WO2021201585A1 - Nouveau composé pour le traitement du cancer et composition contenant celui-ci - Google Patents

Nouveau composé pour le traitement du cancer et composition contenant celui-ci Download PDF

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WO2021201585A1
WO2021201585A1 PCT/KR2021/003975 KR2021003975W WO2021201585A1 WO 2021201585 A1 WO2021201585 A1 WO 2021201585A1 KR 2021003975 W KR2021003975 W KR 2021003975W WO 2021201585 A1 WO2021201585 A1 WO 2021201585A1
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dihydro
triazin
phenoxy
triphenylphosphonium
phenethylamino
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PCT/KR2021/003975
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English (en)
Korean (ko)
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윤경섭
박선영
이지혜
정세영
김용배
김홍렬
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주식회사 하임바이오
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Publication of WO2021201585A1 publication Critical patent/WO2021201585A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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 novel compounds for the prevention, improvement or treatment of cancer, compositions comprising the same, and various uses thereof.
  • Cancer is one of the most common causes of death worldwide. About 10 million new cases occur each year, accounting for about 12% of all deaths, making it the third leading cause of death.
  • lung cancer remains the most deadly malignant tumor in the world.
  • the 5-year survival rate for all patients diagnosed with lung cancer remains between 15 and 20%.
  • Lung cancer includes two main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
  • SCLC represents 15 to 18% of all lung cancers, and NSCLC accounts for about 80% to 85% of lung cancers.
  • Other types of lung cancer such as adenoid cystic carcinoma, lymphoma and sarcoma, as well as benign lung tumors such as hamartoma are rare.
  • SCLC small cell and non-small cell lung cancer are treated differently.
  • SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer.
  • SCLC tends to become widespread at the time of diagnosis, it is difficult to achieve cure.
  • Treatment usually includes surgery or chemotherapy for small-localized tumors, depending on the development of the cancer, possibly in combination with radiation therapy.
  • One object of the present invention is to provide a novel compound capable of preventing, ameliorating or treating cancer.
  • Another object of the present invention is to provide a composition capable of preventing, improving or treating cancer, including the compound described above.
  • Another object of the present invention is to provide a method for preventing, ameliorating or treating cancer using the above compound.
  • 'halogen means fluorine, chlorine, bromine or iodine, unless otherwise noted.
  • the term 'C 1 ⁇ C 6 of 'Alkyl' refers to a linear or branched hydrocarbon residue having 1 to 6 carbon atoms, unless otherwise stated, and 'C 1 to C 6
  • the 'alkylene group' means a divalent residue derived from a straight or branched hydrocarbon chain having 1 to 6 carbon atoms, unless otherwise stated.
  • the alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
  • the term 'C 6 -C 14 aryl' is a mono- or poly-cyclic carbocyclic ring having 6 to 14 carbon atoms, having one or more fused or non-fused aromatic rings, unless otherwise specified.
  • 'C 6 -C 14 Arylene group' refers to a divalent residue derived from the above-described ring system, unless otherwise specified.
  • the aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl and andracenyl.
  • the term 'heteroaryl having 5 to 14 nuclear atoms' is at least one selected from O, N and S, for example, 5 to 14 members containing 1 to 4 heteroatoms. of a monocyclic or bicyclic or higher aromatic group, and the 'heteroarylene group having 5 to 14 nuclear atoms' refers to a divalent residue derived from the above aromatic group, unless otherwise specified.
  • Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, benzo[d]oxazolyl, isoxazolyl, oxazolopyridinyl, pyrazolyl, triazolyl, thia zolyl, benzo[d]thiazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, naphthooxazolyl and similar groups; It is not limited to these.
  • bicyclic heteroaryl examples include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso quinolinyl, purinyl, furopyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl and the like.
