DK166382B - BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR PRODUCTS CONTAINING THESE - Google Patents

Description

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The present invention relates to novel benzamide derivatives, more particularly N-aminoethyl-substituted benzamides, which are characterized in that they have the general formula 50 ΛΎ '·' - '(I) 10 in which R 1 cyano or trifluoromethyl, and R 2 represents hydrogen or R 1 and R 2 individually represent chlorine or, when adjacent, together represent a methylenedioxy group, or are pharmaceutically useful acid addition salts thereof.

In animal studies, it has been found that the compounds of the above formula I as well as their pharmaceutically useful acid addition salts have monoamine oxidase (MAO) inhibitory properties.

The present invention further relates to medicaments containing a compound of general formula I or a pharmaceutically useful acid addition salt thereof, an antidepressant or anti-Parkinson's agent containing a compound of general formula I or a pharmaceutically useful acid addition salt thereof, and a process for the preparation of the compounds of this invention or their pharmaceutically useful acid addition salts.

The term "halogen" used in the present specification comprises the four halogens fluorine, chlorine, bromine and 30 iodine. The term "leaving group" in the sense of the present invention means known groups or substituents, e.g. halogen, preferably chlorine or bromine, arylsulfonyloxy, e.g. tosyloxy, and alkylsulfonyloxy, e.g. mesyl-oxy.

The term "pharmaceutically useful acid addition salts" includes salts with inorganic and organic acids, 2

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eg. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, citric, formic, maleic, acetic, succinic, tartaric, methanesulfonic and p-toluenesulfonic acids. Such salts can be readily prepared by any skilled person in view of the state of the art and having regard to the nature of the compound to be converted to a salt.

Preferred compounds of formula I are those wherein R 1 is halogen, cyano or trifluoromethyl, and R 2 is hydrogen or R 1 and R 2 are each chlorine.

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

The compounds of formula I or their pharmaceutically useful acid addition salts can be prepared according to the invention by a) a compound of the general formula

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<RTI ID = 0.0> / C - OH (XI) </RTI> in il in which R 1 and R 2 have the above meaning, in the form of the free acid or in the form of a reactive functional derivative thereof, reacted with ethylenediamine or b) a compound with the general formula 0

II

<IJI> 35! " 14

r1 / .. V

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wherein R 2 and R 2 are as defined above, R 3 is hydrogen and R 4 is a leaving group, or R 3 and R 4 together form a further bond, react with ammonia, or c) in a compound of the general formula In which R 1 and R 2 have the above meaning and R 5 represents a group which can be converted to an amino group, the group R 5 converts to the amino group, whereupon an resulting compound is optionally converted into a pharmaceutical. usable acid addition salt.

As reactive functional derivatives of the acids of formula II, e.g. halides such as chlorides, symmetrical or mixed anhydrides, esters, e.g. methyl esters, p-nitrophenyl esters or N-hydroxy-succinimide moieties, azides and amides, e.g. considering imidazolides, or succinimides.

The reaction of an acid of formula II or of a reactive functional derivative thereof with ethylenediamine according to variant a) of the above process can be carried out according to conventional methods. Thus, e.g. a free acid of formula II is reacted with ethylene diamine in an inert solvent in the presence of a condensing agent. If a condensing agent is used a carbodiimide, e.g. dicyclohexylcarbo diimide, the reaction is conveniently carried out in an alkane carboxylic acid ester, e.g. ethyl acetate, an ether, e.g. tetrahydrofuran or dioxane, a chlorinated hydrocarbon, e.g. methylene chloride or chloroform, an aromatic hydrocarbon, e.g. benzene, toluene or xylene, acetonitrile or dimethylformamide at a temperature 10 4

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between approx. -20 ° C and room temperature, preferably at ca. 0 ° C. If phosphorus trichloride is used as a condensing agent, the reaction is conveniently carried out in a solvent, e.g. pyridine, at a temperature between ca. 0 ° C and the reflux temperature of the reaction mixture, preferably at ca. 90 ° C. In another embodiment of variant a), ethylenediamine is reacted with one of the further above reactive functional derivatives of an acid of formula II. Thus, e.g. a halide, e.g. the chloride, of an acid of formula II at ca. 0 ° C is reacted with ethylenediamine in the presence of a solvent, e.g. diethyl ether.

