CA1064930A

CA1064930A - Substituted benzamides and derivatives thereof

Info

Publication number: CA1064930A
Application number: CA254,480A
Authority: CA
Inventors: Michel Thominet; Gerard Bulteau; Jacques Acher; Jean-Claude Monier
Original assignee: Societe dEtudes Scientifiques et Industrielles de lIle de France SA
Current assignee: Societe dEtudes Scientifiques et Industrielles de lIle de France SA
Priority date: 1975-06-10
Filing date: 1976-06-09
Publication date: 1979-10-23
Also published as: RO70265A; HU172195B; ES448643A1; NO146058B; JPS5231041A; DE2623075A1; BE842059A; PL102929B1; CH596175A5; NL186382B; PT65164A; BG27360A3; IE43375L; HK46979A; SE415971B; FR2313935A1; PL190247A1; PL103075B1; PH13912A; AT358571B

Abstract

ABSTRACT OF THE DISCLOSURE

Novel benzamides are provided which correspond to the formula:

in which A represents a hydrogen atom, a C1-5 alkyl group, or a C2-5 alkenyl group; X represents a hydrogen atom, a C1-5 alkoxy group, a C1-5 alkyl group, a C2-5 alkenyloxy group, or a C2-5 alkenyl group; Y represents a hydrogen atom, a halogen atom, a nitro group, a C1-5 alkyl group, a C1-5 alkoxy group, an amino group, a substituted amino group such as for example alkyl-amino, acylamino, benzylamino or alkoxycarbonylamino; Z repre-sents a hydrogen atom, a halogen atom, a C1-5 alkoxy group, a C1-5 alkylsulphonyl group, a SO2NR1R2 group in which R1 and R2, which may be the same or different, are hydrogen or a lower C1-5 alkyl group, or form, together with the nitrogen atom to which they are attached, a heterocycle optionally containing another hetero atom; W represents an alkylene group with 1 to 4 carbon atoms which may form a straight or branched chain; B
represents a group NR1R2 in which R1 is a C1-5 alkyl group, R2 is a C1-5 alkanol group, and the group R1 may be joined to the alkyl chain of the group R2 via a nitrogen atom, or a racemic, dextrorotary or levorotary heterocyclic radical of the follow-ing formula:

Description

3~

The object of the present invention are new substi-tuted benzamides of general formula (I), their quaternary ammonium salts, their oxides, their addition sAlts with pharma-cologically acceptable acids, their dextrorotary and levorotary isomers, and processes for their preparation.
The invention also concerns medicaments whose active principle consists of benzamides of the invention.
; The benzamides which are the object of the invention have the following formula:
CO-NH-W-B

~ ~ OA
Z ~"ILx in which:
A represents a hydrogen atom, a Cl 5 alkyl group, or a C2 5 alkenyl group, X represents a hydrogen atom, a Cl 5 alkoxy group, a Cl 5 alkyl group, a C2 5 alkenyloxy group, or a C2 5 alkenyl group, Y represents a hydrogen atom, a halogen atom, a nitro group, a Cl 5 alkyl group, a Cl 5 alkoxy group, an amino group, or a substituted amino group such as ~or example alkylamino, acyl-amino, benzylamino or alkoxycarbonylamino, Z represents a hydrogen atom, a halogen atom, a Cl 5 alkoxy group, a Cl 5 alkylsulphonyl group, a S02NRlR2 group in which Rl and R2, which may be the same or different, are hydrogen or a lower Cl 5 alkyl group, or form, together with the nitrogen atom to which they are attached, a heterocycle possibly containing another hetero atom, : W represents an alkylene group with 1 to 4 carbon atoms which may form a straight or branched chain, 93(~
B represents a group NRlR2 in which Rl is a Cl 5 alkyl group and R2 ;5 a Cl 5 alkanol group, and the group Rl may be joined to the alkyl chain of the R2 group via a nitrogen atom, or a racemic, dextrorotary or levorotary heterocyclic radical of formula (IV):
~(CH2)m N (IV) in which:
R is a Cl 5 alkyl group containing a reactive function such as alcohol, thiol, ketone, thioketone, ether oxide, thioether, etc., and m is an integer equal to 1, 2 or 3.
The benzamides of the invention may be prepared by reacting a compound oF formula:
COD
~ OA

in wh~ch:
D represents a hydroxy group or an organic residue,and A,X,Y, and Z have the afore-mentioned meanings, with an amine of general formula (III):
H2N - W - B (III) in which W and B have the afore-mentioned meanings, or by reacting their reactive derivatives.
Of the substituted amino groups represented by Y, the alkylamino may be selected from Cl 5 mono- or dialkylamino groups, acylamino may be selected from the acetamido, formamido,

