WO1995011247A1 - Novel taxoids, preparation thereof and pharmaceutical compositions containing them - Google Patents

Abstract

Novel taxoids have general formula (I), wherein Ar is an aryl radical, R is an optionally substituted benzoyl radical, furoyl or thenoyl or a radical having the formula R1-O-CO-, wherein R1 is an optionally substituted alkyl radical, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl, heterocyclyl, and X is an oxygen or sulphur atom. The novel products of general formula (I) have remarkable antitumor activity.

Description

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

The present invention relates to new taxoids of general formula:

leur préparation et les compositions pharmaceutiques qui les contiennent. Dans la formule générale (I) : Ar représente un radical alcoyle contenant 1 à 6 atomes de carbone, alcenyle contenant 2 à 6 atomes de carbone, cycloalcoyle contenant 3 à 6 atomes de carbone ou aryle, R représente un radical benzoyle éventuellement substitué, furoyle ou thénoyle ou un radical Rj-O-CO- dans lequel R représente :

their preparation and the pharmaceutical compositions containing them. In the general formula (I): Ar represents an alkyl radical containing 1 to 6 carbon atoms, alkenyl containing 2 to 6 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms or aryl, R represents an optionally substituted benzoyl radical, furoyl or thenoyl or a radical Rj-O-CO- in which R represents:

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

Preferably Ar represents a phenyl or α- or β-naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl radicals, arylalkyls, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alcoylamino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, carboyoyl, dialkoyloyl, dialkoyloyl, carbamoyl, dialkyloyloyl, carbamoyl, trialkyloyl, carbamoyl, carbamoyl, carboyoyl, carboyoyl, carbamoyl, carbamoyl, carbamoyl, carbamoyl, carboyoyl) it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or α- or β-naphthyl radicals , or Ar represents an aromatic heterocyclic radical having 5 links and containing one or more atoms, identical or different, chosen from nitrogen atoms , oxygen or sulfur, optionally substituted by one or more substituents, identical or different, chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms, amino, alkylamino containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which 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 whose aryl part contains 6 to 10 carbon atoms, cyano, carboxy, carbamoyl, alkylcarbamoyl in which the alkyl part contains 1 to 4 carbon atoms, dialkoylcarbamoyl in which each alkyl part contains 1 to 4 carbon atoms or alkoxycarbonyl in which the alkoxy part contains 1 to 4 carbon atoms.

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

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

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

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

Xι-C (= X) -X ₂ (II) in which X is defined as above, X represents a halogen atom such as a chlorine atom or an imidazolyl-1 radical and X ₂ represents a halogen atom 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:

dans laquelle Ar et R sont définis comme précédemment, ou bien G représente un groupement protecteur de la fonction hydroxy et G₂ représente un atome d'hydrogène, ou bien G\ et G₂ forment ensemble un hétérocycle, et G3 et G4 représentent chacun un atome d'hydrogène ou un groupement protecteur de la fonction hydroxy, pour obtenir un produit de formule générale :

dans laquelle Ar, R, X, Gι_, G₂ et G3 sont définis comme précédemment, dont les groupements protecteurs sont remplacés par des atomes d'hydrogène pour donner un produit de formule générale (I). Les agents réactifs qui permettent de préparer un carbonate ou un thiocarbonate à partir d'un α-céto-alcool énolisé de formule générale (III) sont généralement choisis parmi le N.N'-carbonyldiimidazole, le N,N'-thiocarbonyl- diimidazole, le phosgène, le thiophosgène, les chloroformiates d'alcoyle et les chlorothioformiates d'alcoyle. Lorsque G représente un atome d'hydrogène, les groupements protecteurs représentés par Gj sont généralement choisis parmi les radicaux méthoxyméthyle, éthoxy-1 éthyle, benzyloxyméthyle, triméthylsilyle, triéthylsilyle, (β-triméthylsilyl) éthoxyméthyle ou tétrahydropyra nyle.

in which Ar and R are defined as above, or either G represents a protective group for the hydroxy function and G ₂ represents a hydrogen atom, or else G \ and G ₂ together form a heterocycle, and G3 and G4 each represent a hydrogen atom or a protecting group for the hydroxy function, to obtain a product of general formula:

in which Ar, R, X, Gι_, G ₂ and G3 are defined as above, whose protective groups are replaced by hydrogen atoms to give a product of general formula (I). Reactive agents which make it possible to prepare a carbonate or a thiocarbonate from an enolized α-keto-alcohol of general formula (III) are generally chosen from N.N'-carbonyldiimidazole, N, N'-thiocarbonyl-diimidazole , phosgene, thiophosgene, alkyl chloroformates and alkyl chlorothioformates. When G represents a hydrogen atom, the protective groups represented by Gj are generally chosen from the methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, (β-trimethylsilyl) ethoxymethyl or tetrahydropyra nyl radicals.

When G} and G ₂ together form a heterocycle, this is preferably an oxazolidine ring optionally mono-substituted or gem-disubstituted in position-2. The protective radicals represented by G3 and G4 are generally chosen from 2,2,2-trichloroethoxycarbonyl radicals and trialkylsilyl radicals such as trimethylsilyl and triethylsilyl.

When G3 and G4 each represent a protecting group for the hydroxy function, the latter is preferably a 2,2,2-trichloroethoxycarbonyl radical.

