DE2517183A1 - BASIC SUBSTITUTED 5-SULFAMOYL-ANTHRANILIC ACID DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

hoechst 251/183

Corporation

File number: HOE 75 / f 096

Date: April 17, 1975 Dr.HG / W

Basically substituted 5-sulfamoyl-anthranilic acid derivatives and methods of making them

The invention relates to compounds of the general formula I

1 2 wherein R is a hydrogen atom or the methyl group, R and R Hydrogen atoms, optionally branched, unsaturated, alkyl, cycloalkyl or interrupted by oxygen or sulfur Cycloalkylalkyl radicals each having up to 10 carbon atoms, if appropriate by halogen atoms, lower alkyl or alkoxy radicals

substituted phenyl or phenylalkyl radicals with up to 10 ΟΙ?
Atoms, where the radicals R and R, bridged by 0, N or S or by a direct CC bond, can form a 3- to 8-membered heterocycle with the sulfonamide nitrogen, R- is a hydrogen atom or an optionally unsaturated alkyl radical up to 4 C atoms, R a Y ^»r asserstoffatom, an optionally unsaturated alkyl radical having up to 4 carbon atoms, an optionally mono or polysubstituted by halogen atoms, amino groups, or low molecular weight alkyl, alkylamino, dialkylamino or alkoxy benzyl radical, one of the isomeric pyridylmethyl, purylmethyl or thienylmethyl radicals or the group

6 098A4 / 1U2 ~ ² ~

a pyrrolidino, piperidino, hexamethyleneimine,

Morpholino, thiomorpholino or ΪΓ-alkylpiperazino radical and Z one optionally by aliphatic or araliphatic Alcohols with up to 10 carbon atoms esterified carboxyl group, a carbonamide group, which may be one or two times through aliphatic, araliphatic or aromatic radicals each with up to 8 carbon atoms, which are interrupted or bridged by 0, N or S. can be, can be substituted or mean the cyano group, as well as the salts of these compounds with physiological compatible acids and, if Z is a carboxyl group, with physiologically compatible bases.

The invention also relates to processes for the preparation of the 5-sulfamoyl-anthranilic acid derivatives of the general formula T, characterized in that one

a. a compound of the general formula II

with piperazine or N-methylpiperazine, or b. a compound of the general formula III

III

reacts with an amine of the general formula IV,

, iv

where in the general formulas II to IV the radical X is a halogen atom, such as chlorine, bromine or fluorine, the nitro group or an alkyl or arylsulfonylox.yrest, such as

60984 4/1142 ~ ³

show the methane, ethane, benzene or 4-toluenesulfonyloxy radical means and the remaining radicals have the meaning given above,

and if necessary then in the according to a. or b. received Compounds of the general formula I have a cyano group to the carbonamide group or carboxyl group or a substituted one Carboxyl group saponified to form a carboxyl group, a carboxyl group is usually esterified or amidated, an unsubstituted one Carbonacaidgruppe converted into the cyano group by dehydration, benzyl residues bound via K or 0 catalytic hydrogenation splits off if at least one of the radicals R and R to R is a 7, 'hydrogen atom, in the usual way Way alkylated, alkenylated or aralkylated or, if at least one of the radicals R to R is an unsaturated aliphatic radical, double bonds are catalytically hydrogenated, and the process products then with physiologically acceptable acids or, if Z is a carboxyl group, with physiologically compatible bases in their salts or corresponding salts in the free carboxylic acids or piperazine bases convicted.

In the patent application P 24 42 851.1 (HOE 74 / F 263) are antihypertensive effective 3-sulfamoylbenzoic acid derivatives of the general formula

1 2

already described, in which R, R, R and Z largely correspond to the above meanings, but in the 6-position (R) hydrogen, Kalogen or a lower alkyl radical is present.

In a further embodiment of this older invention it has now been found that with this type of connection the antihypertensive Properties, especially with regard to the duration of action, '.veiter can be improved if in the general formula in

6098U / 1U2 '~ ⁴ "

6-position (instead of the remainder R ^) an optionally one or disubstituted amino group is present.

12th

The radicals R and R can, for example, be the methyl or ethyl radical, an allyl, one of the isomeric propyl, butyl, pentyl or hexyl radicals, a 2-methoxyethyl, 2-methylmercaptoethyl, 2-ethoxyethyl, 2-ethylmercaptoethyl, 3-methoxypropyl, Gyclopentyl-, Cyclohexyl-, Gyclohexenyl-, Cycloheptyl-, Cyclooctyl-, Cyclopentylmethyl, tetrahydrofurfuryl radical, the phenyl, Benzyl or one of the isomeric phenylethyl or phenylpropyl radicals, where the phenyl radical is one or more times by Chloratorae, Methyl or methoxy groups can be substituted, the piperonyl, Mean cinnamyl or phenoxyethyl radical. Furthermore, the Group R

for example a pyrrolidino, piperidino, hexamethyleneimino, Morpholino, thiomorpholino, isoindolino, IT-phenyl piperazino- or 4-phenylpiperidino radical.

• 3 »j

The radicals R and R can, for example, methyl, ethyl, allyl

4- or one of the isomeric propyl and butyl radicals, the radical R in addition, for example, one of the isomeric methoxybenzyl, chlorobenzyl, methylbenzyl, dirnethoxybenzyl, dichlorobenzyl, Chloromethoxybenzyl and chloromethylbenzyl residues, the piperonyl residue, one of the isomeric aminobenzyl and dimethylaminobenzyl radicals, the 2-furylmethyl or 2-thienylmethyl radical or one of the mean isomeric pyridylmethyl radicals.

Examples of esters of the carboxylic acids of the general formula I are the methyl or ethyl esters, the isomeric propyl and butyl esters and the allyl and benzyl esters in question. Suitable In addition to the unsubstituted amide, amides are, for example, methyl amide, dimethyl amide, ethyl amide, diethyl amide, the isomeric propyl, dipropyl, butyl and dibutyl amides, the allylamide, the cyclopentyl, cyclohexyl, ϊΤ-methylcyclohexyl, cycloheptyl, Cyclohexylmethyl, N-methylcyclohexylmethyl, tetrahydrofurfuryl, Ii-methyl-tetrahydrofurfuryl and 2-ethoxyethyl

6 0 9 8 U / 1 1 A?

amide, the anilide, N-methylanilide, N-ethylanilide, ΕΓ-benzylanilide, Benzylamide, N-methylbenzylamide, di'benzylamide, diphenylamide and their derivatives substituted in the phenyl radical by chlorine atoms, methyl or kethoxy groups, furfurylamide, IT-Me thy If urfurylamide, the isomeric pyridylmethylamides and U-methy1-pyridylmethylamides, the pyrrolidide, piperidide, morpholide, thiomorpholide as well as the ΪΤ-methyl-, N-benzyl- and N-phenylpiperazid.

