Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to new taxoids of general formula:
• Ar represents an aryl radical, an alkyl containing 1 to 4 carbon atoms, an alkenyl containing 2 to 4 carbon atoms, a cycloalkyl containing 3 to 6 carbon atoms or a cycloalkenyl containing 3 to 6 carbon atoms
• R represents a hydrogen atom or an alkanoyl, alkoxyacetyl or alkyl radical
• Ri represents a benzoyl, thenoyl or furoyl radical or an R2-O-CO- radical in which R2 represents:
• 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 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkoylamino of which each alkyl part 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, cycloalken
• R3 represents - a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms,
• R3 cannot represent an unsubstituted phenyl radical, - or a saturated or unsaturated heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 atoms of carbon, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.
• the aryl radicals represented by Ar and R3 are phenyl or ⁇ - or ⁇ -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, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkyoyino, dialcoylamino, carboxyamcoyloxy , azido, trifluoromethoxy 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 alkyl portions
• the heterocyclic radicals represented by Ar and 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
• Ar represents a phenyl, thienyl-2 or -3 or furyl-2 or -3 radical optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl, alkoxy radicals, amino, alkyllamino, dialcoylamino, acylamino, alkoxycarbonylamino and trifluoromethyl and R3 represents a phenyl radical substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialkoylamino radicals, acylamino, alkoxy ⁇ carbonylamino and trifluoromethyl.
• Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom, or by an alkyl radical
• R3 represents a phenyl radical substituted by a halogen atom.
• the new taxoids of general formula (I) can be obtained by esterification of a product of general formula:
• G1 represents an alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl) or alkyl (methyl) radical or a protecting group for the hydroxy function by means of an acid of general formula:
• R5 When R4 represents a hydrogen atom, R5 preferably represents a methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, ( ⁇ -trimetylsilylethoxy) methyl or tetrahydropyranyl radical.
• R4 and R5 together form a heterocycle the latter is preferably an oxazolidine ring optionally mono-substituted or gem-disubstituted in position -2.
• G represents an acetyl or alkyl radical or an alkoxyacetyl radical.
• the esterification of the product of general formula (II) can be carried out by reacting the acid of general formula (III) preferably in the form of halide, such as chloride, on the product of general formula (II) previously metallized .
• the metallation is generally carried out using an alkali metal alkyl such as butyllithium, operating in an inert organic solvent such as an ether such as tetrahydrofuran at a temperature below -50 ° C and, preferably in the vicinity of - 78 ° C. Esterification is generally carried out by operating at the same temperature in the same solvent.
• R4 represents a hydrogen atom
• R5 is defined as above and G1 represents an alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl), alkyl (methyl) radical
• the replacement of the protective groups by atoms of hydrogen can be carried out by treating the product of general formula (IV) with 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.
• a mineral acid hydroochloric acid, sulfuric acid, hydrofluoric acid
• organic acid acetic acid, methanesulfonic acid
• R- is defined as above, R6 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 R5 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 members, and Gi represents an r chemical alkanoyl
• the product of general formula (IV) is treated with formic acid at a temperature in the region of 20 ° C.
• the acylation of the product of general formula (V) by means of a product of general formula (VI) is carried out in an inert organic solvent chosen from esters such as ethyl acetate, acetate d isopropyl or n.butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane in the presence of an inorganic 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.
• Ri represents a benzoyl radical or an R2-O-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 a or several alkoxy radicals containing 1 to 4 carbon atoms
• R7 represents a hydrogen atom
• the replacement of the protective groups 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, 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 acid can be used in a catalytic or
• the protective group R5 is replaced by a hydrogen atom first, operating under the acid conditions described in point 1 ) above, then optionally replaces the protective group G with a hydrogen atom by treatment in an alkaline medium or by the action of a zinc halide under conditions which do not affect the rest of the molecule.
• the alkaline treatment is carried out by the action of ammonia in a hydro-alcoholic medium or hydrazine in an alcoholic medium at a temperature in the region of 20 ° C.
• the treatment with a zinc halide is carried out in methanol at a temperature in the region of 20 ° C. 4) when Gi represents an alkoxyacetyl radical and R4 and R5 are defined as in point 2-a) above, the protective group G * is optionally replaced by treatment in an alkaline medium or by treatment with a zinc halide in the conditions described in point 3) above, then treats the product of general formula (V) obtained under the acylation conditions described in point 2-a) above.
