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WO2024075736A1 - Composé azoté, composition comprenant ledit composé azoté et marqueur pour la prédiction du degré d'une tumeur - Google Patents

Composé azoté, composition comprenant ledit composé azoté et marqueur pour la prédiction du degré d'une tumeur Download PDF

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Publication number
WO2024075736A1
WO2024075736A1 PCT/JP2023/036077 JP2023036077W WO2024075736A1 WO 2024075736 A1 WO2024075736 A1 WO 2024075736A1 JP 2023036077 W JP2023036077 W JP 2023036077W WO 2024075736 A1 WO2024075736 A1 WO 2024075736A1
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nitrogen
containing compound
atom
group
composition
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Japanese (ja)
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美樹夫 林
幸樹 池田
亮一 岩田
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KANSAI MEDICAL UNIVERSITY EDUCATIONAL Corp
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KANSAI MEDICAL UNIVERSITY EDUCATIONAL Corp
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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
    • A61K31/33—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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • compositions containing the nitrogen-containing compounds Disclosed herein are nitrogen-containing compounds, compositions containing the nitrogen-containing compounds, and predictive markers for tumor malignancy.
  • Non-Patent Document 1 In Japan, there are said to be approximately 2,200 glioblastoma patients and 110,000 lung cancer patients. Glioblastoma in particular is often accompanied by infiltration that cannot be surgically removed, and even with the combination of radiation therapy and the commercially available drug temozolomide, the two-year survival rate is low at 27% (Non-Patent Document 1), and current treatment methods are not sufficiently effective.
  • Cancer stem cells often cannot be removed by surgical treatment and tend to proliferate repeatedly. Therefore, there is a need to develop therapeutic drugs that target and kill cancer stem cells.
  • One of the objectives of the present invention is to provide a compound that inhibits the proliferation of cancer stem cells.
  • R 1 and R 2 are the same or different and represent a hydrogen atom, a C1-6 linear or branched alkyl group which may have a halogen atom as a substituent and which may have a halogen atom as a substituent, a C1-6 linear or branched alkoxy group, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group or a cyano group.
  • R 3 represents a C1-6 branched or linear alkyl group which may have a halogen atom as a substituent.
  • X 1 , X 2 and X 3 represent a carbon atom or a nitrogen atom, and one or two of X 1 , X 2 and X 3 are nitrogen atoms.
  • X 4 represents a carbon atom or a nitrogen atom.
  • Item 5 A composition comprising the nitrogen-containing compound according to any one of items 1 to 4, or a pharma- ceutically acceptable salt thereof.
  • Item 6. The composition according to Item 5, which is used to treat a malignant tumor.
  • Item 8 The composition according to Item 5, which is used to inhibit the proliferation of tumor stem cells of a malignant tumor.
  • Item 9. The composition according to any one of Items 5 to 8, wherein the malignant tumor is glioblastoma or lung cancer.
  • cancer stem cells such as glioblastoma cancer stem cells and lung cancer stem cells.
  • A shows the relationship between the expression of mucolipin MCOLN1 and patients' overall survival rate.
  • B shows the relationship between the expression of mucolipin MCOLN1 and patients' Disease/Progression (D/P)-free survival rate.
  • C shows the relationship between the expression of mucolipin MCOLN2 and patients' overall survival rate.
  • D shows the relationship between the expression of mucolipin MCOLN2 and patients' Disease/Progression (D/P)-free survival rate.
  • E shows the relationship between the expression of mucolipin MCOLN3 and patients' overall survival rate.
  • F shows the relationship between the expression of mucolipin MCOLN3 and patients' Disease/Progression (D/P)-free survival rate.
  • LCMS liquid chromatography mass spectrometry
  • 1 shows the concentration-dependent cell growth inhibitory activity of KMU84, KMU98, KMU110, and KMU101 examined using L1 cells.
  • A shows the results of immunostaining with anti-MCOLN3 antibody
  • B shows the results of an antibody absorption test in which an antigen peptide was reacted with anti-MCOLN3 antibody
  • C shows the cell proliferation rate of lung cancer stem cells in the presence of SR33805.
  • the LC-MS results of the synthesized KMU110 are shown.
