WO1995013270A1 - Novel taxicine derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Novel taxicine derivatives of general formula (I), their preparation and pharmaceutical compositions containing them wherein Ar is an aryl, alkyl, alkenyl, cycloalkyl or cycloalkenyl radical, R is a benzoyl radical or a radical of general formula R1-O-CO- wherein R1 is an alkyl, alkenyl, alcynyl, cycloalkyl, bicycloalkyl, phenyl or heterocyclyl radical, R2 and R3 are each a hydroxy radical or an oxo group or together form an optionally substituted methylenedioxy radical, R6 and R7 are each a hydrogen atom, or R6 is a hydrogen atom and R7 is a R'7-CO- radical wherein R'7 is an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl radical or R6 and R7 together form an optionally substituted methylene radical, and R10 is an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl radical. Said novel taxicine derivatives of general formula (I) have remarkable antileukemia and antitumor properties.

Description

 NEW TAXICIN DERIVATIVES. THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS YES CONTAINING THEM

The present invention relates to new taxicin derivatives of general formula:

their preparation and the pharmaceutical compositions containing them. In the general formula (I),

\ r represents an aryl radical, an alkyl containing 1 to 4 carbon atoms, an alkenyl containing 2 to 4 carbon atoms? carbon, cycloalkyl containing 3 to 6 carbon atoms or cycloalkenyl containing 3 to 6 carbon atoms,

R represents a benzoyl, thenoyl or furoyl radical or a radical of general formula R ^ -O-CO- in which Rj represents an alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, phenyl or heterocyclyl radical,

R2 and R3 each represent a hydroxy radical or an oxo group or together form a radical of formula

-OC (-R ₄ ) (- R ₅ ) -O- (II) in which R4 and R5, identical or different, represent a hydrogen atom, an alkyl radical or an optionally substituted phenyl radical, Rg and R7 each represent a hydrogen atom or else Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl radical or else R and R7 form together a radical of formula

-C (-R ₈ ) (- R ₉ ) (III) in which Rg and R9, identical or different, represent an alkyl radical or an optionally substituted phenyl radical, and RJO represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl radical or heterocyclyl optionally substituted. * More particularly, the present invention relates to the products of general formula (I) in which:

Ar represents an aryl radical,

R represents a benzoyl radical or an Rj-O-CO- radical in which R _j represents:

- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from fluorine or chlorine atoms and hydroxy radicals, alkoxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 with 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkoxycarbonyl in which the alkyl part contains 1 to 4 ato carbon,

a phenyl radical optionally substituted by one or more radicals chosen from alkyl radicals containing 1 to 4 carbon atoms and alkoxy radicals containing 1 to 4 carbon atoms,

- or a saturated nitrogen heterocyclyl radical containing 5 to 6 members optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and

R2 and R3 each represent a hydroxy radical or an oxo group or together form a radical of formula (II) in which R4 and R5, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl radicals , mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialcoylcarbamoyl, cyano, nitro and trifluoromethyl, it being understood that the alkyl radicals and the alkyl moieties of the other radicals 1 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 else Rg represents a hydrogen atom and R7 represents a radical R '7-CO- in which R'7 represents

-; .n straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 atoms of carbon or bicycloalkyl containing 7 to 10 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 with 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms,

- or an optionally substituted aryl radical,

- or a saturated or unsaturated heterocyclyl radical having 4 to 6 members, containing one or more identical or different heteroatoms chosen from nitrogen, oxygen or sulfur atoms and being optionally substituted, it being understood that the cycloalkyl radicals, cycloalkenyls or bicycloalkyls may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, or else Rg and R7 together form a radical of formula (III) in which

Rg and R9, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or phenyl optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and the alkyl radicals, alkenyls, alkynyls, aryls, aralkyls, alkoxy, alkylthio, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, carbamoyl, dialcoylcarbamoyl, triano 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 , and RlO represents:

- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 2 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, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms,

- or an optionally substituted aryl radical, - or a saturated or unsaturated heterocyclyl radical having 4 to 6 members, containing one or more identical or different heteroatoms chosen from nitrogen, oxygen or sulfur atoms and being optionally substituted, 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.

Preferably, the aryl radicals represented by Ar, R'7 and Rio are phenyl or α- or β-naphthyl radicals optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine ) and the radicals alkyl, alkenyls, alkynyls, aryls, aralkyls, alkoxy, alkyloylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alcoylamino, carboxyalkyl dialkoylcarbamoyl, 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 that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are radicals phenyls or a- or β-naphthyls.

Preferably, the heterocyclic radicals represented by Ar, R7 and R o are aromatic heterocyclic radicals having 5 members and containing 1 or more atoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted with one or more substituents, identical or different, chosen from halogen atoms (chlorine, fluorine, bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, amino, alkylamino containing 1 to 4 atoms carbon, dialkoylamino of which each alkyl part contains 1 to 4 carbon atoms, alkoxycarbonylamino 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 in which the alkyl part contains 1 to 4 carbon atoms, dialkoylcarbamoyl in which each alkyl part contains 1 to 4 carbon atoms or alkyloxycarbonyl in which the alkyl part contains 1 to 4 carbon atoms.

More particularly still, the present invention relates to the products of general formula (I) in which

Ar represents a phenyl radical optionally substituted by a fluorine or chlorine atom or by an alkyl (methyl), alkoxy (methoxy), dialcoylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tert-butoxycarbonylamino) or trifluoromethyl radical or a thienyl-2 or -3 or furyl-2 or -3 radical, R represents a benzoyl radical or an R -O-CO- radical in which Ri represents a tert-butyl radical, I; and R3 represent a hydroxy radical or an oxo group or together form a ical of f Dimule (II) in which R4 and R5 represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, preferably methyl, or a phenyl radical optionally substituted by one or more methoxy radicals. Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 represents a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkoxy radicals containing 1 to 4 carbon atoms or a thienyl-2 or -3 or furyl-2 or -3 radical, or else Rg and R7 together form a radical of formula (III) in which Rg represents a hydrogen atom and Rg represents a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkoxy radicals containing 1 to 4 carbon atoms, and

RO represents a straight or branched alkyl radical containing 1 to 8 carbon atoms or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkoxy radicals containing 1 to 4 carbon atoms or a thienyl radical -2 or -3 or furyl-2 or -3. According to the invention, the new products of general formula (I) in which R2 and R3 each represent a hydroxy radical or together form a radical of formula (II) can be obtained by esterification of a product of general formula:

in which R ₄ , R5, Rg, R9 and Rio are defined as above, by means of an acid of general formula:

in which Ar and R are defined as above, and either Ru represents a hydrogen atom and R12 represents a protective group for the hydroxy function, or alternatively Ru and R12 together form a 5 or 6-membered saturated heterocycle, or a derivative of this acid to obtain a product of general formula:

in which Ar, R, R4, R5, Rg, R, Rio, Ru and R12 are defined as above, followed by the replacement of the protective groups represented by Rl2 and / or Ru and R 2 by hydrogen atoms, and optionally hydrolysis of the acetal functions -OC (-R4) (- R5) -O- to obtain a product of general formula (I) in which R2 and R3 each represent a hydroxy radical, or optionally oxidation, when Rg represents a hydrogen atom, to a product of general formula:

in which R4, R5 and Rio are defined as above, Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 is identical to R9, then optionally hydrolysis of the .. product of general formula (NIT '-χ> ur to obtain a product of general formula (I) in which Ar and R are defined above, R2 and R3 each represent a hydroxy radical, Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 is identical to R ₉ .

Esterification using an acid of general formula (N) can be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridine) in an organic solvent (ethers , esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between -10 and 110 ° C.

Esterification can also be carried out using the acid of general formula (V) in the form of anhydride, operating in the presence of an activating agent (aminopyridine) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, hydrocarb: ~ es aliphatic halogens, aromatic hydrocarbons) at a temperature included ^* -, between 0 and 110 ° C.

The esterification can also be carried out using the acid of general formula (V) in the form of halide or in the form of a mixed anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base ( tertiary aliphatic amine) by operating in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 110 ° C.

The replacement of the protective groups Rχ2 and / or Ru and R 2 by hydrogen atoms, can be carried out according to their nature, as follows:

1) when Ru represents a hydrogen atom and R 2 represents a protecting group for the hydroxy function chosen, preferably, from the methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, (β-trimethylsilylethoxy) methyl or tetrahydropyrannyl radicals , its replacement by a hydrogen atom can be carried out by treating the product of general formula (NI) with a mineral acid (hydrochloric, sulfuric, hydrofluoric acid) or organic acid (formic, acetic, methanesulfonic, trifluoromethanesulfonic, p.toluene- sulfonic) used alone or as a mixture, operating in an organic solvent chosen from alcohols, ethers, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between -10 and 60 ° C.

2) when Ru and R12 together form a 5 or 6-membered saturated heterocycle and more particularly an oxazolidine ring of general formula:

in which Ar and R are defined as above, R 3 and R 4, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms optionally substituted by an aryl radical, preferably 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 alternatively R 3 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 R14 represents a hydrogen atom, or else Ri 3 and R14 form together with the carbon atom to which they are linked a cycle having 4 to 7 links, the replacement of the protective groups by hydrogen atoms can be carried out, according to the meanings of R, R13 and R14, in the following manner: a) when R represents a tbutoxycarbonyl radical, Ri 3 and R14, identical or different, represent an alkyl radical or an aryl radical (phenyl), or else Rl3 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R14 represents a hydrogen atom, or else R13 and R14 together form a ring having from 4 to 7 links, the treatment of a product of general formula (NI) with a mineral or organic acid optionally in an organic solvent such as an alcohol leads to the product of general formula:

in which Ar, R4, R5, Rg, R7 and Rχo are defined as above, which is acylated by means of benzoyl chloride, thenoyl or furoyl or a product of general formula:

R -O-CO-X (X) in which Ri is defined as above and X represents a halogen atom (fluorine, chlorine) or a residue -O-Rχ or -O-CO-OR to provide a product of formula general (VII).

Preferably, the product of general formula (VI) is treated with formic acid at a temperature in the region of 20 ° C. Preferably, the acylation of the product of general formula (IX) by means of a product of general formula (X) is carried out in an inert organic solvent chosen from esters such as ethyl acetate, acetate d isopropyl or n.butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane in the presence of an inorganic 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 a benzoyl radical or a Ri-O-CO- radical in which Ri is defined as above, R13 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted by a or several alkoxy radicals containing 1 to 4 carbon atoms and R 4 represents a hydrogen atom, the replacement of the protective groups by hydrogen atoms is carried out in the presence of a mineral acid (hydrochloric acid, sulfuric acid) or organic (acetic acid, mefhanesulfonic acid, trifluoromethanesulfonic acid, toluenesulfonic acid) used alone or as a mixture, 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, preferably between 15 and 30 ° C. The acid can be used in a catalytic or stoichiometric amount.

Generally, the hydrolysis of the acetal function -OC (-R4) (- R5) -O- is carried out in an acid medium by operating in an organic solvent chosen from ethers (tetrahydrof uranium), esters (ethyl acetate ), ketones (acetone), nitriles (acetonitrile), aliphatic hydrocarbons (hexane), halogenated aliphatic hydrocarbons (dichloromethane) and aromatic hydrocarbons (benzene, toluene) at a temperature between 0 ° C and the reflux temperature of the reaction mixture. Generally, a mineral acid (hydrochloric acid) is used which can be diluted or concentrated. According to the conditions of implementation, the hydrolysis of acetal -O-C (-R4) (-R5) -O- is carried out simultaneously with the replacement of the protective groups R12 and / or Ru and R 2.

Generally, the oxidation to a product of general formula (VII) is carried out using an oxidizing agent such as 2,3-dichloro-5,6-dikano-1,4-benzoquinone in hydro-organic medium such as water-dichloromethane mixture at a temperature between 0 and 50 ° C.

Generally, the subsequent hydrolysis of the acetal function -O-C (-R4) (-R5) -O- of the product of general formula (VII) can be carried out under the conditions described above.

The products of general formula (IV) can be obtained by reduction of a product of general formula:

in which R4, R5, Rg, R9 and Rio are defined as above.

Generally, the reduction is carried out using a hydride such as diisobutylaluminum hydride, operating in an anhydrous organic solvent at a temperature of between -10 and 30 ° C under conditions which do not affect the rest of the molecule.

The products of general formula (XI) can be obtained by esterification of a product of general formula:

by means of an acid of general formula:

R10-COOH (XIII) in which Rio is defined as above, or of a derivative of this acid such as a halide, an anhydride or an anhydride with an aliphatic or aromatic acid, under the conditions described above for the esterification of '' a product of general formula (IN ^* using an acid of general formula (N).

The products of general formula (XII) can be obtained by cyclization of a product of general formula:

in which R4, R5, Rg and R9 are defined as above, R15 represents a residue of sulfonic ester such as a methanesulfonyl or p.toluenesulfonyl residue.

Generally, the cyclization is carried out by treating a product of general formula (XIV) with an excess of a quaternary ammonium salt such as tetra-n-butylammonium acetate by operating in an organic solvent such as a ketone such as butanone at a temperature between 20 ° C and the reflux temperature of the reaction mixture.

The products of general formula (XIV) can be obtained by selective hydrolysis of a product of general formula:

in which R4, R5, Rg, R9 and R15 are defined as above and Rig preferably represents a trialkylsilyl radical such as a tert-butyldimethylsilyl radical. Generally, the hydrolysis is carried out using an organic base or a fluoride such as tetra-n-butylammonium fluoride hydrated by operating in an organic solvent such as an ether such as tetrahydrofuran at a temperature between 0 and 50 ° C. The products of general formula (XV) can be obtained by the action of a sulfonic acid halide such as chloride of methanesulfonic acid or p.toluenesulfonic on a product of general formula:

in which R4, R5, Rg, R9 and Rig are defined as above by operating in an anhydrous organic solvent such as a halogenated aliphatic drocarbon such as dichloroethane in the presence of an organic base such as a tertiary aliphatic amine, such as triethylamine, or pyridine or (dimethylamino) -4 pyridine at a temperature between 0 ° C and the reflux temperature of the reaction mixture.

The products of general formula (XVI) can be obtained by the action of a trialkylsilyl halide such as tert-butyldimethylsilyl chloride on a product of general formula:

in which R4, R5, Rg and R9 are defined as above.

Generally, the reaction is carried out in an organic solvent such as an amide such as dimethylformamide in the presence of a condensing agent such as imidazole, operating at a temperature between 0 and 50 ° C.

The product of general formula (XVII) can be obtained by oxidation of a product of general formula: (XVIII)

in which R4, R5, Rg and R9 are defined as above.

Generally, the reaction is carried out using osmium tetroxide in the presence of N-methylmorpholine-N-oxide by operating in a hydro-organic medium such as a water-tetrahydrofuran mixture at a temperature between 0 and 50 ° C. .

The products of general formula (XVIII) can be obtained by saponification of a product of general formula:

in which R4, R5, Rg and R9 are defined as above and Ph represents a phenyl radical.

Generally, the saponification is carried out by means of a mineral base such as an alkali metal hydroxide (soda, potash) or an alkali metal carbonate (sodium carbonate, potassium carbonate) by operating in a hydro¬ organic medium. such as a water-tetrahydrofuran mixture at a temperature between 20 ° C. and the reflux temperature of the reaction mixture.

The products of general formula (XIX) can be obtained by the action of an aldehyde or a ketone of general formula:

Rg-CO-R ₉ (XX) in which Rg and R9 are defined as above, optionally in the form of acetal, on a product of general formula:

in which R4, R5 and Ph are defined as above. Generally, the reaction is carried out in the presence of an acid such as p.toluenesulfonic acid, operating in an organic solvent such as an aromatic hydrocarbon such as benzene or toluene at a temperature between 0 and 50 ° C.

The products of general formula (XXI) can be obtained by saponification and then acetalization of triacetoxy-2, 9α, 10β cinnamoyl-5α hydroxy-lβ oxo-13 taxadiene-4 (20), ll.

