US20020082291A1 - New use of taxoid derivatives - Google Patents
New use of taxoid derivatives Download PDFInfo
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- US20020082291A1 US20020082291A1 US09/482,015 US48201500A US2002082291A1 US 20020082291 A1 US20020082291 A1 US 20020082291A1 US 48201500 A US48201500 A US 48201500A US 2002082291 A1 US2002082291 A1 US 2002082291A1
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- 0 [4*][C@H]1C(=O)[C@]2(C)[C@@H]([5*])C[C@H]3OC[C@@]3(OC(C)=O)[C@@]2([H])C[C@H](OC(=O)C2=CC=CC=C2)[C@]2(O)C[C@H](OC)C(C)C1C2(C)C Chemical compound [4*][C@H]1C(=O)[C@]2(C)[C@@H]([5*])C[C@H]3OC[C@@]3(OC(C)=O)[C@@]2([H])C[C@H](OC(=O)C2=CC=CC=C2)[C@]2(O)C[C@H](OC)C(C)C1C2(C)C 0.000 description 5
- LABYYDJFAGQSRH-JOJVYKSRSA-N [H][C@]12C[C@H](OC(=O)C3=CC=CC=C3)[C@]3(O)C[C@H](O)C(C)=C([C@@H](O)C(=O)[C@]1(C)[C@@H](O)C[C@H]1OC[C@]12OC(C)=O)C3(C)C Chemical compound [H][C@]12C[C@H](OC(=O)C3=CC=CC=C3)[C@]3(O)C[C@H](O)C(C)=C([C@@H](O)C(=O)[C@]1(C)[C@@H](O)C[C@H]1OC[C@]12OC(C)=O)C3(C)C LABYYDJFAGQSRH-JOJVYKSRSA-N 0.000 description 1
- MQCUATFFBYDTNO-MWTLLJAYSA-N [H][C@]12C[C@H](OC(=O)C3=CC=CC=C3)[C@]3(O)C[C@H](OC(=O)[C@]([H])(O)[C@@]([H])(NC(=O)OC(C)(C)C)C4=CC=CC=C4)C(C)=C([C@@H](OC)C(=O)[C@]1(C)[C@@H](OC)C[C@H]1OC[C@]12OC(C)=O)C3(C)C Chemical compound [H][C@]12C[C@H](OC(=O)C3=CC=CC=C3)[C@]3(O)C[C@H](OC(=O)[C@]([H])(O)[C@@]([H])(NC(=O)OC(C)(C)C)C4=CC=CC=C4)C(C)=C([C@@H](OC)C(=O)[C@]1(C)[C@@H](OC)C[C@H]1OC[C@]12OC(C)=O)C3(C)C MQCUATFFBYDTNO-MWTLLJAYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- 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
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
Definitions
- the present invention relates to a new pharmaceutical form of taxoid derivatives. More precisely, it relates to the oral administration of a compound of general formula (I) or a pharmaceutically acceptable salt or solvent thereof:
- Z represents a hydrogen atom or a radical of general formula:
- R 1 represents
- a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms, alkoxy radicals comprising 1 to 4 carbon atoms, and trifluoromethyl radicals,
- an alkyl radical comprising 1 to 8 carbon atoms
- an alkenyl radical comprising 2 to 8 carbon atoms
- an alkynyl radical comprising 3 to 8 carbon atoms
- a cycloalkenyl radical comprising 4 to 6 carbon atoms
- these radicals being optionally substituted with one or more identical or different substituents chosen from halogen atoms, hydroxyl radicals, alkoxy radicals comprising 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion comprises 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals which are optionally substituted at position 4 with an alkyl radical comprising 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, cycloalkyl radicals comprising 3 to 6 carbon atoms, cycloalkenyl radicals comprising 4 to 6 carbon atoms, phenyl radicals which are optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms, and alkoxy radicals comprising 1 to 4 carbon atoms, cyano or carboxy
- a phenyl or ⁇ - or ⁇ -naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms and alkoxy radicals comprising 1 to 4 carbon atoms,
- a 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals, or
- a saturated heterocyclic radical comprising 4 to 6 carbon atoms, and optionally substituted with one or more identical or different alkyl radicals comprising 1 to 4 carbon atoms;
- R 3 represents
- a phenyl or ⁇ - or ⁇ -naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, phenyl, ⁇ - or ⁇ -naphthyl, 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, it being understood that the alkyl radicals and alkyl portions of radicals comprise 1 to 4 carbon atoms, and the alkyl radical
- a 5-membered aromatic heterocyclic radical comprising one or more identical or different hetero atoms chosen from nitrogen, oxygen and sulphur atoms, and optionally substituted with one or more identical or different substituents chosen from halogen atoms and alkyl, phenyl, ⁇ - or ⁇ -naphthyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl radicals, it being understood that the alkyl radicals and alkyl portions of radicals comprise 1 to 4 carbon atoms, and the alkenyl and alkynyl radicals comprise 2 to 8 carbon atoms;
- R 4 represents
- an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain
- an alkenyloxy radical comprising 3 to 6 carbon atoms in an unbranched or branched chain
