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WO2009078586A1 - Composition de prévention et de traitement du cancer contenant des dérivés phényl-amino-thiazolone inhibant l'activité de protéines phosphatases ou des sels pharmaceutiquement acceptables de ceux-ci servant de principe actif - Google Patents

Composition de prévention et de traitement du cancer contenant des dérivés phényl-amino-thiazolone inhibant l'activité de protéines phosphatases ou des sels pharmaceutiquement acceptables de ceux-ci servant de principe actif Download PDF

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Publication number
WO2009078586A1
WO2009078586A1 PCT/KR2008/006716 KR2008006716W WO2009078586A1 WO 2009078586 A1 WO2009078586 A1 WO 2009078586A1 KR 2008006716 W KR2008006716 W KR 2008006716W WO 2009078586 A1 WO2009078586 A1 WO 2009078586A1
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Prior art keywords
linear
group
thiazol
branched
cancer
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PCT/KR2008/006716
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English (en)
Inventor
Seong Eon Ryu
Hwang Seo Park
Suk Kyeong Jung
Dae Gwin Jeong
Sang Hyeup Lee
Seung Jun Kim
Young Jae Bahn
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Korea Research Institute of Bioscience and Biotechnology KRIBB
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Korea Research Institute of Bioscience and Biotechnology KRIBB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to phenyl- amino-thiazolone derivatives which inhibit the activity of protein phosphatases (PPases) such as PTPlB (protein tyrosine phosphatase IB), LAR (leukocyte antigen-related), CD45 (cluster of differentiation 45), Yop (Yersinia enterocolytica tyrosine phosphatase), PPl (protein phosphatases 1), VHR (vaccinia human-related) as well as Cdc25 (cell division cycle 25), and more particularly, to a composition for the prevention and treatment of cancer, which contains the phenyl-amino-thiazolone derivatives and pharmaceutically acceptable salts thereof as an active ingredient.
  • PPases protein phosphatases
  • PTPlB protein tyrosine phosphatase IB
  • LAR leukocyte antigen-related
  • CD45 cluster of differentiation 45
  • Yop Yersinia enterocolytica tyrosine phosphatase
  • Protein phosphorylation and dephosphorylation are widely known as important regulatory mechanisms which are used for cellular signal transduction in various stages of the cellular functions. On the whole, cellular signals are mediated through phosphorylation and dephosphorylation, catalyzed by kinases and protein phosphatases, respectively. Due to their characteristic activities, particularly, protein phosphatases (PPases), which are responsible for dephosphorylation, are known to play pivotal roles in the in vivo modulation and regulation of fundamental cellular signaling mechanisms for metabolism, growth, proliferation and differentiation.
  • PPases protein phosphatases
  • Cdc25 (Cdc25A, Cdc25B, and Cdc25C), functioning to remove phosphate from tyrosine, PTPlB, Prl-3, LAR, CD45, Cdc25A, Yop, PPl, VHR and the like. [3] Hereinafter, the results of the prior researches related to these PPases will be described. [4] l. Cdc25
  • Cdc25 phosphatase is a kind of dual specific phosphatase for acting on both phosphor-tyrosine and phosphor-threonine.
  • the Cdc25 phosphatase is responsible for the activation of cyclin dependent kinase (CDK) by removing inhibitory phosphate from tyrosine and threonine residues of CDK, which is implicated in the cell division cycle.
  • CDK cyclin dependent kinase
  • a high level of CDK induces the activation of the MPF (M phase promoting factor) to increase the miotic activity in the M phase of cell cycle, resulting in cell pro- liferation. Accordingly, inhibiting the activity of the Cdc25 phosphatase interfere with cell division to thus prevent cell proliferation.
  • MPF M phase promoting factor
  • Cdc25 has been reported to have three homologues, Cdc25A, Cdc25B, and Cdc25C, in human cells.
  • Cdc25A or Cdc25B is inferred to play an important role in carcinogenesis because it is the most highly expressed in cancer cells, for example, breast cancer, rectal cancer, non- Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and the like, and recent studies have revealed that Cdc25 A is also included in the adhesion-dependent proliferation of sensitive myeloid leukaemia cells.