  • R 1 is hydrogen, a C 1 -C 6 alkyl group, or -L 1 -R 7 ;
  • R 2 is hydrogen or a C 1 -C 6 alkyl group
  • R 3 to R 6 are each independently hydrogen, a C 1 to C 6 alkyl group, or -L 2 -R 8 ;
  • L 1 is a direct bond, a C 6 ⁇ C 14 arylene group or a heteroarylene group having 5 to 14 nuclear atoms;
  • R 7 is hydrogen or -OL 3 -R 9 ;
  • L 2 is a direct bond or a C 1 ⁇ C 6 alkylene group
  • R 8 is a C 6 ⁇ C 14 aryl group or a heteroaryl group having 5 to 14 nuclear atoms
  • L 3 is a direct bond or a C 1 ⁇ C 20 alkylene group
  • R 9 is hydrogen or a substituent represented by the following formula (2);
  • the alkyl group of R 1 to R 6 , the arylene group and heteroarylene group of L 1 , the aryl group and heteroaryl group of R 8 , and the alkylene group of L 2 and L 3 are each independently at least one C 1 ⁇ C 6 is unsubstituted or substituted with an alkyl group, and when substituted with a plurality of substituents, they are the same or different from each other;
  • Z is a monovalent anion
  • R 1 may be a C 1 -C 6 alkyl group or -L 1 -R 7 , preferably -L 1 -R 7 .
  • L 1 may be a C 6 ⁇ C 14 arylene group.
  • R 7 may be -OL 3 -R 9 .
  • R 3 To R 6 are each independently hydrogen or a C 1 ⁇ C 6 Alkyl group; hydrogen or -L 2 -R 8 .
  • R 3 and R 4 may be each independently hydrogen, a C 1 ⁇ C 6 alkyl group, or -L 2 -R 8 .
  • R 5 and R 6 may each independently be hydrogen or a C 1 to C 6 alkyl group.
  • L 2 may be a C 1 ⁇ C 6 alkylene group.
  • R 8 may be a C 6 ⁇ C 14 aryl group.
  • L 3 may be a C 1 ⁇ C 20 alkylene group, preferably a C 1 ⁇ C 12 alkylene group, more preferably a C 2 ⁇ C 12 alkylene group.
  • R 9 may be a substituent represented by Formula 2 above.
  • Z may be a pharmaceutically acceptable monovalent anion, preferably halogen, and more preferably fluorine, chlorine, bromine or iodine.
  • the compound may be a compound represented by the following formula 3, a compound selected from a pharmaceutically acceptable salt, optical isomer, hydrate, and solvate thereof:
  • n is an integer from 1 to 20, preferably an integer from 1 to 15, more preferably an integer from 1 to 12;
  • R 2 to R 6 and Z is as defined in Formula 1 above.
  • the compound may be a compound represented by the following Chemical Formula 4 or 5:
  • X is a monovalent anion, preferably halogen, more preferably fluorine, chlorine, bromine or iodine;
  • R 1 to R 6 is as defined in Formula 1 above.
  • the compound may be a compound represented by the following Chemical Formula 6 or 7:
  • n is an integer from 1 to 20, preferably an integer from 1 to 15, more preferably an integer from 1 to 12;
  • X is a monovalent anion, preferably halogen, more preferably fluorine, chlorine, bromine or iodine;
  • R 2 to R 6 and Z is as defined in Formula 1 above.
  • the compound may be a compound selected from the following compounds, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
  • the present invention also provides pharmaceutically acceptable salts of the compounds.
  • Said pharmaceutically acceptable salts are salts that are generally considered by those skilled in the art to be suitable for medical applications (eg, since such salts are not deleterious to the subject to be treated with said salts), or within each treatment. salts that cause acceptable side effects in In general, the pharmaceutically acceptable salts are salts considered acceptable by regulatory authorities such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceutical and Medical Devices Agency (PMDA) of the Ministry of Health, Labor and Welfare of Japan. .
  • FDA U.S. Food and Drug Administration
  • EMA European Medicines Agency
  • PMDA Pharmaceutical and Medical Devices Agency
  • the present invention in principle provides an intermediate, for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof.
  • an intermediate for example in the preparation of a compound according to the invention or a physiologically functional derivative thereof, or a pharmaceutically acceptable salt of a compound according to the invention or a physiologically functional derivative thereof.
  • salts of the compounds according to the invention which are not themselves pharmaceutically acceptable.
  • Said salts include water-insoluble salts, in particular water-soluble salts.
