CA1233828A - Substituted imidazoles - Google Patents

Abstract

Substituted imidazoles Abstract Substituted imidazoles of the general formula (I) or salts thereof, in which Ph represents phenyl that is unsubstituted or substituted by lower alkyl or by lower alkoxy, and R1 and R2 each represents lower alkyl, processes for their manufacture, their use and pharma-ceutical preparations.
The compounds of the formula I have, for example, antidepressive properties.

Description

~,~t~

4~1~722/+

Substituted imidazoles The invention relates to ~ubstituted imidazoles of the general formula Ph - lH - N ~ N (I), or salts thereof, in which Ph represents phenyl that is unsubstituted or substituted by lower alkyl or by lower alkoxy, and Rl and R2 each represents lower alkyl, to their use, to processes for their manufacture and to pharmaceutical preparations that contain a compound of the formula I or a pharmaceutically acceptable salt thereof.
Phenyl that is substituted by lower alkyl or by lower alko~y has especially one or more, for example . ~ C

- 2 -two, also three, lower alkyl or lower alkoxy radicals bonded especially in the ortho- and/or meta-position(s).
Hereinbefore and hereinafter, radicals or compounds designated "lower" should preferably be understood as meaning those containing up to and including 7, especially up to and including 4, carhon atoms.
The general terms used have the following meanings:
Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n butyl, isobutyl, sec.-butyl or tert.-butyl, and also includes corresponding pentyl, hexyl or heptyl radicals.
Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, pentyloxy, isobutoxy or tert.-butoxy.
Salts of compounds of the formula I are their acid addition salts, preferably phar~aceutically acceptable acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulphuric acid, a phosphoric acid or a hydro-halic acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, for e~ample acetic acid, optionally unsaturated dicarboxylic acids, for example malonic, maleic or fumaric acid, or hydroxy-carboxylic acids, for example tartaric or citric acid, or with sulphonic acids, such as lower alkanesulphonic acids or optionally substituted benzenesulphonic acids, for example methane- or p-toluene-sulphonic acid.
Salts ~hat are unsuitable for pharmaceutical uses are also included, since they can be used, for example, for the isolation and purification of free compounds according to the invention and their phar~aceutically acceptable salts.
The compounds accordin~ to the invention have,

- 3 ~

for example, valuable pharmacological properties. In particular, they are capable of selectively and rever-sibly inhibiting the monoaminooxidase (MAo) of type A.
These properties can be demonstrated both in the rat liver and in the rat brain where in each case the breaking down of serotonin is selectively inhibited.
The determination of the MAO activity in the rat liver or rat brain was carried out analogously to the method of R~J o Wurtman et al., Biochem. Pharmacol. 1~, 1439 (1963), the inhibition of MAO being ascertained at a dose upwards from approximately 1 mg/kg after peroral administrativn of the active ingredient.
Accordingly, the compounds according to the invention can be used for the prophylactic and thera-peutic treatment of depressive conditions.
The invention therefore relates also to the prophylactic and therapeutic treatment of the human and animal body and to the use of the compounds according to the invention for the treatment of depressive conditions.
The invention relates, for example, to compounds of the formula I, or their salts, in which Ph represents phenyl that is unsubstituted or mono- or poly-substituted, for example di-substituted, by lower alkyl, especially ~ower alkyl having up to and including 4 carbon atoms, and R1 and R2 each represents lower alkyll especially lower alkyl having up to and including 4 carbon atoms.
The invention relates, for example, to compounds of the formula I, or their salts, in which Ph represents phenyl that is mono- or poly-substituted, for example di-substituted, by lower alkoxy, especially lower alkoxy having up to and including 4 carbon atoms, such as methoxy, and R1 and R2 each represents lower alkyl~ especially lower alkyl having up to and including 4 carbon atoms, such as methyl.
The invention relates especially to compounds of the formula I, or their salts, in whlch Ph represents phenyl that is unsubstituted or mono-substituted in the 2- or 3-position by lower alkyl or lower alkoxy, each having up to and including 4 carbon atoms, such as methyl or methoxy, or di-substituted in the 2- and 6-positions by lower alkyl having up to and including 4 carbon atoms, such as methyl, and Rl and R2 each represents lower alkyl having up to and including 4 carbon atoms, such as methyl.
The invention relates especially to compounds of the formula I~ or their salts, in which Ph represents unsubstituted phenyl, and R1 and R2 each represents lower alkyl having up to and including 4 carbon atoms, such as methyl.
The invention relates specifically to the novel compounds mentioned in the Examples and their salts.
The invention relates also to a process for the manufacture of the compounds of the formula I and their salts, characterised in that a) a compound of the formula Rl I

Ph - CH - Xl (IIa), in which X1 represents reactive esterified hydroxy, is reacted with a compound of the formula -- 5 ~ , t~

I

Xz-N ~N (lIb), in which X2 represents hydrogen or a metallic radical, or b) in a compound of the formula Rl I (III
Ph - CH - Het in which Het represents a radical that can be converted into 2-R2-imidazol-1-yl, Het is converted into 2-R2-imidazol-1-yl, or c) in a compound of the formula Ph - A - N ~ (IV) in which A represents a grouping that can he converted into -CH(Rl)- and the radical R2' represents a radical that can be converted into R2 or represents - 6 - ~3~

R2, or in which A represents the grouping -CH(Rl)-and R2' represents a radical that can be converted into R2, A is converted into -CHlRl)- and/or R2 is converted into R2, or d) a compound of the formula 71~ l Ph - C = N N A Q

_ .

in which A~ represents an anion of a protonic acid, is reduced to the corresponding compound of the formula 1, or e) a compound of the formula I (VI) Ph - CH - X3 in which X3 represents a group that can be converted by cyclisation into 2-R2-imida201-l-yl, is cyclised, or f) a compound of the formula ., ~

~3~ 8 l4 i5 Ph - CH - N ~N (VI I a) I I

is reacted with a compound of the formula R-X6 (VIIb) in which one of the radicals X4 and X6 represents reactive esterified hydroxy and the other represents a metallie radical, X5 represents the radical R2 and R represents the radical Rl, or in which one of the radicals X5 and X6 represents reaetive esterified hydroxy and the other represents a metallic radical, X4 represents the radical R1 and R represents the radical R2, or g) for the manufaeture of compounds of the formula I
or their salts in which Ph represents phenyl substituted by lower alkoxy~
in a eompound of the formula Ph' - ~H - N ~N (VI I I ) I _!

in which Ph' represents a radical tnat can be converted into Ph, Ph' is converted into Ph, it being possible for the starting compounds listed in variants a) to g) optionally to be in salt form, and, t -- 8 ~

if desired, a compound of the formula I obtainable according to the invention is converted into a different compound of the formula I, and/or, if desired, a resulting salt is converted into the free compound of the formula I or into a different 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, a resulting isomeric mixture is separated into the individual components.
The reactions described hereinbefore and hereinafter in variants a) to g) are carried out in a manner known ~r se, for example in the absence or, customarily, in the presence of a suitable solvent or diluent or a mixture thereof, the reactions being carried out, as required, while cooling, at room temperature or while heating, for example in a tempera-ture range of from approximately -10 to approxi-mately +250C, preferably from approximately 20 to approximately 150C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.
Some of the starting materials of the formulae IIa and IIb, III, IV, V, VI, VIIa and VIIb and VIII, which are listed hereinbefore and hereinafter and which were developed for the manufacture of the compounds of the formula I, are known or they can be manufactured according to methods known per se, for example analogously to the process variants described here-inbefore and hereinafter.

Variant a):
Reactive esterified hydroxy represents especially hydroxy esterified by a strong inorganic acid or organic sulphonic acid, for example halogen, such as chlorine, bromine or iodine, sulphonyloxy, such as ,~

_ 9 ~

hydroxysulphonyloxy, halosulphonyloxy, for exa~ple fluorosulphonyloxy, optionally substltuted, for e~a~ple halo-substituted, lower alkanesu]phonyloxy, for example methane- or trifluoromethane-sulphonyloxy, cycloalkane-sulphonyloxy, for example cyclohexanesulphonyloxy, or optionally substituted, for example lower-alkyl- or halo-substituted, benzenesulphonyloxy, for example ~-bromophenyl- or p-toluene-sulphonyloxy.
A metallic radical is, for example, an alkali metal radical, especially a lithium radical, and also a copper(I) radical, or a lithium copper(I) radical derived from lithium cuprates.
The reaction is carried out especially in the presence of a condensation agent, such as a suitable base.
As bases there come into consideration, for example, alkali ~etal hydroxides, hydrides, amides, alkoxides, carbonates, triphenylmethylides, di-lower alkylamides, aminoalkylamides or lower alkylsilyl-amides, naphthaleneamines, lower alkylamines, basic heterocycles, ammonium hydroxide and carbocyclic amines. There may be mentioned by way of example:
sodium hydroxide, hydride or amide, potassium tert.-butoxide or carbonate, lithium triphenylmethyli~e or diisopropylamide, potassium 3-(aminopropyl)-amide or bis-(trimethylsilyl)-amide, dimethylaminonaphthalene, di- or tri-ethylamine, pyridine, benzyltrimethyl-ammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyslo[5.4.0]undec-7-ene (DBU).
If X2 represents hydrogen, the addition of a further base is unnecessary if the compound of the formula IIb acting as a base is used in excess. If X2 represents a metallic radical, the reaction with compounds of the formula IIb is advantageously effected without the addition of bases.

