Patent EA-000567-B1 (EA)
Title: Taxoids, methods of preparation thereof and pharmaceutical composition based on same, stable, uniform cream based thereof
Inventor: BOUCHARD HERVE
IPC: A61K31/00
Filed: 1996-03-25
Abstract: 1. Taxoids of general formula (I):   wherein Z is a radical of general formula (II):   wherein R1 is a benzoyl radical or radical R2-O-CO-, wherein R2 is alkyl a radical having 1-6 carbon atoms, R3 is phenyl. R4 is alkoxy radical having 1-6 carbon atoms in linear or ramified chain, R5 is alkoxy radical havinf 1-6 carbon atoms in linear or ramified chain optionally sudstituted by alkoxy-radical having 1-4 carbon atoms. 2. Taxoids of Claim 1, characterized in that Z is radical of general formula (II), in which: R1 is benzoyl radical or radical R2-O-CO-, wherein R2 is tret-butyl radical; and R3 is phenyl. 3. Taxoids of Claim 1, characterized in that Z is radical of general formula (II), in which: R1 is a benzoyl radical or radical R2-O-CO-, in which R2 is tret-butyl radical; and R3 is phenyl. R4 and R5 are identical or different and each represents methoxy-, ethoxy-, or propoxy-radical. 4. Method of taxoids preparation as defined in any one of Claims 1, 2 or 3, characterized in that Z is radical of general formula (II) and a compound of formula (III) is esterified   in which R4 and R5 have values defined in Claims 1, 2 or 3, using an acid of general formula (IV):   in which R1 and R3 have as defined above values R6 and R7 form together saturated five- or six member heterocycle, or using a derivative of this acid to obtain ester of general formula (V):   in which R1, R3, R4, R5, R6 and R7 have as defined above values, protection groups of which, represented by R6 and R7 are replaced by hydrogen atoms. 5. Method of Claim 4, characterized in that esterification is effected using an acid of general formula (IV) in the presence of a condensation agent and an activation agent in an organic solvent at a temperature between -10 degree C and 90 degree C. 6. Method of Claim 4, characterized in that if R6 and R7 form together a saturated five- or six member heterocycle of general formula (VI):   in which R1 has as defined above value, R8 and R9, identical or different, represent a hydrogen atom or phenyl, substituted by one or by a plurality of alkoxy radicals having 1-4 carbon atoms, a protection group, formed by R6 and R7 are replaced by hydrogen atoms in the following way: when R1 is benzoyl radical or radical R2O-CO-, in which R2 has a value, defined above; R8 is phenyl, substituted by one or by a plurality alkoxy radicals having 1-4 carbon atoms; and R9 is hydrogen atom. protection group, formed by R6 and R7, is replaced by hydrogen atoms in the presence of inorganic or organic acid, used separately or in a mixture, in stoichiometric or catalytic amount, operating in an organic solvents selected from alcohols at a temperature between -10 degree C and 60 degree C, preferably at 15-30 degree C. 7. Method of Claim 4, as defined in any one of Claims 1, 2 or 3, in which Z is radical of general formula (II), R4 and R5 have values defined in any one of Claims 1, 2 or 3, characterized in that a product of general formula (XVI):   in which R1, R3, R6 and R7 have values defined in any one of Claims 1, 2, 3, or 4, is treated using a compound of general formula (X): (R)3-Si-Hal (X), in which values of radical R, identical or different, represent alkyl radical having 1-6 carbon atoms, to obtain a compound of general formula (XVII):   in which R, R1, R3, R6 and R7 have the above-defined value which transform into functional derivatives by position 10 using compounds of general formula (XII): R'4-X1 (XII) in which R'4 is such a radical, that R'4-O is identical to R4, which has a value, defined in any of 1, 2 or 3 or 3 Claims and X1 is halogen atom or residue of reaction-capable ester, obtaining a compound of general formula (XVIII)   in which R, R1, R3, R4, R6 and R7 have the above-defined value, silylated protection of which is replaced by a hydrogen atom to obtain a product of general formula (XIX)   which, after interacting with a compound of general formula (XV) forms a compound of general formula (V), protection groups of which are replaced by hydrogen atoms to obtain a product of general formula (I), in which Z is radical of general formula (II). 8. Method of preparation taxoids, as defined in any one of Claims 1, 2 or 3, characterized in that activated Raney nickel in the presence of aliphatic alcohol having 1-3 carbon atoms are interacted with a compound of general formula (XXI)   in which R4 has a value, defined in any of 1, 2 or 3 Claims, R' and R'' is a hydrogen atom and Z1 is a hydrogen atom or radical of general formula (XXII)   in which R1 and R3 have a value, defined in any 1-3 Claims, and R6 and R7have a value, defined in Claim 4, to obtain a compound of formula (XXIII)   and in case, when Z1 is a radical of general formula (XXII) protection groups, defined as R6 and R7, are replaced by hydrogen atoms in conditions of Claim 6. 