FR2541996A1 - BENZAMIDE DERIVATIVES - Google Patents

Abstract

IT HAS BEEN SURPRISINGLY FOUND THAT THE BENZAMIDES OF FORMULA: (CF DRAWING IN BOPI) OR R AND R EACH INDEPENDENTLY REPRESENT A HYDROGEN, A HALOGEN, A LOWER ALCOHYL, A LOWER ALCOXY, A CYANO, A TRIFLUOROMETHYL, A SULFAMOYL, A LOWER MONO-ALCOYL-SULFAMOYL OR A LOWER DI-ALCOYL-SULFAMOYL OR TOGETHER, IF NEIGHBORED, A METHYLENEDIOXY GROUP, WITH THE PRECISION THAT, IF R REPRESENT 3, IF R REPRESENT IN DIFFERENT HYDROGEN, AS WELL AS THEIR PHARMACEUTICALLY APPLICABLE ACID ADDITIONAL SALTS PRESENT WITH LOW TOXICITY INTERESTING PROPERTIES OF INHIBITION OF MONOAMINE OXIDASE AND CAN THEREFORE BE USED TO TREAT DEPRESSIVE CONDITIONS AND DISEASES. AMONG THE COMPOUNDS OF FORMULA I, ARE NEW THOSE WHERE R REPRESENTS A HALOGEN, A CYANO OR A TRIFLUOROMETHYL IN THE PARA POSITION AND R REPRESENTS A HYDROGEN, OR WHERE R AND R TOGETHER REPRESENT A 2,4-DICHLORO-, A 3,4 -DICHLORO OR 3,4-METHYLENEDIOXY; STILL NEW COMPOUNDS MAY BE PREPARED BY KNOWN METHODS.

Description

The present invention relates to

  mide, especially Naminoethyl substituted benzamide derivatives of the general formula ## STR1 ## each of R 1 and R 2 independently of one another is hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl,

  sulfamoyl, a mono-lower alkyl-sulfamoyl or a di-

  lower alkyl-sulfamoyl, or together, when adjacent, a methylenedioxy group, with the precision that if R represents a bromine at the 3-position; R is different from a hydrogen,

  as well as their pharmaceutically acid addition salts

acceptable.

  These compounds are for one part already known, for example, from the German patent application 2,458,908, but it has surprisingly been found that they present with low toxicity.

  interesting pharmacodynamic properties and

are applicable.

  It has indeed been found in experiments carried out in animals that the compounds of formula I

  above, as well as their phar-

  maceuticalally acceptable activities

  The invention relates to compounds of the general formula

  as well as their pharmaceutical acid addition salts

  only applicable as pharmaceutically active substances

  medicaments which contain a compound of general formula I or a pharmaceutically applicable acid addition salt thereof, the preparation of such

  medicines and the application of compounds of general formula

  I and their pharmaceutical addition salts

  applicable to combating or preventing diseases or to improving health, in particular for combating or preventing depressive propensities and Parkinson's disease. Among the compounds of formula I above, benzamides of the general formula

  R 1 represents a halogen, a cyano or a trifluoro-

  21 is methyl, and R is hydrogen, or R 1 and R are each chlorine or together, if they are adjacent to a methylenedioxy group, and their acid addition salts are still novel and as such also The invention finally relates to a process for the preparation of the compounds of formula above and their salts

  addition of pharmaceutically applicable acids.

  The term "lower alkyl" used in this

  Description relates to hydrocarbon chain radicals

  straight and branched having from 1 to 6, preferably from 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. The term "lower alkoxy" refers to lower alkyl ether groups wherein the term "lower alkyl" has the meaning given above. The term "halogen" includes the four halogens fluorine, chlorine, bromine and iodine L In the context of the invention, the term "leaving group" refers to groups known as halogen, preferably chlorine or bromine, arylsulphonyloxy, such as p-methyloxy, alkylsulphonyloxy, eg mesyloxy, and the like.

  The expression "pharmaceutical acid addition salts"

  applicable includes salts formed 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, etc. These salts can be prepared simply by any specialist considering the state of the art and taking into account the nature of

compound to transform into a salt.

  The preferred compounds of formula I are those where R 1 and R 2 each independently represent a hydrogen, a halogen, a lower alkyl, a

  lower alkoxy, cyano or trifluoromethyl.

  Particularly preferred are the compounds of formula I where R and R 2 each independently represent one of

  the other is hydrogen, halogen or lower alkyl.

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

or 3,4.

