GB2067552A

GB2067552A - Anthracycline derivatives

Info

Publication number: GB2067552A
Application number: GB8034323A
Authority: GB
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1980-01-16
Filing date: 1980-10-24
Publication date: 1981-07-30
Also published as: GB2067552B

Abstract

Anthracycline derivatives I of the formula:- <IMAGE> and salts thereof, wherein R1 = H or CH3, R2 = H or CH3, R1 = R2 = CH3 excepted, R4 = C1-C4 alkyl, R5 = H or OH, R3 = daunosaminyl, 4-epidaunosaminyl, 3,4-bis-epi-daunosaminyl or 4-deoxy-daunosaminyl or an N-trifluoroacetyl derivative thereof, may be prepared by condensing an anthracyclinone (I, R3 = R5 = H) with an appropriate trifluoroacetyl-daunosamine derivative. Any O-trifluoroacetyl group present may be removed by treatment with methanol in the presence of N(C2H5)3 and the N-trifluoroacetyl group can be removed by mild alkaline hydrolysis. The anthracycline derivatives I are useful as antitumour agents, and may be formulated as pharmaceutical compositions.

Description

SPECIFICATION Anthracycline derivatives The invention relates to new antitumour agents and to a process for their preparation.

The invention provides anthracycline derivatives of the general formula

wherein one of R, and R2 represents a hydrogen atom, the other of R, and R2 represents a hydrogen atom or a methyl group, R3 represents a daunosaminyl, 4-epi-daunosaminyl, 3,4-bisepi-daunosaminyl or 4-deoxydaunosaminyl group or an N-trifluoroacetyl derivative thereof, R4 represents an alkyl group having from 1 to 4 carbon atoms, and R5 represents a hydrogen atom or a hydroxy group, and pharmaceutically acceptable salts thereof.

The starting materials for the preparation of the new anthracycline glycosides of formula I are the hitherto unknown aglycones of the general formula II

wherein R1, R2 and R4 have the meanings given above and R5 represents a hydrogen atom.

The synthesis of the anthracyclinones II may be accomplished as outlined in the following scheme:

Compound Ill is selectively transformed in the monoketal IV, the reaction being carried out in a solvent such as benzene or toluene, in the presence of ethylene glycol and anhydrous paratoluenesulphonic acid. Compound IV, on treatment with lithium aluminium hydride in anhydrous tetrahydrofuran, affords V which in turn, is converted into VI by treatment with paratoluenesulphonic acid in benzene or toluene.

By reduction of VI with lithium aluminium hydride in anhydrous tetrahydrofuran, VII is obtained and then converted into VIII on treatment with tmchloroperbenzoic acid in methylene dichloride or chloroform. By means of benzyl bromide in the presence of a base such as sodium hydride VIII is converted into IX. The oxirane ring of IX is cleaved by R4Mg X (R4 being as defined above and X representing a halogen atom) on heating in benzene to give compound X.

Catalytic hydrogenation of X on Pd/C affords Xl, which is oxidized to XII on treatment with dicyclohexyl carbodiimide/dimethylsulfoxide in benzene. By a Friedel-Craft's type reaction with a phthalic acid monomethyl ester monochloride substituted or not in the aromatic ring, in the presence of aluminium chloride, and subsequent hydrolysis and treatment with liquid hydrofluoric acid, XIII is obtained and then converted into the ketal XIV by conventional methods.

Compound XIV, on treatment with N-bromosuccinimide in carbon tetrachloride in the presence of light and subsequent acidic methanolysis, is transformed into XV which, in turn, by means of aluminium chloride in methylene dichloride and then of trifluoroacetic acid affords II together with small amounts of the 7 epimers, which can be converted into II, having the 7-a- OH, following the equilibration procedure described in J. Am. Chem. Soc. 98, 1 967 (1976).

