WO1996001259A1

WO1996001259A1 - Novel taxoids, preparation thereof and pharmaceutical compositions containing same

Info

Publication number: WO1996001259A1
Application number: PCT/FR1995/000885
Authority: WO
Inventors: Hervé Bouchard; Jean-Dominique Bourzat; Alain Commerçon
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1994-07-04
Filing date: 1995-07-03
Publication date: 1996-01-18
Also published as: FR2721928A1; AU2929095A

Abstract

Novel taxoids of general formula (I). In general formula (I), X is an oxygen or sulphur atom; Z is a hydrogen atom or a radical of general formula (II), wherein R1 is an optionally substituted benzoyl radical or a radical R2-O-CO- where R2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl or heterocyclyl radical, and R3 is an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl or aromatic heterocyclic radical. The novel products of general formula (I), wherein Z is a radical of general formula (II), have remarkable antitumoral and antineoplastic properties.

Description

NEW TAXQIPES. THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS YES CONTAINING THEM

The present invention relates to new taxoids of general formula:

OCOC ₆ H ₅ in which:

- X represents an oxygen or sulfur atom,

- Z represents a hydrogen atom or a radical of general formula

in which: Ri represents a benzoyl radical optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms or trifluoromethyl, thenoyl or furoyl or an R2-O-CO- radical in which R2 represents: - a straight or branched alkyl radical containing 1 to 8 carbon atoms, straight or branched alkenyl containing 2 to 8 atoms 4th carbon, straight or branched alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from atoms halogen and hydroxy radicals, alkoxy containing 1 to 4 carbon atoms, dialkoylamino each alkyl part of which contains 1 to 4 carbon atoms, piped ridino, morpholino, pipérazinyl-1 (optionally substituted in -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms , cycloalkenyl containing 4 to 6 carbon atoms, phenyl (optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms), cyano, carboxy or alkoxycarbonyl in which the alkyl part contains 1 with 4 carbon atoms, - a phenyl or α- or β-naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms or a 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals, - or a saturated heterocyclyl radical containing 4 to 6 carbon atoms optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms,

R3 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, straight or branched alkenyl containing 2 to 8 carbon atoms, straight or branched alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, phenyl or α- or β-naphthyl optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto radicals, formyl, acyl, acylamino, aroylamino, alkoxycarbonyl amino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro, trifluoromethoxy and trifluoromethyl, or an aromatic heterocycle having 5 members and containing one or more heteroatoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms and optionally substituted by one or more s ubstituents, identical or different, chosen from halogen atoms and alkyl, aryl, amino, alkyllamino, dialkoylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxy, carbamoyl, alkylcarbamoyl, dialcoylcarbamoyl or alkoxycarbon radicals substituents of the phenyl, α- or β-naphthyl and aromatic heterocyclyl radicals, the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the radicals aryls are phenyl or α- or β-naphthyl radicals.

Preferably, the aryl radicals which can be represented by R3 are phenyl or α- or β-naphthyl radicals optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals , alkenyls, alkynyls, aryls, arylalkyls, alkoxy, alkylthio, aiyloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alcoylamino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, dialkoylcarbamoyl, cyano, nitro and trifluoromethyl radicals being alkyl and nitro and trifluoromethyl radicals, including alkyls and trifluoromethyls, alkyls and trifluoromethyls being alkyl other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or a- or β-naphthyl radicals.

Preferably, the heterocyclic radicals which can be represented by R3 are aromatic heterocyclic radicals having 5 members and containing one or more atoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted by one or more substituents, identical or different, chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms carbon, aryloxy containing 6 to 10 carbon atoms, amino, alkylamino containing 1 to 4 carbon atoms, dialkoylamino in which each alkyl part contains 1 to 4 carbon atoms, acylamino in which the acyl part contains 1 to 4 carbon atoms, alkoxycarbonylamino containing 1 to 4 carbon atoms, acyl containing 1 to 4 carbon atoms, arylcarbonyl the aryl part of which contains 6 to 10 carbon atoms, cyano, carboxy, carbamoyl, alkylcarbamoyl in which the alkyl part contains 1 to 4 carbon atoms, dialkoylcarbamoyl in which each alkyl part contains 1 to 4 carbon atoms or alkoxycarbonyl in which the alkoxy part contains 1 to 4 carbon atoms.

