DE2907379A1 - BENZYLIDENE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

SYNTHELABO - SET .21

DESCRIPTION

The invention relates to benzylidene derivatives, a process for their preparation and these compounds as Medicines containing active ingredients. 10

In the applicant's patent application P 26 34 288.1, o-phenyl-benzylidene derivatives of the following are all common formula

OH

X
15th

"~ C = NC H ₂ n-COR

described in the

-X ₁ , X "and X_, which can be identical or different, independently of one another hydrogen atoms, halogen atoms, in particular chlorine atoms or fluorine atoms, or methyl groups or methoxy groups, - η an integer with a value of at least 1 and at most 10 and

- R is a hydroxyl group or a group of the following formulas:

-OM, -NH ₂ , -NH (CH ₂ J ₃ -COOH, -NH (CH ₂ ) ₃ -COOM (where M is an alkali metal atom, especially a sodium atom), -NH (CH ₀ ) o-COOC ^ H-, -NH-cycloalkyl, -NH-phenyl, -NH-benzyl (where the benzyl group can have a substituent from the group consisting of halogen atoms and the trifluoromethyl group), -NH-alkyl, -N (alkyl) _ and -N ( Alkyl) (benzyl)

mean, where the Alky! groups, the straight-chain or can be branched, 1 to 4 carbon atoms and the

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Cycloalkyl groups contain 3 to 6 carbon atoms, with the exception of the compound in which X. and X _{3 are} hydrogen atoms, X _{2 is} a chlorine atom in the 5-position, η = 1 and R is a hydroxyl group.

The present invention now relates to compounds of the general formula I.

OR ¹

in the

- X ₁ , X ", X_ and X ₄ independently of one another hydrogen atoms, halogen atoms, methyl groups (-CH ₃ ), methoxy groups (CH ₃ O-), nitro groups (-NO"), trifluoromethyl groups (-CF ₃ ), tert-butyl groups (-C (CH ₃ J ₃ ) or acetyl amino groups (CH ₃ CONH-),

- η is an integer with a value from 1 to 10,

- R is a hydroxyl group (-0H), a group of the formula -OM (where M stands for an alkali metal atom), an amino group (-NH-) 1 a cycloalkylamino group (-NH-cycloalkyl), a phenylamino group (-NH-phenyl), a benzylamino group (-NH-benzyl) / an alkylamino group (-NH-alkyl), a dxalkylamino group (-N (alkyl)) or an alkylbenzylamino group (-N (alkyl) (benzyl)) and

- R ^{1 is} a hydrogen atom or an alkyl group

mean, where the alkyl groups have 1 to 4 carbon atoms,
with the exception of the compounds in which R ^{1 is} a hydrogen

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represents atom when X., Χ_ and X _{3 are} independently hydrogen atoms, halogen atoms, methyl groups or methoxy groups and X _{4 is} a hydrogen atom and with the exception of the compound in which R ^{1 is} a hydrogen atom, X .., X ₃ and X. hydrogen atoms, X "a chlorine atom in the 5-position (5-Cl), η = 1 and R a hydroxyl group.

Compounds preferred according to the invention are those in which R is a hydroxyl group, a group of the general Represents formula -OM or an amino group when η has the value 3.

The invention also relates to a process for the preparation of the compounds of the general formula I _x, which is characterized in that a ketone of the general formula II

"OH

C = O

II

with a compound of the general formula III

III

in the form of the base or the hydrochloride and, if desired, the compounds of the general formula I obtained, in which R ^{1 represents} a hydrogen atom, alkylated.

The reaction is preferably carried out in an alcoholic

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see solvents, such as methanol or ethanol, at a temperature of 10 ⁰ C to the boiling point of the solvent and in the presence of an alkali metal or an alkali metal alcoholate.

A variant of the process according to the invention for the preparation of the compounds of the general formula I ₁

in which R ^{1 denotes} a hydrogen atom and R denotes an amino group, consists in combining a hydroxybenzophenone of the general formula II with a compound of the general formula
15th

H ₀ N (CH ₉ ) CN • HCl

(i.e. the intermediate product in the preparation of the compounds of general formula III 20th

implement and then a solvolysis of the condensation to effect obtained nitrile of the general formula IV, proceeding according to the following reaction scheme:

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SYNTHELABO - SET .21

OH

C = O

ί- (CH ₂ ) _n -CN · HCl>

C = N- (CH ₀ ) CN

X.

