CH653670A5 - BENZAMIDE DERIVATIVES. - Google Patents

Description

The present invention relates to benzamide derivatives. In particular, it relates to N-aminoethyl-substituted benzamides of the general formula

O

65

R

• C • NH

^ \ / \ M / \ / 2

»• N •

y

* v

H

wherein R1 and R2 independently of one another each represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono-lower alkylsulfamoyl or di-non-deralkylsulfamoyl or, if they are adjacent, together represent a methylenedioxy group, and pharmaceutically usable acid addition salts from that.

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

The present invention relates to compounds of the general formula I and their pharmaceutically usable acid addition salts as active pharmaceutical ingredients, medicaments containing, as an active component, 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 and their pharmaceutically usable acid addition salts for the production of antidepressants and antiparkinson agents.

Of the compounds encompassed by the present formula I, the benzamides are of the general formula

3,653,670

Preferred compounds of the formula I are those in which R1 and R2 independently of one another denote hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl.

Those compounds of the formula I in which R1 and R2 independently of one another are each hydrogen, halogen or lower alkyl are particularly preferred.

Very particularly preferred compounds of the formula I are:

N- (2-aminoethyl) -p-chlorobenzamide, N- (2-aminoethyl) -p-fluorobenzamide, N- (2-aminoethyl) -p-bromobenzamide, N- (2-aminoethyl) -3,4-dichlorobenzamide, N- (2-aminoethyl) -2,4-dichlorobenzamide and 15 N- (2-aminoethyl) benzamide.

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

20th

O

25th

\ /

| l] R11 'VV1

II

C - OH

II

O

^ '\ / C \ N / "\ / NH2

: • N

R

11

/ ^

H

21st

wherein R11 and R21 have the above meaning, in the form of the free acid or in the form of a reactive functional I a derivative thereof with ethylenediamine, or b) a compound of the general formula

O

35 II

in which R11 is halogen, cyano or trifluoromethyl and R21 is hydrogen or R11 and R21 are each chlorine or, if they are adjacent, together a methylenedioxy group, and their acid addition salts are new and as such are also the subject of the present invention.

The present invention finally relates to a process for the preparation of the compounds of the formula Ia above and their pharmaceutically usable acid addition salts. 45

The term "lower alkyl" used in this description refers to straight-chain and branched hydrocarbon radicals with 1-6, preferably 1 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert. Butyl and the like. The term "lower alk-50 oxy" 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" means 55 groups known in the context of the present invention such as halogen, preferably chlorine or bromine, arylsulfonyloxy such as tosyloxy, alkylsulfonyloxy such as mesyloxy and the like.

The term "pharmaceutically acceptable 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, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. 65 Such salts can be readily prepared by any person skilled in the art in view of the state of the art and considering the nature of the compound to be salted.

III

S x.

! !! 's U

ll / W21R r R R

wherein R'1 and R21 have the above meaning, R3 is hydrogen and R4 are a leaving group or R3 and R4 together represent an additional bond, reacted with ammonia, or c) in a compound of the general formula

O II

• O • P "

^ \ / - \ .. / \ / K

N •

IV

R11 '^ V1

H

60

wherein R11 and R21 are as defined above and R5 is a residue which can be converted into an amino group, the residue R5 is converted into the amino group and, if desired, a compound obtained is converted into a pharmaceutically acceptable acid addition salt.

Suitable reactive functional derivatives of the acids of formula II include, for example, halides, e.g. Chlorides, symmetrical or mixed anhydrides, esters, e.g. Methyl esters, p-nitrophenyl esters or N-hydroxysuccinimide esters, azides and amides, e.g. Imidazolides or succinimides.