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The compounds of formula III in which R

4 represents hydrogen and R represents a leaving group, 15 are, for example, N- (2-haloethyl) benzamides, e.g.

N- (2-chloroethyl) -benzamides, N- (2-methylsulfonylethyl) -benzamides or N- (2-p-toluenesulfonylethyl) -benzamides.

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The compounds of formula III, in which R and R together form an additional bond, are benzoyl aziridines such as p-chlorobenzoyl aziridine.

According to variant b), a compound of formula III can be reacted with ammonia in a manner known per se at a temperature between ca. -40 ° C and 50 ° C, optionally in the presence of a solvent, e.g. dimethylformamide, dimethylacetamide or dimethylsulfoxide. Appropriate work is done in the presence of a solvent at about room temperature. If a benzoyl aziridine of formula III is used, preferably in the presence of an inert solvent, e.g.

Dimethylformamide, toluene or benzene.

The conversion of the group R5 to an amino group of variant c) also occurs in a manner known per se, depending on the nature of group R5. If this is an amide, the conversion is conveniently carried out by acidic or basic hydrolysis.

For the acidic hydrolysis, a solution of a mineral acid is advantageously used, e.g. hydrochloric acid, aqueous hydrogen bromide, 5

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sulfuric or phosphoric acid, in an inert solvent such as an alcohol, e.g. methanol or ethanol, or an ether, e.g. tetrahydrofuran or dioxane. For the basic hydrolysis, aqueous solutions of alkali metal hydroxides, e.g. potassium or sodium hydroxide solution. As solvent aids, the inert organic solvents mentioned above may be added in connection with the acid hydrolysis. The reaction temperature can be varied by acidic and basic hydrolysis within a range from about room temperature to reflux temperature, preferably working at the boiling temperature of the reaction mixture or slightly below. If R5 is a phthalimido group, in addition to the acidic and basic hydrolysis, an aminolysis with an aqueous solution of a lower alkylamine, e.g. methylamine or ethylamine. As an organic solvent, a lower alkanol, e.g. ethanol. This reaction is preferably carried out at room temperature. A third method of converting phthalimido to amino 20 consists in reacting compounds of formula IV with hydrazine in an inert solvent, e.g. ethanol, a mixture of ethanol and chloroform, tetrahydrofuran or aqueous ethanol. The reaction temperature can be varied within a range of from about room temperature 25 to approx. 100 ° C, preferably operating at the boiling temperature of the selected solvent. The resulting product can be shaken with dilute mineral acid and then obtained by basing the acidic solution. The t-butoxycarbonylamino group is conveniently converted to the amino group with trifluoroacetic acid or formic acid in the presence or absence of an inert solvent at about room temperature, while the conversion of the trichloroethoxycarbonylamino group occurs with zinc or cadmium under acidic conditions. The acidic conditions are conveniently obtained by the reaction being carried out in acetic acid in the presence or absence of a further indifferent

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pure solvent such as an alcohol, e.g. methanol. The benzyloxycarbonylamino group can be converted to the amino group in known manner by acid hydrolysis as described above or hydrogenolytic. For example, an azido group may be reduced, for example, to the amino group with elemental hydrogen in the presence of a catalyst, e.g. palladium / coal, Raney nickel or platinum oxide. A hexa-methylenetetraammonium group can also be converted to the amino group by acidic hydrolysis by known methods.

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

The compounds of formula III used in variant b) are also known or analogous to known compounds and can be prepared in a manner known per se. Thus, for example, for the preparation of compounds of formula III in which R 4 represents 20 hydrogen and R represents a leaving group, a compound of formula II, or a reactive functional derivative thereof, can be reacted with ethanolamine under the reaction conditions indicated for variant a) whereupon the resulting N- (2-hydroxyethyl) benzamide is obtained in a manner known per se, e.g. by reaction with a halogenating agent, e.g. phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride or phosphorus oxychloride, an arylsulfonyl halide, e.g. tosyl chloride, or an alkylsulfonyl halide, e.g. mesyl chloride is converted to the desired compound of formula III. A compound of formula III in which R and R together represent an additional bond may e.g. is obtained by reacting a reactive functional derivative of a compound of formula II with ethyleneimine. The reaction may proceed under the reaction conditions specified for variant a).

