WO2010140835A2 - Nouveaux composés de pyridone ou sel pharmaceutiquement acceptable de ceux-ci, méthode de production de ceux-ci, et composition pharmaceutique les contenant dans le traitement du cancer - Google Patents

Nouveaux composés de pyridone ou sel pharmaceutiquement acceptable de ceux-ci, méthode de production de ceux-ci, et composition pharmaceutique les contenant dans le traitement du cancer Download PDF

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WO2010140835A2
WO2010140835A2 PCT/KR2010/003539 KR2010003539W WO2010140835A2 WO 2010140835 A2 WO2010140835 A2 WO 2010140835A2 KR 2010003539 W KR2010003539 W KR 2010003539W WO 2010140835 A2 WO2010140835 A2 WO 2010140835A2
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oxo
dihydropyridin
hydroxy
acrylamide
hydroxyacrylamide
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WO2010140835A3 (fr
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한균희
최은현
이철호
박정은
조미선
서정제
김환묵
박성규
이기호
이창우
이기훈
김현정
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BIORUNX
Korea Research Institute of Bioscience and Biotechnology KRIBB
Industry Academic Cooperation Foundation of Yonsei University
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BIORUNX
Korea Research Institute of Bioscience and Biotechnology KRIBB
Industry Academic Cooperation Foundation of Yonsei University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel pyridone compound or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
  • Cancer is characterized by "uncontrolled cell growth,” which results in the formation of cell masses called tumors that infiltrate surrounding tissues and, in severe cases, metastasize to other organs of the body. Academia is also called neoplasia.
  • Cancer is an intractable chronic disease that, even if treated with surgery, radiation, and chemotherapy, in many cases does not heal fundamentally, suffers the patient, and ultimately leads to death. More than 20 million people worldwide suffer from cancer, and more than 6 million people die of cancer each year, and 11 million people are expected to die by 2020, so cancer is an urgent need to find a cure. Disease. Cancer varies from country to country, but in developed countries and Korea accounts for more than 20% of all deaths. However, despite many efforts, the exact cause or mechanism of cancer development is still unknown. There are many factors that cause cancer, but they can be divided into internal and external factors. It is not known exactly how normal cells are transformed into cancer cells, but at least 80-90% is known to be influenced by external factors such as environmental factors. Internal factors include genetic factors, immunological factors, and external factors include chemicals, radiation, and viruses. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, which occur when the balance between them is broken down by internal or external factors described above.
  • Cancer is classified into blood cancer and solid cancer, and it occurs in almost every part of the body such as lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer.
  • chemotherapy agents except surgery or radiation therapy, are collectively called anticancer agents, and most of them show anticancer activity by inhibiting the synthesis of hexane.
  • Chemotherapeutic agents are broadly classified into antimetabolites, alkylating agents, antimitotic drugs, and hormones.
  • Metabolism inhibitors inhibit the metabolic processes required for cancer cell proliferation, including folic acid derivatives such as methotrexate, purine derivatives such as 6-mercaptopurine and 6-thioguanine, and 5 Pyrimidine derivatives such as 5-fluorouracil and cytarabine.
  • Alkylating agent is an anti-cancer effect by modifying the structure of the DNA and cutting the chain by introducing an alkyl group to the guanine of DNA, such as chlorambucil (cycloambucil) and cyclophosphamide (cyclophosphamide), nitrogen mustard compounds, thio Ethyleneimine compounds such as thiotepa, alkylsulfonate compounds such as busulfan, nitrosourea compounds such as carmustine, and triazene compounds such as dacarbazine. have.
  • chlorambucil cycloambucil
  • cyclophosphamide cyclophosphamide
  • nitrogen mustard compounds such as thio Ethyleneimine compounds such as thiotepa
  • alkylsulfonate compounds such as busulfan
  • nitrosourea compounds such as carmustine
  • triazene compounds such as dacarbazine.
  • Mitosis inhibitors are mitotic phase specific drugs that inhibit mitosis and inhibit cell division, including anticancer drugs such as actinomycin D, doxorubicin, bleomycin, and mitomycin; Plant alkaloids such as vincristine and vinblastine; Taxoids, such as mitosis inhibitors including taxane rings, are included.