More particularly, the present invention relates to the products of general formula (I) in which X represents an oxygen atom, Z represents a hydrogen atom or a radical of general formula (II) in which R represents a benzoyl radical or a R2-O-CO- radical in which R2 represents a tert-butyl radical and R3 represents an alkyl radical containing 1 to 6 carbon atoms, alkenyl containing 2 to 6 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, optionally phenyl substituted by one or more, identical or different atoms or radicals chosen from halogen atoms (fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy), dialkoylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tert -butoxycarbonylamino) or trifluoromethyl or a furyl-2 or -3, thienyl-2 or -3 or thiazolyl-2, -4 or -5 radical.

More particularly still, the present invention relates to the products of general formula (I) in which X represents an oxygen atom, Z represents a hydrogen atom or a radical of general formula (II) in which R _± represents a benzoyl radical or an R2-O-CO- radical in which R2 represents a tert-butyl radical and R3 represents an isobutyl, isobutenyl, butenyl radical, cyclohexyl, phenyl, furyl-2, furyl-3, thienyl-2, thienyl-3, thiazolyl-2, thiazolyl-4 or thiazolyl-5.

The products of general formula (I) in which Z represents a radical of general formula (II) have remarkable antitumor and antileukemic properties.

According to the invention, the products of general formula (I) can be obtained by the action of a carbonyl or thiocarbonyl derivative, which makes it possible to form a carbonate or a thiocarbonate, of general formula:

X! -C (= X) -X ₂ (III) in which X is defined as above, Xj represents a halogen atom such as a chlorine atom or an imidazolyl-1 radical and X2 represents a halogen atom such as a chlorine atom or an imidazolyl-1 radical or an alkoxy radical containing 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, on a product of general formula:

OCOC ₆ H ₅ in which Z \ represents a hydrogen atom or a radical of general formula

in which R and R3 are defined as above, or either R4 represents a hydrogen atom and R5 represents a protective group for the hydroxy function, or else R4 and R5 together form a heterocycle, to obtain a product of general formula:

OCOC ₆ H ₅ optionally followed by the replacement of the protective groups R5 and / or R4 and R5 carried by Z \ by hydrogen atoms.

When Z \ represents a radical of general formula (V), preferably, R4 represents a hydrogen atom and R5 represents a protecting group for the hydroxy function or else R4 and R5 together form a saturated heterocycle with 5 or 6 members.

When R4 represents a hydrogen atom, R5 preferably represents a methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, β-trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydro-pyrannyl radical.

When R4 and R5 together form a heterocycle, the latter is preferably an oxazolidine ring optionally mono-substituted or gem-disubstituted in position -2. The reactive agents which make it possible to prepare a carbonate or a thiocarbonate from a keto-alcohol are generally chosen from N-carbonyldiimidazole, phosgene, thiophosgene, alkyl chloroformiates and alkyl chlorothiormormates.

Depending on the reaction conditions of the product of general formula (III) with the product of general formula (IV), it is possible to use an intermediate of a product of general formula:

OCOC ₆ H ₅ in which X, X2 and Z \ are defined as above.

Generally, the reaction of a product of general formula (III) with a product of general formula (IV) is carried out by operating in an organic solvent preferably chosen from aromatic hydrocarbons such as benzene, toluene or xylenes and the ethers such as ethyl ether, diisopropyl ether or tetrahydrofuran optionally in the presence of a condensing agent preferably chosen from tertiary amines such as triethylamine, dimeftylaniline, 4-dimethyl ylamino pyridine or 4-pyrrolidino pyridine at a temperature between -40 ° C and the reflux temperature of the reaction mixture. It may be advantageous to activate the hydroxy function in position 10 of the product of general formula (IV) in the form of an alkali metal alcoholate which can be obtained by the action of an organometallic derivative such as a metal alkyl such as butyllithium , an alkylmagnesium halide or an amide such as lithium diisopropylamide.

Generally, the product of general formula (VII) is obtained by operating at a temperature below 50 ° C in the absence of condensing agent. The product of general formula (VI) is then obtained by heating the product of general formula (VII) at a temperature above 50 ° C in the presence of a condensing agent as defined above.

