DD260928A5 - PROCESS FOR THE PREPARATION OF NEW ARALKYLIMIDIZOL DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel aralkylimidazole derivatives. According to the invention, 1-phenyl-lower alkylimidazole-4 and / or 5-carboxamides of the formula (I) are prepared in which Ph is phenyl substituted by lower alkyl and / or halogen, alk is lower alkylidene, one of the radicals R1 and R2 is optionally lower alkyl or lower alkanoyl substituted carbamyl and the other is hydrogen, lower alkyl or optionally substituted by lower alkyl or lower alkanoyl carbamyl and R3 is hydrogen or lower alkyl. They are prepared by reacting in a compound of formula (III) wherein R 1 is R 1 or X and R 2 is X or R 1 is X and R 2 is R 2, where X is mono- or disubstituted by lower alkyl or by lower alkanoyl monosubstituted carbamoyl group, the radical X or the radicals X in optionally mono- or disubstituted by lower alkyl or by lower alkanoyl monosubstituted carbamyl over. Formulas (I) and (III)

Description

Field of application of the invention

The invention relates to a process for the preparation of novel aralkylimidazole derivatives, in particular new i-phenyl-lower alkylimidazole-4 and / or 5-carboxamides having valuable pharmacological properties, in particular having anticonvulsant activity.

The compounds according to the invention are used as medicaments, for example for the treatment of epilepsy.

Characteristic of the known state of the art

There is no information available which compounds have hitherto been used for the treatment of convulsions of various genesis, for example for the treatment of epilepsy.

There are also no known data on processes for the preparation of Aralkylimidazolderivaten.

Object of the invention

The aim of the invention is to provide novel anticonvulsant compounds which are useful in the treatment of convulsions of various origins.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, new aralkylimidazole derivatives, in particular i-phenyl-lower alkylimidazole-4 and / or 5-carboxamides of the formula

< ³

wherein Ph is phenyl substituted by lower alkyl and / or halogen, alk is lower alkylidene, one of R ₁ and R _{2 is} carbamyl optionally substituted by lower alkyl or lower alkanoyl and the other is hydrogen, lower alkyl or carbamoyl optionally substituted by lower alkyl or lower alkanoyl, and R _{3 is} hydrogen or lower alkyl, with the proviso that in compounds of formula I in which R ₁ and R _{2 are the} same and are each carbamyl or N-methyl-carbamyl, at least one substituent of Ph in O position is bound when R _{3 is} hydrogen.

The phenyl radical Ph contains, for example, up to and with 3, in particular 1 or 2, of the substituents mentioned, preferably 1 lower alkyl or halogen substituent or 1 or 2 halogen substituents, furthermore 1 lower alkyl and 1 halogen substituent, preferably at least one of said substituents in one O-position is bound. Examples which may be mentioned are: O-halophenyl, 2,6-, furthermore 2,5-, 2,3- and 2,4-dihalophenyl and O-lower alkylphenyl, in particular 2,6-difluorophenyl. Optionally substituted by lower alkyl or lower alkanoyl carbamoyl R ₂ and optionally Ri is for example carbamyl or N-lower alkyl, Ν, Din-Diniederalkyl- or secondarily N-Niederalkanoylcarbamyl.

Above and below, "lower" organic groups and compounds are preferably to be understood as meaning those which contain up to and including 7, in particular up to and including 4, carbon atoms (C atoms).

Lower alkyl is, for example, C 1 -C ₄ -alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, furthermore secondary butyl, isobutyl or tert-butyl, but may also be a C ₅ -C ₇ -alkyl, such as pentyl, hexyl or heptyl group ,

Halogen is, for example, halogen of the atomic number up to and including 35, such as fluorine, chlorine or, secondarily, bromine.

Lower alkylidene is, for example, C 1 -C ₄ -alkylidene, in particular 1,1-C 1 -C -alkylidene, such as methylene, furthermore ethylidene, 1,1-propylidene or 1,1-butylidene, but may also be 2,2-C ₃ -C ₄ Alkylidene, such as 2,2-propylidene (isopropylidene) or 2,2-butylidene.

N-lower alkylcarbamyl is, for example, N-Ci-Q-alkylcarbamyl, such as methyl or ethylcarbamyl, NCi-Cy-alkyl, especially N-Ci-C ₄ -Alkykcarbamyl, such as methyl or ethylcarbamyl.

Ν, Ν-Diniederalkylcarbamyl is, for example, NjN-di-Cr-Gi-alkylcarbamyl, such as dimethylcarbamyl, further diethyl or di-npropylcarbamyl.

N-lower alkanoylcarbamyl is, for example, C ₂ -C ₇ -alkanyol, in particular C ₁ -C -alkanoylcarbamyl, such as acetyl, propionyl or butyrylcarbamyl, but may also be formylcarbamyl or N-C 1 -C 12 -alkanoyl, such as pivaloylcarbamyl.

The compounds of the formula I have valuable pharmacological properties, in particular a pronounced anticonvulsant activity, which can be demonstrated, for example, in the mouse on the basis of a clear metrazol antagonism in the doses region from about 10 mg / kg p.o. as well as on mice and rats by means of a pronounced protective effect against convulsions triggered by electroshock in the dose range from about 3.5 mg / kg p. o. show. Accordingly, the compounds of the formula I are excellently suitable for the treatment of convulsions of various origins, for example for the treatment of epilepsy. They can accordingly be used as anticonvulsive, for example antiepileptic, active pharmaceutical ingredients.

The invention relates in the first place to the preparation of compounds of the formula I in which Ph by lower alkyl and / or halogen mono-, di- or trisubstituted phenyl, alk represents lower alkylidene, one of the radicals Ri and R ₂ carbamyl, N-lower alkylcarbamyl, Ν , Ν-di-lower alkylcarbamyl or N-loweralkanoylcarbamyl and the other is hydrogen, loweralkyl, carbamyl, N-loweralkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl or N-loweralkanoylcarbamyl and R _{3 is} hydrogen or loweralkyl, with the proviso that in compounds of formula I in which Ri and R _{2 are} identical and are each carbamyl or N-methylcarbamyl, at least one substituent of Ph in O-position is bound when R _{3 is} hydrogen, preferably those in which at least one of said substituents of Ph in O-position and / or alk is methylene, R _{1 is} hydrogen or carbamyl and R _{2 is} carbamyl.

