FR2712289A1 - New taxicin derivatives, their preparation and pharmaceutical compositions containing them. - Google Patents

Abstract

New taxicin derivatives of general formula (I), their preparation and the pharmaceutical compositions which contain them. In general formula (I), Ar represents an aryl radical, R represents a benzoyl radical or a radical of general formula R1 -O-CO- in which R1 represents an alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, phenyl or heterocyclyl radical , R2 and R3 each represent a hydrogen atom or together form an optionally substituted methylene radical, R6 and R7 each represent a hydrogen atom, or alternatively R6 represents a hydrogen atom and R7 represents an R'7 -CO radical - in which R'7 represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl radical or else R6 and R7 together form an optionally substituted methylene radical, and R1 0 represents an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl radical . The new taxicin derivatives of general formula (I) exhibit remarkable anti-leukemia and anti-tumor properties. (CF DRAWING IN BOPI)

Description

NEW TAXICINE DERIVATIVES. THEIR PREPARATION AND

  PHARMACEUTICAL COMPOSITIONS OR CONTAINING THEM

  The present invention relates to novel taxicin derivatives of the general formula:

R2 0 OR3

R-NH O

Ar z 0111 1

OH i -

R60: OO0R1 o

GOLD,

  their preparation and the pharmaceutical compositions containing them In the general formula (I), Ar represents an aryl radical, R represents a benzoyl radical or a radical of general formula R 1 -O-CO- in which R 1 represents an alkyl or alkenyl radical, alkynyl, cycloalkyl, bicycloalkyl, phenyl or heterocyclyl, R2 and R3 each represent a hydrogen atom or together form a radical of formula

-C (-R4) (- RS5) - (II)

  in which R4 and R5, which may be identical or different, represent a hydrogen atom, an alkyl radical or an optionally substituted phenyl radical, R6 and R7 each represent a hydrogen atom or R6 represents a hydrogen atom and R7 represents a hydrogen atom; R'7-CO- radical in which R'7 represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl radical or R6 and R7 together form a radical of formula -CR (-R) (-R9) (mII) in which R8 and R9, which may be identical or different, represent an alkyl radical or a phenyl-substituted radical, and R101 represents an alkyl, alkenyl, alkynyl, cycloalkyl or phenyl radical;

  optionally substituted heterocyclyl.

  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 a radical R 1 -O-CO- in which R 1 represents: a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 atoms of carbon, these radicals being optionally substituted with one or more substituents chosen from fluorine or chlorine atoms and hydroxy, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino in which each alkyl part contains 1 to 4 carbon atoms, piperidino , morpholino, piperazinyl-1 (optionally substituted in -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose part alkyl 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, the alkyl part of which contains 1 to 4 carbon atoms, - a radical phenyl optionally substituted by one or more radicals chosen from alkyl radicals containing 1 to 4 carbon atoms and alkoxy containing 1 to 4 carbon atoms, or a saturated nitrogen containing heterocyclyl radical containing 5 to 6 members optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, and R2 and R3 each represent a hydrogen atom or together form a radical of formula (II) in which R4 and R5, which are identical or different, represent a hydrogen atom e or an alkyl radical containing 1 to 4 carbon atoms or phenyl optionally substituted with one or more atoms or radicals, which may be identical or different, chosen from halogen atoms and alkyl or alkenyl radicals,

  alkynyls, aryls, aralkyls, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyl

  alkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 atoms of carbon, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and that the aryl radicals are phenyl or a- or [3-naphthyl radicals, or R 6 represents a hydrogen atom and R 7 represents a radical R Wherein 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 atoms of carbon, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxy, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino in which each alkyl part contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted in -4 by an alkyl radical containing 1 to 4 carbon atoms or a phenylalkyl radical, the alkyl part of which contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms.

  carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxy

  carbonyl 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 from 4 to 6 ring members, containing one or more identical or different heteroatoms chosen from the atoms of nitrogen, oxygen or sulfur and being optionally substituted, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, or R 6 and R 7 together form a radical of formula (III) in which R8 and Rg, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or phenyl optionally substituted with one or more atoms or radicals, identical or different, chosen among the halogen atoms and the alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, rylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and that the aryl radicals are phenyl or a- or 3-naphthyl radicals, and R10 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, dialkylamino each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted in -4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical, the alkyl part of which contains 1 to 4 atoms of carbon), 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 4 to 6-membered saturated radical 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 a or more alkyl radicals

containing 1 to 4 carbon atoms.

  Preferably, the aryl radicals represented by Ar, R'7 and R10 are phenyl or a- or f [-naphthyl radicals optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl radicals; , dialkylcarbamoyl, cyano, nitro and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are radicals

phenyls or? - or? - naphthyls.

  Preferably, the heterocyclic radicals represented by Ar, R7 and Ro10 are aromatic heterocyclic radicals having 5 members and containing 1 or more atoms, which are identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted by 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 carbon atoms,

  dialkylamino in which each alkyl part contains 1 to 4 carbon atoms, alkoxy-

  carbonylamino containing 1 to 4 carbon atoms, acyl containing 1 to 4 carbon atoms, arylcarbonyl in which the aryl part contains 6 to 10 carbon atoms, cyano, carboxy, carbamoyl, alkylcarbamoyl, the alkyl part of which contains 1 to 4 carbon atoms, dialkylcarbamoyl of which each alkyl part contains 1 to 4 carbon atoms or alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms. Even more particularly, 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) or dialkylamino radical.

  (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tertbutoxycarbonyl)

  nylamino) or trifluoromethyl or a thienyl-2 or -3 or furyl-2 or -3 radical, R represents a benzoyl radical or a radical R1-O-CO- in which R1 represents a tert-butyl radical, R2 and R3 represent each a hydrogen atom 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, R6 represents a hydrogen atom and R7 represents a radical R In which R '7 represents a phenyl radical optionally substituted with 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 radical; or furyl-2 or -3, or R6 and R7 together form a radical of formula (III) in which R8 represents a hydrogen atom and R9 represents a phenyl radical optionally substituted by one or more atoms or radicals chosen from among the atoms of alogen and l alkoxy radicals containing 1 to 4 carbon atoms, and R10 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 radicals alkoxy containing 1 to 4

  carbon atoms or a thienyl-2 or -3 or furyl-2 or -3 radical.

  According to the invention, the new products of general formula (I) can be obtained by esterification of a product of general formula:

R4 R5

HO ,, / (IV)

0 "-

- OCOR1 Q

O

R8%

  R, in which R4, R5, R8, R9 and Ro10 are defined as above, by means of an acid of general formula:

R-I-R1 1 O

Ar - OH (V)

O-R, 2

  wherein Ar and R are defined as above, and either R11 is hydrogen and R12 is a hydroxy protecting group, or R11 and R12 together form a saturated 5- or 6-membered heterocycle, or a derivative of this acid to obtain a product of general formula:

R4 R5

/ \

O O

  RNR 1 i (VI) OR 1 2 OCOR 1 o R 6 in which Ar, R 4, R 5, R 8, R 8, Ro 10, R 11 and R 12 are defined as above, followed by the replacement of the protective groups represented by R 12 and / or R 11 and R 12 by hydrogen atoms, and optionally by hydrolysis of the -OC (-R4) (-R5) -O- acetal functions to obtain a product of general formula (I) in which R2 and R3 each represent an atom of hydrogen, or optionally oxidation, when R8 represents a hydrogen atom, into a product of general formula: R4 sRs

O 0

R-NH o

X (VII)

Ar -

  Wherein R4, R5 and R10 are defined as above, R6 represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 is identical to R9, then optionally hydrolyzing the product of general formula (VII) to obtain a product of general formula (I) in which Ar and R are defined as above, R2 and R3 each represent a hydrogen atom, R6 represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 is identical to

R9.

  The esterification using an acid of general formula (V) 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 of between -10 and 90 ° C.

  The esterification may also be carried out using the acid of general formula (V) in anhydride form, operating in the presence of an activating agent (aminopyridine) in an organic solvent (ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, hydrocarbons

  aromatics) at a temperature between 0 and 90 C.

  The esterification can also be carried out using a racide of general formula (V) in the form of a 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 (aliphatic amine). tertiary) by operating in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons,

  aromatic hydrocarbons) at a temperature between 0 and 80 ° C.

  The replacement of the protective groups R 1 and / or R 1 and R 12 by hydrogen atoms can be carried out according to their nature, as follows: 1) when R 11 represents a hydrogen atom and R 12 represents a protective group of the hydroxyl function chosen, preferably, from the methoxymethyl, ethoxy-ethyl, beta-methyloxymethyl, trimethylsilyl, triethylsilyl, (3-trimethylsilylethoxy) methyl or tetrahydropyranyl radicals, its replacement with a hydrogen atom may be carried out by treating the product of general formula (VI) with a mineral acid (hydrochloric acid, sulfuric acid, hydrofluoric acid) or organic

  formic acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, toluene

  sulfonic acid) used alone or in admixture by operating in an organic solvent selected from alcohols, ethers, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles

  temperature between -10 and 60 C.

  2) when R11 and R12 together form a saturated 5- or 6-membered heterocycle and more particularly an oxazolidine ring of general formula: ## STR2 ##

R. 3 R14

  in which Ar and R are defined as above, R13 and R14, which are identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or 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 with one or more alkoxy radicals containing 1 to 4 carbon atoms, or R13 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted with a trihalomethyl radical such as trichloromethyl and R14 represents a hydrogen atom, or else R13 and R14 together with the carbon atom to which they are bonded form a 4 to 7-membered ring, replacement of the protective groups with hydrogen atoms can be carried out, depending on the the meanings of R 2, R 13 and R 14, as follows: a) when R 2 is butoxycarbonyl, R 13 and R 14, which may be identical or different, represent an alkyl radical or a radical or aryl (phenyl), or R 13 represents a radical; trihalomethyl 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 ring members, the treatment of a product of general formula (VI) with an acid mineral or organic optionally in an organic solvent such as an alcohol leads to the product of general formula:

R4 \ 0R

O \ O

H2N 0

(IX) Ar Z 01 "

R60: O-

OR- OCOR1 o

OR7

  wherein Ar, R4, R5, R6, R7 and Ro10 are defined as above, which is acylated by means of benzoyl chloride or a product of the general formula: R1-O-CO-X (X) wherein R1 is defined as above and X represents a halogen atom (fluorine, chlorine) or a residue -O-R1 or -O-CO-O-R1 to provide a product

of general formula (VII).

