NO845031L - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2- (1-IMIDAZOLYL) -ETHANOL DERIVATIVES - Google Patents

Abstract

New therapeutically active 2- (1-imidazolyl) -ethanol derivatives of the general formula. wherein R represents hydrogen, an alkyl group having 1-3 carbon atoms or a halogen atom; 1 * 2 means one of the remains. means hydrogen or a methyl residue; R 1 represents hydrogen, an alkyl radical having 1 to 3 carbon atoms. or a halogen atom; R represents hydrogen, an alkyl or alkoxy acid residue with. 1-3 carbon atoms, a halogen atom or a trifluoromethyl radical, and. m means one of the numbers 1 or 2 ,. and their acid addition salts. The compounds are valuable pharmaceuticals with antidepressant properties and exert in particular a thymoleptic and stimulant effect. Preparation of the compounds is described.

Description

This invention relates to the preparation of new 2-(1-imidazolyl)-ethanol derivatives with the general formula

and acid addition salts thereof.

In this formula means:

R, hydrogen, an alkyl group with 1-3 carbon atoms or a halogen atom; 1*2 one of the remainders:

R_ is hydrogen or a methyl residue;

R^hydrogen, an alkyl residue with 1-3 carbon atoms or

a halogen atom;

R, - hydrogen, an alkyl or alkoxy acid residue with 1-3 carbon atoms, a halogen atom or a trifluoromethyl residue, and

with one of the numbers 1 or 2.

In the process for the preparation of compounds of formula I, new intermediates of the general formula IV indicated below are used.

As the new compounds of the general formula I contain an asymmetric carbon atom, they can exist both as racemates and in the form of their enantiomers.

In preferred compounds of the general formula I, R 2 means hydrogen. Particular mention should be made of the compounds 2-(1-imidazolyl)-1-(2-pyridyl)-1-(2-methyl)-ethanol, 2-(1-imidazolyl)-1-(2-pyridyl)-1-phenyl- ethanol,

2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-chlorophenyl)-ethanol, 2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-bromo-phenyl) )-ethanol and

2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-tolyl)-ethanol and their acid addition salts.

The new compounds of the general formula I and their acid addition salts represent valuable pharmaceuticals.

In some specific investigations, it has been shown that they have strong antidepressant properties and in particular exert a thymoleptic and central stimulating effect.

A test for determining the antidepressant effect is the tetrabenazine antagonism, the reversal of the ptosis caused by tetrabenazine. The experiment is carried out on mice, and 5 animals are used for each dose. One hour after administration of the test compound, the animals are given 40 mg/kg of tetrabenazine. Assessment of the ptosis occurs 75-120 minutes after the tetrabenazine administration, according to the indications of B. Rubin, M. H. Malone et al., J. Pharmacol. Exp. Ther. 120, 125-136 (1957).

In another - biochemical - investigation, it is assumed that in various forms of depression there is a reduced amount of biogenic amines, especially norepinephrine, in certain brain areas. The biogenic amines can be increased by preventing uptake in the neurons. A suitable experimental device shows that the new compounds particularly inhibit the reuptake of norepinephrine in the neurons. The experiment is carried out according to the specifications of A. S. Horn, Mol. Pharmacol. 1971, pp.66-80, on

a homogenized, isolated rat cerebrum. A synaptosome suspension thus obtained is incubated with deuterium-treated norepinephrine and different concentrations of a solution of the test compound in water for 10 minutes at 37°C. After the end of the incubation, the medium is separated by filtration, and the radioactivity of the synaptosome suspension is measured. A control experiment without test compound is carried out to determine the absorbed amount of the radioactive amine.

The amount of the test compound in moles which is sufficient to prevent absorption by 50% is denoted as ICj-0.