The invention concerns mainly the production of compounds of formula I, wherein Ph is substituted by C ₁ -C ₄ -alkyl monosubstituted phenyl, wherein _Ci-C4 alkyl such. B. is methyl and halogen has the atomic number up to and including 35 and z. B. is fluorine or secondarily chlorine, alk is 1,1- or 2,2-Ci- C ₄ alkylidene, such as methylene or ethylidene, one of the radicals R ₁ and R ₂ carbamyl, N-Ci- C ₄ alkyl or Ν, Ν-di - ^ - Ci-alkylcarbamyl, such as methyl or dimethylcarbamyl, or NC ₂ -C ₇ -Alkanoylcarbamyl, such as acetyl or Pivaloylcarbamyl, and the other hydrogen, carbamyl, NC ₁ -C ₄ -alkyl or Ν, Ν-di - ^ - Ci-alkylcarbamyl, such as methyl or dimethylcarbamyl, or NC ^ C ^ AIkanoylcarbamyl, such as acetyl or Pivaloylcarbamyl, and R _{3 is} hydrogen or in second line for C 1 -C ₄ -alkyl, such as methyl, with the proviso that in compounds of formula I in which R ₁ and R _{2 are} identical and are each carbamyl or N-methylcarbamyl, at least one substituent from Ph in O-position, when R _{3 is} hydrogen, preferably those in which at least one of said substituents is bound by Ph in O position and / or alk methylene, R _{1 is} water toff or carbamyl and R _{2 is} carbamyl.

The invention preferably relates to the preparation of compounds of formula I, wherein Ph is OC ^ C ^ AIkylphenyl, 0-halophenyl or 2,6-, further 2,5-dihalo-phenyl, wherein C ₁ -C ₄ -A ^ yI z. B. is methyl and halogen has the atomic number to and with 35 and independently of one another, for example fluorine or secondarily chlorine or bromine, alk1,1-C! -C ₄ -alkenes, such as methylene, one of the radicals Ri and R _{2 is} carbamyl, N-Cv-Cj-alkylcarbamyl, such as methylcarbamyl, Ν, Ν-di - ^ - Ci-alkylcarbamyl, such as dimethylcarbamyl, or N-Cr-Cj-alkanoylcarbamyl, such as acetylcarbamyl, and the other hydrogen, carbamyl, NCiQ -Alkylcarbamy ^ such as methyl or ethylcarbamyl, N ^ -Di-Ci-Ci-alkylcarbamyl, such as dimethylcarbamyl, or N-Ca-Q-alkanoylcarbamyl, such as acetylcarbamyl, and R _{3 is} hydrogen, preferably those in which alk methylene R _{1 is} hydrogen or carbamyl and R _{2 is} carbamyl and more particularly those in which alk is methylene, R 1 is hydrogen and R _{2 is} carbamyl.

The invention particularly relates, on the one hand, to the preparation of compounds of the formula I in which Ph is O-C 1 -C ₄ -alkylphenyl, such as O-methylphenyl, O-halophenyl, such as O-chloro- or O-fluorophenyl, or 2,6-dihalophenyl, such as 2,6-difluorophenyl, alk is methylene, R _{1 is} hydrogen, R _{2 is} carbamyl, N-Ci-d-alkylcarbamyl, such as N-methylcarbamyl, N ₁ N-di-Ci-C ₄ -alkylcarbamyl, as Ν, Ν-dimethylcarbamyl, or NC ₂ -C ₄ alkanoylcarbamyl, such as N-acetylcarbamyl, and R _{3 is} hydrogen, preferably those in which R _{2 is} carbamyl.

In particular, the invention relates to the preparation of compounds of the formula I in which Ph is 2,6-dihalophenyl, such as 2,6-difluorophenyl, alk is methylene, Ri is carbamyl, NCid-alkylcarbamyl, such as N-methylcarbamyl, N ₁ N- di-C ₁ -C ₄ alkylcarbamoyl, such as Ν, Ν-dimethylcarbamyl, or secondarily NC ^ Gj-Alkanoylcarbamyl such as N-Acetylcarbamyl means, R ₂ is hydrogen, Ci-C ₄ alkyl, such as methyl, or carbamyl or N-Ci-C ^ alkylcarbamyl identical to R ₁ , such as N-methylcarbamyl, Ν, Ν-di-C 1 -C -alkylcarbamyl, such as Ν, Ν-dimethylcarbamyl, or secondarily N-C 1 -C -alkanoylcarbamyl, such as N-acetylcarbamyl, and R _{3 is} hydrogen, preferably those in which Ri and R _{2 are} carbamyl.

The invention relates in the first place to the preparation of compounds of the formula I in which Ph is O-C 1 -C ₄ -alkylphenyl, such as O-methylphenyl, O-halophenyl, such as O-fluoro or O-chlorophenyl, or 2,6-dihalophenyl such as 2,6-difluorophenyl, furthermore 2,4-dihalophenyl, such as 2,4-difluorophenyl, or 2,5-dihalophenyl, such as 2,5-difluoro or 2-fluoro-5-chlorophenyl, alk Methylene, Ri is hydrogen, R _{2 is} carbamyl and R _{3 is} hydrogen.

The invention preferably relates to the preparation of the compounds of formula I mentioned in the examples.

The process according to the invention for the preparation of the compounds of the formula I is based on processes known per se. It is characterized in that one

a) into a compound of the formula

\ (ID,

or a salt thereof introduces the radical of formula Ph-alk- or b) in a compound of formula

Ph-alk-SjI ("ID.

wherein R ₁ 'is a radical R ₁ or X and R ₂ ' is a radical X or R ₁ 'is a radical X and R ₂ ' is a radical R ₂ , where X is an optionally mono- or disubstituted by lower alkyl or monosubstituted by lower alkanoyl carbamoyl convertible group, the radical X or the radicals X in optionally mono- or disubstituted by lower alkyl or monosubstituted or substituted by lower alkanoyl carbamoyl or

c) for the preparation of compounds of the formula I in which R 1 is hydrogen or lower alkyl, R _{2 is} di-lower alkylated carbamyl and R _{3 is} hydrogen, a compound of the formula

Ph-alk-NH ₂ (IV)

with an isonitrile of the formula

Xs _n / C

wherein X _{3 represents} a nucleofuge leaving group, condensed and, if desired, each an optionally obtained isomer mixture is separated into the components and isolated the desired isomers, a compound obtainable according to the method converted into another compound of formula I and / or a process according to the available diastereomer or enantiomer in the Diastereomers and / or enantiomers separates.

The implementation of the process according to the invention and the preparation of new starting materials or intermediates is carried out analogously to the reaction and formation of known starting materials or intermediates. In this case, although not expressly mentioned below, the customary auxiliaries, such as catalysts, condensation and Solvolysemittel and / or solvents or diluents, and reaction, such as temperature and pressure conditions, and optionally used protective gases.

The introduction of the radical of the formula Ph-alk in compound II according to process variant a) is carried out, for example, by reaction with a reactive ester of a corresponding phenyl-substituted phenyl-lower alkanol.

Reactive esters of phenyl-substituted phenyl-lower alkanols have, for example, the formula Ph-alk-X ₄ (VI), where as reactive esterified hydroxy X ₄ preferably with a mineral acid or an organic sulfonic acid, such as with a hydrohalic acid or an aliphatic or aromatic sulfonic ester esterified hydroxy, ζ , Β. Chlorine, bromine or iodine, or methane, ethane, benzene or p-toluenesulfonyloxy, is suitable.

