WO2023022430A1 - Nouveau composé macrocyclique, sa méthode de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou de maladies auto-immunes, le contenant en tant que principe actif - Google Patents

Nouveau composé macrocyclique, sa méthode de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou de maladies auto-immunes, le contenant en tant que principe actif Download PDF

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WO2023022430A1
WO2023022430A1 PCT/KR2022/011939 KR2022011939W WO2023022430A1 WO 2023022430 A1 WO2023022430 A1 WO 2023022430A1 KR 2022011939 W KR2022011939 W KR 2022011939W WO 2023022430 A1 WO2023022430 A1 WO 2023022430A1
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cancer
formula
diaza
compound
dipyridagina
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PCT/KR2022/011939
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Korean (ko)
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이광호
두기랄라크리시나바부
이유진
최길돈
채종학
정명은
조병철
윤미란
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한국화학연구원
연세대학교 산학협력단
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Publication of WO2023022430A1 publication Critical patent/WO2023022430A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to a novel macrocycle compound, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer or autoimmune disease containing the same as an active ingredient.
  • metabolic anticancer agents that target tumor-specific metabolic pathways to selectively inhibit cancer are rapidly emerging. Because cancer uses selective metabolic pathways for proliferation and survival, metabolic reorientation is a key feature of cancer phenotypes. Therefore, many studies have been conducted on how cancer cells with specific genetic mutations propagate by readjusting specific metabolic circuits.
  • Glucose and glutamine are the main metabolic fuels used in cancer growth. Most cancers utilize high levels of glucose metabolism to meet the protein anabolic and catabolic demands necessary to maintain rapid tumor growth. At this time, when metabolic stress caused by anticancer drugs is used, alternative nutrients such as amino acids are used to overcome the metabolic stress.
  • 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, non-essential amino acids and fatty acids, which are important precursors for macromolecular synthesis.
  • glutamine and glutamine-derived metabolites are known to participate in energy production, redox homeostasis, gene transcription, and intracellular signaling in cancer cells.
  • KEAP1 known as the third most frequently mutated gene in lung adenocarcinomas, frequently co-occurs with KRAS oncogenic mutations. It has been reported that cancers with KEAP1- or NRF2- mutations are highly dependent on upregulated glutamine degradation, and that this property can be used therapeutically through pharmacological inhibition of glutaminase (Non-Patent Document 2, R Romero, et al, Nature Medicine, November 2017, Vol. 23, No. 11).
  • Non-Patent Document 3 Michihito Kono, et al, Arthritis & Rheumatology, 2019 Nov; 71(11): 1869-1878).
  • One object of the present invention is to provide a novel macrocycle 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.
  • the present invention provides a compound represented by Formula 1 below, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
  • L is a C 1-20 straight chain alkylene, wherein one or more carbon atoms of the alkylene may be substituted with an oxygen atom.
  • Step 1 Provided is a method for preparing a compound represented by Chemical Formula 1 including the step (Step 1) of preparing a compound represented by Chemical Formula 1 by amidation reaction between a compound represented by Chemical Formula 2 and a compound represented by Chemical Formula 3.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer or autoimmune disease, containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. do.
  • the present invention is a health functional food composition for preventing or improving cancer or autoimmune diseases, containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by Formula 1 described herein is expected to be useful for cancer or autoimmune diseases because of its excellent cytotoxicity against cancer cells while exhibiting excellent inhibitory activity against glutaminase.
  • a compound represented by Formula 1 below, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof are provided.
  • L is C 1-20 alkylene, wherein one or more carbon atoms of the alkylene may be substituted with an oxygen atom.
  • L is a C 1-20 straight chain alkylene, wherein one or more carbon atoms of the alkylene may be substituted with an oxygen atom.
  • L is -OC 1-15 straight-chain alkylene-O-, wherein one or more carbon atoms of the alkylene may be substituted with oxygen atoms, but the oxygen atoms are not bonded to each other.
  • L is -OL 1 -
  • L 1 is -[(CH 2 )pO]m-
  • p is an integer from 1 to 10
  • m is an integer from 1 to 5
  • the number of carbons and oxygens in L 1 The sum is within 12.