  As the compounds of formula I, it is preferable

  the following: N (2-aminoethyl) -β-chlorobhanzamide; N (2Aminoethyl-p-fluorobenzamid, N (2-aminoethyl) -p-bromo-zmoide, N (2Aminoethyl) -3,4-dichlorobenzamide, N (2-Aminothyl) -2,4-dichlorobenzamide and N (2-Aminoethyl) benzamide According to the invention, the compounds of

  formula Ia and their pharmaceutically acid addition salts

  A) by reacting a compound of the general formula ## STR1 ## have the meaning given above, in the form of the free acid. or in the form of one of

  its reactive functional derivatives, with 11 ethylene-

  diamine, or b) by reacting a compound of the general formula ## STR1 ## have the meaning given above, R 3 represents a hydrogen and R represents an outgoing group or R 3 and R 4 together represent an additional bond, with ammonia, or c) in a compound of the general formula O on C / O \ R 5

N I

  R 1 and R 21 have the meaning given above and R 5 represents a group convertible into an amino group, transforming the radical R into the amino group, and if desired by transforming a compound obtained in a salt

  of pharmaceutically applicable acid addition.

  As reactive functional derivatives of the acids of formula II, mention should be made, for example, of halides, eg chlorides, symmetrical or mixed anhydrides, esters, eg methyl ester, pnitrophenyl ester or N-hydroxy-succinimidester, azides and the like.

  amides, eg imidazolides or succinimides.

  The reaction of an acid of formula II or a reactive functional derivative thereof can be conducted with

  ethylenediamine according to variant (a) of the process

  In this process, a free acid of formula I can be reacted with ethylenediamine in the presence of a condensation agent in an inert solvent.

  carbodiimide, such as dicyclohexylcarbonyl

  dilmide, as a condensing agent, the reaction is

  practice 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 ° C and room temperature, preferably about 0 ° C. If phosphorus trichloride is used as a condensing agent, the reaction is carried out in practice 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 the invention,

  According to variant (a), ethylenediamine is reacted with one of the above-mentioned reactive functional derivatives of an acid of formula II. Thus, a halide, for example chloride, can be reacted with

  acid of formula II at about 0 ° C with ethylene

  diamine in the presence of a solvent, such as diethyl ether The compounds of formula III or R represents a hydrogen and R 4 an outgoing group, are for example

  N- (2-haloethyl) = benzamides, such as N- (2-chloroethyl) -

  embedded image The compounds of formula I wherein R 1 and R 4 together represent an additional bond are benzoylaziridines, as po ex. p-chlorobenzoylaziridine, etch According to variant b), a compound of formula II can be conventionally reacted with ammonia at a temperature of between approximately -40 ° C. and 50 ° C., if

  it is desired in the presence of a solvent, such as dimethyl

  formamide, dimethylacetamide, dimethylsulfoxide, etc. In practice, the reaction is carried out in the presence of a solvent at around room temperature. If a n-benzoylaziridine 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 O

41996

  The transformation of the radical R into amino according to variant c) is also carried out in a known manner according to

  type of radical R If it is an amide, transform it

  in practice by acid or base hydrolysis.

  For the acidic hydrolysis, a solution of a mineral acid, such as hydrochloric acid, aqueous hydrobromic acid, sulfuric acid, phosphoric acid, etc., is preferably used in an inert solvent such as an alcohol. , eg methanol or ethanol, an ether, e.g. tetrahydrofuran or dioxane for hydrolysis

  basic aqueous solutions of hydro-

  alkali metal oxides, such as potassium hydroxide or sodium hydroxide solution Inert organic solvents, as mentioned above for acid hydrolysis, may be added as third solvents. The reaction temperature may be varied for acid hydrolysis and in the range of ambient temperature to reflux temperature, and

  preferably at the boiling point of the reaction mixture

  If R is a phthalimido, it is also possible, in addition to the acidic and basic hydrolysis, to carry out an aminolysis with an aqueous solution of a lower alkylamine, such as methylamine or ethylamine. This reaction is preferably carried out at room temperature. A third process for converting phthalimido to amino consists of a lower alkanol, such as ethanol.

  reacting the compounds of formula IV with hydra-

  in an inert solvent such as ethanol, a mixture of ethanol and chloroform, tetrahydrofuran or aqueous ethanol. The temperature of the reaction can be varied within a range from about room temperature to about 1000 ° C. , and we work from

  preferably at the boiling point of the chosen solvent.