~, ~
, .

- l o -The reaction is preferably carried out with those compounds of the formula IIb in which X2 represents hydrogen.

Variant b)-.
A radical Het that can be converted into 2-R2-imidazol-l-yl can be, for example, 3-R2-pyrazol-1-yl.
The conversion thereof into 2-R2-imidazol-1-yl can be effected, for example, by photoisomerisationr for example by irradiation, such as with a high pressure mercury lamp.
~ radical Het that can be converted into 2-R2-imidazol-l-yl can also be 2-R2-imidazolin-1-yl, especially 2-R2-imidazol-2-in-1-yl, which can be converted into 2-R2-imidazol-~-yl, for example, by dehydrogenation.
For the dehydrogenation there are used suitable dehydrogenation agents, for example elements from the sub-groups, preferably those of sub-group VIII of the Periodic Table, for example pailadium, Raney nickel or platinum, or corresponding noble metal derivatives, for example platinum oxide or ruthenium triphenyl phosphide chloride, it being possible for the agents to be supported on suitable carriers, such as carbon.
Further preferred dehydrogenation agents are, for example, quinones, such as ~-benzoquinones, for example tetrachloro-~-benzoquinone or 2,3-dichloro-5,6-dicyano-p-benzoquinone, and phenanthrene-9,10-quinone. It is also possible to use N-halosuccinimides, such as N-chlorosuccinimide, manganese compounds, such as barium manganate or manganese dioxide, and sulphur and selenium derivatives, such as sulphur, selenium, selenium dioxide or diphenylselenium bis-trifluoroacetate.

~ ~3~

Variant c):
~ structural element A that can be converted into the grouping -CH(Rl)- represents, for example, the g p ng C(R1 )(ZO)- in which Rl' represents either the radical Rl having a radical Zl that can be converted into hydrogen, and ZO represents hydrogen, or Rl' represents Rl and ZO represents a radical Zl that can be converted into hydrogen, or in which Rl' and ZO together form lower alkenylidene or a tautomeric form thereof. Likewise, radicals R2' that can be converted into P~2 are lower alkyl radicals substituted by a radical Zl that can be converted into hydrogen.
Zl can be converted into hydrogen, for example, by reduction and accordingly represents, for example, hydroxy, etherified hydroxy, such as lower alkoxy, halogen, sulphonyloxy, such as optionally substituted, for example halo-substituted, lower alkanesulphonyloxy, cyclo-lower alkanesulphonyloxy or optionally substi-tuted, for example lower alkyl- or halo-substituted, benzenesulphonyloxy, mercapto or etherified mercapto, such as lower alkylthio.
The reductive conversion of A into the grouping -CH~RI)- and/or of R2' into R2 is effected in a manner known per se, for example with the aid of a reducing agent, for example by hydrogenation in the presence of a hydrogenation catalyst, by reduction with a hydride transfer reagent cr by reduction with a metallic reduction system comprising metal and a proton-removing agent.
As hydrogenation catalysts there come into consideration, for example, elements of sub-group VIII
of the Periodic Table of Elements, or derivatives thereof, such as palladium, platinum, platinum oxide, ruthenium, rhodium, tris-(triphenylphosphine)-) ~
.

- 12 ~ 8 rhodium(I) halide, for example the chloride, or Raney nickel; which are optionally supported on a carrier, such as active carbon, an alkali metal carbonate or sulphate or on a silica gel. As hydride transfer reagents there come into consideration, for example, suitable light metal hydrides, especially alkali metal aluminium hydrides or borohydrides, such as lithium aluminium hydride, lithi~m triethyl borohydride, sodium borohydride, sodium cyanoborohydride, or tin hydrides, such as triethyl- or tributyl-tin hydride, or diborane.
The metal component of the metallic reduction system is, for example, a base metal, such as an alkali metal or alkaline earth metal, for example lithium, sodium, potassium, magnesium or calcium, or a transition metal, for example zinc, tin, iron or titanium, whilst as proton-removing agent there come into consideration, for example, protonic acids, such as hydrochloric or acetic acid, lower alkanols, such as ethanol, and/or amines or ammonia. Such systems are, for example, sodium/ammonia, zinc/hydrochloric or acetic acid, or zinc/ethanol.
In preferred embodiments of this process, for example, hydroxy or optionally etherified mercapto are reduced by catalytic hydrogenation, for example in the presence of Raney nickel, and halogen or sulphonyloxy are reduced, for example, by hydride transfer reagents, by tributyltin hydride, lithium aluminium hydride or sodium cyanoborohydride or sodium/ammonia.
In addition, hydroxy can be replaced by hydrogen by treatment with phosphorus (red) and hydrogen iodide or iodine.
Preferably, radicals Zl that can be replaced by hydrogen heing located in the benzylic position and are replaced by hydrogen.
Zl can also represent carboxy. The decarboxy-- 13 - ~ ~3~

lation of corresponding compounds of the formula IV can customarily be carried out at elevated temperatures, for example at a temperature upwards from approximately 50C, especially in a temperature range of from approximately 100 to approximately 300C. The decarboxylation can be assisted, for example, by the presence of bases, such as high-boiling nitrogen bases, for example, collidine, and/or in the presence of noble metals, such as copper or copper bronze.
There are especially used as starting materials those compounds of the formula IV that have only one radical Zl that can be converted into hydrogen.

Variant d):
The reduction of the iminium salts of the formula V to form the tertiary amines of the formula I is effected, for example, with the aid of a reducing agent, for example of the type listed in variant c).
Examples oE possible suitable methods of reduction are catalytic hydrogenation, treatment with a hydride transfer reagent, for example sodium borohydride, or the use of the metallic reduction system zinc/hydro-chloric acid.
It is also possible to use formic acid as reducing agent.

Variant e):
A grouping X3 that can be converted by cyclisation into 2-R2-imidazol-1-yl represents, for example, the group of the formula - N = CH - CH2 ~ NH - CO - R2 IVIa).

The cyclisation of the group VIa is effected, for example, by customary treatment of corresponding , .

., 3~

compounds of the formula VII with an acidic agent, especially a mineral acid anhydride, such as a phosphorus oxyhalide, for example the oxychloride, or phosphorus pentahalider for example the pentachloride.
The system trlphenylphosphine/hexachloroethane/tri-ethylamine is especially suitable. The procedure is especially carried out analogously to the method described by W. Steglich et al., Liebigs ~nn. Chem.
1 _ , 1916-1927.
X3 can also represent a group oE the formula ~ C ~

IH -CHO (VIb) in which the formyl group can also be in acetalised form, for example in the form of formyl acetalised by an alcohol, such as lower alkanol or lower alkanediol.
The cyclisation can be carried out, for example, in the presence of an acidic agent, for example a protonic acid, such as a mineral acid r for example a hydrohalic, sulphuric or polyphosphoric acid, a sulphonic acid, for example trifluoromethane- or p-toluene-sulphonic acid, or a strong carboxylic acid, for example an optionally substituted lower alkane-carboxylic acid, for exa~ple glacial acetic acid or trifluoroacetic acid. Also suitable are, for example, the mineral acid anhydrides mentioned above.

Variant f):
Reactive esterified hy~roxy X4 or X5 or X6 has, for example, the meanin~ given for Xl in variant a), whilst a metallic radical X4 or X5 or X6 ~t - 15 - ~2~3~

represents, for example, an alkali metal radical, such as a lithium, sodium or potassium radical, a magnesium halide radical, such as a magnesium bromide radical, a copper radical, or a lithium copper radical derived from lithium cuprates.
In a modiEication of the process, it is possible, for example, to start from a compound of the formula VIIa in which X4 and X5 each represents hydrogen and to treat this compound with a strong base, such as butyllithium, and to react the resulting compound of the formula VIIa in which X4 and X5 each represents a metallic radical, such as lithium, with at least two moles of a compound of the formula VIIb. In this operation there can first be obtained, ln situ, a compound of the formula VIIa in which one of the radicals X4 and X5 represents a metallic radical and the other represents Rl or R2, respectively, which compound then reacts further under the reaction conditions directly to form the corresponding compound of the formu~a I~
This reaction is advantageously initially carried out at low temperatures, for example in a temperature range of from ~78C to room temperature.