- an alkynyloxy radical comprising 3 to 6 carbon atoms in an unbranched or branched chain
- a cycloalkyloxy radical comprising 3 to 6 carbon atoms
- these radicals being optionally substituted with one or more identical or different halogen atoms or with an alkoxy radical comprising 1 to 4 carbon atoms, an alkylthio radical comprising 1 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, a cyano or carbamoyl radical, or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion comprises 1 to 4 carbon atoms or in which each alkyl portion forms, with the nitrogen atom to which it is attached, a saturated 5- or 6-membered heterocyclic radical optionally comprising a second hetero atom chosen from oxygen, sulphur and nitrogen atoms, and optionally substituted with an alkyl radical comprising 1 to 4 carbon atoms, a phenyl radical or a phenylalkyl radical in which the alkyl portion comprises 1 to 4
- R 5 represents
- an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain
- an alkenyloxy radical comprising 3 to 6 carbon atoms
- an alkynyloxy radical comprising 3 to 6 carbon atoms
- a cycloalkyloxy radical comprising 3 to 6 carbon atoms
- these radicals being optionally substituted with one or more identical or different halogen atoms or with an alkoxy radical comprising 1 to 4 carbon atoms, an alkylthio radical comprising 2 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, a cyano or carbamoyl radical, or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion comprises 1 to 4 carbon atoms or in which each alkyl portion forms, with the nitrogen atom to which it is attached, a saturated 5- or 6-membered heterocyclic radical optionally comprising a second hetero atom chosen from oxygen, sulphur and nitrogen atoms, and optionally substituted with an alkyl radical comprising 1 to 4 carbon atoms, a phenyl radical or a phenylalkyl radical in which the alkyl portion comprises 1 to 4
- R 3 is an aryl radical represented by a phenyl or ⁇ - or ⁇ -naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from fluorine, chlorine, bromine, and iodine atoms, and alkyl, alkenyl, alkynyl, phenyl, ⁇ - or ⁇ -naphthyl, arylalkyl, 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, it being
- R 3 can also be a 5-membered aromatic heterocyclic radical comprising one or more identical or different hetero atoms chosen from nitrogen, oxygen and sulphur atoms, and optionally substituted with one or more identical or different substituents chosen from fluorine, chlorine, bromine, and iodine atoms, alkyl radicals comprising 1 to 4 carbon atoms, aryl radicals comprising 6 to 10 carbon atoms, alkoxy radicals comprising 1 to 4 carbon atoms, aryloxy radicals comprising 6 to 10 carbon atoms, amino radicals, alkylamino radicals comprising 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion comprises 1 to 4 carbon atoms, acylamino radicals in which the acyl portion comprises 1 to 4 carbon atoms, alkoxycarbonylamino radicals comprising 1 to 4 carbon atoms, acyl radicals comprising 1 to 4 carbon atoms, arylcarbonyl
- the radicals R 4 and R 5 which may be identical or different, represent unbranched or branched alkoxy radicals comprising 1 to 6 carbon atoms, and 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 compounds of formula (I) in which Z represents a hydrogen atom or a radical of formula (II) in which R 1 represents a benzoyl radical or a radical R 2 —O—CO— in which R 2 represents a tert-butyl radical; R 3 represents an alkyl radical comprising 1 to 6 carbon atoms, an alkenyl radical comprising 2 to 6 carbon atoms, a cycloalkyl radical comprising 3 to 6 carbon atoms, a phenyl radical optionally substituted with one or more identical or different atoms or radicals chosen from fluorine and chlorine atoms, and methyl, methoxy, dimethylamino, acetylamino, tert-butoxycarbonylamino, trifluoromethyl, 2- or 3-furyl, 2- or 3-thienyl and 2-, 4- or 5-thiazolyl radicals; and R 4 and R 5 , which may be identical or different, represent an unbranched or
- the present invention relates to the compounds of formula (I) in which Z represents a hydrogen atom or a radical of formula (II) in which R 1 represents a benzoyl radical or a radical R 2 —O—CO— in which R 2 represents a tert-butyl radical, 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, represent a methoxy, ethoxy or propoxy radical.
