IE840512L - Benzamide derivatives - Google Patents

Abstract

Benzamides of the formula <IMAGE> wherein R<1> and R<2> each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulphamoyl, mono(lower alkyl)sulphamoyl or di(lower alkyl)sulphamoyl or R<1> and R<2> on adjacent carbon atoms together signify a methylenedioxy group, with the proviso that R<2> is different from hydrogen when R<1> signifies bromine in the 3-position, and their pharmaceutically usable acid addition salts have interesting monoamine oxidase inhibiting properties with low toxicity and can accordingly be used for the treatment of depressive states and Parkinsonism. Those compounds of formula I in which R<1> signifies halogen, cyano or trifluoromethyl in the para-position and R<2> signifies hydrogen or R<1> and R<2> together signify 2,4-dichloro, 3,4-dichloro or 3,4-methylenedioxy are novel; these novel compounds can be manufactured according to methods known per se. [GB2135998A]

Description

The present Invention is concerned with ben2anU.de derivatives. In particular, it is concerned with N-amino-ethyl-substituted benzamidea of the general formula C 11 \ /-\../ \ / 2 • N • •V 1 2 wherein R and R each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluororaethyl, sulphamoyl, mono(lower alkyl)sulphamoyl or di(lower alkyl)sulphamoyl or R1 and 2 R on adjacent carbon atoms together signify a msthylensdioxy group, with 2 the proviso that R is different from hydrogen when R1 signifies bromine in the 3-position, and pharmaceutical^ usable acid addition salts thereof.

Some of these compounds are known from, for example, German Offenlegungsschrift 2.458.908, but it has surprisingly been found that they exhibit interesting and therapeutically usable pharmacodynamic properties with low toxicity. Thus, in animal experiments it has been found that the compounds of formula I above and their phasmaceutlcally usable acid addition salts have monoamine oxidase (MAO) inhibiting properties.

Objects of the present invention are compounds of general formula X and their pharmaceutical^ usable acid addition salts as pharmaeeuticaily active substances, medicaments containing a compound of general formula I or a pharsaaceutically usable acid addition salt thereof, the manufacture of such medicaments and compounds of general formula I and their pharmaceuticals usable acid addition salts for use in the control or prevention of .illnesses or in the improvement of health, especially in the control or prevention of depressive states and Parkinsonism.

Of the compounds embraced by formula I above the b&nzaxoides of the general formula 0 I 'J H '-V1 wherein R11 signifies fluorine, bromine, iodine, cyano °1 or t:rifluoromstthyl &nd R signifies 11 01 hydrogen or S * and R "* each signify chlorine or R11 and R21 on adjacent carbon atoms together signify a methy-lenedioxy group, and their acid addition salts are novel and as such are likewise an object of the present invention.

A final object of the present invention is a process for the mcsnufacture of the compounds of formula la above and their pharmaceutically usable acid addition salts The term "lower alkyl" used in this description refers to straight-chain and branched-chain hydrocarbon groups containing 1-6, preferably 1-4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n~buty(l, isobutyl, and tert.-butyl. The term "lower alkoxy" refers to lower alkyl ether groups in which the term "lower alkyl" 4 has the above significance. The term "halogen" embraces the four halogens fluorine, chlorine, bromine and iodine. The term "leaving group" signifies in the scope of the present invention known groups such as, for extmplc, halogen, preferably chlorine or bromine, arylsulphonyloxy such as, for example, tosyloxy and alJcYlsulphoriy]oxy such as, for example mesyloxy.

The term "pharmaceutical^ usable acid addition salts" embraces salts with inorganic and orgcinic acids such 10 as, for example, hydrochloric acid, hydrobraniic acid, nitric acid, sulphuric acid, phosphorjc acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, niethancsulDhonic acid and p-toluenesulphonic acid.

Such salts can be manufactured readily by any person skilled ] 15 in the art having regard to the state of the art and bear™ ing in mind the nature of the compound to be converted into a salt.

Preferred compounds of formula I are those in which 1 2 R and R each independently signify hydrogen, halogen, 20 lower alkyl, lower alkoxy, cyano or trifluoromethyl.

Especially preferred compounds of formula I are those in which R~ and each independently signify hydrogen, halogen or lower alkyl.

If the compounds of formula I are disubstituted, 25 then the substituents are preferably situated in the 2,3-, 2,4-, 2,5-, 3,4- or 3,6-position, especially in the 2,4- or 3,4-position.

