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WO2012131035A1 - Composition comprenant du docétaxel - Google Patents

Composition comprenant du docétaxel Download PDF

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Publication number
WO2012131035A1
WO2012131035A1 PCT/EP2012/055786 EP2012055786W WO2012131035A1 WO 2012131035 A1 WO2012131035 A1 WO 2012131035A1 EP 2012055786 W EP2012055786 W EP 2012055786W WO 2012131035 A1 WO2012131035 A1 WO 2012131035A1
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WIPO (PCT)
Prior art keywords
composition
compound
cancer
docetaxel
disease
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Ceased
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PCT/EP2012/055786
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English (en)
Inventor
Fiona Mclaughlin
Joe Lewis
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Elara Pharmaceuticals GmbH
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Elara Pharmaceuticals GmbH
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Filing date
Publication date
Application filed by Elara Pharmaceuticals GmbH filed Critical Elara Pharmaceuticals GmbH
Publication of WO2012131035A1 publication Critical patent/WO2012131035A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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

Definitions

  • composition comprising docetaxel
  • the present invention relates to a composition comprising docetaxel or a solvate thereof.
  • the invention also relates to said composition for use as a medicament, especially for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, to the use of said composition for preparing a medicament for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, and to a method for treating or preventing hyperproliferative diseases, such as tumor or cancer diseases or precancerosis, by administering said composition.
  • Docetaxel (also known under the trade name Taxotere® from Sanofi Aventis) is a well- known anti-mitotic chemotherapy agent mainly used in the treatment of non-small cell lung, breast, ovarian, advanced stomach, head and neck and metastatic prostate cancer.
  • Docetaxel belongs to the taxanes and is a semisynthetic analogue of paclitaxel. It is synthesized by esterification of 10-deacetyl baccatin III, which is in turn extracted from European yew tree.
  • the antitumor activity of docetaxel is attributed to its effect on microtubule dynamics: It stabilizes GDP-bound tubulin in the microtubule, thus blocking dynamic instability and preventing depolymerisation (i.e. it works as a polymerization agonist), even if hydrolysis of GTP reaches the tip of the microtubule. As a result, mitosis in the respective tumor cell is blocked.
  • WO 2010/075859 describes sulphonanilide compounds which are supposed to act as inhibitors of tubulin polymerization (i.e. they work as a polymerization antagonist). Their antitumor activity is thus based on depolymerisation of tubulin, which leads to mitotic arrest and apoptosis of the tumor cell.
  • docetaxel has a good microtubule-targeting activity, due to possible side effects and the possible development of drug resistance, there is an ongoing need to provide further active compounds or compositions with an improved activity in the treatment of hyperproliferative diseases, such as cancer diseases. It was surprisingly found that the combined administration of docetaxel or solvate thereof and certain sulphonanilide compounds described in WO 2010/075859, namely the compounds of the formula I described hereinbelow, provides a higher
  • docetaxal and the sulphonanilide compounds should have an antipodal activity on microtubule dynamics.
  • the invention relates to a composition
  • a composition comprising docetaxel or a solvate thereof and at least one compound of formula I or a pharmacologically acceptable salt thereof
  • R 1 is selected from Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy;
  • R 2 is selected from hydrogen and Ci-C3-alkyl;
  • R 3 is selected from Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the composition of the invention and at least one
  • the present invention relates to the composition of the invention for the use as a medicament and to the composition of the invention for treating or preventing a hyperproliferative disease.
  • the present invention relates to the use of docetaxel or a solvate thereof in combination with at least one compound I or a pharmacologically acceptable salt thereof for the preparation of a medicament for treating or preventing a hyperproliferative disease.
  • the present invention relates to the use of a composition according to the invention for the preparation of a medicament for treating or preventing a hyperproliferative disease.
  • the present invention relates to a method for treating or preventing a hyperproliferative disease, said method comprising administering an effective amount of docetaxel or a solvate thereof in combination with an effective amount of at least one compound of formula I or a pharmacologically acceptable salt thereof to a subject in need thereof.
  • the present invention relates to a method for treating or preventing a hyperproliferative disease, said method comprising administering an effective amount of a composition according to the invention to a subject in need thereof.
  • docetaxel intends to include both the compound (2R,3S)-4-Acetoxy-2a-benzyloxy-13-[3-(N-tert-butoxycarbonyl)amino-2-hydroxy-3- phenyl]propionyl-5p,20-epoxy-1 ,7p,10p-trihydroxy-9-oxotax-1 1-en-13a-ylester (lUPAC) and the solvates thereof as defined below.
