SK158096A3 - New taxoids, preparation thereof and pharmaceutical compositions containing them - Google Patents

Abstract

New taxoids having general formula (I), (II) preparation thereof and pharmaceutical compositions containing them. In general formula (I): Ra is hydrogen, hydroxy, alkoxy, acyloxy, alkoxyacetoxy, and Rb is hydrogen or Ra and Rb form together with the carbon atom to which they are linked a ketone function, Z is a hydrogen atom or a radical having general formula (II) wherein R1 is an optionally substituted benzoyl radical, a thenyl or furoyl radical or a radical R2-O-CO- wherein R2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl or heterocyclyl radical; R3 is an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphtyl or heterocyclic aromatic radical, and R4 and R5, similar or different, represent an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, aryl or heterocyclyl radical, with the condition that R5 does not represent a methyl radical. The new products having general formula (I) wherein Z is a radical having general formula (II) have remarkable antitumoral and antileukaemic properties.

Description

SUMMARY OF THE INVENTION

The invention relates to taxoids of the formula I

-in which

R ^a represents a hydrogen atom, a hydroxy group, a C 1 -C 4 alkoxy group, a C 1 -C 4 acyloxy group or an alkoxy acetoxy group in which the alkoxy radical contains 1 to 4 carbon atoms,

R ^f is hydrogen or

R ² and R ^a taken together with the carbon atom to which they are attached, a ketone fraction,

Z is hydrogen or a group of formula II

(II) in which

R ¹ represents a benzoyl group optionally substituted by one or more of the same or different substituents selected from the group consisting of halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or trifluoromethyl, tenoyl or furoyl or a group of formula

R 2 -O-CO in which

R ² is

- (C 1 -C 8) alkyl, (C 2 -C 8) alkenyl, (C 3 -C 8) alkynyl, (C 3 -C 6) cycloalkyl, (C 4 -C 6) cycloalkenyl, (C 7 -C 7) cycloalkyl group up to 10 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl group, C 1-4 alkoxy group, dialkylamino group in which each alkyl radical contains 1 to 4 carbon atoms atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted in the 4-position with C 1-4 alkyl or phenylalkyl in which the alkyl radical contains 1 to 4 carbon atoms, cycloalkyl containing C 6 -C 6 cycloalkenyl, phenyl optionally substituted by one or more substituents selected from halogen, C 1-4 alkyl and C 1-4 alkoxy , cyano, carboxyl or alkoxycarbonyl in which the alkoxy radical contains 1 to carbon atoms,

a phenyl or α- or β-naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, or a 5-membered heterocyclic an aromatic group selected preferably from the group consisting of furyl and thienyl groups,

- or a saturated heterocyclic group having 4 to 6 carbon atoms and optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms, and

R ³ represents a straight or branched (C 1 -C 8) alkyl group, a straight or branched (C 2 -C 8) alkenyl group, a straight or branched (C 2 -C 8) alkynyl group, a cycloalkyl group containing 3 to 6 carbon atoms, phenyl or or a β-naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio -hydroxy, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkylcarbamoyl with a 5-membered heterocyclic aromatic group containing one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen atoms, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, dialkylcarbamoyl or alkoxycarbonyl, wherein in the substituents of the phenyl or β-naphthyl group and the heterocyclic aromatic group the alkyl groups and the alkyl radicals of the other groups contain 1 to 4 carbon atoms, that the alkenyl and alkynyl groups having 2 to 8 carbon atoms and that the aryl groups are phenyl or β-naphthyl, and

R ⁴ and R ^s are the same or different, represent

straight or branched (C 1 -C 8) alkyl, straight or branched (C 2 -C 8) alkenyl, straight or branched C 2 -C 8 alkynyl, (C 3 -C 6) cycloalkyl, C 4 -C 4 cycloalkenyl up to 6 carbon atoms or a bicycloalkyl group having 7 to 11 carbon atoms, these groups being optionally substituted with one or more substituents selected from the group consisting of halogen atoms, hydroxy, C1-C4alkoxy, dialkylamino, wherein each alkyl radical contains 1 to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted in the 4-position with a C1-4 alkyl or phenylalkyl group in which the alkyl moiety the height of which contains 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms, an optionally substituted phenyl group, a cyano group, a carboxyl group or an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms,

an aryl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl a dialkylcarbamoyl group, a cyano group, a nitro group, an azido group, a trifluoromethyl group or a trifluoromethoxy group, or a saturated or unsaturated 4- to 6-membered heterocyclic group which is optionally substituted by one or more alkyl groups containing from 1 to 4 carbon atoms, wherein pla those ⁱⁿ which R can not be methyl, and Further, the cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.

Preferably, aryl groups R ³ , R ⁴ and / or R 5 ^are phenyl or α- or β-naphthyl, which is optionally substituted by one or more substituents selected from the group consisting of halogen atoms (fluorine, chlorine, bromo, iodo), alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro, azido, trifluoromethyl and trifluoromethoxy, the alkyl groups and the alkyl radicals of the other groups being the same yn from 1 to 4 carbon atoms, the alkenyl and alkynyl sku6 pins from 2 to 8 carbon atoms and that the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl group, and that ^R can not be methyl.

Preferably, the heterocyclic groups R ³ , R ⁴ and / or R ^{5 are} 5-membered heterocyclic aromatic groups containing one or more of the same or different atoms from the group consisting of nitrogen, oxygen or sulfur and which are optionally substituted with one or more identical or different substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom), (C 1 -C 4) alkyl group, (C 6 -C 10) aryl group, alkoxy group 1-4 carbon atoms, aryloxy of 6-10 carbon atoms, amino, C1-4 alkylamino, dialkylamino in which each alkyl radical contains 1-4 carbon atoms, acylamino, wherein the acyl residue contains 1 to 4 carbon atoms, and C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 acyl, arylcarbonyl in which the aryl radical contains 6 to 10 carbon atoms, cyano, carboxyl, carbamoyl, alkylcarbamoyl in which the alkyl radical it contains 1 to 4 carbon atoms, a dialkylcarbamoyl group in which each alkyl radical contains 1 to 4 carbon atoms, or an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms.

More specifically, the invention relates to compounds of formula I wherein R ^a is hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 acyloxy or alkoxy acetoxy wherein the alkyl moiety contains 1 to 4 carbon atoms. to 4 carbon atoms, R ^a is H, Z is H or a group of formula II, wherein R ¹ represents a benzoyl radical or a radical of the formula R ² -O-CO- in which ^R2 represents a tert-butyl R ³ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms

Ί carbon atoms, C 3 -C 6 cycloalkyl, phenyl optionally substituted by one or more of the same or different substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom), alkyl group (methyl group), alkoxy a group (methoxy group), a dialkylamino group. (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (t-butoxycarbonylamino) or trifluoromethyl, or 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- thiazolyl, 4-thiazolyl or 5-thiazolyl and R ' ¹ is phenyl optionally substituted by one or more identical or different substituents selected from the group consisting of halogen atoms, alkyl, alkoxy, amino, alkylamino- dialkylamino, acylamino, alkoxycarbonylamino, azido, trifluoromethyl and trifluoromethoxy, or 2-thienyl, 3-thienyl, 2-furyl or 3-furyl, and R ³ is optionally substituted alkyl of 1 to 4 carbon atoms, it being understood that ^R can not be methyl.

Even more particularly, the invention relates to compounds of formula I, wherein R ^a is a hydrogen atom or a hydroxyl or acetyloxy or methoxyacetoxy radical, R ^a is H, Z is H or a group of formula II, wherein R ¹ It represents a benzoyl radical or a radical of the formula R ² -O-CO- in which ^R2 represents a tert-butyl radical and ^R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, and is phenyl optionally substituted by halogen, and ^R is an alkyl group having 2-4 carbon atoms.

The compounds of formula I in which Z is a group of formula II have remarkable antitumor and anti-leukemic properties.

According to the invention a compound of formula I, wherein R ^a is hydrogen, alkoxy, acyloxy or alkoxyacetoxy radical, R ^a is H and R ^{4, R} and Z are defined as above, may be obtained by an alkali metal halide (sodium chloride, sodium iodide, potassium fluoride) or an alkali metal azide (sodium azide) or a quaternary ammonium salt or an alkali metal phosphate with a compound of formula III

wherein Z, R ⁴ and R ^s are as defined above, R ^a is hydrogen, alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl radical and R ^a is hydrogen, and optionally followed by the replacement of the protective group carried by the symbols R ^and hydrogen.

Generally, the reaction is carried out in an organic solvent selected from ethers (tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether) and nitriles (acetonitrile), alone or in admixture, at a temperature between 20 ° C and the boiling point of the reaction mixture.

A compound of formula III in which Z is a group of formula II can be obtained by esterification of a compound of formula IV

OCOR ⁴ where R ⁴ and R ^s are as defined above and R ^a is hydrogen, alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl radical and R ^a is H, with an acid of the formula V

OH (A) wherein R ¹ and R ³ are defined as above, and either R ^e represents H and R ⁷ represents a group protecting the hydroxyl function, or R ^A and R ⁷ together form a 5- or 6-membered saturated heterocyclic group, or using a derivative thereof, to give an ester of formula VI

wherein R ^a, R ^a, R ^1, R ^3, R ^4, R ^s, R ⁷ R®, and are as defined above, followed by replacement of the protective group represented by R ⁷ and / or R® and ^R7 by hydrogen atoms and R ', when it is acyloxy, alkoxyacetoxy or protected hydroxy, is hydroxy.

Said esterification using an acid of formula V may be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) and at a temperature between -10 and 90 ° C.

Said esterification can also be carried out using an acid of formula V in the anhydride form, in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) and temperature between 0 and 90 ° C.

Said esterification may also be carried out using an acid of formula V in the form of a halide or anhydride 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) and at a temperature between 0 and 80 ° C.

When R ^a is a hydroxy-protecting group, R ^{a is} preferably 2,2,2-trichloroethoxycarbonyloxy.

Preferably R @ 5 is hydrogen and R @ ⁷ is hydroxy-protecting group or R @ 8 and R @ ⁷ together form a 5 or 6-membered saturated heterocyclic group.

When R ⁶ is hydrogen, R ^{7 is} preferably methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, β-trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydropyranyl.

When R @ ⁷ and R @ ⁷ together form a heterocyclic group, the heterocyclic group is preferably an oxazolidine ring which is optionally mono-substituted or gem-disubstituted at the 2-position.

The replacement of R ⁷ and / or R ⁷ and / or R ⁷ with hydrogen atoms and optionally R ^and hydroxy can be carried out according to the nature of the groups to be replaced as follows:

1) If R® is H and R ⁷ represents a group protecting the hydroxyl function and R ^a is alkoxy, acyloxy or alkoxyacetoxy radical, replacement of the protective groups by hydrogen atoms is carried out using a mineral acid (sulfuric hydrochloric acid, sulfuric acid, hydrofluoric acid) or an organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid), alone or in admixture with each other, working in an organic solvent selected from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles, operating at a temperature between -10 and 60 ° C,

2) if the R® is H and R ⁷ represents a group protecting the hydroxyl function, R represents ^a 2,2,2-trichloroethoxycarbonyloxy radical, replacement of the protective groups R ⁷ carried out at the conditions described above in 1) and the replacement of R 'is carried out by treatment with zinc, optionally in combination with copper, in the presence of acetic acid at a temperature between 30 and 60 ° C or using a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, propanol, isopropanol) or in an aliphatic ester (ethyl acetate, isopropyl acetate, n-butyl acetate) in the presence of zinc, optionally in combination with copper,

3) when R ⁸ and R ⁷ together form a 5- or 6-membered saturated heterocyclic group and in particular an oxazolidine ring of formula VII

(VII) wherein R ¹ is as defined above, ^R and R ^9, identical or different, are H, alkyl having 1 to 4 carbon atoms, arylalkyl in which the alkyl portion contains 1 to 4 carbon atoms and the aryl radical preferably represents a phenyl group which is optionally substituted by one or more alkoxy groups having 1 to 4 carbon atoms, or an aryl group preferably representing a phenyl group which is optionally substituted by one or more alkoxy groups having 1 to 4 carbon atoms, or else R® is alkoxy of 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 represents a hydrogen atom, or R ^a and R ⁹ together form with the carbon atom to which they are attached is 4- to 7-membered and R ^a represents an acyloxy or alkoxyacetoxy group or a 2,2,2-trichloroethoxycarbonyloxy group, then the replacement of the protecting group consisting of R ⁶ and R ⁷ with hydrogen atoms and the replacement of R ⁶ with a hydroxy group can be carried out depending on R® meanings, R ^1, and R ⁹ R® follows:

(a) where R ^x is tert-butoxycarbonyl, R ® and R ⁹ , which are the same or different, are alkyl or aralkyl (benzyl) or aryl (phenyl) or also R ® is trihalomethyl or a phenyl radical substituted with a trihalomethyl radical and R ⁹ represents a hydrogen atom, or alternatively R ^a and R ⁹ together form a 4- to 7-membered ring, treatment of the ester of formula VI with an inorganic or organic acid, optionally in an organic solvent such as an alcohol, leads to a compound of formula VIII

OH

(VIII) in which R *

R ⁴ and R ^s are defined as above, which is then acylated using benzoyl chloride in which the phenyl ring is optionally substituted, thenoyl chloride, furoyl chloride or a compound of formula IX

R-O-CO-X (IX) wherein R ² is as defined above and X is halogen (fluoro, chloro) or -OR ² or -O-CO-OR ² to form a compound of formula X

R ¹ -NH 0

I!

? H

(X) wherein R ', R ^a, R ^1, R ^3, R and ^R are as defined above, wherein in the compound the protecting group R ^and, if represents a protected hydroxy group, optionally replaced by hydroxy.

Preferably, the compound of formula VI is reacted with formic acid at a temperature near 20 ° C.

Preferably, the acylation of a compound of formula VIII using a benzoyl chloride in which the phenyl moiety is optionally substituted, tenoyl chloride or furoyl chloride or a compound of formula IX is carried out in an inert organic solvent selected 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 a mineral 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 at a temperature near 20 ° C.

Preferably, the replacement of the protecting group R ^and , when 2,2,2-trichloroethoxycarbonyloxy, is carried out under the conditions described in paragraph 2 above).

b) Where R ¹ is an optionally substituted benzoyl, tenoyl or furoyl group or R ²⁰ -CO-, in which R ² is as defined above, R ⁸ represents a hydrogen atom, an alkoxy group containing 1 to 4 carbon atoms or a phenyl group substituted by one or more alkoxy groups having 1 to 4 carbon atoms and R ⁹ being a hydrogen atom, then the replacement of the protecting group consisting of R ⁶ and R ⁷ by hydrogen atoms is carried out in the presence of a mineral acid (hydrochloric acid, acid) sulfuric acid) or an organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid), alone or in admixture with each other, and used in a stoichiometric or catalytic amount, working in an organic solvent selected from alcohols, ethers, esters , aliphatic hydrocarbons, halogen aliphatic hydrocarbons and aromatic hydrocarbons, at a temperature of between -10 and 60 ° C, preferably at a temperature of between 15 and 30 ° C, while the replacement of the protecting group of the general group R 'when 2,2,2-trichloroethoxy15 carbonyloxy- the hydrogen atom is carried out under the conditions already described in paragraph 2),

4) where the R ^a represents a alkoxyacetyl R® and R ⁷ have the same meanings as in 1), then the first replacement of the protective group ^R7 by a hydrogen atom under the conditions described in 1), and is optionally replaced with R by hydroxy treatment by treatment in an alkaline medium or by treatment with zinc halide under conditions which do not attack the rest of the molecule. Generally, the alkaline treatment is carried out by treatment with ammonia in an aqueous-alcoholic medium at a temperature close to 20 ° C. The reaction with the zinc halide is preferably generally carried out using zinc iodide in methanol at a temperature close to 20 ° C,

(5) where R ^a represents an alkoxyacetoxy group and R ® and R ⁷ have the meanings given in paragraph (2), then the replacement of the group R ^{with a} hydroxy group is carried out in an alkaline medium or by reaction with zinc halide under the conditions described in paragraph 3 ), whereupon the compound of formula VI obtained is treated under the deprotection and acylation conditions described in paragraph 2a) above,

6) where the R ^a represents an alkoxyacetoxy radical and R® and R ⁷ are as defined in paragraph 2b), followed by replacement of the R group ^and a hydroxyl radical by treatment in an alkaline medium or by treatment with a zinc halide under the conditions of point 3), whereupon the obtained compound is processed under the conditions described in 2b).

According to the invention, the compounds of formula III, wherein R ⁴ and R ^s are as defined above, R ^a is hydrogen, alkoxy, acyloxy or alkoxyacetoxy radical and R ^a represents a hydrogen atom, or alternatively R ^a and R ^this forms together with the carbon atom to which they are attached a ketone function and Z represents a hydrogen atom, prepared by reacting a trifluoromethanesulfonic acid derivative such as anhydride or N-phenyltrifluoromethanesulfonimide with a compound of formula XI

wherein R ^a , R ^a , R ⁴ and R ⁵ are as defined above.

Generally, the reaction is carried out in an inert organic solvent (optionally halogenated aliphatic hydrocarbons, aromatic hydrocarbons) in the presence of an organic base such as an aliphatic tertiary amine (triethylamine) or pyridine at a temperature between -50 and 20 ° C.

The compounds of formula XI, wherein R ⁴ and R ^s are as defined above, R ^a is hydrogen, alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl radical and ^Rb represents a hydrogen atom may be prepared by reaction of hydrofluoric acid or trifluoroacetic acid in a basic organic solvent such as pyridine optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms or triethylamine optionally in combination with an inert organic solvent such as methylene chloride or acetonitrile or tetrahydrofuran at a temperature between 20 and 80 ° C with a compound of formula XII

wherein R ⁴ and R ^s are as defined above, R 'is H, alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxyl group, R ^is a hydrogen atom and the symbols ^G1, which may be identical or different, are trialkylsilyl.

A compound of formula XII can be obtained by reacting a compound of formula XIII

R-Y (XIII) wherein R is an alkyl, alkanoyl, alkoxyacetyl or hydroxy function and Y is a halogen atom, with a compound of formula XIV

wherein R ^4, R ^a and G ¹ are defined as above.

When R is alkyl or alkoxyacetyl, it is particularly preferred 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 is triethylamine or pyridine, at a temperature close to 0 ° C.

When R is an alkyl group, it is particularly preferred to pre-metallize the hydroxy function at the 10-position using an alkali metal hydride (sodium hydride) or a metal alkyde (butyllithium).

A compound of formula XIV and optionally a compound of formula XII can be obtained by reacting an organometallic derivative of formula XV

R ⁴ -M (XV) wherein R ⁴ is as defined above and M represents a metal atom, preferably a lithium or magnesium atom, with a compound of formula XVI

(XVI) wherein R ', R ^a, R ^x and G are defined as above.

Generally, the reaction is carried out in an organic solvent such as ether (tetrahydrofuran) at a temperature below -50 ° C, preferably at a temperature near -78 ° C.

The compound of formula (XVI) may be obtained by esterification of a compound of formula (XVII)

o wherein R 1, R ^b and G ^x are as defined above, using an acid of formula XVIII

^The R-COOH (XVIII) wherein ^R is as defined above, or a derivative of this acid such as a halide or anhydride, in the presence of a coupling agent and an inorganic or organic base.