The reaction of an acid of formula II or a reactive functional derivative thereof with ethylenediamine according to variant a) of the above process can be carried out according to

653 670 4

carry out usual methods. So you can e.g. reacting a free IV with hydrazine in an inert solvent, such as ether acid of the formula II, with ethylenediamine in the presence of an anol, a mixture of ethanol and chloroform, tetrahy condensing agent in an inert solvent, or aqueous ethanol. The reaction zen. If a carbodiimide, such as dicyclohexylcarbodiimide, can be used as the temperature condensing agent in a range from about room temperature, the reaction will be varied from 5 to about 100 ° C., preferably in an alkane carboxylic acid ester such as ethyl boiling point of the chosen solvent. This did, an ether such as tetrahydrofuran or dioxane, a product can be shaken with dilute mineral acid from chlorinated hydrocarbon such as methylene chloride or shaken and then obtained by basing the chloroform, an aromatic hydrocarbon such as acidic solution. The t-butoxycarbonylami-benzene, toluene or xylene, acetonitrile or dimethylform 10 norest is expediently used with trifluoroacetic acid or amamide, at a temperature between about -20 ° C. and the sensic acid in the presence or absence of an inert room temperature, preferably at about 0 ° C. solvent at about room temperature in the amino group If phosphorus trichloride is used as the condensing agent, while the conversion of the Triehloräthoxycar-so the reaction is conveniently in a solvent, bonylamino group with zinc or cadmium under acidic conditions such as pyridine, at a temperature between about 0 ° C. and the 15 conditions. The acidic conditions are reached at the reflux temperature of the reaction mixture, preferably moderately, by carrying out the reaction in acetic acid at about 90.degree. In another embodiment, in the presence or absence of an additional inert form of variant a), ethylenediamine is mixed with one of the white solvents, such as an alcohol, e.g. Methanol, through the above-mentioned reactive functional derivatives. The benzyloxycarbonylamino radical can be reacted in a known acid of the formula II. So you can e.g. a 20 way by acid hydrolysis as described above halide, e.g. the chloride, an acid of the formula II at or hydrogenolytically converted into the amino group-about 0 ° C. with ethylenediamine in the presence of a solvent. An azido group can be converted using known methods, such as diethyl ether. for example with elemental hydrogen in the presence of a

The compounds of the formula III in which R3 is a hydrogen catalyst, such as palladium / carbon, Raney nickel, platinum

and R4 represent a leaving group, for example, N-25 oxide and the like, are reduced to the amino group.

(2-Haloethyl) benzamides, such as N- (2-chloroethyl) benzamides. A hexamethylene tetrammonium group can be

N- (2-methylsulfonylethyl) benzamide or N- (2-p-toluene - if known methods by acid hydrolysis in the ami-

sulfonylethyl) benzamides and the like. The connections are transferred.

of the formula III, in which R3 and R4 together form an additional compound used as starting materials in variant a)

Represent bond are benzoylaziridines, e.g. p-chlorine bonds of the formula II or their reactive functional

benzoylaziridine and the like. nelle derivatives are known or can be

According to variant b), the position of the known compounds can be obtained in a manner known per se.

a compound of the formula III with ammonia at a temperature of about -40 ° C. and 50 ° C., which is used as the starting material in variant b), desired compounds of the formula III are also known or else in the presence of a solvent, such as dimethylform 35 ioga to known compounds and can be prepared in a manner known per se, amide, dimethylacetamide, dimethyl sulfoxide and the like. So you can implement, for example. It is expedient to work in the presence of a to prepare compounds of the formula III in which R 3 is a solvent at about room temperature. If a hydrogen and R4 is a leaving group, a ver-benzoylaziridine of the formula III is used, preference is given to a bond of the formula II or a reactive functional in the presence of an inert solvent, such as dimethyl 40 derivative thereof, under the reac- tions indicated for variant a). formamide, toluene or benzene. reaction conditions with ethanolamine and the obtained N- (2-hydroxyethyl) benzamide in a manner known per se. The conversion of the radical R into amino according to the Va manner, e.g. by reaction with a halogenating agent, variant c) is also carried out in a manner known per se, in such a way as phosphorus trichloride, phosphorus tribromide, and phosphorpenependence on the nature of the radical R. If this is an amide, 45 tachloride, phosphorus oxychloride and the like, an aryl, the conversion is expediently carried out by acidic or basic sulfonyl halide, such as tosyl chloride, or an alkylsulfonic hydrolysis. For the acidic hydrolysis, pre-nyi halide, such as mesyl chloride, is used to convert the desired compound, in some cases a solution of a mineral acid, such as salting of the formula III. A compound of foracid, aqueous hydrogen bromide, sulfuric acid, phosphorus in which R3 and R4 together are an additional bond acid and the like, in an inert solvent such as a significant one, for example by reacting a reactive alcohol, e.g. Methanol or ethanol, an ether, e.g. functional derivative of a compound of tetrahydrofuran or dioxane. For the basic hydrolysis formula II can be obtained with ethyleneimine. The reaction can be aqueous solutions of alkali metal hydroxides, such as can be used under the reaction potassium or sodium hydroxide solution given for variant a). Inert organic conditions occur