  • the results of 1 H-NMR of the synthesized KMU110 are shown below.
  • the LC-MS results of the synthesized KMU84 are shown.
  • the results of 1 H-NMR of the synthesized KMU84 are shown below.
  • the LC-MS results of the synthesized KMU98 are shown.
  • the results of 1 H-NMR of the synthesized KMU98 are shown below.
  • the LC-MS results of the synthesized KMU101 are shown.
  • the results of 1 H-NMR of the synthesized KMU101 are shown below.
  • the LC-MS results of the synthesized KMU111 are shown.
  • the results of 1 H-NMR of the synthesized KMU111 are shown below.
  • the LC-MS results of the synthesized KMU112 are shown.
  • the results of 1 H-NMR of the synthesized KMU112 are shown below.
  • This specification discloses a nitrogen-containing compound that binds to a mucolipin protein, or a pharma- ceutically acceptable salt thereof, a method for producing the nitrogen-containing compound, a mucolipin protein as a predictive marker for predicting the malignancy of a tumor, a method for detecting the predictive marker, an apparatus for detecting the predictive marker, a program for detecting the predictive marker, and the like.
  • mucolipin proteins may include Mucolipin-1 (e.g., UniProtKB/Swiss-Prot: Q9GZU1), Mucolipin-2 (e.g., UniProtKB/Swiss-Prot: Q8IZK6), and Mucolipin-3 (e.g., UniProtKB/Swiss-Prot: Q8TDD5).
  • Mucolipin-1 is a protein encoded by the MCOLN1 gene, which is registered in NCBI under Gene ID: 57192.
  • Mucolipin-2 is a protein encoded by the MCOLN2 gene, which is registered in NCBI under Gene ID: 255231.
  • Mucolipin-3 is a protein encoded by the MCOLN3 gene, which is registered in NCBI under Gene ID: 55283.
  • the tumor may be either a malignant tumor or a benign tumor, but is preferably a malignant tumor.
  • the tumor includes both non-epithelial and epithelial malignant tumors.
  • the tumor may be a central nervous system malignant tumor; a respiratory system malignant tumor arising from the trachea, bronchi, or lungs; a digestive system malignant tumor arising from the nasopharynx, esophagus, stomach, duodenum, jejunum, ileum, cecum, appendix, ascending colon, transverse colon, sigmoid colon, rectum, or anus; liver cancer; pancreatic cancer; a urinary system malignant tumor arising from the bladder, ureter, or kidney; a female reproductive system malignant tumor arising from the ovaries, fallopian tubes, uterus, or the like; breast cancer; prostate cancer; skin cancer; an endocrine system malignant tumor arising from the hypothalamus, pituitary gland, thyroid gland,
  • Gliomas may include glioblastoma, anaplastic oligodendroglioma, anaplastic astrocytoma, diffuse midline glioma, oligodendroglioma, diffuse astrocytoma, pilocytic astrocytoma, subependymal giant cell glioma, pleomorphic xanthoastrocytoma, etc.
  • Glioblastoma, anaplastic oligodendroglioma, anaplastic astrocytoma, diffuse midline glioma, etc. are classified as high-grade gliomas, while oligodendroglioma, diffuse astrocytoma, pilocytic astrocytoma, subependymal giant cell glioma, etc. are classified as low-grade gliomas.
  • the malignancy of brain tumors is generally expressed in four stages, from grade 1 to grade 4, depending on the type of tumor, with grades 3 and 4 being considered highly malignant. The higher the grade, the lower the two-year and five-year survival rates tend to be.
  • Nitrogen-containing compound or a pharma- ceutically acceptable salt thereof, and a method for producing a nitrogen-containing compound (1) Nitrogen-containing compound
  • This embodiment relates to a nitrogen-containing compound.
  • the nitrogen-containing compound can bind to a mucolipin protein.
  • the nitrogen-containing compound can block ion flow through an ion channel constituted by the mucolipin protein.
  • C in the descriptions such as “C1-6”, “C1-4”, and “C3-6” indicates carbon.
  • C1-6 indicates that the number of carbon atoms is 1 to 6
  • C1-4 indicates that the number of carbon atoms is 1 to 4
  • C3-6 indicates that the number of carbon atoms is 3 to 6.