  • Cdc25 inhibitors can be targets for developing anticancer agents, extensive and intensive research has been studied on the inhibitors (Ontani, T. et al., J. of Antibiotics 2000, 53, 337; Lazo, J. S. et al., Bioorg. Mded. Chem. Lett. 2000, 8, 1451).
  • PTPIB as the first identified intercellular protein phophastase, was isolated from the human placenta and found to have a molecular weight of -50 kDa, and then cloned.
  • PTPlB is highly expressed in various human cells. Particularly, PTPlB acts to inhibit the phosphorylation not only of insulin receptor (IR) but also of insulin receptor substrate (IRS-I) in the signal transduction pathway of insulin. It was demonstrated through the biochemical experiment conducted by Kennedy and Ramachandran, in which PTPlB knock-out mice were observed to exhibit the increase of insulin sensitivity and, when injected with insulin, to increase the phosphorylation of insulin receptors in hepatic and muscular cells ⁇ Science 1999, 283, 1544).
  • IR insulin receptor
  • IRS-I insulin receptor substrate
  • Diabetes mellitus type II an insulin-indepedent diabetes, is a metabolic disorder that is primarily characterized by insulin resistance of the organs (muscles, liver, lipocytes) where insulin disfunctions, although the pancreas normally secretes insulin.
  • the dephosphorylation of the insulin receptor (IR) was found to be directly responsible for insulin resistance and be implicated in diabetes mellitus type II. Having potential activity to overcome insulin resistance and normalize the level of glucose and insulin in the blood without causing hypoglycemia, accordingly, PTPlB inhibitors, acting against the dephosphorylation of IR, have been extensively studied with the aim of developing therapeutic agents for diabetes mellitus type II.
  • CD45 plays an essential role in terminating the signal transduction responsible for the uncontrollable growth of cells.
  • CD45 a transmembrane PTPase (Protein Tyrosine Phosphatase) was known as an important role in signal transduction in T-cell or B-cells.
  • JAK Janus kinase
  • STAT signal transducer and activators of transcription
  • CD45 negatively regulates interleukin-3 -mediated cellular proliferation, erythropoietin-dependent hematopoieisis and antiviral responses. This indicates that CD45 suppresses the activity of the immune system of attacking foreign invaders, leading to the suppression of cancer cell proliferation and autoimmune diseases. Based on this finding, CD45 inhibitors can be available to prevent transplant rejection. In fact, extensive research into CD45 inhibitors has been conducted and the results thereof are disclosed in many patents and articles, issued to AstraZeneca Company (W 0 0146125, 0145681, 0145680, R. A. Urbanek et al, J. Med. Chem.
  • VHR a dual specific phosphatase, extracellularly regulates extracellular signal receptor kinase 1 (ERKl) and ERK2, both belonging to a subclass of mitogen- activated protein kinase (MAPK), to mediate mitogenic signaling.
  • ERKl extracellular signal receptor kinase 1
  • ERK2 extracellular signal receptor kinase 1
  • ERK2 extracellular signal receptor kinase 1
  • MAPK2 mitogen- activated protein kinase
  • the present inventors conducted intensive and thorough research on the development of compounds which can inhibit the activity of the protein phosphatases, found those compounds through a computer-aided drug design protocol including the homology modeling and the structure-based virtual screening, and identified the inhibitory activity against the protein phosphatases by those compounds, resulting in the completion of the present invention. Disclosure of Invention
  • An object of the present invention is to provide a composition for the prevention and treatment of various cancers, which contains phenyl-amino-thiazolone derivatives inhibiting the activity of protein phosphatases (PPases) or pharmaceutically acceptable salts thereof as an active ingredient.
  • PPases protein phosphatases
  • the present invention provides a composition for the prevention and treatment of various cancers, which contains phenyl-amino-thiazolone derivatives inhibiting the activity of protein phosphatases (PPases) or pharmaceutically acceptable salts thereof as an active ingredient.
