FR2732341A1 - NOVEL TAXOIDS, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Novel taxoids of general formula (I), the preparation thereof and pharmaceutical compositions containing them are described, wherein Z is a hydrogen atom or a radical of general formula (II), where R1 is an optionally substituted benzoyl, thenoyl or furoyl radical or a radical R2-O-CO- where R2 is an optionally substituted phenyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, or heterocyclyl radical, R3 is an aromatic heterocyclic, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or naphthyl radical, R4 is a hydrogen atom or a hydroxy radical or an optionally substituted alkynyloxy, alkoxy, alkenyloxy, alcanoyloxy, alkenoyloxy, alkynoyloxy, alkoxyacetyl, alkylthioacetyl, alkyloxycarbonyloxy radical, or a cycloalkyloxy, cycloalkenyloxy, benzoyloxy or heterocyclylcarbonyloxy radical, R5 is a hydrogen atom or an unsaturated 5 or 6-membered heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or phenyl radical, or R4 and R5 together with the carbon atom to which they are attached form a carbonyl grouping. The novel products of general formula (I), wherein Z is a radical of general formula (II), have a remarkable anti-tumour activity.

Description

dans laquelle:
Z représente un atome d'hydrogène ou un radical de formule générale:

dans laquelle:
R1 représente un radical benzoyle éventuellement substitué par un ou plusieurs atomes ou radicaux, identiques ou différents, choisis parmi les atomes d'halogène et les radicaux alcoyles contenant 1 à 4 atomes de carbone, alcoxy contenant 1 à 4 atomes de carbone ou trifluorométhyle, thénoyle ou furoyle ou un radical R2-O-CO- dans lequel R2 représente:: - un radical alcoyle contenant 1 à 8 atomes de carbone, alcényle contenant 2 à 8 atomes de carbone, alcynyle contenant 3 à 8 atomes de carbone, cycloalcoyle contenant 3 à 6 atomes de carbone, cycloalcényle contenant 4 à 6 atomes de carbone, bicycloalcoyle contenant 7 à 10 atomes de carbone, ces radicaux étant éventuellement substitués par un ou plusieurs substituants choisis parmi les atomes d'halogène et les radicaux hydroxy, alcoxy contenant 1 à 4 atomes de carbone, dialcoylamino dont chaque partie alcoyle contient 1 à 4 atomes de carbone, pipéridino, morpholino, pipérazinyl-1 (éventuellement substitué en -4 par un radical alcoyle contenant 1 à 4 atomes de carbone ou par un radical phénylalcoyle dont la partie alcoyle contient 1 à 4 atomes de carbone), cycloalcoyle contenant 3 à 6 atomes de carbone, cycloalcényle contenant 4 à 6 atomes de carbone, phényle (éventuellement substitué par un ou plusieurs atomes ou radicaux choisis parmi les atomes d'halogène et les radicaux alcoyles contenant 1 à 4 atomes de carbone ou alcoxy contenant 1 à 4 atomes de carbone), cyano, carboxy ou alcoxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone, - un radical phényle ou a- ou Snaphtyle éventuellement substitué par un ou plusieurs atomes ou radicaux choisis parmi les atomes d'halogène et les radicaux alcoyles contenant 1 à 4 atomes de carbone ou alcoxy contenant 1 à 4 atomes de carbone ou un radical hétérocyclique aromatique à 5 chaînons choisi de préférence parmi les radicaux furyle et thiényle, - ou un radical hétérocyclyle saturé contenant 4 à 6 atomes de carbone éventuellement substitué par un ou plusieurs radicaux alcoyles contenant 1 à 4 atomes de carbone,
R3 représente un radical alcoyle droit ou ramifié contenant 1 à 8 atomes de carbone, alcényle droit ou ramifié contenant 2 à 8 atomes de carbone, alcynyle droit ou ramifié contenant 2 à 8 atomes de carbone, cycloalcoyle contenant 3 à 6 atomes de carbone, phényle ou a- ou Fnaphtyle éventuellement substitué par un ou plusieurs atomes ou radicaux choisis parmi les atomes d'halogène et les radicaux alcoyles, alcényles, alcynyles, aryles, aralcoyles, alcoxy, alcoylthio, aryloxy, arylthio, hydroxy, hydroxyalcoyle, mercapto, formyle, acyle, acylamino, aroylamino, alcoxycarbonylamino, amino, alcoylamino, dialcoylamino, carboxy, alcoxycarbonyle, carbamoyle, alcoylcarbamoyle, dialcoylcarbamoyle, cyano, nitro et trifluorométhyle, ou un hétérocycle aromatique ayant 5 chaînons et contenant un ou plusieurs hétéroatomes, identiques ou différents, choisis parmi les atomes d'azote, d'oxygène ou de soufre et éventuellement substitué par un ou plusieurs substituants, identiques ou différents, choisis parmi les atomes d'halogène et les radicaux alcoyles, aryles, amine, alcoylamino, dialcoylamino, alcoxycarbonylamino, acyle, arylcarbonyle, cyano, carboxy, carbamoyle, alcoylcarbamoyle, dialcoylcarbamoyle ou alcoxycarbonyle, étant entendu que, dans les substituants des radicaux phényle, a- ou Fnaphtyle et hétérocyclyles aromatiques, les radicaux alcoyles et les portions alcoyles des autres radicaux contiennent 1 à 4 atomes de carbone et que les radicaux alcényles et alcynyles contiennent 2 à 8 atomes de carbone et que les radicaux aryles sont des radicaux phényles ou cr- ou Fnaphtyles,
R4 représente un atome d'hydrogène ou un radical hydroxy ou un radical alcoxy contenant 1 à 6 atomes de carbone en chaîne droite ou ramifiée, alcényloxy contenant 3 à 6 atomes de carbone en chaîne droite ou ramifiée, alcynyloxy contenant 3 à 6 atomes de carbone en chaîne droite ou ramifiée, cycloalcoyloxy contenant 3 à 6 atomes de carbone, cycloalcényloxy contenant 3 à 6 atomes de carbone, alcanoyloxy dont la partie alcanoyle contient 1 à 6 atomes de carbone en chaîne droite ou ramifiée, alcénoyloxy dont la partie alcénoyle contient 3 à 6 atomes de carbone en chaîne droite ou ramifiée, alcynoyloxy dont la partie alcynoyle contient 3 à 6 atomes de carbone en chaîne droite ou ramifiée, alcoxyacétyle dont la partie alcoyle contient 1 à 6 atomes de carbone en chaîne droite ou ramifiée, alcoylthioacétyle dont la partie alcoyle contient 1 à 6 atomes de carbone en chaîne droite ou ramifiée, alcoyloxycarbonyloxy dont la partie alcoyle contient 1 à 6 atomes de carbone en chaîne droite ou ramifiée, ces radicaux étant éventuellement substitués par un ou plusieurs atomes d'halogène ou par un radical alcoxy contenant 1 à 4 atomes de carbone, alcoylthio contenant 1 à 4 atomes de carbone, ou un radical carboxy, alcoyloxycarbonyle dont la partie alcoyle contient 1 à 4 atomes de carbone, cyano, carbamoyle, N-alcoylcarbamoyle ou
N,N-dialcoylcarbamoyle dont chaque partie alcoyle contient 1 à 4 atomes de carbone ou forme avec l'atome d'azote auquel elle est liée un radical hétérocyclique saturé contenant 5 ou 6 chaînons et éventuellement un second hétéroatome choisi parmi les atomes d'oxygène, de soufre ou d'azote éventuellement substitué par un radical alcoyle contenant 1 à 4 atomes de carbone ou un radical phényle ou un radical phénylalcoyle dont la partie alcoyle contient 1 à 4 atomes de carbone, ou bien R4 représente un radical benzoyloxy ou hétérocyclylcarbonyloxy dans lequel la partie hétérocyclique représente un hétérocycle aromatique 5 ou 6 chaînons contenant un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, de soufre ou d'azote,
R5 représente un atome d'hydrogène ou un radical alcoyle droit ou ramifié contenant 1 à 6 atomes de carbone, alcényle droit ou ramifié contenant 2 à 6 atomes de carbone, alcynyle droit ou ramifié contenant 2 à 6 atomes de carbone, cycloalcoyle contenant 3 à 6 atomes de carbone, cycloalcényle contenant 4 à 6 atomes de carbone, aryle, hétérocyclyle aromatique contenant 5 à 6 chaînons, ou bien
R4 et R5 forment ensemble avec l'atome de carbone auquel ils sont liés un groupement carbonyle.NEW TAXOIDS. THEIR PREPARATION AND COMPOSITIONS
PHARMACEUTIOUES YES CONTAIN THEM
The present invention relates to new taxi'ides of general formula:

