AU692269B2 - Taxoids, preparation thereof and pharmaceutical compositions containing them - Google Patents

Description

WO 95/33736 1 PCT/FR95/00735 -MOB& TAXOIDS, fTffR- PREPARATION AND TEB PHARMACEUTICAL

A

COMPOSITIONS -WEgg CONTAIN N Ti G_ r,.

The present invention relates to nevel taxoids of general formula:

O

0 H HO OCOR,

OCOR

4 in which:

R

a represents a hydrogen atom or a hydroxyl radical, an alkoxy radical containing 1 to 4 carbon atoms, an acyloxy radical containing 1 to 4 carbon atoms or an alkoxyacetoxy radical in which the alkyl part contains 1 to 4 carbon atoms and R, represents a hydrogen atom, or alternatively Ra and Rb form, together with the carbon atom to which they are attached, a ketone function, Z represents a hydrogen atom or a radical of general formula: R NH 0 t

(IIH)

3

OH

in which: r 0' vL~ ''I l l f f n l I, I Ri represents a benzoyl radical optionally substituted with one or more atoms or radicals, which may be identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, trifluoromethyl, thenoyl and furoyl radicals, or a radical R 2 -O-CO- in which R 2 represents: an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, or a bicycloalkyl radical containing 7 to 10 carbon atoms, these radicals optionally being substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl part contains 1 to 4 carbon atoms, piperidino and morpholino radicals, 1-piperazinyl radicals (optionally substituted at -4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals (optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms), cyano or

IT~,

3 carboxyl radicals and alkoxycarbonyl radicals in which the alkyl part contains 1 to 4 carbon atoms, a phenyl or a- or P-napthyl radical which is optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms or a 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals, or a saturated heterocyclic radical containing 4 to 6 carbon atoms optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms,

R

3 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, a straight or branched alkenyl radical containing 2 to 8 carbon atoms, a straight or branched alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, or a phenyl or a- or Pnaphthyl radical which is optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, or a 5-membered aromatic heterocycle containing one or more hetero atoms, which may be I- I I 4 identical or different, chosen from nitrogen, oxygen and sulphur atoms and optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms, and alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl radicals, it being understood that, in the substituents of the phenyl, a- or P-naphthyl and aromatic heterocyclic radicals, 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 phenyl or a- or p-naphthyl radicals, and

R

4 and R 5 which may be identical or different, represent a straight or branched alkyl radical containing 1 to 8 carbon atoms, a straight or branched alkenyl radical containing 2 to 8 carbon atoms, a straight or branched alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which alkyl part contains 1 to 4 carbon atoms, piperidino and morpholino

C-

\i-nj 0

LU

I, I III II radicals, 1-piperazinyl radicals (optionally substituted at -4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals which are optionally substituted, cyano and carboxyl radicals and alkyloxycarbonyl radicals in which the alkyl part contains 1 to 4 carbon atoms, or an aryl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro, azido, trifluoromethyl and trifluoromethoxy radicals, or a 4- to 6-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that R 5 cannot represent a methyl radical, it being understood that the cycloalkyl, cycloalkenyl and bicycloalkyl radicals may optionally be substituted with one or more alkyl radicals containing 1 to 4 carbon atoms.

The aryl radicals which may be represented by

<I-

rV II I I I R R 4 and/or R s are preferably phenyl or a- or Pnaphthyl radicals optionally substituted with one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine or iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroityl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro, azido, trifluoromethyl and trifluoromethoxy radicals, 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 that the radical R 5 cannot represent a methyl radical.

The heterocyclic radicals which may be represented by R 3

R

4 and/or R s are preferably 5-membered aromatic heterocyclic radicals containing one or more atoms, which may be identical or different, chosen from nitrogen, oxygen and sulphur atoms, optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms (fluorine, chlorine, bromine or iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, aryloxy

C-

,C-

L. II I radicals containing 6 to 10 carbon atoms, amino radicals, alkylamino radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl part contains 1 to 4 carbon atoms, acylamino radicals in which the acyl part contains 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbon atoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl part contains 6 to 10 carbon atoms, cyano, carboxyl and carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl part contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl part contains 1 to 4 carbon atoms, and alkoxycarbonyl radicals in which the alkoxy part contains 1 to 4 carbon atoms.

The present invention more particularly relates to the products of general formula in which Ra represents a hydroxyl radical, an alkoxy radical containing 1 to 4 carbon atoms, an acyloxy radical containing 1 to 4 carbon atoms or an alkoxyacetoxy radical in which the alkyl part contains 1 to 4 carbon atoms and Rb represents a hydrogen atom, Z represents a hydrogen atom or a radical of general formula (II) in which R i represents a benzoyl radical or a radical R 2

-O-

CO- in which R 2 represents a tert-butyl radical, and R 3 represents an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl radical optionally substituted with one

C\

-I-I Il I or more atoms or radicals, which may be identical or different, chosen from halogen atoms (fluorine or chlorine) and alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tert-butoxycarbonylamino) or trifluoromethyl radicals or a 2- or 3-furyl, 2- or 3-thienyl or 4- or 5-thiazolyl radical, and R 4 represents a phenyl radical which is optionally substituted with one or more atoms or radicals, which may be identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, azido, trifluoromethyl and trifluoromethoxy radicals, or a 2or 3-thienyl or 2- or 3-furyl radical, and R 5 represents an optionally substicuted alkyl radical containing 1 to 4 carbon atoms, it being understood that R s cannot represent a methyl radical.

Even more particularly, the present invention relates to the products of general formula in which Ra represents a hydrogen atom or a hydroxyl or acetyloxy or methoxyacetoxy radical and Rb represents a hydrogen atom, Z represents a hydrogen atom or a radical of the general formula (II) in which R I represents a benzoyl radical or a radical R 2 -O-CO- in which R, represents a tert-butyl radical, and R 3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, and R 4 represents a phenyl

U-

s 9 radical which is optionally substituted with a halogen atom, and R 5 represents an alkyl radical containing 2 to 4 carbon atoms.

The products of general formula in which Z represents a radical of general formula (II) have noteworthy antitumour and antileukaemia properties.

According to the invention, the products of general formula in which Ra represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical, Rb represents a hydrogen atom, and R 4

R

s and Z are defined as above, may be obtained by the action of an alkali metal halide (sodium chloride, sodium iodide or potassium fluoride) or an alkali metal azide (sodium azide) or a quaternary ammonium salt or an alkali metal phosphate on a product of general formula: 0 R 0O-SO -CF 3 Z-0 A (III) HO OCOR

OCOR.

in which Z, R 4 and R s are defined as above, R a represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl radical, and Rb represents a hydrogen atom, followed, if necessary, by replacement of the protecting group carried by Ra by a hydrogen atom.

I II The reaction is generally carried out in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether or methyl tert-butyl ether) and nitriles (acetonitrile) alone or as a mixture, at a temperature between 20 0 C and the boiling point of the reaction mixture.

The product of general formula (III) in which Z represents a radical of general formula (II) may be obtained by esterification of a product of general formula: Ra- O-SO 2

-CF

3 HO (IV) H HO OCOR

OCOR

4 in which R 4 and Rg are defined as above, R, represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl radical, and Rb represents a hydrogen atom, using an acid of general formula: R' N, R O

R

3

OH

O-R

in which R i and R 3 are defined as above, or R, represents a hydrogen atom and R. represents a protecting group for the hydroxyl function, and either p /s I '2 X 11 R, and R 7 together form a 5- or 6-mervb saturated heterocycle, or using a derivative of this acid, to give an ester of general formula:

NO

RO (VI) -RR H HO OCOR

OCOR

in which R, R Rb, R R 3

R

4

R

5 R and R 7 are defined as above, followed by replacement of the protecting groups represented by R. and/or R, and R7 by hydrogen atoms and optionally R a when it represents an acyloxy or alkoxyacetoxy radical or a protected hydroxyl radical, by a hydroxyl radical.

The esterification using an acid of general formula may be carried out in the presence of a coupling agent (carbodiimide or reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at a temperature between -10 and 0

C.

The esterification may also be performed using the acid of general formula in anhydride form, working in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, 12 ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at a temperature between 0 and 90 0

C.

The esterification may also be performed using the acid of general formula in halide form or in anhydride form with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base (tertiary aliphatic amine), working in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at a temperature between 0 and 0

C.

When Ra represents a protecting group for the hydroxyl function, R. is preferably a 2,2,2trichlorcethoxycarbonyloxy radical.

Preferably, R 6 represents a hydrogen atom and R, represents a protecting group for the Lydroxyl function, or alternatively R 6 and R together form a or 6-membered saturated heterocycle.

When R, represents a hydrogen atom, R 7 preferably represents a methoxymethyl, l-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, g-trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydropyranyl radical.

When R 6 and R, together form a heterocycle, this heterocycle is preferably an oxazolidine ring optionally mono-substituted or gem-disubstituted in position -2.

K,

Replacement of the protecting groups R 7 and/or R, and R, by hydrogen atoms and optionally of R a by a hydroxyl radical may be carried out, depending on their nature, in the following way: 1) when R 6 represents a hydrogen atom and R 7 represents a protecting group for the hydroxyl function and Ra represents an alkoxy, acyloxy or alkoxyacetoxy radical, replacement of the protecting groups by hydrogen atoms is carried out using an inorganic acid (hydrochloric acid, sulphuric acid or hydrofluoric acid) or an organic acid (acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid or p-toluenesulphonic acid) used alone or as a mixture, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles, at a temperature between -10 and 600C, 2) When R, represents a hydrogen atom and R, represents a protecting group for the hydroxyl function and R a represents a 2,2,2-trichloroethoxycarbonyloxy radical, replacement of the protecting group R 7 is carried out under the conditions described above in 1) and that of Ra is carried out by treatment using zinc, optionally combined with copper, in the presence of acetic acid at a temperature between 30 and 60 0 C, or using an inorganic or organic acid such as hydrochloric acid or 7 ~-~III r IF I I 14 acetic acid dissolved in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, propanol or isopropanol) or in an aliphatic ester (ethyl acetate, isopropyl acetate or n-butyl acetate) in the presence of zinc which is optionally combined with copper, 3) when R 6 and R 7 together form a 5- or 6-membered saturated heterocycle and more particularly an oxazolidine ring of general formula: Ri-N O

(VII)

R

8 R 9 in which R, is defined as above, R 8 and R 9 which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical in which the alkyl part contains 1 to 4 carbon atoms and the aryl part preferably represents a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R 8 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 R 9

U'I"

'K r represents a hydrogen atom, or alternatively R 8 and R, form, together with the carbon atom to which they are attached, a 4- to 7-membered ring, and R, represents an acyloxy or alkoxyacetoxy or 2,2,2trichloroethoxycarbonyloxy radical, replacement of the protecting group formed by R 6 and R, by hydrogen atoms and of Ra by a hydroxyl radical may be carried out, depending on the meanings of Ra, Ri, R 8 and in the following way: a) when R I represents a tert-butoxycarbonyl radical, R 8 and R 9 which may be identical or different, represent an alkyl radical or an aralkyl (benzyl) or aryl (phenyl) radical, or alternatively R 8 represents a trihalomethyl radical or phenyl radical substituted with a trihalomethyl radical, and R 9 represents a hydrogen atom, or alternatively R, and R, together form a 4- to 7-membered ring, treatment of the ester of general formula (VI) with an inorganic or organic acid, optionally in an organic solvent such as an alcohol, gives the product of general formula: R

O

O-SO,-CF

3 HN 0 R-

X(VIII)

OH 0 H HO OCOR

OCOR

4 in which Ra, Rb,, R 3

R

4 and R 5 are defined as above,

T

v u T

I

16 which compound is acylated using benzcyl chloride in which the phenyl ring is optionally substituted, thenoyl chloride, furoyl chloride or a product of general formula:

R

2 -O-CO-X (IX) in which R, is defined as above and X represents a halogen atom (fluorine or chlorine) or a residue -O-R 2 or -O-CO-O-R 2 in order to obtain a product of general formula: Rb R O RaE 0 a O-S, 2

-CF

3

R

3 H o l

(X)

6H 0 O HO OCOR

OCOR

4 in which Ra, Rb, R 1

R

3

R

4 and R 5 are defined as above, the protecting group Ra of which compound, when it represents a protected hydroxyl radical, is replaced, if necessary, by a hydroxyl radical.

Preferably, the product of general formula (II) is treated with formic acid at a temperature in the region of 20 0

C.

Acylation of the product of general formula (VIII) using a benzoyl chloride in which the phenyl radical is optionally substituted, thenoyl chloride or furoyl chloride or a product of general formula (IX) is preferably carried out in an inert organic solvent V t I; 17 chosen from esters such as ethyl acetate, isopropyl acetate or n-butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane, in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. The reaction is carried out at a temperature between 0 and 50°C, preferably in the region of 20 0

C.

Replacement of the protecting group of R., when it represents a 2,2,2-trichloroethoxycarbonyloxy radical, is preferably carried out under the conditions described above in 2), b) when R3 represents a benzoyl radical which is optionally substituted, a thenoyl or furoyl radical or a radical R 2 0-CO- in which R, is defined as above, R 8 represents a hydrogen atom, an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, and R 9 represents a hydrogen atom, replacement of the protecting group formed by R 6 and R, by hydrogen atoms is carried out in the presence of an inorganic acid (hydrochloric acid or sulphuric acid) or an organic acid (acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid or p-toluenesulphonic acid) used alone or as a mixture, in a stoichiometric or catalytic amount, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and O L L 18 aromatic hydrocarbons, at a temperature between -10 and 0 C, preferably between 15 and 30 0 C, and replacement of the protecting group of Ra, when it represents a 2,2,2-trichloroethoxycarbonyloxy radical, by a hydrogen atom is carried out under the conditions described above in 2).

4) when Ra represents an alkoxyacetyl radical and R, and R, are defined as in point 1) above, firstly, the protecting group R, is replaced by a hydrogen atom, working under the acidic conditions described in point 1) above, optionally followed by replacement of R a by a hydroxyl radical, by treatment in an alkaline medium or by the action of a zinc halide under conditions which do not affect the rest of the molecule. The alkaline treatment is generally carried out by the action of ammonia in an aqueous-alcoholic medium at a temperature in the region of 20 0 C. The treatment with a zinc halide, preferably zinc iodide, is generally carried out in methanol at a temperature in the region of 20 0

C.

5) when Ra represents an alkoxyacetoxy radical and R 6 and R, are defined as in point 2-a) above, the radical Ra is replaced by a hydroxyl radical by treatment in alkaline medium or by treatment using a zinc halide under the conditions described in point 3) above, followed by treatment of the product of general formula (VI) obtained under the deprotection and acylation conditions described in point 2-a) above.

19 6) when Ra represents an alkoxyacetoxy radical and R 6 and R, are defined as in point 2-b) above, the radical

R

a is replaced by a hydroxyl radical by treatment in an alkaline medium or by treatment using a zinc halide under the conditions described in point 3) above, followed by treatment of the product obtained under the conditions described in point 2-b) above.

According to the invention, the products of general formula (III) in which R 4 and R, are defined as above, Ra represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical, and Rb represents a hydrogen atom, or alternatively Ra and Rb form, together with the carbon atom to which they are attached, a ketone function, and Z represents a hydrogen atom, may be obtained by the action of a trifluoromethanesulphonic acid derivative, such as the anhydride or the N-phenyltrifluoromethanesulphonimide, on a product of general formula: Rb R O a OHq HO

(XI)

oco0 HO OCOR

OCOR

in which Ra, Rb, R 4 and R 5 are defined as above.

The reaction is generally carried out in an inert organic solvent (optionally halogenated aliphatic 1

II,

hydrocarbons, or aromatic hydrocarbons) in the presence of an organ z base such as an aliphatic tertiary amine (triethylamine) or pyridine, at a temperature between and +20 0

C.

The products of general formula (XI) in which

R

4 and R 5 are defined as above, Ra represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl radical, and RP represents a hydrogen atom, may be obtained by the action of hydrofluoric acid or trifluoroacetic acid in a basic organic solvent, such as pyridine optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, or triethylamine optionally in combination with an inert organic solvent such as methylenechloride or acetonitrile or tetrahydrofuran, at a temperature between 20 and 80 0 C, on a product of general formula: Rb R a a O-G, G O (XII) G,-O

H:

HO OCOR

OCORA

in which R 4 and R 5 are defined as above, Ra represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl radical, Rb represents a hydrogen atom, and the symbols G 1 which are identical,

-I

21 represent a trialkylsilyl radical.

The product of general formula (XII) may be obtained by the action of a product of general formula: R-Y (XIII) in which R represents an alkyl, alkanoyl or alkoxyacetyl radical or a protecting group for the hydroxyl function and Y represents a halogen atom, on a product of general formula:

(XIV)

G,-O

OCOR

4 in which R 4

R

5 and G i are defined as above.

When R represents an alkyl or alkoxyacetyl radical, it is particularly advantageous to work in a basic organic solvent such as pyridine or in an inert organic solvent such as methylene chloride, chloroform or 1,2-dichloroethane, in the presence of a tertiary amine such as triethylamine or pyridine, at a temperature in the region of 0 0

C.

When R represents an alkyl radical, it is particularly advantageous to metallate the hydroxyl function at -10 beforehand using an alkali metal hydride (sodium hydride) or a metal alkylide (butyllithium).

The product of general formula (XIV) and, 7' 1

L

I optionally, the product of general formula (XII) may be obtained by the action of an organometallic derivative of general formula:

R

4 -M (XV) in which R 4 is defined as above and M represents a metal atom, preferably a lithium or magnesium atom, on a product of general formula:

(XVI)

G,-0 O Y //L6 in which Ra, Rb, R 5 and G, are defined as above.

The reaction is generally carried out in an organic solvent such as an ether (tetrahydrofuran) at a temperature below -50°C, preferably in the region of -78 0

C.

The product of general formula (XVI) may be obtained by esterification of a product of general formula:

I;

N0/ i i I

O-G

0

(XVII)

in

A

which 0 Rb and G 1 are defined as above, using an acid of general formula: Rs-COOH (XVIII) in which R 5 is defined as above, or using a derivative of this acid such as a halide or an anhydride, in the presence of a coupling agent or of an inorganic or organic base.

The product of general formula (XVII) may be obtained by the action of a product of general formula XIII) on a product of general formula: HO 0 O-G G,-O

(XIX)

H 0 O OH 0 o in which G i is defined as above, under the conditions described above for the action of a product of general formula (XIII) on a product of general formula (XIV).

The product of general formula (XIX) may be I t 111 1 I I 24 prepared by the action of phosgene, or one of the derivatives thereof such as triphosgene, on a product of general formula: Go

(XX)

HO OH

OH

in which G 1 is defined as above, working in a basic organic solvent such as pyridine, at a temperature below -50°C, preferably in the region of -78 0

C.

The product of general formula (XX) may be prepared by the action of a halotrialkylsilane on a product of general formula: HO 0 O-G] HO

(XXI)

HO OH

OH

in which G, is defined as above, working in a basic organic solvent.

The product of general formula (XXI) may be prepared under the conditions described by D.G.I.

Kingston et al., Journal of Nat. Prod., 56, 884 (1993).

The product of general formula in which Ra and Rb each represent a hydrogen atom may be obtained by SVFT C'' electrolytic reduction of a product of general formula in which Ra represents a hydroxyl radical or an acyloxy or alkoxyacetoxy radical or under the conditions described in International Application PCT WO 93/06093.

