AU609758B2

AU609758B2 - Benzamide derivatives

Info

Publication number: AU609758B2
Application number: AU83079/87A
Authority: AU
Inventors: Mose Da Prada; Renato Joos; Emilio Kyburz; Pierre-Charles Wyss
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1983-03-03
Filing date: 1987-12-24
Publication date: 1991-05-09
Anticipated expiration: 2004-02-27
Also published as: IT1173365B; BE899059A; JPS59167552A; FR2541996B1; ES537045A0; NO165999C; IL71078A; FI840734L; NO165999B; DK147584A; KR840009077A; AU2506684A; MC1568A1; DE3407654C2; FI79297B; ES8506600A1; GB2135998B; ES537046A0; ES8504680A1; AU8307987A

Description

'V

IC-.

6u IV, 1S S F Ref: 41987 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: Class Int Class t. j

S

'-S

Complete Specification Lodged: Accepted: Published: Priority: Related Art: This document contains the amendments made under Section 49 and is correct for printing.

Name and Address of Applicant: F Hoffmann-La Roche Co Aktiengesellschaft Grenzacherstrasse 124-184 4002 Basle

SWITZERLAND

Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Address for Service: Complete Specification for the invention entitled: Benzamide Derivatives The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3

I

.5 f T E N D O L L A R S 8 4 5 2 EESTAMP T YALUE F- FIVE DOLLARS TN DOLLARS 7 CHED S- MAL rFCER The present invention is concerned with benzamide derivatives and processes for their manufacture. In particular, it is concerned with processes of manufacturing N-aminoethyl-substituted benzamides of the general formula 0

II

S/C\ NH 2

H

wherein R signifies halogen, cyano or trifluoromethyl and R 1 2 1 2 signifies hydrogen or R and R each signify chlorine or R and R S on adjacent carbon atoms together signify a methylenedioxy group, and S pharmaceutically usable acid addition salts thereof.

Objects of the present invention are compounds of general formula I and their pharmaceutically usable acid addition salts as pharmaceutically active substances and the manufacture of such compounds.

see According to another aspect of the invention a process is given for S" the manufacture of compounds of formula I 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" SD/748C 2 L:1 DF/160W 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, arylsulphonyloxy such as, for example, tosyloxy, alkylsulphonyloxy such as, for example, mesyloxy, and the like.

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.

Particularly preferred compounds of formula I are: S" (2-Aminoethyl) -p-chlorobenzamide, 0 N-(2-aminoethyl) -p-fluorobenzamide, (2-ami noethyl) -p--bromobenzamide, N- (2-aminoethyl)-3,4-dichlorobenzamide, S: N-(2-aminoethyl) -2,4-dichlorobenzamide The compounds of formula I and their pharmaceutically usable acid addition salts can be manufactured in accordance with the invention by a) reacting a compound of the general formula 0* S 0 /C OH S0 R R wherein R and R 2 have the above significance, 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 0 R 3 R 4 1 2 wherein R and R have the above significance, R 3 signifies hydrogen and R signifies a leaving group 3 4*Otr are aO A/-C7 or R and R together signify an aitein~ a bond, with ammonia, 'or Sc) converting the group R 5 in a compound of the 4 general formula .1 5 C

R

H IV

R

1 .R2 1 2 wherein R and R have the above 5 significance and R signifies a group convertible into the aiino 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 Itb formula II there come into consideration, for example, halides chlorides), symmetric or mixed anhydrides, esters methyl esters, p-nitrophenyl esters or Nhydroxysuccinimide 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'tII can be reacted with ethylenediamine in the presence of a .condensation agent in an inert solvent. If a carbodiimide such as dicyclohexylcarbodiimide 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 tetrahydrofuran or dioxan, 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 at about O0C. 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 0 C and the reflux temperature of the reaction mixture, preferably at about 900C. In another embodiment of variant ethylenediamine is reacted with one of the aforementioned reactive functional derivatives of an acid of formula II. Thus, for example, a halide the chloride) of an acid of formula I- can be reacted at about 00C with ethylenediamine in the presence of a sblvent such as diethyl ether.

3 The compounds of formula III in which R signifies hydrogen and R signifies a leaving group are, for example, 9* S* N-(2-haloethyl)benzamides such as N-(2-chloroethyl)benzamide, N-(2-methylsulphonylethyl')benzamide or toluenesulphonyl)ethyl]benzamide and the like. The com- 3 4 pounds of formula III in whih R 3 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 -400C and 500C, 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 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 R 5 into the amino group in accordance with variant c) of the above process is likewise carried out in a manner known per se depending on the nature of the group -R 5 If R 5 ignifies 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 as hydrochloric acid, aqueous hydrogen bromide, sulph.uric acid, phosphoric acid and the like in an ihert solvent such as an alcohol methanol or ethanol) or an .ether 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 10 can be carried out in a temperature range of about room oo 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 phthalimido 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 ethylamie. 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 5 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 basification. 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 -7alcohol methanol). The benzyloxycarbonylamino 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 se; 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 s: 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 pre- Spared in a manner known per se. Thus, for example, the 3 compounds of formula III in which R signifies hydrogen 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-hydroxyethyl)benzamide into the desired compound of formula III in a manner known per se; for example, by reaction with a halogenating agent such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride and the like, an arylsu-lphonyl halide such as tosyl chloride or an alkylsulphonyl halide such as mesyl chloride. A compound 3 4 of formula III in which R and R together signify an additional bond can be prepared, for example, by reacting a reactive functional derivative of a coinpound of formula II with ethyleneimine. The reaction can be carried out under the reaction conditions described above in connection with variant a).