The preparation of the starting materials with the general formula II is known in principle from German patents 1,282,239, 1,373,341, 1,396,621, 1,438,339, 1,587,693 and 1,584,918. If the compounds of the general formula II are not described above, they can be prepared analogously to the process variants indicated there. For example, the compounds of the general formula II, in which Z is a free, esterified or amidated carboxyl group and X is a chlorine atom, are obtained by reacting the compounds of the general formula V in which Y is the ITitro group, a chlorine atom or the p-toluenesulfonyloxy radical means with a 3 to 5 molar excess of an amino compound of the general formula IV at temperatures between 100 and 160 ^° C.

To display "of the starting substances of the general formula II wherein Z represents the cyano group, one starts from compounds of the general formula V wherein Y represents a fluorine atom, and the reaction with the base of general formula IV at temperatures between 60 and 120 ⁰ C. the end.

After process variant a), the compounds of the general Formula II reacted with N-methylpiperazine or piperazine, and the end products of general formula I are obtained by nucleophilic substitution of the radical X. With a particular advantage the reaction is carried out with an excess of the piperazine base and about 3 "to 5 molar equivalents are used. In this g

609844/114 2

In this case, you can work without adding a solvent. A. larger excess of base is particularly important if Piperazine is the basic reactant, to a disubstitution to avoid on the piperazine ring. When reacted with 17-methylpiperazine on the other hand, the reaction can also be carried out with equimolar amounts of the reactants with the addition of an indifferent one water-miscible solvents such as ethanol, isopropanol, dimethylformamide, dioxane, tetrahydrofuran, ethylene glycol monoethyl ether or diethylene glycol dimethyl ether.

The reaction temperature is determined to a greater extent by nature

1 2

the radicals R, R and Z influenced. In general, the reactivity of X is on the one hand in the series unsubstituted, monosubstituted, disubstituted sulfonamide group and on the other hand in the series free carboxyl group, carbonamide or carboxylic acid ester group, Kitrilegruppe increases, with the effects of both groups add up. For example the carboxylic acids of the general formula II with unsubstituted sulfonamide groups react only with great difficulty with piperazine bases. Only if X is the particularly mobile fluorine atom does the reaction succeed at temperatures between 120 and 150 C. In free carboxylic acids with a disubstituted sulfonamide group, the introduction of the piperazino radical is much easier. In In this case, the reaction temperatures are 120-150 C, even if X represents the less mobile chlorine atom. Particularly It is easy to introduce the piperazino radical in connection with the general formula II with an esterified or amidated one Carboxyl group.

If the SuIfonamidgruppe is unsubstituted, X represents a chlorine atom and Z is an esterified or amidated carboxyl group, the reaction temperatures are between 120 and 140 ⁰ C. An additional single or double substitution of the sulfonamide group lowers the reaction temperature by about 10 to 2O ⁰ C, Am leichtesten react nitriles of the general formula II, especially when the sulfonamide group is twice sub-

60984A / 1142 " ⁷ "

- ι

is established. In this pall the exchange of a chlorine

. K
Fluorine atom "at temperatures around 70 C.

atoms "already" at temperatures around 100 ⁰ C, the exchange of a

The reaction solution is carried to isolate the end products. advantageously in water and adjusts the mixture with sodium hydroxide solution or hydrochloric acid to the pH value that is the isoelectric Point corresponds to the end product, a. This is approximately between 8.5 and 9 "for end products with a free carboxyl group and approximately between 9 »5 and 10, if in the end products Z a carboxylic acid ester, Carbonamido or titrile group means. In the As a rule, the end products of general formula I immediately separate in crystalline form a "b, especially when carboxyl and SuIfonamidgruppe unsubstituted or low molecular weight substituted are. In the case of end products with a higher molecular weight, it can be advantageous to deposit them directly as an acid salt, as these are usually only slightly soluble in water. It is particularly advantageous to isolate them as hydrochlorides by the reaction solution enters into excess 1 η hydrochloric acid. This isolation method fails if the remainder -N (R R) still contains a second nitrogen atom. It is advantageous to clean the end products by recrystallizing them from water,! »! Ethanol, Ethanol, isopropanol, dioxane, tetrahydrofuran, dimethylformamide, Nitromethane or mixtures of these solvents.

Some of the starting materials with the general formula III are described in patent application P 24 42 851.1 (HOE 74 / F 263). For example, the starting materials of the formula III used with particular advantage, in which X is a chlorine atom, by reacting compounds of the general formula VI

VI

where Z is the cyano group and Y is a chlorine or fluorine atom, with the corresponding piperazine base at temperatures

6098 AA / 1 U2

between 60 and 120 C.

Compounds of the general formula "VI, wherein Z is a free, esterified or amidated carboxyl group means, react with N-methylpiperazine or piperazine only then predominantly under Formation of the starting materials with the general formula, III, if Y represents a fluorine atom. When using these fluorine compounds, the reaction temperatures are between 40 and 100 C.

According to process variant b), the compounds with the general formula III are treated with an amine of the general formula IV implemented. The following amines can be used as reaction partners, for example:

Benzylamine, 2-, 3- and 4-methoxybenzylamine, 2-, 3- and 4-ethoxybenzylamine _? 2-, 3- and 4-chlorobenzylamine, 2-, 3- and 4-methylbenzylamine, 2,4-di-ethoxybenzylamine, piperonylamine, 3, 4,5-trimethoxybenzylamine, 2-chloro-4-niethoxybenzylamine, 2,4-dichlorobenzylamine, 2 -Methyl-4-chlorobenzylamine, 4-bromobenzylamine, 3,5-dimethylbenzylarain, 2-, 3- and 4-aminobenzylanine, 2-, 3- and 4-dimethylaminobenzylamine, N-methylbenzylamine, N-ethylbenzylamine, N-isobutylbenzylamine, 2 -Chlor-N-methylbenzylamine, 4-methoxy-N-methylbenzylamine, 4-dimethylamino-N-methylbenzylamine, 2-, 3- and 4-pyridylmethylamine, 2-, 3- and 4-5Γ-methylpyridylmethylamine, 2-furylmethylamine, IT -Me thy 1-2-fury line thy lamin, 2-thienylmethylamine, N-methyl-2-thienyl-methylamine, methylamine, dimethylamine, ethylamine, diethylamine, the isomeric propyl, dipropyl, butyl and dibutyl amines, allylamine, diallylamine , Pyrrolidine, piperidine, hexamethyleneimine, llorpholine, thiomorpholine, N-methylpiperazine, U-ethylpiperazine and ΪΓ-butylpiperazine.

