WO2009018344A1 - Agents anticancéreux - Google Patents

Agents anticancéreux Download PDF

Info

Publication number
WO2009018344A1
WO2009018344A1 PCT/US2008/071598 US2008071598W WO2009018344A1 WO 2009018344 A1 WO2009018344 A1 WO 2009018344A1 US 2008071598 W US2008071598 W US 2008071598W WO 2009018344 A1 WO2009018344 A1 WO 2009018344A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
cancer
mmol
nmr
mhz
Prior art date
Application number
PCT/US2008/071598
Other languages
English (en)
Inventor
Krzysztof Pankiewicz
Liqiang Chen
Robert Vince
Original Assignee
Regents Of The University Of Minnesota
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 Regents Of The University Of Minnesota filed Critical Regents Of The University Of Minnesota
Publication of WO2009018344A1 publication Critical patent/WO2009018344A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • Nicotinamide adenine dinucleotide plays an important role in biology and medicine.
  • the NAD binding sites of many enzymes have sufficient variation to allow the development of agents highly selective for an enzyme of particular interest.
  • selective inhibition of NAD-dependent IMP-dehydrogenase IMPDH
  • IMPDH NAD-dependent IMP-dehydrogenase
  • IMPDH emerged as an important therapeutic target for diseases that include cancer (Chen, L.et al., Curr. Med. Chem. 2008, 15, 650-670; and Pankiewicz, K. W., et al., In ASC Symposium Series; Pankiewicz, K. W., Goldstein, B. M. Eds., Oxford University Press: Washinghton, 2003).
  • Inhibitors of IMPDH in general, show a significant ability to trigger differentiation and/or apoptosis (Gu, J. J., et al., Blood 2005, 105, 3270-3277; Inai, K., et al., Leuk Res 2000, 24, 761-768; and Inai, K., et al., Adv Exp Med Biol 1998, 431, 549-553).
  • Histone deacetylases enzymes that catalyze the removal of acetyl-groups from lysine residues of histones, represent a new class of anticancer targets (Mei, S., et al., Int J Oncol 2004, 25, 1509-1519).
  • HDACs inhibitors alter gene transcription and exert anti-tumor effects through growth arrest, apoptosis, differentiation, and inhibition of tumor angiogenesis.
  • differentiation triggered by HDAC inhibitors is based on a fundamentally different mechanism than that caused by inhibition of IMPDH (Kim, D. H.;et al., J Biochem MoI Biol 2003, 36, 110-119; Grunstein, M. Nature 1997, 389, 349-352; Mahlknecht, U., et al., MoI Med 2000, 6, 623-644; and Kouraklis, G., Theocharis, Oncol Rep 2006, 15, 489-494).
  • class I, II and IV HDACs require zinc for catalytic deacetylation while class III HDACs consists of seven sirtuins which are NAD dependent and do not share homologies with the zinc dependent histone deacetylases (Mai, A., et al., J Med Chem 2005, 48, 7789-7795; Yang, T., Sauve, A. A. Aaps J 2006, 8, E632-643; and Sauve, A. A., et al., MoI Cell 2005, 17, 595-601).
  • the zinc dependent HDACs inhibitors can be divided into several classes such as short-chain fatty acids, benzamides, and hydroxamic acids. Three structural regions can be distinguished in these molecules; a cap (usually aromatic) region, a linker, and a metal binding group. For the metal binding group, hydroxamic acids usually exhibit higher potency then the corresponding benzamides.
  • SAHA suberoylanilide hydroxamic acid
  • CML is a malignant cancer of the bone marrow that causes rapid growth of blood forming cells (myeloid precursors) in the bone marrow, peripheral blood, and body tissues.
  • the hallmark of CML is the Philadelphia chromosome translocation, which fuses the her and c-abl genes resulting in expression of a constitutively active tyrosine kinase.
  • BC blast crisis
  • HDAC/IMPDH histone deacetylase inhibitors
  • the invention provides a compound of formula I:
  • A is:
  • n 1 , 2, 3, 4, 5, or 6; or a salt thereof.
  • the invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method for treating cancer in a patient, comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to the patient.
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in medical treatment or diagnosis.
  • the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, to prepare a medicament useful for treating cancer in an animal.
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of cancer.
  • the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with other anticancer drugs for treating malignancies.
