MXPA98002933A - Novedous derivatives of amina of 2", 3" -didesoxiglicosidos of epipodofilotoxina, method of preparation of the same and use of them with a drug and for treatments antican - Google Patents

Abstract

A compound of the general formula (I) is described: wherein X, Y R 1 and R 2 are defined in the description a method of preparation for the same and the use thereof as a drug and to treat the cancer

Description

NOVIDAE DERIVATIVES OF AMINA OF 2". 3" -DIDES0XIGLIC0SID0S OF EPIPODOFILOTOXINA. METHOD OF PREPARATION OF THE SAME AND USE OF THEM AS A DRUG AND ANTICANCER TREATMENTS The present invention relates to amino derivatives of novel 2", 3" -dideoxy glycosides of epipodophyllotoxin, the method of preparing these, their use as a drug and their use for anticancer treatments. The class of epipodofiloides, which has the base structure of basic podophyllotoxin, is among the derivatives that arise from natural lignans. Among them are the isynthetic derivatives such as etoposide or teniposide which are commonly used in the preparation of drugs for the treatment of cancer. These are considered as important products in this field. Etoposide has antitumor properties and makes it possible to treat, in particular, small lung cancer cells and testicular cancer. The disadvantage of these products is the lack of solubility in water, and consequently they encounter difficulties in terms of formulation and administration. The object of the present invention is to show that the derivatives of '-methylepipodophyllotoxin which possess, in position 4, a substitution of the structure of 2"-desociglycosides, makes it possible to form compounds whose additional salts possess aqueous solubility, by incorporating one or more nitrogens, making it possible to address the problem and show the desired anti-cancer activity EP-01996.618 discloses water-soluble 4'-demethylepipodophyllotoxin derivatives of the formula: where Ri = Me, Xi = NH2, N ß2, X2 = OH Patent EP-0,415,453 mentions derivatives of ß-D-alltroside of 4 '-demethylpipodophyllotoxin of formula where Ri - Me R2, R3 - OH and NH2 or F and NH2 as well as JP 0.161.423. Other publications mention similar derivatives (Carbohydr Res. 1990, 206, 219; Chem. Pharm. Bull., 1986, 34, 3733; Chem Pharm. Bull 1986, 34, 3741; Chem. Lett., 1987, 799). The fact that a glycoside having a 2"-deoxy position is used is quite special, it makes it possible to obtain compounds that are more lipophilic than the hydroxylated analogues and, consequently, have a broader spectrum of anti-tumor activity. better penetration of the membrane and be able to more easily reach the biological objective such as, for example, solid tumors that are not highly irrigated.In addition, the advantage of having a functional amino group, for example, in the 3"position confers a possibility of salification and, therefore, of solubility in water, which is sufficient for a better formulation a better administration. Therefore, the present invention relates to a compound of the general formula I OH in which the group in 3"N (R? R2) is in the position β (2-deoxy-D-Arabino series) or position a (2-deoxy-D-ribo series) in relation to the ring, Rl and R2 which are identical or different, represent a hydrogen atom, an alkyl group Ci to Ce, capable of forming a ring, it being possible for this ring to contain a heteroatom such as oxygen or nitrogen, an aminoalkyl group Ci to Cß or a group cyanomethyl X and Y can be identical or different and represent OH, CH3, CH2-NH2, X and Y can also be attached and can form a ring, such as for example a 2-methyl, 1,3-dioxane, thus forming a bicyclic glycoside base structure of 4,6-ethylidene-3-amino-2,3-dideoxy-β-D-arabino or pyranoside-ribo-hexo It also refers to its addition salts with inorganic or organic acids that salify the nitrogen atom (s), in particular the hydrochlorides Conveniently, the group NR1R2 is a group NH2 or N (CH3) 2. The group NR1R2 can also be e is an amino group substituted once or twice with a methyl, CH2CN, CH2-CH2-NH2, to form a ring such as morpholine. Conveniently, the compounds of the general formula I are chosen with a glycoside for which X and Y form a ring with a bond 0CH (CH3) 0CH, such as 4,6-ethylidene-3-amino-2,3-dideoxy- β-D-arabino-hexopi ranoside ol, 6-ethylidene-3-amino-2,3-β-D-ribo-hexopi ranoside.

In particular, the compounds according to the invention are selected from the following compounds: - 4 '-demethyl-4-0 (3-amino-4,6-ethylidene-2,3-dideoxy-β-D-arabino-hexopyranosyl) epipodophyllotoxin, - 4' -demethyl-4-0 (3-amino- 4,6-ethylidene-2,3-dideoxy-β-D-ribohex pi ranosil) epipodophyllotoxin, - 4 '-demethyl-4-0 (3-dimethylamino-4,6-ethylidene-2,3-dideoxy-β- D-arabinohexopi ranosil) epipodophyllotoxin, - 4 '-demethyl-4-0 (3-dimethylamino-4,6-ethylidene-2,3-dideoxy-β-D-ribohexopy ranosil) epipodophyllotoxin, - 4' -demethyl-4- 0 (3-cyanomethylamino-4,6-ethylidene-2,3-dideoxy-ß-D-ribohexopy ranosil) epipodophyllotoxin, - '-memethi4-4-0 (3- (N-morpholino) -4,6-ethylidene -2, 3-dideoxy-ß-D-ribohexopy ranosil) epipodophyllotoxin, - 4'-demethyl-4-0 [3 (2-aminoethylamino) -4,6-ethylidene-2,3-dideoxy-β-D-ribohexopi ranosil) epipodophyllotoxin, - 4 '-demethyl-4-0 (3-amino-2,3,6-tridesoxy-β-D-ribohexopy ranosil) epipodophyllotoxin, - 4' -demethyl-4- (3,6-diamino) -2,3,6-tridesoxy-ß-D-ribohexo-pyranosyl) epipodophyllotoxin, The present invention also relates to pharmaceutical compositions comprising n at least one compound of the general formula I according to the invention and an appropriate excipient. The pharmaceutical compositions can be provided in an appropriate manner by administration via the injectable route or orally in the form of a capsule, gelatin capsules or tablets, in the dose of 1 to 200 mg / m 2 through the injectable route and from 5 to 500 mg / m2 by means of the oral route for a period of 24 hours. These derivatives can be administered in this manner in clinical medicine in humans to treat forms of cancer such as small lung cancer cells, testicular cancer, embryonic tumors, neuroblastomas, kidney cancer, Hodgkin's and non-Hodgkin's lymphomas, acute leukemias. , colorectal cancers, melanomas, placental choriocarcinomas and mammary adenocarcinomas. The present invention also relates to methods for preparing the compounds of the formula I as well as their addition salts with pharmaceutically acceptable inorganic or organic acids. Therefore, the present invention relates to the method for preparing the compounds of the general formula I according to the invention, wherein a compound of the formula III or IV or V Ul IV it is reacted with 4'-demethyl-4'-benzyloxycarbonylepipodo-filotoxin with BF3 etherate, or trimethylsilyl trifluoromethanesulfonate in an inert solvent at low temperature; in formulas III and IV, the subsequent ones in position 3 can be a or β, NR1R2 can be an amino protected with a group Z, in formula V, P represents a protective alcohol group and the products resulting from this condensation are deprotected and hydrogenate to give the compounds of the formula I, the primary amines in the 3-position of the glycosyl are methylated with for-ally and sodium cyanoborohydride. The intermediate of formula IV is prepared by reacting a mixture of diacetoxiazidoglycoside VI with tert-butyldi ethylsilyl chloride in the presence of imidazole, in which the products resulting from this reaction are separated, in which each of these products are deacetylated, cyclized to 4,6-ethylidene with acetaldehyde in a catalytic acid medium. Other characteristics of the method according to the invention will emerge in the light of the following description, in particular of the synthesis method referred to in scheme 1.