The replacement of the protective groups R5 and / or R4 and R5 carried by Z \ by hydrogen atoms can be carried out, according to their nature, as follows: 1) when R4 represents a hydrogen atom and R5 represents a protective group of the hydroxy function, the replacement of the protective groups by hydrogen atoms is carried out by means of a mineral acid (hydrochloric acid, sulfuric acid, hydrofluoric acid) or organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p.toluenesulfonic acid) used alone or as a mixture, operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between -10 and 60 ° C or by catalytic hydrogenation or by the action of a hydrofluoric acid-triethylamine or hydrofluoric acid-pyridine complex.

2) when R4 and R5 together form a 5 or 6-membered saturated heterocycle and more particularly an oxazolidine ring of general formula:

in which R _± is defined as above, Rg and R7, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical in which the alkyl part contains 1 to 4 carbon atoms and the aryl part preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical representing, preferably a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or Rg represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R7 represents a hydrogen atom, or else Rg and R7 together with the carbon atom to which they are linked form a ring having 4 to 7 links, replacing the g protective group formed by Rg and R7 by hydrogen atoms can be carried out, according to the meanings of R, Rg and R7, in the following way: a) when Rj represents a tert-butoxycarbonyl radical, Rg and R7, identical or different , represent an alkyl radical or an aralkyl (benzyl) or aryl (phenyl) radical, or else Rg represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical, and R7 represents a hydrogen atom, or else Rg and R7 form together a cycle having from 4 to 7 links, the treatment of the ester of general formula (VI) with a mineral or organic acid optionally in an organic solvent such as an alcohol leads to the product of general formula:

in which X and R3 are defined as above, which is acylated by means of benzoyl chloride in which the phenyl ring is optionally substituted, of thenoyl chloride, of furoyl chloride or of a product of general formula: R ₂ -O -CO-Y (X) in which R2 is defined as above and Y represents a halogen atom (fluorine, chlorine) or a residue -O-R2 or -O-CO-O-R2, to obtain a product of formula general (I) in which Z represents a radical of general formula (II). Preferably, the product of general formula (Vf) is treated with formic acid at a temperature in the region of 20 ° C.

Preferably, the acylation of the product of general formula (IX) by means of a benzoyl chloride in which the phenyl radical is optionally substituted, of thenoyl chloride, of furoyl chloride or of a product of general formula (X ) is carried out in an inert organic solvent chosen from esters such as ethyl acetate, isopropyl acetate or n.butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1-dichloro, 2 ethane in the presence of a mineral base such as sodium bicarbonate or organic such as triethylamine. The reaction is carried out at a temperature between 0 and 50 ° C, preferably close to 20 ° C. b) when R \ represents an optionally substituted benzoyl radical, thenoyl or furoyl or an R2O-CO- radical in which R2 is defined as above, Rg represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms and R7 represents a hydrogen atom, the replacement of the protective group formed by Rg and R7 by hydrogen atoms is carried out in the presence of an acid mineral (hydrochloric acid, sulfuric acid) or organic (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p.toluenesulfonic acid) used alone or as a mixture in quantity stoichiometric or catalytic, operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature between -10 and 60 ° C, preferably between 15 and 30 ° C. The product of general formula (IV) can be obtained under the conditions described in French patent FR 2698 871

According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II) can be obtained by esterification of a product of general formula (I) in which Z represents a hydrogen atom with means of an acid of general formula:

in which R, R3, R4 and R5 are defined as above, or of a derivative of this acid, followed by the replacement of the protective groups R5 and / or R4 and R5 by hydrogen atoms under the conditions described above. Esterification using an acid of general formula (XI) can be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between -10 and 90 ° C. Esterification can also be carried out using the acid of general formula (XI) in the form of anhydride, operating in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 90 ° C. The esterification can also be carried out using the acid of general formula (XI) in the form of halide or in the form of anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base (aliphatic amine tertiary) by operating in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 80 ° C. The new products of general formula (I) obtained by implementing the methods according to the invention can be purified according to known methods such as crystallization or chromatography.

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

In vitro, the measurement of the biological activity is carried out on the tubulin extracted from pig brain by the method of M.L. Shelanski et al., Proc. Natl. Acad. Sci. USA, 7Q, 765-768 (1973). The study of the depolymerization of microtubules into tubulin is carried out according to the method of G. Chauvière et al., C.R. Acad. Sci., 293. series II, 501-503 (1981). In this study, the products of general formula (I) in which Z represents a radical of general formula (II) have been shown to be at least as active as taxol and Taxotere.

