GB2090136A

GB2090136A - Antiviral compositions containing sulphonamide derivatives

Info

Publication number: GB2090136A
Application number: GB8133392A
Authority: GB
Original assignee: Mochida Pharmaceutical Co Ltd
Current assignee: Mochida Pharmaceutical Co Ltd
Priority date: 1980-11-10
Filing date: 1981-11-05
Publication date: 1982-07-07
Also published as: FR2493702B1; DE3144689A1; GB2090136B; JPS5781411A; JPS58914A; FR2493702A1; JPS5817167B2

Abstract

Antiviral compositions contain as active component aminosulfonylhalogenobenzoic acid derivatives of the formula: <IMAGE> wherein X and Y, independently of each other, denote hydrogen, fluorine, chlorine, bromine, amino or nitro, R1 denotes hydrogen or lower alkyl, R2 denotes hydrogen, amino, lower alkyl, hydroxyalkyl, lower alkoxy, aryl, guanyl, guanidino, ureido, oxamoylamino or chloro-substituted pyridazinoamino, or R1 and R2 together with the nitrogen atom in the formula (I) may form a saturated heterocyclic group having 4 or 5 carbon atoms, which may be substituted by oxygen, amino or alkylamino, and the salts thereof.

Description

SPECIFICATION Antiviral compositions and a method for treating virus diseases DESCRIPTION The present invention relates to antiviral compositions and, more particularly, to antiviral compositions which contain aminosulfonylhalogenobenzoic acid derivatives or salts thereof which are effective for therapeutic treatment of various infectious diseases which are caused from viruses, for example, upper respiratory infection, pneumonia, Brouchitis and so on.

The present invention further relates to a method of treating virus diseases by said compositions.

Vaccines which have been used for viral diseases are slow-acting and their utility is limited only to preventive use. Moreover, since antigenicity of objective viruses often changes, the effect of vaccines have not been sufficient.

Under these circumstances, the present inventors have carried out intensive studies to find out pharmaceuticals which have fast-acting therapeutic effects.

As a result, the inventors found out that aminosulfonylhalogenobenzoic acid derivatives meet the above requirement, thus completed the present invention.

SUMMARY OF THE INVENTION Accordingiy, the object of the present invention is to provide pharmaceutical compositions having antiviral activity which contain aminosulfonylhalogenobenzoic acid derivatives which are effective for therapeutic treatment of various infectious diseases caused from viruses, such as upper respiratory infection, pneumonia, Brouchitis and so on.

Another object of the present invention is to provide a method of treating virus diseases by said compositions.

Further objects and advantages and features of the present invention will become apparent during the course of the description which follows.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to antiviral compositions which contain as an active component aminosulfonylhalogenobenzoic acid derivatives of the formula (I):

wherein X and Y, independently of each other, denote hydrogen atom, fluorine atom, chlorine atom, bromine atom, amino group or nitro group, Rl denotes hydrogen atom or lower alkyl group, R2 denotes hydrogen atom, amino group, lower alkyl group, hydroxyalkyl group, lower alkoxy group, aryl group, guanyl group, guanidino group, ureido group, oxamoylamino group or chloro-substituted pyridazinoamino group, or R and R2 together with the nitrogen atom in the formula may form a saturated heterocyclic group having 4 or 5 carbon atoms in which the carbon atoms may be substituted by an oxygen atom or non-substituted or lower alkyl-substituted nitrogen atom, or the salts thereof.

The compounds which are the main ingredients of antiviral compositions according to the present invention can be prepared as follows. Namely, halogenobenzoic acid is heated in chlorosulfonic ecid to obtain chiorosulfonylhaiogenobenzoic acid. (Brit. 8961,137) Chlorosu!fonylhalogenobenzoic acid thus obtained is reacted with an amine of the formula

at room temperature in a solvent such as water, dioxane, THF, chloroform, dichloromethane, benzen and so on or in a mixed solvent of water with one of these organic solvents, in the presence of deoxidizing agent, for example, inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and so on or an organic base such as triethyl amine, pyridine and so on, or using per se as deoxydizing agent.

