CH621776A5 - Process for the preparation of novel heterocyclically substituted 5-sulphamoylbenzoic acid derivatives - Google Patents

Abstract

Novel heterocyclically substituted 5-sulphamoylbenzoic acid derivatives of the accompanying formula I, in which the symbols R<1>, R<2>, X and A have the meaning given in Patent Claim 1, are prepared by introducing the radical X into appropriate 3-nitro-5-sulphamoylbenzoic acids or their esters, which carry a halogen atom in the 4-position and whose 5-sulphamoyl group is protected, reducing the reaction product to the corresponding 3-amino compound, reacting this with dicarboxylic acid derivatives, reducing the 3-imido or 3-amido compounds thus obtained and hydrolysing the reaction product thus obtained to remove the protective group B and the ester group R<3>. The alkyl radicals R<2> can then be introduced by alkylation. Starting from the compounds of the formula I prepared according to the invention, in which X denotes a -SR<4> group, the corresponding compounds in which X denotes a -SOR<4> or -SO2R<4> group are obtained by oxidation. The novel compounds are highly active saluretics and diuretics. They are used mainly for the treatment of oedematous diseases of various origins. <IMAGE>

Description

The invention relates to a method according to the preamble of patent claim 1.

The compounds of the formula I which can be prepared by this process are highly effective pharmaceuticals, in particular diuretics and saluretics. Diuretics based on 5-sulfamylbenzoic acids include known from CH-PS 390 936. Preferred compounds of the formula I are those in which the symbols R1, R2, X and A have the following meanings:

R1 and R2 are both hydrogen; or R1 is hydrogen; and R2 is alkyl of 1 to 4 carbon atoms;

X is one of the groups -OR4 or -SR4, where R4 is phenyl or mono- or polysubstituted by chlorine, hydroxyl, trifluoromethyl, alkyl having 1 to 3 carbon atoms, monoalkylamino, dialkylamino or alkoxy by 1 or 2 carbon atoms Phenyl are preferred; and

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r8

r9

r10

y

1

h ch3

ch3

CI

2nd

ch3

ch.

ch3

ci

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h c2h5

c2h5

CI

4th

ca ch3

ch3

CI

5

h ch3

ch3

F

6

h ch3

cha

Br

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e?

IS

ü

-ch2-ch2-ch2 - ch2-ch2-

CI

8th

-ch2-ch2-

-ch2-

ch3

CI

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Instead of the acids listed above, the corresponding esters, for example the methyl or ethyl esters, can also be used.

The nitration of the benzoic acid derivatives of the formula VIII can be carried out in various ways. For example, you can enter the benzoic acid derivatives in one of the nitration mixtures that are customary for the nitration-free aromatics (cf. textbook “Organicum”, edition 1967, page 288). The process can also be carried out by dissolving the benzoic acid of the formula VIII in oleum and controlling the nitration by dropping nitric acid.

It is surprising that it is possible to nitrate only by introducing protective group B into the sulfonamide radical of the benzoic acid derivatives of the formula VIII, without the other groups in the molecule being changed. The reaction temperature is relatively low, preferably temperatures of 55 to 70 ° C are maintained.

When carrying out the nitration reaction, a nitrating acid from oleum and fuming nitric acid is advantageously introduced, the compound to be nitrated is added and the reaction mixture is heated to 55 to 60 ° C. The progress of the nitriding can be followed by thin layer chromatography. The nitration products can be isolated in a customary manner, for example by adding the reaction mixture to ice and filtering off the precipitated crystals.

For nitration, acids or esters of the formula VIII, in which Y, B and R3 have the meanings given, can be used. If one starts from esters of the formula VIII, in addition to the esters, the acids of the formula IX (R3 = H) are also obtained in small amounts in the nitration. The mixture can be used in a conventional manner, e.g. by treating with aqueous sodium carbonate. The compounds of the formula IX obtained in which R3 is hydrogen can now be esterified in a conventional manner. For this purpose, for example, the carboxylic acid is converted into its acid chloride which, after the addition of alcohols, changes into the corresponding esters of the formula IX. Lower alcohols having 1 to 4 carbon atoms, e.g. Methanol, ethanol, propanol, butanol, isopropanol, isobutanol and tert-butanol. The alcohol is advantageously used in a 5 to 20-fold molar excess or is used simultaneously as a solvent. The tert-butyl esters can also be prepared by other processes known from the literature.

In the next step, the esters of the formula IX are converted into compounds of the formula X by reaction with compounds of the formula X-H. Surprisingly, it has been found that compounds of the formula IX in which R3 is alkyl having 1 to 4 carbon atoms can be reacted with compounds of the formula X-H with good results under anhydrous conditions.

The following compounds are suitable as compounds of the formula XH: phenol, 4-methylphenol, 3-methylphenol, 2-methylphenol, 4-chlorophenol, 3-trifluoromethylphenol, 3,5-dimethylphenol, 2,4-dimethylphenol , 4-methoxyphenol, 3-methoxyphenol, 4-propylphenol, thiophenol and analogously substituted thiophenols as well as 4-fluorophenol. If the compound of formula X-H contains additional functional groups, e.g. further hydroxy or amino groups, these are expediently protected by conventional protective groups, e.g. blocked by acyl groups.

The reaction can be carried out without a solvent, but more advantageously in the presence of a solvent. Organic solvents such as ether and tert-carboxamides, in particular diethylene glycol ether (Diglym), dimethylformamide or hexamethylphosphoric acid tris-amide (HMPT) are particularly suitable solvents.

The reaction of the compounds of formula IX with compounds of formula X-H is advantageously carried out in the presence of bases. Alcoholates and alkali amides are particularly suitable as bases. In addition, the compounds of formula X-H can be used in the form of their alkali or alkaline earth metal salts. If thiophenol and phenol derivatives are used as compounds of the formula X-H, these are expediently used in the form of their anions, the alkali metal salts in particular, and here in particular the sodium and potassium salts, having proven successful.

The reaction can be carried out in the presence or absence of a solvent. If one works without a solvent, the components are expediently heated to temperatures of 100 to 200 ° C., preferably 140 to 180 ° C. The products obtained can be isolated in the customary manner, for example by dissolving the melt products in a solvent and then precipitating them by adding water or an organic non-solvent.

However, it is particularly advantageous to carry out the reaction with phenolates or thiophenolates in solvents at temperatures from 100 to 200 ° C., preferably 120 to 160 ° C. Suitable solvents are organic solvents, in particular tertiary carboxamides, polyethers or high-boiling solvents, such as HMPT or tetramethylene sulfon. The conversion of the esters of the formula IX into tertiary carboxamides, for example dimethylformamide or dimethylacetamide, is particularly advantageous. Depending on the choice of reaction temperature, the reaction is complete after 1 to 6 hours. The end products of the formula X can be isolated in a customary manner, for example by first filtering off the inorganic salts and then precipitating the reaction product by adding a non-solvent, or by introducing the reaction mixture into water or ice and separating the precipitated reaction product.

The reduction of the nitro group in the benzoic acid derivatives of the formula X can be carried out in a conventional manner, e.g. by catalytic hydrogenation. Raney nickel is preferred as the catalyst. However, catalytic hydrogenation can also be carried out using the common noble metal catalysts, e.g. Palladium / carbon or platinum oxide can be carried out (see Organikum pp. 271 to 277 and 507 to 510).

Suitable solvents for carrying out the reduction are preferably organic solvents, e.g. Methanol or ethanol, ethyl acetate, dioxane or other polar solvents, especially amides, such as dimethylformamide, dimethylacetamide or HMPT.

The hydrogenation is conveniently carried out at room temperature and under normal pressure or at elevated temperature and pressure, e.g. 50 ° C and 100 atm, carried out in an autoclave.

Starting from the amino compounds of the formula XI, the 3-imidobenzoic acid derivatives of the formula XIII (Z = 0) can be obtained in various ways. This conversion can take place, for example, by reacting the amino compounds of the formula XI with dicarboxylic acid derivatives of the formula XII capable of imide formation, in which Z is oxygen and L is a leaving group, preferably halogen, a trialkylammonium group or the residue OR 'of an activated ester, means implements. In order to avoid undesired acylation reactions at other points in the molecule, it is advisable to use any hydroxyl and / or amino groups present during the reaction

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to block the compound of formula XII by customary protecting groups.

Dicarboxylic acids which can be converted into dicarboxylic acid halides are, for example, succinic acid, methyl succinic acid, 2,3-dimethyl succinic acid, glutaric acid, 2-methyl glutaric acid, phthalic acid, cis-cyclopropanedicarboxylic acid, cyclo-butane-1,2-cis-dicarboxylic acid, cyclohexane-1,2-cis dicarboxylic acid, bromosuccinic acid and diglycolic acid. The reaction of these dicarboxylic acid derivatives with the amino compounds of the formula XI generally takes place under the conditions of the known Schotten-Baumann reaction.

