CS231079B1 - Processing method of pharmaceuticaly effective 1,4-diamino antraquinone derivative - Google Patents

Description

The invention relates to a process for the preparation of pharmacologically active 1,4-diaminoanthraquinone derivatives. In the preparation or industrial production of 1,4-diaminoanthraquinone and its N-alkyl and Ν, Ν-dialkylderivatives, known as disperse or direct dyes, an easy exchange of hydroxy groups on anthraquinone with amino groups usually occurs by the action of the appropriate amines on leukoform 1,4 Similarly, the preparation of the 1,4-diaminoanthraquinone derivatives substituted in the 5- and 8-anthraquinone positions is similar.

Recently, the preparation of 1,4-diaminoanthraquinone derivatives optionally substituted in the 5- and 8- positions, bearing alkyl further substituted on the arao groups attached to the anthraquinone core, has been of interest for its potential use in the treatment of some forms of cancer. hydroxyalkylamino, alkylamino or other, for example, cycloaliphatic radicals containing nitrogen or oxygen atoms. No. 204,010, ethanol is used as the medium for the reaction of leucochinizarin and the corresponding amine, wherein the reaction is heterogeneous and both the starting leucochinizarin and the product present in the leukoform remain undissolved. Also in it. No. 2,835,661, the reactions of the leukoform of the anthraquinone hydroxy derivatives with the corresponding amino compounds are carried out in organic solvents such as tetramethylenediamine and 2-ethoxyethanol or lower alcohols. By these methods, 1,4-diaminoanthraquinone derivatives are obtained in leukoform, which is difficult to oxidize in suspension to the corresponding desired anthraquinone products, so that either a portion remains non-oxidized by air, it must be filtered off at yield, or complete oxidation is achieved

231 079 by the action of oxidizing agents such as nitrobenzene or chloranil, which constitutes a certain complication for the preparation of pure substances suitable for processing into pharmaceutical preparations. It has now been found that these deficiencies can be substantially reduced by carrying out the process according to the invention.

A process for the preparation of pharmacologically active 1,4-diamino anthraquinone derivatives of the formula I

where R-j

R ₂ are the same or different and are hydrogen, straight or branched chain alkyl wherein the alkyl contains 1 to 4 carbon atoms and may be further substituted with hydroxy or methylamino, cycloalkyl of 5 to 6 carbon atoms, and R ₁ and R ₂ together may form a 3 to 6 membered saturated heterocyclic ring with the nitrogen atom, which may contain another nitrogen atom or an oxygen atom,

Z represents a divalent, straight or branched carbon hydrogen bridge of 1 to 6 carbon atoms,

X and Y are the same or different and represent hydrogen, hydroxyl or -NH - Z - N < 1 &gt; by reacting the corresponding dihydroxyanthraquinones and amines in an aqueous, aqueous organic or organic medium according to the invention II, R '(II)

- 3 231 079 wherein the symbols Z, R R, Rg are as previously defined, react with the starting anthraquine compound and its reduced and non-reduced forms of the formulas IV and III

(IV)

wherein X and Y are as previously defined, wherein the ratio of the components IV and III used is 1: 0.25 to 4.

The reaction can be advantageously carried out in water, further in organic solvents such as aliphatic lower alcohols, alkoxyalcohols or other non-oxidizing solvents.

The choice of amines of formula II which can be used in the reaction is very wide and their choice depends primarily on the determination of the products. Unsymmetrically substituted derivatives of 1,2-diaminoethane or 1,3-diaminopropane, for example 2- (2-methylaminoethyl aminc-ethylamine) or 3 (2-hydroxyethylamino) ethylamine or morpholinoethylamine, are most frequently used for the preparation of substances having antineoplastic properties. The amount of amine used is at least stoichiometric (2 moles of amine per mole of tricyclic starting material), preferably greater, 2-3 times the stoichiometric amount, or the amine is used as a solvent.

The starting compounds of the formula III which are applied partially in reduced form as the leuco compound are most often quinizarin (leucochinizarin), 5-hydroxyquinizarin (and the corresponding leukoderivative) or 1,4,5,8-tetrahydroxyanthraquinone (and its leukoderivative).

