NZ207272A

NZ207272A - Benzamide derivatives and pharmaceutical compositions

Info

Publication number: NZ207272A
Application number: NZ207272A
Authority: NZ
Inventors: Prada M Da; R Joos; E Kyburz; P C Wyss
Original assignee: Hoffmann La Roche
Priority date: 1983-03-03
Filing date: 1984-02-24
Publication date: 1987-07-31
Also published as: MC1568A1; JPH0430389B2; IL71078A0; PT78187A; NO840797L; PH19623A; AU570431B2; GB2135998A; NO165999C; ES8506600A1; ES537045A0; AR243155A1; FI79297B; ES530230A0; IT1173365B; FR2541996A1; FI840734A; AU2506684A; ES537046A0; AU609758B2

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £07272 * 20727 i"* r» - . ... „ n r* (7^ V, Li. NO Pnor.ty ,3,,3.^3i Complete Specif,cat,on 71^-2^801 ssjggS**-^ fl6lfc34.ie5(A' canon Date: .., P.O. jn--rn2! N- ••'Xq6 NEW ZEALAND PATENTS ACT, 1953 ' >1 No.: Date: I I U- COMPLETE SPECIFICATION 6&<zam\O£ .BG»gAMIME DERIVATIVES i/We. F. HOFFMANN-LA ROCHE S CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss Company, hereby declare the invention for which Ec/ we pray that a patent may be granted to raac/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by la) 207^ - la - The present invention is concerned with benzamide derivatives. In particular, it is concerned with N-amino-ethyl-substituted benzamides of the general formula ^'\ A /-'s /"K2 " J H vv 1 wherein R and R~ each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulphamoyl, mono (lower alkyl)sulphamoyl or di(lower alkyl)sulphamoyl or R1 and 2 R on adjacent carbon atoms together signify a methylenedioxy group, with the proviso that R2 is different from hydrogen when R* signifies isopropoxy or butoxy in the 2-position or bromine in the 3-position, and pharmaceutically usable acid addition salts thereof. Some of these compounds are known from, for example, United States Patent Number 3,959,369, 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 pharmaceutically usable acid addition salts have monoamine oxidase (MAO) inhibiting properties. Objects of the present invention are medicaments containing a compound of general formula I or a pharma- £.utically usable acid addition salt thereof and the \ £ N Y manufacture of such medicaments. The compounds of general formula I and their pharmaceutically usable gJ^W&ldditicn salts are useful in the control or prevention of illnesses or in the improvement of health, - 2 - 207272 especially in the control or prevention of depressive states and Parkinsonism. Of the compounds embraced by formula I above the benzamides of the general formula r> 0 II C • ia .* \ A / W 2 i ii R wherein signifies halogen, cyano 21 or trifluoromethyl and R signifies 11 21 hydrogen or R and R each signify chlorine or R^ and R2^" 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 manufacture of the compounds of formula Ia 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-butyl, isobutyl, tert. butyl and the like. The term "lower alkoxy" refers to lower alkyl ether groups in which the term "lower alkyl" has the above 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 halogen, preferably * ^ ^.-chlorine or bromine, arylsulphonvloxv such as, for example, 'ipsyloxy, alkvlsulphonyloxv such as, for example, mesyloxy, Id the like. - 3 - 2072 The term "pharmaceutically usable acid addition salts" embraces salts with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p—toluenesulphonic acid and the like. Such salts can be manufactured readily by any person skilled in the art having regard to the state of the art and bearing in mind the nature of the compound to be converted into a salt. Preferred compounds of formula I are those in which I 2 R and R each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl. Especially preferred compounds of formula I are I 2 those in which R and R each independently signify hydrogen halogen or lower alkyl. Preferred compounds of formula Ia are those wherein II 21 R signifies halogen, cyano or trifluoromethyl and R signi 11 21 fies hydrogen or R and R each signify chlorine. Especially preferred compounds of formula Ia are II 21 those in which R signifies halogen and R signifies 11 21 hydrogen or R and R each signify chlorine. If the compounds of formula I or Ia are disubsti-tuted, 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 or Ia are: ; 0 N-(2-Aminoethy1)-p—chlorobenzamide, -N-(2-amincethyl)-p—fluorobenzamide, 4 ^ ^2-aminoethyl) -p— bromobenzamide, N-(2-aminoethy1)-3,4-dichlorobenzamide, tr I *3^ > "■ I ^ *7 yt - 4 - N-(2-aminoethyl)-2,4-dichloroben2amide and N-(2-aminoethyl)benzamide, 5 The compounds of formula Ia and their pharma ceutically usable acid addition salts can be manufactured in accordance with the invention by a) reacting a compound of the general formula 10 o n C - OH 1 » II 11 21 wherein R and R have the above significance, 20 in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine, or b) reacting a compound of the general formula 25 0 il y'N. 111 1 II *1 . I aii'XViR 8 30 11 21 wherein R and R have the above 3 significance, R signifies hydrogen 4 and R signifies a leaving group ie 3 4 •53 or R ana R together signify an additional bond, with ammonia, or c) converting the group R^ in a compound of the i general formula - D - 2->"272 .AA./X/1 II ,11 / V N H 21 IV 10 15 20 11 21 wherein R and R have the above significance and signifies a group convertible into the amino group, into the amino qroup, and d) if desired, converting a compound of formula Ia 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). 