Particularly preferred compounds of formula I are: N- (2-Aminoethyl) -p*-chlorobenzamide, 30 N-(2-aminoethyl)~p-fluorobenzamide, N-(2-aminoethyl)-p-bromobenzajnide, N- (2-aminoathyl) -3,4-dichlorobensamJ.de, 5 N- (2-aminoethyl) - 2, ® C " f \ ' « e I H OH IX 11 21 wherein R~ and R have the above significance, LO in the form of fcha free acid or in the form of a re&ctive functional derivative thereof with ©thylenediamine, or b) reacting a compound of the general formula 0 it /C\ ,11 / ^ 21 3 4 R R 11 ,1 wherein R and R~" have the above 15 significance, R3 signifies hydrogen and R^ signifies a leaving group 3 4 or R and R together signify an additional bond, with ammonia, or 20 c) 5 converting the group R in a compound of the general formula 0 ii r .'*^./cnu/"s«/r ,11 / ^ •V1 rv 11 21 wherein R and R " have the above 5 significance and R signifies a group convertible into the amino group, into the amino group, and, if desired, converting a compound obtained into a pharmaceutically usable acid addition salt.

As reactive functional derivatives of the acids of formula II there come into consideration, for example, halides (e.g. chlorides), symmetric 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 conventional methods. Thus, for example, a free acid of formula II can be reacted with ethylenediamine in the presence of a condensation agent in an inert solvent. If a carbodiimide such as dicyclohexy1-carbodiimide is used as the condensation agent, then the reaction is conveniently carried out in an alkanecarboxylic acid ester such as ethyl acetate, an ether such as tetra-hydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, an aromatic hydrocarbon such as benzene, toluene or xylene, acetonitrile or di-methylformamide at a temperature between about -20°C and room temperature, preferably at about 0°C. If phosphorus trichloride is used as the condensation agent, then the reaction is conveniently carried out in a solvent such as pyridine at a temperature between about 0°C and the reflux temperature of the reaction mixture, preferably at about 5 90°C. In another embodiment of variant a), ethylenediamine is reacted with one of the aforementioned reactive functional derivatives of an acid of formula II. Thus, for example, a halida (e.g. the chloride) of an acid of formula II can be reacted at about 0°C with ethylene-10 diamine in the presence of a solvent such as diethyl ether.

The compounds of formula III in which R3 signifies 4 hydrogen and R signifies a leaving group are, for example, N- (2-haloethvl) bcnzamidet; such as, for example, N-(2-chloro-cthyl)bcnzamidc\ N- (2-mcthylsulphonylethyl) Jjenzanri.de or 15 N- [2-p~to.luenesulphonyl) ethylj bensMmide. The com- "3 4 pounds of formula III in which R and R together signify an additional bond ara benzoylasiridines such as, for example, p-chlorobenzoylaziridine.

In accordance with variant b) of the above process, 20 a compound of formula III can be reacted with ammonia in a manner known per se at a temperature between about -40°C and 50°C, if desired in the presence of a solvent such as, for example, diir.ethylforir.amide, dimethy lacetamide .jr.d dirrethyl aulplioxidc. The reaction is conveniently carried out 25 in the presence of a solvent at about room temperature.

When a benzoylaziridine of 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 group into the amino group 30 in accordance with variant c) of the above process is lilte- wise carried out in a manner known per se depending on the 5 5 nature of the group R . If R signifies an amide group, then the conversion is conveniently carried out by acidic or basic hydrolysis. The acidic hydrolysis is advantage-35 ously carried out using a solution of a mineral acid such 8 as, for example, hydrochloric acid, aqueous hydrogen bromide sulphuric acid and phonphoric acid in an inert solvent such as an alcohol (e.g. methanol or ethanol) or an ether (e.g. tetrahydrofuran or dloxan). The basic hydrolysis can be carried out using aqueous solutions of alkali metal hydroxides such as potassium hydroxide or sodium hydroxide. Inert organic solvents such as those mentioned above in connection with the acidic hydrolysis can be added as solubilizers. The acidic and basic hydrolysis can be carried out in a temperature range of about room temperature to the reflux temperature of the mixture, with the boiling point of the mixture or a temperature slightly thereunder being preferred. If R^ signifies the phthali-mido group, then this can be converted into the amino group not only by acidic and basic hydrolysis, but also by aminolysis with an aqueous solution of a lower alkylamine such as methylamine or ethylamine. As the organic solvent there can be used a lower alkanol such as ethanol. This reaction is preferably carried out at room temperature A third nethod for the conversion of the phthalimido group into the amino group comprises reacting compounds of formula IV in which R"* signifies the phthalimido group with hydrazine in an inert solvent such as ethanol, a mixture of ethanol and chloroform, tetrahydrofuran or aqueous ethanol. The reaction temperature can be varied in a range of about room temperature to about 100°C, with the boiling point of the chosen solvent being preferred. The resulting product can be extracted with dilute mineral acids and can subsequently be obtained from the acidic solution by basifi-cation. The t-butoxycarbonylamino group is conveniently converted into the amino group using trifluoroacetic acid or formic acid in the presence or absence of an inert solvent at about room temperature, while the conversion of the trichloroethoxycarbonylamino group into the amino group is carried out using zinc or cadmium under acidic conditions , The acidic conditions are conveniently achieved by carrying out the reaction in acetic acid in the presence or absence of an additional inert solvent such as an s alcohol (e.g. methanol) „ The benzyloxycarbonylaraino group can be converted into the amino group in a known manner by acidic hydrolysis as described above or hydrogenolytically. The azido group can be reduced to the amino group according to methods known per se5 for example, using elemental hydrogen in the presence of a catalyst such as, for example palludiuu/carbon, Raney-nickel and platinum oxiue. A hexafflethylenetetraaramonium group can also be converted into the amino group by acidic hydrolysis according to known methods.