The products of general formula in which Ra and Rb form, together with the carbon atom to which they are attached, a ketone function may be obtained by oxidation of a product of general formula in which Ra represents a hydroxyl radical and Rb represents a hydrogen atom, using, for example, pyridinium chlorochromate, pyridinium dichromate, potassium dichromate, ammonium dichromate or manganese dioxide.

The neve products of general formula (I) obtained using the processes according to the invention may be purified according to the known methods, such as crystallization or chromatography.

The products of general formula in which Z represents a radical of general formula (II) have noteworthy biological properties.

In vitro, measurement of the biological activity is carried out on tubulin extracted from pig brain by the method of M.L. Shelanski et al., Proc.

Natl. Acad. Sci. USA, 70, 765-768 (1973). Study of the depolymerization of microtubules into tubulin is carried out according to the method of G. Chauviere et al., C.R. Acad. Sci., 293, 2nd series, 501-503 (1981).

In this study, the products of general formula in SI, S4 I I which Z represents a radical of general formula (II) proved to be at least as active as taxol and Taxotere.

In vivo, the products of general formula (I) in which Z represents a radical of general formula (II) proved to be active in mice grafted with melanoma B16 at doses between 1 and 10 mg/kg via the intraperitoneal route, as well as on other liquid or solid tumours.

The i4e-I; products have antitumour properties and more particularly an activity on tumours which are resistant to Taxol or to Taxotere Such tumours comprise tumours of the colon which have a high expression of the mdr 1 gene (multi-drug resistance gene). Multi-drug resistance is a common term relating to the resistance of a tumour to various products having various structures and mechanisms of action.

Taxoids are generally known for being highly recognized by experimental tumours such as P388/DOX, a cell line selected for its resistance to doxorubicin (DOX) which expresses mdr 1.

The examples which follow illustrate the present invention.

EXAMPLE 1 To a solution of 0.193 g of 20-epoxy-1l-hydroxy-10 -methoxyacetoxy-9-oxo-4apropanoyloxy-7j-trifluoromethanesulphonyloxy-ll-taxen- 13a-yl (2R,4S)-3-tert-butoxycarbonylamino-2-hydroxy-4phenylpropionate in 2.5 cm 3 of acetonitrile and

A

0.250 cm 3 of tetrahydrofuran are successively added 0.096 g of powdered 4A molecular sieves and 0.290 g of sodium chloride. The reaction mixture is kept stirring at a temperature in the region of 75°C for 5 hours, and then, at a temperature in the region of 20 0 C, 75 cm 3 of dichloromethane and 50 cm 3 of saturated aqueous sodium chloride solution are added. The organic phase is separated out after settling of the phases has taken place, washed twice with 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 0.150 g of a product is obtained, which is purified by chromatography on 80 g of silica (0.063-0.2 mm) contained in a column 1 cm in diameter (eluent: dichloromethane/methanol: 98/2 by volume), collecting cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0

C.

0.080 g of 2a-benzoyloxy-5,20-epoxy-l-hydroxy-103methoxyacetoxy-7P,8-methylene-19-nor-9-oxo-4propanoyloxy-ll-taxen-13-yl (2R,4S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate is obtained, the characteristics of which are as follows: H NMR spectrum (400 MHz, CDC1 3 6 in ppm): 1.24 J 7.5 Hz, 3H CH 3 ethyl); 1.24 6H CH 3 1.27 (s, 9H C(CH 3 3 1.42 (mt, 1H H 1.68 and 2.24 (2 mts, 1H each: CH, at 19); 1.86 1H: OH at 1.86 1 i"\ I-st 28 3H CHO 2.12 and 2.86 (d and dt respectively, J 16 and 5 Hz, 1H each: CH 2 at 6) from 2.15 to 2.30 and 2.41 (mt and dd respectively, J 16 and 9 Hz, 1H each:

CH

2 at 14) 2.64 (mt, 2H: CU 2 ethyl); 3.26 (mt, 1H: OH at 3.52 3H OCH 3 4.07 (d,J =7 Hz, 1H :H at 3) 4.04 and 4.33 (2d, J 9 Hz, 11H each: CU 2 at 20) 4.22 (limiting AB, J 16 Hz, 2H: OCOCH 2 4.62 (mt, 1H :H at 4.70 CJ 4 Hz, 1H H at 5.28 (md, 2H: H at 3' and CONH); 5.67 (d,J 7 Hz, 1H H at 2); 6.26 (broad t, J 9 Hiz, 1H H at 13); 6.42 lH H at 10); from 7.25 to 7.45 (mt, 5H aromatic H at 7.52 J =7.5 Hz, 2H :OCOC.H. meta-H); 7.62 J= Hz, 1H :OCOC 6 H. para-H) 8.16 J =7.5 Hz, 2H1

OCOCH

5 ortho-H) '2oe-Benzoyloxy-5l,20-epoxy-/3-hydroy-103methoxyacetoxy- 9-oxo-4ci-propanoyloxy-73trifluoromethanesulphonyloxy-11-taxen-3u-y1 (2R,4S) -3tert-butoxycarbonylamino- 2-hydroxy- 4-phenyipropionate may be prepared the following way: A solution of 0.760 q of -epoxy-1/3-hydroxy-l0/3-methoxyacetoxy-9-oxo-4vpropanoyloxy- 73- trifluoromethanesulphonate- 11- taxenl3ae-yl (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4methoxyphenyl) -4-phenyl-1, in 6.6 cm' of 0.1N hydrochloric ethanol solution is kept stirring at a temperature in the region of 0 0 C for 22 hours. The reaction medium is concentrated to dryness ~4under reduced pressure (2.7 kPa) at 20 0 C. The crude

-M

29 reaction material is dissolved in 80 cm 3 of dichloromethane and 80 cm 3 of saturated aqueous sodium bicarbonate solution. The organic phase is separated out after settling of the phases has taken place and then extracted with twice 50 cm 3 of dichloromethane. The organic phases are combined, washed with 50 cm 3 of distilled water and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 20 0 C. 0.9 g of a white foam is obtained, which is purified by chromatography on 150 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent: dichloromethane/methanol: 95/5 by volume), collecting 15 cm fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 20 0 C. 0.456 g of 2a-benzoyloxy-5P,20epoxy- 1-hydroxy- 10-methoxyacetoxy-9-oxo-4propanoyloxy-73-trifluoromethanesulphonyloxy-ll-taxen- 13a-yl (2R,4S)-3-tert-butoxycarbonylamino-2-hydroxy-4phenylpropionate is obtained, the physical characteristics of which are as follows: 'H NMR spectrum (400 MHz, CDC1 3 6 in ppm): 1.24 (s, 9H CH 3 and CH 3 ethyl); 1.34 9H C(CH 3 3 1.74 (s, 1H OH at 1.88 3H CH 3 2.05 (broad s, 3H

CH

3 2.24 and 2.86 (2 mts, 1H each: CH 2 at 2.33 J 9 Hz, 2H CH, at 14); 2.68 (mt, 2H CH, ethyl); 3.30 (mt, 1H OH at 3.52 3H OCH 3 3.93 (mt, 1H H at 4.19 (limiting AB, J 16 Hz, W 0.

I 2H :OCOCH 2 O) 4.20 and 4.36 (2d, J 9 Hz, 1H each: CH 2 at 20); 4.64 (broad d, J 5.5 Hz, 1H H at 4.86(broad d, J 10 Hz, 1H H at 5.22 (mt, lH H at 5.30 J T 10 Hz, 1H CONH); 5.51 (dd, J 10 and 7.5 Hz, 1H H at 5.75 J 7 Hz, 1H H at 2) 6.20 (mt, 1H :H at 13) 6.71 1H H at from 7.30 to 7.45 (mt, 5H aromatic H at 7.52 (t, J =7.5 Hz, 2H OCOC.H. meta-H); 7.64 J =7.5 Hz, 1H :OCCC 6 H. para-H) 8.13 J =7.5 Hz, 2H :OCOC 6

H

ortho-H).

20-epoxy- 1g-hydroxy-10Pmethoxyacetoxy- 9-oxo-4a-propanoyloxy-7g3trifluoromethanesuiphonyloxy-il- taxen-13ca-yl C2R,4S,5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1,3-oxazolidine-5-carboxylate may be prepared in the following way: To a solution of 0.590 g of 2ca-benzoyloxyi 3 l3a-dihydroxy-53, 20-epoxy-l0jS-methoxyacetoxy-9-oxo- 4ca-propanoyloxy-7,3- trifluoromethanesulphonyloxy-lltaxene in 10 cm 3 of anhydrous ethyl acetate are successively added 0.463 g of C2R,4S,5R)-3-tertbutoxycarbonyl- 2- (4-methoxyphenyl) -4 -phenyl-l, 3acid, 0.319 g of dicyclohexylcarbodiimide and 0.028 g of 4-dimethylaminopyridine. The reaction mixture is stirred for 15 hours, under an argon atmosphere, at a temperature in the region of 20'C, followed by addition of 75 cm 3 of dichloromethane and 50 cm 3 of saturated 31 aqueous ammonium chloride solution. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 0.980 g of product are obtained, which is purified by chromatography on 150 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent: dichloromethane/methanol: 95/5 by volume), collecting 15 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 0.740 g of 2a-benzoyloxy- 5,20-epoxy-1I-hydroxy-103-methoxyacetoxy-9-oxo-4apropanoyloxy- 7- trifluoromethanesulphonyloxy-11-taxen- 13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate is obtained in the form of a white foam, the physical characteristics of which are as follows: 1 H NMR spectrum (400 MHz, CDC1 3 6 in ppm) 1.06 (s, 12H CH3 and C(CH 3 3 1.20 3H CH 1.27 J Hz, 3H CH 3 ethyl); 1.67 1H OH at 1.71 3H CH 3 1.83 3H CH 3 from 2.00 to 2.30 and 2.83 (2 mt, 1H each CH, at from 2.00 to 2.30 (mt, 2H CH 2 ethyl); 2.08 and 2.22 (2 dd, J 16 and 9 HZ, 1H each CH 2 at 14); 3.52 3H OCH 3 3.82 3H ArOCH 3 3.82 (mt, 1H H at 4.12 and 4.29 (2d, J 9 Hz, 1H each CH, at 20); 4.18 (limiting AB,

C

I i I 32 J 16 Hz, 2H :OCOCH 2 O) 4.51 J 5 Hz, 1H :H at 4.80 (broad d, J 10 Hz, 1H from 5.35 to 5.45 (mt, 1H :H at 5.43 (dd, J =10.5 and 7.5 Hz, 1H :H at 5.68 U' 7 Hz, 1H H at 6.01 (mt, 1H H at 13); 6.38 (mt, 1H :H at 6.60 (s, 1H :H at 10); 6.92 J 8.5 Hz, 2H :aromatic H ortho to the OCH 3 7. 39 J 8. 5 Hz, 2H aromatic H meta to the OCH 3 from 7.30 to 7.45 (mt, 5H aromatic H at 31) 7.50 J 7.5 Hz, 2H :OCOC.H 5 meta-H) 7.65 J =7.5 Hz, 1H :OCOC 6

H

5 para-H) 8.03 j Hz, 2H OCOC.H. ortho-H) 2cu-Benzoyloxy-1g, 13o,-dihydroxy-5g, 10O3-methoxyacetoxy- 9-oxo-4u-propanoyloxy-7Ptrifluoromethanesulphonyloxy- 11- taxene may be prepared in the following way: To a solution of 0.660 g of 2ca-benzoyloxy- 5f,20-epoxy-10/-methoxyacetoxy-9-oxo-4u-propanoyloxy- 1/,70',13-trihydroxy-11-taxene in 6.6 cm 3 of anhydrous dichioromethane and 0.338 cm 3 of pyridine, maintained under an argon atmosphere, and at a temperature in the region of 0 0 C, is added dropwise 0.354 cm 3 Of trifluoromethanesulphonic anhydride. The orangecoloured solution obtained is stirred for 10 minutes at a temperature in the region of 0 0 C and for 30 minutes at a temperature in the region of 20*C, followed by addition of 3 cm 3 of water and 50 cm 3 Of dichioromethane. The organic phase is separated out after settling of the phases has taken place, washed 33 with twice 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 0.800 g of product is obtained, which is purified by chromatography on 100 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter (eluent: dichloromethane/methanol: 95/5 by volume), collecting 15 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 0.591 g of 2a-benzoyloxy-l,13adihydroxy-5P,20-epoxy-103-methoxyacetoxy-9-oxo-4apropanoyloxy- 7- trifluoromethanesulphonyloxy-11-taxene is obtained in the form of a white foam, the physical characteristics of which are as follows: 1 H NMR spectrum (400 MHz, CDC13, 6 in ppm) 1.05 (s, 3H 1.19 3H CH 3 1.23 J 7.5 Hz, 3H CH, ethyl); 1.62 1H OH at 1.89 3H CH,); 2.12 J 5 Hz, 1H OH at 13); 2.24 and 2.90 (2 mts, 1H each CH 2 at 2.25 3H 2.30 (limiting AB, 2H CH 2 at 14); 2.64 (mt, 2H :CH 2 ethyl); 3.52 3H OCH 3 4.02 J 7 Hz, 1H H at 4.15 and 4.35 (2d, J 9 Hz, 1H each CH, at 4.20 (limiting AB, J 16 Hz, 2H OCOCH0O); 4.85 (mt, 1H H at 13); 4.91 (broad d, J 10 Hz, 1H H at 5.57 (dd, J 10 and 7 Hz, 1H H at 5.69 J 7 Hz, 1H H at 6.73 1H H at 10); 7.50 (t, J 7.5 Hz, 2H OCOCgH meta-H); 7.63 J 7.5 Hz, T 1H OCOC.H. para-H) 8. 11 J 7. 5 Hz, 2H :OCOC 6

H,

ortho-H) 20-epoxy-l0g-methoxyacetoxy- 9-oxo-4ci-propanoyloxy-3, 7f,3a-trihydroxy-l1-taxene may be prepared in the following way: To a solution of 1.21 g of 2cu-benzoyloxy- 7f 3 3u-ditriethylsilyloxy-53, 20-epoxy-l/3-hydroxy-10gmethoxyacetoxy-9.-oxo-4cu-propanoyloxy-ll-taxene in 15 cm 3 of dichloromethane are added, at a temperature in the region of 20*C, 23 cm 3 of triethylaxaine-hydrofluoric acid complex. The reaction mixture is stirred for hours at a temperature in the region of 20 0 C, followed by addition of 50 cm 3 of dichloromethane and 100 cm 3 Of saturated aqueous sodium hydrogen carbonate solution.

The organic phase is separated out after settling of the phases has taken place, washed with twice 50 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 1.04 g of 2u-benzoyloxy-5g,20-epoxy-03methoxyacetoxy-9-oxo-4i-propanoyloxy-3, 7/3,l3catrihydroxy-ll-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: 1H1 NMR spectrum (400 MHz, CDCl 3 6 in ppm) 1.11 (s, 6H CHO); 1.25 LT 7.5 Hz, 3H1 CH 3 ethyl); 1.65 1H1 OH at 1.70 3H1 CHO 3 1.88 and 2.60 (2 mts, 1H each :CH 2 at 2.08 3H1: CHO); 2.30 (limiting AB, 2H CH, at 14); 2.39 J 4 Hz, 1H OH at 2.63 (mt, 2H CH 2 ethyl); 3.55 3H

OCH

3 3.90 J 7 Hz, 1H H at 4.17 and 4.32 (2d, J 9 Hz, 1H each CH 2 at 20); 4.25 (limiting AB, J 16 Hz, 2H OCOCH20); 4.51 (mt, 1H H at 4.89 (mt, 1H H at 13); 4.95 (broad d, J 10 Hz, 1H H at 5.64 J 7 Hz, 1H H at 6.43 1H H at 7.48 J 8 Hz, 2H OCOCH 5 meta-H); 7.61 J 8 Hz, 1H OCOC 6

H

s para-H); 8.13 J 8 Hz, 2H OCOCHs ortho-H).

2o-Benzoyloxy-7, 13o-ditriethylsilyloxy- 5P,20-epoxy-10-hydroxy-10m-methoxyacetoxy-9-oxo-4apropanoyloxy-11-taxene may be prepared in the following way: To a solution of 0.900 g of 2a-benzoyloxyl3,10-dihydroxy-7,13-bis(triethylsilyloxy)-53,20epoxy-9-oxo-4u-propanoyloxy-ll-taxene in 15 cm 3 of pyridine is added, at a temperature in the region of 0°C, 0.520 cm 3 of methoxyacetyl chloride. The reaction mixture is stirred for 2 hours at a temperature in the region of 200C, followed by addition of 100 cm 3 of dichloromethane and 50 cm 3 of saturated aqueous ammonium chloride solution. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous ammonium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 1.3 g of product are C\ 36 obtained, which product is purified by chromatgraphy on 150 g of silica (0.063-0.2 mm) contained in a column cm in diameter (eluent: ethyl acetate/cyclohexane 25/75 by volume), collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40*C. 0.780 g of 2ca-benzoyloxy- 7/,13a-bis(triethylsilyloxy) -5/,20-epoxy-1f3-hydroxyl0/-methoxyacetoxy-9-oxo-4ot-propanoyloxy-11-taxene is obtained in the form of a white foam, the physical characteristics of which are as follows: 'H NMR spectrum (400 MHz, CDC1 3 6 in ppm) from 0.50 to 0.70 (mt, 12 H :CE 2 ethyl); 0.92 J 7.5 Hz, 9H

:CE

3 ethyl); 1. 00 J 7.5 Hz, 9H CH 3 ethyl); 1. 3H :CHO); 1. 17 3H :CHO); 1, 29 J 7. 5 Hz, 3H CH 3 ethyl at 1.61 1H :O0H at 1.68 (s, 3H :CHO); 1. 84 and 2.51 (2 mts, lE each CE 2 at 6) 2.09 and 2.21 (2 dd, LT 16 and 9 Hz, 1H each CE 2 at 14); 2.10 3H CE 3 2.60 (mt, 2H CH- 2 ethyl at 4); 3.50 3H :OCHO); 3.78 J =7 Hz, 1H :H at 3) 4.12 and 4.30 (2d, J 9 Hz, 1H each :CE 2 at 20) 4.15 (limiting AB, J 16 Hz, 2H :OCOCH 2 O) 4.49 (dd, J 11 and 7 Hz, 1H H at 4.90 (mt, 2H H at 5 and H at 13); 5.62 J 7 Hz, 1H H at 6.52 lHi: H at 10); 7.45 J =7.5 Hz, 2H1: OCOC, 6 H, meta-H; 7.58 J 7.5 Hz, 1H1 OCOCH 5 para-H) 8.09 J 7. 5 Hz, 2H :OCOC 6 H. ortho-H) 2u-Benzoyloxy-1g, 1013-dihydroxy-73, 13u-

I

bis(triethylsilyloxy)-53,20-epoxy-9-oxo-4upropanoyloxy-11-taxene may be prepared in the following way: To a solution of 1.105 g of 13,2a-carbonato- 7S,13a-bis(triethylsilyloxy) -53,20-epoxy-10methoxyacetoxy-9-oxo-4c-propanoyloxy-1-taxene in 50 cm 3 of tetrahydrofuran anhydride are added, at a temperature in the region of -78 0 C, 1.8 cm 3 of a 1M solution of phenyllithium in tetrahydrofuran. The reaction mixture is stirred for 15 minutes at a temperature in the region of -78°C, followed by addition of 10 cm 3 of saturated aqueous ammonium chloride solution. At a temperature in the region of 0 C, 20 cm 3 of saturated aqueous ammonium chloride solution and 50 cm 3 of dichloromethane are added. The organic phase is separated out after settling of the phases has taken place, washed with twice 10 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 1.3 g of product are obtained, which product is purified by chromatography on 150 g of silica (0.063-0.2 mm) contained in a column 5 cm in diameter (eluent: ethyl acetate/cyclohexane: 10/90 by volume), collecting 18 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 0.840 g of 2o-benzoyloxy-l,103-