Generally, the saponification is carried out by means of a mineral base such as a hydroxide or an alkali metal carbonate such as potassium carbonate by operating in an organic solvent chosen from aliphatic alcohols containing 1 to 4 carbon atoms such as methanol, ethanol or isopropanol, and halogenated aliphatic hydrocarbons such as dichloromethane at a temperature between 0 and 50 ° C.

Generally, acetalization is carried out by reaction of a ketone of general formula: R4-CO-R5 (XXII) in which R4 and R5 are defined as previously on cinnamoyl-5α tetrahydroxy-lβ, 2α, 9α, 10β oxo -13 taxadiene-4 (20), ll.

Generally, the reaction is carried out under the conditions described above to carry out the compensation of a product of general formula (XX) with a product of general formula (XXI).

Triacetoxy-2α, 9α, 10β cinnamoyl-5 hydroxy-lβ oxo-13 taxadiene- 4 (20), 11 can be obtained according to the process described in international application WO 93 02064. The acid of general formula (V) in which Ru and R12 together form a heterocycle can be obtained by saponification of an ester of general formula:

(XXIII)

in which Ar, R, R13 and R14 are defined as above and R 7 represents an alkyl radical containing 1 to 4 carbon atoms optionally substituted by a phenyl radical.

Generally, the saponification is carried out using a mineral base (hydroxide, carbonate or bicarbonate of alkali metal) in hydro-alcoholic medium (methanol-water) at a temperature between 10 and 40 ° C. The ester of general formula (XXIII) can be obtained by the action of a product of general formula:

^R 13 \

_/ = 0 (XXIV)

R _M in which R13 and R14 are defined as above in the form of a dialkylacetal or an alkyl ether of enol, on an ester of general formula:

R-NH

in which Ar, R and Ri 7 are defined as above, operating in an inert organic solvent (aromatic hydrocarbon) in the presence of a strong mineral acid (sulfuric acid) or organic acid (p.toluenesulfonic acid optionally in the form of pyridinium salt) at a temperature between 0 ° C and the boiling temperature of the reaction mixture.

The ester of general formula (XXV) can be obtained by the action of benzoyl chloride or of a product of general formula (X) on an ester of general formula:

in which Ar and R 7 are defined as above, operating in an organic solvent (ester, halogenated aliphatic hydrocarbon) in the presence of an inorganic or organic base at a temperature between 0 and 50 ° C.

The product of general formula (XXVI) can be obtained by reduction of an azide of general formula:

^ ^ COOR _{17 (} xxvii ₎

Ar £

ÔH in which Ar and Ri 7 are defined as above, using hydrogen in the presence of a catalyst such as palladium on black, operating in an organic solvent (ester). The product of general formula (XXVII) can be obtained by the action of an azide such as trimethylsilyl azide in the presence of a zinc halide or alkali metal azide (sodium, potassium, lithium) in a hydro-organic medium ( water-tetrahydrofuran) at a temperature between 20 ° C and the boiling temperature of the reaction mixture on an epoxide of general formula:

(XXVIII)

in which Ar and R17 are defined as above, optionally prepared in situ.

The epoxide of general formula (XXVIII) can be obtained, optionally in situ, by dehydrohalogenation of a product of general formula:

18 ^Λ 19 in which Ar is defined as above, Hal represents a halogen atom, preferably a bromine atom, and R and Ri 9, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical, at least one of which is an alkyl radical or a phenyl radical, by means of an alkaline alcoholate, optionally prepared in situ, in a inert organic solvent such as tetrahydrofuran at a temperature between -80 ° C and 25 ° C.

The product of general formula (XXIX) can be obtained by the action of an aldehyde of general formula:

Ar-CHO (XXX) in which Ar is defined as above on a halide of general formula:

R 18 R 19 in which Hal, R g and R19 are defined as above, previously anionized.

Generally, one operates in an inert organic solvent chosen from ethers (ethyl ether) and halogenated aliphatic hydrocarbons (methylene chloride) at a temperature between -80 and 25 ° C, in the presence of a tertiary amine (triethylamine) and an enolization agent (di-n.butylboron triflate). The product of general formula (XXXI) can be obtained by the action of a halide of a haloacetic acid, preferably bromide of bromoacetic acid, on the corresponding oxazolidinone.

The acid of general formula (V) in which Ru represents a hydrogen atom and R12 represents a protecting group for the hydroxy function can be obtained by saponification of an ester of general formula:

^RR "

. _,, ^ -COOR ₁₇ (XXXII) Vl:

° - ^R 12 in which Ar, R, u, R 2 and R17 are defined as above, under the conditions described above for the saponification of a product of general formula (XXIII). The product of general formula (XXXII) can be obtained according to the usual methods for preparing ethers, and more particularly according to the methods described by JN. DENIS et al., J. Org. Chem., 51, 46-50 (1986). The product of general formula (XXVI) can also be obtained by hydrogenolysis of a product of general formula:

CH- ^"

(XXXIII)

in which Ar and Ri 7 are defined as above and Ph represents an optionally substituted phenyl radical.

Generally, hydrogenolysis is carried out using hydrogen in the presence of catalyst. More particularly, a palladium on carbon containing 1 to 10% by weight of palladium or palladium dihydroxide to 20% by weight of palladium is used as catalyst. The hydrogenolysis is carried out in an organic solvent or in a mixture of organic solvents. It is advantageous to operate in acetic acid possibly associated with an aliphatic alcohol containing 1 to 4 carbon atoms such as an acetic acid-methanol mixture at a temperature between 20 and 80 ° C.

The hydrogen necessary for hydrogenolysis can also be supplied by a compound which liberates hydrogen by chemical reaction or by thermal decomposition (ammonium formate). It is advantageous to operate under a hydrogen pressure of between 1 and 50 bars.

The product of general formula (XXXIII) can be obtained by hydrolysis or alcoholysis of a product of general formula:

(XX ^V ÏV)

in which Ar and Ph are defined as above.

It is particularly advantageous to carry out an alcoholysis using an alcohol of form R17-OH in which R17 is defined as above by operating in ili .u acid. Preferably, the alcoholysis is carried out using methanol in the presence of a strong mineral acid such as hydrochloric acid at a temperature close to the reflux temperature of the reaction mixture. The product of general formula (XXXIV) can be obtained by saponification of an ester of general formula:

in which Ar and Ph are defined as above and R20 represents an alkyl, phenylalkyl or phenyl radical, followed by the separation of the 3R.4S diastereoisomer of general formula (XXXII) from the other diastereoisomers.

Generally, the saponification is carried out using a mineral or organic base such as ammonia, lithine, soda or potash in a suitable solvent such as a methanol-water or tetrahydrofuran-water mixture at a temperature between -10 ° C and 20 ° C.

The separation of the 3R.4S diastereoisomer can be carried out by selective crystallization in a suitable organic solvent such as ethyl acetate.

The product of general formula (XXXV) can be obtained by cycloaddition of an imine of general formula:

^A '\

NS _/ P ( ^XXXVI >

^CH3 in which Ar and Ph are defined as above, on an acid halide of general formula:

(XXXVII)

in which R20 is defined as above and Y represents a halogen atom such as a bromine or chlorine atom.

Generally the reaction is carried out at a temperature between 0 and 50 ° C. in the presence of a base chosen from aliphatic tertiary amines (triethylamine) or pyridine in an organic solvent chosen from optionally halogenated aliphatic hydrocarbons (methylene chloride , chloroform) and aromatic hydrocarbons (benzene, toluene, xylenes). The product of general formula (XXXVII) can be obtained under conditions analogous to those described by M. Furukawa et al., Chem. Pharm. Bull., 25 (1), 181-184 (1977).

According to the invention, the products of general formula (I) in which Ar, R, R2, R3 and Rio are defined as above, Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R '7 is defined as above can be obtained by esterification of a product of general formula:

(XXXVIII)

in which R4, R5 and R'7 are defined as above using an acid of general formula (V) to obtain a product of general formula:

(XXXIX)

in which Ar, R, R4, R5, R'7, RQ, RU and R12 are defined as above, followed by the replacement of the protective groups R12 and / or Ru and Rχ2 by hydrogen atoms and optionally hydrolysis of the acetal function -OC (-R4) (-R5) -O- to obtain a product of general formula (I) in which R2 and R3 each represent a hydroxy radical.

Generally, the esterification of the product of formula (XXXVIII) with the acid of general formula (V) is carried out under the conditions described above to esterify a product of general formula (IV) with an acid of general formula (V).

Generally, the replacement of the protective groups R12 and / or Ru and R 2 of the product of general formula (XXXIX) and the possible hydrolysis of the acetal function -OC (-R4) (-R5) -0- are carried out under the conditions described above for the product of general formula (VI).

A product of general formula (XXXVIII) can be obtained by reduction of a product of general formula:

in which R4, R5, R'7 and Rio are defined as above under the conditions described above for the reduction of a product of general formula (XI).

A product of general formula (XL) can be obtained by oxidation of a product of general formula (XI) in which Rg represents a hydrogen atom and R9 represents an alkyl or phenylalkyl radical in which the phenyl nucleus is optionally substituted.

Generally, the oxidation is carried out using an oxidizing agent such as 2,3-dichloro-5,6 dicyano-1,4-benzoquinone-1,4 in a hydro-organic medium such as a water-dichloromethane mixture at a temperature between 0 and 50 ° C.

The products of general formula (I) in which R2 and R3 represent a hydroxy radical or an oxo group, that is to say the products of general formula:

(XLI) (XLII)

in which Ar, R, Rg, R7 and R o are defined as above, can be obtained by oxidation of a product of general formula (I) in which R2 and R3 each represent a hydroxy radical. Generally, the oxidation is carried out using pyridinium chlorochromate, pyridinium dichromate, potassium bichromate, ammonium dichromate or manganese oxide at a temperature between 0 and 50 ° C. Depending on the nature of the oxidant used, the oxidation is carried out in an anhydrous organic medium or in a hydroorganic medium.

It may be advantageous, prior to oxidation, to selectively protect the hydroxy function of the side chain by means of a protective group chosen from the radicals methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, β-trimethylsilyléiioxymethyl, or tetrahydropyrannyl, which is n. iplaced by a hydrogen atom ^ after the end of oxidation, generally by treatment in an acid medium.

The new products of general formula (I) obtained by implementing the methods according to the invention can be purified according to known methods such as crystallization or chromatography.

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

In vitro, the measurement of the biological activity is carried out on the tubulin extracted from pig brain by the method of M.L. 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., C.R. Acad. Sci., 293. series II, 501-503 (1981). In this study, the products of general formula (I) were at least as active as Taxol® and Taxotère®

The new products show activity on tumors that are resistant to Taxol® or Taxotere®. Such tumors include colon tumors which have high expression of the mdr 1 gene (multi-drug resistance gene). Multi-drug resistance is a common term referring to the resistance of a tumor to different products with different structures and mechanisms of action. Taxoids are generally known to be highly recognized by experimental tumors such as P388 / DOX, a cell line selected for its resistance to doxorubicin (DOX) and which expresses mdr 1.

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. Conditions pathological pathologies 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, systems lymphatic or renal, mammary or blood cells, liver, digestive system, pancreas and 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, chorio-carcinoma, 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 nonaqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate. The sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water. The aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition.

It is understood that all the products entering into the compositions according to the invention must be pure and non-toxic for the quantities used.

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

Therapeutic treatment can be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapies or modifiers of biological responses. Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (α, 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, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomusine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs like mercaptopurine and thioguanine, natural products like vinca alkaloids like vinblastine, vincristine and vendesine, epipodophyllotoxins like etoposide and teniposide, antibiotics like dactinomycin , daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes c like L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, derivatives of methylhydrazine like procarbazine, adrenocotic suppressants like mitotane and aminoglutethymide, hormones and antagonists like adrenocorticosteroids like prednisone, progestins like hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, estrogens like diethylstilbestrol and ethynylestradiol, antioestrogens like tamoxifen, androgens like testosterone propionate and fluoxymesterone.

The doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum therapeutic response. The doses vary according to the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation. The products according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients can respond quickly to relatively high or low doses and then need low or no maintenance doses. Generally, low doses will be used at the start of treatment and, if necessary, increasingly large doses will be administered until an optimum effect is obtained. For other patients it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the physiological needs of the patient concerned. It is also possible that for some patients it is necessary to use only one or two daily administrations.

In humans, the doses are generally between 0.01 and 200 mg / kg. Intraperitoneally, the doses will generally be between 0.1 and 100 mg / kg and, preferably between 0.5 and 50 mg / kg and, even more specifically between 1 and 10 mg / kg. Intravenously, the doses are generally between 0.1 and 50 mg / kg and, preferably between 0.1 and 5 mg / kg and, even more specifically between 1 and 2 mg / kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the effectiveness of the treatment must be taken into account. .

The following examples illustrate the present invention. EXAMPLE 1

To a solution of 6 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4 oxazolidinecarboxylate-5- (2R, 4S, 5R) acetoxy-4 (4-methoxy-benzoyl) oxy-2α epoxy- 5β, 20 hydroxy-lβ O-isopropylidene-9, 10β taxene-11 yle-13α in 0.9 cm3 of ethyl acetate maintained under an argon atmosphere and with stirring, added at a temperature in the region of 20 ° C , 1 μl of concentrated hydrochloric acid (37%). The reaction medium is stirred for 1 hour at a temperature in the region of 20 ° C. The solution is diluted with 10 cm 3 of ethyl acetate. The organic layer is washed with 10 cm 3 of distilled water, dried over n sulfate. ^ Nesium, filtered and concentrated to dryness under reduced pressure (2 7 IcPa) έ 40 ° C. A yellow oil is obtained which is purified by plate chromatography, eluting twice with a cyclohexane-ethyl acetate mixture (60-40 by volume ¹ The fraction containing only the sought product is extracted by a mixture dichloromethane-methanol (85:15 by vo_αmes), filtered through glass -. ^f Ritte then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C is thus obtained 1 mg of tert-butoxycarbonylamino-phenyl-3 3-hydroxy-2-propionate- (2R, 3S) acetoxy-4 (met> - -v-4 benzoyl) oxy-2α epoxy-5β, 20 hydroxy-lβ O-isopropylidene-9, 10β ta -11 yle-13α in the form of a yellow oil the characteristics of which are the following ...

- proton nuclear magnetic resonance spectrum (400 MHz; CDCI3; chemical shifts in ppm; coupling constants J in Hz):

1.55-2.40 (mt, 4H: -CH ₂ - 7, -CH ₂ - 14); 2.25 (s, 3H: -CO-CH3); 2.87 (d, J = 5.5, 1H: -H 3); 3.90 (s, 3H: -O-CH3); 4.18 and 4.31 (2d, J = 9, 1H each: -CH ₂ -O- 20) 4.39 (d, J = 10, 1H: -H 9); 4.62 (broad s, 1H: -H 2 '); 4.69 (d, J = 10, 1H: -H 10) 4 95 (d wide, J = 9, IF ^"• * 5); 5.30 (d wide, J = 10, 1H: -H 3 '); 5.66 (d, J = 10, 1H D-NH-); 5.75 (d, J, 1H: -H 2); 6.11 (wide t, J = 9, 1 ": -H 13); 6.95 (d, J =

5, 2H: -H aro atiqu ortho du -O-CH3); 7.2 ^" '5 [m î: -CgH ₅ in 3' (-H 2

- -H 6)]; 8.05 (d, J = c H: -H aromatic in rr ^* u -O-CrÎ3).