in which:
Z represents a hydrogen atom or a radical of general formula:

in which:
R1 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: - an alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 with 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 radicals, alkoxy containing 1 to 4 carbon atoms, dialkoylamino, each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, 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 in which the alkyl part contains 1 to 4 carbon atoms, - a phenyl or a- or Snaphthyl 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 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals, - or a saturated heterocyclyl radical containing 4 to 6 atoms of ca rbone 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 a- or Fnaphthyle 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, formyl, radicals acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkoylamino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialcoylcarbamoyl, cyano, nitro and trifluoromethyl, or one or more hetero rings or hetero rings, having one or more different, or one or more hetero rings, or having one or more hetero rings, or having one or more hetero rings, nitrogen, oxygen or sulfur atoms and optionally substituted by one or more substituents, identical or different, chosen from halogen atoms and alkyl, aryl, amine, alkyllamino, dialkoylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxy, carbamoyl, alkylcarbamoyl, dialkoylcarbamoyl or alkoxycarbonyl radicals, it being understood that in radicals, phenyl , a- or Fnaphthyle and aromatic heterocyclyl, the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl radicals or cr- or Fnaphtyles,
R4 represents a hydrogen atom or a hydroxy radical or an alkoxy radical containing 1 to 6 carbon atoms in a straight or branched chain, alkenyloxy containing 3 to 6 carbon atoms in a straight or branched chain, alkynyloxy containing 3 to 6 carbon atoms straight or branched chain, cycloalkoyloxy containing 3 to 6 carbon atoms, cycloalkenyloxy containing 3 to 6 carbon atoms, alkanoyloxy in which the alkanoyl part contains 1 to 6 carbon atoms in straight or branched chain, alkenoyloxy in which the alkenoyl part contains 6 carbon atoms in a straight or branched chain, alkynoyloxy of which the alkynoyl part contains 3 to 6 carbon atoms in a straight or branched chain, alkoxyacetyl of which the alkyl part contains 1 to 6 carbon atoms in a straight or branched chain, alkylthioacetyl of which alkyl contains 1 to 6 carbon atoms in straight or branched chain, alkyloxycarbonyloxy of which the alkyl part contains 1 to 6 atoms of carbon in a straight or branched chain, these radicals being optionally substituted by one or more halogen atoms or by an alkoxy radical containing 1 to 4 carbon atoms, alkylthio containing 1 to 4 carbon atoms, or a carboxy, alkyloxycarbonyl radical the alkyl part contains 1 to 4 carbon atoms, cyano, carbamoyl, N-alkylcarbamoyl or
N, N-dialkoylcarbamoyl each alkyl part of which contains 1 to 4 carbon atoms or forms, with the nitrogen atom to which it is linked, a saturated heterocyclic radical containing 5 or 6 members and optionally a second heteroatom chosen from oxygen atoms , sulfur or nitrogen optionally substituted by an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms, or else R4 represents a benzoyloxy or heterocyclylcarbonyloxy radical in in which the heterocyclic part represents a 5 or 6-membered aromatic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur or nitrogen atoms,
R5 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms, straight or branched alkenyl containing 2 to 6 carbon atoms, straight or branched alkynyl containing 2 to 6 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, aryl, aromatic heterocyclyl containing 5 to 6 members, or else
R4 and R5 together with the carbon atom to which they are linked form a carbonyl group.

 Preferably, the aryl radicals which can be represented by R3 and R5 are phenyl or a- or Snaphthyl 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, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkyoyino, dialcoylamino, carboxyamcoyloxy and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or a- or Fnaphthyles.

 Preferably, the heterocyclic radicals which can be represented by R3 and R5 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 a or several 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, 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, ca rboxy, carbamoyl, alkylcarbamoyl in which the alkyl part contains 1 to 4 carbon atoms, dialcoylcarbamoyl in which each alkyl part contains 1 to 4 carbon atoms or alkoxycarbonyl in which the alkoxy part contains 1 to 4 carbon atoms.

Preferably, the radical R4 represents a hydrogen atom or a hydroxy radical or a straight or branched alkoxy or alkanoyloxy radical containing 1 to 6 carbon atoms optionally substituted by a methoxy, ethoxy, methyltio, ethylthio, carboxy, methoxycarbonyl, ethoxycarbonyl radical, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl,
N-pyrrolidinocarbonyl or N-piperidinocarbonyl.

 Preferably, the radical R5 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms.

 More particularly, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which R1 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 atoms or radicals, identical or different chosen from halogen atoms (fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy), dialcoylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tertbutoxycarbonylamino) or trifluoromethyl or a furyl-2 radicals or -3, 2-thienyl or -3 or 2-thiazolyl, -4 or -5 and R4 represents a hydroxy radical or an alkanoyloxy radical in which the alkanoyl part contains 1 to 6 atoms carbon in a straight or branched chain, and R5 represent a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms, or else R4 and R5 form together with the carbon atom to which they are linked a carbonyl group .

More particularly still, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which R1 represents a benzoyl radical or a radical
R2-O-CO- in which R2 represents a tert-butyl radical and R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, furyl-2, furyl3, thienyl-2, thienyl-3, thiazolyl-2 or thiazolyl radical or thiazolyle-5, R4 represents a hydroxy radical or an acetyloxy radical and R5 represents a hydrogen atom.

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

dans laquelle R4 et R5 sont définis comme précédemment, au moyen d'un acide de formule générale:

dans laquelle R1 et R3 sont définis comme précédemment, ou bien R6 représente un atome d'hydrogène et R7 représente un groupement protecteur de la fonction hydroxy, et ou bien R6 et R7 forment ensemble un hétérocycle saturé à 5 ou 6 chaînons, ou d'un dérivé de cet acide pour obtenir un ester de formule générale:

dans laquelle R1, R3, R4, Rg, R6 et R7 sont définis comme précédemment, suivi du remplacement des groupements protecteurs représentés par R7 et/ou R6 et R7 par des atomes d'hydrogène.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:

in which R4 and R5 are defined as above, by means of an acid of general formula:

in which R1 and R3 are defined as above, or else R6 represents a hydrogen atom and R7 represents a protective group for the hydroxy function, and either R6 and R7 together form a 5 or 6-membered saturated heterocycle, or a derivative of this acid to obtain an ester of general formula:

in which R1, R3, R4, Rg, R6 and R7 are defined as above, followed by the replacement of the protective groups represented by R7 and / or R6 and R7 by hydrogen atoms.

 Esterification using an acid of general formula (IV) can be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester1 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 (IV) in the form of a symmetrical 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 900C.

 The esterification can also be carried out using the acid of general formula (IV) in the form of halide or in the form of mixed anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base (amine tertiary aliphatic) by operating in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 800 C.

 Preferably, R6 represents a hydrogen atom and R7 represents a group protecting the hydroxy function or else R6 and R7 together form a saturated heterocycle with 5 or 6 members.

 When R6 represents a hydrogen atom, R7 preferably represents a methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, Strimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydropyrannyl radical.

