WO1995013271A1 - Novel taxoids, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Novel taxoids of general formula (I), their preparation and pharmaceutical compositions containing them. In general formula (I), Ar is an aryl, alkyl, alkenyl, cycloalkyl or cycloalkenyl radical; R is a hydrogen atom or an alkanoyl, alkyloxyacetyl or alkyl radical; R1 is a benzoyl radical or a radical of formula R2-O-CO-, wherein R2 is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl, heterocyclyl radical and R3 is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted aryl (excepting non-substituted phenyl) or heterocyclyl radical. The novel products of general formula (I) have remarkable antitumor activity.

Description

 NEW TAXOIDS. THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS YES CONTAINING THEM

The present invention relates to new taxoids of general formula:

their preparation and the pharmaceutical compositions containing them. In the general formula (I), Ar represents an aryl radical, an alkyl containing 1 to 4 carbon atoms, an alkenyl containing 2 to 4 carbon atoms, a cycloalkyl containing 3 to 6 carbon atoms or a cycloalkenyl containing 3 to 6 carbon atoms, R represents a hydrogen atom or an alkanoyl, alkoxyacetyl or alkyl radical, Ri represents a benzoyl, thenoyl or furoyl radical or an R2-O-CO- radical in which R2 represents:

- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl of which the alkyl part contains 1 to 4 atom s of carbon,

- or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, - or a saturated or unsaturated heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and R3 represents - a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted in - 4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 atoms carbon), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms,

- or an optionally substituted aryl radical, it being understood that R3 cannot represent an unsubstituted phenyl radical, - or a saturated or unsaturated heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 atoms of carbon, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.

Preferably the aryl radicals represented by Ar and R3 are phenyl or α- or β-naphthyl radicals optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals , alkenyls, alkynyls, aryls, arylalkyls, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkyoyino, dialcoylamino, carboxyamcoyloxy , azido, trifluoromethoxy and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or α- or β-naphthyl radicals, and that the radical R3 cannot represent an unsubstituted phenyl radical.

Preferably, the heterocyclic radicals represented by Ar and R3 are aromatic heterocyclic radicals having 5 members and containing one or more atoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted by one or more substituents, identical or different, chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms carbon, aryloxy containing 6 to 10 carbon atoms, amino, alkylamino containing 1 to 4 carbon atoms, dialkoylamino in which each alkyl part contains 1 to 4 carbon atoms, acylamino in which the acyl part contains 1 to 4 carbon atoms, alkoxycarbonylamino containing 1 to 4 carbon atoms, acyl containing 1 to 4 carbon atoms, arylcarbonyl the aryl part of which contains 6 to 10 carbon atoms, cyano, carboxy, carbamo yl, alkylcarbamoyl in which the alkyl part contains 1 to 4 carbon atoms, dialkoylcarbamoyl in which each alkyl part contains 1 to 4 carbon atoms or alkoxycarbonyl in which the alkoxy part contains 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyls may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.

More particularly, Ar represents a phenyl, thienyl-2 or -3 or furyl-2 or -3 radical optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl, alkoxy radicals, amino, alkyllamino, dialcoylamino, acylamino, alkoxycarbonylamino and trifluoromethyl and R3 represents a phenyl radical substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialkoylamino radicals, acylamino, alkoxy¬ carbonylamino and trifluoromethyl.

More particularly still, Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom, or by an alkyl radical

(methyl), alkoxy (methoxy), dialkoylamino (dimethylamino), acylamino (acetylamino) or alkoxycarbonylamino (tert-butoxycarbonylamino) or thienyl-2 or -3 or furyl-2 or -3 and R3 represents a phenyl radical substituted by a halogen atom.

Of even more particular interest are the products of general formula (I) in which Ar represents a phenyl radical and R ^* represents a benzoyl radical or tert.butoxycarbonyl and R3 represents a phenyl radical substituted by a halogen atom.

According to the invention, the new taxoids of general formula (I) can be obtained by esterification of a product of general formula:

in which Ar and Ri are defined as above, and either R4 represents a hydrogen atom and R5 represents a protective group for the hydroxy function, or else R4 and R5 together form a 5 or 6-membered saturated heterocycle, G1 represents an alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl) or alkyl (methyl) radical or a protecting group for the hydroxy function by means of an acid of general formula:

R3-CO-OH (III) in which R3 is defined as above, or an activated derivative of this acid, to obtain a product of general formula:

OCOR ₃ in which Ar, Rj, R3, R4, R5 and

are defined as above, including the replacement of the protective groups R5, when R4 represents a hydrogen atom, or else R4 and R5, when R4 and R5 together form a saturated heterocycle with 5 or 6 members, and optionally

by hydrogen atoms leads to the product of general formula (I) optionally passing, according to the meanings of R-, R4 and R5, through a product of general formula:

in which Ar and R are defined as above, which is acylated by means of benzoyl chloride, thenoyl or furoyl or a product of general formula:

R ₂ -O-CO-X (VI) in which R2 is defined as above and X represents a halogen atom

(fluorine, chlorine) or a residue -O-R2 or -O-CO-O-R2.

When R4 represents a hydrogen atom, R5 preferably represents a methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, (β-trimetylsilylethoxy) methyl or tetrahydropyranyl radical. When R4 and R5 together form a heterocycle, the latter is preferably an oxazolidine ring optionally mono-substituted or gem-disubstituted in position -2.

Preferably, G represents an acetyl or alkyl radical or an alkoxyacetyl radical. The esterification of the product of general formula (II) can be carried out by reacting the acid of general formula (III) preferably in the form of halide, such as chloride, on the product of general formula (II) previously metallized . The metallation is generally carried out using an alkali metal alkyl such as butyllithium, operating in an inert organic solvent such as an ether such as tetrahydrofuran at a temperature below -50 ° C and, preferably in the vicinity of - 78 ° C. Esterification is generally carried out by operating at the same temperature in the same solvent.

According to the nature of the protective groups of the product of general formula

(IV), their replacement by hydrogen atoms can be carried out as follows:

1) when R4 represents a hydrogen atom, R5 is defined as above and G1 represents an alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl), alkyl (methyl) radical, the replacement of the protective groups by atoms of hydrogen can be carried out by treating the product of general formula (IV) with a mineral acid (hydrochloric acid, sulfuric acid, hydrofluoric acid) or organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p.toluenesulfonic acid) used alone or as a mixture, operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between -10 and 60 ° C.

2) when R4 and R5 together form a 5 or 6-membered saturated heterocycle and more particularly an oxazolidine ring of general formula:

in which R- is defined as above, R6 and R7, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical in which the alkyl part contains 1 to 4 carbon atoms and the aryl part preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical representing, preferably a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or R5 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R7 represents a hydrogen atom, or else Rg and R7 together with the carbon atom to which they are linked form a ring having 4 to 7 members, and Gi represents an r adical alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl) or alkyl (methyl), the replacement of the protective groups by hydrogen atoms can be carried out, according to the meanings of Rj, Rg and R7, as follows: a) when R * [represents a t.butoxycarbonyl radical, Rg and R7, identical or different, represent an alkyl radical or an aralkyl (benzyl) or aryl (phenyl) radical, or else Rg represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R7 represents a hydrogen atom, or else R and R7 together form a ring having 4 to 7 members, the treatment of a product of general formula (IV) with a mineral or organic acid optionally in an organic solvent such as an alcohol leads to a product of general formula (V) which is acylated by means of a product of general formula (VI). Preferably, the product of general formula (IV) is treated with formic acid at a temperature in the region of 20 ° C. Preferably, the acylation of the product of general formula (V) by means of a product of general formula (VI) is carried out in an inert organic solvent chosen from esters such as ethyl acetate, acetate d isopropyl or n.butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane in the presence of an inorganic base such as sodium bicarbonate or organic such as triethylamine. The reaction is carried out at a temperature between 0 and 50 ° C, preferably close to 20 ° C.

b) when Ri represents a benzoyl radical or an R2-O-CO- radical in which R2 is defined as above, Rg represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted by a or several alkoxy radicals containing 1 to 4 carbon atoms and R7 represents a hydrogen atom, the replacement of the protective groups by hydrogen atoms is carried out in the presence of a mineral acid (hydrochloric acid, sulfuric acid) or organic (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p.toluenesulfonic acid) used alone or as a mixture, operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature between -10 and 60 ° C, preferably between 15 and 30 ° C. The acid can be used in a catalytic or stoichiometric amount.

3) when Gi represents an alkoxyacetyl radical and R4 and R5 are defined as in point 1) above, the protective group R5 is replaced by a hydrogen atom first, operating under the acid conditions described in point 1 ) above, then optionally replaces the protective group G with a hydrogen atom by treatment in an alkaline medium or by the action of a zinc halide under conditions which do not affect the rest of the molecule. Generally, the alkaline treatment is carried out by the action of ammonia in a hydro-alcoholic medium or hydrazine in an alcoholic medium at a temperature in the region of 20 ° C. Generally, the treatment with a zinc halide, preferably zinc iodide, is carried out in methanol at a temperature in the region of 20 ° C. 4) when Gi represents an alkoxyacetyl radical and R4 and R5 are defined as in point 2-a) above, the protective group G ^* is optionally replaced by treatment in an alkaline medium or by treatment with a zinc halide in the conditions described in point 3) above, then treats the product of general formula (V) obtained under the acylation conditions described in point 2-a) above.

5) when G represents an alkoxyacetyl radical and R4 and R5 are defined as in point 2-b) above, the protective group G1 is optionally replaced by treatment in an alkaline medium or by treatment with a zinc halide under the conditions described in point 3) above, then treats the product obtained under the conditions described in point 2-b) above.

The products of general formula (II) can be obtained by electrolytic reduction of a product of general formula:

OCOC ₆ H ₅ in which Ar, Ri and R4 are defined as above, R5 is defined as above and may also represent a hydrogen atom, G'i represents a hydrogen atom or an alkanoyl (acetyl), alkoxyacetyl radical (methoxyacetyl) or alkyl (methyl) or a protecting group for the hydroxy function according to the following scheme:

' _f i6H ^π i5

it being understood that, when n is equal to 2, the cleavage product is benzaldehyde and, when n is equal to 4, the cleavage product is benzyl alcohol, followed optionally protection of the hydroxy functions defined by -OR5 and -O-G'i to obtain the product of general formula (II).