9. Method of Claim 8, characterized in that the operation is performed at temperature from -10 degree C to 60 degree C. 10. Taxoid of Claim 1, characterized in that it is 4α acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-dimethoxy-9-oxo-tax-11-ene 13α-yl-(2R,3S)-3-tert.butoxycarbonylamino-2-hydroxy-3-phenyl-propionate. 11. Taxoid of Claim 1, characterized in that it is 4α acetoxy-2α-benzoyloxy-1β-hydroxy-5β, 20-epoxy-7β-methoxy-10β-etoxy-9-oxo-tax-11-ene-13α-yl-3-tert.butoxycarbonylamino-2-hydroxy-3-phenyl-propionate. 12. Taxoid of Claim 1, characterized in that it is 4α acetoxy-2α-benzoyloxy-1β-hydroxy-5β, 20-epoxy-7β-methoxy-10β-(1 propyl)oxy-9-oxo-tax-11-ene-13α-yl-3-tert.butoxycarbonylamino-2-hydroxy-3-phenyl-propionate. 13. Method of obtaining a compound of Claim 10, characterized in that at the first step 4α acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β,7β,10β-trihydroxy-9-oxo-tax-11-ene-13α-yl-(2R,4S,5R)-3-tert.butoxycarbonyl-2-(4-metoxyphenyl-4-phenyl-1,3-oxazolidine-5carboxylateis treated with dimethylsulfoxide in the presence of acetic acid, at the second step the obtained 4α acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β -hydroxy-7β 10β-bis(methylthiometoxy)-9-oxo-tax-11-ene-13α-yl-(2R,4S 5R)-3-tert.butoxycarbonyl-2-(4-metoxyphenyl-4-phenyl-1,3-oxazolidine-5-carboxylate are subjected to interaction with ethanol suspension of Raney nickel, and at the third step the obtained 2α-benzoyloxy-5β, 20-epoxy-1β -hydroxy-7β, 10β-dimethoxy-9-oxo-tax-11-ene-13α-yl-(2R, 4S, 5R)-3-tert.butoxycarbonyl-2-(4-metoxyphenyl-4-phenyl-1,3-oxazolidine-5carboxylate are subjected to the interaction with ethanol suspension of hydrochloric acid. 14. Taxoids of general formula (I), in which Z is a hydrogen atom, and R4 and R5 have values, defined in Claim 1. 15. Method of preparation taxoids, as defined in Claim 14, characterized in that 10-desacetyl-baccatine III of formula (IX):   is treated with silylhalogen of general formula: (R)3-Si-Hal (X), in which values of R radical, identical or different, represent alkyl radical having 1-6 carbon atoms, to obtain a compound of general formula (XI):   in which R has a value, defined above, which is treated by a compound of general formula (XII): R'4-X1 (XII) in which R'4 is such a radical, that R'4-O is identical to R4, which has a value, defined in any of 1, 2 or 3 or 3 Claims and X1 is halogen atom or residue of reaction-capable ester, obtaining a compound of general formula (XIII)   n which R, and R4, have the above-defined value, silylated protection of which is replaced by a hydrogen atom to obtain a product of general formula (XIV):   in which R4 has the above-defined value which is selectively esterified in position 7 treating by a compound of formula (XV) R'5-X2 (XV) R'5 is such a radical, that R'5-O is identical to R5, which has a value, defined in any of 1, 2 or 3 or 3 Claims an X2 is a halogen atom to obtain a compound of general formula (I), in which Z is a hydrogen atom. 16. 4α acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β -hydroxy-7β,10β-bis(methylthiometoxy)-9-oxo-tax-11-ene-13α-yl-(2R, 4S, 5R)-3-tert.butoxycarbonyl-2-(4-metoxyphenyl-4-phenyl-1,3-oxazolidine-5-carboxylate. 17. Pharmaceutical composition based on taxoid compound, characterized in that as a taxoid compound it contains at least one compound of any one of Claims 1, 2 or 3, in which Z is a radical of general formula (II), associated with one or a plurality of pharmaceutically acceptable diluents or additions and, optionally, with one or a plurality of compatible and pharmaceutically active compounds. 18. Pharmaceutical composition of Claim 17, characterized in that containing at least one compound of Claim 10, associated with one or a plurality of pharmaceutically acceptable diluents or additions and, optionally, with one or a plurality of compatible and pharmaceutically active compounds. 19. Pharmaceutical composition of Claim 17, characterized in that containing at least one compound of Claim 11, associated with one or a plurality of pharmaceutically acceptable diluents or additions and, optionally, with one or a plurality of compatible and pharmaceutically active compounds. 20. Pharmaceutical composition of Claim 17, characterized in that containing at least one compound of Claim 12, associated with one or a plurality of pharmaceutically acceptable diluents or additions and, optionally, with one or a plurality of compatible and pharmaceutically active compounds.