The production of the new compounds takes place in a manner known per se as follows:

a) by reacting 2-(1-imidazolyl)-ethanone derivatives with the general formula:

where

A means one of the residues

and R3 has the above meaning, if A means pyridyl, with organometallic reagents such as a phenyl or thienylmagnesium halide, resp., if A means the residue R2, a pyridylmagnesium halide, or a corresponding lithium compound, or b) by reacting an imidazole with the general formula where R3 has the meaning given above, with an oxirane of the general formula

where R^ and R_ have the meaning indicated above.

With method a), preferably 2-4 mol of the organometallic reagent are used for 1 mol of the compound of formula II. Solvents used in particular are the solvents or solvent mixtures that are common for a Grignard reaction. These preferably include ether, e.g. diethyl ether, dimethyl ether, tetrahydrofuran or dioxane. The reaction temperatures can be varied within a wide range, and if you use Grignard reagents, you preferably work at temperatures between 0°C and the reflux temperature of the solvent or solvent mixture. When using lithium compounds, you preferably work between 0°C and -60°C.

The reaction of compounds of the general formula III with oxiranes of the general formula IV according to method b) usually takes place in the presence of an alkali alcoholate, preferably the methylates or ethylates of sodium or potassium and in the presence of a diluent. Inert solvents in particular are used as diluents. These include e.g. dimethylformamide, acetonitrile, methylene chloride or aromatic hydrocarbons such as benzene or toluene.

The reaction temperatures can be varied within a wide range. Usually one works between 10°C and 150°C, preferably between 30°C and 100°C.

When carrying out the procedure, one applies to

1 mol oxirane with formula IV 1-3 mol imidazole resp. 2-methylimidazole and 1-2 mol of an alkali alcoholate. The oxiranes of formula IV, which are prepared as described below, are preferably reacted without isolation with said imidazole or 2-methylimidazole.

The isolation of the final products of the general formula I produced by methods a) and b) usually takes place in the usual way. They can optionally be transferred to their physiologically acceptable acid addition salts by known methods.

For the production of acid addition salts, acids which are suitable for the formation of therapeutically applicable salts are used in particular, such as hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid or methane or toluenesulfonic acid and the like .

The imidazol1-methyl-aryl ketones with the general formula II are known or can be prepared in a known manner from the corresponding aryl acyl halides by reaction with imidazole or 2-methyl-imidazole in the presence of diluents, e.g. dimethylformamide or methylene chloride, and an acid-binding agent, in particular an excess of imidazole (see DOS 3 101 895).

The oxiranes of the general formula IV can be prepared on

in a manner known per se by reacting a corresponding ketone

with the general formula

where

Rlog R2 has the meaning given above, either with dimethyl oxosulfonium methylide with the formula

or with dimethylsulfonium methylide of the formula

in the presence of a diluent, for example dimethyl sulfoxide, at temperatures between 20°C and 80°C (see also E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 87, 1353 (1965) and Heterocycles 8, 397 ( 1977)) .

The new compounds can be used in various pharmaceutical compositions.

Suitable forms of application are e.g. tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Suitable tablets can, for example, be prepared by mixing the active substance or substances with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatins, lubricants such as magnesium stearate or talc , and/or agents to achieve a depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Similarly, dragees can be produced by coating cores prepared analogously to the tablets with agents that are common in dragee coatings, for example collidon or shellac, gum arabic, talc, titanium dioxide or a sugar. To achieve a depository effect or to avoid unreliabilities, the core can also consist of several layers. Likewise, the dragee coating can also consist of several layers to achieve a depot effect, as the excipients used above for the tablets can be used.

Juices of the new active substances or active ingredient combinations may also contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-enhancing agent, for example flavoring agents, such as vanillin or orange extract. They may also contain suspending aids or thickeners such as sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates.

Injection solutions can be prepared in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoates, or stabilizers such as alkali salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.

The capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers such as milk sugar or sorbitol and encapsulating them in gelatin capsules.

Suitable suppositories can, for example, be prepared by mixing with suitable carriers such as neutral fat types or polyethylene glycol or derivatives thereof.