SCHEME 1 TDD Sia. imidazole ccimnccNN Camf orsul phonic TMSOTf CH2CI2 TH? IIJ 4O It is carried out in accordance with a methodology that has been described (J: C: Florent and C. onneret, J. Chem. Soc. Chem. Comm. 1987, 1171 and B. Abbaci, JC Florent and C. Monneret, Bull Soc. Chim. Fr. 1989, 667) from glucal 1. The azide ion is condensed to give an intermediate glycoside 2 whose anomeric OH is protected with a silyl group that has been described (C. Kolar and G. Kneissl Angew, Chem. Int. Ed. 29, 809 (1990)) to give the mixture of 2 epimeric azides: 3 and 4 which can be separated by chromatography in this step. The diols in the 4,6 position are obtained by basic deacetylation in the presence of sodium methoxide: compounds 5 and 12. The diol azide β compound 5 is cyclized to ethylidene conventionally with the aid of acetal acetaldehyde using acid catalysis to give the compound 6 whose azide is reduced in an amine 7 so as to be protected with benzyloxycarbonyl group (Z) in compound 8, which is necessary to carry out the coupling with demethylepipodophyllotoxin, itself protected in its 4 'phenol with a benzyloxycarbonyl group, this intermediate will be called DMEPT4'- 0Z. This coupling is carried out, firstly, by separating the protective silyl with F- ions, followed by the treatment with etherate BF3 at low temperature in the same medium. Deprotection of the Z groups by hydrogenolysis provides compound 10 of the general formula I (NR1R2 = ßNH2; XY = 0CH (CH3) 0CH2). Compound 11 of the general formula I (NR1R2 = BNME22; XY = 0CH (CH3) 0CH2) is obtained by methylation of the preceding primary amine by the action of formalin and sodium cyanoborohydride. The azide glycoside intermediate 12 follows the same sequence of reactions as its epimer and provides, in an identical manner, the coupling derivative with DMEPT4'-0Z starting with the 13 to 3"azide: in this case, the coupling is carried out The first technique consists in treating the ribohexopi-ranoside derivative 13 with trimethylsilyl trifluoromethanesulfonate (TMSOTf) at -40 ° C in CH2CI2 The second technique consists of using etherate BF3 in CH2CI2 at -15 ° C. The obtained intermediate 14 is then catalytically reduced to give corresponding to general formula I, where NR1R2 = aNH2 and XY = 0CH (CH3) 0CH2.The same methylation as for compound 10βNH2, using formalin and cyanoborohydride, leads to corresponding dimethylamino derivative: general formula I (NR1R2 = a2, XY = 0CH (CH3) 0CH2) Using the primary amine 15, it is possible to alkylate the nitrogen with a halogenated derivative such as iodoacetonitr ilo under weakly basic conditions with triethylamine in DMF and giving the derivative 16 of the general formula I where NR1R2 = aNHCH2CN; XY = 0CH (CH3) 0CH2. In the same way, the derivative 17 is obtained by forming the morpholine ring by cyclization of the diiodinated ether in the same primary amine intermediate. The same alkylation with the iodoethylamine protected by a group Z in the compound 15 gives the derivative 18 which is catalytically reduced in 19, a diamino derivative corresponding to the general formula I with NR1R2 = 0.NHCH2CH2NH2; XY - 0CH (CH3) 0CH2. The compounds of the formula I where XY do not form a ring is obtained in the following manner shown in scheme 2: SCHEME 2 Silylated azide is selectively tosylated with tosyl chloride in pyridine to 21, the tosylation of the primary alcohol is exchanged with an iodine derivative 22. In this step, the secondary alcohol in position 4 is protected with a chloroacetate to give the Functionalized 2-deoxyazucher ready to be condensed with DMEPT4'-0Z under the usual conditions with BF3 etherate in methylene chloride at low temperature. The intermediate 24 obtained makes it possible, passing over the Amberlite IRA410 resin treated in a basic medium, to deprotect the chloroacetate group in the compound 25 and the final catalytic hydrogenation makes it possible, in one step, to deprotect the functional group Z in the 4-position for reduce the carbon 6"in methyl in order to provide the derivative 26 corresponding to the general formula I where NR1R2 = 3" to NH2; X = OH; Y = CH3. The intermediate 24 obtained above can react with the azide ion in DMF at room temperature to give 3"aN3, 6" -N3 containing an azidoacetate in the 4"27 position, which can be cut in a 4" alcohol by a treatment similar to the preceding one: the passage over the exchange resin Amberlite IRA410 to give the diazidoalcohol 28. The final step of catalytic reduction makes it possible to obtain the diamino derivative 29 corresponding to the general formula I (where NR1R2 = 3"aNH2; X = OH Y = CH2NH2) The salts formed from the nitrogenous compounds are, for example, hydrochlorides and are formed in conventional manner by treating a methanolic solution of the nitrogenous compound with a stoichiometric, in relation to the sites to be salted, the hydrochloric metal solution The crystallized hydrochloride can optionally be obtained by precipitation in the reaction medium by means of the addition of ethyl ether. Following examples are given as a guide and to illustrate the various steps of synthesis, but without implying limitation.

EXAMPLE 1 GENERAL FORMULA I: NR1R2 = BNH2: XY = 0CH (CH3) 0CH2 4'- DEMETIL- -0 (3-AMIN0-2.3-DIDES0XI-4.6-ETILIDEN- & -D- ARABINOHEXOPIRANOSIDEPIPODOFILOTOXINA (COMPOUND 10) Step 1 A solution of tri-O-acetyl-D-glucal 1 (50 g, 183 mmol) in water (400 ml) is heated for 3 hours at 80 ° C. The reaction medium is then cooled to 20 ° C before the addition of sodium azide (17.9 g, 275 mmol) and acetic acid (38 ml, 600 mmol). After stirring at room temperature for 24 hours, the medium is neutralized with NaHCO 3 (salt). The phase is extracted with ethyl acetate (3 x 500 ml). The organic phases are combined, dried over MgSO 3 and then concentrated under reduced pressure. This gives 51 g of raw product 2 immediately treated as follows.

Characteristics: TLC: cyclohexane / AcOEt: 1/1; Rf = 0.43 C10H15N3O6M = 273 Step 2 Tert-butyldimethylsilyl-3-azido-2,3-dideoxy-4,6-di-0-acetyl-β-D-arabinohexopi-ranoside 3 and tert-butyldin-ethylsilyl-3-azido-2.3- dideoxy-4,6-di-0-acetyl- &-D-ribohexopyranoside 4. 6 g of imidazole (87.8 mmol) and 13.24 g of tert-butyldimethylsilyl chloride (87.8 mmol) are successively added, under argon, to a solution of the crude mixture 2 (16.1 g, 58 mmol) obtained in step 1 in anhydrous dichloromethane (200 ml) previously cooled to 0 ° C. After stirring for 15 minutes at 0 ° C and 19 hours at 20 ° C, the reaction medium is poured into 500 ml of H2O. The aqueous phase is extracted with CH2Cl2 (200 ml) then after drying over MgSO4, the organic phase is concentrated under reduced pressure and the residue (18.7 g) is subjected to chromatography on a silica gel (cyclohexane / AcOEt: 9/1). In this way, 10.7 g of 3 (syrup, 48%) and 4.7 g of 4 (syrup, 21%) are isolated; while the intermediate fractions contain a mixture of 3 and 4 (3.3 g, 15%). Characteristics: 3 TLC: cilcohexane / AcOEt: 4/1 Rf = 0.45 C a] 20 D = -10 o (c = 1.4, CHCI3) MS: m / z 405 (M + NH «) C16 H29 N3 SYM = 387 Rf = 0. 52 [COD = +10 ° (c = 1; CHCl3) MS: m / z 405 (M + NH4) + C16H29N3SÍM = 387 1H NMR 200 MHz CDC13 d Derivative 3: 0.13 (3 H, s, S1CH3), 0.14 ( 3H, s Yes CH3); 0.92 (9H, s, tBu9, 1.72 (1H, m, J2a-l = 9.5 Hz, J2a-2β = 12.5 Hz, J2a-3 = 12.5 Hz, H2a), 2.05 (3 H, s, COCH3), 2.15 ( 3HM S, COCH3), 2.25 (1H, ddd, J2e-1 = 1.5 HZ, J2e-2a = 12.5 HZ, J2 ß - 3 = 4.5 HZ, H2 «), 3.55 - 3.62 (2H, m, H3 and Hs); 4.10 (1H, dd, Jß-5 = 2.5 Hz, He), 4.20 (1H, dd, Jß-5 = 6 Hz, Jß-6 '= 12 Hz, H-6), 4.86 (1H, t, J = 9.5 Hz, H; 4.86 (1H, dd, Ji- 2a = 9.5 HZ, J? -2t = 1.5 Hz, Hi) Derivative 4: 0.1 (6H, s, Si (CH3) 2), 0.88 (9H, s, tBu), 1.64 (1H, ddd, J2a-2e = 14 Hz, J2a-1 = 8.5 HZ, J2a-3 = 3.5 Hz, J2a), 2.03 (1H, ddd, J2e-2a = 14 HZ, J21 - 1 = 2 HZ, J2e-3 = Hz, H2.); 2.05 (3H, s, COCH3); 2.13 (3H, s, COCH3); 4.05 - 4.12 (1H, m, Hs); 4.17 - 4.22 (3H, m, H3, He and He ') 4.89 (1H, dd, JA-S = 9.5 Hz, J4-3 = 3.5 Hz, HA, 5.02 (1H, dd, J? -2a = 8.5 Hz, J? -2e = 2 H, Hi).

