WO2015058868A1 - Compositions et procédés pour le traitement du cancer - Google Patents

Compositions et procédés pour le traitement du cancer Download PDF

Info

Publication number
WO2015058868A1
WO2015058868A1 PCT/EP2014/062159 EP2014062159W WO2015058868A1 WO 2015058868 A1 WO2015058868 A1 WO 2015058868A1 EP 2014062159 W EP2014062159 W EP 2014062159W WO 2015058868 A1 WO2015058868 A1 WO 2015058868A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
cancer
formula
general formula
Prior art date
Application number
PCT/EP2014/062159
Other languages
English (en)
Inventor
José Mª JIMENO DOÑAQUE
Original Assignee
Pangaea Biotech, S.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pangaea Biotech, S.L. filed Critical Pangaea Biotech, S.L.
Publication of WO2015058868A1 publication Critical patent/WO2015058868A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the invention relates to the field of cancer therapeutics and, more in particular, to compounds which are capable of inhibiting proliferation of cancer cells by inhibiting AEG-1.
  • the invention also relates to methods of using these compounds in therapy as well as to sustained release compositions containing the compounds of the invention for application to the surgical site after tumor resection.
  • AEG-1 Astrocyte Elevated Gene-1
  • MTDH Metadherin
  • LYRIC Lysine Rich CEACAM1 co-isolated
  • AEG-1 plays a crucial role in the pathogenesis of glioblastomas and has also been proposed as a rational and viable target for malignant glioma (Emdad et al, 2010, Mol. Cancer Ther.; 9: 79-88).
  • the authors of the present invention have used an in silico model to identify chemical entities which are proposed to bind to the NFkB binding domain of AEG-1.
  • This approach together with a follow-up intensive screening program has led to the identification of a new chemical entity (PB0412-3) which is active at low micromolar and nanomolar concentrations in a well characterized panel of human solid tumors cell lines.
  • PB0412-3 a new chemical entity which is active at low micromolar and nanomolar concentrations in a well characterized panel of human solid tumors cell lines.
  • antiproliferative effects in human cancer cells are observed at nontoxic concentrations of the compound in human non-tumoral cells thus sustaining a positive therapeutic index.
  • Figure 1 Identification of AEG-1 and p65 protein alignment and inhibition model AEG-1 and p65 cross talk.
  • the insert in the upper panel shows the sequence alignment between residues of A140-D156 of AEG-1 and residues D243-D259 of p65.
  • Figure 2 A: HPLC analysis of PB0412-3.
  • B HPLC-MS of PB0412-3 showing that the molecular weight obtained corresponds to the expected molecular weight of PB0412- 3.
  • C 1H NMR of PB0412-3 showing that the signals obtained allow the correct assignment of all proton of the molecule.
  • Figure 3 IC50s of PB0412-3 on the solid tumor cell lines NCI-H460, SKOV3, DLD-1, PC-3, SK-MES-1, A549, PC9, AU565, BxPC-3, on the glial and neural crest derived cell lines A172, T98G, T98GII, SH-SY5Y, U178, SK-N-SH, LN229, U373, WM115, WM793 and UACC903 and on the non-tumoral chondrocytes, human fibroblasts, myofibroblasts and gingival epithelial cells.
  • the horizontal bar indicates the cut-off value used to define sensitive/resistant cancer cells to PB0412-3.
  • Figure 4 A: Dose-response toPB0412-3 exposure on the proliferation of the cell linesPC9 (lung adenocarcinoma), DLD-1 (colon adenocarcinoma), AU565 (breast adenocarcinoma), PC-3 (prostate adenocarcinoma), SK-MES-1 (squamous cell adenocarcinoma), BxPC3 (pancreas adenocarcinoma),H460 (Lung large cell carcinoma),A549 (lung adenocarcinoma), SKOV3 (ovary adenocarcinoma),LN229 (glioblastoma), U373 (glioblastoma), T98G (glioblastoma),A172 (glioblastoma), U178 (glioblastoma), SH-SY5Y (neuroblastoma) , SK-N-SH (neuroblastoma), UACC903 (mela
  • D Dose-response toPB0412-3 exposure on the proliferation of the subpanel comprising the non-tumor cell lines HACAT(human keratinocytes), human fibroblasts, myofibroblasts and gingival epithelial.
  • E Dose-response toPB0412-3 exposure on the proliferation of the subpanel comprising the neural crest derived cell lines LN229 (glioblastoma), U373 (glioblastoma), T98G (glioblastoma), A172 (glioblastoma), U178 (glioblastoma), U178 (glioblastoma), SH-SY5Y (neuroblastoma), SK-N-SH (neuroblastoma), UACC903 (melanoma), WM115 (melanoma), and WM793 (melanoma).
  • the invention relates to a compound having the general formula:
  • each Ri is independently selected from the group consisting of hydrogen, a d- C 6 alkyl group, a C 2 -C6 alkenyl group, a halogen atom, a hydroxyl group, an alkoxy group, an aryloxy group, a substituted or unsubstituted amido group, a substituted or unsubstituted carboxyl group, a phosphate group, a sulfonate group and a nitro group,
  • n is an integer ranging from 1 to 5
  • each R 2 is independently selected from the group consisting of hydrogen, a substituted or unsubstituted carboxyl group, a hydroxyl group, an alkoxy group and an aryloxy group,
  • n is an integer ranging from 0 to 10
  • X is an oxygen atom or a nitrogen atom substituted with hydrogen or with a Ci- C 6 alkyl group
  • each Y is independently a halogen atom
  • o is an integer ranging from 1 to 3
  • R3 is selected from the group consisting of hydrogen and a substituted or unsubstituted Ci-C 6 alkyl group
  • R4 is hydrogen and R 5 is a group having the structure:
  • each Re is independently selected from the group consisting of hydrogen, a d- C 6 alkyl group, a cycloalkyl group, a C 2 -C 6 alkenyl group, a halogen atom, a hydroxyl group, an alkoxy group, an aryloxy group, a substituted or unsubstituted amido group, a substituted or unsubstituted carboxyl group, a phosphate group, a sulfonate group and a nitro group
  • R 7 and Rs are independently selected from hydrogen or a Ci-C 6 alkyl group
  • each R 9 or Ri 1 is independently selected from the group consisting of hydrogen, a Ci-C 6 alkyl group, a cycloalkyl group, a C 2 -C 6 alkenyl group, a halogen atom, a hydroxyl group, an alkoxy group, an aryloxy group, a substituted or unsubstituted amido group, a substituted or unsubstituted carboxyl group, a phosphate group, a sulfonate group, a trifluoromethansulfonate group and a nitro group,
  • Rio is selected from hydrogen or a Ci-C 6 alkyl group
  • p is an integer ranging from 1 to 5
  • q is an integer ranging from 1 to 4,
  • r is an integer ranging from 1 to 3
  • s is an integer ranging from 1 to 10
  • R4 and R 5 form together with the nitrogen atom to which they are bond a five membered ring having the structure
  • each R 4 is independently selected from the group consisting of hydrogen, a Ci-C 6 alkyl group, a cycloalkyl group, a C 2 -C6 alkenyl group, a halogen atom, a hydroxyl group, an alkoxy group, an aryloxy group, an aryl group, a substituted or unsubstituted amido group, a substituted or unsubstituted carboxyl group, a phosphate group, a sulfonate group and a nitro group,
  • - t is an integer ranging from 1 to 4,
  • R 12 and Ri3 are independently selected from the group consisting of hydrogen and a substituted or unsubstituted Ci-C 6 alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a C 2 -C6 alkenyl group,
  • Ci-C 6 alkyl group refers to a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 2,3-dimethylbutyl and the like.
  • Alkyl groups included in compounds of this invention may be optionally substituted with one or more substituents.
  • C 2 -C6 alkenyl group means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon double bond.
  • Representative straight chain and branched (C2- C6) alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1 -pentenyl, 2- pentenyl, 3-methyl-l-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.
  • Alkenyl groups may be optionally substituted with one or more substituents.
  • alkoxy group refers to an alkyl group which is attached to another moiety via an oxygen linker.
  • alkoxy groups include: -OCH 3 (methoxy), -OCH 2 CH 3 (ethoxy), -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 (isopropoxy), -OCH(CH2) 2 , -O-cyclopentyl, and -O-cyclohexyl.
  • aryl or “Ar” are phenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, A- fluorophenyl, 2-bromophenyl,
  • aryloxy group refers to an aryl group which is attached to another moiety via an oxygen linker.
  • heteroaryl means a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a 5 or 6 membered ring.
  • the 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and/or optionally one oxygen or sulphur atom.
  • the 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms.
  • the 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl.
  • monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl.
  • the bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl.
  • bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, cinnolinyl, dihydroquinolinyl, dihydroisoquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, tetrahydroquinolinyl, and thienopyridinyl.
  • amido refers to the group - C(0)NH2.
  • substituted refers to the group -C(0)NHR, in which R is acyl, as that term is defined above.
  • a non-limiting example of an amido group is -NHC(0)CH 3 .
  • sulphonate refers to the group -SO 3 .
  • carboxyl group means the group -COOH.
  • Suitable substituents for an alkyl, alkenyl, aryloxy, alkoxy, amido or carboxyl groups include those substituents which form a stable compound of the invention without significantly adversely affecting the reactivity or biological activity of the compound of the invention.
  • substituents for an alkyl or alkenyl include an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, optionally substituted alkoxy.
  • the alkyl or alkenyl are unsubstituted.
  • the term "halogen" or "halo" means -F, -CI, -Br or -I.
  • nitro group refers to the -N0 2 group.
  • a range of the number of atoms in a structure is indicated (e.g., a C1-C6), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • a range of 1-6 carbon atoms (e.g., C1-C6) as used with respect to any chemical group (e.g., alkyl, aryl, alkenyl, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, and/or 6 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1 -2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3- 6 carbon atoms, 4-5 carbon atoms and 4-6 carbon atoms, as appropriate.
  • 1 -2 carbon atoms 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon
  • the presence of a double bond is indicative that the molecule can be as cis or trans isomer.
  • cis-trans isomers which are sometimes referred to as geometrical isomers, occur when double bonds prevent rotation of atoms around a bond.
  • Z isomer according to the E-Z notation both of the larger groups lie on the same side of the molecule.
  • trans-isomer E isomer, according to the E-Z notation
  • the larger groups are on opposite sides of the molecule.
  • the isomer resulting from the double bond connecting the thiazolidindione and the ring carrying the R 3 group is the Z isomer.
  • the isomer resulting from the double bond connecting the thiazolidinedione ring and the ring carrying the R 3 group is the E isomer.
  • the compounds of the invention are provided as mixture of the E and Z isomer.
  • the compound according to the invention has the general formula (la): 10
  • the compound according to the invention has the general formula
  • the compound of the invention has the structure
  • R 3 , Y and o are as defined in claim 1, wherein A has the structure
  • the compound according to the invention has the formula
  • Ri is not a carboxamide group. In another embodiment, if m is 1 , then Ri is not located in the ortho position. In another embodiment, if m is 1 , then Ri is not a carboxamide group located in the ortho position. In another embodiment, if o is 1 , then Y is an halogen, more preferably a chloride group.
  • solvates e.g., hydrates
  • Solvates refer to crystalline forms wherein solvent molecules are incorporated into the crystal lattice during crystallization.
  • Solvate may include water or non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc.
  • Solvates, wherein water is the solvent molecule incorporated into the crystal lattice are typically referred to as "hydrates”. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
  • the compound including solvates thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof.
  • the compounds or solvates may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs.”
  • polymorphs typically known as "polymorphs.”
  • the disclosed compounds and solvates e.g., hydrates
  • Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties.
  • Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • different polymorphs may be produced, for example, by changing or adjusting the conditions used in solidifying the compound. For example, changes in temperature, pressure, or solvent may result in different polymorphs.
  • one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the invention also provides "salts" of the compounds described in the present description.
  • said salts can be acid addition salts, base addition salts or metal salts, and can be synthesized from the parent compounds containing a basic or acid moiety by means of conventional chemical processes known by the persons skilled in the art.
  • Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of the two.
  • Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred.
  • said acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc.
  • inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate
  • base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts such as, for example, ethylenediamine, ethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • organic base salts such as, for example, ethylenediamine, ethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum and lithium salts.
  • compositions of the invention are formulated with a pharmaceutically acceptable carrier.
  • the invention relates to a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically active carrier.
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non- inflammatory, non- immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, ibid.
  • Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9 mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like.
  • Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, et al, "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986).
  • the pharmaceutical composition is a sustained-release composition.
  • sustained release is used in a conventional sense relating to a delivery system of a compound which provides the gradual release of this compound during a period of time and preferably, although not necessarily, with relatively constant compound release levels over a long period of time.
  • polymeric materials can be used to achieve controlled or sustained release of the therapies of the invention (see e.g., Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J., Macromol.
  • polymers used in sustained release formulations include, but are not limited to, poly(2- hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolides (PLG), polyanhydrides, poly(N- vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactides (PLA), poly(lactide-co-glycolides) (PLGA), and polyorthoesters.
  • the polymer used in a sustained release formulation is inert, free of leachable impurities, stable on storage, sterile, and biodegradable.
  • a controlled or sustained release system can be placed in proximity of the prophylactic or therapeutic target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • Controlled release systems are discussed in the review by Langer (1990, Science 249: 1527-1533). Any technique known to one of skill in the art can be used to produce sustained release formulations comprising one or more therapeutic agents of the invention. See, e.g., U.S. Pat. No.
  • the pharmaceutical composition comprises a compound according to the present invention and a bio-erodible polymer wherein the compound is adsorbed onto the surface of the bioerodible polymer.
  • bioerodible polymer refers to a polymer which decomposes when placed inside an organism, as measured by a decline in the molecular weight of the polymer over time.
  • Polymer molecular weights can be determined by a variety of methods including size exclusion chromatography (SEC), and are generally expressed as weight averages or number averages.
  • SEC size exclusion chromatography
  • a polymer is bioerodible if, when in phosphate buffered saline (PBS) of pH 7.4 and a temperature of 37 degrees C, its weight-average molecular weight is reduced by at least 25 percent over a period of 6 months as measured by SEC.
  • PBS phosphate buffered saline
  • Suitable bioerodible polymers for use in the present invention are described in United States Patents No.
  • Useful bioerodible polymers include polyesters, such as poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(hydroxybutryate); polyanhydrides, such as poly(adipic anhydride) and poly(maleic anhydride); polydioxanone; polyamines; polyamides; polyurethanes; polyesteramides; polyorthoesters; polyacetals; polyketals; polycarbonates; polyorthocarbonates; polyphosphazenes; poly(malic acid); poly(amino acids); polyvinylpyrrolidone; poly(methyl vinyl ether); poly(alkylene oxalate); poly(alkylene succinate); polyhydroxycellulose; chitin; chitosan; and copolymers and mixtures thereof.
