HUT75063A - Novel taxoids, their preparation and pharmaceutical compositions containing them - Google Patents

Description

The present invention relates to novel taxoids of formula (I), to processes for their preparation and to pharmaceutical compositions containing them as active ingredients.

In the general formula (I)

Ar is aryl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkenyl;

R is hydrogen or alkanoyl, alkoxyacetyl or alkyl;

R ₃ is benzoyl, tenoyl or furoyl; or

-0-C0 ₂ R group, wherein

R ₂ is C 1 -C 8 straight or branched alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl,

C3-6cycloalkyl, C4-6cycloalkenyl or C7-11bicycloalkyl, which may optionally be substituted with one or more halogen atoms and / or hydroxyC1-4alkoxy, in each alkane having C1-4alkylamino, piperidino, morpholino, 1-piperazinyl (optionally substituted in the 4-position with C 1-4 alkyl or C 1-4 alkylalkyl), C 3-6 cycloalkyl, C 4-6 substituted with a cycloalkenyl, phenyl, cyano, carboxy or alkoxycarbonyl group having 1 to 4 carbon atoms - or • · · · optionally substituted with one or more halogen and / or C 1 -C 4 alkyl, C 1 -C 4 alkoxy substituted phenyl, or optionally substituted one or more C 1-4 alkyl, saturated or unsaturated 4- to 6-membered heterocyclic groups; and

R ₃ is C 1 -C 8 straight or branched alkyl,

C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, or C 7 -C 11 bicycloalkyl, optionally substituted with one or more halogen and / or hydroxy, C1-C4 alkoxy, C1-C4 dialkylamino, piperidino, morpholino, 1-piperazinyl (optionally substituted in the 4-position with C1-C4 alkyl or C1-C4 alkyl moiety) -alkyl), C3-C6 cycloalkyl, C4-C6 cycloalkenyl, optionally substituted phenyl, cyano, carboxy or C1-C4 alkoxycarbonyl - or optionally substituted aryl, with the proviso that R ₃ is a saturated substituent other than unsubstituted phenyl or optionally substituted with one or more C 1-4 alkyl groups tt or unsaturated 4- to 6-membered heterocyclic group;

With the proviso that the cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted with one or more C 1-4 alkyl groups.

In compounds wherein Ar and R _{3 are} represented by the group, the aryl group is preferably optionally substituted with one or more halogen (fluorine, chlorine, bromine, iodine) and / or alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, (alkoxy) -carbonyl) amino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro, azido, trifluoromethoxy, phenyl, or α- or β-naphthyl substituted with trifluoromethyl, with the proviso that the alkyl moieties and other moieties have C 1 -C 4, alkenyl and alkynyl C 2 -C 8 and aryl phenyl or - or β-naphthyl groups, and R ₃ is other than unsubstituted phenyl.

In compounds wherein Ar and R _{3 are} heterocyclic groups, the heterocyclic group is preferably a five membered aromatic heterocyclic group containing one or more heteroatoms, which may be nitrogen, oxygen or sulfur, preferably optionally one or more. the same or different halogen (fluorine, chlorine, bromine, iodine) and / or C 1-4 alkyl, C 6-10 aryl, C 1-4 alkoxy, C 6-10 aryloxy, amino -, C1 -C4 alkylamino, both alkyl units of C1 -C4 dialkylamino, acyl units of C1 -C4 acylamino, C1 -C4 alkoxycarbonylamino, C4-acyl, C6-C10 aryl, arylcarbonyl, cyano, carboxy, carbamoyl, C1-C4-alkylcarbamoyl, and both alkyl units having C1-C4-alkyl dialkylcarbamoyl- C 1 -C 4 alkoxy substituted alkoxycarbonyl, with the proviso that the cycloalkyl, cycloalkenyl or bicycloalkyl groups may optionally be substituted with one or more C 1-4 alkyl groups.

Ar is more particularly optionally substituted with one or more same or different halogen atoms and / or alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, (alkoxycarbonyl) amino, trifluoro, phenyl, 2- or 3-thienyl, or 2- or 3-phenyl substituted with methyl, and R ₃ represents one or more same or different halogen atoms and / or alkyl, alkoxy, amino, alkylamino; , phenyl, dialkylamino, acylamino, (alkoxycarbonyl) amino, trifluoromethyl.

Ar is more particularly optionally substituted with chlorine or fluorine, or with alkyl, (methyl), alkoxy, (methoxy), dialkylamino, (dimethylamino), acylamino, (acetylamino) - or (alkoxycarbonyl) amino, [(tert-butoxycarbonyl) amino] - or

2- or 3-thienyl or 2- or 3-furyl, and R ₃ is phenyl substituted with halogen.

Particularly valuable are compounds of formula I wherein Ar is phenyl and R _{3 is} benzoyl or tert-butoxycarbonyl and R _{3 is} phenyl substituted with halogen.

According to the invention, the novel taxoids of formula (I) may be prepared by reacting a compound of formula (II)

Ar and R _r are as defined above; and

R ₄ is hydrogen; and

R ₅ is a hydroxy protecting group for a functional group, or

R ₄ and R ₅ together form a saturated five- or six-membered heterocyclic ring;

G ₁ is a protecting group for alkanoyl, (acetyl), alkoxyacetyl, methoxyacetyl or alkyl, (methyl) or hydroxy, with an acid of formula (III): wherein:

R ₃ is as defined above, or by esterification of this acid with an active derivative thereof, to give a compound of formula IV wherein Ar, R ₄ , R ₃ , R ₄ , R ₅ and G _x are as defined above, which _R5 or deprotection, of the compounds of formula (IV) in which R

R ₄ is hydrogen;

or by deprotection of R ₄ and R _{5 for} compounds of formula IV wherein R ₄ and R ₅ together form a saturated five or six membered heterocycle;

• • · · · · · · · · · · · · · · · · ·· ·· · • and optionally the obtained compounds of formula (I) replacement of G to _L hydrogen atoms, optionally substituted with - R _lz R ₄ and R _s is a compound of formula (V) wherein Ar and R are as defined above as an intermediate which is benzoyl, tenoyl or furoyl chloride or a compound of formula (VI)

R ₂ is as defined above, and

X is halogen (fluorine, chlorine), or -OR ₂ or

-O-CO-OR ₂ - acylated.

In the case where R ₄ is hydrogen, R _s is preferably methoxymethyl, 1-ethoxyethyl, (benzyloxycarbonyl) methyl, trimethylsilyl, triethylsilyl, [β- (trimethyl -silyl) -ethoxy] -methyl or tetrahydropyranyl.

In the case where R ₄ and R ₅ together form a heterocycle, it is preferably an oxazolidine ring which is optionally substituted in the 2-position or geminal disubstituted.

Preferably G ₄ is acetyl, alkyl or alkoxyacetyl.

The esterification of a compound of formula (II) may be accomplished by reacting an acid of formula (III), preferably a halide form such as chloride, with a compound of formula (II) previously converted to a metal derivative. Generation of metal derivatives is generally an alkali metal alkyl9 9

derivative, for example, butyl lithium in an organic inert solvent such as an ether such as tetrahydrofuran at a temperature below -50 ° C, preferably near -78 ° C. Esterification is generally carried out at the same temperature and solvent.

Deprotection of the compounds of formula (IV) may be accomplished by the following methods, depending on the type of protecting group:

1) compounds of formula IV in which:

R ₄ is hydrogen;

R ₅ have the same meanings as defined above; and

G _L is alkanoyl, (acetyl), alkoxyacetyl, (methoxyacetyl), alkyl, (methyl);

deprotection may be carried out on a compound of formula IV and a mineral acid (hydrochloric acid, sulfuric acid, hydrogen fluoride) or an organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid) or a mixture of these acids. in an organic solvent such as an alcohol, ether, ester, aliphatic hydrocarbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbon or nitrile at a temperature of -10 ° C to 60 ° C.

2) compounds of formula IV in which

R ₄ and R _{5 taken} together are a saturated five- or six-membered heterocycle, more particularly an oxazolidine ring compound of formula VII -

R _x is as defined above;

R ₆ and R ₇ may be the same or different and are selected from hydrogen or C 1-4 alkyl or C 1-4 alkyl-aralkyl, the aryl of which is optionally substituted by one or more C 1-4 -alkoxy groups, or aryl, preferably phenyl optionally substituted with one or more C 1 -C 4 alkoxy groups; or R ₆ is C 1 -C 4 alkoxy or a trihalomethyl group such as trichloromethyl or a phenyl substituted by a trihalomethyl group such as trichloromethyl; and

R ₇ is hydrogen, or

R _a and R _{7 taken} together with the carbon atom to which they are attached form a 4-7 membered ring; and

G _x is alkanoyl, (acetyl), alkoxyacetyl, (methoxyacetyl) or alkyl (methyl), deprotection can be performed as follows for R _x , R _s and R ₇ :

(a) In the case where:

R _x is tert-butoxycarbonyl;

R ₆ and R ₇ may be the same or different and are alkyl, aralkyl, (benzyl), or aryl, (phenyl); or · · V V V «« «♦ ♦ ♦ ♦

R _g is trihalomethyl or phenyl substituted by trihalomethyl; and

R ₇ is hydrogen; obsession

R ₆ and R ₇ together form a 4-7 membered ring;

reacting a compound of formula (IV) and a mineral or organic acid, optionally in an organic solvent, such as an alcohol, with a compound of formula (V), which is acylated with a compound of formula (VI). Preferably, the compound of formula (IV) is reacted with formic acid at a temperature in the region of 20 ° C. The acylation of a compound of formula V with a compound of formula VI is preferably carried out in an inert organic solvent such as an ester such as ethyl acetate, isopropyl acetate or butyl acetate, a halogenated aliphatic hydrocarbon such as methylene chloride or In 2-dichloroethane, it is carried out in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. The reaction is carried out at a temperature of 0 ° C to 50 ° C, preferably at 20 ° C.

(b) In the case where:

R _r is benzoyl or _R2 -C0- group of the formula wherein R ₂ is as defined above;

R _e is hydrogen, C 1 -C 4 alkoxy or phenyl substituted with one or more C 1 -C 4 alkoxy groups; and

R ₇ is hydrogen;

then deprotection can be performed with a mineral acid (hydrochloric acid, sulfuric acid) or an organic acid (acetic acid, methanesulfonic acid, trifluoro11, methanesulfonic acid, para-toluenesulfonic acid). or in the presence of a mixture thereof in an organic solvent such as an alcohol, an ether, an ester, an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon or an aromatic hydrocarbon at a temperature of -10 ° C to 60 ° C, preferably 15 ° C to 30 ° C. The acid may be used in catalytic or stoichiometric amounts.

3) In the case where

G ₁ is alkoxyacetyl; and

R ₄ and R ₅ are as defined in point 1);

first removing the R ₅ protecting group by proceeding under the acidic conditions specified in 1), and optionally thereafter replacing the protecting group G _{4 with} hydrogen by alkali treatment or by a zinc halide under conditions not affecting the rest of the molecule. Generally, the alkaline treatment is carried out with ammonia in an aqueous alcoholic medium or with hydrazine hydrate in an alcoholic medium at a temperature in the region of 20 ° C. In general, the reaction with a zinc halide is preferably carried out using zinc iodide, which is carried out in methanol at a temperature in the region of 20 ° C.