25 30 35 !0j%9S7 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 alkanecarboxylie 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-lo'methylformaiaide at a temperature between about -20°C and room temperature, preferably at about 0°C. If phosphorus - 6 - 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 5 temperature of the reaction mixture, preferably at about 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 halide (e.g. the chloride) of an acid of 10 formula II can be reacted at about 0°C with ethylene- diamine in the presence of a solvent such as diethyl ether. 3 The compounds of formula III in which R signifies 4 hydrogen and R signifies a leaving group are, for example, N-(2-haloethyl)benzamides such as N-(2-chloroethyl)benza- mide, N-(2-methylsulphonylethyl)benzamide or N-[2—(p— toluenesulphonyl)ethyl]benzamide and the like. The com- 3 4 pounds of formula III in which R and R together signify an additional bond are benzoylaziridines such as, for example, p-chlorobenzoylaziridine and the like. In accordance with variant b) of the above process, 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 dimethylformamide, dimethylacetamide, dimethyl sulphoxide and the like. The reaction is conveniently carried out in the presence of a solvent at about room temperature. When a benzovlaziridine 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 in accordance with variant c) of the above process is like-35 wise carried out in a manner known per se depending on the nature of the group R^. If signifies an amide group, then the conversion is conveniently carried out by acidic or basic hydrolysis. The acidic hydrolysis is advantageously carried out using a solution of a mineral acid such 15 20 25 30 as hydrochloric acid, aqueous hydrogen bromide, sulphuric acid, phosphoric acid and the like in an inert solvent such as an alcohol (e.g. methanol or ethanol) or an ether (e.g. tetrahydrofuran or dioxan). 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 methylaraine 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 method for the conversion of the phthalimido group into the amino group comprises reacting compounds of formula IV in which R5 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 - 8 - alcohol (e.g. methanol). The benzyloxycarbonylami.no 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 sej for example, using elemental hydrogen in the presence of a catalyst such as palladium/ carbon, Raney-nickel, platinum oxide and the like. A hexamethylenetetraammonium 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 20 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 compounds of formula III in which signifies hydrogen 4 and R signifies a leaving group can be prepared by 25 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-hydroxyethyl)benzamide into the desired compound of formula III in a manner known 30 per se; for example, by reaction with a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxvchloride and the like, an arylsulphonyl halide such as tosyl chloride or an alkylsulphonyl halide such as mesyl chloride. A compound 35 of formula III in which R^ and 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 5 10 15 20 25 30 - 9 - with variant a). The compounds of formula IV 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 II 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 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. In accordance with an alternative process, the compounds of formula IV in which R5 signifies phthalimido, azido or hexaroethyltetraammonium can be prepared by reacting a compound of formula III with potassium phthal-imide, an alkali metal azide or hexamethylenetetramine. The reaction is carried out in a manner known per se under 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 this activity the compounds of formula I and their pharmaceutically usable 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 standard methods. Thus, the substances to be tested were administered p.o. to rats. Two hours thereafter the - 10 - animals were killed and the MAO inhibiting activity was measured in homogenates of the brain and the liver according to the method described in Biochem. Pharmacol. 