SK49995A3 - Taxane derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Novel taxane derivatives of general formula (I), their preparation by electrochemical reduction of a taxane derivative of general formula (III) and pharmaceutical compositions containing a product of general formula (I) in which R3 is a radical of general formula (II) having outstanding antitumor and antileukemia properties. In general formula (I), one of the symbols R1 or R2 is a hydrogen atom while 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 an R5-O-CO- radical in which R5 is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical and R6 is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl optionally substituted aryl or heterocyclyl radical.

Description

Technical field

The invention relates to novel taxane derivatives of the general formula

wherein one of R ¹ or R ² is hydrogen and the other of hydroxy is hydroxy

R ³ is hydrogen or a radical of the formula II

in which

Ar represents an aryl group and

R ⁴ represents a benzoyl radical or a radical ^R -0-C 0, wherein ^R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and

R ^e represents an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl or aryl group or a heterocyclic group.

In particular, the invention relates to compounds of formula I in which:

R, R ¹ and R ² are defined as above,

R ³ represents a hydrogen atom or a group of the formula II in which

Ar represents an aryl group and

R ⁴ represents a benzyl group or a group of the formula

^R -0-C0-, wherein R is ^a straight or branched alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl group having 7 to 10 carbon atoms, these groups being optionally substituted by one or more substituents selected from the group consisting of a fluorine atom, a chlorine atom, a hydroxy group, a 1-4 carbon atom alkoxy group, a dialkylamino group, wherein each alkyl moiety contains 1 to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl (optionally substituted at the 4-position with alkyl containing 1 to 4 carbon atoms or phenylalkyl, wherein the alkyl moiety contains 1 to 4 carbon atoms )> cycloalkyl group containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, a phenyl group, a cyano group, a carboxyl group and an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms, or R ^a is phenyl optionally substituted by one or more substituents selected from the group consisting of alkyl having 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms, or R ^a is a 5- or 6-membered saturated heterocyclic group optionally substituted by one or more alkyl radicals containing 1 up to 4 carbon atoms, wherein the cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms, and

R ⁶ represents a straight or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms or a bicycloalkyl group having 7 to 11 carbon atoms, these groups being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, a hydroxy group, an alkyloxy group having 1 to 4 carbon atoms, a dialkylamino group in which each alkyl moiety it contains 1 to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl (optionally substituted at the 4-position with 1-4 carbon atoms or phenylalkyl, the alkyl radical of which contains 1 to 4 carbon atoms), cy (C 3 -C 6) -cloalkyl, optionally substituted phenyl, cyano, carboxyl and alkyloxycarbonyl, the alkyl radical of which contains 1 to 4 carbon atoms, or aryl optionally substituted by one or more substituents selected from the group consisting of halogen atoms, a (C 1 -C 4) alkyl group and a (C 1 -C 4) alkyloxy group, or

A 4- to 6-membered saturated or unsaturated nitrogen heterocyclic group optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms, wherein the cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms; up to 4 carbon atoms.

Preferably, the aryl radicals which can be represented by Ar, and R ⁶ phenyl or .alpha.- or .beta.-naphthyl which are optionally substituted by one or miekoľkými substituents selected from halogen atoms (fluorine, chlorine) and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxy-alkyl, mercapto, formyl, acyl, acylamino, aroylamino- an alkoxycarbonylamino group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a dialkylcarbamoyl group, a cyano group and a trifluoromethyl group, provided that the alkyl groups and alkyl radicals are other groups contain 2 to 8 carbon atoms and the aryl groups are phenyl or alpha- or beta-naphthyl groups.

Preferably, heterocyclic groups Ar are 5-membered aromatic heterocyclic groups containing one or more of the same or different atoms selected from the group consisting of nitrogen, oxygen and sulfur and optionally substituted with one or more of the same or different substituents selected from the group consisting of atoms halogens (chlorine, fluorine), (C 1 -C 4) alkyl, (C 6 -C 10) aryl, amino, (C 1 -C 4) alkylamino, dialkylamino, wherein each alkyl radical contains 1 to 4 carbon atoms, 1 to 4 carbon alkoxycarbonylamino, 1 to 4 carbon acyl, arylcarbonyl having 6 to 10 carbon atoms, cyano, carboxyl, carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains l to 4 carbon atoms, and alkyloxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms.

More particularly, the invention relates to compounds of formula I wherein R ¹ and R ² are as defined above, R ³ represents a group of formula II wherein Ar is a phenyl group optionally substituted by a fluorine or chlorine atom, an alkyl (methyl) (alkoxy), dialkylamino, (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (t-butoxycarbonylamino) or trifluoromethyl, or 2- or 3-thienyl or 2- or 3-furyl group, R ⁴ represents a benzoyl radical or a radical ^with R -O-CO-, wherein ^R is tert-butyl and R ⁶ is phenyl optionally substituted with halogen.

Compounds of formula I wherein R ¹ , R ² and R ^e are as defined above and R ³ is a group of formula II have antitumor and anti-leukemic properties.

The novel compounds of the formula I can be obtained according to the invention by electrolytic reduction of a compound of the formula III

wherein R ³ and R ^e are as defined above.

Within the scope of the invention, the reduction of the carbonyl group -C0 is carried out electrochemically according to the following equation:

The electrolytic reduction of the product of formula III is carried out in a catholyte-containing electrolyzer consisting of a carrier electrolyte containing ammonium ions (NH4 +) and a solvent or solvent mixture in which the compound of formula III is dissolved in a concentration ranging from 0.1 g / l to a concentration saturated solution.