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

The compounds of formula III used as starting materials in variant b) of the above process are likewise known or are analogues of known compounds and can be prepared in a manner known per se. Thus, for example, the 3 compounds of formula IXI In which R signifies hydrogen 4 and R signifies a leaving group can be prepared by reacting a compound of formula II or a reactive functional derivative thereof with ethanolamine under the reaction conditions described above in connection with variant a) and converting the resulting N-(2-hydroxyethy1)benzamide into the desired compound of formula III in a manner known per se; for example, by reaction with a halogenating agent such as, for example, phosphorus trichloride, phosphorus tri bromide, phosphorus pentachloride and phosphorus oxychloride an arylsulphonyl halide such as tosyl chloride or an alkylsulphonyl halide such as mesyl chloride. A compound of formula III in which R and RJ together signify an additional bond can be prepared, for example, by reacting a reactive functional derivative of a compound of formula II with ethyleneimine. The reaction can be carried out under the reaction conditions described above in connection 1 0 with variant a).

The compounds of formula XV used as starting materials in variant c) of the above process are likewise known or are analogues of known compounds and can be prepared in a manner known per se. Thus, for example, a compound of formula IX or a reactive functional derivative thereof can be reacted under the conditions described above in connection with variant a) with a compound of the general formula 10 h2n-ch2-ch2-r5 v wherein R^ has the above significance.

The compounds of formula V are known or can be prepared in analogy to the preparation of the known compounds.

Xn accordance with an alternative process, the 15 compounds of formula IV in which R^ signifies phthalimido, azido or hexamathyltetraammonium can be prepared by reacting a compound of formula III with potassium phthal-imide, an alkali metal aside or hexamethylenetetramine. The reaction is carried out in a manner known per se under 20 the reaction conditions described above in connection with variant b).

As mentioned above, the compounds of formula I and their pharmaceutically usable acid addition salts have monoamine oxidase (MAO) inhibiting activity. On the basis of 25 this activity the compounds of formula I and their pharmaceutically usabJe acid addition salts can be used for the treatment of depressive states and Parkinsonism.

The MAO inhibiting activity of the compounds in accordance with the invention can be determined using 30 standard methods. Thus, the substances to be tested were administered p.o. to rats. Two hours thereafter the 1 1 animals were killed and tha MAO inhibiting activity was measured in horaogenates of the brain and the liver according to the method described in Biochem. Pharmacol. 12 (1963) 1439-1441, but using phenethylamine (2-10 ^ mol" l-^") in place of tyramin® as the substrate. The thus-determined activity of representative compounds in accordance with the invention as well as their toxicity are evident from the following ED^Q values (pmol/kg, p.o, in rats) and I«0g0 values (mg/kg, p.o. in mice), respectively: 10 Compound o in O W LD50 N-(2-Aminoethyl)-p-chlorobanzamide 5.5 1000-2000 N-(2-Aminoethyl)-p-fluorobanzamide 4 >5000 N-(2-Aminoethyl)-p-bromobenzamide 4 500-1000 15 N~(2-Aminoethyl)-3,4-dichloro-beazamide 10.3 1000-2000 N- (2-ftsiinoethyl) -2,4,-dichloro-banaaraide 1.5 625-1250 N-(2-Aminoethyl)bsnsamide 20 >5000 The compounds of formula I and their pharmaceuti-20 cally usable acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or 25 suspensions). The administration can, however also be carried out rectally (e.g. in the form of suppositories) or parenterally (e.g. in the form of injection solutions).

For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules, the compounds of formula 30 I and their pharmaceutically usable acid addition salts can be processed with pheraiaceutically inert, inorganic or organic excipients. Examples of such excipients which can I 2 be used for tablets, dragees and hard gelatine capsules are, for example, lactose, maize starch or derivntivos therof, talc: or stearic acid or its salts.

Suitable excipients for soft gelatine capsules are, 5 for example, vegetable oils, waxes, fats and semi-solid and liquid polyols.

Suitable excipients for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. 10 Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerine and vegetable oils.

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats and 15 semi-liquid or liquid polyols.

The pharmaceutical preparations can also contain preserving agents, solubilising agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for 20 varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain 3till other therapeutically valuable substances.

