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WO2024167385A1 - Nouveau composé et ses utilisations - Google Patents

Nouveau composé et ses utilisations Download PDF

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Publication number
WO2024167385A1
WO2024167385A1 PCT/KR2024/095093 KR2024095093W WO2024167385A1 WO 2024167385 A1 WO2024167385 A1 WO 2024167385A1 KR 2024095093 W KR2024095093 W KR 2024095093W WO 2024167385 A1 WO2024167385 A1 WO 2024167385A1
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Prior art keywords
cancer
compound
chemical formula
present
hydrogen
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English (en)
Korean (ko)
Inventor
이경률
백세연
안신병
전상민
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Scl Therapeutics Co Ltd
Ajou University Industry Academic Cooperation Foundation
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Scl Therapeutics Co Ltd
Ajou University Industry Academic Cooperation Foundation
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Publication of WO2024167385A1 publication Critical patent/WO2024167385A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms

Definitions

  • the present invention relates to novel mifepristone derivative compounds and various uses thereof.
  • Cancer is one of the most common causes of death worldwide. Approximately 10 million new cases occur each year, accounting for about 12% of all deaths, making it the third leading cause of death.
  • cancer growth refers to the infinite proliferation characteristic of cancer cells. Normal cells stop dividing when they have completed the number of divisions programmed in their genes or when there is not enough space for new cells to occupy. However, cancer cells fail to control their division, and when they run out of space to expand themselves, they secrete matrix metalloproteases that decompose the cell matrix to remove the surrounding space and expand the space for themselves.
  • cancer metastasis refers to the characteristic of cancer cells separating from the primary site and moving to another location.
  • cancer cells In order to do this, 1 cancer cells must be removed from the primary site (cancer tissue), 2 invade and pass through the tissue walls that make up blood vessels or lymphatic vessels, and 3 attach and fuse with the matrix of the moved tissue to settle in a new location. Therefore, an approach based on a different mechanism from cancer growth is required.
  • the present invention has been devised to solve the above problems, and relates to a novel compound capable of simultaneously inhibiting the proliferation and metastasis of cancer, and a pharmaceutical use thereof.
  • One purpose of the present invention is to provide a novel compound capable of preventing, improving or treating cancer.
  • Another object of the present invention is to provide a composition comprising the above compound capable of preventing, improving or treating cancer.
  • Another object of the present invention is to provide a method for preventing, improving or treating cancer using the above compound.
  • cancer means a disease characterized by uncontrolled cell growth, and a tumor is formed as a result of this abnormal cell growth, which infiltrates surrounding tissues and, in severe cases, metastasizes to other organs of the body. It is also academically called a neoplasm. Cancer is an incurable chronic disease that, in many cases, cannot be fundamentally cured even with surgery, radiation, and chemotherapy, causing pain to the patient and ultimately leading to death. There are various causes of cancer, but they are divided into internal and external factors. It has not been precisely identified how normal cells are transformed into cancer cells, but it is known that a significant number of cancers are caused by external factors such as environmental factors. Internal factors include genetic factors and immunological factors, and external factors include chemicals, radiation, and viruses.
  • the cancer may preferably be breast cancer, uterine cancer, esophageal cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, ovarian cancer, cervical cancer, kidney cancer, blood cancer, pancreatic cancer, prostate cancer, testicular cancer, laryngeal cancer, oral cancer, head and neck cancer, thyroid cancer, liver cancer, bladder cancer, osteosarcoma, lymphoma, leukemia, etc., and is not limited thereto as long as it is a type of cancer in which the progression of the cancer, such as tumor differentiation and/or proliferation, is dependent on the cancer cells and/or cancer stem cells described in the present invention.
  • the cancer stem cell refers to a comprehensive cancer cell that has the unique ability of stem cells, such as self-renewal ability or differentiation ability, and it is estimated that cancer stem cells exist in between 0.1% and 5% in cancer tissues.
