WO1994011547A1 - Process for the preparation of taxane derivatives, novel taxanes so obtained and antitumour and antileukaemia compositions containing same - Google Patents

Abstract

Process for the electrochemical preparation of taxane derivatives of general formula (I), based on a taxane derivative of general formula (III). The invention also concerns pharmaceutical compositions with outstanding antitumour and antileukaemia properties which contain a novel product of general formula (I) wherein R3 is a radical of general formula (II). In general formulae (I) and (III), R is a hydrogen atom or an acetyl or alkoxyacetyl radical, one of the symbols R1 or R2 is a hydrogen atom and the other is a hydroxy radical, R3 is a hydrogen atom or a radical of general formula (II) wherein Ar is an aryl radical and R4 is a benzoyl radical or a R5-O-CO- radical in which R5 is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical.

Description

Process for the preparation of taxane derivatives, new taxanes thus obtained and the anti-tumor and anti-eucemic compositions which contain it

The present invention relates to a new process for the preparation of 5 taxane derivatives of general formula:

OCOC ₆ H ₅ in which: one of the symbols R or R2 represents a hydrogen atom and the other represents a hydroxy radical, 10 - R3 represents a hydrogen atom or a radical of general formula:

ÔH in which

Ar represents an aryl radical, and

R4 represents a benzoyl radical or an R5-O-CO radical in which R5 represents an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical.

More particularly, the present invention relates to a process for the preparation of products of general formula (I) in which R and R2 being defined as above, R3 represents a hydrogen atom or a radical of general formula (H) in which:

Ar represents a phenyl or α- or β-naphthyl radical optionally substituted by one or more atoms or radicals chosen from fluorine or chlorine atoms and alkyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl radicals , mercapto, acylamino, aroylamino,

Alkoxycarbonylamino, amino, alkyllamino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkoylcarbamoyl, cyano and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and the aryl radicals are the phenyl or α- or β-naphthyl radicals, or a heterocyclic radical aromatic having 5 links 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) and alkyl radicals containing 1 to 4 carbon atoms, 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, dialkoylamino of which each alkyl part contains 1 to 4 carbon atoms, acylamino of which the acyl part contains 1 to 4 carbon atoms, alkoxycarbo nylamino 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 carbon, 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,

R4 represents a benzoyl radical or an R5-O-CO- radical in which R5 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 atoms of carbon, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from fluorine or chlorine atoms and hydroxy, alkoxy radicals containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which 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, the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms e, phenyl, cyano, carboxy or alkoxycarbonyl in which the alkyl part contains 1 to 4 carbon atoms,

a phenyl radical optionally substituted by one or more radicals chosen from alkyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, acylamino, aroylamino, alkoxycarbonylamino radicals, amino, alkyllamino, dialkoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkoylcarbamoyl, cyano and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms - or a heterocyclyl nitrogen saturated radical containing 4 to 6 members optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and more particularly, the present invention relates to the preparation of the products of general formula (I) in which Rj and R2 being defined as above, R3 represents a radical of general formula (H) in which Ar represents a phenyl radical optionally substituted by a fluorine or chlorine atom or by an alkyl radical (methyl), alkoxy (methoxy), dialcoylamino (dimethylamino), acylamino, alkoxycarbonylamino or trifluoromethyl or a thienyl-2 or -3 or furyl-2 or -3 radical and R4 represents a benzoyl radical or an R5-O-CO- radical for which R5 represents a butyl radical.

The products of general formula (I) in which Rj and R2 are defined as above, and R3 represents a radical of general formula (π) in which Ar represents a heterocyclyl radical defined as above and R4 represents a benzoyl radical or a radical of formula general R5-O-CO in which R5 is defined as above, constitute new products which have remarkable antitumor and antileukemic properties.

According to the present invention, the products of general formula (I) can be obtained by electrolytic reduction of a product of general formula:

OC OC ₆ H ₅ in which R represents a hydrogen atom or an acetyl or alkoxyacetyl radical and Rj, R2 and R3 are defined as above. According to the invention, the reduction of the RO- group is carried out electrochemically according to the following reaction:

; R ₁ = H and R ₂ = OH)

The electrolytic reduction from a product of general formula (III) is carried out in an electrolyzer containing a catholyte consisting of a support electrolyte containing magnesium, calcium, cerium, strontium or lithium ions or optionally, when R represents an acetyl radical or alkoxyacetyl, ammonium ions (NH4 ⁺ ) and a solvent or a mixture of solvents or a hydro-organic mixture in which the product of general formula (III) is dissolved at a concentration between 0.1 g 1 and the saturation of the solution.

The quantity of theoretical electricity necessary to effect the reduction of a product of general formula (lu) into product of general formula (I; Rj = OH and R2 = H) and (I; Ri = H and R2 = OH) is 2 faradays (or 193,000 coulombs) per molecule.

Depending on the conditions for implementing the electrolytic process, it is possible to preferentially obtain the product of general formula (I) for which Rj represents a hydroxy radical and R2 represents a hydrogen atom depending on the nature of the electrolyte and l acidity of the medium. Generally, epimerization is not observed when the electrolytic reduction is carried out in the presence of ammonium ions, the anodic compartment containing a protonic acid.

