DD228249A5 - PROCESS FOR PREPARING SUBSTITUTED IMIDAZOLES - Google Patents

Abstract

The invention relates to a process for the preparation of substituted imidazoles for use as medicaments. The aim of the invention is the provision of new compounds with valuable pharmacological, in particular antidepressant properties. According to the invention, substituted imidazoles of the general formula or salts thereof are prepared in which Ph is unsubstituted or lower alkyl or lower alkoxy-substituted phenyl and R 1 and R 2 are each lower alkyl, and pharmaceutical preparations containing these compounds.

Description

Berlin, April 19, 1935 AP C 07 Ώ / Ζ72. 059 64 807/12

Process for the preparation of substituted imidazoles

Field of application of the invention

The invention relates to a process for the preparation of substituted imidazoles having valuable pharmacological properties. The compounds prepared according to the invention are used as medicaments, for example as antidepressants.

Characteristic of the known technical solutions

From the following patents: EP-A-66144, EP-A-94167, DE-A-2 604 047, US-A-3 927 017 imidazoles having valuable pharmacological properties are known.

Object of the invention

The aim of the invention is the provision of new compounds with valuable pharmacological properties, which can be used in particular as antidepressants.

Explanation of the essence of the invention

The invention has for its object to produce by analogy new compounds with the desired properties.

-Ia-

According to the invention substituted imidazoles of the general formula

l ¹ A

Ph - CH - N N (I)

or salts thereof, wherein Ph is unsubstituted or lower alkyl or lower alkoxy-substituted phenyl and R ₁ and R are each lower alkyl, their use, processes for their preparation and pharmaceutical preparations containing a compound of formula I or a pharmaceutically acceptable salt thereof.

By lower alkyl or lower alkoxy substituted phenyl has in particular one or more, for. B, two, further three, in the ortho and / or raeta position bonded in the first, lower alkyl or Niederalkoxyreste on.

Above and below, by "lower ¹ * designated radicals or compounds are preferably to be understood as those containing up to and with 7, especially up to and with 4 carbon atoms.

The all-inclusive terms used have the following meanings:

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and further includes corresponding pentyl, hexyl or heptyl radicals.

Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, pentyloxy, isobutyloxy and tert -butyloxy.

Salts of compounds of formula I are their acid addition salts, preferably pharmaceutically acceptable acid addition salts. These are used, for example, with strong inorganic acids, such as mineral acids, e.g. Sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, e.g. Acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. Malonic, maleic or fumaric acid, or hydroxycarboxylic acids, e.g. Tartaric or citric acid, or with sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, e.g. Methane or p-toluene-sulfonic acid formed. Also included are unsuitable salts for pharmaceutical uses, since these can be used, for example, for the isolation or purification of free compounds according to the invention and those pharmaceutically usable salts thereof.

The compounds of the invention have e.g. valuable pharmacological properties. In particular, they have the ability to selectively and reversibly inhibit Type A monoamine oxidase (MAO). These properties can be detected in both rat liver and rat brain, where the degradation of serotonin is selectively inhibited. The determination of the MAO activity in the rat liver or in the rat brain was carried out analogously to the methodology of R.J. Wurtman et al., Biochem. Pharmacol. 12, 1439 (1963), wherein the MAO inhibition is observed from a dose of about 1 mg / kg after oral administration of the active ingredient.

Accordingly, the compounds of the invention can be used for the prophylactic and therapeutic treatment of depressive conditions.

Another object of the invention is therefore the prophylactic and therapeutic treatment of the human, further of the animal body and the use of the compounds of the invention for the treatment of depressive states.

The invention relates, for example, to compounds of the formula I or their salts, in which Ph is unsubstituted or mono- or polysubstituted, e.g. two-membered, by lower alkyl, in particular having up to and 4 C atoms, substituted phenyl and R. and R_ are each lower alkyl, in particular having up to and 4 C atoms, mean.

The invention relates, for example, to compounds of the formula I or their salts, in which Ph is mono- or polysubstituted, e.g. is di-substituted by lower alkoxy, in particular with up to and with 4 C atoms, such as methoxy, substituted phenyl, and R. and R are each lower alkyl, in particular with bis and with 4 C atoms, such as methyl.

More particularly, the invention relates to compounds of formula I or their salts wherein Ph is unsubstituted or in position 2 or 3 simply by lower alkyl or lower alkoxy each with bis and 4 C atoms such as methyl or methoxy, or in positions 2 and 6 twice phenyl which is substituted by lower alkyl having up to and including 4 C atoms, such as methyl, and R 'and R "are each lower alkyl having up to and including 4 C atoms, such as methyl.

The invention relates in particular to compounds of the formula I or salts thereof, in which Ph is unsubstituted phenyl and R.sup.10 and R.sup.4 are each lower alkyl having up to and including 4 C atoms, such as methyl.

The invention relates in particular to the novel compounds mentioned in the examples and their salts.

A further subject of the invention is a process for the preparation of the compounds of the formula I and their salts, which comprises

a) a compound of the formula

I ¹

Ph-CH-X ₁ (Ha),

wherein X. is reactive esterified hydroxy, with a compound of the formula

I ²

X ₀ -NN (Hb),

* - II

wherein X- represents hydrogen or a metallic radical, or

b) in a compound of the formula

Ph-CH-Het (III),

wherein Het is a radical which can be converted into 2-R_-imidazol-1-yl, Het is converted into 2-R-imidazol-1-yl, or

c) in a compound of the formula

/ w

Ph-AN N (IV) ₁

wherein A is a -CH (R.) - transferable grouping and the radical R 'is a radical convertible into R or R ", or wherein A is the grouping -CH (R.) - and R' is one in R Means "convertible radical, A in -CH (R ₁ ) - and / or R 'converted into R, or

d) a compound of the formula

R ₁ ·

I ® / W Θ Ph - C = N N A (V),

wherein A is an anion of a protonic acid, reduced to the corresponding compound of formula I, or

e) a compound of the formula

Ph-CH-X ₃ (VI),

wherein X- is a group convertible by cyclization into 2-R-imidazol-1-yl group, cyclized, or

f) a compound of the formula

ΐ * Λ

Ph-CH-NN (Vila)

with a compound of the formula R -X- (VIIb) in which one of the radicals X and X _{ft is} reactive esterified hydroxy and the other is a metallic radical, X is the radical R "and R is the radical R, or wherein one of the radicals X ,. and _{X.sup.fi is} reactive esterified hydroxy and the other is a metal radical, X is the radical R and R is the radical R, or

g) for the preparation of compounds of the formula I or salts thereof, in which Ph represents phenyl substituted by lower alkoxy, in a compound of the formula

I ¹ / W

Ph ¹ - CH - NN (VIII)

wherein Ph ^{1 is} a radical which can be converted into Ph, Ph ^{1 is converted} into Ph,

wherein the starting compounds listed in variants a) to g) can optionally also be in salt form, and, if desired, a compound of the formula I obtainable according to the invention is converted into another compound of the formula I and / or, if desired, an available salt into the free compound the formula I

or converted into another salt and / or, if desired, a free compound of the formula I obtainable according to the invention is converted into a salt and / or, if desired, an isomer mixture obtainable is separated into the individual components.

The reactions described above and below in variants a) to g) are carried out in a manner known per se, for example in the absence or usually in the presence of a suitable solvent or diluent or a mixture thereof, cooling with cooling, at room temperature or under heating, for example in a temperature range of about -10 ° to about +250 ⁰ C _1, preferably from about 20 ° to about 150 ⁰ C ₁ and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and / or working under anhydrous conditions.

The above and below listed starting material of the formulas Ha and Hb, III, IV, V, VI, VIIa and VIIb and VIII, which is for the. The preparation of the compounds of the formula I has been developed is partly known or can also be prepared by methods known per se, for example analogously to the process variants described above and below.

Variant a) :

Reactive esterified hydroxy means, in particular, hydroxy esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, e.g. Fluorosulfonyloxy, optionally, e.g. by halogen, substituted lower alkanesulphonyloxy, e.g. Methane or trifluoromethane-sulfonyloxy, cycloalkanesulfonyloxy, e.g. Cyclohexanesulfonyloxy, or optionally, e.g. by lower alkyl or halogen, substituted benzenesulfonyloxy, e.g. p-bromophenyl or p-toluenesulfonyloxy.

