Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to new taxoids of general formula:
• R a represents a hydrogen atom or a hydroxy, alkoxy radical containing
• Z represents a hydrogen atom or a radical of general formula:
• Rj 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
• phenyl or ⁇ - or ⁇ -naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms or a radical 5-membered aromatic heterocyclic preferably chosen from furyl and thienyl radicals,
• 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 ⁇ - or ⁇ -naphthyl optionally substituted by one or more atoms or radicals chosen from atoms '' halogen and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamin
• the aryl radicals which can be represented by R3, R4 and / or R5 are phenyl or ⁇ - or ⁇ -naphthyl radicals optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and the radicals alkyl, alkenyls, alkynyls, aryls, arylalkyls, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino carboxyalkyl , dialkoylcarbamoyl, cyano, nitro, azido, trifluoromethyl and trifluoromethoxy, it being understood that the alkyl radicals and the alkyl portions of the other radicals
• R4 and / or 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 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, aryloxy containing 6 with 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 carbon, acyl containing 1 to 4 carbon atoms, arylcarbonyl of which the aryl part contains 6 to 10 carbon atom
• the present invention relates to the products of general formula (I) in which R a represents a hydroxy radical, an alkoxy containing 1 to 4 carbon atoms, an acyloxy containing 1 to 4 carbon atoms or an alkoxyacetoxy in which the alkyl part contains 1 to 4 carbon atoms and R5 represents a hydrogen atom, Z represents a hydrogen atom or a radical of general formula (II) in which R ⁇ represents a benzoyl radical or an R2-O-CO- radical in which R2 represents a tert-butyl radical and R3 represents an 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), dialkoylamino (d
• the present invention relates to the products of general formula (I) in which R a represents a hydrogen atom or a hydroxy or acetyloxy or methoxyacetoxy radical and R ⁇ represents a hydrogen atom, Z represents a atom hydrogen or a radical of general formula (H) in which Rj represents a benzoyl radical or an R2-O-CO- radical in which R2 represents a tert-butyl radical and R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl radical, furyl-2, furyle-3, thienyl-2, thienyl-3, thiazolyl-2, thiazolyl-4 or thiazolyl-5 and R4 represents a phenyl radical optionally substituted by a halogen atom and R5 represents an alkyl radical containing 2 to 4 carbon atoms.
• Rj represents a benzoyl radical or an R2-O-CO- radical in which
• the products of general formula (I) in which R a represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical, R ⁇ represents a hydrogen atom, R4, R5 and Z are defined as above can be obtained by the action of an alkali metal halide (sodium chloride, sodium iodide, potassium fluoride) or an alkali metal azide (sodium azide) or a quaternary ammonium salt or an alkali metal phosphate on a product of general formula:
• R a represents a hydrogen atom or an alkoxy, acyloxy, alkoxyacetoxy radical or a hydroxy radical protected
• R ⁇ represents a hydrogen atom, followed, if necessary, by the replacement of the protective group carried by R a by a hydrogen atom.
• reaction is carried out in an organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether) and nitriles (acetonitrile) alone or as a mixture at a temperature between 20 ° C. and the boiling point of the mixture. reactive.
• organic solvent chosen from ethers (tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether) and nitriles (acetonitrile) alone or as a mixture at a temperature between 20 ° C. and the boiling point of the mixture. reactive.
• R4, R5 are defined as above, and R a represents a hydrogen atom or an alkoxy, acyloxy, alkoxyacetoxy radical or a protected hydroxy radical, and R ⁇ represents a hydrogen atom, by means of a acid of general formula:
• Rj and R3 are defined as above, or else Rg represents a hydrogen atom and R7 represents a protective group for the hydroxy function, and either Rg and R7 together form a 5 or 6-membered saturated heterocycle, or of a derivative of this acid to obtain an ester of general formula:
• R a , R, Ri, R3, R4, R5, R ⁇ and R7 are defined as above, followed by the replacement of the protective groups represented by R7 and / or R and R7 by hydrogen atoms and optionally R a , when 'It represents an acyloxy, alkoxyacetoxy radical or a hydroxy radical protected by a hydroxy radical.
