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Claims for Patent: 6,372,780

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Claims for Patent: 6,372,780

Title: Methods of treating cell lines expressing multidrug resistance P-glycoprotein
Abstract:Now taxoids of general formula (I) ##STR1## their preparation and pharmaceutical compositions containing them. The new products of general formula (I) in which Z represents a radical of general formula (II): ##STR2## display noteworthy antitumor and antileukaemic properties.
Inventor(s): Bouchard; Herve (Ivry-sur-Seine, FR), Bourzat; Jean-Dominique (Vincennes, FR), Commer.cedilla.on; Alain (Vitry-sur-Seine, FR)
Assignee: Aventis Pharma S.A. (Antony Cedex, FR)
Application Number:09/752,779
Patent Claims: 1. A method for treating abnormal cell proliferation of at least one cell line expressing a multidrug resistance P-glycoprotein (mdr1), said method comprising administering to a mammal in need or desire thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: ##STR23##

wherein:

Z represents a hydrogen atom or a radical of formula (II): ##STR24##

wherein:

R.sub.1 represents:

a benzoyl radical which is unsubstituted or substituted with at least one identical or different atom or radical selected from halogen atoms, alkyl radicals containing from 1 to 4 carbon atoms, alkoxy radicals containing from 1 to 4 carbon atoms, and trifluoromethyl radicals;

a thenoyl or furoyl radical; or

a radical R.sub.2 --O--CO-- in which R.sub.2 represents:

an alkyl radical containing from 1 to 8 carbon atoms,

an alkenyl radical containing from 2 to 8 carbon atoms,

an alkynyl radical containing from 3 to 8 carbon atoms,

a cycloalkyl radical containing from 3 to 6 carbon atoms,

a cycloalkenyl radical containing from 4 to 6 carbon atoms, or

a bicycloalkyl radical containing from 7 to 10 carbon atoms,

these radicals being unsubstituted, or substituted with at least one substituent selected from halogen atoms, hydroxyl radicals, alkoxy radicals containing from 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains from 1 to 4 carbon atoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals which are unsubstituted or substituted at position 4 with an alkyl radical containing from 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, cycloalkyl radicals containing from 3 to 6 carbon atoms, cycloalkenyl radicals containing from 4 to 6 carbon atoms, phenyl radicals which are unsubstituted or substituted with at least one atom or radical selected from halogen atoms, alkyl radicals containing from 1 to 4 carbon atoms, and alkoxy radicals containing from 1 to 4 carbon atoms, cyano radicals, carboxyl radicals, and alkoxycarbonyl radicals in which the alkyl portion contains from 1 to 4 carbon atoms,

a phenyl or .alpha.- or .beta.-naphthyl radical which is unsubstituted, or substituted with at least one atom or radical selected from halogen atoms, alkyl radicals containing from 1 to 4 carbon atoms, and alkoxy radicals containing from 1 to 4 carbon atoms,

a 5-membered aromatic heterocyclic radical, or

a saturated heterocyclic radical containing from 4 to 6 carbon atoms, which is unsubstituted or substituted with at least one alkyl radical containing from 1 to 4 carbon atoms;

R.sub.3 represents:

an unbranched or branched alkyl radical containing from 1 to 8 carbon atoms,

an unbranched or branched alkenyl radical containing from 2 to 8 carbon atoms,

an unbranched or branched alkynyl radical containing from 2 to 8 carbon atoms,

a cycloalkyl radical containing from 3 to 6 carbon atoms,

a phenyl or .alpha.- or .beta.-naphthyl radical which is unsubstituted or substituted with at least one atom or radical selected from halogen atoms and 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, or

a 5-membered aromatic heterocycle containing one or more identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and which is unsubstituted or substituted with at least one identical or different substituent selected from halogen atoms and alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, and alkoxycarbonyl radicals,

with the provisos that, in the substituents of the phenyl, .alpha.- and .beta.-naphthyl, and aromatic heterocyclic radicals, the alkyl radicals and the alkyl portions of the other radicals contain from 1 to 4 carbon atoms, and that the alkenyl and alkynyl radicals contain from 2 to 8 carbon atoms, and that the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals;

R.sub.4 represents:

an alkoxy radical containing from 1 to 6 carbon atoms in an unbranched or branched chain,

an alkenyloxy radical containing from 3 to 6 carbon atoms in an unbranched or branched chain,

an alkynyloxy radical containing from 3 to 6 carbon atoms in an unbranched or branched chain,

a cycloalkyloxy radical containing from 3 to 6 carbon atoms, or

a cycloalkenyloxy radical containing from 4 to 6 carbon atoms,

these radicals being unsubstituted or substituted with at least one halogen atom or with an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 1 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, a cyano or carbamoyl radical, or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion contains from 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical containing or not containing a second heteroatom selected from oxygen, sulfur, and nitrogen atoms, which is unsubstituted or substituted with an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms; and

