DE2132987A1 - N-Benzyl-3-sulfamoylebenzamides and their pharmacologically acceptable salts - Google Patents

Description

DR. ING. F.

no ,. Tv «, ij. rui. 3 0 1 O O η ο τ

^ PK ::. ν r: r. :> ί -.Γί.ν Z I 3 2 9 8 7

l'.v; . '.? <r. \ :: wL.-iλ
8 M Ü NSKEN 8 0

1A 39739

Description of the patent application

Parke, Davis & Company Detroit, Michigan, USA

concerning:

" N-Benzyl-3-sulfamoylbenzamides and their pharmacologically acceptable salts "

The present invention relates to new benzamides useful as pharmacological agents and to methods for their manufacture. It relates particularly to new N-benzyl-3-sulfamoylbenzamides the general formula:

Il

X ( / 'VC- NH- CH

• I

CH ₂ -R

in which R is a hydrogen atom or a methyl group, R _{2 is} a hydrogen atom or a methyl or hydroxyl group and X is

10938Λ / 2009

Bromine or chlorine atom or a methyl, methoxy or ethoxy group and Y a hydrogen or chlorine atom or mean a methoxy group and their pharmacologically acceptable salts.

• *

According to the present invention are the N-benzyl-3-sulfamoylbenzamides of the formula given above, prepared by reacting a reactive derivative of a 3-sulfamoylbenzoic acid the formula:

R ₁ -HNO ₂ S

COOH

(II)

with a benzylamine of the formula:

CH NH,

(III)

where R ₁ , Rp, X and Y each have the meaning given above. The reactive derivatives of 3-sulfamoylbenzoic acid that can be used are the acid halides and lower alkyl esters. Acid halides, in particular the acid chloride, are preferred. The responsive one

10988A / 20 09

3-sulfamoylbenzoic acid derivative and the amine can approximately equimolar amounts can be used. The best results however, are obtained when the amine is used in excess. When reacting with the preferred acid chloride generally the two molar amount of amine is used, the excess being used as a binder for dsi during the reaction The hydrogen chloride released is used. If necessary, can also other bases, such as a tertiary amine, e.g. pyridine or triethylamine or an alkali metal carbonate as acid binding agent can be used instead of an excess of amine. The response will be best in a non-responsive one Solvent carried out. Suitable solvents for the lower alkyl esters include water, lower alkanols and lower alkanones. In the reaction, in which the preferred acid chloride is used, various ethers, aromatic hydrocarbons and chlorinated hydrocarbons be used as! solvent. A preferred solvent is tetrahydrofuran. The reaction temperature and duration can vary within a wide range, namely the temperature from 0 to 85 ° C. and the reaction time from 3 minutes to 4 to 6 hours. When the preferred acid chloride is used, the reaction is essentially after 30 to 90 min at a temperature in the range of 25 to 75 ° C completely.

The reactive derivatives of 3-sulfamoylbenzoic acids, those used as starting materials for the above process are made as follows: A benzoic acid of the formula:

109884/2009

X // '> \ COOH (IV)

is reacted with chlorosulfonic acid and the 3- (chlorosulfonyl) benzoic acid intermediate product formed the formula:

X // \\ COOH (V)

is reacted with ammonia or methylamine, whereby a 3-sulfamoylbenzoic acid of the formula II is formed. In these formulas, X has in each case the meaning given above. The 3-sulfamoylbenzoic acid halides and lower alkyl esters w are then prepared from the free acid by processes known in organic chemistry for converting a carboxylic acid into the corresponding derivatives. The processes for preparing these starting materials will be shown in detail later.

The compounds according to the invention can be in the form of the in of the formula 'I specified acid or as alkali salts. Pharmaceutically acceptable alkali salts are formed by reaction with a strong base of an alkali metal, such as an alkali hydroxide, e.g. sodium hydroxide,

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an alkali alkoxide such as sodium methoxide or an alkali hydride. Such salts are equivalent to the basic compound for the purposes of the invention.

