CA2203155C - Water-soluble epipodophyllotoxin derivatives, preparation method therefor, and use thereof as a drug and for treating cancer - Google Patents

Abstract

Derivatives of general formula (I), wherein R is an acyl grouping and R' is a hydrogen atom, a monoester phosphate residue or a substituted carbamate grouping, salt forms thereof and a preparation method therefor, are disclosed. The use of said water-soluble compounds as a drug, as well as for preparing a drug for treating cancer, is also disclosed.

Description

WATER-SOLUBLE DERIVATIVES OF EPIPODOPHYLLOTOXINE, THEIR PROCESS OF PREPARATION, THEIR USE
OF THE MEDICINAL PRODUCT, AND THEIR USE FOR
ANTICANCER TREATMENTS.
Among the class of epipodophylloids, certain compounds such as etoposide Teniposide, derivatives of epipodophyllotoxin, Synthetics, derived from natural lignan, are used in the preparation of medicines to treat many forms of cancer. They are io considered, currently as major products of the arsenal therapeutic.
Among the various cancers treated with this type of compound, mention may be made of small cell lung cancer, embryonic tumors, neuroblastoma, kidney cancer, lymphoma, Hodgkin's disease, leukemia is acute, and even breast cancer. Etoposide is advantageously used in combination with other anticancer products and in particular derivatives Platinum like Platinum Cis.
The important disadvantage of this derivative, and similarly for its derivative related teniposide, is its lack of water solubility. He does not exist 2o of water-soluble commercial forms for administrations IV. On the contrary, the dissolution is currently done in partially non-aqueous solvents, requires administration in slow infusion and causes some undesirable or even toxic effects.
There is thus a need for water-soluble forms for derived products ~ s of this class of compounds, to improve administration in the patient, as well as its bioavailability. The present invention thus relates to water-soluble etoposide derivatives through the presence of groups functional phosphates or carboxylates including organic addition salts or minerals form soluble entities in water. This formulation ~ o aqueous has the advantage of being less toxic and more easily administrable than the forms currently marketed.
The preparation of etoposide derivatives has given rise to a great deal of work and numerous patents, and in particular diester derivatives 2 ", 3" and triesters

2 "

3 ", 4 'of etoposide have been claimed in FR-2,699,535-A1.
s Some of these derivatives have an activity equal to or greater than etoposide and a lower toxicity. An additional improvement is brought now through an aqueous solubility that gives them a ease of administration and suggests increased bioavailability through a better passage in the different biological membranes.
The literature mentions patents relating to compounds related to etoposide seeking to improve water solubility, in particular (US
s 4 904 768, EP 0 369 369-A2, EP 0 196 618-A1, EP 0 320 988, EP
0 415 453-A2).
The advantage of modules is the aqueous solubility of the compounds by phosphate groups has been used in some cases favorably either in the field of anticancer agents WO 8707609, or in the field of lo analgesics (BE 893,563) despite everything nothing suggests that the compound thus obtained can fully preserve an interesting biological activity in itself as well as that of the derivative from which it is derived.
It has been found that phosphate and carboxylate derivatives have a water solubility for injectable administration, and more I s exhibit improved anticancer activity compared to etoposide.
The present invention therefore relates to a compound of general formula I

RR
O
I '~ o i ~ "- ~
O
i f Me ~ 4, OMe O
I
In which R 'represents either a hydrogen atom or a group phosphate monoester, a carbamate group of -CO-N (R1R2) type where N (R 1 R 2) represents aminodiacetic groups and an amine polycyclic substance such as 3-amino-quinuclidine, an acyl group of phosphonoacetic type H203P-CH2-CO, ie a radical R, R 2 represents an acyl group of formula where Z represents an oxygen atom, sulfur, a group 502, an alkylene linear or branched to C1 ~, in this case A represents a substituted or unsubstituted phenyl ring, to the condition that:
in the case where R '= R, that is to say the triacylated derivatives, A represents a core aromatic having a salifiable function, except 4-hydroxy-phenyl, in the case where R '~ R, A represents a benzyl, naphthyl or heteroaryl radical, substituted phenyl or not, in this case the phenyl can be substituted one, two, three, four or five several times regardless of its position on the aromatic nucleus by groups identical or different, chosen from groups such as halogen, F, Cl, Br, alkoxy linear or cyclic in CI ~, alkyl C, -C6, methylene dioxy, OCF3, CF3, N02, CN, OCHZ
Aryl, OH, OPO3H2, CH2PO3H2, OCH2CO2H, COOH, CH2COOH, COCH3, CHO, AZ can also represent a group OCH2COZH, SOZCHZCOOH, P03H2, as well as their salt with acids or bases, mineral or organic, therapeutically acceptable and water-soluble, with the exception of compounds for which R '= H, and Z represents an atom of oxygen or a sulfur atom, and A represents an aryl selected from phenyl, phenyl-alkyl, linear or branched C1-C4, naphthyl, and these same radicals substituted with one to three substituents chosen from linear or branched C1-C4 alkoxy radicals, eventually perhalogen with chlorine or fluorine atoms, linear or branched alkyl in C1-C4, and halogen atoms, in particular chlorine or fluorine.
The invention extends to a compound of general formula I
QO
RO '~ O
RO 'O
". ...

n ~ eo ~ ~ '''~ onn ~
O ~ R ' 3a in which R 'represents a hydrogen atom, ie a phosphate group monoester, a carbamate group of the type -CO-N (R1R2) where N (R, R2) represent aminodiacetic groups or a polycyclic amine, a grouping phosphonoacetic acid H203P-CH2-CO, either CO-CH2SO2-CH2COOH or COCH2-OCH2 COOH, a radical R, R represents a cyclohexyloxyacetyl or an acyl group of formula or Z represents an oxygen atom, sulfur, a group 502, an alkylene linear or branched to C 1-4, A represents an unsubstituted phenyl, naphthyl or benzyl ring or substituted up to five times substituted by identical or different groups chosen from halogen, F, Cl, Br, linear alkoxy or C 1 -C 6 cyclic, alkyl groups C, -C6, methylene dioxy, OCF3, CF3, NO2, CN, OH, OPO3H2, CH2PO3H2, PO3H2, OCH2CO2H, COOH, CH2COOH, COCH3, CHO.
Advantageously, the compounds of general formula I will be chosen with R ' representing a phosphate monoester group (P03H2), carbamate CONR, R2 and NR ~ R2 representing an aminodiacetic group or a 3-aminoquinuclidine, R ' also representing a phosphonoacetic group and their salts.
Preferably, R is chosen from the radicals:
phenoxyacetyl, 3,4-methylenedioxyphenoxyacetyl, 4-methoxyphenoxyacetyl, 4-hydroxyphenoxyacetyl, 4-phosphonooxyphenoxyacetyl, 4-carboxymethylphenoxy acetyl, 4-carboxymethoxyphenoxyacetyl, 4-carboxyphenoxyacetyl, 4-trifluoromethylphenoxyacetyl, 4-trifluoromethoxyphenoxyaetyl, 4-cholorophénoxyacétyl,

