NO167921B - PROCEDURE FOR THE PREPARATION OF 7-OCSOMITOSAN DERIVATIVES - Google Patents

Description

The present invention relates to a method for the production of 7-oxomitosan compounds. These compounds are mitomycin A and analogues thereof. Mitomycin A is an antibiotic whose use is known, and the 7-0-substituted mitosan analogues thereof can be used in a similar way.

Nomenclature; The systematic name for mitomycin A according to Chemical Abstracts based on a recent revision (Shirhata et al,, J. Am. Chem. Soc ., Vol 105, 1983, p. 7199) is: p.aS-( la8 , 86 ,' 8act, 8b 8 ) 1 -8-R (aminocarbonyl) ok sy) methyl^] - 6,8-dimethoxy-l-la,"3 ,8,8a, 8b-hexahydro-5-methyl-arizono [2 ' , 3 ' , 3,43-pyrrolo-, 2- £} indole-4, 7-dione.

According to this name, the azirinopyrroloindole ring system is numbered as follows:

A nomenclature trivial system that has found widespread use in the mitomycin literature names the ring system above, which contains several of the characteristic substituents of the mitomycins, such as mitosan.

According to this system, mitomycin A is 7,9α-dimethoxymitosane, and mitomycin C is 7-amino-9α-methoxymitosane. As regards the stereochemical configuration of the compounds according to the invention, it is intended that when they are indicated by the generic name "mitosan" or by a structural formula, they should be identified with the same stereochemical configuration as that of mitomycin A or C.

Mitomycin C is an antibiotic produced by fermentation and currently sold with the approval of the "Food and Drug Administrat ion" for the treatment of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and for palliative treatment when other mortalities have failed ("Mutamycin", Physicians Desk Reference, 37th ed., 1983, pp. 747 and 748). Mitomycin C and its preparation by fermentation are known from US patent 3,660,578.

The structure of mitomycins A, B and C and porfiromycin was first published by J.S. Webb et al., J. Am. Chem. Soc, Vol. 84, 1962, pp. 3185-3187. One of the chemical transformations that was addressed in this structural investigation for the comparison of mLtcmycin A with mitomycin C was the transformation of the former, 7,9a-dimethoxymitosan, by reaction with ammonia, into the latter, 7-amino-9a-methoxymitosan. Replacement of the 7-methoxy group in mitomycin A has proven to be a reaction of considerable interest in the preparation of active anti-tumor derivatives of mitomycin A. It has recently been shown that the stereochemical configurations in 1-, la- , the 8a and 8b positions are as shown above in connection with the nomenclature according to Chemical Abstracts (Shirhata et al., J. Am. Chem. Soc, Vol. 105, 1983, p. 719 9-7200). Previous literature refers to the enantiomer.

The following articles and patent documents concern, among other things, conversion of mitomycin A into a 7-substituted aminomitomycin C derivative with anti-tumour activity. The purpose of this research was the preparation of derivatives which were more active and especially less toxic than mitomycin C: Matsui et al., J. Antibiotics, Vol. XXI, 1969, p. 189-198, Konishita et al., J. Med. Chem, Vol. 14, 1971, pp. 103-109, Iyengar et al., J. Med. Chem., Vol. 24, 1981, pp. 975-981.

Iyengar, Sami, Remers and Bradner, Abstracts of Papers, 1983. Annual Meeting of The American Chemical Society, Las Vegas, Nevada, March 1982, Abstract No. MEDI 72,

US Patents 3,332,944, 3,420,846, 3,450,705, 3,514,452, 4,231,916 and 4,268,676.

European patent application 116,208 and GB patent application 2,140,799 relate to the production of 7-substituted aminomitomycin C derivatives where the substituent contains a disulfide bond.

7-Alkoxy-substituted mitosans, which are structurally related to mitomycin A, are in an article by Urakawa et al.,

J. Antibiotics, Vol 23, 1980, p. 804-809 described as valuable antibiotics with activity against experimental tumors in animals.

