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WO2025080100A1 - Nouveau composé di-amide, son procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou de maladies auto-immunes le comprenant en tant que principe actif - Google Patents

Nouveau composé di-amide, son procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou de maladies auto-immunes le comprenant en tant que principe actif Download PDF

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Publication number
WO2025080100A1
WO2025080100A1 PCT/KR2024/096315 KR2024096315W WO2025080100A1 WO 2025080100 A1 WO2025080100 A1 WO 2025080100A1 KR 2024096315 W KR2024096315 W KR 2024096315W WO 2025080100 A1 WO2025080100 A1 WO 2025080100A1
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methyl
thiadiazole
carboxamide
pyridin
butyl
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English (en)
Korean (ko)
Inventor
이광호
조병철
시리악라자트
윤미란
이은지
권영주
최길돈
정명은
채종학
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Korea Research Institute of Chemical Technology KRICT
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Korea Research Institute of Chemical Technology KRICT
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Priority claimed from KR1020240136688A external-priority patent/KR102855423B1/ko
Application filed by Korea Research Institute of Chemical Technology KRICT filed Critical Korea Research Institute of Chemical Technology KRICT
Publication of WO2025080100A1 publication Critical patent/WO2025080100A1/fr
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a compound that inhibits glutaminase and is useful for cancer or autoimmune diseases.
  • metabolic anticancer drugs that selectively suppress cancer by targeting tumor-specific metabolic pathways have emerged rapidly. Since cancer uses selective metabolic pathways for proliferation and survival, metabolic reorganization is a key characteristic of the cancer phenotype. Therefore, many studies are being conducted to determine which specific metabolic circuits cancer cells with specific genetic mutations reorganize to proliferate.
  • Glucose and glutamine are the primary metabolic fuels used for cancer growth. Most cancers utilize high levels of glucose metabolism to meet the protein anabolic and catabolic demands required to sustain rapid tumor growth. When metabolic stress is applied, such as by anticancer drugs, alternative nutrients such as amino acids are used to overcome this.
  • Glutamine is the most abundant amino acid found in blood and is a major source of carbon and nitrogen atoms required for the biosynthesis of nucleotides, nonessential amino acids, and fatty acids, which are important precursors for macromolecular synthesis. Glutamine and glutamine-derived metabolites are also known to participate in energy production, redox homeostasis, gene transcription, and intracellular signaling in cancer cells.
  • glutamine metabolism in cancer cells can affect the progression and deterioration of cancer by activating various signaling systems related to energy metabolism and redox reactions as well as the continuous proliferation of cancer cells, and by acting toward suppressing cell aging processes and apoptosis. Therefore, targeting glutamine metabolism is an attractive therapeutic option in many cancer subtypes.
  • glutaminase an enzyme related to glutamine metabolism
  • glutaminase an enzyme related to glutamine metabolism
  • glutaminolysis a series of processes in which glutamine is converted to glutamate and then to alpha-ketoglutarate (AKG)
  • AKG alpha-ketoglutarate
  • glutaminase is known to be related to autoimmune diseases (Non-patent literature 3, Michihito Kono, et al, Arthritis & Rheumatology, 2019 Nov;71(11):1869-1878).
  • Korean Patent Publication No. 10-2015-0091389 discloses glutaminase inhibitor compounds, among which the CB-839 compound is attracting attention as an anticancer agent.
  • the present inventors synthesized novel compounds to develop a new inhibitor of glutaminase, confirmed that they exhibited inhibitory activity against glutaminase, and completed the present invention.
  • One object of the present invention is to provide a novel di-amide compound that inhibits glutaminase.
  • Another object of the present invention is to provide a novel pharmaceutical composition for preventing or treating cancer or autoimmune diseases.
  • a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided.
  • L is C2-6 alkylene
  • R 1 and R 2 are each independently C1-10 alkyl, C6-10 aryl substituted C1-10 alkyl or C1-10 alkyl substituted with 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S,
  • aryl and heteroaryl are each independently substituted with one or more selected from the group consisting of unsubstituted or halogen, C1-10 alkyl unsubstituted or substituted with one or more halogens, C1-10 alkoxy unsubstituted or substituted with one or more halogens, and 3 to 6 membered cycloalkyloxy substituted with one or more halogens.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer or autoimmune disease, containing a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food composition for preventing or improving cancer or autoimmune disease, containing a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for treating cancer or an autoimmune disease by administering an effective amount of a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the present invention provides a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer or autoimmune disease.