  Preferably, the product of general formula (VI) is treated with the acid

  formic at a temperature 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, sodium acetate and the like. isopropyl or n-butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane in the presence of a mineral base such as sodium or organic bicarbonate such as triethylamine. The reaction is carried out at a

  temperature between 0 and 50 C, preferably about 20 C.

  b) when R represents a benzoyl radical or a radical R 1 -O-CO- in which R 1 is defined as above, R 13 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted with a or more alkoxy radicals containing 1 to 4 carbon atoms and R14 represents a hydrogen atom, the replacement of the protective groups by hydrogen atoms is carried out in the presence of a mineral acid (acid

  hydrochloric acid, sulfuric acid) or organic (acetic acid, methane

  sulfonic acid, trifluoromethanesulfonic acid, toluenesulphonic acid) used alone or in admixture, by operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature of between -10.degree. and 60 C, preferably between 15 and 30 C. The acid can be used in catalytic or stoichiometric amount. Generally, the hydrolysis of the -OC (R4) (Rs) -O- acetal function takes place in an acid medium by operating in an organic solvent chosen from ethers (tetrahydrofuran), 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. Depending on the conditions of use, the hydrolysis of the acetal -O-C (R4) (R5) -O- is carried out simultaneously with the replacement of the groups

protectors R11 and / or R11 and R12.

  Generally, the oxidation to a product of general formula (VII) is carried out by means of an oxidizing agent such as 2,3-dichloro-5-dicyano-benzoquinone in a hydro-organic medium such as a mixture of dichloromethane with a

  temperature between 0 and 50 C.

  Generally, the subsequent hydrolysis of the -OC (-R4) (Rs) -O- acetal function 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: R> <(XI) 0 Z: \ o OCOR1 o R8 g 1l

  wherein R4, R5, R8, R9 and R0lo 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 between -10 and 30 C under conditions that 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:

R4 R5

oR oR (XII)

0 _ OH

  R-8-R9 by means of an acid of the general formula: Ro10-COOH (XIII) in which Ro10 is defined as above, or 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 (IV) using an acid of general formula (V).

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

R X5

(XIV) O O.R15

0 - OH

  R8 R9 wherein R4, R5, R8 and R9 are as previously defined, R15 represents a

  sulfonic ester residue such as a methanesulfonyl residue or p. toluènmesulfonyle.

  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 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: RxRs

R9

  in which R4, R5, R8, R9 and R15 are defined as above and R16

  preferably represents a trialkylsilyl radical such as a radical tert-

  butyldimethylsilyl. Generally, the hydrolysis is effected by means of an organic base or a fluoride such as tetra-n-butylammonium hydride hydrated by operating in an organic solvent such as an ether such as teirahydrofuran at a temperature

between 0 and 500C.

  The products of general formula (XV) may be obtained by the action of a sulphonic acid halogenide such as methanesulphonic acid or toluenesulphonic acid chloride on a product of general formula:

! 0 0O

R

  wherein R4, R5, R8, R9 and R15 are removed as before and R16

  preferably represents a trialkylsilyl radical such as a tert-

  butyldimétyMyle. Generally, the hydrolysis is carried out in the form of an organic base or a fluoride such as tetra-n-butylammonium fluoride hydrated by operating in an organic solvent such as an ether as tetrahydrofuran at a temperature

between 0 and $ 0 C.

  The products of general formula (XV) can be obtained by the action of a halide of sulphonic acid such as methanesulphonic or p-toluenesulphonic acid chloride on a product of general formula: R 4 Rs

<0 'OH

-R1 6

0 OH

  Wherein R4, R5, R8, R8 and R16 are defined as above by operating in an anhydrous organic solvent such as a halogenated aliphatic hydrocarbon such as dichloromethane 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 tertbutyldimethylsilyl chloride on a product of general formula: ## STR2 ##

O - OH

R86 0

  In which R4, R5, R8 and R8 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:

R4 R5

N0

(XVIII)

\ - Z

  In which R4, R5, R8 and R9 are defined as above Generally, the reaction is carried out by means of 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 of between 0 and 50 ° C. The products of general formula (XVIII) can be obtained by saponification of a product of general formula:

R4 R5

0 (XIX)

  Wherein R4, R5, R8 and R9 are defined as above and Ph represents a

phenyl radical.

  Generally, the saponification is carried out using a mineral base such as an alkali metal hydroxide (sodium hydroxide, potassium hydroxide) or an alkali metal carbonate

  (sodium carbonate, potassium carbonate) operating in a hydro-

  organic compound 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:

R8-CO-R9 (XX)

  in which R8 and R9 are defined as above, optionally in acetal form, on a product of general formula: ## STR2 ##

  wherein 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 by operating in an organic solvent such as an aromatic hydrocarbon such as benzene or toluene at a temperature between 0 and C. The products of general formula (XXI) can be obtained by saponification and then acetalization of triacetoxy-2a, 9a, cinnamoyl-5a-hydroxy-5

oxo-13-taxadiene-4 (20), 11.

  Generally, the saponification is carried out using a mineral base such as an alkali metal hydroxide or carbonate such as potassium carbonate, operating in an organic solvent chosen from aliphatic alcohols containing 1 to 4 carbon atoms such as such as ethanol, ethanol or isopropanol, and halogenated aliphatic hydrocarbons such as dichloromethane at a

  temperature between 0 and 50 C.

  Generally, the 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 cinnamoyl5a

  tetrahydroxy-13,2a, 9a, 10-oxo-13-taxadiene-4 (20), 11.

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

  on a product of general formula (XXI).

  Triacetoxy-2α, 9α, 10α-cinnamoyl-5α-hydroxy-11-oxo-13-taxadiene

  4 (20), 11 can be obtained according to the process described in the international application

WO 93/02064.

  The acid of general formula (V) in which R 11 and R 12 together form a heterocycle can be obtained by saponification of an ester of general formula: Ar COOR1 R-N o (XXIII)

-R1 3 R14

  in which Ar, R, R13 and R14 are defined as above and R15 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 alkali metal bicarbonate) in a 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 1 3

= O (XXIV)

R1 4

  wherein R13 and R14 are defined as previously in the form of a dialkyl-

  acetal or an enol alkylether on an ester of the general formula: R-NH / k.COOR1 (XXV)

Ar -

OH

  in which Ar, R and R15 are defined as above by operating in an inert organic solvent (aromatic hydrocarbon) in the presence of a strong mineral acid (sulfuric acid) or organic acid (p-toluenesulphonic acid optionally in the form of pyridinium salt) to 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:

H2 N ,, 0 COOR1 5

  Wherein Ar and R 15 are defined as above, by operating in an organic solvent (ester, halogenated aliphatic hydrocarbon) in the presence of a base

  mineral or organic at a temperature between 0 and 50 C.

  The product of general formula (XXVI) can be obtained by reducing an azide of general formula: ## STR5 ## in which Ar and R 15 are defined as above, by means of hydrogen in the presence of a catalyst such as palladium on black operating in a solvent

organic (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 of between 20 ° C. and the boiling point of the reaction mixture on an epoxide of general formula:

> (XXVIII)

  Ar COOR, in which Ar and R15 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:

OH O O

Ar> "N <O (XXIX) Hal, -I

R1 6 R 17

  in which Ar is defined as above, Hal represents a halogen atom, preferably a bromine atom, and R16 and R17, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical, at least one being an alkyl radical or a phenyl radical, by means of an alkaline alkoxide, optionally prepared in situ, in an inert organic solvent such as tetrahydrofuran at a temperature of

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:

0 0

? N_ .. (XXXI)

R1 6 R1 7

  in which Hal, R16 and R17 are defined as previously, previously

anionized.

  Generally, the reaction is carried out in an inert organic solvent chosen from ethers (ethyl ether) and halogenated aliphatic hydrocarbons (methylene chloride) at a temperature of between -80 and 25 ° C. in the presence of an amine

  Tertiary (triethylamine) and an enolising 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 the bromide of the acid

  bromoacetic acid, on the corresponding oxazolidinone.

  The acid of general formula (V) in which R1 represents a hydrogen atom and R12 represents a protecting group of the hydroxy function can be obtained by saponification of an ester of general formula: N COOR15 (XXXII)

O-R1 2

  in which Ar, R, R11, R12 and R15 are defined as above, under the conditions described above for the saponification of a product of formula

General (XXIII).

  The product of general formula (XXXII) can be obtained according to the usual methods of preparation of the ethers, and more particularly according to the processes

  described by J-N. DENIS et al., J. Org. Chem., E1.46-50 (1986).

  The product of general formula (XXVI) can also be obtained by hydrogenolysis of a product of general formula: ## STR2 ##

- (XXXIII)

A, COOR1 5

  Wherein Ar and R15 are defined as above and Ph represents an optionally substituted phenyl radical. Generally, the hydrogenolysis is carried out by means of hydrogen in the presence of catalyst. More particularly, palladium on carbon containing 1 to 10% by weight of palladium or dihydroxide is used as the catalyst.

  from palladium to 20% by weight of palladium.

  The hydrogenolysis is carried out in an organic solvent or in a mixture

  of organic solvents. It is advantageous to operate in the optional acetic acid

  associated with an aliphatic alcohol containing 1 to 4 carbon atoms such as a

  acetic acid-methanol mixture at a temperature between 20 and 80 C.

  Hydrogen required for hydrogenolysis can also be provided by a compound that liberates hydrogen by chemical reaction or thermal decomposition (ammonium formate). It is advantageous to operate under pressure

  of hydrogen of between 1 and 50 bar.

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

0 112 (XXXIV)

O - Ph ,,

CH3

  in which Ar and Ph are defined as above.

  It is particularly advantageous to perform an alcoholysis using an alcohol of formula R 15 -OH in which R 15 is defined as previously in

operating in acidic medium.

  Preferably, the alcoholysis is carried out by means of methanol in the presence of a strong mineral acid such as hydrochloric acid at a temperature close to

  reflux temperature of the reaction mixture.

  The product of general formula (XXXIV) can be obtained by saponification of an ester of general formula: ## STR5 ## in which Ar and Ph are defined as above and R 18 represents a alkyl, phenylalkyl or phenyl radical, followed by separation of the diastereoisomer

  3R, 4S of general formula (XXXII) other diastereoisomers.

  Generally, the saponification is carried out using a mineral or organic base such as ammonia, lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as a mixture of methanol-water or tetrahydrofuran-water at a temperature of

  temperature between -10 C and 20 C.

  The separation of the 3R, 4S diastereoisomer can be carried out by crystallization

  selectively 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: Ar. Nh Ph (XXXVI)

CH3

  in which Ar and Ph are defined as above, on an acid halide of general formula: R 18 -CO-O

(XXXVII)

  o) where R18 is defined as above and Y is an atom

  halogen such as bromine or chlorine.

  Generally, the reaction is carried out at a temperature of between 0 and C in the presence of a base chosen from aliphatic tertiary amines.

  (triethylamine) or pyridine in an organic solvent selected from hydrocarbons.

  optionally halogenated aliphatic bures (methylene chloride, chloroform) and

  aromatic hydrocarbons (benzene, toluene, xylenes).

  The product of general formula (XXXVI) can be obtained under the conditions similar to those described by M. Furukawa et al., Chem. Pharm. Bull.,

f2 (1), 181-184 (1977).

The new products of general formula (I) obtained by the implementation of the processes according to the invention can be purified according to known methods such as

  than crystallization or chromatography.

