Patent EA-001516-B1 (EA)
Title: Taxoids, preparation thereof and pharmaceutical compositions containing same
Inventor: BOUCHARD HERVE
IPC: A61K31/535
Filed: 1997-03-05
Abstract: 1. New taxoids of formula I:   in which Z represents a radical of general formula (II):   in which: R1 represents a benzoyl radical or alkoxycarbonyl; R3 represents phenyl; R4 represents a hydroxy radical or an alkoxy radical containing 1 to 4 carbon atoms with unbranched or branched chain, an alkanoyloxy, in which the alkenoyl portion contains 2 to 4 carbon atoms in an unbranched or branched chain; R5 represents an alkoxy radical containing 1 to 4 carbon atoms with unbranched or branched chain. 2. New taxoids according claim 1 in which Z represents a radical of general formula (II), wherein R4 represents a hydroxy radical or an alkyloxy radical, unbranched or branched, containing 1 to 4 carbon atoms. 3. New taxoids according claim 1 in which Z represents a radical of general formula (II), wherein R1 represents a benzoyl radical or tert-butyloxycarbonyl, R4 represents a hydroxy radical or a methoxy radical, and R5 represents a methoxy radical. 4. A process for the preparation of a compound according to any of claims 1-3, wherein Z represents a radical of general formula (II), said process comprising esterifying a product of general formula:   in which R4 and R5 are defined in claims 1, 2 or 3, wherein R4 furthermore can represent the protective group hydroxy function, selected from alkoxyacetyl radicals by means of acid of general formula:   in which R1 and R3 are defined in claims 1, 2 or 3, or R6 represents hydrogen atom and R7 represent the protective group hydroxy function and/or R6 and R7 together form a saturated 5- or 6-membered heterocycle, or with the help of a derivative of this acid, to obtain an ester of general formula:   in which R1, R3, R4, R5, R6 and R7 are defined as above, and then substitute the protective groups represented by R7 and/or R6 and R7 are replaced with hydrogen atoms and, optionally, the R4 radical is replaced with a hydroxy radical. 5. The process according to claim 4, wherein the esterification is carried out by means of an acid of general formula (IV), in the presence of a condensing agent and of an activating agent, in an organic solvent at a temperature of between -10 and 90 degree C. 6. The process according to claim 4, wherein the esterification is carried out by means of an acid of general formula (IV) in the form of a symmetric anhydride, working in the presence of an activating agent, in an organic solvent at a temperature of between 0 and 90 degree C. 7. The process according to claim 4, wherein the esterification is carried out using the acid of general formula (IV) in the form of a halogenide or in the form of an anhydride mixed with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base, working in an organic solvent at a temperature of between 0 and 80 degree C. 8. The process according to claim 4, wherein the protective groups R7 and/or R6 and R7 are replaced with hydrogen atoms, according to their nature, in the following manner: 1) when R6 represents a hydrogen atom and R7 represents a group protecting the hydroxy function, the replacement of the protective groups with hydrogen atoms is carried out by means of a mineral acid or an organic acid, used alone or in the form of a mixture, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles, at a temperature of between -10 and 60 degree C, 2) when R6 and R7 together form a saturated 5- or 6-membered heterocycle of general formula:   in which R1 is defined as above, R8 and R9, which are identical or different, represent a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical in which the alkyl portion contains 1 to 4 carbon atoms and the aryl portion represents a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical representing a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or R8 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and R9 represents a hydrogen atom, or R8 and R9 together form, with the carbon atom to which they are linked, a cycle having 4 to 7 members, the replacement of the protective group formed by R6 and R7 with hydrogen atoms is carried out, according to the meanings of R1, R8 and R9, working in the following manner:  a) when R1 represents a tert-butoxycarbonyl radical, R8 and R9, which are identical or different, represent an alkyl radical or an aralkyl or aryl radical, either R8 represents a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical, and R9 represents a hydrogen atom, or R8 and R9 together form a 4- to 7-membered cycle, the ester of general formula (V) is treated with an mineral or organic acid, optionally in an organic solvent such as an alcohol, to obtain the compound of general formula:   in which R3, R4 and R5 are defined as above, which is acylated by means of benzoyl chloride in which the phenyl cycle is optionally substituted by thenoylchloride, furoylchloride or a compound of general formula VII: R2-O-CO-X                            (VIII) in which R2 represents alkoxyl and X represents a halogen atom or a residue -O-R2 or -O-CO-O-R2, to obtain a compound according to one of claims 1, 2 or 3, wherein Z represents a radical of general formula (II), b) when R1 represents a benzoyl radical or alkoxycarbonyl, R8 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms and R9 represents a hydrogen atom, the protective group formed by R6 and R7 is replaced with hydrogen atoms is carried out in the presence of an mineral acid or an organic acid, used alone or in the form of a mixture, in a stoichiometric or catalytic quantity, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature of between -10 and 60 degree C. 9. A process for the preparation of a compound according to any of claims 1, 2 or 3 wherein Z represents a radical of general formula (II), wherein a product of general formula IX: R'4 -X1 ..............(IX) in which R'4 is such that R'4-O is identical to R4 defined in any of claims 1, 2 or 3 and X1 represents a halogen atom, is reacted with a product of general formula:   in which R5 is as defined in one of claims 1, 2 or 3 and Z1 represents a radical of general formula:   in which R1 and R3 are defined as in claims 1, 2 or 3, and R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, and/or R6 and R7 together form a saturated 5- or 6-membered heterocycle, and then the protective groups represented by Z1 are optionally replaced under the conditions described in claim 8. 10. The process according to claim 9, wherein the product of general formula (IX) is reacted with the product of general formula (X), after metalation of the hydroxyl function at the 10-position by means of an alkali metal hydride, an alkali metal amidide or an alkali metal alkylide, working in an organic solvent chosen from dimethylformamide or tetrahydrofuran, at a temperature of between 0 and 50 degree C. 11. 3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-(2R,3S)-propionate-4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10α-dihydroxy-7β-methoxy-9-oxo-11-taxen-13α-yl. 12. 3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-(2R,3S)-propionate-4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10α-dimethoxy-9-oxo-11-taxen-13α-yl. 13. A pharmaceutical composition comprising at least one composition according to claim 1, 2 or 3 wherein Z represents a radical of general formula (II), in combination with one or more pharmaceutically acceptable diluents or adjuvants and optionally one or more compatible and pharmacologically active compounds. 14. A pharmaceutical composition comprising at least one compound according to claim 11 in combination with one or more pharmaceutically acceptable diluents or adjuvants and optionally one or more compatible and pharmacologically active compounds. 15. A pharmaceutical composition comprising at least one compound according to claim 12 in combination with one or more diluents or pharmaceutically acceptable adjuvants and optionally one or more compatible and pharmacologically active compounds. 16. The compounds of general formula (I) as it is defined in claim 1, wherein Z represents a hydrogen atom as the intermediates for obtainig the compounds according one of claims 1-3.