R.sub.5 represents:

an alkoxy radical containing from 1 to 6 carbon atoms in an unbranched or branched chain,

an alkenyloxy radical containing from 3 to 6 carbon atoms,

an alkynyloxy radical containing from 3 to 6 carbon atoms,

a cycloalkyloxy radical containing from 3 to 6 carbon atoms, or

a cycloalkenyloxy radical containing from 3 to 6 carbon atoms,

these radicals being unsubstituted or substituted with at least one halogen atom or with an alkoxy radical containing from 1 to 4 carbon atoms, an alkylthio radical containing from 2 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains from 1 to 4 carbon atoms, a cyano or carbamoyl radical, or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion contains from 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical containing or not containing a second heteroatom selected from oxygen, sulfur, and nitrogen atoms, which is unsubstituted or substituted with an alkyl radical containing from 1 to 4 carbon atoms or a phenyl radical or a phenylalkyl radical in which the alkyl portion contains from 1 to 4 carbon atoms.

2. A method according to claim 1, wherein Z represents a hydrogen atom or a radical of formula (II), wherein:

R.sub.1 represents a benzoyl radical or a radical R.sub.2 --O--CO-- wherein R.sub.2 represents a tert-butyl, furyl, or thienyl radical;

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

R.sub.4 and R.sub.5, which may be identical or different, each represent an unbranched or branched alkyloxy radical containing from 1 to 6 carbon atoms.

3. A method according to claim 2, wherein Z represents a hydrogen atom or a radical of formula (II), wherein:

R.sub.1 represents a benzoyl radical or a radical R.sub.2 --O--CO--, wherein 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; and

R.sub.4 and R.sub.5, which may be identical or different, each represent a methoxy, ethoxy, or propoxy radical.

4. A method according to claim 3, wherein Z represents a hydrogen atom or a radical of formula (II), wherein:

R.sub.1 represents R.sub.2 --O--CO--, wherein R.sub.2 represents a tert-butyl radical;

R.sub.3 represents phenyl; and

R.sub.4 and R.sub.6 which may be identical or different, each represent a methoxy, ethoxy, or propoxy radical.

5. A method according to claim 4, wherein the compound of formula (I) is 4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydroxy-7.be ta.,10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate, or a pharmaceutically acceptable salt or solvate thereof.

6. A method according to claim 1, wherein the abnormal cell proliferation is colon cancer.

7. A method according to claim 1, wherein the method is performed concurrently with at least one additional therapeutic treatment.

8. A method according to claim 7, wherein the additional therapeutic treatment comprises administering an effective amount of at least one antineoplastic drug, monoclonal antibody, immunotherapy, radiotherapy, or biological response modifier.

9. A method according to claim 8, wherein Z represents a hydrogen atom or a radical of formula (II), wherein:

R.sub.1 represents R.sub.2 --O--CO--, wherein R.sub.2 represents a tert-butyl radical;

R.sub.3 represents phenyl; and

R.sub.4 and R.sub.5, which may be identical or different, each represent a methoxy, ethoxy, or propoxy radical.

10. A method according to claim 9, wherein the compound of formula (I) is 4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydroxy-7.be ta. ,10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl(2R,3S)-3-tert-butoxycarbon ylamino-2-hydroxy-3-phenyl-propionate, or a pharmaceutically acceptable salt or solvate thereof.

11. A method according to claim 1, wherein the compound of formula (I) is administered parenterally.

12. A method according to claim 11, wherein the compound of formula (I) is administered intravenously, intraperitoneally, intramuscularly, or subcutaneously.

13. A method according to claim 12, wherein Z represents a hydrogen atom or a radical of formula (II), wherein:

R.sub.1 represents R.sub.2 --O--CO--, wherein R.sub.2 represents a tert-butyl radical;

R.sub.3 represents phenyl; and

R.sub.4 and R.sub.5, which may be identical or different, each represent a methoxy, ethoxy, or propoxy radical.

14. A method according to claim 13, wherein the compound of formula (I) is 4.alpha.-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1.beta.-hydroxy-7.be ta. ,10.beta.-dimethoxy-9-oxo-11-taxen-13.alpha.-yl(2(2R,3S)-3-tert-butoxycarb onylamino-2-hydroxy-3-phenyl-propionate, or a pharmaceutically acceptable salt or solvate thereof.
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