FI79297C - Process for the preparation of pharmacologically active benzamide derivatives - Google Patents

Description

1 79297

Process for the preparation of pharmacologically active benzamide derivatives

The invention relates to an analogous process for the preparation of new pharmacologically active N- (2-aminoethyl) benzamide derivatives of the general formula (Ia) and their pharmaceutically usable acid addition salts, wherein R 11 is halogen, cyano or trifluoromethyl and R 21 is hydrogen or R 11 is hydrogen or are both chlorine or, when joined to adjacent carbon atoms, together form a methylenedioxy group.

Structurally related compounds are known, for example, from German Application 2,458,908, however, it has surprisingly been found that the compounds according to the invention have interesting and therapeutically useful pharmacodynamic properties which are less toxic. Namely, it has been shown in animal experiments that the compounds of formula (Ia) above, as well as their pharmaceutically usable acid addition salts, have monoamine oxidase (MAO) inhibitory properties.

U.S. Pat. Nos. 3,825,594, 3,823,134 and 2,785,200 also disclose benzamide derivatives very structurally related to the compounds of the invention which have a central nervous system depressant effect and which can be used as sedatives, hypnotics, anticonvulsants and sedatives. . The compounds of the invention, on the other hand, have monoamino oxidase inhibitory properties and are therefore suitable as antidepressants, i.e. stimulants.

The compounds of formula (Ia) are therapeutically useful, in particular in the treatment of depressive conditions and Parkinson's disease.

Halogen means four halogens, fluorine, chlorine, bromine and iodine. The term "leaving group" 10 means, within the scope of the present invention, groups known, such as halogen, preferably chlorine or bromine, arylsulfonyloxy, such as tosyloxy, alkylsulfonyloxy, such as mesyloxy or the like.

The term "pharmaceutically acceptable acid addition salt" includes salts of inorganic and organic acids, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, acetic acid, succinic acid, tartaric acid, tartaric acid, tartaric acid, salts. Such salts are readily prepared by one skilled in the art.

If the compounds of the formula I are disubstituted, the substituents are particularly preferably in either the 2,4- or 3,4-positions.

Particularly preferred compounds of formula I are: N- (2-aminoethyl) -p-chlorobenzamide, N- (2-aminoethyl) -p-fluorobenzamide, N- (2-aminoethyl) -p-bromobenzamide, N- (2-aminoethyl) -p-chlorobenzamide, -aminoethyl) -3,4-dichlorobenzamide and N- (2-aminoethyl) -2,4-dichlorobenzamide.

The compounds of formula (Ia) and their pharmaceutically acceptable acid addition salts are prepared according to the invention in such a way that 35 a) the compound of general formula (II) 3 79297 o

OF

I (II) s in which R11 and R21 are the same as above are reacted in the form of the free acid or a reactive functional derivative thereof with ethylenediamine, or b) a compound of general formula (III) 0

M

15 f | f ||, <IK> RX ^ <J3 * 4

No. 21 wherein R 11 and R 21 are the same as above, R 3 is hydrogen and R 4 is a leaving group such as methylsulfonyloxy is reacted with ammonia, or c) in a compound of general formula (IV): 0 • "β 5 25 \\\ H ( IV> wherein R11 and R21 are the same as above and R5 is a nitrogen-containing amino-convertable residue such as amide, especially t-butoxycarbonylamino, trichloroethoxycarbonylamino or benzyloxycarbonylamino, phthalimide, azide or hexamethylenetethanate, ammonium if desired, converting the resulting compound of formula 35 (Ia) into a pharmaceutically acceptable acid addition salt.

4 79297

Suitable reactive functional derivatives of the acid of the formula (II) are, for example, halides, for example chloride, symmetrical anhydrides or mixed anhydrides, esters, for example methyl ester, p-nitrophenyl ester or N-hydroxysuccinimide ester, azides or amides, for example imidides.

