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Details for Patent: 5,889,043

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Details for Patent: 5,889,043

Title: Taxoids, preparation thereof and pharmaceutical Compositions containing same
Abstract:The present invention relates to new taxoids of general formula: ##STR1## in which: Z represents a hydrogen atom or a radical of general formula: ##STR2##
Inventor(s): Bouchard; Herve (Thiaia, FR), Bourzat; Jean-Dominique (Vincennes, FR), Commer.cedilla.on; Alain (Vitry-sur-Seine, FR)
Assignee: Rhone-Poulenc Rorer S.A. (Antony, FR)
Filing Date:Sep 26, 1997
Application Number:08/913,972
Claims:1. A taxoid of general formula: ##STR28## in which: Z represents a hydrogen atom or a radical of general formula: ##STR29## 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 alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, and trifluoromethyl radicals, or R.sub.1 represents a thenoyl radical, a furoyl radical or a radical R.sub.2 --O--CO-- in which R.sub.2 represents:

an alkyl radical containing 1 to 8 carbon atoms, and alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms, or a bicycloalkyl radical containing 7 to 10 carbon atoms, these radicals being unsubstituted or substituted with one or more substituents selected from halogen atoms, hydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals (unsubstituted or substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals (unsubstituted or substituted with one or more atoms or radicals selected from halogen 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;

a phenyl or .alpha.- or .beta.-naphthyl radical unsubstituted or substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, and 5-membered aromatic heterocyclic radicals;

or a saturated heterocyclic radical containing 4 to 6 carbon atoms, unsubstituted or substituted with one or more alkyl radicals containing 1 to 4 carbon atoms;

R.sub.3 represents an unbranched or branched alkyl radical containing 1 to 8 carbon atoms, an unbranched or branched alkenyl radical containing 2 to 8 carbon atoms, an unbranched or branched alkynyl radical containing 2 to 8 carbon atoms, an unbranched or branched alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl or .alpha.- or .beta.-naphthyl radical unsubstituted or substituted with one or more atoms or radicals selected from halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro, and trifluoromethyl radicals, and a 5-membered aromatic heterocycle containing one or more identical or different hetero atoms selected from nitrogen, oxygen and sulphur atoms and unsubstituted or substituted with one or more identical or different substituents selected from halogen atoms, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, and alkoxycarbonyl radicals, wherein for the substituents of the phenyl, .alpha.- or .beta.-naphthyl and aromatic heterocyclic radicals, the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals;

R.sub.4 represents an alkanoyloxy radical in which the alkanoyl portion contains 2 to 6 carbon atoms in an unbranched or branched chain with the exception of an acetyl radical, an alkenoyloxy radical in which the alkenoyl portion contains 3 to 6 carbon atoms in an unbranched or branched chain, or an alkynoyloxy radical in which the alkynoyl portion contains 3 to 6 carbon atoms in an unbranched or branched chain, these radicals being unsubstituted or substituted with one or more halogen atoms, an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 1 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical which may contain a second hetero atom selected from oxygen, sulphur or nitrogen atoms, unsubstituted or substituted with an alkyl radical containing 1 to 4 carbon atoms, a phenyl radical, or a phenylalkyl radical in which the alkyl portion contains 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 a cycloalkenoyloxy radical in which the cycloalkenoyl portion contains 4 to 8 carbon atoms, or alternatively R.sub.4 represents a benzoyloxy radical or 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;

R.sub.5 represents an alkoxy radical containing 1 to 6 atoms in an unbranched or branched chain, unsubstituted or substituted with an alkoxy radical containing 1 to 4 carbon atoms, an alkenyloxy radical containing 3 to 6 carbon atoms, an alkynyloxy radical containing 3 to 6 carbon atoms, a cycloalkyloxy radical containing 3 to 6 carbon atoms, or a cycloalkenyloxy radical containing 3 to 6 carbon atoms, these radicals unsubstituted or substituted with one or more halogen atoms, an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 1 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical, an N-alkylcarbamoyl radical, or an N,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical which may contain a second hetero atom selected from oxygen, sulphur and nitrogen atoms, unsubstituted or substituted with an alkyl radical containing 1 to 4 carbon atoms, a phenyl radical, or a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms.

