SK92794A3 - Baccatine iii and 10-deacetyl baccatine iii derivatives, their preparation and pharmaceutical compositions containing same - Google Patents

Abstract

Novel taxane derivatives of general formula (I), their preparation, and pharmaceutical compositions containing same. In general formula (I), Ar is an aryl radical; R1 is hydrogen or acetyl; R is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl, with the proviso that when Ar is an aryl radical and R1 is hydrogen or acetyl, R is a tert.butyl or ethyl radical. The novel products of general formula (I) have remarkable antitumoral activity.

Description

Novel Baccatin III and 10-Deacetylbaccatin III derivatives, processes for their preparation and pharmaceutical compositions thereof;

They contain.

t i ϊ i Technical field i [

The invention relates to novel baccatin III and 10-deacetylbaccatin III derivatives, to a process for their preparation and to pharmaceutical compositions containing them. ^r ii t technikyŕ Background

and

In C.R.Acad.Sci. 299, Ser. II, No. 15, 1039-1043 (1984)

t.

the products of formula (I) below, in >

wherein R1 represents a hydrogen atom or an acetyl group, R represents an ethyl group and Ar represents an unsubstituted phenyl group;

EP-0 253 738 describes products of the general formula I in which R 1 represents a hydrogen atom or an acetyl group, R 1 represents a tert-butyl group and Ar represents a phenyl unsubstituted group.

WO 92/09589 describes products of formula I wherein R 1 is hydrogen or acetyl, R is tert-butyl and Ar is phenyl which is substituted or optionally substituted with alpha or naphthyl. I

The products according to the invention are known from these hitherto known products differ in different spectrum of effect

I i

The essence of the invention; »

The invention relates to novel taxane derivatives of general formula I

i t

!

of formula I

In which

Ar represents an aryl group,

R x represents a hydrogen atom or an acetyl group and

R represents a straight or branched (C 1 -C 6) alkyl group, (C 3 -C 8) alkenyl, (C 3 -C 8) alkynyl, (C 3 -C 6) cycloalkyl, (C 4 -C 6) cycloalkyl or bicycloalkyl a group containing up to 10 carbon atoms, these groups being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, a hydroxy group, an alkyloxy group having 1 to 4 carbon atoms, a dialkylamino group in which each alkyl radical contains 1 up to 4 carbon atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted in the 4-position with an alkyl group containing up to 4 carbon atoms or a phenylalkyl group in which the alkyl radical contains 1 to 4 carbon atoms, a cycloalkyl group containing 3 up to 6 u atoms C 1-4 alkyl, cycloalkenyl, phenyl, cyano, carboxyl or alkyloxycarbonyl in which the alkyl radical contains 1 to 4 carbon atoms, or phenyl optionally substituted with one or more substituents selected from the group consisting including halogen atoms, a C 1 -C 4 alkyl group and a C 1 -C 4 alkyloxy group, or a 5- or 6-membered saturated or unsaturated nitrogen heterocyclic group optionally substituted by one or more C 1 -C 4 alkyl groups Wherein the cycloalkyl, cycloalkenyl or bicycloalkyl group may be optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms, and when Ar is unsubstituted phenyl and R 1 is hydrogen or acetyl R is not a ethyl or t-butyl group, and when Ar is a substituted phenyl group or an optionally substituted alpha or beta-naphthyl group and R 1 is a hydrogen atom or an acetyl group, R cannot be a tert-butyl group.

Preferably Ar represents a phenyl group or an alpha- or beta-naphthyl group which is or by several substituents of a halogen atom (fluorine atom optionally substituted by one selected from the group consisting of chlorine atom, bromine atom, iodine atom), alkyl group, alkenyl group, alkynyl group , aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino , amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, the alkyl and other radicals of the other groups containing 1 to 4 carbon atoms , alkenyl groups and alkynyl groups contain 3 to 8 carbon atoms and the aryl groups are phenyl or alpha or beta-naphthyl.

More preferably, Ar is a phenyl group which is optionally substituted by one or more of the same or different substituents selected from the group consisting of halogen atoms, alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl.

Even more preferably, Ar is a phenyl group which is optionally substituted with a chlorine or fluorine atom or an alkyl (methyl) group, an alkoxy (methoxy group), a dialkylamino (dimethylamino) group, an acylamino (acetylamino) group or alkoxycarbonylamino (t-butoxycarbonylamino).

The novel taxane derivatives of the formula I can be obtained according to the invention by reacting a reactive derivative of the formula II

RO-CO-X (II) wherein R is as defined above and X represents a halogen atom (fluorine atom, chlorine atom) or the radical -O-R, -O-CO-OR or -O-Ph, in which Ph represents a phenyl group which is substituted with an electrophile (electron-attracting group), preferably a nitro group, in the para or ortho position, or a 1,2,2,2-tetrachloroethoxy radical, with a baccatin III or a 10-deacetylbaccatin III derivative of general formula of formula III (III)

in which Ar is as defined above, Gi is a hydroxy-protecting group such as 2,2,2-trichloroethoxycarbonyl or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl, in which each alkyl radical contains 1 to 4 carbon atoms and each aryl radical preferably represents a phenyl group, and Ga represents an acetyl group or a hydroxy-protecting group such as 2,2,2-trichloroethoxycarbonyl, to give the product of formula IV

in which Ar, R, Gi and Gz are as defined above, followed by replacement of the G 1 and G 2 groups with hydrogen atoms to give the product of formula (I).

Generally, the reaction of a reactive derivative of formula II with a baccatin or 10-deacetylbaccatin derivative of formula III when X is halogen or -OR or -O-CO-OR is carried out in an organic solvent such as an ester such as ethyl acetate, in the presence of a mineral or organic base such as sodium bicarbonate.

Usually the reaction is carried out at a temperature of 0 to 50 ° C, preferably at a temperature close to 20 ° C.

In general, the reaction of a reactive derivative of the formula II with a baccatin III or a 10-deacetylbaccatin III derivative of the formula III when X is -O-Ph is carried out in an organic solvent selected from ethers such as tetrahydrofuran, nitriles such as acetonitrile, amides such as dimethylformamide, and halogenated aliphatic hydrocarbons such as dichloromethane at 50 to 100 ° C.

Generally, the reaction of a reactive derivative of formula II with a derivative of baccatin III or 10-deacetylbaccatin III of formula III when X is a 1,2,2,2-tetrachloroethoxy group is carried out in an inert organic solvent selected from the group consisting of ethers such as tetrahydrofuran, nitriles such as acetonitrile, amides such as dimethylformamide, and aromatic amines such as pyridine at a temperature close to 0 ° C.

In general, the replacement of the protecting groups Gi and G _{from the} product of formula IV by hydrogen atoms is carried out by treatment with zinc in acetic acid at 30 to 60 ° C or by using a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1. up to 3 carbon atoms in the presence of zinc when Gi and / or Gz is 2,2,2-trichloroethoxycarbonyl, or in an acidic environment such as hydrochloric acid in a solution in an aliphatic alcohol containing 1 to 3 carbon atoms ( methanol, ethanol, propanol, isopropanol) or an aqueous solution of hydrofluoric acid at 0 to 40 ° C when Gn and / or Ga is a silylated group.

The baccatin III or 10-deacetylbaccatin III derivative of the general formula III can be obtained by reacting a mineral or organic acid, optionally in an alcohol, under conditions which have no effect on the protective groups Gi and G- with a product of the general formula V

(V) wherein Ar, Gi and Gz are as defined above, Boe represents a tert-butoxycarbonyl group, and R.- and R ₃ , which are the same or different, represent a hydrogen atom or a C 1 -C 4 alkyl group which: is optionally substituted with one or more aryl groups (phenyl groups), or an aryl group (phenyl group) or R a and R a together with the carbon atom to which they are attached a 4-7 membered ring.

The product of formula (V) may be obtained by reaction of an oxazolidine derivative of formula (VI)

Ar COOH

M

(VI) wherein Ar, Boe, R = and Ra are as defined above, and which is optionally in the form of an anhydride, with a taxane derivative of formula VII

(VII) wherein G 1 and G 2 are as defined above.

Said esterification is generally carried out in the presence of a condensing agent such as a carbodiimide such as dicyclohexylcarbodiimide or a reactive carbonate such as 2-dipyridyl carbonate, and an activating agent such as a dialkylaminopyridine like

4-dimethylaminopyridine, and in an organic solvent such as an aromatic hydrocarbon (benzene, toluene, xylene, ethylbenzene, isopropylbenzene, chlorobenzene), ether (tetrahydrofuran), nitrile (acetonitrile) or ester (ethyl acetate) at 0 to 90 ° C.

The oxazolidine derivative of formula (VI) may be obtained by saponification in a basic medium of an ester of formula (VIII)

Ar 'COOR ^ n'

Boc-N O ^R 2 ^r 3 liters

(VIII) in which Ar, R and R ₃ are as defined above, and R is, · an alkyl radical containing 1 to 4 carbon atoms which is optionally substituted by phenyl.

Generally, this saponification is carried out using a mineral base such as lithium hydroxide in an alcohol containing alcohol.

com 1-4 carbon atoms such as ethanol

The ester of formula (VIII) may be obtained by reaction of a methoxyalkene which is optionally substituted with one or more aryl groups (2-methoxypropene), a gem-dimethoxyalkane which is optionally substituted with one or more aryl groups (2,2-dimethoxypropane), or gem-dimethoxycycloalkane having 4 to 7 carbon atoms (1,1-dime-;

(phenylcyclohexane) with a phenylisopropylamine derivative of the general formula

IX

ArCOOR,> -4 (CH ₃ ) ₃ CO-CO-NH 4 (IX) 1

in which Ar and R6 are as defined above, in racemic form or preferably in the form of 2R, 3S.

Generally, the reaction of methoxyalkene or gem-dimethoxyalkane or gem-dimethoxycycloalkane with the product of formula IX is carried out in an inert organic solvent and in the presence of a strong acid such as p-toluenesulfinic acid, optionally in the form of pyridinium salt. mixture. Particularly preferred solvents for this purpose are aromatic hydrocarbons (benzene, toluene, xylene).

The product of formula (IX) may be obtained by acylation of a beta-phenyl derivative of formula (X)

Coor ₄ \

OH (X) wherein Ar and R-t are as defined above.

