DE3422735A1 - 6-Deoxyanthracyclinones, anthracycline glycosides, process for their preparation and pharmaceuticals which contain these - Google Patents

Abstract

A process for the preparation of 6-deoxyanthracyclinones of the general formula (I) <IMAGE> in which R is a hydrogen atom, a hydroxyl group or a lower alkoxy group, is described. The process provides a total synthesis of the 6-deoxyanthracyclinones of the formula (I) using a 1,2,3,6-tetrahydrophthalate as starting material. The resulting racemic mixture of the compounds of the formula (I) can, if required, be subjected to optical resolution by the conventional method of conversion into diastereomeric derivatives using a chiral resolving agent. On the other hand, the racemic mixture can be used as such for condensation with a suitably protected halogeno-sugar derivative to obtain alpha -glycosidic derivatives of the formula (XV) <IMAGE> in which R1 is a hydrogen atom or a hydroxyl group, one of R2 and R3 is hydrogen and the other is hydrogen or a hydroxyl group, and X is a hydrogen atom or a trifluoroacetyl group. The N-trifluoroacetyl 7S:9S and 7R:9R derivatives of alpha -glycosides of the formula (XV) can ... <??>Original abstract incomplete.

Description

6-Deoxyanthracyclinones, anthracycline glycosides, processes for their preparation and pharmaceuticals containing them

The present invention relates to a process for the preparation of 6-deoxyanthracyclinones, to certain of them 6-Deoxyanthracyclinone, on certain anthracycline glycosides, prepared from these, on those anthracycline glycosides in pharmaceutical compositions and the preparation of these anthracycline glycosides.

The invention relates first to a process for the preparation of 6-deoxyanthracyclinones of the general Formula (I)

(D,

wherein R is a hydrogen atom, a hydroxyl group or a means lower alkoxy group. The procedure illustrated in the following reaction scheme comprises:

(1) the acetylation of dimethyl 1,2,3,6-tetrahydrophthalate

(II) by treatment with acetic anhydride in the presence of tin tetrachloride, followed by treatment with a mild base or a mild acid,

(2) the reaction of the resulting dimethyl 1,2,3,6-tetrahydro-4-acetylphthalate (III) with tosylhydrazine,

(3) reducing the resulting dimethyl 1,2,3,6-tetrahydro-4- (1-tosylhydrazoethyl) phthalate (IV) with catechol borane and subsequent rearrangement of the double bond from an endocyclic to an exocyclic one Position in the presence of sodium acetate,

(4) oxidizing the resulting 1,2-di (methoxycarbonyl) -4-ethylidene-cyclohexane (V) with potassium permanganate and treating the resulting ot-hydroxyketone with ethylene glycol in the presence of a catalytic component of p-toluenesulfonic acid,

(5) condensing the resulting 2-methoxycarbonyl-5- [2-methyl-dioxolan-2-yl] -6-oxa-bicyclo [3.2.1] octan-7-one (VI) with a compound of the general formula (VIII), in which R has the above meaning (obtained by the action an alkyllithium compound to a compound of the general formula (VII), in which R has the above meaning),

(6) the opening of the lactone ring and removal of the protecting group of the dioxolane-protected keto group in the compound of the general formula (IX) obtained, wherein R is the above Has meaning through methanolysis,

(7) reducing the keto groups of the compound of the general formula (X) obtained, wherein R is as defined above has, by treatment with a pyridine-borane complex in the presence of trifluoroacetic acid and conversion the methoxycarbonyl group into a benzyloxycarbonyl group by treatment with phenyldiazomethane,

(8) esterifying the hydroxy groups and deesterifying the benzyloxycarbonyl group in the compound of the general formula (XI) obtained, in which R has the above meaning, by treatment with acetic anhydride in pyridine in the presence of 4-dimethylaminopyridine followed by holding on Reflux with cyclohexene in the presence of a palladium on carbon catalyst,

(9) cyclizing the resulting compound of the general Formula (XII) wherein R 'represents a hydrogen atom, an acetoxy group or a lower alkoxy group Treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid and hydrolyzing the acetoxy groups with sodium methylate,

(10) oxidizing the 1-hydroxyethyl group of the resulting compound of the general formula (XIII), wherein R has the above meaning, with silver carbonate and oxidative
Demethylating the compound obtained with aluminum trichloride in nitrobenzene and

(11) protecting the 13-keto group of the resulting compound
of the general formula (XIV) by treatment with
Ethylene glycol, bromination of the compound obtained

C-7 by treatment with bromine or N-bromosuccinimide in the presence of 2,2'-azobis (isobutyronitrile ·) and hydrolyze the 7-bromo and 13-ketal groups.

H ₃ COOC

(ID

H ₃ CCOC

H ₃ CCOC

H ₃ COOC

H ₃ COOC

(III)

(IV)

, CCOC ^^^ y ^

(V)

(VI)

it «■ * ■ ν vf ν

AH

COL

OCH,

R OCH.

COL

(VII)

(VT)

(VIII)

OCH

(IX)

OCH

3 OCH

OCH

R OCH-

(XU)

(XIII)

The starting compounds for the process of the invention are known. 2-Bromo-1,4,5-trimethoxynaphthalene (VII, R = OCH ₃ )

by RL Haman, RB Barber and H. Rapoport, J.Org.Chem. 44 , 2153 (1979). The coupling reaction between the compounds (VIII) and (VI) proceeds regioselectively in high yield to give the key intermediate (IX). The organometallic species only touches the carbonyl group of the methyl ester and not that of the lactone.