- the present invention relates to 4 ⁇ -acetoxy-2 ⁇ -benzoyloxy-5 ⁇ ,20-epoxy-1 ⁇ -hydroxy-7 ⁇ ,10 ⁇ -dimethoxy-9-oxo-11-taxen-13 ⁇ -yl (2R, 3S)-3tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of formula (Ia)
- R represents a radical such that —OR has the same meaning as R 4 defined above
- X represents a reactive ester residue such as a sulphuric or sulphonic ester residue or a halogen atom
- 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 compound of formula (IV) in which R represents a radical such that —OR has the same meaning as R 5 defined above, to give the compound of formula (I) in which Z is equal to hydrogen.
- the next step comprises esterifying position 13, according to any known process in which the derivatives of formula (I), in which Z represents hydrogen, are reacted in the presence of a ⁇ -lactam, for example, according to the process described in European patent 617,018, the disclosure of which is incorporated by reference herein, or in the presence of an oxazolidine as described, for example, in International Publication WO 96/30355 mentioned above.
- an ester of formula (I) is obtained in which Z is other than hydrogen and R represents hydrogen.
- the next step comprises reacting the positions 7 and 10 simultaneously by the action of a reagent formed in situ from a sulphoxide of formula (V) and acetic anhydride (Pummerer-type reaction):
- R represents a radical such that —OR has the same meaning as R 4 or R 5 defined above, to form an alkylthioalkyloxy-type intermediate on positions 7 and 10.
- the action of the reagent formed in situ from a sulphoxide of formula (V), preferably dimethyl sulphoxide and acetic anhydride, is carried out in the presence of acetic acid or an acetic acid derivative such as haloaetic acid, at a temperature ranging from 0 to 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 (IIa) below:
- R 1 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, or haloaryl substituents, it being possible for the substituents to optionally form a 4- to 7-membered ring.
- the hydroxy protecting groups G in formula (IIa) can be chosen from all of the hydroxy protecting groups described in books such as Greene and Wuts, Protective Groups in Organic Synthesis, 1991, John Wiley & Sons, and MacOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press, the disclosures of which are incorporated by reference herein, so long as they can be deprotected under conditions which minimally degrade, or do not degrade, the rest of the molecule.
- the following protecting groups may be used:
- ethers preferably ethers such as methoxymethyl ether, 1-ethoxyethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, benzyl ethers optionally substituted with one or more identical or different groups such as methoxy, chloro, or nitro, 1-methyl-1-methoxyethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether and silyl ethers such as trialkylsilyl ethers, and
- carbonates such as trichlorethyl carbonates.
- radicals R a and R b of formula (IIb) are chosen from those described in International Publication WO 94/07878, the disclosure of which is incorporated by reference herein.
- 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 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 as the alkylating agent.
- 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
- mono- or dimetallic base mixtures such as those described, for example, in publications such as P. Caubère Chem. Rev. 1993, 93, 2317-2334 or M. Schlosser Mod. Synth. Methods (1992), 6, 227-271, the disclosures of which are incorporated by reference herein.
- the alkyllithium/alkali metal t-butoxide or alkali metal amide/alkali metal t-butoxide combinations are particularly preferred.
- One of the two bases can be generated “in situ”.
- 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:
- ethers such as tetrahydrofuran or dimethoxyethane
- polar aprotic solvents such as dimethylformamide, or aromatic solvents such as toluene
- alkylesters such as ethylacetate.
- the molar ratio between the anionization agent and the substrate is greater than 2, and more preferably ranges from 2 to 20.
- the molar ratio between the alkylating agent and the substrate is greater than 2, and preferably ranges from 2 to 40.
- reaction temperature ranging from ⁇ 30° C. to 80° C.
- reaction time advantageously ranges from a few hours to 48 hours depending on the reagents chosen.
- the resulting compound can then be esterified according to known processes, for example, those described in European patent EP 617,018 or International Publication WO 96/30355, mentioned above.
- the procedure begins with the dialkylation of 10-deacetylbaccatin, using an alkylating agent in the presence of a strong base.
- 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.
- 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 can also begin with the dialkylation of 1 0-deacetylbaccatin, using an alkylating agent in the presence of a strong base.
- 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.
- a baccatin suitably protected in positions 7 and 10 is esterified in position 13 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.
- Formulations suitable for oral administration mean formulations which are in a form suitable to be administered orally to a patient.
- the formulations may be presented as any suitable oral dosage form, such as, for example, capsules, cachets or tablets, each comprising a predetermined amount of the active ingredient, a powder or granules, a solution or a suspension in an aqueous liquid or a non-aqueous liquid, and an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- composition means a composition comprising a compound of formula (I) and at least one component chosen from pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
- suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances.
- antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
- suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, vegetable oils (such as olive oil), organic esters such as ethyl oleate, and suitable mixtures thereof.