The invention further provides a process for the preparation of an anthracycline derivative of the general formula I in which R5 represents a hydrogen atom and R1, R2, R3 and R4 are as herein defined, the process comprising condensing an anthracyclinone of the general formula II as herein defined with a 1-halo-N, O-bis-trifluoroacetyl-daunosamine, l-halo-N, O-bis-trifluoroace- tyl-4-epi-daunosamine, 1-halo-N, O-bis-trifluoroacetyl-3-4-bis-epi-daunosamine or 1-halo-N-trifluo- roacetyl-4-deoxy-daunosamine in an organic solvent, such as dichloromethane or chloroform, in the presence of a soluble silver salt, such as silver tirfluoromethane-sulphonate, as catalyst, and removing, if present, the O-trifluoroacetyl group by treatment with methanol in the presence of triethylamine as catalyst, and optionally removing the N-trifluoroacetyl group by mild alkaline hydrolysis.

The doxorubicin derivatives of the general formula I in which R5 represents a hydroxy group and R,, R2, R3 and R4 are as herein defined can be prepared from the corresponding daunorubicin derivatives of the general formula I in which R5 represents a hydrogen atom and R,, R2, R3 and R4 are as herein defined. This preparation, within the scope of the invention, comprises reacting the daunorubicin derivative I with bromine and treating the resultant 14bromo-derivative with aqueous sodium formate. The reaction conditions are preferably those described in United States Patent Specification No 3803124.

The 1-halo substituent in the daunosamine derivative which is condensed with the anthracyclinone of the general formula II is preferably a 1-chloro substituent. The reaction conditions of this condensation are preferably those described in United States Patent Specification No 4046878.

These processes are illustrated with reference to the formula XVI.

a) Re = NHCOCF3, R8 = OCOCF3, R7 = R9 = H b) Re = NHCOCF3, Rg = OCOCF3, R7 = R8 = H c) R7 = NHCOCF3, R9 = OCOCF3, Re = R8 = H d) R6 = NHCOCF3, R7 = R8 = R9 = H e) Re = NHCOCF3, R8 = OH, R7 = R9 = H f) R6 = NHCOCF3, R9 = OH, R7 = Rs = H g) R7=NHCOCF3, R9=OH, Re=R8=H h) Re = NH2, R8 = OH, R7 = R9 = H i) R6 = NH2, R9 = OH, R7 = R8 = H j) R7 = NH2, R9 = OH, Re = R8 = H k) Re = NH2, R7 = R8 = Rg = H The condensation leads to compounds XVI a-d.

Compounds XVI a-c, on treatment with methanol and catalytic amounts of triethylamine, are converted to XVI e-g in which the sugar amino group is still protected as trifluoroacetyl derivative. The latter can be hydrolyzed to give the free amino derivatives XVI h-j by mild alkaline treatment as described in the Examples below, similar hydrolysis of XVI d giving XVI k.

The conversion of XVI h-k into I (R5 = OH) is performed in accordance with the method claimed in United States Patent Specification No. 3,803,124 for the chemical transformation of daunorubicin into doxorubicin.

The new compounds I display antimitotic acitivity and are useful therapeutic agents for the treatment of tumour diseases. Accordingly the invention further provides a pharmaceutical composition comprising an anthracyline derivative of the general formula I or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent in carrier.

The following Examples illustrate the invention.

EXAMPLE 1 4-Demethoxy-8-methyldaunomycincone (Il: Rl = R2 = R5 = H, R4 = CH3) a) 1,4-Dimethoxy-6-(1', 1 '-ethylendioxyethyl)-tetral-8-one (IV) 25 g of 1 ,4-dimethoxy-6-acetyl-tetral-8-one (lit) were dissolved in 400 ml of anhydrous benzene containing 56.6 ml of ethylene glycol and 1.87 g of anhydrous para-toluenesulphonic acid. 1 equivalent of water was azeotropically distilled and a saturated aqueous solution of sodium bicarbonate was added until the pH was approximately 8. The reaction mixture was then extracted with benzene. The organic layer was washed with water and evaporated to dryness.