When G4 represents a hydrogen atom and G3 represents a protecting group for the hydroxy function, the latter is preferably a trialkylsilyl radical such as trimethylsilyl or triethylsilyl.

When G represents a hydrogen atom and Gj and G3 each represent a protective group for the hydroxy function, it is particularly advantageous to use identical protective groups G and G3 each representing a trialkylsilyl radical such as trimethylsilyl or triethylsilyl. When a product of general formula (III) in which -OG ₂ represents a hydroxy radical in position α is used, the protection of this hydroxy function is not necessary.

Depending on the conditions for carrying out the reaction of the product of general formula (II) with the product of general formula (III), it is possible to use an intermediate of product of general formula:

dans laquelle Ar, R, G^, G₂, G3, X et X₂ sont définis comme précédemment.

in which Ar, R, G ^, G ₂ , G3, X and X ₂ are defined as above.

Generally, the reaction of a product of general formula (II) with a product of general formula (III) is carried out by operating in an organic solvent preferably chosen from aromatic hydrocarbons such as benzene, toluene or xylenes and the ethers such as ethyl ether, diisopropyl ether or tetrahydrofuran or pyridine optionally in the presence of a condensing agent preferably chosen from tertiary amines such as triethylamine, dimethylaniline, 4-dimethylamino pyridine or pyrrolidino-4 pyridine at a temperature between -40 ° C and the reflux temperature of the reaction mixture. It may be advantageous to activate the hydroxy function in position 10 of the general cheese product (III) in the form of an alkali metal alcoholate which can be obtained by the action of an organometallic derivative such as a metal alkyl such as butyllithium , an alkylmagnesium halide, an amide such as lithium diisopropylamide. Generally, the product of general formula (V) is obtained by operating at low temperature, that is to say at a temperature below 50 ° C in the absence of condensing agent. The product of general formula (IV) is then obtained by heating the product of general formula (V) at a temperature above 50 ° C in the presence of a condensing agent as defined above. The replacement of the protective groups G, and / or G ₂ and G ^ and G3 with hydrogen atoms can be carried out, according to their nature, as follows: 1) when G represents a hydrogen atom, G represents a group protector of the hydroxy function defined as above and G3 represents a trialcoylsilyl radical, the replacement of the protective groups by hydrogen atoms is carried out by means of a mineral or organic acid used alone or as a mixture, operating in an organic solvent chosen from alcohols, ethers, esters, hydrocarbons aliphatic, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between -10 and 60 ° C or by catalytic hydrogenation or by the action of a hydrofluoric acid-triethylamine or hydrofluoric acid-pyridine complex.

2) when G ₂ represents a hydrogen atom, G ^ represents a protective group for the hydroxy function and G3 represents a 2,2,2,2-ethoxycarbonyl trichloro radical, replacing the 2,2,2-trichloro-ethoxycarbonyl radical by a hydrogen atom is carried out by means of zinc, possibly associated with copper, 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 (methanol, ethanol, propanol, isopropanol) or in an aliphatic ester (ethyl acetate, isopropyl acetate, n.butyl acetate) in the presence zinc possibly associated with copper and that of G is then carried out under the conditions described under 1) above.

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

in which R is defined as above, G5 and G5, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical in which the alkyl part contains 1 to 4 carbon atoms and the aryl part preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical representing, preferably a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or G5 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and Gβ represents a hydrogen atom, or alternatively G5 and G together with the carbon atom to which they are linked form a cycle having 4 to 7 links, replacing the grou protective layer formed by G5 and GÔ by hydrogen atoms can be carried out, according to the meanings of R, G5 and G5, in the following manner: a) when R represents a tert-butoxycarbonyl radical, G5 and G, identical or different, represent an alkyl radical or a aralkyl (benzyl) or aryl (phenyl) radical, or G5 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical, and G represents a hydrogen atom, or else G5 and Gβ together form a ring having from 4 to 7 links, the treatment of the ester of general formula (IV) with a mineral or organic acid optionally in an organic solvent such as an alcohol leads to the product of general formula:

OCOC₆H₅ dans laquelle X, Ar et G3 sont définis comme précédemment, qui est acylé au moyen de chlorure de benzoyle dans lequel le noyau phényle est éventuellement substitué, de chlorure de thénoyle, de chlorure de furoyle ou d'un produit de formule générale :

OCOC ₆ H ₅ in which X, Ar and G3 are defined as above, which is acylated by means of benzoyl chloride in which the phenyl ring is optionally substituted, of thenoyl chloride, of furoyl chloride or of a product of formula general:

Ri-O-CO-Y (VIII) in which R is defined as above and Y represents a halogen atom (fluorine, chlorine) or a residue -OR ^ or -O-CO-O-Ri, to obtain a product of general formula:

OCOC ₆ H ₅ in which Ar, R and G3 are defined as above, the protective group G3 of which is replaced, if necessary, by a hydrogen atom under the conditions described above under 1) or 2) to obtain a product of general formula (I) . Preferably, the product of general formula (IV) is treated with formic acid at a temperature in the region of 20 ° C.