- excipients include lactose, milk, sugar, sodium citrate, calcium carbonate, and dicalcium phosphate.
- disintegrating agents include starch, alginic acids and certain complex silicates.
- lubricants include magnesium stearate, sodium lauryl sulphate, talc, and high molecular weight polyethylene glycols.
- Liquid dosage form means that the dose of the active compound to be administered to the patient is in liquid form, such as, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan and phospholipids, a mixture of these substances, and the like
- Solid dosage form means the dosage form of the compound according to the invention is in solid form, such as, for example, capsules, tablets, pills, powders, dragees or granules.
- the compound according to the invention is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or with (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, for example, glycerol, (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, for example paraffin, (f) absorption
- fillers or extenders
- Formulation II 0.2 mg/ml of the compound of formula (la) was mixed in a solution comprising 5% ethanol, 5% Polysorbate 80, and 90% of an aqueous 5% glucose solution.
- mice 15 female C3H/HeN mice, each weighing approximately 20 g, were each administered Formulation II orally in a dose of 20.6 mg.kg ⁇ 1 per administration per mouse,12.8, 8.4 and 5.5 each day for 5 days.
- mice The animals subjected to the experiment, generally mice, were subcutaneously grafted bilaterally with 30 to 60 mg of a mammary tumor fragment (adenocarcinoma MA17/A) on day 0. The animals bearing tumors were mixed before being assigned to the various treatment and control groups. Chemotherapy generally began from 3 to 7 days after grafting, depending on the type of tumour, and the animals were observed every day. The different animal groups were weighed 3 or 4 times a week until the maximum weight loss was attained, and the groups were then weighed at least once a week until the end of the trial.
- a mammary tumor fragment adenocarcinoma MA17/A
- T/C tumor growth inhibitor
- T/C value in percent is an indication of antitumor effectiveness:
- T / C ⁇ ( % ) Median ⁇ ⁇ tumor ⁇ ⁇ weight ⁇ ⁇ of ⁇ ⁇ the ⁇ ⁇ Treated Median ⁇ ⁇ tumor ⁇ ⁇ weight ⁇ ⁇ of ⁇ ⁇ the ⁇ ⁇ Control ⁇ 100
- T/C ⁇ 42% is the minimal level to declare activity.
- a T/C ⁇ 10% is considered to indicate high antitumor activity and is the level used by NCI to justify further development (Decision Network-2 level, DN-2).
- the T/C value can be converted to an arbitrary activity rating according to the NCI criteria: NCI activity % T/C Highly active ++ ⁇ 10 Active + 11-42 Inactive ⁇ >42
- T ⁇ C represents the time in days for the tumors of the treated group (T) and the tumors of the non-treated group (C) to reach a predetermined value (750 mg for example).
- a predetermined value 750 mg for example.
- This method is described in T. H. CORBETT et al., Cancer, 40, 2660-2680 (1977); F.M. SCHABEL et al., Cancer Drug Development, Part B. Methods in Cancer Research, 17, 3-51, New York Academic Press Inc. (1979), the disclosure of which is incorporated by reference herein.
- a product is considered to be active if log 10 cells killed is greater than or equal to 0.7.
- a product is considered to be very active if log 10 cells killed is greater than 2.8.
- Results Time for Average body median Dosage weight change in Median tumor tumor in Total % per mouse weight in mg to reach T-C log Route mg/kg/ Schedule dose in Drug death (days post last on day 12 T/C in % 750 mg in cell Com- Agent volume dose in days mg/kg or death) treatment (day) (range) day 12 in days days kill ments Product p.o.