This reaction is generally carried out by reacting di-tert-butyl dicarbonate in an inert organic solvent such as an ester such as methyl acetate or ethyl acetate at a temperature of 0 to 40 ° C, preferably at a temperature close to 20 ° C.

The beta-phenyl derivative of formula (X) may be obtained by reduction of the hydroxy-azide of formula (XI) -

COOR, \

OH (xi);

wherein Ar and R <. have the meanings given above

Generally, this reduction is carried out using hydrogen in the presence of a catalyst such as palladium on carbon in an inert organic solvent such as ethyl acetate. Reduction;

preferably carried out at a temperature of 0 to 50 ° C. It is preferred to use ear;

rotate hydrogenation at a pressure of 0.1 to 0.5 MPa

The product of formula XI can be obtained by reacting an alkali metal azide such as sodium azide with a beta-phenylglycidic acid ester of formula XII,

ABOUT

A

ArC00R (XII) wherein Ar and R ₄ are as defined above.

Generally, the reaction is carried out in a hydroorganic mixture, such as a mixture of water and tetrahydrofuran, at the reflux temperature of the reaction mixture.

The ester of formula XII can be obtained by dehydrohalogenation of the product of formula XIII

(XIII) in which Ar is as defined above, Hal represents a halogen atom, preferably a bromine atom, and R 5 and R c, which are the same or different, represent an alkyl group having 1 to 4 carbon atoms or a phenyl group.

Generally, this reaction is carried out in the presence of an excess of an alkali metal alkoxide, optionally prepared in situ, in an inert organic solvent such as tetrahydrofuran at a temperature of -80 to 25 ° C.

The product of formula (XIII) may be obtained by reaction of an aldehyde of formula (XIV)

Ar-CHO (XIV) wherein Ar is as defined above, with an acid halide of formula XV

(XV) in which Hal, R and _R are as defined above, and which is anionized.

Generally, this reaction is carried out in an inert organic solvent selected from ethers (ethyl ether) and halogenated aliphatic hydrocarbons (methylene chloride) at -80 to 25 ° C and in the presence of a tertiary amine (triethylamine) and an anionizing agent (di-n-butylboronate) .

The product of formula (XV) can be obtained by reacting a haloacetic acid halide, preferably bromoacetic acid bromide, with the corresponding lithium oxazolinone salt.

The novel taxane derivatives of the formula I can also be obtained according to the invention by reaction of an acid of the formula XVI

Ar>

RO-CO-NH

COOH \

og ₃ (XVI) in which

Ar and R are as defined above, and G ₃ is a hydroxy-protecting group such as methoxymethyl,

1-ethoxyethyl, benzyloxymethyl, (beta-trimethylsilylethoxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl or 2,2,2-trichloroethoxycarbonyl, optionally in the form of an anhydride, with a taxane derivative of formula VII and followed by replacement of the protective groups Gi, G.- and G ₃ by hydrogen atoms.

Generally, this esterification is carried out in the presence of a condensing agent such as carbodiimide such as dicyclohexylcarbodiimide or a reactive carbonate such as 2-pyridyl carbonate, and an activating agent such as aminopyridine such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine in an organic solvent such as an aromatic hydrocarbon xylenes, ethylbenzene, isopropylbenzene, chlorobenzene), ether (tetrahydrofuran), nitrile (acetonitrile), ester (ethyl acetate), at 0 to 90 ° C.

The replacement of the protecting groups is generally carried out by treatment with acetic acid at a temperature of 30 to or of an organic acid or acetic acid, at up to 3 carbon atoms in the presence of a protecting group, or in acid.

Gi, Gz and Ga with zinc hydrogen atoms in the presence of ° C or using a mineral such as hydrochloric acid solution in an aliphatic alcohol containing that any carbonyl of any of the protecting groups is zinc in the case of 2,2,2-trichloroethoxy if a silylated group.

The acid of formula XVI with an ester of formula XVII can be obtained by saponification of R O -CO-NH

(XVII) wherein R, Ar and G ₃ are defined as above and R? means an alkyl group having 1 to 4 carbon atoms optionally substituted by a phenyl group using a mineral base such as an alkali metal hydroxide (lithium hydroxide, sodium hydroxide), an alkali metal carbonate or bicarbonate (sodium bicarbonate, potassium carbonate), in a hydroalcoholic medium such as a mixture of methanol and water at a temperature of 10 to 40 ° C, preferably at a temperature close to 20 ° C.

The product of formula (XVII) may be obtained under the conditions customary for the preparation of ethers, and in particular by the methods described by J. N. Denis in J. Org. Chem., 51, 46-50 (1986), from the product of formula (XVIII.

RO - CO - NH, COOR ₇

OH (XVIII) in which R, Ar and R? are as defined above.

The product of formula XVIII can be obtained by reacting the product of formula II with a product of formula XIX

Ar>

h ₂ n

COORf \

OH (XIX) in which Ar and R? are as defined above. Generally, this reaction is carried out in an organic solvent such as methylene chloride in the presence of a mineral base such as sodium bicarbonate.

The product of formula (XIX) may be obtained by reduction of the azide of formula (XX)

(XX) in which Ar and R? are as defined above, obtained by known methods for opening the epoxide of formula XXI

0 / \ (XXI) Ar — L --- ³ COOR ₇

in which Ar and R? are as defined above, using azide Sodium in warm ethanol.

The epoxide of formula XXI can be obtained under the conditions described by F. W. Bachelor and R. K. Bansal in J. Org. Chem., 34, 3600-04 (1969).

In the following, the invention will be explained in more detail by means of specific examples thereof, which are illustrative only and do not limit the scope of the invention, which is clearly defined by the wording of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 0.5 g of (2R, 3S) -4-ethoxy-2alpha-benzoyloxy-5beta, 20epoxy-1-hydroxy-9-oxo-bis- (2,2,2-trichloroethoxy) -7beta, 10betacarbonyloxy-11 -taxene-13a-ph-yl-3-amino-2-hydroxy-3-phenylpropionate in 12.5 cm ^{3 of} ethyl acetate, maintained under argon, 12.5 cm ^{3 of} saturated sodium bicarbonate solution and 12 cm ^{3 of} distilled water are added. water and then 93 mg of adamantyl fluoroformate at a time. The reaction mixture is stirred for 7 hours at a temperature close to 20 ° C. The aqueous phase is separated by decantation and then extracted three times with 15 cm @ ^{3 of} ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is concentrated under reduced pressure (2.7 kPa) at 40 ° C.

0.57 g of a white solid foam is obtained, which is purified by chromatography on 12 g of silica gel (0.04-0.063 mm) packed in a 1.5 cm column, eluting with a dichloromethane / methanol (98: v / v) mixture. : 2 and 5 cm ³ fractions are collected. Fractions 22 to 34 are combined and concentrated under reduced pressure (0.27 kPa) at 40 ° C.

0.52 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-

5-beta, 20-epoxy-1-hydroxy-9-oxo-bis- (2,2,2-tri chloroethoxy) -7beta, 10beta-carbonyloxy-11-taxen-13alpha-yl-3adamantyloxycarbonylamino-3-phenyl- 2-hydroxypropionate as a white solid foam.

A solution of 0.52 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-bis- (2,2,2-tri chloroethoxy) -7beta, 10beta- carbonyloxy-11-taxen-13a-ph-yl-3-adamantyloxycarbonylamino-3-phenyl-2-hydroxypropionate in a mixture of 10 cm ^{3 of} methanol and 10 cm ³ of acetic acid is heated under stirring and under argon to a temperature close to 60 ° C, g of zinc powder is added to the solution. The reaction mixture is then stirred for 30 minutes at 60 ° C, then cooled to a temperature close to 20 ° C and filtered through a glass frit lined with celite. The glass frit is washed three times with 5 cm @ ^{3 of} dichloromethane and the filtrates are combined and then concentrated under reduced pressure (2.7 kPa) at a temperature close to 40 ° C.

20 cm ^{3 of} dichloromethane are added to the residue at a temperature close to 40 ° C. 0.48 g of a white solid foam is obtained, which is purified by chromatography on 12 g of silica gel (0.04-0.063 mm) packed in a 2.5 cm column, eluting with a dichloromethane / methanol (97: v / v) mixture. : 3 and 5 cm ³ fractions are collected. Fractions 17 to 37 are combined and concentrated under reduced pressure (0.27 kPa) at 40 ° C for 5 hours.

There was thus obtained (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-11-taxen-1,3alpha-3-adamantyloxycarbonylamino-3-phenyl-2. hydroxypropionate in the form of a white fluffy solid.

Yield: 0.2 g

Optical rotation [alpha] ²⁰ = -32 ° (c = 0.5, methanol)

D

Nuclear Magnetic Resonance Spectrum:

(400MHz, CDCla)

1.14 (s, 3H): CHa 16 or 17), 1.26 (s, 3H: -CHa 16 or 17),

1.4 to 2.1 (m, 15H: -CHa- and CH- adamantyl),

1.7 (s, 1H: -OH 1), 1.77 and 1.88 (2s, 3H each: -CHa 18 and -CHa 19), 1.85 (m, 1H: -CCH) -H 6) .

2.31 (d, 2H, J = 9: CH _2-14);

2.4 (s, 3H: --COCH3),

2.6 (m, 1H: - (CH) -H 6),

3.35 (d, 1H, J = 5: -OH 2 '),

3.93 (d, 1H, J = 7: -H3),

4.2 and 4.32 (2d, 1H each, J = 8: - (CH _z) -20);

4.2 3 (s, 1H: --OH 10),

4.25 (m, 1H: --H7),

4.64 (Π), 1Η: -Η 2 '),

4.96 (d, 1H, J = 9: -5),

5.21 (s, 1H: - 10),

5.27 (d, 1H, J = 9: - 3 '),

5.44 (d, 1H, J = 9: -NHCO-),

5.69 (d, 1H, J = 7: -2),

6.24 (t, 1H, J = 9: -H 13),

7.3 to 7.45 (m, 5H: -C6 H5),

7.51 / t, 2H, J = 8.5: -0C0C ₆ H ₅ (~ H 3 and H 5) /.

7.62 (t, 1H, J = 8.5: --OCOC3 H5 (--H4)),

8.13 (d, 2H, J = 8.5: OCOC6 H5 (-H2 and -H6)).

