DE3100968A1 - Anthracycline derivatives, a process for their preparation and pharmaceuticals containing these compounds - Google Patents

Abstract

The invention relates to anthracycline derivatives of the general formula I <IMAGE> in which one of the substituents R1 and R2 is a hydrogen atom and the other is a hydrogen atom or a methyl group; R3 is a daunosaminyl, 4-epi-daunosaminyl, 3,4-bis-epi-daunosaminyl or 4-deoxydaunosaminyl group or an N-trifluoroacetyl derivative thereof; R4 is an alkyl group with 1 to 4 carbon atoms; and R5 is a hydrogen atom or a hydroxyl group, and the pharmaceutically acceptable salts thereof. The anthracycline derivatives I are suitable as antitumour agents. Pharmaceuticals which contain these compounds are also described.

Description

description

The invention relates to new anti-tumor agents and a method for their Manufacture and pharmaceuticals containing these agents.

The invention relates to anthracycline derivatives of the general formula I in which one of the substituents R1 and R2 is a hydrogen atom and the other is a hydrogen atom or a methyl group; R3 represents a daunosaminyl, 4-epi-daunosaminyl, 3, 4-bis-epi-daunosaminyl or 4-deoxydaunosaminyl group or an N-trifluoroacetyl derivative thereof; R4 represents an alkyl group having 1 to 4 carbon atoms; and R5 represents a hydrogen atom or a hydroxy group, and the pharmaceutically acceptable salts thereof.

The starting materials for the preparation of the new anthracycline glycosides of the formula I are hitherto unknown aglycones of the general formula II in which R1, R2 and R4 have the meanings given above and R5 stands for a hydrogen atom.

The synthesis of the anthracyclinones II can be carried out according to the following scheme: Compound III is selectively converted to monoketal IV, the reaction being carried out in a solvent such as benzene or toluene in the presence of ethylene glycol and anhydrous p-toluenesulfonic acid. Compound IV on treatment with lithium aluminum hydride in anhydrous tetrahydrofuran yields compound V, which in turn is converted to compound VI by treatment with p-toluenesulfonic acid in benzene or toluene.

By reducing VI with lithium aluminum hydride in anhydrous Tetrahydrofuran is obtained in VII and this is made in VIII by treatment with m-chloroperbenzoic acid converted to methylene dichloride or chloroform. With benzyl bromide in the presence a base such as sodium hydride converts VIII to IX. The oxirane ring of IX is represented by R4Mg X (R4 has the above definition and X means a halogen atom) at Heat Cleaved in benzene, whereby the compound X is obtained will. Catalytic hydrogenation of X on Pd / C provides XI, which by treatment is oxidized with dicyclohexyl-carbodiimide / dimethyl sulfoxide in benzene in XII. By a Friedel-Craft reaction with phthalic acid inonomethyl ester monochloride, which is im aromatic ring is substituted or unsubstituted, in the presence of aluminum chloride and subsequent hydrolysis and treatment with liquid hydrofluoric acid XIII and this compound is converted into the ketal by conventional methods XIV converted.

Compound XIV is prepared by treatment with N-bromosuccinimide in carbon tetrachloride converted into XV in the presence of light and subsequent acidic methanolysis, the in turn by aluminum chloride in methylene dichloride and then with trifluoroacetic acid provides compound II along with small amounts of the 7-epimers. these can into the compound II with the grouping 7-a-OH according to the equilibrium procedure, described in J. Am. Chem. Soc. 98, 1967 (1976).

Another object of the invention is a method for production of anthracycline derivatives of the general formula I, in which R5 represents a hydrogen atom and R1, R2, R3 and R4 have the meanings given above. In this procedure one proceeds in such a way that one anthracyclinone with the general given herein Formula II with a 1-halogen-N, O-bis-trifluoroacetyl-daunosamine, 1-halogen-N, O-bis-trifluoroacetyl-4-epi-daunosamine, 1-halo-N, O-bis-trifluoroacetyl-3,4-bis-epi-daunosamine or 1-halo-N-trifluoroacetyl-4-deoxy-daunosamine in an organic solvent such as dichloromethane or chloroform in the presence a soluble silver salt, e.g. silver trifluoromethane sulfonate, as a catalyst converts and that, if present, the O-trifluoroacetyl group by treatment with methanol in the presence removed from triethylamine as a catalyst and optionally removing the N-trifluoroacetyl group by mild alkaline hydrolysis.

