WO2023195803A1 - Composition pharmaceutique pour prévenir ou traiter le cancer de la tête et du cou associé à une mutation ron - Google Patents

Composition pharmaceutique pour prévenir ou traiter le cancer de la tête et du cou associé à une mutation ron Download PDF

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WO2023195803A1
WO2023195803A1 PCT/KR2023/004675 KR2023004675W WO2023195803A1 WO 2023195803 A1 WO2023195803 A1 WO 2023195803A1 KR 2023004675 W KR2023004675 W KR 2023004675W WO 2023195803 A1 WO2023195803 A1 WO 2023195803A1
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alkyl
ron
oxo
oxy
carboxamide
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이하늘
김민화
고은희
류현
신지민
고지현
배승건
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웰마커바이오 주식회사
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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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating head and neck cancer associated with RON mutations and a method for preventing or treating head and neck cancer using the same.
  • Head and neck cancer is known to be the 6th most common cancer among all cancers, occurring in approximately 600,000 people worldwide every year.
  • the head and neck region refers to the area between the lower part of the brain and the upper part of the chest.
  • the head and neck region contains organs such as the nasal cavity, tongue, mouth, larynx, and salivary glands that perform functions such as eating and vocalization. Cancers that occur in these organs are collectively referred to as head and neck cancer.
  • Cetuximab is a therapeutic agent mainly used to treat head and neck cancer, and is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). EGFR is overexpressed in cancer cells, and the antibody inhibits the proliferation of cancer cells by specifically binding to EGFR.
  • EGFR epidermal growth factor receptor
  • RON Recepteur d'origine nantais
  • RON Recepteur d'origine nantais
  • the activity of RON plays an important role in tumor development, progression, and metastasis. It has been reported that overexpression or overactivity of RON contributes to inducing tumor invasion and metastasis and inhibiting apoptosis. Substances that can specifically inhibit the abnormal activity of RON can effectively treat various diseases related to RON, especially tumors such as head and neck cancer.
  • RON Recepteur d'origine nantais
  • MSP Macrophage-stimulating protein
  • Non-patent Document 1 Zhou YQ et al., Oncogene 2003, 22(2): 186-197
  • the object of the present invention is to provide a pharmaceutical composition for preventing or treating head and neck cancer containing a compound capable of preventing or treating head and neck cancer containing an RON mutation, or a pharmaceutically acceptable salt thereof as an active ingredient, and prevention of head and neck cancer using the same. Or the purpose is to provide a treatment method.
  • the present invention provides a pharmaceutical composition for preventing or treating head and neck cancer, comprising the compound represented by Formula 1 or Formula 6 of the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the present invention provides a step of detecting a mutation in RON in a biological sample derived from an individual suffering from head and neck cancer, wherein the RON mutation is RON ⁇ 155 with deletion of exons 5, 6, and 11. , RON ⁇ 160 with deletion of exons 5 and 6 or RON ⁇ 165 with deletion of exon 11; and administering the pharmaceutical composition of the present invention to an individual in whom a mutation in RON has been detected.
  • the present invention is a step of identifying a mutation in RON in a biological sample derived from an individual with head and neck cancer, wherein the RON mutation is RON ⁇ 155 with deletion of exons 5, 6, and 11, RON ⁇ 160 with deletion of exons 5 and 6 or RON ⁇ 165 with deletion of exon 11; and providing information that the pharmaceutical composition of the present invention is suitable for the prevention or treatment of head and neck cancer to an individual in whom the RON mutation has been detected.
  • the present invention provides the use of the pharmaceutical composition for preventing or treating head and neck cancer.
  • the pharmaceutical composition for preventing or treating cancer according to the present invention is applicable to head and neck cancer patients with RON mutations.
  • the pharmaceutical composition is resistant to cetuximab, which is used in conventional anticancer treatment, and can be useful in the treatment of head and neck cancer patients with mutations in RON ⁇ 155, RON ⁇ 160, or RON ⁇ 165.
  • Figure 1 shows the cell death rate after treatment with RON siRNA in the CAL27 cell line, a mutant RON ⁇ 155 type head and neck cancer cell line, and the FaDu cell line, a mutant RON ⁇ 165 type head and neck cancer cell line, and that this cell death is caspase-dependent. It shows that it is induced by apoptosis, which occurs.
  • Figure 2 shows the cell proliferation inhibition effect according to RON genotype after treating four types of head and neck cancer cell lines with the compounds of Examples 1 to 5 and the positive control group.
  • Figure 3 shows the apoptosis efficacy according to RON genotype after treating four types of head and neck cancer cell lines with the compounds of Examples 1 to 5 and the positive control group.
  • Figure 4 shows tumor growth after administering the compound of Example 1 at a dose of 3 mg/kg, 10 mg/kg, or 30 mg/kg in a mouse model transplanted with the FaDu cell line, a human-derived head and neck cancer cell line of the mutant RON ⁇ 165 type. The growth rate was confirmed.
  • Figure 5 shows tumor tissue after administering the compound of Example 1 at a dose of 3 mg/kg, 10 mg/kg, or 30 mg/kg to mice transplanted with the FaDu cell line, a human-derived head and neck cancer cell line of the mutant RON ⁇ 165 type. It was immunochemically stained.
  • Figure 6 shows the tumor growth rate after administration of the compound of Example 1 at a dose of 10 mg/kg, 30 mg/kg, or 50 mg/kg in a transplant animal model derived from a patient with mutant RON ⁇ 165 type head and neck cancer.
  • Figure 7 shows analysis of RON mutation sequences in head and neck cancer cell lines.
  • One aspect of the present invention provides a pharmaceutical composition for preventing or treating head and neck cancer, comprising a compound represented by Formula 1 or Formula 6, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the compound of Formula 1 used in the present invention is represented as follows.
  • R 1 and R 2 are each independently H, halogen, C 1-10 alkoxy, or haloC 1-10 alkyl;
  • R 3 and R 4 are each independently H, halogen, C 1-10 alkyl, or C 1-10 alkoxy;
  • R 5 is H, halogen, or C 1-10 alkyl
  • R 6 and R 7 together with the N atom to which they are attached form a 4- to 10-membered heterocycle, or R 6 is -C 2 H 4 -O-CH 3 and R 7 is H, methyl or t-part. It is toxycarbonyl;
  • the heterocycle may or may not have 1 or 2 heteroatoms selected from the group consisting of N, O, and S, and the heterocycle may contain halogen and C 1-6 It is substituted or unsubstituted with one or more selected from alkyl.