• Esterification using an acid of general formula (V) can be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between -10 and 90 ° C.
• a condensing agent carbbodiimide, reactive carbonate
• an activating agent aminopyridines
• 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 (V) in the form of anhydride, operating in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 90 ° C.
• an activating agent aminopyridines
• 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 (V) in the form of halide or in the form of anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base (aliphatic amine tertiary) by operating in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 80 ° C.
• a base aliphatic amine tertiary
• R a represents a protecting group for the hydroxy function
• R a is preferably a 2,2,2-trichloro-2,2 ethoxycarbonyloxy radical.
• R6 represents a hydrogen atom and R7 represents a protecting group for the hydroxy function or else R and R7 together form a 5 or 6-membered saturated heterocycle.
• R7 preferably represents a methoxymethyl, 1-ethoxy-ethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, ⁇ -trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydro-pyrannyl radical.
• Rg and R7 together form a heterocycle this is preferably an oxazolidine ring optionally mono-substituted or gem-disubstituted in position -2.
• the replacement of the protective groups R7 and / or R ⁇ and R7 by hydrogen atoms and possibly of R a by a hydroxy radical can be carried out, according to their nature, as follows: 1) when R ⁇ represents a hydrogen atom and R7 represents a protective group for the hydroxy function, R a represents an alkoxy, acyloxy or alkoxyacetoxy radical, 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 while 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,
• R ⁇ represents a hydrogen atom and R7 represents a protective group for the hydroxy function
• R a represents a 2,2,2,2-trichloroethoxycarbonyloxy radical
• the replacement of the protective group R7 is carried out under the conditions described above under 1) and that of R a by treatment with zinc, optionally combined with copper, in the presence of acetic acid at a temperature between 30 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 (methanol, ethanol, propanol, isopropanol) or in an aliphatic ester (ethyl acetate, isopropyl acetate n.butyl acetate) in the presence of zinc possibly associated with copper,
• R is defined as above, Rg and R9, 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 Rg represents an alkoxy radical containing 1 to 4 atoms of carbon or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted by a trihalomethyl radical such as trichloromethyl and R9 represents a hydrogen atom, or else Rg and R9 form together with the carbon atom to which they are linked a ring having 4 with 7 links, and R a represents an acyloxy or alky
• R a , Rb, 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:
• R a , R ⁇ , Ri, R3, R4 and R5 are defined as above, in which the protective group R a , when it represents a protected hydroxy radical, is replaced, if necessary, by a hydroxy radical.
• the product of general formula (VI) is treated with formic acid at a temperature in the region of 20 ° C.
• the acylation of the product of general formula (VIII) 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 (IX ) 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 Iriethylamine.
• the reaction is carried out at a temperature between 0 and 50 ° C, preferably close to 20 ° C.
• the replacement of the protective group of R a when it represents a 2,2,2,2-trichloroethoxycarbonyloxy radical, is carried out under the conditions described above under 2), b) when R represents an optionally substituted benzoyl radical, thenoyl or furoyl or an R2O-CO- radical in which R2 is defined as above, Rg represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms and R9 represents a hydrogen atom, the replacement of the protective group formed by R ⁇ and R7 by hydrogen atoms is carried out in the presence of a mineral acid (hydrochloric acid, sulfuric acid) or organic acid (acetic acid , methanesulfonic acid, trifluoromethanesulfonic acid, p.toluenesulfonic acid) used alone or as a mixture in stoichiometric or cata
• R a represents an alkoxyacetyl radical and R ⁇ and R7 are defined as in point 1) above
• the protective group R7 is replaced by a hydrogen atom first, operating under the acid conditions described in point 1) above, then optionally replaces R a with a hydroxy radical 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 at a temperature in the region of 20 ° C.
• the treatment with a zinc halide, preferably zinc iodide is carried out in methanol at a temperature in the region of 20 ° C.
