DE1768818A1 - Anthranilic acid amide - Google Patents

Description

The present invention relates to hitherto unknown compounds in the form of N-substituted anthranilic acids with basic substitution in the amide group, which acteam as analgesics and are very suitable for drugs because they have low toxicity. They are distinguished by the fact that they have little or no antipyretic effect and show no Straub effect in muses. The compounds according to the invention are not destroyed in the stomach and in many cases they can be taken orally with an excellent effect
administered. They make amine salea, for example
Hydrochloride or Citrate, which is good in many cases
crystallize and are suitable for the manufacture of solid dosage forms such as pills or tablets for oral administration.

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BATHROOM 0

The compounds of the present invention are of the general nature

Formula I.

where R. a lower alkyl group with 1 to 5 carbon atoms, in particular a methyl group, or hydrogen, R «an alkylene group with 2 to 5 carbon atoms, preferably ethylene or propylene, IU and R, either both methyl or both ethyl or one ethyl and the other methyl and £ e and R ^ hydrogen, provided that IU and Rg are not simultaneously hydrogen, alkyl having 1 to 5 carbon atoms or halogen or a halogen-like group, in particular Cl ₁ Br or CP, and to the amino group in O - position, m-position or both in o- and m-position. In the cases where R ₁ , R, or R, vind Re or Bg are alkyl, the methyl group is in many cases the most effective among the alkyl groups. .

To illustrate the biological action of the previously unknown compounds according to the invention, the results are compiled in Table I with those with mice the hot plate method. For each individual substance, the dose (in mg / kg body weight) is

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give, at 30 minutes after subcutaneous injection the ··? Dose a doubling of the reaction time observed without injection is obtained »where the reaction time is the period of time that elapses until the muse become restless and raise their paws. Codeine is used as a reference substance, and it appears that the novel compounds of the present invention have an activity at least as large as that of codeine. On the other hand, they do not show the disadvantages of codeine, in particular no narcotic effect in humans.

Table II shows the results obtained when the analgesic effect was measured using the acetic acid test in mice. After receiving intraperltoeally injected doses of 0.2 ml of 0.5% acetic acid, mice show a typical syndrome consisting of periodic curvature of the body. The number of bends can be counted by means of a counting device. The comparison with an untreated control group allows the quantitative determination of the analgesic effect.

Table I.

Anaigetic effect, measured in doses in mg / kg bc, which doubled the reactivity 30 minutes after injection in mice by the hot plate method

cause time

H- (2-methylphenyl) anthranil
acid (2-dimethylaminoethyl)
amide

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Porting of table I

N- (3-methylphenyl) anthranilic acid (3-dimethyiaminopropyl ) amide

N- (2,3-xylyl) anthranilic acid (2-dime ethyl aminopropyl) acid

N- (2-methyl-3 «chlorophenyl) anthranil acid (2 «diniethylaminoethyl) amide

N- (3-Trifluoriae thyl phenyl) -anthranilic acid- (2-dimethylaminoethyl) amide

Codeine

39 16

39 33

T a b e 1 1 e II

Anaigetic effect as measured by the acetic acid tea in mice

N- (2-chlorophenyl) anthranilic acid (3-dimethylaainopropyl) amide

U- (3-chlorophenyl) anthranilic acid (3-dimethylaminopropyl) amide

N- (2-Methyl-3-chlorophenyl) anthranileic acid (2-dimethylaminopropyl) amide

N- (3-trifluoromethylphenyl) anthranilic acid (3-dimethylaminopropyl) amide

imidopyrine

mg / kg β.ο.

17.0

7.8

13.0

12.5 41.0

The animals are injected subcutaneously 30 minutes before the acetic acid injection. The number of curvatures will last for 20 minutes after the injection

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1768518

Acetic acid counted. The percentage reduction in the curvature syndrome is calculated relative to the number of curvatures in the animals of the control group. In the table, the indicated SosiB _f in which the number of the curvatures iat reduced by 50 #. Amidopyrine has been used as a reference substance.

The trials clearly show a considerable improvement the effect in comparison with known anaigetics

The same effect can be obtained with oral administration, although the experiments have been carried out by parenteral administration of the amine in the form of its salts, namely the hydrochlorides and the citrates. Both the AmIn All the above or other salts of the amine are also for oral or parenteral administration good in human therapy suitable.