A compound of formula XVII can be obtained by reacting a compound of formula XIII with a compound of formula XIX

wherein G ¹ is as defined above, under the conditions described above for the reaction of a compound of Formula XIII with a compound of Formula XIV.

A compound of formula XIX can be prepared by reacting phosgene or one of its derivatives, such as triphosgene, with a compound of formula XX

wherein G ¹ is as defined above, working in a basic organic solvent such as pyridine at a temperature below -50 ° C, preferably at a temperature near -78 ° C.

A compound of formula XX can be prepared by reacting a halootrialkylsilane with a compound of formula XXI

wherein G ¹ is as defined above, working in a basic organic solvent.

The compound of formula XXI can be prepared under the conditions described by D. G. I. Kingston et al. in the Journal of Nat. Prod., 56, 884 (1993).

The compounds of formula I, wherein R ^a and R ^a each is a hydrogen atom can be obtained by electrolytic reduction of a compound of formula I, wherein R ^a represents a hydroxyl, acyloxy or alkoxyacetoxy radical, or under the conditions described in International Application PCT WO 93/06093.

A compound of formula I, wherein R ^a and R ^a taken together with the carbon atom to which they are attached, form a keto function, may be obtained by oxidation of a compound of formula I, wherein R ^a is hydroxy and R ^is hydrogen, using, for example, pyridinium chlorochromate, pyridinium dichromate, potassium dichromate, ammonium dichromate or manganese dioxide.

The novel compounds of the formula I obtained by carrying out the process according to the invention can be purified by known methods, including crystallization and chromatography.

Compounds of formula I wherein Z is a group of formula II exhibit remarkable biological properties.

In vitro measurement of biological activity is performed on tubulin extracted from pig brain by the method of M. L. Shelanski et al. described in Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). The study of microtubule depolymerization in tubulin is performed by the method of G. Chauvier et al. described in C. R. Acad. Sci., 293, serum. II, 501-503 (1981). In this study, compounds of formula I in which Z is a group of formula II have been shown to be at least as effective as taxol and Taxotere.

In vivo, compounds of formula I in which Z is a group of formula II are effective in mice grafted with melanin B16 at doses between 1 and 10 mg / kg by intraperitoneal administration, said compounds being equally effective in other liquid formulations. or solid tumors.

The novel compounds have antitumor properties and in particular activity against tumors that are resistant to Taxol ¹¹ or Taxotere ¹¹ . Such tumors include colon tumors that have overexpression of the mdr 1 gene (global resistance gene). Global resistance is an expression that usually refers to the resistance of tumors to different active substances with different chemical structures and different mechanisms of action. Taxoids are generally known to have a strong response in experimental tumors such as P388 / DOX tumors, a doxorubicin (DOX) resistant cell line that expresses the mdr 1 global resistance gene.

In the following, the invention will be explained in more detail by means of specific examples thereof, which examples are intended to be illustrative only and are not to be construed as limiting the scope of the invention, which is clearly defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 0.193 g of (2R, 4S) -2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-4α-propanoyloxy-7β-trifluoromethanesulfonyloxy-11-taxen-13α-yl-3- tert-butoxycarbonylamino-2-hydroxy-4-phenylpropionate in 2.5 cm @ ^{3 of} acetonitrile and 0.250 cm @ ^{3 of} tetrahydrofuran are added successively to 0.096 g of molecular sieve 4A in powder form, 0.290 g of sodium chloride. The reaction mixture is then maintained under stirring at a temperature in the region of 75 DEG C. for 5 hours, at which time 75 cm @ ^{3 of} dichloromethane and 50 cm @ ^{3 of a} saturated aqueous sodium chloride solution are added. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.150 g of product is obtained, which product is purified by chromatography on 80 g of silica gel (0.063-0.2 mm), which is a column with a diameter of 1 cm, eluting with a dichloromethane / methanol (98/2 by volume) mixture and collecting it. with a 10 cm ³ fraction. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.080 g of (2R, 4S) -2a-benzoyl-5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-7B, 8-methylene-19-nor-9-oxo-4a-propanoyloxy-11-taxene is obtained. -13?-yl-3-tert. butoxycarbonylamino-2-hydroxy-3-phenylpropionate having the following characteristics:

¹ H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

1.24 (t, J = 7.5 Hz, 3H: _CH3 of ethyl); 1.24 (s, 6H: _CH3); 1.27 (s, 9H: C _{(CH3) 3);} 1.42 (mt, 1H: H7); 1.68 and 2.24 (2 mts, 1H each: CH ₃ at 19); 1.86 (s, 1H OH at position 1); 1.86 (s, 3H: _CH3);

2.12 and 2.86 (respectively. Da dt, J = 16 and J = 16 and 5 Hz, 1H each: _{CH, and} 6); from 2.15 to 2.30 and 2.41 (respectively mt and dd, J = 16 and

Hz, 1H each: _CH2 at position 14); 2.64 (mt, 2H: _CH2 of ethyl); 3.26 (mt, 1H: OH at position 2 '); 3.52 (s, 3H, _OCH3); 4.07 (d, J = 7Hz,

1H: H at 3); 4.04 and 4.33 (2d, J = 9 Hz, 1H each: CH2 at position 20);

4.22 (AB limit, J = 16 Hz, 2H: OCOCH _of O); 4.62 (mt, 1H: H at position 2 '); 4.70 (d, J = 4 Hz, 1H: H at position 5); 5.28 (md, 2H: H at position 3 'and CONH); 5.67 (d, J = 7 Hz, 1H: H at position 2); 6.26 (broad t, J =

Hz, 1H: H at position 13); 6.42 (s, 1H: H at position 10); from 7.25 to 7.45 (mt, 5H: aromatic H at position 3 '); 7.52 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.62 (t, J = 7.5 Hz, 1H: H _{p e} 0C0C H at the para position); 8.16 (d J = 7.5 Hz, 2H: OCOC HHV ortho).

(2 R, 4 S) -2 a-benzoyloxy-5B, 20-epoxy-10.beta.-hydroxy-trihydroxy-9-oxo-4-propanoyloxy-7 B-trifluórmetánsulfonyloxyll-taxen-13-yl 3-tert-butoxycarbonylamino-2- hydroxy-4-phenylpropionate can be prepared as follows.

A solution of 0.760 g of (2R, 4S, 5R) -2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-4α-propanoyloxy-7β-trifluoromethanesulfonate-11-taxen-13α-yl-3- t. butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine in 6.6 cm ^{3 of a} 0.1N solution of hydrochloric acid in ethanol is kept under stirring at a temperature close to 0 ° C for 22 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 20 ° C. The crude reaction product is dissolved in 80 cm @ ^{3 of} dichloromethane and 80 cm @ ^{3 of a} saturated aqueous sodium bicarbonate solution. The organic phase is separated by decantation and then extracted twice with 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 ° C.

0.9 g of white product is obtained in the form of a rigid, brittle foam which is purified by chromatography on 150 g of silica gel (0.063-0.2 mm) which is on a column of 3 cm diameter, eluting with a mixture of dichloromethane and of methanol at 95: 5 by volume and fractions of 15 cm ³ are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 20 ° C.

0.456 g of (2R, 4S) -2a-benzoyloxy-5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-4a-propanoyloxy-7B-trifluoromethanesulfonyloxy-11-taxen-13a-yl-3 is obtained. tert. butoxycarbonylamino-2-hydroxy-4-phenylpropionate having the following physical characteristics:

¹ H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 55 in ppm)

1.24 (s, 9 H: CH _and CH ₃ and ethyl); 1.34 (s, 9H: C _{(CH3) 3);} 1.74 (s, 1H: OH at position 1); 1.88 (s, 3H: _CH3); 2.05 (broad s., 3H: _CH3);

2.24 and 2.86 (2 mts, 1H each: _CH2 at 6); 2.33 (d, J = 9Hz,

2H: _CH2 at position 14); 2.68 (int, 2H: _CH2 of ethyl); 3.30 (mt, 1H: OH at position 2 '); 3.52 (s, 3H, _OCH3); 3.93 (mt, 1H: H at position 3); 4.19 (limiting AB, J = 16 Hz, 2H: OCOCH3); 4.20 and 4.36 (2 d, J = 9 Hz,

1H each: _CH2 at 20); 4.64 (broad d, J = 5.5 Hz, 1H: H at position 2 ');

4.86 (broad d, J = 10 Hz, 1H: H at position 5); 5.22 (mt, 1H: H at position 3 ');

5.30 (d, J = 10Hz, 1H: CONH); 5.51 (dd, J = 10 and 7.5 Hz,

1H: H at 7); 5.75 (d, J = 7 Hz, 1H: H at position 2); 6.20 (mt, 1H: H at position 13); 6.71 (s, 1H: H at position 10); from 7.30 to 7.45 (mt, 5H: aromatic H at position 3 '); 7.52 (t, J = 7.5 Hz, 2H: OCOC H H at the meta position);

7.64 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.13 (d, J = 7.5)

Hz, 2H: OCOC H H (ortho).

es ¹ (2R, 4S, 5R) -2α-Benzoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-4α-propanoyloxy-7β-trifluoromethanesulfonyloxy-11α-taxene-13α-3- t. butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate can be prepared as follows.

To a solution of 0.590 g of 2a-benzoyloxy-1β, 13α-dihydroxy-5β, 20-epoxy-10β-methoxyacetoxy-9-oxo-4α-propanoyloxy-7β-trifluoromethanesulfonyloxy-11-taxene in 10 cm ^{3 of} anhydrous ethyl acetate is gradually added 0.463 g (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid, 0.319 g dicyclohexylcarbodiimide and 0.028 g 4-dimethylaminopyridine. The reaction mixture is stirred for 15 hours under argon at a temperature in the region of 20 DEG C. and then 75 cm @ ^{3 of} dichloromethane and 50 cm @ ^{3 of a} saturated aqueous ammonium chloride solution are added. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa) at 40 ° C.

0.980 g of product is obtained, which product is purified by chromatography on 150 g of silica gel (0.063-0.2 mm), which contains a column with a diameter of 3 cm, eluting with a dichloromethane / methanol (95: 5 by volume) mixture and collecting it. with a 15 cm ³ fraction. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.740 g of (2R, 4S, 5R) -2a-benzoyloxy-5B, 20-epoxylB-hydroxy-10B-methoxyacetoxy-9-oxo-4a-propanoyloxy-7B-trifluoromethanesulfonyloxy-11a-taxen-13a-yl-3 is obtained. - tert-butoxycarbonyl-3- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate in the form of a white, brittle foam with the following physical characteristics:

^ H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 6 in ppm)

1.06 (s, 12H: _CH3 and C _{(CH3) 3);} 1.20 (s, 3H: _CH3); 1.27 (t, J = 7.5 Hz, 3H: _CH3 of ethyl); 1.67 (s, 1H: OH at position 1); 1.71 (s, 3H: _CH3); 1.83 (s, 3H: _CH3); from 2.00 to 2.30 and 2.83 (2 mts, 1H each: _CH2 at 6); 2.00 to 2.30 (mt, 2H: _CH2 of ethyl); 2.08 and 2.22 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.52 (s, 3H, _OCH3); 3.82 (s, 3H: _ArOCH3); 3.82 (mt, 1H: H at position 3); 4.12 and 4.29 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.18 (AB limit.,

J = 16 Hz, 2H, OCOCH ₂ O); 4.51 (d, J = 5 Hz, 1H: H at position 2 '); 4.80 (broad d, J = 10 Hz, 1H: H 5); from 5.35 to 5.45 (mt, 1H: H at position 3 '); 5.43 (dd, J = 10.5 and 7.5 Hz, 1H: H at position 7); 5.68 (d,

J = 7 Hz, 1H: H at position 2); 6.01 (mt, 1H: H at position 13); 6.38 (mt, 1H: H at position 5 '); 6.60 (s, 1H: H at position 10); 6.92 (d, J = 8.5 Hz, 2H: aromatic H ortho to the _OCH3); 7.39 (d, J = 8.5 Hz, 2H: aromatic H at the meta position with respect to OCH _a ); from 7.30 to 7.45 (mt, 5H: aromatic H at position 3 '); 7.50 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.65 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.03 (d, J = 7.5Hz,

2Η: OCOC H H (ortho).

5

2a-Benzoyloxy-1β, 13α-dihydroxy-5β, 20-epoxy-1β-methoxy-acetoxy-9-oxo-4α-propanoyloxy-7β-trifluoromethanesulfonyloxy-11taxene can be prepared as follows.

To a solution of 0.660 g of 2a-benzoyloxy-5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-4a-propanoyloxy-1B, 7B, 13a-trihydroxy-11-taxene in 6.6 cm ^{3 of} anhydrous dichloromethane and 0.338 cm ^{3 of} pyridine maintained in an argon atmosphere at a temperature close to 0 ° C, 0.354 cm ³ of trifluoromethanesulfonic anhydride are added dropwise. The orange solution obtained is stirred for 10 minutes at a temperature in the region of 0 ° C and then for 30 minutes at a temperature in the region of 20 ° C, then 3 cm ^{3 of} water and 50 cm ^{3 of} dichloromethane are added. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.800 g of product is obtained, which product is purified by chromatography on 100 g of silica gel (0.063-0.2 mm), which contains a column with a diameter of 2 cm, eluting with a dichloromethane / methanol (95: 5 by volume) mixture. with a 15 cm ³ fraction. 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-1B, 13a-5B, 20-epoxy-10Bmethoxyacetoxy-9-oxo-4a-propanoyloxy-7B-trifluoromethanesulfonyloxy-11-taxene is obtained in the form of a white rigid brittle foam with the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl _α , δ in ppm)

1.05 (s, 3H: _CH3); 1.19 (s, 3H: _CH3); 1.23 (t, J = 7.5Hz,

3H: _CH3 of ethyl); 1.62 (s, 1H: OH at position 1); 1.89 (s, 3H: _CH3);

2.12 (d, J = 5 Hz, 1H: OH at position 13); 2.24 and 2.90 (2 mts, 1H each: _CH2 at 6); 2.25 (s, 3H: _CH3); 2.30 (limiting AB, 2H: CH ₌ H) _;

14); 2.64 (mt, 2H: _CH2 of ethyl); 3.52 (s, 3H, _OCH3); 4.02 (d,

J = 7 Hz, 1H: H at 3); 4.15 and 4.35 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.20 (AB limit., J = 16Hz, 2H: OCOCH2 O); 4.85 (mt, 1H; H at position 13); 4.91 (d, broad, J = 10 Hz, 1H: H at position 5);

5.57 (dd, J = 10 and 7 Hz, 1H: H at position 7); 5.69 (d, J = 7 Hz, 1H: H at position 2); 6.73 (s, 1H: H at position 10); 7.50 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.63 (t, J = 7.5 Hz, 1H: OCOC HH at para); The delta 8.11 (d, J = 7.5 Hz, 2H: _OCOC6 H _p H at the ortho position).

2a-Benzoyloxy-5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-4-propanoyloxy-1B, 7B, 13a-trihydroxy-11-taxene can be prepared as follows.

To a solution of 1.21 g of 2α-benzoyloxy-7β, 13α-ditriethylsilyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-4α-propanoyloxyoxy-11-taxene in 15 cm ^{3 of} dichloromethane 23 cm @ ³ of triethylamine hydrofluoric acid complex are added at a temperature in the region of 20 DEG C. ³ . The reaction mixture is stirred for 20 hours at a temperature in the region of 20 DEG C., then 50 cm @ ^{3 of} dichloromethane and 100 cm @ ^{3 of a} saturated aqueous solution of sodium hydrogen carbonate are added. The organic phase is decanted, washed twice with 50 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

1.04 g of 2a-benzoyloxy-5B, 20-epoxy-10B-methoxy-acetyl-9-oxo-4a-propanoyloxy-1B, 7B, 13a-trihydroxy-11-taxene is obtained in the form of a white rigid brittle foam with the following physical features;

--H-nuclear magnetic resonance spectrum:

(400 MHz, CDC1 _3, in ppm)

1.11 (s, 6H: _CH3); 1.25 (t, J = 7.5 Hz, 3H: _CH3 of ethyl); 1.65 (s, 1H: OH at position 1); 1.70 (s, 3H: _CH3); 1.88 and 2.60 (2 mts, 1H each: _CH2 at 6); 2.08 (s, 3H: CH _a); 2.30 (AB limit, 2H):

CH ₂ in 14); 2.39 (d, J = 4 Hz, 1H: OH at position 7); 2.63 (mt, 2H: _CH2 of ethyl); 3.55 (s, 3H, OCH, 3.90 (d, J = 7 Hz, 1H: H at position 3), 4.17 and 4.32 (2 d, J = 9 Hz, 1H each: CH at _the 20): 4.25 (AB limit, J = 16 Hz, 2H: OCOCH2 O) 4.51 (mt, 1H: H at position 7);

4.89 (mt, 1H: H at position 13); 4.95 (d, broad, J = 10 Hz, 1H: H at position 6)

5); 5.64 (d, J = 7 Hz, 1H: H at position 2); 6.43 (s, 1H: H at position 10);

7.48 (t, J = 8 Hz, 2H: H _{p e} OCOC H at the meta position); 7.61 (t, J = 8Hz,

1H: OCOC ₍ H _with H at para); 8.13 (d, J = 8 Hz, 2H: H _{p e} OCOC H at the ortho position).

2a-Benzoyloxy-7B, 13a-ditriethylsilyloxy-5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-4a-propanoyloxy-11-taxene can be prepared as follows.

To a solution of 0.900 g of 2a-benzoyloxy-1B, 10B-dihydroxy-7B, 13a-bis (triethylsilyloxy) -5B, 20-epoxy-9-oxo-4a-propanoyloxy-11taxene in 15 cm ^{3 of} pyridine is added 0.520 cm ^{3 of} methoxyacetyl chloride at a temperature close to 0 ° C. The reaction mixture is stirred for two hours at a temperature in the region of 20 DEG C. and then 100 cm @ ^{3 of} dichloromethane and 50 cm @ ^{3 of a} saturated aqueous ammonium chloride solution are added. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous ammonium chloride solution, dried over magnesium sulfate, 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 gel (0.063-0.2 mm), which contains a column with a diameter of 2.5 cm, eluting with a mixture of ethyl acetate and cyclohexane in a volume ratio of 25: 75 and 10 cm ³ fractions are collected. 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 2a-benzoyloxy-7B, 13a-bis (triethylsilyloxy) -7B, 13a-5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo4a-propanoyloxy-11-taxene is obtained in the form of a white solid. brittle foams with the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm) from 0.50 to 0.70 (mt, 12H: CH _of ethyl); 0.92 (t, J = 7.5Hz,

9Η: CH _and ethyl); 1.00 (t, J = 7.5, 9H, _CH3 of ethyl); 1.10 (s, 3H: _CH3); 1.17 (s, 3H: CH _a); 1.29 (t, J = 7.5Hz)

3H: _CH3 of ethyl at position 4); 1.61 (s, 1H: OH at position 1); 1.68 (s, 3H: _CH3); 1.84 and 2.51 (2 mts, 1H each: CH2 at position 6); 2.09 and 2.21 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.10 (s, 3H: _CH3);

2.60 (mt, 2H: CH _and ethyl at position 4); 3.50 (s, 3H, _OCH3); 3.78 (d, J = 7 Hz, 1H: H at position 3); 4.12 and 4.30 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.15 (limiting AB, J = 16 Hz, 2H: OCOCH2 O); 4.49 (dd, J = 11 and 7 Hz, 1H: H at position 7); 4.90 (mt, 2H; H at position 5 and H at position 13); 5.62 (d, J = 7 Hz, 1H: H at position 2); 6.52 (s, 1H: H at position 10); 7.45 (t, J = 7.5 Hz, 2H: H _e OCOC ₅ H at the meta position); 7.58 (t, J = 7.5 Hz, 1 H, OCOC H _E H at _the para position); 8.09 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

The 2a-Benzoyloxy-1B, 10B-dihydroxy-7B, 13α-bis (ditriethylsilyloxy) -5B, 20-epoxy-9-oxo-4α-propanoyl-11-taxene can be obtained as follows.