• R a represents an alkoxyacetoxy radical and R ⁇ and R7 are defined as in point 2-b) above
• the radical R a is replaced by a hydroxy radical by treatment in an alkaline medium or by treatment with a halide of zinc under the conditions described in point 3) above, then treats the product obtained under the conditions described in point 2-b) above.
• the products of general formula (III) in which R4 and R5 are defined as above, R a represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical, and R D represents a hydrogen atom, or although R a and R ⁇ form together with the carbon atom to which they are linked, a ketone function and Z represents a hydrogen atom can be obtained by the action of a derivative of trifluoromethanesulfonic acid such as the anhydride or N-phenyl trifluorométhanesiilf onimide on a product of general formula:
• 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 a represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxy radical
• Rb represents a hydrogen atom
• a basic organic solvent such as pyridine optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, or triethylamine optionally in combination with an organic solvent inert such as methylene chloride or racetonitrile or tetrahydrofuran at a temperature between 20 and 80 ° C on a product of general formula:
• R-Y (XIII) in which R represents an alkyl, alkanoyl or alkoxyacetyl radical or a protecting group for the hydroxy function and Y represents a halogen atom on a product of general formula:
• R represents an alkyl or alkoxyacetyl radical
• a basic organic solvent such as pyridine or in an inert organic solvent such as methylene chloride, chloroform or 1,2-dichloroethane in the presence of 'a tertiary amine such as triethylamine or pyridine at a temperature in the region of 0 ° C.
• R represents an alkyl radical
• the product of general formula (XIV) and optionally the product of general formula (XII) can be obtained by the action of an organometallic derivative of general formula: R4-M (XV) in which R4 is defined as above and M represents an atom metallic, preferably a lithium or magnesium atom, on a product of general formula: in which R a , Rb, R5 and Gi are defined as above.
• reaction is carried out in an organic solvent such as an ether (tetrahydrofuran) at a temperature below -50 ° C, preferably close to -78 ° C.
• organic solvent such as an ether (tetrahydrofuran)
• the product of general formula (XVI) can be obtained by esterification of a product of general formula:
• the product of general formula (XVII) can be obtained by the action of a product of general formula (XIII) on a product of general formula: in which G is defined as above under the conditions described above for the action of a product of general formula (XIII) on a product of general formula (XIV).
• the product of general formula (XIX) can be prepared by the action of phosgene or one of its derivatives such as triphosgene on a product of general formula:
• Gi is defined as above by operating in a basic organic solvent such as pyridine at a temperature below -50 ° C, preferably close to -78 ° C.
• the product of general formula (XX) can be prepared by the action of a halotrialcoylsilane on a product of general formula:
• the product of general formula (XXI) can be prepared under the conditions described by DGI guitarist et al., Journal of Nat Prod. , 5__L 884 (1993).
• the products of general formula (I) in which R a and Rb each represent a hydrogen atom can be obtained by electrolytic reduction of a product of general formula (I) in which R a represents a hydroxy radical or an acyloxy radical or alkoxyacetoxy or under the conditions described in international PCT application WO 93/06093.
• 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.
• the new products have anti-tumor properties and more particularly an activity on tumors which are resistant to Taxol® or Taxotère®.
• Such tumors include colon tumors which have high expression of the mdr 1 gene (multi-drug resistance gene).
• Multi-drug resistance is a common term referring to the resistance of a tumor to different products with different structures and mechanisms of action.
• Taxoids are generally known to be highly recognized by experimental tumors such as P388 / DOX, a cell line selected for its resistance to doxorubicin (DOX) which expresses mdr 1.
• the reaction medium is kept stirring at a temperature in the region of 75 ° C for 5 hours then, at a temperature in the region of 20 ° C, supplemented with 75 cm3 of dichloromethane and 50 cm3 of a saturated aqueous sodium chloride solution.
• the organic phase is decanted, washed with 2 times 40 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.
• 0.150 g of a product is obtained which is purified by chromatography on 80 g of silica (0.063-0.2 mm) contained in a column 1 cm in diameter (eluent: dichloromethane-methanol: 98/2 by volume) collecting 10 cm3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• the crude reaction product is dissolved in 80 cm3 of dichloromethane and 80 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 20 ° C.
