WO2019235879A1 - Composition pour prévenir ou traiter le cancer, contenant un nouvel inhibiteur de mtor - Google Patents

Composition pour prévenir ou traiter le cancer, contenant un nouvel inhibiteur de mtor Download PDF

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WO2019235879A1
WO2019235879A1 PCT/KR2019/006873 KR2019006873W WO2019235879A1 WO 2019235879 A1 WO2019235879 A1 WO 2019235879A1 KR 2019006873 W KR2019006873 W KR 2019006873W WO 2019235879 A1 WO2019235879 A1 WO 2019235879A1
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methylene
pyrazol
thioxo
thiazolidin
cancer
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PCT/KR2019/006873
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English (en)
Korean (ko)
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김성훈
김종현
한균희
한정민
이철호
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재단법인 의약바이오컨버젼스연구단
연세대학교 산학협력단
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Publication of WO2019235879A1 publication Critical patent/WO2019235879A1/fr

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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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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 a composition for preventing or treating cancer comprising a novel mTOR inhibitor, and more particularly to a pharmaceutical composition for preventing or treating cancer comprising a novel compound represented by the formula (1) showing mTORC1 inhibitory activity as an active ingredient. It is about.
  • Amino acids not only serve as raw materials for protein synthesis, but also act as nutrients that regulate protein metabolism.
  • the activity of amino acids available intracellularly is mediated by the mechanistic target of rapamycin complex 1 (mTORC1), which regulates various cellular responses such as protein synthesis, autophagy, and cell growth, as well as cancer, obesity, It is also closely related to various human diseases such as diabetes and neurodegeneration.
  • mTORC1 mechanistic target of rapamycin complex 1
  • the mTOR (mammalian target of rapamycin), also known as FRAP (FKBP12 and rapamycin related proteins), does not phosphorylate phospholipids, but the 289-kDa serine / threonine kinase of the PIKK family (phosphoinositide 3-kinase-like kinase) to be.
  • FRAP FKBP12 and rapamycin related proteins
  • This protein is also present in the C-terminal kinase domain, FKBP12-rapamycin binding domain, 20 N-terminal HEAT repeats involved in protein-protein interactions, FAT (FRAP-ATM-TRRAP) domain, and C-terminal FAT domain, which is also present in other PIKKs. Include several domains, including
  • mTOR kinases are central regulators of cell growth and proliferation and play important roles in cell metabolism and angiogenesis.
  • mTOR is activated by the PI3K / Akt axis, which in turn is the downstream effector of the PI3K / Akt signaling pathway, in particular the two major regulators of the cellular protein translation machinery, ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E binding protein (4E-BP1 (MTOR signal pathway is described in Zoncu et al. (2011) Nature Rev. Mol. Cell Biol. 12, 21-35).
  • S6K1 ribosomal protein S6 kinase
  • 4E-BP1 eukaryotic initiation factor 4E binding protein
  • mTORC1 regulates various upstream signals such as cell growth, protein synthesis, and growth factor regulation.
  • Tuberous Sclerosis Complex (TSC) which transmits growth factors and energy signals to mTORC1
  • GAP GTPase-activating protein
  • MTORC1 is negatively regulated by promoting.
  • Rheb can migrate to late endosomes / lysosomes and is required for mTORC1 activation induced by amino acids.
  • Rag GTPases and Ragulator complexes act as amino acid inducible docking sites for mTORC1.
  • Rag GTPases essentially form a heterodimer of RagA / C or RagB / D to mediate amino acid induced mTORC1 activation.
  • the amino acid induces the transfer of mTORC1 to the lysosome, in which Rag hetero dimers containing RagB with GTP are interacted with mTORC1.
  • mTORC1 Leucine and glutamine can activate mTORC1 by Rag GTPase-dependent and independent mechanisms, respectively.
  • glutamine can still activate mTORC1 via ADP ribosylation factor 1 (ARF1) GTPase. Therefore, mTORC1 can be regulated differently by glutamine and leucine.
  • ADP ribosylation factor 1 ADP ribosylation factor 1 (ARF1) GTPase. Therefore, mTORC1 can be regulated differently by glutamine and leucine.
  • ADP ribosylation factor 1 ADP ribosylation factor 1
  • mTOR also called FRAP, RAPT1 or RAFT1
  • mTOR is expressed in almost all organs and tissues and is involved in the PI3K-Akt signal transduction system.