Mitomycin A is the most important mitomycin produced by fermentation, and is the commercially available form. Known technology for converting mitomycin C to mitomycin A has a number of shortcomings. Hydrolysis of mitomycin C to the corresponding 7-hydroxy-9a-methoxymitosane and subsequent methylation of this compound necessitates the use of diazomethane, a compound whose handling on a production scale is very risky, and the 7-hydroxy intermediate is also very unstable (Matsui et al ., J. Antibiotics, Vol. XXI, 1968, p. 189-198). An attempt to avoid these difficulties includes the use of 7-acyloxymitosanes (Japanese Patent Document J. 556073-085,

Farmdoc No. 56227 D/31). Alcoholysis of mitomycin A as described by Urakawa et al., J. Antibiotics, Vol 23, 1980, p. 804-809 is limited to the exclusive production of specific 7-alkoxy structural types because the availability and reactivity of the alcoholic starting materials.

Attempts have also been made to alkylate 7-rhydroxymitosane down to dimethyl-formamide-dimethyl acetal, which is known as an excellent methylating agent, as e.g. used for the production of methyl esters. Thereby, selective methylation of the C-10 carbamoyl part was achieved, while surprisingly no methylation of the 7-OH function occurred (US patent 4,487,769). This observation supports the fact that alkylating agents do not react with 7-hydrozymitosane in a predictable manner.

From US patent 4,069,024 it is known to alkylate the 3-enol hydroxyl group in a cephalosporin product using a 1-lower alkyl triazene compound. However, it is from Ukraine. Kim. Zhur., Vol 21, from 1985, p. 469-498 (Chemical Abstracts, Vol 50, 1956, 5549) known that succinimide is alkylated by 1-methyl-3-p-tolyltriazene to form N-methylsuccinimide. As is known, 7-oxomitosan contains a C-10 carbamoyl residue with which the triazine reagent will be able to react in a completely parallel manner. Moreover, it is from M. Matsui et. al., J. Antibiotics, Vol 21, 1968, p 196 S.M. Sami et al., J. Med. Chem., Vol 27, 1984, p. 701-708, and US Patent 4,746,746 known that anilines, which are a reaction product of the triazene alkylation process, e.g. reacts with 7-methoxymitosanes. With knowledge of these publications and the above-mentioned Farmdoc publication, it is therefore surprising that 7-methoxymitosane in the method according to the present invention does not react further to said 7-phenyl-anine omitosans.

As mentioned, diazomethane is until now the only known reagent which reacts selectively with the 7-hydroxy function, while other tried alkyl reagents react with the residue in the 1a-N position and with the C-10 carbamoyl residue or a combination of these. Moreover, as mentioned, it is known that triazene reagents react with imides, whereby those skilled in the art will expect that the triazene reagent will react with the C-10 carbamoyl residue in a similar way to the alkylating agent dimethylformamide-dimethyl acetal, which selectively alkylates said C-10 carbamoyl residue. Thus, on the basis of the known technique, it will not be obvious to those skilled in the art to subject 7-hydroxymitosane to alkylation using triazene reagents if the purpose is selective alkylation of the 7-hydroxy function.

The invention relates to a method for the preparation of compounds with the formula (IX)

where

R<5> is hydrogen or C1-6 alkyl, and

R 1 is C 1 -g alkyl or substituted C 1 -g alkyl, where the substituents are selected from C 1 -6 alkoxy, pyridyl, morpholino, benzyl and 1,3-dioxolane.

Many of the compounds of formula (IX) are known compounds which exhibit in vivo inhibitory activity against experimental tumors in animals. According to this method, a number of hitherto unknown compounds with the formula (IX) have also been prepared. In particular, the compounds identified here as compounds according to Examples 14, 15, 16 and 19 are hitherto unknown compounds, which also exhibit antitumor activity against experimental tumors in animals. They are used in a similar way to mitomycin C. Depending on their toxicity, the dosages used are set in relation to the toxicity of mitomycin C. In cases where the new compound is less toxic, a higher dose is used.

The method according to the invention for producing compounds with the formula (IX) is characterized by the fact that a mitosan with the formula (X)

is employed with a triazene of the formula (XI)

5 6

where R and R have the meanings given above and Ar is the organic residue of a diazotizable aromatic amine.

The term "C1_6 alkyl" and "C1_4 alkoxy" as used in the description and in the claims (unless the context indicates otherwise) means unbranched or branched alkyl or alkoxy groups. Preferably, these groups contain 1-4 carbon atoms, and most preferably they contain 1 or 2 carbon atoms.

According to the present invention, a method for the production of compounds with the formula (IX) has been developed, which is characterized by the fact that a mitosan with the formula (X) is reacted with a triazene with the formula (XI) as shown in scheme 1.

where R and R^ have the meanings given above, and Ar is then the organic residue of a diazotizable aromatic amine.

