FI70882C - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC ANIMAL THERAPEUTIC - Google Patents

Description

PD_ „ANNOUNCEMENT„ „Λ Λ Λ jgHA Μ 11 ^ UTLÄG G NIN G SSKRI FT 70882 C (45) Ρ" te.itti issued

Dimensions r.e J-Jele.t C7 10 100G

(51) Kv.lk. '/ Lnt.ci. * C 07 C 97/26, 103/44, C 07 D 295/12, 203/12, 263/04 FINLAND FINLAND (21) Patent application - Patentansökning 782481 (22 ) Application date - Ansökningsdag 15-08.78 (23) Starting date - Giltighetsdag 1 5.08.78 (41) Has become public - Blivit offentllg 1 6.02.79

National Board of Patents and Registration Date of publication and publication - $ 1} ^

Patent- oeh registerstyrelsen '' Ansökan utlagd och utl.skrlften published lo .U / .00 (86) Kv. application - Int. trap (32) (33) (31) Claim claimed privilege - Begärd prloritet 15-08.77 »30.01.78, 30.01.78, 30.01.78, 05.05.78 USA 82 ^ 872, 873040, 873041, 873174, 903292

Proven-Styrkt (71) American Cyanamid Company, Wayne, New Jersey, USA (72) Keith Chadwick Murdock, Pearl River, New York, Frederick Emil Durr,

The present invention relates to a process for the preparation of new therapeutically useful anthraquinone derivatives. This invention relates to a process for the preparation of new therapeutically useful anthraquinone derivatives. The present invention relates to a process for the preparation of new therapeutically useful anthraquinone derivatives. For the preparation of anthraquinone derivatives and their tautomeric forms and pharmaceutically acceptable acid addition salts according to I, XR1

r5 O NH-Q-N

Ec V / R2

I I

_ O NH-Q-N

7 wherein AB is CH = CH or CH 2 -CH 2, Q is (CH 2) n where n is an integer from 2 to 4, and R 2 is independently hydrogen, C 1-4 alkyl, monohydroxy-C 2-4 alkyl, wherein the nitrogen atom - the carbon atom in the Λ-position relative to the nitrogen atom is not attached to a hydroxy atom, or and R2 independently of one another denotes dihydroxy-C3-8-alkyl, the carbon atom in the Λ-position relative to the nitrogen atom not having a hydroxy group, or and R2 independently of one another formyl, trifluoroacetyl or a group of the formula - (CH2) n- ° -R or _ (CH2) n_N: \ R4 wherein n is an integer from 2 to 4, R is C1-4 alkyl and R8 and R2 represent each other independently hydrogen or C 1-4 alkyl, or R 1 and R 2 and the nitrogen atom to which they are attached, or R 8 and R 4 and the nitrogen atom to which they are attached together form a morpholino, piperazino or oxazolidinyl group or a group of the formula 2 m where m is an integer from 2 to 4, R 3 is hydrogen or hydroxy, R 8 is hydrogen or hydroxy and R 1 is hydrogen, hydroxy or a group of the formula / * 8 -NH-CH 2 -CH 2 -N 2 R 9 wherein R 8 and R 2 represent hydrogen or β-hydroxyethyl, provided that a) R 1, R 2, R 9, R 9 and R 2 do not simultaneously mean hydrogen, b) when R 8, R 8 and R 4 represent hydrogen, R 1 / R 2 is not hydrogen / monohydroxyalkyl, and when n is 2, R 1 / R 2 is not - (CH 2) 2 -. O- (CH2) 2-, hydrogen / CH3, hydrogen / C2Hg or C2H5 / C2H5, and when n is 3, R1 / R2 is not CH3 / CH3 or - (CH2) 4-, c) when Rg and R? represent hydroxy and when n is 2, R 1 / R 2 is not CH 8 / CH 8, C 4 H 9 / C 4 H 9 or - (CH 2) 4 -; when n is 3, R 1 / R 2 is not hydrogen / hydrogen, CH 3 / CH 8, C 3 H 7 / C 3 H? or - (CH 2) 2 -O- (CH 2) 2 -; when n is 4, R 1 / R 2 is not C 2 H 9 / C 2 H 9, C 4 H 9 / C 4 H 9 or - (CH 2) 4 -, and 3 70882 d) when R 8 is hydroxy, one of the substituents R 8 and R 2 is hydrogen; when R 1 is hydrogen, both substituents R 8 and R 2 represent hydrogen.

These compounds have been found to have antitumor activity.

The compounds of formula I wherein A-B is CH 2 -CH 2 are generally stable compounds and are known as the leuko forms of the corresponding anthraquinones. These leuko forms are known to exist in their corresponding tautomeric forms, and the group of compounds of formula I also comprises these forms. The leuko forms (here leuko bases) and their tautomeric forms can be represented by the following formulas: / R 10 is nh-q-n / (I ', leuko base) n O NH-Q-N 2

7 1 N

1 / R1 R5 O «j-Q-N ^ r6vV \ A R2 Τι (I", tautomeric '_ form) VVV x «, R? O N-Q-N' R2

The antarcinone derivatives of formula I, their tautomeric forms and their pharmaceutically acceptable acid addition salts can be prepared by reacting a compound of formula R 7 Ö x 4 70882 wherein AB, R 1, R 8 and R 2 are as defined above and X is hydroxy or halogen. to react with a compound of formula h2n-qn <^ R2 wherein Q, R1 and R2 have the same meaning as above, and if desired the group NR1R2 in the obtained compound is converted into another group NR1R2 as defined above, and / or the compound of formula I obtained , wherein AB is CH 2 -CH 2, is converted to a compound of formula I wherein AB is CH = CH, and / or the resulting compound of formula I is converted to a pharmaceutically acceptable acid addition salt.

The product is usually obtained as a reddish brown to blue-black crystalline substance with a characteristic melting point and absorption spectrum, which can be purified by extraction with a lower alkanol because the free bases are for the most part insoluble in water and some of them insoluble in organic solvents. Organic bases (1,1 'and I ") form non-toxic addition salts and various pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid addition salts prepared by mixing the organic free base with 1.2 to 8 equivalents of acid, preferably in neutral in acids, with acids such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfamic acid, citric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, acetic acid, benzoic acid, gluconic acid, ascorbic acid, ascorbic acid. Acid addition salts of organic bases are, in general, crystalline solids, relatively soluble in water, methanol and ethanol, but relatively insoluble in non-polar organic solvents such as diethyl ether, benzene, toluene and the like.

The preparation of compounds of formula I as described above is preferably carried out by heating the reactants at a temperature of about 40 to 110 ° C for about 2 to about 10 hours in a reaction inert solvent such as water, a lower alkanol, for example methanol, ethanol, propanol, i. in propanol, butanol isomer or the like, or in an amide solvent such as formamide, dimethylformamide or the like, or in a solvent N, N, N ', N'-tetramethylethylenediamine or a mixture thereof.