The following examples shall serve to further illustrate the invention.

Example 1

2-( 1- imidazolyl)- 1-( 3- pyridyl)- 1- phenyl- ethanol

A suspension of 9.35 g (0.05 mol) 2-(1-imidazolyl)-1-(3-pyridyl)ethanone (m.p. 126-127°C) in 120 ml of tetrahydrofuran is added at 50°C to a phenylmagnesium bromide solution , obtained from 2.4 g (0.1 mol) of magnesium and 15.7 g (0.1 mol) of bromobenzene in 80 ml of tetrahydrofuran. The reaction mixture is allowed to stand for 5 hours at 50°C and, after cooling, an aqueous ammonium chloride solution is added. The organic phase is separated, dried and evaporated. The remaining residue is dissolved in 2N hydrochloric acid. The acidic aqueous solution is extracted with ether and made alkaline with concentrated ammonia. When shaking with methylene chloride, white crystals are separated which are suctioned off. 5.3 g (40% of the theoretical) of 2-(1-imiuazolyl)-1-(3-pyridyl)-1-phenyl-ethanol (m.p. 185-187°C) are obtained. The analyzed compound has a melting point of 187-188°C (from acetonitrile).

Analogously, you get:

2-(1-imidazolyl)-1-(3-pyridyl)-1-(p-tolyl)-ethanol,

m.p. 181-182°C (from acetonitrile):

2-(1-imidazolyl)-1-(3-pyridyl)-1-(2-thienyl)-ethanol,

m.p. 188-188.5°C (from acetonitrile);

2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-chloro-phenyl)-ethanol,

o

m.p. 194-195 C (from ethanol).

Example 2

2-( 1- imidazolyl)- 1-( 2- pyridyl)- 1-( 2- thienyl)- ethanol

A solution of 65.2 g (0.4 mol) of 2-bromothiophene in 100 ml of ether is added dropwise at -5° to 0°C to a solution of butyllithium (250 ml of a 15% solution in hexane, ^0.39 mol) in 300 ml of ether. After stirring for 1 hour, a solution of 30 g (0.16 mol) 2-(1-imidazolyl)-1-(2-pyridyl)-ethanone (m.p. 115-116°C) in 300 ml is added portionwise to the reaction mixture dioxane. The cooling bath is removed and the whole thing is left to react for a further 2 hours. Aqueous ammonium chloride solution is then added to the reaction mixture. The precipitated crystals are suctioned off, and after drying they are recrystallized from methanol/petroleum ether. 19.2 g (44.2% of the theoretical) of 2-(1-imidazolyl)-1-(2-pyridyl)-1-(2-thienyl)-ethanol with a melting point of 204-205°C are obtained. The analyte base is transferred to the hydrochloride with an equivalent of hydrochloric acid. Temp. 219-220°C (from ethanol).

In the same way was prepared: 2-(1-imidazolyl)-1-(2-pyridyl)-1-[2-(5-methyl-thienyl)]-ethanol, m.p. 158-159°C (from acetonitrile).

Example 3

2-( 1- imidazolyl)- 1-( 2- pyridyl)- 1-[ 2-( 5- chlorothienyl)]- ethanol

Analogous to example 2, reaction of an ethereal solution of 5-chloro-thienyl(2)-lithium [prepared from 11.8 g (0.1 mol) of 2-chlorothiophene and 62.5 ml of a 1, 6 molar solution of butyllithium in hexane at -50 to -60°C] and a solution of 9.36 g (0.05 mol) 2-(1-imidazolyl)-1-(2-pyridyl)- ethanone in 100 ml dioxane at -18° to -25°C 2-(1-imidazolyl)-1-(2-pyridyl)-1-[2-(5-chlorothienyl)]-ethanol with melting point 167-168°C (from methanol).

