DE2235400C3 - ^ Chlor-S-sulfamoyl-anthranilic acids, their salts, processes for the preparation of these compounds and medicaments containing these compounds - Google Patents

Description

in which X is an oxygen or sulfur atom, Ri is a straight- or branched-chain lower alkyl group with up to 10 carbon atoms represented by one or several hydroxyl or lower alkoxy groups can be substituted, a cyclohexyl, an allyl or propargyl or a benzyl or furfuryl group and R2 is a straight or branched chain Alkyl group with up to 4 carbon atoms or a benzyl, phenethyl, furfuryl, thenyl, pyrrolylethyl or cyclohexyl group, as well as their physiologically acceptable metal or Ammonium salts.

2. A process for the preparation of the compounds according to claim 1, characterized in that in each case in a manner known per se
a) a compound of the general formula

Cl

NH ₁ SO ₂

NHR ₂

COOH

30th

(II)

60

The invention relates to 4-chloro-5-sulfamoyl-anthranilic acids with valuable therapeutic properties, their physiologically acceptable metal or ammonium salts, a process for the preparation of these compounds and medicaments containing them according to the preceding claims.

It is known that compounds of the general formula

Cl R "

R'NHSO,

COOH

in which R 'is a hydrogen atom, an alkyl, aralkyl or alkoxy group and R "is a furfuryiamino group or a benzylamino, dibenzylamino, pyrrolylethylamino or thenylamino when R 'is hydrogen, diuretic and saluretic Possess properties. For example, the compound of formula A in which R 'is hydrogen and R " a furfuryiamino group, known as "fursemide" or "furosemide", and widely used as an effective diuretic Common The compounds of the formula A including furosemide, however, have a certain toxicity

It has now been shown, unexpectedly, that compounds of the general formula

Cl

R ₁ -X-CH ₂ -NHSO ₂

NHR,

COOH

or an alkali salt? this compound with a formaldehyde solution or with paraformaldehyde and with a compound of the general formula

R ₁ -XH (III)

40

converts, where Ri, R2 and X are those in claim 1 have given meaning and

b) if X is an oxygen atom, the product obtained above optionally reacts with a compound of the formula

R'X H

in which R 'has the meaning given for Ri in claim 1, but differs from Ri in the End product differs and

c) optionally converting the free acid obtained into a physiologically compatible metal or ammonium salt or converting the salt into the acid.

3. Medicines, characterized in addition to the usual pharmacologically applicable carriers, by a content of a compound according to claim 1.

in which X is an oxygen or sulfur atom, Ri is a straight or branched chain lower alkyl group with up to 10 carbon atoms, which can be substituted by one or more hydroxyl or lower alkoxy groups, a cyclohexyl, an allyl or propargyl or a benzyl or furfuryl group and R ₂ a straight or branched chain alkyl group with up to 4 carbon atoms or a benzyl, phenethyl, furfuryl, thenyl, pyrrolylethyl or cyclohexyl group, as well as their physiologically acceptable metal - or ammonium salts, diuretic and saluretic activities which are at least as high as those of the known compounds of formula A, while they are less toxic.

The general formula (I) given above embraces two subgroups of compounds of the following Formulas:

CI

R ₁ -O-CH ₂ NHSO ₂
Cl

R ₁ -S-CH ₂ -NHSO ₂

NHR ₂

COOH
NHR ₂

COOH

where Ri and R2 have the meaning given above. The novel compounds of the formula 1 according to the invention are prepared according to the invention by one is a compound of the general formula

Cl

N H. S O,

NHR,

COOH

or an alkali salt of such a compound with a formaldehyde solution or with paraformaldehyde and with a compound of the general formula

R ₁ -XH

(111)

where Ri, R2 and X are those given in formula I. Have meaning, implemented in a manner known per se

An acid of the formula I, which has been obtained as indicated above, can optionally be in a physiologically suitable metal or ammonium salt are transferred. When an alkali salt of the acid is Formula II is used as the starting material and the Reaction is carried out so that the product of formula I is obtained in the form of a salt with the same cation, such a salt can optionally be converted into the free acid or another physiologically suitable salt be converted by known methods.

The reaction can be carried out either at room temperature or at elevated temperatures, preferably below 100 ^° C., and it will

Cl

NHR ₂

Conveniently carried out in an excess of the compound R ₁ -XH (III)

The reaction can be carried out under mildly acidic or alkaline conditions pH not exceeding 10 if desired, can a slightly alkaline pH within about 7 to about 10 by the addition of an alkali bicarbonate can be set.