  • Docetaxel may also be termed as (2R,3S)-N-(tert-Butoxycarbonyl)-2-hydroxy-3-phenyl-p-alanin-(4-acetoxy-2a- benzoyloxy-5p,20-epoxy-1 ,7 ⁇ , 10p-trihydroxy-9-oxo-1 1 -taxen-13a-ylester),
  • Benzenepropanoic acid beta-(((1 ,1 -dimethylethoxy)carbonyl)amino)-alpha-hydroxy-, (2aR,4S,4aS,6R,9S,1 1 S,12S,12aR,12bS)-12b-(acetyloxy)-12-(benzoyloxy)- 2a,3,4,4a,5,6,9, 10,1 1 ,12,12a,12b-dodecahydro-4,6, 1 1 -trihydroxy-4a,8, 13,13- tetramethyl-5-oxo-7,1 1 -methano-1 H-cyclodeca(3,4)benz(1 ,2-b)oxet-9-yl ester,
  • the composition according to the invention may be a physical mixture of docetaxel or a solvate thereof and the at least one compound of the formula I or its salt. Accordingly, the invention also provides a mixture comprising docetaxel or a solvate thereof and at least one compound of the formula I or a pharmacologically acceptable salt thereof. However, the composition may also be any combination of docetaxel or a solvate thereof and at least one compound I, it not being required for docetaxel or a solvate thereof and compound(s) I to be present together in the same formulation.
  • kits of parts An example of a composition according to the invention, in which the docetaxel or a solvate thereof and at least one compound I are not present together in the same formulation, is a kit of parts.
  • a kit of parts two or more components of a kit are packaged separately, i.e., not p re-formulated.
  • kits include one or more separate containers, such as blister packages, vials, cans, bottles, pouches, bags or canisters, each container containing a separate component of the composition.
  • the present invention also relates to kit of parts comprising docetaxel or a solvate thereof and at least one compound I or a pharmacologically acceptable salt thereof.
  • One example is a two-component kit.
  • the present invention also relates to a two-component kit, comprising a first component which, in turn, comprises docetaxel or a solvate thereof and optionally a liquid or solid carrier and, if appropriate, at least one customary auxiliary, and a second component which, in turn, comprises at least one compound I or a pharmacologically acceptable salt thereof and optionally a liquid or solid carrier and, if appropriate, at least one customary auxiliary.
  • Suitable liquid and solid carriers and customary auxiliaries are described below.
  • the composition of the invention is not a physical mixture of docetaxel or a solvate thereof and the at least one compound of formula I or its salt, but any combination of docetaxel or a solvate thereof and at least one compound I, in which the two components are not present together in the same formulation, such a kit of parts, especially a two-(or more)-component-kit.
  • the time interval between the treatment with docetaxel or a solvate thereof and the at least one compound I or its salt is preferably in the range of from some seconds up to one month, preferably from some seconds up to two weeks, more preferably from some seconds up to one week and in particular from some seconds up to three days.
  • These time intervals refer to the shortest administration intervals of the single, different components within a therapeutic phase. It is, however, of course possible that in a therapeutic phase only one component of the composition of the invention is administered.
  • a therapeutic phase is characterized in that between two phases, administration of docetaxel or a solvate thereof and the at least one compound I or its salt is interrupted for at least one week, preferably for at least two weeks and more preferably for at least three weeks.
  • the time interval between the end of a phase and the beginning of the subsequent phase with a different active compound is preferably in the range of from one week to two months, preferably from two weeks to one month.
  • docetaxel or a solvate thereof is administered as allowed by the regulatory agencies, and the at least one compound I or its salt is administered during the same time period once or several times, e.g. 4 to 35 times, preferably 6 to 30 times and specifically 6 to 15 times.
  • docetaxel or a solvate thereof is administered 1 , 2 or 3 times within three weeks with approximately equal intervals bet- ween the single administrations (if it is administered twice or thrice), and the at least one compound I or its salt is administered during this time 4 to 35 times, preferably 6 to 30 times and specifically 6 to 15 times, where the at least one compound I or its salt can be administered once or several times a day, e.g. once, twice or three times a day, specifically twice a day.
  • Ci-C3-Alkyl is a straight-chain or branched alkyl group having from 1 to 3 carbon atoms. Examples are methyl, ethyl, n-propyl and isopropyl.
  • Ci-C3-Haloalkyl is a straight-chain or branched alkyl group having 1 to 3 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1 , 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by halogen atoms as mentioned above. Examples are chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl,
  • difluoromethyl trifluoromethyl, bromomethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 -fluoroethyl, 2-chloroethyl, 2- bromoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl,
  • Ci-C3-Alkoxy is a straight-chain or branched alkyl group having from 1 to 3 carbon atoms, which is bound to the remainder of the molecule via an oxygen atom. Examples include methoxy, ethoxy, n-propoxy and isopropoxy.