In vivo, the products of general formula (I) in which Z represents a radical of general formula (II) have been shown to be active in mice grafted with melanoma B16 at doses of between 1 and 10 mg g intraperitoneally, as well than other liquid or solid tumors.

The new products have anti-tumor properties and more particularly an activity on tumors which are resistant to Taxol® or Taxotère®. Such tumors include colon tumors which have high expression of the mdr 1 gene (multi-drug resistance gene). Multi-drug resistance is a common term referring to the resistance of a tumor to different products with different structures and mechanisms of action. Taxoids are generally known to be highly recognized by experimental tumors such as P388 / DOX, a cell line selected for its resistance to doxorubicin (DOX) which expresses mdr 1.

The following example illustrates the present invention.

EXAMPLE

A solution containing 500 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5 (2R.4S.5R) of acetoxy-4α benzoyloxy-2α epoxy-5β, 20 dihydroxy-lβ.lOβ methylene-7,8β oxo-9 nor-19 taxene- 11 yle-13α and 270 mg of carbonyl-l, l'-diimidazole in 15 cm3 of anhydrous toluene is heated, under an argon atmosphere, to a temperature close to 55 ° C for 45 minutes. After cooling to a temperature in the region of 20 ° C, the reaction mixture is directly purified by chromatography at atmospheric pressure on 50 g of silica (0.063-0.2 mm) contained in a column 2.4 cm in diameter [eluent: ethyl acetate-dichloromethane (20-80 by volume)], collecting 20 cm 3 fractions. The fractions containing only the sought products are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 0.32 g of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5 (2R.4S.5R) of 4-acetoxy-benzoyloxy-2α epoxy-5β is thus obtained. , 20 hydroxy-lβ (imidazolyl-1 carbonyloxy) -10β methylene-7,8β oxo-9 nor-19 taxene-11 yle-13α in the form of a white meringue and 0.04 g of tert-butoxycarbonyl-3 (methoxy -4 phenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5 (2R.4S.5R) acetoxy- 4a benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 hydroxy-lβ methylene-7,8β nor- 19 taxadiene-9.11 yle-13α in the form of a white meringue.

A solution containing 320 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5 (2R.4S.5R) of acetoxy-4α benzoyloxy-2α epoxy-5β, 20 hydroxy-lβ (1-imidazolyl carbonyloxy) -10β methylene- 7.8β oxo-9 nor-19 taxene-11 yle-13α, 31 mg of carbonyl-l.l'-diimidazole and 16 mg of N, N'-dimethylamino -4 pyridine in 4 cm3 of anhydrous toluene is heated, under an argon atmosphere, to a temperature in the region of 110 ° C for 20 hours. After cooling to a temperature in the region of 20 ° C, the reaction mixture is purified directly by chromatography at atmospheric pressure on 20 g of silica (0.063-0.2 mm) contained in a column 1.6 cm in diameter [eluent : methanol-dichloromethane (3-93 by volume)], collecting 10 cm 3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 0.13 g of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) of acetoxy-4α benzoyloxy-2α carbonyldioxy-9 is thus obtained. , 10 epoxy-5β, 20 hydroxy-1 β methylene-7,8β nor-19 taxadiene-9,11 yle-13α in the form of a white meringue.