Variant g):
Ph' represents, for example, phenyl substituted by hydroxy.
Such compounds of the formula VIII can be converted into compounds of the formula I by etherifi-cation with a lower alkylating agent. Lower alkylating agents include, for example, lower alkanols or reactive esters thereof, such as corresponding halo-derivatives, such as chlorine, bromine or iodine derivatives, sulphonyloxy derivatives, such as hydroxysulphonyloxy derivatives, halosulphonyloxy derivatives, for example - 16 - 123~82~

fluorosulphonyloxy derivatives, optionally substituted, for example halo-substituted, lower alkanesulphonyloxy derivatives, fo~ example methane- or trifluoromethane-sulphonyloxy derivatives, cycloalkanesulphonyloxy derivatives, for example cyclohexanesulphonyloxy derivatives, or optionally substituted, for example halo- or lower alkyl-substituted, benzenesulphonyloxy derivatives, for example ~-bromophenyl- or p-toluene-sulphonyloxy derivatives. There also come into consideration as lower alkylating agents, for example, di-lower alkyl sulphate, diazo-lower alkane, tri-lower alkylsulphonium hydroxide, tri-lower alkylselenium hydroxide, tri-lower alkyloxosulphonium hydroxide or tri-lower alkylanilinium hydroxide, and also penta-lower alkoxyphosphine.
When using reacti~e esters of lcwer alkanols or di-lower alkyl sulphates as lower alkylating agents, the ethe~ification is effected especially in the presence of one of the bases mentioned above, whilst the reaction with a diaza-lower alkane is optionally carried out in the presence of a Lewis acid. Lewis acids are, for example, halides of boron, aluminium, tin(II), antimony(III), arsenic(III), 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, in the presence of a dehydrating agent.
As strong acids there may be mentioned especially strong protonic acids, for example mineral acids, such as hydrohalic acids, sulphuric acid or a phosphoric acid, strong carboxylic acids, such as an optionally substituted, for example halo-substituted, lower alkane-carboxylic acid or benzoic acid, for example glacial acetic acid or trifluoroacetic acid, or sulphonic acids, such as optionally substituted, for example halo-substituted, lower alkanesulphonic acids, or optionally substituted, for e~ample halo- or lower alkyl-substituted, benzenesulphonic acids, for example E~toluenesulphonic acid.
Suitable dehydrating agents are, for example, carbodiimides, for example N,N'-di-lower alkyl or N,N'-dicycloalkyl carbodiimides, such as N,N'-diethyl, N,N'-diisopropyl or N,N'-dicyclohexyl carbodiimide, advantageously with the addition of N-hydroxy-succinimide or optionally substituted, for example halo-, lower alkyl- or lower a~koxy substituted, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide, N,N'-diimidazolecarbonyl, a suitable phosphoryl or phosphine compound, for example diethyl-phosphonyl cyanide, diphenylphosphonylazide or triphenylphosphine disulphide, a 1-lower alkyl-2-halopyridinium halide, for example 1-methyl-2-chloropyridinium iodide, a suitable 1,2-dihydroquinoline, for example N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, or 1,1'-(carbonyldioxy)-dibenzotriazole.
Ph' also represents, for example, phenyl containing a diazonium grouping -N2~A~ in which A~ represents an anion of a strong protonic acid.

For the conversion of such compounds of the formula VIII into corresponding compounds of the formula I, the diazonium grouping -N2A~ is substituted by lower alkoxy, especially by treatment with a lower alkanol.
In an advantageous modification of this process variant, the compounds of the formula VIII can be formed _ situ and react further under the .~

reaction conditions, without being isolated, to form the compounds of the formula I. In this variant, firstly a compound of the formula VIII in which Ph' represents phenyl containing an amino group is used as the starting material, and this compound is diazotised with nitrites, such as alkali metal nitrites, or nitro-lower alkanes in the presence of protonic aclds, for example those of the type men~ioned above, and the com-pounds of the formula VIII in which Ph'represents phenyl containing a dia~onium grouping N~2A~, which compounds are formed in situ, are reacted, without being isolated, with a lower alkanol. Advantageously a reaction temperature of from approximately -10 to approximately +40C is selected for this reaction.
The invention relates especially to the manufacturing processes described in the Examples.
A compound according to the invention can be converted into a different compound according to the invention by methods that are known ~ se.
Thus, for example, a lower alkyl radical can be introduced into the phenyl ring Ph by alkylation, for example, with a reactive ester of a lower alkanol in the presence of a Lewis acid (Friedel Crafts alkylation).
T~e manufacture of the starting materials described in variants a) to g) is effected using methods that are known per se.
Thus, for example, the starting material of the formula III can be manufactured by reacting compounds of the formula IIa with compounds of the formula X2-Het (IIIa) analogously to the procedure described in variant a).
In analogous manner, it is possible to obtain starting compounds of the formulae IV, VIIa and VIII, for example, by reacting compounds of the formulae - 19 ~

Ph-A-Xl (IVa) and (IIb) [resulting in compounds of the formula IV], or reacting compounds of the formulae Ph-CH(X4)-Xl (VIIc) and X2-N ~ N (VIId) [resulting in compounds of the formula VIIa], or reacting co~pounds of the formulae Ph'-CH(Rl)-Xl (IIIa) and ~IIb) [resulting in compounds of the formula VIII].
Compounds of the formula VI in which X3 represents a yrouping of the formula VIa can be obtained, for example, by acid-catalysed reaction of compounds of the formula CH -C ~
~ \ H

NH-C-R2 (VIc) with compounds of the formula I (VId).
H2N - HC - Ph - 20 ~

Compounds of the formllla VI in which X3 represents a grouping of the formula VIb or VIb' can be ob-tained, for example, by condensa-tion of compounds of -the formula NH
~ (VIe) R - C

in which X8 represents a leaving group, such as lower alkoxy or amino, and compounds of the formula 0~ 11 C - CH2 HN HC Ph ~VIf) or an acetale H / thereof, the secondary amino group r~a~ additionally contain an acyl group, for example lower alkanoyl, such as acetyl.

A further variant for the manufacture of a compound of the formula VI, in which X3 represents the grouping of the formula VIb or VIb' respectively, consists in the reaction of a compound of the formula VId with a compound of the formula VIe and subsequent condensation of a compound ob-tainable of the formula Ph-CH(Rl)-NH-C(R2)=NH (VIg) with a monohalogeno-acetaldehyde or preferably an acetale thereof.
Likewise a compound of the formula Ph-CH(Rl)-N=C~R2)-X8 (VIh) may be reacted with an acetale of an aminoacetaldehyd.

A compound of the formula VI in which X3 represents the grouping VIb or VIb' respectively may be preferably formed in situ and is directly reacted, under the reaction condi-tion, to the corresponding compound of the formula I.

Salts of compounds of the formula I can be manufactured in a manner known ~ se. Thus, for example, acid addition salts of compounds of the formula I are obtained by treatment with an acid or a - 20a -suitable ion exchange reagent. Salts can be converted in customary manner into the free compounds; acid addition salts can be converted, for example, by treatment with a suitable basic agent.
Depending upon the procedure and reaction conditions used, the compounds according to the invention having salt-forming, especially basic, properties may be obtained in free form or in the form of salts.
As a result of the close relationship between the 2 1 -- ~ r ~

novel compound in free form and in the orm of its salts, hereinbefore and hereinafter the free compound or its salts should be understood as meaning also the corresponding salts or free compound, respectively, where appropriate and expedient.
The novel compounds, including salts of salt-forming compounds, can also be obtained in the form of their hydrates or may include other solvents used for crystallisation.
Depending upon the starting materials and procedures chosen, the novel compounds may be obtained in the form of one of the possible isomers or in the form of mixtures thereof, for example, depending upon the number of asymmetric carbon atoms, in the form of pure optical isomers, such as antipodes, or in the form of isomeric mixtures, such as racemates, diastereoisomeric mixtures or racemic mixtures.
Resulting diastereoisomeric mixtures and racemic mixtures can be separated into the pure isomers diastereoisomers or racemates in known manner on the basis of the physico-chemical differences between the constituents, for example by fractional crystal-lisationO
Resulting racemates can also be separated into the optical antipodes according to known methods, for example ky recrystallisation from an optically active solvent, by chromatography over chiral adsorbents, with the aid of suitable micro-organisms, by cleaving with specificl immobilised enzymes, by means of the formation of inclusion compounds, for example using chiral crown ethers, in which case only one enantiomer is complexed, or by conversion into diastereoisomeric salts, for example by reaction of a basic end product racemate with an optically active acid, such as a carboxylic acid, for example tartaric or malic acid, or a sulphonic acid, for example camphorsulphonic acid, and separation of the diastereoisomeric mixture obtained in this manner, for example on the basis of their different solubilities, into the diastereo-isomers, from which the desired enantiomer can be freed by the action of suitable agents. Advantageously, the more active enantiomer is isolated.
The invention also relates to those forms of the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out, or a starting material is used in the form of a derivative or salt, and/or its racemates or antipodes or, especially, is formed under the reaction conditions.
In the process of the present invention it is preferable to use those starting materials which result in the compounds described at the beginning as being especially valuable. The invention relates also to novel starting materials, which were developed especially for the manufacture of the compounds according to the invention, to their use and to processes for their manufacture, the variables Rl, R2 and Ph having the meanings indicated for the preferred groups of compounds of the formula I.
The invention relates also to the use of the compounds of the formula or of pharmaceutically acceptable salts of such compounds having salt-forming properties, especially as active ingredients having pharmacological, more especially antidepressive, action. They can be used, preferably in the form of pharmaceutically acceptable preparations, in a metl,od for the prophylactic and/or therapeutic treatment of the animal or human body, especially as anti-depressants for the treatment of depression.