  • the dual inhibitors of the invention show inhibitory activity against both IMPDH and HDACs. Both enzymes are important targets for anticancer drugs.
  • Compound 119 described herein is one of the most potent differentiation agents ever reported.
  • alkyl denotes both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (Ci-C 4 )alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • a specific value for aryl is phenyl, indenyl, or naphthyl.
  • a specific value for heteroaryl is furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
  • A is:
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • B is In one embodiment of the invention, L is a saturated or unsaturated, branched or unbranched, Ci-Cio hydrocarbon.
  • L is a saturated or unsaturated, branched or unbranched, Ci-C 5 hydrocarbon.
  • L is a saturated or unsaturated, branched or unbranched, C 4 -C 7 hydrocarbon.
  • L is a saturated or unsaturated, branched or unbranched, Ci -C 3 hydrocarbon.
  • L is,
  • L is,
  • the compound of formula I is selected from,
  • the compound of formula I is:
  • the cancer is leukemia.
  • the cancer is chronic myelogenous leukemia.
  • the cancer is prostate or colon cancer.
  • the cancer is a solid cancer.
  • the treatment destroys cancer stem cells.
  • a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ - glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the 1 ablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • Monomethyl ester 118 A solution of suberic acid monomethyl ester (116, 411 mg, 2.18 mmol), EDC (650 mg, 3.28 mmol), HOBt (295 mg, 2.18 mmol) and aniline 117 (458 mg, 2.41 mmol) in anhydrous CH 2 Cl 2 (15 mL) was stirred at room temperature for 48 hours. After concentration, the residue was diluted with EtOAc (100 mL) and washed with 0.1 N HCl (50 mL), water (50 mL), sat. NaHCO 3 (50 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4 and filtered.
  • Representative compounds of the invention 16a-19b were prepared as illustrated and described below.
  • R CN a Reaction conditions: (a) aniline 24 or 25, triphosgene, Et 3 N, CH 2 Cl 2 ; (b) TFA, CH 2 Cl 2 ; (c) H 2 N- OTr, EDC, HOBt, DMF; (d) TFA, Et 3 SiH, CH 2 Cl 2 .
  • the filtrate was concentrated and re-dissolved in anhydrous DMF (60 mL). After NaN 3 (1.84 g, 28.3 mmol) was added at rt, the resulting mixture was heated at 50 0 C for 30 minutes and cooled to room temperature. The mixture was then diluted with EtOAc (300 mL) and washed with water (3x60 mL) and brine (2 ⁇ 100 mL). The organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated and re-dissolved in a mixture of THF (60 mL) and water (6 mL). After PPh 3 (4.34 g, 16.6 mmol) was added at room temperature, the reaction mixture was allowed to stir at room temperature overnight and then concentrated.
  • 29 can be prepared as described by Gu, H. H., et al. Bioorg. Med. Lett. 2002, 12, 1323-1326.
  • Ethyl ester 34b Preparation of Ethyl ester 34b. Following procedures similar to those described for ethyl ester 34a, 3-methoxy-4-(oxazol-5-yl) aniline (24, 570 mg, 3.0 mmol) and ethyl 3-aminocinnamate (33b, 382 mg, 2.0 mmol) were combined to give ethyl ester 34b (220 mg, 27%).
  • Ethyl ester 34c Preparation of Ethyl ester 34c. Following procedures similar to those described for ethyl ester 34a, 4-cyano-3-methoxy aniline hydrochloride (25, 554 mg, 3.0 mmol) and ethyl 4-aminocinnamate hydrochloride (33a, 555 mg, 2.0 mmol) were combined to give ethyl ester 34c (710 mg, 97%).
  • Ethyl ester 34d Preparation of Ethyl ester 34d. Following procedures similar to those described for ethyl ester 34a, 4-cyano-3-methoxy aniline hydrochloride (25, 369 mg, 2.0 mmol) and ethyl 3-aminocinnamate (33b, 573 mg, 3.0 mmol) were combined to give ethyl ester 34d (485 mg, 66%).
  • IMPDH Inhibition assays were performed as previously described (Umejiego, N. N. et al., J Biol Chem 2004, 279, 40320-40327). Briefly, assays were set up in duplicate using two different concentrations of IMPDH type 1 (87 and 155 nM) and type 2 (33 and 66 nM) and varying concentrations of inhibitor.