In accordance with the invention the compounds of general formula I and their pharmaceutically usable acid 25 addition salts can be used in the control or prevention of depressive states and Parkinsonism. The dosage can vary within wide limits and is, of course, fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 30 10 to lOO mg of a compound of general formula I should be appropriate, although the upper limit given above can be exceeded should this be found to be indicated. 13 The following Examples Illustrate the present Invention, but are not intended to limit its extent. All temp-erasures are given in degrees Celsius.

Example 1 5 18.5 g of ethyl 4-chlorobenzoate and 24 g of ethyl enediamine are stirred at 130° for 17 hours. The mixture is < cooled to room temperature, evaporated, and the residue is treated with 200 ml of ethyl acetate. The insoluble N,N'~ ethyleaebis(4-chlorobensamide) (2.3 g), m.p. 266-268°, is 10 filtered off under suction, and the filtrate is washed three times with 50 ml of water each time and evaporated. Tha residue is treated with 100 ml of IN hydrochloric acid, the insoluble N,N'-ethylenebis(4-chlorobenzamide) (1.0 g) is filtered off under suction, and the filtrate is evaporated 15 to dryness. The residue is then evaporated twice with 100 ml of ethanol/benzene each time and recrystallized from ethanol/ether. There are obtained 13.7 g of N-(2-aminoethyl) -4-chlorobenzamide hydrochloride, m.p. 216-217°.

Example 2 20 9.25 g of ethyl 4-chlorobenzoate and 16.0 g of N- (t-butoxycarbonyl)ethylenediamine are stirred at 130° for 15 hours. The mixture is cooled to room temperature, taken up in loo ml of water and extracted three times with 50 ml of ethyl acetate each time. The ethyl acetate extract is 25 washed twice with 50 ml of water each time, dried over sodium sulphate and evaporated to dryness. The crystalline residue is taken up in isopropyl ether and filtered off under suction. There are obtained 3.9 g of t-butyl [2— (4— chlorobenzamido)ethyl]carbamate, m.p. 141-143°. 30 A solution of 2.8 g of t-butyl [2-(4-chlorobenz- amido)ethyl]carbamate in 50 ml of formic acid is left to stand at room temperature for 1.5 hours. The mixture is 31 'i than concentrated to dryness, and the residue is dissolved in 50 ml of hydrochloric acid (1:1; V/V). The solution is concentrated, the residue is evaporated twice with ethanol/ benzene and then recrystallized from ethanol. There are obtained 2.1 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride which is identical with the product obtained in Example 1.

Example 3 23 ml (0.17 mol) of triethylamine are added drop-wise at 0° to a suspension of 23.5 g (0.15 mol) of 4-chlorobenzoic acid and 15 ml (0.16 mol) of ethyl chloro-formate in 200 ml of chloroform. After completion of the addition (0.5 hour), the solution obtained is added drop-wise at 0° to a solution of 50 ml (0.75 mol) of ethylene-diamine in 100 ml of chloroform. After completion of the reaction, 115 ml of concentrated hydrochloric acid are added dropwise at 0°. The acidic mixture is filtered and the neutral constituents remaining are removed by extraction with chloroform. The aqueous phase is then made alkaline with sodium hydroxide solution and extracted several times with chloroform. The chloroform extracts are dried and concentrated. The residue is converted into the hydrochloride which is recrystallized from ethanol/ether. There are obtained 15.1 g of N-(2-aminoethyl)-4-chloro-benzamide hydrochloride, m.p. 212-214°. The free base melts at 43-45°.

Example 4 19.1 g (O.l mol) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and brought into solution by adding 15.3 ml (0.11 mol) of triethylamine. 10 ml (0.1 mol) of ethyl chloroformate are then added drop-wise at 0°. After completion of the addition (0.5 hour), 4 the mixture is poured on to ice/water. The methylene chloride phase is separated, dried over magnesium sulphate I 5 and concentrated to about 30 ml. This solution is added dropwise at 0° to a solution of 20 ml (0.3 mol) of ethylene-diamine in 100 ml of tetrfthydrofuran. After completion of the addition (0.5 hour), the mixture is filtered, the 5 filtrate is acidified with dilute hydrochloric acid and the neutral constituents are removed by extraction with ethyl acetate. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several timas with chloroform. After drying and concentrating the chloroform phases, 10 the residue is converted into the hydrochloride. After recsystallization from ethanol/efcher, there are obtained 7.1 g of (2-aminoethyl)-2,4~<3ichlorobenzamide hydrochloride, m.p. 179-182°.