Step (11) can be carried out after that of CM. Wong et al., Can. J. Chem. 51 , 446 (1973), are carried out, ie by bromination with bromine in the presence of 2,2'-azobis (isobutyronitrile) followed by hydrolysis of the 7-bromo derivative and removal of the ketal group by acid treatment or by bromination with N- Bromosuccinimide in the presence of 2,2'-azobis (isobutyronitrile), by irradiation, treatment with silver acetate, hydrolysis of the ketal by acid treatment and finally hydrolysis of the acetate with sodium methoxide.

The optical separation of the compound (IX) can be carried out by the conventional one Method of conversion into diastereoisomeric derivatives carried out using a chiral separating agent will. Separation at this point enables (+) - 4-demethoxy-6-deoxy-4- (R-subst.) - daunomycinones to be obtained (I). The 6-deoxyanthracyclinones (I), with the exception of those in which R represents a hydrogen atom, are new and fall under the scope of the present invention. 4-demethoxy-6-deoxydaunomycinone, prepared by a different process, is described in GB-PS 2,100,257. The inventive The process is more efficient and suitable for large-scale production than the process described above.

The invention also contemplates the general anthracycline glycosides Formula (XV)

0 OH

before, wherein R is a hydrogen atom or a hydroxy group, one of R ~ and R _{3 is} a hydrogen atom and the other is a hydrogen atom or a hydroxy group and X is a hydrogen atom or a trifluoroacet.yl group, with the proviso that when X is a trifluoroacetyl group, then R. is a hydrogen atom. These compounds can be designated as follows: XVa: R ₁ = R ₃ = H, R ₂ = OH, X = COCF ₃ 4-demethyl-6-deoxy-N-trifluoroacetyl-daunorubicin XVb: R ₁ = R ₃ = H, R ₂ = OH, X = H

4-Demethy1-6-deoxy-daunorübicin XVc: R ₁ = R ₂ = OH, R ₃ = H, X = H

4-Demethyl-6-deoxy-doxorubicin XVd: R ₁ = R ₂ = H, R ₃ = OH, X = COCF ₃ 5 4-Demethyl-6-deoxy-N-trifluoroacetyl-4'-epi-daunorubicin XVe: R ₁ = R ₂ = H, R ₃ = OH, X = H

4-Demethyl-6-deoxy-4'-epi-daunorubicin XVf: R ₁ = R ₃ = OH, R ₂ = H, X = H 4-demethyl-6-deoxy-4'-epi-doxorubicin XVg: R ₁ = R ₃ = R ₃ = H, X = COCF ₃ 4-Demethyl-6,4'-dideoxy-N-trifluoroacetyl-daunorubicin

XVh: R ₁ = R ₂ = R ₃ = X = H

4-Demethyl-6,4'-dideoxy-daunorubicin XVi: R ₁ = OH, R ₃ = R ₃ = X = H 4-demethyl-6,4'-dideoxy-doxorubicin.

These anthracycline glycosides can be obtained from 4-demethyl-6-deoxydaunomycinone (I, R = OH) by condensation thereof with a protected halogen sugar of the general formula (XVI) 30th

(XVI) ₇

NHCOCF-,

"2

wherein one of R ₂ and R _{3 is} a hydrogen atom and the other is

represents a hydrogen atom or a trifluoroacetoxy group unä Hal is a calogen atom, preferably a chlorine atom will. This condensation proceeds in the presence of silver trifluoromethanesulfonate according to that described in US Pat. No. 4,107 described method from, wherein an easily separable mixture of 7S: 9S and 7R: 9R O-trifluoroacetylprotected derivatives of the u-glycosides (XVa), (XVd) and (XVg) according to the halogen sugar (XVI) chosen for the reaction will.

The O-trifluoroacetyl group can be removed by methanolysis are obtained, the compounds (XVa), (XVd) and (XVg) which by mild alkaline hydrolysis to the glycosides (XVb), (XVe) or (XVh) can be converted. These 5 give by 14-bromination and treatment with aqueous Sodium formate similar to that described in US Pat. No. 3,803,124 Process the corresponding doxorubicin derivatives (XVc), (XVf) and (XVi). These procedures fall under the scope of the

present invention.
20th

The anthracycline glycosides (XV) have anti-tumor properties and accordingly the present invention further relates to pharmaceutical compositions comprising an anthracycline glycoside of the general formula (XV) or a pharmaceutically acceptable salt of such a glycoside, wherein X is hydrogen means in admixture with a pharmaceutically acceptable diluent or carrier.

