DK158836B - METHOD OF ANALOGUE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ANTHRAQUINO DERIVATIVES - Google Patents

Description

DK 158836 B

The present invention relates to an analogous method for the preparation of novel therapeutically active anthraquinone derivatives of the general formula (I) (κ2 R · I λ Λ XXX), (ι) ίο I7 "T"

R 0 I / R

NH-QN f 9 or the tautomeric forms or pharmacologically acceptable acid addition salts thereof, in which formula AB means CH = CH 15 or CH2-CH2, Q is (CH2) n, where n is an integer from 2 to 4, R1 and R2 each independently means hydrogen, alkyl of 1-4 carbon atoms, monohydroxyalkyl of 2-4 carbon atoms, wherein the carbon atom in α position to the nitrogen atom cannot carry a hydroxy group, dihydroxyalkyl of 3-6 carbon atoms, the carbon atom of α position to the nitrogen atom cannot carry a hydroxy group, formyl, alkanoyl of 2-4 carbon atoms, trifluoroacetyl or a group of formula t? 3

/ R

- (CH 2) n -O-R or - (CH 2) n N 2 \ where n is an integer from 2 to 4, R 1 is alkyl of 1-4 carbon atoms and R 2 and R 4 are each hydrogen or alkyl of 1-4 carbon atoms, or R 1 and R 2 together with their attached N atom 35 or R 3 and R 4 together with their attached N atom means morpholino, piperazino, oxazolidinyl or a group of formula 2

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wherein m is an integer from 2 to 4, 10 R5 is hydrogen or hydroxy, R6 is hydrogen or hydroxy, R7 is hydrogen, hydroxy or a group of the formula R8 / -nh-ch2-ch2-n where R8 and R9 are each independently means hydrogen or β-hydroxyethyl, provided that a) R1, R2, R5, R6 and R7 cannot simultaneously be hydrogen, b) when R5, R6 and R7 are hydrogen, R3 / R2 cannot be H / monohydroxyalkyl, and when n is 2, R - ^ / R₂ cannot be- (CH2) 2-0- (O¾) 2-, H / CH3, H / C2H5 or C2H5 / C2H5i and when n is 3, R - ^ / R2 is not CH3 / CH3 or - (CH2) 5 ~, c) when R5 and R7 are hydroxy and n is 2, R1 / R2 cannot be CH3 / CH3, C4H9 / C4H9 or - (CH2) 5- when n is 3, R1 / R2 cannot be ff / H, CH3 / CH3, C3H7 / C3H7 or - (CH2) 2 "0- (CH2) 2" and when n is 4, R R2 is not C2H5 / C2H5, C4H9 / C4H9 or - (CH2) 4-, d) when R5 is OH, one of the substituents R6 and R7 must be H, and when R5 is H, both R6 and R7 must be H.

The compounds of general formula I, wherein A-B 35 means CH 2 -CH 2, are usually stable compounds and are known as the leukoforms of the corresponding anthraquinones.

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It is known that these leukoforms exist in their respective tautomeric forms and all such forms are equivalent for the purposes of the invention. The leucoforms (here leukobases) and their tautomers can be represented by the general formulas: 5 R1 5 NH-Q-N ^, 6 R 0 - I \ r2 j (IIi leukobases)

ίο * 7 ** / R

R O NH-Q-N ^ 0 A XR ^ / r1 6 R5 -0 f-Q-N \ R2 RU 1 II Π ** I (III, tautomeric forms)

Thus, the invention relates to an analogous process for preparing the compounds of formulas I, II and III.

The process according to the invention is characterized in that a compound of the general formula

c X

r6? 5 0

K * 1 «I

R7 0 1 '

X

30 in which A-B, R5, R6 and R7 have the above meanings, and X is OH or halogen, is reacted with a compound of the general formula R1 R2 35 H2N-Q-N ^ 4

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in which Q, R 1 and R 2 have the above meanings, and the group NR 1 R 2 is optionally converted to another group with a meaning given above, and AB with the meaning CH 2 -CH 2 is optionally converted to CH = CH and the product obtained is optionally introduced into contact with a reagent capable of forming a pharmacologically acceptable salt thereof.

The invention thus also relates to the preparation of the acid addition salts of the novel compounds of formulas I, II and III.

Suitable pharmaceutical therapeutic compositions and compositions may comprise compounds of formulas I, II and III and their pharmaceutically acceptable acid addition salts as well as mixtures thereof as the active ingredients.

The compounds of the invention are usually obtained as reddish-brown to blue-black crystalline substances with characteristic melting points and absorption spectra, and they can be purified with leaching with lower alkanols as the free bases are, for the most part, insoluble in water and some of them are insoluble. .e. in most 20 organic solvents. The present organic bases of formulas I, II and II form non-toxic addition salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Acid addition salts are thus formed by mixing an organic free base with 1, 25 or up to 8 equivalents of an acid, suitably in a neutral solvent, with acids such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfamic acid, citric acid, lactic acid, malic, succinic, tartaric, acetic, benzoic, gluconic and ascorbic. The preferred acids 30 are hydrochloric acid and acetic acid. For the purposes of the present invention, the free bases are equivalent to their non-toxic acid addition salts. The acid addition salts of the present organic bases are usually crystalline solids which are relatively soluble in water, methanol and ethanol but relatively soluble in unpolar organic solvents such as diethyl ether, benzene and toluene.

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It will be apparent to those skilled in the art that all of these salts can be genome-formed into their respective free forms represented by formulas I, II and III using conventional methods, and all such salts and free forms are therefore 5 equivalent for the purposes of the present invention.

A preferred group of the novel compounds which can be prepared according to the invention have the general formula

/ R

OH 0 NH-Q-N ^

10 I

YyV \, 15 OH 0 NH-Q-N '0

V

and the pharmacologically acceptable acid addition salts thereof, in which formulas AB and Q have the meanings set forth above, R 1 is hydrogen, alkyl of 1-4 carbon atoms or monohydroxyalkyl of 2-4 carbon atoms where the carbon atom at the α-position of the nitrogen atom cannot carry a hydroxy group, R 2 means monohydroxyalkyl of 2-4 carbon atoms where the carbon atom in α position to the nitrogen atom cannot carry a hydroxy group, dihydroxyalkyl of 3-6 carbon atoms, where the carbon atom in α position to the nitrogen atom cannot carry a hydroxy group, or a group of formula ^ R3

- (CH 2) n -N

R4 where n, R3 and R4 have the meanings given above.

Another preferred group of the novel compounds of the invention has the general formula

OH 0 NH-Q-N- (CHJ -OH

rVrV

m.,

'OH O NH-Q-N- (CH2) n-OH

6

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and the pharmacologically acceptable acid addition salts thereof, in which formula R is hydrogen or alkyl of 1-4 carbon atoms and A-B, n and Q have the meanings given above.

A third preferred group of the novel compounds of the invention has the general formula ho nhch2ch2nch2ch2oh

iL

Wherein R 1 is hydrogen or -CH 2 CH 2 OH, and the pharmacologically acceptable acid addition salts thereof. The preferred salts are the hydrochlorides and acetates.

The reaction according to the invention is preferably carried out by heating the reactants to a temperature of from ca. 40 to approx. 110 ° C for a period of approx. 2 to approx. 10 hours in a solvent inert to the reaction, e.g. water, a lower alkanol, e.g. methanol, ethanol, propanol, i-propanol or any of the isomeric butanols, or in an amide solvent such as formamide or dimethylformamide, or in a solvent such as N, N, N} NT-tetramethylethylenediamine, or mixtures thereof. The above temperatures, times and solvents and combinations thereof will in most cases be sufficient for carrying out the process of the present invention. Other solvents and reaction parameters may sometimes be desirable or required and the choice of such additional solvents and reaction parameters will be obvious to one skilled in the art.

In most cases, the product is a solid that crystallizes spontaneously or after grafting or scraping from the reaction solvent upon cooling, and it can be isolated.

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7 is filtered or decanted. In other cases, the reaction mixture may be concentrated, e.g. at elevated temperatures under vacuum, and after cooling, the product will crystallize and can be isolated by filtration or decantation as set forth above. In some other cases, it may be necessary to evaporate the reaction mixture to dryness to isolate the product, or optionally to mix or dilute the reaction mixture with another miscible solvent such as water, on which the product is isolated, e.g.

10 by filtration or extraction. One skilled in the art will be able to choose the most convenient method, and all of these fall within the scope of the invention. The insulated product can be purified e.g. by crystallization, chromatography (thin layer chromatography or column chromatography) or preferably by leaching with a lower alkanol.

Other methods such as maceration or crushing in a solvent, e.g. an organic solvent such as ethanol can be used, and all the purification processes are considered equivalent for the present purpose.

It will be appreciated by those skilled in the art that when a product is desired in the leukoform, the tricyclic starting material must be in the leuco-worm and care must be taken to protect such compounds, especially at elevated temperatures, i. above room temperature, against oxidizing agents such as

25 oxygen. Thus, when a leukoproduct is desired, the reaction is usually and effectively carried out in an atmosphere with the exclusion of air. Thus, for example, the reaction can be conducted in a nitrogen or argon atmosphere, and this precaution should also be taken during the purification steps, especially those requiring elevated temperatures. When an aromatic product is desired and an aromatic starting material is used, such precautions are usually not necessary.

It is well known to those skilled in the art that, if desired, the leukoform can be readily converted to the aromatic form using various methods. Oxidation with atmospheric

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Thus, air is one method and other methods are treatment with e.g. hot nitrobenzene, chloranil, hydrogen peroxide or sodium perborate. All of these and other methods of converting the leukoform into the aromatic form are considered equivalent in the context of the present invention.

When NR1] * 2 is a primary or secondary amine, i.