The compounds of formula IV used as starting materials in variant c) of the above process are likewise known or are ahalogues 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 cpnditions described above in connection with variant a) with a compound of the general formula 0 0 2

N-CH

2

-CH

2 -R

V

5 wherein R has the above significance.

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

In accordance with an alternative process, the S 55 compounds of formula IV in which R signifies phthalimido, azido or hexamethyltetraammonium can be prepared by reacting a compound of formula III with potassium phthalimide, 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 formu- I and their pharmaceutically usabJe acid addition salts can be used for the treatment of depressive states and Parkinsonism.

9 i The following Examples illustrate the present invention, but are not intended to limit its extent. All temperatures are given in degrees Celsius.

Example 1 tooo *of *0 S Oo S S

S

20** 0

.O

18,5 g of ethyl 4-chlorobenzoate and 24 g of ethylenediamine are stirred at 1300 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'ethylenebis(4-chlorobenzamide) (2.3 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 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 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. 216-2170° Example 2 9.25 g of ethyl 4-chlorobenzoate and 16.0 g of N- (t-butoxycarbonyl)ethylenediamine are stirred at 1300 for 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 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 chlorobenzamido)ethyl]carbamate, m.p. 141-143°.

A solution of 2.8 g of t-butyl [2-(4-chlorobenzamido)ethyl]carbamate in 50 ml of formic acid is left to stand at room temperature for 1.5 hours. The mixture is 4 in 7 I- 1 r

E

;i then concentrated to dryness,'and the residue is dissolved in 50 ml of hydrochloric acid *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 S S

S.

S

S.

S

*5

S

S' S 4 5*

I

*5 23 ml (0.17 mol) of triethylamine are added dropwise at 00 to a suspension of 23.5 g (0.15 mol) of 4chlorobenzoic acid and 15 ml (0.16 mol) of ethyl chloroformate in 200 ml of chloroform. Af'-r 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 ethylenediamine in 100 ml of chloroform. After completion of the reaction, 115 ml of concentrated hydrochloric acid are added dropwise at 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-chlorobenzamide hydrochloride, m.p. 212-2140.* The free base melts at 43-45.

Example 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 triethyiamine.

ml (0.1 mol) of ethyl chloroformate are then added dropwise at After completion of the addition (0.5 hour), the mixture is poured on to ice/water. The methylene chloride phase is separated, dried over magnesium sulphate 11 7 11A and concentrated to about 30 ml. This solution is added dropwise at 0° to a solution of 20 ml (0.3 mol) of ethylenediamine in 100 ml of tetrahydrofuran. After completion of 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 chloroform. 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°.

944* S. S V S *i V

S.

I SV S

S.

.5 sR4~ I TMS/656T 0L ii; f

C,

r o 0 Examnla To a suspension of 11.8g (0.08 mol) of 4-cyanobenzoic acid in 60 ml of chloroform are added dropwise at 100, 11 ml (0.08 mol) of triethylamine and then 7.6 ml (0.04 mol) of ethyl chloroformate. After working-up, this solution is then added dropwise to a solution of 21.4 ml of ethylenediamine in 350 ml of chloroform. After adding 45 ml of dimethylformamide, the mixture is heated to 60° for 1 houjr. After filtration, the filtrate is concentrated, under reduced pressure and then excess ethylenediamine is removed in a high vacuum. The residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate. The.

aqueous phase is made alkaline with 28% sodium hydroxide solution and extracted three times with chloroform.

After drying and concentrating the chloroform extracts, the residue is converted into the hydrochloride. By recrystallization from ethanol/ Sether there are obtained 3.5 g of N-(2-aminoethyl)-4-cyanobenzamide hydrochloride, m.p. 212-215° (decomposition). The free base melts at 124- 126°.

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

Example 6 S* A solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride in 150 ml of ether is added dropwise at -100 over a period of 0.5 hour to a solution of 10 m' (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 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 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 T.