Instead of the dicarboxylic acid halides, the anhydrides of the dicarboxylic acids mentioned can also be used. The carboxylic acid derivatives of the formula XV which form in many cases

/ a-cooh coor go directly into the imido compounds of the formula XIII with elimination of water. The implementation can be easily followed by thin-layer chromatography. Depending on the choice of reaction conditions, especially when the reaction mixture is heated to temperatures of 150 to 250 ° C., the ring-closed products are obtained in high yields.

The anhydride is advantageously used in a larger excess, for example in a 2 to 3-fold excess, and the reaction is carried out in the absence of a solvent. When using unsaturated dicarboxylic acid anhydrides e.g. Maleic anhydride occurs in the reaction with amino compounds of the formula XI at temperatures of 150 to 250 ° C when melting together a viscous oil, which after some time with elimination of water in the unsaturated imido compounds of the formula XVI

HO

wherein the symbols R1 to R3, B and X have the meanings given and R6 and R7, which are the same or different, each represent hydrogen or one of the substituents mentioned in A, passes over. The double bond of this imido compound allows a variety of reactions,

for example, it can be hydrogenated, producing an imido compound of the formula XIII, in which Z is oxygen and A is an ethylene group.

The starting compounds of the formula XIII, in which Z represents two hydrogen atoms, can be obtained by various processes. For example, they can be obtained from the amino compounds of the formula XI by reaction with co-substituted carboxylic acid derivatives of the formula XII, in which Z represents two hydrogen atoms, under the conditions of the Schotten-Baumann reaction and subsequent cyclization of the resulting amido compound of the formula XVII

coor "

wherein H-L is split off can be obtained.

Examples of suitable carboxylic acid derivatives of the formula XII are: co-chloropropionic acid chloride, w-chloropropionic acid bromide, co-chlorobutyric acid chloride, w-bromobutyric acid chloride, w-bromobutyric acid phenyl ester, and the chloride of trimethylammonium butyric acid chloride.

The bases required to split off the H-L group are preferably tertiary organic bases, such as pyridine, triethylamine or N, N-dimethylaniline, which can be used in a stoichiometric amount or in a large excess, the bases simultaneously serving as solvents in the latter case.

Complex borohydrides or diborane in the presence of Lewis acids are suitable as reducing agents for the reduction of the compounds of the formula XIII. Diborane can be used in the presence of Lewis acids to reduce lactams of the formula XIII (Z = 2H). In contrast, if imides of the formula XIII (Z = 0) are used, it is expedient to use complex borohydrides in the presence of Lewis acids in order to obtain good yields. In general, the reducing agents are taken under appropriate protective measures, e.g. into the reaction mixture using nitrogen as the inert gas. When using diborane as a reducing agent, it is easier for the reaction to be carried out by taking it up in a solvent and using this solution for the reduction. Particularly suitable solvents are ether, e.g. Tetrahydrofuran or diethylene glycol dimethyl ether.

As complex borohydrides e.g. Alkali boronates, such as lithium borohydride, sodium borohydride or potassium borohydride, or the alkaline earth boronates, such as calcium borohydride, but also zinc borohydride and aluminum borohydride. When adding Lewis acids, these borohydrides reduce the amide or. Imide groups, surprisingly, without significantly attacking the carboxylic acid ester function.

Suitable Lewis acids for carrying out the process are in particular aluminum chloride, titanium tetrachloride, tin tetrachloride, cobalt (II) chloride, iron (III) chloride,

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Mercury I chloride, zinc chloride and boron trifluoride and its adducts, for example boron trifluoride etherate. There is a possibility that during the implementation of the boron trifluoride etherate, e.g. with sodium borohydride, diborane can be formed in situ (see L. Fieser, M. Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, Vol. 1, p. 199).

In order to achieve a high conversion and particularly pure end products, it is advantageous to submit the Lewis acid together with the compound of the formula XIII and to enter the complex borohydride. It is particularly favorable to use the Lewis acid in excess and the complex borohydride in at least a stoichiometric amount, based on the amide group to be reduced. Particularly favorable results are obtained, for example, if titanium tetrachloride is used as the Lewis acid and NaBH4 is added in three times the stoichiometric amount, while when using boron trifluoride etherate, the complex borohydride can be used in stoichiometric amount, based on the amide groups to be reduced. .

For carrying out the reduction it is irrelevant whether the compounds of the formula XIII to be reduced are used in the form of the imido compounds (Z = 0) or as amido compounds (Z = 2H). Surprisingly, the imido compounds pass directly into the sulfamoylbenzoic acid derivatives of the formula XIV in a one-pot reaction. The reduction is conveniently carried out in a solvent, the solvent being e.g. Ethers such as tetrahydrofuran or diethylene glycol dimethyl ether (Diglym) come into consideration. The solvent in which the reaction is carried out may be the same as that in which the solvent is dissolved. However, different solvents can also be used.

The reduction can be carried out within a wide temperature range. For example, it can be carried out at room temperature or slightly elevated temperature. While secondary amides with diborane and lactams react with diborane and Lewis acid, preferably at a slightly elevated temperature (40 to 60 ° C), the reduction with complex borohydrides and Lewis acids, especially with imides, is often very favorable in the temperature range from 0 to 20 ° C. If you accept a somewhat longer reaction time, the reduction can also be carried out in the cold. The reaction time generally depends on the reaction components used and the temperature selected.

In a preferred embodiment of the process according to the invention, the compound of the formula XIII is introduced in an inert solvent together with the Lewis acid and a solution of the complex borohydride, optionally a suspension of the complex borohydride, in the same or another solvent is added at room temperature and stir for a short time. However, the boron hvdrid can also be added directly to the solution in solid form. To accelerate the reaction, the reaction can optionally also be carried out at a higher temperature or, after the addition of the reducing agent has ended, heated to 40 to 70 ° C. for about one hour. Another embodiment consists in presenting the compound of formula XIII to be reduced together with the complex borohydride and adding the Lewis acid at room temperature. Sodium borohydride in particular is used as the complex borohydride. Here, too, it can be advantageous to heat to about 40 to 70 ° C. for about an hour after the addition of the Lewis acid has been achieved in order to achieve a rapid reaction. The reaction can be carried out using thin layer chromatography on

Occurrence of the intense light blue fluorescence (in the range of 366 nm) of the resulting compound of formula XIV can be followed. In the reduction according to the invention, any double bonds present in group A can also be reduced at the same time.

The reduction of the imido or amido compounds of the formula XIII can be carried out with the same success if the alkylene chain A carries substituents which are easily split off to form a carbon-carbon double bond. If, for example, 2-bromo-succinic acid is used as the reaction partner for the preparation of the starting compounds of the formula XIII, A3-pyrroline derivatives of the formula XIV are obtained, in which A denotes a —CH = CH group.

The A3-pyrrolidine derivatives can be chemically modified in a manner known per se, so that they can be catalytically hydrogenated to the sulfamoylbenzoic acid derivatives of the formula XIV which are substituted in the 3-position heterocyclically, in which A represents an ethylene group, hydrogenated or subjected to conventional addition reactions.

The compounds of the formula XIV obtained in the reduction are then subjected to hydrolysis, the protective group B and, if appropriate, the ester group R3 being split off. The hydrolysis is expediently carried out under basic compounds, for example by heating the compounds of the formula XIV in sodium hydroxide solution or potassium hydroxide solution for several hours on a steam bath. In general, the ester group R3 is split off simultaneously.

In addition, the 5-sulfamoylbenzoic acids of the formula I in which R1, R2 and R3 are hydrogen can be obtained directly if the reaction mixture obtained in the reduction of the compounds of the formula XIII is partially concentrated after destruction of the excess reducing agent, base is added and warmed for a long time. Sodium hydroxide solution, for example, can be used as the base. In this case, the sulfamoyl-benzoic acids of the formula I can be isolated directly in the form of their salts. However, there is also the possibility of releasing the acids from this by acidifying the salts.

The compounds of the formula I thus prepared, in which R1 and R2 are hydrogen, can subsequently be converted into the corresponding compounds of the formula I in which R2 is an alkyl group having 1 to 4 carbon atoms by alkylation with R2-donating agents.

The compounds of the formula I obtained as end products can be isolated in various ways. A preferred method of elaboration is to precipitate the solution of the reaction product by adding a non-solvent. This method is particularly suitable in cases in which compounds of the formula I in which R3 is alkyl having 1 to 4 carbon atoms are obtained. When using diethylene glycol dimethyl ether as a solvent, water is particularly suitable as a non-solvent. The resulting 5-sulfamoylbenzoic acid of formula I usually crystallize out in high purity and almost quantitatively.

