FR2711370A1 - New taxoids, their preparation and pharmaceutical compositions containing them. - Google Patents

Abstract

New taxoids of general formula (I), their preparation and the pharmaceutical compositions which contain them. In general formula (I): Ar represents an aryl radical, R represents a benzoyl radical or a radical of formula R1 -O-CO- in which R1 represents an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl, heterocyclyl and X represents an oxygen or sulfur atom. The new products of general formula (1) exhibit remarkable anti-tumor activity. (CF DRAWING IN BOPI)

Description

leur préparation et les compositions pharmaceutiques qui les contiennent.NEW TAXOIDES. PREPARATION AND COMPOSITIONS
PHARMACEUTICLES THAT CONTAIN THEM
The present invention relates to novel taxoids of the general formula:

their preparation and the pharmaceutical compositions which contain them.

In the general formula (I):
Ar represents an aryl radical,
R represents a benzoyl radical or a radical R 1 -O-CO- in which R 1 represents:
a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxy, alkyloxy radicals containing 1 to 4 carbon atoms, and dialkylamino of which each alkyl part contains 1 to 4 carbon atoms. carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted in 4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms; carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 atoms of carbon,
or a phenyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms,
or a saturated or unsaturated nitrogen containing heterocyclyl radical containing 4 to 6 members and optionally substituted with 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 with one or more alkyl radicals containing 1 to 4 carbon atoms and
X represents an oxygen atom or a smile.

 Preferably Ar represents a phenyl or a- or frnaphthyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl and arylalkyl radicals, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and the aryl radicals are phenyl or a- or frnaphthyl radicals, or Ar represents a heterocyclic radical aromatic having 5 knuckles and containing one or more atoms, identical or different, selected from nitrogen atoms, oxygen or sulfur, optionally substituted with one or more substituents, identical or different, selected from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms, amines, alkylamino containing 1 to 4 carbon atoms, dialkylamino in which each alkyl part contains 1 to 4 carbon atoms, acylamino the part of which acyl contains 1 to 4 carbon atoms, alkoxycarbonylamino contains 1 to 4 carbon atoms, acyl contains 1 to 4 carbon atoms, arylcarbonyl the aryl portion of which contains 6 to 10 carbon atoms, cyano, carboxy, carbamoyl, alkylcarbamoyl, the portion of which alkyl contains 1 to 4 carbon atoms, dialkylcarbamoyl wherein each alkyl portion contains 1 to 4 carbon atoms or alkoxycarbonyl, the alkoxy portion of which contains 1 to 4 carbon atoms.

 More particularly, Ar represents a phenyl, thienyl-2 or -3 or furyl-2 or -3 radical optionally substituted by one or more atoms or radicals, which may be identical or different, chosen from halogen atoms and alkyl, alkoxy radicals, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl.

 Even more particularly, Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom, or by an alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino) or alkoxycarbonylamino (tert-butoxycarbonylamino) radical. or thienyl-2 or -3 or furyl-2 or -3.

 Of even more particular interest are the products of general formula (I) wherein Ar represents a phenyl radical and R represents a benzoyl or tert.butoxycarbonyl radical.

dans laquelle Ar et R sont définis comme précédemment, G1 représente un groupement protecteur de la fonction hydroxy et G2 représente un atome d'hydrogène ou un groupement protecteur de la fonction hydroxy, pour obtenir un produit de formule générale:

dans laquelle Ar, R, X, G1 et G2 sont définis comme précédemment, dont les groupements protecteurs sont remplacés par des atomes d'hydrogène pour donner un produit de formule générale (I).According to the invention, the new taxoids of general formula (I) can be obtained by the action of a reagent making it possible to form a carbonate of general formula
X1-C (= X) -X2 (u) wherein X is defined as previously, X1 represents a halogen atom such as a chlorine atom or an imidazolyl-1 radical and X2 represents an atom
halogen such as a chlorine atom or an imidazolyl-1 radical or an alkoxy radical
containing 1 to 4 carbon atoms, optionally substituted by one or more
halogen atoms, on a product of general formula:

in which Ar and R are as defined above, G1 represents a protecting group for the hydroxy function and G2 represents a hydrogen atom or a group protecting the hydroxy function, to obtain a product of general formula:

in which Ar, R, X, G1 and G2 are defined as above, the protective groups of which are replaced by hydrogen atoms to give a product of general formula (I).

