HUT72651A - Etoposide derivatives, pharmaceutical compns. contg. them, process for their preparation, and their use in the preparation of a drug for treating cancer - Google Patents

Abstract

In the formula (I) of the compounds of the present invention, R 'is hydrogen or R, R is a group of formula (a) or an acyl residue of formula (b) wherein X, Y and Z are independently oxygen or sulfur, C 1 -C 4 straight or branched alkyl, C 3-6 cycloalkyl or aryl, preferably phenyl, C 1-4 straight or branched phenyl alkyl, or naphthyl, optionally substituted with one to three hydroxyl groups; in the case of chlorine or fluorine with perhalogenated C 1-4 straight or branched alkoxy, benzyloxy, phenyl, 1-4 carbon atoms

Description

substituted with a linear or branched alkyl group or a halogen atom, preferably a chlorine atom or a fluorine atom, with the proviso that when R 'is R, R is 4-fluorophenoxyacetyl,

4-benzyloxy-phenoxyacetyl, 4-hydroxy-phenoxyacetyl, 4-methyl-phenoxyacetyl, 3,4,5-trimethoxy-phenoxyacetyl, 3,4- methylenedioxyphenoxyacetyl, 2,3-dimethoxyphenoxyacetyl, 4- (trifluoromethoxy) phenoxyacetyl, 4-phenylphenoxyacetyl, 1-naphthoxy- acetyl, cyclohexylacetyl, 4-methylphenoxyacetyl or 3,4-dimethoxyphenoxyacetyl.

The invention further relates to the preparation of the above compounds.

and pharmaceutical compositions containing them.

• · · • · · «· ·

p ' ^u -v • ·· • «• ·· • · ··· • ·

Represents:

DANUBIA PATENT AND TRADEMARK OFFICE LTD.

Budapest

- ^V L- ^C 't

These ophthalmic derivatives are for use in the manufacture of a medicament for use in the preparation of a medicament for the treatment of cancer.

PlERRE FABRE MEDICAMENT, Boulogne, FR

The inventors:

ROBIN Jean-Pierre

Le Mans, FR

Robert KISS,

Bruxelles, BE

IMBERT Thierty,

Viviers-les-Montagnes, FR

Date of filing: 20.12.1993.

Priority: 22.12.1992 (92/15460) FR

International Application Number: PCT / FR93 / 01270

International Publication Number: WO 94/14829

81847-1913 / SL

The present invention relates to etoposide derivatives, their preparation and their use as an anticancer drug. Ethoposide of formula (A) (wherein R is methyl) and certain derivatives thereof, such as teniposide (wherein R is 2-thienyl in formula (A)), are known anti-cancer agents useful in human clinical medicine. They can be prepared, for example, from naturally occurring materials such as podophyllotoxin B and glycosylated materials such as 4,6-ethylidene-B-D-glucopyranose.

The preparation of etoposide is described, for example, in U.S. Pat

No. 524,844 and J. Med. Chem. 14, 936 (1971), J. Org. Chem. 46, 2826 (1981), Heterocycles 32, 859 (1991); Tetrahedron 47, 4675 (1991); Synthesis (1991), 275.

Ethoposide and analogue teniposide are commercially available and can be used as medicaments in the treatment of various cancerous tumors and recurrent acute leukemia.

However, these compounds have the disadvantage that they cause various undesirable side effects, such as low white blood cell count and decreased platelet count.

Various etoposide derivatives are also known (EP 0,401,800, EP 0,461,556, EP 0,455,159, EP 0,433,678, EP 0,358,197, EP 0,415,453, EP 0,320,988, EP 0,423,747, EP 0,394,907 and EP 0,445,021).

Some of the known derivatives are intermediates al3 · ♦ • • ι *.

Can be used in the production of etoposide.

Surprisingly, it has been found that certain etoposide derivatives have enhanced anti-cancer activity and, in addition, low toxicity, and are therefore useful as medicaments for the treatment of chronic diseases.

The present invention therefore relates to compounds of formula I and their physiologically acceptable salts thereof

R 'is hydrogen or R,

R is a group of formula (a) or an acyl residue of formula (b) wherein

X, Y and Z are each independently oxygen or sulfur,

A is a linear or branched C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or an aryl group, preferably a phenyl group, in its alkyl moiety a C 1 -C 4 linear or branched phenyl alkyl group or naphthyl group, where the aryl group is optionally one to three hydroxy groups; C1-4 straight or branched alkoxy optionally halogenated with chlorine or fluorine, benzyloxy

or with a halogen atom, preferably a chlorine atom or a fluorine atom, with the proviso that when R 'is R, R is 4-fluorophenoxyacetyl, 4-benzyloxy-phenoxyacetyl, 4-hydroxy-phenoxyacetyl, 4-methyl-phenoxyacetyl, 3,4,5-trimethoxy-phenoxyacetyl, 3,4- methylenedioxyphenoxyacetyl, 2,3-dimethoxyphenoxyacetyl, 4- (trifluoromethoxy) phenoxyacetyl, 4-phenylphenoxyacetyl, 1-naphthoxy- acetyl, cyclohexylacetyl, 4-methylphenoxyacetyl or 3,4-dimethoxyphenoxyacetyl.

C 1-4 straight or branched chain alkyl groups include, for example, methyl, ethyl, propyl and butyl, and the same differentiation applies to the alkyl portion of the phenylalkyl group and the alkoxy group.

Preference is given to compounds of general formula (I) wherein R 'is hydrogen.

Preferred R is ethoxyacetyl, phenoxyacetyl, 4-methoxy-phenoxyacetyl, 2-methoxy-phenoxyacetyl, 4-nitro-phenoxyacetyl, 2-nitro-phenoxy acetyl, 2,4-dichlorophenoxyacetyl,

2,4,5-trichlorophenoxyacetyl, 2,4,6-trichlorophenoxyacetyl, 4-fluorophenoxyacetyl, 2-fluorophenoxyacetyl, hydroxy-phenoxyacetyl, 4-benzyloxy-phenoxyacetyl, 4-methylphenoxyacetyl, 3,4,5-trimethoxy-phenoxyacetyl, 3,4-methylene- dioxyphenoxyacetyl, 2,3-dimethoxyphenoxyacetyl. ♦ »» · »··

- 5-group, 4- (trifluoromethoxy) -phenoxyacetyl, 4-phenyl-phenoxyacetyl, 2-naphthoxyacetyl, 1-naphthoxyacetyl, cyclohexylacetyl , 4-methylphenoxyacetyl or 3,4-dimethoxyphenoxyacetyl.

The invention further relates to a process for the preparation of a compound of formula I by reacting a glycosyl intermediate of formula II with an intermediate of formula III wherein

R and R 'are as defined above and the resulting compound of formula (I) is phenol functional.

is deprotected if desired.

The process of the present invention is illustrated in Scheme A for starting materials of formula (II) and (III) wherein R is phenoxyacetyl and R 'is hydrogen or benzyloxycarbonyl.

Of course, the synthesis of all compounds of Formula I can be modeled from the reaction shown in the Scheme.

In the reaction scheme, all R groups are replaced by phenoxyacetyl. Z also represents a benzyloxycarbonyl group.

During the synthesis, 4,6-ethylidene-S-D-glucose is prepared which is protected on the anomeric hydroxyl group with a benzyloxycarbonyl group. This compound is then esterified to yield

The two alcohol groups at the 2- and 3-positions are esterified with phenoxy-a6 cetyl to provide a protected glycosyl intermediate. The protecting group is then catalytically hydrogenated on a Pd / C catalyst to remove the protecting group.

The preparation of these compounds is described in detail in EP 0,445,021.

This intermediate is then condensed at its 4'-phenol with a Z-protected 4'-demethylpipodophyllotoxin derivative, the preparation of which is described in detail in EP 0,401,800. The condensation is carried out at low temperature, near -20 ° C, in the presence of a Lewis acid such as BF3 etherate in a chlorinated hydrocarbon, preferably methylene chloride, to give a compound of formula (I) wherein R 'is benzyloxycarbonyl.

Because of the anomeric hydroxyl group on the glycosyl intermediate, there is always the problem of the stereochemistry of the resulting compound and its regulation.

The process of the invention produces minimal amounts of the unwanted alpha-anomer, and thus the compound of the invention can be obtained directly without further purification.

The final step of the compound of the present invention wherein R 'is hydrogen is accomplished by conventional catalytic hydrogenation in the presence of Pd / C at room temperature.

The present invention is illustrated in more detail by the following examples. ; ·· *:. *. ·· j. ··· «·« · · ·· ·. Without limiting the scope of the examples to the examples.

Example 1

4'-Phenoxyacetyl-4'-demethyl-4-O- [2,3-his (phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin kg (5.62 mol) 4 '- (2 phenoxyacetyl) -4'-demethyl-epipodophyllotoxin and 3.2 kg (6.74 mol, 1.2 equivalents) of 2,3-bis (2-phenoxyacetyl) -4,6-ethylidene-SD-glucose A mixture of 18 liters of dry dichloromethane was cooled to -18 ° C and 1.73 liters (14.05 mol, 2.5 equivalents) of boron trifluoride etherate was added slowly. The mixture is reacted for 2 hours at -18 ° C and the reaction is followed by thin layer chromatography. Pyridine (910 mL, 2 equivalents) was added and the solution was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (70-200 µm) eluting with MeOH (2%) / CH 2 Cl 2. After evaporation, 4.73 kg of an amorphous white powder are obtained. Part of this is crystallized for analytical tests.