Following the production process, the compounds of formula I obtained can be further converted. For example, double bonds present in these compounds can be hydrogenated in a conventional manner, generally using catalytic hydrogenation. Conversely, double bonds can be introduced subsequently using elimination reactions, for example by splitting off hydrogen halide from halogenated compounds, by splitting off water from hydroxy compounds and by other known splitting reactions.

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If the free carboxylic acids of the formula I are obtained when the process according to the invention is carried out, these can subsequently be esterified by reaction with alcohols of the formula R3OH or their functional derivatives. Conversely, carboxylic acid esters of the formula I obtained in which R3 is alkyl having 1 to 4 carbon atoms can first be converted into the corresponding free carboxylic acids. The conversion into the free carboxylic acids can be carried out, for example, by hydrolysis, in particular by alkaline hydrolysis. If R3 is a tert-butyl group, this group can be removed by splitting off isobutylene by treatment with trifluoroacetic acid.

For converting the compounds of formula I obtainable according to the invention into their physiologically tolerable salts, bases, e.g. Alkali, alkaline earth or ammonium hydroxides or carbonates used.

As already mentioned, the hydroxy or amino protective groups introduced as intermediates are preferably split off hydrolytically. The cleavage is preferably carried out only after the reduction.

The oxidation of compounds of the formula I obtained, in which X denotes a group -SR4, to corresponding compounds, in which X denotes a group -SOR4 or -S02R4, can be carried out by methods known from the literature. For example, the compounds with the group -SOR4 can be obtained by oxidation with peracetic acid in dimethylformamide at low temperatures, while at higher temperatures and by adding excess oxidizing agent, compounds with the group -S02R4 can be obtained.

As already mentioned, the compounds obtainable according to the invention are highly effective pharmaceuticals, in particular diuretics and saluretics. A number of particularly important compounds are listed below: 3-N-pyrrolidino-4-p-chlorophenoxy-5-sulfamoylbenzoic acid 3-N-pyrrolidino 4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid

3-N-pyrrolidino-4- (3'-methylpbenoxy) -5-sulfamoylbenzoic acid

3-N-Pyyrolidino-4- (2'-methylphenoxy) -5-suifamoylbenzoic acid

3-N-pyrrolidino-4- (2 ', 4'-dimethylphenoxy) -5-sulfamoyl-benzoic acid

3-N-pyrrolidino-4- (3 \ 5'-dimethylphenoxy) -5-sulfamoyl-benzoic acid

3-N-pyrrolidino-4- (4'-hydroxyphenoxy) -5-sulfamoylbenzoic acid

3-N-pyrrolidino-4- (4'-methoxyphenoxy) -5-sulfamoylbenzoic acid

3-N-pyrrolidino-4- (4'-trifluoromethyl-phenoxy) -5-sulfamoyl-benzoic acid

3-N-pyrrolidino-4- (3'-trifluoromethyl-phenoxy) -5-sulfamoyl-benzoic acid

3-N-pyrrolidino-4- (4'-propylphenoxy) -5-sulfamoylbenzoic acid

3-N-pyrrolidino-4-n-butoxy-5-sulfamoylbenzoic acid 3-N-pyrrolidino-4-phenylthio-5-sulfamoylbenzoic acid 3-N-pyrrolidino-4- (4'-dimethylaminophenoxy) -5-sulfamoylbenzoic acid

3-N-pyrrolidino-4- (4'-aminophenoxy) -5-sulfamoylbenzoic acid

3-N-pyrrolidino-4-phenylsulfinyl-5-sulfamoylbenzoic acid 3-N-pyrrolidino-4-phenylsulfonyl-5-sulfamoylbenzoic acid 3-N- (3-methylpyrrolidino) -4-p-chlorophenoxy-5-sulfamoylbenzoic acid

3-N- (3-methylpyrrolidino) -4- (4'-methylphenoxy) -5-sulfamoyl-benzoic acid

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3-N- (3-methylpyrrolidino) -4- (3'-methylphenoxy) -5-sulfamoyl-benzoic acid

3-N- (3-methylpyrrolidino) -4- (2'-methylphenoxy) -5-sulfamoyl-benzoic acid

3-N- (3-methylpyrrolidino) -4- (2 ', 4'-dimethylphenoxy) -5-sulf-

amoylbenzoic acid 3-N- (3-methylpyrrolidino) -4- (3 ', 5'-dimethylphenoxy) -5-

-sulfamoylbenzoic acid 3-N- (3-methylpyrrolidino) -4- (4'-hydroxyphenoxy) -5-sulf-

amoylbenzoic acid 3-N- (3-methylpyrrolidino) -4- (4'-trifluoromethylphenoxy) -

-5-sulfamoylbenzoic acid 3-N- (3-methylpyrrolidino) -4- (3'-trifluoromethylphenoxy) -

-5-sulfamoylbenzoic acid 3-N- (3-methylpyrrolidino) -4- (4'-propylphenoxy) -5-sulfamoylbenzoic acid

3-N- (3-methylpyrrolidino) -4-phenylthio-5-sulfamoylbenzoic acid

3-N- (3-methylpyrrolidino) -4- (4'-dimethylaminophenoxy) -5-

-sulfamoylbenzoic acid 3-N- (3-methylpyrrolidino) -4- (4'-aminophenoxy) -5-sulfamoyl-benzoic acid

3-N- (3-methylpyrrolidino) -4-phenylsulfinyl-5-sulfamoyl-benzoic acid

3-N- (3-methylpyrrolidino) -4-phenylsulfonyl-5-sulfamoyI-benzoic acid

3-N- (3,3-Dimethylpyrrolidino) -4-phenoxy-5-sulfamoyl-benzoic acid

3-N- (3,3-dimethylpyrrolidino) -4- (4'-methylphenoxy) -5-

sulfamovlbenzoic acid 3-N- (3,4-dimethylpyrrolidino) -4-phenoxy-5-sulfamoyl-benzoic acid

3-N- (3,4-dimethylpyrrolidino) -4- (4'-methylphenoxy) -5-

-sulfamoylbenzoic acid 3-N-A3-pyrrolino-4-phenoxy-5-sulfamoylbenzoic acid 3-N-A3-pyrrolidino-4- (4'-methylphenoxy) -5-sulfamoyl-benzoic acid

3-N-A3-pyrrolino-4- (4'-chlorophenoxy) -5-sulfamoylbenzoic acid

3- [1- (3-phenylpyrrolidinyl)] - 4-phenoxy-5-sulfamoylbenzoic acid

3- [1- (3-phenylpyrrolidinyl)] - 4- (4'-methylphenoxy) sulfamoyl benzoic acid

3-N- (3-chloropyrrolidino) -4-phenoxy-5-sulfamoylbenzoic acid 3-N- (3-bromopyrrolidino) -4-phenoxy-5-sulfamoylbenzoic acid 3-N-piperidino-4-p-chlorophenoxy-5-sulfamoylbenzoic acid 3 -N-piperidino-4- (4'-methylphenoxy) -5-suIfamoylbenzoic acid 3-N-piperidino-4- (3'-methylphenoxy) -5-sulfamoylbenzoic acid 3-N-piperidino-4- (2'-methylphenoxy) - 5-sulfamoylbenzoic acid 3-N-piperidino-4- (2 ', 4'-dimethylphenoxy) -5-sulfamoylbenzoic acid

3-N-piperidino-4- (3 ', 5'-dimethylphenoxy) -5-sulfamoylbenzoic acid

3-N-piperidino-4- (4'-hydroxyphenoxy) -5-sulfamoylbenzoic acid

3-N-piperidino-4- (4'-trifluoromethyl-phenoxy) -5-sulfamoyl-benzoic acid

3-N-piperidino-4- (4'-propylphenoxy) -5-sulfamoylbenzoic acid 3-N-piperidino-4-phenylthio-5-sulfamoylbenzoic acid 3-N-piperidino-4- (4'-dimethylaminophenoxy) -5-sulfamoyl- benzoic acid

3-N-piperidino-4- (4-aminophenoxy) -5-sulfamoylbenzoic acid 3-N-piperidino-4-phenylsulfinyl-5-sulfamoylbenzoic acid 3-N-piperidino-4-phenylsulfonyl-5-sulfamoylbenzoic acid 3-N-piperidino-4 - (4'-Methoxyphenoxy) -5-sulfamoybenzoic acid.

Regarding the above list, it should be noted that with every compound instead of the word part «5-sulfamoyl-» also

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the following parts of the word "5-N-methylsulfamoyl-" or "5-N - ethylsulfamoyl-" can be used. In addition, the abovementioned compounds can also be obtained in the form of their esters, so that instead of the word ending “-benzoic acid”, the following word endings “methyl benzoate, ethyl benzoate and benzoate - tert-butyl ester” can be used.

