixture was stirred under reflux for 30 min. The orange solution was cooled and neutralized with 10% NaHC0 ₃ solution. The precipitate was filtered off, washed with H ₂ 0 and dried in vacuo over CaCl ₂ . The crude product was stirred with ethanol and the insoluble fraction was filtered off. 24d precipitated from the ethanolic filtrate on standing.

¹ H NMR (DMSO-de): δ (ppm) 3.81 (s, 3H, OCH ₃ ), 6.79-6.82 (m, 2H, C ³ - / C ⁵ -H2-MeO- Pyr ), 7.26-7.50 (m, 4H, 4-F-Ph), 8.06 (d, 1H, 5.3 Hz, C ⁶ -H 2-MeO-Pyr), 12.65 (bs, 2H , exchangeable, 2 NH) Example 25

2-chloro-4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridine (25a)

According to general method A, the title compound was prepared starting from 24a (0.5 g; 1.6 mmol) and methyl iodide (0.35 g; 2.5 mmol) after a reaction time of 12 hours and purification by column chromatography (Al ₂ 0 ₃ , CH ₂ CI ₂ / ethyl acetate 1 + 1) obtained. Mp 236 ° C

IR (ATR): 3126, 3057, 2929, 1591, 1529, 1499, 1389, 1231 (CF), 1159, 996, 976, 844, 780 cm ^"1

H-NMR (DMSO-de): δ (ppm) 2.62 (s, 1H, CH ₃ ), 7.27-7.36 (m, 3H, 2-CI-Pyr and 4-F-Ph), 7.45-7.55 (m, 3H, 2-CI-Pyr and 4-F-Ph), 8.24 (d, 1H, 5.1 Hz, C ⁶ -H 2-CI-Pyr), 12 , 85 (bs, 1H, interchangeable, NH)

2-fluoro-4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridine (25b)

According to general method A, the title compound was obtained starting from 24b (0.95 g; 3.3 mmol) and methyl iodide (1.4 g; 9.9 mmol) after a reaction time of 40 hours. The crude product was boiled with CH ₂ CI ₂ / ethyl acetate (1 + 1). The combined organic extract was decolorized with Al ₂ O ₃ and the residue obtained after concentrating the filtrate was stirred out with a little EtOH. Mp 224 ° C

IR (ATR): 3073, 1609, 1497, 1421, 1234, 1219 (CF), 1159, 1002, 883, 851, 833, 815 cm ^"1

¹ H NMR (DMSO-de): δ (ppm) 2.62 (s, 3H, CH ₃ ), 7.08 (s, 1H, C ³ -H 2-F-Pyr), 7.26-7 , 35 (m, 3H, C ⁵ -H 2-F-Pyr and 4-F-Ph), 7.46-7.54 (m, 2H, 4-F-Ph), 8.08 (d, 1H , 5.3 Hz, C ⁶ -H 2-F-Pyr), 12.85 (bs, 1 H, exchangeable, NH) 4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] -2-isopropoxypyridine (25c)

NaH (55-65%; 1.0 g; approx. 23 mmol) was added to a solution of 24c (4.0 g; 13.8 mmol) in absolute THF (60 mL). This initial charge was stirred for 5 min at room temperature and a solution of methyl iodide (2.2 g; 17.3 mmol) in absolute THF (5 mL) was added dropwise and with H ₂ O cooling. The reaction mixture was stirred at room temperature for 1 h. The clear, brown solution was concentrated and the residue was taken up in H ₂ O. The aqueous solution was neutralized with 10% hydrochloric acid and extracted with ethyl acetate (2 ×). The combined organic extract was washed with saturated NaCl solution, dried over Na ₂ S0 ₄ and concentrated. The semi-solid residue was boiled (2 ×) with fert-butyl methyl ether and filtered. The clear, ethereal filtrate was concentrated and the solid residue was stirred with a little fert-butyl methyl ether, filtered off and dried. Additional reaction product could be obtained by separating the mother liquor by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / ethyl acetate 1 + 1). Mp 141 ° C

IR (ATR): 2928, 1610, 1544, 1509, 1412, 1314, 1222 (CF), 1104, 1005, 954, 865, 843, 816 cm ^"1

¹ H-NMR (CD ₃ OD): δ (ppm) 1, 28 (d, 6H, 6.1 Hz, 2 CH ₃ ), 2.63 (s, 3H, SCH ₃ ), 5.08- 5, 14 (m, 1H, methine-H), 6.76 (s, 1H, C ³ -H 2-iso-O-pyr), 6.88 (dd, 1H, 1, 4 / 5.4 Hz, C ⁵ - H 2-iso-O-Pyr), 7.10-7.19 (m, 2H, 4-F-Ph), 7.40-7.47 (m, 2H, 4-F-Ph), 7.95 (dd, 1H, 0.7 / 5.4 Hz, C ⁶ -H 2-iso-O-Pyr)

4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] -2-methoxypyridine (25d)

A solution of 24d (1.0 g; 3.3 mmol) and methyl iodide (5.6 g; 39 mmol) in methanol (50 mL) was stirred under reflux for 3 h. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was taken up in ethanol. The insoluble fraction was filtered off and the filtrate was concentrated. The residue was taken up in CH ₂ CI ₂ / EtOH (9 + 1). The insoluble fraction was filtered off and the filtrate was separated by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1). Mp 158 ° C IR (ATR): 1618, 1608, 1497, 1391, 1222 (CF), 1212, 1036, 835, 825 cm ^"1