  • mTOR forms mTORC1 complex and mTORC2 complex with adapter proteins such as raptor and rictor, respectively, and transmits signals from the extracellular matrix.
  • mTORC1 activates the translation of cancer-related proteins (cyclin D1, myc, HIF-1 ⁇ , etc.) by phosphorylating S6K, 4EBP-1 and the like, and mTORC2 phosphorylates Ser473 of Akt, thereby activating survival signals of cancer cells. It is thought to let you do it.
  • the improvement of the mTOR signal transduction system is recognized in many carcinomas, including kidney cancer, osteosarcoma, lung cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer and liver cancer.
  • One of the mTOR inhibitors, rapamycin binds to FKBP12 (FK-506 binding protein) within the cell to form a complex, and the rapamycin / FKBP12 complex binds to mTOR, which inhibits kinase activity of mTOR and protein synthesis also increases cell proliferation. Inhibits.
  • FKBP12 FK-506 binding protein
  • mTOR may be an effective therapeutic target for cancer treatment, and compounds having an effect of inhibiting kinase activity of mTOR may exhibit excellent therapeutic effects against cancer treatment, particularly cancers with mTOR signal enhanced. .
  • ARSs aminoacyl-tRNA-synthetases
  • LPS Leucine-tRNA-synthase
  • LRS detects a substance that inhibits its function as a leucine sensor, it inhibits the binding of LRS and RagD to inhibit the activation of mTORC1, and consequently has an effect on potential therapeutic indications for mTOR inhibitors such as cancer. Will indicate.
  • the present inventors have made diligent efforts to find a novel compound that can inhibit the activity of mTOR to exhibit a therapeutic effect against cancer, and as a result, the compound represented by the formula (1) inhibits mTOR activity and cancer
  • the present invention has been completed and found that the effect of inhibiting the growth of cells is very good and can have a cancer prevention or treatment effect.
  • compositions for preventing or treating cancer comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient
  • compositions for preventing or treating cancer consisting essentially of the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 is hydrogen; Substituted or unsubstituted C 1 -C 5 straight or branched alkyl; C 2 -C 5 alkenyl; C 3 -C 10 heteroarylalkyl; Or C 1 -C 5 hydroxyalkyl,
  • R 2 is hydrogen; Substituted or unsubstituted C 1 to C 5 straight or branched alkyl,
  • R 3 is hydrogen; Substituted or unsubstituted C 1 -C 5 straight or branched alkyl; C 6 -C 15 aryl; Or C 3 -C 15 heteroaryl,
  • X is oxygen; sulfur; Or nitrogen,
  • Y 1 and Y 2 are each independently oxygen or sulfur
  • n 0, 1 or 2.
  • Another object of the present invention to provide a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a preventive or therapeutic agent for cancer.
  • Still another object of the present invention is to provide a method for preventing or treating cancer, comprising administering to a subject in need thereof an effective amount of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer, consisting essentially of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 is hydrogen; Substituted or unsubstituted C 1 -C 5 straight or branched alkyl; C 2 -C 5 alkenyl; C 3 -C 10 heteroarylalkyl; Or C 1 -C 5 hydroxyalkyl,
  • R 2 is hydrogen; Substituted or unsubstituted C 1 to C 5 straight or branched alkyl,
  • R 3 is hydrogen; Substituted or unsubstituted C 1 -C 5 straight or branched alkyl; C 6 -C 15 aryl; Or C 3 -C 15 heteroaryl,
  • X is oxygen; sulfur; Or nitrogen,
  • Y 1 and Y 2 are each independently oxygen or sulfur
  • n 0, 1 or 2.
  • the present invention provides a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a preventive or therapeutic agent for cancer.
  • the present invention comprises administering to a subject in need thereof an effective amount of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • alkyl in the present invention means an aliphatic hydrocarbon group which may be straight or branched, containing 1 to 5 carbon atoms in the chain. Preferred alkyl groups contain 1 to 3 carbon atoms in the chain. More preferred alkyl groups contain about 1, 2 or 3 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkyl chain. "Lower alkyl” means a group having from 1 to 5 carbon atoms in the chain, which may be straight or branched. "Alkyl” may be unsubstituted or may be optionally substituted by one or more substituents which may be the same or different.