  • Ci-C3-Haloalkoxy is a straight-chain or branched alkoxy group having from 1 to 3, wherein at least one, e.g. 1 , 2, 3, 4 or all of the hydrogen atoms are replaced by a halogen atoms, in particular fluorine atoms, such as in fluoromethoxy, difluoromethoxy, trifluoromethoxy, (R)-l -fluoroethoxy, (S)-l -fluoroethoxy, 2-fluoroethoxy, 1 .1 - difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1 ,1 ,2,2-tetrafluoroethoxy, (R)-l -fluoropropoxy, (S)-l -fluoropropoxy, (R)-2-fluoropropoxy, (S)-2-fluoropropoxy, 3-fluoropropoxy, 1 ,1 -difluor
  • Suitable pharmacologically acceptable salts used in the composition of the present invention are salts of compounds I, wherein R 2 is a hydrogen atom. This hydrogen atom is acidic and thus can be removed by a base.
  • Suitable salts include alkali metal salts, such as the sodium or potassium salt, alkaline earth metal salts, such as the magnesium or calcium salt, and ammonium salts, such as ammonium or
  • the neutral forms of the compounds may be regenerated by contacting the salt with an acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the compounds used according to the present invention can be used in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide docetaxel or a solvate thereof or a compound of general formula I.
  • a prodrug is a pharmacologically active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound as used in this invention following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds as used in the present invention by chemical or biochemical methods in an ex vivo environment.
  • prodrugs can be slowly converted to the compounds used in the present invention when placed in a transdermal patch reservoir with a suitable enzyme.
  • suitable enzyme e.g., acetylase
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • prodrugs involving esters see Svensson and Tunek, Drug Metabolism Reviews 16.5 (1988), and Bundgaard, Design of Prodrugs, Elsevier (1985).
  • Examples of a masked acidic anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)
  • drugs containing an acidic NH group such as compounds I
  • compounds I have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 0 039 051 (Sloan and Little, Apr. 1 1 , 1981 ) discloses
  • the compounds used in the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • docetaxel can be used in unsolvated form or as a solvate, preferably as a hydrate and especially as its trihydrate.
  • docetaxel as used in the context of the present invention relates both to the unsolvated form of docetaxel as well as to its solvates, preferably hydrates and especially its trihydrate.
  • Certain compounds used in the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses
  • the compounds used in the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • An isotopic variation of an agent of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes, such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the agent of the present invention and
  • pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. All isotopic variations of the compounds and compositions of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • R 1 is preferably Ci-C3-alkoxy or Ci-C3-haloalkoxy and more preferably Ci-C3-alkoxy. In particular it is methoxy.
  • R 2 is preferably hydrogen or methyl and in particular hydrogen.
  • R 3 is preferably Ci-C3-alkyl or Ci-C3-haloalkyl, more preferably Ci-C3-alkyl and is in particular methyl.
  • R 1 is methoxy
  • R 2 is hydrogen
  • R 3 is methyl
  • the compound of formula I is a compound of formula la
  • R 1 , R 2 and R 3 have one of the above-given general or, in particular, one of the above-given preferred meanings.
  • R 1 is methoxy
  • R 2 is hydrogen
  • R 3 is methyl
  • docetaxel calculated as trihydrate
  • the at least one compound of formula I are preferably contained in a weight ratio of from 20:1 to 1 :20, more preferably from 5:1 to 1 :20, even more preferably from 2:1 to 1 :15, in particular from 1 :1 to 1 :15 and specifically from 1 :2 to 1 :15, e.g. 1 :5 to 1 :15 or 1 :5 to 1 :13.
  • the above weight ratios refer to the total amount of docetaxel (calculated as trihydrate) and the at least one compound of formula I (or la) used in a therapeutical phase or during the whole therapy. In case that in a therapeutical phase only one component is used, the weight ratios refer to the total amounts of docetaxel (calculated as trihydrate) and the at least one compound of formula I (or la) used during the whole therapy.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the composition according to the invention and at least one physiologically acceptable carrier and/or auxiliary substance.
  • the invention provides a therapeutical composition which, in addition to docetaxel or a solvate thereof and the at least one compound of formula I or its salt, comprises at least one further pharmaceutically active compound that is useful to treat one of the aforementioned or below mentioned diseases or disorders.
  • a therapeutical composition which, in addition to docetaxel or a solvate thereof and the at least one compound of formula I or its salt, comprises at least one further pharmaceutically active compound that is useful to treat one of the aforementioned or below mentioned diseases or disorders.
  • Such therapeutical compositions are useful because the therapeutic efficiency of the composition of the invention can be amplified by the presence of said at least one further pharmaceutically active compound and vice versa.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising docetaxel or a solvate thereof, at least one compound I or a salt thereof and a further therapeutic agent useful for the treatment or prevention of a disease or disorder selected from hyperproliferative diseases or disorders, and, optionally, a pharmaceutically acceptable carrier or excipient.