Preferably, the reduction _. takes place 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 the characteristics of which are as follows: a) the cathode consists of an electrically conductive material on which the reduction takes place at a potential greater than that of the reduction of the solvent or of one of the constituents of the support electrolyte, or at a potential such as reduction of solvent or one of the constituents of the support electrolyte is not large enough to hinder the reduction of the product, b) the cathode compartment contains the catholyte which consists of a solution of the product of general formula (III) in an organic or hydroorganic medium and an electrolyte containing magnesium, calcium, ^ffl cerium, strontium or lithium or possibly ammonium (NH4 ⁺ ). When operating in the presence of ammonium ions, the pH can be kept slightly alkaline, that is to say preferably between 7 and 9, by addition of ammonia, 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 a cation exchange membrane, d) the anode compartment contains either the anolyte consisting of preferably by the same solvent or mixture of solvents and the same support electrolyte as that used in the cathode compartment, or else an acid diluted in the same solvent or mixture of solvents as that contained in the catholyte, e) the anode is made of an electrically conductive material, the nature of which is not essential for the implementation of the process.

Generally, the anode consists of a material that conducts electricity that cannot be attacked under the conditions of electrolysis, such as, for example, polished, solid or supported platinum, graphite or vitreous carbon. Preferably, the cathode consists of a sheet of mercury. The support electrolyte consists of a magnesium or calcium salt or optionally of ammonium, such as magnesium chloride, calcium chloride, cerium chloride ^m , strontium chloride, lithium chloride or ammonium chloride, soluble in solvent or mixture of solvents. Generally, practical solvents are used which readily dissolve the products of general formula (I) and (III) and which allow easy isolation of the products of general formula (I; Ri = OH and R2 = H) and (I; Ri = H and R2 ≈ OH). Preferably, the solvents will be chosen from aliphatic alcohols containing 1 to 4 carbon atoms such as methanol, ethanol, isopropanol or tbutanol and the hydro-organic mixture is an alcohol-water mixture.

The pH must be compatible with the stability of the substrate and it can be kept slightly alkaline during the electrolysis, that is to say preferably between 7 and 9, by addition of ammonia in aqueous solution or by bubbling ammonia gas when using ammonium chloride. The nature of the diaphragm separating the anolyte from the catholyte is not an essential characteristic of the invention. This is how any diaphragm of known type can be used, constituted by a porous material such as sintered glass, porcelain with or without conductive gel limiting the diffusion of reagents or by ion exchange membranes, preferably cation exchange membranes. . When the anolyte contains a dilute acid, it is particularly advantageous to use a cation exchange membrane in order to maintain the pH in the catholyte by migration of H ⁺ ions through the membrane during electrolysis. The membranes can be of homogeneous or heterogeneous type and they can optionally be reinforced by a weft. Preferably used membranes which do not swell, which do not emboss and which are stable in the presence of the various constituents of the anolyte and the catholyte.

According to a preferred embodiment of the invention, the anode, the cathode and the separating diaphragm are arranged in horizontal parallel planes in the case of a cathode formed by a sheet of mercury.

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

The electrolysis is carried out at controlled potential, this can be fixed approximately between -1.65 and -2.1 volts relative to a reference electrode to the calomel, depending on the nature of the cation of the electrolyte.

The theoretical amount of electricity used is 2 Faradays (or 193,000 coulombs) per mole of a product of general formula (III). Practically the amount of electricity used can be 2 to 5 times the theoretical amount, but can also be very much higher. Preferably, the reaction is followed by the disappearance of the starting product which is determined by thin layer chromatography.

The catholyte can be circulated for example under the action of a pump. The circuit can also include ancillary devices such as temperature exchangers or expansion vessels; such an expansion vessel makes it possible in particular to supply the catholyte with a product of general formula (III) and also makes it possible to draw up for the extraction of the products of general formula (I).

The anolyte can also be subjected to circulation. According to a preferred embodiment of the invention, the catholyte circuit is similar to that of the anolyte, which makes it possible to balance the pressures on either side of the separating diaphragm.

According to another particular embodiment of the invention, there are spacers in the anode and cathode compartments. These spacers serve to avoid, on the one hand, the deformations of the ion exchange membrane and, on the other hand, the contacts of this membrane with the electrodes. They also serve to improve the homogeneity of concentration of the catholyte.

In the absence of an interlayer, the speed of circulation of the catholyte in the cathode compartment is usually greater than 10 cm / s, preferably greater than 50 cm / s. When using an interlayer, the apparent speed of the catholyte (speed in the cathode compartment assumed to be without interlayer) is usually greater than 1 cm / s, preferably greater than 10 cm / s.

According to another embodiment of the invention, the cell can consist simply of a container, parallelepiped or cylindrical, made of a material inert with respect to the constituents of the electrolytes.

In general, any electrolytic cell comprising an anode and a cathode separated by one or more diaphragms ensuring ionic conductivity can be used, the arrangement of the elements not being essential for the implementation of the process. The products of general formula (I) obtained by implementing the process according to the invention are separated by application of the usual methods.

