LU85231A1 - BENZAMIDE DERIVATIVES - Google Patents

Description

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel, Switzerland RAN 4081/75 ï 5 * 10 benzamide derivatives ig The present invention relates to benzamide derivatives.

In particular, it relates to N-aminoethyl-substituted - = benzamides of the general formula 0

s II

, · Cv ·, NH0 20 em "YY ·% -v 1 2 wherein R and R independently of one another are each water-25 substance, halogen, lower alkyl, lower alkoxy, cyano," trifluoromethyl, sulfamoyl, mono-lower alkyl sulfamoyl or di-lower alkyl sulfamoyl or, if they are adjacent, together mean a methylenedioxy group, with the proviso that if R is bromine in the m 2 30 3-position, R is other than hydrogen, and pharmaceutically acceptable acid addition salts thereof.

Some of these compounds are already known from, for example, German Offenlegungsschrift 2,458,908, but it has surprisingly been found that they have interesting and therapeutically useful pharmacodynamic properties with low toxicity. In

Kbr / 2212.83 - 2 -

Animal experiments have shown that the compounds of the above formula I and their pharmaceutically usable acid addition salts monoamine oxidase (MAO) have inhibitory properties.

s 5? The present invention relates to compounds of the general formula I and their pharmaceutically usable acid addition salts as active pharmaceutical ingredients, medicaments containing a compound of the general formula I or a pharmaceutically usable acid addition salt thereof, the preparation of such medicaments and the use of compounds of the general formula I. as well as their pharmaceutically usable acid addition salts for the control or prevention of 15 diseases or for the improvement of health, in particular for the control or prevention of depressive conditions and Parkinsonism.

.3 Of the compounds encompassed by the present formula I, the benzamides of the general formula 0

II

C, · jra, la i'YYN · 7

11 21 wherein R is halogen, cyano or trifluoromethyl and R

11 21

Hydrogen or R and R each chlorine or, if they are adjacent, together represent a methylenedioxy group 30, and their acid addition salts are still new and as such are also an object of the present invention.

The present invention finally relates to a process for the preparation of the compounds of the above formula Ia and their pharmaceutically usable acid addition salts.

- 3 -

The term "lower alkyl" used in this description refers to straight-chain and branched hydrocarbon radicals having 1-6, preferably 1-4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, g isobutyl, tert . Butyl and the like. The term "lower alkoxy" refers to lower alkyl ether groups in which the term "lower alkyl" has the above meaning. The term "halogen" includes the four halogens fluorine, chlorine, bromine and iodine. The term "leaving group" 10 in the context of the present invention means known groups such as halogen, preferably chlorine or bromine, arylsulfonyloxy such as tosyloxy, alkylsulfonyloxy such as mesyloxy and the like.

1g The expression "pharmaceutically usable acid addition salts" includes salts with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, - formic acid, maleic acid, acetic acid, succinic acid, 20 tartaric acid, methanesulfonic acid and p-toluenesulfonic acid the like. Such salts can be readily prepared by any person skilled in the art in view of the prior art and considering the nature of the compound to be salted.

25th

Preferred compounds of the formula I are those in which R and R are each independently hydrogen,

Halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl mean.

30th

Compounds of 1 2 are particularly preferred

Formula I, wherein R and R each independently represent hydrogen, halogen or lower alkyl.

2q If the compounds of the formula I are disubstituted, the substituents are preferably in the 2,3-, 2,4-, 2,5-, 3,4- or 3,6-position, particularly preferably in the 2,4- or 3,4-position.

- 4 -

Very particularly preferred compounds of the formula I.

are: N- (2-aminoethyl) -p-chlorobenzamide, 5 N- (2-aminoethyl) -p-fluorobenzamide, r, N- (2-aminoethyl) -p-bromobenzamide, N- (2-aminoethyl) -3 , 4-dichlorobenzamide, N- (2-aminoethyl) -2,4-dichlorobenzamide and N- (2-aminoethyl) benzamide.