The reaction is carried out, for example, under basic conditions, such as in the presence of a basic condensing agent or by using the component II as a salt, if necessary with heating, preferably in a solvent or diluent. Basic condensing agents are, for example, with the component II salt-forming basic condensing agents, such as alkali metal alcoholates, z. For example, sodium, potassium tert-butoxide or Natriumäthanolat, alkali metal or Erdalkalimetallamide, z. For example, sodium amide or lithium diisopropylamide. As mentioned, the conversion of component II into one of its salts is advantageously carried out in advance, e.g. by reaction with one of the bases mentioned.

Solvents are preferably the corresponding alcohols for carrying out the reaction in the presence of an alkoxide and when carrying out in the presence of metal amides, for example, aprotic organic solvents such as N-Niederalkylalkansäureamide, Phosphorsäureniederalkylamide or Diniederalkylsulfoxide, z. For example, dimethylformamide, hexamethylphosphoric triamide or dimethyl sulfoxide. The reaction preferably proceeds in the heat, e.g. B. in the temperature range of about 20-150 ⁰ C, preferably from about 25-100 ⁰ C.

Starting from compounds II, wherein Ri and R _{2 are} different, mixtures of the two possible isomers can be obtained, which must be separated to isolate only one isomer.

The process is therefore particularly suitable for the preparation of compounds wherein Ri and R _{2 are} identical optionally mono- or di-lower alkylated carbamoyl groups.

Starting materials II can be prepared, for example, by reacting in a compound of formula

_Η γ ^ MD.

wherein one of R / and R2 'is a halocarbonyl or lower alkoxycarbonyl group and the other is hydrogen, lower alkyl or a halocarbonyl or lower alkoxycarbonyl group, the halocarbonyl or lower alkoxycarbonyl group (s) by reaction with ammonia or a mono- or di-lower alkylamine optionally in mono or lower alkylated carbamyl. In turn, compounds VII can be prepared by reacting imidazole-4,5-dicarboxylic acid, if necessary in the presence of catalytic amounts of dimethylformamide or pyridine, with thionyl chloride to form 4,5-dicarboxylic acid chloride or in the presence of catalytic amounts of mineral acids, e.g. Hydrochloric acid or sulfuric acid, with a lower alkanol to give a 4,5-dicarboxylic acid lower alkyl ester. A general mode of formation is to react a compound of the formula Ph-C (= O) -R (VIII) wherein R is hydrogen or lower alkyl in the presence of an acidic condensing agent, e.g. Example of sulfuric acid in boiling ethanol or tetrahydrofuran, with a compound of formula H ₂ NC (RZ) = C (R ₂ ¹ I-NH ₂ (IX), wherein one of the radicals R ₁ 'and R ₂ ' is hydrogen, lower alkyl or Cyano and the other cyano, in the reaction product of the formula H ₂ NC (R i ') = C (R ₂ ') - N = C (R) -Ph (X), means the C-N double compound ^ .B Natrimborhydrid in methanol / tetrahydrofuran, reduced for single bond and the reaction product, for example in boiling diethylene glycol dimethyl ether, with formic acid or in the presence of an acidic catalyst with an orthoformate, eg., At about 80-100 ° C with triethyl orthoformate condensed and the cyano group (s) by basic hydrolysis in carbamyl or by reaction with a lower alkanol under acidic conditions and then with a lower alkyl or di-lower alkylamine and mild hydrolysis of the formed N-lower alkyl or Ν, Din-di-lower alkylamidine in N-lower alkyl or Ν , Ν-Diniederalkylcarbamyl over rführt.

According to process variant b) in optionally mono- or di-lower alkyl or lower alkanoylated carbamyl radicals convertible groups X are, for example, free, esterified or present in a salt or anhydride carboxy groups, the cyano group or optionally lower alkylated or lower alkanoylated amidino groups. Esterified carboxy groups are, for example, carboxy groups esterified with a lower alkanol or lower alkyl mercaptan, i. H. Lower alkoxy or Niederalkylthiocarbonylgruppen, but can also with any other alcohol or mercaptan, ζ. B. with an optionally substituted phenol, be esterified.

Carboxylic groups present in salt form are, for example, carboxy groups present in an ammonium salt form derived from ammonia or a mono- or di-lower alkylamine, and also in metal, e.g. B. alkali or alkaline earth metal salt form present carboxy groups.

Anhydride carboxy groups are, for example, carboxy groups present in a halide form, such as chlorocarbonyl, but may also be anhydrided with a reactive carboxylic acid and, for example, alkoxycarbonyloxycarbonyl or trifluoroacetoxycarbonyl.

Optionally lower alkylated or lower alkanoylated amidino groups are, for example, unsubstituted or N-lower alkylated, N, N-lower alkylated or N-lower alkanoylated amidino groups.

The conversion of said groups X in optionally substituted as indicated carbamyl is carried out in customary, z. By solvolysis, i. Hydrolysis or ammonia or aminolysis (reaction with ammonia or a mono- or di-lower alkylamine).

By hydrolysis, for example, unsubstituted or N-mono- or N, N-di-lower alkylated or N-lower alkanoylated amidino groups X can be converted into carbamyl groups which may be lower alkylated or lower alkanoylated or cyano X, respectively. The hydrolysis of said amidino groups is carried out, for example, under acidic conditions, for. B. in the presence of mineral acids, eg. B. of hydrochloric or sulfuric acid. The hydrolysis of cyano, for example, in the presence of a basic hydrolysis agent, such as an alkali metal hydroxide, z. B. of caustic soda or potassium hydroxide solution. It can by Peroxyverbindungen, z. B. of hydrogen peroxide, are facilitated and, for example, in a lower alkanol, for. In ethanol, as a diluent.

By means of ammonia or aminolysis, for example, free or esterified carboxy groups X present in a salt or anhydride form can be converted into unsubstituted or lower alkylated carbamyl. If necessary, it is carried out in the presence of a condensing agent, advantageously in an inert solvent. Condensation agents are, for example, basic condensation agents, especially ammonia or amines used for the aminolysis in excess starting from present in anhydride form carboxy further alkali metal hydroxides or carbonates, or tertiary organic nitrogen bases, such as Triniederalkylamine or tertiary heteroaromatic nitrogen bases, ζ. For example, triethylamine or pyridine. Toluene, for example, is particularly suitable as the inert solvent in the solvolysis of esterified carboxy groups. Free carboxy groups can be obtained by dehydration of the intermediately formed ammonium salts, for. By heating or exposure to dehydrating agents such as acid anhydrides, e.g. As phosphorus pentoxide, acetyl chloride and the like, or carbodiimides, z. B. N ^ '- Dicyclohexylcarbodiimid be converted into optionally lower alkylated carbamyl.

