CH637379A5 - Pyrrolobenzoic acid derivatives - Google Patents

Description

637379

2nd

PATENT CLAIM Pyrrolo-benzoic acid derivatives of the formula I

R-

R

R1 and R1 ', which are the same or different, each represent hydrogen, halogen, trifluoromethyl, alkyl or alkoxy having 1 to 4 carbon atoms or an optionally protected hydroxyl or amino group in the different positions of the ring, or both together 3,4 -Methylene dioxy group;

B is a group of the formula

, 2nd

(I),

10th

/

I.

J *

B-

t i l

B = N02S

COOR

wherein

R is hydrogen or alkyl of 1 to 4 carbon atoms;

R1 and R1 ', which are the same or different, each represent hydrogen, halogen, trifluoromethyl, alkyl or alkoxy having 1 to 4 carbon atoms or an optionally protected hydroxyl or amino group in the different positions of the ring, or both together the 3,4-methylene -dioxy group;

B is a group of the formula

, 2nd

15 where R2, R3 and R4, which are the same or different, are lower alkyl, R2 can also be hydrogen and / or two of the groups R2, R3 and R4 can also be cyclically linked to one another;

R5 and R6, which are the same or different, are each hydrogen or alkyl having 1 or 2 carbon atoms; and X is oxygen, sulfur, NH or CH2, and their salts with bases and acids.

The compounds of formula I are valuable precursors for the manufacture of drugs, particularly 25 salidiuretics and diuretics. the new pyrrolo-benzoic acid derivatives of the formula IV

where R2, R3 and R4, which are the same or different, are lower alkyl, R2 can also be hydrogen and / or two of the groups R2, R3 and R4 can also be cyclically linked to one another;

R5 and R6, which are the same or different, are each hydrogen or alkyl having 1 to 2 carbon atoms; and

X is oxygen, sulfur, NH or CH2, and their salts with bases and acids.

40

H2no2S '

(IV),

COOR

wherein

45

The invention relates to new pyrrolo-benzoic acid derivatives of the formula I.

R-

R

R is hydrogen or alkyl of 1 to 4 carbon atoms;

R1 methyl or chlorine; and X are oxygen, and their pharmaceutically acceptable salts suit bases and acids are produced.

These compounds are characterized by valuable diure-50 table and salidiuretic properties.

The compounds of formula I can be prepared by using a compound of formula II

COOR

wherein

R is hydrogen or alkyl of 1 to 4 carbon atoms;

(II),

COOR

Î ... R

3rd

637379

wherein R, R ', R1 to R4 and X have the meaning given above, with a 2,5-dialkoxytetrahydrofuran of the formula III

Alk-0

R

SO alk

(III),

in which the radicals R5 and R8 have the meaning given above and Alk means alkyl having 1 to 4 carbon atoms, preferably methyl.

E.g. hydrolytic removal of the protective group gn of the sulfamoyl function can then give the corresponding pyrrolobenzoic acid derivatives, in which B represents two hydrogen atoms.

Some of the starting compounds of the formula II are known from DE-OS 2 461 601 or can be prepared analogously to this. The reaction of the amines of formula II is usually carried out in weak organic acids, preferably in glacial acetic acid, at the boiling point.

The use of the protective group on the sulfamoyl function surprisingly increases the yield compared to the analogous reaction in the presence of a free sulfamoyl function, as is known, for example, from BE-PS 828 441, and an almost quantitative yield can be achieved.

The compounds of the formula I are valuable intermediates for the preparation of medicaments, in particular for diuretics, as are described in BE-PS 828 441. These compounds can be obtained which, in the 3-position, carry an appropriately R5> R6-substituted pyrrolidine ring, by catalytic hydrogenation, e.g. using noble metal catalysts such as Pd / activated carbon, Pt02, Rh / carbon or Pt / activated carbon. The reduction can also be carried out with other reducing agents known for pyrroles, e.g. Zinc / glacial acetic acid or hydroiodic acid and red phosphorus.

Following the reduction, the sulfonamide protective group and, if appropriate, the ester residue A can then be split off by acidic or alkaline hydrolysis.