-NH2 or -NHR1, further alkylation will convert the group to the desired group of formula 10 R1

-N

X R2

This conversion can be readily accomplished with well-known alkylating agents. Examples of such alkylating agents include alkyl halides, alkyl sulfates, and substituted and unsubstituted acrylonitriles. Aldehydes and ketones condensed under reducing conditions can also be used.

All such conversions and other conversion methods are considered equivalent to the present invention.

A preferred embodiment of the process according to the invention can be illustrated by the following reaction scheme: 9

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R5 O OH

RV:; Sr ^ Yi ^ i / r1 5 [ίΐ ^] + * 2 * ~ ΰ '*' * 2 7 IT (V) \ RO OH \ (IV) 5 / r1 10 6- ^ X ^ YES "^ R 2 / R 15 / R 7 O NH-QN

/ R

j /. (II)

5 '/ R

Rb O NH-Q-N '

Vyu <·;

25 R

wherein R1, R2, R5, R6 and R7 and Q have the above meanings. According to this reaction scheme, a leuko-1,4-dihydroxy-anthraquinone (IV) is condensed with a suitable alkylenediamine 30 (V) in a solvent such as N, N, NJN '-tetramethyl 1 ethylene diamine, ethanol, water, dimethylformamide or mixtures thereof. know from approx. 40 to approx. 60 ° C under a nitrogen atmosphere for several hours to form the corresponding leukobases (II). The leucobases (II) can be readily oxidized to the fully aromatic derivatives (I) using various methods such as oxidation with air, treatment with 10

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hot nitrobenzene or treatment with chloranil, hydrogen peroxide or sodium perborate. The product can then be contacted with a pharmacologically acceptable quaternary in s-ring reagent or salt-forming reagent under quaternary or salt-forming conditions.

A further preferred embodiment of the process according to the invention can be illustrated by the following reaction scheme A:

10 OH 0 OH

/ r1 I 4 H2N-Q-N / 2

\ R

15 OH 0 OH ^ R1 OH O NH-Q-N ^ 0 ΛΑΑ OH, OH 0 FH-Q-N ^ 9

* R NO

OH 0 NH-Q-NX

25 TYt / h1

OH 0 NH-Q-N

V

Wherein R -, -, R 2 and Q have the above meanings.

A more preferred embodiment of the process of the invention is represented by the above Scheme A, wherein Q is as previously defined, R 1 is hydrogen or alkyl of 1-4 carbon atoms, R 2 is monohydroxyalkyl of 2-4 carbon atoms.

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The carbon atom at α position to the nitrogen atom cannot carry a hydroxy group, dihydroxyalkyl of 3-6 carbon atoms, the carbon atom at α position to the nitrogen atom cannot carry a hydroxy group or a group of formula 5 R3

"(CH 2) n" N

R4 wherein n, R3 and R4 have the above meanings, contacting the formed compound with a pharmacologically acceptable acid, preferably acetic or hydrochloric acid, to form a pharmacologically acceptable acid addition salt thereof.

Another, more preferred embodiment of the process of the invention is represented by the above Scheme A, wherein R 1 is hydrogen or alkyl of 1-4 carbon atoms and R 2 is - (CH 2) nOH and n and Q have the above however, the ratio of the total number of carbon atoms to the sum of the total number of oxygen atoms plus the total number of nitrogen atoms in each of the side chains in the 1-position and the 4-position is at most 4 and the product is contacted with a pharmacologically acceptable acid, preferably acetic acid or hydrochloric acid, to form a pharmacologically acceptable acid addition salt thereof.

The most preferred embodiment of the process of the invention is represented by the above Scheme A, where n is preferably 2 and R 1 is hydrogen or -CH 2 CH 2 OH and R 2 is -CH 2 CH 2 OH and the product is contacted with a pharmacologically acceptable acid, preferably acetic acid or hydrochloric acid, to form a pharmacologically acceptable acid addition salt thereof.

When the reactants used in the process of the invention contain certain special substituents, it has been found that it is possible to carry out the process in a particularly effective manner by a specific choice of reaction variables such as time, temperature and solution.

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agents.

The invention, as mentioned, encompasses the conversion of the prepared compounds into acid addition salts. Many methods of salt formation are known and these are considered equivalent for the purpose of the present invention. Thus, for example, the compounds can be dissolved or suspended in a solvent such as a lower alkanol, e.g. methanol, ethanol or isopropanol, and treated with the salt-forming reagent itself in solution in the same or in another solvent. Thus, for example, a suspension or solution of the compound in ethanol can be treated with dilute or concentrated acetic acid or hydrochloric acid, or with ethanolic hydrochloric acid, and the corresponding salt can be isolated e.g. by filtration. The salt-forming reagent can also be added in pure form. Thus, a solution or suspension of the compound can be treated with glacial acetic or gaseous HCl and the corresponding acid addition salt isolated.

The compounds of formulas X, II and II and the pharmacologically acceptable acid addition salts thereof and mixtures thereof can be used as active ingredients in pharmaceutical therapeutic preparations and mixtures.

The compounds of this invention and their compositions inhibit the growth of a. transplanted mouse tumors and induce regression and / or alleviation of leukemia of related mammalian cancer disorders when administered in amounts of from ca.

5 mg to approx. 200 mg per kg body weight per day. A preferred dose range for optimum results will range from approx. 5 mg to approx. 50 mg per kg body weight per per day and dosage units are used such that a total of about 30 3.5 g of active compound for an individual with approx. 70 kg body weight over a 24 hour period. This dose can be adjusted to achieve the optimal therapeutic response. For example, several divided doses may be administered or the dose may be proportionally reduced depending on the nature of the therapeutic situation. A definite practical advantage is that the active compound can be administered by any convenient means.

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13 way, e.g. orally, intravenously, intramuscularly or subcutaneously.

For example, the active ingredients may be administered orally with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules or compressed into tablets or they may be incorporated directly into the food. For oral therapeutic administration, the active compounds can be incorporated into inert molding agents and used in the form of tablets to be aspirated, buccal tablets, dragees, capsules, elixirs, suspensions, syrups, waffles and the like. Such materials and compositions should contain at least 0.1% of the active compound.

The percentage content of the compositions may, of course, vary and may conveniently be between ca. 2 and approx. 60% by weight of the unit. The amount of active ingredient in such therapeutically useful compositions is such that a suitable dosage is obtained. Preferred compositions are prepared such that an oral dosage unit contains between about 5 and approx. 200 mg of active compound.

The tablets, dragees, pills, capsules and the like may also contain the following ingredients: A binder such as tragacanth, acacia, corn starch or gelatin, extenders or inert molding agents such as dicalcium phosphate, a desiccant such as corn starch, potato starch, magnesium acid, and the like. , and a sweetener such as sucrose, lactose or saccharin may be added, or a flavoring such as peppermint, winter vegetable oil or cherry flavoring.

When the dosage unit is a capsule, it may contain, in addition to the above materials, a liquid carrier. Various other materials may be present in the form of coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active ingredient, sucrose as

- - - DK 158836 B

14 sweeteners, methyl and propyl parabens as preservatives, a dye and a flavoring, e.g. cherry or orange flavor. Of course, all materials used in preparing the dosage units must be pharmaceutically pure and practically non-toxic in the amounts used. Furthermore, the active ingredients can be incorporated into sustained release preparations.

The active ingredients may also be administered parenterally or intraperitoneally. solutions of the active ingredient 10 as free base or pharmacologically acceptable salt can be prepared in water which is suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions are also prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under usual storage and use conditions, these compositions contain a preservative to prevent microorganism growth.

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and 20 sterile powders for preparing sterile injection solutions or dispersions. In all cases, preparations must be sterile and liquid to such an extent that it can be easily injected with a syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing e.g. water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and 30 vegetable oils. The proper fluidity can e.g. is maintained using a coating such as lecithin, by adhering to the required particle size in the case of dispersions and by using surfactants. Inhibition of the action of microorganisms can be provided by various antibacterial and antifungal agents, e.g. parabens, chlorobutanol, phenol, sorbic acid 15

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and thimerosal. In many cases, it is preferred to add isotonic agents, e.g. sugars or sodium chloride. Prolonged absorption of the injection preparations can be achieved by using agents which delay absorption, e.g. aluminum monostearate and gelatin.

Sterile injection solutions are prepared by incorporating the active ingredient in the required amount in a suitable solvent with various of the other ingredients listed above, as needed, followed by sterile filtration. Usually, dispersions are prepared by incorporating the various sterile active ingredients into a sterile carrier containing the basic dispersion medium and the necessary other ingredients from the above.

In the case of sterile powders for the preparation of sterile injection solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which provide a powder of the active ingredient plus any additional desired ingredients from a prior sterile filtered solution.

For purposes of the present invention, the term "pharmaceutically acceptable carrier" includes all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents and absorption delay agents and the like. The use of these substances and agents for pharmaceutically active substances is well known. Apart from such media or agents which are incompatible with the active ingredient, any agent or medium may be used in the therapeutic compositions of the present invention. Additional active ingredients may also be incorporated into the compositions.

It is particularly advantageous to formulate parenteral dosage unit form to facilitate administration and for uniform dosing. Dosage unit forms herein are understood to be physically separate units which are suitable as unitary dosages for mammals to be treated, each unit containing a predetermined amount of active material intended to induce the desired therapeutic effect 16

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in connection with the necessary pharmaceutical carrier. The description of the novel dosage unit forms of the present invention is dictated by and directly dependent on (a) the unique nature of the active material and the particular therapeutic effect to be achieved, and (b) the limitations necessarily encountered in the art in the preparation of such active material for the treatment of diseases of living individuals with a condition of disease in which the health is impaired, as herein described in the Detainer *.

