WO2021221208A1 - Dérivé de dihydropyrano[3,2-g]chromén-2-one et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant en tant que principe actif - Google Patents

Dérivé de dihydropyrano[3,2-g]chromén-2-one et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant en tant que principe actif Download PDF

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WO2021221208A1
WO2021221208A1 PCT/KR2020/005716 KR2020005716W WO2021221208A1 WO 2021221208 A1 WO2021221208 A1 WO 2021221208A1 KR 2020005716 W KR2020005716 W KR 2020005716W WO 2021221208 A1 WO2021221208 A1 WO 2021221208A1
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cancer
substituted
straight
oxy
dimethyl
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PCT/KR2020/005716
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English (en)
Korean (ko)
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김소영
임춘영
이선주
최환근
강석용
이두현
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재단법인 대구경북첨단의료산업진흥재단
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Priority to PCT/KR2020/005716 priority Critical patent/WO2021221208A1/fr
Publication of WO2021221208A1 publication Critical patent/WO2021221208A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • It relates to a dihydropyrano[3,2-g]chromen-2-one derivative and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
  • Cancer is a clinical problem that should be considered very seriously as human lifespan is extended, and has a significant social and economic impact on human health care systems. Despite advances in diagnosis, prevention, and treatment of cancer in modern medicine, there are still millions of patients worldwide. Examples of carcinogens that cause cancer include smoking, ultraviolet rays, chemicals, food, and other environmental factors.
  • Chemical cancer prevention is primary prevention to suppress the occurrence of cancer in apparently healthy people, secondary prevention to reverse the carcinogenic process in people with benign cancer, and suppression of malignancy, metastasis, complications, etc. It can be applied step by step as a tertiary prevention to prevent recurrence in those who have been treated. Therefore, it can be very usefully used not only for cancer prevention but also as a therapeutic agent.
  • Non-Patent Document 1 ELSEVIER Volume 3, Issue 4, December 2011, Pages e299-e307.
  • deckercin shows a strong lethal action on cancer cells, it has a much lower lethal action on normal cells compared to the lethal action on cancer cells, so it has the potential to be used as an anticancer agent.
  • Existing deckercin was first isolated from the ether extract of body herbs, and then it was reported that it was isolated from Korean Angelica and oilseeds. has an important meaning.
  • the present invention relates to a derivative having a novel structure in which a substituent having pyrimidine as a linker is introduced into deckercinol and its use for treating cancer. and cancer cell proliferation inhibitory effect.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
  • Another object of the present invention is to provide a health functional food composition for the prevention or treatment of cancer containing the compound as an active ingredient.
  • Another object of the present invention is to provide a method for treating cancer, comprising administering the compound to a subject in need thereof.
  • Another object of the present invention is to provide a use of the compound for the manufacture of a medicament for use in the prevention or treatment of cancer.
  • One aspect of the present invention provides a compound represented by Formula 1 described herein, a stereoisomer, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
  • Another aspect of the present invention provides a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.
  • another aspect of the present invention provides a method for treating cancer comprising administering the compound to a subject in need thereof.
  • Another aspect of the present invention provides the above compound for use in the prevention or treatment of cancer.
  • Another aspect of the present invention also provides the use of the compound for the manufacture of a medicament for use in the prevention or treatment of cancer.
  • the example compounds provided in one aspect of the present invention have an effect that can be usefully used for the prevention or treatment of cancer by inhibiting the kinase with high activity.
  • the embodiment of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.
  • the embodiments of the present invention are provided in order to more completely explain the present invention to those of ordinary skill in the art.