  • anticancer drugs such as actinomycin D, doxorubicin, bleomycin, and mitomycin
  • Plant alkaloids such as vincristine and vinblastine
  • Taxoids such as mitosis inhibitors including taxane rings
  • hormones such as corticosteroids and progesterone and platinum-containing compounds such as cisplatin are used as anticancer agents.
  • RUNX is a Runt-related transcription factor (RUNX) and is a new tumor suppressor that has recently been identified for cancer suppression activity.
  • RUNX has a runt domain called PEBP2 / CBF (polyoma virul enhancer binding protein 2 / core binding factor), which is a signaling target for the TGF- ⁇ superfamily and plays an important role in the development of mammals. Do it.
  • the rungs family consists of RUNX1 (PEBP2aB / CBFA2 / AML1), RUNX2 (PEBP2aB / CBFA1 / AML3) and RUNX3 (PEB2aC / CBFA3 / AML2). These three Rungs families play important roles in normal development and differentiation and oncogenesis.
  • RUNX1 which plays an important role in the hematopoietic process, is the most frequent part of chromosomal translocation in leukemia and accounts for about 30% of the causes of acute leukemia.
  • RUNX2 is essential for bone development and is associated with cleido-cranial dysplasia, an autosomal dominant bone disease.
  • RUNX3 is a cancer suppressor. Deletion of the Runx3 gene in mice causes gastric cancer, and since its function was first reported, it has been reported that RUNX3 is inactivated in several solid cancers. In gastric cancer, RUNX3 has been reported to have hemizygous defects on the chromosome or inactivated by methylation of the RUNX3 promoter region.
  • RUNX3 is known to function as a cancer suppressor by inducing apoptosis or inhibiting the cell cycle similarly to a p53 cancer suppressor.
  • RUNX3 induces apoptosis-inducing gene, Bim, which plays a key role in apoptosis induced by TGFbeta, and induces p21, which plays an important role in cell cycle arrest. It has been reported to inhibit cell growth.
  • histone deacetylase (HDAC) inhibitors can be used to restore transcriptional blockade by DNA methylation on the RUNX3 promoter, leading to expression of RUNX3, and to deacetylation of RUNX3 by HDAC at the PTM stage.
  • HDAC histone deacetylase
  • Inhibition of RUNX3 protein can regulate stabilization and transcriptional activity, so it is possible to control chemotherapy by regulating PTM level as well as epigenetics.
  • Histones are basic proteins that bind to the nucleus DNA of eukaryotic cells and undergo reversible acetylation of the amino groups of lysine residues at specific positions in each molecule of histones.
  • the acetylation of histones is involved in the regulation of the expression of genetic information, which is related to the formation of higher levels of chromatin and the cell division cycle, and histone acetyltransferases (HATs) and histone deacetylases. Stable (HDACs).
  • HDAC is an enzyme that deacetylates the positive charge of the lysine residue present in the amino terminus of histones to recharge, thereby inhibiting transcription, and is highly expressed under poor environmental conditions such as hypoxia, low glucose, and cell cancer, thereby inhibiting cell proliferation.
  • hypoxia low glucose
  • cell cancer thereby inhibiting cell proliferation.
  • the role of promoting cell proliferation by inhibiting the expression of the factor is recognized as an important factor in regulating the cancerous and differentiation of cells.
  • HDAC histone deacetylation
  • the first compound used as an HDAC inhibitor is n-butyrate, which is not only applied to the treatment of colorectal cancer, but also used in biochemistry and molecular biology experiments as an HDAC enzyme inhibitor.
  • the effective concentration of n-butyrate is in the level of milimolar (mM), which is not suitable for the analysis of HDAC functions such as affecting other enzymes, cytoskeleton, and cell membranes in the cell.
  • mM milimolar
  • the present inventors have effectively studied the new mechanism of anticancer agent that effectively inhibits the enzymatic activity of histone deacetylase and increases the expression and activity of RUNX to selectively induce terminal differentiation of tumor cells, inhibit tumor growth and induce apoptosis.