 When R6 and R7 together form a heterocycle, the latter is preferably an oxazolidine ring optionally mono-substituted or gem-disubstituted in position -2.

dans laquelle R1 est défini comme précédemment, R8 et Rg, identiques ou différents, représentent un atome d'hydrogène ou un radical alcoyle contenant 1 à 4 atomes de carbone, ou un radical aralcoyle dont la partie alcoyle contient 1 à 4 atomes de carbone et la partie aryle représente, de préférence, un radical phényle éventuellement substitué par un ou plusieurs radicaux alcoxy contenant 1 à 4 atomes de carbone, ou un radical aryle représentant, de préférence un radical phényle éventuellement substitué par un ou plusieurs radicaux alcoxy contenant 1 à 4 atomes de carbone, ou bien R8 représente un radical alcoxy contenant 1 à 4 atomes de carbone ou un radical trihalométhyle tel que trichlorométhyle ou un radical phényle substitué par un radical trihalométhyle tel que trichlorométhyle et Rg représente un atome d'hydrogène, ou bien R8 et Rg forment ensemble avec l'atome de carbone auquel ils sont liés un cycle ayant 4 à 7 chaînons, le remplacement du groupement protecteur formé par R6 et R7 par des atomes d'hydrogène peut être effectué, selon les significations de R1, R8 et Rg, de la manière suivante::
a) lorsque R1 représente un radical tert-butoxycarbonyle, R8 et Rg, identiques ou différents, représentent un radical alcoyle ou un radical aralcoyle (benzoyle) ou aryle (phényle), ou bien R8 représente un radical trihalométhyle ou un radical phényle substitué par un radical trihalométhyle, et Rg représente un atome d'hydrogène, ou bien R8 et Rg forment ensemble un cycle ayant de 4 à 7 chaînons, le traitement de l'ester de formule générale (V) par un acide minéral ou organique éventuellement dans un solvant organique tel qu'un alcool conduit au produit de formule générale::

dans laquelle R3, R4 et R5 sont définis comme précédemment, qui est acylé au moyen de chlorure de benzoyle dans lequel le noyau phényle est éventuellemnt substitué, de chlorure de thénoyle, de chlorure de furoyle ou d'un produit de formule générale:
R2-O-CO-X (VIII) dans laquelle R2 est défini comme précédemment et X représente un atome d'halogène (fluor, chlore) ou un reste -O-R2 ou -O-CO-O-R2, pour obtenir un produit de formule générale (I) dans laquelle Z représente un radical de formule générale (in). The replacement of the protective groups R7 and / or R6 and R7 with hydrogen atoms can be carried out, depending on their nature, as follows: 1) when R6 represents a hydrogen atom and R7 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 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 600C, 2) when R6 and R7 together form a 5 or 6-membered saturated heterocycle and more particularly an oxazolidine ring of general formula e:

in which R1 is defined as above, R8 and Rg, 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 else R8 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 Rg represents a hydrogen atom, or else R8 and Rg together with the carbon atom to which they are linked form a cycle having 4 to 7 links, replacing the gro highly protective formed by R6 and R7 by hydrogen atoms can be carried out, according to the meanings of R1, R8 and Rg, as follows:
a) when R1 represents a tert-butoxycarbonyl radical, R8 and Rg, which may be identical or different, represent an alkyl radical or an aralkyl (benzoyl) or aryl (phenyl) radical, or else R8 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical, and Rg represents a hydrogen atom, or else R8 and Rg together form a ring having 4 to 7 members, the treatment of the ester of general formula (V) with a mineral or organic acid optionally in a solvent organic such as an alcohol leads to the product of general formula:

in which R3, R4 and R5 are defined as above, which is acylated by means of benzoyl chloride in which the phenyl nucleus is optionally substituted, of thenoyl chloride, of furoyl chloride or of a product of general formula:
R2-O-CO-X (VIII) in which R2 is defined as above and X 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 (in).

 Preferably, the product of general formula (V) is treated with formic acid at a temperature in the region of 20 "C to provide the product of general formula (VII).

 Preferably, the acylation of the product of general formula (VII) by means of a benzoyl chloride in which the phenyl radical is optionally substituted, of thenoyl chloride or of furoyl chloride or of a product of general formula (VIII ) 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 500C, preferably close to 20 "C.

 b) when R1 represents an optionally substituted benzoyl radical, thenoyl or furoyl or an R2O-CO- radical in which R2 is defined as above, R8 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a radical phenyl substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms and Rg represents a hydrogen atom, the replacement of the protective group formed by R6 and R7 by hydrogen atoms is carried out in the presence of a mineral acid (hydrochloric acid, sulfuric acid) or organic (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p.toluenesulfonic acid) used alone or as a mixture in stoichiometric or catalytic amount, operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature included between -10 and 60 "C, preferably between 15 and 300C.

dans laquelle R représente un radical trifluorométhanesulfonyloxy (-O-S02-CF3) ou forme une liaison avec l'atome de carbone du radical méthyle en a de façon à former un cycle cyclopropane, par action d'un produit de formule générale: :
R4-X1 (X) dans laquelle R4 représente un radical alcoxy, alcényloxy, alcynyloxy éventuellement substitué, alcanoyloxy, alcénoyloxy, alcynoyloxy alcoxyacétyle, alcoylthioacétyle, alcoyloxycarbonyloxy, ou un radical cycloalcoyloxy, cycloalcényloxy, benzoyloxy ou hétèrocyclylcarbonyloxy définis comme précédemment et X1 représente un atome d'halogène ou un reste d'ester réactif tel qu'un reste d'ester sulfurique ou sulfonique, suivie éventuellement, lorsque R représente un radical trifluorométhanesulfonyloxy, du traitement du produit obtenu de formule générale:

dans laquelle R4 est défini comme ci-dessus, pour obtenir un produit de formule générale (III).According to the invention, the products of general formula (III), that is to say the products of general formula (I) in which Z represents a hydrogen atom,
R4 represents an alkoxy, alkenyloxy, optionally substituted alkynyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, alkoxyacetyl, alkoylthioacetyl, alkyloxycarbonyloxy, or a cycloalkyloyloxy, cycloalkenyloxy, benzoyloxy or heterooxy group from the product of general formula:

in which R represents a trifluoromethanesulfonyloxy radical (-O-SO2-CF3) or forms a bond with the carbon atom of the methyl radical a so as to form a cyclopropane ring, by the action of a product of general formula:
R4-X1 (X) in which R4 represents an optionally substituted alkoxy, alkenyloxy, alkynyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy alkoxyacetyl, alkoylthioacetyl, alkoyloxycarbonyloxy, or a cycloalkyloxycarboxyloxy, cycloalkyloxyoxycycloalkoxy group, halogen or a reactive ester residue such as a sulfuric or sulfonic ester residue, optionally followed, when R represents a trifluoromethanesulfonyloxy radical, by the treatment of the product obtained of general formula:

in which R4 is defined as above, to obtain a product of general formula (III).

 Generally, the action of a product of general formula (X) on a product of general formula (IX) can be carried out, after metallation of the hydroxy function in position 10 by means of an alkali metal hydride such as sodium hydride, an alkali metal amide such as lithium amide or an alkali metal alkyl such as butyllithium, operating in an organic solvent such as dimethylformamide or tetrahydrofuran at a temperature between -20 and 50 " vs.