Example 5 15 22.1 ml (0.16 mol) of triethylamine are added drop- wise at 10° to a suspension of 23.5 g (0,15 mol) of 2-chloro-bensoic acid in 200 ml of chloroform. 14.8 ml (0.155 mol) of ethyl chloroformate are then added dropwise at the same temperature„ After completion of the addition (1 hour), 20 the mixture is poured on to ice/water. The chloroform phase is separated, dried over magnesium sulphate and gently concentrated to about 60 ml. The thus-obtained solution is added dropwise at 10° to a solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 mJL of chloroform. After completion 25 of the addition, the difficultly soluble neutral constituents are filtered off, the filtrate is concentrated and excess ethylenediamine is removed in a high vacuum. The residue obtained (31.5 g) is converted into the hydrochloride which is purified by recrystalli2ation from ethanol/ 30 ether. There are obtained 19.2 g of N~(2-aminoethyl)-2-chlorobenzamide hydrochloride (see Example 6 of German Offenlegungsschrift 2,362.568), m.p. 155-158°. An analytically pure sample melts at 159-161°.

In an analogous manner, from 23.5 g (0.15 mci) 35 of 3-chlorobenzoic acid there were obtained 13.5 g of N- 1 G (2-aminoethyl)-3-chlorobenzamide hydrochloride (see Example 7 of German Offenlegungsschrift 2.616.486), m.p, 201-203°. The free base melts at 69-71° (from ethyl acetate/n-hexane).

Example 6 5 24,4 g (0.2 mol) of benzoic acid are reacted with triethylamine and ethyl chloroformate in a manner analogous to that described in Example 5 and added dropwise at 10° to a solution of 53.5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform. After removing the difficultly 10 soluble neutral constituents by filtration, the chloroform solution is concentrated and excess ethylenediamine is removed in a 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 extracted several times with 15 ethyl acetate. The ethyl acetate extracts are dried over magnesium sulphate and concentrated. The crude product is converted into the hydrochloride which is purified by recrystallization from ethanol, there being obtained 5.2 g of N-(2-amlnoethyl)benzamide hydrochloride [J. Amer. Chera. 20 Soc. 61, 822 (1939)], m.p. 163-165°.

Example 7 To a suspension of 6.4 g (0.04 mol) of 4-methoxy-benzoic acid in 60 ml of chloroform are added dropwise at 10° 5.5 ml (0.04 mol) of triethylamine and then 3.8 ml 25 (0.04 mol) of ethyl chloroformate. The solution obtained is then added dropwise at 5° to a solution of 10.7 ml (0.16 mol) of ethylenediamine in loo ml of chloroform. After stirring at room temperature for 2 hours, the mixture is filtered. The filtrate is concentrated under reduced 30 pressure and then excess ethylenediamine is removed in a high vacuum. The residue i3 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. 17 After drying and concentrating the chloroform extracts, the residue is converted into the hydrochloride. By re-crystallization from ethanol/other there are obtained 3.4 g of N-(2-aminoethyl)-4-anisamide hydrochloride (see Example 7 of German Offenlegungsschrift 2.616.486), m.p. 186-189°. The free base melts at 37-38°.

In a manner analogous to that described above, from 20.4 g (0.15 tool) of 4-methylbenzoic acid there were obtained 8.7 g of N-(2-aminoethyl)-4-toluamide hydrochloride (see Example 7 of German Offenlegungschrift 2.616.486), m.p. 164-166°; from 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid there were obtained 9.1 g of N-(2-aminoethyl)-3,4-dichlorobenz&mide hydrochloride, m.p. 183-185°; the free base melts at 98-100"; from 12.2 g (0.08 molbe2-methoxybenzoic acid there were obtained 9.3 g of N-( 2-aminoethyl)-2~ajnisamide hydrochloride (see Example 6 of German Offenlegungsschrift 2.362.568), m.p. 109-111°? from 12.2 g (0.08 mol) of 3-me'choxybenzoic acid there were obtained 6.2 g of N-(2-aminoethyl)-3-anisamide hydrochloride, m.p. 96-98°; from 3.9 g (0.015 mol) of 5-(dimethylsulphamoyl)-2-methoxybenzoic acid there were obtained 1.4 g of N-(2-aminoethyl)-5-(dimethylsulphamoyl)-2-anisamide hydrochloride, m.p. 193-195° (decomposition). The free base melts at 118-123°.

Example 8 In a manner analogous to that described in Example 7, 11.8 g (0.08 mol) of 4-cyanobensoic acid are reacted with 18 triethylamine and ethyl chloroformate and worked™up and then added dropwise to a solution of 21.4 ml of ethylene-diamine in 350 ml of chloroform. After adding 45 ml of dimethylformamide, the mixture is heated to 60° for 5 1 hour. After filtration, the filtrate is con centrated, and the residue Is treated in the same manner as described in Example 7. There are obtained 3.5 g of N-(2-aminoethyl)-4-cyanobenzamida hydrochloride, m.p. 212-215° (decomposition). The free base melts at 124~126°„ 10 In an analgous manner, from 4.5 g (0,023 mol) of 4-trifluoromethylben20ic acid there were obtained 3.1 g of N-(2-aminoethyl)-a,a,a-trifluoro-4~toluamide hydrochloride, m.p. 196-199°; the free base melts at 66-68°.