The starting materials of the formula III can, if they are not known, be prepared in customary manner, for example by reacting a compound of the formula

^{1 d} (XI)

with a compound of the formula Ph-alk-X ₄ (Vl), where X _{4 is} reactive esterified hydroxy, ζ. B. chlorine, bromine or iodine or methane or p-Toluolsulfönyloxy, means. The reaction of compounds XI and VI is carried out in particular in an analogous manner as described under process variant a). Compounds III obtainable by the process according to the invention, in which R ₁ 'and / or R ₂ ' are esterified carboxy or cyano, can subsequently, for. B. by treatment with sodium or potassium hydroxide in aqueous ethanolic solution to the corresponding carboxylic acids (III, R ₁ 'and / or R ₂ ' = carboxy) are hydrolyzed in a further reaction step, for. B. by thionyl chloride in toluene / pyridine or phosphorus pentachloride in tetrahydrofuran or by phosphorus oxychloride, in the acid chlorides (III, R ₁ 'and / or R ₂ ' = chlorocarbonyl) can be converted. Primarily obtained nitriles (III, R ₁ 'and / or R ₂ ' = cyano) may also be obtained by reaction with a mineral acid, for example with hydrochloric or hydrobromic acid or sulfuric acid and an alcohol, for. B. a lower alkanol or benzyl alcohol and further reaction of the imino ether formed with ammonia or a mono- or di-lower alkylamine in the corresponding amidines (111; R ₁ 'and / or R ₂ ' = optionally lower alkylated amidino) are converted.

In an alternative procedure, compounds III are obtained by reacting a compound of formula Ph-C (= O) -R (VIII) wherein R is hydrogen or lower alkyl, e.g. Example in the presence of sulfuric acid in boiling ethanol or tetrahydrofuran, with a compound of formula H ₂ NC (Ri ') = C (R2') - NH ₂ (IX) reacted the reaction product of the formula H ₂ NC (RZ) = C ( R ₂ ¹ IN = C (R) -Ph (X) or H ₂ NC (R ₂ ') = C (R,') - N = C (R) -Ph (UIe) the CN double compound, eg with Sodium borohydride in methanol / tetrahydrofuran, reduced to single bond and the reaction product, for example in boiling diethylene glycol dimethyl ether, with formic acid or in the presence of an acidic catalyst with an orthoformate, eg., At about 80-100 ° C with triethyl orthoformate, condensed. This process variant is particularly suitable for the preparation of dinitriles (III, R ₁ '= R ₂ ' = cyano) which, if desired, hydrolyzed to the dicarboxylic acid (III, R ₁ '= R ₁ ' = carboxy) as described above and optionally subsequently esterified or anhydrided or in a corresponding bis-amidine III, in which Ri 'and R ₂ ' are each an optionally N-mono- or N, N-lower alkylated amidino group, can be converted.

In starting materials V for process variant c), nucleophilic leaving groups X _{3 are,} for example, disubstituted amino groups, such as dilower alkylamino, eg. Dimethylamino, or 5- to 7-membered alkyleneamino, e.g. As pyrrolidino or piperidino, or aza, oxa- or thiaalkyleneamino, z. N'-methylpiperazino, morpholino or thiomorpholino. The reaction of compounds IV and V is carried out in customary manner, for example by heating in an inert solvent, such as an aromatic or araliphatic hydrocarbon, for. As benzene, toluene or xylene, in the temperature range of about 80 to 180 ° C, preferably from about 110-150 ⁰ C.

Starting materials IV can be prepared, for example, by reacting compounds of the formula Ph-alk-X ₄ (VI, X ₄ = chlorine, bromine or iodine) with ammonia under basic conditions or by reducing corresponding nitriles of the formula Ph-CN (XIII), for example by means of a Dileichtmetallhydrides, for example by means of lithium aluminum hydride, are produced. Starting materials V are obtained, for example, by converting a 2-isocyanoacetic acid lower alkyl ester into the corresponding 2-isocyano-N, N-lower alkyl acetamide by treatment with a di-lower alkylamine and mixing this with an N, N-disubstituted formamide acetal, for example with an N, N-di-lower alkylacetamide. , 5- to 7-membered Ν, Ν-alkylene or N, N-aza-, Ν, Ν-oxa or NN-thiaalkylene-formamiddiniederalkylacetaLz. B. with N, N-dimethylformamide dimethylacetal reacted. A particularly elegant process for the preparation of compounds I in which R _{1 is} hydrogen or lower alkyl and R _{3 is} hydrogen, according to a compound of the formula Ph-alk-NH ₂ (IV) in an inert solvent with a corresponding isonitrile of the formula CN- C (R ₂ ') = CH-X ₃ (XII), wherein R ₂ ' is Ν, Ν-di-lower alkylcarbamyl or esterified carboxy, to give a compound I, wherein R _{1 is} hydrogen or lower alkyl, R ₂ Ν, Ν-di-lower alkyl and R _{3 is} hydrogen, or to a compound III, wherein R is hydrogen or lower alkyl, R ₂ 'esterified carboxy and R _{3 is} hydrogen. The latter is then converted by reaction with ammonia or a lower alkylamine according to process variant b) into the corresponding compound I in which R _{2 is} carbamyl or N-lower alkylcarbamyl. Suitable nucleofuge leaving groups are, for example, the dimethylamino indicated for process variant c), or 5- to 7-membered alkyleneamino, eg. As pyrrolidino or piperidino, or aza, oxo or thiaalkyleneamino, z. N'-methylpiperazino, morpholino or thiomorpholino. Preferably, one works with heating, for. B. in the temperature range of about 80-180 ⁰ C, z. B. in boiling heat.

Compounds obtainable by the process can be converted into other compounds of the formula I by converting one or more variables of the general formula I into others.

Thus, one can unsubstituted carbamyl R ₂ and optionally Ri in N-mono- or Ν, Ν-diniederalkylcarbamyl, as well as N-Mononiederalkylcarbamyl R ₂ and optionally R ₁ in Ν, Ν-Diniederalkylcarbamyl, for example by treatment with a reactive ester of a lower alkanol, such as a lower alkyl halide, e.g. B. bromide or iodide, lower alkyl sulfonate, z. For example, methanesulfonate or p-toluenesulfonate, or a Diniederalkylsulfat, z. Example, dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium amide or sodium hydride or sodium hydroxide or potassium hydroxide solution and a phase transfer catalyst such as tetrabutylammonium bromide or benzyltrimethylammonium chloride. In an analogous manner, it is also possible to convert carbamyl R ₂ and / or R ₁ into N-lower alkanoylcarbamyl, although more strongly basic condensing agents, such as alkali metal amides or alcoholates, eg. As sodium amide or sodium, may be required.

Depending on the number of asymmetric carbon atoms, the novel compound may be present in the form of a pure optical isomer (enantiomer or diastereomer) or as mixtures thereof (racemates, diastereoisomer mixtures or racemic mixtures).

Obtained isomer mixtures of imidazole-4 (5) -carboxamiden and their niederalk at the amido group (ano) ylated derivatives and according to the method available diastereomer mixtures and racemic mixtures can be due to the physical. chemical differences of the components in a known manner in the pure position isomers, diastereomers or racemates

be separated, for example by chromatography and / or fractional crystallization. Preserved diastereomer mixtures, eg. As racemates, can also be broken down by known methods in the optical antipodes, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reaction of an acidic precursor, for. Example of the formula III (X = carboxy), with a forming with the racemic acid salts optically active base and separation of the diastereomeric salts thus obtained, for. Due to their different solubilities, into the diastereomers from which the antipodes can be released by the action of suitable agents. Suitable optically active bases are, for example, corresponding alkaloids, such as brucine, strychnine, ephedrine, quinine, quinidine or andronine, as well as menthylamine or a-phenylethylamine.

