DE19541146A1 - Imidazole derivatives and their use as nitric oxide synthase inhibitors - Google Patents

Abstract

The invention relates to the compounds of the formula (I), and to the preparation and use thereof in drugs.

Description

The invention relates to substituted phenylimidazole derivatives and pyridylimidazole derivatives as well as their manufacture and use in pharmaceuticals, in particular their use as nitric oxide synthase inhibitors.

It is known that one of the enzymes with a hemoglobin group in the active center Belongs to nitric oxide synthase (NOS) and that phenylimidazole binds to this.

It has now been found that the affinity of imidazole derivatives to NOS in not can be increased in a predictable manner if they carry suitable substituents. Man contains compounds which selectively in very low concentrations (IC₅₀) the inducible, inhibit human nitric oxide synthase (hiNOS) and with excellent effectiveness in vivo.

The selective nitric oxide synthase inhibitors are suitable as drugs for Treating central nervous system diseases such as multiple sclerosis in all Course forms, Alzheimer's disease, HIV dementia, amyotrophic lateral sclerosis and comparable sclerotic diseases, cerebral ischemia, and others neurodegenerative diseases. They are also suitable for treating diseases such as sepsis or septic shock, hypotension, ARDS (adult respiratory distress syndrome), for the treatment of autoimmune and / or inflammatory diseases such as rheumatoid arthritis, osteoarthritis, insulin dependent diabetes mellitus (IDDM), inflammatory disease of the pelvis / bowel (bowel disease), meningitis, Glomerulonephritis, acute and chronic liver diseases, diseases caused by Rejection (for example, for immunosuppression in transplants such as allogeneic Heart, kidney or liver transplants) or inflammatory skin diseases such as Psoriasis.

The invention relates to the new compounds of the formula I.

wherein
AR² can be the same or different one or two times,
R¹ is hydrogen, halogen, -SH or -SC _1-4 -alkyl,
Z nitrogen or -CH = optionally substituted by AR² or R³,
A is a bond, straight-chain or branched C _1-4 -alkylene, straight-chain or branched C _2-4 -alkenylene, straight-chain or branched C _2-4 -alkynylene,
R² is hydrogen, halogen, NO₂, -C≡N, CF₃, -CCl₃, -S (O) _m -C _1-4 -alkyl, -OR⁵, -S-R⁶, -CO-R⁷, -NR⁸R⁹, -CH ( CN) -COOH, -CH (CN) -COO-C _1-6 -alkyl, = C (CN) -COOH, = C (CN) -COOC _1-6 -alkyl, -NH-SO₂-R¹⁰, -C (NH₂) = NOH, imidazol-1-yl, 4-CH₃-thiazol- 2-yl, -NH-CO-NH₂, -NH-CS-NH₂, NH-CO-NH (C _1-4 -alkyl), -NH-CS-NH (C _1-4 -alkyl), pyrrol-1-yl, -C (= NR) -NHR¹¹, -NH-C (= NR) -NR¹¹R¹², -S- (C = NR) - NR¹¹R¹², a phenyl or biphenyl radical optionally substituted one or more times with halogen, -SC _1-4 -alkyl or -OC _{1-4 -alkyl, pyridyl, imidazolosulfonyl,}
R³ is hydrogen, halogen, NO₂, OH, NH₂ or imidazol-1-yl,
AR² and R³ together form -O- (CH₂) _n -O-,
m, n 1 or 2,
R⁵ is hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 carbon atoms, which can contain 1-2 double and / or triple bonds and in which a -CH₂ group is replaced by oxygen, sulfur, phenyl or _{C 3-6} cycloalkyl optionally substituted with methyl or halogen can be replaced, C _3-7 cycloalkyl optionally substituted with methyl or halogen, -CO-R¹⁵, -CS-NH (C _1-4 -alkyl), -CH ( NH₂) -COO _1-6 -alkyl, -Si (CH₃) ₂ tert. butyl, quinolin-yl, N1-methyl-imidazol-2-yl, thiophenyl, thiacyclohexyl, tetrahydrofuranyl, -CS-SC _1-4 -alkyl, -CS-CH₂-SC _1-4 -alkyl, -C (= NR) NR¹¹R¹², optionally with halogen, NO₂, C _1-4 -alkylthio, C _1-4 -alkoxy or C _1-4 -alkyl substituted phenyl, tetrahydropyrimidine, tetrahydropyridine,
R⁶ has the meaning of R⁵,
R⁷ hydrogen, C _1-8 -alkyl, C _3-7 -cycloalkyl, -CH₂-SC _1-4 -alkyl, - (CH₂) ₂-SC _1-4 -alkyl, -OC _1-6 -alkyl, NH₂, NH (C _1-4 -alkyl), N (C _1-4 -alkyl) ₂, -SC _1-4 -alkyl, CF₃, -C₂F₅, OH, phenyl,
R⁸, R⁹ are identical or different and are hydrogen, C _1-4 -alkyl, C _1-4 -alkanoyl or, together with the nitrogen atom, form a 5- to 6-membered saturated heterocycle which has a further O-, N- or S- Contain atom and can be substituted 1-2 times with C _{1-4 -alkyl,}
R¹⁰, R¹¹, R¹² and R are hydrogen, C _1-6 -alkyl, C _3-7 -cycloalkyl, phenyl,
R¹⁵ optionally substituted with halogen, NH₂, C≡N, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkanoyloxy, thiophene or phenyl substituted C _1-17 alkyl, optionally substituted with CH₃ or phenyl C _3-7 cycloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, -COOH, -COOC _1-6 alkyl, NR¹³R¹⁴,
R¹³, R¹⁴ are identical or different and are hydrogen or optionally halogen-substituted C _1-4 -alkyl,
and their isomers and tautomers and physiologically acceptable salts, wherein

• (1) if R¹ and R³ are hydrogen and Z = -CH, -AR² in the 2-position cannot be H, OH; Cl, Br, CF₃, -CHO, -O-CO-CH₃, -CH₂-Br, -CH₂OH, - (CH₂) ₂-OH, (CH₂) ₂-Br, -CH = CH₂, -O-CH₂-CH = CH₂, -O-CH₂-C≡CH, -O-CH₂-CN, -SH, -CHOH-CH₃, -CH = CH- Be phenyl,
• (2) if in the 3-position of the pheny! Ring F, Cl, OH, CH₃ or NO₂, R¹, R³ and -AR² does not mean H or imidazole at the same time,
• (3) if R¹ = H and in the 4-position of the phenyl ring OCH₃, OH, NH₂, fluorine or CH₂-NH₂ is, cannot be H, OCH₃ or OH in the 2-position,
• (4) if R¹ = H and in the 2-position of the phenyl ring is NO₂, Br or OH, in 5- Position not be Cl or CH₃,
• (5) if R¹ = H and Z -CH =, R⁵ or R⁶ can not be optionally substituted benzyl be.

The compounds of formula I and formula IA also encompass the possible tautomeric ones Forms, the E or Z isomers or, if a chiral center is present, the racemates or enantiomers.

Inorganic and organic acids such as, for example, are suitable for salt formation Oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, Phosphoric acid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid and others.

The inorganic or organic bases are also suitable for salt formation Formation of physiologically compatible salts are known, such as alkali hydroxides, such as sodium and potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, Amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, tris- (hydroxymethyl) methylamine etc.

Straight-chain or branched alkylene with 1-4 carbon atoms contains z. B. Methylene, ethylene, propylene, butylene, 1-methylmethylene, 1-ethylmethylene, 1- Methylethylene, 1-ethylethylene, 1-methylpropylene, 1-propylmethylene, 2-methylpropylene and others.

Among straight-chain or branched alkenylene and alkynylene with 2-4 carbon atoms are alkenyl or alkynyl groups with 1-2 double and / or triple bonds in all possible positions as well as with all possible methyl or ethyl substitutions understand.

Alkyl means in each case a straight-chain or branched alkyl group such as. B. methyl, ethyl, Propyl, isopropyl, n-butyl, sec. Butyl, tert. Butyl, n-pentyl, sec. Pentyl, tert. Pentyl, Neopentyl, n-hexyl., Sec. Hexyl, heptyl, octyl, nonyl, decyl, 1-6 carbon atoms being preferred are.

As the hydrocarbon radical R⁵, alkyls, alkenyls and alkynyls come into consideration.

The alkenyl and alkynyl substituents are each straight-chain or branched and contain preferably 2-10 carbon atoms. For example, the following radicals may be mentioned: vinyl, 2- Propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2- Methyl-2-propenyl, 3-methyl-2-propenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- Butynyl.

In the hydrocarbon residue can be a -CH₂ group through the remainder

and / or by the cycloalkyl radical

with p = 0, 1, 2 or 3 and
X, Y = hydrogen or halogen.

Cycloalkyl is in each case cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or To understand cycloheptyl.

Halogen in each case means fluorine, chlorine, bromine or iodine.

The hydrocarbon radical R⁵ and R⁶ can be substituted at any point with up to 3 chlorine, 3 fluorine, bromine or iodine and / or once or twice with OH, -OC _1-4 -alkyl, -SH, -S- C _{1- 4-} alkyl, -NH (C _1-4 -alkyl), -N (C _1-4 -alkyl) ₂, -NH₂, -NH-CO- (CH2) ₂-SC _1-4 -alkyl, -NH- pyridin-2-yl, -C≡N, -COOH, CO-OC _1-6 -alkyl, CO-NH- (C _1-4 -alkyl), -CO-N- arginine, -CO-CH₃, tetrahydrofuranyl, 2,2-dimethyl-1,3-dioxolane, -S (O) _m -C _1-4 -alkyl, -NH-C (= NR) -NR¹¹R¹², -C (= NH) -NH₂, C (= NH ) -C _1-4 alkyl, -CH (NH₂) -COOH, -CH (NH2) -COOC _1-6 -alkyl, C _3-7 -cycloalkyl, NHSO₂R, phenyl, which is 1- to twice with halogen, NO₂ , -SH, -SC _1-4 -alkyl, -OC _1-4 -alkyl or phenyl, or a 5- or 6-membered heteroaryl radical containing 1-3 nitrogen atoms and / or 1-2 sulfur atoms and with C _1-4 alkyl can be substituted.

The alkyl, alkenyl and alkynyl radical R¹⁵ can be one to two times with the same or be substituted for different radicals or also be present in a permanent manner.

If R⁸, R⁹ together with the nitrogen atom form a 5- or 6-membered heterocycle which contains another O, N or S atom and can be monosubstituted or disubstituted _{with 1-2 C 1-4 -alkyl, so} come as heterocycles z. B. morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, N-methyl-piperazine or 2,6-dimethylmorpholine into consideration.

Examples of heteroaryl radicals that may be mentioned are: pyrazole, imidazole, thiophene, thiazole, Thiadiazole, pyridine, pyrimidine and triazine.

Compounds of the formula I which contain the -A-R² substituents in 2- or 4-position of the phenyl or in the 3- or 5-position of the pyridine.

The preferred meaning of -A-R² is straight-chain or branched alkylene with 1-8 C- Atoms, straight-chain or branched alkenylene with 2-8 carbon atoms, straight-chain or to consider branched alkynylene with 2-8 carbon atoms, one of the methylene groups can be replaced by oxygen or sulfur or by two methylene groups Oxygen and / or sulfur can be replaced. If a substituent R² is present, it stands this is preferably terminal.

The invention also relates to the use of substituted phenylimidazole derivatives and substituted pyridylimidazole derivatives, their isomeric and tautomeric forms and their Salts for the manufacture of a medicament for the treatment of diseases in which the Inhibition of nitric oxide synthase is beneficial.

According to the invention, the inhibitors of nitric oxide synthase are used Compounds of Formula IA

wherein
AR² can be the same or different one or two times,
R¹ is hydrogen, halogen, -SH or -SC _1-4 -alkyl,
Z nitrogen or -CH = optionally substituted by AR² or R³,
A is a bond, straight-chain or branched C _1-4 -alkylene, straight-chain or branched C _2-4 -alkenylene, straight-chain or branched C _2-4 -alkylene,
R² is hydrogen, halogen, NO₂, -C≡N, CF₃, -CCl₃, S (O) _m -C _1-4 -alkyl, -OR⁵, -S-R⁶, -CO-R⁷, -NR⁸R⁹, -CH (CN ) -COOH, -CH (CN) -COO-C _1-6 -alkyl, = C (CN) -COOH, = C (CN) -COOC _1-6 -alkyl, -NH-SO₂-R¹⁰, -C ( NH₂) = NOH, imidazol-1-yl, 4-CH₃-thiazol- 2-yl, -NH-CO-NH₂, -NH-CS-NH₂, NH-CO-NH (C _1-4 -alkyl), - NH-CS-NH (C _1-4 alkyl), pyrrol-1-yl, -C (= NR) -NHR 11, -NH-C (= NR) -NR 11 R 12, -S- (C = NR) -NR 11 R 12 , a phenyl or biphenyl radical optionally substituted one or more times with halogen, -SC _1-4 -alkyl or OC _{1-4 -alkyl, pyridyl, imidazolosulfonyl,}
R³ is hydrogen, halogen, NO₂, OH, NH₂ or imidazol-1-yl,
AR² and R³ together form -O- (CH₂) _n -O-,
m, n 1 or 2,
R⁵ is hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 carbon atoms, which can contain 1-2 double and / or triple bonds and in which a -CH₂ group is replaced by oxygen, sulfur, phenyl or _{C 3-6} cycloalkyl optionally substituted with methyl or halogen can be replaced, C _3-7 cycloalkyl optionally substituted with methyl or halogen, -CO-R¹⁵, -CS-NH (C _1-4 -alkyl), -CH ( NH₂) -COO _1-6 -alkyl, -Si (CH₃) ₂ tert. butyl, quinolin-yl, N1-methyl-imidazol-2-yl, thiophenyl, thiacyclohexyl, tetrahydrofuranyl, -CS-SC _1-4 -alkyl, -CS-CH₂-SC _1-4 -alkyl, -C (= NR) NR¹¹R¹², optionally with halogen, NO₂, C _1-4 -alkylthio, C _1-4 -alkoxy or C _1-4 -alkyl substituted phenyl, tetrahydropyrimidine, tetrahydropyridine,
R⁶ has the meaning of R⁵,
R⁷ hydrogen, C _1-8 -alkyl, C _3-7 -cycloalkyl, -CH₂-SC _1-4 -alkyl, - (CH₂) ₂-SC _1-4 -alkyl, -OC _1-6 -alkyl, NH₂, NH (C _1-4 -alkyl), -N (C _1-4 -alkyl) ₂, -SC _1-4 -alkyl, CF₃, -C₂F₅, OH, phenyl,
R⁸, R⁹ are identical or different and are hydrogen, C _1-4 -alkyl, C _1-4 -alkanoyl or, together with the nitrogen atom, form a 5- to 6-membered saturated heterocycle which has a further O-, N- or S- Contain atom and can be substituted 1-2 times with C _{1-4 -alkyl,}
R¹⁰, R¹¹, R¹² and R are hydrogen, C _1-6 -alkyl, C _3-7 -cycloalkyl, phenyl,
R¹⁵ optionally substituted with halogen, NH₂, -C≡N, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkanoyloxy, thiophene or phenyl substituted C _1-17 -alkyl, optionally with CH₃
or phenyl substituted C _3-7 cycloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, -COOH, -COOC _1-6 alkyl, NR¹³R¹⁴,
R¹³, R¹⁴ are identical or different and are hydrogen or optionally halogen-substituted C _1-4 -alkyl,
and their isomers and tautomers and physiologically acceptable salts,
in which
R¹, -A-R² and R³ do not mean hydrogen at the same time, for the manufacture of a medicament for the treatment of diseases caused by the action of nitric oxide in pathological concentrations.

The compounds of formula I and their physiologically acceptable salts are on Because of their affinity for and inhibition of the action of nitric oxide synthases and here in particular the inducible nitric oxide synthase as a drug usable. The compounds according to the invention are suitable on the basis of their active profile Used to treat diseases caused by excess nitric oxide in the body caused or intensified or under inducing and pathological conditions be aggravated.