A metallic radical is, for example, an alkali metal, in particular lithium radical, furthermore a copper I or lithium-copper (I) radical derived from lithium cuprates.

The reaction is carried out in particular in the presence of a condensing agent, such as a suitable base.

Suitable bases are, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylidene, dicarboxylic acid, aminoalkylamides or lower alkylsilylamides, naphthalenamine, lower alkylamines, basic heterocycles, ammonium hydroxide and carbocyclic amines. Examples are sodium hydroxide, hydride, amide, potassium tert-butoxide, carbonate, lithium triphenylmethylid, diisopropylamide, potassium 3- (aminopropyl) amide, bis (trimethylsilyD'-amide, dimethylaminonaphthalene, di or triethylamine, pyridine, benzyltrimethylammonium hydroxide, 1,5-diazabicyclo-4,3'-cf [non-5-ene (DBN), and 1,8-diaza-bicycloj_5, 4cf] undec-7-ene (DBU ) called.

If X is hydrogen, the addition of additional base is not necessary if the base-active compound of the formula Hb is used in excess. The reaction with compounds of the formula Hb, when X _{7 is} a metallic radical, is advantageously carried out without addition of base.

The reaction is preferably carried out with those compounds of the formula Hb in which X _{7 is} hydrogen.

Variant b):

A radical Het convertible to 2-R-imidazol-1-yl may be e.g. 3-R-pyrazol-1-yl.

Its conversion into 2-R ₇ -imidazol-1-yl can be carried out, for example, by photoisomerization, for example by irradiation, as with a high-pressure mercury lamp.

A radical Het convertible into 2-R-imidazol-1-yl may also be 2-R-imidazolin-1-yl, in particular 2-R-imidazol-2-yn-1-yl, which may be e.g. can be converted by dehydrogenation in 2-R-imidazol-d-yl.

For dehydrogenation, suitable dehydrating agents are used, for example subgroup elements, preferably those of subgroup VIII of the Periodic Table, for example palladium, Raney nickel or platinum, or corresponding noble metal derivatives, for example platinum oxide or ruthenium triphenyl phosphide chloride, where the agents are supported on suitable support materials, Further preferred dehydrating agents are, for example, quinones, such as p-benzoquinones, for example tetrachloro-p-benzoquinone or 2,3-dichloro-5,6-dicyano-p-benzoquinone, and phenanthrene-9,10-quinone Further, N-halosuccinimides such as N-chlorosuccinimide, manganese compounds such as barium manganate or manganese dioxide, and sulfur and selenium derivatives such as sulfur, selenium, selenium dioxide or diphenylselenium bis-trifluoroacetate can be used.

Variant c) :

A structural element A which can be converted into the grouping -CH (R ₁ ) - represents, for example, the grouping -C (R ') (Z) -, where R j is either the radical R ₁ which has a hydrogen-convertible radical Z ₁ , and Z is hydrogen, or Rj is R ₁

and Z is a hydrogen-convertible radical Z, or wherein R ₁ ¹ ο I ¹ I

and Z together form lower alkenylidene or a tautomeric form thereof. Similarly, in R "UberfUhrbare radicals R 'by a hydrogen-convertible radical Z ₁ substituted lower alkyl radicals.

For example, Z ₁ can be converted into hydrogen by reduction and accordingly, for example, hydroxy, etherified hydroxy, such as lower alkoxy, halogen, sulfonyloxy, as appropriate,

e.g. by halogen, substituted lower alkanesulphonyloxy, cycloloweralkanesulphonyloxy or optionally, e.g. by lower alkyl or halogen, substituted benzenesulfonyloxy, mercapto or etherified mercapto, such as lower alkylthio.

The reductive conversion of A into the grouping -CH (R ₁ ) - or R 'in R "is carried out in a conventional manner, for example by means of a reducing agent, for example by hydrogenation in the presence of a hydrogenation catalyst, by reduction with a hydride transferring Reagent or by reduction with a metal reduction system of metal and proton-releasing agent.

As hydrogenation catalysts there are e.g. Elements of VIII. Subgroup of the Periodic Table of the Elements or their derivatives, such as palladium, platinum, platinum oxide, ruthenium, rhodium, tris (triphenylphosphine) rhodium (I) halide, e.g. Chloride, or Raney nickel, which are optionally supported on a support material such as activated carbon, alkali metal carbonate or sulfate or a silica gel, in question. Suitable hydride-transferring reagents are, for example, suitable light metal hydrides, in particular alkali metal aluminum hydrides or borohydrides, such as lithium aluminum hydride, lithium triethyl borohydride, sodium borohydride, sodium cyanoborohydride, or tin hydrides, such as triethyl- or tributyltin hydride, or diborane. The metal component of the metallic reduction system is, for example, a non-noble metal such as alkali or alkaline earth metal, e.g. Lithium, sodium, potassium, magnesium or calcium, or transition metal, e.g. Zinc, tin, iron or titanium, while as proton releasing agent e.g. Protonic acids, such as hydrochloric or acetic acid, lower alkanols, such as ethanol, and / or amines or ammonia, come into question. Such systems are for example sodium / ammonia, zinc / salt or acetic acid or zinc / ethanol.

In preferred embodiments of this process, for example, hydroxy or optionally etherified mercapto by

catalytic hydrogenation, e.g. in the presence of Raney nickel, and halogen or sulphonyloxy, e.g. by hydride-transferring reagents, tributyltin hydride, lithium aluminum hydride or sodium cyanoborohydride or sodium / ammonia.

Hydroxy can also be replaced by treatment with phosphorus (red) and hydrogen iodide or iodine by hydrogen.

Hydrogen-displaceable radicals Z ₁ which are displaceable in the benzylic position and are replaced by hydrogen are preferably replaced by hydrogen.

Z can also be carboxy. The decarboxylation of corresponding compounds of formula IV can be carried out usually at elevated temperatures, for example from a temperature of about 50 ⁰ C, especially in a temperature range of about 100 ° to about 300 ⁰ C. The decarboxylation can be effected, for example, by the presence of bases such as high boiling nitrogen bases,. for example, collidine, and / or in the presence of precious metals such as copper or copper bronze.

In the first place, one starts from compounds of the formula IV which have only one hydrogen-convertible radical Z.

Variant d) :

The reduction of the iminium salts of the formula V to the tertiary amines of the formula I is carried out, for example, with the aid of a reducing agent, e.g. Example of suitable means of reduction is the catalytic hydrogenation, treatment with a hydride-transferring reagent, e.g. Sodium borohydride, or the use of the metallic reduction system called zinc / hydrochloric acid.

As the reducing agent, formic acid may be further used.

Variant e) ;

A group X "which can be converted by cyclization into 2-R.-imidazol-1-yl represents, for example, the group of the formula

- N = CH - CH ₂ - NH - CO - R ₂ (VIa).

The cyclization of the group VIa is carried out, for example, by customary treatment of corresponding compounds of the formula VII with an acidic agent, in particular a mineral anhydride, such as a phosphorus oxyhalide, for example chloride, or phosphorus pentahalide, for example chloride. Particularly suitable is the system triphenylphosphine / hexachloroethane / triethylamine. In the first place, the procedure is analogous to that of W. Steglich et al., Liebigs Ann. Chem. 1978 , 1916-1927.

X "can continue for a group of formula

* 2 (VIb) or Ϊ ² C / \ NH C / \ N N CH ₂ -CHO CH ₂ -CHO

(VIb ¹ )

wherein the formyl group may also be present in acetalized form, for example as acetalized formyl with an alcohol such as lower alkanol or lower alkanediol.

The cyclization can be carried out, for example, in the presence of an acidic agent, for example a protic acid, such as a mineral acid, e.g. Hydrogen halide, sulfuric or polyphosphoric acid, a sulfonic acid, e.g. Trifluoromethane or p-toluenesulfonic acid, or a strong carboxylic acid, e.g. optionally substituted lower alkanecarboxylic acid, e.g. Glacial acetic acid or trifluoroacetic acid. Furthermore, for example, the aforementioned mineral acid anhydrides are suitable.

Variant f):

Reactive esterified hydroxy X. or X and X _£ has, for example, in variant a) for X. meaning, while a metallic radical X, or X. ₁ or X _{ft is,} for example, an alkali metal, such as lithium, sodium or potassium radical, a magnesium halide, such as bromide radical, a copper or derived from Lithiumcupraten lithium-copper radical.