  • the cancer stem cell has the characteristic of proliferating slowly, unlike general cancer cells, under normal tumor growth conditions (the "normal tumor growth conditions” above refer to a state in which nutrients (glucose) necessary for cell growth are sufficient and the tumor microenvironment is abundant and there is no cell stress).
  • the expression of transcriptional regulators such as PGC-1 ⁇ is controlled, so that the function of major metabolic regulators is different from that of general cancer cells.
  • “virtual screening” refers to one of the numerous procedures that are taken during the process of developing a new drug, and more specifically, it refers to the procedure of discovering effective substances and leading substances through screening compounds selected from basic research and confirming candidate substances. This can reduce the time and cost required for developing a new drug, and after a target disease is selected, it is possible to discover effective new drug substances targeting it, and it is also possible to selectively find substances expected to have a drug effect by computer using 3D-reconstructed gene protein information.
  • the virtual screening technology can be utilized not only for library production, but also for active screening of an actually existing library and a specific action point. However, it is not limited to this if it is a general and universal screening technology.
  • 'halogen' used herein means fluorine, chlorine, bromine or iodine.
  • 'C1 ⁇ C6 alkyl' as used herein, unless otherwise stated, means a straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • aryl' refers to a mono- or poly-cyclic carbocyclic ring system of n carbon atoms having one or more aromatic rings which are fused or non-fused, examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, and andracenyl.
  • a compound of the following chemical formula A was derived as an anticancer candidate substance through the virtual screening described above, and a derivative thereof was synthesized.
  • the derivative of the above chemical formula A may be a compound represented by the following chemical formula B.
  • R 1 and R 6 are each independently hydrogen or alkyl
  • R 2 is hydrogen or halogen
  • R 3 is hydrogen
  • R 4 , R 5 are different from each other and are each independently -C(O)-alkyl optionally substituted with halogen, alkyne, or -OR 7 , wherein R 7 can be hydrogen or -C(O)-alkyl optionally substituted with halogen.
  • the derivative of the chemical formula A may be a novel compound synthesized in the present invention and represented by the following chemical formulas 1 to 6.
  • the above chemical formula 1 is a step of synthesizing (a) Pregna-1,4-dien-3-one, 9-fluoro-11beta-hydroxy-16beta-methyl-17,20:20,21-bis[methyl-enebis(oxy)] according to the reaction scheme 1 described in the present invention; (b) a step of synthesizing Pregna-1,4-dien-3-one,9-fluoro-11beta-(4'-chloro)-benzoxy-16beta-methyl-17,20:20,21-bis[methylenebis(oxy)]; And (c) a step of synthesizing Pregna-1,4-diene-3,20-dione,9-fluoro-11-beta-(4'-chloro)-benzoxy,17-alpha,21-dihydroxy-10,13,16-beta-trimethyl; produced by a production method including the step of synthesizing Pregna-1,4-diene-3,20-dione,9-fluoro
  • the above chemical formula 2 is a step of synthesizing (a) Pregna-1,4-dien-3-one, 9-fluoro-11beta-hydroxy-16beta-methyl-17,20:20,21-bis[methyl-enebis(oxy)] according to the reaction scheme 2 described in the present invention; (b) a step of synthesizing Pregna-1,4-dien-3-one,9-fluoro-11beta-benzoxy-16beta-methyl-17,20:20,21-bis[methylenebis(oxy)]; And (c) a step of synthesizing Pregna-1,4-diene-3,20-dione, 9-fluoro-11-beta benzoxy, 17-alpha, 21-dihydroxy-10,13,16-beta-trimethyl; Pregna-1,4-diene-3,20-dione, 21-chloro-9-fluoro-11-beta benzoxy, 17-hydroxy-10,13,16-beta-trimethyl, which is
  • the above chemical formula 3 is a step of synthesizing (a) Pregna-1,4-dien-3-one, 9-fluoro-11beta-hydroxy-16beta-methyl-17,20:20,21-bis[methyl-enebis(oxy)] according to the reaction scheme 3 described in the present invention; (b) a step of synthesizing Pregna-1,4-dien-3-one,9-fluoro-11beta-(4'-isopropyl)-benzoxy-16beta-methyl-17,20:20,21-bis[methylenebis(oxy)]; And (c) a step of synthesizing Pregna-1,4-diene-3,20-dione, 9-fluoro-11-beta-(4'-isopropyl)-benzoxy, 17-alpha, 21-dihydroxy-10,13,16-beta-trimethyl; It can be named as Pregna-1,4-diene-3,20-dione,21-chloro-9-fluoro