The compounds according to the invention can be used both in anhydrous Form as well as solvated, including hydrated, form. In general they are hydrated and pharmacologically acceptable solvents solvated forms of the anhydrous or unsolvated form are equivalent for the purposes according to the invention.

If appropriate, the compounds according to the invention can also can be obtained in optically active forms by using an optically active benzylamine compound as a starting material used.

The compounds according to the invention are new chemical substances which are suitable as pharmacological agents, especially as antiviral agents. As such, they have ^: Proven to be active against various strains of rhinovirus.

The activity of the compounds according to the invention against viruses can be determined according to a method described by Rightsel, et al. (J. Immunol., Vol. 76, pp. 464 to 474 (1956); Univ. Mich. Med. Bull., Vol. 24, pp. 222 to 234 (1958)) and quantitatively measured. In this study, the effect of a compound of interest on the host cell and on the cytopathogenic effect (CPE) of the virus, which is present in an amount equal to 32 times the dose at which 50 % of the tissue culture is infected

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(32 TCID ₅₀ ) and numerically indicated by the "virus rating" (VR). The VR is a measure of the inhibition of the CPE of the virus by the compound of interest in amounts which are non-toxic or partially toxic to the host cells. The calculation of the VR for a particular compound to be examined is carried out as follows (Ehrlich, et al., Ann. NY, Acad. Sci., Vol. 130, pp. 5 to 16, especially p. 7, 1965).

The investigation is carried out with vinyl plastic plates with a P single layer of H.Ep. cells No. 2. Each compound to be tested is normally tested on triplicate plates at 5 concentrations - undiluted and in 3.2, 10, 32 and 100 fold dilutions. The value obtained for the CPE of the treated infected cells at each concentration is subtracted from that of the untreated but infected control cells and the difference (CT) for all concentrations is summed up. If the compound being tested is partially toxic to the host cell at any concentration, the difference (CT) for that concentration is halved before being included in the summation. The VR is then finally hold ER- h by dividing the sum by 10 degrees. A VR of 1.0 or above is considered a sign of anti-virus activity. An example of a typical test result and the calculation of the VR for one of the compounds according to the invention is given in Table I. The virus values for other representative compounds of the invention obtained from tests by this method against rhinovirus IA are given in Table II. ■ ' ^v

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TABEL

Investigation of the antiviral effect of N- (C £ -Methylbenzyl) 3- (methylsulfamoyl) -p-anisamide against rhinovirus IA on plastic plates (in triple trays)

treated
(C): Ver CPE 1 32 TCID ₅₀ C-T 4th 4th not
same 4th

Treated (T) ι

Undiluted sample

diluted 3.2 X ³

diluted 10 X diluted 32 X diluted 100 X

o ^p o ^p o ^p 12 ^P 2 2 2 6th 3 3 3 3 4th 4th 4th 0 4th 4th 4th 0

VR = / "£ (CT) ^P / 2 + O (CT) _7 / 10 = / 12/2 + 9 J / 10 = 1.5

CPE: 0 = no cytopafhogenic effect; 4 = complete destruction the cell.

Aqueous suspension, 500 µg / ml of the compound to be tested.

3
diluted with medium # 199; Diagnostic Procedures for Viral and Rickettsial Diseases, 3rd Edition, American Public Health Association, Inc., New York, 1964, pp. 158-163 and Proc. Soc. Exper. Biol. & Med., 73, 1 to 8, 1950.

partly toxic for the host cell.