The starting substances of the formula II are either known, or they can be prepared by known methods, for. B. by reacting S-SulfamoyM-chloro-e-halogenobenzoic acid with an amine of the formula R ₂ NH ₂ .

To prepare a compound of the formula Ia, the starting substance of the formula II or an alkali salt is used this compound with a formaldehyde solution or with paraformaldehyde and an alcohol of the formula

R ₁ OH

CHIa)

implemented. This reaction proceeds according to the following scheme:

+ CH ₂ O + R ₁ OH-

H ₂ N-SO ₂ COOH

(H) (HIa)

R ₁ -O-CH ₂ -NH-SO ₂ COOH

(la)

where Ri, R _{2 have} the meaning given above.

Optionally, an excess of the alcohol RiOH or a mixture of this alcohol with water can be used as Solvents can be used.

The new compounds of the formula Ia can be obtained in a particularly pure form via another Compound of this formula by replacing the radical Rj. For this purpose, a compound of Formula Ic given below, in which Ri 'is the formula for Ri in Formula I has the meaning given, in an excess of an alcohol of the formula RiOH (HIa), in the Ri has the meaning given above, but not is identical to Ri 'in formula Ic, and the solution is preferably heated. This procedure can be illustrated are by the following scheme:

Λ / \ excess

R ₁ O-CH ₂ -NHSO ₂ COOH R ₁ O-CH ₂ -NHSO ₂ COOH

(Ic) (Ia)

To prepare a compound of the formula Ib, the starting substance of the formula II or an alkali salt is used this compound with a formaldehyde solution or paraformaldehyde and a mercaptan of the formula

R ₁ SH (1Mb)

in the presence of a lower alcohol, e.g. B. of methanol implemented. It is believed that the Reaction proceeds according to the following scheme:

NHR ₂

4 CH ₂ O + R ₁ SH

H ₂ N-SO ₂ COOH

(II)

(HIb)

R ₁ -S-CH ₂ -HN-SO ₂ COOH

fib)

It is also assumed that the above given reaction as an intermediate product a compound of the general formula

CI

R ₆ O-CH ₂ -NH-SO ₂

NHR,

COOH

(IV) arises, which then reacts with the mercaptan RiSH.

In the formulas given above, Ri and R _{2 have} the meaning given above and R ₆ is a lower alkyl group.

A compound of the formula Ib can also be prepared by reacting a compound of the formula Id with a mercaptan of the formula IHb, preferably at an elevated temperature. Such a transformation runs according to the following scheme:

Cl

NHR,

+ R ₁ SH

R ₁ '"-O- CH ₂ -HN-SO ₂ COOH

(Id) (IUb)

R ₁ -S-CH ₂ -HN-SO ₂ COOH

(Ib)

where Ri and R _{2 have} the meaning given above and Ri '"has the same meaning as Ri in formula 1 and Ri and Ri'" can be the same or different.
On application technology progress:
As stated above, the new compounds of the formula I are suitable as diuretic and saluretic agents and are consequently particularly suitable for the clinical treatment of edema. They can be administered in doses ranging from 10 to 500 mg.

Initial studies in rats with some compounds of the invention have shown that they are stronger or equally effective as furosemide in terms of their diuretic activity and that they der os are much less toxic. The following values were obtained for the LD50 in rats:

connection

LD ₅₀ (g / kg)

N-furfuryl-4-chloro-5- (ethoxymethyl-6.4
sulfamoyD-anthranilic acid

N-FurfuryI -4-chloro-5- (methoxymethyl-8.9
sulfamoyl) anthranilic acid

N-furfuryl-4-chloro-5- (butoxymethyl-9.8
sulfamoyl) anthranilic acid

N-furfuryl-4-chloro-5- (pentoxy methyl-5.7
sulfamoy!) - anthranilic acid

Furosemide 4

A comparison of the acute and subchronic diuretic effects of N-furfuryl-4-chloro-5- (butoxymethylsulfamoylj-anthranilic acid with that of furosemide showed that they were essentially equally effective. In addition, showed up at daily administration of the aforementioned compounds according to the invention to rats within 21 Days no observable toxic side effects.

Investigations of subacute month-long toxicities in beagles (greyhounds) at oral doses of 50 mg / kg body weight (approximately 50 times the maximum intended human dose) that N-furfuryl-4-chloro-5- (butoxymethylsulfamoyl) -antranilic acid is an extremely effective diretic that has no toxicity whatsoever.