  • One aspect of the present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is unsubstituted or substituted C 6-10 aryl
  • the substituted C 6-10 aryl, 5-10 membered heterocycloalkyl and 5-10 membered heteroaryl are independently,
  • a 2 C 6-10 aryl substituted with one or more substituents, 5 to 10 membered heterocycloalkyl and 5 to 10 membered heteroaryl;
  • the substituted 6-8 membered heterocycloalkyl is a 6-8 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of C 1-10 straight-chain or branched alkyl and aminocarbonyl,
  • a 1 and A 2 are independently hydrogen, C 1-10 straight or branched chain alkyl, diC 1-10 straight or branched alkylamino C 1-10 straight or branched chain alkyl, or C 2-10 straight-chain or branched alkenylcarbonylamino; and
  • R 2 and R 3 are independently hydrogen, unsubstituted or substituted with one substituent C 1-10 straight-chain or branched alkyl, diC 1-10 straight-chain or branched alkylamino C 1-10 straight-chain or branched chain alkyl, C 1-10 straight-chain or branched alkoxy C 1-10 straight-chain or branched alkyl, or unsubstituted or substituted C 6-10 aryl,
  • one substituent is an unsubstituted or substituted 6-8 membered heterocycloalkyl comprising at least one N, or an unsubstituted or substituted 6-8 membered heteroaryl comprising at least one N, wherein the substituted 6 to 8 membered heterocycloalkyl and 6 to 8 membered heteroaryl are independently 6 to 8 membered heterocycloalkyl and 6 to 8 membered heteroaryl substituted with C 1-10 straight or branched chain alkyl;
  • the substituted C 6-10 aryl is an unsubstituted or substituted 6-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O, C 1-10 straight-chain or branched alkoxy , -NA 3 A 4 and C 2-10 linear or branched chain alkenylcarbonylamino at least one substituent selected from the group consisting of substituted C 6-10 aryl, the substituted 6 to 8 atoms
  • Heterocycloalkyl is a 6-8 membered heterocycloalkyl substituted with C 1-10 straight-chain or branched alkyl, wherein A 3 and A 4 are independently C 1-10 straight-chain or branched alkyl, or diC 1-10 straight-chain or branched alkylamino C 1-10 straight-chain or branched alkyl.
  • R 1 is unsubstituted or substituted C 6-10 aryl
  • the substituted C 6-10 aryl, 5-10 membered heterocycloalkyl and 5-10 membered heteroaryl are independently,
  • a 2 C 6-10 aryl substituted with one or more substituents, 5 to 10 membered heterocycloalkyl and 5 to 10 membered heteroaryl;
  • the substituted 6-8 membered heterocycloalkyl is a 6-8 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of C 1-5 straight or branched chain alkyl and aminocarbonyl,
  • a 1 and A 2 are independently hydrogen, C 1-5 straight or branched chain alkyl, diC 1-5 straight or branched alkylamino C 1-5 straight or branched chain alkyl, or C 2-5 straight-chain or branched alkenylcarbonylamino; and
  • R 2 and R 3 are independently hydrogen, unsubstituted or substituted with one substituent C 1-5 straight-chain or branched alkyl, diC 1-5 straight-chain or branched alkylamino C 1-5 straight-chain or branched-chain alkyl, C 1-5 straight-chain or branched alkoxy C 1-5 straight-chain or branched alkyl, or unsubstituted or substituted C 6-10 aryl;
  • one substituent is an unsubstituted or substituted 6-8 membered heterocycloalkyl comprising at least one N, or an unsubstituted or substituted 6-8 membered heteroaryl comprising at least one N, wherein the substituted 6 to 8 membered heterocycloalkyl and 6 to 8 membered heteroaryl are independently 6 to 8 membered heterocycloalkyl and 6 to 8 membered heteroaryl substituted with C 1-5 straight or branched chain alkyl;
  • the substituted C 6-10 aryl is an unsubstituted or substituted 6-8 membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O, C 1-5 straight or branched chain alkoxy , -NA 3 A 4 and C 2-5 Straight or branched chain alkenylcarbonylamino at least one substituent selected from the group consisting of substituted C 6-10 aryl, the substituted 6 to 8 atoms
  • Heterocycloalkyl is a 6-8 membered heterocycloalkyl substituted with C 1-5 straight or branched chain alkyl, wherein A 3 and A 4 are independently C 1-5 straight or branched chain alkyl, or diC 1-5 straight-chain or branched alkylamino C 1-5 straight-chain or branched alkyl.