2. A taxoid according to claim 1 in 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--CO-- in which R.sub.2 represents a tert-butyl radical;

R.sub.3 represents an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 atoms, a phenyl radical unsubstituted or substituted with one or more identical or different atoms or radicals selected from halogen atoms, alkyl, alkoxy, dialkylamino, acylamino, alkoxycarbonylamino, trifluoromethyl, 2- or 3-furyl, 2- or 3-thienyl, and 2-, 4- or 5-thiazolyl radicals;

R.sub.4 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

R.sub.5 represents an unbranched or branched alkyloxy radical containing 1 to 6 carbon atoms.

3. 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--CO-- in which R.sub.2 represents a tert-butyl radical, R.sub.3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, R.sub.4 represents a methoxyacetoxy, cyclopropylcarbonyloxy, cyclopentylcarbonyloxy, 2-pyridylcarbonyloxy or 3-pyridylcarbonyloxy radical, and R.sub.5 represents a methoxy radical.

4. A process for preparing the taxoid according to claim 1 in which Z represents a radical of general formula (II), comprising esterifying a product of general formula: ##STR30## in which R.sub.4 and R.sub.5 are defined as in claim 1 by means of an acid of general formula: ##STR31## in which R.sub.1 and R.sub.3 are defined as in claim 1, and either R.sub.6 represents a hydrogen atom and R.sub.7 represents a group protecting the hydroxyl function, or R.sub.6 and R.sub.7 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: ##STR32## in which R.sub.1, R.sub.3, R.sub.4, R.sub.5, R6 and R.sub.7 are defined as above, followed by replacing the protective groups represented by either one or both of R.sub.7 or R.sub.6 and R.sub.7, 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.degree. and 90.degree. C.

6. The process according to claim 4, 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 between 0.degree. and 90.degree. C.

7. The process according to claim 4, wherein the esterification is performed using the acid of general formula (IV) in halide form or in the form of a mixed anhydride with an aliphatic or aromatic acid, which may be prepared in situ, in the presence of a base, working in an organic solvent at a temperature between 0.degree. and 80.degree. C.

8. The process according to claim 4, wherein either one or both of the protective groups R.sub.7 or R.sub.6 and R.sub.7 are replaced by hydrogen atoms in the following manner:

1) when R.sub.6 represents a hydrogen atom and R.sub.7 represents a group protecting the hydroxyl function, the protective groups a re 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.degree. and 60.degree. C.;

2) when R.sub.6 and R.sub.7 together form a saturated 5- or 6- membered heterocycle of general formula: ##STR33## in which R.sub.1 is defined as above and R.sub.8 and R.sub.9, which may be identical or different, represent a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, an aralkyl radical in which the alkyl portion contains 1 to 4 carbon atoms, or an aryl radical, or alternatively R.sub.8 represents an alkoxy radical containing 1 to 4 carbon atoms, a trihalomethyl radical, or a phenyl radical substituted with a trihalomethyl radical and R.sub.9 represents a hydrogen atom, or alternatively R.sub.8 and R.sub.9, together with the carbon atom to which they are linked, form a 4- to 7-membered ring; the protective group formed by R.sub.6 and R.sub.7 is replaced by hydrogen atoms in the following manner:

a) when R.sub.1 represents a tert-butoxycarbonyl radical and R.sub.8 and R.sub.9, which may be identical or different, represent an alkyl, aralkyl, or aryl radical, or alternatively R.sub.8 represents a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and R.sub.9 represents a hydrogen atom, or alternatively R.sub.8 and R.sub.9 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 the product of general formula: ##STR34## in which R.sub.3, R.sub.4 and R.sub.5 are defined as above, which product of formula VII is acylated by means of benzoyl chloride in which the phenyl ring is unsubstituted or substituted or acylated by means of thenoyl chloride, furoyl chloride, or a product of general formula:

in which R.sub.2 is defined as above and X represents a halogen atom or a residue --O--R.sub.2 or --O--CO--O--R.sub.2, to obtain a product of general formula (I) in which Z represents a radical of general formula (II);

b) when R.sub.1 represents an unsubstituted or substituted benzoyl radical, thenoyl radical, or furoyl radical, or a radical R.sub.2 --O--CO in which R.sub.2 is defined as above, R.sub.8 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 R.sub.9 represents a hydrogen atom; the protective group formed by R.sub.6 and R.sub.7 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.degree. to 60.degree. C.