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The compounds of formula IV used in variant c) are also known or analogous to known compounds and can be prepared in a manner known per se. Thus, for example, a compound of formula II or a reactive functional derivative thereof under the reaction conditions specified for variant a) can be reacted with a compound of the general formula

, o h2n-ch2-ch2-r5 V

in which R 1 has the above meaning. The compounds of formula V are known compounds or can be obtained analogously to the preparation of the known compounds. -

According to an alternative method, the compounds of formula IV wherein R is phthalimido, azido or hexamethylenetetraammonium can also be obtained by reacting a compound of formula III with phthalimide potassium, an alkali metal azide or hexamethylene tetramine. The reaction is carried out in a manner known per se under the reaction conditions specified for variant b).

The compounds of formula I and their pharmaceutically useful acid addition salts have - as already mentioned above - monoamine oxidase (MAO) inhibitory activity. Because of this activity, the compounds of formula I and their pharmaceutically useful acid addition salts can be used to treat depressive conditions and Parkinsonism.

The MAO inhibitory activity of the compounds of this invention can be determined using standard methods.

Thus, the preparations to be tested are administered orally to rats. Two hours later, the animals are killed and the MAO inhibitory activity is measured in homogenates of the brain and liver according to that of Biochem. Pharmacol. 12 (1963) 35 1439-1441 but using phenethylamine (2 * 10 moles) as substrate instead of

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Tyramine. The activity thus obtained of some of the compounds of this invention as well as their toxicity can be seen in the following ED ED values (pnol / kg, p.o. in rat) or LD5Q values (mg / kg, p.o. in mice):

Compound ED, LDC

YOU

N- (2-Aminoethyl) -p-chlorobenzamide 5.5 1000-2000 N- (2-Aminoethyl) -p-fluorobenzamide 4> 5000 N- (2-Aminoethyl) -p-bromobenzamide 4 500-1000 N- (2-Aminoethyl) -3,4-dichloro-benzamide 10.3 1000-2000 N- (2-Aminoethyl) -2,4-dichlorobenzamide 1.5 625-1250 -

The compounds of formula I or their pharmaceutically useful acid addition salts can be used as solvent, e.g. in the form of pharmaceutical preparations.

The pharmaceutical compositions may be administered orally, e.g. in the form of tablets, lacquer tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration may also be done rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

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For the preparation of tablets, lacquer tablets, dragees and hard gelatin capsules, the compounds of formula I or their pharmaceutically useful acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients. As such extenders, e.g. for tablets, dragees and o 9

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Hard gelatin capsules are used for lactose, corn starch or derivatives thereof, talc, stearic acid or the salts thereof.

For soft gelatin capsules, as extenders, e.g. vegetable oils, waxes, grease and semi-solid and liquid polyols are suitable.

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For the preparation of solutions and syrups, e.g. water, polyols, sucrose, invert sugar and glucose suitable as extenders.

For injection solutions, e.g. water, alcohols, polyols, glycerol and vegetable oils suitable as excipients.

For suppositories, e.g. natural or hardened oils, waxes, greases, semi-liquid or liquid polyols suitable as extenders.

In addition, the pharmaceutical compositions may also contain preservatives, solvents, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, aromatizers, salts for changing the osmotic pressure, buffering agents, coating agents or antioxidants. The compositions may also contain other therapeutically valuable substances.

As mentioned, compounds of the general formula I or their pharmaceutically useful acid addition salts can be used to control or prevent depressive conditions and Parkinsonism. The dosage can be varied within wide limits and must, of course, in each case be adapted to the individual conditions. In general, a daily dose of approx. From 10 to 100 mg of a compound, the general formula I by oral administration is recommended to be appropriate, however, the upper limit just specified may also be exceeded if this proves advisable.

The following examples further illustrate the invention.

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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 and evaporated and added

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200 ml of ethyl acetate for the residue. The insoluble N, N'-ethylene bis (4-chlorobenzamide) (2.3 g), m.p. 266-268 ° C, are separated by Nutsch filtration and the filtrate is washed three times with 50 ml of water each time and evaporated. 10 100 ml of 1 N hydrochloric acid are added to the residue, the insoluble N, N'-ethylenebis (4-chlorobenzamide) (1.0 g) is separated by Nutsch filtration and the filtrate is evaporated to dryness. The residue is then evaporated twice with 100 ml of ethanol / benzene each time and recrystallized from a mixture of ethanol and ether. 13.7 g of N- (2-aminoethyl) -4-chlorobenzamide 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 each time. The ethyl acetate extract is washed twice with 50 ml of water each time, dried over sodium sulfate and evaporated to dryness. The crystalline residue is taken up in isopropyl ether and separated by Nutsch filtration. 3.9 g of t-butyl * [2- (4-chlorobenzamido) ethyl] carbamate are obtained, m.p. 141-143 ° C.

