Patent EA-000709-B1 (EA)
Title: Novel taxoids, preparation thereof and pharmaceutical compositions containing same and intermediate compounds
Inventor: BOUCHARD HERVE
IPC: C07D305/14
Filed: 1996-03-25
Abstract: 1. A taxoid of general formula (1)   in which Z represents a radical of general formula (II)   in which R1 represents a benzoyl radical or a radical  R2-O-CO- in which R2 represents an alkyl radical containing 1 to 8 carbon atoms,  R3 represents a phenyl; R4 represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 6 carbon atoms in an unbranched or branched chain these radicals being substituted with an alkoxy radical containing 1 to 4 carbon atoms, or R4 represents a cycloalkanoyloxy radical in which the cycloalkanoyl portion contains 4 to 8 carbon atoms or R4 represents a heterocyclic carbonyloxy radical in which the heterocyclic portion represents a 5- or 6-membered aromatic heterocycle containing one or more hetero atoms selected from oxygen, sulphur and nitrogen atoms; R5 represents an alkoxy radical containing 1 to 6 atoms in an unbranched or branched chain, optionally substituted with an alkylthio radical containing 1 to 4 carbon atoms. 2. A taxoid according to claim 1, in which Z represents a radical of general formula (II) in which  R1 represents a benzoyl radical or a radical R2-O-CO- in which R2 represents a tert-butyl radical, R3 represents a phenyl; R4 represents an alkyloxyacetoxy radical in which the alkyl portion contains 1 to 4 carbon atoms, a cycloalkanoyloxy radical in which the cycloalkanoyl portion contains 4 to 8 carbon atoms, or a pyridylcarbonyloxy radical; and R5 represents an unbranched or branched alkyloxy radical containing 1 to 6 carbon atoms, optionally substituted with an alkylthio radical containing 1 to 4 carbon atoms. 3. A taxoid according to claim 1, in which Z represents a radical of general formula (II), in which R1 represents a benzoyl radical or a radical R2-O-CO- in which R2 represents a tert-butyl radical, and R3 represents a phenyl; R4 represents a methoxyacetoxy-, cyclopropylcarbonyloxy-, cyclopentylcarbonyloxy-, 2-pyridylcarbonyloxy- or 3-pyridylcarbonyloxy radical, and R5 represents a methoxy radical. 4. A process for preparing the taxoid according to claims 1, 2 or 3, in which Z represents a radical of general formula (II), wherein a compound of general formula (III)   in which R4 and R5 are defined as in claim 1, 2 or 3, esterified by means of an acid of general formula (IV)   in which R1 and R3 are defined as in claim 1, R6 and R7 together form a saturated 5- or 6-membered heterocycle, or by means of a derivative of this acid, to obtain an ester of general formula (V)   in which R1, R3, R4, R5, R6 and R7 are defined as above, followed by replacing the protective groups represented by R6 and R7, with hydrogen atoms. 5. The process according to claim 4, wherein the esterification is performed by means of an acid of general formula (IV) in the presence of a condensing agent and an activating agent in an organic solvent at a temperature between -10 and 90 degree C. 6. The process according to claim 4, wherein R6 and R7 together form a saturated 5- or 6- membered heterocycle of general formula (VI)   in which R1 is defined as above, R8 and R9, which may be identical or different, represent an alkyl radical or an aralkyl radical containing 1-4 carbon atoms , or aralkyl radical, alkyl portion o f which containing 1-4 carbon atoms, and an aryl portion of represents preferably represents a phenyl radical, or an aryl radical, preferably represents a phenyl radical, optionally substituted by one or more alkoxy radicals containing 1-4 carbon atoms; then a protective group formed by R6 and R7 is replaced by hydrogen atoms in the following manner: a) when R1 represents a tert-butoxycarbonyl radical,  R8 and R9, which may be identical or different, represent an alkyl radical or aralkyl radical, or aryl radical, then a protecting group formed by an ester of general formula (V) is treated with an inorganic or organic acid, where appropriate in an organic solvent, such as an alcohol to obtain a compound of general formula (VII)   in which R3, R4 and R5 are defined as defined in claim 5 which is acylated by means of benzoyl chloride or by a compound of general formula (VIII) R2-O-CO-X (VIII) in which R2 is defined as above and X represents a halogen atom or a residue -O-R2 or -O-CO-O-R2, to obtain a product of general formula (I) in which Z represents a radical of general formula (II); b) when R1 represents a benzoyl radical, or a radical R2-O-CO in which R2 is defined as above, R8 represents a hydrogen atom, or a phenyl radical substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms and R9 represents a hydrogen atom; then the protective group formed by R6 and R7 is replaced by hydrogen atoms in the presence of an inorganic acid used alone or mixed in a stoichiometric or catalytic amount, working in an organic