The usability of the compounds of the formula I for the preparation of the pyrrolidino compounds was also not foreseeable, since there was fear that the protective group of the sulfonamide radical could also be attacked under the hydrogenation conditions which are required for the pyrrole radical.

If R1 and R1 'are OH and / or NH2 groups, they can be protected in compounds of the formula II, for example by the benzyl radical.

A large number of valuable intermediates of the formula I can be prepared by the process described. In addition to the compounds mentioned in the examples, e.g. prepare the following: 4-phenoxy-3 (l-pyrrolo) -5-N, N-dimethylamino-methylene-aminosulfonyl-benzoic acid

4- (4'-methylenephenoxy) -3 (1-pyrrolo) -5 -N, N-dimethylamino-

-methyl-amino-sulfonyl-benzoic acid ethyl ester

4- (3'-methylphenoxy) -3 (l-pyrrolo) -5-N, N-dimethylamino-

-methyl-amino-sulfonylbenzoic acid methyl ester

4- (3'-methoxyphenoxy) -3 (l-pyrrolo) -5-N, N-dimethylamino-

-methyl-amino-sulfonylbenzoic acid butyl ester

4- (3'-hydroxyphenoxy) -3 (l-pyrrolo) -5-N, N-dimethylamino-

-methyl-amino-sulfonylbenzoic acid methyl ester

4- (4'-methylphenoxy) -3- (3'-methyl-l-pyrrolo) -5-N, N-dime-

methylamino-methylene-amino-sulfonylbenzoic acid methyl ester

4-phenoxy-3- (3'-methyl-l-pyrrolo) -5-N, N-dimethylamino-

-methyl-amino-sulfonylbenzoic acid ethyl ester

4-benzyl-3 (l-pyrrolo) -5-N, N-dimethylamino-methylene-amino-

-sulfonylbenzoic acid

4- (4'-Methylbenzyl) -3 (l-pyrrolo) -5-N, N-dimethylamino-5-methyl-aminosulfonylbenzoic acid, methyl ester 4-benzyl-3- (3'-methyl-l-pyrrolo) -5 -N, N-dimethylamino - methylene-amino-sulfonylbenzoic acid methyl ester 4- (4'-methylbenzyl) -3- (3'-methyl-l-pyrrolo) -5-N, N-dimethylamino-methylene-aminosulfonylbenzoic acid methyl ester io 4- (4'-Chlorobenzyl) -3 (l-pyrrolo) -5-N, N-dimethylamino-methyl-aminosulfonylbenzoic acid methyl ester 4- (4'-methylanilino) -3 (l-pyrrolo) -5- N, N-dimethylamino-methyl-aminosulfonylbenzoic acid methyl ester 4- (4'-methoxyanilino) -3 (l-pyrrolo) -5-N, N-dimethylamino-15-methylene-aminosulfonylbenzoic acid methyl ester 4- (3'- Methoxyanilino) -3 (l-pyrrolo) -5-N, N-dimethylamino - methylene-aminosulfonylbenzoic acid ethyl ester 4- (4'-chloroanilino) -3 (l-pyrrolo) -5-N, N-dimethylamino-me- butylenes-aminosulfonylbenzoic acid 20 4- (4'-fluoroanilino) -3 (1-pyrrolo) -5-N, N-dimethyIamino-methylene-aminosulfonylbenzoic acid methyl ester 4- (4'-methylanilino) -3- (3rd '-methyl-l-pyrrolo) -5-N, N-dimethyl-amino-methyl Methyl n-amino-sulfonylbenzoate 4- (4'-chloroanilino) -3- (3'-methyl-l-pyrrolo) -5-N, N-dimethyl-25 amino-methylene-amino-sulfonylbenzoic acid methyl ester.

The compounds of formula IV can be obtained from appropriately substituted compounds of formula I in which X represents an oxygen atom by acidic or alkaline hydrolysis. Free carboxylic acids 30 of the formula IV obtained can then be esterified or converted into their salts.

The compounds of formula IV have surprisingly been found to be highly effective diuretics and saluretics; this was not to be foreseen insofar as the corresponding unsubstituted compound (R1 = H) shows only weak diuretic activity and is exceeded many times over by the 4-chloro and 4-methyl-substituted compounds.