The doxorubicin derivatives of the general formula I, in which R5 stands for a Hydroxyl group and R1, R2, R3 and R4 have the meanings given above, can from the corresponding Daunorubicinderivaten of the general formula I at where R5 is a hydrogen atom and R1, R2, R3 and R4 are those given above Have meanings, are made.

This production, which is within the scope of the present invention, sees the implementation of the Daunorubicinderivats I with bromine and the treatment of the resulting 14-bromo derivative with aqueous sodium formate. The reaction conditions are preferable those described in U.S. Patent 3,803,124.

The 1-halogen substituent in the daunosamine derivative associated with the anthracyclinone of the general formula II is condensed, is preferably a 1-chloro substituent. The reaction conditions of this condensation are preferably those described in U.S. Patent 4,046,878.

These processes are explained in more detail with reference to Formula XVI.

a) R6 = NHCOCF3, R8 = OCOCF3, R = R9 = H b) R6 = NHCOCF3, R9 = OCOCF3, R7 = R8 = H c) R7 = NHCOCF3, R9 = OCOCF3, R6 = R8 = H d) $ 6 = NHCOCF3, R7 = R8 = R9 = H e) R6 = NHCOCF3, R8 = OH, R7 = R9 = H f) R6 = NHCOCF3, R9 = OH, R7 = R8 = H g) R7 = NHCOCF3, R9 = OH, R6 = R8 = H h) R6 = NH2, R8 = OH, R7 = R9 = H i) R6 = NH2, R9 = OH, R7 = R8 = H j) R7 = NH2, R9 = OH, R6 = R8 = H k) R6 = NH2, R7 = R8 = R9 = H.

The condensation leads to the compounds XVIa-d.

The compounds XVIa-c by treatment with methanol and with catalytic amounts of triethylamine converted into XVIe-g, in which the sugar amino group is still protected as a trifluoroacetyl derivative. The latter can be hydrolyzed are, whereby the free amino derivatives XVIh-j by mild alkaline treatment, as described in the following examples. A similar hydrolysis from XVId delivers XVIk. The conversion of XVIh-k into I (R5 = OH) is carried out according to the method carried out in U.S. Patent 3,803,124 for the chemical conversion of daunorubicin described in doxorubicin.

The new compounds I show an antimitotic activity and are useful therapeutic agents for treating tumor diseases. A The invention therefore also relates to a medicament which is an anthracycline derivative of the general formula I or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

The invention is illustrated in the examples.

Example 1 4-Demethoxy-8-methyldaunomycincon (11: R1 = R2 = R5 = H; R4 = CH3) (a) 1,4-Dimethoxy-6- (1t, 1'-ethylenedioxyethyl) -tetral-8-one (IV) 25 g of 1,4-dimethoxy-6-acetyl-tetral-8-one (III) were in 400 ml of anhydrous benzene containing 56.6 ml of ethylene glycol and 1.87 g Containing anhydrous p-toluenesulfonic acid, dissolved.

1 equiv. Water was distilled off azeotropically and a saturated, Aqueous solution of sodium bicarbonate was added until the pH was approximately 8 was.

The reaction mixture was then extracted with benzene. The organic Layer was washed with water and dried to dryness evaporated. Crystallization from methanol yielded 19 g of the ketal in pure form (melting point 138 up to 1400C).

(b) 1,4-Dimethoxy-6- (l ',?' -äthylenedioxyethyl) -tetral-8-ol (V) 40 g 1,4-dimethoxy-6- (1 ', 1'-ethylenedioxyethyl) -tetral-8-one IV, prepared according to the example 1 (a), were dissolved in 400 ml of anhydrous tetrahydrofuran and mixed with 12.5 g of lithium aluminum hydride offset. After 2 hours the reaction was complete. After conventional work-up measures 40 g of the compound named in the title were obtained (melting point 93 to 95.degree. C. after crystallization from methanol).