  • the above chemical formula 4 is a step of synthesizing (a) Pregn-4-ene-3,20-dione, 10,13-dimethyl-17,21-[(1-methoxypropylidene)bis(oxy)] according to the reaction scheme 4 described in the present invention; And (b) a step of synthesizing Pregn-4-ene-3,20-dione-10,13-dimethyl-21-chloro-17-hydroxy-17-propionate; and may be named Pregn-1,4-diene-3,20-dionee-10,13-dimethyl-21-chloro-17-hydroxy-17-propionate.
  • the above chemical formula 5 is synthesized from mifepristone according to the reaction scheme 5 described in the present invention, and may be named as 11beta-[4’-(N,N’-dimethylamino)phenyl]-17alpha-(prop-1-ynyl)-delta4,9-estradiene-3-one-17beta-hydroxy-(2’-chloro)acetate.
  • the above chemical formula 6 is a step of synthesizing (a) Pregna-1,4-dien-3-one, 9-fluoro-11beta-hydroxy-16beta-methyl-17,20:20,21-bis[methyl-enebis(oxy)] according to the reaction scheme 6 described in the present invention; (b) a step of synthesizing Pregna-1,4-dien-3-one,9-fluoro-11beta-(4'-chloro)-benzoxy-16beta-methyl-17,20:20,21-bis[methylenebis(oxy)]; (c) a step of synthesizing Pregna-1,4-diene-3,20-dione,9-fluoro-11-beta-(4'-chloro)-benzoxy,17-alpha,21-dihydroxy-10,13,16-beta-trimethyl; And (d) a step of synthesizing Pregna-1,4-diene-3,20-dione,21-chloro-9-flu
  • the present invention provides the novel compound described above, and a process for preparing the same (synthetic process), and also provides a pharmaceutically acceptable salt of the compound.
  • the pharmaceutically acceptable salt is a salt generally considered by those skilled in the art to be suitable for medical applications (for example, because such a salt is not harmful to a subject to be treated with the salt), or a salt which causes acceptable side effects in the respective treatment.
  • the pharmaceutically acceptable salt is a salt considered acceptable by a regulatory authority such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Ministry of Health, Labour and Welfare of Japan.
  • the present invention also includes salts of the compound according to the present invention which are not pharmaceutically acceptable per se, for example, as intermediates in the preparation of the compound according to the present invention or a physiologically functional derivative thereof, or as intermediates in the preparation of the pharmaceutically acceptable salt of the compound according to the present invention or a physiologically functional derivative thereof.
  • the salt includes a water-insoluble salt, and in particular, a water-soluble salt.
  • a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming a salt, i.e. whether said compound according to the invention or a physiologically functional derivative thereof has a group capable of carrying a charge, such as, for example, an amino group, a carboxylic acid group, etc.
  • Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, especially pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmacy, which are water-insoluble or especially water-soluble acid addition salts.
  • salts with bases may also be suitable.
  • Acid addition salts can be formed, for example, by mixing 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.
  • pharmaceutically acceptable base addition salts include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates).
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using 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, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide, Included, but not limited to, 2-hydroxyethanesulfonate, hydroxy
  • Salts which are not pharmaceutically acceptable and which can be obtained, for example, as process products during the production of the compounds according to the invention on an industrial scale, are also encompassed by the present invention and, if desired, can be converted into pharmaceutically acceptable salts by methods known to the skilled person.