  • polyesters such as poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(hydroxybutryate
  • polyanhydrides such as poly(adipic anhydride) and poly
  • the bioerodible polymer is a polyanhydride formed by the polymerization of monomers selected from:
  • Aromatic-ali hatic dicarbox lic acid havin the general formula as well as any combination of aliphatic dicarboxylic acids, aromatic dicarboxylic acids and aromatic-aliphatic dicarboxylic acids, wherein R n is a divalent organic group.
  • Polyanhydrides composed of the monomers: sebacic acid (SA), bis(p- carboxyphenoxy)propane (CPP), isophthalic acid (IPh), and dodecanedioic acid (DD) are preferred.
  • Further examples for other polyanhydrides include, but are not limited to poly(malic anhydride), poly (adipic anhydride) or poly (sebacic anhydride).
  • the polymer is poly(l,6-bis(p-carboxyphenoxy)hexane-co-sebacic acid) (poly(CPH-SA) or poly(l,3-bis(p-carboxyphenoxy)propane-co-sebacic acid) (poly(CPP-SA), wherein the ration of CPP to SA can vary.
  • combinations such as pCPP:SA or 20:80, 50:50 can be used.
  • the polymer is Polifeprosan 20, which comprises pCPP and SA at a 20:80 ratio.
  • the polymer is poly [bis(p-carboxyphenoxy) propane anhydride] or a co-polymer thereof with sebacic acid.
  • the olymer has the following structure:
  • the m:n ratio is from 100: 1 to 1 : 100.
  • the m to n ratio of the polymer is 2:8.
  • composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal (e.g., topical), transmucosal, and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the pharmaceutical composition of the invention is formulated in order to enable the compounds of the invention to passively accumulate in tumors by the enhanced permeation and retention (EPR) effect as well as to facilitate access of the compounds to peripheral compartments and to cross the blood brain barrier.
  • EPR enhanced permeation and retention
  • the compounds according to the invention are formulated in encapsulated form.
  • the pharmaceutical composition according to the invention is a polymer micelle, a liposome or a nanoemulsion.
  • Polymer micelles are particularly attractive due to their ability to deliver hydrophobic therapeutic agents.
  • the nanoscopic size of polymeric micelles allows for passive accumulation in diseased tissues, such as solid tumors, by the enhanced permeation and retention (EPR) effect.
  • EPR enhanced permeation and retention
  • polymer micelles may be further decorated with cell-targeting groups and permeation enhancers that can actively target diseased cells and aid in cellular entry, resulting in improved cell-specific delivery.
  • lipids are useful for the liposomes described herein.
  • suitable lipids include phosphatidylcholine (PC), phosphatidylserine (PS), as well as mixtures of dioleoyltrimethylammonium propane (DOTAP) and dioleoylphosphatidylethanolamine (DOPE) and/or cholesterol (chol); a mixture of dimethyldioctadecylammonium bromide (DDAB) and DOPE with or without cholesterol.
  • the ratio of the lipids can be varied to optimize the efficiency of loading of the compounds according to the invention.
  • the liposome can comprise a mixture of one or more cationic lipids and one or more neutral or helper lipids.
  • a desirable ratio of cationic lipid(s) to neutral or helper lipid(s) is about l :(0.5-3), preferably l :(l-2) (molar ratio).
  • liposomes as described herein are sterically stabilized liposomes.
  • Sterically stabilized liposomes are liposomes into which a hydrophilic polymer, such as PEG, poly(2-ethylacrylic acid), or poly(n-isopropylacrylamide (PNIPAM) has been integrated.
  • a hydrophilic polymer such as PEG, poly(2-ethylacrylic acid), or poly(n-isopropylacrylamide (PNIPAM) has been integrated.
  • PEG poly(2-ethylacrylic acid), or poly(n-isopropylacrylamide (PNIPAM)
  • PEG poly(2-ethylacrylic acid)
  • PNIPAM poly(n-isopropylacrylamide
  • modified liposomes can be particularly useful, as they typically are not cleared from the bloodstream by the reticuloendothelial system as quickly as are comparable liposomes that have not been so modified.
  • a cationic liposome comprising
  • a solution of a PEG polymer in a physiologically acceptable buffer at a ratio of about 0.1 : 100 (nmol of PEG:nmol of liposome), suitably, about 0.5:50, for example, about 1 :40 (nmol of PEG:nmol of liposome).
  • the resultant solution is incubated at room temperature for a time sufficient to allow the polymer to integrate into the liposome complex.
  • Suitable ratios of lipidxompound according to the invention is about 0.1 : 1 to about 1 : 100, about 0.05: 1 to about 1 :50, about 1 :1 to about 1 :20, about 2: 1 to about 10:0.1, about 0.5: 1 to about 2: 1, or about 1 : 1.
  • the liposomes of the present invention suitably comprise an anti-trans ferrin receptor single chain antibody molecule (TfRscFv) on their surface. It has been determined that this targeting molecule enhances delivery across the blood-brain barrier and targeted delivery to brain cancer cells.
  • TfRscFv anti-trans ferrin receptor single chain antibody molecule
  • the compounds of the invention are formulated as a complex with a polypeptide.
  • the polypeptide is albumin.
  • the compounds of the invention are formulated as nanoparticles.
  • a "nanoparticle” is a colloidal, polymeric, or elemental particle ranging in size from about 1 nm to about 1000 nm.
  • Nanoparticles can be made up of silica, carbohydrate, lipid, or polymer molecules. Molecules can be either embedded in the nanoparticle matrix or may be adsorbed onto its surface.
  • the nanoparticle may be made up of a biodegradable polymer such as poly(butylcyanoacrylate) (PBCA).
  • PBCA poly(butylcyanoacrylate)
  • elemental nanoparticles include carbon nanoparticles and iron oxide nanoparticles, which can then be coated with oleic acid (OA)-Pluronic(R).
  • OA oleic acid
  • R oleic acid
  • a drug e.g., a hydrophobic or water insoluble drug
  • Other nanoparticles are made of silica.
  • Nanoparticles can be formed from any useful polymer.
  • polymers include biodegradable polymers, such as poly(butyl cyanoacrylate), poly(lactide), poly(glycolide), poly-s-capro lactone, poly(butylene succinate), poly(ethylene succinate), and poly(p-dioxanone); poly(ethyleneglycol); poly-2- hydroxyethylmethacrylate (poly(HEMA)); copolymers, such as poly(lactide-co- glycolide), poly(lactide)- poly(ethyleneglycol), poly(poly(ethyleneglycol)cyanoacrylate- co- hexadecylcyanoacrylate, and poly [HEMA-co-methacry lie acid]; proteins, such as fibrinogen, collagen, gelatin, and elastin; and polysaccharides, such as amylopectin, a- amylose, and chitosan.
  • biodegradable polymers such as poly(
  • Nanoparticles include solid lipid nanoparticles (SLN).
  • lipid molecules for solid lipid nanoparticles include stearic acid and modified stearic acid, such as stearic acid-PEG 2000; soybean lechitin; and emulsifying wax.
  • Solid lipid nanoparticles can optionally include other components, including surfactants, such as Epicuron(R) 200, poloxamer 188 (Pluronic(R) F68), Brij 72, Brij 78, polysorbate 80 (Tween 80); and salts, such as taurocholate sodium.
  • Agents can be introduced into solid lipid nanoparticles by a number of methods discussed for liposomes, where such methods can further include high-pressure homogenization, and dispersion of microemulsions.
  • Nanoparticles can also include nanometer- sized micelles.
  • Micelles can be formed from any polymers described herein.
  • Exemplary polymers for forming micelles include block copolymers, such as poly(ethylene glycol) and poly(8-caprolactone). (e.g., a PEO- b-PCL block copolymer including a polymer of ⁇ -caprolactone and a-methoxy- co-hydroxy-poly(ethylene glycol)).
  • the properties of the nanoparticle are altered by coating with a surfactant.
  • a surfactant Any biocompatible surfactant may be used, for example, polysorbate surfactants, such as polysorbate 20, 40, 60, and 80 (Tween 80); Epicuron(R) 200; poloxamer surfactants, such as 188 (Pluronic(R) F68) poloxamer 908 and 1508; and Brij surfactants, such as Brij 72 and Brij 78.
  • Nanoparticles can optionally be modified to include hydrophilic polymer groups (e.g., poly(ethyleneglycol) or poly(propyleneglycol)), for example, by covalently attaching hydrophilic polymer groups to the surface or by using polymers that contain such hydrophilic polymer groups (e.g., poly[methoxy poly (ethyleneglycol) cyanoacrylate-co-hexadecyl cyanoacrylate]). Nanoparticles can be optionally cross- linked, which can be particularly useful for protein-based nanoparticles.