The physicochemical properties of the aminosulfonylhalogenobenzoic acid derivatives thus produced are shown in Table 1. TABLE 1 Physicochemical Properties (the term (dec) means "decomposition")

Melting Point Compound ( C) Property 1 S-aminesulfonyl-4- 237 - 238 whlte crystalline powder; fluorobenzolg acid insoluble in benzene, hexane; soluble in hot water, methanol 2 3-aminosulfonyl-4- 260 - 263 whie crystalline powder; chlorobenzoic acid insolubel in benzene, hexane;; soluble in hot water, methanol 3 3-aminosulfonyl-4- 268 - 270 whlte crystalline powder; vromobenzoic acid insoluble in benzene, hexane; soluble in hot water, methanol 4 3-aminosulfonyl-4- 273 - 276 whlte crystalline powder; iodobenzoic acid insoluble in benzene, hexane; soluble in hot water, methanol 5 4-chloro-3-methylamino- 236.5 - 239 whlte crystalline powder; sulfonylbenzoic acid insoluble in benzene, hexane;; soluble in hot water, methanol 6 4-chloro-3-ethylamino- 190.5 - 192.5 whlte crystalline powder; sulfonylbenzoic acid insoluble in benzene, hexane; soluble in hot water, methanol 7 4-chloro-3-dimethyl- 248.5 - 249.5 whlte crystalline powder; aminosulfonylbenzoic acid insoluble in benzene, hexane; soluble in hot water, methanol TABLE 1 (Continued0

Melting Point Compound ( C) Property 8 4-chloro-3-methoxyamino- 205 - 206 white crystalline powder;; sulfonylbenzoic acid insoluble in benzene, hexane; solube in hot wateer, methanol 9 4-chloro-3-hydroxyethyl- 177 - 178 white crystalline powder; aminosulfonylbenzoic acid insoluble in benzene, hexane; solube in hot wateer, methanol 10 4-chloro-3-N-methyl- 155.5 - 156.5 white crystalline powder; hydroxyetylaminosulfonyl- insoluble in benzene, hexane; benzoic acid solube in hot wateer, methanol 11 4-chloro-3-hydrazino- 286.5 - 288 white crystalline powder;; sulfonylbenzoic acid (dec) insoluble in benzene, hexane; solube in hot wateer, methanol 12 4-chloro-3-isopropyl- 189 - 191 white crystalline powder; aminosulfonylbenzoic acid insoluble in benzene, hexane; solube in hot wateer, methanol 13 3-anilinosulfonyl-4- 208 - 210 white crystalline powder; cghlorovbenzoic acid insoluble in benzene, hexane; solube in hot wateer, methanol 14 4-chloro-3-[2-(6-chloro- 186 - 188 white crystalline powder; ; pyridazine-3-yl)hydrazino- insoluble in benzene, hexane; 1-yl]sulfonylbenzolc acid solube in hot wateer, methanol TABLE 1 (Continued)

Melting Point Compound ( C) Property 15 4-chloro-1-mopholino- 187 - 189.5 white crystalline powder ; sulfonylbenzoic acid insoluble in benzene, hexane; solubel in hot water, methanol 16 4-chloro-3-(pyrrolidinyl-1- 237 - 239 white crystalline powder ; sulfonyl0benzoic acid insoluble in benzene, hexane;; solubel in hot water, methanol 17 4-chloro-3-(4-methyl- 120 - 121 white crystalline powder ; piperazine-1-yl)-sulfonyl- insoluble in benzene, hexane; benzoic acid solubel in hot water, methanol 18 2-amino-5-aminosulfonyl- > 300 white crystalline powder ; 4-chlorobenzoic acid insoluble in benzene, hexane; solubel in hot water, methanol 19 5-aminosulfonyl-4-chloro- 234 - 236 white crystalline powder ; 3-nitrobenzoic acid insoluble in benzene, hexane;; solubel in hot water, methanol 20 5-aminosulfonyl-4-chloro- 242 - 245 white crystalline powder ; 2-fluorobenzoic acid insoluble in benzene, hexane; solubel in hot water, methanol 21 5-aminosulfonyl-2-chloro- 245 - 248 white crystalline powder ; 4-fluorobenzoic acid insoluble in benzene, hexane;; solubel in hot water, methanol TABLE 1 (Continued)