  • the compounds according to the present invention may have an asymmetric carbon center and therefore may exist as R or S isomers or racemic compounds, and all of these optical isomers and mixtures may be included in the scope of the present invention.
  • the compounds of the present invention as well as their salts may contain various amounts of solvent. Therefore, solvates, in particular hydrates, of the compounds of the present invention as well as solvates, in particular hydrates, of salts of the compounds of the present invention may be included within the scope of the present invention. More particularly, the present invention may include hydrates of the compounds, salts and/or physiologically functional derivatives according to the present invention, which comprise 1, 2 or 1/2 water molecules with respect to the stoichiometry.
  • the compound of the present invention refers to the compound described above.
  • a compound selected from the compounds of the present invention, pharmaceutically acceptable salts, crystal forms, co-crystals, optical isomers, derivatives, hydrates, and solvates thereof can be used for the prevention, improvement, or treatment of a desired disease.
  • the target disease may be a skeletal disease, joint disease, vascular disease, blood disease, skin disease, kidney disease, cardiovascular disease, brain nerve disease, ophthalmic disease, digestive disease, urinary disease, gynecological disease, respiratory disease, infectious disease, allergic disease, rheumatic disease, autoimmune disease, disease caused by transplantation or transplant side effects, or proliferative disease (tumor).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound selected from the compounds of the present invention, pharmaceutically acceptable salts, crystal forms, co-crystals, optical isomers, derivatives, hydrates, and solvates thereof.
  • the pharmaceutical composition can prevent, improve or treat cancer.
  • prevention, improvement or treatment comprehensively includes activities of inhibiting the generation or growth of cancer, or improving symptoms of cancer invasion, metastasis or recurrence.
  • the cancer that is intended to be improved or treated with a pharmaceutical composition containing the compound of the present invention as an effective ingredient may be at least one selected from the group consisting of 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, multiple myeloma, leukemia, lymphoma, squamous cell carcinoma, kidney cancer, urethral cancer, bladder cancer, head and neck cancer, brain cancer, and central nervous system cancer, preferably lung cancer, and more preferably non-small cell lung cancer.
  • the pharmaceutical composition may be characterized as being in the form of a capsule, tablet, granule, injection, ointment, powder or beverage, and the pharmaceutical composition may be characterized as being intended for humans.
  • the pharmaceutical composition of the present invention is not limited thereto, but may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and sterile injectable solutions, respectively, 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, pigments, fragrances, etc. for oral administration, and may include buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, and the like for injections.
  • compositions of the present invention may be prepared in various ways by mixing with the pharmaceutically acceptable carriers described above.
  • pharmaceutically acceptable carriers for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it can be manufactured in the form of unit dose ampoules or multiple doses.
  • it can be formulated in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.
  • examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil.
  • fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.
  • the routes of administration of the pharmaceutical composition 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 rectal. Oral or parenteral administration is preferred.
  • the parenteral administration 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 may vary depending on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, administration route, excretion rate, drug combination, and the severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition 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 may be administered at 0.0001 to 50 mg/kg or 0.001 to 50 mg/kg per day. Administration may be once a day or divided into several times. The 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 a pill, a dragee, a capsule, a liquid, a gel, a syrup, a slurry, or a suspension.
  • composition of the present invention can be used alone or in combination with methods using surgery, radiotherapy, hormone therapy, chemotherapy, and biological response modifiers.
  • the present invention also provides a method for preventing, improving or treating cancer, comprising administering to a subject in need of administration (e.g., a human) a pharmaceutical composition comprising a compound selected from the compound of the present invention, a pharmaceutically acceptable salt, crystalline form, co-crystal, optical isomer, derivative, hydrate, and solvate thereof as an active ingredient in a pharmaceutically effective amount.