The electrolytic reduction from the product of general formula (VIII) is carried out in an electrolyser containing a support catholyte in which the product of general formula (VIII) is dissolved at a concentration of between 0.1 g / l and the saturation of the solution in product of general formula (Vϋl).

Preferably, the reduction is carried out in a diaphragm electrolyser.

According to one embodiment of the method according to the invention, the electrolytic reduction is carried out in an electrolyser comprising a cathode, a cathode compartment, a separating diaphragm, an anode compartment and an anode whose characteristics are the following: a) the cathode consists of a sheet of mercury, b) the cathode compartment contains the catholyte which consists of a solution of the product of general formula (VHI) in an organic medium, c) the separating diaphragm consists of a porous material such as a plate, a sleeve or a candle of sintered glass or porcelain or by an ion exchange membrane, preferably by a cation exchange membrane, d) the anode compartment contains the anolyte preferably consisting of the same solvent or mixture of solvents and the same support electrolyte as that which is used in the cathode compartment, e) the anode is constituted by a cond material electricity generator whose nature is not essential to the implementation of the process.

Generally, the anode consists of an electrically conductive material that cannot be attacked under the conditions of electrolysis, such as, for example, polished, solid or conductive platinum, graphite or vitreous carbon.

The support electrolyte consists of a quaternary ammonium salt such as tetraethylammonium acetate or tetraethylammonium tetrafluoroborate, or their mixtures soluble in the solvent or the mixture of solvents. Generally, solvents are used which readily dissolve the products of general formula (II) and (VIII) and which are not very resistant such as alcohols such as methanol, nitriles such as acetonitrile or amides such as dimethylformamide. The pH must be compatible with the stability of the substrate. The medium can be buffered by adding a weak acid such as acetic acid in equimolar concentration with quaternary ammonium acetate.

According to a preferred embodiment of the method, the anode, the cathode and the separating diaphragm are in horizontal parallel planes, the cathode consisting of a sheet of mercury.

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

The electrolysis is carried out at a controlled potential which can be between -1.90 and -2.10 volts with respect to a reference electrode saturated with calomel.

It is necessary to deaerate the solution by bubbling an inert gas such as argon for ten minutes before the start of electrolysis, the inert atmosphere being maintained for the duration of the electrolysis.

The product of general formula (VIII) can be obtained: 1) by the action of an alkali metal halide (sodium chloride, potassium fluoride) or an alkali metal azide (sodium azide) or a salt of quaternary ammonium or of an alkali metal phosphate on a product of general formula:

in which Ar, Ri, R4 and G'1 are defined as above and R5 is defined as above and can also represent a hydrogen atom.

Generally, the reaction is carried out in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl tbutyl ether) and nitriles (acetonitrile) alone or as a mixture at a temperature between 20 ° C. and the boiling temperature of the reaction mixture.

The product of general formula (IX) can be obtained by the action of a derivative of trifluoromethanesulfonic acid such as anhydride or N-phenyl trifluoromethanesulf onimide on a taxoid of general formula:

in which Ar, R, R4 and G'j are defined as above and R5 is defined as above

Generally, the reaction is 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 a temperature between -50 and + 20 ° C.

The taxoid of general formula (X), in which G'i represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical, can be obtained from a product of general formula:

in which Ar, R and R4 are defined as above, R5 is defined as above and G represents an acetyl, alkoxyacetyl or alkyl radical or a protecting group for the hydroxy function and G'2 represents a protecting group for the hydroxy function by replacing the protective groups G'2 and optionally G'1 by hydrogen atoms.

The radicals G ' _j and G'2, when they represent a group protecting the hydroxy function, are preferably 2,2,2-trichloroethoxycarbonyl, (2-trichloromethyl-propoxy) -2 carbonyl or trialkylsilyl radicals, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl in which the alkyl parts contain 1 to 4 carbon atoms and the aryl parts are preferably phenyl radicals.

When G'i and G'2 represent a 2,2,2-trichloroethoxycarbonyl or (2-trichloromethylpropoxy) -2 carbonyl radical, the replacement of the groups protective by hydrogen atoms is carried out by zinc, possibly associated with copper, in the presence of acetic acid at a temperature between 20 and 60 ° C or by means of a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n.butyl acetate in the presence of zinc optionally associated with copper.

When G'2 represents a silylated radical and G'j represents an alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl) or alkyl (methyl) radical, the replacement of the protective group G'2 by a hydrogen atom can be carried out by means of , for example, gaseous hydrochloric acid in ethanolic solution at a temperature close to 0 ° C or by the action of a hydrofluoric acid-triethylamine or hydrofluoric acid-pyridine complex in an organic solvent such as dichloromethane, tetrahydrofuran or acetonitrile at a temperature close to 20 ° C, under conditions which have no effect on the rest of the molecule.

When R4 and R5 together form an oxazolidine ring of general formula (VII) in which Rg represents a hydrogen atom and R7 represents a substituted phenyl radical, treatment in an acid medium results in a product of general formula (X) in which R4 and R5 each represents a hydrogen atom. It is then necessary to selectively protect the hydroxy function represented by -O-R5 in the product of general formula (X), preferably in the form of a silylated radical, before preparing the product of general formula (IX).

The product of general formula (XI) in which G'i represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical can be obtained under the conditions described in European patents EP 0 336 840 and EP 0 336 841 and in international application PCT / WO 9209589 by esterification of baccatin III or of 10-deacetyl baccatin III whose hydroxy functions at 7 and possibly -10 are protected, it being understood that to obtain a product of general formula (XI) in which G represents an alkoxyacetyl or alkyl radical, it is necessary to first treat the 10-deacetyl baccatin III protected at -7, preferably with a silylated radical, with an alkoxyacetic acid halide or with an alkyl halide.

Generally, the introduction of an alkoxyacetyl group is carried out by treating the 10-deacetyl baccatin III protected at -7 with an acid halide. alkoxyacetic by operating in a basic organic solvent such as pyridine at a temperature in the region of 20 ° C.

Generally the introduction of an alkyl radical is carried out by treating the 10-deacetyl baccatin III protected in -7 and metallized in -10, using for example an alkali hydride (sodium hydride) or a metal alkyl (butyllithium), by an alkyl halide.

2) by esterification of a product of general formula:

in which Gi is defined as above, by means of an acid of general formula:

Ru N '

Ar OH (XIII)

OR _fi in which Ar, R, R4 and R5 are defined as above, or a derivative of this acid.

Esterification using an acid of general formula (XIII) can be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridine) in an organic solvent (ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between -10 and 90 ° C.

Esterification can also be carried out using the acid of general formula (XIII) in the form of anhydride, operating in the presence of an activating agent (aminopyridine) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 90 ° C.

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

The product of general formula (XII) can be obtained by the action of an alkali metal halide (sodium chloride, potassium fluoride) or an alkali metal azide (sodium azide) or an ammonium salt quaternary or of an alkali metal phosphate on a product of general formula:

in which G1 is defined as above.

Generally the reaction is carried out in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl t.butyl ether) and nitriles (acetonitrile) alone or as a mixture at a temperature between 20 ° C. and the boiling temperature of the reaction mixture. . The product of formula (XIV) in which G1 represents a hydrogen atom or an alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl) or alkyl (methyl) radical can be obtained by the action of a derivative of trifluoromethanesulfonic acid such as that the anhydride or N-phenyltrifluoromethanesulfonimide on baccatin III or deacetyl-10 baccatin III, which can be extracted according to known methods from yew leaves (Taxus baccata), possibly followed by protection in position 10, it being understood that in order to obtain a product of general formula (XIV) in which G represents an alkoxyacetyl or alkyl radical, it is necessary to treat the 10-deacetyl-baccatin III protected in -7 beforehand, preferably with a silylated radical, with a halide of alkoxyacetic acid or with an alkyl halide.

Generally, the reaction of a derivative of trifluoromethanesulfonic acid is carried out in an inert organic solvent (aliphatic hydrocarbons optionally halogenated, aromatic hydrocarbons) in the presence of a base organic such as an aliphatic tertiary amine (triethylamine) or pyridine at a temperature between -50 and + 20 ° C.

Generally the introduction of an alkoxyacetyl group is carried out by treating the 10-deacetyl baccatin III protected in -7 with an alkoxyacetic acid halide by operating in a basic organic solvent such as pyridine at a temperature in the region of 20 ° C. .

Generally the introduction of an alkyl radical is carried out by treating the 10-deacetyl baccatin III protected in -7 and metallized in -10, using for example an alkali hydride (sodium hydride) or a metal alkyl (butyllithiu), with an alkyl halide.

According to the invention, the new products of general formula (I) can be obtained by esterification of a product of general formula:

in which Ar, Rj, R4, R5 and Gj are defined as above and G2 represents a protective group for the hydroxy function chosen, preferably from trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which the alkyl parts contain 1 to 4 atoms of carbon and the aryl parts are preferably phenyl radicals, using an acid of general formula (III), to obtain a product of general formula:

in which Ar, R- ^* _, R3, R4, R5, G1 and G2 are defined as above, the protective group G2 of which is selectively replaced by a hydrogen atom, to obtain a product of general formula:

in which Ar, Ri, R3, R4, R5 and G are defined as above, which, by the action of a derivative of trifluoromethanesulfonic acid, such as anhydride or N-phenyl trifluoromethanesulfonimide, is transformed into a product of formula general:

(XVIII)

in which Ar, Ri, R3, R4, R5 and Gj are defined as above, in which the protective groups represented by R5 or by R4 and R5 are replaced by hydrogen atoms to give a product of general formula:

in which Ar, Ri, R3 and G1 are defined as above, which, by the action of an alkali metal halide (sodium chloride, potassium fluoride, sodium chloride) or an alkali metal azide (sodium azide ) or a quaternary ammonium salt or an alkali metal phosphate, leads to the product of general formula (I) in which R represents an acetyl, alkoxyacetyl or alkyl radical which can be transformed into a product of general formula (I ) in which R represents a hydrogen atom.

The esterification of a product of general formula (XV) using an acid of general formula (III) is carried out under the conditions described above for the esterification of a product of general formula (II) using an acid of general formula (III).

The replacement of the protective group G2 with a hydrogen atom is generally carried out by treating the product of general formula (XVI) with hydrofluoric acid or trifluoroacetic acid in the presence of an organic base such as pyridine or an amine aliphatic tertiary such as triethylamine by operating in an organic solvent such as an ether (tetrahydrofuran) or a nitrile (acetonitrile).