In an analogous manner, from 7 ml (0.05 mol) of 2,4-dichlorobenzoyT 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- 4 b I a t

P

C

d

I

y i

J'

u I;

[)O

i' B

C

(i (l 4 (2U f i, o e b 2

I~

rip

P

~PI

8,:

D

ii r I'th SD/748C 12 tained in Example 4. I Example 7 7 g (0.039 mol) of methyl 3,4-methylenedioxybenzoate and 8.5 ml (0.126 mol) of ethylenediamine are heated to 1000 (bath temperature) for 2.5 hours. After cooling, the excess ethylenediamine is removed in a high vacuum. The S 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/ hexane, there are obtained 3.4 g of N-(2-aminoethyl)-1,3m.p. 120-123'. The hydrochloride melts at 210-213. o -'Example 8 10.7 g (0'.05 mol) of rrethyl 4-bromobenzoate and 10.4 ml (0.15 mol) of ethylenediamine are heated to 1300 (bath temperature) for 30 minutes. After working-up in a manner analogous to that described in Example 7 and recrystal- 200.: lization from methanol/ether, there are obtained 6.5 g of N-(.2-aminoethyl)-4-bromobenzamide hydrochloride, m.p.

229-23.2°.

-13i-AL Example 9 7.7 g (0.05 mol) of methyl 4-fluorobenzoate and 10 ml (0.15 mol) of ethylene diamine are heated to 1300 (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. 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-fluorobenzamide, m.p. 57-600.

The hydrochloride melts at 214-216°.

Example A solution of 1.3 ml (0.0 mol) of 4-chlorobenzoyl chloride in 15 ml of chloroform is added dropwise at 00 to a solution of 1.02 g (0.01 mol) of acetylethylenediamine [J.

Amer. Chem. Soc. 61, 822 (1939)] and 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform. After 15 minutes, 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°.

0 2 SBR:eah 231F -14- 1' P3L.I r i.

i 4 4 so *0 0 0

U

2

OS

4 3 O In order to cleave the protecting group, the N-(2acetylaminoethyl)-4-chlor.obenzamide 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 solution, the crude product is recrystallized from ethanol/ ether. There are obtained 1.2 g of N-(2-aminoethyvl-4chlorobenzamide hydrochloride, m.p. 211-213°, which is identical with the product obtained in Example 1.

Example 11 2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are added dropwise at O0 to a solution of 1.2 ml (0.02 mol) of ethanoldmine 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 purification on silica gel using chloroform and chloroform/ methanol as the eluting agent, there are obtained 3.1 g of N-(2-hydroxyethyl)-4-chlorobenzamide.

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)-4chlorobenzamide 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 2.1 g of N-( 2 -methylsulphonyloxyethyl)-4-chlorobenzamide in crystalline form which is used in the next step without further purification.

The N- (2-methylsulphonyloxyethyl)-4-chlorobenzamide 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 product of example

I.

I

15

Claims

1. Benzamide derivatives of the general formula 0 2 2 wherein R signifies halogen, cyano or trifluoromethyl and R 2 signifies hydrogen or R and R 2 each signify chlorine or R and R 2 on adjacent carbon atoms together signify a methylenedioxy group, and pharmaceutically usable acid addition salts thereof.

2. Compounds according to claim 1, wherein R 1 signifies halogen, 2*2 cn o 1 2 cyano or t-ifluoromethyl and R 2 signifies hydrogen or R and R each signify chlorine.

3. Compounds according to claim 2, wherein R signifies halogen and R signifies hydrogen or R 1 and R 2 each signify chlorine.

4. N-(2-Aminoethyl)-p-chlorobenzamide or a pharmaceutically usable .5 acid addition salt thereof. N-(2-Aminoethyl)-p-fluorobenzamide or a pharmaceutically usable S acid addition salt thereof.

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

7. N-(2-Aminoethyl)-3,4-dichlorobenzamide or a pharmaceutically usable acid addition salt thereof.

8. N-(2-Aminoethyl)-2,4-dichlorobenzamide or a pharmaceutically usable acid addition salt thereof.

9. A process for the manufacture of compounds of formula I as defined in claim 1 and of pharmaceutically usable acid addition salts thereof, which process comprises a) reacting a compound of the general formula 0 C OH Ii II I I R R 2 SD/748C 16 17 wherein R' and R 2 have the significance given in claim 1, in the form of the free acid or in the form of a reactive functional derivative thereof with ethylenediamine, or reacting a compound of the general formula 0 II i Ii T: III i2 3 4 R '2 R 3 R wherein R and R 2 have the significance given in claim 1, R 3 S signifies hydrogen and R signifies a leaving group or R 3 and R taken together are a N-C bond, with ammonia, or converting the group R in a compound of the general formula 0* 0 0 r* /z R IV i 1 1 wherein R and R 2 have the significance given in claim 1 and R S 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. *o A process for preparing a benzamide derivative substantially as hereinbefore described with reference to any one of the examples.

11. Benzamide derivatives, whenever prepared by the process claimed in claim 9 or claim

12. A benzamide derivative, substantially as hereinbefore described with reference to any one of the examples. DATED this FIFTH day of FEBRUARY 1991 F. Hoffmann-La Roche Co. Aktiengesellschaft Patent Attorneys for the Applicant SPRUSON FERGUSON TMS/1247u 7r 1 7N