Example 9 15 A solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride in 150 ml of ether is added dropwise at -10° over a period of 0.5 hour to a solution of 10 ml (0.15 mol) of ethylenediamine in 150 ml of ether. The mixture is left: to warm to room temperature, filtered and the white residue 20 is rinsed twice with ether. After concentrating the ether solution, the residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate in order to remove the neutral constituents. The aqueous phase is made alkaline with sodium hydroxide solution and ex-25 tracted several time3 with chloroform. After evaporating the chloroform, converting the residue into the hydrochloride and recrystallization from ethanol/ether, there are obtained 1.8 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride which is identical with the product ob-30 tained in Example 1.

In an analogous manner, from 7 ml (0.05 mol) of 2,4-dichlorobenzoyl chloride there were obtained 1.7 g of N-(2-aminoethyl)-2,4-dichlorobenzamide hydrochloride of melting point 178-179° which is identical with the product ob™ I 9 tained in Example 4.

Example 10 7 g (0.039 mol) of mathyl 3,4-rasthylenedioxybenzoate and 8.5 ml (0.126 mol) of ethylenediamine are heated to 100° (bath temperature) for 2.5 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 evaporating the solvent and recrystallising the residue from chloroform/ hexane, there are obtained 3.4 g of N~(2-aminoethyl)-1,3-benzdioxol-5-carboxamide, m.p. 120-123°. The hydrochloride malts 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° (bath temperature) for 30 minutes. After working-up in a manner analogous to that described in Example 10 and recrystal-lization from mathanol/ether, there are obtained 6.5 g of N-(2-aminoethyl)-4-bromobensamide hydrochloride,-m.p. 229-232°.

Example 12 10.7 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 2 hours and, after cooling, excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydrochloric acid. The difficultly soluble neutral constituents 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 ex 20 tracted three times with chloroform. The chloroform extracts are dried over magnesium sulphate and concentrated. The residue ts converted into the hydrochloride which Is recrystallized from ethanol/sther. There are obtained 3.8 g 5 of N-(2-aminoethyl)-4-anisamide hydrochloride (see Example 7 of German Offenlegungsschrift 2.616.486), m.p. 201-204°.

In an analogous manner, from 20 g (0.1 mol) of methyl 4-chloro-2-methoxybenzo&te and 20.1 ml (0.3 mol) of ethylenediamine there were obtained 8.9 g of N-(2-amino-10 ethyl)-4-chloro-2-anisamide hydrochloride, m.p. 132-135° (decomposition).

Example 13 7.7 g (0.05 mol) of mathyl 4~fluorobenzoate and 10 ml (0.15 mol) of ethylene diamine are heated to 130° 15 (bath temperature) for 2 hours. The mixture is poured on to ice/hydrochloric acid and extracted with ethyl acetate in order to remove the neutral constituents. The aqueous phase is made alkaline with sodium hydroxide solution and extracted several times with chloroform. 20 After drying and concentrating the chloroform extracts, the residue (7.6 g) is recrystallized from ethyl acetate/ hexane, there being obtained N-(2-aminoethyl)-4-fluoro-benzamide, m.p. 57-60°. The hydrochloride melts at 214-216°. 25 Example 14 A solution of 1.3 ml (0.01 mol) of 4-chloro-benzoyl chloride in 15 ml of chloroform is added drop™ wise at 0° to a solution of 1.02 g (0.01 mol) of acetyl-ethylenediamine [J. Amer. Chem. Soc. 61, 822 (1939)] and 30 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform. After 15 minutes, the resulting crystals are filtered off, washed with chloroform and dried. There are obtained 1.9 g of N™(2-acetylaminoethyl)-4-chlorobenzamide, m.p. 222-224°. 2 1 In order to cleave the protecting group, the N-(2-acetylaminoethyl)-l-chlorobenzamide obtained is heated to reflux for 22 hours in a mixture of 24 ml of 2N hydrochloric acid and 15 ml of ethanol. After concentrating the 5 solution, the crude product is recrystallized from ethanol/ ether. There are obtained 1.2 g of N-(2-aminoethyl-4-chlorobenzamide hydrochloride, m.p. 211-213°, which is identical with the product obtained in Example 1.

