DE3407654A1 - BENZAMIDE DERIVATIVES - Google Patents

Description

6j \ jO Munich ΰθ * .. ".!." W. ^v "._" * .J "*

^uc '* ^Ui "^{ni> if} " Vr ^ of ^^ n-La Roche & Co. Aktiengesellschaft, Basel, Switzerland

■ (? ■ \. Mn

RAN 4081/75

Benzamide derivatives

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

.0 '"■ · ■■■■

12th
wherein R and R independently of one another each denote hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono-lower alkylsulfamoyl or di-lower alkylsulfamoyl or, if they are adjacent, together denote a methylenedioxy group, with. the proviso that if R is bromine in

3-position means R is different from hydrogen, as well as 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 utilizable pharmacodynamic properties with low toxicity. In

Kbr / 22J.2.8.3

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

The present invention relates to compounds of general formula I and their pharmaceuticals usable acid addition salts as pharmaceutical active ingredients, medicaments containing a compound of general formula I or a pharmaceutically usable acid addition salt thereof, the production of such medicaments ~ Means and the use of compounds of general formula I and their pharmaceutically acceptable acid addition salts in combating or preventing Illnesses or in improving health, especially in combating or preventing depressive ones Conditions and parkinsonism.

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

C • NH ₂ Ia

25th

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,

and their acid addition salts are still new and as such also Subject of the present invention.

Finally, the present invention provides a process for the preparation of the compounds of the above Formula Ia and its pharmaceutically acceptable acid addition salts.

As used in this specification, the term "lower alkyl" refers to straight and branched chain hydrocarbon radicals with 1-6, preferably 1-4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, η-butyl,

g isobutyl, tert. Butyl and the like. The phrase "down 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"

^ q means known in the context of the present invention Groups such as halogen, preferably chlorine or bromine, arylsulfohyloxy, such as tosyloxy, alkylsulfonyloxy such as mesyloxy, and the like.

\ ~ The expression "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,

2Q tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Such salts can, in view of the state of the art and taking into account the nature of the in a Salt to be converted compound can be readily prepared by any person skilled in the art.

Preferred compounds of the formula I are those

1 2

where R and R independently of one another are each hydrogen, Halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl mean.

Such compounds are particularly preferred

1 2

Formula I, in which R and R independently of one another are each hydrogen, Mean halogen or lower alkyl. '

gc If the compounds of the formula I are disubstituted, they are located 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.

Very particularly preferred compounds of the formula I are:

N- (2-aminoethyl) -p-chlorobenzamide, N- (2-aminoethyl) -p-fluorobenzamide, N- (2-Aminoäthyl) -p-brombenaamid, N- (2-Aminoäthyl) -3, 4-dichlorbenzam.id, N- (2-aminoethyl) -2,. 4-dichlorobenzamide and

N- (2-aminoethyl) benzamide. 10

The compounds of the formula Ia and their pharmaceutically usable acid addition salts can be used according to the invention manufacture by

a connection the general formula O
Il C - OH IN II

RR

11 21
where R and R have the above meaning,

in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine, or
25th

b) a compound of the general formula

.1 y? ₃ U ^1ΐτ

-ι Λ Κ

11 21
where R. and R have the above meaning,

3 4

R is hydrogen and R is a leaving group

3 4
or R and R together form an additional bond

represent,
reacts with ammonia, or

c). in a compound of the general formula

¹¹ 5

/ ^c \ _M / "\ / ^R _"

. N IV

11 21 '5

wherein R and R have the above meaning and R is a

means radical convertible into an amino group, converting the radical R into the amino group, and, if desired, a compound obtained is converted into a pharmaceutically acceptable acid addition salt.

As reactive functional derivatives of acids of the formula II come, for example, halides, e.g. chlorides, symmetrical or mixed anhydrides, esters, e.g. methyl ester, p-nitrophenyl ester or N-hydroxy ~ succinimide esters, azides and amides, e.g. imidazolides or Succinimides.