40 Example 1

Preparation of a compound according to the invention 3-N-pyrrolo-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester

45 100 g of 3-amino-4-phenoxy-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 53 g of 2,5-dimethoxytetrahydrofuran are refluxed in 100 g of glacial acetic acid for 15 minutes. The mixture is cooled to 10 ° C., the crystals which have separated out are filtered off, washed with 20 ml of cold ice cream and dried in vacuo.

96 g of colorless to brownish crystals of mp: 173 to 175 ° C. are obtained.

For further purification, if necessary, recrystallization from isopropanol or ethyl acetate.

55 Use of a compound according to the invention Conversion to 4-phenoxy-3- (l-pyrrolidinyl) -5-sulfamoyl-benzoic acid

10 g of 3-N-pyrrolo-4-phenoxy-5-N, N-dimethylaminomethy-60 lenaminosulfonyl-benzoic acid methyl ester are in 100 ml of methanol and with the addition of 1 g of 10% palladium / activated carbon for 5 hours at 100 ° C and 100 atm. hydrated. The catalyst is filtered off hot. On cooling, 8 g of methyl 4-phenoxy-3- (l-pyrrolidinyl) -5-N, N-di-65 methylaminomethyleneaminosulfonylbenzoate crystallize from the melting point of 187 to 189 ° C.

The product obtained is suspended in 100 ml of 2N NaOH and heated to reflux until a clear solution. By

637379

4th

Acidification with 2N HCl to pH 3 to 4 precipitates the free acid 4-phenoxy-3- (l-pyrrolidinyl) -5-sulfamoyl-benzoic acid. Recrystallization from CH30H / H20 Light yellow crystals with a melting point of 226 to 228 ° C.

Preparation of the compounds according to the invention

Example 2

3-N-Pyrrolo-4- (4'-methylphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester a) 3-nitro-4- (4'-methylphenoxy) -5-N, N-dimethylaminome -thylenamino-sulfonyl-benzoic acid methyl ester

A solution of 235 g (0.67 mol) of 3-nitro-4-chloro-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester and 140 g (0.96 mol) of potassium 4-methylphenolate in 11 absolute Dimethylformamide (DMF) is stirred at 90 to 100 ° C for 2 hours. The cold solution is then slowly dripped into 4 to 5 liters of ice water with vigorous stirring. The precipitated product is filtered off, washed with HzO and recrystallized from CH3OH.

Light yellow crystals with a melting point of 200 to 201 ° C.

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

171 g of 3-nitro-4- (4'-methylphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonylbenzoate are methylated with Raney nickel as a catalyst in dimethylformamide at 50 ° C and 50 atm. Hydrogenated in an autoclave for 8 hours. The mixture is then filtered, the filtrate is concentrated and the residue is recrystallized from CH 1 OH.

Colorless crystals with a melting point of 172 to 173 ° C.

c) 3-N-Pyrrolo-4- (4'-methylphenoxy) -5-N, N-dimethylamino-methyleneamiiiosulfonyl-benzoic acid methyl ester

19.5 g (0.05 mol) of 3-amino-4- (4'-methylphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 7 ml (- 0.075 mol) of 2,5-dimethoxytetrahydro -furan are heated to reflux in 150 ml of glacial acetic acid.

After an hour of reaction, the mixture is dropped into ice water. The precipitated light brown product is filtered off and recrystallized from CH3OH / a little acetone. 17.5 to 18 g of mp: 178-179 ° C. are obtained.

Example 3

3-N-Pyrrolo-4- (4'-methoxyphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester a) 3-nitro-4- (4'-methoxyphenoxy) -5-N, N-dimethylamino -methylamino-sulfonyl-benzoic acid methyl ester

0.4 mol (126 g) of 3-nitro-4-chloro-5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester and 72.5 g (- 0.5 mol) of sodium 4-methoxyphenolate are in 600 ml Section. DMF heated to reflux for 2 hours. The reaction mixture is then stirred into 4 l of ice water and the precipitated product is filtered off with suction.