  • the L is , , , , , , , or am.
  • any one compound selected from the group of compounds below, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is provided.
  • alkylene or “alkyl” includes straight or branched chain saturated hydrocarbon moieties, unless otherwise specified.
  • C 1-6 alkyl means an alkyl having a backbone of 1 to 6 carbons. Specifically, C 1-6 alkyl is 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.
  • the compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • organic acids such as dioates, 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.
  • Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulphate, sulphite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i.
  • the acid addition salt according to the present invention can be prepared by a conventional method.
  • a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid thereto It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
  • hydrate refers to a compound of the present invention that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or a salt thereof.
  • the hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water.
  • Such hydrates may be prepared by crystallizing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof of the present invention from water or a water-containing solvent.
  • solvate refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.
  • Step 1 Provided is a method for preparing a compound represented by Chemical Formula 1 including the step (Step 1) of preparing a compound represented by Chemical Formula 1 by amidation reaction between a compound represented by Chemical Formula 2 and a compound represented by Chemical Formula 3.
  • step 1 is a step of amidation reaction between the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3, and the compound represented by Chemical Formula 2 is reacted with the compound represented by Chemical Formula 3 to obtain Chemical Formula 1
  • step 1 is a step for preparing a compound represented by At this time, an organic solvent such as DMF or toluene may be used as the solvent, and the amidation reaction may be performed using conditions commonly used for the reaction.
  • the preparation method is not limited to one embodiment of the present invention presented as an example, and can be performed by modifying solvents, reactants, temperature conditions, etc. under conventional organic chemistry knowledge.
  • compositions for preventing or treating cancer or autoimmune disease containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound is characterized by inhibiting glutaminase.
  • the compound has cytotoxicity to cancer cells, and the cancer cells may be cancer cells resistant to conventional anticancer drugs, for example, cancer cells resistant to Ceritinib.
  • the cancer may be bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer.
  • the autoimmune disease is psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic disease (eg, allergic rhinitis), vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema , allogeneic or xenogeneic transplantation (organs, bone marrow, stem cells and other cells and tissues) transplant rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjögren's syndrome, thyroiditis (e.g., Hashimoto and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjun
  • the term *?**?*contained as an active ingredient*?**?* means that it is contained in a dose range that brings about the effect of prevention, improvement, or treatment of cancer or autoimmune disease, and ,
  • the dosage range may vary depending on the severity and dosage form, and the number of applications may also vary depending on the age, weight, and constitution of the target subject.
  • the compound represented by Formula 1 in the pharmaceutical composition of the present invention is, for example, 0.001 mg/kg or more, preferably 0.1 mg/kg or more, more preferably 10 mg/kg or more, more preferably 100 mg/kg or more, even more preferably 250 mg/kg or more, and most preferably 0.1 g/kg or more.
  • the upper limit of the amount of the compound represented by Formula 1 included in the pharmaceutical composition of the present invention can be selected and implemented within an appropriate range by those skilled in the art.
  • the pharmaceutical composition according to the present invention may include an effective amount of the compound represented by Formula 1 alone or may include one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • the pharmaceutically acceptable carrier, excipient or diluent refers to a material that is physiologically acceptable and does not cause an allergic reaction such as gastrointestinal disorder or dizziness or similar reaction when administered to humans.
  • the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.
  • fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers and preservatives may be further included.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, and emulsions.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • a pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. depending on how
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, which is prepared in an ampoule or vial unit dosage form can be manufactured with
  • the composition may be sterilized and/or contain preservatives, stabilizers, hydration agents or emulsification accelerators, salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, and may contain conventional methods such as mixing and granulation. It can be formulated according to the coating or coating method.
  • Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally boric acid such as starch, agar, alginic acid or its sodium salt. release or effervescent mixtures and/or absorbents, colorants, flavors, and sweeteners.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally
  • prevention means suppressing the symptoms of cancer or autoimmune disease by administering, ingesting or applying the pharmaceutical composition or health functional food composition of the present invention to a subject not suffering from cancer or autoimmune disease.
