CS264757B1 - Process for preparing pharmacologically active derivatives of 1,4-diaminoanthraquinone - Google Patents

Abstract

A process for the preparation of pharmacologically active derivatives of 1,4-diaminoanthraquinone of the general formula I wherein R is hydrogen, straight or branched chain alkyl, wherein alkyl is 1 to 4 carbon atoms and may be further substituted by hydroxy, X and Y are the same or different and represent a hydrogen atom, a chlorine atom or a hydroxyl group, by reacting a mixture of a reduced and non-reduced form of the corresponding 1,4-dihydroxy-anthraquinones of formula II and III wherein X and Y are as previously defined with amines of formula IV NH2-CH2CH2NHR (IV) wherein R is as previously defined such that the reaction temperature ranges from 10 to 40 ° C. Preparation of a suitable intermediate form for further use with the possibility of including filtration, compared to the previously obtained greasy consistency of the intermediate produced.

Description

The invention relates to a method for the preparation of pharmacologically active derivatives of 1,4-diaminoanthraquinone. In the preparation or industrial production of 1,4-diaminoanthraquinone and its N-alkyl and N,N'-dialkyl derivatives, the easy exchange of hydroxy groups on the anthraquinone compound for amino groups is usually used, which occurs by the action of the appropriate amines on the reduced, so-called leuco form of 1,4-diaminoanthraquinone. The procedure is similar in the preparation of derivatives of 1,4-diaminoanthraquinone also substituted in the 5- and 8-positions.

Recently, derivatives of 1,4-diaminoanthraquinone optionally substituted in the 5- and 8-positions, in which the amino groups attached to the anthraquinone core contain a 2-aminoethyl residue, optionally further substituted at the terminal nitrogen atom, and their preparation have become a subject of interest for their potential use in the pharmacotherapy of malignant growth.

In the preparation of pharmacologically significant compounds of the anthraquinone series by the reaction of the corresponding amines with leucoquinizarin or its derivatives, substituted in the 5- and 8-positions, at higher temperatures (40 to 80 °C), the process according to Czechoslovak Patent Application No. AO 204 010 and DOS 2 835 661 yields intermediates in the leuco form, which are difficult to oxidize to the anthraquinone form, and moreover in a greasy form, which is difficult to handle. Compared to these two methods, the process according to Czechoslovak Patent Application No. AO 231 079 is advantageous in that the oxidation of the intermediate is facilitated due to the use of a mixture of the leuco form and the anthraquinone form of the starting material for the reaction with the corresponding amine. However, when using 1,2-diaminoethane and N-monosubstituted 1,2-diaminoethanes for the reaction, the sticky consistency of the intermediates and products makes handling difficult and prevents the inclusion of a purification operation, such as solid fusion filtration.

It has now been found that the above-mentioned deficiency can be eliminated by carrying out the preparation according to the method of the invention. Method for the preparation of pharmacologically active 1,4-diaminoanthraquinone derivatives of the general formula I

where R represents a hydrogen atom, a straight or branched chain alkyl, where the alkyl represents 1 to 4 carbon atoms and may be further substituted by a hydroxy group, X and Y are the same or different and represent a hydrogen atom, chlorine or a hydroxyl group, by reacting a mixture of reduced

and unreduced forms of the starting 1,4-dihydroxyanthraquinones general formulas II and III J ^x OH A OH A 1A Y In the Olympics \h ⁽ⁱⁱ⁾ Γ Three ^rivers >' O OH

where the symbols X and Y have the previously given meaning, in an organic polar medium, with an amine of the general formula IV

NH ₂ -CH ₂ CH ₂ NHR (IV) where R has the previously stated meaning, according to the invention, consists in the reaction temperature being lower than 40 °C, preferably 20 to 25 °C. The reaction can be carried out in an organic polar medium, which can be formed by solvents such as aliphatic lower alcohols, alkoxy alcohols, tertiary amines, an excess of the reacting amine and other polar solvents and mixtures thereof.