  According to the invention, the products of general formula (I) in which Ar, R, R2, R3 and R10 are defined as above, R6 represents a hydrogen atom and R7 represents an R'7-CO- radical in which R'7 represents an alkyl radical or a phenylalkyl radical of which the phenyl radical is optionally substituted can be obtained by esterification of a product of general formula: ## STR2 ##

HO - OCOR1 0

OCOR '7

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

R-N - R1

(XXXIX)

Ar -111 O-Rl 2H

HO - OCOR

= COR 7 1 0

OCOR '1?

  in which Ar, R, R4, R5, R'7, Ro10, R11 and R12 are defined as above, followed by the replacement of the protective groups R12 and / or R11 and R12 with hydrogen atoms and, optionally, hydrolysis of the acetal function -OC (R4) (Rs) -O- to obtain a product of general formula (I) in which R2 and

  R3 each represents a hydrogen atom.

  Generally, the esterification of the product of formula (XXXVII with the acid of general formula (V) is carried out under the conditions described previously for

  esterifying a product of general formula (IV) with an acid of general formula (V).

  Generally, the replacement of the protective groups R12 and / or R11 and R12 of the product of general formula (XXXIX) and the possible hydrolysis of the acetal function -O-C (R4) (Rs) -O- are carried out under the described conditions.

  previously for the product of general formula (VI).

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

1 HO O-- OCOR1 0

OCOR '7

  in which R4, R5, R'7 and Rj0 are defined as previously 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 R8 represents a hydrogen atom and Rg represents an alkyl or phenylalkyl radical whose phenyl nucleus is

optionally substituted.

  Generally, the oxidation is carried out using an oxidizing agent such as 2,3-dichloro-5,6-dicyanobenzoquinone in a hydro-organic medium such as a mixture

  water-dichloromethane at a temperature between 0 and 50 C.

  The new products of general formula (I) have remarkable biological properties In vitro, the measurement of the biological activity is carried out on tubulin extracted from porcine 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 microtubes

  tubulin is administered 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 Taxotere.

  The novel products of general formula (I) in which R 1 represents a radical of general formula (H) exhibit a significant inhibitory activity of abnormal cell proliferation and have therapeutic properties allowing the treatment of patients with pathological conditions associated with cell proliferation abnormal. Pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs, including, but not limited to, muscle, bone or connective tissue, skin, brain, lungs, sexual organs, lymphatic or renal systems, mammary or blood cells, liver, digestive system, pancreas and thyroid or adrenal glands. These pathological conditions may also include psoriasis, solid tumors, cancers of the ovary, breast, brain, prostate, colon, stomach,

  kidney or testes, Kaposi's sarcoma, cholangiocarcinoma, chorio-

  carcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanoma, multiple myeloma, chronic lymphocytic leukemia, acute or chronic granulocytic lymphoma. The new products according to the invention are particularly useful for the treatment of roveal 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 conditions

pathological.

  The products according to the invention can be administered to a patient according to different forms adapted to the chosen route of administration which, preferably, is

  the parenteral route. Parenteral administration includes administra-

  intravenous, intraperitoneal, intramuscular or subcutaneous More specifically

  Most preferred is intraperitoneal or intravenous administration.

  The present invention also includes the pharmaceutical compositions

  which contain at least one product of general formula (I) in a quantity

  sufficient for use in human or veterinary therapy. The components

  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

  emulsifiers, dyes, preservatives or stabilizers.

  The choice of adjuvants or excipients may be determined by the solubility and chemical properties of the product, the particular mode of administration and the

good pharmaceutical practices.

  For parenteral administration, solutions or suspensions are used.

  sterile aqueous or non-aqueous For the preparation of non-aqueous solutions or suspensions may be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as oleate d. 'ethyl. The aqueous sterile solutions may consist of a solution of a pharmaceutically acceptable salt dissolved in water. Aqueous solutions are suitable for intravenous administration in that the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. The sterilization can be performed by heating or by any other means that does not alter

not the composition.

  It is understood that all products entering the compositions

  according to the invention must be pure and non-toxic for the quantities used.

  The compositions may contain at least 0.01% of therapeutic product.

  actively active. The amount of active product in a composition is such that a suitable dosage may be prescribed. Preferably, the compositions are prepared in such a way that a unit dose contains from about 0.01 to 1000 mg.

  of active ingredient for parenteral administration.

  Therapeutic treatment can be performed concurently with other

  therapeutic treatments including antineoplastic

  monoclonal bodies, immunological therapies or radiotherapies or modifiers of biological responses. The modifiers of the responses include,

  but not limited to, lymphokines and cytokines such as

  kines, interferons (a, [or b) and TNF. Other chemotherapeutic agents useful in treating disorders due to abnormal proliferation of cells include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomusine, semustine and streptozocine, triazenes such as dacarbazine, antimetabolites such as folic acid analogues such as methotrexate, pyrimidine analogues such as fluorouracil and cytarabine, purine analogues such as mercaptopurine and thioguanine, natural products such as vinca alkaldides such as vinblastine, vincristine and

  sellers, epipodophyllotoxins such as etoposide and teniposide, anti-

  such as dactinomycin, daunorubicin, doxorubicin, wheat

  such as Lasparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as

  procarbazine, adrenocorticoid suppressors such as mitotane and amino

  glutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, estrogens such as diethylstilbestrol and ethynylestradiol, antiestrogens such as tamoxifen ,

  androgens such as testosterone propionate and fluoxymesterone.

  The doses used to carry out the methods according to the invention are those which allow a prophylactic treatment or a maximum of response

  therapeutic. The doses vary according to the form of administration, the particular product

  link selected and the specific characteristics of the subject to be treated. In general, the doses are those that are therapeutically effective for the treatment of disorders due to abnormal cell proliferation. The products according to the invention

  may be administered as often as necessary to achieve a therapeutic effect

  desired tick. Some patients can respond quickly to

  strong or weak and then require low or no maintenance doses.

  Generally, low doses will be used at the start of treatment and, if necessary,

  More and more doses will be administered until an optimum effect is achieved. For other patients it may be necessary to administer doses

  1 to 8 times a day, preferably 1 to 4 times, depending on the physiological

  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 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, still more

  specifically between 1 and 10 mg / kg. Intravenously, doses are usually

  preferably between 0.1 and 50 mg / kg and preferably between 0.1 and 5 mg / kg and more specifically between 1 and 2 mg / kg. It is understood that, in choosing the most appropriate dosage, the route of administration, the weight of the patient, his general health, his age and all the factors that may be taken into account must be taken into account.

  affect the effectiveness of the treatment.

  The following examples illustrate the present invention.

XEMPLEL1

  To a solution of 6 mg of 4-tert-butoxycarbonyl-3- (4-methoxyphenyl) phenyl-4-oxazolidinecarboxylate-5- (2R, 4S, SR) 4-acetoxy-4-methoxybenzoyloxyoxy-2-epoxy. 5p, 20-hydroxy-13-isopropylidene-9a, taxen-11-yl-13a in 0.9 cm3 of ethyl acetate maintained under argon and with stirring, added at a temperature 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 C. The solution is diluted with 10 cm3 of ethyl acetate. The organic phase is washed with 10 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. A yellow oil is obtained which is purified by chromatography. preparative on a plate, eluting twice with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction

  containing the product sought is extracted with a dichloromethane-

  methanol (90-10 by volume), filtered on sintered glass and then concentrated to dryness under

  reduced pressure (2.7 kPa) at 40 C. Thus 1 mg of tert-butoxy-

  3-carbonylamino-3-phenyl-2-hydroxy-2-propionate (2R, 3S) 4-acetoxy-4-methoxy-benzoyloxy-2-epoxy-5,5-hydroxy-1-hydroxy-O-isopropylidene-9a, 10P taxen-11-yl 13a in the form of a yellow oil, the characteristics of which are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3, 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-C13); 2.87 (d, J = 5.5, 1H: -11H 3); 3.90 (s, 3H: -O-CH 3); 4.18 and 4.31 (2d, J = 9, 1H each: -Ct12-O-20); 4.39 (d, J = 10, 1H: -H11 9); 4.62 (bs, 1H: -11 2 '); 4.69 (d, J = 10, 1H: -110); 4.95 (d, J = 9, 1H: -H 5); 5.30 (d, J = 10, 1H: -3 '); 5.66 (d, J = 10, 1H: -CO-N'H-); 5.75 (d, J = 5.5, 1H: -H11 2); 6.11 (broad t, J = 9, 1H: -H 13); 6.95 (d, J = 8.5, 2H: -11 aromatics in ortho -O-CH 3); 7.25-7.45 [mrt, 5H: -C6H5 at 3 '(-H 2

  at -11 (6)]; 8.05 (d, J = 8.5, 2H: -H11 aromatics in nmeta of -O-CH3).

  3-tert-butoxycarbonyl-3- (4-methoxyphenyl) -phenyl-4-oxazolidine

  4-acetoxy-4 (4-methoxybenzoyl) oxy-2a epoxy-513, hydroxy-1 [O-isopropylidene-9a, 103-taxen-11-yl-13a carboxylate-5- (2R, 4S, 5R) may be prepared as follows: To a solution of 10 mg of acetoxy-4a (4-methoxybenzoyl) oxy-2a epoxy-5, 3, 20, dihydroxy-11, 13a O-isopropylidene-9a, 10 [3-taxene-11 in 2 cm 3 of anhydrous toluene in the presence of 4A molecular sieve maintained under argon and with stirring, is added at a temperature of 20 C, 33 mg of acid

  tert-butoxycarbonyl-3 (4-methoxy) -phenyl-2-phenyl-4-oxazolidinecarboxylic-5-

  (2R, 4S, 5R), 17 mg of N, N'-dicyclohexylcarbodiimide and 5 mg of 4-dimethylamino-

  pyridine. The reaction medium is stirred for 1 hour 30 minutes at a temperature in the region of 90 ° C. After cooling, the solution is diluted with cm 3 of a mixture of ethyl ether-dichloromethane (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 plate chromatography, eluting twice with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction containing only the desired product is extracted with a dichloromethane-methanol mixture (90-10 by volume), filtered on sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. Thus 6 mg is obtained of

  tert-butoxycarbonyl-3 (4-methoxyphenyl) -2-phenyl-4-oxazolidinecarboxylate

  (2R, 4S, 5R) 4-acetoxy-4- (4-methoxybenzoyl) oxy-2α-epoxy-5,3,20-hydroxy-1,3-isopropylidene-9a, 103-taxene-11-yl-13a in the form of a paste brown, the characteristics of which are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl3, chemical shifts in ppm, coupling constants J in Hz): 1.55-1.70; 1.80 - 2.00 and 2.05 to 2.35 (4mt, respectively 1H-1H and 2H: -CH 2 -7 and -CH 2 -6); 2.04 and 2.21 (2mt, 1H each: -CH 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: -H11 9); 4.58 (d, J = 5, 5, 1H: -H 2 '); 4.63 (d, J = 10, 1H: -H 10); 4.89 (broad, J = 9, 1H: -H 5); 5.43 (d, J = 5.5, 1H: -H 3 '), 69 (d, J = 5.5, 1H: -H 2); 6, 15 (broad t, J = 9, 1H: -H 13); 6.35 (brs, 1H: -H '); 6.90 (d, J = 8, 5, 2H: -H aromatics in ortho -O-CH3 for -C6H5 at 5 '); 6.95 (d, J = 8.5, 2H: -f- aromatics ortho -O-CH3); from 7.25 to 7.45 [mt, 7H: -C6H5 in 3 '(-H 2 to -11H 6) and -H aromatics in meta of -O-CH3 for -C6H5 in

  5 ']; 7.98 (d, J = 8.5, 2H: -H aromatics in meta of -O-CH3).