  • Such compositions are also useful to obtain synergistic therapeutic effects and also to prevent drug resistance of tumor cells, for example. It is also for these reasons, that current chemotherapy generally involves administering a cocktail of different cytotoxic and/or cytostatic compounds to improve the effectiveness of the treatment and reduce the possibility of tumor cell adaptation.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising docetaxel or a solvate thereof and at least one compound of formula I or a salt thereof in combination with radiation therapies.
  • composition of the present invention may be admixed with a pharmaceutically acceptable diluent, excipient or carrier, or a mixture thereof.
  • a pharmaceutically acceptable diluent e.g., as pure substances or as a mixture of pure substances
  • docetaxel or a solvate thereof and the at least one compound of formula I or its salt can be administered as such, i.e. as pure substances or as a mixture of pure substances, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy.
  • compositions may be for human or animal usage in human and veterinary medicine.
  • Suitable pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 80%, more preferably from 20% to 70% of total active compounds.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compounds with encapsulating material as a carrier providing a capsule in which the active component(s), with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component(s) is/are dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. Liquid forms are particularly preferred for topical applications to the eye. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component(s) in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component(s) in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • These preparations may contain, in addition to the active component(s), colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical composition is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • HIF inhibitors can prevent the development of tumor resistance towards chemotherapeutic drugs and can make cancer cells more sensitive towards radiotherapy (see e.g. Palayoor ST, et al., Int J Cancer, 2008 Nov 15;123(10):2430-7 and Gregg L. Semenza, Nature Reviews, Oct. 2003, vol. 3).
  • useful further therapeutic agents that can be combined with the composition of the invention to produce the pharmaceutical composition of the invention include, without limitation, a HIF-1 inhibitor, a cytotoxic compound and cytostatic compounds.
  • a HIF-1 inhibitor can be e.g.
  • PX-478 S-2-amino- 3-[4'-/V,/V,-bis(2-chloroethyl)amino]phenyl propionic acid /V-oxide dihydrochloride
  • a topoisomerase-1 inhibitor such as 8,9-dimethoxy-5-(2-/V,/V-dimethylaminoethyl)-2,3- methylenedioxy-5/-/-dibenzo[c,/7][1 ,6] naphthyridin-6-one (also known as ARC-1 1 1 or topovale) or (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 /-/-pyrano[3',4':6,7] indolizino [1 ,2-£>]quinoline-3,14-(4/-/ ,12/-/)-dione monohydrochloride (also referred to as tropotec
  • the MEK1 inhibitor PD98059 a soluble guanyl cyclase stimulator such as 3-(5'hydroxymethyl-2'-furyl)- 1 -benzylindazole (YC-1 ); a heat-shock protein 90 inhibitor, in particular radicicol, the radicicol analogue KF58333 or geldanamycin; a microtubule disrupting agent, in particular, e.g. taxol, vincristine or 2-methoxyestradiol; a histone deacetylase inhibitor, e.g. FK228; a thioredoxin inhibitor, in particular, PX-12 or pleurotin; UCNO-1 ;
  • cytotoxic or cytostatic compounds are known to the expert artisan skilled in the therapy of hyperproliferative diseases or disorders such as a tumor or cancer disease.
  • cytotoxic and cytostatic compounds include, but are not limited to, pure or mixed anti-estrogens, such as faslodex, tamoxifen or raloxifen; any inhibitors of topoisomerase I or II, such as camptothecin (topo I) or etoposide (topo II); any compound that acts through inhibiting aromatase activity, such as anastrozole or letrozole; any preparation that interferes with HEF2 signalling, such as herceptin; any compound that interchelates DNA, such as doxorubicin.
  • cytostatic or cytotoxic drugs which can be combined with the compounds of the present invention are alkylating substances, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, anti-androgenes, anti-estrogens, platinum compounds, hormones and antihormones, interferons and inhibitors of cell cycle- dependent protein kinases (CDKs), inhibitors of cyclooxygenases and/or
  • lipoxygenases biogeneic fatty acids and fatty acid derivatives, including prostanoids and leukotrienes, inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethyleneimenes, methylmelamines, trazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkylsulfonates, folic acid analogs, anthracendiones, substituted urea, methylhydrazin derivatives, in particular acediasulfone, aclarubicine, ambazone, aminoglutethimide, L- asparaginase, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, carpecitabine, carmustine, celecoxib, chlorambucil, cis-platin, cladribine,
  • cyclophosphamide cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide fosfestrol, furazolidone, gemcitabine, gonadotropin releasing hormone analog, hexamethylmelamine, hydroxycarbamide, hydroxymethylnitrofurantoin,
  • hydroxyprogesteronecaproat hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon ⁇ , irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, mechlorethamine, medroxyprogesterone acetate, megastrolacetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustards, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine
  • sulfaguanidine sulfaguanole, sulfamethizole, sulfamethoxazole, co-trimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tertiposide, testolactone, testosteronpropionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, UCN-01 , vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and
  • compositions of the present invention are administered simultaneously for cancer therapy and, consequently, it is also envisioned that more than one cytostatic and/or cytotoxic drug can be comprised in compositions of the present invention.