  • R 1 is unsubstituted or substituted C 6-8 aryl
  • unsubstituted or substituted 5 to 8 membered heteroaryl comprising at least one heteroatom selected from the group consisting of N, O and S, or
  • the substituted C 6-8 aryl, 5-8 membered heterocycloalkyl and 5-8 membered heteroaryl are independently,
  • the substituted 6-membered heterocycloalkyl is a 6-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of C 1-5 straight or branched chain alkyl and aminocarbonyl,
  • a 1 and A 2 are independently hydrogen, C 1-5 straight or branched chain alkyl, diC 1-5 straight or branched alkylamino C 1-5 straight or branched chain alkyl, or C 2-5 straight-chain or branched alkenylcarbonylamino; and
  • R 2 and R 3 are independently hydrogen, unsubstituted or substituted with one substituent C 1-5 straight-chain or branched alkyl, diC 1-5 straight-chain or branched alkylamino C 1-5 straight-chain or branched chain alkyl, C 1-5 straight or branched chain alkoxy C 1-5 straight or branched chain alkyl, or unsubstituted or substituted C 6-8 aryl,
  • one substituent is an unsubstituted or substituted 6-membered heterocycloalkyl containing at least one N, or an unsubstituted or substituted 6-membered heteroaryl containing at least one N, and the substituted 6-membered heterocycloalkyl Alkyl and 6-membered heteroaryl are independently 6-membered heterocycloalkyl and 6-membered heteroaryl substituted with C 1-5 straight or branched chain alkyl,
  • the substituted C 6-8 aryl is unsubstituted or substituted 6-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O, C 1-5 straight-chain or branched alkoxy, - One or more substituents selected from the group consisting of NA 3 A 4 and C 2-5 straight-chain or branched alkenylcarbonylamino are substituted C 6-8 aryl, and the substituted 6-membered heterocycloalkyl is 6-membered heterocycloalkyl substituted with C 1-5 straight-chain or branched alkyl, wherein A 3 and A 4 are independently C 1-5 straight-chain or branched alkyl, or diC 1-5 straight-chain or It may be a branched chain alkylamino C 1-5 straight chain or branched chain alkyl.
  • R 1 is unsubstituted or substituted C 6 aryl
  • the substituted C 6 aryl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are independently,
  • the substituted 6-membered heterocycloalkyl is a 6-membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of C 1-3 straight-chain or branched alkyl and aminocarbonyl,
  • a 1 and A 2 are independently hydrogen, C 1-3 straight-chain or branched alkyl, diC 1-3 straight-chain or branched alkylamino C 1-3 straight-chain or branched alkyl, or C 2-3 straight-chain or branched alkenylcarbonylamino; and
  • R 2 and R 3 are independently hydrogen, unsubstituted or substituted with one substituent C 1-3 straight-chain or branched alkyl, diC 1-3 straight-chain or branched alkylamino C 1-3 straight-chain or branched chain alkyl, C 1-3 straight-chain or branched alkoxy C 1-3 straight-chain or branched alkyl, or unsubstituted or substituted C 6 aryl,
  • one substituent is an unsubstituted or substituted 6-membered heterocycloalkyl containing at least one N, or an unsubstituted or substituted 6-membered heteroaryl containing at least one N, and the substituted 6-membered heterocycloalkyl Alkyl and 6-membered heteroaryl are independently 6-membered heterocycloalkyl and 6-membered heteroaryl substituted with C 1-3 straight-chain or branched alkyl,
  • the substituted C 6 aryl is an unsubstituted or substituted 6-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N and O, C 1-3 straight-chain or branched alkoxy, -NA 3
  • One or more substituents selected from the group consisting of A 4 and C 2-3 straight-chain or branched alkenylcarbonylamino are substituted C 6 aryl
  • the substituted 6-membered heterocycloalkyl is C 1-3 6-membered heterocycloalkyl substituted with straight-chain or branched alkyl of, wherein A 3 and A 4 are independently C 1-3 straight-chain or branched alkyl, or diC 1-3 straight-chain or branched alkylamino It may be C 1-3 straight-chain or branched alkyl.
  • R 1 is,
  • the compound represented by Formula 1 may be any one compound selected from the following compound group.
  • the compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.
  • Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • bases can be used to prepare pharmaceutically acceptable metal salts.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
  • the corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
  • the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like, which can be prepared therefrom.
  • hydrate refers to a compound of the invention comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolec ⁇ Lar forces. or salts thereof.
  • the hydrate of the compound represented by Formula 1 of the present invention may include a stoichiometric or non-stoichiometric amount of water that is bound by non-covalent intermolecular forces.
  • the hydrate may contain 1 equivalent or more, preferably, 1 to 5 equivalents of water.
  • Such a hydrate may be prepared by crystallizing the compound represented by Formula 1 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.
  • solvate means a compound of the invention or a salt thereof which contains either a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therefor include solvents that are volatile, non-toxic, and/or suitable for administration to humans.
  • isomers refers to a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but differs structurally or sterically.
  • isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.
  • It provides a method for preparing a compound represented by the formula (1), including a; reacting the compound represented by the formula (4) prepared in the above step with the compound represented by the formula (5) to prepare a compound represented by the formula (1).
  • X 1 and X 2 are independently halogen
  • R 1 is as defined herein.