(2R, 3S) -4-acetoxy-2H-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-tri chloroethoxy) carbonyloxy-1-taxen-13alpha- The 3-amino-2-hydroxy-3-phenylpropionate is obtained as follows.

g (4S, 5R) -4-Acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha- yl-3-tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-oxazolidine-5-carboxylate was stirred with formic acid at 20 ° C. Concentration to dryness, removal of the residue with dichloromethane and purification by flash chromatography eluting with a 95: 5 mixture of dichloromethane and methanol yielded 6.3 g of (2R, 3S) -4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy -1-hydroxy-9-oxo-7beta, 10beta-bis (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13a-.alpha.-3-amino-2-hydroxy-3-phenylpropionate as a white solid foam. Optical rotation [.alpha.] D @ ²⁰ = -39.7 DEG (c = 1, methanol).

D

By reaction of 10 g of (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-oxazole-5-carboxylic acid, 12.6 g of 4-acetoxy-2α-benzoyloxy-5beta, 20-epoxy-1, 13alpha-dihydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxene in toluene at a temperature near 80 ° C in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine gave 14 g (4S, 5R) -4-Acetoxy-2H-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 1020 beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen -13alpha-yl-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-oxazole di-5-carboxylate as a white fluffy solid

Optical rotation [.alpha.] D @ ²⁰ = -37.2 DEG (c = 1, methanol).

r>

(4S, 5R) -3-tert-butoxy-2,2-dimethyl-4-phenyl-oxazolidin-5-carboxylic acid can be prepared as follows:

To a stirred solution of 12.8 g of (4S, 5R) -ethyl-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyloxazole di-5-carboxylate in 200 cm ^{3 of} ethanol is added a solution of 4, 62 g of lithium hydroxide hydrate in 80 cm ^{3 of} water. After further stirring for 10 minutes, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. The residue obtained is dissolved in 70 cm ^{3 of} water, then extracted three times with 20 cm ^{3 of} isopropyl oxide. The aqueous phase is then acidified to a pH close to 2.6 by the addition of about 100 cm @ ^{3 of} an aqueous hydrochloric acid solution, followed by extraction with 50 cm @ ^{3 of} dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. 11.3 g of (4S, 5R) -3-tert-butoxy-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid are thus obtained in the form of a yellow oil having an optical rotation of [alpha] ²⁰ = -3. .3 ° r?

(c = 0.8, chloroform).

(4S, 5R) -ethyl-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyloxazolidine-5-carboxylate can be obtained as follows.

A solution of 11.7 g of (2R, 3S) -ethyl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, 3.6 cm @ ^{3 of} 2-methoxypropene and 0.06 g of paratoluenesulfonic acid in 120 cm @ ^{3 of} toluene is stirred for one hour. at a temperature in the region of 20 ° C. The reaction mixture is then brought to reflux and 0.05 g of paratoluenesulfonic acid is added. While the solution is added dropwise

18.3 cm @ ^{3 of} 2-methoxypropene in 82 cm @ ^{3 of} toluene, in order to maintain a constant volume of the reaction mixture, the distillate is collected in a graduated cylinder. After 1 hour and 20 minutes distillation is added. and

0.06 g of paratoluenesulfonic acid, followed by distillation for a further 10 minutes. The volume of collected distillate is thus 100 cm ³ . The reaction mixture is cooled to a temperature in the region of 20 DEG C. and 25 cm @ ^{3 of} saturated aqueous sodium hydrogen carbonate solution are then added thereto. The aqueous phase is decanted and then extracted twice with 10 cm ^{3 of} dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C.

20.8 g of a yellow oil are obtained, which is purified by chromatography on 630 g of silica gel (column diameter: 5.5 cm), eluting with a cyclohexane / ethyl acetate mixture (7.0: 30 by volume), collecting 100 fractions. cm ³ . Concentration to dryness from fractions 3 to 9 under reduced pressure at 40 ° C gave 13 g of (4S, 5R) -ethyl-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyloxazolidine-5-carboxylate as a yellow oil. whose optical rotation is [.alpha.] D @ ²⁰ = -7.3 DEG (c = 1, chloroform).

l>

(2R, 3S) -ethyl 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate can be obtained as follows.

To a stirred solution of (2R, 3S) -ethyl 3-amino-2-hydroxy- ³ -phenylpropionate (16 g) in dichloromethane (160 cm ³ ) was added sodium bicarbonate (7.1 g), followed by pouring a solution of dihydrochloride (22.1 g) over 40 min. tert-butyl dicarbonate in 40 cm ^{3 of} dichloromethane. The reaction mixture is stirred for 3.25 hours at a temperature in the region of 20 DEG C. and then 150 cm @ ^{3 of} water are added. The organic phase is decanted and the aqueous phase is extracted with 50 cm ³ of dichloromethane, then the combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure (2.7 kPa) at a temperature close to 30 ° C. The residue is triturated in 50 cm ^{3 of} isopropyl ether. The solid obtained is filtered off and then dried under reduced pressure (2.7 kPa) at a temperature close to 20 ° C. There was thus obtained (2R, 3S) -ethyl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate (11.9 g) as a white powder, m.p. 124 ° C. This product has an optical rotation [.alpha.] D @ ²⁰ = 6.3 DEG (c = 1, chloroform).

(2R, 3S) -ethyl 3-amino-2-hydroxy-3-phenylpropionate can be prepared as described by H.Honig et al. in Tetrahedron, 46, p. 3841 (1990).

4-Acetoxy-2alpha-benzyloxy-5beta, 20-epoxy-1,13alpha-dihydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-1-chloroethoxy) carbonyloxy-11taxene may be used as described above. in the European patent

EP 0 253 738.

EXAMPLE 2 To a solution of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-tri chloroethoxy) carbonyloxy-11 -taxen-13alpha-γ-3-amino-2-hydroxy-3-phenylpropionate in 10 cm ^{3 of} dichloromethane, maintained under argon, 44 mg of sodium bicarbonate and 0.13 g of di-t-pentyl dicarbonate are added in one portion .

The reaction mixture is stirred for 24 hours at a temperature in the region of 20 DEG C. and then a mixture of 20 cm @ ^{3 of} distilled water and 20 cm @ ^{3 of} dichloromethane is added. The aqueous phase is separated by decantation and then extracted with 20 cm @ ^{3 of} dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (2.7 kPa) at 40 ° C. It will be obtained

0.66 g of white solid foamy product, which is purified by chromatography on 13 g of silica gel (0.04-0.063) packed in a 1.5 cm column, eluting with a dichloromethane / methanol (98/2 by volume) mixture. and collecting 5 cm ³ fractions. Fractions 10 to 17 are pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. 0.52 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,3-trichloroethoxy) carbonyloxy- 11-Taxen-13a-phenyl-3-t-pentyloxy-23-carbonylamino-3-phenyl-2-hydroxypropionate as a white fluffy product.

If the procedure is analogous to that described in Example 1, except starting from 0.52 g of (2R, 3S) -4-a ce. t-oxy-2a? -benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl-3? -tert-pentyloxycarbonylamino-3-phenyl-2-hydroxypropionate, then 0.18 g of (2R, 3S) is obtained -

4-Acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-11-taxen-13alpha-γ-3-tert-pentoxycarbonylamino-3-phenyl-2-hydroxypropionate in the form of a white fluffy product having the following characteristics:

optical rotation [alpha] ²⁰ = -35 ° (c = 0.4 methanol), nuclear magnetic resonance spectrum:

(400 MHz, CDCl 3) delta (ppm) 0.8 (T, 3H, J = 7: CH 2 CH 3 · carbamate), 1.15 (s, 3H: -CH and 16 or 17), 1.25 (S, 3H; -CH 3 16 or 17), 1, 32 (S, 6H: -C (CHa) 2 carbamate), 1.69 (Q, 2H, J = 7: -CHaCHa of carbamate), 1.73 (S, 1 H: OH 1), 1, 77 (S, 3H: -CH 19), 1, 85 / M, H: - (CH) -H 6 ', 1.87 (s, 3H: ' -CH 18), 2.29 (D, 2H, J = 9: -CH-14) 2.39 (S, 3H): -COCH) 2.59 / M, 1 H: - (CH) -H 6 ', 3.4 (m, 1H: - OH 2 '), 3.92 (d, 1H, J = 7: H 3) 4.19 and 4.32 (2d, 1H each, J = 8: - (CH: 4.24 (M, 2H, -OH 10 and -H 7), 4.64 (M, H: -H 2 '), 4.95 (d, 1 H, J = 9: -H 5) 5.22 (S, H: -H 10),

5.28 (D, lH, J = 9: -H 3 '), 5.47 (D, lH, J = 9: -HCO) 5.68 (D, 1 H, J = 7: -H 2), 6.22 (T, lH, J = 9: -H 13) 7.45 (m, 5H: -) -C sH_s), 7.51 / T, 2H, J = 8.5: -OCOC 3 H-, (-H 3 and -H 5) /, 7.63 / T, 1H, J = 8.5: -OCOCeOH (-H 4) /, 8.11 (d, 2H, J) = 8.5: -CO 2 C 6 H 5 (-H 2 and -H 6)].

Example 3

To a solution of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha -yl-3-amino-2-hydroxy-3-phenylpropionate in 10 cm ^{3 of} ethyl acetate, maintained under argon, 10 cm ^{3 of} saturated sodium hydrogen carbonate solution and 10 cm ^{3 of} distilled water are added, followed by dropwise addition of 0, 57 cm @ ^{3 of a} solution of isopropyl chloroformate in toluene.

The reaction mixture is stirred for 30 minutes at a temperature close to 20 ° C. The aqueous phase is separated by decantation and then extracted three times with 10 cm @ ^{3 of} ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.6 g of white solid fluffy product is obtained, which is purified by chromatography on 20 g of silica gel (0.04-0.063 mm) packed in a column of 2 cm diameter, eluting with a dichloromethane / methanol (97% by volume) mixture. : 3 and 5 cm ³ fractions are collected. Fractions 2 to 11 are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. 0.38 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy- 11-Taxen-13a-β-γ-3-isopropylcarbonylamino-3-phenyl-2-hydroxypropionate as a white solid fluffy product.