The transformation of a product of general formula (XVII) into a product of general formula (XVIII) is carried out under the conditions described above to prepare the product of general formula (IX) from the product of general formula

(X).

The replacement of the protective groups represented by R5 or by R4 and R5 is carried out under the conditions described above for the replacement of the protective groups of the product of general formula (IV). The transformation of a product of general formula (XIX) into a product of general formula (I), in which R represents an alkanoyl, alkoxyacetyl or alkyl radical, is carried out under the conditions described above for the transformation of a product of general formula (IX) as a product of general formula

(VIII). The optional replacement of the radical R of the product of general formula (I), in which R represents an alkanoyl, alkoxyacetyl or alkyl radical, by a hydrogen atom can be carried out under the conditions described above for the replacement of the protective groups of a product of general formula (IV) by hydrogen atoms. The product of general formula (XV) can be obtained under the conditions described in international PCT application WO 94/20484.

The new products of general formula (I) obtained by implementing the methods according to the invention can be purified according to known methods such as crystallization or chromatography. The products of general formula (I) have remarkable biological properties.

In vitro, the measurement of the biological activity is carried out on the tubulin extracted from pig brain by the method of M.L. Shelanski et al., Proc. Natl.

Acad. Sci. USA, 7J), 765-768 (1973). The study of the depolymerization of microtubules into tubulin is carried out according to the method of G. Chauvière et al., CR Acad. Sci., 293, Series II, 501-503 (1981). In this study, the products of general formula (I) were shown to be at least as active as taxol and Taxotere.

In vivo, the products of general formula (I) have been shown to be active in mice grafted with melanoma B16 at doses between 1 and 10 mg / kg intraperitoneally, as well as on other liquid or solid tumors.

The new products show activity on tumors that are resistant to Taxol® or Taxotère®. Such tumors include colon tumors which have high expression of the mdr 1 gene (multi-drug resistance gene). Multi-drug resistance is a common term referring to the resistance of a tumor to different products with different structures and mechanisms of action. Taxoids are generally known to be highly recognized by experimental tumors such as P388 / DOX, a cell line selected for its resistance to doxorubicin (DOX) and which expresses mdr 1.

The following examples illustrate the present invention.

EXAMPLE 1

To a solution of 91.5 mg of amino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) of diacetoxy-4α, 10β (fluoro-4 benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ methylene- 7β, 8β oxo-9 nor-19 taxene-11 yle-13α in 0.2 cm3 of dichloromethane, maintained under an argon atmosphere, 12.5 mg of sodium hydrogencarbonate are added and then, drop by drop, at a temperature close to 20 ° C, a solution of 32 mg of di-t.butyl dicarbonate in 0.1 cm3 of dichloromethane. The solution obtained is stirred for 22 hours at a temperature in the region of 20 ° C. and then added with a mixture of 0.5 cm3 of distilled water and 5 cm3 of dichloromethane. The aqueous phase is extracted with 0.5 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 99.2 mg of a yellow meringue are thus obtained which is purified by preparative chromatography on 6 thin-layer silica plates (Kieselgel 60F254, Merck) 0.25 mm thick, eluting twice with a methanol mixture - dichloromethane (2-98 by volume). After elution of the zone corresponding to the desired product with a methanol-dichloromethane mixture (10-90 by volume) then evaporation under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 32.7 mg of t are obtained .butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) diacetoxy-4α, 10β (4-fluoro benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ methylene-7β, 8β oxo-9 nor-19 taxene-11 yle-13α in the form of a white meringue, the characteristics of which are as follows:

- proton nuclear magnetic resonance spectrum (400 MHz; CDCI3; chemical shifts in ppm): 1.28 (s, 3H: -CH3 in 16 or 17); 1.30 s, 9H: - C (CH ₃ ) ₃ ]; 1.37 (mt, 1H: -H at 7); 1.58 (s, 3H: -CH ₃ in 16 or 17) 1.68 and 2.25 (t and m, 1H each: CH2 of cyclopropane); 1.87 (s, 3H: -CH3 at 18); 2.12 and 2.47 (d and td, 1H each: -CH ₂ in 6); 2.22 (s, 3H: -COCH3 in 10); 2.22 and 2.40 (m, 1H each: -CH.2 in 14); 2.38 (s, 3H: -COCH ^ in 4); 3.26 (broad s, 1H: -OH in 2 ') 4.05 and 4.30 (d, 1H each: -CH ₂ - in 20); 4.10 (d, 1H: -H at 3); 4.64 (broad s, 1H -H in 2 '); 4.75 (d, 1H -H in 5); 5.30 (d, large, 1H: -H_ in 3 '); 5.31 (d, 1H -CONH-); 5.65 (d, 1h: -H in 2); 6.29 (broad t, 1H: -H at 13); 6.32 (s, 1H: -H in 10); 7.20 [t, 2H: -OCOCgH ₄ F (-H in 3 and -H in 5)]; from 7.30 to 7.45 (mt, 5H: CgH ₅ in 3 '); 8.19 [dd, 2H: -OCOCgH F (-H in 2 and -H in 6).

Amino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) diacetoxy-4α, 10β (fluoro-4 benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ methylene-7β, 8β oxo-9 nor- 19 taxene-11 yle-13α can be prepared as follows:

A solution of 130 mg of t.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) of diacetoxy-4α, 10β (fluoro-4 benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ methylene-7β, 8β oxo-9 nor-19 taxene-11 yle-13 in 1.3 cm3 of formic acid is stirred for 2 hours at a temperature in the region of 20 ° C and then concentrated to dryness under reduced pressure (0.27 kPa) at 30 ° C. The white meringue obtained is purified directly by chromatography at atmospheric pressure on 40 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol-dichloromethane mixture (elution gradient of 2.5-97.5 to 5-95 by volume), the fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. 91.5 mg of 3-amino-2-hydroxy-3-phenylpropionate- (2R, 3S) diacetoxy-4α, 10β (4-fluoro-benzoyloxy) -2α epoxy-5β, 20 hydroxy-1β methylene-7β are thus obtained. , 8β oxo-9 nor-19 taxene-11 yle-13α in the form of a white meringue. T.butoxycarbonyl-3 dimethyl-2,2 ρhenyl-4 oxazolidinecarboxylate-5-

(4R.5S) of 4-diacetoxy, 10β (4-fluoro-benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ methylene-7β, 8β oxo-9 nor-19 taxene-11 yle-13α can be prepared in the manner next :

To a solution of 190 mg of t.butoxycarbonyl-3 dimethyl-2,2-phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) of diacetoxy-4, 10β epoxy-5β, 20 dihydroxy-lβ, 2α methylene-7β, 8β oxo-9 nor-19 taxene-11 yle-13α in 4 cm3 of anhydrous tetrahydrofuran, maintained under an argon atmosphere, 0.38 cm3 d is successively added, at a temperature close to -78 ° C. '' a 1.3 M solution of n-butyllithium in hexane then 0.0585 cm3 of 4-fluoro benzoyl chloride. The solution is stirred for 45 minutes at a temperature in the region of -78 ° C. and then 0.38 cm3 of a 1.3 M solution of n.butyllithium in hexane and then 0.0585 are successively added at the same temperature. cm3 of 4-fluoro benzoyl chloride. The solution is stirred for 35 minutes at a temperature in the region of -78 ° C. and then 1 cm 3 of a saturated aqueous solution of ammonium chloride is added. The reaction mixture is brought to a temperature in the region of 20 ° C. in 15 minutes. After decantation, the aqueous phase is extracted with 2 times 1 cm 3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 245 mg of a yellow oil are thus obtained which is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol-dichloromethane mixture. (elution gradient from 0.5-99.5 to 2.5-97.5 by volume). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. This gives 130 mg of t.butoxycarbonyl-3 dimethyl-2,2-phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) of diacetoxy-4, 10β (fluoro-4 benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ methylene-7β, 8β oxo-9 nor-19 taxene-11 yle-13 in the form of a white meringue.

T.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R.5S) of diacetoxy-4α, 10β epoxy-5β, 20 dihydroxy-lβ, 2α methylene-7β, 8β oxo-9 nor-19 taxene-11 yle-13α could be prepared as follows: The electrochemical reduction of tbutoxycarbonyl-3 dimethyl- is carried out

2,2-phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) of diacetoxy-4, 10β benzoyloxy-2α epoxy-5β, 20 hydroxy-lβ methylene-7β, 8β oxo-9 nor-19 taxene-11 yle-13α in an electrolysis cell with the following characteristics:

- the cell is a 100 cm3 glass vase divided into 2 compartments by a cation exchange membrane,

- the cathode is a sheet of mercury whose useful surface is approximately 4 cm2,

- the anode is a platinum grid,

- the reference electrode is a saturated calomel electrode. In the cathode compartment, 10 cm 3 of a solution containing:

- t.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) diacetoxy-4α, 10β benzoyloxy-2α epoxy-5β, 20 hydroxy-lβ methylene-7β, 8β oxo-9 nor- 19 taxene-11 yle-13 27.3 mg

- tetraethylammonium tetrafluoroborate q.s.p. 0.15 M / l

- tetraethylammonium acetate q.s.p. 0.05 MA

In the anode compartment, 10 cm 3 of a 0.1 M aqueous sulfuric acid solution are introduced.

After deaeration of the solution for 10 minutes by bubbling a stream of argon which is maintained throughout the duration of the electrolysis, the potential of the cathode is fixed at -1.95 volts relative to the reference electrode . The solution is electrolysed for 54 minutes, that is to say the time necessary for the passage of 100 coulombs. After concentration to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 35 ° C, the residue is taken up in 10 cm3 of ethyl acetate and 10 cm3 of distilled water. After extraction and decantation, the aqueous phase is extracted twice with 5 cm3 of ethyl acetate. The organic phases are combined, washed with 10 cm3 of 0.2 m aqueous phosphate buffer (pH = 7), dried over magnesium sulfate, filtered and then concentrated to dec under reduced pressure. 24 mg of a pale yellow merngue are thus obtained which is purified by preparative chromatography on 4 thin layer silica plates (Kieselgel 60F254, Merck; thickness 0.25 mm), eluting with a methanol-acetonitrile-dichloromethane mixture (5- 5-90 by volume). After identification under UV (254 nm) and elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (1-1 by volume) then evaporation under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 9.6 mg of t.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) of diacetoxy-4α, 10β epoxy-5β, 20 dihydroxy-lβ, 2α methylene-7β, 8β are obtained. oxo-9 nor-19 taxene- 11 y le- 13α in the form of a white meringue.