4-nitrophenoxyacetyl, 4-fluorophenoxyacetyl, cyclohexyloxy-WO 96 / I2727 PCT / F'R.95101388 acetyl, phenylsulfonylacetyl, pentafluorophenoxyacetyl, 2 and 4 formyl-phenoxyacetyl, 4-cyanophenoxyacetyl.
The present invention also relates to processes for the preparation of a compound of formula I, shown in Scheme 1 (route A), for which reacts a glycosylated intermediate of general formula II.
'~ C ~ - ~~ OH
RO Ra 11 with an intermediate of general formula III to provide an intermediate 1 o IV
Oh ~ j ~ o M e ~ atr ~ e 'R4 R having the previous si ~ nitlcations. R ~ is a protective group by For example, benzyloxycarbonyl has a resting earbamate. This method of prepa- ration is described in the prior patent FR 2,699,553 to Example I7.
To provide a compound of formula IV wherein R4 is a group protector and R d ~ ~ mi previously. This derivative IV is unprotected on its position 4 '(R.4), either by hydrogenol ~~ or by hydrolysis weakly to provide the derivative I (R '= H). It is also possible to prepare the compounds of formula I where R '= R by this method, using the intermediate of formula III in which R ~ represents an acyl group R, this method is also described in the prior patent FR 2,699,553 to Example 1. According to the compatibilities of the substituents R of glucosyl, it is It is also possible to synthesize the compounds of formula I from etoposide itself (route B).
In a first step, the etoposide can be protected in position 4 '(I ~,) I ~ ar a group R ~. = benzyloxycarbonyl, or by a quinuclidine group carbamate (R ~ = CCNH3-quinucliinyl) obtained by successive reaction of WO 96/12727 PCT / FIt95 / 01388 phosgene followed by amino-3-quinuclidine on etoposide, to provide the intermediary V.
In general, the intermediates V are acylated by chlorides derived from the groups R defined above, (formed by action of the oxalyl chloride) in the presence of pyridine in methylene chloride at low temperature, provided that the other functions of group R
are inert under these conditions, otherwise, the phenolic substituents, carboxylic or phosphoric acids are protected as ethers or of benzyl esters respectively, which allows deblocking, at the ~ o following of the synthesis, by hydrogenolysis (V giving IR '= H). Drifts for which R '= R are prepared from etoposide by triacylation on positions 2 ", 3" and 4 '(channel C).
In the case of functional derivatives R Sensitive to cnnrtitinnc hydrogenolysis, as for example but not exclusively, the presence ~ s Cl or NO2, the protective group chosen on the 4 'position can to be a carbamate derivative of CONH-3-quinuclidinyl type or a carbonate or of a low molecular weight ester, such as chloroacetates which can cleave later among other things in weakly basic conditions as an aqueous solution of low temperature sodium bicarbonate 2o without influencing the stereochemistry of the trans lactone.
The final step I (R '= H) giving I (R' ~ H) consists of a phosphorylation to form a phosphate monoester of the phenol (s) with POC13 in presence of pyridine followed by slow hydrolysis in acidic aqueous medium.
Obtaining derivatives having in the 4 'position a carbamate residue 2s diacetic type R '- CON (CH2CO2H) 2 are prepared by action of phosgene on the compound of formula I (R '= H) to form the intermediate uninsulated chlorocarbonate (R '= COC1) and then reacting it with Benzyl diester of aminodiacetic acid followed by hydrogenolysis to then release the acid functions in free form.
~ o Phosphonoacetic derivatives in position 4 'are obtained by making react free phenol in this position with the acid chloride of the acid . diethylphosphonoacetic acid (Synthesis 1978, 131) or dibenzyl acid prosphonoacetic (Tet.Let.: 1974, No. 9, 711) and then hydrolysing the phosphoric ester functions by trimethylsilyl bromide, in particular ~ s presence of pyridine in acetonitrile, in the case of esters ethylic, or by hydrogenolysis, in the case of benzyl esters. Derivatives of . . , ",, . ,. ,,, ., ". ~," ~, formula I where R '= R, that is to say having the same acyl substitution on the 2 ", 3" and 4 'positions are obtained, by the C route, by triacylation of etoposide itself with acyl groups AZCH2CO having a carboxylic function on the group A defined previously, protected s for example in the form of benzyl ester, which is deprotected by hydrogenolysis later.
The carboxylic derivatives, or the phosphate or phosphonate derivatives and obtained are salified in water, possibly in the presence of a cosolvent organic, by the addition of organic or inorganic bases in proportion ) o stoichiometric with respect to the acidities present, and for example with N-methylglucamine, triethanolamine, lysine, etc.
The amorphous or crystallized salts are obtained by simple lyophylization.
Diagram 1 Channel A Channel B Channel C
II III Etoposide Etoposide ~ O ~ O
O O--OO ~
RRO HO HO O
O ~ O
O
nr ,,,! ~~ ~ ~ rrr. ,, lO
\\ O \ 'O
ii Me OMe Me OMe IV GOLD, GOLD, 1) Diacylation Deprotection 2) Deprotection I (R '= H) I (R'-H) Triacylation R '= R
r; C ~ ,! CLF ~

6a The invention also extends to the preparation of a compound of formula general I, such as defined above, characterized in that fetoposide is reacted protected in 4 'position with a benzyloxycarbonyl or quinuclidinecarbamate group formula V
~ O

HO
HO
O i C?
~ 0.,. ...
O
'',., ~ ' ~ '' the ~ Or ~~ rle 4 ' V
wherein R4 is as previously defined, with an acylating reagent of type AZ-CH 2 CO, in which A and Z are as defined above, to conduct after hydrogenolysis or hydrolysis to the compound of formula I such that R '= H.
The invention also extends to the use of a compound of formula I of the present invention for the preparation of a medicament for the treatment cancer.

wo 96ni727 The lure of hvdro ~ colubilitP
The solubility in water of the salts of the phosphate or carboxylate derivatives by addition of physiologically acceptable organic amines as per N-methylglucamine, triethanolamine, lysine, or salts with s mineral cations such as sodium, obtained in freeze-dried form or by extemporaneous addition of a base to the free acid compound, provided the following results as an example.
io Salt Solubility Compounds% (w / v) expressed in g for 100m1 of water Example N-methyl glucamine 0.5 Example N-methylglucamine Example N-methylglucamine 10 Example N-methylglucamine 10 Trithanolamine Example 20 Example lysine 20 Example Sodium 1 Example N-methylglucamine 10 Example N-methylglucamine 10 Example N-methylglucamine 10 Example N-methylglucamine 10 Example N-methyl glucamine 0.5 The derivatives thus prepared are stable under the usual pH conditions neutral and acid and temperature. Phosphate derivatives at the 4 'position have a chemical stability to be able to lend themselves to different ts pharmaceutical formulations.

w0 96/12727 The molecules were tested in vitro in biological experimentation and showed their interest as anticancer agents in the following tests.
The measurement of the inhibition of the activity of topoisomerase II is made according to s the protocol described in the literature: "Nuclear topoisomerase II levels correlation with the sensitivity of mammalian cells to intercalating agents Epipodophyllotoxins, HICKSON, et al., J. Biol Chem (1988), 263, 17724-1772.
This measure provided the following results.
to Compounds Test of inhibition of the activity of the topoisomrase II (ED $ p M) Etoposide 5.6. 10-5 Etopofos> 10_4 Example 1 5.6. 10-6 Example 3 3.2. 10-7 Example 4 1.8. 10-6 Example 6 3.2. 10-7 Example 7 5.6. 10-5 Example 11 5.6. 10-6 Example 21 5.6. 10-6 Example 26 5.6. 10-6 Example 27 7.6. 10-7 The comparison of etoposide with its soluble 4'-phosphate analogue ~ etopofos (US-4,904,768) shows a loss of activity it ~ vitro. Here the compounds of the invention are also, if not more, active than etoposide.
The groups R and R 'defined previously give the compounds of the invention a 10 to 100 fold increase in the inhibition of enzymatic activity in vitro compared to etoposide.

