PT100493A - Isoxazolyl-imidazole derivatives, pharmaceutical compositions containing them and process for their preparation - Google Patents

Abstract

The invention relates to imidazole derivatives of general formula I <IMAGE> in which R1 represents hydrogen, a C1-C10 hydrocarbon radical or possibly substituted hetero-aryl or a cyclic ether radical, R2 represents hydrogen, halogen, an amino, nitro-azide, thiocyanate or cyano group which may be substituted, an alkyl radical with a straight or branched C1-C10 chain which may be substituted with halogen, or -OR1 where R1 has the above definitions and R2 may be present one or more times, and R1 and R2 represent together with an oxygen atom a saturated or unsaturated ring of 5 to 7 atoms which may also contain a further hetero atom, R3 represents hydrogen, an alkyl group with a straight or branched C1-C6 chain or an alkoxy alkyl group with C1-C4 in the alkoxy radical and C1-C2 in the alkyl radical, and R4 represents <IMAGE> or <IMAGE> in which R5 represents hydrogen, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, an alkoxy alkyl group with C1-C4 in the alkoxy radical and C1-C2 in the alkyl radical, an alkoxy carbonyl group with C1-C6 in the alkoxy radical, a benzyl or phenyl group, and their addition salts to acids.

Description

Description relating to the German, industrial and commercial SCHERING AKTIENGE-SELLSCHAFT patent, established in Berlin and Bergkamen (postal address: 170-178 Miillerstrasse, Berlin 65), Federal Republic of Germany (inventors: Dr. Martin Kruger, H.

Rolf Russe, Dr. Herbert Schneider Dr. Ralph Schmiechen and Dr. Le-choslaw Turski, residing in the Federal Republic of Germany), for "ISOXAZOLIL-IMIDA-ZOL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND PROCESS FOR THEIR PREPARATION".

The present invention relates to novel isoxazolyl imidazole derivatives, to their preparation and use in pharmaceutical compositions. It is known from EP-A-323 799 that imidazole derivatives have affinity for benzodiazepine receptors and have effects on the central nervous system. Surprisingly, the imidazoles of the present invention are characterized by markedly improved metabolic stability, whereby their use is favored for the preparation of pharmaceutical compositions.

The present invention relates to imidazole derivatives of the general formula I E.I.-1 (I) ϊ ϊ

in which R 1 is hydrogen, a C 1 -C 10 hydrocarbon radical or optionally substituted heteroaryl, or a cyclic ethereal radical; R 2 represents hydrogen, halogen, an amino, nitro, azido, thiocyanato or optionally substituted cyano group, a straight or branched chain C 1 -C 10 alkyl radical 11

optionally substituted with halogen, or -OR wherein R 2 has the above definitions and R may be present one or more times; and R 2 and R 3 together with the oxygen atom represent a saturated or unsaturated 5 to 10 ring atom which may contain a further heterogenous atom,

R 1 represents hydrogen, a straight or branched chain C 1 -C 6 alkyl group, or a C 1 -C 4 -alkoxy-alkyl group on the alkoxy and C 1 -C 2 -alkyl in the alkyl radical; and

in which R represents hydrogen, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 4 alkoxy-C 1 -C 4 -alkyl group on the alkoxy and C 1 -C 2 -alkyl in the alkyl radical, a C 1 -C 6 alkoxycarbonyl group on the alkoxy radical, a benzyl or phenyl group, as well as the acid addition salts thereof.

The substituents on the phenyl radical may be in the ortho, meta or para positions, in particular the radical R may appear once or twice and the radicals R and -OR are the same or different.

By halogen are respectively fluorine, 2

f-chloro, bromo or iodo. 1

As hydrocarbon radicals R may be any saturated or unsaturated, straight-chain or branched, optionally substituted, alkyl groups, preferably up to 6 carbon atoms, and also saturated or unsaturated cycloalkyl groups or cycloalkylalkyl groups with respectively 3 to 7 carbon atoms, a CH 2 group may optionally be substituted by an oxygen atom, as well as optionally substituted aryl or aralkyl groups having a maximum of 10 carbon atoms.