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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, after which it is again evaporated twice with ethanol / benzene, and o

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The residue is recrystallized from ethanol. 2.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride is obtained, which is identical to the product obtained in Example 1.

Example 3

To a suspension of 23.5 g (0.15 mole) of 4-chlorobenzoic acid and 15 ml (0.16 mole) of chloroformic acid ethyl ester in 200 ml of chloroform is added, dropwise 23 ml 10 (0.17 mole) at 0 ° C. triethylamine. After the addition is complete (1/2 hour), the resulting solution is added dropwise at 0 ° C to a solution of 50 ml (0.75 mol) of ethylenediamine in 100 ml of chloroform. At the end of the reaction, 115 ml of concentrated hydrochloric acid are added dropwise at 0 ° C. The acid mixture is filtered and the remaining neutral constituents are removed by chloroform extraction. The aqueous phase is then made alkaline with sodium hydroxide solution and extracted several times with chloroform. The chloroform extracts are dried and evaporated.

The residue is converted to the hydrochloride and recrystallized from a mixture of ethanol and ether. 15.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained, m.p. 212-214 ° C. The free base melts at 43-45 ° C.

Example 4 19.1 g (0.1 mole) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and dissolved by the addition of 15.3 ml '(0.11 mole) of triethylamine. Then, at 0 ° C, 10 ml (0.1 mol) of chloromyric acid ethyl <5u ester is added dropwise. After the addition is complete (1/2 hour), pour into a mixture of ice and water. The methylene chloride phase is separated, dried over magnesium sulfate and evaporated to ca. 30 ml. This solution is added dropwise at 0 ° C to a solution of 20 ml (0.3 mol) of ethylenediamine in 100 ml of tetrahydrofuran. After the addition is complete- o

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12t (1/2 hour), filter, and after acidifying the filtrate with dilute hydrochloric acid, the neutral constituents are removed by extraction with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After drying and evaporation of the chloroform phases, the residue is converted to the hydrochloride. After recrystallization from a mixture of ethanol and ether, 7.1 g of N- (2-aminoethyl) -2,4-dichloro-benzamide hydrochloride is obtained, m.p. 179-182 ° C.

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Example 5

To a suspension of 23.5 g (0.15 mol) of 2-chloro-benzoic acid in 200 ml of chloroform is added dropwise at 10 ° C 22.1 ml (0.16 mol) of triethylamine. Then 14.8 ml (0.155 mol) of chloroformic acid ethyl ester are added dropwise at the same temperature. After the addition is complete (1 hour), the reaction mixture is poured into a mixture of ice and water. The chloroform phase is separated, dried over magnesium sulfate and gently evaporated to ca. 60 ml. The solution thus obtained is added dropwise at 10 ° C to a solution of 40.1 ml (0.6 mole) of ethylenediamine in 400 ml of chloroform. After the addition is complete, the heavily soluble neutral constituents are separated by filtration and the filtrate is evaporated and freed in high vacuum for excess ethylenediamine. The resulting residue (31.5 g) is converted to the hydrochloride and further purified by recrystallization from a mixture of ethanol and ether. 19.2 g of N- (2-aminoethyl) -2-30 -chlorobenzamide hydrochloride (cf. Example 6 of German Publication No. 2,362,568) are obtained with m.p. 155-158 ° C.

An analyzer sample melts at 159-161 ° C.

By analogy, starting from 23.5 g of 35 (0.15 mole) of 3-chlorobenzoic acid, 13.5 g of N- (2-aminoethyl) -3- -chlorobenzamide hydrochloride (cf. Example 7 in German public) is obtained. -

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13 Equation Writing No. 2,616,486) with m.p. 201-203 ° C. The free base melts at 69-71 ° C (from a mixture of ethyl acetate and n-hexane).

