Patent EA-001533-B1 (EA)
Title: Novel taxoids, preparation thereof and pharmaceutical compositions containing same
Inventor: BOUCHARD HERVE
IPC: C07D305/14
Filed: 1996-12-19
Abstract: 1. New taxoids of general formula:   wherein: Z represents a radical of general formula:   in which: R1 represents a benzoyl radical or a radical R2-O-CO- in which R2 represents an alkyl radical comprising 1 to 8 carbon atoms and R3 represents a phenyl or α- or β-naphthyl; and either R4 represents a hydrogen atom, R6 and R7 together form a ketone function; and R and R5 together form a bond; or R4 represents a hydrogen atom or an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain, an alkoxyacetyl wherein the alkyl portion comprises 1 to 6 carbon atoms in an unbranched or branched chain, a carbamoyloxy radical, alkylcarbamoyloxy wherein the alkyl portion comprises 1 to 4 carbon atoms, or dialkylcarbamoyloxy wherein each alkyl portion comprises 1 to 4 carbon atoms; R5 represents a hydrogen atom; or R4 and R5 together form a ketone function; R6 represents a hydrogen atom; and R and R7 together form a bond. 2. New intermediate products of formula I':   wherein Z' represents a hydrogen atom or either R4 represents a hydrogen atom or an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain, an alkoxyacetyl wherein the alkyl portion comprises 1 to 6 carbon atoms in an unbranched or branched chain, a carbamoyloxy radical, alkylcarbamoyloxy wherein the alkyl portion comprises 1 to 4 carbon atoms, or dialkylcarbamoyloxy wherein each alkyl portion comprises 1 to 4 carbon atoms; R5 represents a hydrogen atom; or R4 and R5 together form a ketone function; R6 represents a hydrogen atom; and R and R7 together form a bond. 3. A process for preparing a compound according claim 1 in which either R4 represents a hydrogen atom, R6 and R7 together form a ketone function, and R and R5 together form a bond, or R4 represents a hydroxyl radical, R5 represents a hydrogen atom, R6 represents a hydrogen atom, and R and R7 together form a bond; characterised in that a reducing agent is put into reaction with a compound of general formula:   in which Z1 represents a radical of general formula:   in which R1 and R3 are defined as in claim 1 and R8 represents a group protecting the hydroxyl function; and X represents, together with the oxygen atom to which it is linked, a leaving group selected from radicals: alkylsulphonyl comprising 1 to 4 carbon atoms which can be unsubstituted or substituted with several halogen atoms; arylsulphonyl in which the aryl portion is a phenyl which can be unsubstituted or substituted with one or several identical or different atoms or radicals: halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms, nitro- or trifluoromethyl groups; with obtaining a compound of the general formula:   wherein Z1, R, R4, R5, R6 and R7 are defined as above; in the form of a mixture of a compound of general formula I wherein R4 represents a hydrogen atom, R6 and R7 together form a ketone function, and R and R5 together form a bond and the compounds of general formula I wherein R4 represents a hydroxyl radical, R5 represents a hydrogen atom, R6 represents a hydrogen atom, and R and R7 together form a bond, which are separated by the ordinary methods, and further R8 is replaced with a hydrogen atom. 4. The process according to claim 3, wherein the reducing agent is selected from alumohydrides or borohydrides such as alkaline or alkaline earth metals borohydrides in the presence of an aliphatic alcohols comprising 1 to 4 carbon atoms such as ethanol and the reaction is carried out at a temperature between 0 to 50 degree C. 5. The process according to claim 3, wherein when the protecting group is a silyl radical, it is replaced by a hydrogen atom by using an inorganic acid in an aliphatic alcohol comprising 1 to 3 carbon atoms at a temperature between -10 to 20 degree C or by using a hydrofluoric acid-triethylamine complex working in an inert organic solvent at a temperature of between 0 to 50 degree C. 6. A process for preparing a compound according to claim 1 in which R4 represents an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain, an alkoxyacetyl wherein the alkyl portion comprises 1 to 6 carbon atoms in an unbranched or branched chain, or R4 represents a carbamoyloxy radical, alkylcarbamoyloxy wherein the alkyl portion comprises 1 to 4 carbon atoms, or dialkylcarbamoyloxy wherein each alkyl portion comprises 1 to 4 carbon atoms; R5 represents a hydrogen atom; R6 represents a hydrogen atom; and R and R7 together form a bond, characterised in that the compound of general formula: R'4Y (IX) in which R'4 is such that R'4-O- is identical to R4 defined above and Y represents a leaving group, is put into reaction with the compound of general formula:   wherein Z1 is defined above, R4 represents a hydroxyl radical, R6 represents a hydrogen atom; and R and R7 together form a bond, and further R8 is replaced with a hydrogen atom in conditions according claim 5. 