Light yellow crystals from CH = OH with a melting point of 199-201 ° C.

b) 3-amino-4- (4'-methoxyphenoxy) -5-N, N-dimethylamino-

methylenamiiw-sidfonyl-benzoic acid methyl ester The reaction is carried out analogously to Example 2b. Recrystallization from CH, OH; colorless crystals of mp: 141-143 ° C.

c) 3-N-Pyrrolo-4- (4'-methoxyphenoxy) -5-N, N-dimethylamino-methylene-aminosulfonyl-benzoic acid methyl ester

20.37 g (0.05 mol) of 3-amino-4- (4'-methoxyphenoxy) -5 - N, N-dimethyiaminomethylenaminosulfonyl-benzoic acid-

methyl ester and 7 ml of 2,5-dimethoxytetrahydrofuran are refluxed in 150 ml of glacial acetic acid for about 1 hour. The cold mixture is then stirred into ice water, the precipitated product is suctioned off and washed with water. Crude product 20.8 g.

(The crude product can be used as an intermediate product without further purification, i.e. catalytically hydrogenated and hydrolyzed, see p. 5.)

Example 4

3-N-pyrrolo-4- (3'-methoxyphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester a) 3-nitro-4- (3'-methoxyphenoxy) -5-N, N- dimethylamino-methylenamino-sulfonyl-benzoic acid methyl ester

Analogous to example 3a, but with sodium 3-methoxyphenolate and a reaction time of 3 hours.

Light yellow crystals from glycol monomethyl ether with a melting point of: 201 ° C.

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

Analogous to example 2b. Recrystallization from glycol monomethyl ether, colorless crystals with a melting point of 176-178 ° C.

c) 3-N-Pyrrolo-4- (3'-methoxyphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

12.7 g (0.03 mol) of 3-amino-4- (3'-methoxyphenoxy) -5 - N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 4.6 ml of 2,5-dimethoxytetrahydrofuran are dissolved in 150 ml of glacial acetic acid heated to reflux for 30 minutes. The product is then precipitated by stirring in 1.5 l of ice water and recrystallized from CH30H / H20. Beige crystals of mp: 165-166 ° C.

Example 5

3-N-Pyrrolo-4- (4'-chlorophenoxy) -5-N, N-dimethylaminomethylthyleneaminosulfonyl-benzoic acid methyl ester a) 3-nitro-4- (4'-chlorophenoxy) -5-N, N-dimethylaminome -thylenamino-sulfonyl-benzoic acid methyl ester

A solution of 164 g of 3-nitro-4-chloro-5-N, N-dimethyi-aminomethyleneamino-sulfonyl-benzoic acid methyl ester and 117 g of potassium p-chlorophenolate in 800 ml of freshly distilled DMF is refluxed for 2-3 hours. The reaction mixture is dropped into 4 times the amount of ice / H20 with vigorous stirring. The product which precipitates is separated off and boiled with CH3OH / acetone.

Mp: 227-228 ° C.

b) 3-Amino-4- (4'-chlorophenoxy) -5-N, N-dimethylaminomethylene aminosulfonyl benzoic acid methyl ester

130 g of the nitro compound (5a) are in 1 1 DMF with Raney nickel for 9 hours at 50 atm. and hydrogenated at 50 ° C. After the Raney nickel has been suctioned off, the solution is concentrated and the residue is boiled out with CH3OH.

Colorless substance with a melting point of: 207-208 ° C.

c) 3-N-Pyrrolo-4- (4'-chlorophenoxy) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester

20.6 g of the amino compound (5b) are mixed with 7 ml of 2.5

-Dimethoxytetrahydrofuran heated in reflux for 1 hour in 150 ml of glacial acetic acid. The substance is then precipitated by pouring the reaction mixture into 1.5 l of ice water, suction filtered and recrystallized from CH3OH.

Light brown crystals of mp: 165 ° C.