The reaction of an acid of the formula II or a reactive functional derivative thereof with ethylenediamine according to variant a) of the above process can be carried out by customary methods. For example, a free acid of the formula II can be reacted with ethylenediamine in the presence of a condensing agent in an inert solvent. If a carbodiimide such as dicyclohexylcarbodiimide is used as the condensing agent, the reaction is expediently carried out in an alkanecarboxylic acid ester such as ethyl acetate, an ether such as tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, an aromatic hydrocarbon such as benzene, toluene or xylene , Acetonitrile or dimethylformamide, at a temperature between about -20 ⁰ C and room temperature, preferably at about 0 ⁰ C, carried out. If phosphorus trichloride is used as a condensing agent,

so the reaction is conveniently carried out in a solvent such as pyridine at a temperature between about 0 ⁰ C and the reflux temperature of the reaction mixture, preferably at about 90 ⁰ C is performed. 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. For example, a halide, for example the chloride, of an acid of the formula II can be reacted at about 0 ^° C. with ethylenediamine in the presence of a solvent such as diethyl ether. ·

The compounds of the formula III in which R is hydrogen and R is a leaving group, are for example N- (2-haloethyl) benzamides, such as N- (2-chloroethyl) benzamides, N- (2-methylsulfonylethyl) benzamides or N- (2-p-toluenesulfonylethyl) benzamides and the same. The compounds of the formula III, in which R and R together have an additional Representing bonds are benzoylaziridines such as p-chlorobenzoylaziridine and the like.

According to variant b) can in a known manner a compound of formula III with ammonia at a temperature between about -40 ⁰ C and 50 ⁰ C, if desired in the presence of a solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like implement. It is expedient to work in the presence of a solvent at about room temperature. If a behzoylaziridine of the formula III is used, the reaction is preferably carried out in the presence of an inert solvent such as dimethylformamide, toluene or benzene.

The conversion of the radical R into amino according to the variant c) also takes place in a manner known per se, depending on the nature of the radical R. Is this one. Amide, the conversion is expediently carried out by acidic or basic hydrolysis. For the acidic hydrolysis, it is advantageous to use a solution of a mineral acid, such as hydrochloric acid, aqueous hydrogen bromide, sulfuric acid,

Phosphoric acid and the like, in an inert solution. medium, such as an alcohol, for example methanol or ethanol, an Aöfchör, 2.B. Tetrahydrofuran or dioxane. For base hydrolysis, aqueous solutions of alkali metal B may be used metal hydroxides, such as potassium or sodium hydroxide. Inert organic solvents, such as those described above for • the acidic. .Hydrolysis are mentioned, can be added as a solubilizer. For the acidic and basic hydrolysis, the reaction temperature can be varied in a range from about room temperature to reflux temperature, the reaction mixture being preferably carried out at the boiling point or a little below it. If R is phthalimido, in addition to the acidic and basic hydrolysis, aminolysis with an aqueous solution of a lower alkylamine, such as methylamine or ethylamine, can also be carried out. A lower alkanol such as ethanol can be used as the organic solvent. This reaction is preferably carried out at room temperature. A third method for converting phthalimido into amino 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 within a range of from about room temperature to about 100 ⁰ C, preferably being be.i boiling temperature of the chosen solvent works. The resulting product can be shaken out with dilute mineral acid and then obtained by basifying the acidic solution. The t-Butoxycarbonylaminorest is expedient with trifluoroacetic acid or. Formic acid is converted into the amino group in the presence or absence of an inert solvent at about room temperature, while the conversion of the trichloroethoxycarbonylamino group with zinc or cadmium takes place under acidic conditions. The acidic conditions are expediently achieved by carrying out the reaction in acetic acid in the presence or absence of an additional inert solvent such as an alcohol, for example methanol,

performs. The benzyloxycarbonylamino radical can in a known manner by acid hydrolysis as described above or converted into the amino group by hydrogenolysis. An azido group can 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, are reduced to the amino group. A hexamethylenetetrammonium group can also be used known methods can be converted into the amino group by acid hydrolysis.

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

Those used as starting materials in variant b) Compounds of the formula III are also known or analogs to known compounds and can in per se be produced in a known manner. For example, for the preparation of compounds of the formula III,

3 4

wherein R is hydrogen and R is a leaving group, a compound of the formula II or a reactive one React functional derivative thereof under the reaction conditions specified for variant a) with ethanolamine and the N- (2-hydroxyethyl) benzamide obtained in itself known manner, e.g. by reaction 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 into the desired one Convert compound of formula III. A connection

3 4
of the formula III, in which R and R together represent an additional bond, can be obtained, for example, by reacting a reactive functional derivative of a compound of the formula II with ethyleneimine. The implementation can take place among those indicated for variant a)

. Reaction conditions take place.