  • hydrophilic polymer groups e.g., poly(ethyleneglycol) or poly(propyleneglycol)
  • Nanoparticles can be optionally cross- linked, which can be particularly useful for protein-based nanoparticles.
  • Therapeutic agents can be introduced to nanoparticles by any useful method. Agents can be incorporated into the nanoparticle at, during, or after the formation of the nanoparticle.
  • the pharmaceutical composition is formulated using a carbohydrate-based polymer.
  • Carbohydrate-based polymers such as chitosan can be used as a transport vector e.g., in the formation of micelles or nanoparticles.
  • chitosan polymers can be amphiphilic, these polymers are especially useful in the delivery of hydrophobic agents (e.g., those described herein).
  • Exemplary chitosan polymers include quaternary ammonium palmitoyl glycol chitosan.
  • the pharmaceutical composition of the invention is a nanoemulsion.
  • Nano emulsion as used herein means a colloidal dispersion of droplets (or particles) which at least some of the droplets have diameters in the nanometer size range.
  • the nanoemulsions are comprised of omega-3, -6 or -9 fatty acid rich oils in an aqueous phase and thermo-dynamically stabilized by amphiphilic surfactants, which make up the interfacial surface membrane, produced using a high shear microfluidization process usually with droplet diameter within the range of about 80- 220 nm.
  • the invention relates to a compound or composition according to the invention for use in medicine.
  • the invention relates to a a compound or composition according to the invention for use in the prevention or treatment of a proliferative disorder.
  • the invention relates to a method for the treatment or prevention of a proliferative disorder in a subject in need thereof which comprises the administration to said subject of a therapeutically effective amount of the compound or composition according to the invention.
  • the term "effective amount” refers to an amount of a compound of this invention which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a disease or disorder, e.g., a proliferative disorder, prevent the advancement of a disease or disorder, e.g., a proliferative disorder, cause the regression of a disease or disorder, e.g., a proliferative, prevent the recurrence, development, onset or progression of a symptom associated with a disease or disorder, e.g., a proliferative disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • the precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of cell proliferation, and the mode of administration. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used. In cases where no amount is expressly noted, an effective amount should be assumed.
  • the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorder or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least about 150 ⁇ g/kg, preferably at least about 250 ⁇ g/kg, at least about 500 ⁇ g/kg, at least about 1 mg/kg, at least about5 mg/kg, at least about 10 mg/kg, at least about 25 mg/kg, at least about 50 mg/kg, at least about 75 mg/kg, at least about 100 mg/kg, at least about 125 mg/kg, at least about 150 mg/kg, or at least about 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks,
  • the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a proliferative disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a disease or disorder, e.g., a proliferative disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of the invention).
  • the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a disease or disorder, e.g., a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient.
  • the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of a disease or disorder, e.g., a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.
  • a compound of the invention is administered as a preventative measure to a patient, preferably a human, having a genetic predisposition to any of the disorders described herein.
  • the terms “subject”, “patient” and “mammal” are used interchangeably.
  • the terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non- primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human.
  • a non- primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
  • a primate e.g., a monkey, chimpanzee and a human
  • the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In another embodiment, the subject is a human.
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit
  • the subject is a human.
  • a "proliferative disorder” or a “hyperproliferative disorder,” and other equivalent terms, means a disease or medical condition involving pathological growth of cells.
  • Proliferative disorders include cancer, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g., diabetic retinopathy or other retinopathies, cardiac hyperplasia, reproductive system associated disorders such as benign prostatic hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoid tumors.
  • the proliferative disorder is cancer.
  • Cancers that can be treated or prevented by the methods of the present invention include, but are not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medull
  • the cancer is selected from the group consisting of a lung cancer, breast cancer, ovarian cancer, pancreatic cancer, liver cancer, head and neck cancer, prostate cancer, tongue cancer, colorectal cancer, esophageal cancer, renal cancer, endometrial cancer, melanoma, gall bladder cancer, sarcoma, bone cancer, gastric cancer, ovarian cancer, cervical cancer and brain cancer.
  • the lung cancer is adenocarcinoma, large cell carcinoma or squamous cell carcinoma
  • the breast cancer is adenocarcinoma
  • the pancreas cancer is adenocarcinoma
  • the colorectal cancer is adenocarcinoma
  • the prostate cancer is an adenocarcinoma
  • the gall bladder cancer is an adenocarcinoma
  • the sarcoma is a soft tissue sarcoma
  • the gastric cancer is a esophageal epidermoid or adenocarcinoma
  • the brain cancer is neuroblastoma, ependimoma, medulloblastoma, astrocytoma, glioblastoma or a brain metastasis.
  • the tumor is a glial-derived tumor.
  • the glial-derived tumor is glioblastoma multiforme.
  • the tumor is a neural crest-derived tumor.
  • the neural crest-derived tumor is neuroblastoma, melanoma, feochromocytoma, paraganglioma, Ewing's sarcoma, small cell prostate cancer, a tumor of the Ewing's sarcoma family of tumors (EFST) or a carcinoid.
  • EFST Ewing's sarcoma family of tumors
  • Metastasis refers to the spread of a cancer from one organ or tissue to another non- adjacent organ or tissue. Cancer cells can break away, leak, or spill from a primary tumor and enter lymphatic and blood vessels, circulate throughout the bloodstream, and be deposited elsewhere in the body. This occurrence is referred to as "metastasis.” Metastasis is one of the hallmarks of malignancy of cancers.
  • the methods of the invention can additionally comprise of administration of compositions formulated as depot preparations. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • compositions can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • the therapeutic methods according to the invention involve the use of a sustained release composition and the administration of the sustained release composition to the surgical site after resection of the tumor.
  • the tumor is glioblastoma and the composition is administered locally by implantation of a composition comprising a compound according to the invention and a bio-erodible polymer.
  • the invention relates to a method for producing a compound having the general formula:
  • R l s R 2 , R 3 , R4, R5, X, Y, ni, n and o are as defined above
  • R l s R 2 , R3, R4, R5, X, Y, ni, n and o are as defined above, under conditions adequate for Knoevenagel condensation between the thiazolidindione group in the compound having the formula (II) and the aldehyde group in the compound of formula (III).
  • Knoevenagel condensation refers to a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule of water is eliminated (hence condensation).
  • the product is often an alpha, beta conjugated enone.
  • the reaction is carried out in the presence of an amine compound as catalyst.
  • the amine compound is piperidine.
  • the Knoevenagel condensation takes place between the active hydrogen in the thiazolidindione group in the compound of formula (II) and the aldehyde group in the compound of formula (III).
  • the compound of formula (II) has the following structure
  • the compound of formula (III) has the following structure
  • the invention relates to a method for the production of a compound having the general formula