  The resulting product can be extracted by shaking with a dilute mineral acid and then obtained by basifying the acid solution. In practice, the t-butoxycarbonyl radical is converted with trifluoroacetic acid or formic acid in the presence or in the presence of the absence of an inert solvent at about room temperature to give the amino group, whereas the conversion of the trichloroethoxycarbonylamino group is carried out with zinc or cadmium under acidic conditions.

  in practice the acidic conditions by driving the reaction

  in the presence or absence of an additional inert solvent, such as an alcohol,

  eg methanol The benzyl radical can be converted

  oxycarbonylamino in known manner by acid hydrolysis as mentioned above or by hydrogenolysis to give the amino group An azido group can be reduced by known methods in aino group, for example with elemental hydrogen in the presence of a catalyst, such as palladium / coal, Raney nickel, oxide

  platinum, etc. One can transform a hexagonal group

  methylenetetraammonium according to methods also

  known by acid hydrolysis to give the amino group.

  The compounds of formula II employed as starting products in variant a) or their reactive functional derivatives are known or can be obtained by analogy

  with the preparation of the known compounds.

  The compounds of formula III employed as starting materials in variant b) are also known or are analogs of known compounds and can be prepared in a known manner.

ES X 996

  react, to prepare compounds of formula III where R represents a hydrogen and R an outgoing group, a compound of formula II or one of its functional derivatives reactive under the conditions mentioned for variant a) with ethanolamine and transform the N ( 2-hydroxy-

  ethyl) benzamide obtained in a known manner, for example by reaction with

  with a halogenating agent, such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, etc., a darylsulfonyl halide, such as tosyl chloride, or a dicycloalkyl halide, such as mesyl, to give the desired compound of formula III A compound of formula IIX wherein R 3 and R 3 together represent an additional bond, for example by reaction of a reactive functional derivative of a

  compound of formula II with thyleneimine

  The compounds of formula IV used as starting materials in variant c) are also known or are analogs of known compounds and can be prepared in a known manner. for example, reacting a compound of formula II or one of its reactive functional derivatives under the reaction conditions indicated for variant a) with a compound of general formula

H 2 NCH 2 CH 2 R 5 V

  o R has the meaning given above

  of formula V are known or can be obtained by

  In another process, it is also possible to obtain the compounds of the formula ## STR1 ## where R 5 represents a phthalimido, an azido or a hexamethyl-tetraammonium O by reaction.

  of a compound of formula III with potassium phthalide

  The reaction is carried out conventionally under the reaction conditions indicated for variant b). The compounds of formula I and their pharmaceutically applicable acid addition salts have as before It has been said that an activity of inhibition of monoamine oxidase (Mh O). On the basis of this activity can be used the compounds of formula I and their addition salts of pharmaceutically applicable acids to treat

  depressive states and Parkinson's disease.

  The inhibitory activity of the NAO of the compounds according to the invention can be determined using standard methods. Thus, the test preparations are administered in rats. Two hours later the animals are sacrificed and the inhibitory activity of the animals is measured. MAO in homogenates of this material with the method according to Biochem Pharmacol, 12 (1963) 1439 = 1441, but using phenethylamine (2 x 10 = Moletl), instead of tyramine as substrate L The activity of some compounds according to the invention thus determined, as well as their toxicity, can be seen from the values of DE 50 f D Mole / kg po in rats) or LD 50 (mg / kg p Oo in mice). ) below:

  The compounds of formula I and their

  The pharmaceutically applicable acids may be administered as medicaments, eg in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered orally, eg in the form of tablets, coated tablets, sugared alcohols,

  hard and soft gelatin capsules, solutions, emulsifiers

  However, the administration may also be performed rectally, eg in the form of suppositories, or parenterally, eg under

form of injectable solutions.

  To prepare tablets, coated tablets, dragees and hard gelatin capsules one can

  mix the compounds of formula I and their additive salts with

  of pharmaceutically applicable acids with inorganic or organic pharmaceutically acceptable compounds Compound DE 50 LD 50 N- (2Aminoethyl) -p-chlorobenzamid 5.5 1000-2000 N- (2-Aminoethyl) -Pfluorobenzamide 4> 5000 N- (2- Aminoethyl) -P-brennobanzamide 4,500-1,000

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> 5000

  Such excipients can be used as

  Examples of tablets, dragées and gelatine capsules are lactose, cornstarch or its derivatives, talc, stearic acid or its salts, and the like. For soft gelatine capsules, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. may be used as excipients. Preparations of the solutions and syrups may be used as excipients, eg water, polyols, sucrose, invert sugar, glucose, etc. For injectable solutions it is possible to use as excipients p ex water, alcohols, polyols, glycerin, vegetable oils, etc.

  For suppositories it is possible to use as exci-

  such as natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc. The pharmaceutical preparations may furthermore contain preservatives, third parties

  solvents, stabilizers, wetting agents,

  emulsifiers, softeners, colorants, flavoring agents, salts for modifying osmotic pressure, buffers, coating agents or antioxidants. They may also contain

  still other therapeutically useful substances.