As straight or branched chain saturated alkyl radicals, there may be mentioned respectively lower alkyl radicals such as methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, isobutyl, tert.-butyl as well as pentyl, hexyl , 2-methyl-butyl, 2,2-dimethyl-propyl.

As unsaturated alkyl radicals R the following alkenyl and alkynyl radicals may be mentioned: 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, 2-propynyl radicals.

As the substituent of the suitable alkyl group R 1 is a halogen atom, such as in particular fluorine, chlorine or bromine, hydroxy, C 1 -C 4 -alkoxy and amino, optionally mono or disubstituted with lower alkyl groups. Where fluorine is present as the substituent, the perfluoroalkyl compound should preferably be considered.

Cycloalkyl radicals include respectively saturated radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. As the unsaturated radical may refer, for example, to the cyclopentenyl group.

Where the hydrocarbon radical is a cycloalkyl-alkyl group, the cyclopropyl-methyl, cyclopropyl-ethyl and cyclopentyl-methyl groups are preferred.

Cycloalkyl groups interrupted by a suitable oxygen atom are e.g. the cyclic ethereal groups 3-tetrahydrofuranyl and 3-tetrahydro-pyranyl. I

In case the hydrocarbon radical represents an aryl or aralkyl group, it may be substituted one to three times with halo, nitro, cyano, hydroxy, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, alkylthiol C1 -C4 alkyl, C1 -C4 alkylsulfinyl, C1 -C4 alkylsulphonyl, or an amino group optionally mono or di-substituted by C1 -C4 alkyl, acyl or sulfonyl. 2

In case R represents an amino group, it may be mono or disubstituted with C 1 -C 4 alkyl or C 1 -C 4 alkanoyl.

As the preferred aryl radical is meant the phenyl radical which may optionally be substituted once or twice with halogen or an optionally substituted cyano, nitro or amino group such as 2,4-dichloro-phenyl, 2-cyano-phenyl, 4-amino-phenyl. The ar-alkyl radical R may have the straight or branched chain alkyl radical and may be mono or disubstituted on the aryl radical, preferably with halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl or optionally substituted amino. Preferred are ar-C1 -C2 -alkyl radicals in the alkyl radical, which may be substituted on the aryl radical with 1-2 halogen atoms, in particular bromo or chloro, such as benzyl, phenethyl, (-methylbenzyl λ

Where R represents a heteroaromatic radical, it may have 5 or 6 ring atoms and contain one to two hetero atoms such as sulfur, nitrogen and / or oxygen, and may be substituted with the substituents indicated for the aryl radicals . Preferred are heteroaromatic groups having 6 ring atoms, with 1-2 nitrogen atoms, and heteroaromatic groups having 5 ring atoms, cpm 1-2 oxygen, sulfur and / or nitrogen atoms, which may be substituted with halogen such as pyridine, pyrimidine, pyrazine, pyridazine, furan,? -thiophene, pyrrole, imidazole, thiazole. - 4 -

In the case where R1 and R2 form a ring together with the oxygen atom, the hydrocarbon bridge may have 1-3 carbon atoms, such as methylene, ethylene, ethylidene, and propylene, and may furthermore have a another hetero atom, preferably oxygen.

For the substituent, preference is given to hydrogen, C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl in the alkoxy and C 1 -C 2 -alkyl radical in the alkyl radical, the definition of substituents to the

And the hydrocarbon radical R being an alkyl or cycloalkyl radical, preferably saturated and unsubstituted. 2

As preferred R substituents may be taken as hydrogen or -OR.

Physiologically tolerable acid addition salts are derived from organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, as well as alkanesulphonic acids, such as methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, among others.

The compounds of the present invention have an agonist, inverse agonist and antagonist effect on the known properties of benzodiazepines and, thanks to their biological effectiveness, are suitable as psycho drugs, especially anxiolytics for medicine. The effect of the compounds of general formula I on the central nervous system and their metabolic stability were determined by assays performed by methods known per se. The compounds of the present invention are characterized not only by their anxiolytic efficacy, but also have a better metabolic stability compared to the known imidazoles of EP-323,799. (5-ethyl-1,2,4-oxadiazol-3-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole (A).