  • IMPDH and inhibitors were added to 100 ⁇ l reaction buffer (50 mM Tris, pH 8.0, 100 mM KCL, 1 mM DTT, 100 ⁇ M IMP, 100 ⁇ M NAD) at 25 degrees C, mixed gently and the production of NADH was monitored by following changes in absorbance at 340 nm on a Molecular Devices M5e multimode plate reader. Steady state velocities were used to determine IC50 and K, App values by fitting the velocities vs. inhibitor concentration to the sigmoidal concentration-response curve (variable slope) and the Morrison equation respectively using
  • HDAC inhibition assays were performed using the HDAC Activity/Inhibitor Screening Assay Kit (Cayman Chemical) per the manufacturers instructions. Inhibitors were suspended in either DMSO or Methanol. End point readings were used to determine IC 5O values by fitting the fractional fluorescence vs. inhibitor concentration to the sigmoidal concentration-response curve (variable slope) using GraphPad Prism. Curves were corrected for Auto-fluorescence by making a standard concentration curve, substituting compound for solvent using the background well conditions.
  • K562 cells Inhibition of proliferation of K562 cells. About 2000 cells/well of logarithmically growing human myelogenous leukemia K562 cells were plated into 96-well plates and incubated at 37 °C for 24 hours. Compounds at final concentrations up to 100 ⁇ M were added in duplicate wells in 0.15% DMSO (final concentration), mixed and incubated for 72 hours. At the end of the incubation period 20 ⁇ l of MTS reagent was added, mixed and further incubated for 3 hours and then absorbance read at 490 nm in a plate reader. Control cells exhibited 3-doublings (doubling time was 24 hours).
  • K562 cells Differentiation of K562 cells.
  • Logarithmically growing K562 cells (1.0 x 10 3 cells/0.1 ml) were plated in triplicate into 96-well plates in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum and antibiotics and incubated at 37 0 C in an atmosphere of air and 5% CO 2 . Twenty-four hours later compounds were added and further incubated for 5 days. For examining effect of compounds on cytotoxicity, 20 ⁇ l of MTS reagent was added and further incubated for 3 hours and the absorbance was read at 490 nm.
  • IMPDH/HDAC inhibitors Evaluation of the therapeutic potential of IMPDH/HDAC inhibitors in xenograft mouse model for CML.
  • the therapeutic potential of IMPDH/HDAC inhibitors can be determined as described by Patterson at al., Developments in Nucleic Acids, IHL Press, 2004, see ref. 44). Evaluation of the therapeutic potential of IMPDH/HDAC inhibitors in mouse model for CML.
  • BCR-ABL myeloproliferative disease
  • MPD myeloproliferative disease
  • Common features of the disease include high peripheral blood counts (typically several hundred thousand per microliter) with granulocyte predominance, splenomegaly, extramedullary hematopoiesis in liver and pulmonary hemorrhages owing to extensive granulocyte infiltration in the lung. This model was used extensively in studies of the role of domains and downstream signaling pathways of BCR/ABL.
  • C2-MAD mycophenolic adenine dinucleotide
  • K562 is a human CML blast phase cell line.
  • the therapeutic potential of IMPDH inhibitors should also be tested in primary tumor cells. Development of CML is a complex process that involves not only the effects of BCR/ABL, but also the context of its host cells and the rest of the in vivo environment.
  • the therapeutic potential of IMPDH inhibitors in treating BCR/ABL induced CML-like disease can be examined using the mouse bone marrow transduction and transplantation (BMT) model for CML.
  • BMT mouse bone marrow transduction and transplantation
  • BCR/ABL and vector control retroviruses are generated by transiently transfecting BCR- ABL retroviral DNA or vector control into BOSC23 retroviral packaging cell line as described.
  • Freshly isolated mouse bone marrow cells from 5-fluorouracil (5-FU) treated Balb/C mice is transduced with the above retroviruses.
  • 5-FU treatment is to eliminate the proliferating hematopoietic precursor cells and to enrich and stimulate hematopoietic stem cells
  • HSCs The infected bone marrow cells are transplanted into lethally irradiated syngeneic recipient mice.
  • the recipient mice are treated with selected IMPDH inhibitors as described earlier.
  • the toxicity of the candidate inhibitors (LDi 0 ) will be determined prior to the treatment. 10-20% of LDio dose is typically used for the treatment.