  • a novel pyridone compound was synthesized, and it was confirmed that this compound exhibited tumor cell growth inhibitory effect by inducing the increase of RUNX3 activity through excellent HDAC inhibitory activity, and completed the present invention.
  • the present invention is to provide a novel pyridone compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1-4 alkyl; C 2-4 alkenyl; Unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Thienyl; Unsubstituted naphthalenyl or naphthalenyl substituted with halogen; Quinolinyl; Indanyl; Benzothiophenyl; Furanyl or benzofuranyl,
  • R 2 is hydroxy; C 1-3 alcohol; Or NHR 4 ,
  • R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 2-4 alkenyl; Nitro; Phenyl; Unsubstituted phenoxy or phenoxy substituted with C 1-4 alkoxy or halogen; Or benzyloxy,
  • R 4 is hydroxy; Or aminophenyl,
  • L is a bond; C 1-4 alkylene; Or C 2-4 alkylene, and
  • R 1 is methyl; 2-propenyl; Unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 2-thienyl; 1-naphthalenyl; 2-naphthalenyl; 1-bromo-2-naphthalenyl; 6-bromo-2-naphthalenyl; 1-quinolinyl; 2-indanyl; Benzothiophen-2-yl; 2-furanyl or benzofuran-2-yl.
  • R 2 is hydroxy; Methoxy; Or NHR 4 .
  • R 3 is F; Cl; Br; methyl; ethyl; Isopropyl; Tet-butyl; Methoxy; Ethoxy; Propoxy; CF 3 ; OCF 3 ; Ethenyl; Nitro; Phenyl; Unsubstituted phenoxy or phenoxy substituted with methoxy or F; Or benzyloxy.
  • R 4 is hydroxy or 2-aminophenyl.
  • L is a bond; Ethylene; Trimethylene; Or propenylene ( )to be.
  • R 1 is phenyl substituted with one R 3 .
  • R 1 is phenyl substituted with two R 3 , wherein R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; Or nitro.
  • R 3 is F; Cl; methyl; Methoxy; CF 3 ; Or nitro.
  • R 1 is phenyl substituted with three R 3 , wherein R 3 is halogen; Or C 1-4 alkoxy.
  • R 3 is F; Or methoxy.
  • R 1 is 3-methoxyphenyl; 3-trifluoromethoxyphenyl; 3-chlorophenyl; 3-bromophenyl; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; 1-quinolinyl; 4-isopropylphenyl; 4-nitrophenyl; 2-bromophenyl; 2-methoxyphenyl; Or 2,5-ditrifluoromethylphenyl.
  • R 1 is phenyl substituted with R 3 at position 2 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; Or C 1-4 haloalkoxy,
  • R 1 is phenyl substituted with R 3 at position 3 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 2-4 alkenyl; Nitro; Phenoxy; Or benzyloxy, or
  • R 1 is phenyl substituted with R 3 at position 4 of phenyl, and R 3 is halogen; C 1-4 alkyl; C 1-4 alkoxy; C 1-4 haloalkyl; C 1-4 haloalkoxy; Nitro; Phenyl; Phenoxy unsubstituted or substituted with C 1-4 alkoxy or halogen; Or benzyloxy.
  • R 1 is C 1-4 alkyl; C 2-4 alkenyl; Indanyl; Or furanyl, and L is a bond,
  • R 1 is unsubstituted phenyl or phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Quinolinyl; Benzothiophenyl; Or benzofuranyl, wherein L is methylene,
  • R 1 is phenyl substituted with 1 to 3 R 3 ; Thienyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is ethylene, or
  • R 1 is phenyl substituted with 1 to 3 R 3 ; Pyridinyl; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is trimethylene, or
  • R 1 is phenyl substituted with 1 to 3 R 3 ; Unsubstituted naphthalenyl or halogen substituted naphthalenyl; Or quinolinyl, wherein L is propylene ( )to be.