  Acetoxy-4a (4-methoxybenzoyl) oxy-2a epoxy-5p, dihydroxy-13,13a isopropylidene-9a, 10P taxene-1 may be prepared in the following manner: A solution of 23mg of acetoxy 4a (4-methoxybenzoyl) oxy-2a epoxy-5p, 20-hydroxy-1-O-isopropylidene-9a, 10P oxo-13-taxene-11 in 2 cm3 of anhydrous toluene maintained under argon and with stirring, is added at

  a temperature of 0.degree. C., 38 .mu.l of diisobutylaluminum hydride.

  The reaction medium is stirred for 3 hours 30 minutes at a temperature of

  close to 0 C and then 38 i of diisobutylaluminium hydride.

  The reaction mixture is stirred for 17 hours at a temperature in the region of 20 ° C., then 76 μl of diisobutylaluminum hydride is added to a

temperature close to 0 C.

  After stirring for 6 hours at a temperature in the region of 20 ° C., 76 μl of diisobutylaluminum hydride are added, followed by a second portion of 76 μl of sodium hydride.

  diisobutylaluminum after 18 hours of stirring.

  The medium is then stirred for 4 days at a temperature in the region of C and then 3.5 cm3 of methanol are added. After stirring for 15 minutes, the insoluble material is filtered and the solvents are evaporated 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 desired product as well as the unreacted starting material are extracted with a dichloromethane-methanol mixture (90-10 by volume), filtered on sintered glass and then concentrated to dryness under reduced pressure (2.7 × kPa) at 40 ° C. 9 mg acetoxy-4a (4-methoxybenzoyl) oxy-2a epoxy-5S3,20 dihydroxy-1,13a O -isopropylidene-9a, 10 [taxene-11 in the form of an orange paste

  and 10 mg of unreacted starting material.

  4-acetoxy-4a (4-methoxybenzoyl) oxy-2a epoxy-513,20-dihydroxy-13,13a-isopropylidene-9a, 10-oxo-13-taxene-11 has the following characteristics: proton nuclear magnetic resonance spectrum ( 400 MHz, CDCl3, chemical shifts in ppm, coupling constants J in Hz): 1.18 (s, 3H: -CHI3 16 or 17); 1.45 (s, 3H: -CHI3 16 or 17); 1.53 and 1.60 [2s, 3H

  each: (-CH3) 2]; from 1.55 to 1.70 - 1.89 and from 2.10 to 2.35 (4mt, respectively 1H -

  1H and 2H: -CH2-7 and -CH12-6); 1.70 (s, 3H: -CH 3 19); 1.99 (brs, 3H: -CIH 18); 2.03 (d, J = 7 Hz, 1H: -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, 1H each: -CH 2 O-O-20); 4.39 (d, J = 10, 1H: -H 9); 4.73 (d, J = 10, 1H: -a 10); 4.85 (mt, 1H: -H 13); 4.98 (broad, J = 9, 1H: -H 5); 5.72 (d, J = 5.5, 1H: -H 2); 6, 96 (d, J = 8.5, 2H: -H aromatics ortho -O-CH3); 8.07

  (d, J = 8.5, 2H: -H aromatics in meta of -O-CH3).

  4α-acetoxy-4α (4-methoxybenzoyl) oxy-2α epoxy-51,20-hydroxy-11-isopropylidene-9a, [oxo-13-taxene-11 can be prepared in the following manner: A solution of 47 mg of acetoxy-4a epoxy-51,20 Oisopropylidene-9a,

  1015 O- (4-methoxy) benzylidene-11, 2a oxo-13-taxene-11 in 2 cm3 of dichloromethane

  methane kept stirring is added at a temperature of 20 C,

  0.10 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 54 μl of distilled water.

  The reaction medium is stirred for 24 hours at a temperature of 20 C and then diluted with a dichloromethane-ethyl ether mixture. The organic phase is washed twice with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.113 g of an oil is obtained. orange which is purified by preparative plate chromatography eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction containing only the desired product is extracted with a dichloromethane-methanol mixture (90-10 by volume), filtered on sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. This gives 37 mg of acetoxy-4a (4-methoxybenzoyl) oxy-2a epoxy-5p, 20-hydroxy-10-isopropylidene-9a, 10P 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; CDCl3 chemical shifts in ppm; J coupling constants in Hz): 1.32 (s, 3H: -CH3 16 or 17); 1.50 (s, 3H: -CH3 16 or 17); from 1.50 to 1.70 1.89 and from 2.05 to 2.35 (3mt, respectively 1H -1H and 2H: -CH2-7 and -CH26); 1.58 [s, 6H: (-CH3) 2]; 1.73 (s, 3H: -CH 3 19); 1.90 (s, 1H: -Oa in 1); 1.98 (s, 3H: -CH3 18); 2.18 (s, 3H: -CO-CH 3); 2.65 and 2.89 (2d, J = 20, 1H each: -CH 2 -14); 2.98 (d, J = 5.5, 1H: -H 3); 3.90 (s, 3H: -O-Cl3); 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: -a 10); 4.95 (broad d, J = 9, 1H: -a 5); 5.83 (d, J = 5.5, 1H: -H 2); 6.98 (d, J = 8.5, 2H: -H aromatics

  ortho -O-CH3); 8.05 (d, J = 8.5, 2H: -a aromatics in meta of -OCH3).

  Epoxy-4a acetoxy-5p, 20-O-isopropylidene-9a, [3 O- (4-methoxy) benzylidene-1 [1,2a] oxo-13-taxene-11 can be prepared in the following manner: A solution of 48 mg of epoxy-51,20-hydroxy-4a-Oisopropylidene-9a, 103 O- (4-methoxy) benzylidene-1p, 2a oxo-13-taxene-11 in 7 cm3 of anhydrous dichloromethane maintained under argon atmosphere and under After stirring, 117 ml of acetic anhydride and 109 mg of 4-dimethylaminopyridine are added at a temperature of 20 C. The reaction medium is stirred for one day at a temperature in the region of 50 ° C. and then 60 μl of acetic anhydride and 50 mg of 4-dimethylaminopyridine are added again. The reaction medium is stirred for a further day at a temperature in the region of 50 ° C. and then allowed to cool to a temperature in the region of 20 ° C.. It is diluted with dichloromethane and the organic phase is washed 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. 77 mg of a yellow oil are obtained which is purified on a preparative plate, eluting in a cyclohexane-acetate mixture. ethyl (60-40 by volume). The fraction containing only the desired product is extracted with a dichloromethane-methanol mixture (90-10 by volume), filtered on sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. This gives 47 mg epoxy-5p acetoxy-4a, 20 O-isopropylidene-9a, 10l3 O- (4-methoxy) benzylidene-13, 2a 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, CDC13 chemical shifts in ppm, J coupling constants in Hz): 1.33 (s, 3H: -CH3 16 or 17); 1.48 (s, 3H: -CH3 16 or 17); 1.54 and 1, 66 [2s, 3H each: (-CH3) 2]; from 1.50 to 1.70 - from 1.85 to 2.05 and from 2.05 to 2.35 (3mt, respectively 1H - 1H and 2H: -CH2-7 and -CH2-6); 1.68 (s, 3H: -CH 3 19); 1.95 (s,

  3H: -CH3 18); 2.03 (s, 3H: -CO-CH 3); 2.55 and 2.64 (2d, J = 20, 1H each: -CH2-

  14); 2.63 (d, J = 5.5, 1H: -H 3); 3.84 (s, 3H: -O-CH 3); 4.32 (d, J = 5.5, 1H: -a 2); 4.35 (d, J = 10, 1H: -a 9); 4.58 (ab limit, J = 9, 2H: -CH 2 O- 20); 4.75 (d, J = 10, 1H: -H 10); 4.97 (broad, J = 9, 1H: -H 5); 5.84 (s, 1H: -O-CH-O-); 6.93 (d, J = 8.5, 2H: -H aromatics ortho -O-CH3); 7.38 (d, J = 8.5, 2H: -H aromatics

in meta of -O-CH3).

  The epoxy-5,20-hydroxy-4a O-isopropylidene-9a, 10 [3 O- (4-methoxy) benzylidene-13,2a oxo-13-taxene-1 may be prepared in the following manner: A solution of 119 mg of O- (4-methoxy) benzylidene-1113,2a dihydroxy-4a, 5-methylsulphonyloxy-5-O-isopropylidene-9a, 1013 oxo-13-taxene-11 in 3.7 cm3 of butanone maintained under argon atmosphere and while stirring, 564 mg of tetra-n-butylammonium acetate are added at a temperature of 85 ° C. The reaction medium becomes orange and is stirred overnight at a temperature in the region of 85 ° C. and then diluted with ethyl acetate. The organic phase is washed with a 0.1N aqueous solution of hydrochloric acid and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 178 mg of an orange oil are obtained which is purified by preparative plate chromatography, eluting in a cyclohexane-ethyl acetate mixture (60-40 by volume). The fraction containing only the desired product is extracted with a dichloromethane-methanol mixture (90-10 by volume), filtered on sintered glass and then concentrated to dryness under reduced pressure (2.7 kPa) at 400C. This gives 67 mg

  epoxy-5p, 4-hydroxy-4a-O-isopropylidene-9a, 103 O- (4-methoxy) benzylimide

  dene-1p, 2a oxo-13-taxene-11 in the form of a white powder whose characteristics are as follows: proton nuclear magnetic resonance spectrum (400 MHz, chemical CDC13 shift in ppm, coupling constants J in Hz) : 1.15-1.30 and 1.90-2.20 (2mt, respectively 1H and 3H: -C112-7 and -CH2-6); 1.39 (s, 3H: -CH3 16 or 17); 1.48 (s, 3H: -CH3 16 or 17); 1.54 and 1.63 [2s, 3H each: (-CH3) 2]; 1.70 (s, 3H: -CH 3 19); 1.92 (d, J = 5.5, 1H: -H 3); 2.06 (s, 3H: -CIH3 18); 2.72 (s, 1H: -O 10 O 4); 2.73 and 3.17 (2d, J = 20, 1H each: -CH214); 3.83 (s, 3H: -O-CH 3); 4.33 and 4.66 (2d, J = 8.5, 1H each: CH12-O20); 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, J = 9, 1H: -H 5); 5.82 (s, 1H: -O-CH-O-); 6.93 (d, J = 8.5, 2H: -H aromatics in

  ortho of -O-CH3); 7.33 (d, J = 8.5, 2H: -H aromatics in meta of -OCH3).