The reaction of an acid of formula (II) or a reactive functional derivative thereof with ethylenediamine according to variant a) of the above process can be carried out using conventional methods. Thus, for example, the free acid of formula (II) may be reacted with ethylenediamine in the presence of a condensing agent in an inert solvent. When a carbodiimide, for example dicyclohexylcarbodiimide, is used as a condensing agent, the reaction may be carried out in an alkane carboxylic acid ester such as ethyl acetate, an ether such as tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or hydrogen chloride such as methylene chloride or chloroform, aromatic or in xylene, acetonitrile or dimethylformamide at -20 ° C to room temperature, preferably at about 0 ° C. When phosphorus trichloride is used as the condensing agent, the reaction is preferably carried out in a solvent, for example pyridine, at a temperature of 0 ° C to the reflux temperature of the reaction mixture, preferably at about 90 ° C. In another embodiment of option a), ethylenediamine is reacted with another reactive functional derivative of an acid of formula (II) mentioned above. Thus, for example, a halide of an acid of formula (II), for example chloride, may be reacted with ethylenediamine at about 0 ° C in the presence of a solvent, for example diethyl ether.

Compounds of formula (III) wherein R 3 is hydrogen and R 4 is a leaving group include, for example, N- (2-haloethyl) benzamides such as N- (2-chloroethyl) benzamide, 79297 N- (2-methylsulfonylethyl) benzamide or N- (2-p-toluenesulfonylethyl) benzamide or the like.

According to option b), the compound of formula (III) can be reacted in a known manner with ammonia at a temperature of -40 ° C to 50 ° C, if desired in the presence of a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like. In the presence of a solvent, it is preferable to work at about room temperature.

The conversion of the residue R5 to the amino takes place according to option c) in a known manner depending on the quality of the residue R5. If this is an amide, the conversion is conveniently carried out by acidic or basic hydrolysis. For acid hydrolysis, a mineral acid poly solution such as hydrochloric acid, aqueous hydrogen bromide, sulfuric acid, phosphoric acid or the like in an inert solvent such as an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxane is preferably used. Aqueous solutions of alkali metal hydroxides such as potassium or sodium hydroxide can be used for basic hydrolysis. In addition, the inert organic solvents mentioned above in connection with acid hydrolysis can be used as solvents. The reaction temperature in both acidic and basic hydrolysis can range from room temperature to reflux temperature, preferably at or slightly below the boiling point. If R5 is phthalimido, in addition to acidic and basic hydrolysis, aminolysis can also be performed with an aqueous solution of a simple alkylamine such as methylamine or ethylamine. As the organic solvent, a simple alkanol such as ethanol can be used. This reaction is preferably carried out at room temperature. In a third process for converting phthalimide to amino, the compounds of formula (IV) are reacted with hydrazine in an inert solvent such as ethanol, a mixture of ethanol and chloroform, tetrahydrofuran or aqueous ethanol. The reaction temperature may range from room temperature to about 100 ° C, but it is preferable to work at the boiling temperature of the selected solvent. The resulting product can be extracted with dilute mineral acid and recovered by basifying the acidic solution.

Acidic conditions are conveniently achieved by carrying out the reaction in acetic acid with or without another inert solvent such as an alcohol, for example methanol. The benzyloxycarbonylamino residue can be converted into an amino group in a known manner either by the acid hydrolysis described above or hydrogenolytically. The azido group can be reduced to the amino group in a known manner, for example, with elemental hydrogen in the presence of a catalyst such as palladium / carbon, Raney nickel, platinum oxide or the like. The hexamethylenetetraammonium group can likewise be converted into an amino group by acid hydrolysis according to a known method.

The compounds of formula (II) or their reactive functional derivatives used as starting materials in option a) are known or can be obtained analogously to the preparation of known compounds.

The compounds of formula (III) used as starting materials in option b) are likewise known or can be prepared analogously to known compounds and can be prepared by methods known per se. Thus, for example, to prepare compounds of formula (III) wherein R 3 is hydrogen and R 4 is a leaving group, a compound of formula (II) or a reactive functional derivative thereof may be reacted with ethanolamine under the reaction conditions given in option 35 a) and the resulting N - (2-hydroxyethyl) benzamide 7 79297 to the desired compound of formula (III) in a manner known per se, for example by reaction with a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride or the like, arylsulphonyl halide, alkyl alkyl halide .

The compounds of formula (IV) used as starting materials in option c) are also known or can be prepared by a preparation method known per se. Thus, for example, a compound of formula (II) or a reactive functional derivative thereof may be reacted with a compound of general formula (V) under the reaction conditions given in option a) H2 N-CH2 -CH2 -R5 (V) wherein R5 is the same as above .