A number of primary aliphatic amines can be used for the reaction, but the method according to the invention is particularly significant in reactions with amines of the general formula IV, i.e. monoalkyl derivatives of 1,2-diaminoethane, especially if the alkyl substituent carries an additional hydrophilic group, for example a hydroxyl group. The amount of amine used in the reaction is at least stoichiometric (2 moles of amine per 1 mole of tricyclic starting material), preferably larger, namely 3 to 4 times the stoichiometric amount, or the amine is used as a solvent.

The starting compounds of general formula III, which are applied partly in reduced form as leuco compounds II, are most often quinizarin, (leucoquinizarin), 5-hydroxyquinizarin (and the corresponding leuco derivative), 5,8-dichloroquinizarin (and the leuco derivative) and 1,4,5,8-tetrahydroxyanthraquinone (and its leuco derivative). The isolated reaction products are further processed by oxidation to a single product in the oxo form corresponding to formula I and for pharmaceutical purposes are converted into the form of salts with hydrochloric acid or other suitable organic acids.

The preparation of anthraquinone cancerostatics is illustrated by the following examples.

Example >

In an inert gas atmosphere (nitrogen, argon), 7.1 g (0.0235 mol) of a mixture of 1,4,5,8-tetrahydroxyanthraquinone and its leuco derivative, which contains 70% of this leuco derivative, is introduced into a mixture of 20 g (0.192 mol) of 2-(2-hydroxyethylamino)ethylamine and 20 ml of ethanol over a period of 10 minutes. The reaction temperature during the introduction and for a further 6 to 8 hours is maintained in the range of 20 to 25 °C.

The end of the reaction is determined by chromatography on a thin layer of silica gel. After the disappearance of the starting materials, the crystalline product, consisting of a mixture of 1,4-bis £2-(2-hydroxyethylamino) ethylaminoj -5,8-dihydroxyanthraquinone and its leukoderivative, is filtered off with suction. The yield is 7.5 g of a dark blue crystalline substance, in which the content of both components is determined by liquid chromatography. The oxidation of 7.7 g of the mixture is carried out in an environment of 25 ml of ethanol or 2-ethoxyethanol by the action of 6 g of chloranil and takes place quantitatively at a temperature of 20 to 25 °C in 8 hours. The end of the oxidation can be determined by chromatography on a thin layer of silica gel.

The product formed by 1,4-bis[2-(2-hydroxyethylamino)ethylamino]-5,8-dihydroxyanthraquinone is converted into a hydrochloric acid salt by adding 10 ml of ethanol containing 4 N hydrogen chloride in 1000 ml. The resulting dihydrochloride is precipitated by adding 100 ml of diethyl ether and filtered off with suction. The yield of a dark blue substance with a melting point of 203 to 205 °C is 7.7 g (0.014 9 mol), i.e. 63.5% of the starting hydroxyanthraquinone substance.

Thin layer chromatography

Solutions of the reaction mixture are spotted onto a thin layer of silica gel, for example Silufol. A suitable developing system is, for example, a mixture of ethyl acetate:ethanol:ammonia in the ratio 5:2:1.

Liquid chromatography

To determine the content of components in the reaction product, liquid chromatography on a reversed stationary phase (Separon SW - C^g) is performed using a mobile phase of methanol: ammonia 8% mixed in a ratio of 8:3 and with spectrometric detection at 254 nm. The quality of the product after oxidation is assessed by liquid chromatography on an amine stationary phase (Separon SIX - NHg) with elution of mobile phases with the composition ethyl acetate: ethanol: conc. ammonia in a ratio of 24:2:1. A spectrophotometric detector set to a wavelength of 289 nm is used for detection.

Example 2

The same procedure as in Example 1, except that 7.1 g of a mixture of 1,4,5,8-tetrahydroxyanthraquinone and its leuco derivative contains these components in a ratio of 1:9, i.e. 90% leucoform, is reacted with 2-(2-hydroxyethylamino)ethylamine. The reaction product obtained, isolated by suction, is oxidized in 2-ethoxyethanol using 7.5 g of chloranil.