12 5 (1963) 1439-1441/ but using phenethy1amine (2*10~^ mol* 1 ^") in place of tyramine 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 ED5Q values (^mol/kg, p.o. in 10 rats) and values (mg/kg, p.o. in mice), respectively: 15 20 Compound ED50 LD50 N-(2-Aminoethyl)-p-chlorobenzamide 5 .5 1000-2000 N-(2-Aminoethyl)-p-fluorobenzamide 4 >5000 N-(2-Aminoethyl)-p-bromobenzamide 4 500-1000 N-(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 20 >5000 The compounds of formula I and their pharmaceuti-25 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 30 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, 35 dragees and hard gelatine capsules, the compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients. Examples of such excipients which can .... it 1 A,.. * . . - 11 - be used for tablets, dragees and hard gelatine capsules are lactose, maize starch or derivatives thereof, talc, stearic acid or its salts etc. 5 Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc. n 10 Suitable excipients for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are, 15 for example, water, alcohols, polyols, glycerine, vegetable oils etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-20 liquid or liquid polyols etc. The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening 25 agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances. JO In accordance with the invention the compounds of general formula I and their pharmaceutically usable acid addition salts can be used in the control or prevention of depressive states and Parkinsonism. The dosage can vary within wide limits and is, of. course, fitted to the indi-35 vidual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 100 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. * - 12 - The following Examples illustrate the present invention, but are not intended to limit its extent. All temperatures are given in degrees Celsius. 5 Example 1 18.5 g of ethyl 4-chlorobenzoate and 24 g of ethylenediamine are stirred at 130° for 17 hours. The mixture is 10 cooled to room temperature, evaporated, and the residue is treated with 200 ml of ethyl acetate. The insoluble N,N'-ethylenebis(4-chlorobenzamide) (2.3 g), m.p. 266-268°, is filtered off under suction, and the filtrate is washed three times with 50 ml of water each time and evaporated. The 15 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 to dryness. The residue is then evaporated twice with lOO ml of ethanol/benzene each time and recrystallized from 20 ethanol/ether. There are obtained 13.7 g of N-(2-amino-ethyl)-4-chlorobenzamide hydrochloride, m.p. 216-217°. Example 2 25 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 100 ml of water and extracted three times with 50 ml of ethyl acetate each time. The ethyl acetate extract is 30 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°. 35 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 - 13 - then 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/ 5 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. 10 Exanrole 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-15 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 20 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 25 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-cn.loro-benzamide hydrochloride, m.p. 212-214°. The free base melts at 43-45°. 30 Exairrole 4 19.1 g (0.1 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 (O.l mol) of ethyl chloroformate are then added drop-wise at 0°. After completion of the addition (0.5 hour), I the mixture is poured on to ice/water. The methylene chloride phase is separated, dried over magnesium sulphate 207272 - 14 - 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 tetrahydrofuran. After completion of 5 the addition (0.5 hour), the mixture is filtered, the 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 times with chloro-10 form. After drying and concentrating the chloroform phases, the residue is converted into the hydrochloride. After recrystallization from ethanol/ether, there are obtained 7.1 g of N-(2-aminoethyl)-2,4-dichlorobenzamide hydrochloride, m.p. 179-182°. 15 Example 5 22.1 ml (0.15 mol) of triethylamine are added drop-wise at 10° to a suspension of 23.5 g (0.15 mol) of 2-chloro-20 benzoic 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), the mixture is poured on to ice/water. The chloroform phase is separated, cried over magnesium sulphate and gently 25 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 ml of chloroform. After completion of the addition, the difficultly soluble neutral constituents are filtered off, the filtrate is concentrated and 30 excess ethylenediamine is removed in a high vacuum. The residue obtained (31.5 g) is converted into the hydrochloride which is puxified by recrystallization from ethanol/ ether. There are obtained 19.2 g of N-(2-aminoethyl)-2-chlorobenzamide hydrochloride (see Example 6 of United 35 states Patent No. 4,131,685 ), m.p. 155-153°. An analytically pure sample melts at 159-161°. i In an analogous manner, from 23.5 g (0.15 mol) of 3-chlorobenzoic acid there were obtained 13.5 g of N- - 15 - 207272 (2-aminoethyl)-3-chlorobenzamide hydrochloride, m.p. 201-203°. The free base melts at 69-71° (from ethyl acetate/n-hexane). 