Abstract
Description
-
- in which:
-
- in which:
- R1 represents
- a benzoyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms, alkoxy radicals comprising 1 to 4 carbon atoms, and trifluoromethyl radicals,
- a thenoyl or furoyl radical,
- a radical R2—O—CO— in which R2 represents:
- an alkyl radical comprising 1 to 8 carbon atoms,
- an alkenyl radical comprising 2 to 8 carbon atoms,
- an alkynyl radical comprising 3 to 8 carbon atoms,
- a cycloalkyl radical comprising 3 to 6 carbon atoms,
- a cycloalkenyl radical comprising 4 to 6 carbon atoms, or
- a bicycloalkyl radical comprising 7 to 10 carbon atoms,
- these radicals being optionally substituted with one or more identical or different substituents chosen from halogen atoms, hydroxyl radicals, alkoxy radicals comprising 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion comprises 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals which are optionally substituted at position 4 with an alkyl radical comprising 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, cycloalkyl radicals comprising 3 to 6 carbon atoms, cycloalkenyl radicals comprising 4 to 6 carbon atoms, phenyl radicals which are optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms, and alkoxy radicals comprising 1 to 4 carbon atoms, cyano or carboxyl radicals, and alkoxycarbonyl radicals in which the alkyl portion comprises 1 to 4 carbon atoms,
- a phenyl or α- or β-naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms, alkyl radicals comprising 1 to 4 carbon atoms and alkoxy radicals comprising 1 to 4 carbon atoms,
- a 5-membered aromatic heterocyclic radical, preferably chosen from furyl and thienyl radicals, or
- a saturated heterocyclic radical comprising 4 to 6 carbon atoms, and optionally substituted with one or more identical or different alkyl radicals comprising 1 to 4 carbon atoms;
- R3 represents
- an unbranched or branched alkyl radical comprising 1 to 8 carbon atoms,
- an unbranched or branched alkenyl radical comprising 2 to 8 carbon atoms,
- an unbranched or branched alkynyl radical comprising 2 to 8 carbon atoms,
- a cycloalkyl radical comprising 3 to 6 carbon atoms,
- a phenyl or α- or β-naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, phenyl, α- or β-naphthyl, 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, it being understood that the alkyl radicals and alkyl portions of radicals comprise 1 to 4 carbon atoms, and the alkenyl and alkynyl radicals comprise 2 to 8 carbon atoms, or
- a 5-membered aromatic heterocyclic radical comprising one or more identical or different hetero atoms chosen from nitrogen, oxygen and sulphur atoms, and optionally substituted with one or more identical or different substituents chosen from halogen atoms and alkyl, phenyl, α- or β-naphthyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl radicals, it being understood that the alkyl radicals and alkyl portions of radicals comprise 1 to 4 carbon atoms, and the alkenyl and alkynyl radicals comprise 2 to 8 carbon atoms;
- R4 represents
- an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain,
- an alkenyloxy radical comprising 3 to 6 carbon atoms in an unbranched or branched chain,
- an alkynyloxy radical comprising 3 to 6 carbon atoms in an unbranched or branched chain,
- a cycloalkyloxy radical comprising 3 to 6 carbon atoms, or
- a cycloalkenyloxy radical comprising 4 to 6 carbon atoms,
- these radicals being optionally substituted with one or more identical or different halogen atoms or with an alkoxy radical comprising 1 to 4 carbon atoms, an alkylthio radical comprising 1 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, a cyano or carbamoyl radical, or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion comprises 1 to 4 carbon atoms or in which each alkyl portion forms, with the nitrogen atom to which it is attached, a saturated 5- or 6-membered heterocyclic radical optionally comprising a second hetero atom chosen from oxygen, sulphur and nitrogen atoms, and optionally substituted with an alkyl radical comprising 1 to 4 carbon atoms, a phenyl radical or a phenylalkyl radical in which the alkyl portion comprises 1 to 4 carbon atoms;
- R5 represents
- an alkoxy radical comprising 1 to 6 carbon atoms in an unbranched or branched chain,
- an alkenyloxy radical comprising 3 to 6 carbon atoms,
- an alkynyloxy radical comprising 3 to 6 carbon atoms,
- a cycloalkyloxy radical comprising 3 to 6 carbon atoms, or
- a cycloalkenyloxy radical comprising 3 to 6 carbon atoms,
- these radicals being optionally substituted with one or more identical or different halogen atoms or with an alkoxy radical comprising 1 to 4 carbon atoms, an alkylthio radical comprising 2 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion comprises 1 to 4 carbon atoms, a cyano or carbamoyl radical, or an N-alkylcarbamoyl or N,N-dialkylcarbamoyl radical in which each alkyl portion comprises 1 to 4 carbon atoms or in which each alkyl portion forms, with the nitrogen atom to which it is attached, a saturated 5- or 6-membered heterocyclic radical optionally comprising a second hetero atom chosen from oxygen, sulphur and nitrogen atoms, and optionally substituted with an alkyl radical comprising 1 to 4 carbon atoms, a phenyl radical or a phenylalkyl radical in which the alkyl portion comprises 1 to 4 carbon atoms.
- Preferably, R3 is an aryl radical represented by a phenyl or α- or β-naphthyl radical optionally substituted with one or more identical or different atoms or radicals chosen from fluorine, chlorine, bromine, and iodine atoms, and alkyl, alkenyl, alkynyl, phenyl, α- or β-naphthyl, arylalkyl, 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, it being understood that the alkyl radicals and alkyl portions of the other radicals comprise 1 to 4 carbon atoms, and the alkenyl and alkynyl radicals comprise 2 to 8 carbon atoms.