9. A process for preparing a taxoid according to claim 1 for which Z represents a hydrogen atom, R.sub.4 and R.sub.5 are defined as in claim 1, comprising treating a 10-deacetylbaccatin III of formula: ##STR35## with a silyl halide of general formula:

in which the symbols R, which may be identical or different, represent an alkyl radical containing 1 to 4 carbon atoms, unsubstituted or 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: ##STR36## defined as above, which product of formula (XI) is treated with a product of general formula:

in which R'.sub.4 is such that R'.sub.4 --O-- is identical to R.sub.4 defined above and X.sub.1 represents a halogen atom, to obtain a product of general formula: ##STR37## in which R and R.sub.4 are defined as above, the silyl protective groups of which are replaced by hydrogen atoms to obtain a product of general formula: ##STR38## in which R.sub.4 is defined as above, which is etherified selectively at position 7 by the action of a product of general formula:

in which R'.sub.5 is such that R'.sub.5 --O-- is identical to R.sub.5 defined above and X.sub.2 represents a reactive ester residue or a halogen atom, to give the product of general formula (I) in which Z represents a hydrogen atom.

10. A process for preparing a taxoid according to claim 1 in which Z represents a radical of general formula (II), R.sub.4 and R.sub.5 are defined as in claim 1, comprising treating a product of general formula: ##STR39## in which R.sub.1, R.sub.3, R.sub.6 and R.sub.7 are defined as in claim 1 by means of a product of general formula:

in which the symbols R, which may be identical or different, represent an alkyl radical containing 1 to 4 carbon atoms unsubstituted or 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: ##STR40## in which R, R.sub.1, R.sub.3, R.sub.6 and R.sub.7 are defined as above, which is reacted with a product of general formula:

in which R.sub.4 is such that R'.sub.4 --O-- is identical to R.sub.4 defined as in claim 1 and X.sub.1 represents a halogen atom or a reactive ester residue, to give a product of general formula: ##STR41## in which R, R.sub.1, R.sub.3, R.sub.4, R.sub.6 and R.sub.7 are defined as above, the silyl protective group of which is replaced by a hydrogen atom to give a product of general formula: ##STR42## wherein R.sub.1, R.sub.3, R.sub.4, R.sub.6 snd R.sub.7 are defined as above, which, by the action of a product of general formula (XV), yields the product of general formula (V): ##STR43## 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).

11. A process of preparing a taxoid according to claim 1, 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: ##STR44## in which R.sub.4 is defined as in claim 1 and R' and R", which may be identical or different, represent a hydrogen atom, an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, an alkynl 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, unsubstituted or substituted, or alternatively 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 Z.sub.1 represents a hydrogen atom or a radical of general formula: ##STR45## in which R.sub.1 and R.sub.3 are defined as in claim 1 and R.sub.6 and R.sub.7 are defined as in claim 4, to obtain a product of general formula: ##STR46## in which R.sub.4 and R.sub.5 are defined as above, followed, when Z.sub.1 represents a radical of general formula (XXII), by replacement of the protective groups represented by either or both of R.sub.6 or R.sub.6 and R.sub.7 by hydrogen atoms under the conditions of claim 8.

12. The process according to claim 11, performed at a temperature between -10.degree. and 60.degree. C.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. A pharmaceutical composition comprising at least one taxoid according to claim 1 in which Z represents a radical of general formula (II), and one or more pharmaceutically acceptable carriers.

19. A pharmaceutical composition comprising the compound of claim 13 and one or more pharmaceutically acceptable carriers.

20. A pharmaceutical composition comprising the compound of claim 14 and one or more pharmaceutically acceptable carriers.

21. A pharmaceutical composition comprising the compound of claim 15 and one or more pharmaceutically acceptable carriers.

22. A pharmaceutical composition comprising the compound of claim 16 and one or more pharmaceutically acceptable carriers.

23. A pharmaceutical composition comprising the compound of claim 17 and one or more pharmaceutically acceptable carriers.

24. The taxoid according to claim 1, wherein the R.sub.2 5-membered aromatic heterocyclic radical substituent is a furyl or thienyl radical.

25. The method of claim 8, wherein the aryl portion of either or both of the R.sub.8 or R.sub.9 aralkyl radicals is a phenyl radical unsubstituted or substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms.

26. The method of claim 8, wherein either or both or the R.sub.8 or R.sub.9 aryl radicals is a phenyl radical unsubstituted or substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms.

27. The process of claim 8, wherein the trihalomethyl radical is a trichloromethyl radical.

28. The process of claim 8, wherein the organic solvent is an alcohol.

29. The pharmaceutical composition of one of claims 18 to 23, wherein the pharmaceutically acceptable carrier is a diluent or adjuvant.

30. The pharmaceutical composition of one of claims 18 to 23, further comprising another pharmacologically active compound.
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