Step 3: Tert-butyldimethylsilyl-3-azido-2,3-dideoxy-β-D-arabino-hexopy-ra 5 a solution of 1 M sodium methoxide (1.9 ml) is added, under argon, to a solution of derivative 3 (3 g, 7.7 mmol) obtained in step 2 in anhydrous methanol (40 ml). After reacting for 1 hour 30 minutes at 20 ° C, the reaction medium is adjusted to pH = 7 by the addition of H + resin (Amberlite ™ IRC 50 S). The reaction mixture is filtered and the filtrate is concentrated under reduced pressure, giving 2. 27 g of 5 (97%). Characteristics: TLC: cyclohexane / AcOEt: 2/1; Rf = 0.36 [aP ° D = -26 ° (c = 1; CHC13) MS: m / z 304 (M + H) +321 (M + NH + pf = 70-72 ° C C12H25N3O4SYM = 303 Step 4 Terc butyldimethylsilyl-3-azido-2,3-dideoxy-4,6-0-ethylidene-6-D-arabinohexopi-ranoside (6) 0.94 ml (6.6 mmol) of diethylacetal acetaldehyde are added and then 15 mg of paratoluenesulfonic acid (0.08 mmol) ) to a solution of 5 (0.20 g, 0.6 mmol) obtained in step 3 in 5 ml of acetonitrile.The reaction medium is stirred at room temperature for 1 hour and then diluted with ethyl acetate (20 ml) before wash with a solution of sodium hydrogen carbonate (pH = 9) (20 ml) and then with water (20 ml) The organic phase is dried over MgSO4 < 4 and then concentrated under reduced pressure to give 0.25 g of product The purification by silica gel (cyclohexane / AcOEt: 95/5) makes it possible to isolate 0.19 g of 6 pure (86%) Characteristics: TLC: cyclohexane / AcOEt: 7/3, Rf = 0.89 [a] 20D = -190 (C ii, CHCl 3) MS: m / z 347 (M + NHA) + C 14 H 2 7N3O4SÍM = 329 CHN Calculated 51.04 8.26 12.75 Obtained 51.64 8.43 12.51 Step 5 Tert-Butyldimethylsilyl-3-amino-2,3-dideoxy-4,6-0-ethylidene- &-D-arabinohexopyranoside (7) Add 50 μl of triethylamine and then 0.5 g of 10% palladium on carbon to a solution of 6 (2 g; 6 mmol) obtained in step 4 in 30 ml of ethyl acetate. The reaction medium is placed under a hydrogen atmosphere (atmospheric pressure). After stirring for 6 hours at room temperature, the catalyst is removed by filtration and the organic phase is concentrated under reduced pressure to give 1.82 g of pure 7 (98%). Characteristics: TLC: cyclohexane / AcOEt: 1/1; Rf = 0.23 [oc] 20D = -28 ° (c 1.3, CHCl3) MS: m / z 304 (M + H) + CIAH29N0ASIM = 303 Step 6 Te rc-but i ldime ti lsi 1 i 1 -3-aroi nobenci loxi ca rboni 1 -2.3-dideoxy-4,6-0-ethylidene-ß-D-arabinohexopi ranoside (8) Benzyloxycarbonyl oxide (1.12 ml, 7.88 mmol) is added, under argon, to a solution, previously cooled to 0 ° C , of acetal 7 (1.82 g, 6 mmol) obtained in step 5 in a mixture of anhydrous dichloromethane (30 ml) and anhydrous triethylamine (1.27 ml, 9.1 mmol). After stirring for 8 hours, the reaction medium is poured into 100 ml of H 2 O and the aqueous phase is extracted with CH 2 Cl 2 (100 ml). The organic phase is dried over MgSO, concentrated under reduced pressure and the residue is purified by silica gel chromatography (cyclohexane / AcOEt: 6/1 and 4/1) to isolate 1.9 g of 8 (72%). Characteristics: TLC: cyclohexane / AcOEt: 1/1; Rf = 0.64 [a] 20 D = -27 ° (c 1.14, CHCl 3) MS: m / z 347 (M + H) + m.p. = 102 ° C C2 H35 O6SÍM = 437 CHN Calculated 60.38 8.06 3.20 Obtained 60.27 8.10 3.29 Step 7 4 '-Benzyloxycarbonylepipodof ilotoxin 3-anobenzyloxycarbonyl-2,3-dideoxy-4,6,0-ethylidene- &-D-arabinohexo pi ranoside (9) Added 5.06 ml of tetrabutylammonium fluoride (1.1 M solution in THF, 5.5 mmol) to the sugar 8 (2.0 g, 4.57 mmol) obtained in step 6 in the anhydrous dichloromethane solution (100 ml). When the complete disappearance of 8 is observed by means of TLC (2 hours of stirring), the reaction medium is cooled to -20 ° C. DMEPT4'-0Z (2.57 g, 4.8 mmol) and then 8.44 ml of BF3-Et2? (68.6 mmol) and then added successively. After reacting for 1 hour at -20 °, the reaction medium is poured into 200 ml of a saturated NaHCO 3 solution (addition of NaHCO 3 salts) (pH = 9). The organic phase is dried over MgSO? it is concentrated under reduced pressure and then the crude residue (6.2 g) is subjected to chromatography on a silica gel (CH2Cl2 / Acetone: 98/2 and then 97/3) to give 9 (2.1 g).; 54%). Characteristics: TLC: CH2C12 / Acetone: 92/8; Rf = 0.61 [a] 2oD = -74o (c 1.1, CHCl3) MS: m / z 857 (M + NH¿) + m.p. = 175 ° C C45H45NO15M = 839 CHN Calculated 64.36 5.40 1.67 Obtained 64.21 5.30 1.58 Step 8 Add 30 μl of triethylamine and then 150 mg of 10% palladium on carbon to a solution of 9 (0.28 g, 0.33 mmol) in 20 ml of ethyl acetate. The reaction medium is placed under a hydrogen atmosphere (atmospheric pressure). After stirring for 1 1/2 hours at room temperature, the catalyst is removed by filtration and the organic phase is concentrated under reduced pressure and then subjected to chromatography on a silica gel (CH2Cl2 / MeOH: 97/3 and then / 5) to give 172 mg of the pure compound 10 (90%). (Recrystallization from CH2Cl2 / pentane). Characteristics: TLC: CH2Cl2 / MeOH: 95/5; Rf = 0.31 [a] 20D -120o (C 1.05, CHCl3) MS: m / z 594 (M + NA) + 610 (M + K) + m.p. = 219 ° C C29H33NO11M = 571 C H N Calculated 60.94 5.82 2.45 Obtained 60.45 5.78 2.58 1H NMR 300 MHz CDCI3 d 1.36 (3H, d, J = 5Hz, CH3-CH); 1.51 (1H, m, H2"a), 2.05 (1H, m, H2 - •), 2.88 (1H, m, H3), 3.02 (2H, m, H3" and HA-); 3-28 (1H, m, J2-1 = 5.2 Hz, H2); 3.30 (1H, m, Hs -); 3.57 (1H, t, J = 10 Hz, H6-a); 3.75 (6H, s, OCH3); 4.15 (1H, dd, J = 5 Hz, H = 10 Hz, H6"e), 4.41 (1H, dd, J = 9H, Hp,), 4.21 (1H, t, J = 9H, Hi 1b ); 4.59 (1H, d, J = 5.2 Hz, Hi), 4.75 (1H, q, J = 5 Hz, H7 -), 4.85 (1H, dd, J = 9H, J = 2Hz, Hi-); 4.94 (1H, d, J = 3.3 Hz, HU), 5.98 (1H, d, OCHAO), 6.00 81H, d, OCHBO), 6.24 (2H, s, H2 and H6), 6.55 (1H, s, Hs) 6.75 (1H, s, Hs) Preparation of the hydrochloride A solution of 0.098 M hydrochloric methanol is added. (1.09 ml, 0.106 mmol) to amine 10 (61 mg, 0.10 mmol) in anhydrous dichloromethane solution (6 ml). The reaction medium is stirred for 10 minutes. The expected product is precipitated after the addition of ether (20 ml). 56 mg (86%) of the hydrochloride of 10 are recovered. Characteristics: m.p. = 230 ° C C29H32 O11C1M = 606 Solubility test: 2.56 mg in 0.3 ml of water C = 0.014 M EXAMPLE 2 GENERAL FORMULA I (NR1R2 = BNME2: XY = 0CH (CH3) 0CH2) 4 -DEMETHYL-4-0- (3-DIMETHYLAMIN0-2.3-DIDE0XI-4,6-ETHYLLEN-R-D-ARABINOHEXOPIRANOSIDEPODOPHYLOTOXIN (COMPOUND 11) Successively add formaldehyde (13.5μl) and sodium cyanoborohydrate (85mg) to a solution of the compound (0.19 g, 0.35 mmol) in anhydrous dichloromethane (15 ml). After stirring for 45 minutes at room temperature, these same reagents are added and the reaction is continued for 45 minutes. The reaction medium is diluted with CH2Cl2 (30 ml) and washed with water (40 ml). The organic phase is dried over MgSOA and concentrated under reduced pressure. The residue is chromatographed on a silica gel (CH2Cl2) / MeOH: 97/3). This gives 101 mg of compound 11 (51%). Characteristics: TLC: CH2Cl-2 / Me0H: 95/5; Rf = 0.4 [a] 20D -121o (C = 1; CHCl3) MS: m / z 600 (M + H) + P.f. = 270 ° C C31H37NO11M = 599 1H NMR 300 MHZ CDC13 d 1.38 (3H, d, J = 5 Hz, CH3-CH); 1.55 (1H,, H2"a), 1.96 (1H, m, H2 -.), 1.96 (1H, m, H2".); 2.33 (3H, s, CH3-N); 2.91-2.82 (1H, m, H3); 2.91-2.82 (1H, m, Hs-a); 3.38 (H, t, JA "-5" = 9 Hz, JA "-3" = 9 Hz, HA -); 3.58 (1H, t, Je-a-s "= 10 Hz, Jß '.- s" = 5Hz, Jß-i-ß-a = 10 Hz, Hß "e), 4.21 / 1H, t, J9b-9a = 9 Hz, J9b-3 = 8 Hz, H9b), 4.42 (1H, dd, J9a-9b) = 9HZ, J9a-3) = 10.5 Hz, H -9a); 4.59 (1H, d, Jl-2 = 5.2 Hz, Hi), 4.74 (1H, q, J = 5 Hz, CH-CH3), 4.82 (1H, dd, Ji "-2" a = 9.5 Hz, J? - 2"? = 2 Hz, H? ~); 4.95 (1H, d, JA -3 = 3.2 Hz, HA); 5.97 (1H, d, OCHAO); 6.00 (1H, d, OCHBO); 2H, S, H2 and He); 6.55 (1H, s, He); 6.76 (1H, s, Hs).