If the procedure is analogous to that described in Example 1, but starting from 0.35 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy- 1-hydroxy-9-oxo-7beta, 1 Obeta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13a-phenyl-3-isopropoxycarbonylamino-3-phenyl-2-hydroxypropionate, then 0.11 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-1-taxen-13alpha-yl-3-isopropoxycarbonylamino-3 -phenyl-2-hydroxypropionate in the form of a white solid fluffy product having the following characteristics:

Optical rotation [.alpha.] D @ 20 = -31 DEG (c = 0.5, methanol)

l>

nuclear magnetic resonance spectrum:

(300 MHz, CDCl 3) delta (ppm)

1.11 and 1.17 (2d, 3H each, J = 7: -CH (CHa) _s ), 1.13 (s, 3H: --CH3 16 or 17), 1.26 (s, 3H: --CH3 16 or 17), 1.7 (s, 1H: --OH 1), 1.77 and 1.85 (2s, 3H each: -CHs 18 and -CH ₃ 19) 1.85 (m, 1H: - (CH) - H 6), 2.25 (m, 2H: --CH2 - 14), 2.38 (s, 3H: --COCH3), 2.58 (m, 1H: - (CH) - H 6), 3.5 (m, 1H: --OH 2 '), 3.92 (d, 1H, J = 7: -H3), 4.19 and 4.32 (2d, 1H each, J = 8: - (CH =) - 20), 4.23 (m, 2H: -H10 and -H7), 4.64 (s, 1H: --H 2 '), 4.81 (m, lH, J = 7: -CH _(a) 2), 4.96 (d, 1H, J = 9: -H 5), 5.23 (S, 1H: -H 10) 5.29 (d, 1H, J = 9, -H 3 '), 5.57 (d, 1H, J = 9: -NHCO-) 5.68 (d, 1H, J = 7: -H 2), 6.23 (t, 1H, J = 9: -H 13), 7,3, up to 7.5 (m, 5H: -C (sHs)),

7.51 / t, 2H, J = 8.5: 7.63 / t, 1H, J = 8.5: 8.12 / d, 2H, J = 8.5: ~ 0C0Ce.Hr. (-H 5) /, -OCOC & Hs (—H 4) /, -OCOC _& H _S (-H 2 and -H 6) / Example 4

To a solution of 0.794 (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11- Taxen-13alpha-yl-3-amino-2-hydroxy-3-phenylpropionate in 30 cm ^{3 of} dimethylformamide, maintained under argon, was added at once with 0.209 g of 1-methylcyclohexyl-4-nitrophenyl carbonate. The reaction mixture is then stirred at 80 DEG C. for 9 hours, cooled to a temperature in the region of 20 DEG C. and then 300 cm @ ^{3 of} distilled water and 100 cm @ ^{3 of} ethyl acetate are added. The aqueous phase is separated by decantation and then extracted twice with 50 cm ^{3 of} ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C to give a white solid fluffy product which is purified by chromatography on 20 g of silica gel (0.04-). 0.063 mm) packed in a 2.5 cm column, eluting with a 99/1 mixture of dichloromethane and methanol to collect 15 cm ³ fractions. Fractions 18 to 32 are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

0.2 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2, -trichloroethoxy) carbonyloxy is thus obtained. 11-Taxen-13alpha-yl-2-hydroxy-3- (1-methylcyclohexyl) oxycarbonylamino-3-phenylpropionate as a white fluffy product.

Solution 0.47 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5-beta, -20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2, -) Trichloroethoxy) carbonyloxy-11-taxen-13a-phyl-2-hydroxy-3- (1-methylcyclohexyl) oxycarbonylamino-3-phenylpropionate in a mixture of 10 cm ^{3 of} methanol and 10 cm ³ of acetic acid is heated under stirring and under argon to to a temperature in the region of 60 DEG C., followed by the addition of 0.94 g of zinc powder. The reaction mixture is then stirred for 15 minutes at 60 ° C, then cooled to a temperature close to 20 ° C and filtered through a glass frit lined with celite. The glass frit is washed three times with 10 cm ^{3 of} dichloromethane, the filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C.

20 cm @ ^{3 of} dichloromethane are added to the residue, the separated residue is separated by filtration and the filtrate is concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 40 DEG. 0.55 g of a white solid fluffy product is obtained which is purified by chromatography on 14 g of silica gel (0.04-0.063 mm) packed into a 1 cm column, eluting with a dichloromethane / methanol (98: v / v) mixture. 2 and 5 cm ³ fractions are collected. Fractions 23 to 37 are combined and concentrated under reduced pressure (0.27 kPa) at 40 ° C for 5 hours.

There was thus obtained (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-9-oxo-11-taxen-13alpha-yl-2-hydroxy-3- (1- methylcyclohexyl) oxycarbonylamino-3-phenylpropionate as a white, fluffy solid having the following characteristics:

optical rotation [alpha] ²⁰ = -36 ° (c = 0.47, methanol),

l>

nuclear magnetic resonance spectrum:

(400 MHz, CDCl 3) δ in ppm 1, 10 to 2.10 (mt, 10H: --CH2 ₎ - cyclohexyl), 1.15 (S, 3H: - CH_a 16 or 17). 1.25 (S, 3H: -CH 3 16 or 17), 1.37 (S, 3H: -CH.3 in position 1 cyclohexyl), 1.70 (S, H: -OH 1), 1.78 (S, 3H: -CH3 19), 1.86 / Mt, H: - (CH) -H 6 ', 1.87 (S, 3H: -CHs), 2.30 (Mt, 2H: -CHz- 14),

2.40 (s, 3Η: -COCH 3),

2.60 (mt, 1H: - (CH) -H 6),

3.38 (d, 1H, J = 3.5: --OH 2 '),

3.92 (d, 1H, J = 7: -H3),

4.20 (d, 1H, J = 8: - (CH) --H2O),

4.23 (mt, 1H: --H7),

4.25 (s, 1H: --OH 10),

4.33 (d, 1H, J = 8: - (CH) -H2O),

4.66 (broad s, 1H: -H 2 '),

4.96 (broad d, 1H, J = 10: -H 5), 5.22 (s, 1H: -H 10),

5.30 (dd, 1H, J = 10 and 2-H 3 '), 5.49 (d, 1H, J = 10: -NH-3'),

5.69 (d, 1H, J = 7: -H 2),

6.24 (t, 1H, J = 9: -H 13),

7.45 (mt, 5H: --CeH3 at position 3 ' (--H2 _to --H6)),

7.51 / t, 2H, J = 7.5: --OCOC _& H =. (-H 3 and -H 5) /,

7.62 (t, H, J = 7.5: --OCOC3 H5 (--H4)),

8.11 / d, 2H, J = 7.5: _& -OCOC _(--H 2 and H 6) /.

(2R, 3S) 4-acetoxy-2.alpha.-benzoyloxy-5-beta, 20-epoxy-l-hydroxy-9-oxo-7.beta, 10.beta.-bis (2,2,2-trichloroethoxycarbonyl) carboxylic>: y11- Taxen-13alpha-yl-3-amino-2-hydroxy-3-phenylpropionate can be prepared as described in International Patent Application PCT WO 92/08589.

1-Methylcyclohexyl-4-nitrophenyl carbonate can be prepared as follows.

To a solution of 1.14 g of 1-methylcyclohexanol in 15 cm @ ^{3 of} dichloromethane, maintained under argon, is added 0.79 g of anhydrous pyridine at a temperature close to 20 DEG C. and then a solution of 2.01 g of 4-nitrophenyl chloroformate is added dropwise. in 15 cm ^{3 of} dichloromethane. The reaction mixture is then stirred for 24 hours at a temperature in the region of 20 ° C and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. A white, fluffy solid is obtained which is purified by chromatography on 60 g of silica gel (0.04-0.2 mm) packed in a 3 cm diameter column using a 50:50 mixture of dichloromethane and cyclohexane as the eluent. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. 1.3 g of 1-methylcyclohexyl-4-nitrophenyl carbonate are thus obtained in the form of a colorless oil.

Example 5

If the procedure of Example 4 is followed except that it is based on (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5,20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- ( 2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-2-hydroxy-3- (1-methyl-1-trifluoromethyl) ethoxycarbonylamino-3-phenylpropionate, obtained by reaction of (1-methyl-1-trifluoromethyl) ethyl -4-nitrophenyl carbonate with (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-

1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trifluoroethoxy) carbonyloxy-11-taxen-13alpha-yl-3-amino-2-hydroxy-3-phenylpropionate, then 0.075 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-11-taxen-13alpha-yl-

2-hydroxy-3- (1-methyl-1-trifluoromethyl) ethoxycarbonylamino-3-phennylpropionate as a white, fluffy solid having the following characteristics:

[.alpha.] D @ ²⁰ = -28 DEG (c = 0.44, methanol)

nuclear magnetic resonance spectrum:

(400MHz, CDCls) delta (ppm) 1.15 (S, 3H: --CH3 16 or 17), 1.25 (s, 3H: --CH3) 16 or 17), 1.54 and 1.60 / 2s, 3H each: -C (CH ₃ ) ₂ -, 1.70 (S, 1H: --OH D, 1.77 (s, 3H: --CH3) 19), 1.84 (S, 3H: --CH3 18), 1.85 (mt, 1H: - (CH) -H 6), 2.25 (d, 2H, J = 9) : -CH2-)

2.37 (S, 3H: -COCHs) 2.60 / mt, 1 H: - (CH) -H 6 ', 3.36 (D, 1 H, J = 5: -OH 2 ') 3.92 (D, 1 H, J = 7: -H3), 4.18 / D, 1H, J = 8: - (CH) -H20 / à 4.211 (s, 1H) -OH 10), 4.23 (Mt, 1H: H 7), 4.33 (d), 1H, J = 8: - (CH) -H20 / 4.63 (š ir.s, 1H: -H 2 '), 4.95 (Bd, 1H, J = 10: -H 5), 5.21 (S, 1 H: -H 10), 5.25 (broad • d, 1H, J = 10: -H 3 '), 5.68 (D, 1 H, J = 7: -H 2) 5.73 (D, lH, J = 10: -NH- 3 ') 6.62 (t, 1 H, J = 9: -H 13) 7.30 to 7.45 / mt, 5H, H-C _{& S} at pol < ohe 3 '(-H 2 to - H 6) 7.52 / T, 2H, J = 7.5: -OCOC _e .H _s (H 3 and H 5) /, 7.63 / T, lH, J = 7.5: -OCOC & Hc (H 4) /. 8.12 (d, 2H, J) = 7.5: -OCOC6H5 (H 2 and H 6)].