TABLE

Residual% compound after incubation. with mouse liver homogenate A 31 B 95 C 71 D 100 A = 4- (5-ethyl-1,2,4-oxadiazol-3-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole B = 4- (3-ethyl-isoxazol-5-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole C = 4- (5-ethylisoxazol-3-yl) -5-methyl-1 - (3-phenoxyphenyl) imidazole D = 4- (3-methoxymethyl-isoxazol-5-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole The stability of the compounds was determined as follows: Compound (1æg / 50æl ethanol) was set at pH 7.3 with 750æl of Krebs-Henseleit-Ringer phosphate buffer; at room temperature, 750 Âμl of a liver homogenate was added and mixed. 250 μl of this mixture was removed for determination of zero, and the mixture was incubated at 37 ° C in a water bath under continuous stirring. After 120 minutes, aliquots of 250 μl were withdrawn, 3 ml of diethyl ether was added, stirred for 5 minutes to extract and then centrifuged for 10 minutes under cooling, frozen, and the ether and dried under anhydrous nitrogen flow. The residue was respectively dissolved in 200 μl of ethanol, and the solution was analyzed by HPLC. The liver used was obtained from NMRI mice and after collection, immediately homogenized in 4 parts of a 0.25 molar sucrose solution in a Potter-Elvehjem mixer. The homogenate was by -

filtered through a linen cloth and diluted with the same sucrose solution at 1:10 (weight: volume). Aliquots of the solution were stored at -18 ° C.

The results of this assay are presented in the Table, the amount of compounds used being expressed as% of zero value, which was not catabolized by the metabolizing enzymes of the liver.

Thanks to their pharmacological properties, the compounds of the present invention can be formulated so as to obtain psycho-pharmaceutical compositions, e.g. for enteral and parenteral administration.

For use of the compounds of the present invention as pharmaceutical compositions, they may be incorporated into a galenic formulation containing, in addition to the active ingredient, organic or inorganic inert excipients suitable for enteral or parenteral administration, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.

The pharmaceutical compositions may be in solid form, e.g. as tablets, dragees, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. They may optionally also contain adjuvants, such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for osmotic pressure change or buffers.

Particularly suitable for parenteral administration are injectable solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil.

Surfactant adjuvants, such as bile acid salts, or animal or vegetable phospholipids, but also mixtures thereof, as well as liposomes or their components, may also be used as support systems.

For oral administration tablets, dragées or capsules with talc and / or a suitable excipient are suitable,

or hydrocarbon starter, such as e.g. lactose, corn starch or potato starch. The application may also be made in liquid form, such as, e.g., as syrup, to which a sweetener has been added.

The compounds of the present invention are incorporated in a dosage of 0.05 to 10 mg of active ingredient in a physiologically tolerable excipient.

The compounds of the present invention are administered as anxiolytics at a dosage of 0.1 to 300 mg / day, preferably 1-30 mg / day in analogy to diazepam. The preparation of the compounds of the general formula I according to the present invention is carried out by processes known per se, for example

a) by reacting an aniline of general formula II

(II),

T the

in which R 1 and R 2 have the above definitions, with a 2-azadiene of the general formula III

R 3

-N (III),

In which R and R are as defined for formula I, and X and Y represent leaving groups in the presence of acids; or -

b) by making an imidazole derivative of the general formula IV (IV)

in which R1 and R2 have the definitions given for formula I, with an aromatic compound of the general formula V R2

(V),

Z 1 2 λ in which R 1 and R 2 have the definitions given for general formula I, and Z represents a leaving group; or

c) reacting an imidazole derivative of the general formula VI

(SAW)

i 2 R

in which R 1, R 2 and R 3 have the definitions given for general formula I, with an acetylene derivative of the general formula VII (VII), in which R has the definitions given for general formula I, in order to obtain a derivative of the isoxazolyl imidazole of general formula Ia 9