These include multiple sclerosis, Alzheimer's disease, HIV dementia, and amyotrophs Lateral sclerosis and similar sclerotic diseases, and cerebral ischemia other neurodegenerative diseases associated with inflammation become. They are also suitable for treating diseases of the cardiovascular system such as sepsis or septic shock, ARDS (adult respiratory distress syndrome), rheumatoid arthritis, osteoarthritis, insulin-dependent diabetes mellitus (IDDM), inflammatory disease of the pelvis / bowel (bowel disease), meningitis, Glomerulonephritis, acute and chronic liver diseases, diseases caused by Rejection (e.g. allogeneic heart, kidney or liver transplants) or inflammatory skin diseases like psoriasis and others.

In order to use the compounds according to the invention as medicaments, they are described in the In the form of a pharmaceutical preparation, which in addition to the active ingredient for the enteral pharmaceutical, organic or inorganic inert ones suitable for parenteral administration Carrier materials such as water, gelatine, gum arabic, milk sugar, Contains starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be in solid form, for example as tablets, coated tablets, Suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions are present. If necessary, they also contain auxiliaries such as Preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffer.

For parenteral use, injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated Castor oil, suitable.

Surface-active auxiliaries such as salts of bile acids can also be used as carrier systems or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components are used.

Tablets, coated tablets or capsules with talc are particularly suitable for oral use and / or hydrocarbon carriers or binders, such as lectose, corn or Potato starch, suitable. It can also be used in liquid form, such as For example, as a juice to which a sweetener may be added.

The dosage of the active ingredients can vary depending on the route of administration, age and weight of the Patients, type and severity of the disease to be treated and similar factors vary ies. The daily dose is 1-2000 mg, preferably 20-500 mg, the dose being as Single dose to be administered once or divided into 2 or more daily doses can be.

The compound according to the invention is prepared according to known methods Methods. For example, compounds of the formula I are obtained by

• a) a compound of the formula II, wherein Z, AR² and R³ have the above meaning, and Flu represents a leaving group, in the presence of a base with imidazole optionally substituted with R¹,
  or
• b) a compound of the formula III wherein Z, R¹, AR² and R³ have the above meaning and Flu represents a leaving group, introduces nucleophilic AR² or R³ in the presence of a base,
• c) a compound of the formula IV wherein Z, R¹, R³ have the above meaning, by means of aldol reactions with malonitrile, malon derivatives or other alpha-CH acidic compounds or via Wittig reactions or modified Wittig reactions or by nucleophilic attack, for example with Grignard reagents, to form compounds of formula I and then, if desired, halogenated or, if necessary, selectively reduced or thioethers or ethers cleaved or nitriles saponified or acids esterified or amidated or ethers or esters synthesized from phenols or amino groups exchanged or boiled via the Sandmeyer reaction or sulfides oxidized to sulfones or sulfoxides or sulphoxides are reduced to sulphides or amines are converted to amides or sulphonamides or alkylated or decarboxylated or isomers or salts are formed.

Here, Flu can mean, for example, tosylate, mesylate, triflate, nonaflate or halogen. The aromatic is in the presence of bases at room temperature or elevated temperature in implemented aprotic solvents. In some places the implementation is facilitated or the Yield improved when copper or copper salts are added.

Alkaline compounds such as potassium carbonate, sodium hydroxide, Alkaline alcoholates such as potassium tertiary butylate and, in particular, metal hydrides such as Sodium hydride suitable. Sometimes the alkali compounds can also take Phase transfer conditions are implemented. If you get mixtures of compounds with the substituent imidazolyl-, (2'-R¹-imidazolyl-), -R² or -R³ in various numbers and or in different positions, these are separated in the usual way.

Suitable solvents for the reaction are aprotic polar solvents such as Dimethylformamide, N-methylpyrrolidone or DMSO.

The optionally subsequent saponification of an ester group can be basic or acidic take place by being at room temperature or elevated temperature up to the boiling point of the reaction mixture in the presence of alkali hydroxides in ethanol or others Alcohols or acids such as e.g. Hydrolyzed hydrochloric acid and possibly imidazolium salts further processed.

The esterification of the carboxylic acid takes place in a manner known per se with diazomethane or the corresponding alcohol in acid or in the presence of an activated acid derivative. As activated acid derivatives come, for example, acid chloride, imidazolide or anhydride Question.

The amidation takes place on the free acids or on their reactive derivatives as in for example acid chlorides, mixed anhydrides, imidazolides or azides Reaction with the corresponding amines at room temperature or elevated temperature.

In addition, a nitro group or halogen, especially bromine. This creates mixtures, the substituted imidazole can contain and are to be separated in the usual way. If a nitrile is present, it can be saponified by known processes or in the corresponding amine, tetrazole or Amidoxime are transferred.

The nitro group or optionally the cyano group is reduced to the amino group catalytically in polar solvents at room temperature or elevated temperature below Hydrogen pressure. The catalysts are metals such as Raney nickel or Noble metal catalysts such as palladium or platinum, optionally in the presence of Barium sulfate or suitable on carriers. Instead of hydrogen, ammonium formate can also be used in be used in a known manner. Reducing agents such as tin (II) chloride or titanium (III) chloride can be used as well as complex metal hydrides possibly in the presence of Heavy metal salts. It can be advantageous to introduce the ester group before the reduction. Nitro groups can also selectively in the usual way with Na₂S or sodium dithionite be reduced. Reduction with zinc in acetic acid has proven itself.

If an alkylation of an amino group is desired, customary methods can be used for example be alkylated with alkyl halides.

The introduction of the cyano group can take place with the aid of the Sandmeyer reaction; for example, those formed as intermediates from the amino compounds with nitrites can be used React diazonium salts with alkali metal cyanides in the presence of Cu-I-cyanide.

The introduction of the halogens chlorine, bromine or iodine via the amino group can, for example wise according to Sandmeyer, by using the intermediate formed with nitrites Diazonium salts with Cu (I) chloride or Cu (I) bromide in the presence of the corresponding acid such as hydrochloric acid or hydrobromic acid or reacts with potassium iodide.

The introduction of a NO₂ group succeeds through a number of known Nitration methods. For example, with nitronium tetrafluoroborate in inert -8- Solvents such as halogenated hydrocarbons or nitrated in sulfolane or glacial acetic acid become. It is also possible to introduce z. B. by nitrating acid in water or conc. Sulfuric acid as a solvent at temperatures between 0 ° C and 30 ° C.

Amidoxime is made from the corresponding nitrile with hydroxylamine hydrochloride, e.g. in alcohol-water mixtures as a solvent.

The activated sulfonic acid derivative such as the sulfonic acid chloride is reacted in the usual way with nucleophilic N-derivatives (such as H₂N (C _1-4 alkyl) or H₂N-CH₂CONH₂ or H₂N-CH₂-R).

The isomer mixtures can by customary methods such as crystallization, Chromatography or salt formation separated into the enantiomers or E / Z isomers become.

The salts are prepared in a customary manner by adding a solution of the compound of the formula I with the equivalent amount or an excess of an acid which is optionally in solution, are added and the precipitate is separated off or in a customary manner the solution worked up.

If the preparation of the starting compounds is not described, these are known or can be prepared analogously to known compounds or processes described here.

The following examples may show the structures according to the invention and their production. However, the compounds according to the invention are not limited to the examples mentioned limited.

New compounds have been characterized by one or more of the following methods:
Melting point, mass spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy (NMR). NMR spectra were measured with a Bruker 300 MHz device, the (deuterated) solvents are specified and abbreviated as follows: CDCl₃ (chloroform), DMSO (dimethyl sulfoxide). Shifts are given in delta and ppm. Furthermore: THF (tetrahydrofuran), DMF (N, N-dimethylformamide), NMP (N-methylpyrrolidone), EE (ethyl acetate). All solvents are PA quality, unless otherwise stated. All reactions are carried out under protective gas, unless they are aqueous solutions. It means:

mult. (Multiplet, several signals), s (singlet), d (doublet), dd (double doublet etc.), tr (Triplet), H (hydrogen protons), J (coupling constant), ml (milliliter), RT (Room temperature). Melting points are given in degrees Celsius and are not corrected. The yields in percent relate to the starting material, not to the conversion.

The following is an example of some preliminary stages and intermediate products described.

example 1 4-bromo-3-bromomethylbenzonitrile

1.96 g of 4-bromo-3-methylbenzonitrile are dissolved in 15 ml of carbon tetrachloride, with 1.2 Equivalent N-bromosuccinimide and a spatula tip of AIBN (azoisobutyronitrile) are added and refluxed under irradiation with a 500 W Lempe. After The reaction is concentrated and chromatographed on a 4 cm thick column with hexane / EE in the gradient. The yield is 35%.

Various intermediate products are prepared analogously from commercially available methyl aromatics.

Example 2 4-bromo (3-methylthiomethyl) benzonitrile

Dissolve 1.37 g of 4-bromo-3-bromomethylbenzonitrile in 8 ml of NMP at 5 ° and add 0.42 g Sodium thiomethylate, dissolved in 5 ml of NMP, is slowly added dropwise at an internal temperature of 5 °. 2 h Stir for hours at this temperature, then for a further 2 hours at RT. Between EE and Distribute water, wash the organic phase with brine, dry with magnesium sulfate and rotate in. Column chromatography with hexane / EA gives 79% product.

Various benzyl thioethers are prepared in the same way.

Biphenyl methylthioethers are also produced in the same way, for example from 2-Bromo-5-phenylbenzyl bromide becomes 2-bromo-5-phenylbenzylthiomethyl ether.

Example 3

As described above, 2-fluoro-3-methylpyridine is converted into 2-fluoro (3- methylthiomethyl) pyridine produced. In the same way, various pyridylmethyl thioether shown.

Example 4 2,5 bis (methylthiomethyl) bromobenzene

592 mg of 4- (bromomethyl) -2-bromo-benzyl bromide are dissolved in 4.81 ml of NMP and slowly at RT with vigorous stirring with 2.2 equivalents, that is 267 mg, sodium thiomethylate offset. After 12 hours, it is diluted with water and extracted with ethyl acetate, the organic Phase dried with magnesium sulfate and concentrated. 370 mg result, i.e. H. 77.1% of a slightly colored oil.

Various aromatic thioethers and bis-thioethers are produced in this way.

Example 5 2-bromobenzyl ethyl thioether

15 g of ortho-bromobenzyl bromide are mixed with 9 g of sodium thioethylate in portions were added to the educt in 60 ml of NMP with water bath cooling, after 15 h stirring at RT and pour into water, extraction with EA, drying and concentration 4.62 g of crude product obtained which is uniform in NMR. The yield is 45%.

In an analogous manner, one obtains from commercially available or preparable in the manner described Precursors of various substituted benzyl ethyl thioethers.

Example 6 (2-chloro-6-fluoro-benzyl) methyl thioether

2.6 ml (20 mmol) of 2-chloro-6-fluoro-benzyl chloride result after the addition of 1.2 equivalents Sodium thiomethylate after 1 hour at RT in 20 ml of dried NMP 2 new products. The mixture is poured onto water and extracted with ethyl acetate, the organic phase dried with magnesium sulfate and concentrated. The result is 59% (2-chloro-6-fluoro-benzyl) - methyl thioether and 9.8% (2-chloro-6-methylthio-benzyl) methyl thioether.

Example 7

Benzoic acids as precursors are appropriately esterified. So give 24.94 g of 3-bromo-4- methylbenzoic acid with 19.35 g of potassium carbonate, 12.5 ml of iodomethane in 200 ml of acetone 3 hours reflux, cool, suction, concentrate and column chromatography with hexane / BE 3-Bromo-4-methylbenzoic acid methyl ester in 96% yield.

Example 8 S- (ortho-bromo-benzyl) -L-cysteic acid ethyl ester

2.5 g of bromobenzyl bromide are mixed with 1 equivalent of L-cysteic acid ethyl ester hydrochloride and 2.2 equivalents of potassium carbonate dissolved in 10 ml of DMF. After 3 hours at 80 ° Sucked off, washed with EA, concentrated and column chromatographed with hexane / EA. 358 mg of product are obtained.

Example 9 2- (2-bromophenyl) ethanol

15 mmol of 2-bromophenylacetic acid in 15 ml of THF become 15 ml of THF with 2 equivalents Lithium aluminum hydride was added dropwise. Hydrogen is produced. After the implementation is acidified with dil. sulfuric acid, extracted with EA, the organic phase with Sulfuric acid, then washed with water, then with soda solution. You dry and rotate a. The yield is 81%.

In an analogous procedure, 2- (2-chlorophenyl) propanol is formed (the yield is 96%) and like reduction products.

Example 10 3- (2-chlorophenyl) propanol tert-butyldimethylsilyl ether

At an internal temperature of 5 °, 2.23 g of 3- (2-chlorophenyl) propanol in 15 ml of NMP with 3.54 g Add imidazole and 2 equivalents of tert-butyldimethylsilyl chloride and stir for 1 hour. Then stir for a further 12 hours at RT. Shake between EE and water, with dil. Acid wash, wash organic phase with brine, dry with magnesium sulfate and rotate in. Column chromatography with hexane gives a 100% yield.

Other preliminary stages are etherified in the same way.

A few selected examples of the compounds according to the invention are given below.

Example 11 [2- (1-imidazolyl) phenyl] isobutyl thioether

162 mg of 2- (1-imidazolyl) fluorobenzene in 3 ml of NMP are mixed with 1.5 equivalents of 2-methyl-1- mercaptopropane and 1.5 equivalents of 80% sodium hydride for 4 hours at 120 °. It is diluted with water, extracted with EA, the organic phase is washed with brine, it is dried with magnesium sulfate and concentrated. Column chromatography with hexane / EA 1: 1 provides 76% yield. 1H NMR (CDCl3): 7.7 (1H), 7.17 to 7.5 (mult. 6H), 2.13 (d 2H), 1.8 (heptet 1H), 0.97 (d 6H).

In the same way, the following are produced from the substituted fluorobenzene:

Example 12

[2- (1-imidazolyl) phenyl] cyclohexyl ether. The yield is 93%. [1H] -NMR (acetone d6): 7.81 (1H), 7.05 to 7.37 (mult. 6H), 4.44 (mult. 1H), 1.2 to 2.0 (mult. 10H).

Example 13

[2- (1-Imidazolyl) phenyl] - (3-methylbut-1-yl) ether, yield 73%, oil.

Example 14

[2- (1-Imidazolyl) phenyl] tert-butyl ether, yield: 73%. [1H] -NMR (CDCl3): 7.82 (1H), 7.15 to 7.4 (mult. 6H), 1.11 (s 9H).

Example 15

[2- (1-Imidazolyl) phenyl] cyclopentyl ether, yield: 49%. [1H] -NMR (CDCl3): 7.8 (1H), 6.98 to 7.33 (mult. 6H), 4.8 (mult. 1H), 1.5 to 0.9 (mult. 8H).

Example 16

[2- (1-Imidazolyl) phenyl] - (tetrahydrofuran-2-ylmethyl) ether. The yield is 10%. Melting point: oil.

Example 17 3-chloro-2- (1-imidazolyl) pyridine

1.48 g of 2,3 dichloropyridine are dissolved in NMP and 0.68 g of imidazole and 1.66 g are added dried potassium carbonate. The mixture is then heated to 150 ° for 6 hours. The The mixture is poured onto water, extracted with ethyl acetate and the organic phase with Magnesium sulfate dried and concentrated. This results after column chromatography with EA 39% product. [1H] -NMR (CDCl3): 7.2 to 8.5 (mult. 6H).

Example 18 2-nitro-4-methyl-phenyl-1- (1-imidazole)

300 mg of 3-nitro-4-fluoro-toluene are in 2 ml of NMP with 132 mg of imidazole and 280 mg Potassium carbonate (ground) heated to 100 °. After the reaction has taken place, the mixture becomes Poured into water, extracted with ethyl acetate, the organic phase with magnesium sulfate dried and concentrated. 98.2% of product result. [1H] -NMR (CDCl3): 7.61 (1H), 7.21 (1H), 7.05 (1H), 7.80 (d 1H), 7.52 (dd J = 8 / 1.5 Hz, 1H), 7.33 (d J = 8 Hz 1H), 2.52 (s 3H).