Example 6

To a suspension of 6.4 g (0.04 mole) of 4-methoxy-benzoic acid in 60 ml of chloroform is added dropwise 5.5 ml (0.04 mole) of triethylamine, then 3.8 ml of 10 (0). Chloromyric acid ethyl ester. 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. After stirring for two hours at room temperature, filter. The filtrate is evaporated under reduced pressure and then freed in high vacuum for excess ethylenediamine. The residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase is made alkaline with 28% sodium hydroxide solution and extracted three times with chloroform. After drying and evaporation of the chloroform extracts, the residue is converted to the hydrochloride. Recrystallization from a mixture of ethanol and ether gives 3.4 g of N- (2-aminoethyl) -4-anisamide hydrochloride (cf. Example 7 of German Publication No. 2,616,486) with 25 m.p. 186-189 ° C. The free base melts at 37-38 ° C.

In the same way as described above, the following compounds are obtained: 30

From 20.4 g (0.15 mole) of 4-methylbenzoic acid: 8.7 g of N- (2-aminoethyl) -4-toluamide hydrochloride (cf. Example 7 of German Publication No. 2,616,486) m.p. 164-166 ° C; 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; o 14

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from 12.2 g (0.08 mol) of 2-methoxybenzoic acid: 9.3 g of N- (2-aminoethyl) -2-anisamide hydrochloride (cf. Example 6 of German Publication No. 2,362,568) with m.p. 109-111 ° C; 5 from 12.2 g (0.08 mol) of 3-methoxybenzoic acid: 6.2 g of N- (2-aminoethyl) -3-anisamide hydrochloride, m.p. 96-98 ° C; 10 from 3.9 g (0.015 mol) of 5- (dimethylsulfamoyl) -2-methoxybenzoic acid: 1.4 g of N- (2-aminoethyl) -5- (dimethylsulfamoyl) -2-anisamide hydrochloride, m.p. 193-195 ° C (dec.). The free base melts at 118-123 ° C.

Example 7 11.8 g (0.08 mol) of 4-cyanobenzoic acid is reacted and worked up in the same manner as in Example 6 with triethylamine and chloroformic acid ethyl ester, and then added dropwise to a solution of 21.4 ml of ethylenediamine in 350 ml of chloroform. The reaction mixture is heated after addition of 45 ml of dimethylformamide for an additional 1 hour to 60 ° C. After separation by filtration, the filtrate is evaporated and the residue is further treated in the same manner as in Example 6.

3.5 g of N- (2-aminoethyl) -4-cyanobenzamide hydrochloride are obtained, m.p. 212-215 ° C (dec.). The free base melts at 124-126 ° C.

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Similarly, starting from 4.5 g (0.023 mol) of 4-trifluoro-methylbenzoic acid, 3.1 g of N- (2-amino-ethyl) -α, α, α-trifluoro-4-toluamide hydrochloride is obtained. with m.p. 196-199 ° C. The free base melts at 66-68 ° C.

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Example 8

To a solution of 10 ml (0.15 mole) of ethylene diamine in 150 ml of ether is added dropwise at a temperature of -10 ° C over a half hour, a solution of 6.2 ml (0.05 mole) of 4-chlorobenzoyl chloride. in 150 ml of ether. It is warmed 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 10 and extracted several times with ethyl acetate to remove the neutral constituents. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After evaporation of the chloroform, conversion of the residue to the hydrochloride, and recrystallization from a mixture of ethanol and ether, 1.8 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, which is identical to that of Example 1, are obtained. product obtained.

Similarly, from 7 ml (0.05 mol) of 2,4-dichlorobenzoyl chloride 1.7 g of N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride having a melting point of 178-179 ° C is obtained. , which is identical to the product obtained in Example 4.

Example 9 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 1/2 hours to 100 ° C (bath temperature). After cooling 30, the excess ethylenediamine is removed in high vacuum.

The residue is acidified with dilute hydrochloric acid and extracted with chloroform. The aqueous phase is made alkaline with sodium hydroxide solution and then extracted several times with chloroform. After evaporation of the solvent and recrystallization of the residue from a mixture of chloroform and hexane 3.4 g of N- (2-aminoethyl) is obtained.

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16 -1,3-benzdioxole-5-carboxamide, m.p. 120-123 ° C. The hydrochloride melts at 210-213 ° C.