Test report

Oral efficacy in rats was determined on male Sprague-Dawley rats weighing 175 to 200 g, which were divided into groups of 8 animals per group. The rats were given no food or water for 18 hours prior to drug administration. The compounds to be investigated were administered orally with the aid of the gastric tube in the form of a well homogenized suspension (ground in a mortar) in a volume of 25 ml / kg of isotonic saline solution. Control animals received comparable amounts of drug-free saline. The rats were placed in metabolism cages in twos and the urine was collected for 5 hours. The volume and the sodium excretion within 5 hours were given as%, based on the amount absorbed. The potassium and sodium excretion were also reported as total meq. in 5 hours from 8 rats. For comparison, an oral dose of 50 mg / kg was administered in all cases. The chloride determination was carried out with the aid of a Hg (NO ₃ ) 2 / HNO3 system with diphenylcarbazone as an indicator. The Na ⁺ and Ka ⁺ were determined using an adsorption spectrometer. Urine samples were collected to calculate data after 5 and 24 hours.

The values given in the table below were obtained.

45 R ₁ X =

DIURESE (ml) SALURESH
(Na / K)

0-5h 5-24h 0-5h 5-24h

Furfuryloxy

Allyloxy

Ethoxy

Benzyloxy

Isopropoxy
Cyclohexyloxy

jS-ethoxyethoxy

Isopropylthio

Propylthio

Ethylthio
Benzylthio

Hexyloxy

Heptyloxy

Butoxy *)

Methoxy *)
Pentoxy *)

Furosemide

*) Average value from several tests.

19.6 2.5 2.8 0.7 17.9 3.5 2.7 0.7 17.2 3.4 2.5 0.8 19.9 3.2 3.0 0.9 19.1 2.7 3.3 0.8 21.9 2.8 2.8 0.7 19.5 2.7 3.4 0.8 16.1 1.8 3.3 0.9 19.4 1.8 3.1 0.7 18.6 2.5 3.0 0.8 16.5 2.4 3.1 0.6 20.2 2.8 3.3 1.0 21.3 2.8 3.2 0.9 20.2 2.6 2.3 0.7 8.7 2.2 2.3 1.1 18.6 1.9 3.2 0.9 18.0 2.7 3.3 0.7

The compounds of the formula I according to the invention are in the form of the free bases and in the form of theirs physiologically suitable metal salts suitable for oral and parenteral administration. Hence they can as such or in a mixture with suitable pharmacologically acceptable carriers in solid or liquid form Shape, e.g. B. with water, vegetable oils, starch, lactose, talc or with additives such. B. Stabilizers, preservatives, Wetting agents or emulsifying agents can be used. The products can be in the form of Tablets. Dragees, capsules, solutions, suspensions or emulsions are prepared. Particularly beneficial the compounds are administered orally in the form of tablets or dragees.

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

example 1

N-furfuryl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid

16.5 g of N-furfuryl ^ -chloro-S-sulfamoyl-anthranilic acid and 5 g of sodium bicarbonate were dissolved in a mixture of 33 cm ^{3 of} methanol and 7.5 cm ^{3 of} a 37% strength aqueous formaldehyde solution and the mixture was left to stand at room temperature for 16 hours and then filtered. ^{5 cm 3 of} glacial acetic acid were added to the filtrate and the crystals formed were filtered off, washed with methanol and dried. 14.3 g were obtained

N-furfuryl-chloro-S-methoxymethylsulfamoyl-anthranilic acid, Mp 163-164 ° C, yield 76.4%. The compound was revealed by thin layer chromatography as pure and its structure was determined by the UV and NMR spectrum and acidimetric titration as well as elemental analysis confirmed. The following results were obtained:

Calculated for CmH ₁₅ CIN ₂ O ₆ S:

C 44.86, H 4.03, N 7.48, S 8.56, Cl 9.46,

O 25.6%;

found:

C 45.04. H 4.13, N 7.94, S 8.32, Cl 9.44,

O 25.38%.

In a parallel experiment, the same reaction mixture was left to stand at room temperature for 16 hours. The mixture, the pH of which was approximately 10, was then filtered and concentrated ^{with 7 cm 3.} HCl acidified to a pH of about 1. The precipitate formed was filtered off, washed with methanol and chloroform and dried. This gave 11.5 g of N-furfuryl-4-chloro-5- (methoxymethyl-sulf-

amoyl) anthranilic acid, m.p. 156-158 ° C. The melting point rose to 162.5 to 165 ° C. after recrystallization

Example 2

N-furfuryl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid

The same reaction mixture as in Example 1 was heated to reflux temperature for 1 hour, filtered to remove the insoluble constituents and cooled. Then 5 cm ^{3 of} glacial acetic acid were added and the crystalline product isolated as in Example 1, yield 12 g of N-furfuryl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid, melting point 163 ° to 164.5 ° C.