  • blocking it means preventing symptoms of cancer or autoimmune disease from occurring in advance.
  • the term "treatment” is a result of administering the pharmaceutical composition of the present invention to a subject suffering from cancer or autoimmune disease, as well as cure of symptoms of cancer or autoimmune disease, as well as treatment of symptoms of cancer or autoimmune disease. It includes partial cure, improvement and remission.
  • 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 with a reasonable benefit / risk ratio applicable to medical treatment or improvement, and the effective dose level is the type and severity of the subject, age, It may be determined according to factors including sex, activity of drug, sensitivity to drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field.
  • the compound represented by Formula 1 may be used in the form of not only pharmaceutically acceptable salts thereof, but also solvates and hydrates prepared therefrom.
  • composition for preventing or treating cancer containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent or used in combination with other anticancer agents in use. there is.
  • the pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can enhance anticancer effects by administering in combination with an anticancer agent.
  • a health functional food composition for preventing or improving cancer or autoimmune diseases containing the compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the term "improvement" means that the pharmaceutical composition or food composition of the present invention is administered, ingested, or applied to a subject suffering from cancer or autoimmune disease to reduce or alleviate the symptoms of cancer or autoimmune disease. am.
  • the present invention relates to the prevention or prevention of cancer or autoimmune diseases, including the step of administering to a subject in need of a compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof described herein. Treatment methods are provided.
  • the present invention provides a use of a compound represented by Formula 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof described herein in the prevention or treatment of cancer or autoimmune disease. .
  • CB-839 known as an inhibitor of glutaminase, was used as a reference and was purchased from SelleckChem Korea Co., Ltd.
  • tert-butyl(tert-butoxycarbonyl)(6-((trimethylsilyl)ethynyl)pyridazin-3-yl)carbamate (2.83 g, 7.23 mmol) and K 2 CO 3 ( 4.00 g, 28.9 mmol) was dissolved and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was redissolved in a mixture of DCM and H 2 O and neutralized to pH 7 with 1N HCl solution. The organics were separated, washed with brine, dried over MgSO 4 , filtered and concentrated. The crude material was used in the next step without further purification.
  • tert-Butyl(6-(4-cyanobutyl)pyridazin-3-yl)carbamate (620 mg, 2.24 mmol) was charged to a round bottom flask equipped with an open top reflux condenser. To the flask was added hydrazinecarbothioamide (225 mg, 2.47 mmol) and trifluoroacetic acid (5 mL). The reaction slurry was heated at 65 °C for 3 hours. The crude material was concentrated and redissolved in DCM three times. 1 mL of 4 N HCl in dioxane was added dropwise to the mixture. The solvent was removed under reduced pressure and ether was added to remove. The residue was purified using MPLC (including an alumina basic column) (0 ⁇ 30% MeOH/DCM) to obtain the compound of Preparation 12 as an off-white solid (235 mg, yield: 42%).
  • MPLC including an alumina basic column
  • Example 1 6,9-dioxa-2,13-diaza-1,14(3,6)-dipyridagina-5,10(1,3)-dibenzenacyclooctadecapane-3, Preparation of 12-dione (6,9-dioxa-2,13-diaza-1,14(3,6)-dipyridazina-5,10(1,3)-dibenzenacyclooctadecaphane-3,12-dione)
  • the reactants were the compound of Preparation Example 3 and the compound of Preparation Example 2, and were prepared in the same manner as in Example 1 to obtain the compound of Example 2 (yield: 6%).
  • Example 3 15,20-dioxa-4,11-diaza-5,10 (3,6)-dipyridagina-1,14 (1,3)-dibenzenacycloicosapan-3,12 Preparation of -dione (15,20-dioxa-4,11-diaza-5,10(3,6)-dipyridazina-1,14(1,3)-dibenzenacycloicosaphane-3,12-dione)
  • the reactants were the compound of Preparation Example 4 and the compound of Preparation Example 2, and were prepared in the same manner as in Example 1 to obtain the compound of Example 3 (yield: 18%).
