HUT73250A - Novel taxoids, preparation thereof and pharmaceutical compositions containing same - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel taxoids of formula I wherein Ar is aryl; R is hydrogen, acetyl or alkoxyacetyl; Rp is benzoyl or R2-O-CO- in which R2 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocycle; R3 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, aryl or heterocycle, and their pharmaceutical compositions containing cell proliferation inhibitors. The compounds of formula (I) according to the invention are prepared by reacting a compound of formula (II): wherein Ar and R 1 are as defined above; R4 is hydrogen and R5 is a protecting group, or R4 and R5 form a heterocycle; G] _ protecting group; and G2 acetyl or a protecting group, esterified with an acid or active derivative of formula (III) to form a compound of formula (IV), and R5, G1 and optionally G2 are replaced by hydrogen, and optionally substituted with a compound of formula (V). Compound (I) is obtained by acylation through a compound of formula I.

Description

The present invention relates to novel taxoids of formula I wherein Ar is aryl; R is hydrogen, acetyl or alkoxyacetyl; R 1 is benzoyl or R 2 -O-CO- wherein R 2 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocycle; R3 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, aryl or heterocyclic ring, and their preparation, and cell proliferative inhibitors thereof.

Compounds of formula (I) according to the invention are prepared by reacting a compound of formula (II) wherein Ar and R 1 are as defined above; R 4 is hydrogen and R 5 is protecting group, or R 4 and R 5 form a heterocyclic ring; G 1 - protecting group; and G2 is an acetyl or protecting group - is esterified with an acid or active derivative of formula (III) to give a compound of formula (IV), and then the protecting group R5, G1 and optionally G2 are replaced by a hydrogen atom; via acylation of the compound of formula (I).

S.B.G. & Κ.

International Patent Office H-1062 Budapest, Andrássy út 113. Phone: 34-24-950, Fax: 34-24-323

60.951 / BE a

New taxoids, their preparation and pharmaceutical compositions containing them

RHONE-POULENC RORER S. A ANTONY, FR

inventors:

BOUCHARD Hervé, IVRY-SUR-SEINE, FR

BOURZAT Jean-Dominique, VINCENNES, FR

COMMERQON Alain, VITRY-SUR-SEINE, FR

PULICANI Jean-Pierre, ANTONY, FR

Date of filing: 28/02/1994

Priority 02.03.1993 (93/02370) FR

International Application Number: PCT / FR94 / 00222

International Publication Number: WO 94/20484

The present invention relates to novel taxoids of general formula (I), to their preparation and to pharmaceutical compositions containing them as active ingredient.

In the general formula (I)

Ar is aryl;

R is hydrogen, acetyl or alkoxyacetyl;

R 1 is benzoyl or R 2 -O-CO- wherein R 2 is

- straight or branched chain alkyl of 1 to 8 carbon atoms,

C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, or C 7 -C 11 bicycloalkyl, which may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-4 alkoxy, both alkyl having C 1-4 dialkylamino, piperidino, morpholino, 1-piperazinyl optionally substituted in position 4 with a C 1-4 alkyl group or a C 1-4 alkyl group; phenylalkyl substituted with -, C3-6cycloalkyl, C4-6cycloalkenyl, phenyl, cyano, carboxy or alkoxycarbonyl, the alkyl of which contains 1-4 carbon atoms, or

- phenyl optionally substituted with one or more atoms or groups, namely, halogen, (C 1 -C 4) -alkyl or (C 1 -C 4) -alkoxy; or · · ··· < _β * · * · ·· · «. '· · - 3 -

- a saturated or unsaturated 4- to 6-membered heterocyclic ring optionally substituted with one or more C 1-4 -alkyl groups; and

R ₃ is C 1 -C 8 straight or branched alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 4 -C 6 cycloalkenyl, or C 7 -C 11 bicycloalkyl, which may be optionally substituted with one or more substituents, halogen, hydroxy, C 1-4 alkoxy, both alkyl having C 1-4 dialkylamino, piperidino, morpholino, 1-piperazinyl optionally substituted at position 4 with a C 1-4 atom substituted with alkyl or a C 1-4 -alkyl-containing phenalkyl, C 3-6 -cycloalkyl, C 4-6 -cycloalkenyl or phenyl optionally substituted with one or more substituents selected from the group consisting of cyano, carboxy and alkoxycarbonyl substituted alkyl having 1 to 4 carbon atoms, or

- an aryl group substituted with one or more atoms or groups, namely a halogen atom, a C 1 -C 4 alkyl or a C 1 -C 4 alkoxy group, with the proviso that R ₃ is other than unsubstituted phenyl, or

- a saturated or unsaturated 4- to 6-membered heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of halogen, C1 -C4 alkyl and C1 -C4 alkoxy, wherein the above cycloalkyl, cycloalkenyl and bicycloalkyl groups are optionally substituted; substituted with one or more C 1-4 alkyl groups.

Preferably, the aryl groups at Ar or R3 are phenyl or α- or β-naphthyl optionally substituted with one or more substituents selected from the group consisting of halogen (such as fluorine, chlorine, bromine or iodine), alkyl, alkenyl, , alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino -, arylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro, trifluoro -methyl, wherein the alkyl moieties of the alkyl groups and the other groups contain from 1 to 4 carbon atoms, the alkenyl and alkynyl groups contain from 2 to 8 carbon atoms, the aryl groups are phenyl or O1 or β-naphthyl and R3 cannot be unsubstituted phenyl .

Heterocyclic groups at the Ar or R3 site are preferably five-membered aromatic heterocycles containing one or more identical or different heteroatoms, namely nitrogen, oxygen or sulfur, and optionally with one or more identical or different substituents, such as halo, chloro, , bromine or iodine), C 1-4 alkyl,

C 6 -C 10 aryl, C 1 -C 4 alkoxy, C 6 -C 10 aryloxy, amino, C 1 -C 4 alkylamino, both alkyl having 1-4 carbon dialkylamino, 1-4 carbon atoms. acylamino, C 1-4 alkyl, alkoxycarbonylamino, C 1-4 acyl, C 6-10 arylcarbonyl, cyano, nitro, trifluoromethyl, substituted with a carboxy, carbamoyl, C 1-4 alkylcarbamoyl, both alkyl groups having a C 1-4 dialkylcarbamoyl, or a C 1-4 alkoxy alkoxycarbonyl group.

More preferably, Ar is phenyl, 2- or 3-thienyl, 2 or 3-furyl, or 2-, 4-, or 5-thiazolyl optionally substituted with one or more identical or different atoms or groups, namely halogen, alkyl -, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, nitro or trifluoromethyl - and R ₃ is phenyl which is one or substituted with several identical or different atoms or groups, namely, halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino or trifluoromethyl, or 2- or 3-thienyl, 2- or 3-furyl or 2-, 4 or 5-thiazolyl optionally substituted with one or more identical or different atoms or groups, namely, halogen, alkyl, alkoxy, amino, , alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, or trifluoromethyl.

More preferably, Ar is phenyl optionally substituted with a chlorine or fluorine atom, an alkyl such as methyl, alkoxy such as methoxy, dialkylamino such as dimethylamino, acylamino, e.g. acetylamino, alkoxycarbonylamino such as t-butoxycarbonylamino or carbamoyl, or 2- or 3-thienyl, 2- or 3-furyl or 2-, 4- or 5-thiazolyl, and R ₃ is phenyl substituted with one or more halogen or alkyl, such as ethyl or tert-butyl, alkoxy such as methoxy, nitro or trifluoromethyl.

Even more preferred are the compounds of formula I wherein Ar is phenyl, benzoyl or tert-butoxycarbonyl, and R ₃ is 2-fluorophenyl, 3-fluorophenyl, 4-fluorine phenyl, pentafluorophenyl, 4-ethylphenyl-4-tert-butylphenyl, 3-nitrophenyl, 4-nitrophenyl or trifluoromethyl.

According to the invention, the novel taxoids of formula (I) can be prepared by reacting a compound of formula (II)

Ar and Rp are as defined above and either

R ₄ is hydrogen and R 5 is a hydroxy protecting group, or R ₄ and R 5 together form a 5- or 6-membered saturated heteroaryl,

G 1 is a hydroxy protecting group, and

G ₂ is esterified with an acetyl group or a hydroxy protecting group, with an acid of formula III wherein R ₃ is as defined above, or an active derivative thereof, in the resulting compound of formula IV wherein Ar, R 1 -, R ₃ , R ₄ , R 5, G ₁ - and G ₂ are as defined above - when R ₄ is hydrogen then R 5 is protecting, and when R ₄ and R 5 together form a 5- or 6-membered saturated heterocycle then R ₄ , R ₅ , G 1 and optionally G ₂ are substituted with hydrogen, then optionally, depending on the meaning of R ₄ , R ₄ and R 5, via a compound of formula V wherein R is as defined above, this compound with benzoyl chloride or a compound of formula VI wherein R ₂ is as defined above and X is halogen such as fluorine or chlorine or -O-R ₂ or -O-CO-OR ₂ by acylation of the acid residue to give the compound of formula (I).

When R _{4 is} a hydrogen atom, R 5 is preferably methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, (β-trimethylsilylethoxy) - methyl or tetrahydropyranyl. When R ₄ and R 5 together form a heterocycle, it is preferably an oxazolidine moiety substituted at the 2-position with a mono- or gem-disubstituted moiety.

When G ₄ and G ₂ are hydroxy protecting groups, these groups are generally different. G ₄ is preferably a trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or trialkylsilyl group having alkyl moieties of 1 to 4 carbon atoms and preferably aryl groups and G ₂ is an alkoxyacetyl group such as methoxyacetyl.

The esterification of the compound of formula (II) may be accomplished by reacting the acid of formula (III) with a compound of formula (II) which is previously converted to a metal salt in the form of a halide such as chloride. The metal

is carried out in an inert organic solvent such as an ether such as tetrahydrofuran at a temperature below -50 ° C, preferably about -78 ° C, with an alkali metal alkyl compound such as butyllithium. Esterification is generally carried out at the same temperature in the same solvent.

Depending on the nature of the protecting groups for the compound of formula (IV), the substitution with hydrogen may be accomplished by the following methods:

1) if R4 is hydrogen, R5 is as defined above, G 4 a silylated radical and G ₂ is acetyl, the protecting groups are replaced by hydrogen atoms to that of the compound of formula (IV), alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles in an organic solvent at a temperature of -10 to 60 ° C with an inorganic acid such as hydrochloric acid, sulfuric acid, hydrofluoric acid or an organic acid such as formic acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p -toluene sulfonic acid - or a mixture of such acids.

2) when R 4 and R 5 together form a 5- or 6-membered saturated heterocyclic ring, preferably an oxazolidine ring of formula VII wherein R 4 is as defined above, R 8 and R 7 are the same or different and are hydrogen, C 1 -C 4 alkyl. , an aralkyl group having an alkyl moiety of 1 to 4 carbon atoms and an aryl moiety preferably being phenyl optionally substituted with one or more C 1-4 alkoxy groups,

or an aryl, preferably phenyl, optionally substituted with one or more C 1 -C 4 alkoxy groups, or R 9 is a C 1 -C 4 alkoxy group, or a trihalogenated methyl group such as trichloromethyl, or a phenyl group which is a trihalogenated methyl group; substituted with, for example, trichloromethyl, and R 7 is hydrogen, or R 8 and R 7 together with the carbon atom to which they are attached form a 4- to 7-membered ring, G ₁ is a silylated group, and G _{2 is} an acetyl group, then protecting groups, depending on the meaning of Rj, Rg and R7, may be substituted as follows:

a) when R 1 - is tert-butoxycarbonyl, R 8 and R 7 are the same or different, respectively alkyl, aralkyl such as benzyl or aryl such as phenyl, or R 9 is a trihalogenated methyl group or a trihalogenated methyl group substituted phenyl, and R7 is hydrogen, or Rg and R7 together form a 4- to 7-membered ring, optionally treating a compound of formula IV with an inorganic or organic acid in an organic solvent such as an alcohol to give a compound of formula V which is then acylated with a compound of formula VI. The compound of formula (IV) is preferably treated with formic acid at a temperature in the region of 20 ° C. Acylation of the compound of formula (V) with the compound of formula (VI) may be carried out with esters such as ethyl acetate, isopropyl acetate or butyl acetate, or halogenated aliphatic hydrocarbons such as methylene chloride or 1,2-dichloro. in an organic solvent selected from ethane in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine at a temperature of 0 to 50 ° C, preferably about 20 ° C.

b) when R] _ is benzoyl or _R2-O-CO- group, wherein R ₂ is as defined above; R 8 is hydrogen, C 1-4 alkoxy, or phenyl substituted with one or more C 1-4 alkoxy groups; and Ry is hydrogen, the protecting groups in the presence of an inorganic acid such as hydrochloric or sulfuric acid or an organic acid such as acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or mixtures thereof, alcohols, ethers, esters, aliphatic hydrocarbons , in an organic solvent selected from halogenated aliphatic hydrocarbons or aromatic hydrocarbons, at a temperature of from -10 ° C to 60 ° C, preferably from 15 ° C to 30 ° C. The acid may be used in catalytic or stoichiometric proportions.

3) When Ge is a silylated group, G ₂ is an alkoxyacetyl group, and R 4 and R 5 are as defined in (1) above, the protecting groups G 1 and R 5 are first substituted with hydrogen atoms as described in (1) above, and optionally, the G ₂ protecting group is also replaced with a hydrogen atom in an alkaline medium under conditions not affecting the rest of the molecule. The alkaline treatment is usually carried out in aqueous-alcoholic medium at about 20 ° C with ammonium hydroxide or in methanol with a zinc halide such as zinc bromide or iodate at about 20 ° C.

4) When G 1 is a silylated group, G 2 is an alkoxyacetyl group, and R 4 and R 5 are as defined in 2) above, it is prepared in an acidic medium under conditions not affecting other parts of the molecule, such as an alcohol such as ethanol. dilute hydrochloric acid at about 0 ° C, first removing the protecting group G ₁ , then optionally replacing the protecting group G ₂ as described in (3) above and finally the compound of formula (V) thus obtained in (2a) above and deprotection and acylation.

5) When G 1 is a silylated group, G 2 is an alkoxyacetyl group, and R 4 and R 5 are as defined in 2 b) above, then first in an acidic medium under conditions not affecting other parts of the molecule, such as an alcohol such as ethanol - dilute hydrochloric acid solution at about 0 ° C, first deprotecting G ₃ , optionally replacing G ₂ with hydrogen as described in 3) above, and treating the resulting compound with 2b above .

The compounds of formula (II) according to the invention are compounds of formula (VIII): wherein Ar, R 1 and R ₄ are as defined above, R ₁₅ is hydrogen or a hydroxy protecting group, R 4 is hydrogen, G 1) -. can be prepared by electrolytic reduction of a hydrogen atom or a hydroxy protecting group and G ' ₂ is a hydrogen atom, an acetyl group or a hydroxy protecting group according to the following scheme:

+ n. e + n. H ⁺ (VIII) (II), • · · ·

- 12 in which, if n is 2, the leaving product is benzaldehyde and if n is 4, the leaving product is benzyl alcohol followed by -OR'5, -Ö-G'i and -O- G'2 protected hydroxy groups are liberated.

The electrolyte reduction of compound (VIII) is carried out in an electrolyzer which contains a catholyte additive in which the compound (VIII) is present in a dissolved state at a concentration between 0.1 g / l and a saturation state.

The reduction is preferably carried out in a diaphragm electrolyzer.

In one embodiment of the process of the invention, the reduction is carried out in an electrolyzer comprising a cathode, a cathode chamber, a separating diaphragm, an anode chamber, and an anode having the following characteristics:

(a) the cathode is a layer of mercury,

b) the cathode chamber contains the catholyte which is an organic solvent solution of the compound of the formula VIII,

c) the diaphragm is a sheet, sleeve or probe made of a porous material, such as sintered glass or porcelain, or an ion-permeable membrane, preferably a cation-permeable membrane,

d) the anode chamber contains the anode liquid, which is preferably made with the same solvent or solvent mixture and the same additive as the catholyte,

e) the anode is made of an electrically conductive material whose characteristics are not critical to the practice of the invention.