  • alkenyl refers to a monovalent straight or branched hydrocarbon radical having 2 to 5 carbon atoms and at least one double bond in the chain, examples of which are ethenyl, propenyl, 1-but-3 -Enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like, wherein the alkenyl radicals can be independently substituted by one or more groups independently of the substituents described herein, This includes radicals having "cis” and “trans” orientations, or alternatively "E” and “Z” orientations.
  • Alkenyl may be unsubstituted or may be optionally substituted by one or more substituents which may be the same or different.
  • the “aryl” refers to a single ring (eg, phenyl), multiple rings (eg, biphenyl) or multiple condensed rings (one or more of which are aromatic; for example, 1,2, Monovalent aromatic carbocyclic radical with 3,4-tetrahydronaphthyl, naphthyl), which may be mono-, di- or tri-substituted with any substituent.
  • the "heteroaryl” includes a fused ring system containing one to four heteroatoms selected from nitrogen, oxygen or sulfur and having 5 to 15 atoms, at least one of which is aromatic.
  • Monovalent aromatic radicals having 6-, 7- or 7-membered rings.
  • heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl , Quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, puteri Dinyl, purinyl, oxdiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
  • heteroarylalkyl means an alkyl residue (as defined above) substituted with a heteroaryl residue (as defined above). More preferred heteroarylalkyl radicals may be 5- or 6-membered hetero aryl-C 1-3 -alkyl. Heteroarylalkyl may be mono-, di- or tri-substituted with any substituent.
  • the "hydroxyalkyl” means a linear or branched monovalent hydrocarbon radical substituted with one or two hydroxy groups and containing 1 to 5 carbon atoms, for example, but not limited to, hydroxy Methyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2- hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl , 2,3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2- (hydroxymethyl ) -3-hydroxypropyl and the like.
  • halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • substituents include those found in the exemplary compounds and embodiments disclosed herein, and halogens (chloro, urethral, bromo or fluoro groups), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino , Carboxy, nitro, ano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfone Amides, ketones, aldehydes, esters, urea, urethanes, oximes, hydroxylamines, alkoxyamines, aralcoxiamines, N-oxides, hydrazines
  • R 1 is preferably hydrogen; Substituted or unsubstituted C 1 -C 3 straight or branched alkyl; C 2 -C 3 alkenyl; C 3 -C 6 heteroarylalkyl; Or C 1 -C 3 straight or branched hydroxyalkyl, more preferably hydrogen; Substituted or unsubstituted C 1 -C 2 straight alkyl; C 2 -C 3 alkenyl; C 3 -C 5 heteroarylalkyl; Or C 1 -C 2 straight hydroxyalkyl, most preferably hydrogen, methyl, ethyl, ethenyl, propenyl, furylmethyl and hydroxyethyl.
  • R 2 is preferably hydrogen; Or substituted or unsubstituted C 1 -C 3 straight or branched alkyl, more preferably substituted or unsubstituted C 1 -C 2 alkyl, most preferably in the group consisting of hydrogen, methyl and ethyl Can be selected.
  • R 3 is preferably substituted or unsubstituted C 1 ⁇ C 3 straight or branched alkyl; C 6 -C 10 aryl; Or C 3 -C 10 heteroaryl, more preferably substituted or unsubstituted C 1 -C 2 alkyl; C 6 -C 10 aryl; Or C 3 to C 5 heteroaryl, most preferably selected from the group consisting of substituted or unsubstituted methyl, phenyl, naphthyl and pyridyl.
  • the substituent is preferably halogen; C 1 -C 5 straight or branched alkyl; And it may be selected from the group consisting of C 1 ⁇ C 5 alkoxy, more preferably halogen; C 1 -C 4 straight or branched alkyl; And it may be selected from the group consisting of C 1 ⁇ C 3 alkoxy, most preferably may be selected from the group consisting of chlorine, fluorine, methyl, butyl, isopropyl and methoxy.
  • Y 1 is sulfur
  • Y 2 may be oxygen
  • the compound of Formula 1 may be selected from the following compounds:
  • the compound of formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt.
  • the salts acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful. Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid.
  • Maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid and the like can be used.
  • suitable inorganic acids include hydrochloric acid, sulfuric acid or phosphoric acid. Can be used.
  • the compound of formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates, racemates, or stereoisomers that can be prepared by conventional methods.
  • the compound of Formula 1 of the present invention may be prepared according to the following method, but is not limited thereto.
  • R 1 , R 2 , R 3 , X, Y 1 , Y 2 and n are as defined above.