When in the compound of formula III to a hydroxy group in position 7 as a 7alpha, then the particular form the compound of formula I, wherein R ^x is H, R ² is hydroxy and the hydroxy group at 7-position is in the form of 7alpha.

Where the electrolytic reduction takes place in an acid medium and in the presence of calcium ions, the electrolytic reduction of a compound of formula III leads in particular to a product of formula I, wherein R ^x is hydrogen and R ² is hydroxy, independently of the configuration of hydroxy functions in position 7.

The amount of electrical charge that is theoretically necessary to effect the reduction of a compound of formula III to a compound of formula I is 2 Faraday (or 193000 coulombs) per molecule.

Preferably, said reduction is carried out in a membrane electrolyzer.

According to one embodiment of the method according to the invention, the electrolytic reduction is carried out in an electrolyzer equipped with a cathode, cathode compartment, separation membrane, anodic compartment and anode, the individual parts of the electrolyzer having the following characteristics:

(a) the cathode is comprised of a current conducting material, said cathode being subjected to said reduction at a potential greater than that of a solvent or one of the carrier electrolyte components, or at a potential where the solvent or one of the carrier electrolyte components is not sufficiently significant to interfere with the reduction of said compound,

b) the cathode compartment comprises a catholyte formed by a solution of a compound of formula III in an organic or aqueous-organic medium and an electrolyte containing ammonium ions (NH4 +); the pH can be maintained in a slightly alkaline range, i.e. preferably in the range of 7 to 9, by the addition of ammonia; catholyte may also be acidic and contain calcium ions provided e.g. calcium chloride and with respect to the preferential yield of product of formula I in kto8 rom R ^x is hydrogen and R ² is hydroxy,

c) the separation membrane consists of a porous material such as a glass frit or porcelain plate, sheath or candle, or an ion exchange membrane, preferably a cation exchange membrane,

d) the anode compartment comprises an anolyte consisting preferably of the same solvent or the same solvent mixture and the same carrier electrolyte as used in the cathode compartment; the anolyte can also be formed by an acidic solution that allows the pH in the catholyte to be maintained through the cation exchange membrane during electrolysis; preferably a dilute solution of hydrochloric acid in methanol is used,

e) the anode is a current conducting material, and the nature of the anode is not a determining factor in the practice of the method of the invention.

Generally, the anode is a current conducting material which resists the conditions of electrolysis, in particular polished platinum, optionally arranged on a conductive support, graphite or glass carbon.

The cathode preferably comprises a mercury level.

The carrier electrolyte forms an ammonium salt, such as ammonium chloride, dissolved in a solvent or solvent mixture. Usually, protic solvents that readily dissolve the compounds of formulas I and III, and which allows for easy isolation of the compounds of formula I ^(R1 = H and ^R2 = OH and ^R1 = OH and ^R2 = H). Preferably, an aliphatic alcohol containing 1 to 4 carbon atoms, such as methanol, ethanol, isopropanol or tert-butanol, is used as the solvent.

The pH value must be compatible with the stability of the substrate and can be maintained in a mild alkaline area during electrolysis, i.e. a pH value of 10%. preferably between 7 and 9, adding an aqueous ammonia solution or bubbling ammonia gas if the electrolysis is carried out in the presence of ammonium ions or can be maintained in the acidic region by adding hydrochloric acid if the electrolysis is carried out in the presence of calcium ions provided for example with calcium chloride .

The nature of the membrane separating the anolyte from the catholyte is not a critical parameter of the invention. Accordingly, a membrane of any known type consisting of a porous material such as glass frit or porcelain, optionally containing a conductive gel to limit the diffusion of the reactants, or an ion exchange membrane, preferably a cation exchange membrane, may be used. These membranes may be of a homogeneous or heterogeneous type and may optionally be crosslinked. Preferably, membranes are used which do not expand and do not encapsulate and which are stable in the presence of the individual components of the anolyte and the catholyte.

In one embodiment of the method of the invention, the anode, cathode and separation membrane are arranged in parallel planes, preferably in horizontal planes, when the cathode forms a mercury level.

The temperature of the electrolytic bath generally ranges from 0 to 30 ° C.

The electrolysis is performed at a controlled potential, which potential can be set to a value between about -1.75 and -1.9 volts relative to the reference calomel electrode, preferably -1.85 volts.

The theoretical amount of electrical charge required to conduct electrolysis is 2 Faraday (or 193,000 coulombs) per mole of the compound of Formula III. In practice, the need for electric charge may be 2 to 5 times that of the theoretical amount.

The catholyte can be circulated, for example, by means of a pump.

Such a circulation circuit may additionally comprise accompanying devices such as heat exchangers and expansion vessels. In particular, such an expansion vessel makes it possible to supply the catholyte with a compound of the formula III and also allows the catholyte to be withdrawn in order to isolate the compound of the formula I.

Likewise, the anolyte can be circulated. According to a preferred embodiment of the invention, the circumference of the catholyte is the same as the circumference of the anolyte, which makes it possible to achieve equilibrium on both sides of the separation membrane.

According to another specific embodiment of the invention, baffles are provided in the anode and cathode compartments. These baffles serve to prevent both the ion-exchange membrane deformations and the contact of the membrane with the electrodes. These baffles also serve to improve the homogeneity of the catholyte concentration.