In most cases, the product is solid and crystallizes by itself, or by the addition of seed crystals or by scraping, from the reaction solution as it cools and can be collected by filtration or decantation. In other cases, the reaction mixture may be concentrated, for example at a higher than normal temperature in vacuo, and on cooling the product crystallizes and may be collected by filtration or decantation as above. In certain other cases, it may be necessary to evaporate the solvent into the images to recover the product, or alternatively to mix or dilute the reaction mixture with another miscible solvent, such as water, after which the product is collected by filtration or extraction. The assembled product can be purified, for example, by crystallization, chromatography (using plate or column chromatography) or, preferably, extraction with a lower alkanol. Other methods such as maceration or crushing in a solvent, for example an organic solvent such as ethanol, are also useful.

If a product in the form of a leuko is desired, the tricyclic starting material must be in the form of a leuko, and such starting materials must be carefully protected, especially at oxidizing temperatures above normal (i.e., above room temperature) from oxidizing agents such as, for example, oxygen.

Thus, if a leuko product is desired, the reaction is carried out normally and efficiently in an atmosphere protected from air. Thus, the reaction can be carried out, for example, under a nitrogen or argon atmosphere, and this precaution must also be used in connection with purification processes, in particular processes which require higher than normal temperatures. When an aromatic product is desired and an aromatic starting material is used, such precautions are not usually necessary.

If desired, the leuko form can be easily converted to the aromatic form by methods known per se. One such method is 6 70882 oxidation with air. Other methods include, for example, treatment with hot nitrobenzene, chloranine, hydrogen peroxide, and sodium borate.

The specific group NR 1 R 2 present in the compound of formula I can be converted into another group NR 1 R 2 as defined above by methods known per se.

For example, the group NR 1, R 2, wherein R 1 and / or R 2 represents hydrogen, can be easily alkylated, e.g., with an alkyl halide, alkyl sulfate, substituted or unsubstituted acrylonitrile, or the like. Aldehydes and ketones which are condensed under reduction conditions may also be useful.

Conversion of compounds of formula I to acid addition salts can be accomplished, for example, by dissolving or suspending the compound in a solvent such as a lower alkanol (e.g., methanol, ethanol, isopropanol) and treating with a salt-forming reagent dissolved in the same or a different solvent. The ethanolic suspension or solution of the compound may be treated with, for example, dilute or concentrated acetic acid, hydrochloric acid or the like, or an ethanolic solution of HCl, and the corresponding salt may be collected, for example, by filtration. The salt-forming reagent can also be added in pure form. Thus, a solution or suspension of the product can be treated with glacial acetic acid or HCl in gaseous form, and the corresponding acid addition salt is collected.

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as active ingredients in pharmaceutical compositions. The compounds of formula I have been shown to inhibit the growth of a mouse-transplanted tumor and cause regression and / or alleviation of blood cancer and related cancers in mammals when administered in doses ranging from about 5 mg to about 200 mg per kilogram of body weight per day. The preferred dosage regimen for optimal results is from about 5 mg to about 50 mg per kilogram of body weight per day, and such dosage units are used to administer a total of about 350 mg to about 3.5 grams of active compound over 24 hours to a patient weighing about 70 kg. The compounds of formula I may be administered by any suitable route such as orally, intravenously, intramuscularly or subcutaneously.

7 70882

They can also be administered parenterally or intraperitoneally. Solutions of the active ingredient in free base or pharmacologically acceptable salt form can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerin, liquid polyethylene glycols, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations contain antiseptics to prevent the growth of microorganisms.

The antitumor activity of the compounds of formula I has been demonstrated by the following standard experiments.

Lymphocyte cancer P388 test

The mice used in the experiments are DBA / 2 mice, all of the same sex, with a minimum weight of 17 g and weight differences of up to 3 grams. The experimental group includes 5 or 6 animals. Tumor transplantation is performed by intraperitoneal injection of 0.1 ml of diluted aqueous humor containing 106 lymphocytic P388 cells. Test compounds are administered intraperitoneally (for tumor implantation) on the first, fifth, and ninth days at different dosages. The animals are weighed and the number of survivors is recorded at regular intervals during the 3C day. Calculate the mean survival time and the ratio of survival times between treated animals (T) / control animals (C). The positive control compound is 5-fluorouracil administered at an injection dose of 60 mg / kg. The results of this experiment for the compounds representative of this invention are shown in Table I. The efficacy criterion is T / C x 100> 125%.

Table I

70882

Lymphocyte cancer P388 test

Compound Dose Mean T / C x 100 mg / kg survival. time% _ (days) __

Leuko-1,4-bis / 7 2-amino-100 19.0 158 noethyl) amino7-5,8- 50 23.0 192 dihydroxy-anthraquinone 25 19.0 158 12 18.0 150

Check 0 12.0 5-fluorouracil__60__19.5__162

Leuko-1,4-bis / 2- (2-200 2.0 18.0 ethylethylamino-100 26.0 236.0 amino) ethylamino7 ”5.8-50 28.0 255.0 dihydroxy-anthraquinone 25 21.0 191.0 12.5 16.0 145.0 6.2 15.0 136

Check 0 11.0 5-fluorouracil__60__17.0__170

Leuko-1,4-bis / 2-di-200 18.0 200 methylaminopropyl-100 15.0 167 liamino-5,8-dihydro-50 14.0 156 s i-anthraquinone 25 13.0 144 12.5 11.0 122

Control 0 9.0 5-Fluorouracil__60__18.5__206 1,4-Bis / J- (2-hydroxy-12.5 13.0 130 ethylamino) -ethyl- 6.2 20.0 200 Nitro7-5,8-dihydroxy-3.1 22.0 220 Anthraquinone-dihydro-1.5 > 29.0> 290 chlorides 0.78> 29.0> 290 0.39 27.0 270 0.19 25.0 250 0.09 21.0 210 0.04 20.0 200

Check 0 10.0 5-fluorouracil 60 20.0 200 9 70882

Table I (continued) Lymphocyte Cancer P388 Assay

Compound Dose Average T / C x 100

Tvg./kg. eloonjääm. time% (days)

Leuko-1,4-bisZ2- (1-pipe- 200 7.0 78 racinyl) ethylamino-100 21.0 233 5,8-dihydroxy-anthraquino-50 16.0 178 ni 25 15.0 167 12.5 14.0 156

Control 0 9.0 and 5-fluorouracil__60__18.5__206_ 1.4-bis72- (methylamino) -25 9.0 86 ethylamino7-5,8-dihydroxy-12.5 16.0 152! Si-anthraquinane-dihydro-6.2 20.0 190 Chloride 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;

Check 0 10.5 - | 5-fluoriurasiili__60__18.0__171_;

Leuko-1,4-bis {2- (2-hydroxy-12.0,114-ethylamino) -ethylamino-12.5 23.5 224! no / -5,8-dihydroxy-antra- 6.2 23.0 219 quinone 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 f 0.09 21.5 205 0.04 18.5 176