The anode is generally made of an electrically conductive material that is not attacked by electrolysis conditions, such as solid polished platinum or graphite or sintered glass above the electrolyte container.

The electrolyte additive is a quaternary ammonium salt, such as tetramethylammonium acetate, tetraethylammonium acetate, tetraethylammonium tetrafluoroborate, or a mixture thereof which is soluble in a solvent mixture.

In general, solvents which are highly soluble and have low resistance to compounds of formulas II and VIII, such as alcohols such as methanol, nitriles such as acetonitrile or amides such as dimethylformamide, are used.

The pH should be such that the substrate is stable. The medium must be buffered with a weak acid, such as acetic acid dissolved in a quaternary ammonium salt.

In a preferred embodiment of the invention, the anode, the cathode and the separating diaphragm are arranged in parallel vertical planes, and the cathode is formed by a layer of mercury.

The temperature of the electrolysis bath is generally maintained between 0 and 30 ° C, preferably below 20 ° C.

The electrolysis is carried out at a controlled voltage, which is in the range of -1.85 to -2.10 volts relative to a saturated calomel electrode.

The solution must be purged with an inert gas such as argon for 12 minutes before electrolysis and the inert gas atmosphere maintained throughout the electrolysis.

For the preparation of a compound of formula II wherein G _1; G2 and R5 each represent a hydroxy protecting group, before forming a -O-G'2 protecting group in a compound of formula VIII to form -O-G'j. and -O-R'5 protecting group.

The compound of formula (VIII) is formed with a halogenated silane of formula (IX), wherein X is halogen and the substituents of Rg are the same or different, to form the silylated ether protecting groups -O-G'1 and -O-R'5. in particular trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or trialkylsilyl, the alkyl moieties of which contain from 1 to 4 carbon atoms and the groups are preferably phenyl.

The compound of formula (VIII) wherein G'1, G'2 and R'5 are each hydrogen, usually in a basic organic solvent such as pyridine or in an inert organic solvent such as dichloromethane or chloroform, in the presence of an organic base such as triethylamine or Hünig's base at about 20 ° C.

The compound of Formula VIII is preferably a basic organic solvent such as pyridine at a temperature of about 20 ° C to form an alkoxyacetyl protecting group -O-G'2 with a compound of Formula X wherein Rg is 1-4. C is alkyl and Y is halogen.

In accordance with the present invention, compounds of formula II can also be prepared by reacting a compound of formula XI wherein G 1 and G ₂ are as defined above in an organic solvent such as toluene with an activating agent such as 4-. (dimethylamino) pyridine and optionally a condensing agent such as an imide such as dicyclohexylcarbodiimide at a temperature between 0 and 90 ° C with an acid of formula XII wherein Ar, R 1, R 4 and R 5 or a derivative thereof, such as a halide, anhydride or mixed anhydride.

The compound of formula (I) may be prepared by electrolytic reduction of a compound of formula (XIII) wherein G'4 and G 'are as defined above and G'3 is hydrogen or a hydroxy protecting group identical to G' ^. . The reduction is carried out under the same conditions as described for the electrolytic reduction of compound (VIII).

Prior to the esterification, it may be necessary to selectively replace the protecting group G'3 with a hydrogen atom or to selectively protect the hydroxy groups at positions 7-10.

The following examples illustrate the invention.

Example 1

1.5 g of [4,8-β-diacetoxy-1,2a-dihydroxy-5S, 20-epoxy-9-oxo-7S-triethylsilyloxy-11-taxen-13a-yl] - (4S, 5R) - 3-tert-Butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is dissolved in 16 ml of tetrahydrofuran and 1.1 ml of 1.6 M hexane in butane is added dropwise under argon atmosphere at -78 ° C. -olda-

- :. ·:: * «· ··» · .. · ». · Lake. After the addition was complete, the reaction mixture was stirred for 20 minutes at about -78 ° C and 0.3 ml of 3-fluorobenzoyl chloride was added dropwise at the same temperature. After stirring at -78 ° C for 3 hours, the temperature was allowed to rise to about 0 ° C, then 5 ml of saturated aqueous ammonium chloride solution was added. The organic layer was separated by decantation, washed with distilled water (2 x 10 mL), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. That's how it got

1.7 g of a white foam are purified by chromatography on a 2.5 cm diameter column of 50 g (0.063-0.2 mm particle size) silica gel, eluting with a 99: 1 mixture of dichloromethane and methanol, while collecting 3 ml fractions. The fractions containing only the desired product were collected and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. In this way, 0.48 g of [4,? -Diacetoxy-5S, 20-epoxy-2- (3-fluorobenzoyloxy) -1-hydroxy-9-oxo-7S-triethylsilyloxy-11-taxene was obtained. -13a-yl] - (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is obtained in the form of a white foam.

0.48 g of [4,10S-diacetoxy-5H, 20-epoxy-2- (3-fluorobenzoyloxy) -1-hydroxy-9-oxo-7S-triethylsilyloxy-11-taxene-13o]. ? -yl] - (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate in 4.8 ml of formic acid for 2.5 hours at a temperature in the region of 20 ° C. and then concentrated to dryness under reduced pressure (0.7 kPa, then 0.07 kPa) at 30 ° C. To the residue was added dichloromethane (20 mL) followed by saturated aqueous sodium (20 mL)

solution of bicarbonate. The organic layer was separated by decantation and extracted with dichloromethane (20 mL). The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. This gives 0.33 g of a white foam which is purified by chromatography on a 2 cm diameter column of 20 g (0.063-0.2 mm particle size) silica gel, eluting with a 99: 1 mixture of dichloromethane and methanol, with 10 ml fractions. We collected. The fractions containing only the desired product were collected and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. There were thus obtained 0.091 g of [4,10E-diacetoxy-1,7S-dihydroxy-5S, 20-epoxy-2- (3-fluorobenzoyloxy) -9-oxo-11-taxen-13a-yl] - (2R). 3S) -3-amino-3-phenyl-2-hydroxypropionate is obtained in the form of a white foam.

mg of [4,7-β-diacetoxy-1,7S-dihydroxy-5S, 20-epoxy-2- (3-fluorobenzoyloxy) -9-oxo-11-taxen-13a-yl] - (2R, 3S) -3-Amino-3-phenyl-2-hydroxypropionate was dissolved in ethyl acetate (2.5 ml), saturated aqueous sodium bicarbonate solution (2.5 ml) and distilled water (2.5 ml) were added under argon and 0.014 mL (14 μΐ) of benzoyl chloride. After stirring for 15 minutes at a temperature in the region of 20 ° C, the aqueous phase was separated by decantation and extracted with ethyl acetate (3 x 3 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gave 88 mg of a white foam, which was purified by chromatography on 3 g ··· (0.063-0.2 mm particle size) silica gel column, eluting with a 98: 2 mixture of dichloromethane and methanol with 1.5 ml. fractions. 14-21. fractions were collected and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C to give 80 mg of [4,105-diacetoxy-1,75-dihydroxy-55,20-epoxy-2a- (3-fluorobenzoyl). oxy) -9-oxo-11-taxen-13a-yl] - (2R, 3S) -3-benzoylamino) -3-phenyl-2-hydroxypropionate in the form of a white foam having the following characteristics:

rotation: [α] ²⁰ D = -45 ° (c = 1.0, methanol);

- Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ ppm):

1.15 (s, 3H: _-CH3 16 or 17); 1.25 (s, 3H: _-CH3 16 or 17); 1.69 (s, 3H: _-CH3 19); 1.80 (s, 3H: _-CH3 18); 1.89 [mt, 1H: - (CH) -H6]; 1.94 (s, 1H: -OH 1); 2.26 (s, 3H: _-COCH3 the 10-position); 2.32 (d, J = 9Hz, 2H: CH _2-14); 2.37 (s, 3H: _-COCH3 the 4-position); 2.53 (d, J = 4Hz, 1H: -OH 7); 2.55 [mt, 1H:

- (CH) --H6]; 3.69 (d, J = 5 Hz, 1H: -OH 2 '); 3.80 (d, J = 7Hz,

1H: -H3); 4.18 and 4.30 (2d, J = 8 Hz, 1H each: - _(CH2) 20); 4.40 (mt, 1H: --H5); 5.65 (d, J = 7Hz, 1H: --H - 2); 5.77 (dd, J = 9.5 and 3 Hz, 1H: --H - 3 '); 6.21 (t, J = 9 Hz, 1H: -H-13); 6.28 (s, 1H: --H 10); 7.00 (d, J = 9.5 Hz, 1H: -NHCO-);

7.30-7.50 [mt, 7H: C ₆ H ₅ at the 3'-position, -NHCOC ₆ H ₅ (4 H), -OCOC ₆ H ₄ F (--H 4)]; 7.50 [t, J = 7.5 Hz, 2H: -NHCOC ₆ H ₅ (-H 3 and

-H 5)]; 7.50 [mt, 1H: -OCOC ₆ H ₄ F (-H 5)]; 7.63 (d, J = 7.5 Hz,

2H: -NHCOC ₆ H ₅ (-H 2 and -H 6)]; 7.81 (broad d, J = 9 Hz, 1H:

-OCOC ₆ H ₄ F (-H 2)]; 7.94 (d, J = 7.5 Hz, 1H: -OCOC ₆ H ₄ F (-H 6)).

[4,10B-Diacetoxy-1,2a? -Dihydroxy-5β, 20-epoxy-9-oxo-7β- (triethylsilyloxy) -11-taxen-13β-yl] - (4S, 5R) 3- (tert-Butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is prepared as follows:

[4,10B-Diacetoxy-1-hydroxy-2 '- (benzoyloxy) -5B, 20-epoxy-9-oxo-7B-triethylsilyloxy-11-taxen-13a-yl] - (4S) The electrolytic reduction of 5R) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is carried out in an electrolytic cell having the following characteristics:

- the cell is a 50 ml glass container divided into two parts by a cation exchange membrane,

- the cathode is a layer of mercury with a useful surface of about 12 cm 2,

- the anode is a platinum lattice,

- the reference electrode is a saturated calomel electrode.

Fill the cathode vessel with 50 ml of the following solution:

- [4,10B-Diacetoxy-1-hydroxy-2 '- (benzoyloxy) -5B, 20-epoxy-9-oxo-7β-triethylsilyloxy-11-taxen-13-yl] - ( 4S, 5R) -3- (tert-Butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate ... 2.0 g

- methanol ................................................ 50 ml

- 0.2 M tetraethylammonium acetate ............. as required

- acetic acid ............................................. 0.28 ml

10 ml of a solution of the same composition but no substrate was charged into the anode container.

The cell is immersed in a bath of melting ice. The internal temperature remains about 10 ° C. After the solution was purged with a stream of argon for about 10 minutes, the cathode voltage was recorded at -2.05 volts.

When the charge per mole of substrate exceeds the faraday 1, the hydrogen ions consumed are replaced by the addition of 0.114 mL of acetic acid. Each time the electrical resistance increases, 0.26 g of tetraethylammonium acetate is also charged into the anode vessel.

After passing through 960 coulomb charge, the electrolysis is stopped. The solvent was evaporated under reduced pressure below 35 ° C and the residue was taken up in 50 ml of water. The reaction mixture was extracted with ethyl acetate (50 mL, then 25 mL x 2). The organic phase was rinsed with 50 mL of aqueous sodium bicarbonate solution and dried over magnesium sulfate. After filtration of the reaction mixture and evaporation of the solvent under reduced pressure at a temperature below 35 ° C, 1.86 g of a white solid is obtained, which is purified by chromatography on 100 g (0.063-0.2 mm particle size) silica gel column. Elution was carried out with a 99: 1 by volume mixture of dichloromethane and methanol and 6 ml fractions were collected. 140-220 containing the desired product in purified state. fraction was collected and evaporated to dryness under reduced pressure (0.27 kPa) to give 0.77 g of [4,10S-diacetoxy-1,2a-dihydroxy-5S, 20-epoxy-9-oxo-7S- (triethylsilyl). oxy) 11-taxen-13a-yl] - (4S, 5R) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate as a white foam.

[4,10E-Diacetoxy-1-hydroxy-2a- (benzoyloxy) -5S, 20-epoxy-9-oxo-7S-triethylsilyloxy-11-taxen-13a-yl] - (4S, 5R) -3- (tere21

butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate

It can be prepared as described in International Patent Application Publication No. WO 9209589.

Example 2

0.8 g of [4-acetoxy-1,2a-dihydroxy-5S, 20-epoxy-10S- (methoxyacetyloxy) -9-oxo-7S- (triethylsilyloxy) -11-taxene-13a -yl] - (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was dissolved in 16 ml of anhydrous tetrahydrofuran and then at -78 ° C under argon. 0.65 ml of a 1.6 M solution of butyllithium in hexane is added dropwise. After the addition was complete, the reaction mixture was stirred for 30 minutes at about -78 ° C and 0.157 ml of 3-fluorobenzoyl chloride was added dropwise, maintaining the same temperature. The reaction mixture was stirred at -78 ° C for 3 hours, then warmed to about 0 ° C and 2 ml of saturated aqueous ammonium chloride solution was added. The organic layer was separated by decantation and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting white foam (0.91 g) was purified by chromatography on a 1.5 cm column (25 g, 0.063-0.2 mm particle size), eluting with a 99: 1 mixture of dichloromethane and methanol, to give 3 ml fractions. We collected. 35-42. fractions were collected and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 0.51 g of [4-acetoxy-1,7S-dihydroxy-22-5Sb, 20-epoxy-2- (3-fluorobenzoyloxy) -10S- (methoxyacetyloxy) -9-oxo -11-taxen-13a-yl] - (4S, 5R) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is obtained in the form of a white foam.

mg of [4-acetoxy-1,7S-dihydroxy-5Eb, 20-epoxy-2- (3-fluorobenzoyloxy) -10S- (methoxyacetyloxy) -9-oxo-11-taxen-13α yl] - (4S, 5R) -3- (terbutoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was dissolved in 1.5 ml of methanol and added at a temperature of about 20 ° C. 5 ml of 1M methanolic ammonia solution. The reaction mixture was stirred for 1 hour at about 20 ° C and then concentrated to dryness under reduced pressure (2.7 kPa) at 20 ° C. The residue was purified by chromatography on 1.5 cm (0.04-0.063 mm particle size) silica gel column, eluting with a 98: 2 mixture of dichloromethane and methanol, collecting 1 ml fractions. 62-76. fractions were collected and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 12 mg of [4-acetoxy-5β, 20-epoxy-2- (3-fluorobenzoyloxy) -9-oxo-1,7S, 10S-trihydroxy-11-taxen-13a-yl] - (4S 5R) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is obtained in the form of a white foam.

mg [4-Acetoxy-5S, 20-epoxy-2- (3-fluorobenzoyloxy) -9-oxo-1,7S, 10β-trihydroxy-11-taxen-13a-yl] - (4S, 5R) 3- (tert-Butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was dissolved in 0.12 ml of formic acid and stirred for 2.5 hours at a temperature in the region of 20 ° C. dichloride and 0.5 mL of saturated aqueous sodium bicarbonate solution. The aqueous phase was separated by decantation and extracted with dichloromethane (1 mL). The combined organic phases were dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. In this way, 10 mg of [4-acetoxy-5S, 20-epoxy-2- (3-fluorobenzoyloxy) -9-oxo-1,7β, β-trihydroxy-11-taxen-13a-yl] - (2R 3S) -3-amino-2-hydroxy-3-phenylpropionate is obtained in the form of a white foam.