Example 19 [3-Trifluoromethyl-2- (1-imidazolyl) phenylmethyl] methyl thioether

448 mg of (2-fluoro-3-trifluoromethyl-benzyl) methylthioether are mixed with 1 equivalent of imidazole and 1 equivalent of powdered potassium carbonate and 30 mg of copper powder for 2 hours Heated to 200 °. It is diluted with EA, filtered off with suction and the mother liquor is concentrated. To Column chromatography with hexane with increasing addition of EA gives 240 mg Product. The yield is 44%. [1H] -NMR (CDCl3): 7.7 (mult. 2H), 7.54 (mult. 2H), 7.21 (singlet 1H), 7.05 (1H), 3.24 (s 2H), 2.0 (s 3H).

Under the conditions described above for the reactions with imidazole, one obtains from Fluoro-chloro or bromoaromatics claimed compounds, some of which below Examples are given.

Example 20

1- [5-chloro-2- (1-imidazolyl) phenyl] ethanol, yield: 25%, oil.

Example 21

2-Bromo-3-fluoro-phenyl- (1-imidazole), yield: 8%, melting point: 52 °.

Example 22

2-Hydroxymethyl-3-fluoro-phenyl- (1-imidazole), yield: 11%, 1H-NMR (DMSO d6): 7.96 (1H), 7.5 (1H), 7.1 (1H), 7.25 to 7.5 (add. 3H), 4.3 (s 2H).

Example 23

[4- (1-Imidazolyl) -phenyl] -3-chlorophenol, yield: 80%, 1H-NMR (CDCl3): 7.7 (1H), 7.22 (1H), 7.09 (1H), 7.30 (d 1H), 6.86 (dd 1H), 7.01 (d 1H).

Example 24

1- [2- (1-imidazolyl) -4-chloro-phenyl] -ethanol, yield: 22%, 1H-NMR (DMSO d6): 7.82 (1H), 7.4 (1H), 7.1 (1H), 7.7 (mult. 3H), 4.5 (mult. 1H), 5.3 (s broad 1H), 1 , 2 (d 3H).

Example 25

2-cyano-5-fluoro-phenyl-1- (1-imidazole), yield: 28%, 1H-NMR (CDCl3): 7.9 (1H), 7.85 (1H), 7.38 (1H), 7.22 (mult. 3H).

Example 26

2-cyano-5- (1-imidazolyl) -phenyl-1- (1-imidazole), yield: 7%, 1H-NMR (CDCl3): 7.97 (1H), 7.79 (1H), 7.31 (1H), 7.23 (1H), 6.98 (1H), 6.91 (1H), 7.68 ( d 1H), 7.58 (d 1H), 7.40 (dd 1H).

Example 27

2-Hydroxy-3- (1-imidazolyl) -4-methoxyphenyl-1- (1-imidazole), yield: 17%, Melting point 253 °.

Example 28

2- (1-imidazolyl) -5-nitrophenol, yield: 12%, 1H-NMR (DMSO d6): 8.14 (1H), 7.1 (1H), 7.6 (1H), 7.88 (d 1H), 7.80 (dd 1H), 7.69 (d1H).

Example 29

2- (1-Imidazolyl) -6-methyl-phenyl] -methylether Yield: 99%, 1H-NMR (CDCl3): 7.2 (mult. 5H), 7.82 (1H), 3.38 (s 3H), 2.36 (s 3H).

Example 30

2-methoxy-4-methoxy-phenyl-1- (1-imidazole), yield: 51%, 1H-NMR (CDCl3): 6.5 to 7.8 (mult. 6H), 3.80 (s 3H), 3.83 (s 3H),

Example 31

2-methyl-4-methoxyphenyl-1- (1-imidazole), yield: 60%, melting point: 47 °.

Example 32

2-methoxy-5-methoxy-phenyl-1- (1-imidazole), yield: 50%, 1H-NMR (DMSO d6): 7.0 to 8.0 (mult. 6H), 3.78 (s 3H), 3.80 (s 3H).

Example 33

2-methoxy-4-nitro-phenyl-1- (1-imidazole), yield: 7%, melting point: 136 °.

Example 34

2-methoxy-5- (imidazol-1-yl) -phenyl-1- (1-imidazole), yield: 10%, melting point: 116 °.

Example 35

2-methoxy-5-tert. butyl-phenyl-1- (1-imidazole), yield: 21%, melting point: 79 °.

Example 36

2-Trichloromethyl-3-fluoro-phenyl-1- (1-imidazole), yield: 7%, melting point: oil.

Example 37

2-nitro-5-cyano-phenyl-1- (1-imidazole), yield: 78%, melting point: 161 °, 1H-NMR (CDCl3): 7.6 (1H), 7.12 (1H), 7.0 (1H), 8.22 (d 1H), 7.96 (dd 1H), 7.59 (1H).

Example 38

2-nitro-5-chloro-phenyl-1- (1-imidazole), yield: 51%, 1H-NMR (CDCl3) 7.05 (1H), 7.22 (1H), 7.63 (1H), 8.0 (d 1H), 7.6 (dd 1H), 7.49 (d 1H, J = 1.5Hz).

Example 39

2-nitro-4-methoxyphenyl-1- (1-imidazole), yield: 35%, melting point: 98 °.

Example 40

2-thiomethyl-5-nitro-phenyl-1- (1-imidazole), yield: 37%, melting point: 225 °.

Example 41

(2- [2- (1-Imidazolyl) phenyl] ethyl) methyl thioether, yield: 29%, melting point: 79 °.

Example 42

6-chloro-2- (1-imidazolyl) -acetophenone, yield: 11%, 1H-NMR (CDCl3): 7.74 (1H), 7.13 (1H), 6.1 (1H), 7.2 (mult. 2H), 7.27 (1H), 1.55 (s 3H).

Example 43

(rac) - [2- (1-Imidazolyl) phenylmethyl] - (1-phenyl-ethyl) thioether, yield: 38%, 1 H-NMR (CDCl3): 7.1 to 7.62 (mult. 12H), 3.3 (mult. 2H), 3.89 (quartet 1H), 1.51 (d 3H).

Example 44

[2- (1-Imidazolyl) -phenylmethyl] -ethylthioether, yield: 82%, 1H-NMR (CDCl3): 7.72 (1H), 7, 22 (1H), 7.2 (1H), 7.23 to 7.5 (mult.4H), 3.52 (s 2H), 2.47 (quartet 2H), 1.2 (tr3H).

Example 45

[2- (1-Imidazolyl) phenylmethyl] isopropyl thioether, yield: 58%, 1H-NMR (CDCl3): 7.72 (1H), 7.2 to 7.5 (mult. 6H), 3.53 (s 2H), 2.8 (mult. 1H), 1.2 (1H), 1.22 each (d 3H).

Example 46

[2- (1-Imidazolyl) phenyl] methyl thioether, yield: 65%, melting point: 208 °.

Example 47

[2- (1-Imidazolyl) phenylmethyl] methyl thioether, yield: 59%, 1H-NMR (CDCl3): 7.72 (1H), 7.22 2H (1H), 7.38 (mult. 2H), 7.45 (mult. 2H), 3.50 (s 2H), 2.01 (s 3H).

Example 48

2-fluoro-4-nitro-phenyl-1- (1-imidazole), yield: 84%. 1H-NMR (CDCl3): 7.95 (1H), 7.36 (1H), 7.29 (1H), 7.63d (dd 1.H), 8.2 (mult. 2H).

Example 49

2-fluoro-phenyl-1- (1-imidazole), yield: 59%, oil.

Example 50

3-chloro-4-methoxyphenyl-1- (1-imidazole), yield: 12%, 1H-NMR (CDCl3): 7.75 (1H), 7.18 (1H), 7.18 (1H), 7.0 to 7.42 (add. 3H), 3.95 (s 3H).

Example 51

2-Nitro-4-chloro-phenyl-1- (1-imidazole), yield: 53%, 1H-NMR (CDCl3): 7.62 (1H), 7.07 (1H), 7.23 (1H), 8.02 (d 1H), 7.75 (dd 1H), 7.44 (d 1H).

Example 52

2-nitro-4- (1-imidazolosulfonyl) -phenyl-1- (1-imidazole), yield 65% oil,

Example 53

2- (1-imidazolyl) -4-bromobiphenyl, yield: 23%, 1H-NMR (CDCl3): 7.34 (mult.5H), 7.08 (mult. 3H), 7.63 (dd 1H), 7.56 (d 1H), 6.8 (1H)

Example 54

[4- (1-Imidazolyl) phenyl)] methylthioether, yield: 65%, melting point: 93 °.

Example 55

[3- (1-Imidazolyl) phenyl)] methylthioether, yield: 69%, 1H-NMR (CDCl3): 7.85 (1H), 7.1-7.4 (mult. 6H) 2.52 (s 3H).

Example 56

3-chloro-4-nitro-phenyl-1- (1-imidazole), yield: 17%, 1H-NMR (CDCl3): 7.29 (1H), 7.35 (1H), 7.95 (1H), 8.47 (dd 1H), 8.11d8 (1H), 7.62 (d 1H J = 1.5Hz).

Example 57

2-Bromo-phenyl-1- (1-imidazole), yield: 29%, melting point: 55 °.

Example 58

3-fluoro-4cyano-phenyl-1- (1-imidazole), yield: 16%, 1H-NMR (CDCl3): 7.95 (1H), 7.78 (1H), 7.3 (mult. 4H).

Example 59

2-fluoro-4- (1-imidazolyl) -biphenyl, yield: 11%, 1H-NMR (CDCl3): 7.5 (mult. 6H), 7.27 (mult. 4H), 7.92 (s 1H).

Example 60

3-methoxy-4-methoxy-phenyl-1- (1-imidazole), yield: 44%. 1H-NMR (DMSO d6): 8.12 (1H), 7.64 to 7.1 (5H), 3.82 (s 3H), 3.87 (s 3H).

Example 61

[3- (1-Imidazolyl) benzyl)] methylthioether, Yield: 54%. 1 H-NMR (CDCl3): 7.9 (1H), 7.3 to 7.5 (mult. 6H), 3.72 (s 2H), 2.03 (s 3H).

Example 62

3,4-methylenedioxyphenyl-1- (1-imidazole), yield: 42%, melting point: 84 °.

Example 63

[(2- (1-Imidazolyl) phenyl) -1-ethyl)] methylthioether, yield: 58%. 1H-NMR (CDCl3): 7.1 to 7.62 (mult. 12H), 3.3 (mult. 2H), 3.89 (quartet 1H), 1.51 (d 3H).

Example 64

2- (1-Imidazolyl) -3-trifluoromethyl-pyridine, yield: 18% 1H-NMR (CDCl3): 7.2 to 8.8 (mult. 6H).

For example, preference is given to the correspondingly substituted chloroaromatics get the following connections in the same way:

Example 65

2- (1-imidazolyl) -3-bromopyridine. Yield: 37%. Melting point: 87.8 °.

Example 66

[6-Methylthio-2- (1-imidazolyl) phenylmethyl] methyl thioether, yield: 72%, 1 H-NMR (CDCl3): 7.74 (1H), 7.05 to 7.33 (mult. 5H), 3.74 (s2H), 2.57 (s 3H), 2.09 (s 3H).

Example 67

[4-Chloro-2- (1-imidazolyl) phenylmethyl] methyl thioether, yield: 9.1%. Oil.

Example 68

[5-Phenyl-2- (1-imidazolyl) phenylmethyl] methyl thioether, yield: 16%. Melting point: 123.8 °.

Example 69

[4-Methoxy-2- (1-imidazolyl) phenylmethyl] methyl thioether, yield: 19%. 1 H-NMR (CDCl3): 7.71 (1H), 7.38 (1H), 7.20 (s 2H), 6.96 (dd 1H), 6.78 (d 1H), 3.82 (s 3H), 3.44 (s 2H), 2.01 (s 3H).

Example 70

2,6 dichloro-4-nitro-phenyl-1- (1-imidazole), yield: 71%. Melting point: 173.6 °.

Example 71

3- [2- (1-Imidazolyl) -phen-1-yl] propyl-methylthioether, yield: 12%, 1H-NMR (CDCl3): 7.60 (1H), 7.21 (1H), 7.06 (1H), 7.2 to 7.47 (mult. 4H), 2.6 (mult. 2H), 2.4 (mult. 2H ), 2.02 (s 3H), 1.71 (mult. 2H).

Example 72

[2-chloro-4- (1-imidazolyl) phenylmethyl] methyl thioether, yield: 5.1%. Oil.

For example, from the correspondingly substituted fluoroaromatic compounds, the following are preferred Get connections in the same way:

Example 73

5-nitro-2- (1-imidazolyl) benzaldehyde. Yield: 39%. 1 H-NMR (CDCl3): 9.93 (broad s 1H), 8.91 (1H), 8.59 (dd 1H), 7.81s (1H), 7.68 (1H), 7.37 (1H), 7.30 (1H).

Example 74

[4-Trifluoromethyl-2- (1-imidazolyl) phenylmethyl] methyl thioether, yield: 8%. 1H- NMR (CDCl3): 7.20 to 7.72 (mult. 6H), 3.51 (s 2H), 2.03 (s 3H),

Example 75

5-methyl-2-nitro-phenyl-1- (1-imidazole). Yield: 99%. 1H-NMR (CDCl3): 7.62 (1H), 7.21 (1H), 7.06 (1H), 7.95 (d 8H₂, 1H), 7.40 (dd 1H), 7.25 (d 1H), 2.50 (s 3H),

Example 76

4-methyl-2-nitro-phenyl-1- (1 -imidazole). Yield: 98.2% 8751 H-NMR (CDCl3): 7.61 (1H), 7.21 (1H), 7.05 (1H), 7.80 (d 1H), 7.52 (dd 1H), 7.33 (d 8H), 2.52 (s 3H).

Example 77

[3- (methylthiomethyl) -2- (1-imidazolyl) phenylmethyl] methyl thioether-. Yield: 7.5%. 1 H-NMR (CDCl3): 7.62 (1H), 7.4 (mult. 3H), 7.25 (1H), 7.07 (1H), 3.30 (s 4H), 2.01 (s 6H).

Example 78

[3-Trifluoromethyl-2- (1-imidazolyl) phenylmethyl] methyl thioether. Yield: 44%. 1H- NMR (CDCl3): 7.7 (mult. 2H), 7.54m2 (1H), 7.21 (singlet 1H), 7.05 (1H), 3.24 (s 2H), 2.0 (s 3H).

Example 79

2-cyano-6-trifluoromethyl-phenyl-1- (1-imidazole). Yield: 43%. H-NMR (CDCl3): 8.10 (1H), 8.03 (1H), 7.80 (1H), 7.64 (1H), 7.32 (1H), 7.13 (1H).

Example 80

[2- (1-Imidazolyl) -pyridin-3-methyl] -methylthioether, yield: 45%, 1H-NMR (CDCl3): 8.06 (1H), 7.5 (1H), 7.20 (1H), 8.47m1 (1H), 7.87 (mult. 1H), 7.35 (mult. 1H), 3.63 ( s 2H), 2.09 (s 3H).

Example 81

5-nitro-2- (1-imidazolyl) -phenylmethyl-methylthioether. Yield: 20%, 1H-NMR (DMSO d6): 8.4 (1H), 8.24 (1H), 7.79 (1H), 7.47 (1H), 7.27 (dd 2H).

Example 82

2- (1-imidazolyl) -3-trifluoromethyl-phenol. Yield 69%, melting point: oil.

Example 83

5-fluoro-2-nitro-phenyl-1- (1-imidazole), melting point 78-84 °.

The following are also preferred from the correspondingly substituted bromoaromatics Get connections in the same way:

Example 84

[4- (methylthiomethyl) -2- (1-imidazolyl) phenylmethyl] methyl thioether-, yield: 48%. Melting point: oil.