4) In the case where

G; is alkoxyacetyl; and

R ₄ and R ₅ are as defined in 2-a);

the replacement of the G _x protecting group is carried out, if necessary, by treatment with alkali or with a zinc halide under the conditions set out in 3), and the resulting compound V is further reacted under the acylation conditions set out in 2-a).

5) In the case where

_R G is an alkoxy acetyl radical; and

R ₄ and R ₅ are as defined in 2-b);

the replacement of the G _x protecting group may be carried out, if necessary, by treatment with alkali or a zinc halide under the conditions set out in 3), and the resulting compound is further reacted under the conditions set out in 2-b).

Compounds of formula (II) are compounds of formula (VIII):

Ar, R _x and R ₄ are as defined above;

_R5 are hydrogen hereinbefore defined and upward;

G ' _x can be prepared by electrolytic reduction of a hydrogen atom or a protecting group for alkanoyl, (acetyl), alkoxyacetyl, (methoxyacetyl) or alkyl, (methyl) or a hydroxy-functional group - the following equation by - (VIII), (II), which of course in the case where n is 2, the product leaving benzaldehyde, and when n is 4, leaving the product as benzyl alcohol - optionally a reduction of -0R ₅ and -O-G Protection of the hydroxy groups defined by the groups represented by the formula '-1' is carried out in order to obtain the compound of the formula II.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The electrolytic reduction of the compounds of formula VIII is carried out in an electrolyzer comprising a catholyte carrier at a concentration of 0.1 g / l of the compound of formula VIII to a concentration of a saturated solution of the compound of formula VIII. dissolved.

The reduction is preferably carried out in a diaphragm electrolyzer.

In one embodiment of the process of the invention, the electrolytic reduction comprises a cathode, a cathode space, a separating diaphragm, an anode space, and an anode having the following characteristics -

(a) the cathode consists of a layer of mercury,

b) the cathode space contains the catholyte consisting of a solution of the compounds of the formula VIII in an organic medium,

c) the separating diaphragm consists of a porous material such as a sintered glass or porcelain plate, a sleeve or a probe or an ion exchange membrane, preferably a cation exchange membrane,

d) the anode space contains the anode fluid, which preferably consists of the same solvent or solvent mixture and electrolyte carrier as the cathode space,

e) the anode consists of an electrical conductor, the characteristics of which are not essential to the process being carried out in an electrolyzer.

• ·

The anode is generally an electrically conductive material that is not damaged by electrolysis conditions, such as platinum, graphite, or glassy carbon on a polished, solid, or conductive support.

The electrolyte carrier is a quaternary ammonium salt, for example, (tetraethylammonium) acetate or (tetraethylammonium) (tetrafluoroborate), or mixtures thereof, in a solvent or mixture of solvents.

In general, solvents that are highly soluble in compounds of Formulas II and VIII and have low electrical resistance are used, such as alcohols such as methanol, nitriles such as acetonitrile or amides such as dimethylformamide.

The pH of the mixture should be compatible with the stability of the substrate. The medium may be buffered by the addition of a weak acid, such as acetic acid, in equimolar amounts to the quaternary ammonium acetate.

In a preferred embodiment of the method, the anode, cathode and separation diaphragm are arranged in parallel vertical planes, and the cathode consists of a layer of mercury.

The temperature of the electrolysis bath is generally between 0 ° C and 30 ° C.

Electrolysis is carried out at a controlled voltage, which may be between -1.90 and -2.10 V with respect to a reference saturated calomel electrode.

The solution should be degassed by purging with argon gas for a few tens of minutes prior to electrolysis, and the inhaled atmosphere maintained throughout the electrolysis.

Compounds of formula VIII may be prepared:

- 1) An alkali metal halide (sodium chloride, potassium fluoride) or an alkali metal azide (sodium azide) or a quaternary ammonium salt or an alkali metal phosphate and a compound of formula IX

Ar, R _1f R ₄ and G _r are as defined above; and R ₅ have the same meanings as defined above and hydrogen in addition - the reaction.

The reaction is generally carried out in an organic solvent such as an ether (tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether) or a nitrile (acetonitrile) or a mixture thereof at a temperature between 20 ° C and the boiling point of the solvent.

Compounds of formula (IX) may be prepared from a trifluoromethanesulfonic acid derivative such as anhydride or N-phenyl trifluoromethanesulfonimide and a taxoid of formula (X) wherein:

Ar, R _x , R ₄ and G'x are as defined above; and R ₅ is as defined above.

The reaction is usually carried out in an inert organic solvent (aliphatic hydrocarbons optionally halogenated, aromatic hydrocarbons) in the presence of an organic base such as an aliphatic tertiary amine (triethylamine) or pyridine at temperatures between -50 ° C and 20 ° C. .

Taxoids of formula (X) wherein G ' ₄ is hydrogen, acetyl, alkoxyacetyl or alkyl may be prepared from a compound of formula (XI):

Ar, R | and R ₄ is as defined above;

R ₅ have the same meanings as defined above; and

G ' ₁ is a protecting group for acetyl, alkoxyacetyl or alkyl, or a hydroxy functional group; and G ' ₂ represents a protecting group for a hydroxy function by replacing the protecting groups G' ₂ and optionally G ' _{4 with} hydrogen atoms.

In the case where _G represent 'and G' ₂ protective groups of hydroxy-functional group is a group, it is preferably (2,2,2-trichloroethoxycarbonyl) carbonyl, 2- [2- (trichloromethyl) propoxy ] -carbonyl group or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl groups in which the alkali moieties have from 1 to 4 carbon atoms and the aryl moieties are preferably phenyl.

In the case where G'x and G ' ₂ are (2,2,2-trichloroethoxy) carbonyl or 2- [2- (trichloromethyl) propoxy] carbonyl, the protecting groups are attached to hydrogen atoms. exchange with zinc (optionally copper-coupled) in the presence of acetic acid at a temperature between 20 ° C and 60 ° C, or with a mineral or organic acid such as hydrochloric or acetic acid, in a C 1-3 aliphatic alcoholic solution or in an aliphatic in a solution of an ester such as ethyl acetate, isopropyl acetate or butyl acetate in the presence of zinc (optionally associated with copper).

In the case where G ' ₂ is a silyl group and G'x is an alkanoyl, (acetyl), alkoxyacetyl, methoxyacetyl or alkyl, (methyl) group, the G' ₂ protecting group it may be carried out, for example, using hydrogen chloride gas in ethanolic solution at a temperature of about 0 ° C, or by using a hydrogen fluoride / triethylamine complex or a hydrogen fluoride / pyridine complex in an organic solvent such as methylene chloride, tetrahydrofuran or acetonitrile. At temperatures around 20 ° C, under conditions that do not affect the rest of the molecule.

In the case where R ₄ and R ₅ together form an oxazolidine ring compound of formula (VII)

R ₆ is hydrogen, and

R ₇ is a substituted phenyl - reaction in an acidic medium with a compound of formula (X)

R ₄ and R ₅ each represent hydrogen. Thus, it is necessary to selectively protect the hydroxy function represented by the group -O-R _{s in} the compound of formula (X), preferably in the form of a silylated group, before preparing the compound of formula (IX).

Compounds of Formula XI - wherein: · · ··· • · «

* G! is hydrogen or acetyl, alkoxyacetyl or alkyl - protected in position 7 and optionally in position 10 as described in EP 0 336 840, EP 0 336 841 and WO 9209589 by esterification of baccatine III or 10-deacetylbaccatine III containing hydroxy-functional groups, provided that in the preparation of compounds of formula XI in which

G ' _x is an alkoxyacetyl or alkyl group - 10-deacetyl baccatine III having a silyl protecting group preferably in the 7-position must be previously reacted with an alkoxyacetyl halide or an alkyl halide.

Generally, the alkoxyacetyl group is introduced by reacting the 7-protected 10-deacetylbaccatine III compound with an alkoxyacetyl halide in an organic basic solvent such as pyridine at a temperature in the region of 20 ° C.

In general, the introduction of the alkyl group is carried out by reacting the 10-deacetylbaccatine III compound protected at the 7-position and metallized at the 10-position with, for example, an alkali metal hydride (sodium hydride) or a metal alkyl (butyl lithium). with a halide.

- 2) A compound of formula XII: wherein:

G _x has the same meaning as given above for an acid of formula XIII in the formula

Ar, R _1, R ₄ and R ₅ are as defined above - or esterification of this acid with a derivative.

The esterification with an acid of formula XIII can be carried out in the presence of a condensing agent (carbodiimide, active carbonate) and an activating agent (aminopyridine) in an organic solvent (ether, ester, ketone, nitrile, aliphatic hydrocarbon, halogenated aliphatic hydrocarbon, aromatic hydrocarbon). 10 ° C to 90 ° C.

The esterification may also be carried out using an acid of formula XIII as an anhydride in the presence of an activating agent (aminopyridine) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, 0 ° C to 90 ° C.

The esterification can also be carried out by using the acid of formula XIII in the form of its halide or an anhydride of an aliphatic or aromatic acid, optionally in situ, in the presence of a base (aliphatic tertiary amine) in an organic solvent (ethers, esters, ketones). , nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at temperatures between 0 ° C and 80 ° C.

The compound of formula (XII) may be prepared from an alkali metal halide (sodium chloride, potassium fluoride), an alkali metal methide (sodium azide), a quaternary ammonium salt or an alkali metal phosphate and a compound of formula XIV. compound - in the formula

G _x has the same meaning as given above.

In general, the reaction is carried out in an organic solvent such as ethers (tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether) or nitriles (acetonitrile) or a mixture thereof at a temperature between 20 ° C and the boiling point of the reaction mixture.

Compounds of formula XIV wherein:

G _r is hydrogen, alkanoyl, (acetyl), alkoxyacetyl, (methoxyacetyl) or alkyl (methyl) - a trifluoromethanesulfonic acid derivative such as anhydride or N-phenyl trifluoro; by reaction of methanesulfonimide with baccatine III or 10-deacetylbaccatine III. The latter compounds can be extracted from the leaves of yew (Taxus baccata) by known methods and optionally protected at position 10; of course, in order to produce a compound of formula XIV wherein G ₂ is an alkoxyacetyl or alkyl group, 10-desacetylbaccatine III, preferably protected in the 7-position, must be previously reacted with an alkoxyacetyl halide or alkyl halide.

In general, the reaction of a trifluoromethanesulfonic acid derivative is carried out in an inert organic solvent (optionally halogenated aliphatic hydrocarbons, aromatic hydrocarbons) in the presence of an organic base such as a tertiary aliphatic amine (triethylamine) or pyridine at -20 ° C and + 20 ° C. temperature.

Generally, for the introduction of the alkoxyacetyl group, the 7-protected 10-deacetylbaccatine III compound is reacted with an alkoxyacetyl halide in a basic organic solvent such as pyridine at a temperature in the region of 20 ° C.

In general, for introduction of the alkyl group, the 10-deacetylbaccatine III compound protected at the 7-position and metallized at the 10-position with an alkali metal hydride (sodium hydride) or an alkali metal alkyl (butyllithium) is reacted with an alkyl halide.