Preferably, the acylation of the product of general formula (VII) by means of a benzoyl chloride in which the phenyl radical is optionally substituted, of thenoyl chloride, of furoyl chloride or of a product of general formula (VIII ) is carried out in an inert organic solvent chosen from esters such as ethyl acetate, isopropyl acetate or n.butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1-dichloro, 2 ethane in the presence of a mineral base such as sodium bicarbonate or organic such as triethylamine. The reaction is carried out at a temperature between 0 and 50 ° C, preferably close to 20 ° C. b) when R represents an optionally substituted benzoyl radical, thenoyl or furoyl or an RjO-CO- radical in which Ri is defined as above, G5 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a radical phenyl substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms and G _β represents a hydrogen atom, the replacement of the protective group formed by G5 and Gβ by hydrogen atoms is carried out in the presence of an acid mineral (hydrochloric acid, sulfuric acid) or organic (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p.toluenesulfonic acid) used alone or as a mixture in stoichiometric or catalytic amount, operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a specified temperature is between -10 and 60 ° C, preferably between 15 and 30 ° C.

The replacement of the protective groups Gj, G ₂ and G3 of the product of general formula (V) by hydrogen atoms under the conditions described above leads to a product of general formula:

OCOCH,

OCOC ₆ H ₅ in which Ar, R and X ₂ are defined as above, which constitute another object of the present invention.

When the thiocarbonyldiimidazole reacts with a product of general formula (III) in which G preferably represents a trialkylsilyl radical, a product of general formula can intermediate form:

dans laquelle Ar, R et G3 sont définis comme précédemment, dont le groupement thocarbonylimidazole et éventuellement G3 sont remplacés par des atomes d'hydrogène. Lorsque G3 représente un radical trialcoylsilyle, le remplacement du groupement thiocarbonylimidazole et de G3 par des atomes d'hydrogène est effectué, de préférence, par traitement au moyen d'acide chlorhydrique en milieu hydro¬ organique tel qu'un mélange acétate d'éthyle-eau à une température comprise entre 0 et 50°C. Lorsque G3 représente un radical trichloro-2,2,2 éthoxycarbonyle, le remplacement du groupement thiocarbonyimidazole est d'abord effectué par traitement en milieu acide comme indiqué ci-dessus, et est suivi du remplacement du radical trichloro-2,2,2 éthoxycarbonyle par un atome d'hydrogène dans les conditions décrites précédemment. Les nouveaux produits de formule générale (I) obtenus selon le procédé de la présente invention peuvent être éventuellement purifiés par des méthodes physiques ou physico-chimiques telles que la cristallisation ou la chromatographie.

in which Ar, R and G3 are defined as above, in which the thocarbonylimidazole group and optionally G3 are replaced by hydrogen atoms. When G3 represents a trialkylsilyl radical, the replacement of the thiocarbonylimidazole group and of G3 with hydrogen atoms is preferably carried out by treatment with hydrochloric acid in hydro¬ organic medium such as an ethyl acetate mixture- water at a temperature between 0 and 50 ° C. When G3 represents a 2,2,2,2-ethoxycarbonyl trichloro radical, the replacement of the thiocarbonyimidazole group is first carried out by treatment in an acid medium as indicated above, and is followed by the replacement of the 2,2,2-trichloroethoxycarbonyl radical by a hydrogen atom under the conditions described above. The new products of general formula (I) obtained according to the process of the present invention can be optionally purified by physical or physicochemical methods such as crystallization or chromatography.

The products of general formula (III) can be obtained from a product of general formula:

dans laquelle Ar et R sont définis comme précédemment selon les méthodes habituelles de protection des fonctions hydroxy. Plus particulièrement, les produits de formule générale (III) peuvent être obtenus dans les conditions décrites dans le brevet européen EP 0 336 841 ou dans les demandes internationales PCT WO 92/09589 ou WO 94/07878.

in which Ar and R are defined as above according to the usual methods for protecting the hydroxy functions. More particularly, the products of general formula (III) can be obtained under the conditions described in European patent EP 0 336 841 or in international PCT applications WO 92/09589 or WO 94/07878.

The products of general formula (XI) in which, Ar and R being defined as above and the hydroxy function in position -7 of the ring is in 7β form can be obtained according to the methods described more particularly in international PCT applications WO 92/09589 and WO 94/07878.

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

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 carried out on tubulin extracted from pig brains by the method of ML Shelanski et al., Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). The study of the depolymerization of microtubules into tubulin is carried out according to the method of G. Chauvière et al., CR Acad. Sci., 293, Series II, 501-503 (1981). In this study, the products of general formula (I) were shown to be at least as active as taxol and Taxotere.

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

The following example illustrates the present invention.

EXAMPLE 1

A solution of 3.3 g of t.butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 trihydroxy- l, 7α, 10β oxo-9 taxene -11 yle-13α and 2 g of carbonyl-l.l'-diimidazole in 50 cm3 of anhydrous toluene, maintained under an argon atmosphere, is heated to a temperature in the region of 50 ° C for 2 hours 30 minutes. After cooling to a temperature in the region of 20 ° C, the solvent is removed by distillation under reduced pressure (0.27 kPa). 5.55 g of a yellow solid are thus obtained which is purified by chromatography on 300 g of silica (0.063-0.2 mm) contained in a column 6 cm in diameter, eluting with a gradient of elution acetate of ethyl-dichloromethane from 0-100 to 20-80 (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 40 ° C for 2 hours. 2.98 g of t.butoxycarbonylamino-3-triethylsilyloxy-2-phenyl-3-propionate- (2R, 3S) of acetoxy-4α-benzoyloxy-2 epoxy-5β, 20 dihydroxy-1, 7α (imidazolyl-1 carbonyloxy) are thus obtained -10β oxo-9 taxene-11 yle-13 in the form of a white meringue.