  • R 1 is methyl; Ethenyl; 2-indanyl; Or 2-furanyl, wherein L is a bond,
  • R 1 is phenyl substituted with 1 to 3 R 3 ; 2-pyridinyl; 3-pyridinyl; 4-pyridinyl; 1-naphthalenyl; 2-naphthalenyl; 1-quinolinyl; Benzothiophen-2-yl; Or benzofuran-2-yl, wherein L is methylene,
  • R 1 is phenyl substituted with 1 to 3 R 3 ; 2-thienyl; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; Or 1-quinolinyl, wherein L is ethylene,
  • R 1 is phenyl substituted with 1 to 3 R 3 ; 3-pyridinyl; 1-naphthalenyl; 1-naphthalenyl; 6-bromo-2-naphthalenyl; or 1-quinolinyl, wherein L is trimethylene, or
  • R 1 is phenyl substituted with 1 to 3 R 3 ; 1-naphthalenyl; 2-naphthalenyl; 6-bromo-2-naphthalenyl; Or 1-quinolinyl, wherein L is propenylene ( )to be.
  • Preferred compounds among the pyridone compounds of formula 1 of the present invention are specifically as follows:
  • the compounds of the present invention can be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.
  • Acid addition salts formed by free acid are useful.
  • Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • organic acids and inorganic acids may be used as the free acid
  • hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid
  • methanesulfonic acid, p -toluenesulfonic acid, acetic acid, and trifluoro may be used as the organic acid.
  • Acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, Galacturonic acid, glutamic acid, glutaric acid (glutaric acid), glucuronic acid (glucuronic acid), aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid and the like can be used.
  • Bases may also be used to prepare pharmaceutically acceptable metal salts.
  • An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • Pharmaceutically acceptable salts of the compound represented by Formula 1 include salts of acidic or basic groups which may be present in the compound of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group
  • other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts. It can be prepared through.
  • the present invention provides a process for preparing the compound of formula 1.
  • the compound of Formula 1 may be prepared as in Scheme 1 below.
  • step 6) by reacting the compound of formula 8 prepared in step 5) Is a double bond).
  • R 1 , R 2 , L are as defined in the formula (1), X is a halogen atom.
  • An example of a method for preparing a pyridone compound of Formula 1 of the present invention is as follows.
  • step 2 injecting pyridinium dichloromate and celite in an methylene chloride 0.1M solution of the compound of formula 5 prepared in step 2) under anhydrous and agitation, stirring at room temperature for 12 hours, and then generating The mixture was filtered through methylene chloride and concentrated under reduced pressure, and the obtained primary compound was purified by silica gel column chromatography to obtain a compound of formula 6.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the cancer may include lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, Endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, Chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, etc.
  • CNS central nervous system
  • the compound according to the present invention is excellent in tumor cell growth inhibitory effect, it can be usefully used for the treatment of cancer diseases.
  • compositions comprising a compound of formula 1 according to the invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.
  • Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • compositions according to the invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, external preparations, suppositories or sterile injectable solutions according to conventional methods.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like. Can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used.
  • Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • utopsol macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • Preferred dosages of the compounds according to the invention depend on the condition and body weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times daily.
  • compositions according to the invention can also be used in the form of their pharmaceutically acceptable salts, and can also be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.
  • the pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • the present invention provides a method for treating cancer comprising administering to a patient an effective amount of a pyridone compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the cancer may include lung cancer, non-small cell lung cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, Endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, Chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary central nervous system lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, etc.
  • CNS central nervous system
  • the optimal amount and dosage interval of the individual doses of the compounds of the present invention will be determined by the nature and extent of the disease being treated, the dosage form, the route and site, and the age and health of the particular patient being treated, and ultimately the physician It will be appreciated by those skilled in the art that the appropriate dosage will be determined. Such dosing can be repeated as often as appropriate. If side effects occur, the dosage and frequency can be altered or reduced in accordance with normal clinical practice.
  • the compound according to the present invention is excellent in RUNX3 activity inducing effect, HDAC inhibitory activity and tumor cell growth inhibitory effect, it can be usefully used for the prevention or treatment of cancer.
  • FIG. 1 shows that 4 ⁇ 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compound prepared in Examples 42, 44, 55, and 69 was intravenously. A total of 10 mg / kg doses per day was then used to show changes in body weight of the animals during the administration period.
  • FIG. 2 shows that 4 ⁇ 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compounds prepared in Examples 42, 44, 55, and 69 were intravenously. A total of 10 mg / kg 20 mg / kg daily showed tumor size change during the administration period.