  • the nitrogen-containing compound according to this embodiment is represented by the following general formula (I).
  • n and n are the same or different and each represents an integer of 1 to 3.
  • m and n are the same or different and each represents an integer of 1 or 2. More preferably, m and n are all 1.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a C1-6 linear or branched alkyl group which may have a halogen atom as a substituent, a C1-6 linear or branched alkoxy group which may have a halogen atom as a substituent, a halogen atom, an amino group, a hydroxyl group, a nitro group, a carboxy group or a cyano group.
  • Examples of the C1-6 linear alkyl group in R 1 and R 2 include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, and an n-hexyl group.
  • Examples of the C3-6 branched alkyl group include an isopropyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, an isopentyl group, a neopentyl group, a 3-methylpentyl group, a 3,3-dimethylbutyl group, and a 3-ethylbutyl group.
  • the C1-6 linear or branched alkyl group is preferably a C1-3 linear or branched alkyl group (i.e., a methyl group, an ethyl group, an n-propyl group, or an isopropyl group), more preferably a C1-3 linear alkyl group (i.e., a methyl group, an ethyl group, or a 3-propyl group), even more preferably a C1-2 alkyl group (i.e., a methyl group or an ethyl group), and even more preferably a C1 alkyl group (i.e., a methyl group).
  • halogen atoms as substituents include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.
  • the alkyl group in the C1-6 linear or branched alkoxy group which may have a halogen atom as a substituent in R 1 and R 2 is the same as the above C1-6 linear alkyl group and C3-6 branched alkyl group.
  • the halogen atom as a substituent include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the halogen atom in R 1 and R 2 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • R 1 and R 2 are preferably a hydrogen atom.
  • R3 represents a C1-6 branched or linear alkyl group which may have a halogen atom as a substituent.
  • the definitions of the halogen atom and the C1-6 branched or linear alkyl group are the same as those of R1 and R2 .
  • R 3 is preferably a C3-6 branched alkyl group which may have a halogen atom as a substituent (i.e., isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, neopentyl, 3-methylpentyl, 3,3-dimethylbutyl, and 3-ethylbutyl), more preferably a C3-4 branched alkyl group which may have a halogen atom as a substituent (i.e., isopropyl, sec-butyl, isobutyl, or tert-butyl), even more preferably a C3-4 branched alkyl group which has no substituent (i.e., isopropyl, sec-butyl, isobutyl, or tert-butyl), and even more preferably a C3 branched alkyl group which has no substituent (i.e., isopropyl,
  • halogen atoms as substituents include chlorine, fluorine, bromine, and iodine atoms.
  • X 1 , X 2 and X 3 each represent a carbon atom or a nitrogen atom, and one or two of X 1 , X 2 and X 3 are a nitrogen atom.
  • X4 represents a carbon atom or a nitrogen atom.
  • X1 and X4 are both nitrogen atoms and X2 and X3 are both carbon atoms
  • X3 and X4 are both nitrogen atoms and X1 and X2 are both carbon atoms are excluded from the above general formula (I).
  • the nitrogen-containing compound represented by general formula (I) is more preferably a nitrogen-containing compound represented by the following formula (8), (9), (101), (110), or (11):
  • the nitrogen-containing compound represented by the above formula (8) is more preferably a nitrogen-containing compound represented by the following formula (84): .
  • the nitrogen-containing compound represented by the above formula (9) is more preferably a nitrogen-containing compound represented by the following formula (98): .
  • the nitrogen-containing compound represented by the above formula (101) is more preferably a nitrogen-containing compound represented by the following formula (101a): .
  • the nitrogen-containing compound represented by the above formula (11) is more preferably a nitrogen-containing compound represented by the following formula (111) or (112): ,
  • compositions of nitrogen-containing compounds are not particularly limited.
  • examples of such salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, and nitrate; and organic acid addition salts such as acetate, tartrate, maleate, succinate, citrate, methanesulfonate, malate, oxalate, and benzenesulfonate.
  • These salts can be produced, for example, by treating the nitrogen-containing compounds represented by the above general formula (I) with an acid.