• 0.9 g of a white meringue is obtained which is purified by chromatography on 150 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent: dichloromethane-methanol: 95-5 by volume) by collecting 15 cm3 fractions.
• reaction mixture is stirred for 15 hours, under an argon atmosphere, at a temperature in the region of 20 ° C., then added with 75 cm3 of dichloromethane and 50 cm3 of a saturated aqueous solution of ammonium 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.
• Benzoyloxy-2 ⁇ dihyd_x.xy-l ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxy- lO ⁇ oxo-9 propanoyloxy-4cc trifluoromemanesulfonyloxy-7 ⁇ taxene-11 can be prepared as follows:
• 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.
• 0.800 g is obtained which is purified by chromatography on 100 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter (eluent: dichloromethane-methanol: 95-5 by volume), collecting fractions of 15 cm3.
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• Benzoyloxy-2 ⁇ ditriethylsilyloxy-7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 hydroxy-l ⁇ methoxyacetoxyl-lO ⁇ oxo-9 propanoyloxy-4 ⁇ taxene-11 can be prepared as follows:
• the organic phase is decanted, washed with 2 times 40 cm3 of a saturated aqueous solution of ammonium chloride, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 1.3 g are obtained which are purified by chromatography on 150 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter (eluent: ethyl acetate-cyclohexane: 25-75 by volume), collecting 10 cm 3 fractions.
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• Benzoyloxy-2 dihydroxy-l ⁇ .lO ⁇ bis (ditriethylsilyloxy) -7 ⁇ , 13 epoxy-5 ⁇ , 20 oxo-9 propanoyloxy-4 ⁇ taxene-11 can be prepared as follows:
• Carbonate-l ⁇ , 2 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 methoxy ⁇ acetoxy- lO ⁇ oxo-9 propanoyloxy-4 ⁇ taxene-11 can be prepared in the following manner:
• 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.
• 2.6 g are obtained which are purified by chromatography on 100 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent: ethyl acetate-cyclohexane: 5-95 by volume ) by collecting fractions of 12 cm3.
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• Carbonate-l ⁇ , 2 ⁇ dihydroxy-4 ⁇ , 10 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy- 5 ⁇ , 20 oxo-9 taxene-11 can be prepared as follows:
• Bis (triethylsilyloxy) -7 ⁇ , 13 e ⁇ oxy-5 ⁇ , 20 oxo-9 tetrahydroxy-l ⁇ , 2 ⁇ , 4 ⁇ , lO ⁇ taxene-11 can be prepared as follows: To a solution of 3.80 g of epoxy-5 ⁇ , 20 oxo-9 pentahydroxy-l ⁇ , 2 ⁇ , 4 ⁇ , 10 ⁇ , 13 triethylsilyloxy-7 ⁇ taxene-11 in 100 cm3 of dichloromethane, is added, with stirring and at a similar temperature at 0 ° C, 1.20 cm3 of pyridine and 2.48 cm3 of chlorotriethylsilane. The reaction mixture is stirred for 3 hours at a temperature in the region of 0 ° C.
• the solvents are evaporated under reduced pressure (0.27 kPa) to a temperature in the region of 40 ° C, the solid residue is taken up in 5 cm3 of dichloromethane, filtered through cotton and rinsed with 5 cm3 of ethyl acetate-dichloromethane mixture (50-50 by volume).
• the organic phases are concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C.
• T-butoxycarbonylamino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) epoxy-5 ⁇ , 20 hydroxy-l ⁇ methoxyacetoxy-lO ⁇ oxo-9 propanoyloxy-4 (thénoyloxy-2) -2 ⁇ trifluorométhanesulfonyloxy-7 ⁇ taxene- 11 yle-13 ⁇ can be prepared as follows:
• reaction mixture is then diluted with 10 cm3 of dichloromethane, washed with 2 times 1 cm3 of distilled water. After extraction of the aqueous phase with 1 cm 3 of dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered through sintered glass and concentrated under reduced pressure (0.27 kPa) at a temperature in the region of 40 ° C. 74.4 mg of a yellow lacquer is thus obtained which is purified by chromatography at atmospheric pressure on 8 g of silica (0.063-0.2 mm) contained in a column 1.5 cm in diameter (gradient of elution: ethyl acetate-dichloromethane from 5-95 to 20-80 by volume), collecting 8 cm 3 fractions.