According to the invention, the novel compounds of formula (I) can be prepared as a compound of formula (XV):

Ar, R _{lz R4, R5} and G ₃ have the same meanings as defined above; and

G ₂ is a protecting group for a hydroxy function, preferably a trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl group in which the alkyl groups have from 1 to 4 carbon atoms and the aryl groups preferably, by esterifying phenyl groups with an acid of formula (III) to form a compound of formula (XVI):

Ar, R _r , R ₃ , R ₄ , R _s , G ₃ and G ₂ have the same meaning as above - then selectively replacing the protecting group G ₂ with a hydrogen atom (XVII). ) to a compound of the general formula - in the formula

Ar, R _1f R ₃ , R ₄ , R ₅ and G ₂ are as defined above, which, by reaction with a trifluoromethanesulfonic acid derivative such as anhydride or N-phenyl trifluoromethanesulfonimide, has the formula:

Ar, R ₁ , R ₃ , R ₄ , R ₅ and G ₄ have the same meanings as defined above, wherein the protecting groups designated R ₅ or R ₄ and R ₅ are replaced by hydrogen atoms of formula XIX - in which

Ar, R ₁ R ₃ and G _x have the same meaning as given above - which is obtained with an alkali metal halide (sodium chloride, potassium fluoride, sodium chloride), an alkali metal azide (sodium azide) or a quaternary ammonium with a salt or an alkali metal phosphate to form a compound of formula I wherein

R is acetyl, alkoxyacetyl or alkyl which can be converted to a compound of formula I wherein R is hydrogen.

The esterification of a compound of formula (XV) with an acid of formula (III) may be carried out under the conditions described above for the esterification of a compound of formula (II) with an acid of formula (III).

Removal of the G ₂ protecting group is generally accomplished by treating a compound of formula XVI with hydrogen fluoride or trifluoroacetic acid in the presence of an organic base such as pyridine or a tertiary aliphatic amine such as triethylamine in an organic solvent such as ether (tetrahydrofuran) or a nitrile (acetonitrile).

A compound of formula (XVII) is converted to a compound of formula (XVIII) as described above for the preparation of compound (IX) from compound (X).

Replacement of the protecting groups R ₅ or R ₄ and R ₅ groups candidate is carried out under conditions such as that described protective groups of the compound of formula (IV) above replacing.

A compound of Formula XIX is a compound of Formula I in the formula

The conversion of R to alkanoyl, alkoxyacetyl or alkyl is carried out under the conditions described for the

Tieke one (IX) general formula Compound VIII (VIII) formula compound in shaping. The so (I) general formula in compounds that of appearance

R is alkanoyl, alkoxyacetyl or alkyl, optionally the replacement of R with hydrogen may be carried out under conditions as described above for deprotection of a compound of formula IV.

The compound of formula (XV) may be prepared as described in WO 94/20484.

The novel compounds of formula (I) obtained by the processes of the present invention may be purified by known methods such as crystallization or chromatography.

The compounds of formula I show remarkable biological activity.

Biological activity was measured in vitro on porcine tubulin isolated from M.L. Shelanski et al., Proc. Natl. Acad.

Sci. USA, 7, 765-768 (1973)]. A study of depolarization of tubulin microtubules in G. Chauviere et al., C.R. Acad. Sci., 293, Ser. II, 501-503 (1981)]. In this study, the compounds of formula I were found to be at least as effective as taxol and taxotere.

The compounds of formula (I) have been found to be active in vivo in mice treated with B16 melanoma at doses ranging from 1 to 10 mg / kg administered intraperitoneally and in other liquid or solid tumors.

The new compounds are effective against Taxol or Taxotere resistant tumors. Such tumors are those of the colon with high expression of the mdr 1 gene (multi-drug resistant gene). Multi-drug resistance is a commonly known term that refers to the resistance of a tumor to substances of different structures and mechanisms of action. Taxoids are generally known to be well recognized by experimental tumors, such as P388 / DOX, a cell line selected for doxorubicin (DOX) resistance that expresses mdr 1.

·· · · ·

The following examples serve to illustrate the invention.

Example 1

91.5 mg of {4α, 10β-diacetoxy-2α - [(4-fluorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor- 12.5 mg of sodium hydrogen in a solution of 11-taxen-1 3oc-yl} - [(2R, 3S) -3-amino-2-hydroxy-3-phenylpropionate] in 0.2 ml of dichloromethane are maintained under argon atmosphere. carbonate was added and a solution of 32 mg of di-tert-butyl dicarbonate in 0.1 ml of dichloromethane was added dropwise at a temperature in the region of 20 ° C. The resulting solution was stirred at a temperature in the region of 20 ° C for 22 hours and then added to a mixture of 0.5 ml of distilled water and 5 ml of dichloromethane. The aqueous phase was extracted with dichloromethane (0.5 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gave 99.2 mg of a yellow foam which was purified by preparative thin layer chromatography (2 x 98% v / v on 0.25 mm silica gel plate (Kieselgel 50F254, Merck)). The band containing the expected product was eluted with methanol / dichloromethane (10:90 v / v) and after evaporation under reduced pressure (0.27 kPa) at about 40 ° C, 32.7 mg of {4a, 10? -Diacetoxy-2? [(4-Fluorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13a-yl} - [(2R, 3S) ) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate] is obtained in the form of a white foam having the following characteristics:

• · · • · · · · · · ·

³ H NMR Spectrum (400 MHz; CDCl ₃ ; chemical shift, ppm): 1.28 (s, 3H: -CH ₃ -16 or -17); 1.30 [s, 9H: -C (CH ₃ ) ₃ ]; 1.37 (mt, 1H: --H - 7); 1.58 (s, 3H: -CH ₃ -16 or -17); 1.68 and 2.25 (t and m, 1H each: _CH2 cyclopropane); 1.87 (s, 3H: -CH ₃ -18); 2.12 and 2.47 (d and td, each H -CH ₂ -6); 2.22 (s, 3H: -COCH ₃ -10); 2.22 and 2.40 (m, 1H each: _-CH2 -14); 2.38 (s, 3H: _-COCH3 -4); 3.26 (s broad, 1H: -OH-2 '); 4.05 and 4.30 (d, 1H each: _-CH2 -2O); 4.10 (d, 1H:

H-3); 4.64 (s broad, 1H: -H-2 '); 4.75 (d, 1H: -H-5); 5.30 (d, broad, 1H: -H-3 '); 5.31 (d, 1H: -CONH-); 5.65 (d, 1H-H-2); 6.29 (broad t, 1H: -H-13); 6.32 (s, 1H: -H-10); 7.20 [t, 2H: -OCOC ₆ H ₄ F (-H-3 and -H-5)]; 7.30-7.45 (mt, 5H: C ₆ H ₅ -3 '); 8.19 [dd, 2H: -OCOC ₆ H ₄ F (-H-2 and H-6)].

{4cc, 10β-Diacetoxy-2α - [(4-fluorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-7β, 83-methylene-9-oxo-19-nor-11-taxene 13oc-yl} - [(2R, 3S) -3-amino-2-hydroxy-3-phenylpropionate] can be prepared as follows:

130 mg of {4a, 10β-diacetoxy-2α - [(4-fluorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxene -13a-yl] - [(4R, 5S) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] in 1.3 ml of formic acid at about 20 ° C After stirring for 1 hour, the mixture was concentrated to dryness under reduced pressure (0.27 kPa) at 30 ° C. The resulting white foam was purified directly by atmospheric pressure chromatography on a 2.5 cm diameter column of silica gel (0.063-0.2 mm) eluting with methanol / dichloromethane (elution gradient 2.5: 97.5 by volume 5:95). by volume). Only the fractions containing the expected product were combined and evaporated to dryness under reduced pressure (0.27 kPa) at 40 ° C. In this way, 91.5 g of {4α, 10β-diacetoxy-2α - [(4-fluorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19- nor-11-taxen-13a-yl) - [(2R, 3S) -3-amino-2-hydroxy-3-phenylpropionate] is obtained in the form of a white foam.

{4a, 10β-Diacetoxy-2α - [(4-fluorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-7β, 8β-β-methyl-9-ol-19-nor-11-yl- taxen-13a-yl} - [(4R, 5S) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] can be prepared as follows:

190 mg (4α, 10β-3ί3θθ1οχί-5β, 20-βροχί-1β, 2α-0ίΗ1όηοχί-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13a-yl) - [(4R, 5S) Of a solution of 3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] in 4 ml of anhydrous tetrahydrofuran under argon atmosphere at -78 ° C were treated sequentially with 0.38 ml of 1.3 M butyl lithium in hexane followed by 4-fluorobenzoyl chloride (0.0585 mL). The solution is stirred for 45 minutes at about -78 ° C and 0.38 ml of a 1.3 M solution of butyllithium in hexane is then added successively at 0, 0585 ml of 4-fluorobenzoyl chloride. The solution was stirred for 35 minutes at about -78 ° C and then 1 ml of a saturated aqueous ammonium chloride solution was added. The reaction mixture was allowed to warm to about 20 ° C over 15 minutes. After decantation, the aqueous phase was extracted with ethyl acetate (1 mL). The organic phases were combined, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. In this way, 245 mg of a brown oil are obtained, which is purified by chromatography on a 28 cm @ 2 of silica gel (0.063 cm @ 2) using a. -0.2 mm) using a methanol / dichloromethane solvent mixture (elution gradient: 0.5: 95.5 to 2.5: 97.5 by volume). Only the fractions containing the expected product were combined and evaporated to dryness under reduced pressure (0.27 kPa) at 4 ° C. In this way, 130 mg of (4a, 10β-diacetoxy-2α - [(4-fluorobenzoyl) oxy] -5β, 20epoxy-13-hydroxy-7β, 83-methylene-9-oxo-19-nor-11 -taxen-13a-yl} - [(4R, 5S) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] is obtained in the form of a white foam.

(4a, 10β-Diacetoxy-5β, 20-epoxy-1β, 2a-dihydroxy-73.8β-methylene-9-oxo-19-nor-11-taxen-13a-yl) - [(4R, 5S) - 3- (tert-Butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] may be prepared as follows:

[4a, 10β-Diacetoxy-2α-benzoyloxy) -5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13a-yl] - [ Electrolysis of (4R, 5S) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] was carried out in an electrolysis cell characterized as follows:

the cell is a 100 ml glass vessel divided into two parts by a cation exchange membrane,

- the anode is a platinum lattice,

- the reference electrode is a saturated mesh electrode.

Place 10 ml of the following solution in the cathode chamber:

[4a, 10β-Diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxene * ·

• · · ·· ·

-13oc-yl] - [(4R, 5S) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate]

27.3 mg (tetraethylammonium) - (tetrafluoroborate) as required

0.15 M / L (tetraethylammonium) acetate as needed

0.05 M / L acetic acid as needed

0.05 M / L methanol / ml required

10 ml of 0.1 M aqueous sulfuric acid solution was charged into the anode compartment.

After the solution was degassed by bubbling with argon for 10 minutes, maintaining the argon current throughout the electrolysis, the cathode voltage was set at -1.95 volts relative to the reference electrode.

The solution is electrolyzed for 54 minutes, that is, enough time to pass 100 Coulomb. After evaporating the solution to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 35 ° C, the residue is taken up in 10 ml of ethyl acetate and 10 ml of distilled water. After extraction and decantation, the aqueous phase was extracted with ethyl acetate (2 x 5 mL). The organic phases were combined, washed with 10 ml of 0.2 M aqueous phosphate buffer, pH 7, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. This gave 24 mg of a light yellow foam which was purified by preparative thin layer chromatography on 4 silica plates (Kieselgel 60F254, Merck; 0.25 mm thick) using methanol: acetonitrile / dichloromethane (5: 5: 90 by volume) as eluent. . U.V. light (254 nm) and eluting with methanol / dichloromethane (1: 1 by volume), the spot corresponding to the main product was evaporated under reduced pressure (0.27 kPa) at about 40 ° C. mg (4α, 1Οβ-diacetoxy-5β, 20-θροχί-1β, 2α-άί1ιίάηοχί-7β, 8β-Γηθίί1έη-9-οχο-19-nor-11-taxen-13α-ϋ) - [(4R, 5S) -3 (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] is obtained in the form of a white foam.