The compounds of the formula IV used as starting materials in variant c) are also known or S analogues to known compounds and can in per se be produced in a known manner. So you can, for example, a compound of formula II or a reactive functional derivative thereof under the reaction conditions specified for variant a) with a Compound, the general formula

H ₂ N-CH ₂ -CH ₂ -R ⁵ V

where R has the above meaning,
realize. The compounds of the formula V are known or can be obtained in analogy to the preparation of the known compounds.

According to an alternative procedure, the connections of the formula IV, in which R is phthalimido, azido or hexamethylenetetrammonium, also by reaction a compound of formula III with phthalimide potassium, a Alkali metal azide or hexamethylenetetramine can be obtained. The implementation takes place in a manner known per se under the for the variant b) specified reaction conditions.

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

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

Animals killed and the MAO inhibitory activity in homogenates of the brain and liver according to the in Biοehem. Pharmacol. 12 (1963) 1439-1441 described method, each

"" "" ■ _5 "i

but using phenethylamine (2 »10 mol-I) instead of tyramine as substrate, measured. The activity of some compounds according to the invention determined in this way and their toxicity can be seen from the following ED _5Q values (umol / kg, po on the rat) and LD-Q values (mg / kg, po on the mouse):

link ^ED 50 ^LD 50 N- (2-aminoethyl) -p-chlorobenzamide 5.5 1000-2000 N- (2-aminoethyl) -p-fluorobenzamide 4th > .500.0 N- (2-aminoethyl) -p-bromobenzamide 4th 500-1000 N- (2-aminoethyl) -3,4-dichloro-
benzamide 10.3 1000-2000 N- (2-aminoethyl) -2,4-dichloro-
benzamide 1.5 625-1250. N- (2-aminoethyl) benzamide 20th > 500 0

The compounds of the formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can orally, e.g. in the form of tablets, coated tablets, coated tablets, hard and soft gelatine capsules, solutions, emulsions or Suspensions. The administration can also rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

For the production of tablets, coated tablets, coated tablets and hard gelatin capsules can contain the compounds of the formula I and their pharmaceutically acceptable acid addition salts processed with pharmaceutically inert, inorganic or organic excipients. As such excipients For tablets, coated tablets and hard gelatine capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid can be used

or their salts etc. use.

For soft gelatin capsules are suitable as excipients E.g. vegetable oils, waxes, fats, semi-solid and liquid Polyols etc.

Suitable excipients for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose etc.
10

Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerine, vegetable oils Etc.

■ Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.

■ The pharmaceutical preparations can also Preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, Flavoring agents, salts for changing the osmotic pressure, buffers, coating agents or antioxidants contain. They can also contain other therapeutically valuable substances.

According to the invention, compounds of the general formula I and their pharmaceutically usable ones can be used Use acid addition salts in the fight against or prevention of depressive states and Parkinsonism. The dosage can vary within wide limits and is of course in each individual case the individual circumstances adapt. In general, when administered orally, a daily dose of about 10 to 100 mg Compound of the general formula I may be appropriate, but the upper limit just given is also exceeded should this prove to be appropriate.

The following examples are intended to illustrate the present invention, but not to restrict 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

The 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 suction filtered and the filtrate three times washed with 50 ml of water and evaporated. 100 ml of IN hydrochloric acid are added to the residue, the insoluble N, N'-ethylene bis (4-chlorobenzamide) (1.0 g) suction filtered and the filtrate evaporated to dryness. Then the residue evaporated twice with 100 ml of ethanol / benzene each time and recrystallized from ethanol / ether. You get 13.7 g of N- (2-aminoethyl) -1-chlorobenzamide hydrochloride, M.p. 216-217 °.

Example 2

9.25 g of ethyl 4-chlorobenzoate 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 each time, 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 carbonate, melting point 141-143 °, are obtained.

■.

A solution of 2.8 g of t-butyl C2- (4-chlorobenzamido) ethyl] carbamate in 50 ml of formic acid is left to stand for 1.5 hours at room temperature. Then the reaction mixture is concentrated to dryness, and the residue in 50 ml hydrochloric acid (1: 1; V / V) dissolved. 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.