The 1-substituted 3-aryltriazenes of the formula (XI), and more particularly the 1-alkyl-3-aryltriazenes, constitute a class of reactants which are known to be used for reaction with carboxylic acid to form the corresponding lower alkyl esters. The 1-methyl-3-(4-methylphenyl)triazene can be prepared according to the general methods described by E.H. White et al. in Org. Syn., Vol. 48, 1968, p. 102-105 and as described herein in method 1. However, this method only works well with water-soluble amines, and another method, which is described by E.H. White et al., Tetrahedron Letters, No. 21, 1961, p. 761 and also described herein in method 2, is more suitable for the preparation of triazenes from water-insoluble amines.

The reactant 1-methyl-3-(4-methylphenyl)triazene, which is prepared in the manner described above, has previously been used for the preparation of methyl esters of carboxylic acids such as 2,4-dinitro-benzoic acid (E.H. White et al., Org . Syn., Vol. 48, 1968, p. 102-105) and cephalosporanic acids which give the desired A 3 compound without isomerization of the a 2 isomer (Mangia, Tetrahedron Letters, no. 52, 1978, p. 5219-20 The reactant has also been used for the preparation of a 3-methoxycephalosporin derivative by reaction with the corresponding 3-hydroxy-3-cef em-4-car boksylate in benzene solution at reflux temperature (US patent 4,069,324).

Other 1-(lower alkyl)-3-aryltriazenes of the formula (XI) can be prepared in a similar manner by reacting other lower alkyl anines with aryldiazonium salts. Any arylamine with 6-12 carbon atoms, which readily forms a diazonium salt, can be used as

starting material for the aryl part of the 1,3-disubstituted triaz.

For the production of mitomycin A, it is preferred to use 3-methyl-1-(4-methylphenyl)triazene as the methylation reactant. Preferably, at least two mold parts of the latter are used per moldel 7-hydroxy-9a-methoxymitosane, and the reaction is preferably carried out in a liquid organic solvent for the 7-hydroxy-9a-methoxy-symitosane starting material. Preferred solvents are lower alkanols, lower alkanoic acids-lower alkyl esters, di-lower alkyl ethers, cyclic aliphatic ethers and lower polyhalogenated aliphatic hydrocarbons. These solvents contain up to 6 carbon atoms, but the solvents that boil at temperatures below 100°C are preferred. Particularly preferred solvents are ethylene chloride, methanol, diethyl ether, ethyl acetate and mixtures thereof. The reaction can be carried out at the reflux temperature of the reaction mixture or up to 60°C. At higher temperatures, the mitosan reactant has a tendency to decompose, resulting in a lower yield. It is preferred to carry out the reaction at room temperature or below, e.g. in the range from 0 to 25°C.

A suitable way to determine when the turnover of has ended is by thin-layer chromatography. Mitomycin A is dark purple in color and can be easily distinguished from the starting material and from by-products. In the solvent system methylene chloride/methanol = 90:10, mitomycin A exhibits Rf = 0.36. Chromatography on neutral aluminum oxide can be used to purify products.

The above-mentioned reaction conditions and precautions can generally be used for the preparation of 7-R^O-mitosanes with the formula (IX) by the method according to the invention.

The value of compounds of the formulas (IX) in antineoplastic therapeutic methods is demonstrated by the results of in vivo screening processes, where the compounds are administered in different dosage amounts to mice, in which a P-388 leukemic condition has been introduced.

The compounds according to the invention are considered to have antibacterial activity against gram-positive and gram-negative micro-organisms in a similar way to that observed for the naturally occurring mitomycins, and are thus potentially valuable as therapeutic agents for the treatment of bacterial infections in humans and

animals.