  • HIF inhibitors render cancer cells more vulnerable to
  • the composition of the present invention can be co-administered with other active medicinal agents and/or administered in conjunction with other anticancer, antitumor, or antiproliferative disease therapies.
  • the invention provides a method for treating a hyperproliferative disease or disorder comprising administering a compound according to the invention to a patient prior to, during and/or after said patient was subjected to a radiation therapy, a chemotherapy, an immunotherapy, a laser/microwave thermotherapy or a gene therapy using antisense DNA and RNA (for examples see Moeller et al., Cancer Cell 2004 5429-441 ).
  • the invention provides, as already outlined above, the use of the composition according to the invention or of a therapeutic or pharmaceutical composition according to the invention for the preparation of a medicament for the therapy, including the treatment or prevention, of a disease or disorder selected from hyperproliferative diseases or disorders.
  • the composition of the invention shows anti-proliferative effects.
  • the hyperproliferative disease is preferably selected from tumour or cancer diseases, precancerosis, dysplasia, histiocytosis, vascular proliferative diseases and virus-induced proliferative diseases.
  • the hyperproliferative disease is a tumor or cancer disease selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T-cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, glioma, bone cancer and soft-tissue sarcomas, common solid tumors of adults, such as head and neck
  • DLBCL diffuse large B
  • genitourinary cancers e.g., prostate, bladder, renal (in particular malignant renal cell carcinoma (RCC)), uterine, ovarian, testicular, rectal, and colon
  • lung cancer e.g., small cell carcinoma and non-small cell lung carcinoma, including squamous cell carcinoma and adenocarcinoma
  • breast cancer pancreatic cancer, melanoma and other skin cancers, basal cell carcinoma, metastatic skin carcinoma, squamous cell carcinoma of both ulcerating and papillary type, stomach cancer, brain cancer, liver cancer, adrenal cancer, kidney cancer, thyroid cancer, medullary carcinoma, osteosarcoma, soft-tissue sarcoma, Ewing's sarcoma, veticulum cell sarcoma, and Kaposi's sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, an
  • the precancerosis treatable with the composition of the present invention are preferably selected from the group consisting of precancerosis, in particular actinic keratosis, cutaneaous horn, actinic cheilitis, tar keratosis, arsenic keratosis, x-ray keratosis, Bowen's disease, bowenoid papulosis, lentigo maligna, lichen sclerosus, and lichen rubber mucosae; precancerosis of the digestive tract, in particular erythroplakia, leukoplakia, Barrett's esophagus, Plummer-Vinson syndrome, crural ulcer, gastropathia hypertrophica gigantea, borderline carcinoma, neoplastic intestinal polyp, rectal polyp, porcelain gallbladder; gyn
  • Dysplasia is frequently a forerunner of cancer, and is can be found in e.g. the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism. Dysplasia characteristically occurs where there exists chronic irritation or inflammation.
  • Dysplastic disorders which can be treated with the composition of the present invention include, but are not limited to, anhidrotic ectodermal dysplasia, anterofacial dysplasia, asphyxiating thoracic dysplasia, atriodigital dysplasia, bronchopulmonary dysplasia, cerebral dysplasia, cervical dysplasia, chondroectodermal dysplasia, cleidocranial dysplasia, congenital ectodermal dysplasia, craniodiaphysial dysplasia,
  • craniocarpotarsal dysplasia craniometaphysial dysplasia, dentin dysplasia, diaphysial dysplasia, ectodermal dysplasia, enamel dysplasia, encephalo-ophthalmic dysplasia, dysplasia epiphysialis heminelia, dysplasia epiphysialis multiplex, dysplasia epiphysalis punctata, epithelial dysplasia, faciodigitogenital dysplasia, familial fibrous dysplasia of jaws, familial white folded dysplasia, fibromuscular dysplasia, fibrous dysplasia of bone, florid osseous dysplasia, hereditary renal-retinal dysplasia hidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia, lymphopenic thymic dysplasia, mammary dysplasia, mandibulofacial dysplasi
  • the progesterone receptor also known as NR3C3 (nuclear receptor subfamily 3, group C, member 3), is an intracellular steroid receptor that specifically binds progesterone.
  • PR is encoded by a single PGR gene residing on chromosome 1 1 q22, it has two main forms, A and B, that differ in their molecular weight.
  • Progesterone and the progesterone receptor have been implicated in many diseases, such as cancer, diabetes and hormone resistance syndromes. It was found that the compound of the formula I, as defined herein, acts as an antagonist of the progesterone receptor and is capable of inhibiting progesterone receptor-mediated transcriptional activity.
  • the composition of the invention can be used to treat said diseases.