solvent selected from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature between -10 to 60 degree C 7. A process for preparing a taxoid according to claims 1, 2 or 3 in which Z represents a radical of general formula (II), R4 and R5 are defined as in claims 1 2 or 3, comprising that a product of general formula (XVI):    in which R1, R3, R6 and R7 are defined as in claims 1, 2 or 3 is treated by means of a product of general formula (X) (R)3-Si-Hal (X) in which the symbols R, which may be identical or different, represent an alkyl radical containing 1 to 4 carbon atoms optionally substituted with a phenyl radical, a cycloalkyl radical containing 3 to 6 carbon atoms, or a phenyl radical, to obtain a product of general formula (XVII) in which R, R1, R3, R6 and R7 are defined as above, which is reacted with a product of general formula R'4-X1 (XII) in which R'4 is such that R'4-O- is identical to R4 defined as in claims 1, 2 or 3 and X1 represents a halogen atom or a reactive ester residue, to give a product of general formula (XVIII)   in which R, R1, R3, R4 R6 and R7 are defined as above, the silyl protective group of which is replaced by a hydrogen atom to give a product of general formula (XIX)   which, by the action of a product of general formula (XV), yields the product of general formula (V), the protective groups of which are replaced by hydrogen atoms to give a product of general formula (I) in which Z represents a radical of general formula (II). 8. A process of preparing a taxoid according to claims 1, 2 or 3 comprising reacting activated Raney nickel, in the presence of an aliphatic alcohol containing 1 to 3 carbon atoms or an ether, with a product of general formula (XXI)   in which R4 is defined as in claims 1, 2 or 3, R' and R", which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, an alkynyl radical containing 3 to 6 carbon atoms, a cycloalkyl radical containing 2 to 6 carbon atoms, or a cycloalkenyl radical containing 3 to 6 carbon atoms, optionally substituted, or R' and R", together with the carbon atom to which they are linked, form a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 4 to 6 carbon atoms, and Z1 represents a hydrogen atom or a radical of general formula (XXII)   in which R1 and R3 are defined as in claims 1, 2 or 3 and R6 and R7 are defined as in claim 4, to obtain a product of general formula (XXIII)   followed, when Z1 represents a radical of general formula (XXII), by replacement of the protective groups R6 and R7 by hydrogen atoms under the conditions of claim 4. 9. The process according to claim 8, performed at a temperature between -10 and 60 degree C. 10. A taxoid according to claim 1, wherein represents 4.alpha.-acetoxy-2.alpha.- benzoyloxy-5.beta.,20-epoxy-1.beta.-hydroxy-7.beta.-methoxy-10.beta.-methox yacetoxy-9-oxo-11-taxen-13.alpha.-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 11. A taxoid according to claim 1, wherein represents 4.alpha.-acetoxy-2.alpha.-benzoyloxy-1.beta.-hydroxy-5.beta., 20-epoxy-7.beta.-methoxy-10.beta.-cyclopropylcarbonyloxy-9-oxo-11-taxen-13. alpha.-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 12. A taxoid according to claim 1, wherein represents 4.alpha.-acetoxy-2.alpha.-benzoyloxy-1.beta.-hydroxy-5.beta.,20-epoxy-7.beta.-methoxy-10.beta.-cyclopentylcarbonyloxy-9-oxo-11-taxen-13.alpha.-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 13. A taxoid according to claim 1, wherein represents 4.alpha.-acetoxy-2.alpha.-benzoyloxy-1.beta.-hydroxy-5.beta., 20-epoxy-7.beta.-methoxy-10.beta.-(2-pyridyl)carbonyloxy-9-oxo-11-taxen-13.alpha.-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 14. A taxoid according to claim 1, wherein represents 4.alpha.-acetoxy-2.alpha.-benzoyloxy-1.beta.-hydroxy-5.beta.,20-epoxy-7.beta.-methoxy-10.beta.-(3-pyridyl)carbonyloxy-9-oxo-11-taxen-13.alpha.-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. 15. A pharmaceutical composition based on taxoid composition, wherein comprising at least one taxoid according to claims 1, 2 or 3 in which Z represents a radical of general formula (II), and one or more pharmaceutically acceptable carriers and if necessary one or more pharmaceutically active compounds. 16. A pharmaceutical composition of claim 15, comprising the compound of claim 10 and one or more pharmaceutically acceptable carriers and if necessary one or more pharmaceutically active compounds. 17. A pharmaceutical composition of claim 15, comprising at least one compound of claim 11 and one or more pharmaceutically acceptable carriers and if necessary one or more pharmaceutically active compounds. 18. A pharmaceutical composition of claim 15, comprising at least one compound of claim 12 and one or more pharmaceutically acceptable carriers and if necessary one or more pharmaceutically active compounds. 19. A pharmaceutical composition of claim 15, comprising at least one compound of claim 13 and one or more pharmaceutically