¹ H-NMR (CD ₃ OD): δ (ppm) 2.67 (s, 3H, SCH ₃ ), 3.90 (s, 3H, OCH ₃ ), 6.87-6.89 (m, 1H, C ³ -H 2-MeO-Pyr), 6.98 (dd, 1H, 1.5 / 5.5 Hz, C ⁵ -H2-MeO-Pyr), 7.16-7.24 (m, 2H, 4-F-Ph), 7.46-7.53 (m, 2H, 4-F-Ph), 8.03 (dd, 1H, 0.7 / 5.5 Hz, C ⁶ -H 2-MeO pyr)

4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] -1H-pyridin-2-one (25e)

25e was the only reaction product in the treatment of 23d (8.8 g; 31 mmol) with potassium rhodanide in DMF at the boiling point analogously to the method described for 24a. Mp 314 ° C (decomposed). After cyclization to 1,3-dihydro-imidazolthione, the methyl group is transferred from the methoxy substituent to the nucleophilic sulfur atom of the thione with the formation of 2-methylsulfanyl-3H-imidazole on the one hand and 2-hydroxypyridine / 1H-pyridine-2- ons other hand.

IR (ATR): 1634 (Pyridon I), 1610, 1557 (Pyridon II), 1493, 1220 (CF), 968, 837, 800 cm ^"1

¹ H NMR (DMSO-de): δ (ppm) 2.61 (s, 3H, SCH ₃ ), 6.16 (bs, 1 H, C ³ -H pyridone), 6.34 (s, 1 H , C ⁵ -H pyridone), 7.25-7.33 (m, 3H, C ⁶ -H pyridone and 4-F-Ph), 7.46-7.53 (m, 2H, 4-F-Ph ), 11, 38 (bs, 1H, exchangeable, pyridone-NH), 12.71 (bs, 1 H, exchangeable, imidazole-NH)

Benzyl- {4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl} amine (25f)

According to General Method C, the title compound, starting from 25b (0.2 g; 0.7 mmol) and benzylamine (0.8 g; 7.5 mmol), was reacted for 5 hours at 160 ° C and separated by column chromatography (Al ₂ θ ₃ , CH ₂ CI ₂ / ethyl acetate 1 + 1) obtained. Mp 152 ° C (decomposed)

IR (ATR): 3234 (NH), 3006, 2916, 1601, 1583, 1501, 1451, 1432, 1353, 1225 (CF), -1074, 844, 813, 729, 695 cm ^{"1 1} H-NMR (CD ₃ OD): δ (ppm) 2.59 (s, 3H, CH ₃ ), 4.37 (s, 2H, CH ₂ ), 6.56-6.59 (m, 2H, C ³ - / C ⁵ -H 2-amino-pyr), 7.04-7.44 (m, 9H, Ph and 4-F-Ph), 7.83 (d, 1H, 5.6 Hz, C ⁶ -H 2-amino-pyr)

{4- [5- (4-Fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl> - (4-methoxybenzyl) amine (25g)

According to General Method C, the title compound was prepared from 25b (0.44 g; 1.5 mmol) and 4-methoxybenzylamine (2.0 g; 14.6 mmol) after 7 hours of reaction at 160 ° C and separation by column chromatography ( Si0 ₂ , CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 207 ° C

IR (ATR): 1598, 1558, 1510, 1244, 1217 (CF), 846, 812 cm ^"1

¹ H-NMR (CD ₃ OD): δ (ppm) 2.61 (s, 3H, SCH ₃ ), 3.75 (s, 3H, OCH ₃ ), 4.30 (s, 2H, CH ₂ ), 6.56-6.59 (m, 2H, C ³ - / C ⁵ -H 2-amino-pyr), 6.81-7.30 (m, 6H, 4-MeO-Ph and 4- F-Ph ), 7.39-7.46 (m, 2H, 4-F-Ph), 7.84 (d, 1H, 6.0 Hz, C ⁶ -H 2-amino-pyr)

{4- [5- (4-Fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl} - (4-methylbenzyl) amine (25h)

According to General Method C, the title compound, starting from 25b (0.2 g; 0.7 mmol) and 4-methylbenzylamine (0.85 g; 7.0 mmol), was reacted for 6 hours at 160 ° C. and subjected to column chromatography Separation (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 185 ° C

IR (ATR): 1600, 1559, 1502, 1427, 1218 (CF), 844, 809 cm ^"1

¹ H-NMR (CD ₃ OD): δ (ppm) 2.29 (s, 3H, CH3), 2.60 (s, 3H, SCH3), 4.32 (s, 2H, CH2), 6.57-6.60 (m, 2H, C3 - / C5-H 2-amino-pyr), 7.05-7.50 (m, 8H, 4-Me-Ph and 4-F-Ph), 7.83 (d, 1 H, 5.3 Hz, C6-H2-amino-pyr ) (4-chlorobenzyl) - {4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridine -2-yl} amine (25i)

According to general method C, the title compound was started from 25b (0.2 g; 0.7 mmol) and 4-chlorobenzylamine (1.0 g; 7.0 mmol) after 5.5 hours of reaction under reflux and column chromatography separation ( Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 195 ° C

IR (ATR): 3409, 1597, 1549, 1502, 1489, 1422, 1218 (CF), 843, 814, 793 cm ^"1

¹ H-NMR (CD ₃ OD): δ (ppm) 2.60 (s, 3H, SCH ₃ ), 4.38 (s, 2H, CH ₂ ), 6.57-6.60 (m, 2H, C ³ - / C ⁵ -H 2-amino-pyr), 7.05-7.14 (m, 2H, 4-F-Ph), 7.22-7.30 (m, 4H, 4-CI- Ph), 7.38- 7.45 (m, 2H, 4-F-Ph), 7.83 (d, 1H, 5.7 Hz, C ⁶ -H 2-amino-pyr)

(3,4-dichlorobenzyl) - {4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl} amine (25j)

According to General Method C, the title compound was prepared from 25b (0.2 g; 0.7 mmol) and 3,4-dichlorobenzylamine (1, 2 g; 6.8 mmol) after a reaction at 160 ° C. for 7.5 hours and column chromatography separation (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 212 ° C

