NL8400459A - BENZAMIDE DERIVATIVES. - Google Patents

Description

<-V "N.0. 32261 1

Benzamide derivatives

The present invention relates to benzamide derivatives.

In particular, it relates to N-aminoethyl substituted benzamides of the general formula 1, wherein R 1 and R 4 independently of each other are hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono- lower alkylsulphamoyl or di-lower alkylsulfamoyl or, when adjacent, together represent a methylenedioxy group, provided that when R 1 represents bromo in position 3, R 4 is different from hydrogen, as well as pharmaceutically applicable acid addition salts thereof.

These compounds are already partly known, for example, from German Offenlegunsschrift 2,458,908, but it has surprisingly been found that they exhibit interesting and therapeutically useful pharmacodynamic properties at low toxicity. Namely, it has been shown in animal experiments that the compounds of the above formula I, as well as their pharmaceutically applicable acid addition salts, have monoamine oxidase (MA.0) inhibitory properties.

The object of the invention are compounds of the general formula 1, as well as their pharmaceutically applicable acid addition salts as pharmaceutically active substances, medicaments containing a compound of the general formula 1 or a pharmaceutically applicable salt thereof, the preparation of such medicaments and the use of compounds of the general formula 1 as well as their pharmaceutically usable acid addition salts in the control, respectively. prevention of depressive states and parkinsonism.

Among the compounds encompassed by the previous formula 1, the benzamides of the general formula la, wherein R 1, halogen, cyano or trifluoromethyl and R 1, are hydrogen or R 1 and R 2, each chlorine or, when adjacent, together represent a methylenedioxy group, and its acid addition salts are still new and as such are also the subject of the present invention.

Finally, the subject of the present invention is a process for the preparation of compounds of the above formula la and their pharmaceutically applicable acid addition salts.

The term "lower alkyl" as used herein refers to straight or branched chain hydrocarbon radicals having from 1 to 6, preferably from 1 to 4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like The term "lower al-40 koxy" refers to lower alkyl ether groups, wherein the term 8400459 * 2 * king "lower alkyl" has the above meaning. The term "halogen" includes the four halogens fluorine, chlorine, bromine and iodine. The term "cleavable group" means groups known in the context of the present invention, such as halogen, preferably chlorine or bromine, arylsulfonyloxy, such as, for example, tosyloxy, alkylsulfonyloxy, as well as, for example, mesyloxy and the like.

The term "pharmaceutically applicable acid addition salts" includes salts with inorganic and organic acids, such as hydrogen chloride, hydrobromide, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. Such salts can readily be prepared by any person skilled in the art in view of the prior art and taking into account the nature of the compound to be converted into a salt.

Preferred compounds of formula I are those wherein R 1 and R 1 each independently represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl.

Particular preference is given to those compounds of the formula I in which R 1 and R 1 independently represent hydrogen, halogen or lower alkyl.

When the compounds of the formula I are disubstituted, the substituents are preferably in the positions 2,3, 2,4, 2,5, 3,4 or 3,6, particularly preferably in the positions 2,4 or 3 , 4.

Compounds of the formula I which are very particularly preferred; N- (2-aminoethyl) -p-chlorobenzamide, N- (2-aminoethyl) -p-fluorobenzamide, N- (2-aminoethyl) -p-bromobenzamide, 30 N- (2-aminoethyl) -3,4-dichlorobenzamide , N- (2-aminoethyl) -2,4-dichlorobenzamide and N- (2-aminoethyl) benzamide.

The compounds of the formula Ia and their pharmaceutically applicable acid addition salts can be prepared according to the invention in that a) a compound of the general formula II in which R 1 and R 1 have the above meaning in the form of the free acid or in the form of a reactive functional derivative thereof with ethylene diamine 40 conversion, or 8400459 '... b) a compound of the general formula 3, in which R11 and R21 have the above meaning, R1 hydrogen and R2 represent a cleavable group or R2 and R2 together represent an additional bond, react with ammonia, or C) in a compound of the general formula 4, in which and R 2 ^ have the above meaning and R 2 represents a residue which can be converted into an amino group, converts the residue into the amino group and, if desired, a compound obtained in a pharmaceutically applicable acid additive. ditto salt.