Example 85

[5- (methylthiomethyl) -2- (1-imidazolyl) phenylmethyl] methyl thioether, yield: 38%. Melting point: oil.

Example 86

[5-cyano-2- (1-imidazolyl) phenylmethyl] methyl thioether. Yield: 34%, 1 H-NMR (CDCl3): 7.22 to 7.82 (mult. 6H), 3.53 (s 2H), 2.09 (s 3H),

Example 87

2-E- [2- (1-Imidazolyl) phenyl] acrylic acid ethyl ester. Yield: 33%. 1H-NMR (CDCl3): 7.1 to 7.8 (mult. 8H), 6.39 (d 1H, J = 16 Hz), 4.22 (quartet 2H), 1.29 (tr 3H).

Example 88

2- (1-imidazolyl) styrene. Yield: 11%. 1 H-NMR (CDCl3): 7.7 to 7.20 (mult. 6H), 7.10 (s 1H), 6.44 (dd 1H olef.), 5.75 (d 1H), 5.32 (d 1H).

Example 89

[4,5-Dimethoxy-2- (1-imidazolyl) phenylmethyl] methyl thioether. Yield: 22%. Melting point: oil.

Example 90

6-methyl-2-nitro-phenyl-1- (1-imidazole). Yield 31%. Melting point: oil.

Example 91

[5 -Methoxy-2- (1-imidazolyl) phenylmethyl] methyl thioether. Yield: 61%. 1 H-NMR (CDCl3): 7.63 (1H), 6.84 to 7.70 (mult. 5H), 3.86 (s 3H), 3.41 (s 2H), 2.02 (s 3H).

Example 92

[5-Bromo-2- (1-imidazolyl) -benzoic acid methyl ester. Yield: 61%. Melting point: 68 °.

Example 93 S-ethyl thiocarbonic acid O- [2- (1-imidazolyl) phenyl] ester

400 mg 2- (1-imidazolyl) -phenol are dissolved in 5 ml NMP, with 1.1 equivalents 80% Sodium hydride (in oil) was added and the mixture was then stirred at 30 ° for 30 minutes. Under cooling 1.1 equivalents of S-ethyl chlorothioformate are entered and a further 2 Stirred for hours at RT. The mixture is poured onto water with ethyl acetate extracted, the organic phase dried with magnesium sulfate and concentrated. It column chromatography results in 84% (520 mg) of product. 1H-NMR (CDCl3): 7.68 (1H), 7.18 (1H), 7.10 (1H), 7.3 to 7.5 (mult. 4H), 2.84 (quartet 2H), 1.28 (tr 3H).

Example 94 Cyclobutanecarboxylic acid [2- (1-imidazolyl) phenyl] ester

1.1 equivalents of 80% sodium hydride are added to 0.25 g of 2- (1-imidazolyl) phenol in 3 ml of DMF (in oil) and the mixture was then stirred at 30 ° for 30 minutes. 1 equivalent Cyclobutanecarboxylic acid chloride is slowly added and the mixture is stirred at RT overnight. The The mixture is poured onto water, extracted with ethyl acetate, the organic phase with Magnesium sulfate dried and concentrated. Column chromatography with EA / ethanol 9: 1 gives 46% product. 1H-NMR (CDCl3): 7.1 to 7.65 (mult. 7H), 3.24 (pentet 1H), 1.8 to 2.3 (mult. 6H).

The esters and ethers mentioned below are obtained quite analogously:

Example 94a

1- [2- (1-Imidazolyl) phenyl] - (2-methoxy-ethyl) ether, yield: 40%. 1H-NMR (DMSO d6): 7.1 to 7.96 (mult. 7H), 3.3 (s 3H), 3.65 (mult. 2H), 4.20 (mult. 2H).

Example 95

[2- (1-Imidazolyl) -phenyl] - (3-methyl-but-2-enyl) ether, yield: 62%, 1H-NMR (CDCl3): 7.02 to 7.8 (mult. 7H), 4.52 (d 2H), 5.37 (mult. 1H), 16.8 (s 3H), 1.75 (s 3H).

Example 96

[2- (1-Imidazolyl) phenyl] - (2-chloro-prop-2-enyl) ether, yield: 51%. 1H-NMR (CDCl3): 7.92 (1H), 7.4 (1H), 7.05 (1H), 7.1 to 7.4 (mult. 4H), 4.8 (s 2H), 5.5 (1H), 5 , 65 (1H).

Example 97

[2- (1-Imidazolyl) phenyl] - (E-but-2-enyl) ether, yield: 40%. Melting point: oil.

Example 98

[2- (1-Imidazolyl) phenyl] allyl ether, yield: 55%, melting point: oil.

Example 99

[2- (1-Imidazolyl) phenyl] - (3-chloro-but-2enyl) ether, yield: 73%.

Example 100

[2- (1-Imidazolyl) phenyl] - ([cyclopropyl] methyl) ether, yield: 25%, melting point: oil.

Example 101

[2- (1-Imidazolyl) phenyl] - (2,2-dichloro-2,1,1-trifluoroeth-1-yl) ether, - Yield: 52%. Melting point: oil.

Example 102

[2- (1-Imidazolyl) phenyl] - (2-neopentyl) ether, yield: 44%. 1H-NMR (acetone d6): 7.8 (1H), 7.33 (1H), 7.05 (1H), 7.2 (mult. 3H), 3.75 (s 2H), 0.95 (s9H).

Example 103

[2- (1-Imidazolyl) phenyl] - (2-methylthioeth-1-yl) ether, yield: 42%. 1H-NMR (CDCl3): 7.81 (1H), 7.16 (1H), 7.3 (1H), 7.3 (mult. 1H), 7.05 (mult. 2H), 4.2 (mult. 2H), 2, 82 (mult. 2H); 2.10 (mult. 3H).

Example 104

[2- (1-Imidazolyl) phenyl] - (2-bromo-prop-2-enyl) ether, yield: 44%, melting point: oil.

Example 105

[4-chloro-2- (1-imidazolyl) phenyl] - (2-chloro-prop-2-enyl) ether, yield: 47%, 1 H-NMR (CDCl3): 7.8 (1H), 7.2 to 7.3 (mult. 4H), 6.98 (1H) 4.6 (s 2H), 5.45 (s 2H).

Example 106

[3-methyl-4- (1-imidazolyl) -phenyl] - (2-chloro-prop-2-enyl) ether, yield: 49%, Melting point: oil.

Example 107

[2- (1-Imidazolyl) phenyl] - (2,2-spiro [2 ′, 2′-dichlorocyclopropyl] prop-1-yl) ether, yield: 51%, Melting point: oil.

Example 108

[2- (1-Imidazolyl) phenyl] - [(2,2-dichloro-3-methyl) cycloprop-1-yl] meth - 1-yl) ether, yield: 34%, oil.

Example 109

[2- (1-Imidazolyl) phenyl] -4- [1H] quinolinyl) ether, yield: 17%, oil.

Example 110

[2- (1-Imidazolyl) -phenyl] - (1,1-dimethyl-1-acetoxyacetic acid) ester, yield: 69% Melting point: oil.

Example 111

[2- (1-Imidazolyl) phenyl] cyclohexanecarboxylic acid ester, yield: 84%, melting point: 68 °.

Example 112

[2- (1-Imidazolyl) -phenyl] -n-hexanecarboxylic acid ester, yield: 78%, 1H-NMR (acetone d6): 7.7 (1H), 7.07 to 7.55 (mult. 6H), 0.9 to 2.50 (mult.13H).

Example 113

[2- (1-Imidazolyl) -phenyl] -n-heptadecanecarboxylic acid ester, yield: 52%, melting point: 101 °.

Example 114

[2- (1-Imidazolyl) -phenyl] -perfluoropropane carboxylic acid ester, yield: 23%, 1H-NMR (CDCl3): 8.5 (1H), 8 (1H), 7.77 (1H), 7.3 (mult. 4H).

Example 115

[2- (1-Imidazolyl) -phenyl] -N, N-dimethylcarbamic acid ester, yield: 27%, 1H-NMR (CDCl3): 7.73 (1H), 7.09 to 7.51 (mult. 6H), 2.85 (s 3H), 3.0 (s 3H).

Example 116

[2- (1-Imidazolyl) -phenyl] -N- (2-chloroethyl) -N-methylcarbamate, yield: 55%, 1 H-NMR (CDCl3): 7.64 (1H), 7.1 to 7.4 (mult. 6H), 3.5 (mult. 4H), 3.01 (s 3H).

Example 117

[2- (1-Imidazolyl) -phenyl] -decanoic acid ester, yield: 98%, 1H-NMR (CDCl3): 7.68 (1H), 7.18 (1H), 7.10 (1H), 7.24 to 7.44 (mult. 4H), 2.42 (dd 2H), 1.28 (mult. 14H ), 0.89 (tr 3H).

Example 118

[2- (1-Imidazolyl) -phenyl] -cyclopropanecarboxylic acid ester, yield: 44%, 1H-NMR (CDCl3): 7.68 (1H), 7.18 (1H), 7.10 (1H), 7.28 to 7.48 (mult. 4H), 1.7 (mult. 1H), 1.0 (mult. 4H).

Example 119

[2- (1-Imidazolyl) -phenyl] -isobutyric acid ester, yield: 97%, 1H-NMR (CDCl3): 7.68 (1H), 7.18 (1H), 7.10 (1H), 7.20 to 7.50 (mult. 4H), 2.67 (heptet 1H), 1.11 (d 6H).

Example 120

[2- (1-Imidazolyl) -phenyl] -3-methylbutyric acid ester, yield: 72%, 1H-NMR (CDCl3): 7.68 (1H), 7.18 (1H), 7.10 (1H), 7.24 to 7.44 (mult. 4H), 2.31 (d 2H), 2.07 (heptet 1H), 0.91 (d 6H).

Example 121

[2- (1-Imidazolyl) -phenyl] -omega-chloropentanoic acid ester, yield: 97%, melting point: 218.6 °.

Example 122

[2- (1-Imidazolyl) -phenyl] -3-phenylpropionic acid ester, yield: 96%, 1H-NMR (CDCl3): 7.05 to 7.69 (mult 6 H), 2.95 (mult. 2H), 2.7 (mult. 2H).

Example 123

[2- (1-Imidazolyl) phenyl] - (tert. Butyl acetic acid) ester, yield: 80%, melting point: 111 °.

Example 124

[2- (1-Imidazolyl) -phenyl] - (trans-phenylcyclopropanecarboxylic acid) ester, - Yield: 70%, Melting point: oil.

Example 125

[2- (1-Imidazolyl) phenyl] - ([1-methylthio] acetic acid) ester, yield: 17%, 1 H-NMR (CDCl3): 7.72 (1H), 7.2 (1H), 7.14 (1H), 7.22 to 7.52 (mult. 4H), 3.3 (s 2H), 2.1 ( s 3H).

Example 126

[2- (1-Imidazolyl) phenyl] oxalic acid half ester, yield: 42%, melting point: oil.

Example 127 [2- (1-imidazolyl) phenoxy] acetonitrile

500 mg (3,086 mmol) 2- [2- (1-imidazolyl) -phenol are dissolved in 15 ml anhydrous DMF and 185.2 mg (26.172 mmol) of an 80% NaH suspension are added. After 11/2 Hours of stirring at room temperature are 404.7 mg (3.373 mmol) of bromoacetonitrile added and the batch was stirred overnight at room temperature. The mixture will be on 100 ml of H₂O given and extracted 3 times with 70 ml of ethyl acetate each time. The United organic extracts are washed twice with 50 ml of saturated NaCl solution each time, over NaSO₄ dried and the organic solvent spun off. After chromatography of the Crude product of SiO₂ (EE / hexane → EE as eluent) are 365.4 mg (58.8%) of the desired product.

Example 128 4- [2- (1-imidazolyl) phenoxy] butyric acid nitrile

500 mg (3.086 mmol) 2- (1-imidazolyl) -phenol are added analogously to Example 127 with 499.2 mg (3.373 mmol) of 4-bromobutyronitrile reacted. After the work-up described above and chromatography, 445 mg (62.7%) of product are obtained.

Example 129 5- [2- (1-imidazolyl) phenoxy] pentanoic acid nitrile

500 mg (3.086 mmol) 2- (1-imidazolyl) -phenol are as described in Example 127 with 546.4 mg (3.373 mmol) of 5-bromophentanoic acid nitrile reacted. After work-up and Chromatography gives 752.9 mg (99.9%) of product.

Example 130 6- [2- (1-imidazolyl) phenoxy] hexanoic acid nitrile

500 mg (3.086 mmol) 2- (1-imidazolyl) -phenol are added as usual with 593.6 mg (3.373 mmol) 6-bromohexanoic acid nitrile implemented. Obtained after work-up and chromatography one 750.8 mg (94.2%) of product.

Example 131 7- [2- (1-imidazolyl) phenoxy] heptanoic acid nitrile

500 mg (3.086 mmol) 2- (1-imidazolyl) -phenol are added as usual with 640.9 g (3.373 mmol) 7-Bromoheptanoic acid nitrile implemented. After working up and chromatography, 810 is obtained mg (96.4%) of product.

Example 132 6- [2- (1-imidazolyl) phenoxy] -2,2-dimethylhexanoic acid nitrile

100 mg (0.617 mmol) 2- (1-imidazolyl) -phenol are added as usual with 138.5 mg (0.679 mmol) 2,2-dimethyl-6-bromohexanoic acid nitrile reacted. After work-up and Chromatography gives 103 mg (58.2%) of product.

Example 133 2- [2- (1-Imidazolyl) phenoxy] acetic acid tert-butyl ester

100 mg (0.617 mmol) 2- (1-imidazolyl) -phenol are treated with NaH in analogy to Example 127 and tert-butyl bromoacetate reacted in DMF. After work-up and Chromatography gives 84.9 mg (49.6%) of product.

Example 134 Ethyl 4- [2- (1-imidazolyl) phenoxy] butyric acid

2 g (12.344 mmol) 2- (1-imidazolyl) -phenol are in analogy to Example 127 with NaH and 4-Bromobutyric acid ethyl ester implemented in DMF. After work-up and chromatography 1.23 g (36%) of product are obtained.

Example 135 5- [2- (1-Imidazolyl) phenoxy] pentanoic acid methyl ester

2 g (12.344 mmol) 2- (1-imidazolyl) -phenol are in analogy to Example 127 with NaH and 5-bromopentanoic acid methyl ester implemented in DMF. After the usual work-up 2.7 g (75.1%) of product isolated.

Example 136 Ethyl 6- [2- (1-imidazolyl) phenoxy] hexanoate

2 g (12.344 mmol) 2- (1-imidazolyl) -phenol are as already described (Example 127) with 6-Bromohexanoic acid ethyl ester and NaH reacted in DMF. The product is in 59.2% Yield (2.32 g) isolated.

Example 137 7- [2- (1-Imidazolyl) phenoxy] heptanoic acid ethyl ester

1 g (6.172 mmol) 2- (1-imidazolyl) -phenol are according to Example 127 with 7- Bromoheptanoic acid ethyl ester and NaH reacted in DMF. The yield is after Work up 0.416 g (31.3%).

Example 138 2- [4- (1-Imidazolyl) phenoxy] acetic acid methyl ester

In 50 ml of DMSO 4 g of 4- (imidazol-1-yl) phenol, 4.8 ml of methyl bromoacetate and Given 6.5 g of cesium carbonate. After stirring for 1 day, the reaction mixture is in water given and extracted with methylene chloride. The organic phase is separated off with Washed water, dried and the solvent removed in vacuo. To Recrystallization from petroleum ether gives the title compound with the melting point 116-117 ° C.