IR (ATR): 3409, 1600, 1552, 1509, 1490, 1424, 1225 (CF), 842, 827, 813 cm ^"1

¹ H-NMR (CD ₃ OD): δ (ppm) 2.60 (s, 3H, SCH ₃ ), 4.39 (s, 2H, CH ₂ ), 6.56-6.62 (m, 2H, C ³ - / C ⁵ -H 2-amino-pyr), 7.06-7.50 (m, 7H, 3,4-di-CI-Ph and 4-F-Ph), 7.84 (d, 1H, 5.5 Hz, C ⁶ -H 2-amino-pyr)

{4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl} phenylamine (25k)

According to General Method C, the title compound, starting from 25b (0.2 g; 0.7 mmol) and aniline (0.65 g; 7.0 mmol), was reacted after 6 hours Reflux and column chromatography separation (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 228 ° C

IR (ATR): 3031, 1610, 1590, 1561, 1504, 1433, 1265, 1225 (C-F), 839, 827, 749, 695 cm 1

¹ H-NMR (DMSO-de): δ (ppm) 2.62 (s, 3H, CH ₃ ), 5.95-6.13 (m, 2H, C ³ - / C ⁵ -H2-amino-pyr ), 6.68-7.60 (m, 9H, Ph and 4-F-Ph), 7.97-8.01 (m, 1H, C ⁶ -H 2-amino-pyr), 8.99 ( bs, 1 H, exchangeable, anilino-NH), 12.68 (bs, 1H, exchangeable, imidazole-NH)

{4- [5- (4-fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl} phenylethylamine (251)

According to General Method C, the title compound was based on 25b (0.2 g; 0.7 mmol) and 2-phenylethylamine (0.85 g; 7.0 mmol) after 5.5 hours of reaction at 160 ° C and column chromatography Separation (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 99 ° C

IR (ATR): 3409, 1604, 1546, 1504, 1220 (C-F), 838, 813, 698 cm -1

¹ H NMR (CD ₃ OD): δ (ppm) 2.61 (s, 3H, SCH ₃ ), 2.81 (t, 2H, 7.7 Hz, NCH ₂ ), 3.41 (t, 2H) , 7.7 Hz, CH ₂ Ph), 6.55-6.57 (m, 2H, C ³ - / C ⁵ -H 2-amino-pyr), 7.08-7.26 (m, 7H, Ph and 4-F-Ph), 7.42-7.49 (m, 2H, 4-F-Ph), 7.82 (d, 1H, 6.1 Hz, C ⁶ -H 2-amino-pyr )

(RS) - {4- [5- (4-Fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl} - (1-phenylethyl) amine (25m).

According to general method C, the title compound was prepared from 25b (0.2 g; 0.7 mmol) and (RS) -1-phenylethylamine (0.80 g; 6.6 mmol) after 7 hours of reaction at 160 ° C and column chromatography separation (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 117-119 ° C

| R (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (CF), 1157, 838, 814, 699 cm ^{"1 1} H NMR (DMSO-de): δ (ppm) 1.37 (d, 3H, 5.5 Hz, CH ₃ ), 2.58 (s, 3H, SCH ₃ ), 4.82-5.03 (m, 1H, methine-H), 6.39-7.74 (m, 12H, Ph, 2-amino-pyr and 4-F-Ph), 12.57 (bs, 1H, exchangeable, NH)

(R) - {4- [5- (4-Fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl} - (1-phenylethyl) amine (25n)

According to general method C, the title compound was started from 25b (0.2 g; 0.7 mmol) and R) -I-phenylethylamine (0.80 g; 6.6 mmol) after 7 hours of reaction at 170 ° C. and column chromatography separation (Si0 ₂ 60, CH ₂ CI ₂ / ethyl acetate 1 + 1) obtained. Mp 117-119 ° C

IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (CF), 1157, 838, 814, 699 cm ^"1

¹ H NMR (CD ₃ OD): δ (ppm) 1.44 (d, 3H, 6.9 Hz, CH ₃ ), 2.59 (s, 3H, SCH ₃ ), 4.62-4.69 (m, 1 H, methine-H), 6.47-6.57 (m, 2H, C ³ - / C ⁵ -H2-amino-pyr), 7.05-7.42 (m, 9H, Ph and 4-F _: Ph), 7.80 (d, 1H, 5.5 Hz, C ⁶ -H 2-amino-pyr)

(S) - {4- [5- (4-Fluorophenyl) -2-methylsulfanyl-3H-imidazol-4-yl] pyridin-2-yl} - (1-phenylethyl) amine (25o)

According to General Method C, the title compound was prepared from 25b (0.2 g; 0.7 mmol) and (S) -1-phenylethylamine (0.80 g; 6.6 mmol) after reaction for 13 hours at 170 ° C and column chromatography separation (Si0 ₂ 60, CH ₂ CI ₂ / ethyl acetate 1 + 1) obtained. Mp 117-119 ° C

IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (CF), 1157, 838, 814, 699 cm ^"1

¹ H NMR (CD ₃ OD): δ (ppm) 1.44 (d, 3H, 6.9 Hz, CH ₃ ), 2.59 (s, 3H, SCH ₃ ), 4.62-4.69 (m, 1H, methine-H), 6.47-6.57 (m, 2H, C ³ - / C ⁵ -H2-amino-pyr), 7.05-7.42 (m, 9H, Ph and 4-F-Ph), 7.80 (dd, 1 H, 0.5 / 5.5 Hz, C ⁶ -H 2-amino-pyr) Benzyl- {4- [5- (4-fluorophenyl) -2-methyisulfanyl-3H-imidazol-4-yl] pyridin-2-yl} methylamine (25p)