  • R l s R 2 , m and n are as defined above and Q is a reactive group that is capable of reacting with the carboxyl group in the compound of formula (V) resulting in a linking group X as defined above,
  • the reacting is carried out under conditions adequate for reacting the carboxyl group in compound (V) with the Q group in the compound of formula (IV).
  • the Q group is amine group and the reaction is an amidation reaction.
  • the compound of formula (IV) has the following structure
  • the invention relates to a method for producing a compound having the general formula
  • R 3 , Y, o, R4 and R 5 are as defined above and wherein P is an reactive functional group, wherein said reacting is carried out under conditions adequate for reacting the reactive functional group P in the compound of formula (VII) with the hydroxyl group in the compound of formula (VI).
  • the reactive group P is specific for hydroxyl groups. Suitable P groups for use in the present method include, without limitation, a carboxyl, an ester, a halide, an acyl halide, a isocyanato, epoxy, anhydride, azlactonyl or oxazolinyl group.
  • the reactive group P is a halogen, preferably bromide, and the reaction between the reactive group in the compound of formula (VII) and the hydroxyl group in the compound of formula (VI) is a Williamson reaction.
  • Williamson reaction refers to a reaction between an organohalide and an alcohol to form an ether.
  • the Williamson reaction takes place between the P group in the compound of formula (VI) and the hydroxyl group in the compound of formula (VI).
  • the compound of formula (VI) has the following structure
  • the compound of formula (VII) has the following structure
  • the invention relates to a method for producing a compound according of formula (I) comprising
  • the invention relates to a method for the production of a compound having the general formula (I)
  • R l s R 2 , R 3 , R4, R5, ni, n, o, X and Y are as defined above,
  • the compound of general formula (VIII) has the structure
  • the compound of general formula (IX) has the structure
  • the invention relates to a method for the production of a compound having the general structure
  • R l s R 2 , R3, R4, R5, X, Y, ni, n and o are as defined above
  • the reactive group P is a halogen and wherein the reaction between said reactive group in the compound of formula (XI) and the hydroxyl group in the compound of formula (X) is a Williamson reaction.
  • the compound of formula (X) has the structure
  • the compound of formula (XI) has the following structure
  • the invention relates to a method for the production of a compound having the general formula (X) comprising reacting a compound having the general structure
  • R l s R 2 , R 3 , X, Y, m and n are as defined above
  • the com ound of formula XII has the following structure
  • the compound for formula (XIII) has the following structure
  • the invention relates to a method for producing a compound having the general formula (XI) comprising reacting a compound having the general formula
  • the compound of formula (IX) has the following structure
  • the invention relates to a method for producing a compound having the general formula:
  • step (iii) reacting the compound having the general structure (XII) obtained in step (i) with the compound having the general structure (XI) obtained in step (ii) to obtain a compound according to claim 1.
  • HPLC was carried out using the HPLC separation module Alliance Water 2695 (Waters) and the Detector Water 2998 photodiode array Column X-Bridge BEH130 5 ⁇ 4,6x100 mm (Waters). The flow was of lmL/min using as eluent 0,45% TFA in water and 0,36% TFA in acetonitrile.
  • Mass spectrometry was carried out an ESI mass spectrometer model Micromass ZQ (Waters) was used with Sunfire CI 8 column (100 x 2.1 mm x 3.5 mm, 100 AD , Waters) and Masslynx 4.1 software (Waters). The flow rate was 0.3 mL/min using MeCN (0.07 % formic acid) and H20 (0.1 % formic acid).
  • the microwave discover CEM model Discover system ChemDriver 908010 was purchased from Waters.
  • RP-HPLC analysis were carried in XBridgeTM BEH130 CI 8 reversed -phase HPLC analytical column (4,6 x 100 mm, 3,5 ⁇ ) was obtained from Waters (Ireland).
  • Analytical RP-HPLC was performed on a Waters instrument comprising a separation module (Waters 2695), an automatic injector (Waters 717 autosampler), a photodiode array detector (Waters 2998), and a software system controller (Empower).
  • UV detection was at 220 nm, and linear gradients of 50% ACN to 100% ACN in 8 min. Eluents ACN (0.036% TFA), H 2 0 (0.045% TFA) were run at a flow rate 1.0 mL.min "1 over 8 min.
  • HPLC purification was carried out with a Semi-Preparative RP-HPLC SunFireTM Prep C18 OBDTM reversed-phase HPLC analytical column (19x100 mm, 5 ⁇ ) was acquired from Waters (Ireland).
  • Semi-preparative RP-HPLC was performed on a Water Delta 600 system comprising a sample manager (Water 2700), a controller (Water 600), a dual ⁇ absorbance detector (Water 2487), a fraction collector II, and a software system controller (MassLynx).
  • UV detection was at 220 nm, and linear gradients of 40% of ACN to 60% of ACN in 20 minute, eluent ACN (0, 1% TFA) and H 2 0 (0, 1% TFA) were run at a flow rate of 16 mL-min "1 over 20 min.
  • HPLC mass spectrometry analysis
  • HPLC-electrospray mass spectrometry analysis was performed with a SunFireTM CI 8 reversed-phase HPLC analytical column (2.1 mm x 100 mmm, 5 ⁇ ) procured from Waters (Ireland).
  • ESMS was performed on a Water Micromass ZQ spectrometer comprising a separation module (Water 2695), an automatic injector (Water 717 autosampler), a photodiode array detector (Water 2998) and a software system controller MassLynx v. 4.1.
  • UV detection was at 220 nm, mass scans were acquired in positive ion mode, and linear gradients of 50%> of ACN to 100% of ACN in 8 min. Eluent ACN (0.07% formic acid) and H 2 0 (0.1% formic acid) were run at flow rate of 0.3mL.min _1 over 8 min.
  • NMR analysis was performed with a SunFireTM CI 8 reversed-phase HP
  • MTT Thiazolyl Blue Tetrazolium Bromide
  • AEG-1 is a positive regulator of NFKB, particularly it has been shown that both AEG-1 and NFKB are transported to the nucleus forming a AEG-l/p65 complex. Moreover, this complex formation is accompanied by a decrease of thep50/p50 dimers and by an increase of the p65/p50 dimers, which is the activated form of NFKB that binds to DNA. Many of these complexes have been crystallized, such as the p65/p65homodimer (PDB code: 2RAM), the ⁇ 65/ ⁇ complex (PDB code: 1K3Z), and the p50/p65 heterodimer (PDB code: 2I9T) allowing their structural study at molecular level.
  • PDB code p65/p65homodimer
  • PDB code ⁇ 65/ ⁇ complex
  • 2I9T the p50/p65 heterodimer
  • the inventors have carried out a molecular modelling study of the complex formed between AEG-1 and NFKB in order to discover small molecule disruptors of its formation, and can therefore be used as novel chemotherapeutic agents.
  • ligand-based virtual screening (VS) (Comb. Chem. High Throughput Screen. 2011, 14, 450) of a large database of commercial compounds was used to search for molecules with the potential ability to bind the ⁇ binding domain of AEG-1 using a technology that allows the flexible alignment of the database molecules with a reference compound or protein fragment, comparing its similarity by means of their Molecular Interaction Fields (MIFs) (Drug Discov. Today, 2010, 15, 23).
  • MIFs Molecular Interaction Fields
  • AEG-1 In order to search for inhibitors of the AEG-l/NftcB complex, a fragment of AEG-1 had to be modelled since no resolved crystal structure of this human protein or any other similar exist.
  • AEG-1 interacts with the transcriptional activator by using the residues 101-205 of its protein sequence (Cancer Res 2008, 68, 1478). Furthermore, several crystals of Nf B (p65 and p50) are available and can be used to model this protein in the complex with AEG-1.
  • the dimerization region of p65 in its homodimer complex (PDB code: 2RAM).
  • the first three alignments did not yield a satisfactory result.
  • the last sequence alignment found a region of similarity, pointing out that AEG-1 could interact with p65 in a similar way as p65 with itself.
  • the residues of AEG-1 A140-D156 (enclosed in the 101-205 sequence) can be aligned with the residues D243-D259 of p65, exhibiting a 24% identity and a rather high similarity of 41%, as shown in Figure 1.
  • the p65 dimerization fragment was used as the template for modeling the interacting fragment of AEG-1 (see Methods section).