The following examples illustrate the invention. 30th

Example 1: Dimethyl-1,2,3,6-tetrahydro-4-acetyl-

phthalate (III)

10 g of dimethyl 1,2,3,6-tetrahydrophthalate (II) were treated at -5 ⁰ C with 25 ml of acetic anhydride in the presence of 9 ml of tin tetrachloride. The reaction mixture was poured into ice water and extracted with diethyl ether. The organic

Phase was washed with saturated aqueous sodium bicarbonate solution and then with water and then evaporated to dryness in vacuo. The oil obtained was dissolved in benzene and treated with a methanolic hydrogen chloride solution. The solution was evaporated to dryness and the residue was purified by chromatography on a silica gel column to give 9 g of the title compound in an overall yield of 75%. Mass spectrum: m / z 240 (M ")
IR (KBr): 1720 cm " ¹ (C = O of the ester); 1660 cm" ¹ (C = O of the α, ß-unsaturated ketone) PMR (CDCl ₃ ): uaδ 2.33 (s, COCH ₃ ), 3.70 (s, -COOCH ₃ ) and

6.91 (m, HC = C).

Example 2: 1,2-Di (methoxycarbonyl) -4-ethylidenecyclohexane (V)

17 g of dimethyl 1,2,3, δ-tetrahydro-4-acetyl phthalate, prepared as described in Example 1, were refluxed in anhydrous ethanol with 14.6 g of tosylhydrazine. After removal of the solvent 24 mp 162-163 ⁰ C, g Dimethyl-1,2,3,6-tetrahydro-4- (1-tosylhydrazonoäthy1) phthalate (IV) crystallized from water., M / z 408 (M ⁺ "). This compound was dissolved in chloroform and treated at 0 ⁰ C and 14 ml Brenzkatechinboran. sodium acetate was added to the reaction mixture, which was then held at reflux. After washing with water, the solvent was evaporated and the residue purified by chromatography on a silica gel purified to give 10 g of the title compound (yield 80%): m / z 226 (M ⁺ ")

PMR (CDCl ₃ ): inter alia b 1.6 (d, J = 8 Hz, CH ₃ -CH =), 5.3 (q, J = 8 Hz, CH ₃ -CH =).

Example 3: 2-methoxycarbonyl-5- (2-methyldioxolane-2-

yl) -6-oxa-bicyclo [3.2.1] octan-7-one (VI)

8g of 1,2-di- (methoxycarbonyl) -4-ethylidene-cyclohexane prepared as described in Example 2, were in aqueous

- V9 -

Dissolved acetone containing 4.8 ml of acetic acid. An aqueous potassium permanganate solution was added and the mixture was left to stand for 60 minutes at room temperature, excess oxidizing agent was then destroyed and the reaction mixture diluted with water was extracted with ethyl acetate. The organic phase, which had been washed with water and dried over anhydrous sodium sulfate, was evaporated to dryness in vacuo. The residue (9 g) was dissolved in benzene and refluxed for 60 minutes in the presence of a catalytic portion of p-toluenesulfonic acid. 4 ml of ethylene glycol were added and the reaction mixture was refluxed for a further 2 hours. After conventional work-up, the residue obtained by evaporation of the solvent was purified by chromatography on a silica gel column using a toluene-acetone mixture (15: 1 by volume) as the eluent. 3.0 g of the title compound were isolated (yield 33%), melting point 69-71 ° C., m / z 271 (MH ⁺ ').
IR (KBr): 1790 cm "(C = O five-membered ring lactone),

1735 cm " ¹ (C = O ester), 1720 cm" ¹ (C = O ketone) PMR (CDCl ₃ ): inter alia Ö 1.25 (s, CH ₃ ), 3.65 (s, COOCH ₃ ) and 3 , 9

(s, -0-CH ₀ -CH ₀ -O-).

Example 4: 2- (1,4, S-Trimethoxy-S-naphthylcarbonyl) -5- (2-methyldioxolan-2-yl) -6-oxa-bicyclo [3.2.1] octan-7-one (IX , R = OCH ₃ )

7 ml of a 1.65 M hexane solution of n-butyllithium was dissolved in 30 ml of anhydrous tetrahydrofuran. To the solution a solution of 3.3 g 1,4,5-trimethoxy-3-bromonaphthalene (VI, R = OCH ₃₎ was added in 30 ml of anhydrous tetrahydrofuran at -78 ⁰ C. 2.5 g of 2-methoxycarbonyl-5- (2-methyl-dioxolan-2-yl) -6-oxabicyclo [3.2.1] octan-7-one, prepared as described in Example 3, were added to 50 ml of anhydrous Tetrahydrofuran was dissolved and added to the reaction mixture. The reaction mixture was for 1 h at -78 ⁰ C allowed to stand and then quenched with acetic acid. The solvent was removed in vacuo. The residue was chromatographed by silica gel

Purified graph to give 3 g (73% yield) of the title compound, m / z 456 (M ⁺ ").
IR (KBr): 1775 cm " ¹ (C = O five-membered ring lactone), 1680 cm (C = O benzylic ketone) PMR (CDCl ₃ ): ao 6 1.3 (s, CH ₃ ), 3.75 (s, OCH ₃ ), 3.95-4.05

(m, two OCH- and -0-CH ₀ -CH ₀ -O-), 6.8 (s, aromatic CH) and 6.8-8.1 (m, three H's).