mg [4-Acetoxy-5β, 20-epoxy-2- (3-fluorobenzoyloxy) -9-oxo-1,7β, 10β-trihydroxy-11-taxen-13α-yl] - (2R, 3S) -3-Amino-2-hydroxy-3-phenylpropionate is dissolved in 2 ml of anhydrous tetrahydrofuran, and 1.4 mg of sodium bicarbonate and 3.6 mg of ditert-butyl dicarbonate are added under an argon atmosphere at a temperature in the region of 20 ° C. The reaction mixture is stirred for 8 hours at about 20 ° C and then concentrated to dryness under reduced pressure (2.7 kPa) at about 30 ° C. To the solid residue was added methylene chloride (2 mL) and distilled water (1 mL). After stirring, the organic phase was separated by decantation, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting white foam (21 g) was purified by silica gel layer chromatography (20 mm x 20 cm, 1 mm thick gel) to 10 mg fractions. After identifying the zone containing the desired product in the adsorbed state by UV rays, this zone is scraped off and the collected silica gel is washed twice with 10 ml of dichloromethane and 5 times with 1 ml of methanol on a sintered glass. The filtrates were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. In this way, 4 mg of [4-acetoxy-5Bb, 2024] are obtained

-epoxy-2- (3-fluorobenzoyloxy) -9-oxo-1,7S, ΙΟβ-trihydroxy-11-taxen-13a-yl] - (2R, 3S) -3 - [(tert-butoxy) carbonyl) amino] -2-hydroxy-3-phenylpropionate in the form of a white foam having the following characteristics:

- Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl3, δ ppm):

1.15 (s, 3H: --CH3 16 or 17); 1.25 (s, 3H: --CH3 16 or 17);

1.37 [s, 9H: - (CH ₃ ) ₃ ]; 1.78 (s, 3H: -CH3 19); 1.82 (s, 1H: --OH at position 1); 1.87 (s, 3H: _-CH3 18); 1.87 [mt, 1H: - (CH) -H_6];

2.27 (d, J = 9Hz, 2H: CH _2-14); 2.37 (s, 3H: -COCH 3); 2.60 [mt, 1H: - (CH) -H_6]; 3.93 (d, J = 7Hz, 1H: --H3); 4.18 [d, J = 8Hz, 1H: - (CH) -H2O]; 4.23 (mt, 1H: --H7); 4.32 [d, J = 8 Hz,

1H; - (CH) -H 2 O]; 4.61 (broad S, 1H: --H2 '); 4.96 broad d, J = 10 Hz, 1H: -H5); 5.21 (s, 1H: --H 10); 5.33 (broad d, J = 10

Hz, 1H: --H3 '); 5.41 (d, J = 10 Hz, 1H: -CONH-); 5.67 (d, J = 7Hz, 1H: -H2); 6.21 (t, J = 9 Hz, 1H: --H13); 7.30-7.50 [mt, 7H: C ₆ H ₅ at the 3'-position, -OCOC ₆ H ₄ F (--H 4)]; 7.51 [mt, 1H: -OCOC ₆ H ₄ F (-H 5)]; 7.81 (br d, J = 9 Hz, 1H, -OCOC ₆ H ₄ F (H 2)]; 7.92 (d, J = 7.5 Hz, 1H: ₄ -OCOCgH F (--H 6 )].

A [4-Acetoxy-1,2a-dihydroxy-5E, 20-epoxy-10S- (methoxyacetyloxy) -9-o-o-7β- (triethylsilyloxy) -11-taxen-13a-yl] - (4S, 5R) -3- (tert-Butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is prepared as follows:

[4-acetoxy-l-hydroxy-2a (benzoyloxy) -5β, 20-εροχί-10β- (methoxy-acetyl) -9-οχο-7β- (triethyl silyloxy) -11-taxen -13a-yl] - (4S, 5R) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is reduced by electrolysis. The properties of the electrolyzing cell are as follows:

• · ·· · · ····

- the cell is a glass vial divided into two parts by a cation exchange membrane,

- the cathode is a layer of mercury with a useful surface area of about cm ² ,

- the anode is a platinum lattice,

- the reference electrode is a saturated calomel electrode.

Fill the cathode vessel with 50 ml of the following solution:

- [4-Acetoxy-1-hydroxy-2C] - (benzoyloxy) -5S, 20-epoxy-10S-

- (methoxy-acetyl) -9-οχο-7β- (triethyl silyloxy) -11-taxen-13.alpha.-yl] - (4S, 5R) -3- (N-tert-butoxycarbonyl) -2, 2-Dimethyl-4-phenyl-5-oxazolidinecarboxylate 0.401 g

- methanol ..................................... 27 mL

- tetraethylammonium tetrafluoroborate ........... 0.1 M

- tetrabutylammonium acetate ............. 0.02 M as needed

- acetic acid ..................................... 0.02 M

About 10 ml of about 0.2 M hydrochloric acid in methanol was charged into the anode vessel.

The cell is immersed in a bath containing melting ice. The internal temperature remains about 7 ° C. After the solution was purged with an argon stream for about 10 minutes, the cathode voltage was fixed at -1.9 volts and after passing 150 coulombs at -2.0 volts.

As the electrical resistance increases, 3.8M methanolic hydrochloric acid solution is charged into the anode vessel.

After passing through a charge of 450 coulombs, the electrolysis is stopped. Solvent under reduced pressure, temperature below 35 ° C ♦ · ·

After evaporation at 26, the residue is taken up in 25 ml of ethyl acetate and 25 ml of deionized water. The aqueous phase was separated by decantation and extracted twice with 12.5 ml of ethyl acetate. The organic phase was rinsed with 25 mL of sodium phosphate pH 7.4 and dried over magnesium sulfate. After filtration of the reaction mixture and evaporation of the solvent under reduced pressure at a temperature below 35 ° C, 0.355 g of a white foam is obtained, which is purified by chromatography on 10 g (0.04-0.063 mm particle size) silica gel column. Elution was carried out with 98: 2 dichloromethane / methanol and 15 ml fractions were collected. 21-25 containing the desired product in purified state. fraction was collected and evaporated to dryness under reduced pressure (0.27 kPa) at 35 ° C to give 195 mg of [4-acetoxy-1,2a-dihydroxy-5S, 20-epoxy-10S- (55%). methoxyacetyloxy) -9-oxo-7S- (triethylsilyloxy) -11-taxen-13a-yl] - (4S, 5R) -3- (tert-butoxycarbonyl) -2,2-dimethyl- 4-Phenyl-5-oxazolidinecarboxylate is obtained in the form of a white foam.

[4-Acetoxy-1-hydroxy-2 '- (benzoyloxy) -5S, 20-epoxy-10S- (methoxyacetyloxy) -9-o-o-7β- (triethylsilyloxy) -11] -taxen-13a-yl] - (4S, 5R) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is prepared as follows:

1.46 g of 4-acetoxy-2α- (benzoyloxy) -1,13a-dihydroxy-5β, 20-epoxy-10S- (methoxyacetyloxy) -9-o-o-7β- (triethylsilyloxy) ) -11-Taxene is dissolved in 15 ml of toluene and 0.96 g of (4S, 5R) -3- (tert-butoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid, 0.66 g are added. N, N'-dicyclohexylcarbodiimide and 0.12 g of 4- (di-27 · · · · *

methylamino) pyridine. After stirring for 3 hours at about 80 ° C, the reaction mixture was cooled to 20 ° C and poured into 50 ml of dichloromethane and 150 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer was separated by decantation, washed twice with 20 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This gives 2.5 g of a white foam which is purified by chromatography on 75 g (0.063-0.2 mm particle size) silica gel column packed in a 3 cm diameter column. Elution was carried out with a 99: 1 mixture of dichloromethane and methanol and 3 ml fractions were collected. 42-59. fraction was collected and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C to give 1.9 g of [4-acetoxy-1-hydroxy-2a- (benzoyloxy) -5β, 20-epoxy-ΙΟβ - (methoxyacetyloxy) -9-oxo-7β- (triethylsilyloxy) -11-taxen-13a-yl] - (4S, 5R) -3- (tert-butoxycarbonyl) -2 2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is obtained.

(4S, 5R) -3- (Terbutoxycarbonyl) -2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid can be prepared as described in International Patent Application Publication No. WO 9209589.

4-Acetoxy-2a- (benzoyloxy) -1,13α-hydroxy-5β, 20-epoxy-10β- (methoxyacetyloxy) -9-o-o-7β- (triethylsilyloxy) -11. -taxene is prepared as follows:

3.29 g of 4-acetoxy-2- (benzoyloxy) -1,10β, 13a-trihydroxy

-5β, 20-εροχί-9-οχο-7β- (triethylsilyloxy) -11-taxene is dissolved in 125 ml of anhydrous pyridine and 2.71 g of methoxy is added dropwise over 5 minutes under argon at about 5 ° C.

- 28-acetyl chloride. After the addition was complete, the reaction mixture was stirred for 14 hours at about 5 ° C and then for 24 hours at about 20 ° C, then poured into 250 ml of dichloromethane and 1000 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer was separated by decantation, washed twice with 100 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting white foam (4.1 g) was purified by chromatography on a column (3 cm in diameter) of silica gel (80 g, 0.063-0.2 mm), eluting with a 99: 1 mixture of dichloromethane and methanol. The fractions containing only the compound to be prepared were collected and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. There were thus obtained 2.9 g of 4-acetoxy-2 '- (benzoyloxy) -1,13' -dihydroxy-5S, 20-epoxy-10S (methoxyacetyloxy) -9-oxo-7S- (triethyl). silyloxy) -11-taxene was obtained as a white foam.

4-Acetoxy-2 - (benzoyloxy) -1,10S, 13a-trihydroxy-5S, 20-epoxy-9-oxo-7S- (triethylsilyloxy) -11-taxene is described in J-N. Denis et al., J. Med. Chem. Soc., 110, 5917 (1988).

Example 3 [4-Acetoxy-2 '- (benzoyloxy) -5β, 20-epoxy-1,7S, 10S-trihydroxy-9-oxo-11-taxen-13a-yl] - (2R, 3S) - 3 - [(tert-butoxycarbonyl) amino] -3-phenyl-2-hydroxypropionate is reduced by electrolysis. The properties of the electrolyzing cell are as follows:

- the cell is a glass vial divided into two parts by a cation exchange membrane,

- the cathode is a layer of mercury with a useful surface area of about 4 cm ² ,

- the anode is a platinum lattice,

- the reference electrode is a saturated calomel electrode.

Place 40 ml of the solution of the following composition in the cathode vessel:

- [4-Acetoxy-2- (benzoyloxy) -5β, 20-epoxy-1,7β, 10β-trihydroxy]

-9-oxo-11-taxen-13α-yl] - (2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -3-phenyl-2-hydroxypropionate ....... .................. 402 mg (73% pure by analysis, eg 293 mg pure docetaxel)

- methanol ................................................. .4 0 ml

- tetraethylammonium tetrafluoroborate ...................... 0.87 g

- tetraethylammonium acetate ............................. 2.61 g

- acetic acid ............................................... 0 , 4 ml

About 10 ml of a 1% aqueous sulfuric acid solution was charged into the anode vessel.

After purging the solution by passing a stream of argon for about 10 minutes, the cathode voltage is adjusted to -1.85 volts at the beginning of the electrolysis and then gradually lowered to -2.02 volts until the end of the electrolysis.

After passing through a charge of 480 coulombs, the electrolysis is stopped. The solvent was evaporated under reduced pressure at a temperature below 35 ° C. The residue was taken up in ethyl acetate (20 ml) and extracted with ethyl acetate (3 x 20 ml). The organic layer was rinsed with saturated aqueous sodium chloride solution (20 mL) and dried over magnesium sulfate. After filtration and evaporation of the solvent under reduced pressure at a temperature below 35 ° C, the crude product obtained is purified by chromatography on a silica gel column (50 g, 0.063-0.2 mm particle size, 24 mm diameter). Elution is carried out with dichloromethane containing 1, 2 and 3% by volume of methanol. The fractions containing the desired product in purified state were collected and evaporated to dryness under reduced pressure (0.27 kPa) at a temperature below 35 ° C to give 136 mg of [4-acetoxy-56,20-epoxy-1,2a] in 53% yield. 76,106-Tetrahydroxy-9-oxo-11-taxen-13a-yl] - (2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -3-phenyl-2-hydroxypropionate is obtained in the form of a white foam. of.

The resulting compound can be acylated at the 2-position after protection of the 76,106-hydroxy groups and the side chain 2-position.

Example 4 [4-Acetoxy-2- (benzoyloxy) -56,20-epoxy-1,106-dihydroxy-7a- (triethylsilyloxy) -9-oxo-11-taxen-13a-yl] - (2R, 3S) -3 - [(tert-Butoxycarbonyl) amino] -3-phenyl-2- (triethylsilyloxy) propionate is reduced by electrolysis. The properties of the electrolyzing cell are as follows:

- the cell is a glass vial divided into two parts by a cation exchange membrane,

- the cathode is a layer of mercury of approximately 12 cm ^{2 in} surface area,

- the anode is a platinum lattice,

- the reference electrode is a saturated calomel electrode.

• · • ♦ • · · ·

Fill the cathode vessel with 25 ml of the following solution:

- [4-Acetoxy-2- (benzoyloxy) -5S, 20-epoxy-1,10S-dihydroxy-7a- (triethylsilyloxy) -9-oxo-11-taxen-13a-yl] - ( 2R, 3S) -3 - [(tert-Butoxycarbonyl) amino] -3-phenyl-2- (triethylsilyloxy) propionate ................ ............... 500 mg

- methanol ............................................. 25 mL

- tetraethylammonium acetate for total volume, if necessary ............ 0.1 M

- Acetic acid ............................................ 0.05 ml

Fill the anode vessel with 25 ml of the same composition but without the substrate.

The cell is immersed in a bath containing melting ice. The reaction temperature remains about 4 ° C. After purging the solution by passing a stream of argon for about 10 minutes, the cathode voltage is adjusted to -1.95 volts at the beginning of the electrolysis.

After passing through a charge of 340 coulombs, the electrolysis is stopped. To the resulting solution was added six volumes of 50% saturated aqueous sodium bicarbonate solution and extracted three times with 25 ml of ethyl acetate. The organic layer was rinsed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration and evaporation of the solvent under reduced pressure below 35 ° C, the crude product obtained is purified by chromatography on a 50 g silica gel column packed in a 20 mm diameter column. Elution was carried out with a mixture of dichloromethane and methanol at 4 bar. 12-59, containing the desired product in a purified state · · · · · · · · · · · · · · · · · · · · · · · · · · · · fractions were collected and evaporated to dryness under reduced pressure (0.27 kPa) at a temperature below 35 ° C to give 248 mg of [4-acetoxy-5S, 20-epoxy-1,2a, 10S-trihydroxy-7a] in 55% yield. (triethyl silyloxy) -9-oxo-ll-taxen-13.alpha.-yl] - (2R, 3S) -3 - [(tert-butoxy-carbonyl) amino] -3-phenyl-2- (triethyl silyloxypropionate is obtained in the form of a white foam.

The resulting compound can be acylated at the 2-position after protection of the ΙΟβ-hydroxy group.

Example 5

10-Deacetyl baccatin III is reduced by electrolysis. The properties of the electrolyzing cell are as follows:

- the cell is a 100 ml glass container divided into two parts by a cation exchange membrane,

- the cathode is a layer of mercury of approximately 12 cm ^{2 in} surface area,

- the anode is a platinum lattice,

- the reference electrode is a saturated calomel electrode.

Fill the cathode vessel with 50 ml of the following solution:

- 10-Desacetyl Baccatin III ......................... 500mg

- tetramethylammonium acetate ......................... 0.1M

- acetic acid ............................................ 0.1M

- methanol ........................................... 50ml

About 10 ml of 0.15 M aqueous sulfuric acid solution was charged into the anode vessel.

• · · · · · · · · · · · · · · · · · · ·

After purging the solution by passing a stream of argon maintained throughout the reaction for about 10 minutes, the cathode voltage is adjusted to -1.9 volts relative to the reference electrode.