WO 96/12727 PCTlFR95 / 01388 In view of these results, we can appreciate the interest of compounds with a anticancer activity equal to or greater than that of etoposide, and a less toxicity, on different forms of cancer, particularly small cell lung cancer, embryonic tumors, s neuroblastoma, kidney cancer, pediatric tumors, lymphomas hodgkins and non-Hodgkimians, acute leukaemias, choriocarcinomas placental, mammary adenocarcinoma.
These derivatives can also be used in pathologies induced by human papilloma virus as well as rheumatoid arthritis with or without lo cancerous diseases.
In addition these derivatives can be used to increase the effectiveness therapeutically inhibitory compounds of topoisomerase II and in particular the treatment of tumors normally refractory to therapy usual, that is to say, colorectal cancers and melanomas. In addition we ts can appreciate the interest of these products having, on the one hand a important water solubility that allows intravenous and oral administration easy, and on the other hand a better bioavailability than that of etoposide.
The present invention also relates to pharmaceutical compositions comprising at least one compound of general formula I according to the invention and a suitable excipient.
The pharmaceutical compositions can be presented in a suitable way for administration by injection or orally in the form of capsules, capsules, tablets at a dosage of 2 to 200 mg / m 2 per injectable and 5 to 400 mg / m2 per 24 hours for the oral route.
2s By way of example and without limitation the following examples describe the preparation of the compounds of the invention R - ~ ~ ~~ O, R '= phosph F ~ 1 ~ 1- formula I
4'-demethyl-4-O- (2,3-bis-phenoxyacetyl-4,6-ethylidene ~ 3-D-glucosyl) -~ o epipodophyllotoxin-4'-deoxy-4'-phosphate.
To a solution of 4'-demethyl-4-O- (2,3-bis-phenoxyacetyl-4,6-ethylidene) D-glucosyl) -epipodophyllotoxin (1 g, 1.16 mmol) in 50 ml THF
at 10 ° C are added 0.22 ml (2.33 mmol) of P ~~ C13 then 0 ~ ml (3.5 mmol) triethylamine. The agitation is maintained 30 minutes at this ~ s temperature. The hydrolysis is then carried out by addition. in the middle of 20 ml of N hydrochloric acid and then stirred overnight at room temperature.
The reaction medium is extracted with ethyl acetate to obtain the derivative crystallizing phosphate in isopropyl ether with a yield quantitative.
s The features are as follows F ° C ~ 175 ° C Anal. C45H45020P: 1, SH20; PM = 963.831 CH
Calc. % 56.07 5.02 Tr.% 56.18 4.73 Mass Spectrum (FAB) m / e 959 (M + Na) 1 H 200 MHz CDC13 NMR δ 1.30 (3H, d, J = 4.4 Hz, Hg +); 2.9 (1H, m, H3); 3.1 (1H, m, H2); 5.0 (1H, dd, J = 8.8 Hz, H2 "); 5.3 (1H, dd, J ---9.2 Hz, H3 ~~); 5.5 (1H, s, OCHAO); 5.7 (1H, s, OCHBO); 6.25 (2H, s, H2 ~ H6 ~); 6.44 (1H, s, Hg).
Is IR v (KBr) 2941, 1774, 1599, 1487.
N-methylglucamine salt The previous phosphate derivative is suspended in water and added 2 equivalents of N-methylglucamine in 0.1M solution in water. The The solution is stirred under ultrasound and diluted to 200 ml. After filtration 2o solution is ice-cold and freeze-dried for 12 hours. The residue is then taken back in acetone and crystallized, filtered dried to provide 350 mg of a solid white F ~ 135 ° C.
Anal. C59H79N2O3O P, H20 MW = 1345, 256 CHN
Calc's. 52.68 6.06 2.08 Tr. 52.69 5.86 1.68 IR v (KBr) 3426, 1772, 1599, 1487.
NMR 1H 200 MHz CDCl3 δ 1.22 (3H, d, J = 4.8 Hz, Hg +); 2.3 (6H, s, N
CH3), 2.6-3.0 (2H, m, H2-H3); 5.36 (1H, dd, J = 7.8 Hz, H 3 -); 5.74 (1H, s, OCHAO); 5.97 (1H, s, OCHBO); 6.15 (2H, s, H2 ~ -H6-); 6.5 (1H, s, Hg); 7.10 (1H, s, HS); 6.65 (2H, d, J = 8Hz, Ar Ortho); 6.8 to 6.96 (2H, d, J = 8Hz Ar ortho and 2H, t, J = 7Hz, Ar para); 7.24 (4H, m, Ar meta).
Sodium salt The preceding phosphate derivative is stirred in solution in acetone with a ion exchange resin (Dowex 50 x 8 - 100) prepared by elution with the soda N. The medium is elongated with water, filtered and concentrated. The residue aqueous is lyophillised to provide the sodium di-salt F ° ~ 190 ° C Anal C45H43Na2020P3.3H20 MW = 1040.208 CH
s Calc. 51.96 4.81 Tr. 51.56 4.51 By the same method as that of Example 1 but using the intermediate compounds of formula I (R '= H) corresponding to the new following derivatives have been prepared ~ o R =, R '= phosph Exem ~ - formula I
4'-demethyl-4-O- (2,3-bis-cyclohexyloxyacétyl-4, G-ethylidene ~ 3-D-glucosyl) -épipodophyllotoxine-4'-deoxy-4'-phosphate.
Yield = 90%
~ F ° ~ ~ 160 ° Cnal. C45H45 ~ 20P ~ H2 ~ MW = 966.920 CH
Calc. 55.89 6.15 Tr. 55.70 6.11 N-methylglucamine salt 4'-Demethyl-4-O- (2,3-bis-cyclohexyloxyacetyl-4, G-ethylidene-D) glucosyl) -epipodophyllotoxin-4'-deoxy-4'-phosphate, N-di-salt methylglucamine.
Yield = 50%
F ° - 112 ° C Anal. C59H9, N2O30P, 4.20PM, MW = 1411.420 2s CHN
Calc. 50.21 7.07 1.99 Tr. 50.16 6.60 2.30 R = CF3 ~ _ ~ OO R '= phosph Ex-it 3 - Formula I
4'-Demethyl-4-O- (2,3-bis (4-trifluoromethoxyphenoxyacetyl) -4,6-ethylidene- (3-D-glucosyl) -epipodophyllotoxin-4'-deoxy-4'-phosphate, di-N-methylglucamine salt.
Yld = 68 o ~

F - 132 ° C Anal. C61 H77N2O2F6P, 2, 6H20MM = 1541, 840 CHN
Calc. 47.52 5.37 1.82 Tr. 47.15 5.51 2.11 R = F ~~, R '= hos h \ / PP
Exe ~ 4 - Formula I
4'-demethyl-4-O- (2,3-bis- (4-fluorophénoxyacétyl) -4,6-ethylidene ~ 3-D-glucosyl) -epipodophyllotoxin-4'-deoxy-4'-phosphate di-N-methyl salt glucamine.
Yield = 60%
lo F - 130 ° C Anal. CS ~ H77N203pF2P, 2.7 H2OMS = 1363.240 CHN
Calc. 50.17 5.88 1.98 Tr. 49.74 5.67 1.92 o ~ o ~ h R = ~~, R '= phosph ~ s Form 5 - Formula I
4'-demethyl-4-O- (2,3-bis- (3,4-méthylènedioxyphenoxyacétyl) -4,6 ethylidene- (1D-glucoxyl) -epipodophyllotoxin-4'-deoxy-4'-phosphate di-N-methylglucamine salt.
Yield = 50%
2o F - 120 ° C Anal. C61H79N2034P ~ H2 ~ MW = 1433.274 CH IV
Calc. 51.08 5.70 1.95 Tr. 50.68 5.58 1.94 R = R '~ 10-P- / - ~ ~~' 1 I
Example 6 - Formula I
4 '- (4-phosphonooxyphénoxyacétyl) -4'-demethyl-4-O- (2,3-bis- (4-phosphonooxyphénoxyacétyl) -4,6-ethylidene ~ 3-D-gIucosyl) =
epipodophyllotoxin.
The phenol derivative of formula I corresponding to R = R '_ ~ 0 4-hydroxyphenoxyacetyl is described in the patent FR 2 699 535-A1 to Example 16 prepared by the A. lg route of this derivative (9.6 mmol) is placed wo 96nzn ~

in SO ml of THF at -10 ° C. under a nitrogen atmosphere and 1.2 ml is added (8.7 mmol) of triethylamine and then dropwise 0.53 ml (5.8 mmol) of POC13, stirring is maintained for 30 minutes. After filtration of the hydrochloride triethylamine formed, the THF is evaporated. The residue is taken up in 1N HCl and stirred at room temperature for 30 minutes. The white precipitate is filtered, washed with water and dried under vacuum at 60 ° C overnight. We get 800 mg derivative in the form of free phosphate. Yield = 80%.
F ~ 160 ° C Anal. C53H53031P3 MW = 1278.898 Mass Spectrum (FAB) ~~ m / e: 1277 (M + -1) IR (KBr) v (cm-1) 3404, 1768, 1603, 1500, 1485, 1203, 1086.
1H NMR 200M (DMSO) δ: 1.23 (3H, d, J = 4.26Hz Hg -1); 3.03 (2H, m, H2-H3); 5.37 (2H, m, H2 ~~ -H3 ~~); 5.77 (1H, s, O-CHA-p); 5.97 (1H, s, O-CHgO); 6.3 (2H, s, H 2, -H 6 -).
The preparation of the glucamine salt is similar to Example 1 ~ but with the addition of 3 equivalents of N-methylglucamine. The compound is obtained directly after lyophilization, with a yield of 88 giving the following analyzes F ~ 155 ° C Anal. C74 H104N3O6P3 MW = 1864.54 CHN
'-o Calc. 47.67 5.62 2.25 Tr. 47.26 5.62 2.38 IR (KBr) ν (cm-1): 3458, 1768, 1604, 1500, 1485, 1199, 1084.