Example 3

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 are at 0 ° 2 3 ml (0.17 mol) Triethylamine added dropwise. When the addition is complete (1/2 hour), the solution obtained becomes a solution of 50 ml at 0 ° (0.75 mol) of ethylenediamine added dropwise to 100 ml of chloroform. After the reaction has ended, 115 ml of conc. Hydrochloric acid was added dropwise. The acidic mixture is filtered and the remaining neutral parts are extracted removed with chloroform. The aqueous phase is then made alkaline with sodium hydroxide solution and several times with chloroform extracted. The chloroform extracts are dried and narrowed. The residue is converted into the hydrochloride and recrystallized from ethanol / ether. You get 15.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, m.p. 212-214 °. The free base melts at 43-45 °.

Example 4

19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are in Suspended 200 ml of methylene chloride and brought into solution by adding 15.3 ml (0.11 mol) of triethylamine. then 10 ml (0.1 mol) of ethyl chloroformate are added dropwise at 0 °. When the addition is complete (1/2 hour), it is increased Poured ice / water. The methylene chloride phase is separated off, dried over magnesium sulfate and made up to approx. 30 ml constricted. This solution is added dropwise at 0 ° to a solution of (0.3 mol) ethylenediamine in 100 ml of tetrahydrofuran. When the addition is complete (1/2 hour), it is filtered and, after acidification of the filtrate with dilute hydrochloric acid the neutral parts are removed by extraction with ethyl acetate. The aqueous phase becomes alkaline with sodium hydroxide solution and extracted several times with chloroform. To

■ ι

Drying and concentrating the chloroform phases, the residue is converted into the hydrochloride. One receives after recrystallization from ethanol / ether 7.1 g of N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride, 179-182 °. 5

Example 5

To a suspension of 23.5 g (0.15 mol) of 2-chlorobenzoic acid 22.1 ml (0.16 mol) of triethylamine are added dropwise to 200 ml of chloroform at 10 °. Then 14.8 ml (0.155 mol) ethyl chloroformate was added dropwise at the same temperature. After the addition (1 hour) the reaction mixture is poured onto ice / water. The chloroform phase is separated off over magnesium sulfate dried and gently concentrated down to approx. 60 ml * The solution thus obtained becomes a Solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform dripped. When the addition is complete, the sparingly soluble neutral components are filtered off and the filtrate is concentrated and freed from excess ethylenediamine in a high vacuum. The residue obtained (31.5 g) is in the Hydrochloride transferred and further purified by recrystallization from ethanol / ether. 19.2 g of N - (. 2-

1) -

.Aminoethyl) -2-chlorobenzamide hydrochloride, m.p. 155-158 °.

An analytically pure sample melts at 159-161 °.

In an analogous manner, starting from 23.5 g

(0.15 mol) 3-chlorobenzoic acid 13.5 g N- (2-Aminoäthyi) -3-

2)

• obtained chlorobenzamide hydrochloride, m.p. 201-203 °. the free base melts at 69-71 ° (from ethyl acetate / n-hexane).

see Example 6 of the German Offenlegungsschrift 2,362,568

see Example 7 of the German Offenlegungsschrift

. 2,616,486

Example 6

.24.4 g (0.2 mol) of benzoic acid are used in the example 5 described manner with triethylamine and ethyl chloroformate reacted and at 10 ° to a solution of 53.5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform dripped. After the sparingly soluble neutral parts have been filtered off, the chloroform solution is concentrated and aminated Freed from excess ethylenediamine in a high vacuum. The oily residue (36.3 g) is dissolved in 200 ml of 2N sodium hydroxide solution taken up, saturated with solid sodium chloride and extracted several times with ethyl acetate. The ethyl acetate extracts are dried over magnesium sulfate and concentrated. That The crude product is converted into the hydrochloride and further purified by recrystallization from ethanol, where 5.2 g of N- (2-aminoethyl) benzamide hydrochloride are obtained, mp 163-165 °.

Example 7 20

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 ethyl chloroformic acid ester dripped. The reaction solution obtained is then at 5 ° to a solution of 10.7 ml (0.16 mol) of ethylenediamine added dropwise to 100 ml of chloroform. After two hours of stirring at room temperature, it is filtered. The filtrate is concentrated under reduced pressure and then freed from excess ethylenediamine in a high vacuum.

The residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase is made alkaline with 28% sodium hydroxide solution and extracted three times with chloroform. After drying and concentration of the chloroform extracts, the residue is ins Hydrochloride transferred. Recrystallization from ethanol / ether gives 3.4 g of N- (2-aminoethyl) -4-

³⁾ J. Amer. Chem. Soc. 61, 822 (1939)

2)

anisamide hydrochloride, m.p. 186-189 °. The free base melts at 37-38 °.

