FR2697841A1 - New taxane derivatives, their preparation and the pharmaceutical compositions containing them. - 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

dans laquelle:
un des symboles R1 ou R2 représente un atome d'hydrogène et l'autre représente un radical hydroxy, - R3 représente un atome d'hydrogène ou un radical de formule générale:

dans laquelle
Ar représente un radical aryle, et
R4 représente un radical benzoyle ou un radical Rs-O-CO dans lequel R5 représente un radical alcoyle, alcényle, cycloalcoyle, cycloalcényle, bicycloalcoyle, phényle ou hétérocyclyle.NEW TAXANE DERIVATIVES. THEIR PREPARATION AND THE
PHARMACEUTICAL COMPOSITIONS YES CONTAINING THEM
The present invention relates to new taxane derivatives of general formula:

in which:
one of the symbols R1 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 Rs-O-CO radical in which R5 represents an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical.

More particularly, the present invention relates to the products of general formula (I) in which R1 and R2 being defined as above, R3 represents a hydrogen atom or a radical of general formula (II) in which:
Ar represents a phenyl or a- or Fnaphthyl 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, mercapto radicals , acylamino, aroylamino, alkoxycarbonylamino, amino, alkyllamino, dialcoylamino, carboxy, alkoxycarbonyl, 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 and the radicals are carbon atoms and phenyl or a- or frnaphthyl radicals,
R4 represents a benzoyl radical or an Rs-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, cycloalkyl containing 3 to 6 atoms of carbon, 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 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 of 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 e of which the alkyl part contains 1 to 4 carbon atoms, - a phenyl radical optionally substituted by one or more radicals chosen from alkyl radicals containing 1 to 4 carbon atoms and alkoxy radicals containing 1 to 4 carbon atoms, - or a radical saturated nitrogen heterocyclyl containing 5 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 carbon.

 More particularly still, the present invention relates to the products of general formula (I) in which R1 and R2 being defined as above, R3 represents a radical of general formula (II) in which Ar represents a phenyl radical optionally substituted by an atom of fluorine or chlorine or by an alkyl (methyl), alkoxy (methoxy), dialkoylamino (dimethylamino), acylamino, alkoxycarbonylamino or trifluoromethyl radical and R4 represents a benzoyl radical or an Rs-O-CO- radical for which R5 represents a t radical .butyle.

 The products of general formula (I) in which R1 and R2 are defined as above and R3 represents a radical of general formula (II) have remarkable antitumor and antileukemic properties.

dans laquelle R représente un atome d'hydrogène ou le radical acétyle et R3 est défini comme précédemment.According to the present invention, the new products of general formula (I) can be obtained by electrolytic reduction of a product of general formula:

in which R represents a hydrogen atom or the acetyl radical and R3 is defined as above.

According to the invention, the reduction of the RO- group is carried out electrochemically according to the following reaction:

 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 or calcium ions or optionally, when R represents the acetyl radical, ammonium ions (NH4 + ) and a solvent or a mixture of solvents or a hydro-organic mixture in which the product of general formula (dissolved) is dissolved at a concentration of between 0.1 g'l and the saturation of the solution .

 The quantity of theoretical electricity necessary to effect the reduction of a product of general formula (m) into product of general formula a; R1 = OH and R2 = H) and a; R1 = H and R2 = OH) is 2 faradays (or 193,000 coulombs) per molecule.

 According to the conditions for implementing the electrolytic process, it is possible to obtain only the product of general formula (I) for which R1 represents a hydroxy radical and R2 represents a hydrogen atom.

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

 According to an 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 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 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 (leaked) in an organic or hydroorganic medium and an electrolyte containing magnesium or calcium ions 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 the anolyte preferably consisting of the same solvent or mixture of solvents and the same support electrolyte as that used in the cathode compartment, e) the anode is made of an electrically conductive material, the nature of which is not essential for the process work.

 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 or optionally ammonium salt, such as magnesium chloride, calcium chloride or ammonium chloride, soluble in the solvent or the mixture of solvents. Generally, protic 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; R1 = OH and R2 = H) and (I; R1 = 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 t.butanol 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 . 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, which can be fixed.

approximately between 1.80 and -1.95 volts with respect to a calomel reference electrode, preferably at -1.85 volts.

 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.