  • a pharmaceutical composition comprising a compound selected from the compound of the present invention, a pharmaceutically acceptable salt, crystalline form, co-crystal, optical isomer, derivative, hydrate, and solvate thereof as an active ingredient in a pharmaceutically effective amount.
  • the “administration” means providing a predetermined compound of the present invention to the subject by any appropriate method.
  • the "subject" requiring the administration in the present invention may include both mammals and non-mammals.
  • mammals may include, but are not limited to, humans, non-human primates such as chimpanzees, and other apes and monkey species; livestock animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and experimental animals such as rodents such as rats, mice, and guinea pigs.
  • examples of non-mammals in the present invention may include, but are not limited to, birds and fish.
  • the term "pharmaceutically effective amount” refers to a sufficient amount of an agent to provide a desired biological result. That result may be a reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desirable alteration in a biological system.
  • an "effective amount” for therapeutic uses is the amount of a compound disclosed herein required to provide a clinically significant reduction in a disease.
  • An appropriate “effective” amount in any individual case can be determined by those skilled in the art using routine experimentation. Accordingly, the expression “effective amount” generally refers to an amount of an active agent that has a therapeutic effect.
  • the present invention also provides a food composition for preventing or improving cancer, comprising a compound selected from the compounds of the present invention, food acceptable salts, crystal forms, co-crystals, optical isomers, derivatives, hydrates, and solvates thereof.
  • the food composition herein is used in various ways for the indication aimed at in the present invention, that is, for the prevention or improvement of cancer, and the food composition including the compound of the present invention can be manufactured in the form of various foods, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, etc.
  • the amount can be added at a ratio of 0.1 to 100% of the total weight.
  • the food composition is manufactured in the form of a beverage, there is no special limitation other than containing the food composition at the indicated ratio, and various flavoring agents or natural carbohydrates, etc. can be contained as additional ingredients like conventional beverages.
  • natural carbohydrates can include monosaccharides such as glucose, disaccharides such as fructose, sucrose, and polysaccharides, dextrin, cyclodextrin, and conventional sugars, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agent thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agent (saccharin, aspartame, etc.) can be mentioned.
  • the food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agent such as synthetic flavoring agent and natural flavoring agent, coloring agent, pectic acid and its salt, alginic acid and its salt, organic acid, protective colloid thickener, pH regulator, stabilizer, preservative, glycerin, alcohol, carbonating agent used in carbonated beverage, etc.
  • flavoring agent such as synthetic flavoring agent and natural flavoring agent
  • coloring agent such as synthetic flavoring agent and natural flavoring agent
  • pectic acid and its salt such as synthetic flavoring agent and natural flavoring agent
  • coloring agent such as synthetic flavoring agent and natural flavoring agent
  • pectic acid and its salt such as synthetic flavoring agent
  • alginic acid and its salt such as organic acid
  • protective colloid thickener such as sodium bicarbonate
  • pH regulator such as sodium bicarbonate
  • stabilizer such as sodium bicarbonate
  • preservative such as sodium bicarbonate
  • glycerin such as sodium bicarbonate
  • alcohol such as
  • the compound provided in the present invention can simultaneously inhibit the proliferation and metastasis of cancer, it is expected to be actively utilized in the medical and health fields.
  • Figure 1 shows the cancer cell survival inhibition effect of a novel compound synthesized in the present invention according to one specific example of the present invention.
  • Figure 2 shows the cancer cell tumor formation inhibitory effect of a novel compound synthesized in the present invention according to one specific example of the present invention.
  • Figure 3 shows the cancer cell invasion inhibition effect of a novel compound synthesized in the present invention according to one specific example of the present invention.
  • the inventors of the present invention conducted a virtual screening of various candidate substances to discover a cancer cell and/or cancer stem cell treatment substance having an anticancer effect, and as a result, derived a compound of the following chemical formula A as an anticancer candidate substance and synthesized a derivative thereof.