L

38 dihydroxy-7g,l3c.-bis (triethylsilyloxy) -5A,2O-epoxy-9oxo..4c-propanoyloxy-ll-taxene is obtained in the form of a white foam, the physical characteristics of which are as follows: 1H NMR pr (400 M~Hz, CDC1 3 6 in ppm) from 0.53 (mt, 6 H :CH 2 A:Ithyl) 0. 65 (mt, 6 H CH. ethyl) 0. 92 J= 7.5 Hz, 9H CH. ethyl); 1.00 J= 7.5 Hz, 9H CR 3 ethyl) 1. 07 3H CHO); 1. 14 (s, 3H CR 3 1. 26 J 5 Hz, 3 H :CR 3 e thyl a t 4); 1.40 IR OH at 1) 1. 71 3H :CHO); 1. 88 and 2.45 (2 mts, IR each: CH. at 6) 2. 00 3H CH 3 2.06 and 2.18 (2 dd, J 16 and 9 Hz, lH each: CR 2 at 14); 2. 60 J 7. 5 Hz, 2H CR 2 ethyl at 4) 3. 84 (d, J 7 Hz, lH H at 4.14 and 4.30 (2d, J 8.5 Hz, lH each CR, at 20) 4.26 J 0.5 Hz, lH OH at 4.40 (dd, J 11 at 7 Hz, IH H at 4.90 (broad d, J 10 Hz, 1H H at 4.94 (broad t, 9 Hz, 1H H at 13); 5.12 J =0.5 Hz, lH K at 5.58 JT 7 Hz, lH H at 7.45 J =7.5 Hz, 2H :OCOC.H. meta-H); 7.60 J 5 Hz, lR OCOC 6

H

para H) 8 .0 9 J 5 Hz, 2H :OCOCH,, ortho 1, ,2a-Carbonato-73, 13cu-bis (triethylsilyloxy) 53, 20-epoxy-10jS-methoxyacetoxy-9-oxo-4!-propanoyloxyli-taxene may be prepared in the following way: To a solution of 2.0 g of 1l3,2c-carbonato- 7/3, 3ce-bis (triethylsilyloxy) -53, 20-epoxy-4a-hydroxyl03-methoxyacetoxy-9-oxo-l1-taxene in 90 cm' of dichloromethane are added 3.7 g of (U 4-dimethylaminopyridine and 3.64 cm' of propionic anhydride. The reaction medium is heated at a temperature in the region of 42°C for 8 hours. 50 cm 3 of saturated aqueous sodium chloride solution and 50 cm 3 of dichloromethane are added. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 2.6 g of product are obtained, which product is purified by chromatography on 100 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent: ethyl acetate/cyclohexane 5/95 by volume), collecting 12 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 1.97 g of p1,2acarbonato-78,13a-bis(triethylsilyloxy)-5,20-epoxy-10Omethoxyacetoxy-9-oxo-4c-propanoyloxy-11-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: H NMR spectrum (400 MHz, CDC13, 6 in ppm): from 0.50 to 0.75 (mt, 12H CH, ethyl); 0.94 J 7.5 Hz, 9H

CH

3 ethyl); 1.03 J 7.5 Hz, 9H CH 3 ethyl); 1.21 (mt, 6H CH3 and CH, ethyl); 1.28 3H 1.75 3H CH 3 1.90 and 2.60 (2 mts, 1 H each: CH, at 2.13 3H CH); 2.15 and 2.38 (2 dd, J 16 and 9 Hz, 1 H each: CH, at 14); 2.43 (mt, 2H CH 2 ethyl); 3.43 J 5.5 Hz, 1H H at 3.51 3H OCH 3 4.18 2H OCOCH 2 4.46 (dd, J 11 and 7 Hz, 1H H at 4.48 and 4.65 (2d, J 9Hz, 2H CH, at 4.51 J 5.5 HZ, 1 H H at 4.93 (broad d, J Hz, 1 H H at 5.02 J 9 Hz, 1 H H at 13); 6.51 1H H at 13, 2a-Carbonato-73,13a-bis(triethylsilyloxy) 20-epoxy-4a-hydroxy-100-methoxyacetoxy-9-oxo-11taxene may be prepared in the following way: To a solution of 4.12 g of 10,2a-carbonato- 4a,10(-dihydroxy-7p,13c-bis(triethylsilyloxy)-53,20epoxy-9-oxo-ll-taxene in 80 cm 3 of pyridine are added, with stirring and at a temperature in the region of 0°C, 2 g of powdered 4A molecular sieves and 2.86 cm 3 of methoxyacetyl chloride. The reaction mixture is stirred for 15 minutes at a temperature in the region of 0 C and the reaction medium is then allowed to warm slowly to a temperature in the region of 20 0 C. After stirring for 4 hours at a temperature in the region of 20°C, cm 3 of saturated aqueous ammonium chloride solution and 100 cm 3 of dichloromethane are added. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous ammonium chloride solution, with twice 25 cm 3 of saturated aqueous copper sulphate solution ana with twice 25 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, I II L Y 41 filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 5.3 g of product are obtained, which product is purified by chromatography on 200 g of silica (0.063-0.2 mm) contained in a column 4 cm in diameter (eluent: ethyl acetate/cyclohexane 25/75 by volume), collecting 12 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 4.21 g of 13,2a-carbonato- 7, 13a-bis(triethylsilyloxy) 20-epoxy-4-hydroxy- 10-methoxyacetoxy-9-oxo-11-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: 1 H NMR spectrum (400 MHz, CDC1 3 6 in ppm): 0.59 (mt, 6H CH, ethyl); 0.73 (mt, 6H CH 2 ethyl); 0.91 J Hz, 9 H CH 3 ethyl); 1.02 J 7.5 Hz, 9H CH 3 ethyl); 1.15 3H CH 3 1.18 3H CH 3 1.65 (s, 3H CH 3 1.98 and 2.51 (2 mts, 1 H each CH, at 6); 2.15 3H CH 3 2.54 and 2.72 (2 dd respectively, J 16 and 9 Hz and J 16 and 3 Hz, 1H each CH 2 at 14); 2.93 1H OH at 3.03 J 5 Hz, 1H H at 3.51 3H OCH 3 4.16 (mt, 1H H at 4.17 (AB, J 18 Hz, 2H OCOCH 2 4.37 J 5 Hz, 1H H at 4.54 (AB, J 9 Hz, 2H CH, at 20); 4.76 (broad d, J 10 Hz, 1H H at 4.81 (dd, J 9 and 3 Hz, 1H H at 13); 6.51 1H H at 13,2a-Carbonato-4a, 10-dihydroxy-7,13abis(triethylsilyloxy) -5p,20-epoxy-9-oxo-11-taxene may r i L .i\ r Ir~e 42 be prepared in the following way: To a solution of 0.400 g of 7P,13- 20-epoxy-9-oxo-1S,2~,4a,103tetrahydroxy-11-taxene in 10 cm 3 of dichloromethane are added, with stirring and at a temperature in the region of -78 0 C, 1 cm 3 of pyridine and 0.560 g of triphosgene.

The reaction mixture is stirred for 2 hours at a temperature in the region of -78 0 C and the reaction medium is then allowed to warm slowly to a temperature in the region of 20°C. 30 cm 3 of saturated aqueous ammonium chloride solution and 20 cm 3 of dichloromethane are added. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 0.400 g of a yellow foam is obtained, which is purified by chromatography on 25 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter (eluent: ethyl acetate/cyclohexane 20/80 by volume), collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 0.330 g of 1S,2a-carbonato-4,10Pdihydroxy-70,13-bis(triethylsilyloxy)-53,20-epoxy-9oxo-ll-taxene is obtained in the form of a white foam, the physical characteristics of which are as follows: 1H NMR eyactrum (400 MHz, CDCl 3 6 in ppm) 0.54 (mt, 43 6H CH 2 ethyl); 0.63 (mt, 6H CH 2 ethyl); 0.92 J Hz, 9H CH 3 ethyl); 1.03 J 7.5 Hz, 9H CH 3 ethyl); 1.11 3H CH 3 1.19 3H CH); 1.72 (s, 3H CH 3 1.98 and 2.46 (2 mts, 1H each CH 2 at 6); 2.06 3H CH 3 2.55 at 2.66 (2 dd, J 16 and 9 Hz and J 16 and 3 Hz respectively, 1H each: CH, at 14); 3.00 1H OH at 3.13 J 5 Hz, 1H H at 4.06 (dd, J 11 and 7 Hz, 1H H at 4.20 (d, J 2.5 Hz, 1H OH at 10); 4.33 J 5 Hz, 1H H at 4.55 (AB, J 9 Hz, 2H CH, at 20); 4.76 (broad d, J 10 Hz, 1H H at 4.82 (dd, J 9 and 3 Hz, 1H H at 13); 5.19 J 2.5 Hz, 1H H at 7P,13a-Bis(triethylsilyloxy)-5,20-epoxy-9oxo-13,2 ,4a, 10S-tetrahydroxy-l1-taxene may be prepared in the following way: To a solution of 3.80 g of 5P,20-epoxy-9-oxo- 10,2c,4a, 103,13Q-pentahydroxy-7-triethylsilyloxy-1ltaxene in 100 cm 3 of dichloromethane are added, with stirring and at a temperature in the region of 0°C, 1.20 cm 3 of pyridine and 2.48 cm 3 of chlorotriethylsilane. The reaction mixture is stirred for 3 hours at a temperature in the region of 0°C.

100 cm 3 of saturated aqueous sodium chloride solution are added. The organic phase is separated out after settling of the phases has taken place, washed with twice 100 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate,

Y

filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 5.34 g of an orangecoloured oil are obtained, which product is purified by chromatography on 300 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent: ethyl acetate/cyclohexane 25/75 by volume), collecting cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0

C.

4.18 g of of 73,13c-bis(triethylsilyloxy)-53,20-epoxy- 9-oxo-l,2 ,4a,10-tetrahydroxy-11-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: 1H NMR spectrum (400 MHz, CDC1 3 6 in ppm) 0.53 (mt, 6H CH, ethyl); 0.75 (mt, 6H CH 2 ethyl); 0.91 J= Hz, 9H CH 3 ethyl); 1.01 3H CH 3 1.03 (t, J 7.5 Hz, 9H CH 3 ethyl); 1.09 3H CH 3 1.63 3H 1.97 3H CH 3 from 1.95 to 2.10 and 2.40 (2 mts, 2H each CH 2 at 14 and CH, at 3.17 (s, 1H OH); 3.18 J 5.5 Hz, 1H H at 3.43 J 10 Hz, 1H OH at 3.76 (dd, J 10 and 5.5 Hz, 1H H at 3.96 (dd, J 11 and 6 Hz, 1H H at 7); 4.10 1H OH); 4.18 J 3 Hz, 1H OH at 4.44 and 4.73 (2d, J 9 Hz, 1H each: CH, at 20); 4.64 (broad d, J 10 Hz, 1H H at 4.74 (mt, 1H H at 13); 5.14 J 3 Hz, 1H H at -I L EXAMPLE 2 To a solution of 20.5 mg of 53,20-epoxy-lhydroxy-103-methoxyacetoxy-9-oxo-4-propanoyloxy-2- (2thenoyloxy)-7-trifluoromethanesulphonyloxy-ll-taxen- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate in 0.2 cm 3 of acetonitrile and 0.025 cm 3 of tetrahydrofuran are added 45 mg of sodium chloride and a spatulaful of activated 4A molecular sieves. The mixture obtained is maintained at reflux, for 2 hours, under an argon atmosphere. After cooling to a temperature in the region of 20 0 C, the solvents are evaporated off under reduced pressure (0.27 kPa) at a temperature in the region of 40 0 C, and the solid residue is taken up in 5 cm 3 of dichloromethane, filtered on cotton wool and rinsed with 5 cm 3 of an ethyl acetate/dichloromethane mixture (50/50 by volume). The organic phases are concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 0 C. 17.1 mg of a yellow foam are thus obtained, which product is purified by thin-layer preparative chromatography [2 Merck preparative plates, Kieselgel 60F254, thickness 0.25 mm, deposited as a solution in dichloromethane, eluent: methanol/dichloromethane mixture (6/94 by volume)].

After elution of the zone corresponding to the main product with a methanol/dichloromethane mixture (10/90 by volume), filtration on sintered glass and then evaporation of the solvents under reduced pressure II-_s 46 (0.27 kPa) at a temperature in the region of 40 0

C,

10.0 mg of 5,,20-epoxy-1p-hydroxy-l003-meth7oxyacetoxy- 7, 8j-methyJlene-9-oxo-4o-propanoyloxy-2u- (2-thenoyloxy) butoxycarbonylamino- 2-hydroxy-3 -phenyipropionate are obtained in the form of a white resin, the characteristics of which are as follows: 1H NMR spectrum (400 MI~z, CDC1 3 6 in ppm) :1.18 (t, J 7.5 Hz, 3H :OH 3 ethyl); 1.22 6H CHO); 1.32 9H :C(CHO) 3 1.41 (mt, 1H :H at 1.69 and 2.23 (2 mt.s, 1H each OH 2 at 19) 1. 81 1H OH at 1); 1.85 3H1: CHO); 2.12 and 2.50 (d and dt respectively, J 16 and J 16 and 4.5 Hz, 1H1 each

CH

2 at 6) 2.25 and 2.39 (2 dd, J =16 and 9 Hz, 1H1 each :CH 2 at 14) 2.63 (mt, 2H1 :OH 2 ethyl); 3.23 (mt, 1H OH at 3.52 3H1: OCH 3 4.03 J =7 Hz, 1H1 H at 4.12 and 4.44 (2d, J 9 Hz, 1H each OH 2 at 20); 4.20 (limiting AB, J 16 Hz, 2H 000011320); 4.62 (mt, 1H H at 4.70 J 4 Hz, 111: H at 5.22 (mt, 1H :H at 5.28 J 10 Hz, 111: CONH); 5.58 j 7 Hz, 111: H at 6.23 (broad t, J 9 Hz, 111 H at 13); 6.41 111 H at 10); 7.18 (dd, J 5 and 3.5 Hz, 1H1 H at 4 of the 2-thenoyl); from 7.30 to 7.50 (mt, 5H1: aromatic H at 7.67 (broad d, J 5 Hz, 1H1 H at 5 of the 2-thenoyl); 7.96 (broad d, J 3.5 Hz, 1H1 H at 5 of the 2-thenoyl).

53, 20-Epoxy-1/3-hydroxy-l0g3-methoxyacetoxy-9oxo-4oa-propanoyloxy-2e- (2-thenoyloxy) -7f3- 47 trifluoromethanesulphonyloxy-ll-taxen-13-yl (2R,3S)-3tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate may be prepared in the following way: A solution of 75 mg of 53,20-epoxy-lhydroxy-103-methoxyacetoxy-9-oxo-4u-propanoyloxy-2a-(2thenoyloxy)-7g-trifluoromethanesulphonyloxy-11-taxen- 13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4methoxyphenyl)-4-phenyl-l,3-oxazolidine-5-carboxylate in 0.77 cm 3 of a 0.1N solution of hydrochloric acid in ethanol is stirred at a temperature in the region of 0 C for 2 hours. The reaction mixture is then diluted with 10 cm 3 of dichloromethane and washed with twice 1 cm 3 of distilled water. After extraction of the aqueous phase with 1 cm 3 of dichloromethane, the organic phases are combined, dried over magnesium sulphate, filtered on sintered glass and concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 0 C. 74.4 mg of a yellow resin are thus obtained, which product is purified by chromatography at atmospheric pressure on 8 g of silica (0.063-0.2 mm) contained in a column 1.5 cm in diameter (elution gradient: ethyl acetate/dichloromethane from 5/95 to 20/80 by volume), collecting 8 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 0 C for 2 hours. 56.3 mg of 53,20-epoxy-1l-hydroxy-103-methoxyacetoxy-9-oxo-4apropanoyloxy-2a-(2-thenoyloxy)-75- 'I u trifluoromethanesulphonyloxy-1-taxen-13u-yl (2R,3S) -3tert-butoxycarbonylamino-2 -hydroxy-3 -phenyipropionate are thus obtained in the form of a pale yellow foam, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz, CDC1 3 b5 in ppm) :1.20 (s, 6H :CHO); 1.22 J 7.5 Hz, 3H :CH 3 ethyl); 1.36 9H C(CHO) 3 1.71 111: OH at 1.89 3H CHO); 2.05 3H CHO); 2.25 and 2.86 (2 mts, 1H each CH 2 at 6) 2.33 J 9 Hz, 2H :CH 2 at 14); 2.66 (mt, 2H :CH 2 ethyl); 3.28 J =5 Hz, 1H :OH at 3.52 3H :OCHO); 3.90 J =7 Hz, 1H H at 3) 4.20 (limiting AB, J 16 Hz, 2H :OCOCH 2 4.27 and 4.50 (2d, J 9 Hz, 1H each :Cl! 2 at 20); 4.61 (mt, 1H H at 4.88 (broad d, J =10 Hz, 1H :H at 5.20 (broad d, J 10 Hz, 1H1 H at 5.30 J Hz, 1H :CONE); 5.50 (dd, J 10 and 7 Hz, 1H1 H at 5.65 J 7 Hz, 1H! H at 6.18 (broad t, J 9 Hz, 1H1 H at 13); 6.70 1H H at 10); 7.18 (dd, J 5 and 3.5 Hz, 11!I H at 4 of the 2-thenoyl); from 7.30 to 7.50 (mt, 5H :aromatic H at 7.69 (dd, J and 1.5 Hz, 1H H at 5 of the 2-thenoyl); 7.92 (dd, J 3.5 and 1.5 Hz, 1H H at 5 of the 2-thenoyl).