7. The process according to claim 6, wherein prior to the reaction of the compound of general formula IX, the hydroxyl function at position 10 is metalated by using hydride, amide, or alkali metal alkyl derivative. 8. The process for preparing a compound according to claim 1 in which Z represents a radical of general formula (II), R4 and R5 together form a ketone function, R6 represents a hydrogen atom, and R and R7 together form a bond; characterised in that it comprises oxidation of a compound of the general formula:   wherein Z1 is defined above in claim 3, R4 represents a hydroxyl radical, R5 represents a hydrogen atom, R6 represents a hydrogen atom, and R and R7 together form a bond, and further protecting group can be replaced with a hydrogen atom in conditions according to claim 5. 9. The process according to claim 8, wherein the oxidation is carried out by using oxygen, ammonium peruthenate, manganese dioxide, copper acetate or pyridinium chlorochromate. 10. A process for preparing a compound according to claim 1, wherein R4, R5 and R6 each represent a hydrogen atom, and R and R7 together form a bond; which can be obtained from a compound of general formula V, wherein Z1 is such as it is determined in claim 1, R4 represents a hydroxyl radical, R5 and R6 each represent a hydrogen atom, and R and R7 together form a bond; by converting the hydroxyl radical represented by R4 to a dithiocarbonate and then reducing the product obtained by using a trialkyltin hydride, which may be followed by replacing the protecting group represented by R8 by a hydrogen atom in conditions according to claim 5. 11. A process for preparing a compound according to claim 1 in which the product according to claim 2 is esterified by acid of general formula:   wherein either R9 represents a hydrogen atom and R10 represents a group protecting the hydroxyl function, or R9 and R10 together form a saturated 5- or 6-membered heterocycle, or by a derivative of said acid followed by replacing the protecting groups by hydrogen atoms under standard conditions. 12. A process for preparing a compound according claim 2 in which either R4 represents a hydrogen atom, R6 and R7 together form a ketone function, and R and R5 together form a bond, or R4 represents a hydroxyl radical, R5 represents a hydrogen atom, and R and R7 together form a bond; characterised in that a reducing agent is put into reaction with a compound of general formula:   wherein Z1 represents a hydrogen atom or a group protecting the hydroxyl function; and X represents, together with the oxygen atom to which it is linked, a leaving group selected from the following radicals: alkylsulphonyl comprising 1 to 4 carbon atoms which can be unsubstituted or substituted with one or several halogen atoms; arylsulphonyl in which the aryl portion is a phenyl which can be unsubstituted or substituted with one or several identical or different atoms or radicals: halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms, nitro- or trifluoromethyl groups; with obtaining a compound of the general formula:   wherein Z1, R, R4, R5, R6 and R7 are defined as above; in the form of a mixture of a compound of general formula I' wherein R4 represents a hydrogen atom, R6 and R7 together form a ketone function, and R and R5 together form a bond and the compounds of general formula I' wherein R4 represents a hydroxyl radical, R5 represents a hydrogen atom, R6 represents a hydrogen atom, and R and R7 together form a bond, which are separated by the ordinary methods, and further protecting group Z1 can be replaced with a hydrogen atom. 13. The process according to claim 12, wherein the reducing agent is selected from alumohydrides or borohydrides such as alkaline or alkaline-earth metals borohydrides in the presence of an aliphatic alcohols comprising 1 to 4 carbon atoms such as ethanol and the reaction is carried out at a temperature between 0 to 50 degree C. 14. The process according to claim 12, wherein when the protecting group is a silyl radical, it is replaced by a hydrogen atom by using an inorganic acid in an aliphatic alcohol comprising 1 to 3 carbon atoms at a temperature between -10 to 20 degree C or by using a hydrofluoric acid-triethylamine complex working in an inert organic solvent at a temperature of between 0 to 50 degree C. 15. A process for preparing a compound according to claim 2 in which R4 represents an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain, an alkoxyacetyl wherein the alkyl portion comprises 1 to 6 carbon atoms in an unbranched or branched chain, or R4 represents a carbamoyloxy radical, alkylcarbamoyloxy wherein the alkyl portion comprises 1 to 4 carbon atoms, or dialkylcarbamoyloxy wherein each alkyl portion comprises 1 to 4 carbon atoms; R5 represents a hydrogen atom; R6 represents a hydrogen atom; and R and R7 together form a bond, characterised in that the compound of general formula: R'4Y (IX) in which R'4 is such that R'4-O- is identical to R4 defined above and Y represents a leaving group, is put