Control 0 10.5 - 5-fluorouracil__60__18.0__171__ 1.4-bis / 2- (2-aminoethyl-200 17.0 162 amino) -ethylamino / -5.8-100 16.0 152 dihydroxy-anthraquinone 50 14.0 133 25 13.0 124

Control 0 10.5 - 5-fluorouracil i__60__17.0__162_ ’10 70882

Table I (continued)

Lymphocyte cancer P388 test Central

Compound Dose survival. time T / C x 100 m.g. Ag. (days)% ----- η

Leuko-1,4- [2- (di (Hydroxy-200 19.0 190 roxyethyl) amino] ethyl-100 17.0 170 liara / -5,8-dihydroxy-50 16.0 160 anthraquinone 25 15.0 150 12.5 13.5 135 6.2 12.0 120

Control 0 10.0 5-fluorouracil__40__18.0__180_ 1,4-bisZ2- (2-hydroxy-1-12.12.0 120 propylamino) ethylamino 12.5 24.0 240 n--5,8-dihydroxyantra-6.2 23.0 230 quinone dihydrochloride 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-bi3 / 2-72- (1-morpholino-200.9.5 95 no) -ethylamino / ethyl-100 20.0 200 amino7-5,8-dihydroxy-50 18.5 185 anthracone I-tetrahydro - 25 19.5 195 chlorides 12.5 15.0 150 6.2 14.0 140 3.1 13.0 130

Control 0 10.0 5-fluorouracil__40__18.0__180_ 1.4-bis Q- (3-hydroxy-1-25.55 77 propylamino) ethyl 12.5> 30.0> 273 andno7-5,8-dihydroxy-6.25 26.0 236 anthraquinone dihydrochloro 3.1 25.0 227 ridi 1.56 22.0 200 0.78 21.5 195

Check 0 11.0 5-fluorouracil__40____.0.0164_

Table I (cont'd) 11 70882

Lymphocyte cancer P388 test

Compound Dose Average T / C x 100 m.g. /kg. eloanjääm. time% (days)

Leuko-1,4-bis / 2- (3-hydroxy-200 14.0 127 roxy-1-propylamino) -100 38.0 345 ethylamino7-5,8-dihydroxy 50 34.0 309 anthraquinone 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_j 1,4-bis / 2- [di - ((Hydroxy-200> 30.0> 333 | diethyl) -amino] -ethyl-100 22.0 244] amino / -5,8-dihydroxy-50 20.5 228 anthraquinane dihydro- 25 21.5 239 chloride 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

Check 0 9.0 5-fluorourine i__60__20.5__228_

Leuko-1,4-bisZ3- (2-hydroxy-33.5305-ethylamino) -1-propylamino] -5,8-dihydroxy-12.5 × 9.0 173 6.25 18.0 164 3.12 15.0 136

Check 0 11.0 5-fluorouracil__40__17.5__159_ ’

Leuko-1,4-bis (2- (2-hydro-20Θ 9.0 82 roxy-1-propylamino) -100 26.5 241 ethylamino] -5,8-dihydro-50 24.0 218 raxian anthraquin 25 20.5 186 \ 12.5 i 21.5 j 195 I 6.25 20.0 f 182!

Check I 0 j 11.0 j 5-fluorouracil_j_40_! 17.5_j 159_f 70882

Table I (continued) Lymphocyte Cancer P388 Assay

Compound Dose Mean T / C x 100 m.g.Ag. eloanjääm. time% (days) 1,4-bis / X- (2-hydroxy- Γ 100 12.5 114 ethylamino) -1-propyl- η 5 32.5 291 amino7-5,8-dihydroxy-26.5 241 anthraquinone dihydro-12.5 22.5 205 chlorides 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) -100 28.5 285 Ethylamine7_5,8-dihydroxy 50 21.5 215 Anthraquinone 25 20.0 200 12.5 20.5 205 6.25 18.5 185 3.12 19.5 195 1.56 17.0 170 0.78 14.0 140

Control 0 5-fluorouracil__60__20.5__205 1,4-bis [2- (2-methylamino-100 22.0 220 ethylamino) ethylamino? - 50 22.0 220 5,8-dihydroxyanthraquinone-25 19.5 195 tetrahydrochloride 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-fluorouracil i__40__16.0__160 1,4-bis- (2-aminoethyl-12.5 8.0 73 amino) -5,8-dihydroxy-6.2 15.5 141 anthraquinone dihydro-3.1 30.0 273 chloride 1.56 20.0 182 0.78 24.5 I 223 0.39 25.5 232 0.19 23.0 209

Check 0 11.0! 5-fluoroururil i_j_60__20.5 _; _ 186 13 70882

Lymphocyte Cancer P388 Assay The method used is otherwise the same as previously described for the Lymphocyte Cancer P388 Assay, but the test compounds are administered at various doses orally and not intraperitoneally. The results of this experiment obtained with typical compounds of this invention are shown in Table II. The efficiency criterion is T / C x 100 125%.

Table II

Lymphocyte cancer P388 test (oral administration)

Compound Dose Avg. survival T / C x 100 mg / kg residence time% in days (days) _ 1-9__ 1,4-bis- (2-dimethylamino-100 17.5 159 ethylamino) -anthraquinane 50 13.5 123 25 14.0 127

Check 0 11.0 5-fluorluracil 20_ 13.5_ 127_

Lymphocyte blood cancer L1210 test

The method is otherwise the same as in the lymphocyte cancer P388 assay, which was administered intraperitoneally, but the tumor was transplanted into the lymphocyte cancer L1210, which was seeded at a concentration of 105 cells per mouse, and the mean survival time was calculated. The results obtained with a representative compound of this invention are shown in Table III below.

Table III

70882

Lymphocyte Cancer L1210 Test Compound Dose Mean T / C x 100 mg / kg Survival Time „(days) 1,4-bis- (2-dimethyl-50 12.0 135 aminoethylamino) - 25 11.0 124 anthraquinone 12 9 , 4 106

Control 0 8.9 5-fluorouracil 20 17f6 188

Mslanotic dark cell cancer B16 The animals used are C57BC / 6 mice, all of the same sex, with a minimum weight of 17 g and a maximum weight difference of 3 g. There are normally 10 animals in the experimental group. A 1 gram aliquot of melanotic dark cell tumor B16 is homogenized in 10 ml of cold equilibrated saline and 0.5 ml aliquots of homogenate are inoculated intraperitoneally into each test mouse. Test compounds are administered intraperitoneally on days 1-9 (relative to tumor implantation) at various doses. Animals are weighed and survivors are recorded regularly for 60 days. Calculate the mean survival time and the ratio of survival times between treated animals (T) / control animals (C). The positive control compound is 5-fluorouracil administered at an injection dose of 20 mg / kg. The results of this experiment for the compounds representative of this invention are shown in Table IV. The efficiency criterion is T / C x 100 - 125%.