The results are as follows:

Total formula: ¢ 53 ^ 00 ^

Molecular weight: 990

Yield: 85%

132-134 ° C [α] ²² _D = -67 ° (c = 1; CHCl 3).

Example 2 '- (2-Methoxy-phenoxyacetyl) -4' -demethyl-4-O- [2,3-bis (2-methoxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

The procedure described in Example 1 was followed except that 2,3-bis [2- (2-methoxyphenoxy) acetyl)) - 4,6-ethylidene-ED-glucose and 4 '- [2- ( 2-methoxy-phenoxy) -acetyl)] ¹ -4 demethyl-demethylepipodophyllotoxin using the 2,3- (2-phenoxy-acetyl) -4, 6-ethylidene-glucoside and ED-4 (2-phenoxy-acetyl) - Instead of 4'-demethyl-epipodophyllotoxin.

Molecular formula. C ₅ gH ₅ gO ₂ 2

Molecular weight: 1080

Yield: 75%

Melting point: 113-115 ° C [α] ²² _D : 52 ° (C = 1; CHCl ₃ )

Example 3 '- (4-Methoxyphenoxyacetyl) -4' - demethyl-4-O- [2,3-

-bis (4-methoxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

In Example 1 was repeated except that 2,3-bis [2- (4-methoxyphenoxy) acetyl] -4,6-ethylidene-4 SD-glucose and ¹ - [2- (4 -methoxy-phenoxy) -acetyl] -4 '-demethyl-epipodophyllotoxin was used to add 2,3- (2-phenoxyacetyl) -4,6-ethylidene-ED-glucose and 4' - (2-phenoxyacetyl) 9. · «.. ...., ...., • J * ·. ··· '·' · »·· ·· ... * ♦ · ·

Instead of -4'-demethyl-epipodophyllotoxin.

Total formula: ¢ 551155022

Molecular weight: 1080

Yield: 73%

107 DEG-109 DEG C. [.alpha.] D @ ²² = -61 DEG (C = 1; CHCl3).

Example 4

4 ^1- (2-Nitrophenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (2-nitrophenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

The procedure described in Example 1 was followed except that 2,3-bis [2- (2-nitrophenoxy) acetyl] -4,6-ethylidene-ED-glucose and [2- (2-nitrophenoxy) acetyl ] - {4 ', 4-demethyl-epipodophyllotoxin ^1} for using the 2,3- (2-phenoxyacetyl) -4,6-ethylidene-SD-glucose and 4' - (2-phenoxy-acetyl) - Instead of 4'-demethyl-epipodophyllotoxin.

Formula: C53H47O25N3

Molecular weight: 1125

Yield: 79%

135-137 ° C. example

4 '- (4-Nitrophenoxyacetyl) -4'-demethyl-4-O - [2,3-bis (4-nitrophenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin ···· • · · · ··· * ·· 9 * • · ·· «· * 999

The procedure described in Example 1 was followed except that 2,3-bis [2- (4-nitrophenoxy) acetyl] -4,6-ethylidene-SD-glucose and 4 '- [2- (4-nitrophenoxy) ) -acetyl] -4'-demethyl-epipodophyllotoxin is used in 2,3- (2-phenoxyacetyl) -4,6-ethylidene-ED-glucose and 4 '- (2-phenoxyacetyl) -4'-demethyl. -epipodophyllotoxin.

Formula: C53H47O25N3

Molecular weight: 1125

Yield: 82%

Melting point: 143-145 ° C [α] ²² D = -72 ° (C = 1; CHCl 3).

Example 6

4 '- (2,4-Dichloro-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (2,4-dichloro-phenoxy-acetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

The procedure of Example 1 was followed except that 2,3-bis [2- (2,4-dichlorophenoxy) acetyl] -4,6-ethylidene-SD-glucose and 4 '- [2- (2,4-Dichloro-phenoxy) -acetyl] -4'-demethyl-epipodophyllotoxin is used with 2,3- (2-phenoxyacetyl) -4,6-ethylidene-ED-glucose and 4 '- (2-phenoxy) -acetyl) -4'-demethyl-epipodophyllotoxin.

Formula: C53H44O19Cl5

Molecular weight: 1197

Yield: 85%

Melting point: 115-117 ° C · · · · · · · · · · ·

• ·. ···. ··· ··· · · ·· - .. · ·· «[θ '] ²² _d = -51 ° (C = 1; CHC1 ₃ )

Example 7

4 ^1- (2,4,5-Trichlorophenoxyacetyl) -4-dimethyl-4-O- [2,3-bis (2,4,5-trichlorophenoxyacetyl) -4,6- ethylidene-glucosyl] epipodophyllotoxin

The procedure described in Example 1 was followed except that 2,3-bis [2- (2,4,5-trichlorophenoxyacetyl)] - 4,6-ethylidene-SD-glucose and 4 '- [ 2- (2,4,5-trichlorophenoxy) acetyl] -4'-demethyl-epipodophyllotoxin is used to add 2,3- (2-phenoxyacetyl) -4,6-ethylidene-ED-glucose and 4'- (2-phenoxyacetyl) -4'-demethyl-epipodophyllotoxin.

Formula: C53H41O19Cl9

Molecular weight: 1300.5

Yield: 75%

126-128 ° C [α] ²² _D = -43 ° (C = 1; CHCl 3).

Example 8 * - (2,4,6-Trichlorophenoxyacetyl) -4 * -demethyl-4-O- [2,3-bis (2,4,6-trichlorophenoxyacetyl) -4 6-ethylidene-glucosyl] epipodophyllotoxin

The procedure described in Example 1 was followed except that 2,3-bis [2- (2,4,6-trichlorophenoxyacetyl)] - 4,6-ethylidene-ED-glucose and 4 '- [ 2- (2,4,6-trichlorophenoxy) -ac-12 ''. * ·. ··. ··· »; •: ··. ··· ··· · · methyl] -4 used ^one demethyl-demethylepipodophyllotoxin of 2,3- (2-phenoxyacetyl) -4,6-ethylidene-ED-glucose and 4 '- (2-phenoxy-acetyl ) In place of -4'-demethyl-epipodophyllotoxin.

Formula: C53H41O19Cl9

Molecular weight: 1300.5

Yield: 80%

Melting point: 120-122 ° C [α] ²² _D = _-10 ° _{(c = 1;} CHCl 3)

Example 9

4 '- (2-Fluoro-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (2-fluoro-phenoxy-acetyl) -4-ethylidene-glucosyl] epipodophyllotoxin

The procedure described in Example 1 was followed except that 2,3-bis [2- (2-fluorophenoxyacetyl)] -4,6-ethylidene-SD-glucose and 4 '- [2- (2 -fluorophenoxy) -acetyl] -4'-demethyl-epipodophyllotoxin is used in combination with 2,3- (2-phenoxyacetyl) -4,6-ethylidene-BD-glucose and 4 '- (2-phenoxyacetyl) -. Instead of 4'-demethyl-epipodophyllotoxin.

Formula: C53H47O19F3

Molecular weight: 1140

Yield: 57%

Melting point: amorphous [α] ²² _D =

-58 ° (C = 1; CHCl 3).

Example 10

4'-Ethoxy-acetyl-4'-demethyl-4-0- [2,3-bis (ethoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin

The procedure described in Example 1 was followed except that 2,3-bis [2-ethoxyacetyl) -4,6-ethylidene-BD-glucose and 4 '- [2-ethoxyacetyl) -4'- demethylepipodophyllotoxin using the 2,3- (2-phenoxyacetyl) -4,6-ethylidene-β-D-glucose and 4 '- instead of (2-phenoxy-acetyl) -4-demethyl epipodophyllotoxin ^1.

Formula: C41H50O19

Molecular weight: 846

Yield: 71%

195-198 ° C [α] ²² _D = ₆₄ ° _{(c = 1,} CHCl 3).

Example 11

4 * - [2,2- (2,3-dioxy-naphthylidene) acetyl] -4'-demethyl-4-O- [2,3-bis [2,2- (2,3-dioxy-naphthylidene) acetyl] -4,6-ethylidene-glucosyl] epipodophyllotoxin

In Example 1 was repeated except that 2,3-bis (2,2-naphthylidene-dioxy-acetyl) -4,6-ethylidene-ED-glucose and 4 ¹ - (2,2-naftilidén- dioxyacetyl) epipodophyllotoxin is used instead of 2,3- (2-phenoxyacetyl) -4,6-ethylidene-ED-glucose and 4 '- (2-phenoxyacetyl) -4'-demethyl-epipodophilotoxin.