10th

The compounds of the formula Ia and their pharmaceutically usable acid addition salts can be prepared according to the invention by 15 a) a compound of the general formula 0

-0H

i y ~ rII7 ^ '* ^ 21

20 R R

11 21 in which R and R 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 25 b) a compound of the general formula 0 y \ / \ / \ 30 Λ '·' ¥ 3 '4 111 * 4 11 21 where R and R are as defined above, 2 3 4 R is hydrogen and R is a leaving group 3' 4 35 or R and R together represent an additional bond, reacted with ammonia, or - 5 - c) in a compound of the general formula 0 11 5

5 / \ / C \ / '\ / R

S. . Η · IV

Û- 21

Rxx γχ ’il 21 5 10 wherein R and R have the above meaning and R is a radical which can be converted into an amino group, 5 converts the radical R to the amino group and, if desired, converts a compound obtained into a pharmaceutically acceptable acid addition salt.

15

Suitable reactive functional derivatives of the acids • w of formula II include, for example, halides, e.g.

Chlorides, symmetrical or mixed anhydrides, esters, Z e.g. Methyl ester, p-nitrophenyl ester or N-hydroxy-20 succinimide ester, azides and amides, e.g. Imidazolides or succinimides.

The reaction of an acid of formula II or a reactive functional derivative thereof with ethylene-25 diamine according to variant a) of the above process can be carried out by customary methods. So you can e.g. react a free acid of formula II with ethylenediamine in the presence of a condensing agent in an inert solvent. If a carbodiimide, such as dicyclohexylcarbodiimide, 30 is used as the condensing agent, the reaction is expediently 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 ε or chloroform, an aromatic hydrocarbon, such as 35 Benzene, toluene or xylene, acetonitrile or dimethylformamide, at a temperature between about -20 ° C and room temperature, preferably at about 0 ° C.

If phosphorus trichloride is used as the condensing agent, the reaction is expediently carried out in a solvent, such as pyridine, at a temperature between about 0 ° C. and the reflux temperature of the reaction mixture, preferably at about 90 ° C. In another embodiment of variant a), ethylenediamine is reacted with one of the reactive functional derivatives of an acid of the formula II mentioned above. So you can e.g. a halide, e.g. react the chloride, an acid of the formula II at about 0 ° C. with ethylenediamine in the presence of a solvent, such as diethyl ether.

3rd

The compounds of formula III, wherein R is water 4

Substance and R are a leaving group are, for example, N- (2-haloethyl) benzamides, such as N- (2-chloroethyl) benza-15 mide, N- (2-methylsulfonylethyl) benzamide or N- (2-p-toluenesulfonylethyl) ) benzamides and the like. The compounds 3 4 - of formula III, wherein R and R together form an additional

Represent bond are benzoylaziridines, e.g.

S p-chlorobenzoylaziridine and the like.

20th

According to variant b), a compound of the formula III can be reacted with ammonia at a temperature between about -40 ° C. and 50 ° C., if desired in the presence of a solvent, such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like. It is expedient to work in the presence of a solvent at about room temperature. If you have a 9th

Benzoylaziridine of the formula III used, is preferably carried out in the presence of an inert solvent, such as dimethylformamide, toluene or benzene.

£ «* 5

The radical R is converted into amino according to variant c) in a manner known per se, depending on the nature of the radical R. If this is a 35 amide, the conversion is expediently carried out by acidic or basic hydrolysis. Used for the acidic hydrolysis advantageously a solution of a mineral acid, such as hydrochloric acid, aqueous hydrogen bromide, sulfuric acid,

Phosphoric acid and the like in an inert solvent such as an alcohol e.g. Methanol or ethanol, an ether, e.g. Tetrahydrofuran or dioxane. Aqueous solutions of alkali metal hydroxides, such as potassium or sodium hydroxide, can be used for the basic hydrolysis. Inert organic solvents, as mentioned above for acid hydrolysis, can be added as solubilizers. The reaction temperature for the acidic and basic hydrolysis can be varied in a range from about room temperature to the reflux temperature, preferably at a boiling temperature of the reaction mixture or a little less. If R5 is phthali-mido, then in addition to acidic and basic hydrolysis, amino lysis can also be carried out with an aqueous solution of a lower alkylamine, such as methylamine or ethylamine. As an organic solvent, one can use an alkanol such as ethanol. This reaction is preferably carried out at room temperature. A; The third method for converting phthalimido into amino 20 consists in reacting 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 25 to about 100 ° C, preferably at the boiling point of the chosen solvent. The resulting product can be shaken out with dilute mineral acid and then obtained by basing the acidic solution. The t-butoxy-30 carbonylamino radical is expediently converted into the amino group with trifluoroacetic acid or formic acid in the presence or absence of an inert solvent at about room temperature, while the trichloroethoxycarbonylamino group is converted with zinc or cadmium under 35 acidic conditions. The acidic conditions are conveniently achieved by reacting the reaction in acetic acid in the presence or absence of an additional inert solvent such as an alcohol, e.g. Methanol, - 8 - carries out. The benzyloxycarbonylamino radical can be converted in a known manner by acid hydrolysis as described above or by hydrogenolysis into the amino group. An azido group can be prepared using known methods, for example using elemental hydrogen in the presence of a catalyst such as palladium / carbon, Raney nickel, î *

Platinum oxide and the like can be reduced to the amino group. A hexamethylenetetrammonium group can also be converted into the 10 amino group by acid hydrolysis using known methods.