- 23 ~ c~

The invention relates a~so to pharmaceutical preparations that contain as active ingredients the compounds according to the invention or pharma-ceutically acceptable salts thereof and to processes for their ~anufacture.
The pharmaceutical preparations according to the invention, whieh eontain the compounds according to the invention or pharmaceutically acceptable salts thereof, are for enteral, sueh as oral and rectal, and parenteral administration to (a) warm-blooded animal(s), the preparations eontaining the pharma-eologieal aetive ingredient alone or together with a pharmaceutically aceeptable carrier. The daily dose of the aetive ingredient depends upon age and individual eondition and upon the method of administration.
The aetive ingredients ean also be applied to the skin with the aid of transdermal therapeutie systems (TTS) which serve to provide a eontrolled pereutaneous supply of active ingredient for systemic treatment, for example in the form of an adhesive plaster of rounded shape approximately from 2 to 50 cm2 in size. The release of active ingredient can take plaee, for example, over a period of from approximately 24 hours to one week.
Such transdermal systems have a multi-layered structure and eomprise, for example, from the outside to the inside, an impermeable eover film, an aetive ingredient reservoir, an adhesive or stieky layer and a pull-off film to be removed before applieation. In the ease of the eorresponding matrix or monolithie systems, the aetive ingredient is distributed in a polymer layer from whieh it is released by diffusion. It is also possible to use membrane-controlled systems in which a semipermeable or mieroporous control membrane that determines the speed of diffusion is located - 2~

between the active ing-edient reservoir and the skin.
As regards dosage, the amount of active ingredient absorbed per time unit depends, for example, on the size of the contact surface between the active ingredient reservoir and the skin.
The novel pharmaceutical preparations contain, for example, from approximately 10% to approximately ~0~, preferably from approximately 20% to approximately 60~, of active ingredient. Pharmaceutical preparations according to the invention for enteral and parenteral administration are, for example, those in dosage unit forms, such as dragées, tablets, capsules or suppositories, and also ampoules. They are manufactured in a manner known per se, for example, by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, to form tablets or dragée cores.
Suitable carriers are, especially, fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatine, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross-linked po]yvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating agents and lubricants, for example silica, talc, ~ 25 - ~ ~3~

stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are provided with suitable coatings that may be resistant to gastric juices r there being used~
inter alia, concentrated sugar solutions that may contain gum arabie, tale, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the manufacture of eoatings resistant to gastric juices, solutions of suitable cellulose preparations, sueh as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragée coatings, for example for identification purposes or to indicate different doses of active ingredient.
Further orally administrable pharmaceutical preparations are dry-filled eapsules consisting of gelatine, and also soft, sealed capsules eonsisting of gelatine and a plasticiser, such as glycerine or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, sueh as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and optionally stabilisers.
In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also be added.
There eome into consideration as reetally administrable pharmaeeutieal preparations, for example, suppositories that eonsist of a combination of the aetive ingredient and a suppository base. Suitable as suppository bases are, for example, natural or synthetie triglycerides, paraffin hydroearbons, poly-ethylene glycols or higher alkanols. It is also ~3~

possible to use gelatine rectal capsules that contain a combination of the active ingredient and a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, also suspensions of the active ingredient, such as corresponding oily injection suspensionsl there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or tri-glycerides, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and, optionally, also stabilisers.
The dosage of the active ingredient depends upon the species of warm-blooded animal, age and individual condition, and on the method of administration. In normal cases, the estimated approximate daily dose for a warm-blooded animal weighing approximately 75 kg is, in the case of oral administration, from approximately 100 to approximately 500 mg, especially from 200 to approximately 300 mg, advantageously in several equal partial doses.
The following Examples illustrate the invention described above but do not limit the scope thereof in any way. Temperatures are given in degrees Centigrade.

~3;~

Example 1 24.4 g (0.2 mol) of l-phenylethanol and 27.6 g (0.2~ mol) of methanesulphoch]oride are dissolved in 250 ml of toluene and, while stirring at 10, a solution of 28.2 g (0.28 mol) of triethylamine in 50 ml of toluene is introduced dropwise over a period of 30 minutes. The reaction mixture is stirred for 12 hours at room temperature and then the triethylamine hydro-chloride that has formed is filtered off. The residue is washed with toluene and the combined filtrates are concentrated to dryness by evaporation under a water-jet vacuum. While stirring at ~5, the resulting oil is added dropwise in the course of 15 minutes to a solution of S0 g (0.6 mol) of 2-methyl-imidazole and the mixture is kept at 100 for 6 hours. 200 ml of ether and 200 ml of water are added to the reaction mixture and the organic phase is separated off and washed three times with water.
The organic phases are extracted by shaking three times using 100 ml of 2N hydrochloric acid each time, and the aqueous acidic phases are rendered alkaline with concentrated sodium hydroxide solution and again extracted by shaking with ether. The organic phases are dried over magnesium sulphate and the solvent is removed under a water-jet vacuum. The oil that is obtained as a crude product is distilled at 120 (13.3 Pa) under a high vacuum and, after recrystal-lisation from cyclohexane, yields pure l-(l-phenyl-ethyl)-2-methylimidazole which melts at 8~-85.
22.8 g (0.12 mol) of the resulting base are dissolved in 100 ml of ethyl acetate and the solution is rendered acidic (pH ~1) with alcoholic hydrochloric acid. ~fter the addition of 25 ml of ether, the precipitate that has formed is filtered off, washed with ether and dried at 60 in vacuo. The resulting pure l-(l-phenyl-- 28 ~

ethyl~-2-methylimidazole hydrochloride melts at 229-22g.5.

Example 2 In a manner analogous to that described in Example 1, oily 1-[1 (p-methylphenyl)-ethyl1-2-methyl-imidazole is obtained from 40.86 g l0-3 mol~ of 1-(~-methylphenyl)-ethanol and 73.9 g (0.9 mol~ of 2-methylimidazole. The hydrochloride prepared therefrom melts at 237-238.

Example 3 In a manner analogous to that described in Example 1, 21.3 g of oily 1-[1-(2,4-dimethylphenyl)-ethyl]-2-methylimidazole are obtained as a crude product from 30.1 g (0.2 mol) of 1-(2,4-dimethylphenyl)-ethanol and 49.3 g (0.6 mol) of 2-methylimidazole. The hydro-chloride prepared therefrom in analogous manner melts at 238-239.
The 1~(2,4-dimethylphenyl)-ethanol required as starting material is prepared as follows:
44.5 g (0.3 mol) of 2,4-dimethylacetophenone are dissolved in 200 ml of isopropanol and, while stirring at 60, an ice-cold solution of 5.7 g (0.15 mol) of sodium borohydride in 50 ml of water is slowly added dropwise thereto. The reaction mixture is heated at reflux temperature for 4 hours, then cooled, and 200 ml of 1 molar sodium dihydrogen phosphate solution are added. The isopropanol is extensively remove~ under a water-jet vacuum and the residue is extracted by shaking with ether. The organic phases are washed with brine and dried over magnesium sulphate and the solvent is removed under a water-jet vacuum. The resulting residue is distilled under a water-jet vacuum and yields 1-(2,4-dimethylphenyl)-ethanol having a boiling point (1866.5 Pa) of 120 [Ishizaka, Chem. Ber. 47, 2461, B.p.14 = 124-125].

_a~
In a manner analogous to that described in Example 1, oily 1-[1-(2-methylphenyl)-ethyl]-2-methylimidazole is obtained as a crude product from 27.3 g (0.2 mol) of 1-[~2-methylphenyl)-ethyl]-ethanol and 49.3 g (0.6 mol) of 2-methylimidazole. The hydrochloride melts at 237-238.
The 1-(2-methylphenyl)-ethanol required as starting material is prepared analogously to Example 3 (V. Auwers et al. Chem. Ber. 58, 46, B.p.20 =
107-108).