In the absence of the barrier, the rate of circulation of the catholyte in the cathode space is usually greater than 10 cm / s, preferably greater than 50 cm / s. If a baffle is used, then the apparent catholyte velocity (i.e., velocity in the cathode space seemingly without baffle) is usually greater than 1 cm / s, preferably greater than 10 cm / s.

According to a further embodiment of the invention, the cell can be simply formed by a cuboid or cylindrical vessel made of a material which is inert to the components of the electrolyte. The vessel comprises a working electrode the nature of which is the same as that of the first type of cell. The shape of the working electrode is adapted to the shape of the container.

The electrolysis cell generally comprises an anode and a cathode, which are separated by one or more membranes providing ion conductivity, the arrangement of the individual elements of the cell being not an essential parameter of the method of the invention.

The compounds of formula (I) obtained by carrying out the process of the invention are separated using conventional methods.

An embodiment of the process according to the invention leads to a mixture of the corresponding products of the formula I in which R ^{@ 1} is hydroxy and R @ ² is hydrogen using the starting product of formula III, in which the hydroxy configuration at the 7-position has the form 7beta. on the one hand, R ^{@ 1} is hydroxy and R @ ² is hydrogen, the separation of the products thus obtained can be carried out by one of the known methods, for example by chromatography.

Compounds of formula III in which R ⁶ is a phenyl group and R ³ is a hydrogen atom correspond to 10-deacetylbaccatin III, which can be isolated using known methods from extracts of various yew species (Taxus sp.).

The compounds of formula III, wherein R ³ is a group of formula II, wherein Ar is aryl and Ar is benzoyl, the corresponding 10-deacetyl taxol and analogs thereof, which may be obtained by methods described in EP 0253739, EP 0 336 840, EP 0 400 971 and EP 0 428 376 or PCT International Patent Application WO 9209589.

Compounds of formula III in which R ⁶ represents a phenyl group and R ³ represents a group of formula II in which Ar represents an aryl group and R "represents a tert-butoxycarbonyl group can be obtained by the methods described in European patents EP 0 253 738, EP 0 336 841, or PCT International Patent Application WO 9209589.

Compounds of formula III in which R ⁶ represents a phenyl group and R ³ represents a group of formula II in which R ⁴ represents a group R ⁵ -O-CO- can be obtained by treatment with a reactive derivative of formula IV

^The R-O-CO-X (IV) wherein X is a halogen (chlorine, fluorine) or a radical -0-R, or ^a radical -O-CO-R ^5, a derivative of 10-deacetylbaccatin III of general formula V

wherein Ar is as defined above, G ¹ is a hydrogen atom or a hydroxy function, such as 2,2,2-trichloroethoxycarbonyl or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl, in which each alkyl moiety contains 1 to 1 4 carbon atoms and each aryl radical preferably represents a phenyl group, and G ² represents a hydrogen atom or a hydroxy function protecting group, which is preferably a 2,2,2-trichloroethoxycarbonyl group, to form a compound of formula VI ₅ ^Ar > R -O- CO-NH

wherein Ar, ^R, G ¹ and G ² are defined as above, followed by replacement of the protective groups G ¹ and G ² by hydrogen atoms.

Generally, the treatment of a reactive derivative of formula IV with a baccatin III or 10-desacetylbaccatin III derivative of the formula V is carried out in an organic solvent such as an ester such as ethyl acetate in the presence of a mineral or organic base such as sodium bicarbonate at 0 to 50 ^e. c, preferably at a temperature near 20 ° C.

In general, the replacement of the protecting groups G ¹ and G ^{2 of the} product of formula VI with hydrogen atoms is carried out by treatment with zinc in the presence of acetic acid at 30 to 60 ° C or with 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 G ¹ and / or G ² represents a 2,2,2-trichloroethoxycarbonyl group, or in an acid medium such as hydrochloric acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol , ethanol, isopropanol) or aqueous hydrofluoric acid at 0 to 40 ° C when G ¹ and / or G ² is a silylated group or an alkoxyacetyl group.

Compounds of formula III wherein R ³ is a group of formula II and R ^e is as defined above may be obtained by esterification of a compound of formula VII

wherein Ar, R ^4, G ^x and G ² are defined as above and R ⁷ is H and R ^a represents a group protecting the hydroxyl function, or alternatively R ⁷ and R ^a together the form a 5- or 6-membered saturated heterocycle, using an acid of formula VIII

R ⁶ -COOH (VIII) wherein ^R is as defined above, or a derivative of this acid, to give a compound of formula IX

(IX) wherein Ar, R ^4, R ^6, R ^7, R®, G ¹ and G ² are defined as above, in which the replacement of the protective group ^R, if R ⁷ is a hydrogen atom, or alternatively R and R ^{7 in} the case where R ⁷ and R ^a together form a 5- or 6-membered saturated heterocycle, G ^x and G ² or hydrogen to form a compound of formula III, wherein R has the meanings according to ^4, R ^7, and R ⁸ proceeds through the compound of formula X

OCO 1 wherein Ar, R ⁵ , G ¹ and G ² have the meanings given above, which is acylated using benzoyl chloride or the product of formula IV, before possibly replacing the G ¹ and G ² groups with hydrogen atoms.