R 2 and R 5 are as defined for formula I; or

d) reacting an imidazole derivative of general formula VIII

(IX),

10 1 2 3

in which R 1, R 2 and R 3 have the definitions given for the general formula I, with a nitriloxide of the general formula IX in which R 2 has the definitions given for general formula I, to obtain an isoxazolyl imidazole derivative of the general formula Ib

In which R 1, R 2, R 3 and R 4 have the definitions given for general formula I; and if desired, the compounds are then etherified with R 2 = H in the presence of bases, or if a nitro group is reduced to give an amino group, and if desired, this group can be alkylated or acylated or exchanged with halogen , azide, cyano or thiocyanate, or if their acid addition salts form. The transformation of anilines of the general formula II with 2-azadienes of the general formula III according to the invention in order to obtain the imidazole derivatives of the general formula I is carried out in the presence of acids at temperatures of 0-150 ° C. The leaving groups X and Y may be the same or different; C 1 -C 3 dialkyl amines are especially suitable for alkyl radicals such as dimethyl amine, diethyl amine and di-propyl amine, and cyclic amines such as pyrrolidine. The transformation is for example carried out by stirring the aniline derivative and azadiene in an organic acid such as formic acid, acetic acid, propionic acid or trifluoroacetic acid, first at room temperature, and then warming to the boiling temperature of the reaction mixture. The acid can serve simultaneously as a reaction agent and also as a solvent. However, solvents such as alcohols, ethers, ketones, esters such as ethyl acetate, hydrocarbons such as toluene, or halogenated hydrocarbons such as carbon tetrachloride may also be added. The amount of acid can vary within wide limits, however I used in excess. Preferably an excess of 3-10-fold acid is used, relative to aniline and azadiene.

The molar ratios of aniline and azadiene are not critical to the success of the transformation. In general, approximately equal molar amounts of the reaction partners are used, with a molar ratio of 1 mole of aniline to 1-3 mole of azadiene being preferred. The transformation according to the present invention may, in principle,

aiMgijtossKj

in the solvents indicated, with catalytic amounts of mineral acids, such as sulfuric acid, hydrochloric acid, perchloric acid, or organic acids such as p-toluenesulfonic acid and trifluoroacetic acid. The advantage of the process according to method a) of the present invention resides in the chemi-sative synthesis of imidazole derivatives forming an isomer in a single process step. The N-arylation of the imidazole derivatives of general formula IV can be carried out, e.g., according to the method described by N.W. Gilman et al. , J. Heterocycl. Chem. , 1157 (1977). To this end it is necessary for the aromatic compound of the general formula V to be substituted with at least one group with negative electronic charge and with a leaving group. Groups with negative electronic charge are especially suitable for the NO 2 CN groups and as a leaving group halogens, in particular fluorine and iodine, may be considered. The arylation according to method b) is carried out in the presence of bases such as alkali metal hydroxides, alkali metal hydride, optionally in the presence of phase transfer catalysts, butyllithium or lithium diisopropylamide, preferably with alkali metal hydride .

Suitable temperatures are from -78 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

As aprotic solvents for aprotic polar solvents, such as, for example, aliphatic and cyclic diols, such as diethyl ether, tetrahydrofuran, among others, and dimethylformamide may be considered. The transformation of the nitriloxides of the general formulas VI and IX with acetylene derivatives of the general formulas VII and VIII can be carried out e.g. according to the methods described by K.B.G. Torsell (K.B.G. Torsell, Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis, 1988 VCH Verlagsgesellschaft mbH). In general, nitriloxide is produced first, which is then transformed without being isolated with an acetylene derivative. 12

The molar ratios of nitrilo-oxide and acetylene may vary within wide limits. Approximately equal molar amounts of re-action partners are generally used, however, it may often be advantageous to use the acetylene derivative in larger amounts. The transformation is carried out at temperatures of -78 ° C to 150 ° C, preferably -20 ° C to 50 ° C, in an aprotic solvent.

Suitable solvents are, for example, aliphatic and cyclic ethers such as diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons such as dichloroethane, methylene chloride, chloroform, hydrocarbons such as hexane, pentane and dimethylsulfoxide.