 Generally, the transformation of a product of general formula (XI) into a product of general formula (III) is carried out in the presence of an alkali metal halide (sodium iodide, potassium fluoride) or a metal azide alkaline (sodium azide) or an ammonium salt by operating in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl t.butyl ether) and nitriles (acetonitrile) alone or as a mixture at a temperature between 20 "C and the boiling temperature of the reaction mixture.

qui peut être obtenu par action d'un halogénoformiate de formule générale:
Hal-CO-O-R10 (XIII) dans laquelle R10 représente un radical trichloro-2,2,2 éthyle ou (trichlorométhyl-2 propyle)-2 sur le produit de formule::

qui peut être extrait à partir des feuilles d'ifs (Taxus baccata), pour obtenir un produit de formule générale:

dans laquelle G1 représente un radical trichloro-2,2,2 éthoxycarbonyloxy ou (trichlorométhyl-2 propoxy-2 carbonyloxy, suivie du remplacement des groupements protecteurs G1 par des atomes d'hydrogène. The product of formula (IX) in which R represents a trifluoromethanesulfonyloxy radical can be obtained by the action of a derivative of trifluoromethanesulfonic acid such as the anhydride or N-phenyl trifluoromethanesulfonimide in an inert organic solvent (optionally halogenated aliphatic hydrocarbons, aromatic hydrocarbons) in the presence of an organic base such as an aliphatic tertiary amine (triethylamine) or pyridine at a temperature between -50 and +20 C, on the product of formula:

which can be obtained by the action of a haloformate of general formula:
Hal-CO-O-R10 (XIII) in which R10 represents a 2,2,2,2-trichloroethyl or (2-trichloromethyl-propyl) -2 radical on the product of formula:

which can be extracted from yew leaves (Taxus baccata), to obtain a product of general formula:

in which G1 represents a 2,2,2,2-ethoxycarbonyloxy or (2-trichloromethyl-2-propoxy-carbonyloxy) radical, followed by the replacement of the protecting groups G1 by hydrogen atoms.

 Generally, the reaction of a haloformate of general formula (XIII) with a product of formula (XIV) is carried out in an inert organic solvent such as an aromatic hydrocarbon (benzene, toluene, xylenes) in the presence of an organic base chosen from tertiary aliphatic amines (triethylamine) and pyridine at a temperature between 0 and 40 C, preferably close to 20 "C.

 Generally, the replacement of the protective groups G1 by hydrogen atoms is carried out by zinc, optionally associated with copper, in the presence of acetic acid at a temperature between 20 and 60 "C or by means of a mineral acid or organic such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or in an aliphatic ester such as ethyl acetate, isopropyl acetate or acetate n.butyl in the presence of zinc possibly associated with copper.

According to the invention, the products of general formula (III), that is to say the products of general formula (I) in which Z represents a hydrogen atom and
R4 represents a hydroxy radical, can be obtained by the action of an alkali metal halide (sodium iodide, potassium fluoride) or an alkali metal azide (sodium azide) or an ammonium salt by operating in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl t.butyl ether) and nitriles (acetonitrile) alone or as a mixture at a temperature between 20 "C and the boiling temperature of the reaction mixture on a product of formula (IX) in which R represents a trifluoromethanesulfonyloxy radical.

qui, par action d'un halogénoformiate de formule générale (XIII) dans les conditions décrites ci-dessus, conduit au produit de formule générale:

dans laquelle G1 est défini comme précédemment, dont le groupement protecteur G1 est remplacé par un atome d'hydrogène dans les conditions décrites ci-dessus pour donner un produit de formule::

qui, après traitement par un dérivé de l'acide trifluorométhanesulfonique et cyclisation au moyen d'un halogénure de métal alcalin ou d'un azoture de métal alcalin ou d'un sel d'ammonium dans les conditions décrites ci-dessus, conduit au produit de formule générale (III) dans laquelle Z représente un atome d'hydrogène, et R4 et R5 représentent chacun un atome d'hydrogène.According to the invention, the products of general formula (III), that is to say the products of general formula (I) in which Z represents a hydrogen atom and
R4 and R5 each represent a hydrogen atom, can be obtained by electrolytic reduction of a product of formula (XIV) to obtain a product of formula:

which, by the action of a haloformate of general formula (XIII) under the conditions described above, leads to the product of general formula:

in which G1 is defined as above, the protective group G1 of which is replaced by a hydrogen atom under the conditions described above to give a product of formula:

which, after treatment with a derivative of trifluoromethanesulfonic acid and cyclization using an alkali metal halide or an alkali metal azide or an ammonium salt under the conditions described above, leads to the product of general formula (III) in which Z represents a hydrogen atom, and R4 and R5 each represent a hydrogen atom.

According to the invention, the products of general formula (III), that is to say the products of general formula (I) in which Z represents a hydrogen atom and
R4 and R5 together form a carbonyl group, can be obtained by oxidation of a product of general formula (IX) using, for example, pyridinium chlorochromate, pyridinium dichromate, potassium dichromate, ammonium dichromate or manganese oxide, followed, when R represents a trifluoromethanesulfonyloxy radical, treatment of the product obtained with an alkali metal halide or an alkali metal azide or an ammonium salt under the conditions described above.

dans laquelle R, R1, R3, R6 et R7 sont définis comme précédemment, suivie, lorsque
R représente un radical trifluorométhanesulfonyloxy, du traitement du produit obtenu par un halogénure de métal alcalin ou d'un azoture de métal alcalin ou d'un sel d'ammonium dans les conditions décrites ci-dessus, puis du remplacement des groupements protecteurs R7 ou R6 et R7 dans les conditions décrites précédemment pour obtenir un produit de formule générale (I).According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II), R4 represents an alkoxy, alkenyloxy, optionally substituted alkynyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy alkoxyacetyl, alkylthioacetyl, alkyloxycarbonyloxy, or a cycloalkyloxy, cycloalkenyloxy, benzoyloxy or heterocyclylcarbonyloxy radical defined as above and R5 represents a hydrogen atom, can also be obtained by the action of a product of general formula (X) on a product of general formula:

in which R, R1, R3, R6 and R7 are defined as above, followed, when
R represents a trifluoromethanesulfonyloxy radical, for the treatment of the product obtained with an alkali metal halide or an alkali metal azide or an ammonium salt under the conditions described above, then the replacement of the protective groups R7 or R6 and R7 under the conditions described above to obtain a product of general formula (I).

dans laquelle R1 et R3 sont définis comme précédemment, R6 représente un atome d'hydrogène et R7 représente un groupement protecteur de la fonction hydroxy et peut représenter en outre un atome d'hydrogène ou bien R6 et R7 forment ensemble un hétérocyle saturé à 5 ou 6 chaînons tel que défini précédemment, R4 représente un radical hydroxy ou un radical alcanoyloxy ou un radical alcoxyacétyle, R5 représente un atome d'hydrogène et R représente un radical trifluorométhanesulfonyloxy ou forme une liaison avec l'atome de carbone du radical méthyle en a, suivie, lorsque R représente un radical trifluorométhanesulfonyloxy, du traitement par un halogénure de métal alcalin ou un azoture de métal alcalin ou un sel d'ammonium dans les conditions décrites précédemment et éventuellement du remplacement des radicaux
R7 et R6 et R7 par des atomes d'hydrogène dans les conditions décrites précédemment pour obtenir un produit de formule générale (I).According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II), and R4 and R5 each represent a hydrogen atom, can be obtained by electrolytic reduction of a product of formula general ::

in which R1 and R3 are defined as above, R6 represents a hydrogen atom and R7 represents a protecting group for the hydroxy function and can also represent a hydrogen atom or else R6 and R7 together form a saturated heterocyl at 5 or 6-membered as defined above, R4 represents a hydroxy radical or an alkanoyloxy radical or an alkoxyacetyl radical, R5 represents a hydrogen atom and R represents a trifluoromethanesulfonyloxy radical or forms a bond with the carbon atom of the methyl radical at a, followed, when R represents a trifluoromethanesulfonyloxy radical, treatment with an alkali metal halide or an alkali metal azide or an ammonium salt under the conditions described above and optionally the replacement of the radicals
R7 and R6 and R7 by hydrogen atoms under the conditions described above to obtain a product of general formula (I).

 According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II) and R4 and R5 together form a carbonyl group can be obtained by oxidation of a product of general formula (XIX) in which R, R1, R3, R6 and R7 are defined as above, using, for example, pyridinium chlorochromate, pyridinium dichromate, potassium bichromate, ammonium dichromate or manganese oxide, followed, when R represents a trifluoromethanesulfonyloxy radical, of the treatment of the product obtained with an alkali metal halide or an alkali metal azide or an ammonium salt under the conditions described above and the replacement of the radicals R7 or R6 and R7 with hydrogen atoms.