  O- (4-methoxy) benzylidene-13.2α, dihydroxy-4α, methylsulfonyl-

  oxy-5a O-isopropylidene-9a, [oxo-13-taxene-11 can be prepared in the following manner:

  To a solution of 0.27 g of O- (4-methoxy) benzylidene-13.3,2a tert-butyl-

  dimethylsilyloxy-4-hydroxy-4α-methylsulfonyloxy-5α-O-isopropylidene-9a, [3 oxo-13-taxene-1 in 5 cm3 of anhydrous tetrahydrofuran with stirring is added at a temperature of 20 C, 136 mg of tetrahydrofluoride. n-butylammonium trihydrate. The reaction medium changes from yellow to orange and is stirred for one hour at a temperature in the region of 20 ° C. and then diluted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at C. 0.264 g of an orange oil is obtained. 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 desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C., thus obtaining 0.209 g of O- (4-methoxy) benzylidene-1p, 2a dihydroxy-4a, methylsulfonyloxy-5a-O-isopropylidene-9a, [3 oxo-13-taxene-11 in the form of a white powder whose characteristics are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3 chemical shifts in ppm; coupling constants J in Hz): 1.19 (s, 3H: -CH3 16 or 17); 1.42 (s, 3H: -CH3 16 or 17); 1.47 and 1.52 [2s, 3H each: (-CH3) 2]; from 1.55 to 1.75 - 1.91 and 2.05 (3mt, respectively 2H-1H and 1H: -CHI2-7 and -CH2-6); 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 -OI); 2.67 (d, J = 5.5, 1H: -H 3); 2.85 and 3.35 (2d, J = 20, 1H each: -CH 2 -14); 2.98 (s, 3H: -OSO 2 -CH 3); 3.62 (s, 1H: -OH 4); 3.66 and 4.04 (2dd, respectively J = 11 and 10.5 then J = 11 and 3.5, 1H each: -CHI2-OH); 3.85 (s, 3H: -O-CH 3); 4.23 (d, J = 10, 1H: -H 9); 4.34 (d, J = 5.5, 1H: -H 2); 4.85 (d, J = 10, 1H: -H 10); 4.95 (brs, 1H: -H 5); 5.81 (s, 1H: -O-CH-O-); 6.93 (d, J = 8.5, 2H: -H aromatics ortho -O-CH3); 7.37 (d, J = 8.5, 2H: -H aromatics

in meta of -O-CH3).

  O- (4-methoxy) benzylidene-1p, 2a-tert-butyldimethylsilyloxy-4-hydroxy-methylsulfonyloxy-5α-O-isopropylidene-9a, 103 oxo-13-taxene-11 can be prepared in the following manner: A solution of 0.374 g of O- (4-methoxy) benzylidene-11,2a-tert-butyldimethylsilyloxy-dihydroxy-4a, 5a O-isopropylidene-9a, 10b, oxo-13-taxene-11 in a mixture of 36.6 cc of pyridine anhydrous and 7.3 cm3 of anhydrous dichloromethane in the presence of molecular sieve 4 maintained under an argon atmosphere and with stirring, 258 μl of mesyl chloride are added at a temperature in the region of 0 ° C. The reaction mixture is allowed to rise to a

  temperature close to 20 C and 14 mg of 4-dimethylaminopyridine 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 acidic pH and 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 mixture cyclohexane-ethyl acetate (60-40 by volume). 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- (4-methoxy) benzylidene-1g, 2-tert-butyldimethylsilyloxy are thus obtained. 4-hydroxy-4α-methylsulfonyloxy-5α-O-isopropylidene-9α, 10O-oxo-13-taxene-11 in the form of white crystals, the characteristics of which are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3 chemical shifts in ppm) coupling constants J in Hz): -0.18 and -0.04 [2s, 3H each: - Si (CH3) 2]; 0.78 [s, 9H: -Si-C (CHI3) 3]; 1.12 (s, 3H: -CH3 16 or 17); 1.38 (s, 3H: -CH3 16 or 17); 1.46 and 1.51 [2s, 3H each:

  (-CH13) 2]; from 1.60 to 1.75 - 1.88 and 2.04 (3mt, respectively 2H - 1H and 1H: -CHI2-

  7 and -CH 2 -6); 1.66 (s, 3H: -CH 3 19); 2.11 (s, 3H: CH13 18); 2.63 (d, J = 4.5, 1H: -113); 2.71 and 3.75 (2d, J = 20, 1H each: -CHI2-14); 2.98 (s, 3H: -OSO 2 -CHI 3); 3.51 (s, 1H: -OH 4); 3.58 and 4.15 (2d, J = 11, 1H each: -CH 2 -O-Si-); 3.83 (s, 3H: -O-CH 3); 4.24 (d, J = 4.5, 1H: -H 2); 4.26 (d, J = 10, 1H: -H 9); 4.81 (brs, 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 aromatics ortho -O-CH3); 7.38 (d, J = 8.5, 2H: -H aromatics in meta

-O-CH3).

  O- (4-methoxy) benzylidene-13,2a tert-butyldimethylsilyloxy-dihydroxy-4a, 5a O-isopropylidene-9a, [oxo-13-taxene-11 can be prepared in the following manner: A solution of 0.26 g of O- (4-methoxy) benzylidene-1B, 2a trihydroxy-4a, 5a, 20-O-isopropylidene-9a, 10-oxo-13-taxene-11 in 14 cm3 of anhydrous dimethylformamide maintained under argon atmosphere and with stirring, 0.171 g of imidazole and then 0.393 g of toluene are added at a temperature in the region of 20 ° C.

  tert-butyldimethylsilane chloride.

  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.degree. 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-cyclohexane mixture. ethyl acetate (70-30 by volume). The fractions containing only the desired product are combined and concentrated to dryness under pressure (2.7 kPa) at 40 C. 0.32 g of O- (4-methoxy) benzylidene-13,2a tert-butyldimethylsilyloxy are thus obtained. 4-dihydroxy-4a, O-isopropylidene-9a, [oxo-13-taxene-11 in the form of a yellow oil, the characteristics of which are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3 chemical shifts in ppm, coupling constants J in Hz): -0.21 and -0.07 [2s, 3H each: - Si (CH13) 2]; 0.75 Ls, 9H: -Si-C (ClI3) 3]; 1.07 (s, 3H: -CH3 16 or 17); 1.36 (s, 3H: -CH3 16 or 17); 1.46 and 1.50 [2s, 3H each:

  (-CH13) 2]; 1.51 - from 1.55 to 1.75 and 1.88 (3mt, respectively 1H - 2H and 1H: -C12-

  7 and -CH12-6); 1.65 (s, 3H: -CH 3 19); 2.06 (s, 3H: -CHI3 18); 2.65 and 3.84 (2d, J = 1H each: -CII2-14); 2.66 (d, J = 5, 1H: -H 3); 2.75 (brs, 1H: -10 5); 3.45 and 4.18 (2d, J = 10, 1H each: -CHII2-O-Si-); 3.59 (brs, 1H: -11H 5); 3.72 (s, 1H: -1OH 4); 3.82 (s, 3H: -O-ClCl 3); 4.23 (d, J = 5, 1H: -11 2); 4.26 (d, J = 10, 1H: -119); 4.85 (d, J = 10, 1H: -H11); 5.74 (s, 1H: -O-CHII-O-); 6.88 (d, J = 8.5, 2H: -H11 aromatic ortho -O-CH3); 7.39 (d, J = 8.5, 2H: -11 aromatics in meta

-O-CH3).

  O- (4-methoxy) benzylidene-1p, 2a trihydroxy-4a, 5a, 20 O-isopropyl-

  lidene-9a, 1013 oxo-13-taxene-1 may be prepared in the following manner: To a solution of 0.626 g of O- (4-methoxy) benzylidene-1 [, 2a-hydroxy-5a-O-isopropylidene-9a, In a mixture of 8.9 cm 3 of tetrahydrofuran and 4.4 cm 3 of distilled water maintained under an argon atmosphere and with stirring, the mixture is added at a temperature in the region of 12 ° C (13-oxadipadien-4 (20)). C., 2.29 g of 4-methyl-4-oxide morpholine monohydrate followed by 1 cm 3 of tetroxide

  of osmium at 2.5% w / w in tert-butanol.

  The reaction mixture is stirred for 24 hours at a temperature in the region of 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 sintered glass filled with celite. The filtrate is neutralized with a 0.1N aqueous solution of hydrochloric acid 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 acidic pH, then once with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.68 g of crude reaction product 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-cyclohexane mixture. ethyl acetate (80-20 by volume). The fractions containing only the product sought on the one hand, and that containing only the starting material on the other hand are combined and concentrated to dryness under reduced pressure (2.7 kPa) at C. This gives 0.273 g of O- (4-methoxy) benzylidene-13.3α, trihydroxy-4α, α, 20-O-isopropylidene-9a, 10l3 oxo-13-taxene-11 in the form of a powder

  white and 0.188 g of O- (4-methoxy) benzylidene-1p, 2a-hydroxy-5a isopro-

  pylidene-9a, 103 oxo-13-taxadiene-4 (20), 11 unreacted.

  O- (4-methoxy) benzylidene-13,2a trihydroxy-4a, 5a, 20-O-isopropylidene

  dene-9a, 103 oxo-13-taxene-11 has the following characteristics: proton nuclear magnetic resonance spectrum (400 MHz, chemical shift CDC13 in ppm, coupling constants J in Hz): 1.16 (s, 3H: - CH3 16 or 17); 1.40 (s, 3H: -CH3 16 or 17); 1.47 and 1.51 [2s, 3H each: (-CH 3) 2]; 1.45 to 1.75 and 1.86 (2mt, respectively 3H and 1H: CH 2 -7 and -CHI 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 -OJ); 2.45 (brs, 1H: -OH 5); 2.75 (d, J = 5.5, 1H: -H 3); 2.80 and 3.42 (2d, J = 20, 1H each: -CH 2 -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 (brs, 1H: -H 5); 3.84 (s, 3H: O-CH 3); 4.23 (d, J = 10, 1H: -H 9); 4.34 (d, J = 5.5, 1H: -Hi 2); 4.85 (d, J = 10, 1H: -H 10); 5.82 (s, 1H: -O-CH-O-); 6.93 (d, J = 8.5, 2H: -H aromatics ortho -O-CH3); 7.37 (d, J = 8.5, 2H: -H aromatics in meta of the

-O-CH3).