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

*; r *

The D compounds of the formula III used as starting materials in variant b) are also known or 20 analogs to known compounds and can be prepared in a manner known per se. For example, for the preparation of compounds of the formula III, 3 4 in which R is hydrogen and R is a leaving group, a compound of the formula II or a reactive functional derivative thereof is reacted with ethanolamine under the reaction conditions given for variant a) and the resulting N - (2-Hydroxyethyl) benzamide in a manner known per se, for example by reacting with a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride and the like, an arylsulfonyl halide such as tosyl chloride, or an alkylsulfonyl halide such as mesyl chloride

Transfer compound of formula III. A compound 3 of formula m, wherein R and R together represent an additional bond, can be obtained, for example, by reacting a reactive functional derivative of a compound of formula II with ethyleneimine. The implementation can be carried out under the - 9 -

Reaction conditions take place.

The compounds of formula IV used as starting materials in variant c) are also known or are analogs to known compounds and can be prepared in a manner known per se. For example, a compound of formula II or a reactive functional derivative thereof can be used with a compound of the general formula under the reaction conditions given for variant a)

h2n-ch2-ch2-r5 V

5 where R has the above meaning, 15 implement. The compounds of formula V are known or can be obtained analogously to the preparation of the known compounds.

: According to an alternative method, the compound fertilizers of formula IV, in which R is phthalimido, azido or hexamethylenetetrammonium, can also be obtained by reacting a compound of formula III with phthalimide potassium, an alkali metal azide or hexamethylenetetramine. The reaction is carried out in a manner known per se under the 25 reaction conditions given for variant b).

As already mentioned above, the compounds of the formula I and their pharmaceutically usable acid addition salts have monoamino oxidase (MAO) inhibitory activity. Because of this activity, the compounds of formula I and their pharmaceutically acceptable acid addition salts can be used for the treatment of depressive conditions and Parkinsonism.

The MAO inhibitory activity of the compounds according to the invention can be determined using standard methods. The preparations to be tested were p.o. administered to rats. Two hours later, the - 10 -

Animals were killed and the MAO inhibitory activity in homogenates of the brain and liver according to that in Biochem. Pharmacol. 12 (1963) 1439-1441 described method, but measured using phenethylamine (2 * 10 Mo1 * 1) .. 5 instead of tyramine as the substrate. The activity of some of the compounds according to the invention determined in this way and their toxicity is shown in the following EDj. Q values (μπιοΐ / kg, p.o. on the rat) or LD ^ q values (mg / kg, p.o.

"Visible on the mouse): 10 ___

Compound ED50 LD50 N- (2-aminoethyl) -p-chlorobenzamide 5.5 1000-2000 N- (2-aminoethyl) -p-fluorobenzamide 4> 5000 15 n- (2-aminoethyl) -p-bromobenzamide 4 500-1000 N- (2-aminoethyl) -3,4-dichlorobenzamide 10.3 1000-2000 N- (2-aminoethyl) -2,4-dichlorobenzamide 1.5 625-1250 N- (2-aminoethyl) benzamide 20> -5000

The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as healing agents, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be rectal, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

S,

For the production of tablets, coated tablets, coated tablets

and hard gelatin capsules can contain the compounds of the formula I.

and their pharmaceutically usable acid addition salts 35 are processed with pharmaceutically inert, inorganic or organic excipients. As such excipients one can e.g. For tablets, coated tablets and hard gelatin capsules use lactose, corn starch or derivatives thereof, talc, stearic acid - 11 - or its salts etc.

Suitable excipients for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.

£

Suitable excipients for the production of solutions and syrups are e.g. Water, polyols, sucrose, invert sugar, glucose etc.

10 The following are suitable excipients for injection solutions, e.g. Water, alcohols, polyols, glycerin, vegetable oils etc.