  According to the invention, the compounds of general formula I and their pharmaceutically applicable acid addition salts can be used to combat

  or to prevent depressive states and Par-

  kinson The dose may vary within wide limits and must be naturally adapted in each individual case to the individual circumstances. In general, in the case of oral application, a daily dose of approximately 10 to 100 mg of a compound of formula I but we can also exceed the upper limit

  above if it should be indicated.

  The following examples are intended to clarify the invention without, however, limiting it in any way.

  All temperatures are given in degrees Celsius.

*

Example

  It is stirred for 17 hours at 1300 1805 g of ethyl ester

  4-chlorobenzoric acid and 24 g of ethylenediamine.

  The reaction mixture is cooled to room temperature, concentrated, and the residue is mixed with ethyl acetate. The filtrate is filtered with an insoluble Ni-N-methylenbis (chlorobenzamide) filter funnel (2.3 g), mp 266-268 ° C. and washed and the filtrate is concentrated three times with 50 ml of water each time. The residue is mixed with 100 ml of 1 N hydrochloric acid,

  filter with a filter funnel -NO N ethylenebis-

  (4-chlorobenzamide) insoluble (1 g), and the filtrate is concentrated to dryness. The residue is concentrated twice more with 100 ml of ethanol / benzene each time and recrystallized from ethanol. / Ethero On

  13 g of N = {(2 aminoethyl) hydrochloride are obtained.

chlorobenzamide, Pf 2161217

Example 2

  After stirring for 130 h, 9.25 g of ethyl ester

  of 4-chlorobenzoic acid and 16.0 g of N- (t-butoxy)

  carbonyl) ethyl & nediamine The reaction mixture is cooled

  at room temperature 2 to 1 absorbed in ml of water and extracted 3 flis with each time

  ml of ethyl acetate The extract of

  ethyl acetate with 50 ml of water each time, dried over sodium sulphate and concentrated to dryness. The crystalline residue is taken up in isopropyl ether and filtered with a filter funnel. 3.9 g of toluene are obtained. Bu-tyl-1 2 (4-chlorobenzamido) ethyl carbamate, mp 1411 L430. The mixture is left to stand for 1 hour at room temperature.

  a solution of 2.8 g of t-butyl-1 2- (4-chloro)

  benzamido) -ethyllcarbamate in 50 ml of formic acid.

  The reaction mixture is then concentrated to dryness and the residue is dissolved in 50 ml of hydrochloric acid (1: 1, v / v). The solution is concentrated and the reconcentration is concentrated.

  again 2 times with ethanol / benzene, and recrystalline

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

Example 3

  In a suspension of 23.5 g (0.15 mol) of 4-

  chlorobenzoic acid and 15 ml (0.16 mol) of chloroformic acid ethyl ester in 200 ml of chloroform are added dropwise to 23 ml (0.17 mol) of triethylamine. After completion of the addition (1 h) the resulting solution is poured dropwise into a solution of 50 ml (0.75 mol) of ethylenediamine in 100 ml of chloroform. After the end of the reaction, 115 ml of ethyl acetate are added dropwise. concentrated hydrochloric acid The acid mixture is filtered and the remaining neutral fractions are removed by extraction with chloroform. The aqueous phase is then made alkaline with sodium hydroxide solution.

  sodium hydroxide and extracted several times with chloroform.

  The chloroform extracts are dried and concentrated.

  The residue is transformed into the hydrochloride and recreated

  from 1 lethahol / ether 15.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, mp 212-214 The free base melts at 43-45 ° C.

Example 4

  19.1 g (0.1 mole) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and the solution is brought into solution by adding 15.3 ml (0.11 mol) of triethylamine. then drip at OO

  ml (0.1 Mole) of ethyl ester of chloroform

  After the end of the addition (h), the mixture is poured into a mixture of water and ice. The methylene chloride phase is separated, dried over magnesium sulphate and concentrated to about 30 ml. This solution is poured dropwise. at 0 in a solution of 20 ml (0.3 mol)

  of ethylenediamine in 100 ml of tetrahydrofuran.

  After the end of the addition (h) is filtered, and after acidification of the filtrate with diluted hydrochloric acid, the neutral fractions are removed by extraction with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide solution. and extracted several times with chloroform After drying and concentration of

  chloroform phases, the residue is converted into

  drate is obtained after recrystallization from

  Ethanol / Ether 7.1 g of N- (2-amincethyl) hydrochloride

  2,4-dichlorobenzamide, mp 179-182.