According to the invention, the products of general formula (I) in which Z represents a radical of general formula (II), R4 represents a hydroxy radical or an optionally substituted alkoxy, alkenyloxy, alkynyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy alkoxyacetyl, alkoylthioacetyl radical , alkyloxycarbonyloxy, or a cycloalkyloxy, cycloalkenyloxy, benzoyloxy or heteroeyclylcarbonyloxy radical defined as above and R5 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl or heterocyclyl chain radical obtained; of general formula:
R5 -X2 (XXI) in which R5 is defined as above and X2 represents an alkali metal atom such as a lithium atom or an organomagnesium residue (Mg-Y in which
Y represents a halogen atom) on a product of general formula (XX) in which R4 and R5 together form a carbonyl group, operating in an inert organic solvent such as an ether (tetrahydrofuran) at a temperature between -78 and 300C, to obtain a product of general formula:

R, R1, R3, Rg, R6 and R7 are defined as above, optionally followed by the action of a product of general formula (X) under the conditions described above, then, when R represents a trifluoromethylsulfonyloxy radical, treatment with an alkali metal halide or an alkali metal azide or an ammonium salt under the conditions described above, then replacing the protective groups R7 or R6 and R7 with hydrogen atoms under the conditions described above.

 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, ZQ 765-768 (1973). The study of the depolymerization of microtubules into tubulin is carried out according to the method of G. Chauvière et al.,
CR Acad. Sci., 2, 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 / kg intraperitoneally, as well as other liquid or solid tumors.

 The new products have anti-tumor properties and more particularly an activity on tumors which are resistant to Taxon) or to Taxotere. Such tumors include colon tumors which have high expression of the mdr 1 gene (multi-drug resistance gene). Multi <trug 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) and which overexpresses mdr 1.

The following examples illustrate the present invention
EXAMPLE 1
To a solution of 200 mg of tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) of diacetoxy-4a, 10C3 benzoyloxy-2a carbonyldioxy 1cl, 1413 epoxy-5 (3.20 oxo-9 trifluoromethanesulfonate- 713 taxene-11 yl-13a in 2 cm3 of acetonitrile and 0.2 cm3 of tetrahydrofuran, 200 mg of powdered molecular sieve 4 are added at a temperature in the region of 20 ° C., then 300 mg of sodium chloride. After 30 minutes at a temperature in the region of 20 ° C., the suspension obtained, maintained under an argon atmosphere, is brought to reflux for 3 hours.

After cooling to a temperature in the region of 20 ° C., the reaction mixture is diluted with 10 cm 3 of ethyl acetate and then filtered through sintered glass lined with
Celite. After concentrating the filtrate to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 400C, the residue obtained is taken up in 10 cm3 of ethyl acetate. The organic phase is washed with twice 3 cm3 of water. distilled, 3 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered through sintered glass, and concentrated to dryness under reduced pressure (0.27 ka) at a temperature in the region of 40 "C. thus 203 mg of a pale yellow meringue which is purified by preparative thin layer chromatography [10 Merck preparation plates, Kieselgel 60F254, thickness 0.5 mm, deposit in solution in dichloromethane, eluting with a methanoldichloromethane mixture (5- 95 by volume)]. After elution of the zone corresponding to the main product by a methanol-dichloromethane mixture (15-85 by volume), filtration through sintered glass, then evaporation of the solvents under reduced pressure (0.27 kPa) at a temperature urea close to 40 "C, 92 mg of tertbutoxycarbonylamino-3-hydroxy-2-phenyl-propionate- (2R, 3S) of diacetoxy-4a, 1013 benzoyloxy-2a carbonyldioxy- 113,1413 epoxy-513,20 methylene-7P are obtained , 8 (3 oxo-9 nor-19 taxene-1 1 yle-13a in the form of a white meringue, the characteristics of which are as follows: - 1 H NMR spectrum (400 MHz; CDC13. temperature of 333 "K, chemical shifts 6 in ppm; coupling constants J in Hz) 1.36 (s, 3H: CH3); 1.39 (s, 9H: C (CH3) 3); 1.43 (s , 3H: CH3); from 1.35 to 1.50 (mt, 1H: H in 7); 1.74 and 2.32 (2 dd, respectively J = 7 and 5 and J = 10 and 5, 1H each: CH2 in 19); 1.90 (s, 3H:
CH3); 2.15 and 2.46 (respectively d large and dt, J = 16 and J = 16 and 4.5, 1H each:
CH2 in 6); 2.22 and 2.41 (2 s, 3H each: COCH3); 3.36 (mf, 1H: OH in 2 '); 4.03 (d, J = 7.1H: H in; 4.14 and 4.30 (2 d, J = 9.1H each: C H2 in; 4.73 (mt, 2H: Hen5andHen2 '); 4.86 (d, J = 7.1H: Hen14); 5.34 (AB limit, 2H: Hen3 'and CONH); 6.12 (d, J = 7.1H: H in 2); 6.34 (s, 1H: H in 10); 6.44 (wide d, J = 7, 1H: H in 13); from 7.25 to 7.40 (mt, 5H: Aromatic H in 3 '); 7.52 (t , J = 7.5, 2H:
OCOC6H5 H in meta); 7.62 (t, J = 7.5, 1H: OCOC6H5H in para); 8.08 (d, J = 7.5, 2H: OCOC6H5 H ortho).

Tert-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) diacetoxy-4 &alpha;, 10ss benzoyloxy-2a carbonyldioxy- 113,1413 epoxy-5ss, 20 oxo-9 trifluoromethanesulfonate-713 taxene-11 yl- 13a can be prepared as follows:
A solution of 710 mg of tert-butoxycarbonyl-3 (methoxy4 phenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) of diacetoxy-4a, 1013 benzoyloxy2a carbonyldioxy-113,1413 epoxy-5ss, 20 oxo-9 trifluoromethanesulfonate-7ss taxene-11 yl-13a in 8.4 cm3 of a 0.1N solution of hydrochloric ethanol is stirred at a temperature in the region of 00C for 2 hours 30 minutes under an argon atmosphere. 0.09 cm3 of a 6N solution of hydrochloric ethanol is then added at a temperature close to OOC. The solution is kept at a temperature close to 00C for 20 hours, then the reaction mixture is diluted with 60 cm3 of dichloromethane. and 10 cm3 of distilled water. After decantation, the organic phase is washed with 10 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered through sintered glass and then concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40 C. This gives 710 mg of an ivory meringue which is purified by chromatography at atmospheric pressure on 75 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol-dichloromethane mixture (1-99 by volume), collecting 10 cm 3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 "C for 2 hours This gives 622 mg of tert-butoxycarbonylamin3 hydroxy-2 phenyl-3 propionate- (2R, 3S) of diacetoxy-4a, 1013 benzoyloxy-2a carbonyldioxy- 113,1413 epoxy-513,20 oxo-9 trifluoromethanesulfonate-7ss taxene- 11 yle-13a in the form of a cream meringue.

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl4 oxazolidine- 1,3 carboxylate-5 (2R, 4S, 5R) diacetoxy-4 &alpha;, 10ss benzoyloxy-2a carbonyldioxy- 113,1413 epoxy-513,20 oxo-9 trifluoromethanesulfonate-713 taxene-11 yle-13a can be prepared as follows:
To a solution of 100 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) of acetoxy-4a benzoyloxy-2a carbonyldioxy-113,14 ( 3 epoxy-5ss, 20 hydroxy-1013 oxo-9 tnfluorométhanesulfonate-7P taxêneîî yle-13a in 0.5 cm3 of anhydrous toluene and 0.007 cm3 of acetic acid, 30 mg of 30 mg are added successively. dicyclohexylcarbodiimide and 3.5 mg of N, N'-dimethylamino4 pyridine. After 45 minutes at a temperature in the region of 20 "C, the reaction mixture is purified (direct deposition on the column) by chromatography at atmospheric pressure on 12 g of silica ( 0.063-0.2 mm) contained in a column 2 cm in diameter (elution gradient: ethyl acetate-dichloromethane from 0-100 to 4-96 by volume), collecting 10 cm 3 fractions. containing the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 C for 2 hours. insi 93.9 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) diacetoxy-4 &alpha;, 10ss benzoyloxy-2a carbonyldioxy-1 (3 , 1413 epoxy-5ss, 20 oxo-9 trilluoromethanesulfonate-713 taxene-1 1 yl-13a in the form of an ivory meringue.