To a solution of 1.105 g of 1B, 2a-carbonate-7B, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-10B-methoxyacetoxy-4α-propanoyloxy-11-taxene in 50 cm ^{3 of} anhydrous tetrahydrofuran is added 1.8 cm ³ M solution of phenyl lithium in tetrahydrofuran at or near 78 ° C. The reaction mixture is stirred for 15 minutes at -78 ° C, then 10 cm ^{3 of} saturated aqueous ammonium chloride solution are added. At a temperature in the region of 20 DEG C., 20 cm @ ^{3 of} saturated aqueous ammonium chloride solution and 50 cm @ ^{3 of} dichloromethane are added. The organic phase is decanted, washed twice with 10 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa) at 40 ° C.

1.3 g of product are obtained, which product is purified by chromatography on 150 cm @ ^{3 of} silica gel (0.063-0.2 mm), which contains a column with a diameter of 5 cm, eluting with a mixture of ethyl acetate and cyclohexane (10:90 by volume). and fractions of 18 cm ³ are collected. 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 2a-benzoyloxy-ΙΒ, 10B-dihydroxy-7B, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-9-oxo-4α-propanoyloxy-11-taxene is obtained in the form of a white, rigid foam with the following: physical characteristics:

^ H-NMR:

(400 MHz, CDCl ₃ , <5 ppm)

0.53 (mt, 6H: CH _of ethyl); 0.65 (mt, 6H: ethyl _CH2); 0.92 (t, J = 7.5, 9H: _CH3 of ethyl); 1.00 (t, J = 7.5 Hz, 9H: CH _and ethyl); 1.07 (s, 3H, CHJ; 1.14 (s, 3H: _CH3); 1.26 (t, J = 7.5

Hz, 3H: _CH3 of ethyl at position 4); 1.40 (s, 1H: OH at position 1); 1.71 (s, 3H):

: _CH3); 1.88 and 2.45 (2 mts, 1H each: _CH2 at 6); 2.00 (s, 3H: _CH3); 2.06 and 2.18 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.60 (q, J = 7.5 Hz, 2H: _CH2 of ethyl 4 in); 3.84 (d, J = 7Hz, 1H);

: H at 3); 4.14 and 4.30 (2 d, J = 8.5 Hz, 1H each: _CH2 at 20); 4.26 (d, J = 0.5 Hz, 1H: OH at position 10); 4.40 (dd, J = 11 and 7 Hz)

1H: H at 7); 4.90 (broad d, J = 10 Hz, 1H: H at position 5); 4.94 (t, broad, J = 9 Hz, 1H: H at position 13); 5.12 (d, J = 0.5 Hz, 1H: H at position 10); 5.58 (d, J = 7 Hz, 1H: H at position 2); 7.45 (t, J = 7.5Hz,

2H: OCOC HH in meta); 7.60 (t, J = 7.5 Hz, 1H: OCOC H H at para position); 8.09 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

To a solution of 2.0 g of 1B, 2a-carbonate-7B, 13α-bis (triethylsilyloxy) -5β, 20-epoxy-4α-hydroxy-10β-methoxyacetoxy-9-oxo-11-taxene in 90 cm ^{3 of} dichloromethane, 3.37 g of 4-dimethylaminopyridine and 3.64 cm @ ³ of propionic anhydride are added. The reaction mixture is heated at a temperature near 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 decanted, washed twice with 40 cm ^{3 of} saturated aqueous sodium chloride solution, 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 gel (0.063-0.2 mm), which contains a column with a diameter of 3 cm, eluting with a mixture of ethyl acetate and cyclohexane (5:95 by volume) and 12 cm ³ fractions are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

1.97 g of 16,2a-carbonate-76,13a-bis (triethylsilyloxy) -56,20-epoxy-106-methoxyacetoxy-9-oxo-4-α-propanoyloxy-11taxene are obtained in the form of a white brittle foam. This product has the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl _a, δ ppm) 0.50 to 0.75 (mt, 12H: CH _of ethyl); 0.94 (t, J = 7.5, 9H: _CH3 of ethyl); 1.03 (t, J = 7.5, 9H: _CH3 of ethyl); 1.21 (mt, 6H: _CH3 and _CH3 of ethyl); 1.28 (s, 3H: _CH3); 1.75 (s, 3H: _CH3);

1.90 and 2.60 (2 mts, 1H each: CH ₌ at position 6); 2.13 (s, 3H: CH3);

2.15 and 2.38 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.43 (mt, 2H: _CH2 of ethyl); 3.43 (d, J = 5.5 Hz, 1H: H at position 3); 3.51 (s, 3H, _OCH3) 4.18 (s, 2H, OCOCH ₂ O); 4.46 (dd, J = 11 and 7 Hz,

1H: H at 7); 4.48 and 4.65 (2 d, J = 9 Hz, 2H: _CH2 at 20);

4.51 (d, J = 5.5 Hz, 1H: H at position 2); 4.93 (broad d, J = 10 Hz, 1H: H at position 5); 5.02 (t, J = 9 Hz, 1H: H at position 13); 6.51 (s, 1H: H at position 10).

16,2a-Carbonate-76,13a-bis (triethylsilyloxy) -56,20-epoxy-4α-hydroxy-10 6-methoxyacetoxy-9-oxo-11-taxene can be prepared as follows.

To a solution of 4.12 g of 16,2a-carbonate-4a, 106-dihydroxy-76,13a-bis (triethylsilyloxy) -56,20-epoxy-9-oxo-11-taxene in 80 cm ^{3 of} pyridine is added with stirring while stirring at a temperature close to 0 ° C, powdered molecular sieve 4A (2 grams) and 2.86 cm ^{3 of} methoxyacetyl chloride. The reaction mixture is stirred for 15 minutes at a temperature near 0 ° C, then the temperature is allowed to slowly rise to a temperature near 20 ° C. After stirring at this temperature for 4 hours, 50 cm ^{3 of} saturated aqueous ammonium chloride solution and 100 cm ^{3 of} dichloromethane are added. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous ammonium chloride solution, washed twice with 25 cm ^{3 of} saturated aqueous copper sulphate solution and washed twice with 25 cm ^{3 of} saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated to dryness. under reduced pressure (2.7 kPa) at 40 ° C. 5.3 g of product are obtained, which product is purified by chromatography on 200 g of silica gel (0.063-0.2 mm), which contains a column with a diameter of 4 cm, eluting with a 25:75 mixture of ethyl acetate and cyclohexane. and collecting 12 cm ³ fractions. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

4.21 g of IB, 2a-carbonate-7B, 13a-bis (triethylsilyloxy) -5B, 20-epoxy-4a-hydroxy-10B-methoxyacetoxy-9-oxo-11-taxene are obtained in the form of a white rigid brittle foam. , which has the following physical characteristics:

¹ H-nuclear magnetic resonance spectrum:

(400 MHz, CDC1 _3, in ppm)

0.59 (mt, 6H: CH _and ethyl); 0.73 (mt, 6H: ethyl _CH2); 0.91 (t, J = 7.5, 9H: _CH3 of ethyl); 1.02 (t, J = 7.5, 9H: _CH3 of ethyl); 1.15 (s, 3H, CHJ; 1.18 (s, 3H, CHJ; 1.65 (s, 3H: _CH3); 1.98 and 2.51 (2 mts, 1H each: _CH2 at position 6 ), 2.15 (s, 3H, CH _a), 2.54 and 2.72 (2 dd, respectively. J = 16 and 9 Hz and J = 16 and 3 Hz,

1H each: _CH2 at position 14); 2.93 (s, 1H: OH at position 4); 3.03 (d, J = 5 Hz, 1H: H at position 3); 3.51 (s, 3H, _OCH3); 4.16 (mt, 1H: H at position 7);

4.17 (AB, J = 18 Hz, 2H, OCOCH ₂ O); 4.37 (d, J = 5 Hz, 1H: H at position 2); 4.54 (AB, J = 9 Hz, 2H: CH2 at position 20); 4.76 (broad d, J =

Hz, 1H: H at position 5); 4.81 (dd, J = 9 and 3 Hz, 1H: H at position 13);

6.51 (s, 1H: H at position 10).

IB, 2a-Carbonate-4a, 10B-dihydroxy-7B, 13a-bis (triethylsilyloxy) -5B, 20-epoxy-9-oxo-11-taxene can be prepared as follows.

To a solution of 0.400 g of 7B, 13a-bis- (triethylsilyloxy) -56,20epoxy-9-oxo-1B, 2a, 4a, 10B-tetrahydroxy-11-taxene in 10 cm ^{3 of} dichloromethane is stirred and at a temperature close to -78 ° C add 1 cm ^{3 of} pyridine and 0.560 g of triphosgene. The reaction mixture is stirred for two hours at a temperature close to -78 ° C, then the temperature of the reaction mixture is allowed to slowly rise to a temperature close to 20 ° C. 30 cm ^{3 of} saturated aqueous ammonium chloride solution and 20 cm ^{3 of} dichloromethane are added. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.400 g of product is obtained in the form of a yellow, rigid, brittle foam which is purified by chromatography on 25 g of silica gel (0.063-0.2 mm), which contains a column with a diameter of 2 cm, eluting with a mixture of ethyl acetate and cyclohexane by volume. 20:80 and fractions of 10 cm ³ are collected. The fractions containing only the desired product are combined, concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.330 g of IB, 2a-carbonate-4a, 10B-dihydroxy-7B, 3a-bis (triethylsilyloxy) -5B, 20-epoxy-9-oxo-11-taxene is obtained in the form of a white, rigid foam. This product has the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 6 in ppm)

0.54 (mt, 6H: ethyl _CH2); 0.63 (mt, 6H: ethyl _CH2); 0.92 (t, J = 7.5, 9H: _CH3 of ethyl); 1.03 (t, J = 7.5, 9H: _CH3 of ethyl); 1.11 (s, 3H: _CH3); 1.19 (s, 3H: _CH3); 1.72 (s, 3H: _CH3); 1.98 and 2.46 (2 mts, 1H each: _CH2 at 6); 2.06 (s, 3H:

CH ₃ ); 2.55 and 2.66 (2 dd, respectively J = 16 and 9 Hz and J = 16 and 3 Hz,

1H each: _CH2 at position 14); 3.00 (s, 1H: OH at position 4); 3.13 (d, J = 5 Hz, 1H: H at position 3); 4.06 (dd, J = 11 and 7 Hz, 1H: H at position 7); 4.20 (d, J = 2.5 Hz, 1H: OH at position 10); 4.33 (d, J = 5 Hz, 1H: at position 2);

4.55 (AB, J = 9 Hz, 2H: _CH2 at 20); 4.76 (broad d, J = 10 Hz,

1H: H at position 5); 4.82 (dd, J = 9 and 3 Hz, 1H: H at position 13); 5.19 (d, J = 2.5 Hz, 1H: H at position 10).

7B, 13a-Bis (triethylsilyloxy) -5B, 20-epoxy-9-oxo-1B, 2α, 4α, 10β-tetrahydro-11-taxene can be prepared as follows.

To a solution of 3.80 g of 5B, 20-epoxy-9-oxo-1B, 2a, 4a, 10B, 13apentahydroxy-7B-triethylsilyloxy-11-taxene in 100 cm ^{3 of} dichloromethane is added under stirring at a temperature close to 0 ° C. , 20 cm ^{3 of} pyridine and 2.48 cm ^{3 of} chlorotriethylsilane. The reaction mixture is stirred for three hours at a temperature close to 0 ° C. Add 100 cm ^{3 of} saturated aqueous sodium chloride solution. The organic phase is decanted, washed twice with 100 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 5.34 g of an orange oil are obtained, which is purified by chromatography on 300 g of silica gel (0.063-0.2 mm), which contains a column with a diameter of 3 cm, eluting with a 25:75 mixture of ethyl acetate and cyclohexane. and fractions of 40 cm ³ are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

4.18 g of 7B, 13a-bis (triethylsilyloxy) -5B, 20-epoxy-9-oxo-1B, 2a, 4a, 10B-tetrahydro-11-taxene are obtained in the form of a white brittle solid foam. This product has the following physical characteristics:

^ H-NMR:

(400 MHZ, CDCl 3, S in ppm) 0.53 (mt, 6H: CH2 ₎ ethyl); 0.75 (mt, 6H: CH 2 ethyl); 0.91 (T, J = 7.5Hz, 9H: CH ₃ ethyl); 1.01 (s, 3H: CH); 1.03 3 (T, J = 7.5Hz, 9H: CH _and ethyl); 1.09 (s, 3H: CH _a ); 1.63 (S, 3 H: CH ₃ ); 1.97 (s, 3H: _CH3); and from 1.95 to 2.10 and 2.40 (2 mt s, 2H each: CH at 14 and CH at 2 2 6); 3.17 (s, 1H: OH); 3.18 (d, J = 5.5Hz, 1H: H at 3); 3 43 (d, J = 10 Hz, 1H: OH v 2); 3.76 (dd, J = 10 and 5.5 Hz, 1H : H at 2); 3.96 (dd, J = 11 a 6 Hz, 1H: H at position 6; 7); 4.10 (s, IH) : OH); 4. 18 (d, J = 3Hz) 1H: OH in 10); 4.44 and 4.73 (2 d, J = 9 Hz, 1 H each: CH 2 in 20) ; 4.64 (broad d) J = 10 Hz 1H : H at 5); 4.74 (mt, 1H: H at 13); 5.14 (d, J = 3Hz, 1 H) : H in 10).

Example 2

To a solution of 20.5 mg of (2R, 3S) -5B, 20-epoxy-1B-hydroxy-10Bmethoxyacetoxy-9-oxo-4? -Propanoyloxy-2? - (2-tenoyloxy) -7? -Trifluoromethanesulfonyloxy-11-taxene -13a-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 0.2 cm ^{3 of} acetonitrile and 0.025 cm ^{3 of} tetrahydrofuran was added with 45 mg of sodium chloride and a spatula of activated molecular sieve 4A. The resulting mixture was heated to reflux under nitrogen for 2 hours. After cooling to a temperature in the region of 20 ° C, the solvents are evaporated off under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, then the residue is taken up in 5 cm ^{3 of} dichloromethane, filtered through cotton and rinsed with 5 cm ³ of ethyl acetate / dichloromethane. ratio 50:50. The organic phases are concentrated under reduced pressure (0.27 kPa) at a temperature of 40 ^{& C.} This gives 17.1 mg of product as a yellow crunchy foam solid. The product was purified by preparative thin layer chromatography (2 Merck preparative plates, Kieselgel 60F254, 0.25 mm thick, loaded in dichloromethane), eluting with methanol / dichloromethane (6:94 v / v). After elution of a zone corresponding to the main product of a mixture of methanol and dichloromethane (10:90 by volume), filtration through a glass frit and evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature close to 40 ° C, 10.0 mg (2R, 3S) is obtained. -5B, 20-epoxy-1B-hydroxy10B-methoxyacetoxy-7,8B-methylene-9-oxo-4α-propanoyloxy-2α- (2-phenoyloxy) -19-nor-11-taxen-13a-yl-3 -tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white lacquer having the following characteristics:

¹ H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

1.18 (t, J = 7.5 Hz, 3H: _CH3 of ethyl); 1.22 (s, 6H: _CH3); 1.32 (s, 9H: C _{(CH3) 3);} 1.41 (mt, 1H: H at position 7); 1.69 and 2.23 (2 mts, 1H each: _CH2 at 19); 1.81 (s, 1H: OH at position 1); 1.85 (s, 3H):

CH ₃ ); 2.12 and 2.50 (d, respectively. Dt, J = 16 and J = 16 and 4.5 Hz, 1H each: _CH2 at 6); 2.25 and 2.39 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.63 (mt, 2H: CH _and ethyl); 3.23 (mt, 1H: OH at position 2 '); 3.52 (s, 3H, _OCH3); 4.03 (d, J = 7 Hz, 1H: H at position 3);

4.12 and 4.44 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.20 (limiting AB., J = 16 Hz, 2H: OC0CH ₂ O); 4.62 (mt, 1H: H at position 2 '); 4.70 (d, J = 4 Hz, 1H: H at position 5); 5.22 (mt, 1H: H at position 3 '); 5.28 (d, J = 10Hz, 1H: CONH); 5.58 (d, J = 7 Hz, 1H: H at position 2); 6.23 (broad t, J = 9 Hz, 1H: H at position 13); 6.41 (s, 1H: H at position 10); 7.18 (dd, J = 5 and 3.5 Hz, 1H: H at the 4-tenoyl); from 7.30 to 7.50 (mt, 5H: aromatic H at position 3 '); 7.67 (broad d, J = 5 Hz, 1H: H at the 2-tenoyl); 7.96 (broad d, J = 3.5 Hz, 1H: H at the 2-tenoyl).

(2R, 3S) -5B, 20-Epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo4a-propanoyloxy-2- (2-tenoyloxy) -7B-trifluoromethanesulfonyloxy-1-taxen-13a-yl-3-tert-butoxycarbonylamino The 2-hydroxy-3-phenylpropionate can be prepared as follows.

A solution of 75 mg of (2R, 4S, 5R) -5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-4α-propanoyloxy-2- (2-tenoyloxy) -7B-trifluoromethanesulfonyloxy-11-taxene -13a-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate in 0.77 cm ^{3 of a} 1.0 N solution of hydrochloric acid in ethanol is stirred at a temperature of near 5 ° C for two hours. The reaction mixture is then diluted with 10 cm ^{3 of} dichloromethane, washed twice with 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 through a sintered glass filter and concentrated under reduced pressure (0.27 kPa) at a temperature close to 40 ° C. 74.4 mg of a yellow lacquer are obtained, which is purified by chromatography at atmospheric pressure on 8 g of silica gel (0.063-0.2 mm) containing a column of 1.5 cm diameter, eluting with a gradient of ethyl acetate / dichloromethane from a volume ratio of 5:95 to a volume ratio of 20:80 of the above components, and 8 cm ³ fractions were collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for two hours.