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637379

Example 6

3-N-Pyrrolo-4- (4'-fluorophenoxy) -5-N, N-dimethylaminomethylthyleneaminosulfonylbenzoic acid methyl ester a) 3-nitro-4- (4'-fluorophenoxy) -5-N, N-dimethylaminome -thylenamino-sulfonyl-benzoic acid methyl ester

A solution of 210 g (0.6 mol) of 3-nitro-4-chloro-5-N, N - dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 120 g of sodium 4-fluorophenolate in 800 ml abs. DMF is stirred for 3-4 hours at 120-130 ° C. The cold solution is then slowly dripped into 4-5 l of ice water with vigorous stirring. The precipitated product is filtered off with suction, washed well with water, digested with hot acetone and then recrystallized from glycol monomethyl ether.

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

b) 3-Amino-4- (4'-fluorophenoxy) -5-N, N-dimethylaminomethyl methyleneaminosulfonylbenzoate

140 g of the nitro compound (6a) are dissolved in DMF and with Raney nickel at 50 ° C and 50 atm. Hydrogenated 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 CH3OH and then with ether. The practically pure substance can be recrystallized from glycol monomethyl ether.

Colorless crystals of mp: 234-236 ° C.

c) 3-N-Pyrrolo-4- (4'-fluorophenoxy) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester

17.5 g of “amine ester” (6b) and 6.5 ml of 2,5-dimethoxytetrahydrofuran are refluxed in 150 ml of glacial acetic acid for about 1 hour. The mixture is then added dropwise to 1.5 l of ice water and the precipitated product is filtered and recrystallized from CHjOH.

Light brown crystals of mp: 180 ° C.

Example 7

3-N-Pyrrolo-4-phenylthio-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester

15.8 g of 3-amino-4-phenylthio-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 9.2 g of 2,5-dimethoxy-tetrahydrofuran are heated under reflux in 150 ml of glacial acetic acid for 1 hour. By pouring it into ice water, the product precipitates and can still be digested with hot CH3OH. The residue is recrystallized from glycol monomethyl ether.

Light yellow crystals of mp: 210-211 ° C.

Example 8

3-N-Pyrrolo-4- (4'-methylphenylthio) -5-N, N-dimethylamino ~ methyleneaminosulfonylbenzoic acid methyl ester a) 3-nitro-4- (4'-methylphenylthio) -5-N, N-dimethylamino -methylamino-sulfonyl-benzoic acid methyl ester

70 g of 3-nitro-4-chloro-5-N, N-dimethylaminomethylene-amino-sulfonyl-benzoic acid methyl ester are dissolved in 450 ml of abs. Suspended DMF and heated to 80 ° C. A solution of 40 g of potassium p-thiocresolate in 400 ml of abs is slowly added dropwise. DMF and stir at 80 ° C for 2 hours. The mixture is finally stirred into 41 ice water, the precipitated product is suctioned off, washed well with water and recrystallized from glacial acetic acid.

Yellow crystals of mp: 163-164 ° C.

b) 3-Amino-4- (4'-methylphenylthio) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester

67.7 g of 3-nitro-4- (4'-methylphenylthio) -5-N, N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester are dissolved in 800 ml of abs. DMF dissolved, Raney nickel added and 8 hours at 50 ° C and 50 atm. Hydrogen introduced.

After the catalyst has been separated off, the solution is stirred into 2 l of ice water and the precipitated product is isolated. Recrystallization from CH3OH (addition of activated carbon). Colorless crystals with a melting point of 179 ° C.

c) 3-N-Pyrrolo-4- (4'-methylphenylthio) -5-N, N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester

18.3 g of “amine ester” (8b) are dissolved in 150 ml of glacial acetic acid and heated to boiling. Then 7 ml of 2,5-dimethoxytetrahydrofuran are added. After about 10 minutes, the product suddenly crystallizes out. The mixture is stirred for a further 15 minutes at reflux, the precipitated crystals are suctioned off in the cold and washed with glacial acetic acid.

Light yellow crystals of mp: 242-243 ° C.

Example 9

3-N-Pyrrolo-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester a) 3-nitro-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylamino -methylamino-sulfonyl-benzoic 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 -benzyloxyphenolat added. The reaction mixture is heated under reflux for 3-4 hours while stirring well. After cooling, the cloudy solution is dropped into 3 l 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-aminosulfonyl-benzoic acid methyl ester are obtained in yellow crystals. Mp: 132 ° C.