10 Regression and cancer relief are achieved, for example, by oral administration or by injection. For example, a single oral or intravenous dose or repeated daily doses may be administered. Daily doses up to approx. 5 or LO days are often sufficient. It is also possible to give one daily dose or one dose every other day or at larger intervals. It is apparent from the dosing system that the amount of the major active ingredient administered is sufficient to induce regression and relief of leukemia and the like without the occurrence of severe cytotoxic adverse adverse effects for the host individuals having the cancer idea.

This quantity is also referred to here as the effective amount. In the present context, cancer diseases include malignant diseases of the blood such as leukemia and other completely malignant diseases such as melanocarcinoma, lung carcinoma and breast tumors. Regression and relief should mean stopping or delaying the growth of the tumor or other disease manifestation, compared to the course of the disease when treatment is not taken.

The novel compounds of the invention are also capable of inhibiting the growth of transplanted mouse tumors, as demonstrated by the following standard experiments.

Lymphocytic leukemia P388 test 35 As a test animal, same-sex mice (DBA / 2) with a minimum weight of 17 g and all within a weight variation range are used.

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17 range of 3 g. 5 or 6 animals are used per day. experimental group. Tumor transplantation is performed by intraperitoneal injection of 0.1 ml of diluted ascites fluid containing 106 cells of lymphocytic leukemia P388. The test compounds are administered 5 intraperitoneally on days 1, 5 and 9 (relative to the tumor inoculation) at various doses. The animals are weighed and the number of surviving animals is regularly recorded for 30 days. The mean survival time and the ratio of survival time of treated animals (T) to survival time of control animals (C) are calculated. The positive control compound is 5-fluoruacil given by injection in an amount of 60 mg / kg. The test results with representative compounds are given in the following Table I. The criterion for effective treatment is that T / C x 100> 125%.

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Table I

IN"

Lymphocytic leukemia P388 test

Dose Average T / CX 100 Compound mg / kg Survival (Percent) _ Time (days) _ Leukoif 4-bis [(2-dimethyl-100 24.5 245 aminoethyl) amino] -5,8-di-50 24 , 5 245 hydroxy-anthraquinone 25 19.0 190 12 17.5 175

6 16.0 16Q

3 14.5 145 1.5 13.0 130

Control 0 10.0 5-Fluorouracil 60 19.0 190 1,4-Bis [(2-dimethylamino-25.0 278 ethyl) -amino] -5,8-dihydro-20.5 228-droxy-anthraquinone 12 23.0 256 6 21.0 = 233 3 19.5 217

Control 0 9.0 5-Fluoruracil 60 19.5 217

Leuko-1,4-bis (2-morpholino-200 13.0 137 ethylamino) -5,8-dihydroxy-100 12.0 126-anthraquinone 50 11.0 · 116 25 12.0 126

Control 0 9.5 5-Fluorouracil 60 19.5 205 1,4-Bis (2-morpholinoethyl-2Q0 14,0 147 amino) -5,8-dihydroxy-an-100 12.0 126 thraquinone

Control 0 9.5 - 5-Fluoruracil 60 '19.5 · 205

Leukosi, 4-bis [(2-diethyl-200 17.0 179 aminoethyl) amino] -5,8-di-100 17.0 179 hydroxy-anthraquinone 50 15.0 158 25 13.0 137 12 12.0 126

Control 0 9.5 5-Fluoruracil 60 19.5 205

19 DK 158836 B

Table i (continued)

Average

Dose Survival T / C x 100 Compound_rog / kq time (days) (Percent) 1.4-Bis [(2-diethylamino-200 20.0 210 ethyl) -amino) -5,8-dihydroxylo 18.0 189 -anthraquinone 50 15.0 158 25 16.0 168 12 12.0 126

Control 0 9.5 5-Fluoruracil 60 19.5 205

Leuko-1,4-bis [2- (1-pyrrolidin 200 23.0 209 dinyl) ethyl] amino] -5,8-di-100 19.0 173 hydroxy-anthraquinone 50 16.0 145 25 15, 0 136

Control. 0.1, 5-Fluorouracil 60 20.0 182 1.4- Bis [[2- (1-pyrrolidinyl) - 100 24.0 218 ethyl] amino] -5,8-dihydroxy-50 * 23.0 209-anthraquinone 25 21.0 191 12 18.0 164 * «

Control 0 11.0 5-Fluorouracil 60 20.0 182 1.4- Bis [3-dimethylaminopropyl] 15.5 129 pyl) amino] -5,8-dihydroxy 15.5 129 anthraquinone 12 15.0 125

Control 0 12.0 5-Fluoruracil 60 19/5 162

Leuko-1,4-bis [(2-aminoethyl) - 100 19.0 158 amino] -5,8-dihydroxy-anthra 23.0 192 quinone 19.0 158 12 18.0 150

Control 0 12.0 5-Fluoruracil 60 19.5 162

Leukryl, 4-bis (3-aminopropyl-200 18.0 150 amino) -5,8-dihydroxy-anthra 100 18.0 150 quinone 50 16.0 133.

25 18.0 150 12 16.0 133

Control 0 12.0 5-Fluoruracil '60 19.5 162

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Table I (continued)

Average

Dose Survival T / C x 100 Compound_ mg / kg time (days) _ (Percent)

Leuko-1,4-bis [2- (2-methyl-200 2.0 18.0 aminoethylamino) ethylamino] - 100 26.0 236.0 -5,8-dihydroxy-anthraquinone 50 28.0 255.0 21.0 191.0 12.5 16.0 145.0 6.2 15.0 136

Control 0 11.0 5-Fluoruracil 60 17.0 170

Leuko-1,4-bis [2-dimethyl-200 18,0 200 aminopropylamino] -5,8-di-100 15,0 167 hydroxy-anthraquinone 50 14.0 156 25 13.0 144 12.5 11.0 122

Control 0 9.0 5-Fluoruracil 60 18.5 206 1.4-Bis [2- (2-hydroxyethyl-12.5 13.0 130 amino) ethylamino] -5,8-di-6.2 20.0 200 hydroxy -anthraquinone dihydro 3.1- 22.0. 220 chloride 1.5> 29.0> 290 0.78> 29.0> 290 0.39 27.0 270 0.19 25.0 250 0.09 21.0 210 O ', 04 "20.0 "200

Control O 10.0 5-Fluoruracil 60 20.0 200

Leuko-1,4-bisE2- [beta] -piperidone [7,0- 78-nyl] ethylamino] -5,8-di-100 21,0 233 hydroxy-anthraquinone 50 16,0 178 25 15,0 167 12,5 14 , 0 156

Control - .0 9.0 5-Fluorouracil 60 18.5 "206 1.4-Bis [2- (methylamino) ethyl 9.0 86 amino] -5,8-dihydroxy-anthra 12.5 16.0 152 quinone dihydrochloride 6.2 20.0 190 3.1 22.0 210 1.5 22.5 214 0.78 18.5 176 0.39 19.5 186 0.19 18.5 176 - 0.09 18 , 0 _ 171 0.04 17.0 162

Control O 10.5 - 5-Fluoruracil 60 18.0 171

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Table I (continued)

Average

Dose Survival T / C x 100 Compound_mg / kg Time (days) _ (Percent)

Leuko-4-bis [2- (2-hydroxy-12/0 114 ethylamino) ethylamino] -5,8-12,5 23,5 224-dihydroxy-anthraquinone 6.2 23.0 219 3.1 26.0 248 1.5> 30.0> 286 0.78 28.0 267 0.39 22.0 209 0.19 21.5 205 0.09 21.5 205 0.04 18.5 176

Control 0 10.5 5-Fluoruracil 60 18.0 171

Leuko-1,4-bis (4-aminobutyl-400 20.0 190 amino) -5,8-dihydroxy-anthra 300 18.0 171 quinone 200 17.0 162 100 14.0 133

Control 0 10.5 5-Fluoruracil 60 17.5 162

Leuko-1,4-bis [2- (methyl-5,0 55 amino) ethylamino] -5,8-di-19,0 173 hydroxy-anthraquinone 12,5 19,0 173 6.2 21,0 191 3.1 15.0 136 1.5 13.0 118

Control 0 11.0 5-Fluoruracil -60 18.5 168

Leuko-1,4-bis [2- (2-isopropyl-8,0 73-pylamino) ethylamino} -5,8-di-50 19.0 173 hydroxy-anthraquinone 17.0 155 12.5 15.0 136

Control O 11.0 5-Fluorouracil 60 20.5 · 186 1,4-Bis [2- (2-aminoethyl-200 17.0 162 amino) ethylamino] -5,8-di-100 16.0 152 hydroxy anthraquinone 50 14.0 133 25 13.0 124

Control 0 10.5 5-Fluorouracil 60 17.0 162

Leuko-1,4- [2- [di (β-hydroxy-200 19,0 190 ethyl) amino] ethylamirp] -5,8-100 17,0 170 -dihydroxy-anthraquinone 50 16.0 160-25 0. 150 12.5 13.5 135 6.2 12.0 120

Control 0 10.0 5-Fluoruracil 40 18.0 180

_ k, τ DK 158836 B

Table I (continued) 22 »»

Average

Dose Survival T / C x 100 Compound_mg / kg Time (Days) _ (Percent) 1.4-Bis [2- (2-hydroxy-1-propyl-12.0 120 amino) ethylamino] 1,4-di-12 , 24.0 240 Hydroxy-anthraquinone dihydro 6.2 23.0 230 Chloride 3.1 22.0 220 1.56 19.0 190 0.78 19.0 190 0.39 17.5 175

Control 0 10.0 5-Fluorouracil 40 18.0 180 1.4-Bis [2- [2- (1-morpholino) - 200 9.5 95 ethylamino] ethylamino] -5,8-di-100 -anthraquinone tetra-50 18.5 185 hydrochloride 19 19.5 195 12.5 15.0 150 6.2 14.0 140 3.1 13.0 130