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TABLE II Virus Levels versus Rhinovirus IA

Connection . . VR

4-Bromo-N- (ÖC-methylbenzyl) -3-sulfamoyl- benzamide 2.2

4-bromo-N- (0 (-methylbenzyl) ~ 3- {methyl sul- ^ famoyl) benzamide 1.8

4-chloro-N- (of-methylbenzyl) -3- (methyl sul-

f amoyl) benzamide 2.0

N- (O (-methylbenzyl) -3- (methyl sulfarnoyl) -ptoluamide . 1.1

4-ethoxy-N - (<X-methylbenzyl) -3- (methyl sul-

f amoyl) benzamide 1.3

N- (p-methoxy-ß (-methylbenzyl) -3- (methyl -... sulf amoyl) -p-anisamide 1.5

N- (p-chloro-oc-methylbenzyl) -3- (methyl sul-

-f amoyl) -ρ-an is am id 2.7

4-bromo-N- _! ^ <- (hydroxymethyl) benzyl_ _< 7-3-

(methylsulfamoyl) benzamide 3.0

N- (Oi-ethylbenzyl) -3- (methyl sulfamoyl) panisamide 1.2

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The invention is illustrated in more detail by the following examples.

example 1

A solution of 165 g of 4-bromo-3-sulfamoylbenzoic acid chloride in 700 ml of tetrahydrofuran was slowly added to a solution of 134 g of Qi-methylbenzylamine (dl form) in 300 ml Tetrahydrofuran was added and the resulting mixture was stirred at room temperature for 3 to 4 hours and then under reduced pressure Pressure restricted. The viscous residue was triturated with water and the aqueous mixture for 1 week at room temperature ditched. The gummy pest was then dissolved in warm 10% aqueous sodium hydroxide and the alkaline solution acidified with hydrochloric acid. The 4-bromine-N- (δ-methylbenzyl) -3-sulfamic benzamide which then separates out on cooling was isolated, m.p. 65-67 ° C.

The solid product obtained as above was dissolved in 500 ml of ethanol and the ethanolic solution with the aid of activated charcoal clarified. A solution of 20.5 g of sodium methoxide and 300 ml of ethanol was then added to the clear solution, and that The resulting mixture was allowed to stand at room temperature for 30 minutes. It was then concentrated to half its volume, cooled and slowly poured into ether with stirring. Man received a solid precipitate of 4-bromo-N- (CX-methylbenzyl ) -3-sulfamoylbenzarnide monosodium salt monohydrate, that was isolated and dried.

Be is ρ ie 1 2

A solution of 20.7 g of 4-bromo-3- (methylsulfamoyl) benzoic acid-

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Chloride in 100 ml of tetrahydrofuran was carefully added Stir to a solution of 16.0 g of dl-of-methylbenzylamine in 100 ml of tetrahydrofuran was added and the resulting mixture was stirred for 30 min at room temperature. It then became Heated under reflux for 1 h and concentrated under reduced pressure. The oily residue was treated with water and the aqueous mixture, which was left to stand overnight, became a solid precipitate of 4-bromo-N- (0 \ -methylbenzyl ) -3- $ nethylsülfamoyl) benzamide obtained, m.p. 157 bis 158 ° C after recrystallization from 50% aqueous ethanol.

Example 3 .

A solution of 15.6 g of 4-bromo-3- (methylsulfamoy1) -benzoic acid chloride in 100 ml of tetrahydrofuran was added to a solution of 12.1 g of (-) - oc-methylbenzylamine in 100 ml of tetrahydrofuran while stirring at room temperature the resulting mixture was refluxed for 1 hour, cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was triturated with water to give a colorless product which was isolated, washed with water and dried. It was d- ^ bromo-N - ^ - methylbenzyl) -3- (methylsulfamoyl) -benzamide, melting point 150 ° to 151 ° C. after recrystallization from aqueous ethanol; / oc 7 _n + 28.5 (2.03 % in methanol). .

At s ρ ie 1 4 "- '■ ..-: -.-- -.; .- ..