  • the reaction may be carried out by mixing and heating Compound 2 and Compound 3 in the presence or absence of a solvent in the presence of Lewis or photocatalyst.
  • useful catalysts include HCl, HBr, H 2 SO 4 , acetic acid, trifluoro acid, p-toluenesulfonic acid, trimethylsilylchloride, trimethylsilyl iodide, boron trifluoride etherate, copper chloride (I) Ferric chloride, indium (III) chloride, ytterbium triflate, cerium (III) chloride, zirconium (IV) chloride, zirconium chloride (IV), lithium bromide, phenylpyruvic acid, calcium chloride, polyphosphate ester, or solid Clay acid catalysts such as montmorillonite KSF clay or combinations of these catalysts.
  • Useful solvents may preferably include polar solvents such as acetonitrile, acetic acid, methanol, ethanol, or other alcohols, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone or dioxane.
  • polar solvents such as acetonitrile, acetic acid, methanol, ethanol, or other alcohols, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methyl pyrrolidone or dioxane.
  • Heating can be done under conventional heating conditions or microwave conditions.
  • the preparation method may prepare the compound of Formula 1 by applying the compound 2 and compound 3 in a conventional condensation reaction.
  • the compound of Chemical Formula 1 may be prepared by knoevenagel condensation reaction of Compound 2 and Compound 3 in an organic solvent, followed by stirring at 50 to 80 ° C. for 10 to 20 hours. Can be.
  • the product prepared according to Scheme 1 may be purified through additional steps such as washing, concentrating, ethyl acetate extraction, drying, column chromatography, and the like through IR, NMR, melting point (mp) measurement, and the like. Characterize can be analyzed.
  • Compound 2 and Compound 3 in Scheme 1 may each use a commercially available compound, or for example, Compound 2 may be used according to Scheme 2 below, and Compound 3 may be synthesized according to Scheme 3 below. You can also:
  • R 1 , R 2 , R 3 , X, Y 1 , Y 2 and n are as defined above.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof inhibits the binding of LRS and RagD, thereby inhibiting the activity of mTORC1, which is known to be highly active in cancer cells. It was confirmed to be very excellent. In addition, it was confirmed that the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be cytotoxic to cancer cells and thus directly inhibit the growth of cancer cells.
  • the pharmaceutical composition according to the present invention may contain the compound of Formula 1 or a pharmaceutically acceptable salt thereof alone or may further contain one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration.
  • Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like.
  • carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like, and may further include stabilizers and preservatives.
  • Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • Other pharmaceutically acceptable carriers may be referred to those known in the art.
  • the pharmaceutical composition of the present invention can be administered to any mammal, including humans.
  • it can be administered orally or parenterally.
  • Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration.
  • the pharmaceutical composition of the present invention can be prepared in an injectable formulation and administered by lightly pricking the skin with a 30 gauge thin needle or by applying it directly to the skin.
  • composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.
  • compositions of the present invention may be formulated using methods known in the art as powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like.
  • oral preparations can be obtained by tablets or dragees by combining the active ingredient with a solid brother and then grinding it, adding the appropriate adjuvant and processing it into a granule mixture.
  • excipients examples include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, starch including corn starch, wheat starch, rice starch and potato starch, and the like. Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.
  • Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants. These formulations are described in prescriptions generally known in all pharmaceutical chemistries.
  • the total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol which is administered in multiple doses for a long time.
  • the pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease.
  • the total dose of the pharmaceutical composition of the present invention may be about 0.01 ug to 1,000 mg, most preferably 0.1 ug to 100 mg per kg of patient body weight per day.
  • the dosage of the pharmaceutical composition of the present invention is effective for the patient in consideration of various factors such as the age, weight, health condition, sex, severity of the disease, diet and excretion rate, as well as the route and frequency of treatment.
  • the pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.
  • the cancer is not limited thereto, but may be a cancer showing rapamycin resistance, preferably leukemia, brain tumor, kidney cancer, gastric cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, melanoma, thyroid cancer, head and neck cancer, Lymphoma, gallbladder cancer, esophageal cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colon cancer, peritoneal cancer, peritoneal metastasis cancer and pancreatic cancer.
  • rapamycin resistance preferably leukemia, brain tumor, kidney cancer, gastric cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, melanoma, thyroid cancer, head and neck cancer, Lymphoma, gallbladder cancer, esophageal cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colon cancer, peritoneal cancer, peritoneal metastasis cancer and pancreatic cancer.