Example 5 25 g (0O113 mol) of 1-(1-phenylethenyliden-1-yl)-2-methylimidazole hydrochloride are added to 200 ml of saturated potash solution and then extracted by shaking three times using 100 ml of ether each time. The organic extracts are dried over magnesium sulphate and concentrated to dryness by evaporation in vacuo. The resulting residue is dissolved in 500 ml of methanol and, with the addition of 1 g of 5~ palladium-on-carbon, hydrogenated at room temperature and normal pressure. The catalyst is filtered off and washed with methanol and the combined methanolic solutions are concentrated to dryness by evaporation ln vacuo. The resulting oily residue is crystallised from cyclohexane and yields pure 1~ phenylethyl)-2-methyli~idazole having a melting point of 84-85.
The starting material is obtained, for example, as follows:
a) 130 g (0.68 mol) of ~-chlorophenylacetyl chloride are added dropwise at 20-30 to 500 ml of ethanol and _ 30 - ~ ~3~8~

the whole is stirred for 3 hours at 30-40. The solvent is removed in vacuo and yields crude 2-chloro-2-phenylacetic acid ethyl ester. The result-ing product (137 g) is dissolved in 2 litres of toluene, and 170 g (2.07 mol) of 2-methylimidazole are added to the solution. The reaction mixture is kept at 100 for 12 hours while stirring. The resulting reaction mixture is extracted by shaking four times using 500 ml of water each time and the aqueous phases are then washed with a small ~uantity of toluene, and the combined organic phases are dried over magnesiu~
sulphate. After removal of the solvent in vacuo, crude, oily 2-phenyl-2-~2-methylimidazol-l-yl)-acetic acid ethyl ester is obtained. The compound distils at 145 (26.6~ Pa). The pure hydrochloride melts at 157-159.

b) 1~2.9 g (0.5~5 mol) of 2-phenyl-2-(2-methy~-imidazol-l-yl)-acetic acid ethyl estsr are dissolved in 1.5 litres of isopropanol and, while stirring at 5, a solution of 23 g (0.6 mol) of sodium borohydride in 150 ml of water is added dropwise over a period of 30 minutes. The mixture is stirred without cooling for 6 hours, the temperature of the mixture reaching 45-50~. When cold, the mixture is rendered acidic (pH = l-2) with a mixture of concentrated hydrochloric acid and water (l:l) and the solvent is extensively removed ln vacuo. ~aturated potash solution is added to the residue at low temperature until an alkaline reaction is obtained, and then the whole is extracted by shaking three times using 300 ml of ether each time. The combined organic phases are dried over magnesium sulphate and the solvent is re-moved in vacuo. The resulting oily residue is crystallised from ether/cyclohexane and yields pure 2-phenyl-2-(2-methvlimidazol-l-yl)-ethan-l-ol having a melting point of 114-116.
105.3 g of the resulting base are dissolved in 300 ml of ethanol, and alcoholic hydrochloric acid is added until an acidic reaction is obtained. ~fter the addition of 200 ml of ethyl acetate and approximately 200 ml of ether, the product that has formed is filtered off, washed with ethyl acetate and dried in vacuo at 60. The pure 2-phenyl-2-(2-methyl-imidazol-l-yl)-ethanol hydrochloride melts at 144-146.
115 g (0.481 mol) of 2-phenyl-2-(2-methyl-imidazol-l-yl)-ethanol hydrochloride are dissolved in 1 litre of chloroform and boiled under reflux for 10 hours with 120 g (1 mol) of thionyl chloride. The reaction mixture is concentrated to dryness by evaporation in vacuo and the crude product is further used directly. 120.4 g of the crude 1-[2-(1-chloro-2-phenylethyl)]-2-methylimidazole hydrochloride are dissolved in 1 litre of chloroform and stirred with 152 g (1.0 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene for 12 hours at room temperature.
The reaction mixture is freed of solvent in vacuo and 500 ml of cyclohexane and 500 ml of water are added. The aqueous phase is separated off and the organic phase is washed three times using 100 ml of water each time. The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo. The crude l-(l-phenylethenyliden-l-yl)-2-methylimidazole is obtained in the form of an oil. The base has a boiling point of ~.p. 130 (6.66 Pa).
82 g of the crude base are dissolved in 200 ml of ethyl acetate, and approximately 7N alcoholic hvdrochloric acid is added until an acidic reaction is obtained.
~fter the addition of 50 ml oE ether, the product that has for~ed is filtered off, washed with ether and dried in vacuo at 60. The pure 1~ phenylethenyliden-t-yl) 2-methylimidazole hydrochloride melts at 258--260.

Example_6 8.6 g (0.05 mol) of 1-(1-phenylethyl)-imidazole are dissolved in 80 ml of absolute tetrahydrofuran and, at -70, 30 ml ~2 mol) of n-butyllithium solution in hexane are added dropwise thereto. The mixture is stirred for 30 minutes at -70, and then 7.1 g (0.05 mol) of methyl iodide in 20 ml of tetrahydrofuran are added dropwise. The cooling means is removed and the mixture is brought slowly to room temperature and then left at this temperature for 2 hours. For working up, 25 ml of 2N sodium hydroxide solution are added and the tetrahydrofuran is extensively removed in vacuo. The residuQ is extracted by shaking with ether and the organic phases are dried over magnesium sulphate and the solvent is removed in vacuo. The resulting oily residue is dissolved in ethyl acetate; ethereal hydro--chloric acid is added until an acidic reaction is obtained and the product that for~s is filtered off.
After recrystallisation from isopropanol/ether, the pure 1-~1-phenylethyl)-2-methylimidazole hydrochloride melts at 228-229.

Example 7 In a manner analogous to that described in Example 1, oily 1-[1-(3-methylphenyl)-ethyl]-2-methylimidazole is obtained as a crude product from 13.6 g (0.1 mol) of 1-[1-(3-methylphenyl)-ethyl]-ethanol and 24.6 g (0O3 mol) of 2-methylimidazole. The hydrochloride melts at 228-230.

~3~

Example 8 In a manner analogous to that described in Example 1, crude 1-[1-(phenyl)-propyl]-2-methylimidazole is obtained in the form of an oil from 13.6 g (0.1 mol) of 1-phenylpropan-1 -ol and 25 g (0.3 mol) of 2-methyl-imidazole. The hydrochloride melts at 177-179.

Example 9 In a manner analogous to that described in Example 1, crude, oily 1-[1-(2-ethylphenyl~-ethyl]-2-methyl~
imidazole is obtained from 15.0 g (0.1 mol) of 1-(2-ethylphenyl)-ethanol and 25 g (0.3 mol) of 2-methyl-imidazole. The hydrochloride melts at 211-213.

Example 10 In a manner analogous to that described in Example 1, crystalline 1-[1-(2,6-dimethylphenyl)-ethyl]-2-methylimidazole having a melting point of 100-1 03 is obtained from 15.0 g (0.1 mol) of 1-(2,6-dimethyl-phenyl)-ethanol and 25 g (0.3 mol) of 2-methyl-imidazole. The hydrochloride melts at 265-267.

Example 11 18.8 g (0.1 mol) of 1-[1 -(phenyl)-ethyl]-2-methyl-4,5-dihydroirnidazole are dissolved in 4000 ml of methylene chloride and, while stirring and with the exclusion of moisture, 282 g (1.1 mol) of barium manganate are added. The mixture is stirred under reflux for 24 hours. 20 g of magnesium sulphate are then added, the solid portions are filtered off and the residue is washed with methy1 ene chloride. The organic filtrates are concentrated to dryness by evaporation ln vacuo and the resulting oil is dissolved in ethyl acetate. After the addition of ethereal hydrochloric acid until an acidic reaction is obtained, the - 34 - ~ ~3~

hydrochloride that is formed is filtered off and recrystallised from isopropanol/ether. The pure l-[l-(phenyl)-ethyl]-2-methylimidazole hydrochloride melts at 228-229.
The starting material is obtained as follows:

~) N-[l-(phenyl)-ethyl]-aminoethylamine 30 g (0.25 mol) of acetophenone are dissolved in 300 ml of methanol and, after the addition of 30 g (0.5 mol) of ethylenediamine and l.0 g of platinum-on-carbon, hydrogenated with hydrogen at 20 and normal pressure over a period of 22 hours. The catalyst is re-noved from the resulting solution by filtration, the solvent is removed _ vacuo and the residue is distilled under a water-jet vacuum. The N-[1-(phenyl)-ethyl]-aminoethylamine, obtained in the form of an oil, boils at 115-118 (1466.5 Pa).

b) 16.4 g (0.1 mol) of N-[l-(phenyl)-ethyl~-amino-ethylamine are dissolved in 100 ml of ethanol and, at 0, 16.0 g (0.1 mol~ of acetamido acid ethyl ester hydrochloride are introduced. The mixture is stirred for 3 hours at ~ and the solvent is removed ln vacuo. The resulting oil is extracted by shaking with water and ether, and the ethereal extract is dried over magnesium sulphate and the solvent is removed in vacuo. The residue is dissolved in ethyl acetate, and -oxalic acid is added until an acidic reaction is obtained. ~fter the addition of a little ether, the product that has formed is filtered off and recrystal-lised from isopropanol/ether. The pure l-[1-(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 1N potassiu~

35 ~ 3~

hydroxide solution and ether. The free base is obtained which boils at 130 (1.33 Pa).