  • the cancer cell invasion inhibition effect was confirmed through a soft agar assay. As a result, all the compounds tested had a significant cancer cell invasion inhibition effect.
  • the inventors of the present invention conducted a virtual screening of various candidate substances to discover a cancer cell and/or cancer stem cell treatment substance having an anticancer effect, and as a result, derived a compound of the following chemical formula A as an anticancer candidate substance and synthesized a derivative thereof.
  • the TLC plate used was TLC Silica Gel 60 GF254 from a Chinese manufacturer, and the HPLC test method referred to the USP test conditions for clobetasol propionate using a 4.6 mm X 15 cm column and C18 packing (pore size 5 um).
  • betamethasone Pregna-1,4-diene-3,20-dione, 9-fluoro-11beta,17alpha,21-trihydroxy-16beta-methyl
  • betamethasone Pregna-1,4-diene-3,20-dione, 9-fluoro-11beta,17alpha,21-trihydroxy-16beta-methyl
  • betamethasone Pregna-1,4-diene-3,20-dione, 9-fluoro-11beta,17alpha,21-trihydroxy-16beta-methyl
  • cortexolone Pregna-4-ene-3-one-10,13-dimethyl-17alpha,21-dihydroxy
  • tetrahydrofuran 20 ml of 2 mol/L hydrochloric acid was added to the reaction solution.
  • betamethasone Pregna-1,4-diene-3,20-dione, 9-fluoro-11beta,17alpha,21-trihydroxy-16beta-methyl
  • A549 cells a non-small-cell lung carcinoma (NSCLC) cell line
  • NSCLC non-small-cell lung carcinoma
  • FBS fetal bovine serum
  • penicillin-streptomycin 1% penicillin-streptomycin
  • HEPES 1% HEPES at 5% CO 2 and 37°C.
  • DMSO Dimethyl sulfoxide
  • RU486 mifepristone
  • ⁇ 10 4 cells were seeded in a 96-well plate and cultured for 24 hours with DMEM medium containing 1 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M of each compound. After removing the supernatant and washing with PBS, the cells were additionally cultured for 4 hours with serum-free DMEM medium containing MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide), the medium was removed, and 100 ⁇ L of DMSO was added and stirred for 1 minute to dissolve the purple foam. This was measured at 595 nm. The results are shown in Fig. 1.
  • S001 to S006 had a cancer cell survival inhibition effect in proportion to the concentration.
  • S005 showed an excellent cancer cell survival inhibition effect at a low concentration of 1 ⁇ M or less
  • S001 to S003 showed an excellent cancer cell survival inhibition effect compared to the positive control group, RU486, at a concentration of 25 ⁇ M or higher.
  • the cancer cell survival inhibition effect of S002 and S003 was very remarkable.
  • Tumors are a general term for all abnormally formed masses, and cancer cells have the characteristic of forming a lump (colony) by infinitely dividing and proliferating beyond normal division control.
  • cells were seeded at a very low concentration (3 ⁇ 10 3 ) in a 12-well plate and then cultured in DMEM medium containing 1 nM, 10 nM, 100 nM, 1 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M of each compound for 2 weeks. After that, the degree of colony formation was observed using the crystal violet staining method to confirm the anticancer effect.
  • the supernatant was removed, washed with PBS, and the remaining cells were stained with a crystal violet solution (20% methanol and 0.5% crystal violet) for 10 minutes at room temperature. After washing three times and culturing in a 1% SDS solution for solubilization, the absorbance at a wavelength of 570 nm was measured. The results are shown in Fig. 2.
  • S001 to S005 showed excellent tumor formation inhibition effects starting from a concentration of 1 ⁇ M.
  • S005 showed a tumor formation inhibition effect of more than 50% compared to the negative control DMSO at a concentration of 100 nM, showing that the effect was significant at low concentrations, similar to the cancer cell survival inhibition effect of Example 2-1.