  • the present invention provides the use of a compound represented by the above formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of cancer or an autoimmune disease.
  • the compound represented by chemical formula 1 described herein exhibits excellent inhibitory activity against glutaminase and excellent cytotoxicity against cancer cells, and is therefore expected to be useful for cancer or autoimmune diseases.
  • Figure 1a shows the results of measuring glutamine levels after treating ALK-TKI resistant cells with a compound according to the present invention.
  • Figure 1b shows the results of measuring glutamate levels after treating ALK-TKI resistant cells with a compound according to the present invention.
  • Figure 2a shows the change in tumor volume after administration of compound Example 22 to mice administered with H3122-LR pool cell line for a certain period of time, with CB-839 as a control.
  • Figure 2b shows the change in body weight after administration of compound Example 22 to mice administered with H3122-LR pool cell line for a certain period of time, with CB-839 as a control.
  • the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below.
  • the embodiments of the present invention are provided to more completely explain the present invention to a person having average knowledge in the relevant technical field.
  • alkylene or "alkyl”, unless otherwise specified, includes straight-chain or branched-chain saturated hydrocarbon residues.
  • C1-6 alkyl means an alkyl having a skeleton of 1 to 6 carbons. Specifically, C1-6 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, and the like, and C6 alkyl is a fully saturated hydrocarbon having 6 carbons, including straight-chain or branched-chain structural isomers.
  • Alkyl means a monovalent substituent
  • alkylene means a divalent substituent.
  • alkenyl means an unsaturated hydrocarbon residue containing one or more double bonds between carbons in the chain, for example, 1-3, 1-2 double bonds.
  • cycloalkyl means a cyclic hydrocarbon residue which is a saturated hydrocarbon residue forming a ring
  • 3-6cycloalkyl means a cyclic hydrocarbon residue containing from 3 to 6 carbon atoms as ring atoms.
  • cycloalkenyl means a cyclic hydrocarbon residue containing one or more, for example one or two, double bonds in the ring, which is non-aromatic.
  • heterocycloalkyl means a monovalent saturated moiety consisting of 1 to 3 rings containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S. It may be bicyclic or tricyclic containing 2 or 3 rings, wherein these 2 or 3 rings may be bridged, fused or spiro-shaped heterocycloalkyl. When composed of multiple rings, the heteroatoms may be present in all or only some of the rings.
  • “Atomic heterocycloalkyl” means a heterocycloalkyl having 3 to 10 ring atoms. Meanwhile, when referring to a 3-10 membered heterocycloalkyl group containing at least one N, it refers to a group that necessarily contains at least one nitrogen atom (N) as a heteroatom forming the ring.
  • aryl refers to an aromatic radical having a single ring or two or three fused hydrocarbon aromatic rings
  • C6-10 aryl refers to an aromatic ring compound containing 6 to 10 ring-forming carbons, including phenyl and naphthyl.
  • heteroaryl means, unless otherwise specified, a single ring or an aromatic radical having two or three fused rings, which has one or more aromatic rings (the remaining ring atoms are C) containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S as ring atoms. When composed of multiple rings, the heteroatoms may be present in all or only some of the rings.
  • “5-10 membered heteroaryl” means a heteroaryl having 5-10 ring atoms. On the other hand, when referring to a 5-10 membered heteroaryl containing one or more Ns, it means that it necessarily contains one or more nitrogen atoms (N) as a ring heteroatom.
  • N nitrogen atoms
  • Alkoxy refers to a substituent in which alkyl is connected through an oxygen atom
  • C1-10 alkoxy refers to a substituent in which C1-10 alkyl is connected to an oxygen atom and substituted through oxygen.
  • Cycloalkyloxy refers to a substituent in which cycloalkyl is linked through an oxygen atom.