  • a homology modelling routine was performed using in-house technologies, building a fragment of AEG-1 from a p65 template structure (PDB code: 2RAM) with sufficient sequence identity.
  • the fragment of AEG-1 exhibits a turn structure.
  • R246 of p65 is positioned in the same manner as R142 in AEG-1, and the hydrophobic cluster between V244 and 1250, in p65, that maintains the turn rigid, is also similar to the hydrophobic cluster formed by V141 and VI 47 in AEG-1.
  • the side chain of p65 V248 can be assimilated with the side chain methyl of T143 in AEG-1.
  • This server uses a structural alphabet and a coarse grained force field for building the three dimensional structure of the submitted peptide sequence and, remarkably, the best scored solution of the server resulted in a very similar turn structure as already predicted by the homology modelling protocol.
  • R142 forms a salt bridge with D217
  • T142 maintains van der Waals contacts with V248 and Q145 forms two hydrogen bonds with H245.
  • a pharmacophore model of p65 can be extracted, which represents the most important residues for the interaction with AEG-1.
  • the pharmacophore can be used to perform the VS experiment in order to identify a small molecule with the same functional groups of this protein fragment that could bind to AEG-1. If the molecule is able to block the AEG-l/p65 complex, the activation of ⁇ could be stopped.
  • This p65 pharmacophore is formed by 3 interaction points: a hydrogen acceptor point (or carboxylate group) in D217, a hydrophobic point in V248 and a hydrogen donor group in H245.
  • the hydrogen acceptor is at a distance of around 7 A from the hydrophobic point, whereas this residue is at a distance of around 9 A from the hydrogen donor point.
  • the length of the whole interaction area is of 15 A, approximately, which can be covered by a medium size ( ⁇ 500 g/mol) molecule.
  • VS was carried out with a large database of commercial molecules from several vendors (Asinex, Chembridge, Chem Div, Life Chemicals, National Cancer Institute, Princeton Biomolecular Research, Enamine and SPECS) were joined in a unique database of 6,981,556 molecules.). Beforehand, the database was filtered for molecules having a carboxylate moiety, which can mimic the D217 pharmacophoric point. This subset of molecules was further divided into two group accounting for those molecules with a molecular weight between 750 and 350 g/mol (Group- 1, 154,019 entities) and those molecules with a molecular weight between 349 and 200 g/mol (Group-2, 121,099 entities). The latter group consisted of smaller and more rigid molecules, which may have interesting pharmacokinetic properties. Results of the Virtual screening and proposition of candidates
  • the total database was filtered for compounds with a carboxyl group, leaving 217,667 molecules.
  • the 3D structures of the molecules was prepared by accounting for the protonation state at physiological pH and the diverse internal ring conformations, resulting in 275 , 118 entities that were submitted to the virtual screening (VS) program.
  • VS virtual screening
  • the VS program compares MIFs amongst two molecules. It performs a flexible superimposition of the MIFs of two molecules in 3D space, and estimates their best similarity (Hercules score). Those molecules that have functional groups that create similar MIFs to the reference structure are ranked higher than those that do not fulfil this requirement. Accordingly, Hercules is able to rank the database of commercial compounds proposing the molecules with a higher probability to be disruptors of the AEG-l/p65 complex. From the pool of 217,667 molecules, 60 molecules were selected which showed the best characteristics. 16 entities selected on the basis of chemical eye and initial estimates of availability. Such 16 entities were subjected to an in-depth analysis of availability, cost and previous evidence of antitumor activity. 4 chemical entities finally were selected as the panel for in vitro studies.
  • IC50 values of PB0412 on the proliferation of the A549, H460 and PC9 cell lines were of, respectively, 14,2 ⁇ , 42.4 ⁇ and 33.9 ⁇ .
  • different modifications in the acidic group of the molecule were carried out.
  • the molecule has two absorption maxima in the UV at 243.7 and 341.1 (Fig.
  • This candidate showed in IC50 values of 1.4 ⁇ , 1.7 ⁇ , 0.7 ⁇ for the A549,
  • reaction mixture was poured onto cold water.
  • the precipitated solid is decanted and washed with 3v of water of 20 mL each.
  • the solid is then dissolved in ethyl acetate and washed successively with 2v x 20 mL of 5% NaHC03 solution and saturated sodium chloride.
  • the ethyl acetate solution was dried with anhydrous magnesium sulphate, filtered and dried by evaporation of the solvent.
  • the resulting solid is dissolved in 50% acetonitrile/water and lyophilized.
  • the acetonitrile is evaporated and the residue dissolved in ethyl acetate and washed with 3v x 20 mL water and saturated sodium chloride, the resulting solution is dried with anhydrous magnesium sulphate, the solvent is evaporated, dissolved in 50% acetonitrile water and lyophilized.
  • the mixture is poured over cold water and the precipitated solid decanted and washed with water.
  • the solid is dissolved in ethyl acetate and washed successively with 2x20mL of a 5% NaHC0 3 solution and saturated sodium chloride.
  • the ethyl acetate solution is dried with anhydrous magnesium sulphate, filtered, the solvent evaporated and dissolved in 50% acetonitrile in water and lyophilized.
  • the mixture was poured over cold water and the precipitated solid decanted and washed with water.
  • the solid was dissolved in ethyl acetate and washed successively with 2x20 mL of a 5% NaHC0 3 solution and saturated sodium chloride.
  • the ethyl acetate solution was dried with anhydrous magnesium sulphate, filtered, the solvent evaporated and dissolved in 50% acetonitrile water and lyophilized.
  • reaction mixture was poured onto cold water.
  • the precipitated solid was decanted and washed with 3v of water of 20 mL each.
  • the solid was then dissolved in ethyl acetate and washed successively with 2v x 20 mL of 5% NaHCC"3 solution and saturated sodium chloride.
  • the ethyl acetate solution was dried with anhydrous magnesium sulphate, filtered and dried by evaporation of the solvent.
  • the resulting solid was dissolved in 50% acetonitrile/water and lyophilized.
  • reaction mixture was poured onto cold water.
  • the precipitated solid is decanted and washed successively with water.
  • the solid is dried with P 2 0 5 and purified by HPLC.
  • Benzoic acid-3[[2-chloro-6-methoxy-4-[[3-[2-[(4-methylphenyl)amino]-2- oxoethyl]-2,4-dioxo-5-thiazolidinylidene]methyl]-phenoxy]methyl] 50 mg, 8.82xl0 "5 mol
  • cyclohexylamine 11 ⁇ , 8.82xl0 "5 mol
  • PyAOP 46 mg, 8.82x10 " 5 mol
  • DIEA 23 ⁇ , 1.33xl0 "4 mol
  • the mixture is poured onto cold water and the precipitated solid decanted and washed with 3v x 20 mL of water.
  • the solid is dissolved in ethyl acetate and washed successively with 2v x 20mL of a 5% NaHC0 3 solution and saturated sodium chloride.
  • the ethyl acetate solution is dried with anhydrous magnesium sulphate, filtered and the solvent is evaporated and dissolved in 50% acetonitrile water and lyophilized. 46 mg of PB0412-3 were obtained, which results in a 80% yield.
  • the in vitro characterization of PB0412-3 was conducted in a cell panel which has been genotypically and pheno typically broadly characterized at the molecular level and demonstrative of human cancer sub-types.
  • This panel includes 21 cell lines representative of solid tumors, cell lines representative of glial-derived cell tumors (e.g. glioblastoma) and cell lines representative of neural crest-derived tumors (Neuroblastoma and Melanoma).
  • the panel also incorporates 4 human non tumoral cell lines to assess the in vitro therapeutic index.
  • the panel is clinically relevant as it has been characterized for cross resistance parameters too.
  • Table 1 The composition of the panel as well as the mutational/expression/functionality gene status of the cells forming the panel is shown in Table 1.
  • Table 1 Properties of the panel of cell lines tested for sensitivity to PB0412-3.
  • the cell panel includes cell lines representative of different tumor lines (lung prostate, breast and pancreas cancer), cell lines representative of glial-derived tumors, cell lines representative of neuroblastoma, which is a neural crest derived tumor and cell lines representative of the cells present in the reactive tumor stroma.
  • HM Hypermethylation.
  • IHC Immunocytochemistry.
