IE903418A1 - (+)-(2-Hydroxy-2-adamantyl)-1-imidazolyl-3-tolymethane and¹the salts thereof, a process for the preparation thereof,¹pharmaceuticals containing this compound, and the use¹thereof - Google Patents

Abstract

The invention relates to the dextrorotatory, (+) enantiomer of (2-hydroxy-2-adamantyl)-1-imidazolyl-3-tolylmethane and its physiologically tolerated acid addition salts. The said compounds are used as psychopharmaceuticals, in particular as antidepressants. Also described are pharmaceutical compositions which contain the said compounds as active substances. The pharmaceutical compositions can be administered orally, parenterally, intraperitoneally and/or rectally.

Description

( + )- (2-Hydroxy-2-adamantyl) -1-imidazolyl-3-tolylmethane and the salts thereof, a process for the preparation thereof, pharmaceuticals containing this compound, and the use thereof The invention relates to the dextrorotatory, ( + ) enantiomer of (2-hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane, including the salts thereof, a process for the preparation thereof, pharmaceuticals containing this compound, and the use thereof as pharmaceuticals.

The invention particularly relates to the physiologically tolerated salts of the (+) enantiomer of (2-hydroxy-2adamantyl)-l-imidazolyl-3-tolylmethane.

It has already been described (German Patent Applications P 36 28 545.5 and P 37 07 151.3) that substituted arylmethylazoles and the salts thereof derived from the reaction of 1-(airylmethyl) azoles with ketones and aldehydes are suitable, by reason of their psychopharmaco20 logical, especially their antidepressant effect, for the treatment of depressive states.

It has now been found, surprisingly, that the dextrorotatory, (+) enantiomer of (2-hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane of the formula I, and the physiologi25 cally tolerated acid addition salts thereof, especially the hydrochloride and the (2S,3S)-hydrogentartrate, display very particularly pronounced effects in animal models which are predictive of an antidepressant effect in humans. (2-Hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane in the form of the racemate as is produced on chemical synthesis has already been mentioned in German Patent Application P 36 28 545.5 as having antidepressant activity in predictive animal models.

On pharmacological investigation of the (+) enantiomer of the compound of the formula I, unexpectedly strong effects of this substance were found in animal models which are regarded as predictive of an antidepressant effect in humans. The other antipode, the levorotatory, (-) enantiomer of the compound I has, by contrast, no pharmacological activity.

It is extremely surprising that it is precisely the (+) enantiomer of the formula I which likewise displays a good antidepressant effect because other (+) enantiomers from the same class of compounds, for example (+)-(2hydroxy-2-adamantyl)-1-imidazolyl-(3-chlorophenyl) methane, display a lower effect than the corresponding racemates (see also Comparison Examples 1 and 2). The high activity of the (+) enantiomer of the formula I was thus by no means predictable, on the contrary the person skilled in the art was obliged to conclude from the lower effect of (+)-(2-hydroxy-2-adamantyl)-1-imidazolyl-(325 chlorophenyl) me thane that other ( + ) enantiomers from this class of substances would have no greater effect than the racemates either.

The pharmacological tests were carried out using known models which are regarded as predictive for an antidepressant effect in humans. These are, for example: the effect on tetrabenazine ptosis in the mouse and the potentiation of yohimbine toxicity in mice. Another assessment criterion which was used was, for example, the test of the induction of stereotypy in rats.

The compound of the formula I as pure (+) enantiomer was compared in the pharmacological tests using the abovementioned animal models with other compounds from the 1(1-phenyl-2-hydroxyethyl)imidazole class which are very active in these models, as are described in German Patent Applications P 36 28 545.5 and P 37 07 151.3, including the racemic compound I.

As is evident from the tables which follow, the dextrorotatory, ( + ) enantiomer of the compound I is superior in all the test models to the other said compounds of the class of substances, even including a pure (+) enantiomer .

The invention also relates to a process for preparing the dextrorotatory enantiomer of (2-hydroxy-2-adamantyl)-120 imidazolyl-3-tolylmethane of the formula I, which comprises converting the racemate of the compound I with one equivalent of (2S,3S)-(-)-tartaric acid in a suitable solvent or solvent mixture into the hydrogentartrate, and carrying out fractional crystallization of the diastereo25 meric hydrogentartrate which is formed from a suitable solvent or solvent mixture, and subsequently subjecting the dextrorotatory (2-hydroxy-2-adamantyl)-1-imidazolyl3-tolylmethane (2S,3S)-hydrogentartrate which has crystallized out to one or more recrystallizations from a suitable solvent or solvent mixture until the specific rotation remains constant.