According to General Method C, the title compound was prepared from 25b (0.2 g; 0.7 mmol) and N-methylbenzylamine (0.85 g; 7.0 mmol) after 7 hours of reaction at 180 ° C and two column chromatography separations (SiO ₂ 60, CH ₂ CI ₂ / ethyl acetate 1 + 1) obtained. Mp 79 ° C

IR (ATR): 2924, 1601, 1494, 1407, 1219 (CF), 837, 810, 730, 696 cm ^"1

¹ H-NMR (CD ₃ OD): δ (ppm) 2.60 (s, 3H, SCH ₃ ), 2.97 (s, 3H, NCH ₃ ), 4.64 (s, 2H, CH ₂ ), 6.64-6.66 (m, 2H, C ³ - / C ⁵ -H 2-amino-pyr), 7.02-7.45 (m, 9H, Ph and 4-F-Ph), 7, 96 (d, 1H, 5.0 Hz, C ⁶ -H 2-amino-pyr)

The compounds listed in Table 2 below were obtained by the above method:

Table 2:

E.g. drive VerName structure

25q (4-fluoro-phenyl) - {4- [5- (4-fluorophenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

25r (4-chlorophenyl) - {4- [5- (4-fluorophenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

25s {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} -m-tolylamines

Example 26

4- [2-benzylsulfanyl-5- (4-fluorophenyl) -3H-imidazol-4-yl] -2-chloropyridine (26a)

According to General Method A, the title compound was prepared from 24a (0.3 g; 1.0 mmol) and benzyl chloride (0.12 g; 1.0 mmol) after a reaction time of 6 hours and purification by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / EtOH 9 + 1) obtained. Mp 223 ° C

IR (ATR): 2939, 1591, 1530, 1505, 1233 (CF), 997, 838, 782, 700 cm ^"1

¹ H-NMR (DMSO-de): δ (ppm) 4.43 (s, 2H, CH ₂ ), 7.27-7.47 (m, 11 H, 2-CI-Pyr, Ph and 4-F -Ph), 8.26 (d, 1H, 5.2 Hz, C ⁶ -H 2-CI-Pyr), 12.94 (bs, 1H, exchangeable, NH)

4- [2-Benzylsulfanyl-5- (4-f luorphenyl) -3H-imidazol-4-yl] -2-fluoropyridine (26b)

According to General Method A, the title compound was prepared starting from 24b (5.1 g; 17.6 mmol) and benzyl bromide (9.2 g; 54 mmol) after a reaction time of 1.5 hours and separation by column chromatography (Al ₂ 0 ₃ , CH ₂ CI ₂ / ethyl acetate 1 + 1). Mp. 174 ° C

IR (ATR): 3028, 2948, 1611, 1496, 1413, 1228 (CF), 1203, 1003, 879, 838, 698 cm ^"1

¹ H NMR (DMSO-de): δ (ppm) 4.43 (s, 2H, CH ₂ ), 7.11 (s, 1H, C ³ -H 2-F-Pyr), 7.25-7 , 51 (m, 10H, C ⁵ -H 2-F-Pyr, Ph and 4-F-Ph), 8.10 (d, 1 H, 5.3 Hz, C ⁶ -H 2-F-Pyr) , 12.93 (bs, 1H, interchangeable, NH)

Benzyl- {4- [2-benzylsulfanyl-5- (4-fluorophenyl) -3H-imidazol-4-yl] pyridin-2-yI} - amine (26c)

According to General Method C, the title compound was prepared from 26b (0.2 g; 0.53 mmol) and benzylamine (0.60 g; 5.6 mmol) after 6 hours of reaction at 180 ° C and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / ethyl acetate 1 +1). Mp 185 ° C IR (ATR): 3407 (NH), 3025, 2855, 2713, 1599, 1550, 1489, 1356, 1220 (CF), 1155, 840, 814, 693 cm ^"1

1

H-NMR (CD ₃ OD): δ (ppm) 4.21 (s, 2H, NCH ₂ ), 4.38 (s, 2H, SCH ₂ ), 6.52-6.55 (m, 2H, C ³ - / C ⁵ -H 2-amino-pyr), 7.03-7.38 (m, 9H, Ph and 4-F-Ph), 7.83 (d, 1H, 5.7 Hz, C ⁶ -H 2-amino-pyr)

(RS) - {4- [2-Benzylsulfanyi-5- (4-fluorophenyl) -3H-imidazol-4-yl] pyridin-2-yl} - (1-phenylethyl) amine (26d)

According to General Method C, the title compound was obtained starting from 26b (0.2 g; 0.53 mmol) and (RS) -l-phenylethylamine (0.65 g; 5.4 mmol) after 15 hours of reaction at 150 ° C and column chromatography separation (Si0 ₂ 60, CH ₂ CI ₂ / ethyl acetate 1 + 1) obtained. Mp 145 ° C

IR (ATR): 3028, 1606, 1546, 1494, 1450, 1221 (C-F), 1157, 837, 813, 697 cm -1

¹ H NMR (CD3OD): δ (ppm) 1.44 (d, 3H, 6.8 Hz, CH ₃ ), 4.22 (s, 2H, CH ₂ ), 6.44-6.54 (m , 2H, C ³ - / C ⁵ -H 2-amino-pyr), 7.04-7.35 (m, 9H, Ph and 4-F-Ph), 7.80 (d, 1H, 5.4 Hz, C ⁶ -H 2-amino-pyr)

{4- [2-Benzylsulfanyl-5- (4-fluorophenyl) -3H-imidazol-4-yl] pyridin-2-yl} - (4-methoxybenzyl) amine (26e)