The implementation of the method according to the invention leading, optionally from a determined product of general formula (III) to the mixture of the corresponding products of general formula (I) for which, on the one hand, Ri represents a hydroxy radical and R2 represents a hydrogen atom and, on the other hand, Ri represents a hydrogen atom and R2 represents a hydroxy radical, the separation of the products thus obtained can be carried out according to known methods such as chromatography.

The products of general formula (III) in which R represents a hydrogen atom or an acetyl radical, R3 represents a hydrogen atom correspond respectively to 10-deacetyl baccatin III and to baccatin III which can be isolated, according to the known methods, using extracts from different varieties of yew (Taxus sp.).

The products of general formula (III) in which R represents a hydrogen atom or an acetyl radical, R3 represents a radical of general formula (II) in which Ar represents an aryl radical and R4 represents a benzoyl radical respectively correspond to 10-deacetyl taxol and to taxol which can be obtained according to the methods described in European patents EP 0 253 739, EP 0 336 840, EP 0400 971 and EP 0428 376 or in the international PCT application WO 9209589.

The products of general formula (III) in which R represents a hydrogen atom or an acetyl radical and R3 represents a radical of general formula (II) in which Ar represents an aryl radical and R4 represents a tbutoxycarbonyl radical can be obtained according to Methods described in European patents EP 0 253 738 and EP 0 336 841 or in the international PCT application WO 9209589.

The products of general formula (III) in which R represents a hydrogen atom or an acetyl or alkoxyacetyl radical and R3 represents a radical of general formula (II) in which R4 represents a benzoyl radical or an R5-O-CO- radical can be obtained by the action of benzoyl chloride or a reactive derivative of general formula:

R5-O-CO-X (IV)

in which X represents a halogen atom (fluorine, chlorine) or a residue -O-R5 or -O-CO- R5 on a derivative of baccatin read or of deacetyl-10 baccatin read of general formula:

OC OC ₆ H ₅ in which Ar is defined as above, Gi represents a group protecting the hydroxy function such as a trialkylsilyl, dialkoylarylsilyl, alkyldiarylsilyl or triarylsilyl group in which each alkyl part contains 1 to 4 carbon atoms and each aryl part preferably represents a phenyl radical and G2 represents a hydrogen atom or an acetyl or alkoxyacetyl (methoxyacetyl) radical, to give a product of general formula:

0C0C ₆ H ₅ in which Ar, R5, G and G2 are defined as above, followed by the replacement of the protective group Gi and optionally of the radical G2 by hydrogen atoms. Generally, the action of the reagent of general formula (IV) on the derivative of baccatin III or of 10-deacetyl baccatin read of general formula (V) is carried out in an organic solvent such as an ester such as acetate d ethyl in the presence of a mineral or organic base such as sodium bicarbonate at a temperature between 0 and 50 ° C, preferably close to 20 ° C. Generally the replacement of the protective group Gi and of the radical

G2 of the product of general formula (VI) with a hydrogen atom is carried out by treatment in an acid medium such as for example hydrochloric acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, isopropanol) or aqueous hydrofluoric acid at a temperature between 0 and 40 ° C when G represents a silylated radical and G2 represents an alkoxyacetyl radical.

The new products of general formula (I) in which Ri and R2 are defined as above and R3 represents a radical of general formula (II) in which Ar is represents a heterocyclyl radical defined as above and R4 represents a benzoyl radical or a radical of general formula R5-O-CO in which R5 is defined as above, manifest 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 glands or adrenal. 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 adjuvants, carriers or pharmaceutically acceptable 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. 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. The 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, b or d) 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, lomusine, 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 c like L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid 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 examples illustrate the present invention.

EXAMPLE 1

We proceed to the electrolytic reduction of tbutoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 trihydroxy-l, 7β, 10β oxo-9 taxene-11 yle -13 (or docetaxel or Taxotère®) in an electrolysis cell with the following characteristics:

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

- the cathode is a sheet of mercury whose useful surface is approximately 10 cm2,

- the anode is a platinum grid, - the reference electrode is a saturated calomel electrode.

In the cathode compartment, 4 cm3 of a solution containing:

- tbutoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 trihydroxy-l, 7β, 10β oxo-9 taxene-11 yle-13α 51.1 mg

- calcium chloride q.s.p. . 0.05M

- methanol q.s.p. 10 cm3

In the anode compartment, 10 cm 3 of the same mixture not containing the substrate 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 electrode of reference.

The solution is electrolyzed for the time necessary for the passage of 14.2 coulombs.

To the electrolyzate, 20 μl of acetic acid are added. After removing the solvent under reduced pressure at a temperature below 35 ° C, the residue is taken up in 10 cm3 of ethyl acetate and 10 cm3 of water. Extraction is carried out with 10 cm 3 and 2 times 5 cm 3 of ethyl acetate. After drying of the organic phase, separated by decantation, over magnesium sulfate, the solvent is evaporated off under reduced pressure at a temperature below 35 ° C. 42.3 mg of crude product are thus obtained, the constituents of which are separated by preparative chromatography on a thin layer of silica gel (thickness: 0.25 mm), eluting with a dichloromethane-methanol-acetonitrile mixture (84-8-8 volumes) There is thus obtained, with a yield of 15%, 7.4 mg of tbutoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 dihydroxy-l , 7β oxo-9 taxene-11 yle-13α, that is to say a product of general formula (I) for which Ri represents a hydroxy radical and R2 represents a hydrogen atom, and, with a yield of 20 %, 9.6 mg of tbutoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 dihydroxy-l, 7α oxo-9 taxene 11 yle-13α, that is to say a product of general formula (I) for which R 1 represents a hydrogen atom and R 2 represents a hydroxy radical. EXAMPLE 2