R = Ii0-IP- / R, = O PO
Exe ~ mol -7 - formula I
OH
2s 4'-demethyl-4-O- (2,3-bis (4-phosphonooxyphenoxyacetyl) -4,6-ethylidene--3-D-glucosyl) -épipodophyllotoxine-4'-deoxy-4'-phosphate.
By the same sequence of reactions as for Example 6 but using the derivative of formula I (R = 4-hydroxyphenoxyacetyl and R '= H). Described in the Patent FR 2,699,535-A 1 to Example 20. The compound is obtained with a 3o yield of F ~ 130 ° C Anal. C66H19g N3O43P3, 6H20MM = 1822, 503 CHN
Calc. 43.49 6.08 2.31 Tr. 43.30 x, 88 2.77 IR (KBr) ν (cm-1): 3429, 1763, 1508, 1199, 1084.
_ /
R _ R ~ ~ i203P-- ~ ~ - ~ O
Example 8 - Formula I
4 '- (4-phosphonométhylphénoxyacétyl) -4'-demethyl-4-O- (2,3-bis- (4-Phosphonomethylphenoxyacetyl) -4,6-ethylidene-3-D-glucosylepipodo-phyllotoxine.
1st stage: 4-benzyloxyphenylmethyldiethylphosphonate lg (4.3 × 10 moles) of 4-benzyloxybenzyl chloride are worn for 6 hours.
reflux with 0.9 ml (5.15 × 10 -3 moles) of triethylphosphite. The environment ~ O reaction is filtered on 150 g of SiO2, eluted with a mixture of heptane ethyl acetate (20-80) to provide after evaporation 1.4 g of the derivative phosphonate (Yield = 100%).
2nd stage: 4-hydroxyphenylmethyldiethylphosphonate In an autoclave, 1.1 g (3.3 × 10 -3 moles) of the benzyloxy derivative of the first stage ts are hydrogenated under a hydrogen pressure of 7 bar in the presence of 200 mg of 10% palladium on charcoal in 15 ml of acetate mixture of ethyl-ethanol (90-10) at a temperature of 80 ° C for 12 h under agitation. After filtration of the catalyst, the filtrate is evaporated under pressure reduced to obtain 800 mg (100% yield) of the phenol derivative.
Stage 3: Diethyl phosphonomethylphenoxyacetic acid To a THF solution (250 ml) of 2.7 g (11 mmol) of the phenol derivative 1.3 g (26 mmol) of NaH (50% dispersion) are added to room temperature, then 1.8 g (13 mmol) of bromoacetic acid are introduced and the reaction medium is refluxed for 8 hours. The environment The reaction mixture is poured into 1 l of ice water and extracted with ethyl ether.
The aqueous phases are acidified to pH 1.2 and extracted with ethyl acetate, dried, evaporated to provide 3.1 g (yield 94%) of the acetic derivative.
1H 200MHz NMR (CDCl3) 8 8.09 (solid 1H, exchangeable) 7.16-7.26 (dd, 2H, J = 8Hz, 2Hz, aromatic H), 6.85 (2H, d, J = 8Hz, aromatic H), 0 4.6 (2H, s, OCH 2 CO 2 H), 4.0 (4H, m, OCH 2 phosphonate ester), 3.12 (2H, d, J - 21.7Hz, CH2P), 1.23 (6H, t, J - 7Hz, phosphonate ester OCH2CH3).
4th stage: condensation of the acid obtained in the 3rd stage on etoposide 3 g (10.2 mmol) of previously obtained acid at the 3rd stage in solution >; in methylene chloride (15 ml and 0.2 ml of DMF at 0 ° C.
under nitrogen, ls 1.4 g (11.2 mmol) of oxalyl chloride are added dropwise after a large release of CO2 is allowed to return the reaction medium to ordinary temperature. Cooled again to 0 ° C to introduce a solution containing 1 g (1.7 mmol) of etoposide, 2 g (25.5 mmol) of pyridine in methylene chloride (45 ml) dropwise. Finally addition the medium is stirred again for 4 h with return to temperature ordinary. After evaporation under reduced pressure, the reaction medium is taken up with toluene and evaporated, the residue is stirred with acetate ethyl and N hydrochloric acid. After extraction, the organic phase is washed 1 o with an ice-cold solution of sodium bicarbonate and then with a solution saturated with NaCl, decanted, dried, evaporated, it provides a brown foam which is chromatographed on SiO2 (eluent CH2Cl2 - MeOH-98-2) and gives after evaporation a solid residue of 220 mg (yield 10%), mass (FAB) m / e 1441 (M +).
is 1 H NMR 200MHz provides the characteristic peaks of these molecules (CDCl 3) δ 7.20 (6H, m, H arom-phosphonate), 6.65-6.93 (6H, d, J =
8.4Hz, H arom. phenoxy) 6.75 (1H, s, HS), 6.47 (1H, s, Hg), 6.24 (2H, s, H2 ~ and H6 ~), 5.87 (1H, s, OCHAO), 5.61 (1H, s, OCHBO), 5.35 (1H, t, H3 ~~), 5.05 (1H, t, H2 ~~), 3.0 (6H, d, J = 21Hz, CH2 phosphonate).
2o Se stage: Hydrolysis of phosphoric esters 220 mg (0.16 mmol) of the phosphoric triester derivative obtained at the 4th stage are placed in CH3CN (50 ml) at 0 ° C under nitrogen, 0.26 ml is added of pyridine (3.2 mmol) and then dropwise 0.49 g (3.2 mmol) of bromide of trimethylsilyl. Stirring is maintained for 24 hours with return to temperature 2s ambient. It is evaporated to dryness, the medium is taken up in N HCl and the product precipitates, the white precipitate is filtered off and rinsed with water until neutral. The The precipitate is solubilized in methanol, filtered and evaporated. The residue is taken back in water, crystallized, to provide 120 mg of the phosphoric derivative (Yield 57%).
~ o F ° = 190 ° C Anal C56 H59 028 P3 ~ SH20 MW = 1301, 41 CH
Calc% 51.68 5.34 Tr% 51.91 4.90 IR v (KBr) 3431, 2922, 1774, 1608, 1512, 1485 1H 200MHz NMR (CD30D) δ 7.15-7.23 (6H, m, H methyl arom.
phosphoric), 7.04 (1H, s, HS), 6.9 (2H, d, H arorl phenoxy), 6.8 (2H, d, H arom phenoxy), 6.67 (2H, d, H arom phenoxy), 6.50 (1H, s, Hg), 6.35 (2H, s, H 2 -, H 6 -), 5.85 (1H, s, OCHAO), 5.58 (1H, s, OCHBO), 3.05.
(2H, d, CH 2 P), 2.9 (1H, dd, H 3), 1.3 (3H, d, H 2 -).
By the same reaction as for Example 8 4th stage or Example 25, is prepared (route C) by triacylation on etoposide the following compounds to from the corresponding AZ-CH2-CO2H acids _ / \
F- formula I ~ co ~~~
4 '- (phosphonoacetyl) -4'-demethyl-4-O- (2,3-bis-phenoxyacetyl-4,6 to ethylidene- (3-D-glucosyl) epipodophyllotoxin.
To a solution of 400 mg (2 mlnoles) of diethyl phosphonoacetic acid in 5 ml of CH 2 Cl 2 and 3 drops of DMF under nitrogen at 0 ° C., are added 266 mg (2.1 mmol) of oxalyl chloride. The agitation is maintained for 15 minutes at 0 ° C, then a solution of 500 mg (0.583 mmol) of 4'-demethyl-4-0-ls (2,3-bis-phenoxyacetyl-4,6-ethylidene-1-D-glucosyl) -epipodophyllotoxin in 5 ml of CH2Cl2 and 184 mg (188 ~ 1, 23 mmol) of pyridine are introduced into the reaction medium at 0 ° C. The contact is maintained 2.5 h, then the reaction medium is poured on N. HCl The organic phase is decanted, washed with NaCl solution, dried, evaporated. The residue is crystallized in ethyl ether to give a white precipitate (450 mg, yield 75%).
320 mg (0.31 mmol) of this derivative are placed under stirring in 10 ml acetonitrile in the presence of 470 mg (0.4 ml, 0.31 mmol) of bromide trimethylsilyl and 240 mg (0.25 ml, 0.31 mmol) of pyridine, room temperature for 6 hours.
After evaporation, the residue is taken up in N HCl to provide a solid white which is filtered, washed with water, dried. 180 mg (Yield 57%) of the phosphonic derivative Mp - 140 ° C. Anal C47 H47 021 P, 2H2O (MW = 1014, 996) CH
Calc% 55.61 5.06 Tr% 55, 87 4, 80 IR v (KBr) 3431, 1774, 1601, 1487 1H 200MHz NMR (CDCl3) δ 7.16-7.27 (4H, m, H m Arom., 6.68-6.95 (7H, m, H op Arom, HS), 6.44 (1H, s, Hg), 6.24 (2H, s, H2 -H6-), 5.82 WO 96/12727 PC "T / FR95 / 01388 (1H, s, OCHAO), 5.56 (1H, s, OCHBO), 5.32 (1H, dd, H3-), 5.02 (1H, t, H2 ~~), 3.2 (m, 3H, CH2P, H2), 1.32 (d, 3H, J - 4.4Hz, Hg +).
, - ~ 0 R = C ~ / \ O ~ R '= C ~~ ~ O ~
Example 10 - Formula I
4 '- (phosphonoacetyl) -4'-demethyl-4-O- (2,3-bis- (4-trifluorométhoxyphénoxyacétyl) -4,6-ethylidene ~ iD-glucosylceramide) -epipodophyllotoxin. N-methylglucamine salt.
This derivative is obtained by the same method as for example 9 but starting from the derivative of formula I for which R = 4-trifluoro methoxyphenoxyacetyl and R '= H.
Preparation of N-methylglucamine salt: 810 mg is introduced (0.7 mmol) of the phosphonic derivative in ethanol (15 ml) and 0.5 ml of acetone and then 14.1 ml of an O, 1N solution of N-methylglucamine (1.41 mmol) in ethanol are added dropwise with stirring.
The agitation is maintained for 1 hour. The reaction medium is evaporated and the residue taken up in water and then filtered (0.45 ~ c filter). The aqueous solution is lyophylized, and the residue is taken up in isopropanol, crystallized, filtered, dried to provide 740 mg (65% yield) of N-methylglucamine salt.
Mp = 120 ° C Anal C63 H79 N2 F6 033 P, 3, SH20 -o MW = 1600, 47 CHN
Calc% 47.28 5.42 1.75 Tr% 46.95 5.47 2.07 IR v (KBr) 3426, 1774, 1601, 1500, 1487 R = ~ \ O ~ R '= CON
2s - formula I
4 '- (dicarboxyméthylaminocarbonyl) -4'-demethyl-4-O- (2,3-bis- (p-hydroxy-phenoxyacetyl) -4,6-ethylidene ~ -D-glucosyl) -epipodophyllotoxin.
1st stage: preparation of diesterbenzyl of aminodiacetic acid To a solution of 10 g (49.6 mmol) of benzyl ester hydrochloride glycine in 200 ml of CH3CN are added 13.7 g (99 mmol) of K2CO3, and 8 ml (49.6 mmol) of benzyl bromoacetate dropwise.
The medium is stirred at room temperature for 2 days. 200 ml of water are added and the medium is acidified to pH 2-3 with concentrated HCl, then extract by ethyl acetate, to obtain 12 g (yield 80%) of the diester used in the next step.
2nd stage: carbamate preparation A solution of phosgene (0.79 ml, 1.5 mmol) in toluene at 1.93 M is introduced into 50 ml of acetonitrile and then cooled to -10 ° C. under atmosphere nitrogen. 820 mg (0.76 mmol) of 4'-démetéhyl-4-0- (2,3-bis- (p-benzyloxyphénoxyacétyl) -4,6-ethylidene ~ Id-glucosyl) -epipodophyllotoxin in 13 ml of acetonitrile and 0.24 g of isopropylethylamine. The reaction medium is stirred for 2 hours at -10 ° C.
then there introduced 0.24 g of the benzyl diester of aminodiacetic acid, obtained in 1st stage, in 6 ml of acetonitrile at -5 ° C. The agitation is maintained 6 h. The The reaction medium is then evaporated and then filtered through SiO 2 and eluted with solvent gradient: petroleum ether - ethyl acetate 70.30 then 60.40 and Finally 50.50 to obtain 700 mg (65% yield) of the benzyl diester derivative.
3rd stage: Hydro-enolysis of benzyl functions 700 mg of the derivative obtained in the 2nd stage are placed in solution in a mixture of 13 ml of ethyl acetate and 3 ml of ethanol, in an autoclave under hydrogen atmosphere in the presence of 70 mg of 10% palladium on carbon.
2o stirring is maintained for 24 h and then the reaction medium is filtered, evaporated. The residue is crystallized from isopropyl ether to obtain 480 mg (yield 92%) of the diacid derivative.
F ° - 150 ° C Anal C50 H49 NO24 PM = 1047.94 CHN
2s Calc% 57.31 4.71 1.34 Tr% 57.07 4.96 1.13 IR v (KBr) 3433, 1768, 1603, 1512, 1485, 1460, 1236, 1199 1H 200MHz NMR (DMSO) δ 9.03 and 8.98 (2H, 2s, CO2H, exchangeable), 6.45-6.67 (OH, m, H5, Hg, ArH), 6.21 (2H, s, H2-, H6-), 6.0 (1H, s, ~ OCHAO), 5.79 (1H, s, OCHBO), 5.32 (2H, m, H2 ~~ and H3 ~~), 3.39 (s, N
CH 2 -CO 2 H), 1.20 (3H, d, H 2 -).
By the same method as Example 11 - 2nd stage, but ~ using the corresponding intermediate compounds of formula I (R '- H), the the following new derivatives have been prepared.
3 ~