The compounds of formula (V) are known or can be prepared analogously to known methods for the preparation of compounds.

Alternatively, compounds of formula (IV) wherein R 5 is phthalimido, azido or hexamethylenetetrammonium can be obtained by reacting a compound of formula (III) with phthalimidic acid, an alkali metal azide or hexamethylenetetramine. The reaction is carried out in a manner known per se under the reaction conditions given in option b).

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts have - as previously mentioned - monoamine oxidase (MAO) inhibitory activity. Because of this activity, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used in the treatment of depressive conditions and Parkinson's disease.

The MAO inhibitory effect of the compounds of the invention can be determined using standard methods. Thus, test preparations were administered orally to rats. Two hours later, the animals were sacrificed, and the inhibitory effect of MAO on brain and liver homogenates was measured by the method described in Biochem. Pharmacol. 12 (1963) 1439-1441, with the difference that phenethylamine (2.10 "5 Mol.l" 1) has been used as a substrate instead of tyramine. The observed activities of some of the compounds of the invention, as well as their toxicity, are evident from the ED50 (pmol) / kg / oral rat) or LD50 (mg / kg, oral mouse) values shown in the table below. The last two compounds were not assigned an ED50 value (i.e., the dose required to produce a 50% MAO inhibitory effect), but instead were determined to have a% inhibitory effect in% at a dose of 100 pmol / kg p.o.

Compound EDS 0 LD5 0 20 N- (2-aminoethyl) -p-chlorobenzamide 5.5 1000-2000 N- (2-aminoethyl) -p-fluorobenzamide 4> 5000 N- (2-aminoethyl) -3,4-25 bromobenzamide 4,500-1000 N- (2-aminoethyl) -3,4-dichlorobenzamide 10.3 1000-2000 N- (2-aminoethyl) -2,4-dichlorobenzamide 1.5 625-1250 30

Compound% inhibition LP · 0 (100 pmol / kg) N- (2-aminoethyl) -α, o, α-trifluoro-4-toluamide 61.1 625-1250 35 N- (2-aminoethyl) -4- cyanobenzamide 28.1> 5000 g 79297

The compounds of formula (I) as well as their pharmaceutically acceptable acid addition salts can be used, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, as tablets, litmus tablets, granules, hard or soft gelatine capsules, solutions, emulsions or suspensions. The dosage can also be carried out rectally, for example, suppositories, or parenterally injectable solutions.

For the preparation of tablets, litmus tablets, granules and hard gelatine capsules, the compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used together with inert inorganic or organic additives. Lactose, corn starch or derivatives thereof, talc, stearic acid or their salts, etc. can be used as such additives in the manufacture of tablets, granules and hard gelatine capsules.

Suitable additives for the preparation of soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

Suitable additives for the preparation of solutions and syrups are, for example, water, polyols, sucrose, inert sugar, glucose, etc.

Suitable additives for injectable solutions are, for example, water, polyols, glycerin, vegetable oils, etc.

Suitable additives for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or flowable polyols, etc. The pharmaceutical preparations can additionally contain preservatives, solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, flavoring agents, buffers, coatings or antioxidants. They may also contain other therapeutically valuable substances.

According to the invention, the compounds of general formula (I) 10 79297 and their pharmaceutically acceptable acid addition salts can be used for the treatment of depressive conditions and Parkinson's disease. The dosage can vary widely and will, of course, be fitted to the circumstances in each particular case. In general, when administered orally, the daily dose of a compound of general formula (I) may be about 10 to 100 mg, however, this upper limit may also be exceeded if necessary.

The following examples illustrate the present invention without, however, limiting it in any way. All temperatures are given in degrees Celsius.

Example 1 18.5 g of 4-chlorobenzoic acid ethyl ester and 24 g of ethylenediamine are stirred for 17 hours at 130 ° C. The reaction mixture is cooled to room temperature, concentrated and the residue is diluted with 200 ml of ethyl acetate. Insoluble N, N'-ethylenebis (4-chlorobenzamide) (2.3 g) m.p. 266-268 ° C, filtered and washed three times with 50 ml of water and concentrated by evaporation. 100 ml of 1N hydrochloric acid are added to the residue and insoluble N, N'-ethylenebis (4-chlorobenzamide) (1.0 g) is filtered off and the filtrate is evaporated to dryness. The residue is then evaporated to dryness twice by adding 25 ml of ethanol-benzene each time and recrystallized from ethanol-ether. 13.7 g of N- (2-aminoethyl) -4-chlorobenzamide / 1 hydrochloride are obtained, m.p. 216-217 ° C.