Example 3

N-furfuryl-4-chloro-5- (ethoxyinethylsulfamoyl) anthranilic acid

16.5 g of N-furfuryl-4-chloro-5-sulfamoylanthranilic acid were heated in 33 cm ^{3 of} aqueous 95% ethanol containing 2.77 g of formaldehyde until completely dissolved. The solution was heated to reflux temperature for 1 hour, filtered while still hot, cooled to room temperature and left to stand for 16 hours. The precipitated crystals were filtered off and dried. 11.7 g of N-furfuryl-4-chloro-5- (ethoxymethylsulfamic!) Anthranilic acid, melting point 132 ° to 134 ° C., were obtained. One sample had a melting point of 144 to 147 ° C after recrystallization.

Elemental analysis for Ci ₅ HI _{7 ClN 2} O ₆ S:
Calculated: C 46.35, H 4.38, N 7.21%;
Found: C 46.25, H 4.32, N 7.09%.

The UV and NMR spectrum were consistent with the structure.

Example 4

N-furfuryl-4-chloro-5- (butoxymethylsulfamoyl) anthranilic acid

16.5 g of N-furfuryl ^ -chloro-S-sulfamoyl-anthranilic acid, 7.5 cm ³ of a 37% aqueous formaldehyde solution and 50 cm ³ of butanol was heated for 3 h on a water bath to 75 to 8O ⁰ C. The hot reaction mixture was filtered, cooled to room temperature and left to stand for 16 hours. The precipitated crystals were filtered, washed with butanol and with methylene chloride and dried to give 15.1 g of N-furfuryl-4-chloro-5- (butoxymethylsulfamoyl) anthranilic acid, mp. 139-140 ⁰ C.

40

45

55

60 Elemental analysis for C ₁₇ H ₂ ] C
Calculated: C48.98, H 5.04, N 6.72%;
found: C 48.96, H 5.14, N 6.74%.

The UV and NMR spectrum were consistent with the structure.

Concentration of the mother liquor gave a further 2.8 g of the product, melting point 137 to 139 ° C.

Example 5

N-furfuryl-4-chloro-5- (butoxymethylsulfamoyl) anthranilic acid

20 g of N-furfuryl-4-chloro-5- (methoxymethylsulf-

amoyl) anthranilic acid were dissolved in 60 cm ³ of butanol and the solution was heated for 3 h at 75 to 8O ⁰ C, cooled to room temperature and allowed to stand h 16th The precipitated crystals were filtered off, washed with methylene chloride and dried. 19 g of N-furfuryl-4-chloro-5- (butoxymethylsulfamoyl) anthranilic acid, melting point 142 to 145 ° C., were obtained

Example 6

N-furfuryl-4-chloro-5- (allyloxymethyIsulfamoyl) -anthranilic acid

20 g of N-furfuryl-4-chloro-5- (methoxymethylsulf-

amoyl) anthranilic acid were dissolved in 60 cm ³ of allyl alcohol and the solution heated 1 h at 8O ⁰ C, cooled and allowed to stand for 16 h at room temperature. The precipitated crystals were filtered off, washed with allyl alcohol and chloroform and dried

obtained 15.3 g of N-furfuryM-chloro-S-iallyloxymethylsulfamoyl) anthranilic acid, melting point 136 to 138.5 ° C.
Elemental analysis for CIbHuCIN ₂ ObS:

Calculated: N 6.99, Cl 8.85, S 8.00%;

found: N 6.91, Cl 9.02, S 7.99%.

Example 7

N-furfuryl-4-chloro-5- (propargoxymethylsulfamoy ^ -anthranilic acid

20 g of N-furfuryl-4-chloro-5- (methoxymethylsulf-

amoyl) anthranilic acid were ^{dissolved in 220 cm 1 of} propargyl alcohol at 80 ° C. and kept at this temperature for a further hour. The solution was then cooled and left at room temperature for 16 hours. The precipitated crystals were filtered off, washed with propargyl alcohol and with chloroform, and dried. 21.9 g of N-furfuryl-4-chloro-5- (propargoxymethylsulfamoyl) anthranilic acid, melting point 161 to 162 ° C., were obtained. After recrystallization, the melting point rose to 172-174 ° C.
Elemental analysis for Ci ₆ Hi ₅ CIN ₂ ObS:

Calculated: N 7.03, Cl 8.89, S 8.04%;

found: N 7.04, Cl 9.25, S 7.93%.