There was thus obtained 56.3 mg of (2R, 3SB) -5,20-epoxy-1B-hydroxy10B-methoxyacetoxy-9-oxo-4α-propanoyloxy-2- (2-tenoyloxy) -7B-trifluoromethanesulfonyloxy-11-taxen-13a- yl 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate as a pale yellow, brittle foam. The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

1.20 (s, 6H: _CH3); 1.22 (t, J = 7.5 Hz, 3H: _CH3 of ethyl)? 1.36 (s, 9H: C _{(CH3) 3);} 1.71 (s, 1H: OH at position 1)? 1.89 (s, 3H: _CH3); 2.05 (s, 3H: _CH3); 2.25 and 2.86 (2 mts, 1H each: CH2 at position 6); 2.33 (d, J = 9 Hz, 2H: CH2 - at position 14); 2.66 (mt, 2H: _CH2 of ethyl); 3.28 (d, J = 5 Hz, 1H: OH at position 2 '); 3.52 (s, 3H, _OCH3); 3.90 (d, J = 7 Hz, 1H: H at position 3); 4.20 (AB limit, J = 16 Hz, 2H: OCOCH2 O); 4.27 and 4.50 (2 d, J = 9 Hz, 1H each: ΟΗ ₌ at 20);

4.61 (mt, 1H: H at position 2 '); 4.88 (broad d, J = 10 Hz, 1H: H at position 5);

5.20 (broad d, J = 10 Hz, 1H: H at position 3 '); 5.30 (d, J = 10Hz, 1H; CONH); 5.50 (dd, J = 10 and 7 Hz, 1H: H at position 7); 5.65 (d, J =

Hz, 1H: H at position 2); 6.18 (broad t, J = 9 Hz, 1H: H at position 13);

6.70 (s, 1H; H at position 10); 7.18 (dd, J = 5 and 3.5 Hz, 1H: H at the 4-enoyl); from 7.30 to 7.50 (mt, 5H: aromatic H at position 3 '); 7.69 (dd, J = 5 and 1.5 Hz, 1H: H at the 2-tenoyl); 7.92 (dd, J = 3.5 and 1.5 Hz, 1H: H at the 2-tenoyl).

(2 R, 4 S, 5 R) -5B, 20-epoxy-10.beta.-hydroxy-trihydroxy-9-oxo-4-propanoyloxy-2a- (2-tenoyloxy) -7B-trifluoromethanesulfonyloxy-taxen-13-yl 3- tert-butoxycarbonyl-2- (4-methoxyphenyl) 4-phenyl-1,3-oxazolidine-5-carboxylate can be prepared as follows.

To a solution of 55.2 mg of 5B, 20-epoxy-1β, 13α-dihydroxy-10β-methoxyacetoxy-9-oxo-4α-propanoyloxy-2α- (2-tenoyloxy) -7β-trifluoromethanesulfonyloxy-11-taxene at 0, 1 cm ^{3 of} anhydrous toluene is gradually added to 41 mg of (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid, mg dicyclohexylcarbodiimide and 3 mg of N, N-dimethylamino-4-pyridine. The reaction mixture is stirred for two hours in an argon atmosphere at 20 ° C, then loaded onto 15 g of silica gel (0.063-0.2 mm) containing a 1.5 cm diameter column for elution using elution gradient of a mixture of ethyl acetate and dichloromethane from 5:95 to 10:90 by volume of the above components and collecting 10 cm ³ fractions. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for two hours.

There was thus obtained (2R, 4S, 5R) -5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-4α-propanoyloxy-2α- (2-tenoyloxy) -7B-trifluoromethanesulfonyloxy-11-taxene -13a-yl-3-tert-butoxy-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white solid brittle product. This product has the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDC1 _3, in ppm)

1.04 (with, 9H: C (CH _; J ₃ ) '· 1.04 (t, J = 7.5Hz) 3H CH ₃ ethyl); 1.14 (with, 3H: CH ₃ ); 1.16 (s, 3H: _CH3); 1.61 (WITH , 1H: OH at position 1); 1.68 (with, 3H: CH ₃ ); 1.81 (s, 3H: _CH3); from 2, 00 up to 2.30 (mt, 4H: CH 2 ethyl in CH 2 V 14) ; 2.03 and 2.80 (2 mts r 1H each: _CH2 V 6); r 3, 50 (s, , 3H: OCH) 3 ^Z ; 3.77 (d, J = 7Hz, 1H : H at 3); 3.81

(s, 3H: _ArOCH3); 4.13 (AB limit, J = 16 Hz, 2H: OCOCH2 O);

4.18 and 4.39 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.48 (d, J = 4 Hz, 1H: H at position 2 '); 4.78 (broad d, J = 10 Hz, 1H: H at position 5); from 5.35 to 5.50 (mt, 2H: H at position 3 ' and H at position 7); 5.55 (d, J = 7Hz, 1H);

H in 2); 5.96 (broad t, J = 9 Hz, 1H: H at position 13); 6.34 (mt, 1H: H at position 5 '); 6.56 (s, 1H: H at position 10); 6.88 (d, J = 8 Hz, 2H: aromatic H ortho to the _OCH3); 7.13 (dd, J = 5 and 3.5 Hz, 1H: H at the 2-tenoyl); from 7.30 to 7.45 (mt, 5H: aromatic H at position 3 '); 7.36 (d, J = 8 Hz, 2H: aromatic H at the meta position with OCH _a ); 7.62 (broad d,

J = 5 Hz, 1H: H at the 2-tenoyl); 7.80 (broad d, J = 3.5 Hz,

1H: H at [delta] 2-tenoyl).

5B, 20-Epoxy-1B, 13a-dihydroxy-10B-methoxyacetoxy-9-oxo4a-propanoyloxy-2- (2-tenoyloxy) -7B-trifluoromethanesulfonyloxy-11-taxene can be prepared as follows.

To a solution of 50 mg of 5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-4apropanoyloxy-2- (2-tenoyloxy) -1B, 7β, 13α-trihydroxy-11-taxene in 0.5 cm ^{3 of} anhydrous dichloromethane and 0, 0.0265 cm @ ³ of trifluoromethanesulfonic anhydride are added dropwise to 0.065 cm @ ^{3 of} pyridine, maintained under argon at 0 ° C. The resulting orange solution was stirred for 10 min at around 0 DEG C. and then for 45 minutes at a temperature close to 20 °, then was added 0.1 cm ³ of methanol and dichloromethane in a ratio of 5:95 vom objemo39. The solution is then chromatographed under atmospheric pressure on 10 g of silica gel (0.063-0.2 mm) contained in a 1.5 cm column using an elution gradient of methanol / dichloromethane from 2:98 to v / v. 5:95 of the above ingredients and 8 cm ³ fractions are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours.

There was obtained 55.2 mg of 5B, 20-epoxy-1B, 13a-dihydroxy-10amethoxyacetoxy-9-oxo-4a-propanoyloxy-2- (2-tenoyloxy) -7B-tri-fluoromethanesulfonyloxy-11-taxene as a white solid brittle foam.

5β, 20-Epoxy-1B, 7B, 13a-trihydroxy-10B-methoxyacetoxy-9oxo-4α-propanoyloxy-2α- (2-tenoyloxy) -11-taxene can be prepared as follows.

To a solution of 0.302 g of 5B, 20-epoxy-1B-hydroxy-10B-methoxyethoxy-9-oxo-4α-propanoyl-2- (2-tenoyloxy) -7B, 13α-bis (triethylsilyloxy) -11-taxene in 5 cm ^{3 of} dichloromethane, at a temperature close to 20 ° C, 6 cm ³ of triethylamine hydrofluoric acid complex (Et ₃ N ₃ HF) are added. The reaction mixture is stirred for 24 hours at a temperature in the region of 20 DEG C., then 50 cm @ ^{3 of} dichloromethane and 100 cm @ ^{3 of a} saturated aqueous sodium hydrogen carbonate solution are added. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.24 g of 5B, 20-epoxy-1B, 7B, 13a-trihydroxy10B-methoxyacetoxy-9-oxo-4a-propanoyloxy-2α- (2-tenoyloxy) -11taxene is obtained in the form of a white, brittle foam. The product obtained has the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl _α , δ in ppm)

1.07 (s, 3H: _CH3); 1.10 (s, 3H: CH3); 1.22 (t, J = 7.5 Hz,

3Η: CH _and ethyl); 1.62 (s, 1H: OH at position 1); 1.69 (s, 3H: _CH3);

1.89 and 2.63 (2 mts, 1H each: CH2 at position 6); 2.03 (d, J = 5.5Hz,

1H; OH at 13); 2.07 (s, 3H: _CH3); 2.27 (d, J = 9 Hz, 2H: _CH2 at position 14); 2.35 (d, J = 4.5 Hz, 1H, OH at position 7); 2.59 (mt, 2H, _CH2 of ethyl); 3.52 (s, 3H, _OCH3); 3.84 (d, J = 7 Hz, 1H: H at position 3);

4.23 and 4.43 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.25 (AB limit., J = 16 Hz, 2H: OCOCH2 O); 4.49 (mt, 1H: H at position 7); 4.87 (mt, 1H: H at position 13); 4.95 (broad d, J = 10 Hz, 1H: H at position 5);

5.53 (d, J = 7 Hz, 1H; H at position 2); 6.42 (s, 1H: H at position 10); 7.14 (dd, J = 4.5 and 3.5 Hz, 1H: H at the 2-tenoyl); 7.61 (dd, J = 4.5 and 1.5 Hz, 1H: H at the 2-tenoyl); 7.83 (dd, J = 3.5 and 1.5 Hz,

1H: H at 32 (2-tenoyl).

5B, 20-Epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-4? -Propanoyloxy-2? - (2-tenoyloxy) -7?, 13? -Bis (triethylsilyloxy) -11-taxene can be prepared as follows.

To a solution of 0.5 g of 5B, 20-epoxy-1B, 10B-dihydroxy-9-oxo-4apropanoyloxy-2- (2-tenoyloxy) -7B, 13a-bis (triethylsilyloxy) -11taxene in 10 cm ^{3 of} pyridine is added 0.286 cm ^{3 of} methoxyacetyl chloride at a temperature close to 0 ° C. The reaction mixture is stirred for 10 hours at a temperature in the region of 20 DEG C., then 100 cm @ ^{3 of} dichloromethane and 50 cm @ ^{3 of a} saturated aqueous ammonium chloride solution are added. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure at 40 ° C. The residue (0.6 g) is purified by chromatography on 50 g of silica gel (0.063-0, 2 mm) contained in a 2 cm diameter column, eluting with a 5:95 by volume mixture of ethyl acetate and cyclohexane. and 10 cm ³ fractions are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

0.320 g of 5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-4? -Propanoyloxy-2? - (2-tenoyloxy) -7?, 13? -Bis (triethylsilyloxy) -11-taxene is obtained in the form of a white brittle a product with the following physical characteristics:

^ • H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm) from 0.50 to 0.70 (mt, 12 H: CH ₂ ethyl); 0.92 (t, J = 7.5Hz,

9H: _CH3 of ethyl); 0.98 (t, J = 7.5 Hz, 9H: CH _and ethyl); 1.09 (s,

3H: _CH3); 1.15 (s, 3H: CH _a); 1.27 (t, J = 7.5 Hz, 3H: CH _and ethyl at position 4); 1.59 (s, 1H: OH at position 1); 1.65 (s, 3H: CH3; 1.85 and 2.52 (2 mts, 1H each: CH2 at position 6); 2.07 and 2.18 (2 dd, J = 16 and 9 Hz, 1H each) : _CH2 at position 14); 2.08 (s, 3H, CHJ; 2.58 (mt,

2H: _CH2 of ethyl 4 in); 3.50 (s, 3H, 0CH _3); 3.73 (d, J = 7Hz,

1H: H at 3); 4.13 (limiting AB., J = 16 Hz, 2H, OCOCH ₂ O); 4.20 and 4.41 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.49 (dd, J = 11 and 7 Hz, 1H: H at position 7); 4.89 (broad t, J = 9 Hz, 1H: H at position 13);

4.91 (broad d, J = 10 Hz, 1H: H at position 5); 5.53 (d, J = 7 Hz, 1H: H at position 2); 6.51 (s, 1H: H at position 10); 7.12 (dd, J = 4.5 and 3 Hz, 1H: H at the 2-tenoyl); 7.61 (d, J = 4.5 Hz, 1H: H at the 2-tenoyl);

7.83 (d, J = 3 Hz, 1H: H at the 2-tenoyl).

5β, 20-Epoxy-1B, 10B-dihydroxy-9-oxo-4α-propanoyloxy-2a (2-tenoyloxy) -7β, 13α-bis (triethylsilyloxy) -11-taxene can be prepared as follows.

To a solution of 0.5 g of 1B, 2a-carbonyldioxy-5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-4o-propanoyloxy-7B, 13a-bis (triethylsilyloxy) 11-taxene in 20 cm ^{3 of} tetrahydrofuran is added under an argon atmosphere and at a temperature close to -78 ° C, add 1.5 cm ^{3 of} IN solution

2-thienyllithium in tetrahydrofuran. The reaction mixture is stirred for 35 minutes at a temperature close to -78 [deg.] C. and then 1 cm &lt; ^{3 &gt; of} saturated aqueous ammonium chloride solution is added. 10 cm ^{3 of} saturated aqueous ammonium chloride solution and 50 cm ^{3 of} dichloromethane are then added at a temperature in the region of 20 ° C. The organic phase is decanted, washed twice with 10 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.65 g of solid is obtained, which is purified by chromatography on 90 g of silica gel (0.063-0.2 mm) contained in a 1 cm diameter column, eluting with ethyl acetate / cyclohexane (10: v / v): 90 and 10 cm ³ fractions are collected. 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 5β, 20-epoxy-1B, 10B-dihydroxy-9-oxo-4apropanoyloxy-2α- (2-tenoyloxy) -7B, 13α-bis (triethylsilyloxy) -11taxene is obtained in the form of a white, brittle product with the following physical characteristics:

^ H-NMR:

(400 MHz, CDCl ₃ , δ in ppm)

0.57 (mt, 6H: CH3 ethyl); 0.68 (mt, 6H: CH3 ethyl); 0.95 (t, J = 7.5, 9H: _CH3 of ethyl); 1.01 (t, J = 7.5, 9H: _CH3 of ethyl); 1.07 (s, 3H: _CH3); 1.17 (s, 3H: CH3); 1.27 (t, J =

7.5 Hz, 3H: _CH3 of ethyl at position 4); 1.73 (s, 3H: _CH3); 1.90 and 2.47 (2 mts, 1H each: _CH2 at 6); 2.02 (s, 3H: _CH3); 2.09 and 2.18 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.60 (mt, 2H: _CH2 of ethyl 4 in); 3.82 (d, J = 7 Hz, 1H: H at position 3); 4.24 and 4.44 (2d,

J = 9 Hz, 1H each: _CH2 at 20); 4.26 (d, J = 0.5 Hz, 1H: OH at position 10); 4.42 (dd, J = 11 and 7 Hz, 1H: H at position 7); 4.93 (broad d,

J = 10 Hz, 1H: H at position 5); 4.97 (broad t, J = 9 Hz, 1H: H at position 13); 5.13 (d, J = 0.5 Hz, 1H: H at position 10); 5.53 (d, J = 7 Hz, 1H: H at position 2); 7.15 (dd, J = 4.5 and 3 Hz, 1H: H at the 2-thionyl); 7.63 (d, J = 4.5 Hz, 1H: H at the 2-tenoyl); 7.85 (d, J = 3Hz,

1H: H at 32 (2-thienoyl).

Example 3

To a solution of 154 mg of (2R, 3S) -2α-benzoyloxy-4α-butanoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-7β-trifluoromethanesulfonyloxy-11-taxen-13α-yl-3-tert Butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 2 cm ^{3 of} acetonitrile and 200 μΐ of tetrahydrofuran is added successively to 96 mg of molecular sieve 4Ä in powder form, 225 mg of sodium chloride. The reaction mixture is kept under stirring at a temperature close to 75 ° C for 5 hours and then 15 cm ^{3 of} dichloromethane and 10 cm ^{3 of} saturated aqueous sodium chloride solution are added at room temperature. The organic phase is decanted, washed twice with 20 cm ^{3 of} saturated aqueous sodium chloride solution, dried, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 13.3 mg of product are obtained, which product is purified by chromatography on 80 g of silica gel (0.063-0.2 mm) contained in a 1 cm diameter column, eluting with a 98/2 mixture of dichloromethane and methanol and 10 cm ³ fractions are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

63 g of (2R, 3S) -2α-benzoyloxy-4α-butanoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-7β, 8-methylene-19-nor-9oxo-11-taxen-13o are obtained: -yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product with the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 5 in ppm)

0.92 (t, J = 7.5 Hz, 3H: CH _and propyl); 1.26 (s, 6H: _CH3); 1.31 (s, 9H: C _{(CH3) 3);} 1.42 (mt, 1H: H at position 7); 1.71 and 2.26 (2 mts, 1H each: _CH2 at 19); 1.60 to 1.85 (mt, 2H: _CH2 of propyl); 1.86 (s, 3H: _CH3); 1.88 (s, 1H: OH at position 1); 2.12 and 2.50 (respectively. Broad d. And mt, J = 16 Hz, 1H each: _CH2 at 6); 2.23 and 2.39 (respectively. Mt and dd, J = 16 and 9 Hz, 2H: _CH2 at position 14); 2.49 and 2.65 (2 mts, 1H each: OCOCH ₂ propyl); 3.25 (mt, 1H: OH at position 2 '); 3.51 (s, 3H, _OCH3); 4.05 and 4.32 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.10 (d, J = 7 Hz, 1H: H at position 3); 4.16 and 4.22 (2 d, J = 16 Hz, 1H each: OCOCH ₂ O); 4.62 (mt, 1H: H at position 2 '); 4.68 (broad d, J =

4.5 Hz, 1H: H at position 5); 5.25 (broad d, J = 10 Hz, 1H: H at position 3 ');

5.30 (d, J = 10Hz, 1H: CONH); 5.65 (d, J = 7 Hz, 1H: H at position 2);

6.23 (broad t, J = 9 Hz, 1H: H at position 13); 6.42 (s, 1H: H at position 10); from 7.25 to 7.45 (mt, 5H: aromatic H at position 3 '); 7.51 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.62 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.16 (d, J = 7.5 Hz, 2H: OCOC HH at ortho position).

δ S (2R, 3S) -2α-Benzoyloxy-4α-butanoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-7β-trifluoromethanesulfonyloxy-11taxen-13 α-γ-3- t. butoxycarbonylamino-2-hydroxy-3-phenylpropionate can be prepared as follows.

A solution of 400 mg of (2R, 4S, 5R) -2α-benzoyloxy-4α-butanoyloxy5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-7β-trifluoromethanesulfonyloxy-11-taxen-13 α- y 1 - 3 -terc. but oxycarbonyl - 2 - (4 -Me- trimethoxyphenyl) -4-phenyl-l, 3-oxazolidin-5-carboxylate in 6.4 cm ³ O, 1 N HCl in ethanol is kept stirring at a temperature of 0 ^and C for 6 hours and then at a temperature in the region of 20 ° C for 15 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 20 ° C. The crude reaction product is dissolved in 20 cm @ ^{3 of} dichloromethane and 10 cm @ ^{3 of a} saturated aqueous sodium bicarbonate solution. The aqueous phase is separated by decantation and then extracted twice with 20 cm @ ^{3 of} dichloromethane. The organic phases are combined, washed with 30 cm ^{3 of} distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 20 ° C. 410 mg of product are obtained, which product is purified by chromatography on 60 g of a 1 cm diameter silica gel (0.063-0.2 mm), eluting with a dichloromethane / methanol (98.5: 1 by volume) mixture. , 5 and 10 cm ³ fractions are collected. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 20 ^e C.

