EP1105119A2 - Nouvelle utilisation de derives taxoides - Google Patents

Nouvelle utilisation de derives taxoides

Info

Publication number
EP1105119A2
EP1105119A2 EP99944532A EP99944532A EP1105119A2 EP 1105119 A2 EP1105119 A2 EP 1105119A2 EP 99944532 A EP99944532 A EP 99944532A EP 99944532 A EP99944532 A EP 99944532A EP 1105119 A2 EP1105119 A2 EP 1105119A2
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
radical
radicals
alkyl
atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99944532A
Other languages
German (de)
English (en)
Inventor
Marie-Christine Bissery
Patricia Vrignaud
Simon Roberts
Clive Brealey
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Aventis Pharma SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP98115650A external-priority patent/EP0982028A1/fr
Application filed by Aventis Pharma SA filed Critical Aventis Pharma SA
Publication of EP1105119A2 publication Critical patent/EP1105119A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates a new use of taxoid derivatives. It relates more precisely to a method for treating abnormal cell proliferation of different resistant cell lines expressing multidrug resistance P-glycoprotein. This type of cells are representative of colon cancer cells.
  • the present invention is related to the treatment of abnormal cell proliferation of different resistant cell lines expressing multidrug resistance P-glycoprotein and is also related to the treatment of abnormal cell proliferation of different resistant cell lines expressing multidrug resistance P- glycoprotein and is also related to the treatment of colon tumors of mammals including men by administrating a compound of general formula (I) or a pharmaceutically acceptable salt or solvante thereof :
  • Z represents a hydrogen atom or a radical of general formula :
  • R represents a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen 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 or furoyl radical or a radical R 2 -O-CO- in which R 2 represents :
  • bicycloalkyl radical containing 7 to 10 carbon atoms these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals (optionally 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 (optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atom
  • R 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, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl or ⁇ - or ⁇ -naphthyl radical optionally substituted with one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy
  • R 4 represents an alkoxy radical containing 1 to 6 carbon atoms in an unbranched or branched chain, an alkenyloxy radical containing 3 to 6 carbon atoms in an unbranched or branched chain, an alkynyloxy radical containing 3 to 6 carbon atoms in an unbranched or branched chain, a cycloalkyloxy radical containing 3 to 6 carbon atoms or a cycloalkenyloxy radical containing 4 to 6 carbon atoms, these radicals being optionally substituted with one or more halogen atoms or with an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 1 to 4 carbon atoms or a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano or carbamoyl radical or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl
  • the aryl radicals which can be represented by R 3 are phenyl or ⁇ - or ⁇ -naphthyl radicals optionally substituted with one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, on the understanding that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms
  • the radicals R 4 and R 5 which may be identical or different, represent unbranched or branched alkoxy radicals containing 1 to 6 carbon atoms, optionally substituted with a methoxy, ethoxy, ethylthio, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-pyrrolidinocarbonyl or N-piperidinocarbonyl radical.
  • the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which R, represents a benzoyl radical or a radical R 2 -O-CO- in which R 2 represents a tert-butyl radical and R 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 carbon atoms, a phenyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms (fluorine, chlorine) and alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tert-butoxycarbonylamino) or trifluoromethyl radicals, or a 2- or 3-furyl, 2- or 3-thieny
  • the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which R, represents a benzoyl radical or a radical R 2 -O-CO- in which R- j represents a tert-butyl radical and R 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 4 and R 5 , which may be identical or different, each represent a methoxy, ethoxy or propoxy radical.
  • R 3 represents a phenyl radical and Ri represents a ter-butoxycarbonyl radical
  • R-t and R 5 which may be identical or different, represent a methoxy, ethoxy or propoxy radical.
  • the present invention relates to 4 ⁇ -acetoxy-2 ⁇ - benzoyloxy-5 ⁇ ,20-epoxy- 1 ⁇ -hydroxy-7 ⁇ , 1 O ⁇ -dimethoxy-9-oxo- 11 -taxen- 13 ⁇ -yl (2R,3S)-3 tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of formula (la)
  • R-X (IV) in which R represents a radical as defined above and X represents a reactive ester residue such as a sulphuric or sulphonic ester residue or a halogen atom, to give a product bearing the unit -OR in position 10 and silyl groups in positions 7 and 13.
  • the silyl protecting groups are replaced with hydrogen atoms to give a compound still bearing the group -OR in position 10 and OH groups in positions 7 and 13.
  • the latter derivative is etherified selectively in position 7 by reaction with the derivative of formula IV to give the derivative of formula (I) in which Z is equal to hydrogen.