15 For suppositories, excipients are e.g.

natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.

j The pharmaceutical preparations can also contain 20 preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other thera-25 valuable substances.

According to the invention, compounds of the general formula I and their pharmaceutically usable acid addition salts can be used in combating or preventing 30 depressive states and Parkinsonism. The dosage can vary within wide limits and is of course to be adapted to the individual circumstances in each individual case. In general, a daily dose of about 10 to 100 mg of a compound of the general formula I should be appropriate for oral administration, although the upper limit just indicated can also be exceeded if this should prove to be appropriate.

The following examples are intended to illustrate the present invention, but in no way limit it.

All temperatures are given in degrees Celsius.

- 12 - 5 10 15 20 25 30 35 - 13 -

Example 1 18.5 g of ethyl 4-chlorobenzoate and 24 g of ethylene diamine 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),

Mp. 266-268 °, is suction filtered, and the filtrate washed three times with 50 ml of water and evaporated. The residue 10 is mixed with 100 ml of 1N hydrochloric acid, the insoluble N, N'-ethylenebis (4-chlorobenzamide) (1.0 g) is filtered off with suction, and the filtrate is evaporated to dryness. The residue is then evaporated twice with 100 ml of ethanol / benzene and recrystallized from ethanol / ether. Man er-15 holds 13.7 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, mp. 216-217 °.

Example 2 20 9.25 g of 4-chlorobenzoic acid ethyl ester and 16.0 g of N- (t-

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, dried over sodium sulfate and evaporated to dryness. The crystalline residue is taken up in isopropyl ether and suction filtered. 3.9 g of t-butyl [2- (4-chlorobenzamido) ethyl] carbamate are obtained, mp 141-143 °.

30th

A solution of 2.8 g of t-butyl [2- (4-chlorobenzamido) ethyl carbamate in 50 ml of formic acid is left to stand at room temperature for 1.5 hours. The reaction mixture is then evaporated to dryness, and the residue is dissolved in 35 ml of hydrochloric acid (1: 1; v / v). The solution is concentrated, evaporated again twice with ethanol / benzene, and the residue is recrystallized from ethanol. 2.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, - 14 - are obtained, which is identical to the product obtained in Example 1.

Example 3 5 i 23 ml (0.17 mol.) At 0 ° C. are added to a suspension of 23.5 g (0.15 mol) of 4-chlorobenzoic acid and 15 ml (0.16 mol) of ethyl chloroformate in 200 ml of chloroform ) Triethylamine dropped. After the addition (1/2 hour) 10, the solution obtained 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 conc. Dropped in hydrochloric acid. The acidic mixture is filtered and the remaining neutral parts are removed by extraction 15 with chloroform. The aqueous phase is then made alkaline with sodium hydroxide solution 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. 20 15.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, mp. 212-214 °, are obtained. The free base melts at 43-45 °.

Example 4 25 19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and dissolved by adding 15.3 ml (0.11 mol) of triethylamine. Then 10 ml (0.1 mol) of ethyl chloroformate are added dropwise at 0 °. After the addition (1/2 hour) is poured onto 30 ice / water. The methylene chloride phase is separated off, 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 tetrahydrofuran. After the end of the addition (1/2 hour), the mixture is filtered, 35 and after acidifying the filtrate with dilute hydrochloric acid, the neutral parts are removed by extraction with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After - 15 -

Drying and concentration of the chloroform phases, the residue is converted into the hydrochloride. After recrystallization from ethanol / ether, 7.1 g of N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride, mp. 179-182 °.

5

Example 5

22.1 ml of 10 (0.16 mol) of triethylamine are added dropwise to a suspension of 23.5 g (0.15 mol) of 2-chloro-benzoic acid in 200 ml of chloroform at 10 °. Then 14.8 ml (0.155 mol) of ethyl chloroformate are added dropwise at the same temperature. After the addition has ended (1 hour), the reaction mixture is poured onto ice / water. The chloroform phase is separated off, dried over magnesium sulfate and gently 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. When the addition is complete, the sparingly soluble neutral parts are filtered off, and the filtrate is concentrated and the excess ethylenediamine is removed in a high vacuum. The residue obtained (31.5 g) is converted into the hydrochloride and recrystallized

Ethanol / ether further purified. 19.2 g of N- (2- 1) are obtained.

Aminoethyl) -2-chlorobenzamide hydrochloride, mp 155-158 °.