Crystallization from methanol afforded 19 g of the ketal in pure form (m. p. 138-140 ).

b) 1,4-Dimethoxy-6-(1', 1'-ethylenedioxyethylJ-tetral-8-ol (V) 40 g of 1 ,4-dimethoxy-6-(1 ',1 '-ethylenedioxyethyl)-tetral-8-one IV, prepared as described in Example la, were dissolved in 400 ml of anhydrous tetrahydrofuran and 12.5 g of lithium aluminium hydride were added; after 2 hours the reaction was complete and, after conventional work-up procedures, 40 g of the title compound were obtained (m.p. 93-95"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 as described in Example 1 b, were dissoved in 1.7 1 of benzene and a slow flow of argon was bubbled through the solution for 10 minutes. 4 g of para-toleunesulphonic acid monohydrate were added and the reaction mixture was refluxed for 1 hour under an argon atmosphere. After cooling the solution and washing it with an aqueous solution of sodium bicarbonate and with water until neutrality, the solution was evaporated to dryness. The residue was then dissolved in methylene dichloride and 24 g of the desired product was obtained on treatment with diisopropyl ether (m.p.

12 124 C).

d) 1, 4-Dimethoxy-6-( 1 '-hydroxyethyl)-6, 7-dihydrotetralin (VII) 4.5'g of lithium aluminium hydride were added portionwise to 150 ml anhydrous tetrahydrofuran, and after cooling on a water bath, 14.4 g of 1,4-dimethoxy-6-acetyl-6,7-dihydrotetralin VI, prepared as described in Example 1 c, dissolved in 50 ml of anhydrous tetrahydrofuran, were added dropwise. within 30 minutes the reaction was over, and after conventional work-up procedures, 14 g of pure product (m.p. 100-102"C) were obtained.

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 in oil were added portionwise to 200 ml an hydros tetrahydrofuran. 10.2 g of 1 ,4-dimethoxy-6-(1 '-hydroxyethyl)6,7-dihydrotetralin (VII), prepared as described in Example 1d, and 8 ml of benzyl bromide in 20 ml tetrahydrofuran were then added. After refluxing for 12 hours, the reaction mixture was cooled and methanol was added to eliminate the excess sodium hydride. After washing with water, the solution was evaporated to dryness and the residue crystallized from methanol. 6.5 g of the title product (m.p. 69-70"C) were obtained.

f) 1, 4-Dimethoxy-6-( 1 '-benzyloxyethyl)-6, 7-epoxytetralin (IX) 8.6 g of 70% tmchlornperbenzoic acid were dissolved in 130 ml of methylene dichloride and 10 g of 1 ,4-dimethoxy-6-(1 '-benzyloxyethyl)-6,7-dihydrotetralin (VIII), prepared as described in Example 1 e, were added. Within 1 hour the reaction was complete. After washing with water and evaporating to dryness, the crude product is chromatographed (silica gel, petroleum ether; petroleum ether:diethyl ether) to afford 6.5 g of 1 ,4-dimethoxy-6-(1 '-benzyloxyethyl)-6,7-epoxytetralin (m.p. 102-105", after crystallization from diethyl ether:petroleum ether).

g) 1,4-Dimethoxy-6-(1 '-benzyloxyethyl)-6-hydroxy-7-methyl-tetralin (X: R4 = CH3) Under nitrogen atmosphere, 3.6 g of magnesium turnings were suspended in 150 ml of anhydrous diethyl ether and a rapid stream of methyl bromide was bubbled through the suspension. The reaction took place rapidly and 150 ml of diethyl ether were added. After consumption of the magnesium, the diethyl ether was distilled off and replaced with 300 ml of anhydrous benzene. 3 g of 1 ,4-dimethoxy-6-)1 '-benzyloxyethyl)-6,7-epoxytetralin (IX), prepared as described in Example 1f, dissolved in 150 ml of anhydrous benzene, were rapidly added. The reaction mixture was refluxed for 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, on treatment with petroleum ether, 2 g of 1 ,4-dimethoxy-6-(1 '-benzyloxyethyl)-6-hydroxy-7-methyltetralin (m.p. 113-115 C) were obtained.