In a modification of the process, it is possible, for example, to start from a compound of the formula VIIa in which X and X are each hydrogen and treat them with a strong base, such as butyllithium, and the compound of the formula VIIa in which X, and X_ each represent a metallic radical such as lithium, react with at least 2 moles of a compound of formula VIIb. In this case, it is initially possible to obtain in situ a compound of the formula VIIa in which one of the radicals X, and X,. is a metallic radical and the other is R- or R, which reacts under the reaction conditions directly further to the corresponding compound of formula I.

Advantageously, this reaction is first carried out at low temperatures, e.g. in a temperature range of -78 ° C to room temperature, performed.

Variant g) : Ph ^{1 represents} , for example, phenyl substituted by hydroxy.

Such compounds of formula VIII may be converted to the compounds of formula I by etherification with a lower alkylating agent. The lower alkylating agents include, for example, lower alkanols or reactive esters thereof, such as corresponding halogen, such as chloro, bromo or iodo, sulfonyloxy, such as hydroxysulfonyloxy, Halogensulfonyloxy-, eg Fluorsulfonyl ^ox y ~ i optionally, for example substituted by halogen, lower alkanesulfonyloxy -, eg methane or Trifluormethansulfonyloxy-, cyclo-

alkanesulfonyl, e.g. Cyclohexanesulfonyloxy, or optionally, e.g. by lower alkyl or halogen, substituted benzenesulfonyloxy derivatives, e.g. p-bromophenyl or p-toluenesulfonyloxy derivatives. Likewise, as lower alkylating agents, e.g. Diniederalkylsulfat, Diazoniederalkan, Triniederalkylsulfonium-, Triniederalkylselenium-, Triniederalkyloxosulfonium- or Triniederalkyl anil inium hydroxide, further Pentaniederalkoxyphosphin, into consideration.

When using reactive esters of lower alkanols or Diniederalkylsulfaten as Niederalkylierungsmitteln the etherification takes place in particular in the presence of one of the abovementioned bases, while the reaction with a Diazoniederalkan is optionally carried out in the presence of a Lewis acid. Lewis acids are, for example, halides of boron, aluminum, tin (II), antimony (III), arsenic (IIl), silver (I), zinc (II) and iron (III).

The etherification with the aid of a lower alkanol is carried out, for example, in the presence of a strong acid or, under anhydrous conditions, a dehydrating agent.

Strong acids are, in particular, strong protic acids, for example mineral acids, such as hydrohalic acids, sulfuric or phosphoric acids, strong carboxylic acids, such as an optionally, e.g. by halogen, substituted lower alkanecarboxylic acid or benzoic acid, e.g. Glacial acetic acid or trifluoroacetic acid, or sulfonic acids, as appropriate, e.g. by halogen, substituted lower alkanesulfonic acid or optionally, "e.g. by halogen or lower alkyl, substituted benzenesulfonic acid, e.g. p-toluenesulfonic acid, called.

Suitable dehydrating agents are, for example, carbodiimides, for example Ν, Ν'-di-lower alkyl or N ₁ N ¹ -dicycloalkyl-carbodiimide, such as Ν, Ν'-diethyl, N ₁ N ¹ -diisopropyl or Ν, Ν'-dicyclohexyl-carbodiimide, advantageously with addition of N-hydroxysuccinimide or optionally, for example by halogen, lower alkyl or lower alkoxy,

substituted 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide, Ν, Ν'-diimidazolecarbonyl, a suitable phosphoryl or phosphine compound, e.g. Diethylphosphonyl cyanide, diphenylphosphonyl azide or triphenylphosphine disulfide, a 1-lower-alkyl-2-halo-pyridinium halide, e.g. 1-methyl-2-chloro-pyridinium iodide, a suitable 1,2-dihydroquinoline, e.g. N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, or 1,1 '- (carbonyldioxy) -dibenzotriazole.

For example, Ph 'also means a diazonium moiety -N "

Θ Θ

A containing phenyl, wherein A is an anion of a strong protonic acid.

In order to convert such compounds of the formula VIII into corresponding compounds of the formula I, the diazonium grouping -N_A is substituted by lower alkoxy, in particular by treatment with a lower alkanol.

In an advantageous modification of this process variant, the compounds of formula VIII can be formed in situ and continue to react under the reaction conditions without isolation to the compounds of formula I. The starting point is a compound of the formula VIII in which Ph ^{1 is} an amino-containing phenyl, diazotized with nitrites, such as alkali metal nitrites, or nitro-lower alkanes in the presence of protic acids, for example those of the abovementioned type, and the compounds formed in situ are used .The formula VIII, wherein Ph 'is a diazonium group N "A having phenyl, without their isolation with a lower alkanol. Advantageously, a reaction temperature of about -10 ° to about +40 ⁰ C is selected for this reaction.

Above all, the invention relates to the production method described in the exemplary embodiments.

A compound according to the invention can be converted into another compound according to the invention by methods known per se.

Thus, for example, a lower alkyl radical can be introduced into the phenyl ring Ph by, for example, alkylating with a reactive ester of a lower alkanol in the presence of a Lewis acid (Friedel-Crafts alkylation).

The preparation of the starting materials described in variants a) to g) is carried out using methods known per se.

Thus, for example, the starting material of the formula III can be prepared by reacting compounds of the formula Ha with compounds of the formula X "- Het (HIa) analogously to the procedure described in variant a).

In an analogous manner, it is also possible to obtain starting compounds of the formulas IV ₁ VIIa or VIII, for example by reacting compounds of the formulas Ph-AX. (IVa) and (Hb) [leads to compounds of the formula iv] or Ph-CH (X) -X (VIIc) and

/ W

X-N N (VIId) [leads to compounds II of formula VIIa]

and Ph'-CH (R) -X (HIa) and (Hb) [leads to compounds of formula VIIlJ.

Compounds of the formula VI in which X "is the moiety of the formula VIa are obtainable, for example, by acid-catalyzed reaction of compounds of the formulas

R ₂ -CO-NH-CH ₂ -CH (= O) (VIc) with compounds of the formula

H ₂ N - CH (R ₁ ) - Ph * (VId).

Compounds of formula VI wherein X ₁ ~ represents the group of formula VIb VIb or ^1, for example, by condensation of compounds of the formula

R ₂ - Ό (= ΝΗ) - Xg (VIe) ₁

wherein X "is a leaving group, such as lower alkoxy or amino, and compounds of the formula

Ph - CH (R ₁ ) - NH - CH ₂ --CH (= O) (VIf)

accessible, wherein the secondary amino group also additionally an acyl radical, such as lower alkanoyl, e.g. Acetyl, may have.

A further variant for the preparation of a compound of the formula VI in which X_ is the grouping of the formula VIb or VIb ¹ consists, for example, in the reaction of a compound of the formula VId with a compound of the formula VIe and condensation of the compound of the formula Ph- CH (R) -NH-C (R) = NH (VIg) with a monohaloacetaldehyde or especially an acetal thereof. Likewise, a compound of the formula Ph-CH (R ₁ ) -N = (R.) - X ₀ (VIh) with

1 Zo

react an acetal of Aminoacetaldehyds.

A compound of formula VI, wherein X represents the group VIb VIb or ^1, in particular can be formed in situ and further react under the reaction conditions, to the corresponding compound of formula I.

Salts of compounds of the formula (I) can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of the formula (I) are obtained by treatment with an acid or a suitable ion exchange reagent. Salts may be converted to the free compounds in a conventional manner, acid addition salts e.g. by treating with a suitable basic agent.

Depending on the procedure or reaction conditions, the novel compounds having salt-forming, in particular basic properties, can be obtained in free form or in the form of salts.

As a result of the close relationship between the new compound in free form and in the form of its salts, the corresponding salts or the free compound are to be understood as meaningful and appropriate in the preceding and following by the free compound or its salts.

The novel compounds, including their salts of salt-forming compounds, can also be obtained in the form of their hydrates or include other solvents used for crystallization.

The new compounds may, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or mixtures thereof, e.g. depending on the number of asymmetric carbon atoms, as pure optical isomers, such as antipodes, or as mixtures of isomers, such as racemates, diastereoisomer mixtures or racemate mixtures.