25 An analytically pure sample melts at 159-161 °.

13.5 g of N- (2-aminoethyl) -3-2) chlorobenzamide hydrochloride were obtained in an analogous manner, starting from 23.5 g (0.15 mol) of 3-chlorobenzoic acid, mp. 201-203 °. The 30 free base melts at 69-71 ° (from ethyl acetate / n-hexane).

1) cf. Example 6 of German Offenlegungsschrift 2,362,568 35 2) cf. Example 7 of German Offenlegungsschrift 2,616,486-16 Example 6 24.4 g (0.2 mol) of benzoic acid are reacted in the manner described in Example 5 with triethylamine and ethyl chloroformate 5 and at 10 ° to a solution of 53 5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform was added dropwise. After filtering off the sparingly soluble neutral parts, the chloroform solution is concentrated and the excess ethylenediamine is removed in a high vacuum. The 10 oily residue (36.3 g) is taken up in 200 ml of 2N sodium hydroxide solution, 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 into the hydrochloride and further purified by recrystallization from ethanol, 5.2 g of N- (2-aminoethyl) benzamide hydrochloride being obtained, mp. 163-165 °.

Example 7 20

5.5 ml (0.04 mol) of triethylamine and then 3.8 ml (0.04 mol) are added to a suspension of 6.4 g (0.04 mol) of 4-methoxybenzoic acid in 60 ml of chloroform at 10 °. Chloroformic acid ethyl ester dropped. The reaction solution obtained 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, the mixture is filtered. The filtrate is concentrated under reduced pressure and then freed from excess ethylenediamine in a high vacuum.

30 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 the chloroform extracts have been dried and concentrated, the residue is converted into the hydrochloride. Recrystallization from ethanol / ether gives 3.4 g of N- (2-aminoethyl) -4-_ J. Amer. Chem. Soc. 6_1, 822 (1939) 2) - 17 - anisamide hydrochloride, mp. 186-189 °. The free base melts at 37-38 °.

In an analogous manner to that described above, he received 5: *

Starting from 20.4 g (0.15 mol) of 4-methylbenzoic acid - ’2) 8.7 g of N- (2-aminoethyl) -4-toluamide hydrochloride,

164-166 °; 10 starting from 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid 9.1 g of N- (2-aminoethyl) -3,4-dichlorobenzamide hydrochloride, mp. 183-185 °; the free base melts at 98-100 °; 15 starting from 12.2 g (0.08 mol) of 2-methoxybenzo-1) - - acid 9.3 g of N- (2-aminoethyl) -2-anisamide hydrochloride,

M.p. 109-111 °; 20 _ starting from 12.2 g (0.08 mol) of 3-methoxybenzoic acid 6.2 g of N- (2-aminoethyl) -3-anisamide hydrochloride,

Mp 96-98 °; starting from 3.9 g (0.015 mol) of 5- (dimethylsul-25 famoyl) -2-methoxybenzoic acid 1.4 g of N- (2-aminoethyl) - 5- (dimethylsulfamoyl) -2-anisamide hydrochloride, mp.

193-195 ° (dec.). The free base melts at 118-123 °.

30 _ 2) cf. Example 7 of German Offenlegungsschrift 2,616,486 cf. Example 6 of German Offenlegungsschrift 35 2,362,568 "1) - 18 -

Example 8 11.8 g (0.08 mol) of 4-cyanobenzoic acid are reacted and worked up in a manner analogous to that in Example 7 with triethylamine and 5 ethyl chloroformate and then added dropwise to a solution of 21.4 ml of ethylenediamine in 350 ml of chloroform. After the addition of 45 ml of dimethylformamide, the reaction mixture is heated at 60 ° for 1 hour. After filtering off, the filtrate is concentrated, 10 and the residue is further treated in the same manner as in Example 7. 3.5 g of N- (2-aminoethyl) -4-cyanobenzamide hydrochloride, mp. 212-215 ° (dec.) Are obtained. The free base melts at 124-126 °.

15 Starting from 4.5 g (0.023 mol) of 4-trifluoromethylbenzoic acid, 3.1g of N- (2-amino- ^ ethyl) -a, a, a-trifluoro-4-toluamide hydrochloride were obtained in an analogous manner,

M.p. 196-199 °; the free base melts at 66-68 ".