(c) 1,4-Dimethoxy-6-acetyl-6,7-dihydro-tetralin (VI) 40 g of 1,4-dimethoxy-6- (1 ', 1'-ethylenedioxyethyl) -tetral-8-ol (V), prepared according to Example 1 (b), were dissolved in 1.7 liters of benzene and a slow one A stream of argon was bubbled through the solution for 100 minutes. 4 g of p-toluenesulfonic acid monohydrate were added and the reaction mixture was left under an argon atmosphere for 1 h heated to reflux. After cooling the solution and washing with an aqueous Sodium bicarbonate solution and with water until neutral, the solution became Evaporated dry. The residue was then dissolved in methylene dichloride, and there were 24 g of the desired product by treatment with diisopropyl ether obtained (m.p. 123 to 1240C).

(d) 1,4-Dimethoxy-6- (1'-hydroxyethyl) -6,7-dShydrotetralin (VII) 4.5 g of lithium aluminum hydride were added portionwise to 150 ml of anhydrous tetrahydrofuran given. After cooling on a water bath, there was 14.4 g of 1,4-dimethoxy-6-acetyl-6,7-dihydrotetralin VI, prepared according to Example 1 (c), dissolved in 50 ml of anhydrous tetrahydrofuran, added dropwise.

The reaction was complete within 30 minutes. According to conventional Work-up measures gave 14 g of pure product (melting point 100 to 1020 ° C.).

(e) 1,4-Dimethoxy-6- (1 -benzyloxyethyl) -6,7-dihydrotetralin (VIII) Under a nitrogen atmosphere, 6.5 g of a 50% dispersion of sodium hydride were added in oil added in portions to 200 ml of anhydrous tetrahydrofuran. 10.2 g of 1,4-dimethoxy-6- (l'-hydroxyethyl) -6,7-dihydrotetralin (VII), prepared according to Example 1 (d), and 8 ml of benzyl bromide in 20 ml of tetrahydrofuran were then added. After refluxing for 11/2 hours, the reaction mixture became cooled and mixed with methanol to eliminate excess sodium hydride. After washing with water, the solution was evaporated to dryness and the residue was crystallized from methanol. There were 6.5 g of those mentioned in the heading Compound (m.p. 69-700C) was obtained.

(f) 1,4-Dimethoxy-6- (1'-benzyloxyethyl) -6,7-epoxytetralin (IX) 8.6 g of 70% strength m-chloroperbenzoic acid were dissolved in 130 ml of methylene dichloride and with 10 g of 1,4-dimethoxy-6- (1'-benzyloxyethyl) -6,7-dihydrotetralin (VIII) according to Example 1 (e), added. The reaction was complete within 1 hour. To Washing with water and evaporation to dryness the crude product was chromatographed (Silica gel, petroleum ether; petroleum ether: diethyl ether), whereby 6.5 g of 1,4-dimethoxy-6- (1 '-benzyloxyethyl) -6,7-epoxytetralin were obtained (melting point 102 to 1050 after crystallization from diethyl ether / petroleum ether).

(g) 1,4-Dimethoxy-6- (1'-benzyloxyethyl) -6-hydroxy-7-methyltetralin (X: R4 = CH3) Under a nitrogen atmosphere, 3.6 g of magnesium turnings were in Suspended 150 ml of anhydrous diethyl ether and a rapid stream of methyl bromide was bubbled through the suspension. The reaction was quick and it 150 ml of diethyl ether were added. After the magnesium had been consumed, the diethyl ether became distilled off and through 300 ml of anhydrous Replaced benzene. 3 g 1,4-dimethoxy-6- (1'-benzyloxyethyl) -6,7-epoxytetralin (IX), prepared according to Example 1 (f) was dissolved in 150 ml of anhydrous benzene and added rapidly. The reaction mixture was refluxed one night, then cooled and treated with 7 g of ammonium chloride in 25 ml of water and washed with water.