• · • ♦ ·

Formula: C ??? (Rc ₎ qQ22

Molecular weight: 1182

Yield: 64%

Melting point: 157-159 ° C [α] ²² _D = -40 ° (C = 1; CHCl ₃ )

Example 12

4'-Benzylthioacetyl-4'-demethyl-4 - [[2,3-bis (benzylthioacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

The procedure described in Example 1 was followed except that 2,3-bis (2-benzylthioacetyl) -4,6-ethylidene-β-D-glucose and 4 ¹ - (2-benzylthioacetate) were used. acetyl) -4'-demethyl-epipodophyllotoxin is used to add 2,3- (2-phenoxyacetyl) -4,6-ethylidene-BD-glucose and 4 ^1- (2-phenoxyacetyl) -4'-demethyl-epipodophyllotoxin. instead.

Formula: Cs6 ^H 56 ° 16 ^s 3

Molecular weight: 1080

Yield: 49%

Melting point: amorphous [α] ²² _D = -48 ° (C = 1; CHCl 3).

Example 13

4'-Phenylthio-acetyl-4'-demethyl-4-0- [2,3-bis (phenylthio-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin

In the same manner as in Example 1, 2,3-bis (2-phenylthioacetyl) -4,6-ethylidene-β-D-glucose and 4 (2-phenylthioacetyl) were used. ) -4'-Demethyl-epipodophyllotoxin is used in place of 2,3- (2-phenoxyacetyl) -4,6-ethylidene-SD-glucose and 4- (2-phenoxyacetyl) -4'-demethyl-epipodophyllotoxin.

Formula: C53H5QO16S3

Molecular weight: 1038

Yield: 82%

Melting point: amorphous [α] 22 _{D = -60} ° ( _{C = 1;} CHCl 3)

Example 14

4 '- (4-Fluoro-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (4-fluoro-phenoxy-acetyl) -4, ethylidene-glucosyl] epipodophyllotoxin

The procedure described in Example 1 was followed except that 2,3-bis (4-fluorophenoxyacetyl) -4,6-ethylidene-β-D-glucose and 4 '- (4-fluorophenoxy) acetyl] -4 used ^one demethyl-demethylepipodophyllotoxin and the final product on silica CH2C13 / MeOH 99: purified amorphous powder: 1 mixture as eluent.

IR (Nujol, cm ^-1 )). 1755, 1590, 1480, 1150, 1080, 820,

720.

1 H-NMR (400 MHz, CDCl 3): δ, ppm = 6.9 (m, 8H, Ar);

6.79 (m, 2H, Ar); 6.77 (s, 1H, H-5); 6.67 (m, 2H,

Price); 6.51 (S, 1H, H-8); 6.26 (s, 2H, H-2 ', H-6);

5.92 (d, 1H, J = 1.0

Hz,

OCHA); 5.71 (d, 1H,

J = 0.9

Hz, OCHBO); 5.34 (t,

1H,

J3-2 = 9.4

Hz,

H-3); 5.03 (dd, 1H, J2-1 = 7.9

Hz,

J2-3 = 9.2

Hz,

H-2); 4.91 (d, 1H, J = 2 = 7.8 Hz, H-1); 4.86 (S,

2H, 4'ArOCH ₂ ); 4.83 (m, 1H, J = 3.5 Hz, J = 3.0 Hz, H-4);

4.69 (q, 1H, J7-CH3 = 4.9 Hz, H-7); 4.58 (d, 1H,

J1-2 = 5.3 Hz, H-1); 4.56 (7AB, 2H, J = 16.8 Hz,

J6.6 Hz, ArOCH ₂ ); 4.39 (dd, 1H, J = 8.9 Hz, J = 10.8 Hz, H-3a (A)); 4.37 (d AB, 1H, J = 16.4 Hz,

ArOCH); 4.22 (t, 1H, J = 8.20 Hz, H-3a (B)); 4.20 (m, 1H, H-6B); 4.15 (dAB, 1H, J = 16.3 Hz, ArOCHB-);

3.66 (s, 6H, OCH ₃ ); 3.59 (t, 1H, JAB = 10.2 Hz,

H-6B); 3.52 (t, 1H, J 4-5 = 9.45 Hz, H-4); 3.42 (ddd, 1H, J 5-6 = 4.8 Hz, J 5-4 = 9.45 Hz, H-5);

3.15 (dd, 1H, J2-3 = 14.1 Hz, J2-1 = 5.20 Hz, H-2);

2.85 (m, 1H, H-3); 1.35 (d, 3H, JCH 3-7 = 5.0 Hz, CH ₃ ).

Elemental analysis for C53H47F3O19:

Found: C, 60.92; H, 4.53; Found: C, 59.34; H, 4.42.

Example 15

4 '- (4-benzyl (oxy-phenoxy-acetyl) ^-4-1 4-demethyl Ο- [2,3-bis (4-benzyloxy-phenoxy-acetyl) -4,6-ethylidene-glucosyl ] epipodophyllotoxin.

We use the procedure described in Example 1 to make the difference1 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 17 gels to 2,3-bis (4-benzyloxy-phenoxyacetyl) -4,6-ethylidene-β-D-glucose and 4 '- (4-benzyloxy-phenoxyacetyl) -4 '-Demethyl-epipodophyllotoxin is used. The final product is shown in Figure 14.

is isolated by chromatography as described in Example 1b as an amorphous powder.

IR (Nujol, v cm ^-1 ). 1760, 1690, 1590, 1490, 1200, 1055, 710.

¹ H-NMR (400 MHz, CDCl 3): δ, ppm = 7.45-7.22 (m,

15H, F); 6.92-6.70 (m, 10H); 6.68 (1.1H, H-5);

6.50 (d, 2H, J = 9.1 Hz); 6.38 (s, 1H, H-8); 6.18

(S, 2H, H-2 ', H-6'); 5.80 (S, 1H, OCHA); 5 55 (D, 1H, J = 0.9 Hz, OCHBO); 5.29 (T, 1H, J = 9.45 Hz, H-3); 4.97 (dd, 1H, J = 9.45 Hz, , H-3); 4.97 (dd, 1H, J = 7, 93 Hz, J = 9 Hz, H-2); 4.94 (S, 2H, PhCH ₂ O-4 '); 4.84 (d, 1H, J = 5.8 Hz, H-I ); 4.84 (S, 2H, PhCH ₂ O); 4.80 (q AB, 2H, J = 11.8 Hz, PhCH ₂ O) ; 4.77 (s, 2H ,, ArOCH ₂ -4 ' ); 4.74 (d, 1H, J4-3 = 3.8 Hz, H-4); 4.61 (q, l H,

J 7 -CH ₃ = 5.0 Hz, H-7); 4.48 (d, 1H, J = 2 = 6 Hz, H1); 4.47 (q AB, 2H, J = 16.5 Hz, J = 3.24

Hz, ArOCH ₂ CO); 4.32 (t, 1H, J = 10.9 Hz, J = 8.6 Hz, H-3a (A)); 4.30 (d AB, 1H, J = 16.5 Hz,

ArOCHfiCO); 4.15 (t, 1H, J = 8.7 Hz, H-3a (B));

4.13 (dd, 1H, JAB = 10.26 Hz, J6-5 = 4.7 Hz,

H-6A); 4.04 (d AB, 1H, J = 16.4 Hz, ArOCHACO);

3.56 (s, 6H, OCH 3); 3.51 (t, 1H, JAB = 10.2 Hz,

H-6B); 3.44 (t, 1H, J 4-5 = 9.4 Hz, H-4);

· * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

3.35 (ddd, 1H, J5 ~ 4 = 9.66 Hz, J5-6 = 4.7

Hz, H-5 '); 3.08 (dd, 1H, J2-3 = 14.1 Hz, J2-1 = 5.2 Hz, H-2); 2.75 (m, 1H, H-3); 1.26 (d, 3H, JCH ₃ -7 = 5.0 Hz, CH ₃ ).

Example 16

4 '- (4-Hydroxy-phenoxy-acetyl) -4'-demethyl-4-O- [2,3-bis (4-hydroxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin

2.27 g of 4 '- (4-benzyloxy-phenoxyacetyl) -4'-demethyl-4-O-

- [2,3-Bis (4-benzyloxy-phenoxyacetyl) -4,6-ethylidene] -epipodophilotoxin (Example 15) was dissolved in 25 ml of ethyl acetate and 0.9 g of 10% Pd / Hydrogenated in the presence of C at 8,45 x 10 2 Pa for 8 hours. The medium was filtered and concentrated under reduced pressure. The debenzylated product was purified by chromatography on silica gel eluting with CH ₂ Cl ₂ / MeOH 97: 3. 1.40 g of product are obtained, corresponding to an 80% yield.

Melting point: -163 ° C.

IR (Nujol, vfcm ¹ )). 3360, 1745, 1500, 1200, 1070, 820,

710.