  • the final step consists in esterifying in position 13, according to a process which is known per se, the derivatives of formula (la), in which Z represents hydrogen, in the presence of a ⁇ -lactam according, for example, to the process described in patent EP 617,018, or in the presence of an oxazolidine as described, for example, in patent WO 96/30355 mentioned above.
  • the final step, which allows the desired compound of formula (la) to be obtained, is carried out on the intermediate compound obtained above, by the action of activated Raney nickel.
  • the action of the reagent formed in situ from sulphoxide of general formula (V), preferably dimethyl sulphoxide and acetic anhydride, is carried out in the presence of acetic acid or an acetic acid derivative such as a haloacetic acid, at a temperature of between 0 and 50°C.
  • the action of the activated Raney nickel in the presence of an aliphatic alcohol or an ether is carried out at a temperature of between -10 and 60°C.
  • A represents hydrogen or a side chain of formula (Ha) below :
  • G represents a protecting group for the hydroxyl function
  • R, and R 3 have the same meaning as in formula (II) or an oxazolidine unit of formula (Id) :
  • R, and R 3 have the same meaning as in formula (II)
  • R a and R b which may be identical or different, represent hydrogen or alkyl, aryl, halo, alkoxy, arylalkyl, alkoxyaryl, haloalkyl, haloaryl, it being possible for the substituents optionally to form a 4- to 7-membered ring.
  • 10-deacetylbaccatin as starting material, i.e. the product of formula (III), which allows appreciable economy as regards the process and moreover avoids the intermediate protection and deprotection steps necessary in the old processes.
  • ethers and preferably ethers such as methoxymethyl ether, 1-ethoxyethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, benzyl ethers optionally substituted with one or more groups such as methoxy, chloro, nitro, 1-methyl- 1 -methoxy ethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether and silyl ethers such as trialkylsilyl ethers, • carbon
  • radicals R a and R b of general formula (lib) are chosen from those described in patent WO 94/07878 and the derivatives more particularly preferred are those in which R a is hydrogen and R b is a p-methoxyphenyl radical.
  • the alkylating agent is chosen from : • alkyl halides, and preferably from alkyl iodides (RI)
  • alkyl sulphates such as methyl sulphate
  • oxoniums such as trialkyloxonium boric salts, in particular trimethyloxonium tetrafluoroborate (Me 3 OBF 4 ).
  • Methyl iodide is preferably used.
  • the alkylating agent is used in the presence of an anionization agent such as one or more strong bases, in anhydrous medium.
  • alkali metal hydrides such as sodium or potassium hydride
  • alkali metal alkoxides such as potassium tert-butoxide
  • methyl iodide in the presence of potassium hydride.
  • the reaction is preferably carried out in an organic medium which is inert under the reaction conditions.
  • organic medium which is inert under the reaction conditions.
  • solvents it is preferred to use :
  • polar aprotic solvents such as dimethylformamide, or aromatic solvents such as toluene
  • alkylesters such as ethylacetate.
  • a molar ratio between the anionization agent and the substrate of greater than 2 and preferably between 2 and 20.
  • a molar ratio between the alkylating agent and the substrate of greater than 2 and preferably between 2 and 40.
  • reaction temperature between -30°C and 80°C.
  • reaction time advantageously ranges between a few hours and 48 hours depending on the reagents chosen.
  • the process then proceeds, in a known manner, to the esterification step according, for example, to the processes described in patents EP 617,018 or WO 96/30355 mentioned above.
  • the procedure first begins with the dialkylation of 10-deacetylbaccatin, using an alkylating agent in the presence of a strong base, in a second step, the 10-deacetylbaccatin dietherified in positions 7 and 10 is coupled, in position 13, with a suitably protected ⁇ -lactam in the presence of an activating agent chosen from tertiary amines and metal bases which ensure the formation of an alkoxide in position 13. Deprotection of the side chain is then achieved by the action of an inorganic or organic acid.
  • the procedure first begins with the dialkylation of 10-deacetylbaccatin, using an alkylating agent in the presence of a strong base, in a second step, the 10-deacetylbaccatin dietherified in positions 7 and 10 is coupled, in position 13, with an oxazolidine in the presence of a coupling agent such as diimides in the presence of an activating agent such as dialkylaminopyridines. Opening of the oxazolidine is achieved by the action of an inorganic or organic acid.
  • the procedure begins with the esterification in position 13 of baccatin suitably protected in positions 7 and 10, with a ⁇ -lactam or an oxazolidine in the presence of a coupling agent and/or an activating agent as described in the above two processes.
  • the dietherification in positions 7 and 10 is carried out by an alkylating agent in the presence of a strong base. Deprotection of the side chain is then achieved by the action of an inorganic or organic acid.
  • the compounds of formula I have anti-tumor properties, more particularly, activity against tumors which are resistant to Taxol® and Taxotere®.
  • tumors include, for example, colon tumors which have an elevated expression of multidrug resistance P-glycoprotein.
  • Multi-drug resistance is the usual term relating to the resistance by a tumor against various compounds having differing structures and mechanisms of action.