The solution is electrolyzed for 160 minutes, i.e. the time required to pass through a charge of 700 coulombs (e.g., 7.6 faraday / mol). The solvent was evaporated under reduced pressure at a temperature below 35 ° C, taken up in a mixture of ethyl acetate (20 ml) and water (saturated with sodium chloride) (20 ml) and adjusted to pH 7 with 0.2M aqueous sodium phosphate solution. . After decantation, the organic phase is extracted with 10 ml portions of ethyl acetate until exhausted. The organic phase was dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure at a temperature below 35 ° C. The crude product (370 mg) thus obtained was purified by chromatography on a Kisesegel 60 F 254 Merek silica gel column 2 cm in diameter and 3 cm high. As eluent, first, a total of 500 ml of a 5: 4.75: 4.75 v / v methanol / methylene chloride / ethyl acetate mixture, then a total of 250 ml of a 10:45:45 v / v methanol / methylene chloride / ethyl acetate mixture, and finally a total of 250 ml. of methanol / ethyl acetate (10:90 by volume). Fractions containing the first eluent from 50 ml, the total amount of the second eluent and the first 90 ml of the last eluent were collected, evaporated and the product was dried to give 337.4 mg of 4% (83%). Β-Diacetoxy-1,2a, 7β, 13a-tetrahydroxy-5β, 20-epoxy-9-oxo-11-taxane is obtained.

··· ·

Example 6

1.5 g of [4a-acetoxy-1S, 2a-dihydroxy-5S, 20-epoxy-10S- (methoxyacetoxy) -9-oxo-7S- (triethylsilyloxy) -11-taxen-13a-yl ] (2R, 4S, 5R) -3- (tert-Butoxycarbonyl) -2- (4-methoxyphenyl) -1,3-oxazolidine-5-carboxylate is dissolved in 20 ml of tetrahydrofuran under argon and stirred at -78 ° C. 2.30 ml of a 1.4M solution of butyllithium in hexane, followed by 510 mg of 4-methoxybenzoyl chloride. The solution is stirred for 30 minutes and then 3 ml of a saturated aqueous solution of ammonium chloride are added. The reaction mixture was heated to about 20 ° C over 1 hour and then poured into a mixture of ethyl acetate (100 mL) and saturated aqueous ammonium chloride (100 mL). The aqueous phase was separated by decantation and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with distilled water (50 mL), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting white foam (2.15 g) was purified by chromatography on a silica gel column (1500 g, 0.063-0.2 mm particle size, 4 cm diameter). Elution was carried out with a mixture of ethyl acetate and cyclohexane (30:70 by volume) and 10 ml fractions were collected. The fractions containing only the desired product were collected and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C to give 0.760 g of [4a-acetoxy-5S, 20-epoxy-1S-hydroxy-1OS- (methoxy) acetoxy) -2a- [4-methoxy (benzoyloxy)] - 9-oxo-7S- (triethyl silyloxy) -11taxen-13.alpha.-yl] - (2R, 4S, 5R) -3- (tert -butoxycarbonyl) -2- (4-methoxyphenyl) -1,3-oxazolidine-5-carboxylate is obtained in the form of a white foam having the following characteristics:

• »· • 4

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 0.59 (q, J = 7.5 Hz,

6H: -CH ₂ -ethyl); 0.93 (t, J = 7.5 Hz, 9H: -CH ₃ -ethyl); 1.10 [s, 9H: - (CH ₃ ) ₃ ] _; 1.19 (s, 3H: _-CH3 16 or 17); 1.20 (s, 3H: -CH ₃ or 17); 1.67 (s, 3H: _-CH3 19); 1.70 (s, 3H: _-CH3 18); 1.73 (s, 1H: --OH at position 1); 1.86 [mt, 1H:> (CH) -H-6]; 1.87 (s, 3H: -COCH ₃ ); 2.12 and 2.20 (2 dd, J = 16 and 9 Hz, 1H, each CH ₂ -14); 2.49 [mt, 1H:> (CH) -H-6]; 3.52 (s, 3H: _-COCH3); 3.71 (d, J = 7Hz, 1H: --H3); 3.83 (s, 3H: _Ar-OCH3 5'-n); 3.89:

(s, 3H: _Ar-OCH3 to 2-n); 4.10 [d, J = 8 Hz, 1H:> (CH) -H 20]; 4.18 (ab limit, J = 16 Hz, 2 H: -OCO- -CH ₂ O-); 4.24 [D, J = 8 Hz, 1H:> (CH) -H2O]; 4.43 (dd, J = 7 and 11 Hz, 1H: -H 7); 4, 58 (D,

J = 5.5 Hz, 1H: -H2 '); 4.86 (broad d, J = 10 Hz, 1H: --H5);

5.43 (d, J = 5.5 Hz, 1H: -H 3 '); 5.62 (d, J = 5.5 Hz, 1H: -H2); s d, J = = 10 Hz, 1H: -H5); 6.07 (t, J = 9 Hz, 1H : -H 13); 6.3 9 (wide s, 1H: -H5 '); 6.44 (s, 1H: --H 10); 6 93 (D, J = 7.5 Hz, 2H: -C ₆ H ₅ at the 5 'position (-H 3 and -H 5)]; 6.98 (D, J = = 8.5 Hz,

2H: aromatic -H ortho to -OCH ₃ ); 7.30-7.45 [mt, 7H: ₅ -CgH the 3'-position and ₆ -Ο Η ₅ at the 5 '(--H 2 and --H 6)];

7.99 (d, J = 8.5 Hz, 2H: aromatic H in comparison to the meta position with OCH ₃₎ (-H 5)]; 7.81 (br d, J = 9 Hz, 1H: -O-CO 2 H ₄ F (-H 2)]; 7.92 (d, J = 7.5 Hz, 1H: -OCOC ₆ H ₄ F (-H 6) )].

0.750 g of [4a-acetoxy-5B, 20-epoxy-1B-hydroxy-10B- (methoxyacetoxy) -2a- [4-methoxy (benzoyloxy)] -9-οχο-7β- (triethylsilyl) oxy) -11-taxen-13a-yl] - (2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -1,3-oxazolidine-5-carboxylate 13 ml of 0.1 M hydrochloric acid in ethanol and stirred for 16 hours at about 20 ° C, then under reduced pressure (2.7 kPa) at 40 ° C36.

evaporate to dryness. The crude reaction product was dissolved in a mixture of methylene chloride (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic layer was separated by decantation and extracted with dichloromethane (2 x 50 mL).

The combined organic phases are washed with 50 ml of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting white foam (1.0 g) was purified by chromatography on 1000 g (0.063-0.2 mm particle size) silica gel column packed in a 4 cm diameter column. Elution was carried out with a mixture of ethyl acetate and cyclohexane (30:70 by volume) and 10 ml fractions were collected. The fractions containing only the desired product were collected and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C to give 0.250 g of [4a-acetoxy-1S, 7S-dihydroxy-5S, 20-epoxy-10S- ( methoxyacetoxy) -2a- [4-methoxy (benzoyloxy)] -9-oxo-11-taxen-13a-yl] (2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenyl-propionate is obtained in the form of a white foam having the following characteristics:

- NMR (400MHz, CDCl3, δ in ppm): 1.15 (s, 3H: _-CH3 16 or 17); 1.27 (s, 3H: _-CH3 16 or 17); 1.67 [s, 3H: - (CH ₃ ) ₃ ];

1.69 [s, 3H: - (CH ₃ ) ₃ 19]; 1.80-1.95 [mt, 1H: > (CH) -H61; 1.87 (s, 3H: _-CH3 18); 2.30 (mt, 2H, CH ₂ -14); 2.40 (s, 3H: -COCH ₃ ); 2.55 [mt, 1H: > (CH) -H_6]; 3.49 (s, 3H: -COCH ₃ ); 3.78 (d, J = 7Hz, 1H: --H3); 3.89 (s, 3H: Ar 0CH _3); 4.17 [d, J = 8 Hz, 1H:> (CH) -H2O]; 4.24 (limiting ab, J = 16 Hz, 2H: -OCO-CH ₂ -O-); 4.31 [d, J = 8 Hz, 1H:> (CH) -H2O]; 4.64 (broad s, 1H: --H2 '); 4.95 (broad d, J = 10 Hz, 1H: --H5); 5.25 (broad d, J = 10 Hz, 1H:

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 37-Η 3 ′); 5.52 (d, J = 10 Hz, 1H: -CONH-); 5.64 (J = 7 Hz, 1H:

-H 2); 6.22 (t, J = 9 Hz, 1H: --H13); 6.40 (s, 1H: --H 10); 6.98 (d, J = 8.5 Hz, 2H: aromatic -H ortho to -OCH8); 7.25-7.45 (mt, 5H: -C ₆ H ₅ at 3 ') 8.05 (d, J = 8.5 Hz, 2H: aromatic -H in the meta position relative to -OCH ).

Example 7

0.200 g of [4α-acetoxy-1β, 7β-dihydroxy-5β, 20-epoxy-10β- (methoxyacetoxy) -2a- [4-methoxy (benzoyloxy)] -9-oxo-11α-taxen-13α -yl] - (2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate is dissolved in 15 ml of methanol at 20 [deg.] C. and 1 g is added in several portions. powdered 4 A molecular sieve and 0.700 g of zinc iodide. The solution is stirred for 5 hours and then 10 ml of distilled water are added. The reaction mixture was filtered and the precipitate was rinsed with ethyl acetate (5 mL) and distilled water (5 mL). The organic phase is separated by decantation, the aqueous phase is concentrated under reduced pressure and taken up in a mixture of 20 ml of ethyl acetate and 20 ml of distilled water. The combined organic layers were washed with 20 mL of saturated sodium thiosulfate solution and 20 mL of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). This gave 0.100 g of a yellow oil which was purified by preparative chromatography on a 2 mm silica gel plate eluting with a 95: 5 mixture of dichloromethane and methanol. In this way, 0.048 g of [4a-Acetoxy-5β, 20-epoxy-2a- [4-methoxy-benzoyloxy) -9-oxo-1β, 7β, 10β-trihydroxy-11-taxen-13a-yl] - ( 2R, 3S) -3 - [(tert-Butoxycarbonyl) V »·· • ·· · · ν · V * 9 # ♦« · * ·· 9 • * · · 9 · · · ··· ·· · «··« ν%

-amino] -2-hydroxy-3-phenylpropionate in the form of a white foam having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 1.14 (s, 3H: -CH3

obsession 17) ; 1.24 (s, 3H: _-CH3 16 or 17); 1.37 [s, 3H: - (CH ₃ ) ₃ ] _; 1.72 (S, 1H: -OH 1-position); [S, 3H: - (CH ₃ ) 3 19]; 1.75-1.90 [Mt, 1H > (CH) -H 6] ; 1.87 (s, 3H: - ch ₃ 18); 2.28 (d, J = 9 Hz,

2H: -CH ₂ - 14); 2.40 (s, 3H: -COCH 3); 2.61 [mt, 1H:> (CH) -H-6];

3.32 (d, J = 4.5 Hz, 1H: -OH at 2 '); 3.89 (s, 3H: -OCH3); 3.92

(D, J = 7Hz, 1H: -H 3); 3.89 (s, 3H: -OCH3); 3.92 (d, J = 7 Hz, 1H -H 3); 4.20 [d, J '= 8 Hz, 1H: > (CH) -H 2 O]; 4.21 (wide s, 1H -OH at position 10); 4.23 (mt, 1H: --H7); 4.33 [d, J = 8 Hz, 1H > (CH) -H 2 O]; 4.63 (mt, 1H: --H 2 '); 4.95 (broad d, J = 10 Hz, 1H: --H5); 5.21 ( broad s, 1H -H 10); 5.27 (wide d, J = = 10 Hz, 1H, 3 ¹ -H); 5.43 (d, J = 10 Hz, 1H: -CONH-); 5.67 (J = = 7 Hz, 1H: --H2); 6 23 (t, J = 9 Hz, 1H: --H 13); 6.98 (d, J = = 8, 5 Hz, 2H: aromatic -H is -OCH3-: ortho to); 7.25 -7.45 (mt, 5H: -ΟθΗβ at the 3 'position) 8.08 (d, J = 8.5 Hz, 2 H:

aromatic -H in the meta position relative to -OCH ₃ ).

Example 8

The procedure described in Example 6 was followed using the appropriate starting materials, such as [4a-acetoxy-5S, 20-epoxy-2- [4- (fluoro-benzoyloxy)] - 1S-hydroxy-10S- (methoxyacetoxy) ) -9-O-o-7β- (triethylsilyloxy) -11-taxen-13a-yl] - (2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxy) phenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate having the following characteristics:

• ·

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 0.60 (q, J = 7.5 Hz,

6H: -CH ₂ - ethyl); 0.94 (t, J = 7.5 Hz, 9H: -CH 3 ethyl); 1.08 (s, 9H: - (CH ₃ ) ₃ J; 1.18 (s, 3H: -CH ₃ 16 or 17); 1.19 (s, 3H: -CH ₃ or 17); 1.65 (s, 3H: _-CH3 19); 1.68 (s, 3H: _-CH3 18); 1.71 (s, 1H: --OH at position 1); 1.86 [mt, 1H:> (CH) -H 61; 1.87 (s, 3H: -COCH ₃ ); 2.09 and 2.18 (2dd, J = 16 and 9 Hz, 1H each: -CH ₂ ~ 14); 2.48 [mt, 1H:> (CH) -H 6]; 3.52 (s, 3H: -OCH ₃ ); 3.72 (d, J = 7Hz, 1H: -H 3); 3.81 ( s, 3H: Ar-OCH ₃ ); 4.09 [d, J = 8 Hz, 1H:> (CH) -H 2 O] 4.16 (ab limit, J = 16 Hz, 2H: -OCO-CH ₂ O); 4.19 [d, J = 8 Hz, 1H:> (CH) -H ₂ O] 4.43 (dd, J = 11 and 7 Hz, 1H: -H 7) 4.57 (d, J = 5.5 Hz, 1H: -H2 '); 4.85 (broad d, J = 10 Hz, 1H: -H5); 5.43 (d, J = 5.5 Hz, 1H: -H3 '), 5.60 (d, J = 7Hz, 1H: -H2), 6.06 (t, J = 9Hz, 1H: -H13), 6.39 (broad s) , 1H: -H 5 '); 6.43 (s, 1H: -H 10); 6.92 (d, J = 7.5 Hz, 2H: aromatic -H ortho to fluoro); 30-7.45 [mt, 7H: - CgHg a

3'-position and -CgHg at 5'-position (-H2 and -H6)]; 8.03 (d, J = 8.5 Hz, 2H: aromatic -Hs in the meta position relative to fluorine).

In the same manner as in Example 6, [4a-acetoxy-1E, 7S-dihydroxy-5S, 20-epoxy-2- [4- (fluoro-benzoyloxy)] - 10S-methoxy-acetoxy-9-oxo 11-Taxen-13a-yl] - (2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate having the following characteristics:

- NMR (400MHz, CDC1 _3, δ ppm): 1.15 (s, 3H: _-CH3 16 or 17); 1.27 (s, 3H: _-CH3 16 or 17); 1.35 [s, 9H: -C (CH ₃ ) ₃ ];

1.70 (s, 3H: _-CH3 19); 1.87 (s, 3H: _-CH3 18); 1.89 [mt, 1H:

> (CH) -H 61; 2.27 and 2.33 (2 dd, J = 17 and 9 Hz, 1H each: CH _2-14); 2.40 (s, 3H: -COCH ₃ ); 2.58 [mt, 1H: > (CH) -H61; 3.33 • · ·· ····

(extended mf, 1H: -OH at 2 '); 3.53 (s, 3H: -OCH3); 3.81 (d, J = 7 Hz, 1H -H 3); 4.17 [d, J = 8 Hz, 1H:> (CH) -H2O] ; 4.42 (Dd, J = 11 and 7 Hz, 1H: --H7); 4.66 (broad s, 1H: -H2 ') ; 4.96 (Dd, J = 10 and 1.5 Hz, 1H: --H5); 5.27 (broad d, J = 10 Hz, 1H: H 3 '); 5.37 (d, J = 10 Hz, 1H: -CNOH-); 5.66 (d, J = 7 Hz, 1H: : -H 2); 6.25 ( broad t, J = 8.5 Hz, 1H: -H13); 6.39 (s, 1H: -H 10); 7.19 (d, J = 8.5 Hz, 2H: aromatic -H relative to fluorine ortho position Section); 7 , 30-7.45 (mt, 5H: -CgHg at 3 '); 8.13 (dd, J =

= 8.5 and 6Hz, 2H: aromatic -H in the meta position relative to fluorine).