Example 5

  In a suspension of 23.5 g (0.15 mol) of 2-

  chlorobenzoic acid in 200 ml of chloroform is poured drop

  dropwise to 22.1 ml (0.16 mol) of triethylapine.

  14.8 ml (0.155 mol) of chloroformic acid ethyl ester are then added dropwise at the same temperature. After the end of the addition (1 h) the

  reaction mixture on a mixture of water and ice.

  The chloroform phase is separated, dried over sulfate

  of magnesium and gently concentrated to about 60 ml.

  The solution thus obtained is dripped

    in a solution of 401 l ml (006 mol) of ethylene-

  After the end of the addition, the neutral fractions are filtered off and the filtrate is concentrated by filtration and the excess of ethylenediamine is removed under high vacuum. The residue obtained is converted (31.5 g) into chloroform. )

  hydrochloride and further purified by recrystalline

  from ethanol / ether

  19.2 g of N = (2-aminoethyl) -2-chlorohydrochloride

  Denzamide) to Pf 155 = 158 A pure sample with

  iyse melts at 159161 o Analogously we get from 23.5 g

  (0.15 Moles) of 3 ochlorobenzo 2 acid than 13.5 g of

  2) N (2-aminoethyl) drate = 3 = chlorobenzamide 2) The free base melts at 6971 l (from ethyl acetate / n-hexane) o 1) Example 6 German Published Patent Application No. 2,362,568 (2) See Example 7 of the German Patent Application No. 2,616,486

254 Ā 996

Example 6

  24.4 g (0.2 moles) of benzoic acid as described in Example 5 are reacted with triethylamine and chloroformic acid ethyl ester and poured dropwise at room temperature. in a solution of 53.5 ml (0 <8 mol) of ethylenediamine in 750 ml of

  chloroform After filtering off the fractions

  The solution of chloroform is concentrated and liberated from the excess of ethylenediamine under high vacuum. The oily residue (36.3 g) is taken up in 200 ml of 2N sodium hydroxide solution. Saturated with solid sodium chloride and mixed 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 it is further purified by recrystallization from ethanol, and 5.2a is obtained.

  N- (2-aminoethyl) benzamide hydrochloride of 3), mp 163-

 .

Example 7

  In a suspension of 6.4 g (0.04 mol) of 4-methoxy-benzoic acid in 60 ml of chloroform, 5.5 ml (0.04 mol) of triethylamine is added dropwise to the mixture. 8 ml (0.04 mol) of chloroformic acid ethyl ester The reaction solution obtained is then added dropwise to a solution of 7 ml (0.16 mol) of ethylenediamine in 100 ml. After stirring for 2 h at room temperature, the mixture is filtered under reduced pressure and then freed from excess. 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 3 times with chloroform After drying and

  The residue is converted to the hydrochloride by recrystallization from ethanol / ether. 3.4 g of N- (2-aminoethyl) -4-anisamide hydrochloride 2) are obtained. The free base melts at 37-38 ° C. In a manner analogous to that described above, we obtain:

  Starting from 20.4 g (0.15 mol) of 4-methyl

  benzoic acid, 8.7 g of N- (2-aminoethyl) hydrochloride

2) 6 '

4-coluamide Pf 164-166;

  starting from 17.2 g (0.09 mol) of 3,4-dichloroacid

  benzoic acid, 9.1 g of N- (2-aminoethyl) hydrochloride

  3,4-dichlorobenzamide, mp 183-185; free base background

at 98-100; starting from 12.2 g (0.08 mol) of 2-methoxy

  benzoic acid, 9.3 g of N- (2-aminoethyl) hydrochloride

1) 2-anisamide, mp 109-111;

  starting from 12.2 g (0.08 mol) of 3-methoxy

  benzoic acid, 6.2 g of N- (2-aminoethyl) hydrochloride

3-anisamide, mp 96-98;

  2) See example 7 of the patent application published in Germany.

Germany under No. 2,616,486.

  1) See example 6 of the patent application published in Germany.

Germany under No. 2,362,568.

  starting from 3.9 g (0.015 mol) of 5- (dimethyl)

  sulfamoyl) -2-methoxybenzoate, 1.4 g of N- (2-aminoethyl) 5- (dimethylsulfamoyl) -2-anisamide hydrochloride, m.p.

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

Example 8

  11.8 g (0.08 mol) of 4-cyanoacidic acid are reacted.

  benzoic acid analogously to Example 7 with

  triethylamine and the ethyl ester of chlorinated

  formic and purified and then poured dropwise into a solution of 21.4 ml of ethylenediamine in 350 ml

  chloroform The reaction mixture is warmed

  1 to 60 minutes after the addition of 45 ml of dimethylformamide.

  filtrate and treat the residue further in the same way.