  • a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming a salt, ie whether said compound according to the invention or a physiologically functional derivative thereof is, for example
  • Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceuticals, which are water-insoluble or particularly water-soluble acid addition salts. is salt Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable. Acid addition salts are prepared, for example, by combining a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. It can be formed by mixing.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. It can be formed by mixing.
  • pharmaceutically acceptable base addition salts include alkali metal salts (eg, sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations) may be included.
  • alkali metal salts eg, sodium or potassium salts
  • alkaline earth metal salts eg, calcium or magnesium salts
  • suitable organic ligands eg, ammonium, quaternary ammonium and amines formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates
  • Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulphate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide , 2-hydroxy-ethanesulfonate, hydroxynaphthoate
  • Salts which are not pharmaceutically acceptable and which can be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are also included in the invention and, if desired, are prepared by methods known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt.
  • the compounds according to the present invention may have an asymmetric carbon center, they may exist as R or S isomers or racemic compounds, and all optical isomers and mixtures thereof may be included in the scope of the present invention.
  • the compounds of the present invention may contain varying amounts of solvent, for example, when isolated in crystalline form. Accordingly, solvates, particularly hydrates, of the compounds of the present invention as well as solvates, particularly hydrates, of the salts of the compounds of the present invention may be included within the scope of the present invention. More particularly, the present invention may comprise hydrates of the compounds, salts and/or physiologically functional derivatives according to the invention, comprising 1, 2 or 1/2 water molecules with respect to stoichiometry. .
  • a pharmaceutical composition comprising as an active ingredient a compound selected from the compound represented by Formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate, and solvate thereof.
  • the pharmaceutical composition can prevent, improve or treat cancer.
  • the cancer includes liver cancer, biliary tract cancer, gallbladder cancer, esophageal cancer, stomach cancer, ovarian cancer, breast cancer, uterine cancer, colon cancer, rectal cancer, cervical cancer, prostate cancer, skin cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin's disease, lung cancer, bronchial cancer It may be at least one selected from the group consisting of cancer, multiple myeloma, leukemia, lymphoma, squamous cell cancer, kidney cancer, urethral cancer, bladder cancer, head and neck cancer, brain cancer and central nervous system cancer, preferably lung cancer.
  • treatment and “improvement” may include, without limitation, any action in which a cancer-related disease is improved or beneficial using the pharmaceutical composition.
  • prevention may include, without limitation, any act of blocking the symptoms of cancer-related diseases by using the pharmaceutical composition of the present invention, or suppressing or delaying the symptoms.
  • the pharmaceutical composition may be characterized in the form of capsules, tablets, granules, injections, ointments, powders or beverages, and the pharmaceutical composition may be characterized in that it is intended for humans.
  • the pharmaceutical composition of the present invention is not limited thereto, but each can be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, dyes, fragrances, etc., for oral administration, and in the case of injections, buffers, preservatives, pain-freezing agents A topical agent, solubilizer, isotonic agent, stabilizer, etc.
  • the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • a pharmaceutically acceptable carrier as described above.
  • it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
  • the route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/day per day kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
  • composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
  • compositions represented by Formula 1 selected from the compound represented by Formula 1, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof of the present invention to a subject (eg, human) in need of administration It relates to a method for preventing, improving or treating cancer, comprising administering a compound to be used in a pharmaceutically effective amount.
  • administration means providing a given compound of the present invention to a subject by any suitable method.
  • the "subject" in need of the administration may include both mammals and non-mammals.
  • mammals include humans, non-human primates such as chimpanzees, and other apes and monkey species; livestock animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals such as rodents such as rats, mice and guinea pigs, but are not limited thereto.
  • non-mammals in the present invention may include, but are not limited to, birds and fish.
  • the cancer includes liver cancer, biliary tract cancer, gallbladder cancer, esophageal cancer, stomach cancer, ovarian cancer, breast cancer, uterine cancer, colon cancer, rectal cancer, cervical cancer, prostate cancer, skin cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin's disease, lung cancer, bronchial cancer It may be at least one selected from the group consisting of cancer, multiple myeloma, leukemia, lymphoma, squamous cell cancer, kidney cancer, urethral cancer, bladder cancer, head and neck cancer, brain cancer and central nervous system cancer, preferably lung cancer.