Table IV

15 70882

Melanotic tunic cell carcinoma B16 test

Compound Dose Average T / C x 100 mg./kg. survival time% _ (days) __ 1,4-bis (13-diirethylamino-20.0125 propyl) -amino-S, 8-dihydroxy-anthraquinone

Check 0 16.0 5-fluorouracil_ 20__26.5__166_

Leuko-1,4-bis (12-amino-12 32.0 200 ethyl) amino] -5 / 8-dihydroxy-anthraquinone

Check 0 16.0 5-fluorouracil__20__26.5__166_

Leuko-1,4-bis (3-amino-propionyl) -5,8-dihydroxy-27.0 169 cis-anthraquinone 12 23.5 147 6 22.5 141

Check 0 16.0 5-fluorouracil__20__26.5__166_

Leuko-1,4-bis / 2-dimethyl-100 21.0 124 aminopropylamino7-5,8- 50 28.5 168 dihydroxy-anthraquinone 25 24.5 144 12.5 20.5 121 6 19.5 115

Control 0 17.0 5-fluorouracil i__20__30.0__176_ 1.4-bis / 2- (2-hydroxyethyl-12 11.0 73 amino) -ethylamino7-5.8-6 15.0 100 dihydroxyanthraquinone-3> 28.5> 190 dihydrochloride 1.5> 34.0> 227 0.7> 34.0> 227 0.3 34.0 227

Check 0 15.0 5-fluorouracil__60__23.0__153_

Leuko-1,4-bis (4-amino-100 21.0 124 butylamino) -5.8- 50 20.0 118 dihydroxy-anthraquinone 25 18.5 109 12 16.0 94

Check 0 17.0 5-fluorouracil_ 20_30.0__176__ 16 70882

Table IV (continued)

Melanotic dark cell cancer Bl6 test

Compound Dose Average T / C x 100 mg./kg. survival time% ___ (days) ___

Leuko-1,4-bis / 2- (2-hydroxy-6,5,5,5-ethylamino) -ethylamino-3,20.5,128 n-5,8-dihydroxy-1.5 30.0 187 anthraquinone 0.75 28.5 178 0.37 22.0 137

Check 0 16.0 5-fluorouracil__20__27.5__172__

Leuko-1,4-bis (2- (methyl-amino) -ethylamino] -5,8- '' 194 dihydroxy-anthraquinone ^ 22 ^ 0.7 27.5 172

Check 0 16.0 5-fluorouracil_20_27.5_i_172__

Ridgway bone sarcoma The animals used are AKö ^^ / J mice, all of the same sex, minimum weight 17 g, with weight differences not exceeding 3 g. There are normally 8 animals in the experimental group. The tumor is administered subcutaneously by trocar in five 2 mm fragments per mouse. The test compounds are administered intraperitoneally every four days in a total of six injections from day 15 (counting on tumor implantation) at different doses. Animals are weighed and survivors are counted regularly for 90 days. Tumor regressions are recorded for all animals. Table V shows the results of this experiment performed with a representative compound of this invention, expressed as a percentage of animals that experienced tumor regression.

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The following examples illustrate the invention.

Example 1

Leuko-1,4-bis (2-mofolinoethylamino) -5,8-dihydroxyanthraquinone

A solution of 15.62 g of N- (2-aminoethyl) morpholine in 40 ml of N, N, N ', N'-tetramethylethylenediamine is deaerated by bubbling nitrogen for 15 minutes. A 10.97 gram portion of leuko-1,4,5,8-tetrahydroxyanthraquinone is added with slow stirring and the suspension is heated in an oil bath at 49-51 ° C. The mixture is allowed to cool under a nitrogen atmosphere. 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 (2-morpholinoethylamino) -5,8-dihydroxy-anthraquinone A 13.90 gram portion of leuko-1,4-bis (2-morpholinoethylamino) -5,8-dihydroxy-anthraquinone is oxidized in 100 ml of nitrobenzene with heating to give 10.30 g of the expected product are obtained in the form of black rods, m.p. 241-243 ° C.

Example 3

Leuko-1,4-bisZT (2-diethylaminoethyl) amino] -5,8-dihydroxyanthraquinone

The procedure of Example 1 is repeated using 13.95 g of N, N-diethylethylenediamine instead of N- (2-aminoethyl) morpholine to give 13.97 g of the desired product as a red-brown solid, m.p. 182-185 ° C.

Example 4 1,4-BisZT (2-diethylaminoethyl) amino] -5,8-dihydroxy-anthraquinone A 10.90 gram portion of leuko-1,4-bis (Δ2-diethylaminoethyl) -amino] -8,8-dihydroxyanthraquinone is oxidized as described in Example 2. to give 6.35 g of the desired product as blue-black needles, m.p. 202-204 ° C.

70882 19

Example 5

Of leuco-1,4-bis / 2- (1-pyrrolidinyl) etyyliamino7 ~ 5,8-dihydroxy-anthraquinone

The procedure of Example 1 is repeated using 12.05 g of N-2-pyrrolidinoethylamine instead of N- (2-aminoethyl) morpholine, and 80 ml of N, N, N ', N'-tetramethylethylenediamine to give 13.24 g of the desired product as a reddish brown. as a solid, m.p. 180-185 ° C.

Example 6 1,4-Bis-2- (1-pyrrolidinyl) ethyl laming-5,8-dihydroxyanthraquinone 8.61 gram portion of leuko-1,4-bis [Z2- (1-pyrrolidinyl) ethyl] amino] 5,8-Dihydroxyanthraquinone is oxidized as described in Example 2. The reaction mixture is evaporated to dryness and the residue is recrystallized from toluene to give 5.12 g of the desired product as blue-black crystals, m.p. 193-196 ° C.

Example 7

Of leuco-1,4-bisZ2- (methylamino) -etyyliaminoy-S, 8-dihydroxy-anthraquinone

The procedure of Example 5 is repeated using 8.90 g of N-methylethylenediamine instead of N-2-pyrrolidinoethylamine to give 13.73 g of the desired product as a dark green solid, m.p. 157-160 ° C.

Example 8

Leuko-1,4-bis (2-aminoethylamino) -5,8-dihydroxy-anthraquinone A reaction mixture containing 10.97 g of leuko-1,4,5,8-tetrahydroxy-anthraquinone in 80 ml of N, N, Ν ' The deaerated, N'-tetramethylethylenediamine containing 7.22 g of ethylenediamine is heated and stirred under nitrogen at 48-50 ° C for one hour. The mixture is allowed to stand under a slow stream of nitrogen to give a solid which is collected and washed with ethyl acetate, acetonitrile and petroleum ether to give 13.8 g of the desired product as a red-black solid which does not melt yet at 350 ° C; IR 6.34, 8.20 μm.