In the case where the starting compounds are volatile, such as acetylene, it is advantageous to use the respective liquid compounds which have a group which can be readily eliminated then in the reaction. As the readily removable group is suitable e.g. the trialkylsilyl group. The elimination is carried out prior to the treatment of the reaction mixture, by known methods, e.g. by addition of bases at room temperature. Suitable bases are e.g. hydroxides and alkali alcoholates, such as sodium and potassium hydroxide, sodium and potassium methylate or sodium and potassium ethylate, or fluorides such as cesium fluoride, or tetra-n-butyl ammonium fluoride. The advantage of the process according to methods c) and d) of the present invention resides in the myoselective synthesis of isoxazole derivatives forming an isomer in a single process step. The possible subsequent etherification of the compounds of general formula I with R = H is by known methods. For example, a reactive derivative R -X may be reacted in a polar solvent in the presence of a base at temperatures from room temperature to the boiling temperature of the solvent, optionally also in the presence of a catalyst of phase transfer. As the reactive radical X, a halogen atom, such as chlorine, bromine or iodine, as well as mesyl or tosyl groups is suitable. As bases may be considered alkali compounds, such as sodium hydroxide 13 -

or of potassium, or sodium or potassium carbonate, among others. The reduction of the nitro group to the amino group can be done e.g. catalytically, hydrogenating under normal pressure or under pressure in polar solvents at room temperature. As catalyst, palladium can be used in finely distributed form, on a support such as charcoal or platinum; in the case of compounds with halogen atoms Raney nickel is used as the preferred catalyst. Suitable polar solvents for reduction are e.g. alcohols or diols such as methanol, ethanol, diethyl ether, tetrahydrofuran or mixtures thereof. The introduction of the cyano group can be carried out with the aid of the Sandmeyer reaction; the diazonium salts formed intermediarily from the amino compounds with the nitrites can be reacted with alkali cyanides in the presence of copper (I) cyanide. The introduction of the halogen atoms chlorine, bromine or iodine through the amino group can be done through the Sandmeyer reaction, by reacting the diazonium salts formed intermediately with the nitrites, with copper (I) chloride or copper bromide ( I) in the presence of the respective acid - hydrochloric acid or hydrobromic acid - or by reacting with potassium iodide. The introduction of fluorine is done e.g. by the reduction of Balz-Schiemann's diazonium tetrafluoroborate. The introduction of the azido or thiocyanate group may also be carried out by the Sandmeyer reaction of the diazonium salt with alkali azide or alkali thiocyanate.

If alkylation or acylation of the amino group is desired, it may be alkylated or acylated by the usual processes, e.g. with alkyl halides or acyl halides.

To form the addition salts with physiologically tolerable acids, a compound of the general formula I is dissolved in a small amount of alcohol and reacted with a concentrated solution of the desired acid. 14 -

Where the preparation process of the starting compounds is not described, they are known or may be prepared in analogy to known compounds or processes described herein. For example, the synthesis of 2-azadienes is made according to Liebigs Ann. Chem. 1980, 344 and Liebigs Ann. Chem. 1986, 1749.

The nitriloxides of the general formulas VI and IX may be prepared e.g. according to EP-A-305 322 and according to K.B.G. Torsell Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis 1988. The acetylenes of the general formula VIII used as the starting compounds are for the most part known, or may be prepared eg according to L. Brandsma, Preparative Acetylenic Chemistry, Second Edition , 1988.

The following examples are intended to illustrate the present invention.

Process for preparing 2-azadienes Azadienyl: a) 3-Ethyl-5- (N-dimethylamino-methyleneaminomethyl) -isoxazole

Stir 9 g of 5-aminomethyl-3-ethylisoxazole in 12 ml of dimethylformamide dimethyl acetal for 8 hours at 80 ° C (bath temperature) under anhydrous conditions. After distillation with a bead condenser at 145øC and 0.03 Torr, 12.8 g (98% of theory) of the desired compound is obtained. b) (E, Z) -1-Dimethylamino-3- (3-ethyl-isoxazol-5-yl) -4- (1-pyrrolidinyl) -2-azapenta-1,3-diene