Example 15 10 2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are added dropwise at 0° to 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. The mixture is then poured into dilute hydrochloric acid and extracted twice with 15 methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and concentrated. After purification on silica gel using chloroform and chloroform/ methanol (9:1) as the eluting agent, there are obtained 3.1 g of M— (2—hydrojcyethyl) —4—chlorobenzamide. 20 A solution of 0.6 ml of methanesulphonyl chloride in 3 ml of methylene chloride is added dropwise at 0° 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. After 15 minutes, the mixture is 25 poured on to ice/water and extracted. There are obtained 2.1 g of N-(2-mathvlsulphonyloxyethyl)-4-chlorobenzamide in crystalline form which is used in the next step without further purification.

' The N-(2-methylsulphonyloxyethyl)-4-chlorobenzamide 30 obtained is dissolved in 5 ml of dimethylformamide and added dropwise at room temperature to a solution of ammonia J in dimethylformamide. After stirring for 2 hours, the mixture is worked-up and there is obtained N-(2-aminoethyl) -4-chlorobenzamide which is Identical with the pro- duct obtained in Example X.

Exaaiple A Interlocking gelatine capsules (5 mcr) Ingredients: 5 1« K-3 (2-Aminoethyl) —2,4-dichlorobenzoamide hydrochloride 5,78 mg 2, Lactose (powdered) 80.22 mg 3, Maize starch 40,00 mg 4, Talc 3.60 mg 10 5. Magnesium stearate 0,40 mg 6, Lactose (crystalline) 110,00 mg Capsule fill weight 240.00 mg corresponding to 5 rag of base.

Procedure: 15 1-5 are mixed and the mixture is sieved through a sieve having a mesh size of 0.5 mm. 6 is then added acid the resulting mixture is mixed. This finished mixture is filled into interlocking gelatine capsules of suitable size (e.g. No. 2) having an individual fill weight of 20 240 mg.

Example B Tablets (5 mg) Ingredients: 1. N~(2-Aminoethyl)-2,4~dichlorobenzamide 25 hydrochloride 5.78 mg 2. Lactose (powdered) 104.22 mg 3. Maize starch 45.00 mg 2 3 4= Polyvinylpyrrolidone K 30 15=00 mg 5. Maize starch 25.00 mg 6. Talc 4 • 50 mg 7. Magnesium 3tearate 0.50 mg 5 Tablet weight 200.00 ag *) corresponding to 5 mg of bass.

Procedure; 1-3 are mixed and the mixture is sieved through a sieve having a mesh size: of 0.5 mm. This powder mixture 1.0 is moistened with an alcoholic solution of 4 and kneaded. The moist mass is granulated, dried and converted into a suitable particle size. 5, 6 and 7 are added In succession to the dried granulate and tha resulting mixture is mixed. The finished mixture Is pressed to tablets of 15 suitable size having an individual weight of 200 mg.

Example C Interlocking gelatine capsules (10 mg) Ingredients; 1. N~(2-Aminoethyl)~p~chlorobenzamida 20 hydrochloride 11.84 mg 2. Lactose (powdered) 74.16 mg 3. Maize starch 40.00 mg 4. Tale 3.60 mg 5. Magnesium stearate 0.40 mg 25 6. Lactose (crystalline) 110.00 mg Capsule fill weight 240.00 mg corresponding to 10 mg of base. 8 4 Procedure: 1-5 are mixed and the mixture is sieved through a sieve having a mash size of 0.5 maw 6 is then added and the resulting mixture is mixed. This finished mixture is 5 filled into interlocking galatine capsules of suitable size (e.g. No. 2) having an individual fill weight of 240 mg.

Example D Tablets (10 mg) Ingredients: 1 0 1.

N-(2-Aminoethyl)-p-chlorobenzamide hydrochloride 11.84 1 mg 2.

Lactose (powdered) 103.16 iag 3.

Maize starch 40.00 mg 4.

Polyvinylpyrrolidone K 30 15.00 mg 15 5.

Maize starch 25.00 mg 6.

Talc 4.50 mg 7.

Magnesium stearate 0.50 mg Tablet weight 200.00 mg ' corresponding to 10 mg of base. 2 0 Procedure: 1-3 are mixed and the mixture is sieved through a sieve having 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 converted into a 25 suitable particle size. 5, 6 and 7 are added in succession to the dried granulate and the resulting mixture is mixed. The finished mixture is pressed to tablets of suitable size having an individual weight of 200 mg.

Claims (27)

CLAIMS:

1. Bensamide derivatives of the general formula 0 II C " ,NH-, !.^V » * R ~V J H S-N2 1 *> wherein R and R" each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cysino, trifluorosaathyl, sulphamoyl, mono(lower alkyl)sulpharaoyl or di(lower alkyl)sulphamoyl or 1 2 R and R on adjacent carbon atoms together signify a methylanedioxy group, with the 2 proviso that R is different from hydrogen when signifies bromine in the 3-position, and pharmaceutically usable acid addition salts thereof for use as pharmaceutically active substances.