The sulfamoylbenzoic acid derivatives of the formula I obtainable according to the invention and their physiologically tolerable salts are highly effective diuretics and saluretics which can be used as pharmaceuticals in human and veterinary medicine. The compounds can be administered in doses of 0.5 to 100 mg enterai or parenterally. Capsules, pills, tablets or solutions with various additives can be considered as administration forms. Enteral administration can be done, for example, orally using a probe. For parenteral administration, both injections into the vascular system, e.g. intravenously, or injections into the muscles or under the skin. The compounds of the formula I and their physiologically tolerable salts are suitable for the treatment of edema diseases, for example cardiac, renal or hepatic edema, and other such phenomena attributable to disturbances in the water and electrolyte balance. The compounds can be administered alone or in combination with other salidiuretically active substances, the effectiveness of which may be based on a different mode of action. They can also be administered together with various other medicinal products, and the application can be carried out separately, alternately or in combination. Medicaments which are particularly suitable for combination with the compounds obtainable according to the invention are, for example, SPIRONOLACTON, TRIAMTEREN, AMILORID and other K + -retinating compounds which can be applied alternately with long-acting salidiuretics of the CHLORTHALIDON type. In addition, the compounds can contain potassium-containing compounds, e.g. Salts which substitute for the K + loss observed in salidiuresis are administered, it being possible for the application to be carried out together or separately.

example 1

4-phenoxy-3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 4-chloro-5-N, N-dimethyIaminomethylenaminosulfonyl-

benzoic acid

90 ml (1.25 mol) is added to a solution of 58.9 g (0.25 mol) of 4-chloro-5-sulf-amoylbenzoic acid in 183 g (2.5 mol) of dimethylformamide (DMF) at -10 ° C. Thionyl chloride added dropwise. The solution is then allowed to come to room temperature, stirred for 2 hours and poured onto ice, the precipitate is filtered off and washed neutral with water. 4-Chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid (in very good yield) is obtained as crystals of mp: 266 to 267 ° C.

b) 3-nitro-4-chloro-5-N, N-dimethy! aminomethyleneamino-

sulfonylbenzoic acid

42 ml of fuming nitric acid are added dropwise to 60 ml of 20% oleum while cooling with ice, after which 34.9 g (0.12 mol) of 4-chloro-5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid are slowly added. After stirring at 55 to 60 ° C. for 24 hours, the solution is cooled to room temperature, poured onto ice and the precipitate is washed neutral with water. 3-Nitro-4-chloro-5 - N, N-dimethylaminomethyleneaminosulfonylbenzoic acid is obtained in crystals of mp. 274 to 276 ° C.

c) 3-Nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

50.4 g (0.15 mol) of 3-nitro-4-chloro-5-N, N-dimethylamino-methylenaminosulfonylbenzoic acid are dissolved in a solution of 150 ml of thionyl chloride, which contains 5 drops of DMF,

Boiled under reflux for 1 hour. After the excess thionyl chloride has been stripped off in vacuo, the solid acid chloride is suspended in 200 ml of methanol. The suspension will

Boiled under reflux for an hour, then cooled, filtered and washed with cold methanol.

This gives 3-nitro-4-chloro-5-N, N-dimethylaminomethyl-lenaminosulfonylbenzoesäuremethylester, crystals of mp. 168 to 169 ° C.

d) 3-nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

A solution of 105 g (0.3 mol) of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 47.5 g (0.36 mol) of potassium phenolate in 600 ml of DMF is refluxed for 2 hours cooked. After cooling and filtering the potassium chloride, the solution is poured onto ice / water and stirred for 1 hour. The precipitate is filtered, washed with water and dried.

After the crude product has been dissolved in 900 ml of acetone, it is clarified with coal, evaporated to 500 ml and diluted with 1 liter of methanol. After stirring for 1 hour, the precipitate is filtered at 10 ° C. and washed with cold methanol.

This gives 3-nitro-4-phenoxy-5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester, as crystals of mp: 191 to 193 ° C.

e) 3-Amino-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester

61 g (0.15 mol) of 3-nitro-4-phenoxy-5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester are hydrogenated with Raney nickel in methanol at room temperature and normal pressure for 8 hours. After filtration, the catalyst is suspended in warm DMF, filtered and the DMF filtrate is poured onto ice / water.

3-Amino-4-phenoxy-5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester, crystals of mp: 255 to 256 ° C.

f) 3-N-succinimido-4-phenoxy-5-N, N-dimethylamino-methylene aminosulfonylbenzoic acid methyl ester

30 g of 3-amino-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester are fused with 26 g of succinic anhydride at 180 ° C. After about

The resulting imide is precipitated with methanol for 2 hours. By recrystallization from n-butanol, the imide is obtained in very good yield, mp: 283 to 284 ° C.

g) 4-Phenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester

23 g (0.05 mol) of 3-N-succinimido-4-phenoxy-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester are suspended in 200 ml of diethylene glycol dimethyl ether (diglyme) and 13 ml of BF3 etherate (0.1 mol) are added.

A solution of 3.8 g (0.1 mol) of NaBH4 in 200 ml of diglyme is then slowly added dropwise, with cooling, and a temperature range of -10 to + 5 ° C. is maintained. Then allowed to warm to room temperature, whereby a clear solution is formed. The reaction is complete after 1.25 hours. The product precipitates when water is added. Recrystallization from methanol gives 4-phenoxy-3- (1-

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-pyrroIidinyl) -5-N, N-dimethylaminomethyleneaminosulfonyl-benzoic acid ester of mp: 189 to 190 ° C.

h) 4-phenoxy-3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid

13 g (- 0.03 mol) of 4-phenoxy-3- (l-pyrrolidinyl) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester are suspended in 100 ml of 2N NaOH and saponified at 80 to 90 ° C. with good stirring. When a clear solution has formed, stirring is continued for 1 hour at the same temperature. Then it is cooled to 0 ° C. and 110 ml of 2N hydrochloric acid are slowly added with good stirring. The mixture is stirred vigorously after Y2 hours and then the very finely precipitated product is suctioned off sharply. The substance is recrystallized from methanol / water. Light yellow plates with a melting point of 226 to 228 ° C.

Example 2

The reaction sequence given in Example 1 is repeated up to step c). The 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester obtained is then heated with potassium phenolate at 190 to 200 ° C. for 2 hours.

The reaction mixture is cooled, taken up in acetone and, after the inorganic constituents have been separated off, worked up in the manner described in step d). This gives 3-nitro-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester which can be converted into the desired end product analogously to the manner given in Example 1.

Example 3

a) The reaction sequence given in Example 1 is repeated, with the difference that the catalytic hydrogenation of the 3-nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester is carried out in an autoclave at 50 ° C. and 50 atm. After cooling, the desired 3-amino-4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonylbenzoesäuremethylester is isolated in the manner described in Example le).

b) The reaction sequence given in Example 1 is repeated, with the difference that the catalytic hydrogenation of the 3-nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester in dimethylformamide (DMF) is carried out with Raney nickel at room temperature and normal pressure becomes. After filtering the catalyst, the DMF solution is poured onto ice. 3-Amino-4-phenoxy-5-N, N-dimethylaminomethyIenamino-sulfonylbenzoic acid methyl ester of mp: 255 to 256 ° C.

Example 4

The reaction sequence given in Example 1 is repeated with the difference that the starting compound is 4-chloro-5-N, N-dimethylaminomethyIenaminosulfonylbenzoeic acid methyl ester.

a) 4-Chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

90 ml (1.25 mol) of thionyl chloride are added dropwise to a solution of 74.9 g (0.3 mol) of methyl 4-chloro-5-sulfamoylbenzoate in 183 g (2.5 mol) of dimethylformamide at −10 ° C., and worked up as described in Example 1. This gives 4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester, mp: 174 to 176 ° C.

b) 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneamino

methyl sulfonylbenzoate

36.5 g (0.12 mol) of 4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester are reacted under the same conditions as given in Example 1b). A mixture of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid and 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester is obtained. The mixture is separated by treatment with 5% aqueous sodium carbonate. This gives 3 -nitro-4-chloro-5-N, N-dimethy laminomethyleneaminosulfonylbenzoic acid methyl ester of mp. 168 to 169 ° C. and after acidification 3-nitro-4-chloro-5-N, N-dimethylamino methosulfonylbenzoic acid from Mp. 270 to 272 ° C, which can also be converted into the ester in the manner described in Example lc).

The further reaction then takes place in the reaction sequence described in Example 1.