Example 6

To a solution of 0.741 (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-1-chloroethoxy) carbonyloxy-11-taxen-13alpha-yl-3-amino-2-hydroxy-3-phenylpropionate in 10 cm ^{3 of} anhydrous pyridine, maintained under argon, is added dropwise a solution of 0.211 g of 1-methyl-cyclopropyl-1,2,2, 2,2-tetrachloroethyl carbonate in 4 cm ^{3 of} anhydrous pyridine. The reaction mixture is then stirred for one hour at a temperature in the region of 20 DEG C. and then 10 cm @ ^{3 of} distilled water and 10 cm @ ^{3 of} dichloromethane are added. The aqueous phase is separated by decantation and then extracted twice with 10 cm @ ^{3 of} dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 0.9 g of a white solid is obtained, which is purified by chromatography on 60 g of silica gel (0.063-0.2 mm) packed in a column with a diameter of 1.5 mm, eluting with a mixture of dichloromethane and methanol in hexane. a 99: 1 volume ratio and 15 cm ³ fractions were collected. Fractions 30 to 37 are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

There was thus obtained (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy- 11-Taxen-13a-1-yl-2-hydroxy-3- (1-methylcyclopropyl) oxycarbonylamino-3-phenylpropionate as a white fluffy product.

A solution of 0.58 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy- 11-Taxen-13alpha-γ-2-hydroxy-3- (1-methylcyclopropyl) carbonylamino-3-phenylpropionate in a mixture of 25 cm ^{3 of} methanol and 25 cm ³ of acetic acid is heated under stirring under argon to a temperature close to 60 ° C followed by 2.3 g of zinc powder. The reaction mixture is then stirred for 15 minutes at 60 ° C, then cooled to a temperature close to 20 ° C and filtered through a glass frit lined with celite. The glass frit is then washed three times with 15 cm @ ^{3 of} methanol and the filtrates are combined and then concentrated under reduced pressure (2.7 kPa) at a temperature close to 40 ° C.

50 cm @ ^{3 of} distilled water are added to the residue, the crystallized solid is collected by filtration, washed four times with 10 cm @ ^{3 of} distilled water and dried under reduced pressure (2.7 kPa) at 20 DEG C. for 16 hours.

0.32 g of white solid fluffy product is obtained, which is purified by chromatography on 30 g of silica gel (0.063-0.2 mm) packed into a 1 cm diameter column, eluting with a mixture of dichloromethane and methanol (98 by volume). 2 and 5 cm ³ fractions are collected. Fractions containing only the desired product are combined and concentrated under reduced pressure (0.27 kPa) at 40 ° C for 5 hours.

0.11 g of (2R, 3S) -4-acetoxy-2alpha-benzoyl-xy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-11-taxen-13alpha-yl-2 is thus obtained. hydroxy-3- (1-methylcyclopropyl) oxycarbonylamino-3-phenylpropionate as a white solid. a fluffy product having the following characteristics:

optical rotation [.alpha.] D @ ²⁰ = -33 DEG (c = 0.52, methanol),

D nuclear magnetic resonance spectrum:

(400 MHz, CDCl 3) delta (ppm)

0.48 and 0.80 (2mt, 2H each: -CH 2 - cyclopropyl), 1.13 (S, 3H: -CHs 16 or 17), 1.25 (S, 3H: -CHs 16 or 17), 1.42 (S, 3H: -CHs in position 1 cyclopropyl), 1.76 (s, 3H: - CH_3 19) 1.75 to 1.90 / mt, 1H: - (C H) -H 6), 1.83 (S, 3H: —CH_a 18), 2.28 (D, 2H, J = 8.5: -CH2- 14), 2.38 (S, 3H: -COCHs) 2.58 / Mt, 1H: - (CH) -H 6 ', 3.33 (Unresolved peak, 1H, -OH 2 '), 3.91 (D, lH, J = 7: -H3), 4.19 (d), 1H, J = 8: - (CH) -H 20 /. 4.20 (s, 1 H: -OH 10), 4.23 (Mt, 1H: -H 7), 4.31 (d), 1H, J = 8: - (CH) -H 20 /. 4.63 (š ir.s, 1H: -H 2 '), 4.94 (š ir.d, 1H, J = 10: -H 5), 5.20 (S, H: -H 10), 5.28 (broad.d, 1H, J = 10: -H 3 '), 5.51 (D, lH, J = 10: -NH 3 ') / 5.68 (D, lH, J = 7: -H 2) 6.22 (t, 1 H, J = 8.5: -H 13) T 7.25 to 7.45 (mt, 5H: -C6 H5) in position 3 ' (-H 2 to 7.51 m / z, 2H, J = 7.5: -OCOCe H _s (-H 3 and H 5) /, 7.62 m / z, 1H, J = 7.5: -OCOCe H ₃ (-H 4) /, 8.12 (d, 2H, J) = 7.5: -OCOCe Hs (-H 2 and H 6) / ·

1-Methylcyclopropyl-1,2,2,2-tetrachloroethyl carbonate can be prepared as follows.

To a solution of 0.567 g of 1-methylcyclopropanol in 10 cm ^{3 of} dichloromethane maintained under argon at a temperature close to 5 ° C is added 0.38 cm ^{3 of} anhydrous pyridine and then, while maintaining this temperature, 0.72 cm ³ 1,2,2 , 2-ťetrachlóretylchlórformiátu. The reaction mixture is then stirred for 3 hours at a temperature in the region of 20 DEG C. and then 10 cm @ ^{3 of a} 1N aqueous hydrochloric acid solution are added. The aqueous phase is separated by decantation and then extracted with 10 cm @ ^{3 of} dichloromethane. The organic phases are combined, washed with 10 cm ^{3 of} saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

1.15 g of a pale yellow oil is obtained, which is purified by chromatography on 25 g of silica gel (0.063-0.2 mm) packed in a 1 cm diameter column using a 50:50 mixture of dichloromethane and cyclohexane as the eluent. and collecting 12 cm ³ fractions. The fraction is concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

There was thus obtained 1-methylcyclopropyl-1,2,2,2-tetrachloroethyl carbonate (0.14 g) as a colorless oil.

Example 7

If the procedure of Example 6 was followed, but starting from 0.60 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-tri chloroethoxy) carbonyloxy-11-taxen-13alpha-γ 12 -hydroxy-3- (2-chloro-1,1-dimethyl) ethoxycarbonylamino-3-phenylpropionate, obtained by the reaction of (2- chloro-1,1-dimethyl) ethyl-1,2,2,2-tetrachloroethyl carbonate with (2R, 3S) -4-acetoxy-2alpha-benzoyloxy5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-tri34-chloroethoxy) carbonyloxy-11-taxen-13a-phenyl-3-amino-2-hydroxy-3-phenylpropionate, then 0.203 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy- 5beta, 20-epoxy-1,7beta, 10beta-9-oxo-11-taxen13alpha-yl-2-hydroxy-3- (2-chloro-1,1-dimethyl) ethoxycarbonylamino-3-phenylpropionate as a white solid fluffy product which has the following characteristics:

optical rotation / alpha / ²⁰

D

-34 ° (c = 0.45, methanol), nuclear magnetic resonance spectrum:

(400 MHz, CDCl3) delta (ppm) 1.16 and 1.28 (2s, 3H each: -CHa 16 and -CHa 17) 1.41 and 1.44 / 2s, 3H each: -C ( CHa) ₂ /, 1.69 (s, 1H: --OH 1), 1.78 (s, 3H: --CH2), 1.80 up to 1.95 / mt, 1H: - (CH) -H 6 /, 1.87 (s, 3H: --CH3 18), 2.31 (ab, 2H, J = 16 and 9: -CH ₂ - 14), 2.37 (s, 3H: --COCH3), 2.60 (mt, 1H: - (CH) -H 6), 3.35 (mf, 1H: --OH 2 '), 3.65 and 3.76 (2d, 1H each, J = 11: -CHaCl) r 3.95 (d, HH, J = 7: -H3), 4.17 (broad s, 1H: -OH 10), 4.23 and 4.32 (2d, 1H each, J = 8: -CH = -20 ) 4.24 (mt, 1H: --H 7), 4.65 (broad s, 1H: -H 2 '), 4.95 (broad d, 1H, J = 10: -H5), 5.22 (s, 1H: -H 10), 5.30 (broad d, 1H, J = 10: -H3 ') T 5.58 (d, 1H, J = 10: -NH3 '), 5.71 (d, 1H, J = 7: -H 2), 6.27 (t, 1H, J = 9: -H 13) 7.30 up to 7.50 / mt, 5H: --C6 H5; position 3 '( -H 2 7.50 (t, 2H, J = 7.5: --OCOC6 H5) (-H 3 and -H 5) /. 7.61 m / z, 1H, J = 7.5: --OCOC6 H5 (H 4) /, 8.12 (d, 2H, J = 7.5: --OCOC6 H5) (-H 2 and -H 6) /.

r to - H 6) /,

Example 8

If the procedure of Example 6 was followed except that starting from 0.35 g of (2R, 3S) -4-acetoxy-.alpha. -Benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10betabi. s- (2,2,2-tri chloroethoxy) carbonyloxy-11-taxen-13a-phenyl-2-hydroxy-3-cyclohexylcarbonylamino-3-phenylpropionate, obtained by the reaction of cyclohexyl-1,2,2,2-tetrachloroethyl carbonate with ( 2 R, 3 S) -

4-Acetoxy-2a-pha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-yl-3- amino-2-hydroxy-3-phenylpropionate, yielding 0.090 g of (2R, 3S) -4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-11 -taxene-13a1a-2-hydroxy-3-cyclohexylcarbonyl-amino-3-phenylpropionate in the form of a white, fluffy product having the following characteristics:

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

1.16 and 1.28 (2s, 3H each: -CHa 16 and -CHa 17),

0.95 and 1.95 (mt, 10H: --CH2 --cyclohexyl),

1.77 (s, 3H: --CH2 19),

1.80 to 1.95 (mt, HH: - (CH) -H 6),

1.87 (s, 3H: --CH2 18),

2.27 (ab, 2H, J = 16 and 9: --CH-- 14),

2.42 (s, 3H: --COCH3),

2.61 (mt, 1H: - (CH) -H 6),

3.40 (broad s, 1H: --OH 2 '),

3.94 (d, 1H, J = 7: -H3),

4.15 to 4.30 (s, 2H: -OH 10 and -H 7),

4.20 and 4.33 (2d, 1H each, J = 8: -CH-20),

4.52 (mt, 1H: --CH cyclohexyl),

4.68 (broad s, 1H: -H 2 '),

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

5.23 (s, 1H: --H 10),

5.34 (broad d, 1H, J = 10: -H 3 '),

5.58 (d, 1H, J = 10: -NH3 '),

5.70 (d, 1H, J = 7: -H2),

6.27 (t, 1H, J = 9: -H 113) 7.25 to 7.50 m / z, 5H: -CoH5 v position 3 '(-H 2 to - H 6) /, 7.53 m / z, 2H, J = 7.5: -OCOC6H5 (-H 3 and -H 5) /. 7.64 m / z, 1H, J = 7.5: -OCOC6H5 (-H 4) /, 8.13 (d, 2H, J) = 7.5: -OCOC6H5 (-H 2 and -H 6) /.