Example 2 9.25 g of 4-chlorobenzoic acid ethyl ester and 16.0 g of N- (t-butoxycarbonyl) ethylenediamine are stirred for 15 hours at 130 ° C. The reaction mixture is cooled to room temperature, taken up in 100 ml of water and extracted three times with 50 ml of ethyl acetate. The ethylene acetate extract is washed twice with 50 ml of water, dried over sodium sulfate and evaporated to dryness. The crystalline residue is taken up in isopropyl ether and filtered. 3.9 g of t-butyl [2- (4-chlorobenzamido) ethyl] carbamate are thus obtained, m.p. 141-143 ° C.

A solution of 2.8 g of t-butyl [2- (4-chlorobenzamido) ethyl] carbamate in 50 ml of formic acid is allowed to stand for 1.5 hours at room temperature. The reaction mixture is then evaporated to dryness and the residue is dissolved in 50 ml of hydrochloric acid (1: 1; v / v). The solution is evaporated and evaporated twice to dryness with ethanol-benzene and the residue is recrystallized from ethanol-10. 2.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are thus obtained, which is identical to the product obtained in Example 1.

Example 3

To a suspension of 23.5 g (0.15 mol) of 4-chloro-15-benzoic acid and 15 ml (0.16 mol) of chloroformic acid ethyl acetate in 200 ml of chloroform are added dropwise at 0 ° C 23 ml ( 0.17 mol) of triethylamine. After the addition (½ hours), the solution obtained is added dropwise at 0 [deg.] C. to a solution of 50 ml (0.75 mol) of ethylenediamine 100 in 20 ml of chloroform. After completion of the reaction, 115 ml of concentrated hydrochloric acid are added dropwise at 0 ° C. The acidic mixture is filtered and the remaining neutral portion is separated by extraction with chloroform. The aqueous phase is then made alkaline with sodium hydroxide and extracted several times with chloroform. The chloroform phases are dried and evaporated. The residue is converted into the hydrochloride and recrystallized from ethanol ether. The yield is 15.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, m.p. 212-214 ° C. The free base melts at 43-45 ° C.

Example 4 19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and brought into solution by adding 15.3 ml (0.11 mol) of triethylamine. 10 ml (0.1 mol) of chloroformic acid ethyl ester are then added dropwise at 0 ° C. After the complete addition of i2 79297 (½ hours), the mixture is poured into a mixture of ice and water. The methylene chloride phase is separated off, dried over magnesium sulphate and evaporated to about 30 ml. This solution is added dropwise at 0 [deg.] C. to a solution of 20 ml (0.3 mol) of ethylenedi-5-amine in 100 ml of tetrahydrofuran. After the addition is complete (½ hours), the filtrate is filtered and the filtrate is acidified with dilute hydrochloric acid and the neutral portion is separated by extraction with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide and extracted several times with chloro-10 form. After drying and evaporation of the chloroform phase, the residue is converted into the hydrochloride. After recrystallization from ethanol-ether, the yield is 7.1 g of N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride, m.p. 179-181 ° C.

15 Example 5

To a suspension of 5.4 g (0.04 mol) of 4-methoxybenzoic acid in 60 ml of chloroform is added dropwise at 10 ° C 5.5 ml (0.04 mol) of triethylamine, followed by 3.8 ml of (0.04 mol) of ethyl chloroacetic acid. The resulting reaction solution is then added dropwise at 5 ° C to a solution of 10.7 ml (0.16 mol) of ethylenediamine in 100 ml of chloroform. The mixture is stirred for two hours at room temperature, then filtered. The filtrate is evaporated under reduced pressure and then the excess ethylenediamine is removed in vacuo. The residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase is made alkaline with 28% NaOH and extracted three times with chloroform. After drying and evaporation of the chloroform extract, the residue is converted into hydro-30 chloride. After recrystallization from ethanol ether, 3.4 g of N- (2-aminoethyl) -4-anisamide dihydrochloride (cf. Example 7 in German Application 2,616,486) are obtained, m.p. 186-189 ° C. The free base melts at 37-38 ° C (not a compound of the invention).