A solution of 170 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5 (2R.4S.5R) acetoxy-4α benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 hydroxy-lβ methylene-7,8β nor-19 taxadiene-9.11 yle-13α in 1.8 cm3 of a 0.1N hydrochloric acid solution in ethanol is stirred at a temperature close to 5 ° C, for 3 hours. A further 0.9 cm3 of 0.1N hydrochloric acid in ethanol is added. After 2 hours at a temperature in the region of 20 ° C., the reaction mixture is diluted with 10 cm 3 of dichloromethane, 4 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate. After decantation, the organic phase is washed with 4 cm3 of a saturated aqueous solution of sodium hydrogencarbonate, 2 times 4 cm3 of distilled water, dried over sodium sulfate. magnesium, filtered through sintered glass and concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. This gives 124 mg of a white meringue which is purified by preparative thin layer chromatography [5 Merck preparative plates, Kieselgel 60F254, thickness 0.5 mm, deposit in solution in dichloromethane, eluent: methanol-dichloromethane mixture ( 2.5-97.5 by volume)]. After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (10-90 by volume), filtration on sintered glass, then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 62 mg of a white meringue are obtained which are purified by preparative thin layer chromatography [2 Merck preparative plates, Kieselgel 60F254, thickness 1 mm, deposit in solution in dichloromethane, eluent: methanol-dichloromethane mixture (2.5 -97.5 by volume)]. After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (10-90 by volume), filtration through sintered glass, then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 38 mg of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) acetoxy-4α benzoyloxy-2α carbonyldioxy-9,10 epoxy-5β, 20 hydroxy-lβ methylene-7,8β nor are obtained -19 taxadiene-9.11 yle-13α in the form of a white meringue the characteristics of which are as follows: - NMR spectrum * H (400 MHz; CDC1 _3. Δ in ppm): 1.23 (s, 3H: CH ₃ ; 1.30 (s, 3H: CH ₃ ); 1.40 (s, 9H: C (CH ₃ )); 1.51 - 1.67 and 1.78 (3 mts, IH each: CH ₂ in 19 and H in 7); 1.73 (s, IH: OH in 1); 1.75 (d, J = 1 Hz, 3H: CH ₃ ); 2.14 and 2.30 to 2.40 (respectively d large (J = 16 Hz) and mt, IH each: CH2 in 6); 2.20 and 2.38 (2dd, J = 15 and 8.5 Hz, IH each: CH ₂ in 14); 2 , 28 (s, 3H: COCH3); 3.29 (d, J = 6.5 Hz, IH: H in 3); 3.39 (d wide. J = 5 Hz, 1H: OH in 2 '); 4.07 and 4.31 (2d, J = 9 Hz, 1H each: CH ₂ in 20); 4.61 (dd, J = 5 and 2.5 Hz, 1H: H in 2 '); 4.73 (broad d. J = 4 Hz, 1 H: H at 5); 5.23 (broad d, J = 10 Hz, 1H: H in 3 '); 5.34 (d, J = 10 Hz, 1 H: CONH); 5.68 (d, J = 6.5 Hz, 1H: H in 2); 6.16 (broad t, J = 8.5 Hz, 1 H: H at 13); from 7.25 to 7.45 (mt, 5H: aromatic H in 3 '); 7.48 (t, J = 7.5 Hz, 2H: OCOCgH ₅ H in meta); 7.58 (t, J = 7.5 Hz, 1 H: OCOCgH ₅ H para); 8.10 (d, J = 7.5 Hz, 2H: OCOCgH ₅ H in ortho).

Tert-butoxycarbonyl-3 (4-methoxy ρhenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 dihydroxy-l, 10β methylene-7,8β oxo-9 nor-19 taxene-11 yle-13α can be prepared as follows: To a solution of 1.8 g of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5 (2R.4S.5R) of acetoxy-4α benzoyloxy-2α epoxy- 5β, 20 dihydroxy-lβ.lOβ oxo-9 trifluoromethanesulfonate-7β taxene-11 yle-13 and in 20 cm3 of acetonitrile and 3 cm3 of tetrahydrofuran are added 1.5 g of sodium chloride and 0.5 g of molecular sieve 4Â. The reaction mixture is brought to reflux, under an inert argon atmosphere, for 1 hour, brought to a temperature in the region of 20 ° C., and filtered through sintered glass. The solid residue is rinsed with 10 cm3 of ethyl acetate. The filtrates are combined, dried over magnesium sulfate, filtered through sintered glass and concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 1.6 g of a yellow meringue are thus obtained which are purified by chromatography at atmospheric pressure on 60 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter [eluent: acetate ethyl-dichloromethane (20-80 by volume)] by collecting 10 cm 3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 0.91 g of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5 (2R.4S.5R) of acetoxy-4α benzoyloxy-2α epoxy-5β is thus obtained. , 20 dihydroxy-lβ.lOβ methylene- 7,8β oxo-9 nor-19 taxene-11 yle-13α in the form of a white meringue.