In a manner analogous to that described above, the following were obtained:

Starting from 20.4 g (0.15 mol) of 4-methylbenzoic acid

2) 8.7 g of N- (2-aminoethyl) -4-toluamide hydrochloride, M.p. 164-166 °;

starting from 17.2 g (0.09 mol) 3,4-dichlorobenzoic acid 9.1 g of N- (2-aminoethyl) -3,4-dichlorobenzamide hydrochloride, M.p. 183-185 °; the free base melts at 98-100 °;

starting from 12.2 g (0.08 mol) of 2-methoxybenzoic acid, 9.3 g of N- (2-aminoethyl) -2-anisamide hydrochloride M.p. 109-111 °;

Starting from 12.2 g (0.08 mol) of 3-methoxybenzoic acid 6.2 g of N- (2-aminoethyl) -3-anisamide hydrochloride, M.p. 96-98 °;

starting from 3.9 g (0.015 mol) of 5- (dimethylsulfamoyl) -2-methoxybenzoic acid 1.4 g of N- (2-aminoethyl) -5- (dimethylsuifamoyl) -2-anisamide hydrochloride, M.p. 193-195 ° (dec.). The free base melts at 118-123 °.

see Example 7 of the German Offenlegungsschrift

2,616,486

see Example 6 of the German Offenlegungsschrift 2,362,568

1 Q _

Example 8

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

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

Example 9

To a solution of 10 ml (0.15 mol) of ethylenediamine in 150 ml of ether is added at -10 ° in the course of half a Hour a solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl-. · * "" ** 25 chloride dripped into 150 ml of ether. One leaves on space warm up to temperature, filtered and washed the white residue twice with ether. After concentrating the ethereal solution the residue is acidified with dilute hydrochloric acid and with ethyl acetate to remove the neutrals extracted several times. The aqueous phase is made alkaline with sodium hydroxide solution and several times with chloroform extracted. After the chloroform has been evaporated off, the residue is converted into the hydrochloride and recrystallization 1.8 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained from ethanol / ether 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-dichlorobertzamide hydrochloride were added of melting point 178-179 "obtained with the product obtained in Example 4 is identical.

Example 10

7 g (0.039 mol) methyl 3,4-methylenedio'xybenzoate and 8.5 ml (0.126 mol) of ethylenediamine are heated to 100 ° (bath temperature) for 2 1/2 hours. After cooling down the excess ethylenediamine is removed in a high vacuum. The residue is diluted with hydrochloric acid acidified 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 are 3.4 g of N- (2-aminoethyl) -. 1,3-benzdioxole-5-carboxamide obtained, m.p. 120-123 °. That Hydrochloride melts at 210-213 °.

Example 11

10.7 g (0.05 mol) of methyl 4-bromobenzoate and 10.4 ml (0.15 mol) of ethylenediamine are heated to 130 ° for 30 minutes (Bath temperature) heated. After working up in a manner analogous to that described in Example 10, the mixture is crystallized out after recrystallization Methariol / ether 6.5 g of N- (2-aminoethyl) -4-bromobenzamide hydrochloride obtained, m.p. 229-232 °. 30th

Example 12

To 6.65 g (0.04 mol) of 4-methoxybenzoic acid methyl ester 10.7 ml (0.16 mol) of ethylenediamine are given. The solution is heated to 130 ° for two hours (bath temperature) and after cooling in a high vacuum, freed from excess ethylenediamine. The residue is diluted with Acidified hydrochloric acid. The poorly soluble neutral parts

are removed by filtration and subsequent extraction with ethyl acetate. The aqueous phase will 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 turns into the hydrochloride transferred and recrystallized from ethanol / ether

sated. 3.8 g of N- (2-aminoethyl) -4-anisamide-10 are obtained

hydrochloride ²⁾ , m.p. 201-204 °.

In an analogous manner, starting from 20 g (0.1 mol) * - * 4-chloro-2-methoxybenzoic acid methyl ester and 20.1 ml

(0.3 mol) ethylenediamine 8.9 g of N- (2-aminoethyl) -4-chloro-2-anisamide hydrochloride obtained, m.p. 132-135 ° (dec. l.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 ° (bath temperature) for 2 hours. The reaction mixture is on Poured ice / hydrochloric acid and extracted with ethyl acetate to remove the neutral parts. The aqueous phase is with Sodium hydroxide solution made alkaline and extracted several times with chloroform. After drying and concentrating the chloroform extracts the residue (7.6 g) is recrystallized from ethyl acetate / hexane, N- (2-aminoethyl) -4-fluorobenzamide obtained, m.p. 57-60 °. The hydrochloride melts at 214-216 °. .