Resulting diastereomer mixtures and mixtures of racemates can be separated separately in a known manner in the pure isomers, diastereomers or racemates due to the physico-chemical differences of the constituents, for example by fractional crystallization.

Obtained racemates can also be decomposed by known methods into the optical antipodes, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents with the aid of suitable microorganisms, by cleavage with specific immobilized enzymes, via the formation of inclusion compounds, e.g. using chiral crowns

ether, wherein only one enantiomer is complexed, or by conversion to diastereomeric salts, e.g. by reacting a basic end-product racemate with an optically active acid such as carboxylic acid, e.g. Tartaric or malic acid, or sulphonic acid, e.g. Camphorsulfonic acid, and separation of the diastereomeric mixture thus obtained, e.g. due to their different solubilities, into the diastereomers from which the desired enantiomer can be released by the action of suitable means. Advantageously, one isolates the more effective enantiomer.

The invention also relates to those embodiments of the process according to which one starts from an intermediate compound obtainable at any stage of the process and carries out the missing steps or uses a starting material in the form of a derivative or salt and / or its racemates or antipodes or especially under the reaction conditions. '

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable. Novel starting materials which have been specially developed for the preparation of the compounds according to the invention, their use and processes for their preparation likewise form an object of the invention, the variables R ₁ , R "and Ph having the meanings given for the respectively preferred compound groups of the formula I. ,

The invention also relates to the use of the compounds of the formula (I) or of pharmaceutically acceptable salts of such compounds having salt-forming properties, in particular as pharmacological, primarily antidepressant active, active substances. They may be used, preferably in the form of pharmaceutically acceptable preparations, in a method for the prophylactic and / or therapeutic treatment of the animal or human body, in particular as antidepressants for the treatment of depression.

The invention also relates to pharmaceutical preparations containing the compounds of the invention or pharmaceutically acceptable salts thereof as active ingredients, as well as processes for their preparation.

The pharmaceutical compositions of the invention containing the compound of the invention or pharmaceutically acceptable salts thereof are those for enteral, such as oral, rectal, and parenteral administration to warm-blooded animals, the pharmacologically active ingredient being alone or in combination with a pharmaceutically acceptable Carrier material is included. The daily dosage of the drug depends on the age and the individual condition, as well as on the mode of administration.

The active substances may further with the aid of transdermal therapeutic systems (TTS), which serve the controlled percutaneous drug delivery for systemic treatment, for example in the form of a plaster of rounded shape with a

2 large of about 2 to 50 cm are brought to the skin. For example, the drug delivery may be over a period of about 24 hours to a week.

Such Transdermal systems are multi-layered and consist of e.g. from the outside inwards from an impermeable covering film, a drug reservoir, an adhesive or adhesive layer as well as a peel-off film to be removed before application. In the case of the corresponding matrix or monolith systems, the active ingredient is distributed in a polymer layer, from which it is released by diffusion. It is also possible to use membrane-controlled systems in which a diffusion-determining semipermeable or microporous control membrane is located between the active substance reservoir and the skin. For the dosage, the amount of active ingredient absorbed per unit time is e.g. depends on the size of the contact area between the drug reservoir and the skin.

The novel pharmaceutical preparations contain, for example from about 1O to about 80 ^ £, preferably eta £ 20 to about 60 ^ ₁ of the active ingredient. Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in dosage unit forms, such as dragees, tablets, capsules or suppositories, furthermore ampoules. These are produced in a manner known per se, for example by means of conventional mixing, granulating, coating, solution or lyophilization processes. Thus, one can obtain pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable excipients, processed into tablets or DragSe cores ,

Suitable carriers are, in particular, fillers, such as sugars, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphate, e.g. Tricalcium phosphate or calcium hydrogen phosphate, also binders such as starch pastes using e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, if desired, disintegrants such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow, control and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, possibly gastric juice-resistant coatings, which u.a. concentrated sugar solutions, which may contain arabic gum, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxyl

propylmethyl cellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible for stabilizers to be added.

As rectally applicable pharmaceutical preparations are e.g. Suppositories which consist of a combination of the active ingredient with a SupposLtoriengrundmasse. As suppository base, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a basic bulking agent may also be used. As basic materials there are e.g. liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons in question.

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or vehicles such as fatty oils, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate or triglycerides, used or aqueous injection suspensions containing viscosity increasing agents, e.g. Sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also stabilizers.

The dosage of the active ingredient depends on the species of the genus, the age and the individual condition as well as the mode of administration. Normally, an approximately daily dose of about 100 to about 500 mg, in particular 200 to about 300 mg, advantageously in several equal divided doses is to be estimated for a warm-blooded animal weighing about 75 kg when administered orally.

embodiment

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees centigrade.

Example 1 ; 24.4 g (0.2 mol) of 1-phenyl-ethanol and 27.6 g (0.24 mol) of methanesulfonyl chloride are dissolved in 250 ml of toluene and at 10 ° in the course of 30 minutes, a solution of 28.2 g Dropped (0.28 mol) of triethylamine in 50 ml of toluene with stirring. The reaction mixture is stirred for 12 hours at room temperature and then the precipitated triethylaranine hydrochloride is filtered off. The residue is washed with toluene and the combined filtrates are evaporated to dryness in a water-jet vacuum. The resulting OeI is added dropwise with stirring at 95 in the course of 15 minutes to a solution of 50 g (0.6 mol) of 2-methylimidazole and kept at 100 ° for 6 hours. The reaction mixture is mixed with 200 ml of ether and 200 ml of water, the organic phase separated and washed 3 times with water. The organic phases are extracted by shaking 3 times with 100 ml hydrochloric acid 2N, the aqueous, acidic phases with conc. Sodium hydroxide solution made alkaline and again extracted with ether. The organic ones

- 23a -

Phases are dried over magnesium sulfate and the solvent is removed under a water-jet vacuum. The crude OeI is distilled under high vacuum at 120 ° C. (13.3 Pa) and gives, after recrystallization from cyclohexane, pure 1- (1-phenylethyl) -2-methyl -imidazole, which melts at 84-85 °. 22.8 g (0.12 mol) of the resulting base are dissolved in 100 ml of ethyl acetate and with alcoholic hydrochloric acid

- 24 -

acidified (pH ~ 1). After addition of 25 ml of ether, the precipitate is filtered off, washed with ether and dried at 60 ° in vacuo. The resulting pure 1- (1-phenylethyl) -2-methylimidazole hydrochloride melts at 229-229.5 °.

Example 2: In an analogous manner as described in Example 1 is from 40.86 g (0.3 mol) of l- (p-methyl-phenyl) -ethanol and 73.9 g (0.9 mol) of 2-methyl imidazo1 oily 1- (p-methyl-phenyl) -ethyl] -2-methyl-imidazole. The hydrochloride prepared from it melts at 237-238 °.

Example 3 : In an analogous manner as described in Example 1 from 30.1 g (0.2 mol) of l- (2,4-dimethyl-phenyl) ethanol and 49.3 g (0.6 mol) of 2-methylimidazole 21.3 g of oily [1- (2,4-dimethylphenyl) ethyl] -2-methylimidazole are obtained as crude product. The analogously prepared hydrochloride melts at 238-239 °.

The required as starting material l- (2,4-dimethyl-phenyl) -ethanol is prepared as follows:

44.5 g (0.3 mol) of 2,4-dimethylacetophenone are dissolved in 200 ml of isopropanol and slowly added dropwise at 60 ° with stirring an ice-cold solution of 5.7 g (0.15 mol) of sodium borohydride in 50 ml of water. The reaction mixture is heated at reflux temperature for 4 hours, cooled and treated with 200 ml of 1 molar sodium dihydrogen phosphate solution. The isopropanol is largely removed in a water-jet vacuum and the residue is extracted by shaking with ether. The organic phases are washed with brine, dried over magnesium sulfate and the solvent removed in a water-jet vacuum. The residue obtained is distilled under a water jet vacuum to give 1- (2,4-dimethyl-phenyD-ethanol of bp. (1866.5 Pa) 120 ° Ishizaka, Chem. Ber. 47, 2461, bp ₁₄ = 124-125 ° ].