  In example 7, 3.5 g of hydrochloride are obtained.

  N- (2-aminoethyl) -4-cyanobenzamide, mp 212-215 (dec).

Free base melts at 124-126 -

  Starting from 4.5 g (0.023 mol) of 4-trifluoro-

  methylbenzoic is obtained analogously 3.1 g of

  N- (2-aminoethyl) -La, a-trifluoro-4- hydrochloride

  toluamide, mp 196-199; the free base melts at 66-68.

Example 9

  In a solution of 10 ml (0.15 mol) of ethylene

  To a solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride in 150 ml of ether is added dropwise at -10 for 1 h to 150 ml of ether. The mixture is allowed to warm to room temperature. , we

  filter 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 fractions. The aqueous phase is made alkaline with sodium hydroxide solution. and is extracted several times with chloroform. After evaporation of chloroform, transformation of the residue into the hydrochloride and recrystallization from ethanol / ether on

  obtains 118 g of N- (2-aminoethyl) hydrochloride.

  chlorobenzamide which is identical to the product obtained

in example 1.

  Analogously, starting from 7 ml (0.05 mol) of 2,4-dichlorobenzoyl chloride, 1 g (7 g) of N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride was obtained. identical to the product obtained in

example 4.

Example 10

  It is heated for 1 hour at 100 (bath temperature)

  7 g (00039 mol) of 304-acid methyl ester

  methylenedioxybenzoic acid and 8.5 ml (00126 mol) of ethylene

  After cooling, remove the excess of ethyl

  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 sodium hydroxide solution.

  chloroform After evaporation of the solvent and recryst

  the residue is crystallized from chloroform / hexane

  3.4 g of N- (2-aminoethyl) -103-denzdioxol-5-

  carboxamide, mp 120-123 o The hydrochloride melts at

210 213 e.

Example

  10.7 g (0.05 mol) of methyl ester of 4-bromobenzoic acid and 10.4 ml (0.15 mol) of ethylenediamine are heated for 30 minutes at 1300 (bath temperature). analogously to what is said in Example 10, after recrystallization from

  from the methanol / ether, 6.5 g of No hydrochloride (2-

* aminoethyl) -4-4 bromobenzamide, mp 229-232 o

Example 12

  0 to 6.65 g (0.04 mol) of 4- acid methyl ester

  methoxybenzoate is added 10.7 ml (0.16 mol) of

  The solution is heated for 2 hours at 130 ° C. (bath temperature) and after cooling the excess ethylenediamine is removed under high vacuum. The residue is acidified with dilute hydrochloric acid. The neutral fractions which are not readily soluble are removed. by filtration and then by extraction with ethyl acetate. The aqueous phase is made alkaline with 28% strength sodium hydroxide solution, saturated with

  sodium chloride and extracted 3 times with chloroform.

  The chloroform extracts are dried over magnesium sulphate and concentrated. The residue is converted to the hydrochloride salt and recrystallized from ethanol.

  Ethero 3 D 8 g of N- (2-aminohydrochloride) is obtained.

  2) Ethyl) 4 anisamide) Pe 201-04 o Analogous melamine is obtained from 20 g

  (O I Mole) 4-chloro-2- acid methyl ester

  metnoxybenzofc and 20.1 mi (0.3 moles) of ethylenediamine

  8.9 g of N- (2-aminoethyl) hydrochloride = 4-chloro

  301 2 anisamide, Pf 132-135 (deco)> 2) See example 7 of the published German patent application No. 2,616,486

2541,996

Example 13

  7.7 g (0.05 mol) of methyl ester of 4-fluorobenzoic acid and 10 ml (0.15 mol) of ethylenediamine are heated for 2 hours at 130 ° C. (bath temperature). on a mixture of ice and hydrochloric acid and extracted with ethyl acetate to remove the neutral fractions The aqueous phase is alkaline with sodium hydroxide solution and is extracted several times with chloroform After drying and

  concentration of chloroform extracts on recrystalline

  read the residue (7.6 g) from ethyl acetate /

  hexane, and N- (2-aminoethyl) -4-fluorobenzene is obtained

  mide, Pf 57-60 o The hydrochloride melts at 124-216 o

Example 14

  In a solution of 1.02 g (0.01 mol) acetyl-

  ethylenediamine 3) and 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform are added dropwise at 0.degree.

  a solution of 1.3 ml (0.01 mol) of chloride of 4-

  chloronenzoyl in 15 ml of chloroform After 15 minutes the resulting crystals are filtered off, washed with chloroform and dried.