A solution of 1.5 g of t.butoxycarbonylamino-3 triéfhylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2 époxy-5β, 20 dihydroxy- l, 7α (imidazolyl-1 carbonyloxy) -10β oxo-9 taxene-11 yle-13α and 33 mg of N, N'-dimethylamino-4 pyridine in 15 cm3 of anhydrous toluene is heated, under an argon atmosphere, to a temperature close to 110 ° C for 5 hours 3 minutes. 45 mg of N, N'-dimethylamino-4 pyridine are then added, then the mixture is heated to a temperature in the region of 110 ° C., under an argon atmosphere, for 17 hours. After cooling to a temperature in the region of 20 ° C, the solvent is evaporated off under reduced pressure (0.27 kPa). 1.64 g of a brown solid are thus obtained 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. ethyl-dichloromethane from 2-98 to 10-90 (by volume) and collecting 15 cm 3 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. This gives 593.7 mg of t.butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 dihydroxy-l, 7α taxadiene-9.11 yle- 13cc in the form of a white meringue. A solution of 590 mg of t.butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 proρionate- (2R, 3S) acetoxy-4α benzoyloxy-2 carbonyldioxy-9,10 epoxy-5β, 20 dihydroxy-1,7 ta ,adiene-9 , 11 yle-13α in 12.5 cm3 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 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 2.5 cm in diameter, eluting with a methanol-dichloromethane elution gradient from 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. 295 mg of a yellow solid are thus obtained which is purified by preparative chromatography on 12 thin-layer silica plates (Kieselgel 60F254, Merck; thickness: 0.25 mm), eluting with a methanol-dichloromethane mixture (2.5- 97.5 by volume). After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (10-90 by volume) then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 53.6 mg is obtained of t.butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 dihydroxy-l, 7α taxadiene-9,11 yle-13 in the form of a white meringue, the characteristics of which are as follows: - rotary power: [] ²⁰ rj> = + 26 ° (c = 0.132; methanol)

- proton nuclear magnetic resonance spectrum (400MHz; deuterated chloroform; chemical shifts in ppm; coupling constants J in Hz): 1.20 (s, 3H: -CH ₃ in 16 or 17); 1.30 (s, 3H: -CH ₃ at 16 or 17); 1.40 [s, 9H: -C (CH ₃ ) ₃ ]; 1.66 (s, 3H: -CH ₃ in 19); 1.66 (s, 3H: -CH ₃ in 18); 1.73 (s, 1H: -OH in 1); 1.80 (broad s, 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: -H at 3); 3.28 (broad d, J = 4.5, 1H: -OH in 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 in 20); 4.63 (mt, 1H: -H in 2 '); 4.89 (dd, J = 10 and 5, 1H: -H at 5); 5.25 (broad d, J = 10, 1H: -H in 3 '); 5.38 (d, J = 10, 1H: -CONH-); 5.81 (d, J = 6, 1H -H in 2); 6.17 (broad t, J = 9, 1H: -H at 13); from 7.30 to 7.45 [mt, 5H: -CÔH ₅ in 3 '(-H 2 to H 6)]; 7.52 [t, J = 7.5, 2H: -OCOC ₆ H ₅ (-H 3 and -H 5)]; 7.65 [t, J = 7.5, 1H: -OCOC ₆ H ₅ (-H 4)]; 8.10 [d, J = 7.5, 2H: OCOC ₆ H ₅ (-H 2 and -H 6)].

T.butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α epoxy-5β, trihydroxy-l, 7α, 10β oxo-9 taxene-11 yle- 13 can be prepared as follows:

To a solution of 3.95 g of t.butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 trihydroxy-l, 7α, 10β oxo-9 taxene-11 yle-13α in a mixture of 40 cm3 of dichloromethane and 4 cm3 of pyridine, 4.15 cm3 of triethylsilyl chloride and then 600 mg of N, N'-dimefhylamino-4 are added, under an argon atmosphere pyridine. The reaction mixture is stirred for 17 hours at a temperature in the region of 20 ° C. under an argon atmosphere, then is diluted by adding 30 cm3 of distilled water and 80 cm3 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 concentration to dryness under reduced pressure (0.27 kPa) at 40 ° 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 column 4.5 cm in diameter, 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 40 ° C for 2 hours. 4.51 mg of butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 trihydroxy-1, 7α, 10β oxo-9 taxene are thus obtained -11 yle-13α in the form of a white meringue. To a degassed solution of 19.52 g of t.butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 trihydroxy- l, 7β, 10β oxo- 9 taxene-11 yle-13α in 150 cm3 of anhydrous tetrahydrofurarme, 25 mg of sodium hydride (50% by weight in the) are added, in fractions, under an argon atmosphere, at a temperature close to 20 ° C. petrolatum oil). 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 oil) are added in portions at a temperature in the region of 20 ° C. petroleum jelly). After 10 minutes, an excess of solid ammonium chloride is added, followed by 2 cm 3 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 40 ° 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 in a column 8 cm in diameter, eluting with a methanol-dichloromethane mixture (2-98 by volume) and collecting 65 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. This gives 14.43 g of t.butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2 epoxy-5β, 20 trihydroxy-l, 7α, 10β oxo-9 taxene -11 yle-13α in the form of a cream meringue.