  • the reactants were the compound of Preparation Example 5 and the compound of Preparation Example 2, and were prepared in the same manner as in Example 1 to obtain the compound of Example 4 (yield: 31%).
  • the reactants were the compound of Preparation Example 6 and the compound of Preparation Example 2, prepared in the same manner as in Example 1 to obtain the compound of Example 5 (yield: 2.4%).
  • the reactants were the compound of Preparation Example 7 and the compound of Preparation Example 2, and were prepared in the same manner as in Example 1 to obtain the compound of Example 6 (yield: 7%).
  • the reactants were the compound of Preparation Example 8 and the compound of Preparation Example 2, and were prepared in the same manner as in Example 1 to obtain the compound of Example 7 (yield: 78%).
  • the reactants were the compound of Preparation Example 9 and the compound of Preparation Example 2, and were prepared in the same manner as in Example 1 to obtain the compound of Example 8 as a brown solid (yield: 24%).
  • the reactants were the compound of Preparation Example 10 and the compound of Preparation Example 2, prepared in the same manner as in Example 1 to obtain the compound of Example 9 as a brown solid (yield: 27%).
  • the reactants were the compound of Preparation Example 11 and the compound of Preparation Example 2, prepared in the same manner as in Example 1 to obtain the compound of Example 10 as a brown solid (yield: 36%).
  • the reactants were the compound of Preparation Example 1 and the compound of Preparation Example 12, prepared in the same manner as in Example 1 to obtain the compound of Comparative Example 1 (yield: 13%).
  • the reactants were the compound of Preparation Example 9 and the compound of Preparation Example 13, prepared in the same manner as in Example 1 to obtain the compound of Comparative Example 2 as a yellow solid (yield: 25%).
  • the reactants were the compound of Preparation Example 9 and the compound of Preparation Example 12, prepared in the same manner as in Example 1 to obtain the compound of Comparative Example 3 (yield: 15%).
  • the inhibitory activity IC 50 for glutaminase was measured.
  • the experimental method is as follows.
  • the GLS1 inhibitor screening assay kit (catalogue number # 79596) provided by BPS Bioscience was used. First, 8 ⁇ L of a solution containing 10 ng of GLS1 (extended glutaminase) was dispensed into each well of a 384 plate (black, low volume, round bottom). 2 ⁇ L of the prepared compound solution 5 times thicker than the final concentration was added to the enzyme solution and reacted at room temperature for 2 hours. After the reaction was over, L-glutamine, NAD+, and a coupling reagent were mixed using GLS1 buffer, and 10 ul of this mixture was dispensed into each well.
  • Glutaminase inhibitory activity IC 50 values were determined by measuring the activity of glutaminase at six different compound concentrations and analyzing the results with GraphPad Prism. The results are shown in Table 3 below.
  • Example Glutaminase IC 50 ( ⁇ M)
  • Example Glutaminase IC 50 ( ⁇ M) CB-839 0.2 7 0.68 One 0.18 8 0.31 2 0.18 9 One 3 0.87 10 2 4 0.78 Comparative Example 1 0.5 5 0.43 Comparative Example 2 1.7 6 0.57 Comparative Example 3 0.8
  • the average glutaminase inhibitory activity IC 50 of Examples 1 to 10 is 0.7 ⁇ M, and in particular Examples 1, 2 and 8 show values as low as 0.3 ⁇ M.
  • the exemplary compounds of the present application have structural characteristics in which pyridazinylene is symmetrically bonded.
  • the Comparative Example compounds are compounds in which 1 or 2 thiadiazolylene are bonded. Comparing Comparative Example 1 and Example 1, the IC 50 of Example 1 is low, so that pyridazinylene is symmetrically bonded. It can be seen that the Example compounds have excellent glutaminase inhibitory activity.
  • glutaminase inhibitory activity is excellent compared to when pyridazinylene is bound to only one side or thiadiazolylene is bound to both sides is evaluated as
  • IC 50 was measured through cell viability according to the concentration using CB-839 as a reference in the LR (Ceritinib (LDK378) resistant) pool cell line, which is an ALK-TKI resistant cell. .