Preparation of the Hydrochloride A solution of 0.098 M hydrochloric methanol (1.72 ml, 0.17 mmol) is added to the amine 11 (101 Mg, 0.17 mmol) in anhydrous dichloromethane solution (7 ml). The reaction medium is stirred for 10 minutes. The expected product is precipitated after the addition of ether (20 ml). 80 mg (81%) of the hydrochloride of compound 11 is recovered. Characteristics: P.f. = 199 ° C C31H33NO11CIM = 635 Solubility test: 2.5 mg in 0.1 ml of water C = 0.038 M EXAMPLE 3 GENERAL FORMULA I (NR1R2 = tt-NH2: XY = OCHCCte) 0Ofe) 4'-DEMETIL-4-0- (3-AMIN0-2.3-DIDES0XI-4.6-ETILIDEN-B-D- RIBOHEXOPIRANOSIDEPIPODOPHYLOTOXIN (COMPOUND 19) Step 1 Te r-buti ldimeti lsi 1 i 1 -3-azido-2,3-dideoxy-β-D-ribohexopy ranoside (Compound 12) In a manner similar to that of Step 3 of Example 1, but using compound 4, compound 12 which is used directly in Step 2.

Step 2: Ter-butyldimethylsilyl-3-azido-2,3-dideoxy-4.6-Q-ethylidene-BD-ribohexopi-ranoside (13) 1.1 ml (8 mmol) of acetaldehyde diethyl acetal and then 52 mg of camphor sulfonic acid (0.24 g) are added. moles) to the solution of compound 12 (0.25 g; 0.8 mmol) obtained in Step 1 in 10 ml of acetonitrile. The reaction medium is stirred at room temperature for 9 hours and then diluted with ethyl acetate (30 ml) before washing with a sodium hydrogen carbonate solution (pH = 9) and then with water (30 ml). The organic phase is dried over MgSOA and then concentrated under reduced pressure to give 0.3 g of crude product. Purification on a silica gel (cyclohexane / AcOEt: 15/1) makes it possible to isolate 0.15 g of pure compound 13 (55%). Characteristics: TLC: cyclohexane / AcOET: 4/1; Rf = 0.77 [a] 20D = -35o (c -?.? CHC13) CIAH2 N30ASÍM = 329 Step 3 '-Benzyloxyacetylepipodofilotoxin-3-azido-2,3-dideoxy-4.6-0-ethyliden-β-D-ribohexopi ranoside (Compound 14). First synthesis route: Trimethyl silyl trifluoromethanesulfonate (TMSOTf) (446 μl, 2.46 mmol) is added to a mixture of DMEPT 4'-0Z (438 mg, 0.82 mmol) of compound 13 (270 mg); 0.82 mmol) obtained in Step 2 of the molecular sieve 4 A (1.5 g) in anhydrous dichloromethane (30 ml) cooled to -40 ° C. After reacting for 1 hour to 15 minutes at -40 ° C, the reaction medium is neutralized with triethylamine (342 μl), filtered and then washed with a saturated solution of NaCl (20 ml). The organic phase is dried over MgSOA, concentrated under reduced pressure and chromatographed after the crude residue on a silica gel (cyclohexane / AcOEt: 65/35) to give 14 (260 mg, 45%). Second synthesis route: Boron trifluoride etherate (BF-3.Et20) (425 μl, 3.46 mmol) is added to a mixture of 4'0Z DMEPT (1.85 g, 3.46 mmol) of compound 13 (1.20 g, 3.64 mmol) obtained in Step 2 in anhydrous dichloromethane (100 ml) cooled to -15 ° C. After reacting for 2 hours at -15 ° C, the reaction medium is diluted with 100 ml with CH 2 Cl 2 and then poured into 200 ml of a saturated solution of NaHCO 3. The organic layer is dried over NgSO, reconcentrated under reduced pressure and then chromatographed the crude residue (2.9 g) on silica gel (cyclohexane / AcOEt: 65/35) to give 14 (1.19 g, 47%) (recrystallization Et2? / hexane). Characteristics: TLC: cyclohexane / AcOEt: 6/4; Rf = 0.41 cyclohexan / AcORt: 65/3; Rf = 0.27 [a] 20D = 105 ° (c = 1.05; CHCl3) MS: m / z 749 (M + NHA) + P.f. - 1.39 ° C C37H37N3O13M = 731 Step 4 Epipodof i lotixin-3-amino-2,3-dideoxy-4,6-ethylidene-β-D-ribohexopi-ranoside 15 Add 20 μl of triethylamine and then 20 mg of 10% palladium on ca The solution was dissolved in compound 14 (110 mg, 0.15 mmol) obtained in Step 3 in a mixture of 10 ml of ethanol and 5 ml of ethyl acetate. The reaction medium is placed in a hydrogen atmosphere (atmospheric pressure). After stirring for 2 hours at room temperature, the catalyst is removed by filtration and the organic phase is concentrated under reduced pressure, and then chromatographed on silica gel (CH-2Cl2 / MeOH: 97/3 and then 95/5) to give 63 mg of pure compound 15 (72%). Characteristics: TLC: CH2CI-2 / MeOH: 95/5; Rf = 0.39 [a] 2 ° D = -100 ° (c = 1.05; CHCl3) MS: m / z 572 (M + 1) 589 (M + NHA) + P.f. = 217ßC C 29 H 33 NO 11 M = 571 1 H NMR 300 MHz CDCl 3 d: 1.35 (3 H, d, J = 5 Hz, CH 3 -CH); 1.73 (1H, m, H2"a), 1-90 (1H, m H2" e "), 2.83 (1H, m, H3), 3.22 (1H, dd, J2-1 = 5.2 Hz, J2-3 = 14 Hz, H-2), 3.42 (1H, dd, J «« - 3- = 9.5 Jz, JA-5"= 3.5 Hz, HA); 3.74 (6H, s, OCH3); 3.49 -3.60 (2H, m, H3 - and He -); 3.94-4.02 (1H,, Hs -); 4.10 (2H, m, and Hiib); 4.42 (1H, dd, J? »- 3 = 9 Hz, J-ia-iib = 9.5 Hz, Hm); 4.57 (1H, d, J-1-2 = 5.2 Hz, Hi); 4.78 (1H, q, J = 4 Hz, H7 -); 4.91 (1H, d, JA-3 = 3.4 Hz, HA); 5.38 (1H, dd, J -? - 2-t = 2 Hz, J1--2-. = 9 Hz, J-i); 5.93 (1H, s, OCHAO); 5.97 (1H, s, OCHBO); 6.25 (2H, s, H-2, and H6 '); 6.51 (1H, s, He); 6.86 (1H, s, H-s).