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and performs the missing steps or uses a starting material in the form of a salt or forms in particular under the reaction conditions. New starting materials which have been specially developed for the preparation of the compounds according to the invention, in particular the starting material selection which leads to the compounds of the formula I indicated at the outset as preferred, d. H. the processes for their preparation and their use as intermediates also form an object of the invention.

The novel compounds of formula I can, for. B. in the form of pharmaceutical preparations which contain a therapeutically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients which are used for enteral, z. As oral or parenteral administration are suitable. Thus, one uses tablets or gelatin capsules containing the active ingredient together with diluents, for. As lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants, for. For example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol have. Tablets may also bind, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. For example, starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Furthermore, the novel compound of the formula I can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these z. As in lyophilized preparations containing the active substance alone or together with a carrier material, for. As mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, eg. As preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired substances, for. As preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which may contain other pharmacologically active substances, are prepared in a conventional manner, for. Example by means of conventional mixing, granulation, coating, solution or lyophilization, prepared and contain from about 0.1% to 100%, in particular from about 1% to 50%, lyophilizates up to 100% of the active material.

The dosage may depend on various factors, such as route of administration, species, age and / or individual condition. The doses to be administered daily are between about 5 and about 50 mg / kg when administered orally and between about 0.5 g and about 5.0 g for warm-blooded animals weighing about 70 kg.

embodiment

The following examples serve to illustrate the invention; Temperatures are given in degrees centigrade.

Example 1:

5.34 g of 1- (2,3-difluorobenzyl) imidazole-4-carboxylic acid ethyl ester are dissolved in 80 ml of methanol and transferred to an autoclave. It presses 20.0 g of ammonia and heated to 100 ° C for 19 hours. After blowing off the excess ammonia, the precipitated product is filtered off and recrystallized from ethanol. 1- (2,3-Difluorobenzyl) imidazole-4-carboxamide of mp. 221-222 ° C.

 In an analogous manner one obtains

1- (2,4-difluorobenzyl) imidazole-4-carboxamide, mp 220-221 ⁰ C. 1- (2,5-difluorobenzyl) imidazole-4-carboxamide, m.p. 214-215 ° C (from dioxane); 1- (2,6-difluorobenzyl) imidazole-4-carboxamide, mp 227-229 ⁰ C (from ethanol). 1- (2,3-difluorobenzyl) imidazole-5-carboxamide, mp 199-200 ⁰ C (from isopropanol). . 1- (2,4-difluorobenzyl) imidazole-5-carboxamide, mp 207-208 ⁰ C (from isopropanol); 1- (2,5-difluorobenzyl) imidazole-5-carboxamide, m.p. 211-212 ° C (from isopropanol); 1- (2,6-Difluorobenzyl) imidazole-5-carboxamide, m.p. 184-185 ° C (from methanol); 1- (2,6-Difluorobenzyl) imidazole-4,5-dicarboxamide, m.p. 218-22O ⁰ C (from dioxane / ether); 1- (o-chlorobenzyl) imidazole-4,5-dicarbamide, m.p. 237-238 ° C (from acetic acid / water); 1- (o-methylbenzyl) imidazole-4,5-dicarboxamide, m.p. 219-221 ° C (from dioxane); 1- (2,6-Difluorobenzyl) -2-methyl-imidazole-4,5-dicarboxamide, m.p. over 300 ^° C (from acetic acid / water); 1- (2,6-difluorobenzyl) -4-methyl-imidazole-5-carboxamide, m.p. 233-235 ° C; i-io-chlorobenzylM-methyl-imidazole-B-carboxamide, m.p. 252-254 ° C; 1- (2,6-difluorobenzyl) -5-methyl-imidazole-4-carboxamide, m.p. 235-236 ° C; i-io-chlorobenzyl-S-methyl-imidazole ^ -carboxamide, m.p. 193-195 ° C; 1- (2,6-difluorobenzyl) -2-methyl-4-carboxamide, m.p. 266-267 ° C; 1- [1- (2,6-difluorophenyl) äthyi] imidazole-4-carboxamide, mp. 220 ⁰ C, and 1- [1- (2,6-difluorophenyl) äthyi] imidazole-5-carboxamide, mp. 163 -165 ⁰ C.

The starting materials, for example, ζ. Β. be prepared as follows:

a) 1.32 g of sodium are dissolved in 150 ml of ethanol. 6.72 g of imidazole-4-carboxylic acid ethyl ester and 9.9 g of 2,3-difluorobenzyl bromide are added and the mixture is heated to reflux for 3.5 hours while stirring. The reaction mixture is evaporated under reduced pressure, the evaporation residue is stirred with ice-water and extracted by shaking three times with 50 ml of ethyl acetate. The extracts are combined, washed with water and with saturated brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. This gives 1- (2,3-difluorobenzyl) -imidazole-4 (5) -carbonsäureäthylester as isomer mixture, which by chromatography on silica gel as a stationary and toluene / isopropanol (9: 1) as a mobile phase in the components, 1- (2 , 3-Difluorobenzyl) -imidazole-4-carboxylic acid ethyl ester, mp 95-100 ⁰ C (from toluene / hexane) and 1- (2,3-difluorobenzyl) imidazole-5-carboxylic acid ethyl ester (oil), can be separated.

b) 13.0 g of 2,6-difluorobenzyl alcohol and 8.4 g of methanesulfonyl chloride are dissolved in 90 ml of methylene chloride and treated dropwise with stirring in an ice bath with 17.6 ml of triethylamine in 18 ml of methylene chloride. The Eintropfgeschwindigkeit is regulated so that the internal temperature does not exceed 1O ⁰ C. It is allowed to stir for 40 minutes in an ice bath, mixed with 90 ml of ice water and allowed to stir for a further 60 minutes. The organic phase is separated off, dried over magnesium sulphate and treated with 21 g of the monosodium salt of imidazole-4,5-dicarboxylic acid diethyl ester (obtainable, for example, by reaction of diethyl imidazole-4,5-dicarboxylate with 2.53 g of sodium, dissolved in 60 ml of ethanol). added. The mixture is stirred for 3 hours at room temperature, washed three times with water, dried over magnesium sulfate, evaporated to dryness, dissolved in toluene / ethyl acetate (1: 1), filtered through silica gel, evaporated again to dryness and crystallized from ether / petroleum ether to. The 1- (2,6-difluorobenzyl) imidazole-4,5-dicarboxylic acid diethyl ester of the mp. 68-70 ⁰ C.