20 70882

Example 9

Leuko-1/4-bis / 2- (2-hydroxyethylamino) ethylamino] -5,8-dihydroxyanthraquinone

A suspension of 12.5 g of 2- (2-aminoethylamino) ethanol in 40 N, N, N ', N'-tetramethylethylenediamine is stirred and deaerated by bubbling nitrogen for 15 minutes. A portion of 10.97 grams of leuko-1,4,5,8-tetrahydroxy-anthraquinone is 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 allowed to stand and cool under nitrogen for 12 hours. The solid is collected by decantation, soaked in ethanol, collected and washed with ethanol to give 15.06 g of the desired product as a green-gray solid, m.p. 129-131 ° C.

Example 10

Leuko-1,4-bis [2- [3β (hydroxyethyl) amino] ethylamino] -5,8-dihydroxyanthraquinone

A solution of 17.8 g of N, N-di (2-hydroxyethyl) ethylenediamine in 100 ml of methanol is cooled in an ice bath, stirred and deaerated by bubbling nitrogen through the mixture for 15 minutes. With stirring, a 10.97 gram portion of leuko-1,4,5,8-tetrahydroxyanthraquinone is gradually added and cooling is continued. The suspension is heated and stirred under nitrogen in an oil bath at 50-52 ° C for one hour and then the mixture is allowed to stand and cool under nitrogen overnight. The solid was collected and washed with ethanol to give 14.8 g of a tan solid, m.p. 165-168 ° C.

Example 11 1,4-Bis / 2- (methylamino) ethylamino] -5,8-dihydroxy-anthraquinone dihydrochloride

To a suspension of 11.60 g (0.03 mol) of leuko-1,4-bis- [2- (methylamino) ethylamino] -5,8-dihydroxyanthraquinone in 200 ml of 2-methoxyethanol was gradually added, with stirring, 15 ml of 8N chlorine. hydrogen ethanol solution. The system was cooled in an ice bath and stirred with the gradual addition of 7.50 g (0.0305 moles) of chloranil powder. The mixture was stirred overnight at room temperature and diluted with 600 mL of ether. The solid was collected and washed with tetrahydrofuran11a. The product (14.16 g) was recrystallized by dissolving 21 70882 in 130 ml of water and adding 650 ml of acetone to give 13.15 g of a blue-black solid which did not yet melt at 350 ° C, IR 6.20 6.39 , 8.26, 12.13 μm.

Example 12 1,4-BisZ3- (2-aminoethylamino) ethylamino] -5,8-dihydroxyanthraquinone

Following the general procedure of Example 3, a mixture of 10.97 g of leuko-1,4-5,8-tetrahydroxyanthraquinone, 80 ml of N, N, N ', N'-tetramethylethylenediamine and 21.84 g (0.24 moles) of diethylenetriamine , a thick, solidified mass formed rapidly, which prevented efficient mixing, so that the reaction time was extended to 24 hours. The mixture was allowed to cool and the supernatant was decanted off and discarded. The solution containing the coagulated mass in 100 ml of methanol was filtered and then allowed to oxidize in air for four days in a partially covered flask. The separated gelatinous mass became solid when the oxidized mixture was stirred with 200 ml of acetonitrile and then the mixture was allowed to stand for one hour. After the solid was collected and washed first with acetonitrile and then with ether, 10.88 g of a blue-black powder were obtained which did not yet melt at 350 ° C; IR 6.21, 6.42, 8.31 μm.

Example 13

Leuko-1,4-bis [2-dimethylaminopropylamino] -5,8-dihydroxyanthraquinone 12.26 g of 2-dimethylaminopropylamine reacted for one hour with 10.97 g of leuko-1,4,5,8-tetrahydroxyanthraquinone in 100 ml ethanol, 7.29 g of red-brown crystals are obtained which turn black at 255 ° C but do not yet melt at 350 ° C; IR 6.31, 8.11, 12.01 μm.

Example 14

Leuko-1,4-bisZ2- (2-methylaminoethylamino) ethylamino] -5,8-dihydroxyanthraquinone

To a solution of 14.10 g of 1-methyl-diethylenetriamine in 50 ml of ethanol and 40 ml of N, N, Ν ', N'-tetramethylethylamine is added 10.97 g of leuko-1,4,5,8-tetrahydroxyanthraquinone as described above. - „70882 22 in mark 1. The mixture is heated at 50 ° C and stirred under nitrogen for 1 hour, cooled in an ice bath, the solid collected and washed with cold ethanol to give 7.23 g of green-black crystals, m.p. 108-111 ° C.

Example 15

Of leuco-1,4-bis / 2- (1-piperazinyl) ethylamino / -5,8-dihydroxy-anthraquinone

Applying the procedure of Example 14 using 1550 g of N- (2-aminoethyl) piperazine, 3.92 g of a black powder which does not melt at 350 ° C are obtained and discarded. A mixture of mother liquor and ethanol washings, which was in place and partially reduced by evaporation on storage without stirring for two weeks in a capped bottle, precipitated a solid which was collected and washed with ethanol to give 6.19 g of the title compound as a black solid, m.p. 200-203 ° C.

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

Oxidation with chloranil of 28.25 g of the product of Example 8 by the method of Example 11 gives 29.66 g of a crude, blue-black solid which is then extracted with 800 ml of water for 14 hours. The solids are removed by centrifugation and the supernatant is freeze-dried to leave 16.38 g of a blue-black solid that does not melt at 350 ° C.

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

Oxidation with chloranil of 17.86 g of the product of Example 9 by the method of Example 11 gives (without recrystallization) 21.34 g of a blue-black solid, m.p. 203-205 ° C. Example 18 1,4-Bis / 2- (2-methylaminoethylamino) ethylamino-5,8-dihydroxy-anthraquinone tetrahydrochloride 23 7 0 8 8 2

The product of Example 14 (11.70 g) is oxidized with chloranil by the method of Example 11 to give 18.03 g of a blue-black solid, m.p. 190-203 ° C.

Example 19 1,4-Bis / 2- (2-hydroxyethylamino) ethylamino] -5,8-dihydroxy-anthraquinone

In a variant of the synthesis of Example 9, 100 ml of ethanol are used as solvent. The mother liquor from the Leuko product is allowed to stand for two weeks in a capped bottle, whereupon the oxidized product separates. It is collected and washed with ethanol, then recrystallized from ethanol to give blue-black crystals, m.p. 175-177 ° C.

Example 20

Leuko-1,4-bis [5- (2-hydroxyethylamino) -1-propylamino] -5,8-dihydroxyanthraquinone

The procedure of Example 1C is applied 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, the product precipitating as a sticky substance. After decanting off the solution on the surface, the sticky substance is crystallized by mixing it with 100 ml of tetrahydrofuran. Washing with ethanol gives 12.56 g of a greenish-black solid, m.p. 101-104 ° C.