  • the C 1-10 alkyl may include C 1-6 alkyl, C 1-3 alkyl, C 3-10 alkyl, C 3-6 alkyl, C 6-10 alkyl, etc.
  • the C 1-10 alkoxy may include C 1-6 alkoxy, C 1-3 alkoxy, C 3-10 alkoxy, C 3-6 alkoxy, C 6-10 alkoxy, etc.
  • the 4 to 10 membered heterocycle may include a 4 to 7 membered heterocycle, a 4 to 6 membered heterocycle, a 5 to 7 membered heterocycle, a 5 or 6 membered heterocycle, etc.
  • R 1 and R 2 may each independently be H, halogen, methoxy, or -CF 3 .
  • the halogen may be F, Cl, Br or I.
  • R 3 and R 4 may each independently be H, halogen, methyl, methoxy, or ethoxy.
  • the halogen may be F, Cl, Br or I.
  • R 4 may be halogen, methyl, methoxy, or ethoxy.
  • the halogen may be F, Cl, Br or I.
  • R 5 may be H or halogen.
  • the halogen may be F, Cl, Br or I.
  • R 6 and R 7 together with the N atom to which they are bonded forming; where R a and R b are each independently C 1-3 alkylene; A is -N(-R 9 )- or -O-, and R 9 may be C 1-6 alkyl.
  • R 6 and R 7 together with the N atom to which they are bonded are azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolyl, oxazoli Dinyl, oxazolyl, isoxazolidinyl, isoxazolyl, thiazolidinyl, thiazolyl, isothiazolidinyl, isothiazolyl, piperidinyl, pyridinyl, piperazinyl, diazinyl, morpholino, thiomo It may form polyno, azepanyl, diazepanyl, or a heterocycle group substituted with C 1-6 alkyl.
  • R a and R b may each independently be -CH 2 -, -C 2 H 4 -, or -C 3 H 6 -.
  • R 9 may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc. there is.
  • R 1 and R 2 are each independently H, halogen, methoxy, or -CF 3 ;
  • R 3 and R 4 are each independently H, halogen, methyl, methoxy, or ethoxy;
  • R 5 is H or halogen;
  • R 6 is -C 2 H 4 -O-CH 3 and
  • R 7 is H, methyl or t-butoxycarbonyl, or R 6 and R 7 are combined with each other to form morpholino or methylpiperazinyl.
  • the halogen may be F, Cl, Br or I.
  • the compound of Formula 1 may be represented by the following Formula 2:
  • R 1 to R 7 are as defined in Formula 1.
  • R 1 and R 2 may each independently be H, halogen, or -CF 3 .
  • R 3 and R 4 may each independently be H, halogen, methyl, methoxy, or ethoxy, where R 3 and R 4 are not H at the same time.
  • R 5 may be H or halogen.
  • R 1 and R 2 are each independently H, halogen, or -CF 3 ;
  • R 3 and R 4 are each independently H, halogen, methyl, methoxy, or ethoxy;
  • R 5 is H or halogen;
  • R 6 is -C 2 H 4 -O-CH 3 and
  • R 7 may be H, methyl or t-butoxycarbonyl.
  • the compound of Formula 1 may be represented by the following Formula 3:
  • R 1 to R 7 are as defined in Formula 1.
  • R 1 and R 2 may each independently be H, halogen, or -CF 3 .
  • R 4 may be halogen, methyl, methoxy, or ethoxy.
  • R 5 may be H or halogen.
  • R 1 and R 2 are each independently H, halogen, or -CF 3 ;
  • R 4 is halogen, methyl, methoxy, or ethoxy;
  • R 5 is H or halogen;
  • R 6 is -C 2 H 4 -O-CH 3 ;
  • R 7 may be H, methyl or t-butoxycarbonyl.
  • the compound of Formula 1 may be represented by the following Formula 4:
  • R 1 to R 5 are as defined in Formula 1; R a and R b are each independently C 1-3 alkylene; A is -N(-R 9 )- or -O-, and R 9 may be C 1-6 alkyl.
  • R 1 and R 2 may each independently be H, halogen, or -CF 3 .
  • R 3 and R 4 may each independently be H, halogen, methyl, methoxy, or ethoxy, where R 3 and R 4 are not H at the same time.
  • R 5 may be H or halogen.
  • R a and R b together with N and A to which they are attached may form morpholino or methylpiperazinyl.
  • the compound of Formula 1 may be represented by Formula 5 below.
  • R 1 to R 5 are as defined in Formula 1; R a and R b are each independently C 1-3 alkylene; A is -N(-R 9 )- or -O-, and R 9 may be C 1-6 alkyl.
  • R 1 and R 2 may each independently be H, halogen, or -CF 3 .
  • R 4 may be halogen, methyl, methoxy, or ethoxy.
  • R 5 may be H or halogen.
  • R a and R b together with N and A to which they are attached may form morpholino or methylpiperazinyl.
  • the compound represented by Formula 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of Formula 1 used in the composition according to the present invention can be prepared by the method disclosed in Republic of Korea Patent No. 10-2221689, and can be prepared by other known methods and/or various methods based on technology in the field of organic synthesis. It can be manufactured by. Based on the above methods, various derivatives can be synthesized using an appropriate synthesis method depending on the type of substituent.
  • L is -NH- or -CH 2 -
  • R 1 to R 4 are each independently hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkyl Nyl, C 3-7 cycloalkyl, C 6-10 aryl, 5- to 9-membered heteroaryl, or 3- to 9-membered heterocycloalkyl,
  • X is O, S, -CH(-Rx)- or -N(-Rx)-,
  • Rx is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 3- to 9-membered heterocycloalkyl,
  • R 5 and R 6 are each independently hydrogen, amino, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino-C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylamino, or C 1-6 alkyl -amino-C 1-6 alkoxy,
  • R 5 and R 6 are each independently substituted or unsubstituted with 3- to 9-membered cycloalkyl or 3- to 9-membered heterocycloalkyl,
  • the cycloalkyl or heterocycloalkyl is halogen, oxo, cyano, hydroxy, hydroxy-C 1-6 alkyl, amino, diC 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and With or without one or more substituents selected from the group consisting of C 1-6 alkoxy-C 1-6 alkyl,
  • the heterocycloalkyl contains 1 to 4 heteroatoms selected from the group consisting of N, O and S.
