FR2493702A1 - ANTIVIRAL COMPOSITIONS CONTAINING AMINOSULFONYLHALOGENOBENZOIC ACID DERIVATIVES - Google Patents

Abstract

THE INVENTION CONCERNS ANTIVIRAL COMPOSITIONS CONTAINING AMINOSULFONYLHALOGENOBENZOIC ACID DERIVATIVES; THESE COMPOSITIONS CONTAIN AS ACTIVE COMPONENTS OF DERIVATIVES OF THE FORMULA: (DRAWING CF IN BOPI) IN WHICH X AND Y REPRESENT INDEPENDENTLY OF ONE OF THE OTHER AN ATOM OF HYDROGEN, FLUOR, CHLORINE OR BROMINE OR A RADICAL AMINO OR NITRO , R REPRESENTS A HYDROGEN ATOM OR A LOWER RADICAL ALKYL, R REPRESENTS A HYDROGEN ATOM OR A RADICAL AMINO, LOWER ALKYL, HYDROXYALKYL, LOWER ALCOXY, ARYL, GUANYL, GUANYLINOTIO, UXOINO, GUANYLINO, GUANYL, GUANYLINO-OXIDO-CHINO-OZOIDO , OR R AND R CAN FORM TOGETHER WITH THE NITROGEN ATOM ON WHICH THEY ARE FIXED A SATURATED HETEROCYCLIC RADICAL HAVING 4 OR 5 CARBON ATOMS OF WHICH CARBON ATOMS CAN BE REPLACED BY AN OXYGEN ATOM OR AN ATOM OF NITROGEN NOT SUBSTITUTED OR SUBSTITUTED BY A LOWER RADICAL ALKYL, AND THEIR SALTS. THESE COMPOSITIONS ARE EFFECTIVE FOR TREATING VARIOUS INFECTIOUS DISEASES CAUSED BY VIRUSES SUCH AS UPPER RESPIRATORY TRACT INFECTION, PNEUMONIA, BRONCHITIS.

Description

The present invention relates to compositions

  antiviral agents containing aminosulfonyl acid derivatives

haloaénobenzofque.

  More particularly, the invention relates to

  antiviral positions that contain acid derivatives

  aminosulfonylhalogenobenzoic acid or their salts which are

  for the treatment of various infectious diseases

  caused by the virus, for example upper respiratory tract infections, pneumonia,

bronchitis and others.

  The invention furthermore relates to a method of treating

  viral diseases with these compositions.

  Vaccines used against viral diseases act slowly and are only useful as a preventive measure. In addition, as the antigenicity of the target viruses

  often varies, the effect of vaccines has been shown to be insufficient.

  health. The Applicant has therefore carried out very

  important to discover drugs with ef-

  rapid therapeutic effects and found that aminosulfonylhalobenzoic acid derivatives are suitable for this purpose.

  effect; the invention is based on this discovery.

The invention has for objects:

  pharmaceutical compositions having an activity

  which contain amino acid derivatives

  sulphonylhalobenzoic acid which are effective for the treatment of

  of various infectious diseases caused by

  viruses, such as respiratory tract infections,

  higher res, pneumonia, bronchitis and others; and a method of treating viral diseases with

these compositions.

  Other features and advantages of the invention

  will emerge from the description which follows.

  The invention relates to antiviral compositions

  which contain as active components

  of aminosulfonylhalobenzoic acid of formula (1): 24937o02 COOH y SO N (1 2 \ R2 X

  where X and Y, independently of one another, represent

  a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an amino radical or a nitro radical, R1 represents a hydrogen atom or a lower alkyl radical, R2 represents a hydrogen atom, an amino radical, a lower alkyl radical, a hydroxyalkyl radical, a lower alkoxy radical, a radical

  aryl, a guanyl radical, a guanidino radical, a radical

  cal uceido, an oxsamoylamino radical or a pyridazino-

  chloro-substituted amino, or R1 and R2 may together form

  with the nitrogen atom to which they are attached.

  saturated heterocyclic dical having 4 or 5 carbon atoms and the carbon atoms of which may be replaced by an oxygen atom or an unsubstituted nitrogen atom or

  substituted by a lower alkyl radical, and their salts.

  The compounds which are the main ingredients of the antiviral compositions of the invention can be prepared as follows. Haloaenobenzoic acid is heated in chlorosulfonic acid to give an acid

  chlorosulfonylhaloaénobenzoique. (GoB patent 896,137).