The compound of formula VII can be obtained by electrolytic reduction of a compound of formula XI

OCOC ₆ H ₅ (XI) wherein Ar, R ⁴ , R ⁷ , R ^a , G ¹ represent a hydrogen atom or a hydroxy function protecting group, which is preferably a silylated group, and G ² represents a hydrogen atom or a hydroxy function protecting group which is preferably alkoxyacetyl, followed by the replacement of the protective groups R ^7, R ^a, G ¹ and G ² by hydrogen atoms.

Compounds of formula I wherein R ³ is hydrogen are useful for the preparation of compounds of formula I wherein R ³ is a group of formula II by methods analogous to those described in European patents EP 0 253 738, EP 0 253,739, EP 0 336,840, EP

336 841, EP 0 400 971 and EP 0 428 376 or PCT International Patent Application WO 9209589.

The novel compounds of formula I, wherein R ¹ and R ² are as defined above and R ³ is a group of formula II, have a significant inhibitory effect on abnormal cell proliferation and therapeutic properties allowing the treatment of patients suffering from pathological conditions accompanying such abnormal cell proliferation . These pathological conditions include abnormal cell proliferation of malignant and non-malignant cells of various tissues and / or organs, including, for example, muscle, bone or joint tissues, skin, brain, lung, genital organs, lymphatic or renal systems, milk or blood cells, liver, digestive tract , pancreas and thyroid and adrenal glands. These pathological conditions may also include psoriasis, solid tumors, ovarian cancer, breast cancer, brain cancer, prostate cancer, colon cancer, stomach cancer, kidney cancer or testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms Hodgkin's disease, melanomas, multiplex myelomas, chronic lymphocytic leukemia, and acute or chronic granulocyte lymphomas. The novel compounds of the invention are particularly useful for the treatment of ovarian cancer. The compounds of the invention may be used to prevent or delay the symptoms or relapses of said pathological conditions or to treat such pathological conditions.

These products can be administered to the patient in a variety of forms adapted to the chosen mode of administration, with oral administration being the preferred mode of administration. Parenteral administration includes intravenous administration, intraperitoneal administration, intramuscular administration, or subcutaneous administration. A particularly preferred administration is intraperitoneal administration or intravenous administration.

The invention also encompasses pharmaceutical compositions comprising at least one compound of Formula I in a sufficient amount adapted for use in human or veterinary therapy. These compositions may be prepared by conventional methods using one or more ingredients, carriers or excipients which are pharmaceutically acceptable. Suitable carriers include diluents, sterile aqueous media, and various non-toxic solvents. Preferably, the compositions are in the form of aqueous solutions or suspensions and injectable solutions which may contain emulsifying agents, coloring agents, preservatives or stabilizers.

The choice of excipients or excipients may dictate the solubility and chemical properties of the active compound used, the type of administration used, and pharmaceutical usage.

For parenteral use, aqueous or non-aqueous sterile solutions or suspensions are used. Natural vegetable oils such as olive oil, sesame oil or paraffin oil, or injectable organic esters such as ethyl oleate may be used to prepare non-aqueous solutions or suspensions. Aqueous sterile solutions may form a solution of a pharmaceutically acceptable salt in water. Aqueous solutions are suitable for intravenous administration when their pH is appropriately adjusted and their isotonicity is ensured, for example by a sufficient amount of sodium chloride or glucose. Sterilization may be accomplished by heating or by any other suitable means which does not adversely affect the properties of the composition.

Of course, all compounds used in the compositions of the invention must be pure and nontoxic in the amounts used.

Said compositions may comprise at least 0.01% of a therapeutically active compound. The amount of active compound in the composition is such that it permits the prescription of a suitable dosage. Preferably, the compositions are prepared in such a manner that a unit dose of the composition contains about 0.01 to 1000 mg of the active compound for administration by the parenteral route.

Treatment with the compounds of the invention may be performed concomitantly with other therapies, including administration of antineoplastic drugs or monoclonal antibodies, immunological therapy or radiotherapy, or administration of biological response modifiers. Biological response modifiers include, for example, lymphokines and cytokines such as interleukins, interferons (alpha, beta or gamma) and TNF. Other chemotherapeutic agents useful for treating disorders associated with abnormal cell proliferation include, for example, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophpsphamide, melphalan and chlorambucil, alkylisulfonates such as busulfan, nitrosoureas such as carmustine, lomusine, lomusine, lomusine, lomusine 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 alkaloids de vinea such as vinblastine, vineristine and vendeslide, epipodine, epipodine, epipodine teniposide, antibiotics such as dac18 tinomycin, daunorubicine, doxorubicine, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, procarbhydrazine derivatives adrenocorticoid suppressors such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megastroacetate, oestrogens such as diethylstilbestroles, and tamoxifestone ester, and tamil oestrogen esters, such as tamoxifluorone;

Useful dosages are those that allow for prophylactic treatment or elicit maximal therapeutic response. These doses depend on the form of administration, the particular compound employed and the characteristics of the patient. Generally, these doses are those that are therapeutically effective in the treatment of disorders associated with abnormal cell proliferation. The compounds of the invention may be administered as often as necessary to achieve the desired therapeutic effect. In some patients, a rapid response may be achieved after relatively high or low doses, with little or no maintenance at all. Generally, low doses are administered at the start of treatment, where necessary, the doses are increasingly administered until the optimum effect is achieved. In other patients, it may be necessary to administer maintenance doses 1- to 8-times a day, preferably 1- to 4-times a day, depending on the physiological need of the particular patient. It is also possible that in some patients only one to two daily administrations are necessary.