Example 8

N-furfuryl-4-chloro-5- (benzyloxymethylsulfamoyl) anthranilic acid

10 g of N-furfuryl-4-chloro-5- (methoxymethylsulf-

amoy ^ anthranilic acid were dissolved at 80 ⁰ C in 30 cm ³ of benzyl alcohol, maintained for 1 hour at this temperature, the solution was cooled and allowed to stand for 16 h at room temperature. The precipitated crystals were filtered off, washed with benzyl alcohol and chloroform, and dried. 11.2 g of N-furfuryl-chloro-S-fbenzyloxymethylsulfaiTioyl-anthranilic acid, melting point 133 to 134 ° C., were obtained.

After recrystallization, the melting point rose to 134 to 136 ° C.
Elemental analysis for C ₂₀ HI _{9 ClN 2} ObS:

Calculated: N 6.22, Cl 7.86, S 7.11%;

found: N 6.21, Cl 8.1, S 6.99%.

Example 9

N-furfuryl-4-chloro-5- (furfuryloxymethylsulfamoyl) anthranilic acid

20 g of N-furfuryl-4-chloro-5- (methoxymethylsulf-

^{amoyl) anthranilic acid were dissolved in 60 cm 3 of} furfuryl alcohol at 80 ° C., left to stand at this temperature for a further hour, the solution was cooled and left to stand at room temperature for 16 h. The precipitated crystals were filtered off, washed with furfuryl alcohol and with chloroform and dried. 11 g of N-furfuryl-4-chloro-5- (furfuryloxymethysulfamoyl) anthranilic acid, melting point 141 to 143 ° C., were obtained. After recrystallization, the melting point rose to 145 to 146 ° C.
Elemental analysis for Ci ₈ H _{17 ClN 2} O ₇ S:

Calculated: N 6.36, Cl 8.04, S 7.27%;

found: N 638, Cl 7.96, S 7.34%.

Example 10

N-Cyclohexyl-chloro-S-methoxymethylsulfamoyl) anthranic acid

33 g of N-cyclohexyM-chloro-S-suIfamoyl-anthranilic acid, 1.5 cm ^{J of} a 36% strength aqueous formaldehyde solution, 7 cm ^J methanol and 1.0 g sodium bicarbonate were heated to reflux temperature for 1 h. The reaction mixture was then cooled, acidified to pH 1 with 10% strength aqueous hydrochloric acid, and the precipitate was filtered off, washed with methanol and dried. 1.7 g of N-cyclohexyl-4-chloro-5- (methoxymethylsulfamic!) Anthranilic acid, melting point 170 ° C. (decomp.), Were obtained after recrystallization from methanol.

Example Il

Na salt of N-furfuryl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid

16.5 g of N-furfuryl-4-chloro-5-sulfamoyl-anthranilic acid and 5 g of sodium bicarbonate were dissolved in a mixture of 33 cm ^{3 of} methanoi and 7.5 cm ^{3 of} a 37% strength aqueous formaldehyde solution and the mixture at room temperature for 16 hours ditched. The solution was filtered and the filtrate was diluted with diethyl ether. The precipitate was filtered off with suction, washed with ether and dried. 11.2 g of sodium salts were obtained

N-furfuryl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid.

Example 12

N-furfuryl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid

5 g of N-furfuryl-4-chloro-5- (butoxymethylsulfamoyl) anthranilic acid and 15 cm ^{3 of} methanol were _{heated to reflux temperature for 2} hours, a clear solution being formed. It was heated for an additional fifteen minutes, began to occur in the reaction mixture wherein a precipitate, and then further 3V ₂ h. The reaction mixture was cooled and filtered, and the resulting crystals were washed with methanol and methylene chloride. 3.4 g of N-furfuryl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid, melting point 155 ° to 160 ° C., were obtained.

Example 13

N-furfuryl-4-chloro-5- (pentoxymethylsulfamoyl) anthranilic acid

20 g N-furfuryl ^ -chlor-S-imethoxymethylsulf-

amoyl) anthranilic acid was dissolved in 60 cm ^{3 of} pentanol and the solution was heated to 80 to 90 ° C. for 3 h, cooled and left to stand at room temperature for 24 h. The crystals were filtered off, washed with methylene chloride and dried at 50.degree. 15 g of N-furfuryl-chloro-S-ipentoxymethyisulfamoyl-anthranilic acid were obtained, m.p. 136 to 137 ° C.
Elemental analysis for Ci8H ₂ jCIN2O _b S:

Calculated: N 6.50, Cl 83, S 7.44%;

found: N 6.48, Cl 8.00, S 7.5%.