Melting Point Compound ( C) Property 22 5-aminosulfonyl-1-bromo- 220 - 234 white crystalline powder 4-chlorobenzoic acid insoluble in benzene, hexane solubel in hot water, methanol 23 5-aminosulfonyl-2,4- 232 - 233.5 white crystalline powder dichlorobenzoic acid insoluble in benzene, hexane solubel in hot water, methanol 24 3-aminosulfonyl-4,5- 266 - 268 white crystalline powder dichlorobenzoic acid insoluble in benzene, hexane solubel in hot water, methanol 25 2,4-dichloro-5-guanidino- 262 - 254 white crystalline powder aminosulfonylbenzoic acid insoluble in benzene, hexane solubel in hot water, methanol 26 2,4-dichlor-5-guanidino- 198 - 199 white crystalline powder aminosulfonylbenzoic acid (dec) insoluble in benzene, hexane solubel in hot water, methanol 27 2,4-dichlor-5-semi- 220 (dec) white crystalline powder carbazidesulfonylbenzoic insoluble in benzene, hexane acid solubel in hot water, methanol 28 2,4-dichloro-5-oxaminic acid 217 - 219 white crystalline powder hydradinosulfonylbenzoic (dec) insoluble in benzene, hexane acid solubel in hot water, methanol TABLE 1 (Continued)

Melting Point Compound ( C) Property 29 3-aminosulfonyl-5 242 - 243 white crystalline powder;; bromobenzoic acid insoluble in benzene, hexane; soluble in hot water, methanol 30 2-aminosulfonyl-5- 241 - 244 white crystalline powder; bromobenzoic acid insoluble in benzene, hexane; soluble in hot water, methanol 31 2-aminosulfonyl-5- 162 - 163.5 white crystalline powder; chlorobenzic acid insoluble in benzene, hexane; soluble in hot water, methanol The aminosulfonylhalogenobenzoic acid derivatives thus produced can be converted to the pharmaceutically acceptable salts.The salt may be sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, barium salt and so on.

The following is the explanation of the effectiveness, safety, method for application and dosage of aminosulfonylhalogenobenzoic acid derivatives thus obtained.

EXPERIMENTAL EXAMPLE 1 Antiviral activity in cultured cells Antiviral activity of compound of the invention was determined according to the method described by Marks (Antimicrob, Agents Chemother., Volume 6, Pages 34-38, 1974).

Monolayer culture of MDCK, Vero and HEL cells were inoculated with 0.1 ml of serial 1 O-fold dilution of the virus in Eagle's minimum essential medium supplemented with 0.1 or 0.2% bovine serum albumin, one hour after the treatment with 0.1 ml solution of the compound. After the incubation for 2 or 3 days at 370C in 5% CO2, cytopathic effect induced by 1 OOTCID50 of the virus was observed under a microscope. Minimum inhibitory concentration of the compound was defined as the lowest concentration of the compound which shows complete inhibition against cytopathic effect induced by the virus. The results are shown in Table 2.

TABLE 2 In Vitro Antiviral Activity

Minimum Inhibitory Conce Virus influenza A0 influenza A2 Parainfluenza Coxsackie Compound (WSN) (Kumamoto) Type 3 Rhino Type B5 ECHO 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 EXPERIMENTAL EXAMPLE 2 Following the method of Example 1, minimum inhibitory concentration of compounds of the invention which completely inhibits cytopathic effect induced by 10 TCID50 of the virus were determined.The results are shown in Table 3. The used viruses were as follows: Influenza Ao A Influenza A1 B Influenza A2 C Influenza B D Parainfluenza Type 3 E ECHO F Coxzackie Type Bs G Rhino H Respiratory virus Vesicular stomatitis J TABLE 3 In Vitro Antiviral Activity

Minimum Inhibitory Concentration (C19/ml) NVirus Compound A B C D E F G H I J .. | 5 ..

5 30 300 300 300 300 300 100 300 300 300 6 30 300 300 300 300 300 300 300 100 300 7 30 300 300 300 300 300 300 300 300 300 8 30 300 300 100 300 300 300 300 300 300 9 30 300 100 300 100 300 300 300 100 300 10 30 300 300 300 300 100 300 300 300 300 11 10 300 100 100 300 300 300 300 300 100 12 30 100 300 300 300 300 300 300 300 300 13 30 300 300 300 300 300 100 300 300 300 14 30 300 300 300 300 100 300 300 300 300 15 30 300 300 300 300 100 300 300 300 300 16 30 300 300 300 300 3u0 100 300 300 300 17 10 100 300 100 300 300 100 300 300 300 18 30 100 300 300 300 300 300 300 300 300 19 30 300 300 300 300 100 300 300 300 300 20 30 300 300 300 300 300 30 300 300 100 21 30 300 300 300 300 300 300 300 300 300 22 30 300 30 300 300 3 30 300 300 300 23 10 300 300 100 100 100 100 100 30 100 24 10 100 10 100 30 100 300 30 300 30 25 100 300 300 300 300 300 300 100 300 300 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 30 300 300 300 300 100 300 300 300 300 31 j 30 300 30 100 300 300 300 100 300 300 All of the compounds 1-31 showed antiviral activity of wide spectrum although each compound had its specificity with respect to viruses on which it is more effective.