Preparation of the Hydrochloride 890 μl of 0.098 M hydrochloric methanol solution (0.087 mmol) was added to the amine 15 (50 mg, 0.087 mmol) obtained in Step 4. After stirring for 10 minutes and the addition of ether (10 ml), crystals or hydrochloride (52 mg, 98%) are obtained by filtration. Characteristics: P.f. = 175 ° C C-29H-3AN0-H C1M = 607 Solubility test: 2.2 mg in 0.2 ml of water C = 0.02 M EXAMPLE 4 GENERAL FORMULA I: NR1R-2 = tt-NME-2; XY = 0CH (CH3) 0CH2 4'-DEMETIL-4-0 (3-N-DIMETHYLAMIN0-2.3-DIDE0XI-4.6-0-ETHYLIDEN-B-D-RIB0HEX0PIRAN0SIL) EPIP0D0FIL0T0XIN 20 Successively add formaldehyde (10.3 μl) and sodium cyanoborohydrate (12 ml) to a solution of the compound (29 mg: 0.05 mmol) obtained in Step 4 of Example 3 in 1 ml of acetonitrile. After stirring for 2 hours at room temperature, it is diluted in reaction medium with CH 2 Cl 2) (20 ml) and washed with water (20 ml). The organic phase is dried over MgSOA and concentrated under reduced pressure. The residue is again added to the reaction under the same conditions and after an identical treatment is chromatographed on a silica gel (CH2CI-2 / MeOH: 97/3). Characteristics: TLC: CH2Cl2 / Me0H: 95/5; Rf = 0.5 [cx] 20D - -85 ° (c = 1.06; CHCl3) MS: m / z 600 (M + 1) + P.f. = 140 ° C C31H37NO11M = 599 1 H NMR 300 MHz CDCl 3 d: 1.35 (3H, d, J = 5 Hz); 1.55 (1H, m, H2"a), 2.20 (1H, m H2" e "), 2.36 (3H, s, CH-3N), 2.62 (1H, m, 2.62, H3"), 2.85 (1H,, H-3), 3.23 (1H, dd, J2-1 = 5.2 Hz, J2-3 = 14 Hz, H-2), 3.52 (1H, dd, JA "-3 = e Hz, JA" -3" = 9HZ, HA "); 3.61 (1H, t, Js" a-6"e = 10 Hz, Jß'a-5" = 10 Hz, Hß'a); 3.75 (3H, s, CH3O); 4.22 - 4.02 (1H, m, Hs "), 4.22 - 4.02 (1H, m, He-a), 4.22-4.02 (1H, m, H9b), 4.43 (1H, dd, J9a- 9b) = 9Hz, J9b -3 = 10.5 Hz, H9b), 4.62 - 4.57 (1H, m, J-1-2 = 5.2 Hz, Hi), 4.62 - 4.57 (3H, m, J = 5Hz, CH-CH-3), 4.88 ( 1H, d, JA-3 = 3.4 Hz, HA), 5.96 (1H, d, 0CH-A0), 5.98 (1H, d, OCHBO); 6.25 (2H, s, H2 and H-6 '); 6.52 (1H, s, He); 6.80 (1H, s, H-5).

Preparation of the Hydrochloride The hydrochloric methanol solution was added at 0.098 M to the amine 20 (59 mg, 0.1 mmol) in an anhydrous methanol solution (2 ml) (1 ml, 0.1 mmol). The reaction medium is stirred for 10 minutes. The specimen is precipitated after the addition of ether (20 ml). It is recovered at 33 mg (53%) of the crystals.

Characteristics: P.f. = 150 ° C C-31H38NO11CIM = 635 Solubility test: 2.6 mg in 0.1 ml of water C = 0.04 M EXAMPLE 5 GENERAL FORMULA I: NR-1R-2 = OC-NHCH2CN: XY = OCH (CH3) OCH2 4'DEMETYL-4-0- (3-CYAN0METILAMIN0-2.3-DIDE0XI-4.6-ETILIDEN- & D - RIBOEXOPIRANOSIDEPODOFILOTOXINA (COMPOUND 16).

Add 200 μl of triethylamine (1.47 mmol) and then 100 μl of iodoacetonitrile (1.47 mmol) to a solution of 15 (120 mg, 0.21 mmol) obtained from Step 4 of Example 3 in 4 ml of dimethyl formamide. The reaction medium is stirred for 20 hours at room temperature and is also diluted with ethyl acetate (30 ml) before washing with water (4 x 30 ml). The organic phase is dried over MgSOA, concentrated under reduced pressure and then chromatographed on a silica gel (CH2Cl2 / acetine: 92/8) to give 71 mg of compound 16 uro (55%). Characteristics: TLC CH2Cl2 / Me0H: 95 (5; Rf = 0.25 [a] 20D = 80 ° (c = 0.80; CHCI3) MS: m / z 611 (M + H) + 628 (M + NHA) + C31H3 -2O11M = 610 1H NMR 300 MHz CDCI3 d: 1.35 (3H, d, J = 5Hz, CH- 3CH), 1.69 (1H, m, J2 --.- 1 = 9.5 H, J2"-a-2" e = 13 Hz, J2"a-3 = 3 Hz, J2" a) 1-93 (1H, m, J - e), 2.86 (1H, m, H3), 3.25 (1H dd, J2-1 = J2-3 = 14 Hz, H-2), 3.51 - 3.56 (2H, m, HA- and Hfe-a) 3.56 (2H, m, CH-2CN), 3.76 (6H, s, OCH3), 3.88 (1H, m, Hs) ") 4.17 (2H, t, Jlla-3 = 8 HZ, J-lla-llb = 10 Hz, H-3" and Hllb) 4.14 (1H, dd, Jsa "-6" b = 10 Hz, J6"- B-5"= 5 Hz, He" b), 4.41 (1H, dd, J-? Ia-3 = 9 Hz, Jiia-iib = 10 Hz, Hp »), 4.60 (1H, d, J1-2 = 5.3 Hz, Hi), 4.75 (1H, q, J = 5 Hz, H7 ••) 4.90 (1H, d, JA-3 = 3.3 Hz, HA), 5.17 (1H, dd, J? -2"c = 2 Hz, J-1--2"» = 9.5 Hz, Hi "), 5.99 (1H, s, OCHA 0), 6.00 (1H, s, OCHBO), 6.25 (2H, s, H-2, and H -6-), 6.54 (1H, s, He), 6.79 (1H, s, Hs).