T.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) diacetoxy-4α, 10β benzoyloxy-2α epoxy-5β, 20 hydroxy-lβ methylene- 7β, 8β oxo-9 nor- 19 taxene-11 yle-13α can be prepared as follows:

To a solution of 1.8 g of t.butoxycarbonyl-3 dimethyl-2,2-phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) of diacetoxy-4, 10β benzoyloxy-2α epoxy-5β, 20 hydroxy-lβ oxo-9 trifluoromethanesulfonate-7β taxene-11 yle-13 in 20 cm3 of anhydrous acetonitrile and 4 cm3 of anhydrous tetrahydrofuran, maintained under an argon atmosphere, 4 g of sodium chloride and 300 mg of molecular sieve are added 4A activated powder. The reaction mixture is heated for 2 hours with stirring and under an argon atmosphere, at a temperature in the region of 80 ° C, then cooled to a temperature in the region of 20 ° C and filtered through sintered glass lined with celite. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 4.9 g of an orange-brown residue are thus obtained which is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.2 mm) contained in a column 4.5 cm in diameter, eluting with a ethyl acetate-dichloromethane mixture (elution gradient from 0-100 to 10-90 by volume). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. 1.35 g of t.butoxycarbonyl-3-dimethyl-2,2-phenyl-4-oxazolidinecarboxylate-5- (4R, 5S) of diacetoxy-4, 10β-benzoyloxy-2 epoxy-5β, 20 hydroxy-lβ methylene-7β are thus obtained. , 8β oxo-9 nor-19 taxene-11 yle-13α in the form of a white meringue.

T.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R.5S) of diacetoxy-4, 10β benzoyloxy-2 epoxy-5β, 20 hydroxy-lβ oxo-9 trifluoromethanesulfonate-7β taxene-11 yle -13α can be prepared as follows:

To a solution of 3.85 g of t.butoxycarbonyl-3 dimethyl-2,2-phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) of diacetoxy-4α, 10β benzoyloxy-2α epoxy-5β, 20 dihydroxy-lβ, 7β oxo-9 taxene-11 yl-13 in 40 cm3 of anhydrous dichloromethane, maintained under an argon atmosphere, 1.3 cm3 of pyridine and 100 mg of activated 4Â molecular sieve powder are added. The reaction mixture is cooled to a temperature in the region of -30 ° C. 1.2 cm 3 of trifluoromethanesulfonic anhydride are added slowly, the mixture being stirred at a temperature in the region of 0 ° C for 1 hour. It is again cooled to a temperature in the region of -30 ° C and then 1.2 cm3 of trifluoromethanesulfonic anhydride are added, the mixture is stirred at a temperature of 0 ° C for 1 hour and 10 cm3 of distilled water are added. The reaction mixture is brought to a temperature in the region of 20 ° C, filtered through sintered glass lined with celite. The sintered glass is rinsed with 50 cm3 of an ethyl acetate-dichloromethane mixture (1-1 by volume). The aqueous phase is separated by decantation and then extracted with 10 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. We 4.39 g of a yellow solid is thus obtained which is purified by chromatography at atmospheric pressure on 350 g of silica (0.063-0.2 mm) contained in a column 4.5 cm in diameter, eluting with an acetate mixture of 'ethyl-dichloromethane (elution gradient from 0-100 to 5-95 by volume). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. 4.07 g of tbutoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazoli- dinecarboxylate-5- (4R, 5S) of diacetoxy-4α, 10β benzoyloxy-2α epoxy-5β, 20 hydroxy-lβ oxo-9 are thus obtained trifluoromethanesulfonate-7β taxene-11 yle-13α in the form of a white meringue.

T.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5-

(4R.5S) of diacetoxy-4α, 10β benzoyloxy-2α epoxy-5β, 20 dihydroxy-lβ, 7β oxo-9 taxene-11 yle-13α can be prepared under the conditions described in international PCT application WO 9209589.

EXAMPLE 2 To a solution of 500 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylic-5- (2R, 4S, 5R) of acetoxy-4α dihydroxy-lβ, 2α epoxy-5β, 20 methoxyacetoxy-10β oxo-9 triethylsilyloxy-7β taxene-11 yle-13α in 7 cm3 of tetrahydrofuran maintained under stirring and under an argon atmosphere, successively added at a temperature in the region of -78 ° C, 0.9 cm3 of a 1.4 M solution of n-butyllithium in hexane and 279 mg of 3-benzoyl trifluoromethoxy chloride. The solution is thus kept stirred for 45 minutes and then 10 cm 3 of a saturated aqueous ammonium chloride solution are added. The reaction medium is brought to a temperature in the region of 20 ° C in 1 hour. The solution obtained is poured into a mixture of 50 cm3 of ethyl acetate and 50 cm3 of a saturated aqueous solution of ammonium chloride. The aqueous phase is separated by decantation and then extracted with 2 times 50 cm3 of ethyl acetate. The organic phases are combined, washed with 50 cm3 of distilled water and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 620 mg of a white meringue are obtained which is purified by chromatography on 200 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter [eluent: ethyl acetate- cyclohexane (10- 90 by volume)] by collecting fractions of 30 cm3. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 244 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylic-5 (2R, 4S, 5R) of 4-acetoxy are obtained. epoxy-5β, 20 hydroxy-lβ methoxyacetoxy-10β oxo-9 triethylsilyloxy-7β (trifluoromethoxy-3 benzoyloxy) -2α taxene-11 yle-13α in the form of a white meringue and the characteristics of which are as follows:

- proton NMR spectrum (400 MHz; CDCI3; δ in ppm): 0.59 (q, J = 7.5 Hz, 6 H: SiCH ₂ ethyl); 0.94 (t, J = 7.5 Hz, 9H: ethyl CH3); 1.08 (s, 9H: (CH ₃ ) ₃ ); 1.19 (s, 3H: CH ₃ ); 1.21 (s, 3H: CH3); 1.62 (s, 1H: OH in 1); 1.67 (s, 3H: CH3); 1.70 (s, 3H: CH3); 1.83 (s, 3H: COCH3); 1.85 and 2.50 (2 mts, 1 H each: CH ₂ in 6); 2.08 and 2.19 (2 dd, J = 16 and 9 Hz, 1 H each: CH ₂ at 14); 3.53 (s, 3H: OCH3); 3.73 (d, J = 7 Hz, 1 H: H at 3); 3.84 (s, 3H: ArOCH3); 4.07 and 4.22 (2 d, J = 8.5 Hz, 1 H each: CH ₂ in 20); 4.18 (limit AB, J = 16 Hz, 2H: OCOCH ₂ O); 4.43 (dd, J = 11 and 6.5 Hz, 1H: H at 7); 4.58 (d, J = 5 Hz, 1H: H in 2 '); 4.87 (broad d, J = 10 Hz, 1 H: H at 5); 5.43 (mt, 1H: H at 3 '); 5.62 (d, J = 7 Hz, 1H: H in 2); 6.07 (wide t, J = 9 Hz, 1H: H at 13); 6.40 (mt, 1H: H in 5 '); 6.46 (s, 1H: H at 10); 6.93 (d, J = 8 Hz, 2H: aromatic H in ortho of OCH3); from 7.30 to 7.50 (mt, 7H: aromatic H and aromatic H in meta of OCH3); 7.49 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 7.53 (t, J = 7.5 Hz, 1H: H in 5 of the aromatic in 2); 7.90 (broad s, 1H: H in 2 of the aromatic in 2); 7.99 (d, J = 7.5 Hz, IH: H in 6 of the aromatic in 2).

To a solution of 240 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylic-5- (2R, 4S, 5R) of acetoxy-4 epoxy-5β, 20 hydroxy -lβ methoxyacetoxy-lOβ oxo-9 triethylsilyloxy-7β (trifluoromethoxy-3 benzoyloxy) -2α taxene-11 yl-13 in 4 cm3 of dichloromethane, 3.3 cm3 of triethylamine complex is added at a temperature close to 20 ° C. -hydrofluoric acid. The reaction mixture is stirred for 4 hours at a temperature in the region of 20 ° C., then 10 cm 3 of dichloromethane and 50 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate are added. The organic phase is decanted, washed with 2 times 50 cm3 of a saturated aqueous solution of sodium chloride then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 205 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylic-5- (2R, 4S, 5R) of acetoxy-4α dihydroxy-lβ, 7β epoxy-5β are obtained. , 20 methoxyacetoxy-10β oxo-9 (3-trifluoromethoxy-benzoyloxy) -2α taxene-11 yle-13 in the form of a white meringue and the characteristics of which are as follows: - NMR spectrum of the proton (400 MHz, CDCI3 , δ in ppm): 1.06 (s, 9H: ^ 3) 3); 1.24 (s, 3H: CH ₃ ); 1.28 (s, 3H: CH3); 1.56 (s, 3H: CH ₃ ); 1.65 (s, 3H: CH ₃ ); 1.85 (s, 3H: COCH3); 1.85 and 2.53 (2 mts, 1 H each: CH ₂ in 6); 2.08 and 2.21 (2 dd, J = 16 and 9 Hz, 1 H each: CH ₂ at 14); 2.35 (mf, 1H: OH in 1); 3.53 (s, 3H: OCH3); 3.72 (d, J = 7 Hz, 1 H: H at 3); 3.83 (s, 3H: A1-OCH3); 4.08 and 4.22 (2 d, J = 8.5 Hz, 1 H each: CH2 in 20); 4.25 (limit AB, J = 16 Hz, 2H: OCOCH2O); 4.37 (dd, J = 11 and 8 Hz, 1H: H at 7); 4.58 (d, J = 5 Hz, 1H: H in 2 '); 4.90 (broad d, J = 10 Hz, 1 H: H at 5); 5.43 (mt, 1H: H at 3 '); 5.62 (d, J = 7 Hz, 1H: H in 2); 6.13 (broad t, J = 9 Hz, 1 H: H at 13); 6.31 (s, 1H: H at 10); 6.39 (mt, 1H: H in 5 "); 6.93 (d, J = 8 Hz, 2H: aromatic H in OCH3 ortho); from 7.30 to 7.50 (mt, 7H: aromatic H and H aromatic in meta of OCH3); 7.49 (broad d, J = 7.5 Hz, IH: H in 4 of aromatic in 2); 7.54 (t, J = 7.5 Hz, IH : H in 5 of aromatic in 2); 7.88 (broad s, IH: H in 2 of aromatic in 2); 7.98 (d, J = 7.5 Hz, IH: H in 6 aromatic in 2).