The invention also relates to methods of making the compounds mentioned above. In this regard, the invention is characterized in that a benzamide with the formula II which is basically substituted in the amide group

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^ The meaning given above and R ₇

where R ^ i ₈ ρ

means a halogen atom or a reactive group with a substituted aminobensol of the formula III

III

is reacted, in which R, - and Rg have the meaning given above, or that a mixed anhydride of the anthranilic acid substituted by Re and Rg with the above meaning and of the carbonic acid monoalkyl ester with the general formula

CO.O.00.OR ₈

where Rq is alkyl with the diamine

is reacted or that N- (2,3-R ₅ RgCgH. ^ isatoic anhydride with the general formula

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is reacted with the diamine RR ^ NR ₂ NHR _1. If the first- mentioned procedure is used, the reaction should take place in an organic solvent such as dimethylformamide or amyl alcohol, and with the addition of an acid binder, for example potassium carbonate, and optionally copper as a catalyst.

After isolation of the amine, for example, by distilling from the solvent and optionally carrying out redistillation, and a recrystallization, the amide may, if desired, by methods known per se into one of the above-mentioned amine salts are converted. ·

The invention is further illustrated below with the aid of the examples.

Example 1-

30 g of H- (3-dimethylaminopropyl) -o-chlorobenzamide (0.125 Hol), 75 ml of dimethylformamide, 45 g of m-aminobenzene methyl trifluoride (0.28 Hol), 19 g of anhydrous granulated potassium carbonate and 1 g of copper bronze are mixed at room temperature, after which the mixture

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Ίϊϊββίβ

Is heated to reflux for 8 hours. After cooling , the mass is filtered clear and the dimethylformamide is removed by distillation at about 12 mm Hg.

There remains a dark oil, which is redistilled, wherein said at 0.2 mm Hg between 195 ° C and 200 ⁰ C condensing fraction is recovered. This fraction consists of the free amide, the yield is 15 g.

The amide is dissolved in 200 ml of ether and to the solution dry hydrogen chloride is introduced to give an oil separates. This oil is dissolved in 100 ml of acetone. When gasoline is added to this solution, an oil separates out, which is then dissolved in 100 ml of chloroform. Upon addition of 800 ml ethers to this solution to a sticky mass separates which becomes crystalline on standing and can be dried at 70 ⁰ C. In this V / else be 9i5 g of the hydrochlorides de β H- (3-Tr lfluorme thylphenyl) -anthranll acid- (3-dlnte thylaminopropyl) -amld with a F won * 132 to 135 ⁰ C.

Example 2

28.4 g of N- (2-dimethylaminoethyl) -o-chlorobeiusaaid (0.125 hol). 75 ml of amyl alcohol, 29.96 g of o-Ioluidln (0.28 Hol), 19 g of anhydrous granulated potassium carbonate (1.4 mol) and 1 g of copper bronze are cut at room temperature. The mix will

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Heated to reflux for 3 hours, cooled and filtered until clear. The amyl alcohol is distilled at about 12 am Hg removed.

What remains is a dark oil that is distilled

ο where the 0.1 to 0.2 mm Hg between 184 C and 195 C

condensing fraction is collected.

This Prakbion consists of the amide obtained g in the amount of 6 and can be recrystallized from ether to give a white powder, the yield 3.5 g auemacht and having a P = ⁰ 111 G has to 113 ⁰ C.

The free amide is dissolved in 400 ml of ether and dry hydrogen chloride is introduced, a pale yellow oily mass separating out. On standing, this mass crystallizes to form a product that is hard as glass. The product is comminuted and dried at 80 ⁰ C.

The crystalline product consisting of the hydrochloride dea H- (2-methylphenyl) -anthranilsäure- (2-dimethylaminoethyl) -amida, for a 1 "144 to 146 ⁰ C is found. The yield is 3.4 g.

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Example 3

• 56.8 g H «(2> methylaminoethyl) - o-chlorobenzene (0.125 mol), 150 ml dimethylformamide, 70 g 3 ~ chloro-2-methylanilln (0.28 mol), 35 g of anhydrous granulated potassium carbonate (1.4 moles), 1 g Copper bronze and 1 g copper-I-chloride are made at room temperature door mixed.