  • Taxoids are generally known to be highly recognized by experimental tumors such as P388/DOX, a P388 murine leukemia cell line selected for doxorubicin (DOX) resistance, which express P-glycoprotein.
  • the compounds according to the present invention are less recognized by P388/DOX. More particularly, the compounds are less recognized than Taxotere®.
  • the compounds of formula (I) are mainly used for preparing a medecine for treating abnormal cell proliferation of cell lines expressing the multidrug resistance P-glycoprotein.
  • the compound of formula I are mainly used for preparing a medecine for treating colon cancer.
  • the compound and mainly compound of formula (I) where P and R 5 are each methoxy has the property to be active compared to the other known taxoids such as Taxol® or Taxotere® to treat the cancer cells lines expressing the multidrug resistance P-glycoprotein. It is also active against tumor cells resistant to
  • the product of formula (I) can be used concurrently with at least other therapeutic treatment. It is more preferably used with other therapeutic treatment comprising antineoplastic drugs, monoclonal antibodies, immunotherapies, radiotherapies, or biological response modifiers.
  • the product of formula (I) is preferably administered by parenteral administration such as intravenous, intraperitoneal, intramuscular or subcutaneous administration.
  • Product of formula (la) is a potent anti-cancer agent in pre-clinical models. In vitro antiproliferative properties on resistant cell lines
  • Docetaxel was found to be cross-resistant to cell lines expressing the multidrug resistance P-glycoprotein (RIGEL I. and HORWITZ S.B., Studies with RP 56976 (Taxotere®: a semisynthtetic analogue of Taxol, J. Natl. Cancer Inst, 83, 288-291, 1991).
  • the cytotoxicity of product la was examined against different resistant cell lines expressing the multidrug resistance P-glycoprotein, in comparison with docetaxel after 4 days of continuous exposure using standard methods.
  • the resistance factor was calculated by dividing the IC50 value obtained on resistant cells by the IC50 value obtained on sensitive cells.
  • product of formula la was found more active than docetaxel on all the resistant tumor cell lines which have been evaluated. Interestingly, product of formula la was found minimally cross-resistant (resistance factor: 1.8 to 4.3) in the P388/TXT, P388 NCR, HL60/TAX and Calcl8/TXT cell lines that are moderately cross- resistant to docetaxel (resistance factor: 4.8 to 23.5) and which could be more representative of the clinical situation.
  • Product of formula la was also evaluated on the murine P388/CPT5 cell line with acquired resistance to camptothecin that do not express the P-glycoprotein. A strong decrease in the cross-resistance was found for product of formula la and docetaxel (resistance factor: 4.8 and 10.5) as compared to camptothecin (resistance factor: 286). This result suggests a potential application of product of formula la in the treatment of tumors with acquired resistance to camptothecin derivatives.
  • the antiproliferative properties of the product of formula la and docetaxel were examined on the human colon adenocarcinoma CaCo-2 cell line (ATCC HTB37) that was shown to present a basal level of expression of P-glycoprotein encoded by the mdrl gene.
  • the methodology was used, i.e., 96 well plates, time of contact of the drugs (96 hours) and neutral red coloration of viable cell. Results expressed as IC50, were summarized in the next table.
  • Product of formula la is cytotoxic on CaCo-2 cells with IC50 included in the range described on the other human cell line tested, i.e., HL60, Calcl ⁇ and KB (see previous paragraph).
  • IC50 included in the range described on the other human cell line tested, i.e., HL60, Calcl ⁇ and KB (see previous paragraph).
  • docetaxel displays a higher IC50 on CaCo-2 cells, corresponding to 4.9 times the values observed with Product of formula la. Therefore, the higher antiproliferative activity of Product of formula la, compared to docetaxel, on CaCo-2 cells is in agreement with a lower recognition of Product of formula la than docetaxel by the P-glycoprotein intrinsically expressed by this cell line.
  • T/C tumor growth inhibition
  • T/C > 42 %, - is inactive
  • a T/C ⁇ _42 %, + is the minimum level for activity.
  • a T/C ⁇ 10 %, ++ is considered as a high antitumor activity level which justifies further development (DN-2 level).
  • DN-2 level the two following end points were also used: - tumor growth delay, T-C, where T and C are the median times in days required for the treatment group and the control group tumors to reach a predetermined size (750 to l500 mg).
  • regressions can be either partial (more than 50 % reduction in tumor mass) or complete. Complete regressions are included in the partial regressions.
  • the end point used for assessing activity in intraperitoneally implanted leukemia was percent increase in host life span (% ILS), calculated in relation to median day of death.
  • the NCI criteria for activity are as follows:
  • Toxicity was based on drug deaths (> 10 %) or a weight loss nadir > 20 %. Docetaxel was used for comparison trials when needed. Colon tumors
  • Colon 51 Product of formula la was administered i.v. on day 4, 6, 8. At the HNTD (9.3 mg/kg/injection), it was found highly active with a 0 % T/C and a 2.6 log cell kill. The dosage below yielded a 2.2 log cell kill. Docetaxel was also found highly active with a 3.1 log cell kill.
  • HNTD highest nontoxic dose
  • bwl body weight loss
  • DD drug death
  • bwl body weight loss.
  • HNTD highest nontoxic dose
  • bwl body weight loss
  • DD drug death
  • TFS tumor free survivors observed on day 139.