Example 5

The nitration described in Example 1 is carried out with the difference that the ethyl ester is used instead of the methyl ester.

a) 4-chloro-5-N, N-dimethylaminomethyleneaminosulfonyl-

ethyl benzoate

To a solution of 65 g (0.25 mol) of 4-chloro-4-sulf-amoylbenzoic acid ethyl ester in 183 g (2.5 mol) of DMF, 90 ml (1.25 mol) of thionyl chloride are added dropwise and as in Example 1 worked up. 4-Chloro-5-N, N - dimethylaminomethyleneaminosulfonylbenzoic acid ethyl ester, crystals of mp: 119 to 121 ° C.

b) 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneamino

ethyl sulfonylbenzoate

Under the same conditions as given in Example 4, 38.3 g (0.12 mol) of 4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid ethyl ester are reacted. The separation of the nitroester and the nitro acid is carried out as indicated in Example 4. 3-Nitro-4-chloro-5-N, N-dimethylaminamethyleneaminosulfonylbenzoic acid ethyl ester, crystals of mp. 182 to 184 ° C. and after acidification of the aqueous solution 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid, crystals of mp. 270 to 272 ° C, identical in mp. And mixture with the carboxylic acid described in Example lb).

Example 6

3-nitro-4-phenoxy-5-sulfamoylbenzoic acid

The reaction sequence described in Example 1 is repeated up to the stage of the 3-nitro-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid ester. 100 g of 3-nitro-4-phenoxy-5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester in 500 ml of 2N NaOH are then boiled under reflux for 2 hours. After cooling, it is acidified with concentrated hydrochloric acid. 3-Nitro-4-phenoxy-5-sulfamoylbenzoic acid is obtained as crystals of mp: 254 to 255 ° C.

Example 7

Methyl 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoate

36.2 g of 4-phenoxy-3- (l-pyrrolidinyl) -5-sulfamoybenzoic acid are concentrated in 200 ml of methanol and 7 ml. H2S04 ge5

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dissolves and heated to reflux for 4 to 6 hours. The ester crystallizes on cooling.

Recrystallization from methanol, mp: 191 ° C.

Example 8

4-phenylthio-3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid

The reaction sequence given in Example 1 for the preparation of 3-nitro-4-chloro-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester is repeated:

a) 3-Nitro-4-phenylthio-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester

A solution of 21 g (0.06 mol) of 3-nitro-4-chloro-5-N, N - dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester 7.7 g (0.07 mol) of thiophenol and 8.2 g (0.077 mol) of Na- trium carbonate in 100 ml DMF is boiled under reflux for 2 hours. After cooling and filtering, the solution is poured onto ice / water and stirred for 1 hour. The precipitate is filtered, washed with water and dried. The crude product is recrystallized from acetone / methanol. 3-Nitro-4-phenylthio-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester is obtained as crystals of mp: 207 ° C.

b) 3-A mino-4-phenylthio-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester

2 g (0.0047 mol) of 3-nitro-4-phenylthio-5-N, N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester are hydrogenated with Raney nickel in 30 ml of DMF at room temperature and normal pressure for 8 hours. The catalyst is filtered off with suction, washed with warm DMF and the DMF filtrate is poured onto ice / water.

The 3-amino-4-phenylthio-5-N, N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester is obtained from acetone as crystals of mp. 214 to 215 ° C.

c) 3-N-succinimido-4-phenylthio-5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester

35 g (0.089 mol) of 3-amino-4-phenylthio-5-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester is finely triturated with 26.6 g (0.2668 mol) of succinic anhydride and melted at 175 ° C. for 2 hours. After cooling to 150 ° C., the mixture is diluted with 100 ml of DMF and the solution is slowly added to ice / water. The precipitate is filtered off, dried and recrystallized from DMF / CH3OH. Mp: 261 to 263 ° C.

d) 4-phenylthio-3- (l-pyrrolidinyl) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester

To a solution of 32 g of 3-N-succinimido-4-phenylthio-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 17.5 ml of BF3 etherate in 135 ml of absolute diglyme is a solution of 5.1 with good stirring g NaBH ,, in 135 ml abs. Diglyme added dropwise at a temperature of 0 to 10 ° C. After 2 hours, the mixture is hydrolyzed and the product is precipitated by adding more water.

e) The precipitated crude product is refluxed with 2N NaOH until a clear solution is obtained. The 4-phenylthio-3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with 2N HCl and recrystallized from CHsOH / H..O.

Mp: 237 to 238 ° C.

Example 9

4-phenylthio-3- [1- (3-methylpyrrolidinyl)] - 5-sulfamoyl-benzoic acid

5 a) 3-Amino-4-phenylthio-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester A solution of 110 g of 3-nitro-4-phenylthio-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester in 400 ml DMF is over - 10 g Raney nickel hydrogenated for 8 hours at 40 ° C. and 100 atm. The catalyst is filtered and the solution is poured onto ice. The precipitate is filtered, dried and recrystallized from acetone.

Mp: 214 to 215 ° C.

15 b) 3N- (3-methylsuccinimido) -4-phenylthio-5-N, N-dimethyl-aminomethyleneaminosulfonylbenzoic acid, methyl ester 40 g (- 0.1 mol) of 3-amino-4-phenylthio-5-N, N-dimethyl-aminomethyleneaminosulfonylbenzoic acid, methyl ester are melted with 34 g (0.3 mol) of methyl succinic anhydride 2.5 hours at 175 ° C. After cooling to 150 ° C., the mixture is diluted with 100 ml of DMF and the solution is slowly added to ice / water. The precipitate is filtered off and recrystallized from CHjOH.

Mp: 206 to 207 ° C.

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c) 4-Phenylthio-3- [1- (3-methylpyrrolidinyl)] - 5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

To a solution of 29.4 g of 3-N- (3-methylsuccinimido) -4-phenylthio-5-N, N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester and 15.9 ml of BF3 etherate in 120 ml of 30 abs. Diglyme, a solution of 4.65 g of NaBH4 in 120 ml of abs is dropped at 0 to 10 ° C. Diglyme added. After stirring for 2 hours, the reaction product is carefully precipitated with water.

Recrystallization from CH .OH. Mp: 147 to 148 ° C.

35

d) 4-phenylthio-3- [1- (3-methylpyrrolidinyl)] - 5-sulfamoyl-benzoic acid

4 g of the ester [Example 9c)] are refluxed in 40 ml of 2N NaOH for 2 hours. A clear solution is created. After cooling and acidifying with 2N HCl to pH 2 to 3, the 4-phenylthio-3- [1- (3-methylpyrrolidinyl)] - 5-sulfamoylbenzoic acid precipitates. It is recrystallized from CHa0H / H20. Yellow crystals of mp. 216 to 217 ° C.

45 Example 10

4-phenylsulfinyl-3- [1 - (methylpyrrolidinyl)] -5-sulfamoyl-benzoic acid

A solution of 6 g of 4-phenylthio-3- [l- (methylpyrrolidi-50 nyl)] - 5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid in 70 ml of glacial acetic acid and 15 ml of 30% H- 02 is at 5 to 20 ° C stirred. After 20 hours, the solution is poured onto "ice water". The precipitate is washed with water, dried and hydrolyzed with 30 ml of 2N NaOH at 55 100 ° C. for 2 hours. The hydrolyzate is filtered and acidified to pH 2 to 3 in the cold with stirring with 2N HCl; this precipitates 4-phenylsulfoxy-3- [l- (methylpyrrolidinyl)] - 5-sulfamoylbenzoic acid. By recrystallization from methanol / water, yellow crystals of mp: 143 60 to 145 ° C. are obtained with decomposition.

Example 11

4- (4'-nitrophenoxy) -3- (l-pyrrolidinyl) -5-sulfamoylbenzoe-

acid

65 a) 3-N-Succinimido-4- (4'-nitrophenoxy) -5-N, N-dimethyl-aminomethyleneaminosulfonylbenzoic acid, methyl ester 35 g of 3-N-succinimido-4-phenoxy-5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid, methyl ester

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- 20 to - 10 ° C in portions in 200 ml of smoking nitric acid. The mixture is stirred for 10 minutes and then the mixture is poured onto about 2 liters of ice / water. The mixture is stirred for 1 hour, the precipitated product is suctioned off and washed well with water. The 3-N-succinimido-4- (4'-nitrophenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester is obtained in very good yield as a white crystalline powder, mp. 260 to 261 ° C.

b) 4- (4'-Nitrophenoxy) -3- (l-pyrrolidinylj-5-N, N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester 30 g of the imide [Example IIa)] are suspended in about 250 ml of absolute diglyme and 22 ml of BF3 etherate admitted. A solution of 3.2 g NaBH4 in 250 ml abs is then added dropwise at 50 to 60 ° C. Diglyme added. After 1.5 hours, the excess reducing agent is hydrolyzed with a little water and the 4- (4'-nitrophenoxy) -3- (l-pyrrolidininyl) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester precipitates with ice water. Pale yellow crystals from methanol, mp: 216 to 217 ° C.

c) 4- (4'-Nitrophenoxy) -3- (l-pyrrolidinyl) -5-siilfamoybenzoic acid

24 g of the ester [Example 1 lb)] are heated for about 1.5 hours in 200 ml of NaOH and a little methanol as solubilizer on the steam bath until the solution is clear. After cooling, the free acid is then precipitated with 2N HCl.