  N- (2-acetylaminoethyl) -4-chlorobenzamide, mp 222-224.

  To separate the protecting group it is heated to

  reflux for 22 hours the N- (2-acetylaminoethyl) -4-chloro

  Denzamide obtained in a mixture of 24 ml of 2N hydrochloric acid and 15 ml of ethanol. After concentrating the reaction solution, the crude product is recrystallized from ethanol / ether.

  N- (2-aminoethyl) -4-chlorobenzamide hydrochloride, Pf 211-

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

3) J Amer Chem Soco 61, 822 (1939) -

Example 15

  In a solution of 1.2 ml (0.02 mol) of ethanolamine and 3 ml (about 0.02 mol) of triethylamine in 30 ml of methylene chloride is added dropwise to 2.6 ml (0 ml). , 02 Mole) of 4-chlorobenzoyl chloride. The mixture is then poured on hydrochloric acid

  diluted and extracted twice with methylene chloride.

  The methylene chloride extracts are dried over

  Magnesium fate and concentrated after purification on silica gel with chloroform and chloroform /

  methanol 9: 1 as eluent, 3.1 g of N- (2-

hydroxyethyl) -4-chlorobenzamide.

  In a solution of 1.5 g (0.0075 mol) of N- (2-

  4-chlorobenzamide and 1 ml of triethylamine in 15 ml of methylene chloride are added dropwise at 0 to a solution of 0.6 ml of acid chloride.

  methanesulfonic acid in 3 ml of methylene chloride.

  After 15 minutes, the reaction mixture is poured into a mixture of ice and water and extracted.

  2.1 g of N- (2-methylsulfonyl-oxyethyl) -4-

  crystalline chlorobenzamide, which can be

  use without further purification in the next step.

  N- (2-methylsulfonyloxyethyl) -4-chloro

  benzamide obtained in 5 ml of dimethylformamide and poured dropwise into a solution of ammonia in dimethylformamide at room temperature.

  stirring for 2 hours, purify and obtain N- (2-

  aminoethyl) -4-chlorobenzamide, which is identical to

obtained in Example 1.

254 1996

Example A

  5 mg gelatin capsule Composition:

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

  dichlorobenzamide 2 Pulverized lactose 3 o March starch 4 Talc o Magnesium stearate 6 Crystalline lactose, 78 mg *), 22 mg, 00 mg 3.60 mg 0840 mg 11000 mg Weight of one capsule 24000 mg Preparation procedure On Mixture 1-5 was passed through a sieve of 0.5 mm mesh opening. The mixture was poured into the appropriate size gelatin capsules (po X).

No. 2) each containing 240 mg.

*) corresponds to 5 mg of base,

Example B

Tablet of 5 mq Composition:

  1 N- (2-aminoethyl) hydrochloride

  2,4-dichlorobenzamide 2 Pulverized lactose 3 Corn starch 4 Polyvinylpyrrolidone K 30 Corn starch 6 Talc 7 Magnesium stearate Weight of a caprim, 78 mg *) 104 22 mg, 00 mg, 00 mg, 00 mg 4, 50 mg 0, 50 mg, 00 mg Procedure 1-3 is mixed and passed through a sieve with a mesh size of 0.5 mm. This powder mixture is moistened with an alcoholic solution of 4 and kneaded on The dried mass is dried and prepared to a suitable particle size. To the dried granulate is added successively 5, 6 and 7 and the mixture is compressed.

  appropriate size of a theoretical weight of 200 mg.

*) corresponds to 5 mg of base

Example C

  10 mg gelatin capsule Composition:

  1 N- (2-aminoethyl) -hydrochloride

  chlorobenzamide 11.84 mg *) 2 Sprayed lactose 74.16 mg 3 Corn starch 40.00 mg 4 Talc 3.60 mg Magnesium stearate 0.40 mg 6 Crystalline lactose 110.00 mg Weight of the contents of one capsule 240 Preparation Method 1-5 is mixed and passed through a sieve of 0.5 mm mesh size. The mixture is then added 6 and mixed. Pour this ready-to-pour mixture into gelatin size capsules. appropriate

  (eg, n 2) each containing 240 mg.

*) corresponds to 10 mg of base

Example D

10 mg tablet Composition:

  1 N- (2-aminoethyl) -hydrochloride

  chlorobenzamide 2 Pulverized lactose 3 Corn starch 4 Polyvinylpyrrolidone K 30 Corn starch 6 Talc 7 Magnesium stearate Weight of one tablet 11.84 mq 103.16 mg, 00 mg, 00 mg, 00 mg 4.50 mg 0.50 mg, 00 mg Procedure 1-3 are mixed and passed through a sieve with a mesh size of 0.5 mm. This powder mixture is moistened with an alcoholic solution of 4 and

  kneads The wet mass is granulated, dried and

  with a suitable particle size With dried granules

  5, 6 and 7 are successively added and mixed.