Activity against P-388 mouse leukemia

Table I contains the results of laboratory experiments with CDF1 mice, which have been implanted intraperitoneally with a tumor inoculum in the form of 10 ascites cells of P-388 mouse leukemia and have been treated with different doses of either a test compound of the formula (I) or ( II), or with mitomycin C. The compounds were administered by intraperitoneal injection. Groups of 6 mice were used for each dose and were treated with a single dose of the compound days after inoculation. A group of 10 saline-treated control mice was included in each series of experiments. The groups treated with mitomycin C were included as a positive control. A 30-day record was kept of the mean survival time expressed in days for each group of mice, and the number of survivors at the end of the 30-day period was noted. The mice were weighed before treatment and again on the sixth day. The weight change was taken as a measure of the drug's toxicity. Mice weighing 20 g were used, and a weight loss of up to 2 g was not considered unusually large. The results were specifically expressed in %T/C, which is the ratio of the mean survival time of the treated group to the mean survival time of the saline-treated control group, multiplied by 100. The saline-treated control animals usually died within 9 days. The "maximum effect" in the following table is expressed in % T/C, and the dose producing this effect is indicated. The values in parentheses are those with mitomycin C as the positive control values achieved in the same trial. Thereby, the relationship between the relative activity of the listed substances and mitomycin C can be assessed. The minimal effect expressed in % T/C was considered to be 125. The minimal effective dose, which is indicated in the following table, is the dose which gives a % T/C of approx. 125. The two values entered in each case in the "average weight change" column are the average weight change per mice at the maximum effective dose and at the minimum effective dose, respectively.

In view of the observed anti-tumor activity in experimental animal tumors, the compounds according to the invention can be used to inhibit tumors in mammals. To this end, these are systematically administered to a mammal,

suffering from a tumor, in a largely non-toxic dose with an antitumor effect.

The compounds produced according to the invention are primarily intended for use in injection form in a similar manner and with the same purpose as mitomycin C. Slightly larger or smaller doses can be used depending on the particular tumor sensitivity. They can be readily distributed as dry pharmaceutical preparations containing diluents, buffers, stabilizers, solubilizers and ingredients that contribute to pharmaceutical utility. These preparations are then prepared with an injectable liquid medium, which is made to order, immediately before use. Suitable injectable fluids include water, isotonic saline and the like.

In the following methods and examples, all melting points are uncorrected. The proton nuclear magnetic resonance spectra (<1>H NMR) were recorded in a "Varian XL100", "Joel FX-90Q" or "Bruker WM 360" spectrometer, either in pyridine-dj. or D^O as indicated. When pyridine-d^ is used as solvent, the pyridine resonance at 5=8.57 is used as an internal reference,

whereas, on the other hand, TSP is used as an internal reference with D^O as solvent. Chemical shifts are given in £ units,

and coupling constants in Hertz. Splitting patterns are indicated as follows: s = singlet, d = doublet, t = triplet, q = quartet,

m = multiplet, bs = broad signal, dd = doublet of doublet, dt = doublet of triplet. IR spectra were determined in either a "Beckman Model 4240" spectrometer or a "Nicolet 5DX FT" IR spectrometer and are given in reciprocal centimeters. UV spectra were determined either in a "Cary Model 290" spectrometer or a "Hewlitt Packard 8450A" spectrometer equipped with a multi-diode detector. Thin layer chromatography was performed on 0.25 mm "Analtech silica gel GF" plates. Flash chromatography was performed with either "Woelm" neutral alumina (DCC grade) or "Woelm" silica gel (32-63°) and the solvents listed. All solvent evaporations were carried out at reduced pressure and at below 40°C.

The 1-alkyl-3-aryltriazenes constitute a class of reactants, which are known to be able to be used for reaction with carboxylic acids to form the corresponding lower alkyl esters. 1-methyl-3-(4-methylphenyl)triazene can be prepared in the following way:

Procedure 1

E.H. White et al., Org. Cyn., Vol. 48, 1968, pp. 102-195.

1-methyl-3-p-tolyltriazene. 50.2 g (0.47 mol) p-toluidine is placed in a 2 liter flask equipped with a 200 ml separatory funnel and an efficient stirrer, and the coupling is immersed in an ice-salt bath at approx. -10°C. A solution of 46.8 g (0.55 mol) of potassium nitrite in 150 ml of water is placed in the separatory funnel, and a mixture of 250 g

crushed ice and 140 ml of concentrated hydrochloric acid are added with stirring to the p-toluidine. The potassium nitrite solution is added slowly with continued stirring for 1-2 hours, until a positive starch-potassium iodide test is obtained (note 1), and the mixture is stirred for a further 1 hour to ensure that all the toluidine has been reacted.

