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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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:
• R a represents a hydrogen atom or 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 Rj- represents a hydrogen atom or R a and R ⁇ together form with the carbon atom to which they are linked a ketone function,
• - Z represents a hydrogen atom or a radical of general formula:
• R 1 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:
• alkyl radical containing 1 to 8 carbon atoms 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 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy, alkoxy radicals 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
• 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 f uryl 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 halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto radicals, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkoylamino, dialcoylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoy
• cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more radicals alkyls containing 1 to 4 carbon atoms.
• 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, acyl containing 1 to 4 carbon atoms, arylcarbonyl of which the aryl part contains 6 to 10 carbon atoms
• the present invention relates to the products of general formula (I) in which R a represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms, acyloxy containing 1 to 4 carbon atoms or alkoxyacetoxy of which the alkyl part contains 1 to 4 carbon atoms, R ⁇ y represents a hydrogen atom and Z represents a hydrogen atom or a radical of general formula (II) in which Rj represents a benzoyl radical or an R2-O-CO- radical in which R2 represents a tert-butyl radical and R3 represents an alkyl radical containing 1 to 6 carbon atoms, alkenyl containing 2 to 6 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, phenyl optionally substituted by one or more atoms or identical or different radicals chosen from halogen atoms (fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy), dialcoylamino (di) in
• the present invention relates to the products of general formula (I) in which R a represents a hydrogen atom or an acetoxy radical, or a methoxyacetoxy radical, Rb represents a hydrogen atom, Z represents a atom hydrogen 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 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.
• R4 represents a phenyl radical optionally substituted by a halogen atom
• R a represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical or a protected hydroxy radical, followed, if necessary, by the replacement of the protective group carried by R a by a hydrogen atom.
• the process is carried out in a basic organic solvent alone or as a mixture chosen from pyridine, pyridines substituted by one or more alkyl radicals or quinoline at a temperature between 30 and 80 ° C. It is particularly advantageous to operate in pyridine.
• the product of general formula (III) can be obtained by esterification of a product of general formula:
• R and R3 are defined as above, or else R ⁇ 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 of a derivative of this acid to obtain an ester of general formula:
• R a, R ⁇ , Ri- R3, R4, R5, R e t 7 are defined as above, followed by replacement of the protective groups represented by R7 and / or Rg and R7 by hydrogen atoms and optionally R ' with a hydroxy radical.
• Esterification using an acid of general formula (N) 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 (N) in the form of anhydride by 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 (N) 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
• an organic solvent ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons
• R a represents a protected hydroxy radical
• the protective group is preferably a 2,2,2,2-trichloroethoxycarbonyl radical.
• Rg represents a hydrogen atom and R7 represents a protecting group for the hydroxy function, or else Rg 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 tetrahydrOpyrannyl 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 Rg and R7 by hydrogen atoms and possibly R a by a hydroxy radical can be carried out, according to their nature, as follows:
• Rg 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 atoms of hydrogen is carried out using 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 a solvent organic chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between -10 and 60 ° C,
• Rg represents a hydrogen atom and R7 represents a protective group for the hydroxy function
• R a represents a 2,2,2,2-ethoxycarbonyloxy trichlorc 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,
• Rg and R9 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 carbon atoms 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 together with the carbon atom to which they are linked form a ring having 4 to 7 members, and R a represents an acyloxy or alk
• R a , Rb, R, R3, R4 and R5 are defined as above, in which the protective group of R a is replaced, if necessary, by a hydrogen atom.
• the product of general formula (NI) is treated with formic acid at a temperature in the region of 20 ° C.
• the acylation of the product of general formula (NIII) by means of a benzoyl chloride in which the phenyl radical is optionally substituted, of thenoyl chloride, of furoyl chloride or of a product of general formula (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 triethylamine.
• 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-trichloroethoxycarbonyl radical, is carried out under the conditions described above under 2),
• Ri represents an optionally substituted benzoyl radical 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 a or several alkoxy radicals containing 1 to 4 carbon atoms
• R9 represents a hydrogen atom
• the replacement of the protective group formed by Rg and R7 by hydrogen atoms is carried out in the presence of a mineral acid (hydrochloric acid, sulfuric acid) or organic acid (acetic acid, methane-sulfonic acid, trifluoromethanesulfonic acid, p.toluene-sulfonic 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 between -10 and 60 ° C
• R a represents an alkoxyacetoxy radical and Rg 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 not touch 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 Rg 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 (IN) in which R4 and R5 are defined as above, R a represents a hydrogen atom or an alkoxy, acyloxy or alkoxyacetoxy radical can be obtained by the action of a derivative of the trifluoromethanesulfonic acid such as anhydride or ⁇ -phenyl trifluoromethanesulf onimide on a product of general formula:
• R 4 in which R4 and R5 are defined as above, R a represents a hydrogen atom or an alkoxy, acyloxy, alkoxyacetoxy or a protected hydroxy radical, and Rb represents a hydrogen atom, followed by the replacement of R a , when it represents a protected hydroxy radical, by a hydroxy radical.