  • Halogen means a halogen atom such as F, Cl, Br, I, and when it is said to be “halo” substituted, it means substituted with one or more halogen atoms. In this case, the halogen atoms to be substituted can be selected within the range of 1 to 5.
  • a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided.
  • L is C2-6 alkylene
  • R 1 and R 2 are each independently C1-10 alkyl, C6-10 aryl substituted C1-10 alkyl or C1-10 alkyl substituted with 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S,
  • aryl and heteroaryl are each independently substituted with one or more selected from the group consisting of unsubstituted or halogen, C1-10 alkyl unsubstituted or substituted with one or more halogens, C1-10 alkoxy unsubstituted or substituted with one or more halogens, and 3 to 6 membered cycloalkyloxy substituted with one or more halogens.
  • L is (CH 2 ) n , where n is an integer from 2 to 6, or n is an integer from 3 to 5, or n is 4.
  • R 1 and R 2 are each independently C1-6 alkyl, C1-6 alkyl substituted with C6 aryl, or C1-6 alkyl substituted with 5-6 membered heteroaryl containing 1-3 N,
  • aryl and heteroaryl are each independently unsubstituted or substituted with halogen, C1-6 alkyl unsubstituted or substituted with one or more halogens, C1-6 alkoxy unsubstituted or substituted with one or more halogens, and 3 to 5 membered cycloalkyloxy substituted with one or more halogens, and are substituted with 1 to 3 members.
  • the above aryl is phenyl and the above heteroaryl is pyridyl.
  • R 1 and R 2 are each independently methyl, phenylmethyl or pyridylmethyl,
  • the phenyl of the above phenylmethyl and the pyridyl of the pyridylmethyl are each independently unsubstituted or substituted with 1 to 3 groups selected from the group consisting of F, Cl, methyl, methoxy, CF 3 , OCF 3 and 3,3-difluorocyclobutyloxy.
  • the compound represented by the above chemical formula 1 is one selected from the group of compounds below.
  • the compound represented by the above chemical formula 1 of the present invention can be provided in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • the acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like.
  • these pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Includes phthalate, terephthalate, benzenesulfonate, toluenesulf
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • the present invention provides a method for producing a compound represented by the chemical formula 1.
  • L, R 1 and R 2 are the same as defined in the chemical formula 1 above,
  • Y is C1-C10 alkyl.
  • the step of forming an amide bond between the above H 2 NR 1 and H 2 NR 2 can be performed sequentially.
  • the step of forming an amide bond between H 2 NR 2 can be performed after isolating the compound of chemical formula 2', or, in some cases, can be performed by introducing H 2 NR 2 without isolating the compound of chemical formula 2'.
  • R 1 and R 2 may be different or the same, but if they are the same, they can be performed at once without having to proceed sequentially.
  • L, R 1 and R 2 are the same as defined in the chemical formula 1 above,
  • Y is C1-C10 alkyl.
  • R 1 and R 2 may be different or the same, and in different cases, the amine reactants may be introduced at once in the form of a mixture. In the same case, the amine may be introduced as a single amine compound rather than a mixture.
  • the above manufacturing method is not limited to one embodiment of the present invention presented as an example, and can be performed by modifying the solvent, reactant, temperature conditions, etc. under general organic chemical knowledge.
  • the above compound is characterized by inhibiting glutaminase.
  • the above compound is cytotoxic to cancer cells, and the cancer cells may be cancer cells resistant to existing anticancer drugs, and for example, cancer cells resistant to Ceritinib.
  • cancer includes pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, tongue cancer, astrocytoma, small intestine cancer, meningioma, esophage
  • the above autoimmune disease may be any one of psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease (e.g., allergic rhinitis), vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, rejection of allogeneic or xenogeneic transplantation (organ, bone marrow, stem cell and other cells and tissues), graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cir
  • the term “containing as an active ingredient” means containing in a dosage range that brings about the effect of preventing, improving, or treating cancer or autoimmune disease, and the dosage range may vary depending on the severity and formulation, and the number of applications may also vary depending on the age, weight, and constitution of the subject.