The reaction temperatures required for the implementation

lie between 80 and 150 ⁰ C, where for the relationship between

1 ? Reaction temperature and the nature of the radicals Z, X and SO ₂ N (RR)

in the same way those explained in procedure a) Dependencies apply. The nature of the base also has a certain influence on the reaction temperature. Easiest to respond the cyclic secondary bases, such as morpholine and N-methylpiperazine, the benzylanines a little heavier,

6 0 9 8 U kl 1 U 2 - S -

the pyridyl, furyl and thienyl methylamines, as well as the noncyclic aliphatic secondary amines, least of all the primary aliphatic amines.

It is also advantageous to use process variant Td) an excess of the "basic reactant and works without the addition of a solvent. However, you can also use a smaller excess, down to a molar equivalent of the base, work with the addition of an inert solvent. Again, those described under process variant a) come as such Solvent in question. The work-up of the reaction solution and the purification of the end products are also carried out advantageously as described there.

The process products of the general formula I obtained can subsequently be modified in many ways.

For example, a free carboxyl group can be esterified or amidated in the usual way, and a cyano group can be converted into a carbonamide group or saponify carbonamides or carboxylic acid esters to give the corresponding carboxylic acids.

To esterify the carboxylic acids, they can be converted into the carboxylic acid chloride hydrochloride using thionyl chloride, for example and react this with an excess of the alcohol in question. Also the implementation of the alkali salts of the relevant Carboxylic acids with corresponding bromides or sulfuric acid esters in dimethylformamide are advantageous in many cases Esterification method. Amides are obtained from the carboxylic acids, for example via the above-mentioned carboxylic acid chloride hydrochloride or by aminolysis of corresponding activated esters, such as the cyanomethyl ester or the p-nitrophenyl ester.

The conversion of esters, amides or nitriles of the general formula I into the corresponding carboxylic acids is advantageously carried out with dilute sodium or potassium hydroxide solution, the partial saponification of a nitrile to the amide advantageously with dilute salt

609844/1 142 - 10 -

or sulfuric acid under reflux axis.

The subsequent hydrogenation of olefinic double bonds in the radicals R ″ to R of the process products is advantageous by catalytic hydrogenation in the presence of Raney nickel "Carried out at increased pressure. Should subsequently be carried out using oxygen or nitrogen-bonded benzyl radicals are eliminated, hydrogenation is advantageously carried out in the presence of palladium in the Shaking duck. Benzyl residues on the sulfonamide nitrogen remain under these conditions intact. Suitable solvents for these hydrogenations are, for example, methanol, ethanol, tetrahydrofuran and dioxane.

1 2 ¹ ^ 4-

Should one or more radicals R, R, R, R or R subsequently are introduced into compounds of the general formula I, these are added in the customary manner and, if appropriate, in stages with the halides or sulfonic acid esters corresponding to these radicals, such as benzyl bromide, allyl bromide, Ethyl iodide or dimethyl sulfate.

The products of the process are converted into the corresponding salts, if appropriate with a neutralization equivalent a base or one to two IT neutralization equivalents of an acid; also the conversion of these salts into the free ones Links.

For example, the free carboxylic acids can be removed by dissolving them in the equivalent amount of an aqueous alkali metal or alkaline earth metal hydroxide solution or an aqueous amine solution and subsequent freeze-drying in the corresponding alkali, alkaline earth or transfer ammonium salts.

The corresponding acid salts, for example the mono- and dihydrochloride, the neutral and acidic sulfate, the acetate, the p-toluenesulfonate, the amidosulfonate or the Get maleate. These salts can also be prepared in organic solvents, for example by introducing gaseous HCl in a solution of the free compound in vinegar

609844/1 142 -11.

ester, acetone, dioxane or ethanol, the corresponding mono- or dihydrochloride usually separating out in crystalline form.

In addition to the process products mentioned in the examples, for example the following "compounds according to the invention Process are produced:

2-Benzylamino-4- (4-methylpiperazin-1-yl) -5-sulfamoylbenzoic acid-ethylamide, -dimethylamide, -pyrrolidide, -morpholide, -isobutylamide, -furfurylamide, -N-methyIfurfurylamide, -tetrahydrofurfurylamide, -2-ether, -Diethylamide, -2-ethoxyethylamide, -methyl ester, -n-butyl ester and benzyl ester, 2 ~ Benzylamino-4- (4-meth7 / lpiperazin-1-yl) -5-methylsulfamoyl-benzoic acid methyl ester, -isobutyl ester, -allyl ester, - Benzyl ester, amide, methyl amide, diethyl amide, morpholide, piperidide, benzyl:, rlaTiiid, -N-methylanilide, allylamide and 2-ethoxyanilide, 2-benzylamino-4- (4-methyl-piperazine-1- yl) ~ 5-dimethylsulfamoylbenzoic acid-ethyl ester, -n-propyl ester, -allyl ester, -benzyl ester, -cyclohexyl ester, -dimethylamide, -cyclohexylamide, -sl ± j ± · -

araid, -4-chloroanilide, -4-methoxybenzylamide, -diethylamide _f -IT-methylf urylamide, -4-pyridylmethylamide, -2 ~ ethoxyeth: / l-amide and -xT-methylbenzylamide, 2-benzylamino-4- (4 -methylpiperazin-1 -yl) 5-inorpholinosulfonylbenzoic acid methyl ester, allyl ester, nbutyl ester, cyclohexyl ester, benzyl ester, amide, methyl amide, dimethyl amide, diethyl amide, cyclohexyl amide, pyrrolidide, amidorphylmethyl, -3- , -3-hydroxypropylamide, -IT-methylanilide, -benzylamide, -3-methoxyanilide and -furfurylamide, 2-benzylamino ~ 4- (4-methylpiperazin-1-yl) -5-pyrrolidinosulphonylbenzoic acid, 2-benzylamino-4- ( 4-methylpiperazin-1-yl) -5-pyrrolidinosulfonylbenzoic acid ethyl ester, -n-propyl ester, -benzyl ester, -amide, -dimethylamide ,. -ethylamide, -pyrrolidide, -morpholide, -N-methylbenzylamide, -cyclohexylamide and -allyl-amide, 2-benzylamino-4- (4-methylpiperazin-1-yl) -5-diethylsulfamoylbenzoic acid, 2-3enzylamino-4- (4 -methylpiperazin-4-yl) ~ 5-diethylsulfamoylbenzoic acid ethyl ester, -n-butyl ester, -benzyl ester, -amide, -dimethylamide, ethylamide, morpholide, -thiomorpholide, -cyclohexylmethylamide. anilide, benzylamide and furfurylamide, 2-benzylaniino-4- (4-methylpiperazin-1-yl) -5-n-propylsulfamic! -benzoic acid, 2-benzylamino-4- (4-methylpiperazin-1-yl) -5 -N-methylbenzylaminosulfonyl-