Solvents as mentioned above for the acid hydrolysis 55 j) depending on the variant c) used as starting materials can be added as solvent. The compounds of the formula IV are also known, or the ana-reaction temperature for the acidic and basic hydrogid to known compounds and can be prepared in a manner known per se in a range from about room to reflux temperature. For example, the temperature can be varied, preferably at a boiling point, a compound of the formula II or a reactive reaction mixture or a little less. 60 functional derivative thereof among those for variant a) R phthalimido, so besides the acidic and basic reaction conditions given with a compound of all-hydrolysis also aminolysis with an aqueous solution according to the formula of a lower alkylamine, such as methylamine or ethylamine,

be performed. A lower alkanol such as ethanol can be used as the organic solvent. This 6s

The reaction is preferably carried out at room temperature H2N-CH2-CH2-R5 V. A third method for converting phthalimido into amino acid is to implement compounds of the formula in which R5 has the above meaning. The connections

of the formula V are known or can be obtained analogously to the preparation of the known compounds.

According to an alternative process, the compounds of the formula IV in which R5 is phthalimido, azido or hexamethylenetetrammonium can also be obtained by reacting a compound of the formula III with phthalimide potassium, an alkali metal azide or hexamethylenetetramine. The reaction is carried out in a manner known per se under the 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. The animals were sacrificed two hours later and the MAO inhibitory activity in homogenates of the brain and liver after that in Biochem. Phar-macol. 12 (1963) 1439-1441, but using phenethylamine (2-10 ~ 5 mol-1'1) instead of tyramine as the substrate. The activity of some compounds according to the invention determined in this way and their toxicity can be seen from the following ED50 values (jamol / kg, p.o. on the rat) or LD50 values (mg / kg, p.o. on the mouse):

ED50 LD50 connection

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- (2nd -Aminoethyl) - 3,4-dichloro-benzamide

N- (2-aminoethyl) -2,4-dichlorobenzamide 1.5 625-1250

N- (2-aminoethyl) benzamide 20> 5000

10.3 1000-2000

25th

The compounds of formula I and their pharmaceutically usable acid addition salts can be used as medicaments, 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.

For the production of tablets, coated tablets, dragées and hard gelatin capsules, the compounds of the formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients. As such excipients one can e.g. for tablets, dragees and hard gelatin capsules, lactose, corn starch or derivatives thereof, talc, stearic acid 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.

Suitable excipients for injection solutions are e.g. Water, alcohols, polyols, glycerin, vegetable oils etc.

For suppositories, excipients are e.g. naturally

5 653 670

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

The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, flavoring 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 I and their pharmaceutically usable acid addition salts can be used in the control or prevention of depressive states and Parkinsonism. The dosage can vary within wide limits and must of course 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, but 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 not to limit it in any way. All temperatures are given in degrees Celsius.

example 1

18.5 g of ethyl 4-chlorobenzoate 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'-ethylenebis (4-chlorobenzamide) (2.3 g), mp 30 266-268 °, is filtered off with suction and the filtrate is washed three times with 50 ml of water each time and evaporated. The residue 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. Then the residue was evaporated again twice with 100 ml of ethanol / benzene and recrystallized from ethanol / ether. 13.7 g of N- (2-aminoethyl) - 4-chlorobenzamide hydrochloride, mp. 216-217 °.