Tert-butoxycarbonyl-3 (4-methoxy-nyl) -2 ρhenyl-4 o '"zolidine-carboxylate-5- (2R, 4S, 5R) acetoxy-4 (4-methoxy benzoyl) 2-oxy; < y-5β, 20 hydroxy-lβ O-isopropyιidene-9α, 10β taxene-11 yle-13α can be prepared as follows:

To a solution of 10 mg of acetoxy-4α (4-methoxy benzoyl) oxy-2 epoxy-5β, 20 dihydroxy-lβ, 13α O-isopropylidene-9α, 10β taxene-11 in 2 cm3 of anhydrous toluene in the presence of a sieve molecular 4A maintained under atmosphere argon and with stirring, at a temperature in the region of 20 ° C, 33 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4 oxazolidinecarboxylic-5- (2R.4S.5R) is added , 17 mg of N, N'-dicycldhexylcarbodiimide and 5 mg of 4-dimethylamino-pyridine. The reaction medium is stirred for 1 hour 30 minutes at a temperature in the region of 110 ° C. After cooling, the solution is diluted with 15 cm3 of an ethyl ether-dichloromethane mixture (3-1 by volume). The organic phase is washed once with 15 cm3 of a saturated aqueous solution of sodium bicarbonate, then with twice 15 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2, 7 kPa) at 40 ° C. A white powder is obtained which is purified by chromatography on a plate, eluting twice with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction containing only the sought product is extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 6 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidinecarboxylate-5- (2R.4S.5R) of acetoxy-4 (4-methoxy-benzoyl) -oxy 2-epoxy-5β are thus obtained , 20 hydroxy-lβ O-isopropylidene-9α, 10β taxene-11 yle-13α in the form of a brown paste with the following characteristics: - nuclear magnetic resonance spectrum of the proton (400 MHz; CDCU; chemical shifts in ppm ; coupling constants J in Hz):

1.55-1.70; 1.80 - 2.00 and 2.05 to 2.35 (4 mt, respectively 1H - 1H and 2H: -CH _.2 -? And -CH ₂ - 6); 2.04 and 2.21 (2mt, 1H each: -C £ L ₂ - 14); 2.78 (d, J = 5.5, 1H: -H 3); 3.82 and 3.90 (2s, 3H each: 2-O-CH ₃ ); 4.09 and 4.23 (2d, J = 9, 1H each: -CH ₂ -O- 20); 4.40 (d, J = 10, 1H: -H 9); 4.58 (d, J = 5.5, 1H: -H 2 '); 4.63 (d, J = 10, 1H: -H 10); 4.89 (broad d, J = 9, 1H: -H 5); 5.43 (broad d, J = 5.5, 1H: -H 3 '); 5.69 (d, J = 5.5, 1H: -H 2); 6.15 (broad t, J = 9, 1H: -H 13); 6.35 (br s, 1H: -H 5 '); 6.90 (d, J = 8.5, 2H: -H aromatic ortho from -O-CH ₃ for -CgHg in 5 '); 6.95 (d, J = 8.5, 2H: -H aromatic in ortho of -O-CH ₃ ); from 7.25 to 7.45 [mt, 7H: -CΛir in 3 '(- H 2 to -H 6) and -H aromatic in meta of -O-CH-, for the

5 ']; 7.98 (d, J = 8.5, 2H: -H aromatic in meta of -O-CH ₃ ).

Acetoxy-4α (4-methoxy benzoyl) oxy-2 epoxy-5β, 20 dihydroxy-lβ, 13 O-isopropylidene-9α, 10β taxene-11 can be prepared as follows:

To a solution of 23 mg of acetoxy-4α (4-methoxy benzoyl) oxy-2cc epoxy-5β, 20 hydroxy-lβ O-isopropylidene-9α, 10β oxo-13 taxene-11 in 2 cm3 of anhydrous toluene maintained under an argon atmosphere and with stirring, 38 μl of diisobutylaluminum hydride are added at a temperature of 0 ° C.

The reaction medium is ^" stirred for 3 hours 30 minutes at a temperature in the region of 0 ° C., then 38 μl of diisobutylaluminum hydride are added. The reaction mixture is stirred for 17 hours at a temperature in the region of 20 ° C and then 76 μl is added diisobutylaluminum hydride at a temperature in the region of 0 ° C.

After 6 hours of stirring at a temperature in the region of 20 ° C., 76 μl of diisobutylaluminum hydride are added, then 76 μl of diisobutylaluminum hydride a second time after 18 hours of stirring.

The medium is then stirred for 4 days at a temperature in the region of 20 ° C. and then 3.5 cm 3 of methanol are added. After 15 minutes of stirring, the insoluble material is filtered and the solvents are evaporated off under reduced pressure (2.7 kPa) at 40 ° C. 19 mg of a yellow oil are obtained which is purified on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fractions containing only the sought product and the unreacted starting product are extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 9 mg of acetoxy-4α (methoxy-4> enzoyl) oxy-2α epoxy-5β, 20 dihydroxy-lβ, 13α O-isopropylidene-9α, 10β taxene-11 in the form of an orange paste and 10 mg unreacted starting material.

Acetoxy-4 (4-methoxy benzoyl) oxy-2 epoxy-5β, 20 dihydroxy-lβ, 13 O-isopropylidene-9α, 10β taxene-ll has the following characteristics: - nuclear magnetic resonance spectrum of the proton (400 MHz ; CDC; chemical shifts in ppm; coupling constants J in Hz): 1.18 (s, 3H: -CH ₃ 16 or 17); 1.45 (s, 3H: -CH ₃ 16 or 17); 1.53 and 1.60 [2s, 3H each: (-CH ₃ ) ₂ ]; from 1.55 to 1.70 - 1.89 and from 2.10 to 2.35 (4 mt, respectively 1H - 1H and 2H: -CH ₂ - 7 and -CH ₂ - 6); 1.70 (s, 3H: -CH ₃ 19); 1.99 (broad s, 3H: -CH ₃ 18); 2.03 (d, J = 7 Hz, 1 H: -OH at 13); 2.12 and 2.31 (2mt, 1H each: -CH ₂ - 14); 2.27 (s, 3H: -CO-CH ₃ ); 2.97 (d, J = 5.5, 1H: -H 3); 3.89 (s, 3H: -O-CH_ ₃ ); 4.16 and 4.33 (2d, J ≈ 8, H each: -CH ₂ -O- 20 ⁾ ; 4.39 (d, J = 10, 1H: -H 9); 4.73 (d, J = 10, 1H: -H 10); 4.85 (mt, 1H: -H 13); 4.98 (broad d, J = 9, 1H: -H 5); 5.72 (d, J = 5.5, 1H: -H 2); 6.96 (d, J = 8.5, 2H: -H aromatic in ortho of -O-CH ₃ ); 8.07 (d, J = 8.5, 2H: -H aromatic in meta of -O-CH,). Acetoxy-4 (4-methoxy benzoyl) oxy-2α epoxy-5β, 20 hydroxy-lβ O-isopropylidene-9α, 10β oxo-13 taxene-11 can be prepared as follows:

To a solution of 47 mg of acetoxy-4 epoxy-5β, 20 O-isopropylidene-9, lOβ O-methoxy-4 benzylidene-lβ, 2α oxo-13 taxene-11 in 2 cm3 of dichloromethane maintained under stirring, 0.10 g of dichloro-2,3-dicyano-5,6-benzoquinone-1.4 and 54 μl of distilled water are added at a temperature in the region of 20 ° C.

The reaction medium is stirred for 24 hours at a temperature in the region of 20 ° C. and then diluted with a dichloromethane-ethyl ether mixture. The organic phase is washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.113 g of an orange oil is obtained which is purified by chromatography on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction containing only the sought product is extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 37 mg of acetoxy-4 (4-methoxy-benzoyl) oxy-2α epoxy-5β, 20 hydroxy-lβ O-isoproρylidene-9, 10β oxo-13 taxene-11 are thus obtained in the form of a white powder, the characteristics are as follows: - proton nuclear magnetic resonance spectrum (400 MHz; CDC; chemical shifts in pp; coupling constants J in Hz): 1.32 (s, 3H: -CH ₃ 16 or 17); 1.50 (s, 3H: -CH ₃ 16 or 17); from 1.50 to 1.70 - 1.89 and from 2.05 to 2.35 (3 mt, respectively IH -IH and 2H: -CH ₂ - 7 and -CH ₂ - 6); 1.58 [s, 6H: (-CH ₃ ) ₂ ]; 1.73 (s, 3H: -CH ₃ 19); 1.90 (s, 1H: -OH in 1); 1.98 (s, 3H: -CH_ ₃ 18); 2.18 (s, 3H: -CO-CH ₃ ); 2.65 and 2.89 (2d, J = 20, H each: -Cfl _2-14); 2.98 (d, J = 5.5, 1H: -H 3); 3.90 (s, 3H: -O-CH3); 4.13 and 4.32 (2d, J = 9, 1H each: -CH ₂ -O- 20); 4.48 (d, J = 10, 1H: -H 9); 4.82 (d, J = 10, 1H: -fl 10); 4.95 (broad d, J = 9, 1H: -H 5); 5.83 (d, J = 5.5, 1H: -H 2); 6.98 (d, J = 8.5, 2H: -H aromatic in ortho of -O-CHJ; 8.05 (d, J = 8.5, 2H: -H aromatic in meta of -O-CH- .

Acetoxy-4α epoxy-5β, 20 O-isopropylidene-9, 10β O-methoxy-4 benzylidene-1 β, 2α oxo-13 taxene-11 can be prepared as follows:

To a solution of 48 mg of epoxy-5β, 20 hydroxy-4α O-isopropylidene-9, lOβ O-methoxy-4 benzylidene-lβ, 2cc oxo-taxene-11 in 7 cm3 of anhydrous dichloromethane maintained under an atmosphere of argon and with stirring, we add 117 μl of acetic anhydride and 109 mg of 4-dimethylaminopyridine at a temperature in the region of 20 ° C.

The reaction medium is stirred for one day at a temperature in the region of 50 ° C., then 60 μl of acetic anhydride and 50 mg of 4-dimethylaminopyridine are again added. The reaction medium is stirred for an additional day at a temperature in the region of 50 ° C and then allowed to cool to a temperature in the region of 20 ° C. Diluted with dichloromethane and the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 77 mg of a yellow oil are obtained which is purified on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction containing only the sought product is extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 47 mg of acetoxy-4α epoxy-5β, 20 O-isopropylidene-9α, 10β O-methox) are thus obtained. benzylidene-lβ, 2a. oxo-13 taxene- 1 in the form of a white powder, the characteristics of which are as follows:

- proton nuclear magnetic resonance spectrum (400 MHz; CDCK; chemical shifts in ppm; coupling constants J in Hz): 1.33 (s, 3H: -CH ₃ 16 or 17); 1.48 (s, 3H: -CH ₃ 16 or 17); 1.54 and 1.66 [2s, 3H each: (-Cϋ ₃ ) ₂ J; from 1.50 to 1.70 - from 1.85 to 2.05 and from 2.05 to 2.35 (3mt, respectively IH

- IH and 2H: -CH ₂ - 7 and -CH ₂ - 6); 1.68 (s, 3H: -CH ₃ 19); 1.95 (s, 3H: -CH ₃ 18); 2.03 (s, 3H: -CO-CH ₃ ); 2.55 and 2.64 (2d, J = 20, H each: -CJH _2-14); 2.63 (d,

J = 5.5, 1H: -H 3); 3.84 (s, 3H: -O-CH3) ^{; 4 _{'32 (d'} = J 5 _'5, 1H:} "- ^{2): 4' 35 (d 'J =} 10, IH: H 9); 4.58 (AB limit, J = 9, 2H: - CH ₂ -O- 20); 4.75 (d, J = 10, 1H: -H 10);

4.97 (broad d, J = 9, 1H: -H 5); 5.84 (s, 1H: -O-CH-O-); 6.93 (d, J = 8.5, 2H: -H aromatic in ortho of -O-CH-0; 7.38 (d, J = 8.5, 2H: -H aromatic in meta of

-O-CH ₃ ).

Epoxy-5β, 20 hydroxy-4 O-isopropylidene-9α, 10β O-methoxy-4 benzylidene-1 β, 2 oxo-13 taxene-11 can be prepared as follows:

To a solution of 119 mg of O-methoxy-4 benzylidene-lβ, 2α dihydroxy-4α, 20 methylsulfonyloxy-5α O-isopropylidene-9α, 10β oxo-13 taxene-11 in 3.7 cm3 of butanone maintained under an atmosphere of argon and with stirring, 564 mg of tetra-n-butylammonium acetate are added at a temperature in the region of 85 ° C. The reaction medium becomes orange and is stirred overnight at a temperature in the region of 85 ° C. then diluted with ethyl acetate. The organic phase is washed with a 0.1N aqueous solution of hydrochloric acid and then a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° vs. 178 mg of an orange oil are obtained which are purified by chromatography on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction containing only the sought product is extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 67 mg of epoxy-5β, 20 hydroxy-4α O-isopropylidene-9, 10β O-methoxy-4 benzylidene-lβ, 2α oxo-13 taxene-11 are thus obtained in the form of a white powder whose characteristics are the following :

- proton nuclear magnetic resonance spectrum (400 MHz; CDCY; chemical shifts in ppm; coupling constants J in Hz):

1.15-1.30 and 1.90-2.20 (2mt, respectively 1H and 3H: -CH ₂ - 7 and -CH ₂ - 6); 1.39 (s, 3H: -CH ₃ 16 or 17); 1.48 (s, 3H: -CH ₃ 16 or 17); 1.54 and 1.63 [2s, 3H each: (- H ₃ ) ₂ ]; 1.70 (s, 3H: -CH ₃ 19); 1.92 (d, J = 5.5, 1H: -H 3); 2.06 (s, 3H: CH ₃ 18); 2.72 (s, 1H: -OH 4); 2.73 and 3.17 (2d, J = 20, H each: -CH ₂ - 14); 3.83 (s, 3H: -O-CH ₃ ); 4.33 and 4.66 (2d, J = 8.5, 1H each: -CH ₂ -O- 20); 4.33 (d, J = 10, 1H: -H 9); 4.38 (d, J = 5.5, 1H: -H 2); 4.72 (d, J = 10, 1H: -H 10); 4.80 (broad d, J = 9, 1H: -H 5); 5.82 (s, 1H: -O-CH-O-); 6.93 (d, J = 8.5, 2H: -H aromatic ortho to -O-CH ₃ ); 7.33 (d, J = 8.5, 2H: -H aromatic in meta of -O-CH ₃ ).

O-methoxy-4 benzylidene-lβ, 2 dihydroxy-4, 20 methylsulfonyl-oxy-5 O-isopropylidene-9α, 10β oxo-13 taxene-11 can be prepared as follows:

To a solution of 0.27 g of 4-O-methoxy-benzylidene-lβ, 2 tert-butyl-dimethylsilyloxy-20 hydroxy-4α methylsulfonyloxy-5α O-isopropylidene-9α, 10β oxo-13 taxene-11 in 5 cm3 of tetrahydrofuran anhydrous with stirring, 136 mg of tetra-n-butylammonium fluoride trihydrate are added at a temperature in the region of 20 ° C.

The reaction medium changes from yellow to orange and is stirred for one hour at a temperature in the region of 20 ° C. then diluted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.264 g of an orange oil is obtained which is purified by flash chromatography on 200 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter, eluting in a cyclohexane-ethyl acetate mixture (60-40 by volume). The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.209 g of O-methoxy-4 benzylidene-lβ, 2α dihydroxy-4α, 20 is thus obtained.