In a manner analogous to that described above, 9.179297 are prepared starting from 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid, 9.1 g of N- (2-aminoethyl) -3,4-dichlorobenzamide. -hydrochloride, m.p. 183-185 ° C; the free base melts at 98-100 ° C.

Example 6 11.8 g (0.08 mol) of 4-cyanobenzoic acid are reacted with triethylamine and chloroformic acid ethyl ester according to Example 7 and then added dropwise to a solution of 21.4 ml of ethylenediamine 350 in 10 ml of chloroform. 45 ml of diethylformamide are then added to the reaction mixture and the mixture is heated at 60 [deg.] C. for 1 hour. After filtration, the filtrate is evaporated and the residue is treated in the same manner as in Example 5. The yield is 3.5 g of N- (2-aminoethyl) -4-cyanobenzamide hydrochloride, m.p. 212-215 ° C (dec.). The free base melts at 124-125 ° C.

Starting from 4.5 g (0.023 mol) of 4-trifluoromethylbenzoic acid, 3.1 g of N- (2-aminoethyl) -α, α, g-trifluoro-4-toluamide hydrochloride, m.p. 196-199 ° C; the free base melts at 66-68 ° C.

20 Example 7

To a solution of 10 mL (0.15 mol) of ethylenediamine in 150 ml of ether is added dropwise at -10 ° C for half an hour, a solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride in 150 ml of in ether. The mixture is allowed to warm to room temperature, filtered and the white residue is washed twice with ether. After evaporation of the ether solution, the residue is acidified with dilute hydrochloric acid and extracted with ethyl acetate several times to separate the neutral portion. The aqueous phase is made alkaline with NaOH and extracted several times with chloroform. After evaporation of the chloroform, the residue is converted into the hydrochloride and recrystallized from ethanol ether to give 1.8 g of N- (2-aminoethyl-11) -4-chlorobenzamide hydrochloride, which is identical to the product obtained in Example 1.

14 79297

In an analogous manner, starting from 7 ml (0.05 mol) of 2,4-dichlorobenzoyl chloride, 1.7 g of N- (2-aminoethyl) -2,4-dichlorobenzamide / hydrochloride with a melting point of 178-179 ° C are obtained and which is identical to the product obtained in Example 5 4.

Example 8 7 g (0.039 mol) of 3,4-methylenedioxybenzoic acid methyl ester and 8.5 ml (0.126 mol) of ethylenediamine are heated for 2 hours at 100 ° C (bath temperature). After cooling, excess ethylenediamine is removed in vacuo. The residue is acidified with dilute hydrochloric acid and extracted with chloroform. The aqueous phase is made alkaline with NaOH and then extracted several times with chloroform. After evaporation of the solvents, the residue is recrystallized from chloroform-hexane to give 3.4 g of N- (2-aminoethyl) -1,3-benzodioxole-5-carboxamide, m.p. 120-123 ° C. The hydrochloride melts at 210-213 ° C.

Example 9 10.7 g (0.05 mol) of 4-bromobenzoic acid methyl ester 20 and 10.4 ml (0.15 mol) of ethylenediamine are heated for 30 minutes at 130 ° C (bath temperature). Working analogously according to the procedure described in Example 8 and recrystallizing from methanol ether, 6.5 g of N- (2-aminoethyl) -4-bromobenzamide hydrochloride are obtained, m.p. 229-232 ° C.

Example 10 7.7 g (0.05 mol) of 4-fluorobenzoic acid methyl ester and 10 ml (0.15 mol) of ethylenediamine are heated for two hours at 130 ° C (bath temperature). The reaction mixture is poured into a mixture of ice and hydrochloric acid and extracted with ethyl acetate to separate the neutral portion. The aqueous phase is made alkaline with NaOH and extracted several times with chloroform. After drying and evaporation of the chloroform extracts, the residue (7.6 g) is recrystallized from ethyl acetate from hexane to give N- (2-aminoethyl) -4-fluoro-IS 79297 benzamide, m.p. 57-60 ° C. The hydrochloride melts at 214-216 ° C.