  Compress the mixture ready to compress into tablets

  of appropriate size with a theoretical weight of 200 mg.

*) corresponds to 10 mg of base.

25.41996

Claims (14)

  Benzamide derivatives of the general formula ## STR1 ## R 1 2 - CN / \ /   R 1 and R 2 each independently represent a hydrogen, a halogen, a lower alkyl, a lower alkoxy, a cyano, a trifluoromethyl, a sulfamoyl, a mono-lower alkylsulfamoyl or a di-lower alkyl -sulfamoyl or together, if they are neighbors, a methylenedioxy group, with the precision that if R 1 represents a bromine in position 3 e R is different from a hydrogen, as well as their pharmaceutically acid addition salts   applicable as pharmaceutical active substances.   Compounds according to claim 1, wherein R 1 and R 2 represent   feel each independently of each other a hydro-   gene, a halogen, a lower alkyl, a lower alkoxy   cyano or trifluoromethyl.   Compounds according to claim 2, wherein R 1 and R 2 are   feel each independently of each other a hydro-   gene, a halogen or a lower alkyl.   Compounds according to one of claims 1-3, characterized 1 2   R 2 and R 2, if different from a hydrogen, are in the 2,3, 2,4, and 5 position. 3,4 or 3,6.   Compounds according to claim 4, characterized in that   that R and R are in the 2,4 or 3,4 position.   6 N- (2-aminoethyl) -benzamide as compound according to claim 3.   Compounds according to one of claims 1-6 as   antidepressant agents or anti-Parkinson's agents 8 o Benzamide derivatives of general formula o I Q e H Jli i Rll Z due 21   o R represents a halogen, a cyanc or a trifluoro-   methyl and R 21 represents a hydrogen atom, or R 1 and R 21 each represent a chlorine or together, if adjacent, a methylenedioxy group, as well as their pharmaceutically applicable acid addition salts. Compounds according to claim 8, wherein R 1 represents halogen, cyano or trifluoromethyl and R 21 represents hydrogen or R and R 21 represent each a chlorine.   Compounds according to claim 9, wherein R 1 represents a halogen and R 21 represents a hydrogen or R 1 and R 21 each represent a chlorine.   11 N- (2-aminoethyl) -p-chlorobenzamide or a salt thereof   addition of pharmaceutically applicable acids.   12 N- (2-aminoethyl) -p-fluorobenzamide or one of its   pharmaceutically applicable acid addition salts.   13 N- (2-aminoethyl) -p-bromobenzamide or a salt thereof   addition of pharmaceutically applicable acids.   14 N- (2-aminoethyl) -3,4-dichlorobenzamide or one of its   pharmaceutically applicable acid addition salts.   N- (2-aminoethyl) -2,4-dichlorobenzamide or a pharmaceutically applicable acid addition salt thereof   16, Compounds according to one of claims 8-15 as pharmaceutical active substances.   Compounds according to one of claims 8-15 as   anti-depressive agents or anti-Parkinson agents.   Process for the preparation of compounds of the formula Ia defined in claim 8 as well as their pharmaceutically applicable acid addition salts, characterized in that a) a compound of the general formula II is reacted. ## STR2 ##   o Ri 11 and R 21 have the meaning given in the   8, in the form of the free acid or in the form of one of its reactive functional derivatives, with ethylenediamine, or b) a compound of the general formula II is reacted. R 11 SR 2R R ll / '2 1   or R1 and R21 have the meaning given in the   8, R is hydrogen and R is an leaving group or R and R together represent an additional bond, with ammonia, or c) in a compound of the general formula * # N 1 \ N / IV l U H il / d 21   o Ru and R 2 have the meaning given in the   8, and R 5 represents a radical which can be converted into an amino group, the radical R is converted to the amino group, and if desired, a compound obtained is converted into a salt.   of pharmaceutically applicable acid addition.   19 Medicinal product containing a compound defined in one of the claims 1-6 and 8-15.   Anti-depressive agent or anti-Parkinson agent containing   a compound defined in one of claims 1-6 and 8-15.   21 Application of a compound defined in one of the   1-6 and 8 = 15 to fight or prevent diseases. 22 Application of a defined compound in one of the   claims 1-6 and 8 = 15 to combat or prevent   depressive states and Parkinson's disease.