h) 1,4-Dimethoxy-6-(1 '-hydroxyethyl)-6-hydroxy- 7-methyl-tetralin (Xl: R4 = H) 2.3 g of 1.4-dimethoxy-6-( 1 ,4-dimethoxy-6-(1 '-benzyloxyethyl)-6-hydroxy-7-methyltetralin (X: R4 = CH3), pre- pared as described in Example Ig, were dissolved in 50 ml absolute ethanol. 400 mg of paratoleunesulphonic acid monohydrate and 330 mg of 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 and the solution was evaporated to dryness to afford 1.6 g of 1,4dimethoxy-6-(1 '-hydroxyethyl)-6-hydroxy-7-methyl-tetralin (m.p. 119"C, after crystallization from benzene).

i) 1, 4-Dimethoxy-6-acetyl-6-hydroxy- 7-methyl-tetralin (XII: R4 = C H 3) Under a nitrogen atmosphere, 0.5 g of 1 ,4-dimethoxy-6-('-hydroxyethyl)-6-hydroxy-7-methyl- tetralin (Xl: R4 = CH3), prepared as described in Example 1 h, were dissolved in 2.7 ml of anhydrous dimethylsulphoxide and 2.7 ml of anhydrous benzene; 0.1 4 ml of pyridine and 0.07 ml of trifuloroacetic acid and 1.12 g dicyclohexylcarbodiimide were added. After standing for one night at ambient temperature the reaction mixture was poured into an aqueous solution of oxalic acid, extracted with benzene and washed with water. After removal of the solvent in vacuo, the residue was dissolved in acetone, the solid filtered off and the solvent evaporated off again in vacuo.After chromatography on silica gel using chloroform as eluant 0.2 g of 1,4dimethoxy-6-acetyl-6-hydroxy-7-methyl-tetralin were obtained (m.p. 114-115.5 C).

j) 4-Demethoxy-6. 7, 1 1-trideoxy-6, 11-dimethoxy-8-methyl-daunomycinone (XIII: R, = R2 = H, R4 = CH3) 2.3 g of phthalic acid monomethylester monochloride, dissolved in 4 ml of anhydrous methylene dichloride, were added dropwise to a suspension of 1.5 g of anhydrous aluminium chloride in 5 ml of anhydrous methylene dichloride cooled to - 10"C. 0.5 g of 1,4-dimethoxy6-acetyl-6-hydroxy-7-methyl-tetralin (XII: R = CH2), prepared as described in Example li. in 5 ml of methylene dichloride were added dropwise.The reaction mixture was kept for 5 hours at a temperature ranging between - 10 and - 5"C. It was then diluted with 100 ml of methylene dichloride and washed until neutrality. The solution was evaporated to dryness and the residue dissolved in 1 2 ml of 96% ethanol.

1.6 g of potassium hydroxide in 8 ml of water were added and the reaction mixture was heated for 2 hours at 60 C. The solvent was evaporated off in vacuo. The residue was dissolved in water and extracted with chloroform, the aqueous layer is acidified with 2N hydrochloric acid and extracted with chlorofrom: the solvent was evaporated therefrom and the residue was poured in a KCI-F vessel and 10 ml anhydrous hydrofluoric acid are added. After 3 hours the hydrofluoric acid was distilled off in vacuo. and the residue was dissolved in chloroform and washed until neutrality. After evaporation and chromatography on silica gel using chloroform as eluant, 250 my of 4-demethoxy-6,7.1 11-trldeoxy-6,11-dimethoxy-8-methyl-daunomycinone (m.p.