WO 96/12727 PC "T / FR95 / 01388 R = O ~ O ~ R '= CON (CltC00li ~
- formula I
4 '- (dicarboxyméthylaminocarbonyl) -4'-demethyl-4-O- (2,3-bis cyclohexyloxy acetyl-4,6-ethylidene- (1D-glucosyl) -epipodophyllotoxin.
Yld = 98 F ° = 170 ° C Anal C50 H61 N022 MW = 1028.037 '~ R = C ~ ~ ~ ~, R' = CON (lCOO
- formula I
4 '- (dicarboxyméthylaminocarbonyl) -4'-demethyl-4-O- (2,3-bis (p-trifluoro methoxyphenoxyacetyl) -4,6-ethylidene- (iD-glucosyl) -epipodophyllo 1 o toxin.
Yield = 87%
F - 150 ° C Anal C52 H47 N024 F6 MW = 1183.94 CHN
Calc% 52.75 4.00 1.20 ls Tr% 52.64 4.10 1.30 R = / ~ ~, R '= CON (CltC00 Example 14 - Formula I
4 '- (dicarboxyméthylaminocarbonyl) -4'-demethyl-4-O- (2,3-bis phenoxyacetyl-4,6-ethylidene ~ 3-D-glucosyl) -épipodophyllotoxine.
2o yield = 25 F - 170 ° C. Anal CSp H49 N 022, H20 MW = 1033.955 CHN
Calc% 58.08 4.97 1.35 Tr% 58.43 5.05 1.28 ? s R = HOC6-1, .. ~
/ \ O '' O, R'_ Example 15 - Formula I p 4'-demethyl-4-O- (2,3-bis- (4-carboxyméthoxyphénoxyacétyl) -4,6 ethylidene-3-D-glucosyl-epipodophyllotoxin, N-methylglucamine salt.
1st stage: benwle 4-hydroxyphenoxyacetate To a suspension of 10 g (59 mmol) of p-hydroxyphenoxyacetic acid in 100 ml of CH 2 Cl 2 at 0 ° C. under a nitrogen atmosphere are added 0.2 ml of DMF and then dropwise 9 g of oxalyl chloride (71 mmol).
Stirring is maintained for 12 hours at room temperature and then 7.7 g (71 mmol) of benzyl alcohol are introduced and stirring is maintained 8 h to ambient temperature. The reaction medium is thrown on a solution iced ammonia and extracted with methylene chloride. The sentence The organic material is washed with N HCl, decanted, dried and evaporated. The residue is filtered over 150 g of SiO2 ~ and eluted with a heptane-ethyl acetate mixture lo (75-25) to provide 3.8 g (25% yield) of a white solid.
1H 200MHz NMR (CDCl3) δ 7.36 (SH, s, Ar), 6.75 (4H, d, ArOH), 5.24 (2H, s, CH 2 Ar), 4.61 (2H, s, OCH 2 CO).
2nd stage: 4-benzyloylcarbonylmethoxyphenoxyacetic acid 3.8 g of the phenol obtained in the first stage are refluxed with THF (200 ml) 15 in the presence of 1.3 g of NaH (60% dispersion) and 2 g of acid bromoacetic for 48 h. The reaction medium is then poured onto ice and extracted with isopropyl ether and then with ethyl acetate. The phase aqueous solution is acidified and extracted with CH2Cl2 for 2.8 g (yield 60%) of solid cream.
1H 200MHz NMR (CDCl3) δ 7.35 (SH, s, Ar), 6.78 (4H, s, ArO), 5.15 (2H, s, CH 2 Ar), 4.55 (2H, s, OCH 2 ester), 4.45 (2H, s, OCH 2 acid) Stage 3: Completion of 2nd stage acid with 4'-benzyloxycarbonyl etoposide 1.75 g (5.5 mmol) of the 2nd stage acid in solution in 40 ml of CH 2 Cl 2 with 0.2 ml of DMF is added at 0 ° C. under an atmosphere nitrogen dropwise 770 mg (6.1 mmol) of oxalyl chloride. The agitation is maintained 2 h at room temperature. We then add, after returning to 0 ° C
a solution of 1 g (1.38 mmol) of 4'-benzyloxycarbonyl etoposide and 1.1 g (1.38 mmol) of pyridine in 10 ml of CH 2 Cl 2. After 3 hours stirring at room temperature, the reaction medium is concentrated, taken up in ethyl acetate and washed with water, then with an ice-cold solution sodium bicarbonate, after a further washing with N HCl and then with a saturated solution of NaCl, the organic phase is decanted, dried, evaporated to provide 800 mg (yield 66 io) which are directly hydrogenolysed at next stage (TLC SiO 2 heptane -AcOEt 20-80 Rf = 0.9) 4th stage: Hydrogenolysis 800 mg (0.6 mmol) of derivative obtained at the 3rd stage are placed under atmosphere of hydrogen at atmospheric pressure in 15 ml of acetate of ethyl and 5 ml of ethanol in the presence of 100 mg of palladium significant agitation for one hour. The catalyst is filtered and the filtrate evaporated. The residue is taken up in acetone and filtered again and evaporated to fburnir quantitatively (650 mg) the debenzylated derivative. This derivative is converted to N-methylglucamine salt by addition of 2 equivalents of a 0.1 M solution of N-methylglucamine in the mixture EtOH, H 2 O -acetone.
After stirring for 1 h, the solution is evaporated, taken up in H 2 O, filtered through to filter 0.45 ~, and lyophylized, then 700 mg of the derivative is obtained carboxylic acid.
F - 130 ° C Anal C63 Hg2 N2 033 6H2 O MS = 1503.422 CHN
Calc% 50.33 6.30 1.86 Tr% 49.89 5.93 2.19 ts IR v (KBr) 3427, 1772, 1618, 1508, 1425, 1205, 1087 1H 200MHz NMR (DMSO) b 7.14 (1H, s, HS), 6.59-6.70 (8H, m, OArO), 6.47 (1H, s, Hg), 6.13 (2H, s, H2- and H6-), 5.96 (1H, s, OCHAO), 5.73 (1H, s, OCHBO), 5.33 (2H, m, H2 ~~ and H3 ~~), 2.46 (6H, s, NCH3), 1.20 (3H, d, J = 4Hz, Hg ~~).
2o By the same sequence of reactions of Example 15, but using the reagents derivatives of general formula I (R '= H) are obtained R = HOC ~ ~ O ~ O ~ R
Exemyle 16 - Formula I
4'-demethyl-4-O- (2,3-bis (4-carboxyphenoxyacetyl) -4,6-ethylidene- (3-D-) 2s glucosyl) -epipodophyllotoxin Using 4-benzyloxycarbonylphenoxyacetic acid, one obtains according to the The process of Example 15 is the carboxylic derivative with a yield of 45%.
F-170 ° C Anal C47 H44 021.1.3H20 MW = 968.469 CH
3% Calc% 58.28 4.81 Tr% 58.19 4.85 N-methylglucamine salt Mp = 138 ° C Anal C61 H7g N2O31, SH20 MW = 1425.355 CHN
~ s Calc% 51.40 6.22 1.97 Tr% 51.27 5.85 2.19 PC'T '/ FR95 / 01388 R = HOCO / \ O '''O ~ R ~ _ FxemTl7 - formula I
4'-demethyl-4-O- (2,3-bis- (4-carboxyméthylphénoxyacétyl) -4,6-ethylidene s ~ iD-glucosyl) epipodophyllotoxin.
Using 4-benzyloxycarbonylmethylphenoxyacetic acid, we obtain according to Example 15, the acetic derivative (Yield 66%).
F - 150 ° C Anal C49 H4g 021, 2H2OMS = 1008, 932 CH
Calc% 58.33 5.19 Tr% 57, 74 4, 85 Mass Spectrography (FAB) m / e 972 (M +) By the method of Example 15 3rd stage only, the following derivatives are prepared is R = / \ ~~, R ~ =
- formula I
4'-demethyl-4-O- (2,3-bis- (phénylsulfonylacétyl) - ~ 3-D-glucosyl) -epipodophyllotoxin.
Yield = 92%
mp = 248 ° C Anal. C45 H44 O 19 S2 MW = 976, 790 CH
Calc. % 56.72 4.65 Tr.% 56.40 4.66 FF /
R _- F / \ p ~ 0, R '__ Example 19 - IF formula 2s 4'-demethyl-4-O- (2,3-bis (pentafluorophenoxyacetyl) -3-D-glucosyl) epipodophyllotoxin.
Yield = 75% Anal. C45 H34 017 F10 MW = 1036.75 CH
Calc. % 52.13, 3.30 '' ° Tr.% 51.88 3.25 R = F3C / \ ~~, R '_ Example 20 - Formula I
4'-demethyl-4-O- (2,3-bis- (4-trifluorométhylphénoxyacétyl) - ~ iD-glucosyl) -epipodophyllotoxin.
Yield = 53% Anal. C47 H42 O 17 F6 MS = 992, 820 CH
Calc. % 56.86 4.26 Tr.% 56.78 4.22 R = / \ ~~, R 'qohospha - formula I
4'-demethyl-4'-deoxy-4'-phosphate-4-O- (2,3-bis- (phenylsulfonylacetyl) -4,6-ethylidene ~ 3-D-glucosyl) -épipodophyllotoxine.
N-methylglucamine di-salt Using the method of Example 1, but with the compound of the example 18, the phosphate derivative in the form of N-methylglucamine salt is obtained.
is Yield = 60% Anal. Csg H7g N2 032 PS2; 3,8H20 F ~ 148 ° C
PM = 1492.85 CHN
Calc. % 49.79 5.59 1.97 Tr.% 47.47 5.85 1.88 FF
R = F / \ o "p, R '~ hospha - IF formula 4'-demethyl-4'-deoxy-4'-phosphate-4-O- (2,3-bis- (2,3,4,5,6-pentafluoro phenoxyacetyl) -4,6-ethylidene ~ 3-D-glucosyl) -épipodophyllotoxine. Disalt N-methylglucamine.
2s Using the method of Example 1 but with the compound of the example 19, the phosphate derivative in the form of N-methylglucamine salt is obtained.
Yld = 78 F ~ 140 ° C Anal. Csg H6g F10 N2 030 P; 3, SH20 MW = 1507.147 CHN
3o Calc. % 45.11, 4.88 1.78 Tr.% 45.34 4.67 1.82 R = F3C ~ ~ O ~ ~ R '= Phosph - formula I
4'-demethyl-4'-deoxy-4'-phosphate-4-O- (2,3-bis- (4-trifluoromethyl méthylphénoxyacétyl) -4,6-ethylidene ~ 3-D-glucosyl) -épipodophyllotoxine.
Di-salt of N-methylglucamine.
Using the method of Example 1 but with the compound obtained Example 20, the phosphate derivative in the form of N-methylglucamine is got.
Yld = 33 F = 120 ° C Anal. C61 H77 N2 030 F6 P; 4.15 H 2 O PM = 1538.170 CHN
Calc. % 47.63 5.59 1.82 Tr.% 47,16 5,12 1,84 R = R '= HO ~ ~ O
~ s F-xemyl 24 - Formula I
Path C
4'-demethyl-4 '- (4-carboxyphénoxyacétyl) -4-O- (2,3-bis- (4-carboxy-phenoxyacetyl) -4,6-ethylidene- (3-D-glucosyl) -epipodophyllotoxin glucamine.
1st stage: Condensation of 4-benzyloxycarbonylphenoxyacetic acid with etoposide To a solution of 4.9 g (17 mmol) of 4-benzyloxycarbonyl-phenoxyacetic acid in 100 ml of CH2Cl2 and 0.2 ml of DMF are added to 0 ° C under nitrogen, dropwise 2.4 g (18.7 mmol) of chloride oxalyl 2s after 2 h stirring at room temperature, is introduced to this solution 2 g (3.4 mmol) of etoposide in solution in 15 ml of CH 2 Cl 2 and 3.2 g (41 mmol) pyridine dropwise at 0 ° C. After return to temperature during 3 hours, the reaction medium is poured over HCI N and extracted by CH2Cl2 and washed with a solution of NaHCO3, and saturated NaCl 3o successively to obtain after evaporation a crude product which is c: ~ romatographed on SiO2 by elution in a heptane-AcOEt mixture (60-~ 4G. 1.8 g (38% yield) of trisubstituted derivative is obtained which is used DIRECTLY in the next step.