Control 0 10.0 5-Fluoruracil 40 18.0 180 1.4-Bis [2- (3-hydroxy-1-propyl-8.5 77 amino) ethylamino] 5,8-dihydroxy-12,5> 30, 0> 273 anthraquinone dihydrochloride 6.25 26.0 236 3.1 25.0 227 1.56 22.0 200 0.78 21.5 · 195

Control 0 11.0 - 5-Fluorouracil 40 18.0 164 "

Leuko] -4 / bis [2- (3-hydroxy-1-200 14.0 127-propylamino) ethylamino] -5,8-100 38,0 345-dihydroxy-anthraquinone 50 34.0 309 25 22.0 200 12.5 19.5 177 6.25 16.5 150 3.1 18.5 168 1.56 19.5 177 0.78 '18.0 164

Control 0 11.0 5-Fluorouracil 40 17.0 155 1.4- Bis [2- [di (β-hydroxyethyl) - 200> 30.0> 333 amino] ethylamino] -5,8-di-100 22.0 244 hydroxy-anthraquinone dihydro-50 20.5 228 chloride 21.5 239 12.5 18.5 206 - 6.2 18.5 .206 - 3.1 19.0 211 1.56 16.0 178 0.78 14.5 161

Control 0 9.0 5-Fluoruracil 60 20.5 228 23

Table I (continued) DK 158836 B

Average

Dose Survival T / c x loo Compound_mg / kq Time (days) _ (Percent)

Leuko-1,4-bis [3- (2-hydroxy-200 33.5 305 ethylamino) -1-propylamino] - 100 27.5 250 -5,8-dihydroxy-anthraquinone 50 25.0 227 18.5 168 12.5 19.0 173 6.25 18.0 164 3.12 15.0 136

Control 0 11.0 5-Fluoruracil 40 17.5 159

Leuko 1,4-bis [2- (2-hydroxy-200 9.0 82 -1-propylamino) ethylamino] - 100 26.5 241 -1,4-dihydroxy-anthraquinone 50 24.0 218 25 20 , 5 186 12.5 21.5 195 6.25 20.0 182

Control O 11.0 5-Fluorouracil 40 17.5 159 1.4- Bis [3- (2-hydroxyethyl-100 12.5 114 amino) -1-propylamino] -5,8- 50 32,0 291 -dihydroxy-anthraquinone 26.5 241 dihydrochloride 12.5 22.5 205 6.25 19.0 173 3.12 19.0 173 1.56 16.0 '145 0.78 15.0 136

Control 0 11.0 5-Fluorouracil 40 17.5 159 1.4- Bis [2- (1-aziridino) ethyl] 28.5 285 amino] -5,8-dihydroxy-anthra 50 21.5 215 quinone , 0 200 12.5 20.5 205 6.25 18.5 185 • 3.12 19.5 .195 1.56 1.7.0 170 0.78 14.0 140

Control 0 5-Fluoruracil 60 20.5 205 1.4-Bis [2- (2-methylamino-100 22.0 220 ethylamino) ethylamino] -5,8-50 22,0 220 -dihydroxy-anthraquinone t-19, 5 195 trahydrochloride 12.5 17.0 170 6.25 16.0 160 '1.12 13.5 * 135 1.56 13.0 130

Control 0 10.0 5-Fluoruracil 40 16.0 160 '24

DK 158836B

Table I (continued)

Average

Dose Survival T / C x 100

Compound_mg / kg time (days) _ (Percent) Administration 1.4-Bis (2-aminoethylamino) - 12.5 8.0 73 -5,8-dihydroxy-anthraquinone 6.2 15.5 141 -dihydrochloride 3.1 30 , 0 273 1.56 20.0 182 0.78 24.5 223 0.39 25.5 232 0.19 23.0 209

Control 0 11.0 5-Fluorouracil 60 20.5 186 1.4-Bis (2-dimethylaminoethyl-200 15.0 136 day 1, 5 amino) -anthraquinone 100 18.5 168 and 9 50 15.0 136

Control 0 11.0 5-Fluorouracil 60 18.5 168 1.4-Bis (2-morpholinoethyl-400 23.0 219 days 1-9 amino) -anthraquinone 200 15.0 143 100 15.0 143 50 13.0 124

Control 0 10.5 5-Fluorouracil 20 29.0 276

1.4-Bis (2-diethylaminoethyl-200 14.0 140 day 1, E

amino) -anthraquinone 100 12.0 120 and 9 50 13.0 130

Control 0 10.0 5-Fluoruracil 60 17.5 175

1.4- Bis (2-piperidinoethyl-200 14.0 127 day 1, E

amino) anthraquinone 100 12.0 109 and 9 50 11.0 100

Control 0 11.0 5-Fluoruracil 60 19.0 173

Leuko-1,4-bis (2-aminoethyl-200 27.0 245 day 1, E

amino) anthraquinone 100 24.0 218 and 9 50 20.0 182 25 21.0 191 12 21.0 191

Control 0 11.0 5-Fluorouracil 60 22.0 200 1.4-Bis (2-aminoethylamino) -, 22 22 24 24 day 1, anthraquinone 12 18.0 '200 5 and 9 6 16.5 183 3 16.0 178 1.5 16.5 183 0.7 15.5 172

Control 0 9.0 5-Fluoruracil 60 21.0 233

Average

Dose Survival T / C x 100

Compound_mg / kg time (days) _ (Percent) Administration ø 25

Table I (continued)

DK 158836 B

1,4-Bis (2-methylaminoethyl-12 22.0 244 day 1, amino) -anthraquinone 6 21.0 233 5 and 9 3 17.0 189

Control 0 9.0 5-Fluorouracil 60 19.5 217 1,4,5-Tris [(2-aminoethyl) - 12 15.0 130 amino] -8-hydroxy-anthra-6 15.0 130 quinone 3 15, 0 130 1,5 15,0 130 1,4-Bis [(2-dimethylamino-50 18 157 ethyl) amino] -5,6-dihydroxy anthraquinone 12 16 139

Control 0 .11,5 5-Fluorouracil 60 19.0 165 1.4- Bis (3'-aminopropylamino) - 22.0 183 -5,8-dihydroxy-anthraquinone 12. 19.0 158

Control 0 12.0 5-Fluoruracil 60 19.5 162

DK 158836B

26

Lymphocytic leukemia P388 test

The test method used is the same as for the lymphocytic leukemia P388 test described above except that the test compounds are administered orally at different doses instead of intraperitoneally. The test results are given in the following Table II. The criterion for effective treatment is that T / C x 100> 125%.

Table II

10 Lymphocytic leukemia P388 test for oral administration

Dose Average mg / kg survival T / C x 100 Compound_day 1-9 time (days) _ (Percent) 1.4-Bis (2-dimethylamino-100 17.5 159 ethylamino) anthraquinone 50 13.5 123 25 14.0 127

Control 0 11.0 - 5-Fluorouracil 20 - 13.5 127

Leuko 15 - big [(2-dimethyl-16.0 160 aminoethyl) amino] -5,8-di-13.5 135 hydroxy-anthraquinone 12 12.5 125

Control O 10.0 5-Fluorouracil 60 19.0 190 1.4-Bis [(2-dimethylamino-12 16.0 139 ethyl) -amino] -5,8-dihydroxy-6 16.0 139-anthraquinone 3 15.0 130

Control O 11.5 5-Fluoruracil 60 20.0 174 5-Fluoruracil is administered intraperitoneally

DK 158836 B

27

LvTnococcal leukemia L1210 test

The test method is the same as for the intraperitoneal test for lymphocytic leukemia P388 except that the tumor transplant consists of inoculating lymphocytic leukemia 5 L1210 at a concentration of 105 cells / mouse and an average survival time is calculated. The results are given in the following Table III.

Table III

10 Lymphocytic leukemia L1210 test

Dose Average m9 / kg survival T / C x 100

Compound day 1-9 time (days) _ (Percent) 1,4-Bis (2-dimethylamino-50 12.0 135 ethylamino) -anthraquinone 11.0 124 12 9.4 106

Control O 8.9 5-Fluoruracil 20 17.6 188 20 Melanotic melanoma B16

As experimental animals, mice (C57BC / 6) of the same sex with a minimum weight of 17 g and all within a weight variation range of 3 g are used. experimental group. One gram of melanotic melanoma B16 tumor is homogenized in 10 ml of cold balanced saline solution and 0.5 ml of the homogenate is implanted intraperitoneally in each of the test animals. The test compounds are administered intraperitoneally on days 1 to 9 (relative to the tumor inoculation) at various doses. The animals are weighed and surviving animals are regularly recorded for a period of 60 days. The mean survival time and the ratio of survival time of treated animals (T) to control animals (C) are calculated. The positive control compound is 5-fluorouracil, which is injected in an amount of 20 mg / kg. The test results are given in Table IV below. The criterion for effective treatment is that T / C x 100 is> 125%.