It is possible in principle to use as solvent all conventional organic solvents or mixtures of such solvents, where appropriate including those which, when miscible with water, contain a proportion of up to 15% by volume - 4 water. It is advantageous to use for the racemate resolution of the compound I tetrahydrofuran, 1,2-dimethoxyethane, dioxane, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone or methyl or ethyl ace5 tate, with the addition of up to 30% by volume methanol or ethanol. Particularly suitable solvents are mixtures of acetone and/or acetonitrile containing 4 - 20% by volume methanol. The process according to the invention can be carried out within a very wide temperature range.

The formation of the hydrogentartrate of the racemate of the compound I is expediently carried out at a temperature between room temperature and the boiling point of the solvent. The hydrogentartrate which is formed is crystallized out by cooling, advantageously slowly, i.e. within several hours, to a temperature which is some degrees Celsius above the solidification point of the solution, advantageously down to a temperature between +5eC and +30eC.

The free base, the (+)-(2-hydroxy-2-adamanty1)-120 imidazolyl-3-tolylmethane, can be liberated from the pure ( + )-(2-hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane (2S,3S)-hydrogentartrate which is obtained according to the invention by methods which are known in principle, for example by adding a strong base such as a hydroxide of an alkali metal or alkaline earth metal, or a strong organic base, such as a trialkylammonium hydroxide or a trialkylamine, for example triethylamine, expediently in the presence of water and advantageously in the presence of an organic solvent which is immiscible with water, such as, for example, dichloromethane, in which the compound I dissolves at least in part. The liberation of the compound I from its acid addition salts such as, for example, the (2S,3S)-hydrogentartrate or the hydrochloride can also be carried out using a basic, advantageously strongly basic, ion exchanger.

The (+)-(2-hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane, the compound I, can be converted into acid - 5 addition salts by adding an equivalent amount of a physiologically tolerated acid, expediently also using a solvent or liquid diluent.

All acids which form physiologically tolerated salts are 5 suitable for forming acid addition salts. These include both inorganic acids and mono-, bi- and trifunctional organic acids, such as, for example, hydrochloric, hydrobromic or hydriodic, sulfuric, phosphoric, nitric, benzenesulfonic, toluenesulfonic, sulfamic, methyl10 sulfuric, acetic, propionic, oleic, palmitic, stearic, malonic, maleic, succinic, glutaric, malic, tartaric, citric, fumaric, lactic, glycolic, pyruvic, benzoic, toluic, glutamic, furancarboxylic, salicylic or mandelic acid. Preferred salts are with physiologically tolerated inorganic acids, strongly to moderately strongly acidic derivatives of such acids or with succinic acid, L(+)- or D(-)-tartaric acid, malic acid, fumaric acid, (S)-(+)- or (R)-(-)-mandelic acid.

As is evident from the results of the pharmacological tests, the ( + ) enantiomer of the compound I, which was tested in the form of the (2S,3S)-hydrogentartrate, proved to be superior to other compounds with a pronounced antidepressant effect from the same class of substances, and nomifensin. (+ ) - (2-Hydroxy-2-adamantyl)-1-imidazolyl-3-tolylmethane, the compound according to the invention, and its acid addition salts, are, on the basis of their effects in predictive animal models, distinguished as substances which have particular antidepressant activity and thus represent valuable psychopharmaceuticals and can be used as pharmaceuticals for treating depressive states. The dose level administered depends on the type of treatment desired, on the mode of administration, the condition, the type and the weight of the treated individual. On oral dosage, satisfactory results are achieved with doses from 0.1 mg upwards, preferably from 0.4 mg upwards to 60 - e mg, preferably up to 15 mg, of a compound of the formula I per kg of body weight.

On oral administration, the compounds according to the invention antagonize with an ED50 of 0.8 - 1.9 mg/kg the tetrabenazine ptosis in the mouse. The appropriate amount of a homogenate of the particular substance in aqueous carboxymethylcellulose or methylhydroxyethylcellulose is fed by gavage to six male animals 30 min before the treatment with tetrabenazine (40 mg/kg intraperitone10 ally)· The tetrabenazine ptosis is antagonized by this pretreatment.