  The chlorosulfonylhalobenzoic acid is reacted

  thus obtained with an amine of formula HNw R1 at the time

  ordinary temperature in a solvent such as water, dioxane

  ne, tetrahydrofuran, chloroform, dichloro-

  thane, benzene and the like or in a solvent mixture consisting of water and one of these organic solvents,

  presence of an acid acceptor, for example a mid base

  such as sodium hydroxide, Dotas hydroxide

  sium, sodium carbonate, potassium carbonate,

2493O02

  sodium bicarbonate and the like or an organic base such as triethylamine, pyridine and the like, or

  using the amine HN "R1 as acid acceptor.

  The physicochemical properties of the acid derivatives

  of aminosulfonylhaloghenobenzoic acid thus obtained

in Table 1.

Physicochemical properties

,,, ...., ........_ _,

  Compose Point Ofition Properties

  Acid White crystalline powder; insoluble

  1,3-aminosulphonyl-4,337,238 ble in benzene and hexane; fluorobenzaoic soluble in hot water and methanol.

  Acid White crystalline powder; insoluble

  2-aminosulphonyl-4- (hydroxyl) -2,663; 263 bbl in benzene and hexane; chlorobenzene soluble in hot water and methanol.

  Acid White crystalline powder; insoluble

  3-aminosulfonyl-4- (268) -270 ble in benzene and hexane; bromobenzoic acid soluble in hot water and methanol.

  Acid White crystalline powder; insoluble

  4-aminosulfonyl-4- 273-276b in benzene and hexane; iodobenzoic acid soluble in hot water and methanol.

  Acid White crystalline powder; insoli-

  4-chloro-3-methylamino-2365 239 ble in benzene and hexane; sulfonylbenzoic acid soluble in hot water and methanol.

_ ,,,,,,,, ,,, ..,. ,,,,,,

  Acid White crystalline powder; insoluble

  4-chloro-3-ethylamino-benzene in hexane and benzene; Sulfonylbenzoic 190.5 - 192, soluble in hot water and

m6f thanol.

. ,,,., _ ,,, L, '' '' '

w '-r- (A4 -'j

TABLE 1

TABLE 1 - continued

_. _ .. .............

  Melting point Properties compound (C) I

,. ,, -......__

  4-Cliloro-3-dimethylacrylic acid White crystalline powder; insol 7 aminosulfonylbenzoSaue 248.5 - 249e5 ble in benzene and hexane; soluble in hot water and methanol, .... white crystalline acid; insolu 8-chloro-3-methoxyamino-205,201 in benzene and hexane; sulphonylbenzoic oluble in hot water and ethanol. Crystal white crystalline acid; insolu 9-chloro-3-hydroxyethyl-177-ol in benzene and hexane; aminosulfonyl benzoic soluble in hot water and ethanol.

_ ,,,. ,, ......

  Acid White crystalline powder; insolu.

4-chloro-3-N-methyl-

  hydroxyethylaminosulfonyl-1555-1565 oluble in enne and hexane; oluble in hot water and the

benzolc ethanol.

  White crystalline waxy acid; insolu.

  4-chloro-3-hydrazino-286.5 -288 ble in benzene and hexane; sulfonylbenzoic (dec) soluble in hot water and ethanol.

L ,, ..., ...

  Acid | white crystalline oudre; insoluble

  4-chloro-3-isopropyl ether in benzene and hexane; Aminosulfonylbenzoic acid 189 - 191 luble in hot water and ethanol. rla N o r TABLE 1 - continued

T - - -

  Melting point Properties Compound (OC) Acid White crystalline powder; insolu 13 3-anilinosulfonyl-4,208-bg in benzene and hexane; chlorobenzoate soluble in hot water and methanol. 4-chlorophenol white crystalline powder, insoluble 4-chloro-3- [2- (6-benzene and hexane; 14 chloropyridazin-3-yl) hydrazino-186 - 188 soluble in water; hot water e and loxane sulfonylbenzoic soluble in hot water and methanol Acid White crystalline powder, insolu 16 4-chloro-3- (pyrrolidinyl-1 237 239 wheat without benzene and hexane, sulfonyl) benzoic acid soluble in hot water and methanol White Crystalline powder, insoluble 17 4-chloro-3- (4-methylpiperazine-120,121 ble in benzene and hexane, 1-vl) sulfonylbenzolcue soluble in hot water and methanol Acid White crystalline powder, insoluble 2-amino-5-aminosulfonyl-4> 300 ble in benzene and hexane, chlorobenzoic acid soluble in hot water and methanol. -4% OC: Shelf TABLE 1 - continued Melting Point Compound (oC) Properties

  Acid White crystalline powder; insol-

  5-aminosulfonyl-4- (2,34) - 236 ble in benzene and hexane; 1-chloro-3-nitrobenzene soluble in hot water and methaol.