Example 139 3- [4- (1-imidazolyl) -3- (methylthiomethyl) phenoxy] butyric acid nitrile

To 0.15 g of 4- (1-imidazolyl) -3- (methylthiomethyl) -phenol in 3.5 ml of DMF 2 Equivalent 80% sodium hydride (in oil) added and after brief stirring at RT 1.08 Equivalent 4-bromobutyronitrile added slowly. The mixture is stirred at RT overnight. The The mixture is poured onto water, extracted with ethyl acetate, the organic phase with Magnesium sulfate dried and concentrated. Column chromatography with EE gives 81% Product. 1H-NMR (CDCl3): 7.62 (1H), 6.82 to 7.2 (mult. 5H), 4.14 (tr 2H), (1H), 2.62 (tr 2H), 3.41 (s 2H), 2.2m2 (1H), 2.05 (s 3H).

Analogously the following are obtained:

Example 140

1- [4- (1-imidazolyl) -3- (methylthiomethyl) phenyl] prop-2-yne ether, yield: 85%, Melting point: oil.

Example 141

1- [4- (1-Imidazolyl) -3- (methylthiomethyl) phenyl] -2-chloroprop-2eneth-r, yield: 56% and 32% of the product of Example 140, melting point: oil.

Example 142

[4- (1-Imidazolyl) -3- (methylthiomethyl) phenyl] benzyl ether, yield: 81.6%, melting point: Oil.

Example 143 1- [2- (1-Imidazolyl) phenyl] - (3-methylthio) propyl ether

In 10 ml of THF, 240 mg of 2- (1-imidazolyl) phenol, 1 equivalent of 3- Dissolved methylthiopropan-1-ol and 1 equivalent of triphenylphosphine. At 4 ° internal temperature 0.23 ml of diethyl azodicarboxylate are slowly added dropwise. After a few hours at RT is worked up. The mixture is concentrated and placed on a column of silica gel chromatographed. Mobile phase: hexane / EE. The yield is 60%. 1H-NMR (CDCl3): 7.79 (1H), 7.4 to 7.0 (mult. 6H), 4.12m2 (1H), 2.57 (mult. 2H), 2.02 (mult. 2H), 2.07 (s 3H).

In the same way one obtains:

Example 144

[2- (1-Imidazolyl) phenylmethyl] - (ortho-methylthio) phenol ether, yield: 72%, Melting point: 83 °.

Example 145

L- [2- (1-imidazolyl) benzyl alcohol] - (S-methylcysteic acid) ester, yield: 41%, melting point: 78 °.

Example 146

[2- (1-Imidazolyl) benzyl alcohol] - (2-S-methylthioacetic acid) ester, yield: 75%. 1 H-NMR (CDCl3): 7.7 (1H), 7.2 (mult. 7H), 5.0 (s 2H), 3.2 (s 2H), 2.18 (s 3H).

Example 147

[2- (1-Imidazolyl) phenyl] - [(2,2dimethyl-1,3dioxolane) -4-methyl] ether, yield: 62%, Melting point: oil.

Example 148

[2- (1-Imidazolyl) phenyl] - (3-thiacyclohex-1-yl) ether, yield: 75%, melting point: oil.

Example 149

[2- (1-Imidazolyl) -phenyl] - (2-thiophenyl) methyl ether, yield: 17%, 1H-NMR (CDCl3): 7.81 (1H), 6.95 to 7.4 (mult. 9H), 5.25 (s 2H).

Example 150

[2- (1-Imidazolyl) -phenyl] -but-1-yn-3-yl ether, yield: 26%, 1H-NMR (CDCl3): 7.81 (1H), 7.07 to 7.4 (mult. 6H), 4.82 (mult. 1H), 2.48 (mult. 1H), 1.60 (d 3H).

Example 151

1- [2- (1-Imidazolyl) phenoxyethyl] - (2-chloroethyl) ether, yield: 19%, 1H-NMR (acetone d6): 7.92 (1H), 7.05 to 7.7 (mult. 6H), 4.41 (dd 2H), 3.95 (dd 2H).

Example 152

[2- (1-Imidazolyl) phenoxy-2-eth-1-yl] - (2-hydroxyethyl) thioether, yield: 33%, 1 H-NMR (CDCl3): 7.87 (1H), 7.40 to 7.00 (mult. 6H), 4.21, 3.69, 2.88, 2.61 each (tr 2H).

Example 153

[2- (1-Imidazolyl) phenyl] - (1,3-bis-methylthiopropan-2-yl) ether, yield: 44%, 1 H-NMR (CDCl3): 7.8 (mult. 1H), 7.0 to 7.4 (mult. 6H), 4.25 (mult. 1H), 2.8 (mult. 1H), 2.1 (mult. 1H).

Example 154

[4- (1-Imidazolyl) -3-methylthiomethyl-phenyl] - (2-methylthioeth-1-yl) ether, yield: 45%, Melting point: oil.

Example 155

[2- (1-Imidazolyl) phenylmethyl] - (2-thiomethylethyl) ether, yield: 33%, 1H-NMR (CDCl3): 7.72 (1H), 7.20 (mult. 2H), 7.3 (1H), 7.6 (mult. 4H), 4.30 (s 2H), (1H), 3, 62 (tr 2H), (1H), 2.70 (tr 2H), 2.12 (s 3H).

Example 156 2-chloro-4-methoxy-phenyl-1- (1-imidazole)

378 mg of 2-amino-4-methoxyphenyl-1- (1-imidazole) are half-concentrated with 5 ml Hydrochloric acid dissolved at about 50 °, sodium nitrite solution is added in portions at ice bath temperature added, stirred for 15 minutes at this temperature. The diazonium salt solution becomes 440 mg of copper-I-chloride, which is concentrated in 4 mol. Hydrochloric acid are dissolved, added in portions. After a few hours, it is poured onto soda solution, extracted with EA, suctioned off over Celite and dries with magnesium sulfate. Concentration and column chromatography provide 61% of the named connection. 1 H NMR (CDCl3): 7.05 to 7.61 (mult 5 H), 6.87 (1H), 3.83 (s 3H).

Example 157

4-bromo-2-fluoro-phenyl-1- (1-imidazole), yield: 32%, 1H-NMR (CDCl3): 7.85 (1H), 7.47 (1H), 7.4 (1H), 7.27 (mult. 3H).

Example 158

3,4-dichlorophenyl-1- (1-imidazole), yield: 59%, 1H-NMR (CDCl3): 7.85 (mult. 1H), 7.25 (mult. 3H), 7.55 (mult. 2H).

Example 159

2,5-dichlorophenyl-1- (1-imidazole), yield: 33%, melting point: 100 °.

Example 160

2,4-dichlorophenyl-1- (1-imidazole), yield: 42%, 1H-NMR (DMSO d6): 7.82 (mult. 2H), 7.55 (mult. 2H), 7.41 (1H), 7.11 (1H).

Example 161

4-chloro-2-fluoro-phenyl-1- (1-imidazole), yield: 64%, 1H-NMR (CDCl3): 7.795 (s 1H), 7.3 (mult. 5H).

Example 162 2- (1-imidazolyl) -3-methylthiopyridine,

180 mg (1 mmol) of 2- (1-imidazolyl) -3-chloropyridine are dissolved in 2 ml of NMP with 1.5 equivalents Sodium thiomethanolate heated to 110 ° for 4 hours. The mixture is poured onto water, extracted with ethyl acetate, the organic phase dried with magnesium sulfate and constricted. After column chromatography with EA, 190 mg of the title compound result. Yield: 99%, 1H-NMR (CDCl3): 7.19 to 8.3 (mult. 6H), 2.42 (s 3H).

Example 163 [2- (1-imidazolyl) phenyl] ethyl thioether

In 3 ml of NMP, a total of 3 equivalents are added to 223 mg of 2-bromo-phenyl-1- (1-imidazole) Sodium thioethylate in NMP gradually increases. After 8 hours at 1200 shows Thin layer chromatography a lot of product. Working up as in Example 162 provides one 51% yield. 1 H NMR (CDCl3): 7.64 (1H), 7.22 (1H), 7.13 (1H), 7.22 (mult. 2H), 7.4 (mult. 2H), 2.8 (quartet 2H), 1.23 (tr 3H).

Example 164 3- [3- (1-Imidazolyl) phenyl] prop-1-yl methyl thioether

3- [3- (1-Imidazolyl) phenyl] prop-1-yl bromide (300 mg) are dissolved in 3 ml of NMP. To Addition of 1.1 equivalents of sodium thiomethanolate is stirred for 24 hours at RT. The The mixture is poured onto water, extracted with ethyl acetate and the organic phase with Magnesium sulfate dried and concentrated. After chromatography (EA / Hex 2: 3) 27% product. 1H-NMR (CDCl3): 7.83 (1H), 7.4 to 7.2 (mult. 6H), 2.8 (1H), 2.54 (1H), 1.95 each (mult. 2H), 2.12 (s 3H).

One synthesizes analogously:

Example 165

[2- (1-Imidazolyl) phenyl] iso-propyl thioether with thioisopropylate, yield: 79%, 1H-NMR (CDCl3): 7.67 (1H), 7.19 (1H), 7.15 (1H), 7.3 to 7.5 (mult 4H), 3.12 (heptet 1H), 1.2 (d 6H).

Example 166

[2- (1-Imidazolyl) -phenyl] -tert.butylthioether with tert. Butyl mercaptan, yield: 69%, 91H- NMR (CDCl3): 7.77 (1H), 7.75 (1H), 7.14 to 7.5 (mult. 5H), 1.07 (s 9H).

Example 167

[2- (1-Imidazolyl) phenyl] - (3-furanylmeth-1-yl) thioether with furfuryl mercaptan, Yield: 27%.

Example 168

2,3-bismethylthio-phenyl-1- (1-imidazole) with thiomethylate, yield: 45%, 1H-NMR (CDCl3): 7.7 (1H), 7.2 (mult. 3H), 7.4 (dd 1H), 7.08 (d 1H), 2.50 (s 3H), 2.09 (s 3H ).

Example 169

[5-Nitro-2- (1-imidazolyl) -phenyl] -methylthioether with thiomethylate, yield: 18%, 1H- NMR (CDCl3): 7.7 (1H), 7.28 (1H), 7.18 (1H), 8.1 (mult. 2H), 7.4 (1H), 2.53 (s 3H).

Example 170

[5-chloro-2- (1-imidazolyl) phenyl] methyl thioether with thiomethylate, yield: 50%, 1H- NMR (CDCl3): 7.1 to 7.62 (mult. 6H), 2.40 (s 3H).

Example 171

[5-Nitro-2- (1-imidazolyl) -phenyl] -ethylthioether with thioethylate, yield: 25%, 1H-NMR (CDCl3): 7.7 (1H), 7.25 (1H), 7.18 (1H), 8.21 (1H), 8.09 (1H), 7.4 (1H), 2.99 ( quartet 2H), 1.34 (tr3H).

Example 172

[5-chloro-2- (1-imidazolyl) -phenyl] -ethylthioether with thioethylate, yield: 82%, 1H-NMR (CDCl3): 7.62 (1H), 7.09 (1H), 7.20 (1H), 7.15 to 7.33 (mult.3H), 2.83 (quartet 2H), 1.28 ( tr 3H).

Example 173

(1- [2- (1-Imidazolyl) -phenyl] -eth-1-yl) methylthioether with thiomethylate, yield: 34%, 1H- NMR (CDCl3): 7.1 to 7.7 (mult. 7H), 3.62 (quartet 1H), 1.52 (d 3H).

Example 174

(1- [2- (1-Imidazolyl) -phenyl] -eth-1-yl) -ethylthioether with thioethylate, yield: 28%, Melting point: oil.

Example 175

[2- (1-Imidazolyl) -phenyl] - (1-phenyleth-1-yl) thioether with 1 phenylethanethiol, Yield: 75%, 1H-NMR (CDCl3): 7.05 to 7.55 (mult. 12H), 4.05 (1H), 1.50 (d 3H).

Example 176

[2- (1-Imidazolyl) -phenyl] -but-2-ylthioether with 1-methylpropyl mercaptan, yield: 74%, 1 H-NMR (CDCl3): 7.66 (1H), 7.20 (1H), 7.15 (1H), 7.54 (dd 1H), 7.3 (mult. 3H), 2.9 (mult . 1H), 1.50 (m 2H), 1.15 (m 3H), 0.9 (tr 3H).

Example 177

[2- (1-Imidazolyl) -phenyl] - (2-phenyleth-1-yl) thioether with 2-phenylethanethiol, Yield: 60%, 1H-NMR (CDCl3): 7.69 (1H), 7.1 to 7.5 (mult. 11H), 3.0 (mult. 2H), 2.83 (mult. 2H).

Example 178

[2- (1-Imidazolyl) phenyl] cyclohexyl thioether with cyclohexyl mercaptan, yield: 80%, Melting point: Oil:

Example 179

[2- (1-Imidazolyl) phenyl] decyl thioether with decyl mercaptan, yield: 58%, 1H-NMR (CDCl3): 7.65 (1H), 7.13 to 7.45 (mult. 6H), 2.75 (mult. 2H), 0.9 to 1.6 (mult. 19H).

Example 180

[2- (1-Imidazolyl) -phenyl] - (2-N, N-dimethylaminoeth-1-yl) thioether with N, N- Dimethylaminoethanethiol, yield: 40%, melting point: oil.

Example 181

[2- (1-Imidazolyl) phenyl] benzyl thioether with thiomethylbenzene, yield: 75%, Melting point: 87 °.

Example 182

[2- (1-Imidazolyl) phenyl] - (2-thiophenyl) thioether with 2-mercaptothiophene, yield: 28%. Melting point: oil.

Example 183

2- [2- (1-imidazolyl) -benzylthio] -N-methylacetamide with methyl mercaptoacetamide, Yield: 44%, 1H-NMR (CDCl3): 7.68 (1H), 7.22 (1H), 7.17 (1H), 7.25 to 7.5 (mult. 4H), 3.53 (s 2H), 3.14 (s 2H), 2.77 (d 3H).

Example 184

[2- (1-imidazolyl) -phenylmethyl] - [1N-methyl-imidazol-2-yl] thioether with 2-mercapto-1- methylimidazole, yield: 14%, melting point: 226 °.

Example 185

3- [2- (1-Imidazolyl) -benzylthio] -propionic acid methyl ester with Methyl mercaptopropionate, yield: 49%, 1H-NMR (CDCl3): 7.7 (1H), 7.2 to 7.5 (mult. 6H), 3.55 (s 2H), 3.7 (s 3H), 2.7 (dd 2H), 2.5 (dd 2H).

Example 186

2- [2- (1-imidazolyl) -benzylthio] -3,4,5,6-tetrahydropyrimidine hydrobromide with 2-mercapto tetrahydropyrimidine 1.3, yield: 35%, melting point: 269 °.

Example 187

[3- (1-Imidazolyl) -4-phenyl-phenyl] methyl thioether with sodium thiomethylate yield: 81%, Melting point: oil.

Example 188

[3- (1-Imidazolyl) -4-phenyl-phenyl] methyl thioether with sodium thioethylate, yield: 77%, Melting point: oil.

Example 189

2- [2- (1-Imidazolyl) -benzylmercapto] -acetic acid ethyl ester with ethyl-2-mercaptoacetate, Yield: 62%, 1H-NM (CDCl3): 7.7 (1H), 7.2 to 7.55 (mult. 6H), 4.15 (quartet 2H), 3.69 (s 2H), (1H), 3.12 (s 2H), 1.28 (tr 3H).

Example 190

[2- (1-Imidazolyl) benzyl] benzyl thioether with benzyl mercaptan, yield: 71%, 1H-NMR (CDCl3): 7.68 (1H), 7.1 to 7.45 (mult. 12H), 3.68 (s 2H), 3.42 (s 2H).

Example 191 S- [2- (1-imidazolyl) benzyl] isothiourea hydrobromide

318 mg 2- (1-imidazolyl) -benzyl bromide hydrobromide are mixed with 153 mg thiourea in 5 ml of ethanol refluxed for 5 hours. After cooling, vacuum and wash the Crystals are obtained 250 mg of S- [2- (1-imidazolyl) benzyl] isothiourea hydrobromide. Melting point: 247 °. The crude product dissolves in saturated sodium hydrogen carbonate solution, after a short time the free base S- [2- (1-imidazolyl) benzyl] isothiourea precipitates again. It is suctioned off and washed with water.