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5 (2R.4S.5R) acetoxy-4α benzoyloxy-2α epoxy-5β, 20 dihydroxy-l.lOβ oxo-9 trifluoromethanesulfonate-7β taxene-11 yle-13 can be prepared as follows:

To a solution of 1.9 g of tert-butoxycarbonyl-3 (methoxy-4 ρhenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) acetoxy-4 benzoyloxy-2α epoxy- 5β, 20 trihydroxy-lβ, 7β, 10β oxo-9 taxene-11 yle-13 in 20 cm3 of anhydrous dichloromethane and 0.68 cm3 of anhydrous pyridine, maintained under an argon atmosphere, at a temperature in the region of -35 ° C , 0.54 cm3 of trifluoromethanesulfonic anhydride is added dropwise. The reaction mixture is stirred for 10 minutes at -35 ° C, 90 minutes at a temperature in the region of -5 ° C, then added to a temperature in the region of -15 ° C of 5 cm 3 of distilled water. After decantation, the aqueous phase is extracted with 2 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered through sintered glass and concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 2.4 g of a yellow oil are thus obtained which are purified by atmospheric pressure chromatography on 100 g of silica (0.063-0.2 mm) contained in a column 3.2 cm in diameter [eluent: methanol-dichloromethane (2-98 by volume)], collecting 15 cm3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 1.23 g of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylate-5 (2R.4S.5R) of acetoxy-4α benzoyloxy-2α epoxy-5β are thus obtained. , 20 dihydroxy- lβ.lOβ oxo-9 trifluoromethanesulfonate-7β taxene-11 yle-13α in the form of a pale yellow meringue.

Tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4 benzoyloxy-2α epoxy-5β, 20 trihydroxy-1, 7β, 10β oxo-9 taxene-11 yle-13α can be prepared in the following manner:

A solution of 3.95 g of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylate-5- (2R, 4S, 5R) acetoxy-4 benzoyloxy-2α epoxy- 5β, 20 hydroxy-lβ oxo-9 bis- (2,2,2,2-ethichloro) carbonyloxy-7β, 10β taxene-11 yl-13α in a mixture of 20 cm3 of methanol and 7 cm3 of acetic acid is heated with stirring, under an argon atmosphere, to a temperature in the region of 60 ° C., then added with 2 g of zinc powder. The reaction mixture is then stirred for 15 minutes at 60 ° C then cooled to a temperature in the region of 20 ° C and filtered through sintered glass lined with celite. The sintered glass is washed with 2 times 15 cm 3 of methanol. The filtrate is concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 100 cm 3 of dichloromethane are added to the residue. The organic phase is washed with 2 times 10 cm3 of a saturated aqueous solution of sodium hydrogencarbonate and then with 10 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered through sintered glass, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 5.57 g of a white meringue are obtained which is purified by chromatography on 300 g of silica (0.063-0.2 mm) contained in a column 6 cm in diameter (elution gradient: methanol-dichloromethane of 0-100 to 2-98 by volume) by collecting fractions of 100 cm3. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours. 2.52 g of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidinecarboxylate-5- (2R, 4S, 5R)) of 4-acetoxy-benzoyloxy-2α epoxy-5β, 20 trihydroxy are thus obtained -1.7β, 10β oxo-9 taxene-11 yle-13α in the form of a white meringue.

The new products of general formula (I) in which Z represents a radical of general formula (II) demonstrate a significant inhibitory activity of abnormal cell proliferation and have therapeutic properties allowing the treatment of patients with pathological conditions associated with abnormal cell proliferation. Pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs, including, but not limited to, muscle, bone or connective tissue, skin, brain, lungs, sexual organs, the lymphatic or renal systems, the mammary or blood cells, the liver, the digestive system, the pancreas and the thyroid or adrenal glands. These pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas. The new products according to the invention are particularly useful for the treatment of ovarian cancer. The products according to the invention can be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.

The products according to the invention can be administered to a patient in different forms adapted to the chosen route of administration which, preferably, is the parenteral route. Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. More particularly preferred is intraperitoneal or intravenous administration.

The present invention also comprises the pharmaceutical compositions which contain at least one product of general formula (I) in a sufficient amount suitable for use in human or veterinary therapy. The compositions can be prepared according to the usual methods using one or more pharmaceutically acceptable adjuvants, carriers or excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents. Preferably, the compositions are in the form of aqueous solutions or suspensions, injectable solutions which may contain binding emulsifiers, dyes, preservatives or stabilizers.

The choice of adjuvants or excipients can be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practices. For parenteral radπώiistration, aqueous or non-aqueous sterile solutions or suspensions are used. For the preparation of non-aqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate . The sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water. The aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition.

It is understood that all the products entering into the compositions according to the invention must be pure and non-toxic for the quantities used.

The compositions can contain at least 0.01% of therapeutically active product. The amount of active ingredient in a composition is such that a suitable dosage can be prescribed. Preferably, the compositions are prepared in such a way that a unit dose contains from 0.01 to 1000 mg approximately of active product for parenteral administration.