20-Epoxy- lg-hydroxy-100-methoxyacetoxy-9oxo-4ce-propanoyloxy-2x- (2-thenoyloxy) -7j3trifluoromethanesulphonyloxy-11-taxen-3v-yl (2R, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1,3-oxazolidine-5-carboxylate may be prepared in the following way: 49 To a solution of 55.2 mg of 5/,20-epoxy- 13 3-dihydroxy-l0/3-methoxyacetoxy-9-oxo-4apropanoyloxy-2a- (2-thenoyloxy) -7/3trifluoromethanesuiphonyloxy-il-taxene in 0.1 cm 3 of anhydrous toluene are successively added 41 mg of (2R, 4S, SR) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1,3-oxazolidine-5-carboxylic acid, 26 mg of dicyclohexylcarbodiimide a.nd 3 mg of 4-(N,Ndimethylamino)pyridine. The reaction mixture is stirred for 2 hours, under an argon atmosphere and at a temperature in the region of 20 0 C, and then placed on a chromatography column at atmospheric pressure (15 g of silica (0.063-0.2 mm) contained in a column 1.5 cm in diameter (elution gradient: ethyl acetate/dichloromethane from 5/95 to 10/90 by volume), collecting 10 cm 3 fractions). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at for 2 hours. 75.3 mg of 5/,20-epoxy-l/3-hydroxy-l03methoxyacetoxy-9-oxo-4a-propanoyloxy-2e- (2-thenoyloxy) 7/3-trifluoromethanesulphonyloxy-ll- taxen- l3c-yl (2R,4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxy-phenyl) -4phenyl-l, 3-oxazolidine-5-carboxylate are thus obtained in the form of a white foam, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz, CDCl 3 5 in ppm) 1. 04 (s, 9H C (CH 3 1. 04 LJ 7. 5 Hz, 3H :CH 3 ethyl) 1. 14 3H :CHO); 1.-16 3H :CII) 1. 61 1H OH at 1) 1.-68 3H CHO); 1.-81 3H :CHO); from 2.00 to 2.30 (mt, 4H :CH. ethyl and CH, at 14) 2.03 and 2.80 (2 mts, 1H each CH. at 3.50 3H OCH 3 3.77 J 7 Hz, 1H H at 3.81 3H :ArOCH 3 4.13 (limiting AB, J =16 Hz, 2H OCOCHO) 4. 18 and 4.39 (2d, J 9 Hz, 1H each CH 2 at 20) 4.48 J 4 Hz, 1H :H at 4.78 (broad d, J 10 Hz, IH :H at from 5.35 to 5.50 (mt, 2H :H at 3' and H at 7); 5.55 J 7 Hz, IH :H at 5.96 (broad t, J 9 Hz, 1H :H at 13); 6.34 (mt, 1H %H at 6.56 (s, IH H at 10); 6.88 J =8 Hz, 2H :aromatic H ortho to the OCHO); 7.13 (dd, JLT 5 and 3.5 Hz, lH :H at 4 of the 2-thenoyl); from 7.30 to 7.45 (mt, 5H aromatic H at 7.36 J 8 Hz, 2H :aromatic H meta to the OCHO); 7. 62 (broad d, J 5 Hz, lH H at 5 of the 2 thenoyl); 7.80 (broad d, J 3.5 Hz, 1H H at 5 of the 2-thenoyl).

53, 20-Epoxy-1, ,13u-dihydroxy-103methoxyacetoxy-9-oxo-4cL-propanoyoxy-2u- (2-thenoyloxy) 7g-trifluoromethanesulphonyloxy-1l-taxene may be prepared in the following way: To a solution of 50 mg of 5f3,20-epoxy-l03methoxyacetoxy-9-oxo-4ci-propanoyloxy-2e- (2-thenoyloxy) l/,7/,13a-trihydroxy-l1-taxene in 0.5 cm 3 of anhydrous dichioromethane and 0.0255 cm 3 of pyridine, maintained under an argon atmosphere and at a temperature in the region of 0 0 C, is added dropwise 0.0265 cm 3 of trifluoromethanesuiphonic anhydride. The orange- 51 coloured solution obtained is stirred for 10 minutes at a temperature in the region of 0 0 C and for 45 minutes at a temperature in the region of 20 0 C, followed by addition of 0.1 cm of a methanol/dichloromethane S mixture (5/95 by volume). The solution is placed on a chromatography column at atmospheric pressure (10 g of silica (0.063-0.2 mm) contained in a column 1.5 cm in diameter (elution gradient: methanol/dichloromethane from 2/98 to 5/95 by volume), collecting 8 cm' fractions). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 0 C for 2 hours.

55.2 mg of 5j,20-epoxy-1l,l3a-dihydroxy-103methoxyacetoxy-9-oxo-4a-propanoylxy-2a-(2-thenoyloxy)- 73-trifluoromethanesulphonyloxy-11-taxene are thus obtained in the form of a white foam.

5/,20-Epoxy-1,73,13a-trihydroxy-10methoxyacetoxy-9-oxo-4-propanoyloxy-2a-(2-thenoyloxy)- 11-taxene may be prepared in the following way: To a solution of 0.302 g of 5g,20-epoxy-lphydroxy-10-methoxyacetoxy-9-oxo-4a-propanoyloxy-2a-(2thenoyloxy)-7/,13a-bis (triethylsilyloxy)-11-taxene in cm 3 of dichloromethane are added, at a temperature in the region of 20C, 6 cm 3 of triethylamine-hydrofluoric acid complex (Et 3 N.3HF). The reaction mixture is stirred for 24 hours at a temperature in the region of 20 0

C,

followed by addition of 50 cm 3 of dichloromethane and 100 cm 3 of saturated aqueous sodium hydrogen carbonate rnA- *'fV

T

II I 52 solution. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 0.24 g of 5P,20-epoxy- 10,7, 13-trihydroxy-10/-methoxyacetoxy-9-oxo-4propanoyloxy-2- (2-thenoyloxy) -11-taxene is thus obtained in the form of a white foam, the characteristics of which are as follows: 1H NMR spectrum (400 MHz, CDC1 3 6 in ppm): 1.07 (s, 3H CH) 1.10 3H CH 3 1.22 J 7.5 Hz, 3H

CH

3 ethyl); 1.62 1H OH at 1.69 3H CH,); 1.89 and 2.63 (2 mts, 1H each: CH 2 at 2.03 J 5.5 Hz, 1H OH at 13); 2.07 3H CH 3 2.27 J 9 Hz, 2H CH, at 14); 2.35 J 4.5 Hz, 1H OH at 2.59 (mt, 2H CH, ethyl); 3.52 3H OCH); 3.84 J 7 Hz, 1H H at 4.23 and 4.43 (2d, J 9 Hz, 1H each CH, at 20); 4.25 (limiting AB, J 16 Hz, 2H OCOCH0O); 4.49 (mt, 1H H at 4.87 (mt, 1H H at 13); 4.95 (broad d, J 10Hz, 1H H at 5.53 J 7 Hz, 1H H at 6.42 1H H at 7.14 (dd, J 4.5 and 3.5 Hz, 1H H at 4 of the 2-thenoyl); 7.61 (dd, J 4.5 and 1.5 Hz, 1H H at of the 2-thenoyl); 7.83 (dd, J 3.5 and 1.5 Hz, 1H H at 3 of the 2-thenoyl).

5/,20-Epoxy- 1-hydroxy-103-methoxyacetoxy-9oxo-4a-propanoyloxy-2- (2-thenoyloxy)-73,13 1 V' k

A

bis(triethylsilyloxy)-11-taxene may be prepared in the following way: To a solution of 0.5 g of 5A,20-epoxy-13,103dihydroxy-9-oxo-4a-propanoyloxy-2a-(2-thenoyloxy)- 7,13a-bis(triethylsilyloxy)-11-taxene in 10 cm 3 of pyridine is added, at a temperature in the region of 0 C, 0.286 cm 3 of methoxyacetyl chloride. The reaction mixture is stirred for 10 hours at a temperature in the region of 20°C, followed by addition of 100 cm 3 of dichloromethane and 50 cm 3 of saturated aqueous ammonium chloride solution. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous ammonium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 C. The residue obtained (0.6 g) is purified by chromatography on 50 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter (eluent: ethyl acetate/cyclohexane 5/95 by volume), collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 0

C.

0.320 g of 5P,20-epoxy-l-hydroxy-10j-methoxyacetoxy-9oxo-4a-propanoyloxy-2a-(2-thenoyloxy)-7, 13ubis(triethylsilyloxy)-11-taxene is obtained in the form of a white foam, the physical characteristics of which are as follows: 1 H NMR spectrum (400 MHz, CDC13, 6 in ppm) from 0.50 It (t 54 to 0.70 (mt, 12 H :OH 2 ethyl) :0.92 J 7.5 Hz, 9H CH 3 ethyl); 0.98 J =7.5 Hz, 9H O H 3 ethyl); 1. 09 3H :CH 3 1. 15 3H CHO 1. 27 J 7. 5 Hz, 3H CH. ethyl at 1. 59 1H OH at 1); 1. 65 3H CO 3 1. 85 and 2.52 (2 mts, ili each :CH 2 at 2.07 and 2.18 (2 dd, J =16 and 9 Hz, 1H each: CH. at 14) 2. 08 3H OH 3 2. 58 (mt, 2H CH 2 ethyl at 4) 3.50 3H1 00113) 3.73 J 7 Hz, 1H1: H at 3) 4.13 (limiting AB, J 16 Hz, 2H 00001120) 4.20 and 4.41 (2d, J 9 Hz, 1H each O H. at 20) 4.49 (ad, J =11 and 7 Hz, 111: H at 4.89 (broad t, J 9 Hz, 1H =H at 13); 4.91 (broad d, J 10 Hz, 111 H at 5.53 J 7 Hz, 111 H at 6.51 111 H at 7.12 (dd, J 4.5 and 3 Hz, 1H :H at 4 of the 2-thenoyl); 7.61 J 4.5 Hz, 111: H at 5 of the 2-thenoyl); 7.b3 J 3 Hz, 1H :H at 3 2-thenoyl).

20-Epoxy-1g3,I10/-dihydroxy-9-oxo-4upropanoyloxy-2ci- thenoyloxy) -7g3, 3ctbis(triethylsilyloxy)-11-taxene may be prepared in the following way: To a solution of 0.5 g of 1/3,2acarbonyldioxy-53, 20-epoxy-10g3-methoxyacetoxy-9-oxo-4o!propanoyloxy-73,13oa-bis(triethylsilyloxy) -li-taxene in cm 3 of tetrahydrofuran, under an argon atmosphere and at a temperature in the region of -78oO, are added cm 3 of a IM solution of 2-thienyllithium in tetrahydrofuran. The reaction mixture is stirred for minutes at a temperature in the region of -781C, followed by addition of 1 cm 3 of saturated aqueous ammonium chloride solution. At a temperature in the region of 20 0 C, 10 cm 3 of saturated aqueous ammonium chloride solution and 50 cm 3 of dichloromethane are added. The organic phase is separated out after settling of the phases has taken place, washed with twice 10 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 0.65 g of a solid is obtained, which is purified by chromatography on 90 g of silica (0.063-0.2 mm) contained in a column 1 cm in diameter (eluent: ethyl acetate/cyclohexane 10/90 by volume), collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40°C. 0.511 g of 5P,20-epoxy-l1,103dihydroxy-9-oxo-4a-propanoyloxy-2oa-(2-thenoyloxy)- 7P,13a-bis(triethylsilyloxy)-11-taxene is obtained in the form of a white foam, the physical characteristics of which are as follows: 'H NMR (600 MHz, CDC13, 6 in ppm): 0.57 (mt, 6 H CH, ethyl); 0.68 (mt, 6 H CHW ethyl); 0.95 J 7.5 Hz, 9H CH 3 ethyl); 1.01 J 7.5 Hz, 9H CH 3 ethyl); 1.07 3H CH 3 1.17 3H CH 3 1.27 J Hz, 3H CH3 ethyl at 1.73 3H CH 3 1.90 and 2.47 (2 mts, 1H each; CH, at 2.02 3H CH 3 2.09 and 2.18 (2 dd, J 16 and 9 Hz, 1H each CH, at L:raF~

II

56 14); 2.60 (mt, 2H CH, ethyl at 3.82 J 7 Hz, 1H H at 4.24 and 4.44 (2d, J 9 Hz, 1H each CH 2 at 20); 4.26 J 0.5 Hz, IH OH at 10); 4.42 (dd, J 11 and 7 Hz, 1H H at 4.93 (broad d, J 10 Hz, 1H H at 4.97 (broad t, J 9 Hz, 1H H at 13); 5.13 J 0.5 Hz, 1H H at 10); 5.53 J 7 Hz, 1H H at 7.15 (dd, J 4.5 and 3 Hz, 1H H at 4 of the 2-thenoyl); 7.63 J 4.5 Hz, 1H H at of the 2-thenoyl); 7.85 J 3 Hz, 1H H at 3 of the 2-thenoyl).

EXAMPLE 3 To a solution of 154 mg of 2a-benzoyloxy-4abutanoyloxy-5g,20-epoxy-13-hydroxy-103-methoxyacetoxy- 9-oxo-7g-trifluoromethanesulphonyloxy-11-taxen-13Q-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate in 2 cm 3 of acetonitrile and 200 ~l of tetrahydrofuran are successively added 96 mg of powdered 4A molecular sieves and 225 mg of sodium chloride. The reaction mixture is kept stirring at a temperature in the region of 75 0 C for 5 hours, followed, at a temperature in the region of 20 0 C, by addition of 15 cm 3 of dichloromethane and 10 cm 3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, washed with twice 20 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to 57 dryness under reduced pressure (2.7 kPa) at 40 0

C.

133 mg of product are obtained, which product is purified by chromatography on 80 g of silica (0.063- 0.2 mm) contained in a column 1 cm in diameter, eluting with a dichloromethane/methanol mixture (98/2 by volume) and collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. 63 mg of 2a-benzoyloxy-4abutanoyloxy-5,20-epoxy-13-hydroxy-101S-methoxyacetoxy- 7/,8-methylene-19-nor-9-oxo-1-taxen-13o-yl (2R,3S)-3tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are obtained in the form of a white foam, the physical characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CDC1 3 6 in ppm): 0.92 (t, J 7.5 Hz, 3H CH 3 of the propyl); 1.26 6H CH); 1.31 9H C(CH) 3 1.42 (mt, 1H H at 1.71 and 2.26 (2 mts, 1H each CH, at 19); from 1.60 to 1.85 (mt, 2H CH 2 of the propyl); 1.86 3H CH 3 1.88 1H OH at 2.12 and 2.50 (broad d and mt respectively, J 16 Hz, 1H each CH, at 2.23 and 2.39 (mt and dd respectively, J 16 and 9 Hz, 2H CH 2 at 14); 2.49 and 2.65 (2 mts, 1H each OCOCH, of the propyl); 3.25 (mt, 1H OH at 3.51 3H OCH); 4.05 and 4.32 (2 d, J 9 Hz, 1H each CH 2 at 20); 4.10 J 7 Hz, 1H H at 4.16 and 4.22 (2 d, J 16 Hz, 1H each: OCOCHO); 4.62 (mt, 1H H at 4.68 (broad d, J 4.5 Hz, 1H H at 5.25 (broad d, J 58 Hz, lH H at 5.30 J =10 Hz, 1H :CONH); 5.65 J =7 Hz, 1H :H at 6.23 (broad t, J 9 Hz, 1H :H at 13); 6.42 1H :H at 10); from 7.25 to 7.45 (mt, 5H :aromatic H at 7.51 JT Hz, 2H :OCOC 6 H. meta-H); 7.62 J 7.5 Hz, 1H

OCOC

6

H

5 para-H) 8.16 J 7.5 Hz, 2H :OCOC6H 5 ortho-H).

2ou-Benzoyloxy-4oe-butanoyloxy-53, 20-epoxy-1Phydroxy-.10)3-methoxyacetoxy- 9-oxo-7g3trifluoromethanesulphonyloxy-11-taxen-13a-yl (2R, 3S) -3tert-butoxycarbonylamino-2 -hydroxy-3 -phenylpropionate may be prepared in the following way: A solution of 400 mg of 2cu-benzoyloxy-4ubutanoyloxy-53, 20-epoxy-1f3-hydroxy-10j3-methoxyacetoxy- 9-oxo-7g-trifluoromethanesulphonyloxy-11-taxen-13a-yl (2R,4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1,3-oxazolidine-5-carboxylate in 6.4 cm' of 0.1N hydrochloric ethanol solution is kept stirring at a temperature in the region of 0 0 C for 6 hours, and then at a temperature in the region of 201C for 15 hours.

The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at 201C. The crude reaction product is dissolved in 20 cm 3 of dichloromethane and cm 3 of saturated aqueous sodium bicarbonate solution.

The aqueous phase is separated out after settling of the phases has taken place and then extracted with twice 20 cm 3 of dichloromethane. The organic phases are combined, washed with 30 cm 3 of distilled water and then 59 dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 20°C. 410 mg of a product are obtained, which product is purified by chromatography on 60 g of silica (0.063-0.2 mm) contained in a column 1 cm in diameter, eluting with a dichloromethane/methanol mixture (98.5/1.5 by volume) and collecting 10 cm 3 fractions.

The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 20 0 C. 307 mg of 2a-benzoyloxy-4a- 20-epoxy-13-hydroxy-10-methoxyacetoxy- 9-oxo-7-trifluoromethanesulphonyloxy-1l-taxen-13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate are obtained in the form of a white foam, the physical characteristics of which are as follows: 1H NMR spectrum (400 MHz; CDCl 3 6 in ppm) 0.93 (t, J 7.5 Hz, 3H CH 3 of the propyl); 1.22 3H CH 3 1.24 3H CH 3 1.35 9H C(CH 3 3 from 1.65 to 1.85 (mt, 2H CH 2 of the propyl); 1.74 1H OH at 1.88 3H CH 3 2.04 3H CH3); 2.25 and 2.86 (2 mts, 1H each CH 2 at 2.33 J 9 Hz, 2H CH 2 at 14); 2.52 and 2.66 (2 mts, J 14.5 and Hz, 1H each OCOCH, of the propyl); 3.33 J 4 Hz, 1H OH at 3.52 3H OCH 3.94 J 7 Hz, 1H H at 4.16 and 4.21 (2 d, J 16 Hz, 1H each: OCOCH0O); 4.19 and 4.35 (2 d, J 9 Hz, 1H each CH, at 20); 4.62 (mt, 1H H at 4.86 (broad d, J Hz, lH :H at 5.22 (broad d, J 10 Hz, 1H :H at 5.33 J 10 Hz, 1H :CONH); 5.50 (dd, J 11 and 8 Hz, 1H H at 5.73 J 7 Hz, 1H :H at 6.16 (broad t, J 9 Hz, 1H :H at 13); 6.71 (s, 1H :H at 10); from 7.25 to 7.45 (mt, 5H aromatic H at 7.51 J =7.5 Hz, 2H1 0C0C.H. meta-H); 7. 63 J =7.5 Hz, 1H OCOC 6

H

5 para-H); 8.12 J Hz, 2H1 OCOCAH at ortho-H) 2oi-Benzoyloxy-4cu-butanoyloxy-53, 20-epoxy-/3hydroxy-10p-methoxyacetoxy-9-oxo-7g3trifluoromethanesulphonyloxy- 11- taxen- 13c-yl (2R,4S,5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1,3-oxazolidine-5-carboxylate may be prepared in the following way: To a solution of 400 mg of 2u-benzoyloxy-4ubutanoyloxy-l3, 3a-dihydroxy-53, 20-epoxy-10gmethoxyacetoxy-9-oxo-7f3-trifluoromethanesulphonyloxyil-taxene in 10 cm 3 of anhydrous ethyl acetate are successively added 247 mg of (2R,4S,5R)-3-tertbutoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1, 3acid, 186 mg of dicyclohexylcarbodiiride and 12.5 mg of 4-dimethylaminopyridine. The reaction mixture is stirred for 15 hours, under an argon atmosphere and at a temperature in the region of 20*C, and then concentrated to dryness under reduced pressure (2.7 kPa) at 40-C. 1 g of a product is obtained, which is purified by chromatography on 100 g of silica K~ ~S 61 (0.063-0.2 mm) contained in a column 3 cm in diameter, eluting with a dichioromethane/methanol mixture (95/5 by volume) and collecting 12 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40*C. 410 mg of 2cx-benzoyloxy-4a- 20-epoxy-10-hydroxcy-10f3-methoxyacetoxy- 9-oxo-7f-trifluoromethanesulphonyloxy-11-taxen-13u-yI (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1, 3-oxazolidine-5-carboxylate are obtained in the form of a white foam, the physical characteristics of which are as follows: 3-H NMR spectrum (400 MHz; CDCl 3 6 in ppm) 0. 92 (t, J 7. 5 Hz, 3H CH 3 of the propyl) 1. 07 9H: C (CH 3 1. 17 6H CHO f rom 1. 55 to 1. 70 (mt, 3H CH 2 of the propyl and OH at 1) 1. 64 3H :CHO) 1. 84 3H1 CHO 2. 08 and f rom 2. 15 to 2. 30 (dd and mt respectivrely, J 16 and 9 Hz, 1H1 each CH 2 at 14); from 2.15 to 2.30 and 2.82 (2 mts, 1H1 each :CH 2 at 6); from 2.15 to 2.30 (mt, 2H OCOCH 2 of the propyl); 3.51 311 OCHO); 3.82 3H1 ArOCHO); 3.83 J 7 Hz, 1H H at 4.12 and 4.28 (2 d, J =9 Hz, 111 each CH 2 at 20) 4.14 and 4.22 (2 d, J 16 Hz, 1H each :OCOCH 2 O) 4.52 (broad d, J =4.5 Hz, lH :H at 4.79 (broad d, J 10 Hz, 1H1 H at from 5.35 to 5.50 (mt, 111 H at 5.44 (dd, J 9 and 7 Hz, 1H1 H at 5.67 J 7 Hz, 1H H at 5.99 (broad t, J 9 Hz, 1H H at 13); 6.40 (mult., 1H H

(IT/

at 6.59 1H H at 10); 6.92 J 8.5 Hz, 2H aromatic H ortho to the OCH 3 from 7.25 to 7.45 (mt, 5H aromatic H at 7.37 J 8.5 Hz, 2H aromatic meta to the OCH) 7.48 J 7.5 Hz, 2H

OCOC

6 Hs meta-H); 7.63 J 7.5 Hz, 1H OCOC 6

H

5 para- H) 8.11 J 7.5 Hz, 2H OCOCHs ortho-H).