The 4- (4'-nitrophenoxy) -3- (l-pyrrolidinyI) -5-sulfamoyl-benzoic acid is recrystallized from glycol monomethyl ether / water. Light brown crystals of mp. 235 to 238 ° C with decomposition.

Example 12

4- (4'-aminophenoxy) -3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid

18.5 g of 4- (4'-nitrophenoxy) -3- (l-pyrrolidinyl) -5-sulfamoyl-benzoic acid are dissolved in dimethylformamide and hydrogenated with Ra-ney-nickel at room temperature and normal pressure for 8 hours. After filtration, the 4- (4'-aminophenoxy) -3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with water. Brown crystals from DMF / HaO, mp: 234 to 240 ° C with decomposition. The compound crystallizes with yi mol of dimethylformamide, which does not escape even by drying in vacuo at 120 to 150 ° C.

Example 13

4- (4'-Hydroxyphenoxy) -3- (l-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-nitro-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid, methyl ester 87.5 g (0.25 mol) of 3-nitro-4-chloro-5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester are dissolved in 500 ml of anhydrous dimethylformamide and 77.5 g (0.35 mol) of sodium 4-benzyl-oxyphenolate are added. The reaction mixture is refluxed for 3 to 4 hours with thorough stirring. After cooling, the cloudy solution is dropped into 3 liters of ice / water. The yellow precipitate is filtered off, washed well with water and recrystallized from methanol. 94 g of 3-nitro - 4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester are obtained in yellow crystals with a melting point of 132 ° C.

b) 3-Amino-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester

94 g of 3-nitro-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester are dissolved in 1.5 liters of dimethylformamide and hydrogenated with Raney nickel at room temperature and normal pressure for 6 to 7 hours. Then it is filtered and the clear solution is dropped in ice / water. The precipitated 3-amino-4- (4'-benzyloxy-phenoxy) -5-N, N-dimethylaminomethyleneaminosulfonyl, o benzoic acid methyl ester is recrystallized from methanol. About 70 g are obtained in white crystals of Schmp.

170 ° C.

c) 3-N-Succinimido-4- (4'-benzyloxyphenoxy) -5-N, N-dime-15 methylaminomethyleneaminosulfonylbenzoic acid methyl ester

48.3 g (0.1 mol) of 3-amino-4- (4'-benzyloxyphenoxy) -5 - N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester in 250 ml abs. Dissolved dioxane and heated to boiling. A solution of 24.5 g (■ - ■ 0.16 mol) of succinic acid dichloride in 100 ml of abs. Acetone and a solution of 16 ml pyridine (■ - 0.2 mol) in 100 ml abs. Acetone in the boiling solution. After about 2 hours under reflux, the reaction mixture is evaporated and methanol 25 is added to the residue. The resulting imide crystallizes out and can be recrystallized from methanol and a little acetone. About 45 g of white crystals of mp 228 ° C. are obtained.

d) 4- (4'-Benzyloxyphenoxy) -3- (l-pyrrolidinyl) -5-N, N-dime-30 methylaminomethyleneaminosulfonylbenzoic acid methyl ester

■ 35.5 g imide in 200 ml abs. Diglyme suspended and 16.8 ml of BFS etherate added. A solution of 5 g of NaBH.j in 200 ml of abs is then added dropwise at room temperature. Diglyme and stir for about an hour. The over-35 excess reducing agent is carefully destroyed by adding water and a little diluted HCl (foaming!), And the product is finally precipitated with 1 liter of water. By recrystallization from methanol, 31.6 g of 4- (4'-benzyloxyphenoxy) -3- (l-pyrrolidinyl) -5-N, N-dimethyl-40 aminomethyleneaminosulfonylbenzoic acid methyl ester of mp 152 ° C. is obtained.

e) 4- (4'-Benzy! oxyphenoxy) -3- (l-pyrrolidinyl) -5-sulfamoyl-benzoic acid

45 31 g of the ester [Example 13d] are suspended in about 300 ml of 2N NaOH and heated on the steam bath. When a clear solution has formed, the mixture is allowed to cool and the 4- (4'-benzyloxyphenoxy) -3- (l-pyrrolidinyl) -5-sulfamoyl-benzoic acid precipitates with 2N HCl (pH - 3). The acid is recrystallized from methanol. White-yellow crystals with a melting point of 226 to 228 ° C.

NMR data: (D "-DMSO, 60 MHz, TMS) 8 = 1.73 (quasi-s; 4H), 8 = 3.24 (quasi-s; 4H), 5 = 5.05 (s; 2H ), 5 = 6.6 to 7.9 (m; 13H).

55 f) 4- (4'-Hydroxyphenoxy) -3- (l-pyrrolidinyl) -5-suljamoyl-benzoic acid

9.5 g of [4- (4'-benzyloxyphenoxy) -3- (l-pyrrolidinyl) -5 - sulfamoylbenzoic acid are dissolved in water by adding the equivalent amount of KOH and treated with Raney nickel at 60 50 ° C. and 100 at Autoclave hydrogenated for 5 hours. It is then filtered and the 4- (4'-hydroxyphenoxy) -3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with 2N HCl (pH ■ - • 3). By recrystallization from CH: i0H / H20 6.2 g of light yellow needles of mp. 271 to 273 ° C.

65 NMR data: (D (i-DMSO, 60 MHz, TMS) 5 = 1.73 (quasi-s; 4H), 5 = 3.24 (quasi-s; 4H), 6 = 6.64 (quasi -s; 4H), 5 = 7.24 (s; 2H), 5 = 7.58 (d; 1H), 5 = 7.88 (d; 1H), 8 = 9.0 [s (broad); 1H].

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Example 14

4- (4'-Methylphenoxy) -3- (3-pyrrolin-l-yl) -5-sulfamoyl-benzoic acid a) 3-N- (3-chlorosuccinimido) -4- (4'-methylphenoxy) -5-N , N - methyl dimethylaminomethyleneaminosulfonylbenzoate

25 g of 3-amino-4- (4'-methylphenoxy) -5-N, N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester are melted together with 25.9 g of chlorosuccinic anhydride at 180 ° C. The reaction is complete after about 2.5 hours and the resulting imide is precipitated with CHaOH. White crystals of mp: 294 to 295 ° C (the substance sinters at 215 to 216 ° C).

b) 20 g of imide are suspended in diglyme and 10.3 ml of BF3 etherate are added. A diglyme solution of 3.1 g of NaBH4 is then added dropwise at room temperature and the mixture is subsequently stirred for 2 to 3 hours. The product is precipitated as an oil with a little 2N HCl and a lot of water, separated off and immediately saponified with 2N NaOH on the steam bath. The product is precipitated from the clear solution with 2N HCl. It is a mixture of 4- (4'-methylphenoxy) -3-pyrrolin-l-yl) -5-sulfamoylbenzoic acid and 4- (4'-methylphenoxy) -3- (3-chloro-l-pyrrolidinyl ) -5-sulfamoylbenzoic acid. The mixture is dried, dissolved in DMSO and the 5-fold molar amount of potassium t-butoxide is added. The mixture is heated to 120 ° C. for 2 to 3 hours, then acidified at room temperature with 2N HCl and the product precipitates with H20. The 4- (4'-methylphenoxy) -3- (3-pyrrolin-l-yl) -5-sulfamoyl-benzoic acid is obtained by recrystallization from CH30H / H20 or acetonitrile as white-yellow crystals with a melting point of 270 to 272 ° C.

Example 15

4- (4'-Methylphenoxy) -3- (3-phenyl-l-pyrrolidinyl) -5-sulf-amoylbenzoic acid a) 3-nitro-4- (4'-methylphenoxy) -5-N, N-dimethylaminomethylaminosulfonylbenzoic acid methyl ester

A solution of 235 g (0.67 mol) of 3-nitro-4-chloro-5 - N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 140 g (- 0.96 mol) of potassium 4-methylphenolate in 1 liter of abs . DMF is stirred at 90 to 100 ° C for 2 hours. Then the cold solution is slowly dripped into 4 to 5 liters of ice water with vigorous stirring. The precipitated product is filtered off, washed with water and recrystallized from CH3OH.

Yellow crystals of mp: 200 to 201 ° C.

b) 3-Amino-4- (4'-methylphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester

171 g of 3-nitro-4- (4'-methylphenoxy) -5-N, N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester are hydrogenated with Raney nickel in a solvent mixture of CH3OH ethyl acetate / DMF at 50 ° C. and 100 atm for 8 hours. It is then filtered off, washed with DMF and the filtrate is concentrated. The residue is recrystallized from CH ^ OH. White crystals of mp: 172 to 173 ° C.

c) 3-N- (3-phenylsuccinimido) -4- (4'-methylphenoxy) -5-NJSl - dimethylaminomethyleneaminosulfonylbenzoic acid, methyl ester

15 g of the amino compound [Example 15b)] are melted together with 20 g of phenylsuccinic anhydride at 180 to 190 ° C. for 2 hours. The imide precipitates out by adding methanol. It is recrystallized from ethanol.