 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 process 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, R1 represents a hydroxy radical and R2 represents a hydrogen atom and, on the other hand, R1 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 and R3 represents a hydrogen atom correspond respectively to deacetyl-10 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 and R3 represents a radical of general formula (II) in which Ar represents an aryl radical and R4 represents a benzoyl radical respectively correspond to deacetyl- 10 taxol and taxol which can be obtained according to the methods described in European patents EP 0253 739,
EP 0 336 840, EP 0 400 971 and EP 0 428 376 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 t.butoxycarbonyl radical can be obtained according to the methods described in European patents EP 0 253 738 and EP 0 336 841 or in the international PCT application
WO 9209589.

dans laquelle Ar est défini comme précédemment, G1 représente un groupement protecteur de la fonction hydroxy tel qu'un radical trichloro-2,2,2 éthoxycarbonyle ou trialcoylsilyle, dialcoylarylsilyle, alcoyldiarylsilyle ou triarylsilyle dans lequel chaque partie alcoyle contient 1 à 4 atomes de carbone et chaque partie aryle représente de préférence un radical phényle et G2 représente un radical acétyle ou un groupement protecteur de la fonction hydroxy tel qu'un radical trichloro-2,2,2 éthoxycarbonyle pour donner un produit de formule générale:

dans laquelle Ar, Rg, G1 et G2 sont définis comme précédemment, suivie du remplacement des groupements protecteurs G1 et G2 par des atomes d'hydrogène.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 R4 represents a radical Rs-O-CO- can be obtained by action of '' a reactive derivative of general formula:
R5-O-CO-X (IV) in which X represents a halogen atom (fluorine, chlorine) or a residue -O-Rs or -O-CO- R5 on a derivative of baccatin III or deacetyl- 10 baccatin III of general formula::

in which Ar is defined as above, G1 represents a protecting group for the hydroxy function such as a 2,2,2-trichloroethoxycarbonyl or trialcoylsilyl, dialkoylarylsilyl, alkoyldiarylsilyl or triarylsilyl radical in which each alkyl part contains 1 to 4 carbon atoms and each aryl part preferably represents a phenyl radical and G2 represents an acetyl radical or a protecting group for the hydroxy function such as a 2,2,2,2-trichloroethoxycarbonyl radical to give a product of general formula:

in which Ar, Rg, G1 and G2 are defined as above, followed by the replacement of the protective groups G1 and G2 by hydrogen atoms.

 Generally, the action of the reagent of general formula (IV) on the derivative of baccatin m or of deacetyl-10 baccatin III 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 500C, preferably close to 20 "C.

 Generally the replacement of the protective groups G1 and G2 of the product of general formula (VI) by hydrogen atoms is carried out by treatment with zinc in the presence of acetic acid at a temperature between 30 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 in the presence of zinc when G1 and / or G2 represent a 2,2,2-trichloro radical ethoxycarbonyl, or 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 400C when G1 and / or G2 represent a silylated radical.

The products of general formula (I) for which R3 represents a hydrogen atom are useful for preparing the products of general formula (I) for which R3 represents a radical of general formula (II) according to methods analogous to those which are described in European patents EP 0 253 738,
EP 0 253 739, EP 0 336 840, EP 0 336 841, EP 0400 971 or EP 0 428 376 or in the international PCT application WO 9209589.

 The new products of general formula (I) in which R1 and R2 being defined as above, R3 represents a radical of general formula (II) manifest a significant inhibitory activity of abnormal cell proliferation and have therapeutic properties allowing the treatment of patients having 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, lymphatic or renal systems, mammary or blood cells, liver, digestive system, pancreas and thyroid or adrenal glands.These pathological conditions may also include psoriasis, solid tumors, ovarian cancer, breast, brain, prostate, colon, stomach, kidney or testes, Kaposi's sarcoma, cholangioearcinoma, 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 includes 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, b or d) and TNF. Other chemotherapeutic agents useful in the treatment of disorders caused by abnormal proliferation cells 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 such as mercaptopurine and thioguanine, natural products such as vinca alkaloids such as vinblastine, vincristine and vendesine, epipodophyllotoxins com me etoposide and teniposide, antibiotics like dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes like L-asparaginase, various agents like platinum coordination complexes like cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocotic suppressants such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as 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 mglkg and, preferably between 0.5 and 50 mglkg and, even more specifically between 1 and 10 mgSkg. Intravenously, the doses are generally between 0.1 and 50 mglkg and, preferably between 0.1 and 5 mg / kg and, even more specifically between 1 and 2 mglkg. 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
Electrolytic reduction of t.butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) of acetoxy4 benzoyloxy-2a epoxy- 5 t3, 20 trihydroxy-1,7ss, 10ss oxo-9 taxene-11 yle-13a (or Taxotere) in an electrolysis cell having the following characteristics: - the cell is a 10 cm3 glass vase divided into two 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, 4 cm3 of a solution containing: - tbutoxycarbonylamino-3-phenyl-3-hydroxy-2-propionate- (2R, 3S) of 4-acetoxy-benzoyloxy-2a epoxy-5ss, 20 trihydroxy-1,7ss are introduced , 10ss oxo-9 taxene-11 yle-13a (or Taxotere) ... .......... ... 51.1 mg - calcium chloride .... .... . qs. 0.05M - methanol ........... ................ ................ qs 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 the organic phase, separated by decantation, on magnesium sulfate, the solvent is evaporated off under reduced pressure at a temperature below 35 C. This gives 42.3 mg of crude product, the constituents of which are separated by preparative chromatography on thin layer of silica gel (thickness: 0.25 mm), eluting with a dichloromethane-methanolacetonitrile mixture (84-8-8 by volume) 7.4 mg of t.butoxycarbonylamino is thus obtained with a yield of 15% -3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy4 benzoyloxy-2a epoxy-5ss, 20 dihydroxy-1,7ss oxo-9 taxene-11 yle-13a, i.e. a one product of general formula (I) for which R1 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) of acetoxy4 benzoyloxy-2a epoxy-5ss, 20 dihydroxy-1,7a oxo-9 taxene 11 yle-13a, that is to say a product of formula ge mineral (I) for which R1 represents a hydrogen atom and R2 represents a hydroxy radical
EXAMPLE 2
The electrolytic reduction of 3-benzoylamino-3-phenyl-2-hydroxy-propionate- (2R, 3S) of benzoyloxy-2a diacetoxy-4,10ss epoxy-5ss, 20 dihydroxy-1,7ss oxo-9 taxene-11a-13a 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.