- 2 --~ 3~

propionamido, butyramido, benzamido, phthalimido groups, etc.
In the starting compound (II) the organic residue includes groups capable of forming reactive acid derivatives.
These may be lower alkyl esters such as methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, etc. esters, reactive acid esters such as cyanomethyl or methoxymethyl esters, or N-hydroxyimide esters, or optionally substituted aromatic esters, acid halides; acid hydrazides; acid azides; symmetrical ; anhydrides; mixed anhydrides, for example formed with carbonic acid esters or haloformic esters; azolides, such as tri-azolides, tetrazolides or imidazolides; acid isothiocyanates;
substituted ~-trihaloacetophenones; substituted ~-oxobenzene-acetonitriles; benzamides substituted in the nucleus. The invention is however not limited to the afore-mentioned deriva-tives.
According to the process of the invention, the amine may take part in the reaction in the form of one of its reactive derivatives, which may optionally be isolated. As examples there may be mentioned the reaction products of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl or orthophenylene chlorophosphites, alkyl or aryl dichlorophosphites, the amine Isothiocyanate, the sym-metrical or non-symmetrical sulphamide of the amine, the corre-sponding symmetrical urea, and the corresponding enamines. The afore-mentioned reactive derivatives may react with the acid in situ or after preliminary isolation.
It is also possible to carry out the reaction between the free acid and free amine in the presence of a condensation agent, such as for example silicon tetrachloride, phosphoric anhydride, a carbodiimide such as dicyclohexyl carbodiimide, or alkoxyacetylenes such as methoxy- or ethoxyacetylene.

93~) The amidation reaction of the invention may be carried out in the presence or absence of a solvent. The systems used as solvent, which are inert with respect to the amidation reaction, are for example alcohols, polyols, benzene, toluene, dioxane, chloroform or diethyleneglycol dimethyl ether. It is also possible to use an excess of the amine used as starting substance as solvent. It may be preferable to heat the reaction mixture during the amidation, for example to the boiling point of the afore-mentioned solvents.
The compounds obtained according to the invention may be reacted if necessary with pharmaceutically acceptable mineral or organic acids, such as hydrochloric acid, hydro-bromic acid, sulphuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid or methanesulphonlc acid, to give acid addition salts.
It may also be reacted, if necessary, with alkyl halides or sulphates to give quaternary ammonium salts.
In order to illustrate the technical characteristics of the present invention, some examples of carrying out the ; 20 invention will be descr~bed, it being understood that these are not limiting as regards their method of operation and the uses to whlch they may be applied.

N-~1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide 48 g of ethyl 2-methoxy-5-sulphamoyl benzoate, 17 g of water and 32 g of 1-~2-hydroxyethyl)-2-aminomethyl pyrroli-dine were added into a 250 ml flask. The mixture was heated on a water bath until a test sample was found to be completely soluble in dilute acetic acid. The solution was cooled and then diluted with 300 ml of water. The crystals formed were suction filtered, washed with water, and dried at 40C. The a3~

benzamide obtained was puriFied by conversion into the acetate ~ollowed by liberation of the base.
39 9 of N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide were obtained. (Yield = 59%;
melting point 135-136C~.