  • the compound represented by Chemical Formula 1 in the pharmaceutical composition of the present invention is contained in an amount of, for example, 0.001 mg/kg or more, preferably 0.1 mg/kg or more, more preferably 10 mg/kg or more, still more preferably 100 mg/kg or more, still more preferably 250 mg/kg or more, and most preferably 0.1 g/kg or more.
  • the quantitative upper limit of the compound represented by Chemical Formula 1 contained in the pharmaceutical composition of the present invention can be selected and implemented within an appropriate range by a person skilled in the art.
  • the above pharmaceutically acceptable carrier, excipient or diluent refers to a substance that is physiologically acceptable and does not typically cause allergic reactions such as gastrointestinal upset, dizziness or similar reactions when administered to humans.
  • the carrier, excipient and diluent include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.
  • fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.
  • the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof can be administered in various oral and parenteral dosage forms during clinical administration.
  • it is prepared using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing one or more compounds with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • a pharmaceutical composition containing the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or buffer in water to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form.
  • the composition may be sterilized and/or contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying promoters, salts for regulating osmotic pressure and/or buffers, and other therapeutically useful substances, and may be formulated according to conventional methods such as mixing, granulating, or coating.
  • Oral dosage forms include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches, and these dosage forms contain, in addition to the active ingredient, diluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine), lubricants (for example, silica, talc, stearic acid and its magnesium or calcium salts, and/or polyethylene glycol).
  • diluents for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine
  • lubricants for example, silica, talc, stearic acid and its magnesium or calcium salts, and/or polyethylene glycol.
  • Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidine, and, if desired, disintegrating agents or effervescent mixtures such as starch, agar, alginic acid or its sodium salt, and/or absorbents, coloring agents, flavoring agents, and sweetening agents.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidine
  • disintegrating agents or effervescent mixtures such as starch, agar, alginic acid or its sodium salt, and/or absorbents, coloring agents, flavoring agents, and sweetening agents.
  • treatment includes complete cure of symptoms of cancer or autoimmune disease as well as partial cure, improvement and alleviation of symptoms of cancer or autoimmune disease as a result of administering the pharmaceutical composition of the present invention to a subject suffering from cancer or an autoimmune disease.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment or improvement, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field.
  • the compound represented by the above chemical formula 1 can be used in the form of not only its pharmaceutically acceptable salt but also a solvate, hydrate, etc. that can be prepared therefrom.
  • a pharmaceutical composition for preventing or treating cancer containing the compound represented by the above chemical formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient may be administered as an individual therapeutic agent, or may be used in combination with other anticancer agents currently in use.
  • a pharmaceutical composition for preventing or treating cancer containing the compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can enhance the anticancer effect by co-administration with an anticancer agent.
  • a health functional food composition for preventing or improving cancer or autoimmune disease containing a compound represented by the above chemical formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the term “improvement” means alleviating or alleviating the symptoms of cancer or an autoimmune disease by administering, ingesting, or applying the pharmaceutical composition or food composition of the present invention to a subject suffering from cancer or an autoimmune disease.
  • the compound of chemical formula 1, which is a glutaminase inhibitor according to the present invention, can be prepared from the compound of chemical formula 2 as an intermediate according to two methods.
  • the two types of amines can be reacted sequentially, or they can be introduced in a mixed form at once and reacted.
  • the compound of chemical formula 5 is activated and can be carried out by employing known amidation reaction conditions.
  • the compound of chemical formula 4 is added at a low temperature, for example, 20° C. or lower, 10° C. or lower, and then the temperature is raised to room temperature.
  • the reaction is performed until completion, for example, 1 hour or longer, 6 hours or longer, or 12 hours or longer.
  • the reaction can be performed in an organic solvent, and it is preferable to use an aprotic organic solvent. Dichloromethane, acetone, ethyl acetate, THF, DMF, DMSO, benzene, toluene, diethyl ether, etc. can be used.
  • a base can be added due to the generated hydrogen chloride, etc., and an amine base or an inorganic base can be used.
  • an amine base it is preferable to use a tertiary amine such as triethylamine or pyridine. Afterwards, a further purification process can be performed.