  • the term 'treatment' refers generically to ameliorating the symptoms of cancer, which may preferably include treating, substantially preventing, or ameliorating the condition, wherein It includes, but is not limited to, alleviating, healing or preventing the symptoms or most of the symptoms.
  • the present invention provides a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a preventive or therapeutic agent for cancer.
  • the present invention provides a method for preventing or treating cancer, comprising administering to a subject in need thereof an effective amount of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the term 'effective amount' of the present invention when administered to an individual, refers to an amount that exhibits an effect of improving, treating, preventing, detecting, diagnosing, or inhibiting or reducing cancer
  • the term 'individual' refers to an animal, preferably a mammal. It may be an animal including a human, in particular, cells, tissues, organs and the like derived from the animal. The subject may be a patient in need of the effect.
  • Compound represented by the formula (1) according to the present invention is very excellent in inhibiting the effect of inhibiting the growth of mTORC1 and cancer cells can be very useful in the prevention or treatment of cancer.
  • FIG. 1A and 1B show the results of immunoblotting of the phosphorylation of S6K after treatment with the compound of Example 1-1 or a salt thereof in NIH3T3 cells carrying the mTOR C1483Y mutation (FIG. 1A) and a graph showing the quantification thereof (FIG. 1B) (Leu: Leucine).
  • Figure 2 shows the results of immunoblotting of RagD GTP hydrolysis after treatment of the compound of Example 1-1 or a salt thereof in SW620 cells (Leu: Leucine)
  • Figure 3 shows the result of confirming whether the interaction of LRS and RagD is inhibited by immunoprecipitation method after treatment of the compound of Example 1-1 or a salt thereof to SW620 cells.
  • Example 4 shows neocortex and hippocampus of brain after intraperitoneal administration of salt (100 mg / kg) or rapamycin (Rapa, 2 mg / kg) of the compound of Example 1-1 to 7-week-old C57BL / 6 male mice. The result of confirming whether phosphorylation of S6K and expression of protein through immunoblotting.
  • FIG. 5 shows the immunoblotting of S6K phosphorylation and protein expression in neocortex and hippocampus of brain after intraperitoneal administration of salts of the compound of Example 1-1 to 7-week-old C57BL / 6 male mice at various concentrations. This is the result of the test.
  • the compound of Formula 1 was prepared according to the method described in Korean Patent Application No. 10-2018-0048774, and the compounds used in the following experiments are as follows, and the structures of the compounds are shown in Table 1 above.
  • Example 1-1K The compound of Example 1-1 (1eq) and potassium hydroxide (1.1eq) were added to the methanol solution, respectively, and stirred at 60 ° C for 30 minutes to dissolve completely. The mixture was stirred again at 60 ° C. for 1 hour and cooled to room temperature after the reaction ended. The reaction product was obtained by filtration and washed with an appropriate amount of methanol to give the potassium salt of the compound of Example 1-1 (Example 1-1K).
  • Colon cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC). Cell lines were divided into 24 well plates and cultured for 24 hours, and then treated for 1 hour and 30 minutes in a medium containing no leucine amino acid, and then cultured for 15 minutes in a medium containing leucine again. The compounds of Examples 1-1 to 1-61 were added upon incubation in a medium containing leucine at a final concentration of 20 uM. 20 ug of cell lysate was isolated by electrophoresis and analyzed by Western blotting using phospho-p70 S6 Kinase (Thr380) antibody (# 9206, Cell Signaling Technology) to see the mTORC1 activity. Inhibition of mTORC1 activity was evaluated by comparing the negative control group treated with DMSO only and the compound treated group of each well.
  • ATCC American Type Culture Collection
  • Example Inhibitory effect (%) Example Inhibitory effect (%) 1-1 98.54 ⁇ 0.33 1-22 77.21 ⁇ 0.84 1-43 52.34 ⁇ 3.97 1-2 74.4 ⁇ 0.2 1-23 15.74 ⁇ 10.22 1-44 50.76 ⁇ 5.28 1-3 53.97 ⁇ 1.49 1-24 93.18 ⁇ 2.50 1-45 64.18 ⁇ 3.13 1-4 68.36 ⁇ 1.69 1-25 36.86 ⁇ 3.47 1-46 74.39 ⁇ 0.62 1-5 45.82 ⁇ 3.59 1-26 59.73 ⁇ 3.55 1-47 74.36 ⁇ 1.23 1-6 86.58 ⁇ 2.50 1-27 51.70 ⁇ 7.12 1-48 69.53 ⁇ 2.04 1-7 88.23 ⁇ 0.55 1-28 47.13 ⁇ 3.15 1-49 68.36 ⁇ 2.99 1-8 97.1 ⁇ 1.8 1-29 4.02 ⁇ 6.64 1-50 38.