The compound I as the (+) enantiomer and its acid addition salts potentiate the toxicity of yohimbine in mice with an ED50 of 2.0 - 5.0 mg/kg on oral administration.

An essential finding is that the compound I according to the invention and its salts do not cause any stereotypy in rats and mice after dosage in a therapeutically relevant range.

The antidepressant effect and the utilizability for the treatment of depressive states was further demonstrated by the inhibition of the reuptake of noradrenaline on preparations of synaptosomes from mouse brain.

The (+) enantiomer of the compound I and its acid addition salts are particularly valuable owing to a structure which differs from the antidepressants hitherto disclosed. Its effect is equivalent or superior to, while the toxicity is lower than, that of known commercial products.

The present invention includes pharmaceutical prepara30 tions which, besides non-toxic, inert pharmaceutically suitable excipients, contain the active compound according to the invention or are composed of the active compound according to the invention, as well as processes for producing these preparations.

Non-toxic, inert, pharmaceutically suitable excipients means solid, semisolid or liquid diluents, fillers and formulating auxiliaries of every type.

Examples of suitable forms for the use of the compounds according to the invention are tablets, coated tablets, capsules, pills, aqueous solutions, suspensions and emulsions, where appropriate sterile injectable solutions, non-aqueous emulsions, suspensions and solutions.

The therapeutically active compounds ought to be present in the abovementioned pharmaceutical preparations expediently in a concentration of about 0.01, preferably of about 0.10 to 99.0, preferably to 50.0, per cent by weight of the complete mixture.

The abovementioned pharmaceutical preparations can, apart from the active compounds according to the invention, also contain other pharmaceutical active compounds.

The abovementioned pharmaceutical preparations are produced in a conventional manner by known methods, for example by mixing the active compound or compounds with the excipient or excipients.

The active compound or the pharmaceutical preparations can be administered orally, parenterally, intraperitoneally and/or rectally.

The compound of the present invention which can be used as antidepressant, and its salts, can be used for producing pharmaceutical products which contain an effective amount of the active substance together with excipients and which are suitable for enteral and parenteral admini30 stration. Tablets or gelatin capsules which contain the active compound together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose - 8 and/or glycine and lubricants such as diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, are preferably used. Tablets additionally contain binders such as magnesium aluminum silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and, if necessary, colorants, flavorings and sweeteners. Injectable solutions are preferably isotonic aqueous solutions or suspensions which can be sterilized and contain auxiliaries such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts to regulate the osmotic pressure and/or buffer substances. The pharmaceutical products according to the invention, which, if desired, can contain pharmacologically valuable substances, are produced, for example, using conventional mixing, granulating and coating processes and contain 0.1% to about 75%, preferably about 1% to about 50%, of the active compound.

Oral administration takes place in pharmaceutically customary preparations, for example in the form of tablets, coated tablets or capsules which contain per daily dose, for example, 5, preferably 15, to 300 mg, preferably to 150 mg, of the active compound mixed with — a conventional excipient and/or constituent, it being possible to give single doses of 5 to 50 mg, preferably once to three times a day.

However, it may be necessary to deviate from the said dosages and to do so specifically as a function of the species and body weight of the subject to be treated, the nature and severity of the disease, the type of preparation and the administration of the pharmaceutical, and the period or interval within which administration takes place. Thus, it may suffice in some cases to manage with less than the abovementioned amount of active compound, while in other cases the abovementioned amount of active compound must be exceeded. The particular required - 9 optimal dosage and mode of administration of the active compounds can easily be established by any person skilled in the art on the basis of his expert knowledge.

The examples which follow illustrate the preparation of the compounds.

Example 1 ( + )- (2-Hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane (25.35) -hydrogentartrate: .44 g (63.4 mmol) of (2-hydroxy-2-adamantyl)-1-imidazo10 lyl-3-tolylmethane (prepared as in German Patent Application P 36 28 545.5, Example 106) and 9.52 g (63.4 mmol) of (2S,3S)-(-)-tartaric acid were dissolved in 125 ml of acetone at the boiling point. Crystallization took place when the solution was slowly cooled to room temperature.