307 mg of (2R, 3S) -2o: -benzoyloxy-4α-butanoyloxy5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-7B-trifluoromethanesulfonyloxy-11-taxen-13a-yl-3 are obtained. -tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product having the following physical characteristics:

H -H nuclear magnetic resonance spectrum:

(400 MHz, CDCl _α , δ in ppm)

0.93 (t, J = 7.5 Hz, 3H: _CH3 of propyl); 1.22 (s, 3H: _CH3);

1.24 (s, 3H: _CH3); 1.35 (s, 9H: C _{(CH3) 3);} from 1.65 to 1.85 (mt, 2H: CH _and propyl); 1.74 (s, 1H: OH at position 1); 1.88 (s, 3H: _CH3); 2.04 (s, 3H: CHJ, 2.25 and 2.86 (2 mts, 1H each: _{CH, and}

V 6); 2.33 (d, J = 9 Hz, 2H: CH at position 14 _a); 2.52 and 2.66 (2 mts,

J = 14.5 and 6.5 Hz, 1H each: OCOCH3 propyl); 3.33 (d, J =

Hz, 1H: OH at position 2 '); 3.52 (s, 3H, _OCH3); 3.94 (d, J = 7Hz,

1H: H at 3); 4.16 and 4.21 (2 d, J = 16 Hz, 1H each: OCOCH ₂ O);

4.19 and 4.35 (2 d, J = 9 Hz, 1H each: CH ₌ at 20)? 4.62 (mt, 1H:

H at 2 '); 4.86 (broad d, J = 10 Hz, 1H: H at position 5); 5.22 (broad d,

J = 10 Hz, 1H: H at position 3 '); 5.33 (d, J = 10Hz, 1H: CONH); 5.50 (dd, J = 11 and 8 Hz, 1H: H at position 7)? 5.73 (d, J = 7 Hz, 1H: H at position 2); 6.16 (broad t, J = 9 Hz, 1H: H at position 13); 6.71 (s, 1H: H at position 10); from

7.25 to 7.45 (mt, 5H: aromatic H at position 3 '); 7.51 (t, J = 7.5Hz,

2H: _OCOC6 H _p H at the meta position); 7.63 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position) 8.12 (d, J = 7.5 Hz, 2H: OCOC _much H_H at the ortho position).

(2R, 4S, 5R) -2α-Benzoyloxy-4α-butanoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-7β-trifluoromethanesulfonyloxy-11-taxen-3-tert-butoxycarbonyl-2- (4- methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate can be prepared as follows.

To a solution of 400 mg of 2α-benzoyloxy-4α-butanoyloxy-1β, 13-dihydroxy-5β, 20-epoxy-10β-methoxyacetoxy-9-oxo-7β-trifluoromethanesulfonyloxy-11-taxene in 10 cm ^{3 of} anhydrous ethyl acetate was gradually added 247 mg (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidinecarboxylic acid, 186 mg dicyclohexylcarbodiimide and 12.5 mg 4-dimethylaminopyridine. The reaction mixture is stirred for 15 hours under argon at a temperature in the region of 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 1 g of product is obtained, which product is purified by chromatography on 100 g of silica gel (0.063-0.2 mm) contained in a column of 3 cm diameter, eluting with a 95/5 mixture of dichloromethane and methanol and collected. 12 cm ³ fractions. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

410 mg of (2R, 4S, 5R) -2a-benzoyloxy-4a-butanoyloxy5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-7B-trifluoromethanesulfonyloxy-11-taxen-13a- is obtained. yl-3-tert. butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate in the form of a white, brittle product with the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

0.92 (t, J = 7.5 Hz, 3H: _CH3 of propyl); 1.07 (s, 9H: C _{(CH3) 3);} 1.17 (s, 6H: _CH3): 1.55 to 1.70 (mt, 3H: CH ₂ OH, and propyl

in. 1)? 1.64 (s, 3H: _CH3); 1.84 (s, 3H: _CH3); 2.08 and 2.15 to 2.30 (mt and príp.dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); from 2.15 to 2.30 and 2.82 (2 mts, 1H each: 0Η ₌ at 6); from 2.15 to 2.30 and 2.82 (2mts, 1H each: 0Η ₌ at 6); from 2.15 to 2.30 (mt,

2H, OCOCH ₂ of propyl); 3.51 (s, 3H, _OCH3); 3.82 (s, 3H):

ArOCH ₃ ); 3.83 (d, J = 7 Hz, 1H: H at position 3); 4.12 and 4.28 (2d, J =

Hz, 1H each: _CH2 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, 1H: H at position 2 '); 4.79 (broad d, J = 10 Hz, 1H: H 5); from 5.35 to 5.50 (mt, 1H: H at position 6);

3 '); 5.44 (dd, J = 9 and 7 Hz, 1H: H at position 7); 5.67 (d, J = 7Hz,

1H: H at (2); 5.99 (broad t, J = 9 Hz, 1H: H at position 13); 6.40 (mt,

1H: H at position 5 '); 6.59 (s, 1H: H at position 10); 6.92 (d, J = 8.5Hz,

2H: aromatic H at the ortho position of 0CH _3); from 7.25 to 7.45 (mt, 5H: aromatic H at position 3 '); 7.37 (d, J = 8.5 Hz, 2H: aromatic H meta to the _OCH3); 7.48 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.63 (t, J =

7.5 Hz, 1H, OCOC H _E H at _the para position); 8.11 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

2a-Benzoyloxy-4α-butanoyloxy-1B, 13B-dihydroxy-5B, 20epoxy-10B-methoxyacetoxy-9-oxo-7B-trifluoromethanesulfonyloxy-11taxene can be prepared as follows.

To a solution of 389 mg of 2a-benzoyloxy-4α-butanoyloxy-5B, 20epoxy-10B-methoxyacetoxy-9-oxo-1β, 7β, 13α-trihydroxy-11-taxene in 6 cm ^{3 of} anhydrous dichloromethane and 390 μΐ of pyridine maintained in an argon atmosphere , at a temperature close to 0 ° C, add 410 μΐ of trifluoromethanesulphonic anhydride dropwise. The orange solution obtained is stirred for 15 minutes at a temperature in the region of 0 DEG C. and then 3 cm @ ^{3 of} water and 50 cm @ ^{3 of} dichloromethane are added. The organic phase is decanted, washed twice with cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2.7 kPa) at 40 ° C. 510 mg of product are obtained, which product is purified by chromatography on 70 g of silica gel (0.063-0.2 mm), which contains a column with a diameter of 1 cm, eluting with a dichloromethane / methanol (95: 5 by volume) mixture and collecting it. 10 cm ³ fractions. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

410 mg of 2a-benzoyloxy-4α-butanoyloxy-1β-13α-dihydroxy-5β, 20-epoxy-10β-methoxyacetoxy-9-oxo-7β-trifluoromethanesulfonyloxy-11-taxene are obtained as a white brittle product, followed by physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDC1 _3, in ppm)

1.06 (t, J = 7.5 Hz, 3H: _CH3 of propyl) 1.06 (s, 3H: _CH3); 1.20 (s, 3H: _CH3); 1.63 (s, 1H: OH at position 1); 1.77 (mt, 2H: CH3 of propyl); 1.87 (s, 3H: _CH3); 2.18 (d, J = 5 Hz, 1H: OH at position 13); from 2.15 to 2.40 (AB limit, 2H: CH2 at position 14); from 2.15 to 2.40 and 2.89 (2 mts, 1H each: _{CH, and} 6); 2.25 (s, 3H: _CH3); 2.59 (limiting AB, J = 16 and 7.5 Hz, 2H, OCOCH ₂ of propyl); 3.51 (s,

3H, _OCH3); 4.03 (d, J = 7 Hz, 1H: H at position 3); 4.16 and 4.24 (2 d, J = 16 Hz, 1H each: OCOCH ₂ O); 4.18 and 4.35 (2 d, J = 9 Hz,

1H each: CH _and at 20); 4.85 (mt, 1H: H at position 13); 4.92 (d, broad,

J = 10 Hz, 1H: H at position 5); 5.57 (dd, J = 10.5 and 7 Hz, 1H: H at position 7); 5.68 (d, J = 7 Hz, 1H: H at position 2); 6.73 (s, 1H: H at position 10); 7.51 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.63 (t, J = 7.5 Hz, 1H: _OCOC6 H at the para position); 8.10 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

2a-Benzoyloxy-4α-butanoyloxy-5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-1B, 7B, 13a-trihydroxy-11-taxene can be prepared as follows.

To a solution of 580 mg of 2α-benzoyloxy-4α-butanoyloxy-7β, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-11-taxene in 5 cm ^{3 of} dichloromethane 5.5 cm ³ of triethylamine-hydrofluoric acid complex are added at a temperature in the region of 20 ° C. The reaction mixture is stirred for 23 hours at a temperature in the region of 20 DEG C., then 50 cm @ ^{3 of} dichloromethane and 100 cm @ ^{3 of a} saturated aqueous sodium bicarbonate solution are added. The organic phase is decanted, washed twice with 20 cm ^{3 of} saturated aqueous sodium chloride solution, 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 gel (0.063-0.2 mm), which contains a column with a diameter of 2 cm, eluting with a 5:95 by volume mixture of methanol and dichloromethane and collecting them. 10 cm ³ fractions. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

389 mg of 2a-benzoyloxy-4α-butanoyloxy-5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-1B, 7B, 13a-trihydroxy-11-taxene are obtained in the form of a white, brittle product with the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

1.05 (t, J = 7.5 Hz, 3H: _CH3 of propyl); 1.11 (s, 6H: _CH3);

1.67 (s, 3H: CH _a); 1.71 (s, 1H: OH at position 1); 1.75 (mt, 2H: _CH2 of propyl); 1.85 and 2.45 to 2.65 (2 mts, 1H each: _CH2 at 6); 2.05 (s, 3H: _CH3); 2.24 (d, J = 5Hz, 1H: OH); 2.28 (limiting AB., J = 16 and 9 Hz, 2H: _CH2 at position 14); 2.40 (d, J = 4Hz,

1H: OH); OH); 2.56 (limiting AB., 2H, OCOCH ₂ of propyl); 3.51 (s,

3H: OCH _a ); 3.88 (d, J = 7 Hz, 1H: H at position 3); 4.15 and 4.32 (2d,

J = 9 Hz, 1H each: _CH2 at 20); 4.23 (limiting AB., J = 16 Hz, 2H, OCOCH ₂ O); 4.48 (mt, 1H: H at position 7); 4.86 (mt, 1H: H at position 13); 4.94 (d, broad, J = 10 Hz, 1H: H at position 5); 5.62 (d, J = 7 Hz, 1H: H at position 2); 6.43 (s, 1H: H at position 10); 7.49 (t, J = 7.5 Hz, 2H: OCOC H H at the meta position); 7.62 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.12 (d, J =

7.5 Hz, 2H: OCOC H H (ortho).

2a-Benzoyloxy-4α-butoynoyloxy-7β, 13α-bis (triethylsilyloxy) -5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-11-taxene can be prepared as follows.

To a solution of 906 mg of 2a-benzoyloxy-4α-butanoyloxy-1β, 10β-dihydroxy-7β, 13α-bis (triethylsilyloxy) -5B-20-epoxy-9-oxo49

11-Taxene in 18 cm ^{3 of} pyridine is added 1.03 cm ^{3 of} methoxyacetyl chloride at a temperature close to 0 ° C. The reaction mixture is stirred for 14 hours at a temperature in the region of 20 DEG C. and then 20 cm @ ^{3 of} dichloromethane and 20 cm @ ^{3 of a} saturated aqueous ammonium chloride solution are added. The organic phase is decanted, washed four times with 20 cm ^{3 of} saturated aqueous copper sulphate solution, twice with 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.

800 mg of product are obtained, which product is purified by chromatography on 100 g of silica gel (0.063-0.2 mm), which contains a column of 2.5 cm diameter, eluting with a 2:98 by volume mixture of methanol and dichloromethane. and fractions of 15 cm ³ are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

580 mg of 2a-benzoyloxy-4α-butanoyloxy-7B, 13abis (ditriethylsilyloxy) -5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-11-taxene are obtained as a white brittle product, with physical the characteristics listed below:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDC1 _3, in ppm)

0.60 and 0.68 (2 mts, 6H each: _CH2 of ethyl); 0.95 and 1.04 (2t,

J = 7.5, 9H each: _CH3 of ethyl); 1.09 (t, J = 7.5Hz, 3H):

CH _{3 of} propyl); 1.13 (s, 3H, CHJ; 1.18 (s, 3H: _CH3); 1.64 (s, 1H: OH at position 1); 1.68 (s, 3H: CH _a); 1.84 (mt, 2H: _CH2 of propyl); 1.89 and 2.50 (2 mts, 1H each: _CH2 at 6), 2.11 and 2.23 (2 dd, J = 16 and 9 Hz, each 1H, CH ₌ at 14) 2.13 (s, 3H:

CH ₃ ); 2.55 (mt, 2H: OCOCH ₂ of propyl); 3.53 (s, 3H, OCH _a);

3.82 (d, J = 7 Hz, 1H: H at position 3); 4.13 and 4.31 (2 d, J = 9 Hz,

1H each: _CH2 at 20); 4.16 (limiting AB., J = 16 Hz, 2H, OCOCH ₂ O); 4.52 (dd, J = 11 and 7 Hz, 1H: H at position 7); 4.91 (mt, IH):

H at 13); 4.93 (d, broad, J = 10 Hz, 1H: H at position 5); 5.64 (d, J =

Hz, 1H: H at position 2); 6.54 (s, 1H: H at position 10); 7.47 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.61 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.11 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

2-Benzoyl-4α-butanoyloxy-1β, 10β-dihydroxy-7β, 13α-bis (triethylsilyloxy) -5α, 20-epoxy-9-oxo-11-taxene can be prepared as follows.

To a solution of 907 mg of 4α-butanoyloxy-1B, 2a-carbonate-7B, 13abis (triethylsilyloxy) -5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-11taxene in 50 cm ^{3 of} anhydrous tetrahydrofuran is added 2.34 cm ^{3 of} IM of a solution of phenyllithium in tetrahydrofuran at a temperature near -78 ° C. The reaction mixture is stirred for 1 hour at a temperature close to -78 ° C, then 10 cm ^{3 of} saturated aqueous ammonium chloride solution are added. At a temperature in the region of 20 DEG C., 20 cm @ ^{3 of} saturated aqueous ammonium chloride solution and 50 cm @ ^{3 of} dichloromethane are added. The organic phase is decanted, washed twice with 10 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, 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 cm @ ^{3 of} silica gel (0.063-0.2 mm), which contains a column with a diameter of 5 cm, eluting with a mixture of ethyl acetate and cyclohexane (10:90 by volume). and 10 cm ³ fractions are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

906 mg of 2a-benzoyloxy-4α-butanoyloxy-1B, 10B-dihydroxy-7B, 13a-ditriethylsilyloxy-5B, 20-epoxy-9-oxo-oxo-11taxa is obtained in the form of a white, brittle product with the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

0.56 and 0.67 (2 mts, 6H each: _CH3 of ethyl); 0.95 and 1.03 (2t,

J = 7.5, 9H each: _CH3 of ethyl); 1.08 (s, 3H: _CH3); 1.10 (t, J = 7.5 Hz, 3H: _CH3 of propyl); 1.18 (s, 3H: _CH3); 1.60 (s, 1H: OH at position 1); 1.73 (s, 3H: _CH3); 1.84 (mt, 2H: CH _of C 51 polyl); 1.91 and 2.48 (2 mts, 1H each: _{CH, and} 6); 2.03 (s, 3H: _CH3); 2.11 and 2.22 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.58 (mt, 2H: OCOCH ₂ of propyl); 3.87 (d, J = 7 Hz, 1H: H at position 3); 4.18 and 4.3 2 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.28 (d, J =

Hz, 1H: OH (10); 4.42 (dd, J = 10.5 and 6.5 Hz, 1H: H at position 7); 4.93 (broad d, J = 10 Hz, 1H: H at position 5); 4.98 (t, J = 9 Hz, 1H: H at position 13); 5.17 (d, J = 2 Hz, 1H: H at position 10); 5.62 (d, J = 7Hz, 1H);

H in 2); 7.49 (t, J = 7.5 Hz, 2H: OCOC H H at the meta position); 7.61 (t, J =

7.5 Hz, 1H, OCOC H _E H at _the para position); 8.12 (d, J = 7.5 Hz, 2H: H OCOC _much in _the ortho position).

4α-Butanoyloxy-1β, 2a-carbonate-7β, 13α-bis (triethylsilyloxy) -5β, 20-epoxy-10β-methoxyacetoxy-9-oxo-11-taxene can be prepared as follows.

To a solution of 870 mg of IB, 2a-carbonate-7B, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-4α-hydroxy-10β-methoxyacetoxy-9-oxo-11-taxene in 15 cm ^{3 of} dichloromethane is added 1 , 46 g of 4-dimethylaminopyridine and 3.90 cm @ ³ of butyric anhydride. The reaction mixture is heated to a temperature in the region of 42 ° 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 decanted, washed twice with 40 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa) at 40 ° C.

2.0 g of product are obtained, which product is purified by chromatography on 170 g of silica gel (0.063-0.2 mm), which contains a column with a diameter of 3 cm, eluting with a mixture of ethyl acetate and cyclohexane (5:95 by volume) and Fractions of 15 cm ³ are collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

1.00 g of 4α-butanoyloxy-1B, 2a-carbonate-7B, 13α-ditriethylsilyloxy-5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-11-taxene are obtained in the form of a white brittle product having the following physical characteristics :

¹ H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

0.50 to 0.70 (mt, 12H: _CH2 of ethyl); 0.90 to 1.10 (mt, 21H: _CH3 of ethyl, and _CH3 of propyl); 1.18 (s, 3H: _CH3); 1.28 (s, 3H):

CH ₃ ); 1.73 (mt, 2H: _CH2 of propyl); 1.75 (s, 3H: CHJ, 1.92 and 2.59 (2 mts, 1H each: _CH2 at 6), 2.13 (s, 3H: _CH3); 2.14 and 2.35 and 2.45 (respectively. dd and mt, J = 16 and 9 Hz, 1H each: _CH2 at position 14); from 2.35 to 2.45 (mt, 2H: 0C0CH ₂ of propyl), 3.42 (d, J = 6.5 Hz, 1H: H at position 3); 3.51 (s, 3H, _OCH), 4.18 (s, 2H,

OCOCH ₂ O); 4.46 (dd, J = 10 and 6.5 Hz, 1H: H at position 7); 4.50 and 4.63 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.51 (d, J = 6.5 Hz, 1H: H at position 2); 4.93 (broad d, J = 10 Hz, 1H: H at position 5); 5.02 (broad t, J = 9 Hz, 1H: H at position 13); 6.51 (s, 1H: H at position 10).