Example 4

2-( 1- imidazolyl)- 1-( 2- pyridyl)- 1- phenyl- ethanol

7.2 g of magnesium shavings are reacted in 200 ml of ether with 47.1 g (0.3 mol) of bromobenzene at 30-35°C and then a solution of 18.7 g (0.1 mol) of 2-( 1-imidazolyl)-1-(2-pyridyl)-ethanone in 200 ml of dioxane. The reaction mixture is heated for 4 hours under reflux and aqueous ammonium chloride is added after cooling. The precipitated crystals are separated and taken up with dilute hydrochloric acid. The aqueous solution is then shaken with methylene chloride, made alkaline with concentrated ammonia and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. 14.7 g (55.4% of the theoretical) of 2-(1-imidazolyl)-1-(2-pyridyl)-1-phenylethanol with a melting point of 175-177°C are obtained.

The pure title compound has, after recrystallization from alcohol, a melting point of 177-178°C.

Analogue was produced:

2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-tolyl)-ethanol,

m.p. 195-196°C (from ethanol):

2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-methoxy-phenyl)-ethanol,

m.p. 154-155°C (from acetonitrile);

2-(1-imidazolyl)-1-(3-pyridyl)-1-(p-chlorophenyl)-ethanol,

m.p. 176-178°C (from methanol/ether);

2-(2-methyl-1-imidazolyl)-1-(2-pyridyl)-1-(p-chlorophenyl)-ethanol, m.p. 209-210°C (from ethanol);

2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-bromophenyl)-ethanol, m.p. 193-194°C (from ethanol).

Example 5

2-( 1- imidazolyl)- 1-( 2- pyridyl)- 1- phenyl- ethanol

A solution of 4.7 g (0.024 mol) 2-phenyl-2-(2-pyridyl)-oxirane in 30 ml dimethylformamide is added dropwise to a mixture of 2.2 g (0.04 mol) sodium methylate, 15 ml methanol and 4.5 g (0.066 mol) of imidazole. The reaction mixture is heated for 4 hours to 80°C and then evaporated in vacuo. The residue is distributed between chloroform and water. The organic phase is separated, dried over sodium sulphate and evaporated. The precipitated crystals are suspended with ether, filtered off with suction and recrystallized from toluene.

4.8 g (76% of the theoretical) of 2-(1-imidazolyl)-1-(2-pyridyl)-1-phenyl-ethanol with a melting point of 176-178°C are obtained (see also example 4).

The 2-phenyl-2-(2-pyridyl)-oxirane used as starting material was prepared as follows: To a suspension of 2.56 g (0.053 mol) of sodium hydride (50% in oil) in 50 ml of dimethylsulfoxide is added dropwise under stirring a solution of 7.1 g (0.039 mol) of 2-benzoylpyridine in 100 ml of dimethylsulfoxide. 12 g (0.06 mol) of trimethylsulfonium iodide are then added. The resulting reaction mixture is then stirred for 4 hours, 300 ml of water is carefully added and extracted with ether. The organic phase is washed with water and evaporated after drying over sodium sulphate. The residue (7.5 g) is dissolved in a little chloroform and placed on a silica gel column. After separation of a contaminant with petroleum ether (40-60°C), the main reaction product is eluted with a chloroform-ethyl acetate mixture (8:2). 6 g (78% of the theoretical) of 2-phenyl-2-(2-pyridyl)-oxirane are obtained as an oil with the following characteristic data: NMR data* 8.60 ppm (1H, m, pyridyl/6<1> still.);

7.11-7.77 (8H, m, pyridyl/3',4',5' still,

and phenyl); 3.53 ppm (1H, d, J=6Hz, oxirane);

3.22 ppm (1H, d, J=6Hz, oxirane)

Starting from 4-benzoylpyridine, one obtains in an analogous way:

2-phenyl-2-(4-pyridyl)-oxirane:

NMR data* 8.55 ppm (2H, d, J=6Hz, pyridyl/2<1>,6' still.);

7.23 ppm (2H, d, J=6Hz, pyridyl/3',5' still.);

7.36 ppm (5H, s, phenyl);

3.37 ppm (1H, d, J=6Hz, oxirane);

3.15 ppm (1H, d, J=6Hz, oxirane).