  Acid White crystalline powder; insol-

  -aminosulfonyl-4-chloro-242- 245 ble in benzene and hexane; 2 Fluorobenzoic acid soluble in hot water and methanol.

  Acid White crystalline powder; insol -

  -aminosulfonyl-2-chlorobenzene in benzene and hexane; 21 lrbezou 2 4-fluorobenzole soluble in hot water and methanol.

_, J ,. _ ....

  Acid White crystalline powder; insoluble

  -aminosulfonyl-2-bromobenzene in benzene and hexane; 4chlorobenzoic acid soluble in hot water and methanol.

  Acid White crystalline powder; insoluble

  5-aminosulfonyl-2,4-232-233.5 ble in benzene and hexane; 3 dichlorobenzoic acid soluble in hot water and methanol. Acid White crystalline powder; insolu-3-aminosulfonyl-4,5-266-268b in benzene and hexane; 24 dichlorobenzoaue soluble in hot water and 24 dichlorobenzoic methanol. K) TABLE 1 - continued CompoIsé Flusion Point (C) Properties Acid White crystalline powder; insolu

2,4-dichloro-5-

  2,4-dichloro-5-benzohexane in benzene and hexane; guanidinosulfonylbenzoic acid soluble in hot water and methanol. Acid White crystalline powder; insolu 26 2,4-dichloro-5,199 - 199 ble in benzene and hexane; guanidinoaminosul.fonylbenzoi'que (dec) soluble in hot water and methanol. 24Acideiho White crystalline powder; insolu 2,4-dichloro-5-ol in benzene and hexane; 27 semnicarbazidesulfonylbenzoic acid 220 (dec) ble in benzene and hexane; - soluble in hot water and methanol. Acid White crystalline powder; insolu 28 2,4-dichloro-5- (2-oxamoyl) 217-219b in benzene and hexane, hydrazinosulfonyl benzo (dec) soluble in hot water and methanol 3-aminosulfonyl-5-white crystalline powder insoluble 3-Ammoniumsulfonyl 22 43 in benzene and hexane 29 chlorobenzoic 242 - 243 soluble in hot water and methanol White Crystalline powder, 3-aminosulphonyl-insoluble in benzene and hexane, bromobenzoic acid 241 - 244 soluble in hot water and methanol Acid 2 Acid n White Crystalline Insoluble 2-aminosulphonyl 162-53.5 b in benzene and hexane; 3 chlorobenzoic acid in hot water and ammonia.

  Amino acid derivatives should be converted

  sulphonylhalobenzoic acid thus produced in

  coming to the pharmacy. These salts may be the salts of

  dium, potassium, lithium, ammonium, calcium, barium and others. Efficacy, safety, directions for use and

  the dosage of aminosulphonylhydroxy acid derivatives

  benzoic acid thus obtained are described below.

  Experimental Example 1. Antiviral activity on cells

in culture.

  The antiviral activity of the compounds of the invention

  was determined according to the method described by Marks (Antimicrob, Agents Chemother., Vol. 6, pages 34-38,

1974).

  Monolayers of cell cultures

  MDCK, Vero and HEL were inoculated with 0.1 ml of

  Serial numbers of a virus in Eagle's minimum essential medium supplemented with 0.1 or 0.2% bovine serum albumin, one hour after treatment with

  0.1 ml of a solution of the studied conosé. Arrears 2 or. 3 days of incu-

  at 37 ° C in a 5% CO2 atmosphere, the cytoplasmic effect

  topathogen-of 100 TCID50 of the virus was studied at the micros-

  cope. The minimum inhibitory concentration of the compound a

  has been defined as the lowest concentration of

  positively inhibiting the cytopathic effect of the virus.

  The results are shown in Table 2.