The 2a-Benzoyloxy-4a-butanoyloxy-1,13adihydroxy-53,20-epoxy-10-methoxyacetoxy-9-oxo-7ptrifluoromethanesulphonyloxy-11-taxene may be prepared in the following way: To a solution of 389 mg of 2a-benzoyloxy-4abutanoyloxy-5P,20-epoxy-10/-methoxyacetoxyl-9-oxo- 13,7,13a-trihydroxy-ll-taxene in 6 cm 3 of anhydrous dichloromethane and 390 gl of pyridine, maintained under an argon atmosphere and at a temperature in the region of 0 C, are added dropwise 410 gl of trifluoromethanesulphonic anhydride. The orangecoloured solution obtained is stirred for 15 minutes at a temperature in the region of 0°C, followed by addition of 3 cm 3 of water and 50 cm 3 of dichloromethane. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 510 mg of product are obtained, which product is purified by chromatography on 70 g of silica (0.063-0.2 mm) contained in a column 1 63 1 cm in diameter, eluting with a dichioromethane/methanol mixture (95/5 by volume) and collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 410 mg of 2ca-benzoyloxy-4ca-butanoyloxy-l1~3a- 20-epoxy-10j5-methoxyacetoxy-9-oxo-73trifluoromethanesulphonyloxy-11-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: 'H NMR spectrum (400 MHz; CDC1 3 i5 in ppm) 1. 06 (t, J 5 Hz, 3H CH 3 of the propyl) 1. 06 3H CHO) 1.20 3H CHO); 1.63 1H OH at 1.77 (mt, 2H CH 2 of the propyl); 1. 87 3H CHO); 2.18 (d, J 5 Hz, 1H OH at 13); from 2.15 to 2.40 (limiting AB, 211 CH- 2 14); from 2.15 to 2.40 and 2.89 (2 mts, 1H each CH 2 6) 2.25 3H :CHO); 2.59 (limiting AB, J 16 and 7.5 Hz, 2H :OCOCH' 2 of the propyl) 3.51 (s, 3H OCHO); 4.03 J =7 Hz, lH H3) 4.16 and 4.24 (2 d, J 16 Hz, 1H1 each :OCOCH 2 O) 4.18 and 4.35 (2 d, J 9 Hz, 1H each CH 2 20) 4.85 (mt, lIH H13) 4.92 (broad d, J 10 Hz, 1H H5); 5.57 (dd, J 10.5 and 7 Hz, 1H H 5.68 J 7 Hz, 1H H 6.73 (s, 1H H 10); 7.51 J =7.5 Hz, 2H OCOC.H. meta-H); 7. 63 J 5 Hz, 1H :OCOC.H. para-H) 8. 10 (d, J 7.5 Hz, 2H OCOC.H. ortho-H) 2oe-Benzoyloxy-4ou-butanoyloxy-5P, methoxyacetoxy-9-oxo-1p,7p,13oe-trihydroxy-11-taxene may 0 w 64 be prepared in the following way: To a solution of 580 mg of 2a-benzoyloxy-4abutanoyloxy-7j,13a-bis(triethylsilyloxy)-53,20-epoxy- 1-hydroxy-10-methoxyacetoxy-9-oxo-ll-taxene in 5 cm 3 of dichloromethane are added, at a temperature in the region of 20°C, 5.5 cm 3 of triethylamine-hydrofluoric acid complex. The reaction mixture is stirred for 23 hours at a temperature in the region of 200C, followed by addition of 50 cm 3 of dichloromethane and 100 cm 3 of saturated aqueous sodium hydrogen carbonate solution.

The organic phase is separated out after settling of the phases has taken place, washed with twice 20 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 520 mg of product are obtained, which product is purified by chromatography on 70 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with a methanol/dichloromethane mixture (5/95 by volume) and collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 389 mg of 2abenzoyloxy-4a-butanoyloxy-53,20-epoxy-10fmethoxyacetoxy-9-oxo-1g,7,13-trihydroxy-ll-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: H NMR spectrum (400 MHz; CDCL 3 6 in ppm) 1.05 (t,

K

I J 7. 5 Hz, 3H :CH 3 of the propyl);11 6H :cH 3 1.67 3H :CH 3 1.71 1H :OH at 1.75 (Lnt, 2H :CH, of the propyl); 1.85 and from 2.45 to 2.65 (2 mts, 1H each CH, at 6) 2.05 3H :CHO); 2.24 J =5 Hz, 1H OH); 2.28 (limiting AB, J 16 and 9 Hz, 2H CH 2 at 14) 2. 40 J 4 Hz, 1H :OH) 2.5 6 (limiting AB, 2H OCOCH 2 of the propyl) 3.51 3H OCHO) 3.88 J =7 Hz, 1H :H at 3) 4.15 and 4.32 (2 d, J =9 Hz, IH each :CH 2 at 20) 4.23 (limiting AB, J 16 Hz, 2H :OCOCH 2 4.48 (mt, 1H :H at 4.86 (mt, 1H :H at 13); 4.94 (broad d, JT 10 Hz, 1H :H at 5.62 J =7 Hz, 1H :H at 6.43 1H :H at 7.49 J =7.5 Hz, 2H :OCOC.H. raeta-H) 7.62 (t, J =7.5 Hz, 1H OCOC.H. para-H) 8.12 J 7.5 Hz, 2H OCOCAH ortho-H) 2cu-Benzoyloxy-4oe-butanoyloxy-73, 13oubis (triethylsilyloxy) -53, 20-epoxy-1/3-hydroxy-013methoxyacetoxy-9-oxo-l1-taxene may be prepared in the following way: To a solution of 906 mg of 2cu-benzoyloxy-4abutanoyloxyl-13,103-dihydroxy-73,l3Ybis(triethylsilyloxy) -51,20-epoxy-9-oxo-11-taxene in 18 cm' of pyridine are added, at a temperature in the region of V 0 C, 1.03 cm 3 of methoxyacetyl chloride. The reaction mixture is stirred for 14 hours at a temperature in the region of 20o(C, followed by addition of 20 cm 3 of dichloromethane and 20 cm 3 Of saturated aqueous ammonium chloride solution. The organic phase 66 is separated out after settling of the phases has taken place, washed with 4 times 20 cm 3 of saturated aqueous copper sulphate solution, with twice 40 cm 3 of saturated aqueous ammonium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 800 mg of a product are obtained, which product is purified by chromatography on 100 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol/dichloromethane mixture (2/98 by volume) and collecting 15 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0

C.

580 mg of 2a- benzoyloxy-4a-butanoyloxy-7,13bis(triethylsilyloxy)-5p,20-epoxy-l-hydroxy-10methoxyacetoxy-9-oxo-ll-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: 1H NMR spectrum (400 MHz; CDCl 3 5 in ppm) 0.60 and 0.68 (2 mts, 6i each CH 2 of the ethyl); 0.95 and 1.04 (2 t, J 7.5 Hz, 9H each CH 3 of the ethyl); 1.09 (t, J 7.5 Hz, 3H CH 3 of the propyl); 1.13 3H CH,); 1.18 3H 1.64 1H OH at 1.68 (s, 3H CH 3 1.84 (mt, 2H CH 2 of the propyl); 1.89 and 2.50 (2 mts, 1H each CH, at 2.11 and 2.23 (2 dd, J 16 and 9 Hz, 1H each CH, at 14); 2.13 3H

CH

3 2.55 (mt, 2H OCOCH, of the propyl); 3.53 (s, 3H OCH 3 3.82 J 7 Hz, 1H H at 4.13 v 4 67 and 4.31 (2 d, J 9 Hz, 1H each CH, at 20); 4.16 (limiting AB, J 16 Hz, 2H OCOCH 2 4.52 (dd, J 11 and 7 Hz, 1H H at 4.91 (mt, 1 H H at 13); 4.93 (broad d, J 10 Hz, 1H H at 5.64 J 7 Hz, 1H H at 6.54 1H H at 10); 7.47 J Hz, 2H OCOC 6

H

5 at meta-H); 7.61 J 7.5 Hz, 1H OCOC 6

H

5 para-H); 8.11 J 7.5 Hz, 2H OCOCg 6

H

ortho-H).

2a-Benzoyloxy-4a-butanoyloxy-1, 103dihydroxy-7j,13o-bis(triethylsilyloxy)-5p,20-epoxy-9oxo-11-taxene may be prepared in the following way: To a solution of 907 mg of 4a-butanoyloxy- 13,2-carbonato-7P,13-bis(triethylsilyloxy)-5p,20epoxy-10-methoxyacetoxy-9-oxo-ll-taxene in 50 cm' of anhydrous tetrahydrofuran are added, at a temperature in the region of -78 0 C, 2.34 cm 3 of a 1M solution of phenyllithium in tetrahydrofuran. The reaction mixture is stirred for 1 hour at a temperature in the region of -78 0 C, followed by addition of 10 cm 3 of saturated aqueous ammonium chloride solution. At a temperature in the region of 201C, 20 cm 3 of saturated aqueous ammonium chloride solution and 50 cm 3 of dichloromethane are added. The organic phase is separated out after settling of the phases has taken place, washed with twice 10 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 1.3 g of product are r"- 68 obtained, which product is purified by chromatography on 150 g of silica (0.063-0.2 mm) contained in a column cm in diameter, eluting with an ethyl acetate/cyclohexane mixture (10/90 by volume) and collecting 18 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0

C.

906 mg of 2a-benzoyloxy-4a-butanoyloxyl-lg,10dihydroxy-73,13a-bis(triethylsilyloxy)-5P, 20-epoxy-9oxo-11-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CDC1 3 5 in ppm) 0.56 and 0.67 (2 mts, 6H each CH, of the ethyl); 0.95 and 1.03 (2 t, J 7.5 Hz, 9H each CH 3 of the ethyl); 1.08 (s, 3H CH 3 1.10 J 7.5 Hz, 3H CH 3 of the propyl); 1.18 3H CH 3 1.60 1H OH at 1.73 (s, 3H CH); 1.84 (mt, 2H CH 2 of the propyl); 1.91 and 2.48 (2 mts, 1H each CH, at 2.03 3H CH3); 2.11 and 2.22 (2 dd, J 16 and 9 Hz, 1H each CH 2 at 14); 2.58 (mt, 2H OCOCH 2 of the propyl); 3.87 J 7 Hz, 1H H at 4.18 and 4.32 (2d, J 9 Hz, 1H each CH, at 20); 4.28 J 2 Hz, 1H OH at 4.42 (dd, J 10.5 and 6.5 Hz, 1H H at 4.93 (broad d, J 10 Hz, 1H H at 4.98 J 9 Hz, 1H H at 13); 5.17 J 2 Hz, 1H H at 10); 5.62 J 7 Hz, 1H H at 7.49 J 7.5 Hz, 2H OCOC6Hs at meta-H); 7.61 J 7.5 Hz, 1H OCOC 6

H

para-H); 8.12 J 7.5 Hz, 2H OCOCH 5 ortho-H).

69 4o-Butanoyloxy-13,2o-carbonato-73,13bis(triethylsilyloxy)-5?,20-epoxy-10-methoxyacetoxy-9oxo-11-taxene may be prepared in the following way: To a solution of 870 mg of 1/,2a-carbonato- 7/3,13a-bis(triethylsilyloxy)-5, 20-epoxy-4c-hydroxy- 103-methoxyacetoxy-9-oxo-ll-taxene in 15 cm 3 of dichloromethane are added 1.46 g of 4dimethylaminopyridine and 3.90 cm 3 of butyric anhydride.

The reaction medium is heated at a temperature in the region of 42 0 C for 45 hours. 50 cm 3 of saturated aqueous sodium chloride solution and 50 cm 3 of dichloromethane are added. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 2.0 g of product are obtained, which product is purified by chromatography on 170 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter, eluting with an ethyl acetate/cyclohexane mixture (5/95 by volume) and collecting 15 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0

C.

1.00 g of 4d-butanoyloxy-13,2u-carbonato-7,13'ditriethylsilyloxy-5,20-epoxy-10j-methoxyacetoxy-9oxo-ll-taxene is obtained in the form of a white foam, the physical characteristics of which are as follows: 0 1 H NMR spectrum (400 MHz; CDCl 3 6 in ppm) :from 0.50 to 0.70 (mt, 12HE CH 2 of the ethyl) 0.90 and 1.10 (mt, 21H CE 3 of the ethyl and CH, of the propyl) 1. 18 (s, 3H CHO); 1.28 3H :CEO); 1.73 (mt, 2H :CE. of the propyl); 1.75 3H1: CE 3 1. 92 and 2. 59 (2 mt s, 1H each :CE 2 at 6) 2.13 3H1- CEO); 2. 14 and from 2. to 2.45 (dd and mt respectively, JT 16 and 9 Hz, 1H each CE 2 at 14) from 2.35 to 2.45 (mt, 2E OCOCH 2 of the propyl); 3.42 J 6.5 Hz, 1E H at 3.51 3H :OCE 3 4.18 2H1 OCOCH 2 4.46 (ad, J and 6.5 Ez, lE E at 4,50 and 4.63 (2 d, J 9 Hz, 1H each CE 2 at 2 0) 4. 51 J 6. 5 Ez, 1HE H at 2); 4.93 (broad d, J 10 Ez, 1H1 E at 5.02 (broad t, J 9 Hz, IE E at 13); 6.51 111 E at EXAMPLE 4 By performing the process as in Example 3, and starting with 2oa-benzoyloxy-4oa-phenylacetoxy-53, epoxy-1j3-hydroxy-10P-methoxyacetoxy-9-oxo-73trifluoromethanesulphonyloxy-11-taxen-13ot-yl (2R,3S) -3tert-butoxycarbonylamino- 2-hydroxy- 3-.phenylpropionate, 5g-2 0-epoxy-1g-hydroxy-103methoxyacetoxy-7g, 8-methylene-19-nor-9-oxo-4iphenylacetoxy-11-taxen-13u-yl (2R,3S) -3-tertbutoxycarbonylamino-2 -hydroxy-3 -phenyipropionate is obtained, the characteristics of which are as follows: 1H1 NMR spectrum (400 MHz; CDC1,; 6 in ppm) 1.24 (s, 71

CH

3

CH

3 and C(CH 3 3 1.40 (mt, 1H: H at 1.66 and 2.24 (2 ad, J 6 and 5 Hz and J =10 and 6 Hz, 1H each :CH 2 at 19); 1.92 1H OH at 1.96 3H CH,) 2.07 and 2.46 (broad d and dt respectively, J 16 Hz and J 16 and 4.5 Hz, 1H each :CH 2 at 6) 2.32 and 2.54 (dd and broad dd respectively, J 16 and 9 Hz, 1H each :CH 2 at 14) 3. 24 (mt, 1H :OH at 2'1) 3.53 3H :OCHO); 3.90 and 4.14 (2 d, J 15 Hz, 1H each OCOCH 2 Ar) 4. 00 and 4.16 (2 d, J 9 Hz, 1H each

CH

2 at 20) 4.20 and 4.26 (2 a, J 16 Hz, 1H each:

OCOCH

2 O) 4.23 J 7 Hz, 1H :H at 3) 4.55 (broad d, J 4.5 Hz, 1H H at 4,63 (mt, 1 H :H at 5.31 (limiting AB, 2H :H at 3' and CONH); 5.71 j= 7 Hz, 1H H at 6.34 (broad t, J 9 Hz, 1H H at 13); 6.44 1H :H at 10); from 7.10 to 7.45 (mt, H aromatic H ana aromatic H at 7.51 J Hz, 2H :OCOC.H. meta-H); 7.63 J =7.5 Hz, 1H

OCOC

6 para-H); 8.16 J =7.5 Hz, 2H :OCOC6H ortho-H).

By performing the process under similar conditions to those described in Example 3, 2ca-benzoyloxy-53,20-epoxy-f3-hydroxy-103methoxyacetoxy-9-oxo-4oe-phenylacetoxy-7Ptrifluoromethanesulphonyloxy-11-taxen-3a-yl (2R,3S) -3tert-butoxycarbonylanino-2 -hyaroxy- 3-phenylpropionate is pr~epared, the characteristics of which are as follows: 'H NMR spectrum (400 MHz; CDC1 3 6 in ppm) 1.24 (s, 6H CH3); 1.36 9H C(CH 3 3 1.74 1H, OH at 1.87 3H 2.14 3H CH); 2.19 and 2.83 (2 mts, 1H each CH2 at 2.39 and 2.48 (2 broad dd, J 16 and 9 Hz, 1H each CH, at 14); 3.38 J Hz, 1H OH at 3.53 3H OCH 3 3.90 and 4.14 (2 d, J 15 Hz, 1H each OCOCH 2 Ar); 4.01 (d, J 7 Hz, 1H H at 4.11 and 4.20 (2 d, J 9 Hz, 1H each CH, at 20); 4.17 and 4.25 (2 d, J 16 Hz, 1H each OCOCH0O); 4.65 (mt, 1H H at 4,68 (broad d, J 10 Hz, 1 H H at 5.28 (broad d, J 10 Hz, 1H H at 5.35 J 10 Hz, 1H CONH); 5.50 (dd, J 10 and 7 Hz, 1H H at 5.77 J 7 Hz, 1H H at 6.28 (broad t, J 9 Hz, 1H H at 13); 6.74 1H H at 10); from 7.15 to 7.45 (mt, 10 H aromatic H and aromatic H at 7.51 J 7.5 Hz, 2H OCOCH 5 meta-H); 7.66 J 7.5 Hz, 1H OCOC 6 Hs para-H); 8.08 J 7.5 Hz, 2H OCOCH, ortho-H).