To a solution of 200 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylic-5- (2R, 4S, 5R) of acetoxy-4α dihydroxy-lβ, 7β epoxy -5β, 20 methoxyacetoxy-10β oxo-9 (3-trifluoromethoxy benzoyloxy) -2 taxene-11 yl-13α in 3 cm3 of anhydrous dichloromethane and 0.120 cm3 of pyridine, maintained under an argon atmosphere, at a temperature close to 0 ° C, 0.125 cm3 of trifluoromethanesulfonic anhydride is added dropwise. The orange solution obtained is stirred for 20 minutes at a temperature in the region of 0 ° C., then 3 cm3 of water and 30 cm3 of dichloromethane are added. The organic phase is decanted, washed with 2 times 20 cm3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 233 mg is obtained which is purified by chromatography on 200 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter [eluent: dichloromethane-methanol (98-2 by volume)] by collecting fractions of 10 cm3. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 192 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylic-5- (2R.4S.5R) of acetoxy-4α epoxy-5β, 20 hydroxy-lβ are obtained. methoxyacetoxy-10β oxo-9 trifluoromethanesulfonyloxy-7β (3-trifluoromethoxy benzoyloxy) -2 taxene-11 yl- 13α in the form of a white meringue and the characteristics of which are as follows: - NMR spectrum of the proton (400 MHz, CDCI3, δ in ppm): 1.07 (s, 9H: ^ 3) 3); 1.18 (s, 3H: CH ₃ ); 1.20 (s, 3H: CH3); 1.65 (s, 1H: OH in 1); 1.72 (s, 3H: CH3); 1.84 (s, 3H: CH3); 1.92 (s, 3H: COCH3); 2.07 and 2.10 to 2.25 (respectively dd (J = 16 and 9 Hz) and mt, 1H each: CH2 at 14); from 2.10 to 2.25 and 2.83 (2 mts, 1 H each: CH in 6); 3.52 (s, 3H: OCH3); 3.83 (s, 3H: ArOCH ₃ ); 3.85 (mt, 1H: H in 3); 4.08 and 4.26 (2 d, J = 8.5 Hz, 1 H each: CH ₂ in 20); 4.14 and 4.22 (2 d, J = 16 Hz, 2H: OCOCH ₂ O); 4.56 (d, J = 5 Hz, 1H: H in 2 '); 4.86 (broad d, J = 10 Hz, 1 H: H at 5); 5.43 (dd, J = 11 and 8 Hz, 1H: H at 7); 5.46 (mt, 1H: H in 3 '); 5.66 (d, J = 7 Hz, 1H: H in 2); 6.06 (wide t, J = 9 Hz, 1 H: H at 13); 6.40 (mt, 1H: H in 5 '); 6.63 (s, 1H: H at 10); 6.93 (d, J = 8 Hz, 2H: aromatic H in ortho of OCH3); from 7.30 to 7.50 (mt, 7H: aromatic H and aromatic H in meta of OCH3); 7.50 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 7.56 (t, J = 7.5 Hz, 1H: H in 5 of the aromatic in 2); 7.89 (broad s, 1H: H in 2 of the aromatic in 2); 7.99 (d, J = 7.5 Hz, IH: H in 6 of the aromatic in 2). A solution of 190 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 4-phenyl-oxazolidine-1,3 carboxylic-5- (2R, 4S, 5R) -acetoxy-4α epoxy-5β, 20 hydroxy-lβ methoxyacetoxy-10β oxo-9 trifluoromethanesulfonyloxy-7β (trifluoromethoxy-3 benzoyloxy) -2 taxene-11 yl-13α in 3.2 cm3 of a 0.1N solution of hydrochloric ethanol is kept under stirring a temperature close to 20 ° C for 20 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The crude product obtained is dissolved in 50 cm3 of dichloromethane and 50 cm3 of a saturated aqueous solution of sodium bicarbonate. The organic phase is separated by decantation and then extracted with 2 times 50 cm3 of dichloromethane. The organic phases are combined, washed with 50 cm3 of distilled water and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 175 mg of a white meringue are obtained which are purified by preparative chromatography on a 0.5 mm thick silica plate [eluent: dichloromethane-methanol (94-6 by volume)]. 66 mg of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) of acetoxy-4α epoxy-5β, 20 hydroxy-lβ methoxyacetoxy-10O oxo-9 trifluoromethanesulfonyloxy-7β (trifluoromethoxy-3 benzoyloxy) are obtained. ) -2α taxene-11 yle-13α in the form of a white meringue and the characteristics of which are as follows:

- Proton NMR spectrum (400 MHz, CDCI3, δ in ppm): 1.22 (s, 3H: CH3); 1.26 (s, 3H: CH3); 1.37 (s, 9H: (CH ₃ ) ₃ ); 1.72 (s, 1H: OH in 1); 1.91 (s, 3H: CH3); 2.07 (s, 3H: CH3); 2.26 and 2.89 (2 mts, 1H each: CH2 in 6); 2.36 (mt, 2H: CH, at 14); 2.37 (s, 3H: COCH3); 3.36 (d, J = 5 Hz, 1H: OH in 2 '); 3.54 (s, 3H: OCH3); 3.97 (d, J = 7.5 Hz, 1H: H at 3); 4.16 and 4.26 (2 d, J = 16 Hz, 2H: OCOCH ₂ O); 4.17 and 4.34 (2 d, J = 8.5 Hz, 1 H each: CH ₂ in 20); 4.62 (broad d, J = 5 Hz, 1H: H in 2 '); 4.94 (broad d, J = 10 Hz, 1 H: H at 5); 5.24 (broad d, J = 10 Hz, 1H: H in 3 '); 5.36 (d, J = 10 Hz, 1 H: CONH); 5.49 (dd, J = 11 and 8 Hz, IH: H in 7); 5.73 (d, J = 7 Hz, 1H: H in 2); 6.17 (broad t, J = 9 Hz, 1H: H at 13); 6.73 (s, 1H: H at 10); from 7.30 to 7.50 (mt, 5H: aromatic H); 7.50 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 7.57 (t, J = 7.5 Hz, 1H: H in 5 of the aromatic in 2); 7.99 (broad s, 1H: H in 2 of the aromatic in 2); 8.07 (d, J = 7.5 Hz, 1H: H in 6 of the aromatic in 2).

To a solution of 66 mg of tert-butoxycarbonylamino-3 hydroxy-2 ρhenyl-3 ρroρionate- (2R, 3S) of acetoxy-4α hydroxy-lβ epoxy-5β, 20 methoxyacetoxy-lOβ oxo-9 trifluoromethanesulfonyloxy-7β (trifluoromethoxy- 3 benzoyloxy) -2α taxene-11 yle-13α in 0.855 cm3 of acetonitrile and 0.085 cm3 of tetrahydrofuran, 200 mg of powdered 4Â molecular sieve and 100 mg of sodium chloride are successively added. The reaction mixture is kept stirring at a temperature in the region of 75 ° C for 5 hours and then, at a temperature in the region of 20 ° C, supplemented with 75 cm3 of dichloromethane and 50 cm3 of a saturated aqueous solution of sodium chloride. The organic phase is decanted, washed with 2 times 40 cm3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 110 mg is obtained which is purified by preparative chromatography on a 0.5 mm thick silica plate, eluting with a cyclohexane-ethyl acetate mixture (1-1 by volume). 30 mg of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-4 propionate- (2R, 3S) of acetoxy-4α hydroxy-lβ epoxy-5β, 20 methoxyacetoxy-10O methylene-7β, 8 nor-19 oxo-9 are obtained. (3-benzoyloxy trifluoromethoxy) -2α taxene-11 yle-13α and the characteristics of which are as follows:

- Proton NMR spectrum (400 MHz, CDCI3, δ in ppm): 1.22 (s, 3H: CH3); 1.25 (s, 3H: CH3); 1.28 (s, 9H: (CH ₃ ) ₃ ); 1.38 (mt, 1H: H at 7); 1.65 and 2.25 (2 mts, 1 H each: CH2 in 19); 1.80 (s, 1H: OH in 1); 1.85 (s, 3H: CH3); 2.09 and 2.45 (respectively d and dt, J = 16 Hz and J = 16 and 4 Hz, 1 H each: CH2 in 6); 2.32 (mt, 2H: CH ₂ at 14); 2.32 (s, 3H: COCH3); 3.28 (mf, 1H: H in 2 '); 3.49 (s, 3H: OCH3); 4.00 and 4.27 (2 d, J = 8.5 Hz, 1 H each: CH ₂ in 20); 4.08 (d, J = 7.5 Hz, 1 H: H at 3); 4.18 (limit AB, J = 16 Hz, 2H: OCOCH ₂ O); 4.57 (broad s, 1H: H in 2 '); 4.72 (broad d, J = 4 Hz, 1 H: H at 5); 5.21 (broad d, J = 10 Hz, 1 H: H in 3 '); 5.30 (d, J = 10, 1H: CONH); 5.62 (d, J = 7 Hz, 1H: H in 2); 6.19 (broad t, J = 9 Hz, 1 H: H at 13); 6.39 (s, 1H: H at 10); from 7.25 to 7.50 (mt, 5H: H aromatics); 7.44 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 7.55 (t, J = 7.5 Hz, 1H: H in 5 of the aromatic in 2); 7.99 (broad s, 1H: H in 2 of the aromatic in 2); 8.08 (d, J = 7.5 Hz, 1H: H in 6 of the aromatic in 2). EXAMPLE 3