• reaction is carried out in an inert organic solvent (aliphatic hydrocarbons possibly halogenated, aromatic hydrocarbons) in 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
• 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, optionally in association with an inert organic solvent such as methylene chloride or l acetonitrile or tetrahydrofuran at a temperature between 20 and 80 ° C on a product of general formula:
• R4 and R5 are defined as above, R a represents an alkoxy, acyloxy or alkoxyacetoxy radical, Rb represents a hydrogen atom and the symbols Gj, which are identical represent a triacoylsilyl radical.
• R4 and Gi are defined as above.
• R represents an alkanoyl 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
• 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 (XNI) can be obtained by esterification of a product of general formula: in which R a , Rb and G are defined as above, by means of an acid of general formula:
• the product of general formula (XNII) can be obtained by the action of a product of general formula (XIII) on a product of general formula:
• 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: in which 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 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 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.
• 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 cm 3 of dichloromethane, washed with 2 times 1 cm * - * of distilled water. After re-extracting 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 close to 40 ° C.
• Epoxy-5 ⁇ , 20 dihydroxy-l ⁇ , 13 ⁇ methoxyacetoxy-10O 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 in the region of 0 ° C, 45 minutes at a temperature in the region of 20 ° C, then added with 0.1 cm3 of a methanol-dichloromethane mixture (5-95 by volume).
• the solution is deposited on an atmospheric pressure chromatography column (10 g of silica (0.063-0.2 mm) contained in a column of 1.5 cm 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.
• 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 silica (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 10 cm 3 fractions).
• the fractions containing only the sought product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C for 2 hours.
• Aa (2-thenoyloxy) -2 ⁇ 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 silica (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:
• Carbonyldioxy-l ⁇ , 2 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxy-10 ⁇ oxo-9 propanoyloxy-4 ⁇ taxene-11 can be prepared as follows: To a solution of 2.0 g of carbonyldioxy-l ⁇ , 2 bis (triethylsilyloxy) -7 ⁇ , 13 epoxy-5 ⁇ , 20 hydroxy-4 ⁇ methoxyacetoxy-10 ⁇ oxo-9 taxene-11 in 90 cm3 of dichloromethane, 3.37 g of 4-dimeftylaminopyridine and 3.64 are added cm3 of propionic anhydride. The reaction medium is heated to a temperature in the region of 42 ° C for 8 hours.
• Carbonyldioxy-l ⁇ , 2 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 epoxy-5 ⁇ , 20 hydroxy-4 ⁇ methoxyacetoxy-10 ⁇ oxo-9 taxene-11 can be prepared as follows:
• Carbonyldioxy-l ⁇ , 2 ⁇ dihydroxy-4 ⁇ , 10 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 oxo-9 taxene-11 can be prepared as follows:
• the organic phase is decanted, washed with 2 times 100 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. 5.34 g of an orange oil are obtained which are purified by chromatography on 300 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent: ethyl acetate-cyclohexane: 25-75 by volume) by collecting 40 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 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.
• 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 benzoyloxy-2 ⁇ butanoyloxy-4 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxyl-lO ⁇ oxo-9 trihydroxy-l ⁇ , 7 ⁇ , 13 ⁇ taxene-11 in 6 cm * - * of anhydrous dichloromethane and 390 ⁇ l of pyridine, maintained under an argon atmosphere, 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 * - * 'of water and 50 cm3 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 fractions of 10 cm3.
• Benzoyloxy-2 ⁇ butanoyloxy-4 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxy-lO ⁇ oxo-9 trihydroxy-l ⁇ , 7 ⁇ , 13 ⁇ taxene-11 can be prepared as follows: To a solution of 580 mg of benzoyloxy-2 ⁇ butanoyloxy-4 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 hydroxy-l ⁇ methoxyacetoxy-lO ⁇ oxo-9 taxene-11 in 5 cm3 of dichloromethane, 5.5 cm3 of triethylamine complex are added at a temperature close to 20 ° C. hydrofluoric acid.