A few examples illustrate the process:

Example 192

S- [2- (2- (1-imidazolyl)) phenyleth-1-yl] isothiourea hydrobromide. Yield: 97%, Melting point: 229 °.

Example 193

S- [3- (2- (1-imidazolyl)) phenylpropyl] isothiourea hydrobromide. Yield: 69%, 1H- NMR (DMSO d6): 9.45 (1H), 9.0 (1H), 8.02 (1H), 7.92 (1H), 7.4 to 7.7 (mult. 4H), 3.13m2 (1H), 2.6 (mult. 2H), 1.8 (mult. 2H).

Example 194

N-phenyl-S- [2- (1-imidazolyl) benzyl] isothiourea hydrobromide. Yield: 60%, Melting point: 217 °.

Example 195

S- [1- (2- (1-imidazolyl)) phenyleth-1-yl] isothiourea hydrobromide. Yield: 81% Melting point: 164 °.

Example 196

N, N-dimethyl-S- [2- (1-imidazolyl) benzyl] isothiourea hydrobromide. Yield: 87%, Melting point: 183 °.

Example 197 [2- (1-Imidazolyl) benzyl] propargyl thioether

A solution of S- [2- (1-imidazolyl) benzyl] isothiourea hydrobromide (Ex. 191) is used boiled in a solution of 1.5 g of potassium hydroxide cookies and 3 g of water. One admits 2 ml of the reaction solution carefully dichloromethane, so that 2 phases are formed. To do this there 80 mg of propargyl bromide and 10 mg of triethylbenzylammonium bromide and stirred for 3 Hours at RT. It is diluted with water, extracted with dichloromethane, the organic Phase washed with brine, dried with magnesium sulfate and concentrated using a rotary evaporator. Column chromatography with hexane / EA in a ratio of 1: 1 gives 50% product. 1 H-NMR (CDCl3): 7.71 (1H), 7.21 (1H), 7.20 (1H), 7.24 to 7.55 (mult. 4H), 3.71 (s 2H), 3.17 ( d 2H), 2.27 (mult. 1H).

In the same way one obtains:

Example 198

[2- (1-Imidazolyl) benzyl] - (2-bromo-prop-2-enyl) thioether, yield: 68%, 1 H-NMR (CDCl3): 7.71 (1H), 7.2 to 7.54 (mult. 6H), 5.23m1 (1H), 5.03 (mult. 1H), 3.56 (s 2H), 3, 39 (s 2H).

Example 199

S- [2- (1-Imidazolyl) -benzyl] -thiocarbonic acid-O-ethyl ester, yield: 45%, 1H-NMR (CDCl3): 7.63 (1H), 7.1 (1H), 7.2 (1H), 7.2 to 7.6 (mult.4H), 3.9 (s 2H), 4.29 ( quartet 2H), (1H), 1.29 (tr 3H).

Example 199a

(2 - (- 1-Imidazolyl) -benzylthio) -acetone, yield: 55%, 1H-NMR (CDCl3): 7.7 (1H), 7.2 to 7.5 (mult.), 3.51 (s 2H), 3.16 (s 2H), 2.22 (s 3H).

Example 199b

S- [2- (1-imidazolyl) -benzyl] -N, N-dimethyl-thio-carbamate, yield: 69%, melting point: 60 °.

Example 200

[2- (1-Imidazolyl) -benzyl] - (1-propen-2-yl) thioether, yield: 58%, 1H-NMR (CDCl3): 7.71 (1H), 7.21 (1H), 7.20 (1H), 7.22 to 7.52 (mult. 4H), 5.7 (mult. 1H), 5.1 (mult. 2H ), 3.49 (s 2H), (1H), 3.09 (d 2H).

Example 201 2- (1-imidazolyl) benzyl bromide hydrobromide

2.61 grams of 2- (1-imidazolyl) benzyl alcohol are heated in 47% HBr at 140 ° for 4 hours. It is concentrated and the crude product is carefully dried. The yield is 98%. 1 H-NMR (DMSO d6): 9.51 (1H), 8.10 (1H), 7.98 (1H), 7.79 (1H), 7.6 to 7.7 (mult. 3H), 4.68 ( s 2H).

According to this example, methoxyaromatics are converted under appropriate conditions Get phenols, for example:

Example 202

2-Hydroxy-3-methyl-phenyl-1- (1-imidazole), yield: 88%, melting point: oil.

Example 203

2-Hydroxy-3- (imidazol-1-yl) -4-hydroxyphenyl-1- (1-imidazole), yield: 77%, melting point: <300 °.

Example 204

2-hydroxy-5-tert. butyl-phenyl-1- (1-imidazole), yield: 90%, melting point: 198 °.

Example 205

2-Hydroxy-4- (imidazol-1-yl) -phenyl-1- (1-imidazole), yield: 70%, melting point: <300 °.

Example 206

2-methyl-4-hydroxyphenyl-1- (1-imidazole), yield: 85%, 1H-NMR (DMSO d6): 9.52 (1H), 6.7 to 7.7 (mult. 6H), 2.02 (s 3H) .ethyl-1-bromide hydrobromide, yield: 100%, 1H- NMR (CDCl3): 9.55 (1H), 7.5 to 8.1 (mult. 6H), 5.19 (quartet 1H), 2.01 (d 3H).

Example 207

2-nitro-4-hydroxyphenyl-1- (1-imidazole), yield: 54%, melting point: 228-230 °.

Example 208

2-Hydroxy-5-hydroxyphenyl-1- (1-imidazole), yield: 65%, 1H-NMR (DMSO d6): 7.9 (1H), 7.03 (1H), 7.4 (1H), 9.2 (1H), 9.33 (1H), 6.65 to 6.9 (mult.3H).

Example 209

2- [2- (1-imidazolyl) -phenyl] -ethylbromide hydrobromide, yield 100%, 1H-NMR (DMSO d6): 9.5 (1H), 8.1 (1H), 7.95 (1H), 7.5 (1H), 7.7 (mult. 4H), 3.70 (tr 2H), 3, 02 (tr 2H).

Example 210

2,4-dihydroxyphenyl-1- (1-imidazole), yield: 65%, melting point: 195 °.

Example 211

3- [2- (1-Imidazolyl) phenyl] propyl-1-bromide hydrobromide, yield: 99%, 1 H-NMR (DMSO d6): 9.5 (1H), 8.1 (1H), 7.95 (1H), 7.7 to 7.4 (mult. 4H), 3.49m2 (1H), 2.64 ( mult. 2H), 1.99 (mult. 2H).

Example 212 [2- (1-Imidazolyl) phenyl] methyl thioether hydrobromide

95 mg of [2- (1-imidazolyl) phenyl] methyl thioether are stirred in 2 ml of 47% HBr and constricted. One dries on the Kugelrohr. The hydrobromide is obtained quantitatively Yield. Melting point: 176 °.

Example 213

2-hydroxy phenyl-1- (1-imidazole). Yield 96%.

Example 214

3-chloro-4-hydroxyphenyl-1- (1-imidazole), yield: 87%, melting point: 216 °.

Example 215

3,4-dihydroxy-phenyl-1- (1-imidazole), yield: 88%, 1H-NMR (DMSO d6): 8.0 (1H), 7.5 (1H), 7.1 (1H), 9.2 (s broad 2H), 6.92 (1H), 6.8 (mult. 2H).

Example 216

4-Nitro-2- (1-imidazolyl) -benzylbromide hydrobromide, yield: 90%, 1H-NMR (DMSO d6): 9.63 (1H), 8.71 (1H), 7.95 to 8.5 (mult. 4H) (1H), 4.81 (s 2H).

Example 217

3- [3- (1-Imidazolyl) -phenyl] -propyl-1-bromide hydrobromide, yield: 92.6%, melting point: Oil.

Example 218 2-amino-4-cyano-phenyl-1- (1-imidazole)

In a mixture of 2 ml of THF and 3 ml of ethanol, 214 mg of 2-nitro-4-cyano-phenyl- 1- (1-imidazole) was mixed with 110 mg of ammonium chloride in 1 ml of water. After adding 630 mg zinc powder is stirred for 3 hours at RT. One dilutes with EE, sucks off over Celite, wash the filtrate once with ammonium chloride solution and with brine until neutral. Drying and concentrating give 93% product. Melting point: 214 °.

Analog are produced:

Example 219

2-Amino-5-chloro-phenyl-1- (1-imidazole), yield: 95%, melting point: 136 °.

Example 220

2-Amino-4-aminophenyl-1- (1-imidazole), yield: 54%, 1H-NMR (CDCl3): 7.6 (1H), 7.20 (1H), 7.05 (1H), 6.9 (muli: 1H), 6.1 (mult. 2H).

Example 221

4-Amino-2-hydroxyphenyl-1- (1-imidazole) Yield: 69%, melting point: 232 °.

Example 222

4-Amino- [2- (1-imidazolyl) -thiophenol] -methylether, yield: 100%, 1H-NMR (CDCl3): 7.7 (1H), 7.15 (1H), 7.16 (1H), 6.6 (1H), 6.72 (1H), 7.30 (1H), 2.20 (s 3H).

Example 223

4-Amino-2-fluoro-phenyl-1- (1-imidazole), yield: 95%, melting point: 69-72 °.

Example 224

2-Amino-4-chloro-phenyl-1- (1-imidazole), yield: 100%, melting point: 144 °.

Example 225

4-Amino-3-chloro-phenyl-1- (1-imidazole), yield: 100%, melting point: 114 °.

Example 226

2-Amino-4-methoxyphenyl-1- (1-imidazole), yield: 100%, 1H-NMR (CDCl3): 7.8 (1H), 7.30 (1H), 7.1 (1H), 6.99 (dd 1H), 6.33 (singlet 1H), 6.31 (mult. 1H), 3.80 ( s 3H).

Example 227 Ethyl 3- [2- (1-imidazolyl) phenyl] propionate

1.44 g of ethyl E-3- [2- (1-imidazolyl) phenyl] acrylic acid are dissolved in 50 ml of ethanol at low pressure hydrogenated with 144 mg of 10% palladium / carbon catalyst. The reaction takes 2 hours RT. It is suctioned off, concentrated and 89% product is obtained. 1H-NMR (CDCl3): 7.61 (1H), 7.22 (1H), 7.09 (1H), 7.2 to 7.4 (mult.4H), 4.09 (quartet 1H), 2.43 (tr 2H), (1H), 2.83 (tr 2H), 1.21 (tr 3H).

A selection from other catalytic hydrogenations:

Example 228

Ethyl 2-cyano-3- [2- (1-imidazolyl) phenyl] propionate, yield: 48%, oil.

Example 229

Ethyl 3- [3- (1-imidazolyl) phenyl] propionate, yield: 95.4%, 1H-NMR (CDCl3): 7.87 (1H), 7.4 to 7.2 (mult. 6H), 4.12 (quartet 2H), 3.03 (tr 2H), (1H), 2.68 (tr 2H), 1, 22 (tr 3H).

Example 230

4- (1-Imidazolyl) -3- (methylthiomethyl) benzylamine, yield: 33%, melting point: oil.

Example 231 2- [2- (1-imidazolyl) phenoxy] ethylamine

528.4 mg (2.65 mmol) of 2- [2- (1-imidazole) phenoxy] acetonitrile are dissolved in 25 ml of methanol with a added catalytic amount of Raney nickel. Now ammonia is pressed on and with hydrogen hydrogenated at 50 ° C. for four hours (80 bar, autoclave). After the reaction has taken place, the catalyst becomes suctioned off and the solvent spun off. The residue is on silica gel with dichloromethane / iso chromatographed propanol / ammonia as eluent. 147.1 mg (27.3%) are isolated.

Example 232 4- [2- (1-imidazolyl) phenoxy] butylamine

415 mg (1.82 mmol) of the compound shown according to Example 128 are as in Example 231 described implemented. After work-up and chromatography, 349.3 mg (83.8%) are obtained Amine.

Example 233 5- [2- (1-imidazolyl) phenoxy] pentylamine

723 mg (3 mmol) of the compound shown in Example 129 is as in Example 231 described implemented. After work-up and chromatography, 389.2 mg (52.9%) are obtained Amine.

Example 234 6- [2- (1-imidazolyl) phenoxy] hexylamine

720.8 mg (2.82 mmol) of the nitrile prepared according to Example 130 are as in Example 231 described implemented. After working up and chromatography, 575 mg (78.7%) of amine are obtained.

Example 235 7- [2- (1-imidazolyl) phenoxy] heptylamine

780 mg (2.9 mmol) of the compound shown according to Example 131 are obtained in analogy to Example 231 implemented. Work-up and chromatography yield 529.5 mg (66.8%) of amine.

Example 236 2-Cyano-E-3- [2- (1-Imidazolyl) -pheny-] -acrylic acid ethyl ester

5 mmol of ethyl cyanoacetate is added to toluene with 5 mmol of 2- (1-imidazolyl) benzaldehyde Adding a small amount of acid to the boiled water separator. After cooling down, needles fall out, which are washed with toluene and dried at 60 °. The yield is 79%, melting point: 129.5. The aldehyde is according to standard methods from the glycol acetal by cleavage with half-concentrated hydrochloric acid / THF / water 1: 1: 1 available in 98% yield. The acetal is created by stirring the aldehyde with glycol and para-toluenesulfonic acid in 69% yield or by Reaction of 2-bromobenzaldehyde acetal with imidazole.

Example 237 ethyl ortho-bromocinnamate

ortho-bromocinnamic acid (5.22 g) is mixed with 3.05 g of ethyl bromide, 3.86 g of potassium carbonate and 25 ml of DMF Esterified after 2 hours at 60 °. The mixture is poured onto water, with ethyl acetate extracted, the organic phase dried with magnesium sulfate and concentrated. The result is 99% Crude product which is further reacted (Example 87).

Analogously one obtains

Example 238

ethyl meta-bromocinnamate, yield 99%, oil.

Example 239 E-3- [2- (1-imidazolyl) phenyl] allyl alcohol and E-3- [2- (1-imidazolyl) phenyl] acrolein

When reducing E-3- [2- (1-imidazolyl) -phenyl] -acrylic acid ethyl ester (242 mg) with DiBAH in 5 ml of toluene at 78 ° and then 1 hour at 0 ° is obtained after working up a mixture of Aldehyde and allyl alcohol, chromatographed with EE with the addition of ethanol as an eluent is separated. Yield aldehyde: 13%, 1H-NMR (CDCl3): 9.57 (d 1H), 7.1 to 7.8 (mult.8H), 6.69 (dd 1H).

Yield alcohol: 48%, 1H-NMR (CDCl3): 7.7 to 7.07 (mult. 7H), 6.37 (mult. 2H), 4.28 (dd 2H).

Analogously one obtains

Example 240

E-3- [3- (1-imidazolyl) phenyl] allyl alcohol, yield: 88%, oil.

Example 241

3- [2- (1-imidazolyl) -phenyl] -propanol and 3- [2- (1-imidazolyl) -phenyl] -propanal from 3- [2- (1- Imidazolyl) -phenyl] -propionic acid ethyl ester, yield aldehyde: 13%, 1H-NMR (CDCl3): 9.68 (1H), 7.61 (1H), 7.09 (1H), 7.2 to 7.45 (mult. 5H), 2.83m2 (1H), 2.57 (mult. 2H). Alcohol: 1H-NMR (CDCl3): 7.59 (1H), 7.07 (1H), 7.18 (1H), 7.2 to 7.47 (mult. 4H), 3.55 (mult. 2H), 2.57 (mult. 2H), 1.7 (mult. 2H).

Example 242 3- [3- (1-imidazolyl) phenyl] propanol

With LiAlH₄ (1.1 equivalents in THF) and ethyl 3- [3- (1-imidazolyl) phenyl] propionate is obtained after reaction and pouring the crude product onto sodium tartrate in water after extraction. Yield: 99.7%, 1H-NMR (CDCl3): 7.84 (1H), 7.4 to 7.2 (mult. 6H), 3.7m2 (1H), 2.8m2 (1H), 1.95 mult. 2H).