In humans, said doses are generally between 0.01 and 200 mg / kg. For intraperitoneal administration, doses generally range between 0.1 and 100 mg / kg, preferably between 0.5 and 50 mg / kg, and more particularly between 1 and 10 mg / kg. For intravenous administration, doses generally range between 0.1 and 50 mg / kg, preferably between 0.1 and 5 mg / kg and even more specifically between 1 and 2 mg / kg. Of course, in order to determine the most appropriate dosage, it will be necessary to take into account the route of administration, the weight of the patient, his general health, age, and other factors that could affect the effectiveness of the treatment.

In the following, the invention will be explained in more detail by means of specific examples thereof, which are illustrative only and are not intended to limit the scope of the invention, which is clearly defined by the definition of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

In this example, 4-acetoxy-2alpha-benzyloxy-5beta, 20-epoxy-1beta, 7beta, 10beta-trihydroxy-9-oxo-11-taxen-13alpha-yl-3-tert-butoxycarbonylamino-3-phenyl-2- hydroxypropionate configuration (2R, 3S) (or Taxotere) in an electrolysis cell having the following characteristics:

the cell consists of a glass vessel containing 25 cm ³ , divided into two spaces by a cation exchange membrane, the cathode is a mercury level with an effective surface of about 12 cm ² , the anode is a platinum mesh, the reference electrode is a saturated calomel electrode.

25 cm ^{3 of a} solution containing:

(2R, 3S) 4-acetoxy-2.alpha.-benzyloxy5beta, 20-epoxy, 7.beta, lObetatrihydroxy-9-oxo-ii-taxen-13.alpha.-ylterc.butoxykarbonylamino-3-fenyl20

-2-hydroxypropionate (or Taxoter) with a purity of 73% 500 mg ammonium chloride 0 IM

33% aqueous ammonia solution 0,5 cm ³ methanol make up to 25 cm ³ .

The water content is 2% by volume.

10 cm ^{3 of the} same mixture, but without substrate, are introduced into the anode compartment.

After venting the solution for 10 minutes with argon bubbling (argon flow is maintained throughout the electrolysis period), the cathode potential relative to the reference electrode is set to -1.85 vol.

Ammonia gas was bubbled through the electrolyte twice and then argon for several minutes to maintain a mildly alkaline reaction, i. greater than 7. The electrolysis solution is for 2 hours and 20 minutes, i. for the time necessary to pass 380 coulombs.

1.4 cm ³ of acetic acid are added to the electrolysate to neutralize ammonia to pH 6. After removal of the solvent under reduced pressure and a temperature below 35 ° C, the extract is taken up with 25 cm ^{3 of} permuted water and extracted three times with 25 cm ^{3 of} ethyl acetate. the organic phase is washed with a saturated aqueous sodium chloride solution. After drying the organic phase, separated by decantation, over magnesium sulfate, the solvent is evaporated under reduced pressure and a temperature below 35 ° C. 510 mg of crude product are obtained, the components of which are separated by flash chromatography on 50 g of silica gel (0.04-0.063 mm) packed in a 2 cm diameter column, eluting with a 93/3 mixture of dichloromethane and methanol under pressure. argon (0.4 MPa) and fractions of about 5 cm ³ are collected. Fractions 30 to 41 are combined and concentrated to dryness under reduced pressure (0.27 kPa) at a temperature below 35 ° C. 167 mg of product are obtained, which product is purified by preparative thin layer chromatography (silica gel, 0.25 mm layer thickness, elution being carried out with a 40: 55: 5 by volume mixture of dichloromethane, ethyl acetate and methanol). About 118 mg of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta, 7beta, 9alpha, 10betatetrahydroxy-11-taxen-13alpha-yl-2-tert-butoxycarbonylamino-3-phenyl- 2-hydroxypropionate, i.e. a compound of formula I wherein R ¹ is hydrogen and R ² is hydroxy, the product obtained having the following characteristics:

nuclear magnetic resonance spectrum:

(400 MHz, CDC1, chemical shifts in ppm, coupling constants J in Hz): 30 (s, 3H: _-CH3 17 or 17), l, 40 / l, 9H: --C _{(CH3) 3,} ls , 3H: -CH ₃ 16 or 17/1, 70 (1s, 3H: -CH ₃ 18 or -CH ₃ 19), 1,82 (1s, 3H: -CH ₃ 18 or -CH ₃ 19), 1 90 (m, 1H) - (CH) 6],

2.09 (m, 1H) - (CH) f 14 /,

2.28 (br s, 3H, -COCH _3),

2.37 (m, 1H) - (CH) H14),

2.52 (m, 1H) - (CH) H 6],

3.03 (d, 1H: --H3),

4.20 (d, 1H: - (CH) H20),

4.30 (m, 3H: - (CH) H20, -H7, -H9),

4.60 (broad s, 1H: -H 2 '),

4.90 (m, J = 10Hz, 2H: -H5 and -H10),

5.28 (broad d, 1H: -H 3 '), 5.68 (d, 1H: -CONH-),

5.80 (d, 1H: --H2),

6.10 (broad t, 1H: -H 13),

7.30 to 7.44 (m, 5H: --CH3 ');

7.50 (t, J = 7.5 Hz, 2H: -OCOC H (-H 3 and -H 5)), δ 5

7.60 / t, J = 7.5 Hz, H: -OCOC _{e (--H} 4) /.