To a solution of 40 ml of dl-oC-methylbenzylamine in -20.0 ml Water were carefully 33.3 g of 4-chloro-3- (methylsulfamoyDbenzoic acid chloride added and the resulting mixture left to stand overnight at room temperature. It was then made sour with concentrated salty acid

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(pH about -5) and the oily substance which separated out was isolated by decantation and at room temperature kept until set (approximately 2 weeks). The solid product was 4-chloro-N- (Oc-methylbenzyl) -3- (methylsulfamoyl) benzamide; Mp. 150 to 152 ° C after recrystallization from aqueous ethanol.

Example 5 *.

A solution of 10.0 g of 4-bromo-3- (methylsulfamoyDbenzoic acid chloride in 50 ml of tetrahydrofuran was slowly stirred at room temperature to a solution of 10.2 g p-chloro-oc-methylbenzylamine (dl-form) in 25 ml tetrahydrofuran was added and the resulting mixture was refluxed for 1 hour, overnight at room temperature left to stand and filtered. The filtrate was concentrated under reduced pressure and the residue with water triturated, "giving a solid product. The product was 4-bromo-N- (p-chloro-0t-methylbenzyl) -3- (methyl sulfamoyl) benzamide; Mp. 164 to 165 ° C after recrystallization from aqueous ethanol.

Example 6

To a solution of 9.68 g of dEX-methylbenzylamine in 75 ml Tetrahydrofuran was carefully stirred into a solution of 10.0 g of 4-methoxy-3-sulfamoylbenzoe ~ at room temperature acid chloride in 50 ml of tetrahydrofuran was added and the resulting mixture was refluxed for 1 hour and concentrated under reduced pressure. The residue was diluted with water and the aqueous mixture was cooled, whereby a rubber-like precipitate formed, which contained the crude product 4-Methoxy-N- (Q (-methylbenzyl) -3-sulfamoYlbenzamide. This

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A gummy solid was isolated and dissolved in a solution of 2.16 g of sodium methoxide in 50 ml of methanol. To At room temperature for 30 minutes, the solution was concentrated under reduced pressure and the residue was dissolved in water. the Aqueous solution was treated with activated charcoal and filtered, and the filtrate was lyophilized, leaving a solid residue of 4-methoxy-N- (α-methylbenzyl) -3-sulfamoylbenzamide monosodium salt originated.

Example 7

A solution of 1-2.1 g of 4-methoxy ~ 3- (methylsulfamoyl) benzoic acid chloride in 500 ml of tetrahydrofuran was slowly stirred at room temperature to a solution of 111 g of dl-öt-methylbenzylamine in 250 ml of tetrahydrofuran was added and the resulting mixture was refluxed for 1 h, overnight ' left to stand at room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue rubbed with water. A solid product was obtained which was N- (O (-ethylbenzyl) -3- (methyl sulfamoyl) -p-anisainide. 174 to 175 ° C after recrystallization from aqueous ethanol.

A mixture of 12.3 g of N- (Of-Me thylbenzyl) -3- (methyl sulf amoyl) -p-anisamide, 1.91 g of sodium methoxide and 100 ml of methanol were heated under reflux for 20 min, filtered while hot and the filtrate was concentrated under reduced pressure. The residue was triturated with ether and the ethereal mixture was cooled, whereby a solid precipitate of N-PC-1-iethylbenzyl) -3- (methylsulfamoyl) -p-anisamide monosodium salt monohydrate arose, which was isolated, washed well with ether and dried became.

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Example 8

A solution of 12.4 g of 3- (methylsulfamoyl) -p-toluene acid chloride in 100 ml of tetrahydrofuran was carefully stirred at room temperature to give a solution of 12.1 g dl-of-methylbenzylamine in 100 ml of tetrahydrofuran was added and the resulting mixture was stirred at room temperature for 30 minutes. It was then refluxed for 1 hour and under restricted pressure. The oily residue became treated with water and the aqueous mixture left to stand overnight at room temperature. A solid was obtained Product, the N- (oc-methylbenzyl) -3- (methyl sulf amoyl) ~ p ~ toluamid was. Pp. 153 to 154 ° C after recrystallization, from aqueous ethanol.