Example 11

To a solution of 1.02 g (0.01 mol) of acetylethylenediamine (see J. Amer. Chem. Soc. 61, 822 (1939)) and 1.4 ml (0.01 mol) of triethylamine in 25 ml: chloroform, a solution of 1.3 ml (0.01 mol) of 4-chlorobenzoyl chloride in 15 ml of chloroform is added dropwise at 0 ° C. After 15 minutes, the crystals formed are filtered off, washed with chloroform and dried. Yield 1.9 g of N-acylaminoethyl) -4-chlorobenzamide, m.p. 222-224 ° C.

To decompose the protecting group, the resulting N- (2-acetylaminoethyl) -4-chlorobenzamide is heated for 22 hours in a mixture of 24 ml of 2N hydrochloric acid and 15 ml of ethanol-15. The reaction solvent is evaporated and the crude product is recrystallized from ethanol ether. The yield is 1.2 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, m.p. 211-213 ° C, which is identical to the product obtained in Example 1.

Example 12 To a solution of 1.2 ml (0.02 mol) of ethanolamine and 3 ml (0.02 mol) of triethylamine in 30 ml of methylene chloride are added dropwise at 0 ° C 2.6 ml ( 0.02 mol) of 4-chlorobenzoyl chloride. The mixture is then poured into dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extracts are dried over magnesium sulfate and evaporated. They are then purified using Kieselgel and using chloroform and chloroform / methanol 9: 1 as eluent to give 3.1 g of N- (2-hydroxyethyl) -4-chlorobenzamide.

To a solution of 1.5 g (0.0075 mol) of N- (2-hydroxyethyl) -4-chlorobenzamide and 1 ml of triethylamine in 15 ml of methylene chloride is added dropwise at 0 ° C a solution of 0 .6 ml of methanesulfonic acid chloride in 3 ml of methylene chloride. After 15 minutes, the mixture is poured into water-ice and extracted. Santo is 2.1 g of N- (2- [79,797 methylsulfonyloxyethyl) -4-chlorobenzamide in crystalline form, which is used for further mucus purification for the following lie.

The prepared N- (2-methylsulfonyloxyethyl) -4-5 chlorobenzamide is dissolved in 5 ml of dimethylformamide and added dropwise at room temperature to a solution of ammonia in dimethylformamide. After stirring for 2 hours, N- (2-aminoethyl) -4-chlorobenzamide is obtained, which is identical to the product 10 obtained in Example 1.

Claims (4)

An analogous process for the preparation of new pharmacologically active N- (2-aminoethyl) -5-benzamide derivatives of the general formula (Ia) and their pharmaceutically usable acid addition salts, wherein R 11 is halogen, cyano or trifluoromethyl and R21 is hydrogen or R11 and R21 are both chlorine or, when joined to adjacent carbon atoms, together form a methylenedioxy group, characterized in that a) a compound of general formula (II) 20: wherein R11 and R21 are as defined above, are obtained react in the form of a free acid or a reactive functional derivative thereof with ethylenediamine, or b) a compound of general formula (III):: /.1 v '- · 35 n R3 R4 (III> 35. r21 ie 79297 wherein R11 and R21 are the same as above, R 3 is hydrogen and R 4 is a leaving group such as methylsulfonyloxy is reacted with ammonia, or c) in a compound of general formula (IV) ¾. ! wherein R11 and R21 are the same as above and R5 is a nitrogen-containing amino-convertable residue such as amide, especially t-butoxycarbonylamino, trichloroethoxycarbonylamino or benzyloxycarbonylamino, phthalimide, azide or hexamethylene tetraammonium a compound of formula (Ia) as a pharmaceutically acceptable acid addition salt. Process according to Claim 1, characterized in that the starting material used is a compound of the formula (II), (III) or (IV) in which R 11 is chlorine and R 21 is hydrogen. Process according to Claim 1, characterized in that the starting material used is a compound of the formula (II), (III) or (IV) in which R 11 is fluorine and R 21 is hydrogen. Process according to Claim 1, characterized in that the starting material used is a compound of the formula (II), (III) or (IV) in which R 11 and R 21 are both chlorine and R 21 is in position 2. 19 79297