EXPERIMENTAL EXAMPLE 3 Protective action against the death of mice infected with Influenza Ao virus After the influenza Ao virus was inoculated to groups of ten ICR female mice (16-18 g) intranasally under light anesthesia with ether, compound of the invention was given orally or intraperitoneally as multiple doses of twice a day starting one hour after infection and continued for 14 days. The result of the treatment was shown as the increase in percentage of survivors at 1 5th day.

The results are shown in Tables 4 and 5.

TABLE 4 Result of Intraperitoneal Administration

Dosage Survival Dosage Survival Compound mg /kg rate % Compound mg /kg rate % Control 0 30 20 1 30 40 3 100 40 100 50 300 50 10 30 300 50 4 2 30 40 1000 60 100 60 TABLE 5 Result of Intraperitoneal Administration

Dosage Survival Dosage Survival Compound mg /kg rate % Compound mg /kg rate % Control 0 19 100 50 5 100 40 20 100 50 6 100 40 21 100 40 7 100 40 30 50 22 8 100 50 @ 100 70 9 100 40 10 40 23 10 100 60 . 30 50 10 30 10 40 11 24 30 50 30 60 12 100 40 100 70 13 100 40 25 100 40 14 100 40 26 100 40 15 100 50 27 100 40 16 100 40 28 100 40 10 40 29 100 40 17 30 50 30 100 40 18 100 40 31 100 40 TABLE 6 Result of Oral Administration

Dosage Survival Dosage Survival Compound mg /kg rate % Compound mg /kg rate % Control 0 19 300 50 5 300 50 20 300 50 6 300 50 21 300 40 7 300 50 . 100 50 22 8 300 40 300 70 9 300 50 30 40 23 10 300 40 100 60 100 40 30 40 300 60 24 100 60 12 300 40 300 80 13 300 40 25 30 50 5 300 50 27 300 40 6 300 40 28 300 50 100 50 29 300 60 17 300 70 30 300 50 18 300 50 31 300 40 All of the compounds 1-31 showed protective action against death due to the infection, and especially, the compounds 11, 1 7, 22, 23 and 24 showed extremely excellent activity.

EXPERIMENTAL EXAMPLE 4 Acute toxicity in mice Compound of the invention was dissolved in saline and given orally or intraperitoneally (1 0 ml/kg) to groups of ten ddY male mice (24-26 g). The mortarity rate was observed after 7 days. LD50 was determined according to the method of Wilcoxon - Litchfield. The results are shown in Tables 7 and 8.

TABLE 7 LD,, value (mg /kg)

Intra- Intra Compound Oral peritoneal Compound Oral peritoneal administration administration administration administration 1 > 10,000 3,290 3 > 10,000 > 5,000 2 10,000 3,520 4 > 10,000 > 5,000 TABLE 8 LD50 value (mg /kg)

Intra- Intra Compound Oral peritoneal Compound Oral peritoneal administration administration administration administration 5 > 3,000 > 1,000 19 > 3,000 > 1,000 6 > 3,000 > 1,000 20 > 3,000 > 1,000 7 > 3,000 > 1,000 21 > 3,000 > 1,000 8 > 3,000 > 1,000 22 > 3,000 > 1,000 9 > 3,000 > 1,000 23 > 3,000 > 1,000 10 > 3,000 > 1,000 24 > 3,000 > 1,000 11 > 3,000 746 25 > 3,000 987 12 > 3,000 > 1,000 26 > 3,000 > 1,000 12 > 3,000 968 27 > 3,000 > 1,000 14 > 3,000 > 1,000 28 > 3,000 > 1,000 15 > 3,000 > 1,000 29 > 3,000 > 1,000 16 > 3,000 > 1,000 30 > 3,000 > 1,000 17 > 3,000 > 1,000 31 > 3,000 > 1,000 18 > 3,000 > 1,000 As apparent from the above experimental examples, all of the compounds 1-31 have antiviral activity of wide spectrum and are of extremely high safety. Therefore, they have very high clinical utility for treating various infectious diseases which are caused from virus infection, for example, upper respiratory infection, pneumonia, Brouchitis and so on.