As reactive functional derivatives of the acids of the formula II, for example, halides, eg chlorides, symmetrical or mixed anhydrides, esters, eg the methyl ester, p-nitrophenyl ester or N-hydroxysuccinimide ester, azides and amides, eg imidazolides or succinimides, eligible.

The reaction of an acid of the formula II or a reactive functional derivative thereof with ethylenediamine according to variant a) of the above-mentioned process can be carried out by conventional methods. For example, one can react a free acid of the formula II with ethylenediamine in the presence of a condensing agent in an inert solvent. When a carbodiimide, such as dicyclohexylcarbodiimide, is used as the condensing agent, the conversion is expediently made into an alkane carboxylic acid ester, such as ethyl acetate, an ether, such as tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as dichloromethane or chloroform, an aromatic hydrocarbon, such as benzene, toluene. or 25 xylene, acetonitrile or dimethylformamide, conducted at a temperature between about -20 ° C and room temperature, preferably at about 0 ° C. When phosphorus trichloride is used as the condensing agent, the reaction is conveniently carried out in a solvent, such as pyridine, at a temperature between about 0 ° C and reflux temperature of the reaction mixture, preferably at about 90 ° C. In another embodiment of the variant a), ethylenediamine is reacted with one of the above reactive functional derivatives of an acid of the formula II. For example, a halide, e.g., the chloride, of an acid of the formula II can be reacted with ethylene-35 diamine at about 0 ° C in the presence of a solvent, such as diethyl ether.

The compounds of the formula III, wherein R 2 hydrogen and R 2 represent a cleavable group, are for example N- (2-haloethyl) benzamides, such as N- (2-chloroethyl) benzamide, N- (2-methylsulfo-40-nylethyl) ) benzamide or fi- (2-p-toluenesulfonylethyl) benzamide and the like. The compounds of formula III wherein Rp and together represent an additional bond are benzoylaziridines such as, for example, p-chlorobenzoylaziridine and the like.

According to variant b), a compound of the formula III with ammonia at a temperature between about -40 ° C and 50 ° C, if desired in the presence of a solvent, such as dimethylformamide, dimethyl acetamide, dimethyl sulfoxide and like, convert. It is expedient to operate in the presence of a solvent at about room temperature. If a benzoyl-10 aziridine of the formula III is used, it is preferred to work in the presence of an inert solvent such as dimethylformamide, toluene or benzene.

The conversion of the residue to amino according to variant c) also takes place in a manner known per se, depending on the nature of the residue R '*. If it is an amide, the conversion is expediently effected by acidic or basic hydrolysis. For the acid hydrolysis, a solution of an inorganic acid, such as hydrochloric acid, hydrous bromide, sulfuric acid, phosphoric acid and the like, is advantageously used in an inert solvent, such as an alcohol e.g. methanol or ethanol, an ether, e.g. tetrahydrofuran or dioxane. For basic hydrolysis, aqueous solutions of alkali metal hydroxides, such as potassium or sodium hydroxides, can be used. Inert organic solvents, as mentioned above for acid hydrolysis, can be added as a solution promoting agent. The reaction temperature can be varied for the acid and basic hydrolysis in a range from about room to reflux temperature, preferably working at or below the boiling temperature of the reaction mixture. In the case of R- * phthalimido, in addition to the acidic and basic hydrolysis, an aminolysis with an aqueous solution of a small alkylamine, such as methylamino or ethylamine, can also be carried out. A small alkanol, such as methanol, can be used as the organic solvent. This reaction is preferably carried out at room temperature. A third method for the conversion of phthalimido to amino is to convert compounds of the formula IV with hydrazine in an inert solvent such as ethanol, a mixture of ethanol and chloroform, tetrahydrofuran or aqueous ethanol. The reaction temperature can be varied in a range from about room temperature to about 100 ° C, preferably working at the boiling temperature of the selected solvent. The resulting product can be shaken out with dilute mineral acid and then by alkali 8400458

«. β V.