N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl~-2-methoxy-5-ethylsulphonyl benzamide hydrochloride 38.8 g of 2-methoxy-5-ethylsulphonyl benzoic acid methyl ester, 13.5 ml of water and 28.4 9 of 1-(3-hydroxy-propyl)-2-aminomethyl pyrrolidine were added into a 250 ml flask. The mixture was heated 10 hours at 85-90C. After evaporation, the residue was dissolved in 200 ml of ethanol and the solution was acidiFied to a p~t of 1 with alcoholic hydrochloric acid. Tetrahydrofuran was added and the crystals formed were filtered, washed and dr;ed in an oven at 50C. 35 g of N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethylsulphonyl benzamide hydrochloride were obtained by re-crystallization from alcohol (Yield - 55.5%; m.p. 184-186C).

N-(l'-acetyl-2'-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide 4~ 9 of ethyl 2-methoxy-5-sulphamoyl benzoate were reacted with 31.5 9 of N-acetyl-2-aminomethyl pyrrol;dine in a similar manner to that described above, and resulted in 34.5 9 of N-(l'-acetyl-2'-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide. (Yield 52.5%; m.p. 204C).

N-(N'-ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2-methoxy-4-amino-5-chlorobenzamide _ 6.1 9 of 2-methoxy-4-amino-5-chlorobenzoic acid and 8 9 of N-ethyl-N-2-hydroxyethyl ethylene d;amine were added into a 250 ml flask. The mixture was heated to 100C and 6.5 9

3~

of phosphoric anhydride were then added. The mixture was carefully heated to 110C, and the temperature was then rapidly raised to 150-160C. This tempera~ure was maintained for 1/2 hour and then, after cooling to 100C, 100 ml of water were added. Soda was added after the components had completely -i dissolved. The mixture was cooled and then the precipitate was filtered, washed with water and dried.
6.6 g of N-(N'-ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2-methoxy-4-amino-5-chlorobenzamide were obtained. (Yield -69.8%, m.p. 111-112C).

N-(1-(2'-benzhydryloxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide 99 g of 1-(2'-benzhydryloxyethyl)-2-aminomethyl pyrrolidine and 500 ml of methyl ethyl ketone were added into a 4 litre flask. The mixture was cooled to 15C and a solution of 80 g of 2-methoxy-5-sulphamoyl benzoyl chloride in 1500 ml of methyl ethyl ketone was added. The mixture was stirred for 2 hours at ambient temperature. The precipitate formed was filtered, washed with a small amount of methyl ethyl ketone, and dried. The hydrochloride obtained was made alkaline while hot with ammon~a, and the product was crystallized by coolin~.
The crystals were filtered, washed, and dried in an oven at 50C. 88 g of N-(1-(2'-benzhydryloxyethyl)-2-pyrrolidinyl-methyl)-2-methoxy-S-sulphamoyl benzamide were obtained after recrystallization from ethanol, filtration through carbon black, and drying. (Yield = 52.6%; m.p. 124C).

1-(2'-methoxy-4'-nitrobenzamidopropyl)-4-hydroxyethyl piperazine 45 9 of 1-(2'-hydroxyethyl)-4-(3'-aminopropyl)-piperazine and 180 ml of chloroform were added into a 1 litre flask. A solution of 51 9 of 2-methoxy-4-nitrobenzoyl chloride was poured into the mixture at a temperature of 5 to 10C. At the end of the addition the mixture was brought to ambient temperature and then heated for 1 hour to 1 hour 15 minutes at 40-45C. Water was added and the chloroform was evaporated off. The solution obtained was filtered using carbon black and the benzamide base was precipitated by adding 50 9 of potassium carbonate. After decanting, the product was dissolved in methyl chloride and the aqueous solution was extracted with methylene chloride.
The organic phase was dried with potassium carbonate, and the methylene chloride was then distilled in vacuo. The oily benzamide obtained was purified by forming the hydro-chloride and treatment with ammonia.
59 g of 1-(2'-methoxy-4'-nitrobenzamidopropyl)-4-hydroxyethyl piperazine were obtained in the form of an oil.
(Yield ~ 67.2%).
Purity by quantitative determinat;on in a non-aqueous medium with perchloric acid: 97.8%.