  • the formulation of the compound administered as described above is not particularly limited, and may be administered as a solid formulation, a liquid formulation, or an aerosol formulation for inhalation, and a liquid formulation for oral or parenteral administration immediately before use. It can be administered in a solid form preparation intended to be converted into However, the present invention is not limited thereto.
  • a pharmaceutically acceptable carrier may be additionally administered together with the compound of the present invention.
  • the pharmaceutically acceptable carrier may include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a dye, a flavoring agent, etc.
  • a buffer Preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc.
  • bases, excipients, lubricants, preservatives, etc. can be used for topical administration.
  • the formulation of the compound of the present invention can be prepared in various ways by mixing with the pharmaceutically acceptable carrier as described above.
  • the pharmaceutically acceptable carrier for example, in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. have.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like may be further included.
  • Routes of administration of the compounds according to the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or work. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
  • a "pharmaceutically effective amount” refers to an amount sufficient of an agent to provide a desired biological result. The result may be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable change in the biological system.
  • an “effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease.
  • An appropriate “effective” amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Accordingly, the expression “effective amount” generally refers to the amount in which the active substance has a therapeutic effect.
  • the active substance is an inhibitor of the formation of nicotinamide phosphoribosyltransferase (NAMPT).
  • NAMPT nicotinamide phosphoribosyltransferase
  • the compound of the present invention may vary depending on various factors including the activity of the specific compound used, age, weight, general health, sex, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the compound may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/kg or 0.001 to 0.001 to daily It can be administered at 50 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
  • the compounds of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
  • the compounds provided by the present invention can effectively prevent, ameliorate or treat various cancers.
  • Example 1 is Example 1 (MHT-T C10), Example 2 (PHT-T C10), Example 5 (MHT-T C6) and Example 10 (PHT-T C6) for the A549 cell line in Experimental Example 1. After treatment with each concentration of the compound, the change in cell viability was measured and the result is shown as a graph.
  • Figure 2 shows the H1299 cell line in Experimental Example 1 after treatment with the compounds of Example 1 (MHT-T C10), Example 2 (PHT-T C10) and Example 10 (PHT-T C6) by concentration, cells
  • MHT-T C10 MHT-T C10
  • PHT-T C10 PHT-T C6
  • PHT-T C6 PHT-T C6
  • Figure 3 shows the change in cell viability after treating the compound of Example 1 (MHT-T C10) and Example 2 (PHT-T C10) for 24 hours or 48 hours by concentration with respect to the A549 cell line in Experimental Example 2
  • the measurement results are presented in a graph.
  • Example 4 shows the changes in cell viability after treatment with the compounds of Example 1 (MHT-T C10) and Example 2 (PHT-T C10) for 24 hours or 48 hours by concentration with respect to the H1299 cell line in Experimental Example 2
  • the measurement results are presented in a graph.
  • Figure 5 shows the compound of Example 15 (PAT) and Example 16 (PHT) and the compound of Comparative Example 1 (MAT) and Comparative Example 2 (MHT) for A549 cell line in Experimental Example 2 for 24 hours or 48 hours by concentration After treatment for a period of time, the result of measuring the change in cell viability is shown as a graph.
  • Example 6 shows the compounds of Example 1 (MHT-T C10), Example 2 (PHT-T C10), Example 15 (PAT) and Example 16 (PHT) for the A549 cell line in Experimental Example 3, and Comparative Examples After treating the compound of 1 (MAT) by concentration, the result of measuring the change in ATP production is shown as a graph.
  • Example 7 shows Example 1 (MHT-T C10), Example 2 (PHT-T C10), Example 5 (MHT-T C6) and Example 10 (PHT-T) for the SNU-780 cell line in Experimental Example 4; After treatment with the compound of C6) by concentration, the result of measuring the change in cell viability is shown as a graph.
  • Figure 8 shows the cell viability of the SNU-780 cell line in Experimental Example 5 after treatment with the compounds of Example 1 (MHT-T C10) and Example 2 (PHT-T C10) for 24 hours or 48 hours by concentration. The result of measuring the change is presented as a graph.