(IV)

or Na OH

'C = N- (CH ₀ ) -CO-NH ₀ 2 η 2

or HCOOH

X,

HCl gas

The compounds of the general formula IH used as starting materials and their preparation are already in has been described in the literature.

The general ketones used as starting materials Formula II is prepared

1. either by reacting a compound of the general formula

OCH.

with a compound of the general formula

COCl

after which the intermediate product obtained is liertj or thy thy with aluminum chloride or boron trichloride
2. by implementing a connection of the following general

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SYNTHELABO - SET 21

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my formula

O-CE

X ₂

with a compound of the general formula

MgBr

after which the intermediate is hydrolyzed to give a compound of the following general formula

obtained with aluminum chloride or boron trichloride demethylated to the compound of general formula II.

The ketones of the general formula II are new compounds with the exception of the compound in which X ₁ , X_ and χ independently of one another represent hydrogen atoms, halogen atoms, methyl groups, methoxy groups or tert-butyl groups when the group X is a hydrogen atom.

The ketones of the general formula II, the valuable intermediates for the preparation of the invention Compounds of the general formula I represent, are also the subject of the present invention.

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The preparation of the ketones of the general formula I is described in the examples, which deal with the preparation deal with the products of general formula I, explained.

The following examples serve to further illustrate the invention.

The structure of the compounds formed was confirmed by analysis and IR and NMR spectra.

In the following examples are also some connections which correspond to the general formula of the earlier patent application given above (compounds 24 to 47).

example 1

Sodium salt of 4- / N- (o & -phenyl-2-hydroxy-5-trifluoromethyl-benzylidenyl) -amino_7-butyric acid (formula I: Xj = 5-CF3, X ₂ = X ₃ = X ₄ = H, R ¹ = H, R = ONa, η = 3)

1. 2-Hydroxy-5-trifluoromethyl-diphenylmethanone 1.1 A 250 ml three-necked flask is charged with a rising condenser and a dropping funnel is, with 1.68 g (0.0691 mol) magnesium, 25 ml anhydrous ether and 1 iodine crystal. One heated to the Boil at reflux and give about 10% of a solution of 19.52 g (0.1243 mol) of bromobenzene in 30 ml of anhydrous Ether to. After the reaction gets off to a good start, one admits the rest in such a way that the reaction mixture boils under reflux. After the addition is complete, the mixture is further heated to the boil Reflux until the magnesium has completely disappeared. Then, while maintaining the Reflux 9.5 g (0.0472 mol) of 2-methoxy-5-tri-

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SYIiTHELÄBO - SET .21.

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fluoromethyl-benzonitrile in 80 ml of anhydrous ether and then heated to reflux for 4 hours. Then you hydrolyze in the cold and under nitrogen with 40 ml of 2N hydrochloric acid. A precipitate forms, which one filtered off, washed with ether and dried. It is the imine hydrochloride of the following formula

OCH-.
/

_; HCL

CP_ ^c
15th

This hydrochloride is taken up with 50 ml of toluene and 50 ml of 25 percent sulfuric acid and heated reflux for 8 hours. The organic phase is then decanted and washed several times with water, dry over magnesium sulfate, filtered and the toluene evaporated. 2-Methoxy-5-trifluoromethyl-diphenylmethanone is obtained. Bp = 170 ° C / 0.07 mm Hg.

1.2 Into a 250 mL flask with 2.8 g (0.01 mol) of 2-methoxy-5-trifluoromethyl-diphenylmethanon and 100 ml of methylene chloride and cooled to -60 ⁰ C. Then 10 g of boron trichloride are added and the mixture is stirred for 1 hour at room temperature. It is then poured into 1.5 l of ice-cold water, 250 ml of methylene chloride are added, the mixture is stirred, the organic phase is decanted off, washed twice with water, dried over magnesium sulfate, filtered and the solvent is evaporated off.

Light yellow crystals are obtained, which are recrystallized from petroleum ether while being decolorized with vegetable charcoal. 2-Hydroxy ~ 5-trifluoromethyl ~ diphe-

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nylmethanon which melts at 84-85 ⁰ C.