DK 158836B

* 28

Table IV

Melanotic melanoma Bie test

Average

Dose Survival T / C x 100 Compound_mg / kg Time (days) _ (Percent)

Leuko-1,4-bis [(2-dimethyl 25.0 151 aminoethyl) amino] -5,8-di-12 23/0 139 hydroxy-anthraquinone 6 21.5 130 3 21/0 127

Control 0 16.5 5-Fluorouracil 20 25.0 151 1.4-Bis [(2-dimethylamino-24.5 136 ethyl) amino] -5,8-dihydroxy-12 28.5 158-anthraquinone 6 27.0 150 3 25.5 142

Control 0 18.0 5-Fluoruracil 20 26.0 144

Leukor-1 # 4-bis [(2-diethyl-23.0 139 aminoethyl) amino] -5,8-dihydroxy-anthraquinone

Control 0 16.5 5-fluorouracil 20 25.0 151 1,4-Bis (2-diethylamino-20,5 125 ethyl) amino] -5,8-dihydroxy-anthraquinone

Control 0 16.5 5-Fluoruracil 20 25.0 151

Leuko-1,4-bisph 2- (1-pyrro-23.0 144-lidinyl) ethyl] -amino} -r5: 8- 25 22,0 137 -dihydroxy-anthraquinone 12 21.0 131

Control 0 16.0 5-Fluorouracil 20 26.5 166 1.4-Bis [2- (1-pyrrolidinyl) -24.5 153 ethyl],] - 5,8-dihydroxy-12 22,0 137-anthraquinone 6 22.0 137

Control 0 16.0 5-Fluoruracil 20 26.5 166

DK 158836 B

29

Table IV (continued)

Average

Dose Survival T / C x 100

Compound µmg / kg time (days) (Percent) 1.4-Bis [(3-dimethylaminopropyl 20.0 125 pyl) amino] -5,8-dihydroxy-anthraguinone

Control 0 16.0 5-Fluoruracil 20 26.5 166

Leuko-1,4-bis [(2-aminoethyl) - 12 32.0 200 amino] -5,8-dihydroxy-anthraquinone

Control 0 16.0 5-Fluoruracil 20 26.5 166

Leuko [4-bis (3-aminopropyl-31.5 197 amino) -5,8-dihydroxy-anthra 27.0 169 guinone 12 23.5 147 6 22.5 141

Control 0 16.0 5-Fluoruracil 20 26.5 166

Leuko-1,4-bis [2- (2-methyl-12,573 amino) ethylamino] -5,8-dihydro 35,0 206-hydroxy-anthraquinone 12.5 39.5 232 6.2 28 , 5 168

Control 0 17.0 · 5-Fluoruracil 20 30.0 176

Leuko-1,4,4-bis [2- (1-piperazin-34,5,203-nyl) ethylamino] -5,8-di-30,5,179 hydroxy-anthraquinone 12,5 26,0 153 6 22, 0 129 3 20.5 121

Control 0 17.0 5-Fluorouracil 20.0 176 1.4- Bis [2- (2-aminoethylamino) - 50 2-4.0 150 ethylamino] -5,8-dihydroxy-22.5 141-anthraquinone 12 22 , 0 138 6 20.0 125

Control 0 16.0 5-Fluorouracil 20 27.0 169 Ί, 4-bis [2-dimethyl-100 21.0 124 aminopropylamino] -5,8-di-50 28,5 168 hydroxy-anthraquinone 24.5 144 12.5 20.5 '121 6 19.5 115

Control O 17.0 5-Fluoruracil 20 30.0 176

DK 158836 B

Table IV (continued)

Average

Dose Survival T / C x 100 Compound_mq / kg Time (Days) _ (Percent) 1.4-Bis [2- (2-Hydroxyethyl-12 11.0 73 amino) ethylamino] -5,8-di-6 15.0 100 hydroxy-anthraquinone dihydro-3> 28.5> 190 chloride 1.5> 34.0> 227 0.7> 34.0> 227 0.3 34.0 227

Control 0 15.0 5-Fluoruracil 60 23.0 153

Leuko-4-bis [2- (2-isopropyl-5,639 amino) ethylamino] + 5,8 'd.i.-* 31.0 188 hydroxy-anthraquinone 12 30.0 182 6 25.0 151

Control 0 16.5 5-Fluorouracil 20 16.5 100 1.4-Bis [2- (methylamino) ethyl 12.5 11.5 59 amino] -5,8-dihydroxy-anthra-6.2 26.5 136 quinone dihydrochloride 3.1 49.0 251 1.5 33.0 169 0.78 '35.0 179 0.39 25.0 128 0.19 29.5 151

Control 0 19.5 5-Fluoruracil 60 25.0 · 128

Leuko-1,4-bis (4-aminobutyl-100 21.0 124 amino) -5,8-dihydroxy-anthra 20.0 118 quinone 18.5 109 12 16.0 94

Control 0 17.0 - 5-Fluorouracil 20 30.0 176 - I I - .........— 1 II · - i (! —II!

Leuko-1,4-bis [2- (2-hydroxy-6 9,5 59 ethylamino) ethylamino] -5,8-3 -3,5,5,5-dihydroxy-anthraquinone 1/5 30,0 187 0,75 28 , 5 178 0.37 22.0 137

Control 0 16.0 5-Fluoruracil 20 27.5 172

Leuko-1,4-bis [2- (methylamino) - 12 28.0 175 ethylamino] -5,8-dihydroxy 6 32.5 203-anthraquinone 3 31.0 194 1.5 36.0 225 '0.7 27 , 5 - 172

Control 0 16.0 5-Fluorouracil 20 27.5 172 t 31

Average

Dose Survival T / C x 100

Compound_mq / kg time (days) (Percent)

DK 158836 B

Table IV (continued) 1.4-Bis (2-dimethylaminoethyl-50 23.0 139 amino) anthraquinone 19.5 118 12 13.5 84

Control 0 16.5 5-Fluorouracil 20 25.5 155 1.4-Bis (2-morpholinoethyl-400 24.0 133 amino) anthraquinone 200 20.0 111

Control 0 18.0 5-Fluoruracil 20 26.0 144

Leuko-β 4-bis (2-aminoethyl-100 25.0 143 amino) anthraquinone 50 35.5 203 25 33.0 187 12 27.5 157 6 22.0 126

Control 0 17.5 - 5-Fluorouracil 20 26.0 149 "1.4-Bis" (2-aminoethylamino) - 12 31.0 182-anthraquinone 6 30.5 179 3 29.0 171 1.5 23.5 138 22.0. 129

Control 0 17.0 5-Fluorouracil 20 26.0 153 1.4- Bis (2-methylaminoethyl 12 33.0 187 amino) anthraquinone 6 37.5 214 3 36.0 206 1.5 28.5 163 0.7 24, 5 140

Control O 17.5 5-Fluorouracil 26.0 149 1,4,5-Tris [(2-aminoethyl) amino] -8-hydroxy-anthraquinone 6 26.0 163

Control O 16.0 5-Fluorouracil 20 26.5 166 1.4-Bis [(2-dimethylaminoethyl) -50 23 153 amino] -5,6-dihydroxy-anthra 24 24 160 quinone 12 23 153 6 22.5 150

Control 0 16.0 5-Fluoruracil 20 26.5 166

DK 158836 B

32

Table IV (continued)

Average

Dose Survival T / C x 100 Compound_mg / kg Time (days) _ (Percent) 1,4-Bis (3-aminopropylamino) - 12 24.0 150 -5,8-dihydroxy-anthraquinone 6 30.0 187

Control O 16.0 5-Fluorouracil 20 26.5 166 10

Ridcfway osteoaent sarcom

As a test animal, mice (AKD2 / F1 / J) of the same sex with a minimum weight of 17 g and all within a weight variation range of 3 g are used.

15 group. The tumor is administered subcutaneously by trocar in the form of 5 2 mm fragments per second. mouse. The test compounds are administered intraperitoneally every 4 days for a total of 6 inoculations beginning on the 15th day (relative to the tumor inoculations) at various doses. The animals are weighed, and surviving 20 individuals are regularly recorded over 90 days. The regression of tumors is recorded for all experimental animals. Table V lists the test results expressed by the percentage of animals exhibiting tumor regression.

. . 33 DK 158836 B

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DK 158836 B

34

The process according to the invention is illustrated in more detail in the following examples.

Example 1 Leuko-1,4-bis (morpholinoethyl) -aminol-5,8-dihydroxy-anthraquinone

A solution of 15.62 g of N- (2-aminoethyl) morpholine in 40 ml of N, N, N ', N' -tetramethylethylenediamine is aerated by passing nitrogen for 15 minutes. 10.97 g of leuko-1,4,5,8-10 tetrahydroxyanthraquinone are added slowly with stirring and the suspension is heated on an oil bath maintained at 49-51 ° C. The mixture is allowed to cool under nitrogen.

The solid is collected and washed with ethanol to give 18.07 g of the desired product as an olive solid, m.p. 223-227 ° C.

Example 2 1-4-Bis-morpholinoethylaminol-5,8-dihydroxy-anthracininone 13.90 g of leuko-1,4-bis (2-morpholinoethylamino) -5,8-20 dihydroxy-anthraquinone in 100 ml of nitrobenzene are oxidized by heating 10.30 g of the desired product in the form of black rod-shaped crystals, m.p. 241-143 ° C.

Example 3 Leuko-1,4-bis Γ (2-diethylaminoethyl) aminol-5,8-dihydroxanthanquinone

Analogous to the procedure described in Example 1, however, using 13.95 g of N, N-diethylethylenediamine in place of the N- (2-aminoethyl) morpholine, and giving 13.97 g of the desired product in the form of a reddish brown solid with m.p. 182-185 ° C.

Example 4 1,4-Bis (2-diethylaminoethyl) amino) -5,8-dihydroxanethraauinone 10.90 g of leuko-1,4-bis [(2-diethylaminoethyl) amino] -5,8-dihydroxyanthraquinone is oxidized analogously to Example 2,

DK 158836 B

35 and 6.35 g of the desired product are obtained in the form of blue-black needles with m.p. 202-204 ° C.

Example 5 Leuko-1,4-bis [2- (1-pyrrolidinyl) ethylamino] -5,8-dihydroxane-thracruinone

Analogous to the procedure described in Example 1, however, using 12.05 g of N-2-pyrrolidinoethylamine instead of N- (2-aminoethyl) morpholine and 80 ml of 10 N, N, N ', N1 -tetramethylethylenediamine to give 13.24 g of the desired product as a reddish brown solid, m.p. 180-185 "C.