8.10 / d, J = 7.5 Hz, 2H: -OCOC _{e (--H} 2 and H 6) /.

Fractions 44 to 61 are combined and concentrated under reduced pressure (0.27 kPa) below 35 ° C to give 90 mg of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy- lbeta.

7beta, 9beta, 10beta-tetrahydroxy-11-taxen-13alpha-yl-2-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate, i.e. a compound of formula I wherein R ¹ is hydroxy and R ² is hydrogen wherein the product obtained has the following characteristics:

nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , chemical shifts in ppm, coupling constants J in Hz) 1.30 (s, 3H: -CH ₃ 16 or 17), 1.40 µs, 9H: -C (CH ₃ ) ₃ , 1s, 3H: -CH ₃ 16 or 17 1, 70 (1s, 3H: -CH ₃ 18 or -CH 3 _and 19), 1, 80 (1s, 3H: -CH ₃ 18 or -CH ₃ 19),

2.00 (m, 2H) - (CH) H6 and - (CH) H14),

2.25 (br s, 3H, -COCH _3),

2.40 (m, 2H) - (CH) H6 and - (CH) H14),

3.04 (d, 1H: --H3),

4.12 (t, 1H: --H 7),

AZZ 4.24 4.36 (m, 3H: _CH2 20 H 9),

4.60 (broad s, 1H: -H 2 '),

5.00 (broad d, 1H: -H 5),

5.24 (d, J = 6 Hz, 1H: --H 10),

5.30 (broad d, 1H: --H 3 '),

5.70 (broad d, 1H: -CONH-),

6.12 (broad t, 1H: -H 13),

6.24 (d, 1H: --H2),

7.30 to 7.43 (m, 5H, C H 3 _e ').

7.50 / t, J = 7.5 Hz, 2H: -OCOC _{e (--H} 3 and --H 5) /.

7.60 / t, J = 7.5 Hz, 1H: -OCOC _{e (--H} 4) /.

8.10 (d, J = 7.5 Hz, 2H: --OCOC H (--H2 and --H6)).

WITH

Example 2

In this example, (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta, 7beta,

10beta-trihydroxy-9-oxo-11-taxen-13alpha-yl-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate (or Taxotere) in an electrolyser cell having the following characteristics:

the cell consists of a glass vessel with a volume of 25 cm ³ , divided into two spaces by a cation exchange membrane, the cathode is a mercury level with an effective surface of about 4 cm ² , the anode is a platinum mesh, the reference electrode is a saturated calomel electrode.

10 cm ^{3 of a} solution containing:

(2R, 3S) -4-Acetoxy-2alpha-benzyloxy5beta, 20-epoxy-1beta, 7beta, 10betatrihydroxy-9-oxo-11-taxen-13alpha-yl-3-tert-butoxycarbonylamino-3-phenyl-2-hydroxypropionate 32.3 mg of calcium chloride

Make up 0,05 M methanolic hydrochloric acid solution to 4.10 ^-3 M water methanol make up to

The water content is about 5%

10 of hydrochloric acid in methanol are introduced into the anode compartment.

cm ³ , volume.

cm ^{3 of} 0.2 M solution

After venting the solution for 10 minutes with a stream of argon, which is maintained throughout the electrolysis period, the potential of the cathode relative to the reference electrode is set to

-1.9 volts.

The solution was electrolyzed for 43 minutes, i. for the time necessary to pass 30.9 coulombs.

In order to partially neutralize the acidity of the electrolysate, 400 microliters of 0.1 M methanolic sodium acetate solution was added.

The solvent was removed by distillation under reduced pressure and a temperature below 35 ° C. The residue is taken up in 10 cm ^{3 of} ethyl acetate and 10 cm ^{3 of} permuted water. After decantation, the aqueous phase is extracted three times with 5 cm @ ^{3 of} ethyl acetate.

The organic phase is washed with 10 cm @ ^{3 of a} 0.2 M aqueous sodium phosphate buffer solution (pH = 7). After decantation, the organic phase is dried over magnesium sulphate. Filtration and concentration to dryness under reduced pressure and a temperature below 35 ° C afforded 26.2 mg of crude product, the components of which were separated by preparative thin layer chromatography (0.25 mm) on six silica gel plates (Kieselgel 60 F). 254, Merck), eluting with a 72: 4: 24 by volume mixture of dichloromethane, methanol and acetonitrile.

Thus, 16.7 mg of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta, 7beta, 9alpha, 10betatetrahydroxy-11-taxen-13alpha-yl-3-tert. butoxycarbonylamino-3-phenyl-2-hydroxypropionate.

Example 3

In this example, the electrolytic reduction of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta, 7alpha, 10beta-trihydroxy-9-oxo-11-taxene-13alpha-3-tert-butoxycarbonylamino -3-phenyl-2-hydroxypropionate (or 7-epi-Taxotere) in an electrolyzer cell having the following characteristics:

the cell consists of a glass container containing 25 cm ³ , divided into two spaces by a cation exchange membrane, the cathode is a mercury level with a useful surface area of about 4 cm ^{2, the} anode is a platinum mesh, the reference electrode is a saturated calomel electrode.

505 mg of 7-epi-Taxotere is reduced using two subsequent electrolysis operations.