The t.butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2 epoxy-5β, 20 trihydroxy-l, 7β, 10β oxo-9 taxene-11 yl- 13cc can be prepared under the conditions described in EP-0 336 841.

EXAMPLE 2

A solution of 3.0 g of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2 epoxy-5β, 20 trihydroxy- l, 7, 10β oxo-9 taxene -11 yle-13α, obtained under the conditions described in Example 1, and 2.3 g of thiocarbonyl-l.l'-diimidazole in 50 cm3 of anhydrous toluene, maintained under an argon atmosphere, is heated to a temperature close to 60 ° C for 4 hours. After cooling to a temperature in the region of 20 ° C, the solvent is evaporated off under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 5.35 g of a brown-red solid are thus obtained which are purified by atmospheric pressure chromatography on 300 g of silica (0.063-0.2 mm) contained in a column 6 cm in diameter (gradient of elution: ethyl acetate-dichloromethane from 10-90 to 20-80 by volume), collecting fractions of 100 cm3. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. This gives 463 mg of tert-butoxycarbonylamino-3 (imidazolyl-1-thiocarbonyloxy) -2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α thiocarbonyldioxy-9,10 epoxy-5β, 20 dihydroxy- 1.7α taxadiene-9.11 yle-13 in the form of a yellow meringue.

To a solution of 293 mg of tert-butoxycarbonylamino-3 (imidazolyl-1-thiocarbonyloxy) -2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α thiocarbonyldioxy-9,10 epoxy-5β, 20 dihydroxy -1.7 taxadiene-9.11 yl-13α in 3 cm3 of ethyl acetate, at a temperature in the region of 20 ° C., a solution containing 0.030 cm3 of distilled water and 0.030 cm3 of hydrochloric acid is slowly added concentrated to 37% (w / v). The solution is magnetically stirred for 8 hours at a temperature in the region of 20 ° C, for 17 hours at a temperature in the region of 17

(2.7kPa) at 40 ° C. 207 mg of an ivory meringue are obtained which is purified by preparative thin layer chromatography [4 Merck preparation plates, Kieselgel 60F254; thickness: 1 mm; deposition in solution in dichloromethane; elution with a methanol-dichloromethane mixture (5-95 by volume)]. After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (10-90 by volume), then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 99 mg of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 ρropionate- (2R, 3S) acetoxy-4α benzoyloxy-2cc carbonyldioxy-9,10 epoxy-5β, 20 dihydroxy-l, 7β taxadiene-9,11 yle- 13α sub shape of a white meringue, the characteristics of which are as follows: - proton NMR spectrum (400 MHz; CDCI3; δ in ppm): 1.20 (s, 3H: CH3); 1.28 (s, 3H: CH ₃ ); 1.41 (s, 9H: C (CH ₃ ) ₃ ); 1.70 (s, 3H: CH ₃ ); 1.78 (s, 3H: CH ₃ ); 1.78 (s, 1H: 0H in 1); 1.94 and 2.55 (2 mts, 1 H each: CH ₂ in 6); 2.04 (d, J = 5.5 Hz, 1 H: OH at 7); 2.9 and 2.45 (2 mts, 1 H each: CH ₂ in 14); 2.33 (s, 3H: COCH3); 3.14 (d, J = 5.5 Hz, 1 H: H at 3); 3.63 (broad d, 1H: OH in 2 '); 4.10 (mt, 1H: H at 7); 4.27 and 4.40 (2 d, J = 9 Hz, 1 H each: CH ₂ in 20); 4.67 (mt, 1H: H in 2 '); 4.94 (dd, J = 10 and 1.5 Hz, 1H: H at 5); 5.27 (broad d, J = 10 Hz, 1 H: H in 3 '); 5.48 (d, J = 10 Hz, 1 H: CONH); 5.79 (d, J = 5 Hz, 1H: H in 2); 6.15 (broad t, J = 9 Hz, 1 H: H at 13); from 7.30 to 7.45 (mt, 5H: 3 'aromatic H); 7.51 (t, J = 7.5 Hz, 2H: OCOCgH.- H in meta); 7.65 (t, J = 7.5 Hz, 1 H: OCOC ₆ H ₅ H in para);

8.10 (d, J = 7.5 Hz, 2H: OCOC ₆ H ₅ H in ortho).

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine- 1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 hydroxy- 1 oxo - 9 bis- (2,2,2-trichloroethoxycarbonyloxy) -7β, 10β taxene-11 yl-13 can be prepared under the conditions described in international PCT application WO 94/07878.

EXAMPLE 4

A solution of 1.0 g of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 dihydroxy- l, 10β oxo-9 triethylsilyloxy-7β taxene-11 yle-13α and 0.47 g of carbonyl-1,1'-diimidazole in 30 cm3 of anhydrous toluene, maintained under an argon atmosphere, is heated to a temperature in the region of 50 ° C for 6 hours. At the end of this time, 0.4 g of carbonyl-1,1 '-diimidazole are added to the solution, and the mixture is heated to a temperature in the region of 50 ° C, under an inert argon atmosphere, for 1 hour. After cooling to a temperature in the region of 20 ° C, the solvent is evaporated 18