In an analogous manner one obtains:

1- (2,4-Difluorobenzyl) imidazole-4-carboxylic acid ethyl ester, mp. 89-90 ⁰ C, and 1- (2,4-difluorobenzyl) imidazole-5-carboxylic acid ethyl ester, mp. 70-72 ⁰ C;

1- (2,5-Difluorobenzyl) imidazole-4-carboxylic acid ethyl ester, m.p. 138-139 ° C, and 1- (2,5-difluorobenzyl) imidazole-5-carboxylic acid ethyl ester, m.p. 74-75 ° C;

. 1- (2,6-difluorobenzyl) imidazole-4-carboxylic acid ethyl ester, mp 114-115 ⁰ C, and 1- (2,6-difluorobenzyl) imidazole-5-carboxylic acid ethyl ester, mp 63-64 ° C.

and starting from 4-methylimidazole-5-carboxylic acid ethyl ester 1- (2,6-difluorobenzyl) -4-methyl-imidazole-5-carboxylic acid ethyl ester, mp. 59-61 ⁰ C (from hexane) and 1- (2,6-difluorobenzyl ) -5-methyl-imidazole-4-carboxylic acid ethyl ester, m.p.

107-108 ⁰ C (from toluene / ether), Ho ChlorbenzylM-methyl-imidazol-S-carboxylic acid ethyl ester, mp. 74-76 ° C, and 1- (o-ChlorbenzyO-ö-methyl-imidazol ^ -carbonsäureäthylester, mp. 100-104 ⁰ C;

and from Imidazol ^ ö-dicarboxylic acid diethyl ester 1- (2,6-difluorobenzyl) imidazole-4,5-dicarboxylic acid diethyl ester, mp. 71-73 ° C (ausPetroläther), i-io-ChlorbenzyOimidazol- ^ EJ-dicarboxylic acid diethyl ester, m.p. 69-70 ⁰ C (ausÄther / hexane) and 1- (o-methyl benzyl) -imidazole-4,5-dicarbonsäurediäthylester (oil);

and starting from diethyl 2-methylimidazole-4,5-dicarboxylate 1- (2,6-difluorobenzyl) -2-methyl-imidazole-4,5-dicarboxylic acid diethyl ester, mp. 63-64 ⁰ C (from ether / hexane).

c) 16.37 g of 1- (2,6-difluorophenyl) ethanol are dissolved in 74 ml of hexane, mixed with 74 ml of 48% hydrobromic acid and heated for 90 minutes with stirring to reflux. The mixture is allowed to cool, the organic phase is separated off and the aqueous phase is extracted 3 times with hexane. The combined hexane phases are dried over magnesium sulfate and filtered. The resulting solution of 1- (2,6-difluorophenyl) ethyl bromide is added to a previously mixed with a solution of 2.39 g of sodium in 50 ml of ethanol solution of 14.5 g of imidazole ^ fBJ-carboxylic acid ethyl ester in 100 ml of ethanol. The hexane is distilled off, then heated to reflux for 3 hours and obtained after work-up analogous to 1 a) 1- [1- (2,6-difluorophenyl) ethyl] imidazole-4-carboxylic acid ethyl ester, mp 96-97 ⁰ C, and 1- [1- (2,6-difluorophenyl) ethyl] imidazole-5-carboxylic acid ethyl ester, mp. 106-107 ⁰ C.

Example 2:

By reacting 1- (2,6-difluorobenzyl) imidazole-4-carboxylic acid ethyl ester with the appropriate amount of methylamine or dirriethylamine in a manner analogous to that described in Example 1, 1- (2,6-difluorobenzyl) imidazole-4- (N -methyl) carboxamide, mp 155-157 ° C (from ethyl acetate) and 1- (2,6-difluorobenzyl) imidazole-4- (N, N-dimethyl) carboxamide, mp. 113-115 ⁰ C (from ethyl acetate / Hexane), further by reaction of 1- (2,6-difluorobenzyl) imidazoi-4-carboxylic acid ethyl ester with the appropriate amount of ethylamine 1 - (2,6-difluorobenzyl) imidazole-4- (N-ethyl) carboxamide, mp 112- 114 ° C, and by reacting 1- (2,6-difluorobenzyl) imidazole-5-carboxylic acid ethyl ester with methylamine 1- (2,6-difluorobenzyl) imidazole-5- (N-methyOcarboxamid, mp. 128-130 ⁰ C.

Example 3:

4.0 g of Ho-fluorobenzyltimidazoM-carboxylic acid methyl ester are dissolved in 80 ml of methanol and transferred to an autoclave.

It presses 20.0 g of ammonia and heated to 100 ° C for 19 hours. After blowing off the excess ammonia, the precipitated product is filtered off and recrystallized from ethanol. 1- (o-fluorobenzyl) imidazole-4-carboxamide of the mp.

In an analogous manner one obtains:

1- (2,6-difuorobenzyl) imidazole-4-carboxamide, m.p. 227-229 ° C (methanol);

1- (o-chlorobenzyl) imidazole-4-carboxamide, m.p. 238-239 ° C;

1- (o-methylbenzene) imidazole-4-carboxamide, m.p. 245-245.5 ⁰ C and

1- (3,4-Difluorobenzyl) imidazole-4-carboxamide, m.p. 184-185 ° C.

The starting materials may, for. B. be prepared as follows:

8 g of o-fluorobenzylamine and methyl 6,6 g of 2-isocyanato-3-dimethylaminoacrylate are dissolved in 66 ml of xylene and heated to reflux for 3 hours with stirring. After cooling to room temperature, it is diluted with ethyl acetate and shaken twice with 50 ml of 2N hydrochloric acid and then with water. The aqueous phases are washed twice with 50 ml of ethyl acetate. All aqueous phases are combined, made alkaline with concentrated ammonia and extracted by shaking three times with 100 ml of dichloromethane each time. The extracts are combined, washed twice with water, dried over magnesium sulfate and evaporated to dryness. The evaporation residue is dissolved in ethyl acetate, filtered through silica gel, concentrated and

brought to crystallization by adding diethyl ether. This gives i-lo-fluorobenzyDimidazol ^ -carboxylic acid methyl ester, mp. 87-89 ° C.

In an analogous manner one obtains:

1- (2,6-difluorobenzyl) imidazole-4-carbonsäuremethylester, mp 107-109 ⁰ C.

i-lo-ChlorbenzyDimidazol- ^ ^ carbonsäuremethyleste mp. 82-83X;

1- (o-methylbenzyl) imidazole-4-carboxylic acid methyl ester, mp 89-9O ⁰ C and

1- (3,4-Difluorbenzyljimidazol-4-carbonsäuremethylester, mp. 139-141 ⁰ C.

Example 4:

15.7 g of 2,6-difluorobenzylamine and 11.2 g of 2-isocyano-3-dimethylamino-acrylic acid (N, N-dimethyl) amide are dissolved in 150 ml of toluene and heated to reflux for 3 hours with stirring. After cooling to room temperature, it is diluted with ethyl acetate and shaken twice with 50 ml of 2N hydrochloric acid and then with water. The aqueous phases are washed twice with 50 ml of ethyl acetate. All aqueous phases are combined, made alkaline with ammonia and extracted three times with 100 ml trichloromethane (chloroform). The extracts are combined, washed twice with water, dried over magnesium sulfate and evaporated to dryness. The evaporation residue is dissolved in ethyl acetate, filtered through silica gel, concentrated and brought to crystallization by addition of diethyl ether. This gives 1- (2,6-difluorobenzyl) imidazole-4- (N, N-dimethyl) carboxamide, mp. 113-115 ° C (from ether / hexane).