• the protective group G1 is optionally replaced by treatment in an alkaline medium or by treatment with a zinc halide under the conditions described in point 3) above, then treats the product obtained under the conditions described in point 2-b) above.
• OCOC 6 H 5 in which Ar, Ri and R4 are defined as above, R5 is defined as above and may also represent a hydrogen atom, G'i represents a hydrogen atom or an alkanoyl (acetyl), alkoxyacetyl radical (methoxyacetyl) or alkyl (methyl) or a protecting group for the hydroxy function according to the following scheme:
• the electrolytic reduction from the product of general formula (VIII) is carried out in an electrolyser containing a support catholyte in which the product of general formula (VIII) is dissolved at a concentration of between 0.1 g / l and the saturation of the solution in product of general formula (V ⁇ l).
• the reduction is carried out in a diaphragm electrolyser.
• the electrolytic reduction is carried out in an electrolyser comprising a cathode, a cathode compartment, a separating diaphragm, an anode compartment and an anode whose characteristics are the following: a) the cathode consists of a sheet of mercury, b) the cathode compartment contains the catholyte which consists of a solution of the product of general formula (VHI) in an organic medium, c) the separating diaphragm consists of a porous material such as a plate, a sleeve or a candle of sintered glass or porcelain or by an ion exchange membrane, preferably by a cation exchange membrane, d) the anode compartment contains the anolyte preferably consisting of the same solvent or mixture of solvents and the same support electrolyte as that which is used in the cathode compartment, e) the anode is constituted by a cond material electricity generator whose
• the anode consists of an electrically conductive material that cannot be attacked under the conditions of electrolysis, such as, for example, polished, solid or conductive platinum, graphite or vitreous carbon.
• the support electrolyte consists of a quaternary ammonium salt such as tetraethylammonium acetate or tetraethylammonium tetrafluoroborate, or their mixtures soluble in the solvent or the mixture of solvents.
• solvents are used which readily dissolve the products of general formula (II) and (VIII) and which are not very resistant such as alcohols such as methanol, nitriles such as acetonitrile or amides such as dimethylformamide.
• the pH must be compatible with the stability of the substrate.
• the medium can be buffered by adding a weak acid such as acetic acid in equimolar concentration with quaternary ammonium acetate.
• the anode, the cathode and the separating diaphragm are in horizontal parallel planes, the cathode consisting of a sheet of mercury.
• the temperature of the electrolysis bath is generally between 0 and 30 ° C.
• the electrolysis is carried out at a controlled potential which can be between -1.90 and -2.10 volts with respect to a reference electrode saturated with calomel.
• the product of general formula (VIII) can be obtained: 1) by the action of an alkali metal halide (sodium chloride, potassium fluoride) or an alkali metal azide (sodium azide) or a salt of quaternary ammonium or of an alkali metal phosphate on a product of general formula:
• Ar, Ri, R4 and G'1 are defined as above and R5 is defined as above and can also represent a hydrogen atom.
• the reaction is carried out in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl tbutyl ether) and nitriles (acetonitrile) alone or as a mixture at a temperature between 20 ° C. and the boiling temperature of the reaction mixture.
• organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl tbutyl ether) and nitriles (acetonitrile) alone or as a mixture at a temperature between 20 ° C. and the boiling temperature of the reaction mixture.
• the product of general formula (IX) can be obtained by the action of a derivative of trifluoromethanesulfonic acid such as anhydride or N-phenyl trifluoromethanesulf onimide on a taxoid of general formula: in which Ar, R, R4 and G'j are defined as above and R5 is defined as above
• reaction is carried out in an inert organic solvent (aliphatic hydrocarbons optionally halogenated, 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.
• organic base such as an aliphatic tertiary amine (triethylamine) or pyridine
• R and R4 are defined as above
• R5 is defined as above
• G represents an acetyl, alkoxyacetyl or alkyl radical or a protecting group for the hydroxy function
• G'2 represents a protecting group for the hydroxy function by replacing the protective groups G'2 and optionally G'1 by hydrogen atoms.