After one day (24 h) the crystals were filtered off with suction and washed with acetone, and were dried at 98°C/4-7 mbar for 15 h. 10.3 g of (2-hydroxy-2-adamantyl )-l-imidazolyl-3-tolylmethane (2S,3S)-hydrogentartrate were obtained ([a]“ * ( + ) 6.09° (C = 1.0; CH3OH)). This product was dissolved in a boiling mixture of 130 ml of acetone and 13 ml of methanol and was left to crystallize out while slowly cooling to room temperature. After one day (24 h), the crystals were filtered off with suction, washed and dried as described above. 6.32 g of product were obtained ([α]β2: ( + ) 6.57° (C = 1.0; CH3OH)). These 6.32 g were recrystallized in an analogous manner from 80 ml of acetone and 8 ml of methanol, resulting in 4.68 g of product ([α]“: ( + ) 6-90 “ (C = 1.0; CH3OH)).

Another recrystallization from 95 ml of acetone and 6 ml of methanol yielded 3.48 g (2 23.2% of theory) of pure ( + )-(2-hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane (25.35) -hydrogentartrate, [a]22: (+) 6.93 ’ (C = 1.0; CH3OH); melting point 115 - 117eC.

The mother liquors from the last and penultimate re35 crystallization were combined and evaporated in vacuo, and the remaining residue (2.60 g) was recrystallized from 30 ml of acetone and 3 ml of methanol In a manner analogous to that described above. 1.9 g of product were obtained and were recrystallized twice more in an analogous manner from corresponding acetone/methanol mixtures. After this a further 1.20 g (_ 8.0% of theory) of pure (+)-(2-hydroxy-2-adamantyl)-l-imidazolyl-3tolylmethane (2S,3S)-hydrogentartrate were obtained, [a]22: ( + ) 6·92° (C = 1.0; CH3OH); melting point 115 10 117eC. In total, 4.68 g (2 31.2% of theory) of the pure (2S,3S)-hydrogentartrate of the (+) enantiomer of compound I were obtained in this way.

C25H32N2O7 (472.55) calc.: C 63.54 H 6.83 N 5.93 0 23.70 % found: C63.2 H6.4 N 5.9 023.5 % Example 2 (+)-(2-Hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane: A mixture of 7.09 g (15 mmol) of (+)-(2-hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane (2S,3S)-hydrogentartrate (prepared as in Example 1), 150 ml of CH2C12, 16.5 ml of 2N sodium hydroxide solution and 20 ml of water was shaken at room temperature until two clear phases had been produced. The phases were separated and then the aqueous was extracted twice with CH2C12. The combined CH2C12 phases were washed once with water, dried, filtered and evaporated in vacuo. The amorphous foam-like residue was heated to boiling with 100 ml of ether for 10 min, resulting in a crystalline solid. This was filtered off with suction, washed with ether and dried. 4.35 g (90% of theory) of pure (+)-(2-hydroxy-2-adamantyl)-1-imidazolyl3-tolylmethane were obtained, [a]22: ( + ) 23.90 e (C = 1.0; CH3OH); melting point 199 - 200eC.

C21H26N2O (322.46) calc.: C 78.22 H 8.13 N 8.69 % found: C77.6 H8.1 N 8.6 % Example 3 ( + )-(2-Hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane hydrochloride: 6.45 g (20 mmol) of (+)-(2-hydroxy-2-adamantyl)-l-imidaz5 olyl-3-tolylmethane (prepared as in Example 2) were dissolved in 92 ml of ethyl acetate and 5 ml of methanol with heating, cooled to room temperature, and 3.8 ml of a 5.9 molar solution of HCl in ether were added dropwise.

A crystalline precipitate separated out after a few minutes . The crystals were then stirred while cooling in an icebath for 1 h, filtered off with suction and washed with cold ethyl acetate and ether. Drying of the substance resulted in 6.32 g (2 88% of theory) of pure ( + )(2-hydroxy-2-adamantyl)-l-imidazolyl-3-tolylmethane hydrochloride, [α]£2 s ( + ) 15.31 (C = 0.993, CH3OH); melting point 194 - 195°C.

C21H27C1N2O (358.92) calc.: C 70.27 H 7.58 Cl 9.88 N 7.81 found: C69.6 H7.7 Cl 9.4 N7.6 0 Pharmacological tests 1. Test of the effect on tetrabenazine ptosis (TBZ method) Tested on mice (NMRI) male, weighing 18-22 g: Male mice (SPF-71, KF:NMRI); weighing 18-22 g, were assigned at random to treatment groups each containing 6 animals. The test substances were suspended in 1% strength Tylose/water and administered orally in 10 ml/kg of body weight. A control group received the solvent or suspending agent (1% Tylose).