2. Compounds according to claim 1, wherein R^ and R2 each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trif1uoromethy1. 1 2

3. Compounds according to claim 2, wherein R and R each independently signify hydrogen, halogen or lower alkyl,

4. Compounds according to any one of claims 1-3, wherein 1 2 R and R are situated in the 2,3-, 2,4-, 2,5-, 3,4- or 3,6-position when they are different from hydrogen. 1 2

5. Compounds according to claim 4, wherein R and R are situated in the 2,4-, or 3,4-position.

6. N-(2-AminoethylJbenzamida as a compound according to claim 3.

7. Benzamide derivatives of the general formula ,11 0 u • C 2 1 ! H ' V'v la wherein R*1 signifies fluorine, chlorine, 21 5 bromine or cyano and R signifies hydrogen, and pharmaceutically usable acid addition salts thereof for use as pharmaceutically active substances.

8. N-(2-Aminoethyl)-p-chlorobenzaml.de or a pharmaceutically usable acid addition salt thereof for use as pharmaceutietlly 10 active substances.

9. Compounds according to any one of claims 1 to 8 for use as antidepressants or antl-Parl

10. Benzamlde derivatives of the general formula 0 il ^/"\ym2 ra \ « R ^ \ / " *» ' " N 15 wherein R signifies fluorine, bromine, iodine, 21 cyano or trlfluoromethyl and R signifies hydrogen or R11 and R21 each signify chlorine or R11 and 21 R on adjacent carbon atoms together signify a methylenedioxy group, 20 and pharmaceutically usable acid addition salts thereof. 27

11. Compounds according to claim 10, wherein R11 signifies fluorine, bromine, iodine, cyano or trifluoro- 21 11 21 sac* thy I and R signifies hydrogen or R and R each signify chlorine.

12. Compounds according to claim 11, wherein R^ 21 signifies fluorine, bromine or iodine and R signifies 11 21 hydrogen or R and R each signify chlorine.

13. N-(2-Aminoethyl)-p-fluorobenzamlde or a pharmaoeutically usable acid addition salt thereof.

14. N-(2-Aminoethyl)-p-bromobensamide or a pharmaceutically usable acid addition salt thereof.

15. H-(2-Aminoethyl)-3,4-dichlorobensem3.de or a pharmaceutically usable acid addition salt thereof.

16. M~(2-Aminoethyl)-2,4-dichlorobenzamlde or a pharmaceutically usable acid addition salt thereof.

17. Benzamlde derivatives of the general formula 0 •>"n./CxN'*s./NH2 la I II r wherein R11 signifies iodine or trifluoromethyl and R21 signifies hydrogen or R11 and R2^1 each 11 21 signify chlorine or R and R on adjacent carbon atoms together signify a methylenedioxy group, and pharmaceutically usable acid addition salts thereof.

18. Compounds according to any one of claims 10 to 17 for use as pharmaceutically active substances. 28

19. Compounds according to any one of claims 10 to 17 for use as antidepressants os> anti-Parkinson agents.

20. A process for the manufacture of compounds of formula la defined in claim 10 and of pharmaceutically usable acid addition salts thereof, which process comprises a) reacting a compound of the general formula 0 » /C - OH II I \\ 11 21 wherein R and R " have the significance given in claim 10, l o in the form of the fres acid or In the form of a reactive functional derivative thereof with ethylenediamine, or b) reacting a compound of the general formula C II I » T, I 4 11 21 wherein R and R A- have the significance given in 3 4 15 claim 10, R signifies hydrogen and R signifies a 3- 4 leaving group or R and R together signify an additional bond, with ammonia, or c) converting the group R^ in a compound of the 20 general formula 0 II g /°\M /*\ i « ; * iv Rii' 11 21 wherein R an <3 R have the significance 5 given in claim 10 end R signifies a s"oup convertible into the amino group, Into the amino group, and, if desired, converting a compound obtained into a pharmaceutically usable acid addition salt.

21. A medicament comprising a pharmaceutically acceptable carrier and a compound defined in any one of claims 1 to 8 and 10 to 17.

22. An antidepressant or anti-Parkinson agent comprising a pharmaceutically acceptable carrier and a compound defined in any one of claims 1 to 8 and 10 to 17.

23. A compound defined in any one of claims 1 to 8 and 10 to 17 for use in the control or prevention of illnesses.

24. A compound defined In any one of claims 1 to 8 and 10 to 17 for use In the control or prevention of depressive states and Parkinsonism.

25. B^nzamide derivatives according to any one of claims 10 to 17, whenever prepared by the process claimed in claim 20 or by &xx obvious chemical equivalent thereof.

26. Benzamide derivatives of formula I or la as defined in claim 1 or claim 10 substantially as hereinbefore described.

27. A process for the manufacture of compounds of formula la as defined in claim 10 substantially as hereinbefore described. F . R. KELLY & CO. , AGENTS FOR THE APPLICANTS.