  • the hyperproliferative disorders treatable according to the invention are those which benefit from a reduced progesterone receptor signalling, i.e. disorders associated with an increased progesterone receptor signalling, if compared to healthy tissue.
  • a reduced progesterone receptor signalling i.e. disorders associated with an increased progesterone receptor signalling
  • preferred diseases, conditions and/or disorders which can be treated are selected from the group consisting of mammary tumors (see e.g.
  • Whether a disease is associated with an increased progesterone receptor activity can be measured by a variety of art known methods including determination of PR expression level in the diseased tissue by, e.g. immunological methods, which determine the amount of expressed protein, by methods determining the amount of transcribed PR encoding nucleic acids, e.g.
  • the disorders which benefit from a reduced progesterone receptor signalling are those which show in the diseased tissue an increase in progesterone receptor signalling by at least 10%, preferably by at least 20%, 30%, 40%, 50%, 60%, 70%, if compared to healthy tissue.
  • this increase is measured on the basis of a nucleic acid comprising a PR-receptor recognition element and the increase of the expression of a reporter driven by this element.
  • the androgen receptor also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus.
  • the androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor. Testosterone, dihydrotestosterone and the androgen receptor have been implicated in many diseases such as cancer. It was found that the compound of the formula I, as defined herein, acts as an antagonist of the androgen receptor and is capable of inhibiting androgen receptor-mediated activity.
  • the composition of the invention can be used to treat diseases associated with androgen receptor-mediated activity.
  • the hyperproliferative disorders treatable according to the invention are those which benefit from a reduced androgen receptor signalling, i.e. disorders associated with an increased androgen receptor signalling, if compared to healthy tissue.
  • a reduced androgen receptor signalling i.e. disorders associated with an increased androgen receptor signalling
  • This particular suitability of the composition of the present invention is based on the fact that the composition of the present invention potentially through inhibiting cellular replication, but possibly also through an additional activity exerts an inhibition of androgen receptor signalling.
  • preferred diseases, conditions and/or disorders which can be treated are prostate cancer.
  • the hyperproliferative diseases and disorders to be treated according to the present invention are preferably selected from tumor or cancer disease and precancerosis.
  • lung cancer e.g. small cell carcinoma and non-small cell lung carcinoma, including squamous cell carcinoma and
  • the hyperproliferative diseases are selected from non-small cell lung cancer, metastatic breast cancer and node positive breast cancer and prostate cancer.
  • the composition of the invention is used for treating prostate cancer.
  • composition according to the invention can be administered by various well known routes, including oral, rectal, intragastrical, intracranial and parenteral administration, e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes.
  • parenteral administration and particular intravenous e.g. intravenous, intramuscular, intranasal, intradermal, subcutaneous, and similar administration routes.
  • the composition of the invention is formulated as a syrup, an infusion or injection solution, a tablet, a capsule, a capslet, lozenge, a liposome, a suppository, a plaster, a band-aid, a retard capsule, a powder, or a slow release formulation.
  • the diluent is water, a buffer, a buffered salt solution or a salt solution and the carrier preferably is selected from the group consisting of cocoa butter and vitebesole.
  • compositions of the invention are forms suitable for injection and include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the final solution or dispersion form must be sterile and fluid.
  • a solution or dispersion will include a solvent or dispersion medium, containing, for example, water-buffered aqueous solutions, e.g. biocompatible buffers, ethanol, polyol, such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof, surfactants or vegetable oils.
  • the composition of the invention can also be formulated into liposomes, in particular for parenteral
  • Liposomes provide the advantage of increased half life in the circulation, if compared to the free drug and a prolonged more even release of the enclosed drug.
  • Sterilization of infusion or injection solutions can be accomplished by any number of art recognized techniques including but not limited to addition of preservatives like antibacterial or anti-fungal agents, e.g. parabene, chlorobutanol, phenol, sorbic acid or thimersal.
  • isotonic agents such as sugars or salts, in particular sodium chloride may be incorporated in infusion or injection solutions.
  • sterile injectable solutions containing one or more of the compounds of the composition of the invention is accomplished by incorporating the respective compound(s) in the required amount in the appropriate solvent with various ingredients enumerated above as required followed by sterilization. To obtain a sterile powder the above solutions are vacuum-dried or freeze-dried as necessary.
  • Preferred diluents of the present invention are water, physiological acceptable buffers, physiological acceptable buffer salt solutions or salt solutions.
  • Preferred carriers are cocoa butter and vitebesole.
  • binders such as lactose, mannitol, crystalline sorbitol, dibasic phosphates, calcium phosphates, sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone and the like;
  • lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerids and sodium stearyl fumarates,
  • disintegrants such as starches, croscaramellose, sodium methyl cellulose, agar, bentonite, alginic acid, carboxymethyl cellulose, polyvinyl pyrrolidone and the like.