Shake for 12 hours at 80 ° C (bath temperature) 12.7 g of 3-ethyl-5- (N-dimethylamino-methyleneaminomethyl) -isoxazole 11.4 ml of 90% dimethylformamide dimethylacetal and 5.8 ml pyrrolidine. 4.17 g (21% of theory) of the formed compound are obtained after distillation with a bead condenser at 210 ° C-220 ° C and 0.1 Torr. 15 -

Azadiene 2: a) 3-Methoxymethyl-5- (N, N, N-dimethylamino-methyleneaminomethyl) -iso-xazole The synthesis is carried out analogously to example 1a). b) (E, Z) -1-Dimethylamino-3- (3-methoxymethylisoxazol-5-yl) -4- (1-pyrrolidinyl) -2-azapenta-1,3-diene The synthesis is carried out in analogy with example 1b). EXAMPLE 4! a) 4- (3-Ethyl-isoxazol-5-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole

Upon cooling, dissolve 3.6 g of azadiene 1 in 12 ml of glacial acetic acid and stir for 15 minutes at room temperature. Then, add 2.2 g of 3-phenoxyaniline and stir the mixture for 48 hours at room temperature and 3 hours at 100 ° C. Distill the glacial acetic acid and add sodium bicarbonate solution to the residue, and extract with ethyl acetate. Purify the crude compound by column chromatography. 1.53 g (37% of theory) of the title compound are obtained, m.p. 97Â ° C (isopropyl ether).

In analogy to example 1a) there may be obtained: b) 4- (3-Methoxymethyl-isoxazol-5-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole by transformation of the azadiene 2; m.p. 83Â ° C (isopropyl ether). c) 4- (3-Ethyl-isoxazol-5-yl) -5-methyl-3- (4-chlorophenoxy) -phenyl] -imidazole by transformation of the azadiene 1 as an oil. EXAMPLE 2 a) 5-Methyl-1- (3-phenoxyphenyl) -imidazole-4-carbaldehyde

Dissolve 4.13 g of 5-methyl-1- (3-phenoxy-phenyl) -imidazole-4-carbonitrile in 200 ml of toluene. At -60 ° C to -70 ° C dropwise add 15 ml of &quot; Dibah &quot; 1.2 molar in toluene. Stir for 2 hours at -70 ° C, dropwise add at -70 ° C 2.5 ml of water and allow the mixture to warm to room temperature. Adjust to pH 4 with 2N hydrochloric acid solution, and extract the mixture with toluene and ethyl acetate. Combine the organic phases and dry over magnesium sulfate. After purification by column chromatography, 2.46 g (59% of theory) of the title compound are obtained as an oil. b) 5-Methyl-1- (3-phenoxyphenyl) imidazole-4-carbaldehyde oxime hydrochloride

Dissolve 2.23 g of 5-methyl-1- (3-phenoxyphenyl) imidazolidyl-4-carbaldehyde in 60 ml of ethanol and add 0.70 g of hydroxyl ammonium chloride. Stir the mixture for 2.5 hours at 80 ° C (bath temperature). Distil the solvent and dissolve the residue in 3 ml of ethanol. The compound crystallizes. This affords 2.46 g (93% of theory) of the title compound, mp 183øC. c) 4- (5-Methoxymethyl-isoxazol-3-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole

Dissolve 660 mg of 5-methyl-1- (3-phenoxyphenyl) imidazole-4-carbaldehyde oxime hydrochloride in 4 ml of dimethylformamide. At 0 ° C add 0.28 ml of triethylamine and add dropwise over one hour a solution of 360 mg of N-bromosuccinimide in 2 ml of dimethylformamide. Then add 1.7 ml of methyl propargyl ether and 0.28 ml of triethylamine, and stir the mixture for 14 hours at room temperature. Add another 360 mg of N-bromosuccinimide in 2 ml of dimethylformamide and • 0.28 ml of triethylamine, and stir the mixture for 18 hours! at room temperature. After concentrating, add water and ex-