• the radicals G ' j and G'2 when they represent a group protecting the hydroxy function, are preferably 2,2,2-trichloroethoxycarbonyl, (2-trichloromethyl-propoxy) -2 carbonyl or trialkylsilyl radicals, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl in which the alkyl parts contain 1 to 4 carbon atoms and the aryl parts are preferably phenyl radicals.
• G'i and G'2 represent a 2,2,2-trichloroethoxycarbonyl or (2-trichloromethylpropoxy) -2 carbonyl radical
• the replacement of the groups protective by hydrogen atoms is carried out by zinc, possibly associated with copper, in the presence of acetic acid at a temperature between 20 and 60 ° C or by means of a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n.butyl acetate in the presence of zinc optionally associated with copper.
• acetic acid at a temperature between 20 and 60 ° C or by means of a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl a
• G'2 represents a silylated radical and G'j represents an alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl) or alkyl (methyl) radical
• the replacement of the protective group G'2 by a hydrogen atom can be carried out by means of , for example, gaseous hydrochloric acid in ethanolic solution at a temperature close to 0 ° C or by the action of a hydrofluoric acid-triethylamine or hydrofluoric acid-pyridine complex in an organic solvent such as dichloromethane, tetrahydrofuran or acetonitrile at a temperature close to 20 ° C, under conditions which have no effect on the rest of the molecule.
• the product of general formula (XI) in which G'i represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical can be obtained under the conditions described in European patents EP 0 336 840 and EP 0 336 841 and in international application PCT / WO 9209589 by esterification of baccatin III or of 10-deacetyl baccatin III whose hydroxy functions at 7 and possibly -10 are protected, it being understood that to obtain a product of general formula (XI) in which G represents an alkoxyacetyl or alkyl radical, it is necessary to first treat the 10-deacetyl baccatin III protected at -7, preferably with a silylated radical, with an alkoxyacetic acid halide or with an alkyl halide.
• an alkoxyacetyl group is carried out by treating the 10-deacetyl baccatin III protected at -7 with an acid halide.
• alkoxyacetic by operating in a basic organic solvent such as pyridine at a temperature in the region of 20 ° C.
• an alkyl radical is carried out by treating the 10-deacetyl baccatin III protected in -7 and metallized in -10, using for example an alkali hydride (sodium hydride) or a metal alkyl (butyllithium), by an alkyl halide.
• an alkali hydride sodium hydride
• a metal alkyl butyllithium
• Esterification using an acid of general formula (XIII) can be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridine) in an organic solvent (ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between -10 and 90 ° C.
• a condensing agent carbbodiimide, reactive carbonate
• an activating agent aminopyridine
• organic solvent ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons
• Esterification can also be carried out using the acid of general formula (XIII) in the form of anhydride, operating in the presence of an activating agent (aminopyridine) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 90 ° C.
• an activating agent aminopyridine
• an organic solvent ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons
• the esterification can also be carried out using the acid of general formula (XIII) in the form of halide or in the form of anhydride with an acid.
• aliphatic or aromatic optionally prepared in situ, in the presence of a base (tertiary aliphatic amine), 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 product of general formula (XII) can be obtained by the action of an alkali metal halide (sodium chloride, potassium fluoride) or an alkali metal azide (sodium azide) or an ammonium salt quaternary or of an alkali metal phosphate on a product of general formula:
• reaction is carried out 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. .
• 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. .
• the product of formula (XIV) in which G1 represents a hydrogen atom or an alkanoyl (acetyl), alkoxyacetyl (methoxyacetyl) or alkyl (methyl) radical can be obtained by the action of a derivative of trifluoromethanesulfonic acid such as that the anhydride or N-phenyltrifluoromethanesulfonimide on baccatin III or deacetyl-10 baccatin III, which can be extracted according to known methods from yew leaves (Taxus baccata), possibly followed by protection in position 10, it being understood that in order to obtain a product of general formula (XIV) in which G represents an alkoxyacetyl or alkyl radical, it is necessary to treat the 10-deacetyl-baccatin III protected in -7 beforehand, preferably with a silylated radical, with a halide of alkoxyacetic acid or with an alkyl halide.
• reaction of a derivative of trifluoromethanesulfonic acid is carried out in an inert organic solvent (aliphatic hydrocarbons optionally halogenated, aromatic hydrocarbons) in the presence of a base organic such as an aliphatic tertiary amine (triethylamine) or pyridine at a temperature between -50 and + 20 ° C.