  • Triethylamine (2.80 mL, 20.1 mmol) was added to a solution of adipohydrazide (1.00 g, 5.74 mmol) in dichloromethane (60 mL) under stirring at room temperature (R.T).
  • Ethyl 2-chloro-2-oxoacetate (2.35 g, 17.2 mmol) was added dropwise to the reaction mixture at 0 °C.
  • the reaction mixture was slowly warmed to room temperature and maintained for 24 h.
  • the reaction mixture was diluted with dichloromethane, filtered, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography using 1-10% methanol in dichloromethane as an eluent to obtain the target product as a yellow solid (1.03 g, 48%).
  • Phosphorus pentasulfide (2.23 g, 10.0 mmol) was added to a solution of Preparation 1 (1.50 g, 4.01 mmol) in toluene (26.7 mL) at room temperature under stirring. The reaction mixture was heated at 70 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and methanol, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using 1-10% methanol in dichloromethane as an eluent to obtain the target compound as a yellow solid (862 mg, 58%).
  • Methaneamine (33.5 mg, 1.08 mmol) was added to a solution of the compound of Preparation Example 2 (400 mg, 1.08 mmol) in ethanol (4.0 mL) at room temperature under stirring. The reaction mixture was heated at 80 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using 1-10% methanol in dichloromethane as an eluent to obtain the target compound as a white solid (75.0 mg, 21%).
  • the target compound was obtained as a yellow solid (23.3 mg, 20%).
  • the target compound was obtained as a yellow solid (80.2 mg, 20%).
  • the target compound was obtained as in Example 1.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained in the same manner as in Example 1 using the starting material of Manufacturing Example 3.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained in the same manner as in Example 1 using the starting material of Manufacturing Example 4.
  • the target compound was obtained in the same manner as in Example 1 using the starting material of Manufacturing Example 4.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained in the same manner as in Example 1 using the starting material of Manufacturing Example 4.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained in the same manner as in Example 1 using the starting material of Manufacturing Example 4.
  • the target compound was obtained in the same manner as in Example 1 using the starting material of Manufacturing Example 3.
  • the target compound was obtained in the same manner as in Example 1 using the starting material of Manufacturing Example 4.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained in the same manner as in Example 1 using the compound of Manufacturing Example 5 as a starting material.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained in the same manner as in Example 1 using the compound of Manufacturing Example 5 as a starting material.
  • the target compound was obtained as in Example 1.
  • the target compound was obtained in the same manner as in Example 1 using the compound of Manufacturing Example 5 as a starting material.
  • the target compound was obtained in the same manner as in Example 1 using the compound of Manufacturing Example 5 as a starting material.
  • the target compound was obtained in the same manner as in Example 1 using the compound of Manufacturing Example 5 as a starting material.
  • the target compound was obtained in the same manner as in Example 1 using the compound of Manufacturing Example 5 as a starting material.
  • the target compound was obtained in the same manner as in Example 1 using the compound of Manufacturing Example 5 as a starting material.
  • the inhibitory activity IC 50 for glutaminase was measured when the example compound was treated.
  • the experimental method is as follows.
  • GLS1 inhibitor screening assay kit (catalog number #79596) provided by BPS Bioscience was used. First, 8 ⁇ L of a solution containing 10 ng of GLS1 (elongated glutaminase) was dispensed into each well of a 384 plate (black, low volume, round bottom). 2 ⁇ L of a compound solution prepared at a concentration 5 times higher than the final concentration of the enzyme solution was added and reacted at room temperature for two hours. After the reaction was complete, L-glutamine, NAD+, and coupling reagent were mixed using GLS1 buffer solution, and 10 ⁇ L of this mixture was dispensed into each well.
  • GLS1 inhibitor screening assay kit catalog number #79596
  • the enzyme activity was confirmed by measuring the fluorescence value.
  • the IC 50 values of glutaminase inhibitory activity were determined by measuring the activity of glutaminase at six different compound concentrations and analyzing the results using GraphPad Prism. The results are shown in Table 2 below.