The mixture is refluxed for 8 hours, cooled, filtered clear and / or distilled at about 12 mm Hg, the dimethylformamide is removed. The residue consists of a dark oil which is distilled, a ^{fraction which condenses at 0.1 to 0.2 mm Hg between 200 and 210 °} C. is collected. This fraction consists of the amide and is obtained in a yield of 8 g. / duroh

The amide is dissolved in 200 ml of ether and dry hydrogen chloride is introduced, giving an oily mass separates. This mass is recovered and dissolved in about 50 ml of acetone. About 2 liters of ether are added to this solution until an ul is deposited, which is obtained and la 50 al Acetone is dissolved. By adding about 2 liters of ether a milky mixture is obtained, which after standing for one A yellowish substance is deposited day and night. Dleere Subs tan "is a hydrochloride of K- ^ -methyl phenyl) - anthranilic acid (2-dimethylaminoethyl) amides.

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D getro then 5 g. It has a P «144 to 147 ^W C.

The flydrochlorid is isolated and dried at 60 ⁰ C and weighs

At game 4

Ee a mixed anhydride of the OT (2-methyl-3-chloa> · phenyl) -anthranilic acid and the carbonic acid monoethyl ester is produced. For this purpose, a mixture of 26 g N- (2-methyl-3-ehlorphenyl) anthranilic acid (0.1 mol) and prepared Itnylchlorformiat, to which 10.6 g of triethylamine (0.105 mol) was added dropwise at 25 ⁰ C in the course of 30 minutes to be given. The product formed is left to stand at 25 ^° C. for 24 hours, after which it is heated on a steam bath for 8 hours, then it is cooled and 300 ml of benzene are added. The mixture is stirred thoroughly and filtered to give a clear solution of the mixed anhydride in benzene. This solution is evaporated in vacuo to completely remove the benzene, whereby the mixed anhydride is obtained in the form of a viscous, yellow oil with an ester-like odor. The yield is 34 gi, which corresponds to about 100% of the theoretical yield.

12.8 g dirnethylaminopropylamine (0.125 mol) are with 52 ml of water are mixed, after which the mixture is heated to reflux and 3314 g (0.1 mol) of the above prepared mixed anhydride in small amounts in the course of -20 Mi-

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utes be added ffaoh addition of the mixed anhydrides of the Misohung more $ 1 minutes is boiled to reflux, where "cooled to room temperature after it and diluted hydrochloric acid is added to adjust the pH value to provide to 1. Some insoluble by-products precipitate · They are removed by filtration and sodium hydroxide solution is added to the aqueous phase in order to adjust the pH to 10 · This causes an oil to separate out, which is converted into Xther by shaking and dried with sodium sulfate is, after which-the ether is removed and the oily residue is distilled. The yield of the desired amine with a boiling point of 210 to 220 ^° C. at 0.1 mm Hg is 20 g, which corresponds to 58% of theory.

The amide base obtained in this way is dissolved in 130 ml of ether, after which dilute hydrochloric acid is added to adjust the pH to set to 1 and 100 ml of water are added. The aqueous phase is removed, filtered clear with Deoalit and evaporated to dryness in vacuo on the steam bath. The residue is recrystallized from 100 ml of acetone. The yield is 17 g of the hydrochloride of Äf- (2-Kethyl-3-chlorophenyl) antliranile acid (3-dimethylaminopropyl) amides, which corresponds to 77 * the theoretically possible yield, based on

ο amide base. The product has an F ■ 194 to 196 C.

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BATH 109853/1916

Example 5

For the production of ff- (2,3-xylyl) anthranilic acid (3-dimethylaminopropyl) amide becomes N- (2,3-xylyl) -isatoic anhydride first manufactured in the following way.

To a mixture of 79 g of phosgene (0.8 mol) in 425 g of toluene, to which 54 g of N- (2,3-xylyl) anthranilic acid (0.224 mol) have been added, are added dropwise, after cooling to O ⁰ O 44, 8 g of triethylamine (0.448 mol) are added, the addition taking place over the course of 60 minutes. The temperature rises during the addition, but cooling is provided to keep the temperature no higher than 25 ° C. The reaction mixture is then left to stand at 25 ^° C. for 24 hours, after which it is ^{heated to 95 °} C. for 4 hours and then evaporated to dryness in vacuo. The cuckoo is then heated with 1200 ml of benzene for 30 minutes, after which an insoluble by-product formed is removed by filtration.

