Details for Patent: 6,232,477

Title:	Methods of preparing new taxoids and pharmaceutical compositions containing them
Abstract:	Methods of preparing new taxoids of general formula (I) are presented: ##STR1## in which: R.sub.4 represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 6 carbon atoms in an unbranched or branched chain, this radical unsubstituted or substituted with one or more halogen atoms, an alkoxy radical containing 1 to 4 carbon atoms, or alternatively R.sub.4 represents a cycloalkanoyloxy radical in which the cycloalkanoyl portion contains 4 to 8 carbon atoms, or alternatively R.sub.4 represents a benzoyloxy radical; R.sub.5 represents an alkoxy radical containing 1 to 4 carbon atoms, substituted by an alkylthio radical containing 1 to 4 carbon atoms; and Z represents a hydrogen atom or a radical of general formula: ##STR2##
Inventor(s):	Bouchard; Herve (Thiais, FR), Bourzat; Jean-Dominique (Vincennes, FR), Commer.cedilla.on; Alain (Vitry-sur-Seine, FR)
Assignee:	Aventis Pharma S.A. (Antony, FR)
Filing Date:	Mar 17, 2000
Application Number:	09/528,448
Claims:	1. A method of preparing a taxoid of general formula: ##STR36## in which: Z represents a hydrogen atom or a radical of general formula: ##STR37## in which: R.sub.1 represents a benzoyl radical unsubstituted or substituted with one or more identical or different atoms or radicals selected from halogen atoms, and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl radicals, a thenoyl radical, a furoyl radical, and a radical R.sub.2 --O--C(.dbd.O)--, in which R.sub.2 represents an alkyl radical containing 1 to 8 carbon atoms, an alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, a phenyl atoms, alkyl radicals containing 1 to 4 carbon atoms, and alkoxy radicals containing 1 to 4 carbon atoms), cyano radicals, carboxyl radicals, and alkoxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms; R.sub.3 represents a phenyl radical; R.sub.4 represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 6 carbon atoms in an unbranched or branched chain; and R.sub.5 represents an alkoxy radical containing 1 to 4 carbon atoms in an unbranched or branched chain, substituted by an alkylthio radical containing 1 to 4 carbon atoms, comprising: silylating a baccatin of formula (IX) ##STR38## to obtain a silylated baccatin, where the silylation occurs at position 7; acetylating said silylated baccatin to obtain a protected baccatin, wherein said acetylation occurs at position 10; coupling the protected baccatin with an oxazolidine ring optionally monosubstituted or gem-disubstituted at position 2 to produce a coupled ester; deprotecting said coupled ester with an acid to produce a desilylated taxoid; reacting said desilylated taxoid in a Pummerer reaction to produce a methylthiomethylether derivative; and deprotecting said methylthiomethylether derivative with an acid to produce the desired taxoid. 2. The method for preparing a taxoid according to claim 1 in which Z represents a radical of general formula (II), in which R.sub.1 represents a benzoyl radical or a radical R.sub.2 --O--C(.dbd.O)-- in which R.sub.2 represents a tert-butyl radical; R.sub.3 represents a phenyl radical; R.sub.4 represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 4 carbon atoms; and R.sub.5 represents an alkoxy radical containing 1 to 4 carbon atoms substituted by a methylthio radical. 3. The method for preparing a taxoid according to claim 1 for which Z represents a hydrogen atom or a radical of general formula (II) in which R.sub.1 represents a benzoyl radical or a radical R.sub.2 --O--C(.dbd.O)-- in which R.sub.2 represents a tert-butyl radical; R.sub.3 represents a phenyl radical; R.sub.4 represents an acetoxy or methoxyacetoxy radical; and R.sub.5 represents a methylthiomethoxy radical. 4. The method of preparing a taxoid of claim 1, wherein R.sub.4 is acetoxy. 5. The method of claim 1 wherein the taxoid (2R,3S)-3-benzoyl-2-hydroxy-3-phenyl propionate of 4,10.beta.-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,13.alpha.-dihy droxy-7.beta.-methylthiomethyloxy-9-oxo-tax-11-ene (XXXIV) ##STR39## is prepared. 6. The method of claim 1 wherein the taxoid (2R,4S,5R) -3-benzoyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylate of 4,10.beta.-diacetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1,13.alpha.-dihy droxy-7.beta.-methylthiomethyloxy-9-oxo-tax-11-ene (XXXIII) ##STR40## is prepared. 7. A method of preparing a pharmaceutical composition, comprising preparing least one taxoid by the method of claim 1, in which Z represents a radical of general formula (II), and combining said at least one taxoid with one or more pharmaceutically acceptable carriers. 8. A method of preparing a pharmaceutical composition, comprising preparing at least one taxoid by the method of claim 5 or claim 6, and combining said at least one taxoid with one or more pharmaceutically acceptable carriers. 9. The method of claim 8, wherein the pharmaceutically acceptable carrier is a diluent or adjuvant. 10. The method of claim 8, further comprising another pharmacologically active compound. 11. The method of claim 9, further comprising another pharmacologically active compound. 12. A method of preparing a taxoid of general formula (XIV) ##STR41## comprising: silylating the baccatin of formula (IX) ##STR42## to obtain a silylated baccatin wherein said silylation occurs at position 7; acetylating said silylated baccatin to obtain a protected baccatin of formula (XXX), wherein said acetylation occurs at position 10; coupling the protected baccatin of formula (XXX) ##STR43## with a compound of formula (XXXa) ##STR44## to produce a coupled ester of formula (XXXI); ##STR45## deprotecting said coupled ester with an acid to produce a desilylated taxoid of formula (XXXII); ##STR46## reacting said desilylated taxoid in a Pummerer reaction to produce a methylthiomethylether derivative of formula (XXXIII); ##STR47## and deprotecting said methylthiomethylether derivative with an acid to produce a compound of formula (XXXIV).