Example ! 2 5~0 g (0.0409 mol) of R-(+)-1-phenylethanol ([~122 = +39.5) and 5.2 g (0.055 mol) of methane-sulphochloride are dissolved in 100 ml of ether and cooled to 0, and at this temperature a solution of 5.1 g (0.060 mol) of triethylamine in 50 ml of ether is added drop~ise. The mixture is stirred for 1 hour at 0 and the precipitate that has formed is filtered off. The filtrate is concentrated by evaporation as gently as possible under a water~jet vacuum, and the residue is dissolved in 20 ml of toluene and, at 90, added dropwise to a solution of 80 2 g (0.1 mol) of 2-methylimidazole. The mixture is heated at 90 for 1 hour. For working up, the mixture is dilute~ with ether and with water and then extracted by shaking three times with 50 ml of 2N hydrochloric acid. The hydrochloric acid extracts are rendered alkaline with concentrated sodium hydroxide solution and extracted with ether. The resulting ethereal solutions are dried over magnesium sulphate and concentrated to dryness.
The residue that remains is crystallised twice from cyclohexane and yields pure laevorotatory 1~ phenyl-ethyl)-2-methylimidazole havin~ a melting point of 113-1 15 [~ 2 = -15 + 1 . (Enantiomer purity approximately 95% according to NMR.) The hydrochloride melts at 243-244.

Example 13 In the same manner as that demonstrated in Example 11, dextrorotatory 1-[1-(phenyl)-ethyl]-2-methyl-- 3~ 3~

imidazole ha~ing a ~elting point of 113-1 15 [~]20 = ~15 (+ 1) is obtained from 5O0 g of S(-)-1-phenylethanol ([~12 = -41.3). The hydrochloride melts at 243-244.

Example 14 In a manner analogous to that described in Example 1, 1-[1-~3-methoxyphenyl)-ethyl]-2-methylimidazole is obtained in the form of an oil from 20.2 g (0.1 mol~ of 1-~3-methoxyphenyl)-ethanol and 25 g (0.3 mol~ of 2-methylimidazole. The hydrochlcride melts at 197-1 99o.

Example 15 6.0 g (0.0297 mol) of 1-[1-(2-hydroxyphenyl)-ethyl]-2-methylimidazole and 25 ml of hexametapol are suspended in 25 ml of tetrahydrofuran and, while stirring at 20, 1.3 g (0.030 mol) ~f sodiu~
hydride suspension (55%) are added in portions. The mixture is stirred for 2 hours at 20. ~ solution of

4.25 g (0.030 mol) of methyl iodide in 25 ml of hexametapol is then added dropwise thereto 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 ~ethylene chloride. The organic phases are separated off, w~shed with water and dried over magnesium sulphate. After removal of the solvent, crude 1-[1-(2-methoxypher1yl)-ethyl]-2-methylimidazole is obtained in the orm of an oil. The hydrochloride melts at 201-203.
The 1-[1~(2-methoxyphenyl)-ethyl]-2-methyl-imidazole required as starting material can be obtained as follows:
20.0 g (0.1 mol) of ~-methylene-1-(2-hydroxy-benzyl)-2-methylimidazole are ~issolved in 500 ml of ethanol and, after the addition of 1 g of palladium-on-carbon, hydrogenated at room temperature and norntal pressure. The catalyst is then filtered off and the solvent is extensively removed ln vacuo; fumaric acid is added to the residue until a ~eakly acidic reaction is obtained. After the addition of ethyl acetate, the product that has formed is filtered off, recrystallised from alcoholfethyl acetate and dried. The pure 1 [1-(2-hydroxyphenyl)-ethyl]-2-methylimidazole melts at 148-1 50.
For further reaction, 10 g (0.03 mol) of the fumarate are cleaved with 2N sodiu~ hydroxide solution and ether to form the free base. The free base is obtained which is reacted as described.

Example 16 In a manner analogous to that described in Example 1, a crude product is obtained from 18.2 g (0.1 mol) of 1-(2,3-dimethoxyphenyl)-ethanol and 25 g (0.3 mol) of 2-methylimidazole. The free base is chromatographed over silica gel with methylene chloride/1-59~ methanol and yields pure 1-11-(2,3-dimethoxyphenyl)-ethyl]-2-methylimidazole having a melting point of 122-124.
The hydrochloride melts at 175-178.

Example 17 In a manner analogous to that described in Example 1, 7.9 g of pure 1-[1-(2,4,6-trimethylphenyl)-ethyl]-2-methylimidazole having a melting point of 129-131 is obtained from 16.4 g (0.1 mol) of 1-(2,4,6-trimethylphenyl)-ethanol and 25 g (0.3 mol) of 2-methyl imidazole. The hydrochloride melts at 267 (decomposition) .

- 38 - ~3~

Example 18 In a manner analogous to that described in Exarnple 1 r from 9.1 g (0.05 mol) of 1-(2,6-dimethoxyphenyl)-ethanol and 1 2.5 g (O.l5 mol) oE 2-methyli-nidazole there are obtained 3.7 g of crude 1-[1-(2,6-dimethoxy-phenyl)-ethyl]-2-methylimidazole which yields pure hydrochloride having a melting point of 214-216.
The starting material can be prepared as follows:
16.6 g (0.1 mol) of 2,6-dimethoxybenzaldehyde are dissolved in 200 ml of absolute tetrahydrofuran, and 60 ml of a 2.58 molar methylmagnesium iodide solution in tetrahydrofuran are added dropwise thereto at 10.
The reaction mixture is kept at room temperature for 2 hours and then a solution of 30 g of ammonium chloride in 200 ml of water is added. The resulting mixture is extracted by shaking with ether, and the organic phases are washed with brine and dried over magnesium sulphate. After removal of the solvent, the residue is crystallised from isopropyl ether/petroleum ether. The resulting 1-t2,6-dimethoxyphenyl)-ethanol melts at 56-58.

Example 19 In a manner analogous to that described in Example 1, 1.95 g of oily 1-[1-(2,3-dimethylphenyl) -ethyl]-2-methylimidazole are obtained from 3 g (0.02 mol) of 1-(2,3-dimethylphenyl)-ethanol and 4.92 g (0.06 mol) of 2-methylimidazole. The pure 1-[1-(2,3-dimethylphenyl)-ethyl]-2-methylimidazole hydrochloride, which has a melting point of 244-246, is prepared from 1.92 g of the crude base with ethereal hydrochloric acid.

Example 20 9. 25 g (0.05 mol) of 1-phenylethyl bromide are dissolved with 20. 5 g (0. 25 mol) of 2-methylimidazole _ 39 _ ~ ~33~2~

in lO0 ml of toluene and, ~hile stirring, heated at 100 ~or ~ hours. The reaction mixture is coole~; 2N
hydrochloric acid is added until an acidic reaction is obtained and the acidic aqueous phase is separated off.
The toluene solution is extracted by shaking three times usin~ 50 ml of lN hydrochloric acid each ti~e and the combined acidic aqueous phases are rendered alkaline with concentrated sodium hydroxide solution.
The resulting mixture is extracted by shaking with ether, and the ethereal solution is dried over magnesium sulphate and the solvent is removed in vacuo. The resulting residue is dissolved in ethyl acetate, and ethereal hydrochloric acid is added until an acidic reaction is obtained. ~fter a further addition of ether, the product that has formed is filtered off, washed with ether and recrystallised from cyclohexane. The pure 1-(l-phenylethyl)-2-methyl-imidazole melts at 84-85.
As described in Example 1, the hydrochloride is prepared from the base. The pure l-(l-phenylethyl)-2-methylimidazole hydrochloride melts at 229-229.5.