  • Example 1-1 As shown in Table 2, the compounds according to the present invention can be seen that significantly inhibit the activity of mTORC1 at 20uM.
  • Example 1-1 Example 1-1K (Potassium salt of Example 1-1) Example 1-6, Example 1-7, Example 1-8, Example 1-9, and Example 1 -13, Example 1-17, Example 1-24, Example 1-30, Example 1-33, Example 1-35, Example 1-37, Example 1-39, Example 1-52 , Examples 1-56, Examples 1-57, Examples 1-59 and Examples 1-61 were found to exhibit an excellent inhibitory effect of more than 85% at a concentration of 20uM.
  • the compound of Formula 1 according to the present invention was excellent in inhibiting mTOR which is closely related to the occurrence of cancer, it could be determined that it may exhibit a cancer prevention or treatment effect.
  • Colon cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC). Cell lines were aliquoted into 24 well plates and incubated for 24 hours, and then each selected compound (final concentration 0.1, 0.5, 1, 2, 5, 10, 20 uM) was added upon incubation for 6 hours in medium containing 10% FBS. . 20 ug of cell lysate was isolated by electrophoresis and analyzed by Western blotting using phospho-p70 S6 Kinase (Thr380) antibody (# 9206, Cell Signaling Technology) to see the mTORC1 activity. Inhibition of mTORC1 activity was evaluated by comparing the negative control group treated with DMSO only and the compound treated group of each well.
  • ATCC American Type Culture Collection
  • Example Inhibitory effect IC50 (uM) Example Inhibitory effect IC50 (uM) 1-1 0.045 ⁇ 0.002 1-35 0.0872 ⁇ 0.0146 1-6 0.1237 ⁇ 0.0235 1-37 0.0799 ⁇ 0.0113 1-7 0.0917 ⁇ 0.0012 1-39 0.1076 ⁇ 0.0133 1-8 0.086 ⁇ 0.002 1-52 0.0934 ⁇ 0.0197 1-9 0.1623 ⁇ 0.0279 1-56 0.083 ⁇ 0.010 1-13 0.1298 ⁇ 0.0073 1-57 0.103 ⁇ 0.015 1-17 0.069 ⁇ 0.004 1-59 0.216 ⁇ 0.038 1-24 0.0890 ⁇ 0.0094 1-61 0.094 ⁇ 0.019 1-30 0.0942 ⁇ 0.0019 1-1K 0.024 ⁇ 0.004 1-33 0.0896 ⁇ 0.0289
  • the compounds showing excellent inhibitory activity were selected to further evaluate the inhibitory activity of mTORC1.
  • each compound was confirmed that the IC50 is 1uM or less, and further it was confirmed that some compounds exhibit a very excellent effect of IC50 100nM or less.
  • the present inventors after confirming that the compounds of the formula (1) in Example 2 has a very good effect of inhibiting the activity of mTOR, to determine the mechanism by which these compounds inhibit the activity of mTOR.
  • leucyl tRNA synthetase functions as a key mediator of amino acid signaling to mTORC1.
  • LRS binds directly to Rag GTPase, a signaling mediator to mTORC1, and acts as a GTPase-activating protein (GAP) for Rag GTPase, thereby activating mTORC1.
  • GAP GTPase-activating protein
  • GTP-agarose bead pulldown assay was performed to analyze RagD bound to GTP.
  • SW620 cells were treated with 10 uM of Example 1-1 compound or salt thereof for 1 hour, deficient in leucine for 90 minutes, and then restimulated with leucine for 15 minutes. After washing the cells with cold PBS, GTP-binding buffer (20 mM Tris-HCl, pH 7.5, 5 mM MgCl 2, 2 mM PMSF, 20 ⁇ g / ml leupeptin, 10 ⁇ g / ml aprotinin, 150 mM NaCl, 1% Triton) Cells were obtained from X-100, 1xphosphatase inhibitor cocktail).
  • GTP-binding proteins were analyzed by performing immunoblot analysis with anti-RagD or ARF1 antibodies.