Example 9

A solution of 13.9 g of 4-ethoxy-3- (methylsulfamoyl) benzoic acid chloride was slowly added at room temperature with stirring to a mixture consisting of 5.05 g of triethylamine, 6.05 g of 'dl-O (-methylbenzylamine and 100 ml of tetrahydrofuran in 100 ml of tetrahydrofuran was added and the resulting mixture was heated under reflux for 30 minutes, cooled and filtered, the piltrate was concentrated under reduced pressure and the residue was triturated with water, a solid precipitate of 4-ethoxy-N ~ -0> ⁽ -methylbenzyl ) -3- (methyl sulf amoyl) benzamide was formed, which was isolated, washed with water and dried under reduced pressure and purified by recrystallization from aqueous alcohol.

Example 10

A solution of 13.2 g of 4-methoxy-3- (methylsulfamoyl) benzoe-

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acid chloride in 100 ml of tetrahydrofuran was added slowly Room temperature with stirring to a mixture of 5.05 g of triethylamine, 7.5 g of dl- ^ X-methyl-p-methoxybenzylamine and 100 ml Tetrahydrofuran was added and the resulting mixture was refluxed for 30 minutes, cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was triturated with water / water, a solid precipitate of N- (p-Methoxy «O (-methylbenzyl) -3 <" - (methyl sulf amoyl) -p-anisamide arose, which was isolated, washed with water, dried and purified by recrystallization from aqueous ethanol was, m.p. 148-149 ° C.

Example 11

A solution of 10.0 4-methoxy-3- (methylsulfamoyl) benzoic acid chloride in 50 ml of tetrahydrofuran was slowly stirred at room temperature to a solution of 10.4 g p-chloro-O (-methylbenzylamine (dl-form) in 25 ml tetrahydrofuran added and the resulting mixture heated under reflux for 1 h, left to stand overnight at room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was triturated with water. A solid product was obtained which contained N- (p-chloro-o-methylbenzyl) Was 3- (methylsulfamoyl) -p-anisamide. Mp. 160 to 16 ° C after recrystallization from aqueous ethanol.

B e i s ρ ie 1 12

To a solution of 13.7 g of ß-aminophenylethanol in 100 ml Tetrahydrofuran became a with stirring at room temperature Solution of 15.6 g of 4-bromo-3- (methylsulfamoyl) benzoic acid ~ chloride in 100 ml of tetrahydrofuran was carefully added and the resulting mixture was stirred at room temperature for 30 min. Bs was then concentrated under reduced pressure, the return

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2137987

stood well stirred with water and the aqueous mixture cooled and filtered, a solid product was formed 4-Br om-N- / ä - (hydroxymethyl) benzyl__7 ~ 3- (methyl sul f amoyl) benzamide was. Mp. 166 to 167 ° C after recrystallization from aqueous ethanol φ

B e i s ρ i e 1 ~ 3_

A solution of 10.0 g of 4-methoxy- \ 3- (methyl sul f amoyl) benzoic acid chloride in 75 ml of tetrahydrofuran was carefully stirred at room temperature to form a solution of 8.88 g added dl-tf-ethylbenzylamine in 75 ml of tetrahydrofuran and the resulting mixture was refluxed for 30 minutes, cooled and filtered. The filtrate was reduced under The pressure was concentrated and the residue was triturated with water. After cooling, the aqueous mixture gave a solid precipitate of N- (0 (-Ethylbenzyl) -3- (methylsulf amoyl) p-anisamide, which is isolated, washed with water, dried and purified by recrystallization from aqueous ethanol became. Mp 188-189 ° C.

Starting materials

The various starting materials and intermediates used in the previous examples were obtained by the methods described below.