White crystals of mp: 249 to 250 ° C.

d) 4- (4'-Methylphenoxy) -3- (3-phenyl-l-pyrrolidinyl) -5-sulfamoylbenzoic acid

24.5 g imide [Example 15c)] are in 225 ml abs. Diglyme suspended and 24 ml BFS etherate added. A solution of 4.5 g of NaBH4 in 200 ml of diglyme is then added dropwise at room temperature and the mixture is heated at 60 to 80 ° C. for 1 hour with stirring. The product is precipitated with ice / water, separated off and immediately saponified with 2N NaOH. The free acid is precipitated from the clear solution in the cold with 2N HCl. Recrystallization from glacial acetic acid / H20 or CH3OH /

h2o.

Mp: 204 to 206 ° C.

Example 16

4- (4'-Methoxyphenoxy) -3- (3-methyl-l-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-nitro-4- (4'-methoxyphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester

The reaction is carried out analogously to Example 15a) with potassium 4-methoxyphenolate. The crude product is used directly for the hydrogenation.

b) 3-Amino-4- (4'-methoxyphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester

The crude 3-nitro compound [Example 16a)] is hydrogenated with Raney nickel in DMF for 8 hours at 50 ° C. and 50 atm. The amine formed is separated from the Raney nickel and precipitated from the DMF solution with water. Recrystallization from methanol; white crystals of mp: 141 to 143 ° C.

c) 3-N- (3-Methylsuccinimido) -4- (4'-methoxyphenoxy) -5 - N, N-dimethy laminomethy lenaminosulfony methylbenzate

16 g (0.045 mol) of the amino compound [Example 16b)] are fused with 14 g of methyl succinic anhydride at 180 ° C. After about 2 hours, CH3OH is added to the still liquid mixture while cooling. The imide slowly crystallizes out. It is recrystallized from CH3OH / acetone. White crystals of mp: 207 to 208 ° C.

d) 4- (4'-Methoxyphenoxy) -3- (3-methyl-l-pyrrolidinyl) -5-sulfamoylbenzoic acid

16.5 g (0.033 mol) imide [Example 16c)] in 150 ml abs. Diglyme suspended and 9 ml of boron trifluoride etherate added. A solution of 2.7 g of NaBH4 in 150 ml of diglyme is then added dropwise with stirring at 0 to 10.degree. The mixture is stirred for 15 minutes at room temperature and the product is precipitated with a little HCl and a lot of water. The crude product is suspended in 2N NaOH and warmed to a clear solution. Acidification to pH 3 gives the free acid, which can be recrystallized from CH30H / H20.

Light yellow crystals with a melting point of 190 ° C.

Example 17

4- (4'-Fluorophenoxy) -3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-nitro-4- (4'-fluorophenoxy) -5-N, N-dimethylaminomethylene aminosulfonylbenzoic acid methyl ester A solution of 210 g (0.6 mol) 3-nitro-4-chloro-5-N, N - dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 120 g sodium 4-fluorophenolate in 800 ml abs. DMF is stirred for 3 to 4 hours at 120 to 130 ° C. Then the cold solution is slowly dripped into 4 to 5 liters of ice water with vigorous stirring. The precipitated product is filtered off, washed well with water, with acetone in the

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621776

Heat digested and then recrystallized from glycol monomethyl ether.

Light yellow crystals with a melting point of 224 to 225 ° C.

b) 3-Amino-4- (4'-fluorophenoxy) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester

140 g of the nitro compound [Example 17a)] are dissolved in DMF and hydrogenated with Raney nickel at 50 ° C. and 50 atm for 8 hours. Then the Raney nickel is sucked off and the solution is dropped into ice water. The precipitated substance is separated off and washed with CHsOH and then with ether. The practically pure substance can be recrystallized from glycol monomethyl ether.

White crystals of mp: 234 to 236 ° C.

c) 3-N-succinimido-4- (4'-fluorophenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester 31.6 g (0.08 mol) of the amino compound [Example 17b]

are melted together with 20 g of succinic anhydride at 180 to 200 ° C. After 1.5 to 2 hours, the imide is precipitated by adding CH3OH and a little H20. It is recrystallized from glycol monomethyl ether.

White crystals of mp: 291 to 293 ° C.

d) 4- (4'-fluorophenoxy) -3- (l-pyrrolidinyl) -5-sulfamoyl-benzoic acid

34 g of imide [Example 17c)] in 300 ml of abs. Diglyme suspended and 19 ml BF, 3-etherate added. A solution of 5 g NaBH4 in 200 ml abs is then added dropwise at a temperature of 0 to 15 ° C. Diglyme added. Then it is stirred for about 1 hour at 30 to 40 ° C until a clear solution is obtained. The product is precipitated with ice water and immediately saponified with 2N NaOH. The free acid is precipitated from the clear solution in the cold with 2N HCl.

Recrystallization from CHa0H / H „0. Mp: 250 to 252 ° C, light yellow crystals.

Example 18

4- (4'-fluorophenoxy) -3- (3'-methyl-l-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-N- (3'-methylsuccinimido) -4- (4'-fluorophenoxy) -5 -N, N - ethyl dimethylaminomethyleneaminosulfonylbenzoate

The reaction is carried out analogously to Example 17c) with methyl succinic anhydride. The imide precipitated after the reaction is washed with CH3OH and ether after suction filtering. White crystals of mp: 228 to 229 ° C.

b) 4- (4'-fluorophenoxy) -3- (3'-methyl-l-pyrrolidinyl) -5-sulfamoylbenzoic acid

Analogous to example 17d. Recrystallization from CH30H / H20 60:40 or acetonitrile.

Mp: 242 to 243 ° C, light yellow crystals.

Example 19

4- (4'-chlorophenoxy) -3- (3'-methyl-l-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-nitro-4- (4'-chlorophenoxy) -5-N, N-dimethylaminome- methyl aminosulfonyl benzoate A solution of 164 g of 3-nitro-4-chloro-5-N, N-dimethyl-aminomethylene aminosulfonyl benzoic acid methyl ester and 117 g of potassium p-chlorophenolate in 800 ml of freshly distilled DMF is heated under reflux for 2 to 3 hours. The reaction mixture is dropped into 4 times the amount of ice / H 0 with vigorous stirring. The product which precipitates is separated off and boiled with CH3OH / acetone.

Mp: 227 to 228 ° C.

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b) 3-A mino-4- (4'-chlorophenoxy) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester 130 g of the nitro compound [Example 19a)] are in 1 liter of DMF with Raney nickel for 9 hours at 50 atm and 50 ° C io hydrogenated. After the Raney nickel has been filtered off with suction, the solution is concentrated, and the residue is boiled with CH3OH.

White matter of mp: 207 to 208 ° C.

15 c) 3-N- (3'-Methylsuccinimido) -4- (4'-chlorophenoxy) -5-N, N - dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

30 g of the amino compound [Example 19b)] are melted with 27.4 g of methyl succinic anhydride for 2 hours at 190 to 200 ° C. The imide is then precipitated by adding CH3OH and a little HaO and recrystallized from CHaOH.

White crystals with a melting point of 162 to 164 ° C (highly viscous oil that only melts at 197 to 198 ° C).

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b) 4- (4'-Chlorophenoxy) -3- (3'-methyl-l-pyrrolidinyl) -5 - sulfamoylbenzoic acid

15.3 g of imide [Example 19c)] are suspended in 150 ml of absolute diglyme and 8 ml of BF3 etherate are added. A solution of 2.35 g of NaBH4 in 100 ml of abs is then added dropwise at 0 to 10.degree. Diglyme added. The mixture is stirred for an hour at room temperature and then the product is precipitated with water. The crude product thus obtained is immediately saponified with 2N NaOH under reflux. The acid is obtained from the clear, cooled solution with 2N HCl; Recrystallization from CH30H / H20 or acetonitrile.

Light yellow crystals of mp: 257 to 258 ° C.

40 Example 20

4-phenoxy-3- (3 ', 3'-dimethyl-l-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-N- (3', 3'-dimethylsuccinimido) -4-phenoxy-5-N, N -di-45 methylaminomethyleneaminosulfonylbenzoic acid methyl

ester

47 g of 3-amino-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester are melted with 47.9 g of 3,3-dimethylsuccinic anhydride at 180 to 190 ° C. for about 1 to 2 hours. The imide is then precipitated with CH, -OH and a little H..O and recrystallized from CH3OH.

White crystals of mp: 217 to 218 ° C.