  • ARF1 was used as a negative control.
  • Example 1-214 compound (indicated by "0186" in the figure) described in Korean Patent Laid-Open Publication No. 10-2017-0107404 was used.
  • Example 3-1 it was confirmed that the compound according to the present invention or a salt thereof has an activity of inhibiting GTP hydrolysis of RagD by LRS.
  • SW620 cells were treated with 10 uM of Example 1-1 compound or salt thereof for 1 hour, deficient in leucine for 90 minutes, and then restimulated with leucine for 15 minutes.
  • Cells were lysed using a lysis buffer containing protease inhibitors and primary antibodies were added to the cell lysates for immunoprecipitation and left to stir at 4 ° C. for 2 hours. 50% protein agarose G-sepharose slurry was added and left for another 4 hours. After washing three times with cold lysis buffer, the precipitate was dissolved in SDS sample buffer, separated by SDS-PAGE and immunoblotted with anti-LRS or anti-RagD antibody.
  • Example 1-214 compound (indicated by "0186" in the figure) described in Korean Patent Laid-Open Publication No. 10-2017-0107404 was used.
  • both RagD and LRS were detected in the control (Con) cells not treated with the compound, indicating that RagD and LRS interacted directly.
  • RagD was hardly detected in the precipitate using the anti-LRS antibody in cells treated with the compound of Example 1-1 or a salt thereof according to the present invention, and LRS was almost detected in the precipitate using the anti-RagD antibody. It was found that these interactions were directly inhibited by the compound of Example 1-1 or a salt thereof.
  • Example 1-1 The salt of the compound is 100 mg / kg (in 10% DMAC, 15% Tween 80, 75% 0.1M Na2HPO4, pH9.4), and rapamycin is 2 mg / kg (in 10% DMAC, 15% Tween). 80, 75% saline).
  • the inventors tried to evaluate the mTOR inhibitory activity of each salt concentration of the compound of Example 1-1 based on the results.
  • the degree of phosphorylation of S6K in the neocortex and hippocampus of the brain and The expression level of the protein was analyzed.
  • the compound of Chemical Formula 1 according to the present invention showed excellent mTOR inhibitory activity and blood-brain barrier permeability, it could be seen that it can be very useful as a therapeutic agent for mTOR pathway-related brain disease.
  • RFP fluorescently labeled cell line was prepared.
  • Colon cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC).
  • NucLight Red Lentivirus Reagent (EF1a, Puro) (# 4476, Essen Bioscience) was purchased for the preparation of RFP fluorescent labeled SW620 cell lines.
  • the cells were transfected into the cells by adding NucLight Red Lentivirus Reagent to SW620 cell lines for 24 hours and incubated under 37 ° C. and 5% CO 2 conditions in RPMI 1640 medium containing 10% FBS and 1% penicillin / streptomycin. Thereafter, puromycin was added to the medium at a concentration of 0.5 ug / ml, and then cultured under 37 ° C and 5% CO 2 conditions for 4 days.
  • RFP fluorescently labeled SW620 cell line was dispensed into 96 well plates for 24 hours, and then the compounds having excellent mTORC1 inhibitory activity among the compounds of Examples 1-1 to 1-61 in the medium containing 10% FBS for 24 hours Treatment (final concentrations 0.000282, 0.000847, 0.00254, 0.0076, 0.0229. 0.0686, 0.206, 0.617, 1.85, 5.56, 16.67, 50 uM).
  • Cell phase difference and red fluorescence images were obtained using the Incucyte Zoom (Essen Bioscience) long-term cell observation analysis system at two-hour intervals after compound treatment and quantitative analysis of RFP fluorescence was performed using the Incucyte Zoom basic analyzer (Essen Bioscience) program. Was carried out.
  • RFP fluorescence values for each concentration of the compound were calculated using the GraphPad Prism tool program to calculate the GI50 (50% growth inhibition).
  • the SW620 cell growth inhibition effect was evaluated by comparing the RFP fluorescence of each well with the DMSO-only negative control group and the compound-treated group.
  • the compounds according to the present invention was inhibited the growth of SW620 cells, in particular it was confirmed that exhibits an excellent growth inhibitory effect of less than GI50 100nM.
  • the compounds of the formula (1) according to the present invention because of the excellent effect of inhibiting the growth of cancer cells, can be usefully used for the treatment of cancer.