  • FIG. 3 shows that 4 ⁇ 10 7 cells / ml of the human-derived gastric cancer cell line MKN28 was transplanted into a female SPF BALB / c nude mouse (6 weeks old), and then the compounds prepared in Examples 42, 44, 55, and 69 were intravenously injected. Tumor weight was measured on the last day (10th day) after total administration of 20mg / kg 10 times a day.
  • the target compound was obtained as follows.
  • oxalyl chloride (2M methylene chloride, 3 equiv) and dimethyl sulfoxide (5 equiv) in 0.1M solution of methylene chloride was anhydrous, injected at -78 °C and the compound obtained in step 1-2 under 10 minutes stirring Injected and stirred at the same temperature for 15 minutes.
  • triethylamide (10 equiv) was injected at the same temperature and stirred at -78 ° C to room temperature for 1 hour. Water was stopped to stop the reaction and extracted with methylene chloride. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered with methylene chloride and concentrated under reduced pressure.
  • Example 2 In a preparation similar to the preparation described in Example 1, the compounds of Examples 2 to 183 were prepared. Chemical structures and physical properties of the prepared compounds are shown in Table 1 below.
  • Runx activity was used for screening by constructing a cell line that constantly expressed a reporter vector with a fragment that repeatedly linked the Runx binding site.
  • Cell lines were cultured in a 37 ° C., 5% CO 2 concentration incubator in DMEM medium containing 10% FBS. Seed to 1x10 4 cells / well in a 96 well plate. After 24 hours of incubation, the compounds were treated at a concentration of 1 ⁇ M with replacement of medium containing 10% FBS and the medium was added at 100 ⁇ l / well. After 24 hours of incubation, Luciferase activity was measured.
  • Luciferase activity assay was performed using Promega's Bright-Glo Luciferase Assay System (E2620).
  • the process of preparing the reaction solution is as follows. Take out and dissolve one bottle of Bright-Glo buffer (100ml) and one bottle of Bright-Glo Substrate (powder) stored at -20 °C, and mix 100ml of Bright-Glo buffer in Bright-Glo Substrate until the substrate is completely dissolved. gave.
  • Assay process is as follows. Plates containing cultured cells were removed from the incubator, and the same volume of Luciferase Reagent (100 ⁇ l) as the culture medium was added to each well using a multi-pipette. After complete cell lysis (Cell lysis) was allowed to stand for 2 minutes at room temperature luc activity was measured on a Luminometer. The Luminometer used Promega's GloMax-MultiDetection System (E7031).
  • RUNX activity analysis degree of the compounds prepared in the above Example is shown in Table 2 below.
  • HDAC activity analysis was performed based on the biomolar (ACOMOL) HDAC Fluorimetirc Assay / Drug Discovery Kit (AK-500) analysis system.
  • the analysis consists of two steps.
  • the first step is an enzyme reaction step in which the HDAC reacts with the substrate.
  • an HDAC inhibitor was added to measure the degree of inhibition of HDAC enzyme activity.
  • the compounds of the above examples as HDAC enzyme activity inhibitors were prepared in 96-well plates at concentrations of 0.03, 0.1, 0.3, 1, 3 and 10 ⁇ M, respectively, in a reaction buffer (50 mM Tris / Cl, pH 8.0).
  • HeLa nuclear extract was used as the HDAC enzyme source, and the reaction buffer (50 mM Tris / Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) was used to obtain a final concentration of 0.5ul. Diluted to add 15 ⁇ l.
  • the 50 mM Fluor de Lys TM substrate was added to the reaction buffer (50 mM Tris / Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 ) so that the final concentration was 100 ⁇ M. 25 ⁇ l was added by dilution and enzymatic reaction was performed at 37 ° C. for 30 minutes.
  • the second step was a detection step, in which a fluorescent label lysine developer of 20X concentration (Flour de Lys TM developer) was diluted with reaction buffer to a 1X concentration, 50 ⁇ l was added and reacted for 15 minutes at room temperature.
  • HDAC inhibitory activity (IC 50 ) degree of the representative compounds prepared in the above Examples are shown in Tables 3 and 4.