2. Sodium salt of 4- / N- (od-phenyl-2-hydroxy-5-trifluoromethyl-benzylidenyl) -amino ./- butyric acid. 1.15 g of 97% 4-amino- butyric acid ^ 300 ml of methanol and 0.62 g of sodium methylate and stirred for 2 to 3 minutes. 2.8 g of 2-hydroxy-5-trifluoromethyl-diphenylmethanone and 300 ml of ethanol are then added. It is evaporated at atmospheric pressure (100 ⁰ C) and finally all of the solvent is evaporated off in vacuo, the residue is cooled and dissolved in 1 l of cold water. It is acidified with citric acid to a pH value of 4, extracted with chloroform, the chloroform phase is dried over magnesium sulfate, filtered and the chloroform is evaporated. An oil is obtained which crystallizes from petroleum ether. It is filtered off, suctioned off, washed with petroleum ether, suctioned off and recrystallized from ether, treating with biochar. The acid, which ^{melts at 154 to 155 °} C., is obtained. 2.5 g of the acid are dissolved in 150 ml of methanol and 0.38 g of sodium methylate are added. It is evaporated to dryness and the sodium salt is obtained, which is dried in a desiccator ^{at 80 ° C. for 1 hour.} F = 216-217 ⁰ C.

Example 2

4- {Ν2Γο £ - (2 ', 4'-DiChor-PhSnVl) -S-chloro ^ -hydroxy-benzylidenyl7 ~ amino]> —Butyric acid amide

(Formula I: X ₁ = 5-Cl, X ₂ = H, X ₃ = 2'-Cl, X ₄ = 4'-Cl, R = NH ₂ , R ^s = H and η = 3)

1. 2-Hydroxy-2 ', 4x, 5-trichloro-diphenylmethanone

1.1 To a solution of 25.7 g of p-chlorophenol and 30.3 g of triethylamine, kept under reflux while stirring a solution is slowly added to 1.2 liters of ether

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of 2,4-dichlorobenzoyl chloride in ether. The mixture is then refluxed with stirring for 3 hours and the products are then left in contact overnight. The triethylamine hydrochloride precipitate is filtered off and washed with ether. The organic phase is washed with water, with water containing bicarbonate and again with water. It is dried over magnesium sulfate, filtered and concentrated to about three quarters, the 2,4-dichloro-benzoic acid p-chlorophenyl ester precipitating out. It is cooled, filtered, suctioned off and dried in a desiccator at 60 ^° C. F = 124 - 125 ^° C.

1.2 35.5 g of the ester obtained in the previous stage are heated until they melt, the mixture is stirred and 35.5 g of aluminum trichloride are added. The mixture is then heated to 190 ^° C. and stirred for 15 minutes at this temperature. After cooling, the residue is triturated and hydrolyzed. It is poured into 800 g of a mixture of water, ice and 100 ml of concentrated hydrochloric acid with stirring. It is then extracted with chloroform, dried over magnesium sulfate, filtered and evaporated to dryness. It is recrystallized from petroleum ether, filtered off with suction and dried in a desiccator. The product melts at 96 - 97 ⁰ C.

A solution of 12.8 2. 4- {jH-SSC ^[2-liter, 4 ^{I-dichloro-phenyl)} -5-σhlor-2-hydroxybenzylidenyl _l 7-amino / -buttersäureamid Evaporate g of the ketone obtained in Step , 5.8 g of γ- amino-butyric acid amide in the form of the hydrochloride and 2.4 g of sodium methylate in 500 ml of methanol to dryness. Then 350 ml of the alcohol are evaporated four times in succession and the last two evaporation processes are terminated

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reduced pressure. The residue is dissolved in chloroforri / washed with water, dried over magnesium sulfate / filtered and evaporated to dryness. The residue is recrystallized from ether, filtered through a frit and filtered off with suction. It is then treated in methanol with activated charcoal, filtered and evaporated to dryness. It is recrystallized from alcohol, filtered, washed with ether, filtered off with suction and dried with heating in a desiccator. F = 14-1 142 ⁰ C.

Example 3

4- {N- / 66- (4 '-chlorophenyl) -S-tert-butyl ^ -hydroxy-benzylidenyl / -amino} -butyric acid

(Formula I: X ₁ = 5-C (CH ₃ ) ₃ , X ₃ = H, X ₃ = 4'-Cl, X ₄ = H, η = 3, R ¹ = H, R = OH)

1. S-tert-butyl ^ -chloro ^ -hydroxy-diphenylmethanone

1.1 128 g of p-chloro-benzoyl chloride and 0.25 g of freshly melted and ground zinc chloride are added to 120 g of p-tert-butyl anisole in 180 ml of tetrachloroethane, while stirring. The mixture is heated to 140 ^° C. for 40 hours while stirring, the solvent is evaporated and the mixture is distilled under reduced pressure. The distillate crystallizes from petroleum ether. 5-ter-t-butyl-4'-chloro-2-methoxy-diphenylmethanone is recrystallized from petroleum ether by treatment with vegetable charcoal. F = 46 - 47 ⁰ C.