  • the nitrogen-containing compound represented by the above general formula (I) is a compound represented by the following general formula (IA): (m, n, R 1 , and R 2 are the same as above.)
  • the following general formula (IB) and ( R3 is the same as above.) can be produced by subjecting the compound to amide bonding under known conditions.
  • reaction between compound (IA) and compound (IB) is a method in which compound (IA) is reacted with the carboxylic acid of compound (IB) by a conventional amide bond formation reaction.
  • the conditions for known amide bond formation reactions can be widely applied to the amide bond formation reaction.
  • the mixed acid anhydride method that is, a method in which compound (IB) is reacted with an alkyl halocarboxylic acid to form a mixed acid anhydride, which is then reacted with compound (IA)
  • the active ester method that is, a method in which compound (IB) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, or an active amide with benzoxazoline-2-thione, which is then reacted with compound (IA)
  • the carbodiimide method that is, a method in which compound (IA) is reacted with compound (IB) using dicyclohexyl carboxylate (DCM) as the amide
  • DCM dicyclohexyl carboxylate
  • the mixed acid anhydride used in the above mixed anhydride method (a) is obtained by a conventional Schotten-Baumann reaction, and this is usually reacted with compound (IA) without isolation to produce the nitrogen-containing compound of general formula (I).
  • the Schotten-Baumann reaction is carried out in the presence of a basic compound.
  • Basic compounds used include compounds commonly used in the Schotten-Baumann reaction, such as organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine, dimethylaminopyridine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO); carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; and inorganic bases such as metal alcoholates such as potassium hydride, sodium hydride, potassium, sodium, sodium amide, sodium methylate, and sodium ethylate.
  • organic bases such as triethylamine, trimethylamine, pyridine, dimethyl
  • the reaction is usually carried out at about -20 to 100°C, preferably about 0 to 50°C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours.
  • the reaction of the resulting mixed acid anhydride with compound (IA) is usually carried out at about -20 to 150°C, preferably about 10 to 50°C, and the reaction time is about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours.
  • the mixed acid anhydride method is generally carried out in a solvent.
  • the solvent used may be any of those commonly used in the mixed acid anhydride method, including halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; esters such as methyl acetate, ethyl acetate, and isopropyl acetate; aprotic polar solvents such as N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixtures of these solvents.
  • halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride
  • aromatic hydrocarbons such as benzene,
  • alkyl halocarboxylic acid used in the mixed acid anhydride method examples include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc.
  • the proportions of carboxylic acid (IB), alkyl halocarboxylic acid, and compound (IA) used are usually equimolar, but the alkyl halocarboxylic acid and compound (IB) can each be used in an amount within the range of about equimolar to 1.5 times the molar amount of compound (IA).
  • the reaction is carried out in a suitable solvent in the presence or absence of a basic compound.
  • the solvent and basic compound used here may be any of the solvents used in the method of reacting compound (IA) with a carboxylic acid halide in other method (d) described below.
  • the amount of activator used should be at least equimolar to compound (IA), and preferably equimolar to 5 times the molar amount.
  • WSC equimolar to compound
  • the reaction is usually carried out at about -20 to 180°C, preferably at about 0 to 150°C, and is generally completed within about 5 minutes to 90 hours.
  • a wide variety of known basic compounds can be used as the basic compound, for example, any of the basic compounds used in the Schotten-Baumann reaction described above can be used.
  • Solvents that can be used include, for example, the solvents used in the mixed acid anhydride method described above, as well as alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, acetonitrile, pyridine, acetone, and water.
  • alcohols such as methanol, ethanol, isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, acetonitrile, pyridine, acetone, and water.
  • the ratio of compound (IA) to the carboxylic acid halide used is not particularly limited and may be appropriately selected within a wide range. Generally, the latter is used in an amount at least equimolar to the former, and preferably in an amount of about equimolar to 5 times the former.
  • the reaction is usually carried out at about -20 to 180°C, preferably about 0 to 150°C, and is generally completed within about 5 minutes to 50 hours.