Example 4

The procedure is as in Example 3, starting from (2R, 3S) -2a-benzoyloxy-4a-phenylacetoxy-5B, 20-epoxy-1B-hydroxy10B-methoxyacetoxy-9-oxo-7B-trifluoromethanesulfonyloxy-13a-yl- 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtains:

(2R, 3S) -2α-Benzoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-7β, 8-methylene-19-nor-9-oxo-4α-phenylacetoxy-11-taxen-13α-yl3 -tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

1.24 (s, 15H: _CH3 - _CH3 and C _{(CH3) 3);} 1.40 (mt, 1H: H at position 7); 1.66 and 2.24 (2 dd, J = 6 and 5 Hz and J = 10 and 6 Hz, 1H each:

CH ₂ in 19); 1.92 (s, 1H: OH at position 1); 1.96 (s, 3H: _CH3); 2.07 and 2.46 (respectively. Broad d. And dt, J = 16 Hz and J = 16 and 4.5 Hz, 1H each: _CH2 at 6); 2.32 and 2.54 (respectively. Broad d and dd., J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.24 (mt, 1H: OH at position 2 '); 3.53 (s, 3H, _OCH3); 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: _CH2 at 20); 4.20 and 4.26 (2 d, J = 16 Hz, 1H each, OCOCH ₂ 0); 4.23 (d, J = 7 Hz, 1H, H at position 3); 4.55 (broad d, J = 4.5 Hz, 1H: H at position 5)? 4.63 (mt, 1H: H at position 2 '); 5.31 (AB limit., 2H: H at position 3 'and CONH); 5.71 (d, J = 7 Hz, 1H: H at position 2); 6.34 (broad t, J = 9 Hz, 1H: HV 13); 6.44 (S,

1H: H at position 10); from 7.10 to 7.45 (mt, 10H: aromatic H and aromatic H at position 3 '); 7.51 (t, J = 7.5 Hz, 2H: OCOC _with H _and H at the meta position);

7.63 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.16 (d, J = 7.5 Hz, 2H; OCOC HH ortho).

When operating under conditions analogous to those described in Example 3, the following were prepared:

(2R, 3S) -2a-Benzoyloxy-56,20-epoxy-1H-hydroxy-10B-methoxyacetoxy-9-oxo-4a-phenylacetoxy-7B-trifluoromethanesulfonyloxy-11-taxen-13o-yl-3-tert. butoxycarbones lamino- 2-hydroxy-3-phenylpropionate.

The product obtained has the following characteristics:

¹ H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

1.24 (s, 6H: CH _a); 1.36 (s, 9H: C _{(CH3) 3);} 1.74 (s, 1H: OH at position 1); 1.87 (s, 3H, CHJ; 2.14 (s, 3H: _CH3); 2.19 and 2.83 (2 mts, 1H each: CH at 6 _a), 2.39 and 2.48 ( 2 dd broad, J = 16 and 9 Hz, 1H each: CH3 at position 14), 3.38 (d, J = 4.5 Hz, 1H: OH at position 2 &apos;), 3.53 (s, 3H) OCH _a), 3.90 and 4.14 (2 d, J = 15 Hz, 1H each:

OCOCH., Ar); 4.01 (d, J = 7 Hz, 1H: H at position 3); 4.11 and 4.20 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.17 and 4.25 (2 d, J = 16 Hz, 1H each: OCOCH ₂ O); 4.65 (mt, 1H: H at position 2 '); 4.68 (d, broad, J =

Hz, 1H: H at position 5); 5.28 (broad d, J = 10 Hz, 1H: H at position 3 '); 5.35 (d, J = 10Hz, 1H: CONH); 5.50 (dd, J = 10 and 7 Hz, 1H: H at position 7); 5.77 (d, J = 7 Hz, 1H: H at position 2); 6.28 (broad t, J = 9 Hz, 1H: H at position 13); 6.74 (s, 1H: H at position 10); from 7.15 to 7.45 (mt, 10H: aromatic H and aromatic H at position 3 '); 7.51 (t, J = 7.5Hz,

2H: H _{p e} OCOC H at the meta position); 7.66 (t, J = 7.5 Hz, 1H: H OCOC _{much steam,} HV); 8.08 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

When operating under conditions analogous to those described in Example 3, the following were prepared:

(2R, 4S, 5R) -2α-Benzoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyethoxy-9-oxo-4α-phenylacetoxy-7β-trifluoromethanesulfonyloxy-11-thien-13a-yl- 3-t. butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate.

The product obtained has the following characteristics:

^ H-NMR:

(400 MHz, CDCl ₃ , δ in ppm, temperature 333 ° K)

1.06 (s, 9H: C _{(CH3) 3);} 1.12 (s, 3H: _CH3); 1.24 (s, 3H):

CH ₃ ); 1.66 (s, 1H: OH at position 1); 1.83 (s, 3H, CHJ; 1.86 (s, 3H: _CH3); 2.14 and 2.79 (2 mts, 1H each: the ΟΗ ₌ 6), 2.24 and 2.30 ( 2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.45 and 3.58 (2 d,

J = 15 Hz, 1H each: 0C0CH ₂ Ar); 3.54 (s, 3H, _OCH3); 3.85 (s,

3H: _ArOCH3); 3.94 (d, J = 7 Hz, 1H: H at position 3); 4.08 and 4.17 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.14 and 4.22 (2 d, J = 16

Hz, 1H each: OCOCH3); 4.59 (broad d, J = 10 Hz, 1H: H at position 5);

4.63 (d, J = 5.5 Hz, 1H: H at position 2 '); 5.45 (d, J = 5.5 Hz, 1H: H at position 3 '); 5.47 (mt, 1H: H at position 7); 5.72 (d, J = 7 Hz, 1H: H at position 2);

6.14 (broad t, J = 9 Hz, 1H: H at position 13); 6.34 (s, 1H: H at position 5 ');

6.65 (s, 1H: H at position 10); 6.94 (d, J = 8.5 Hz, 2H: aromatic H).

ortho to OCH ₃ ); 7.20 to 7.45 (mt, 12H, aromatic H and arom. H meta to the _OCH3 and aromatic H. 3 '); 7.48 (t, J = 7.5)

Hz, 2H: OCOC H H (meta); 7.64 (t, J = 7.5 Hz, 1H: OCOC6 H5 ESe)

H in para); 7.98 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

When working under conditions analogous to those described in Example 3, the following are prepared:

2a-Benzoyloxy-1β, 13α-dihydroxy-5β, 20-epoxy-1β-methoxyacetoxy-9-oxo-4α-phenylacetoxy-7β-trifluoromethanesulfonyloxy-11-taxene.

The product obtained has the following characteristics:

H -H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, CDCl ₃ , 5 V ppm)

1.07 (s, 3H: CH _a); 1.21 (s, 3H: _CH3); 1.64 (s, 1H: OH at position 1);

1.87 (s, 3H: _CH3); 2.18 (d, J = 4.5 Hz, 1H: OH at position 13); 2,20 a

2.88 (2 mts, 1H each: _CH2 at 6); 2.30 (s, 3H: _CH3); 2.25 to 2.35 (mt, 2H: _CH2 at position 14); 3.52 (s, 3H, _OCH3); 3.90 and 3.97 (2 d, J = 15 Hz, 1H each: 0C0CH ₂ Ar); 4.08 (d, J = 7Hz, 1H)

H in 3); 4.12 and 4.27 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.16 and 4.24 (2 d, J = 16 Hz, 1H each: OCOCH2 O); 4.80 (broad d, J =

Hz, 1H: H at position 5); 4.92 (mt, 1H: H at position 13); 5.55 (dd, J = 10 and

6.5 H2, 1H: H at position 7); 5.71 (d, J = 7 Hz, 1H: H at position 2); 6.74 (s,

1H: H at position 10); from 7.25 to 7.45 (mt, 5H: aromatic H) 7.48 (t, J =

7.5 Hz, 2H: _OCOC6 H _p H at the meta position); 7.64 (t, J = 7.5Hz, 1H)

OCOC ₍ H _with H in para); 8.03 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

When working under conditions analogous to those described in Example 3, prepare:

2α-Benzoyloxy-56,20-epoxy-10β-methoxyacetoxy-9-oxo-4α-phenylation-ethoxy-β, 7β-trihydroxy-11-taxene.

The product obtained has the following characteristics: @ 1 H-NMR:

(400 MHz, CDC1 _3, in ppm)

1.12 (s, 3H: _CH3); 1.14 (s, 3H: _CH3); 1.66 (s, 1H: OH at position 1);

1.67 (s, 3H: _CH3); 1.84 and 2.56 (2 mts, 1H each: CH ₃ at 6);

2.11 (s, 3H: _CH3); 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: _CH2 at position 14); 3.54 (s, 3H, _OCH3); 3.94 (limiting AB, J = 15 Hz, 2H: OCOCH3, Ar);

3.94 (d, J = 7 Hz, 1H: H at position 3); 4.12 and 4.25 (2 d, J = 9 Hz,

1H each: CH _and at 20) 4.26 (AB limit., J = 16 Hz, 2H:

OCOCH ₂ O); 4.50 (mt, 1H: H at position 7); 4.87 (broad d, J = 10 Hz, 1H:

H at 5); 4.96 (mt, 1H: H at position 13); 5.66 (d, J = 7Hz, 1H);

6.44 (s, 1H: H at position 10); from 7.25 to 7.45 (mt, 5H:

H aromatics); 7.47 (t, J = 7.5 Hz, 2H: _OCOC6 H _p H at the meta position); 7.62 (t, J = 7.5 Hz, 1H: OCOC H H at para position); 8.04 (d, J = 7.5Hz,

2H: OCOC H H (ortho).

es'

When working under conditions analogous to those described in Example 3, the following are prepared:

2a-Benzoyloxy-7B, 13a-bis (triethylsilyloxy) -5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-4a-phenylacetoxy-11-taxene.

The product obtained has the following characteristics:

0.60 and 0.72 (2 mts, 6H each: _CH2 of ethyl); 0.94 and 1.05 (2 t,

J = 7.5, 9H each: _CH3 of ethyl); 1.15 (s, 3H: _CH3); 1.22 (s, 3H: _CH3); 1.66 (s, 3H: _CH3); 1.69 (broad s, 1H: OH at position 1);

1.84 and 2.51 (2 mts, 1H each: _CH2 at 6); 2.20 (s, 3H: CH3);

2.24 and 2.36 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.54 (s, 3H, _OCH3); 3.82 and 3.96 (2 d, J = 15 Hz, 1H each:

OCOCH ₂ Ar); 3.89 (d, J = 7 Hz, 1H: H at position 3); 4.06 and 4.16 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.20 (limiting AB., J = 16 Hz, 2H, OCOCH ₂ O); 4.52 (dd, J = 10 and 6 Hz, 1H: H at position 7); 4.79 (broad d,

J = 10 Hz, 1H: H at position 5); 4.96 (broad t, J = 9 Hz, 1H: H at position 13);

5.66 (d, J = 7 Hz, 1H: H at position 2); 6.58 (s, 1H: H at position 10); from

7.25 to 7.45 (mt, 7H: aromatic H and OCOC3 H H at meta); 7.61 (t,

J = 7.5 Hz, 1H: OCOC3 H (H at the para position); 8.00 (d, J = 7.5 Hz, 2H: OCOC3 H5 ortho). es'

When operating under analogous conditions to those described in Example 3, the following are prepared:

2α-Benzoyloxy-1β, 10β-dihydroxy-7β, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-9-oxo-4α-phenylacetoxy-11-taxene.

The product obtained has the following characteristics:

0.53 and 0.72 (2 mts, 6H each: _CH2 of ethyl); 0.94 and 1.05 (2 t,

J = 7.5, 9H each: _CH3 of ethyl); 1.10 (s, 3H: _CH3); 1.20 (s, 3H: _CH3); 1.64 (s, 1H: OH at position 1); 1.70 (s, 3H: _CH3); 1.86 and 2.45 (2 mts, 1H each: _CH2 at 6); 2.10 (s, 3H: _CH3); 2,20 a

2.32 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.80 and 3.96 (2 d, J = 16 Hz, 1H each: OCOCH _and Ar); 3.95 (d, J = 7Hz, 1H);

H in 3); 4.07 and 4.17 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.29 (broad s, 1H: OH at position 10); 4.43 (dd, J = 11 and 7 Hz, 1H: H at position 7);

4.79 (broad d, J = 10 Hz, 1H: H at position 5); 5.03 (broad t, J = 9 Hz)

1H: H at position 13); 5.19 (broad s, 1H: H at position 10); 5.63 (d, J = 7 Hz, 1H: H at position 2); from 7.25 to 7.45 (mt, 7H: aromatic H. and OCOC H _E H at _the meta position); 7.60 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.00 (d, J = 7.5 Hz, 2H: OCOC H H at ortho position).

e s

V. If analogous conditions are used to those described in Example 3, the following are prepared:

IB, 2a-carbonate-7B, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-10B-methoxyacetoxy-9-oxo-4α-phenylacetoxy-11-taxene.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

0.61 and 0.74 (2 mts, 6H each: _CH2 of ethyl); 0,92 a 1.05 (2 t, J = 7.5 Hz, 9H each: CH _and ethyl); 1.20 (s, 3H: CHU; 1.30 (s, 3H: CH ); 1.73 (s, 3H: CH2); 1.83 and 2.54 (2 mts, 1H each); d: CH ₂ v 6); 2.18 (s, 3H: CH3; 2.27 and 2.48 (2 dd, J = 16 and 9 Hz, 1H 3.50 (d, J = 6.5) Hz, 1H: H in 3); 3.53 (s, 3H, _OCH3); 3.65 (AB limit., J = 14 Hz, 2 H OCOCH Ar); 2 ' 4.18 (AB limit, 2H: OCOCH2 O); 4.45 a 4.53 (2d, J = 9 Hz, 1H each: _CH2 at 20); 4.46 (mt, 1H: H) v 7); 4.53 (d, J = 6.5) Hz, 1H: H at position 2); 4.68 (broad d, J = 10 Hz, 1 H: H v 5); 5.06 (t broad, J = 9 Hz, 1H: H at position 13); 6.53 (s, 1H: H)

v 10); from 7.25 to 7.45 (mt, 5H: aromatic H).

Example 5

When operating under the conditions described in Example 3, from (2R, 3S) -2α-benzoyloxy-4α, 10β-bis (methoxy-acetoxy) -5B, 20-epoxy-1β-hydroxy-9-oxo -7B-Trifluoromethoxysulfonyloxy-11-taxen-13a-yl-3-tert-butoxycarbonyl-2-hydroxy-3-phenylpropionate is prepared by:

(2R, 3S) -2a-Benzoyloxy-4a, 10B-bis (methoxyacetoxy) -5B, 20-epoxylB-hydroxy-7B, 8-methylene-19-nor-9-oxo-11-taxen-13a-yl-3 tert. butoxycarbonylamino-2-hydroxy-3-phenylpropionate.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm, temperature 333 ° K)

1.26 (s, 3H: _CH3); 1.29 (s, 3H: _CH3); 1.35 (s, 9H: C _{(CH3) 3);} 1.42 (mt, 1H: H at position 7); 1.71 and 2.29 (respectively dd and mt,

J = 6.5 and 5 Hz, 1H each: _CH2 at 19); 1.81 (s, 1H: OH at position 1);

1.91 (s, 3H: _CH3); 2.15 and 2.54 (optionally broad and dt J = 16 Hz and J = 16 and 4.5 Hz, 1H each: CH2 at position 6); 2.32 (limiting AB., 2H: _CH2 at position 14); 3.50 and 3.53 (2 s, 3H each: _OCH3); 3.60 (mt, 1H: OH at position 2 '); 4.11 and 4.56 (2 d, J = 16 Hz, 1H each: OCOCH2 O); 4.12 and 4.31 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.17 (d,

J = 7 Hz, 1H: HV 3); 4.19 and 4.24 (2 d, J = 16 Hz, 1H each: OCOCH ₂ O); 4.67 (mt, 1H: H at position 2 '); 4.78 (d, J = 4.5 Hz, 1H: H at position 5); 5.29 (broad d, J = 10 Hz, 1H: H at position 3 '); 5.47 (d,

J = 10 Hz, 1H: CONH); 5.70 (d, J = 7 Hz, 1H: H at position 2); 6.21 (broad t, J = 9 Hz, 1H: H at position 13); 6.44 (s, 1H: H at position 10); 7.30 (t, J = 7.5 Hz, 1H: H at the aromatic position at the 3 'position); 7.39 (t, J =

7.5 Hz, 2H: H at the meta position aromatic at 3 '); 7.45 (d, J = 7.5 Hz, 2H: H at the ortho aromatic position at 3 '); 7.51 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H each); 7.61 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.12 (d, J =

7.5 Hz, 2H: OCOC H H (ortho).

When operating under conditions analogous to those described in Example 3, the following are prepared:

(2R, 3S) -2a-Benzoyloxy-4a, 10B-bis (methoxyacethoxy) -5B, 20-epoxylB-hydroxy-9-oxo-7B-trifluoromethanesulfonyloxy-11-taxen-13a-yl3-tert. butoxycarbony lamino-2-hydroxy-3-phenylpropionate.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm, temperature 333 ° K)

1.22 (s, 3H: _CH3); 1.27 (s, 3H: _CH3); 1.38 (s, 9H: C _{(CH3) 3);}

1.64 (s, 1H: OH at position 1); 1.92 (s, 3H: _CH3); 2.11 (s, 3H: _CH3); 2.25 and 2.92 (2 mts, 1H each: _CH2 at 6); 2.26 and 2.36 (2 dd, J = 16 and 9 Hz, 1H each: CH at position 14 _a); 3.47 and 3.52 (2 s, 3H each: OCH 3; 3.66 (s broad, 1H: OH at position 2 '); 3.99 (d, J = 7 Hz,

1H: H at 3); 4.15 and 4.57 (2 d, J = 16 Hz, 1H each: OCOCH2 O); 4.19 (limiting AB., J = 16 Hz, 2H, OCOCH ₂ O); 4.24 and 4.35 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.70 (mt, 1H; H at position 2 '); 4.95 (broad d, J = 10 Hz, 1H: H at position 5); 5.29 (broad d, J = 10 Hz, 1H: H at position 3 '); 5.49 (d, J = 10Hz, 1H: CONH); 5.53 (dd, J = 11 and 8 Hz, 1H: H at position 7); 5.76 (d, J = 7 Hz, 1H: H at position 2); 6.18 (broad t, J = 9 Hz, 1H: H at position 13); 6.74 (s, 1H: H at position 10); 7.30 (t, J = 7.5 Hz, 1H: H at the aromatic position at the 3 'position); 7.38 (t, J =

7.5 Hz, 2H: H at the meta position aromatic at 3 '); 7.45 (d, J = 7.5Hz,

2H: H in ortho aromatic at 3 '); 7.49 (t, J = 7.5Hz, 2H):

OCOC H H in meta); 7.63 (t, J = 7.5 Hz, 1H: OCOC H H at the para position); 8.09 (d, J = 7.5 Hz, 2H: OCOC3 H5 ortho).