- Preferably, R3 can also be a 5-membered aromatic heterocyclic radical comprising one or more identical or different hetero atoms chosen from nitrogen, oxygen and sulphur atoms, and optionally substituted with one or more identical or different substituents chosen from fluorine, chlorine, bromine, and iodine atoms, alkyl radicals comprising 1 to 4 carbon atoms, aryl radicals comprising 6 to 10 carbon atoms, alkoxy radicals comprising 1 to 4 carbon atoms, aryloxy radicals comprising 6 to 10 carbon atoms, amino radicals, alkylamino radicals comprising 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion comprises 1 to 4 carbon atoms, acylamino radicals in which the acyl portion comprises 1 to 4 carbon atoms, alkoxycarbonylamino radicals comprising 1 to 4 carbon atoms, acyl radicals comprising 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion comprises 6 to 10 carbon atoms, cyano, carboxyl or carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion comprises 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion comprises 1 to 4 carbon atoms or alkoxycarbonyl radicals in which the alkoxy portion comprises 1 to 4 carbon atoms.
- Preferably, the radicals R4 and R5, which may be identical or different, represent unbranched or branched alkoxy radicals comprising 1 to 6 carbon atoms, and 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.
- More specifically, the present invention relates to the compounds of formula (I) in which Z represents a hydrogen atom or a radical of formula (II) in which R1 represents a benzoyl radical or a radical R2—O—CO— in which R2 represents a tert-butyl radical; R3 represents an alkyl radical comprising 1 to 6 carbon atoms, an alkenyl radical comprising 2 to 6 carbon atoms, a cycloalkyl radical comprising 3 to 6 carbon atoms, a phenyl radical optionally substituted with one or more identical or different atoms or radicals chosen from fluorine and chlorine atoms, and methyl, methoxy, dimethylamino, acetylamino, tert-butoxycarbonylamino, trifluoromethyl, 2- or 3-furyl, 2- or 3-thienyl and 2-, 4- or 5-thiazolyl radicals; and R4 and R5, which may be identical or different, represent an unbranched or branched alkoxy radical comprising 1 to 6 carbon atoms.
- Still more specifically, the present invention relates to the compounds of formula (I) in which Z represents a hydrogen atom or a radical of formula (II) in which R1 represents a benzoyl radical or a radical R2—O—CO— in which R2 represents a tert-butyl radical, R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, and R4 and R5, which may be identical or different, represent a methoxy, ethoxy or propoxy radical.
- Of even more special interest are the compounds of formula (I) in which Z represents a radical of formula (II) in which R1 represents a tert-butoxycarbonyl radical, R3 represents a phenyl radical, and R4 and R5, which may be identical or different, represent a methoxy, ethoxy or propoxy radical.
-
-
- is selectively protected in positions 7 and 13, for example with a silyl diether, and then reacted with a compound of general formula (IV):
- R—X (IV)
- in which R represents a radical such that —OR has the same meaning as R4 defined above, and X represents a reactive ester residue such as a sulphuric or sulphonic ester residue or a halogen atom, to give a compound bearing the unit —OR in position 10 and silyl groups in positions 7 and 13. Next, 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 compound of formula (IV) in which R represents a radical such that —OR has the same meaning as R5 defined above, to give the compound of formula (I) in which Z is equal to hydrogen.
- The next step comprises esterifying position 13, according to any known process in which the derivatives of formula (I), in which Z represents hydrogen, are reacted in the presence of a β-lactam, for example, according to the process described in European patent 617,018, the disclosure of which is incorporated by reference herein, or in the presence of an oxazolidine as described, for example, in International Publication WO 96/30355 mentioned above. After deprotection of the protecting groups in positions 7 and 10, an ester of formula (I) is obtained in which Z is other than hydrogen and R represents hydrogen. The next step comprises reacting the positions 7 and 10 simultaneously by the action of a reagent formed in situ from a sulphoxide of formula (V) and acetic anhydride (Pummerer-type reaction):
- R—SO—R (V)
- in which R represents a radical such that —OR has the same meaning as R4 or R5 defined above, to form an alkylthioalkyloxy-type intermediate on positions 7 and 10.
- 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.
- Generally, the action of the reagent formed in situ from a sulphoxide of formula (V), preferably dimethyl sulphoxide and acetic anhydride, is carried out in the presence of acetic acid or an acetic acid derivative such as haloaetic acid, at a temperature ranging from 0 to 50° C.
- Generally, 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.
- In French patent application FR 97-14442, the disclosure of which is incorporated by reference herein, another process for preparing a derivative according to the present invention has been described. This process allows, in a single step, the direct, selective and simultaneous alkylation of the two hydroxyl functions in positions 7 and 10 of formula (VI) below:
-
- in which G represents a hydroxy protecting group, and R1 and R3 have the same meaning as in formula (II) above,
-
- in which R1 and R3 have the same meaning as in formula (II), and Ra and Rb, which may be identical or different, represent hydrogen or alkyl, aryl, halo, alkoxy, arylalkyl, alkoxyaryl, haloalkyl, or haloaryl substituents, it being possible for the substituents to optionally form a 4- to 7-membered ring.