  • Example HDACIC 50 ( ⁇ M)
  • Example HDACIC 50 ( ⁇ M)
  • Example HDACIC 50 ( ⁇ M)
  • Example HDACIC 50 ( ⁇ M) Example HDACIC 50 ( ⁇ M)
  • Example HDACIC 50 ( ⁇ M) 91 0.06 122 > 10 153 0.42 92 0.24 123 > 10 154 4.47 93 0.75 124 0.09 155 0.63 94 0.67 125 0.08 156 > 10 95 0.11 126 0.07 157 0.03 96 0.18 127 0.07 158 0.02 97 0.47 128 0.05 159 0.02 98 0.07 129 0.47 160 0.04 99 0.76 130 0.30 161 100 0.15 131 0.05 162 > 10 101 0.61 132 0.27 163 > 10 102 0.06 133 > 10 164 > 10 103 0.08 134 > 10 165 > 10 104 0.11 135 > 10 166 105 0.16 136 0.36 167 1.06 106 0.08 137 0.02 168 > 10 107 0.38 138 0.04 169 > 10 108 0.11 139 0.03 170 > 10 109 0.37 140 0.001 171 > 10 110 0.13 141 > 10
  • Human tumor cell lines PC-3 prostate cancer, ATCC, USA
  • MDA-MB-231 breast cancer, ATCC, USA
  • ACHN renal cancer, ATCC, USA
  • HCT-15 colon cancer, ATCC, USA
  • NCI -H23 Lung Cancer, ATCC, USA
  • NUGC-3 Semach Cancer, ATCC, USA
  • FBS Fetal Bovine Serum
  • an appropriate concentration (approximately 5 x 10 4 cells / ml) of cells in RPMI 1640 medium containing 5% fetal bovine serum was dispensed into a 96 well plate and then treated at 5% CO 2 , 37 ° C. Incubated. After dispensing the cells, fix the cells by adding 50 ⁇ l of 50% trichloroacetic acid per well in a time zero (T 0 ) plate to determine the cell concentration after one day and immediately before processing the compounds. It was set as. In the case of cells treated with the compound, 50 ⁇ l of 50% trichloroacetic acid was added to the wells after 48 hours to fix the cells.
  • the compound according to the present invention can be seen that the tumor cell growth inhibition effect is excellent.
  • the compound prepared in Examples 42, 44, 55, and 69 was intravenously injected 20 mg per day. A total of 10 mg / kg were administered, and 10 mg of suberoylanilide hydroxamic acid (SAHA) was administered intravenously once daily for 10 days.
  • SAHA suberoylanilide hydroxamic acid
  • the weight change of the animals is shown in FIG. 1, the change in tumor size is shown in FIG. 2, and the tumor weight at the last day (day 10) is shown in FIG. 3.
  • mice administered intravenously with the compounds according to the invention did not show any unusual general symptoms during the test period.
  • results of the last day (10 days) of the change in the body weight of the mouse compared to the solvent control compound sample of the present invention 20mg / kg administration group there was no weight loss.
  • the results of the last day (day 10) showed 25.6% and 28.3% in the compound sample of the present invention (Examples 42, 44, 55, 69) compared to the solvent control group (20 mg / kg), respectively. , 40.6% (p ⁇ 0.05), 27.6% of tumor growth inhibitory effect was observed.
  • Positive control (SAHA / 20 mg / kg / Q1D: 10 times) group showed 44.6% of tumor growth inhibitory effect.
  • the tumors were sacrificed at the end of the experiment (day 10), and the weights of the tumors were measured.
  • the compound samples of the present invention were compared with the solvent control (Examples 42, 44, 55, and 69).
  • Tumor weight reductions of 27.9%, 32.4%, 42.6% (p ⁇ 0.01) and 26.0% were observed in the administration group (20 mg / kg), respectively.
  • a positive control (SAHA / 20 mg / kg / Q1D: 10) group showed a 45.6% reduction in tumor weight.
  • Human gastric cancer cell line MKN28 was cultured in an incubator at 37 ° C., 5% CO 2 with RPMI 1640 medium containing 10% Fetal bovine serum (FBS).