Example 21 10.9 g (0.1 mol) of acetiminomethyl ether hydro-chloride are added to 23.02 g (0.11 mol) of N-(l-phenylethyl)-2-aminoacetaldehyde dimethyl acetal and the whole is dissolved in 200 ml of methanol and left to stand for 4 days at room temperature. The reaction mixture is freed of solvent in vacuo and the oily residue is ~issolved in 250 ml of water and added to 500 ml of concentrated hydrochloric acid. The mixture is concentrated to dryness by evaporation at tO0 and the resulting residue is rendered alkaline with a saturated potash solution. The resulting mixture is extracted by shaking three times with 500 ml of ether 3~

and the ethereal phases are dried over magnesium sulphate and the solvent is removed ~n vacuo. The oily residue is distilled under a high vacuum (6.66 Pa), B.p. = 115-12Q. The resulting product is dissolved in ethyl ~cetate, and ethereal hydrochloric acid is added until an acidic reaction is obtained.
The product that forms is filtered off and recrystal-lised from isopropanol/ether. The pure 1-(2-phenyl-ethyl~-2-methylimidazole 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, after the addition of 10 g of palladium-on-carbon, catalytically hydrogenated at room temperature and normal pressure.
After the absorption of hydrogen is complete, the catalyst is filtered off and the solvent is removed in vacuo. The resulting residue is dîstilled under a high vacuum at 60-65 (7.99 Pa) and yields pure N-(l-phenylethyl)-2-aminoacetaldehyde dimethyl acetal.

b) 82 g (2 mol) of acetonitrile are dissolved in 65 g (2 mol) of methanol and added to 500 ml of 4N ethereal hydrochloric acid. The reaction mixture is left to stand at room temperature and the product that is formed is filtered off. The resulting product is washed with ether and dried at room temperature ln vacuo. The resulting acetiminomethyl ether hydro-chloride melts at 97.

Example 22 9.1 g (0.05 mol) of 1-[2-methoxybenzyl]-imidazole are dissolved in 90 ml of tetrahydrofuran and, at - 4 1 - ~L~3;~

-78, 7. 1 9 (O. 11 mol, correspondin~ to 55.4 ml of 2 molar solution) of butyllithiu~ in 50 ml of tetrahydroEuran are added dro~wise. The mixture is stirred for 2 hours at -78 and then 17.0 g (0.12 mol) of methyl iodide, dissolved in 20 ml of tetrahydrofuran, are added dropwise. The reaction mixture is heated to room temperature and stirred at this temperature for 30 hours. 50 ml of w~ter are then slowly added dropwise and the tetrahydrofuran is extensively removed in vacuo.
After the addition of 2N sodium hydroxide solution until a strongly alkaline reaction is obtained, the residue is extracted by shaking with ether. The organic phases are dried over magnesium sulphate and the solvent is removed ln vacuo. The resulting oily residue is dissolved in ethyl acetate, and ethereal hydrochloric acid is added until an acidic reaction is obtained. T~e product that is formed is filtered off and recrystallised from isopropanol/ether. The pure 1-[1-(2-methoxyphenyl)-ethyl]-2-methylimidazole hydrochloride melts at 201-203.
The starting material can be obtained as follows:
In a manner analogous to that described in Example 1, 9.78 g of pure, oily 2-methoxybenzylimidazole are obtained from 13.8 9 (0.1 !nol) of 2-methoxybenzyl alcohol and 34 g (0.5 mol) of imidazole. The resulting product is distilled under a 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 Inethanol;
6 ml (60 mmol) of concentrated hydrochloric acid are added and, at 0, 2.68 g (26 mmol) of tert.-butyl nitrite are added dropwise. The mixture is stirred for - 42 ~ ~ ~ 3 ;~

30 minutes at 0, then slowly heated to reflux over the course of 1 hour and kept at this temperature for 30 minutes. The reaction mixture is concentrated under a water-jet vacuum; 2N sodiun hydroxide solution is added until an alkaline reaction is obtained and the mixture is then diluted with brine and extracted by shaking with ether. The ethereal extracts are dried over magnesium sulphate, the solvent is removed in vacuo, and alcoholic hydrochloric acid is added to the residue until an acidic reaction is obtained. After the addition of ethyl acetate, the product that has formed is filtered off and dried. ~ter recrystal-lisation from alcohol/ethyl acetate, the pure 1-[1-(4-methoxyphenyl)-ethyl]-2-methylimidazole hydrochloride is obtained having a melting point of 200-202.
The starting material can be obtained as follows:
16.5 g (0,,1 mol) of ~-nitroacetophenone are dissolved in 160 ml OL Inethanol and, while cooling, 3.7 g (0.1 mol~ of sodium borohydri~e are slowly introduced. When the addition is complete, the mixture is slowly heated to 60 and is kept at this tempera-ture until the evolution of gas has ceased. After cooling, approximately 150 ml of 1 molar sodium dihydrogen phosphate solution are added and the methanol is extensively removed in vacuo. The residuQ is extracted by shaking with ether and the organic phases are dried over magnesium sulphate and the solvent is removed in vacuo. The resulting l-[~-nitrophenyl]-ethanol is further used in the form of a crude oil.
Pure 1-[1-(4-nitrophenyl)-ethyl]--2-methyliinidazole having a melting point of 78-79 (recrystallis~tion from diisopropyl ether/petroleum ether) are obtained as described in Example 1 fro~ 16 g (0.096 mol) of l-(p-nitrophenyl)-ethanol and 23.6 g - ~3 ~ 3~

(0.29 mol) of 2 methylimidazole.
14.0 g (0.06 mol) of 1-[1-(4-nitrophenyl)-ethyl]-2-methylimidazole are dissolved in 150 ml of ethanol; 2 g of R~ney nickel are added and catalytic hydrogenation is carried out with hydrogen at normal pressure and 20 over a period of 15 hours.
The catalyst is then filtered off, the solvent is removed ln vacuo and the residue is crystallised from ethyl acetate. The pure 1-[1-(4-aminophenyl)-ethyl~-2-methylimidazole melts at 149-151. The dihydro-chloride (from alcohol/ethyl acetate with alcoholic hydrochloric acid) melts at 165-167.

Example 24 In a manner analogous to that described in E~ample 23, pure 1-[1-(2-methoxyphenyl)-ethyl]-2-methyl-imidazole hydrochloride having a melting point of 201-203 can be obtained from 20.1 g (Oo1 mol) of 1-[1-(2-aminophenyl)-ethyl]-2-methylimidazole.
The dihydrochloride (from alcohol/ethyl acetate with alcoholic hydrochloric acid) melts at lÇ5-167.
xample 25 Tablets containing 0.020 g of 1-(1-phenyl-ethyl)-2-methylimidazole can be manufactured, for example, as follows:
omposition (for 10,000 tablets):
active ingredient200.00 g lactose 290.80 g potato starch 274.70 g stearic acid 10.00 g talc 200.00 g magnesium stearate 2.50 g colloidal silica 32.00 g 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 the stearic acid and granulated through a sieve. After drying, the remaining potato starch, the talc, the magnesiu~ stearate and the colloidal silica are mixed in and the mixture is compressed to form tablets which each weigh 0O1 g and, if desired, can be provided with dividing notches for more accurate adjustment of the dose.
xample 26 Capsules containing 0.025 g of 1~
phenylethyl~-2-methylimidazole can be manufactured as follows:

Compositio_ (for 1,000 capsules):
active ingredient 25.00 g lactose 249.00 g gelatine 2.00 g corn starch 10.00 g talc 15.00 g water q.s.

The active ingredient is mixed with the lactose and the mixture is moistened uniformly with an aqueous solution of the gelatine and then granulated through a sieve of 1.2-1.5 mm mesh width. The granulate is mixed with the dried corn starch and the talc, and 300 mg portions are introduced into hard gelatine capsules (size 1).