- It is preferred to use 10-deacetylbaccatin, i.e., the product of formula (III), as starting material, as the resulting process is more economical. It also avoids the intermediate protection and deprotection steps necessary in the known processes.
- The hydroxy protecting groups G in formula (IIa) can be chosen from all of the hydroxy protecting groups described in books such as Greene and Wuts, Protective Groups in Organic Synthesis, 1991, John Wiley & Sons, and MacOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press, the disclosures of which are incorporated by reference herein, so long as they can be deprotected under conditions which minimally degrade, or do not degrade, the rest of the molecule. For example, the following protecting groups may be used:
- ethers, preferably ethers such as methoxymethyl ether, 1-ethoxyethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, benzyl ethers optionally substituted with one or more identical or different groups such as methoxy, chloro, or nitro, 1-methyl-1-methoxyethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether and silyl ethers such as trialkylsilyl ethers, and
- carbonates such as trichlorethyl carbonates.
- More particularly, the radicals Ra and Rb of formula (IIb) are chosen from those described in International Publication WO 94/07878, the disclosure of which is incorporated by reference herein. The derivatives more particularly preferred are those in which Ra is hydrogen and Rb is a p-methoxyphenyl radical.
- The alkylating agent is chosen from:
- alkyl halides, preferably from alkyl iodides (RI),
- alkyl sulphates, such as methyl sulphate, and
- oxoniums, such as trialkyloxonium boric salts, in particular trimethyloxonium tetrafluoroborate (Me3OBF4).
- Methyl iodide is preferably used as the alkylating agent.
- The alkylating agent is used in the presence of an anionization agent such as one or more strong bases, in anhydrous medium.
- Among the bases which can be used in anhydrous medium, mention may be made of:
- alkali metal hydrides, such as sodium or potassium hydride,
- alkali metal alkoxides, such as potassium tert-butoxide,
- silver oxide Ag2O,
- 1,8-bis(dimethylamino)naphthalene, and
- mono- or dimetallic base mixtures, such as those described, for example, in publications such as P. Caubère Chem. Rev. 1993, 93, 2317-2334 or M. Schlosser Mod. Synth. Methods (1992), 6, 227-271, the disclosures of which are incorporated by reference herein. The alkyllithium/alkali metal t-butoxide or alkali metal amide/alkali metal t-butoxide combinations are particularly preferred. One of the two bases can be generated “in situ”.
- Among all of the possible combinations of alkylating agent and anionization agent, it is preferred to use 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. Among the solvents, it is preferred to use:
- ethers such as tetrahydrofuran or dimethoxyethane;
- when silver oxide is used as the anionization agent, it is preferred to use polar aprotic solvents such as dimethylformamide, or aromatic solvents such as toluene; and
- when 1,8-bis(dimethylamino)naphthalene is used as the anionization agent, it is preferred to use alkylesters such as ethylacetate.
- Preferably, the molar ratio between the anionization agent and the substrate is greater than 2, and more preferably ranges from 2 to 20.
- It is also preferred that the molar ratio between the alkylating agent and the substrate is greater than 2, and preferably ranges from 2 to 40.
- It is preferred to use a reaction temperature ranging from −30° C. to 80° C.
- The reaction time advantageously ranges from a few hours to 48 hours depending on the reagents chosen.
- After the alkylating step is carried out on 10-deacetylbaccatin, the resulting compound can then be esterified according to known processes, for example, those described in European patent EP 617,018 or International Publication WO 96/30355, mentioned above.
- Thus, according to a first, 3-step process, the procedure begins with the dialkylation of 10-deacetylbaccatin, using an alkylating agent in the presence of a strong base. In the second step, described in European patent 617,018 mentioned above, the 10-deacetylbaccatin dietherified in positions 7 and 10 is coupled, in position 13, with a suitably protected β-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.
- According to a second, 3-step process, the procedure can also begin with the dialkylation of 1 0-deacetylbaccatin, using an alkylating agent in the presence of a strong base. However, in the second step, described in International Publication WO 96/30355, 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.
- According to a third process, a baccatin suitably protected in positions 7 and 10 is esterified in position 13 with a β-lactam or an oxazolidine in the presence of a coupling agent and/or an activating agent as described in the above two processes. After deprotection in positions 7 and 10, 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.