  • the selection of the human solid tumor cell line panel has been done, in strict adherence to our drug discovery and development procedures to warrant the incorporation of a constellation of solid tumor sub-types that are scientifically and clinically representative.
  • the elements of the panel are based on a rational foundation. This panel represents the elements to allow, in adherence with the established eligibility criteria, the identification of a candidate as a lead for further development
  • AEG-1 is instrumental in the pathogenesis of neural crest derived tumors such as Neuroblastoma.
  • Neural Crest derived has been also incorporated into the panel. This allows the assessment of the antiproliferative profile of PB0412-3 in Neuroblastoma and in melanoma, both Neural Crest Derived tumors.
  • AEG-1 is highly expressed in malignant tumors as compared with intrapatient normal tissue pairs.
  • a representative panel of four human non tumoral cell lines has been also studied to generate objective evidence of compound's therapeutic index.
  • the results of the in vitro experiments are summarized in Table 2.
  • DLD-1 Colon Adenocarcinoma 1,3 12 8,6 0,9 7,7 0,019 NA NA
  • Table 2 Results of the in vitro characterization of PB0412-3 in a cell panel. The experiment was conducted in a small panel of human tumor cell lines of lung, prostate, breast, pancreas and glioblastomas, as well as 2 human non-tumoral cell lines. The results include the IC50 ( ⁇ ) of PB0412-3 and the IC50s in response to cisplatin, TMZ and MTIC.
  • the in vitro results are summarized in Table 2 and in Fig. 4A.
  • the compound shows consistent in vitro activity at low micromolar concentrations in different tumor types.
  • the data indicates (see Table2) that the in vitro antitumor activity of PB0412-3 is independent of EGFR and KRAS mutations, p53 mutation status, PIK3A mutations, HER2 amplification, MGMT methylation status as well as BRAF-1 mutation genotype.
  • the antiproliferative effects of PB0412-3 in human cancer cells appear to be independent of such molecular indicators of tumor cell's aggressivity.
  • the median IC50 in the solid tumor panel is 1.22 ⁇ (0.7-1.5) (Fig. 4C).
  • glioma (Glioblastoma Multiforme/GBM) subpanel demonstrates high sensitivity of this tumor type to PB0412-3 with an IC50 mean of 11 1 nM (60-220). These significant (p ⁇ 0.0001) differences in sensitivity cope with the model of inhibition since AEG-1 is a main multionco genie driver in brain tumors.
  • Figures 3, 4Band 4E integrate the evidence generated; a distinct sensitivity profile within the different human tumor cell lines exposed to PB0412-3 does emerge from this.
  • This evidence distinct sensitivity to PB0412-3 of GBM, Neuroblastomas and melanoma, reinforces the notion of a specific mode of action based on AEG-1 disruption.
  • the mean IC50 for the GMN lines is of 400 nM.
  • the IC50s of the melanoma human cells is 490 nM, 592 nM and 1.7 ⁇ .
  • the low nanomolar active concentrations of PB0412-3 in the two neuroblastoma cell lines included in the panel IC50s of 130 nanomolar and 80 nanomolar respectively.
  • Table 2 shows the antiproliferative pattern of PB0412-3 in a panel of human normal cell lines.
  • the selection of tissue types has been prospective and based on literature 's(peer review journals) AEG-1 expression data in normal tissues.
  • the panel includes chondrocytes, fibroblasts , prostate myofibroblasts and epithelial gingival cells.
  • the correlative IC50' values for these cell types is 2.60 ⁇ , 1.5 ⁇ , 1.56 ⁇ and 2.67 ⁇ respectively (Fig. 4D).
  • the mean IC50 of PB0412-3 in non- cancer cell lines is of 2.08 ⁇ , therefore demonstrating a positive in vitro therapeutic index and putting into perspective a positive pharmacological window.
  • the lowest IC50to PB0412-3 exposure in human non cancer cell lines is 1.5 ⁇ .
  • a value of 1.3 ⁇ was established as the cut-off for sensitivity/resistance to PB0412-3; i.e. human tumor cell lines with IC50'shigher than 1.3 ⁇ ⁇ considered resistant to PB0412-3; this strict and rational criteria defines as resistant to PB0412-3 (4/21 or 23% of human cell lines integrated in the panel).
  • AEG-1 functionality leads to pleiotropic drug resistance to conventional and new generation anticancer agents (see AEG-l/MTDH/Lyric implicated in Multiple Human Cancers, in Advances in Cancer Research, Sarker, ed., August 2013, Academic Press, ISBN: 978-0-12-401676-7).
  • our findings support the notion of a lack of impact of AEG-1 levels in the sensitivity to PB0412-3.
  • the median AEG-1 expression level is 1.1(0.2-3.9).
  • glioblastoma cell lines bear high expression levels, the highest within the panel2 and6.4, and are highly sensitive to PB0412-3 (IC50s60 nM, 60 nM and 290 M in the glioblastoma LN229 and T98G cell lines).
  • a solid body of evidence correlates mutations of BRAF-1 gene, most common as V600e mutation, with increased tumor's resistance to anticancer agents.
  • Mutated BRAF-1 gene is a frequent finding in human malignant melanoma: all the 3 human melanoma cancer cell lines included in the panel harbour V600E BRAF-1 mutation.
  • Cell lines WM115 and UACC903 are sensitive to PB0412-3 with IC50's of 490 nM and 592 nM respectively.
  • the WM793 human melanoma bears a pb0412_3 IC50 of 1.7 micromolar. This evidence sustains the notion of a BRAF-1 independent sensitivity of human malignant melanoma to PB0412-3.
  • PB0412-3 PB0412-3 IC50's in GBM are significantly lower than the IC50s of Carmustine (BCNU) for the same cell lines, which are in the range of 15 to 50 ⁇ . Accordingly, these results show that PB0412-3 is significantly more potent than the most active nitrosoureas, which are the compounds currently available to treat glioblastoma patients.
  • the panel includes the comparative data with Cisplatin, TMZ and MTIC in the human cell line panel.
  • Cisplatin is a DNA interacting agent that represents the paradigm of broad spectrum antitumor activity. These data indicate that PB0412-3 is much more potent, in a molar basis, than Cisplatin.
  • PB0412-3 mean IC50 is of 238 nM (60-400 nM), whereas the median IC50 for TMZ >100 micromolar (>100->100) and the median IC50 for MTIC is > 100 ⁇ (>100->100).
  • PB0412-3 is 1000-fold more potent than TMZ and MTIC.
  • PB0412-3 was tested for its ability to inhibit proliferation of neuroblastoma cells.
  • Neuroblastoma is the most common pediatric tumor.
  • the rate of resistant patients is significant, 30%and the prognosis in advanced relapsed patients is poor with median survival rates between 12 and 18 months.
  • TMZ is a therapeutic option in children bearing advanced relapsed neuroblastoma
  • the effect of PB0412-3 and TMZ was tested in the SH-SYSY and SK-NSH neuroblastoma cell lines. The results are shown in Table 2.
  • PB0412-3 The mean IC50's for PB0412-3 are 130 nM and 80 nM respectively, whereas the mean IC50's for TMZ are 54.5 ⁇ and >100 ⁇ respectively and the mean IC50's for MTIC are >100 and >100 respectively.
  • PB0412-3 is between 500-1000 fold more potent than TMZ and its active metabolite MTIC.
  • the methylation status of the MGMT relates to sensitivity of GBM and neuroblastoma to TMZ and to its active metabolite MTIC.
  • unmethylated (and hence functional) MGMT results in resistance to TMZ, to its active metabolite and to radiation therapy in GBM and neuroblastoma.
  • IC50's of PB0412-3 no differences in the IC50's of PB0412-3 were found between human cancer cell lines SH-SYSY (which bears a functional, unmethylated MGMT gene) and the SK-N-SH cell lines (which bears a nonfunctional, methylated MGMT gene).
  • the mean IC50s of PB0412-3 for the different groups of cells lines tested is of 2,08 ⁇ for the non tumoral cell lines, 1,22 ⁇ for the human solid tumor cell lines, 400 nM for the human glial (GBM) and neural crest derived tumor cells.
  • GBM human glial
  • Such deltas are statistically significant.
  • 33% of human solid tumor cell lines tested appear to be resistant to PB0412-3 exposure; in contrast 9% of Glial and Neural Crest derive malignancies shown to be resistant to PB0412-3.
  • PB0412-3 is highly potent in human glioblastoma multiforme, neuroblastoma and malignant melanoma (p ⁇ 0.0001vs. other solid tumors).
  • GBM is an AEG- 1 functionality dependent on AEG-1 tumor, AEG-1 is a major oncogenic driver in a neuroblastoma, which is representative of neural crest-derived tumors.
  • IC50s are below 500 nM including two human GBM tumors bearing PB0412-3 IC50's of 60 nM.
  • the 2 human neuroblastoma tumors tested harbour PB0412-3 IC50's of 80 nM and 130 nM respectively.
  • PB0412-3 bears a positive therapeutic index with a mean IC50's in 4 non-tumoral human samples 2.08 ⁇ .
  • Post CT Post-treatment