  • PPases protein phosphatases
  • the phenyl-amino-thiazolone derivatives according to the present invention effectively inhibit the activity of protein phosphatases, such as Cdc25A and Cdc25B, and can be useful in the prevention and treatment of various cancers caused by the activity thereof, such as breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, bone marrow cancer, and the like.
  • protein phosphatases such as Cdc25A and Cdc25B
  • FIG. 1 illustrates the arrangement of catalytic domain sequences of Cdc25 A
  • FIG. 2 illustrates 3-dimentsional (3D) structures of Cdc25A and Cdc25B according to an embodiment of the present invention
  • FIG. 3 is a graph showing the 3D structure conformational energy of Cdc25A formed by the homology modeling, and 3D structure conformational energies of X-ray crystal structures of Cdc25 A and Cdc25B (red line: Cdc25 A formed by the homology modeling, green line: X-ray crystal structure of Cdc25 A, black line: X-ray crystal structure of Cdc25B) according to an embodiment of the present invention.
  • Red line Cdc25 A formed by the homology modeling
  • green line X-ray crystal structure of Cdc25 A
  • black line X-ray crystal structure of Cdc25B
  • the present invention provides a composition, containing a derivative which inhibits the activity of protein phosphatases, represented by the following Chemistry Figure 1, as an active ingredient.
  • R 1 is C 4 -C 7 aryl C 1 -C 10 linear or branched alkyl group, C 4 -C 7 heteroaryl C 1 -C 10 linear or branched alkyl group, C 11 -C 1 cycloaryl C r C 10 linear or branched alkyl group, C 4 -C 7 aryl C r C I0 linear or branched alkenyl group, C 4 -C 7 heteroaryl Ci-C 10 linear or branched alkenyl group or C 4 -C 7 cycloaryl C 1 -C 10 linear or branched alkenyl group, C 4 - C 7 aryl C 1 -C 10 linear or branched alkylidenyl group, C 4 -C 7 heteroaryl C J -C 10 linear or branched alkylidenyl group, C 4 -C 7 cycloaryl Ci-C 10 linear or branched alkylidenyl group, C 4 -C 7 aryl Ci-C 10
  • R 2 and R 3 are independently H, halogen, Ci -C 4 linear or branched alkyl group, or hydroxy group.
  • R 1 C 4 -C 7 aryl Q-C 5 linear or branched alkyl group, C 4 -C 7 heteroaryl Cj-C 5 linear or branched alkyl group, C 4 -C 7 cycloaryl C 1 -C 5 linear or branched alkyl group, C 4 -C 7 aryl Ci-C 5 linear or branched alkenyl group, C 4 -C 7 heteroaryl Ci-C 5 linear or branched alkenyl group or C 4 -C 7 cycloaryl Q-C 5 linear or branched alkenyl group, C 4 -C 7 aryl C 1 ⁇ C 5 linear or branched alkylidenyl group, C 4 -C 7 heteroaryl C 1 -C 5 linear or branched alkylidenyl group, C 4 -C 7 cycloaryl Q-C 5 linear or branched alkylidenyl group, C 4 -C 7 aryl Ci-C 5 linear or branched alky
  • R 2 and R 3 are independently H, F, Cl, Br, OH, Q-C 4 linear or branched alkyl group, or hydroxy group.
  • R 2 and R 3 are independently H, F, Cl, Br, OH, methyl, ethyl, propyl, and the like.
  • the derivatives of Chemistry Figure 1 according to the present invention may be also provided in the form of a pharmaceutically acceptable salt.
  • An acid addition salt formed by a pharmaceutically acceptable free acid may be useful as a salt.
  • the acid addition salt may be obtained from an inorganic acid, such as hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, nitrous acid or phosphorous acid, and a non-toxic acid, such as aliphatic mono- and dicarboxylate, phenyl-sub- stituted alkanoate, hydroxy alkanoate and alkanedioate, aromatic acid, aliphatic and aromatic sulfonic acid.