  • the above amide bond forming reaction can also be carried out by reacting compound (IB) with compound (IA) in the presence of a condensing agent such as a phosphorus compound, e.g., diphenylphosphinic chloride, phenyl-N-phenylphosphoramidochloridate, diethylchlorophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, or bis(2-oxo-3-oxazolidinyl)phosphinic chloride.
  • a condensing agent such as a phosphorus compound, e.g., diphenylphosphinic chloride, phenyl-N-phenylphosphoramidochloridate, diethylchlorophosphate, diethyl cyanophosphate, diphenylphosphoryl azide, or bis(2-oxo-3-oxazolidinyl)phosphinic chloride.
  • the reaction is carried out in the presence of the solvent and basic compound used in the method of reacting the carboxylic acid halide with compound (IA), usually at about -20 to 150°C, preferably about 0 to 100°C, and generally completes in about 5 minutes to 30 hours.
  • the condensing agent and compound (IB) are each used in at least equimolar amounts, preferably equimolar to 2 times the molar amount, of compound (IA).
  • composition This embodiment relates to a composition comprising the nitrogen-containing compound described in 1. and 2. above.
  • the composition can be used to treat malignant tumors.
  • the composition can be used to prevent recurrence of malignant tumors.
  • the composition can be used to inhibit proliferation of tumor stem cells of malignant tumors.
  • the composition can prevent recurrence and metastasis of malignant tumors by inhibiting proliferation of tumor stem cells of malignant tumors.
  • prevention includes preventing and/or delaying the onset or recurrence of a tumor.
  • treatment includes shrinking and/or eliminating an existing tumor.
  • treatment may include treatment by administration of the composition alone, as well as combined use with radiation therapy or surgical treatment.
  • the maximum daily dose of the composition is 0.001 to 10 mg per kg of body weight, calculated as the nitrogen-containing compound represented by formula (I).
  • composition may be administered once a day at the above dosage, or, if necessary, the above dosage may be administered in 2, 3, 4, or 5 separate doses, preferably 2 or 3 separate doses, per day.
  • the composition can be prepared by combining the nitrogen-containing compound represented by the general formula (I) with a suitable carrier or additive for formulation.
  • suitable carrier or additive for formulation.
  • carriers and additives used in the preparation of the composition include various types of carriers and additives commonly used in ordinary pharmaceuticals depending on the dosage form of the composition, such as excipients, binders, disintegrants, lubricants, colorants, flavorings, odorants, surfactants, etc.
  • the dosage form is not particularly limited, and examples include tablets, powders, granules, capsules (including hard capsules and soft capsules), liquids, pills, suspensions, jelly preparations, and emulsions.
  • examples include injections, drips, suppositories, nasal drops, and pulmonary preparations.
  • carriers may include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, and gum arabic; simple syrup, glucose liquid, starch liquid, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol, and potassium phosphate.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerin, sodium alginate, and gum arabic
  • simple syrup glucose liquid, starch liquid, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose,
  • Binders such as dry starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearic acid, starch, and lactose; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; absorption promoters such as sodium lauryl sulfate; moisturizers such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; lubricants such as refined talc, stearates, powdered boric acid, and polyethylene glycol.
  • disintegrants such as dry starch, sodium alginate, powdered agar, powdered laminaran, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium
  • tablets include oral tablets (plain tablets, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, multi-layered tablets, etc.), chewable tablets (including those taken by chewing in the mouth), buccal tablets (including those taken after dissolving in the mouth, such as troches), sublingual tablets, and buccal tablets.
  • the following carriers can be used: excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc.; binders such as powdered gum arabic, powdered tragacanth, gelatin, etc.; disintegrants such as laminaran, agar, etc.
  • the capsule is prepared by mixing the active ingredient with the various carriers listed above and filling the mixture into a hard or soft capsule.
  • the composition When the composition is a liquid, it need only be in a liquid form, and may be an aqueous or oily suspension, solution, syrup, elixir, or drink.
  • the liquid is prepared in the usual manner using ordinary additives.
  • the container into which the liquid is filled so long as it can be sealed, and it may be a glass container, an aluminum container, or a plastic container.