  • Docetaxel (as well as its solvates) is preferably administered as is recommended by the producer, i.e. preferably in an amount of from 60 to 100 mg/m 2 , more preferably from 70 to 80 mg/m 2 , specifically about 75 mg/m 2 per single
  • the average single administration (single dose) of the compound I or its salt in the therapeutic or prophylactic use of the invention is preferably in the range from 10 to 100, preferably from 20 to 70, more preferably from 25 to 60, in particular from 25 to 50 mg/m 2 , calculated as free compound I.
  • the frequency of the administration of the active compounds and specific therapy regimen reference is made to what has been said above.
  • treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day, if desired.
  • the duration of therapy and the dosing frequency with the composition of the invention will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient.
  • the pharmaceutically effective amount of a given compound or composition will also depend on the administration route. In general, the required amount will be higher, if the administration is through the gastrointestinal tract; e.g. by suppository, rectal, or by an intragastric probe, and lower, if the route of administration is parenteral, e.g. intravenous.
  • composition of the invention a prophylactic administration of the pharmaceutical composition according to the invention may be possible.
  • the composition of the invention is preferably administered in above outlined preferred and particular preferred doses on a daily basis. This administration can be continued until the risk of developing the respective disorder has lessened. In most instances, however, the composition of the invention will be administered once a disease/disorder has been diagnosed. In these cases, it is preferred that a first dose of the composition of the invention is administered one, two, three or four times daily. Preferably, the administration is discontinued for one day, one week or one month and then repeated until the symptoms of the respective disease are no longer worsening or until they are improving.
  • the specific ligand binding to the receptors is defined as the difference between the total binding and the nonspecific binding determined in the presence of an excess of unlabelled ligand.
  • the results are expressed as a percent of control specific binding (measured specific binding/control specific binding) x 100) obtained in the presence of the above compound.
  • IC50 values concentration causing a half-maximal inhibition of control specific binding
  • This analysis was performed using a software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot ® 4.0 for Windows ® ( ⁇ 1997 by SPSS Inc.).
  • the tested compound was found to be an antagonist of the progesterone and androgen receptor.
  • the IC50 value was 3.1x10 8 M
  • the Ki value was 2.5x10 8 M
  • ⁇ was 0.9
  • the IC50 value was 9.6x10- 8 M
  • the Ki value was 4.3x10 8 M
  • n H was 0.9.
  • Docetaxel was obtained as the clinical formulation from SanofiAventis, solution 80 mg/mg, purchased from local Pharmacy.
  • the compound of formula la.1 was synthesized as described in WO 2010/075869.
  • the compound of formula la.1 was formulated for oral administration in 10% DMSO, 10% cremaphor EL and 80% H 2 0.
  • CWR22 tumors were taken from an in vivo passage, cut into small fragments and transplanted s.c. into the flank of 88 nude mice. At day 13 tumors were palpable. Mice were randomized to 10 groups with 8 mice each and treatment was initiated according to the protocol. The b.i.d. treatments were performed daily at 7 a.m. and 5 p.m.; the injection volume was 5 ml/kg. The different groups were sacrificed at different days for ethical reasons (large tumors). The treatments are compiled in the table below.
  • the compound of formula la.1 induced a moderate but not significant (p > 0.05) tumor growth delay. That effect was slightly dependent on dose, but not clearly on schedule.
  • the compound of formula la.1 clearly improved efficacy of docetaxel in a docetaxel moderately responsive prostate carcinoma.

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Abstract

La présente invention concerne une composition comprenant du docétaxel, ou l'un de ses solvates, et un composé de phényl-sulfonamide représenté par la formule (I). L'invention concerne également ladite composition convenant comme médicament, en particulier pour le traitement ou la prévention d'affections hyperproliférantes telles que les tumeurs, les cancers, ou les états précancéreux. L'invention concerne aussi l'utilisation de ladite composition pour l'élaboration d'un médicament destiné au traitement ou à la prévention d'affections hyperproliférantes telles que les tumeurs, les cancers, ou les états précancéreux. L'invention concerne enfin un procédé permettant, par administration de ladite composition, de traiter ou de prévenir des affections hyperproliférantes telles que les tumeurs, les cancers, ou les états précancéreux. Dans la formule (I), R1 est C1-C3-alkyle, C1-C3-haloalkyle, C1-C3-alcoxy ou C1-C3-haloalcoxy; R2 est hydrogène ou C1-C3-alkyle; et R3 est C1-C3-alkyle, C1-C3-haloalkyle, C1-C3-alcoxy ou C1-C3-haloalcoxy.