A mixture of 300 mg of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α (3-chloro benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ methoxyacetoxy-lOβ oxo- 9 trifluoromethanesulfonyloxy-7β taxene-11 yle-13α, 500 mg of sodium chloride and 100 mg of activated 4Â molecular sieve, in 3 cm3 of acetonitrile and 0.6 cm3 of tetrahydrofuran is heated under reflux for 3 hours. After cooling to a temperature in the region of 20 ° C, the mixture is filtered through a sintered vere garnished with celite. The filtrate is washed with 5 cm3 of water, then the organic phase is decanted, dried over magnesium sulfate. After filtration on sintered glass and concentration under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 410 mg of a pale yellow meringue is obtained which is purified by preparative thin layer chromatography [12 plates Merck preparations, Kieselgel 60F254; 0.25 mm thick; deposition in solution in dichloromethane; eluent: methanol-dichloromethane mixture (7-93 by volume)]. After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (10-90 by volume), filtration through sintered glass, then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 136.8 mg of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α (3-chloro-benzoyloxy) -2 epoxy-5β, 20 hydroxy-lβ methoxyacetoxy-lOβ methylene are obtained. - 7.8β oxo-9 nor-19 taxene-11 yle-13α in the form of a white meringue, the characteristics of which are as follows:. - Proton NMR spectrum (400 MHz; CDCI3 _; δ in ppm): 1.22 (s, 6H: CH3);

1.26 (s, 9H: (CH ₃ ) ₃ ); 1.37 (mt, 1H: H at 7); 1.67 and 2.34 (2 mts, 1 H each: CH ₂ in 19); 1.78 (s, 1H: OH in 1); 1.85 (s, 3H: CH3); 2.10 and 2.44 (respectively d and dt, J = 16 Hz and J = 16 and 4 Hz, 1 H each: CH2 in 6); 2.23 (mt, 2H: CH2 at 14); 2.34 (s, 3H: COCH3); 3.26 (mt, 1H: OH in 2 '); 3.49 (s, 3H: OCH3); 3.98 and

4.27 (2 d, J = 8.5 Hz, 1 H each: CH ₂ in 20); 4.07 (d, J = 7.5 Hz, 1 H: H at 3); 4.15 and 4.22 (2 d, J = 16 Hz, 2H: OCOCH ₂ O); 4.57 (mt, 1H: H in 2 '); 4.73 (broad d, J = 4 Hz, 1 H: H at 5); 5.22 (broad d, J = 10 Hz, 1H: H in 3 '); 5.30 (d, J = 10 Hz, 1 H: CONH); 5.60 (d, J = 7 Hz, 1H: H in 2); 6.20 (broad t, J = 9 Hz, 1 H: H at 13); 6.40 (s, 1H: H 10); 7.20 to 7.50 (mt, 5H: aromatic H); 7.44 (t, J = 7.5 Hz, 1H: H in 5 of the aromatic in 2); 7.57 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 8.02 (d, J = 7.5 Hz, 1H: H in 6 of the aromatic in 2); 8.14 (broad s, 1H: H in 2 of the aromatic in 2). Tert-butoxycarbonylamino-3 hydroxy- 2 phenyl-3 propionate- (2R, 3S) acetoxy-4 (3-chloro benzoyloxy) -2 epoxy-5β, 20 hydroxy-lβ methoxyacetoxy- lOβ oxo-9 trifluoromethanesulfonyloxy-7β taxene -11 yl-13 can be prepared as follows: A solution of 770 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R ) acetoxy-4 (3-chloro benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ oxo-9 trifluoromethanesulfonyloxy-7β taxene-11 yl-13α in 20 cm3 of a 0.1N hydrochloric acid solution in l ethanol is stirred at a temperature in the region of 5 ° C for 16 hours. The reaction mixture is then diluted with 50 cm3 of dichloromethane, washed with 2 times 10 cm3 of distilled water. After extraction of the aqueous phase with 10 cm 3 of dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 710 mg of a yellow solid are thus obtained which is purified by chromatography at atmospheric pressure on 50 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with an elution gradient : ethyl acetate-dichloromethane from 10-90 to 20-80 by volume and collecting fractions of 10 cm3. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 594 mg of tert-butoxycarbonylamino-3-hydroxy-2-phenyl-3-propionate- (2R.3S) of acetoxy-4α (3-chloro-benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ methoxyacetoxy-10β are thus obtained. oxo-9 trifluoromethanesulfonyloxy-7β taxene-11 yle-13α in the form of a pale yellow meringue the characteristics of which are as follows: - NMR spectrum of the proton (400 MHz; CDCI3; δ in ppm): 1.23 (s, 3H: CH3); 1.24 (s, 3H: CH3); 1.38 (s, 9H: (CH ₃ ) ₃ ); 1.68 (s, 1H: OH in 1); 1.90 (s, 3H: CH3); 2.08 (s, 3H: CH3); 2.26 and 2.88 (2 mts, 1 H each: CH2 in 6); 2.31 (mt, 2H: CH ₂ at 14); 2.41 (s, 3H: COCH3); 3.35 (mt, 1H: OH in 2 '); 3.54 (s, 3H: OCH3); 3.95 (d, J = 7.5 Hz, 1 H: H at 3); 4.15 and 4.35 (2 d, J = 8.5 Hz, 1 H each: CH ₂ in 20); 4.16 and 4.25 (2 d, J = 16 Hz, 2H: OCOCH ₂ O); 4.64 (mt, 1H: H in 2 '); 4.95 (broad d, J = 10 Hz, 1 H: H at 5); 5.26 (broad d, J = 10 Hz, 1H: H in 3 '); 5.37 (d, J = 10 Hz, 1 H: CONH); 5.48 (dd, J = 10.5 and 8 Hz, 1H: H at 7); 5.70 (d, J = 7 Hz, 1H: H in 2); 6.19 (broad t, J = 9 Hz, 1 H: H at 13); 6.73 (s, 1H: H at 10); from 7.30 to 7.50 (mt, 5H: aromatic H); 7.48 (t, J = 7.5 Hz, 1H: H in 5 of the aromatic in 2); 7.62 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 8.00 (d, J = 7.5 Hz, 1H: H in 6 of the aromatic in 2); 8.11 (s broad, 1H: H in 2 of the aromatic in 2).

Tert-butoxycarbonyl-3 ^" (4-methoxy phenyl) -2 4-phenyl-oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4α (3-chloro-benzoyloxy) -2 epoxy-5β , 20 hydroxy-lβ oxo-9 trifluoromethanesulfonyloxy-7β taxene-11 yle-13α can be prepared as follows:

To a solution of 680 mg of tert-butoxycarbonyl-3 (4-methyl-phenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4cc (3-chloro benzoyl- oxy) -2 epoxy-5β, 20 dihydroxy-lβ, 7β oxo-9 taxene-11 yle-13 in 7 cm3 of dichloromethane and 0.43 cm3 of anhydrous pyridine, the molecular sieve is added at a temperature close to 20 ° C. 4A powder. To the suspension thus obtained, 0.445 cm 3 of triflic anhydride is added, at a temperature in the region of -30 ° C, under an inert atmosphere of argon. After having allowed the temperature of the reaction mixture to rise to the vicinity of 20 ° C. in approximately 1 hour, 5 cm3 of distilled water and 50 cm3 of dichloromethane are successively added, then the sieve is filtered through a sintered glass filled with celite. After decantation, the aqueous phase is extracted with 2 times 5 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered through sintered glass, and concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 1.13 g of a brown meringue are thus obtained which are purified by chromatography at atmospheric pressure on

60 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with an elution gradient of ethyl acetate-dichloromethane from 0-100 to 10-90

• in volumes and collecting 10 cm3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 762 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) of acetoxy-4α (3-chloro-benzoyloxy) are thus obtained. 2α epoxy-5β, 20 hydroxy-lβ oxo-9 trifluoromethanesulfonyloxy-7β taxene-11 yle-13 in the form of a yellow-orange meringue the characteristics of which are as follows: - NMR spectrum of the proton (400 MHz; CDCI3; δ in ppm): 1.08 (s, 9H: (0 ^* 13) 3); 1.20 (s, 6H: CH3); 1.61 (s, 1H: OH in 1); 1.71 (s, 3H: CH ₃ ); 1.85 (s, 3H: CH); 1.95 (s, 3H: COCH3); 2.08 and 2.10 to 2.30 (respectively dd (J = 16 and 9 Hz) and mt, 1H each: CH2 at 14); from 2.10 to 2.30 and 2.84 (2 mts, 1 H each: CH ₂ in 6); 3.53 (s, 3H: OCH3); 3.85 (s, 3H: ArOCH ₃ ); 3.85 (mt, 1H: H at 3); 4.09 and 4.28 (2 d, J = 8.5 Hz, 1 H each: CH ₂ in 20); 4.15 and 4.23 (2 d, J = 16 Hz, 2H: OCOCH ₂ O); 4.58 (d, J = 5 Hz, 1H: H in 2 '); 4.87 (broad d, J = 10 Hz, 1 H: H at 5); 5.42 (dd, J = 10 and 7 Hz, 1H: H at 7); 5.45 (mt, 1H: H in 3 '); 5.65 (d, J = 7 Hz, 1H: H in 2); 6.06 (wide t, J = 9 Hz, 1 H: H at 13); 6.42 (mt, 1H: H in 5 '); 6.61 (s, 1H: H at 10); 6.94 (d, J = 8.5 Hz, 2H: aromatic H in ortho of OCH3); from 7.30 to 7.50 (mt, 8H: aromatic H and aromatic H in meta of OCH3); 7.45 (t, J = 7.5 Hz, 1H: H in 5 of the aromatic in 2); 7.62 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 7.92 (d, J = 7.5 Hz, 1H: H in 6 of the aromatic in 2); 8.01 (s broad, 1H: H in 2 of aromatic in 2).