Example 3

Analogously to Example 1, with the difference that NHgCHgCHgNHR is used for the reaction, whereby, after subsequent oxidation, substances included in the general formula I, listed in the following table, are obtained.

Table

X Y R t melting point (°C) for dihydrochloride

OH OH -H 350 OH OH _{-CH2CH2CH2OH ​ ​} 210 to 216 OH OH -CH„CH-OH 177 to 185 ^CH3

Example4

In an inert gas atmosphere (nitrogen, argon), a mixture containing 2 g of 1,4-dihydroxyanthraquinone and 8 g of its leuco derivative (total 0.04 mol) is introduced into a mixture of 20 g (0.192 mol) of 2-(2-hydroxyethylamino) ethylamine and 40 ml of ethanol over a period of 10 minutes at a temperature of 20 to 25 °C. The reaction mixture is stirred in an inert atmosphere at a temperature of 20 to 25 °C for 6 hours. The progress and end of the reaction are monitored by thin-layer chromatography on silica gel. After the disappearance of the starting materials, a stream of air is introduced into the reaction mixture to oxidize the leuco form of the product to a single product, 1,4-bis [2-(2-hydroxyethylamino)ethylamino] anthraquinone. The yield of the blue substance with a freezing point of 156-158 °C is 12.1 g (0.029 mol; 73.3%). When converting into the salt form, the reaction product is dissolved in anhydrous ethanol and the solution is saturated with gaseous hydrogen chloride. The separated red hydrochloride is filtered off with suction and dried.

Analogously to the above example, instead of 1,4-dihydroxyanthraquinone and its leuko derivative, the corresponding 5-chloro derivative or 5,8-dichloro derivative can also be used for the reaction.

The reaction progress can be monitored by thin layer chromatography on silica gel (developing system ethyl acetate-ethanol-conc. ammonia in the ratio 4:1, 2:1).

Product quality can be assessed using liquid chromatography.

Example 5

In an inert gas atmosphere, 7.1 g of a mixture containing 30% 1,4,5,8-tetrahydroxyanthraquinone and 70% of its leuco derivative are introduced into a mixture of 20 g (0.192 mol) of 2-(2-hydroxyethylamino)ethylamine and 20 ml of 2-ethoxyethanol over a period of 10 minutes. During the introduction period and for a further 6 to 8 hours, the reaction temperature is maintained between 20 and 25 °C. After the disappearance of the starting materials, the crystalline product is filtered off with suction. The yield is 7.4 g of a mixture of 1,4-bis ^2-(2-hydroxyethylamino)ethylaminoj-5,8-dihydroxyanthraquinone and its leuco derivative.

The oxidation of the obtained 7.4 g of the reaction product is carried out in 100 ml of 2-methoxyethanol after acidification of 10 ml of ethanol containing hydrogen chloride with a concentration of 3.6 g HCl/100 ml, and with the addition of 4.5 chloranil at a temperature of 15 °C. After the disappearance of the leuco compound, the product is precipitated from the solution by adding ethyl ether, the precipitate is filtered off with suction. It is formed by a dark substance with a freezing point of 203 to 205 °C; the yield is 8.4 g.

Claims (1)

Process for the preparation of pharmacologically active derivatives of 1,4-diaminoanthraquinone of formula I yNHCHjCHjNHR NHCH ₂ CH ₂ NHR (I) wherein R is hydrogen, alkyl of straight or branched chain, wherein alkyl is 1-4 carbon atoms and may be further substituted by hydroxy X and Y are the same or different and represent a hydrogen atom, a chlorine atom or a hydroxyl group by reacting a mixture of the reduced and non-reduced forms of the corresponding 1,4-dihydroxyanthraquinones of the general formula II and ΙΪΙ; X OH OH X O OH Y OH OH OH (II) (III) wherein X and Y are as previously defined with amines of formula IV NH ' ₂ -CH ₂ CH ₂ NHR (IV) wherein R is as previously defined, characterized in that the reaction temperature is in the range of 10 to 40 ° C in the range of 20 to 25 ° C.