Example 5: 1- (1, 4, S-trimethoxy-S-naphthylmethyl ^ - benzyloxycarbonyl) -4- (1-hydroxyethyl) - ^ 4-hydroxycyclohexane (XI, R = OCH ₃ )

1.6 g of 2- (1,4,5-trimethoxy-2-naphthylcarbonyl) -5- (2-methyldioxolan-2-yl) -6-oxa-bicyclo [3.2.1] octan-7-one , prepared as described in Example 4, were dissolved in methanol and treated at room temperature for 1 hour with a solution of hydrogen chloride in anhydrous methanol. After evaporation of the solvent, 1.5 g of 1- (1,4,5-trimethoxy-3-naphthylcarbonyl) -2-methoxycarbony1-4-acetyl-4-hydroxycyclohexane (X, R = OCH ₃ ) were obtained in almost quantitative yield, m / z 444 (M ⁺ "). IR (film): 3460 cm" ¹ (OH, 1730 cm " ¹ (C = O ester), 1710 cm" ¹ (C = O ketone) and 1665 cm "(C = O benzylic ketone).

PMR (CDCl ₃ ): among others ö 2.3 (s, CH ₃ CO), 3.75-4.05 (s, four OCH ₃ ),

6.8 (s, aromatic H) and 6.85-8.0 (m, three aromatic H).

1.5 g of this compound were dissolved in 15 ml of trifluoroacetic acid dissolved and refluxed with 1.4 ml of pyridine-borane complex. After removing the solvent, the residue was treated with a 10% aqueous sodium hydroxide solution. After mild Acidification, the free acid was extracted with ethyl acetate. The solvent was evaporated and the residue directly treated with an ethereal solution of phenyldiazomethane, whereby the title product was obtained. This was purified by chromatography, m / z 508 (M *),

PMR (CDCl ₃ ): δ 1.25 (d, CH ₃ -CH) ₇ 3.70-3.95 (s, three OCH ₃ ), 5.15 (d, CH ₃ Ph) and 6.4- 8.1 (m, nine aromatic H)

- 34 -

Example 6: 1, 2, 3,4, 4a, 5,12,12a-octahydro-2- (1-hydroxyethyl) -2-hydroxy-6,7,11-trimethoxy-12-oxonaphthacene (XIII, R = OCH ₃ )

0.48 g of 1- (1,4,5-trimethoxy-3-naphthylmethyl) -2-benzyloxycarbonyl-4- (1-hydroxyethyl) -4-hydroxy-cyclohexane, prepared as described in Example 5, were treated with acetic anhydride and pyridine in the presence of 4-dimethylaminopyridine. After one night at room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic Layer was washed with water and concentrated.

The crude product was dissolved in methanol and refluxed with cyclohexene in the presence of 10% by weight palladium-on-carbon. The catalyst was then filtered off and, after concentration to a small volume, the solution was treated with trifluoroacetic anhydride and trifluoroacetic acid ^{at 0 ° C. for 60 min.} The solution was then diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate solution and with water, dried and concentrated to dryness in vacuo. The residue was dissolved in methanol in the presence of a catalytic portion of sodium methylate

solved. Conventional work-up and purification by chromatography gave 0.18 g of the title compound (yield 49%), m / z 400 (M ⁺ ").

IR (KBr): 3450 cm " ¹ (OH), 1675 cm (C = O benzylic ketone) PMR (CDCl ₃ ): ao δ 1.2 (d, CH ₃ -CH), 3.7-3.9 ( s, three OCH ₃ )

and 6.4-8.0 (m, three aromatic H).

Example 7: 1,2,3,4,4a, 5,12,12a-octahydro-2-acetyl-2-hydroxy-6,7,11-trimethoxy-12-oxo-naphthacene

0.8 g of silver carbonate were added to a solution of 0.09 g of 1,2,3,4,4a, 5,12,12a-octahydro-2- (1-hydroxyethyl) -2-hydroxy-6,7,11- trimethoxy-12-oxonaphthacene, prepared as described in Example 6, added in benzene and the mixture under reflux held. After filtering off the solid and evaporating the solvent in vacuo, 0.08 g of the title compound were obtained in

obtained a yield of 90%.

IR (KBr): 3360 cm " ¹ (OH), 1705 cm" ¹ (C = O ketone), 1680 cm " ¹

(C = O, benzylic ketone)
PMR (CDCl ₃ ): inter alia δ 2.2 (s, CH ₃ CO), 3.65-3.90 (s, three OCH ₃ ).

Example 8: 6,7-Dideoxycarminomycinone (XIV, R = OH)

0.06 g 1, 2,3,4,4a, 5,12,12a-octahydro-2-acetyl-2-hydroxy-6,7,1 1-trimethoxy-12-oxonaphthacene, prepared as described in Example 7, were dissolved in nitrobenzene and treated with 0.12 g of aluminum trichloride. The mixture was kept at 70 ^° C. until starting material was no longer detectable. The reaction mixture was poured into an aqueous saturated oxalic acid solution and extracted with ethyl acetate. The organic phase was separated off, washed with water, dried and evaporated to dryness. The residue, purified on a silica gel column, gave pure 6,7-dideoxycarminomycinone, yield 40%, m / z 352 (M '), IR (KBr): 3420 cm " ¹ (OH), 1705 cm" ¹ (C = O ketone) and

1625 cm " ¹ (C = O chelated quinone) PMR (CDCl ₃ ): ua 6 1.7-2.2 (m, CH ₂ ), 2.3 (s, CH 3 CO), 2.8-3.2

(m, two benzylic CH ₂ ), 7.0-7.9 (m, four aromatic -tic H), 12.6 (s, phenolic OH) and 12.9 (s,

phenolic OH).