186-188 C) were obtained.

k) 4-Demethoxy-6. 7, 1 1-trideoxy-6, 1 1-dimethoxy-8-methyl-9-(1', 1 '-ethylenedioxyethyl)-daunomy- cinone(XlV: Ra = R = H. R, = CH,) 1 g of 4-demethoxy-6.7,1 1rideoxy-6.1 11-dimethoxy-8-methyl-daunomycinone (Xlil: R = R, = H, R,l = CH:,), prepared as described in Example 1 j, were added to 1.5 ml of ethylene glycol and 1 g of anhydrous para-toluenesulphonic acid in 100 ml of anhydrous benzene. The water formed during the reaction was azeotropically distilled until the starting material disappeared.After washing and chromatography of the crude produce on silica gel using chloroform as eluant. 0.9 g of 4-demethoxy-6,7,1 1-trideoxy-6,1 1-dimethoxy-8-methyl-9-(1',11- ethylenedioxyethyl)-daunomycinone (m.p. 1 64-1 66 C) were obtained.

I) 4-Demethoxy-6. 7, 1 1-trideoxy-6, 1 1-dimethoxy-8-methyl-daunomycinone (XV: R, = R2 = H, R4 = CH,) 3 g of 4-demethoxy-6.7,11 -trideoxy-6, 11 -dimethoxy-8-methyl-9-( ',1 '-ethylenedioxy-ethyl)daumomycinone (XIV: R, = R, = H, R4 = CH3). prepared as described in Example 1 k, were dissolved in 95 ml of carbon tetrachloride on heating by a 500 watt tungsten iamp; 1.68 g of N-bromosuccinimide were added and the reaction mixture was refluxed for 20 minutes.

The solvent was partially distilled off, the solid was filtered off and washed with diethyl ether; the washings were evaporated to dryness and the residue was dissolved in 95 ml of anhydrous methanol. After refluxing for 1 hour, 38 ml of 10% aqueous hydrochloric acid were added and the mixture was refluxed for an additional hour. After conventional work-up procedures and chromatography on silica gel (chloroform as eluant), 0.7 g of 4-demethoxy-6,7,1 1-trideoxy- 6,7,11 -trimethoxy-8-methyl-daunomycinone was obtained as an oil.

m) 4-Demethoxy-8-methyl-daunomycinone and its 7-epimer(ll: R = R2 = H, R4 = R5 = CH3) 1 g of 4-demethoxy-6,7,11 -trideoxy-6,7,11 -trimethoxy-8-methyldaunomycinone (XV: R1 = R? = H, R4 = CH3), prepared as described in Example 11, was dissolved under a nitrogen atmosphere in 100 ml of an hydros methylene dichloride cooled to O"C and 2 g of anhydrous aluminium chloride were added. The reaction went to completion on standing at O"C for 45 minutes.

30 g of oxalic acid in 60 ml of water added under stirring which was continued for 30 minutes. After extraction with methylene dichloride and washing with water, the solvent was evaporated off and the residue was dissolved in 1 5 ml of trifluoroacetic acid containing 2% of water. On standing for 1 night at ambient teniperature the reaction went to completion. The solvent was distilled off in vacuo and the residue, dissolved in chloroform, washed until neutrality.

The organic layer was again evaporated to dryness and the residue was dissolved in acetone and treated with 10"/o aqueous amrnonia until basic. Within 20 minutes the reaction was complete and, after usual work-up procedures, afforded two products: 4-demethoxy-8-methyldaunomycinone and its 7-epimer.

The residue was chromatograFhed on silica gel (chloroform:acetone 98:2 by volume as eluant) to afford 0.2 g of the desired aglycone (m.p. 227-228'C). The 7-epimeric aglycone can be converted into the aglycone having the natural configuration by treatment with dilute trifluoroacetic acid, according to the procedure described in J. Am. Chem. Soc, 98 1967 (1976).