  • the following carriers can be used: diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc.; pH adjusters such as sodium citrate, sodium acetate, sodium phosphate, etc.; buffers such as dipotassium phosphate, trisodium phosphate, sodium hydrogen phosphate, sodium citrate, etc.; stabilizers such as sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc.; and sugars such as mannitol, inositol, maltose, sucrose, lactose, etc., as molding agents for lyophilization.
  • diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated iso
  • glucose or glycerin may be contained in the pharmaceutical preparation in an amount sufficient to adjust the solution to an isotonicity, and conventional solubilizers, pain relievers, local anesthetics, etc. may also be added.
  • conventional solubilizers, pain relievers, local anesthetics, etc. may also be added.
  • subcutaneous, intramuscular, and intravenous injections can be prepared by conventional methods.
  • the composition When the composition is in the form of a drip infusion, it can be prepared by dissolving the nitrogen-containing compound to be administered in an isotonic electrolyte infusion preparation based on physiological saline, Ringer's solution or the like.
  • cancer stem cell-like cells As cancer stem cell-like cells, we used cancer stem cell-like cells established from high-grade gliomas (four types: MD13, Me83, 1123, 30R) [References: Neuro Oncol 22(3): 333-44, 2020; Cancer Cell 24(3): 331-46, 2013], lung squamous cell carcinoma-derived cancer stem cell-like cells (two types: L1, L14), and metastatic brain tumor-derived cancer stem cell-like cells (two types: B34, B67).
  • Cancer tissue (0.1-1 g) excised during surgery was finely chopped with scissors. The minced tissue was transferred to a test tube containing 2 mL of cell detachment solution (Accumax(TM); Nacalai Tesque) and shaken (20 times/min) for 5 minutes in a 37°C incubator. 8 mL of cell culture medium was added, mixed, and centrifuged (40 x g, 5 minutes). The supernatant was discarded, and 10 mL of cell culture medium was added, mixed, and cultured on an ultra-low attachment surface dish (100 mm; Corning). Culture was performed in a humid environment of 5% CO2 /95% air at 37°C.
  • the cell culture medium used was D-MEM/Ham's F-12 (Wako Pure Chemical Industries, Ltd.) supplemented with NaHCO3 (49 mM), glucose (26 mM), L-glutamine (3 mM), MACS NeuroBrew-21 (5 mL; Miltenyi Biotec), epidermal growth factor (EGF, 20 ng/mL; PeproTech), fibroblast growth factor (bFGF, 20 ng/mL; PeproTech), penicillin (100 U/mL), and streptomycin (0.1 mg/mL).
  • Cell proliferation assay Cancer stem-like cells were transferred to a test tube and centrifuged (40 ⁇ g, 5 min). The supernatant was discarded, 2 mL of trypsin-EDTA solution (Sigma-Aldrich) was added, and the cells were incubated in a 37°C incubator for 5 min. Cell culture medium was added, mixed, and centrifuged. The supernatant was discarded, and cell culture medium was added. The cell number was counted, and 2000 cells were transferred to a 96-well ultra-low attachment surface plate (Corning). The cells were cultured for 4 days in 0.1 mL of cell culture medium containing each test drug. The number of live cells was counted using the viable cell count measurement reagent SF (Nacalai Tesque).
  • Mucolipin expression and survival rate Mucolipin protein was expressed in the pathological tissue specimens of four out of five cases of glioblastoma, a high-grade glioma ( Figure 1). This suggests that mucolipin expression is characteristic of glioblastoma.
  • survival curves are shown in Figure 2.
  • a and B show the relationship between the expression of mucolipin MCOLN1 and patient survival
  • C and D show the relationship between the expression of mucolipin MCOLN2 and patient survival
  • E and F show the relationship between the expression of mucolipin MCOLN3 and patient survival.
  • A, C, and E show the overall survival rate
  • B, D, and F show the Disease/Progression (D/P)-free survival rate.
  • the top 100 drugs based on the obtained MTS score were docked to the protein in question.
  • each of the 31 new nitrogen-containing compounds was confirmed by measuring their cell proliferation inhibitory activity against glioblastoma cells (MD13), cancer stem cell-like cells derived from metastatic brain tumors (B34), and cancer stem cell-like cells derived from lung squamous cell carcinoma (L1).