• the reaction mixture is stirred for 2 hours, under an argon atmosphere, at a temperature in the region of 20 ° C., then deposited on a chromatography column at atmospheric pressure (15 g of SiUce (0.063-0.2 mm) contained in a column 1.5 cm in diameter (elution gradient: ethyl acetate-dichloromethane from 5-95 to 10-90 by volume), collecting fractions of 10 cm3).
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours.
• Epoxy-5 ⁇ , 20 dihydroxy-l ⁇ , 13 ⁇ methoxyacetoxy- lO ⁇ oxo-9 propanoyloxy- ⁇ a (thenoyloxy-2) -2 ⁇ trifluoromethanesulfonyloxy-7 ⁇ taxene-11 can be prepared as follows:
• the orange solution obtained is stirred for 10 minutes at a temperature close to 0 ° C, 45 minutes at a temperature close to 20 ° C, then added with 0.1 cm3 of a methanol / dichloromethane mixture (5/95 in volumes).
• the solution is deposited on an atmospheric pressure chromatography column (10 g of silica (0.063-0.2 mm) contained in a column 1.5 cm in diameter (elution gradient: methanol-dichloromethane from 2-98 to 5-95 by volume) by collecting fractions of 8 cm3).
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours.
• Epoxy-5 ⁇ , 20 trihydroxy-l ⁇ , 7 ⁇ , 13 methoxyacetoxy-10O oxo-9 propanoyl-oxy-4 ⁇ (2-thenoyloxy) -2 ⁇ taxene-11 can be prepared as follows:
• Epoxy-5 ⁇ , 20 hydroxy-l ⁇ methoxyacetoxy-10 ⁇ oxo-9 propanoyloxy-4 ⁇ (thenoyloxy-2) -2 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ taxene-11 can be prepared as follows:
• the organic phase is decanted, washed with 2 times 40 cm3 of a saturated aqueous solution of ammonium chloride, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• the residue obtained (0.6 g) is purified by chromatography on 50 g of SiUce (0.063-0.2 mm) contained in a column 2 cm in diameter (eluent: ethyl acetate-cyclohexane: 5-95 by volume ) by collecting 10 cm3 fractions. The fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.
• Epoxy-5 ⁇ , 20 dihydroxy-l ⁇ , 10 ⁇ oxo-9 propanoyloxy-4 ⁇ (2-thenoyloxy) -2 bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ taxene-11 can be prepared as follows:
• the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at 20 ° C.
• the crude reaction product is dissolved in 20 cm3 of dichloromethane and 10 cm3 of a saturated aqueous solution of sodium bicarbonate.
• the aqueous phase is separated by decantation and then extracted with 2 times 20 cm3 of dichloromethane.
• the organic phases are combined, washed with 30 cm3 of distilled water and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 20 ° C.
• Tert-butoxycarbonyl-3 (4-methoxy-phenyl) -2 4-phenyl-oxazolidine- 1,3-carboxylate-5 (2R, 4S, 5R) of benzoyloxy-2 ⁇ butanoyloxy-4 ⁇ epoxy-5 ⁇ , 20 hydroxy- l ⁇ methoxyacetoxy-lO ⁇ oxo-9 trifluoromethanesulfonyloxy-7 ⁇ taxene-11 yle-13 ⁇
• 2-benzoyloxy-butanoyloxy-4 ⁇ dihydroxy-l ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxy-lO ⁇ oxo-9 trifluoromethanesulfonyloxy-7 ⁇ taxene-11 is added successively 247 mg of tert-butoxycarbonyl-3 (4-methoxyphenyl) -2 phenyl-4 oxazolidine-1,3 carboxyUque-5 (2R, 4S, 5R), 186 mg of dicyclo
• reaction mixture is stirred for 15 hours, under an argon atmosphere, at a temperature in the region of 20 ° C., then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 1 g of a product is obtained which is purified by chromatography on 100 g of silicon (0.063-0.2 mm) contained in a column 3 cm in diameter, eluting with a dichloromethane-methanol mixture (95-5 in volumes) and collecting 12 cm3 fractions.