[4α, 10β-όίηοβΰοχί-2α- (benzoyloxy) -5β, 20-epoxy-13-hydroxy-7β, 8β-Γηθίί1έη-9-οχο-19-ηοΓ-11-ί3Χθη-13α-ί1] - [ (4R, 5S) -3- (tert-Butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] can be prepared as follows:

1.8 g of [4α, 10β-όί3θθόοχί-2α- (benzoyloxy) -5β, 20-βροχί-1β-όίόηοχί-9-οχο-7β- (trifluoromethanesulfonyloxy) -11-taxen-13a-yl. ] - [(4R, 5S) -3- (tert-Butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] in a solution of 20 ml of anhydrous acetonitrile and 4 ml of anhydrous tetrahydrofuran under argon atmosphere sodium chloride and 300 mg of powdered activated 4A molecular sieve are added. The reaction mixture was heated at 80 ° C for 2 hours with stirring under argon, then cooled to about 20 ° C and filtered through a sintered glass filter lined with Celite. The filtrate was concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The thus obtained 4.9 g brown-orange residue is purified by chromatography on a 4.5 cm diameter column containing 40 g of silica gel (0.063-0.2 mm) at atmospheric pressure, eluting with a gradient of ethyl acetate / dichloromethane (0: 1). 100 to 10:90). Only the fractions containing the expected product were combined and evaporated to dryness under reduced pressure (0.27 kPa) at 40 ° C. In this way, 1.35 g of [4α, 10β-diacetoxy-2α-benzoyloxy) -5β, 20-epoxy-1β-hydroxy-7β, 8β-ηηβηϋέη-9-oxo-19-nor-11-taxen 13a-yl] - [(4R, 5S) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] is obtained in the form of a white foam.

[4a, 10C-Diacetoxy-2ot- (benzoyloxy) -5β, 20-epoxy-4-hydroxy-9-o-o-7β-trifluoromethanesulfonyloxy-11-taxen-13a-yl] - [(4R, 5S) -3- (tert-Butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] can be prepared as follows:

3.85 g of [4a, 10C-diacetoxy-2a- (benzoyloxy) -5β, 20-β-dihydroxy-1β, 7β-dihydroxy-9-oxo-11α-taxen-13a-yl] - [(4R, 5S) ) To a solution of -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] in 40 ml of anhydrous methylene chloride in argon gas was added 1.3 ml of pyridine and 100 mg of activated 4A molecular sieve in powder form. . The reaction mixture was cooled to about -30 ° C. Trifluoromethanesulfonic anhydride (1.2 ml) was added slowly and stirred at 0 ° C for 1 hour. After cooling again to -30 ° C, 1.2 ml of trifluoromethanesulfonic anhydride are added, the mixture is stirred at 0 ° C for 1 hour and 10 ml of distilled water are added. The temperature of the reaction mixture was adjusted to 20 ° C and filtered through a Celite glass filter. The filter was washed with 50 mL of ethyl acetate / dichloromethane (1: 1 v / v). The aqueous phase was separated by decantation and extracted with dichloromethane (10 mL). The combined organic phases were dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. In this way, 4.39 g of a yellow solid are obtained, which is purified by chromatography on a 4.5 cm diameter column containing 350 g of silica gel (0.063-0.2 mm) at atmospheric pressure. ethyl acetate / dichloromethane (elution gradient 0: 100 to 5:95 by volume). Only the fractions containing the expected product were combined and evaporated to dryness under reduced pressure (0.27 kPa) at 40 ° C. In this way, 4.07 g of [4α, 1Οβ-diacetoxy-2α-benzoyloxy) -5β, 20-θροχί-1β-ήίάηοχί-9-οχο-7β-trifluoromethanesulfonyloxy-11-taxene was obtained. -13a-yl] - [(4R, 5S) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] is obtained in the form of a white foam.

(4α, 10β-3ί3θβΰοχί-2α- (benzoyloxy) -5β, 20-β-χΰχί-1β, 7β-ß-benzyloxy-9-oxo-11-taxen-13a-yl) - [(4R, 5S) -3- ( tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate] may be prepared as described in WO 9209589.

Example 2

500 mg [4a-Acetoxy-?, 2α-ß-1αίάηοχί-5β, 20-θροχί-10β- (methoxy-acetoxy) -9-o-o-7β- (triethylsilyloxy) -11-taxen-13a-yl] - [(2R, 4S, 5R) -3- (tert-Butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] in tetrahydrofuran (7 mL) kept under argon and a stirred solution of 0.9 ml of a 1.4 M solution of butyllithium in hexane and 279 mg of 3- (trifluoromethoxy) benzoyl chloride are added successively at -78 ° C. The solution is stirred for 45 minutes and then 10 ml of a saturated aqueous solution of ammonium chloride are added. The reaction mixture was returned to 20 ° C over 1 hour. The resulting solution was poured into a mixture of 50 mL of ethyl acetate and 50 mL of saturated aqueous ammonium chloride solution. The aqueous phase was separated by decantation and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with distilled water (50 mL), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 620 mg of a white foam are obtained, which is purified by chromatography on a column of 200 g of silica gel (0.063-0.2 mm) (eluent: ethyl acetate / cyclohexane (10:90 v / v)) to collect 30 ml fractions. Only the fractions containing the expected product were combined and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. In this way, 244 mg of {4a-acetoxy-53,20-epoxy-1-hydroxy-10β- (methoxyacetyl) -9-o-o-7β- (triethylsilyloxy) -2a- [3- (trifluoro-) methoxy) benzoyloxy] -11-taxen-13a-yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl- 1,3-oxazolidine-5-carboxylate] is obtained in the form of a white foam having the following characteristics:

- ^{ς Η} NMR (400 MHz, CDC1 _3, δ ppm): 0.5 9 (q, J = 7.5 Hz,

6H: SiCH ₂ -ethyl); 0.94 (t, J = 7.5 Hz, 9H: CH ₃ -ethyl); 1.08 [s,

9H: (CH ₃ ) ₃ ]; 1.19 (s, 3H: CH ₃ ); 1.21 (s, 3H: CH ₃ ); 1.62 '(s, 1H: OH-1); 1.67 (s, 3H: CH ₃ ); 1.70 (s, 3H: CH ₃ ); 1.83 (s, 3H: COCH ₃ ); 1.85 and

2.50 (2 mts, 1H each: _CH2 -6); 2.08 and 2.19 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 -14); 3.53 (s, 3H: OCH ₃ ); 3.73 (d, J = 7Hz, 1H: H-3); 3.84 (s, 3H: ArOCH ₃ ); 4.07 and 4.22 (2d, J = 8.5 Hz, 1H each: _CH2 at -2O); 4.18 (limiting AB, J = 16 Hz, 2H: OCOCH ₂ O); 4.43 (dd, J = 11 and 6.5 Hz, 1H: H-7); 4.58 (d, J = 5Hz, 1H: H-2 '); 4.87 (d broad, J = 10 Hz, 1H: H-5); 5.43 (mt, 1H: H-3 '); 5.62 (d, J = 7Hz, *

1Η: Η-2); 6.07 (t broad, J = 9 Hz, 1H: H-13); 6.40 (mt, 1H: H-5 ');

6.46 (s, 1H: H-10); 6.93 (d, J = 8 Hz, 2H: Ar-H-ortho to the OCH ₃ ); 7.30-7.50 (mt, 7H: ArH and ArH-meta in OCH ₃ -

group); 7.49 (d wide, J = 7.5 Hz, H: H-4 the 2 aromatic group); 7 , 53 (t, J = 7.5 Hz; H: H-5 the 2 aromatic group); 7.90 (s , wide, H: H-2 the 2 aromatic group); 7 , 99 (d, J = 7.5 Hz, H: H-6 the 2

aromatic group).

240 mg of {4oc-acetoxy-53,20-epoxy-1-hydroxy-10β-methoxy-acetoxy) -9-o-o-7β-triethylsilyloxy-2oc- [3- (trifluoromethoxy) - benzoyloxy] -11-taxen-13-yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3 oxazolidine-5-carboxylate] in methylene chloride (4 ml) at a temperature in the region of 20 ° C

3.3 ml of [triethylamine] - [hydrogen fluoride] complex are added. After stirring for 4 hours at a temperature in the region of 20 DEG C., a mixture of methylene chloride (10 mL) and saturated aqueous sodium bicarbonate solution (50 mL) was added. The organic phase is decanted off, washed twice with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 205 mg of {4a-acetoxy-1β, 7β-dihydroxy-5β, 20-θρχχί-10β-methoxy-acetoxy-9-oxo-2a- [3- (trifluoromethoxy) -benzoyloxy] -11-taxene -13a-yl) - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] - It is obtained in the form of a white foam having the following characteristics:

- ⁴ H NMR Spectrum (400 MHz; CDCl ₃ ; δ ppm): 1.06 [s, 9H: (CH ₃ ) ₃ ]; 1.24 (s, 3H: CH ₃ ); 1.28 (s, 3H: CH ₃ ); 1.56 (s, 3H: CH ₃ ); 1.65 (s,

3H: _CH3); 1.85 (s, 3H: COCH ₃ ); 1.85 and 2.53 (2 mts, each H CH ₂ -6); 2.08 and 2.21 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 -14);

2.35 (unres. Mult., 1H: OH-1); 3.53 (s, 3H: OCH ₃ ); 3.72 (d, J = 7Hz, 1H: H-3);

3.83 (s, 3H: ArOCH _3); 4.08 and 4.22 (2d, J = 8.5 Hz, each

1H: CH at -2O _2); 4.25 (limiting AB, J = 16 Hz, 2H: OCOCH ₂ O); 4.37 (dd, J = 11 and 8 Hz, 1H: H-7); 4.58 (d, J = 5Hz, 4.90 (d wide, J = 10)

Hz, 1H: H-5); 5.43 (mt, 1H: H-3 '); 5.62 (d, J = 7Hz, 1H: H-2); 6.13 (broad t, J = 9 Hz, 1H: H-13); 6.31 (s, 1H: H-10); 6.39 (mt, 1H: H-5 '); 6.93 (d, J = 8 Hz, 2H: Ar-H-ortho to OCH ₃ ); 7.30-7.50 (mt, 7H: Ar-H and Ar-H-meta relative to OCH ₃ ); 7.49 (d broad, J = 7.5 Hz, 1H: H-4 at position 2 of the aromatic group); 7.54 (t, J = 7.5 Hz, 1H: H-5 at position 2 of the aromatic group); 7.88 (s broad, 1H: H-2 at position 2 of the aromatic group); 7.98 (d, J = 7.5 Hz, 1H: H-6 at position 2 of the aromatic group).