  • the diseases are examined following the guidelines recommended by the hematopathology subcommittee of the Mouse Models of Human Cancers Consortium. Generally, beginning at 2 weeks after bone marrow transplantation, mice are monitored with peripheral WBC counts and blood smears using blood from tail bleeds. Immunophenotyping and histopathological analyses of affected tissues or tumor cells can be performed as previously described.
  • Compound 119 was evaluated against a panel of NCI cancer cell lines. Results are shown in the table below (IC 5 O, last column). A low micromolar activity was found against the majority of cell lines tested. Only 6 cell lines out of 55 did not respond. Sub-micromolar activity was found against Leukemia - all major types of leukemia (four out of five cell lines); colon cancer - two out of four cell lines; melanoma - two out of eight cell lines; and breast cancer - two out of seven cell lines
  • Ovarian Cancer OVCAR-4 6 2 5.27 5.3 uM
  • Ovarian Cancer OVCAR-5 6 3 5.27 5.3 uM
  • Ovarian Cancer OVCAR-8 6 5 5.48 3.31 u M
  • the growth inhibitory activity of Compound 119 was compared to that of Gleevec and mycophenolic acid (MPA) in certain NCI cell lines. In general the profiles were similar. Selective results are shown below.
  • Compounds of the invention include compounds that are useful for treatment of chronic myelogenous leukemia (CML) resistant to gleevec (imanitib), a first line targeted therapy drug that inhibits the bcr-abl tyrosine kinase specific for CML.
  • Representative compounds of the invention also show a potent anti-leukemic activity in cells resistant to tiazofurin, an inhibitor of IMP- dehydrogenase, approved for the treatment of patients in blast crisis (BC) of CML.
  • Bcr-Abl tyrosine kinase Numerous second generation inhibitors of the Bcr-Abl tyrosine kinase are in clinical trials (such as nilotinib, Novartis; dasatinib, BMS; and others, see Jorgensen, H. G., et al., Blood 2001, 109, 4016-4019; Copland, M., et al., ; Blood2006, 107, 4532-4539; and Jorgensen, H. G., et al., Leukemia 2005, 19, 1184-1191). Few of them are active against all mutants in gleevec-resistant leukemia. Since compounds of the present invention in certain embodiments do not target the Bcr- AbI tyrosine kinase they are expected to show a potent anti-leukemic activity in cells resistant to gleevec and to the second generation drugs.
  • a unique ability of compounds of certain embodiments of the present invention to differentiate more than 80% of K562 leukemic cells at a low nanomolar concentration indicates a great therapeutic potential. Not only do these compounds convert leukemic cells into non- proliferating, mature cells (able to produce hemoglobin), but they also affect (differentiate) leukemic stem cells, which do not respond to known therapeutic agents. However, when differentiated, cancer stem cells and/or cancer cells described as tumor-propagating cells, become susceptible to drugs including compounds of this invention. At the same low nanomolar concentration the compounds of certain embodiments of the present invention inhibit 100% of proliferation of K562 leukemic cells. The remaining undifferentiated cells may have underwent apoptosis.
  • dual inhibitors of certain embodiments of the present invention Due to a unique ability of dual inhibitors of certain embodiments of the present invention to differentiate cancer cells, such as converting CML cells into non-proliferating cells able to produce hemoglobin, their therapeutic potential is of great interest and extends well beyond CML.
  • the differentiating activities of dual inhibitors are expected to affect cancer stem cells, especially C ML stem cells, which do not respond to known therapeutic agents (see Graham, S. M., et al., BloodlOOl, 99, 319-325; Goodsell, D. S., Stem Cells 2003, 21, 620-621; Scadden, D. T., Best Pract Res Clin Haematol 2007, 20, 19-27; Jordan, C.
  • HDAC/IMPDH dual inhibitory activity
  • a cancer cell differentiation/apoptotic potential offers a new opportunity for successful treatment of not only leukemic malignances but also cancers such as prostate and colon where, e.g., all three components (HDAC, IMPDH, and differentiation/apoptosis) play an important role in controlling the progress of such diseases. Eradication of cancer stem cells is a new goal of modern cancer chemotherapy