• the reaction mixture is stirred for 23 hours at a temperature in the region of 20 ° C., then 50 cm3 of dichloromethane and 100 cm3 of a saturated aqueous solution of sodium hydrogencarbonate 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.
• 520 mg is obtained which is purified by chromatography on 70 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with a methanol-dichloromethane mixture (5- 95 by volume) and collecting 10 cm 3 fractions.
• Benzoyloxy-2 ⁇ butanoyloxy-4 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 hydroxy-l ⁇ methoxyacetoxy-lO ⁇ oxo-9 taxene-11 can be prepared as follows: To a solution of 906 mg of benzoyloxy-2 ⁇ butanoyloxy-4 ⁇ dihydroxy- l ⁇ , 10 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ e ⁇ oxy-5 ⁇ , 20 oxo-9 taxene-11 in 18 cm3 of pyridine, 1.03 cm3 of methoxyacetyl chloride is added at a temperature close to 0 ° vs.
• the reaction mixture is stirred for 14 hours at a temperature in the region of 20 ° C., then 20 cm 3 of dichloromethane and 20 cm 3 of a saturated aqueous ammonium chloride solution are added.
• 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.
• Butanoyloxy-4 ⁇ carbonate-l ⁇ , 2 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 methoxyacetoxy-lO ⁇ oxo-9 taxene-11 can be prepared in the following manner: To a solution of 870 mg of carbonate- l ⁇ , 2 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy-5 ⁇ , 20 hydroxy-4 ⁇ methoxyacetoxy-10 ⁇ oxo-9 taxene-11 in 15 cm3 of dichloromethane, 1.46 g of 4-dimemylaminopyridine and 3.90 cm3 of anhydride are added butynical. The reaction medium is heated to a temperature in the region of 42 ° C for 45 hours.
• Carbonate-l ⁇ , 2 ⁇ cyclopropanoyloxy-4 ⁇ bis (triethylsilyloxy) -7 ⁇ , 13 ⁇ epoxy- 5 ⁇ , 20 methoxyacetoxy-lO ⁇ oxo-9 taxene-11 can be prepared in the following manner: With a solution of 100 mg of carbonate- l ⁇ , 2cc bis (triethylsilyloxy) -7 ⁇ , 13 epoxy-5 ⁇ , 20 hydroxy-4 ⁇ methoxyacetoxy-10 ⁇ oxo-9 taxene-11 in 7 cm3 of tetrahydrofuran, 345 ⁇ l of an IM solution of hexamethyldisilazane of Uthium is added dropwise in hexane, at a temperature close to -30 ° C.
• reaction mixture is stirred for 15 minutes at this temperature and then 39 ⁇ l of cyclopropanoyl chloride are added dropwise.
• the reaction mixture is stirred for 30 minutes at a temperature close to 0 ° C. and then hydrolyzed by the addition of 1 cm 3 of a saturated solution of ammonium chloride 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.
• 120 mg of a product are obtained which is purified by chromatography on 70 g of silicon (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with an ethyl acetate-cyclohexane mixture (20 -80 by volume) and 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 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. These pathological conditions can also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or kidney cancer.
• 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.
• 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.
• 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.
• 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.
• the 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 (ce, ⁇ or ⁇ ) and TNF.
• chemotherapeutic agents useful in the treatment of disorders due to the 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, anti-metabugs such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs like mercaptopurine and iMoguanine, natural products like vinca alkaloids like vinblastine, vincristine and vendesine, epipodophyllotoxins like etoposide and teniposide, antibiotics like dactinomycin , daunorubicin, doxorubicin,
• 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 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 order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the effectiveness of the treatment must be taken into account. .
• the following example illustrates a composition according to the invention.
• Example 1 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 read by adding 18 cm 3 of physiological saline. The composition is administered by infusion for 1 hour by introduction into physiological saline.

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• 1994
  • 1994-06-09 FR FR9407052A patent/FR2721026B1/fr not_active Expired - Fee Related
• 1995
  • 1995-06-07 EP EP95922572A patent/EP0764156A1/de not_active Ceased
  • 1995-06-07 CA CA002190657A patent/CA2190657A1/fr not_active Abandoned
  • 1995-06-07 AU AU27420/95A patent/AU2742095A/en not_active Abandoned
  • 1995-06-07 JP JP8500462A patent/JPH10500981A/ja active Pending
  • 1995-06-07 WO PCT/FR1995/000738 patent/WO1995033739A1/fr not_active Application Discontinuation

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