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) acetoxy-4a benzoyloxy-2a carbonyldioxy-lss, 14ss epoxy 5 (3.20 hydroxy -1013 oxo-9 trifluoromethanesulfonate-713 taxene-11 yle-13a can be prepared as follows:
To a suspension of 6.02 g of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) of acetoxy-4a benzoyloxy-2a carbonyldioxy-lss, 14ss epoxy-513.20 dihydroxy-7ss, 10ss oxo-9 taxene-11 yle-13a and 2 g of molecular sieve 4 in powder in 60 cm3 of anhydrous dichloromethane and 4 cm3 of anhydrous pyridine, added dropwise under atmosphere of argon, at a temperature in the region of -30 C, 1.55 cm3 of trifluoromethanesulfonic anhydride. The temperature is allowed to rise to a temperature in the region of -50 ° C. in approximately 30 minutes, then the reaction mixture is kept stirring at a temperature close to -5 ° C. for 2 hours. After cooling to a temperature of -30 ° C. , the excess reagent is neutralized by the addition of 5 cm 3 of distilled water. The reaction mixture, returned to a temperature in the region of 20 "C., is filtered through a sintered glass lined with Celite. The solid residue is rinsed with 20 cm 3 of an ethyl acetate-dichloromethane mixture (50-50 by volume). decantation of the filtrate, the aqueous phase is reextracted with twice 5 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered through sintered glass, and concentrated to dryness under reduced pressure (0.27 kPa) at a temperature close to 40 "C. 9.2 g of a yellow meringue are thus obtained which are purified by chromatography at atmospheric pressure on 400 g of silica (0.063-0.2 mm) contained in a column 6 cm in diameter (elution gradient: ethyl acetate-dichloromethane from 2-98 to 6-94 by volume), collecting 60 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. This gives 3.76 g of tert-butoxycarbonyl-3 (methoxy4 phenyl) -2 phenyl4 oxazolidine- 1,3 carboxylate-5 (2R, 4S, 5R) acetoxy4a benzoyloxy-2a carbonyldioxy- 113,1413 epoxy-5 (3,20 hydroxy-1,013 oxo-9 trifluoromethanesulfonate-7ss taxene-1 1 yl- 13a in the form of a pale yellow meringue.

Tert-butoxycarbonyl -3 (4-methoxyphenyl) -2 phenyl4 oxazolidine- 1,3 carboxylate-5 (2R, 4S, 5R) acetoxy-4a benzoyloxy-2a carbonyldioxy- 113,1413 epoxy513,20 dihydroxy-713, 1013 oxo-9 taxene-11 yle-13a can be prepared as follows:
To a suspension of 9.2 g of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) of acetoxy-4a benzoyloxy-2a carbonyldioxy-1S, 14IJ epoxy-5ss, 20 oxo-9 bis- (2,2,2,2-trichloroethoxy) carbonyloxy 7 (3,1013 taxene-11 yl-13a and 9.1 g of zinc powder in 60 cm3 of methyl acetate, maintained under an argon atmosphere, at a temperature in the region of 20 "C., 16 cm 3 of acetic acid are added dropwise in approximately 15 minutes. After 1 hour at a temperature in the region of 20" C, the reaction mixture is filtered through sintered glass lined with celite. The solid residue is rinsed with 100 cm3 of ethyl acetate. The filtrate is concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40 "C.

The residue obtained is taken up with 400 cm3 of ethyl acetate. The organic phase is washed with twice 50 cm3 of a saturated aqueous solution of sodium hydrogencarbonate, then twice 50 cm3 of distilled water, dried over magnesium sulfate, filtered through sintered glass and concentrated to dryness under reduced pressure (0 , 27 kPa) at a temperature in the region of 40 "C. This gives 9.8 g of a white meringue which is purified by chromatography at atmospheric pressure on 400 g of silica (0.063 0.2 mm) contained in a column 6 cm in diameter (methanol-dichloromethane elution gradient from 2.5-97.5 to 3-97 by volume), collecting 60 cm3 fractions The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 400C for 2 hours. This gives 6.02 g of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) acetoxy-4a benzoyloxy-2a carbonyl dioxy-113,1413 epoxy-5ss, 20 dihydroxy-713, îO13 oxo-9 taxene-11 yl -13a in the form of a white meringue.

Tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) acetoxy-4a benzoyloxy-2a carbonyldioxy-lp, l413 epoxy 5 (3.20 oxo -9 bis- (2,2,2-trichloroethoxy) carbonyloxy-713.10 (3 taxene- 1 1 yl-13 &alpha; can be prepared as follows:
To a suspension of 6.5 g of acetoxy4a benzoyloxy-2a carbonyldioxy1ss, 14ss epoxy-5 (3.20 hydroxy-1 3a oxo-9 bis- (trichloro-2,2,2 ethoxy) carbonyloxy713,1013 taxene-11, 3.6 g of tert-butoxycarbonyl-3 (4-methoxyphenyl) acid -2 phenyl4-oxazolidine-1,3 carboxylic-5 (2R, 4S, 5R) and 200 mg of powdered 4A molecular sieve in 30 cm3 of toluene anhydrous and 5 cm 3 of ethyl acetate, 2.3 g of dicyclohexylcarbodiimide are added successively, under an argon atmosphere, at a temperature close to 20 ° C., then 255 mg of N, N'-dimethylamino4 pyridine. suspension obtained is stirred at a temperature in the region of 20 "C under an argon atmosphere for 50 minutes and then concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 40" C. The residue obtained is purified by chromatography at atmospheric pressure on 250 g of silica (0.063-0.2 mm) contained in a column 4.5 cm in diameter (elution gradient: ethyl acetate-dichloromethane from 2-98 to 5-9 5 by volume) collecting 40 cm3 fractions The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 "C for 2 hours. This gives 9.2 g of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl4 oxazolidine-1,3 carboxylate-5 (2R, 4S, 5R) of acetoxy4a benzoyloxy-2a carbonyldioxy-113,1413 epoxy- 5 (3.20 oxo-9 bis- (2,2,2-trichloroethoxy) carbonyloxy-7ss, 10ss taxene-Il yle-13a in the form of a white meringue.

Acetoxy-4a benzoyloxy-2a carbonyldioxy-113,1413 epoxy-5 (3.20 hydroxy 1 3a oxo-9 bis- (2,2,2-trichloroethoxy) carbonyloxy-7 (3, 10 (3 taxene-11 can be prepared as follows:
To a solution of 4 g of acetoxy-4a benzoyloxy-2a epoxy-5ss, 20 pentahydroxy-113,713,1013,13a, 1413 oxo-9 taxene-11 in 40 cm3 of anhydrous pyridine, maintained under an argon atmosphere, at a temperature close to 0 C, 4.4 cm3 of 2,2,2-trichloroethyl chloroformate is added dropwise. The solution is stirred for 1 hour at a temperature close to 0 C, 27 hours at a temperature close to 20 "C, then 2.2 cm3 of 2,2,2 ethyl trichloro chloroformate are added at the same temperature. After 15 hours at a temperature in the region of 20" C, 60 cm3 of distilled water are added dropwise then 200 cm3 of dichloromethane. After decantation, the aqueous phase is reextracted with twice 30 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered through sintered glass and concentrated to dryness under reduced pressure (0.27 kPa) at a temperature close to 40 "C. This gives 12.8 g of a brown oil which is purified by chromatography at atmospheric pressure on 250 g of silica (0.063-0.2 mm) contained in a column 3.5 cm in diameter (elution gradient: ethyl acetate-dichloromethane from 0-100 to 5-95 by volume), collecting 30 cm3 fractions.The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0 , 27 kPa) at 40 "C for 2 hours. This gives 6.5 g of acetoxy-4a benzoyloxy-2a carbonyldioxy-113,14p epoxy-5ss, 20 hydroxy- 1 3a oxo-9 bis- (trichloro-2 , 2,2 ethoxy) carbonyloxy-7 (3,1013 taxene-11 in the form of a pale yellow meringue.