According to General Method C, the title compound, starting from 26a (0.2 g; 0.5 mmol) and 4-methoxybenzylamine (2.0 g; 14.6 mmol), was reacted for 22 hours under reflux and separated by column chromatography (Al ₂ 0 ₃ , CH ₂ CI ₂ / ethyl acetate 1 + 1) obtained. Mp 196-200 ° C

IR (ATR): 1605, 1574, 1507, 1245, 1225 (C-F), 843, 814, 698

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 4.29 (s, 2H isomers "A" + "B", NCH ₂ ), 4.35 (s, 2H "A" + "B", SCH2), 6.43-6.47 (m, 1 H "A" + 2H "B", C ⁵ -H "A" and C ³ - / C ⁵ -H "B" 2-amino-pyr), 6.65 (s, 1H "A", C ³ -H2-amino-pyr), 6.80-6.84 (m, 2H "A" + "B", 4-MeO-Ph), 7.14 -7.51 (m, 11 H "A" + "B", 4-MeO-Ph, Ph and 4-F-Ph), 7.79 (d, 1H "B", 5.4 Hz, C ⁶ -H 2- amino-pyr), 7.91 (d, 1H "A", 5.4 Hz, C ⁶ -H 2-amino-pyr), 12.67 (bs, 1 H, exchangeable, imidazole-NH ), Amino-NH not visible

4- [2-benzylsulfanyl-5- (4-fluorophenyl) -3H-imidazol-4yl] -2-methoxy-pyridine (26f)

A suspension of 25a (0.1 g; 0.25 mmol) in methanolic NaOCH ₃ solution (30%, 2 mL) was diluted with methanol (5 mL) and stirred under reflux for 13 h. The reaction mixture was diluted with H ₂ 0 and the aqueous solution extracted with CH ₂ CI ₂ (3 ^χ ). The combined organic extract was washed with saturated NaCl solution, dried over Na ₂ S0 ₄ and concentrated. The oily residue was purified by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / ethyl acetate 1 + 1).

¹ H-NMR (CDCI ₃ ): δ (ppm) 3.91 (s, 3H, OCH ₃ ), 4.29 (s, 2H, CH ₂ ), 6.91-6.95 (m, 1 H, 2-MeO-Pyr), 7.02-7.11 (m, 2H, 4-F-Ph), 7.27-7.38 (m, 7H, Ph and 4-F-Ph), 8.05 (d, 1H, 5.4 Hz, C ⁶ -H 2-MeO-Pyr), NH not visible

Example 27

2-chloro-4- [5- (4-fluorophenyl) -2- (4-methanesulfinyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridine (27a)

NaH (55-65%; 0.1 g; approx. 2 mmol) was added to a solution of 24a (0.31 g; 1.0 mmol) in absolute THF (15 mL). The initial charge was stirred for 5 min at room temperature and 4-methylsulfinyl-benzyl chloride (3, 0.19 g; 1, 0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The yellow-brown solution was diluted with H ₂ 0 and neutralized with 10% citric acid. The THF was removed and the aqueous solution extracted with ethyl acetate (2x). The combined organic extract was washed with saturated NaCl solution (2 ×), dried over Na ₂ S0 ₄ and concentrated. The solid residue was purified by column chromatography (SiQ ₂ 60, CH ₂ Cl ₂ / EtOH 9.5 + 0.5). Mp 179 ° C IR (ATR): 3049, 1592, 1505, 1374, 1224 (CF), 1086, 1030 (S = 0), 1014, 989, 839, 816, 781 cm ^"1 (C-Cl)

¹ H NMR (DMSO-d ₆ ): δ (ppm) 2.71 (s, 3H, CH ₃ ), 4.48 (s, 2H, CH ₂ ), 7.25-8.24 (m, 10H) , 2-CI-Pyr, 4-MeS (0) -Ph and 4-F-Ph), 8.26 (d, 1H, 5.3 Hz, C ⁶ -H 2-CI-Pyr), 12.94 (bs, 1H, interchangeable, NH)

2-fluoro-4- [5- (4-fluorophenyl) -2- (4-methanesulfinyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridine (27b)

According to general method A, the title compound was started from 24b (4.2 g; 14.5 mmol) and 3 (4.1 g; 22 mmol) after a reaction time of 2 hours and separation by column chromatography (1. Al ₂ 0 ₃ , CH ₂ CI ₂ / ethyl acetate 1 + 1, 2. Si0 ₂ 60, CH ₂ CI ₂ / Et0H 9 + 1) obtained. Mp 150 ° C

IR (ATR): 3061, 1610, 1506, 1408, 1227 (CF), 1030 (S = 0), 1016, 995, 978, 882, 839, 815 cm ^"1

¹ H-NMR (DMSO-de): δ (ppm) 2.71 (s, 3H, CH ₃ ), 4.49 (s, 2H, CH ₂ ), 7.10 (s, 1 H, C ³ - H2-F-Pyr), 7.30-7.37 (m, 3H, C ⁵ -H 2-F-Pyr and 4-F-Ph), 7.47-7.67 (m, 6H, 4- F-Ph and 4-MeS (0) -Ph), 8.11 (d, 1H, 4.8 Hz, C ⁶ -H 2-F-Pyr), 12.95 (bs, 1H, exchangeable, NH)

Benzyl- {4- [5- (4-fluorophenyl) -2- (4-methanesulfinyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridin-2-yl} amine (27c)

According to General Method C, the title compound was prepared starting from 27b (0.3 g; 0.68 mmol) and benzylamine (0.75 g; 7.0 mmol) after 7 hours of reaction at 170 ° C and separation by column chromatography (Si0 ₂ 60, CH ₂ CI ₂ / ethanol 19 + 1). Mp 149 ° C