N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethyl-; sulphonyl benzamide hydrochloride _ __ 39 ~ of 1-(2-hydroxy~thyl)-2-aminomethyl pyrrolidine, 250 ml of methyl ethyl ketone, and, while maintaining the temperature between 5 and 10C, 70 g of 2-methoxy-5-ethyl-sulphonyl benzoyl chloride were added into a 500 ml flask.
After stirring overnight the crystallized product was suction filtered, washed with methyl ethyl ketone, and dried at 45C.
The crude product was recrys~allized in 200 ml of alcohol at 95C. 73 9 of N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethylsulphonyl benzamide hydrochloride were obtained.
(Yield - 66.5%; m.p. 175-178C).

936~

N-(N'-ethyl-N'-(2'-hydroxyethyl)aminoethyl)-2--methoxy-5-sulphamoyl benzamide 78 g of ethyl 2-methoxy-5-sulphamoyl benzoate, 27 ml of water and 51 y of N-ethyl-N-2-hydroxyethyl ethylene diamine were added into a 250 ml flask. The mixture was heated for 10 hours on a water bath. The solution was diluted, and the benzamide base then crystallized. It was purified by forming the hydrochloride and reprecipitating the base wlth ammonia.
The crystals obtained were suction filtered, washed with water until chloride ions had all been removed, and dried in an oven ; at 40C.
66 9 of N-(N'-ethyl-N'-(2'-hydroxyethyl)am;noethyl)-2-methoxy-5-sulphamoyl benzamide were obtained. (Y;eld ~ 6~%;
m.p. 149-150C).

N-(1-(3'-hydroxypropyl)-2-pyrroiidinylmethyl)-2-methoxy-5-sulphamoyl benzamide hydrochloride 38.9 g of ethyl 2-methoxy-5-sulphamoyl benzoate, 13.5 ml oF water and 28.4 y oF N-1-(3'-hydroxypropyl)-2-aminomethyl pyrrolidine were added into a 250 ml flask. The mixture was heated for 10 hours at 80C; aFter cooling, 100 ml oF benzene were added and the solvents were distilled ofF. The mixture was cooled and 500 ml of water were then added. The crystals formed were filtered oFf, washed with water, and dried in an oven at 50C.
~0 y oF N-(1-(3'-hydroxypropyl)-2-pyrrolidinyl-methyl)-2-methoxy-5-sulphamoyl benzamide were obtained.
(Yield - 72%).
The benzamide was converted into the hydrochloride by dissolution in absolute alcohol and treatment with 50 ml of 25 concentration ethanolic hydrochloric ac;d. The solid obtained was recrystallized in methyl alcohol.

38 9 of N-(1-(3'-hydroxypropyl)-2-pyrrolidinyl-methyl)-2-rnethoxy-5-sulphamoyl benzamide hydrochloride were obtained. (Yield 62.2%; m.p. 226-229C).

1-52'-methoxy-4'-aminobenzamidopropyl)-4-hydroxyethyl piperazine diphosphate 2.8 g of 2-methoxy-4-aminobenzoic acid, 3.4 g o~ 1-(2'-hydroxyethyl)-4-(3'-aminopropyl)piperazine, 60 ml of pyridine were added ;nto a 250 ml flask, and 2.3 9 of silicon tetrachloride were added drop by drop. The mixture was heated for three hours at the reflux temperature. The pyridine was distilled off in vacuo. 30 ml of water were added, followed by hydrochloric acid until the pH value was 1. The mlxture was heated to the boil, filtered a~ter checking that the p~l was always acid, and then ammonia was added while hot.
After cooling, the precipitated liquid was decanted.
3.9 g of 1-(2'-methoxy-4'-aminobenzamidopropyl)-4-hydroxyethyl piperazine were obtained. (Yield: 69.6%).
Pur~ty by quantitat~ve determination in a non-aqueous medium, 97.5%.
The base obtained was dissolved in alcohol and then converted lnto its phosphate with phosphoric acid. The phosphate obtained was a double phosphate which crystallized with 3 moles of water. 3.2 g of 1-(2'-methoxy-4'-aminobenz-amidopropyl)-~-hydroxyethyl piperazine diphosphate were obtained (m.p. 144-145C).