The filtered benzene solution is treated with charcoal and evaporated to 200 ml, followed by cooling. As a result, the anhydride crystallizes and is recovered. It has a P * 130 to 152 ⁰ C and is obtained in a yield of 32 g, which corresponds to 54.59 ^ 'of theory.

Because becomes a mixture of 12.8g of dimethylaminopropyl amine and 52 ml of water and this mixture is made

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_B A0

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heated to reflux after 26.7 g of the N- (2,3-xylyl) -i8atoic anhydride B prepared above had been added in small amounts over the course of 20 minutes. Ee is refluxed for an additional 15 minutes, after which the mixture is cooled to room temperature and dilute hydrochloric acid is added to adjust the pH to 1. An insoluble by-product occurs, which is removed, after which a sodium hydroxide solution is added to the aqueous phase in order to adjust the pH to 10. Babel separates the amine base as an oil, which is shaken out with the aid of ether, after which the ethereal solution is dried with sodium sulfate and the ether is removed by evaporation. An ul remains which is distilled. The distillate consists of N- (2,3-XyIyl) -anthranilsäure- (3-dimethylaminopropyl) amide, which boils at a pressure of 0.1 mm Hg at 197 to 201 ⁰ C. The yield is 17 g, which corresponds to the theoretically possible yield.

The recovered amide base is dissolved in 150 ml of ether, after which dilute hydrochloric acid is added to adjust the pH to 1 and another 100 ml of water are added. The aqueous phase is removed and the vacuum is evaporated to dryness in a steam bath. The residue obtained is recrystallized as 200 ml of acetone, whereby a yield of the hydrochloride of 15 g is obtained, which corresponds to 99-4% , based on the amide base. The melting point is 188 to 191 ^° C.

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Example 6

To a mixture of 79 g of phosgene (0.8 mol) in 425 g of toluene and 51 g of N- (3-methylphenyl) anthranilic acid (0.224 mol) are added dropwise, after cooling to ⁰ ° C., 44.8 g of triethylamine (0.448 col) with the dropwise addition being carried out over a period of about 60 minutes.

During the dropwise addition the temperature rises, but it is kept at a temperature not exceeding ^{25 ° C by cooling.} The mixture is left to stand at this temperature for 24 hours, after which it is ^{heated to 95 0} O for 4 hours. It is then evaporated to dryness in vacuo. The residue thus obtained is refluxed with 1200 ml of benzene for 30 minutes, whereby it dissolves and leaves a small amount of insoluble by-product which is removed from the solution by filtration. The solution in benzene is treated with charcoal while hot and then evaporated to 800 ml, cooled and mixed with 1100 ml of benzene with vigorous stirring. The anhydride precipitates in a yield of 34 g, which corresponds to 60 # of the theoretical yield, and has a melting point between 183 and 185 ^° C.

11 g of 2-dimethylaminoethylamine (0.125 mol) are now mixed with 52 ml of water, after which the mixture is heated to boiling under reflux and 25.3 g of N- (3-methylphenyl ^ isatoic anhydride (0> 1 mol), obtained as described above ,

- 15 109853/1916

be admitted. The reaction mixture is refluxed for another 15 minutes and then cooled to room temperature. The pH is adjusted to 1 with dilute hydrochloric acid, as a result of which an insoluble by-product separates out, which is removed by filtration. Sodium hydroxide solution is then added to the aqueous phase in order to adjust the pH to 10. As a result, the amide base separates out as an oil, which is shaken out with ether, after which the ether phase is dried with sodium sulfate and the ether is removed. The residue is an oil which is distilled to give a yield of 20 g, corresponding to 67 # of the theoretically Eiöglichen Auebeute, product is recovered having a boiling point 197-200 ⁰ C at 0.2 mm Hg. To prepare the hydrochloride of the K- (3-methylphenyl) anthranilic acid (2-methylaminoethyl) amide obtained in this way, it is dissolved in 150 ml of ether, after which dilute hydrochloric acid is added to pH 1, after which 100 ml of water are added. The aqueous phase is clear and is isolated and evaporated to dryness in vacuo on the steam bath. The residue is dissolved in chloroform, placed in a Petri dish and evaporated and dried in a vacuum desiccator. The product is hygroscopic. The yield is 19 g, corresponding to 84.5 #) based on the amide base.