The tetrabenazine solution used was prepared from the methanesulfonate (_ 76.8% base), and an amount corresponding to 40 mg/kg tetrabenazine base was administered - 12 intraperitoneally 30 min after the test substances. 30 min after administration of tetrabenazine, the ptosis was assessed using the following scale: Ptosis_Score Eyes closed 4 Eyes 3/4 closed 3 Eyes J closed 2 Eyes { closed 1 Eyes open 0 The ptosis scores were added and the result for the groups was related to the maximum score achievable (6 x 4 = 100%). The ED50 (mg/kg) was determined by linear regression as the dose at which the degree of ptosis is 50% of the value determined for the control group. 2. Potentiation of the yohimbine toxicity in mice.

The toxicity of yohimbine, a blocker of presynaptic alpha-receptors, is potentiated by antidepressants (literature: R.M. Quinton, Brit. J. Pharmac. 21., 55-56 (1963)). Male mice, NMRI strain, 20-22 g, were assigned to test groups of n=10. The test product was suspended in 1% strength aqueous Tylose* mucilage and administered orally in a volume of 10 ml/kg. Controls received only the vehicle.

After a pretreatment time of 1 hour, all the animals received a subcutaneous dose of 20 mg/kg yohimbine hydrochloride, which is not by itself toxic. 18 hours after this treatment the number of animals which had died was determined. (Calculation of the LD50 by probit analysis). 3. Test of the induction of stereotypy in rats The tests were carried out on male Wistar rats, 130140 g. The stereotypy was assessed at 15-minute intervals in the first two hours after administration of the substance and then at half-hour intervals up to the 6th hour. The following scale was used.

Signs Score Behavior like control group Increased snuffling Snuffling and rearing up Increased motor activity, few shakes of the head and forepaws Occasional licking, biting, chewing Continual as 4 The scores were calculated as the total divided by the number of observations. for 6 hours The ED50 is the dose at which half the maximum possible 15 score (5 points multiplied by the number of observations) is reached. 4. Inhibition of reuptake of noradrenaline in synaptosomes Method Synaptosomes are isolated from rat brain by the method of Whittaker (Handbook of Neurochemistry 2, 327-364, Editor A. Lajtha; London and New York, 1969) and the monoamine uptake is measured by the method of Schacht and Heptner (Biochemical Pharmac. 23> 3413-3422). The 1AC-noradrena25 line uptake was measured in a Krebs-Henseleit bicarbonate buffer pH 7.4 which contained 11 millimoles glucose. 2.5 ml of the synaptosome suspension were incubated with labeled noradrenaline at 37 C in the presence of or without test substance. The incubation time was 4 minutes. Further uptake was then stopped by cooling in ice. In order to eliminate non-specific adsorption, control samples were incubated at 0°C with otherwise identical conditions. - 14 The amounts of noradrenaline taken up were measured using the membrane filtration technique with a Millipore sampling manifold with cellulose nitrate filters of diameter 25 mm and pore size 0.6 micrometer. The synap5 tosomes were collected under reduced pressure, and the radioactivity was determined in a Packard Tricarb scintillation counter. The amount of accumulated noradrenaline indicated as percentage of the radioactivity added to the incubation mixture.

The IC50 values (inhibitory concentration) in the following tables indicate the concentrations of test substances which inhibit the uptake of uC-noradrenaline by 50%.