EXAMPLE 6 GENERAL FORMULA I: NR1R-2 = a MORPHOLINO: XY = 0CH (CH-3) OCH2 4'-DEMETIL-4-0- (3 N-M0RF0LIN0-2.3-DIDE0XI-4.6-ETILIDEN-BD-RIBOHEXOPIRANOSIDEPIPODOPHILOTOXIN (COMPOUND 17) 58 μl of triethylamine (0.42 mmol) and then 512 mg of diiodoethyl ether (1.57 mmol) are added to a solution of compound 15 (60 mg, 0.10 mmol) obtained in Step 4 of Example 3 in 12 ml of dimethylformamide. The reaction medium is stirred for 96 hours at room temperature and in the dark and then diluted with ethyl acetate (30 ml) before washing with water (4 x 30 ml). The organic phase is dried over MgSOA, concentrated under reduced pressure and then chromatographed on a silica gel (CH2Cl2 / acetone: 92/8) to give 46 mg of pure compound 17 (68%).

Characteristics: TLC: CH2CI2 / acetone: 92/8, Rf = 0.31 [apo = -98 ° (c = 1.04; CHC) C33H39NO12M = 641 1 NMR 300 MHz CDCI3 d: 1.33 (3H, d, J = 5Hz, CH3CH); 1-55 (1H, m, J2"a-1 ~ = 9.5 Hz, J2" a-2"e = 13 Hz, J2" a-3 = 3 Hz, H2"a), 2.15 (1H, m, H2 -.), 2.84-2.90 (5H, m, CH2 N and H3); 2.80 (1H, dd, J3"-A" = 3Hz, J3"-2" a = 3Hz, J3"-2" t = 3Hz, H3-); 3.23 (1H, dd, J2-1 = 5.2 Hz, J2-3 = 14 Hz, H2); 3.48 (1H, t, J2"a- 6" b = 12 HZ, J6"a-5" = 12 Hz, H6"a), 3.57 (1H, dd, J3" aA "= 3Hz, JA" a-5"= 9 Hz, HA"); 3.66-3.76 (10H, m, OCH3 and OCH2); 4. 08-4.16 (2H, m, Hs - and Hs • b); 4.20 (1H, t, J? Ia-3 = 8 Hz, Jlla-llb = 9HZ, Hila); 4.43 (1H, dd, Jllh-3 = HZ, Jllb-lla = 9 Hz, Hiib); 4.57-4.62 (2H, m, Hi and H7"), 4.89 (1H, d, JA-3 = 3.4 Hz, HA), 5.20 (1H, dd, Ji" -2"ß = 2 Hz, J? 2- «= 9.5 Hz, Hi), 5.97 (1H, s, OCHAO), 6.00 (1H, s, OCHBO), 6.25 (2H, s, H2 and He,), 6.54 (1H, s, He), 6.73 (1H, s, Hs).