First electrolysis

10 cm @ ^{3 of a} solution containing the following are introduced into the cathode compartment of the electrolyser cell described above.

7-epi-Taxotér ammonium chloride

33% aqueous ammonia methanol

101.6 mg 0.1M

Add 0,2 cm ³ to 10 cm ³ .

The water content is 2% by volume.

10 cm ^{3 of a} 1.0 M ammonium chloride solution in methanol are introduced into the anode space.

After venting the solution for 10 minutes with a stream of argon, which is maintained throughout the electrolysis period, the potential of the cathode relative to the reference electrode is set to -1.8 volts. The solution is electrolyzed for 64 minutes, i.e., for the time necessary to pass 73 coulombs. To neutralize the ammonia, about 0.6 cm ³ of acetic acid are added to the electrolyte.

Second electrolysis

20 cm @ ^{3 of a} solution comprising:

7-epi-Taxomer 401.1 mg ammonium chloride 0.1M

Make up to 20 cm ^{3 with a} 33% aqueous ammonia solution 0,4 cm ³ methanol.

10 cm ^{3 of a} 0.1 M ammonium chloride solution in methanol are introduced into the anode space. After venting for 10 minutes with a stream of argon, which is maintained throughout the electrolysis period, the potential of the cathode relative to the reference electrode is set to -1.8 volts. The solution is electrolyzed for 2 hours and 19 minutes, i.e. for the time necessary to pass 255 coulombs.

The two electrolysates thus obtained are combined. After removal of the solvent under reduced pressure and a temperature below 35 ° C, the residue is taken up in 30 cm ^{3 of} ethyl acetate and 30 cm ^{3 of} water. The organic phases are combined and washed with 30 cm @ ^{3 of a} 0.2M aqueous sodium phosphate buffer solution (pH = 7) and then dried over magnesium sulphate.

Filtration and evaporation of the solvent under reduced pressure and a temperature below 35 ° C yielded a crude product, the components of which were separated by preparative thin layer chromatography (1 mm) on 11 silica gel plates (Kieselgel 60 F 254, Merck). elution is carried out using a 72: 24: 4 by volume mixture of dichloromethane, acetonitrile and methanol.

317 mg of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta, 7alpha, 9alpha, 10betatetrahydroxy-11-taxen-13alpha-yl-3-tert. .butoxycarbonylamino-3-phenyl-2-hydroxypropionate having the following characteristics:

nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , dv ppm) 1.28 (s, 3H: -CH ₃ 16 or 17), 1.40 / s, 9H: -C (CH ₃ ) _3.1 , 3H: -CH ₃ 16 or 17 /, 1.54, 1.69, 1.70 (3s, 3H each: -CH ₃ 16 or 17, -CH

2.20 to 2.4 (RNT, 7 H: -COC _{3, 14-CH2, CH2} 6);

2.50 (broad s, 1H: --OH 10),

2.94 (br s, 1H: --OH 9),

3.40 (d, 1H: --H3),

3.50 (broad s, 1H: --OH 2 '),

3.70 (d, 1H: --OH 7),

4.24 (dd, 1H: --H 9),

4.30 and 4.40 (2 d, H each: _CH2 20);

4.52 (broad dd, 1H: -H 7),

4.60 (broad s, 1H: -H 2 '),

4.88 (dd, 1H: --H 5),

4.24 (dd, 1H: --H 9),

19).

5.20 (d, J = 10 Hz, 1H: --H 10),

5.28 (very broad d, 1H: -H 3 '),

5.52 (broad d, 1H: -COH-),

5.85 (d, 1H: --H2),

6.14 (broad t, 1H: -H 13),

7.30 to 7.42 (m, 5H: --H: --H3 '), 7.50 (t, J = 7.5 Hz, 2H: --OCOC H (--H3 and --H5)),

7.60 / t, J = 7.5 Hz, 1H:

-OCOC H (-H 4) /, es '-' ''

8.10 (d, J = 7.5 Hz, 2H: --OCOC H (--H2 and --H6)).

G S

The 7-epi-Taxomer may be obtained by treating sodium Taxotere in tetrahydrofuran under an inert atmosphere with sodium hydride.

Example 4 mg of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta, 7beta, 9alpha, 10beta-tetrahydroxy-11-taxen-13alpha-3ter-butoxycarbonylamino-3-phenyl-2-hydroxypropionate Dissolve in cm ³ of Emulphor EL 620 and 1 cm ^{3 of} ethanol and dilute the solution by adding 18 cm ^{3 of} saline. This composition is administered by a 1-hour infusion in physiological saline.