5 lification, the acidic solution is obtained. The tert-butoxycarbonylamino moiety is conveniently reacted with trifluoroacetic acid or formic acid in the presence or absence of an inert solvent at about room temperature in the amino group, while the trichloroethoxycarbonylamino group is reacted with zinc or cadmium under acidic conditions. The acidic conditions are effectively achieved by carrying out the reaction in acetic acid in the presence or absence of an additional inert solvent, such as an alcohol, e.g., methanol. The benzyloxycarbonylamino residue can be converted to the amino group in a known manner by acid hydrolysis as described above or by hydrogenolysis. An azido group can be reduced to the amino group by known methods, for example with elemental hydrogen in the presence of a catalyst, such as palladium / carbon, Raney nickel, platinum oxide and the like. A hexamethylene tetrammonlum-15 group can be converted to the amino group by acid hydrolysis by methods also known in the art.

The compounds of the formula II and II, respectively, used as starting materials in variant a). the reactive functional derivatives thereof are known or can be obtained analogously to the preparation of the known compounds.

The compounds of the formula III used as starting materials in variant b) are also known or analogous to known compounds and can be prepared in a manner known per se. For example, for the preparation of compounds of the formula III, wherein R25 represents hydrogen and a cleavable group, one can react a compound of the formula II or a reactive functional derivative thereof with ethanolamine under the reaction conditions indicated for variant a) and obtain the resulting N- (2-hydroxyethyl) benzamide in a manner known per se, eg by reaction with a halogenating agent, such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride and the like, an aryl sulfonyl halide, such as tosyl chloride, or an alkyl sulfonyl halide, such as mecyl chloride, in the convert desired compound of formula 3. A compound of the formula III, wherein R 1 and R 2 together represent an additional bond, can be obtained, for example, by reacting a reactive functional derivative of a compound of the formula 2 with ethyleneimine. The reaction can take place under the reaction conditions indicated for variant a).

The compounds of formula IV used as starting materials in variant c) are also known or analogous to known compounds 8400459 6 and can be prepared in a manner known per se. For example, one can react a compound of the formula II or a reactive functional derivative thereof under the reaction conditions indicated for variant a) with a compound of the general formula 5, in which R- * has the above meaning. The compounds of the formula V are known or can be obtained analogously to the preparation of the known compounds.

According to another method, the compounds of the formula IV, wherein R 1 represents phthalimido, azido or hexamethylene tetra-ammonium, can also be obtained by reacting a compound of the formula 3 with phthalimide potassium, an alkali metal azide or hexamethylene tetramine. The reaction takes place in a manner known per se under the reaction conditions indicated for variant b).

The compounds of the formula I and their pharmaceutically usable acid addition salts, as already mentioned above, have monoamine oxidase (MAO) inhibitory activity. Because of this activity, the compounds of formula I and their pharmaceutically applicable acid addition salts can be used for the treatment of depressive states and parkinsonism.

The MAO inhibitory activity of the compounds of the invention can be determined using standard methods. Thus, the preparations to be tested were administered p.o. to rats. Two hours later, the animals were sacrificed and the MAO inhibitory activity in homogenized brain and liver products was determined according to Biochem. Pharmacol. 12_ (1963) 1439-1441, but measured using phenethylamine (2.10 µmol -1- * -) instead of tyramine as substrate. The activity of some compounds according to the invention thus determined, as well as the toxicity thereof, is evident from the following E5Q * values (pmol / kg, p.o. in the rat) 30 and 50, respectively. LD ^ Q values (mg / kg, p.o. in mouse): 8400459 * 7

Compound ED ^ q LD50 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-10,3 1000-2000 benzamide N- (2-aminoethyl) -2,4-dichloro 1,5 625-1250 benzamide N- (2-aminoethyl) benzamide 20> 5000

The compounds of the formula I as well as their pharmaceutically usable acid addition salts can find use as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceuticals can be administered orally, e.g. in the form of tablets, lacquer tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, the administration can also take place orally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

For the manufacture of tablets, lacquers, dragees and hard gelatin capsules, the compounds of formula 1 and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic extenders. As such excipients, it is possible to use, for example, for tablets, dragees and hard gelatin capsules lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, etc.

For soft gelatin capsules, as excipients, e.g. vegetable oils, waxes, fats, partially solid and liquid poly-2-ols, etc. are suitable.

As excipients, for example, water, polyols, sucrose, invert sugar, glucose, etc. are suitable as preparation agents and syrups.

For injection solutions, for example, excipients are water, 22-alcohol, alcohols, polyols, glycerol, vegetable oils, etc.