20 Example 9

A solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl-25 chloride in 150 ml of ether is added to a solution of 10 ml (0.15 mol) of ethylenediamine in 150 ml of ether at -10 ° in the course of half an hour dripped. The mixture is allowed to warm to room temperature, filtered and the white residue is washed twice with ether. After concentration of the ether solution, the residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate to remove the neutral 30 parts. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After evaporation of the chloroform, transfer of the residue into the hydrochloride and recrystallization from ethanol / ether, 1.8 g of N- (2-35 aminoethyl) -4-chlorobenzamide hydrochloride is obtained with that obtained in Example 1 Product is identical.

- 19 -

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 were obtained with a melting point of 178-179 °, which corresponds to that in Example 4 product obtained 5 is identical.

. Example 10 7 g (0.039 mol) of methyl 3,4-methylenedioxybenzoate and 8.5 ml (0.126 mol) of ethylenediamine are heated to 100 ° (bath temperature) for 2 1/2 hours. After cooling, the excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydrochloric acid and extracted with chloroform. The 15 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 chloroform / hexane, 3.4 g of N- (2-aminoethyl) -1,3-benzdioxol-5-carboxamide are obtained, mp. 120-123 °. The 20 hydrochloride melts at 210-213 °.

Example 11 10.7 g (0.05 mol) of methyl 4-bromobenzoate and 25 10.4 ml (0.15 mol) of ethylenediamine are heated to 130 ° (bath temperature) for 30 minutes. After working up analogously to that described in Example 10, 6.5 g of N- (2-aminoethyl) -4-bromobenzamide hydrochloride are obtained after recrystallization from methanol / ether, mp. 229-232 °.

30th

Example 12

10.6 ml (0.16 mol) of ethylenediamine are added to 6.65 g (0.04 mol) of methyl 4-methoxybenzoate ^. The solution is heated to 130 ° (bath temperature) for two hours and, after cooling in a high vacuum, freed from excess ethylenediamine. The residue is acidified with dilute hydrochloric acid. The sparingly soluble neutral parts - 20 - are removed by filtration and subsequent extraction with ethyl acetate. The aqueous phase is made alkaline with 28% sodium hydroxide solution, saturated with sodium chloride and extracted three times with chloroform.

5 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 ^, mp. 201-204 °.

10th

8.9 g of N- (2-aminoethyl) -4-chloro-2 were obtained in an analogous manner, starting from 20 g (0.1 mol) of methyl 4-chloro-2-methoxybenzoate and 20.1 ml (0.3 mol) of ethylenediamine -anisamide hydrochloride obtained, mp. 132-135 ° (dec.).

15

Example 13 - 7.7 g (0.05 mol) of methyl 4-fluorobenzoate and 10 ml (0.15 mol) of ethylenediamine are heated to 130 ° C. (bath temperature) for 2 hours. The reaction mixture is poured onto ice / hydrochloric acid and extracted with ethyl acetate to remove the neutral parts. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. After drying and concentrating the chloro-25 form extracts, the residue (7.6 g) is recrystallized from ethyl acetate / hexane, giving N- (2-aminoethyl) -4-fluorobenzamide, mp. 57-60 °. The hydrochloride melts at 214-216 °.

30 Example 14

To a solution of 1.02 g (0.01 mol) of acetylethylene-3) diamine and 1.4 ml (0.01 mol) of triethylamine in 25 ml ^ chloroform is added a solution of 1.3 ml (0, 01 mol) 35 _ 2) cf. Example 7 of German Offenlegungsschrift 2,616,486 3) J. Amer. Chem. Soc. 6_1, 822 (1939) - 21 - 4-chlorobenzoyl chloride dropped in 15 ml of chloroform. After 15 minutes, the crystals formed are filtered off, washed with chloroform and dried. 1.9 g of N- (2-acetylaminoethyl) -4-chlorobenzamide, mp. 222-224 °.

5

What is obtained is used to cleave the protective group

iT

N- (2-Acetylaminoathyl) -4-chlorobenzamide in a mixture of 24 ml of 2N hydrochloric acid and 15 ml of ethanol was heated to reflux for 22 hours. After concentrating the reaction solution, the crude product is recrystallized from ethanol / ether. This gives 1.2 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, mp. 211-213 °, which is identical to the product obtained in Example 1.