Example 243 2-fluoro-4- (1-pyrrolo) -phenyl-1- (1-imidazole)

133 mg of 4-amino-2-fluoro-phenyl-1- (1-imidazole) are dissolved in acetic acid (1 ml) with 1 equivalent of 2.5- Dimethoxytetrahydrofuran refluxed for 2 hours. It is poured onto saturated potassium hydrogen carbonate solution, extracted 2 times with EE and washes the org. Phase. With magnesium sulfate will dried, concentrated in a rotary evaporator and column chromatography carried out with EA. Yield: 69%, 1H-NMR (CDCl3): 6.4 to 7.43 (mult. 9H), 7.8 (s broad 1H).

The following are represented in the same way:

Example 243 b

4-chloro-2-pyrrolo-phenyl-1- (1-imidazole), yield 100%, melting point: 84 °.

Example 244

5-chloro-2-pyrrolo-phenyl-1- (1-imidazole), yield: 94%, melting point: 115 °.

Example 245

3-chloro-4-pyrrolo-phenyl-1- (1-imidazole), yield: 61%, 1H-NMR (CDCl3): 6.38 (mult. 2H), 6.92 (mult. 2H), 7.23 to 7.9 (mult. 6H).

Example 246 1- [2- (1-imidazolyl) phenyl] ethanol

1.72 g of 2- (1-imidazolyl) benzaldehyde are mixed with 3.7 ml of methyl magnesium bromide (3M solution) in 12 ml of THF reacted. After 2 hours, ammonium chloride solution is added and the mixture is extracted with EA, washes with brine, dries and concentrates. According to column chromatography with EA, the yield is 51%. 1 H NMR (CDCl3): 7.07 to 7.79 (mult. 7H), 4.74 (quartet 1H), 1.41 (d 3H).

Example 247 2- [2- (1-imidazolyl) phenoxy] acetic acid

1.3 g (4.74 mmol) of the ester prepared according to Example 133 are mixed with 10 ml of a mixture KOH / CH₃OH / H₂O (3.6 g, 24 ml, 120 ml) added and at room temperature until complete Saponification stirred. It is acidified with 10% sulfuric acid and then over Extrelut given with CH₂Cl₂. The filtrate is evaporated and the residue of SiO₂ with a Chromatographed solvent mixture of CH₂Cl₂ / isopropanol / water. The yield is 759.2 mg (73.7%).

Example 248 4- [2- (1-imidazolyl) phenoxy] butyric acid

0.600 g (2.19 mmol) of the ester prepared according to Example 134 are produced in analogy to Example 247 saponified. 412.1 mg (76.5%) of product are isolated.

Example 249 5- [2- (1-imidazolyl) phenoxy] pentanoic acid

1.35 g (4.92 mmol) of the ester prepared according to Example 135 are produced in analogy to Example 247 saponified. The yield of product is 604.3 mg (49.1%).

Example 250 6- [2- (1-imidazolyl) phenoxy] hexanoic acid

1.1 g (4.64 mmol) of the ester prepared according to Example 136 is described as in Example 247 saponified and processed. 784.2 mg (78.6%) are isolated.

Example 251 7- [2- (1-imidazolyl) phenoxy] heptanoic acid

0.148 g (0.464 mmol) of that shown in Example 137 are saponified analogously to Example 247 and worked up. 132.8 mg (98.5%) of product are isolated.

Example 251b

2- [2- (1-Imidazolyl) benzylthio] acetic acid, yield: 81%, melting point: 140 °.

Example 252 4- (1-imidazolyl) -3- (methylthiomethyl) phenol

In DMF, 1.5 mmol of 4- (1-imidazolyl) -3- (methylthiomethyl) phenol methyl ether with 5 mmol Sodium thiomethylate refluxed for 2 hours. One pours on sat. Potassium hydrogen carbonate solution, extracted 2 times with EA and washes the org. Phase with brine. With Magnesium sulfate is dried, concentrated using a rotary evaporator and obtained after column chromatography with EA / ethanol one 64% yield. Melting point: 129 °.

Analogously one obtains:

Example 253

3- (1-Imidazolyl) -4- (methylthiomethyl) phenol, yield: 43%, 1H-NMR (CDCl3): 7.77 (1H), 7.24 (1H), 7.18 (1H), 7.3 (1H), 7.0 (1H), 6.8 (1H), 3.40 (s 2H), 2.02 (s 3H).

Example 254 2- (1H-imidazol-1-yl) -3-pyridinol

2-Chloro-3-phenylmethoxypyridine (1.4 g) and imidazole (4.3 g) are on an oil bath for 4 days Heated to 120 ° C. The mixture is cooled to room temperature and washed with 5N NaOH and Added chloroform. The organic phase is separated off, dried and concentrated. The The residue is purified by chromatography and 2- (1-imidazolyl) -3-phenylmethoxy is obtained pyridine. 2- (1-imidazolyl) -3-phenylmethoxypyridine and 0.01 g of Pd / C are added to 2 ml of methanol given, stirred under hydrogen for 1 hour, filtered off and the solvent stripped off. Man receives the title compound with a melting point of 162-164 ° C.

Example 255 [2- (1-imidazolyl) benzyl] methyl sulfone

3.05 g of [2- (1-imidazolyl) benzyl] methyl thioether are added at 50 in 75 ml of dichloromethane 7.08 g meta-chloroperbenzoic acid. The mixture is stirred overnight and then diluted with dichloromethane, extracted 2 times with 1 N sodium hydroxide solution, 2 times with water and the organic phase is dried with it Magnesium sulfate. After rotating in and column chromatography with EA / ethanol one obtains beside little sulfoxide the sulfone in 78% yield. Melting point: 156 °. 1H-NMR (CDCl3): 7.71 (1H), 7.70 (1H), 7.52 (mult. 2H), 7.34 (mult. 1H), 7.22 (s 2H), 4.13 (s 2H), (1H ), 2.83 (s 3H).

Analogously one obtains:

Example 256

[2- (1-Imidazolyl) phenylmethyl] methyl sulfoxide, yield: 67%, melting point: 94 °, 1 H-NMR (CDCl3): 7.67 (1H), 7.22 (1H), 7.15 (1H), 7.33 to 7.57 (mult. 4H), 3.75 (ABquartett 2H), 2.50 ( s 3H).

Example 257

[2- (2- (1-Imidazolyl) -phenyl) eth-1-yl] -methylsulfone, yield: 71%, 1H-NMR (CDCl3): 7.72 to 7.12 (mult. 7H), 3.02 (mult. 4H), 2.72 (s 3H).

Example 258

[2- (1-Imidazolyl) phenyl] methyl sulfone, yield: 67%, melting point: 139-141 °.

Example 259

[2- (1-Imidazolyl) -5-phenyl-benz-1-yl] -methylsulfone, yield: 34%, 1H-NMR (CDCl3): 7.29 to 7.77 (mult. 10H), 7.91 (d 1H), 4.20 (s 2H), 2.89 (s 3H).

Example 260

[2- (1-Imidazolyl) -5-methoxy-benzyl] -methylsulfone, yield: 25%, melting point: 115.9 °.

Example 261

[2- (1-Imidazolyl) -5-cyano-benzyl] -methylsulfoxide, yield: 26%, 1H-NMR (CDCl3): 7.20 to 7.9 (mult. 6H), 3.79 (mult. 2H), 2.60 (s 3H),

Example 262

[2- (1-Imidazolyl) -5-phenyl-benzyl] -methylsulfoxide, yield: 77%, 1H-NMR (CDCl3): 7.20 to 7.80 (mult. 11H), 3.82 (dd 2H), 2.56 (s 3H).

Example 263

[2- (1-Imidazolyl) -5-methoxy-benzyl] methyl sulfoxide, yield: 68.8%, melting point: 103.1 °.

Example 264

[2- (1-Imidazolyl) -5-amido-benzyl] methyl sulfoxide, yield: 22%, melting point: 226 °.

Example 265

[2- (1-Imidazolyl) -5-cyano-benzyl] -methylsulfone, Yield: 25%, 1H-NMR (CDCl3): 7.27-8.05 (mult. 6H), 4.20 (s 2H), 2.99 (s 3H).

Example 266

[2- (1-Imidazolyl) -5-amido-benzyl] methylsulfone, yield: 36%, melting point: 189.5 °.

Example 267

[2- (2- (1-Imidazolyl) -phenyl) -et-1-yl] -methylsulfoxide, yield: 61%, 1H-NMR (CDCl3): 7.72 to 7.12 (mult. 7H), 3.0 (tr 2H), 2.7 (mult. 2H), 2.46 (s 3H).

Example 268

[2- (1-Imidazolyl) -benzyl] -ethylsulfone, yield: 76%, 1H-NMR (CDCl3): 7.72 to 7.2 (mult. 7H), 4.03 (s 2H), 2.95 (quartet 2H), 1.82 (tr 3H).

Example 269

[2- (1-Imidazolyl) -benzyl] -isopropylsulfone, yield: 75%, 1H-NMR (CDCl3): 7.72 to 7.2 (mult. 7H), 4.00 (s 2H), 3.07 (heptet 1H), 1.45 (d 6H).

Example 270

[2- (1-Imidazolyl) benzyl] ethyl sulfoxide, yield: 77%, 1H-NMR (CDCl3): 7.67 to 7.17 (mult. 7H), 3.7 (quartet 2H), 2.7 (mult. 2H), 1.28 (tr 3H).

Example 271

[2- (1-Imidazolyl) benzyl] isopropyl sulfoxide, yield: 82%, 1 H-NMR (CDCl3): 7.72 to 7.2 (mult. 7H), 3.6 (s 2H), 2.74 (heptet 1H), 1.2 (dd 6H).

Example 272

[2- (2- (1-imidazolyl) -phenoxy) -eth-1-ylmethylsulfone, yield: 31%, 1H-NMR (CDCl3): 7.7 (1H), 7.45 to 7.04 (mult. 6H), 4.47 (dd 2H), 3.39 (mult. 2H), 2.61 (s 3H).

Example 273

[2- (2- (1-imidazolyl) -phenoxy) -eth-1-ylmethylsulfoxide, yield: 32%, 1H-NMR (CDCl3): 7.74 (1H), 7.45 to 7.04 (mult. 6H), 4.47 (mult. 2H), 3.2 (1H), 3.1 (1H), 2.54 (s 3H) .

Example 274

[(2- (1-Imidazolyl) pyridyl-3-meth) yl] methylsulfone, yield: 35%, 1H-NMR (CDCl3): 8.62 (dd 1H), 8.12 (dd 1H), (1H), 8.00 (s 1H), 7.5m2 (1H), 7.24 (s 1H), 4.29 (s 2H), 2.92 ( s 3H).

Example 275

[2- (2- (1-Imidazolyl) phenyl] isopropyl sulfoxide, yield: 34%, melting point: 91.5 °.

Example 276

[2- (2- (1-Imidazolyl) phenyl] isopropyl sulfone, yield: 57%, melting point: 80.8 °.

Example 277

[2- (1-imidazolyl) -5-hydroxy-benzyl] methylsulfone, yield: 62.6%, melting point: <300 °.

Example 278

[2- (1-Imidazolyl) -5-hydroxy-benzyl] methyl sulfoxide, yield: 90%, melting point: oil.

Example 279

[3- (1-Imidazolyl) benzyl] methyl sulfone, yield: 82%, melting point: 144.5 °.

Example 280

[3- (1-Imidazolyl) benzyl] methyl sulfoxide, yield: 65%, 1H-NMR (CDCl3): 7.87 (1H), 7.2 bis 7.52 (mult. 6H), 3.99 (d 2H), 2.52 (s 3H).

Example 281

[3- (1-Imidazolyl) -phenyl] -methylsulfone, yield: 56%, 1H-NMR (CDCl3): 8.01 (1H), 7.94 (mult. 2H), 7.7 (mult. 2H), 7.37 (1H), 7.27 (1H); 3.12 (s 3H).

Example 282

[3- (1-Imidazolyl) benzyl] methyl sulfoxide, yield 22%, m.p .: oil.

Example 283

[2- (1-Imidazolyl) -5- (meta-pyridyl) -benzyl] -methylsulfone, yield 25%, melting point: oil.

Example 284

[2- (1-Imidazolyl) -5- (meta-pyridyl) -benzyl] -methyl sulfoxide, yield 11%, melting point: oil.

Example 285

[2- (1-Imidazolyl) phenyl] methyl sulfoxide, yield: 26%, melting point: 147 °.

Example 286

[4- (1-Imidazolyl) -phenyl] -methylsulfone, yield: 25%, 1H-NMR (acetone d6): 8.3 (1H), 7.76 (1H), 7.18 (1H), 7.94 (mult. 2H), 8.10 (mult. 2H), 3.2 (s 3H).

Example 287

[4- (1-Imidazolyl) -phenyl] -methylsulfoxide, yield: 60%, 1H-NMR (CDCl3): 7.23 (1H), 7.32 (1H), 7.92 (1H), 7.58 (mult. 2H), 7.80 (mult. 2H), 2.26 (s 3H).

Example 287a

[3- (Dimethylsulfon-1-yl) -4- (1-imidazolyl) -phenyl] -methylsulfone, yield 34%, melting point: Decomp.

Example 288 [2- (1-imidazolyl) -5- (meta-pyridyl) benzyl] methyl thioether

[5-Bromo-2- (1 -imidazolyl) -benzyl] -methylthioether (142 mg) is added along with 1 equivalent Diethyl-3-pyridylborane, 10 mole percent tetrabutylammonium bromide, 57 mg KOH powder and 58 mg Tetrakistriphenylphosphine-palladium (°) refluxed for 3 hours. The mixture is on water poured, extracted with ethyl acetate, the organic phase dried with magnesium sulfate and constricted. This is followed by column chromatography with EA and ethanol. The yield is 84%. Melting point: 105 °.

Example 289 3- (1-imidazolyl) benzamidine hydrochloride

In a cooled solution of 0.47 g of 3- (1-imidazolyl) benzonitrile in 5 ml of ethanol Passed hydrogen chloride and the reaction mixture was stirred in the sealed flask overnight. After the solvent has been removed, the residue is dissolved in 10 ml of ethanol and poured into the cooled one Ammonia solution passed. The sealed flask is heated to 75 ° C. in an oil bath for 2 hours. After cooling, the title compound is filtered off.

Example 290 N- {2- [2- (1-imidazolyl) phenoxy] ethyl} guanidine hydrochloride

100 mg (10.5 mmol) of the amine prepared according to Example 231 are added to 1.5 ml of DMF, with equivalent amounts of 1-H-pyrazole-carboxamidine hydrochloride and diisopropylethylamine are added and stirred at room temperature until the reaction is complete. After to dryness Was evaporated, is chromatographed on silica gel with CH₂Cl₂, ethanol, H₂O as the eluent. 62.2 mg (40%) are obtained.

Example 291 N- {4- [2- (1-Imidazolyl) phenoxy] butyl} guanidine hydrochloride

100 mg (0.43 mmol) of the amine prepared according to Example 232 are as in Example 290 described implemented. 48.6 mg (88.6%) of the desired compound are isolated.

Example 292 N- {5- [2- (1-Imidazolyl) phenoxy] pentyl} guanidine hydrochloride

100 mg (0.41 mmol) of the compound shown according to Example 233 are as in Example 290 described, implemented. 57 mg (45.4%) of the desired guanidine hydrochloride are obtained.

Example 293 N- {6- [2- (1-Imidazolyl) phenoxy] hexyl} guanidine hydrochloride

100 mg (0.38 mmol) of the compound shown according to Example 234 is as in Example 290 described, implemented. 112.7 mg (86.5%) of the desired compound are obtained.

Example 294 N- {7- [2- (1-Imidazolyl) phenoxy] heptyl} guanidine hydrochloride

100 mg (0.37 mmol) of the compound shown according to Example 235 are as in Example 290 described, implemented. 115.7 mg (89.6%) of the desired guanidine hydrochloride are isolated.