• an inert organic solvent aliphatic hydrocarbons optionally halogenated, aromatic hydrocarbons
• a base organic such as an aliphatic tertiary amine (triethylamine) or pyridine at a temperature between -50 and + 20 ° C.
• an alkoxyacetyl group is carried out by treating the 10-deacetyl baccatin III protected in -7 with an alkoxyacetic acid halide by operating in a basic organic solvent such as pyridine at a temperature in the region of 20 ° C. .
• an alkyl radical is carried out by treating the 10-deacetyl baccatin III protected in -7 and metallized in -10, using for example an alkali hydride (sodium hydride) or a metal alkyl (butyllithiu), with an alkyl halide.
• an alkali hydride sodium hydride
• a metal alkyl butyllithiu
• the new products of general formula (I) can be obtained by esterification of a product of general formula:
• G2 represents a protective group for the hydroxy function chosen, preferably from trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which the alkyl parts contain 1 to 4 atoms of carbon and the aryl parts are preferably phenyl radicals, using an acid of general formula (III), to obtain a product of general formula:
• Ar, Ri, R3 and G1 are defined as above, which, by the action of an alkali metal halide (sodium chloride, potassium fluoride, sodium chloride) or an alkali metal azide (sodium azide ) or a quaternary ammonium salt or an alkali metal phosphate, leads to the product of general formula (I) in which R represents an acetyl, alkoxyacetyl or alkyl radical which can be transformed into a product of general formula (I ) in which R represents a hydrogen atom.
• an alkali metal halide sodium chloride, potassium fluoride, sodium chloride
• an alkali metal azide sodium azide
• a quaternary ammonium salt or an alkali metal phosphate leads to the product of general formula (I) in which R represents an acetyl, alkoxyacetyl or alkyl radical which can be transformed into a product of general formula (I ) in which R represents a hydrogen atom.
• esterification of a product of general formula (XV) using an acid of general formula (III) is carried out under the conditions described above for the esterification of a product of general formula (II) using an acid of general formula (III).
• the replacement of the protective group G2 with a hydrogen atom is generally carried out by treating the product of general formula (XVI) with hydrofluoric acid or trifluoroacetic acid in the presence of an organic base such as pyridine or an amine aliphatic tertiary such as triethylamine by operating in an organic solvent such as an ether (tetrahydrofuran) or a nitrile (acetonitrile).
• an organic base such as pyridine or an amine aliphatic tertiary such as triethylamine
• an organic solvent such as an ether (tetrahydrofuran) or a nitrile (acetonitrile).
• the replacement of the protective groups represented by R5 or by R4 and R5 is carried out under the conditions described above for the replacement of the protective groups of the product of general formula (IV).
• the transformation of a product of general formula (XIX) into a product of general formula (I), in which R represents an alkanoyl, alkoxyacetyl or alkyl radical, is carried out under the conditions described above for the transformation of a product of general formula (IX) as a product of general formula
• 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) have remarkable biological properties.
• the new products show activity on tumors that 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) and which expresses mdr 1.
• Amino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) diacetoxy-4 ⁇ , 10 ⁇ (fluoro-4 benzoyloxy) -2 ⁇ epoxy-5 ⁇ , 20 hydroxy-l ⁇ methylene-7 ⁇ , 8 ⁇ oxo-9 nor- 19 taxene-11 yle-13 ⁇ can be prepared as follows:
• the white meringue obtained is purified directly by chromatography at atmospheric pressure on 40 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol-dichloromethane mixture (elution gradient of 2.5-97.5 to 5-95 by volume), the fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. 91.5 mg of 3-amino-2-hydroxy-3-phenylpropionate- (2R, 3S) diacetoxy-4 ⁇ , 10 ⁇ (4-fluoro-benzoyloxy) -2 ⁇ epoxy-5 ⁇ , 20 hydroxy-1 ⁇ methylene-7 ⁇ are thus obtained. , 8 ⁇ oxo-9 nor-19 taxene-11 yle-13 ⁇ in the form of a white meringue. T.butoxycarbonyl-3 dimethyl-2,2 ⁇ henyl-4 oxazolidinecarboxylate-5-
• the solution is stirred for 45 minutes at a temperature in the region of -78 ° C. and then 0.38 cm3 of a 1.3 M solution of n.butyllithium in hexane and then 0.0585 are successively added at the same temperature.