PCT/EP2012/055786 2011-03-31 2012-03-30 Composition comprenant du docétaxel Ceased WO2012131035A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10858418B2 (en) 2011-06-23 2020-12-08 Ablynx N.V. Techniques for predicting, detecting and reducing aspecific protein interference in assays involving immunoglobulin single variable domains
US11644471B2 (en) 2010-09-30 2023-05-09 Ablynx N.V. Techniques for predicting, detecting and reducing aspecific protein interference in assays involving immunoglobulin single variable domains

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114588270B (zh) 2015-09-16 2024-08-06 Dfb索里亚有限责任公司 包含紫杉烷类纳米颗粒的组合物及其用途
EP3595633B1 (fr) 2017-03-15 2023-07-05 DFB Soria, LLC Thérapie topique pour le traitement de malignités de la peau avec des nanoparticules comprenant un taxane
WO2018170210A1 (fr) * 2017-03-15 2018-09-20 Dfb Soria, Llc Thérapie topique pour le traitement de la néoplasie intraépithéliale vulvaire (vin) et des verrues génitales à l'aide de nanoparticules de taxanes
US11497726B2 (en) 2018-03-16 2022-11-15 Dfb Soria, Ll. Topical therapy for the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer using nanoparticles of taxanes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0039051A2 (fr) 1980-04-24 1981-11-04 Merck & Co. Inc. Derivés des acides hydroxamiques de type des N-bases de Mannich servant comme composés de départ pour la biodisponibilité d'agents anti-inflammatoires non-stéroidiques, procédé de préparation et composition pharmaceutique les contenant
WO2010075869A1 (fr) 2008-12-30 2010-07-08 European Molecular Biology Laboratory (Embl) Toluidine sulfonamides et leur utilisation
WO2010075859A1 (fr) 2009-01-02 2010-07-08 Charlotte Nielsen Dispositif de fixation pour récipient à condiments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0039051A2 (fr) 1980-04-24 1981-11-04 Merck & Co. Inc. Derivés des acides hydroxamiques de type des N-bases de Mannich servant comme composés de départ pour la biodisponibilité d'agents anti-inflammatoires non-stéroidiques, procédé de préparation et composition pharmaceutique les contenant
WO2010075869A1 (fr) 2008-12-30 2010-07-08 European Molecular Biology Laboratory (Embl) Toluidine sulfonamides et leur utilisation
WO2010075859A1 (fr) 2009-01-02 2010-07-08 Charlotte Nielsen Dispositif de fixation pour récipient à condiments

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients", 1994
"Handbook of Pharmaceutical Excipients", AMERICAN PHARMACEUTICAL ASSOCIATION
"Helvetica Chimica Acta", 1995, article "A multilingual glossary of biotechnological terms: (IUPAC Recommendations"
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING CO.
BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
BUNGAARD, J. MED. CHEM., 1989, pages 2503
DAVID MW CORK ET AL.: "Alternative splicing and the progesterone receptor in breast cancer", BREAST CANCER RESEARCH, vol. 10, 2008, pages 207
FUMOLEAU P ET AL: "Docetaxel combined with vinorelbine: phase I results and new study designs.", ONCOLOGY (WILLISTON PARK, N.Y.) JUN 1997 LNKD- PUBMED:9213325, vol. 11, no. 6 Suppl 6, June 1997 (1997-06-01), pages 29 - 31, XP008146307, ISSN: 0890-9091 *
GREGG L. SEMENZA, NATURE REVIEWS, vol. 3, October 2003 (2003-10-01)
MOELLER ET AL., CANCER CELL, 2004, pages 5429 - 441
PALAYOOR ST ET AL., INT J CANCER, vol. 123, no. 10, 15 November 2008 (2008-11-15), pages 2430 - 7
SVENSSON; TUNEK, DRUG METABOLISM REVIEWS, vol. 16, 1988, pages 5
Y. JEONG ET AL.: "Nuclear Receptor Expression defines a Set of Prognostic Biomarkers for Lung Cancer", PLOS MEDICINE, vol. 7, no. 12, December 2010 (2010-12-01)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11644471B2 (en) 2010-09-30 2023-05-09 Ablynx N.V. Techniques for predicting, detecting and reducing aspecific protein interference in assays involving immunoglobulin single variable domains
US10858418B2 (en) 2011-06-23 2020-12-08 Ablynx N.V. Techniques for predicting, detecting and reducing aspecific protein interference in assays involving immunoglobulin single variable domains
US11192938B2 (en) 2011-06-23 2021-12-07 Ablynx N.V. Serum albumin binding proteins containing immunoglobulin single variable domains
US11192937B2 (en) 2011-06-23 2021-12-07 Ablynx N.V. Techniques for predicting, detecting and reducing aspecific protein interference in assays involving immunoglobulin single variable domains
EP2723769B2 (fr) † 2011-06-23 2022-06-15 Ablynx NV Techniques permettant de prédire, détecter et réduire une interférence protéinique aspécifique dans des dosages impliquant des domaines variables uniques d'immunoglobuline
US12006352B2 (en) 2011-06-23 2024-06-11 Ablynx N.V. Techniques for predicting, detecting and reducing aspecific protein interference in assays involving immunoglobulin single variable domains

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