For suppositories, the excipients are, for example, natural or hardened oils, waxes, fats, partly liquid or liquid polyols, etc.

The pharmaceutical preparations may additionally contain preservatives, solution promoters, stabilizers, 8400459.

8 contain moisturizing agents, emulsifying agents, sweetening agents, coloring agents, aromatizing agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.

According to the invention, compounds of the general formula 1 as well as their pharmaceutically usable acid addition salts can be used in the control, respectively. apply the prevention of depressive states and parkin-sionism. The dosage can vary within wide limits and must of course be adapted in each case to the individual facts. In general, when administered orally, a daily dose of about 10 to 100 mg of a compound of the general formula 1 will be suitable, however the upper limit indicated above may also be exceeded if this proves advisable.

The following examples will illustrate the present invention, but in no way limit it. All temperatures are indicated in degrees Celsius.

Example I

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

30 216-217 °.

Example II

9.5 g of 4-Chlorobenzoic acid ethyl ester and 16.0 g of N-tert-butoxycarbonyl) ethylenediamine are stirred at 130 ° for 15 hours. 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 diisopropyl ether and filtered off. 3.9 tert.-butyl [2- (4-chlorobenzamido) -ethyl [carbamate, m.p. 141-143 °.

40 A solution of 2.8 g of tert-butyl [2- (4-chlorobenzamido) -ethyl] - 8400459 * 9 carbamate in 50 ml of formic acid is stored at room temperature for 1.5 hours. The reaction mixture is then concentrated to dryness and the residue is dissolved in 50 ml of hydrochloric acid (1: 1 by volume). The solution is concentrated, re-evaporated twice with ethanol / benzene and the residue is recrystallized from ethanol. 2.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, which is identical to the product obtained in Example 1, are obtained.

Example III

To a suspension of 23.5 g (0.15 mol) 4-chlorobenzoic acid and 15 ml (0.16 mol) chloroformic acid ethyl ester in 200 ml chloroform are added dropwise at 0 ° 23 ml (0.17 mol) triethylamine. After the addition is complete (0.5 hour), the resulting solution is added dropwise at 0 ° to a solution of 50 ml (0.75 mol) of ethylenediamine in 100 ml of chloroform. After the reaction is complete, 115 ml of concentrated hydrochloric acid are added dropwise at 0 °. The acidic mixture is filtered and the remaining neutral components are removed by extraction with chloroform. The aqueous phase is then made alkaline with sodium hydroxide and extracted several times with chloroform. The chloroform extracts are dried and concentrated. The residue is converted into the hydrochloride and recrystallized from ethanol / ether. 15.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained, m.p. 212-214 °. The free bases melt at 43-45 °.

Example IV

19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are suspended in 200 ml of dichloromethane and dissolved by adding 15.3 ml (0.11 mol) of triethylamine. Then 10 ml (0.1 mol) chloroformic acid ethyl ester are added dropwise at 0 °. After the addition is complete (0.5 hour), it is poured on ice / water. The dichloromethane phase is separated, dried over magnesium sulfate and concentrated to about 30 ml. This solution is added dropwise at 0 ° to a solution of 20 ml (0.3 mol) of ethylenediamine in 100 ml of tetrahydric furan. After the addition is complete (0.5 hour), filtration is performed and after acidifying the filtrate with dilute hydrochloric acid, the neutral components are removed by extraction with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide and extracted several times with chloroform. After drying and concentrating the chloroform phases, the residue is converted into the hydrochloride. After recrystallization from ethyl 40 nol / ether, 7.1 g of N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride, 8400459 mp. 179-182 °.

Example 5

To a suspension of 23.5 g (0.15 mol) of 2-chlorobenzoic acid in 200 ml of chloroform are added dropwise 22.1 ml (0.16 mol) of triethylamine at 10 °. Then 14.8 ml (0.155 mol) of chloroformic acid ethyl ester are added dropwise at the same temperature. After the addition was complete (1 hour), the reaction mixture is poured onto ice / water. The chloroform phase is separated, dried over magnesium sulfate and carefully concentrated to about 60 ml. The solution thus obtained is added dropwise at 10 ° to a solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform. After the addition is complete, the sparingly soluble neutral constituents are filtered off and the filtrate is concentrated and freed from excess ethylene-15 diamine under greatly reduced pressure. The resulting residue (31.5 g) is converted into the hydrochloride and further purified by recrystallization from ethanol / ether. They obtain 19.2 g of N- (2-aminoethyl) -2-chlorobenzamide hydrochloride (compare example VI of the German Qffenlegungsschrift 2,362,568), and m.p. 155-158 °. An analytically pure sample melts at 159-161 °.