1.2 to 88 g of the compound obtained in the preceding stage in 150 ml of benzene are added with stirring 46.3 g Alurainiuiatrichlorid and heated for 12 hours at 70 ⁰ C. Then, after cooling, is hydrolysed by concentrated on a mixture of ice and Pour hydrochloric acid and stir. One decants

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Washed with water, dried over magnesium sulfate / filtered and evaporated to dryness. The residue is crystallized from petroleum ether. It is filtered through a frit, suction filtered and recrystallized from methanol, treating with vegetable charcoal. It is dried in a desiccator. F = 64 - 65 ⁰ C.

2. A-IN-β- (4'-chloro-phenyl) -5-tert-butyl-2-hydroxybenzylidenyl / -amino / -butyric acid

A solution of 5.4 g of 4-amino-butyric acid, 3 g of sodium methylate and 15.4 g of the ketone obtained in the previous stage in 500 ml of methanol and 300 ml of alcohol is evaporated to dryness. 600 ml of alcohol are then added and the mixture is evaporated to dryness, finally working under reduced pressure. Repeat this action two more times. The residue is then dissolved in water which has been acidified to pH 4 with citric acid. It is extracted with chloroform, dried over magnesium sulfate, filtered and evaporated to dryness. The precipitate obtained is transferred to a frit using petroleum ether. It is recrystallized from ethyl acetate by treatment with vegetable charcoal. It is then dried in a desiccator with heating. F = 140 - 141 ⁰ C.

Example 4

4- {Ν - / »- (4'-chloro-phenyl) -5-fluoro-2-methoxy-benzylidenyjJ-amino) butyric acid amide

(Formula I: X ₁ = 5-F, X ₃ = 4'-Cl, X ₃ = X ₄ = H, R = NH ₃ , R ¹ = CH ₃ , η = 3)

A solution of 3.4 g of 4- {n- / δ6- (4'-chlorophenyl) -5-fluoro-2-hydroxy-benzylidenyl / -amino} butyric acid amide is evaporated and 0.55 g of sodium methylate in 150 ml of methanol to dryness.

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SYNTHELÄBO - SET 21.

23Q-7379

- 17 -

Then it is dried in a desiccator with heating to 120 ^° C. After cooling, the residue is dissolved in 100 ml of dimethyl sulfoxide, stirred and 3 g of methyl iodide in 25 ml of dimethyl sulfoxide are added dropwise to the stirred solution. The mixture is then stirred for 30 minutes at room temperature. It is evaporated to dryness under reduced pressure, the residue is dissolved in 200 ml of chloroform, washed with water, dried and evaporated to dryness. The residue is transferred to a Pritte with ether. The product is recrystallized from alcohol, washed with acetone and with ether, filtered off with suction and dried with heating in a desiccator. F = 154.5 - 155.5 ⁰ C.

In the following table I are further compounds of the general formula I prepared according to the invention specified.

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Table I.

link 5-NO ₂ ^X 2 ^X 3 ^X 4 η R. R ¹ F ( ⁰ C) 1 5-CH CONH
«3 H 4 ^J -C1 H 3 OH H 240 (decomp.) 2 5-CF- H H H 3 NH ₂ H 240 (decomp.) 3 5-CF ₃ H 4'-CF H 3 ONa H 238 (decomp.) 4th 5-CF ₃ H 3'-CF ₃ H 3 ONa H 218 (decomp.) 5 5-CF ₃ H 4.-CF ₃ H 3 NH ₂ H 119.6 6th 5-CF H 3'-CF ₃ H 3 NH ₂ H 98.7 7th 5-NO ₂ H 4 '-F H 3 OH
ONa H
H 173.5
> 250 8th 5-CF ₃ H 4'-Cl H 3 NH ₂ H 172.5 9 5-F H 41-ρ H 3 NH ₂ H 120.6 10 5-F H 4'-NO ₂ H 3 OH
ONa H
H 169-70
180 (decomp.) 11 5-CF 3 H 4'-NO ₂ H 3 NH ₂ H 190-1 12th CF H H H 3 OH
ONa H
H 154-5
216 (decomp.) 13th 5-C (CH ₃ ) ₃ H H H 3 NH ₂ H 93-94 14th 5-C (CH ₃ J ₃ H 4'-Cl H 3 OH H 140-1 15th 5-NO ₃ H 4'-Cl H 3 NH ₂ H 121-2 16 5-NO ₂ H H H 3 OH
ONa H
H 177-8
227 (decomp.) 17th 5-C (CH ₃ J ₃ H H H 3 NH ₂ H 185-6 18th 5-C (CH ₃ ) ₃ H H H 3 NH ₂ H 135-6 19th 5-Cl H H H 3 OH H 131-2 20th H 4'-Cl 2'-Cl 3 NH ₂ H 141-2