The electrolytic reduction of the 3-benzoylamino-3-phenyl-2-hydroxy-propionate (2R, 3S) of benzoyloxy-2α diacetoxy-4,10β epoxy-5β, 20 dihydroxy-l, 7β oxo-9 taxene-11α-13α is carried out. (or taxol) in an electrolysis cell with the following characteristics:

- the cell is a 10 cm3 glass vase divided into 2 compartments by a cation exchange membrane,

- the cathode is a sheet of mercury whose useful surface is 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:

- 3-benzoylamino-phenyl-3-hydroxy-2-propionate- (2R, 3S) of benzoyloxy-2α diacetoxy-4,10β epoxy-5β, 20 dihydroxy-l, 7β oxo-9 taxene-1 yle-13α 61.9 mg

- ammonium chloride q.s.p. . 0.1M

- ammonia [33% aqueous solution (w / v) 0.2 cm3

- methanol q.s.p. . 10 cm3

In the anode compartment, 10 cm 3 of a 0.1M solution of ammonium chloride in methanol are introduced.

The solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -1.80 volts relative to the reference electrode until the passage of 14 coulombs. The potential is then set at -1.85 volts. After the passage of a total of 42 coulombs, the electrolysis is stopped. 0.1 cm3 of pure acetic acid are added and the solvent is then removed by concentration under reduced pressure at a temperature below 35 ° C. The residue obtained is taken up in 10 cm3 of water and then extracted with 10 cm3 and then twice 5 cm3 of ethyl acetate. The organic phase is washed with 10 cm3 of a 0.2M aqueous phosphate buffer solution at pH = 7.4. After drying and dry concentration of the organic phase, 49.7 mg of a crude product is obtained which is purified by preparative chromatography on a thin layer of silica gel (thickness: 0.25 mm), eluting with a mixture [acetate ethyl-dichloromethane-methanol (55-40-5 by volume)]. Is thus isolated, with a yield of 45%, 26.3 mg of 3-benzoylamino-3-phenyl-2-hydroxy-propionate- (2R, 3S) of benzoyloxy-2α-4-acetoxy-5-epoxy, 20 dihydroxy-1, 7β oxo -9 taxene- 11 yle-13 which has the following characteristics. - proton nuclear magnetic resonance spectrum (400 MHz; CDCI3; chemical shifts in ppm in ppm)

1.14 (s, 3H: -CH3 16 or 17); 1.17 (s, 3H: -CH3 16 or 17); 1.64 (s, 3H: -CH ₃ 19 or 18); 1.68 (s, 3H: -CH3 19 or 18); 1.80 [mt, 1H: - (CH) -H 6]; 2.29 (mt, 2H: -CH2 14); 2.37 (s, 3H: -COCH3); 2.57 [mt, 1H: - (CH) -H 6]; 3.40 and 3.77 (dd, J = 16, 1H each: -C1210); 3.88 (br s, 1H: -OH 2 '); 4.03 (d, J = 7, 1H: -H 3); 4.18 and 4.29 (2d, J = 8, 1H each: -CH ₂ 20); 4.27 (mt, 1H: -H 7); 4.78 (br s, 1H: -H 2 '); 4.93 (broad d, J = 9, 1H: -H 5); 5.68 (d, J = 7, 1H: -H 2); 5.78 (dd, J = 9 and 3, 1H: -H 3 '); 6.10 (mt, 1H: -H 13); 7.20 (d, J = 9, 1H: -CONH-); 7.30 to 7.45 (mt, 5H: -C6H5 3 '); 7.45 to 7.55 [mt, 5H: -OCOC6H ₅ (-l13 and -H 5) and -NHCOC ₆ H ₅ (-H 3, -H 4 and -H 5)]; 7.62 [t, J = 7.5, 1H: -OCOC ₆ H ₅ (-Ii 4)]; 7.75 (d, J = 7.5, 2H: -NHCOC ₆ H ₅ (-H 2 and -H 6)]; 8.12 [d, J = 7.5, 2H: -OCOC ₆ H ₅ ( -H 2 and -H 6)].

EXAMPLE 3

The electrolytic reduction of tbutoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) of acetoxy-4 benzoyloxy-2α epoxy-5β, trihydroxy-l, 7β, 10β oxo-9 taxene-11 yle- is carried out. 13α (or docetaxel) in an electrolytic 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 4 cm2,

- the anode is a platinum grid,

- the reference electrode is a saturated calomel electrode.

In the cathode compartment, 20 cm 3 of a solution containing:

- docetaxel, 404.6 mg

- calcium chloride q.s.p .... 0.05 M

- methanol q.s.p. . 10 cm3

In the anode compartment, 10 cm 3 of a 0.5 M solution of hydrochloric acid in methanol are introduced.

The solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -1.95 volts relative to the reference electrode. After 3 hours 49 minutes of electrolysis, that is to say the time necessary for the passage of 197 coulombs, the electrolysis is stopped. 0.1 cm3 of pure acetic acid are added and 0.5 cm3 of a saturated aqueous solution of sodium hydrogencarbonate. After removing the solvent by concentration under reduced pressure, the residue is taken up in 20 cm3 of ethyl acetate and 20 cm3 of deionized water. After decantation, the aqueous phase is extracted with 2 times 10 cm3 of ethyl acetate. The organic phase is washed with 20 cm3 of a 0.2 M aqueous phosphate buffer solution at a pH close to 7. After drying and dry concentration of the organic phase, 381.2 mg of a crude product are obtained, the constituents are separated by preparative chromatography on a thin layer of silica gel. The crude product is taken up in the minimum of a dichloromethane-methanol mixture (50-50 by volume) then injected onto 8 plates of silica gel (Kieselgel 60 F 254, Merck) 2 mm thick, eluting with a mixture dichloromethane-acetonitrile-methanol (55-40-5 by volume). Is thus isolated, with a yield of 29.2%, 116 mg of tbutoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) benzoyloxy-2α acetoxy-4 epoxy-5β, 20 dihydroxy- l, 7β oxo -9 taxene-11 yle-13 which has the following characteristics: - proton nuclear magnetic resonance spectrum (400 MHz; CDCI3; chemical shifts in ppm; coupling constants J in Hz): 1.22 (s, 3H: - CÏÏ3 16 or 17); 1.26 (s, 3H: -CH3 16 or 17); 1.39 [s, 9H: -0 (013) 3]; 1.69 (s. 3H: -C13 19); 1.79 (s, 3H: -CH3 18); 1.84 [ddd, J = 16, 9 and 2, 1H: - (CH) -H 6]; 2.33 (mt, 2H: -CH ₂ 14]; 2.40 (s, 3H: -COCH3); 2.65 [mt, IH: - (CH) -H 6]; 3.42 (s, IH : -OH 2 '); 3.50 and 3.85 (dd, J = 16, 1H each: -CH2 10); 4.10 (d, J = 7, 1H: -H 3); 4.22 and 4.35 (2d, J = 8, IH each: -CH2 20); 4.33 (mt, IH: -H 7); 4.65 (dd, IH: -H 2 '); 5.00 (dd . J = 2 and 8, IH: -fl 5); 5.30 (wide d, J = 10, IH: -H 3 '); 5.45 (d, J = 10, IH: -CO H-) ; 5.73 (d, J = 7, 1H: -H 2); 6.17 (wide t, J = 8, 1H: -H 13); 7.30 to 7.50 (m, 5H: -C ^ s 3 '); 7.53 [t, J = 7.5, 2H: -OCOC6H ₅ (-ϋ 3 and -H 5)]; 7.67 [t, J = 7.5 Hz, IH: - OCOC ₆ H ₅ (-H. 4)]; 8.15 [d, J = 7.5, 2H: -OCOC ₆ H ₅ (-H 2 and -H 6)].

EXAMPLE 4

The electrolytic reduction of tbutoxycarbonylamino-3 phenyl- 3 hydroxy-2 proρionate- (2R, 3S) of acetoxy-4 benzoyloxy-2 epoxy-5β, 20 trihydroxy-1, 7α, 10β oxo-9 taxene-11 yle- is carried out. 13α in an electrolytic cell with the following characteristics:

- the cell is a 120 cm3 glass vase divided into 2 compartments by a cation exchange membrane,

- the cathode is a sheet of mercury whose useful surface is 12 cm2, - the anode is a platinum grid,

- the reference electrode is a saturated calomel electrode.

20 cm3 of a solution containing: - tbutoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 trihydroxy-1,7α are introduced into the cathode compartment , 10β oxo-9 taxene-llyle-13α 607.4mg

- calcium chloride q.s.p .... 0.05 M

- methanol q.s.p. 50 cm3 In the anode compartment, 10 cm3 of a 0.5 M solution of hydrochloric acid in methanol are introduced.

The solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -2.0 volts relative to the reference electrode. After 2 hours 30 minutes of electrolysis, that is to say the time necessary for the passage of 224 coulombs, the electrolysis is stopped. 10 cm 3 of a 0.1 M solution of sodium acetate in methanol are added. After removing the solvent by concentration under reduced pressure at a temperature below 35 ° C, the residue is taken up in 50 cm3 of ethyl acetate and 50 cm3 of deionized water. After decantation, the aqueous phase is extracted with 2 times 25 cm3 of ethyl acetate. The organic phase is washed with 25 cm3 of a 0.2 M aqueous phosphate buffer solution at a pH close to 7. After drying and dry concentration of the organic phase at a temperature below 35 ° C, 594.8 is obtained mg of a crude product, the constituents of which are separated by preparative chromatography on a thin layer of silica gel. The crude product is taken up with the minimum of a dichloromethane-methanol mixture (50-50 by volume) then injected onto 12 plates of silica gel (Kieselgel 60 F 254, Merck) 2 mm thick, eluting with a mixture dichloromethane-acetonitrile-methanol (80-16-4 by volume). Is thus isolated, with a yield of 38.5%, 229.4 mg of t.butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) of benzoyloxy-2α acetoxy-4 epoxy-5β, 20 dihydroxy- l, 7α oxo-9 taxene- 11 yle-13α which has the following characteristics:

- proton nuclear magnetic resonance spectrum (400 MHz; CDCI3; chemical shifts in ppm; coupling constants J in Hz): 1.10 (s, 3H: -CH3 16 or 17); 1.20 (s, 3H: -CH3 16 or 17); 1.36 [s, 9H: -C (CH ₃ ) ₃ ]; 1.62 (s, 3H: -CH3 19); 1.72 (s, 3H: -CH3 18); 1.73 (s. 1H: -OH 1); 2.15 to 2.45 (mt, 4H: -CH ₂ -14 and -CH ₂ - 6); 2.49 (s, 3H: -COCH3); 3.28 (br s, 1H: -OH 2 '); 3.43 (d broad, J = 16, 1H: - (CH) -H 10); 3.78 (ddd, J = 12, 4 and 2.5, 1H: -H 7); 4.12 (d, J = 16, 1H: - (CH) -H 10); 4.20 (d, J = 7, 1H: -fi 3); 4.38 (ab limit, J = 11, 2H: -CH ₂ - 20); 4.58 (d, J = 12, 1H: -OH 7); 4.62 (br s, 1H: -H 2 '); 4.99 (dd, J = 9 and 5, 1H: -H 5); 5.28 (broad d, J = 10, 1H: -fl 3 '); 5.38 (d, J = 10, 1H: -CONI-); 5.76 (d, J = 7, 1H: -H 2); 6.17 (mt, 1H: -H 13); 7.30 to 7.45 (mt, 5H: -Cgïζ 3 '); 7.52 [t, J = 7.5, 2H: -OCOC ₆ H ₅ (-H 3 and H 5)]; 7.62 [t, J = 7.5, 1H: -OCOC ₆ H ₅ (-H 4)]; 8.12 [d, J = 7.5, 2H: -OCOC ₆ H ₅ (-II 2 and H 6)].

EXAMPLE 5

An initial electrolytic reduction of tbutoxycarbonylamino-3 (3-thienyl) -3 hydroxy-2 propionate- (2R, 3S) of 4-acetoxy-benzoyloxy-2α epoxy-5β, trihydroxy-l, 7α, 10β oxo-9 is carried out. taxene-11 yle-13α in an electrolytic 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 4 cm2,

- the anode is a platinum grid,

- the reference electrode is a saturated calomel electrode.

In the cathode compartment, 10 cm3 of a solution containing: - tbutoxycarbonylamino-3 (3-thienyl) -3 hydroxy-2 propionate- (2R, 3S) of acetoxy-4 benzoyloxy-2α epoxy-5β, 20 trihydroxy are introduced -1.7α, 10β oxo-9 taxene-11 yle-13α 21.6 mg

- calcium chloride q.s.p .... 0.05 M

- methanol q.s.p. 10 cm3 In the anode compartment, 10 cm3 of a 0.1 M solution of hydrochloric acid in methanol is introduced.

The solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -1.95 volts relative to the reference electrode at the start of the electrolysis then at -2.0 volts after the passage of 10.5 coulombs. After 79 minutes of electrolysis, that is to say the time necessary for the passage of 25.6 coulombs, the electrolysis is stopped.

A second electrolytic reduction of t.butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) of acetoxy-4 is carried out. benzoyloxy-2 epoxy-5β, 20 trihydroxy-l, 7α, 10β oxo-9 taxene-11 yle-13α in the same one electrolysis tank.

20 cm3 of a solution containing: - tbutoxycarbonylamino-3 (3-thienyl) -3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 trihydroxy are introduced into the cathode compartment -1.7α, 10β oxo-9 taxene- 11 yle-13α 80.0 mg

- calcium chloride q.s.p .... 0.05 M

- methanol q.s.p. . 10 cm3 In the anode compartment, 10 cm3 of a 0.1 M solution of hydrochloric acid in methanol is introduced.

The solution is deaerated by bubbling argon for 10 minutes, then the potential of the cathode is fixed at -2.0 volts relative to the reference electrode. After 2 hours 4 minutes of electrolysis, that is to say the time necessary for the passage of 66.5 coulombs, the electrolysis is stopped.