Analogously, starting from 23.5 g (0.15 mol) .. 3-chlorobenzoic acid, 13.5 g N- (2-aminoethyl) -3-chlorobenzamide hydrochloride (compare Example VII of German Offenlegunschrift 2,616,486) obtained, m.p. 201-203 °. The free base melts at 69-71 ° (from ethyl acetate / n-hexane).

Example VI

24.4 g (0.2 mol) of benzoic acid are reacted in the manner described in Example V with triethylamine and chloroformic acid ethyl ester and at 10 ° to a solution of 53.5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform added dropwise. After filtering off the sparingly soluble neutral constituents, the chloroform solution is concentrated and liberated from excess ethylenediamine under a greatly reduced pressure. The oily residue (36.3 g) is taken up in 200 ml 2N sodium hydroxide, saturated with solid sodium chloride and extracted several times with ethyl acetate. The ethyl acetate extracts are dried over magnesium sulfate and concentrated. The crude product is converted to the hydrochloride and further purified by recrystallization from ethanol to obtain 5.2 g of N- (2-aminoethyl) benzamide hydrochloride (J. Amer. Chem. Soc. 61, (1939) 822), m.p.

40 163-165 °.

8400459 ψ »" 11

Example VII

To a suspension of 6.4 g (0.04 mol) of 4-methoxybenzoic acid in 60 ml of chloroform at 10 °, 5.5 ml (0.04 mol) of triethylamine and then 3.8 ml (0.04 mol) of chloroformic acid ethyl ester are added dropwise 5 added. The resulting reaction solution is then added dropwise at 5 ° 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, filtration is carried out. The filtrate is concentrated under reduced pressure and then freed from excess ethylene diamine under greatly reduced pressure. 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 and extracted three times with chloroform. After drying and concentrating the chloroform extracts, the residue is converted into the hydrochloride.

Recrystallization from ethanol / ether gives 3.4 g of N- (2-aminoethyl) -4-anisamide hydrochloride (compare example VII of German Offenlegungsschrift 2,616,486), m.p. 186-189 °. The free base melts at 37-38 °.

In an analogous manner as described above: 20 - Starting from 20.4 g (0.15 mol) of 4-methylbenzoic acid, 8.7 g of N- (2-aminoethyl) -4-toluamide hydrochloride (compare example VII of German Offenlegungsschrift 2,616,486), mp 164-116 °; 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 °, the free base melts at 98-110 °; Starting from 12.2 g (0.08 mol) of 2-methoxybenzoic acid, 9.3 g of N- (2-aminoethyl) -2-anisamide hydrochloride (compare example VI of German Offenlegungsschrift 2,362,568), mp 109-111 °; Starting from 12.2 g (0.08 mol) of 3-methoxybenzoic acid, 6.2 g of 30 N- (2-aminoethyl) -3-anisamide hydrochloride, m.p. 96-98 °; Starting 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 ° (dec.). The free base melts at 118-123 °.

Example VIII

11.8 g (0.08 mol) of 4-cyano benzoic acid are reacted in an analogous manner as in Example VII with triethylamine and chloroformic acid ethyl ester and further processed and then added dropwise to a solution of 21.4 ml of ethylenediamine in 350 ml of chloroform. The reaction mixture is heated at 60 ° 40 for 1 hour after addition of 45 ml of dimethylformamide. After filtration, the filtrate is concentrated and 8400459 Λ * 12

W V

the residue is further treated in the same manner as in Example VII. 3.5 g of N- (2-aminoethyl) -4-cyano-benzamide hydrochloride are obtained, m.p. 212-215 ° (dec.). The free base base melts at 124-126 °.