60984 A / 1 U2 "

benzoic acid, 2- (2 -4- (4-methyl-piρerä.zin-1-yl) -5-S13l £ amoylbenzoic acid G-benzyl ester, amide, methyl amide, dimethyl amide, morphlide, n-butyl amide and anilide, 2 - (2-Purylmethylamino) -4- (4-methyl-piperazin-1-yl) -5-dimethylsulfamoylbenzoic acid, 2- (2-pyridylmethylamino) -4- (4-methylpiperazin-1-yl) -5-dimethylsulfamoyrbenzoic acid, 2 - (3-Pyridylmethylamino) -4- (4-methylpiperazin-1-yl) -5-dimethylsulfamoylbenzoic acid, 2- (4-pyridylmethylamino) -4- (4-methylpiperazin-1-yl) -5-dimethyls ⁱ alfamoylt> enzoic acid, 2- (2-methoxy "benzylamino) ~ 4- (4-methylpiperazin-1-yl) -5-dimethylsulfamoylbenzoic acid, and the corresponding -" ethyl benzoate, benzoic acid amide and dimethyl-benzoic acid, 2 -Piperidino-4- (4-methylpiperazin-1-yl) -5-dimethylsulfamoyl "benzoic acid, as well as the corresponding -benzoic acid ethyl ester, -Tdenzoic acid amide and -" benzoic acid dimethylamide, 2-diethylamino-4- (4-methylpiperazin-1-yl) - 5-dimethylsulfamoyl'benzoic acid, and the corresponding - "ethyl benzoate, -" benzoic acid eamide and benzoic acid dimethylainide, 2-n ^ butylamino-4- (4-methylpiperazin-1 ~ yl) -5-dimethylsulfamoyl- "benzoic acid, and the corresponding -benzoic acid ethyl ester, -benzoic acid amide and -benzoic acid dimethylainide, 2- (2-furylmethylamino) - 4- (4-methylpiperazin- ^: l-yl) -5-dimethylsulfamoylbenzoic acid methyl ester, ethyl ester, isopropyl ester, benzyl ester, amide ', methyl amide, dimethyl amide, pyrrolidide, morpholide, allylamide, diethyl amide, -cyclohexylamide and furfurylamide, 2- (2 ~ pyridylmethylamino) -4- (4-in.e thylpiperazin-1 -yl) -5-dimethylsulfamoylbenzoic acid ethyl ester, isobutyl ester, benzyl ester. -amid, -methylamide, -dimethylamide, -morpholide and -pyrrolidid, 2- (3-pyridylmethylamino) -4- (4-methylpiperazin-1-yl) -5-dimethylsulfamoylbenzoic acid ethyl ester, -amid, -äthylamid, -diethylamide, -furfurylamide, -IT-methylbenzylamide and -2-ethoxyethylamide, -2- (3-pyridylmethylamino) -4- (4-methylpiperazin-1-yl) -5-dimethylsulfamoylbenzoic acid ethyl ester, -n-propyl ester, -n-butylamide, -allylamide, -cyclohexylamide, -benzylamide and IT-methylanilide, 2- (2 ~ pyridylmethylamino) -4- (4-methylpiperazin-1-yl) ~ 5-sulf amoylbenzoic acid, as well as the corresponding -benzoic acid ethyl ester, -benzoic acid amide and - benzoic acid dimethylamide, 2- (3-pyridyl-

60984A / 1142 " ¹³ "

methylamino) -4- (4-methylpiperazin-1 -yl) -5-sulf amoylbenz ο e acid e, as well as the corresponding -benzoic acid ethyl ester, -benzoic acid amide and - "benzoic acid dimethylamide, 2- (4-pyridylmethylamino) -4- (4-methylpiperazin-1-yl) -5-sulfamoylbenzoic acid, as well as the corresponding ethyl benzoate, benzoic acid amide and dimethyl benzoic acid, 2-N-methylbenzylamino-4- (4-methylpiperazin-1-yl) -5-sulfamoylbenzoic acid, as well as the corresponding ethyl benzoate, benzoic acid amide and dimethyl benzoic acid, 2-lT-methylbenzylamino-4- (4-methylpiperazin-1-yl) -5-dimethylsulfamoylbenzoic acid, as well as the corresponding -benzoic acid ethyl ester, -benzoic acid amide and -benzoic acid dimethylamide, 2- (2- ' Methoxybenzylamino) -4- (4-meth7 / lpiperazin-1-yl) -5-sulfamoylbenzoic acid, and the corresponding ethyl benzoate, benzoic acid amide and dimethyl benzoic acid, 2- (3-methoxybenzylamino ~ 4- (4-methylpiperazin-1-yl) -5-sulfamoylbenzoic acid, as well as the corresponding ethyl benzoate, benzoic acid amide and dimethyl benzoic acid, 2- (4-methoxy-benzylamino) -5-sulfamoylbenzoic acid, Ethyl benzoate, benzoic acid amide and dimethyl benzoic acid, 2-piperonylamino-4- (4-methylpiperazine-1 ~ yl) -5-sulfamoylbenzoic acid, -benzoic acid ethyl ester, -benzoic acid amide, -benzoic acid dimethylamide and benzoic acid aorpholide, 2,4-bis ~ (4-methylpiperazin-1-yl) -5-sulfamoylbenzoic acid, -benzoic acid ethyl ester, -benzoic acid amide, -benzoic acid dimethylamide and -benzoic acid piperidide, 2-piperonylamino-4- (4-methylpiperazin-1-yl) -5-dimethylsulfamoylbenzoic acid, -benzoic acid ethyl ester, -benzoic acid amide and -benzoic acid pyrrolidide, 2- (2-thienylmethyl ~ amino) -4- (4-methylpiperazin-1-yl) -5-sulfamoylbenzoic acid, -benzoic acid ethyl ester, benzoic acid amide and benzoic acid dimethylamide.

The salts of the compounds according to the invention for therapeutic use are preferably the acid salts, such as, for example the monohydrochloride, the neutral or acid sulphate, the primary, secondary or tertiary phosphate, the methane or p-Toluenesulfate or the salt of an organic acid such as the maleate or citrate in embossing. Pur special However, alkali salts, preferably the monosodium salt, can also be used or monopotassium salt may be suitable.

609844 / 1H2 -H-

As animal experiments on hats and dogs have shown, the compounds according to the invention have therapeutically valuable hypotensive properties Properties.

Because the therapeutic index is very high and not undesirable Side effects have been observed, the compounds according to the invention are valuable agents for the treatment of high blood pressure, especially essential hypertension.