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  • Organic Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne une nouvelle utilisation de dérivés taxoïdes et plus précisément une méthode de traitement de la prolifération cellulaire anormale de différentes lignées cellulaires exprimant de la P-glycoprotéine résistant à l'action de plusieurs médicaments. Ce type de cellules est représentatif des cellules du cancer du côlon. Les produits de l'invention peuvent également être utilisés pour le traitement du cancer du côlon chez les mammifères dont l'homme.
EP99944532A 1998-08-20 1999-08-18 Nouvelle utilisation de derives taxoides Withdrawn EP1105119A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP98115650 1998-08-20
EP98115650A EP0982028A1 (fr) 1998-08-20 1998-08-20 Nouvelle utilisation de dérivés de taxoides
US12384399P 1999-03-11 1999-03-11
US123843P 1999-03-11
PCT/EP1999/006292 WO2000010547A2 (fr) 1998-08-20 1999-08-18 Nouvelle utilisation de derives taxoides

Publications (1)

Publication Number Publication Date
EP1105119A2 true EP1105119A2 (fr) 2001-06-13

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP99944532A Withdrawn EP1105119A2 (fr) 1998-08-20 1999-08-18 Nouvelle utilisation de derives taxoides

Country Status (15)

Country Link
EP (1) EP1105119A2 (fr)
JP (1) JP2002523364A (fr)
KR (1) KR20010079665A (fr)
CN (1) CN1313764A (fr)
AU (1) AU5742099A (fr)
BG (1) BG105273A (fr)
CA (1) CA2341191A1 (fr)
EE (1) EE200100082A (fr)
HU (1) HUP0104000A3 (fr)
IL (1) IL141231A0 (fr)
MX (1) MXPA01001721A (fr)
NO (1) NO20010655D0 (fr)
SK (1) SK2352001A3 (fr)
TR (1) TR200100575T2 (fr)
WO (1) WO2000010547A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2922107B1 (fr) * 2007-10-10 2010-02-26 Aventis Pharma Sa Nouvelles compositions a base de taxoides
PE20121429A1 (es) 2009-10-29 2012-11-06 Aventis Pharma Sa Nuevo uso antitumoral de cabazitaxel

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2697522B1 (fr) * 1992-10-30 1994-11-25 Rhone Poulenc Rorer Sa Procédé de préparation de dérivés du taxane.
MA23823A1 (fr) * 1995-03-27 1996-10-01 Aventis Pharma Sa Nouveaux taxoides, leur preparation et les compositions qui les contiennent
FR2732968B1 (fr) * 1995-04-14 1997-05-16 Rhone Poulenc Rorer Sa Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0010547A2 *

Also Published As

Publication number Publication date
CA2341191A1 (fr) 2000-03-02
WO2000010547A2 (fr) 2000-03-02
HUP0104000A2 (hu) 2002-04-29
TR200100575T2 (tr) 2001-07-23
CN1313764A (zh) 2001-09-19
AU5742099A (en) 2000-03-14
WO2000010547A3 (fr) 2000-06-29
EE200100082A (et) 2002-06-17
SK2352001A3 (en) 2001-07-10
NO20010655L (no) 2001-02-07
HUP0104000A3 (en) 2003-01-28
MXPA01001721A (es) 2005-06-03
KR20010079665A (ko) 2001-08-22
NO20010655D0 (no) 2001-02-07
IL141231A0 (en) 2002-03-10
BG105273A (en) 2001-11-30
JP2002523364A (ja) 2002-07-30

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