The reaction is illustrated in the following examples. The substances obtained by the process according to the invention are intensely colored blue and can be applied, for example, as blue dyes on wool. For pharmaceutical purposes, 4,231,079 is most commonly used

Salts thereof with hydrochloric acid or suitable organic acids, such as citric, ascorbic, acetic acid ·

Example 1

A mixture of 8.0 g of leucochinizarin and 4.1 g of quinizarin is homogenized (optionally under nitrogen or argon atmosphere) with 15 ml of water. and then 12.4 g of 2- (2-aminoethylamino) ethanol are added. After stirring at normal temperature for 1 hour, the reaction is completed by heating to 50 to 70 ° C for 2 to 6 hours, depending on the result of the TLC control. After the disappearance of the starting materials, air is introduced into the reaction mixture at 50 ° C to oxidize the leukoform of the product to the anthraquinone form, which takes about 2 hours and can be checked again by chromatography. The reaction mixture was then evaporated to dryness in vacuo to give a deep colored blue product, chromatographically pure 1,4-bis (2- (2-hydroxyethylamino) ethylamino) anthraquinone.

ehromatografie:

The reaction mixture solutions are spotted onto a thin layer of silica gel, for example Silufol. A suitable developing system is, for example, ethyl acetate: ethanol. Ammonia in ratio 4: 1,2: 1. Characteristics of any substances present:

color R ~ leukoderivative R _f ¹ color ¹

main product blue 0.30 yellow 0.15 reaction product 1: 1 purple 0.50 yellow 0.40 starting material red 0.92 yellow 0.78

(quinizarin)

Example 2

The reaction is carried out as in Example 1 except that sodium chloride in an amount of, for example, 10 g or more is added to a solution of the mody product in water prior to evaporation to dryness, and the resulting solution is then evaporated to form a well-manipulated form of the product. sodium chloride.

Example 3

The reaction is carried out as in Example 1, except that the reaction is carried out as follows

5 231 079 is isolated as the hydrochloric acid salt by adding the dilute acid to the product of Example 1 and heating the resulting mixture at 45-55 ° C for 3 hours, cooling, and purifying the aqueous solution by extraction with chloroform. and evaporation of the aqueous solution to give the red hydrochloride of the product.

Similarly, salts of product and acetic acid or other organic acids are prepared ·

Example 4

Using the same procedure as in Example 1, except that 14 g of 2- (2-methylaminoethylamino-amine) ethylamine was used as the amine instead of 2- (2-aminoethyl) amine) to give 1,4-bis (2- (2-methylaminoethyl) amino) ethylamine. m.p. 131-133 ° C.

Example 5

A mixture of 4 g of 1,4,5,8-tetrahydroxyanthraquinone leukoderivatives prepared from 1,5-diamino-4,8-dihydroxy-2,6-anthraquinone disulfonic acid by treatment with an alkali / sodium dithionite solution and 3,5 g of 1,4, The 5,8-tetrahydroxyanthraquinone is homogenized with 15 ml of water, 10 g of 2- (2-hydroxyethylamino) ethylamine are added and the resulting reaction mixture is heated to 50-70 [deg.] C. with stirring for 6 hours. Chromatography · Once the reaction is complete, the product is oxidized at 80 ° C with a stream of air and after 1-2 hours of oxidation the reaction mixture is evaporated to dryness. 5,8-Dihydroxy-1,4-bis (2- (2-hydroxyethylamino) ethyleamino) anthraquinone is obtained as a dark green-blue product. R ^ value in ethyl acetate:

the ammonia ethanol (4: 1.2: 1) is 0.25.

Example 6

The reaction is carried out in analogy to Example 5 except that the product is isolated in the form of a hydrochloric acid salt, the oxidized reaction mixture is heated at 45-55 ° C with dilute acid for 3 hours, after which the cooled solution is purified by chloroform extraction. water phase evaporates to dryness ·

Other acids such as acetic acid · ιθ can be applied analogously

Example 7 ^{231 0.9}

The reaction is carried out as in Example 1 except that the dry reaction product is dissolved in anhydrous lower alcohol (e.g., ethanol, methanol) and the resulting solution is saturated with gaseous hydrogen chloride. The precipitated hydrochloride is filtered off and dried.

Example 8

The reaction is carried out analogously to Example 5. The obtained dry product is dissolved in an anhydrous lower alcohol such as methanol, and the resulting solution is saturated with hydrogen chloride gas, the precipitated hydrochloride is filtered off and dried.

Example 9

In analogy to Example 1, except that 15 g of 2- (diethylamine-ethylamine) was used as the amine instead of 2K2-aminoethyl-amino-ethanol, 1,4-his (2-diethylaminoethyl-amino) anthraquinone was obtained. m.p. 109-110 ° C.