In particular, tablets, coated tablets, capsules and suppositories can be used as preparation forms for the preparations. They can contain between 10 and 500 mg of the active ingredient per dosage unit, either in free form or in the form of the abovementioned acid or alkali salts, the proportion of fillers and carriers being up to 90 ^c / o of the preparation.

Aqueous solutions are primarily used for intravenous administration the acid salts of the compounds according to the invention, the may optionally also contain solubilizers, in the form of ampoules with a content of 2 to 50 mg of the relevant Active ingredient in question.

All of these preparations can contain other therapeutically active components that are suitable for the treatment of high blood pressure, for example contain saluretics.

609844 / 1U2 - «5 -

Example 1:

2-Benzylamino-4- (4-methylpiperazin..1-yl) -5-sulfamoyl-benzonitrile

31 j 5 g of 2-chloro-4- (4-methylpiperazin-1-yl) -5-sulfamoyrbenzonitril (0.1 mol) are heated with 60 al benzylamine 2 hours with stirring at 15O ⁰ C. The reaction solution, cooled to 100 ^° C., is then introduced into 0.8 1 1N HCl and precipitated by-products are filtered off. When the filtrate is adjusted to pH 9.0 with 5N NaOH, the end product separates out in crystalline form. It is filtered off with suction, washed with Y / ater and recrystallized from ethanol. Yield 19.5 g (50 1 ° of theory), mp. 197 ⁰ C

Example 2;

2-Benzylarai n o -4- ( ^Δ -methylpiperazin-1-yl) -5-sulfamoyl-benzoic acid

19) 3 g of 2-benzylamino-4- (4-methylpipera2in-1-yl) -5 "sulfamoylbenzonitrile (0.05 mol), prepared according to Example 1, are refluxed with 0.5 l of 2N NaOH for 6 hours. After standing A little undissolved material is filtered off overnight at room temperature and the filtrate is adjusted to pH 6.5 with glacial acetic acid. After standing for one hour at room temperature, the crystalline saponification product is filtered off with suction, washed with water and dried on the steam bath. It is then present as tetrahydrate 16.8 g ( $ 71> d.Th.), dec. -P. 227 - 228 ⁰ C.

example

2-Benzylamino-4- (4-methylpiperazin-1-yl) -5-sulfamoyl-benzarflid hydrochloride

19.3 g of 2-benzylamino-4- (4-methylpiperazin-1-yl) -5-sulfamoylbenzonitrile (0.05 mol) are heated with 0.4 l of NaOH for 1 hour on the steam bath with stirring. It is then cooled to room temperature and, after standing overnight, the crystalline precipitate is filtered off with suction. The entire precipitation is carried out with 0 _r 3 1 1n HCl * r

6098U / 1 U2

Stirred at 60 ^° C. for 10 minutes. It is then cooled to room temperature, the crystalline precipitate is filtered off with suction, recrystallized from water and dried on the steam bath, yield 12.8 g (58 $> of theory), decomposition P. 240 - 241 ° 0.

Example 4s

Ethyl 2-Benzylamino-4- (4-methylpiperazin-1-yl) -5-sulfamoyrbenzoic acid, hydrochloride

37.0 g of 2-benzylamino-4-chloro-5-sulfaτnoylbenzoic acid ethyl ester (0.1 mol) are stirred with 50 ml of NI.lethylpiperazin at 130 ° C. for 2 hours. The reaction solution is then introduced into 0.6 1 of water, the crystalline precipitate is filtered off with suction, it is dissolved in 100 ml of methanol with heating and the end product is precipitated by adding 0.2 1 of 1N HCl.
Yield 40.0 g (85 $> of theory), mp 230 -. 231 ⁰ C

Example 5:

2-Benzylamino-5-dimethylsulfamoyl-4- (4-methylpiperagin-1-yl) -benzoic acid ethyl ester hydrochloride

From 39.7 g of 2-benzylamino-4-chloro-5-dimethylsulfamoylbenzoic acid ethyl ester (0.1 mol) and 60 ml of NI / Iethylpiperazine, analogous to Example 4.
Yield 39 »5 F, (79 # of theory), melting point 248-250 ° C and decomp.

Example 6;

2-Benzylamino-5-dimethylsulfamoyl-4- (4-methylpiperazin-1-yl) -benzoic acid

24.9 g of 2-benzylamino-5-dimethylsulfamoyl-4- (4-methylpiperazin-1-yl) -benzoic acid ethyl ester hydrochloride (0.05 mol) are refluxed with 0.3 1 1N NaOH for 2 hours. The one to about 50 ° The cooled and filtered reaction solution is adjusted to pH 6.0 with 50-pros, acetic acid and left laughing at room temperature.

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crystallize at temperature. After suctioning off and washing with water, it is "dried at 60 in vacuo. Yield 18.0 g (83 $> of theory). Dec. point 271 ° C."

Example 7:

Ethyl 2-amino-5-dimethylsulphonyl.4- (4-methylpiperazin -1-yl) benzoate hydrochloride

24.9g of 2-benzylamino-5-dimethylsulfamoyl-4- (4-methylpiperazin ~ i-ylj-benzoic acid ethyl ester hydrochloride (0.05 mol) are added to a mixture of 0.3 1 of tetrahydrofuran and 0.1 1 of water in the presence of Freshly prepared palladium black is hydrogenated in a shaking duck at room temperature.After uptake of 1.2 l of hydrogen within about an hour, the hydrogenation comes to a standstill. The catalyst is separated off, the filtrate is vigorously evaporated and the concentrate is taken up in 0.2 l of water . Stach two hours of standing at room temperature is filtered, the crystalline precipitation and dried at 100 ⁰ G.
Yield 14.5 g ( $ 79> of theory), decomposition P. 262 ⁰ C.

Example 8:

5-Dimethylsulfamoyl-2, -4-bis- (4-methylpi ~ perazin-1 -yl) -benzoic acid ethyl ester

39.0 g of 4-chloro-5-dimethylsulfamoyl-2- (4-methylpiperazin-1-yl) -benzoic acid ethyl ester (0.1 mol) with a melting point of 115 ° C. are refluxed with 40 ml of N-methylpiperazine for 2 hours and the reaction mixture subsequently introduced into 0.4 1 of water. The crystalline end product is separated after three hours of standing at room temperature and dried on the steam bath. The dihydrate is then present. Yield 33.2 g (79 # of theory). M.p. 106-108 ⁰ G.

- 18 4/1142

Example 9?