N-t2-hydroxyethyl)-2-aminomethyl pyrrolidine Step 1: N-(2-hydroxyethyl)-2-nitromethylene pyrrolidine 264 9 of N-(2-acetoxyethyl)-2-pyrrolidinone and, drop by drop, 194 g of dimethyl sulphate, were added into a 3 litre flask. The solution obtained was heated at 60-63C for 1 1/2 93~

hours. The solution was cooled and a solution of sodium ethylate (formed from 35.5 g of sodium) in absolute ethyl alcohol (1080 ml) was added at a temperature of 15C. The mixture was stirred for 1 hour and 141 9 of nitromethane were then added. The reaction mixture was then heated 5 hours at the reflux temperature.
After filtering the sodium methyl sulphate, the alcohol and ethyl acetate were evaporated.
The precipitate formed by adding chloroform was filtered off; after evaporating the solvent the oil obtained was dissolved in 450 ml of dioxane. The crystals obtained were filtered, washed and dried. 132.6 g of N-(2-hydroxyethyl)-2-nitromethylene pyrrolidine were obtained. (Meltiny point:
123-124C).
Step 2: N-(2-hydroxyethyl)-2-aminomethyl pyrrolidine 146 9 of N-(2-hydroxyethyl)-2-nitromethylene pyrrolidine, 350 ml of methyl alcohol and 45 9 of Raney nickel were added into a 1 litre autoclave. Reduction was carried out under 50 kg hydrogen pressure. Absorption began in the cold and was complete after 15 minutes (final temperature 50-60C).
After cooling, the nickel was suction filtered and washed with alcohol. The solvent was evaporated and the res~due was dis-tilled *n vaauo.
88 9 of N-(2-hydroxyethyl)-2-aminomethyl pyrrolidine were obtained. (Yield; 73%; b.p. 10 mm/Hg - 134C, nD
1.4975.
EXAMPLE l?
N-(3-hydroxypropyl)-2-aminomethyl pyrrolidine ; Step 1: N-(3-hydroxypropyl)-2-nitromethylene pyrrolidine 289 g of N-(3-acetoxypropyl)-2-pyrrolidinone and, drop by drop, 185.6 g of dimethyl sulphate were added into a 9;~() 2 litre flask. The mixture was heated for 3 1l2 hours at 60-65C. After cooling, a solution o~ sodium propylate formed from 35.7 g of sodium in propyl alcohol (850 ml) was added at a temperature of 12C. The mixture was stirred for one hour.
After adding 141.3 9 of nitromethane and heating for 4 hours at 50-55C, the sodium methyl sulphate was ~iltered off and the solvents (propyl alcohol and propyl acetate) were evaporated.
1700 ml of chloroform were added and the mixture was filtered. The oil obtained after evaporation of the chloroform was dissolved in 500 ml of methyl isobutyl ketone.
After crystallization, the precipitate was filtered, washed with methyl isobutyl ketone, and dried. 147 g of N-(3-hydroxypropyl)-2-nitromethylene pyrrolidine were obtained.
(M.p.: 63C).
Step 2: N-(3-hydroxypropyl)-2-aminomethyl pyrrolidine N-(3-hydroxypropyl)-2-nitromethylene pyrrolidine, 350 ml of methanol and 45 g of Raney nickel were added into a 5 litre autoclave. The autoclave was flushed out four times with nitrogen and reduction was then carried out under a hydro-; 20 gen pressure of 50 kg at 55C. After 4 hours fresh hydrogen was added to readjust the pressure to 50 kg, and hydrogenation was cont~nu~d for a further 4 hours.
After filtering the mixture, the alcohol was evapo-rated and the product obtained was distilled in uacuo. 94 9 o~ N-(3-hydroxypropyl)-2-am~nomethyl pyrrolidine were obtained.
(Yield 79.3%; b.p. 14 mm/Hg = 146-150C; nD3 = 1.4915).
Purity by quantitative determination in a non-aqueous medium with HC104: 89.9%.
The N-(3-acetoxypropyl)-2-pyrrolidinone, which serves as starting material, was prepared as follows:
208 9 of N-(3-hydroxypropyl)-2-pyrrolidinone and ~ 9 3~