EXAMPLE 2 4-Demethoxy-1 4-dimethyl-8-methyl-daunomycínone (Il: R1 = R4 = CH, R, = H = H).

Example 1 was repeated, but 3.6-dimetlyIphthalic acid monomethylester monochloride was substituted for phthalic acid monomethylester monochoride in step (j), ultimately yielding the title compound.

EXAMPLE 3 4-Demethoxy-2,3-dimethyl-8-methyl-daunomycinone (ll: H1 = R5 H, R2 = H4=CH3) Example 1 was repeated, but 4,5-dimethylphthalic acid monomethyl ester monochloride was substituted for phthalic acid monomethylester monochloride in step (j), untilmately yielding the title compound.

EXAMPLE 4 (+)4-Demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin (XVle: R1 = R2 = R5 = H, R4 = CH3) To a solution of 0.5 g of 4-demethoxy-8-methyl-daunomycinone, prepared as described in Example 1, and 0.35 g of 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-α-L-lyxopyrano- syl chloride (1-chloro-N,O-bis-trifluoroacetyldaunosamine) in 50 ml of anhydrous methylene dichloride, 0.49 g of silver trifluoromethanesulphonate in 10 ml of anhydrous diethyl ether were added under stirring at ambient temperature. After 1 hour the reaction mixture was washed with an aqueous solution of sodium bicarbonate and evaporated to dryness. The residue was dissolved in methanol containing a catalytic amount of triethylamine and allowed to stand at ambient temperature for two hours.

The solvent was removed in vacuo and the residue chromatographed on silica gel (chloroform:acetone 95:5 by volume as eluant) to give 260 mg of (+ )4-demethoxy-8-methyl-Ntrifluoroacetyl-daunorubicin (m.p. 125-128 C) and 130 mg of the diastereomeric (- demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin (m.p. 140-142 C).

EXAMPLE 5 ()4-Demethoxy-8-methyl-daunorubicin (XVlh: R1 = R2 = R5 = H, R4 = CH3) Into a solution of 175 mg of sodium hydroxide in 30 ml of water was bubbled a rapid stream of nitrogen. Then 260 mg of 4-demethoxy-8-methyl-N-trifluoroacetyl-daunorubicin, dissolved in 20 ml of acetone, were added under stirring and the reaction mixture was allowed to stand for 1 hour at room temperature.After acidification with 2N hydrochloric acid and rapid neutralization with an aqueous solution of sodium bicarbonate, the product was extracted with chloroform 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 its hydrochloride were precipitated by addition of diethyl ether and collected (m.p. 145-1 48'C); [a]D = ( + )1 28' (c = 0.1% metha nol).

EXAMPLE 6 (-)4-Demethoxy-8-methyl-daunorubicin (XVlh: R, = R2 = R5 = H, R4 = CH3) Operating as described in Example 5 and using 100 mg of (- )4-demethoxy-8-methyl-N- trifluoroacetyl-daunorubicin as starting material, 5Q mg of (-)4-demethoxy-8-methyl-daunorubi- cin hydrochloride were obtained. m.p. 148-150 C; [ai20= = 250 (c = 0.1% methanol).

EXAMPLE 7 (+ )4-Demethoxy-8-methyI-daunomycinone (ll: R = R2 = H, R4 = H5 = CH3).

4.5 mg of (+ )4-demethoxy-8-methyl-daunorubicin hydrochloride were dissolved in 0.2N hydrochloric acid and the solution was treated at 90 C for 1 hour in a sealed tube. After filtration and washing with water 2.5 mg of (+ )4-demethoxy-8-methyl-daunomycinone were obtained. [a10= + 116 (e = 0.1% dioxan).