Example 15 Λ To a solution of 1.2 ml (0.02 mol) of ethanolamine = 5- and 3 ml (o / 0.02 mol) of triethylamine in 30 ml of methylene chloride, 2.6 ml (0.02 Mol) 4-chlorobenzoyl-chlorxd added dropwise. The mixture is then poured onto dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extracts are dried over magnesium sulfate and concentrated. After purification on silica gel with chloroform and chloroform / methanol 9: 1 as eluent 25, 3.1 g of N- (2-hydroxyethyl) -4-chlorobenzamide are obtained.

To a solution of 1.5 g (0.0075 mol) of N- (2-hydroxy-9 ethyl) -4-chlorobenzamide and 1 ml of triethylamine in 15 ml

A solution of 0.6 ml of methane-30 sulfonic acid chloride in 3 ml of methylene chloride is added dropwise to methylene chloride at 0 °. After 15 minutes, the reaction mixture is poured onto ice / water and extracted. 2.1 g of N- (2-methylsulfonyl-oxyethyl) -4-chlorobenzamide are obtained in crystalline form, which is used 55 in the next step without further purification.

The N- (2-methylsulfonyloxyethyl) -4-chloro-benzamide 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 worked up and N- (2-aminoethyl) -4-chlorobenzamide is obtained, which is identical to the product obtained in Example 1.

5

Sr *

Example A

îr

Gelatin plug capsule of 5 mg 10 each Composition: 1. N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride 5.78 mg *) 2. Milk sugar powder 80.22 mg 3. Corn starch 40.00 mg 15 4 Talc 3.60 mg 5. magnesium stearate 0.40 mg 6. milk sugar krist. 110.00 mg

Capsule filling weight 240.00 mg 20

Production process: 1-5 are mixed and sieved through a sieve with a mesh size of 0.5 mm. Then 6 is added and mixed.

2q This ready-to-fill mixture is filled into gelatin capsules of a suitable size (e.g. No. 2) with a single filling weight of 240 mg.

2Q *) corresponds to 5 mg base w * 35 - 23 - Example B tablet of 5 mg 5 each Composition: V · * e 1.N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride 5.78 mg *) 2 Milk sugar pulp. 104.22 mg OK 3rd corn starch 45.00 mg 4th polyvinyl pyrrolidone K 30 15.00 mg 5th corn starch 25.00 mg 6th talc 4.50 mg 7th magnesium stearate 0.50 mg * 15 tablet weight 200 , 00 mg ~ Procedure: 1-3 are mixed and sieved through a sieve with a mesh size of 0.5 mm. This powder mixture is moistened with an alcoholic solution of 4 and kneaded. The moist mass is granulated, dried and prepared for a suitable grain size. 5, 6 and 7 are successively added to the dried granules and mixed. The 25 ready-to-press mixture is pressed into tablets of a suitable size with a nominal weight of 200 mg.

«*) Corresponds to 5 mg Base 30 35 - 24 -

Example C

Gelatin plug capsule à 10 mg 5 Composition: 1. N- (2-aminoethyl) -p-chlorobenzamide- * * hydrochloride 11.84 mg *) 2. Milk sugar powder 74.16 mg 10 3. Maize starch 40.00 mg 4 Talc 3.60 mg 5. magnesium stearate 0.40 mg 6. milk sugar krist. 110.00 mg

Capsule filling weight 240.00 mg 15

Production process: 1-5 are mixed and sieved through a sieve with a mesh size of 0.5 mm. Then 6 is added and mixed. 20 This ready-to-fill mixture is filled into suitable sized gelatin capsules (e.g. No. 2) with a single filling weight of 240 mg.

25 *) corresponds to 10 mg base «30 35 - 25 -

Example D tablet of 10 mg 5 composition: ή 1. N- (2-aminoethyl) -p-chlorobenzamide ^ hydrochloride 11.84 mg *) 2. milk sugar powder 103.16 mg 3. corn starch 40.00 mg 4. Polyvinylpyrrolidone K 30 15.00 mg 5th corn starch 25.00 mg 6th talc 4.50 mg 7th Magnesium stearate 0.50 mg 15 tablet weight 200.00 mg

Procedure: 1-3 are mixed and sieved through a sieve with 0.5 mm 20 mesh size. This powder mixture is moistened with an alcoholic solution of 4 and kneaded. The moist mass is granulated, dried and prepared for a suitable grain size. 5, 6 and 7 are successively added to the dried granules and mixed. The 2Q ready-to-press mixture is pressed into tablets of a suitable size with a nominal weight of 200 mg.