  • FBS Fetal bovine serum
  • Compounds according to the invention were treated at a concentration of 1 ⁇ M. Cells were harvested after an additional 24 hours of incubation. Total RNA was extracted from the cells using an Easy blue Total RNA extract kit (Intron / Cat. No. 17061) and isolated according to the manufacturer's protocol.
  • cDNA synthesis was synthesized using ImProm-II TM Reverse Transcriptase (Promega / Cat. No. A3802) as olig (dT) primer with 2 ⁇ g total RNA as a template.
  • dT olig
  • primer sets of RUNX3 forward primer: 5'-GCA GGC AAT GAC GAG AAC TA-3 'and RUNX3 reverse primer: 5'-GTC TGG TCC TCC AGC TTC TG-3' were used.
  • I-star Max TM II DNA polymerase Intron / Cat.No. 25173
  • Taq polymerase was used for the PCR reaction.
  • the PCR conditions are shown in Table 6 (PCR reaction solution) and Table 7 (PCR condition (2-step PCR)). It was performed as follows.
  • 293 cell lines derived from human embryonic kidney were cultured in DMEM medium containing 10% FBS and seeded in 60 mm dish with 1x10 6 cells.
  • myc tagged RUNX3 expression vector (10 ⁇ g) was introduced into 293 cells using WelFect-Ex plus (WelGene, Korea) transfection reagent according to the manufacturer's protocol.
  • the compounds according to the invention were treated at a concentration of 1 ⁇ M while replacing with medium containing 10% FBS. After 24 hours of incubation, the cells were recovered and proteins were separated from the cells using RIPA lysis buffer.
  • an anti-myc monoclonal antibody (9E10, SantaCruz) was added to 600 ⁇ g of cell lysate, and the reaction was stirred at 4 ° C. for 16-24 hours to stir well.
  • 40 ⁇ l of agarose-G beads (Millipore) was added to each reaction solution, followed by stirring at 4 ° C. for 4 hours, followed by centrifugation at 12,000 rpm to precipitate the RUNX3-antibody-beads complex, followed by removal of the supernatant. It was. 800 ⁇ l RIPA lysis buffer was added to the precipitate, washed with a stirrer at 4 ° C.
  • the stability of RUNX3 was compared with the amount of RUNX3 expression in 40 ⁇ g of cell lysate after SDS-PAGE and the protein transferred by anti-myc-antibody in western blot.
  • the expression level of tubulin was used as a loading control.
  • Injection solution containing 10 mg of the active ingredient was prepared by the following method.
  • the components of the injection solution are as follows.
  • Syrup containing the compound of Formula 1 as an active ingredient 2% was prepared by the following method.
  • the components of the syrup are as follows.
  • a tablet containing 15 mg of the active ingredient was prepared by the following method.
  • the components of the tablet are as follows.

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Abstract

La présente invention concerne de nouveaux composés de pyridone ou un sel pharmaceutiquement acceptable de ceux-ci, une méthode de production de ceux-ci et une composition pharmaceutique les contenant, utilisés dans le traitement du cancer. Lesdits composés de la présente invention ont un effet supérieur sur l'inhibition de la croissance des cellules cancéreuses en tant qu'inhibiteurs HDAC induisant l'activité RUNX, et peuvent ainsi être utilisés dans le traitement de maladies cancéreuses.
PCT/KR2010/003539 2009-06-01 2010-06-01 Nouveaux composés de pyridone ou sel pharmaceutiquement acceptable de ceux-ci, méthode de production de ceux-ci, et composition pharmaceutique les contenant dans le traitement du cancer Ceased WO2010140835A2 (fr)

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KR20240159800A (ko) 2023-04-27 2024-11-06 동국대학교 산학협력단 Mdh 1 및 2 이중 저해제를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물
KR20250144822A (ko) 2024-03-27 2025-10-13 동국대학교 산학협력단 신규 옥사졸 유도체 및 이를 포함하는 암 예방 또는 치료용 조성물
KR20250144817A (ko) 2024-03-27 2025-10-13 동국대학교 산학협력단 신규 옥사다이아졸 유도체 및 이를 포함하는 암 예방 또는 치료용 조성물

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