IR (ATR): 3238, 3064, 1600, 1558, 1514, 1495, 1227 (CF), 1034 (S = 0), 1006, 982, 839, 814 cm ^{"1 1} H-NMR (CD3OD): δ (ppm) 2.70 (s, 3H, CH ₃ ), 4.21 (s, 2H, NCH ₂ ), 4.32 (s, 2H, SCH ₂ ), 6, 51-6.55 (m, 2H, C ³ - / C ⁵ -H 2-amino-pyr), 7.03-7.42 (m, 13H. Ph, 4-MeS (0) -Ph and 4- F-Ph), 7.82 (d, 1H, 5.5 Hz, C ⁶ -H 2-amino-pyr)

(RS) - {4- [5- (4-fluorophenyl) -2- (4-methanesulfinyl-benzylsulfanyl) -3H-imidazol-4-yl] pyridin-2-yl} - (1-phenylethyl) amine ( 27d)

According to general method C, the title compound was started from 27b (0.3 g; 0.68 mmol) and (ΗSJ-l-phenylethylamine (0.85 g; 7.0 mmol) after 10 hours of reaction at 170 ° C and column chromatographic separation (Si0 ₂ 60, CH ₂ CI ₂ / ethanol 9 + 1) obtained, mp. 193 ° C.

IR (ATR): 2967, 1606, 1547, 1502, 1221 (CF), 1085, 1031 (S = 0), 1014, 838, 814, 670 cm ^"1

¹ H NMR (CD ₃ OD): δ (ppm) 1.45 (d, 3H, 6.8 Hz, CH ₃ ), 2.67 (s, 3H, S (O) CH ₃ ), 4.28 (s, 2H, CH ₂ ), 4.62-4.73 (m, 1 H, methine-H), 6.42-6.53 (m, 2H, C ³ - / C ⁵ -H 2-amino -Pyr), 7.09-7.44 (m, 9H, Ph and 4-F-Ph),), 8.21 (d, 1H, 5.0 Hz, C ⁶ -H 2-F-Pyr ).

Table 3 below shows compounds which are obtained by process C (compound No. 31 but by process D):

Table 3: 1H NMR

M / 43166-PCT

M / 43166-PCT

Example 37a

Cyclohexyl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines (37a)

Starting from 2-fluoro-4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H-imidazol-4-yl] pyridine (1, 2 g, 4 mmol), previously gassed with argon in one 25 ml of a round-necked flask were weighed in, suspended in cyclohexylamine (3.97 g, 0.04 mol), covered with argon, and then heated in an oil bath heated to 160 ° C. under reflux of the amine. The brown suspension is allowed to cool to RT. Then 30 ml Na citrate solution (10% citric acid solution pH 5 with conc. NaOH) are added, 10 min. stirred, extracted with twice 30 ml of ethyl acetate United organic phases are extracted twice with 30 ml of Na citrate solution (10% citric acid solution pH 5 with conc. NaOH) and then with 30 ml of NaHC0 ₃ solution and extracted once with saturated NaCI solution extracted. The organic phase is dried over Na ₂ SO ₄ and concentrated on a rotary evaporator, and the residue is crystallized from 10 ml.

The recrystallization takes place from isopropanol / water (heat approx. 5 ml ISOH, allow to cool, add slowly approx. 5 ml distilled water). Yield: 0.76 g (49.7%) with purity (HPLC) 96.6%.

The compounds of the formula I listed in Table 4 below were obtained by this method:

Table 4:

The compounds listed in Table 5 below were obtained by the above processes:

Table 5:

E.g. drive VerName structure

38 4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H-imidazol-4-yl] pyridin-2-yl amines

39 methyl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

40 ethyl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

41 isopropyl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

Methoxy-ethyl- {4- [5- (4-fluorophenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

N, N-Dimethylamino-ethyl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

Hydroxypropyl- {4- [5- (4-fluorophenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

N '- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} -N, N-diphenylethane-

1, 2-diamine -

Cinnamyl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] - pyhdin-2-yl} amine -

Cyclopropyl- {4- [5- (4-fluoro-phenyl) -

2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

Cyclopropylmethyl- {4- [5- (4-fluorophenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

Cycloheptyl {4- [5- (4-fluoro-phenyl) -

2-methylsulfanyl-1 H-imidazol-4-yl] pyridin-2-yl} amines

Bicyclo [2.2.1] hept-2-yl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

Adamantan-1-yl- {4- [5- (4-fluorophenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

Adamantan-2-yl- {4- [5- (4-fluorophenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

{4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] - pyridin-2-yl} - (tetrahydro-furan-3-yl) - amine-

{4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} - (tetrahydro-pyran-4-yl) amines

(1-ethyl-pyrrolidin-2-ylmethyl) - {4- [5-

(4-fluoro-phenyl) -2-methylsulfanyl

1 H-imidazol-4-yl] pyridin-2-yl} amines

H [1- (5-chlorothiophen-2-yl) ethyl] -

{4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amines

{4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} thiophene-3-ylmethylamine

Benzo [b] thiophen-2-ylmethyl- {4- [5-

(4-fluoro-phenyl) -2-methylsulfanyl

1 H-imidazol-4-yl] pyridin-2-yl} amines

Benzofuran-2-ylmethyl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

H (1-Benzofuran-2-yl-ethyl) - {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

(2,3-Dihydro-benzofuran-2-ylmethyl) - {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} amine

{4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} oxazol-2-ylmethylamines 77 Benzooxazol-2-ylmethyl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

78 2 - ({4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] - pyridin-2-ylamino} -methyl) -4- isopropyloxazol-5- oil

79 N- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} -N '- (2-methylsulfanyl-vinyl) formamidines

80 N- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} -N '- (1-methyl-2-methylsulfanyl- propenyl) - formamidine

81 N- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} -N '- (2-methylsulfanylphenyl) formamidines

82 {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} - (2-methylthiazol-5-ylmethyl) amine