The reading of p-toluenediazonium chloride is then adjusted at 0°C to pH 6.8-7.2 with cold, concentrated, aqueous sodium carbonate, after which the solution turns red to orange and some red material is poured out. The cold, neutral solution is transferred to a separatory funnel and slowly added to a vigorously stirred mixture of 150 g of sodium carbonate, 300 ml of 30-35 percent aqueous methylamine (note 2) and 100 g of crushed ice in a 3 liter flask. The reaction mixture is kept at approx. -10°C during the addition, which takes approx. 45 minutes (note 3). The solution is extracted with three 1 liter portions of ether. The ether extracts are dried with anhydrous sodium sulfate and evaporated in a rotary evaporator at room temperature, whereby 65 g of the impure 1-methyl-3-p-tolyltriazene are obtained (note 4). This is placed in a water-cooled sublimation apparatus, and the triazene is sublimed at 50°C and 1 mm Hg, whereby 43.3 g (0.29 mol, 62%) of yellow, crystalline sublimate, m.p. 77-80°C (note 5). The sublimate can be recrystallized from hexane, whereby the triazene is obtained as white needles, m.p. 80.5-81.5°C. More conveniently, it is dissolved in a minimal amount of ether, and the solution is diluted with 2 volumes of hexane and cooled to 0°C, whereby flat plates with a slightly yellowish tinge are obtained, m.p. 79-81°C. The yield of pure triazene is 33-37 g (47-53%) (note 6).

Notes

1. The individual tests with starch-potassium iodide paper should be carried out 1-2 minutes after the addition of potassium nitrite is complete.

2. 40 percent aqueous methylamine is used.

3. The reaction is complete when a drop of solution no longer gives a red color together with a solution of S-naphthol in aqueous sodium carbonate.

4. The main contaminant is 1,5-di-p-tolyl-3-methyl-1,4-pentazdiene (m.p. 148°C). It can be removed by fractional crystallization, but it is easier to sublime the triazene from the reaction mixture.

5. The sublimate contains traces of 1,3-di-p-tolyltriazene as shown by thin layer chromatography. Recrystallization gives the pure 1-methyl-3-p-tolyltriazene.

6. This method only works well with water-soluble amines. The method 2 described below is more suitable for the production of diazenes with water-insoluble amines.

Procedure 2

(E.H. White et al., Tetrahedron Letters No. 21, 1961, p. 761

1-n-buty1-3-p-chlorophenyltriazene. A solution of 2.87 g (10.1 mmol) of p-chlorobenzenediazonium hexafluorophosphate (recrystallized from acetone-methanol) in dimethylformamide (dimethylamine-free) was slowly added to a stirred mixture of 0.73 g ( 10.0 mmol) n-butylamine, 15 g powdered sodium carbonate

as well as 30 ml of dimethylformamide stirred and kept at -5°C. The diazonium salt solution can be used at room temperature, however, a cleaner product is usually obtained if the diazonium salt solution is prepared in and added from a cooled separating funnel which is kept at approx. -50°C. The mixture was warmed to 0° and stirred until a negative test with 2-naphthol (which usually

only requires a few minutes). Ether was added, the mixture filtered and the filtrate washed thoroughly with water and then dried. (The triazene can at this point be isolated and recrystallized from pentane at lower temperatures).

Procedure 3

7- hydroxy- 9a- methoxymitosane. 2.2 g (6.6 mmol) of mitomycin C was dissolved in 140 ml of 0.1 N methanolic NaOH (50%), and the reaction mixture was stirred at room temperature for 30 hours. The solution was then set to approx. pH 4.0 with 1N HCl and extracted with 4 x 500 ml ethyl acetate. The combined ethyl acetate extracts were dried with Na 2 SO 4 and evaporated under reduced pressure at 30-35°C to give a solid residue, which after dissolution in ether and treatment with excess hexane gave a purple precipitate. The precipitate was collected and dried to give the title compound as a fine purple powder (1.4 g, 63%).

<1>H NMR (pridine-d5, 6): 2.05 (s, 3H), 2.14 (bs, 1H), 2.74 (bs, 1H), 3.13 (d, 1H), 3 .24 (s, 3H), 3.56 (d, 1H), 4.00 (dd, 1H), 4.37 (d, 1H), 5.05 (t, 1H), 5.40 (dd, 1H), 5.90 (bs, 2H).