O-isopropylidene-9, 10β oxo-13 taxene-11 in the form of a white powder, the characteristics of which are as follows:

- proton nuclear magnetic resonance spectrum (400 MHz; CDQL chemical shifts in ppm; coupling constants J in Hz): 1.19 (s, 3H -CH ₃ 16 or 17); 1.42 (s, 3H: -CH ₃ 16 or 17); 1.47 and 1.52 [2s, 3H each (-CH ₃ ) ₂ ]; from 1.55 to 1.75 - 1.91 and 2.05 (3 mt, respectively 2H - 1H and 1H: -CH ₂ - 7 and -CH ₂ - 6); 1.67 (s, 3H: -CH ₃ 19); 2.12 (s, 3H: -CH ₃ 18); 2.32 (dd, J = 10.5 and 3.5, 1H: -CH ₂ -OH); 2.67 (d, J = 5.5, 1H: -H 3); 2.85 and 3.35 (2d, J = 20, 1H each: -CH 14); 2.98 (s,?. " ^•

; 3.62 (s, 1H:) H 4); 3.66 and 4.04 (2dd, respectively J = 1 and ^' ., 5 then J = 11 and 3.5, 1H each: -CH ~ -OH); 3.85 (s, 3H: -O-CH ₃ ); 4.23 (d, J =, 0. 1H: -H 9); 4.34 (d, J = 5.5, 1H: -H 2); 4.85 (d, J = 10, 1H: -H 10); 4.95 (br s, 1H: -H 5); 5.81 (s, 1H: -O-CH-O-); 6.93 (d, J = 8.5, 2H: -H aromatic in ortho of -O-CH.0; 7.37 (d, J = 8.5, 2H: -H aromatic

O-methoxy-4 benzylidene-lβ, 2 tert-butyldimethylsilyloxy-20 h droxy- 4α methylsulfonyloxy-5α O-isopropylidene-9α, 10β oxo-13 taxene-11 can be prepared as follows: To a solution of 0.374 g of 4-O-methoxy-benzylidene-lβ, 2 tert-butyldimethylsilyloxy-20 dihydroxy-4α, 5α O-isopropylidene-9, 10β oxo-13 taxene-11 in a mixture of 35.6 cm3 of anhydrous pyridine and 7, 3 cm3 of anhydrous dichloromethane in the presence of a 4A molecular sieve maintained under an argon atmosphere and under ag donation, 258 μl of mesyl chloride are added at a temperature close to 0 ° C. The reaction mixture is allowed to rise to a temperature in the region of 20 ° C. and 14 mg of 4-dimethylamino-pyridine are added.

The reaction medium is stirred for 48 hours at a temperature in the region of 50 ° C. and then diluted with a dichloromethane-ethyl ether mixture. The organic phase is washed with a 1N aqueous solution of hydrochloric acid to an acidic pH, then once with distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.41 g of an orange oil is obtained which is purified by flash chromatography on 200 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter, eluting in a cyclohexane-acetate mixture d 'ethyl (60-40 by volume). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.33 g of O-methoxy-4 benzylidene-lβ, 2α tert-butyldimethylsilyloxy-20 hydroxy-4 methylsulfonyloxy-5α O-isopropylidene-9α, 10β oxo-13 taxene-11 are thus obtained in the form of white crystals the characteristics are as follows: - nuclear magnetic resonance spectrum of the proton (400 MHz; CDCU; chemical shifts in ppm; coupling constants J in Hz): -0.18 and -0.04 [2s, 3H each: - Si (CH ₃ ) ₂ ]; 0.78 [s, 9H: -Si-C (CH ₃ ) ₃ J; 1.12 (s, 3H: -CH ₃ 16 or 17); 1.38 (s, 3H: -CH ₃ 16 or 17); 1.46 and 1.51 [2s, 3H each: (-CH ₃ ) ₂ ]; from 1.60 to 1.75 - 1.88 and 2.04 (3 mt, respectively 2H - IH and IH: -CH ₂ - 7 and -CH ₂ - 6); 1.66 (s, 3H: -CH ₃ 19); 2.11 (s, 3H: -CH ₃ 18); 2.63 (d, J = 4.5, 1H: -H 3); 2.71 and 3.75 (2d, J = 20, H each: -CH ₂ - 14); 2.98 (s, 3H: -OSO _p -CH ₃ ); 3.51 (s, 1H: -OH 4); 3.58 and 4.15 (2d, J = 11, 1H each: -CH ₂ -O-Si-); 3 δ3 (s, 3H: -O-CH.-.); 4.24 (d, J = 4.5, 1H: -H 2); 4.26 (d, J = 10, 1H: -H 9); 4.81 (br s, 1H: -H 5); 4.84 (d, J = 10, 1H: -H 10); 5.75 (s, 1H: -O-CH-O-); 6.89 (d, J = 8.5, 2H: -H aromatic in ortho of -O-CH.; 7.38 (d, J = 8.5, 2H: -H aromatic in meta of -O-CH ).

O-methoxy-4 benzylidene-lβ, 2 tert-butyldimethylsilyloxy-20 dihydroxy-4α, 5α O-isopropylidene-9α, 10β oxo-13 taxene-11 can be prepared as follows:

To a solution of 0.26 g of O-methoxy-4 benzylidene-lβ, 2α trihydroxy-4α, 5α, 20 O-isopropylidene-9α, 10β oxo-13 taxene-11 in 14 cm3 of anhydrous dimethylformamide maintained under an atmosphere of argon and with stirring, 0.171 g of imidazole and then 0.393 g of tert-butyldimethylsilane chloride are added at a temperature in the region of 20 ° C.

The reaction mixture is stirred for 7 hours at a temperature in the region of 20 ° C. and then diluted with a saturated aqueous solution of sodium chloride. The aqueous phase is extracted with ethyl acetate and the organic phase washed 3 times with distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.43 g of an orange oil is obtained which is purified by flash chromatography on 150 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter, eluting in a cyclohexane-acetate mixture ethyl (70-30 by volume). The fractions containing only the sought product are combined and concentrated to dryness under pressure (2.7 kPa) at 40 ° C. 0.32 g of O-methoxy-4 benzylidene-lβ, 2α tert-butyldimethylsilyloxy-20 dihydroxy-4α, 5α O-isopropylidene-9, 10β oxo-13 taxene-11 are thus obtained in the form of a yellow oil, the characteristics are as follows:

- proton nuclear magnetic resonance spectrum (400 MHz; CDCU; chemical shifts in ppm; coupling constants J in Hz): -0.21 and -0.07 [2s, 3H each: -Si (CH ₃ ) ₂ ] = ° - ⁷⁵ I ^s - ^9H - -Si-C (CH ₃ ) ₃ ]; 1.07 (s, 3H: -CH ₃ 16 or 17); 1.36 (s, 3H: -CH ₃ 16 or 17); 1.46 and 1.50 [2s, 3H each: (-CH ₃ ) ₂ ]; 1.51 - from 1.55 to 1.75 and 1.88 (3 mt, respectively IH - 2H and IH: -CH ₂ - 7 and -CH ₂ - 6); 1.65 (s, 3H: -CH ₃ 19); 2.06 (s. 3H: -CH ₃ 18); 2.65 and 3.84 (2d, J = 20, H each: -CH ₂ - 14); 2.66 (d, J = 5, 1H: -H 3); 2.75 (br s, 1H: -OH 5); 3.45 and 4.18 (2d, J = 10, 1H each: -CH ₂ -O-Si-); 3.59 (br s, 1H: -H 5); 3.72 (s, 1H: -OH 4); 3.82 (s, 3H: -O-CH ₃ ); 4.23 (d, J = 5, 1H: -H 2); 4.26 (d, J = 10, 1H: -H 9); 4.85 (d, J = 10, 1H: -H 10); 5.74 (s, 1H: -O-CH-O-); 6.88 (d, J = 8.5, 2H: -H aromatic in ortho of -O-CH; 7.39 (d, J = 8.5, 2H: -H aromatic in meta of -O-CH ₃ ).

O-methoxy-4 benzylidene-lβ, 2α trihydroxy-4, 5α, 20 O-isopropylidene-9, 10β oxo-13 taxene-11 can be prepared as follows:

To a solution of 0.626 g of O-methoxy-4 benzylidene-lβ, 2α hydroxy-5α O-isoproρylidene-9α, 10β oxo-13 taxadiene-4 (20), ll in a mixture of 8.9 cm3 of tetrahydrofuran and 4.4 cm3 of distilled water maintained under an argon atmosphere and with stirring, 2.29 g of 4-methyl-4-oxide-morpholine monohydrate and then 1 cm3 of tetroxide are added at a temperature close to 20 ° C. 2.5% w / w osmium in tert-butanol. The reaction mixture is stirred for 24 hours at a temperature in the region of 20 ° C, then 0.368 g of Florisil, 4.6 cm3 of distilled water and 70 μl of a 50% aqueous solution of sodium bisulfite are then added. The medium is stirred for 10 minutes at a temperature in the region of 20 ° C. and filtered through a sintered glass lined with celite. The filtrate is neutralized with a 0.1N aqueous hydrochloric acid solution and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue is diluted with ethyl acetate and the organic phase is washed with a 0.1 N aqueous solution of hydrochloric acid to acid pH and then once with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.68 g of crude is obtained reaction which is purified by flash chromatography on 200 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter, eluting in a cyclohexane-ethyl acetate mixture (80-20 by volume). The fractions containing only the desired product on the one hand, and that containing only the starting product on the other hand are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.273 g of O-methoxy-4 benzylidene-lβ, 2 trihydroxy-4α, 5α, 20 O-isopropylidene-9α, 10β oxo-13 taxene-11 in the form of a white powder and 0.188 g of O- are thus obtained. (4-methoxy) benzylidene-lβ, 2α hydroxy-5 O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), it unreacted. O-methoxy-4 benzylidene-lβ, 2α trihydroxy-4, 5α, 20 O-isopropylidene-

9α, 10β oxo-13 taxene-11 has the following characteristics: - proton nuclear magnetic resonance spectrum (400 MHz; CDCU chemical shifts in ppm; coupling constants J in Hz): 1.16 (s, 3H -CH ₃ 16 or 17); 1.40 (s, 3H: -CH ₃ 16 or 17); 1.47 and 1.51 [2s, 3H each (-CH ₃ ) ₂ ]; from 1.45 to 1.75 and 1.86 (2 mt, 3H and 1H respectively: -CH_ ₂ - 7 and -CH ₂ - 6); 1.66 (s, 3H: -CH ₃ 19); 2.07 (s, 3H: CH ₃ 18); 2.40 (dd, J = 9 and 3.5, 1H: -CH ₂ -OH); 2.45 (br s, 1H: -OH 5); 2.75 (d, J = 5.5, 1H: -H 3); 2.80 and 3.42 (2d, J = 20, 1H each: -CH-14); 3.54 and 4.06 (2dd, respectively J = 11 and 9 then J = 11 and 3.5, 1H each: -CH ₂ -OH); 3.67 (s, 1H: -OH 4); 3.77 (br s, 1H: -H 5); 3.84 (s, 3H: -0-CH; 4.23 (d, J = 10, _IH. H 9); 4.34 (d, J = 5.5, H: -H 2); 4.85 (d, J = 10, 1H: -H 10); 5.82 (s, 1H: -O-CH-O-); 6.93 (d, J = 8.5, 2H: -H aromatic in ortho of -O-CH-; 7.37 (d, J = 8.5, 2H: -H aromatic in meta of

-O-CH ₃ ).

O-methoxy-4 benzylidene-lβ, 2α hydroxy-5 O-isopropylidene-9, 10β oxo-13 taxadiene-4 (20), ll can be prepared as follows:

To a solution of 3.04 g of O-methoxy-4 benzylidene-lβ, 2 cinnamoyl-5α

O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll in 220 cm3 of tetrahydrofuran maintained under an argon atmosphere and with stirring, 40 cm3 of a solution are added at a temperature close to 20 ° C. 30% sodium hydroxide.

The reaction mixture is stirred for 48 hours at reflux of the solvent. It is allowed to cool to a temperature in the region of 20 ° C. Distilled water is then added until the insoluble material formed has dissolved and the aqueous phase is extracted with ethyl acetate. The organic phase is washed 4 times with an aqueous solution saturated with sodium chloride, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 2.52 g of a pale yellow meringue are obtained which is purified by flash chromatography on 300 g of silica (0.040-0.063 mm) contained in a column 5 cm in diameter, eluting in a cyclohexane-acetate mixture. ethyl (75-25 by volume). The fractions containing only the sought product and the unreacted starting product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

2.04 g of ϋ-methoxy-4 benzylidene-lβ, 2 hydroxy-5α O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll are thus obtained in the form of a white powder as well as 0.286 g of O-methoxy-4 benzylidene-lβ, 2 cinnamoyl-5α O-isopropylidene-9, 10β oxo-13 taxadiene-4 (20), it unreacted.

O-methoxy-4 benzylidene-lβ, 2α hydroxy-5α O-isopropylidene-9, 10β oxo-13 taxadiene-4 (20), l has the following characteristics: - nuclear magnetic resonance spectrum of the proton (400 MHz; CDGL; chemical shifts in ppm; coupling constants J in Hz): 1.11 (s, 3H: -CH ₃ 16 or 17); 1.36 (s, 3H: -CH, 16 or 17); 1.49 and 1.53 [2s, 3H each: (-CH ₃ ) ₂ ]; from 1.60 to 1.85 (mt, 4H: -CH ₂ - 7 and -CH ₂ - 6); 1.69 (s, 3H: -CH_ ₃ 19); 2.10 (s, 3H: -CH ₃ 18); 2.73 (s, 2H: -CH ₂ - 14); 3.35 (d, J = 5.5, 1H: -H 3); 3.82 (s, 3H: -O-CH ₃ ); 4.20 (br s, 1H: -H 5); 4.30 (d, J = 10, 1H: -H 9); 4.36 (d, J = 5.5, 1H: -H 2); 4.95 (d, J = 10, 1H: -H 10); 5.10 and 5.54 (2s wide, 1H each: = CH ₂ ); 5.75 (s, 1H: -O-CH-O-); 6.90 (d, J = 8.5, 2H: -H aromatic ortho to -O-CH ₃ ); 7.37 (d, J = 8.5, 2H: -H aromatic in meta of -O-CH-.

O-methoxy-4 benzylidene-lβ, 2α cinnamoyl-5α O-isopropylidene-9α, lOβ oxo-13 taxadiene-4 (20), ll can be prepared as follows: To a solution of 7.56 g of cinnamoyl-5α dihydroxy-lβ, 2α

O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll in 600 cm3 of anhydrous toluene maintained under an argon atmosphere and with stirring in the presence of 4A molecular sieve, added at a temperature in the region of 20 ° C , 4.8 cm3 of (4-methoxy) benzaldehyde dimethylacetal then 0.537 g of paratoluene sulphonic acid monohydrate.

The reaction mixture is stirred for 2 hours at a temperature in the region of 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The reaction crude is dissolved in dichloromethane. The organic phase is washed once with a 5% aqueous solution of sodium bicarbonate and then once with distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 12.46 g of a yellow meringue are obtained which is purified by flash chromatography on 900 g of silica (0.040-0.063 mm) contained in a column 9 cm in diameter, eluting in a cyclohexane-ethyl acetate mixture (80-20 by volume). The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

5.63 g of O-methoxy-4 benzylidene-lβ, 2α cinnamoyl-5α O-isopropylidene-9, 10β oxo-13 taxadiene-4 (20), ll are thus obtained in the form of a white powder, the characteristics of which are the following :

- proton nuclear magnetic resonance spectrum (400 MHz; CDC chemical shifts in ppm; coupling constants J in Hz): 1.17 (s, 3H -CH ₃ 16 or 17); 1.40 (s, 3H: -CH ₃ 16 or 17); 1.49 and 1.56 [2s, 3H each (-CH ₃ ) ₂ ]; 1.58 - from 1.75 to 1.90 and 2.02 (3 mt, respectively IH -2H and IH: -CH ₂ - 7 and -CH ₂ - 6); 1.70 (s, 3H: -CH ₃ 19); 2.17 (s, 3H: CH ₃ 18); 2.81 (ab limit, J = 20, 2H: -CH ₂ - 14); 3.22 (d, J = 5.5, 1H: -H 3); 3.81 (s, 3H: -O-Ciy; 4.34 (d, J = 10, 1H: -H 9); 4.39 (d, J = 5.5, 1H: -H 2); 4 , 94 (d, J = 10, IH: -H 10); 5.27 and 5.63 (2s wide, IH each: = CH ₂ ); 5.36 (s broad, IH: -H 5); 5 , 76 (s, IH: -O-CH-O-); 6.36 and 7.64 (2d, J = 16, IH each: -CH = CH-); 6.90 (d, J = 8, 5, 2H: -H aromatic in ortho of -O-CH-J; 7.37 (d, J = 8.5, 2H: -H aromatic in meta of -O-CH.; From 7.35 to 7, 50 (mt, 3H: -JH aromatic in meta and para of the double bond); 7.74 (d, J = 7.5, 2H: -H aromatic in ortho of the double bond).