Example 6 1-4-Bis [2 (1-pyrrolidinyl) ethylamino] -5,8-dihydroxyanthraquinone 8.61 g of leuko-1,4-bis [2- (1-pyrrolidinyl) ethyl] amino-5, 8-dihydroxy-anthraquinone is oxidized analogously to Example 2. The reaction mixture is evaporated to dryness and the residue 20 is recrystallized from toluene to give 5.12 g of the desired product in the form of blue-black crystals, m.p. 193-196 ° C.

Example 7

Leuko-1,4-bis (2-imethylamino) ethylamino! -5,8-dihydroxvanthra-cruinone

Analogous to the procedure described in Example 5, using 8.90 g of N-methylethylenediamine in place of N-2-pyrrolidinoethylamine and 13.73 g of the desired product in the form of a dark green solid is obtained. with m.p. 157-160 ° C.

Example 8

Leuko-1,4-bis (aminoethylamino) -5,8-dihydroxvanthracruinone

A reaction mixture containing 10.97 g of leuko-1,4,5,8-tetrahydroxyanthraquinone in 80 ml of deaerated Ν, Ν, Ν ', Ν'-tetramethylethylenediamine containing 7.22 g of ethylenediamine

DK 158836 B

36 is heated and stirred under nitrogen at 48-50 ° C for 1 hour. The mixture is left under a slow stream of nitrogen to separate a solid which is isolated and washed with ethyl acetate, acetonitrile and petroleum ether. 13.8 g of the desired product are obtained in the form of a red-black solid which has not melted at 350 ° C. IR: 6.34 and 8.20 μιη.

Example 9

Leuko-1,4-bis Γ 2- (2-hydroxyethylamino) ethylaminol -5,8-dihydro-xanthanquinone

A suspension of 12.5 g of 2- (2-aminoethylamino) ethanol in 40 ml of N, N, N ', N1-tetramethylethylenediamine is stirred and purged by passing through nitrogen for 15 minutes. 10.97 g of leuko-1,4,5,8-tetrahydroxyanthraquinone are gradually added with stirring. The suspension is heated and stirred under nitrogen in an oil bath at 50-52 ° C for 5 hours. The mixture is left to stand and cooled under nitrogen for 12 hours. The solid is isolated by decantation, macerated in ethanol, isolated and washed with ethanol to give 15.06 g of the desired compound 20 as an off-white solid, m.p. 129-131 ° C.

Example 10

Leuko-1,4-bis (2-difg-hydroxyethyl) -amino-1-ethylaminol-5,8-dihydroxyanthracminone A solution of 17.8 g of N, N-di (hydroxyethyl) ethylene-diamine in 100 ml of methanol is cooled with an ice bath. is stirred and deaerated by passing nitrogen for 15 minutes. 10.97 g of leuko-1,4,5,8-tetrahydroxy-anthraquinone are gradually added with stirring and continued cooling. The suspension is heated and stirred under nitrogen in an oil bath at 50-52 ° C for one hour, after which the mixture is allowed to cool under nitrogen overnight. The solid is isolated and washed with ethanol to give 14.8 g of a reddish brown solid, m.p. 165-168 ° C.

Example 11 35

DK 158836 B

37 1,4-Bis-β2 - (methylamino) ethylamino) -5,8-dihydroxvanthra-cruinone dihydrochloride

To a suspension of 11.60 g (0.03 mole) of leuko-1,4-bis [2- (methylamino) ethylamino] -5,8-dihydroxyanthraquinone in 5,200 ml of 2-methoxyethanol is gradually added with stirring 15 ml of 8N ethanolic hydrochloric acid. The system is cooled in an ice bath and stirred while gradually adding 7.50 g (0.0305 mole) of chloro-anil powder. The mixture is stirred overnight at room temperature and diluted with 600 ml of ether. The solid is isolated and washed with tetrahydrofuran. 14.16 g of product is obtained, which is recrystallized by dissolving in 130 ml of water, and by adding 650 ml of acetone 13.15 g of a blue-black solid is obtained. The substance is not fused at 350 ° C. IR: 6.20: 6.39; 8.26; 12.13 μτα.

15

Example 12 1,4-Bis [2- (2-aminoethylamino) ethylaminol-5,8-dihydroxanetra-quinone

Analogous to the procedure described in Example 3, a mixture of 10.97 g of leuko-1,4,5,8-tetrahydroxy-anthraquinone, 80 ml of Ν, Ν, Ν ', Ν'-tetramethylethylenediamine and 21.84 g ( Diethylenetriamine, and a thick solidified mass is rapidly formed which impedes effective agitation and therefore the reaction time is extended to 24 hours. The mixture 25 is allowed to cool and the supernatant is decanted and discarded. A solution of the solidified mass in 100 ml of methanol is filtered and then quenched for oxidation in the air for 4 days in a partially covered flask. The separated gelatinous mass becomes solid when the oxidation mixture is stirred with 200 ml of acetonitrile and then left for one hour.

After isolating the solid and washing with acetonitrile and then with ether, 10.88 g of a pale black powder is obtained. The substance is not fused at 350 ° C. IR: 6.21; 6.42; 8.31 μια.

35

DK 158836 B

38

Example 13

Leuko-1,4-b in s Γ 2-dimethylaminopropylamino Ί -5,8-dihydroxyan-thraquinone

Reaction of 12.26 g of 2-dimethylaminopropylamine with 10.97 g of leuko-1,4,5,8-tetrahydroxyanthraquinone in 100 ml of ethanol for one hour gives 7.29 g of reddish-brown crystals which turn black at 255 ° C and not melted at 350 ° C. IR: 6.31; 8.11; 12.02 μια.

Example 14

Leuko-1,4-bis (2- (2-methylaminoethylamino) ethylaminol -5,8-dihydroxy-anthraquinone

To a solution of 14.10 g of 1-methyl-diethylenetriamine in 50 ml of ethanol and 40 ml of Ν, Ν, Ν ', N * -tetramethylethylenediamine 15 is added 10.97 g of leuko-1,4,5,8-tetrahydroxyanthraquinone analogously to the procedure described in Example 1. The mixture is heated to 50 ° C and stirred under nitrogen for one hour, cooled in an ice bath, and the solid is isolated and washed with cold ethanol to give 7.23 g of greenish crystals with 20 m.p. 108-111 "C.

Example 15

Leuko-1,4-bis-2- (1-piperazinyl) ethylaminol-5,8-dihydroxane-thracruinone Analogous to the procedure described in Example 14, 15.50 g of N- (2-aminotehyl) piperazine is reacted and 3 is excreted. 92 g of black powder which does not melt at 350 ° C and discards this powder. The mother liquor and ethanol wash liquors are left in an open flask for 2 weeks and a solid 30 is separated which is isolated and washed with ethanol to give 6 19 g of the above compound in the form of a black solid, mp 200-203 "C,

Example 16 1,4-Bis (2-aminoethylamino) -5,8-dihydroxanethraquinone dihydrochloride

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39

Oxidation with chloranil of 28.25 g of the product of Example 8 gives 29.66 g of an impure blue-black solid which is then extracted with stirring for 14 hours with 800 ml of water. Solids are removed by centrifugation and the above solution is lyophilized to give 16.38 g of a blue-black solid which does not melt at a temperature up to 350 ° C.

Example 17 1-4-Bis-2- (2-hydroxyethylamino) ethyleneaminol-5,8-dihydroxy-anthraquinone dihydrochloride

Chloranil oxidation of 17.86 of the product of Example 11 gives, without recrystallization, 21.34 g of a blue-black solid, m.p. 203-205 "C.

15

Example 18 1,4-Bis Γ 2- (2-methylaminoethylamino) ethylaminol -5,8-dihydroxy anthracruinone tetrahydrochloride 11.70 g of the product of Example 14 is oxidized with chloranil by analogy to the procedure described in Example 11 and there 18.03 g of a blue-black solid are obtained, m.p. 190-203 "C.

Example 19 1,4-Bis Γ 2- (2-Hydroxyethylaminolethylaminol-5,8-dihydroxydractracruinone

A modification of the procedure of Example 9 is used, using 100 ml of ethanol as the solvent. The mother liquor from the leuco product is left for 2 weeks 30 in an open flask, which separates the oxidized product.

It is isolated and washed with ethanol, then recrystallized from ethanol to give blue-black crystals with m.p. 175-177 ° C.

35

Example 20

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40

Leuko-1- [4-bis \ 2- (2-hydroxyethylamino) -1-propylaminol-5,8-dithiohydroxanthanquinone 5 Proceed as described in Example 10, however, using a solution of 14.18 g of 2- (3-aminopropylamino) - ethanol in 100 ml of ethanol. The resulting solution is filtered and the filtrate is diluted with 300 ml of ether to precipitate the product. After decanting the above liquid, the product is crystallized by stirring in 100 ml of tetrahydrofuran.

Washing with ethanol gives 12.56 g of green solid with m.p. 101-104 ° C.

Example 21 1,4-BisΓ3- (2-hydroxyethylaminol-1-propylaminol -5,8-dihydroxy-anthraouinone dihydrochloride

Oxidation of 9.95 g of leuko-1,4-bis [3- (2-hydroxyethylamino) propylamino] -5,8-dihydroxyanthraquinone with chloranil analogous to the procedure of Example 11 gives 11.70 g of blue solid which does not melt at 350 ° C.

Example 22

Leuko 1,4-bis2- (3-hydroxy-1-propylamino) ethylamino-5,8-dihydroxanthantracfuinone Analogous to the procedure described in Example 10, 14.18 g of N- (3-hydroxypropyl) ethylenediamine is reacted in 100 ml of ethanol and obtained 14.63 g reddish brown crystals with m.p.