In case that the compounds of the present invention are administered to a human body, dosage for an adult is 30-5,000 mg per day for the compounds 1-10, 12-16, 18-22 and 29-31; 10-5,000 mg per day for the compounds 11, 1 7, 23 and 24; 50-5,000 mg per day for the compounds 25-28. However, the dosage may be increased or decreased out of the above range according to symptoms and other conditions.

The compounds 1-31 can be formulated as pharmaceutical preparations by conventional method with pharmaceutical carriers, base materials as excipients commonly used for this purpose.

Such preparations can be for example capsules, tablets, powders or oral liquid preparations (including dry sirups) for oral application; rectum suppository for intrarectal application; for injection, they can be for example, freeze-dried preparations which can be dissolved in distilled water for injection immediately before administration; and other preparations such as nose drops or inhalant can also be adopted.

The following are the examples of pharmaceutical preparations, but such preparations should not be limited only to the illustrated ones.

EXAMPLE 1 Tablets Ingredients Amounts I) Compound 11 50 g II) Lactose proper amount III) Crystalline cellulose 60 g IV) Potato starch 54 g V) Magnesium stearate 2 9 200 9 The ingredients (I)-(IV) were homogeneously mixed and 10% paste from the part of the ingredient (IV) which had been previously separated was added to the above mixture to prepare granules, and then the granules were dried. Next, the granules were mixed with the ingredient (V) to provide tablets each weighing 200 mg. If desired, the tablets may be coated with sugar in usual manner.

EXAMPLE 2 10% Powders Ingredients Amounts Compound 17 100 9 Lactose 890 g Magnesium stearate lOg 1000 g After each of the above ingredients was weighed, the ingredients were homogeneously mixed to prepare 5% powders.

EXAMPLE 3 Capsules Ingredients Amounts I) Compound 23 50 g II) Calcium hydrogenphosphate 50 g III) Aluminum silicate proper amount IV) Crystalline cellulose 60 g V) Magnesium stearate 2 9 2009 The above ingredients (l)-(V) were put together and mixed well through a sieve, to give capsules each weighing 200 mg were prepared from the mixture in usual manner.

EXAMPLE 4 Injectable solutions One hundred grams of sodium salt of the Compound 2 were dissolved in 2 1 of distilled water for injection and from this solution, injectable solutions which contain 100 mg of the active compound in 2 ml of the solution per ampoule were prepared in usual manner.

EXAMPLE 5 1% Nose drops Ingredients Amounts Compound 2 (sodium salt) 10 g Sodium chloride 5g Chlorobutanol 59 Distilled water added to become 1,000 ml After each of the above ingredients was weighed and dissolved together in 950 ml of water, the solution was filled up to become 1,000 ml to prepare 1% nose drops.

Claims

1. Antiviral composition which contains as an active ingredient aminosulfonylhalogenobenzoic acid derivatives of the general formula (I):

wherein X and Y, independently of each other, denote hydrogen atom, fluorine atom, chlorine atom, bromine atom, amino group or nitro group, R, denotes hydrogen atom or lower alkyl group, R2 denotes hydrogen atom, amino group, lower alkyl group, hydroxyalkyl group, lower alkoxy group, aryl group, guanyl group, guanidino group, ureido group, oxamoylamino group or chloro-substituted pyridazinoamino group, or R, and R2 together with the nitrogen atom in the formula may form a saturated heterocyclic group having 4 or 5 carbon atoms in which the carbon atoms may be substituted by an oxygen atom or non-substituted or lower alkyl-substituted nitrogen atom, or the salts thereof.

2. (liiiiiposition according to Claim 1, wherein tha aminosult6nThalbgnbbeiizoWcacid fferivative of the general formula (I) is 3-aminosulfonyl-4-chlorobenzoic acid derivative (in the formula, X denotes chlorine atom, Y denotes hydrogen atom, R, denotes hydrogen atom or lower alkyl group, R2 denotes hydrogen atom, amino group, lower alkyl group, hydroxyalkyl group, aryl group or chloro-substituted pyridazinoamino group, or R1 and R2 together with the nitrogen atom in the formula may form a saturated heterocyclic group having 4 or 5 carbon atoms, in which the carbon atoms may be substituted by an oxygen atom or non-substituted or lower alkyl-substituted nitrogen atom).