The solvent was removed in vacuo and treated with Petroleum ether was 2 g of 1,4-dimethoxy-6- (1'-benzyloxyethyl) -6-hydroxy-7-methyl-tetralin (M.p. 113 to 1150C).

(h) 1,4-Dimethoxy-6- (1'-hydroxyethyl) -6-hydroxy-7-methyltetralin (XI: R4 = CH3) 2.3 g of 1,4-dimethoxy-6- (1 -benzyloxyethyl) -6-hydroxy-7-methyltetralin (X: R4 = CH3), prepared according to Example 1 (g), were dissolved in 50 ml of absolute ethanol dissolved. 400 mg p-toluenesulfonic acid monohydrate and 330 mg 5% palladium-on-charcoal, suspended in 5 ml of water were added. After hydrogenation at ordinary pressure the catalyst was filtered off and the solution was evaporated to dryness. The residue was dissolved in chloroform and washed with water. The solution was evaporated to dryness, yielding 1.6 g of 1,4-dimethoxy-6- (1'-hydroxyethyl) -6-hydroxy-7-methyl-tetralin were obtained (melting point 119 ° C. after crystallization from benzene).

(i) 1,4-Dimethoxy-6-acetyl-6-hydroxy-7-methyltetralin (XII: R4 = CH3) Under a nitrogen atmosphere, 0.5 g of 1,4-dimethoxy-6- (1'-hydroxyethyl) -6-hydroxy-7-methyl-tetralin were obtained (XI: R4 = CH3), prepared according to Example 1 (h), in 2.7 ml of anhydrous dimethyl sulfoxide dissolved and there were 2.7 ml of anhydrous benzene, 0.14 ml of pyridine and 0.07 ml Trifluoroacetic acid and 1.12 g of dicyclohexylcarbodiimide were added. After standing overnight at ambient temperature the reaction mixture was dissolved in an aqueous solution poured from oxalic acid, extracted with benzene and washed with water. After removing the solvent in vacuo, the residue was dissolved in acetone and the solids were filtered off. The solvent was again in vacuo evaporated. After chromatography on silica gel using chloroform as The eluent was 0.2 g of 1,4-dimethoxy-6-acetyl-6-hydroxy-7-methyltetralin (m.p. 114 to 115.5 ° C).

(j) 4-Demethoxy-6 7,11-trideoxy-6,11-dimethoxy-8-methyldaunomycinone (XIII: R1 = R2 = H; R4 = CH3) 2.3 g of phthalic acid monomethyl ester monochloride, dissolved in 4 ml of anhydrous methylene dichloride were added dropwise to a suspension of 1.5 g of anhydrous aluminum chloride in 5 ml of anhydrous methylene dichloride, the had been cooled to -10 ° C, given. 0.5 g of 1,4-dimethoxy-6-acetyl-6-hydroxy-7-methyl-tetralin (XII: R4 = CH3), prepared according to Example 1 (i), in 5 ml of methylene dichloride added dropwise.

The reaction mixture was 5 h at a temperature in the range of -10 to -50C held. It was then diluted with 100 ml of methylene dichloride and washed until neutral.

The solution was evaporated to dryness and the residue became dissolved in 12 ml of 965% ethanol.

1.6 g of potassium hydroxide in 8 ml of water was added and the reaction mixture was heated to 60 ° C. for 2 h. The solvent was evaporated in vacuo. The residue was dissolved in water and extracted with chloroform. The aqueous layer was acidified with 2N hydrochloric acid and extracted with chloroform. The solvent was evaporated therefrom and the residue was poured into a KCl-F vessel and with 10 ml of anhydrous hydrofluoric acid are added. After 3 hours the hydrofluoric acid became distilled off in vacuo and the residue was dissolved in chloroform and bis washed to neutrality. After evaporation and chromatography on silica gel using chloroform as the eluent became 250 mg of 4-demethoxy-6,7,11-trideoxy-6,11-dimethoxy-8-methyl-daunomycinone (m.p. 1880C) received.