  TABLE 2 In Vitro Antiviral Activity Inhibition (ng / mx) Influenza A0 (WSN) Influenza A2 Parainfluenza Rhino Coxsackie ECHO CONMSe (Kumamoto) Type 3 Type B5

this.__.._.._..___. __ - _ _.

1 30 30 300 300> 300> 300

2 30 30 300 300> 300> 300

3 100 100 300 300> 300> 300

4 100 100 300 300> 300> 300

1- N 4- o ro -J '1i

Experimental example 2.

  According to the method of Example 1, it was determined

  The minimum inhibitory concentration of the compounds of the invention with respect to the cytophatogenic effect of 10 TCID 50 of virus was born. The results are shown in Table 3. The following viruses were used: Influenza A0 A Influenza A1 B Influenza A2 C Influenza B D Parainfluenza Type 3 E

ECHO F

  Coxsackie Type B5 G Rhino H Respiratory Virus I Vesicular Stomatitis J TABLE 3 In Vitro Antiviral Activity Minimal Inhibitory Ccncentraticn (Pg / mZ)

A B RC D E F G H I J

300 300 300 300 300 100 300 300 300

300 300 300 300 300 300 300 100 300

300 300 300 300 300 300 300 300 300

300 300 100 300 300 300 300 300 300

300 100 300 100 300 300 300 100 300

300 300 300 300 100 300 300 300 300

300 100 100 300 300 300 300 300 100

100 300 300 300 300 300 300 300 300

300 300 300 300 300 100 300 300 300

300 300 300 300 100 300 300 300 300

300 300 300 300 100 300 300 300 300

300 300 300 300 300 100 300 300 300

100 300 100 300 300 100 300 300 300

  - 100 300 300 300 300 300 300 300 300

300 300 300 300 100 300 300 300 300

300 300 300 300 300 30 300 300 100

300 300 300 300 300 300 300 300 300

300 30 300 300 3 30 300 300 300

300 300 100 100 100 100 100 30 100

100 10 100 30 100 300 30 300 30

300 300 300 300 300 300 100 300 300

  TABLE 3 - continued Minimum Inhibitory Concentration (pg / mt) Compound A B C D E F G H I J

  26 100 300 100 300 300 100 300 300 100 300

  27 100 300 300 300 100 300 300 300 300 300

  28 100 300 300 300 300 300 300 100 300 300

  29 30 300 300 100 300 300 300 300 100 300

  30 300 300 300 300 100 300 300 300 300

  31 30 300 30 100 300 300 300 100 300 300

  All compounds 1 to 31 exhibited an activity

  antiviral activity although each compound has had a specificity with regard to viruses against

which he is most effective.

  Experimental example 3. Protective action against death

  of mice infected with influenza AO-

  After inoculating the influenza A virus with

  intranasal route under light ether anesthesia to groups of

  of ten female ICR mice (16-18g),

  the invention were administered orally or intra-

  peritoneal in multiple doses twice a day a

  after the infection, the administration being continued for 14 days. Treatment increased the percentage of

survival on the 15th day.

  The results are given in the Tables

4, 5 and 6.

  Table.4 Results of Intraperitoneal Administration Dose Dose Rate Compound Rate mg / kg exceeded%) Compound mg / kg survival (Control 0 30 20

40 3 100 40

50,300 50

30 300 50

2 30 40 000 60

_ 100 [60 ..__

  Table 5 Results of Intraperitoneal Administration Dose Dose Rate Compound Rate mg / kg Survival (%) Compound mg / kg Survival (%) Control 0 19 100 50

100 40 20 100 50

6 100 40 21 100 40

7 100 40 22 30 - 50

8 100 50 100 70

_ _9I100 40 10 40

23 _

100 60. 30 50

  __ _ _ _ __ _ _ _ _ _ _ ___ _ _ _ _ _ __ _ _ _ _

he 10 30 10 40

___30 50 24 30 60

12 100 l 40! __ 100 70

13 100 40 25 100 40

14 100 40 26 100 40

100 50 27 1 00 40

16 100 40 28 t100 40

17 10 40 29 100 40

17 III _ I

50 30 100 40

18 100 40 31 100 40

  Table 6 Results of Oral Administration Dose Rate of Dose Rate of Concomitant mg / Rg Suvice mg / g Survival (%) m) Control 0 19 300 50

300 50 20 300 50

6 300 50 21 300 40

7 300 50 22 100 50

8 300 40 300 70

9 300 50 23 30 40

23_

300 40 100 60

40 30 40

11I.