Claims (20)

Patent Claims

1. A process for the manufacture of substituted imidazoles of the general formula (I) or their salts, in which Ph represents phenyl that is unsubstituted or substituted by lower alkyl or by lower alkoxy, and R1 and R2 each represents lower alkyl, and of their salts, characterised in that a) a compound of the formula (IIa), in which X1 represents a halogen atom or a sulphonyloxy group, is, under basic conditions, reacted with a compound of the formula (IIb), in which X2 represents hydrogen or an alka.li metal, copper (I) or lithium cuprate radical, or b) in a compound of the formula (III) in which Het represents a 3-R2-pyrazol-1-yl or 2-R2-imidazolin-1-yl radical, the 3-R2-pyrazol-1-yl radical is photoisomerized or the 2-R2-imidazolin-1-yl radical is de-hydrogenated to the corresponding 2-R2-imidazol-1-yl radical, or c) in a compound of the formula (IV) in which A represents lower alkylidene or a grouping >CH-R1 substituted by hydroxy, lower alkoxy, halogen, sulphonyloxy, mercapto or lower alkylthio or by carboxy and the radical R2' represents a radical R2 substituted by hydroxy, lower alkoxy, halogen, sulphonyloxy, mercapto or lower alkylthio or by carboxy or represents R2, or in which A represents the grouping -CH(R1)- and R2' represents a radical R2 sub-stituted hydroxy, lower alkoxy, halogen, sulphonyloxy, mercapto or lower alkylthio or by carboxy, a lower alkenyl-idene radical A or group >CH-R1 substituted by hydroxy, lower alkoxy, halogen, sulphonyloxy, mercapto or lower alkylthio present is reduced and a group >CH-R1 substituted by carboxy present is decarboxylated to the corresponding group -CH(R1)-and a group R2 substituted by hydroxy, lower alkoxy, halogen, sulphonyloxy, mercapto or lower alkylthio present is reduced or the group R2 substituted by carboxy is decarboxylated to the corresponding group R2, or d) a compound of the formula (V) in which A? represents an anion of a hydrohalic acid, is reduced to the corresponding compound of the formula I, or e) a compound of the formulae (VIa) (VIb) which latter may be present in the form of a di-lower alkyl-or lower alkylene-acetal, is converted by acidic cyclisation into the corresponding 2-R2-imidazol-1-yl group, or f) a compound of the formula (VIIa) is reacted with a compound of the formula R°-X6 (VIIb) in which one of the radicals X4 and X6 represents a halogen atom or a sulphonyloxy group and the other represents an alkali metal, magnesium halide or lithium cuprate radical, X5 represents the radical R2 and R° represents the radical R1, or in which one of the radicals X5 and X6 represents a halogen atom or a sulphonyloxy group and the other represents an alkali metal, magnesium halide or lithium cuprate radical, X4 represents the radical R1 and R° represents the radical R2, or g) for the manufacture of compounds of the formula I or their salts in which Ph represents phenyl substituted by lower alkoxy:

in a compound of the formula (VIII) in which Ph' represents a phenyl radical substituted by hydroxy or a diazonium group, the phenyl group Ph' substi-tuted by hydroxy is lower-alkylated or the phenyl group substituted by a diazonium group Ph' is treated with a lower alkanol, it being possible for the starting compounds listed in variants a) to g) optionally to be in salt form, and, if a free compound is required, a resulting salt is converted into the free compound or, if a salt is required, a resulting free compound of the formula I is converted into a salt, and, if a pure enantiomer or diastereomer is required, a resulting isomeric mixture is separated into the components and the required enantiomer or diatsereomer is collected.

2. A process according to claim 1, characterised in that a compound of the formula IIa, wherein X1 denotes lower alkane-sulphonyloxy is formed in situ reacting the corresponding compound of the formula IIa, wherein X1 denotes hydroxy with a lower alkanesulphochloride and reacted further with an excess of a compound of the formula IIb, wherein X2 denotes hydrogen, Ph, R1 and R2 having the meanings given in claim 1.

3. A process according to claim 1, characterised in that a compound of the formula IV, wherein A denotes lower alkyli-dene, R2' denotes a group R2 and Ph has the meaning given in claim 1 is hydrogenated in the presence of a hydrogenation catalyst selected from elements of sub-group VIII of the Periodic Table of Elements and their derivatives.

4. A process according to claim 1, characterised in that a compound of the formula VIb, wherein Ph, R1 and R2 have the meanings given in claim 1, or a di-lower alkyl- or lower alkylene-acetal thereof is treated with a mineral acid.

5. A process according to claim 1, characterised in that a compound of the formula VIIa, wherein X4 denotes a group R
and X5 denotes an alkali metal radical is reacted with a compound of the formula VIIb, wherein R° denotes a group R2 and X6 denotes halogen, Ph, R1 and R2 having the meanings given in claim 1.

6. A process according to claim 1, characterised in that a compound of the formula VIIa, wherein X4 and X5 each denotes an alkali metal radical and Ph has the meaning given in claim 1, is reacted with a compound of the formula VIIb, wherein R° denotes methyl and X6 denotes halogen, so as to produce a compound of the formula I, wherein Ph has the meaning given in claim 1 and R1 and R2 both denote methyl.

7. A process according to claim 1, characterised in that a compound of the formula VIII, wherein Ph' denotes a phenyl group substituted by a diazonium group and R1 and R2 denote methyl, is formed in situ reacting a corresponding compound of the formula VIII, wherein Ph' denotes a phenyl group monosubstituted in 2- or 3-position by amino or a salt thereof in the presence of a mineral acid with a lower alkylnitrite and allowed to react further with a lower alkanol, so as to produce a compound of the formula I, wherein Ph denotes phenyl monosubstituted in 2- or 3-position by lower alkoxy and R1 and R2 denote methyl, or a salt thereof.

8. A process according to claim 1, characterised in that a compound of the formula VIII, wherein Ph' denotes a phenyl group monosubstituted in 2- or 3-position by hydroxy and R1 and R2 denote methyl, or a salt thereof is, in the presence of a basic condensation agent, reacted with a lower alkyl-halide, lower alkylsulphonate or di-lower alkylsulphate, so as to produce a compound of the formula I. wherein Ph denotes phenyl monosubstituted in 2- or 3-position by lower alkoxy and R1 and R2 denote methyl, or a salt thereof.

9. A process according to any of claims 1 to 3 characterised in that compounds of the formulae IIa and IIb or III, wherein Ph represents phenyl, phenyl monosubstituted in 2- or 3-position by lower alkyl or lower alkoxy each having up to and including 4 carbon atoms or phenyl disubstituted in 2,6-position by lower alkyl having up to and including 4 carbon atoms, R1 and R2 represent methyl, X1 and X2 have the meaning given in claims 1 or 2 and Het has the meaning given in claim 1 or 3, or their salts are selected as starting mate-rials so as to produce a compound of the formula I, wherein Ph, R1 and R2 have the meaning given hereinbefore, or a salt thereof.

10. A process according to any one of claims 4 to 6, characterised in that compounds of the formulae IV, V, VIa, VIb or VIIa and VIIb, wherein Ph represents phenyl, phenyl monosubstituted in 2- or 3-position by lower alkyl or lower alkoxy each having up to and including 4 carbon atoms or phenyl disubstituted in 2,6-position by lower alkyl having up to and including 4 carbon atoms, R1 and R2 represent methyl, and X4, X5 and X6 have the meanings diven in claim 5 or 6, or their salts are selected as starting materials so as to produce a compound of the formula I, wherein Ph, R1 and R2 have the meaning given hereinbefore, or a salt thereof.

11. A process according to any of claims 1 to 3 characterised in that compounds of the formulae IIa and IIb or III, wherein Ph represents phenyl, R1 and R2 both denote methyl, X1 and X2 have the meanings given in claim 1 or 2 and Het has the meaning given in claim 1 or 3, or their salts are selected as starting materials so as to produce the compound of the formula I, wherein Ph, R1 and R2 have the meaning given hereinbefore, or a salt thereof.

12. A process according to any one of claims 4 to 6, characterised in that compounds of the formulae IV, V, VIa, VIb or VIIa and VIIb, wherein Ph represents phenyl, R1 and R2 denote methyl, and X4, X5 and X6 have the meanings given in claim 5 or 6, or their salts are selected as starting materials so as to produce the compound of the formula I, wherein Ph, R1 and R2 have the meaning given hereinbefore, or a salt thereof.

13. Substituted imidazoles of the general formula I

(I) or their salts, in which Ph represents phenyl that is unsubstituted or substituted by lower alkyl or by lower alkoxy, and R1 and R2 each represents lower alkyl, and of their salts, whenever manufactured by the process claimed in claim 1 or by any process that is an obvious chemical equivalent thereof.

14. A substituted imidazole, or a salt thereof, of the general formula (I) (I) wherein: Ph represents phenyl that is unsubstituted, or substit-uted by lower alkyl, or by lower alkoxy; and R1 and R2 each rep-resent lower alkyl.

15. An imidazole according to claim 14, wherein Ph repres-ents phenyl; phenyl monosubstituted in the 2- or 3- position by lower alkyl or lower alkoxy, each having up to and including 4 carbon atoms, or phenyl disubstituted in the 2,6- positions by lower alkyl having up to and including 4 carbon atoms, and wherein R1 and R2 both represent methyl, or a salt thereof.

16. 1-(1-Phenylethyl)-2-methylimidazole, or a salt thereof.

17. 1-[1-(2 Methoxyphenyl) ethyl]-2-methylimidazole, or a salt thereof.

18. 1-[1-(2,6-Dimethylphenyl) ethyl]-2-methylimidazole, or a salt thereof.

19. A pharmaceutical composition containing, together with a pharmaceutically acceptable carrier, an imidazole as defined in claims 14 or 15, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition containing, together with a pharmaceutically acceptable carrier, an imidazole as defined in claims 16, 17 or 18, or a pharmaceutically acceptable salt thereof.