Example 21 1,4-Bis / 3- (2-hydroxyethylamino) -1-propylamino] -5,8-dihydroxyanthraquinone dihydrochloride

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

Example 22

Of leuco-1,4-bis / 2- (3-hydroxy-l-propylamino) ethylamino / -5,8-dihydroxyanthraquinone

The procedure of Example 10 is followed using 14.18 g of N- (3-hydroxypropyl) ethylenediamine in 100 ml of ethanol to give 14.63 g of red-brown crystals, m.p. 58-60 ° C.

Example 23 1,4-bis / 2- (3-hydroxy-1-propylamino) ethylamino] -5,8-dihydroxyanthraquinone dihydrochloride 24 70882

Oxidation with chloranil of 10.77 g of the product of Example 22 by the method of Example 11 gave 11.64 g of a dark blue solid, m.p. 210-216 ° C.

Example 24

Leuko-1,4-bis / 2- (2-hydroxy-1-propylamino) ethylamino] -4,5,8-dihydroxyanthraquinone Using 14.18 g of 1- (2-aminoethylamino) -2-propanol in 100 ml of ethanol by the method of Example 10 gives 17 , 61 g of green-black crystals, m.p. 50-60 ° C.

Example 25 1,4-Bis / 2-hydroxy-1-propylamino (ethylamino) -5,8-dihydroxyanthraquinone 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 of chloranil. by the method of Example 11 to give 16.75 g of a purple solid, m.p. 177-185 ° C.

Example 26

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

Following the procedure of Example 10 and using a solution of 17.67 g of 2- [2- (2-aminoethylamino) ethylamino] ethanol in 100 ml of methanol gives a solution which is filtered, then diluted with 300 ml of ether to precipitate a sticky substance which hardens when standing overnight. Curing is completed by dissolving the solid in a solvent. The solid is collected and washed with ether to give 16.82 g of a greenish black solid. This solid remains granular when stored at -25 ° C, but merges to form a solid cake when stored at 25 ° C, m.p. 75-85 ° C.

Example 27 1'4-His / 2- [2- (2-hydroxyethylamino) ethylamino] ethylamino] -5,8-dihydroxyanthracnone tetrahydrochloride

Oxidation with chloranil of 12.10 g of the product of Example 26 by the method of Example 11, and washing the solid three more times with methanol, gives 12.46 g of a dark blue solid product, m.p. 119-202 ° C; IR 6.21, 6.38, 8.33 μm.

25 70882

Example 28 1,4-Bis / 2- (2,3-dihydroxypropylamino) ethylamino] -5,8-dihydroxyanthraquinone dihydrochloride

By the method of Example 10, from a solution of 16.10 g of 3- (2-aminoethylamino) -1,2-propanediol / A.R. Surrey, C.M. Suter and J.S. Buck, J.Am.Chem.Soc., 74, 4102 (1952) / 100 ml of methanol gives a sticky substance which separates from the solvent on cooling in an ice bath and is then decanted. The sticky substance is washed four times by stirring for 1.5 hours at 25 [deg.] C. with 100 ml portions of methanol, cooled in an ice bath and then decanted. A filtered solution of the sticky substance in 280 ml of 2-methoxyethanol is oxidized with 10.01 g of chloranil by the method of Example 16. The product is further washed with ethanol to give 15.25 g of a blue-black solid, m.p. 191-193 ° C.

Example 29

Leuko-1,4-bis / 2- (1-aziridino) ethylamino] -5,8-dihydroxyanthraquinone Using 10.33 g of N- (2-aminoethyl) aziridine in 80 ml of N, N, M1, N'- tetramethylethylenediamine by the method of Example 10 to give a rigid resin. The supernatant solution is discarded the next day, 100 ml of ether are added and the resin is occasionally dissolved in it on the second day, when the resin has largely hardened. Curing is completed by dissolving the solid in three washes with ether to give 17.66 g of a blue-black, granular powder, m.p. 120-132 ° C; IR 6,37,6,89,8,20,12,03 μm.

Example 30 1,4-Bis / 2- (1-aziridino) ethylamino] -5,8-dihydroxy-anthraquinone

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 to dryness at 30 °. A solution of the residue in 40 ml of chloroform is stirred for five minutes with 2 g of decolorizing carbon, filtered and washed with another 25 ml portion of chloroform. Upon addition of 100 ml of ether to the filtrates, a resin precipitates which is removed by decantation and filtration. Crystals precipitate from the filtrates, which are washed with a small amount of acetone. A second portion of crystals precipitated from the chloroform-ether-ether base liquid cooled to -60 ° C, which was washed with ether and methanol. A solution of both batches of crystals in 20 ml of chloroform is mixed with decolorizing carbon, filtered, evaporated at 25 ° C to a volume of 5 ml, diluted with 20 ml of ether and then cooled to -60 ° C. . The amount of blue-black crystals obtained, after washing with ether, is 0.64 g, m.p. 168-170 ° C. When chromatographed on a silica gel plate, the product moves as a blue spot with the chloroform-triethylamine-methanol mixture as eluent in a ratio of 29/3/1 (v / v).

Example 31 1,4-Bis / γ-Z3- (1-morpholino) ethylamino-p-ethylamine-5,8,8-dihydroxyanthraquinone tetrahydrochloride

The process of Example '10 uses a solution of 20.80 g of N- (morpholinoethyl) ethylenediamine in 100 ml of ethanol to give a solution which is filtered and diluted with 900 ml of ether to precipitate a sticky substance. The supernatant is decanted off, the sticky substance is dissolved in 175 ml of 2-methoxyethanol and oxidized to 5.29 g of chloranil by the method of Example 16 to give 17.7 g of a dark blue solid, m.p. 265 ° C.

Example 32

Leuko-1,4-bis / 2- (acetamido) ethylamino] -5,8-dihydroxyanthraquinone

By the method of Example 10, from a solution of 12.26 g of N-acetylethylenediamine in 100 ml of ethanol, 15.27 g of a dark red-brown solid are obtained, m.p. 125 ° C.

Example 33 1,4-Bis / 2- (acetamido) ethylamino] -5,8-dihydroxyanthraquinone

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 for 61 hours by the method of Example 11 to give the highly acidic hydrochloride. a salt which is converted to the free base by washing four times with water. Crystallization from 110 ml of dimethyl sulfoxide (boiling for only 2 minutes without attempting hot filtration) and then washing with dimethyl sulfoxide and ethanol give 7.76 g of a blue-black solid, m.p. 273-274 ° C.

Example 34 1,4-Bis / 2- [N- (2-hydroxyethyl) trifluoroacetamide] ethylamino] -5,8-dihydroxyanthraninone

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 to dryness in vacuo at 30 ° C left a residue which was washed and dissolved with methylene chloride to give 2.11 g of a blue-black solid, m.p. 162 ° C.