  • the C 1-6 alkyl may include C 1-3 alkyl, C 3-6 alkyl, etc. Additionally, the C 1-6 alkoxy may include C 1-3 alkoxy, C 3-6 alkoxy, etc.
  • R 1 to R 4 may each independently be hydrogen, C 1-4 haloalkyl, or halogen.
  • the halogen may be F, Cl, Br or I.
  • R 1 may be hydrogen, trifluoromethyl, or fluoro
  • R 2 may be hydrogen
  • R 3 may be fluoro
  • R 4 may be hydrogen.
  • X may be O or -CH(-Rx)-, and Rx may be hydrogen or C 1-6 alkyl.
  • R 5 and R 6 are each independently hydrogen, amino, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino -C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylamino, C 1-6 alkyl-amino-C 1-6 alkoxy, or 5- to 9-membered heteroaryl, where R 5 and R 6 are each independently C 1-6 alkyl; C 1-6 alkoxy-C 1-6 alkyl-amino, C 1-6 alkyl substituted with any of 3-9 membered cycloalkyl and 3-9 membered heterocycloalkyl or C 1-6 alkyl-amino -C 1-6 alkyl; 3- to 9-membered cycloalkyl; or substituted or unsubstituted
  • the heteroaryl is pyridinyl, imidazolyl, or pyrazolyl
  • the heterocycloalkyl is azetidinyl, pyrrolidinyl, tetrahydropyranyl, morpholino, morpholinyl, and dioxidothiomopoly. or, piperazinyl, piperidinyl, or oxetanyl
  • the cycloalkyl may be cyclobutyl, cyclopentyl, or cyclohexyl.
  • heteroaryl or heterocycloalkyl contains one or more N atoms
  • any one of them may be substituted at the N atom position, but is not particularly limited.
  • R 1 and R 2 are hydrogen, C 1-4 haloalkyl, or halogen
  • R 3 and R 4 are hydrogen or halogen
  • X is O or -CH(- Rx) -
  • Rx is hydrogen or C 1-4 alkyl
  • A is quinoline, quinazoline, pyridine, pyrimidine, thienopyridine, pyrrolopyridine, pyrazolopyridine, imidazopyridine, pyrrolopyrimidine, di hydropyrrolopyrimidine, furopyridine, pyrazolopyrimidine, purine or indazole
  • R 5 and R 6 are each independently hydrogen, amino, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino-C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylamino, C 1-6 alky
  • R 5 and R 6 are each independently hydrogen, nitro, amino, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, amino-C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylamino , C 1-6 alkyl-amino-C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 5- to 9-membered heteroaryl, and the amino, the alkyl,
  • the alkoxy, the aryl, and the heteroaryl are each independently C 1-6 alkyl; C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkyl substituted with any of 3-9 membered cycloalkyl and 3-9 membered heterocycloalkyl
  • R 5 and R 6 may not simultaneously be C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 5- to 9-membered heteroaryl. .
  • R 5 and R 6 are simultaneously C 1-6 alkyl or C 1 substituted with any one of 3- to 9-membered cycloalkyl and 3- to 9-membered heterocycloalkyl.
  • R 6 when R 5 includes rings such as aryl, heteroaryl, etc., R 6 may not include these rings at the same time. Additionally, when R 5 is substituted with a group containing rings such as cycloalkyl or heterocycloalkyl, R 6 may not be simultaneously substituted with a group containing these rings.
  • R 5 is C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, or 5- to 9-membered heteroaryl
  • R 6 is hydrogen, nitro, amino, halogen, hydroxy. , cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino-C 1-6 alkoxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, diC 1-6 alkyl It may be aminocarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylamino, or C 1-6 alkyl-amino-C 1-6 alkoxy.
  • R 5 is C 1-6 alkyl; or C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 alkyl substituted with any of 3-9 membered cycloalkyl and 3-9 membered heterocycloalkyl or C 1-6 alkylamino- It may or may not be substituted with C 1-6 alkyl. Additionally, R 6 may or may not be substituted with 3- to 9-membered cycloalkyl or 3- to 9-membered heterocycloalkyl.
  • the cycloalkyl or heterocycloalkyl is halogen, oxo, cyano, hydroxy, hydroxy-C 1-6 alkyl, amino, diC 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxy-C 1-6 alkyl, wherein the heteroaryl and heterocycloalkyl are each independently selected from the group consisting of N, O and S. It may contain one or more heteroatoms.
  • the compound represented by Formula 6 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of Formula 6 can be prepared by the method shown in the reaction formulas below, but is not limited to being produced by this method.
  • the compound of Formula 6 of the present invention can be prepared by various methods using well-known techniques in the art.
  • reaction equation shows the preparation method of the compound of Formula 6 in each manufacturing step, and various compounds of Formula 6 may be prepared by changing the reagents and solvents used in the following preparation steps or changing the reaction order.
  • the compound of Formula 6 can be prepared according to the procedures in Schemes 1 and 2 below.
  • R 1 , R 2 , and X are as defined in Formula 6 above.
  • carboxylic acid compound (6a) is prepared using lactone-based compound (2) as a starting material, which can be easily obtained commercially or prepared by a known method.
  • Step 1 the compound of formula (3) is prepared by formylation of compound (2), which can be easily commercially obtained, using dimethyldimethoxyacetal.
  • the reaction can be performed at high temperature, but it has the disadvantage of requiring a long reaction time, so the reaction is performed using a microwave reactor.
  • step 2 compound (4) is prepared using the lactone compound (3) formalized in step 1 and triethyloxonium tetrafluoroborate, which can be easily obtained commercially.
  • This reaction is performed under anhydrous conditions and is preferably performed using a solvent such as N,N-dichloromethane or chloroform that does not adversely affect the reaction.
  • the reaction temperature is generally carried out at room temperature.
  • step 3 compound (4) prepared in step 2 is reacted with ethyl-3-amino-3-oxopropionate compound prepared by a known method in the presence of sodium ethoxide to perform cyclization.
  • Compound (5) is prepared. This reaction is preferably carried out using an ethanol solvent that does not adversely affect the reaction.
  • the reaction temperature is not particularly limited, but generally the reaction can be performed under cold to warm temperatures, and is preferably performed at room temperature.
  • a lactone-based compound (2) which can be easily obtained commercially, is used as a starting material in the presence of titanium tetrachloride and pyridine according to a known method.
  • Compound (6) can be prepared by reacting with the ethyl-3-amino-3-oxopropionate compound prepared by. This reaction is preferably carried out using dichloromethane, which does not adversely affect the reaction.