  • These pharmaceutically acceptable salts include sulfate, py- rosulfate, bisulfate, sulphite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexane-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sul
  • the acid addition salt according to the present invention may be prepared by a conventional method, for example, by dissolving the derivative of Chemistry Figure 1 in excess of an acid solution and precipitating the resulting salt in an organic solvent, such as methanol, ethanol, acetone or acetonitrile.
  • an organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • a pharmaceutically acceptable metal salt may be prepared using bases.
  • An alkaline metal or alkaline earth metal salt may be obtained, for example by dissolving the compound in excess of an alkaline metal hydroxide or alkaline earth metal hydroxide solution, filtrating the insoluble compound salt, evaporating the filtrate and drying the salt. Then, preparation of sodium, potassium or calcium salt is appropriate as a metal salt in the manufacture of drugs. Furthermore, the corresponding silver salt may be obtained by reacting an alkaline metal or alkaline earth metal with a suitable silver salt (e.g., silver nitrate).
  • a suitable silver salt e.g., silver nitrate
  • the compounds of the present invention may be also provided in the form of a solvate, particularly a hydrate. Hydration may occur during separation of the compound or after a period of time due to the hydroscopic properties of the compound.
  • the derivatives of Chemical Figure 1 in the present invention have an efficacy of inhibiting the activity of protein phosphatases, particularly Cdc25.
  • Cdc25 phosphatase is a kind of dual specific phosphatase for acting on both phosphor-tyrosine and phosphor-threonine.
  • the Cdc25 phosphatase is responsible for the activation of cyclin dependent kinase (CDK) by removing inhibitory phosphate from tyrosine and threonine residues of CDK, which is implicated in the cell division cycle.
  • CDK cyclin dependent kinase
  • a high level of CDK induces the activation of the MPF (M phase promoting factor) to increase the miotic activity in the M phase of cell cycle, resulting in cell proliferation. Accordingly, inhibiting the activity of the Cdc25 phosphatase interferes with cell division to thus prevent cell proliferation.
  • MPF M phase promoting factor
  • Cdc25 has been reported to have three homologues, Cdc25A, Cdc25B, and Cdc25C, in human cells.
  • Cdc25A or Cdc25B is inferred to play an important role in carcinogenesis because it is the most highly expressed in cancer cells, for example, breast cancer, rectal cancer, non- Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, and the like, and recent studies have revealed that Cdc25A is also included in the adhesion-dependent proliferation of sensitive myeloid leukaemia cells.
  • Cdc25 inhibitors can be targets for developing anticancer agents (Ontani, T. et al., J. of Antibiotics 2000, 53, 337; Lazo, J. S. et al, Bioorg. Mded. Chem. Lett. 2000, 8, 1451).
  • the derivatives of Chemistry Figure 1 according to the present invention inhibit the activities of Cdc25 A and Cdc25B and may be useful in the prevention and treatment of various cancers.
  • the cancers may be breast cancer, rectal cancer, non-Hodgkin's lymphoma, prostate cancer, pancreatic ductal adenocarcinoma, lung cancer, bone marrow cancer, and the like in the composition of the present invention.
  • the present invention provides a method for preventing and treating various cancers comprising administering a therapeutically effective amount of phenyl- amino-thiazolone derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, to a mammal or a patient in need.
  • the mammal is human.
  • the composition may be formulated into oral or non-oral administration forms.
  • oral admiministrations for example, tablets and capsules are available.
  • These formulations may contain a diluent (e.g.: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricant (e.g.: silica, talc, stearic acid, or magnesium or calcium salt thereof and/or polyethylene glycol), in addition to an active ingredient.
  • a diluent e.g.: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricant e.g.: silica, talc, stearic acid, or magnesium or calcium salt thereof and/or polyethylene glycol
  • the tablets may also contain a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone, in some cases, a disintegrant, such as starch, agar, alginic acid or sodium salt thereof or a boiling mixture and/or an absorbent, a colorant, a flavor and a sweetner.
  • a representative non-oral administration may be a formulation for injection, preferably an isotonic aqueous solution or suspension.