  • Example 9 shows the compound of Example 16 (PHT) and the compound of Comparative Example 1 (MAT) and Comparative Example 2 (MHT) with respect to the SNU-780 cell line in Experimental Example 5 for 24 hours or 48 hours by concentration , the result of measuring the change in cell viability is shown as a graph.
  • Example 10 is a graph showing the results of measuring changes in cell viability after treatment with the compounds of Example 2 (PHT-T C10) and Example 10 (PHT-T C6) for each concentration of the SW480 cell line in Experimental Example 6; it has been shown
  • Example 11 is a graph showing the results of measuring the change in cell viability after treating the SW480 cell line in Experimental Example 7 with the compound of Example 2 (PHT-T C10) for 24 hours or 48 hours at each concentration.
  • Example 12 shows Example 1 (MHT-T C10), Example 2 (PHT-T C10), Example 5 (MHT-T C6) and Example 10 (PHT-T C6) for the MCF7 cell line in Experimental Example 8. After treatment with each concentration of the compound, the result of measuring the change in cell viability is shown as a graph.
  • Example 13 shows the change in cell viability after treatment with the compounds of Example 1 (MHT-T C10) and Example 2 (PHT-T C10) for each concentration for 24 hours or 48 hours with respect to the MCF7 cell line in Experimental Example 9;
  • the measurement results are presented in a graph.
  • Example 15 is a graph showing the results of measuring the change in cell viability after treatment with the compound of Example 2 (PHT-T C10) for each concentration in the PC3 cell line in Experimental Example 10.
  • Example 16 shows the changes in cell viability after treatment with the compounds of Example 1 (MHT-T C10) and Example 2 (PHT-T C10) for each concentration for 24 hours or 48 hours with respect to the PC3 cell line in Experimental Example 11; The measurement results are presented in a graph.
  • Example 18 shows the change in cell viability after treatment with the compounds of Example 1 (MHT-T C10) and Example 2 (PHT-T C10) for 24 hours or 48 hours at each concentration with respect to the AGS cell line in Experimental Example 12.
  • the measurement results are presented in a graph.
  • Example 20 shows the cell viability of the MiaPaca-2 cell line in Experimental Example 13 after treatment with the compounds of Example 1 (MHT-T C10) and Example 2 (PHT-T C10) for 24 hours or 48 hours by concentration.
  • the result of measuring the change is presented as a graph.
  • Example 21 shows the compound of Example 16 (PHT) and the compound of Comparative Example 1 (MAT) and Comparative Example 2 (MHT) for the MiaPaca-2 cell line in Experimental Example 13 after treatment for 24 hours or 48 hours by concentration , the result of measuring the change in cell viability is shown as a graph.
  • R 1 is hydrogen, a C 1 -C 6 alkyl group, or -L 1 -R 7 ;
  • R 2 is hydrogen or a C 1 -C 6 alkyl group
  • R 3 to R 6 are each independently hydrogen, a C 1 to C 6 alkyl group, or -L 2 -R 8 ;
  • L 1 is a direct bond, a C 6 ⁇ C 14 arylene group or a heteroarylene group having 5 to 14 nuclear atoms;
  • R 7 is hydrogen or -OL 3 -R 9 ;
  • L 2 is a direct bond or a C 1 ⁇ C 6 alkylene group
  • R 8 is a C 6 ⁇ C 14 aryl group or a heteroaryl group having 5 to 14 nuclear atoms
  • L 3 is a direct bond or a C 1 ⁇ C 20 alkylene group
  • R 9 is hydrogen or a substituent represented by the following formula (2);
  • the alkyl group of R 1 to R 6 , the arylene group and heteroarylene group of L 1 , the aryl group and heteroaryl group of R 8 , and the alkylene group of L 2 and L 3 are each independently at least one C 1 ⁇ C 6 is unsubstituted or substituted with an alkyl group, and when substituted with a plurality of substituents, they are the same or different from each other;
  • Z is a monovalent anion
  • a pharmaceutical composition comprising as an active ingredient a compound selected from the compound represented by Formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate, and solvate thereof.
  • compositions represented by Formula 1 selected from the compound represented by Formula 1, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof of the present invention to a subject (eg, human) in need of administration It relates to a method for preventing, improving or treating cancer, comprising administering a compound to be used in a pharmaceutically effective amount.