Abstract

La présente invention concerne des composés antitumoraux qui ont été conçus pour rompre fonctionnellement la communication entre AEG-1 et la sous-unité p65 de NF-κB. Par conséquent, l'invention concerne des procédés et des compositions pour le traitement du cancer au moyen des composés identifiés dans la présente invention, ainsi que des compositions adéquates pour la libération prolongée des composés de l'invention à administrer au site chirurgical après résection de la tumeur. L'invention concerne en outre des procédés pour la synthèse des composés de l'invention.
PCT/EP2014/062159 2013-10-25 2014-06-11 Compositions et procédés pour le traitement du cancer WO2015058868A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP13382427.6 2013-10-25
EP13382427 2013-10-25

Publications (1)

Publication Number Publication Date
WO2015058868A1 true WO2015058868A1 (fr) 2015-04-30

Family

ID=49517467

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/062159 WO2015058868A1 (fr) 2013-10-25 2014-06-11 Compositions et procédés pour le traitement du cancer

Country Status (1)

Country Link
WO (1) WO2015058868A1 (fr)

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526938A (en) 1982-04-22 1985-07-02 Imperial Chemical Industries Plc Continuous release formulations
US4757128A (en) 1986-08-01 1988-07-12 Massachusetts Institute Of Technology High molecular weight polyanhydride and preparation thereof
WO1991005548A1 (fr) 1989-10-10 1991-05-02 Pitman-Moore, Inc. Composition a liberation entretenue pour proteines macromoleculaires
US5128326A (en) 1984-12-06 1992-07-07 Biomatrix, Inc. Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same
WO1996020698A2 (fr) 1995-01-05 1996-07-11 The Board Of Regents Acting For And On Behalf Of The University Of Michigan Nanoparticules a modification de surface et leurs procedes de fabrication et d'utilisation
US5679377A (en) 1989-11-06 1997-10-21 Alkermes Controlled Therapeutics, Inc. Protein microspheres and methods of using them
WO1999015154A1 (fr) 1997-09-24 1999-04-01 Alkermes Controlled Therapeutics, Inc. Procedes de fabrication de preparations de liberation controlee a base de polymere
WO1999020253A1 (fr) 1997-10-23 1999-04-29 Bioglan Therapeutics Ab Procede d'encapsulage
US5912015A (en) 1992-03-12 1999-06-15 Alkermes Controlled Therapeutics, Inc. Modulated release from biocompatible polymers
US5916597A (en) 1995-08-31 1999-06-29 Alkermes Controlled Therapeutics, Inc. Composition and method using solid-phase particles for sustained in vivo release of a biologically active agent
US7318931B2 (en) 2001-06-21 2008-01-15 Genentech, Inc. Sustained release formulation
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526938A (en) 1982-04-22 1985-07-02 Imperial Chemical Industries Plc Continuous release formulations
US5128326A (en) 1984-12-06 1992-07-07 Biomatrix, Inc. Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same
US4757128A (en) 1986-08-01 1988-07-12 Massachusetts Institute Of Technology High molecular weight polyanhydride and preparation thereof
WO1991005548A1 (fr) 1989-10-10 1991-05-02 Pitman-Moore, Inc. Composition a liberation entretenue pour proteines macromoleculaires
US5679377A (en) 1989-11-06 1997-10-21 Alkermes Controlled Therapeutics, Inc. Protein microspheres and methods of using them
US5912015A (en) 1992-03-12 1999-06-15 Alkermes Controlled Therapeutics, Inc. Modulated release from biocompatible polymers
WO1996020698A2 (fr) 1995-01-05 1996-07-11 The Board Of Regents Acting For And On Behalf Of The University Of Michigan Nanoparticules a modification de surface et leurs procedes de fabrication et d'utilisation
US5916597A (en) 1995-08-31 1999-06-29 Alkermes Controlled Therapeutics, Inc. Composition and method using solid-phase particles for sustained in vivo release of a biologically active agent
WO1999015154A1 (fr) 1997-09-24 1999-04-01 Alkermes Controlled Therapeutics, Inc. Procedes de fabrication de preparations de liberation controlee a base de polymere
US5989463A (en) 1997-09-24 1999-11-23 Alkermes Controlled Therapeutics, Inc. Methods for fabricating polymer-based controlled release devices
WO1999020253A1 (fr) 1997-10-23 1999-04-29 Bioglan Therapeutics Ab Procede d'encapsulage
US7318931B2 (en) 2001-06-21 2008-01-15 Genentech, Inc. Sustained release formulation
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
"Advances in Cancer Research", August 2013, ACADEMIC PRESS, article "AEG-1/MTDH/Lyric implicated in Multiple Human Cancers"
"Controlled Drug Bioavailability, Drug Product Design and Performance", 1984, WILEY
"Medical Applications of Controlled Release", 1974, CRC PRES.
BAKER ET AL.: "Controlled Release of Biological Active Agents", 1986, JOHN WILEY AND SONS
CANCER RES, vol. 68, 2008, pages 1478
CLEEK ET AL.: "Biodegradable Polymeric Carriers for a bFGF Antibody for Cardiovascular Application", PRO. INT'L.SYMP.CONTROL. REL. BIOACT. MATER., vol. 24, 1997, pages 853 - 854
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 3 March 2003 (2003-03-03), XP002724414, Database accession no. 496768-41-3 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 3 March 2003 (2003-03-03), XP002724415, Database accession no. 496768-27-5 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 6 October 2004 (2004-10-06), XP002724413, Database accession no. 757224-15-0 *
DRUG DISCOV. TODAY, vol. 15, 2010, pages 23
DURING ET AL., ANN. NEUROL., vol. 25, 1989, pages 351
EMDAD ET AL., MOL. CANCER THER., vol. 9, 2010, pages 79 - 88
GOODSON, MEDICAL APPLICATIONS OF CONTROLLED RELEASE, vol. 2, 1984, pages 115 - 138
HOWARD ET AL., J. NEUROSURG., vol. 7 1, 1989, pages 105
KUMAR, UDAY CHANDRA ET AL: "Discovery of novel InhA reductase inhibitors: application of pharmacophore- and shape-based screening approach", FUTURE MEDICINAL CHEMISTRY , 5(3), 249-259 CODEN: FMCUA7; ISSN: 1756-8919, 1 March 2013 (2013-03-01), XP009177727, DOI: 10.4155/FMC.12.211 *
L. CHAS. RAIFORD ET AL: "THE CHLORINE DERIVATIVES OF VANILLIN AND SOME OF THEIR REACTIONS", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 52, no. 11, 1 November 1930 (1930-11-01), pages 4576 - 4586, XP055115224, ISSN: 0002-7863, DOI: 10.1021/ja01374a061 *
LAM ET AL.: "Microencapsulation of Recombinant Humanized Monoclonal Antibody for Local Delivery", PROC. INT'L. SYMP. CONTROL REL. BIOACT. MATER., vol. 24, 1997, pages 759 - 760
LANGER, SCIENCE, vol. 249, 1990, pages 1527 - 1533
LEVY ET AL., SCIENCE, vol. 228, 1985, pages 190
LIU ET AL., J. EXP. CLIN. CANCER RES., vol. 28, 2009, pages 19
NING ET AL.: "Intratumoral Radioimmunotheraphy of a Human Colon Cancer Xenograft Using a Sustained-Release Gel", RADIOTHERAPY AND ONCOLOGY, vol. 39, 1996, pages 179 - 189
PRASHANTHA KUMAR B R ET AL: "Novel glitazones: glucose uptake and cytotoxic activities, and structureâ activity relationships", MEDICINAL CHEMISTRY RESEARCH, BIRKHÄUSER-VERLAG, BO, vol. 21, no. 9, 21 September 2011 (2011-09-21), pages 2689 - 2701, XP035092206, ISSN: 1554-8120, DOI: 10.1007/S00044-011-9792-0 *
PRASHANTHA KUMAR B R ET AL: "Synthesis, glucose uptake activity and structureactivity relationships of some novel glitazones incorporated with glycine, aromatic and alicyclic amine moieties via two carbon acyl linker", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 46, no. 3, 15 December 2010 (2010-12-15), pages 835 - 844, XP028142248, ISSN: 0223-5234, [retrieved on 20101223], DOI: 10.1016/J.EJMECH.2010.12.019 *
RANGER; PEPPAS, J., MACROMOL. SCI. REV. MACROMOL. CHEM., vol. 23, 1983, pages 61
S. H. DANDEGAONKER ET AL: "Chlor-hydroxychalkone", MONATSHEFTE FÜR CHEMIE - CHEMICAL MONTHLY, vol. 96, no. 4, 1 January 1965 (1965-01-01), pages 1214 - 1223, XP055115213, ISSN: 0026-9247, DOI: 10.1007/BF00904270 *
SARKAR ET AL., CANCER RES., vol. 68, 2008, pages 1478 - 1484
SONG ET AL.: "Antibody Mediated Lung Targeting of Long-Circulating Emulsions", PDA JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 50, 1995, pages 372 - 397
YOO ET AL., PHARMACOL. THER., vol. 130, 2011, pages 1 - 8
ZHANG ET AL., ZHONGHUA ZHONG LIU ZA ZHI., vol. 35, 2013, pages 22 - 7

Similar Documents

Publication Publication Date Title
TWI598341B (zh) 苯達莫司汀衍生物及其使用方法
AU2006230159A1 (en) Pharmacokinetically improved compounds
Duan et al. Multi-arm polymeric nanocarrier as a nitric oxide delivery platform for chemotherapy of head and neck squamous cell carcinoma
AU2010222848A1 (en) Rho kinase inhibitors
Zolotarskaya et al. Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug
Mamnoon et al. Hypoxia-responsive, polymeric nanocarriers for targeted drug delivery to estrogen receptor-positive breast cancer cell spheroids
KR20140074880A (ko) 암의 치료를 위한 조성물 및 방법
Xu et al. Synthesis, cytotoxicity, and mechanistic investigation of platinum (IV) Anticancer Complexes Conjugated with Poly (ADP-ribose) polymerase inhibitors
Banerjee et al. X-ray crystallography-guided design, antitumor efficacy, and QSAR analysis of metabolically stable cyclopenta-pyrimidinyl dihydroquinoxalinone as a potent tubulin polymerization inhibitor
CN112770755A (zh) 平台药物fl118位置7和9衍生的类似物的组成，合成，制备和应用治疗人类疾病
Sivaiah et al. Synthesis, anticancer activity and molecular docking of new pyrazolo [1, 5-a] pyrimidine derivatives as EGFR/HER2 dual kinase inhibitors
Yang et al. Novel benzo five-membered heterocycle derivatives as P-glycoprotein inhibitors: design, synthesis, molecular docking, and anti-multidrug resistance activity
TW201305130A (zh) 突變雄激素受體拮抗藥
WO2015058868A1 (fr) Compositions et procédés pour le traitement du cancer
Singh et al. Fabrication of TPGS-grafted polyamidoamine dendrimer for enhanced piperine brain delivery and pharmacokinetics
Mukherjee et al. Design and synthesis of a dual imageable theranostic platinum prodrug for efficient cancer therapy
JP6461088B2 (ja) 高分子化カンプトテシン誘導体及び高分子化ｈｓｐ９０阻害剤誘導体を含む医薬組成物
US20230095288A1 (en) Metal salts and uses thereof
TW202028181A (zh) 尼拉帕尼（niraparib）鹽
TW202043203A (zh) 1,2,4-三-3(2h)-酮化合物
WO2022042583A1 (fr) Macromolécule chargée en médicament et sa méthode de préparation
JP2023552368A (ja) Ｙボックス結合タンパク質１阻害剤
CN111511364A (zh) 靶向治疗剂
JP6580030B2 (ja) カンプトテシン誘導体とｈｓｐ９０阻害剤の結合した高分子化合物及びその用途
Wang et al. Preparation of a camptothecin analog FLQY2 self-micelle solid dispersion with improved solubility and bioavailability

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14729352

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14729352

Country of ref document: EP

Kind code of ref document: A1