 The reactive agents which make it possible to prepare a carbonate from an enolised alcohol alcohol are generally chosen from N-carbonyldiimidazole, phosgene and alkyl chloroformates.

The protective groups represented by G 1 are generally chosen from the radicals methoxymethyl, ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, (t-methylsilyl) ethoxymethyl or tetrahydropyranyl and those represented by G 2 are generally chosen from trimethylsilyl and triethylsilyl radicals. It is particularly advantageous to use protective groups
Identical G1 and G2 each representing a trialkylsilyl radical such as trimethylsilyl or triethylsilyl. When a product of general formula (here) in which -O-G 2 represents an α-hydroxy radical is used, the protection of this hydroxy function is not necessary.

dans laquelle Ar, R, G1, G2, X et X2 sont définis comme précédemment.Depending on the conditions for carrying out the reaction of the product of general formula (11) with the product of general formula (m), it is possible to pass intermediately through a product of general formula:

wherein Ar, R, G1, G2, X and X2 are defined as above.

 Generally, the reaction of a product of general formula (H) with a product of general formula (m) is carried out by operating in an organic solvent preferably chosen from aromatic hydrocarbons such as benzene, toluene or xylenes and ethers such as ethyl ether, diisopropyl ether or tetrahydrofuran optionally in the presence of a condensing agent preferably chosen from tertiary amines such as triethylamine, dimethylaniline, dimethylamino-pyridine or pyrrolidine-4 pyridine at a temperature of between -40 ° C. and the reflux temperature of the reaction mixture. It may be advantageous to activate the hydroxyl function in position 10 of the general-purpose product (m) in the form of an alkali metal alcoholate which can be obtained by the action of an organometallic derivative such as a metal alkylation such as butyllithium an alkyl magnesium halide, an amide such as lithium diisopropylamide.

 Generally, the product of general formula (V) is obtained by operating at a low temperature, that is to say at a temperature of less than 50 ° C. in the absence of a condensing agent.The product of general formula (IV) is then obtained by heating the product of general formula (V) to a temperature above 500C in the presence of a condensing agent as defined above.

 Generally, the replacement of the protective groups G 1 and optionally G 2 of the product of general formula (W) with hydrogen atoms is carried out using a mineral acid (hydrochloric acid, sulfuric acid, hydrofluoric acid) or organic acid (formic acid, acetic acid). methanesulfonic acid, trifluoromethanesulfonic acid, toluenesulphonic acid, used alone or in admixture by operating in an organic solvent chosen from alcohols, ethers, aliphatic hydrocarbons, halogenated aliphatic hydeocarbs, aromatic hydrocarbons and nitriles at a temperature of between -10 and 60 "C.

dans laquelle Ar, R et X2 sont définis comme précédemment, qui constituent un autre objet de la présente invention.The replacement of the protective groups G1 and G2 of the product of general formula (V) with hydrogen atoms under the conditions described above leads to a product of general formula:

wherein Ar, R and X2 are defined as above, which constitute another object of the present invention.