  • Another aspect of the present invention is a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, a stereoisomer, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • the compound may prevent or treat cancer by inhibiting kinase, and the cancer may be a solid cancer or a hematologic cancer.
  • the solid cancer is liver cancer, lung cancer, colon cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, uterus It may be selected from the group consisting of cervical carcinoma, vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor, wherein the blood cancer is leukemia, malignant lymphoma and It may be selected from the group consisting of multiple myeloma.
  • the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, Basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, Bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain
  • the kinase is AAK1, ABL1(E255K)-phosphorylated, ABL1(F317I)-nonphosphorylated, ABL1(F317I)-phosphorylated, ABL1(F317L)-nonphosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated (H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1(T315I)-phosphorylated nonphospho
  • PFTAIRE2 PFTK1, PHKG1, PHK G2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA(C420R), PIK3CA(E542K), PIK3CA(E545A), PIK3CA(E545K), PIK3CA(H1047L), PIK3CA(H1047Y), PIK3CA(H1047L), PIK3CA(H1047Y), Q546K), PIK3CB, PIK3CD, PIK3CG, PIK4CB, PIKFYVE, PIM1, PIM2, PIM3, PIP5K1A, PIP5K1C, PIP5K2B, PIP5K2C, PKAC-alpha, PKAC-beta, PKN , PKMYT1, PKN , PKMYT1, PKN.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations during clinical administration.
  • formulation it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. depending on how
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, which is an ampoule or vial unit dosage form.
  • a stabilizer or buffer to prepare a solution or suspension, which is an ampoule or vial unit dosage form.
  • the composition may be sterilized and/or contain adjuvants such as preservatives, stabilizing agents, wetting or emulsifying agents, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and mixing, granulation, in a conventional manner. It can be formulated according to the method of formulation or coating.
  • Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and the like, and optionally boron such as starch, agar, alginic acid or its sodium salt. It may contain releasing or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyviny
  • Another aspect of the present invention is a health functional food composition for preventing or improving cancer containing the compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound may prevent or ameliorate cancer by inhibiting kinase, and the cancer may be a solid cancer or a hematologic cancer.
  • the solid cancer is liver cancer, lung cancer, colon cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, uterus It may be selected from the group consisting of cervical carcinoma, vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma and central nervous system tumor, wherein the blood cancer is leukemia, malignant lymphoma and It may be selected from the group consisting of multiple myeloma.
  • the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, Basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, Bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain
  • the compound represented by Formula 1 according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixing amount of the active ingredient may be suitably determined according to the purpose of its use (for prevention or improvement).
  • the amount of the compound in the health food can be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food.
  • the above amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
  • the health functional beverage composition of the present invention is not particularly limited in other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • natural flavoring agents such as taumatine, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
  • the compound represented by Formula 1 according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pects acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the compound represented by Formula 1 of the present invention may contain natural fruit juice, fruit juice, and pulp for the production of fruit juice beverages and vegetable beverages.
  • Another aspect of the present invention provides a method of treating cancer comprising administering the compound to a subject in need thereof. Another aspect of the present invention also provides the above compound for use in the prevention or treatment of cancer. Furthermore, another aspect of the present invention provides the use of the compound for the manufacture of a medicament for use in the prevention or treatment of cancer.
  • Another aspect of the present invention is a first component containing the compound, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient; and a second component comprising a pharmaceutically treatable amount of an anticancer agent; provides a pharmaceutical kit for preventing or treating cancer, including.
  • the anticancer agent corresponding to the second component may be a conventionally known anticancer agent.
  • first component and the second component may be administered simultaneously or sequentially depending on the patient's condition.
  • the compound represented by Formula 1 provided in one aspect of the present invention has excellent inhibitory activity against which kinase, as a result, the compound represented by Formula 1 of the present invention is AAK1, ABL1 ( T315I)-phosphorylated, ARK5, AURKA, AURKB, BIKE, CAMK1D, CAMK2D, CAMK2G, CAMKK1, CDC2L5, CDK4-cyclinD1, CDK7, CDKL1, CSNK2A2, CTK, DCAMKL3, DYRK2, EGFR) (E74196-A750del), EGFR , EGFR(G719S), EGFR(L747-E749del,A750P), EGFR(L747-S752del,P753S), EGFR(L747-T751del,Sins), EGFR(L861Q), EGFR(S752-I759del), EGFR(L861Q), EGFR
  • the compound represented by Formula 1 provided in one aspect of the present invention has been shown to have excellent activity against several EGFR mutations.