40 Example 2

9.25 g of ethyl 4-chlorobenzoate and 16.0 g of N- (t-Bu-toxycarbonyl) 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 45 50 ml of ethyl acetate. 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 °.

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 50 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 are obtained, which is identical to the product obtained in Example 1.

50-

55

60

Example 3

23 ml (0.17 mol) of triethylamine are added dropwise at 0 ° 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. When the addition is complete (} half an hour), 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.

653 670 6

Dropped in hydrochloric acid. The acidic mixture is filtered, and the product is converted into the hydrochloride and purified by recrystallization - the remaining neutral parts are further extracted by extraction with stallization from ethanol, 5.2 g of N- (2-chloroform being removed. The aqueous phase is then washed with aminoethyl). benzamide hydrochloride (J. Amer. Chem. Soc. sodium hydroxide solution made alkaline and obtained several times with chloroform 61.822 (1939)), mp. 163-165 °.

extracted. The chloroform extracts are dried and 5 Example 7

constricted. The residue is converted into the hydrochloride. To a suspension of 6.4 g (0.04 mol) of 4-methoxybene

and recrystallized from ethanol / ether. 15.1 g of zoic acid in 60 ml of chloroform are obtained at 10 °, 5.5 ml of N- (2-aminoethyl) - 4-chlorobenzamide hydrochloride, mp (0.04 mol) of triethylamine and then 3.8 ml (0 , 04 mol) chlorine-212-214 °. The free base melts at 43-45 °. dropped formic acid ethyl ester. The reaction solution obtained

10 solution is then added dropwise at 5 ° to a solution of 10.7 ml (0.16 mol) of Example 4 ethylenediamine in 100 ml of chloroform. After two

19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are filtered in hours of stirring at room temperature. The fil

200 ml of methylene chloride and suspended by addition of concentrated is concentrated under reduced pressure and then dissolved in 15.3 ml (0.11 mol) of triethylamine. Then the high vacuum is freed from excess ethylenediamine, 10 ml (0.1 mol) of ethyl chloroformate at 0 ° C. The residue is added dropwise acidified with dilute hydrochloric acid. After the addition (1/2 hour) is extracted several times on ice / un <i with ethyl acetate. The aqueous phase is poured water. The methylene chloride phase is separated off, made alkaline with 28% sodium hydroxide solution and dried three times over magnesium sulfate and extracted to about 30 ml with chloroform. After drying and concentrating. This solution is converted at 0 ° to a solution of 20 ml of the chloroform extracts, the residue is converted into hy- (0.3 mol) ethylenediamine in 100 ml of tetrahydrofuran hydrochloride. By recrystallization from ethanol / drips. When the addition has ended (1/2 hour), the mixture is filtered, and ether is obtained 3.4 g of N- (2-aminoethyl) -4-anisamide-hy-after acidifying the filtrate with dilute hydrochloric acid, hydrochloride (cf. Example 7 of the Germans Laid open the neutral parts by extraction with ethyl acetate. 2 616 486), mp. 186-189 °. The free base melts at 37-38 °. The aqueous phase is made alkaline with sodium hydroxide solution. The following were obtained in an analogous manner to that described above:

and extracted several times with chloroform. After drying 25 ~ starting from 20.4 g (0.15 mol) of 4-methylbenzoic acid and concentrating the chloroform phases, the residue is converted into 8.7 g of N- (2-aminoethyl) - 4-toluamide hydrochloride (cf. bei-hydrochloride According to recrystallization game 7 of German Offenlegungsschrift 2,616,486), mp 7.1 g of N- (2-aminoethyl) -2,4-di-164-166 ° from ethanol / ether;

chlorobenzamide hydrochloride, mp. 179-182 °. - starting from 17.2 g (0.09 mol) of 3,4-dichlorobenzo