200 mg of {4a-acetoxy-1β, 73-dihydroxy-53,20-β-chloro-10β- (methoxyacetoxy) -9-oxo-2a- [(3-trifluoromethoxybenzoyl) oxy] -11-taxene -13ct-yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] 3 A solution of trifluoromethanesulfonic anhydride (0.125 ml) was added dropwise to a solution of anhydrous methylene chloride (0.1 ml) and pyridine (0.120 ml) under argon at 0 ° C. The resulting orange solution was stirred at a temperature in the region of 0 ° C for 20 minutes and then 3 ml of water and 30 ml of dichloromethane were added. The organic phase is decanted off, washed twice with 20 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 233 mg are obtained, which is purified by chromatography on a column of 200 g of silica gel (0.063-0.2 mm) (eluent: dichloromethane / methanol (98: 2 v / v)) to collect 10 ml fractions. Only the fractions containing the expected product were combined and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 192 mg of {4a-acetoxy-5β, 20-epoxy-iPhydroxy-103- (methoxyacetoxy) -9-o-o-7β- (trifluoromethanesulfonyloxy) -2a- [3- (trifluoromethoxy) - benzoyloxy] -11-taxen-13a-yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3 -oxazolidine-5-carboxylate] is obtained in the form of a white foam having the following characteristics:

¹ H NMR Spectrum (400 MHz, CDCl ₃ , δ ppm); 1.07 [s, 9H: (CH ₃ ) ₃ ]; 1.18 (s, 3H: CH ₃ ); 1.20 (s, 3H: CH ₃ ); 1.65 (s, 1H: OH-1); 1.72 (s, 3H: CH ₃ ); 1.84 (s, 3H: CH ₃ ); 1.92 (s, 3H: COCH ₃ ); 2.07 and 2.10-2.25 [dd, (J = 16 and 9Hz), respectively. mts, 1H each: _CH2 -14]; 2.10-2.25 and 2.83 (2 mts, each H CH ₂ -6); 3.52 (s, 3H: OCH ₃ ); 3.83 (s, 3H: ArOCH _3); 3.85 (mt, 1H: H-3); 4.08 and 4.26 (2d, J = 8.5 Hz, 1H each: _CH2 at -2O); 4.14 and 4.22 (2d, J = 16 Hz, 2H: OCOCH ₂ O); 4.56 (d, J = 5 Hz, 1H: H-2 '); 4.86 (d broad, J = 10 Hz, 1H: H-5); 5.43 (dd,

J = 11 and 8 Hz, 1H: H-7); 5.46 (mt, 1H: H-3 '); 5.66 '(d, J = 7Hz, 1H: H-2); 6.06 (broad t, J = 9 Hz, 1H: H-13); 6.40 (mt, 1H: H-5 ');

6.63 (s, 1Η.Ή-10); 6.93 (d, J = 8Hz, 2H: Ar at the H-ortho position)

OCH ₃ ); 7.30-7.50 (mt, 7H: Ar-H and Ar-H-meta az

OCH ₃ ); 7.50 (broad d, J = 7.5 Hz, 1H: H-4 on the aromatic group 2); 7.56 (t, J = 7.5 Hz, 1H: H-5 on the aromatic group 2); 7.89 (s broad, 1H: H-2 at position 2 of the aromatic group 2); 7.99 (d, J = 7.5 Hz, 1H: H-6 at position 2 of the aromatic group).

190 mg of {4α-acetoxy-53,20-epoxy-1β-hydroxy-10β-methoxyacetoxy) -9-o-o-7β- (trifluoromethanesulfonyloxy) -2a- [3- (trifluoromethoxy) - benzoyloxy] -1-taxen-13cc-yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1, A solution of 3-oxazolidine-5-carboxylate] in 3.2 ml of 0.1 M hydrochloric acid was stirred at 20 ° C for 20 hours. The reaction mixture was evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The crude product obtained was dissolved in dichloromethane (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The organic layer was separated by decantation and extracted with dichloromethane (2 x 50 mL). The organic layers were combined, washed with distilled water (50 mL), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 175 mg of a white foam are obtained, which is purified by chromatography on a 0.5 mm silica gel preparative plate (eluent: dichloromethane / methanol (94: 6 by volume)). 66 mg {4α-Acetoxy-53,20-epoxy-13β-hydroxy-10β- (methoxyacetoxy) -9-o-o-7β- (trifluoromethanesulfonyloxy) -2a- [3- (trifluoromethoxy) - Benzoyloxy] -11-taxen-13a-yl} - {(2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate} was obtained as a white foam. in the form of:

- ³ H NMR Spectrum (400 MHz, CDCl ₃ , δ ppm): 1.22 (s, 3H: CH ₃ ); 1.26

3H: _CH3); 2.07 (s, 3H: CH ₃ ); 2.26 and 2.89 (each H 2 mt: CH ₂ -6); 2.36 (mt, 2H, _CH2 -14); 2.37 (s, 3H: COCH ₃ );

3.36 (d, • ·

J = 5Hz, 1Η: 0Η-2 ′); 3.54 (s, 3H: OCH ₃ ); 3.97 (d, J = 7.5 Hz, 1H: H-3);

4.16 and 4.26 (2d, J = 16 Hz, 2H: OCOCH ₂ O); 4.17 and 4.34 (2d, J = 8.5

Hz, 1H each: CH at -2O _Z); 4.62 (broad d, J = 5 Hz, 1H: H-2 '); 4.94 (broad d, J = 10 Hz, 1H: H-5); 5.24 (broad d, J = 10 Hz, 1H: H-2 ');

5.36 (d, J = 10 Hz, 1H: CONH); 5.49 (dd, J = 11 and 8 Hz, 1H: H-7); 5.73 (d, J = 7Hz, 1H: H-2); 6.17 (broad t, J = 9 Hz, 1H: H-13); 6.73 (s,

1H: H-1 O); 730-7.50 (mt, 5H: ArH); 7.50 (d wide, J = 7.5 Hz, 1H: H-4 a Aromatic group 2); 7.57 (t, J = 7.5 Hz, 1H: H-5 a Aromatic group 2) ; 7.99 (s wide, 1H: H-2 a Aromatic group 2); 8.07 (d, J = 7.5 Hz, 1H: H-6 a Aromatic group 2).

mg of {4ot-acetoxy-53,20-epoxy-1β-hydroxy-10β- (methoxyacetoxy) -9-o-o-7β- (trifluoromethanesulfonyloxy) -2a- [3- (trifluoromethoxybenzoyl) oxy] -11-taxen-13a-yl} - {(2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate} with 0.855 mL of acetonitrile and 0.085 mL To a solution of tetrahydrofuran in tetrahydrofuran was added sequentially 200 mg of 4A molecular sieve in powder form and 100 mg of sodium chloride. After stirring for 5 hours at a temperature in the region of 75 ° C, the reaction mixture was poured into a mixture of methylene chloride (75 ml) and saturated aqueous sodium chloride solution (50 ml) at a temperature in the region of 20 ° C. The organic layer was decanted, washed with brine (2 x 40 mL), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 110 mg are obtained which is purified by chromatography on a 0.5 mm silica gel preparative plate (eluent: cyclohexane / ethyl acetate (1: 1 by volume)). 30 mg of {4ct-Acetoxy-1β-hydroxy-5β, 20-epo · · · · · · · · · · · · · · · · · xx-ΙΟβ- (methoxyacetoxy) -7β, 8-methylene-19-nor-9-oxo- 2ct- [3- (trifluoromethoxy) benzoyloxy] -11-taxen-13a-yl} - {(2R, 3S) - [(tert-butoxycarbonyl) amino] -2-hydroxy-4 phenylpropionate} having the following characteristics:

¹ H NMR Spectrum (400 MHz, CDCl ₃ , δ ppm): 1.22 (s, 3H: CH ₃ ); 1.25 (s, 3H: CH ₃ ); 1.28 [s, 9H: (CH ₃ ) ₃ ]; 1.38 (mt, 1H: H-7); 1.65 and 2.25 (2 mts, 1H each: _CH2 -19); 1.80 (s, 1H: OH-1); 1.85 (s, 3H: CH ₃ );

2.09 and 2.45 (. D and dt, J = 16Hz and 4Hz, H each: _CH2 -6); 2.32 (mt, 2H, _CH2 -14); 2.32 (s, 3H: COCH ₃ ); 3.28 (unres. Mult., 1H: H-2 '); 3.49 (s, 3H: OCH ₃ ); 4.00 and 4.27 (2d, J = 8.5 Hz 1H each: _CH2 at -2O); 4.08 (d, J = 7.5 Hz, 1H: H-3); 4.18 (AB limit, J = 16 Hz,

2H: OCOCH ₂ O); 4.57 (s broad, 1H: H-2 '); 4.72 (broad d, J = 4 Hz, 1H: H-5); 5.21 (d broad, J = 10 Hz, 1H: H-3 '); 5.30 (d, J = 10 Hz,

1H: CONH); 5.62 (d, J = 7Hz, 1H: H-2); 6.19 (t wide, J = 9 Hz,

1H, H-13); 6.39 (s, 1H: H-10); 7.25-7.50 (mt, 5H: ArH); 7.44 (broad d, J = 7.5 Hz, 1H: H-4 on the aromatic group 2);

7.55 (t, J = 7.5 Hz, 1H: H-5 at position 2 of the aromatic group);

7.99 (s broad, 1H: H-2 at position 2 of the aromatic group); 8.08 (d, J = 7.5 Hz, 1H: H-6 at position 2 of the aromatic group).

Example 3

300 mg of {4oc-acetoxy-2cc - [(3-chlorobenzoyl) oxy] -5β, 20-θροχί-1β-hydroxy-β-methoxyacetoxy-9-ο -ο-7β- (trifluoromethanesulfonyl) oxy) -11-taxen-13a-yl} - {(2R, 3S) -3- [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate], 500 mg of sodium chloride and A mixture of 100 mg of activated 4A molecular sieve in 3 ml of acetonitrile and 0.6 ml of tetrahydrofuran was refluxed for 3 hours. After cooling to about 20 ° C, the reaction mixture is filtered through a Celite glass filter. The filtrate was washed with water (5 mL) and the organic layer was decanted and dried over magnesium sulfate. After filtration on a sintered glass filter, evaporated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C to give 410 mg of a light yellow foam which was prepared by preparative thin layer chromatography [preparative plate, Merck Kieselgel 60F254; thickness 0.25 mm; applying a solution in methylene chloride; eluent: methanol / dichloromethane (7:93 v / v)]. After dissolving the main product band in methanol / dichloromethane (10:90 v / v), the solution is filtered through a glass filter and the solvents are evaporated under reduced pressure (0.27 kPa) at about 40 ° C to give 136.8 mg of {4a -acetoxy-2ct- [3-chlorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-10β- (methoxyacetoxy) -7,8β-methylene-9-oxo-19-nor-11β- Taxen-13a-yl} - {(2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate] is obtained in the form of a white foam having the following characteristics:

- ^r H NMR (400 MHz, CDC1 _3, δ ppm): 1.22 (s, 6H: _CH3); 1.26 [s, 9H: (CH ₃ ) ₃ ]; 1.37 (mt, 1H: H-7); 1.67 and 2.34 (2 mts each)

1H: CH ₂ -19); 1.78 (s, 1H: OH-1); 1.85 (s, 3H: CH ₃ ); 2.10 and 2.44 (d and dt, J = 16 Hz and J = 16 and 4 Hz.), H each: _CH2 -6); 2.23 (mt, 2H, _CH2 -14); 2.34 (s, 3H: COCH ₃ ); 3.26 (mt, 1H: OH-2 '); 3.49 (s, 3H: OCH ₃ ); 3.98 and 4.27 (2d, J = 8.5 Hz each H CH ₂ -20);

4.07 (d, J = 7.5 Hz, 1H: H-3); 4.15 and 4.22 (2d, J = 16Hz,

2H: OCOCH ₂ O); 4.57 (mt, 1H: H-2 '); 4.73 (d broad, J = 4Hz, 1H: H-5);

5.22 (d broad, J = 10 Hz, 1H: H-3 '); 5.3 (d, J = 10 Hz, 1H: CONH);

5.60 (d, J = 7Hz, 1H: H-2); 6.20 (broad t, J = 9Hz, 1H: H-13); 6.40 (s, 1H: H-10); 7.20-7. 50 (mt, 5H: ArH); 7.44 (t, J = 7.5 Hz, 1H-H-5 on the aromatic group 2); 7.57 (d broad, J = 7.5 Hz, 1H: H-4 on the aromatic group 2); 8.02 (d, J = 7.5 Hz, 1H: H-6 at position 2 of the aromatic group); 8.14 (s broad, 1H: H-2 at position 2 of the aromatic group).