  • the positive controls, RU486 and S006, showed significant tumor formation inhibition effects at concentrations of 25 ⁇ M or higher.
  • the cancer cell invasion inhibition effect was confirmed through a soft agar assay. Specifically, 50 ⁇ l of DMEM medium containing 0.7% agar was added to a 12-well plate and solidified (bottom agar), and 300 ⁇ l of DMEM medium containing 3 ⁇ 10 3 cells and 0.35% agar was added on top of the solidified agar and solidified (top agar). After complete solidification, 250 ⁇ l of DMEM medium containing 1 ⁇ l or 10 ⁇ l of each compound was added and cultured in a CO 2 incubator for about 2 weeks, and the number of colonies formed in the 0.7% agar portion (bottom agar) was determined. The results are shown in Fig. 3.
  • the compound provided in the present invention can simultaneously inhibit the proliferation and metastasis of cancer, it is expected to be actively utilized in the medical and health fields.

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Abstract

La présente invention concerne un nouveau composé dérivé de mifepristone et diverses utilisations de celui-ci. Afin de développer un agent thérapeutique efficace contre le cancer, il est nécessaire d'inhiber simultanément la croissance et la métastase de cellules cancéreuses. D'une manière générale, la croissance du cancer signifie la caractéristique de cellules cancéreuses pour proliférer sans fin, et la métastase cancéreuse signifie la caractéristique de cellules cancéreuses de se séparer d'un site primaire et de se déplacer vers un autre emplacement. Par conséquent, la croissance du cancer et la métastase cancéreuse nécessitent des approches de différents mécanismes. Un composé selon la présente invention peut simultanément inhiber la prolifération et la métastase du cancer, et est ainsi supposé avoir une applicabilité active dans les domaines médical et de santé.
PCT/KR2024/095093 2023-02-08 2024-02-07 Nouveau composé et ses utilisations Ceased WO2024167385A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003531852A (ja) * 2000-05-03 2003-10-28 ザ ユニバーシティ オブ ブリストル 癌治療
JP2006516289A (ja) * 2003-01-22 2006-06-29 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィク ミフェプリストンおよびその誘導体のヘッジホッグタンパク質シグナリング経路調節剤としての新規な使用ならびにその適用
JP2010540430A (ja) * 2007-09-20 2010-12-24 バイオ−プロ メディカル リミテッド ミフェプリストンによる複数の子宮平滑筋腫、平滑筋腫、筋腫、子宮類線維腫、子宮内膜症、腺筋症およびこれらに関連する異常を治療する組成物および手段
CN106397527A (zh) * 2016-09-13 2017-02-15 中国科学院昆明动物研究所 米非司酮衍生物及其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003531852A (ja) * 2000-05-03 2003-10-28 ザ ユニバーシティ オブ ブリストル 癌治療
JP2006516289A (ja) * 2003-01-22 2006-06-29 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィク ミフェプリストンおよびその誘導体のヘッジホッグタンパク質シグナリング経路調節剤としての新規な使用ならびにその適用
JP2010540430A (ja) * 2007-09-20 2010-12-24 バイオ−プロ メディカル リミテッド ミフェプリストンによる複数の子宮平滑筋腫、平滑筋腫、筋腫、子宮類線維腫、子宮内膜症、腺筋症およびこれらに関連する異常を治療する組成物および手段
CN106397527A (zh) * 2016-09-13 2017-02-15 中国科学院昆明动物研究所 米非司酮衍生物及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SPILMAN, C.H. ; GIBSON, R.E. ; BEUVING, D.C. ; CAMPBELL, J.A.: "Progestin and antiprogestin effects on progesterone receptor transformation", JOURNAL OF STEROID BIOCHEMISTRY., PERGAMON PRESS PLC., GB, vol. 24, no. 1, 1 January 1986 (1986-01-01), GB , pages 383 - 389, XP025197382, ISSN: 0022-4731, DOI: 10.1016/0022-4731(86)90087-7 *

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