1 H-NMR (400 MHz, CD ₃ COCD ₃ ): δ, ppm = 8.0 (s, 1H,

OH); 7.96 (s, 1H, OH); 7.95 (s, 1H, OH); 7.09 (s,

1H, H-5); 6.86 (d, 2H, J = 9.0 Hz, Ar); 6.77 (d, 2H, J = 9.0 Hz, Ar); 6.74 (m, 6H, Ar); 6.59 (d, 2H, J = 8.9 Hz, Ar); 6.55 (s, 1H, H-8); 6.40 (s, 2H, • · · «* · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Η-2 ′, H-6 ′); 5.98 (d, 1Η, J = 0.8 Hz, OCHAO); 5.84 (s, 1H, OCHBO); 5.40 (t, 1H, J3-2 = 9.2 Hz,

H-3); 5.35 (d, 1H, J = 7.9 Hz, H-1); 5.09 (d, 1H,

J4-3 = 3.3 Hz, H-4); 5.0 (dd, 1H, J ', 2-1 = 7.9 Hz,

J2-3 = 9.4Hz, H-2); 4.85 (s, 2H, ArOCH ₂ CO-4 ');

4.80 (q, 1H, J7 -CH3 = 5.0 Hz, H-7); 4.63 (d, 1H,

J1-2 = 5.3 Hz, H1); 4.59 (s, 2H, ArOC H ₂ CO); 4.43 (d AB, 1H, J = 16.5 Hz, Ar OCHACO); 4.37 (dd, 1H,

J = 10.0 Hz, J = 8.7 Hz, H-3a (A)); 4.27 (dd, 1H,

J = 8.3 Hz, J = 7.6 Hz, H-3a (B)); 4.21 (m, 1H,

H-6 THE) ; 4.06 (d AB, 1H, J = 16.6 Hz, ArOCHBCO); 3.67 (m, OCH 3 , H-6 B, H-4); 3.57 (m, 1H, H-5); 3:19 (dd, 1H, J2-3 = 14.3 Hz, J2-1 = 5.3 Hz, H-2); 3.07 (m, 1H, H-3); 1.26 (d, 3H, JCH ₃ -7 = 5.06) Hz, CH3).

Elemental analysis for C52H5QO22:

H, 4.91; C, 60.78; H, 4.96.

Example 17

4'-demethyl-4-Ο- [2,3-bis (phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin

1st step:

4'-Benzyloxycarbonyl-4'-demethyl-4-O- [2,3-his (phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin (condensation of the glycosyl moiety at 4n protected epi • · · ·

- with 20 podophyllontoxins)

BF3 Etherate (2.9 mL, 2.5 equivalents) was added over 30 minutes to 4'-benzyloxycarbonyl-4'-demethyl-epipodophyllotoxin (5 g, 9.35 mmol) and 6.65 g (14 mmol, 1 mmol). 5 equivalents) of a solution of 2,3-bis (phenoxyacetyl) -4,6-ethylidene-BD-glucose in 50 ml of anhydrous CH ₂ Cl ₂ at -18 ° C under nitrogen and with stirring. The mixture was stirred at -18 ° C for 2 hours and then quenched with pyridine (3 mL). The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Purify by chromatography on silica gel eluting with CH ₂ Cl ₂ . 8.13 g of the glucosyl derivative were obtained in an amorphous form (88% yield).

Step 2:

Hydrogenation at 4 'position The glycosyl derivative of Step 1 in 50 ml of anhydrous acetone was charged to a hydrogenation vessel and 500 mg of 10% Pd / C catalyst was added. A hydrogen inlet was added to the vessel and the solution was stirred with a magnetic stirrer and hydrogen was introduced at a pressure of 0.1013 bar. The mixture was stirred for 2 hours. The catalyst was then filtered off and the solvent removed under reduced pressure. 4.32 g (quantitative yield) of product are obtained in amorphous form.

···· «· · · · · · · · · · · · · · · · · · ··· ·

IR (Nujol) (, cm ^-1 ): 1760 (c = o), 1600, 1050.

1 H-NMR (400 MHz, CDCl ₃ ): δ, ppm = 6.7-7.3 (8H, m. Ar); 6 77 (1H, S, H-5); 6 73 (2H, d, Ar-H) ; 6.49 (1H, and, H-8); 6.24 (2H, s, H-2 ', 6'); 5.9 and 5.64 (2 H, 2d , OCH ₂ O); 5.43 (1H, s, phenol OH); 5.37 (1H, t, J = 9.5 Hz, H-3); 5.05 (1H, dd, H-2);

4.93 (1H, d, J = 7.9 Hz, 1H); 4.82 (1H, d, J = 3.4 Hz, H-4); 4.69 (1H, q, H-7); 4.60 (2H, m, C0 ₂ 0CH); 4.55 (1H, H1); 4.40 and 4.18 (2H, 2d, _OCH2 CO); 4.39 (1H, dd, H-3a (A)); 4.18 (2H, m, H-3a (B) and H-6eq.); 3.75 (6H, s, OCH ₃ );

3.59 (1H, t, H-6ax); 3.52 (1H, m, H-4); 3.44 (1H, m, H-5); 3.15 (1H, dd, J2-1 = 5.2 Hz, J2-3 = 14.1 Hz, H-2); 2.87 (1H, m, H-3); 1.35 (1H, d, J = 5.1 Hz).

Example 18

4'-Demethyl-4-O- [2,3-bis (4-methoxyphenoxyacetyl) -

4,6-ethylidene-glucosyl] epipodophyllotoxin

1st step

The procedure described in Example 17 was followed except that 2,3-bis (4-methoxyphenoxyacetyl) -4,6-ethylidene-SD-glucose and 4'-benzyloxycarbonyl-4'- demethyl-epipodophyllotoxin is used. Thus, 4'-benzyloxycarbonyl-4'-demethyl-4-O- [2,3-bis (4-methoxyphenoxyacetate)

til) -4,6-ethylidene-glucosyl) -epipodophyllotoxin was obtained in 100% yield in amorphous state.

IR (Nujol) (v, cm ^-1 ): 1750, 1590, 1220, 1020. 1 H-NMR (400 MHz, CDCl 3): δ, ppm = 7.32-7.42 (m,

5H, Ph); 6.86 (m, 8H, ArO-5); 6.66 (d, 2H, Ar);

6.48 (S, 1H, H-8); 6.25 (s, 2H, H-2 ', H-6');

5.90 (S, 1H, OCHAO); 5.67 (s, 1H, OCHBO); 5.35 (t, 1H, J = 9.4 Hz, H-3); 5.24 (s, 2H, PhCH ₂ );

5.04 (dd, 1H, J = 7.9 Hz, J = 9.2 Hz, H-2); 4.91 (d, 1H, J = 7.8 Hz, H-1); 4.81 (d, 1H, J = 3.4 Hz,

H-4); 4.68 (q, 1H, J = 4.9 Hz, H-7); 4.55 (d, 1H,

J = 5.15 Hz, H-1); 4.54 (q AB, 2H, J = 4.15 Hz,

J = 16.5 Hz, ArOCH ₂ ); 4.38 (dd, 1H, J = 10.2 Hz,

J = 9.2 Hz, H-3a (A)); 4.36 (d, 1H, J = 16.4 Hz,

ArOCH); 4.20 (m, 2H, H-6A, H3a (B)); 4.11 (d, 1H,

J = 16.4 Hz, ArOCHB); 3.71 (s, 3H, _CH3 OPh); 3.68

(S, 3H, _CH3 OPh); 3.65 (S, 6H, and ₃ ); 3.58 (T, 1H, J = 10.2 Hz, H-6 B); 3.51 (T, 1H, J = 9.4 Hz, H-4 ); 3.42 (ddd, 1H, J5-4 = 9.5 Hz, J5  - 6 = = 5 , 0 Hz, H-5); 3.15 (dd, 1H, J = 5.2 Hz , J - = 1 4.2 Hz, H-2); 2.83 (m, 1H, H-3) ; 1.34 (d, 3H,

J = 4.95 Hz, CH ₃ ).

Step 2

Hydrogenation at 4 'position g 4' protected intermediate 30 ml ethanol / ace · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Hydrogenate in a 4: 1 mixture (0.18 g, 10% w / w Pd / C) at room temperature and atmospheric pressure with stirring for 2 hours. The reaction was monitored by TLC (CH2Cl2 / MeOH 97: 3). The catalyst was finally filtered through a sintered glass filter and washed with ethanol. The filtrate was concentrated under reduced pressure to give the title compound in crystalline form.

Yield 100%.

Melting point: 196 ° C.

IR (Nujol; v, cm ^-1 ): 3400, 1750, 1590, 700.