  O- (4-methoxy) benzylidene-13,2a-hydroxy-6α-isopopylidene-9a, 103 oxo-4-taxadiene (20), 11 can be prepared in the following manner: To a solution of 3.04 g of O- (4-methoxy) benzylidene-1 [3,2a cinnamoyl-5a] -isopropylidene-9a, 10 [oxo-13-taxadiene-4 (20), 11 in 220 cm3 of tetrahydrofuran maintained under argon and with stirring, at a temperature in the region of 20 ° C., 40 cm 3 of a 30% solution of sodium hydroxide is added. The reaction mixture is stirred for 48 hours under 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 matter formed is solubilized and the aqueous phase is extracted with water. ethyl acetate. The organic phase is washed 4 times with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 2.52 g are obtained. a pale yellow meringue 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-ethyl acetate mixture (75-25 by volume) . Fractions containing only the desired product are combined and concentrated to dryness under pressure

reduced (2.7 kPa) to 40 C.

  There is thus obtained 2.04 g of O- (4-methoxy) benzylidene-13.2α-hydroxy-5α-O-isopropylidene-9a, 103 oxo-13-taxadiene-4 (20), 11 in the form of a white powder as well as 0.286 g of O- (4-methoxy) benzylidene-13,2a cinnamoyl-5a

  O-Isopropylidene-9a, 103 oxo-13-taxadiene-4 (20), unreacted.

  O- (4-methoxy) benzylidene-1,2a-hydroxy-5a-O-isopropylidene-9a, [3-oxo-13-taxadiene-4 (20), 11 has the following characteristics: proton nuclear magnetic resonance spectrum ( 400 MHz, CDCl 3 chemical shifts in ppm, coupling constants J in Hz): 1.11 (s, 3H: -CH3 16 or 17); 1.36 (s, 3H: -CH 3 16 or 17); 1.49 and 1.53 [2s, 3H each: (-CH3) 2]; from 1.60 to 1.85 (mt, 4H: -CH 2 -7 and -CH 2 -6); 1.69 (s, 3H: -CIH3 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 (brs, 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 (broad 2s, 1H each: = CH12); 5.75 (s, 1H: -O-CH-O-); 6.90 (d, J = 8.5, 2H: -H aromatics in ortho

  -O-CH3); 7.37 (d, J = 8.5, 2H: -H aromatics in meta of -O-CH 3).

  O- (4-methoxy) benzylidene-1H, 2α-cinnamoyl-5α-O-isopropylidene-9a, 101P oxo-13-taxadiene-4 (20), 11 can be prepared in the following manner: A solution of 7.56 5 g of cinnamoyl-5α-dihydroxy-1,3,2a-isopropylidene-9a, 101 oxo-13-taxadiene-4 (20), 11 in 600 cm3 of anhydrous toluene maintained under argon and with stirring in the presence of molecular sieve 4, is added. at a temperature of 20 C, 4.8 cm3 of

  (4-methoxy) benzaldehyde dimethylacetal and then 0.537 g of paratoluene

sulphonic monohydrate.

  The reaction mixture is stirred for 2 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 reaction product 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). 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 of 9 cm in diameter, eluting in a cyclohexane mixture. ethyl acetate (80-20 by volume). Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at C. There is thus obtained 5.63 g of O- (4-methoxy) benzylidene-11 (, 2a cinnamoyl-5a O-isopropylidene-9a, 10-oxo-13-taxadiene (20), 11 in the form of a white powder whose characteristics are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3 chemical shifts in ppm coupling constants J in Hz): 1.17 (s, 3H: -CII3 16 or 17), 1.40 (s, 3H: -CH3 16 or 17), 1.49 and 1.56 [2s, 3H; each: (- CII3) 2] 1.58 - 1.75 to 1.90 and 2.02 (3mt, respectively 1H-2H and 1H: -CHI2-7 and -CH126), 1.70 (s, 3H: -CII3 19), 2.17 (s, 3H: -CHII3 18), 2.81 (ab limit, J = 20, 2H: -CH2- 14), 3.22 (d, J = 5.5 1H: -i 3); 3.81 (s, 3H: -O-Cl-13); 4.34 (d, J = 10, 1H: -H 9); 4.39 (d, J = 5.5; 1H: -H 2), 4.94 (d, J = 10, 1H: -II 10), 5.27 and 5.63 (broad 2s, 1H each: = CII 2), 5.36 (brs, 1H: -H 5); 5.76 (s, 1H: -O-CII-O-); 6.36 and 7.64 (2d; , J = 16, 1H each: -CH = CH-); 6.90 (d, J = 8.5, 2H: -H aromatics ortho -O-CH3); 7.37 (d, J = 8.5, 2H: -H aromatics in meta of -O-CH3); from 7.35 to 7.50 (mt, 3H: -H aromatics in meta and in para of the double

  bond); 7.74 (d, J = 7.5, 2H: -H aromatics in ortho of the double bond).

  Cinnamoyl-5a dihydroxy-1,2a-O-isopropylidene-9a, 10P oxo-13-taxadiene-4 (20), 11 can be prepared in the following manner: To a solution of 3.21 g of cinnamoyl-5a 13-tetrahydroxy , 2a, 9a, 1013 oxo-13-taxadiene-4 (20), 11 crude in 157 cm3 of anhydrous acetone maintained under argon and with stirring, added at a temperature of 20 C,

  0.253 g of para-toluenesulphonic acid monohydrate.

  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). C. 5.50 g of a white meringue is 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-acetate mixture. of ethyl (80-20 by volume). Fractions containing only the desired product are combined and concentrated to dryness under pressure

reduced (2.7 kPa) to 40 C.

  2.66 g of cinnamoyl-Sa dihydroxy-1,2a-isopropanol are thereby obtained.

  pylidene-9a, 10P oxo-13-taxadiene-4 (20), 11 in the form of white crystals, the characteristics of which are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl3 chemical shifts in ppm, coupling constants) in Hz): 1.20 (s, 3H: -CH3 16 or 17); 1.38 (s, 3H: -CH3 16 or 17); 1.44 and 1.52 [2s, 3H each: (-CH3) 2]; 1.57 - from 1.70 to 1.85 and 2.00 (3mt, respectively 1H-2H and 1H: -CH2-7 and -CH26); 1.64 (s, 3H: -CH 3 19); 2.12 (s, 3H: -CH 3 18); 2.58 (d, J = 7.1H: -OH 2); 2.70 (ab limit, J = 20, 2H: -CH 2 -14); 3.22 (d, J = 7, 1H: -H 3); 3.68 (brs, 1H: -OH 1); 4.07 (t, J = 7, 1H: -H 2); 4.29 (d, J = 10, 1H: -H 9); 4.93 (d, J = 10, 1H: -H 10); 5.33 (brs, 1H: -H 5); 5, 40 and 5.47 (2s wide, 1H each: = CH 2); 6.36 and 7.64 (2d, J = 16, 1H each: -CH = CH-); from 7.35 to 7.50 (mt, 3H: -H aromatics in meta and para of the double bond); 7.75 (d, J = 7.5, 2H: -H

  aromatic in ortho of the double bond).

  Cinnamoyl-5α-tetrahydroxy-1,313,2a, 9a, 10β-oxo-13-taxadiene-4 (20), 11 can be prepared in the following manner: 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-2a, 9a, 1013 cinnamoyl-5a is added at a temperature in the region of 20 ° C.

  hydroxy-1-oxo-13-taxadiene (20), 11 then 54 cm3 of anhydrous dichloromethane.

  The reaction mixture is stirred for 5 hours at a temperature of 20 C, then 18 cm3 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 sulphate. , filtered and then concentrated to dryness under

  reduced pressure (2.7 kPa) at 40 C.

  There is thus obtained 3.71 g of cinnamoyl-5a tetrahydroxy-lt, 2a, 9a, 103

oxo-13-taxadiene-4 (20), 11 crude.

EXEMPLE.2

  By operating as in Example 1, but starting from 18 mg of 4α-acetoxy-13α-hydroxy epoxy-5p, 20-O-isopropylidene-9a, 10P O-benzylidene-11, 2a taxene-11 and 65 mg of 3- tert-butoxycarbonyl-3- (4-methoxyphenyl) -phenyl-4-oxazolidinecarboxylic acid (2R, 4S, 5R) gives 29 mg of 3- (4-methoxyphenyl) -4-phenyloxazolidinecarboxylate; -5 (2R, 4S, 5R) 4-acetoxy-O-benzylidene-1α, 2α-epoxy-5α, 3-isopropylidene-9α, 10β-taxene-11-yl-13a in the form of an orange paste whose characteristics are as follows proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3, at a temperature of 323 K, chemical shifts in ppm, coupling constants J in Hz): 1.55 to 1.75 -1.90 to 2, 05 and 2.05 to 2.30 (3mt, respectively 1H-1H and 2H: -CH2-7 and -CH2-6); 1.75 and 2.02 (2mt, 1H each, -CH 2 -14); 2.43 (d, J = 5.5 Hz, 1H: -i 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 (brs, 2H, -CH 2 -O-20); 4.58 (d, J = 10, 1H: -a 10); 4.95 (d, J = 9, 1H: -H 5); 5.48 (d, J = 4, 1H: -H 3 '); 5.81 (s, 1H: -O-CH-O-); 6.07 (broad t, J = 9, 1H: -13); 6.90 (d, J = 8.5, 2H: -H ortho-aromatic aromatics of -OCH3 for -C6H5 at 5 '); from 7.25 to 7.50 (mt, 12H: -a

  aromatics and aromatics in meta of -OCH3 for -C6H5 in 5 ').

  Acetoxy-4a-hydroxy-13a epoxy-5p, 20-O-isopropylidene-9a, 10O3 Obenzylidene-11,2a taxene-11 can be prepared in the following manner: By operating as in Example 1, but starting from 31 mg of acetoxy-4a epoxy-53,20-O-isopropylidene-9a, 103 O-benzylidene-13.3,2a oxo-13-taxene, 20 mg of acetoxy-4a-hydroxy-13a-epoxy-513,20-isopropylidene are obtained. 9a, 10O-O-benzylidene-1B, 2a taxene-11 in the form of a gray paste as well as 9mg of epoxy-4a acetoxy-5S [, 20-O-isopropylidene-9a, 10 [3

  O-Benzylidene-13,2a oxo-13-taxene-11 unreacted.

  4α-acetoxy-13α-hydroxy-epoxy-51,20-O-isopropylidene-9a, 1013 O-ben-

  zylidene-1i, 2a taxene-11 has the following characteristics: proton nuclear magnetic resonance spectrum (400 MHz, CDCl3 chemical shifts in ppm, coupling constants J in Hz): 1.23 (s, 3H: -CH3 16 or 17); 1.45 (s, 3H: -CH3 16 or 17); 1.50 and 1.64 [2s, 3H each: (-CHI3) 2]; from 1.55 to 1.75 - from 1.90 to 2.05, 2.15 and 2.32 (4mt, 1H each: -CHI2-7 and -CH12-6); 1.68 (s, 3H: -CH 3 19); 1.78 and 2.20 (2dd, respectively J = and 6 then J = 15 and 8, 1H each, -CH 2 -14); 1.88 (d, J = 8, 1H: -OH 13); 1.95 (brs, 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: -H11 2); 4.25 (d, J = 10, 1H: -H 9); 4.58 (brs, 2H, -CIH2-O-20); 4.67 (d, J = 10, 1H: -H 10); 4.73 (mt, 1H: -H 13); 5.00 (d, J = 9, 1H: -H 5); 5.83

  (s, 1H: -O-CHl-O-); from 7.35 to 7.55 (mt, 5H: -H aromatics).