5 Examole 6 24,4 g (0.2 mol) of benzoic acid are reacted with triethylamine and ethyl chloroformate in a manner analogous lO 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 soluble neutral constituents by filtration, the chloroform solution is concentrated and excess ethylenediamine is 15 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 ethyl acetate. The ethyl acetate extracts are dried over magnesium sulphate and concentrated. The crude product is 20 . converted into the hydrochloride which is purified by recrystallization from ethanol, there being obtained 5.2 g of N- (2-aminoethyl)benzaxnide hydrochloride [J. Amer. Chem. Soc. 61, 822 (1939)], m.p. 163-165°. 25 Example 7 30 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 (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 100 ml of chloroform. After stirring at room temperature for 2 hours, the mixture is filtered. The filtrate is concentrated under reduced Opressure and then excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydro-JANW82trioric acid and extracted several times with ethyl acetate. aqueous phase is made alkaline with 28% sodium hydrox- E N U-^'ide solution and extracted three times with chloroform. - 16 - 207272 After drying and concentrating the chloroform extracts, the residue is converted into the hydrochloride. By re-crystallization from ethanol/ether there are obtained 3.4 g of N-(2-aminoethyl)-4-anisamide hydrochloride, 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 mol) of 4-methylbenzoic acid there were obtained 8.7 g of N-(2-aminoethyl)-4-toluamide hydrochloride, m.p. 164-166°C; - from 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid there were obtained 9.1 g of N-(2-aminoethyl)-3,4-dichlorobenzamide hydrochloride, m.p. 183-185°; the free base melts at 98-100°; - from 12,2 g (0.08 molbf2-methoxybenzoic acid there were obtained 9.3 g of N-(2-aminoethyl)-2-anisamiae hydrochloride (see Example 6 of united states Patent Number 4,131,685) , m.p. 109-111°; - from 12.2 g (0.08 mol) of 3-methoxvbenzoic 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 V . In a manner analogous to that described in Example 3 g (0.08 mol) of 4-cyanobenzoic acid are reacted with ■"a / I ? 35 - 17 - 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 5 dimethylformamide, the mixture is heated to 60° for 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-cyanobenzaraide hydrochloride/ m.p. 212-10 215° (decomposition). The free base melts at 124-126' O In an analgous manner, from 4.5 g (0.02 3 mol) of 4-trifluoromethylbenzoic acid there were obtained 3.1 g of n-(2-aminoethyl)-a,a,a-trifluoro-4-toluamide hydrochloride, 15 m.p. 196-199°; the free base melts at 66-68°. Example 9 A solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl 20 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 is rinsed twice with ether. After concentrating the ether 25 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 extracted several times with chloroform. After evaporating 30 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 obtained 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- - 18 - tained in Example 4. Example 10 5 7 g (0.039 mol) of methyl 3,4-methylenedioxybenzoate and 8.5 ml (0.126 mol) of ethylenediamine are heated to 100° (bath temperature) for 2.5 hours. After cooling/ the excess ethylenediamine is removed in a high vacuum. The 10 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 recrystallizing the residue from chloroform/ 15 hexane, there are obtained 3.4 g of NT-(2-aminoethyl)-1,3— benzdioxol-5-carboxamide, m.p. 120-123°. The hydrochloride melts at 210-213°. Example 11 20 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- 25 lization from methanol/ether, there are obtained 6.5 g of N-(2-aminoethyl)-4-bromobenzamide hydrochloride, m.p. 229-232°. Example 12 30 10.7 ml (0.16 mol) of ethylenediamine are added to 6.6 5 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. 35 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- 17 O 7 9 ISw I « fW - 19 - tracted three times with chloroform. The chloroform extracts are dried over magnesivun sulphate and concentrated. The residue is converted into the hydrochloride which is re— 5 crystallized from ethanol/ether. There are obtained 3.8 g of N-(2-aminoethyl)-4-anisamide hydrochloride, m.p. 201-204°. In an analogous manner, from 20 g (0.1 mol) of 10 methyl 4-chloro-2-methoxybenzoate and 20.1 ml (0.3 mol) of ethylenediamine there were obtained 8.9 g of N-(2-aminoethyl) -4-chloro-2-anisamide hydrochloride, m.p. 132-135° (decomposition). 15 Example 13 7.7 g (0.05 mol) of methyl 4-fluorobenzoate and 10 ml (0.15 mol) of ethylene diamine are heated to 130° (bath temperature) for 2 hours. The mixture is poured 20 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. After drying and concentrating the chloroform extracts, 25 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° . 