EXAMPLE 7 GENERAL FORMULA I: NR1R2 = tt-NH2 (CH2 2NH2: XY = 0CH (CH-3) 0CH2 4 -DEMETHYL-4-0 [3- (2-AMIN0ETILAMIN0) -2.3-DIDE0XI-4.6-ETILIDEN-B- D-RIBOHEXOPIRANOSIL] EPIPQDOFILLOTOXINA 18 Triethylamine (127 μl, 0.91 mmol) and N-benzyl-oxycarbonyl-2-iodoethylamine (0.28 g, 0.91 mmol) are added to a solution of the compound (173 mg, 0.30 mmol) obtained in vessel 4 of the Example 3 in 10 ml of dimethylformamide. The reaction medium is stirred for 5 days at room temperature and then diluted with water (30 ml). After extraction with ethyl acetate (30 ml), washing with water (5 x 20 ml), the organic phase is dried over MgSOA, concentrated under reduced pressure and chromatographed on silica gel (CH2Cl2 / MeOH: 97 / 3) to give 155 mg of pure compound 18 (68%). Characteristics: TLC: CH2Cl2 / MeOH: 95/5, Rf = 0.70 [a] 2 ° D = -74 ° (c = 1.17; CHC13) MS: m / z 749 (M + H) + C39HAAN2O13M = 748 which is used directly in the next step of debencylation: Triethylamine (30 μl) is added and then palladium to the % on carbon (0.1 g) to a solution of compound 18 (0.15 g, 0.20 mmol) in a mixture of ethyl acetate and ethanol (10 ml, 1/1). The reaction medium is placed in a hydrogen atmosphere (atmospheric pressure). After stirring for 1 hour 30 minutes at room temperature in the presence of hydrogen at atmospheric pressure, the catalyst is separated by filtration and the organic phase is concentrated under reduced pressure and chromatographed on a silica gel (CH2Cl2 / MeOH (NH3: 97 / 3) to give 107 mg (84%) of compound 19. Characteristics: TLC: CH2Cl2 / MeOH (NH3): 95/5, Rf = 0.22 [a] 2 ° = -77 ° (c = 1; CHC) Pf = 130 ° C C3? H38N0? M = 614 i NMR 300 MHz CDCI3 d: 1.33 (3H, d, J = 5Hz); (1H, m, H2 -a); 2.15 (1H, m, H2"e); 2.33 83H, m, NH2 and NH, interchangeable), 2.84-2.90 (5H,, CH2N and H3), 3.20 (1H, dd, J3"-« "= 3Hz, J3" -2"a = 3Hz, J3" -2"ß = 3Hz, H3"); 3.23 (1H, dd, H2); 3-48 (1H, t, J2"a-6" b = 12 Hz, J6"a-5" = 12 Hz, He "); 3.57 (1H, dd, J3" aA "= 3Hz, JA 'a- 5"= 9 Hz, HA -); 4.08-4.16 (2H, m, Hs "and Hß" b); 4.20 (1H, t, J? Ia-3 = 8 Hz, Jiia-llb = 9Hz, Hiia); 4.43 (1H, dd, J? Ib-3 = 9 Hz, Jiib-iia = 9 Hz, Hiib); 4.57-4.62 (2H, m, H and H7); 4.89 (1H, d, JA-3 = 3.4 Hz, HE HAS ); 5.20 (1H, dd, J? - 2"« = 2 Hz, Ji "-2" a = 9.5 Hz, Hi "); 5.97 and 6.00 (2H, d, OCH2O); 6.25 (2H, s, H2 and Hé,); 6.54 (1H, s, He); 6.73 (1H, s, Hs). Hydrochloride Preparation A hydrochloric methanol solution is added at 0.098 M (2.13 ml, 0.21 mmol) to diamine 19 (64 mg, 0.10 mmol) in anhydrous methanol solution (3 ml). It is stirred to the reaction medium for 10 minutes. The expected product is precipitated after the addition of ether (20 ml). 50 mg (73%) of the hydrochloride is recovered. Characteristics: P.f. = 170 ° C C13H39N2O11M = 649 Solubility test 2.0 mg in 0.05 ml of water C = 0.06 M EXAMPLE 8 GENERAL FORMULA I: NR1R2 = 0C-NH: X = OH: Y = CH3 4 '-DEMETIL-4-0 (3 - (2-AMIN0-2.3.6-TRIDE0XIB-D- RIBOHEXOPIRANOSIL3EPIPODQFILLOTOXINA (COMPOUND 26) Step 1: Ter-butyldimethylsilyl-3-acid-2,3-dideoxy-6-0-tosyl- &-D-ribohexopyranoside 21 A solution of tosyl chloride (1.55 g, 8.15 mmol) in pyridine is added dropwise. (10 ml) was added to a solution of 12 (2.06 g, 6.79 mmol) obtained in Step 1 of Example 3 previously cooled to 0 ° C. After stirring at the same temperature for 1 hour and then for 18 hours at 20 ° C, the reaction medium is diluted with dichloromethane (100 ml). The organic phase is washed with water (2 x 100 ml), dried over MgSOA and concentrated under reduced pressure. The residue is purified on a silica gel (cyclohexane / EtOAc: 8/2). This gives 2.02 g of the compound (65%). Characteristics: TLC: cyclohexane / -EtOAc: 2 / l Rf = 0.46 EM: m / z 475 (M + H) + C19H31 3O6SSIM = 457 Step 2 Te r-bu i ldime i lsi 1 i 1 -3-acid-6-iodo-2.3.6-t rideoxy-β-D-ribohexopi ranoside 22 Compound 21 (2.02 g, 4.41 mmol) obtained in Step 1 in solution in 120 ml of acetone under reflux for 72 hours in the presence of sodium iodide (2.65 g, 17.68 mmol). After cooling, the reaction medium is concentrated under reduced pressure (30 ml) and then diluted with dichloromethane (100 ml). After washing with a 10% aqueous solution of sodium thiosulfate and then drying over MgSOA and evaporating under reduced pressure, a residue is obtained which is purified on silica (cyclohexane / EtOAc: 8/2) giving 1.5 g (82%) ) of the compound Characteristics: 1.06, CHCl3) MS: m / z 431 (M + NHA) + C12 H2A N3 O3 ISIM = 413 C H N Calculated 34.87 5.81 10.17 Obtained 35.07 5.76 10.25 Step 3: Ter-Butyldimethylsilyl-3-acid-6-iodo-4-0-chloroacetyl-2,3,6-trideoxy- &-D-ribohexopy-ranoside (Compound 23) Chloroacetyl chloride (396 mL, 5 mmol) is added to a solution of compound 22 (1.03 g, 2.5 mmol) obtained in the preceding Step in a mixture of dichloromethane (20 ml) and pyridine (404 μl, 5 mmol). After stirring for 1 hour at -10 ° C, the reaction medium is diluted with CH2Cl2 (30 ml) and washed with water (3 x 20 ml). A usual treatment, followed by chromatography on silica (cyclohexane / EtOAc: 10/1) gives 1.1 g (90%) of compound 23. Characteristics: [aP D = -14 ° (c-1.03, CHCl3) MS: m / z 507 (M + NHA) + CIAH25N30AC1ISÍM = 489 C H N Calculated 34.35 5.11 8.59 Obtained 34.69 5.16 8.22 Step 4 4'-Demethyl-4-0 (3-acid-6-iodo-2,3,6-trideoxy-D-ribohexopy ranosyljepipodofillotoxin (Compound 24) Boron trifluoride etherate (BF3 »Et2?) (455) is added μl, 3.7 mmol) to a mixture of DMEPT 4'-0Z (1 g, 1.85 mmol) of compound 23 (1 g, 2.04 mmol) from the preceding step in anhydrous dichloromethane (100 ml) cooled down to minus 15 ° C. cooled for 5 h (-15 ° C ° C), diluted in a merida reaction with CH 2 Cl 2 (100 ml) and then poured into a saturated solution of NaCH 3 (200 ml), the organic phase is dried over MgSOA, concentrated reduced pressure: The crude residue is chromatographed on silica gel (cyclohexane / EtOAc: 7/3) to give compound 24 (0.8 g, 48%) Characteristics: TLC: cyclohexane / EtOAc: 1/1, Rf = 0.58 [ CX] 20 D = -85 ° (c = 1.26; CHCl 3) MS: m / z 909 (M + NHA) + Pf = 143 ° C C37H35N3O13CIIM - 891 Step 5 4 '-Déme i 1 -4-0 (3-acid-6-iodo-2.3.6-rideoxyB-D-ribohexopyranosyl-' -benzyloxycarbonylepipodofillotoxin (Compound 25) OH- resin (Amberlite ™ IRA 419) is added to a solution of acidoglycoside 24 (257 mg, 0.29 mmol) in a mixture of CH2Cl2 / MeOH (15 ml, 2/1) After reacting them for 3 hours at 20 ° C, the reaction is filtered and then concentrated under pressure reduced to give 0.22 g of pure compound (94%) Characteristics: TLC: cyclohexane / EtOAc: 1/1; Rf = 0.46 [a] 20D = -57 »(C = 1.02; CHCl3) Step 6 4'-Demethyl-4-0 (3-amino-2,3,6-trideoxy-D-ribohexopy ranosil Jepipodofillotoxin (Compound 26) Triethylamine (100 μl) is added and then palladium % on carbon (0.2 g) to a solution of compound 25 (0.20 g, 0.25 mmol) from the preceding step in 10 ml of ethyl acetate. After stirring for 30 hours at room temperature in the presence of hydrogen at atmospheric pressure, the catalyst is separated by filtration and concentrated to the organic phase under reduced pressure and then chromatographed on a silica gel (CH2C12 / Me0H: 92/8). to give 50 mg (38%) of 26, Characteristics: TLC: CH2Cl2 / MeOH: 90/8; Rf = 0.33 [a] 20D = -90"(C = 0.5; CHCl3) MS: m / z 530 (M + H) + P.f. = 140PC C27H31NO10M = 529 Preparation of Hydrochloride A hydrochloric methanol solution is added at 0.098 M (1.44 ml, 0.14 mmol) to the preceding 26 amine (70 mg, 0.14 mmol) in anhydrous methanol solution (6 ml). The reaction medium is stirred for 10 minutes. The expected product is precipitated after the addition of ether (20 ml). 40 mg (53%) of the crystallized hydrochloride is recovered. Characteristics: P.f. = 164 ° C C27H32NO10CIM = 565 Solubility test 2.6 mg in 0.2 ml of water C = 0.02 M EXAMPLE 9 GENERAL FORMULA I: NR1R2 - 0.-NH2; X = OH; Y = CH3 4'-DEMETIL-4-0 (3.6-DIAMIN0-2.3.6-TRIDE0XIB-D-RIBOHEXOPIRANOSIL] EPIPODOFILLOTQXIN (COMPOUND 29) Step 1 4'-Demethyl-4 '-benzyloxycarbonyl-4-0 (3,6-diacid-4-acidoacetyl-2.3.6-rideoxyB-D-ribohexopy ranosi 1] epipodofyllotoxin (Compound 27) Acid sodium is added (0.1 g, 1.5 mmol) to a solution of compound 24 (2.54 g, 0.51 mmol) obtained in Step 4 of Example 8 in 10 ml of dimethylformamide The reaction medium is stirred for 64 hours at room temperature, diluted with water (30 ml) and ethyl acetate (30 ml) The organic phase is washed with water (4 x 20 ml), dried over MgSOA, concentrated under reduced pressure and chromatographed on silica gel (cyclohexane / EtOAc: 7/3) to give 0.36 g of the compound (90%) Characteristics: TLC: cyclohexane / EtOAc: 6/4 Rf - 0.44 Ca] 20 D - - 6 »(C = 1; CHCl 3) MS: m / z 831 ( M + NHA) + Pf = 120 ° C C37H35N913M = 813 Step 2 4 '-Demethyl-4' -benzyloxycarbonyl-4-0 (3,6-diacid-2,3,6-trideoxyB-D-ribohexopy ranosil lepipodofillotoxin (Compound 28) The 0H ~ resin (Amberlite ™ IRA 410) is added to a solution of the acidogli coside 27 (70 mg; 0.08 mmol) in 3 ml of a mixture of CH2Cl2 / MeOH (2/1, v / v). After reacting them for 5 hours at 20 ° C, the reaction is filtered and then concentrated under reduced pressure to give 59 mg of pure compound 28 (94%). Characteristics: TLC: cyclohexane / EtOAc: 6/4; Rf 0.25 [a] 20D - -53 ° (C = 1.04; CHCl3) P.f. = 125 * C C35H3AN6O12IM = 730 Step 3 4 -Déme i1-4-0 (3,6-diamino-2.3.6-rideoxiß-D-ribohexopi ranosil] epipodofilio oxina (Compound 29) Add triethylamine (20 μl) and then 10% palladium on carbon (70 mg) to a solution of compound 28 (0.11 g, 0.15 mmol) from the preceding step, in the mixture of ethyl acetate and ethanol (10 ml, 1/1). After removing for 16 hours at room temperature in the presence of hydrogen at atmospheric pressure, the catalyst is dried by filtration and the organic phase is concentrated under reduced pressure to give 78 mg (95%) of compound 29. Characteristics: TLC: CH2Cl2 / MeOH (NH3): 90/10; Rf = 0.06 C-27H32NO? OM - 544 Preparation of the Dihydrochloride A solution of hydrochloric methanol at 0.098 is added M (2.92 ml, 0.28 mmol) to the preceding diamine 29 (78 mg, 0.14 mmol) in anhydrous methanol solution (2 ml). It is stirred to the reaction medium for 10 minutes. The expected product is precipitated after the addition of ether (20 ml). 70 mg (79%) of the crystallized dihydrochloride is recovered. Characteristics: P.f. = 95 ° C C27H3AN-2O10CI2M = 616 Solubility test 2.1 mg in 0.05 ml of water C = 0.07 M BIOLOGICAL EXPERIMENT The molecules were tested using a biological experiment and showed their usefulness as an anticancer agent in leukemia tests, P 388 in vivo in mice. This test is commonly used in the field of research on anticancer substances (protocols for screening chemical agents and natural products against tumors of animals and other biological systems, R. Geran, NH Greenberg, MM MacDonald, AM Schu Acher and BJ Abbott, Cancer Chemotherapy reports 1992, 3, No. 2). However, this model experiments is extremely chemosensitive and a very large number of compounds show good activity, which makes this test barely discriminatory. The test protocol was eliminated to make a more selective one. Tumor cells were administered intravenously and not intraperitoneally. They are distributed in this way quickly through the circulation in the whole body. It was administered after the test product intraperitoneally. Two parameters are defined in order to demonstrate the activity of the compounds: The determination of the average effective dose (EDso) representing the minimum single dose of the compound to be administered in order to achieve a significant survival of the animals compared to the animals of control not treated; Determination of the maximum survival time of the animals regardless of the dose administered by a single injection. The fact of being able to administer a large dose of the compound and observing a high survival makes it possible to obtain a measure of the maximum therapeutic efficacy of the product that can be achieved.