222 g of acetic anhydride were added into a 1 litre flask.
The temperature of the medium raised to 30C. O.S ml o~ 95%
concentration sulphuric acid were added and the mixture was carefully heated on a water bath, and then at 150C for two hours. After cooling, 1.6 9 of sodium acetate were added.
259.5 9 of N-~3-acetoxypropyl)-2-pyrrolidinone were obta;ned by distillation ~n v~cuo. (Yield - 96.4%; b.p. 12 mm/Hg - 165-170C.
The benzamides o~ the invention have valuable thera-peutic properties, particularly as antiemetics. Their lowtoxicity is compatible with use in human therapy without any risk of produciny side effects.
The acute toxicity of the products of the invention was determined in mice by the parenteral route (endovenous or intraperitoneally). The LD50 values, calculated according to Behrens and Karber's method, are given in the following ~able:
!

I LD50 IV mice LD50 IP mice mg/kg ~base) mg/kg (base) ':
N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy- 70 - 72 231 - 240 5-sulphamoyl benzamide .
N-(N'-ethyl-N'-hydroxyethyl-aminoethyl)-2-methoxy-4-amlno- 54 - 58 185 - 202.5 5-chlorobenza~ide N-(N'-ethyl-N'-hydroxyethyl-aminoethyl)-2-methoxy-5- 155 - 162 720 - 750 sulphamoyl benzamide -N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy- 65.5 340 - 350 5-ethylsulphonyl benzamide N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy- 82.4 ~ 84.5 205 - 219 5-ethylsulphonyl benzamide N-(1-(3'-hydroxypropyl)-2-pyrrol;dinylmethyl)-2-methoxy- 53.3 - 54.6 164 - 170 5-sulphamoyl benzamide .

o The antiemetic activity of the products of the in-vention to counteract apomorphine was studies in dogs according to Chen and Ensor's technique as developed by Ducrot and Decourt.
The results obtained are compared with those obtained by ~ourvoisier for the phenothiazines, and with those of Schallek for trimethobenzamide, and are given in the following table. We have calculated the activity index by the sub-cutaneous route, taking chlorpromazine as reference substance.
~ lG ED50 SC Activity ! ~g/kg (base)index, SC
N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy- 88 5.7 5-ethylsulphonyl benzamide N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy- 16.4 30.5 5-ethylsulphonyl benzamide N~ (3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy- 50 10 5-sulphamoyl benzamide chlorpromazlne 500 prochlorperazine 150 3.3 trimethobenzamide 2500 0.2 - These results prove that the compounds o~ the in-vention are noticeably more actlve as antiemetics than are phenothiazines and trimethobenzamide.

Claims

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for preparing compounds of the formula:

in which:
A represents a C1-5 alkyl group, Y represents hydrogen, nitro or amino group, Z represents hydrogen, halogen, sulfamoyl or a C1-5 alkyl-sulphonyl group, W represents an alkylene group with 1 to 4 carbon atoms which may form a straight or branched chain, B represents a group NR1R2 in which R1 is a C1-5 alkyl group, R2 is a C1-5 alkanol group, a 4-hydroxyalkyl-1-piperazinyl group or a racemic, dextrorotary or levorotary heterocyclic radical of the formula:

in which:
R is a C1-5 alkyl group containing hydroxyl group, a low carboxylic acyl or benzhydryloxyalkyl, which comprises reacting a compound of formula:

in which:
D represents hydroxy group, alkoxy or halogen, and A, Y and Z have the afore-mentioned meanings, with an amine of the following general formula:

in which W and B have the afore-mentioned meanings, or by reacting their reactive derivatives.

2. The process of Claim 1, wherein ethyl 2-methoxy-5-sulphamoyl benzoate is reacted with 1-(2-hydroxyethyl)-2-aminomethyl pyrrolidine to form the N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide.

3. The process of Claim 1, wherein 2-methoxy-5-ethylsulphonyl benzoic acid methyl ester is reacted with 1-(3-hydroxypropyl)-2-aminomethyl pyrrolidine to form the N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethyl-sulphonyl benzamide.