{4α-Acetoxy-2 2 - [(3-chlorobenzoyl) oxy] -5β, 20-epoxy-13-hydroxy-β- (methoxyacetoxy) -9-χχο-7β- (trifluoromethanesulfonyloxy) ) -11-taxen-13a-yl} - {(2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate] can be prepared as follows:

770 mg of {4a-acetoxy-2cc - [(3-chlorobenzoyl) oxy] -5β, 20-θροχί-1β-Ηίάηοχί-9-οχο-7β- (trifluoromethanesulfonyloxy) -11-taxen-13cc -Yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] 20 mL 0 A solution of 1 M hydrochloric acid in ethanol was stirred at a temperature in the region of 5 ° C for 16 hours. The reaction mixture was then diluted with dichloromethane (50 mL) and washed with distilled water (2 x 10 mL). After the aqueous phase was extracted with dichloromethane (10 mL), the organic layers were combined, dried over magnesium sulfate, filtered through a sintered glass filter and evaporated under reduced pressure (0.27 kPa) at about 40 ° C. This afforded 710 mg of a yellow solid which was purified by chromatography on a column of 50 g of silica gel (0.063-0.2 mm) at atmospheric pressure of ethyl acetate / dichloromethane 10:90 to 20:80 by volume. eluting with a gradient and collecting 10 ml fractions. Only the fractions containing the expected product were combined and evaporated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. In this way, 594 mg of {4c-acetoxy-2a- [(3-chlorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-10β- (methoxyacetoxy) -9-χχο-7β- (trifluoro) -methanesulfonyloxy-11-taxen-13a-yl} - ((2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate) is obtained, in the form of a light yellow foam having the following characteristics:

¹ H NMR Spectrum (400 MHz; CDCl ₃ ; δ ppm): 1.23 (s, 3H: CH ₃ ); 1.24 (s, 3H: CH ₃ ); 1.38 [s, 9H: (CH ₃ ) ₃ ]; 1.68 (s, 1H: OH-1); 1.90 (s,

3H: _CH3); 2.08 (s, 3H: CH ₃ ); 2.26 and 2.88 (2 mts, each H CH ₂ -6);

2.31 (mt, 2H, _CH2 -14); 2.41 (s, 3H: COCH ₃ ); 3.35 (mt, 1H: OH-2 ');

3.54 (s, 3H: OCH ₃ ); 3.95 (d, J = 7.5 Hz, 1H: H-3); 4.15 and 4.35 (2d,

J = 8.5 Hz, 1H each: _CH2 at -2O); 4.16 and 4.25 (2d, J = 16 Hz,

2H: OCOCH ₂ O); 4.64 (mt, 1H: H-2 '); 4.95 (broad d, J = 10 Hz, 1H: H-5); 5.26 (d broad, J = 10 Hz, 1H: H-3 '); 5.37 (d, J = 10 Hz, 1H: CONH);

5.48 (dd, J = 10.5 and 8 Hz, 1H: H-7); 5.70 (d, J = 7Hz, 1H: H-2); 6.19 (broad t, J = 9Hz, 1H: H-13); 6.73 (s, 1H: H-10); 7.30-7.50 (mt,

5H: aromatic H); 7.48 (t, J = 7.5 Hz, 1H: H-5 on the aromatic group 2); 7.62 (broad d, J = 7.5 Hz, 1H: H-4 on the aromatic group 2); 8.00 (d, J = 7.5 Hz; 1H: H-6 on the aromatic group 2); 8.11 (s broad, 1H: H-2 at position 2 of the aromatic group).

{4a-Acetoxy-2cc - [(3-chlorobenzoyl) oxy] -5β, 20-epoxy-N-hydroxy-9-ol-7β-trifluoromethanesulfonyloxy-11-taxen-13α il} - [(2R, 4S, 5R) -3- (tert-Butoxycarbonyl) -2- (4-methoxyphenyl) -4-Fe43 ···· ··· Nyl-1,3-oxazolidine-5-carboxylate] can be prepared as follows:

680 mg of {4a-acetoxy-2a- [(3-chlorobenzoyl) oxy] -5β, 20-epoxy-1β, 7β-0βΗ10ΓΓχί-9-χχο-11-ίχχχχ-13α-11} - [2R, 4S , 5R) -3- (tert-Butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] with 7 ml of methylene chloride and 0.43 ml of anhydrous pyridine of the prepared solution is added in powder form at a temperature of about 20 ° C. 0.445 ml of trifluoromethanesulfonic anhydride are added to the suspension thus obtained under an inert atmosphere of argon at a temperature of about -30 ° C. The reaction mixture was allowed to warm to about 20 ° C over a period of about 1 hour, after which 5 ml of distilled water and 50 ml of dichloromethane were added successively, and the molecular sieve was filtered through a Celite pad. After decantation, the aqueous phase was extracted with dichloromethane (2 x 5 mL). The organic layers were combined, dried over magnesium sulfate, filtered through a sintered glass filter and concentrated under reduced pressure (0.27 kPa) at -40 ° C. In this way, 1.13 g of a brown foam are obtained, which is purified by chromatography on a 2 cm diameter column of 60 g of silica gel (0.063-0.2 mm) at atmospheric pressure from 0: 100 to 10:90 by volume ethyl acetate / using a gradient of dichloromethane and collecting 10 ml fractions. Only the fractions containing the expected product were combined and concentrated under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. In this way, 762 mg of {4a-acetoxy-2cc - [(3-chlorobenzoyl) oxy] -5β, 20-θροχ1-1β-ήίάηοχ1-9-οχο-7β- (trifluoromethanesulfonyloxy) -11- taxen-13a-yl} - [(2R, 4S, 5R) -3- (tert -Bu ··· toxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine 5-carboxylate] is obtained in the form of a brown-orange foam having the following characteristics:

¹ H NMR Spectrum (400 MHz; CDCl ₃ ; δ ppm): 1.08 [s, 9H: (CH ₃ ) ₃ ]; 1.20 (s, 6H: CH ₃ ); 1.61 (s, 1H-OH-1); 1.71 (s, 3H: CH ₃ ); 1.85 (s, 3H: CH ₃ ); 1.95 (s, 3H: COCH ₃ ); 2.08 and 2.10-2.30 [dd (J = 16 and 9Hz)]. mts, 1H each: _CH2 -14]; 2.10-2.30 and 2.84 (2 mts, each H CH ₂ -6); 3.53 (s, 3H: OCH ₃ ); 3.85 (s, 3H: ArOCH _3); 3.85 (mt, 1H: H-3); 4.09 and 4.28 (2d, J = 8.5 Hz, 1H each; _CH2 -2O); 4.15 and 4.23 (2d, J = 16 Hz, 2H: OCOCH ₂ O); 4.58 (d, J = 5 Hz, 1H: H-2 '); 4.87 (d broad, J = 10 Hz, 1H: H-5); 5.42 (dd, J = 10 and 7 Hz, 1H: H-7);

5.45 (mt, 1H: H-3 '); 5.65 (d, J = 7Hz, 1H: H-2); 6.06 (t wide,

J = 9Hz, 1H: H-13); 6.42 (mt, 1H: H-5 '); 6.61 (s, 1H: H-10); 6.94 (d,

J = 8.5 Hz, 2H: ArH ortho to OCH ₃ ); 7.30 to 7.50 (mt, 8H: aromatic H and aromatic H meta-position relative to the _OCH3 moiety); 7.45 (t, J = 7.5 Hz, 1H: H-5 at position 2 of the aromatic group); 7.62 (d broad, J = 7.5 Hz, 1Η: Η-β at the 2-position aromatic group); 8.01 (s broad, 1H: H-2 at position 2 of the aromatic group).

{4ot-Acetoxy-2a- [(3-chlorobenzoyl) oxy] -5β, 20-β-dihydroxy-1β, 7β-dihydroxy-9-oxo-11-taxen-13-yl} - [(2R, 4S) , 5R) -3-tert-Butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] may be prepared as follows:

800 mg of {4c-Acetoxy-2a- [(3-chlorobenzoyl) oxy] -5β, 20-β-dicyclo-1β-1ιί0ηοχί-9-o-o-7β- (triethylsilyloxy) -11-taxen-13ot -yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] 8 mL of methylene dichloride prepared * · argon atmosphere was added 8.5 ml of [hydrogen fluoride], at about 0 ° C dropwise - [triethylamine] complex (3HF.Et _3N) was added. The solution was stirred at 0 ° C for 4 hours, then diluted with dichloromethane (20 ml) and poured into saturated aqueous sodium bicarbonate solution (40 ml) at 0 ° C. After separation, the aqueous phase was extracted with dichloromethane (3 x 30 mL). The combined organic phases were dried over magnesium sulfate, filtered through a sintered glass filter and evaporated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. This gave 781 mg of a light yellow foam which was purified by chromatography on a 3.5 cm column of silica gel (0.063-0.2 mm) (100 g, 25/75 ethyl acetate / dichloromethane) at atmospheric pressure. and 15 ml fractions. Only the fractions containing the expected product were combined and concentrated under reduced pressure (0.27 kPa) at 40 ° C for two hours. In this way, 686 g of {.beta.-acetoxy-2a- [(3-chlorobenzoyl) oxy] -5β, 2O-epoxy-10,73-dihydroxy-9-oxo-11-taxen-13-yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] is obtained in the form of a white foam. having the following characteristics:

¹ H NMR Spectrum (400 MHz; CDCl ₃ ; δ ppm): 1.08 [s, 9H: (CH ₃ ) ₃ ]; 1.12 (s, 3H: CH ₃ ); 1.25 (s, 3H: CH ₃ ); 1.58 (s, 3H: CH ₃ ); 1.64 (s, 1H: OH-1); 1.66 (s, 3H: CH ₃ ); 1.86 and 2.54 (zt, H each: _CH2 -6); 1.88 (s, 3H: COCH ₃ ); 2.08 and 2.21 (2 dd, respectively J = 16 and 9 Hz, 1H each: _CH2 -14); 2.32 (d, J = 4Hz, H: OH-7), 3.54 (s, 3H: _OCH3);

3.71 (d, J = 7 Hz, 1H: H-3); 3.83 (s, 3H: ArOCH _3); 4.08 and 4.24 (2d, • ··· · «··

J = 8.5 Hz, each 1H, CH ₂ -20); 4.26 (AB limit, J = 16Hz,

2H: OCOCH ₂ O); 4.37 (mt, 1H: H-7); 4.61 (d, J = 5 Hz, 1H: H-2 '); 4.91 (d broad, J = 10 Hz, 1H: H-5); 5.43 (mt, 1H: H-3 '); 5.60 (d, J = 7Hz, 1H: H-2); 6.14 (broad t, J = 9Hz, 1H: H-13); 6.30 (s, 1H: H-10);

6.40 (mt, 1H: H-5 '); 6.94 (d, J = 8.5 Hz, 2H: at position ArH-ortho) a

OCH ₃ ); 7.30 to 7.50 (mt, 8H: aromatic H, and Ar H meta to the _OCH3 moiety); 7.45 (t, j = 7.5 Hz, 1H: H-5 on the aromatic group 2); 7.61 (d broad, J = 7.5 Hz, 1H: H-4 on the aromatic group 2); 7.92 (d, J = 7.5 Hz, 1H: H-6 at position 2 of the aromatic group); 8.03 (s wide

1H: H-2 at position 2 of the aromatic group).