5-Dimethylsulfamoyl-2 ₁ 4-bis (4-methylpiperazin-1 -yl) benzoic acid

24.5 g of 5-dimethylsulfamoyl-2,4-bis (4-methylpiperazin-1 ~ yl) -benzoic acid ethyl ester dihydrate from Example 8 (0.05 mol) are mixed with a mixture of 0.3 1 2N NaOH and 60 ml of dioxane refluxed for 1 hour. It is then cooled to room temperature, the solution is adjusted to pH 8.5 with 5N HOl, evaporated completely in vacuo and the residue is extracted with 2 × 0.2 l boiling ethanol. The combined ethanol solutions are evaporated and the residue is recrystallized from nitromethane. After drying on the steam bath, the compound still contains 1 molar equivalent of crystal ethanol.
Yield 18.0 g (76 fo of theory), Zers.-P. 227-229 ⁰ C.

Example 10:

2-Benzylamino-4- (4-methylpiperazyn -1-yl) -5-morpholinosulphonyl- benzoic acid ethyl ester hydrochloride

43.9 g of 2-Benzylaminc-4-chloro-5-morpholinosulf onylbenzoesäureäthrylester (0.1 mol) of mp. 118 ⁰ C is stirred with 80 ml of N-methyl-piperazine for 2 hours at 125 ⁰ C. The excess base is then drawn off in vacuo and the residue is triturated with 0.4 1 1N HCl. The final product, which is deposited in crystalline form, is filtered off with suction, washed with water and recrystallized from isopropanol while still moist.
Yield 43.0 g (80 jo theory), mp 186 -. 187 ⁰ C

Example 11:

2-Benzylamino -4- (4-m- ethylpiperazin-1-yl ) -5-m orpho linosulfonyl - benzoic acid

41.1 g of 2-benzylamino-4-chloro-5-morpholinosulfonylbenzoic acid (0.1 mol), with a melting point of 224-225 ° C., are mixed with 100 ml of OT methylpiperazine Heated under reflux for 15 hours. The following is

6098U / 1U2 ^ - »> -

the excess base is stripped off in vacuo, the residue is taken up in 0.5 l of water and the filtrate is adjusted to pH 8.0 with glacial acetic acid. After standing for two days at room temperature, the crystalline precipitate is filtered off with suction and the moist product is boiled for 5 minutes with 0.4 1 50% ethanol, most of which remains undissolved. After cooling to room temperature, it is suctioned off and dried on the steam bath .
Yield 41.5 g (87 l = of theory), decomposition P. 235-257 ⁰ C.

Example 12;

Ethyl 4- (4-methylpiperazin-1-yl) -2-taorpholino-5-morpholinosulfonylbenzoate

In the solution of 110 g of 4-chloro-2-morpholino-5-morpholinosulfonylbenzoic acid (0.28 mol) in 0.3 l of dimethylformamide, 20 g of anhydrous potash are added at 90 ° C. with stirring and added dropwise as soon as solution has occurred , then add 50 ml of diethyl sulfate with the same Teitiperat. The mixture is then stirred for a further 30 minutes at room temperature and the hot reaction solution is then introduced into 3.0 l of water. The amorphous precipitate is separated, washed with 250 ml of N-methylpiperazine are added and the mixture heated for 2 hours with stirring at 120 ⁰ C, laughing following the excess base is eliminated in vacuo, the residue triturated with 1.5 1 of water, the crystalline precipitate filtered off and from 50 percent Recrystallized ethanol.
Yield 62 g (46 % of theory), Schmo. 150 ⁰ C.

Example 13:

4- (4-methylpiperazin., 1-yl) -2-morpholino-5-trxorpholinosulfon yl benzoic acid

39 »1 g of 4-chloro-2-morpholino-5-morpholinosulfonyl benzoic acid (0.1 mol) with a melting point of 224-226 ° C. are mixed with 100 ml of TT-methylpiperazine Heated to reflux for 6 hours and the excess base subsequently stripped off in vacuo. You take the residue with 0.3 1 of water, adjust the pH of the solution to 8.0 and

609844/11/4? -20

then add the same volume of ethanol to them. After standing overnight at room temperature, the crystalline precipitate is filtered off with suction, boiled with water and dried on the steam bath. The compound is then in the form of a dihydrate. Yield 56.2 g (75 $ of theory), decomposition P. 246 - 248 ⁰ G.

Example 14:

2,4-Bis- (4-methylpiperazin-1-yl) -5-morpholinosulfonyl- benzoic acid ethyl ester

36.8 g of 2,4-dichloro-5-morpholinosulfonylbenzoesäureäthylester (0.1 mol) of mp. 89 - 90 ⁰ C are warmed for 2 hours at 125 G with 80 ml of N-methylpiperazine. The excess base is then drawn off in vacuo and the residue is recrystallized from water. After drying at 40 ° / 15 Torr over KOH, the compound is in the form of a dihydrate. Yield 4L.0 _g ($ 77> d.Th.J, mp 75 -. 80 ^0C

example

2-Amino-4- (4-methylpiperazin-1-yl) -5-morpholinosulfonyl- benzoic acid ethyl ester

10.8 g of 2-benzylamino-4- (4-methylpiperazin-1-yl) -5-morpholinosulfonyl-benzoic acid ethyl ester hydrochloride (0.02 mol) from Example 10 are in a mixture of 0.2 l of tetrahydrofuran and 20 ml Water is hydrogenated in the presence of palladium black in the shaking duck. The uptake of hydrogen has ended after 2 hours. The catalyst is filtered off, the filtrate is evaporated to a syrup and the concentrate is shaken with 150 ml of 1N bicarbonate solution. The crystalline precipitate is filtered off with suction, washed with water and dried on the steam bath. Yield 7.1 g (86 jo theory), mp 163 -. 170 ⁰ G.

609844 / 1U2 " ²¹

'2517163

Example 16:

2-Amino-4- (4-methylpiperazin-1-yl) -5-sulfamoyl-benzoic acid ethyl ester hydrochloride

9.4 g of ethyl 2-benzylamino-4- (4-methylpiperazin-1-yl) -5-sulfamoylbenzoate hydrochloride (0.02 Hol), from Example 4, are, analogously to Example 15, hydrogenated with palladium black and the Treated evaporation residue with 150 ml of 1N HCl. The crystalline precipitate is filtered off, washed with water and put on the steam bath dried.

Yield 7.0 g (92 J = of theory), melting point 233 ° C. and decomp.

Example 17;

2,4-bis- (4-methylpiperazin-1-yl) "5-raor-: holinosulfonylbenzoic acid

26.6 g of 2,4-bis- (4-methylpiperazin-1-yl) -5-morpholinosulfonylbenzoic acid ethyl ester dihydrate (0.05 mol) from Example 14 are saponified with ITaOH, analogously to Example 9. Final cleaning by recrystallization from ethyl acetate-petroleum ether. The end product contains 2 molar equivalents of crystal ethanol. Yield 20.5 g ( $ 72> of theory), decomposition P. 179-18Q ⁰ O.