¹ H-NMR (400 MHz, CDC1 ₃ ): δ, ppm = 6.79 (m, 5H, ArO, H-5); 6.76 (d, 2H, J = 7.67 Hz, J = 9.0 Hz, ArO); 6.67 (d, 2H, J = 9.0 Hz, ArO); 6.49 (S, . 1H, H-8); 6.23 (s, 2H, H-2 ' , H-6 '); 5.92 (D, 1H, J =

= 1.1 Hz, OCHAO); 5.69 (d, 1H, J = 1.1 Hz, OCHBO);

5.41 (s, 1H, OH); 5.36 (t, 1H, J3-2 = 9.4 Hz,

H-3); 5.05 (dd, 1H, J2-1 = 7.92 Hz, J2-3 = 9.25 Hz, H-2); 4.91 (d, 1H, J1-2 = 7.82 Hz,

H-I); 4.82 (d, 1H, J4-3 = 3.4 Hz, H-4); 4.69 (q,

1H, J = 5.0 Hz, H-7); 4.54 (q AB, 2H, J = 16.4 Hz,

J = 4.3z, ArOCH ₂ ); 4.53 (d, 1H, H1); 4.38 (dd,

1H, J = 8.84 Hz, J = 10.6 Hz, H-3a (A)); 4.37 (d, 1H,

J = 16.4 Hz, ArOCHA); 4.20 (m, 2H, H-6A, H-3a (B);

4.12 (d, 1H, J = 16.4 Hz, ArOCHB); 3.75 (s, 6H,

OCH ₃ ); 3.71 (s, 3H, CH ₃ O-PhOCH ₂ ); 3.68 (s3H,

CH ₃ O-PhOCH ₂ ); 3.59 (t, 1H, J = 10.1 Hz, H-6B);

- 24 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

3.51 (T, 1H, j = 9.5: Hz, H-4); 3.42 ( : ddd, 1H, J = = 4.7 Hz, , J: = 9.6 Hz, H-5); 3.13 (dd, 1H, J2-1 = = 5.2 Hz, , J2 · -3 = 14.1 Hz, H-2); 2.87 ( m, 1H, H-3); 1.34 (D, 3H, J = 4.98 Hz, CH ₃ ).

Elemental analysis for C47H48O19:

H, 5.27; C, 61.40; H, 5.19.

Example 19

4'-Demethyl-4-0- [2,3-bis (4-fluorophenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

1st step

The procedure described in Example 17 was repeated except that 2,3-bis (4-fluorophenoxyacetyl) -4,6-ethylidene-β-D-glucose and 4'-benzyloxycarbonyl-4 '-Demethyl-epipodophyllotoxin is used. The desired 4'-benzyloxycarbonyl-4'-dimethyl-4-O- [2,3- (4-fluoro-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin is obtained in 98% yield; in amorphous state.

IR (Nujol, v, cm -1): 1750, 1590, 1180, 705.

1 H-NMR (400 MHz, CDCl 3): δ, ppm: 7.42-7.32 (m, 5H,

Ph); 6.93 (m, 4H, F-Ph); 6.80 (m, 2H, F-Ph);

6.77 (s, 1H, H-5); 6.67 (m, 2H, F-Ph); 6.51 (s,

1H, H-8); 6.25 (s, 2h, H-2 ', H-6'); 5.92 (d, 1H,

J = 1.12 Hz, OCHAO); 5.71 (d, 1H, J = 0.92 Hz, ·· »♦ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· ·· · ·····

OCHBO); 5.34 (t, 1H, J3-2 = 9.4 Hz, H-3); 5.25 (S, 2H, PhCH ₂ ); 5.03 (dd, 1H, J2-1 = 7.9 Hz,

J2-3 = 9.2 Hz, H-2); 4.91 (d, 1H, J 1-2) = 7.8

HZ, H-1); 4.83 (D, 1H, J = 3.4 Hz, H-4); 4, 69 (q, 1H, J = 5.0 Hz, H-7 ); 4.57 (D, 1H, H-1) ; 4.55 (q AB, 2H, J = 16.5 Hz, J = 67 Hz, ArOCH ₂ ); 4.39 (dd, 1H, J = 10 , 5 Hz, J = 8.7 Hz , H : -3a (A)); 4.37

(d AB, 1H, J = 16.3 Hz, ArOCHA); 4.21 (m, 2H,

H-6A, H-3a (B)); 4.15 (d AB, 1H, J = 16.4 Hz,

ArOCHB); 3.56 (s, 6H, OCH ₃ ); 3.59 (t, 1H, J = 10.2 Hz, H-6B); 3.52 (t, 1H, J 4-5 = 9.45 Hz,

H-4) ; 3.42 (ddd, 1H, J 5-4 = 9.54 Hz, J5 -6 = = 4.8 Hz, H-5); 3.15 (dd, 1H, J = 14.1 Hz, J2-1 = 5.2 Hz, H-2); 2.85 (m, 1H, H- -3); 1.35 (D, 3H,

J = 5.0 Hz, CH ₃ ).

Step 2

Hydrogenation at 4 'position

The 4'-protected intermediate is hydrogenated on Pd / C as described in Example 18. This gives the title compound in crystalline form.

Yield: 94%.

Melting point: 164 ° C.

IR (Nujol, vcm ^-1 ): 3400, 1755, 1595, 1170.

² H-NMR (400 MHz, CDCl ₃ ): δ, ppm = 6.93 (m, 4H, ArO);

6.79 (m, 2H, ArO); 6.76 (s, 1H, H-5); 6.66 (m, 2H, ····································································································

ArO); 6.51 (s, 1H, H-8); 6.23 (s, 2H, H-2 ', H-6');

5.92 (d, 1H, J = 0.97 Hz, OCHAO); 5.71 (d, 1H, J = 0.98 Hz, OCHBO); 5.41 (s, 1H, OH); 5.34 (t, 1H,

J3-2 = 9.4 Hz, H-3); 5.03 (dd, 1H, J2-1)

7.9 Hz, JZ-3 = 9.1 Hz, H-2); 4.92 (d, 1H, J

-2 = 7.8 Hz, H-1); 4.83 (d, 1H, J4-3 = 3.4 Hz,

H-4); 4.69 (q, 1H, J7, _CH3 = 4.9 Hz, H-7);

4.56 (qAB, 2H, J = 6.6 Hz, J = 16.5 Hz, ArOCH ₂ );

4.54 (d, 1H, J 1-2 = 4.86 Hz, H-1); 4.38 (t, 1H,

J = 8.9 Hz, J = 10.3 Hz, H-3a (A)); 4.375 (d, 1H,

J = 16.5 Hz, ArOCHA-); 4.21 (m, 2H, H-3a (B),

H-6A); 4.15 (d, 1H, J = 16.4 Hz, ArOCHB) · 3.76 (s, 6H, _OCH3); 3.59 (t, 1H, JAB = 10.1 Hz,

H-6B); 3.52 (t, 1H, J4-3 = 9.4 Hz, H-4);

3.42 (ddd, 1H, J5-6 = 4.75 Hz, J5-4 = 9.6 Hz,

H-5); 3.12 (dd, 1H, J2-3 = 14.1 Hz, J2-1 = 5.2 Hz,

H-2); 2.87 (m, 1H, H-3); 1.35 (d, 3H, JCH 3-7 = 4.98 Hz, CH ₃ ).

Elemental analysis for C45H42F2O17:

H, 4.74; C, 60.55; H, 4.73.

Example 20

4'-Demethyl-4-O- [2,3-bis (4-hydroxyphenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin ·· * · ·· · ···· * * · · · · · · ······· * · ♦ • · · · · · · ·

1st step

Condensation of the glycosyl moiety with the epipodophyllotoxin moiety

The procedure described in Example 17 was followed except that 2,3-bis (4-benzyloxy-phenoxyacetyl) -4,6-ethylidene-β-D-glucose and 4'-benzyloxycarbonyl were -4'-Demethyl-epipodophyllotoxin is used. Thus, the desired 4'-benzyloxy-carbonyl-4'-demethyl-4-0- [2,3-bis ^{(4-oxy-1-benzyl-phenoxyacetyl)} -4,6-ethylidene-glucosyl] epipodophyllotoxin obtained in 98% yield and amorphous.

IR (Nujol,? (Cm ^-1 )): 1750, 1590, 1490, 1200, 1070,

810, 715.

¹ H-NMR (400 MHz, CDCl 3): δ, ppm = 7.44-7.20 (m,

Ph); 6.85-6.70 (m, OArO); 6.68 (s, 1H, H-5); 6.59

(D, 2 H, J = 9 1 Hz, OArO); 6.38 (s, 1H, H-8); 6.18 (S, 2 H, H-2 ¹ 1 / H-6 '); 5.79 (S, 1H, OCHAO); 5.55 (s, 1H, OCHBO); 5 28 (t, 1H, J = 9.45 Hz, H-3); 5.17 (S, 2 H, PhCH ₂ ) ; 4.97 (Dd, 1H, J2-1 = 7.9 Hz,

J2-3 = 9 Hz, H-2); 4.84 (d, 1H, J 1-2 = 7Hz,

Hl); 4.83 (s, 2H, PhCH ₂ ); 4.79 (AB q, 2H, J = 5.1 Hz, J = 11.6 Hz, PhCH ₂ OArO); 4.74 (d, 1H,

J4-3 = 3.4 Hz, H-4); 4.61 (q, 1H, J = 5.0 Hz,

H-7); 4.50 (d, 1H, J 1-2 = 6.1 Hz, H-1); 4.47 (qAB,

2H, J = 16.5 Hz, J = 3.3 Hz, ArOCH ₂ CO); 4.32 (dd, 1H, J = 10.5 Hz, J = 8.8 Hz, H-3a (A)); 4.29 (d AB, 1H, J = 16.5 Hz, ArOCHBCO); 4.14 (t, 1H, • · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 28 J = 8.2 Hz, H-3a (B)); 4.12 (dd, 1H, J = 4.78 Hz, J = 10.4 Hz, H-6A); 4.04 (d AB, 1H, J = 16.4 Hz, ArOCHACO); 3.48 (s, 6H, OCH ₃ ); 3.51 (t, 1H, J = 10.1 Hz, H-6B); 3.44 (t, J = 4-3 = 9.4 Hz, H-4); 3.35 (ddd, 1H, J 5-4 = 9.6 Hz, J 5-6 = 4.7 Hz, H-5); 3.08 (dd, 1H, J = 5.2Hz, J-14.1Hz, H-2); 2.76 (m, 1H, J = 10.9 Hz, J = 3.1 Hz, H-3); 1.26 (d, 3H, J = 5.0 Hz, CH 3).