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

94 g of 3-nitro-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester are dissolved in 1.5 l of dimethylformamide and hydrogenated with Raney nickel at room temperature and normal pressure for 6-7 hours. It is then filtered off and the clear solution is dropped in ice / water. The precipitated 3-amino-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester is recrystallized from methanol. About 70 g are obtained in white crystals of mp: 170 ° C.

c) 3-N-pyrrolo-4- (4'-benzyloxyphenoxy) -5-N, N-dimethyl-

Aminomethyleneamino-sulfonyl-benzoic acid methyl ester 43.5 g of “amine ester” (9b) and 13 ml of 2,5-dimethoxy-tetrahydrofuran are refluxed for 1 hour in 250 ml of glacial acetic acid. The product is then precipitated by pouring the reaction mixture into ice water, suction filtered, washed with H20 and recrystallized from CH3OH (activated carbon additive).

Melting point: sinters from 80 ° C, turns into highly viscous oil that melts at 105-110 ° C.

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Example 10

3-N-Pyrrolo-4-anilino-5-N, N-dimethylaminomethyleneamino-sulfonyl-benzoic acid methyl ester a) 3-Nitro-4-anilino-5-N, N-dimethylaminomethyleneamino-sulfonyl-benzoic acid methyl ester

52.5 g of 3-nitro-4-chloro-5-N, N-dimethylaminomethylene-amino-sulfonyl-benzoic acid methyl ester in 360 ml abs. DMF dissolved and heated to 100 ° C. 18 ml of aniline are then added dropwise with stirring and the reaction mixture is kept at 100 ° C. for 3 hours. The product is precipitated by pouring the solution into 2 l of ice water, isolated and washed well with H20. For cleaning, the product is boiled out with 250 ml CH3OH and a little acetone. Crystals of mp: 182-183 ° C.

b) 3-Amino-4-anilino-5-N, N-dimethylaminomethyleneamino-sulfonyl-benzoic acid methyl ester

40.7 g of “nitroester” (10a) are dissolved in 600 ml of DMF and with Raney nickel as catalyst for 8 hours at 50 ° C. and 50 atm. hydrated. The filtered solution is stirred into 2 l of ice water, the precipitated product is isolated and recrystallized from glycol monomethyl ether.

Colorless crystals of mp: 227-228 ° C.

c) 3-N-Pyrrolo-4-anilino-5-N, N-dimethylaminomethylene-amino-sulfonyl-benzoic acid methyl ester

11.3 g of “amine ester” (10b) are dissolved in 130 ml of glacial acetic acid and 4.5 ml of 1,2-dimethoxytetrahydrofuran are added. After 15 minutes at reflux, the mixture is stirred into 500 ml of ice water, the precipitated product is isolated and washed several times with water.

Recrystallization from CH3OH / C2H5OH. Mp: 185 ° C.

Example 11

3-N-Pyrrolo-4- (3 ', 4'-methylenedioxyphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester a) 3-nitw-4- (3', 4'-methylenedioxyphenoxy) -5 -N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

96 g of 3-nitro-4-chloro-5-N, N-dimethylaminomethylene-amino-sulfonyl-benzoic acid methyl ester and 58 g of sodium - 3,4-methylenedioxyphenolate are mixed with 500 ml of abs. DMF mixed and stirred at 120 ° C for 2 hours. The mixture is introduced into 4 l of ice water with stirring. The precipitated light yellow product is separated off and recrystallized from n-butanol or CH = OH / acetone. Mp: 216-217 ° C.

b) 3-A mino-4- (3 ', 4'-methylenedioxyphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

76 g of the nitro compound from Example IIa are abs. In about 500 ml of DMF. dissolved and hydrogenated with Raney nickel as a catalyst for 8 hours at room temperature and 50 atm. The filtered solution is then added dropwise to ice water and the precipitated product is recrystallized from CHrOH after separation.

Colorless crystals of melting point: 190-191 ° C.

c) 3-N-Pyrrolo-4- (3 ', 4'-methylenedioxyphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

11.5 g of "amine ester" (Example IIb) together with 4 ml of 2,5-dimethoxytetrahydrofuran in 150 ml of glacial acetic acid are refluxed for 1 hour. The product is precipitated by dropping in 1.5 l of ice water.