{4a-Acetoxy-2ct - [(3-chlorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-9-o-o-7β-triethylsilyloxy-11-taxene-13α -yl) - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate] can be prepared as follows:

2.5 g of [4-c-acetoxy-1,2,4-epoxy-10β-20-epoxy-10β-methoxy-acetoxy] -9-o-o-7β- (triethylsilyloxy) -11-taxen-13a-yl ] - [(2R, 4S, 5R) -3- (tert-Butoxycarbonyl) -2- (4-methoxyphenyl) -3-phenyl-1,3-oxazolidine-5-carboxylate] with 25 ml of tetrahydrofuran To a stirred solution of the reaction mixture prepared under argon atmosphere at -78 ° C was added sequentially 3.90 mL of a 1.6 M solution of butyllithium in hexane and 0.8 mL of meta-chlorobenzoyl chloride. The solution was stirred at -78 ° C for 45 minutes and then 10 ml of a saturated aqueous ammonium chloride solution was added. The reaction mixture was allowed to warm to about 20 ° C over 1 hour and diluted with ethyl acetate (20 mL). The aqueous phase was separated by decantation and extracted with ethyl acetate (2 x 10 mL). THE *· ···· ···· ·· ···" • · · · · · • · · · · · ·

The organic layers were combined, washed with distilled water (10 mL) and dried over magnesium sulfate. After filtration and evaporation under reduced pressure (2.7 kPa) at 40 ° C, 3.47 g of a light yellow foam are obtained, which is purified by chromatography on a 5 cm diameter column containing 250 g of silica gel (0.063-0.2 mm). acetate / dichloromethane, eluting with a gradient of 3:97 to 10:90 by volume, and fractions of 15 mL were collected. Only the fractions containing the expected product _was combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. In this way, 1.41 g of {4c-acetoxy-2a- [(3-chlorobenzoyl) oxy] -5β, 20-epoxy-1β-hydroxy-9-o-o-7β-(triethylsilyloxy) - 11-taxen-13a-yl} - [(2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidin-5-one. carboxylate] in the form of a white foam having the following characteristics:

- ^{Χ Η} NMR (400 MHz, CDC1 _3, δ ppm): 0.60 (q, J = 7.5 Hz,

6H: SiCH ₂ -ethyl); 0.95 (t, J = 7.5 Hz, 9H: CH ₃ -ethyl); 1.08 [s, 9H: (CH ₃ ) ₃ ]; 1.19 (s, 3H: CH ₃ ); 1.21 (s, 3H: CH ₃ ); 1.62 (s, 1H: OH-1);

1.65 (s, 3H: CH ₃ ); 1.70 (s, 3H: CH ₃ ); 1.85 (s, 3H: COCH ₃ ); 1.85 and 2.51 (2 mts, each H CH ₂ -6); 2.08 and 2.19 (2 dd, - J = 16 and 9 Hz, 1H each: _CH2 -14); 3.53 (s, 3H: OCH ₃ ); 3.71 (d, J = 7.5 Hz, 1H:

H-3); 3.84 (s, 3H: ArOCH ₃ ); 4.07 and 4.24 (2d, J = 8.5 Hz, 1H each: _CH2 at -2O); 4.15 and 4.22 (2d, J = 16 Hz, 2H: OCOCH ₂ O); 4.42 (dd,

J = 10 and 6 Hz, 1H: H-7); 4.60 (d, J = 5 Hz, 1H: H-2 '); 4.88 (d wide,

J = 10 Hz, 1H: H-5); 5.42 (mt, 1H: H-3 '); 5.60 (d, J = 7.5 Hz, 1H: H-2); 6.08 (broad t, J = 9Hz, 1H: H-13); 6.40 (mt 1H: H-5 ');

6.45 (s, 1H: H-10); 6.93 (d, J = 8.5 Hz, 2H: · · · · · · · · · · · · · · · ·

OCH ₃ ); 7.3 to 7.50 (mt, 8H: aromatic H, ArH meta to the _OCH3 and H-5 to the 2-position of the aromatic group); 7.61 (d broad, J = 7.5 Hz, 1H: H-4 on the aromatic group 2);

7.94 (d, J = 7.5 Hz, 1H: H-6 at position 2 of the aromatic group);

8.03 (s broad, 1H: H-2 at position 2 of the aromatic group).

[4ct-Acetoxy-1,3,2-dihydroxy-53,20-θρχθί-10β-methoxy-acetoxy-9-o-o-7β- (triethylsilyloxy) -11-taxen-13a-yl] - [ (2R, 4S, 5R) -3- (tert-Butoxycarbonyl) -2- (4-methoxyphenyl) -3-phenyl-1,3-oxazolidine-5-carboxylate] can be prepared according to WO94 / 20484.

The novel compounds of formula (I) exhibit significant inhibitory activity against abnormal cell proliferation and have therapeutic properties which are useful in the treatment of patients with pathological conditions resulting from abnormal cell proliferation. The pathological condition includes malignant or non-malignant abnormal cell growth in various organs and / or tissues including, but not limited to, muscle, bone and connective tissues, skin, brain, lungs, genitals, lymph - or the kidney, breast or blood cells, liver, digestive system, pancreas, thyroid or adrenal gland. The pathological condition may include psoriasis, solid tumors, cancer of the uterus, breast, brain, prostate, colon, stomach, kidney or testis, Kaposi's sarcoma, bile duct carcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanoma, multiple myeloma, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas. The novel compounds of the present invention are particularly useful in the treatment of ovarian cancer. The compounds of the present invention may be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.

The compounds of the invention may be administered to a patient in a variety of forms suitable for the chosen route of administration, preferably parenteral administration. The parenteral route of administration includes intravenous, intraperitoneal;

tonal, intramuscular or subcutaneous routes of administration.

Intraperitoneal or intravenous administration is particularly preferred.

The present invention also encompasses pharmaceutical compositions containing at least one compound of formula (I) in an amount sufficient for human or veterinary use. The pharmaceutical compositions may be prepared according to known procedures using one or more pharmaceutically acceptable excipients, carriers or additives.

Conventional carriers include diluents, aqueous sterile media and various non-toxic solvents. The pharmaceutical compositions are preferably solutions or aqueous suspensions, solutions for injection, which may contain emulsifiers, colorants, preservatives or stabilizers.

The choice of excipients or additives may be determined by the solubility and chemical properties of the compound, the particular route of administration and good practice in the pharmaceutical formulation.

For parenteral administration, aqueous or non-aqueous sterile solutions or suspensions are used. For preparing non-aqueous solutions or suspensions, natural vegetable oils, such as olive oil, sesame oil or paraffin oil, or injectable organic esters, such as ethyl oleate, may be used. Sterile aqueous solutions may contain an aqueous solution of a pharmaceutically acceptable salt. Aqueous solutions are suitable for intravenous administration provided that the pH of the solution is adjusted and isotonic, for example by adding sufficient sodium chloride or glucose. Sterilization may be accomplished by heat treatment or by any other method that does not alter the composition.

Of course, all the ingredients of the composition of the invention in the amounts used should be pure and non-toxic.

The compositions may contain at least 0.01% of a therapeutic agent. The amount of active ingredient in a composition is such that a suitable dosage can be prescribed. Preferably, the compositions are formulated to contain from 0.01 to 1000 mg of active ingredient per unit dose for parenteral administration.

The therapeutic treatment may be combined with other therapeutic treatments, including antineoplastics, monoclonal antibodies, immunological therapies, radiotherapies or biological response modifiers. Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (α, β, δ) and TNF. Other chemotherapeutic agents for treating disorders resulting from abnormal cell proliferation include, but are not limited to, alkylating agents. agents such as nitrogen mustard such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustine and streptozocine, triazines such as dacarbazine, antimetabolites such as folic acid analogues such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs such as mercaptopurine and thioguanine, some natural substances such as vinca alkaloids such as vinblastine, vincristine and vendesine, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycine, daunorubicine, doxorubicine, bleomycine, plicamycin and mitomycin, enzymes such as L-asparaginase, various other agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid suppressors such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins like hydroxyprogesterone-caproate, methoxyprogesterone-acetate and megestrol-acetate, estrogens such as diethylstil ethinyl estradiol, anti-estrogens such as tamoxifen, androgens such as testosterone propionate and fluoxymesterone.

The dosages employed are such that, in carrying out the methods of the present invention, they will provide preventive treatment or maximum therapeutic response. Dosages will vary with the form of application, the compound selected, and the individual characteristics of the patient being treated. Generally, the dosages will correspond to a therapeutically effective dosage for treating disorders resulting from abnormal cell proliferation. The compounds of the invention may be used as often as is necessary to achieve the desired therapeutic effect. Some patients may respond quickly to relatively high or low doses and may not need a low maintenance dose or any dose. Generally, small doses are required at the beginning of the treatment, and if necessary, increasing doses are used until the maximum effect is achieved. For other patients, a maintenance dose of one to eight times daily, preferably one to four times daily, may be required according to the physiological condition of the patient. It is also possible that some patients may require only twice daily dosing.

In human medicine, dosages are generally in the range of 0.01 to 200 mg / kg. For intraperitoneal administration, doses will generally be in the range of 0.1 to 100 mg / kg, preferably 0.5 to 50 mg / kg, more particularly 1 to 10 mg / kg. For intravenous administration, dosages are generally in the range of 0.1 to 50 mg / kg, preferably 0.1 to 5 mg / kg, more particularly 1 to 2 mg / kg. Of course, the choice of the most appropriate dosage should take into account the route of administration, the patient's weight, general health, age and any factors that may influence the effectiveness of the treatment.

The following example illustrates the composition of a pharmaceutical composition according to the invention.

Example 4

40 mg of the compound prepared in Example 1 are dissolved in 1 ml of Emulphor EL 620 and 1 ml of ethanol and diluted with 18 ml of physiological serum.

The drug is administered as a 1 hour infusion added to the saline.