  • MD13 glioblastoma cells
  • B34 cancer stem cell-like cells derived from metastatic brain tumors
  • L1 cancer stem cell-like cells derived from lung squamous cell carcinoma
  • the nitrogen-containing compound (KMU3) represented by the following formula (3) was found to have high cell proliferation inhibitory activity: .
  • the compound represented by formula (3) is a known compound represented by the following formula (3A) (6-(pyrrolidin-3-yloxy)pyridin-3-amine). and a known compound (6-isopropoxypicolinic acid) represented by the following formula (3B): was produced by amide bond formation.
  • the synthesis and purity of the nitrogen-containing compound represented by formula (1) was confirmed by liquid chromatography mass spectrometry (LCMS) under the conditions shown in Figure 3.
  • the LCMS results are shown in Figure 4.
  • the LCMS showed a single peak, indicating that a single compound was produced from the compound represented by formula (1A) and the compound represented by formula (1B).
  • the nitrogen-containing compound represented by formula (1) may be referred to as "KMU3".
  • an analogue of a known compound represented by formula (3A) was bonded to an analogue of a known compound represented by formula (3B) via an amide bond to obtain 17 compounds, among which KMU84 represented by formula (84) was identified as having high cell proliferation inhibitory activity: .
  • KMU84 is a known compound represented by the following formula (84A): and a known compound (6-isopropoxypicolinic acid) represented by the following formula (84B): was produced by amide bond formation.
  • KMU98 represented by the following formula (98), was identified by virtual screening using KMU3 as a teacher. .
  • KMU98 is a known compound represented by the following formula (98A): and a known compound represented by the following formula (98B): was produced by amide bond formation.
  • KMU110 represented by the following formula (110a) was identified.
  • KMU110 is a known compound represented by the following formula (110A): and a known compound represented by the following formula (110B): was produced by amide bond formation.
  • KMU111 and KMU112 are known compounds represented by the following formula (11A): and a known compound represented by the following formula (110B): was produced by amide bond formation.
  • KMU101a represented by the following formula (101a) was identified: .
  • KMU101 is a known compound represented by the following formula (101A): and a known compound represented by the following formula (101B): was produced by amide bond formation.
  • SR33805 The structure of SR33805 is as follows: .
  • Figure 5 shows the concentration-dependent cell proliferation inhibitory activity of KMU3, SR33805, and temozolomide.
  • the black circle indicates KMU3
  • the white circle indicates SR33805
  • the cross indicates temozolomide.
  • MD13 cells were used as glioblastoma cells, and each drug was added to the medium at 10 nM, 100 nM, 1 ⁇ M, and 10 ⁇ M, and the cell viability was measured four days later.
  • KMU3 showed cell proliferation inhibitory activity comparable to that of SR33805.
  • Figure 6 shows the concentration-dependent cell proliferation inhibitory activity of KMU84, KMU98, KMU110, KMU111, KMU112, and KMU101, which was examined using MD13 cells. All compounds other than KMU101 showed 3- to 20-fold higher cell proliferation inhibitory activity than when SR33805 was used. KMU101 showed 1.5-fold higher cell proliferation inhibitory activity.
  • Figure 7 shows the concentration-dependent cell growth inhibitory activity of KMU84, KMU98, KMU110, KMU111, KMU112, and KMU101, which was examined using B34 cells. All compounds examined, except KMU84 and KMU101, showed cell growth inhibitory activity 1.7 to 28 times higher than when SR33805 was used.
  • Figure 8 shows the concentration-dependent cell growth inhibitory activity of KMU84, KMU98, KMU110, and KMU101, which was examined using L1 cells. All compounds examined, except KMU101, showed cell growth inhibitory activity 1.8 to 15 times higher than when SR33805 was used.
  • FIG. 9A shows the results of immunostaining with anti-MCOLN3 antibody
  • Figure 9B shows the results of immunostaining of an antibody absorption test in which an antigen peptide was reacted with anti-MCOLN3 antibody.
  • a positive signal was detected in Figure 9A.
  • the positive signal in Figure 9A was considered to be a signal specific to mucolipin.
  • immunostaining with anti-MCOLN1 antibody showed the same results.