Example 18:

2- Amino-4 ~ (4-aiethylpiperazin-1-yl) -5-nor "oholinosulfony! Benzoic acid

23.8 g of 2-benzylamino-4- (4-methylpiperazin-1-yl) -5-morpholinosulfonylbenzoic acid (0.05 mol) from Example 11 are dissolved in a mixture of 0.8 1 ethanol and 0.15 1 1n HGl in the presence Hydrogenated by palladium black in the shake duck,! fold uptake of 1.2 liters of hydrogen, the hydrogenation comes to a standstill. The catalyst is filtered off and the filtrate is evaporated. Of the The residue dissolves clearly in 150 ml of Y / water. After setting pH 9 with 2N NaOH and standing for four days, crystals have separated out. Lian sucks off and dries on the steam room. the

6098U / 114 2 - 22 -

- ²² -. 2517163

Compound is then used as "prior monohydrate yield 15.3 g (76 jo theory), mp 268 -.. 270 ° dec 0 u..

Example 19?

) -sulfapioylbenzonitrile

23.2 g of 2-amino-4-chloro-5-sulfamoylbenzonitril (0.1 mole) are stirred with 70 ml of ET-methylpiperazine for 2 hours at 12O ⁰ C. The reaction mixture is then stirred into 0.7 l of water, the crystalline precipitate is filtered off with suction and washed well with water. After drying on the steam bath, it is recrystallized from nitromethane. After drying at 60 ° 0, the dihydrate is present. Yield 19.4 g (59 $ of theory), mp. 247 ⁰ C

Example 20;

2-Benzylamino -4 "(4-methylpiperazin-1-yl) -5-methylsulamylbenzoic acid ether ester

38.3 g of 2-benzylamino-4-chloro-5-methylsulfamoylbenzoic acid ethyl ester (0.1 mol) with a melting point of 163-164 ° O are stirred with 80 ml of N-methylpiperazine at 125 ° C. for 2 hours. The reaction mixture is then introduced in 0.6 1 V / water, the crystalline precipitate is filtered off with suction, washed well with water and recrystallized from methanol.
Yield 36.0 g (81 $> of theory), mp. 140 - 142 ⁰ O.

Example 21:

2-Benzylamino-4- (4-methylpiperazin-1-yl) -5-methylsulfamoylbenzoic acid hydrochloride

22.3 g of ethyl 2-benzylamino-4- (4-methylpiperazin-1-yl) -5-methylsulfamoylbenzoate (0.05 mol) are refluxed with 0.4 1 of 2N NaOH for 2.5 hours. Then you wear the clear reaction solution in 0.6 1 2N HCl, sucks the gelatinous

6098AA / 1U2 -23-

Precipitation, washed with water and crystallized from ethanol. Yield 12.5 R ( 59 # of theory), Zers.-P. 213-215 ° C

Example 22:

2 ~ Benzylamino-5- (2-methoxybenzylsulfamoyl) -4- (4-methyl-piperazin -1- yl) -benzoic acid

46.1 g of 2-benzylamino-4-chloro-5- (2-methoxybenzylsulfamoyl) benzoic acid (0.1 mol) with a melting point of 177-179 ° C. are stirred with 150 ml of IT methylpiperazine at 135 ° C. for 3 hours. The reaction solution is then stirred into 1.0 1 of water, the mixture is made with conc. HCl to pH 7 and allowed to crystallize at room temperature over a period of 1 hour. The precipitate is washed well with water and subsequently freed from by-products by boiling with 0.3 l of ethanol.
Yield 23.5 g (45 $> of theory), decomposition P. 240 - 242 ⁰ C.

Example 23:

2-Benzylamino-5- (3- chlorobenzylsulfamoyl) -4- (4- methylpiperazin-1- yl) -benzoic acid ethyl ester hydrochloride

49.4 g of 2-benzylamino-4-chloro-5- (3-chlorbenzylsulfamoyl) -benzoic acid ethyl ester (0.1 mol) of mp 129 -. 130 ⁰ O are mixed with 100 ml of N-methylpiperazine for 2 hours at 125 - 13O ⁰ C touched. When the reaction solution is introduced into 1.5 liters of 1N HCl, the hydrochloride of the end product crystallizes immediately. Purification by recrystallization from methanol.
Yield 46.8 g ($ 79 of theory), melting point 229-231 ° C

Example 24:

2-Benzylamino-5- (3-chlorobenzylsulfamoyl) -4- (4-methylpiperazine - 1-.yl) -beiizoic acid hydrochloride

29 »7 g of 2-benzylamino-5- (3-chlorobenzylsulfamoyl) -4- (4-methyl-

609844/114 2 ~ ²⁴ "

2517163

ethyl piperazin-1-yl) benzoate hydrochloride (0.05 mol) from Example 23 are refluxed for one hour with a mixture of 0.6 1 2N NaOH and 0.2 1 dioxane. After cooling down Little undissolved material is filtered off with suction to room temperature, the end product is precipitated with 5N HCl at pH 1 and crystallized out Methanol around.

Yield 21.5 g ( $ 76> d.Th «), melting point 18O ⁰ G and evolution of gas.

609844/1 1 42

2517163

Example 25

2- (2-? Ur ; 7lmethylamino) -4- (M- i? J3th7 / -lpiperazin-1-yl) -5-sulf anoylbenzoic acid methyl ester .

36 g of 4-chloro-2- (2-furylne th3-lanu.n0) -5-sulfamoylbenzoic acid ethyl ester (0.1 mol) are stirred with 70 ml of IT-ilethylpiperazine at 130 ° C. for 3 hours. The reaction mixture, cooled to 30 ° G, is then diluted with 0.15 liters of ethanol and added to 0.6 liters of water. The end product separates out immediately in crystalline form and is purified by recrystallization from ethanol.
Yield 20.6 g (49? Q d.gh.), mp. 140 ° G

Example 26

2- (2-rurylmethylarr: ino) - ^ - ( 4-yneth ^ lpiperagin-1-yl ) -5-sulfanoylbenaoic acid

8.5 g of 2- (2-Purylmnethylamino) -4- (4-meth3 ^ lpiperazin-1-yl) -5-sulfainoylbenaoic acid ethyl ester from Example 25 (0.02 KoI) are refluxed with 0.3 1 2N EaOH for 1 hour , then the clear reaction solution is adjusted to pH 8 at He.uniteniperatur with 2N HGl, the crystalline filling is sucked in and washed with water. Final cleaning by boiling with 100 ml of methanol, in which the reaction product is also soluble in the VJärne kauri.
Yield 6.7 g (85 ff of theory), Zers.-P. 255 ° G

Ex iel 27

bsnzoic acid e- r orpholide

43.9 S 2-benzylamino ^/ -! - chloro-5-diraethylsulfamoylbenzoesäuremorpholid (0.1 koi) are heated with 100 ml iT Hethylpiperasin 3 hours back flowing and the re action in solution below 0.7 1 v / ater was added. The crystalline precipitated crude product is purified by recrystallization from ethanol.