under reduced pressure (0.27 kPa). 2.3 g of a cream meringue are thus obtained which are purified by chromatography at atmospheric pressure on 70 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a ethyl acetate-dichloromethane mixture (15-85 by volume), collecting 10 cm 3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. This gives 0.53 g of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2 epoxy-5β, 20 hydroxy-1 (imidazolyl-1-carbonyloxy) - 10β oxo-9 triethylsilyloxy-7β taxene-11 yl-13 in the form of a colorless lacquer. A solution of 530 mg of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 hydroxy-1 (imidazolyl-l-carbonyloxy) -10β oxo -9 triethylsilyloxy-7β taxene-11 yle-13α, 23 mg of N, N'-dimethylamino-4 pyridine and 46 mg of carbonyl-l, l'-diimidazole in 6 cm3 of anhydrous toluene is heated to a temperature close to 110 ° C, under an inert argon atmosphere, for 17 hours At the end of this time, 25 mg of N.N'-4-dimethylamino pyridine are added to the solution, and the mixture is heated to a temperature in the region of 110 °. C, under an inert argon atmosphere, for 6 hours. After cooling to a temperature in the region of 20 ° C, the solvent is evaporated off under reduced pressure (0.27 kPa). 1.03 g of a yellow lacquer is thus obtained which is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.2 mm) contained in a column 2.2 cm in diameter, eluting with a ethyl acetate-cyclohexane mixture (50-50 by volume), collecting 5 cm 3 fractions. The fractions containing the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. This gives 230 mg of a cream meringue which is purified by preparative thin layer chromatography [4 Merck preparative plates, Kieselgel 60F254; thickness: 1 mm; deposition in solution in dichloromethane; elution with a methanol-dichloromethane mixture (2.5-97.5 by volume)]. After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (10-90 by volume), then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 10 mg of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R.3S) acetoxy-4α benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 hydroxy-1 triethylsilyloxy-7β taxadiene-9,11 yle-13cc in the form of a beige meringue.

By treating tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 (2.7kPa) at 40 ° C. 207 mg of an ivory meringue are obtained which is purified by preparative thin layer chromatography [4 Merck preparation plates, Kieselgel 60F254; thickness: 1 mm; deposition in solution in dichloromethane; elution with a methanol-dichloromethane mixture (5-95 by volume)]. After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (10-90 by volume), then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 99 mg of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2cc carbonyldioxy-9,10 epoxy-5β, 20 dihydroxy-l, 7β taxadiene-9.11 yle- 13α sub shape of a white meringue, the characteristics of which are as follows: - proton NMR spectrum (400 MHz; CDCI3; δ in ppm): 1.20 (s, 3H: CH3); 1.28 (s, 3H: CH ₃ ); 1.41 (s, 9H: C (CH ₃ ) ₃ ); 1.70 (s, 3H: CH ₃ ); 1.78 (s, 3H: CH ₃ ); 1.78 (s, 1H: 0H in 1); 1.94 and 2.55 (2 mts, 1 H each: CH ₂ in 6); 2.04 (d, J = 5.5 Hz, 1 H: OH at 7); 2.9 and 2.45 (2 mts. 1 H each: CH ₂ in 14); 2.33 (s, 3H: COCH3); 3.14 (d, J = 5.5 Hz, 1 H: H at 3); 3.63 (broad d, 1H: OH in 2 '); 4.10 (mt, 1H: H at 7); 4.27 and 4.40 (2 d, J = 9 Hz, 1 H each: CH ₂ in 20); 4.67 (mt, 1H: H in 2 '); 4.94 (dd, J = 10 and 1.5 Hz, 1H: H at 5); 5.27 (broad d, J = 10 Hz, 1 H: H in 3 '); 5.48 (d, J = 10 Hz, 1 H: CONH); 5.79 (d, J = 5 Hz, 1H: H in 2); 6.15 (broad t, J = 9 Hz, 1 H: H at 13); from 7.30 to 7.45 (mt, 5H: 3 'aromatic H); 7.51 (t, J = 7.5 Hz, 2H: OCOC ₆ H ₅ H in meta); 7.65 (t, J = 7.5 Hz, 1H: OCOCgH _j H in para);

8.10 (d, J = 7.5 Hz, 2H: OCOC ₆ H ₅ H in ortho).

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine- 1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4c benzoyloxy-2α epoxy-5β, 20 hydroxy-1 oxo - 9 bis- (2,2,2-trichloroethoxycarbonyloxy) -7β, 10β taxene-11 yle-13α can be prepared under the conditions described in international PCT application WO 94/07878.