  • mucolipin blockers also have an inhibitory effect on cell proliferation in lung cancer stem cells.
  • FIG. 10 shows the LC-MS results of the synthesized KMU110.
  • Figure 11 shows the 1H -NMR results of the synthesized KMU110.
  • the results of LC-MS and 1H -NMR of the synthesized KMU84 are shown in Figure 12 and Figure 13, respectively.
  • the results of LC-MS and 1H -NMR of the synthesized KMU98 are shown in Figure 14 and Figure 15, respectively.
  • the results of LC-MS and 1H -NMR of the synthesized KMU101 are shown in Figure 16 and Figure 17, respectively.
  • the results of LC-MS and 1H -NMR of the synthesized KMU111 are shown in Figure 18 and Figure 19, respectively.
  • the results of LC-MS and 1H -NMR of the synthesized KMU112 are shown in Figure 20 and Figure 21, respectively.

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Abstract

La présente invention aborde le problème de la fourniture d'un composé azoté efficace pour inhiber la prolifération des cellules souches cancéreuses.　La solution selon l'invention porte sur un composé azoté représenté par la formule générale (I), ou un sel pharmaceutiquement acceptable de celui-ci : [Formule chimique 1] (ici, m et n sont identiques ou différents et représentent un nombre entier de 1 à 3. R1 et R2 sont identiques ou différents et représentent un atome d'hydrogène, un groupe alkyle linéaire ou ramifié en C1-6 ayant éventuellement un atome d'halogène en tant que substituant, un groupe alcoxy linéaire ou ramifié en C1-6, un atome d'halogène, un groupe amino, un groupe hydroxyle, un groupe nitro, un groupe carboxy ou un groupe cyano. R3 représente un groupe alkyle linéaire ou ramifié en C1-6 ayant éventuellement un atome d'halogène en tant que substituant. X1, X2 et X3 représentent un atome de carbone ou un atome d'azote, et un ou deux parmi X1, X2 et X3 sont des atomes d'azote. X4 représente un atome de carbone ou un atome d'azote. Cependant, à l'exclusion (i) de la situation dans laquelle X1 et X4 sont tous les deux des atomes d'azote et X2 et X3 sont tous les deux des atomes de carbone et (ii) la situation dans laquelle X3 et X4 sont tous les deux des atomes d'azote et X1 et X2 sont tous les deux des atomes de carbone.).
PCT/JP2023/036077 2022-10-05 2023-10-03 Composé azoté, composition comprenant ledit composé azoté et marqueur pour la prédiction du degré d'une tumeur Ceased WO2024075736A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090285772A1 (en) * 2007-10-12 2009-11-19 Supergen, Inc. Quinoline derivatives for modulating dna methylation
JP2017510291A (ja) * 2014-02-10 2017-04-13 アンスティテュ・キュリＩｎｓｔｉｔｕｔ Ｃｕｒｉｅ 細胞遊走を調節するためのＭｃｏｌｎ−１モジュレータの使用
WO2022210524A1 (fr) * 2021-03-29 2022-10-06 学校法人関西医科大学 Composé contenant de l'azote, composition comprenant ledit composé contenant de l'azote et marqueur pour la prédiction du degré d'une tumeur

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US20090285772A1 (en) * 2007-10-12 2009-11-19 Supergen, Inc. Quinoline derivatives for modulating dna methylation
JP2017510291A (ja) * 2014-02-10 2017-04-13 アンスティテュ・キュリＩｎｓｔｉｔｕｔ Ｃｕｒｉｅ 細胞遊走を調節するためのＭｃｏｌｎ−１モジュレータの使用
WO2022210524A1 (fr) * 2021-03-29 2022-10-06 学校法人関西医科大学 Composé contenant de l'azote, composition comprenant ledit composé contenant de l'azote et marqueur pour la prédiction du degré d'une tumeur

Non-Patent Citations (1)

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Title
MIN ZHANG, ZHEN WANG, YONGQIANG ZHANG, WENXING GUO, HAITAO JI: "Structure-Based Optimization of Small-Molecule Inhibitors for the β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 61, no. 7, 12 April 2018 (2018-04-12), US , pages 2989 - 3007, XP055617676, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b00068 *

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