• cm3 of 4-fluoro benzoyl chloride The solution is stirred for 35 minutes at a temperature in the region of -78 ° C. and then 1 cm 3 of a saturated aqueous solution of ammonium chloride is added. The reaction mixture is brought to a temperature in the region of 20 ° C. in 15 minutes. After decantation, the aqueous phase is extracted with 2 times 1 cm 3 of ethyl acetate.
• T.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R.5S) of diacetoxy-4 ⁇ , 10 ⁇ epoxy-5 ⁇ , 20 dihydroxy-l ⁇ , 2 ⁇ methylene-7 ⁇ , 8 ⁇ oxo-9 nor-19 taxene-11 yle-13 ⁇ could be prepared as follows: The electrochemical reduction of tbutoxycarbonyl-3 dimethyl- is carried out
• the cell is a 100 cm3 glass vase divided into 2 compartments by a cation exchange membrane
• the cathode is a sheet of mercury whose useful surface is approximately 4 cm2,
• the anode is a platinum grid
• the reference electrode is a saturated calomel electrode.
• the potential of the cathode is fixed at -1.95 volts relative to the reference electrode .
• the solution is electrolysed for 54 minutes, that is to say the time necessary for the passage of 100 coulombs.
• concentration to dryness under reduced pressure (0.27 kPa) at a temperature in the region of 35 ° C the residue is taken up in 10 cm3 of ethyl acetate and 10 cm3 of distilled water.
• the aqueous phase is extracted twice with 5 cm3 of ethyl acetate.
• T.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R, 5S) diacetoxy-4 ⁇ , 10 ⁇ benzoyloxy-2 ⁇ epoxy-5 ⁇ , 20 hydroxy-l ⁇ methylene- 7 ⁇ , 8 ⁇ oxo-9 nor- 19 taxene-11 yle-13 ⁇ can be prepared as follows:
• the reaction mixture is heated for 2 hours with stirring and under an argon atmosphere, at a temperature in the region of 80 ° C, then cooled to a temperature in the region of 20 ° C and filtered through sintered glass lined with celite.
• the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C.
• 4.9 g of an orange-brown residue are thus obtained which is purified by chromatography at atmospheric pressure on 40 g of silica (0.063-0.2 mm) contained in a column 4.5 cm in diameter, eluting with a ethyl acetate-dichloromethane mixture (elution gradient from 0-100 to 10-90 by volume).
• T.butoxycarbonyl-3 dimethyl-2,2 phenyl-4 oxazolidinecarboxylate-5- (4R.5S) of diacetoxy-4, 10 ⁇ benzoyloxy-2 epoxy-5 ⁇ , 20 hydroxy-l ⁇ oxo-9 trifluoromethanesulfonate-7 ⁇ taxene-11 yle -13 ⁇ can be prepared as follows:
• the aqueous phase is separated by decantation and then extracted with 10 cm3 of dichloromethane.
• the combined organic phases are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• We 4.39 g of a yellow solid is thus obtained which is purified by chromatography at atmospheric pressure on 350 g of silica (0.063-0.2 mm) contained in a column 4.5 cm in diameter, eluting with an acetate mixture of 'ethyl-dichloromethane (elution gradient from 0-100 to 5-95 by volume).
• the fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.
• (4R.5S) of diacetoxy-4 ⁇ , 10 ⁇ benzoyloxy-2 ⁇ epoxy-5 ⁇ , 20 dihydroxy-l ⁇ , 7 ⁇ oxo-9 taxene-11 yle-13 ⁇ can be prepared under the conditions described in international PCT application WO 9209589.
• the solution is thus kept stirred for 45 minutes and then 10 cm 3 of a saturated aqueous ammonium chloride solution are added.
• the reaction medium is brought to a temperature in the region of 20 ° C in 1 hour.
• the solution obtained is poured into a mixture of 50 cm3 of ethyl acetate and 50 cm3 of a saturated aqueous solution of ammonium chloride.
• the aqueous phase is separated by decantation and then extracted with 2 times 50 cm3 of ethyl acetate.
• the organic phases are combined, washed with 50 cm3 of distilled water and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 620 mg of a white meringue are obtained which is purified by chromatography on 200 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter [eluent: ethyl acetate- cyclohexane (10- 90 by volume)] by collecting fractions of 30 cm3. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 244 mg of tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 phenyl-4-oxazolidine-1,3 carboxylic-5 (2R, 4S, 5R) of 4-acetoxy are obtained.