Example 35 1,4-Bis / 2-amino-2-carboxyethylamino-5-8,8-dihydroxy-anthraquinone · 3/4 HCl

To a solution of 6.23 g of dl-ok, β-diaminopropionic acid in 30 ml of warm water are added 1.078 g of lithium hydroxide and 60 ml of dimethyl sulfoxide. The system is purged with nitrogen and 4.12 g of leuko-1,4,5,8-tetrahydroanthraquinone are gradually added with stirring. The mixture is stirred and heated in an oil bath at 50 ° C, first for 15 hours under nitrogen, then for 21 hours by oxidizing the starting product by bubbling air through the solution. When chromatographed on a plate using silica gel with a methanol-water-concentrated ammonia mixture (25/5/1 by volume), all the product spots turn blue on completion of the oxidation. After cooling, the solids are removed by filtration and washed once with dimethyl sulfoxide-water (2/1). Upon addition of 400 ml of methanol to the filtrates, the solid precipitates and is collected and washed with methanol. Upon further washing with a total of 13 ml of 0.01 N aqueous acetic acid, virtually all the solids dissolve. Addition of 3 ml of concentrated hydrochloric acid to the acetic acid filtrates precipitates a blue-black solid which is washed with acetone to give 0.24 g of product; IR 5.76, 6.21, 6.40, 8.32, 12.10. Example 36 1,4-bis-N- (1,3-oxazolidin-1-yl) ethylamino] -5,8-dihydroxyanthraquinone-28 7 0 8 8 2

A solution of 1.62 g of a 37% aqueous solution of formaldehyde in 50 ml of water is stirred overnight with 4.44 g of 1,4-bis / 2- (2-hydroxyethylamino) ethylamino] -5,8-dihydroxyanthraquinone. The resulting solid is washed with water to give the desired product, m.p. 203-204 ° C.

Example 37 1,4-BisZ2- (1,3-oxazin-2-one-1-yl) ethylamino] -5,8-dihydroxyanthraclonone

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 of 1,4-bis / 2- (3-hydroxy-1-propylamino) -ethylamino]. , 8-dihydroxyanthraquinone dihydrochloride. After cooling, the mixture is mixed with 0.1 ml of acetic acid. The solid product is collected by filtration and washed with methanol and then with water, m.p. 254-256 ° C.

Example 38 1,4-Bis-2-Z5i (β-hydroxyethyl) amino] ethylamino] -5,8-dihydroxyanthraquinone dihydrochloride

Oxidation of 10.77 g of the product of Example 10 with chloranil by the method of Example 11 gives 11.64 g of a dark blue solid, m.p. 216 ° C.

Example 39 Preparation of 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 at reflux for 3.5 hours. The mixture is cooled and the solid is collected and washed with water to give 2.96 g of the desired product as a dark blue solid, m.p. 170-172 ° C.

Alternatively, the above product can be prepared by stirring and heating at reflux for 5 hours a mixture of 2.4 g of quinizarin, 2.82 g of Ν, Ν-dimethylethylenediamine and 9 ml of Ν, Ν, Ν ', N1-tetramethylethylenediamine. The product is recovered as described above.

Example 40 Preparation of 1,4-bis (2-morpholinoethylamino) anthraquinone 9.60 g batches of quinizarin, 46.90 g of N- (2-aminoethyl) morpholine and 56 ml of water are reacted to give 29 7 0 8 8 2 9 .92 g of the desired product as a blue-black solid, m.p. 158-159 ° C.

Example 41 Preparation of 1,4-bis (2-piperidinoethylamino) anthraquinone

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 and then left to stand overnight. The resinous solid is collected 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 the abbreviated wet column method, on 100 grams of alumina, eluting with chloroform. A total of 180 ml of eluate is collected in eight separate fractions from the time the eluate turns blue until the black band approaches the bottom of the column. Fractions 1-6 are combined and evaporated to dryness to give 1.42 g of blue-black crystals which are recrystallized from ethanol to give 1.35 g of the desired product as blue-black needles, m.p. 140-141 ° C. The product dried in vacuo at 78 ° C melted at 156-157 ° C.

Example 42

Preparation of leuko-1,4-bis (2-dimethylaminoethylamino) anthraquinone

A solution of 26.44 g of N, N-dimethylethylenediamine in 75 ml of Ν, Ν, Ν ', N'-tetramethylethylenediamine is deaerated by passing nitrogen through it for 15 minutes. 12.11 g of leucoquinizarin are then added and the resulting mixture is stirred under heating at 48-50 ° C for 21 hours. After cooling overnight under nitrogen, the solid is collected by filtration and washed three times with slurry with acetonitrile and then twice with petroleum ether. 12.52 g of dark green crystals are obtained, m.p. 150-157 ° C; on a hot microscope stage m.p. is 153-154 ° C.

Example 43

Leuko-1,4-bis, E 2 - (2-methylaminoethylamino) ethyl, β-anthraquinone

A solution of 14.10 g (0.12 mol) of 1-methyl-diethyl-nitrriaamine in 100 ml of ethanol is deaerated by passing nitrogen through bubbles for 15 minutes; then 9.69 g (0.04 mol) of leukocytnizarin are gradually added with stirring. The mixture is stirred under nitrogen and heated in an oil bath at 50 ° C for 21 hours. The mixture is allowed to cool, the product is collected by filtration and washed with acetonitrile and then petroleum ether to give the title compound as a dark green solid.

Example 44 1,4,4-Tris (12-aminoethyl) amino] -8-hydroxy-anthraquinone A 100 ml portion of ethylenediamine is deaerated by bubbling nitrogen for 15 minutes. A 10.97 gram portion of leuko-1,4,5,8-tetrahydroxyanthraquinone is added and the mixture is stirred under nitrogen at 50-51 ° C for one hour. The mixture is cooled and filtered. The uncorked filtrate is allowed to cool and kept at 10 ° C for 2 hours to form a solid which is collected and washed with ethanol to give 2.25 g of the desired product as a dark purple solid. When dissolved in 2-methoxyethanol, it has a UV absorbance peak at 763 nm as opposed to 1,4-bis (aminoalkylamino] -4,6-dihydroxyanthraquinone with a peak near 660 nm.

Example 45 1,4-BisZ- (2-dimethylaminoethyl) amino] -5,6-dihydroxyanthraquinone A 30 g portion of zinc is added portionwise to a boiling mixture of 1.5 liters of glacial acetic acid and 40 ml of water containing 27.2 g of 1.4 , 5,6-tetrahydroksiantrakinonia. The mixture is boiled for 30 minutes, filtered and the filtrate is cooled. The orange-brown crystals formed are collected to give 19.7 g of leuko-1,4,5,6-tetrahydroxyanthraquinone, m.p. 255-257 ° C.