EXAMPLE 4

A solution of 1.0 g of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 ρropionate- (2R, 3S) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 dihydroxy- l, 10β oxo-9 triethylsilyloxy-7β taxene-11 yle-13α and 0.47 g of carbonyl-1,1'-diimidazole in 30 cm3 of anhydrous toluene, maintained under an argon atmosphere, is heated to a temperature in the region of 50 ° C for 6 hours. At the end of this time, 0.4 g of carbonyl-1, l'-diimidazole are added to the solution, and the mixture is heated to a temperature in the region of 50 ° C, under an inert atmosphere of argon, for 1 hour. After cooling to a temperature in the region of 20 ° C, the solvent is evaporated under reduced pressure (0.27 kPa). 2.3 g of a cream meringue are thus obtained which are purified by chromatography at atmospheric pressure on 70 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a ethyl acetate-dichloromethane mixture (15-85 by volume), collecting 10 cm 3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. This gives 0.53 g of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2 epoxy-5β, 20 hydroxy- 1 (imidazolyl-1-carbonyloxy) - 10β oxo-9 triethylsilyloxy-7β taxene-11 yle-13α in the form of a colorless lacquer. A solution of 530 mg of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 hydroxy-1 (imidazolyl-l-carbonyloxy) -10β oxo -9 triethylsilyloxy-7β taxene-11 yle-13α, 23 mg of N, N'-dimethylamino-4 pyridine and 46 mg of carbonyl-l, l'-diimidazole in 6 cm3 of anhydrous toluene is heated to a temperature close to 110 ° C, under an inert argon atmosphere, for 17 hours At the end of this time, 25 mg of N, N'-dimethylamino-4 pyridine are added to the solution, and the mixture is heated to a temperature in the region of 110 °. C, under an inert argon atmosphere, for 6 hours. After cooling to a temperature in the region of 20 ° C, the solvent is evaporated off under reduced pressure (0.27 kPa). 1.03 g of a yellow lacquer is thus obtained which is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.2 mm) contained in a column 2.2 cm in diameter, eluting with a ethyl acetate-cyclohexane mixture (50-50 by volume), collecting 5 cm 3 fractions. The fractions containing the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. This gives 230 mg of a cream meringue which is purified by preparative thin layer chromatography [4 Merck preparative plates, Kieselgel 60F254; thickness: 1 mm; deposition in solution in dichloromethane; elution with a methanol-dichloromethane mixture (2.5-97.5 by volume)]. After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (10-90 by volume), then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 10 mg of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R.3S) acetoxy-4α benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 hydroxy-1 triethylsilyloxy-7β taxadiene-9,11 yle-13 in the form of a beige meringue.

By treating tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 hydroxy-1 triethylsilyloxy-7β taxadiene-9,11 yl-13oc by 0.1N hydrochloric ethanol at a temperature close to 0 ° C, we obtain tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R , 3S) acetoxy-4α benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 dihydroxy-l, 7β taxadiene-9,11 yl-13 identical to the product of Example 3.

Tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R.3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 dihydroxy-l, 10β oxo-9 triethyl- silyloxy-7β taxene-11 yle- 13 can be prepared as follows:

To a solution of 2.0 g of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2 epoxy-5β, 20 trihydroxy-1,7,7β, 10β oxo-9 taxene-11 yle-13α in a mixture of 20 cm3 of dichloromethane and 16 cm3 of pyridine, 8.4 cm3 of triethylsilyl chloride are added under an argon atmosphere. The reaction mixture is stirred at a temperature in the region of 20 ° C., under an argon atmosphere, for 32 hours, then diluted with 10 cm 3 of distilled water and 80 cm 3 of dichloromethane. The decanted organic phase is washed with 2 times 10 cm3 of an aqueous 0.1M hydrochloric acid solution, with 10 cm3 of distilled water, dried over magnesium sulfate, filtered through sintered glass, concentrated to dryness under reduced pressure ( 2.7 kPa) at 40 ° C. 2.95 g of a yellow oil are thus obtained which is purified by chromatography on 300 g of silica (0.063-0.2 mm) contained in a column 6 cm in diameter (elution gradient: methanol-dichloromethane from 0-100 to 2-98 by volume) by collecting fractions of 100 cm3. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. This gives 2.26 g of tert-butoxycarbonylamino-3 triethylsilyloxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 dihydroxy-l, 10β oxo-9 triethylsilyloxy-7β taxene-11 yle- 13α in the form of a white meringue.

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

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

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

For parenteral administration, aqueous or non-aqueous sterile solutions or suspensions are used. For the preparation of non-aqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate . The sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water. 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 (ce, β or δ) and TNF. Other chemotherapeutic agents useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, elphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs like mercaptopurine and thioguanine, natural products like vinca alkaloids like vinblastine, vincristine and vendesine, epipodophyllotoxins like etoposide and teniposide, antibiotics like dactinomycin , daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes c like L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid suppressants such as mitotane and aminoglutethymide, hormones and antagonists like adrenocorticosteroids like prednisone, progestins like hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, estrogens like diethylstilbestrol and rethynylestradiol, antioestrogens like tamoxifen, androgens like androgens testosterone 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. By the intraperitoneal route, the doses will generally be between 0.1 and 100 mg / kg and, preferably between 0.5 and 50 mg / kg and, even more specifically between 1 and 10 mg kg. Intravenously, the doses are generally between 0.1 and 50 mg / kg and, preferably between 0.1 and 5 mg / kg and, even more specifically between 1 and 2 mg / kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the efficacy must be taken into account. of 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 cm 3 of ethanol then the solution is diluted by adding 18 cm 3 of physiological saline. The composition is administered by infusion for 1 hour by introduction into physiological saline.