Example 9

In the same manner as in Example 7, [4a-acetoxy-5S, 20-epoxy-2a- [4-fluoro (benzoyloxy)] -9-oxo-1S, 7S, 10E-trihydroxy-11-taxen-11Sa ¹ -yl] - (2R, 4S) -3 - [(terbutoxycarbonyl) amino] -2-hydroxy-4-phenylpropionate having the following characteristics:

- NMR spectrum (400 nm) MHZ, CDCl3, , δ in ppm): 1.14 (s, 3H: _-CH3 16 obsession 17); 1.26 (s, 3H: -CH ₃ 16 or 17); 1.37 (s, 9H: - (CH ₃ ) ₃ ]; 1.63 (s, 1H: -OH) 1-position); 1.77 (s, 3H: -CH 3) 19); 1.86 [mt,

1H:> (CH) -H6]; 1.87 (s, 3H: _-CH3 18); 2.28 (d, J = 9Hz, 2H:

-CH ₂ - 14); 2.39 (s, 3H: _OCH3); 2.60 [mt, 1H:> (CH) -H-6]; 3.33 (unres. Comp., 1H: --OH at 2 '); 3.92 (d, J = 7Hz, 1H: --H3); 4.19 [d, J = 8 Hz, 1H:> (CH) -H2O]; 4.21 (bs, 1H: -OH at position 10); 4.4 (mt, 1H: --H7); 4.31 [d, J = 8 Hz, 1H:> (CH) -H2O]; 4.64 (broad S, 1H: --H2 '); 4.96 (broad d, J = 10 and 1.5 Hz, 1H: -H5); 5.21 (s, 1H: --H 10); 5.27 (broad d, J = 10 Hz, 1H: --H3 '); 5.43 (d,

J = 10 Hz, 1H: -CONH-); 5.67 (d, J = 10 Hz, 1H: --H2); 6.24 (t, J = 9 Hz, 1H: --H13); 7.19 (t, J = 8.5 Hz, 2H: aromatic -H ortho to flu41); 7.25-7.45 (mt, 5H: -CH2 at position 3 '); 8.12 (dd, J = 8.5 and 6 Hz, 2H: aromatic -Hs in the meta position relative to fluorine).

Example 10

The procedure described in Example 6 was followed using the appropriate starting materials, such as [4a-acetoxy-5β, 20-epoxy-2- [4- (trifluoromethyl) benzoyloxy] -10β-methoxyacetoxy). 9-O-7β- (triethylsilyloxy) -11-taxen-13a-yl] - (2R, 4S, 5R) -3- (terbutoxycarbonyl) -2- (4-methoxyphenyl) -4-Phenyl-1,3-oxazolidine-5-carboxylate is obtained, which has the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 0.60 (q, J = 7.5 Hz,

6H: -CH ₂ - ethyl); 0.96 (t, J = 7.5 Hz, 9H: -CH ₃ ethyl); 1.09 (s, 9H: - (CH3) _3]; 1.18 (s, 3H: --CH3 16 or 17); 1.20 (s, 3H: -CH3 or 17); 1.64 (s , 1H: -OH at position 1), 1.66 (s, 3H: -CH ₃₎

19); 1.68 (s, 3H: _-CH3 18); 1.86 [mt, 1H:> (CH) -H-6]; 1.90 (s,

3H: -COCH3); 2.11 and 2.19 (2 dd, respectively J = 15 and 9 Hz, 1H each: CH _2-14); 2.50 [mt, 1H:> (CH)-CH_θ1! 3.52 (s, 3H: -OCH3); 3.73 (d, J = 7Hz, 1H: --H3); 3.82 (s, 3H: _Ar-OCH3); 4.10 [d, J = 8 Hz, 1H:> (CH) -H2O]; 4.17 (limiting ab, J = 16 Hz, 2H: -OCO-CH ₂ -O-);

4.20 [d, J = 8 Hz, 1H:> (CH) -H2O]; 4.43 (dd, J = 11 and 7 Hz,

1H H 7); 4.58 (D, J = 5 Hz f 1H: -H2 '); 4.86 (wide d, J = 10 Hz, 1H : -H 5); 5.45 (D, J = 5 5 Hz, 1H: --H 3 '); 5.63 (d, J = 7 Hz, 1H : -H 2); 6.05 (T, J = 9 Hz, 1H: --H 13); 6.40 (wide and, 1H H 5 '); 6.45 (s, , 1H: H 10 ); 6.92 [d, J = 7.5 Hz, 2H: -c ₆ h ₅

at the 5 'position (-H 3 and -H 5)]; 7.35-7.45 [mt, 7H: C ₆ H ₅ at the 3'-position and 5 -position -CgHg of ¹ (-H 2 and -H 6)]; 7.76 (d, J = 8.5 Hz, ········· ·····

2Η: aromatic -H ortho to fluorine); 8.14 (d, J = 8.5 Hz, 2H: aromatic -H in the meta position relative to the fluorine).

In the same manner as in Example 6, [4a-acetoxy-1β, 7β, -dihydroxy-5β, 20-epoxy-2a- [4- (trifluoromethyl) benzoyloxy] -10β- (methoxyacetoxy) -9- oxo-11-taxen-13a-yl] - (2R, 4S) -3 - [(terbutoxycarbonyl) amino] -2-hydroxy-4-phenylpropionate having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 1.16 (s, 3H: -CH3 16 or 17); 1.28 (s, 3H: _-CH3 16 or 17); 1.32 (s, 9H: - (CH ₃ ) ₃ ) _;

1.70 (s, 3H: _-CH3 19); 1.85-1.95 [mt, 1H:> (CH) -H-6]; 1.90 (s,

3H: _-CH3 18); 2.31 (split limiting ab, J = 18 and 9 Hz, 2H: CH _2-14); 2.42 (s, 3H: -OCH3); 2.58 [mt, 1H: > (CH) -H61; 3.20 -

- 3.60 (extended mt, 1H: --OH at 2 '); 3.52 (s, 3H: -OCH3) 3.84 (d, J = 7Hz, 1H: -H3); 4.18 [d, J = 8 Hz, 1H:> (CH) -H

20]; 4.26 (limiting ab, J = 16 Hz, 2H: OCOCH ₂ O); 4.28 [d, J = 8

Hz, 1H:> (CH) -H2O]; 4.43 (dd, J = 11 and 7 Hz, 1H: --H7); 4.68

(broad s, 1H: --H2 ¹⁾ ); 4.96 (wide d, J = 10 Hz, 1H: -H 5); 5.30 (broad d, J = 10 Hz, 1H: -H3 '); 5.42 (d, J = 1 0 Hz, 1H -CONH-); 5.67 (d, J = 10 Hz , 1H: -H2) ; 6.28 (t, J = 9 Hz, 1H -H 13); 6.40 (s,: 1H : -H 10) ; 7.30-7.45 (mt, 5H: -C ₆ H ₅ the 3 ' - He- lyen); 7.79 (d, J = 8.5 Hz, 2H: aromatic -H for fluorine compared guard

to-position); 8.24 (d, J = 8.5 Hz, 2H: aromatic -Hs in the meta position relative to fluorine).

Example 11

The procedure described in Example 7 was followed to give [4a-acetoxy-5β, 20-epoxy-2a- [4- (trifluoromethyl) benzoyloxy] -9-χχο-1β, 7β, 10β ·

trihydroxy-11-taxen-13a-yl] - (2R, 4S) -3 - [(terbutoxycarbonyl) amino] -2-hydroxy-4-phenylpropionate having the following characteristics:

NMR (400 MHz, CDC1 _3, δ ppm): 1.14 (s, 3H: _-CH3 16 or 17); 1.26 (s, 3H:

-CH ₃ or 17); 1.34 (s, 9H: - (CH ₃ ) ₃ );

1.79 (s,

3H:

-CH ₃ 19);

1.80

1.95 [mt,

1H

> (CH) -H_6]; 1.89 (s,

3H: -CH ₃

2.28 (mt,

2 H:

-CH ₂ - 14);

2.42

2.61 [mt,

1H

> (CH) -H_6]; 3 (mf, 1H: -OH (d,

J = 7 Hz,

1H

4.35 (extended mf, 1H: --OH at position 10);

4.19 [d, J (mt,

1H

And,

1H

-H d, J = 10 Hz, 1H: -H

5); 5.21 (s,

1H

H

10); 5.30 (wide d,

5.41 (d, J

Hz,

1H

-CONH-); 5.68 (d, J = 7Hz, 1H: --H2)

7.30-7.45 (mt, 5H: --CgHg at 3 '); 7.80 aromatic -H relative to trifluoromethyl (d, J = 8.5 Hz, 2H:

ortho position);

meta-position relative to trifluoromethyl).

Example 12

The procedure described in Example 6 was followed using the appropriate starting materials, such as [4a-acetoxy-5S, 20-epoxy-2a- [2-fluoro (benzoyloxy)] - 16-hydroxy-106- (methoxyacetoxy) -9-O-o-7β- (triethylsilyloxy) -11-taxen-13a-yl] - (2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) ) -4-phenyl-1,3-oxazolidine-5-carboxylate is obtained, which has the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 0.60 (q, J = 7.5 Hz,

6H: -CH ₂ - ethyl); 0.94 (t, J = 7.5 Hz, 9H: -CH 3 ethyl); 1.10 (s,

9H: - (CH ₃ ) ₃ ]; 1.19 (s, 3H: --CH3 16 or 17); 1.68 (s, 3H: -CH ₃₎

19); 1.69 (s, 3H: _-CH3 18); 1.74 (s, 1H: --OH at position 1); 1.81

(S, 3H: -COCH3); 1.86 [mt, 1H:> (CH) -IL 6]; 2.17 and 2.22 (2 dd, = 15 and 9 Hz, 1H each : -CH ₂ - 14 ); 2.48 [mt, 1H > (CH) -H_6] 3.52 (s, 3H: -OCH3); 3.71 (d, J = 7 Hz, 1H: --H3); 3.82 (s, 3H: Ar-OCH ₃ ); 4.10 - 4.25 (mt, 4H: -OCO- CH ₂ O- and -CH ₂ - 20); 4.42 (Dd, J = 11 and 7 Hz, 1H: H 3); 4.58 (d, J = 5 Hz, 1H: -H2 '); 4.86 (wide d, J = 10 Hz, 1H: -H 5) ; 5.45 (very broad s, 1H -H 3 '); 5.67 (d, J = 7Hz, 1H: -H2) ; 6.08 (t, J = 9 Hz, 1H: -H 13); 6.40 (very wide s , 1H: -H 5 '); 6.45 (s, 1H) ,: -H 10);

6.92 [d, J = 7.5 Hz, 2H: _{C6 H5} at 5 '(--H 3 and --H 5)];

7.16 [mt, 1H: -C5H5 at position 2 (-H3)]; 7.35-7.45 [mt, 7H: -CH2] at the 3 'and -C5H5 at the 5' (-H2 and -H6)]; 7.58 [mt, 1H, C ₆ H ₅ in the 2-position (-H 4)]; 7.96 [dd, J = 8.5 and 8 Hz, 1H, C ₆ H ₅ in the 2-position (--H 6)].

In the same manner as in Example 6, [4a-acetoxy-1E, 7β, -dihydroxy-5β, 20-epoxy-2O - [2-fluoro (benzoyloxy)] -10β- (methoxyacetoxy) -9-oxo - 11-taxen-13a-yl] - (2R, 4S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-4-phenylpropionate having the following characteristics:

- NMR (400MHz, CDCl3, δ in ppm): 1.16 (s, 3H: _-CH3 16 or 17); 1.26 (s, 3H: -CH3 16 or 17); 1.40 (s, 9H: - (CH ₃ ) ₃ );

1.72 (s, 3H: -CH3 19); 1.88 (s, 3H: -CH3 18); 1.92 [mt, 1H:

> (CH) -H 61; 2.32 (s, 3H: _OCH3); 2.33 (mt, 2H: CH _2-14); 2.56 [mt, 1H: > (CH) -H61; 3.52 (s, 3H: -OCH3); 3.79 (d, J = 7Hz, 1H:

• · · ♦ · ·

-Η 3); 4.26 (limiting ab, J = 17 Hz, 2H: OCOCH ₂ O); 4.28 (limiting ab, J = 8 Hz, 2H: H _2-20); 4.40 (dd, J = 11 and 7 Hz, 1H: -H7); 4.61 (bs, 1H: -H2 '); 4.95 (broad d, J = 10 Hz, 1H: -H5); 5.24 (broad d, J = 10 Hz, 1H: --H3 '); 5.47 (d, J = 10 Hz, 1H: -CONH-); 5.70 (d, J = 7Hz, 1H: -H2); 6.19 (broad t, J = 9 Hz, 1H: -H 13); 6.38 (s, 1H: -H 10); 7.20 [dd, J = 10.5 and

8.5 Hz, H: ₅ -CgH the 2-position (3-H)]; 7.28 [t, J = 8.5 Hz, 1H: -CgH ₃ at position 2 (-H 5)]; 7.35-7.45 (mt, 5H: --CgH5 at 3 ');

7.60 [m, H -C ₆ H ₅ in the 2-position (-H 4)]; 8.03 (dd, J = 8.5 and

Hz, 1H: -C ₆ H _{5 at} the 2-position (-H 6)].

Example 13

[4 '-acetoxy-5S, 20-epoxy-2' - [2-fluoro (benzoyloxy)] -9-o-o-1β, 7β, 10E-trihydroxy-11a-taxene-13a as in Example 7. 1-yl] - (2R, 4S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-4-phenylpropionate having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ ppm): 1.13 ( s, 3H: -CH ₃ li or 17); 1.24 (s, 3H: _-CH3 16 or 17); 1.3 8 (s, 9H: - (CH ₃ ) ₃ ]; 1.73 (s, 1H: -OH at position 1); 1.78 (s, 3H: -CH3 19); 1.84 (s, 3H: -CH3 18); 1.85 [mt, 1H:> (CH) -H_6]; 2.30 (mt, 2H: -CH ₂ - 14); 2.58 [mt, 1H:> (CH) -H-6]; 3.43 (d, J = 5.5 Hz, 1H: -OH (2-n); 3.90 (d, J = 7Hz, 1H: -H3); 4.23 (s broad, 1H: -OH at position 10); 4.23 (mt, 1H-H7); 4.28 (ab limit, J = 9 Hz, 2H: -CH ₂ - 20); 4.60 (bs, 1H: -H2 '); 4.94 (dd, J = 10 and 1, 5 Hz, 1H: -H 5); 5.21 (s, 1H (-H 10); 5.25 (broad d, J = 10 Hz) , 1H: --H3 '); 5.49 (d, J = 10 Hz, 1H: -CONH-); 5.70 (d, J = 7Hz, 1H: -H2); 6.19 (t, J = 9 Hz, 1H: -H 13); 7.20 [dd, J = 10.5 and 8.5 Hz, 1H

-C ₆ H _{5 at} the 2-position (-H 3)]; 7.29 [t, J = 8.5 Hz, 1H: ₅ -CgH the 2-position (-H 5)]; 7.30 to 7.45 (mt, 5H: ₅ -CgH the 3'-position); 7.59 [mt, 1H: -CH2 in position 2 (-H4)]; 8.03 (dd, J = 8.5 and 8 Hz, 1H: -CH2 in position 2 (-H6)).