A 7.9 gram portion of dimethylaminoethylamine in 75 ml of tetramethylethylenediamine is heated to 80-100 ° C and deaerated with nitrogen. 8.22 g of leuco-1,4,5,6-tetrahydroxyanthraquinone are added portionwise to the mixture with stirring under nitrogen and heated for 6 hours at 90-100 ° C. The mixture is filtered hot. The filtrate is cooled to 4 ° C, treated with ether and, after standing for 48 hours, a dark blue resin is obtained. The supernatant is decanted off, treated with twice the volume of 31,708 8 2 of ether and cooled to give a blue resin. The supernatant is allowed to stand and then more ether is added to give 1.5 g of the desired final product as a blue solid, m.p. 133-135 C.

Claims (5)

70882 32 A process for the preparation of therapeutically useful anthraquinone derivatives of formula I and their tautomeric forms and pharmaceutically acceptable acid addition salts thereof, wherein AB is CH = CH or CH 2 -CH 2, Q is (CH 2) n, where n is an integer from 2 to 4, and R 2 independently of one another is hydrogen, C 1-4 alkyl, monohydroxy-C 2-4 alkyl, in which case the carbon atom in the Λ position relative to the nitrogen atom is not attached to a hydroxy group, or R 1 and R 2 independently represent dihydroxy-C 3-8 alkyl, wherein no carbon group is attached to the carbon atom in the α-position relative to the nitrogen atom, or R 1 and R 0 independently represent formyl, trifluoroacetyl or a group of the formula S R 3 - (OH) -O-R or - (CH_) 2 n 2 n \ R4 where n is an integer from 2 to 4, R is C1-4 alkyl and R3 and R4 independently of one another are hydrogen or C1-4alkyl, or R1 and R2 and a nitrogen atom to which they are affiliated or R 3 and R 4 and the nitrogen atom to which they are attached together form a morpholino, piperazino or oxazolidinyl group or a group of formula 70882 wherein m is an integer from 2 to 4, R g is hydrogen or hydroxy, R 9 is hydrogen or hydroxy and Ry is hydrogen, hydroxy or a group of the formula ^ R8 -NH-CH2CH2-N ^ R9 wherein Rg and Rg are hydrogen or β -hydroxyethyl, provided that a) R,, R_, Rc, R, and R 6 does not simultaneously mean ± 7 o hydrogen, b) when R 8, R 8 and R 7 represent hydrogen, R 1 / R 2 is not hydrogen / monohydroxyalkyl, and when n is 2, R 1 / R 2 is not ~ (CH 2) 2 * * O- ^ CH2 ^ 2 ~ 'hydrogen / CHg, hydrogen / C2Hg or C2H5 / C2H5' 3a when n is 3, R ^ Rj is not CH3 / CH3 or - (CH2) 4-, c) when Rg and R? denote hydroxy and when n is 2, R 1 / R 2 is not CH 8 / CH 8, C 4 H 9 / C 4 H 9 or when n is 3, R 1 / R 2 is not hydrogen / hydrogen, CH 2 / CH 8, C 1-4 / C 6 Ay or - (CH 2) ) 2-O- (CH 2> 2 -; when n is 4, R 1 is not C 2 H 9 / C 2 H 9, C 4 H 9 / C 4 H 9 or - (CH 2) 4 ', and d) when R 8 is hydroxy, one of R 8 and R 2 is hydrogen; when R 9 is hydrogen, both substituents R 8 and R 6 represent hydrogen, characterized in that the compound of formula R 5 OX R 6 TVi 't Ry OX 34 7088 2 wherein AB, R 1, R 8 and R 2 have the same meaning as above and X is hydroxy or halogen, is reacted with a compound of the formula h2n-qn <T \ r2 wherein Q, R1 and R2 are as defined above, and if desired the group NR1R2 in the obtained compound is converted into another group NR1R2 as defined above, and / or the resulting compound of formula I wherein AB is CH 2 -CH 2 is converted to a compound of formula I wherein AB is CH = CH, and / or the resulting compound of formula I is converted to a pharmaceutically acceptable acid addition salt. Process according to Claim 1, characterized in that 1,4-bis-2- (2-hydroxyethylamino) -ethylamino-β-5,8-dihydroxyanthraquinone is prepared. Process according to Claim 1, characterized in that 1,4-bis / 2- (2-hydroxyethylamino) ethylamino] -5 / 8-dihydroxyanthraquinone dihydrochloride is prepared. 70882 A compound for the preparation of a therapeutic anthraquinone derivative with the formula I and a former and a pharmaceutical form of a syringate compound, / R1 R5 o nh-q-n ^ R 1 R? 0 NH-QN ^ ^ R2 i vilken formula AB är CH = CH eller CH2-CH2, Q är (CH2) n, där n är ett heltal 2-4, R ^ and R0 betecknar oberoende av varandra väte, C ^ _ ^ -alkyl, monohydroxy-C2_4-alkyl, colors which may be used as a substituent, in which case Λ-stallning i förhällande for kväveatom, ej bundits en hydroxy-hydroxy, eller och R2 betecknar obero av avandra dihydroxy-C2_6 ~ alkyl, varvid det colatomen, In this case, the compounds of the formula are selected from the group consisting of hydroxyl groups, or R 1 and R 2 in the form of a formula, trifluoroacetyl or groups of the formula X 3 - (CH 2) n -O-R or - (CH 2 -) N. ^ R4 där n är ett heltal 2-4, R är C ^ _ ^ - alkyl och R ^ och R ^ betecknar oberoende av varandra väte eller C ^ _ ^ - alkyl, eller R ^ och R0 samt kväveatomen, account vilken of a bundle, or P-3 and R ^ as well as a quaternary atom, to a mixture of bundle, bildar tillsammans en morpholino-, piperazino- or oxazolidinyl group or a group of formulas 36 70882 där m är ett heltal 2-4, Rg är väte eller hydroxi, Rg ä r Väte eller hydroxi och R? is it possible to use hydroxyl or a group with -NH-CH2CH2-N2 to give Rg and Rg betecnar or? -hydroxyethyl, förutsatt att, a) R 1, R 2, R 8, R 8 and R 2 are selected from the group consisting of R 3, R 8 and R 2 and the same group, from R 3 / R 2 / monohydroxyalkyl, and from 2 to 4 ] / R2 - (CH2) 2 ~ 0- (CH2> 2 ~, v / wg, v / C2Hg or C2Hg / C2Hg, and is 3, is R1 / R2 or CH3 / CH3 or - (CH2) 4 -, c) Rg and R1 are hydroxy and then 2, R1 / R2 is CH3 / CH3, C4H9 / C4H9 or - (CH2) 4 ~; da 3 is 3, R 3 / R 2 and / or CH 3 / CH 3, C 3 H 2 / C 3 H 7 or - (CH 2) 2 -O- (CH 2) 2 -; d & n is 4, is Rj / I ^ ej C2Hg / C2H5, C4H9 / C4Hg or - (CH2) 4 ~, and d) da Rg is hydroxy, there is a substituent Rg and R? hydrogen; dä Rg är väte, är bäda substituenterna Rg och R? Väte, kännetecknat därav, att en förening med formuleln R5 O X R I i! 6 '\ Ά · α R? O x