ORIGIN OF THE TUMOR P 388 leukemia was induced chemically in 1955 with 3-methylcholanthrene in a DBA / 2 mouse (Am. J. Pathol, 33, 603, 1957).

PHARMACOLOGICAL PROCEDURE Tumors are maintained by weekly transitions asecitically in the peritoneum of a DBA / 2 mouse (original line) and the experiments are carried out in female CDFi hybrid mice (balance of females b / c and males XDBA / 2) of 20 + 2 g (Cancer chemother, Rep. 3, 9, 1972). The tumor cells are implanted intravenously (106 cells per mouse) on day 0. The animals are taken randomly and distributed in groups of 2 for each series. The anti-tumor substances are administered intraperitoneally (ip) one day after the inoculation of the leukemic cells (acute treatment). The solutions are injected in an amount of 10 ml / kg of mouse. The criterion for evaluating the activity of the anti-tumor activity is the extension of the survival of the treated animals. 86% of mice die on the seventh day after tumor transplantation. A substance is considered to be active if it induces a survival greater than 8 days.

The following table makes it possible to show the aqueous solubility of the products of the invention, expressed per mg / ml, the activity of these compounds in terms of EDso, the survival expressed in days or in T / C%, which represents the relationship of the average survival of the group of treated animals of the average survival of the group of control animals.

It thus appears that the compounds of the invention retained the level of activity of the reference compounds, such as the Etoposide and have, in addition, the advantage of having an advantageous aqueous solubility for their formulation and administration.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - I in which the on B (series 2-deoxy D Arabino) position D (series 2-deoxy ribo) in relation to the ring, Ri and R2 which are identical or different, represent a hydrogen atom, an alkyl group of Ci to Ce, capable of forming a ring, it being possible for the ring to contain a heteroatom such as oxygen or nitrogen, an aminoalkyl group of Ci to Ce or a cyanomethyl group, X and Y may be identical or different and represent OH, CH 3 CH 2 -NH 2, X and Y can also be linked and can form a ring, such as for example a 2-methyl-l, 3-dioxane, thus forming a bicyclic base structure of glycoside of the type 4,6-ethylidene-3-amino-2 , 3-dideoxyglycoside, and its known pharmaceutically acceptable inorganic or organic addition salts.

2. A compound of the general formula I according to claim 1, further characterized in that the group NR1R2 is a group NH2 or N (CH3).

3. A compound of the general formula I according to claim 1, further characterized in that the group NR1R2 represents a amino group substituted one or two times with a methyl, CH2CN or a CH2-CH2NH2.

4. A compound of the general formula I according to claim 1, further characterized in that X and Y form a ring with a bond 0CH (CH3) 0CH-2.

5. A compound of the general formula I according to claim 1, further characterized in that it is chosen from the following compounds: 4'-demethyl-4- (3-amino-4,6-tylidene-2,3- dideoxy-ß-D-arabinohexopi ranosil) epipodophyllotoxin, 4'-demethyl-4-0- (3-amino-4,6-ethylidene-2,3-dideoxy-ß-Dribohexopi ranosil) epipodophyllotoxin, 4 '-demethyl-4 -0 (3-dimethylamino-4,6-ethylidene-2,3-dideoxy-β-D-arabinohexopy ranosyl) epipodophyllotoxin, 4 '-demethyl-4-0 (3-di-ethylamino-4,6-ethylidene-2, 3-dideoxy-ß-D-ribohexopy ranosil) epipodophyllotoxin, 4'-dethi4-4-0 (3-cyanomethylamino-4,6-ethylidene-2,3-dideoxy-β-D-ribohexopy ranosil) epipodophyllotoxin, 4 '- demethyl-4-0 (3-N-morpholino) 4,6-ethylidene-2,3-dideoxy-β-D-ribohexopyranosyl) epipodophyllotoxin, 4 '-demethyl-4-0 [3 (2-aminoethylamino) -4, 6-e-liden-2,3-dideoxy- &-D-ribohexopy ranosil)] epippodof ilotoxin, 4 '-demethyl-4-0- (3-amino-2,3, -r ridesoxy-β-D-ribohexo- pi ranosi 1) epipodof i lo oxin, 4 '-demeti 1-4-0 (3, 6-diamino-2, 3,6-tridesox i-1, -D-ribohexopi ranosil) epipodophyllotoxin.

6. A compound of the general formula I according to claim 1, further characterized in that it is provided in the form of hydrochlorides.

7. Method for preparing a compound of the general formula I according to claims 1 to 4, further characterized in that a compound of the formula III or IV or V is reacted. II! [V V it is reacted with 4'-demethyl-4'-benzyloxycarbonylepipodophyllotoxin with BF3 etherate, or trimethylsilyl trifluoromethanesulfonate in an inert solvent at low temperature; your IV with 4 '-Demethyl-4' -benzyloxycarbonylepipodo-fillotoxin, with BF3 etherate or with trimethylsilyl trifluoromethanesulforate in an inert solvent at low temperature; in formulas III and IV, the substituent at position 3 can be a or ß, NR1R2 can be an amino protected with a group Z; in the formula V, P represents an alcohol protecting group and the products resulting from this condensation are deprotected and hydrogenated to give the compounds of the formula I; the primary amines are methylated at the 3-position of the glycoside with for-aline and sodium cyanoborohydrate.

8. Method for preparing a compound of the formula I according to claim 7, further characterized in that the compound of the formula IV is prepared has been reacting a diacetoxiacidocido-glycoside VI. vt with tert-butyldimethylsilyl chloride in the presence of imidazole, because the products resulting from this reaction are separated, because each of these products is deacetylated, cyclized to 4,6-ethylidene with the acetaldehyde acetal in a catalytic acid medium. 9.- As a drug, the compounds of the formula I according to claims 1 to 6. 10. The pharmaceutical compositions further characterized in that they contain at least one compound of the formula I according to one of claims 1 to 6 and in an appropriate excipient. . 11. Use of the compound of the formula, according to one of claims 1 to 4, for the preparation of a drug for treating cancer and, in particular, for treating forms of cancer such as, for example, lung cancer small cells, cancer of the testes, embryonic tumors, neuroblastomas, kidney cancer, placental choriocarcinomas, mammary adenocarcinomas, colorectal cancers, melanomas, Hodgkin's and non-Hodgkin's lymphomas and acute leukemias.