By performing the process under similar conditions to those described in Example 3, 2rbenzoyloxy-53, 20-epoxy-1I-hydroxy-10P-methoxyacetoxy-9oxo-4a-phenylacetoxy- 7-trifluoromethanesulphonyloxy- 11-taxen-13-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate is prepared, the characteristics of which are as follows: -H NMR spectrum (400 MHz; CDC1 3 a temperature of 3330 K, 6 in ppm) 1.06 9H CH 3 1.12 3H 7

C

'31 73

CH

3 1.24 3H 1.66 1H OH at 1.83 3H CH); 1.86 3H CH) 2.14 and 2.79 (2 mts, 1H each CH 2 at 2.24 and 2.30 (2 dd, J 16 and 9 Hz, 1H each CH 2 at 14); 3.45 and 3.58 (2 d, J 15 Hz, 1H each OCOCH 2 Ar); 3.54 3H OCH,); 3.85 3H ArOCH 3 3.94 J 7 Hz, 1H H at 4.08 and 4.17 (2 d, J 9 Hz, 1H each CH 2 at 20); 4.14 and 4.22 (2 d, J 16 Hz, 1H each OCOCH 2 4.59 (broad d, J 10 Hz, 1H H at 4.63 J 5.5 Hz, 1H H at 5.45 J 5.5 Hz, iH H at 5.47 (mt, 1H H at 5.72 J 7 Hz, 1H H at 6.14 (broad t, J 9 Hz, 1H H at 13); 6.34 1H H at 6.65 1H H at 10); 6.94 J 8.5 Hz, 2H aromatic H ortho to the OCH); from 7.20 to 7.45 (mt, 12H aromatic H and aromatic H meta to the OCH 3 and aromatic H at 7.48 J 7.5 Hz, 2H OCOC 6

H

meta-H); 7.64 J 7.5 Hz, 1H OCOC 6 Hs para-H); 7.98 J 7.5 Hz, 2H OCOC 6 Hs ortho-H).

By performing the process under similar conditions to those described in Example 3, 2ca-benzoyloxy-13,13a-dihydroxy-58,20-epoxy-106methoxyacetoxy-9-oxo-4o-pbenylacetoxy- 7trifluoromethanesulphonyloxy-11-taxne is prepared, the characteristics of which are as follows: 1H NMR spectrum (400 MHz; CDC1 3 6 in ppm) 1.07 (s, 3H CH3); 1.21 3H: CH3); 1.64 1H OH at 1); 1.87 3H CH3); 2.18 J 4.5 Hz, 1H OH at 13); 2.20 and 2.88 (2 mts, 1H each CH 2 at 2.30 3H I /4 -J l l I from 2.25 to 2.35 (mt, 2H :CH 2 at 14); 3.52 Cs, 3H :OCHO); 3.90 and 3.97 (2 d, J =15 Hz, 1H each:

OCOCH

2 Ar); 4.08 J =7 Hz, 1H H at 4.12 and 4.27 (2 d, J 9 Hz, 1H each :CH 2 at 20) 4.16 and 4.24 (2 d, J 16 Hz, 1H each :OCOCH 2 4. 80 (broad d, J Hz, 1H :H at 5) 4.92 (mt, 1H H at 13); 5.55 (dd, J 10 and 6. 5 Hz, 1H H a t 7) 5. 71 J =7 Hz, 1H :H at 6.74 1H H at 10); from 7.25 to 7.45 (mt, 5H :aromatic 7.48 Ct, J 7.5 Hz, 2H :OCOC 6

H

meta-H); 7.64 JLT 7.5 Hz, 1H :OCOC 6 H. para-H) 8.03 Cd, J 7.5 Hz, 2H COCOCSH. ortho-H) By performing the process under similar conditions to those described in Example 3, 2oa- ,20-epoxy-10/3-methoxyacetoxy-9-oxo-4ephenylacetoxy-1g3,7/3,13o-trihydroxy-11-taxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 M~Hz; CDC1 3 5 in ppm) :1.12 (s, 3H :CHO); 1.14 Cs, 3H: CHO); 1.66 lH OH at 1); 1.67 3H CHO); 1.84 and 2.56 (2 mts, 1H each CH 2 at 2.11 3H CHO); from 2.20 to 2.45 (2 mts, 1H each OH); 2.35 and 2.42 (2 dd, J 16 and 9 Hz, 1H each :CH 2 at 14); 3.54 3H OCH 3 3.94 (limiting AB, J 15 Hz, 2H :OCOC'H 2 Ar); 3.94 J 7 Hz, lH H at 3) 4.12 and 4.25 (2 d, J =9 Hz, 1H each CH 2 at 20) 4.26 (limiting AB, J 16 Hz, 2H OCOCH 2 4.50 (mt, 1H Hat 7) 4.87 (broad d, J =l10Hz, 1H H at 4.96 (mt, 1H1 H at 13); 5.66 J =7 Hz, 1H H at 6.44 1H H at 10); from 7.25 to 7.45 Cmt, aromatic H) 7.47 LT 7. 5 Hz, 2H :OCOC 6

H

meta-H); 7.62 J 7.5 Hz, 1H OCOC 6 H. para-H); 8.04 J 7.5 Hz, 2H OCOC.H. ortho-H) By performing the process under similar conditions to those described in Example 3, 2abenzoyloxy-716, 13a~-bis (triethylsilyloxy) -53, hydroxy-1O/3-methoxyacetoxy- 9-oxo-4cu-phenylacetoxy-1ltaxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CDCl 3 6 in ppm) :0.60 and 0. 72 (2 mts, 6H each CH 2 of the ethyl) 0 .94 and 1. (2 t, J 7.5 Hz, 9H each CH 3 of the ethyl); 1. 15 (s, 3H :CHO); 1.22 3H: CHO); 1.66 3H CH 3 1.69 (broad s, 1H :OH at 1.84 and 2.51 (2 mts, 1H each :CH 2 at 6) 2.20 3H CHO 2. 24 and 2. 36 (2 dd, J =16 and 9 Hz, 1H each CH 2 at 14); 3.54 (s, 3H OCHO); 3.82 and 3.96 (2 d, J 15 Hz, 1H each:

OCOCH

2 Ar) 3.89 J 7 Hz, 1H H at 3) 4.06 and 4.16 (2 d, J =9 Hz, 1H each CH 2 at 20) 4.20 (limiting AB, J 16 Hz, 2H OCOCH 2 O) 4.52 (dd, J and 6 Hz, l1H H at 4.79 (broad d, J 10 Hz, lH H at 4.96 (broad t, J 9 Hz, 1H H at 13); 5.66 J 7 Hz, 1H H at 6.58 1H H at from 7.25 to 7.45 (mt, 7H aromatic H and OCOC.H. meta- 7.61 J =7.5 Hz, 1H OCOC.H. para-H) 8.-00 (d, J =7.5 Hz, 2H :OCOC.H. at ortho-H) By performing the process under similar conditions to those described in Example 3, 2a-benzoyloxy-1, 10P-dihydroxy-7, 13a- 20-epoxy-9-oxo-4aphenylacetoxy-11-taxene is prepared, the characteristics of which are as follows: 1H NMR spectrum (600 MHz; CDCl,; 6 in ppm) 0.53 and 0.72 (2 mts, 6H each CH, of the ethyl); 0.94 and 1.05 (2 t, J 7.5 Hz, 9H each CH3 of the ethyl); 1.10 (s, 3H CH 3 1.20 3H: CH 3 1.64 1H OH at 1); 1.70 3H CH 3 1.86 and 2.45 (2 mts, 1H each CH, at 2.10 3H CH3); 2.20 and 2.32 (2 dd, J 16 and 9 Hz, 1H each CH, at 14); 3.80 and 3.96 (2 d, J 16 Hz, 1H each OCOCH 2 Ar); 3.95 J 7 Hz, 1H H at 4.07 and 4.17 (2 d, J 9 Hz, 1H each CH, at 4.29 (broad s, 1H OH at 10); 4.43 (dd, J 11 and 7 Hz, 1H H at 4.79 (broad d, J 10 Hz, 1H H at 5.03 (broad t, J 9 Hz, 1H H at 13); 5.19 (broad s, 1H H at 10); 5.63 J 7 Hz, 1H H at from 7.25 to 7.45 (mt, 7H aromatic H and OCOC 6

H

s meta-H); 7.60 J 7.5 Hz, 1H OCOC 6

H

5 para-H); 8.00 J 7.5 Hz, 2H OCOC 6

H

s ortho-H).

By performing the process under similar conditions to those described in Example 3, 13,2acarbonato-7, 13-bis(triethylsilyloxy) -5,20-epoxy-10gmethoxyacetoxy-9-oxo-4u-phenylacetoxy-11-taxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CDC13; 6 in ppm) 0.61 and 0.74 (2 mts, 6H each CH 2 of the ethyl); 0.92 and 1.05 (2 t, J 7.5 Hz, 9H each CH, of the ethyl); 1.20 (s,

I

77 3H 1.30 3H: CH3); 1.73 3H CH 3 1.83 and 2.54 (2 mts, 1H each CH 2 at 2.18 3H

CH

3 2.27 and 2.48 (2 dd, J 16 and 9 Hz, 1H each

CH

2 at 14); 3.50 J 6.5 Hz, 1H H at 3.53 (s, 3H OCH3); 3.65 (limiting AB, J 14 Hz, 2H

OCOCH

2 Ar); 4.18 (limiting AB, 2H OCOCH 2 4.45 and 4.53 (2 d, J 9 Hz, 1H each CH 2 at 20); 4.46 (mt, 1H H at 4.53 J 6.5 Hz, 1H H at 4.68 (broad d, J 10 Hz, 1H H at 5.06 (broad t, J 9 Hz, 1H H at 13); 6.53 1H H at 10); from 7.25 to 7.45 (mt, 5H aromatic H).

EXAMPLE By performing the process as in Example 3, and starting with 2a-benzoyloxy-4a, bis(methoxyacetoxy)-5P,20-epoxy-1/,hydroxy-9-oxo-73trifluoromethanesulphonyloxy-ll-taxen-13u-yl (2R,3S)-3tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate, 2-benzoyloxy-4, 103bis(methoxyacetoxy)-5,20-epoxy-1i3-hydroxy-7, 8methylene-19-nor-9-oxo-1-taxen-13-yl (2A,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenylpropionate is prepared, the characteristics of which are as follows: 1H NMR spectrum (400 MHz; CDCI 3 temperature of 3330 K, 6 in ppm) 1.26 3H CH3); 1.29 3H CH3); 1.35 9H C(CH 3 3 1.42 (mt, 1H H at 7); 1.71 and 2.29 (dd and mt respectively, J 6.5 and 5 Hz, 1H each CH 2 at 19); 1.81 1H OH at 1.91 N/

C-

L 78 3H CHO); 2.15 and 2.54 (broad d and dt respectively, J 16 Hz and J 16 and 4.5 Hz, 1H each

:CH

2 at 6) 2.32 (limiting AB, 2H :CH, at 14) 3.50 and 3.53 (2 s, 3H each OCHO); 3.60 (mult. 1H, OH at 2'1) 4. 11 and 4.56 (2 d, J 16 Hz, 1H each :OCOCH 2

O);

4.12 and 4.31 (2 d, J 9 Hz, 1H each :CH 2 at 20); 4.17 J =7 Hz, 1H1 H at 4.19 and 4.24 (2 d, J =16 Hz, 1H each :OCOCH 2 4.67 (mt, 1H :H at 4.78 J 4.5 Hz, 1H :H at 5.29 (broad d, J 10 Hz, 1H :H at 5.47 J =10 Hz, 1H :CONH); 5.70 (d, J 7 Hz, 1H :H at 6.21 (broad t, J 9 Hz, 1H :H at 13); 6.44 1H :H at 10); 7.30 J 7.5 Hz, 1H :para-H of the aromatic at 7.39 JT Hz, 2H :meta-H of the aromatic at 7.45 J 7.5 Hz, 2H :ortho-H of the aromatic at 7.51 J Hz, 2H :OCOCAH meta-H); 7.61 J =7.5 Hz, 1H OCOCAH para-H) 8. 12 J =7.5 Hz, 2H OCOC6H, ortho-H).

By performing the process under similar conditions to those described in Example 3, 2abenzoyloxy-4u, 10f-bis (methoxyacetoxy) -Sf, 20-epoxy-1Pghydroxy- 9-oxo-7/3- trifluoromethanesulphionyloxy- 11- taxen- 13a-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate is prepared, the characteristics of which are as follows: 1H NMR spectrum (400 MHz; CDCl 3 temperature of 3330 K, 8 in ppm) 1.22 3H :CHO); 1.27 3H CHO) 1. 38 9H C (CH 3 1. 64 1H :OH at 1); 79 1.92 3H CH, 3 2.11 3H CH 3 2.25 and 2.92 (2 mts, 1H each CH, at 2.26 and 2.36 (2 dd, J 16 and 9 Hz, 1H each CH, at 14); 3.47 and 3.52 (2 s, 3H each OCH); 3.66 (broad s, 11, OH at 3.99 (d, J 7 Hz, 1H H at 4.15 and 4.57 (2 d, J 16 Hz, 1H each OCOCH, 2 4,19 (limiting AB, J 16 Hz, 2H

OCOCH

2 4.24 and 4.35 (2 d, J 9 Hz, 1H each CH, at 4.70 (mt, 1H H at 4.95 (broad d, J 10 Hz, 1H H at 5 29 (broad d, J 10 Hz, 1H H at 5.49 J 10 Hz, 1H CONH); 5.53 (dd, J 11 and 8 Hz, 1H H at 5.76 J 7 Hz, 1H H at 6.18 (broad t, J 9 Hz, 1H H at 13); 6.74 1H H at 7.30 J 7.5 Hz, 1H para-H of the aromatic at 7.38 J 7.5 Hz, 2H meta-H of the aromatic at 7.45 J 7.5 Hz, 2H ortho-H of the aromatic at 7.49 J 7.5 Hz, 2H OCOC 6

H

meta-H); 7.63 J 7.5 Hz, 1H OCOC.H. para-H); 8.09 J 7.5 Hz, 2H OCOCH, ortho-H).

By performing the process under similar conditions to those described in Example 3, 2ubenzoyloxy-4,100-bis(methoxyacetoxy)-5p,20-epoxy-1hydroxy-9-oxo-7-trifluoromethanesulphonyloxy-11-taxen- 13a-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate is prepared, the characteristics of which are as follows: 1H NMR spectrum (400 MHz; CDC1 3 temperature of 3330 K, 6 in ppm) 1.10 9H (CCH 3 3 1.18 3H iC:' s0 CHO); 1. 20 3H :CHO); 1. 64 1H OH at 1) 1. 3H CHO); 1.86 3H -CHO); 2.12 and-2.26 (2 dd, J 16 and 9 Hz, 1H each CH 2 at 14); 2.24 and 2.86 (2 mts, 1H each :CH. at 6) 3.33 and 3.53 (2 s, 3H OCHO); 3. 65 and 4. 10 (2 d, J 16 Hz, 1H each:

OCOCH

2 O) 3.83 3H: ArOCHO); 3.86 J 7 Hz, 1H H at 4.14 and 4.20 (2 d, J =16 Hz, 1H each:

OCOCH

2 4.19 and 4.32 (2 d, J 9 Hz, IH each :CH. at 4.72 (broad d, J 4.5 Hz, 1H :H at 4.89 (broad a, J 10 Hz, 1H :H at 5 46 (mt, 1H H at 31); 5.45 (dd, J 11 and 8 Hz, 1H H at 5.69 (d, J 7 Hz, 1H :H at 5.94 (broad t, J 9 Hz, 1H1 H at 13); 6.40 (broad s, 1H H at 6.63 1H :H at 10); 6.93 J 8.5 Hz, 2H aromatic ortho-H at OCHO); from 7.30 to 7.45 (mt, 5H aromatic H at 3'1) 7.38 J 8.5 Hz, 2H aromatic meta-H at OCH 3 7.48 J 7.5 Hz, 2H :OCOC 6 H. meta-H); 7.63 J Hz, 1H :OCOC 6 Hr, para-H); 8.08 J =7.5 Hz, 2H

OCOC

6 H. ortho-H) By performing the process under similar conditions to those described in Example 3, 2abenzoyloxy-4u, 10/-bis (methoxyacetoxy) 13cy-dihydroxy- 53, 20-epoxy-9-oxo-7/3-trifluoromethanesulphonyloxy-11taxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CDCl 3 b in ppm) 1.06 (s, 3 H CHO); 1. 20 3 H :CH 3 1. 61 A's, 1H OH a t 1) A 1.89 3H CHO); 2.23 J 5 Hz, 1H1 OH at 13); 81 from 2.20 to 2.35 and 2.92 (2 mts, 1H each CH 2 at 6); 2.26 3H CHO); 2.32 J 9 Hz, 2H CH. at 14); 3.52 and 3.58 (2s, 3H each :OCH 3 4.04 J =7 Hz, 1H :H at 4.19 and 4.32 (2 limiting AB, J =16 Hz, 2H each :OCOCH 2 O) 4. 20 and 4. 38 (2 d, J 9 Hz, 1H each CH 2 at 2 4.82 (mt, 1H H at 13); 4.99 (broad d, J =10 Hz, 1H :H at 5.55 J =10 and 7 Hz, 1H :H at 5.69 J =7 Hz, 1H H at 6.73 (s, 1H :H at 10) 7 .51 J 5 Hz, 2H OCOC.H. meta.- 7.64 J 5 Hz, 1H :OCOC.H. para-H) 8. 13 (d, J 7.5 Hz, 2H OCOC.H. ortho-H) By performing the process tunder similar conditions to those described in Example 3, 2cabenzoyloxy-4ct,l0i6-bis (methoxyacetoxy) -53, 20-epoxy-9oxo-g, 7p, 13ca-trihydroxy-1l-taxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CDC1 3 6 in ppm) .1(s, 6H :CHO); 1.63 1H :OH at 1.70 3H :CH3); 1.92 and 2.63 (2 mts, 1H each CH 2 at 6) 2.08 3H CHO); f rom 2. 20 to 2. 30 (mt, 3H :CH 2 at 14 and OH) 2.40 J 4 Hz, 1M OH); 3.54 and 3.59 (2 s, 3H each 0CM 3 3.92 J 7 Hiz, 1H H at 3) 4.20 and 4.35 (2 d, J 9 Hz, 1H each :CM 2 at 20) 4.24 and 4.28 (2 limiting AB, J 16 Hz, 2H each OCOCH 2 O) 4.50 (mt, 1H :H at 4.86 (mt, lIH H at 13); 5.03 (broad d, J 10 Hz, 1H :H at 5.65 J 7 Hz, IM H at 6.44 1M H at 10); 7.49 J 7.5 Hz, 2H 'iOCOC 6 H. meta-M) 7. 63 J 7. 5 Hz, 1M OCOC 6

H

para-H) 8.14 J 7 .5 Hz, 2H t OCOC 6 H. ortho-i).