5

When operating under conditions analogous to those described in Example 3, the following are prepared:

(2R, 4S, 5R) -2o: -benzoyloxy-4a, 10B-bis (methoxyacetoxy) -5B, 20-epoxy-1B-hydroxy-9-oxo-7B-trifluoromethanesulfonyloxy-11-taxen-13o-yl- 3-t. butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate.

The product obtained has the following characteristics:

H -H nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm, temperature 333 ^e K)

1.10 (s, 9H: C _{(CH3) 3);} 1.18 (s, 3H: CH _a); 1.20 (s, 3H:

CH _a ); 1.64 (s, 1H: OH at position 1); 1.75 (s, 3H: _CH3); 1.86 (s, 3H: _CH3); 2.12 and 2.26 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.24 and 2.86 (2 mts, 1H each: _CH2 at 6); 3.33 and 3.53 (2 s, 3H, _OCH3); 3.65 and 4.10 (2 d, J = 16 Hz, 1H each: OCOCH2 O); 3.83 (s, 3H: _ArOCH3); 3.86 (d, J = 7 Hz, 1H: H at position 3); 4.14 and 4.20 (2 d, J = 16 Hz, 1H each: OCOCH3); 4.19 and 4.32 (2 d,

J = 9 Hz, 1H each: _CH2 at 20); 4.72 (broad d, J = 4.5 Hz, 1H: H at position 2 '); 4.89 (broad d, J = 10 Hz, 1H: HV 5); 5.46 (mt, 1H: H at position 3 '); 5.45 (dd, J = 11 and 8 Hz, 1H: H at position 7); 5.69 (d,

J = 7 Hz, 1H: H at position 2); 5.94 (broad t, J = 9 Hz, 1H: H at position 13);

6.40 (s, broad, 1H: H at position 5 '); 6.63 (s, 1H: H at position 10; 6.93 (d,

J = 8.5 Hz, 2H: aromatic H. ortho to OCH ₃ ); from 7.30 to 7.45 (mt, 5H: aromatic H at position 3 '); 7.38 (d, J = 8.5 Hz, 2H: aromatic H. Meta to 0CH _3); 7.48 (t, J = 7.5 Hz, 2H: H _of 0C0C ₆ H at the meta position); 7.63 (t, J = 7.5 Hz, 1H: OCOC HH at para); 8.08 (d, J = 7.5)

5

Hz, 2H: OCOC H H (ortho).

'es'

When operating under conditions analogous to those described in Example 3, the following are prepared:

2-benzoyloxy-4, ΙΟβ-bis (methoxyacetoxy) -1b, 13-dihydroxy-5B, 20-epoxy-9-oxo-7.beta.-trifluoromethanesulphonyloxy-l-taxen.

The product obtained has the following characteristics:

¹ H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 5 V ppm)

1.06 (S, 3H: _CH3); 1.20 (s, 3H: _CH3); 1.61 (s, 1 H: OH v 1); 1.89 (s, 3H: _CH3); 2.23 (d, J = 5Hz, 1 H: OH at 13); from 2.20 to 2, 35 and 2.92 (2 mts, 1H each: _CH2 at 6) ; 2.26 (s, 3H : _CH3); 2 32 (d, J = 9Hz, 2H) : _CH2 at position 14); 3.52 and 3.58 (2 with, 3H each: OCH ₃ ); 4.04 (d, J = 7 Hz, 1H: H at position 3); 4,19 and 4 32

(2 AB limit., J = 16 Hz, 2H each: OCOCH3); 4.20 and 4.38 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.82 (mt, 1H: H at position 13); 4.99 (broad d, J = 10 Hz, 1H: H at position 5); 5.55 (dd, J = 10 and 7 Hz, 1H):

H at 7); 5.69 (d, J = 7 Hz, 1H: H at position 2); 6.73 (s, 1H: H at position 10);

7.51 (t, J = 7.5 Hz, 2H: OCOC H H at the meta position); 7.64 (t, J = 7.5)

Hz, 1H: OCOC ₍ H _with H at para); 8.13 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

When operating under conditions analogous to those described in Example 3, the following are prepared:

2-benzoyloxy-4, ΙΟβ-bis (methoxyacetoxy) -5B, 20-epoxy-9-oxo-IB, 7b, 13a-trihydroxy-l-taxen.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDC1 _3, in ppm)

1.11 (s, 6H: _CH3); 1.63 (s, 1H: OH at position 1); 1.70 (s, 3H: _CH3); 1.92 and 2.63 (2 mts, 1H each: _CH2 at 6); 2.08 (s, 3H: _CH3); 2.20 to 2.30 (mt, 3H: _CH2 at position 14 in the OH); 2.40 (d, J = 4Hz,

1H: OH); 3.54 and 3.59 (2 s, 3H each: OCH 3; 3.92 (d, J = 7

Hz, 1H: H at position 3); 4.20 and 4.35 (2 d, J = 9 Hz, 1H each: CH2 at position _2);

20); 4.24 and 4.28 (limiting AB 2., J = 16 Hz, 2H each: OCOCH ₂ O);

4.50 (mt, 1H: H at position 7); 4.86 (mt, 1H: H at position 13); 5.03 (broad d,

J = 10 Hz, 1H: H at position 5); 5.65 (d, J = 7 Hz, 1H: H at position 2); 6.44 (s, 1H: H at position 10); 7.49 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.63 (t, J = 7.5 Hz, 1H: _OCOC6 H_H in the para position); 8.14 (d, J = 7.5 Hz, 2H: OCOC HHV ortho).

When operating under conditions analogous to those described in Example 3, the following are prepared:

2? -Benzoyloxy-4?,? -Bis (methoxyacetoxy) -7B, 13? -Bis (triethylsilyloxy) -5B, 20-epoxy-1B-hydroxy-9-oxo-11-taxene.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 5 V ppm)

0.60 and 0.70 (2 mts, 6H each: _CH2 of ethyl); 0.94 and 1.02 (2t, J = 7.5, 9H each: _CH3 of ethyl); 1.12 (s, 3H: CH _a); 1.20 (s, 3H: _CH3); 1.64 (s, 1H: OH at position 1); 1.70 (s, 3H: CH _a); 1.91 and 2.57 (2 mts, 1H each: _CH2 at 6); 2.12 (s, 3H: _CH3); 2.13 and 2.23 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.53 and 3.57 (2 s, 3H each: _OCH3); 3.83 (d, J = 7 Hz, 1H: H at position 3); 4.15 and 4.40 (2 d, J = 16 Hz, 2H, OCOCH ₂ O); 4.19 (AB limit., J = 16

Hz, 2H, OCOCH ₂ O); 4.21 and 4.37 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.51 (dd, J = 11 at 7 Hz, 1H: H at 7); 4.93 (t, J = 9)

Hz, 1H: H at position 13); 5.02 (broad d, J = 10 Hz, 1H: H at position 5); 5.64 (d, J = 7 Hz, 1H: H at position 2); 6.56 (s, 1H: H at position 10); 7.48 (t, J =

7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.63 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.19 (d, J = 7.5 Hz, 2H, OCOC H _{e and} H at the ortho position).

When operating under conditions analogous to those described in Example 3, the following are prepared:

2α-Benzoyloxy-1β, 10β-dihydroxy-7β, 13α-bis (triethylsilyloxy) 5β, 20-epoxy-4α-methoxyacetoxy-9-oxo-11-taxene.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

0.57 and 0.69 (2 mts, 6H each CH 2 ethyl); 0,94 a 1.03 (2 t, J = 7.5 Hz, 9H each : CH ₃ ethyl) ; 1.09 (s, 3H: CH) ; 1.17 (s, 3H: CH ,); 1.58 (s, 1 H: OH v 1); 1.75 (s, 3H: CH ₃ ); 1.93 and 2.49 (2 mts, 1H each: CH 2 v 6); 2.03 (s, 3H: CH ₃ ); 2.09 and 2.18 (2 dd, J = 16 a 9 Hz, 1H each: CH 2 v 14); 3.57 (s, 3H) : OCH ₃ ); 3.88 (d, J = 7 Hz, 1 H: H V 3) ; 4.16 and 4.40 (2 d, J = 16 Hz, 1H each: OCOCH _and O); 4,20 a 4.36 (2 d,

J = 9 Hz, 1H each: CH ₌ at 20); 4.28 (broad s, 1H: OH at position 10); 4.42 (mt, 1H: H at position 7); 4.97 (t, J = 9 Hz, 1H: H at position 13); 5.01 (broad d, J = 10 Hz, 1H: H at position 5); 5.17 (broad s, 1H: HV 10);

5.62 (d, J = 7 Hz, 1H: H at position 2); 7.47 (t, J = 7.5Hz, 2H):

OCOC H H in meta); 7.61 (t, J = 7.5 Hz, 1H: OCOC H H at the para position);

8.18 (d, J = 7.5 Hz, 2H: OCOC3 H5 ortho).

5

When operating under conditions analogous to those described in Example 3, the following are prepared:

4α, 10B-bis (methoxyacetoxy) -IB, 2a-carbonate-7B, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-9-oxo-11-taxene.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 6 in ppm)

0.60 and 0.68 (2 mts, 6H each: CH 2 ethyl); 0.92 and 1.01 (2t, J = 7.5, 9H each: _CH3 of ethyl); 1.19 (s, 3H: _CH3);

1.27 (s, 3H: _CH3); 1.75 (s, 3H: _CH3); 1.91 and 2.63 (2 mts,

1Η each: CH ₂ in 6); 2.08 and 2.41 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.12 (s, 3H: _CH3); 3.44 (d, J = 6.5 Hz, 1H: H at position 3) 7 3.46 and 3.50 (2 s, 3H each: _OCH3); 4.06 and 4.14 (2 d, J = 16 Hz, 1H each: OC0CH ₂ O); 4.16 (s, 2H: OCOCH.O);

4.46 (dd, J = 10 and 7 Hz, 1H: H at position 7); 4.50 and 4.66 (2 d,

J = 9 Hz, 1H each: _CH2 at position 20; 4.51 (d, J = 6.5Hz, 1H);

H in 2); 4.99 (mt, 1H: H at position 13); 5.00 (broad d, J = 10 Hz, 1H: H at position 5); 6.51 (s, 1H: H at position 10).

Example 6

When working under the conditions described in Example 3, (2R, 3S) -2α-benzoyloxy-4α-cyclopropanoyloxy-5B, 20-epoxy-1β-hydroxy-9-oxo-10β-methoxyacetoxy- 7B-Trifluoromethanesulfonyloxy-11-taxen-13a-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is prepared by:

(2R, 3S) -2a-Benzoyloxy-4a-cyclopropanoyloxy-5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-7B, 8-methylene-19-nor-9-oxo-11-taxen-13ayl-3- Boc-amino-2-hydroxy-3-phenylpropionate.

The product obtained has the following characteristics:

1 ^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm, near 333 ° K) from 0.80 to 1.40 (mt, 4H: CH ₂ CH ₂ cyclopropyl); 1.30 (s, 6H: _CH3); 1.35 (s, 9H: C _{(CH3) 3);} from 1.30 to 1.40 (mt, 1H: H at position 6);

7); 1.70 and 2.23 (2 dd, respectively J = 6 and 5.5 Hz and J = 10 and 5.5 Hz, 1H each: CH2 at position 19); 1.80 (mt, 1H: CH of cyclopropyl); 1.85 (s, 1H: OH at position 1); 1.86 (s, 3H: CHJ, 2.11 and 2.44 (respectively. Broad d. P dt, J = 16 Hz and J = 16 and 4.5 Hz, 1H each: _CH2 at 6); 2 34 and 2.50 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.22 (d, J =

Hz, 1H: OH at position 2 '); 3.52 (s, 3H, _OCH3); 4.08 and 4.28 (2 d, J = 9 Hz, 1H each: CH at _of 20); 4.13 (d, J = 7 Hz, 1H: H at position 3);

4.16 and 4.24 (2 d, J = 16 Hz, 1H each: OCOCH _and O); 4.62 (d, J =

4.5 Hz, 1H: H at position 5); 4.70 (d, broad, J = 4 Hz, 1H: H at position 2 ');

5.28 (limiting AB, 2H: H 3 'and CONH); 5.70 (d, J = 7 Hz, 1H: H at position 2); 6.23 (broad t, J = 9 Hz, 1H: H at position 13); 6.42 (s, 1H: H at position 6)

10); 7.20 and 7.45 (mt, 5H: aromatic H at position 3 '); 7.52 (t, J = 7.5)

Hz, 2H, OCOC H _E H at _the meta position); 7.61 (t, J = 7.5 Hz, 1 H, OCOC ₆ H, H at _the para position); 8.14 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

When operating under conditions analogous to those described in Example 3, the following are prepared:

(2R, 3S) -2α-Benzoyloxy-4α-cyclopropanoyloxy-5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-7β-trifluoromethanesulfonyloxy-11-alphaen-13α-γ-1-3- tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.

The product obtained has the following characteristics:

H -H nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 5 5 in ppm) from 0.85 to 1.40 (mt, 4H: CH ₂ CH ₂ cyclopropyl); 1.22 (s, 3H):

CH _a ); 1.24 (s, 3H: _CH3); 1.39 (s, 9H: C (CH _{a) 3);} 1.70 (s, 1H: OH at position 1); 1.83 (mt, 1H: cyclopropyl CH); 1.88 (s, 3H:

CH ₃ ); 2.05 (s, 3H: CHJ, 2.23 and 2.84 (2 mts, 1H each: _CH2 at 6), 2.34 and 2.42 (2 dd, J = 16 and 9 Hz, each 1H, : _CH2 at position 14); 3.35 (d, J = 5.5 Hz, 1H: OH at position 2 '); 3.52 (s, 3H, _OCH), 3.96 (d, J = 7 Hz , 1H: H at position 3); 4.16 and 4.25 (2 d, J = 16 Hz, 1H each: OCOCH ₂ O), 4.17 and 4.28 (2 d, J = 9 Hz, each 1H, : CH ₂

v 20); 4 72 (mt, 1H) : H V 2 ' ); 4.81 (D, br. J = 10 HZ, 1H: H at 5); 5.28 (d broad. , J = 10 Hz, 1H • • H 3 '); 5.36 (d, J = 10 Hz, 1H • • CONH) 5.48 (dd, J = 10,5 a 7 Hz, 1H : H v 7); 5.72 (d, J = 7 Hz, 1H: H at position 2); 6. 11 (mt, 1H : H v 13); 6.71 (with,

1H: H at position 10); 7.25 and 7.45 (mt, 5H: aromatic H at position); 7.52 (t, J = 7.5 Hz, 2H: _OCOC6 H _p H at the meta position); 7.65 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.08 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

When operating under conditions analogous to those described in Example 3, the following are prepared:

(2R, 4S, 5R) -2a-Benzoyl-4a-cyclopropanoyloxy-5B, 20-epoxy-1B-hydroxy-10B-methoxyacetoxy-9-oxo-7B-trifluoromethanesulfonyloxy-11taxen-13a-yl-3- tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl65

1,3-oxazolidine-5-carboxylate.

The product obtained has the following characteristics:

from 0.50 to 1.50 (mt, 5H: CH and CH of cyclopropyl); 1.04 (s, 9H: C _{(CH3) 3);} 1.17 (s, 1H: OH at position 1); 1.72 and 2.32 (2 dd, J =

3H

CH); 1.19 (s, 3H: CH); 1.65 (s, (s, 3H: CH); 1.84 (s, 3H: CH); 2.14 and 9 Hz, 1H each

CH at 14); 2.16 and 2.79 (2 mts, 1H each)

CH and 6); 3.52 (s, 3H: OCH); 3.82 (s, 3H: _ArOCH3); 3.86 (d, J = 7 Hz, 1H: H at position 3); 4.11 and 4.24 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.15 and 4.22 (2 d, J = 16 Hz, 1H each: OCOCH2 O); 4.60 (d, J = 4.5 Hz, 1H: H at position 2 '); 4.74 (d, broad, J = 10 Hz, 1H: H at position 5); 5.44 (dd, J = 10.5 and 8 Hz, 1H: H at position 7); 5.50 (mt, 1H: H at position 3 '); 5.67 (d, J = 7 Hz, 1H: H at position 2); 5.88 (mt, 1H: H at position 13); 6.41 (broad m, 1H: H at position 5 ');

6.61 (s, 1H: H at position 10); 6.92 (d, J = 8.5 Hz, 2H: aromatic H. Ortho to the _OCH3); 7.38 (d, J = 8.5 Hz, 2H: aromatic H at the meta position of _a 0CH); from 7.25 and 7.45 (mt, 5H: aromatic H at position 3 '); 7.49 (t, J = 7.5Hz,

2H: OCOC H H (meta); 7.63 (t, J = 7.5Hz, 1H)

Ô 5

OCOC H H V

5 para); 8.02 (d, J = 7.5Hz, 2H)

OCOC H H (ortho).

5 '

When operating under conditions analogous to those described in Example 3, the following are prepared:

2a-Benzoyloxy-4α-cyclopropanoyloxy-1β, 13α-dihydroxy-1β, 13α-dihydroxy-5β, 20-epoxy-10β-methoxyacetoxy-9-oxo-7β-trifluoromethanesulfonyloxy-11-taxene.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm, 333 ° K temperature) from 0.90 to 1.40 (mt, 4H: CH ₂ CH ₂ cyclopropyl); 1.10 (s, 3H: _CH3); 1.22 (s, 3H: _CH3); 1.61 (s, 1H: OH at position 1); 1.70 and 1.85 (mt, 2H: cyclopropyl CH and OH at position 13); 1.90 (s, 3H: _CH3); 2.22 and 2.86 (2 mts, 1H each: _{CH, and} 6); 2.26 (s, 3H: _CH3); 2.36 (d, J = 9 Hz, 2H: _CH2 at position 14); 3.52 (s, 3H: OCH3; 4.05 (d, J = 7 Hz, 1H: H at position 3)), 4.14 and 4.22 (2 d, J = 16 Hz, 1H each:

OCOCH ₌ O); 4.20 and 4.36 (2 d, J = 9 Hz, 1H each: _CH2 at 20);

4.84 (mt, 1H: H at position 13); 4.85 (d, broad, J = 10 Hz, 1H:

H at 5); 5.54 (dd, J = 11 and 8 Hz, 1H: H at position 7); 5.72 (d, J = 7)

Hz, 1H: H at position 2); 6.73 (s, 1H: H at position 10); 7.51 (t, J = 7.5Hz,

2H: OCOC H H (meta); 7.63 (t, J = 7.5 Hz, 1H: OCOC H H at the para position); 8.12 (d, J = 7.5 Hz, 2H: OCOC3 H5 ortho).

e s

When operating under conditions analogous to those described in Example 3, the following are prepared:

2-benzoyloxy-4-cyklopropanoyloxy-b, 13a-dihydroxy-5B, 20-epoxy-10.beta.-trihydroxy-9-oxo-7.beta.-trifluoromethanesulphonyloxy-l-taxen.