As examples of compounds according to the invention which can be prepared according to the procedures described above

- 16 109853/1916

can be named:

K- (2,3-xylyl) -anthrannelic acid- (3-dimethylaminopropyl) -aaid, bp »210 Ms 212 ⁰ O at 0.1 mm Hg. The hydrochloride has a P β 188 to 191 ⁰ O.

N- (3-trifluoromethylphenyl) -anthranilsäure- (3-dimethylaminopropyl) amide, Kp ■ 195-200 ⁰ O at about 0.2 mm. Hydrochloride P a 132 to 135 ⁰ C.

N- (3-methylphenyl) anthranilic acid (3-dimethylaminopropyl) amide, bp "204 to 210 ⁰ O at 0.1 mm Hg. Hydrochloride P" 123 to 126 ⁰ C.

H- (3-Drifluormethylphenyl) -anthranilsäure- (2-dimethylaminoethyl) amide, Kp β 190-198 ⁰ C at 0.2 mm Hg. The hydrochloride is hygroscopic, P 'below 50 ⁰ C.

K (2-methyl-3-chlorophenyl) -anthranilsäure- (2-dimethylamino-ethyl a) -amide, Kp '200 bia 21O ⁰ C at 0.1 to 0.2 mm Hg. * P hydrochloride 144-147 ° c.

Sr- (2,3-xylyl) -anthranilic acid- (2-dimethylaminoethyl) -aaid, bp β 187 to 200 ⁰ O at 0.1 mm Hg. Hydrochloride P * 138 to 140 ⁰ C.

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N- (3-Me thylphenyl) -anthranilsäure- (2-dimethylaminoethyl) amide, Kp a 194-200 ⁰ C at 0.2 mm Hg. Citrate P "50 bit 53 ⁰ C

N- (2-Me thylphenyl) -anthranil acid (2-dime thylaminoäthyl) amide, Ep * 184-195 ⁰ C at 0.1 to 0.2 mm Hg. Hydrochloride ■ P 144 to 146 ⁰ C.

N- (2-methyl-3-chlorophenyl) -anthranil acid- (3-diäthylaminopropyl) · amide, Kp "200 ° to 210 ⁰ C at 0.2 mm Hg. Citrate P ■ 55" to 60 ⁰ C.

N- (3-trifluoromethylphenyl) -anthranilic acid- (3-diethylaminopropyl) -omide, bp - 185 to 20O ⁰ C at 0.1 to 0.4 mm Hg. Bas Οίο occurred Ιβ'ύ somewhat hygroscopic and has a P = 40 to 44 C.

N- (2,3-xylyl) -anthranilsäure- (3-diäthylaminopropyl) amide, Kp ■ 205-213 ⁰ C at 0.2 mm Hg to 0.4. Citrate P ■ 80 to 85 ⁰ C.

N- (3-methylphenyl) -anthranilsäure- (3-diäthylaminopropyl) -amide, bp = 210-224 ⁰ C at 0.2 mm Hg to 0.5. Citrate P "78 to 85 ⁰ C.

N- (2-methylphenyl) -anthranilic acid- (2-dimethylaminoethyl) -amide, bp. 184 to 195 ⁰ O at 0.1 to 0.2 mm Hg. Ether P 111 to 113 ⁰ C, hydrochloride P = 144 to 146 ⁰ C.

N- (2-Me thylphenyl) -anthrani 1 acid- (3-diethylaminophenyl) amide, Kp '212-218 ⁰ C at 0.2 mm Hg. Citrate P ■ 145 ⁰ C (Zere.).

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N- (2-Me thylphenyl) -anthranil acid (2-dime thylaminopropyl) -amide, bp = 193-198 ⁰ C at 0.5 mm Hg. Hydrochloride P "Us 164 166 ⁰ C.

N- (2-Me thylphenyl) -anthranil acid- (3-dime thylaminopropyl) amide, bp = 200-207 ⁰ C at 0.2 mm Hg. Hydrochloride * P 136 to 139 ⁰ C.

N- (3-Me thylphenyl) -anthranilsäure- (2-dime thylaminopropyl) -amide, bp = 204-210 ⁰ C at 0.1 mm Hg. Hydrochloride P "123 to 126 ⁰ C.