By performing the process under similar conditions to those described in Example 3, 2cx-benzoyloxy-4a, 0p-bis (methoxyacetoxy) -73, l3abis (triethylsiJlyloxy) -5/,20-epoxy-1/-hydroxy-9-oxo-1ltaxene is prepared, the characteristics of which are as follows: 3,H NMR spectrum (400 MHz, CDC1 3 6 in ppm) 0.60 and 0. 70 (2 mts, 6H each CH 2 of the ethyl) 0. 94 and 1. 02 (2 t, J 5 Hz, 9H each :CH 3 of the ethyl) 1. 12 (s, 3H :CHO); 1. 20 3H CHO 1. 64 lH :OH at 1) 1.70 3H CHO); 1.91 and 2.57 (2 mts, 1H each :CH 2 at 2.12 3H CH CI; 2.13 and 2.23 (2 dd, JI 16 and 9 Hz, 1H each :CH 2 at 14) 3. 53 and 3. 57 (2 s,3H each :OCHO); 3.83 J =7 Hz, 1H :H at 3) 4.15 and 4.40 (2 d, J =16 Hz, 2H OCOCH 2 4.19 (limiting AB, J 16 Hz, 2H :OCOCH 2 O) 4.21 and 4.37 (2 d, J 9 Hz, IH each CH 2 at 20) 4. 51 (dd, J 11 and 7 Hz, 1H :H at 4.93 J 9 Hz, 1H H at 13); 5.02 (broad d, J 10 Hz, 1H :H at 5.64 J 7 Hz, 1H :H at 6.56 1H :H at 10); 7.48 J 7.5 Hz, 2H:

OCOC

6 H. meta-H); 7.63 Ct, J 5 Hz, 1H OCOC 6 H. para- H) 8. 19 J =7.5 Hz, 2H OCOC.H. ortho-H) By performing the process under similar conditions to those described in Example 3, 2cu-benzoyloxy-l3, 10/-dihydroxy-73, 3abis (triethylsilyloxy) -53, 20-epoxy-4oe-methoxyacetoxy-9oxo-il-taxene is prepared, the characteristics of which are as follows: 'H NNR spectrum (400 MHz; CDCl 3 6 in ppm) :0.57 and 0.69 (2 mts, 6H each CH 2 of the ethyl); 0.94 and 1.03 (2 t, J 7. 5 Hz, 9H each CH 3 of the ethyl); 1.09 (s, 3H :CHO); 1.17 3H :CHO); 1. 58 1H :OH at 1) 1.75 3H :CH 3 1.93 and 2.49 (2 mts, 1H each CH 2 at 2.03 3H CH 3 2.09 and 2.18 (2 dd, J 16 and 9 Hz, 1H each CH 2 at 14); 3.57 3H OCH 3 3.88 J 7 Hz, 1H :H at 4.16 and 4.40 (2 d, J 16 Hz, 1H each OCOCH 2 O) 4.20 and 4.36 (2 d, J 9 Hz, 1H each CH 2 at 20); 4.28 (broad s, 1H OH at 10); 4.42 (mt, 1H :H at 4.97 J 9 Hz, 1H H at 13); 5.01 (broad d, J 10 Hz, 1H H at 5.17 (broad s, 1H :H at 10); 5.62 J 7 Hz, 1H :H at 7.47 J =7.5 Hz, 2H OCOC 6

H

5 neta-H); 7.61 (t, J =7.5 Hz, 1H OCOCH, 5 para-H) 8. 18 J =7.5 Hz, 2H OCOC 6 H. ortho-H) By performing the process under similar conditions to those described in Example 3, 4v, 10/3-bis (methoxyacetoxy) -13, 2e-carbonato-73, 13cubis(triethylsilyloxy) -5p,20-epoxy-9-oxo-11-taxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CD( '1 3 in ppm) :0.60 and 0. 68 (2 mts, 6H each :CH. of the ethyl) 0. 92 and 1. 01 (2 t, J 7.5 Hz, 9H each :CH 3 of the ethyl); 1.19 (s, 3H :CHO); 1.27 3H CHO); 1.75 3H :CHO); 1.91 and 2.63 (2 mts, 1H each :CH 2 at 6) 2.08 and 2.41 (2 dd, J 16 and 9 Hz, 1H each CH 2 at 14); 2.12 (s, 84 3H CH); 3.44 J 6.5 Hz, 1H H at 3.46 and 3.50 (2 s, 3H each OCH); 4.06 and 4.14 (2 d, J 16 Hz, 1H each OCOCH 2 4.16 2H OCOCH, 2 4.46 (dd, J 10 and 7 Hz, 1H H at 4.50 and 4.66 (2 d, J 9 Hz, 11 each CH, at 20); 4.51 J Hz, 1H H at 4.99 (mt, 1H H at 13); 5.00 (broad d, J 10 Hz, 1H H at 6.51 1H H at EXAMPLE 6 By performing the process as in Example 3, and starting with 2a-benzoyloxy-4-cyclopropanoyloxy- 53,20-epoxy-1-hydroxy-9-oxo-10P-methoxyacetoxy-7Ptrifluoromethanesulphonyloxy-11-taxen-13a-yl (2R,3S)-3tert-butoxycarbonylamino-2-hydroxy-3phenylpropionate,2a-benzoyloxy-4a-cyclopropanoyloxy- 53,20-epoxy-13-hydroxy-10-methoxyacetoxy-7,8methylene-19-nor-9-oxo-11-taxen-13a-yl (2R,3S)-3-tertbutoxycarbonylamino-2-hydroxy-3-phenyipropionate is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CDC13; temperature in the region of 3330 K, 8 in ppm): from 0.80 to 1.40 (mt, 4H CHCH 2 of the cyclopropyl); 1.30 6H CH,); 1.35 9H from 1.30 to 1.40 (mt, 1H H at 1.70 and 2.23 (2 dd, J 6 and 5.5 Hz and J and 5.5 Hz respectively, 1H each CH, at 19); 1.80 (mt, 1H CH of the cyclopropyl); 1.85 1H OH at 1); 1.86 3H CH); 2.11 and 2.44 (broad d and dt respectively, J 16 Hz and J 16 and 4.5 Hz, 1H Y _I I each :CH 2 at 2.34 and 2.50 (2 dd, J 16 and 9 Hz, 1H each CH,, at 14) 3.22 J 4 Hz, 1H OH at 21); 3. 52 3H OCH3); 4. 08 and 4. 28 (2 d, JI 9 Hz, 1H each CH 2 at 20); 4.13 J 7 Hz, 1H :H at 3) 4.16 and 4.24 (2 d, J =16 Hz, 1H each :OCOCH 2 4.62 (d, J 4.5 Hz, 1H :H at 4.70 (broad d, J 4 Hiz, 1H H at 21); 5.28 (limiting AB, 2H1: H31 and CONH); 5.70 J 7 Hz, 111 H at 6.23 (broad t, J 9 Hz, 1H1 :H at 13); 6.42 1H H at 10); from 7.20 to 7.45 (mt, 5H :aromatic H at 7.52 J =7.5 Hz, 2H

OCOC

6 H. meta-H) 7.61 J 7.5 Hz, 1H1 OCOC 6

H

para-H) 8.14 J 7.5 Hz, 2H1: OCOC 6

H

5 ortho-H).

By performing the process under similar conditions to those described in Example 3, 2cu-benzoyloxy-4ci-cyclopropanoyloxy-53,20-epoxy-/3hydroxy- l0i-methoxyacetoxy- 9-oxo-73trifluoromethanesulphonyloxy-l1-taxen-13u-yl (2R,3S) -3tert-butoxycarbonylamino- 2-hydroxy-3 -phenylpropionate is prepared, the characteristics of which are as follows: 1H NMR spectrum (400 MHz; CDC1 3 6 in ppm): from 0. to 1. 40 (mt, 411 CH 2

CH

2 of the cyclopropyl); 1. 22 (s, 311 CHO); 1.24 3H CHO); 1.39 911: C(CH 3 3 1.70 1H :OH at 1.83 (mt, 1H CH o±t the cyclopropyl); 1.88 3H :CHO); 2.05 311 CHO); 2.23 and 2. 84 (2 mts, 1H1 each C11 2 at 6) 2.34 and 2.42 (2 dd, J 16 and 9 Hz, 111 each: CH 2 at 14) 3.35 (d, J 5.5 Hz, 111 OH at 3.52 3H OCH 3 3.96 86 J 7 Hz, lE H at 3) 4.16 and 4.25 (2 d, J 16 Hz, 1H each :OCOCH 2 O) 4.17 and 4.28 (2 d, LT 9 Hz, 1H each CE 2 at 20); 4.72 (mt, 1H :H at 4.81 (broad d, J =10 Hz, 1EH H at 5.28 (broad d, J 10 Hz, 1H: H at 5.36 J =10 Hz, 1H :CONE); 5.48 (dd, J 10.5 and 7 Hz, lE H at 5.72 J 7 Hz, 1H :H at 6.11 (mt, 1HE H at 13); 6.71 (s, 1HE H at 10); from 7.25 to 7.45 (mt, 5HE aromatic H at 3'1) 7. 52 JL= 7. 5 Hz, 2H1 OCOCAE meta-H); 7. LT 7.5 Hz, 1H1 OCOC.H., para-H) 8.08 U Hz, 2H :OCOC 6 H. ortho-H).

By performing the process under similar conditions to those described in Example 3, 2at- 20 -epoxy-1g-hydroxy- 100-methoxyacetoxy-9-oxo-7#3trifluoromethanesuiphonyloxy- 11- taxen-13ot-yI (2R,4S,5R)-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4phenyl-1, 3-oxazolidine-5-carboxylate is prepared, the characteristics of which are as follows: 1H NMR spectrum (400 Mz; CDCl 3 6 in ppm) :from 0.50 to 1. 50 (mt, 5H :CH and CE 2 of the cyclopropyl) 1. 04 9H C (CH 3 1. 17 3H1: CE 3 1. 19 3H: CHO); 1. 65 1H1 OH at 1) 1. 72 3H :CEO); 1. 84 3H11 CEO); 2.14 and 2.32 (2 dd, J 16 and 9 Hz, 111 each CE 2 at 14) 2.16 and 2.79 (2 mts, lE each CH 2 at 3. 52 3H CE 3 3. 82 3H :ArOCH 3 3. 86 J =7 Hz, 1HE H at 4.11 and 4.24 (2 d, J 9 Hz, 1H each :CH 2 at 20); 4.15 and 4.22 (2 d, JT 87 16 Hz, 1H each OCOCH 2 4.60 J =4.5 Hz, 1H :H at 4.74 (broad d, J= 10 Hz, 1Hi H at 5.44 (dd, J 10.5 and 8 Hz, 1H :H at 5.50 (mt, 1H H at 5.67 J 7 Hz, 1H :H at 5.88 (mt, 1H H at 13); 6.41 (mult., 1H :H at 6.61 1H :H at 10); 6.92 J 8.5 Hz, 2H :aromatic H ortho to the OCH 3 7.38 J 8.5 Hz, 2H :aromatic H meta to the OCHO); from 7.25 to 7.45 (mt, 5H :aromatic H at 7.49 J =7.5 Hz, 2H :OCOC 6 H. meta-H) 7. 63 (t, J 5 Hz, 1H OCOC 6 H. para-H) 8.02 J 7. 5 Hz, 2H :OCOC 6 H, ortho-H) By performing the process under similar conditions to those described in Example 3, 2ca-benzoyloxy-4c-cyclopropanoyloxy-1g, 13cy-dihydroxy- 53, 20-epoxy-10,6-methoxyacetoxy-9-oxo-7g3trifluoromethanesuiphonyloxy-li-taxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 M~z; CDCl 3 temperature of 3330* K, 6 in ppm) :f rom 0. 90 to 1. 40 (mt, 4H CH 2

CH

2 of 2 'j the cyclopropyl) 1. 10 3H :CHO 1. 22 3H: CHO 1.-61 1H :OH at 1) f rom 1. 70 to 1. 85 (mt, 2H: CHI of the cyclopropyl and OH at 13); 1.90 3H CHO); 2.22 and 2. 86 (2 mts, 1H each :CH 2 at 6) 2.26 3H CHO 2.36 J =9 Hz, 2H :CII 2 at 14) 3.52 3H OCHO) 4.05 J =7 Hz, 1H H at 3) 4.14 and 4.22 (2 d, J 16 Hz, 1H each OCOCH 2 O) 4.20 and 4.36 (2 d, J 9 Hz, 1H1 each :CH 2 at 2 4. 84 (mt, 1H :H at 13); 4.85 (broad d, J =10 Hz, 1H H at 5.54 (dd, 88 J=11 and 8 Hz, 1H :H at 5.72 J 7 Hz, 1H H at 6.73 IH H at 10); 7.51 J 7.5 Hz, 2H :OCOC.H. meta-H); 7. 63 J 5 Hz, 1H OCOC 6

H

para-H); 8.12 J =7.5 Hz, 21H OCOC 6

H

5 ortho-H).

By performing the process under similar conditions to those described in Example 3, 2o-benzoyloxy-4ct-cyclopropanoyloxy-/3, l3c-dihydroxy- 503,20-epoxy-10f3-methoxyacetoxy-9-oxo-73trifluoromethanesulphonyloxy-11- taxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz; CDC1 3 temperature of 3330 K, 5 in ppm) :from 0.90 to 1.40 (mt, 4H :CH 2

CH

2 of the cyclopropyl) 1. 10 3H :CHO); 1. 22 3H: CHO); 1.61 1H OH at from 1.70 to 1.85 (mt, 2H :CHI of the cyclopropyl and OH at 13); 1.90 3H: CHO 2.22 and 2. 86 (2 mts, 1H each CH 2 at 6) 2. 26 3H :CHO 2.36 J =9 Hz, 2H CH- 2 at 14) 3.52 3H :OCH 3 4.05 J =7 Hz, 1H H at 4.14 and 4.22 (2 d, J 16 Hz, 1H each OCOCH 2 O) 4.20 and 4.36 (2 d, J 9 Hz, 1H each :CH 2 at 20); 4.84 (mt, 1H :H at 13); 4.85 (broad d, J 10 Hz, 1H :H at 5.54 (dd, J 11 and 8 Hz, 1H :H at 5.72 J 7 Hz, 1H :H at 6.73 1H :H at 10); 7.51 J 7.5 Hz, 2H :OCOC.H. meta-H); 7.63 J Hz, 1H :OCOCH 5 para-H); 8.12 J 7.5 Hz, 2H OCOC.H. ortho-H) By performing the process under similar conditions to those described in Example 3, 89 2a-benzoyloxy-4u-cyclopropanoyloxy- 73, 13ubis (triethylsilyloxy) -53, 20-epoxy-1/3-hydroxy-103methoxyacetoxy-9-oxo-11-taxene is prepared, the characteristics of which are as follows: 1 H NMR spectrum (400 MH7z; CDC1 3 5 in ppm) 0. 60 and 0. 68 (2 mts, 6H each CIT ofi the ethyl); from 0. 90 to 1.35 (mt, 4H CH 2 CH, of the cyclopropyl); 0.94 and 1.03 (2 t, J 7. 5 Hz, 9 H each CH 3 of the ethyl) 1. 14 (s, 3H CHO); 1.20 3H CHO); 1. 64 1H OH at 1); 1.71 3H CHO); 1.73 (mt, 1H CH of the cyclopropyl); 1.87 and 2.50 (broad dd and mt respectively; J 14 and 11 Hz, 1H each CH 2 at 6); 2.11 and 2.29 (2 dd, J =16 and 9 Hz, 1H each CH 2 at 14); 2.15 3H CH 3 3.53 3H1: OCHO); 3.86 (d, J 7 Hz, 1H H at 4.14 and 4.26 (2 d, J 9 Hz, 1H1 each :CH 2 at 20); 4.19 (limiting AB, J =16 Hz, 2H1

OCOCH

2 4.52 (dd, J =11 and 7 Hz, 111 H at 7) 4.84 (broad d, J =10 Hz, 111 H at 4.95 (broad t, J 9 Hz, 1H1 H at 13); 5.65 J 7 Hz, 111 H at 2); 6.56 1H :H at 10); 7.50 J 7.5 Hz, 2H1: OCOC.H. meta-H); 7. 62 L7= 7. 5 Hz, 1H1 OCOCAH para- H) 8. 09 J =7.5 Hz, 211H OCOC.H5 ortho-H) By performing the process under similar conditions to those described in Example 3, 2a-benzoyloxy-4a-cyclopropanoyloxy-13, 10/3-dihydroxy- 7/,l3o-bis(triethylsilyloxy) -5f,20-epoxy-9--oxo-11taxene is prepared, the characteristics of which are as follows: 'H NMR spectrum (400 M~z; CDC1 3 3, 6 in ppm); 0.58 and 0.68 (2 mts, 6H each :CH 2 of the ethyl); from 0.90 to 1.35 (mt, 4H :CH 2

CH

2 of the cyclopropyl); 0.94 and 1.03 (2 t, J 5 Hz, 9H each :CH 3 of the ethyl) 1. 12 (s, 3H :CHO) 1 .22 3H :CHO); 1.-5 9 1H :OH at 1); 1.67 (mt, 1H CH of the cyclopropyl); 1.73 3H: CHO); 1. 90 and 2 .44 (2 mts, 1H each :CH 2 at 6) 2.0 6 3H :CHO); 2.10 and 2.25 (2 dd, J 16 and 9 Hz, 1H each :CH 2 at 14); 3.91 J =7 Hz, 1H :H at3); 4.16 and 4.26 (2 d, J 9 Hz, 1H each :CH 2 at 20) 4.28 (d, J =1.5 Hz, lH :OH at 10); 4.42 (dd, J 11 and 6 Hz, 1H H at 4.84 (broad d, J 10 Hz, 1H :H at 5.00 J 9 Hz, 1H :H at 13); 5.16 J 1.5 Hz, 1H :H at 10); 5.62 J 7 Hz, 1H :H at 7.50 J 7.5 Hz, 2H :0COC 6 meta-H) 7. 62 J 7. 5 Hz, 1H :OCOC 6

H

5 para-H) 8. 09 J 7. 5 Hz, 2H1

OCOC

5 HA ortho-H) 1(3, 2c-Carbonato-4cx-cyclopropanoyoxy-73, 13cebis (triethylsilyloxy) -53, 20-epoxy-10/3-methoxyacetoxy-9 oxo-11-taxene may be prepared in the following way: To a solution of 100 mg of 1/,2u-carbonato- 7/3, 3oe-bis (triethylsilyloxy) -53,20-epoxy-4a-hydroxy- 10f-methoxyacetoxy-9-oxo-l1-taxene in 7 cm 3 of tetrahydrofuran are added dropwise, at a temperature in the region of -30WC, 345 p1. of a 1M solution of lithium hexamethyldisilazane in hexane. The reaction mixture is stirred for 15 minutes at this temperature, followed by dropwise addition of 39 Al of cyclopropanoyl, chloride.

91 The reaction mixture is stirred for 30 minutes at a temperature in the region of 0°C, followed by hydrolysis by addition of 1 cm 3 of saturated ammonium chloride solution and 50 cm 3 of dichloromethane. The organic phase is separated out after settling of the phases has taken place, washed with twice 40 cm 3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 120 mg of a product are obtained, which product is purified by chromatography on 70 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with an ethyl acetate/cyclohexane mixture (20/80 by volume) and collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 0 C. 31 mg of 1P,2acarbonato-4a-cyclopropanoyloxy-7S, 13!bis(triethylsilyloxy)-5,20-epoxy-10S-methoxyacetoxy-9oxo-11-taxene are obtained in the form of a white foam, the physical characteristics of which are as follows: 1H NMR spectrum (400 MHz; CDC13; 6 in ppm): 0.60 and 0.66 (2 mts, 6H each CH, of the ethyl); from 0.90 to 1.35 (mt, 4H CH 2

CH

2 of the cyclopropyl); 0.92 and 1.02 (2 t, J 7.5 Hz, 9H each CH 3 of the ethyl); 1.19 (s, 3H 1.29 3H CH 3 1.60 1H OH at 1); 1.62 (mt, 1H CH of the cyclopropyl); 1.73 3H CH); 1.88 and 2.57 (broad dd and mt respectively, J r 92 and 10 Hz, 1H each CH, at 2.15 3H CHI); 2.19 and 2.37 (2 dd, J 16 and 9 Hz, 1H each CH 2 at 14); 3.48 J 7 Hz, 1H H at 3.51 3H

OCH

3 4.16 2H OCOCH0O); 4.44 (mt, 1H H at 7); 4.45 and 4.54 (2 d, J 9 Hz, 1H each CH 2 at 20); 4.49 J 7 Hz, 1H H at 4.85 (broad d, J 10 Hz, 1H I at 5.02 (broad t, J 9 Hz, 1H H at 13); 6.52 1H H at The- eveL products of general formula in which Z represents a radical of general formula (II) exhibit significant inhibitory activity on abnormal cell proliferation and possess therapeutic properties which make it possible to treat patients having pathological conditions associated with abnormal cell proliferation. The pathological conditions include the abnormal cell proliferation of malignant or benign cells of various tissues and/or organs comprising, without any limitation being implied, muscle, bone or conjunctive tissues, the skin, the brain, the lungs, the sexual organs, the lymphatic or renal systems, breast or blood cells, the liver, the digestive system, the pancreas and the thyroid or adrenal glands. These pathological conditions may also include psoriasis, solid tumours, cancers of the ovary, breast, brain, prostate, colon, stomach, kidney or testicles, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour, Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocytic

SI\

111rr 1 I rr -r ~Lb~ll 93 lekaemias and acute or chronic granulocytic lymphomas.