55 b) 4-phenoxy-3- (3 ', 3'-dimethyl-1-pyrrolidinyl) -5-sulfamoyI-

benzoic acid

43 g imide [Example 20a)] are abs in 500 ml. Suspended diglyme and added 35 ml of BF3 etherate. Then 60 drops of a solution of 7 g NaBH, in 400 ml abs. Diglyme and stir at 50 to 60 ° C for about 2 hours. The product is precipitated with HaO and immediately saponified with 2N NaOH. The free acid is precipitated from the clear solution in the cold with 2N HCl.

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Recrystallization from CH30H / H20 or acetonitrile. Light yellow crystals of mp: 244 to 246 ° C with decomposition.

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Example 21

4-phenoxy-3- (l-pyrrolidinyl) -5-dimethylsulfamoylbenzoic acid

7.2 g (0.02 mol) of 4-phenoxy-3- (l-pyrrolidinyl) -5-sulf-amoylbenzoic acid are dissolved in 100 ml in NaOH and mixed with 10 ml of dimethyl sulfate. The mixture is stirred well at room temperature. After about 30 minutes, a white, flaky substance precipitates. It is suction filtered and heated with 2N NaOH on the steam bath. After a clear solution has formed, the mixture is allowed to cool and the 4-phenoxy-3- (l-pyrrolidmyl) -5-dimethyl-sulfamoylbenzoic acid precipitates with 2N HCl. The substance can be recrystallized from methanol / water. Yellow fibers with a mp of 214 to 215 ° C.

Example 22

4-phenylsulfoxy-3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid

A solution of 7.8 g of 4-phenylthio-3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid in 130 ml of glacial acetic acid and 20 ml of 30% Ha02 is obtained from R.T. touched. The progress of the reaction is monitored by thin layer chromatography. After 20 hours, the solution is poured into 800 ml of ice water. The precipitate is filtered off, washed with water and dried. Recrystallization from methanol / water gives 4-phenylsulfoxy-3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid; yellow crystals of mp: 142 to 144 ° C with decomposition.

Example 23

4-phenylsulfonyl-3- (l-pyrrolidinyl) -5-sulfamoylbenzoic acid

A solution of 11.8 g (0.3 mol) of 4-phenylsulfinyl-3 - (l-pyrrolidinyl) -5-sulfamoylbenzoic acid in 130 ml of glacial acetic acid and 20 ml of 30% H, 02 is stirred at room temperature for about 30 hours. The progress of the reaction is monitored by thin layer chromatography (toluene / glacial acetic acid 4: 1).

After the reaction has ended, the solution is dropped into ice water, the precipitate formed is suction filtered, washed with water and recrystallized from CH30H / H20.

Yellow crystals of mp: 170 to 172 ° C with decomposition.

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Example 24 (introduction of protection group B)

a) 3-nitro-4-chloro-5-dimethylaminomethyleneaminosulfonyl-io benzoic acid methyl ester (IX)

30 g of 3-nitro-4-chloro-5-sulfamoyl-benzoic acid methyl ester are dissolved in dimethylformamide. Then slowly add 36 ml of thionyl chloride at -10 ° C, allow to come to room temperature and stir for 2 hours. The product precipitates by adding ice water. It is separated off and, if necessary, recrystallized from acetone / CH3OH.

The reaction steps from Example ld) to h) follow. Mp: 168 to 169 ° C.

b) 3-nitro-4-phenoxy-5-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester (X)

3-Nitro-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester (mp. 180 to 181 ° C) is reacted analogously to the example above. The methyl 3-nitro-4-phenoxy-5-dimethylaminomethyleneaminosulfonylbenzoate of mp 193 to 195 ° C. (from CH3OH) is obtained.

The reaction steps from example le) to h) follow.

c) 3-A mino-4-phenoxy-5-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester (XI) 32 g of 3-amino-4-phenoxy-5-sulfamoyl-benzoic acid methyl-

esters (mp. 179 ° C) are dissolved in dimethylformamide and reacted at 50 ° C with 0.11 mol of dimethylformamide-dimethyl-acetal. The mixture is stirred for a further 1 hour and the product is precipitated with ice water. Recrystall. from CH3OH. Mp: 255 to 256 ° C.

The reaction steps from Example 1 f) to h) follow.

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Claims (12)

621776 2nd PATENT CLAIMS 1. Process for the preparation of new heterocyclically substituted 5-sulfamoylbenzoic acid derivatives of the formula I. r ' r ^ n ° 2S VNOz, (X) coor ' 10th W implements; these to compounds of formula XI nh, cooh in what R1 and R2 are hydrogen; X is one of the groups -OR4 or -SR4, where R4 is unsubstituted or substituted by halogen, trifluoromethyl, hydroxy, amino, mono- or dialkylamino, Cj-C ^ alkyl or Cj-C4-alkoxy or alkyl with 1 to 4 Means carbon atoms; and A is an optionally unsaturated alkylene chain with 1 to 3 carbon atoms, which can be substituted by halogen and / or lower alkyl or aryl, mean, and of their physiologically tolerable salts with bases or acids, characterized in that sulfamoylbenzoic acid derivatives of the formula VIII 15 20th h.1 = n02 £ j (XI) coor 3rd reduced, the 3-amino compounds thus obtained with a 25 compound of formula XII 0: 30th X X ir (XII), wherein Z is an oxygen atom or two hydrogen atoms and the symbols L each represent a removable group or together an oxygen atom, to give compounds of the formula XIII (VIII), vno2s- • coor , 3rd 40 wherein Y is a halogen atom; and R3 is hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms 45 mean, nitrided and the compounds of formula IX obtained H2 = N0oIT 50 VN02 ' (XIII) c00r ' (IX), c00r is implemented, the sulfamoyl group in the compounds of the formulas VIII, IX, X, XI or XIII, at the latest in each case in compounds of the formula XIII, by introducing a protective group B of the formula ,8th if one started from a compound of formula VIII, wherein R3 is hydrogen, esterified to corresponding compounds in which R3 is alkyl having 1 to 4 carbon atoms and with a compound XH, in which X has the meaning given for formula I, to Compounds of formula X 60 R- i. : G - K ~, R ^ i where Rs, R9 and R10 denote identical or different lower alkyl groups, where Rs can also represent hydrogen and / or two of the substituents R8, R9 and R10 can also be cyclically linked to one another, protects the resultant Compound of formula XIII 3rd 621776 in the presence of Lewis acids with hydrogen boron or with complex borohydrides to give compounds of the formula XIV ß = A is an optionally unsaturated alkylene chain with 2 carbon atoms, which can be substituted one or more times by halogen, phenyl or lower alkyl. The compounds of formula I are prepared using the method defined in the characterizing part of patent claim 1. From the compounds of the formula I prepared by this process, in which X denotes a group -SR4, corresponding compounds are obtained by oxidation, (XIV) io in which X denotes a group -SOR4 or -S02R4. The compounds of the formula VIII which serve as starting material can be obtained by various processes. Their preparation is particularly simple if one reduces from 15 known sulfamoylbenzoic acid derivatives of the formula unsubstituted in the sulfamoyl group, cleaves group B and group R3 hydrolytically and, if necessary, converts the process products into their physiologically tolerable salts with acids or bases. 2. The method according to claim 1, characterized in that hydrogenated in a compound of formula I obtained in group A existing double bonds. 3. The method according to claim 1, characterized in that in a compound of formula I obtained, wherein A is a halogen-substituted saturated alkylene chain having 2 or 3 carbon atoms, introduces a double bond by eliminating hydrogen halide. 4. A process for the preparation of compounds of the formula I which are substituted in the 4-position by a group -SOR4, characterized in that a compound of the formula I in which X is -SR4 is prepared by the process according to claim 1, and this oxidized. 5. A process for the preparation of compounds of the formula I which are substituted in the 4-position by a group -S02R4, characterized in that a compound of the formula I in which X is -SR4 is prepared by the process according to claim 1, and this oxidized. 6. A process for the preparation of compounds of the formula I in which the symbols R1, R3, X and A have the meaning given in claim 1 and R2 is an alkyl group having 1 to 4 carbon atoms, characterized in that the process according to Claim 1 produces a compound of formula I and alkylated with R2-donating agents. 20th h2NO2S coor ' starts and these are converted into the desired compounds 25 using condensation processes which are largely known from the literature. In this context, the following publications should be cited: J. Org. Chem. 25 (1960) 352-356; Zh. Org. Khim. 8 (1972) 286-291; Liebigs Ann. Chem. 750 (1971) 42; 30 Zh. Org. Khim. 6 (1970) 9 and 1885; B. 94 (1961) 2731-2737; Ang. Ch. 78 (1966) 147-148; Ang. Ch. 80 (1968) 281 to 282; B. 97 (1964) 483 to 489; 35 B. 96 (1963) 802 to 8012; J. Org. Chem. 27 (1962) 4566-4570; Ang. Ch. 74 (1962) 781-782; Doklady Akad.SSSR 145 (1962) 584. The 40 compounds listed below can be used as starting compounds of the formula VIII.