Cinnamoyl-5α di hydroxy- lβ, 2 O-isopropylidene-9, 10β oxo-13 taxadiene-4 (20), l l can be prepared as follows:

To a solution of 3.21 g of cinnamoyl-5α tetrahydroxy-lβ, 2α, 9, 10β oxo-13 taxadiene-4 (20), ll crude in 157 cm3 of anhydrous acetone maintained under an argon atmosphere and with stirring, 0.253 g of para-toluenesulphonic acid monohydrate is added at a temperature in the region of 20 ° C.

The reaction mixture is stirred for 16 hours at a temperature in the region of 20 ° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The crude product obtained is dissolved in dichloromethane. The organic phase is washed once with a 5% aqueous solution of sodium bicarbonate and then once with distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 5.50 g of a white meringue are obtained which is purified by flash chromatography on 300 g of silica (0.040-0.063 mm) contained in a column 6 cm in diameter, eluting in a cyclohexane-ethyl acetate mixture (80-20 by volume). The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

2.66 g of cinnamoyl-5α dihydroxy-lβ, 2α O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll are thus obtained in the form of white crystals, the characteristics of which are the following:

- proton nuclear magnetic resonance spectrum (400 MHz; CDCU chemical shifts in ppm; coupling constants J in Hz): 1.20 (s, 3H -CH ₃ 16 or 17); 1.38 (s, 3H: -CH ₃ 16 or 17); 1.44 and 1.52 [2s, 3H each at 1.85 and 2.00 (3mt, respectively IH -2H and IH: -CH ₂ - 7

-CH ₃ 19); 2.12 (s, 3H: -CH ₃ 18); 2.58 (d, J = 7, 1H: -OH 0 (ab lim., J = 20, 2H: -CH ₂ - 14); 3.22 (d, J = 7, 1H: -H 3); 3.68 (broad s, H 1); 4.07 (t, J = 7, IH: -H 2); 4.29 (d, J = 10, IH: -H 9); 4.93 (d , J = 10, 11 1 10); 5.33 (wide s, IH: -H 5); 5.40 and 5.47 (wide 2s, IH each: = CH ₂ ); 6 ,. and 7.64 (2d, J = 16, II each: -CH = CH-); from 7.35 to 7.50 (mt, 3H: -H aromatic in meta and in para of the double bond); 7.75 (d, J = 7.5, 2H: -H aromatic in ortho of the double bond).

Cinnamoyl-5α tetrahydroxy-lβ, 2, 9α, 10β oxo-13 taxadiene-4 (20), ll can be prepared as follows: To a suspension of 0.94 g of potassium carbonate in 590 cm3 of anhydrous methanol maintained under an argon atmosphere and with stirring, 4.03 g of triacetoxy-2, 9α, 10β cir_namoyl-5α hydroxy-lβ oxo-13 taxadiene-4 (20), ll are added at a temperature in the region of 20 ° C. then 54 cm3 of anhydrous dichloromethane.

The reaction mixture is stirred for 5 hours at a temperature in the region of 20 ° C., then 18 cm 3 of a 0.1N aqueous solution of hydrochloric acid are added. The solvents are evaporated under reduced pressure (2.7 kPa) at 40 ° C. The residue is dissolved with ethyl acetate and the organic phase is washed once with distilled water, dried over magnesium sulfate, filtered and then concentrated 2 ec under reduced pressure (2.7 kPa) at 40 ° C. This gives 3.71 g of cinnamoyl-5 tetrahydroxy-lβ, 2cc, 9α, 10β oxo-13 taxadiene-4 (20), ll crude.

EXAMPLE 2

By operating as in Example 1, but starting with 18 mg of acetoxy-4α hydroxy-13 epoxy-5β, 20 O-isopropylidene-9α, 10β O-benzylidene-lβ, 2α taxene-1 and 65 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidinecarboxylic-5- (2R, 4S, 5R) acid, 29 mg of tert-butoxycarbonyl-3 (methoxy -4 phenyl) -2 phenyl-4 oxazolidinecarboxylate-5- (2R, 4S, 5R) acetoxy-4α O-benzylidene-lβ, 2α epoxy-5β, 20 O-isopropylidene-9α, 10β taxene-ll yl-13 in the form of an orange paste, the characteristics of which are as follows: - nuclear magnetic resonance spectrum of the proton (400 MHz; CDCU; at a temperature of 323 ° K; chemical shifts in ppm; coupling constants J in Hz): 1 , 55 to 1.75 - from 1.90 to 2.05 and 2.05 to 2.30 (3 mt, respectively IH - IH and 2H: -CH ₂ - 7 and -CH ₂ - 6); 1.75 and 2.02 (2mt, IH each, -CH ₂ - 14); 2.43 (d, J = 5.5 Hz, 1H: -H 3); 3.82 (s, 3H: -OCH ₃ ); 4.17 (d, J = 5.5, 1H: -H 2); 4.25 (d, J = 10, 1H: -H 9); 4.48 (d, J = 4, 1H: -H 2 '); 4.54 (br s, 2H, -CH ₂ -O- 20); 4.58 (d, J = 10, 1H: -H 10); 4.95 (broad d, J = 9, 1H: -H 5); 5.48 (broad d, J = 4, 1H: -H 3 '); 5.81 (s, 1H: -O-CH-O-); 6.07 (broad t, J = 9, 1H: -H 13); 6.90 (d, J = 8.5, 2H: -H aromatic in ortho of -OCH ₃ for

in 5 '); from 7.25 to 7.50 (mt, 12H: -H aromatic and -H aromatic in meta of -OCH ₃ for -C _^ -H _. - in 5 ').

Acetoxy-4α hydroxy- 13α eρoxy-5β, 20 O-isopropylidene-9α, 10β

O-benzylidene-lβ, 2 taxene-11 can be prepared as follows:

By operating as in Example 1, but from 31 mg of acetoxy-4 epoxy-5β, 20 O-isopropylidene-9α, 10β O-benzylidene-lβ, 2α oxo-13 taxene-11, 20 mg of acetoxy-4α hydroxy-13 epoxy-5β, 20 O-isopropylidene-9, 10β O-benzylidene-lβ, 2α taxene-11 in the form of a gray paste as well as 9 mg of acetoxy-4α epoxy-5β , 20 O-isopropylidene-9α, 10β O-benzylidene-lβ, 2α oxo-13 taxene-11 unreacted.

Acetoxy-4α hydroxy-13 epoxy-5β, 20 O-isopropylidene-9α, 10β O-benzylidene-lβ, 2α taxene-11 has the following characteristics:

- proton nuclear magnetic resonance spectrum (400 MHz; CDC chemical shifts in ppm; coupling constants J in Hz): 1.23 (s, 3H -CH ₃ 16 or 17); 1.45 (s, 3H: -CH ₃ 16 or 17); 1.50 and 1.64 [2s, 3H each (-CH ₃ ) ₂ ]; from 1.55 to 1.75 - from 1.90 to 2.05, 2.15 and 2.32 (4 mt, 1 H each: -CH ₂ - 7 and -CH ₂ - 6); 1.68 (s, 3H: -CH ₃ 19); 1.78 and 2.20 (2dd, respectively J = 15 and 6 then J = 15 and 8, 1H each, -CH ₂ - 14); 1.88 (d, J = 8, 1H: -OH 13); 1.95 (broad s, 3H: -CH ₃ 18); 2.15 (s, 3H: -CO-CH ₃ ); 2.64 (d, J = 5, 1H: -H 3); 4.18 (d, J = 5, 1H: -H 2); 4.25 (d, J = 10, 1H: -H 9); 4.58 (br s, 2H, -CH ₂ -O- 20); 4.67 (d, J = 10, 1H: -H 10); 4.73 (mt, 1H: -H 13); 5.00 (broad d, J = 9, 1H: -H 5); 5.83 (s, 1H: -O-CH-O-); from 7.35 to 7.55 (mt, 5H: -H aromatic). Aceto-hydroxy-4 epoxy-5β, 20 O-isoproρylidene-9, 10β O-benzylidene-lβ, 2 oxo-13 taxene-1 can be prepared as follows:

By operating as in Example 1, but starting from 0.292 g of epoxy-5β, 20 hydroxy-4α O-isopropylidene-9α, 10β O-benzylidene-lβ, 2α oxo-13 taxene-11, 0.255 g is obtained acetoxy-4 epoxy-5β, 20 O-isopropylidene-9α, 10β O-benzy-lidene-lβ, 2α oxo-13 taxene-11 in the form of a white powder with the following characteristics:

- Spectrum of ^nuclear magnetic _sonance proton (400 MHz; CDC1 _3; chemical shifts in ppm; coupling constants J in Hz): 1.34 (s, 3H: CH ₃ 16 or 17); 1.48 (s, 3H: -CH ₃ 16 or 17); from 1.50 to 1.70, from 1.85 to 2.20 and 2.30 (3 mt, respectively IH - 2H and IH: -CH_ ₂ -? and -CH ₂ - 6); 1.55 and 1.67 [2s, 3H each: (-CH ^]; 1.68 (s, 3H: -CH ₃ 19); 1.94 (s, 3H: -CH ₃ 18); 2.03 (s, 3H: -CO-CH ₃ ); 2.52 and 2.61 (2d, J = 20, IH each: -Cfl ₂ - 14); 2.63 (d, J = 5.5, IH: -H 3); 4.36 (d, J = 10, 1H: -H 9); 4.37 (d, J = 5.5, 1H: -H 2); 4.62 (broad s, 2H, - H ₂ -O- 20); 4.76 (d, J = 10, IH: -H 10); 4.97 (wide d, J = 9, IH: -H 5); 5.90 (s, 1H: -O-CH-O-); from 7.35 to 7.50 (mt, 5H: -H aromatic).

Epoxy-5β, 2ϋ hydroxy-4 O-isoρropylidene-9, 10β O-benzylidene-lβ, 2α oxo-13 taxene-11 can be prepared as follows:

By operating as in Example 1, but starting with 0.80 g of O-benzylidene-lβ, 2α dihydroxy-4α, 20 methylsulfonyloxy-5α O-isopropylidene-9α, 10β oxo-13 taxene-11, 0.404 g of epoxy-5β, 20 hydroxy-4α O-isopropylidene-9α, 10β O-benzylidene-lβ, 2α oxo-13 taxene-11 are obtained in the form of a white powder, the characteristics of which are as follows: - spectrum proton nuclear magnetic resonance (300 MHz; CDC1 ₃ ; chemical shifts in ppm; coupling constants J in Hz): 1.15 to 1.30 and 1.90 to 2.20 (2mt, respectively IH and 3H : -CH ₂ - 7 and -CH ₂ - 6); 1.35 (s, 3H: -CH ₃ 16 or 17); 1.45 (s, 3H: -CH ₃ 16 or 17); 1.52 and 1.65 [2s, 3H each: (-CH ₃ ) ₂ ]; 1.68 (s, 3H: -CH ₃ 19); 1.92 (d, J = 5.5, 1H: -H 3); 1.96 (s, 3H: CH ₃ 18); 2.66 and 3.12 (2d, J = 20, H each: -CH ₂ - 14); 2.70 (s, 1H: -OH 4); from 4.20 to 4.35 [mt, 3H: - (CH) HO-20 -H 9 and -H 2]; from 4.60 to 4.70 (mt, 2H: -H 10 and - (CH) HO-20); 4.79 (broad d, J = 9, 1H: -H 5); 5.84 (s, 1H: -O-CH-O-); from 7.30 to 7.45 (mt, 5H: -H aromatic).

O-benzylidene-1 β, 2α dihydroxy-4α, 20 methylsulfonyloxy-5α O-isopro-pyiidene-9α, 10β oxo-13 taxene-1 1 can be prepared as follows: By operating as in Example 1, but starting from 1.51 g of 0-benzylidene-lβ, 2 tert-butyldimethylsilyloxy-20 hydroxy-4α methylsulfonyloxy-5α O-isopropylidene-9α, 10β oxo-13 taxene -11, 0.875 g of O-benzylidene-lβ, 2α dihydroxy-4, 20 methylsulfonyloxy-5α O-isopropylidene-9α, 10β oxo-13 taxene-11 are obtained in the form of a white meringue, the characteristics of which are the following :

- proton nuclear magnetic resonance spectrum (400 MHz; CDC1,; chemical shifts in ppm; coupling constants J in Hz): 1.19 (s, 3H: -CH ₃ 16 or 17); 1.42 (s, 3H: -CH ₃ 16 or 17); 1.47 and 1.52 [2s, 3H each: (-CH ₃ ) ₂ ]; from 1.55 to 1.80 - 1.91 and 2.05 (3 mt, respectively 2H - IH and IH: -CH ₂ - 7 and -CH ₂ - 6); 1.69 (s, 3H: -CH ₃ 19); 2.12 (s, 3H: -CH ₃ 18); 2.32 (dd, J = 10.5 and 3.5, 1H: -CH ₂ -OH); 2.68 (d, J = 5.5, 1H: -H 3); 2.84 and 3.32 (2d, J = 20, H each: -CH ₂ - 14); 2.98 (s, 3H: -OSO ₂ -CH ₃ ); 3.57 (s, 1H: -OH 4); 3.67 and 4.07 (2dd, respectively J = 11 and 10.5 then J = 11 and 3.5, 1H each: -CH -OH); 4.24 (d, J = 10.1 H: -H 9); 4.36 (d, J = 5.5, 1H: -H 2); 4.86 (d, J = 10, 1H: -H 10); 4.95 (br s, 1H: -H 5); 5.88 (s, 1H: -O-CH-O-); from 7.40 to 7.50 (mt, 5H: -H aromatic).

O-benzylidene-lβ, 2α tert-butyldimethylsilyloxy-20 hydroxy-4α methyl-sulfonyloxy-5σ. O-isopropylidene-9, 10β oxo-13 taxene-11 can be prepared as follows:

By operating as in Example 1, but starting from 1.58 g of 0-benzylidene-lβ, 2 tert-butyldimethylsilyloxy-20 dihydroxy-4, 5 O-isopropylidene-9, 10β oxo-13 taxene- 11, we obtain 1.51 g of O-benzylidene-lβ, 2 tert-butyldimethylsilyloxy-20 hydroxy-4α methylsulfonyloxy-5 O-isopropylidene-9, 10β oxo-13 taxene-11 in the form of a yellowish meringue with the following characteristics:

- proton nuclear magnetic resonance spectrum (400 MHz; CDC; chemical shifts in ppm; coupling constants J in Hz): -0.18 and -0.05 [2s, 3H each: -Si (CH ₃ ) ₂ J ; 0.78 [s, 9H: -Si-C (CH ₃ ) ₃ ]; 1.14 (s, 3H: -CH ₃ 16 or 17); 1.39 (s, 3H: -CH ₃ 16 or 17); 1, 46 and 1.51 [2s, 3H each: (-CH ^]; from 1.60 to 1.75 - 1.88 and 2.04 (3mt, respectively 2H - IH and IH: -CH ₂ - 7 and -CH ₂ - 6); 1.67 (s, 3H: -CH ₃ 19); 2.11 (s, 3H: -CH ₃ 18); 2.63 (d, J = 4.5, 1H: -H 3); 2.71 and 3.75 (2d, J = 20, IH each: -CH ₂ - 14); 2.98 (s, 3H: -OSO CH ₃ ); 3.53 (s, IH : -OH 4); 3.58 and 4.18 (2d, J = 11, IH each: -CH ₂ -O-Si-); 4.27 (d, J = 4.5, IH: -H 2 ); 4.27 (d, J = 10, 1H: -H 9); 4.81 (br s, 1H: -H 5); 4.85 (d, J = 10, 1H: -H 10); 5.79 (s, 1H: -O-CH-O-); from 7.30 to 7.50 (mt, 5H: -H aromatic).