(k) 4-Demethoxy-6,7,11-trideoxy-6,11-dimethoxy-8-methyl-9- (1 ', 1t-ethylenedioxyethyl) -daunomycinone (XIV: R1 = R2 = H; R4 = CH3) 1 g of 4-demethoxy-6,7,11-trideoxy-6,11-dimethoxy-8-methyldaunomycinone (XIII: R1 = R2 = H; R4 = CH3), prepared according to Example 1 (j), became 1.5 ml of ethylene glycol and placed 1 g of anhydrous p-toluenesulfonic acid in 100 ml of anhydrous benzene. The water formed during the reaction was azeotropically distilled off until the source material was gone. After washing and chromatography of the crude product on silica gel using chloroform as the eluent 0.9 g of 4-demethoxy-6,7,11-trideoxy-6,11-dimethoxy-8-methyl-9- (1 ', 1'-ethylenedioxyethyl) daunomycinone were obtained (M.p. 164 to 1660C).

(1) SDemethoxy-6,7,11-trideoxy-6 11-dimethoxy-8-methyl-daunomycinone (XV: R1 = R2 = H; R4 = CH3) 3 g of 4-demethoxy-6,7,11-trideoxy-6,11-dimethoxy-8-methyl-9- (1 lt ethylenedioxyethyl) daunomycinone (XIV: R1 = R2 = H; R4 = CH3), prepared according to the example 1 (k), were dissolved in 95 ml of carbon tetrachloride by heating with a 500 W tungsten lamp dissolved. 1.68 g of N-bromosuccinimide were added and the reaction mixture was refluxed for 20 min. The solvent was partially distilled off, and the solid was filtered off and washed with ethyl ether. The washing waters were evaporated to dryness and the residue was dissolved in 95 ml of anhydrous methanol dissolved. After refluxing for 1 hour, 38 ml of 10% aqueous hydrochloric acid were added was added and the mixture was refluxed for an additional hour. According to conventional Work-up procedure and after chromatography on silica gel (chloroform as eluent) 0.7 g of 4-demethoxy-6,7,11-trideoxy-6,7,11-trimethoxy-8-methyl-daunomycinone obtained as oil.

(m) 4-Demethoxy-8-methyl-daunomycinone and its 7-epimer (11: R1 = R2 = H; R4 = R5 = CH3) 1 g of 4-demethoxy-6,7,11-trideoxy-6,7,11-trimethoxy-8-methyldaunomycinone (XV: R1 = R2 = H; R4 = CH3), prepared according to Example 1 (1), was made under a nitrogen atmosphere dissolved in 100 ml of anhydrous methylene dichloride which had been cooled to 0 ° C. 2 g of anhydrous aluminum chloride were added. The reaction ran at the 45 minute Let stand at OOC to complete. 30 g of oxalic acid and 60 ml of water were added added with stirring, which was continued for 30 min. After extraction with methylene dichloride and washing with water, the solvent was evaporated and the residue became with 15 ml of trifluoroacetic acid containing 2% water, dissolved. After standing The reaction was complete overnight at ambient temperature. The solvent was distilled off in vacuo and the residue, dissolved in chloroform, until neutral washed.

The organic layer was again evaporated to dryness and the Residue was dissolved in acetone and washed with 1096 aqueous ammonia until basic treated. The reaction was complete after 20 minutes and after the usual work-up measures two products were obtained: 4-demethoxy-8-methyl-daunomycinone and its 7-epimer.

The residue was based on silica gel (chloroform / acetone = 98: 2 on volume, as eluent) chromatographed, yielding 0.2 g of the desired Aglycons (m.p. 227-2280C) were obtained. The 7-epimeric aglycone can be converted into the Aglycon with the natural configuration by treatment with dilute trifluoroacetic acid according to the procedure according to J.Am. Chem. Soc., 98, 1967 (1976).

Example 2 4-Demethoxy-1,4-dimethyl-8-methyl-daunomycinone (II: R1 = R4 = CH3; R2 = R5 = H) Example 1 was repeated, except that the 3,6-dimethylphthalic acid monomethyl ester monochloride was used instead of the phthalic acid monomethyl ester monochloride in step (j). At the end the compound named in the heading was obtained.