4. The process of Claim 1, wherein ethyl 2-methoxy-5-sulphamoyl benzoate is reacted with N-acetyl-2-aminomethyl pyrrolidine to form the N-(1'-acetyl-2'-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide.

5. The process of Claim 1, wherein 2-methoxy-4-amino-5-chlorobenzoic acid is reacted with N-ethyl-N-2-hydroxy-ethyl ethylene diamine to form the N-(N'-ethyl-N'-(2'-hydroxy-ethyl)aminoethyl)-2-methoxy-4-amino-5-chlorobenzamide.

6. The process of Claim 1, wherein 2-methoxy-4-nitrobenzoyl chloride is reacted with 1-(2'-hydroxyethyl)-4-(3'-aminopropyl)piperazine to form the 1-(2'-methoxy-4'-nitro-benzamidopropyl)-4-hydroxyethyl piperazine.

7. The process of Claim 1, wherein 2-methoxy-5-ethylsulphonyl benzoyl chloride is reacted with 1-(2-hydroxy-ethyl)-2-aminomethyl pyrrolidine to form the N-(1-(2'-hydroxy-ethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethylsulphonyl benz-amide.

8. The process of Claim 1, wherein N-ethyl-N-2-hydroxyethyl ethylene diamine is reacted with ethyl 2-methoxy-5-sulphamoyl benzoate to form the N-(N'-ethyl-N'-(2'-hydroxy-ethyl)aminomethyl)-2-methoxy-5-sulphamoyl benzamide.

9. The process of Claim 1, wherein ethyl 2-methoxy-5-sulphamoyl benzoate is reacted with N-1-(3'-hydroxypropyl)-2-aminomethyl pyrrolidine to form the N-(1-(3'-hydroxypropyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide.

10. The process of Claim 1, wherein 2-methoxy-4-aminobenzoic acid is reacted with 1-(2'-hydroxyethyl)-4-(3'-aminopropyl)piperazine to form the 1-(2'-methoxy-4'-amino-benzamidopropyl)-4-hydroxyethyl piperazine.

11. Compounds of the formula:

in which:
A represents a C1-5 alkyl group, Y represents hydrogen, nitro or amino group, Z represents hydrogen, halogen, sulfamoyl or a C1-5 alkyl-sulphonyl group, W represents an alkylene group with 1 to 4 carbon atoms which may form a straight or branched chain, B represents a group NR1R2 in which R1 is a C1-5 alkyl group, R2 is a C1-5 alkanol group, a 4-hydroxyalkyl-1-piperazinyl group or a racemic, dextrorotary or levorotary heterocyclic radical of the formula:

in which:
R is a C1-5 alkyl group containing hydroxyl group, a low carboxylic acyl or benzhydryloxyalkyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

12. The N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.

13. The N-(1-(3'-hydroxypropyl)-2-pyrrolidinyl-methyl)-2-methoxy-5-ethylsulphonyl benzamide, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

14. The N-(1'-acetyl-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoyl benzamide, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

15. The N-(N'-ethyl-N'-(2'-hydroxyethyl)aminomethyl-2-methoxy-4-amino-5-chlorobenzamide, when prepared by the process defined in Claim 5 or by an obvious chemical equiva-lent.

16. The 1-(2'-methoxy-4'-nitrobenzamidopropyl)-4-hydroxyethyl piperazine, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.

17. The N-(1-(2'-hydroxyethyl)-2-pyrrolidinylmethyl)-2-methoxy-5-ethylsulphonyl benzamide, when prepared by the process defined in Claim 7 or by an obvious chemical equiva-lent.

18. The N-(N'-ethyl-N'-(2'-hydroxyethyl)aminomethyl)-2-methoxy-5-sulphamoyl benzamide, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.

19. The N-(1-(3'-hydroxypropyl)-2-pyrrolidinyl-methyl)-2-methoxy-5-sulphamoyl benzamide, when prepared by the process defined in Claim 9 or by an obvious chemical equiva-lent.

20. The 1-(2'-methoxy-4-aminobenzamidopropyl)-4-hydroxyethyl piperazine, when prepared by the process defined in Claim 10 or by an obvious chemical equivalent.