Results of the pharmacological tests ( + )- (2-Hydroxy-2-adamanty 1) -l-imidazolyl-3-tolylmethane 15 (2S,3S)-hydrogentartrate (from Example 1) ED50; mg/kg oral (confidence limits) ED50? mg/kg converted (F:0.6 8) to equimolar amount of base Method 1, mouse Method 2, mouse Method 3, rat Method 4, IC50 = 1.3 (1.0 - 1.6) 1.2 (0.3 - 3.5) 1.75 (0.4 - 6.9) 1.9 (1.0 - 3.5) 1.4 (0.7 - 2.7) LDS0, mg/kg oral 2.9 (0.2 - 41.3) no stereotypy up to 7xlO'®M (from Example 2) 0.9 (0.7 - 1.1) 0.8 (0.2 - 2.4) 1.2 (0.3 - 4.7) 1.3 (0.7 - 2.4) 1.0 (0.5 - 1.8) 2.0 (0.1 - 28.1) 100 mg/kg oral - 15 Results of the pharmacological tests on highly active compounds from the same class of substances (as the compound according to the invention) for comparison: (Unless otherwise mentioned, the compounds listed here are racemates) Method 1 (confidence limits) mouse ED50 0.8 mg/kg oral ·· 1.9 (1.4-2.7) Method 2, mouse LD50 4.4 mg/kg oral Method 3, rat: no stereotypy up to 300 mg/kg oral xlO8 M 15xl08 M (+) enantiomer Method 1 mouse ED50 2.9 (0.8-9.9) mg/kg oral 2.3 (0.9-5.8) - Method 2, mouse LD50 4.6 mg/kg oral 20 8.5 (0.5-130) mg/kg oral Method 3/ rat: no stereotypy up to 30 mg/kg oral Method 4: IC50 = 12xl08 M *) Im: - 16 Method 1, mouse ED50 1.5 mg/kg oral 1.7 (0.5-5.9) Method 2, mouse LD50 7.1 mg/kg oral Method 3, rat: no stereotypy up to 30 mg/kg oral Method 4, IC50 = 12xl0'8 M Method 1, mouse EDS0 3.0 mg/kg oral Method 2, mouse LDS0 3.0 mg/kg oral Method 1, mouse ED50 3.0 mg/kg oral Method 2, mouse LD50 3.2 mg/kg oral Method 1, mouse ED50 3.7 mg/kg oral Method 2, mouse LD50 8.5 Method 3, rat: no stereotypy up to mg/kg oral Method 1, mouse EDS0 3.0 mg/kg oral Method 2, mouse LDS0 5.3 mg/kg oral Method 3, rat: no stereotypy up to mg/kg oral Method 4, IC50 > lxlO’6 M 1, mouse EDS0 1.2 (0.3-5.4) mg/kg oral 2.1 (0.7-5.8) .7 (2.0-16.2) 2, mouse LDSO 24.5 3, rat: no stereotypy up to mg/kg oral 1, mouse ED50 3.9 (2.1-7.3) mg/kg oral 6.1 (0.5-72.9)

Claims (10)

1. Patent Claims HOE 89/F 313 The dextrorotatory, (+) enantiomer of (2-hydroxy-2adamantyl)-l-imidazolyl-3-tolylmethane of the formula I 2.

2. 3.

3. 4.

4. and the physiologically tolerated acid addition salts. The (2S,3S)-hydrogentartrate of the compound of the formula I as claimed in claim 1. The hydrochloride of the compound of the formula I as claimed in claim 1. A process for preparing the dextrorotatory enantiomer of (2-hydroxy-2-adamantyl)-1-imidazolyl-3-tolylmethane of the formula I and the physiologically tolerated acid addition salts thereof, which comprises converting the racemate of the compound I with one equivalent of (2S,3S)-(-)-tartaric acid in a suitable solvent or solvent mixture into the hydrogentartrate, and carrying out fractional crystallization of the diastereomeric hydrogentartrate which is formed from a suitable solvent or solvent mixture, and subsequently subjecting the dextrorotatory (+)-(2-hydroxy-2-adamantyl)-limidazolyl-3-tolylmethane (2S,3S)-hydrogentartrate which has crystallized out to one or more recrystallizations from a suitable solvent or solvent mixture until the specific rotation remains constant, and, where appropriate, converting the enantiomerically pure hydrogentartrate obtained in this way into the free base of (+)-(2-hydroxy-2-adamantyl)-1-imidazolylIE 903418 - 19 3-tolylmethane and, where appropriate, preparing from the latter another physiologically tolerated acid addition salt.

5. The use of one or more compounds of the formula I as claimed in any of claims 1, 2 or 3 as antidepressant.

6. The use of one or more compounds of the formula I as claimed in any of claims 1, 2 or 3 for producing a pharmaceutical with an antidepressant effect.

7. A pharmaceutical with an antidepressant effect, which contains an effective amount of one or more compounds of the formula I as claimed in any of claims 1, 2 or 3.

8. A method for treating depressive states, which comprises administering an effective amount of one or more compounds of the formula I as claimed in any of claims 1, 2 or 3, where appropriate together with pharmaceutically suitable excipients.

9. 9.

10. 10. 12. 12. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified. A process for preparing a compound as claimed in claim 1, substantially as hereinbefore described and exemplified. A compound as claimed in claim 1, whenever prepared by a process claimed in a preceding claim. A pharmaceutical as claimed in claim 7, substantially as hereinbefore described.