Example 14

N-furfuryl-4-chloro-5- (hexoxymethylsulfamoyl) anthranilic acid

20 g of N-furfury1-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid were dissolved in 60 cm ^{3 of} hexanol and heated to reflux temperature for 2 hours, then the solution was cooled and left to stand at room temperature for 16 hours. The precipitated crystalline precipitate was filtered off, with hexanol and with

Washed in chloroform and dried at 50 ° C. N-furfuryl-4-chloro-5- (hexoxymethylsulfamic) anthranilic acid, melting point 112 ° to 114 ° C., was obtained. After recrystallization, the melting point rose to 116 to 117 ° C.
Elemental analysis for CmH ₂₅ CIN ₂ O ₆ S:

Calculated: N 6.29, Cl 7.96, S 7.20%;

found: N 6.1, Cl 8.0, S 7.2%.

Example 15

N-furfuryl-4-chloro-5- (heptoxymethylsulfamoyl) anthranilic acid

20 g of N-furfuryl-4-chloro-5- (methoxymethyl-sulf-

amoyl) anthranilic acid was dissolved in 60 cm 'of heptanol and heated to reflux temperature for 2 hours. The solution was cooled and left to stand at room temperature for 16 hours. The crystalline precipitate was filtered off, washed with heptanol and with methylene chloride and dried. N-furfuryl-4-chloro-5- (heptoxymethylsulfamoyl) anthranilic acid, melting point 131 ° to 133 ° C., was obtained. After recrystallization from aqueous isopropanol, the melting point rose to 133 to 135 ° C.
Elemental analysis for C ₂₀ H _{27 ClN 2} O ₆ S:

Calculated: N 6.10, Cl 7.72, S 6.98%; found: N 6.1, Cl 7.56, S 7.2%.

Example 16

N- (n-butyl) -4-chloro-5- (methoxymethylsulfamoyl) -

anthranilic acid - ¹⁰

24.5 g of N- (n-butyl) -4-chloro-5-sulfamoyl-anthranilic acid, 80 g of sodium bicarbonate, 60 cm ^{3 of} methanol and 120 cm ^{3 of} a 37% strength aqueous formaldehyde solution were heated to reflux temperature for one hour. The reaction mixture was filtered hot and ^{acidified with 8 cm 3 of} acetic acid. The precipitate was stirred for 3 h at room temperature, filtered off, washed with methanol and dried. 22.7 g were obtained

N-yn-butyl ^ -chlor-S-imethoxymethylsulfamoy ^ -anthranilic acid, Mp. 167 to 169 ° C after recrystallization from methanol-dioxane (1: 1) - 99.5% pure.

Example 17

N-Cyclohexyl ^ -chloro-S ^ n -butoxymethylsulfamoyl) anthranilic acid

45

10 g of N-cyclohexyl ^ -chloro-S-imethoxymethylsulfamoyl) anthranilic acid were dissolved in 30 cm ^{3 of} n-butanol at 75 ° C. and the solution was kept at 80 to 90 ° C. for one hour. The solution was then cooled to 40 ⁰ C, 30 cm ³ of petroleum ether added and the mixture stirred for 3 h at room temperature the crystals formed were filtered off, washed with petroleum ether and dried at 50 ° C to give 5.5 g of N-cyclohexyl

4-chloro-5- (n-butoxymethylsulfamoyl) -anthranilic acid,
Mp. 143-145 ° C, 99.2% pure.

Example 18

N-Benzyl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid

60

23.8 g of N-benzyl ^ chloro-S-sulfamoyl-anthranilic acid, 7.0 g of sodium bicarbonate, 50 cm ^{3 of} methanol and 11 cm ^{3 of} a 37% strength aqueous formaldehyde solution were heated to reflux temperature for 1 h. The reaction mixture was filtered hot and at 7 cm ³ Acetic acid acidified. The precipitate was stirred at room temperature for 3 h, filtered off, washed with methanol and dried. 15.6 g of N-benzyl-4-chloro-5- (methoxymethylsulfamoyl) anthranilic acid, melting point 164 to 165 ° C. (decomp.), After recrystallization from methanol and dioxane (2: 1), 98.4% were obtained pure.