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 4-phenyl-oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4α (3-chloro benzoyloxy) -2α epoxy-5β, 20 dihydroxy-lβ, 7β oxo-9 taxene-11 yle-13 can be prepared as follows:

To a solution of 800 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) of acetoxy-4α (3-chloro benzoyl- oxy) -2α epoxy-5β, 20 hydroxy-lβ oxo-9 triethylsilyloxy-7β taxene-11 yl-13 in 8 cm3 of dichloromethane, maintained under an argon atmosphere, added dropwise at a temperature in the region of 0 ° C, 8.5 cm3 of the hydrofluoric acid-triethylamine complex (3HF.Et3N). The solution is stirred for 4 hours at 0 ° C., then diluted with 20 cm 3 of dichloromethane, and poured onto 40 cm 3 of a saturated aqueous solution of sodium hydrogen carbonate maintained at a temperature in the region of 0 ° C. After decantation, the aqueous phase is extracted with 3 times 30 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered through sintered glass, then concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 781 mg of a pale yellow meringue are thus obtained which are purified by chromatography at atmospheric pressure on 100 g of silica (0.063-0.2 mm) contained in a column 3.5 cm in diameter, eluting with a mixture ethyl acetate-dichloromethane (25-75 by volume) and collecting 15 cm 3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 686 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) of acetoxy-4α (3-chloro-benzoyloxy) are thus obtained. 2α epoxy-5β, 20 dihydroxy-lβ, 7β oxo-9 taxene-11 yle-13α in the form of a white meringue, the characteristics of which are as follows:

- proton NMR spectrum (400 MHz; CDCI3; δ in ppm): 1.08 (s, 9H: (CH ₃ ) ₃ ); 1.12 (s, 3H: CH3); 1.25 (s, 3H: CH3); 1.58 (s, 3H: CH3); 1.64 (s, 1H: OH in 1); 1.66 (s, 3H: CH3); 1.86 and 2.54 (2 mts, 1 H each: CH ₂ in 6); 1.88 (s, 3H: COCH3); 2.08 and 2.21 (2 dd, J = 16 and 9 Hz, 1 H each: CH ₂ 14); 2.32 (d, J = 4 Hz, 1H: OH at 7); 3.54 (s, 3H: OCH3); 3.71 (d, J = 7 Hz, 1 H: H 3); 3.83 (s, 3H: ArOCH ₃ ); 4.08 and 4.24 (2 d. ^' J = 8.5 Hz, 1 H each: CH ₂ in 20); 4.26 (limit AB, J = 16 Hz, 2H: OCOCH ₂ O); 4.37 (mt, 1H: H at 7); 4.61 (d, J = 5 Hz, 1H: H in 2 '); 4.91 (broad d, J = 10 Hz, 1 H: H at 5); 5.43 (mt, 1H: H at 3 '); 5.60 (d, J = 7 Hz, 1H: H in 2); 6.14 (broad t, J = 9 Hz, 1 H: H at 13); 6.30 (s, 1H: H at 10);

6.40 (mt, 1H: H in 5 '); 6.94 (d, J = 8.5 Hz, 2H: aromatic H in ortho of OCH3); from 7.30 to 7.50 (mt, 8H: aromatic H and aromatic H in meta of OCH3); 7.45 (t, J = 7.5 Hz, 1H: H 5 of the Aromatic in 2); 7.61 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 7.92 (d, J = 7.5 Hz, 1H: H in 6 of the aromatic in 2); 8.03 (broad s, 1H: H in 2 of aromatic in 2).

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 4-phenyl-oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4 (3-chloro benzoyloxy) -2α epoxy-5β, 20 hydroxy-lβ oxo-9 triethylsilyloxy-7β taxene-11 yle-13α can be prepared as follows:

To a solution of 2.5 g of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) of acetoxy-4α dihydroxy-lβ, 2α epoxy-5β, 20 methoxyacetoxy-10β oxo-9 triethylsilyloxy-7β taxene-11 yle-13α in 25 cm3 of tetrahydrofuran maintained under stirring and under an argon atmosphere, successively added, at a temperature in the region of -78 ° C., 3.90 cm3 of a 1.6M solution of n-butyllithium in hexane and 0.8 cm3 of metachlorobenzoyl chloride. The solution is thus stirred at a temperature in the region of -78 ° C for 45 minutes and then 10 cm 3 of a saturated aqueous solution of ammonium chloride are added. The reaction mixture is brought to a temperature in the region of 20 ° C in 1 hour and diluted with 20 cm3 of ethyl acetate. The aqueous phase is separated by decantation and then extracted with 2 times 10 cm3 of ethyl acetate. The organic phases are combined, washed with 10 cm3 of distilled water, dried over magnesium sulfate. After filtration and concentration to dryness under reduced pressure (2.7 kPa) at 40 ° C., 3.47 g of a pale yellow meringue are obtained which are purified by chromatography on 250 g of silica (0.063-0.2 mm) ) contained in a column 5 cm in diameter, eluting with an ethyl acetate-dichloromethane elution gradient from 3-97 to 10-90 by volume and collecting 15 cm 3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. We obtain

1.41 g of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4α (3-chloro-benzoyloxy) -2α epoxy- 5β, 20 hydroxy-lβ oxo-9 triethylsilyloxy-7β taxene-11 yle-13 in the form of a white meringue, the characteristics of which are as follows:

- proton NMR spectrum (400 MHz; CDCI3; δ in ppm): 0.60 (q, J = 7.5 Hz, 6 H: SiCH ₂ ethyl); 0.95 (t, J = 7.5 Hz, 9H: ethyl CH3); 1.08 (s, 9H: (CH ₃ ) ₃ ); 1.19 (s, 3H: CH3); 1.21 (s, 3H: CH ₃ ); 1.62 (s, 1H: OH in 1); 1.65 (s, 3H: CH3); 1.70 (s, 3H: CH3); 1.85 (s, 3H: COCH3); 1.85 and 2.51 (2 mts, 1 H each: CH ₂ in 6); 2.08 and 2.19 (2 dd, J = 16 and 9 Hz, 1 H each: CH ₂ at 14); 3.53 (s, 3H: OCH3); 3.71 (d, J = 7.5 Hz, 1 H: H at 3); 3.84 (s, 3H: ArOCH ₃ ); 4.07 and 4.24 (2 d, J = 8.5 Hz, 1 H each: CH2 in 20); 4.15 and 4.22 (2 d, J = 16 Hz, 2H: OCOCH ₂ O); 4.42 (dd, J = 10 and 6 Hz, 1H: H at 7); 4.60 (d, J = 5 Hz, 1H: H in 2 '); 4.88 (broad d, J = 10 Hz, 1 H: H at 5); 5.42 (mt, 1H: H in 3 '); 5.60 (d, J = 7.5 Hz, 1H: H in 2); 6.08 (wide t, J = 9 Hz, 1 H: H at 13); 6.40 (mt, 1H: H in 5 '); 6.45 (s, 1H: H at 10); 6.93 (d, J = 8.5 Hz, 2H: H aromatic in ortho of OCH3); from 7.30 to 7.50 (mt, 8H: aromatic H and aromatic H in meta of OCH3 and H in 5 of the aromatic in 2); 7.61 (broad d, J = 7.5 Hz, 1H: H in 4 of the aromatic in 2); 7.94 (d, J = 7.5 Hz, 1H: H in 6 of the aromatic in 2); 8.03 (broad s, 1H: H in 2 of aromatic in 2).

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 4-phenyl-oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) acetoxy-4α dihydroxy-lβ, 2 epoxy-5β, 20 methoxyacetoxy -10β oxo-9 triethylsilyloxy-7β taxene-11 yle-13α can be prepared under the conditions described in international PCT application WO 94/20484.

The new products of general formula (I) demonstrate a significant inhibitory activity against abnormal cell proliferation and have therapeutic properties allowing the treatment of patients with pathological conditions associated with abnormal cell proliferation. Pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs, including, but not limited to, muscle, bone or connective tissue, skin, brain, lungs, sexual organs, the lymphatic or renal systems, the mammary or blood cells, the liver, the digestive system, the pancreas and the thyroid or adrenal glands. These pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas. The new products according to the invention are particularly useful for the treatment of ovarian cancer. The products according to the invention can be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.

The products according to the invention can be administered to a patient in different forms adapted to the chosen route of administration which, preferably, is the parenteral route. Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. More particularly preferred is intraperitoneal or intravenous administration.

The present invention also comprises the pharmaceutical compositions which contain at least one product of general formula (I) in a sufficient amount suitable for use in human or veterinary therapy. The compositions can be prepared according to the usual methods using one or more pharmaceutically acceptable adjuvants, carriers or excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents. Preferably the compositions are in the form of aqueous solutions or suspensions, injectable solutions which may contain emulsifying agents, dyes, preservatives or stabilizers. The choice of adjuvants or excipients can be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practices.

For parenteral administration, aqueous or non-aqueous sterile solutions or suspensions are used. For the preparation of non-aqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate . The sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water. The aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition.

It is understood that all the products entering into the compositions according to the invention must be pure and non-toxic for the quantities used. The compositions can contain at least 0.01% of therapeutically active product. The amount of active ingredient in a composition is such that a suitable dosage can be prescribed. Preferably, the compositions are prepared in such a way that a unit dose contains from 0.01 to 1000 mg approximately of active product for parenteral administration.

Therapeutic treatment can be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapies or modifiers of biological responses. Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (a, β or δ) and TNF. Other chemotherapeutic agents useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs like mercaptopurine and thioguanine, natural products like vinca alkaloids like vinblastine, vincristine and vendesine, epipodophyllotoxins like etoposide and teniposide, antibiotics like dactinomycin , daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocotic suppressants such as mitotane and aminoglutethymide, hormones and antagonists like adrenocorticosteroids like prednisone, progestins like hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, estrogens like diethylstilbestrol and ethynylestradiol, antioestrogens like tamoxifen, androgens like testosterone propionate and fluoxymesterone.

The doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum therapeutic response. The doses vary according to the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation. The products according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to relatively large or low doses and may require low or no maintenance doses. Generally, low doses will be used at the start of treatment and, if necessary, increasing doses will be administered until an optimum effect is obtained. For other patients it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the physiological needs of the patient concerned. It is also possible that for some patients it is necessary to use only one or two daily administrations.

In humans, the doses are generally between 0.01 and 200 mg / kg. Intraperitoneally, the doses will generally be between 0.1 and 100 mg / kg and, preferably between 0.5 and 50 mg / kg and, even more specifically between 1 and 10 mg / kg. Intravenously, the doses are generally between 0.1 and 50 mg / kg and, preferably between 0.1 and 5 mg / kg and, even more specifically between 1 and 2 mg / kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the effectiveness of the treatment must be taken into account. .

The following example illustrates a composition according to the invention.

EXAMPLE

40 mg of the product obtained in Example 1 are dissolved in 1 cm 3 of Emulphor EL 620 and 1 cm 3 of ethanol then the solution is diluted by adding 18 cm 3 of physiological saline.

The composition is administered by infusion for 1 hour by introduction into physiological saline.