Recrystallization from glycol monomethyl ester, mp: 206 ° C.

Example 12

3-N-pyrrolo-4- (4'-methylanilino) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoes'duremethyl ester a) 3-nitro-4- (4'-methylanilino) -5-N, N -dimethylaminomethy-lenamino-sulfonyl-benzoic acid methyl ester

0.2 mol of 3-nitro-4-chloro-5-N, N-dimethylaminomethylene-amino-sulfonyl-benzoic acid methyl ester are dissolved in 500 ml of dimethylformamide at 100 ° C. and then a solution of 0.33 mol of p-toluidine in 20 ml DMF abs. dripped. After 4 hours, the mixture is stirred into ice water and the precipitated product is separated off.

Recrystallization from CH3OH, yellow crystals with mp. 210 ° C.

b) 3-Amino-4- (4'-methylanilino) -5-N, N-dimethyIamino-methylenaminosulfonyl-benzoic acid methyl ester

62.4 g of 3-nitro-4- (4'-methylanilino) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester are dissolved in 1.5 1 of dimethylformamide and in the presence of Ra-ney / nickel for 8 hours 50 ° C and 50 atm. hydrated. The catalyst is then separated off and the filtrate is stirred into ice water.

Mp: 186-188 ° C.

c) 3-N-Pyrrolo-4- (4'-methylanilino) -5-N, N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester

0.1 mol of 3-amino-4- (4'-methylanilino) -5-N, N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester are dissolved in 400 ml of glacial acetic acid and heated to reflux.

After adding 15 ml of 2,5-dimethoxytetrahydrofuran, the mixture is heated for a further 30 minutes and the mixture is then stirred into 3 l of ice water. The precipitated product can be recrystallized from CH3OH.

Mp: 169 to 173 ° C.

The product can be converted into the 3-pyrrolo-4- (4'-methylanilino) -5-sulfamoyl-benzoic acid by saponification with 2N NaOH until the solution is clear. Light yellow crystals from CH; 0H / H, 0 with mp: 226 to 228 ° C.

d) hydrogenation to 4- (4'-methylanilino) -3- (l-pyrrolidinyl) -5-sulfamoyl-benzoic acid

The 3-N-pyrrolo-4- (4'-methylanilino) -5-N, N-dimethylamino-methyleneamino-sulfonyl-benzoic acid methyl ester obtained according to c) is suspended as a crude product in methanol and in the presence of Pd / C as Catalyst at 100 ° C and 150 atm. Hydrogenated for 16 hours. The filtrate is evaporated to dryness and heated with 2N NaOH until a clear solution. The pH is then adjusted to 4 with 2N NaOH and the precipitated product is recrystallized from CHnOH / H, 0.

Yellow crystals of mp: 188 to 191 ° C.

Use of the compounds according to the invention

A. 3-N-Pyrrolo-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid

17 g of 3-N-pyrrole-4- (4'-methylphenoxy) -5-N, N-dimethyl aminomethyleneaminosulfonylbenzoate (see Example 2c) were suspended in 2N NaOH and a little CH3OH and up to the clear solution heated to reflux. Thereafter, the 3-N-pyrrolo - 4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid is precipitated from the cold solution by adding 4N-HCl up to a pH of 3 to 4. The Pro5

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the product is filtered off, washed with H20 and recrystallized from CH3OH / H20.

12.7 g of mp: 205 to 208 ° C. are obtained.

C. 3-N-Pyrrolo-4- (4'-chlorophenoxy) -5-sulfamoylbenzoic acid

The ester from Example 5c is suspended in 2N NaOH and heated to reflux until a clear solution. The mixture is stirred for half an hour and acidified to pH 3 to 4 with 2N hydrochloric acid. The precipitated product is isolated, recrystallized or reprecipitated from CH30H / H20 + carbon and then from diisopropyl ether by adding n-hexane to the filtered hot solution 5.

Beige powder with a melting point of 209-214 ° C.

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