 The new products of general formula (I) obtained according to the process of the present invention may be optionally purified by physical or physico-chemical methods such as crystallization or chromatography.

dans laquelle Ar et R sont définis comme précédemment selon les méthodes habituelles de protection des fonctions hydroxy telles que décrites par exemple par A. E. Greene et coll., J. Org. Chem., fi 46-50 (1986). Plus particulièrement, pour obtenir un produit de formule générale (W) dans laquelle G1 et éventuellement G2 représentent chacun un radical triméthylsilyle ou triéthylsilyle, on traite un produit de formule générale (VI) par un halogénure de triméthyl- ou triéthylsilyle en opérant dans un solvant organique choisi parmi les hydrocarbures aliphatiques halogénés tel que le dichlorométhane en présence d'une base organique telle que la pyridine à une température voisine de 20"C. Lorsque dans la formule générale (vit) la fonction hydroxy en position -7 du cycle est sous forme 7a, la protection ne s'effectue que sur la fonction hydroxy de la chaîne latérale et lorsque dans la formule générale (VII) la fonction hydroxy en position -7 du cycle est sous forme 7ss, la protection s'effectue sur la fonction hydroxy-713 et sur la fonction hydroxy de la chaîne latérale.The products of general formula (m) can be obtained from a product of general formula:

in which Ar and R are defined as above according to the usual methods of protecting the hydroxyl functions as described for example by AE Greene et al., J. Org. Chem., 46-50 (1986). More particularly, to obtain a product of general formula (W) in which G1 and optionally G2 each represent a trimethylsilyl or triethylsilyl radical, a product of general formula (VI) is treated with a trimethyl- or triethylsilyl halide by operating in a solvent. organic compound chosen from halogenated aliphatic hydrocarbons such as dichloromethane in the presence of an organic base such as pyridine at a temperature in the region of 20 ° C. When in the general formula (vit) the hydroxyl function at the -7 position of the cycle is under 7a form, the protection is only performed on the hydroxyl function of the side chain and when in the general formula (VII) the hydroxyl function at the -7 position of the ring is in 7ss form, the protection is performed on the hydroxy function -713 and on the hydroxyl function of the side chain.

 The products of general formula (VII) in which Ar and R being defined as above and the hydroxyl function in position -7 of the ring is in the form 7ss can be obtained according to the processes described more particularly in international applications PCF WO glu09589 and WO 93/16060.

 The products of general formula (VII) in which Ar and R are defined as above and the hydroxyl function at the -7 position of the ring is in the form 7a can be obtained by treating with a base a product of general formula (VI) in which Ar and R being defined as above, the 7-position hydroxy function of the ring is in the form 7 (3.

 Generally, a mineral base such as an alkali metal hydride such as sodium hydride is reacted in an anhydrous organic solvent such as an ether such as tetrahydrofuran at a temperature between 0 and 30 ° C.

 The products of general formula (I) have remarkable biological properties.

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

Acad. Sci. USA, ZQ 765-768 (1973). The study of tubulin microtubule depolymerization is carried out according to the method of G. Chauvière et al., C.R. Acad.

Sci., 2nd, 511, 501-503 (1981). In this study the products of general formula (I) were at least as active as taxol and Taxotere.

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

 The following example illustrates the present invention.

EXAMPLE
A solution of 3.3 g of 2-tbutoxycarbonylamino-3-triethylsilyloxy-3-phenylpropionate (2R, 3S) acetoxy4a benzoyloxy-2a epoxy-5ss, trihydroxy 1,7a, 10ss oxo-9-taxene-11yl-13a and 2 g of carboflyl-1,1'-diimidazole in 50 cm3 of anhydrous toluene, kept under an argon atmosphere, is heated at a temperature in the region of 500 ° C. for 2 hours 30 minutes. After cooling to a temperature in the region of 20 ° C., the solvent is distilled off under reduced pressure (0.27 kPa) to give 5.55 g of a yellow solid which is purified by chromatography on 300 g of silica (0.063-0.2 mm) contained in a 6 cm diameter column eluting with an ethyl acetate-dichloromethane elution gradient of 0-100 to 20-80 (by volume) and collecting fractions of 100 cm3 Fractions containing the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. There is thus obtained 2.98 g of 2-tert-butoxycarbonylamino-3-triethylsilyloxy-3-phenylpropionate (2R, 3S) acetoxy4a benzoyloxy-2a epoxy-5ss, dihydroxy-1,7a (imidazolyl-1 carbonyloxy) -10 ( 3 oxo-9-taxene-11-yl-13a in the form of a white meringue.