10 cm3 of a solution containing: - 3-benzoylamino-3-phenyl-2-hydroxy-propionate- (2R, 3S) of benzoyloxy-2a diacetoxy-4, 10 (3 epoxy-5ss, 20 dihydroxy-) are introduced into the cathode compartment 1.7 (3 oxo-9 taxene-1 yle-13a ... ... 61.9 mg - ammonium chloride ... .................. ......... ...... qs 0.1M - ammonia [33% aqueous solution (w / v) .. ... 0.2 cm3 - methanol ... ... . ............. .. ................. from 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, 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 then the solvent is 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 2 times 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 [ethyledichloromethane-methanol acetate (55-40-5 by volume)]. Is thus isolated, with a yield of 45%, 26.3 mg of benzoylamino-3-phenyl-3-hydroxy-2-propionate- (2R, 3S) of benzoyloxy-2a acetoxy-4 epoxy-5ss, 20 dihydroxy-1,7 ( 3 oxo-9 taxene-li yle-13a.

EXAMPLE 3
40 mg of tbutoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3 S) of benzoyloxy-2a dihydroxy-1,7ss epoxy-5 (3.20 oxo-9 taxene-1 1 yle-13a) obtained are dissolved in the conditions of 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 (13)

1 - New taxane derivatives of general formula:

 in which: - one of the symbols R1 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 Rs-O-CO radical in which R5 represents an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical.  2 - New taxane derivative according to claim 1 for which R1 and R2 being defined as in claim 1, R3 represents a hydrogen atom or a radical of general formula (II) in which Ar represents a phenyl radical or a- or Fnaphthyl 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, mercapto, acylamino, aroylamino, alkoxycarbonylamino, amino radicals alkylamino, dialkoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkoylcarbamoyl, cyano and trriluoromethyl, 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 a- or -naphthyl radicals ,  R4 represents a benzoyl radical or an Rs-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, cycloalkyl containing 3 to 6 atoms of carbon, 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 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 of 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 e, the alkyl part of which contains 1 to 4 carbon atoms, - a phenyl radical optionally substituted by one or more radicals chosen from alkyl radicals containing 1 to 4 carbon atoms and alkoxy radicals containing 1 to 4 carbon atoms, - or a radical saturated nitrogen heterocyclyl containing 5 to 6 songs 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 carbon.  3 - New taxane derivative according to claim 1 for which R1 and R2 being defined as in claim 1, R3 represents a radical of general formula (II) 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 and R4 represents a benzoyl radical or an Rs-O-CO- radical for which R5 represents a t.butyl radical.  4 - Process for the preparation of a taxane derivative according to one of claims 1, 2 or 3 characterized in that the electrolytic reduction of a product of general formula is carried out:

 in which R represents a hydrogen atom or the acetyl radical and R3 is defined according to one of claims 1, 2 or 3.  5 - Process according to claim 4 characterized in that the electrolyte consists of a magnesium or calcium salt or, optionally, when R represents the acetyl radical of an ammonium salt soluble in the mixture of solvents or in the hydroorganic mixture.  6 - Process according to claim 5 characterized in that the salt is chosen from magnesium chloride, calcium chloride and optionally ammonium chloride.  7 - Process according to claim 5 characterized in that the solvents are chosen from aliphatic alcohols and the hydroorganic mixture is an alcohol-water mixture.  8 - Process according to claim 7 characterized in that the solvent is methanol.  9 - Method according to one of claims 1 to 8 characterized in that the electrolysis is carried out in an electrolyser comprising a mercury cathode.  10 - Method according to one of claims 1 to 8 characterized in that the electrolysis is preferably carried out in a diaphragm electrolyser.  11 - Method according to claim 10 characterized in that the diaphragm is constituted by a porous material or by a cation exchange membrane.  12 - Method according to one of claims 1 to 11 characterized in that the electrolysis is carried out at controlled potential.  13 - Pharmaceutical composition characterized in that it contains a sufficient amount of at least one derivative according to one of claims I to 3 for which R3 represents a radical of general formula (II) in the pure state or in combination with one or several pharmaceutically acceptable products.