30 acids 9.1 g of N- (2-aminoethyl) -3,4-dichlorobenzamide hy-example 5 drochloride, mp. 183-185 °; the free base melts

To a suspension of 23.5 g (0.15 mol) of 2-chlorobene at 98-100 °;

zoic acid in 200 ml chloroform are 22.1 ml at 10 ° - starting from 12.2 g (0.08 mol) of 2-methoxybenzo

(0.16 mol) of triethylamine was added dropwise. Then 14.8 ml of acid 9.3 g of N- (2-aminoethyl) - 2-anisamide hydrochloride (cf.

(0.155 mol) ethyl chloroformate in the same 35 Example 6 of German Offenlegungsschrift 2,362,568), temperature added dropwise. When the addition is complete, mp 109-111 °;

(1 hour) the reaction mixture is poured onto ice / water - starting from 12.2 g (0.08 mol) of 3-methoxybenzene. The chloroform phase is separated off, 6.2 g of N- (2-aminoethyl) -3-anisamide hydrochloride, sodium sulfate are dried over magnesic acid and gently poured in to about 60 ml, mp. 96-98 °;

tight. The solution obtained in this way becomes a solution 40 at 10 °, starting from 3.9 g (0.015 mol) of 5- (dimethylsulfamo) from 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform yl) - 2-methoxybenzoic acid 1.4 g of N- (2-aminoethyl) - 5- (di-dripped. After the addition has ended, the sparingly soluble methylsulfamoyl) 2-anisamide hydrochloride, mp. 193-195 ° neutral parts are filtered off, and the filtrate is concentrated and concentrated on (decomp .). The free base melts at 118-123 °.

Excess ethylene diamine removed under high vacuum.

The residue obtained (31.5 g) is converted into the hydrochloride 45 Example 8

transferred and by recrystallization from ethanol / ether 11.8 g (0.08 mol) of 4-cyanobenzoic acid are

further cleaned. 19.2 g of N- (2-aminoethyl) are obtained in the same manner as in Example 7 with triethylamine and chloramethyl

2-chlorobenzamide hydrochloride (cf. Example 6 of the German ethyl sensate reacted and worked up and then to laid-open specification 2 362 568), mp. 155-158 °. An analy- a solution of 21.4 ml ethylenediamine in 350 ml chloro-pure sample melts at 159-1610. 50 dripped form. After the addition of

Analogously, starting from 23.5 g of 45 ml of dimethylformamide, the mixture was heated to 60 ° for 1 hour. To

(0.15 mol) 3-chlorobenzoic acid 13.5 g N- (2-aminoethyl) -3- the filtrate is concentrated, and the re-chlorobenzamide hydrochloride (see Example 7 of the Germans was in the same manner as in Treated further Example 7. Laid-open specification 2 616 486), obtained, mp. 201-203 °. The result is 3.5 g of N- (2-aminoethyl) - 4-cyanobenzamide-hy-free base melts at 69-71 ° (from ethyl acetate / n-hexane). SS drochloride, mp 212-215 ° (dec.). The free base melts

124-126 °.

Example 6 Starting from 4.5 g (0.023 mol) of 4-trifluoromethylbene

24.4 g (0.2 mol) of benzoic acid are converted into 3.1 g of N- (2-aminoethyl) in the manner described in Example 5 with triethylamine and chloroformic acid a, a, a-trifhior-4- toluamide hydrochloride obtained, mp. reäthylester implemented and at 10 ° to a solution of 60 196-199 °; the free base melts at 66-68 °.