The ne;,Q3 products according to the invention are particularly useful for treating cancer of the ovary.

The products according to the invention may be used for preventing or delaying the appearance or reappearance of the pathological conditions or for treating these pathological conditions.

The products according to the invention may be administered to a patient in various forms adapted to the chosen route of administration, which is preferably the parenteral route. Administration via the parenteral route comprises intravenous, intraperitoneal, intramuscular or subcutaneous administrations. Intraperitoneal or intravenous administration is more particularly preferred.

The present invention also comprises the pharmaceutical compositions which contain at least one product of general formula in a sufficient amount suitable for use in human or veterinary therapy. The compositions may be prepared according to the usual methods, using one or more pharmaceutically acceptable adjuvants, vehicles or excipients. Suitable vehicles include diluents, sterile aqueous media and various non-toxic solvents. The compositions are preferably provided in the form of aqueous solutions or suspensions, of injectable solutions which may contain emulsifying agents, dyes, preserving agents or stabilizing agents.

IV

I I I 94 The choice of adjuvants or .pients may be determined by the solubility and the chemical properties of the product, the particular mode of administration and good pharmaceutical practice.

Aqueous or non-aqueous sterile solutions or suspensions are used for parenteral administration. For the preparation of non-aqueous solutions or suspensions, natural vegetable oils such as olive oil, sesame oil or liquid paraffin, or injectable organic esters such as ethyl oleate, may be used. The aqueous sterile solutions may consist of a solution of a pharmaceutically acceptable salt dissolved in water.

The aqueous solutions are suitable for intravenous administration provided that the pH is appropriately adjusted and that the solution is made isotonic, for example with a sufficient amount of sodium chloride or glucose. The sterilization may be performed by heating or by any other means which does not adversely affect the composition.

It is clearly uxrderstood that all the products entering into the compositions according to the invention iust be pure and non-toxic in the amounts used.

The compositions may contain at least 0.01 of therapeutically active product. The amount of active product in a composition is such that a suitable dosage may be prescribed. The compositions are preferably prepared such that a single dose contains from 0.01 to s 1000 mg approximately of active product for administration via the parenteral route.

The therapeutic treatment may be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunotherapies or radiotherapies or biologicalresponse modifiers. The response modifiers include, without any limitation being implied, lymphokines and cytokines such as interleukins, interferons A or 6) and TNF. Other chemotherapeutic agents which are useful in the treatment of disorders due to abnormal cell proliferation include, without any limitation being implied, alkylating agents such as nitrogen mustards, for instance mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulphonates, for instance busulphan, nitrosoureas, for instance carmustine, lomustine, semustine and strep-ozocin, triazenes, for instance dacarbazine, antimetabolites, for instance folic acid analogues such as methotrexate, pyrimidine analogues, for instance fluorouracil and cytarabine, purine analogues, for instance mercaptopurine and thioguanine, natural products such as vinca alkaloids, for instance vinblastine, vincristine and vendesine, epipodophyllotoxins, for instance etoposide and teniposide, antibiotics, for instance dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes, for instance L-asparaginase, various agents, for instance

I.

-I 96 platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives, for instance procarbazine, adrenocorticoid suppressants, for instance mitotane and aminoglutethymide, hormones and antagonists, for instance adrenocorticosteroids, for instance prednisone, progestins, for instance hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, oestrogens, for instance diethylstilbestrol and ethynylestradiol, antioestrogens such as tamoxifen, and androgens, for instance testosterone propionate and fluoxymesterone.

The doses used for implementing the methods according to the invention are those which permit a prophylactic treatment or a maximum therapeutic response. The doses vary according to the form of administration, the particular product selected and the personal characteristics of the subject to be treated.

In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation. The products according to the invention may be administered as often as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to relatively high or low doses, and then require low or zero maintenance doses. Generally, low doses will be used at the start of the treatment and, if necessary, increasingly high doses will be administered until an

I

optimum effect is obtained. For other patients, it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, according to the physiological needs of the patient in question. It is also possible that, for certain patients, only one to two daily administrations are necessary.

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

The example which follows illustrates a composition according to the invention.

EXAMPLE

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

The composition is administered by infusion over 1 hour by introduction into physiological 98 solution.

Claims (8)

1. Taxoids of general formula: R 0 R Z-0 om HO OCORg OCOR, in which: R a represents a hydrogen atom or a hydroxyl radical, an alkoxy radical containing 1 to 4 carbon atoms, an acyloxy radical containing 1 to 4 carbon atoms or an alkoxyacetoxy radical in which the alkyl part contains 1 to 4 carbon atoms and R, represents a hydrogen atom, or alternatively R, and Rb form, together .o 10 with the carbon atom to which they are attached, a S: ketone function, Z represents a hydrogen atom or a radical of *:general formula: RINH 0 R 3 OH in which: R. represents a benzoyl radical optionally substituted with one or more atoms or radicals, which Smay be identical or different, chosen from halogen I w Q. 100 atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, trifluoromethyl, thenoyl and furoyl radicals, or a radical R,-O-CO- in which R 2 represents: an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, or a bicycloalkyl radical containing 7 to 10 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl part contains 1 to 4 carbon atoms, piperidino and morpholino radicals, 1-piperazinyl radicals (optionally substituted at -4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals (optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms), cyano or carboxyl radicals and alkoxycarbonyl radicals in which the alkyl part contains 1 to 4 carbon atoms, a phenyl or a- or 3-napthyl radical which is -I 101 optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms or a 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals, or a saturated heterocyclic radical containing 4 to 6 carbon atoms optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, R, represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, a straight or branched alkenyl radical containing 2 to 8 carbon atoms, a straight or branched alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, or a phenyl or a- or g-naphthyl radical which is optionally substituted with one or more atoms or radicals chosen from halogen ateam and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, or a 5-membered aromatic heterocycle containing one or more hetero atoms, which may be identical or different, chosen from nitrogen, oxygen and sulphur atoms and optionally substituted with one or more substituents, which may be identical or f 102 different, chosen from halogen atoms, and alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl radicals, it being understood that, in the substituents of the phenyl, a- or A-naphthyl and aromatic heterocyclic radicals, 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 phenyl or a- or A-naphthyl radicals, and R 4 and R 5 which may be identical or different, represent a straight or branched alkyl radical containing 1 to 8 carbon atoms, a straight or branched alkenyl radical containing 2 to 8 carbon atoms, a straight or branched alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals optionally being substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl part contains 1 to 4 carbon atoms, piperidino and morpholino radicals, 1-piperazinyl radicals (optionally substituted at -4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which 103 the alkyl part contains 1 to 4 carbon atoms), cycloalkyl r-dicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals which are optionally substituted, cyano and carboxyl radicals and alkyloxycarbonyl radicals in which the alkyl part contains 1 to 4 carbon atoms, or an aryl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro, azido, trifluoromethyl S 15 and trifluoromethoxy radicals, it being understood that "i R, cannot represent a methyl radical or a 4- to

6-memnbered saturated or unsaturated heterocyclic radical optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, 20 it being understood that R s cannot represent a methyl radical, it being understood that the cycloalkyl, cycloalkenyl and bicycloalkyl radicals may optionally be substituted with one or more alkyl radicals containing 1 to 4 carbon atoms. 2. Taxoids according to claim 1, for which Ra represents a hydroxyl radical, an alkoxy radical containing 1 to 4 carbon atoms, an acyloxy radical 104 containing 1 to 4 carbon atoms or an alkoxyacetoxy radical in which the alkyl part contains 1 to 4 carbon atoms, and Rb represents a hydrogen atom, Z represents a hydrogen atom or a radical of general formula (II) in which R, represents a benzoyl radical or a radical R 2 -O- CO- in which R 2 represents a tert-butyl radical, and R 3 represents an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl radical optionally substituted with one or more atoms or radicals, which may be identical or different, chosen from halogen atoms (fluorine or chlorine) and alkyl, alkoxy, dialkylamino, acylamino, alkoxycarbonylamino or trifluoromethyl radicals or a 2- S 15 or 3-furyl, 2- or 3-thienyl or 4- or radical, and R 4 represents a phenyl radical which is optionally substituted with one or more atoms or radicals, which may be identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, 20 alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, azido, trifluoromethyl and trifluoromethoxy radicals, or a 2- or 3-thienyl or 2- or 3-furyl radical, and R 5 represents an optionally substituted alkyl radical containing 1 to 4 carbon atoms, it being understood that R 5 cannot represent a methyl radical. 3. Taxoids according to claim 1, for which R a represents a hydrogen atom or a hydroxyl or acetyloxy v 105 acetyloxy or methoxyacetoxy radical and R, represents a hydrogen atom, Z represents a hydrogen atom or a radical of the general formula (II) in which R I represents a benzoyl radical or a radical R 2 -O-CO- in which R, represents a tert-butyl radical, and R 3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or radical, and R 4 represents a phenyl radical which is optionally substituted with a halogen atom, and R s represents an alkyl radical containing 2 to 4 carbon atoms. 4. Process for the preparation of a product according to one of claims 1 to 3, characterized in that a product of general formula: O SRa O-SO,-CF z-o (II) sv H 6CR HO OCOR 4 in which Z, R 4 and R s are defined as in one of claims 1 to 3, Ra represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl -adical, and Rb represents a hydrogen atom, is treated with an alkali metal halide or an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate, optionally followed by replacement of the I 106 Process for the preparation of a product according to one of claims 1 to 3, for which R 4 and R are defined as in one of claims 1 to 3, and R. and R, each represent a hydrogen atom, characterized in that a product according to one of claims 1 to 3, for which n, represents a hydroxyl, acyloxy or alkoxyacetoxy radical, is reduced electrolytically. 6. Process for the preparation of a product according to one of claims 1 to 3, for which R 4 and R are defined as in one of claims 1 to 3, and R. and Rb form, together with the carbon atom to which they are attached, a ketone function, characterized in that a product according to one of claims 1 to 3, for which R, represents a hydroxyl radical and Rb represents a 15 hydrogen atom, is oxidized.

7. Pharmaceutical composition, o che- ,cterized in that it contains at least one product according to one of claims 1 to 3, for which Z represents a radical of general formula in 20 combination with one or more pharmaceutically acceptable products, whether inert or pharmacologically active.

8. Taxoids according to claim 1 substantially as hereinbefore described with reference to the Examples.

9. Process according to claim 4 substantially as hereinbefore described with reference to the Examples. P \OPER\'DB\27417 95 086 213M9 -107- Process according to claim substantially as hereinbefore described with reference to the Examples.

11. Process according to claim 6 substantially as hereinbefore described with reference to the Examples.

12. Taxoids according to claim 1 when obtained by a process as claimed in any one of claims 4 to 6 or claims 9 to 11.

13. Pharmaceutical composition according to claim 7 substantially as hereinbefore described with reference to the Examples. DATED this TWENTY SEVENTH day of MARCH 1998 Rhone-Poulenc Rorer S.A. By DAVIES COLLISON CAVE Patent Attorneys for the applicant L INTERNATIONAL SEARCH REPORT Iner Ap^pieaton No PCT/FR 95/00735 A. Cl ASSIFICATION OF SUIJIECI' MA'ITIR IPC 6 C070305/14 A61K31/335 According to Intermational Patent Classificauon (IP1' or to both national classification and IPC II. I I.D.S SI-AIHIIED Minimum documentation searched (classificaton system followed by classification symbols) IPC 6 C07D )ocumenLaUon searched other than minimum documentation to the extent that such documents are included in the fields searched I Icctronic data base consulted during the intemational search (name of data base and, where pracucal, search terms used) C. DOCUMiNI'S C(ONSIDI)iil) TO I l Rlil.liVAN'r Category (itation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A US,A,5 254 580 (SHU-HUI CHEN ET AL.) 19 1-3 October 1993 P,A FR,A,2 698 871 (RHONE-POULENC) 10 June 1-3 1994 see claims Slurthcr documents arc listed in the conunuaton of box C. Patent famly members are listed in annex. SSpcal categories of cted documents Spcal categoes of td documen'T later document published after the international filing date or priority date and not in conflict with the applcation but document deinng the general state of the art which is not cted to understand the pnnclple or theory underlying the considered to he of partular relevance invention *li carlier document but published on or after the international document of particular relevance; the claimed invention iling date cannot be considered novel or cannot he considered to document which may throw doubts on priority claim(s) or involve an inventve sicp when the document is taken alone which is cited to establish the puhlication date of another Y' document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document refernng to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvious to a person skilled *P document published prior to the international filing date but in the art. later than the pnority date claimed document member of the same patent family I)ate of the actual completion of the international search Date of mailing of the intch.atonal search report 2 October 1995 10.10.95 Name and mailing address of the ISA Authorized officer Iuropean Patent Office. 1P.1. 5818 Patcntlaan 2 NI. 2280 IIV Rilswl)k Tel. 31.70) 340.2040, Tx. 31 651 epo nl, c Fax. 31-70) 340.3016 Francois, J 'orm PCT SA. 210 (lecond sheet) (July 1992) INTERNATIONAL SEARCH REPORT lnterr al Application No iniorrntiof anl patot rarnily trcnc PCT/FR 95/00735 Patntdocumn fl ubicaion IPatent rarmly I Publication C, edin sercrepor At membecr(s) date US-A-5254580 19-10-93 AU-B- 656475 02-02-95 AU-B- 4155693 06-01-94 CA-A- 2099211 20-07-94 CN-A- 1082541 23-02-94 EP-A- 0577082 05-01-94 EP-A- 0577083 05-01-94 HU-A- 64529 28-01-94 OP-A- 6179665 28-06-94. JP-A- 6179666 28-06-94 NO-A- 932371 03-01-94 NZ-A- 248017 22-12-94 US-A- 5294637 15-03-94 FR-A-2698871 10-06-94 AU-B- 5653194 04-07-94 CA-A- 2150944 23-06-94 CN-A- 1094720 09-11-94 EP-A- 0673372 27-09-95 Fl-A- 952825 08-06-95 WO-A- 9413654 23-06-94 NO-A- 952264 08-06-95 For. PCT ISA231f (patent family annex) Jluly 1992) RAPPORT DE RECHERCHE INTrERNATIONALE Demal Iterationalc No PCT/FR 95/00735 CIB 6 C070305/14 *A61k31/335 Seion la classification titcmationalc des hrcvets (ClID) ou A la fois sclon la classification nationale ct la CID 13. IiOMAINES SURIt .IiSQUR.S L.A KI:CIIICIII-' A P'ORTEl Iocumcnuauon innimaic consulte (systemoi dc classification suivi des symboles dc classemcni) CIB 6 C070 Documcntauon consultcc autre quc la documentation miunimale dans la mesore ou ces documents relevcrnt des domaincs aur lesqucls a portt la recherche Blase de donnecs tlcctroniquc consultec au cours de la recherche intermationalc (norn de la base dc dlonntcs, ct st cela est rtalisablc, tcrins de recherche uijiistsI I)(ti MI.NIS. CONSIDIIRtEi COMMi Cattgonc* Idenuficauon dcc documents ctes, avcc,Ic cast chtant, lzndicauon dcs pastgcs pcrulncnts no. des revendications vittes A US,A,5 254 580 (SHU-HUI CHEN ET AL.) 19 1-3 Octobre 1993 P,A FRqA,2 698 871 (RHONE-POULENC) 10 Juin 1-3 1994 voir revendications Voir la suite du cadre C pour Ia fin dc la liste de~s documents M Les; documents dc farrulIlI" dc brevets sont inchiqus en annexc *Categories speciales; dc document% cits: 'T document ultkneur publit aprts; la date de dtp~t international ou la date dc pnontk et n-appaxsenecnant pas A I 6tat de la A document dtfinissant Vttat gotral dc la techniquc, non technsie pertinent, wait citt pour comprendre It pnincipc considWr comme particulitremencrt perinent 00 la Wonec constiwuant la base dc Itivention documcnt anittnecur, mais publit A la date de dtp~t international *3X' document particutremencrt peinent; I'inventzon revendliqute nec peot flu apres cette date etre consi dtrtc commit nouvelle oti conune impliquant one aclivitt document poovant icter on doute cur unc revendication de inventive par rapport au document considtrt isoltment pnionit flu citt pour dtterminer Ia date dc publication d'onc 'Y document particolitremencrt pcrilnent Vinvcntion reveniliqute auire citation ou pour one raison specl (telle qu indiqote) ne peut W~e considtrtc comme impliquant one activitt inventive document sc WOWran A one divolgation (irale, A un usage, A lorsque Ic document est associt A on ou plosicors ausres une exposition ou tout autrcs moyenis documents de mtme nature, cettc combinasson ttant tvidente document public avant la date de dep~t international, wait powutne personne du meitier posttnictrecit A Ia date dc pnorite revendiqutc document qut fait partie de Ia mtme famille dc brevets lite a dquclic I a recherche internationalc a tM effctivcment achevte Date decxptdition do present rapport de recherche intemationale 2 Octobre 1995 10.10.95 Nomn ct adresse postal de I'adminrctration chargte dc, Ia recherche interationale Fonictionnaire autorlst Office liuropten des llrevets, 11,11, 5818 Ilatentlaan 2 NI. -2280) IIV Rijswijk V'cI. (31-70) 340-2041, Tx. 31 651 epo nIFano s Faxc( 31-70) 340-3016Frnos J Forina PCT'ISA. 210 Ideuxtime feuiiie) ljiliet 1992) RAPPORT DE RECHERCHJE INTERNATIONALE Deriv ntcrtuiorw No RcmscignciccnLs rclaujfs aux i mbres de (amilics dc ticws PCT/FR 95/00735 Document brcvUt Cite Date de Mmrs)dlaD ate de au rapport de recherche publication fmledbree(s) T puliato US-A-5254580 19-10-93 AU-B- 656475 02-02-95 AU-B- 4155693 06-01-94 CA-A- 2099211 20-07-94 ON-A- 1082541 23-02-94 EP-A- 0577082 05-01-94 EP-A- 0577083 05-01-94 HU-A- 64529 28-01-94 JP-A- 6179665 28-06-94. JP-A- 6179666 28-06-94 NO-A- 932371 03-01-94 NZ-A- 248017 22-12-94 US-A- 5294637 15-03-94 FR-A-2698871 10-06-94 AU-B- 5653194 04-07-94 CA-A- 2150944 23-06-94 CN-A- 1094720 09-11-94 EP-A- 0673372 27-09-95 Fl-A- 952825 08-06-95 WO-A- 9413654 23-06-94 NO-A- 952264 08-06-95 Pormuisire PCT ISA 210 (annexe fsmiles de brevets) (lullet 1992) M