58-60 ° C.

Example 23 1,4-Bis Γ 2- (3-Hydroxy-1-propylaminoethyl thylamino 1 -5,8-dihydroxy-anthracfuinone dihydrochloride

Upon oxidation with chloranil of 10.77 g of the product of Example 22, analogous to the process described in Example 35 11, 11.64 g of a dark blue solid, m.p. 210-216 ° C.

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41

Example 24

Leuko-1,4-bis Γ 2- (2-hydroxy-1-propylamino] ethylaminol -5,8-dihydroxvanthraquinone 5 Analogously to the procedure described in Example 16, 14.18 g (1- (2- aminoethylamino)) is reacted -2-propanol in 100 ml of ethanol and 17.61 g of greenish crystals are obtained, mp 50-60 ° C.

Example 25 1,4-Bis Γ 2- (3-Hydroxy-1-propylaminol-ethylaminol -5,8-dihydroxy-anth-racruinone dihydrochloride

A filtered solution of 14.44 g of leuko-1,4-bis [2- (2-hydroxy-1-propylamino) ethylamino] -1,4-dihydroxyanthraquinone in 215 ml of 2-methoxyethanol is oxidized with 7.65 g chloroanil by analogy to the procedure described in Example 11, and 16.75 g of a pink solid are obtained, m.p. 177-185 ° C.

Example 26

Leuko-1,4-bis-2- [2- (2-hydroxyethylamino) ethylaminol-ethylamino] -5,8-dihydroxanethraauinone

Analogous to the procedure described in Example 10, a solution of 17.67 g of 2- [2- (2-aminoethylamino) -25-ethylamino] -ethanol is reacted in 100 ml of methanol to form a solution which is filtered and diluted with 300 ml ether, precipitating a tough mass which becomes hard on standing overnight. The curing is accomplished by careful maceration of the solid in the solvent. The solid is isolated and washed with ether to give 16.82 g of a green solid. The solid remains granular when stored at -25 ° C, but flows together into a solid cake when stored at 25 ° C. Mp. 75-85 ° C.

35

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42

Example 27 1.4-Bis-β-2- (2-hydroxyethylamino) ethylaminol-ethylaminol-5,8-dihydroxanethraquinone tetrahydrochloride

By chloranil oxide ion of 12.10 g of the product of Example 26, analogous to the procedure described in Example 11, after three further washings of the solid with methanol, 12.46 g of a dark blue solid is obtained. Mp. 119-202 ° C. IR: 6.21; 6.38; 8.33 / zm.

Example 28 1.4- Bis2- (2,3-Dihydroxypropylamino) ethylaminol-5,8-dihydroxanthanhydracfuinone dihydrochloride

Analogous to the procedure described in Example 10, a solution of 16.10 g of 3- (2-aminoethylamino) -1,2-15 propanediol (cf. AR Surrey, CM Suter and JS Buck, J. Am. Chem. Soc. 74, 4102 (1952) in 100 ml of methanol to give a cool mass which is isolated from the solvent by cooling in an ice bath and subsequent decantation. The cool mass is washed 4 times by stirring for 1.5 hours at 25 ° C with 20 100 ml portions of methanol, cooling on an ice bath and subsequent decantation A filtered solution of the cool mass in 280 ml of 2-methoxyethanol is oxidized with 10.01 g of chloranil analogous to the procedure described in Example 16. The product is further washed with ethanol, and there is obtained 15.25 g of a blue-black solid, mp 191-193 ° C.

Example 29

Leuko-1,4-bis-2- (1-aziridino) ethylaminol -5,8-dihydroxanthra-cruinone 10.33 g of N- (2-aminoethyl) aziridine in 80 ml of Ν, Ν, Ν ', Ν'-tetramethylethylenediamine is reacted analogously by the method described in Example 10 to obtain a rigid rubber. The next day, the above solution is discarded, 100 ml of ether is added and the gum is periodically macerated therein for another 35 days, thereby almost solidifying the gum. The solidification becomes complete by maceration under three washes of the solid

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43 substance with ether and 17.66 g of a blue-black granular powder is obtained. Mp. 120 ° -132 ° C. IR: 6.37; 6.89; 8.20; 12.03 μια.

Example 30 1,4-BisT2 - (1-aziridinoethylaminol -5,8-dihydroxanthanthraguinone

To a suspension of 4.10 g of the product of Example 29 in 40 ml of chloroform is added a solution of 1.74 g of diethyl azodicarboxylate in 25 ml of chloroform. The mixture is stirred for 20 minutes, the resulting dark blue solution is filtered and the filtrate is evaporated at a temperature not exceeding 30 ° C. A solution of the residue in 40 ml of chloroform is stirred for 5 minutes with 2 g of decolorizing coal, filtered and washed with an additional 25 ml of chloroform. To the filtrate is added an additional 100 ml of ether, which precipitates a rubbery substance which is removed by decantation and filtration. Crystals which are washed with a bit of acetone are separated from the filtrates. The chloroform-ether mother liquor is cooled to -60 ° C and a crystal product is washed which is washed with ether and methanol. A solution of the two crystal products in 20 ml of 20 chloroform is stirred with decolorizing coal, filtered, evaporated at a temperature not exceeding 25 ° C to 5 ml, diluted with 20 ml of ether and then cooled to -60 ° C. The resulting blue-black crystals are washed with ether to give 0.64 g of product, m.p. 168-170 ° C. By thin layer chromatography on silica gel, the product moves as a blue spot with a mixture of chloroform, triethylamine and methanol in the 27: 3: 1 volume ratio.

Example 31 1,4-Bis [2- (β-Morpholino) ethyl amino] -5,8-dihydroxanethracruyl non-tetrahydrochloride

A solution of 20.80 g of N- (morpholinoethyl) ethylenediamine in 100 ml of ethanol is reacted analogously to the procedure described in Example 10, and a solution is formed which is filtered and diluted with 900 ml of ether, which separates a cool lot. The supernatant is decanted and the cool mass is dissolved in 175 ml of 2-methoxyethanol and oxidized

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44 with 5.29 g of chloranil by analogy to the procedure described in Example 16. 17.7 g of a dark blue solid is obtained, m.p. 265 ° C.

Example 32

Leuko-1,4-Bis (2-Acetamido) ethylamino1-5,8-dihydroxvanthra-quinone

A solution of 12.26 g of N-acetylethylenediamine in 100 ml of ethanol is reacted by analogy with the procedure described in Example 10 and 15.27 g of a dark reddish brown substance are obtained, m.p. 125 ° C.

Example 33 1.4- Bis Γ 2- (acetamido) ethylamino 1 -5,8-dihydroxvanthracruinone A suspension of 11.95 g of leuko-1,4-bis [2- (acetamido) ethylamino] -5,8-dihydroxyanthraquinone is oxidized with 6 76 g of chloranil over 61 hours by analogy to the procedure described in Example 11, and a very acidic hydrochloride salt is obtained which is converted to the free base by four washes 20 with water. Crystallization from 110 ml of dimethyl sulfoxide, boiling only for 2 minutes and no hot filtration, and subsequently washing with dimethyl sulfoxide and with ethanol gives 7.76 g of a pale black solid, m.p. 273-274 ° C.

25

Example 34 1,4- Bis2- [2- (2-hydroxyethyl) trifluoroacetamidolethylamino] - 5,8-dihydroxvanthracfuinone

A suspension of 1.50 g of 1,4-bis [2- (2-hydroxyethylamino) ethylamino] -5,8-dihydroxyanthraquinone in 75 ml of ethyl trifluoroacetate and 75 ml of methanol is stirred for 10 minutes. Evaporation of the resulting solution in vacuo at 30 ° C gives a residue which is washed and macerated with methylene chloride, and 2.11 g of a pale black solid are obtained, m.p. 162 ° C.

35

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45

Example 35 1.4 - Bis Γ 2-Amino-2-carboxyethylamino] -5,8-dihydroxanethraqui-non-3/4 HCl

To a solution of 6.23 g of dl-α, β-diaminopropionic acid 5 in 30 ml of warm water is added 1.078 g of lithium hydroxide and 60 ml of dimethyl sulfoxide. The system is rinsed with nitrogen and gradually 4.12 g of leuko-1,4,5,8-tetrahydroxyanthraquinone is added with stirring. The mixture is stirred and heated on an oil bath at 50 ° C, first for 15 hours under nitrogen and then 10 for 21 hours, the first formed product being oxidized by bubbling through an air stream. Thin layer chromatography on silica gel with methanol-water-concentrated ammonia water in a 25: 5: 1 volume ratio indicates that all the product spots are blue when oxidation is complete. After cooling the mixture, the solids are filtered off and washed once with dimethyl sulfoxide water (2: 1). To the filtrates are added 400 ml of methanol and a solid is precipitated which is isolated and washed with methanol. By further washing with a total of 13 ml of 0.01 N aqueous acetic acid, virtually all solid is dissolved. By adding 3 ml of concentrated hydrochloric acid to the acetic acid filtrates, a blue-black solid which is washed with acetone is precipitated and 0.24 g of the product is obtained. IR: 5.76; 6.21; 6.40; 8.32; 12.10 μπι.

Example 36 1.4- Bis Γ 2- (1,3-oxazolidin-1-yl) ethylaminol-5,8-dihydroxyan-thracruinone

A solution of 1.62 g of 37% aqueous formaldehyde solution in 50 ml of water is stirred overnight with 4.44 g of 1,4-bis [2-3 O (2-hydroxyethylamino) ethylamino] -5,8-dihydroxyanthraquinone.

The solid formed is washed with water to give the desired product. Mp. 203-204 ° C.