Example 14

In the same manner as in Example 6, [4a-acetoxy-1S, 7S, dihydroxy-5S, 20-epoxy-2a- [4-tert-butyl (benzoyloxy)] - 10β- (methoxyacetoxy) -9- oxo-11-taxen-13.alpha.-yl] - (2R, 3S) -3 - [(tert-butoxy)

-amino] -2-hydroxy-3-phenylpropionate having the following characteristics:

(s, 3H: _-CH3 16

NMR (400 MHz, CDC1 _3, δ ppm): 1.15

obsession 17); 1.28 (s, 3H: _-CH3 16 or 17); 1.35 (s, 18H: - (CH ₃ ) ₃ ]; 1.70 (s, 3H: _-CH3 19); 1.75 (s, 1H: -OH on 1); 1.88 (s, 3H: -CH ₃ 18); 1.90 [mt, 1H:> (CH) -H6]; 2.28 and 2.37 (2dd, J = 16 and

each (d, J

Hz,

1H

3.5 Hz, 1H: -OH a

3H:

-OCH ₃ ); 2.58 [mt, 1H: &gt;]

(CH) -H 61; 3.34 (d,

J = 5 Hz, 1H:

-OH a

21 ⁽ -n); 3.54

Hz, 1H: --H3); 4.19 [d, J = 8.5 limit, J = 16

Hz, 2H: OCOCH ₂ O-)

4.36 [d, J = 8.5 Hz, 1H:

1H: -H 7)

4.63

-H 2 '); 4

J = 10 Hz,

1H

-H 5); 5.28 (wide d,

J = 10 Hz

5.38 (d, J

Hz, 1H: -CONH-); 5.69 (d,

J = 7 Hz,

1H: -H 10); 7.30 to 7.45 (mt, 5H: ₆ -C ₅ H 3 -position ^1); 7.52 (d, J = 8.5 Hz, 2H: ortho to the ortho to the -C (CH ₃ ) 3); 8.05 (d, J = 8.5 for 2H: aromatic -H for -C (CH ₃ ) ₃ )

In the same manner as in Example 7, [4a-acetoxy-5f, 20-epoxy-2a- [4-nitro-benzoyloxy)] -β-hydroxy-10β-methoxy-acetoxy-9-οχο-7β- ( triethylsilyloxy) -11-taxen-13of-yl] - (2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2 - [(4-methoxy) phenyl] -4-phenyl- 1,3-oxazolidine-5-carboxylate having the following characteristics:

• · ·

relative to the meta-position).

Example 15

NMR (400 MHz, CDCl3, δ in ppm): 1.14 (s, 3H: _-CH3 16 or 17)

IH:

-OH on 1); 1.85 [mt, 1H:

> (CH) -H_6]; 1.86 (s,

2.42 (s,

3H:

5.5 Hz,

IH:

[d, J = 8

Hz,

4.25 (mt,

IH:

(mt, 1H: -H 2 (broad d, 1H:

5.46 (d,

6.25 (t, lo)

2.28 (ab limit, J

1H:> (CH) -H

-H 7); 4.36

-H 10);

J = 10 Hz, 1H:

J = 9 Hz, 1H:

and

Hz,

IH:

(D,

20]; 4.23 [d, J = 8> (CH) -H-6]; 3.38 (d,

J = 7 Hz, (broad

Hz, 1H:

and,

1H: -OH

IH: -H 5)

5.28 (broad d, J = 10 Hz, 1H:

-CONH-); 5.68 (d, J = 7Hz,

4.20

Position 10);

4.64

5.22

-H 3 ')

1H: -H

7.30-7.45 (mt, 5H: -C ₆ H ₅

-hexane; 7.52 (d, J = 8.5 Hz, 2H:

ortho to group); 8.04 (d, J = 8.5 2H: aromatic)

-H a

Example 16

The procedure described in Example 6 was followed using the appropriate starting materials, such as [4a-acetoxy-5B, 20-epoxy-2a- [4-nitro-benzoyloxy]] -hydroxy-105- (methoxyacetoxy) ) -9-oxo-75- (triethylsilyloxy) -11-taxen-13a-yl] - (2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxy) -phenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 0.59 (q, J = 7.5 Hz,

6H: -CH ₂ - ethyl); 0.93 (t, J = 7.5 Hz, 9H: -CH 3 ethyl); 1.07 (s,

9H: - (CH ₃ ) ₃ ]; 1.17 (s, 3H: _-CH3 16 or 17); 1.19 (s, 3H: --CH3 ₎

or 17); 1.64 (s, 3H: _-CH3 19 and 18-CH3); 1.83 [mt, 1H:

> (CH) -H_6]; 1.90 (s, 3H: -OCH3); 2.07 and 2.18 (2 dd, J = 16 and 9)

Hz, each 1H: -CH ₂ - 14); 2.49 [mt, 1H: > (CH) -H61; 3.52 (s, 3H: -COCH 3); 3.72 (d, J = 7Hz, 1H: --H3); 3.82 (s, 3H: _Ar-OCH3), 4.06 [d, J = 8.5 Hz, 1H:> (CH) -H 20]; 4.16 (limiting ab, J = 16 Hz, 2H: OCOCH ₂ O); 4.16 [d, J = 8.5 Hz, 1H:> (CH) -H-20]; 4.41 (dd, J = 11 and 7 Hz, 1H: --H7); 4.58 (d, J = 6Hz, 1H: --H2 '); 4.86 (broad d, J = 10 Hz, 1H: --H5); 5.43 (unres. Comp., 1H: --H3 '); 5.61 (d,

J = 7 Hz, 1H: -H2); 6.03 (broad t, J = 9 Hz, 1H: --H13); 6.40 (unres. Comp., 1H: -H5 '); 6.43 (s, 1H: --H 10); 6.92 [d, J = 8.5 Hz, 2H:

-C ₆ H _{5 at} the 5 '(-H 3 and -H 5)]; 7.41 [d, J = 8.5 Hz, 2H:

-ΟςΗβ at the 5 'position (-H 2 and -H 6)]; 7.42 (mt, 5H: --CgH5 at 3 '); 8.18 (d, J = 8.5 Hz, 2H: aromatic -H in the meta position relative to the nitro group); 8.32 (d, J = 8.5 Hz, 2H: aromatic -H ortho to the nitro group).

In the same manner as in Example 6, [4a-acetoxy-15,75-dihydroxy-55,20-epoxy-2- [4- (nitro-benzoyloxy)] -105-methoxy-acetoxy-9-oxo-11 taxen-13.alpha.-yl] - (2R, 3S) -3 - [(tert-butoxy carbonyl-carbonyl) -amino]

-2-hydroxy) -3-phenylpropionate having the following characteristics:

- NMR (400MHz, CDCl3, δ in ppm): 1.15 (s, 3H: _-CH3 16 or 17); 1.25 (s, 3H: --CH3 16 or 17); 1.35 (s, 9H: - (CH 3) 3);

1.67 (s, 1H: -OH at position 1); 1.78 (s, 3H: -CH3 19); 1.87 [mt, 1H:

> (CH) -H_6]

1.90 (s, 3H: _-CH3 18); 2.28 and 2.34 (2 dd, J and

Hz, each 1H: -CH ₂ - 14); 2.30 (d, J

Hz, 1H: -OH at position 7); 2.43 (s, 3H: -COCH 3); 2.62 [mt, 1H: > (CH) -H_6]; 3.32 (mf,

1H -OH a 2'-n); 3.96 (d, J = 7Hz, 1H: -H3); 4.20 [d, J = 8.5 Hz, 1H:> ( CH) -H_ 20] ; 4.23 (wide s, , 1H: -OH at position 10); 4.25 (mt, 1H -H 7); 4.26 [D, J = 8, 5 Hz, 1H: > (CH) -H_20]; 4.68 (mt, 1H:

-H 2 '); 4.96 (broad d, J

Hz, 1H: --H5); 5.22 (wide S,

1H: -H 10); 5.31 (broad d, J = 10 Hz, 1H: --H3 '); 5.41 (d, J = 10 Hz, 1H: -CONH-); 5.69 d, J

Hz, 1H: --H2); 6.27 (t,

Hz, 1H: --H 13); 7.30-7.50 [mt, 5H: C ₆ H ₅ at the 3'-position; 8.30 (d, J = 8.5 Hz, 2H: aromatic -H is a meta relative to the nitro group

-position); 8.38 (d, J = 8.5 Hz, 2H: aromatic -H ortho to the nitro group).

17, Example

[4 '-acetoxy-5B, 20-epoxy-2' - [4-nitro-benzoyloxy) -9-o-o-1β, 7β, 10S-trihydroxy-11-taxen-13a was prepared as described in Example 7. ? -yl] - (2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate having the following characteristics:

- NMR (400MHz, CDCl3, δ in ppm): 1.15 (s, 3H: _-CH3 16 or 17); 1.25 (s, 3H: _-CH3 16 or 17); 1.35 (s, 9H: - (CH ₃ ) ₃ );

1.67 (s, 1H: -OH at position 1); 1.78 (s, 3H: _-CH3 19); 1.87 [mt, 1H:

> (CH) -H 61; 1.90 (s, 3H: _-CH3 18); 2.28 and 2.34 (2 dd, J = 16 and

Hz, each 1H: -CH ₂ - 14); 2.30 (d, J = 2Hz, 1H: -OH at 750)

-I); 2.43 (s, 3H: -COCH 3); 2.62 [mt, 1H: > (CH) -H_6] ; 3.32 (Mf, 1H -OH (2'-n); 3.96 (d, J = 7 Hz, 1H: - H 3 ); 4.20 [d, J = 8 Hz, 1H:> (CH) -H2O]; 4.23 (wide s, 1H: OH the 10th ); 4.25 (Mt, 1H -H 7); 4.26 [d, J = 8 Hz, 1H:> (CH) -H 20 1; 4.68 (mt, 1H : -H 2 ') ; 4.96 (broad d, J = 10 Hz, 1H: -H5) ; 5 22 (wide s, 1H H 10); 5.31 (broad d, J = 10 Hz, 1H: -H 3 ' ); 5.41 (d, J = 10 Hz, 1H: -CONH-); 5.69 (d, J = 7 Hz, 1H: H 2); 6.27 (t, J = 9 Hz, 1H: -H 13); 7.30-7.50 (mt, 5H: -CgH ₅ the 3 '-Position); 8.30 (D,

J = 8.5 Hz, 2H: aromatic -H in the meta position relative to the nitro group); 8.38 (d, J = 8.5 2H: aromatic -H ortho to the nitro group).

Example 18

The procedure described in Example 6 was followed using the appropriate starting materials, such as [4a-acetoxy-5S, 20-epoxy-2a- [4-ethyl-benzoyloxy]] - 1S-hydroxy-β- (methoxyacetoxy) ) -9-O-o-7β- (triethylsilyloxy) -11-taxen-13a-yl] - (2R, 4S, 5R) -3- (terbutoxycarbonyl) -2- (4-methoxy) phenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ ppm): 0.58 (q, J = 7.5 Hz,

6H: -CH ₂ - ethyl); 0.93 (t, J = 7.5 Hz, 9H: -CH 3 ethyl); 1.07 (s,

9H: ~ (CH ₃ ) ₃ ]; 1.17 (s, 3H: --CH3 16 or 17); 1.19 (s, 3H: -CH 3 or 17); 1.29 (t, J = 7.5 Hz, 3H: Ar-CH ₂ -CH _3); 1.65 (s, 3H: _-CH3 19); 1.67 (s, 3H: -CH3 18); 1.70 (s, 1H: -OH at position 1); 1.84 (s, 3H: -OCH3); 2.09 and 2.18 (2 dd, respectively J = 16 and 9 Hz, 1H each: CH _2-14); 2.74 (t, J = 7.5 Hz, 2H: Ar-CH ₂ ethyl); 3.51 (s, 3H: -OCH3); 3.70 (d, J = 7Hz, 1H: --H3); 3.82 (s, 3H: _Ar-OCH3);

4.09 [d, J = 8 Hz, 1H:> (CH) -H2O];

4.17 (ab limi

2H: -OCOCH ₂ O-); 4.25 [d, J = 8.5

Hz,

J = 11 and 7 Hz, 1H: -H 7)

4.57 (d,

J = 5 Hz, 1H:

(broad d, J = 10 Hz, 1H:

5.41 (mf,

1H

J = 7 Hz,

Hz, (mf, 1H:

-H 5 '); 6.44 (s,

1H: -H 10); 6.92 [d,

-CgH ₅ is

At the 5 'position (-H 3 and -H 5)]; 7.30 (d, J other -H ortho to ethyl);

8.5 Hz,

2H: -C ₆ H ₅ in 5

-CgH ₃ a 3

-position); 7.95 (d, J = 8 Hz, 2H: aromatic)

H

1H

t, J = 16 Hz, .20]; 4.42 (Dd, -H 2 '); 4 , 86 : 3 '); 5.61 (D, H 13); 6.39 = 8.5 Hz, 2 H: 8 Hz, 2 H: aromatic 7.40 [D, J = 7.41 (Mt, 5H: -H a food 1-

ortho to group).

In the same manner as in Example 6, [4a-acetoxy-1 H, 7S-dihydroxy

-5S, 20-Epoxy-2- [4-ethyl-benzoyloxy] -10S- (methoxyacetoxy) -9-2-hydroxy) -3-phenylpropionate having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 1.16 (s, 3H: -CH3 16 or 17); 1.26 (s, 3H: _-CH3 16 or 17); 1.28 (t, J = 7.5 Hz, 3H: -CH ₃ ethyl); 1.35 (s, 9H: - (CH ₃ ) ₃ 1; 1.70 (s, 3H: -CH ₃ 19); 1.76 (s, 1H: -OH in 1); 1.88 ( s, 3H: _-CH3 18); 1.90 [mt, 1H:

> (CH) -H 6]; 2.30 (limiting ab, J = 16 and 9 Hz, 1H each: _CH2 14); 2.38 (d, J = 4.5 Hz, 1H: -OH at position 7); 2.41 (s, 3H: -COCH 3);

2.58 [mt, 1H:> (CH) -H-6]; 2.74 (q, J = 7.5 Hz, 2H: Ar-CH ₂ -ethyl);

3.35 (d, J = 4Hz, 1H: --OH at 2 '); 3.53 (s, 3H: -COCH 3); 3.80 (d, J = 7Hz, 1H: --H3); 4.18 [d, J = 8.5 Hz, 1H:> (CH) -H 201;

4.26 (limiting ab, J = 16 Hz, 1H, OCOCH ₂ O); 4.34 [d, J = 8.5 Hz,

1H:> (CH) -H 201; 4.43 4.25 (mt, 1H: --H7); 4.64 (mt, 1H: --H2 ');

4.96 (broad d, J = 10 Hz, 1H: --H5); 5.27 (broad d, 1H: -H

3 '); 5.39 (d, J = 10 Hz, 1H: -CONH-); 5.67 d, J = 10 Hz,

1H: -H2); 6.24 (t, J = 9 Hz, 1H: --H13); 6.40 (s, 1H: --H 10);

7.34 (d, J = 8 Hz, 2H: aromatic -H ortho to the ethyl group)

-position); 7.30-7.45 (mt, 5H: --C5H5 at position ³¹ ); 8.03 (d, J = 8

Hz, 2H: aromatic -H in meta position with respect to ethyl).