 The new products of general formula (I) in which Z represents a radical of general formula (II) manifest a significant inhibitory activity of abnormal cell proliferation and have therapeutic properties allowing the treatment of patients with pathological conditions associated with cell proliferation abnormal. 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, lymphatic or renal systems, mammary or blood cells, liver, digestive system, pancreas and thyroid or adrenal glands.These pathological conditions may also include psoriasis, solid tumors, ovarian cancer, breast, brain, prostate, colon, stomach, kidney or testes, 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 includes 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 emulsifying agents, 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 administration, 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 in solution in magazine. 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 (a, 13 or b) and TNF. Other chemotherapeutic agents useful in the treatment of disorders caused by abnormal proliferation cells include, without limitation, 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 such as mercaptopurine and thioguanine, natural products such as vinca alkaloids such as vinblastine, vincristine and vendesine, epipodophyllotoxins co even etoposide and teniposide, antibiotics like dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes like L-asparaginase, various agents like platinum coordination complexes like cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocotic suppressants such as mitotane and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate , methoxyprogesterone acetate and megestrol acetate, estrogens like diethylstilbestrol and ethynylestradiol, 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. lt 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. Intraperitoneally, 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 choosing the most appropriate dosage, the route of administration, the weight of the patient, his general state of health, his age and all the factors which may influence the efficacy 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 cm3 of ethanol then the solution is diluted by adding 18 cm3 of physiological saline.

 The composition is administered by infusion for 1 hour by introduction into physiological saline.

Claims (16)

1 - New taxoides of general formula:

 in which Z represents a hydrogen atom or a radical of general formula:

 in which:  R1 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: - an alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 with 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 radicals, alkoxy containing 1 to 4 carbon atoms, dialkoylamino, each alkyl part of which contains 1 to 4 carbon atoms, piperidino, morpholino, 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 in which the alkyl part contains 1 to 4 carbon atoms, - a phenyl or a- or fnaphthyl 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 5-membered aromatic heterocyclic radical preferably chosen from the furyl and thienyl radicals, - or a saturated heterocyclyl radical containing 4 to 6 atoms of ca rbone 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 a- or ssnaphthyl 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, formyl, radicals acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkoylamino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialcoylcarbamoyl, cyano, nitro and trifluoromethyl, or one or more hetero rings or hetero rings, having one or more different, or one or more hetero rings, or having one or more hetero rings, or having one or more hetero rings, nitrogen, oxygen or sulfur atoms and optionally substituted by one or more substituents, identical o u different, chosen from halogen atoms and alkyl, aryl, amino, alkyllamino, dialkoylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxy, carbamoyl, alkylcarbamoyl, dialkoylcarbamoyl or alkoxycarbonyl radicals, it being understood that in radicals, in radicals, phenyl, a- or ssnaphthyl and aromatic heterocyclyl, the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl radicals or a- or ssnaphtyles,  R4 represents a hydrogen atom or a hydroxy radical or an alkoxy radical containing 1 to 6 carbon atoms in a straight or branched chain, alkenyloxy containing 3 to 6 carbon atoms in a straight or branched chain, alkynyloxy containing 3 to 6 carbon atoms straight or branched chain, cycloalkoyloxy containing 3 to 6 carbon atoms, cycloalkenyloxy containing 3 to 6 carbon atoms, alkanoyloxy in which the alkanoyl part contains 1 to 6 carbon atoms in straight or branched chain, alkenoyloxy in which the alkenoyl part contains 6 carbon atoms in a straight or branched chain, alkynoyloxy of which the alkynoyl part contains 3 to 6 carbon atoms in a straight or branched chain, alkoxyacetyl of which the alkyl part contains 1 to 6 carbon atoms in a straight or branched chain, alkylthioacetyl of which alkyl contains 1 to 6 carbon atoms in straight or branched chain, alkyloxycarbonyloxy of which the alkyl part contains 1 to 6 atoms of carbon in a straight or branched chain, these radicals being optionally substituted by one or more halogen atoms or by an alkoxy radical containing 1 to 4 carbon atoms, alkylthio containing 1 to 4 carbon atoms, or a carboxy, alkyloxycarbonyl radical the alkyl part contains 1 to 4 carbon atoms, cyano, carbamoyl, N-alkylcarbamoyl or N, N-dialkoylcarbamoyl each alkyl part of which contains 1 to 4 carbon atoms or forms, with the nitrogen atom to which it is linked, a saturated heterocyclic radical containing 5 or 6 members and optionally a second heteroatom chosen from oxygen atoms , sulfur or nitrogen optionally substituted by an alkyl radical containing 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl part contains 1 to 4 carbon atoms, or else R4 represents a benzoyloxy or heterocyclylcarbonyloxy radical in in which the heterocyclic part represents a 5 or 6-membered aromatic heterocycle containing as heteroatom an oxygen, sulfur or nitrogen atom,  R5 represents a straight or branched alkyl radical containing 1 to 6 carbon atoms, straight or branched alkenyl containing 2 to 6 carbon atoms, straight or branched alkynyl containing 2 to 6 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, aryl, aromatic heterocyclyl containing 5 to 6 members, or else  R4 and R5 together with the carbon atom to which they are linked form a carbonyl group.  2 - New taxoides according to claim 1 for which Z represents a hydrogen atom or a radical of general formula (II) in which R1 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 atoms or radicals, identical or different chosen from atoms 'halogen (fluorine, chlorine) and the radiant alkyls (methyl), alkoxy (methoxy), dialcoylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonyl amino (tert-butoxycarbonylamino) or trifluoromethyl or a furyl-2 or -3 radical, thienyl -2 or -3 or thiazolyle-2, -4 or -5 and R4 represents a hydroxy radical or an alkanoyloxy radical of which the alkanoyl part contains 1 to 6 carbon atoms in straight or branched chain, and R5 r epresent a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms, or else R4 and R5 form together with the carbon atom to which they are linked a carbonyl group.  3 - New taxoides according to claim 1 for which Z represents a hydrogen atom or a radical of general formula (II) in which R1 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, thiazolyl4 or thiazolyl-5 radical, R4 represents a hydroxy radical or an acetyloxy radical and R5 represents a hydrogen atom.  4 - Process for the preparation of a taxoid according to one of claims 1, 2 or 3 characterized in that one esterifies a product of general formula:

 in which R4 and R5 are defined as in one of claims 1, 2 or 3, by means of an acid of general formula:

 in which R1 and R3 are defined as in one of claims 1, 2 or 3, or else R6 represents a hydrogen atom and R7 represents a protective group for the hydroxy function, and either R6 and R7 together form a heterocycle saturated with 5 or 6 links, or a derivative of this acid to obtain an ester of general formula:

 in which R1, R3, R4, Rg, R6 and R7 are defined as above, then replaces the protective groups represented by R7 and / or R6 and R7 by hydrogen atoms.  5 - Process according to claim 4 characterized in that the esterification is carried out using an acid of general formula (IV) in the presence of a condensing agent and an activating agent in an organic solvent at a temperature between -10 and 90 "C.  6 - Method according to claim 4 characterized in that the esterification is carried out using an acid of general formula (IV) in the form of symmetrical anhydride by operating in the presence of an activating agent in a solvent organic at a temperature between 0 and 90 "C.  7 - Process according to claim 4 characterized in that the esterification is carried out using the acid of general formula (IV) in the form of halide or in the form of mixed anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base, operating in an organic solvent at a temperature between 0 and 800 C.  8 - Process according to claim 4 characterized in that the protective groups R7 and / or R6 and R7 are replaced by hydrogen atoms, operating as follows: 1) when R6 represents a hydrogen atom and R7 represents a protecting group for the hydroxy function, the protecting groups are replaced by hydrogen atoms is carried out by means of a mineral or organic 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, 2) when R6 and R7 together form a saturated heterocycle with 5 or 6 members and more particularly an oxazolidine cycle of general formula:

 in which R1 is defined as in one of claims 1, 2 or 3, R8 and Rg, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose 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 R8 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and Rg represents a hydrogen atom, or else R8 and Rg form together with the carbon atom to which they are linked, a cycle having 4 to 7 members, the protective group formed by R6 and R7 is replaced by hydrogen atoms by operating, according to the meanings of R1, R8 and Rg, as follows:  a) when R1 represents a tert-butoxycarbonyl radical, R8 and Rg, which are identical or different, represent an alkyl radical or an aralkyl or aryl radical, or else R8 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical, and Rg represents a hydrogen atom, or else R8 and Rg together form a ring having 4 to 7 members, the ester of general formula (V) is treated with a mineral or organic acid optionally in an organic solvent such as an alcohol to obtain a product of general formula:

 in which R3, R4 and R5 are defined in one of claims 1, 2 or 3, which is acylated by means of benzoyl chloride in which the phenyl nucleus is optionally substituted, of thénoyl chloride, of furoyl chloride or a product of general formula:  R2-O-CO-X (VIII) in which R2 is defined as above and X represents a halogen atom 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 R1 represents an optionally substituted benzoyl radical, thenoyl or furoyl or an R2O-CO- radical in which R2 is defined as above, R8 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a radical phenyl substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms and Rg represents a hydrogen atom, the protective group formed by R6 and R7 is replaced by hydrogen atoms in the presence of a mineral or organic acid used alone or as a mixture in stoichiometric or catalytic quantity, 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.  9 - Process for the preparation of a product according to one of claims 1, 2 or 3 in which Z represents a hydrogen atom, R4 represents an alkoxy, alkanoyloxy, alkoxyacetyl, alkoyloxycarbonyloxy, cycloalkoyloxy, cycloalkenyloxy, benzoyloxy or heterocyclylcarbonyloxy radical R5 represents a hydrogen atom characterized in that a product of general formula is reacted:  R4-X1 (X) in which R4 is defined as above and X1 represents a halogen atom or a residue of reactive ester, on a product of general formula:

 in which R represents a trifluoromethanesulonyloxy radical or forms a bond with the carbon atom of the methyl radical in has so as to form a cyclopropane ring, then, when R represents a trifluoromethanesulfonyloxy radical, treats the product obtained with an alkali metal halide or an alkali azide.  10 - Process for preparing a product according to claim 1 for which Z represents a hydrogen atom and R4 and R5 each represents a hydrogen atom, characterized in that a product of formula is electrolytically reduced

 to obtain a product of formula:

 which are treated with a haloformate of general formula Hal-CO-O-R10 (XIII) in which R10 represents a 2,2,2,2-trichloroethyl radical or (2-trichloromethyl-propyl) -2 to obtain a product of formula general:

 in which G1 represents a 2,2,2,2-ethoxycarbonyl or (2-trichloromethyl-propoxy) -2 carbonyl radical, then replaces the protective group G1 with a hydrogen atom to give a product of formula:

 which is treated with a derivative of trifluoromethanesulfonic acid and then with an alkali metal halide or an alkali metal azide or an ammonium salt to give product of general formula (III) in which Z represents an atom of hydrogen, and R4 and R5 each represents a hydrogen atom.  11 - Process for preparing a product according to claim 1 for which Z represents a hydrogen atom, and R4 and R5 together form a carbonyl group, characterized in that a product of general formula is oxidized:

  using pyridinium chlorochromate, pyridinium dichromate, potassium dichromate, ammonium dichromate or manganese oxide, then, when R represents a trifluoromethanesulfonyloxy radical, treats the product obtained with an alkali metal halide or d '' an alkali metal azide or an ammonium salt.  12 - Process for the preparation of a product according to one of claims 1, 2 or 3 for which Z represents a radical of general formula (II), R4 represents an alkoxy, alkanoyloxy, alkoxyacetyl, alkoxycarbonyloxy, cycloalkoyloxy or cycloalkenyloxy radical and R5 represents a hydrogen atom, characterized in that a product of general formula is made to act:  R4-X1 (X) in which R4 is defined as above and X1 represents a halogen atom or a residue of reactive ester on a product of general formula:

 in which R is a trifluoromethanesulfonyloxy radical or forms a bond with the carbon atom of the methyl radical, R1 and R3 are defined as in one of claims 1, 2 or 3, R6 and R7 are defined as in claim 4 , then, when R represents a trifluoromethanesulfonyloxy radical, treats the product obtained with an alkali metal halide or an alkali metal azide or an ammonium salt, then replaces the protective groups R7 or R6 and R7 with hydrogen atoms for obtain a product of general formula (I).  13 - Process for preparing a product according to claim 1 for which Z represents a radical of general formula (II), and R4 and R5 each represent a hydrogen atom, characterized in that a product of general formula is electrolytically reduced:

 in which R1 and R3 are defined as in claim 1, R6 represents a hydrogen atom and R7 represents a protective group for the hydroxy function and can also represent a hydrogen atom or else R6 and R7 together form a saturated heterocyle with 5 or 6 links, R4 represents a hydroxy radical or an alkanoyloxy radical or an alkoxyacetyl radical and R represents a trifluoromethanesulfonyloxy radical or forms a bond with the carbon atom of the methyl radical at a, then, when R represents a trifluoromethanesulfonyloxy radical, treats the product obtained with an alkali metal halide or an alkali metal azide under the conditions described above and optionally replaces the radicals R7 and R6 and R7 with hydrogen atoms.  14 - Process for preparing a product according to one of claims 1 or 2 for which Z represents a radical of general formula (II) and R4 and R5 together form a carbonyl group characterized in that one oxidizes a product of general formula /

 in which R represents a trifluoromethanesulfonyloxy radical or forms a bond with the carbon atom of the methyl radical in a, R1 and R3 are defined as in one of claims 1 or 2, R6 and R7 are defined as in claim 4, R6 and R7 can also each represent a hydrogen atom by means of pyridinium chlorochromate, pyridinium dichromate, potassium bichromate, ammonium dichromate or manganese oxide, then, when R represents a trifluoromethanesulfonyly radical , treats the product obtained with an alkali metal halide or an alkali metal azide and optionally replaces the radicals R7 or R6 and R7 with hydrogen atoms.  15 - Process for preparing a product according to claim 1 for which Z represents a radical of general formula (II) R4 represents a hydroxy radical or a  alkoxy, alkenyloxy, optionally substituted alkynyloxy, alkanoyloxy radical,  alkenoyloxy, alkynoyloxy alkoxyacetyl, alkylthioacetyl, alkyloxycarbonyloxy, or  a cycloalkyloxy, cycloalkenyloxy, benzoyloxy or heterocyclylcarbonyloxy radical and  R5 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl radical,  unsaturated phenyl or heterocyclyl containing 5 or 6 members, characterized in that  reacts a product of general formula:  Rg-X2 (XXI)  in which R5 is defined as above and X2 represents a metal atom  alkaline such as a lithium atom or an organo-magnesium residue, on a product of  general formula:

 in which R4 and R5 together form a carbonyl group, operating in an inert organic solvent at a temperature between -78 and 300C, to obtain a product of general formula:

 R4-X1 (X) then, when R represents a trifluoromethylsulfonyloxy radical, it is treated with an alkali metal halide or an alkali metal azide or an ammonium salt, then replaces the protective groups R7 or R6 and R7 with d atoms 'hydrogen. R, R1, R3, Rg, R6 and R7 are defined above, then optionally causes a product of general formula to act  16 - 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 whether they are inert or pharmacologically active.