EXAMPLE 8 (-)4-Demethoxy-8-methyl-daunomycinone (ll: R = R2 = H, R4 = R5 = CH) Operating as described in Example 7 and using as starting material 4.66 mg of (- demethoxy-8-methyl-daunorubicin hydrochloride, 3 mg of ( - )4-de methoxy-8-methyl-da u nomy- cinone were obtained [lt]2g= - 116 (c = 0.1 % dioxan).

EXAMPLE 9 ( 4-Demethoxy- 1 4-dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin (XVle: R1 = R4 = CH3; R.= R5 = H) Following the procedure described in Example 4 and using as starting material 4-demethoxy1,4-dimethyl-8-methyl-daunomycinone, prepared according to Example 2, (+ )4-demethoxy-1 ,4- dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin and (- )4-dimethyl-8-methylN-trifluoroacetyldaunorubicin were obtained.

EXAMPLE 10 (+)4-Demethoxy-1,4-dimethyl-8-methyl-daunorubicin (XVlh: R1 = R4 = CH2, R2 = R5 = H) Following the procedure described in Example 5 and using as starting material ( + )4- demethoxy-1,4-dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin, prepared according to Example 9, (+)4-demethoxy-l , 4-dimethyl-8-methyl-daunorubicin hydrochloride was prepared EXAMPLE 11 (- )4-Demetlioxy-1,4-dimethyl-8-methyl-daunorubicin (XVlh: H1 = R4 = CH3, R7 = R, = H) Operating as described in Example 5 and using as starting material (- )4-demethoxy-1 .4- dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin prepared according to Example 9. 1 (- )4-deme- thoxy- 1 .4-dimethyl-8-methyl-daunorubicin hydrochloride was obtained.

Claims

1. An anthracycline derivative of the general formula I as herein defined or a pharmaceutically acceptable salt thereof.

2. (t) - , (+ ) - or (- )-4-demethoxy-8-methykN-trifluoroacetyl-daunorubicin or a hydrochloride thereof.

3 (t + , ( + ) - or (- )-4-demethoxy-8-methyl-daunorubicin or a hydrochloride thereof.

4. ( ) - (+) or (-)-4-demethoxy-1,4-dimethyl-8-methyl-N-trifluoroacetyl-daunorubicin or a hydrochloride thereof.

5. (TD) - , (+) or , - )-4-demethoxy-1 .4-dimethyl-8-methyl-daunorubicin or a hydrochloride thereof.

6 A process for the preparation of an anthracycline derivative of the general formula I as herein defined, the process comprising condensing an anthracyclinone of the general formula II as herein defined with a 1-halo- N.O-bis-trifluoroacetyl-daunosamine, a 1-halo-N,O-bis-trifluoroa- cetyl-4-epi-daunosamine, a 1-halo-N, O-bis-trifluoroacetyl-3. 4-bis-epi-daunosamine or a 1-halo-Ntrifluoroacetyl-4-deoxy-daunosamine in an organic solvent in the presence of a soluble silver salt as catalyst, and removing, if present, the Otrifluoroacetyl group by treatment with methanol in the presence of triethylamine as catalyst, and optionally carrying out either or both of the steps of (a) removing the N-trifluoroacetyl group by mild alkaline hydrolysis, and (b) converting the resultant daunorubicin derivative to a doxorubicin derivative by reaction with bromine and treatment of the resultant 14-bromo-derivative with aqueous sodium formate.

7. A process according to claim 6 in which the silver salt is silver trifluoromethane sulphonate.

8. A process according to claim 6 or claim 7 in which the organic solvent is dichloromethane or chloroform.

9. A process according to any of claims 6 to 8 in which the 1-halo substituent in the daunosamine derivative with which the anthracyclinone is condensed is a 1-chioro substituent.

10. A pharmaceutical composition comprising a compound according to any of claims 1 to 5 in admixture with a pharmaceutically acceptable diluent or carrier.

11. A process for the preparation of an anthracyline derivative of the general formula I as herein defined, the process being substantially as described herein with reference to any of Examples 4 to 6 or 9 to 11.