Example 9: 6-Deo.xycarminomycinon (I, R = OH)

A solution of 6,7-dideoxycarminomycinone, prepared as described in Example 8, in benzene was at reflux temperature 4h treated with 1.2 ml of ethylene glycol in the presence of a catalytic ■ portion of p-toluenesulfonic acid, the corresponding 13-ketal derivative was obtained. This compound was made into carbon tetrachloride dissolved and with 2 ml of a solution of 3.2 g of bromine in 32 ml of carbon tetrachloride at 45 ° C for 6 h in the presence treated by 2,2'-azobis (isobutyronitrile). The chilled The reaction mixture was extracted with 1N aqueous sodium hydroxide and the colored aqueous phase was adjusted to pH 8.5 and extracted with chloroform. The dry

- ^ vaporized organic extracts gave 6-deoxy-13-ketal-carminomycinone. This was dissolved in acetone containing hydrogen chloride (300 ml of a 0.25N solution) and kept at room temperature for 3 hours held to hydrolyze the ketal group. It became what I wanted 6-Deoxycarminomycinon obtained.

Alternative method

A solution of 50 g (0.125 mmol) of the 13-ketal derivative of 6,7-dideoxycarminomycinone in 20 ml of carbon tetrachloride containing 0.14 mmol of N-bromosuccinimide and 0.0 6 mmol of 2,2'-azobis (isobutyronitrile) was refluxed for 25 min. The residue obtained on evaporation of the solvent in vacuo was dissolved in glacial acetic acid dissolved and treated with 80 mg of silver acetate. The mixture was stirred at room temperature for 5 hours. The solvent was evaporated and the residue dissolved in ethyl acetate and filtered.

The filtrate was washed with a saturated aqueous sodium bicarbonate solution and with water, dried and concentrated. The residue was dissolved in aqueous acetic acid (90%, based on the volume) at ⁰ ° C. and stirred for 90 min. After removing the solvent, the residue was dissolved in methanol, sodium methoxide was added and the mixture was stirred for 90 minutes. After neutralization, extraction and washing with water, the residue was purified by flash chromatography with methylene dichloride / acetone (16/1 by volume). The desired 6-deoxycarminomycinone was obtained in an overall yield of 34%, m / z 368 (M ⁺ '), melting point 211-213 ° C., TLC on silica gel plates (Merck F ₃₅₄ ) using toluene / acetone, 4/1 based on volume, as eluting solvent, Rf = 0.3.

PMR (200 MHz, CDCl ₃ ): ö 2.1-2.3 (m, 2H ₇ H-8), 2.3 (s, 3H, -COCH ₃ ), 2.7-3.1 (q, 2H, H-10), 4.1 (d, 1H, OH-7), 4.4 (s, 1H, OH-9), 4.8 (d, 1H, H-7), 7.3 ( d, 1H, H-3), 7.7 (t, 1H, H-2), 7.8 (d, 1H-, H-1), 8.1 (s, 1H, H-6), 12 , 8 (s, 1H, OH-4), 13.2 (s, 1H, OH-11).

Example 10: 2- (1,4-Dimethoxy-3-naphthylcarbonyl) -5- (2-methyl-dioxolan-2-yl) -6-oxa-bicyclo [3.2.1] octan-7-one (IX, R = H)

Following the procedure described in Example 4 a solution of 3.2 g was 1,4-dimethoxy-3-bromonaphthalene in anhydrous tetrahydrofuran at -78 ⁰ C with n-butyllithium and then a solution of 2.7 g to that described in Example 3 compound prepared in anhydrous tetrahydrofuran added. After silica gel column purification, 2.8 g of the title compound were obtained (65% yield), m / z 426 (M ⁺ '), IR (film): 1780 cm " ¹ (C = O, five-membered ring lactone), 1670

cm (C = O, benzylic ketone)

PMR (CDCl ₃ ): δ 1.4 (s, CH ₃ ), 3.85 (s, two OCH ₃ ), 3.9 (s, -0-CH ₂ -CH ₂ -O-), 6, 9 (s, aromatic H) and 7.4-8.4 5 (m, four aromatic H).

Example 11: 1- (1,4-Dimethoxy-3-naphthylmethyl) -2-benzyloxycarbonyl-4- (1-hydroxyethyl) -4-hydroxycyclohexane (XI, R = H)

Working as described in Example 5, treatment of 2- (1,4-dimethoxy-3-naphthylcarbonyl) -5- (2-methyldioxolan-2-yl) -6-oxa-bicyclo [3,2,1] octan-7-one, prepared as described in Example 10, with a solution of hydrogen chloride in methanol 1- (1,4-dimethoxy-3-naphthylcarbonyl) -2-methoxycarbonyl-4-acetyl-4-hydroxy-cyclohexane (X, R = H) in almost quantitative yield, m / z 414 (M '),

IR (film): 3460 cm " ¹ (OH), 1730 cm" ¹ (C = O ester), 1710 cm " ¹

(C = O ketone) and 1670 cm (C = O, benzylic ketone) PMR (CDCl ₃ ): ao δ 2.3 (s, CH ₃ CO), 2.9-3.6 (m, two H), 3.7-3.9 (s, three OCH ₃ ), 6.9 (s, aromatic H).