Example 19

N-furfuryl-4-chloro-5- (isopropoxymethylsulfamic]) anthranilic acid

16.5 g of N-furfuryl-4-chloro-5-sulfamoyl-anthranilic acid in 33 cm ^{3 of} isopropanol containing 5 cm ^{J of} a 37% strength aqueous formaldehyde solution were heated under reflux until a clear solution resulted. This was then refluxed for an additional hour, cooled to room temperature and allowed to recrystallize overnight. The next day the crystals were filtered off, washed with isopropanol and dried at 50.degree. Yield 7.9 g, m.p. 123-125 ° C.

The product crystallized with half a mole of isopropanol. Purity 100%: by thin layer chromatography in chloroform: dioxane (7: 3) the compound was found to be pure (Rf approximately 0.5).

Example 20

N-furfuryl-4-chloro-5- (ethylthiomethylsulfamoyl) anthranilic acid

16.5 g of N-furfuryl ^ -chloro-S-sulfamoyl-anthranilic acid, 10 cm ^{3 of} a 37% aqueous formaldehyde solution, 10 cm ^{3 of} ethanethiol (ethyl mercaptan), 5 g of sodium bicarbonate and 40 cm ^{3 of} methanol were heated in a water bath with stirring, until complete dissolution occurred and then another hour. The reaction mixture was filtered and 80 cm ^{3 of} water and 5 cm ^{3 of} glacial acetic acid were added to the cooled filtrate. The crystals formed were filtered off, washed with isopropanol, water and again isopropanol. The product was recrystallized from isopropanol and dried. 13.6 g of N-furfuryl-4-chloro-5- (ethylthiomethylsulfamoyl) anthranilic acid, melting point 166 ° to 168 ° C., were obtained. The melting point did not change after further recrystallization from n-butanol. The compound was found to be pure by thin layer chromatography, and the structure was confirmed by UV and NMR spectrum.
Elemental analysis for C ₁₅ Hi ₇ CIN ₂ O ₅ S ₂ :

Calculated:

C 44.49, H 4.23, N 6.91, Cl 8.75, S 15.8%;

found:

C 44.65, H 4.36, N 6.88, Cl 8.7, S 15.8%.

Example 21

N-furfuryl-4-chloro-5- (n-propylthiomethylsulfamoyl) anthranilic acid

If, in the procedure of Example 20, the ethanethiol was replaced by an equal amount of n-propanethiol, 8.8 g of the above compound were obtained, melting point 158 to 159 ° C.
Elemental analysis for Ck ₁ Hi ₉ CIN ₂ OsS ₂ :

Calculated:

C 45.87, H 4.57, N 6.68, Cl 8.47, S 15.27%;

found:

C 45.74, H 4.25, N 6.72, Cl 8.3, S 15.1%.

Example 22

N-furfuryl-4-chloro-5- (isopropylthiomethylsulfamoyl) anthranilic acid

If, in the procedure of Example 20, the ethanethiol was replaced by an equal amount of isopropanethiol, 9.1 g of the abovementioned compound were obtained, mp up to 166 ° C.
Elemental analysis for CIhHnCIN ₂ O ₅ S ₂ :

Calculated:

C 45.87, H 4.57, N 6.68, Cl 8.47, S 15.27%;

found:

C 45.70, H 4.63, N 6.67, CI 8.35, S 15.1%.

Example 23

N-Furfuryi-4-chloro-5 - (^ - hydroxyäthyithiomethyisulfamoylj-anthranilic acid

Was replaced with the procedure of Example 20, the Äthanthiol by an equal amount jS-mercaptoethanol, there was prepared 17.6 g of the above compound, mp. 149-150 ⁰ C.
Elemental analysis for Ci5Hi ₇ CIN ₂ ObS ₂ :

Calculated:

C 42.77, H 4.07, N 6.66, Cl 8.42, S 15.23%; found:

C 42.93, H 4.17, N 6.63, Cl 8.37, S 15.2%.

Example 24

N-furfuryl-4-chloro-5- (2,3-dihydroxypropylthio- · ¹⁰ methylsulfamoyl) -anthranilic acid

Was replaced in the procedure of Example 20, the Äthanthiol by an equal amount "thioglycerol, so 16 g of the compound, mp above was obtained. To 14O ⁰ C.
Elemental analysis for Ci ₆ H _{20 ClN 2} O ₇ S ₂ :

Calculated:

C 42.62, H 4.25, N 6.20, Cl 7.87, S 14.19%;

found:

C 42.35, H 4.55, N 6.3, Cl 7.81, S 14.2%.