83 {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} - (2-methylthiazol-4-ylmethyl) amine 84 {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} - [2- (2-methyleneamino-phenylsulfanyl) ethyl] - amine

85 B 2-Bromo-4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridine

86 2-Azido-4- [5- (4-fluoro-phenyl) -2-methylsulfane-1 H -imidazol-4-yl] pyridine

87 D 2-ethoxy-4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridine

88 4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] -2- p-tolyloxypyridine

89 2- (2,6-dichloro-phenoxy) -4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridine

90 D 2-benzyloxy-4- [5- (4-fluoro-phenyl) -

2-methylsulfanyl-1 H-imidazol-4-ylj-pyridine

91 D 4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] -2-phenethyloxypyridine

92 D 2-Cyclohexyloxy-4- [5- (4-fluorophenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridine

93 4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] -2- (tetrahydro-furan-3-yloxy) pyridine

94 D 6- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yloxy} hexahydro-furo [3,2-bjfuran-3- oil

95 4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] -2-

(tetrahydro-f u ran-2-yl methoxy) pyridine

96 4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] -2-

(tetrahydro-pyran-2-ylmethoxy) pyridine

97 2- (Benzofuran-2-ylmethoxy) -4- [5-

(4-fluoro-phenyl) -2-methylsu! Fanyl-

1 H-imidazol-4-yl] pyridine

98 4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] -2-

(Furan-2-ylmethoxy) -pyridine

99 4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] -2-

(Thiophen-2-ylmethoxy) -pyridine

100 4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] -2-

(5-chloro-thiophene-2-ylmethoxy) pyridine

101 4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] -2-

(thiophene-3-ylmethoxy) pyridine -

102 4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] -2-

(Thiazol-2-ylmethoxy) -pyridine

103 Bicyclo [2.2.1] hept-2-yl- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} amines

104 3- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yloxy} -1-azabicyclo [2.2.2] octane

4- [5- (4-Fluoro-phenyl) -2-

105 methylsulfanyl-1H-imidazol-4-yl] -2-methylsulfanyl-pyridines

106 2-benzenesulfonyl-4- [5- (4-fluorophenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridine

107 4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] -2-phenylsulfanyl-pyridine

108 2-ethylsulfanyl-4- [5- (4-fluorophenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridine

109 2- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-ylsulfanyl} ethanol

110 3- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-ylsulfanyl} propan-1-ol

110a N- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} formamides

111 N- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} benzamides

112 4-chloro-N- {4- [5- (4-fluoro-phenyl) -

2-methylsulfanyl-1 H-imidazol-4-yl] pyridin-2-yl} benzamides

120 2- (4-Fluoro-phenyl) -N- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} acetamide

121 2- (2-Fluoro-phenyl) -N- {4- [5- (4-fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} acetamide

122 N- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1H-imidazol-4-yl] pyridin-2-yl} -3-phenyl-propionamide

123 N- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} -3-phenyl-acrylamides

124 {4_ [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} -carbamic acid benzyl ester

125 1-benzoyl-3- {4- [5- (4-fluoro-phenyl)

-2-methylsulfanyl-1 H-imidazol-4-yl]

pyridin-2-yl} -urea

126 N- {4- [5- (4-Fluoro-phenyl) -2-methylsulfanyl-1 H -imidazol-4-yl] pyridin-2-yl} acetamide

Claims

2-thio-substituted midazole derivatives of the formula

wherein

R ^{1 represents} Ci-Cβ-alkyl, C ₃ -C -cycloalkyl or aryl, which may be replaced by a halogen atom, C ^ C _ö -Alky! or halogen-CrCβ-alkyl is substituted;

R is selected under

c) aryl-C 1 -C ₄ -alkyl, where the aryl radical may have one, two or three substituents which are selected independently of one another from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen, dC ₆ - alkylsulfanyl, -C ₆ alkyl sulfinyl, C ₆ alkyl sulfonyl and hydroxy, and

d) -CC ₆ alkyl, which is optionally substituted by CN or halogen;

R ^{d is} selected under a) NR ⁴ R ¹⁰ ;

b) NR ⁷ COR ¹⁰ ;

c) NR ⁷ COOR ¹⁰ ;

d) NR ⁷ CONR ⁷ R ¹⁰ ;

e) NR ⁷ CONR ⁷ COR ¹⁰ ;

f) OR ¹⁰ ;

g) S (0) _m R ¹⁰

h) halogen;

i) OH;

j) N ₃

k) NH ₂

I) SH;

wherein R ^{3 is} not OH, halogen, -C ₆ alkylthio or CC ₆ alkoxy, if

R ^{2 represents} phenyl-C 1 -C ₄ alkyl and the phenyl radical has a C ₆ -C ₆ -alkylsulfanyl, d-Ce-alkylsulfinyl or C ₁ -C ₆ -alkylsulfonyl substituent;

R ^{4 represents} H or a physiologically removable group,

R ⁵ and R ⁶ , which may be the same or different, are H, halogen, OH, C Ce-alkoxy, CC ₆ -alkyl, halogen-d-Ce-alkyl, d-Ce-alkylsulfanyl, NH ₂ , d-Ge - Alkylamino or di-d-Cβ-alkylamino; R ^{7 represents} R ⁴ , Ci-Ce alkyl or benzyl;

R ^{10 has} one of the following meanings:

a) A - B

f) Ci-Ce alkyl which is substituted with 2 or 3 phenyl groups;

g) trifluoromethyl

A represents straight-chain or branched Ci-Cβ-alkylene, C ₂ -C ₆ -alkenylene or C ₃ -alkynylene;

B is selected under

a) H

b) Φ \ V ^ ^ ^R5

\ = φ- \ R ⁶

f) OCι-C ₆ alkyl; g) NR ¹¹ R ¹² ; h) OH;