O-benzylidene-lβ, 2α tert-butyldimethylsilyloxy-20 dihydroxy-4α, 5 O-isopropylidene-9α, 10β oxo-13 taxene-11 can be prepared as follows:

By operating as in Example 1, but starting from 1.5 g of O-benzylidene-lβ, 2α trihydroxy-4, 5α, 20 O-isopropylidene-9, 10β oxo-13 taxene-11, we obtain 1 , 80 g of O-benzylidene-lβ, 2α tert-butyldimethylsilyloxy-20 dihydroxy-4α, 5α O-isopropylidene-9α, 10β oxo-13 taxene-11 in the form of a yellow oil with the following characteristics:

- proton nuclear magnetic resonance spectrum (400 MHz; CDCU; chemical shifts in ppm; coupling constants J in Hz): -0.22 and -0.08 [2s, 3H each: -Si (CH ₃ ) ₂ ] ; 0.76 [s, 9H: -Si-C (CH ₃ ) ₃ ]; 1.09 (s, 3H: -CH ₃ 16 or 17); 1.38 (s, 3H: -CH ₃ 16 or 17); 1.46 and 1.51 [2s, 3H each: (-CH ^]; from 1.50 to 1.75 and 1.89 (2mt, respectively 3H and IH: -CH ₂ - ^{7 and} - ^CH - ₂ - ⁶ ): L ⁶⁶ ( ^s » ^3H : -CPU 19); 2.05 (s, 3H: -CH ₃ 18); 2.65 and 3.84 (2d, J = 20, IH each: -CH ₂ - 14); 2.67 (d, J = 5, IH: -H 3); 2.76 (broad s, IH: -OH 5); 3.47 and 4.19 (2d, J = 10, IH each : -CH ₂ -O-Si-); 3.59 (broad s, IH: -H 5); 3.73 (s, IH: -OH 4); 4.26 (d, J = 5, IH: -H 2); 4.28 (d, J = 10, IH: -H 9); 4.85 (d, J = 10, IH: -H 10); 5.78 (s, IH: -O- CH-O-); from 7.30 to 7.50 (mt, 5H: -H aromatic).

O-benzylidene-lβ, 2α trihydroxy-4α, 5, 20 O-isopropylidene-9, 10β oxo-13 taxene-11 can be prepared as follows:

By operating as in Example 1, but starting from 3.44 g of O-benzylidene-lβ, 2 hydroxy-5α O-isopropylidene-9, 10β oxo-13 taxadiene-4 (20), ll, 1.954 g of O-benzylidene-lβ, 2α trihydroxy-4α, 5, 20 O-isopropylidene-9α, 10β oxo-13 taxene-11 are obtained in the form of a white meringue, as well as 0.993 g of O-benzylidene- lβ, 2 hydroxy-5α O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), l 1 which did not react.

O-benzylidene-lβ, 2α trihydroxy-4, 5, 20 O-isopropylidene-9α, 10β oxo-taxene-11 has the following characteristics:

- proton nuclear magnetic resonance spectrum (400 MHz; CDCU; chemical shifts in ppm; coupling constants J in Hz): 1.17 (s, 3H: -CH ₃ 16 or 17); 1.41 (s, 3H: -CH ₃ 16 or 17); 1.47 and 1.52 [2s, 3H each: (-CJjLJp]; ^{from l} - ^{5 to} - ¹ - ^{80 and} L ⁸⁸ ( ^2mt > 3H and IH respectively: -CH ₂ - 7 and -CH ₂ - 6); 1.69 (s, 3H: -CH ₃ 19); 2.07 (s, 3H: CH ₃ 18); 2.40 (mf, 2H: -CH ₂ -OH and -OH 5); 2.77 (d, J = 5.5, 1H: -H 3); 2.80 and 3.38 (2d, J = 20, 1H each: -Cfl ₂ - 14); 3.58 and 4.10 (2d, J = 11, 1H each: -CH ₂ -OH); 3.65 (s, 1H: -OH 4); 3.79 (br s, 1H: -H 5); 4.23 (d, J = 10, 1H: -H 9); 4.36 (d, J = 5.5, 1H: -H 2); 4.87 (d, J = 10, 1H: -H 10); 5.88 (s, 1H: -O-CH-O-); from 7.35 to 7.50 (mt, 5H: -H aromatic).

O-benzylidene-lβ, 2α hydroxy-5α O-isopropylidene-9, 10β oxo-13 taxadiene-4 (20), ll can be prepared as follows:

By operating as in Example 1, but starting from 0.71 g of O-benzylidene-lβ, 2α cinnamoyl-5α O-isoρropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll, we obtain 0.454 g of O-benzylidene-lβ, 2 hydroxy-5 O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll in the form of a white powder which has the following characteristics:

- proton nuclear magnetic resonance spectrum (400 MHz; CDCU chemical shifts in ppm; coupling constants J in Hz): 1.15 (s, 3H -CH ₃ 16 or 17); 1.40 (s, 3H: -CH ₃ 16 or 17); 1.51 and 1.58 [2s, 3H each (-CH ₃ ) ₂ ]; from 1.60 to 1.85 (mt, 4H: -CH ₂ - 7 and -CH ₂ - 6); 1.72 (s, 3H: -CH ₃ 19) 2.13 (s, 3H: -CH ₃ 18); 2.73 (s, 2H: -CH ₂ - 14); 3.38 (d, J = 5, 1H: -H 3); 4.22 (br s, 1H: -H 5); 4.33 (d, J = 10, H: -H 9); 4.39 (d, J = 5, 1H: -H 2); 4.98 (d, J = 10, 1H: -H 10); 5.13 and 5.58 (2s wide, 1H each: = CH ₂ ); 5.83 (s, 1H: -0-CH-O-); from 7.35 to 7.50 (mt, 5H: -H aromatic).

O-benzylidene-lβ, 2 cinnamoyl-5α O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll can be prepared as follows:

To a solution of 7.60 g of cinnamoyl-5α dihydroxy-lβ, 2α

O-isopropylidene-9, 10β oxo-13 taxadiene-4 (20), ll in 500 cm3 of anhydrous toluene in the presence of 4A molecular sieve maintained under an argon atmosphere and with stirring, added at a temperature in the region of 20 ° C , 4.30 cm3 of benzaldehyde then 0.539 g of para-toluenesulphonic acid monohydrate.

The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The crude product obtained is taken up with dichloromethane. The organic phase is washed once with a 5% aqueous solution of sodium bicarbonate and then once with distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 8.80 g of a yellow oil are obtained (which crystallizes over time) which is purified by flash chromatography on 700 g of silica (0.040-0.063 mm) contained in a column 7 cm in diameter, eluting in a cyclohexane-ethyl acetate mixture (80-20 by volume). The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

6.21 g of O-benzylidene-lβ, 2α cinnamoyl-5 O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll are thus obtained in the form of white crystals, the characteristics of which are as follows :

- proton nuclear magnetic resonance spectrum (400 MHz; CD CL; chemical shifts in ppm; coupling constants J in Hz): 1.18 (s, 3H: -CH ₃ 16 or 17); 1.40 (s, 3H: -CH ₃ 16 or 17); 1.49 and 1.56 [2s, 3H each: (-CE ₃ ) ₂ ]; 1.58 - 1.75 to 1.90 and 2.02 (3mt, respectively IH -2H and IH: -CH ₂ - 7 and -CH ₂ - 6); 1.71 (s, 3H: -CH ₃ 19); 2.17 (s, 3H: CH ₃ 18); 2.80 (ab limit, J = 20, 2H: -Cϋ ₂ - 14); 3.22 (d, J = 55, 1H: -H 3); 4.34 (d, J = 10, 1H: -H 9); 4.42 (d, J = 5.5, 1H: -H 2); 4.94 (d, J = 10, 1H: -H 10); 5.1 and 5.65 (2s wide, JH each: = CH ₂ ); 5.37 (br s, 1H: -H 5); 5.81 (s, 1H: -O-CH-O-); 6.36 and 7.64 (2d, J = 16, 1H each: -CH = CH-); from 7.30 to 7.50 (mt, 8H: -H aromatic in meta and in para of the double bond and aromatic); 7.74 (d, J = 7.5, 2H: -H aromatic in ortho of the double bond).

EXAMPLE 3 To a solution of 2 mg of O-benzylidene-lβ, 2α epoxy-5β, 20

O-isopropylidene-9α, 10β oxo-13 propanoyloxy-4α taxene-11 in 5 cm3 of anhydrous toluene maintained under an argon atmosphere and with stirring, 44 μl of diisobutylaluminum hydride is added at a temperature close to 0 ° C. .

The reaction mixture is stirred for 4 hours 30 minutes at a temperature in the region of 0 ° C., then 44 μl of diisobutylaluminum hydride is added.

The reaction mixture is stirred for 17 hours at a temperature in the region of 20 ° C and then 88 μl of diisobutylaluminum hydride are added at a temperature in the region of 0 ° C.

After 6 hours of stirring at a temperature in the region of 20 ° C., 88 μl of diisobutylaluminum hydride are added, then 88 μl of hydride a second time after 20 hours of stirring.

The mixture is then stirred for 24 hours at a temperature in the region of 20 ° C. and then 4 cm 3 of methanol are added. After 15 minutes of stirring, the insoluble material is filtered and the solvents are evaporated off under reduced pressure (2.7 kPa) at 40 ° C. We 26 mg of a crude product are thus obtained which is purified on a preparative plate, eluting twice with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fractions containing only the sought product and the unreacted starting product are extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

14 mg of O-benzylidene-lβ, 2α epoxy-5β, 20 O-isopropylidene-9, 10β oxo-13 propanoyloxy-4 taxene-11 (unreacted starting product) and 4 mg of are thus obtained. O-benzylidene-lβ, 2α epoxy-5β, 20 hydroxy-13α O-isopropylidene-9α, 10β propanoyloxy-4α taxene-11 in the form of a yellow oil, the characteristics of which are as follows:

- NMR spectrum! H (400 MHz, CDCI3, δ in ppm): 1.15 (t, J = 7.5 Hz, 3H: CH ₃ ethyl); 1.23 (s, 3H: CH3); from 1.40 to 1.80 - 1.95 - 2.11 and 2.33 (mts, 4H: CH ₂ 7 and CH ₂ 6); 1.45 (s, 3H: CH ₃ ); 1.48 (s, 3H: CH ₃ ); 1.63 (s, 3H: CH ₃ ); 1.68 (s, 3H CH ₃ ); 1.78 and 2.20 (2 dd, J = 16 and 9 Hz, 1 H each: CH ₂ 14); 1.95 (s, 3H: CH3) 2.47 (mt, 2H: CH ₂ ethyl); 2.66 (d, J = 5.5 Hz, 1H: H 3); 4.18 (d, J = 5.5 Hz, 1 H H 2); 4.26 (d, J = 10 Hz, 1H: H 9); 4.61 (AB limit, 2H: CH ₂ 20); 4.68 (d. J = 10 Hz, 1 H: H 10); 4.70 (mt, 1H: H 13); 4.95 (broad d, J = 10 Hz, 1 H: H 5); 5.82 (s, 1H: CHAr); from 7.30 to 7.55 (mt, 5H: aromatic).

By operating as in Example 1, the product obtained is esterified using tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4 oxazolidinecarboxylic- 5- (4R, 4S, 5R) acid to obtain the tert -butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidinecarboxylate-5- (4R, 4S, 5R) d'-benzylidene-lβ, 2 epoxy-5β, 20 O-isopropyl-pylidene-9, 10β propanoyloxy -4α taxene-11 yle-13, whose protective groups are replaced by hydrogen atoms to provide tert-butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) propanoyloxy-4α O-benzylidene- lβ, 2 dihydroxy-9, 10β epoxy-5β, 20 taxene-11 yle-13.

O-benzylidene-lβ, 2α epoxy-5β, 20 O-isopropylidene-9α, 10β oxo-13 propanoyloxy-4α taxene-11 can be prepared as follows:

To a solution of 50 mg of O-benzylidene-lβ, 2 epoxy-5β, 20 hydroxy-4α O-isopropylidene-9, 10β oxo-13 taxene-11, prepared under the conditions described in Example 2, in 7 cm3 of anhydrous dichloromethane maintained under an argon atmosphere and with stirring for 10 minutes, added at a temperature in the region of

20 ° C, 130 μl of propionic anhydride and 120 mg of 4-dimethylaminopyridine.

The reaction mixture is stirred for 5 days at a temperature in the region of 45 ° C and then cooled to a temperature in the region of 20 ° C. We dilute with 20 cm3 of a ethyl ether-dichloromethane mixture (80-20 by volume), wash the organic phase 2 times with 10 cm 3 of a saturated aqueous solution of sodium chloride, then dry over magnesium sulfate. After filtration and concentration to dryness under reduced pressure (2.7 kPa) at 40 ° C., 97 mg of a crude product are thus obtained which is purified on a preparative plate, eluting in a cyclohexane-ethyl acetate mixture 60 -40 in volumes). The fraction containing only the sought product is extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

55 mg of O-benzylidene-lβ, 2α epoxy-5β, 20 O-isopropylidene-9α, 0β oxo-13 propanoyloxy-4 taxene-11 are thus obtained in the form of a white powder, the characteristics of which are as follows :

- ¹ H NMR spectrum (400 MHz, CDC1 _3> δ in ppm): 1.10 (t, J = 7.5 Hz, 3H: CH ₃ ethyl); 1.33 (s, 3H: CH ₃ ); from 1.40 to 1.80 - 1.95 and 2.12 (mts, 4H: CH ₂ 7 and CH ₂ 6); 1.49 (s, 3H: CH ₃ ); 1.55 (s, 3H: CH ₃ ); 1.68 (s, 3H: CH ₃ ); 1.72 (s, 3H: CH ₃ ); 1.93 (s, 3H: CH ₃ ); from 2.20 to 2.45 (mt, 2H: CH ₂ ethyl); 2.50 and 2.60 (2 d, J = 20 Hz, 1 H each: CH ₂ 14); 2.64 (d, J = 6 Hz, 1H: H 3); 4.33 (d, J = 6 Hz, 1H: H 2); 4.35 (d, J = 10 Hz, 1H: H 9); 4.62 (AB limit, 2H: CH ₂ 20); 4.65 (d, J = 10 Hz, IH: HK, 4.93 (wide d, J = 10 Hz, IH: H 5); 5.90 (s, IH: CHAr); from 7.30 to 7 , 55 (mt, 5H: aromatics).

EXAMPLE 4

To a solution of 250 mg of O-benzylidene-lβ, 2 epoxy-5β, 20 hydroxy-4 O-isopropylidene-9α, 10β oxo-13 taxene-11 in 40 cm3 of anhydrous toluene maintained under an argon atmosphere and under stirring for 10 minutes, 1.16 cm 3 of isobutyric anhydride and 600 mg of 4-dimethylamino pyridine are added at a temperature in the region of 20 ° C.

The reaction mixture is stirred for 24 hours at a temperature in the region of 115 ° C., then 0.5 - 3 of isobutyric anhydride and 300 mg of 4-dimethylamino-pyridine are added.

The reaction mixture is stirred for 2 days at a temperature in the region of 115 ° C and is then cooled to a temperature in the region of 20 ° C. Diluted with 50 cm3 of an ethyl ether-dichloromethane mixture (80-20 by volume). The organic phase is washed twice with 20 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 1.34 g of a crude product are thus obtained, which product is first purified by flash chromatography on 150 g of silica (0.040-0.063 mm) contained in a column 3.5 cm in diameter, eluting in a mixture. cyclohexane-ethyl acetate (60-40 by volume). The fractions containing only the sought products (starting product which has not reacted in mixture with the desired product) are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

554 mg of a mixture of two products are thus obtained which are purified on a preparative plate, eluting with a dichloromethane-ethyl acetate mixture (90-10 by volume). The fractions containing only the sought product and the unreacted starting product are extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa ) at 40 ° C.