  • the composition is sterilized or/and may contain an auxiliary agent, such as a preservative, a stabilizer, wettable agent, emulsifier, an osmotic pressure-controlling salt and/or a buffer, and other therapeutically effective materials, and may be prepared by a conventional method.
  • an auxiliary agent such as a preservative, a stabilizer, wettable agent, emulsifier, an osmotic pressure-controlling salt and/or a buffer, and other therapeutically effective materials, and may be prepared by a conventional method.
  • the pharmaceutical composition of the present invention may be administered via a non-oral route, such as an intravenous or intramuscular, or orally administered for a specific purpose, and the derivative of Chemistry Figure 1 may be once or many times administered at a dose of 0.01 to 100 rag/kg (body weight) a day, preferably at a dose of 0.1 to 50 mg/kg (body weight) a day.
  • the dosage level of administration to a certain patient depends on the weight of the patient, age, sex, health, diet, administration time, administration method and excretion, and combination of medicines and severity of the disease.
  • Step 1 Homology modeling of Cdc25A
  • FIG. 1 An alignment of sequences in catalytic domains of Cdc25A and Cdc25B is shown in FIG. 1.
  • the Cdc25A was obtained from the SWISS-PROT protein sequence data bank (http://www.expasy.org/sprot/ ;accession number P30304).
  • the ClustalW package program was utilized using the BLOSUM matrix in order to convert the sequence alignment in catalytic domains of Cdc25A and Cdc25B into a point, and parameters such as GAP OPEN, GAP EXTENTION, and GAP DISTENCE are set into 10, 0.05, and 8, respectively.
  • GAP OPEN the sequence alignment in catalytic domains of Cdc25A and Cdc25B
  • FIG. 2 shows the 3D-stracture of the Cdc25A (a), formed by the homology modeling and that of the X-ray crystal of the Cdc25B (b).
  • the two enzymes have similar structures, but the amino acid arrangements and structures in active sites differ between them.
  • Step 2 Screening of compounds capable of recognizing the active sites of proteins
  • 378 ⁇ 566th residue were expressed in the E. coli., using the pET28a (Novagen) along with 6 histidine tags in the N-terminal.
  • the expressed Cdc25 phosphatase was purified with a Ni-NTA affinity resin (Qiagen) and crystallized in a buffer (-75 °C) which contained 20 mM Tris-HCl, pH 8.0, 0.2 M NaCl, and 5 mM DTT until the next enzyme experiment.
  • the reaction mixture includes the compound of Chemistry Figure 1 dissolved in 180 mi of a reaction buffer (20 mM Tris-HCl, pH 8.0, 0.01 % Triton X-100, 5 mM DTT) and 10 mM 6,8-difluoro-4-methylum-belliferyl phosphate (DiFMUP, Molecular probe), 10 mi of enzyme (30 nM Cdc25A or 20 nM Cdc25B), and 10 mi of DMSO.
  • the reaction was carried out at the room temperature for 20 minutes, and terminated by addition of 1 mM sodium orthovanadate (final concentration).
  • the fluorescence was then measured on a plate reader, excited at 355 ran and emitted at 460 ran.
  • the IC50 values were measured 3 times or more, using these methods and the mean values are shown in Table 2.
  • the IC 50 values of 2,3-bis-(2-hydroxy-ethylsulfanyl)-[l,4]naphthoquinone (comparative example 1) and 2-(2-mercaptoethanol)3-methyl-l,4-naphthoquinone (comparative example 2), described in the reference as positive control groups were measured 3 times or more using the same method and the mean values are shown in Table 2.
  • the compounds in the positive control groups have a micromolar inhibitory activity against the Cdc25 phosphatase and are known as the most effective growth inhibitor in various cancer cell lines.
  • Injection was prepared by containing 100 mg of an active ingredient, as well as 180 mg of mannitol, 26 mg Of Na 2 HPO 4 - 12H 2 O, and 2947 mg of distilled water.