EXAMPLE 10 10.7 g (0.05 mole) of 4-bromobenzoic acid methyl ester and 10.4 ml (0.15 mole) of ethylenediamine are heated for 30 minutes to 130 ° C (bath temperature). After the same work-up as described in Example 9, after recrystallization from a mixture of methanol and ether, 6.5 g of N- (2-aminoethyl) -4-bromobenzamide hydrochloride is obtained, m.p. 229-232 ° C.

Example n 7.7 g (0.05 mole) of 4-fluorobenzoic acid methyl ester and 10 ml (0.15 mole) of ethylenediamine are heated for 2 hours to 130 ° C (bath temperature). The reaction mixture is poured into a mixture of ice and hydrochloric acid and extracted with ethyl acetate 20 to remove the neutral ingredients. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After drying and evaporation of the chloroform extracts, the residue (7.6 g) is recrystallized from a mixture of ethyl acetate and hexane to give N- (2-aminoethyl) -4-fluorobenzamide, m.p. 57-60 ° C. The hydrochloride melts at 214-216 ° C.

Example 12 To a solution of 1.02 g (0.01 mole) of acetylethylenediamine (cf. J. Amer. Chem. Soc. 61, 822 (1939)) and 1.4 ml (0.01 mole) of triethylamine in 25 ml of chloroform, a solution of 1.3 ml (0.01 mole) of 4-chlorobenzoyl chloride in 15 ml of chloroform is added dropwise at 0 ° C.

After 15 minutes, the resulting crystals are separated by filtration, washed with chloroform and dried. 1.9 g of N- (2-acetylaminoethyl) -4-chlorobenzamide are obtained, m.p. 222-224 ° C.

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To cleave the protecting group, the resulting N- (2-acetylaminoethyl) -4-chlorobenzamide is heated to reflux in a mixture of 24 ml of 2N hydrochloric acid and 15 ml of ethanol. After evaporation of the reaction solution, the crude product is recrystallized from a mixture of ethanol and ether. 1.2 g of (N- (2-aminoethyl) -4-chlorobenzamide hydrochloride) is obtained, mp 211-213 ° C, which is identical to the product of Example 1.

Example 13

To a solution of 1.2 ml (0.02 mol) of ethanol-amine and 3 ml (^ 0.02 mol) of triethylamine in 30 ml of methylene chloride is added dropwise 2.6 ml (0.02 mol) at 0 ° C. 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. After purification on silica gel with chloroform and a mixture of chloroform and methanol at a ratio of 9: 1 as eluent, 3.1 g of N- (2-hydroxyethyl) -4-chlorobenzamide is obtained.

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. 3 ml of methylene chloride.

After 15 minutes, the reaction mixture is poured into a mixture of ice and water and extracted. 2.1 g of N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide are obtained in crystalline form, which is used in the next step without further purification.

The resulting N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide is dissolved in 5 ml of dimethylformamide and added dropwise to a solution of ammonia 35 in dimethylformamide at room temperature. After stirring for 2 hours, work up and obtain N- (2-aminoethyl) -4-chlorobenzamide, which is identical to the product obtained in Example 1.

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Example A

Composition 1. N- (2-Aminoethyl) -2,4-dichlorobenzamide hydrochloride 5.78 mg 2. Milk sugar, powdered 80.22 mg 10 3. Corn starch 40.00 mg 4. Talk 3.60 mg 5. Magnesium stearate 0.40 mg 6. Milk sugar, cryst. 110.00 mg 15 Capsule filling weight 240.00 mg

Preparation Method: Mix 1-5 and screen through a sieve with a mesh width of 0.5 mm. Then add 6 and mix. This pre-filled mixture is filled into gelatin-sized capsules of an appropriate size (eg, No. 2) with a single filling weight of 240 mg.

25 *) equals 5 mg base - 30 35

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Example B Tablet 5 5 mg 5 Composition: 1. N- (2-Aminoethyl) -2,4-dichlorobenzamide hydrochloride 5.78 mg 2. Milk sugar, powdered 104.22 mg 3. Corn starch 45.00 mg 4 Polyvinylpyrrolidone K 30 15.00 mg 5. Corn starch 25.00 mg 6. Talk 4.50 mg 7. Magnesium stearate 0.50 mg 15 Tablet weight 200.00 mg

Procedures ϊ 1-3 are mixed and sieved through a sieve with a mesh width of 0.5 mm. This powder mixture is wetted with an alcoholic solution of 4 and kneaded. The moist mass is granulated, dried and processed to a suitable grain size. 5, 6 and 7 are added to the dried granules in sequence and mixed. The compression-ready blend 25 is pressed into tablets of an appropriate size with a calculated weight of 200 mg.