30 Examde 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 acetvl-35 ethylenediamine [J. Araer. Chem. Soc. 6_1, 822 (1939)] and £ 4 ml (0.01 mol) of triethvlamine in 25 ml of chloroform. ' O ' y After 15 minutes, the resulting crystals are filtered off, JANj^J^ashed with chloroform and dried. There are obtained 1.9 g of N-(2-acetylaminoethvl)-4-chlorobenzamide, m.p. 222-224°. I 10 - 20 - In order to cleave the protecting group, the N-(2-acetylaminoethyl)-4-chlorobenzamide obtained is heated to reflux for 22 hours in a mixture of 2 4 ml of 2N hydrochloric acid and 15 ml of ethanol. After concentrating the 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. ExamDle 15 2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are — added dropwise at 0° to a solution of 1.2 ml (0.02 nol) of o 15 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 methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and concentrated. After 20 purification on silica gel using chloroform and chloroform/ methanol (9:1) as the eluting agent, there are obtained 3.1 g of N—(2-hydroxvethyl)—4-chlorobenzamide. A solution of 0.6 ml of methanesulphonyl chloride 25 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 ^ poured on to ice/water and extracted. There are obtained 30 2.1 g of N—(2—methylsulphonyloxvethvl)-4—chlorobenzamide in crystalline form which is used in the next step without further purification. w The N-(2-methylsulphonyloxyethyl)-4-chlorobenzamide 35 obtained is dissolved in 5 ml of dimethylformamide and added dropwise at room temperature to a solution of ammonia 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- •~7 - 21 - duct obtained in Example 1. Example A 5 Interlocking gelatine capsules (5 mg) Ingredients: 1. N-(2-Aminoethyl)-2,4-dichlorobenzoamide hydrochloride 5.73 mg 2. Lactose (powdered) 80.22 mg 3. Maize starch 40.00 mg 4. Talc 3.60 rag 15 5. Magnesium stearate 0.40 mg 6. Lactose (crystalline) 110.00 mg 20 35 Capsule fill weight 2 40.00 mg corresponding to 5 mg of base. *) Procedure: 1-5 are mixed and the mixture is sieved through a sieve having a mesh size of 0.5 mm. 6 is then added and 25 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 240 mg. 30 Example B Tablets (5 mg) Ingredients: 1. N-(2-Aminoethyl)-2,4-dichlorobenzamide hydrochloride 5.78 mg 2. Lactose (powdered) 104.22 mg 3. Maize starch 45.00 mg * - 22 - 10 25 35 4. Polyvinylpyrrolidone K 30 15.00 mg 5. Maize starch 25.00 mg 6. Talc 4.50 mg 7. Magnesium stearate 0.50 mg Tablet weight 200.00 mg ') corresponding to 5 mg of base. Procedure: 1-3 are mixed and the mixture is sieved through a sieve having a mesh size of 0.5 mm. This powder mixture 15 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 the resulting mixture is mixed. The finished mixture is pressed to tablets of 20 suitable size having an individual weight of 200 mg. Example C Interlocking gelatine capsules (10 mg) Ingredients: * 1. N-(2-Aminoethyl)-p-chlorobenzamide hydrochloride 11.84 mg 30 2. Lactose (powdered) 74.16 mg 3. Maize starch 40.00 mg 4. Talc 3.60 mg 5. Magnesium stearate 0.40 mg 6. Lactose (crystalline) 110.00 mg * Capsule fill weight 240.00 mg corresponding to 10 mg of base. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> fpft - 23 - Procedure: 1-5 are mixed and the mixture is sieved through a 5 sieve having a mesh size of 0.5 ram. 6 is then added and 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 240 mg. 10 Example D Tablets (10 mg) Ingredients: 15 N-(2-Aminoethyl)-p-chlorobenzamide 20 25 30 35 hydrochloride 11.84 mg 2. Lactose (powdered) 103.16 mg 3. Maize starch 40.00 mg 4 . Polyvinylpyrrolidone K 30 15.00 mg 5. Maize starch 25.00 mg 6. Talc 4.50 mg 7. Magnesium stearate 0.50 mg Tablet weight 200.CO mg *) corresponding to 10 mg of base. 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 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. I V " Kj 207272 - 24 - WHAT WE CLAIM IS: 1. A medicament containing a compound of the general formula # 0 1 ^WC\N /*WNH2 1 R -i 'i H v.V 1 2 wherein R and R each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulphamoyl, mono- flower alkyl)sulphamoyl or di(lower alkyl)- sulphamoyl or 1 2 R and R on adjacent carbon atoms together signify a methylenedioxy group, with the 2 proviso that R is different from hydrogen when R^" signifies isopropoxy or butoxy in the

2-position or bromine in the

3-position, or a pharmaceutically usable acid addition salt thereof as pharmaceutically active substance. 2. A medicament according to claim 1, wherein R"*" and 2 R each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl. 3. A medicament according to claim 2, wherein R"'' and 2 R each independently signify hydrogen, halogen or lower alkyl. 4. A medicament according to any one of claims 1-3, 1 2 wherein 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. V • i'z ~~ 1 I -9JAN 19872; A medicament according to claim 4, wherein R and Ak? are situated in the 2,4-, or 3 ,4-position. 207272 - 25 - 6. A medicament according to claim 3, wherein the compound is N—(2-aminoethyl)benzamide.