  Acetoxy-4a epoxy-5fp, O -isopropylidene-9a, O -benzylidene-11S, 2a oxo-13-taxene-1 may be prepared in the following manner: By operating as in Example 1, but at From 0.292 g of epoxy-5,33,20-hydroxy-4α-O-isopropylidene-9a, 10P O-benzylidene-13,2a oxo-13-taxene-11, one

  0.255 g of acetoxy-4a epoxy-51,20 O-isopropylidene-9a, 100 O-benzyl-

  lidene-11, 2a oxo-13-taxene-11 in the form of a white powder whose characteristics are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3, chemical shifts in ppm, coupling constants J in Hz ): 1.34 (s, 3H: -CH3 16 or 17); 1.48 (s, 3H: -CH3 16 or 17); from 1.50 to 1.70, from 1.85 to 2.20 and 2.30 (3mt, respectively 1H-2H and 1H: -CH 2 -7 and -CH 2 -6); 1.55 and 1.67 [2s, 3H each: (-CH 3) 2]; 1.68 (s, 3H: -CH 3 19); 1.94 (s, 3H: -CHI 18); 2.03 (s, 3H: -CO-CH 3); 2.52 and 2.61 (2d, J = 20, 1H each: -CH 2 -14); 2.63 (d, J = 5.5, 1H: -H 3); 4.36 (d, J = 10, 1H: -H 9); 4.37 (d, J = 5.5, 1H: -H 2); 4.62 (br s, 2H, -CH 2 -O-20); 4.76 (d, J = 10, 1H: -H 10); 4.97 (broad, J = 9, 1H: -H 5); 5.90 (s,

  1H: -O-CH-O-); from 7.35 to 7.50 (mt, 5H: -H aromatics).

  The epoxy-515,20-hydroxy-4a-O-isopropylidene-9a, 10B-O-benzylidene-11B, 2a oxo-13-taxene-11 can be prepared in the following manner: By operating as in Example 1, but starting from 0.80 g

  O-Benzylidene-11, 2α-dihydroxy-4α, 5α-methylsulfonyloxy-5-O-isopropylidene,

  9a-dene, 1015 oxo-13-taxene-11, 0.404 g of epoxy-5β1,20-hydroxy-4α-O-isopropylidene-9a, 10 [O-benzylidene-1, B, 2a oxo-13-taxene-11 under form of a white powder whose characteristics are the following: - proton nuclear magnetic resonance spectrum (300 MHz, CDC13 chemical shifts in ppm, coupling constants J in Hz):

  from 1.15 to 1.30 and from 1.90 to 2.20 (2mt, respectively 1H and 3H: -CH2-7 and -CH2-

  6); 1.35 (s, 3H: -CH3 16 or 17); 1.45 (s, 3H: -CI3 16 or 17); 1.52 and 1, 65 [2s, 3H each: (-CH3) 2]; 1.68 (s, 3H: -CII 3 19); 1.92 (d, J = 5.5, 1H: -H 3); 1.96 (s, 3H: -CHI 18); 2.66 and 3.12 (2d, J = 20, 1H each: - CH214); 2.70 (s, 1H: -OH 4); from 4.20 to 4.35 [mt, 3H: - (CHI) H-O-20 -H 9 and -H 2]; from 4.60 to 4.70 (mrt, 2H: -H 10 and - (CH) H-O-20); 4.79 (d, J = 9, 1H: -H 5); 5.84 (s, 1H: -O-CH-O-); from 7.30 to

7.45 (mt, 5H: -H1 aromatics).

  O-Benzylidene-1 [1,2a dihydroxy-4a, 5-methylsulfonyloxy-5-O-isopropanol

  pylidene-9a, [5 oxo-13-taxene-11 can be prepared in the following manner: By operating as in Example 1, but from 1.51 g

  of O-benzylidene-11, tert-butyldimethylsilyloxy-4-hydroxy-4-methylsulfonyl

  nyloxy-5α-O-isopropylidene-9a, 105 oxo-13-taxene-11, 0.875 g is obtained

  O-benzylidene-11 [, 2a-dihydroxy-4a, 5-methylsulfonyloxy-5-O-isopropyl-

  lidene-9a, 103 oxo-13-taxene-11 in the form of a white meringue whose characteristics are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl3 chemical shifts in ppm, coupling constants J in Hz) 1.19 (s, 3H: -CH3 16 or 17); 1.42 (s, 3H: -CH3 16 or 17); 1.47 and 1.52 [2s, 3H each: (-CH3) 2]; from 1.55 to 1.80 1.91 and 2.05 (3mt, respectively 2H-1H and 1H: -CH2-7 and -CH2-6); 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, 1H 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 2 -OH); 4.24 (d, J = 10, 1H: -H 9); 4.36 (d, J = 5.5, 1H: -H 2); 4.86 (d, J = 10, 1H: -H 10); 4.95 (brs, 1H: -H 5); 5.88 (s, 1H: -O-CH-O-); from 7.40 to 7.50 (mt, 5H: -H aromatics).

  O-Benzylidene-1β, 2α-tert-butyldimethylsilyloxy-20-hydroxy-4α-methyl

  Sulfonyloxy-5a-O-isopropylidene-9a, 10P oxo-13-taxene-11 can be prepared in the following manner: By operating as in Example 1, but starting at 1.58 g

  O-benzylidene-1f, 2a-tert-butyldimethylsilyloxy-4-dihydroxy-4a, isotropic

  pylidene-9a, 103 oxo-13-taxene-11, 1.51 g of O-benzylidene-11, 2a is obtained.

  tert-butyldimethylsilyloxy-20-hydroxy-4α-methylsulfonyloxy-5α-isopropyl

  dene-9a, 10P oxo-13-taxene-11 in the form of a yellowish meringue with the following characteristics: - proton nuclear magnetic resonance spectrum (400 MHz, CDC13 chemical shifts in ppm, coupling constants J in Hz) : -0.18 and -0.05 [2s, 3H each: Si (CH3) 2]; 0.78 [s, 9H: -Si-C (CH13) 3]; 1.14 (s, 3H: -CH3 16 or 17); 1.39 (s, 3H: -CH3 16 or 17); 1.46 and 1.51 [2s, 3H each:

  (CH3) 2]; from 1.60 to 1.75 - 1.88 and 2.04 (3mrt, respectively 2H - 1H and 1H: -CH2-

  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: -113); 2.71 and 3.75 (2d, J = 20, 1H each: -CHI2-14); 2.98 (s, 3H: -OSO 2 -CH 3); 3.53 (s, 1H: -OH 4); 3.58 and 4.18 (2d, J = 11, 1H each: -CH 2 -O-Si-); 4.27 (d, J = 4.5, 1H: -H 2); 4.27 (d, J = 10, 1H: -H 9); 4.81 (brs, 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 aromatics).

  O-Benzylidene-1p, 2a-tert-butyldimethylsilyloxy-dihydroxy-4a, Sa-Oisopropylidene-9a, 10g oxo-13-taxene-11 can be prepared in the following manner: By operating as in Example 1, but starting from 1.5 g of O-benzylidene-1,2a trihydroxy-4a, 5a, 20-O-isopropylidene-9a, 1015 oxo-13-taxene-11 gives 1.80 g of O-benzylidene-13, 2a tertbutyldimethylsilyloxy-dihydroxy-4a, 5a O-isopropylidene-9a, 10P oxo-13-taxene-1 in the form of a yellow oil, the characteristics of which are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3 chemical shifts in ppm, coupling constants J in Hz): -0.22 and -0.08 [2s, 3H each: -Si (CH3) 2]; 0.76 [s, 9H: -SiC (CHI3) 3]; 1.09 (s, 3H: -CH3 16 or 17); 1.38 (s, 3H: -CH3 16 or 17); 1, 46 and 1.51 [2s, 3H each:

  (-CHI3) 2]; from 1.50 to 1.75 and 1.89 (2mt, respectively 3H and 1H: -CH2-7 and -CH2-

  6); 1.66 (s, 3H: -CHI 19); 2.05 (s, 3H: -CH 3 18); 2.65 and 3.84 (2d, J = 20, 1H each: -CH 2 -14); 2.67 (d, J = 5, 1H: -H 3); 2.76 (brs, 1H: OH 5); 3.47 and 4.19 (2d, J = 10, 1H each: -CH 2 -O-Si-); 3.59 (brs, 1H: -H 5); 3.73 (s, 1H: -OO 4); 4.26 (d, J = 5, 1H: -11 2); 4.28 (d, J = 10, 1H: -H 9); 4.85 (d, J = 10, 1H:

  -H 10); 5.78 (s, 1H: -O-CH-O-); from 7.30 to 7.50 (mat, 5H: -H aromatics).

  The O-benzylidene-11 [3,2a trihydroxy-4a, 5a, 20-O-isopropylidene-9a, 103 oxo] taxene-11 can be prepared in the following manner: By operating as in Example 1, but starting from 3.44 g of O-benzylidene-1 [, 2a-hydroxy-5a-O-isopropylidene-9a, 10-oxo-13-taxadiene-4 (20), 11, yielding 1.954 g of O-benzylidene-1, 2a-trihydroxy-4a, 5a, 20-O-isopropylidene-9a, 103 oxo-13-taxene-11 in the form of a white meringue and 0.993 g of O-benzylidene-1,2a-hydroxy-5a-O-isopropylidene-9a, 10P3 oxo-13

  taxadiene-4 (20), 11 which did not react.

  proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3 chemical shifts in ppm, coupling constants J in Hz): 1.17 (s, 3H: -CHI3 16 or 17); 1.41 (s, 3H: -CH3 16 or 17); 1.47 and 1.52 [2s, 3H each: (-CI13) 2]; from 1.50 to 1.80 and 1.88 (2mt, respectively 3H and 1H: -CH2-7 and -CHI12-6); 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: -CH2-

  14); 3.58 and 4.10 (2d, J = 11, 1H each: -CH 2 -OH); 3.65 (s, 1H: -OH 4); 3.79 (brs, 1H: -H 5); 4.23 (d, J = 10, 1H: -H 9); 4.36 (d, J = 5.5, 1H: -H 2); 4.87 (d, J =

  , 1H: -H 10); 5.88 (s, 1H: -O-CH-O-); from 7.35 to 7.50 (mt, 5H: -H aromatics).