Example 9

If the procedure of Example 6 was followed except that starting from 0.75 g of (2R, 3S) -4-acetoxy-2? -Benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10betabi s- (2,2,2-1ri-chloroethoxy) carbonyloxy-11-taxen-13a-phenyl-2-hydroxy-3-cyclobutyloxycarbonylamino-3-phenylpropionate, obtained by the reaction of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy -5beta, 20-epoxy-l-hydroxy-9-oxo-7-beta, 10.beta.-bis (2,2,2-trichloroethoxy) -11-taxen-a-L 3-yl-3-amino-2-hydroxy- 3-phenylpropionate with cyclobutyl-1,2,2,2-tetrachloroethyl carbonate, to give 0.128 g of (2R, 3S) -4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy -9-oxo-11-taxen-13a-1-yl-2-hydroxy-3-cyclobutyloxycarbonylamino-3-phenylpropionate as a white solid fluffy product having the following characteristics:

optical rotation [.alpha.] D @ ²⁰ = -31 DEG (c = 0.47, methanol), nuclear magnetic resonance spectrum:

(400 MHz, CDCl 3) delta (ppm)

1.13 and 1.23 (2 s, 3H each: -CH-CH ₃ 16 and 17).

1.30 and 2.30 (mt, 6H: _CH2 - cyclobutyl): 1.75 (s, 3H: _-CH3 19);

1.75 to 1.90 (mt, 1H: - (CH) -H 6),

1.82 (s, 3H: _-CH3 18);

2.10 to 2.30 (mt, 2H: --CH2 - 14),

2.37 (s, 3H, -COCH _3),

2.57 (mt, 1H: - (CH) -H 6)],

3.32 (broad mp, 1H: --OH 2 '),

3.90 (d, 1H, J = 7: -H3),

4.18 and 4.30 (2d, 1H each, J = 8, - -CH-20) 4.22 (mt, 1H: --H7), 4.62 (d, 1H, J = 2.5: H 2 '), 4.80 (quint., 1 H, J = 7,5 -CH cyclobutyl) 4.92 (broad d, 1H, J = 10: -H 5) F 5.18 (s, 1H: --H 10), 5.27 (broad d, 1H, J = 10: -H 3 ' ) 5.58 (d, 1 H, J = 10: -NH- 3 '), 5.66 (d, 11H, J = 7): -H 2), 6.22 (t, 11H, J = 9); -H 13), 7.25 up to 7.45 / mt, 5H : -C _s Hs v position 3 '( H 2 7.50 / t, 2H, J = 7.5. -OCOCeHs (H 3 and -H 5) /. 7.61 / t, 1H, J = 7.5: -OCOCgHs (H 4) /, 8.11 (d, 2H, J = 7.5): -OCOC & Hs (H 2 and -H 6) / ·

Example 10

When proceeding as in Example 6, except starting from 0.71 g of (2R, 3S) -4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-9-oxo-7beta, 10beta-bis- ( 2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13a-phenyl-2-hydroxy-3- (1-methylcyclopentyl) oxycarbonylamino-3-phenylpropionate, obtained by the reaction of 1-methylcyclopentyl-1,2,2,2 -tetrachloroethyl carbonate with (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9oxo-7-beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11- taxen-13-alpha-yl-3-amino-2-hydroxy-3-phenylpropionate, then 0.103 g of (2R, 3S) -4-acetoxy-2-alpha-benzoyloxy-5beta, 20epoxy-1,7-beta is obtained 1 Obeta-trihydroxy-9-oxo-11-taxen-13 alpha-1-yl-2-oxy-3- (1-methylcyclopenty1) oxycarbonylamino-3-phenylpropionate as a white solid fluffy product having the following characteristics:

optical rotation [alpha] ²⁰ = -28 ° (c = 0.50, methanol),

Z>

nuclear magnetic resonance spectrum:

(400 MHz, CDCl 3) delta (ppm)

1.15 and 1.26 (2s, 3H each: -CHa 16 and -CHa 17),

1.45 (s, 3H: - CH3-methylcyclopentyl),

1.40 to 1.75 and 2.03 (2mt, 6H and 2H, respectively: -CHa- 1-methylcyclopentyl),

1.76 (s, 3H: --CH2 19),

1.80 to 1.90 (mt, 1H: - (CH) -H 6),

1.85 (s, 3H: --CH2 18),

2.30 (d, 2H, J = 9: --CH-- 14),

2.36 (S, 3H: --COCH3),

2.59 (mt, 1H: - (CH) -H 6), 3.30 / mt mp, 1H: - (CH) -H 6 /. 3.30 (mol., 1H: --OH 2 '), 3.94 (d, 1H, J = 8: -CH-20), 4.22 (mt, 1H: -H: -H 7), 4.62 (d, 1H, J = 1.5: -H 2 '), 4.95 (broad d, 1H, J = 10: -H5) / 5.21 (s, 1H: -H 10), 5.26 (broad d, 1H, J = 10: -H3 ') ). 5.43 (d, 1H, J = 10: -NH 3 '), 5.70 (d, 1H, J = 7: -H 2), 6.23 (t, 1H, J = 9: -H 13), 7.30 up to 7.45 / mt, 5H: --C6 H5; position 3 ') - H 2 to -H 6) /, 7.50 (t, 2H, J = 7.5: --OCOC3 H5) (H 3 and -H 5) /. 7.61 / t, lH, J = 7.5: _D HS -0C0C (H 4) /. 8.11 [α] D, 2H, J = 7.5: -OCOC ₆ H = (H 2 and -H 6) /.

Example 11

When proceeding as in Example 6, except starting from (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo-7beta, 10beta-bis - (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13a-phyl-2-hydroxy-3- (3-pentyl) oxycarbonylamino-3-phenylpropionate, obtained by reaction of 3-pentyl-1,2,2,2-tetrachloroethyl carbonate with (2R, 3S) -4-acetoxy-.alpha.-benzoyloxy-5beta, 20-epoxy-1'-hydroxy-9-oxo-7beta, 10beta-6- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13alpha-.alpha.-3-amino- 2-hydroxy-3-phenylpropionate, then 0.115 g (2R, 39%) are obtained

3S) -4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10betatrihydroxy-9-oxo-11-taxen-13alpha-yl-2-hydroxy-3- (3-pentyl) oxycarbonylamino- 3-phenylpropionate in the form of a white solid fluffy product having the following characteristics:

optical rotation [.alpha.] D @ ²⁰ = -31 DEG (c = 0.52, methanol), nuclear magnetic resonance spectrum:

(CDCl 3, 400 MHz) δ (ppm)

0.76 and 0.84 (broad t, 3H each, J = 7.5: -CH ₃ pentyl),

1.15 and 1.26 (2 s, 3H each: -CH-CH ₃ 16 and 17).

1.40 to 1.60 (m, 4H, -CH-pentyl),

1.69 (s, 1H: --OH 1),

1.78 (s, 3H: --CH2 19),

1.80 to 1.95 (mt, 1H: - (CH) -H 6),

1.87 (s, 3H: --CH3 18),

2.31 (ab, 2H, J = 16 and 9: -CH-14),

2.38 (s, 3H, COCH _3),

2.60 (mt, 1H: - (CH) -H 6),

3.31 (d, 1H, J = 3: -OH 2 '),

3.94 (d, 1H, J = 7: -H 3),

4.17 (broad s, 1H: -OH 10),

4.22 and 4.32 (2d, 1H each, J = 8: -CH-20),

4.24 (mt, 1H: --H7),

4.55 (quint., 1H), J = 7.5: -CH (CaH _s ) and /,

4.65 (broad s, 1H: -H 2 '),

4.95 (broad d, 1H, J = 10: -H5),

5.22 (s, 1H: --H 10),

5.32 (broad d, 1H, J = 10: -H3 '),

5.54 (d, 1H, J = 10: -NH-3 '),

5.70 (d, 1H, J = 7: -H 2),

6.24 (t, 1H, J = 9: -H 13),

7.30 to 7.45 (mt, 5H: -C5 H5 at the 3 'position (-H2 to -H6)),

7.50 (t, 2H, J = 7.5: --OCOC _and H = (--H3 and --H5)),

7.61 (t, 1H, J = 7.5: --OCOC6 H5 (--H4)),

8,1.-2 / d, 2H, J = 7.5: -OCOC _{S (--H} 2 and H 6) /.

Example 12

To a solution of 0.16 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-11-taxene-13alpha-2-hydroxy-3- (0) 4-Methoxy-2-benzyloxy-1,1-dimethyl / ethoxycarbonylamino-3-phenylpropionate in 10 cm ^{3 of} dichloromethane, maintained under argon at 0 ° C, is added 0.115 g of 2,3-dichloro-5, 6-dicyanobenzoquinone, and then with 0.2 cm ³ of distilled water. the mixture was stirred for one hour and 30 minutes at a temperature close to 20 DEG C., followed by the addition of 100 cm ³ of dichloromethane. the organic phase is separated by settling, washed with 50 cm ^{3 of} saturated aqueous sodium bicarbonate solution and then 50 cm ^{3 of} distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.