  • the PC9 cell line is a patient-derived non-small cell lung cancer cell line against EGFR (E746-A750del) among EGFR mutations. It was confirmed that the example compounds actually exhibit significant inhibitory activity against the PC9 cell line. Among them, Examples 13, 14, 41, 42, 43, 51, 52, 54, 55, 58, 59, 60, 61, and 62 compounds showed that the % inhibition value in the PC9 cell 10 ⁇ M assay was 80% or more. appeared, it was confirmed that it had a very good PC9 inhibitory activity (see Experimental Example 2).
  • the example compound provided in one aspect of the present invention has an effect that can be usefully used for the prevention or treatment of cancer as it inhibits the kinase with high activity, which is directly supported by the Examples and Experimental Examples to be described later. do.
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • UV detector 254nm
  • Tris (dibenzylideneacetone) dipalladium (0) (15.3 mg, 0.017 mmol) and Xphos (7.97 mg, 0.017 mmol) were added to the mixture, and the mixture was stirred at 100° C. for 1 hour.
  • the reaction mixture was cooled to room temperature, filtered through celite, extracted with ethyl acetate and brine, and the organic layers were combined. The separated filtrate was concentrated under reduced pressure and separated by PTLC to obtain the title compound (17 mg, 20%) as a white solid.
  • a target compound was prepared through a synthesis method similar to that of ⁇ Example 13>.
  • a target compound was prepared through a synthesis method similar to [Step-2] of ⁇ Example 1>.
  • the reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by prep to obtain the target compound (0.025 g, 24%) as an orange solid.
  • Tetrakis (triphenylphosphine) palladium (0) (32.2 mg, 0.028 mmol) was added to the mixture, and the mixture was stirred at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, it was filtered through Celite. The separated filtrate was concentrated under reduced pressure and separated by PTLC to obtain the title compound (38 mg, 68.1%) as a white solid.
  • Tetrakis (triphenylphosphine) palladium (0) (32.2 mg, 0.028 mmol) was added to the mixture, and the mixture was stirred at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, it was filtered through Celite. The separated filtrate was concentrated under reduced pressure and separated by MPLC to obtain the title compound (50 mg, 61.5%) as a white solid.
  • a target compound was prepared through a synthesis method similar to that of ⁇ Example 54>.
  • a target compound was prepared through a synthesis method similar to that of ⁇ Example 12>.
  • a target compound was prepared through a synthesis method similar to that of ⁇ Example 15>.
  • a target compound was prepared through a synthesis method similar to [Step-2] of ⁇ Example 1>.
  • a target compound was prepared through a synthesis method similar to [Step-3] of ⁇ Example 14>.
  • a target compound was prepared through a synthesis method similar to that of [Step-4] of ⁇ Example 14>.
  • a target compound was prepared through a synthesis method similar to that of ⁇ Example 60>.
  • Example 13 compound was requested to DiscoverX to measure enzyme (kinase) selectivity, and the experiment was conducted using a scanMAXTM Kinase analysis panel.
  • the concentration of the drug treated with the enzyme was 1 ⁇ M in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below, and the results are shown in Table 2-5 below.
  • the positive control refers to a compound showing a percentage control of 0%
  • the negative control indicates a percentage control of 100% with DMSO.
  • the enzyme selectivity of the present invention was determined to have activity for each enzyme if the control percentage was ⁇ 35% (ie, less than 35%) for each enzyme.