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SYNTHEIABO - SET 21

- 19 Table I (cont.)

link ^X l ^X 2 ^X 3 ^X 4 η R. R ' F ( ⁰ C) 21st 5-Cl H 4'-Cl 2'-Cl 3 OH H 172-4 ONa H 245 (decomp.) 22nd 5-F H 4'-CF ₃ H 3 fOH
Vh ₂ H
H 140-1
151-2 23 5-F H 4'-Cl H 3 NH ₂ CH ₃ 155 24 5-Cl H 4'-Br H 3 NH ₂ H 169-170 25th 5-Br H 4'-Cl H 3 NH ₂ H 156-157 26th 5-Br H H H 3 NH ₂ H 134-135 27 5-Br H 4'-Br H 3 NH ₂ H 164 _t 5-166.5 28 5-F H 2'-Cl H 3 OH H 85.5-87 29 5-Cl H 4'-Cl H 3 NH ₂ H 161-3 30th 5-Br H H H 3 ONa H 247-8 31 5-Br H 4'-Cl H 3 ONa H 230 32 5-Cl H 4'-Cl H 3 ONa H > 25O 33 5-Br H 4'-Br H 3 ONa H > 250 34 5-Cl H 4'-Br H 3 ONa H > 235 35 5-F H 4'-Cl H 2 ONa H > 240 36 5-F H 4'-Cl H 2 NH ₂ H 157-8 37 5-Cl Ξ H H 3 NH ₂ H 125-6 38 H H 2 '-CH 0 H 3 NH ₂ H 119-20 39 5-F H 4'-Cl H 1 OH H 167-8 40 5-F H 4'-Cl H 4th ONa H > 300 41 5-F H 4'-Cl H 3 OH H 98-9 42 5-F H 4'-Cl H 4th NH ₂ H 140-1 43 5-Cl H 4'-F H 3 NH ₂ H 140-1 44 5-Cl H 4'-F H 3 OH H 127-8

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link ^X l 5-F ^X 2 ^X 3 X
4th η R. R ¹ F ( ⁰ C) 45 5-Cl H 4'-CF3 H 3 ONa H > 250 46 5-Cl H 2'-Cl H 3 OH H 102 47 5-Br H 2'-Cl H 3 NH ₂ H 104 48 5-Br H 2'-Br H 3 NH ₂ H 133 49 5-Br H 2'-Br H 3 OH H 138 50 5-Br H 2'-Cl 4'-Cl 3 OH H 118-119 51 5-Br H 2'-Cl 4'-Cl 3 NH ₂ H 131-132 52 5-Br H 2'-Cl H 3 OH H 130-131 53 5-Cl H 2'-Cl H 3 NH ₂ H 125-126 54 3-Cl H 2'-Br H 3 NH ₂ H 118-119 55 3-d 5-Cl 2'-Cl H 3 NH ₂ H 135-136 56 5-Cl 2'-Cl H 3 OH H 149-150

The compounds according to the invention have been subjected to pharmacological studies which determine their activity on the central nervous system clarify.

The acute toxicity of the compounds was determined in the mouse when administered intraperitoneally. The DL ^ Q value (Lethal dose 50%), which stands for the dose that leads to death in 50% of the animals, varies from 700 to more than 1000 mg / kg.

The effect of the compounds according to the invention was over studied the antagonism to the mortality caused by the administration of bicuculline to mice.

Bicuculline is a relatively selective blocker for post-

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synaptic y-aminobutyric acid-ergic receptors, whose convulsive and lethal effects counteract compounds that reduce the y ~ -aminobutyric acid content of the brain increase, or which have a 3 ~ -aminobutyric acid-mimetic effect.

