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Definitions

• 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.
• 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.
• 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.
• the object of the invention is to provide such connections.
• the present invention therefore relates to the 2-thio-substituted imidazole derivatives of the formula I.
• 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
• 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- ⁇ -C 6 alkylsulfonyl and hydroxy-, and
• R ° is selected under
• 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-C ⁇ -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
• 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;
• n 1, 2, 3, 4 or 5; and the tautomers, optical isomers and physiologically acceptable salts thereof.
• the invention encompasses both tautomeric forms.
• the invention also encompasses the physiologically tolerated salts of the compounds of the formula I.
• these are in particular acid addition salts.
• 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.
• 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
• CrC 6 - alkylene isoamyi, neopentyl and n-hexyl.
• 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.
• substituted carbocycles are methylcyclopropyl or methylcyclohexyl. Unsubstituted radicals are preferred.
• aryl encompasses aromatic ring systems such as phenyl or naphthyl.
• halogen stands for a fluorine, chlorine, bromine or iodine atom, in particular a fluorine or chlorine atom.
• 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.
• 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-C ⁇ -alkyl. Unsubstituted radicals are preferred.
• R 5 and R 6 are preferably and independently of one another H, halogen or CrCe-alkyl.
• 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 CrC ⁇ -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-C ⁇ -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-C ⁇ -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
• 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
• R 10 is cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl or cycloheptyl;
• R 10 is d-Ce-alkyl, in particular methyl, ethyl or isopropyl, or 3,3-diphenylpropyl or 1,3-diphenylprop-2-yl;
• 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
• 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:
• 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.
• 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;
• thienyl 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.
• NH-d-Ce alkyl which is substituted by 2 or 3 phenyl groups, e.g. B. 3,3-diphenylpropylamino, 1,3-diphenylprop-2-ylamino;
• R 10 is C 3 -C 6 cycloalkyl
• R 10 is C 3 -C 6 cycloalkyl-CrC 4 alkyl, e.g. B. cyclopentylmethyl, cyclohexylmethyl;
• 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.
• 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 .
• 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-
• 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.
• the IVa is converted into the oxime (Va) by treatment with ammonium chloride / sodium acetate in an alcoholic solvent, such as methanol.
• the Thion Compound (IIIa) is obtained from the tosylate by treatment with sodium ethylate and reaction of the azirene intermediate formed with potassium thiocyanate.
• suitable solvents such as hydrocarbons, ethers and their mixtures (e.g. hexane, tetrahydrofuran, ethylene glycol dimethyl ether), lithiated with lithium diisopropylamide (LDA) in the ⁇ -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 ⁇ -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 ⁇ -picolyl position.
• the reaction of the ⁇ -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).
• 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.
• 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.
• 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.
• process B starting from appropriately substituted picolines
• process C starting from the 4 (5) - (2-halopyridin-4-yl) - substituted 2-thioimidazoles.
• R 3 represents an alkoxy substituent
• Thioimidazoles can be produced.
• the starting compounds (lb) can be prepared by the processes described above.
• 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 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.
• 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
• 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- ⁇ 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.
• 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.
• IBD inflammatory bowel disease Disease
• 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.
• 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).
• binders for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone
• fillers for example lactose, sugar, corn starch
• lubricants e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide
• 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.
• mammals humans or animals
• 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-w ⁇ o test procedure with whole human blood
• Samples from human potassium EDTA whole blood (400 ⁇ l 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 ⁇ g / 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 TNF ⁇ in the plasma supernatant is then determined by means of ELISA.
• Mono-nuclear cells are made from 1: 3 diluted human potassium EDTA whole blood using density gradient centrifugation (Histopaque®-1,077)
• PBMCs peripheral blood mononuclear cells
• the PBMCs suspension obtained (390 ⁇ l 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 ⁇ l / 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-1 ⁇ and TNF ⁇ in the plasma supernatant is then determined by means of ELISA.
• Micro-titer plates were coated with 50 ⁇ l ATF2 solution (20 ⁇ g / ml) for one hour at 37 ° C. After washing three times with water, 50 ⁇ l of kinase mixture (50 mM tris-HCl 10 mM MgCfe, 10 mM ⁇ -glycerol phosphate, 10 ⁇ g / ml BSA, 1 mM DTT, 100 ⁇ M ATP, 100 ⁇ M Na 3 V0 4 , 10 activated p38 ⁇ ) 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.
• kinase mixture 50 mM tris-HCl 10 mM MgCfe, 10 mM ⁇ -glycerol phosphate, 10 ⁇ g / ml BSA, 1 mM DTT, 100 ⁇ M ATP, 100
• 5a was prepared starting from methyl salicylic acid (10.0 g; 65.7 mmol) according to the method described in the synthesis of 5c.
• 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.
• 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.
• 7a was prepared from 5a (10.0 g; 40.0 mmol) according to the method described in the synthesis of 7c.
• 7b was prepared from 5b (13.0 g; 45.6 mmol) according to the method described in the synthesis of 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 .
• 8a was prepared starting from 7a (1.5 g; 8.1 mmol) according to the method described in the synthesis of 8c.
• 8b was prepared from 7b (2.2 g; 10.1 mmol) according to the method described in the synthesis of 8c.
• 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.
• the title compound was obtained as a by-product in the synthesis of 8a.
• 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.
• 11a was prepared starting from 10a (12.0 g; 0.05 mol) according to the method described in the synthesis of 11b.
• 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).
• 12b was prepared from 11b (2.0 g; 10.0 mmol) using the method described in the synthesis of 12a. Mp: 46 ° 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.
• 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
• 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.
• 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.
• 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
• 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
• 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.
• 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
• 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
• 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
• 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
• 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.
• 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.
• 21c was prepared from 2-bromo-4-methyl-pyridine (9.6 g; 56 mmol) according to the method described in the synthesis of 21a.
• 22b was prepared from 21b (10.0 g; 43 mmol) using the method described in the synthesis of 22a.
• 22d was prepared from 21c (5.0 g; 17 mmol) using the method described in the synthesis of 22a.
• 23c was prepared from 22c (2.0 g; 7.6 mmol) using the method described in the synthesis of 23a.
• 23d was formed by treating 22b (7.5 g; 29 mmol) under the conditions described in the synthesis of 23a.
• 23e was formed by treating 22c (4.0 g; 12.4 mmol) under the conditions described in the synthesis of 23b.
• 24c was prepared from 23c (2.5 g; 7.6 mmol) using the method described in the synthesis of 24a.
• 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
• 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.
• 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.
• 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
• 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

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