Example 14

To a solution of 1.02 g (0.01 mol) of acetylethylene, diamine and 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform is a solution of 1.3 ml (0.01 mol) at 0 °

T)

see example 7 of the German disclosure document 2,616,486

J. Amer. Chem. Soc. 6_1, 822 (1939)

4-chlorobenzoyl chloride was added dropwise to 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, melting point 222-224 °, are obtained. 5

The N- (2-acetylaminoethyl) -4-chlorobenzamide obtained is used in a mixture to split the protective group of 24 ml of 2N hydrochloric acid and 15 ml of ethanol heated to 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-chlorobenzamide hydrochloride are obtained, Mp. 211-213 °, which is identical to the product obtained in Example 1.

Example 15

To a solution of 1.2 ml (0.02 mol) of ethanolamine and 3 ml of W 0.02 mol) of triethylamine in 30 ml of methylene chloride 2.6 ml (0.02 mol) of 4-chlorobenzoyl- ^ O chloride are added dropwise at 0 °; Then the mixture is diluted with hydrochloric acid poured and extracted twice with methylene chloride. The methylene chloride extracts are over magnesium sulfate dried and concentrated. After purification on silica gel with chloroform and chloroform / methanol 9: 1 as the eluent 3.1 g of N- (2-hydroxyethyl) -4-chlorobenzamide are obtained.

To a solution of 1.5 g (0.00 75 mol) of N- (2-hydroxyethyl) -4-chlorobenzamide and 1 ml of triethylamine in 15 ml of methylene chloride, a solution of 0.6 ml of methane ^w sulfonic acid chloride in 3 is added at 0 ° ml of methylene chloride was 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 stage without further purification.

The N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide obtained is dissolved in 5 ml of dimethylformamide and a

ir-

Solution of ammonia in dimethylformamide at room temperature dripped. After stirring for 2 hours, it is worked up and. one receives N- (2-aminoethyl) -4-chlorobenzamide, which with the in Example 1 obtained product is identical. '

Example A.

Gelatin insert capsule a 5 mg Composition:

/ * -. 1. N- (2-aminoethyl) -2, 4-dichlorobenzamide-

hydrochloride 5.78 mg *)

2. Powdered milk sugar 80.22 mg

3. Corn starch 40.00 mg 15

4. Talc 3.60 mg

5. Magnesium stearate 0.40 mg

6. Milk sugar crystall. 110.00 mg

Capsule fill weight 240.00 mg

20th

Production method:

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

*) corresponds to 5 mg base

35

Example B. 5 mg tablet
Composition:

1. N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride 5.78 mg *)

2. Lactose powder. 104.2.2 mg -JO 3. Corn starch 45.00 mg

4. Polyvinylpyrrolidone K 30 15.00 mg

5. Corn starch 25.00 mg. 6. Talk. 4.5 mg

7. Magnesium stearate 0.5 mg

ig tablet weight 200.00 mg

Procedure:

1-3 are mixed and sieved through a sieve with 0.5 mm mesh size. This powder mixture comes with a alcoholic solution of 4 moistened and kneaded. The moist mass is granulated, dried and on a suitable grain size equipped. 5, 6 and 7 are added one after the other to the dried granulate and mixed. the Ready-to-press mixture becomes tablets of suitable size pressed with a target weight of 200 mg.

- *) corresponds to 5 mg base
30th

30th

, J) Oj '. * ·

Example C

Gelatin insert capsule a IO mg
Composition:

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

hydrochloride. 11.84 mg *)

2. Powdered milk sugar. 74.16 mg 3. Corn starch ". 40.00 mg

4. Talc x 3.60 mg

5. Magnesium stearate 0.40 mg

6. Milk sugar crystall. 110.00 mg

Capsule fill weight 240.00 mg

.

Manufacturing process: '.

1-5 are mixed and passed through a sieve with 0.5 mm Sieved mesh size. Then 6 is added and mixed. This ready-to-fill mixture is packed in hard gelatin capsules suitable size (e.g. No. 2) with an individual filling weight of 2 40 mg bottled.