Starting from 4.5 g (0.023 mol) of 4-trifluoromethylbenzoic acid, 3.1 g of N- (2-aminoethyl) -a, a, α-trifluoro-4-toluamide hydrochloride were obtained in an analogous manner, m.p. 196-199 °, the free base melts at 66-68 °. Example IX

To a solution of 10 ml (0.15 mol) of ethylenediamine in 150 ml of ether, a solution 10 of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride in 150 ml of ether is added dropwise at -10 ° in the course of half an hour. added. The mixture is allowed to reach room temperature, filtered and the white residue is rinsed twice with ether. After concentrating the ether solution, the residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate to remove the neutral constituents. The aqueous phase is made alkaline with sodium hydroxide and extracted several times with chloroform. After evaporation of the chloroform, conversion of the residue to the hydrochloride and recrystallization from ethanol / ether, 1.8 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride which is identical to the product obtained in Example I are obtained. is.

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, m.p. 178-179 °, were obtained, which is identical with it in Example IV.

Example X

7 g (0.039 mol) of 3,4-methylenedioxybenzoic acid methyl ester and 8.5 ml (0.126 mol) of ethylenediamine are heated at 100 ° (bath temperature) for 2.5 hours. After cooling, the excess diethylenediamine is removed under greatly reduced pressure. The residue is acidified with dilute hydrochloric acid and extracted with chloroform. The aqueous phase is made alkaline with sodium hydroxide and then extracted several times with chloroform. After evaporation of the solvent and recrystallization of the residue from chloroform-hexane, 3.4 g of N- (2-aminoethyl) -1,3-benzdioxole-5-carboxamide are obtained, m.p.

120-123 °. The hydrochloride melts at 210-213 °.

Example XI

10.7 g (0.05 mol) of 4-bromobenzoic acid methyl ester and 10.4 ml (0.15 mol) of ethylenediamine are heated at 130 ° (bath temperature) for 30 minutes. After further processing in an analogous manner, as described in Example X, 6.5 g of N- (2-amino-8400459 * Τ-) 13 ethyl) -4-bromobenzamide hydrochloride are obtained after recrystallization from methanol / ether, m.p. 229-232 °.

Example XII

10.7 ml (0.16 mol) of ethylenediamine are added to 6.65 g (0. 4 mole) of 4-methoxybenzoic acid methyl ester. The solution is heated at 130 [deg.] For two hours (bath temperature) and freed from excess ethylenediamine after cooling under a greatly reduced pressure. The residue is acidified with dilute hydrochloric acid. The sparingly soluble neutral components are removed by filtration and subsequent extraction with ethyl acetate. The aqueous phase is made alkaline with 28% sodium hydroxide, saturated with sodium chloride and extracted three times with chloroform. The chloroform extracts are dried over magnesium sulfate and concentrated. The residue is converted into the hydrochloride and recrystallized from ethanol / ether. 3.8 g of N- (2-aminoethyl) -4-anisamide hydrochloride (compare Example 15 VII of German Offenlegungsschrift 2,616,486) are obtained, m.p. 201-204 °.

In an analogous manner, starting from 20 g (0.1 mol) of 4-chloro-2-methoxybenzoic acid methyl ester and 20.1 ml (0.3 mol) of ethylenediamine, 8.9 g of N- (2-aminoethyl) -4-chloro-2 anisamide hydrochloride, m.p. 132-135 ° (dec.).

Example XIII

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

Example XIV

To a solution of 1.02 g (0.01 mol) of acetylethylenediamine (J. Arner. Chem. Soc. 61 ^, (1939) 822) and 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform is added A solution of 1.3 ml (0.01 mol) of 4-chlorobenzoyl chloride in 15 ml of chloroform was added dropwise.

After 15 minutes, the crystals formed are filtered off, washed with chloroform and dried. 1.9 g of N- (2-acetylaminoethyl) -4-chlorobenzamide are obtained, m.p. 222-224 °.

For the cleavage of the protecting group, the obtained N- (2-acetylaminoethyl) -4-chlorobenzamide in a mixture of 24 ml of 40 2N hydrochloric acid and 15 ml of ethanol is refluxed for 22 hours. After concentrating the reaction solution, the crude product is recrystallized from ethanol / ether. 1.2 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained, m.p. 211-213 °, which is identical with product obtained in Example I.