Claims

1 - New taxoids of general formula:

in which: Ar represents an aryl radical, an alkyl containing 1 to 4 carbon atoms, an alkenyl containing 2 to 4 carbon atoms, a cycloalkyl containing 3 to 6 carbon atoms or a cycloalkenyl containing 3 to 6 carbon atoms,

R represents a hydrogen atom or an alkanoyl, alkoxyacetyl or alkyl radical, R} represents a benzoyl, thenoyl or furoyl radical or an R2-O-CO- radical in which R2 represents:

- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl of which the alkyl part contains 1 to 4 atom s of carbon, - or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, - or a saturated or unsaturated heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and R3 represents - a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted in - 4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 atoms s of carbon), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms,

- or an aryl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, it being understood that R3 cannot represent an unsubstituted phenyl radical,

- or a saturated or unsaturated nitrogen heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or several alkyl radicals containing 1 to 4 carbon atoms.

2 - New taxoids according to claim 1 for which R and R _j being defined as in claim 1, the aryl radicals represented by Ar and R3 are phenyl or α- or β-naphthyl radicals optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino radicals , alkoxycarbonylamino, amino, alkylamino, dialkoyl-amino, carboxy, alkoxycarbonyl, carbamoyl, dialcoylcarbamoyl, cyano, nitro, azido, trifluoromethoxy and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or α- radicals or β-naphthyls, and that the radical R3 cannot represent an unsubstituted phenyl radical, and the heterocyclic radicals represented by Ar and R3 are aromatic heterocyclic radicals having 5 members and containing one or more atoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted by one or more substituents, identical or different, chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing 1 to 4 atoms carbon, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms, amino, alkylamino containing 1 to 4 carbon atoms, dialcoylamino each alkyl part of which contains 1 to 4 carbon atoms, acylamino of which acyl part contains 1 to 4 carbon atoms, alkoxycarbonyl-amino containing 1 to 4 carbon atoms, acyl containing 1 to 4 carbon atoms, arylcarbonyl of which the aryl part contains 6 to 10 carbon atoms, cyano, carboxy, carbamoyl, alkylcarbamoyl of which the alkyl part contains 1 to 4 carbon atoms, dialkoylcarbamoyl of which each alkyl part contains 1 to 4 atoms of carbon or alkoxycarbonyl, the alkoxy part of which contains 1 to 4 carbon atoms.

3 - New taxoids according to claim 1 for which R and Rj being defined as in claim 1, Ar represents a phenyl radical, 2-thienyl or -3 or furyl-2 or -3 optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialcoylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals and R3 represents a phenyl radical substituted by - one or more atoms or radicals, identical or different, chosen among halogen atoms and alkyl, alkoxy, amino, alkyllamino, dialkoylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals.

4 - Process for the preparation of a new taxoid according to one of claims 1, 2 or 3, characterized in that a product of general formula is esterified:

in which Ar and Rj are defined as in one of claims 1, 2 or 3, either R4 represents a hydrogen atom and R5 represents a protective group for the hydroxy function, or else R4 and R5 together form a saturated heterocycle with 5 or 6 members, G ^* represents an alkanoyl, alkoxyacetyl or alkyl radical or a group protecting the hydroxy function, by means of an acid of general formula:

R3-CO-OH (III) in which R3 is defined as in one of claims 1, 2 or 3, or of an activated derivative of this acid, to obtain a product of general formula:

in which Ar, R] _, R3, R4, R5 and Gj are defined as above, including the replacement of the protective groups R5, when R4 represents a hydrogen atom, or else R4 and R5, when R4 and R5 together form a saturated 5 or 6-membered heterocycle, and optionally G ^* with hydrogen atoms leads to the product of general formula (I) optionally passing, according to the meanings of Rj, R4 and R5, through a product of general formula:

in which R is defined as above, which is acylated by means of benzoyl chloride, thenoyl or furoyl or a product of general formula:

R ₂ -O-CO-X (VI) in which R2 is defined as above and X represents a halogen atom or a residue -O-R2 or -O-CO-O-R2.

5 - Process according to claim 4 characterized in that the esterification of the product of general formula (II) is carried out by reacting the acid of general formula (III), preferably in the form of halide, on the product of formula general (II) previously metallized by means of an alkali metal alkyl operating in an inert organic solvent such as an ether at a temperature below -50 ° C.

6 - Method according to claim 4 characterized in that the replacement of the protective groups of hydroxy functions by hydrogen atoms is carried out:

1) when R4 represents a hydrogen atom, R5 is defined as above and G represents an alkanoyl, alkoxyacetyl or alkyl radical, by treating the product of general formula (IV) with a mineral acid chosen from hydrochloric, sulfuric and hydrofluoric acids or organic chosen from acetic, methanesulfonic, trifluoromethanesulfonic, p.toluene-sulfonic acids used alone or as a mixture, operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, - aromatic hydrocarbons or nitriles at a temperature between -10 and 60 ° C,

2) when R4 and R5 together form xm heterocycle saturated with general form:

in which R- is defined as in one of claims 1, 2 or 3, Rg and R7, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical of which the alkyl part contains 1 to 4 carbon atoms and the aryl part preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, u an aryl radical representing, preferably a phenyl radical optionally substituted by a or more alkoxy radicals containing 1 to 4 carbon atoms, or Rg represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R7 represents x hydrogen atom, or alternatively Rg and R7 together with the carbon atom to which they are linked form a ring having 4 to 7 members, and Gi represents an acetyl or alkyl radical, is carried out, according to the meanings of R] _, Rg and R7, in the manner next :

a) when Rj represents a butoxycarbonyl radical, Rg and R7, identical or different, represent an alkyl radical or an aralkyl or aryl radical, or else Rg represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R7 represents a d atom hydrogen, or else Rg and R7 together form a cycle having from 4 to 7 members, by treating a product of general formula (IV) with a mineral or organic acid optionally in an organic solvent such as an alcohol to obtain a product of general formula (V) which is acylated by means of a product of general formula (VI).

b) when R- represents a benzoyl radical or an R2-O-CO- radical in which R2 is defined as above, Rg represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted by one or more alkoxy radicaxix containing 1 to 4 carbon atoms and R7 represents xm hydrogen atom, by treating xm product of general formula (IV) in the presence of a catalytic or stoichiometric amount of a mineral acid chosen from hydrochloric acids and sulfuric or organic chosen from acetic, methanesulfonic, trifluoromethanesulfonic and p.toluenesulfonic acids used alone or as a mixture, in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature between -10 and 60 ° C.

3) when G represents an alkoxyacetyl radical and R4 and R5 are defined as in point 1) above, by first replacing the protective group R5 with an atom of hydrogen by operating under the acid conditions described in point 1 above, then by replacing the protective group G ^* with xm hydrogen atom by treatment in an alkaline medium using ammonia or hydrazine or by treatment with a zinc halide under conditions which do not affect the rest of the molecule.

4) when G represents an alkoxyacetyl radical and R4 and R5 are defined as in point 2-a) above, optionally replacing the protective group Gi by treatment in an alkaline medium or by treatment with x zinc halide under the conditions described in point 3) above, then by treating the product of general formula (V) obtained under the deprotection and acylation conditions described in point 2-a) above.

5) when Gj represents an alkoxyacetyl radical and R4 and R5 are defined as in point 2-b) above, optionally replacing the protective group Gj by treatment in an alkaline medium or by treatment with a zinc halide under the conditions described in point 3) above, then treat the product obtained under the conditions described in point 2-b) above.

7 - Process for preparing a product according to one of claims 1, 2 or 3 characterized in that one esterifies a product of general formula:

in which Ar and R are defined as in one of claims 1, 2 or 3 and R4, R5 and G- are defined as in claim 4 and G2 represents xm protecting group for the hydroxy function chosen from trialkylsilyl, dialkylarylsilyl radicals , alkyldiarylsilyl or triarylsilyl in which the alkyl parts contain 1 to 4 carbon atoms and the aryl parts are phenyl radicals, by means of an acid of general formula: R3-CO-OH (III) in which R3 is defined as in one of claims 1, 2 or 3 to obtain a product of general formula:

in which Ar, R, R3, R4, R5, G ^ and G2 are defined as above, the protective group G2 of which is selectively replaced by a hydrogen atom, to obtain a product of general formula:

OCOR, in which Ar, Rj, R3, R4, R5 and G are defined as above, which, by the action of xin derived from trifluoromethanesulfonic acid chosen from anhydride or N-phenyl trifluoromethanesulfonimide, is transformed into a product of general formula:

(XVIII)

in which Ar, R, R3, R4, R5 and G are defined as above, of which the protective groups represented by R5 or by R4 and R5 are replaced by hydrogen atoms to give a product of general formula:

OCOR, in which Ar, Rj, R3 and Gj are defined as above, which is treated with an alkali metal halide, an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate, to obtain the product according to one of claims 1, 2 or 3 for which R represents an acetyl, alkoxyacetyl or alkyl radical which is optionally converted into a product according to one of claims 1, 2 or 3 for which R represents a hydroxy radical.

8 - The product of general formula

in which Ar and Ri are defined as in one of claims 1, 2 or 3, and either R4 represents a hydrogen atom and R5 represents a group protecting the hydroxy function, or else R4 and R5 together form a saturated 5 or 6-membered heterocycle, G represents xm alkanoyl, alkoxyacetyl or alkyl radical or a protecting group for the hydroxy function.

9 - New product according to claim 8 characterized in that Ar and R being defined as in one of claims 1, 2 or 3, and, when R4 represents a hydrogen atom, R5 preferably represents a methoxy-methyl radical , 1-ethoxy-ethyl, benzyloxymethyl. trimethylsilyl, triethylsilyl, (β trimetylsilyl- ethoxy) methyl or tetrahydropyranyl and, when R4 and R5 together form a heterocycle, the latter is an optionally mono-substituted or gem-disubstituted oxazolidine ring in position -2 and G represents an alkanoyl radical, alkoxyacetyl or alkyl or a group protecting the hydroxy function.

10 - Process for preparing a product according to one of claims 8 or 9 characterized in that an electrolytic reduction of a product of the general formula is carried out:

OCOC ₆ H ₅ in which Ar, R ^* and R4 are defined as in the xine of claims 1, 2, 3 or 4, R5 is defined as in claim 4 and may further represent a hydrogen atom, G ' j represents a hydrogen atom, an alkanoyl, alkoxyacetyl or alkyl radical or a protective group for the hydroxy function, operating in an electrolyte consisting of a quaternary ammonium salt soluble in the organic solvent or in a hydro-organic mixture at a controlled potential.

11 - Pharmaceutical composition characterized in that it contains at least one product according to one of claims 1, 2 or 3 in combination with one or more pharmaceutically acceptable products whether inert or physiologically active.