Claims (5)

Novel taxoids of formula (I): wherein Ar is aryl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl; R is hydrogen or alkanoyl, alkoxyacetyl or alkyl; R _x is benzoyl, tenoyl or furoyl, or R _{2 is} -O-CO- wherein R ₂ is C 1-8 straight or branched alkyl, C 2-8 alkenyl, C 3-8 alkynyl; . C3-6cycloalkyl, C4-6cycloalkenyl, or C7-11bicycloalkyl, optionally substituted with one or more halogen atoms and / or hydroxyC1-4alkoxy, in each alkane having 1-4C-dialkylamino, piperidino, morpholino, 1-piperazinyl (optionally substituted in the 4-position with C 1-4 alkyl or C 1-4 alkylalkyl), C 3-6 cycloalkyl, C 4-6 substituted by one or more halogen and / or C 1-4 -alkyl, C 1-4 -alkoxy, optionally substituted by one or more halo and / or C 1-4 -alkyl, C 1-4 -alkoxy, or a saturated or unsaturated 4- to 6-membered heterocyclic group optionally substituted with one or more C 1 -C 4 alkyl groups; and R ₃ is C 1 -C 8 straight or branched alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, or C 7 -C 11 bicycloalkyl, which may be optionally substituted with one or more halogen and / or hydroxy, C4-alkoxy, C1-C4 dialkylamino, piperidino, morpholino, 1-piperazinyl (optionally substituted in the 4-position with C1-C4 alkyl or C1-C4 alkyl) substituted phenylalkyl), C 3-6 cycloalkyl, C 4-6 cycloalkenyl, optionally substituted phenyl, cyano, carboxy or C 1-4 alkyl-alkoxycarbonyl - or optionally one or more thereof; aryl substituted with halogen and / or C 1-4 alkyl, C 1-4 alkoxy, provided that R ₃ is other than unsubstituted phenyl, or optionally substituted with one or more C 1-4 alkyl groups, -6-membered nitrogen containing heterocyclic group; and with the proviso that the cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted with one or more C 1-4 alkyl groups. 2. The novel taxoid of claim 1 having the formula R and R _r are as defined in claim 1; and where Ar and R ₃ are aryl, which may be optionally substituted with one or more halogen (fluorine, chlorine, bromine, iodine) and / or alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkyl -thio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, (alkoxycarbonyl) amino, phenyl substituted with amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro, azido, trifluoromethoxy, trifluoromethyl or a-or β-naphthyl, with the proviso that the alkyl moieties and other moieties have C 1 -C 4, the alkenyl and alkynyl C 2 -C 8, and the aryl groups are phenyl or α- or β-naphthyl, and R ₃ is other than unsubstituted phenyl, and provided that Ar and R ₃ are a heterocyclic group, which may be a five membered aromatic heterocyclic group containing one or more identical or different heteroatoms selected from nitrogen, oxygen and sulfur, preferably optionally having one or more identical or different halogen atoms (fluorine). , chlorine, bromine, iodine) and / or C 1-4 alkyl, C 6-10 aryl, C 1-4 alkoxy, C 6-10 aryloxy, amino, C 1-4 alkyl amino, C1 -C4 dialkylamino in each of its alkyl units, C1 -C4 acylamino in its acyl unit, (C1 -C4 alkoxycarbonyl) amino, C1 -C4 acyl, Arylcarbonyl, cyano, carboxy, carbamoyl, alkylcarbamoyl having from 6 to 10 carbon atoms, alkoxy having from 1 to 4 carbon atoms, dialkylcarbamoyl having from 1 to 4 carbon atoms and alkoxy having from 1 to 4 carbon atoms, substituted with a carbonyl group. The novel taxoids of claim 1 having the formula R and R ₁ are as defined in claim 1; Ar is optionally substituted with one or more same or different halogen atoms and / or alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, (alkoxycarbonyl) amino, trifluoromethyl substituted phenyl, 2- or 3-thienyl, or 2- or 3-furyl; and R ₃ represents one or more same or different halogen atoms and / or alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, (alkoxycarbonyl) amino, trifluoromethyl; phenyl substituted with. A process for the preparation of new taxoids according to claim 1, 2 or 3, characterized in that a compound of the formula (II) - in which Ar and R _x are as defined in any one of claims 1, 2 or 3; R ₄ is hydrogen; and R ₅ is a protecting group for a hydroxy function; obsession R _{4 and} R form together a saturated, five- or six-membered heterocyclic ring; G _r is a protecting group for an alkanoyl, alkoxyacetyl or alkyl group or a hydroxy-functional group, with an acid of formula (III) R ₃ is as defined in one of claims 1, 2 or 3, or is esterified with an active derivative of this acid to give a compound of formula (IV) Ar, R _lr R _3, R _4, R ₅ and _G are as defined above - from which the R ₅ protecting group, removing - in the formula (IV) compounds of formula, wherein R ₄ is hydrogen, - or R _{4 and} R deprotecting - compounds of formula IV in which To form R ₄ and R ₅ together a saturated, five- or six-membered heterocycle - and optionally afford a compound of general formula (I) replacement of G to _L hydrogen atoms, optionally - depending on R _x, R ₄ and R ₅ form - (V) Compounds of Formula (I) wherein R is as defined above, as intermediates which are benzoyl, tenoyl or furoyl chloride or Compound (VI) R ₂ is as defined above; and X is halogen, -O-R _2, or -O-CO-OR ₂ - acylated. A process according to claim 4, wherein the esterification of a compound of formula II is carried out by reacting a compound of formula II and a acid of formula III which has been previously metallized with an alkali metal alkyl derivative. preferably in the form of an acid halide, in an inert organic solvent such as ether, at a temperature below -50 ° C. A process according to claim 4, wherein the deprotection of the hydroxy functional groups is carried out by: 1) compounds having the formula R ₄ is hydrogen; R ₅ have the same meanings as defined above; and G ₄ is alkanoyl, alkoxyacetyl or alkyl; reacting a compound of formula (IV) with a mineral acid (hydrochloric acid, sulfuric acid, hydrogen fluoride) or an organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid) or a mixture of these acids in an organic solvent, e.g. in an ester, an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon, an aromatic hydrocarbon or a nitrile at a temperature of -10 ° C to 60 ° C; obsession 2) compounds of the formula R ₄ and R _s together form a saturated (VII) with a heterocycle of the formula wherein R ₁ is as defined in one of claims 1, 2 or 3; R ₆ and R ₇ may be the same or different and are hydrogen, (C 1 -C 4) -alkyl or (C 1 -C 4) -alkyl, preferably having an aryl moiety optionally substituted with one or more (C 1 -C 4) -alkoxy groups. Or an aryl group, preferably a phenyl group optionally substituted with one or more C 1 -C 4 alkoxy groups; obsession R _he is C1-4alkoxy, trihalomethyl group or a trihalomethyl-substituted phenyl; and R ₇ is hydrogen, or R _s and R ₇ together with the carbon atom to which they are attached form a 4-7 membered ring; and G ₇ is acetyl or alkyl; deprotection, depending on the meaning of R _lz R ₆ and R ₇ , can be performed as follows: (a) in the case where: R _x is tert-butoxycarbonyl; R ₆ and R ₇ may be the same or different and are alkyl, aralkyl, or aryl; obsession _R6 represents a trihalomethyl group or a trihalomethyl group-substituted phenyl; and R ₇ is hydrogen; obsession R ₆ and R ₇ together form a 4-7 membered ring; reacting a compound of formula (IV) and a mineral or organic acid, optionally in an organic solvent, such as an alcohol, with a compound of formula (V), which is acylated with a compound of formula (VI); (b) in the case where: R _r is benzoyl or _R2-CO group, wherein R ₂ is as defined above; R ₆ is hydrogen, C 1-4 alkoxy, or phenyl substituted with one or more C 1-4 alkoxy; and R ₇ is hydrogen; the compound of formula (IV) may be catalytic or stoichiometric with mineral acid (hydrochloric acid, sulfuric acid) or organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, para-toluenesulfonic acid) or a mixture thereof in an organic solvent, e.g. , in an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon or an aromatic hydrocarbon, from -10 ° C to 60 ° C; obsession 3) in the case where G ₁ is alkoxyacetyl; and R ₄ and R ₅ are as defined in point 1); We performed first _five deprotection R acting as per the above 1) to acidic conditions, and then replaced by G _x protecting group by a hydrogen atom under alkaline conditions using, or using a zinc halide, ammonia or hydrazine under conditions that do not affect the rest of the molecule ; obsession 4) in the case where G _x is alkoxyacetyl; and R ₄ and R _s are as defined in point 2-a); then exchange G _r protecting group can be carried out as in 3) under conditions with alkali or by means of a zinc halide and then (V) compound is further reacted as defined in point 2-a) deprotection and acylation conditions; obsession 5) in the case where G; is alkoxyacetyl; and R ₄ and R ₅ are as defined in 2-b); the replacement of the G ₄ protecting group is carried out, if necessary, by treatment with alkali or a zinc halide under the conditions set out in 3), and the resulting compound is further reacted under the conditions set out in 2-b). A process for the preparation of a compound according to any one of claims 1, 2 or 3, characterized in that a compound of the formula (XV) - wherein Ar and R ₃ are as defined in any one of claims 1, 2 or 3; R ₄ , R ₅ and G _x are as defined in claim 4; and G ₂ is a protecting group for a hydroxy-functional group such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl, wherein the alkyl groups are C 1 -C 4 and the aryl groups are phenyl. An acid of formula III in the formula R ₃ is as defined in one of claims 1, 2 or 3 - esterified to a compound of formula (XVI) Ar, R _{lz R3, R4, R5,} G _l and G ₂ are as defined above - then G ₂ protecting group is selectively replaced by hydrogen in a compound of formula (XVII): - wherein Ar, R _1f R ₃ , R ₄ , R ₅ and G ₄ have the same meaning as described above, which is converted to a compound of formula XVIII by a trifluoromethanesulfonic acid derivative such as anhydride or N-phenyl trifluoromethanesulfonimide. in the formula Ar, R _lr R _3, R _4, R _5, and G ₄ are as defined above - is converted, wherein protecting groups R ₅ or R ₄ and R ₅ groups candidate replaced by hydrogen atoms to an (XIX) with a compound of the formula: - wherein Ar, R _lr R ₃ and G _x are as defined above - is obtained, which is reacted with an alkali metal halide, an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate, a 1, 2 or 3 claims A compound according to any one of claims 1 to 3 wherein R is acetyl, alkoxyacetyl or alkyl optionally converted into a compound according to any one of claims 1, 2 or 3 wherein R is hydrogen. A compound of formula (II) wherein Ar and R _x are as defined in any one of claims 1, 2 or 3; and R ₄ is hydrogen; and R ₅ is a hydroxy protecting group for a functional group, or R ₄ and R ₅ together form a saturated, five- or six-membered heterocyclic ring; G ₄ is a protecting group for alkanoyl, alkoxyacetyl or alkyl, or hydroxy. A novel compound according to claim 8 having the formula Ar and R _r are as defined in any one of claims 1, 2 or 3; and R ₄ is hydrogen; and _R5 is preferably a methoxymethyl, 1-ethoxyethyl, (benzyloxycarbonyl) methyl, trimethylsilyl, triethylsilyl, [β- (trimethylsilyl) ethoxy] methyl, or tetrahydropyranyl, and in the case where R ₄ and R _{5 taken} together form a heterocycle, which may be optionally substituted in the 2-position with a monosubstituted or geminal disubstituted oxazolidine ring; and G ₄ is a protecting group for an alkanoyl, alkoxyacetyl or alkyl group or a hydroxy function. 10. A process for the preparation of a compound according to claim 8 or 9, characterized in that a compound of the formula VIII: wherein Ar, R _x and R ₄ are the same as 1, 2, 3. or one of claims 5 to 5; and _R5 is as defined in claim 4 and in addition hydrogen; G ' ₄ is a protecting group for a hydrogen atom, an alkanoyl, an alkoxyacetyl or an alkyl group or a hydroxy-functional group - electrolytically reduced at a controlled voltage in a quaternary ammonium salt electrolyte soluble in an organic solvent or in a mixture of water and organic solvent. · · · 11. A pharmaceutical composition comprising at least one compound according to any one of claims 1, 2 or 3 together with one or more pharmaceutically acceptable inert or physiologically active substances.