Therapeutic treatment can be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapies or modifiers of biological responses. Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (α, β or δ) and TNF. Other chemotherapeutic agents useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs like mercaptopurine and thioguanine, natural products like vinca alkaloids like vinblastine, vincristine and vendesine, epipodophyllotoxins like etoposide and teniposide, antibiotics like dactinomycin , daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as coordination of platinum such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid suppressants such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as caproate hydroxyprogesterone, methoxyprogesterone acetate and megestrol acetate, estrogens like diethylstilbestrol and rethynylestradiol, antioestrogens like tamoxifen, androgens like testosterone propionate and fluoxymesterone.

The doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum therapeutic response. The doses vary according to the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation. The products according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to relatively large or low doses and may require low or no maintenance doses. Generally, low doses will be used at the start of treatment and, if necessary, increasing doses will be administered until an optimum effect is obtained. For other patients it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the physiological needs of the patient concerned. It is also possible that for some patients it is necessary to use only one or two daily administrations.

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

The following example illustrates a composition according to the invention. EXAMPLE

40 mg of the product obtained in Example 1 are dissolved in 1 cm 3 of Emulphor EL 620 and 1 cm 3 of ethanol then the solution is diluted by adding 18 cm 3 of physiological saline. The composition is administered by infusion for 1 hour by introduction into physiological saline.

Claims

19

1 - New taxoids of general formula:

OCOC ₆ H ₅ in which: - X represents an oxygen or sulfur atom,

- Z represents a hydrogen atom or a radical of general formula: R _j NH O

ÔH in which:

R- represents a benzoyl radical optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms or trifluoromethyl, thenoyl or furoyl or an R2-O-CO- radical in which R2 represents: - a straight or branched alkyl radical containing 1 to 8 carbon atoms, straight or branched alkenyl containing 2 to 8 carbon atoms, straight or branched alkynyl containing 3 with 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy, alkoxy containing 1 to 4 carbon atoms, dialkoylamino radicals, each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholi no, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl (optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms), cyano, carboxy or alkoxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms,

- a phenyl or a- or β-naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms or a radical 5-membered aromatic heterocyclic preferably chosen from furyl and thienyl radicals,

- or a saturated heterocyclyl radical containing 4 to 6 carbon atoms optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms,

R3 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, straight or branched alkenyl containing 2 to 8 carbon atoms, straight or branched alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, phenyl or α- or β-naphthyl optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto radicals, formyl, acyl, acylamino, aroylarnino, alcoxycarbonyl¬ amino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro, trifliorométhoxy and trifluoromethyl, or an aromatic heterocycle having 5 members and containing one or more heteroatoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms and optionally substituted by one or more substituents, identical or different, chosen from halogen atoms and alkyl, aryl, amino, alkyllamino, dialcoylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxy, carbamoyl, alkylcarbamoyl, dialcoylcarbamoyl or alkoxycarbonyl radicals, being understood as substituents of the phenyl, α- or β-naphthyl and aromatic heterocyclyl radicals, the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the radicals aryls are phenyl or α- or β-naphthyl radicals.

2 - New taxoids according to claim 1 for which X represents an oxygen atom, Z represents a hydrogen atom or a radical of general formula (II) in which Rj represents a benzoyl radical or an R2-O-CO- radical in which R2 represents a tert-butyl radical and R3 represents an alkyl radical containing 1 to 6 carbon atoms, alkenyl containing 2 to 6 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, phenyl optionally substituted by one or more, identical or different atoms or radicals chosen from halogen atoms and alkyl, alkoxy, dialkoylamino, acylamino, alkoxycarbonylamino or trifluoromethyl radicals or a furyl-2 radical or -3, 2-thienyl or - 3 or 2-thiazolyl, -4 or 5.

3 - New taxoids according to claim 1 for which X represents an oxygen atom, Z represents a hydrogen atom or a radical of general formula (II) in which Rj represents a benzoyl radical or an R2-O-CO- radical in which R2 represents a tert-butyl radical and R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, furyl-2, furyl-3, thienyl-2, thienyl-3, thiazolyl-2, thiazolyl-4 or thiazolyl radical 5.