  • Metformin hydrochloride 0.370g (2.234mmol), BH 1.144g (3.351mmol) and p-toluenesulfonic acid monohydrate (p-toluenesulfonic acid monohydrate, PTSA) 0.021g (0.112 mmol) isobutanol (isobutanol) It was put into 30 mL and reacted for 3 h at reflux temperature while stirring. After TLC confirmation, the product was isolated by Flash HPLC. (Column: Silica 15 ⁇ m spherical, mobile phase n-BuOH:AcOH:H 2 O 65:15:20), white solid, yield 89%.
  • Phenformin hydrochloride (0.500mg, 2.069mmol), BH (1.059mg, 3.103mmol), PTSA monohydrate (0.02mg, 0.103mmol) was added with iso-BuOH (50 mL) and reacted at reflux temperature for 3h with stirring. After TLC confirmation, the product was isolated by Flash HPLC. (Column: Silica 15 ⁇ m spherical, mobile phase n-BuOH:AcOH:H 2 O 65:15:20), white solid, yield 87%.
  • Example 15 4-methyl-6-(phenethylamino)-4,5-dihydro-1,3,5-triazine-, which is an HCl salt of phenfoimeglimin, represented by the following formula (8)
  • 2-Aminium chloride (4-methyl-6- (phenethylamino) -4,5-dihydro-1,3,5-triazin-2-aminium chloride) (hereinafter referred to as 'PAT') was prepared and carried out
  • 'PAT' 4-(4-hydroxyphenyl)-6-(phenethylamino)-4,5-dihydro-1, which is an HCl salt of phenoxyphenfoimeglimin, represented by the following formula (9); 3,5-triazine-2-aminium chloride (4-(4-hydroxyphenyl)-6-(phenethylamino)-4,5-dihydro-1,3,5-triazin-2-aminium chloride) (hereinafter, 'PHT') was prepared.
  • 5-triazine-2-aminium chloride (6-(dimethylamino)-4-methyl-4,5-dihydro-1,3,5-triazin-2-aminium chloride) (hereinafter referred to as 'MAT')
  • 5-triazine-2-aminium chloride (6- (dimethylamino) -4- (4-hydroxyphenyl) -4,5-dihydro-1,3,5-triazin-2-aminium chloride) (hereinafter, ' MHT') was prepared.
  • Examples 1 (MHT-T C10), Example 2 (PHT-T C10), Example 5 (MHT-T C6) and Example 10 (PHT-T C6) for each of the lung cancer cell lines A549 and H1299 cell lines ) of the compound was treated by concentration, and the change in cell viability was measured, and the results are shown in graphs in FIGS. 1 and 2 .
  • Example 1 MHT-T C10
  • Example 2 PHT-T C10
  • Example 15 PAT
  • Example 16 PHT
  • Comparative Example 1 MAT
  • Comparative Example 2 MHT
  • Example 1 The compound of Example 1 (MHT-T C10), Example 2 (PHT-T C10), Example 15 (PAT) and Example 16 (PHT) and Comparative Example 1 (MAT) for A549 cell line
  • MHT-T C10 The compound of Example 1
  • PHT-T C10 Example 2
  • PAT Example 15
  • PHT Example 16
  • MAT Comparative Example 1
  • Example 1 For the thyroid cancer cell line SNU-790 cell line, Example 1 (MHT-T C10), Example 2 (PHT-T C10), Example 5 (MHT-T C6) and Example 10 (PHT-T C6)
  • the change in cell viability was measured, and the result is shown as a graph in FIG. 7 .
  • Example 1 MHT-T C10
  • Example 2 PHT-T C10
  • Example 16 PHT
  • Comparative Example 1 MAT
  • Comparative Example 2 MHT
  • the survival of the thyroid cancer cell line was significantly inhibited even when the compounds of Examples 1, 2 and 16 were treated at low concentrations, but the compounds of Comparative Examples 1 and 2 did not affect thyroid cancer cells even when treated at high concentrations. It was confirmed that the survival inhibitory effect was insignificant.