The electrolysis solutions are combined, then the medium is buffered by adding a few cm 3 of a methanolic solution of acetic buffer. After removing the solvent by concentration under reduced pressure at a temperature below 35 ° C, the residue is taken up in 20 cm3 of ethyl acetate and 20 cm3 of deionized water. After decantation, the aqueous phase is extracted with 2 times 10 cm3 of ethyl acetate. The organic phase is washed with 20 cm3 of a 0.2 M aqueous phosphate buffer solution at a pH close to 7. After drying and dry concentration of the organic phase at a temperature below 35 ° C, 95.7 is obtained mg of a crude product, the constituents of which are separated by preparative chromatography on a thin layer of silica gel. The crude product is taken up in the minimum of a dichloromethane-methanol mixture (50-50 by volume) then injected onto 1 plate of silica gel (Kieselgel 60 F 254, Merck) 2 mm thick, eluting with a mixture dichloromethane-acetonitrile-methanol (80-16-4 by volume). Is thus isolated, with a yield of 28%, 28.2 mg of tbutoxycarbonylamino-3 (3-thienyl) -3 hydroxy-2-propionate- (2R, 3S) of benzoyloxy-2α acetoxy-4 epoxy-5β, 20 dihydroxy- 1, 7α oxo-9 taxene-11 yle-13α and, with a yield of 24%, 24.2 mg of benzoyloxy tbutoxycarbonylamino-3 (3-thienyl) -3-hydroxy-2-propionate- (2R, 3S) -2α acetoxy-4 epoxy-5β, 20 dihydroxy-l, 7β oxo-9 taxene- 11 yle-13α which respectively have the following characteristics: a) benzoyl-oxy-2-acetoxy-4-epoxy-5β, 20 dihydroxy-l, 7α oxo-9 taxene-11 yle-13α-3 (tienoxycarbonylamino-3 (thienyl-3) -3 hydroxy-2 propionate- (2R, 3S) : -proton nuclear magnetic resonance spectrum (300 MHz; CDCI3 chemical shifts in ppm; coupling constants J in Hz): 1.16 (s, 3H -CH3 16 or 17); 1.21 (s, 3H: -CH3 16 or 17); 1.35 [s, 9H: -0 (013) 3]; 1.64 (s 3H: -CH3 19); 1.69 (s, 1H: -OH 1); 1.75 (s, 3H: -CH3 18); 1.80 [mt, 1H - (CH) -H 6]; 2.33 (mt, 2H: -CH2 1]; 2.34 (s, 3H: -COCH3); 2.61 [mt, IH - (CH) -H 6]; 3.40 (d, J = 5.5 , IH: -OH 2 '); 3.44 and 3.80 (dd, J = 16, IH each -CH ₂ 10); 4.05 (d, J ≈ 7, IH: -H 3); 4, 18 and 4.30 (2d, J = 8. IH each: -CH ₂ 20) 4.27 (mt, IH: -H 7); 4.62 (dd, J = 5.5 and 2, IH: - H 2 '); 4.94 (d wide, J = 9, IH: -H 5); 5.25 (d, J = 10, IH: -CONH-); 5.33 (d wide, J = 10 , IH: -H 3 ^* ); 5.70 (d, J = 7, IH: -H 2); 6.13 (mt, IH: -H 13); 7.13 (dd, J ≈ 5 and 2 , IH: -H 4 of thiophene); 7.30 (dd, J = 3.5 and 2, IH: -H 2 of thiophene); 7.36 (dd, J = 5 and 3.5, IH: -H 5 thiophene); 7.50 [t, J = 7.5, 2H: -OCOC ₆ H ₅ (-H 3 and -H 5)]; 7.62 [t, J = 7.5, 1H: -OCOC ₆ H ₅ (-H 4)]; 8.12 [d, J = 7.5, 2H: -OCOC ₆ H ₅ (-H 2 and -H 6)]. B) t.butoxycarbonylamino-3 (thienyl- 3) -3-hydroxy-2-propionate- (2R, 3S) of benzoyl-oxy-2α acetoxy-4 epoxy-5β, 20 dihydroxy-l, 7β oxo-9 taxene-11 yl-13α:

- proton nuclear magnetic resonance spectrum (300 MHz; CDCI3; chemical shifts in ppm; coupling constants J in Hz): 1.12 (s, 3H: -CH3 16 or 17); 1.20 (s, 3H: -CH3 16 or 17); 1.35 [s, 9H: -C (O3) 3]; 1.62 (s, 3H: -CH3 19); 1.68 (s, IH: -OH D; 1.72 (s. 3H: -CH3 18); 2.20 to 2.50 (mt, 4H: -CH2 1 and -CH2 6); 2.44 (s, 3H: -COCH3); 3.30 (broad s, IH: -OH 2 '); 3.42 and 4.10 (dd, J = 16.5, IH each: -CH2IO); 3.77 (ddd, J = 11, 6 and 4, IH: -H 7); 4.21 (d, J = 7, IH: -H 3); 4.38 (broad s, 2H: -Ofc 20); 4.54 ( d, J = 11, IH: -OH 7); 4.62 (dd, J = 6 and 2.5, IH: -H 2 '); 4.89 (dd, J = 8.5 and 5.5 . 1H: -H 5); 5.22 (d, J = 10, 1H: -CONH-); 5.34 (wide d, J = 10, 1H: -H 3 "); 5.76 (d, J = 7, 1H: -H 2); 6.17 (mt, 1H: -H 13); 7.12 (broad d, J = 5, 1H: -H 4 of thiophene); 7.30 (broad d , J = 3.5, 1H: -H 2 of thiophene); 7.36 (dd, J = 5 and 3.5, 1H: -H 5 of thiophene); 7.52 [t. J = 7.5 , 2H: -OCOC ₆ H ₅ (-H 3 and -H 5)]; 7.62 [t, J = 7.5, IH: -OCOC ₆ H ₅ (-H 4)]; 8.14 [d , J = 7.5, 2H: -OCOC ₆ H ₅ (-H 2 and -H 6)].