Example 3 4-Demethoxy-2,25-dimethyl-8-methyl-daunomycinone (II: R1 = R5 = H; R2 = R4 = CH3) Example 1 was repeated, except that 4,5-dimethylphthalic acid monomethyl ester monochloride was used used instead of the phthalic acid monomethyl ester monochloride in step (j). At the Finally, the compound named in the heading was obtained.

Example 4 (+) - 4-Demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin (VIe R1 = R2 = R5 = H; R4 = CH3) To a solution of 0.5 g of 4-demethoxy-8-methyl-caunomycinone, prepared according to Example 1, and 0.35 g of 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl a-L-lyxopyranosyl chloride (1-chloro-N, O-bis-trifluoroacetyl-daunosamine) in 50 ml anhydrous Methylene dichloride was 0.49 g of silver trifluoromethanesulfonate in 10 ml of anhydrous Diethyl ether added with stirring at ambient temperature. After 1 h it became The reaction mixture was washed with an aqueous sodium bicarbonate solution and dried to dryness evaporated. The residue was dissolved in methanol, which contained a catalytic amount of triethylamine contained, dissolved and allowed to stand for 2 hours at ambient temperature.

The solvent was removed in vacuo and the residue became on silica gel (chloroform / acetone = 95: 5, expressed by volume, as eluent) chromatographed, whereby 260 mg (+) - 4-demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin (Mp. 125 to 1280C) and 130 mg of the diastereomeric (-) -demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin (M.p. 140 to 1420C).

Example 5 (+) -4-Demethoxy-8-methyl-daunorubicin (XVIh: R1 = R2 = R5 = H; R4 = CH3) To a solution of 175 mg of sodium hydroxide in 30 ml of water, a rapid Bubbled in a stream of nitrogen. Then 260 mg of 4-demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin, dissolved in 20 ml of acetone, added with stirring and the reaction mixture was 1 left to stand at room temperature for h. After acidification with 2N hydrochloric acid and faster The product was neutralized with an aqueous sodium bicarbonate solution Chloroform was extracted and the organic layer was concentrated in vacuo and treated with methanolic hydrogen chloride. 85 mg of 4-demethoxy-8-methyl-daunorubicin in the form of the hydrochloride were precipitated and collected by adding diethyl ether (M.p. 145 to 1480C); [a] D = (+) 1280 (c = 0.15 'methanol).

Example 6 (-) - 4-Demethoxy-8-methyl-daunorubicin (XVIh: R1 = R2 = R5 = H; R4 = CH3) The procedure was as in Example 5, with 100 mg of (-) - 4-demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin were used as the starting material. There were 50 mg (-) - 4-demethoxy-8-methyl-daunorubicin hydrochloride obtained (m.p. 148 to 1500C); [α] D20 = -250 ° (c = 0.1% methanol).

Example 7 (+) - 4-Demethoxy-8-methyl-daunomycinone (II: R1 = R2 = H; R4 = R5 = CH3) 4.5 mg (+) - 4-demethoxy-8-methyl-daunorubicin hydrochloride were dissolved in 0.2 N hydrochloric acid dissolved and the solution was treated in a sealed tube at 90 ° C. for 1 hour. After filtering and washing with water, 2.5 mg of (+) - 4-demethoxy-8-methyl-daunomycinone were obtained obtain; [a] 20 = +1160 (c = 0.194 dioxane).

Example 8 (-) - 4-Demethoxy-8-methyl-daunomycinone (II: R1 = R2 = H; R4 = R5 = CH3) The procedure was as in Example 7, using 4.66 mg of (-) - 4-demethoxy-8-methyl-daunorubicin hydrochloride as the starting material were used. 3 mg (-) - 4-demethoxy-8-methyldaunomycinone were obtained; [a120 = 1160 (c = 0.1% dioxane).