Example 19

In the same manner as in Example 7, [4a-acetoxy-5S, 20-epoxy-2a- [4-ethyl-benzoyloxy)] -9-o-o-1β, 7β, 10β-trihydroxy-11-taxen-13o'- il] - (2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenyl-propionate having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 1.14 (s, 3H: -CH3 16 or 17); 1.26 (s, 3H: _-CH3 16 or 17); 1.28 (t, J = 7.5 Hz, 3H:

-CH ₃ ethyl); 1.38 (s, 9H: - (CH ₃ ) ₃ ); 1.70 (s, 1H: -OH in 1);

1.78 (s, 3H: -CH3 19); 1.85 [mt, 1H:> (CH) -H-6]; 1.86 (s, 3H:

-CH ₃ 18); 2.28 (limiting ab, J = 16 and 9 Hz, 2H: CH _2-14); 2.38 (s, 3H: -COCH 3); 2.60 [mt, 1H:> (CH) -H-6]; 2.73 (q, J = 7.5 Hz,

2H: Ar-CH ₂ -ethyl); 3.35 (unres. Comp., 1H: --OH at 2 '); 3.91 (d, J = 7Hz, 1H: --H3); 4.20 [d, J = 8.5Hz, 1H:> (CH) -H2O]; 4.23 (wide s,

1H: -OH at position 10); 4.25 (mt, 1H: --H7); 4.34 [d, J = 8.5 Hz, 1H:> (CH) -H2O]; 4.64 (mt, 1H: --H2 '); 4.96 (broad d, J = 10 Hz, 1H: --H5); 5.21 (broad s, 1H: -H10); 5.27 (broad d, J = 10 Hz, 1H: --H3 '); 5.45 (d, J = 10 Hz, 1H: -CONH-); 5.67 (d, J = 7Hz, 1H: --H2); 6.22 (t, J = 9 Hz, 1H: --H13); 7.33 (d, J = 8.5 Hz, 2H: aromatic -H ortho to ethyl);

7.30 to 7.45 (mt, 5H: C ₆ H ₅ at the 3'-position); 8.03 (d, J = 8.5 2H:

aromatic -H in the meta position relative to ethyl).

Example 20

The procedure described in Example 6 was followed using the appropriate starting materials, such as [4-ol-acetoxy-5β, 20-epoxy-2α- [pentafluorobenzoyloxy] -1B-hydroxy-β-methoxyacetoxy]. -9-oxo-7β- (triethylsilyloxy) -11-taxen-13a-yl] - (2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxy- Phenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate is obtained having the following characteristics:

NMR (400 MHz, CDC1 _3, δ ppm): 0.57 (q, J = 8 Hz,

3H: -CH ₃

-OH on 1); 1.67 (s, 9H:

-CH ₃ 19,

-CH ₃ 18 and -CO-CH ₃ ); 1.86 [mt, 1H:

> (CH) -H 6]; 2.05 and 2.19 (2 dd, J = 16 and

Hz, each 1H:

-CH ₂ - 14);

[mt, 1H: > (CH) -H6]; 3.52 (s, 3H:

-OCH ₃ );

2.48

3.68 (d, J

4.16 (ab limit, J

Hz, 2H: CH _2-20); 4

7 Hz, 1H: -H 3); 3.82 (S, 16 Hz, 2H: -OCOCH ₂ O-); 4.18 38 (dd, J = 11 and 6.5 Hz, H 2 '); 4, 82 (wide d, J =

3H:

1H

(ab limit, J = 8

H

Hz, (d, J = 5.5 Hz, 1H:

5.40 (unres. Comp., 1H: -H 3 ') ; 5 62 (d, J = 7 Hz, 1H: --H2); 6.07 (broad t, J = 9 Hz, 1H: H 13); 6.37 (mf, 1H: -H5 '); 6.43 (s, 1H: -H 10); 6, 92 [d, J = 8.5 Hz, 2H: - CgH5 at position 5 ' (-H 3 and -H 5)]; 7.35 - 7, 45 [Mt, 2H: -C ₆ H ₅ at the 3'-position and -C 5H5 to 5'- in place (-H 2 and H 6)].

[4a-Acetoxy-1B, 7B-dihydroxy-5S, 20A

taxen-13.alpha.-yl] - (2R, 3S) -3 - [(tert-butoxy carbonyl-carbonyl) -amino] -254

-hydroxy) -3-phenylporionate having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 1.14 (s, 3H: -CH3

or 17) ; 1.27 (s, 3Η: -CH3 16 or 17); 1.42 (s, 9H: - (CH ₃ ) ₃ ]; 1.68 (S, 1H: -OH at 1 .); 1.72 (s, 3H: -CH ₃ 19); 1.85 (s, 3H: -ch ₃ 18) ; 1.91 [mt, 1H: > (CH) -H_6]; 2.20 (s, 3H: -COCH ₃ ); 2 , 23 and 2, 35 (2dd, J = 16 and 9 Hz each 1H: -CH ₂ - 14); 2.38 (D,

J = 4 Hz, 1H: -OH at position 7); 2.57 [mt, 1H:> (CH) -H-6]; 3.39 (d, J = 4 Hz, 1H: --OH at 2 '); 3.53 (s, 3H: -COCH 3); 3.78 (d, J = 7

Hz, 1H: --H3); 4.27 (limiting ab, J = 16 Hz, 1H, OCOCH ₂ O); 4.30

(ab limit, J = 8.5 Hz, 1H: -CH ₂ - 20); 4.39 (Mt, 1H: -H 7) ; 4, 57 (mt, 1H: --H2 '); 4.94 (wide d, J = 10 Hz, 1H -H 5); 5 19 (broad d, 1H) : -H 3 ¹ ); 5.35 (d, J = 10 Hz, 1H -CONH-); 5 , 68 d. J = 7 Hz, 1H: -H 2); 6 , 16 (t, J = 9 Hz, 1H: H 13); 6.38 (S, 1H -H 10); 7,30- 7.45 (mt, 5H: -C ₆ H ₅ a 3'-n).

Example 21

In the same manner as in Example 7, [4a-acetoxy-5S, 20-epoxy-2a- [pentafluoro (benzoyloxy)] - 10S- (methoxyacetoxy) -9-χχο-1β, 7β, 10S-trihydroxy-11 -taxen-13a-yl] - (2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylporionate having the following characteristics:

Nuclear Magnetic Resonance Spectrum (400 MHz, CDCl3, δ in ppm): 1.12 (s, 3H: --CH3 16 or 17); 1.26 (s, 3H: -CH3 16 or 17); 1.43 [s, 9H: - (CH ₃ ) ₃ ];

1.68 (s, 1H: -OH at position 1); 1.78 (s, 3H: -CH3 19); 1.75-1.91 [mt,

1H:> (CH) -H-6]; 1.83 (s, 3H: _-CH3 18); 2.19 (s, 3H: -COCH ₃ );

2.20 and 2.29 (2 dd, J = 16 and 9 Hz, 1H each: CH _2-14); 2.58

[mt, 1H: > (CH) -H61; 3.88 (d, J = 7Hz, 1H: --H3); 4.15-4.30 (unres. Mult., 1H: -OH at position 10); 4.22 (mt, 1H: --H7); 4.30 (ab limit, J = 8.5 Hz, 1H: -CH ₂ - 20); 4.55 (mt, 1H: --H2 '); 4.93 (wide d,

J = 10 Hz, 1H: -H5); 5.19 (broad d, J = 10 Hz, 1H: --H3 ');

5.20 (bs, 1H: -H10); 5.45 (d, J = 10 Hz, 1H: -CONH-);

5.68 d, J = 7 Hz, 1H: --H2); 6.15 (t, J = 9 Hz, 1H: --H13);

7.30-7.45 (mt, 5H: -C ₆ H ₅ at 3 ').

Example 22

The procedure described in Example 6 was followed using the appropriate starting materials, such as [2a, 4a-diacetoxy-1S, 7S-dihydroxy-5S, 20-epoxy-10S-methoxy-acetoxy] -9-oxo-11-taxene. 13a-yl] - (2R, 4S, 5R) -3- (tert-butoxycarbonyl) -2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate having the following characteristics: the next ones:

- NMR (400MHz, CDCl3, δ in ppm): 0.59 (q, J = 7.5 Hz, 6H: -CH ₂ - ethyl); 0.92 (t, J = 7.5 Hz, 9H: -CH 3 ethyl); 1.09 (s,

9H: - (CH ₃ ) ₃ ]; 1.14 (s, 3H: --CH3 16 or 17); 1.16 (s, 3H: -CH ₃ or 17); 1.58 (s, 1H: -OH at position 1); 1.60 (s, 3H: -CH3 19); 1.66 (s, 3H: _-CH3 18); 1.82 (s, 3H: -CO-CH3 at position 4); 1.85 [mt,

1H:> (CH) -H 6 1; 1 95 2.03 (s, 3H: -COCH 3 on 2 n ); 2.18 [dd, J = = 16 and 9 Hz, 1H > (C ! H) -H-14] ; 2.47 [mt, 1H:> (CH) -H 6]; 3.51 (s, 3H: - OCH ₃ ); 3 , 60 (d, J = 7 Hz, 1H: --H3); 3 , 81 (s, 3H: Ar- -OCH3); 4 13 (ab Limi .t, J = 16 Hz, 2H: OCOCH ₂ O -); 4.15 [d, J = = 8 Hz, 1 H:> (CH) -N- 20]; 4.40 [d, J = 8 Hz, 1H :> (CH) -H 2 O]; 4.40 (mt, 1H H 7); 4.53 (d, J = 5 Hz, 1H: -H: 2 '); 4.86 (wide d, J = 10 Hz, 1H H 5); 5.35 (d, J = 7Hz, 1H) -H 2); 5.46 (d, J = 5 Hz, 1H H 3 '); 5.99 (t, J = 9 Hz, 1H: -H 13); 6.37 (s,

ΙΗ: -Η 5 ′); 6.40 (s, ΙΗ: -H 10); 6.92 [d, J = 8.5 Hz, 2H: -CgH5 at ₅ '(-H3 and -H5)]; 7.30-7.50 (mt, 5H: -CgHg at 3 '); 7.40 [d, J = 8.5 Hz, 2H: -CgHg at 5 '(-H2 and

-H 6)].

In the same manner as in Example 6, [2a, 4a-diacetoxy-1S, 7S-dihydroxy-5S, 20-epoxy-10S- (methoxyacetoxy) -9-oxo-11-taxen-13a-yl] - (2R, 3S) ) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenyl propionate having the following characteristics:

- NMR (400MHz, CDCl3, δ in ppm): 1.10 (s, 3H: _-CH3 16 or 17); 1.24 (s, 3H: _-CH3 16 or 17); 1.43 [s, 9H: - (CH ₃ ) ₃ J;

1.65 (s, 3H: _-CH3 19); 1.85 (s, 3H: -CH3 18); 1.90 [mt, 1H:

> (CH) -H 61; 2.13 (s, 3H: -COCH 3 on 2); 2.23 [mt, 1H: > (CH) -H

14]; 2.26 (s, 3H: -COCH 3); 2.36 [mt, 2H: --OH at position 7 and> (CH) --H

14]; 2.58 [mt, 1H: > (CH) -H61; 3.32 (d, J = 5.5 Hz, 1H: -OH a

2'-n); 3.53 (s, 3H: -COCH 3); 3.90 (d, J = 7Hz, 1H: --H3); 4.22 [d, J = 8.5 Hz, 1H: (CH) -H 2 O] -OCOCH 2 O-); 4.39 (mt, 1H: --H7)> (CH) --H2O]; 4.57 (dd, J = 5.5 d, J = 10 Hz, 1H: --H5); 5.20 (

5.37 (d, J = 10 Hz, 1H: -CONH-)

6.15 (t, J = 9 Hz, 1H: --H13);

(mt, 5H: --C ₆ H ₅ at 3 ').

; 4.25 (ab limit, J = 16 Hz, 2H:

; 4.50 [d, J = 8.5 Hz, 1H:

and 2 Hz, 1H: -H 2 '); 4, 96 (wide broad d, J = 10 Hz, 1H: -H 3 '); ; 5.41 d, J = 7 Hz, 1H: -H 2); 6.37 (s, 1H: -H 10); 7.30-7.45

Example 23

In the same manner as in Example 7, [2a, 4a-diacetoxy-1S, 7S-10S-trihydroxy-5E, 20-epoxy-9-oxo-11-taxen-13a-yl] - (2R, 3S) -3- [ (tert-Butoxycarbonyl) amino] -2-hydroxy-3-phenylpropionate

NMR (400 MHz, CDC1 _3, δ ppm): 0.59 (q, (t, J = 7.5 Hz, 9H: _CH3 of ethyl)

J = 7.5 Hz,

1.09 (s, (s, 1H: -OH at position 1);

3H: _-CH3 16 or 17); 1.16 (s,

1.60 (s, 3H:

; 1.66 (s,

3H:

19)

3H:

-CH ₃

1.58

-CH ₃

18);

1.85 [mt ,; 1.95 a

1.82 (s, 3H: --COCH ₃₎

1H:> (CH) -Η 6Ί

[dd, J = 16 and 9 Hz, 1H > (CH) - H 14]; 2.03 (s, 3H: -COCH ₃ at 2 n) 2.18 [dd, J = 16 and 9 Hz, 1H:> (CH) -H 14]; 2.47 [mt, 1H: > (CH) -H 6]; 3.51 (s, 3H: -OCH ₃ ) ; 3.60 (d, J = 7 Hz, 1H: -H3) f 3.81 (s, 3H : Ar-OCH ₃ ); 4, 13 (ab limit, J = 16 Hz, 2H: -OCOCH ₂ O-); 4.15 [d, J = 8 Hz, 1H:> (CH) -H2O] / 4.40 [d, J = 8 Hz, 1H:> (CH) -H2O]; 4.40 (Mt, 1H: -H7); 4.53 (d, J = 5 Hz, 1H -H 2 '); 4.96 (wide d, J = 10 Hz, 1H: --H5); 5 , 35 d, J = 7 Hz, 1H: -H2); 5.46 (sat les d , J = 10 Hz, 1H: -H 3 1 ); 5.99 (t, J = 9 Hz, 1H: -H 13); 6.37 (S, 1H: -H (5 ^L ); 6.40 (s, 1H: -H 10); 6.92 [d, J = 8.5 Hz, 2H: ' ^c 6S5 5 ¹ in place (-H 3 and -H 5)]; 7.30 -

-C ₆ H _{5 at} the 3 'position); 7.40 [d,

2 H:

/

7.50 (mt, 5H:

J = 8.5 Hz

The compounds of the present invention have significant activity against abnormal cell proliferation and their therapeutic properties allow their use in the treatment of patients with a pathological condition associated with abnormal cell proliferation. Pathological conditions include various tissues and / or organs such as muscle, bone or connective tissue, skin, brain, lung, genital, lymphatic and renal system, breast and blood cells, liver. , abnormal proliferation of malignant or non - malignant cells of the digestive tract, pancreas, thyroid and adrenal gland. Such pathological conditions may also include psoriasis, hard tumors, ovarian, uterine, brain, prostate, colon, gastric, kidney and testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma (syncytioma malignum), neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, multiple myeloma (Kahler or Huppert's disease), chronic lymphoid leukemia, acute and chronic granulocytic lymphomas (lymphoid tissues). The novel compounds of the invention are particularly useful in the treatment of ovarian cancer. The compounds of the present invention may be used to prevent or delay the onset or recurrence of a pathological condition or to treat such a pathological condition.

The compounds of the invention may be administered to the patient in a variety of forms, depending on the route of administration chosen, most preferably parenteral. Parenteral routes of administration include intravenous, intraperitoneal, intramuscular and subcutaneous administration. Intraperitoneal and intravenous administration are particularly preferred.

The present invention further relates to pharmaceutical compositions containing at least one compound of formula (I) in an amount sufficient for human or veterinary use. The compositions may be formulated in conventional manner using one or more pharmaceutically acceptable excipients, liquid or solid carriers. Liquid carriers may be diluents, sterile aqueous media or various non-toxic solvents. Preferably the formulations are in the form of an aqueous solution, suspension or injectable solution, which may also contain emulsifying, coloring, preservative or stabilizing agents.

The excipient or carrier will be selected according to the solubility and chemical properties of the compound, the route of administration and general pharmaceutical practice.

For parenteral administration, sterile aqueous or nonaqueous solutions or suspensions are used. Non-aqueous suspensions may be prepared using natural vegetable oils, such as olive or sesame oil, paraffin oil, or injectable organic esters, such as ethyl oleate. Sterile aqueous solutions may consist of an aqueous solution of a pharmaceutically acceptable salt. Aqueous solutions are preferably administered intravenously, since their pH is readily adjustable and isotonicity can be achieved with a sufficient amount of sodium chloride or glucose. Sterilization may be accomplished by heating or by any other method that does not alter the composition of the composition.