Example 10

A mixture of 6.5 g of the 1,4,5,8 tetrahydroxyanthraquinone leukoderivative ^and 5.0 g of 1,4,5,8-tetrahydroxyanthraquinone is homogenized with 30 ml of water and 7.5 g of ethylenediamine are added. The resulting mixture was heated under a nitrogen atmosphere, then at 50-60 ° C for 4-6 hours. The progress of the reaction is checked by chromatography. After completion of the reaction, the reaction mixture is oxidized with air at 40 to 60 ° C for 2 to 4 hours. The precipitated product is filtered and dried

vacuum. To afford 1,4-bis (2-aminoethylamino 5,8--dihydroxyantraquinone as černoraodré substance _Y which hydrochloride has a melting point greater than 300 ° C,

Elemental analysis showed ^C 18 ^H 20 ^N 4 ° 4 ' ^{2 HCL} 1 ° ^{5 H} 2 °

Calculated: N = 12.8%

Cl = 16.2% found: N = 12.4%

Cl = 15.1%

- 7 Example 11 ^{231 079}

By analogy to Example 10 except that 3-dimethylaminopropylamine was used as the amine instead of ethylenediamine, 1,4-bis (3-dimethylaminopropylamino) -5,8-dihydroxyanthraquinone was prepared.

After crystallization from heptane, black-blue crystals are obtained, m.p. 154-157 ° C.

Examples 12 to 16

Analogously to Example 11, the appropriate reaction can be used.

NH ₀ -Z-1 amines to give compounds included in ^R 2 of the general formula (1), as shown in the following table:

Table

X Y -hn-zn < ^r i ^R 2 melting point ° C OH OH -HN-CH ₂ CH ₂ -N (CH 2 ^CH 3) ₂ CH 2 233-235 OH OH -HN-CH ₂ CH ₂ -N ^ ^R 2 168-170 OH OH ^ ch ch _{9 9} ~ -HN-CH-CH ₀ N ^A | ^{ά Δ ά x} ch ₂ -ch ₂ 193-196 OH OH -HN CH -CH-CH-CH _{O 9} -K; ^{ά ά} NH ^{č d} ^ ch ₂ -ch ₂ ' ^x 217-219 OH OH CH-CH \ HN-CH ₉ CH _on N ^d ^ ^{ά ά ά} CH _O X ^H-N, CH 200-203

- 8 Example 17 ^{231 079}

Analogously to Example 11, the reaction can be carried out except that the amine of formula Ifi ₂ - (CH ₂ -NH (CH ₂ ) ₂ NHCH) is used to give 1,4-bis (2 2-methylaminoethylamino) ethyl-- 5,8'-dihydroxyantraquinone amine in the form of tetrahydrochloride, m.p. 190-203 ° C.

'and

Example 18>

By analogy to Example 10, except that N- (2-aminoethyl) morpholine was used as the amine instead of ethylenediamine, 1,4-bis (24-ferpholine-4-ethylamino) -5,8-dihydroxyanthraquinone was prepared. Crystallization from toluene gave blue-blue crystals having a melting point of 240-243 ° C.

Example 19

By analogy to Example 1, except that N-Oyclohexyl-1,3-propylcindiamine is used as the amine in place of 2- (2-aminoethyl-amino) ethanol. 1,4-Bis (cyclohexylaminopropylamino) anthraquinone is prepared. value x Rp = 0.3 when chromatographed on Silufol in ethyl toluene (3: 1) system ·

Example 20

The mixture of 1,4,5-tetrahydroxyanthraquinone leukoderivative and 1,4,5,8-tetrahydroxyanthraquinone is placed in 100 ml of 3-hydroxyethylamine-ethylamine and the resulting reaction mixture is heated at 50-60 ° C under nitrogen for 3 hours. hours · The reaction mixture is filtered and, after cooling and standing for 1 day, dark blue 1,4,5-tris (2- (2-hydroxyethylamino) / ethylamino) -8-hydroxy anthraquinone precipitates in the filtrate, which is chromatographed on Silufol in the system. ethyl acetate-ethanolammonium (4: 1,2: 1) has an Rp value of 0,4 ·

Claims (1)

Process for the preparation of pharmacologically active 1,4-diaminoanthraquinone derivatives of the general formula I (I) wherein R. | and R ₂ are the same or different and represent hydrogen, straight or branched chain alkyl wherein the alkyl contains 1 to 4 carbon atoms and may be further substituted by hydroxy or methylamino, cycloalkyl of 5 to 6 carbon atoms, and further R 1 and R ₂ may together with the nitrogen atom form a 3 to 6 membered saturated heterocyclic ring which may contain another nitrogen atom or an oxygen atom, Z represents a divalent, straight or branched hydrocarbon bridge of 1 to 6 carbon atoms, X and Y are the same or different and represent hydrogen, hydroxyl, or a group --NH - Z - N ^ 1 ** 2 ^XS dihydroxyanthraquinone reacting the corresponding amines in water and 'therein, aqueous-organic or organic medium, wherein the amine of formula II nh ₂ - Z (II) wherein Z, R 1, R ₂ are as previously defined, reacts with the starting anthraquinone compound in its reduced and non-reduced (III) forms of formulas IV and III n where λ. and - are as previously defined, wherein the components IV and III used are 1: 0.25 to 4 · ratio