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• Benzoyloxy-2 ⁇ butanoyloxy-4 ⁇ dihydroxy-l ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxy-lO ⁇ oxo-9 trifluoromethanesulfonyloxy-7 ⁇ taxene-11 can be prepared as follows: To a solution of 389 mg of 2-benzoyloxy-4-butanoyloxy-epoxy-5 ⁇ , 20 methoxyacetoxyl-10 ⁇ oxo-9 trihydroxy-l ⁇ , 7 ⁇ , 13 ⁇ taxene-11 in 6 cm3 of anhydrous dichloromethane and 390 ⁇ l of pyridine, maintained under an atmosphere of 'argon, at a temperature close to 0 ° C, 410 ⁇ l of trifluoromethanesulfonic anhydride are added dropwise.
• the orange solution obtained is stirred for 15 minutes at a temperature close to 0 ° C. and then added with 3 cm 3 of water and 50 cm 3 of dichloromethane.
• 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.
• 510 mg is obtained which is purified by chromatography on 70 g of silica (0.063-0.2 mm) contained in a column 1 cm in diameter, eluting with a dichloromethane / methanol mixture (95-5 by volume) and in collecting 10 cm3 fractions.
• Benzoyloxy-2 butanoyloxy-4 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxy-10 ⁇ oxo-9 trihydroxy- 1 ⁇ , 7 ⁇ , 13 ⁇ taxene-11 can be prepared as follows:
• 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.
• 520 mg is obtained which is purified by chromatography on 70 g of SiUce (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with a methanol-dichloromethane mixture (5-95 by volume) and in collecting fractions of 10 cm3.
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• Benzoyloxy-2 ⁇ butanoyloxy-4 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 epoxy-5 ⁇ , 20 hydroxy-l ⁇ methoxyacetoxy-lO ⁇ oxo-9 taxene-11 can be prepared as follows:
• the organic phase is decanted, washed with 4 times 20 cm3 of a saturated aqueous solution of copper sulphate, 2 times 40 cm3 of a saturated aqueous solution of ammonium chloride then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 800 mg of a product are obtained which is purified by chromatography on 100 g of SiC (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol-dichloromethane mixture (2-98 by volume) and collecting 15 cm 3 fractions.
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 5 ⁇ , 20 methoxyacetoxy-10 ⁇ oxo-9 taxene-11 can be prepared as follows:
• 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.
• 2.0 g are obtained which are purified by chromatography on 170 g of SiUce (0.063-0.2 mm) contained in a column 3 cm in diameter, eluting with an ethyl acetate-cyclohexane mixture (5-95 by volume) and collecting 15 cm3 fractions.
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• Carbonate-l ⁇ , 2 cyclopropanoyloxy-4 ⁇ bis (triethylsUyloxy) -7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxy- 10 ⁇ oxo-9 taxene-11 can be prepared as follows:
• 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.
• the pathological conditions include abnormal cell proliferation of skin or non-skin 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.
• sterile aqueous or non-aqueous solutions or suspensions are used.
• nonaqueous 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.
• the sterilization can be carried out by heating or by any other means which does not alter the composition.
• 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.
• 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 ( ⁇ , ⁇ or ⁇ ) and TNF.
• chemotherapeutic agents useful in the treatment of disorders due to abnormal proliferation of cells include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucU, 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, epipodophyUotoxins like etoposide and teniposide, antibiotics like dac ⁇ iomycin , 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, from 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 may be 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 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 will have to be taken into account. of treatment.
• 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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• 1994
  • 1994-06-09 FR FR9407049A patent/FR2721023B1/fr not_active Expired - Fee Related
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