Claims (1)

to give with ethyl acetate. The concentrated extract is triturated with diethyl ether and filtered. Purify the filtrate by column chromatography. 230 mg (32% of theory) of the title compound are obtained as an oil. In analogy to example 2c) d) 4- (5-Ethyl-isoxazol-3-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole can be obtained by conversion with 1-butyne; oil. e) 4- (5-Ethyl-isoxazol-3-yl) -5-methyl-1- [3- (4-chlorophenoxy) -phenyl] -imidazole by transformation with β-butyne; mp 95 ° C. Imidazole derivatives of the general formula I 1 3 4 0 R R 5 R 4 in which R 2 represents hydrogen, a C 1 -C 4 hydrocarbyl radical or optionally substituted heteroaryl, or a cyclic ethereal radical; R 2 represents hydrogen, halogen, an amino, nitro, azido, thiocyanato or optionally substituted cyano group, a linear or branched chain alkyl radical optionally substituted with halogen, or - or more times; and R 2 and R 2 together with the oxygen atom represent a 5 to 7 membered saturated or unsaturated ring which may contain a further heterogenous atom; R representa is hydrogen, a C lt de de straight chain or branched alkyl group, or an alkoxy-C alquilo alquilo alquiloalkyl group on the alkoxy and C C0 noalkyl group on the alkyl moiety; and R represents Wherein R1 represents hydrogen, a C1 -C6 alkyl group, a C1 -C6 cycloalkyl group, a C1 -C6 alkoxy group, an alkoxy alkyl group having the alkoxy radical and -Cg in the alkyl radical, a C -C-C alc alkoxycarbonyl group on the alkoxy radical, a benzyl or phenyl group, as well as the acid addition salts thereof. 4- (3-ethyl-isoxazol-5-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole; 4- (3-methoxymethyl-isoxazol-5-yl) -5-methyl-1- (3-phenoxyphenyl) -imidazole; 4- (5-methoxymethyl-isoxazol-3-yl) -5-methyl-1- (3-phenoxyphenyl) -imidazole; 4- (5-ethyl-isoxazol-3-yl) -5-methyl-1- (3-phenoxyphenyl) imidazole; 4- (3-ethyl-isoxazol-5-yl) -5-methyl- [3- (4-chlorophenoxy) -phenyl] -imidazole; 4- (5-ethyl-isoxazol-3-yl) -5-methyl-1- [3- (4-chlorophenoxy) -phenyl] -imidazole. Compounds of general formula I according to 19 - represents hydrogen. A pharmaceutical composition comprising as active ingredient compounds according to claims 1 to 3. A process for the preparation of compounds of general formula I according to claim 1, characterized in that a) aniline of general formula II (II), wherein R and R are as defined above, with a 2-aza-diene of general formula III (III), in which R 1 and R 2 have the definitions given for general formula I, and X and Y represent elimination groups in the presence of acids; or b) an imidazole derivative of the general formula IV is acylated (IV), in which R 1 and R 2 have the definitions given for formula I, with an aromatic compound of the general formula V Wherein R 1 and R 2 have the definitions given for formula I, and Z represents a leaving group; or reacting an imidazole derivative of the general formula VI (VI), 21 (Ia) in which R 1, R 2, R 3 and R 4 have the definitions given for general formula I; or d) reacting an imidazole derivative of the general formula VIII (VIII) in which R 1, R 2 and R 3 have the definitions given for general formula I, with a nitriloxide of general formula IX (IX), R 5 -C = N ' which R 1 has the definitions given for general formula I, in order to obtain an isoxazolyl imidazole derivative of the general formula Ib (Ib) 1 2 3 wherein R 1, R 2, R 3 and R 3 have the definitions given for general formula I; 1 and if desired, the compounds with R = H are then etherified in the presence of bases, or if a nitro group is reduced to an amino group, and if desired this is optionally alkylated or acylated or exchanged with halogen, azide, cyano or thiocyanate, or if their acid addition salts form. 6. A process for the preparation of pharmaceutical compositions which comprises incorporating a compound of the general formula I when prepared according to claim 5 with a pharmaceutical excipient. Lisbon, 15 May 1992. - 23 -