Procedure 4

Mitomycin A. 100 mg (0.30 mmol) of 7-hydroxy-9α-methoxymitosane and 100 mg (0.67 mmol) of 3-methyl-1-p-tolyltriazene were dissolved in 2 ml of methylene chloride and 10 ml of diethyl ether. After careful reflux for 6 hours, the solution was stirred for 18 hours at room temperature. Thin layer chromatography (methylene chloride:methanol = 90:10) revealed the appearance of a deep purple spot at R 1 = 0.36 with a trace of contamination at R 1 = 0.41. The reaction mixture was concentrated to dryness and chromatographed on "Woelm" neutral alumina using methylene chloride and methylene chloride:methanol = 30:1 as eluents. Fractions containing the component R^ = 0.36 were pooled and concentrated to dryness. Precipitation of the dry residue from methylene chloride and hexane gave 25 mg (24%) of the title compound as a fine, amorphous, purple powder, m.p. 161°C.

Analysis: calculated for C16HlgN3Og: C: 54.96; H: 5.44; N: 12.02

found: C: 53.96; H: 5.37; N: 11.99

IR(KBr), v , cm"<1>: 3400, 3300, 2950, 1700, 1630, 1575,

IT13.X

1200, 1060.

NMR (pyridine-d5,6): 1.82 (s, 3H), 2.74 (dd, 1H), 3.12 (d, 1H), 3.24 (s, 3H), 3.54 (dd , 1H), 3.96 (dd, 1H), 4.02 (s, 3H), 4.22 (d, 1H), 4.84 (bs, 2H), 5.02 (t, 1H), 5 .38 (dd, 1H).

The yield in method 4 is increased to 63% by using methylene chloride as reaction solvent and room temperature for a period of 24 hours.

Procedure 5

Solid Na2CO3, a 35% aqueous amine solution (amount as in method 1) and ice were placed in a 250 ml one-necked round flask, and the suspension was stirred at -5°C (ice-salt bath). To this suspension was added dropwise a cold suspension of p-chlorobenzenediazonium hexafluorophosphate (Aldrich Chemical Co.) in ice, water and Na 2 CO 3 (solution approx. pH 7). After the addition was complete, the reaction mixture was extracted with diethyl ether. The diethyl ether extract was washed with water, dried with Na 2 CO 3 and concentrated. The yellowish solid residue was purified by column chromatography over "Woelm" alumina using hexane:methylene chloride = 1:1 as eluent (^"H NMR recorded).

Example 1-8

The triazenes 1-6 in the subsequent table 3 were prepared according to the general method 1 described above, where the preparation of the triazene in example 1 is exemplified. The triazenes were purified by column chromatography on "Woelm" alumina.

The triazenes 7-8 in Table 3 were prepared according to the general method 5 described above.

Examples 12-19

General procedure for the production of 7- alkoxy- 9a-methoxymitosanes ( 12- 19

A solution of 2.4 equivalents of the triazene in CH 2 Cl 2 :methanol = 4:1 was added to a solution of 7-hydroxy-9a-methoxymitosane (prepared in method 3) in CH 2 Cl 2 :methanol = 4:1. The reaction mixture was stirred at room temperature, and the course of the reaction was monitored by thin layer chromatography (10% MeOH in CH 2 Cl 2 ). 7-Alkoxy-9a-methoxymitosane compound appears as a dark purple spot in the thin layer chromatogram. The reaction mixture was chromatographed on "Woelm" alumina after the reaction was considered complete on the basis of thin layer chromatography, and the 7-Alkoxy-9a-methoxymitosane was obtained as an amorphous solid. The compounds prepared are listed as Examples 12-19 in Table 4.

Claims (4)

Process for the preparation of 7-oxomitosan compounds with the formula (IX) where R is hydrogen or C 1-6 alkyl, and R 1 is C 1 -g alkyl or substituted C 1 -g alkyl, where the substituents are selected from C 1 -4 alkoxy, pyridyl, morpholino, benzylthio and 1,3-dioxolane, characterized in that a mitosan of the formula (X) is reacted with the triazene of the formula (XI) where R^ and R^ have the meanings given above and Ar is the organic residue of a diazotizable aromatic amine. 2. Method in accordance with claim 1, characterized in that at least two mole parts of the triazene are used in relation to the mitosan with the formula (X). 3. Method in accordance with claim 1, characterized in that the reaction temperature is from 0°C to 60°C. 4. Process in accordance with claim 1, characterized in that the reaction temperature is from 0°C to 25°C.