7. An antidepressant or anti-Parkinson agent containing a compound defined in any one of claims 1-6. 8. Benzamide derivatives of the general formula C y- ,NH, I II Ia ,11 ' V V1 H wherein R signifies halogen, cyano or tri- 21 fluoromethyl and R signifies hydrogen or R^ and R2^" each signify chlorine or R^"1 and 21 R on adjacent carbon atoms together signify a methylenedioxv group, and pharmaceutically usable acid addition salts thereof. 9. Compounds according to claim 8, wherein R1-1 sig- 2i nifies halogen, cyar.o or trifluoromethyl and R "* signifies 11 21 hydrogen or R and R each signify chlorine. 10. Compounds according to claim 9, wherein signifies halogen and R^ signifies hydrogen or R^ and R2"'" each signify chlorine. 11. N—(2-Aminoethyl)-p-chlarobenzamide or a pharmaceutically usable acid addition salt thereof. 12. N- ( 2-Aminoethyl) -p-fluorobenzamide or a pharmaceutically usable acid addition salt thereof. 13. o\N~ (2-Aminoethyl) -p-bromobenzamide or a pharma-ceutica-iuLy usable acid addition salt thereof. r> 10 201272 - 25 - 14. N- (2-Aminoethyl)-3,4-dichlorobenzamiae or a pharma ceutically usable acid addition salt thereof. 5 15. N-(2-Aminoethyl)-2,4-dichlorobenzamide or a pharma ceutically usable acid addition salt thereof. 16. Compounds according to any one of claims

8-15 for use as pharmaceutically active substances. 17. Compounds according to any one of claims 8-15 for use as antidepressants or anti-Parkinson agents. 18. A process for the manufacture of compounds of ^ formula Ia defined in claim 8 and of pharmaceutically usable acid addition salts thereof, which process comprises a) reacting a compound of the general formula 20 25 I II o II C - OH II o 30 11 21 wherein R and R have the significance given in claim 8, in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine, or b) reacting a compound of the general formula C ] 11 I A r III 11 21 wherein R and R have the significance given in claim 8, R signifies hydrogen 4 3 and R signifies a leaving group or R and 4 R together signify an additional bond, 5 with ammonia, or c) converting the group R3 in a compound of the general formula 10 20 25 R11 O 11 5 /R ii N -•vfl 15 11 21 wherein R and R have the significance 5 given in claim 8 and R .signifies a group convertible into the amino group, into the amino qroup, and d) if desired, converting a compound of formula Ia obtained into a pharmaceutically usable acid addition salt. 19. A medicament containing a compound defined in any one of claims 8-15. 20. An antidepressant cr anti-Parkinson agent containing a compound defined in any one of claims 8-15. 30 207272 - 28 - 21. A process for the manufacture of compounds of formula Ia defined in claim 8 and of pharmaceutically usable acid addition salts thereof, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 4, 7 to 11, 13 and 14. 22. Benzamide derivatives according to any one of claims 8-15, whenever prepared by the process claimed in claim 18 or claim 21. 23. A medicament containing a compound defined in any one of claims 1-6 and 8-15, substantially as hereinbefore described with particular reference to any one of the foregoing Examples A to D. 'S '.•? i* vv OF 9 " 7 A . J. PARK h SON r:-.n •- AGENTS FOR THE APPLICANTS ov L jan 198? k?,v c' </div>