Analogue was produced:

2-(4-Chlorophenyl)-2-(2-pyridyl)-oxirane

2-(4-Bromophenyl)-2-(2-pyridyl)-oxirane

2-(2-pyridyl)-2-(2-thienyl)-oxirane

2-(3,4-dichlorophenyl)-2-(2-pyridyl)-oxirane

2-(4-Methoxyphenyl)-2-(3-pyridyl)-oxirane

2-phenyl-2-[5-chloro-pyridyl(2)]-oxirane

<*>1

The H-NMR spectra were recorded with a Bruker WH 90 apparatus

(s = singlet, d = doublet and m = multiplet).

Measurement conditions:

1H frequency: 90 MHz

Temperature: 25°C; solvent: CDCl^

Spectral width: 1160 Hz = 12.88 ppm

Standardization: Internal tetramethylsilane = 0 ppm

as a reference point for the chemical

displacement (signal positions) in the spectrum.

Example 6

2-( 1- imidazolyl)- 1-( 4- pyridyl)- 1- phenyl- ethanol- fumarate

Starting from 4.7 g (0.024 mol) of 2-phenyl-2-(4-pyridyl)-oxirane, one obtains analogously to example 5 2-(1-imidazolyl)-1-(4-pyridyl)-1- phenyl ethanol.

To prepare the fumaric acid salt, the base is dissolved with an equivalent amount of fumaric acid while heating in methanol.

The crystals formed by cooling the solution are recrystallized from methanol. Yield: 6.5 g (71.4% of theory); m.p. 201°C (decomp.).

For the new compounds or their acid addition salts, a dosage of 5-50, preferably 10-30 mg per dose.

Claims (7)

1. Analogous method for the preparation of therapeutically active 2-(1-imidazolyl)-ethanol derivatives with the general formula where means hydrogen, an alkyl residue with 1-3 carbon atoms or a halogen atom, R^" means one of the residues R^ means hydrogen or a methyl residue, R4 means hydrogen, an alkyl residue with 1-3 carbon atoms or a halogen atom, Ri- means hydrogen, an alkyl or alkoxy acid residue with 1-3 carbon atoms, a halogen atom or a trifluoromethyl group, and m means one of the numbers 1 or 2, and their physiologically compatible acid addition salts, characterized by ata) a 2-(1-imidazolyl) -ethanone with the general formula where A means one of the residues and R 3 has the above meaning, is reacted if A means pyridyl, with organometallic reagents, such as a phenyl or thienyl magnesium halide, resp., if A means the residue R 2 , with a pyridyl magnesium halide or a corresponding lithium compound, or b) an imidazole with the general formula where <R> 3 has the above meaning, is reacted with an oxirane of the general formula where R 1 and R 2 have the above meaning, and optionally a compound of the general formula I prepared in this way is transferred to a physiologically acceptable acid addition salt in a manner known per se. 2. Process according to claim 1, characterized in that a compound of the general formula I is prepared where R3 means hydrogen, while the other residues have the meanings specified in claim 1. 3. Process according to claim 1, characterized in that 2-(1-imidazolyl)-1-(2-pyridyl)-1-(2-thienyl)-ethanol is produced. 4. Process according to claim 1, characterized in that 2-(1-imidazolyl)-1-(2-pyridyl)-1-[2-(5-chloro-thienyl)]-ethanol is produced. 5. Process according to claim 1, characterized in that 2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-chloro-phenyl)-ethanol is produced. 6. Process according to claim 1, characterized in that 2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-bromo-phenyl)-ethanol is produced. 7. Process according to claim 1, characterized in that 2-(1-imidazolyl)-1-(2-pyridyl)-1-(p-tolyl)-ethanol is produced.