The product obtained has the following characteristics:

^ H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm, 333 ° K temperature) from 0.90 to 1.40 (mt, 4H: CH ₂ CH ₂ cyclopropyl); 1.10 (s, 3H: _CH3); 1.22 (s, 3H: CH3; 1.61 (s, 1H: OH at position 1); from 1.70 to 1.85 (mt, 2H: CH of cyclopropyl and OH at position 13); 1.90 (s, 3H: _CH3); 2.22 and 2.86 (2 mts, 1H each: _CH2 at 6), 2.26 (s, 3H: _CH3); 2.36 (d, J = 9 Hz, 2H : CH at position 14); 3.52 (s, 3H, _OCH3);

4.05 (d, J = 7 Hz, 1H: H at position 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, 1H each):

_CH2 at 20); 4.84 (mt, 1H: H at position 13); 4.85 (d, broad, J = 10 Hz,

1H: H at position 5); 5.54 (dd, J = 11 and 8 Hz, 1H: H at position 7); 5.72 (d,

J = 7 Hz, 1H: H at position 2); 5.73 (s, 1H: H at position 10); 7.51 (t, J =

7.5 Hz, 2H: OCOC HH in meta); 7.63 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.12 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

When operating under conditions analogous to those described in Example 3, the following are prepared:

2α-Benzoyloxy-4α-cyclopropanoyloxy-7β, 13α-bis (triethylsilyloxy) -5β, 20-epoxy-1β-hydroxy-10β-methoxyacetoxy-9-oxo-11-taxene.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , 5 in ppm)

0.60 and 0.68 (2 mts, 6H each: CH ₌ ethyl); from 0.90 to 1.35 (mt, 4H: CH2-CH2-cyclopropyl); 0.94 and 1.03 (2t, J = 7.5Hz, 9H each: CH _and ethyl); 1.14 (s, 3H: _CH3); 1.20 (s, 3H: _CH3); 1.64 (s, 1H: OH at position 1); 1.71 (s, 3H: _CH3); 1.73 (mt, 1H: cyclopropyl CH); 1.87 and 2.50 (respectively. Broad dd. And mt, J = 14 to 11 Hz, 1H each: _CH2 at 6); 2.11 and 2.29 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 2.15 (s, 3H: CH _a); 3.53 (s, 3H, _OCH3); 3.86 (d, J = 7 Hz, 1H: H at position 3); 4.14 and 4.22 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.19 (limiting AB, J = 16 Hz, 2H: OCOCH.O); 4.52 (dd, J = 11 and 7 Hz, 1H: H at position 7); 4.84 (broad d, J = 10 Hz, 1H: H at position 5); 4.95 (broad t, J = 9 Hz, 1H: H at position 13); 5.65 (d, J =

Hz, 1H: H at position 2); 6.56 (s, 1H: H at position 10); 7.50 (t, J = 7.5Hz)

2H: OCOC H H (meta); 7.62 (t, J = 7.5 Hz, 1H: OCOC H H at the para position); 8.09 (d, J = 7.5 Hz, 2H: OCOC3 H5 ortho).

When operating under conditions analogous to those described in Example 3, the following are prepared: 2a-benzoyloxy-4α-cyclopropanoyloxy-1B, 10B-dihydroxy-7B, 13abis (triethylsilyloxy) -5B, 20-epoxy- 9-oxo-l-taxen.

The product obtained has the following characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

0.58 and 0.68 (2 mts, 6H each: _CH2 of ethyl); 0.90 to 1.35 (mt, 4H: _{CH2 CH2} of cyclopropyl); 0.94 and 1.03 (2t, J = 7.5, 9H each: _CH3 of ethyl); 1.12 (s, 3H: _CH3); 1.22 (s, 3H: CH _a); 1.59 (s, 1H: OH at position 1); 1.67 (mt, 1H: cyclopropyl CH); 1.73 (s, 3H: CH _a); 1.90 and 2.44 (2 mts, 1H each: _CH2 at 6); 2.06 (s, 3H CH _3); 2.10 and 2.25 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.91 (d, J = 7 Hz, 1H: H at position 3); 4.16 and 4.26 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.28 (d, J = 1.5 Hz, 1H: OH at position 10); 4.42 (dd, J = 11 and 6 Hz, 1H: H at position 7); 4.84 (d, broad, J = 10

Hz, 1H: H at position 5); 5.00 (t, J = 9 Hz, 1H: H at position 13); 5.16 (d, J = 1.5 Hz, 1H: H at position 10); 5.65 (d, J = 7 Hz, 1H: H at position 2); 7.50 (t, J = 7.5 Hz, 2H: H _{p e} OCOC H at the meta position); 7.62 (t, J = 7.5 Hz, 1H, OCOC H _E H at _the para position); 8.09 (d, J = 7.5 Hz, 2H: H _{p e} OCOC H at the ortho position).

1B, 2a-Carbonate-4α-cyclopropanoyloxy-7B, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-10B-methoxy-9-oxo-11-taxene can be prepared as follows.

To a solution of 100 mg of 1B, 2a-carbonate-7B, 13α-bis (triethylsilyloxy) -5B, 20-epoxy-4α-hydroxy-10β-methoxyacetoxy-9-oxo-11-taxene in 7 cm ^{3 of} tetrahydrofuran was added dropwise add 345 μΐ of a solution of lithium hexamethyldisilazane in hexane at a temperature close to -30 ° C. The reaction mixture is stirred for 15 minutes at this temperature, then 39 μΐ of cyclopropanoyl chloride is added dropwise. The reaction mixture is then stirred for 30 minutes at a temperature in the region of 0 DEG C. and the hydrolysis mixture is then added by adding 1 cm @ ^{3 of} saturated ammonium chloride solution and 50 cm @ ^{3 of} dichloromethane. The organic phase is decanted, washed twice with 40 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

120 mg of product are obtained, which product is purified by chromatography on 70 g (0.063-0.2 mm) of silica gel contained in a 2 cm diameter column, eluting with a mixture of ethyl acetate and cyclohexane (20:80; v / v). with a 10 cm ³ fraction. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

31 mg of 1B, 2a-carbonate-4a-cyclopropanoyloxy-7B, 13a-bis (triethylsilyloxy) -5B, 20-epoxy-10B-9-oxo-11-taxene are obtained in the form of a white brittle product having the following physical characteristics:

^x H-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ₃ , δ in ppm)

0.60 and 0.66 (2 mts, 6H each: _CH2 of ethyl); 0.90 to 1.35 (mt, 4H: _{CH2 CH2} of cyclopropyl); 0.92 and 1.02 (2t, J = 7.5, 9H each: _CH3 of ethyl); 1.19 (s, 3H: _CH3); 1.29 (s, 3H: _CH3); 1.60 (s, 1H: OH at position 1); 1.62 (mt, 1H: cyclopropyl CH); 1.73 (s, 3H: _CH3); 1.88 and 2.57 (respectively. Broad dd. And mt, J = 15 and 10 Hz, 1H each; _CH2 at position 6); 2.15 (s, 3H CH _3); 2.19 and 2.37 (2 dd, J = 16 and 9 Hz, 1H each: _CH2 at position 14); 3.48 (d, J = 7 Hz, 1H: H at position 6)

3); 3.51 (s, 3H, 0CH _3); 4.16 (s, 2H, OCOCH ₂ O); 4.44 (mt, 1H: H at position 7); 4.45 and 4.54 (2 d, J = 9 Hz, 1H each: _CH2 at 20); 4.49 (d, J = 7 Hz, 1H: H at position 2); 4.85 (d, broad, J = 10 Hz, 1H: H at position 5); 5.02 (broad t, J = 9 Hz, 1H: HV 13)? 6.52 (s, 1H: H at position 10).

The novel compounds of formula I in which Z is a group of formula II exhibit significant inhibitory activity against abnormal cell proliferation and have therapeutic properties which make it possible to treat patients in whom pathological conditions associated with said abnormal cell proliferation are indicated. These pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs, including, but not limited to, muscle, bone or connective tissue, skin, brain, lung, genital organs, lymphatic or renal systems, blood cells or mammary gland cells, liver, digestive tract, pancreas, thyroid or adrenal gland. These pathological conditions may also include psoriasis, solid tumors, ovarian cancer, breast cancer, brain cancer, colon cancer, stomach cancer, kidney cancer or male genital cancer, Karposi's sarcoma, cholangiocarcinoma, choriocarcinoma, choriocarcinoma, neuroblastoma, Wilms' disease, Wilms disease, melanomas, multiplex myelomas, chronic lymphocytic leukemia, acute or chronic granulocyte lymphomas. The novel compounds of the invention are particularly useful for the treatment of ovarian cancer. The compounds of the invention can be used to prevent or delay the occurrence or recurrence of pathological conditions or to treat pathological conditions.

The compounds of the invention may be administered to a patient in a variety of galenic forms adapted to the route of administration chosen, which is preferably parenteral. Parenteral administration includes intravenous administration, intraperitoneal administration, intramuscular administration, or subcutaneous administration. A particularly preferred administration is intraperitoneal administration or intravenous administration.

The present invention also relates to pharmaceutical compositions comprising at least one compound of the formula I in a sufficient amount suitable for use in human or veterinary therapy. These compositions may be prepared by conventional methods using one or more pharmaceutically acceptable excipients or excipients or one or more pharmaceutically acceptable carriers. Suitable carriers include diluents, sterile aqueous media, and various non-toxic solvents. Preferably, the compositions are in the form of aqueous solutions or suspensions or injectable solutions which may contain emulsifying agents, coloring agents, preservatives or stabilizers.

The choice of excipients or excipients can be determined by the solubility and chemical properties of the particular compound employed, the route of administration chosen, and conventional pharmaceutical usage.

For parenteral administration, sterile aqueous or non-aqueous solutions or suspensions are used. Natural vegetable oils such as olive oil, sesame oil or paraffin oil, or injectable organic esters such as ethyl oleate may be used to prepare non-aqueous solutions or suspensions. Aqueous sterile solutions may be formulated with a solution of a pharmaceutically acceptable salt in water. Aqueous solutions are suitable for intravenous administration when their pH is appropriately adjusted and isotonicity is achieved, for example by addition of sufficient sodium chloride or glucose. Sterilization may be accomplished by heating or by any other means which does not affect the quality of the composition.

It is understood that the products introduced into the composition of the invention must be pure and nontoxic in the amounts used.

The compositions of the invention may contain at least 0.01% of a therapeutically active compound. The amount of active compound in the composition will be such as to permit appropriate dosage to be prescribed. Preferably, the composition of the invention is prepared in such a way that a unit dose contains 0.01 to 1000 mg of active ingredient in the case of parenteral administration.

Therapeutic treatment can be performed concurrently with other therapeutic treatments, which include administration of antineoplastic drugs or monoclonal antibodies, immunological therapy or radiotherapy, or administration of biological response modifiers. These biological response modifiers include, but are not limited to, lymphokines and cytokines such as interlucines, interferons (α, β or 6) and TNF. Other chemotherapeutic agents useful in the treatment of disorders caused by abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitromeas such as carmustine, lustustine, lomustine, lomustine, lomustine, lomustine, lomustine antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs such as mercaptopurine and tiguanine, natural products such as vinea alkaloids such as vinblastine, vineristine and vendesin, epipophylidotoxins, such as epipophylidotoxins, , antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procar basin, adrenocorticoid suppressors such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestroacetate, ostrogens such as diethylstilberol and ethinyl estradiol, and thienoestradiol, ethinylestradiol, ethinyl estradiol.

Dosages useful in practicing the method of the invention are those that allow for prophylactic treatment or maximal therapeutic response. These dosages vary according to the route of administration and depending on the particular compound of the invention used and the characteristics of the subject being treated. Generally, such doses are those that are therapeutically effective in treating disorders associated with abnormal cell proliferation. The compounds of the invention may be administered as often as necessary to achieve the desired therapeutic effect. Some patients may experience a relatively high or low dose response quickly, and these patients are then given low maintenance doses or no maintenance doses. Generally, low doses will be administered at the start of treatment and, if necessary, these will be increased until the optimum effect is achieved. In other patients it may be necessary to administer maintenance doses one to eight times, preferably one to four times, daily, depending on the physiological need of the particular patient. It is also possible that in some patients only two daily administrations will be necessary.

In humans, said doses are generally between 0.01 and 200 mg / kg. For intraperitoneal administration, doses will be between 0.1 and 100 mg / kg, preferably between 0.5 and 50 mg / kg, especially between 1 and 10 mg / kg. For intravenous administration, these doses are between 0.1 and 50 mg / kg, preferably between 0.1 and 5 mg / kg, in particular between 1 and 2 mg / kg. Of course, when selecting the most appropriate dosage, it will be necessary to take into account the mode of administration of the active ingredient, the body weight of the patient, his general health, age, and any other factors that may affect the effectiveness of the treatment.

The following example illustrates the composition of the invention.

Example composition of the invention mg of the compound obtained in Example 1 is dissolved in 1 cm ³ of Emulphor EL 620 and 1 cm ^{3 of} ethanol, then the solution is diluted by adding 18 cm ^{3 of} saline. This composition is administered after infusion into physiological saline by infusion over one hour.

PATENT

Pif

1. Taxoids of formula I

in which

R ^a represents a hydrogen atom, a hydroxy group, a C 1 -C 4 alkoxy group, a C 1 -C 4 acyloxy group or an alkoxy acetoxy group in which the alkoxy radical contains 1 to 4 carbon atoms,

R ^a is H or

R ² and R ^a taken together with the carbon atom to which they are attached, a ketone fraction,

Z is hydrogen or a group of formula II

(II) in which

R ¹ represents a benzoyl group optionally substituted by one or more of the same or different substituents selected from the group consisting of halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or trifluoromethyl, tenoyl or furoyl or a group of formula

R ² O-CoV wherein R ² is

C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, C 7 -cycloalkyl group up to 10 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxy, C 1-4 alkoxy, dialkylamino wherein each alkyl moiety contains 1-4 carbon atoms atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted in the 4-position with a C 1-4 alkyl group or a phenylalkyl group wherein the alkyl moiety contains 1 to 4 carbon atoms, a cycloalkyl group containing up to C 6 -C 6 cycloalkenyl, phenyl optionally substituted by one or more substituents selected from halogen, C 1-4 alkyl and C 1-4 alkoxy, cyano, carboxyl or alkoxycarbonyl in which the alkoxy radical contains 1 to carbon atoms,

- a phenyl or α- or β-naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, or a 5-membered heterocyclic an aromatic group selected preferably from the group consisting of furyl and thienyl groups,

- or a saturated heterocyclic group having 4 to 6 carbon atoms and optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms, and

R ³ represents a straight or branched (C 1 -C 8) alkyl group, a straight or branched (C 2 -C 8) alkenyl group, a straight or branched (C 2 -C 8) alkynyl group, a cycloalkyl group containing 3 to 6 carbon atoms, phenyl or or a β-naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, .alkylkarbamoylov a dialkylcarbamoyl, cyano, nitro and trifluoromethyl group, or a 5-membered heterocyclic aromatic group containing one or more of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and optionally substituted by one or more of the same or different substituents selected from the group consisting of halogen atoms, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkoxycarbonyl, wherein in the substituents of the phenyl or α- or β-naphthyl group and the heterocyclic aromatic group the alkyl groups and the alkyl radicals of the other groups contain 1 to 4 carbon atoms, that the alkenes The alkyl and alkynyl groups contain 2 to 8 carbon atoms and that the aryl groups are phenyl or α- or β-naphthyl, and

R ⁴ and R ^s are the same or different, represent

straight or branched (C 1 -C 8) alkyl, straight or branched (C 2 -C 8) alkenyl, straight or branched C 2 -C 8 alkynyl, (C 3 -C 6) cycloalkyl, C 4 -C 4 cycloalkenyl up to 6 carbon atoms or a bicycloalkyl group having 7 to 11 carbon atoms, these groups being optionally substituted with one or more substituents selected from the group consisting of halogen atoms, hydroxy, C1-C4alkoxy, dialkylamino, wherein each alkyl radical contains 1 to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted in the 4-position with a C1-4 alkyl or phenylalkyl group in which the alkyl moiety the height of which contains 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms, an optionally substituted phenyl group, a cyano group, a carboxyl group or an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms,

an aryl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl a dialkylcarbamoyl group, a cyano group, a nitro group, an azido group, a trifluoromethyl group or a trifluoromethoxy group, or a saturated or unsaturated 4- to 6-membered heterocyclic group which is optionally substituted by one or more alkyl groups containing from 1 to 1 4 carbon atoms, p battens that ^R can not be methyl, and Further, the cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.

Claims (6)

The taxoids of claim 1, wherein: R ^a is hydroxy, alkoxy of 1 to 4 carbon atoms, acyloxy of 1 to 4 carbon atoms or an alkoxyacetoxy radical in which the alkyl portion contains 1 to 4 carbon atoms, R ^a is H, Z is H or of formula II in which R ¹ represents a benzoyl radical or a radical of the formula R ² -O-CO- in which ^R2 represents a tert-butyl radical and R ³ is alkyl of 1 to 6 carbon atoms, alkenyl a C 2 -C 6 cycloalkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group optionally substituted by one or more of the same or different substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom), alkyl group, alkoxy -group, dialkylamino, acylamino, alkoxycarbonylamino or trifluoromethyl or 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl and R ⁴ represents a phenyl group optionally substituted by one or several of the same or different substituents selected from the group consisting of halogen atoms, alkyl group, alkoxy group, amino group, alkylamino group, dialkylamino group, acylamino group, alkoxycarbonylamino group, azido group, trifluoromethyl group and trifluoromethoxy group -group, or 2-thienyl, 3-thienyl, 2-furyl or 3-furyl group and ^R represents an optionally substituted alkyl of 1 to 4 carbon atoms, it being understood that ^R can not be methyl. 3. The taxoid according to claim 1 of formula I, wherein R ^a is a hydrogen atom or a hydroxyl or acetyloxy or methoxyacetoxy radical, R ¹³ is H, Z is H or a group of formula II, wherein R ¹ represents a benzoyl radical or a radical of the formula R ² -O-CO- in which ^R2 represents a tert-butyl radical and ^R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl; and R ⁴ represents a phenyl group optionally substituted by a halogen atom, and R ⁵ represents an alkyl group having 2 to 4 carbon atoms. A process for the preparation of a compound according to any one of claims 1 to 3, characterized in that an alkali metal halide or alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate is reacted with a compound of the formula III wherein Z, R ⁴ and R ^s have the meanings given in any one of the claims 1-3, R 'represents a hydrogen atom, an alkoxy group, an acyloxy group, an alkoxyacetoxy group or a protected hydroxy group and R ^' represents a hydrogen atom, then optionally the protecting group represented by R 'represents a hydrogen atom. 5. A process for preparing a compound according to any one of claims 1 to 3 of formula I, wherein R ⁴ and R ^s are as defined in any of claims 1 to 3 and R ^a and R ^a each represent hydrogen, characterized in that the the compound according to any one of claims 1 to 3, wherein R ^a is hydroxy, acyloxy or alkoxyacetoxy, electrolytically reduced. 6. A process for preparing a compound according to any one of claims 1 to 3 of formula I, wherein R ⁴ and R ^s are as defined in any of claims 1 to 3, R ^a and R ^b form together with the carbon to which they are attached, A ketone function, characterized in that a compound according to any one of claims 1 to 3 is oxidized in which R ^a is a hydroxy group and R ^a is a hydrogen atom. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3, wherein Z is a group of formula II in combination with one or more pharmaceutically acceptable substances which are inert or pharmacologically active.