Example 295 N- {6- [4- (1-Imidazolyl) phenoxy] hexyl} guanidine hydrochloride

100 mg (0.386 mmol) 6- [4- (1-imidazolyl) -phenoxy] -hexylamine are as in Example 290 described implemented. After working up, 115.2 mg (88%) of the desired Connection isolated.

Example 296 N- [2- (1-imidazolyl) -phenyl] -N'-methyl-thiourea

0.2 g of 2-aminophenyl-1- (1-imidazole) are dissolved in 4 ml of THF and mixed with 86 μl of methyl isothiocyanate added to 1 ml of THF. The reaction is terminated after gentle warming. The THF will spun off and the residue recrystallized from isopropanol. First some educt precipitates out, next to it a product with a melting point of 287 ° C. dec.

Analogously one obtains:

Example 297

N- [2- (1-imidazolyl) -benzyl] -N'-methyl-thiourea, yield: 31%, melting point: 128 °.

Example 298 [2- (1-Imidazolyl) benzyl] methyl sulfone hydrochloride

[2- (1-Imidazolyl) -benzyl] -methylsulfone (0.75mmol) are dissolved in 6 ml of 1NHCl in ether and 10 ml Stirred ethanol for 6 hours at RT. Add some ether and place in the refrigerator. Crystals are filtered off with suction, washed and dried. Yield: 89%, melting point: 201 °.

Example 299

[5-Cyano-2- (1-imidazolyl) benzyl] methyl thioether hydrochloride, yield: 88%, melting point: 211 ° dec. 1H-NMR (DMSO d6): 9.32d (s 1H), 8.16 (1H), 8.1 (mult. 2H), 7.8 (mult. 2H), 3.77 (s 2H), 1.93 (s 3H).

Hydrochlorides and hydrobromides are represented analogously as

Example 300 [2- (1-Imidazolyl) benzyl] methyl thioether hydrobromide

Dissolve 150 mg of [2- (1-imidazolyl) benzyl] methyl thioether in 3 ml of 47% HBr, after 3 hours at RT Constrict and dry on the bulb tube in a vacuum. Yield: 100%, 1H-NMR (DMSO d6): 9.51s broad (1H), 8.1 (s 1H), (1H), 7.97 (s 1H), 7.7 to 7.50 (mult. 4H), 3.71 (s 2H), 1 , 92 (s 3H).

Other salts are also prepared in the same way as

Example 301 [2- (1-Imidazolyl) benzyl] methyl thioether oxalate

[2- (1-Imidazolyl) benzyl] methyl thioether (110 mg) are dissolved in 2 ml of ethanol with 1 equivalent Oxalic acid is stirred for a total of 12 hours at RT, after 24 hours in the refrigerator it is suctioned off and dried. Yield: 85%, melting point: 102 °.

Example 302

[2 (1-Imidazolyl) benzyl] methyl sulfone oxalate, yield: 88%, melting point: 175 °.

Example 303 [2- (2'-Bromo-imidazol-1-yl) -benzyl] -methylthioether

204 mg of [2- (imidazol-1-yl) -benzyl] -methylthioether are each with 1 equivalent of triphenylphosphine and tetrabromomethane stirred in 6 ml of dichloromethane. The reaction is after 12 hours at RT completed. The mixture is concentrated and everything is placed on a column. Obtained after column chromatography one the title compound in a yield of 59%. 1H-NMR (CDCl3): 7.58 to 7.2 (mult. 6H), 3.35 (d 1H), 3.53 (d 1H), 1.99 (s 3H).

Example 304 2- [4- (1-Imidazolyl) phenoxy] acetic acid hydrochloride

100 ml of 6 N HCl are mixed with 1.2 g of methyl 2- [4- (1-imidazolyl) phenoxy] acetic acid, 4 Stirred for hours and concentrated. The residue is treated with ethanol and the Title compound with a melting point of 116-117 ° C.

Example 305 2- [3- (1-Imidazolyl) phenoxy] acetic acid hydrochloride

4 g of 3- (1-imidazolyl) phenol, 1.8 ml of methyl bromoacetate and 6.5 g are added to 50 ml of DMSO Given cesium carbonate. The mixture is stirred for 1 day, poured into water and with Extracted methylene chloride. The organic phase is separated off, washed with water, dried and the solvent removed. The residue is taken up in 100 ml of 6 N HCl. After stirring for 4 hours, the mixture is concentrated and the residue is treated with ethanol. You get the Title compound with a melting point of 206-208 ° C.

Example 306 2- [2- (1-imidazolyl) phenylmethyl] methanesulfonamide

20 ml of methylene chloride are mixed with 1.0 g of 2- (1-imidazolyl) -benzolmethanamine, 0.43 ml Methanesulfonyl chloride and 1.3 ml of triethylamine were added. After stirring overnight it becomes water added, the organic phase separated, dried and the solvent in vacuo deducted. After recrystallization in alcohol, the Title compound.

Claims (7)

1. Compounds of the formula I wherein
AR² can be the same or different one or two times,
R¹ is hydrogen, halogen, -SH or -SC _1-4 -alkyl,
Z nitrogen or -CH = optionally substituted by AR² or R³,
A is a bond, straight-chain or branched C _1-4 -alkylene, straight-chain or branched C _2-4 -alkenylene, straight-chain or branched C _2-4 -alkylene,
R² is hydrogen, halogen, NO₂, -C≡N, CF₃, -CCl₃, S (O) _m -C _1-4 -alkyl, -OR⁵, -S-R⁶, -CO-R⁷, -NR⁸R⁹, -CH (CN ) -COOH, -CH (CN) -COO-C _1-6 -alkyl, = C (CN) -COOH, = C (CN) -COOC _1-6 -alkyl, -NH-SO₂-R¹⁰, -C ( NH₂) = NOH, imidazol-1-yl, 4-CH₃-thiazol- 2-yl, -NH-CO-NH₂, -NH-CS-NH₂, NH-CO-NH (C _1-4 -alkyl), NH -CS-NH (C _1-4 -alkyl), pyrrol-1-yl, -C (= NR) -NHR¹¹, -NH-C (= NR) -NR¹¹R¹², -S- (C = NR) -NR¹¹R¹², a phenyl or biphenyl radical optionally substituted one or more times with halogen, -SC _1-4 -alkyl or -OC _{1-4 -alkyl, pyridyl, imidazolosulfonyl,}
R³ is hydrogen, halogen, NO₂, OH, NH₂ or imidazol-1-yl,
AR² and R³ together form -O- (CH₂) _n -O-,
m, n 1 or 2,
R⁵ is hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 carbon atoms, which can contain 1-2 double and / or triple bonds and in which a -CH₂ group is replaced by oxygen, sulfur, phenyl or _{C 3-6} cycloalkyl optionally substituted with methyl or halogen can be replaced, C _3-7 cycloalkyl optionally substituted with methyl or halogen, -CO-R¹⁵, -CS-NH (C _1-4 -alkyl), -CH ( NH2) -COO _1-6 -alkyl, -Si (CH₃) ₂ tert. butyl, quinolin-yl, N1-methyl-imidazol-2-yl, thiophenyl, thiacyclohexyl, tetrahydrofuranyl, -CS-SC _1-4 -alkyl, CS-CH₂-SC _1-4 -alkyl, -C (= NR) NR¹¹R¹² , optionally with halogen, NO₂, C _1-4 -alkylthio, C _1-4 -alkoxy or C _1-4 -alkyl substituted phenyl, tetrahydropyrimidine, tetrahydropyridine,
R⁶ has the meaning of R⁵,
R⁷ is hydrogen, C _1-8 -alkyl, C _3-7 -cycloalkyl, -CH₂-SC _1-4 -alkyl, - (CH2) ₂-SC _1-4 -alkyl, -OC _1-6 -alkyl, NH₂, NH (C _1-4 alkyl), N (C _1-4 alkyl) 2, SC _1-4 alkyl, CF₃, -C₂F₅, OH, phenyl,
R⁸, R⁹ are identical or different and are hydrogen, C _1-4 -alkyl, C _1-4 -alkanoyl or, together with the nitrogen atom, form a 5- to 6-membered saturated heterocycle which has a further O-, N- or S- Contain atom and can be substituted 1-2 times with C _{1-4 -alkyl,}
R¹⁰, R¹¹, R¹² and R are hydrogen, C _1-6 -alkyl, C _3-7 -cycloalkyl, phenyl,
R¹⁵ optionally substituted with halogen, NH₂, -C≡N, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkanoyloxy, thiophene or phenyl substituted C _1-17 alkyl, optionally substituted with CH₃ or phenyl C _3-7 cycloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, -COOH, -COOC _1-6 alkyl, NR¹³R¹⁴,
R¹³, R¹⁴ are identical or different and are hydrogen or optionally halogen-substituted C _1-4 -alkyl,
and their isomers and tautomers and physiologically acceptable salts, wherein

• (1) if R¹ and R³ are hydrogen and Z = -CH, AR² in the 2-position cannot be H, OH; Cl, Br, CF₃, -CHO, -O-CO-CH₃, -CH₂-Br, -CH₂OH, - (CH2) ₂-OH, - (CH2) ₂-Br, -CH = CH₂, -O-CH₂- CH = CH₂, -O-CH₂-C≡CH, -O-CH₂-CN, -SH, -CHOH-CH₃, -CH = CH- phenyl,
• (2) if F, Cl, OH, CH₃ or NO₂ is in the 3-position of the phenyl ring, R¹, R³ and AR² cannot be H or imidazole at the same time,
• (3) if R¹ = H and in the 4-position of the phenyl ring is OCH₃, OH, NH₂, fluorine or CH₂- NH₂, H, OCH₃ or OH cannot be in the 2-position,
• (4) if R¹ = H and in the 2-position of the phenyl ring is NO₂, Br or OH, it cannot be Cl or CH₃ in the 5-position,
• (5) if R¹ = H and Z -CH =, R⁵ or R⁶ can not be optionally substituted benzyl.

2. Compounds of formula I according to claim 1, wherein -A-R² straight-chain or branched Alkylene with 1-8 carbon atoms, straight-chain or branched alkenylene with 2-8 atoms, straight-chain or branched alkynylene with 2-8 carbon atoms, where one or two methylene groups can be replaced by oxygen and / or sulfur and a Substituent R² may be present. 3. Use of the compounds of formula I according to claim 1 for the preparation of Medicinal products. 4. Use of the compounds of the formula IA wherein
AR² can be the same or different one or two times,
R¹ is hydrogen, halogen, -SH or -SC _1-4 -alkyl,
Z nitrogen or -CH = optionally substituted by AR² or R³,
A is a bond, straight-chain or branched C _1-4 -alkylene, straight-chain or branched C _2-4 -alkenylene, straight-chain or branched C _2-4 -alkylene,
R² is hydrogen, halogen, NO₂, -C≡N, CF₃, -CCl₃, -S (O) _m -C _1-4 -alkyl, -OR⁵, -S-R⁶, -CO-R⁷, -NR⁸R⁹, -CH ( CN) -COOH, -CH (CN) -COO-C _1-6 alkyl, = C (CN) -COOH, = (CN) -COOC _1-6 -alkyl, -NH-SO₂-R¹⁰, -C (NH₂ ) = NOH, imidazol-1-yl, 4-CH₃-thiazol- 2-yl, -NH-CO-NH₂, -NH-CS-NH₂, NH-CO-NH (C _1-4 -alkyl), NH- CS-NH (C _1-4 -alkyl), -Pyrrol-1-yl, -C (= NR) -NHR¹¹, -NH-C (= NR) -NR¹¹R¹², -S- (C = NR) -NR¹¹R¹², a phenyl or biphenyl radical optionally substituted one or more times with halogen, SC _1-4 4-alkyl or -OC _1-4 4 -alkyl, pyridyl, imidazolosulfonyl,
R³ is hydrogen, halogen, NO₂, OH, NH₂ or imidazol-1-yl,
AR² and R³ together form -O- (CH₂) _n -O-,
m, n 1 or 2,
R⁵ is hydrogen, a substituted or unsubstituted, straight-chain or branched, saturated or unsaturated hydrocarbon radical with 1-14 carbon atoms, which can contain 1-2 double and / or triple bonds and in which a -CH₂ group is replaced by oxygen, sulfur, phenyl or _{C 3-6} cycloalkyl optionally substituted with methyl or halogen can be replaced, C _3-7 cycloalkyl optionally substituted with methyl or halogen, -CO-R¹⁵, -CS-NH (C _1-4 -alkyl), -CH ( NH₂) -COO _1-6 -alkyl, -Si (CH₃) ₂ tert. butyl, quinolin-yl, N1-methyl-imidazol-2-yl, thiophenyl, thiacyclohexyl, tetrahydrofuranyl, -CS-SC _1-4 -alkyl, -CS-CH₂-SC _1-4 -alkyl, -C (= NR) NR¹¹R¹², optionally with halogen, NO₂, C _1-4 -alkylthio, C _1-4 -alkoxy or C _1-4 -alkyl substituted phenyl, tetrahydropyrimidine, tetrahydropyridine,
R⁶ has the meaning of R⁵,
R⁷ is hydrogen, C _1-8 -alkyl, C _3-7 -cycloalkyl, -CH₂-SC _1-4 -alkyl, (CH2) ₂-SC _1-4 -alkyl, -OC _1-6 -alkyl, NH₂, NH (C _1-4 -alkyl), -N (C _1-4 -alkyl) 2, -SC _1-4 -alkyl, CF₃, -C₂F₅, OH, phenyl,
R⁸, R⁹ are identical or different and are hydrogen, C _1-4 -alkyl, C _1-4 -alkanoyl or, together with the nitrogen atom, form a 5- to 6-membered saturated heterocycle which has a further O-, N- or S- Contain atom and can be substituted 1-2 times with C _{1-4 -alkyl,}
R¹⁰, R¹¹, R¹² and R are hydrogen, C _1-6 -alkyl, C _3-7 -cycloalkyl, phenyl,
R¹⁵ optionally substituted with halogen, NH₂, C≡N, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkanoyloxy, thiophene or phenyl substituted C _1-17 alkyl, optionally substituted with CH₃ or phenyl C _3-7 cycloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, -COOH, -COOC _1-6 alkyl, NR¹³R¹⁴,
R¹³, R¹⁴ are identical or different and are hydrogen or optionally halogen-substituted C _1-4 -alkyl,
and their isomers and tautomers and physiologically acceptable salts, for the preparation of a medicament for the inhibition of nitric oxide synthase, where R¹, AR² and R³ are not hydrogen at the same time. 5. Use of the compounds of formula IA according to claim 4 for the preparation of a Medicinal product for the treatment of neurodegenerative, autoimmune and / or inflammatory diseases as well as for the treatment of diseases of the heart Circulatory system and inf! Ammatory skin diseases and for immunosuppression. 6. Use according to claim 5 for the treatment of multiple sclerosis, Alzheimer's Disease, HIV dementia, amyotrophic ateral sclerosis or cerebral ischemia. 7. Process for the preparation of the compounds of formula I according to claim 1, characterized in that one

• a) a compound of the formula II, wherein Z, AR² and R³ have the above meaning, and Flu represents a leaving group, in the presence of a base with imidazole optionally substituted with R¹,
  or
• b) a compound of the formula III wherein Z, R¹, AR² and R³ have the above meaning and Flu represents a leaving group, introduces nucleophilic AR² or R³ in the presence of a base,
• c) a compound of the formula IV wherein Z, R¹, R³ have the above meaning, by means of aldol reactions with malonitrile, malon derivatives or other alpha-CH acidic compounds or via Wittig reactions or modified Wittig reactions or by nucleophilic attack, for example with Grignard reagents, to form compounds of formula I and then if desired halogenated or, if necessary, selectively reduced or thioethers or ethers cleaved or nitriles saponified or acids esterified or amidated or ethers or esters synthesized from phenols or amino groups exchanged or boiled via Sandmeyer reaction or sulfides oxidized to sulfones or sulfoxides or sulfoxides are reduced to sulfides or amines converted to amides or sulfonamides or alkylated or decarboxylated or isomers or salts are formed.