  • the reaction temperature is not particularly limited, but generally the reaction can be carried out at cold to room temperature, and is preferably started at cold temperature. Perform at room temperature.
  • step 5 compound (5) is prepared by formylation and circularization of compound (6) prepared in step 4 using dimethyldimethoxyacetal.
  • the reaction can be performed under elevated and high temperatures, but is preferably performed under elevated temperatures.
  • the carboxylic acid compound (6a) is prepared through a hydrolysis reaction of the circularized compound (5) prepared in Steps 3 and 5 above.
  • the hydrolysis reaction is performed using a basic aqueous solution such as an aqueous sodium hydroxide solution or an aqueous lithium hydroxide solution.
  • This reaction is performed using solvents such as ethanol, methanol, tetrahydrofuran, etc., which do not adversely affect the reaction, in the presence of an aqueous lithium hydroxide solution that can be used in the hydrolysis reaction.
  • the reaction temperature is not particularly limited, and in general, the reaction can be performed at room temperature or at elevated temperature, but is preferably performed at elevated temperature to prepare carboxylic acid compound (6a).
  • R 1 to R 6 , X and Y are as defined in Formula 6, and W is a leaving group.
  • the above Scheme 2 specifically shows each step for preparing the target compound (10) of the present invention, and the compound (10) illustrates the case where L is -NH- in the above formula (6).
  • step 1 a monocyclic or bicyclic compound (7), which can be easily obtained commercially or prepared by a known method, is reacted with a nitrophenol compound, which can be easily obtained commercially, in the presence of a base such as potassium carbonate to produce phenoxy.
  • Compound (8) is prepared.
  • This reaction is generally an ether formation reaction of a phenol compound and is carried out in the presence of a base that can be used in the ether formation reaction.
  • bases that can be used for this purpose include sodium hydrate (NaH), potassium carbonate, sodium carbonate, cesium carbonate, sodium or potassium alkoxide.
  • the reaction is preferably carried out in the presence of a solvent that does not adversely affect the reaction, such as dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide, acetonitrile, or diphenyl.
  • a solvent such as ether.
  • the reaction temperature is not particularly limited, but generally, the reaction can be performed at room temperature to elevated temperature, and is preferably performed under elevated temperature.
  • Step 2 the nitrophenol compound (8) prepared in Step 1 is reduced in the presence of iron and ammonium chloride to prepare the amine compound (9).
  • This reaction is generally a reduction reaction of a nitro compound to an amine and can be carried out using various reducing agents such as hydrogen, iron, tin ( ⁇ chloride, zinc, etc.).
  • the reaction is preferably a reaction.
  • Solvents that do not adversely affect the reaction such as dichloromethane, ethyl acetate, methanol, ethanol, tetrahydrofuran, or N,N-dimethylformamide, are used, and depending on the reaction, water is used as a co-solvent to perform the reaction.
  • the temperature is not particularly limited, but generally the reaction can be carried out at room temperature or at elevated temperature, and is preferably carried out at elevated temperature.
  • Step 3 a general amidation reaction is performed in which the amine compound (9) prepared in Step 2 and the carboxylic acid compound (6a) prepared in Scheme 1 are reacted using a coupling reagent.
  • a coupling reagent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1,3-dicyclohexyl carboimide (DCC), and 1,1, which are readily available commercially.
  • the target compounds produced in the above reaction scheme can be separated and purified using conventional methods, such as column chromatography and recrystallization.
  • halogen means F, Cl, Br or I unless otherwise specified.
  • alkyl refers to a linear or branched, saturated hydrocarbon moiety.
  • C 1-10 alkyl means alkyl with a skeleton of 1 to 10 carbons. Specifically, C 1-10 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl. , hexyl, heptyl, octyl, nonyl, decyl, etc.
  • haloalkyl means alkyl substituted with one or more halogens. Specifically, haloalkyl may be an alkyl substituted with two or more halogens of the same type or with two or more types of halogens substituted.
  • alkoxy refers to a group having the formula -O-alkyl, wherein an alkyl group as previously defined is attached to the parent compound through an oxygen atom.
  • the alkyl portion of the alkoxy group may have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e., C 1 -C 12 alkoxy), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkoxy).
  • alkoxy groups examples include methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), t-butoxy (-OC(CH 3 ) 3 or -O-tBu). etc.
  • aryl refers to an aromatic hydrocarbon radical derived by removing one hydrogen atom from the carbon atom constituting the parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
  • cycloalkyl refers to a saturated monocycle or polycycle containing only carbon atoms in the ring. Cycloalkyls can have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • heteroaryl refers to an aromatic heterocyclyl having one or more heteroatoms in the ring.
  • Non-limiting examples of heteroaryls include pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, and thia.
  • heterocycle refers to an oriented or non-oriented ring having one or more heteroatoms, which may be saturated or unsaturated, and which may be monocyclic or polycyclic.
  • heterocycle means a heterocycle whose skeleton consists of a total of 4 to 10 atoms, including heteroatoms and carbon atoms.
  • the 4- to 10-membered heterocycle is azetidine, diazetidine, pyrrolidine, pyrrole, imidazolidine, imidazole, pyrazolidine, pyrazole, oxazolidine, oxazole, isoxazolidine, It may include isoxazole, thiazolidine, thiazole, isothiazolidine, isothiazole, piperidine, pyridine, piperazine, diazine, morpholine, thiomorpholine, azepane, diazepane, etc.
  • heterocycloalkyl refers to a non-aromatic heterocyclyl having one or more heteroatoms in the ring. Heterocycloalkyl may have one or more carbon-carbon double bonds or carbon-hetero atom double bonds in the ring to the extent that the ring does not have aromaticity due to the presence of the double bond.
  • Non-limiting examples of heterocycloalkyl include azetidinyl, aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholino, thiomorpholino, tetrahydrofuranyl, tetrahydrothio. furanyl, tetrahydropyranyl, pyranyl (which may have one or more substituents on the ring), etc.
  • heteroatom refers to an atom other than carbon (C), and may specifically be a nitrogen (N), oxygen (O), or sulfur (S) atom.
  • the heteroaryl and heterocycloalkyl mentioned above contain one or more heteroatoms, for example, may contain 1, 1 to 2, 1 to 3, or 1 to 4 heteroatoms.
  • substitution refers to the replacement of a hydrogen atom in a molecular structure with a substituent such that a chemically stable compound results from such substitution without exceeding the valence on the designated atom.