1 g of this compound was converted into 0.7 g of the title compound by reduction with a pyridine-borane complex, basic treatment and finally esterification with phenyldiazomethane (overall yield 63%), m / z 478 (M ⁺ "),

IR (film): 3450 cm " ¹ (OH), 1725 cm" ¹ (C = O ester) PMR (CDCl ₃ ): ao ό 1.3 (d, J = 4 Hz, CH ₃ -CH), 3, 85-3.9 (s, two

OCH ₃ ), 5.1 (s, Cfl ^ -benzylisch), 6.6 (s, aromatic H) and 7.2-8.4 (m, nine aromatic hydrogens).

Example 12: 1,2,3,4,4a, 5,12,12a-octahydro-2- (1-hydroxyethyl) -2-hydroxy-6,11-dimethoxy-12-oxo-naphthacene (XIII, R = H)

The procedure was as described in Example 6, 0.4 g of 1- (1 ^ -Dimethoxy ^ -naphthylmethyl ^ -benzyloxycarbonyl ^ - (1- ¹ ^ hydroxyethyl) -4-hydroxycyclohexane, prepared as described in Example 11, with Acetic anhydride in the presence of 4-dimethylaminopyridine and pyridine. The corresponding acetate was treated with cyclohexene in the presence of 10% by weight palladium-on-carbon to remove the benzyl group. The acid was removed by treatment with a mixture of trifluoroacetate

anhydride and trifluoroacetic acid cyclized ^{at 0 ° C.} Finally, removal of the acetyl-O-protecting groups by treatment with sodium methylate gave, after chromatographic purification on a silica gel column, 0.225 g of the title compound (overall yield 66%), IR (film): 3450 cm " ¹ (OH), 1675 cm" ¹ (C = O, benzylic ketone) PMR (CDCl-,): δ 1.3 (d, J = 4 Hz, CH ^ -CH), 1.6-3.5 (m, 3H), 3.85 (s, OCH ₃ ), 3.90 (s, OCH ₃ ), 7.2-8.4 (m, four aromatic H).

Example 13: 1,2,3,4,4a, 5,12,12a-octahydro-2-acetyl-2-hydroxy-6,11-dimethoxy-12-oxo-naphthacene

0.1 g of 1,2,3,4,4a, 5,12,12a-octahydro-2- (1-hydroxyethyl) -2-hydroxy-6,11-dimethoxy-12-oxo-naphthacene, prepared as in Example 12 described, in benzene was treated with 1 g of silver carbonate at reflux temperature. After filtering off the inorganic solids and removing the solvent, 0.1 g of the title product was obtained.
IR (film): 3460 cm " ¹ (OH), 1710 cm" ¹ (C = O ketone), 1680 cm " ¹

(C = O benzylic ketone)
PMR (CDCl ₃ ): ao 6 2.4 (s, CH ₃ CO), 3.85 (s, OCH ₃ ), 3.90 (s, OCH ₃ ), 7.2-8.4 (m, four aromatic H).

Example 14: 4-Demethoxy-6,7-dideoxydaunomycinone

(XIV, R = H)

The procedure was as described in Example 8, a solution of 0.1 g of 1,2,3,4,4a, 5,12,12a-octahydro-2-acetyl-2-hydroxy-6,11-dimethoxy-i2 -oxo-naphthacene, prepared as described in Example 13, was treated in 3 ml of nitrobenzene with 0.25 g of aluminum trichloride overnight at room temperature. After Silikagelsaulenchromatographie 0.055 g (63% yield) of the title compound were obtained, mp. 203-204 ⁰ C.

Example 15: 6-Deoxy-4-demethyldaunorubicin (XVb)

90 mg (0.24 mmol) of racemic 6-deoxycarminomycinone, prepared as described in Example 9, were dissolved in anhydrous dichloromethane and the solution was cooled ^{to 5 to 10 ° C.} A solution of 2.4 mg (0.6 mmol) of 1-chloro-N, 0-ditrifluoroacetyldaunosamine, prepared according to the method described in Cancer Chemotherapy Reports, Part 3, Vol. 6, No. 2, p. 123, described method, in diethyl ether and a solution of 154 mg (0.6 mmol) of silver trifluoromethanesulfonate in dichloromethane were added simultaneously and rapidly with vigorous stirring.

After 5 min, a further 0.3 mmol of halogen sugar and 0.3 mmol Silver trifluoromethanesulfonate added. After 5 minutes the Quenched reaction with collidine. The mixture was filtered with saturated aqueous sodium bicarbonate solution and water, dried and concentrated in vacuo. The reddish oil obtained was diluted with 100 ml of methanol and Left to stand overnight at room temperature to remove the O-trifluoroacetyl group to remove. The resulting crude product was purified by flash chromatography on silica gel with dichloromethane / Methanol / acetone, 20: 1: 1 by volume, purified, the anthracycline-iz-glycosides (XVa) being obtained.

7S: 9S, 20 mg, mp 210-212 ⁰ C;. TLC on silica gel plates (Merck F) using methylene dichloride / acetone, 4: 1 loading; added to volume, as eluant, Rf = 0.27, m / z 593 (M ⁺ *).