- Formulations suitable for oral administration mean formulations which are in a form suitable to be administered orally to a patient. The formulations may be presented as any suitable oral dosage form, such as, for example, capsules, cachets or tablets, each comprising a predetermined amount of the active ingredient, a powder or granules, a solution or a suspension in an aqueous liquid or a non-aqueous liquid, and an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
- Pharmaceutical composition means a composition comprising a compound of formula (I) and at least one component chosen from pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Examples of suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, vegetable oils (such as olive oil), organic esters such as ethyl oleate, and suitable mixtures thereof. Examples of excipients include lactose, milk, sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, and high molecular weight polyethylene glycols.
- Liquid dosage form means that the dose of the active compound to be administered to the patient is in liquid form, such as, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan and phospholipids, a mixture of these substances, and the like.
- Solid dosage form means the dosage form of the compound according to the invention is in solid form, such as, for example, capsules, tablets, pills, powders, dragees or granules. In such solid dosage forms, the compound according to the invention is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or with (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, for example, glycerol, (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, for example paraffin, (f) absorption accelerators, for example, quaternary ammonium compounds, (g) wetting agents, for example, acetyl alcohol and glycerol monostearate, (h) adsorbents, for example, kaolin and bentonite, (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols and sodium lauryl sulfate, (j) pacifying agents, (k) buffering agents, or agents which release the compound according to the invention in a certain part of the intestinal tract in a delayed manner.
- The invention will be more accurately defined by the following examples which must not be considered as limiting the present invention.
- Formulation II: 0.2 mg/ml of the compound of formula (la) was mixed in a solution comprising 5% ethanol, 5% Polysorbate 80, and 90% of an aqueous 5% glucose solution.
- 15 female C3H/HeN mice, each weighing approximately 20 g, were each administered Formulation II orally in a dose of 20.6 mg.kg−1 per administration per mouse,12.8, 8.4 and 5.5 each day for 5 days.
- Animals: The animals subjected to the experiment, generally mice, were subcutaneously grafted bilaterally with 30 to 60 mg of a mammary tumor fragment (adenocarcinoma MA17/A) on day 0. The animals bearing tumors were mixed before being assigned to the various treatment and control groups. Chemotherapy generally began from 3 to 7 days after grafting, depending on the type of tumour, and the animals were observed every day. The different animal groups were weighed 3 or 4 times a week until the maximum weight loss was attained, and the groups were then weighed at least once a week until the end of the trial.
- Efficacy: The efficacy of the new pharmaceutical form was evaluated by:
- the tumor growth inhibitor (T/C)
-
- According to NCI standards, a T/C<42% is the minimal level to declare activity. A T/C<10% is considered to indicate high antitumor activity and is the level used by NCI to justify further development (Decision Network-2 level, DN-2).
- The T/C value can be converted to an arbitrary activity rating according to the NCI criteria:
NCI activity % T/C Highly active ++ ≦10 Active + 11-42 Inactive − >42 - and quantified by the log cell kill which is determined by the following formula:
- log10 cells killed=T−C(days)/3.32×Td
- in which T−C represents the time in days for the tumors of the treated group (T) and the tumors of the non-treated group (C) to reach a predetermined value (750 mg for example). This method is described in T. H. CORBETT et al., Cancer, 40, 2660-2680 (1977); F.M. SCHABEL et al., Cancer Drug Development, Part B. Methods in Cancer Research, 17, 3-51, New York Academic Press Inc. (1979), the disclosure of which is incorporated by reference herein. A product is considered to be active if log10 cells killed is greater than or equal to 0.7. A product is considered to be very active if log10 cells killed is greater than 2.8.
- Results:
Time for Average body median Dosage weight change in Median tumor tumor in Total % per mouse weight in mg to reach T-C log Route mg/kg/ Schedule dose in Drug death (days post last on day 12 T/C in % 750 mg in cell Com- Agent volume dose in days mg/kg or death) treatment (day) (range) day 12 in days days kill ments Product p.o. 20.6 3 to 7 103.0 5/5(7,2d8,10,11) — — — — — — Toxic of 0.2 ml 12.8 64.0 0/5 −17.9(10) 0(0-0) 0 25.9 13.8 3.2 HNTD formula highly IA active 8.4 42.0 0/5 −11.0(9) 0(0-268) 0 18.2 6.1 1.4 Active 5.5 27.5 0/5 +0.2(8) 271(107-432) 38 14.4 2.3 0.5 Inactive Control 704(312-864) 12.1
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JP5566466B2 (en) | 2009-10-29 | 2014-08-06 | アバンテイス・フアルマ・エス・アー | Novel anti-tumor use of cabazitaxel |
WO2012088445A1 (en) | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
US20130331443A1 (en) | 2010-12-22 | 2013-12-12 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
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US5847170A (en) * | 1995-03-27 | 1998-12-08 | Rhone-Poulenc Rorer, S.A. | Taxoids, their preparation and pharmaceutical compositions containing them |
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