35

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46

Example 37 1,4-Bis Γ 2- (1,3-oxazin-2-one-1-yl) ethylamino] -5,8-dihydroxy-anthraouinone

A solution of 0.48 g of sodium in 25 ml of methanol is stirred and heated overnight with 75 ml of diethyl carbonate and 5.45 g, 4-bis [2- (3-hydroxy-1-propylamino) ethylamino] -5, 8-dihydroxyanthraquinone dihydrochloride. After cooling the mixture, it is stirred with 0.1 ml of acetic acid. The solid product is filtered off and washed with methanol and then with water. Mp.

254-256 ° C.

Example 38 1.4-Bis2 ~ (άί (β-hydroxyethyl) amino 1 ethylaminol -5,8-dihydroxy-anthracruinone dihydrochloride 15 Upon oxidation of 10.77 g of the product of Example 10 with chloranil analogous to that of Example 11 described procedure, 11.64 g of a dark blue solid is obtained, mp 216 ° C.

20

Example 39 1-4-Bis (2-dimethylaminoethylamino) anthraquinone

A mixture of 3 g of quinizarin, 10 g of N, N-dimethylethylenediamine and 17.5 ml of water is stirred and heated to reflux for 3.5 hours. The mixture is cooled and the solid is isolated and washed with water to give 2.96 g of the desired product as a dark blue solid, m.p. 170-172 ° C.

In another method, the above product is stirred and refluxed for 5 hours by a mixture of 2.4 g of quinizarin, 2.28 g of N, N-dimethylenediamine and 9 ml of N, N, N tetramethylethylendiamine. The product is isolated as described above. 1

Example 40 1,4-Bis (2-morpholinoethylamino) anthraquinone

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47 9.60 g of quinizarin, 46.90 g of N- (2-aminoethyl) morpholine and 56 ml of water are reacted under nitrogen and 9.92 g of the desired product is obtained in the form of a blue-black solid, m.p. 158-159 ° C.

5

Example 41 1,4-Bis (2-piperidinoethylamino) -anthraauinone

A mixture of 4.07 g of quinizarin, 21.74 g of N- (2-aminoethyl) -piperidine and 26 ml of water is stirred at reflux for 2 hours, then left to stand overnight. A rubbery solid is separated, which is isolated and washed with water by centrifugation to give 1.99 g of a blue-black solid. This solid is dissolved in 15 ml of chloroform and chromatographed using a truncated wet column method of 100 g of alumina and eluted with chloroform. A total of 180 ml of eluate is collected in 8 separate fractions from the time the eluate turns blue until a black band approaches the bottom of the column. Fractions 1-6 are combined and evaporated to give 1.42 g of blue black 20 crystals which are recrystallized from ethanol to give 1.35 g of the desired product in the form of blue black needles, m.p. 140-141 ° C. After drying the product in vacuo at 78 ° C, it melts at 156-157 ° C.

Example 42

Leuco-1,4-bis (2-dimethylaminoethvlamino) anthraquinone

A solution of 26.44 g of Ν, Ν-dimethylethylenediamine in 75 ml of Ν, Ν, Ν1, N'-tetramethylethylenediamine is deaerated by bubbling nitrogen for 15 minutes. Then, 12.11 g of leukoquinizarin are added and the resulting mixture is stirred under nitrogen with heating to 48-50 ° C for 21 hours. After cooling overnight under nitrogen, the solid is filtered off and washed three times by slurry in acetonitrile and twice by slurry in petroleum ether. Thus, 12.52 g of 35 dark green crystals are obtained with m.p. 150-157 ° C. Using a melting point microscope, the melting point is determined

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48 153-154 ° C.

Example 43

Leuko-1,4-bis Γ 2- (2-methylaminoethylamino) ethylaminol-5-thraouinone

A solution of 14.10 g (0.12 mol) of 1-methyl-diethylene triamine in 100 ml of ethanol is deaerated by bubbling nitrogen for 15 minutes, then gradually adding 9.69 g (0.04 mol) of -quinizarin. The mixture is stirred under nitrogen and heated on an oil bath at 50 ° C for 21 hours. The mixture is allowed to cool, the product is filtered off and washed with acetonitrile, and then with petroleum ether to give the above compound as a dark green solid.

15

Example 44 1,4,5-Trisr (2-aminoethyl) amino) -8-hydroxy-anthraauinone 100 ml of ethylenediamine are deaerated by bubbling nitrogen for 15 minutes. 10.97 g of leuko-1,4,5,8-tetrahydroxy-anthraquinone are added and the mixture is stirred under nitrogen at 50-51 ° C for one hour. The mixture is cooled and filtered. The undiluted filtrate is allowed to cool at 10 ° C for 2 hours to form a solid which is isolated and washed with ethanol to give 2.25 g of the above product in the form of a dark brown purple solid which does not melt at up to 360 ° C. In 2-methoxyethanol solution, a long-wave UV absorption peak is seen at 763 nm as opposed to peak near 600 nm for 1,4-bis (aminoalkylamino) -5,8-dihydroxy-anthraquinone.

30

Example 45 1.4-Bis f (2-dimethylaminoethyl) amino-5,6-dihydroxy-anthra-cruinone 30 g of zinc are added portionwise to a boiling mixture 35 of 1.5 liters of glacial acetic acid and 40 ml of water containing 27.2 g of 1.4 , 5,6-tetrahydroxyanthraquinon. The mixture is boiled for 30 minutes

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49 minutes and filter and the filtrate is cooled. The orange-brown crystals formed are isolated and 19.7 g of leuko-1.4.5.6-tetrahydroxyanthraquinone are obtained with m.p. 255-257 ° C.

7.9 g of dimethylaminoethylamine in 75 ml of tetramethylethylenediamine are heated to 80-100 ° C and deaerated with nitrogen.

This mixture is treated portionwise with 8.22 g of leuko-1.4.5.6-tetrahydroxyanthraquinone with stirring under nitrogen and heated to 90-100 ° C for 6 hours. The mixture is filtered hot. The filtrate is cooled to 4 ° C, treated with ether, and after standing for 48 hours a dark blue rubbery substance is obtained.

The above liquid is decanted, treated with the double volume of ether and cooled to give a gummy substance.

The above liquid is then left to stand and treated with more ether to give 1.5 g of the desired final product in form. of a blue solid with m.p. 133-135 ° C.

Claims (4)

1. Analogous Process for Preparing Therapeutically Active Anthraquinone Derivatives of General Formula 5.R1 R6 Jo r -V 10 177 I I / R1 NH-QN CH = CH or CH2-CH2, Q is (CH2) n, where n is an integer from 2 to 4, R 1 and R 2, respectively, mean hydrogen, alkyl of 1-4 carbon atoms, monohydroxyalkyl of 2-4 carbon atoms, wherein the carbon atom in the α position to the nitrogen atom cannot carry a hydroxy group, dihydroxyalkyl of 3-6 carbon atoms, the carbon atom in the α position to the nitrogen atom cannot carry a hydroxy group, formyl, alkanoyl of 2-4 carbon atoms, trifluoroacetyl or a group of formula R3 - (CH2) n-O-R or - (CH2) nN ^ R4 where n is an integer from 2 to 4, R is alkyl of 1-4 carbon atoms, and R 2 and R 4 are each independently hydrogen or alkyl of 1-4 carbon atoms, DK 158836 B or R1 and R2 together with their associated N atom or R 3 and R 4 together with their attached N atom means morpholino, piperazino, oxazolidinyl or a group of the formula 5 -N (CHJm \ v 2. m where m is an integer from 2 to 4, R 5 means hydrogen or hydroxy, R6 is hydrogen or hydroxy, R 7 means hydrogen, hydroxy or a group of the formula / 8-nh-ch 2 -ch 2 -n V 20 = wherein R 2 and R 9 are each independently hydrogen or / 3-hydroxy-ethyl, provided that a) R 1, R 2, R5, R6 and R7 cannot simultaneously be hydrogen, b) when R5, R6 and R7 are hydrogen, R 1 / R 2 cannot be 25 H / monohydroxyalkyl and when n is 2, R 1 / R 2 cannot be - (CH 2) 2-0- (CH2) 2-, H / CH3, H / C2H5 or C2H5 / C2H5, and when n is 3, R1 / R2 cannot be CH3 / CH3 or - (CH2) 5- c) when R5 and R7 is hydroxy, and n is 2, R1 / R2 cannot be CH3 / CH3, C4H9 / C4H9 or - (0¾) 5 “when n is 3, R1 / R2 may not be H / H, CH3 / CH3, C3H7 / C3H7 or - (CH2) 2-0- (CH2) 2-, and when n is 4, R1 / R2 may not be C2H5 / C2H5, C4H9 / C4H9 or - (CH2) 4-, d) when R5 is OH, one of the substituents R6 and R7 must be H, and when R5 is H, both R6 and R7 must be H, characterized in that a compound having the general formula DK 158836 B 5? X 6 in which A-B, R5, R6 and R7 have the above meanings and X means OH or halogen is reacted with a compound of the general formula D H2N-Q-N. R 2 in which Q, R 1 and R 2 have the above meanings, and the group NR 1 R 2 is optionally converted to another group of the meaning given above, 20 and AB with the meaning CH 2 -CH 2 optionally converted to CH = CH and the product obtained optionally contacted with a reagent capable of forming a pharmacologically acceptable salt therewith. Process according to claim 1, characterized in that 1,4-bis [2- (2-hydroxyethylamino) ethylamino] -5,8-dihydroxyanthraquinone is prepared. Process according to claim 1, characterized in that 1,4-bis [2- (2-hydroxyethylamino) -3 ethylamino] -5,8-dihydroxy-anthraquinone dihydrochloride is prepared. Process according to claim 1, characterized in that 1,4-bis- (2-aminoethylamino) - 5,8-dihydroxyanthraquinone and / or its leukobase are prepared.