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Example 4: Analogously to Example 1, 27.3 g (0.2 mol) of l - [(2-methyl-phenyl) -ethyl] -ethanol and 49.3 g (0.6 mol) of 2 are obtained -Methylimidazole oily 1- [l- (2-methyl-phenyl) -ethyl 2-2-methyl-imidazole obtained as a crude product. The hydrochloride melts at 237-238 °.

The l- (2-methyl-phenyl) -ethanol required as starting material is prepared analogously to Example 3 (Auwers, V. et al., Chem. Ber. 58 , 46, Kp ₂₀ = 107-108 °).

Example 5 ; 25 g (0.113 mol) of 1- (1-phenyl-ethenylidene-1-yl) -2-methylimidazole hydrochloride are added to 200 ml of saturated potash solution and shaken out three times with 100 ml of ether each time. The organic extracts are dried over magnesium sulfate and evaporated to dryness in vacuo. The residue obtained is dissolved in 500 ml of methanol and hydrogenated with the addition of 1 g of 5 J ₀ palladium carbon at room temperature and atmospheric pressure. The catalyst is filtered off, washed with methanol and the combined methanolic solutions are evaporated to dryness in vacuo. The resulting oily residue is crystallized from cyclohexane and gives pure 1- (1-phenyl-ethyl) -2-methyl-imidazole, mp. 84-85 °.

The starting material is e.g. obtained as follows:

a) 130 g (0.68 mol) of a-chloro-phenylacetyl chloride are added dropwise at 20-30 ° to 500 ml of ethanol and stirred at 30-40 ° for 3 hours. The solvent is removed in vacuo to give crude 2-chloro-2-phenyl-acetic acid ethyl ester. The product obtained (137 g) is dissolved in 2 l of toluene and the solution is treated with 170 g (2.07 mol) of 2-methylimidazole. The reaction mixture is kept at 100 ° with stirring for 12 hours. The resulting reaction mixture is extracted by shaking 4 times with 500 ml of water, the aqueous phases washed with a little toluene and the combined organic

- 26 -

Phases dried over magnesium sulfate. After removal of the solvent in vacuo crude oily 2-phenyl-2- (2-methyl-imidazol-lyl) -acetic acid ethyl ester is obtained. The compound distills at 145 ° (26.66 Pa). The pure hydrochloride melts at 157-159 °.

b) 142.9 g (0.585 mol) of 2-phenyl-2- (2-methyl-imidazol-1-yl) -acetic acid ethyl ester are dissolved in 1.5 l of isopropanol and, while stirring at 5 °, a solution of 23 g (0 , 6 mol) of sodium borohydride in 150 ml of water was added dropwise over 30 minutes. The mixture is stirred without cooling for 6 hours, the temperature of the mixture reaches 45-50 °. The mixture is cold with a mixture of conc. Hydrochloric acid and water (1: 1) acidified (pH = 1-2) and the solvent is largely removed in vacuo. The residue is added in the cold with saturated potash solution to the alkaline reaction and shaken out 3 times with 300 ml of ether. The combined organic phases are dried over magnesium sulfate and the solvent removed in vacuo. The resulting oily residue is crystallized from ether / cyclohexane to yield pure 2-phenyl-2- (2-methyl-imidazol-1-yl) -ethanol (1), mp 114-116 °.

105.3 g of the base obtained are dissolved in 300 ml of ethanol and treated with alcoholic hydrochloric acid until acidic reaction. After addition of 200 ml of ethyl acetate and about 200 ml of ether, the precipitated product is filtered off, washed with ethyl acetate and dried in vacuo at 60 °. The pure 2-phenyl-2- (2-methyl-imidazol-1-yl) -ethanol hydrochloride melts at 144-146 °.

115 g (0.481 mol) of 2-phenyl-2- (2-methyl-imidazol-1-yl) -ethanol hydrochloride are dissolved in 1 1 of chloroform and refluxed with 120 g (1 mol) of thionyl chloride for 10 hours. The reaction mixture is evaporated to dryness in vacuo and the crude product is used directly. 120.4 g of the crude 1- [2- (1-chloro-2-phenyl-ethyl) 3-2-methyl-imidazole hydrochloride are dissolved in 1 liter of chloroform and 152 g (1.0 mol) of 1S-diaza BicyclofjJ ^ O ^ -undec-y-en stirred for 12 hours at room temperature.

- 27 -

The reaction mixture is freed from the solvent under reduced pressure and combined with 500 ml of cyclohexane and water each time. The aqueous phase is separated and the organic phase washed 3 times with 100 ml of water. The organic phase is dried over magnesium sulfate and the solvent removed in vacuo. The crude 1- (1-phenylethenylidene-1-yl) -2-methyl-imidazole is obtained as OeI. The base has a boiling point of bp 130 ° (6.66 Pa). 82 g of the crude base are dissolved in 200 ml of ethyl acetate and treated with about 7n alcoholic hydrochloric acid until acidic reaction. After addition of 50 ml of ether, the precipitated product is filtered off, washed with ether and dried in vacuo at 60 °. The pure 1- (1-phenyl-ethenylidene-1-yl) -2-methyl-imidazole hydrochloride melts at 258-260 °.

Example 6 : 8.6 g (0.05 mol) of 1- (1-phenyl-1-ethyl) -imidazole are dissolved in 80 ml of abs. Dissolved tetrahydrofuran and added dropwise at -70 ° 30 ml (2 mol) of n-butyl lithium solution in hexane. The mixture is stirred for 30 minutes at -70 ° and then added dropwise 7.1 g (0.05 mol) of methyl iodide in 20 ml of tetrahydrofuran.The cooling is removed, the mixture slowly brought to room temperature and left for 2 hours at this temperature 25 ml of 2N sodium hydroxide solution are added and the tetrahydrofuran is largely removed in vacuo, the residue is extracted by shaking with ether, the organic phases are dried over magnesium sulphate and the solvent is removed in vacuo.The oily residue obtained is dissolved in ethyl acetate with ethereal hydrochloric acid until acidic reaction After recrystallization from isopropanol / ether, the pure 1- (1-phenylethyl) -2-methylimidazole hydrochloride melts at 228-229 °.

Example 7: In an analogous manner as in example 1 from 13.6 g (0.1 mole) of l- [l- (3-methyl-phenyl) -ethyl] -ethanol and 24.6 g (0.3 mol) 2-Methylimidazole oily 1- [l- (3-methyl-phenyl) -ethyfj-2-methylimidazole obtained as a crude product. The hydrochloride melts at 228-230 °.

- 28 -

Example 8: In a manner analogous to that described in Example 1, 13.6 g (0.1 mol) of 1-phenylpropanol (1) and 25 g (0.3 mol) of 2-methylimidazole are converted into crude oil - (phenyl) -propyl [] - 2-methyl-iiiiidazol obtained as OeI. The hydrochloride melts at 177-179 ".

Example 9 : In an analogous manner as described in Example 1, from 15.0 g (0.1 mol) l- (2-ethyl-phenyl) -ethanol and 25 g (0.3 mol) of 2-methylimidazole crude, oily l - [] 1- (2-ethylphenyl) ethyl 3-2-methylimidazole. The hydrochloride melts at 211-213 °.

Example 10 : In an analogous manner as described in Example 1, from 15.0 g (0.1 mol) of l- (2,6-dimethyl-phenyl) ethanol and 25 g (0.3 mol) of 2-methylimidazole crystallized l- [1- (2,6-dimethylphenyl) ethyl] -2-methyl-imidazole, mp 100-103 ", which melts at 265-267 °.

Example 11 18.8 g (0.1 mol) of 1- [1- (phenyl) -ethyl] -2-methyl-4,5-dihydroimidazole are dissolved in 4000 ml of methylene chloride and, with stirring and exclusion of moisture, 282 g (1, 1 mole) of barium manganate. The mixture is stirred at reflux for 24 hours. Subsequently, 20 g of magnesium sulfate are added, filtered from the solid portions and the residue washed with methylene chloride. The organic filtrates are evaporated to dryness in vacuo and the resulting oil is dissolved in ethyl acetate. After addition of ethereal hydrochloric acid until the acidic reaction, the precipitated hydrochloride is filtered off and recrystallized from isopropanol-ether. The pure 1 - [1- (phenyl) ethyl] -2-methylimidazole hydrochloride melts at 228-229.

