Patent EA-000726-B1 (EA)
Title: Novel taxoids, preparation thereof, and pharmaceutical compositions containing same
Inventor: BOUCHARD HERVE
IPC: C07D413/12
Filed: 1996-04-01
Abstract: 1. A taxoid of general formula   in which R represents cyclopropyl, cyclopentyl, phenyl, 2-pyridyl, 2-thienyl or 2-furyl radical, Z represents a radical of general formula:   in which R1 represents a benzoyl radical or a radical R2-O-CO- in which: R2 represents tert-butyl radical, and R3 represents isobutyl, osobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical. 2. A process for preparing a taxoid according to claim 1, characterized in that a compound of general formula (III)   in which R1 and R3 are defined in claim 1, and either R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or R8 and R7 together form a saturated 5- or 6-membered heterocycle, esterified by means of an acid of general formula (IV) R-CO-OH (IV) in which R is defined in claim 1, or by means of a derivative of said acid such as halide, symmetrical anhydride or mixed anhydride to obtain a product of general formula (V)   in which R1, R3, R6 and R7 are defined as above, followed by replacing the protective groups R7 and R6 and R7 with hydrogen atoms. 3. The process according to claim 2, 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 of between -10 and 90 degree  C. 4. The process according to claim 2, wherein the esterification is performed by means of an acid of general formula (IV) in the form of the symmetrical anhydride, working in the presence of an activating agent in an organic solvent at a temperature of between 0 and 90 degree  C. 5. The process according to claim 2, wherein the esterification is performed by means of an acid of general formula (IV) in halide form or in the form of a mixed anhydride 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. 6. The process according to claim 2, wherein when R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, the protective groups are replaced by hydrogen atoms by means of an inorganic or organic acid used alone or mixed, working in an organic solvent selected from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between -10 and 60 degree  C. 7. The process according to claim 2, wherein when R6 and R7 form an oxazolidine ring of general formula (VI)   in which R1 represents a tert-butoxycarbonyl radical and R8 and R9, which may be identical or different, represent an alkyl, aralkyl or aryl radical, or alternatively R8 represents a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and R9 represents a hydrogen atom, or alternatively R8 and R9 together form a 4- to 7-membered ring, the ester of general formula (V) is treated with an inorganic or organic acid, where appropriate in an organic solvent, to obtain a product of general formula (VII)   in which R3 is defined above, which is acylated by means of benzoyl chloride or by means of a product of general formula (VIII) R2-O-COX (VIII) in which R2 is defined 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). 8. The process according to claim 2, wherein when R6 and R7 form an oxazolidine ring of general formula (VI)   R1 represents a benzoyl radical, or a radical R2 O-CO- in which R2 is defined above, R8 represents a hydrogen atom, 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, replacement of the protective group formed by R6 and R7 by hydrogen atoms is performed in the presence of an inorganic or organic acid used alone or mixed in a stoichiometric or catalytic amount, working in an organic solvent at a temperature between -10 and 60 degree C. 9. A process for preparing a product of general formula (I) in which Z represents a radical of general formula (II), comprising esterifying a baccatin III derivative of formula (XI)   esterified by means of an acid of general formula (X)   in which R1 and R3 are defined as in claim 1, and R6 and R7 are defined as in claim 1, or by means of a derivative of said acid, such as halide, symmetrical anhydride or mixed anhydride followed by replacement of the protective groups R7, or R6 and R7, by hydrogen atoms. 10. The process according to claim 9, wherein the esterification is performed according to the process of any claim 3, 4 or 5. 11. The process according to claim 9, wherein the protective groups R7, or R6 and R7, are replaced by hydrogen atoms according to the conditions of claim 6. 12. A pharmaceutical composition, comprising at least one taxoid according to any of claims 1-3 in which Z represents a radical of general formula (II), in combination with one or more pharmaceutically acceptable products which are inert or pharmacologically active.