  • H3122-LR pool an acquired resistant non-small cell lung cancer cell line
  • this resistant cell line showed amplification of NRF2, a biomarker predictive of response to glutaminase inhibitors. Therefore, it was selected as a suitable model to test the anticancer effect of the compound.
  • the experimental method is as follows.
  • Example H3122-LR IC 50 ( ⁇ M) Example H3122-LR IC 50 ( ⁇ M) CB-839 0.055 5 0.53 One 0.21 8 0.065 2 0.21
  • Example 8 was 0.1 ⁇ M or less, indicating that the anticancer effect was excellent.
  • the compound and CB-839 reference were each treated at 0.3 ⁇ M the next day. After culturing for 24 hours, intracellular glutamine/glutamate levels were measured using Glutamine/Glutamate-GloTM Assay kit. At this time, the culture medium was used by adding 5 mM glucose, 2 mM glutamine, and 10% dialyzed FBS to a serum-free medium without glucose, glutamine, and pyruvate.
  • the concentration of glutamine is high, whereas the concentration of glutamate is low when treated with 0.3 ⁇ M of the Example compound. Since glutamine is converted to glutamate by glutaminase, the concentration of glutamine is remarkably higher than that of glutamate, indicating that the compound according to the present invention is absorbed into cells and has excellent glutaminase inhibitory activity even within cells. .

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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nutrition Science (AREA)
  • Polymers & Plastics (AREA)
  • Mycology (AREA)
  • Food Science & Technology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé macrocyclique, son procédé de préparation, et une composition pharmaceutique pour la prévention ou le traitement du cancer ou de maladies auto-immunes, le contenant en tant que principe actif. Un composé représenté par la formule chimique 1 divulgué dans la présente invention présente une excellente cytotoxicité contre les cellules cancéreuses tout en présentant une excellente activité inhibitrice vis-à-vis de la glutaminase, et est donc prévu pour être utile pour le cancer ou des maladies auto-immunes.
PCT/KR2022/011939 2021-08-18 2022-08-10 Nouveau composé macrocyclique, sa méthode de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer ou de maladies auto-immunes, le contenant en tant que principe actif WO2023022430A1 (fr)

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KR1020210108442A KR102649592B1 (ko) 2021-08-18 2021-08-18 신규한 마크로사이클 화합물, 이의 제조방법, 이를 유효성분으로 포함하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물
KR10-2021-0108442 2021-08-18

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013078123A1 (fr) * 2011-11-21 2013-05-30 Calithera Biosciences Inc. Inhibiteurs hétérocycliques de glutaminase
US20150065486A1 (en) * 2013-08-29 2015-03-05 Edward Skolnik Methods for treating polycystic kidney disease
KR20150091389A (ko) * 2012-12-03 2015-08-10 칼리테라 바이오사이언시즈 인코포레이티드 글루타미나제의 헤테로사이클릭 억제제에 의한 암 치료
CN111440199A (zh) * 2020-03-11 2020-07-24 中国药科大学 大环类谷氨酰胺酶gls1抑制剂或其可药用的盐、其制备方法及用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013078123A1 (fr) * 2011-11-21 2013-05-30 Calithera Biosciences Inc. Inhibiteurs hétérocycliques de glutaminase
KR20150091389A (ko) * 2012-12-03 2015-08-10 칼리테라 바이오사이언시즈 인코포레이티드 글루타미나제의 헤테로사이클릭 억제제에 의한 암 치료
US20150065486A1 (en) * 2013-08-29 2015-03-05 Edward Skolnik Methods for treating polycystic kidney disease
CN111440199A (zh) * 2020-03-11 2020-07-24 中国药科大学 大环类谷氨酰胺酶gls1抑制剂或其可药用的盐、其制备方法及用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XU XI, WANG JUBO, WANG MIN, YUAN XINYU, LI LEI, ZHANG CHAO, HUANG HUIDAN, JING TIAN, WANG CHENCHEN, TONG CHAO, ZHOU LIWEN, MENG YI: "Structure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 8, 22 April 2021 (2021-04-22), US , pages 4588 - 4611, XP093036248, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.0c02044 *

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