30 *) equals 5 mg base 35

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Example C

Composition: 1. N- (2-Aminoethyl) -p-chlorobenzamide hydrochloride 11.84 mg 2. Milk sugar, powdered 74.16 mg 10 3. Corn starch 40.00 mg 4. Talc 3.60 mg 5. Magnesium stearate 0.40 mg 6. Milk sugar, cryst. 110.00 mg 15 Capsule filling weight 240.00 mg

Preparation Method: Mix 1-5 through a sieve with a mesh width of 0.5 mm. Then add 6 and mix. This pre-filled mixture is filled into gelatin-sized capsules of an appropriate size (eg, No. 2) with a single filling weight of 240 mg.

25 *) equals 10 mg base 30 35

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Example D Tablet of 10 mg Composition: 1. N- (2-Aminoethyl) -p-chlorobenzamide hydrochloride 11.84 mg 2. Milk sugar, powdered 103.16 mg 10 3. Corn starch 40.00 mg 4. Polyvinylpyrrolidone K 30 15.00 mg 5. Corn starch 25.00 mg 6. Talk 4.50 mg 7. Magnesium stearate 0.50 mg 15

Tablet weight 200.00 mg

Procedure: Mix 1-3 sieves and sieve through a sieve with a mesh width of 0.5 mm. This powder mixture is moistened with an alcoholic solution £ 4 and kneaded. The moist mass is granulated # dried and processed to a suitable grain size. 5, 6 and 7 are sequentially added to the dried granules and mixed. The compression-ready mixture is pressed into tablets of an appropriate size with a calculated weight of 200 mg.

30 -------------------- *) equals 10 mg base 35

Claims (11)

1. Benzamide derivatives, characterized in that they have the general formula 0> VS, V "* wl JH 10. which R · * · means halogen, cyano or trifluoromethyl, and R2 means hydrogen, or R1 and R2 respectively means chlorine or, when adjacent, together represents a methylenedioxy group, or are pharmaceutically useful acid addition salts thereof. Compounds according to claim 1, characterized in that R 1 is halogen, cyano or trifluoromethyl, and R 2 is hydrogen or R 1 and R 2 are each chlorine. Compounds according to claim 2, characterized in that R1 is halogen and R2 is hydrogen, or R1 and R2 are each chlorine. A compound according to claim 1, characterized in that it is N- (2-aminoethyl) -p-chlorobenzamide or a pharmaceutically useful acid addition salt thereof. A compound according to claim 1, characterized in that it is N- (2-aminoethyl) -p-fluorobenzamide or a pharmaceutically useful acid addition salt thereof. A compound according to claim 1, characterized in that it is N- (2-aminoethyl) -p-bromobenzamide or a pharmaceutically useful acid addition salt thereof. A compound according to claim 1, characterized in that it is N- (2-aminoethyl) -3,4-dichlorobenzamide or a pharmaceutically useful acid addition salt thereof. A compound according to claim 1, characterized in that it is N- (2-aminoethyl) -2,4-dichlorobenzamide or a pharmaceutically useful acid addition salt thereof. DK 166382 B Process for the preparation of compounds of the general formula I or claim 1, or pharmaceutically usable acid addition salts thereof, characterized in that 5 a) a compound of the general formula 0 <RTI ID = 0.0> C / OH-II (II) </RTI> Medicament, characterized in that it contains a compound as defined in any one of claims 1-8. Wherein R 1 and R 2 have the above meaning, in the form of the free acid or in the form of a reactive functional derivative thereof, is reacted with ethylenediamine or that b) a compound of the general formula O II (in) l 5 * 3! 4, / V Xv, R R4 R1 in which R1 and R2 are as defined above, R3 is hydrogen and R4 is a leaving group, or R3 and R4 together form an additional bond, react with ammonia, or c) a compound of the general formula 0 "5 • ^ V · 7 sn / N. / R (iv) H in which R 1 and R 2 have the above meaning, and R 5 represents a group which can be converted to an amino group, converts the group R 5 to the amino group, whereupon an resulting compound is optionally converted to a pharmaceutically useful acid addition salt. An antidepressant or anti-Parkinson's agent, characterized in that it contains a compound as defined in any one of claims 1-8.