0 halogen; j) Ci-Ce alkylsulfanyl

R ¹¹ and R ¹² , which may be the same or different, represent H, Ci-Ce-alkyl or phenyl;

5 Hy stands for a 3- to 10-membered non-aromatic mono-, bi- or tricyclic carbocycle which can optionally be fused with a benzene ring);

Ar represents a 5- or 6-membered aromatic heterocycle which has 1, 2, 10 or 3 heteroatoms which are independently selected from 0, S and N and which can optionally be fused with a benzene ring;

Het represents a 5- or 6-membered non-aromatic heterocycle which has 15 1, 2 or 3 heteroatoms which are selected independently of one another from O, S and N, which may optionally be fused with a benzene ring or which may also be bicyclic or can be bridged tricyclic; m represents 0.1 or 2; n for 1,

2,

3,

4 or 5;

5 2. Compounds according to claim 1 of formula I.

wherein

R ^{1 represents} -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or aryl, which is optionally substituted by a halogen atom;

ι R ^{2 is} selected under

e) aryl-C 1 -C ₄ -alkyl, where the aryl radical may have one, two or three substituents, which are selected independently of one another from C ₁ -C 7 -alkyl, d-Ce-alkoxy, halogen, C ₁ -C ₆ - Alkylsulfanyl, dC ₆ -alkylsulfinyl, -CC ₆ -alkylsulfonyl and hydroxy-, and

20 b) CrC ₆ alkyl, which is optionally substituted by CN; and

c) C ₃ -C ₇ cycloalkyl;

>

R ^{3 is} selected from

25 a) NR ⁴ R ¹⁰

b) NR ⁷ COR ¹⁰ ,

30 a) halogen and

b) d-Ce alkoxy,

c) Ci-Ce alkylthio where R ^{3 is} not OH, halogen Ci-Ce-alkylthio or Ci-Ce-alkoxy if R ^{2 is} phenyl -CC-C ₄ -alkyl and the phenyl radical is a dC ₆ -alkylsulfanyl-, Ci-Ce-alkylsulfinyl- or C ₁ -C ₆ alkylsulfonyl substituent;

R ^{4 represents} H;

or if R ^{3 stands} for NR ⁷ COR ^10, stands for R ⁸ ,

R ⁵ and R ⁶ , which may be the same or different, represent H, halogen, Ci-Ce alkoxy or -CC ₆ alkyl;

R ^{7 represents} H, Ci-Ce alkyl or benzyl;

R ^{8 represents} C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or phenyl, where the phenyl group can have one or two substituents which are selected independently of one another from C ₁ -C ₄ alkyl, dd-alkoxy and halogen;

A represents straight-chain or branched Ci-Cβ-alkylene, Ca-Cβ-alkenylene or C ₃ - alkinylene and

m represents 0.1 or 2.

and the tautomers, optical isomers and physiologically acceptable salts thereof. Compounds according to claim 1 or 2 of the formula la

wherein R »1, C RD2, R and m have the meanings given in claim 1.

Compounds according to claim 1 or 2, wherein R ^{3 is}

is where A, R ⁵ and R ^{6 have} the meanings given in claim 1.

Compounds according to claim 1 of formula I, wherein R ^{10 is} one of the following

Leftovers stands: a)

- ^A

wherein Ar represents a 5- or 6-membered aromatic heterocycle which has a heteroatom which is selected from N, O and S; A stands for C1-C3-alkylene and can be substituted with a phenyl radical and R ⁵ and R ⁶ stand for H;

b)

where Het is a 5- or 6-membered, non-aromatic heterocycle which has an O- or N-heteroatom; A is dC ₃ alkylene and R ⁵ and R ^{6 are} H;

c)

L0 where A is dC ₆ alkylene; R ⁵ and R ^{6 are} H and Hy is cyclopentyl or cyclohexyl;

d) cyclopentyl or cyclohexyl;

15

e) phenyl-CrC ₆ -alkyl, where the alkyl radical can have an additional phenyl substituent; and )

20 f) C ₂ -C ₆ alkenyl which is substituted by phenyl.

6. Compounds according to claim 1 of formula I, wherein R ^{3 is} AB and B is selected from NR ¹¹ R ¹² , OCι-C ₆ alkyl and OH and A, R ¹¹ and R ^{12 have} the meanings given in claim 1.

25

7. Compounds according to claim 1 of formula I, wherein R ^{3 is} NR ⁷ COR ⁸ , wherein R ^{8 is} selected from -0-dC ₄ -alkylphenyl, phenyl and C ₂ -C ₆ -alkenyl which is substituted by phenyl.

8. Compounds according to any one of the preceding claims, wherein A is CrC ₂ alkylene.

9. Compounds according to any one of the preceding claims, wherein A is ethylidene.

10. Compounds according to any one of the preceding claims, wherein R ⁵ and R ^{6 are} H.

11. Compounds according to any one of the preceding claims, wherein R ^{1 is} halogen-substituted phenyl, CF3-substituted phenyl or Ci-Cβ-alkyl-substituted phenyl.

12. Compounds according to any one of the preceding claims, wherein R ^{2 is} benzyl or Ci-Ce-alkyl.

13. Pharmaceutical composition containing at least one compound according to one of claims 1 to 12, optionally together with one or more pharmaceutically acceptable carriers and / or additives.

14. Use of at least one compound according to one of claims 1 to 12 for the manufacture of a pharmaceutical composition for the treatment of diseases which are associated with a disorder of the immune system.

15. A method for the treatment of diseases which are associated with a disorder of the immune system, wherein a person in need of such treatment has an immunomodulating effect and / or the cytokine release-inhibiting amount of a compound of formula I according to any one of claims 1 to 12 administered.