300 60 24 100 60

12 300 40 300 80

13 300 40 25 300 50

14 300 40 26 300 40

300 50 27 300 40

16 300 40 28 300 50

17 100 50 29 300 50

300 70 30 300 50

18 300 50 31 300 40

.0

  All coxnosed 1 to 31 showed an effect

  tector against death due to infection and in particular

  compounds 11, 17, 22, 23 and 24 presented an activity

especially excellent.

  Experimental Example 4. Mouse Acute Toxicity Compounds of the invention were dissolved in saline, administered orally or intraperitoneally (10 ml / kg) to groups of 10 male ddy mice (24-26 g). The mortality rate was observed

  after 7 days. The LD50s were determined according to the

  Wilcoxon's thode - Litchfield. The results appear

in Tables 7 and 8.

Table 7

LD50 (mg / kg)

  Adminis- Administra- Adminis-.crinistra-

  Intra-compounding composition Intra-

  Oral peritoneal Drale

  1 {> 10,000 I 3,290 3> 10,000 I> 5,000

  O30> 10 000 3520 4 I> 10000> 5000

Table 8 LD50 (mg / kg)

  Administra- Administra- Administra- Adminis- Administra-

  Intra-oral Oral intravenous contritration oral peritoneal

*> 3,000> 1,000 19> 3,000 I> 1,000

6> 3,000> 1,000 20> 3_000> 1000

6> 3,000> 1,000,201> 3,000> 1,000

8> 3,000> 1,000 21> 3,000> 1,000

  8> 3 ooo0> 1 oo o 22> 3 'o0, J,> 1 ooo

9> 3,000> 1,000 23> 3,000> 1,000

> 3,000> 1,000 24> 3,000> 1,000

  ____________> 000 i '> 1 000 il> 3 000 746 25> 3 000 987

12> 3000> 1000 26> 3000> 1000

13> 3,000,968 27> 3,000> 1,000

  14> 3,000> 1,000 28> 3,000 f> 1,000> 3,000> 1,000 29> 3,000 f> 1,000 _. . i

16> 3,000> 1,000 30> 3,000> 1,000

17> 3,000> 1,000 31> 3,000 d> 1,000

_ 18> 3,000> 1,000__ _

  It is apparent that all of the compounds 1 to 31 of the above experimental examples have broad spectrum antiviral activity and extremely high safety. They are therefore very useful in clinics for treating various

  infectious diseases caused by viruses, for example

  infections of the upper respiratory tract, the

pneumonia, bronchitis and others.

  In the case where the compounds of

  the invention to man the dosage for the adult is

  between 30 and 5000 mg daily for compounds 1 to 10, 12 to 16, 18 to 22 and 29 to 31; 10 to 5000 mg per day for compounds 11, 17, 23 and 24 and 50 to 5000 mg per day for compounds 25 to 28. However, the dosage indicated in the above ranges may be increased or decreased.

  above according to symptoms and other factors.

  tors. Compounds 1-31 can be incorporated into pharmaceutical compositions according to a conventional method.

  with vehicles and pharmaceutical bases as excipients

  maceutiques commonly used for this purpose. These composi-

  For example, they may be capsules,

  tablets, powders or oral liquid preparations

  (including dry syrups) for oral administration; suppositories for rectal administration; lyophilized preparations which can be dissolved in distilled water for injection immediately prior to administration by injection; and other compositions

  such as nasal drops or a product for inhalation.

lation.

  Examples of pharmaceutical compositions

  not limiting in nature are given below.

  Example: Tablets Ingredients Quantities I) Compound 11 50 g

II) Lactose q.s.

  III) Crystalline cellulose 60 g IV) Potato starch 54 g V) Magnesium stearate 2 g 200 g Ingredients (I) to (IV) are homogeneously mixed and a 10% poi of one part is added of the ingredient (IV) which was previously separated to prepare raw granules is dried. Then mix

  granules with ingredient (V) to obtain compounds

  awarded each weighing 200 mq. If desired, we can

  rober sugar the tablets in the usual way.

  Example 2: 10% powders Ingredients Quantities Compound 17 100 g Lactose 890 g Magnesium Stearate 10 g 1000 g Each of the ingredients above is weighed and homogeneously mixed to prepare powders

at 10%.