H- (2-chlorophenyl) -anthranilsäure- (2-dimethylaminoethyl) amide, Kp a 210-215 ⁰ C at 0.2 mm Hg. Hydrochloride I "149 to 151. ⁰ C

N- (2-chlorophenyl) -anthranilsäure- (3-dimethylaminoethyl) amide, Kp = 212 to 217 ⁰ C at 0.2 mm Hg. Hydrochloride P "147-150 ⁰ C.

N- (2-chlorophenyl) -anthranilsäure- (3-diäthylaminopropyl) amide, Kp ■ 225-233 ⁰ C at 0.2 mm Hg to 0.4. Citrate P "117 to 120 ⁰ C.

N- (3-chlorophenyl) -anthranilsäure- (2-dimethylaminoethyl) amide, Kp * 206-210 ⁰ C in o, l mm Hg. Hydrochloride is hygroscopic.

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N- (3-Chl orphenyl) -anthranil acid- (3-dime thylaminopropyl) -amide, b.p. 220-228 ⁰ C s "at 0.4 mm Hg to 0.6. Hydrochloride P" 155 to 157 ⁰ C.

N- (3-chlorophenyl) -anthranilsäure- (3-diäthylaminopropyl) amide, Kp * 223-232 ⁰ C at 0.2 mm Hg to 0.5. Citrate P * 140 ⁰ C (dec.) ·

N- (3-chlorophenyl) -anthranilic acid- (2-dimethylaminopropyl) -amide, Kp a 215 to 220 ⁰ C at 0.2 mm Hg. Hydrochloride F «132 to 135 ⁰ C

l? - (2,3-Xylyl) anthranilic acid (2-dimethylaminopropyl) amide, b.p. "202 to 206 ⁰ C at 0.2 mm Hg. Hydrochloride P" 182 to 185 ⁰ C.

N- (2-Meihyl-3 '' chlorophenyl) -anthranilsäure- (3-dime thylaminopropyl) amide, Kp '210 to 220 ⁰ C at 0.2 mm Hg to 0.4. Hydrochloride P m 146-150 ⁰ C. ,

H- (2-chloro-3-methylphenyl) -anthranilsäure- (2-dimethylaminopropyl) ■ amide, bp ~ 204-208 ⁰ C. Hydrochloride "P," 173 to 176 ⁰ C.

For comparison, certain compounds that are not encompassed by the present invention are after the same Methods have been prepared, for example N- (4-chlorophenyl) anthranilic acid ·? (2-dimethylaminopropyl) -amide with a Kp *

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206 to 209 ⁰ O at 0.2 mm Hg, hydrochloride P «75 to 82 ⁰ O (hygroscopic.).

It has been found that these and similar compounds which are substituted in the p-position in the phonyl group or unsubstituted in this group have no or only a very slight analgesic effect. This applies, inter alia, to the compounds in which R and R are ethyl groups, R _{1 is} hydrogen and R _{2 is} CgH. or C-Hg mean.

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Claims (2)

Claims 1. Basically substituted amides of N-substituted ones. Anthranilic acids with the general formula CO « wherein R _{1 is} a lower alkyl group with 1 to 5 carbon atoms, in particular a K * thylgruppe, or hydrogen, R _{2 is} an alkylene group with 2 to 5 carbon atoms, preferably ethylene or propylene, R, and R. either both methyl or both ethyl or either methyl or Ethyl and Re and Rg are hydrogen, provided that Rc and Rg are not both hydrogen, alkyl having 1 to 5 carbon atoms or halogen or a halogen-like group, in particular Cl, Br or CF., and in the o-position, m Position or in both the o and m positions sur imino group, as well as their position 2. A process for the preparation of the compounds according to Claim 1, characterized in that a substituted one Benzamide of the general formula - 22 - ORIGINAL BATHROOM 109853/1916 R, wherein & until E. have the abovementioned meaning, and mean IL, a Kalogengruppe or a reactive Estergruppe with a substituted aminobenzene of the formula where Rj- and Rg has the meaning given above or a mixed anhydride composed of anthranilic acid substituted in the manner defined above and carbonic acid monoalkyl ester the general formula co.o.co. wherein Rg is alkyl, with the diamine of the formula - 23 109853/1916 _BATH 17§8-18 in which R ₁ to R ^ aside from the meaning given above, vm petzt or the N-substituted Ieato acid anhydride of the general my formula CO-O-CO reacts with the diamine R ₅ R ₄ NR ₂ NHR ₁ , - 24 - 109853/1916