  • RFP fluorescently labeled SW620 cell line was dispensed in 96 well plates for 24 hours, and then the compounds having excellent mTORC1 inhibitory activity among the compounds of Examples 1-1 to 1-61 in the medium containing 10% FBS for 24 hours Treatment (final concentrations 0.000282, 0.000847, 0.00254, 0.0076, 0.0229. 0.0686, 0.206, 0.617, 1.85, 5.56, 16.67, 50 uM).
  • CellTox Green (# G8741, Promega Co., Ltd.), which shows green fluorescence upon cell death, was added to observe the cytotoxicity during compound treatment.
  • Green fluorescence images were obtained using Incucyte Zoom (Essen Bioscience) long-term cell observation analysis system at 2 hour intervals after compound treatment, and quantitative analysis of green fluorescence was performed using Incucyte Zoom basic analyzer (Essen Bioscience) program. Green fluorescence values for each concentration of the compound were calculated using the GraphPad Prism tool program to calculate EC50 (50% cell death). Cytotoxicity against SW620 cells was evaluated by comparing the green fluorescence of each well with the DMSO-only negative control group and the compound-treated group.
  • Cytotoxic EC50 (nM) against colorectal cancer cells SW620
  • Example EC50 (nM) 1-2 8.61 ⁇ 1.12 1-33 50.41 ⁇ 6.85 1-6 97.45 ⁇ 2.73 1-35 79.50 ⁇ 3.92 1-7 58.76 ⁇ 4.61 1-37 28.74 ⁇ 2.82 1-8 19.69 ⁇ 0.80 1-39 56.58 ⁇ 5.22 1-9 84.12 ⁇ 7.18 1-52 70.32 ⁇ 4.98 1-13 53.53 ⁇ 6.47 1-56 33.08 ⁇ 2.14 1-17 20.78 ⁇ 1.11 1-57 93.09 ⁇ 6.53 1-24 21.39 ⁇ 2.08 1-59 41.02 ⁇ 4.15 1-30 80.55 ⁇ 8.19 1-61 82.14 ⁇ 8.44
  • the compounds of Formula 1 according to the present invention was found to induce the death of SW620 cells. In addition, these compounds were found to exhibit excellent cytotoxicity of less than EC50 100nM.
  • the compound of Formula 1 according to the present invention has excellent effects of inducing cancer cell death, and thus may be usefully used as a therapeutic agent for cancer.
  • Compound represented by the formula (1) according to the present invention is very excellent in inhibiting the effect of inhibiting the growth of mTORC1 and the growth of cancer cells can be very useful in the development of cancer prevention or treatment, it has excellent industrial applicability Do.

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Abstract

La présente invention concerne une composition pour prévenir ou traiter un cancer, contenant un nouvel inhibiteur de mTOR et, plus particulièrement, une composition pharmaceutique pour prévenir ou traiter le cancer, contenant, en tant que principe actif, un nouvel inhibiteur qui est représenté par la formule chimique 1 et qui présente une activité inhibitrice de mTORC1.
PCT/KR2019/006873 2018-06-08 2019-06-07 Composition pour prévenir ou traiter le cancer, contenant un nouvel inhibiteur de mtor WO2019235879A1 (fr)

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WO2021167389A1 (fr) * 2020-02-21 2021-08-26 한국과학기술원 Composition pharmaceutique permettant de prévenir ou de traiter le cancer contenant un inhibiteur de signalisation mtor comme principe actif
WO2021167175A1 (fr) * 2020-02-21 2021-08-26 한국과학기술원 Composition pharmaceutique utilisée dans la prévention ou le traitement du cancer comprenant un inhibiteur de signalisation mtor comme principe actif

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WO2004028535A1 (fr) * 2002-09-26 2004-04-08 Pintex Pharmaceuticals, Inc. Composes de modulation de pin-1 et leurs procedes d'utilisation
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WO2004093803A2 (fr) * 2003-04-16 2004-11-04 Pintex Pharmaceuticals, Inc. Composes photochimiotherapeutiques utilises dans le traitement d'etats associes a pin1
CN102078318A (zh) * 2009-11-27 2011-06-01 华东理工大学 5-取代-2，4-噻唑烷二酮类化合物在制备igf1r功能调节药物中的应用
WO2017176040A1 (fr) * 2016-04-04 2017-10-12 연세대학교 산학협력단 Composé hétérocyclique décomposant une protéine ras et utilisations correspondantes

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