4 - Process for the preparation of a taxoid according to one of claims 1 to 3 characterized in that a carbonylated or thiocarbonylated derivative of the general formula is reacted: X! -C (= X) -X ₂ (III) in which X is defined as in one of claims 1 to 3, X- represents a halogen atom or an imidazolyl-1 radical and X2 represents a halogen atom or an imidazolyl-1 radical or an alkoxy radical containing 1 with 4 carbon atoms optionally substituted by one or more halogen atoms, on a product of general formula:

OCOC ₆ H ₅ in which Z \ represents a hydrogen atom or a radical of general formula:

in which Rjet R3 are defined as in one of claims 1 to 3, or else R4 represents a hydrogen atom and R5 represents a group protecting the hydroxy function, and either R4 and R5 together form a heterocycle, to obtain a product of general formula:

possibly followed by the replacement of the protective groups R5 and / or R4 and R5 carried by Z \ by hydrogen atoms.

5 - Process according to claim 4 characterized in that the reaction is carried out in an organic solvent chosen from aromatic hydrocarbons and ethers optionally in the presence of a condensing agent chosen from tertiary amines at a temperature between -40 ° C and the reflux temperature of the reaction mixture, optionally passing through an intermediate of general formula:

OCOC ₆ H ₅ in which X, X2 and Z \ are defined as in claim 4.

6 - Process according to claim 4 characterized in that the replacement of the protective groups R5 and / or R4 and R5 carried by Z \ by hydrogen atoms is carried out in the following manner:

1) when R4 represents a hydrogen atom and R5 represents a protective group for the hydroxy function, the replacement of the protective groups by hydrogen atoms is carried out by means of a mineral or organic acid used alone or as a mixture in operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between -10 and 60 ° C or by catalytic hydrogenation or by the action of a hydrofluoric acid-triethylamine or hydrofluoric acid complex pyridine. 2) when R4 and R5 together form an oxazolidine ring of general formula:

R ₆ R ₇

in which R is defined as in one of claims 1 to 3, Rg and R7, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical of which the alkyl part contains 1 to 4 carbon atoms and the aryl part represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical representing a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or Rg represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R7 represents a hydrogen atom, or else Rg and R7 form together with l carbon atom to which they are linked a cycle having 4 to 7 links, the replacement of the protective group formed by Rg and R7 by hydrogen atoms can be carried out, according to the meanings of Rj, Rg and R7, in the following manner: a) when R represents a tert-butoxycarbonyl radical, Rg and R7, identical or different, represent an alkyl radical or an aralkyl or aryl radical, or although Rg represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical, and R7 represents a hydrogen atom, or else Rg and R7 together form a ring having from 4 to 7 members, the treatment of the ester of general formula (VI) with a mineral or organic acid optionally in an organic solvent such as an alcohol leading to the product of general formula:

in which X and R3 are defined as in one of claims 1 to 3, which is acylated by means of benzoyl chloride in which the phenyl ring is optionally substituted, of thenoyl chloride, of furoyl chloride or of a product of general formula:

R2-O-CO-Y (X) in which R2 is defined as above and Y represents a halogen atom (fluorine, chlorine) or a residue -O-R2 or -O-CO-O-R2, to obtain a product of general formula (I) in which Z represents a radical of general formula (II) b) when R * represents an optionally substituted benzoyl radical, thenoyl or furoyl or an R2O-CO- radical in which R2 is defined as above, Rg represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms and R7 represents a hydrogen atom, replacing the protective group formed by Rg and R7 by hydrogen atoms is carried out in the presence of a mineral or organic acid used alone or as a mixture in stoichiometric or catalytic amount, operating in an organic solvent chosen from alcohols, ethers, esters, hydrocarbons aliphatic, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature between -10 and 60 ° C, preferably between 15 and 30 ° C.

7 - Process for preparing a product according to one of claims 1 to 3 for which Z represents a radical of general formula (II) characterized in that one esterifies a product according to claim 1 for which Z represents a hydrogen atom by means of an acid of general formula: R,

N ^ ⁴ O

(XI)

OH

GOLD. in which R and R3 are defined as in one of claims 1 to 3 and R4 and R5 are defined as in claim 4, or a derivative of this acid, then replaces the protective groups R5 and / or R4 and R5 by hydrogen atoms under the conditions of claim 7.

8 - Pharmaceutical composition characterized in that it contains at least one product according to one of claims 1 to 3 for which Z represents a radical of general formula (II) in association with one or more pharmaceutically acceptable products which they are inert or pharmacologically active.