The starting product is obtained as follows:

^a ) N-ri- (phenyl) -ethyl-1-aminoethyl-amine

30 g (0.25 mol) of acetophenone are dissolved in 300 ml of methanol and after addition of 30 g (0.5 mol) of ethylenediamine and 1.0 g of platinum carbon with hydrogen at 20 ° and atmospheric pressure in the course of 22 hours

- 29 -

hydrogenated. The resulting solution is filtered off from the catalyst, the solvent is removed in vacuo and the residue is distilled in a water-jet vacuum. The N- [1-L- (phenyl) -ethyl] -aminoethylamine obtained as OeI boils at 115-118 ° (1466.5 Pa).

b) 16.4 g (0.1 mol) of N- [1- (phenyl) ethyl]] aminoethylamine are dissolved in 100 ml of ethanol and at 0 ° 16.0 g (0.1 mol) of ethyl acetate hydrochloride are added , The mixture is stirred for 3 hours at 0 ° and the solvent removed in vacuo. The resulting oil is shaken out with water and ether, the ethereal extract is dried over magnesium sulfate and the solvent is removed in vacuo. The residue is dissolved in ethyl acetate and treated with oxalic acid until acidic reaction. After adding a little ether, the precipitated product is filtered off and recrystallized from isopropanol-ether. The pure l-j_l- (phenyl) -ethyl] -2-methyl-4,5-dihydroimidazole oxalate melts at 80-84 ".

For further reaction, 29 g of the oxalate are converted into the free base with potassium hydroxide solution and ether. Pure base is obtained which boils at 130 ° (1.33 Pa).

Example 12 : 5.0 g (0.0409 mol) of R- (+) - 1-phenylethanol ([VL = + 39.5 °] and 5.2 g (0.055 mol) of methanesulfonyl chloride are dissolved in 100 ml of ether Cooled 0 ° and at this temperature, a solution of 5.1 g (0.060 mol) of triethylamine in 50 ml of ether was added dropwise. The mixture is stirred for 1 hour at 0 ° and filtered from the precipitate. The filtrate is evaporated as gently as possible on a water jet vacuum, the residue dissolved in 20 ml of toluene and added dropwise at 90 ° to a solution of 8.2 g (0.1 mol) of 2-methylimidazole. The mixture is heated at 90 ° for 1 hour. For workup, the mixture is diluted with ether and shaken with water and then with 3 times 50'ml 2n hydrochloric acid. The hydrochloric acid extracts are made alkaline with concentrated sodium hydroxide solution and extracted with ether. The resulting ethereal solutions are dried over magnesium sulfate and dried

- 30 -

concentrated. The remaining residue is crystallized twice from cyclohexane to give pure left-handed 1- (1-phenylethyl) -2-methyl-imidazole, mp. 113-115 ° [a] ^ = -15 ° ± 1 °. (Enantiomeric purity about 95 J ₀ according to NMR). The hydrochloride melts at 243-244 "

Example 13 : In the same manner as shown in Example 11, from 5.0 g of S (-) - 1-phenylethanol ([JJ _n ⁼ "41.3 °) dextrorotatory l- [1- (phenyl) -ethyl] 2-methyl-imidazole, mp 113-115 _n - receive + 15 ° (± 1 °) The hydrochloride melts at..

243-244 °.

Example 14 : Analogously to Example 1, 20.2 g (0.1 mol) of 1- (3-methoxyphenyl) ethanol and 25 g (0.3 mol) of 2-methylimidazole 1-ol (3-methoxy-phenyl) -ethyl 2-2-methylimidazole obtained as OeI. The hydrochloride melts at 197-199 °.

Example 15 : 6.0 g (0.0297 mol) of 1- [1- (2-hydroxy-phenyl) -ethyl] -2-methyl-imidazole and 25 ml of hexametapol are suspended in 25 ml of tetrahydrofuran and stirred at 20 ° 1.3 g (0.030 mol) of sodium hydride suspension (55 J ₀ ) was added in portions. The mixture is stirred for 2 hours at 20 °. Subsequently, a solution of 4.25 g (0.030 mol) of methyl iodide in 25 ml of hexametapol is added dropwise and the mixture is kept at 45 ° for 1 hour.

The reaction mixture is poured onto 200 ml of ice-water and extracted by shaking with methylene chloride. The organic phases are separated, washed with water and dried over magnesium sulfate. After removal of the solvent, the crude 1 - [_ 1- (2-methoxy-phenyl) -ethyl-2-methyl-imidazole is obtained as OeI. The hydrochloride melts at 201-203 °.

The required as starting product l- [l- (2-methoxyphenyl) -ethyl-2-methyl-imidazole can be obtained as follows:

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20.0 g (0.1 mol) of α-methylene-1- (2-hydroxybenzyl) -2-methylimidazole are dissolved in 500 ml of ethanol and hydrogenated after addition of 1 g of Pd-carbon at normal pressure, and room temperature. The catalyst is then filtered off, the solvent is largely removed under reduced pressure and the residue is treated with fumaric acid until the reaction is slightly acidic. After addition of ethyl acetate, the precipitated product is filtered off, recrystallized from alcohol-ethyl acetate and dried. The pure 1-p- (2-hydroxyphenyl) ethyl 2-2-methylimidazole melts at 148-150 °.

For further reaction, 10 g (0.03 mol) of the fumarate are cleaved with 2N sodium hydroxide solution and ether into the free base. There is obtained free base, which is reacted as described.

Example 16 ; In an analogous manner as described in Example 1, 18.2 g (0.1 mol) of l- (2,3-dimethoxyphenyl) ethanol and 25 g (0.3 mol) of 2-methylimidazole crude product. The free base is chromatographed on silica gel with methylene chloride / 1-5 J ₀ methanol to give pure l - [] l- (2,3-dimethoxyphenyl) -ethyl ^] -2-methyl-imidazole, mp 122-124 °. The hydrochloride melts at 175-178 °.

Example 17 : Analogously to Example 1, 16.4 g (0.1 mol) of 1- (2,4,6-trimethylphenyl) ethanol and 25 g (0.3 mol) of 2-methylimidazole 7 , 9 g of pure 1- [l- (2,4,6-trimethylphenyl) ethyl ^ -2-methyl-imidazole, mp. 129-131 °. The hydrochloride melts at 267 ° (decomp.).

Example 18 : Analogously to Example 1, 9.1 g (0.05 mol) of 1- (2,6-dimethoxyphenyl) ethanol and 12.5 g (0.15 mol) of 2-methylimidazole are used , 7 g crude l- [l- (2,6-dimethoxyphenyl) ethyl] -2-methyl-imidazole, which gives pure hydrochloride, mp. 214-216 ° results ·.

The starting product can be prepared as follows:

- 32 -

16.6 g (0.1 mol) of 2,6-dimethoxybenzaldehyde are dissolved in 200 ml of abs. Dissolved tetrahydrofuran and added dropwise 60 ml of a 2.58 molar solution of methylmagnesium iodide in tetrahydrofuran at 10 °. The reaction mixture is kept for 2 hours at room temperature and then treated with a solution of 30 g of ammonium chloride in 200 ml of water. The resulting mixture is extracted by shaking with ether, the organic phases are washed with brine and dried over magnesium sulfate. After removal of the solvent, the residue is crystallized from isopropyl ether / petroleum ether. The obtained 1- (2,6-dimethoxyphenyl-ethanol melts at 56-58 °.

Example 19 : Analogously to Example 1, from 3 g (0.02 mol) of l- (2,3-dimethylphenyl) ethanol and 4.92 g (0.06 mol) of 2-methylimidazole, 1.95 g of oily I-Ql- (2,3-dimethyl-phenyl) -ethyl]] - 2-methyl-imidazole obtained. From 1.92 g of the crude base, the pure 1 - (_l- (2,3-dimethylphenyl) ethyl) -2-methyl-imidazole hydrochloride with the mp. 244-246 "is prepared with ethereal hydrochloric acid.