  • the colorectal cancer cell line SW480 cell line was treated with the compounds of Example 2 (PHT-T C10) and Example 10 (PHT-T C6) by concentration, and then the change in cell viability was measured and the results are shown in FIG. shown in a graph.
  • Example 1 MHT-T C10
  • Example 2 PHT-T C10
  • Example 5 MHT-T C6
  • Example 10 PHT-T C6
  • Example 1 The compound of Example 1 (MHT-T C10), Example 2 (PHT-T C10) and Example 16 (PHT), and the compound of Comparative Example 1 (MAT) and Comparative Example 2 (MHT) for the MCF7 cell line
  • MAT Comparative Example 1
  • MHT Comparative Example 2
  • the compounds of Examples 1, 2 and 16 according to the present invention in the breast cancer cell line effectively inhibited the survival of the breast cancer cell line even at low concentrations, whereas the compounds of Comparative Examples 1 and 2 were 500 to 1500 Even after 48 hours of treatment with a high concentration of uM, it was confirmed that the survival rate of the breast cancer cell line was still high at 70-80%.
  • PC3 cell line which is a prostate cancer cell line
  • PHT-T C10 the compound of Example 2
  • Example 1 The compound of Example 1 (MHT-T C10), Example 2 (PHT-T C10) and Example 16 (PHT), and the compound of Comparative Example 1 (MAT) and Comparative Example 2 (MHT) for PC3 cell line
  • MAT Comparative Example 1
  • MHT Comparative Example 2
  • the compounds of Examples 1, 2 and 16 according to the present invention in the prostate cancer cell line effectively inhibited the survival of the breast cancer cell line even at low concentrations, whereas the compounds of Comparative Examples 1 and 2 contained 500 to Even after treatment at a high concentration of 1500 uM for 48 hours, it was confirmed that the survival rate of the prostate cancer cell line was still high at about 80%.
  • Example 1 MHT-T C10
  • Example 2 PHT-T C10
  • Example 16 PHT
  • Comparative Example 1 MAT
  • Comparative Example 2 MHT
  • the compounds of Examples 1, 2 and 16 according to the present invention in the gastric cancer cell line effectively inhibited the survival of the gastric cancer cell line even at low concentrations, whereas the compounds of Comparative Examples 1 and 2 were 500 to 1500 It was confirmed that even when treated with a high concentration of uM for 48 hours, the effect of inhibiting the survival of gastric cancer cell lines was insignificant.
  • the compounds of Examples 1, 2 and 16 according to the present invention in the pancreatic cancer cell line effectively inhibited the survival of the pancreatic cancer cell line even at low concentrations, whereas the compounds of Comparative Examples 1 and 2 were 500 to 1500 It was confirmed that even when treated with a high concentration of uM for 48 hours, the survival inhibitory effect of the pancreatic cancer cell line was insignificant.
  • the present invention relates to a novel compound for the prevention, improvement or treatment of cancer, a composition comprising the same, and a method for preventing, ameliorating or treating cancer using the compound.

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Abstract

La présente invention concerne un nouveau composé permettant de prévenir, d'atténuer ou de traiter le cancer, une composition contenant celui-ci et diverses utilisations associées.
PCT/KR2021/003975 2020-04-03 2021-03-31 Nouveau composé pour le traitement du cancer et composition contenant celui-ci WO2021201585A1 (fr)

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Publication number Priority date Publication date Assignee Title
KR20180031036A (ko) * 2015-07-30 2018-03-27 치아타이 티안큉 파마수티컬 그룹 주식회사 1,3,5-트라이아진 유도체 및 이의 사용 방법
JP2019064976A (ja) * 2017-10-03 2019-04-25 国立大学法人 熊本大学 抗がん剤
KR20200024111A (ko) * 2018-08-27 2020-03-06 주식회사 대웅제약 신규한 헤테로사이클릭아민 유도체 및 이를 포함하는 약학 조성물

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JP2019064976A (ja) * 2017-10-03 2019-04-25 国立大学法人 熊本大学 抗がん剤
KR20200024111A (ko) * 2018-08-27 2020-03-06 주식회사 대웅제약 신규한 헤테로사이클릭아민 유도체 및 이를 포함하는 약학 조성물

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