Example 5:

0.29 g of sodium are dissolved in 30 ml of ethanol. 1.9 g of imidazole-4,5-di (N-methyl) carboxamide and 2.4 g of 2,6-difluorobenzyl bromide are added and the mixture is heated to reflux with stirring. The reaction mixture is evaporated to dryness, the residue taken up in methylene chloride, extracted with water, dried over magnesium sulfate and evaporated. The evaporation residue is dissolved in toluene / ethyl acetate (1: 1), filtered through silica gel, re-evaporated and recrystallized from ethyl acetate. 1- (2,6-Difluorobenzyl) -imidazole-4,5-di (N-methyl) carboxamide, mp. 112-113 ° C. In an analogous manner, also 1- (2,6-difluorobenzyl) imidazole-4,5-di (N, N-dimethyl) carboxarhid, mp 184-185 ⁰ C obtained. The starting materials can be prepared, for example, as follows:

6.36 g ImidazolAö-dicarboxylic acid ethyl ester are dissolved in 140 ml of ethanol and transferred to an autoclave. The mixture is heated to 45g dimethylamine and heated for 45 hours at 100 ⁰ C and 30 hours at 110 ⁰ C. The reaction mixture is evaporated to dryness, purified by chromatography on silica gel with ethyl acetate / methanol (2: 1) and crystallized from ethyl acetate. This gives imidazole-4,5-di (N, N-dimethyl) carboxamide, mp. 108-110 ⁰ C, analogously using methylamine and imidazole ^ o-difN-methyOcarboxamid.

Example 6:

76 mg of sodium are dissolved in 3 ml of ethanol. 333 mg of imidazole-4-carboxamide are added, the mixture is stirred at room temperature for 30 minutes, 64 mg of 2,6-difluorobenzyl bromide, dissolved in 2 ml of ethanol, are added and the mixture is stirred at room temperature for a further 3 hours. The reaction mixture is evaporated to dryness. A mixture of 1- (2,6-difluorobenzyl) imidazole-4 and -5-carboxamide obtained by chromatography on silica gel with ethyl acetate / isopropanol (7: 2) as eluant in the components, 1- (2.6 Difluorobenzyl) imidazole-4-carboxamide, m.p. 227-229 ° C (from ethanol) and 1- (2,6-difluorobenzyl) imidazole-5-carboxamide, m.p. 184-185T (from methanol).

Example 7:

In a heated to 60 ⁰ C mixture of 30.7 g of acetic anhydride and 0.1 ml of sulfuric acid are added in portions with stirring 10.1 g of 1- (2,6-difluorobenzyl) imidazole-4-carboxamide. The mixture is stirred for 30 minutes at 60-70 ⁰ C, poured into 250 ml of ethanol, heated to reflux for 30 minutes, evaporated to dryness under reduced pressure and digested with 250 ml of ethyl acetate. The crystalline precipitate formed immediately is filtered off with suction and recrystallized from ethyl acetate. 1- (2,6-Difluorobenzyl) imidazole-4- (N-acetyl) carboxamide is obtained.

Example 8:

To a solution of 10.0 g of 1- (o-methylbenzyl) imidazole-4,5-dinitrile in 300 ml of ethanol and 25 ml of 5N sodium hydroxide solution are added dropwise at 40-50 ⁰ C 25ml 30% hydrogen peroxide solution. The mixture is stirred for 2 hours at 40-50 ⁰ C, diluted with 500 ml of water and filtered off with suction. After washing with water and recrystallization from dioxane gives 1- (o-methylbenzyl) imidazole-4,5-dicarboxamide, mp. 219-221 ⁰ C.

The starting material can be e.g. produce as follows:

3.70 g of sodium are dissolved in 375 ml of ethanol, mixed with 14.6 g of imidazole-4,5-dinitrile and 16.5 ml of o-methylbenzyl chloride and heated to reflux for 8 hours. It is evaporated to dryness under reduced pressure, taken up in dichloromethane, washed successively with water and with saturated brine, dried over sodium sulfate and evaporated to dryness. The crude product is purified by chromatography on silica gel with toluene / ethyl acetate (5: 1) and crystallized from ethyl acetate / hexane.

This gives 1- (o-methylbenzyl) imidazole-4,5-dinitrile, mp. 80-81 ⁰ C.

Example 9:

In an analogous manner as written in Examples 1 to 8, one also obtains:

1- (2,6-difluorobenzyl) imidazole-5- (N-acetyl) carboxamide;

1- (2,6-difluorobenzyl) imidazole-4,5-di (N-acetyl) carboxamide.

Example 10:

Tablets containing 50 mg each of 1- (2,6-difluorobenzyl) -imidazole-4-carboxamide can be prepared as follows.

Composition (10000 tablets) 500.0 g active substance 500.0 g lactose 352.0 g potato starch 8.0 g gelatin 60.0 g talc 10.0 g magnesium stearate 20.0 g Silicum dioxide (highly dispersed) q.s. ethanol

The active ingredient is mixed with the lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. After drying, the remainder of the potato starch, talc, magnesium stearate and fumed silica are mixed and the mixture is compressed into tablets each of 145.0 mg in weight and 50.0 mg of active ingredient content, which may optionally be provided with partial grooves for finer dosage adjustment ,

Example 11:

Lacquered tablets containing 100 mg of 1- (2,6-difluorobenzyl) imidazole-4-carboxamide can be prepared as follows:

Composition (10000tablets) 100.00 g active substance 100.00 g lactose 70.00 g corn starch 8.50 g talc 1.50 g calcium stearate 2,36g Hydroxypropyl methylcellulose 0.64 g shellac q.s. water q.s. methylene chloride

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened with granules of paste made from 15 g of corn starch and water (with heating). The granules are dried, the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed into tablets (weight: 280 mg) and coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; Final weight of the coated tablet: 283mg.

Example 12:

In a manner analogous to that described in Examples 10 and 11, it is also possible to prepare tablets or coated tablets containing another compound according to Examples 1-9.