53.5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform according to Example 9

drips. After filtering off the sparingly soluble neutral solution, the chloroform solution is concentrated to a solution of 10 ml (0.15 mol) of ethylenediamine and 50 ml of ether is removed in vacuo from the excess ethylenediamine at -10 ° in the course of half an hour in the course of half an hour. The oily solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride in the residue (36.3 g) is added dropwise to 200 ml of 2N sodium hydroxide solution and 150 ml of ether. The mixture is allowed to warm to room temperature, saturated with solid sodium chloride and several times, filtered and the white residue is washed twice with extracted with ethyl acetate. The ethyl acetate extracts become ether after. After the ether solution has been concentrated, the residue is dried over magnesium sulfate and concentrated. The raw state acidified with dilute hydrochloric acid and with ethyl

653 670

Example B

5 mg tablet composition:

1. N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride

2. Milk sugar powder.

3. Corn starch

4. Polyvinylpyrrolidone K 30

5. Corn starch

6. Talk

7. Magnesium stearate

*) 5.78 mg 104.22 mg 45.00 mg 15.00 mg 25.00 mg 4.50 mg 0.50 mg

Production method:

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

10th

Example D

Tablet weight 200.00 mg tablet of 10 mg

*) corresponds to 5 mg base

15

Method:

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 granulate and mixed. The ready-to-press mixture is compressed into tablets of a suitable size with a nominal weight of 200 mg.

Example C

Composition:

1. N- (2-aminoethyl) -p-chlorobenzamide hydrochloride

2. Powdered milk sugar. 2o3. Cornstarch

4. Polyvinylpyrrolidone K 30

5. Corn starch

6. Talk

7. Magnesium stearate

*) 11.84 mg 103.16 mg 40.00 mg 15.00 mg 25.00 mg 4.50 mg 0.50 mg

25th

*) corresponds to 10 mg base

Tablet weight 200.00 mg

Gelatin capsule 10 mg each Composition:

1. N- (2-aminoethyl) -p-chlorobenzamide hydrochloride

2. Milk sugar powder.

3. Corn starch

4. Talk

5. Magnesium stearate

6. Milk sugar krist.

30th

*) 11.84 mg 74.16 mg 40.00 mg 3.60 mg 35 0.40 mg 110.00 mg

*) corresponds to 10 mg base

Capsule filling weight 240.00 mg

40

Method:

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 granulate and mixed. The ready-to-press mixture is compressed into tablets of a suitable size with a nominal weight of 200 mg.

C.

extracted several times to remove the neutral 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-aminoethyl) -4-chlorobenzamide hydrochloride are obtained which is identical to the product obtained in Example 1.

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-di-chlorobenzamide hydrochloride with a melting point of 178-179 ° were obtained with the product obtained in Example 4 is identical.

Example 10

1 g (0.039 mol) of 3,4-methylenedioxybenzoic acid methyl ester 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 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-benzodio-xol-5-carboxamide are obtained, mp. 120-123 °. The hydrochloride melts at 210-213 °.

Example II

10.7 g (0.05 mol) of methyl 4-bromobenzoate and 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 °.

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 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. 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 are obtained (cf. Example 7 of German Offenlegungsschrift 2,616,486), mp. 201-204 °.

Analogously, 8.9 g of N- (2-aminoethyl) -4-chloro-2 were obtained 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.)

Example 13

7.7 g (0.05 mol) of methyl 4-fluorobenzoate and 10 ml (0.15 mol) of ethylenediamine are heated to 130 ° (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 chloroform 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 °.

653 670

Example 14

To a solution of 1.02 g (0.01 mol) of acetylethylenediamine (J. Amer. Chem. Soc. 6J. 822 (1939)) and 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform a solution of 1.3 ml (0.01 mol) of 4-chlorobenzoyl chloride in 15 ml of chloroform is added dropwise at 0 °. 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 °.

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

Example 15

2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are added dropwise to a solution of 1.2 ml (0.02 mol) of ethanolamine and 3 ml (~ 0.02 mol) of triethylamine in 30 ml of methylene chloride. 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, 3.1 g of N- (2-hydroxyethyl) -4-chloro-benzamide are obtained.