  • group A is substituted by substituent B” or “group A has substituent B” means that the hydrogen atom bonded to an atom such as carbon constituting the skeleton of group A is replaced by substituent B, thereby forming a group. It may mean that A and substituent B form a covalent bond.
  • the term “head and neck” refers to the area between the lower part of the brain and the upper part of the chest, and the head and neck region contains organs that function such as eating food or making a voice, such as the nasal cavity, tongue, mouth, larynx, and salivary glands.
  • head and neck cancer refers to cancer that occurs in organs located in the head and neck.
  • Head and neck cancer may be, for example, any one cancer selected from the group consisting of nasal cavity cancer, paranasal sinus cancer, oral cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, cervical esophagus cancer, salivary gland cancer, and tongue cancer.
  • the head and neck cancer may have a RON (Recepteur d'origine nantais) mutation.
  • the head and neck cancer may be resistant to EGFR-targeted treatments.
  • the EGFR-targeted therapeutic agents include Cetuximab, Gefitinib, Erlotinib, Apatinib, Icotinib, Brigatinib, Lapatinib, It may be one or more selected from the group consisting of Canertinib, AEE788, XL647, Zactima, and Panitumumab.
  • RON Recepteur d'origine nantais
  • MST1R Macrophage stimulating 1 receptor
  • RON is a protein receptor belonging to the c-MET family, and is a receptor for serum protein (Macrophage-stimulating protein (MSP)) that is secreted by the liver and regulates the actions of macrophages.
  • MSP Macrophage-stimulating protein
  • Ligand binding at the cell surface induces phosphorylation of RON in the intracellular domain, providing a docking site for downstream signaling molecules.
  • Signals from RON activate the wound healing response by promoting epithelial cell migration, proliferation, and survival at the wound site.
  • RON plays a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Additionally, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligands. RON is mainly expressed in epithelial cells such as liver, lung, intestine, kidney, brain, bone, adrenal gland, and skin.
  • Mutated forms of RON can be found in various solid cancers, such as head and neck cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, and colon cancer.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • pancreatic cancer pancreatic cancer
  • colon cancer a solid cancer that is found in various solid cancers, such as head and neck cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), pancreatic cancer, and colon cancer.
  • the mutated RON may have the base sequence of SEQ ID NO: 1, 2, or 3.
  • MST1R gene is a tyrosine kinase receptor that transmits a signal to the cytoplasm by binding to the MST1 ligand. Regulates various physiological processes including cell survival, migration and differentiation.
  • RON mutation refers to RON ⁇ 155 with a deletion of exons 5, 6, and 11, RON ⁇ 160 with a deletion of exons 5 and 6, or RON ⁇ 165 with a deletion of exon 11.
  • the cDNA of RON ⁇ 155 may have the base sequence of SEQ ID NO: 1
  • the cDNA of RON ⁇ 160 may have the base sequence of SEQ ID NO: 2
  • the cDNA of RON ⁇ 165 may have the base sequence of SEQ ID NO: 3.
  • the term “resistance” means that the drug does not respond sensitively to the drug in question and thus the drug is ineffective.
  • EGFR-targeted therapeutic agent refers to an anti-cancer agent that targets EGFR, and any EGFR-targeted therapeutic agent may be applied as long as it exhibits anti-cancer effects, preferably Cetuximab, Gefitinib, Erlotinib, or Panitumumab, and most preferably cetuximab.
  • the pharmaceutical composition of the present invention contains a pharmaceutically acceptable salt of the compound represented by Formula 1 or Formula 6 above as an active ingredient.
  • the term "pharmaceutically acceptable” means a substance that is not biological or otherwise undesirable, i.e., does not cause any undesirable biological effect or interact in a deleterious manner with any other ingredient of the pharmaceutical composition in which it is contained. refers to a substance that can be administered to a subject along with the composition.
  • the pharmaceutically acceptable salts should have low toxicity to humans and should not have any negative effect on the biological activity and physicochemical properties of the parent compound.
  • the pharmaceutically acceptable salt may be an acid addition salt formed with a pharmaceutically acceptable free acid.
  • the free acid may be an inorganic acid or an organic acid.
  • the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, etc.
  • the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene sulfuric acid, etc. It may be fonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc.
  • the acid addition salt is prepared by a conventional method, for example, by dissolving the compound of Formula 1 or Formula 6 in an excess of acid aqueous solution, and dissolving the salt in a water-miscible organic solvent, such as methanol, ethanol, acetone, or acetonitrile. It can be manufactured by precipitation.
  • a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. It can be manufactured by precipitation.
  • the pharmaceutically acceptable salt may be an alkali metal salt (sodium salt, etc.) or an alkaline earth metal salt (potassium salt, etc.).
  • the alkali metal salt or alkaline earth metal salt can be prepared by, for example, dissolving the compound of Formula 1 or Formula 6 in an excessive amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. You can get it.
  • the compounds of the present invention may have a chiral carbon center and therefore may exist as R or S isomers, racemic compounds, individual enantiomers or mixtures, individual diastereomers or mixtures, all of which are stereoisomers. and mixtures thereof may fall within the scope of the present invention.
  • the compounds of the present invention may include hydrates and solvates of the compounds of Formula 1 or Formula 6.
  • the hydrates and solvates can be prepared using known methods, and are preferably non-toxic and water-soluble.
  • the hydrate and solvate may be a combination of 1 to 5 molecules of water and an alcoholic solvent (particularly, ethanol, etc.), respectively.
  • the pharmaceutical composition of the present invention contains, as an active ingredient, a compound represented by Formula 1 or Formula 6, or a pharmaceutically acceptable salt thereof, in an amount of about 0.1% to about 90% by weight, specifically about 0.1% by weight, based on the total weight of the composition. It may contain from 0.5% by weight to about 75% by weight, more specifically from about 1% by weight to about 50% by weight.
  • the pharmaceutical composition of the present invention may contain conventional, non-toxic pharmaceutically acceptable additives that are blended into preparations according to conventional methods.
  • the pharmaceutical composition may further include a pharmaceutically acceptable carrier, diluent, or excipient.
  • additives used in the composition of the present invention include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, glidants, fillers, flavoring agents, etc. You can.
  • the additives include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, It may contain alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.
  • compositions of the present invention can be formulated in various formulation forms for oral administration (e.g., tablets, pills, powders, capsules, syrups, or emulsions) or parenteral administration (e.g., intramuscular, intravenous, or subcutaneous injection).