Claims (27)

1. A process for the preparation of novel i-phenyl-lower alkylimidazole-4- and / or -5-carboxamides of the formula ^R3 wherein Ph is phenyl substituted by lower alkyl and / or halogen, alk is lower alkylidene, one of R ₁ and R _{2 is} carbamyl optionally substituted by lower alkyl or lower alkanoyl and the other is hydrogen, lower alkyl or carbamoyl optionally substituted by lower alkyl or lower alkanoyl, and R ₃ Is hydrogen or lower alkyl, with the proviso that in compounds of formula I in which R ₁ and R _{2 are the} same and are each carbamyl or N-methylcarbamyl, at least one substituent of Ph in O-position is bonded when R ₃ Represents hydrogen, characterized in that
a) into a compound of the formula (ID, or a salt thereof introduces the radical of formula Ph-alk- or b) in a compound of formula -ljl ⁷ Sji (III), Ph-alk wherein R ₁ 'is a radical R ₁ or X and R ₂ ' is a radical X or R ₁ 'is a radical X and R ₂ ' is a radical R ₂ , where X is an optionally mono- or disubstituted by lower alkyl or monosubstituted by lower alkanoyl carbamoyl convertible group, the radical X or the radicals X in optionally mono- or disubstituted by lower alkyl or monosubstituted or substituted by lower alkanoyl carbamoyl or c) for the preparation of compounds of the formula I, in which R _{3 is} hydrogen and R _{2 is} di-lower alkylated carbamyl, a compound of the formula Ph-alk-NH ₂ (IV) with an isonitrile of the formula
X ₃ . / NC Ri ^ Rz wherein X _{3 represents} a nucleofugic leaving group, condensed and, if desired, in each case an optionally obtained isomer mixture separated into the component and the desired isomers isolated, a process according to available compound converted into another compound of formula I and / or a method according to available diastereomer or enantiomer in the Diastereomers and / or enantiomers separates. 2. The method according to claim 1, characterized in that compounds of formula I, wherein Ph by lower alkyl and / or halogen mono-, di- odertrisubstituiertes phenyl, alk is lower alkylidene, one of the radicals R ₁ and R ₂ carbamyl, N- Lower alkylcarbamyl, N, N-di-lower alkylcarbamyl or N-lower alkanoylcarbamyl and the other hydrogen, Lower alkyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl or N-lower alkanoylcarbamyl and R _{3 is} hydrogen or lower alkyl produces. 3. Process according to Claim 1, characterized in that compounds of the formula I in which Ph is monosubstituted by C ₁ -C ₄ -alkyl or phenyl which is disubstituted by halogen or halogen and C ₁ -C ₄ -alkyl, alk 1,1 - or 2,2-C ₁ -C ₄ alkylidene, one of the radicals R ₁ and R ₂ carbamyl, NC ₁ -C ₄ alkyl or Ν, Ν-di-d-Ct-alkylcarbamyl or NC ₂ -C ₇ -Alkanoylcarbamyl, and the other is hydrogen, carbamoyl, N-Ci-C ₄ -alkyl or N, N-di-C ₁ -C ₄ alkylcarbamyl or NC ^ Cy-Alkanoylcarbamyl and R ₃ is hydrogen or C C ₁ -C ₄ alkyl is prepared. 4. The method according to any one of claims 1-3, characterized in that one produces compounds of formula I in which at least one of said substituents of Ph in O-position is attached. 5. The method according to claim 1, characterized in that compounds of formula I, wherein Ph is OdQ-alkylphenyl, O-halophenyl or 2,6-, further 2,5-dihalogenophenyl, alk 1,1 -C ₁ -C ₄ Alkylidene, one of the radicals R ₁ and R ₂ carbamyl, N-Cr-C ₄ alkylcarbamyl N, N-di-dC ₄ alkylcarbamyl or NC ₂ -C ₇ alkanoylcarbamyl and the other hydrogen, carbamyl, NdC ^ alkylcarbamyl , N, N-di-d-C4-alkylcarbamyl or N-Cr-d-Alkanoylcarbamyl and R ₃ is hydrogen, is prepared. 6. The method according to any one of claims 1-5, characterized in that one produces compounds of formula I in which alk is methylene, R _{1 is} hydrogen or carbamyl and R _{2 is} carbamyl. 7. The method according to any one of claims 1-5, characterized in that compounds of formula I, in which alk methylene, R _{1 is} hydrogen and R _{2 is} carbamyl, produces. 8. The method according to claim 1, characterized in that one compounds of the formula I, wherein Ph is Odd-alkylphenyl, O-Halögenphenyl or 2,6-dihalogenophenyl, alk is methylene, R _{1 is} hydrogen, R _{2 is} carbamoyl, Ndd- Alkylcarbamyl, N, N-di-C ₂ -C ₄ alkylcarbamyl or NC ₂ -C ₄ alkanoylcarbamyl and R _{3 is} hydrogen, produces. 9. Process according to Claim 1, characterized in that compounds of the formula I in which Ph is 2,6-dihalophenyl, alk is methylene, R _{1 is} carbamyl, NC ₁ -C ₄ -alkylcarbamyl, N-di-d-d Alkylcarbamyl or N-Cr-CrAlkanoylcarbamyl, R _{2 is} hydrogen, C ₁ -C ₄ -A ^ yI, carbamyl or NdC ^ alkylcarbamyl identical with R ₁ , NiN-di-C ₂ -C ₄ -alkylcarbamyl or NC ₂ -C ₄ Alkanoylcarbamyl and R _{3 is} hydrogen. 10. The method according to claim 1, characterized in that compounds of the formula I, wherein Ph is 2,6-dihalophenyl, alk is methylene and R _{3 is} hydrogen and wherein either Ri is hydrogen and R _{2 is} carbamyl, Nd-CrAlkylcarbamyl or N --Di-C ₁ -C ₄ -alkylcarbamyl or R _{1 is} carbamyl or NdC ^ alkylcarbamyl and R _{2 is} hydrogen or R ₁ and R _{2 are} both carbamyl. 11. The method according to claim 1, characterized in that, alk represents methylene compounds of the formula I, wherein Ph is o-Cr-C means ₄ -alkylphenyl, o-halophenyl or 2,6-dihalophenyl, R ₁ is hydrogen, R ₂ is carbamyl and R _{3 is} hydrogen. 12. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-4-carboxamide. 13. The method according to claim 1, characterized in that one prepares 1- (0-chlorobenzyl) imidazole-4-carboxamide. 14. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-4,5-carboxamide. 15. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-4- (N-methyl) carboxamide. 16. The method according to claim 1, characterized in that one produces 1- (0-fluorobenzyl) imidazole-4-carboxamide. 17. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-4- (N, N-dimethyl) carboxamide. 18. The method according to claim 1, characterized in that one prepares 1- (2,5-difluorobenzyl) imidazole-5-carboxamide. 19. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-5-carboxamide. 20. The method according to claim 1, characterized in that one produces 1- (2,6-difluorobenzyl) -5-methylimidazole-4-carboxamide. 21. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) -2-methyl-4-carboxamide. 22. The method according to claim 1, characterized in that one prepares 1- (0-methylbenzyl) imidazole-4-carboxamide. 23. The method according to claim 1, characterized in that one prepares 1- [1- (2,6-difluorophenyl) ethyl] imidazole-4-carboxamide. 24. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-4- (N-acetyl) carboxamide. 25. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-4- (N-ethyl) carboxamide. 26. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-5- (N-methyl) carboxamide. 27. The method according to claim 1, characterized in that one prepares 1- (2,6-difluorobenzyl) imidazole-4,5-di (N, N-dimethyl) dicarboxamide. 28. The method according to claim 1, characterized in that one prepares 1- [1- (2,6-difluorophenyl) ethyl] -imidazole-5-carboxamide.