Abstract

L'invention concerne un composé de formule A-X-L-B, ou un sel de celui-ci, ainsi que des compositions comprenant un composé de l'invention, et des procédés thérapeutiques qui comprend l'administration d'un composé de l'invention. Les composés de l'invention sont utiles comme agents thérapeutiques pour le traitement de maladies telles que le cancer.
PCT/US2008/071598 2007-07-30 2008-07-30 Agents anticancéreux WO2009018344A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95280007P 2007-07-30 2007-07-30
US60/952,800 2007-07-30

Publications (1)

Publication Number Publication Date
WO2009018344A1 true WO2009018344A1 (fr) 2009-02-05

Family

ID=40304839

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/071598 WO2009018344A1 (fr) 2007-07-30 2008-07-30 Agents anticancéreux

Country Status (1)

Country Link
WO (1) WO2009018344A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012002577A1 (fr) 2010-06-30 2012-01-05 富士フイルム株式会社 Nouveaux dérivés de nicotinamide et leurs sels
EP2408753A2 (fr) * 2009-03-20 2012-01-25 Brandeis University Composés et procédés pour traiter les infections microbiennes gastro-intestinales mammaliennes
US9447134B2 (en) 2012-08-17 2016-09-20 Brandeis University Compounds and methods for treating mammalian gastrointestinal microbial infections
CN106496071A (zh) * 2015-09-07 2017-03-15 上海医药工业研究院 肉桂酰胺类化合物、其盐、中间体、制备方法及应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132825A1 (en) * 2002-03-04 2004-07-08 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20070129368A1 (en) * 2003-12-12 2007-06-07 Bertrand Leblond Tricyclic hydroxamate and benzamide derivatives, compositions and methods

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132825A1 (en) * 2002-03-04 2004-07-08 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20070129368A1 (en) * 2003-12-12 2007-06-07 Bertrand Leblond Tricyclic hydroxamate and benzamide derivatives, compositions and methods

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2408753A2 (fr) * 2009-03-20 2012-01-25 Brandeis University Composés et procédés pour traiter les infections microbiennes gastro-intestinales mammaliennes
EP2408753A4 (fr) * 2009-03-20 2012-11-07 Univ Brandeis Composés et procédés pour traiter les infections microbiennes gastro-intestinales mammaliennes
US8969342B2 (en) 2009-03-20 2015-03-03 Brandeis University Compounds and methods for treating mammalian gastrointestinal microbial infections
US10125116B2 (en) 2009-03-20 2018-11-13 Brandeis University Compounds and methods for treating mammalian gastrointestinal microbial infections
WO2012002577A1 (fr) 2010-06-30 2012-01-05 富士フイルム株式会社 Nouveaux dérivés de nicotinamide et leurs sels
US9447134B2 (en) 2012-08-17 2016-09-20 Brandeis University Compounds and methods for treating mammalian gastrointestinal microbial infections
CN106496071A (zh) * 2015-09-07 2017-03-15 上海医药工业研究院 肉桂酰胺类化合物、其盐、中间体、制备方法及应用
CN106496071B (zh) * 2015-09-07 2018-07-31 上海医药工业研究院 肉桂酰胺类化合物、其盐、中间体、制备方法及应用

Similar Documents

Publication Publication Date Title
EP3289876B1 (fr) Composés destinés à traiter le cancer
EP0708085B1 (fr) Ethers antiviraux des isostères du substrat de l'aspartate-protéase
KR0141692B1 (ko) 맥관 형성 억제제
JP4405602B2 (ja) ヒストン脱アセチル化酵素阻害剤
MXPA05010424A (es) Derivados de oxima y su uso como agentes farmaceuticamente activos.
EA028918B1 (ru) Производные 5-аминотетрагидрохинолин-2-карбоновых кислот и их применение в качестве активатора растворимой гуанилатциклазы
KR20150123894A (ko) 히스톤 데메틸라아제의 저해제
BG107889A (bg) Тетралонови производни като антитуморни средства
EP1988091A1 (fr) Composés tricycliques
TW201825487A (zh) 作為吲哚胺2,3-二加氧酶和/或色胺酸2,3-二加氧酶選擇性抑制劑的新穎的5或8-取代的咪唑並[1,5-a]吡啶
KR20180021820A (ko) Ido 억제제
CZ20014637A3 (cs) Substituované fenoxyoctové kyseliny
WO2009018344A1 (fr) Agents anticancéreux
CZ20014163A3 (cs) Deriváty purinu, způsob jejich přípravy a farmaceutické kompozice tyto deriváty obsahující
JPH11269140A (ja) 分化誘導剤
JPWO2003007931A1 (ja) スルホンアミド誘導体
KR20180073517A (ko) 트리프톨리드의 c14-히드록실 에스테르화 아미노산 유도체, 및 그의 제조 방법 및 용도
AU2022201524A1 (en) Inhibitors of the n-terminal domain of the androgen receptor
EP1698618B1 (fr) Derive de benzamide
EP1206462B1 (fr) Composes heterocycliques inhibiteurs de l'angiogenese
JP2006522012A (ja) ベンゾキサゾシンおよびそのモノアミン再吸収阻害剤としての用途
TWI659022B (zh) 作為d-胺基酸氧化酶(daao)抑制劑之新穎經取代苯并咪唑衍生物
Zhang et al. Synthesis and biological evaluation of N-(aminopyridine) benzamide analogues as histone deacetylase inhibitors
US6552073B1 (en) Compounds and methods of treating cell proliferative diseases
KR101297652B1 (ko) 항암활성을 지닌 카르보아졸계 화합물

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: 08782534

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: 08782534

Country of ref document: EP

Kind code of ref document: A1