  • oral administration e.g., tablets, pills, powders, capsules, syrups, or emulsions
  • parenteral administration e.g., intramuscular, intravenous, or subcutaneous injection.
  • the composition of the present invention can be formulated into a formulation for oral administration, and additives used in this case include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, It may contain calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc.
  • examples of lubricants include colloidal silicon dioxide, magnesium silicate, etc.
  • examples of diluents include Microcrystalline Cellulose, Lactose Fast Flo (registered trademark) Lactose Anhydrous, Lactose Monohydrate, Silicified MCC HD 90, etc., and disintegrants.
  • (Disintegrant) include Croscarmellose Sodium, Crospovidone, etc.
  • lubricants include Magnesium Stearate, Sodium Lauryl Sulfate, and Stearic Acid.
  • liquid preparations for oral administration include suspensions, emulsions, syrups, etc., and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included.
  • preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • injectables may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, etc.
  • prevention refers to all actions that inhibit or delay the onset of head and neck cancer by administering the pharmaceutical composition.
  • treatment refers to any action that improves or beneficially changes the symptoms of head and neck cancer by administering the pharmaceutical composition.
  • the compound or composition of the present invention can be administered to a patient in a therapeutically effective amount or a pharmaceutically effective amount.
  • therapeutically effective amount refers to the amount of a compound or composition effective in preventing or treating the target disease, which is sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment. This refers to an amount that does not cause side effects.
  • the level of the effective amount is determined by factors including the patient's health status, type and severity of the disease, activity of the drug, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, combination or concurrent use of drugs, and It may be determined based on factors well known in the medical field.
  • the term "administration” means introducing a given drug into an individual by any suitable method, and the route of administration of the substance may be administered through any general route as long as the drug can reach the target tissue. there is.
  • the route of administration is intraperitoneal administration, intravenous administration, intramuscular administration, and subcutaneous administration. It may be intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, etc., but is not limited thereto.
  • the compound or composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Taking all of the above factors into consideration, it is important to administer an amount that can achieve maximum effect with minimal or no side effects, and this can be easily determined by a person skilled in the art.
  • the effective amount of the compound in the composition of the present invention may vary depending on the patient's age, gender, and weight, and is generally about 0.1 mg to about 1,000 mg, or about 5 mg to about 200 mg per kg of body weight daily. It can be administered every other day or divided into 1 to 3 doses per day. However, since it may increase or decrease depending on the route of administration, severity of disease, gender, weight, age, etc., the scope of the present invention is not limited thereto.
  • the compounds or compositions of the invention are administered for tumor therapy in combination with chemotherapy, radiation therapy, immunotherapy, hormonal therapy, bone marrow transplantation, stem cell replacement therapy, other biological treatments, surgical intervention, or combinations thereof. It can be.
  • the compounds or compositions of the present invention can be used as adjuvant therapy in conjunction with other long-term treatment strategies, or for tumor regression in critically ill patients or to maintain the patient's condition after chemotherapy.
  • the pharmaceutical composition of the present invention may further include one or more active ingredients, and the additional active ingredients include anti-proliferative compounds, such as aromatase inhibitors, anti-estrogens, topoisomerase I inhibitors, and topoisomerases.
  • anti-proliferative compounds such as aromatase inhibitors, anti-estrogens, topoisomerase I inhibitors, and topoisomerases.
  • Type II inhibitors microtubule-activating compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic, anti-metabolites, platinum-based Compounds, compounds targeting/reducing protein or lipid kinase activity, anti-angiogenic compounds, compounds targeting, reducing or inhibiting the activity of protein or lipid phosphatases, gonadorelin agonists, anti-androgens, methionine aminopeptidae Inhibitors, bisphosphonates, biological response modifiers, anti-proliferative antibodies, heparanase inhibitors, inhibitors of Ras oncogenic isoforms, telomerase inhibitors, proteasome inhibitors, compounds used in the treatment of hematological malignancies, Flt Compounds that target, reduce or inhibit the activity of -3, Hsp90 inhibitors, kinesin spindle protein inhibitors, MEK inhibitors,
  • the additional active ingredient may be a known anticancer agent.
  • the anticancer agents include DNA alkylating agents such as Mechloethamine, Chlorambucil, Phenylalanine, Mustard, Cyclophosphamide, and Ipoh. Ifosfamide, Carmustine (BCNU), Lomustine (CCNU), Streptozotocin, Busulfan, Thiotepa, Cisplatin, and Carboplatin (Carboplatin);
  • Anti-cancer antibiotics include Dactinomycin (actinomycin D), Doxorubicin (adriamycin), Daunorubicin, Idarubicin, Mitoxantrone, and Plicama. Plicamycin, Mitomycin C, and Bleomycin; and plant alkaloids such as Vincristine, Vinblastine, Paclitaxel, Docetaxel, Etoposide, Teniposide, and Topotecan. and Irinotecan.
  • the EGFR-targeted therapeutic agents include Cetuximab, Gefitinib, Erlotinib, Apatinib, Icotinib, Brigatinib, and Lapatinib. ), Canertinib, AEE788, XL647, Zactima, or Panitumumab.
  • Another aspect of the present invention provides the use of a pharmaceutical composition for preventing and treating head and neck cancer, comprising a compound represented by Formula 1 or Formula 6, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is as described above.
  • Another aspect of the present invention is a step of detecting a mutation in RON in a biological sample derived from an individual with head and neck cancer, wherein the RON mutation is RON ⁇ 155, exon 5, with deletion of exons 5, 6, and 11. RON ⁇ 160 with deletion of exon 11 and 6, or RON ⁇ 165 with deletion of exon 11; and administering the pharmaceutical composition according to one aspect of the present invention to an individual in which a mutation in RON has been detected.
  • the RON, RON mutation, pharmaceutical composition, administration, prevention, and treatment are as described above.
  • the biological sample refers to a sample obtained from the individual.
  • the biological sample may be tissue, blood, plasma, serum, bone marrow fluid, lymph fluid, saliva, tear fluid, mucosal fluid, amniotic fluid, or a combination thereof.
  • the subject may be a mammal, such as a human, cow, horse, pig, dog, sheep, goat or cat.
  • the individual may be a patient suffering from a disease related to a mutation in the RON, for example, head and neck cancer, or may be an individual at a high risk of suffering from head and neck cancer.
  • the method may further include administering an anticancer agent to the subject.
  • the anticancer agent may be administered simultaneously, separately, or sequentially with the pharmaceutical composition.
  • the administration method may be oral or parenteral administration.