Example 20 : 9.25 g (0.05 mol) of 1-phenyl-ethyl bromide are dissolved with 20.5 g (0.25 mol) of 2-methylimidazole in 100 ml of toluene and heated with stirring for 8 hours at 100 °. The reaction mixture is cooled, treated with 2N hydrochloric acid until acidic reaction and the acidic aqueous phase separated. The toluene solution is extracted by shaking 3 times with 50 ml of hydrochloric acid and the combined acidic, aqueous phases with conc. Sodium hydroxide solution made alkaline. The resulting mixture is extracted by shaking with ether, the ethereal solution dried over magnesium sulfate and the solvent removed in vacuo. The residue obtained is dissolved in ethyl acetate and treated with ethereal hydrochloric acid until acidic reaction. After further addition of ether, the precipitated product is filtered off, washed with ether and recrystallized from cyclohexane. The pure 1- (1-phenylethyl) -2-methylimidazole melts at 84-85 °.

- 33 -

As described in Example 1, the hydrochloride is prepared from the base. The pure 1- (1-phenyl-ethyl) -2-methyl-imidazohydrochloride melts at 229-229.5 °.

Example 21 ; 23.20 g (0.11 mol) of N- (1-phenyl-ethyl-2-aminoacetaldehyde dimethyl acetal are admixed with 10.9 g (0.1 mol) of acetiminomethyl ether hydrochloride, dissolved in 200 ml of methanol, and 4 The reaction mixture is freed from the solvent under reduced pressure, the oily residue is dissolved in 250 ml of water and added to 500 ml of concentrated hydrochloric acid The mixture is evaporated to dryness at 100 ° C. and the residue obtained is made alkaline with a saturated solution of potassium carbonate The resulting mixture is extracted by shaking 3 times with 500 ml of ether, the ethereal phases are dried over magnesium sulphate and the solvent is removed in vacuo.The oily residue is distilled under high vacuum (6.66 Pa), bp = 115-120 ° The product obtained is dissolved in ethyl acetate and ethereal hydrochloric acid is added until the reaction is acid, and the precipitated product is filtered off and recrystallised from isopropanol / ether to give pure 1- (2-phenylethyl) -2-methylimidazole L-hydrochloride melts at 228-229 °.

The starting material can be obtained as follows:

a) 60.1 g (0.5 mol) of acetophenone are dissolved in 1000 ml of methanol with 56.78 g (0.54 mol) of 2-aminoacetaldehyde dimethyl acetal and hydrogenated catalytically after addition of 10 g of palladium-carbon at room temperature and atmospheric pressure , After hydrogen absorption is filtered from the catalyst and the solvent removed in vacuo. The resulting residue is distilled under high vacuum at 60-65 ° (7.99 Pa) to give pure N- (1-phenyl-ethyl-2-aminoacetaldehyde dimethyl acetal.

b) 82 g (2 mol) of acetonitrile are dissolved in 65 g (2 mol) of methanol and 500 ml of 4N ethereal hydrochloric acid added. The reaction mixture

- 34 -

is allowed to stand at room temperature and filtered from the precipitated product. The resulting product is washed with ether and dried in vacuo at room temperature. The Acetiminomethylether hydrochloride obtained melts at 97 °.

Example 22 : 9.1 g (0.05 mol) of 1- [2-methoxybenzyl] -imidazole are dissolved in 90 ml of tetrahydrofuran and 7.1 g (0.11 mol, corresponding to 55.4 ml) are dissolved at -78 ° 2 molar solution) of butyllithium in 50 ml of tetrahydrofuran was added dropwise. The mixture is stirred for 2 hours at -78 ° and then added dropwise 17.0 g (0.12 mol) of methyl iodide dissolved in 20 ml of tetrahydrofuran. The reaction mixture is warmed to room temperature and stirred for 30 hours at this temperature. Subsequently, 50 ml of water are slowly added dropwise and the tetrahydrofuran is largely removed in vacuo.

After addition of 2N sodium hydroxide solution until a strongly alkaline reaction, the residue is extracted by shaking with ether. The organic phases are dried over magnesium sulfate and the solvent removed in vacuo. The resulting oily residue is dissolved in ethyl acetate and treated with ethereal hydrochloric acid until acidic reaction. The precipitated product is filtered off and recrystallized from isopropanol-ether. The pure 1 - [[1- (2-methoxy-phenyl) -ethyl] -2-methyl-imidazole hydrochloride melts at 201-203 °.

The starting material can be obtained as follows:

Analogously to Example 1, 13.8 g (0.1 mol) of 2-methoxybenzyl alcohol and 34 g (0.5 mol) of imidazole give 9.78 g of pure oily 2-methoxybenzylimidazole. The product obtained is distilled under high vacuum at 120-130 ° (1.33 Pa).

Example 23 : 4.0 g (20 mmol) of 1- [1- (4-aminophenyl) -ethyl] -2-methylimidazole are dissolved in 100 ml of methanol, 6 ml (60 mmol) of conc. Hydrochloric acid and added dropwise at 0 ° 2.68 g (26 mmol) of tert-butylnitrite. The mixture is stirred for 30 minutes at 0 °, then

- 35 -

slowly heated to reflux for 1 hour and held at this temperature for 30 minutes. The reaction mixture is concentrated in a water jet vacuum, mixed with 2N sodium hydroxide solution until the alkaline reaction, diluted with brine and extracted by shaking with ether. The ethereal extracts are dried over magnesium sulfate, the solvent is removed in vacuo and the residue is treated with alcoholic hydrochloric acid until acidic reaction. After addition of ethyl acetate, the precipitated product is filtered off and dried. After recrystallization from alcohol / ethyl acetate, the pure 1-j ^ l- (4-Me thoxy-phenyl) -e thy l] -2-me thy 1-imidazo 1-hydrochl or id of mp. 200-202 °.

The starting material can be obtained as follows:

16.5 g (0.1 mol) of p-nitroacetophenone are dissolved in 160 ml of methanol and slowly added with cooling 3.7 g (0.1 mol) of sodium borohydride. When the addition is complete, the mixture is slowly heated to 60 ° and kept at this temperature until gas evolution ceases. After Abkühlung_werden about 150 ml of 1 molar sodium dihydrogen phosphate solution was added and the methanol was largely removed in vacuo. The residue is extracted by shaking with ether, the organic phases are dried over magnesium sulfate and the solvent is removed in vacuo. The resulting 1-p-nitrophenyl-ethanol is used as crude OeI.

From 16 g (0.096 mol) of 1- (p-nitrophenyl) ethanol and 23.6 g (0.29 mol) of 2-methylimidazo 1 are as described in Example 1 reineö l- [l- (4-nitrophenyl) -ethyl ] -2-methyl-imidazole, mp. 78-79 ° obtained (recrystallization from diisopropyl ether-petroleum ether).

14.0 g (0.06 mol) of 1- (4-nitrophenyl) -ethyl) -2-methyl-imidazole are dissolved in 150 ml of ethanol, 2 g of Raney nickel are added and hydrogen is added at atmospheric pressure and 20 ° catalytically hydrogenated in the course of 15 hours.

- 36 -

The catalyst is then filtered off, the solvent removed in vacuo and the residue crystallized from ethyl acetate. The pure 1-ol (4-aminophenyl) -ethyl]] - 2-methyl-imidazole melts at 149-151 °. The dihydrochloride (from alcohol-ethyl acetate with alcoholic hydrochloric acid) melts at 165-167 ".

Example 24 : In an analogous manner as described in Example 23, from 20.1 g (0.1 mol) of 1- [1- (2-aminophenyl) -ethyl] -2-methyl-imidazole, the pure 1- [l- (2-Methoxyphenyl) ethyl]] - 2-methyl-1-imidazo-1-hydrochloride of mp 201-203 ".

The dihydrochloride (from alcohol-ethyl acetate with alcoholic hydrochloric acid) melts at 165-167 °.

Example 25 ; Tablets containing 0.020 g of 1- (1-phenyl-ethyl) -2-methyl-imidazole are prepared, for example, as follows:

Composition : (for 10 000 tablets): Active ingredient 200.00 g

Lactose 290.80 g

Potato starch 274.70 g

Stearic acid 10.00 g

Talk. 200.00 g

Magnesium stearate 2.50 g

Colloidal Silica 32.00 g of ethanol q.s.

A mixture of the active ingredient, the lactose and 194.70 g of potato starch is moistened with an ethanolic solution of stearic acid and granulated through a sieve. After drying, the remainder of the potato starch, talc, magnesium stearate and colloidal silica are mixed together and the mixture is compressed into tablets of 0.1 g each which may be desirably provided with partial scores for finer dosage adjustment.