. step

Hydrogenation at 4 'position

To a solution of 1.5 g of the intermediate of Step 1 in 15 ml of distilled ethyl acetate was added 0.6 g of 10% w / w Pd / C and hydrogenated at 3.45 bar of hydrogen pressure and room temperature for 24 hours. The reaction was monitored by TLC (CH 2 Cl 2 / MeOH 95: 5). The catalyst was finally filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: CH 2 Cl 2 / MeOH 97: 3). 940 mg of the desired product are obtained in crystalline form.

Melting point: 16 ° C.

Yield: 85%.

IR (Nujol, v, cm ^-1 ): 3400, 1755, 1600, 1500, 1200, 1080.

¹ H-NMR (400 MHz, CDCl 3): δ, ppm = 6.93-6.61 (m, 6H,

OArO); 6.60 (s, 1H, H-5); 6.55 (d, 2H, J = 9.0 Hz, · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· «« · * · »

OArO); 6.41 (s, 1H, H-8); 6.15 (s, 2H, H-2 ', H-6')

5.85 (S, 1H, OCHAO); 5.66 (s, 1H, OCHBO); 5.37 (s,

1H, ArOH); 5.27 (t, 1H, J3-2 = 9.4 Hz, H-3);

5.01 (S, 1H, OH) ; 4.95 (dd, 1H, J2 - 1 = 7.8 Hz, J2-3 = 9.2 Hz, H-2); 4.81 (d, 1H, J = 7.8 Hz, H-I); 4.75 (d, 1H, J4-3.3 Hz, H-4); 4.62 (Q, IH, J7-CH3 = 4.9 Hz , H-7); 4.46 (q AB, 2 H, J = 16.5 Hz, J = 7.4 Hz, ArOCH ₂ CO); 4.40 (d, 1H, J  = 5 Hz, H-I); 4.30 (dd, 1H, J = 10.5 Hz, J = 8.7 Hz, H3

(THE)); 4.25 (d AB, 1HJ = 16.4 Hz, ArOCHACO); 4.14 (m, 2H, H-6A, H-3a (B)); 4.01 (d AB, 1H, J = 16.4

Hz, ArOCHBCO); 3.67 (s, 6H, OCH 3); 3.52 (t, 1H,

J = 10.2 Hz, H-6B); 3.44 (t, 1H, J4-3 = 9.4 Hz,

H-4); 3.35 (ddd, 1H, J 5-4 = 9.5 Hz, J 5-6 = = 4.7 Hz); 3.0 (dd, 1H, J2-3 = 14.0 Hz, J2-1 = 5.2 Hz, H-2); 2.79 (m, 1H, H-3); 1.27 (d, 3H, JCH ₃ -7 = 4.97 Hz, CH 3).

Elemental Analysis for £ 45 ^ 40 ^ 9:

Found: C, 60.81; H, 4.99; Found: C, 60.23; H, 5.06.

Example 21

4 ¹ -Demethyl-4-O- [2,3-bis (4-benzyloxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

0.72 g of 4'-benzyloxycarbonyl-4'-demethyl-4-O- [2,3-bis (4-benzyloxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] ··· ·· ··

9 • · ·· • · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99 '99

999 · Λ9 ··

99 »

99999

To a solution of epipodophyllotoxin (Example 20 step 1) in 10 ml of a 1: 1 mixture of ethanol / acetone was added 0.14 g of 10% Pd / C catalyst and hydrogenated at atmospheric pressure and room temperature for 1 hour. The reaction was monitored by TLC (CH2Cl2 / MeOH 97: 3). The catalyst was finally filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH ₂ Cl ₂ / MeOH 99: 1. The title compound was obtained in 38% yield.

Melting point: 159 ° C.

IRISH (Nujol, v (cm < ¹ >)): 3440, 1750, 1590, 1490, 1200 1075, 710, 690. 1H NMR (400 MHz, CDCl3): δ, ppm = 7.30- 7.20 (M, 10H, Ph); 6.79-6.70 (m, 6H, OArO); 6.68 (S, 1H, H-5)

6.60 (dm, J = 9.0 Hz, OArO); 6.38 (s, 2H, H-2 ', H-6 ') ; 5.80 (D, 1H, J = 0.75 Hz, OCHAO); 5.56 (D, 1H, J = 0.75 Hz, OCHBO); 5.33 (s, 1H, PhOH-4 ') / 5.29 (S, 1H, J3 -2 = 9,2H _3, J3-4 = 9.4 Hz, H-3) ; 4.98 (Dd, 1H, J2-1 = 7.9 Hz, J2-3 = 9.2

Hz, H-2); 4.84 (d, 1H, J = 7.6 Hz, HI); 4.83 (s, 2H, PhCH ₂ ); 4.80 (AB q, 2H, J = 11.6 Hz, J = 5.0 Hz, PhCH ₂ OArO); 4.75 (d, 1H, J43 = 3.4 Hz, H-4); 4.61 (q, 1H, J7, _CH3 = 4.9 Hz, H-7); 4.47 (q AB, 2H, J = 16.5 Hz, J = 3.4 Hz, ArOC H ₂ CO);

4.45 (d, H, J = 7Hz, H-1); 4.31 (dd, 1H, J = 8.96

Hz, H-3a (A)); 4.30 (d AB, 1H, J = 16.3 Hz,

- 31 ArOCHACO); 4.13 (t, 1H, JAB = 8.1 Hz, H-3a (B));

4.125 (dd, 1H, JAB = 10.6 Hz, J6-5 = 4.7 Hz,

H-6A); 4.05 (d AB, 1H, J = 16.4 Hz, ArOCHBCO); 3.67 (s, 6H, OCH 3); 3.51 (t, 1H, JAB = 10.1 Hz, H-6B); 3.44 (t, 1H, J4-5 = J4-3 = 9.4 Hz, H-

-4); 3.35 (ddd, 1H, J 5-4 = 9.4 Hz, J 5-6 = 4.7

Hz, H-5); 3.06 (dd, 1H, J2-3 = 14 Hz, J2-1 = 5.1)

Hz, H); 2.79 (m, 1H, H-3); 1.265 (d, 3H, JCH, -7 = 4.96 Hz, _CH3).

Elemental analysis for C59H57CÚ9:

H, 5.37; C, 66.26; H, 5.32.

The following compounds of formula I can be prepared as described above:

4 ¹ -Demethyl-4-O- [2,3-bis (4-methylphenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

Melting point: 130 ° C,

TLC (Si0 ₂₎ with heptane / AcOEt (40:60) Rf = 0.35.

4'-Demethyl-4-O- [2,3-bis (3,4,5-trimethoxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

Melting point: 234 ° C.

TLC (Si0 ₂₎ with heptane / EtOAc (30:70), Rf = 0.2.

4'-demethyl-4-0- [2,3-bis (3,4-methylenedioxyphenyl-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodofillotxin

- 32 Melting point: 173 ° C,

TLC _(SiO2) with heptane / EtOAc (30:70), Rf = 0.35).

4'-Demethyl-4-O- [2,3-bis (3,4-dimethoxyphenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

Melting point: 194 ° C.

TLC (Si0 _2): CH ₂ Cl ₂ / MeOH (95: 5) Rf = 0.4.

4 ¹ -Demethyl-4-O- [2,3-bis (4- (trifluoromethoxy) phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

Melting point: -116 ° C,

TLC (Si0 ₂₎ with heptane / EtOAc (50:50), Rf = 0.2.

4 ¹ -demetil- (3,4,5-trimethoxy-phenoxy-acetyl) ^-4-1 4-demethyl Ο- [2,3-bis (3,4,5-trimethoxy-phenoxy-acetyl) -4, 6-ethylidene-glucosyl] epipodophyllotoxin

Melting point: 130 ° C,

TLC (Sio ₂ ): Hept / AcOEt (50:50) Rf = 0.4.

4 ^1- (4- (trifluoromethoxy) phenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (4- (trifluoromethoxy) phenoxyacetyl) -4,6- ethylidene-glucosyl] -epipodophyllotoxin

Melting point:> 260 ° C,

TLC (Si0 ₂₎ with heptane / EtOAc (30:70), Rf = 0.4.