3. Composition according to Claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 3-anlinosulfonyl-4-chloro-5-nitrobenzoic acid.

4. Composition according to Claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 3-aminosulfonyl-4-chloro-5-nitrobenzoic acid.

5. Composition according to Claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is aminosulfonyl-2,4-dihalogenobenzoic acid (in the formula, X and Y denote fluorine atom, chlorine atom or bromine atom, and both of R, and R2 denote hydrogen atom.)

6. Composition according to Claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 3-aminosulfonylhalogenobenzoic acid derivative.

7. Composition according to Claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 5-aminosulfonyl-2,4-dichlorobenzoic acid derivative (in the formula, X and Y denote chlorine atom, R, denotes hydrogen atom, R2 denotes guanyl group, guanidino group, ureido group, oxamoylamino group.)

8. Composition according to Claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 3-aminosulfonyl-5-halogenobenzoic acid derivative (in the formula, X denotes chlorine atom or bromine atom, all of Y, R1 and R2 denote hydrogen atom.)

9. Composition according to Claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (1) is 2-aminosulfonyl-5-chlorobenzoic acid.

10. A composition as claimed in Claim 1 and substantially as described in any one of the specific examples hereinbefore set forth.

11. a method of treating virus diseases comprising administering to a patient suffering therefrom an offective amount of an aminosulfonylhalogenobenzoic acid derlvative of the general formula (1):

wherein X and Y, independently of each other, denote hydrogen atom, fluorine atom, chlorine atom, bromine atom, amino group or nitro group, R1 denotes hydrogen atom or lower alkyl group, R2 denotes hydrogen atom, amino group, lower alkyl group, hydroxyalkyl group, lower alkoxy group, aryl group, guanyi group, guanidino group, ureido group, oxamoylamino group or chloro-substituted pyridazinoamino group, or R, and R2 together with the nitrogen atom in the formula may form a saturated heterocyclic group having 4 or 5 carbon atoms in which the carbon atoms may be substituted by an oxygen atom or non-substituted or lower alkyl-substituted nitrogen atom, or a pharmaceutically acceptable salt thereof.

12. A method according to Claim 1 wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 3-aminosulfcnyl-4-chlcrnbenzoic acid derivative (In the formula, X denotes chlorine atom, Y denotes hydrogen atom, R, denotes hydrogen atom or lower alkyl group, R2 denotes hydrogen atom, amino group, lower alkyl group, hydroxyalkyl group, aryi group or chloro-substituted pyridazinoamino group, or R, and R2 together with the nitrogen atom in the formula may form a saturated heterocyclic group having 4 or 5 carbon atoms, in which the carbon atoms may be substitutec by an oxygen atom or non-substituted or lower alkyl-substituted nitrogen atom.) 13.Method according to Claim 11, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 3-aminosulfonyl-4-chloro-5-nitrobenzoic acid.

14. Method according to Claim 11, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 3-aminosulfonyl-4-chloro-5-nitrobenzoic acid.

1 5. Method according to Claim 1 wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is aminosulfonyl-2,4-dihalogenobenzoic acid (in the formula and Y denote fluorine atom, chlorine atom or bromine atom, and both of R, and R2 denote hydrogen atom) 1 6. Method according.to Claim 11, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) i63-aminosulfonyihalogenobenzoic acid derivative.

1 7. Method according to Claim 1 wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 5-aminosulfonyl-2,4-dichlorobenzoic acid derivative (in the formula, X and Y denote chlorine atom, R1 denotes hydrogen atom, R2 denotes guanyl group, guanidino group, ureido group, oxamoylamino group.)

18. Method according to Claim 11, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 3-aminosulfonyl-5-halogenobenzoic acid derivative (in the formula, X denotes chlorine atom or bromine atom, all of Y, R, and R2 denote hydrogen atom.) 1 9. Method according to.Claim 11, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) nosuifonvl-5-chlorobenzoic acid.

New claims or amendments to claims filed on 11 December 1981 Superseded claims 3, 13 New or amended claims.

3. Composition according to Claim 1, wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (1) is-2-amino-5-aminosulfonyl-4-chlrobenzoic acid.

13. Method according to Claim 1 wherein the aminosulfonylhalogenobenzoic acid derivative of the general formula (I) is 2-amino-5-aminosulflony-4-chlorobenzoic acid.