PMR (2000 MHz, CDCl ₃ ): inter alia δ 1.44 (d, J = 6.6 Hz, 3H, CH ₃ -S '), 2.42 (s, 3H, COCH ₃ ), 3.25-3 .05 (two d, J = 19 Hz, 2H, H-10), 4.22 (s, 1H, OH-9), 5.01 (t, J = 3.6Hz, 1H, H-7), 5.20 (t, J = 2.7 Hz, 1H, HT), 6.66 (bd, J = 9 Hz, 1H, NH), 7.80 (s, 1H, H-6), 12.62

(s, 1H, OH-4), 13.06 (s, 1H, OH-11); m / z 593 (M ⁺ ') 7R: 25174-178 ⁰ 9R, mg, mp C;. TLC on silica gel plates (Merck F254) using methylene dichloride / acetone, 4: 1 by volume, as eluent, Rf = 0.23, m / z 593 (M ⁺ "). PMR (200 MHz, CDCl ₃ ): inter alia δ 1.44 (d, J = 6.5 Hz, 3H, CH ₃ -S '), 2.41

(s, 3H, COCH ₃ ), 2.96 (d, J = 19 Hz, 1H, H-10 ax), 3.30 (dd, J = 1, 19 Hz, 1H, H-10 eq.), 4.25 (s, 1H, OH-9), 5.07 (t, J = 3.3 Hz, 1H, H-7), 5.27 "(t, J = 1.8 Hz, 1H, H -1 '), 6.64 (bd, J = 9 Hz, 1H, NH), 7.74 (s, 1H, H-6), 12.66 (s, 1H, OH-4),

13.10 (s, 1H, OH-11).

Mild alkaline hydrolysis of the compound (XVa) removes the N-trifluoroacetyl group to give the title compound in quantitative yield. TLC on silica gel plates (Merck F ₃₅₄ ) using methylene dichloride / methanol / acetic acid / water, 80: 20: 7: 3 by volume, as eluant, Rf = 0.47.

Example 16: 6-Deoxy-4-demethyldoxorubicin (XVc)

A solution of 6-deoxy-4-demethyldaunorubicin, prepared as described in Example 15, in a mixture of methanol and dioxane was treated with bromine to form the 14-bromo derivative. Treatment of the 14-bromo derivative with an aqueous sodium formate solution at room temperature for 100 h gave 6-deoxy-4-demethyldoxorubicin, m.p. 167-17O ⁰ C. TLC (Merck F _5. ) Using the solvent system CH ₂ Cl ₂ / MeOH / Ac0H / H ₂ 0 (8: 2: 0.7: 0.3 based on volume) Rf = 0.47. ■

Claims (1)