 A solution of 1.5 g of 2-tert-butoxycarbonylamino-3-triethylsilyloxyphenyl-3-propionate (2R, 3S) of 4-acetoxybenzoyloxy-2a-epoxy-5 (3,20-dihydroxy-1,7a (imidaaolyl-1-carbonyloxy) - 10 O-oxo-9-taxene-13-yl and 33 mg of N, N 'dimethylamino-4-pyridine in 15 cm3 of anhydrous toluene is heated, under an argon atmosphere, to a temperature of about 110 ° C for 5 hours 3 minutes.

45 mg of N, N'-dimethylamino-4-pyridine are then added and the mixture is then heated at a temperature in the region of 110 ° C. under an argon atmosphere for 17 hours and after cooling to a temperature in the region of 20 ° C. is evaporated under reduced pressure (0.27 kPa). There is thus obtained 1.64 g of a brown solid which is purified by chromatography on 200 g of silica (0.063-0.2 mm) contained in a column 4 cm in diameter, eluting with an acetate elution gradient of ethyl-dichloromethane 2-98 to 10-90 (by volume) and collecting 15 cm3 fractions. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 400 ° C. for 2 hours. There is thus obtained 593.7 mg of 2-tbutoxycarbonylamino-3-triethylsilyloxy-3-phenyl-2-propionate (2R, 3S) of acetyl-4-benzoyloxy-2a-9,10-carboxy-9-epoxy, 1,7-dihydroxy-1,7-taxa-5-ene. 9,11 yle13a in the form of a white meringue.

 A solution of 590 mg of 3-tert-butoxyearbonylamino-3-triethylsilyloxy-3-phenylpropionate (2R, 3S) acetoxy4a benzoyloxy-2a-9,10-carbonyldioxy epoxy, 1,7-dihydroxy-17a taxadiene-9-yl In 12.5 cm 3 of a 0.1 N solution of hydrochloric acid in ethanol is stirred at a temperature in the region of 0 ° C. for 2 hours 30 minutes. The solvent is evaporated off under reduced pressure (2.7 kPa) at a temperature in the region of 20 ° C. A crude product is obtained which is purified by chromatography on 75 g of silica (0.063-0.2 mm) contained in a column of 2 , 5 cm in diameter eluting with a methanol-dichloromethane elution gradient of 1-99 to 2.5-97.5 (by volume) and collecting 10 cm3 fractions. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. for 2 hours, to give 295 mg of a yellow solid which is purified by preparative chromatography on 12 silica plates. thin layer (Kieselgel 60F254, Merck, thickness 0.25 mm) eluting with a methanoldichloromethane mixture (2.5-97.5 by volume) After solution of the zone corresponding to the main product with a methanol / 2,2-omethanol mixture (10- 90 volumes) and then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C., 53.6 mg of t-butoxycarbonylamino-3-hydroxy-3-phenyl-3-propionate (2R, 3S) are obtained. acetoxy-4a-benzoyloxy-2a-9,10-carboxy-9,5-epoxy, 1,7-dihydroxy-9,11-taxadiene, 13-yl-13a in the form of a white meringue whose characteristics are as follows: - Rotatory power: [a] 20D = + 260 (c = 0.132, methanol) - proton nuclear magnetic resonance spectrum n (400MHz, deuterated chloroform; chemical shifts in ppm; coupling constants J in Hz): 1.20 (s, 3H: -CH3 at 16 or 17); 1.30 (s, 3H: -CH 3 in 16 or 17); 1.40 [s, 9H: -C (CH3) 3] 1.66 (s, 3H: -CH319); 1.66 (s, 3H: -CH 3 in 18); 1.73 (s, 1H: -OH in 1); 1.80 (brs, 3H: -CH 3 in 18); from 2.15 to 2.55 (mt, 4H: -CH 2 at 14 and -CH 2 at 6); 2.44 (s, 3H: -COCH 3); 3.13 (d, J = 6, 1H: -Hen3); 3.28 (d, J = 4.5, 1H: -OHen 2 '); 4.08 (d, J = 11, 1H: -OH at 7); 4.15 (dmt, J = 11, 1H: -H at 5); 4.44 (ab, J = 9, 2H: -CH 2 en 2 O) 4.63 (mt, 1H: -Hen 2 '); 4.89 (dd, J = 10 and 5, 1H: -H at 5); 5.25 (d, J = 10, 1H: -Hen3 '); 5.38 (d, J = 10, 1H: -CONH-); 5.81 (d, J = 6, 1H-H at 2) 6.17 (t broad, J = 9, 1H: -H at 13); from 7.30 to 7.45 [mt, 5H: -C6H5 at 3 '(-H 2 to H 6)]; 7.52 [t, J = 7.5, 2H: -OCOC6Hs (-H 3 and -H 5)]; 7.65 [t, J = 7.5, 1H: -OCOC6H5 (-H4)]; 8.10 [d, J = 7.5, 2H: OCOC6Hs (-H 2 and -H 6)].