0.171 g of white solid fluffy product is obtained, which is purified by chromatography on 10 g of silica gel (0.063-0.2 mm) packed in a 1 cm diameter column using a 95: 5 mixture of dichloromethane and methanol. and collecting 5 cm ³ fractions. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

There was obtained 0.083 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy5beta, 20-epoxy-1,7beta, 10beta-trihydroxy-9-oxo-11-taxen-13alpha-yl-2-hydroxy-3- ( 2-hydroxy-1,1-dimethyl) ethoxycarbonylamino-3-phenylpropionate in the form of a white solid fluffy product having the following characteristics:

optical rotation [.alpha.] D @ ²⁰ = -31 DEG (c = 0.47, methanol), nuclear magnetic resonance spectrum:

(400 MHz, CDCl 3 + CD 3 OD) delta (ppm)

1.01 and 1.10 (2s, 3H each: -CH ₃ 16 and -CH _S 17),

1.18 to 1.22 (2 s, 3H each: C _{(CH3) 2} /,

1.62 (s, 3H: --CH2 19), 1.70 up to 1.85 / mt, 1H: - (CH) -H 6 /, 1.80 (s, 3H: -CH 3 18), 2.04 to 2.17 (2dd, 2H, J = 16 and 19: -CH2-) 2.28 (s, 3H: --COCH3), 2.39 (mt, 1H: - (CH) -H 6), 3.26 and 3.46 / 2d, 2H, L = 13: - C (CH with CH · OH), 3.76 (d, 1H, J = 7: -H3), 4.08 (dd, 1H, J = 13 and 7: -H 7) F 4.13 and 4.19 (2d, 1H each, J = 8: -CH 2 -) 4.46 (d, 1H, J = 2: -H 2 '), 4.85 (broad d, 1H, J = 10: -H5), 5.10 (s, 1H: -H 10), 5.11 (d, 1H, J = 2: -H 3 '), 5.55 (d, 1H, J = 7: -H 2), 6,12 (t, 11H, J = 9: -H 13) 7.15 to 7.35 / mt, 5H: --C6 H5; position 3 '(-H 2 to 7.38 (t, 2H, J = 7.5: --OCOC6 H5) (-H 3 and -H 5) /, 7.49 (t, 1H, J = 7.5: --OCOC6 H5) (H) /. 7.97 (d, 2H, J = 7.5: --OCOC3 H5) (-H 2 and -H 6)].

(2R, 3S) 4-acetoxy-2.alpha.-benzoyloxy-5?, 20-epoxy-7.beta. 1Obeta-trihydroxy-9-oxo-l1-taxen-l3alfa-yl-2-hydroxy-3/2 (4 -methoxy) benzoyloxy (1,1,1-dimethyl) ethoxycarbonylamino-3-phenyl propionate is obtained by reacting zinc in acetic acid with (2R, 3S) -

4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-1'-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11taxa-13a-phly-2-hydroxy-3- (2 - [(4-methoxy) benzoyloxy] -1,1-dimethyl] ethoxycarbonylamino-3-phenylpropionate, which in turn is obtained by reaction of [2- (4-methoxy) benzyloxy] -1,1-dimethylethylene-1, 2,2,2-tetrachloroethyl carbonate with (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20epoxy-1'-hydroxy-9-oxo-7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-1 3-amino-2-hydroxy-3-phenylpropionate.

(4-Methoxy) -1-benzyloxy-2-methyl-2-propanol can be prepared as follows.

To 120 cm ^{3 of} anhydrous dimethylformamide, maintained under an argon atmosphere, at a temperature close to 15 ° C, 9.6 g of an oil supernatant (50¾ by weight) of sodium hydride are added, and then a solution of 10.9 g of l- chloro-2-methyl-2-propanol in 20 cm ^{3 of} anhydrous dimethylformamide. The reaction mixture is then stirred for 2 hours at a temperature in the region of 20 DEG C., then a solution of 12.5 cm @ ^{3 of} 4-methoxybenzyl alcohol in 20 cm @ ^{3 of} anhydrous dimethylformamide is added dropwise at a temperature in the region of 20 DEG. temperature for 48 hours. Thereafter, the reaction mixture is heated at 60 ° C for 8 hours, then cooled to a temperature in the region of 20 ° C and maintained at this temperature for 16 hours.

The reaction mixture is then added to 1200 cm ^{3 of} distilled water and acidified to a pH close to 5 by addition of 175 cm ^{3 of} aqueous hydrochloric acid solution. After addition of 250 cm ^{3 of} dichloromethane, the aqueous phase is separated by decantation, followed by extraction twice with 250 cm ^{3 of} dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered under reduced pressure (2.7 kPa) at 40 ° C and then at 0.27 kPa at 60 ° C. The residual oil is purified by chromatography on 500 g of silica gel (0.063-0.2 mm) contained in a 5 cm diameter column, eluting with dichloromethane alone and collecting 75 cm ³ fractions. Fractions 13 to 45 are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

There was thus obtained 1- (4-methoxy) benzyloxy-2-methyl-2-propanol (13.6 g) as a yellow oil.

[2- (4-Methoxy) benzyloxy] -1,1-dimethyl] ethyl-1,2,2,2-tetrachloroethyl carbonate is obtained by reacting 1- (4-methoxy) benzyloxy-2-methylpropanol with 1,2,2,2- tetrachloroethyl chloroformate in the presence of pyridine at 0 ° C.

Example 13

When proceeding as in Example 4, except that starting from 0.26 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo -7beta, 10beta-bis- (2,2,2-trichloroethoxy) carbonyloxy-11-taxen-13a-phyl-2-hydroxy-3- (1,1-dimethyl-2-propyne) yloxycarbonylamino-3-phenylpropionate, obtained by reaction 1 1-dimethylpropine-4-nitrophenyl carbonate with (2R, 3S) -4-acetoxy-2-alpha-benzoyloxy-5beta, 20-epoxy-1-hydroxy-9-oxo7beta, 10beta-bis- (2,2,2- trichloroethoxy) carbonyloxy-11-taxen-13 alpha-yl-3-amino-2-hydroxy-3-phenylpropionate, then 0.013 g of (2R, 3S) -4-acetoxy-2-alpha-benzoyloxy-5beta, 20- epoxy-1,7 beta, 10beta-trihydroxy-9-oxo-11-taxen-13alpha-yl-2-hydroxy-3 (1,1-dimethylamino-propyne) yloxycarbonylamino-3- Phenylpropionate in the form of a white solid fluffy product having the following characteristics:

nuclear magnetic resonance spectrum:

(400 MHz, CL > C1 ₃₎ d (in ppm) 1.15 (S, 3H: -CHs 16 or 17 ) 1, 26 (S, 3H: -CH 16 or 17 ) 1.60 and 1.64 / 2s, 3H each: ( C (CH ₃ W, 1.67 (S, H: -OH 1), 1.79 (S, 3H: -CH.3 19), 1.87 (S, 3H: -CH3 18), 1, 87 / Mt, H: - (CH) -H 6 ', 2.35 (ab lim lit. ), J = 16 and 9 Hz, 2H: --C 2.38 (s, 3H: -COCHs) 2.43 (S, H: -C? CH), 2.60 / Mt, 1H: - (CH) -H 6 ', 3.27 (d, J = 4.1H: -OH 2 ') / 3.95 (d, J = 7, 1H: -H 2), 4.17 (Bs, 1H: --OH: --OH 10) 4.23 / d, J = 8.1H: - (CH) -H 20 /. 4.23 / Mt, 1H: -H 20 /, 4.32 / d, J = 8.1H: - (CH) -H 20 /. 4.64 (Mt, 1H: -H 2 '), 4.95 (dd, J = 10 and 2, 1H: -H 5), 5.21 (Bs, 1H: -H 10), 5.33 (broad.d, J = 10.1H: --H 3 ' )

• i

5.52 (d, J = 10.1H: -NH- 3 '), 5.71 (s, J = 7.1H: -H 2), 6.26 (t, J = 9.1H: -H 13), 7.30 to 7.45 m / z, 5H: -CeH5 v position 3 '( : -h 2 7.52 / t, J = 7.5.2H: --OCOC6 H5 (-H 3 and -H 5) /. 7.63 / t, J = 7.5.1H: --OCOC6 H5 (-H 4) /, 8.12 / d, J = 7.5.2H: -OCOCcH-. (-H 2 and -H 6) /.

until

(6)], in the form of Cr1,1-Dimethyl-2-propyne-4-nitrophenyl carbonate colored crystals of melting point, obtained by reacting 1,1-dimethyl-2-propinol with 4-nitrophenyl chloroformate.

movo ° C can

The novel products of the formula I have particularly interesting biological effects.

or / and muscular, sexual pancreas,

These novel products of the general formula exhibit abnormal cell proliferation and have the ability to treat a pathological condition associated with said cell ration. These pathological conditions proliferate malignant or non-malignant organs, not limiting bone or connective tissue, organs, lymphatic or gland or blood cells, thyroid and adrenal

i.

I í i ľ

Significantly inhibitory therapeutic factors occurring may also include ovarian cancer, kidney cancer, cancer, choriocarcinoma, melanomas, and acute disease, 1eukemia and disease products, when abnormally proliferate abnormal cells of various tissues in a manner including skin, brain, lung, kidney gastrointestinal tract, glands. These pathological psoriasis, solid tumors, breast cancer, brain cancer, prostate cancer, colon cancer, stomach cancer, testicular cancer, Kaposi's sarcoma, cholagiocarcin, neuroblastoma, Wilms' tumor, Hodgkin's multiple myeloma, chronic lymphocytic or chronically granulocytic. The new inventions are particularly useful in the treatment of ovarian cancer. The products of the invention may be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.

The products of the invention may be administered to the patient in a variety of forms appropriate to the route of administration chosen, which is preferably parenteral. Parenteral administration includes intravenous administration, intraperitoneal administration, intramuscular administration, or subcutaneous administration. More preferred administration is intraperitoneal or intravenous administration.