A solution of 0.6 ml of methanesulfonic acid chloride is added 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 at 0 ° 3 ml of methylene chloride added dropwise. After 15 minutes, the reaction mixture is poured onto ice / 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 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 worked up and N- (2-aminoethyl) -4-chlorobenzamide is obtained, which is identical to the product obtained in Example 1.

Example A

5 mg gelatin capsule

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

4. Talc 3.60 mg

5. Magnesium stearate 0.40 mg

6. Milk sugar krist. 110.00 mg

Capsule filling weight 240.00 mg

*) corresponds to 5 mg base

Production method:

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

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Claims (18)

653 670 PATENT CLAIMS 1. Benzamide derivatives of the general formula usable acid addition salts thereof, characterized in that a compound of the general formula 0 H y il wherein R1 and R2 independently of one another each represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono-lower alkylsulfamoyl or di-niederalkylsulfamoyl or, if they are adjacent, together a methylenedioxy group, and pharmaceutically usable acid addition salts thereof as active pharmaceutical ingredients. 2. The method according to claim 1, wherein R1 and R2 each independently represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl. 3. Compounds according to claim 2, wherein R1 and R2 each independently represent hydrogen, halogen or lower alkyl. 4. N- (2-aminoethyl) benzamide as a compound according to claim 3. 5. Compounds according to any one of claims 1-4 as antidepressants or anti-Parkinson agents. 6. Medicament containing as active component a benzamide derivative of the formula I specified in claim 1 or a pharmaceutically acceptable acid addition salt thereof. 7. Antidepressant or anti-Parkinson agent according to claim 6. 8. Use of a benzamide derivative of the formula I specified in claim 1 or a pharmaceutically acceptable acid addition salt for the preparation of an antidepressant or anti-Parkinson agent. 9. Benzamide derivatives of the general formula i'V "0H . X '^ R21 wherein R11 and R21 have the above meaning, in the form of the free acid or in the form of a reactive functional derivative thereof, with ethylenediamine, and if desired, he-15 converts a compound obtained into a pharmaceutically acceptable acid addition salt. 18. A process for the preparation of compounds of the formula Ia defined in claim 9 and of pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the general formula 0 is drawn II ^ * \ / C \ • • I II ll /%. \ 21 R R 1 R " / \ III R 30 wherein R11 and R21 are as defined above, R3 is hydrogen and R4 are a leaving group or R3 and R4 together are an additional bond, reacted with ammonia and, if desired, converted a compound obtained into a pharmaceutically acceptable acid addition salt. 35 19. Process for the preparation of compounds in Claim 9 defined formula Ia and of pharmaceutically • usable acid addition salts thereof, characterized in that in a compound of general formula 40 n R ^ * \ / C \ / * \ / NH2 '5 H' iiAV Yes IV 45 h R R 21st wherein R11 is halogen, cyano or trifluoromethyl and R21 is hydrogen or R11 and R21 are each chlorine or, if they are adjacent, together represent a methylenedioxy group, and pharmaceutically acceptable acid addition salts thereof. 10. Compounds according to claim 9, wherein R11 is halogen, cyano or trifluoromethyl and R21 is hydrogen or R11 and R21 are each chlorine. 11. Compounds according to claim 10, wherein R11 is halogen and R21 is hydrogen or R11 and R21 are each chlorine. 12. N- (2-aminoethyl) - p-chlorobenzamide as a compound according to claim 11. 13. N- (2-aminoethyl) - p-fluorobenzamide as a compound according to claim 11. 14. N- (2-aminoethyl) - p-bromobenzamide as a compound according to claim 11. 15. N- (2-aminoethyl) - 3,4-dichlorobenzamide as a compound according to claim 11. 16. N- (2-aminoethyl) 2,4-dichlorobenzamide as a compound according to claim 11. 17. A process for the preparation of compounds of the formula Ia defined in claim 9 and of pharmaceuticals in which R11 and R21 are as defined above and R5 is a radical which can be converted into an amino group, the radical R5 is converted into the amino group and, if desired, a compound obtained in transferred a pharmaceutically acceptable acid addition salt. 55 60