3-tert-butoxycarbonylamino-3-triethylsilyloxy-3-phenylpropionate (2R, 3S) 4-acetoxy-benzoyloxy-2a-epoxy-5,1S, trihydroxy-1,7a, 10ss oxo-9-taxene-11yl13a can be prepared as follows:
To a solution of 3.95 g of 3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-3-propionate (2R, 3S) acetoxy-4a benzoyloxy-2a epoxy-5ss, trihydroxy-1,7 α In a mixture of 40 cm 3 of dichloromethane and 4 cm 3 of pyridine, triethylsilyl chloride (4.15 cc) and then N, N'-dimethylamino-4-pyridine (600 mg) are added in a mixture of 40 cc of dichloromethane and 4 cc of pyridine. . The reaction mixture is stirred for 17 hours at a temperature in the region of 20 ° C. under an argon atmosphere, and is then diluted by adding 30 cm 3 of distilled water and 80 cm 3 of dichloromethane. The aqueous phase is separated by decantation and extracted with 30 cm3 of dichloromethane. The organic phases are combined and then dried over magnesium sulfate. After filtration on sintered glass and dry concentration under reduced pressure (0.27 kPa) at 400 ° C., 6.97 g of a yellow-orange meringue are obtained which is purified by chromatography on 300 g of silica (0.063-0.2). mm) contained in a 4.5 cm diameter column eluting with a methanol-dichloromethane mixture (0.5-99.5 by volume) and collecting fractions of 100 cm3. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 400 ° C. for 2 hours. There is thus obtained 4.51 mg of 3-tert-butoxycarbonylamino-3-triethylsilyloxy-3-phenylpropionate (2R, 3S) of acetoxy-4a benzoyloxy-2a epoxy-5ss, trihydroscy-1,7a, 10ss oxo-9-taxene -ll yl-13a in the form of a white meringue.

 To a degassed solution of 19.52 g of t-butoxycarbonylamino-3-hydroxy-3-phenyl-3-phenylpropionate (2R, 3S) acetoxy-4a benzoyloxy-2a epoxy-5ss, trihydroxy1,7ss, 10ss oxo-9-taxene- 11 ml-13a in 150 cm3 of anhydrous tetrahydrofuran, 25 mg of sodium hydride (50% by weight in petrolatum oil) are added in portions under an argon atmosphere at a temperature in the region of 20 ° C. . The yellow solution obtained is stirred for 30 minutes at a temperature in the region of 20 ° C., then 25 mg of sodium hydride (50% by weight in petrolatum oil) are added in portions at a temperature in the region of 20 ° C. . After 10 minutes, add an excess of solid ammonium chloride and then 2 cm3 of distilled water. The mixture is dried over magnesium sulfate. After filtration on sintered glass and concentration to dryness under reduced pressure (2.7 kPa) at 400 ° C., 19.51 g of a meringue are obtained which is purified by chromatography on 800 g of silica (0.063-0.2 mm) contained therein. in a column 8 cm in diameter eluting with a methanol-dichloromethane mixture (2-98 by volume) and collecting fractions of 65 cm3. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 400 ° C. for 2 hours. There is thus obtained 14.43 g of 2-tert-butoxycarbonylamino-3-hydroxy-3-phenyl-3-propionate (2R, 3S) acetoxy-4a benzoyloxy-2a epoxy-5ss, trihydroxy 1,7a, 10ss oxo-9 taxene- 11e-13a in the form of a cream meringue.