Yield 35.0 g (70 # d.gh.), Scto p. 197- IQ8 ⁰ C

609844 / 1H2

Example 28

2-Benzylamino-5-dineth7lsulfamoyl-4- (4-r: iethylpiperazin-'l ~ yl ) -benzoic acid amide

36.3 g of 2-benzylamino-l-chloro-5-dimeth3 ^ 1sulfamoylbenzoesäureasiid with a melting point of 193 ° C v / ground with 90 ^{ml of} li-kethylpiperazine refluxed for 8 hours, the reaction product by pouring the reaction solution into 1 1 V water is deposited in crystalline form and, after drying, is stabilized from ethyl acetate. Yield 26.0 g (-SO y> d.gh.), melting point 225-227 ° 0

Example 29

2-Benzyl amino- '^ - (4- ir-et h.ylpi perazin-i -yl) -5-rr.or pholinosulx onylbenoic acid

3955 g of 2-benzylamino-4-chloro-5-norpholinosulfonylbenzoic acid (0.1 mol) are refluxed with 120 ml of IT-methylpiperazine for 6 hours, then the clear reaction solution is stirred in 0.7 1 V / water and decanted off the amorphous deposited Eeaktioiioprodukt. When heated with 0.3 l of ethanol, the crude product initially dissolves in a clear solution, but shortly afterwards it disappears again in the warmth. After standing for one hour at room temperature, it is suctioned off and dried on the steam bath.
Yield 29 ⁷ g I- (64- ^ d.gh.) Sers.-P. 250 ° 0

Claims (1)

- 27 - HOE 75 / F O96 Claims Compounds of the general formula I 1 2 where R is a carbon atom or the methyl group, R tmd R Hydrogen atoms, optionally branched, unsaturated, through Oxygen or sulfur-interrupted alkyl-, cycloalkj-l- or Cycloalkylalkyl radicals each having up to 10 carbon atoms, if appropriate by halogen atoms, lower alkyl or alkoxy radicals substituted phenyl or phenylalkyl radicals with up to 10 C- 1 2 Atoms, where the radicals R and R, through 0, II or S or through direct C-C bond bridged, with the sulfonamide nitrogen one ■ 5 3- to 8-membered heterocycle can form, R- a ', hydrogen atom or an optionally unsaturated alkyl radical with up to 4 carbon atoms, R a hydrogen atom, an optionally unsaturated alkyl radical with up to 4 carbon atoms, a benzyl radical optionally substituted one or more by halogen atoms, amino groups or low molecular weight alkyl, alkylamino, dialkylamino or alkoxy radicals, one of the isomeric pyridylmethyl, furylmethyl or thienylinethyl radicals or the group a pyrrolidino, piperidino, hexamethyleneimine, Morpholino, thiomorpholine or H-alkylpiperazino radical and Z a carboxyl group optionally esterified by aliphatic or araliphatic alcohols with up to 10 carbon atoms, a Carbonamide group, optionally one or two times by aliphatic, araliphatic or aromatic radicals with each 609844/11 £ 2 - 28 - HOE 75 / F O96 up to 8 carbon atoms, interrupted or bridged by 0, JT or S. can be, can be substituted or mean the cyano group, as well as the salts of these compounds with physiological compatible acids and, if Z is a carboxyl group, with physiologically compatible bases. 2-Benzylamino-4- (4-methylpiperazin-1-yl) -5-sulfamoyl-benzoic acid 2-Benzylamino-4- (4-methylpiperazin-1-yl) -5-sulfamoyl-benzoic acid ethyl ester 2-Benzylamino-5-dimethylsulfamoyl-4- (4-methylpiperazin-1-yl) benzoic acid 2-benzylamino-4- (4-methylpiperazin-1-yl) -5-mox ^{"pholinosulf>} onyl benzoic acid ethyl ester 2-Benzylamino-4- (4-methylpiperazin-1-yl) -5-morpholinosulfonyl benzoic acid 2-Benzylamino-4- (4-methylpiperazin-1-yl) -5-methylsulfamoylbenzoic acid 2- (2-furyl methylamino) -4- (4-methylpiperazin-1-yl) -5-sulfamoyl benzoic acid-ethyle st er 2-Benzylamino-5-dimethylsulfamoyl-4- (4-methylpiperazin-1-yl) -benzoic acid morpholide B Π 9 8 / W ₊ / 1 1 /, - 29 - HOE 75 / F O96 A process for the preparation of 5-sulfamoyl-anthranilic acid derivatives of the general formula I, characterized in that a. a compound of the general formula II II : with piperazine or ri-methylpiperasine, or b. a compound of the general formula III III R ' with an Ami η of the general formula IV, where in the general formulas II to IV the radical X is a halogen atom, v / ie chlorine, bromine or fluorine, ei ie ITitro group or an alkyl or arylsulfonyloxy radical, for example the methane, ethane, benzene or 4-toluenesulfonyloxy radical means and the other radicals have the abovementioned meaning, and optionally then in the according to a. or b. compounds of the general formula I obtained have a cyanogen group to the carbonamide group or carboxyl group or a substituted carbonamide group is saponified to form a carboxyl group, and a carboxyl group is esterified in the usual way or amidated, an unsubstituted carbonamide group converted into the cyano group by dehydration, via N or 0 bound benzyl residues by catalytic hydrogenation 1 k cleaves if at least one of the radicals R and R to R -.30 - HOjD 75 / F O96 denotes a hydrogen atom, "alkylated", alkenylated or alkylated in the usual manner or, if at least one 1 4
the radicals R to R denote an unsaturated aliphatic radical, double bonds are catalytically hydrogenated, and the process products are then converted with physiologically acceptable acids or, if Z denotes a carboxyl group, with physiologically acceptable bases in their salts or corresponding salts in the free carboxylic acids or piperazine bases. Process for the production of pharmaceutical preparations with antihypertensive properties, characterized in that one Compounds according to claim 1, optionally with pharmaceutical. usual carriers and / or stabilizers in one for therapeutic Brings appropriate application form. Pharmaceutical preparations with antihypertensive properties ordering from or containing compounds according to claim 1. Use of compounds according to claim 1 or their salts as or in antihypertensive agents. 4/114?