A.3- (chlorosulfonyl) benzoic acids

(1) 4-Bromo-3- (chlorosulforiyl) benzoic acid. To 1320 ml of chlorosulfonic acid 402 g of p-bromobenzoic acid were added in individual portions at room temperature. After the initially violent The reaction had subsided, the reaction mixture was stirred and 6 h to 1 - '. S heated to 150 ° C, cooled and

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-ie- 2137987

action with ice water decomposed. The failing solid 4-Bromo-3- (chlorosulfonyl) benzoic acid was isolated with Water washed and dried.

(2) 3- (chlorosulfonyl) -4-methoxybenzoic acid. To 1320 ml 304 g of p-methoxybenzenic acid were added in individual portions to chlorosulfonic acid at room temperature. After this the initially vigorous reaction had subsided, the reaction mixture was stirred for several hours at room temperature and then decomposed by treatment with ice water.

k The precipitating solid 3- (chlorosulfonyl) -4-methoxybenzoic acid was isolated, washed with water and dried.

(3) 3- (chlorosulfonyl) -p-toluic acid. To 971 ml of chlorosulfonic acid 200 g of p-toluic acid were added in individual portions at room temperature and the resulting mixture under Stirring heated to 150 ° C. It was then cooled and decomposed by treatment with ice water, leaving a solid "A precipitate of 3- (chlorosulfonyl) -p-toluic acid was formed, which was isolated, washed with water and dried.

(4) 3- (Chlorosulfonyl) -4- »ethoxybenzoic acid was used as colorless solid that can be used without further purification

P could be carried out according to the method (2) given above Reaction of 202 g of p-ethoxybenzoic acid with 806 ml of chlorosulfonic acid obtain.

B. 3-sulfamoylbenzoic acids

(1) 4-Bromo-3- (methyl sulf amoyl) benzoic acid. To 1 1 one 40% aqueous methylamine solution were at room temperature while stirring carefully 121 g of 4-bromo-3- (chlorosulfonyl) benzoic acid admitted and the disfiguring view over soft

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Left to stand at room temperature. It was then acidified with concentrated hydrochloric acid and the acidified mixture cooled, leaving a solid precipitate of 4-bromo-3- (methylsulfamoyl) benzoic acid arose, which was isolated, washed with water and dried under reduced pressure. Mp 210-214 ° C.

(2) 4-Methoxy-3-sulfamoylbenzoic acid. To 300 ml of concentrated Ammonium hydroxide were used in individual at room temperature Portions 75.2 g of 3- (chlorosulfonyl) -4-methoxybenzoic acid added and the resulting mixture allowed to stand for 30 min at room temperature. It was then diluted with 400 ml of water and the aqueous mixture was acidified with concentrated hydrochloric acid and cooled. The solid 4-methoxy-3-sulfamoylbenzoic acid which separates out was isolated and dried.

(3) 4-Methoxy-3- (methylsulfamoyl) benzoic acid was added as a solid, which could be used further without further purification, according to the method given above under ("I) Conversion of 37.9 g of 3- (chlorosulfonyl) -4-methoxybenzoic acid with 100 ml of a 40% aqueous solution of methylamine obtain. ',

(4) 3- (methylsulfamoyl) -p-toluic acid, mp. 209-210 ⁰ C, was prepared according to the above item (1) method by reacting 323 g of 3- (chlorosulfonyl) -p-toluic acid with 1.5 1 a 40% aqueous methylamine solution obtained.

(5) 4-Ethoxy-3- (methylsulfamoyl) benzoic acid, m.p. 209 bis 212 ° C was according to the method given above under (1) by reaction of 122 g of 3- (chlorosulfonyl) -4-ethoxybenzoe- Acid obtained with 1 liter of a 40% strength aqueous methylamine solution.