4 '- (4-phenyl-phenoxy-acetyl) -4-demethyl ¹ 4-0- [2,3-bis (4-phenyl-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epi • · · • · · · ♦ · ··· ♦ · ····

- 33 podophyllotoxins

Melting point: 130 ° C,

TLC (Si0 ₂₎ with heptane / EtOAc (30:70), Rf 0.5.

4 '- (2-naphthoxyacetyl) -4'-demethyl-4-O- [2,3-bis (2-naphthoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin Melting point: 138 ° C.

TLC (Si0 ₂₎ = Hept / AcOEt (30:70) Rf = 0.35.

4 ^1- (1-naphthoxyacetyl) -4'-demethyl-4-O- [2,3-bis (1-naphthoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin Melting point: 125 ° C.

TLC (Si0 ₂₎ with heptane / EtOAc (50:50), Rf 0.5.

4 ^1- (Cyclohexyloxyacetyl) -4'-demethyl-4-O- [2,3-bis (cyclohexyloxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

Melting point: 160 ° C,

TLC (Sio ₂ ): Hept / AcOEt (50:50) Rf = 0.45.

4 '- (4-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (4-phenoxy-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin

Mp 151 ° C,

TLC (Sio ₂ ): Hept / AcOEt (50:50) Rf = 0.4.

4 ^1- (3,4-dimethoxyphenoxyacetyl) -4'-demethyl-4-O- [2,3-

- 34-bis (3,4-dimethoxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin

Melting point: 158 ° C.

TLC (Si0 ₂₎ with heptane / AcOEt (50:50) Rf = 0.27.

4 '- (3,4-methylenedioxy-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (3,4-methylenedioxyphenyl-phenoxyacetyl) -4,6 ethyl!

ylidene-glucosyl] epipodophyllotoxin

Melting point: 158 ° C.

TLC (Sio ₂ ): Hept / AcOEt (20:80) Rf = 0.26.

I

TLC = thin layer chromatography,

Hept = heptane,

AcOEt = ethyl acetate and

CH 2 Cl 2 = methylene chloride.

The compounds have valuable anti-cancer activity in vitro and in vivo bioassays.

According to the colorimetric MTT assay (as performed according to NCI protocol), the compounds have antitumor activity in vitro on six cell lines (from ATCC), such as breast cancer, bladder cancer, lung cancer, and colon cancer modeling cell lines.

Two in vivo tests were performed on P388 leukemia and MXT adenocarcinoma models. The leukemic cells were i.p. injected into animals at day zero. 1, 2, 3

After 35 and 4 days, the animals are treated with the test compound. MXT adenocarcinoma was implanted subcutaneously on day zero. The animals were subjected to 17, 19, 21, 24, 26, 28,

Treated on days 31, 33, and 35. The treated / control index was determined using two mouse models. This index shows the average survival rate of treated animals compared to control animals. The treated / control index is expressed as a percentage, and if the value is greater than 130%, the test drug has a significant antitumor effect. If the treated / control value is greater than 300%, a second index, the LS index (long term survival), which is the percentage of animals surviving for 30 days, is determined. This is only determined on the P388 model because the MXT model is too aggressive and does not allow for such a long period of testing. Ten animals are included in each test group.

The results are given in the following table:

I

Results of in vitro studies

P388 *

MXT treated / control treated / control

(%) (% LS) (%) etoposide 65 (0) * 71 17 > 300 (40) 155 * 1 > 300 (90) 139 ** 18 > 300 (100) 161 ** 3 > 300 (60) 105 * 19 > 300 (90) 160 ** 14 > 300 (60) 138 ** 16 > 300 (80) 107 ** 20 > 300 (90) 136 **

Comment:

* 4 treatments at 40 mg / kg ** 9 treatments at 40 mg / kg.

The advantages of the new active compounds over the known compounds are that they are effective against non-small cell lung cancer in various cancers such as testicular embryonic carcinoma, connective tissue sarcoma, pediatric tumor, bronchial small cell cancer, Hodgkim and non-Hodgkim lymphoma, acute leukemia and breast cancer. and colon cancer, which is currently untreated.

Based on the foregoing, the present invention also relates to (I) the following general principles: (1) · · ···

- compounds of the formula 37, including compounds known in the art as synthesis intermediates and disclaimer-excluded, which serve as pharmaceutical products. The present invention also relates to their use in cancer diseases, preferably testicular embryonic carcinoma, connective tissue sarcoma, pediatric tumor, bronchial small cell cancer, Hodgkim malignant and non-Hodgkim lymphoma, acute leukemia, placental corionary cancer and non-mammary adenoma carcinoma, for the manufacture of a medicament for the treatment of small cell cancer.

The present invention also provides a pharmaceutical composition comprising at least one compound of formula (I), including compounds known in the art as synthesis intermediates and disclaimer-excluded, with suitable excipients.

The pharmaceutical composition may be, for example, an injection or an oral preparation such as a hard gelatin capsule or tablet at a daily dose of 20-200 mg / m ^{2 for} injection and 50-400 mg / m ² for an oral preparation.

Claims (11)