HOFFMANN · EITLE & -PARTNtR PATENT AND LAWYERS PATENTANWÄLTE DIPL.-ING. W. EITLE. DR. RER. NAT. K. HOFFMANN DIPL.-ING. W. LEHN D1PL.-ING. K. FÜCHSLE ■ DR. RER. NAT. B. HANSEN · DR. RER. NAT. HA. BRAUNS DIPL.-ING. K. GORG DIPL.-ING. K. KOHLMANN · LAWYER A. NETTE 40 399 o / IS Farmitalia Carlo Erba S.p.A. Milan / Italy Claims 6-Deoxyanthracyclinones, anthracycline glycosides, processes for their preparation and pharmaceuticals containing them 1. Process for the production of 6-deoxyanthracyc inones of the general formula (I): 10 15 20 25 (D, wherein R is a hydrogen atom, a hydroxyl group or a nied.Alkoxygruppe means, characterized in that a dimethyl-1,2,3,6-tetrahydrophthalate of the formula (II): H ₃ COOC H ₃ COO (II) by treatment with acetic anhydride in the presence of tin tetrachloride and subsequent treatment with a mild one ! ABELLAGTRASSE 4. D-8OOO MÖNCHEN 81 · TELEFON (Ό89;) 911O87 ■ TELEX 5-29619 CPATHEJ · TELECOPIER 9183S5 -S- Base or a mild acid in dimethyl 1,2,3,6-tetrahydro-4-acetylphthalate of formula (III): H ₃ COOC H ₃ COOC (III) transferred, the corresponding dimethyl-1,2,3,6-tetrahydro-4- (1-tosylhydrazonoäthyl) phthalate when reacted with tosylhydrazine (IV): NNHTs H ₃ COO H ₃ COOC (IV) results, which in turn is reduced with catechol borane, whereupon the double bond in the presence of sodium acetate . is rearranged from an endocyclic to an exocyclic position, the 1,2-di (methoxycarbonyl) -4-ethylidenecyclohexane (V): H ₃ COO H ₃ COOC (V) is obtained from which, after an oxidative treatment with potassium permanganate, the corresponding cx-hydroxyketone is obtained is, which then with ethylene glycol in the presence of a catalytic proportion of p-toluenesulfonic acid to 2-methoxy-5- [2-methyldioxolan-2-yl] -6-oxabicyclo [3.2.1] octan-7-one of the formula (VI): is reacted, which, dissolved in anhydrous tetrahydrofuran, at a temperature of -78 ⁰ C for 1 hour with an alkyllithium derivative of the formula (VIII) OCH. (VIII), wherein R has the above meaning, is condensed, wherein the lactone of the formula (IX) OCH (IX) is obtained, whereupon the lactone ring of this compound (IX) opened by methanolysis and at the same time the protective group of the dioxolane-protected keto group by acid treatment is removed, the compound of the formula (X) -X- OCH OCH. wherein R has the above meaning, is obtained, whereupon the Keto group of the compound (X) by treatment with a pyridine-borane complex reduced in the presence of trifluoroacetic acid and the methoxycarbonyl group by treatment with Phenyldiazomethane is converted into a benzyloxycarbonyl group, the compound of the formula (XI) OCH OH OH (XI) is obtained, after which the hydroxyl groups of this compound are esterified and the benzyloxycarbonyl group thereof is deesterified by treatment with acetic anhydride in pyridine in the presence by 4-dimethylaminopyridine followed by reflux with cyclohexene in the presence of a palladium-on-carbon catalyst, wherein the compound of the formula (XII) OCK-, ^ OCOCH. (XII), wherein R 'is a hydrogen atom, an acetoxy group or a lower, Represents alkoxy group, which is obtained by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid cyclized and a subsequent hydrolysis of the acetoxy groups with sodium methylate is subjected, the compound of formula (XIII) OCH (XIII) wherein R has the above meaning, is obtained from which, after an oxidative treatment of the 1-hydroxyethyl group with silver carbonate and demethylating the resulting compound with aluminum trichloride in nitrobenzene to give the compound of the formula (XIV) OH 0 (XIV) 3Q is obtained from which after protection of the 13-keto group by Treatment with ethylene glycol, bromination of the resulting Compound at C-7 with bromine in the presence of 2,2-azobis (isobutyronitrile), followed by hydrolysis of the 7-bromo derivative and removal of the ketal group by acid treatment or on the other hand by bromination with N-bromosuccinimide in the presence of 2,2'-azobis (isobutyronitrile), by irradiation, Treatment with silver acetate, hydrolysis of the ketal by acid - tr - treatment and finally hydrolysis of the acetate with sodium methoxide the desired compounds of formula (I) are obtained. Compound of formula (I) prepared according to Claim 1, namely 4-demethyl ~ 6-deoxy-daunomycinone. Compound of formula (I) prepared according to Claim 1, namely 6-deoxy daunomycinone. Anthracycline glycosides of the general formula (XV) O OH ο wherein R- is a hydrogen atom or a hydroxyl group, one of R_ and R-, is a hydrogen atom and
the other is a hydrogen atom or a hydroxy group and X is a hydrogen atom or a trifluoroacetyl group, with the proviso that when X is a trifluoroacetyl group, R _{1 is} a hydrogen atom. 5. Compound of formula (XV) according to claim 4, namely 4-demethyl-6-deoxy-N-trifluoroacetyl-daunorubicin. 6. Compound of formula (XV) according to claim 4, namely 4-demethyl-6-deoxy-daunorubicin. 7. Compound of formula (XV) according to claim 4, namely 4-demethyl-6-deoxy-doxorubicin. 8. The method of the formula (XV) according to claim 4, namely 4-demethyl-6-deoxy-N-trifluoroacetyl-4'-epidaunorubicin. ζ - 9. Compound of formula (XV) according to claim 4, namely 4-demethyl-6-deoxy-4'-epidaunorubicin. 10. A compound of the formula (XV) according to claim 4, namely 4-demethyl-6-deoxy-4'-epidoxorubicin. 11. Compound of formula (XV) according to claim 4, namely 4-demethyl-6,4'-dideoxy-N-trifluoroacetyldaunorubicin. 12. Compound of formula (XV) according to claim 4, namely 4-demethyl-6,4'-dideoxydaunorubicin. 13. Compound of formula (XV) according to claim 4, namely 4-demethyl-6,4'-dideoxydoxorubicin. 14. Process for the preparation of a compound of the formula (XV): O OH where R ₁ , R _? , R- and X have the meaning given in claim 4, characterized in that a racemic 6-deoxyanthracyclinone of the general formula (I): (D, -x- produced according to claim 1, wherein R represents a hydroxyl group, dissolved in anhydrous dichloromethane, at a temperature of 5 to 10 ⁰ C with a protected halogen sugar of the general formula (XVI): (XVI) ₁ NHCOCF ₃ wherein one of R "and R ,. is a hydrogen atom and the other is a hydrogen atom or a Trifluorace.toxygruppe and Hal is a halogen atom, preferably a chlorine atom, condensed in the nature of silver trifluoromethanesulfonate, a mixture of 7S: 9S and 7R: 9R Ν, Ο-trifluoroacetyl protected derivatives the u-glycosides of formula (XV) is obtained, whereupon the O-trifluoroacetyl protecting group is removed by treatment with methanol at room temperature overnight, the resulting diastereomeric mixture of the N-trifluoroacetyl protected glycosides is obtained by silica gel column chromatography using a mixture of dichloromethane / methanol / acetone (20: 1: 1 V / V) is subjected as the elution system, the corresponding pure 7S: 9S N-trifluoroacetyl-protected glycosides being obtained which, after mild alkaline hydrolysis, give the desired 7S: 9S a-glycosides of the formula (XV), in which R. is hydrogen, and finally, if desired, the α-glycosides obtained with Br om treated in chloroform, the corresponding 14-bromo derivatives being obtained, from which the corresponding doxorubicin analogs (R ₁ = OH) are obtained by subsequent hydrolysis with an aqueous sodium formate solution. -Jg- 15. Medicaments, characterized in that they contain a compound of the general formula (XV) according to claim 14 in addition to customary carriers.