2nd stage: Hydrogenolysis 1.5 g (1.07 mmol) of the above benzyl triester is hydrogenolysed in presence of hydrogen at atmospheric pressure in an EtOH mixture (15 ml) AcOEt (60 ml) with 300 mg of 10% palladium on carbon under good stirring for 8 h at room temperature. The catalyst is filtered, the evaporated filtrate is chromatographed on SiO2 and eluted in a mixture CH2Cl2-MeOH (96.4) to obtain a white solid (600 mg yield 50%). The glucamine salt directly, is obtained by placing 3 equivalents of an aqueous solution ~ 0.1M N-methylglucamine in a mixture ~ o EtOH-H20 (80-20), this solution is added to the solution of triacid in acetone. A gummy precipitate is obtained, the medium is evaporated then taken up by H2O and filtered through a 0.45 ~ filter. The filtrate is then lyophilized to obtain the glucamine salt. Yld = 50 F -135 ° C Anal C77H 101 N3O4.7H2O MS = 1836.103 CHN
Calc% 50.37 6.32 2.29 Tr% 49.99 5.77 2.47 IR v (KBr) 3404, 1772, 1604, 1545, 1385, 1086.
1H 200MHz NMR (DMSO), 7.77-7.85 (6H, m, Ar), 7.1 (1H, s, HS), 6.89, 6.79, 6.64 (6H, d, J = 8.7 Hz, ArO), 7.08 (1H, s, HS), 6.46 (1H, s, Hg), 6.26 (2H, s, H 2 and H 6), 6.13 (1H, s, OCHAO), 5.95 (1H, s, OCHBO), 2.42 (9H, s, N-CH3), 1.20 (3H, d, J = 4.9Hz, Hg +).
R = R '= HO i \ O
- formula I '---- /
4'-demethyl-4'-carboxyméthylphénoxyacétyl-4-O- (2,3-bis- (4-carboxy-Methylphenoxyacetyl) -4,6-ethylidene-1-D-glucosylepipodophyllotoxin.
This derivative is obtained by the same method as for Example 24, but using benzyloxycarbonylmethylphenoxyacetic acid. Yld = 20 F-150 ° C Anal C59 H56 025 1.4H20 MW = 1190.703 CH
o Calc% 59.63 4.81 Tr% 59.19 4.84 R = R '= HOC i \
~ O
Example 26 - Formula ~ / I