Example 9 (+) - 4-Demethoxy-1,4-dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin (XVIe: R1 = R4 = CH3; R2 = R5 = H) Following the procedure of Example 4, using of 4-demethoxy-1,4-dimethyl-8-methyl-daunomycinone, prepared according to Example 2, as starting material (+) - 4-demethoxy-1,4-dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin and (-) - 4-demethoxy-1,4-dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin.

3 e i 5 p i e 1 10 (+) - 4-demethoxy-1,4-dimethyl-8-methyl-daunorubicin (XVIh: Ri = R4 = CH3; R2 = R5 = H) Following the procedure of Example 5 and using of (+) - 4-demethoxy-1,4-dimethyl-8-methyl-N-trifluoro acetyl-daunorubicin, prepared according to Example 9, the starting material was (+) - 4-demethoxy-1,4-dimethyl-8-methyldaunorubicin hydrochloride manufactured.

B e i 5 p i e 11 (-) - 4-demethoxy-1,4-dimethyl-8-methyl-daunorubicin (XVIh: R1 = R4 = CH3; R2 = R5 = H) Following the procedure of Example 5 and using of (-) - 4-demethoxy-1,4-dimethyl-8-methyl-N-trifluoroacetyldaunorubicin according to Example 9, the starting material was (-) - 4-demethoxy-1,4-dimethyl-8-methyl-daunorubicin hydrochloride manufactured.

End of description.

Claims (10)

Anthracycline derivatives, processes for their preparation and pharmaceuticals containing these compounds Patent claims Anthracycline derivatives of the general formula (I) in which one of the substituents R1 and R2 is a hydrogen atom and the other is a hydrogen atom or a methyl group; R3 represents a daunosaminyl, 4-epi-daunosaminyl, 3,4-bis-epi-daunosaminyl or 4-deoxydaunosaminyl group or an N-trifluoroacetyl derivative thereof; R4 represents an alkyl group having 1 to 4 carbon atoms; and R5 represents a hydrogen atom or a hydroxy group, and the pharmaceutically acceptable salts thereof. 2. (+) -, (+) - or (-) - 4-demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin as well as its hydrochloride. 3. (+) -, (+) - or (-) - 4-demethoxy-8-methyl-daunorubicin and its Hydrochloride. 4. (+) -, (+) - or (-) - 4-demethoxy-1,4-dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin as well as its hydrochloride. 5. (+) -, (+) - or (-) - 4-demethoxy-1,4-dimethyl-8-methyldaunorubicin as well as its hydrochloride. 6. Process for the preparation of anthracyclin derivatives of the general formula (I) according to claim 1, characterized in that an anthracyclinone of the general formula (11) in which R1, R2 and R4 have the meanings given in claim 1 and R5 stands for a hydrogen atom, with a 1-halogen-N, O-bis-trifluoroacetyl-daunosamine, a 1-halogen-N, O-bis-trifluoroacetyl- 4-epi-daunosamine, a 1-halo-N, O-bis-trifluoroacetyl-3, 4-bis-epi-daunosamine or a 1-halo-N-trifluoroacetyl-4-deoxy-daunosamine in an organic solvent in the presence of a soluble silver salt is condensed as a catalyst, and the O-trifluoroacetyl group, if present, is removed by treatment with methanol in the presence of triethylamine as a catalyst, and that optionally either one or both of the following steps (a) removal of the N-trifluoroacetyl group by mild alkaline hydrolysis and (b) converting the resulting daunorubicin derivative to a doxorubicin derivative by reacting it with bromine and treating the resulting 14-bromo derivative with aqueous sodium formate. 7. The method according to claim 6, characterized in that as The silver salt used is silver trifluoromethane sulfonate. 8. The method according to claim 6 or 7, characterized in that one used as organic solvent dichloromethane or chloroform. 9. The method according to any one of claims 6 to 8, characterized in that that the 1-halogen substituent in the daunosamine derivative with which the anthracyclinone is condensed, is a 1-chloro substituent. 10. Medicinal product, characterized in that there is a compound according to any one of claims 1 to 5 in admixture with a pharmaceutically acceptable diluent or contains carrier.