  • the method of administration may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal.
  • the composition can be administered systemically or topically, alone or in combination with other pharmaceutically active compounds.
  • the preferred dosage of the pharmaceutical composition varies depending on the patient's condition and weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art.
  • the dosage is, for example, in the range of about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg based on adults. It can be.
  • the administration may be administered once a day, multiple times a day, or once a week, once every two weeks, once every three weeks, or once every four weeks to once a year.
  • Another aspect of the present invention is a step of detecting a mutation in RON in a biological sample derived from an individual with head and neck cancer, wherein the RON mutation is RON ⁇ 155, exon 5, with deletion of exons 5, 6, and 11. RON ⁇ 160 with deletion of exon 11 and 6, or RON ⁇ 165 with deletion of exon 11; and providing information that the pharmaceutical composition according to one aspect of the present invention is suitable for the prevention or treatment of head and neck cancer to an individual in whom a mutation in the RON has been detected. .
  • suitable for anti-cancer treatment means available for anti-cancer treatment
  • providing information that it is suitable for anti-cancer treatment means capable of determining whether the drug can be selected as a drug available for anti-cancer treatment. It means providing information that is available.
  • the biological sample, RON, RON mutation, pharmaceutical composition, subject, prevention, and treatment are as described above.
  • Another aspect of the present invention relates to the use for preparing a medicament for preventing or treating head and neck cancer, comprising the compound represented by Formula 1 or Formula 6, or a pharmaceutically acceptable salt thereof.
  • Step 2 Synthesis of 3-((dimethylamino)methylene)-2-(3H)-dihydrofuranylidene ethyl oxonium tetrafluoroborate
  • step 1 The compound obtained in step 1 (1.085 g, 7.68 mmol) was dissolved in 8 ml of chloroform, triethyloxonium tetrafluoroborate (1.729 g, 7.68 mmol) was added, and the mixture was stirred under nitrogen at room temperature for more than 1 day.
  • the reaction mixture was concentrated under reduced pressure, and it was confirmed using nuclear magnetic resonance that the starting material and product material were produced in a ratio of about 15:85, and the next reaction was performed without purification.
  • Step 3 Synthesis of ethyl 5-(4-fluorophenyl)-6-oxo-2,3,5,6,-tetrahydrofuro[3,2-c]pyridine-7-carboxylate
  • Example 1 4-Ethoxy-N-[3-fluoro-4-( ⁇ 2-[5-(morpholinomethyl)pyridin-2-yl]thieno[3,2-b]pyridine-7 -yl ⁇ oxy)phenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride
  • the title compound was synthesized by the method described in Example 31 of Republic of Korea Patent No. 10-2221689.
  • the title compound was synthesized by the method described in Example 1 of Korean Patent No. 10-2221689.
  • the title compound was synthesized by the method described in Example 78 of Korean Patent Publication No. 10-2021-0015730.
  • the title compound was synthesized by the method described in Example 88 of Korean Patent Publication No. 10-2021-0015730.
  • N- ⁇ 4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl ⁇ - which is compound 1 disclosed in U.S. Patent No. 8,536,200 B2.
  • 4-Ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridinecarboxamide was used, which is a well-known RON inhibitor as BMS-777607.
  • mtRON in CAL27 and FaDu cell lines which are mtRON ⁇ 155 and mtRON ⁇ 165 type head and neck cancer cell lines
  • expression was suppressed using siRNA and then cell death was checked to determine whether cell death was induced.
  • mtRON ⁇ 155, mtRON ⁇ 165 type head and neck cancer cell lines CAL27 (DMEM, manufactured by welgene, cat no: LM001-05, medium composition: 10% FBS, 1% penicillin streptomycin), FaDu (MEM, manufactured by Company: welgene, cat no: LM007-07, medium composition: 10% FBS, 1% penicillin streptomycin) were counted and 1X10 5 cells each were seeded into a 60 mm Cell Culture Dish (SPL, cat no: 20060). It was stored in a 37°C, 5% CO 2 incubator.
  • -9121-010LB was diluted 20-fold with distilled water and washed once with high-pressure sterilization before use) and then treated with 1 ml of 0.05% trypsin-EDTA (Welgene, cat no: LS015-09). Afterwards, all cells were collected, centrifuged at 1500 rpm for 5 minutes, the supernatant was removed, and the cells were resuspended in 1X PBS and stained with trypan blue solution (Gibco, cat no: 15250061). did. Stained cells were counted using a hemocytometer, and cell counting was performed in duplicate to calculate the average and standard deviation.
  • proteins were separated through SDS-PAGE, transferred to membrane Immobilion-PVDF (EMD Millipore, Billerica, MA, USA), and then incubated with various antibodies (anti-RON (Santa Cruz), anti-actin ( Santa Cruz) and anti-cleaved caspase 3 (Cell signaling, Beverly, CA, USA) were used to perform the experiment.
  • membrane Immobilion-PVDF EMD Millipore, Billerica, MA, USA
  • Cal-27 (DMEM, manufacturer: welgene, cat no: LM001-05, medium composition: 10% FBS, 1% penicillin streptomycin), a head and neck cancer cell line of the mtRON ⁇ 155 type, and FaDu, a head and neck cancer cell line of the mtRON ⁇ 165 type.
  • MEM manufacturer: welgene, cat no: LM007-07, medium composition: 10% FBS, 1% penicillin streptomycin
  • YD-10B, YD-15 RPMI, manufacturer: welgene, cat no: LM011-01, medium Composition: 10% FBS, 1% penicillin streptomycin
  • SPL 96-well plate
  • DMSO dimethyl sulfoxide
  • Count Cal-27 a mtRON ⁇ 155 type head and neck cancer cell line, and FaDu, YD-10B, and YD-15, a mtRON ⁇ 165 type head and neck cancer cell line, and inoculate 1 ⁇ 2X10 5 cells each in a 60 mm cell culture dish. (seeding), and 24 hours later, the compounds of Examples 1 to 5 and the positive control group (BMS-777607) were treated at 5 ⁇ M each. After 48 or 72 hours, all medium was transferred to a 15 ml cornical tube, washed once with 1X PBS, treated with trypsin (tyrpsin-EDTA), and all cells were collected. A 15 ml cornical tube was centrifuged at 1500 rpm for 4 minutes and the supernatant was removed. The total cell number was determined by counting each sample twice using a hemocytometer using trypan blue dye.
  • the compound of Example 1 was administered at doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg to a mouse model transplanted with FaDu, a mutant RON ⁇ 165 type head and neck cancer cell line, to determine whether tumor growth was inhibited.