Claims

1 - New taxoids of general formula:

in which: Ar represents an alkyl radical containing 1 to 6 carbon atoms, alkenyl containing 2 to 6 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms or aryl, R represents an optionally substituted benzoyl radical, furoyl or thénoyl or an R -O-CO- radical in which Ri represents: - a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from atoms halogen and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted in -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalky nyle containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms, - or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, - or a saturated or unsaturated nitrogen heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and X represents an oxygen or sulfur atom. 2 - New taxoids according to claim 1, characterized in that R and X being defined as in claim 1, Ar represents a phenyl or a- or β-naphthyl radical optionally substituted by one or more atoms or radicals chosen from atoms of halogen (fluorine, chlorine, bromine, iodine) and the radicals alkyl, alkenyls, alkynyls, aryls, arylalkyls, alkoxy, alkyllio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonamino , dialkoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialcoylcarbamoyl, 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, that the alkenyl and alkynyl radicals contain 2 to 8 atoms of carbon and that the aryl radicals are phenyl or a- or β- naphthyl radicals, or else Ar represents an aromatic heterocyclic radical having 5 ch let us senior and containing one or more atoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted by one or more substituents, identical or different, chosen from halogen atoms (fluorine, chlorine , bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms, amino, alkylamino containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 to 4 carbon atoms, acylamino of which the acyl part contains 1 to 4 carbon atoms, alkoxycarbo-nylamino containing 1 to 4 carbon atoms, acyl containing 1 to 4 carbon atoms , arylcarbonyl of which the aryl part contains 6 to 10 carbon atoms, cyano, carboxy, carbamoyl, alkylcarbamoyl of which the alkyl part contains 1 to 4 carbon atoms, dialcoylcarbamoyl of which each alkyl part contains nt 1 to 4 carbon atoms or alkoxycarbonyl in which the alkoxy part 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 radical optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, alkyllamino, dialkoylamino, 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: Xl-C (= X) -X ₂ (II) in which X represents an oxygen or sulfur atom, X represents a halogen atom such as a chlorine atom or an imidazolyl-1 radical and X ₂ represents a halogen atom 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 defined as in one of claims 1 to 4, either G represents a protective group for the hydroxy function and G represents a hydrogen atom, or G and G ₂ together form a heterocycle, and G3 and G4 each represent a hydrogen atom or a protecting group for the hydroxy function, to obtain a product of general formula:

in which Ar, R, X, Gi, G, G3 and G4 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, diisopropyl ether or tetrahydrofuran possibly in the presence of a condensing agent preferably chosen from tertiary amines such as triethylamine, dimethylaniline, 4-dimethylamino pyridine or 4-pyrrolidino pyridine at a temperature between 0 ° C 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 G \, G ₂ , G3 and X are defined as in claim 5. 7 - Process according to claim 5 characterized in that the replacement of the protective groups Gi, Gi and G ₂ , and G3 is carried out in the following manner: 1) when G represents a hydrogen atom, G represents a protective group for the hydroxy function defined as above and G3 represents a trialcoylsilyl radical, the replacement of the protective groups by hydrogen atoms is carried out by means of an acid mineral or organic used alone or as a mixture, operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between -10 and 60 ° C or by catalytic hydrogenation or by the action of a hydrofluoric acid-triethylamine or hydrofluoric acid-pyridine complex. 2) when G represents a hydrogen atom, Gi represents a protective group for the hydroxy function and G3 represents a 2,2,2-trichloroethoxycarbonyl radical, replacing the 2,2,2-trichloroethoxycarbonyl radical by a d atom hydrogen is carried out using zinc, optionally combined with copper, in the presence of acetic acid at a temperature between 30 and 60 ° C or using a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or in an aliphatic ester in the presence of zinc optionally associated with copper and that of Gi is then carried out under the conditions described under 1) above. 3) when G and G ₂ together form a 5 or 6-membered saturated heterocycle and more particularly an oxazolidine ring of general formula:

in which R is defined as above, G5 and G _β , identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical in which the alkyl part contains 1 to 4 carbon atoms and the aryl part preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical representing, preferably a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or G5 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and G _β represents a hydrogen atom, or else G5 and Gβ together with the carbon atom to which they are linked form a ring having 4 to 7 members, the replacement of the protective group formed by G5 and Gβ by hydrogen atoms can be carried out, according to the meanings of R, G5 and Gβ, in the following manner: a) when R represents a tert-radical butoxycarbonyl, G5 and Gβ, identical or different, represent an alkyl radical or an aralkyl or aryl radical, or else G5 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical, and Gβ represents a hydrogen atom, or G5 and Gβ together form a cycle having from 4 to 7 members, the treatment of the ester of general formula (IV) with a mineral or organic acid optionally in an organic solvent such as an alcohol leads to the product of general formula:

in which X, Ar and G3 are defined as above, which is acylated by means of benzoyl chloride in which the phenyl ring is optionally substituted, of thenoyl chloride, of furoyl chloride or of a product of general formula: Rl- O-CO-Y (VII) in which Ri is defined as above and Y represents a halogen atom (fluorine, chlorine) or a residue -O-Ri or -O-CO-O-Ri, to obtain a product of general formula:

OCOC ₆ H ₅ in which Ar, R and G3 are defined as above, the protective group G3 of which is replaced, if necessary, by a hydrogen atom under the conditions described under 1) b) when R represents an optionally substituted benzoyl radical, thenoyl or furoyl or a radical RiO-CO- in which Ri is defined as above, G5 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms carbon and G _β represents a hydrogen atom, the replacement of the protective group formed by G5 and Gβ by hydrogen atoms is carried out in the presence of a mineral or organic acid used alone or as a mixture in stoichiometric or catalytic quantity, by operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and hydrocarbons aromatic at a temperature between -10 and 60 ° C 8 - The product of general formula: ₂

in which Ar, R and X are defined as in 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 by 1 or more atoms halogen. 9 - Pharmaceutical composition characterized in that it contains at least one product according to one of claims 1, 2, 3 or 4 in combination with one or more pharmaceutically acceptable products whether they are inert or physiologically active.