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C. 3-sulfamoylbenzoic acid chlorides

(1) 4-Bromo-3- (methylsulfamoyl) benzoic acid chloride.4-Bromo-3- (methylsulfamoyl) benzoic acid (85.7 g) was added in portions to 250 ml of thionyl chloride at room temperature and refluxing the resulting mixture for about 2 hours with stirring until evolution of hydrogen chloride stopped. On cooling, a solid precipitate of 4-bromo-3- (methylsulfamoyl) toenzoic acid chloride was obtained was filtered off, washed with ether and dried.

fc Another amount of the product could be obtained by concentrating the filtrate under reduced pressure and washing the solid with ether «

(2) 4-Methoxy-3 ^ sulfamoylbenzoesäurechlorid was by the process described above under (1) Method by the reaction of 67.4 g of 4-methoxy-3-sulfamoylbenzoic acid with 250 ml of thionyl chloride.

(3) 4-M.ethoxy-3- (methyl sulfamic acid benzoic acid chloride. To a suspension of 34.0 g of 4-methoxy-3- (methylsulfamoyl) benzoic acid in 150 ml of benzene were added with stirring and boiling ^ at reflux 16.7 g of thionyl chloride and the resulting ^ standing mixture heated under reflux for a further 3 h with stirring. The mixture was then filtered while hot and the Filtrate cooled. A solid precipitate of 4-methoxy-3- (methyl sulfamic acid benzoic acid chloride) was obtained isolated and dried. Mp 124-127 ° C.

(4) S-CMethylsulfamoyD-p-toluic acid chloride. 3- (methylsulfamoyl) -p-toluic acid (107.5 g) was added in portions to 500 ml of thionyl chloride at room temperature and the resulting mixture was refluxed with stirring until the evolution of hydrogen chloride ceased.

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heard. The mixture was then evaporated under reduced pressure and the residue dissolved in ether. The essential The solution was concentrated to give a dark, semi-solid residue which was redissolved in ether. This second essential solution was clarified by treatment with activated charcoal and evaporated to dryness, leaving a solid residue of 3- (methylsulfamoyl) -p-toluenesulfonic acid chloride was created, which could be used without further purification.

(5) 4-Ethoxy-3- (methylsulfamoyDbenzoic acid chloride. To a Suspension of 87.1 g of 4-ethoxy-3- (methylsulfamoyl) benzoic acid in 500 ml of benzene were stirred and boiled on 40.3 g of thionyl chloride were carefully added to reflux and the resulting mixture was refluxed with stirring until the evolution of hydrogen chloride ceased. The mixture was then cooled and evaporated under reduced pressure, leaving a solid residue of 4-ethoxy-3- (methylsulf amoyDbenzoic acid chloride was formed. Mp 136-138 ° C.

PATENT CLAIMS:

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Claims (6)

DK. ING. Γ. WUESTHOF »I) IVI ,. TNO. f .. rVT.3 ΐ) π. '.:. ν.) · - -'X \ · 1A-39 739 UK. ι:. '<■ *. ι-. :. ' SNS ^ ° Z I J / ti ö / β M Ü N C M E N 90 JlltS'i'H. 2 PATENT CLAIMS N-Benzy1-3-sulfamoy! Benzamide of the formula: R ₁ -HNO ₂ S where R ^. a hydrogen atom or a methyl group, R " a hydrogen atom, a methyl or hydroxy group, X is a bromine or chlorine atom or a methyl, methoxy or ethoxy group and Y is a hydrogen or chlorine atom or a methoxy group and their pharmacologically acceptable salts. 2) 4-Bromo-N- (Oc -methylbenzyl) -3-sulfamoylbenzamide. 3) 4-Bromo-N- (ex-methylbenzyl) -3- (methyl sul famoyl) -benzamide, 4) d-4-Bromo-N- (CX-methylbenzyl) -3- (methyl sulfamoyl) -benzamide. 5) N-iX-MethylbenzyD-S-imethylsulfaraoyD-p-anisamide. 6) N- (p-chloro-i% -methylbenzyl) -3- (methyl sulfamoyl) -panisamide. G2XXIV 10988W2009