4'-demethyl-4'-carboxyméthoxyphénoxyacétyl-4-O- (2,3-bis- (4-carboxy-methoxy phenoxyacetyl) -4,6-ethylidene-3-D-glucosyl) epipodophyllo toxin - N-methylglucamine salt.
This derivative is obtained by the same method as for Example 24, but using benzyloxycarbonylmethoxyphenoxyacetic acid. Yld = 84 F -110 ° C Anal Cgp H107 N3 043, 6.3 H2O MW = 1912.036 CHN
Calc% 50.25 6.30 2.20 Tr% 50,13 6,17 2,56 R._ C / \ O ~ ~ R, = P ~ "~ 2 Example 27 - Formula I
4'-demethyl-4'-deoxy-4'-phosphate-4-O- (2,3-bis- (4-chlorophénoxyacétyl) -4,6-ethylidene ~ -D-glucosyl) -épipodophyllotoxine.
Preparation of intermediates (route B) ts 4'-demethyl-4 '- (3-quinuclidinylaminocarbonyl) -4-O- (2,3-bis- (4-chloro) phenoxy acetyl) -4,6-ethylidene- (3-D-glucosyl) -epipodophyllotoxin.
1st stage: 4 '- (3-quinuclidinylaminocarbonyl) etoposide formula V R4 = COHN 3-quinuclidinyl To a 1.93M solution of phosgene in acetonitrile (8.8 ml, 16.9 mmol) 2o cooled to 0 ° C under nitrogen, is added dropwise a solution of etoposide (5 g, 8.49 mmol) in 200 ml CH3CN and 2.74 g (21.2 mmol) of N, N-diisopropylethylamine in 10 minutes, then introduce 1.07 g (8.49 mmol) of 3-aminoquinuclidine dissolved in 20 ml of CH 3 CN. The medium is stirred for 24 hours. After evaporation, the residue is 2s chromatographed on SiO2 with a mixture of solvents: CHC13-MeOH-NH40H (93-7-0.7) then (90-10-1). We obtain 1.67g (Yield 26%) of product carbamate, homogeneous V CCM which is immediately reacted in the 2nd Stadium.
2nd stage: Condensation with p-chlorophenoxyacetic acid o To a solution of 1.68 g (8.98 mmol) of p-chlorophenoxyacetic acid in chloroform (40 ml) and 0.5 ml of DMF at 0 ° C under an atmosphere of nitrogen, 1.25 g (9.88 mmol) of oxalyl chloride are added dropwise to drop. Stirring is maintained for 1 hour. This solution is then added dropwise to the solution of the etoposide derivative obtained at the first stage (1.66 g, 2.24 mmol) in ~ 50 ml of chloroform and 1.77 g of pyridine wo 96 / 12n ~

PCT '/ FR95 / 01388 0 ° C. This new solution is agitated 5 hours with return to the temperature room. The reaction medium is then poured into N HCl (100 ml) decanted, then washed with saturated NaCl solution, dried, evaporated to provide an oil that is chromatographed on silica. Elution by a mixture of CHCl 3, MeOH, NH 4 OH (95.5, 0.5) provides 1.97 g (80% yield) of the title derivative of Example 26. The hydrochloride (by addition a solution of ether saturated with hydrochloric gas to the solution of the base in acetone. After stirring for 10 nm, the precipitate obtained is filtered slowly, washed with ether and dried (yield 50%).
to F ° -180 ° C Anal C53 H54 Cl2 N2 018, HCl, 2H20 MW = 1150.422 CHN
Calc% 55.33 5.08 2.43 Tr% 55.74 4.96 2.61 Mass Spectrum (FAB) m / e 1077 (M +) 3rd stage: hydrolysis To a solution in 70 ml of acetone of 1.08 g of the 2nd stage derivative, introduced 30 ml of a saturated solution of NaHCO 3. The medium is agitated for 2 days, the acetone is evaporated and the medium is acidified with HCl concentrated to pH 2, then extracted with methylene chloride.
SiO 2 chromatography (elution CH 2 Cl 2 -MeOH 97-3) provides the derivative of the title of Example 27. A new chromatography on SiO2 (elution of petroleum ether - AcOEt 1-1) provides after evaporation a residue which crystallizes in isopropyl ether (200 mg Yield = 21%).
F-125 ° C Anal C45 H42 C12 017 MW = 925.730 Zs CH
Calc% 58.38 4.57 Tr% 58.63 4.69 Mass Spectrum (FAB) m / e 924 (M + -1) IR v (KBr) 3458, 1774, 1618, 1491.
1H 200MHz NMR (CDCl3) δ 7.15-7.22 (4H, m, Ar), 6.75 (1H, s, HS), 6.77 (2H, d, J = 8.8Hz, ArO), 6.64 (2H, d, J = 8.8Hz, ArO), 6.51 (1H, s, Hg), 6.22 (2H, s, H₂ and H6), 5.91 (1H, s, OCHAO); 5.71 (1H, s, OCHBO), 5.33 (1H, t, J = 9Hz, H3 ~~), 5.02 (1H, t, J = 7.8Hz, H2 ~~), 4.91 (1H, d, J = 7.8Hz, H1 ~~), 4.83 (1H, d, ~ = 3.2Hz, H4), 4.69 (1H, q, H7-).
~ 3.1 (1H, dd, H2), 2.9 (1H, m, H3), 1.34 (3H, d, J = SHz, Hg ~~).
Phosphate preparation This derivative is obtained according to the procedure of Example 1 but in using the derivative obtained in the third stage.
N-methylglucamine salt Yield = 70%
s F - 140 ° C Anal C59 H77 Cl2 N2 030 P, 6H20 PM = 1461.49 - CHN
Calc% 48.49 5.8 1.90 Tr% 48.78 5.55 1.88 R = R '= ~ HOC'Ö
~ o Exemyle 28 - formula I o 4'-demethyl-4'-carboxyméthoxyacétyl-4-O- (2,3-bis-carboxyméthoxy-acetyl-4,6-ethylidene-3-D-glucosyl) epipodophyllotoxin.
This derivative is prepared according to the method of Example 24, 1st and 2nd stage in which benzyloxycarbonylmethoxy acetic acid is used instead of 4-benzyloxycarbonylphenoxyacetic acid, to conduct with successive yields of 77% and 75%.
Mp = 138 ° C Anal C41 H44 025 ~ H20 MW = 954.805 CH
Calc% 51.57 4.85 -o Tr% 51.22 4.72 Mass Spectrum (FAB) m / e 959 (M + + Na) R = R '= HOC' ~ SOi ~
- formula I o 4'-demethyl-4'-carboxyméthylsulfonylacétyl-4-O- (2,3-bis-carboxymethyl Sulfonyl acetyl-4,6-ethylidene-3-D-glucosyl) epipodophyllotoxin.
This derivative is prepared as the preceding one according to the method of Example 24, 1st and 2nd stages using benzyloxycarbonylmethylsulfonylacetic acid with successive yields of 55% and 90%.
F - 165 ° C Anal C41 H44 028 S3 ~ H20 MW = 1098.98 CH
Calc% 44.81 4.22 Tr% 44.94 4.34 Mass Spectrum (FAB) m / e 1103 (M ++ Na) Example 30 - Formula IR = Hococ ~ e ~ c ~ co, R '_ 4'-demethyl-4-O- (2,3-bis-4,6-ethylidene-carboxyméthoxyacétyl ~ 3-D-glucosyl) epipodophyllotoxin.
This derivative is obtained by the method described for example 15, 3e and 4e stages but using benzyloxycarbonylmethoxyacetic acid instead benzyloxycarbonylmethoxyphenoxyacetic acid. The successive returns are 42% and 71%.
M.p. -192 ° C Anal C37 H40 021, 0.2 H2O mp = 824.32 CH
Calc% 54.59 5.20 'o Tr% 54.81 5.23 Exem 1 - formula IR = R '= ~ o3c ~ c 4'-demethyl-4'-phosphonoacetyl-4-O- (2,3-bis-phosphonoacetyl-4,6 ethylidene-1-D-glucosyl) epipodophyllotoxin.
This derivative is obtained in the same way as the method of Example 24, 1 er and 2nd stages, but using dibenzylphosphonoacetic acid (Tet.Let.
1974, No. 9, 711). The changes from Example 24 are the following: the first stage is conducted at 0 ° C with return to temperature ambient for 18 hours; the second stage hydrogenolysis is done in the 2o solvent: THF 25 ml and EtOH 50 ml and the reaction is conducted at 0 ° C.
while 4h. Yields are successively 34% and 83%.
F-184 ° C Anal C35 H41 025 P3 ~ 4H20 MW = 1026, 58 Calc% 40.94 4.81 7.02 Tr% 40.95 4.38 7.54 Mass Spectrometer (FAB) m / e 955 (M + + 1) Example 32 - formula IR = ~ ° spc ~ 4co, R '_ 4'-demethyl-4-O- (2,3-bis-phosphonoacetyl-4,6-ethylidene ~ 3-D-glucosyl) ~ o epipodophyllotoxin.
This derivative is obtained in a manner identical to the method of Example 15, 3e and 4th stages, but using dibenzylphosphonoacetic acid, already used for example 31.
The hydrogenolysis stage is carried out using a mixture of solvent: THF-EtOH (30-70) at 0 ° C for 4h. We then obtain the derivative with a overall yield of 45%.