91 mg of O-benzylidene-lβ, 2α epoxy-5β, 20 hydroxy-4 O-isopropylidene-9, 10β unreacted oxo-13 taxene-11 and 110 mg of O-benzylidene-1 are thus obtained. β, 2α epoxy-5β, 20 isobutanoyloxy-4α O-isopropylidene-9α, 10β oxo-13 taxene-11 in the form of a white powder with the following characteristics:

- 1 H NMR spectrum (400 MHz, CDCI ₃ , δ in ppm): 1.11 (d, J = 7.5 Hz, 3H: isopropyl CH ₃ ); 1.24 (s, 3H: isopropyl CH ₃ ); 1.34 (s, 3H: CH ₃ ); from 1.40 to 1.80 - 1.95 - 2.1 1 and 2.31 (mts, 4H: CH 7 and CH ₂ 6); 1.49 (s, 3H: CH ₃ ); 1.54 (s, 3H: CH ₃ ); 1.68 (s, 6H: CH3); 1.94 (s, 3H: CH3); 2.43 (mt, 1H: isopropyl CH); 2.47 and 2.58 (2 d, J = 20 Hz, 1 H each: CH ₂ 14); 2.67 (d, J = 5.5 Hz, 1H: H 3); 4.33 (d, J = 5.5 Hz, 1 H: H 2); 4.36 (d, J = 10 Hz, 1 H: H 9); 4.63 (limit AB, 2H: CH ₂ 20); 4.76 (d, J = 10 Hz, 1 H: H 10); 4.84 (broad d, J = 10 Hz, 1 H: H 5); 5.90 (s, 1H: CHAr); from 7.30 to 7.55 (mt, 5H: aromatic).

O-benzylidene-lβ, 2 epoxy-5β, 20 isobutanoyloxy-4 O-isopropylidene-9α, 10β oxo-13 taxene-1 are reduced under the conditions described in Example 3 for the reduction of O-benzylidene-lβ, 2 epoxy-5β, 20 O-isopropylidene-9, 10β oxo-13 propanoyloxy-4α taxene-11, to obtain lO-benzylidene-lβ, 2 epoxy-5β, 20 isobutanoyloxy-4α O-isopropylidene- 9α, 10β hydroxy-13α taxene-11 which is esterified using tert-butoxycarbonyl-3 (4-methoxy phenyl) -2 phenyl-4 oxazolidinecarboxylic-5- (4R, 4S, 5R) acid to obtain tert- butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidinecarboxylate-5- (4R, 4S, 5R) O-benzylidene- lβ, 2α epoxy-5β, 20 O-isopropylidene-9α, 10β isobutanoyloxy-4α taxene -11 yle-13α, whose protective groups are replaced by hydrogen atoms for provide tert-butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) of isobutanoyloxy-4α O-benzylidene-lβ, 2 dihydroxy-9α, 10β epoxy-5β, taxene-11 yle-13α.

EXAMPLE 5 To a solution of 54 mg of acetoxy-4α O-benzylidene-lβ, 2α epoxy-5β, 20

O-isopropylidene-9-oxo-10β 13 taxène-11, prepared under the conditions described in Example 2, in 3.4 cm3 of dichloromethane rr ^'ntenue under stirring, at a temperature of 20 ° C, 67 mg dich-oro-2,3-dicyano-5,6 benzoquinone-1,4 and 75 μl of distilled water. The reaction mixture is stirred for 18 hours at a temperature in the region of 20 ° C. and then 34 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is added.

The reaction mixture is stirred for 6 hours at a temperature in the region of 20 ° C. and then diluted with ethyl ether. The organic phase is washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

153 mg of an orange paste are obtained which are purified on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction containing only the sought product is extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

11 mg of acetoxy-4α benzoyloxy-2α epoxy-5β, 20 hydroxy-lβ O-isopropylidene-9, J 0β oxo-13 taxene-11 are thus obtained in the form of an orange oil, the characteristics of which are as follows: - ¹ H NMR spectrum (400 MHz, CDC1 ₃ , δ in ppm): 1.31 (s, 3H: CH ₃ ); from 1.40 to 2.00 - 2.13 and 2.27 (mts, 4H: CH ₂ 7 and CH ₂ 6); 1.50 (s, 3H: CH ₃ ); 1.60 (s, 6H: CH ₃ ); 1.76 (s, 3H: CH ₃ ); 2.00 (s, 3H: CH ₃ ); 2.18 (s, 3H: COCH ₃ ); 2.66 and 2.92 (2 d, J = 19 Hz, 1 H each: CH ₂ 14); 3.01 (d, J = 5.5 Hz, 1 H: H 3); 4.14 and 4.36 (2 d, J = 9 Hz, 2H: CH ₂ 20); 4.47 (d, J = 10 Hz, 1H: H 9); 4.81 (d, J = 10 Hz, 1H: H 10); 4.95 (broad d, J = 10 Hz, 1 H: H 5); 5.87 (d, J = 5.5 Hz, 1H: H 2); 7.52 (t, J = 7.5 Hz, 2H: OCOCgH ₅ H meta); 7.63 (t, J = 7.5 Hz, H: OCOCgH ₅ H para); 8.12 (d, J = 7.5 Hz, 2H: OCOCgH ₅ H ortho).

Acetoxy-4 benzoyloxy-2c dihydroxy-l β, 13α epoxy-5β, 20 O-isopropylidene-9α, 10β taxene-11 can be prepared as follows: To a solution of 1 mg of acetoxy-4 benzoyloxy-2α epoxy-5β, 20 hydroxy-lβ O-isopropylidene-9, 10β oxo-13 taxene-11 in 3 cm3 of anhydrous toluene maintained under an argon atmosphere and with stirring for 10 minutes, 19 μl of diisobutylaluminum hydride are added at a temperature close to 0 ° C. The reaction mixture is stirred for 5 hours at a temperature in the region of 0 ° C., then 38 μl of diisobutylaluminum hydride is added.

After 18 hours of stirring at a temperature in the region of 20 ° C., 38 μl of diisobutylaluminum hydride are added, then 38 μl of diisobutylaluminum hydride a second time after 24 hours of stirring. The reaction mixture is stirred for 2 additional days at a temperature in the region of 20 ° C., then 19 μl of diisobutylaluminum hydride are added, then 40 μl after 4 hours 30 minutes of stirring.

The reaction mixture is stirred for 3 days at a temperature in the region of 20 ° C. and then 2 cm 3 of methanol are added. After 10 minutes of stirring, the insoluble material is filtered and the solvents are evaporated off under reduced pressure (2.7 kPa) at 40 ° C.

21 mg of a yellow oil are obtained which is purified on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fractions containing only the sought product and the unreacted starting product are extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

3 mg of unreacted starting material and 4 mg of 4-acetoxy are thus obtained. benzoyloxy-2α dihydroxy-lβ, 13α epoxy-5β, 20 O-isopropylidene- 9α, 10β taxene-1 1 under the faith of an orange oil, the characteristics of which are as follows: - mass spectrum carried out by the desorption technique / chemical ionization using ammonia as reactive gas (TSQ 46 FINNIGAN, fragments in m / z): 571 (MH +); 513 [M - (CH ₃ ) ₂ CO + H] +; 449 (M - PhCOOH + H) +; 431 (M - PhCOOH - H ₂ 0 + H) +.

By esterification of the product obtained by means of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidinecarboxylic-5- (4R, 4S, 5R) acid, tert-butoxycarbonyl-3 (4-methoxy) is obtained. phenyl) -2 pheny -4 oxazolidinecarboxylate-5- (4R, 4S, 5R) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 O-isopropylidene-9α, 10β taxene-11 yl-13, the protecting groups of which are replaced by hydrogen atoms to provide tert-butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 trihydroxy-lβ, 9α, 10β epoxy-5β, 20 taxene-11 yl- 13.

EXAMPLE 6

To a solution of 1.11 g of O-benzylidene-lβ, 2α cinnamoyl-5α O-isopropylidene-9α, 10β oxo-13 taxadiene-4 (20), ll in 40 cm3 of anhydrous acetonitrile maintained under atmosphere of argon and with stirring, 46 mg of palladium dichloride bisacetonitrile are added at a temperature in the region of 20 ° C.

The reaction mixture is stirred for 18 hours at a temperature in the region of 20 ° C., then 46 mg of palladium dichloride bisacetonitrile is added. After 24 hours of stirring, 46 mg of palladium dichloride bisacetonitrile are again added.

The reaction mixture is stirred for 7 hours before adding 46 mg of palladium dichloride bisacetonitrile, then 23 mg after 24 hours of additional stirring. The reaction mixture is stirred for 17 hours and the solvent is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

30 g of a crude product are obtained, which product is purified by flash chromatography on 200 g of silica (0.040-0.063) contained in a column 4 cm in diameter, eluting in a cyclohexane-ethyl acetate mixture (60 -40 in volumes). The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.73 g of O-benzylidene-lβ, 2α cinnamoyl-5α dihydroxy-9α, 10β oxo-13 taxadiene-4 (20), ll are thus obtained in the form of a white powder, the characteristics of which are as follows: - 1 H NMR spectrum (400 MHz, CDCI3, Ô in ppm): 1.23 (s, 3H: CH ₃ ); 1.40 (s, 3H: CH ₃ ); from 1.40 to 1.60 - from 1.70 to 1.90 and 2.02 (mts, 4H: CH ₂ 7 and CH ₂ 6); 1.69 (s, 3H: CH ₃ ); 2.5 (s, 3H: CH ₃ ); 2.63 (d, J = 2 Hz, 1 H: OH at 10); 2.70 (d, J = 4 Hz, 1H: OH at 9); 2.82 (limit AB, J = 19 Hz, 2H: CH ₂ 14); 3.37 (d, J = 6 Hz, 1H: H 3); 4.20 (dd, J = 10 and 4 Hz, 1 H: H 9); 4.34 (d, J = 6 Hz, 1H: H 2); 4.97 (dd, J = 10 and 2 Hz, 1H: H 10); 5.28 and 5.64 (2 sec broad, 1 H each: = CH ₂ ); 5.34 (br s, H: H 5); 5.78 (s, 1H: CHAr); 6.41 and 7.64 (2 d, J = 16 Hz, 1 H each: CH = CH); from 7.35 to 7.50 (mt, 8H: aromatic H); 7.78 (d, J = 7.5 Hz, 2H: Aromatic H in ortho of the double bond).

O-benzylidene-lβ, 2α cinnamoyl-5α O-methoxy-4 benzylidene-9α, 10β oxo-13 taxadiene-4 (20), 11 can be prepared as follows: To a solution of 437 mg of 0-benzylidene-l β, 2 cinnamoyl-5α dihydroxy-

9α, 10β oxo-13 taxadiene-4 (20), l l in 40 cm3 of anhydrous toluene maintained under an argon atmosphere and with stirring, added at a temperature in the region of 20 ° C,

235 μl of 4-methoxy-benzaldehyde dimethylacetal then 27 mg of para-toluenesulphonic acid monohydrate.

The reaction mixture is stirred for 3 days at a temperature in the region of 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The reaction crude is taken up in 150 cm3 of an ethyl ether-dichloromethane mixture (80-20 by volume). The organic phase is washed with 60 cm3 of a saturated aqueous sodium bicarbonate solution and then with 60 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

520 mg of a crude product are obtained which is purified on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fractions containing only the sought product and the unreacted starting product are extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa ) at 40 ° C.

20 mg of unreacted starting product and 410 mg of O-benzylidene-1 β, 2α cinnamoyl-5 O-4-methoxy-benzylidene-9, 10β oxo-13 taxadiene-4 are thus obtained (20), l 1 in the form of a white powder, the characteristics of which are as follows:

- ¹ H NMR spectrum (400 MHz, CDCI3, δ in ppm) (we observe the mixture of two diastereoisomers in the proportions 1/3 and 2/3): 1.20 and 1.23 (2 s, 3H: CH3); 1.37 and 1.41 (2 sec, 3H: CH ₃ ); from 1.40 to 2.10 (mt, 4H: CH ₂ 7 and CH ₂ 6); 1.73 and 2.03 (2 sec, 3H: CH ₃ ); 2.12 and 2.18 (2 sec, 3H: CH ₃ ); 2.78 (AB limit, J = 19 Hz, 2H: CH ₂ 14); 3.22 and 3.26 (d, J = 6 Hz, 1H: H 3); 3.80 and 3.82 (2 sec, 3H: OCH3); 4.36 and 4.40 (2 d, J = 6 Hz, 1 H: H 2); 4.43 and 4.50 (2 d, J = 10 Hz, 1 H: H 9); 5.08 (d, J = 10 Hz, 1H: H 10); 5.28 - 5.62 and 5.65 (respectively mt and 2 s wide, 1H each: = CH ₂ ); 5.35 (br s, 1H: H 5); 5.75 and 5.82 (2 sec, 1 H: CHAr); 6.04 and 6.11 (2 sec, 1 H: CHAr); 6.32 and 7.62 (2 series of 2 d, J = 16 Hz, 1 H each: CH = CH); 6.92 (mt, 2H: aromatic H in ortho of OCH3); from 7.30 to 7.50 (mt, 10H: aromatic H and aromatic H in meta of OCH,); 7.70 (mt, 2H: Aromatic H in ortho of the double bond).

O-benzylidene-lβ, 2 hydroxy-5α O-methoxy-4 benzylidene-9α, 10β oxo-13-taxadiene-4 (20), l 1 can be prepared as follows: To a solution of 100 mg of 0-benzylidene-lβ, 2 cinnamoyl-5 O-methoxy-4 benzylidene-9, 10β o.xo-13 taxadiene-4 (20), ll in 13 cm3 of tetrahydrofuran maintained under an atmosphere of argon and with stirring, is added at a temperature in the region of 20 ° C, 2.3 cm3 of a 30% solution of sodium hydroxide. The reaction mixture is stirred for 90 hours at reflux of the solvent. It is allowed to cool to a temperature in the region of 20 ° C. Distilled water is then added until the insoluble material formed has dissolved and the aqueous phase is extracted twice with ethyl acetate. The organic phase is washed 4 times with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

100 mg of a pale yellow meringue are obtained which is purified on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fractions containing only the sought product are extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

74 mg of O-benzylidene-lβ, 2 hydroxy-5α O-methoxy-4 benzylidene-9α, 10β oxo-13 taxadiene-4 (20), ll are thus obtained in the form of a white powder, the characteristics of which are following: - 1 H NMR spectrum (400 MHz, CDCI3, δ in ppm); (the mixture of two diastereoisomers is observed in the proportions 1/3 and 2/3): 1.14 and 1.17 (2 s, 3H: CH3); 1.32 and 1.36 (2 s, 3H: CH ₃ ); from 1.40 to 2.00 (mt, 4H: CH ₂ 7 and CH ₂ 6); 1.72 (s, Λ: CH ₃ ); 2.05 and 2.11 (2 sec, 3H: CH ₃ ); 2.68 (AB limit, 2H: CH ₂ 14); 3.38 and 3.35 (2 d, J = 6 Hz, 1 H: H 3); 3.79 and 3.81 (2 sec, 3H: OCH3); 4.18 (br s, 1H: H 5); 4.32 and 4.35 (2 d, J = 6 Hz, 1 H: H 2); 4.40 and 4.46 (2 d, J = 10 Hz, 1 H: H 9); 5.10 (d, J = 10 Hz, 1 H: H 10); 5.10 - 5.52 and 5.55 (respectively mt and 2 s wide, IH each: = CH ₂ ); 5.75 and 5.80 (2 sec, 1H: CHAr); 6.04 and 6.08 (2 sec, 1 H: CHAr); 6.92 (d, J = 7.5 Hz, 2H: aromatic H in ortho of OCH3); from 7.30 to 7.50 (mt, 7H: aromatic H and aromatic H in meta of OCH..