  • kinase Example 13 kinase Example 13 AAK1 0.5 CAMK2D 0.9 ABL1(E255K)-phosphorylated 77 CAMK2G 9.3 ABL1(F317I)-nonphosphorylated 51 CAMK4 100 ABL1(F317I)-phosphorylated 41 CAMKK1 0.5 ABL1(F317L)-nonphosphorylated 79 CAMKK2 78 ABL1(F317L)-phosphorylated 55 CASK 91 ABL1(H396P)-nonphosphorylated 95 CDC2L1 94 ABL1(H396P)-phosphorylated 78 CDC2L2 98 ABL1(M351T)-phosphorylated 49 CDC2L5 25 ABL1(M351T)-phosphorylated 79 CDK11 90 ABL1(Q252H)-phosphorylated 84 CDK2 79 ABL1(T315I)-nonphosphorylated 92 CDK3
  • the compound of Example 13 of the present invention is AAK1, ABL1(T315I)-phosphorylated, ARK5, AURKA, AURKB, BIKE, CAMK1D, CAMK2D, CAMK2G, CAMKK1, CDC2L5, CDK4-cyclinD1, CDK7, CDKL1, CSNK2A2, CTK, DCAMKL3 , DYRK2, EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del,A750P), EGFR(L747-S752del,P753S), EGFR(L747-T751del,Sins), EGFR(L861Q) ), EGFR(S752-I759del), EGFR(T790M), EIF2AK1, ERBB4, ERN1, FGR, FLT1, FLT3, FLT3(D8
  • the compound represented by Formula 1 according to the present invention is AAK1, ABL1(T315I)-phosphorylated, ARK5, AURKA, AURKB, BIKE, CAMK1D, CAMK2D, CAMK2G, CAMKK1, CDC2L5, CDK4-cyclinD1, CDK7, CDKL1, CSNK2A2 CTK, DCAMKL3, DYRK2, EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del,A750P), EGFR(L747-S752del,P753S), EGFR(L747-T751del,Sins), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EIF2AK1, ERBB4, ERN1, FGR, FLT1, FLT3, FLT3(D835Y
  • the PC9 cell line is a patient-derived non-small cell lung cancer cell line, and is a cell line for EGFR (E746-A750del) among EGFR mutations.
  • EGFR E746-A750del
  • the compound of Example 13 according to the present invention exhibits excellent inhibitory activity against several EGFR mutations including EGFR (E746-A750del), so whether it exhibits significant inhibitory activity against PC9 cell lines
  • CCK analysis was performed.
  • the PC9 cell line was plated in each well of a 96-well plate (Coming) at 2 ⁇ 103/100 ⁇ l, and allowed to adhere for one day. After removing the culture medium, it was replaced with a culture solution containing 10 ⁇ M of the compound and DMSO control, and then incubated in a 37° C. CO 2 incubator for 72 hours. After 72 hours, take out the plate treated with the compound, and mix well after treatment with 10 ⁇ l/well of Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc) solution. Incubate for 2 hours in a 37° C. CO 2 incubator, and measure the absorbance at 450 nm with a microplate reader. Data were expressed as a percentage relative to the treated cells relative to the vehicle reference, and GI50 values were calculated using GraphPad Prism 6.0 (GraphPad software Inc, San Diego).
  • Example PC9 Example PC9 Example PC9 Example PC9 One C 22 C 43 A 2 C 23 C 44 B 3 C 24 C 45 B 4 C 25 C 46 C 5 C 26 C 47 C 6 C 27 C 48 C 7 C 28 C 49 B 8 B 29 C 50 C 9 C 30 C 51 A 10 C 31 C 52 A 11 C 32 C 53 C 12 C 33 C 54 A 13 A 34 C 55 A 14 A 35 C 56 C 15 C 36 C 57 C 16 C 37 C 58 A 17 C 38 C 59 A 18 C 39 C 60 A 19 B 40 C 61 A 20 C 41 A 62 A 21 C 42 A 63 C
  • Example compounds according to the present invention also exhibit significant inhibitory activity against the PC9 cell line.
  • Examples 13, 14, 41, 42, 43, 51, 52, 54, 55, 58, 59, 60, 61, and 62 compounds showed that the % inhibition value in the PC9 cell 10 ⁇ M assay was 80% or more. appeared to have very good PC9 inhibitory activity.
  • the example compounds provided in one aspect of the present invention can be usefully used for the prevention or treatment of cancer by inhibiting kinases with high activity.

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Abstract

La présente invention concerne un dérivé de dihydropyrano[3,2-g]chromén-2-one et une composition pharmaceutique pour prévenir ou traiter le cancer, comprenant celui-ci en tant que principe actif, et un composé donné à titre d'exemple selon un aspect de la présente invention a un effet qui peut être utilisé efficacement pour la prévention ou le traitement du cancer par l'inhibition de kinases ayant une activité élevée.
PCT/KR2020/005716 2020-04-29 2020-04-29 Dérivé de dihydropyrano[3,2-g]chromén-2-one et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant en tant que principe actif WO2021221208A1 (fr)

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KR20100009295A (ko) * 2008-07-18 2010-01-27 경북대학교 산학협력단 디커신 또는 디커시놀 안젤레이트를 함유한 ｖｅｇｆ에의해 유도된 신생혈관형성 관련 질환의 치료용 조성물
US8383836B2 (en) * 2009-04-21 2013-02-26 Duke University Methods and systems for treating cell proliferation disorders with psoralen derivatives
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