F - 168 ° C Anal C33 H3g 021 P2 MW = 832.606 Mass Spectrum (FAB) m / e 833 (M + + 1).
The following compounds according to the invention have also been prepared 4'-demethyl-4'-deoxy, 4'-phosphate-4-O- (2,3-bis (4-cyanophenoxyacetyl) -4,6-ethylidene-1-D-glucosyl) epipodophyllotoxin. N-methyl salt glucamine.
F - 205 ° C Anal C47 H43 N2 020 P, 6 H20 = 11 112.93 CHN
Calc% 51.56 5.06 2.56 io Tr% 51.11 4.27 2.31 4'-demethyl-4'-deoxy, 4'-phosphate-4-O- (2,3-bis (4-nitrophenoxyacetyl) -4,6-ethylidene-1-D-glucosyl) epipodophyllotoxin. N-methyl salt glucamine.
F - 190 ° C Anal C45 H43 N2 024 P ~ 4 H20 = 1 098.88 ~ s CH
Calc% 49.18 4.68 2.55 Tr% 49.38 4.25 2.46 4'-demethyl-4'-deoxy, 4'-phosphate-4-O- (2,3-bis (4-methylphenoxy) acetyl) -4,6-ethylidene- (1D-glucosyl) epipodophyllotoxin.
2o F - 190 ° C Anal C47 H4g N2 020 P, 1.25 H20 = 987.378 CH
Calc% 57.12 5.21 Tr% 56.6 5.04 4'-demethyl-4-O- (2,3-bis (4-phosphonooxyphénoxyacétyl) -4,6-ethylidene -3 2s-D-glucosyl) epipodophyllotoxin. N-methylglucamine salt.
F - 145-150 ° C Anal Csg Hg0 N2 035 P2, 1.5 H2O = 1,466,240 CHN
Calc% 48.33 5.71 1.91 Tr% 48.46 5.93 2.09 4'-demethyl-4'-deoxy-4'-phosphate-4-O- (2,3-bis (4-hydroxyphenoxy) acetyl) -4,6-ethylidene- (1D-glucosyl) epipodophyllotoxin. N-salt methylglucamine.
F - 145 ° C Anal Csg H7g N2 032 P, H20 = 1,377.26 CHN
3s Calc% 51.45 5.93 2.03 Tr% 51.44 6.17 2.04 FE ~ IIL # .E ~ ECTt ~ IEF ~ HEGLE 91 ~
ISAIEP

Claims (14)

The embodiments of the invention in respect of which an exclusive right of property or privilege is claimed are defined as follows: 1. Compound of general formula I
in which R' represents a hydrogen atom, or a phosphate group monoester, or a carbamate group of the -CO-N(R1R2) type where N (R1R2) represents aminodiacetic groups or a polycyclic amine, or a phosphonoacetic group H2O3P-CH2-CO, i.e. CO-CH2SO2-CH2COOH, either COCH2-OCH2-COOH, or a radical R, R has a cyclohexyloxyacetyl or an acyl group of formula or Z represents an oxygen or sulfur atom, an SO2 group, an alkylene linear or branched in C1-4, A represents a phenyl, naphthyl or benzyl ring Nope substituted or substituted until substituted five times with identical groups Where different selected from halogen, F, Cl, Br, linear alkoxy or C1-6 cyclics, C1-C6 alkyl, methylene dioxy, OCF3, CF3, NO2, CN, OH, OPO3H2, CH2 PO3H2, PO3H2, OCH2CO2H, COOH, CH2COOH, COCH3, CHO. 2. Compound according to claim 1, characterized in that R' represents a phosphate monoester group (PO3H2), carbamate CONR1R2 and NR1R2 represents an aminodiacetic group or a 3-aminoquinuclidine, R' also represents a phosphonoacetic group and their salts. 3. Compound according to claims 1 and 2, characterized in that R is chosen among the radicals:
phenoxyacetyl, 3,4-methylenedioxyphenoxyacetyl, 4-methoxyphenoxyacetyl, 4-hydroxyphenoxyacetyl, 4-phosphonooxyphenoxyacetyl, 4-carboxymethylphenoxyacetyl, 4-carboxymethoxyphenoxyacetyl, 4-carboxyphenoxyacetyl, 4- trifluoromethylphenoxyacetyl, 4-trifluoromethoxyphenoxyacetyl, 4-chlorophenoxyacetyl, 4-nitrophenoxyacetyl, 4-fluorophenoxyacetyl, cyclohexyloxyacetyl, phenylsulfonylacetyl, pentafluorophenoxyacetyl, 2 and 4-formylphenoxyacetyl and 4-cyanophenoxyacetyl. 4. Compound according to one of claims 1 to 3, characterized in that it is selected from organic or mineral salts of:
.cndot. 4'-Demethyl-4'-desoxy-4'-phosphate-4-O-(2,3-bis phenoxyacetyl-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-di(carboxymethyl)aminocarbonyl-4-O-(2,3-bis phenoxyacetyl-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot.4'-demethyl-4'-phosphonoacetyl-4-O-(2,3-bis phenoxyacetyl-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis-(4-trifluoromethyl-phenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-di(carboxymethyl)aminocarbonyl-4-O-(2,3-bis-(4-trifluoromethoxyphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis-(4-trifluoro-methoxyphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodo-phyllotoxin, .cndot. 4'-Demethyl-4'-phosphonoacetyl-4-O-(2,3-bis-(4-trifluoromethoxy-phenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-(4-phosphonooxyphenoxyacetyl)-4-O-(2,3-bis-(4-phosphonooxyphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis-(4-phosphonooxy-phenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-di(carboxymethyl)aminocarbonyl-4-O-(2,3-bis-cyclo-hexyloxyacetyl-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis cyclohexyloxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-(3-quinuclidinyl aminocarbonyl)-4-O-(2,3-bis-(3,4-methylenedioxyphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis-(3,4-methylene-dioxyphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis-(2,3,4,5,6-penta-fluorophenoxyacetyl)-4, 6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis-(4-fluorophenoxy-acetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-.beta.-quinuclidinylaminocarbonyl)-4-O-(2,3-bis-(4-chlorophenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis-(4-chlorophenoxy-acetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis(-phenylsulfonyl-acetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-(4-carboxyphenoxyacetyl)-4-O-(2,3-bis-(4-carboxyphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodo-phyllotoxin, .cndot. 4'-Demethyl-4'-(4-carboxymethylphenoxyacetyl)-4-O-(2,3-bis-(4-carboxymethylphenoxyacetyl}-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-(4-carboxymethoxyphenoxyacetyl)-4-O-(2,3-bis-(4-carboxymethoxyphenoxyacetyl}-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, 4'-Demethyl-4-O-{2,3-bis-(4-carboxymethoxyphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4-O-(2,3-bis-(4-carboxymethylphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-Demethyl-4'-(3-quinuclidinylaminocarbonyl)-4-O-(2,3-bis-(4-nitro-phenoxyacetyl}-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis-(4.-methoxy-phenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)-epipodophyllotoxin, 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis(4-cyanophenoxy-acetyl)-4,6-ethylidene-.beta.-D-glucosyl) epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis(4-nitrophenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl) epipodophyllotoxin, .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis(4-methylphenoxy-acetyl)-4,6-ethylidene-(3-D-glucosyl) epipodophyllotoxin, .cndot. 4-Demethyl-4-O-{2,3-bis(4-phosphonooxyphenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl) epipodophyllotoxin, and .cndot. 4'-demethyl-4'-deoxy-4'-phosphate-4-O-(2,3-bis(4-hydroxy-phenoxyacetyl)-4,6-ethylidene-.beta.-D-glucosyl)epipodophyllotoxin. 5. Compounds according to claim 4, characterized in that the compounds have an acid or basic function, in that the acid or basic functions of these compounds are salified by a salifying agent, in that the agents salifying the acid functions are chosen from amines and cations and in that the agents salifying the basic functions are chosen from acids minerals and organics. 6. Compounds according to claim 5, characterized in that the acids minerals or organic are chosen from hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanolsulfonic acid, maleic acid and tartaric acid. 7. Compounds according to claim 5, characterized in that fies amines and the cations are chosen from N-methylglucamine, lysine, triethanolamine, sodium and potassium. 8. Process for the preparation of a compound according to one of claims 1 to 4, characterized in that a glycosylated intermediate of formula is reacted General II
with an intermediate III
for which R is defined above and R4 is a protecting group that deprotecting to obtain the compounds of formula I in which R' = H. 9. Process for the preparation of a compound according to one of claims 1 to 4, characterized in that the etoposide protected at the 4' position is reacted with a benzyloxycarbonyl or quinuclidinecarbamate group of formula V
wherein R4 is as defined in claim 8 with a reagent acylating of AZ-CH2CO type to lead after hydrogenolysis or hydrolysis to the compound of formula I such that R' = H. 10. Process for the preparation of the salt of a compound according to claims 1 to 7, characterized in that the acid compound is treated with an amount basic stoichiometric, or by ion exchange resin and that we freeze-dried or crystallized. 11. Process for the preparation of the salt of a compound according to claims 1 to 7, characterized in that the basic compound is treated with an amount stoichiometric of the acidic agent and which is freeze-dried or crystallized. 12. Pharmaceutical composition characterized in that it comprises at least a compound of formula I according to one of claims 1 to 7 and an excipient appropriate. 13. Use of a compound of formula I according to one of claims 1 to 7, for the preparation of a medicament intended for the treatment of cancer. 14. Use according to claim 13 characterized in that the medicament is intended for the treatment of sloping cell lung cancer, tumors embryos, neuroblastomas, kidney cancer, tumors pediatric, Hodgkim's and non-Hodgkim's lymphomas, leukemias acute, placental choriocarcinomas, mammary adenocarcinomas, colorectal cancers and melanomas.