Example XV

To a solution of 1.2 ml (0.02 mole) ethanolamine and 3 ml (+ 0.02 mole) triethylamine in 30 ml dichloromethane are added dropwise at 0 ° 2.6 ml (0.02 mole) 4-chlorobenzoyl chloride. The mixture is then poured onto dilute hydrochloric acid and extracted twice with dichloromethane. The dichloromethane extracts are dried over magnesium sulfate and concentrated. After purification on silica gel with chloroform and chloroform / methanol 9: 1 as an eluent, 3.1 g of N- (2-hydroxyethyl) -4-chlorobenzamide are obtained.

To a solution of 1.5 g (0.0075 mol) of N- (2-hydroxyethyl) -4-15 chlorobenzamide and 1 ml of triethylamine in 15 ml of dichloromethane, a solution of 0.6 ml of methanesulfonic acid chloride in 3 ml of dichloromethane is added at 0 ° added dropwise. After 15 minutes, the reaction mixture is poured onto ice / water and extracted. 2.1 g of N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide in crystalline form are obtained, which is used in the next step without further purification.

The N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide obtained is dissolved in 5 ml of dimethylformamide and added dropwise to a solution of ammonia in dimethylformamide at room temperature. After stirring for 2 hours, the mixture is further processed and N- (2-aminoethyl) -25-4-chlorobenzamide is obtained, which is identical with the product obtained in Example I.

Example A

Gelatin capsule with 5 mg. Composition: 30 1. N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride 5.78 mg 1) 2. powdered milk sugar 80.22 mg 3. corn starch 40.00 mg 4. talc 3.60 mg 35 5. magnesium stearate 0.40 mg 6. milk sugar cry. 110.00 mg fill weight of the capsule 240.00 mg 8400459 'corresponds to 5 mg base 40 ► 7. ~. 15

Preparation method: 1-5 are mixed and sieved through a 0.5 mm mesh sieve. Then 6 is added and mixed. This ready-to-fill mixture is filled into suitable size 5 gelatin capsules (e.g. No. 2) with a separate pre-weight of 240 mg. Example B Tablets with 5 mg Composition; 10 1. N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride 5.78 mg 1) 2. milk sugar powder 104.22 mg 3. corn starch 45.00 mg 4. polyvinylpyrrolidone K 30 15.00 mg 5. corn starch 25, 00 mg 15 6. talc 4.50 mg 7. magnesium stearate 0.50 mg weight of the tablets 200.00 mg 20 Method: 1-3 are mixed and sieved through a 0.5 mm mesh sieve. This powder mixture is moistened and kneaded with an alcoholic solution of 4. The wet mass is granulated, dried and prepared for a suitable grain size. 5, 6 and 7 are added successively to the dried granulate and mixed.

This ready-to-compress mixture is pressed into suitably sized tablets with a standard weight of 20Q 11¾.

8400459 is equivalent to 5 mg base.

Example C

Gelatin capsule with 10 mg Composition; 5 1. N- (2-aminoethyl) -p-chlorobenzamide hydrochloride 11.84 mg *) 2. milk sugar powder 74.16 mg 3. corn starch 40.00 mg 4. talc 3.60 mg 5. magnesium stearate 0.40 mg 10 6 milk sugar cry. 110.00 mg fill weight of the capsule 240.00 mg

Preparation method; 1-5 are mixed and sieved through a sieve with a mesh size of 0.5 to 15. Then 6 is added and mixed. This ready-to-fill mixture is filled into gelatin insert capsules of appropriate size (e.g. No. 2) with a separate pre-weight of 240 mg. Example D Tablets with 10 mg 20 Composition; 1. N- (2-aminoethyl) -p-chlorobenzamide hydrochloride 11.84 mg *) 2. milk sugar powder 103.16 mg 3. corn starch 40.00 mg 25 4. polyvinylpyrrolidone K 30 15.00 mg 5. corn starch 25.00 mg 6. talc 4.50 mg 7. magnesium stearate 0.50 mg weight of the tablets 200.00 mg 30

Method; 1-3 are mixed and sieved through a 0.5 mm mesh sieve. This powder mixture is moistened and kneaded with an alcoholic solution of 4. The wet mass is granulated, dried and prepared for a suitable grain size. 5, 6 and 7 are added successively to the dried granulate and mixed. This ready-to-compress mixture is compressed into tablets of a suitable size with a standard weight of 200 mg.