Patent claims Compounds of formula (I) and physiologically acceptable salts thereof, wherein: R 'is hydrogen or R, R is a group of formula (a) or an acyl residue of formula (b) wherein X, Y and Z are each independently oxygen or sulfur, A is a linear or branched C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or an aryl group, preferably a phenyl group, in its alkyl moiety a C 1 -C 4 linear or branched phenyl alkyl group or a naphthyl group, where the aryl group is optionally C 1-4 straight or branched chain alkoxy optionally substituted with chlorine or fluorine atom, benzyloxy group, phenyl group, C 1-4 straight or branched alkyl group or halogen, preferably substituted with chlorine or fluorine; R 'is R, then R is 4-fluorophenoxyacetyl, ··· ······························································· · • · · · ·· ··· - 39 4-benzyloxy-phenoxyacetyl, 4-hydroxy-phenoxyacetyl, 4-methyl-phenoxyacetyl, 3,4,5-trimethoxy-phenoxyacetyl, 3, 4-methylenedioxyphenoxyacetyl, 2,3-dimethoxyphenoxyacetyl, 4- (trifluoromethoxy) phenoxyacetyl, 4-phenylphenoxyacetyl, 1- naphthoxyacetyl, cyclohexylacetyl, 4-methylphenoxyacetyl or 3,4-dimethoxyphenoxyacetyl. Compounds according to claim 1, wherein R 'is hydrogen. Compounds according to claim 1 or 2, wherein R is ethoxyacetyl, phenoxyacetyl, 4-methoxy-phenoxyacetyl, 2-methoxy-phenoxyacetyl, 4- nitro-phenoxyacetyl, 2-nitro-phenoxyacetyl, 2,4-dichlorophenoxyacetyl, 2,4,5-trichlorophenoxyacetyl, 2,4,6-trichlorophenoxyacetyl, 4-fluorophenoxyacetyl, 2-fluorophenoxyacetyl, hydroxy-phenoxyacetyl, 4-benzyloxy-phenoxyacetyl, 4-methylphenoxyacetyl, 3,4,5-trimethoxy-phenoxyacetyl, 3,4-methylene- dioxyphenoxyacetyl, 2,3-dimethoxyphenoxyacetyl, 4- (trifluoromethoxy) phenoxyacetyl, 4-phenylphenoxyacetyl, 2-naphthoxyacetyl, a group, 1-naphthoxyacetyl, cyclohexylacetyl, 4-methylphenoxyacetyl or 3,4-dimethoxyphenoxyacetyl40. · · · · · ··· ·························································• -group. 4. Compounds according to any one of claims 1 to 3, which may be: 4 '- (4-Fluorophenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (4- -fluoro-phenoxy-acetyl) -4, ethylidene-glucosyl) -epipodfillotoxin, 4 '- (4-benzyloxy-phenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (4-benzyloxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4 '- (4-hydroxyphenoxyacetyl) -4'-demethyl-4-O- [2,3- -bis (4-hydroxyphenoxyacetyl) -4,6-ethylidene glucosyl) epipodophyllotoxin, 4'-demethyl-4-0- [2,3-bis (phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4'-demethyl-4-0- [2,3-bis (4-methoxy-phenoxy-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4'-demethyl-4-O- [2,3-bis (4-fluorophenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4'-demethyl-4-0- [2,3-bis (4-hydroxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4-demethyl-4-0- [2,3-bis (4-benzyloxy-phenoxy-acetyl) -4,6-ethylidene-glucosyl) epipodophyllotoxin, 4'-demethyl-4-0- [2,3-bis (4-phenoxy-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin), 4 ¹ -Demethyl-4-O- [2,3-bis (3,4,5-1-trimethoxy-phenoxyacetyl) -4,6-ethylidene-glucosyl) -epipodophyllotoxin. · · · · · · · · · · · · · · · · · ··· - 41 4'-demethyl-4-O- [2,3-bis (3,4-methylenedioxyphenoxy-acetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4'-demethyl-4-O- [2,3-bis (3,4-dimethoxyphenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4'-Demethyl-4-O- [2,3-bis (4-trifluoromethoxy) phenoxyacetyl) -4,6-ethylidene glucosyl) epipodophyllotoxin 4 '- (3,4,5-trimethoxy-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (3,4,5-phenoxyacetyl) -4,6 eti1idén-glucosyl) epipodophyllotoxin 4 '- (4- (trifluoromethoxy) phenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (4- (trifluoromethoxy) phenoxyacetyl) -4,6- ethylidene-glucosyl] epipodophyllotoxin 4 ¹ - (4-phenyl-phenoxy-acetyl) -4-demethyl ¹ 4-0- [2,3-bis (4-phenyl-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 '- (1-Naphthoxyacetyl) -4'-demethyl-4-0- [2,3-bis (1-naphthoxy-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 '- (cyclohexyl-oxy-acetyl) -4-demethyl ¹ 4-0- [2,3-bis (cyclohexyloxycarbonyl-acetyl) -4,6-ethylidene-glucosyl) epipodophyllotoxin, 4 '- (4-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (4-phenoxy-acetyl) -4,6-ethylidene-glucosyl) epipodophyllotoxin, 4 ^1- (3,4-dimethoxyphenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (3,4-dimethoxyphenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, · ··· ·· * • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · „„ „ - 42 4 '- (3,4-methylenedioxyphenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (3,4-methylenedioxyphenoxyacetyl) -4, 6-ethylidene-glucosyl) epipodophyllotoxin. 5. Procedure 1-4. A process for the preparation of a compound according to any one of claims 1 to 3, characterized in that a glycosylated intermediate of formula (II) is reacted with an intermediate of formula (III): R and R 'are as defined above, and if desired, the phenol group of the compound of formula (I) obtained is deprotected. 6. Compounds of formula (I) and physiologically acceptable salts thereof for use as a medicament, wherein: R 'is hydrogen or R, R is a group of formula (a) or an acyl residue of formula (b) wherein X, Y and Z are each independently oxygen or sulfur, A is a C 1-4 straight or branched alkyl group, a C 3-6 cycloalkyl group or an aryl group, preferably a phenyl group, in its alkyl moiety a C 1-4 straight or branched phenyl alkyl group or naphthyl group, where the aryl group is optionally a ···· ·· · ♦ «··« · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «« « - C 1-4 straight or branched alkoxy optionally halogenated with 3 to 3 hydroxy groups, optionally chloro or fluoro, benzyloxy, phenyl, C 1-4 linear or branched alkyl or halo, preferably chloro or fluoro. 7. Medals according to claim 6, wherein R ¹ is hydrogen. The pharmaceutical product of claim 6 or 7, wherein R is ethoxyacetyl, phenoxyacetyl, 4-methoxy-phenoxyacetyl, 2-methoxy-phenoxyacetyl, 4-nitrophenoxyacetyl, 2-nitro-phenoxyacetyl, 2,4-dichlorophenoxyacetyl, a group, 2,4,5-trichlorophenoxyacetyl, 2,4,6-trichlorophenoxyacetyl, 4-fluorophenoxyacetyl, 2-fluorophenoxyacetyl, 4-hydroxy-phenoxyacetyl, 4-benzyloxy-phenoxyacetyl, 4-methylphenoxyacetyl, 3,4,5-trimethoxy-phenoxyacetyl, 3,4- methylenedioxyphenoxyacetyl, 2,3-dimethoxyphenoxyacetyl, 4- (trifluoromethoxy) phenoxyacetyl, 4-phenylphenoxyacetyl, 2-naphthoxy-, acetyl, 1-naphthoxyacetyl, cyclohexylacetyl, 4-me44. 1 · * · ··· ··················································································································································································································································································ising manufacturing-Displays 9. A 6-8. The pharmaceutical product of claims 1 to 4, wherein the compound is: 4'-phenoxyacetyl-4'-demethyl-4-0- [2,3-bis (phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 '- (2-methoxy-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (2-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 '- (4-methoxy-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (4-methoxy-phenoxy-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 '- (2-nitro-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (2-nitro-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 '- (4-nitro-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (4-nitro-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 '- (2,4-dichloro-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (2,4-dichloro-phenoxy-acetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4 '- (2,4,5-trichloro-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (2,4,5-trichloro-phenoxy-acetyl) -4,6 eti1idén-glucosyl] epipodophyllotoxin 4 '- (2,4,6-trichlorophenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (trichlorophenoxyacetyl) -4,6-ethylidene] · »·» Ο «« • * · * · «• * ·» · «· ··« »« _Λ · · · · ··· · · · «4» ν »» -glukozil) -epipodophyllotoxin, 4 '- (2-fluoro-phenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (2-fluoro-phenoxyacetyl) -4-ethylidene-glucosyl] -epipodophyllotoxin, ^{4'-ethoxy-4-demethyl-1} 4-0- [2,3-bis (ethoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin., 4 '- [2,2- (2,3-naphthylenedioxy) acetyl] -4'-demethyl-4-O- [2,3-bis [2,2- (2,3-naphthylidenedioxy) acetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4'-benzylthioacetyl-4'-demethyl-4-O- [2,3-bis (benzylthioacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4'-phenylthioacetyl-4'-demethyl-4-O- [2,3-bis (phenylthioacetyl) -4,6-ethylidene-glucosyl] -epipodophilotoxin, 4 '- (4-fluorophenoxyacetyl) -4'-demethyl-4-O- [2,3-bis (4-fluorophenoxyacetyl) -4-ethylidene-glucosyl) -epipodophyllotoxin, 4 '- (4-Benzyloxy-phenoxyacetyl) -4'-demethyl-4-O - [2,3-bis (4-benzyloxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4 '- (4-hydroxy-phenoxy-acetyl) -4-demethyl ¹ 4-0- [2,3-bis (4-hydroxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4'-demethyl-4-O- [2,3-bis (phenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophilotoxin, 4'-Demethyl-4-O- [2,3-bis (4-methoxyphenoxyacetyl) 4,6-ethylidene-glucosyl) epipodophyllotoxin, 4'-demethyl-4-0- [2,3-bis (4-fluoro-phenoxy-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4'-demethyl-4-0- [2,3-bis (4-hydroxy-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4-demethyl-4-0- [2,3-bis (4-benzyloxy-phenoxy-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin. 4 ¹ -Demethyl-4-O- [2,3-bis (4-methylphenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin ^4-demethyl-1 4-0- [2,3-bis (3,4,5-phenoxyacetyl) -4,6-ethylidene-glucosyl) epipodophyllotoxin, 4'-demethyl-4-0- [2,3-bis (3,4-methylenedioxyphenyl-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4'-demethyl-4-0- [2,3-bis (3,4-dimethoxy-phenoxy-acetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4'-demethyl-4-0- [2,3-bis (4-trifluoromethoxy) phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 '- (3,4,5-trimethoxy-phenoxy-acetyl) -4'-demethyl-4-O- [2,3-bis (3,4,5-phenoxyacetyl) -4,6 ethylidene-glucosyl] -epipodophyllotoxin, 4 '- (4- (trifluoromethoxy (phenoxyacetyl) -4'-demethyl-4-0- [2,3-bis (4- (trifluoromethoxy) phenoxyacetyl) -4,6 ethylidene-glucosyl] epipodophyllotoxin 4 '- (4-phenyl-phenoxy-acetyl) -4'-demethyl-4-0- [2,3-bis (4-phenyl-phenoxyacetyl) -4,6-ethylidene-glucosyl] epipodophyllotoxin 4 ′ - (2-naphthoxyacetyl) -4′-demethyl-4-O- [2,3-bis (2 · «·> · · * * * w w w w w w). ······ · · · · · · · · · · ί - 47-naphthoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophilotoxin, 4 '- (1-Naphthoxyacetyl) -4'-dimethyl-4-O- [2,3-bis (1-naphthoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophilotoxin 4 '- (cyclohexyloxyacetyl) -4'-dimethyl-4-O - [2,3-bis (cyclohexyloxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4 '- (4-methylphenoxyacetyl) -4'-dimethyl-4-O- [2,3-bis (4-methylphenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4 '- (3,4-dimethoxyphenoxyacetyl) -4'-dimethyl-4-O- [2,3-bis (3,4-dimethoxyphenoxyacetyl) -4,6-ethylidene-glucosyl] -epipodophyllotoxin, 4 '- (3,4-methylenedioxyphenoxyacetyl) -4'-dimethyl-4-O- [2,3-bis (3,4-methylenedioxyphenoxyacetyl) -4', 6-ethylidene-glucosyl] epipodophyllotoxin. A pharmaceutical composition, characterized in that at least one of claims 6-9. A compound of formula (I) as claimed in any one of claims 1 to 6 with a pharmaceutical excipient. 11. A 6-9. Use of a compound according to any one of claims 1 to 4 for the treatment of cancer, preferably embryonic carcinoma of the testis, connective tissue sarcoma, pediatric tumor, bronchial small cell cancer, Hodgkim and non-Hodgkim malignant lymphoma, acute leukemia, smallpox chorionera and non-breast cancer for the manufacture of a medicament for the treatment of cell cancer.