  • Example GLS1 IC 50 ( ⁇ M) Example GLS1 IC 50 ( ⁇ M) 1 0.75 21 0.66 2 >10 22 0.032 3 >10 23 0.36 4 >10 24 0.05 5 0.02 25 3.3 6 >10 26 >10 7 >10 27 0.62 8 >10 28 >10 9 >10 29 2.1 10 >10 30 1.1 11 0.39 31 0.87 12 >10 32 7.3 13 6.9 33 3.1 14 5.5 34 0.53 15 >10 35 0.011 16 >10 36 0.03 17 0.044 37 0.046 18 0.037 38 1.7 19 5.6 39 1.3 20 >10
  • H3122-LR pool an acquired-resistant non-small cell lung cancer cell line
  • Example LR pool IC 50 ( ⁇ M) Example LR pool IC 50 ( ⁇ M) 1 1.5 21 1 2 9.9 22 0.028 3 >10 23 0.72 4 >10 24 4.5 5 0.018 25 >10 6 2.2 26 >10 7 >10 27 1.6 8 2.3 28 >10 9 4.6 29 >10 10 0.59 30 0.41 11 0.38 31 1.3 12 1.4 32 0.3 13 2.7 33 0.67 14 >10 34 0.31 15 >10 35 0.026 16 4.5 36 - 17 >10 37 0.045 18 9 38 2.3 19 2.3 39 0.7 20 4.6
  • Example 22 at a lower dose than CB-839 showed similar cancer growth inhibition (TGI 75.67%), and as shown in Fig. 2b, no particular weight loss was observed for either substance, verifying the in vivo activity of Example 22.

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Abstract

La présente invention concerne un nouveau composé inhibiteur de glutaminase et une composition pharmaceutique pour la prévention ou le traitement du cancer ou de maladies auto-immunes, le comprenant en tant que principe actif. Un composé représenté par la formule chimique 1 selon la présente invention présente une excellente activité inhibitrice vis-à-vis de la glutaminase et a une excellente cytotoxicité contre les cellules cancéreuses, et est donc censé être efficace contre le cancer ou des maladies auto-immunes.
PCT/KR2024/096315 2023-10-11 2024-10-11 Nouveau composé di-amide, son procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou de maladies auto-immunes le comprenant en tant que principe actif Pending WO2025080100A1 (fr)

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KR1020240136688A KR102855423B1 (ko) 2023-10-11 2024-10-08 신규한 디-아미드 화합물, 이의 제조방법, 이를 유효성분으로 포함하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150085078A (ko) * 2012-11-21 2015-07-22 아지오스 파마슈티컬스 아이엔씨. 글루타마제 억제제 및 사용 방법
WO2016004404A2 (fr) * 2014-07-03 2016-01-07 Board Of Regents, University Of Texas System Inhibiteurs de gls1 utiles pour le traitement de maladies
KR20170131650A (ko) * 2015-03-30 2017-11-29 칼리테라 바이오사이언시즈, 인코포레이티드 글루타미나제 억제제의 투여 방법
KR20180120701A (ko) * 2016-02-12 2018-11-06 아스테라스 세이야쿠 가부시키가이샤 테트라히드로이소퀴놀린 유도체

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150085078A (ko) * 2012-11-21 2015-07-22 아지오스 파마슈티컬스 아이엔씨. 글루타마제 억제제 및 사용 방법
WO2016004404A2 (fr) * 2014-07-03 2016-01-07 Board Of Regents, University Of Texas System Inhibiteurs de gls1 utiles pour le traitement de maladies
KR20170131650A (ko) * 2015-03-30 2017-11-29 칼리테라 바이오사이언시즈, 인코포레이티드 글루타미나제 억제제의 투여 방법
KR20180120701A (ko) * 2016-02-12 2018-11-06 아스테라스 세이야쿠 가부시키가이샤 테트라히드로이소퀴놀린 유도체

Non-Patent Citations (1)

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Title
LUKASIK, N. ET AL.: "1,3,4-Thiadiazole-based diamides: Synthesis and complexation properties", JOURNAL OF MOLECULAR STRUCTURE, vol. 1146, 2017, pages 713 - 722, XP085138045, DOI: 10.1016/j.molstruc.2017.06.057 *

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