The invention also encompasses pharmaceutical compositions comprising at least one product of Formula Ia in an amount sufficient to be used in human or veterinary medicine. These compositions can be prepared by conventional methods using one or two methods, respectively. one or more pharmaceutically acceptable excipients, carriers, or excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents. Preferably, these pharmaceutical compositions take the form of aqueous solutions or suspensions and injectable solutions which may contain emulsifying agents, coloring agents, preservatives or stabilizing agents.

The choice of additives or excipients may be affected by the solubility and chemical properties of the product used, the route of administration, and conventional pharmaceutical practices.

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

It goes without saying that all products forming part of the pharmaceutical composition must be pure and non-toxic in the amounts used.

These compositions may contain at least 0.01% of the therapeutically active agent. The amount of active ingredient in the composition is such that a suitable dosage can be prescribed. Preferably, these pharmaceutical compositions are prepared so that the unit dose contains 0.01 to 1000 mg of active ingredient in the case of parenteral administration.

The products of the invention may be administered concomitantly with the administration of other therapeutically active agents, including antineoplastic drugs and monoclonal antibodies, as well as with immunological therapy or radiotherapy, or simultaneously with the administration of biological response modifiers. These biological response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (alpha, beta or delta) and TNF.

Other chemotherapeutic agents useful in the treatment of disorders due to abnormal cellular proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechlorethamine, cyclophosphamide, melpalane and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmusin, trisin, and carmusin, carmusin; , antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs such as mercaptopurine to thioquanine, natural products such as vinea rosea alkaloids such as vinblastine, vineristine and vendesin, epipodophyllosine tenin, such as epipodophyllotoxins, such as epipodophyllidosin, , daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid suppressors such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrololacetate, oestrogens such as diethylstilbestiol and testosterone estrogen ester and ethinyl estrone estrogen and ethinyl estrone estrogen.

Useful dosages within the practice of the method of the invention are those that allow for prophylactic treatment or maximal therapeutic response. Doses vary depending on the route of administration, the particular product selected, and the characteristics of the patient being treated. Generally, these doses are those that are therapeutically effective for treating disorders due to abnormal cell proliferation. The products of the invention may be administered as often as necessary to achieve the desired therapeutic effect. For some diseases, a rapid response to relatively high or low doses may be achieved and then only low maintenance doses or no doses should be administered. Generally, only low doses will be administered at the start of treatment, followed by increasing doses if necessary until the optimal effect is achieved. For other diseases, the required maintenance doses may be administered 1 to 8 times daily, preferably 1 to 4 times daily, depending on the physiological need of the patient. It is also possible that, for some diseases, the active ingredient will only need to be administered once or twice a day.

In humans, these doses are generally 0.01 to 200 mg / kg. For intraperitoneal administration, these doses will generally be 0.1 to 100 mg / kg, preferably 0.5 to 50 mg / kg and even more specifically 1 to 10 mg / kg. When administered intravenously, these doses are generally 0.1 to 50 mg / kg, preferably 0.1 to 5 mg / kg and even more specifically 1 to 2 mg / kg. Obviously, the choice of the most appropriate dosage will depend on the route of administration, the weight of the patient, his general health, age and any other factors that may affect the effectiveness of the treatment.

The following example illustrates a composition of the invention.

Example mg of the product obtained in Example 1 is dissolved in 1 cm ³ of Emulphor EL 620 and 1 cm ^{3 of} ethanol, then the solution obtained is diluted with 18 cm ^{3 of} saline. This composition is administered by perfusion of saline for one hour.

Claims (13)

Novel taxane derivatives of general formula in which Ar represents an aryl group, ri represents a hydrogen atom or an acetyl group and R means straight or branched (C1-C6) alkyl C 8 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl or bicycloalkyl C 8 -C 8 alkenyl; C 7 -C 10 optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxy, C 1-4 alkyloxy, dialkylamino wherein each alkyl radical contains 1-4 carbon atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted at the 4-position with a carbon-containing alkyl or phenylalkyl, carbon, 1-4 atoms in which the alkyl radical contains a cycloalkyl group containing a cycloalkenyl group containing a phenyl group, a cyano group or an alkyloxycarbonyl group, the shock contains 1 to 4 carbon atoms, up to up to carbon, carbon and carboxyl alkyl atoms of which group which is optionally substituted or substituted by a number of 1-4 carbon atoms having from 1 to 4 carbon atoms having from 1 to 4 carbon atoms selected from halogen, alkyl and alkyloxy containing 5- or 6-membered saturated or unsaturated a nitrogen-containing heterocyclic group which is optionally substituted by one or more C 1 -C 4 alkyl groups, wherein the cycloalkyl group may be substituted by one or more C 1 -C 4 alkyl groups by several alkyl cycloalkenyl or bicycloalkyl groups and, and when Ar is unsubstituted phenyl and R 1 is hydrogen or acetyl, R cannot be ethyl or tert-butyl, and when Ar is substituted phenyl or optionally substituted alpha or beta-naphthyl and R 1 is hydrogen or acetyl, R cannot be tert-butyl. 2. The novel taxane derivative according to claim 1, wherein Ar represents a phenyl group or an alpha or beta-naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms (such as fluorine atom, chlorine atom, bromine atom and iodine), alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, wherein: alkyl groups and alkyl radicals of the other groups contain 1 to 4 carbon atoms, alkenyl groups and alkynyl groups having 3 to 8 carbon atoms and aryl groups are phenyl or alpha or beta-naphthyl. The novel taxane derivatives of claim 1, wherein Ar is a phenyl group, which is optionally substituted with one or more of the same or different substituents selected from the group consisting of xy, amino, acylamino, trifluoromethyl. halogen, alkyl, alkoalkylamino, dialkylaminoalkoxycarbonylamino, and The novel taxane derivatives according to claim 1, in which Ar represents a phenyl group which is optionally substituted by a chlorine or fluorine atom or an alkyl group, for example a methyl group, an alkoxy group, for example a methoxy group, a dialkylamino group, for example a dimethylamino group. , acylamino, for example acetylamino, or alkoxycarbonylamino, for example tert-butoxycarbonylamino. Process for the preparation of novel taxane derivatives according to one of Claims 1 to 4, characterized in that a derivative of the general formula (I) is reacted. II RO-CO-X (II) wherein R is as defined in claim 1 and X is a halogen atom, for example a fluorine atom or a chlorine atom, or -O-R, -O-CO-OR or -O-Ph, wherein Ph represents a phenyl group substituted by an electrophile, or 1,2,2,2-tetrachloroethoxy group, with a baccatin III or 10-deacetylbaccatin III derivative of the general formula in which Ar is as defined in any one of claims 1 to 4, G _{: 1} is a hydroxy protecting group functions such as 2,2,2-trichloroethoxycarbonyl or trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl, in which each alkyl radical contains 1 to 4 carbon atoms and each aryl radical preferably represents a phenyl group, and G 5 represents an acetyl group or a hydroxy function, such as a 2,2,2-trichloroethoxycarbonyl group, to give a product of the general formula 53 in which Ar, R, Gi and Gz have the meanings given above, the groups Gi and Gz are subsequently replaced with hydrogen atoms. Process according to claim 5, characterized in that the reaction of a reactive derivative of the general formula II in which X represents a halogen atom or an -O-R or -O-CO-OR group with a baccatin III or a 10-deacetylbaccatin III derivative of the general formula III is carried out in an organic solvent such as an ester such as ethyl acetate in the presence of a mineral or organic base such as sodium bicarbonate at a temperature of 0 to 50 ° C, preferably at a temperature near 20 ° C. 7. A process according to claim 5, wherein the reaction of a reactive derivative of formula II wherein X is -O-Ph is carried out in an organic solvent selected from ethers, nitriles, amides and halogenated aliphatic hydrocarbons at a temperature of 50 to 50 ° C. Mp 100 ° C. A process according to claim 5, characterized in that the reaction of a reactive derivative of the general formula II in which X represents a 1,2,2,2-tertrachloroethoxy group is carried out in an organic solvent selected from ethers, nitriles, amides and aromatic amines at near 0 ° C. Process according to Claim 5, characterized in that the replacement of the protecting groups G 1 and G 2 of the product of formula IV by hydrogen atoms is carried out by treatment with zinc in acetic acid at a temperature of 30 to 60 ° C or a mineral or organic acid such as hydrochloric acid or acetic acid. , in a solution in an aliphatic alcohol containing 1 to 3 carbon atoms in the presence of zinc when Gi and / or Gz is 2,2,2-trichloroethoxycarbonyl) or in an acidic environment if Gi and / or Gz is a silylated group . Process for the preparation of a novel taxane derivative according to one of claims 1 to 4, characterized in that the acid of the general formula (XVI) is reacted. Ar COOH /IN ' / RO-CO-NH \ og ₃ (XVI) * wherein Ar is as defined in any one of claims 1 to 4, R is as defined in claim 1 and Ga represent a hydroxy-protecting group such as methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (beta-trimethylsilylethoxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl or 2,2,2- a trichloroethoxycarbonyl group, optionally in the form of an anhydride, with a taxane derivative of the general formula VII is subsequently replaced by protecting groups Gi, Ga and Ga with hydrogen atoms. The method of claim 10, wherein the esterification is carried out in the presence of a condensing agent such as a carbodiimide such as dicyclohexylcarbodiimide or a reactive carbonate such as 2-pyridylcarbonate, and an activating agent such as an aminopyridine such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine. an organic solvent such as an aromatic hydrocarbon, for example (benzene, propylbenzene and chlorobenzene), toluene, xylenes, ethylbenzene, isoether, for example tetrahydrofuran, nitrile, for example acetonitrile, ester, for example ethyl acetate, at 0 to 90 ° C. Process according to claim 10, characterized in that the replacement of the protecting groups Gi, Ga and Gs with hydrogen atoms is carried out by treatment with zinc in the presence of acetic acid at a temperature of 30 to 60 ° C or a mineral or organic acid such as hydrochloric acid or acetic acid. in a solution in an aliphatic alcohol containing 1 to 3 carbon atoms in the presence of zinc when one of the protecting groups is a 2,2,2-trichloroethoxycarbonyl group, or in an acidic environment when one of the protecting groups is a silyl group. IN A pharmaceutical composition comprising a sufficient amount of at least one derivative according to any one of claims 1 to 4 in pure form or in combination with one or more pharmaceutically acceptable products that are inert or physiologically active.