Claims (19)

PATENT 1. The new taxane derivatives of general formula I, wherein one of the symbols R ¹ or R ² is H and the other of the symbols represents a hydroxyl radical R ³ represents a hydrogen atom or a group of the general formula II in which Tura represents an aryl group and R ⁴ represents a benzoyl radical or a radical R ^a -0-CO, wherein ^R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and R ^e represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl or aryl group or a heterocyclic group. The novel taxane derivatives of claim 1, wherein: R ¹ and R ² are as defined in Claim 1, R ³ represents a hydrogen atom or a group of the formula II in which Ar represents an aryl group and R ⁴ represents a benzyl group or a group of the formula ^The R-O-CO-, wherein R is ^a straight or branched alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl group having 7 to 10 carbon atoms, these groups being optionally substituted by one or more substituents selected from the group consisting of fluorine atom, chlorine atom, hydroxy group, 1-4 carbon atom alkoxy group, dialkylamino group, in wherein each alkyl moiety contains 1 to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl (optionally substituted at the 4-position with alkyl containing 1 to 4 carbon atoms or phenylalkyl, wherein the alkyl moiety contains 1 to 4 carbon atoms ), a cycloalkyl-containing group 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, a phenyl group, a cyano group, a carboxyl group and an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms, or R ^a is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl having 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms, or R ^a is a 5- or 6-membered saturated heterocyclic group optionally substituted by one or more alkyl groups having 1-4 carbon atoms, wherein cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted by one or more alkyl groups containing 1-4 carbon atoms, and R ^e represents a straight or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms or a bicycloalkyl group having 7 to 11 carbon atoms, these groups being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, a hydroxy group, a (C 1 -C 4) alkyloxy group, a dialkylamino group in which each alkyl moiety it contains from 1 to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl (optionally substituted in the 4-position with a C1-C4 alkyl or phenylalkyl group, the alkyl radical of which contains 1 to 4 carbon atoms), c (C 3 -C 6) -cycloalkyl, optionally substituted phenyl, cyano, carboxyl and alkyloxycarbonyl, (C 1 -C 4) -alkyl, or aryl optionally substituted by one or more substituents selected from the group consisting of comprising halogen atoms, a (C 1 -C 4) alkyl group and a (C 1 -C 4) alkyloxy group, or A 4- to 6-membered saturated or unsaturated nitrogen heterocyclic group optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms, wherein the cycloalkyl, cycloalkenyl or bicycloalkyl groups may be optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms; up to 4 carbon atoms. The novel taxane derivatives according to claim 1 of the general formula Wherein R ¹ and R ² are as defined in claim 1, R ³ is a hydrogen atom or a group of formula II, wherein R ⁴ is as defined in claim 2 and Ar is an alpha or beta-naphthyl group or a 5-membered aromatic a heterocyclic group containing 1 or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted with one or more identical or different substituents selected from the group consisting of halogen atoms, alkyl, aryl, amino, alkylamino dialkylamino, acylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, or alkoxycarbonyl, and R ^e is phenyl or alpha or beta or beta- or beta- or beta- a group optionally substituted with one or two groups; c with several substituents selected from the group consisting of halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto- a formyl group, acyl group, acylamino group, aroylamino group, alkoxycarbonyl group, carbamoyl group, dialkylcarbamoyl group, cyano group and trifluoromethyl group, wherein the alkyl groups and the al32 radicals of the other groups contain 1 to 4 carbon atoms, alkenyl and alkynyl groups having 2 to 8 carbon atoms and aryl groups are phenyl or alpha or beta-naphthyl. The novel taxane derivatives of claim 1 wherein R ¹ and R ² are as defined in claim 1, R ³ represents a hydrogen atom or a group of formula II wherein Ar is a phenyl group optionally substituted by a fluorine atom or a chlorine atom or alkyl, alkoxy, dialkylamino, acylamino, alkoxycarbonylamino or trifluoromethyl, or 2-thienyl or 3-thienyl or 2-furyl or 3-furyl and R ⁴ is benzoyl or R 4 ^S- O-CO- in which R ⁵ represents a tert-butyl group and R ^e represents a phenyl group optionally substituted by a halogen atom. Process for the preparation of a taxane derivative according to one of claims 1, 2 or 3, characterized in that an electrolytic reduction of the compound of the general formula III is carried out. OCOR ⁶ wherein R ³ and R ⁶ have the meanings specified in any one of claims 1, 2, 3 or 4. 6. The process of claim 5, wherein the electrolyte is an ammonium salt dissolved in a solvent or an aqueous-organic mixture. 7. The process of claim 5 wherein the ammonium salt is ammonium chloride. 8. The process of claim 5, wherein the electrolyte is a calcium salt dissolved in a solvent or aqueous-organic mixture. The method of claim 8, wherein the ** calcium salt is calcium chloride. w A process according to any one of claims 5 or 8, wherein the solvent is an aliphatic alcohol and the aqueous-organic mixture is a mixture of alcohol and water. 11. The process of claim 10 wherein the solvent is methanol. Process according to claim 6, characterized in that the pH of the medium is maintained in a slightly alkaline region by the addition of ammonia. » Process according to claim 8, characterized in that the pH of the medium is maintained in the acidic region by the addition of hydrochloric acid. Method according to one of Claims 1 to 13, characterized in that the electrolysis is carried out in an electrolyzer containing a mercury cathode. Method according to one of Claims 1 to 13, characterized in that the electrolysis is preferably carried out in a membrane electrolyser. 16. The method of claim 15, wherein the membrane is a porous material or a cation exchange membrane. Method according to one of Claims 1 to 16, characterized in that the electrolysis is carried out at a controlled potential. 18. A process for preparing a compound of formula I, wherein R ³ is a group of formula II, wherein characterized by esterification of a compound of formula I wherein R ³ is H, an acid of formula wherein Ar and R ⁴ are the meanings given in any one of claims 1 to 4. 19. A pharmaceutical composition characterized in that it contains a sufficient amount of at least one derivative according to any one of claims 1 to 4 of formula I wherein R ³ is a group of formula II in the pure state or in combination with one or more pharmaceutically acceptable products.