O-benzylidene-lβ, 2α O-methoxy-4 benzylidene-9α, 10β trihydroxy-4, 5σ., 20 oxo-13 taxene-1 1 can be prepared as follows:

To a solution of 74 mg of O-benzylidene-lβ, 2 hydroxy-5α O-methoxy-4 benzylidene-9α, 10β υxo-13 taxadiene-4 (20), ll in a mixture of 12 cm3 of tetrahydrofuran and 6 cm3 of distilled water maintained under an argon atmosphere and with stirring, 230 mg of methyl-4 are added at a temperature in the region of 20 ° C. 4-oxide morpholine monohydrate then 100 μl of osmium tetroxide at 2.5% weight by weight in tert-butanol.

The reaction mixture is stirred for 3 days at a temperature close to

20 ° C, then 500 mg of Florisil, 7 cm3 of distilled water and 100 μl of a 50% aqueous solution of sodium bisulfite are added. The mixture is stirred for 10 minutes at a temperature in the region of 20 ° C. and filtered through a sintered glass lined with celite. The filtrate is neutralized with a 0.1N aqueous hydrochloric acid solution and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue is diluted with ethyl acetate and the organic phase is washed with a 0.1N aqueous solution of hydrochloric acid to acid pH and then once with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

76 mg of crude reaction product are obtained which is purified on a preparative plate, eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fractions containing only the sought product are extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

44 mg of O-benzylidene-lβ, 2 O-methoxy-4 benzylidene- are thus obtained.

9, 10β trihydroxy-4, 5α, 20 oxo-13 taxene-11 in the form of a white powder, the characteristics of which are as follows:

- NMR spectrum * ^• - H (600 MHz, CDCI3, δ in ppm); (the mixture of two diastereoisomers is observed in the proportions 1/3 and 2/3): 1.22 and 1.27 (2 s, 3H: CH3);

1.40 and 1.43 (2 sec, 3H: CH ₃ ); from 1.40 to 2.00 (mt, 4H: CH ₂ 7 and CH ₂ 6); 1.58 and 1.73

(2 s, 3H: CH ₃ ); 2.05 and 2.12 (2 sec, 3H: CH ₃ ); 2.37 (mf, 1H: OH); 2.47 (s, 1H: OH); 2.75 to 2.85 (mt, 1H: H 3); from 2.75 to 2.85 and 3.40 (2 mts, IH each: CH2

14); 3.58 and 4.11 (respectively broad d (J = 9 Hz) and mt, 1 H each: CH2 20);

3.67 (s, 1H: OH); 3.80 (br s, 1H: H 5); 3.84 and 3.85 (2 sec, 3H: OCH3); from 4.30 to

4.45 (mt, 2H: H 2 and H 9); 5.03 (mt, 1H: H 10); 5.85 and 5.90 (2 sec, 1H: CHAr);

6.05 and 6.09 (2 sec, 1 H: CHAr); 6.94 (d, J = 7.5 Hz, 2H: Aromatic H in ortho of

OCHJ; from 7.30 to 7.50 (mt, 7H: aromatic H and aromatic H in meta of

OCH ₃ ).

O-benzylidene-1 β, 2α tert-butyldimethylsilyloxy-20 dihydroxy-4α, 5α O-methoxy-4 benzylidene-9α, 10β oxo-13 taxene-11 can be prepared as follows: To a solution of 30 mg of 0-benzylidene-lβ.2 O-4-methoxy benzylidene

9α, 10β trihydroxy-4, 5α, 20 oxo-13 taxene-11 in 2 cm3 of anhydrous dimethylformamide maintained under an argon atmosphere and with stirring, 17 mg of imidazole are added at a temperature close to 20 ° C. then 39 mg of tert-butyldimethylsilane chloride.

The reaction mixture is stirred for 4 hours at a temperature in the region of 20 ° C. and then diluted with 10 cm 3 of a mixture of distilled water-saturated aqueous solution of sodium chloride (50-50 by volume). The aqueous phase is extracted with 25 cm3 of ethyl acetate and the organic phase washed 3 times with 10 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

34 mg of a transparent lacquer are obtained which is purified on a preparative plate, eluting in a cyclohexane-ethyl acetate mixture (60-40 by volume). The fractions containing only the sought product and the unreacted starting product are extracted with a dichloromethane-methanol mixture (85-15 by volume), filtered through sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa ) at 40 ° C.

This gives 5 mg of unreacted starting material and 20 mg of O-benzylidene-lβ, 2 tert-butyldimethylsilyloxy-20 dihydroxy-4, 5 O-methoxy-4 benzylidene-9, 10β oxo-13 taxene -11 in the form of a white powder, the characteristics of which are as follows:

- NMR spectrum ^• ** H (400 MHz, CDCI3, δ in ppm); (the mixture of two diastereoisomers is observed in the proportions 1/3 and 2/3): - 0.25, - 0.22 and - 0.10, - 0.09 (2 times 2s, 6H: SiCH ₃ ); 0.72 and 0.74 (2s, 9H: SiC (CH ₃ ) ₃ ); 1.12 and 1.15 (2 sec, 3H: CH ₃ ); 1.33 and 1.37 (2 sec, 3H: CH3); from 1.40 to 2.00 (mt, 4H: CH ₂ 7 and CH ₂ 6); 1.55 and 1.68 (2s, 3H: CH ₃ ); 2.03 and 2.09 (2s, 3H: CH ₃ ); 2.63 and 3.80 (respectively d (J = 20 Hz) and mt, 1H each: CH2 14); from 2.65 to 2.75 (mt, 2H: H 3 and OH); 3.46 and 4.19 (2 mts, 1 H each: CH ₂ 20); 3.58 (br s, 1H: H 5); 3.72 (s, 1H: OH); 3.79 and 3.81 (2 sec, 3H: OCH3); 4.22 and 4.26 (2 d, J = 5 Hz, 1 H: H 2); 4.37 and 4.42 (2 d, J = 10 Hz, H: H 9); 5.00 (d, J = 10 Hz, 1 H: H 10); 5.73 and 5.78 (2 sec, 1H: CHAr); 6.01 and 6.04 (2 sec, 1 H: CHAr); 6.82 (d, J = 7.5 Hz, 2H: aromatic H in ortho from OCHJ; from 7.30 to 7.50 (mt, 7H: H aromatic and H aromatic in meta from OCH.

O-benzylidene-1 β, 2α tert-butyldimethylsilyloxy-20 dihydroxy-4α, 5 O-methoxy-4 benzylidene-9α, 10β oxo-13 taxene-11 is transformed into tert-butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 O-benzylidene-lβ, 2 -dihydroxy-9α, 10β epoxy-5β, 20 taxene-11 yle-13α via the following intermediaries:

- O-benzylidene-lβ, 2 tert-butyldimethylsilyloxy-20 hydroxy-4 methanesulfonyloxy- 5a O-methoxy-4 benzylidene-9, 10β oxo-13 taxene-11,

- O-benzylidene-lβ, 2 dihydroxy-4α, 20 methanesulfonyloxy-5 O-methoxy-4 benzylidene-9, 10β oxo-13 taxene-11,

- O-benzylidene-lβ, 2 hydroxy-4α epoxy-5β, 20 O-methoxy-4 benzylidene-9, 10β oxo-13 taxene-11, - O-benzylidene-lβ, 2α acetoxy-4 epoxy-5β, 20 O -4-methoxy-benzylidene-9α, 10β oxo-13 taxene-11,

- O-benzylidene-lβ, 2α acetoxy-4α epoxy-5β, 20 O-methoxy-4 benzylidene-9, 10β hydroxy- 13α taxene-11, and

- tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidinecarboxylate-5- (4R, 4S, 5R) d ^* O-benzylidene-lβ, 2α acetoxy-4α eρoxy-5β, 20 O-methoxy-4 benzylidene-9, 10β taxene-11 yle-13α,

EXAMPLE 7

Dissolve 40 mg of tert-butoxycarbonylamino-3 phenyl-3 hydroxy-2 propionate- (2R, 3S) acetoxy-4 (4-methoxy benzoyl) oxy-2α epoxy-5β, 20 hydroxy-lβ O-isopropylidene-9α , 10β taxene-11 yle-13α in 1 cm3 of Emulphor

EL 620 and 1 cm3 of ethanol then the solution is diluted by adding 18 cm3 of physiological saline.

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

Claims

1 - New derivative of taxicin characterized in that it corresponds to the general formula:

in which :

Ar represents an aryl radical, an alkyl containing 1 to 4 carbon atoms, an alkenyl containing 2 to 4 carbon atoms, a cycloalkyl containing 3 to 6 carbon atoms or a cycloalkenyl containing 3 to 6 carbon atoms,

R represents a benzoyl, thenoyl or furoyl radical or a radical of general formula R -O-CO- in which Ri represents an alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, phenyl or heterocyclyl radical,

R2 and R3 each represent a hydroxy radical or an oxo group or together form a radical of formula

-OC (-R ₄ ) (- R ₅ ) -O- (II) in which R4 and R5, identical or different, represent a hydrogen atom, an alkyl radical or an optionally substituted phenyl radical, Rg and R7 each represent a hydrogen atom or else Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl radical or else Rg and R7 form together a radical of formula

-C (-R) (- R ₉ ) (III) in which Rg and R9, identical or different, represent an alkyl radical or an optionally substituted phenyl radical, and Rχo represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl.

2 - New taxicin derivative according to claim 1 characterized in that:

Ar represents an aryl radical, R represents a benzoyl radical or a radical R ^ -O-CO- in which Rj represents:

- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from fluorine or chlorine atoms and hydroxy radicals, alkoxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part contains 1 with 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkoxycarbonyl in which the alkyl part contains 1 to 4 atom carbon, - a phenyl radical optionally substituted by one or more radicals chosen from alkyl radicals containing 1 to 4 carbon atoms and alkoxy radicals containing 1 to 4 carbon atoms,

- or a saturated nitrogen heterocyclyl radical containing 5 to 6 members optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and

R2 and R3 each represent a hydroxy radical or an oxo group or together form a radical of formula (II) in which R4 and R5, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or phenyl optionally substituted by one or more identical or different atoms or radicals, chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl radicals , acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, dialcoylamino, 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, alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and that the aryl radicals are phenyl or α- or β-naphthyl radicals, Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 represents

- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 2 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, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl, the alkyl part of which gives 1 to 4 carbon atoms, - or a ra dical aryl optionally substituted,

- or a saturated or unsaturated heterocyclyl radical having 4 to 6 members, containing one or more identical or different heteroatoms chosen from nitrogen, oxygen or sulfur atoms and being optionally substituted, it being understood that the cycloalkyl radicals, cycloalkenyls or bicycloalkyls may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, or else Rg and R7 together form a radical of formula (III) in which

Rg and R9, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or phenyl optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and the alkyl radicals, alrόπyles, alkynyls, aryls, araicycles, alkoxy, alkylthio, arylthio, hydroxy, hydroxya_. oyl, mercapto, formyl, acyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, carbamoyl, dialcoylcarbamoyl, cyano, nitro, azido, trifluoromethoxy and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 atoms of , 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, and

R θ represents:

a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 2 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, alkyloxy radicals containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl of which the alkyl part contains 1 to 4 carbon atoms,

- or an optionally substituted aryl radical,

- or a saturated or unsaturated heterocyclyl radical having 4 to 6 members, containing one or more identical or different heteroatoms chosen from nitrogen, oxygen or sulfur atoms and being optionally substituted, it being understood that the cycloalkyl, cycloalkenyl radicals or bicycloalkyls may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.

3 - New derivative of taxicin according to claim 1 characterized in that: Ar represents a phenyl radical optionally substituted by a fluorine or chlorine atom or by an alkyl (methyl), alkoxy (methoxy), dialkoylamino (dimethylamino) atom, acylamino (acetylamino), alkoxycarbonylamino (tert-butoxycarbonylamino) or trifluoromethyl or a thienyl-2 or -3 or furyl-2 or -3 radical, R represents a benzoyl radical or a radical Rχ-0-CO- in which Rj represents a t.butyle radical,

R2 and R3 each represent a hydroxy radical or an oxo group or together form a radical of formula (II) in which R4 and R5 each represent an alkyl radical containing 1 to 4 carbon atoms, preferably methyl, Rg represents an atom hydrogen and R7 represents a radical R'7-CO- in which R'7 represents a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkoxy radicals containing 1 to 4 carbon atoms or a thienyl-2 or -3 or furyl-2 or -3 radical, or else Rg and R7 together form a radical of formula (III) in which Rg represents a hydrogen atom and R9 represents a phenyl radical optionally substituted by one or more atoms or radicals ^{* -} chosen from halogen atoms and alkoxy radicals containing 1 to 4 carbon atoms, and

R ^ O represents an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkoxy radicals containing 1 to 4 carbon atoms or a thienyl radical- 2 or -3 or furyle-2 or -3.

4 - Process for the preparation of a new taxicin derivative according to one of claims 1, 2 or 3, for which R2 and R3 represent a hydroxy radical or an oxo group, characterized in that a product of esterified general formula:

in which R4, R5, Rg, R9 and Rχo ^are defined as above, by means of an acid of general formula:

R- JR ₁ O

0-R ₁₂ in which Ar and R are defined as above, and either R ^** Q represents a hydrogen atom and R12 represents a protective group for the hydroxy function, or else Rχι and Rχ2 together form a saturated heterocycle at 5 or 6 links, or a derivative of this acid to obtain a product of general formula:

in which Ar, R, R4, R5, Rg, R9, Rχo- Rll and R12 are defined as above, followed by the replacement of the protective groups represented by Rχ2 and / or Rχι and Rχ2 pa of the hydrogen atoms, and optionally l hydrolysis of acetal functions -OC (-R4) (- R5) -O- to obtain a product of general formula (I) in which R2 and R3 each represent a hydroxy radical, or optionally oxidation, when Rg represents a hydrogen atom, in a product of general formula:

in which R4, R5 and Rχo are defined as above, Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 is identical to R9, then optionally hydrolysis of the product of formula general (VII) to obtain a product of general formula (I) in which Ar and R are defined as above, R2 and R3 each represent a hydroxy radical, Rg represents a hydrogen atom and R7 represents a radical R'7-CO - in which R'7 is identical to R ₉ .

5 - Process for the preparation of a new taxicin derivative according to one of claims 1, 2 or 3 in which Ar, R, R2, R3 and Rχo are defined as in one of claims 1, 2 or 3, Rg represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 represents an alkyl radical or an aryl radical characterized in that a product of general formula is esterified:

HO ¹ (xxxvm)

in which R4, R5, R'7 and Rχo are defined as above, by means of an acid of general formula:

O-R 12 in which Ar, R, Ru and Rχ2 are defined as in claim 4, to obtain a product of general formula:

in which Ar, R, R4, R5, R'7, Rχo> Rll and Rχ2 ^are defined as above whose protective groups Ri 2 and / or Ru and R 2 are replaced by hydrogen atoms and optionally hydrolyses the acetal function -OC (-R4) (- R5) -O- to obtain a product according to one of claims 1, 2 or 3 for which R2 and R3 each represent a hydroxy radical

6 - Process for the preparation of a new taxicin derivative according to one of claims 1, 2 or 3, for which R2 and R3 represent a hydroxy radical or an oxo group, characterized in that a product is oxidized according to l 'one of the Claims 1, 2 or 3 for which R2 and R3 each represent a hydroxy radical.

7 - Process according to claim 6 characterized in that the oxidation is carried out by means of pyridinium chlorochromate, pyridinium dichromate, potassium bichromate, ammonium bichromate or manganese oxide at a temperature between 0 and 50 ° C.

8 - A new derivative of taxicin characterized in that it corresponds to the general formula:

wherein R4, R5, Rg, R9 and Rio are defined according to one of claims 1, 2 or 3.

9 - A new derivative of taxicin of general formula:

in which R4, R5 and Rio are defined as in one of claims 1, 2 or 3 and R'7 represents an alkyl radical or an optionally substituted phenyl radical.

10 - Pharmaceutical composition characterized in that it contains at least one derivative according to one of claims 1, 2 or 3 in association with one or more diluents or compatible and pharmaceutically acceptable adjuvants inert or physiologically active.