■ j ο The active dosages 50% (DA ™) of the investigated compounds were determined, that is, the dose which protects 50% of the animals against the effects of bicuculline. When administered intraperitoneally, the DA _{5Q values of the compounds according to} the invention vary from 20 to 80 mg / kg.

The compounds of the invention are active anticonvulsants Middle. They can therefore be used in human medicine and in veterinary medicine for the treatment of various Diseases of the central nervous system, for example for the treatment of psychoses and certain nervous diseases, like epilepsy.

The invention therefore also relates to medicaments which use the compounds of general formula I as active ingredients in combination with the usual binders, carrier materials and / or auxiliaries for their administration especially by the oral route (tablets, dragees, gel beads, capsules, lozenges and drinkable Solutions or suspensions) or parenteral routes are suitable.

The daily dose can range from 100 to 1500 ml.

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Claims (6)

PATENT LAWYERS TER MEER-MÜLLER-STEINMEISTER Representatives admitted to the European Patent Office - Professional Representative »before the European Patent Office Mandatalree agreed pres! 'Office europeen des brevets Dipi.-Chem. Dr. N. ter Meer Dipl.-Ing. H. Steinmeister Dipl.-Ing, F. E. Müller Triftstrasse 4, D-8OOO MUNICH 22 Siekerwall 7, 0-4800 BIELEFELD 1 Case: SET 21
tM / ei 2 8, fab, 1979 SYNTHELABO
1, Avenue de Villars 75341 Paris Cedex 07, France Benzylidene derivatives, process for their preparation and them containing medicinal products Priorities: February 27, 1978, France, No. 78 05578 July 13, 1978, France, No. 78 20940 PATENT CLAIMS 1 |. Benzylidene derivatives of the general formula I OR ¹ C = K - CH ₀ -CO-R I, η 2η 909836/0690 SYNTHELABO - SET .21 in the -X ₁ , X ₂ / X ₃ and X. independently of one another hydrogen atoms, halogen atoms, methyl groups, methoxy groups, nitro groups, trifluoromethyl groups, tert-buty groups or acetyl amino groups, - η is an integer with a value from 1 to 10, - R is a hydroxyl group, a group of the formula -OM ο (where M stands for an alkali metal atom), an amino group, a cycloalkylamino group, a phenylamino group, a benzylamino group, an alkylamino group, a dialkylamino group or an alkylbenzylamino group and
R ^{1 represents} a hydrogen atom or an alkyl group, the alkyl groups having 1 to 4 carbon atoms, with the exception of the compounds in which R ^{1 represents} a hydrogen atom when X ₁ , X ₂ and X ₃ independently represent hydrogen atoms, halogen atoms, methyl groups or methoxy groups and X _{4 is} a hydrogen atom and with the exception of the compound in which R ^{1 is} a hydrogen atom, X ₁ , X, and X. are hydrogen atoms, X "is a chlorine atom in the 5-position, η 1 and R is a hydroxyl group. 2. Compounds according to claim 1, characterized that η has the value 3 and R is a hydroxyl group, a group of the formula -OM (wherein M represents an alkali metal atom) or represents an amino group. 3. Compounds according to claim 1, characterized in that the group R ^{1 represents} a hydrogen atom. 4. Process for the preparation of the connections according to 909836/0690 SYNTHELABO - SET 21 290737S Claim 1, characterized in that that a ketone of the general formula II , 0H II ^X 2 J ^ " with a compound of the general formula III NH ₂ -C _n H _2n -COR III in which general formulas the groups X. / X ₂ , X ₃ X ₄ , η and R have the meanings given in claim 1, in the form of the base or the hydrochloride and, if desired, the resulting compound of the general formula I, in which R ^{1 represents} a hydrogen atom, is alkylated to form a compound of the general formula I in which R ^{1 represents} an alkyl group. 5. Medicines, marked thereby net that they contain at least one compound according to claims 1 to 3 as active ingredient and customary binders, carrier materials and / or auxiliaries. 6. Ketones of the general formula II 35 909836/0690 SYNTHELABQ - SET 21 II in the - X ₁ , X ", X, and X ₄ independently of one another are hydrogen atoms, halogen atoms, methyl groups, methoxy groups, nitro groups, trifluoromethyl groups, tert-butyl groups or acetylamino groups mean that represent, with the exception of the compounds of formula II ERAL ^NEN, in the Xw X ₂ and X, independently of one another hydrogen atoms, halogen atoms, methyl groups or methoxy groups if the group X ^ is a hydrogen atom. 909836/0690