EXAMPLE 6

40 mg of t.butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) of benzoyloxy-2α dihydroxy-l, 7β epoxy-5β, 20 oxo-9 taxene-11 yl-13α are dissolved under the conditions from Example 1 in 1 cm3 of Emulphor EL 620 and 1 cm3 of ethanol then the solution is diluted by adding 18 cm3 of physiological saline.

The composition is administered by introduction into an infusion of a physiological solution for 1 hour.

Claims

1 - Process for the preparation of taxane derivatives of general formula

OCOC ₆ H ₅ in which: one of the symbols Ri or R2 represents a hydrogen atom and the other represents a hydroxy radical,

- R3 represents a hydrogen atom or a radical of general formula:

in which Ar represents an aryl radical, and

R4 represents a benzoyl radical or an R5-O-CO radical in which R5 represents an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, characterized in that it is carried out in a solvent or a mixture of solvents or a hydro-organic mixture, the electrolytic reduction of a product of general formula:

OCOC _g H ₅ in which R represents a hydrogen atom or an acetyl or alkoxyacetyl radical and R, R2 and R3 are defined as above in the presence of a support electrolyte. 2 - Process according to claim 1 characterized in that the electrolyte consists of a salt of magnesium, calcium, cerium ^ffl , strontium or lithium or, optionally, when R represents an acetyl or alkoxyacetyl radical of a salt of ammonium soluble in the solvent or mixture of solvents or in the hydroorganic mixture.

3 - Process according to claim 2 characterized in that the salt is chosen from magnesium chloride, calcium chloride, cerium chloride ^m , strontium chloride, lithium chloride and optionally ammonium chloride.

4 - Process according to claim 2 characterized in that the solvents are chosen from aliphatic alcohols and the hydroorganic mixture is an alcohol-water mixture.

5 - Process according to claim 4 characterized in that the solvent is methanol.

6 - Method according to one of claims 1 to 5 characterized in that the electrolysis is carried out in an electrolyser comprising a mercury cathode.

7 - Method according to one of claims 1 to 5 characterized in that the electrolysis is preferably carried out in a diaphragm electrolyser.

8 - Process according to claim 7 characterized in that the diaphragm consists of a porous material or by a cation exchange membrane.

9 - Method according to one of claims 1 to 8 characterized in that the electrolysis is carried out at a controlled potential of between -1.65 and -2.1 volts relative to a reference calomel electrode depending on the nature of the cation electrolyte;

10 - Process according to one of claims 1 to 9 for the preparation of a product of general formula (I) in which in which Ri and R2 being defined as in claim 1, R3 represents a hydrogen atom or a radical of general formula (H) in which:

Ar represents a phenyl or - or β-naphthyl radical optionally substituted by one or more atoms or radicals chosen from fluorine atoms or chlorine and alkyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, acylamino, aroylamino, alkoxycar¬ bonylamino, amino, alkylamino, dialkoylamino, carboxy, alkoxycarbonyl, carboxycarbonyl, carboxycarbonyl, carboxy, alkyl, carboxy , it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and the aryl radicals are the phenyl or α- or β- naphthyl radicals, or a heterocyclic aromatic radical 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 fluorine and chlorine atoms and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms arbone, amino, alkylamino containing 1 to 4 carbon atoms, dialcoylamino in which each alkyl part contains 1 to 4 carbon atoms, acylamino in which the acyl part contains 1 to 4 carbon atoms, alkoxycarbo-nylamino 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, dialcoylcarbamoyl of which each alkyl part contains 1 to 4 carbon or alkoxycarbonyl atoms of which the alkoxy part contains 1 to 4 carbon atoms, and

R4 represents a benzoyl radical or an R5-O-CO- radical in which R5 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 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from fluorine or chlorine atoms and hydroxy radicals, alkoxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 with 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 alkoxycarbonyl in which the alkyl part contains 1 to 4 a carbon tomes, - a phenyl radical optionally substituted by one or more radicals chosen from alkyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, carboxycarbonoxy radicals , carbamoyl, dialcoylcarbamoyl, cyano and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms

- or a saturated nitrogen heterocyclyl radical containing 4 to 6 members optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, 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.

11 - Method according to one of claims 1 to 9 for the preparation of a product of general formula (I) in which R and R2 being defined as in claim 1, R3 represents a radical of general formula (H) in which Ar represents a phenyl radical optionally substituted by a fluorine or chlorine atom or by an alkyl (methyl), alkoxy (methoxy), dialkoylamino (dimethylamino), acylamino, alkoxycarbonylamino or trifluoromethyl radical or a thienyl-2 or -3 or furyl radical -2 or -3 and R4 represents a benzoyl radical or an R5-O-CO- radical for which R5 represents a tbutyl radical.

12 - New taxane derivatives of general formula (I) Ri and R2 are defined as in claim 1 and R3 represents a radical of general formula (H) in which Ar represents a heterocyclyl radical defined as in one of claims 10 or 11 and R4 represents a benzoyl radical or a radical of general formula R5-O-CO in which R5 is defined as in one of claims 1, 10 or 11.

13 - Pharmaceutical composition characterized in that it contains a sufficient amount of at least one derivative according to claim 12 in the pure state or in combination with one or more pharmaceutically acceptable products.