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Abstract

L'invention concerne une composition permettant de prévenir et de traiter des cancers variés. Cette composition inhibe les protéines phosphatases et contient un dérivé phényl-amino-thiazolone servant de principe actif. Les dérivés phényl-amino-thiazolone selon l'invention permettent d'inhiber efficacement les activités de protéines phosphatases telles que Cdc25A et Cdc25B, et peuvent servir à prévenir et à traiter le cancer du sein, le cancer rectal, un lymphome non hodgkinien, le cancer de la prostate, un adénocarcinome du conduit pancréatique, le cancer du poumon, le cancer de la moelle osseuse et analogues.
PCT/KR2008/006716 2007-12-14 2008-11-14 Composition de prévention et de traitement du cancer contenant des dérivés phényl-amino-thiazolone inhibant l'activité de protéines phosphatases ou des sels pharmaceutiquement acceptables de ceux-ci servant de principe actif Ceased WO2009078586A1 (fr)

Applications Claiming Priority (2)

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KR1020070131386A KR100998572B1 (ko) 2007-12-14 2007-12-14 단백질 포스파타제의 활성을 억제하는 페닐아미노티아졸론유도체 또는 이의 약학적으로 허용가능한 염을유효성분으로 함유하는 암 예방 및 치료용 조성물
KR10-2007-0131386 2007-12-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8663632B1 (en) * 2008-03-13 2014-03-04 University Of Kentucky Research Foundation Compositions and methods for selectively targeting cancer cells using a thiaminase compound
CN104059060A (zh) * 2014-05-30 2014-09-24 西安交通大学 一种5-(1h-吲哚-3-亚甲基)-1,3-噻唑烷-4-酮类衍生物及其合成方法和应用
EP3498277A4 (fr) * 2016-08-09 2020-03-25 Industry Academy Cooperation Foundation Of Sejong University Composition pharmaceutique pour un traitement de l'accident vasculaire cérébral basé sur l'inhibition de l'ampk

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005082363A1 (fr) * 2004-02-20 2005-09-09 Board Of Regents, The University Of Texas System Composes de thiazolone permettant de traiter le cancer
WO2007010281A2 (fr) * 2005-07-21 2007-01-25 Betagenon Ab Utilisation de derives et d'analogues de thiazole dans les troubles causes par les acides gras libres
WO2007103754A2 (fr) * 2006-03-02 2007-09-13 Smithkline Beecham Corporation Thiazolones utilisés en tant qu'inhibiteurs de p13-kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005082363A1 (fr) * 2004-02-20 2005-09-09 Board Of Regents, The University Of Texas System Composes de thiazolone permettant de traiter le cancer
WO2007010281A2 (fr) * 2005-07-21 2007-01-25 Betagenon Ab Utilisation de derives et d'analogues de thiazole dans les troubles causes par les acides gras libres
WO2007010273A2 (fr) * 2005-07-21 2007-01-25 Betagenon Ab Utilisation de derives et analogues de thiazole dans le traitement du cancer
WO2007103754A2 (fr) * 2006-03-02 2007-09-13 Smithkline Beecham Corporation Thiazolones utilisés en tant qu'inhibiteurs de p13-kinases

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8663632B1 (en) * 2008-03-13 2014-03-04 University Of Kentucky Research Foundation Compositions and methods for selectively targeting cancer cells using a thiaminase compound
CN104059060A (zh) * 2014-05-30 2014-09-24 西安交通大学 一种5-(1h-吲哚-3-亚甲基)-1,3-噻唑烷-4-酮类衍生物及其合成方法和应用
EP3498277A4 (fr) * 2016-08-09 2020-03-25 Industry Academy Cooperation Foundation Of Sejong University Composition pharmaceutique pour un traitement de l'accident vasculaire cérébral basé sur l'inhibition de l'ampk
EP3498277B1 (fr) * 2016-08-09 2021-10-06 Zincure Corp. Composition pharmaceutique pour un traitement de l'accident vasculaire cérébral basé sur l'inhibition de l'ampk

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KR100998572B1 (ko) 2010-12-07

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