  O-Benzylidene-1,3,2α-hydroxy-5α-O-isopropylidene-9a, 101 oxo-13-taxadiene-4 (20), 11 can be prepared in the following manner: By operating as in Example 1, but starting from 0.71 g of O-benzylidene-1,2a cinnamoyl-5a-O-isopropylidene-9a, 1013 oxo-13-taxadiene-4 (20), 11, give 0.454 g of O-benzylidene-1 [3, 2α-hydroxy-5α-O-isopropylidene-9a, [3-oxo-13-taxadiene-4 (20), 11 in the form of a powder

white.

  proton nuclear magnetic resonance spectrum (400 MHz, CDCl 3 chemical shifts in ppm, J coupling constants in Hz): 1.15 (s, 3H: -CH 3 16 or 17); 1.40 (s, 3H: -CH3 16 or 17); 1.51 and 1.58 [2s, 3H each: (-CH3) 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 (brs, 1H: -H 5); 4.33 (d, J = 10, 1H: -H 9); 4.39 (d, J = 5, 1H: -H 2); 4.98 (d, J = 10, 1H: -H 10); 5.13 and 5.58 (broad 2s, 1H each: = CH 2); 5.83 (s, 1H:

  -O-CH-O-); from 7.35 to 7.50 (mt, 5H: -H aromatics).

  O-Benzylidene-1,2-cinnamoyl-5a-O-isopropylidene-9a, 10-oxo-13-taxadiene-4 (20), 11 can be prepared in the following manner: To a solution of 7.60 g of cinnamoyl-5a dihydroxy-1 [5,2a O-isopropylidene] a, 10P oxo-13-taxadiene-4 (20), 11 in 500 cm3 of anhydrous toluene in the presence of molecular sieve 4A maintained under argon and with stirring, is added at a temperature close to 20 C, 4.30 cmrn3 of

  benzaldehyde and 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. and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The crude product obtained is taken up 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). C. 8.80 g of a yellow oil (which crystallizes with time) is obtained, which is purified by flash chromatography on 700 g of silica (0.040-0.063 mm) contained in a column 7 cm in diameter. eluent in cyclohexane-ethyl acetate (80- by volume). Fractions containing only the desired product are combined and concentrated to dryness under pressure

reduced (2.7 kPa) to 40 C.

  6.21 g of O-benzylidene-15,2ac cinnamoyl-5a O-isopropyl are thus obtained.

* pylidene-9ca, 10f5 oxo-13-taxadiene-4 (20), 11 in the form of white crystals whose characteristics are as follows: proton nuclear magnetic resonance spectrum (400 MHz, CDCl3 chemical shifts in ppm, coupling constants) J in Hz): 1.18 (s, 3H: -CH3 16 or 17); 1.40 (s, 3H: -CH3 16 or 17); 1.49 and 1.56 [2s, 3H each: (- CH3) 2]; 1.58 - 1.75 to 1.90 and 2.02 (3mt, respectively 1H-2H and 1H: -CH2-7 and -CH26); 1.71 (s, 3H: -CH 3 19); 2.17 (s, 3H: -CH 3 18); 2.80 (ab limit, J = 20, 2H: -CH 2 -14); 3.22 (d, J = 5.5, 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); 5.29 and 5.65 (2s wide, i 1H each: - = ClCH 2); 5.37 (brs, 1H: -H 5); 5.81 (s, 1H: -O-CH-O-); 6.36 and 7.64 (2d, J = 16, 1H each: -CI- I- = ClI-); from 7.30 to 7.50 (mt, 8H: -H aromatics in meta and para of the double bond and aromatics); 7.74 (d, J = 7.5, 2H: -H aromatics

in ortho of the double bond).

EXAMPLE 3

  40 mg of 3-tert-butoxycarbonylamino-3-phenyl-2-hydroxy-2-hydroxy-propionate (2R, 3S) of 4-acetoxy-4-methoxy-benzoyloxy-2-epoxy-51,20-hydroxy-13-O-isopropylidene-9a are dissolved , 10P3 taxene-11yl-13a in 1 cm3 of Emulphor EL 620 and 1 cm3 of ethanol, and then the solution is diluted by addition of 18 cm3 of

physiological serum.

  The composition is administered by infusion for 1 hour by

  introduction into physiological saline.

Claims (5)

  1 - New derivative of taxicin characterized in that it corresponds to the general formula: R-NH 0   Wherein Ar represents an aryl radical, R represents a benzoyl radical or a radical of the general formula R 1 -O-CO- in which R 1 represents an alkyl, alkenyl, alkynyl or cycloalkyl radical; , bicycloalkyl, phenyl or heterocyclyl, R2 and R3 each represent a hydrogen atom or together form a radical of formula -C (-R4) (- R5) - (II)   in which R4 and R5, which may be identical or different, represent a hydrogen atom, an alkyl radical or an optionally substituted phenyl radical, R6 represents a hydrogen atom and R7 represents an R'7-CO- radical in which R'7 represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl radical or R6 and R7 together form a radical of formula -C-R (-R8) (- R9) (III)   wherein R8 and R9, which may be identical or different, represent an alkyl radical or an optionally substituted phenyl radical, and R101 represents an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl radical. 2 - New derivative of taxicin according to claim 1 characterized in that: Ar represents an aryl radical, R represents a benzoyl radical or a radical R1-O-CO- in which R1 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, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino in which each alkyl part contains 1 to 4 carbon atoms, piperidino, morpholino piperazinyl-1 (optionally substituted in -4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical, the alkyl part of which contains 1 to 4 carbon atoms; carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkoxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms, - a phenyl radical optionally substituted by a or more radicals selected from alkyl radicals containing 1 to 4 carbon atoms and alkoxy containing 1 to 4 carbon atoms, or a saturated nitrogen containing heterocyclyl radical containing 5 to 6 members optionally substituted with one or more alkyl radicals containing 1 to 4 atoms of carbon, 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 R 2 and R 3 each represent a hydrogen atom or together form a radical of formula ( II) in which R4 and R5, which may be 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, which may be identical or different, chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy and arylthio radicals; , hydroxy,   hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonyl-   amino, amino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamyl,   methyl, cyano, nitro and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and the aryl radicals are phenyl or a- or naphthyl radicals,   R6 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 selected from halogen atoms and hydroxy, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino each of which the alkyl part contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted in -4 with an alkyl radical containing 1 to 4 carbon atoms or with 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 alkyloxy   carbonyl 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 from 4 to 6 ring members, containing one or more identical or different heteroatoms chosen from the atoms of nitrogen, oxygen or sulfur and being optionally substituted, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, or R 6 and R 7 together form a radical of formula (II) in which R8 and R9, which may be 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, which may be identical or different, chosen among the halogen atoms and the alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryl radicals ylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and that the aryl radicals are phenyl or a- or 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, alkyloxy radicals containing 1 to 4 carbon atoms, and dialkylamino of which each pardtie alkyl contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted in -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl part contains 1 to 4 carbon atoms; carbon), cycloalkyl containing 3 to 6   carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxy   carbonyl 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 ring members, containing one or more identical or different heteroatoms chosen from the atoms of nitrogen, oxygen or sulfur 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.   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) or dialkylamino radical;   (dimethylamino), acylamino (acetylamino), alkoxycarbonylanmino (tertbutoxycarbonyl)   nylamino) or trifluoromethyl or a thienyl-2 or -3 or furyl-2 or -3 radical, R represents a benzoyl radical or a radical R1-O-CO- in which R1 represents a t-butyl radical, R2 and R3 represent each a hydrogen atom 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, R6 represents a hydrogen atom and R7 represents a radical R Wherein 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 radical; or formyl-2 or -3, or R6 and R7 together form a radical of formula (III) in which R8 represents a hydrogen atom and R9 represents a phenyl radical optionally substituted by one or more atoms or radicals chosen from among the atoms halogen and alkoxy radicals containing 1 to 4 carbon atoms, and Ro10 represents an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkoxy radicals containing 1 to 4 carbon atoms; 4 carbon atoms or a thienyl-2 or -3 radical or furyl-2 or -3.   4 - Process for the preparation of a new taxicin derivative according to one of the   Claims 1, 2 or 3, characterized in that a product of formula is esterified general: R4 R5 HO It ", (IV) 0 - - OCOR1 0   In which R4, R5, R8, R9 and Ro10 are defined as above, by means of an acid of general formula: R-N-R11 o Ar-OH (V) 0O-R1 2   wherein Ar and R are defined as above, and either R11 is a hydrogen atom and R12 is a hydroxy protecting group, or R11 and R12 together form a saturated 5- or 6-membered heterocycle, or a derivative of this acid to obtain a product of general formula: O O0 R-N-R1 1 0 A. Yes "", X - (VI) Ar 0111 '"' i [o OR1 2 H   OCOR1 o R15 R wherein Ar, R, R4, R5, R8, R9, R1j0, R1l1 and R12 are defined as above, followed by replacement of the protective groups represented by R12 and / or R11 and R12 by hydrogen atoms, and optionally hydrolyzing the acetal functions -OC (-R4) (-Rs) -O- to obtain a product of general formula (I) in which R2 and R3 each represent a hydrogen atom, or optionally a roxidation, when R8 represents a hydrogen atom, into a product of general formula: RXR5 0 c R-NH 0o (VII) Ar OH R60 -   6 = OCOR1 or OR7 in which R4, R5 and Ro10 are defined as above, R6 represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 is identical to R9, then optionally of hydrolyzing the product of general formula (VII) to obtain a product of general formula (I) in which Ar and R are defined as above, R2 and R3 each represent a hydrogen atom, R6 represents a hydrogen atom and R7 represents a radical R'7-CO- in which R'7 is identical to R9.   - Process for the preparation of a new taxicin derivative according to one of the   claims 1, 2 or 3 wherein Ar, R, R2, R3 and Ro10 are defined as   previously, R6 represents a hydrogen atom and R7 represents a R'7-CO- radical in which R'7 represents an alkyl radical or an aryl radical, characterized in that a product of general formula is esterified: R4 R5 ÄsRs HOli "(XXXVIII) H0 - HO 0C0R1 = OCOR 7 1 o 0COR '   in which R4, R5, R'7 and R10 are defined as above, by means of an acid of general formula: R - h 1 Ar - OH O-R1 2   in which Ar, R, R11 and R12 are defined as in claim 4, to obtain a product of general formula: R4> R5 R-H-R11 O (XXXIX) Ar - O-R1 2 HO - OOR -OCOR7R1 0 OCOR '?   in which Ar, R, R4, R5, R'7, R10, R11 and R12 are defined as above, the protective groups R12 and / or R11 and R12 are replaced by hydrogen atoms and optionally hydrolyzes the acetal function -OC (-R4) (- Rs) -O- for   obtain a product according to one of claims 1, 2 or 3 for which R2 and R3   each represent a hydrogen atom.   6 - A new derivative of taxicin characterized in that it corresponds to the general formula: R4 os o 0 0 / oo 7 - o -H 0 - OCOR1o R,   wherein R4, R5, R8, R9 and R10 are defined in accordance with claim 1, 2   or 3. 7 - A new taxicin derivative of the general formula: ## STR1 ##   wherein R4, R5 and R0lo are defined as in one of claims 1, 2 or   And R '7 represents an alkyl radical or an optionally substituted phenyl radical.   8 - Pharmaceutical composition characterized in that it contains at least   a derivative according to one of claims 1, 2 or 3 in combination with one or more   compatible inert pharmaceutically acceptable diluents or adjuvants or physiologically active.