40 *) corresponds to 10 mg base 8400459

Claims (9)

1. Benzamide derivatives of the general formula 1, wherein rA and R2 independently of each other are hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono-lower alkyl sulfa-5 moyl or di-lower alkyl sulfamoyl or, if adjacent together, represent a methylenedioxy group, with the proviso that, in the case where EA represents bromine in position 3, R2 differs from hydrogen, as well as pharmaceutically applicable acid addition salts thereof as pharmaceutical active substances. Compounds according to claim 1, wherein R 1 - * and R 2 independently represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl. Compounds according to claim 2, wherein R 1 and R 2 each independently represent hydrogen, halogen or lower alkyl. Compounds according to any one of claims 1 to 3, characterized in that R 1 and R 2, in case they differ from hydrogen, are in the positions 2,3, 2,4, 2,5, 3,4 or 3.6. Compounds according to claim 4, characterized in that R 1 and R 2 are in positions 2,4 or 3,4. 20 N- (2-aminoethyl) benzamide as a compound according to claim 3. Compounds according to any one of claims 1 to 6 as anti-depressant or anti-Parkinson's agents. 8. Benzamide derivatives of the general formula la, wherein R 1, halogen, cyano or trifluoromethyl and R 21, hydrogen or R 2 R22 each represents chlorine or, when adjacent, together a methylenedioxy group, and pharmaceutically applicable acid addition salts thereof. 9. Compounds according to claim 8, wherein R 1 halogen, cyano or trifluoromethyl and R 2 hydrogen or R 1 and R 22 each represent chlorine. Compounds according to claim 9, wherein R 2 halogen and R 2 hydrogen or R 2 and R 21 each represent chlorine. 11. N- (2-aminoethyl) -p-chlorobenzamide or a pharmaceutically applicable acid addition salt thereof. 12. N- (2-aminoethyl) -p-fluorobenzamide or a pharmaceutically applicable acid addition salt thereof. N- (2-aminoethyl) -p-bromobenzamide or a pharmaceutically applicable acid addition salt thereof. 14. N- (2-aminoethyl) -3,4-dichlorobenzamide or a pharmaceutically applicable acid addition salt thereof. 8400459 N- (2-aminoethyl) -2,4-dichlorobenzamide or a pharmaceutically applicable acid addition salt thereof. Compounds according to any of claims 8-15 as pharmaceutically active substances. Compounds according to any of claims 8-15 as anti-depressant or anti-Parkinson's agents. 18. A process for the preparation of compounds of the formula la defined in claim 8 as well as of pharmaceutically applicable acid addition salts thereof, characterized in that a compound of the general formula 2, wherein R 1 and R claim 8, in the form of the free acid or in the form of a reactive functional derivative thereof reacting with ethylenediamine, or b) a compound of the general formula 3, wherein R 1 and R 15 are those indicated in claim 8 meaning that R 2 hydrogen and R 2 represent a cleavable group or, and together represent an additional bond, converts with ammonia, or c) into a compound of the general formula 4, wherein R 2 and r 2 are as defined in claim 8 and R 1 represents a residue to be converted into an amino group, the residue R 1 converts into the amino group and, if desired, converts a obtained compound into a pharmaceutically applicable acid addition salt. A medicament containing a compound defined in any one of claims 1-6 and 8-15. Anti-depressant or anti-Parkinson's agent, containing a compound defined in any one of claims 1-6 and 8-15 · Use of a compound as defined in any one of claims 1-6 and 8-15 in the control or. disease prevention. 22. Use of one of the compounds defined in claims 1-6 and 8-15 in control and resp. the prevention of depressive states and Parkinsonism. 1 1 + 1 I I ++ IllllHHM- 8400459 - ·> L1 * oo '' · <»>", AA °?. ·., C - OH. "I II '/ y Nnj / \ R11 ^ · * ^ 21 ^ ι'Χ ^, χΚ3 R4 k_ £. O II # \ / ^ \ · / * \ 5 •, 1 N h ~ n-ch, -ch, -r5 9. U ** * · L ·, Ru ^. \ 2iH 8400459>