It is an obvious requirement that all substances in the composition of the invention are pure and non-toxic in the amounts used.

The composition comprises at least 0.01% of a therapeutically active compound. The formulation contains enough active ingredients to determine the appropriate dosage. Preferably, the composition is formulated so that a unit dosage form for parenteral administration contains between 0.01 and 1000 mg of the active ingredient.

The therapeutic treatment may be used in combination with other therapeutic treatments; for example, antineoplastic drugs, drugs containing monoclonal antibodies, immuno-or radiotherapies, or biological response modifiers. The latter include lymphokines and cytokines such as interleukins, interferons (ο?, Β or δ) and TNF. Other chemotherapeutic agents useful in the treatment of abnormal cell proliferation disorders include alkylating agents such as nitrogen mustards such as mechlorteamine, cyclophosphamide, melphalan and chlorambucil; alkyl sulfonates such as busulfan; nitroso compounds such as carmustine, lomustine, semustine, streptozocin; triazides such as dacarbazine; antimetabolites such as folate analogs such as methotrexate; pyrimidine analogs such as fluorouracil or cytarabine; purine analogs such as mercaptopurine or thioguanine natural substances such as vinca alkaloids such as vinblastine, vincristine and vendesin; epipodophyllotoxins such as etoposide or teniposide; antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin or mitomycin; enzymes such as L-asparaginase; various agents, such as platinum coordination complexes such as cisplatin substituted ureas such as hydroxyurea; methylhydrin derivatives such as procarbazine; adrenocorticoid suppressors such as mitotane or aminoglutethimide; hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxo-progesterone caproate, methoxy-progesterone acetate, or esto-61 acetate; estrogens such as diethylstibestrol or ethenylestradiol; anti-estrogens such as tamoxifen; androgens such as testosterone propionate or fluoxymasterone.

In carrying out the methods of the present invention, doses are used which allow prophylactic treatment or to achieve the maximum therapeutic response. The dosage will vary depending on the route of administration employed, the compound chosen and the characteristics of the subject being treated. Generally, doses will be used which are effective in treating diseases caused by abnormal cell proliferation. The compounds of the invention are administered at a frequency necessary to achieve the desired therapeutic effect. Some patients respond quickly to relatively strong or weak doses, then the maintenance dose may be low or zero. Generally, low doses are used at the beginning of the treatment, then the dose is gradually increased until the optimum effect is achieved. In some patients, depending on the physiological needs of the patient, the maintenance dose may need to be administered 1 to 8 times daily, preferably 1 to 4 times daily. In other patients, twice daily dosing may be sufficient.

Doses in humans generally range from 0.01 to 200 mg / kg. Intraperitoneally, doses of 0.1 to 100 mg / kg, preferably 0.5 to 50 mg / kg, more preferably 1 to 10 mg / kg are generally administered. Dosages for intravenous administration are generally between 0.1 and 50 mg / kg, preferably between 0.1 and 5 mg / kg, more preferably between 1 and 2 mg / kg. The appropriate dosage will, of course, be determined by the mode of administration, the patient's body weight, general health, age and all factors that may affect the effectiveness of the treatment.

The following example shows the composition of a composition according to the invention.

Example

40 mg of the compound of Example 1 are dissolved in a mixture of 1 ml of Emulphor EL 620 and 1 ml of ethanol and diluted with 18 ml of physiological serum.

The formulation is administered as an infusion of saline over 1 hour.

Claims (13)

PATENT CLAIMS 1. New taxoids of the formula I in the formula Ar is aryl; R is hydrogen, acetyl or alkoxyacetyl; R] _ is benzoyl or R2-O-CO- group of formula wherein R ₂ is - straight or branched chain alkyl of 1 to 8 carbon atoms, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, or C 7 -C 11 bicycloalkyl, which may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1 -C4 alkoxy, both alkyl having C1 -C4 dialkylamino, piperidino, morpholino, 1-piperazinyl optionally substituted in position 4 with a C1 -C4 alkyl group or a C1 -C4 alkyl group substituted with phenylalkyl, - (C 3 -C 6) cycloalkyl, (C 4 -C 6) cycloalkenyl, phenyl, cyano, carboxy or alkoxycarbonyl (C 1 -C 4) -alkyl, or - phenyl optionally substituted with one or more atoms or groups, namely, halogen, (C 1 -C 4) -alkyl or (C 1 -C 4) -alkoxy; or a saturated or unsaturated 4- to 6-membered heterocyclic ring optionally substituted with one or more C 1 -C 4 alkyl groups; and R ₃ is C 1 -C 8 straight or branched alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, or C 7 -C 11 bicycloalkyl, which are optionally with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-4 alkoxy, both alkyl having C 1-4 dialkylamino, piperidino, morpholino, 1-piperazinyl optionally substituted with and substituted with one C 1 -C 4 alkyl or a C 1 -C 4 alkyl-substituted phenyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, or phenyl optionally substituted with one or more substituents cyano, substituted with a carboxy or alkoxycarbonyl group having 1 to 4 carbon atoms in the alkyl moiety, or - an aryl group substituted with one or more atoms or groups, namely, halogen, C 1-4 alkyl or C 1-4 alkoxy, with the proviso that R 3 is other than unsubstituted phenyl, or - a saturated or unsaturated 4- to 6-membered heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of halogen, C1 -C4 alkyl and C1 -C4 alkoxy, wherein the above cycloalkyl, cycloalkenyl - and bicycloalkyl groups are optionally substituted with one or more C 1-4 alkyl groups. The novel taxoids of claim 1 having the formula R and R 1 are as defined in claim 1; the aryl groups at the Ar and R 3 substituents are phenyl, α, or β-naphthyl, optionally substituted with one or more substituents selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino- , arylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro or trifluoro- substituted with a methyl group, wherein the alkyl moieties of the alkyl groups and the other groups contain from 1 to 4 carbon atoms, the alkenyl and alkynyl groups contain from 2 to 8 carbon atoms, the aryl groups are phenyl or a or β-naphthyl and R3 is not substituted phenyl, and the heterocyclic groups at the Ar or R3 site are five-membered aromatic heterocyclic moieties having one or more identical or different heteroatoms, they contain one or more substituents selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), (C 1 -C 4) alkyl, (C 6 -C 10) aryl, C4 -C4 alkoxy, C6 -C10 aryloxy, amino, C1 -C4 alkylamino, both alkyl groups having C1 -C4 dialkylamino, C1 -C4 alkyl acylamino, Alkoxycarbonylamino, (C4-C4) alkyl, acyl (C1-C4), arylcarbonyl (C6-C10), cyano, nitro, trifluoromethyl, carboxy, carbamoyl, (C1-C4) alkylcarbamoyl containing both alkyl groups They are substituted with C 1-4 dialkylcarbamoyl or C 1-4 alkoxycarbonyl. The novel taxoids of claim 1, wherein R and R 1 are as defined in claim 1; Ar is phenyl, 2- or 3-thienyl, 2- or 3-furyl or 2-, You are 4- 5-thiazolyl optionally substituted with one or more identical or different atoms or groups, such as halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxy; substituted with a carbonylamino or trifluoromethyl group, and R ₃ is a phenyl group having one or more identical or different atoms or groups, namely, halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino -, acylamino, alkoxycarbonylamino, nitro or trifluoromethyl - or 2- or 3-thienyl, 2- or 3-furyl or 2-, 4- or 5-thiazolyl optionally substituted with one or more identical or different atoms or groups, namely halogen, alkyl, alkoxy, amino, alkyl-amino, dialkyl-amino, acyl-amino, • · · · · · ········································································ ·· · Λ - substituted with 67 alkoxycarbonylamino or trifluoromethyl groups. 4. The novel taxoids of claim 1 having the formula R is hydrogen, acetyl or methoxyacetyl -group; Price is phenyl; ^R i is benzoyl or tert-butoxycarbonyl; and ^R 3 is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, pentafluorophenyl, 4-ethylphenyl, 4-tert-butylphenyl, 3-nitrophenyl, 4-nitrophenyl or 4- (trifluoromethyl) phenyl. 5. The method is a new one according to claim 1, 2, 3 or 4 for the preparation of a taxoid, characterized in that it is a general (II) formula compound - which wherein Price and R 1 is as defined in claim 1, 2 or 3. above; and or r ₄ is hydrogen and R5 is a hydroxy protecting agent or r ₄ and R5 together are a 5- or 6-membered saturated heterocyclyl- it is ugly, Gj. is a hydroxy protecting group, and G ₂ is esterified with an acid of formula (III) or an hydroxy protecting group with an acid of formula (III) wherein R ₃ is as defined in claim 1, 2 or 3 or an active derivative thereof; In the compound of the formula wherein Ar, R 1, R ₃ , R ₄ , R ₅ , and G ₂ are as defined above, when R ₄ is hydrogen, R 5 is protected, and when R ₄ and R 5 taken together to form a 5- or 6-membered saturated heterocycle, the protecting groups R ₄ , R 5, G ₁ and optionally G ₂ are replaced by hydrogen, and then optionally, depending on the meaning of R ₁ , R ₄ and R 5, ) through formula compound - wherein R is as defined above - this compound with benzoyl chloride or with a compound of formula (VI) - wherein _R2 is as defined above and X is halogen or _-0-R2 or -O-CO -GUARD Acid residue of formula ₂ - to give the formula (I) was prepared by acylation of. 6. A process according to claim 5, wherein the compound of formula II, previously converted to a metal compound with an alkali metal alkyl compound, is esterified in an inert organic solvent such as an ether at -50 ° C. at a temperature below about 10 ° C with a compound of formula (III), preferably in the form of a halide. The process of claim 4, wherein the protecting groups are replaced by hydrogen atoms i) when R ₄ is hydrogen, R 5 is as defined above, G 1 is a silylated group, and G ₂ is an acetyl group, the compound of formula IV is selected from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles in an organic solvent at temperatures ranging from -10 ° C to 60 ° C ······················································· (Ii) if treated with an inorganic acid such as hydrochloric acid, sulfuric acid, hydrogen fluoride or an organic acid such as formic acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, ii) if R ₄ and R 5 together form a saturated heterocycle of formula VII: wherein R ₄ is 1, 2, or As defined in claim 3, R8 and R7 are the same or different and are selected from hydrogen, C1-C4 alkyl, aralkyl having alkyl having 1 to 4 carbon atoms and aryl being preferably phenyl optionally having one or more C1-C4 alkoxy groups. substituted or aryl, preferably phenyl, optionally substituted with one or more C 1 -C 4 alkoxy groups, or R 8 is a C 1 -C 4 alkoxy group, or a trihalogenated methyl group, or phenyl substituted with a trihalogenated methyl group, and R 7 is hydrogen. , or R 8 and R 7 together with the carbon atom to which they are attached form a 4- to 7-membered ring, G 1 - is a silylated group, and G 8 - is an acetyl group, the protecting groups depending on the meaning of R 1, R 8 and R 7 replace it with hydrogen: (a) when R1 is tert-butoxycarbonyl, R8 and R7 are the same or different, respectively alkyl, aralkyl or aryl, or Rg is a trihalogenated methyl or a phenyl substituted by a trihalogenated methyl, and R7 is hydrogen; , or Rg and R7 together form a 4- to 7-membered ring to form a compound of formula IV Optionally in an organic solvent, such as an alcohol, treated with an inorganic or organic acid to give a compound of formula (V) which is then acylated with a compound of formula (VI); b) when Rp is benzoyl or R2-O-CO- wherein R2 is as defined above; Rg is hydrogen, (C1-C4) -alkoxy or phenyl substituted with one or more (C1-C4) -alkoxy; and R7 is hydrogen, the compound of Formula IV in an organic solvent selected from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons at a temperature of -10 to 60 ° C with a catalytic or stoichiometric amount of inorganic acid - as hydrochloric acid or sulfuric acid, or with an organic acid such as acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, or mixtures thereof; iii) If Gp represents a silylated group, G 2 represents an alkoxy acetyl group, and _R4 and R5 are as defined in i) above, first the Gp and R5 protecting group is replaced with hydrogen atoms as described in i) above, followed by G2 protecting group in an alkaline medium, under conditions not affecting the remainder of the molecule, treatment with ammonia or treatment with a zinc halide in methanol; iv) If a Gp a silylated radical, G 2 represents an alkoxy acetyl radical, and R ₄ and R 5 are as defined above ii-a) defined above, * · · · · · ·. ··· ·· .. * »« * ·., · ·,. · 71, then in an acidic medium, under conditions not affecting the rest of the molecule, the protecting group G 1 is first removed and optionally the protecting group G 2 is replaced by a hydrogen atom as described in (iii) above and finally the resulting compound of formula V treating the compound as described in (ii-a) above for deprotection and acylation; v) When G _{1 -} is a silylated group, G ₂ is an alkoxyacetyl group, and R ₄ and R 5 are as defined in (ii-b) above, first in an acidic medium, under conditions not affecting the rest of the molecule. removing the protecting group G ₁ , optionally replacing the protecting group G ₂ with hydrogen as described in (iii) above, and then treating the compound thus obtained with (ii) - (b) above. 8. A compound of Formula II: wherein Ar and R1 are as defined in claim 1, 2 or 3; and or R ₄ is hydrogen and R 5 is a hydroxy protecting group, or R ₄ and R 5 together form a 5- or 6-membered saturated heterocycle, G 1 is a hydroxy protecting group, and G ₂ is an acetyl group or a hydroxy protecting group. A novel compound according to claim 8, characterized in that Ar and R1 are as defined in claim 1, 2, 3 or 4; and ·· ♦ * • ···· / When R ₄ is hydrogen, R 5 is preferably methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, (β-trimethyl). silylethoxy) methyl or tetrahydropyranyl; and when R4 and R5 together form a heterocycle, it is an oxazolidine ring optionally substituted at the 2-position or gem-disubstituted; G 1 is trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or trialkylsilyl, the alkyl moieties of which contain from 1 to 4 carbon atoms and the aryl groups are preferably phenyl; and G ₂ is alkoxyacetyl. 10. A process for the preparation of a compound according to claim 8 or 9, characterized in that a compound of the formula VIII: wherein: Ar and R1 are as defined in claim 1, 2, 3 or 4; R 15 is hydrogen or a hydroxy protecting group; R4 is hydrogen; G 'is hydrogen or a hydroxy protecting group; and G'2 represents a hydrogen atom, an acetyl group, or a hydroxy protecting group - controlled by electrolysis under controlled voltage in an electrolyte consisting of a quaternary ammonium salt dissolved in an organic solvent or a hydroorganic mixture. - · «··· • ·· ·· ··· * * · · * · · · · · · · · · · · · · · · · · · · · · · - 73 I 11. A process for the preparation of a compound according to claim 8 or 9, characterized in that a compound of formula XI wherein G ₂ is as defined in claim 8 or 9 in an organic solvent is an activating agent, e.g. pyridine and optionally in the presence of a condensing agent, for example an imide, at a temperature of 0 to 90 ° C with an acid of formula XII wherein Ar, R 1, R ₄ and R 5 are as defined in claim 8 or 9, or a derivative thereof, such as a halide, anhydride or mixed anhydride. 12. A process for the preparation of a compound of the formula XI according to claim 11, characterized in that a compound of the formula XIII wherein G 'and G' ₂ are as defined above; and G'3 is a hydrogen atom or a hydroxy protecting group identical to G'-which is reduced by electrolysis at a voltage controlled by an electrolyte consisting of a quaternary ammonium salt in an organic or organic solvent, and the G'3 protecting group is then removed selectively, or the hydroxy groups at the 7- and 10-positions are provided with selective protection. 13. A pharmaceutical composition comprising at least one compound according to claim 1, 2, 3 or 4 and one or more pharmaceutically acceptable inert or physiologically active compounds.