  Example 3: Capsules Ingredients Quantities I) Compound 23 50 g II) Calciun Hydrogen Phosphate 50 g

III) Aluminum silicate qos.

  IV) Crystalline cellulose 60 g V) Magnesium stearate 2 g Ingredients (I) to (V) above are combined and thoroughly mixed by passing through a sieve to prepare capsules in the usual manner.

each weighing 200 mg.

  Example: Injectable solutions 100 g of the sodium salt of compound 2 are dissolved in 2 liters of distilled water for injection and with

  this solution is usually prepared

  containing 2 ml of solution for injection containing

100 mg of the active compound.

  Example 5: Nasal drops-1% Ingredients Quantities Compound 2 (sodium salt) 10 g Sodium chloride 5g Chlorobutanol 5 g Distilled water q.s. ! OOOml

  After having weighed each of the ingredients

  above, they are dissolved together in 950 ml of water and the volume of the solution is brought to 1000 ml to prepare

nasal drops at 1%.

24937G2

Claims (9)

  1. Antiviral composition-containing comr.me ind   active ingredient of aminosulfonylhalcogeno   benzoic compound having the general formula (I): COOH R Y S02N 1 (I)   Wherein X and Y independently of one another represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an amino group or a nitro group; hydrogen atom or a   lower alkyl radical, R2 represents a hydrogen atom   gene, an amino radical, a lower alkyl radical, a   hydroxyalkyl radical, a lower alkoxy radical   an aryl radical, a guanyl radical, a guanidino radical, a ureido radical, an oxamoylamino radical or a chloro-substituted pyridazinoamino radical, or R1 and R2 may together form with the nitrogen atom   on which they are fixed a heterocyclic radical   4 or 5 carbon atoms, the carbon atoms of which can be replaced by an oxygen atom or an unsubstituted or substituted nitrogen atom.   lower alkyl radical, and their salts.   2. Composition according to claim 1, in   which the aminosulfonylhalogenobenzo-   that of general formula (I) is a 3-amino acid derivative   sulfonyl-4-chlorobenzoic acid (in the formula, X represents   is a chlorine atom, Y is a hydrogen atom   R 1 represents a hydrogen atom or a lower alkyl radical, R 2 represents a hydrogen atom, an amino radical, a lower alkyl radical or a radical.   hydroxyalkyl, an aryl radical or a pyridazino radical   chloro-substituted amino or R1 and R2 may together form   with the nitrogen atom on which they are fixed.   saturated heterocyclic dical having 4 or 5 carbon atoms   ne, whose carbon atoms may be replaced by an oxygen atom or an unsubstituted nitrogen atom   or substituted by a lower alkyl radical).   3. Composition according to claim 1,   wherein the aminosulfonylhalogeno acid derivative   benzo compound of general formula (I) is 3-aminosulic acid   sulfonyl-4-chloro-5-nitrobenzoic acid. The composition of claim 1, wherein the aminosulfonylhaloenobenzoic acid derivative   of general formula (I) is 3-aminosulfonyl-4-   chloro-5-nitrobenzoic acid. The composition of claim 1, wherein the aminosulfonylhaloqgenobenzoic acid derivative is   of general formula (I) is a 2,4-aminosulphonyl acid.   dihalobenzoic acid (in the formula, X and Y represent a fluorine atom, a chlorine atom or a bromine atom,   and R1 and R2 each represent a hydrogen atom).   The composition of claim 1, wherein the aminosulfonylhalobenzoic acid derivative   of general formula (I) is a 3-aminosulic acid derivative   fonylhalogénobenzolque. The composition of claim 1 wherein the aminosulfonylhalobenzoic acid derivative   of general formula (I) is a 5-aminosulic acid derivative   2,4-dichlorobenzoic fonyl (in the formula, X and Y   each have a chlorine atom, R 1 represents a hydrogen atom and R2 represents a guanyl radical, a   guanidino radical, a ureido radical or an oxamoyl radical amino).   The composition of claim 1, wherein the aminosulfonylhalobenzoic acid derivative of   general formula (I) is a 3-aminosulfonyl-5-acid derivative   halogenobenzoic acid (in the formula X represents a chlorine atom or a bromine atom and Y, R1 and R2 represent each a hydrogen atom).   The composition of claim 1, wherein the aminosulfonylhalobenzoic acid derivative   of general formula (I) is 2-aminosulfonyl-5-chloroacid robenzoîque.