 3-tert-butoxycarbonylamino-3-hydroxy-3-phenylpropionate (2R, 3S) 4-acetoxy-benzoyloxy-2a epoxy-5ss, trihydroxy-1,7ss, 10ss oxo-9-taxen-11-yl13a can be prepared in the conditions described in EP-0336841.

 The new products of general formula (I) exhibit significant inhibitory activity of abnormal cell proliferation and possess 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, lymphatic or renal systems, mammary or blood cells, liver, digestive system, pancreas and thyroid or adrenal glands.

These conditions may include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancers, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanoma, multiple myeloma, chronic lynphocytic leukemia, acute or chronic granulocytic lymphoma. 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 appearance or reappearance of pathological conditions or to treat these pathological conditions.

 The products according to the invention can be administered to a patient according to different forms adapted to the chosen route of administration which, preferably, is the parenteral route. Parenteral administration includes intravenous, intraperitoneal, intramuscular or subsutaneous 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 may 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. The compositions are preferably 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 may be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practice.

For parenteral administration, sterile aqueous or non-aqueous solutions or suspensions are used. For the preparation of solutions or non-aqueous suspensions may be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate . The aqueous sterile solutions may consist of a solution of a pharmaceutically acceptable salt in solution in water. The aqueous solutions are suitable for intravenous administration insofar as the pH is suitably adjusted and the isotonicity is achieved, for example by a sufficient amount of sodium chloride or glucose. The 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 used in the compositions according to the invention must be pure and non-toxic for the quantities used.

 The compositions may contain at least 0.01 to about therapeutically active product. The amount of active product in a composition is such that a suitable dosage may be prescribed. Preferably, the compositions are prepared such that a unit dose contains from about 0.01 to about 1000 mg of active product for parenteral administration.

 Therapeutic treatment can be performed concurently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapies or modifiers of biological responses. The modifiers of the responses include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (a, ss or b) and TNF. Other chemotherapeutic agents useful in treating disorders due to abnormal proliferation of cells include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melIihalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustine and streptozocine, triazenes such as dacbazine, antimetabolites such as folic acid analogues such as methotrexate, pyrimidine analogs such as fluorourcil and cytarabi preferably 1 to 4 times, depending on the physiological needs of the patient. 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 selecting the most appropriate dosage, account must be taken of the route of administration, the weight of the patient, his general state of health, his age, and all the factors which may affect the effectiveness of the treatment. .

 The following example illustrates a composition according to the invention.

EXAMPLE
40 mg of the product obtained in Example 1 are dissolved in 1 cm 3 of Emulphor
EL 620 and 1 cm3 of ethanol and then the solution is diluted by addition of 18 cm3 of physiological saline.

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

Claims (9)

X represents an oxygen or sulfur atom.  or a saturated or unsaturated nitrogen containing heterocyclyl radical containing 4 to 6 members and optionally substituted with 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 with one or more alkyl radicals containing 1 to 4 carbon atoms, and  or a phenyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms,  a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxy, alkyloxy radicals containing 1 to 4 carbon atoms, and dialkylamino of which each alkyl part contains 1 to 4 carbon atoms. carbon atoms, piperidino, morpholino, pi-zinyl-1 (optionally substituted in -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms atoms, R represents a benzoyl radical or a radical R 1 -O-CO- in which R 1 represents: Ar represents an aryl radical,  in which:

 CLAIMS 1 - New taxoids of general formula:  2 - New taxoids according to revendcation 1 characterized in that R and X being defined as in claim 1, Ar represents a phenyl or a- or frnaphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms ( fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino radicals dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro 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 alkenyl and alkynyl radicals contain 2 to 8 carbon atoms. carbon and that the aryl radicals are phenyl radicals or a- or naphthyl radicals, or Ar represents an aromatic heterocyclic radical having 5 and containing one or more atoms, identical or different, selected from nitrogen, oxygen or sulfur, optionally substituted by one or more substituents, identical or different, selected from halogen atoms (fluorine, chlorine bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms, amino, alkylamino containing 1 to 4 carbon atoms, dialkylamino in which each alkyl part contains 1 to 4 carbon atoms, acylamino whose acyl part contains 1 to 4 carbon atoms, alkoxycarbonylamino containing 1 to 4 carbon atoms, acyl containing 1 to 4 carbon atoms arylcarbonyl, the aryl part of which contains 6 to 10 carbon atoms, cyano, carboxy, carbamoyl, alkylcarbamoyl, the alkyl part of which contains 1 to 4 carbon atoms, and the alkyl part containing 1 to 4 carbon atoms or alkoxycarbonyl whose alkoxy portion contains 1 to 4 carbon atoms.  3 - New taxoids according to claim 1 characterized in that R and X being defined as in claim 1, Ar represents a phenyl, thienyl-2 or -3 or furyl-2 or -3 optionally substituted by one or more atoms or radicals, which may be identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals.  4- New taxoids according to claim 1 characterized in that Ar represents a phenyl radical, R represents a benzoyl or tbutoxycarbonyl radical and X represents an oxygen atom.  5. Process for the preparation of a new taxoid according to one of claims 1 to 4, characterized in that a carbonyl derivative of general formula is reacted:  X1-C (= X) -X2 (II)  wherein X represents an oxygen or sulfur atom, X1 represents an atom  halogen such as a chlorine atom or an imidazolyl-1 radical and X2 represents a  halogen atom such as a chlorine atom or an imidazolyl-1 radical or a radical  alkoxy containing 1 to 4 carbon atoms optionally substituted with one or  several halogen atoms, on a product of general formula:

 wherein Ar and R are as defined in any one of claims 1 to 4, G1 represents a protecting group of the hydroxy function and G2 represents a hydrogen atom or a protecting group of the hydroxy function, to obtain a product of formula general:

  wherein Ar, R, X, G1 and G2 are defined as above, the protective groups of which are replaced by hydrogen atoms to give a product according to one of claims 1 to 4.  6 - Process according to claim 5 characterized in that the reaction is carried out by operating in an organic solvent preferably chosen from aromatic hydrocarbons such as benzene, toluene or xylenes and ethers such as ethyl ether, clilsopropyl ether or tetrahydrofuran optionally in the presence of a condensing agent preferably chosen from tertiary amines such as triethylamine, dimethylaniline, dimethylamino-pyridine or pyrrolidine-pyridine at a temperature between OOC and the reflux temperature of the reaction mixture optionally passing through the general formula:

 in which Ar, R and X are defined as in one of claims 1 to 4 and G1, G2 and X2 are defined as in claim 5.  7 - Process according to claim 5 characterized in that the replacement of the protective groups G1 and optionally G2, when they each represent a trialkylsilyl radical is performed by treatment with a mineral or organic acid operating in a chosen organic solvent among alcohols, ethers, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and nitriles at a temperature between -10 and 600C. 8 - The product of general formula:

 in which Ar, R and X are as defined in any one of claims 1 to 4 and X 2 represents a halogen atom, an imidazolyl-1 or alkoxy radical containing 1 to 4 carbon atoms, optionally substituted with 1 or more carbon atoms, 'halogen.  9 - Pharmaceutical composition characterized in that it contains at least  a product according to one of claims 1, 2, 3 or 4 in combination with one or  several pharmaceutically acceptable products whether inert or physiological  gically active.