»*) Corresponds to 10 mg base 30 35

Claims (22)

26. DS 4081/75 1. Benzamide derivatives of the general formula 0 2. Compounds according to claim 1, wherein R and R each independently represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl. 1 2 3. Compounds according to claim 2, wherein R and R 25 are each independently hydrogen, halogen or lower. Mean alkyl. 4. Compounds according to one of claims 1-3, characterized in that R and R, if they are different from water-30 substance, are in 2,3-, 2,4-, 2,5- , 3,4- or 3,6-position. 3-position means R is different from hydrogen, ^ and pharmaceutically usable acid addition salts thereof ^ as active pharmaceutical ingredients. 12 5. Compounds according to claim 4, characterized in that R and R are in the 2,4- or 3,4-position 35. 5 H 1 / V /C\n/'v./NH2 s1 / 5 h 1 V »v, · Π; '-V 1 2 10 wherein R and R independently of each other hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono-lower alkylsulfamoyl or di-lower alkylsulfamoyl or, if they are adjacent, together a methylenedioxy group 15 mean with the proviso that if R bromine in 2 6. N- (2-aminoethyl) benzamide as a compound according to claim 3. 27. DS 4081/75 7. Compounds according to any one of claims 1-6 as antidepressants or anti-Parkinson agents. 8. Benzamide derivatives of the general formula 5 '0 · /' \ / C \ / '' / NH2 Ia i «5 · Rll'X \ 21 9. Compounds according to claim 8, wherein R is halogen, 21 11 j ^ cyano or trifluoromethyl and R is hydrogen or R 21 20 and R are each chlorine. 11 10. Compounds according to claim 9, wherein R is halogen 21 11 21 and R is hydrogen or R and R are each chlorine. 25th 11. N- (2-aminoethyl) -p-chlorobenzamide or a pharmaceutically usable acid addition salt thereof. f 12. N- (2-aminoethyl) -p-fluorobenzamide or a pharmaceutically usable acid addition salt thereof. 30th 10 R -R 11 21 wherein R is halogen, cyano or trifluoromethyl and R 11 21 is hydrogen or R and R are each chlorine or, if they are adjacent, together represent a methylenedioxy group * 15, and pharmaceutically acceptable acid addition salts thereof. 11 13. N- (2-aminoethyl) -p-bromobenzamide or a pharma "3 usable acid addition salt thereof. 14. N- (2-aminoethyl) -3,4-dichlorobenzamide or a pharmaceutically acceptable acid addition salt thereof. 15. N- (2-aminoethyl) -2,4-dichlorobenzamide or a pharmaceutically acceptable acid addition salt thereof. 28. DS 4081/75 16. Compounds according to any one of claims 8-15 as active pharmaceutical ingredients. 17. Compounds according to any one of claims 8-15 as 5 antidepressants or anti-Parkinson agents. r; 18. A process for the preparation of compounds of the formula Ia defined in claim 8 and of pharmaceutically usable acid addition salts thereof, characterized in that a) a compound of the general formula 0 II ✓ \ / C "0H 15 f, 1 II 11 21 wherein R and R have the meaning given in claim 8 in the form of the free acid or in the form of a reactive (20 capable functional derivative thereof with ethylenediamine 1, or b) a compound of the general formula 0 25 ** / Y Y7 Y 111, Ιΐ'Υ * ^! * 3 R 11 0Λ 30 wherein R and R have the meaning given in Claim 8 3 4 R is hydrogen and R is a leaving group 3 4 or R and R together represent an additional bond,> - with ammonia converts, or 35 c) in a compound of the general formula 29.DS 4081/75 Ο 11 5 ^ * \ / C \ n / * \ / R tv i il? 'IV 5 / * \ x * H R11 -V1 A 11 21 in which R and R have the meaning given in claim 8, 5 "and Ednai in an aminogriçpe means excess radical," * 0 converts the radical R ^ into the amino group , and if desired, convert a compound obtained into a pharmaceutically acceptable acid addition salt. 19. Medicament containing a compound defined in one of claims 15 1-6 and 8-15. 20. Containing antidepressants or anti-Parkinson drugs | a compound defined in any of claims 1-6 and 8-15. 20 25 * * s 35 30. DS 4081/75 21. Use of a compound defined in one of claims 1-6 and 8-15 in the control or prevention of diseases. 22. Use of a compound defined in one of claims 1-6 and 8-15 in the control or prevention of depressive states and Parkinsonism. *** 10 15 20 n 25 KV * - · »30 35