*) corresponds to 10 mg base

35

Example D tablet a. 10 mg Composition:

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

hydrochloride. 11.84 mg *)

2. Powdered milk sugar. 103.16 mg 3. Corn starch 40.00 mg

4. Polyvinylpyrrolidone K 30 15.00 mg

5. Corn starch 25.00 mg

6. Talc 4.5 mg

7. Magnesium stearate 0.50 mg . ^ Tablet weight 200.00 mg

Procedure: -

1-3 are mixed and sieved through a sieve with 0.5 mm 2Q mesh size. This powder mixture comes with a alcoholic solution of 4 moistened and kneaded. The moist mass is granulated, dried and on a suitable grain size equipped. The dried granules 5, 6 and 7 are added one after the other and mixed. The ready-to-press mixture becomes tablets of a suitable size pressed with a target weight of 200 mg.

*) corresponds to 10 mg base
30th

Claims (1)

~~ 3Λ DS 4081/75 Claims l / benzamide derivatives of the general formula 12th where R and R independently of one another are each hydrogen, halogen, lower alkyl, lower alkoxy, cyano, Trifluoromethyl, sulfamoyl, mono-lower alkylsulfamoyl or di-lower alkylsulfamoyl or when they are adjacent are, together a methylenedioxy group, with the proviso that, if R is bromine in 2
3-position means R is different from hydrogen, as well as pharmaceutically acceptable acid addition salts thereof as active pharmaceutical ingredients. · 1 2 2. Compounds according to claim 1, wherein R and R independently of one another are each hydrogen, halogen, lower alkyl, mean lower alkoxy, cyano or trifluoromethyl. 1 2 3. Compounds according to claim 2, wherein R and R each independently represent hydrogen, halogen or lower alkyl. 4. Compounds according to any one of claims 1-3, there- 1 2 characterized in that R and R if they are hydrogen are different, are in the 2,3-, 2,4-, 2,5-, 3,4- or 3,6-position. 5. Compounds according to claim 4, characterized
are located 1 2
shows that R and R are in the 2,4- or 3,4-position 6. N- (2-aminoethyl) benzamide as a compound according to Claim 3. - Z = h- ~ 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 .0 'S * ²¹ .R-R Yes U XI ■ 11 · 21 wherein R is halogen, cyano or trifluoromethyl and R 11 21
Hydrogen or R and R each represent chlorine or, if they are adjacent, together represent a methylenedioxy group, as well as pharmaceutically acceptable acid addition salts thereof. 9. Compounds according to claim 8, wherein R is halogen, 21 11 Cyano or trifluoromethyl and R is hydrogen or R 21
and R each represent chlorine. 10. Compounds according to claim 9, wherein R is halogen 21 11 21 and R is hydrogen or R and R are each chlorine. 11. N- (2-aminoethyl) -p-chlorobenzamide or a pharmaceutical usable acid addition salt thereof. 12. N- (2-aminoethyl) -p-fluorobenzamide or a pharmaceutical usable acid addition salt thereof. 13. N- (2-aminoethyl) -p-bromobenzamide or a pharmaceutical 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. . —M—. 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 antidepressants or anti-Parkinson agents. 18. Process for the preparation of compounds of the in Claim 8 defined formula Ia and pharmaceutically usable acid addition salts thereof, characterized in that that he a) a compound of the general formula O Il Λ ' 11 21 wherein R and R have the meaning given in claim 8 _j in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine implements, - or b) a compound of the general formula 25 O Il • · N · , 21 ^RR 11 21 wherein R and R have the meaning given in claim 8, 3 R is hydrogen and R is a leaving group 3 4 or R and R together represent an additional bond, Reacts with ammonia, or 35 c) in a compound of the general formula DS 4081/75 ■ 11 wherein R and R have the meaning given in claim 8, and R is a radical that can be converted into an Arai group, 10 converts the radical R into the amino group, and, if desired, A compound obtained is converted into a pharmaceutically acceptable acid addition salt. 19. Medicament containing a compound defined in any one of claims 15 1-6 and 8-15. 20. Containing antidepressant or anti-Parkinson agents a compound as defined in any one of claims 1-6 and 8-15. DS 4081/75 21. Use of a compound defined in any one of claims 1-6 and 8-15 in control or prevention of diseases. 5 22. Use of any one of claims 1-6 and 8-15 defined connection in combating or preventing depressive states and Parkinsonism. *** 10