Example 25

N-furfuryl-4-ch! Or-5- (benzyithiomethylsulfamoyl) anthranilic acid

If, in the procedure of Example 20, the ethanethiol was replaced by an equal amount of benzylthiol, 14.8 g of the above compound were obtained, m.p. 160 ° C.
Elemental analysis for C ₂ OH _{2 OClN 2} OsS ₂ :

Calculated:

C 51.33, H 431, N 5.99, Cl 7.57, S 13.70%;

found:

C 51.36, H 4.19, N 5.95, Cl 7.4, S 13.6%.

Example 26

N-furfuryl-4-chloro-5 - (/? - hydroxyethylthiomethylsulfamoyl) anthranilic acid

20 g N-FurfuryM-chlor-S-imethoxymethylsulf-

amoyl) anthranilic acid were ^{suspended in 60 cm 3 of} jS-Mtrcaptoethanol and the suspension was heated in a water bath with stirring to 80 to 90 ° C until a complete solution had occurred and 2 h after that. The clear solution was ^{diluted with 60 cm 3 of} water and left to stand at room temperature for h. The crystalline

45

(■ 5 ne precipitate was filtered off, washed with isopropanol and dried. 15.6 g of N-furfuryl-chloro-Si / S-hydroxyethylthiomethylsulfamoyl-anthranilic acid, melting point 147 ° to 149 ° C., were obtained. When a sample was mixed with the product No lowering of the melting point occurred according to Example 23. The N-furfuryl-4-chloro-5- (methoxymethylsulfamic!) anthranilic acid, which was used as the starting substance, was prepared according to Example 1.

Example 27

N-furfuryl-4-chloro-5- (2,3-dihydroxypropylthiomethylsulfamoyl) anthranilic acid

If the /? - mercaptoethano! by an equal amount of thioglycerin, 18.1 g of the abovementioned compound, melting point 138 ° to 140 ° C., were obtained. When mixing one Sample with the product of Example 24 did not lower the melting point.

Example 28

N-furfuryl-4-chloro-5- (j3-ethoxyethoxymethylsulfamoyl) anthranilic acid

20 g of N-furfuryl-4-chloro-5- (methoxymethylsulf-

amoyl) anthranilic acid were dissolved at 80 ⁰ C in 30 cm ³ of 2-ethoxyethanol and 3 maintained at this temperature h. The solution was then concentrated to half of its original volume, cooled and allowed to stand at room temperature for 16 hours. The crystalline precipitate was filtered off, washed with 2-ethoxyethanol and benzene in a ratio of 1: 9 and dried. 9.4 g of N-furfuryl-4-chloro-5- (ßäthoxyäthoxymethylsulfamoyl) anthranilic acid, melting point 104 to 107 ° C. were obtained.
Elemental analysis for Ci ₇ H _{2 IClN 2} O ₇ S:

Calculated: S 7.40, N 6.4, Cl 8.19%;

found: S 7.38, N 6.3, Cl 8.3%.

Example 29

N-furfuryl-1-chloro-S-cyclohexoxymethylsulfamoyl) anthranilic acid

20 g of N-furfuryl-4-chloro-5- (methoxy-methyisulf-

amoyl) anthranilic acid were dissolved at 80 ⁰ C in 40 cm ³ of cyclohexanol and held for three more hours at this temperature, cooled and allowed to stand for 16 hours at room temperature. The crystalline precipitate was filtered off, washed with cyclohexanol and benzene in a ratio of 1: 9 and dried. To give 6 g of N-furfuryl ^ -chloro-S-icycloiiexoxymethylsulfamoyl) -anthranilic acid mp. 137-140 ⁰ C.
Elemental analysis for QqH ₂₃ CIN ₂ S:

Calculated: S 7.23, N 6.32, CI 8.00%;

found: S 7.20, N 6.3, Cl 8.10%.

Production of an inventive
Medicinal product

Example 30

100 g of N-furfuryl-4-chloro-5- (butoxymethylsulfamoyl) anthranilic acid were thoroughly mixed with 800 g of lactose and the mixture to a particle size of 0.84 mm finely ground and sieved. The mixture was filled into capsules, each of which was 25 and 50 mg active Substance contained.

Claims (1)

Patent claims: 1. 4-chloro-5-sulfamoyl-anthranilic acids of general Formula Cl NHR, (D R ₁ -X-CH ₂ -NHSO ₂ COOH