- 37 -

Example 26 : Capsules containing 0.025 g of 1- (1-phenyl-ethyl) -2-methyl-imidazole can be prepared as follows:

Composition (for 1 000 capsules):

Active ingredient 25.00 g

Lactose 249.00 g

Gelatin 2.00 g

Cornstarch 10.00 g

Talc 15.00 g

Water q.s.

The active substance is mixed with the lactose, the mixture is moistened evenly with an aqueous solution of the gelatin and granulated through a sieve with a mesh size of 1.2-1.5 mm. The granules are mixed with it. dried corn starch and talc, and dispenses 300 mg portions into hard gelatin capsules (size 1).

Claims (11)

- 38 - Invention claim 1. A process for the preparation of compounds of the formula R ₁ i ¹ ^ Ph - CH - N - N (I) * · - - - · or their salts, in which Ph is phenyl which is unsubstituted or substituted by lower alkyl or lower alkoxy, and R ₁ and R _{2 are} each lower-alkyl and, if desired, their pharmaceutical administration form, characterized in that a) a compound of the formula Ph-CH-X ₁ (Ha), wherein X _{1 is} reactive esterified hydroxy, with a compound of the formula ^R 2 ix X ₂ -NN wherein X "represents hydrogen or a metallic radical, or - 39 - b) in a compound of the formula Ph-CH-Het (III), wherein Het is a radical convertible to 2-R "-imidazol-1-yl, Het is converted to 2-R -imidazol-1-yl, or c) in a compound of the formula Ϊ ²
/ \ Ph A-N N (IV), wherein A is a -CH (R ₁ ) - transferable grouping and the radical R 'is a radical convertible into R or R ", or wherein A is the grouping -CH (R ₁ ) - and R' is one in R is convertible radical, A in -CH (R ₁ ) - and / or R 'converted into R ", or d) a compound of the formula Ph - C = NN Α ^Θ (V), wherein A is an anion of a protic acid, reduced to the corresponding compound of formula I, or e) a compound of the formula Ph-CH-X ₃ . (VI) 2. The method of item 1 for the preparation of compounds of the formula Ph - CH - N - N (I) or their salts, wherein Ph is unsubstituted or substituted by lower alkyl phenyl and R. and R_ are each lower alkyl, characterized in that a) a compound of the formula Ph - CH - X ₁ (Ha), wherein X _{1 is} reactive esterified hydroxy, with a compound of the formula - 41a - M N in which Χ «stands for hydrogen or a metallic radical, or - 42 - b) in a compound of the formula Ph-CH-Het (III), in which Het is a radical convertible into 2-R-imidazol-1-yl, Het is converted into 2-R_-imidazol-1-yl, or c) in a compound of the formula Ph A-N N (IV), wherein A is a -CH (R) - transferable grouping and the radical R 'is a radical convertible in R ₉ or R, or wherein A is the group -CH (R ₁ ) - and R' is a convertible into R Rest means A is converted into -CH (R ₁ ) - and / or R 'in R ", or d) a compound of the formula Ph - C = N N A ° (V), wherein A is an anion of a protonic acid, reduced to the corresponding compound of formula I, or e) a compound of the formula Ph-CH-X ₃ (VI), - 43 - wherein X_ is a group convertible by cyclization into 2-R ₂ -imidazol-1-yl, cyclized, or f) a compound of the formula I ⁴ / \ Ph-CH-N N (VIIa) with a compound of the formula R ° -Xg (VIIb) in which one of the radicals X ₄ and X _{ß is} reactive esterified hydroxy and the other is a metallic radical, X _{5 is} the radical R ₂ and R ^{0 is} the radical R * or in which. one of the radicals X ₅ and X_ is reactive esterified hydroxy and the other is a metallic radical, X _{4 is} the radical R and R ^{0 is} the radical R ₂ , wherein the starting compounds listed in variants a) to f) can optionally also be present in salt form, and, if desired, a compound of the formula I obtainable according to the invention is converted into another compound of the formula I and / or, if desired, an available salt into the free compound of the formula I or in another salt and / or, if desired, converting a free compound of the formula I obtainable according to the invention into a salt and / or, if desired, separating an available isomer mixture into the individual components. 3. Process according to item 1 for the preparation of compounds of the formula I or salts thereof, characterized in that Ph is unsubstituted or mono- or polysubstituted by lower alkyl, - 44 - substituted phenyl and R. and _R2 are each lower alkyl · 4. The method of item 1 for the preparation of compounds of formula I or salts thereof, characterized in that Ph mono- or polysubstituted by lower alkoxy
Phenyl, and R. and R ₂ each represent lower alkyl. 5 »Process according to item 1 for the preparation of compounds of the formula I or their salts, characterized in that Ph is unsubstituted or in position 2 or 3 simply by lower alkyl or lower alkoxy each with. To and with 4 C-atoms or in position 2 and 6 two-membered by lower alkyl with up to and 4 C atoms substituted phenyl
and R ₁ and R _{2 are} each lower alkyl having up to and having 4 C atoms. 6. The method according to item 1 for the preparation of compounds of formula I or salts thereof, characterized in that Ph is unsubstituted phenyl and R ^ and R _{2 are} each
Lower alkyl with bis and with 4 C atoms mean. 7. The method according to item 1, characterized in that
1- (1-phenylethyl) -2-methylimidazole or a salt thereof,
will be produced. 8. The method according to item I _1, characterized in that
1- (1- (2-methyl-phenyl) -ethyl) -2-methyl-imidazole or
Salt thereof is produced. 9. The method according to item I _1, characterized in that
1- (1- (2-methoxy-phenyl) -ethyl) -2-methyl-imidazole or
Salt thereof is produced. - 45 - 9 R ΠΓ7 1QC /. * ') \> O Κ'-> O - 40 - wherein X_ is a group convertible by cyclization into 2-R_-imidazol-1-yl, cyclized, or f) a compound of the formula I ⁴ / \ Ph-CH-N N (VIIa) with a compound of formula R -X- (VIIb), wherein one X, and X, is reactive esterified hydroxy and the other is a metallic radical, X ,. the radical R is and R is the radical R, or in which one of the radicals X ₁ . and _{X.sub.ft is} reactive esterified hydroxy and the other is a metallic radical, X is R.sup.4 and R.sup.4 is the radical R, or g) for the preparation of compounds of the formula I or salts thereof, in which Ph represents phenyl substituted by lower alkoxy, in a compound of the formula ^R 2 I ¹ / W Ph '- CH - NN (VIII) where Ph ^{1 is} a radical convertible into Ph, Ph ^{1 is converted} into Ph, wherein the starting compounds listed in variants a) to g) may optionally also be present in salt form, and, if desired, a compound of the formula I obtainable according to the invention - 41 - into a different compound of the formula I and / or, if desired, an available salt is converted into the free compound of the formula I or into another salt and / or, if desired, a free compound of the formula I obtainable according to the invention is converted into a salt and / or _c if desired, an available isonating mixture is separated into the individual components and, if appropriate, the compounds prepared in this way or a pharmaceutically acceptable salt thereof, if appropriate with admixture of customary auxiliaries and excipients, are processed into pharmaceutical preparations. Process according to item 1, characterized in that 1- (1- (p-methylphenyl) ethyl) -2-methylimidazole, 1- (1- (3-methylphenyl) ethyl) -2 -methylimidazole,! - (1- (phenyl) -propyl) -2-methylimidazole, 1- (1- (2-ethylphenyl) ethyl) -2-methyliraidazole, 1- (1- (2,6 -Dimethyl-phenyl) -ethyl) -2-methyl-imidazole, 1- (1- (3-methoxy-phenyl) -ethyl) -2-methyl-imidazole, 1- (1- (2,3-dxmethoxyphenyl) -ethyl) -2-methy1-imidazole, l- (l- (2,4,6-Triraethylphenyl) ethyl) -2-raethyl-imidazole, l- (l- (2i6-Dim _t ethoxyphenyl) ethyl) -2-methyl -iraidazole _t l- (1- (2,3-dimethylphenyl) ethyl) -2-methyl-imidazole, 1- (1- (4-methoxyphenyl) ethyl) -2-methyl-irinidazole or a salt thereof getting produced. 11 «method according to item 1, characterized in that compounds according to one of the items 1-10 are prepared in the form of an enantiomer.