• reaction mixture is stirred for 4 hours at a temperature in the region of 20 ° C., then 10 cm 3 of dichloromethane and 50 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate are added.
• the organic phase is decanted, washed with 2 times 50 cm3 of a saturated aqueous solution of sodium chloride then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 205 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxylic-5- (2R, 4S, 5R) of acetoxy-4 ⁇ dihydroxy-l ⁇ , 7 ⁇ epoxy-5 ⁇ are obtained.
• the orange solution obtained is stirred for 20 minutes at a temperature in the region of 0 ° C., then 3 cm3 of water and 30 cm3 of dichloromethane are added.
• the organic phase is decanted, washed with 2 times 20 cm3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 233 mg is obtained which is purified by chromatography on 200 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter [eluent: dichloromethane-methanol (98-2 by volume)] by collecting fractions of 10 cm3.
• the crude product obtained is dissolved in 50 cm3 of dichloromethane and 50 cm3 of a saturated aqueous solution of sodium bicarbonate.
• the organic phase is separated by decantation and then extracted with 2 times 50 cm3 of dichloromethane.
• the organic phases are combined, washed with 50 cm3 of distilled water and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 175 mg of a white meringue are obtained which are purified by preparative chromatography on a 0.5 mm thick silica plate [eluent: dichloromethane-methanol (94-6 by volume)].
• the reaction mixture is kept stirring at a temperature in the region of 75 ° C for 5 hours and then, at a temperature in the region of 20 ° C, supplemented with 75 cm3 of dichloromethane and 50 cm3 of a saturated aqueous solution of sodium chloride.
• the organic phase is decanted, washed with 2 times 40 cm3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 110 mg is obtained which is purified by preparative chromatography on a 0.5 mm thick silica plate, eluting with a cyclohexane-ethyl acetate mixture (1-1 by volume).
• the mixture After cooling to a temperature in the region of 20 ° C, the mixture is filtered through a sintered vere garnished with celite. The filtrate is washed with 5 cm3 of water, then the organic phase is decanted, dried over magnesium sulfate. After filtration on sintered glass and concentration under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C, 410 mg of a pale yellow meringue is obtained which is purified by preparative thin layer chromatography [12 plates Merck preparations, Kieselgel 60F254; 0.25 mm thick; deposition in solution in dichloromethane; eluent: methanol-dichloromethane mixture (7-93 by volume)].
• reaction mixture is then diluted with 50 cm3 of dichloromethane, washed with 2 times 10 cm3 of distilled water. After extraction of the aqueous phase with 10 cm 3 of dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 710 mg of a yellow solid are thus obtained which is purified by chromatography at atmospheric pressure on 50 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with an elution gradient : ethyl acetate-dichloromethane from 10-90 to 20-80 by volume and collecting fractions of 10 cm3.
• the solution is stirred for 4 hours at 0 ° C., then diluted with 20 cm 3 of dichloromethane, and poured onto 40 cm 3 of a saturated aqueous solution of sodium hydrogen carbonate maintained at a temperature in the region of 0 ° C. After decantation, the aqueous phase is extracted with 3 times 30 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered through sintered glass, then concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C.
• the solution is thus stirred at a temperature in the region of -78 ° C for 45 minutes and then 10 cm 3 of a saturated aqueous solution of ammonium chloride are added.
• the reaction mixture is brought to a temperature in the region of 20 ° C in 1 hour and diluted with 20 cm3 of ethyl acetate.
• the aqueous phase is separated by decantation and then extracted with 2 times 10 cm3 of ethyl acetate.
• the organic phases are combined, washed with 10 cm3 of distilled water, dried over magnesium sulfate.
• the new products of general formula (I) demonstrate a significant inhibitory activity against 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.
• 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.
• Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents.
• 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.
• aqueous or non-aqueous sterile solutions or suspensions are used.
• 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.
• compositions according to the invention 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.
• 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, ⁇ or ⁇ ) and TNF.
• 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,
• 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.
• 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 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. .
• Example 2 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.
• composition is administered by infusion for 1 hour by introduction into physiological saline.

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• 1993
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