  • mice 5-week-old female BALB/c-nude mice were purchased, acclimatized for 1 week , and human-derived head and neck cancer cell line FaDu (2.5 ) was injected.
  • FaDu human-derived head and neck cancer cell line
  • the tumor size reached about 100 mm 3
  • the negative control group and the compound of Example 1 were orally administered at a concentration of 3, 10, or 30 mg/kg.
  • Administration was conducted once a day for 4 weeks, and tumor size and body weight were measured twice a week.
  • tumors were extracted and changes in protein expression were analyzed through immunochemical staining.
  • paraffin slides were prepared using the isolated tumor tissue.
  • the procedure was performed twice for 5 minutes each using Histo-clear (cat # HS-200), and the antigen recovery process was performed by soaking in citrate buffer (pH6.0) (Cat # CBB999) and heating for 15 minutes. .
  • citrate buffer pH6.0
  • Cat # CBB999 citrate buffer
  • a blocking process was performed using Animal-Free Blocker ® and Diluent (cat# SP-5035).
  • pTyr-mtRON antibody anti-CD136(RON)(pY1238/1239) antibody, #MBS 462024), RON(anti-RON antibody, #ab52927), Cleaved caspase 3 (C-cas3(Asp175) antibody, MAB835), Cyclin D1 (Cyclin D1(SP4) antibody, #Z2027RS) antibody was used.
  • Pron and Cyclin D1 antibodies were diluted 1:100 and RON and Cleaved caspas e3 antibodies were diluted 1:50 and reacted overnight at 4°C, being careful not to dry out. I ordered it.
  • the secondary antibody VECTASTAIN Elite rabbit ABC HRP Kit (cat# PK-6101) was reacted at room temperature for 1 hour. After that, add DAB SUBSTRATE KIT (cat# SK-4100), wait at RT for desired color development, and then add a few drops of Richard-Allan Scientific Mounting Media, Non-Aqueous (cat# 4112) to the stained slide. After dropping, covering with a cover slide and drying for more than 1 hour, images were taken with a slide scanner (cat: M8), PreciPoint.
  • Example 1 compound In a mouse model of mutant RON ⁇ 165 type head and neck cancer using a patient-derived xenograft (PDX) mouse model, the negative control, Example 1 compound was administered at doses of 10 mg/kg, 30 mg/kg, and 50 mg. It was administered at a dose of /kg to confirm whether tumor growth was inhibited.
  • PDX patient-derived xenograft
  • mice 6-8 week old female Athymic Nude-Foxn1nu (immune-compromised) mice were purchased, acclimatized for 1 week, and then patient-derived head and neck cancer tumor tissue was transplanted subcutaneously on the left ventral side of the mouse.
  • the negative control group and the compound of Example 1 were orally administered at a concentration of 10, 30, or 50 mg/kg. Administration was conducted once a day for a total of 53 days, and tumor size and body weight were measured twice a week.
  • the PDX experiment was conducted by requesting graduates oncology.
  • RON Exon 5&6 deletion was denatured using the primers Forward: 5'-GAGCTGGTCAGGTCACTAAAC-3' (SEQ ID NO: 6), Reverse: 5'-CAGACACTCAGTCCCATTGAC-3' (SEQ ID NO: 7), denaturation at 95°C, 30 seconds/annealing at 59°C, 30 seconds. PCR was performed under conditions of 72°C and 45 seconds/extension for a total of 35 cycles. For the RON Exon 11 deletion, PCR was performed under the same conditions as above using the primers Forward: 5'-ATCTGTGGCCAGCATCTAAC-3' (SEQ ID NO: 8) and Reverse: 5'-AAAGGCAGCAGGATACCAAG-3' (SEQ ID NO: 9).
  • GAPDH a house keeping gene
  • PCR products were extracted using the QIA quick PCR purification kit (Qiagen, cat# 28106), and sequencing was requested from Cosmogenetech. The sequencing results were analyzed to determine the RON mutation and mutation type.

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Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter le cancer de la tête et du cou associé à une mutation RON. La composition pharmaceutique pour prévenir ou traiter le cancer, selon la présente invention, peut être appliquée à un patient atteint d'un cancer de la tête et du cou ayant une mutation RON. En particulier, la composition pharmaceutique peut être utilisée de manière efficace pour traiter un patient atteint d'un cancer de la tête et du cou qui est résistant au cétuximab ou similaire, classiquement utilisé pour le traitement du cancer, et qui a une mutation RON△155, RON△160 ou RON△165.
PCT/KR2023/004675 2022-04-06 2023-04-06 Composition pharmaceutique pour prévenir ou traiter le cancer de la tête et du cou associé à une mutation ron WO2023195803A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101350006B1 (ko) * 2012-09-06 2014-02-13 씨제이제일제당 (주) 피리돈 유도체를 포함하는 단백질 키나제 억제제
US20140206679A1 (en) * 2011-06-09 2014-07-24 Shanghai Huilun Life Science & Technology Co., Ltd Heterocyclic pyridone compound, and intermediate, preparation method and use thereof
KR20160028399A (ko) * 2014-09-03 2016-03-11 씨제이헬스케어 주식회사 단백질 키나제 억제제에 대한 감수성 예측용 바이오 마커 및 이의 용도
KR20210100557A (ko) * 2020-02-06 2021-08-17 웰마커바이오 주식회사 Kras 돌연변이와 관련된 암의 예방 또는 치료용 약학 조성물
KR20210111711A (ko) * 2020-03-03 2021-09-13 웰마커바이오 주식회사 Kras 돌연변이 및 활성화된 ron이 존재하는 암의 예방 또는 치료용 약학 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140206679A1 (en) * 2011-06-09 2014-07-24 Shanghai Huilun Life Science & Technology Co., Ltd Heterocyclic pyridone compound, and intermediate, preparation method and use thereof
KR101350006B1 (ko) * 2012-09-06 2014-02-13 씨제이제일제당 (주) 피리돈 유도체를 포함하는 단백질 키나제 억제제
KR20160028399A (ko) * 2014-09-03 2016-03-11 씨제이헬스케어 주식회사 단백질 키나제 억제제에 대한 감수성 예측용 바이오 마커 및 이의 용도
KR20210100557A (ko) * 2020-02-06 2021-08-17 웰마커바이오 주식회사 Kras 돌연변이와 관련된 암의 예방 또는 치료용 약학 조성물
KR20210111711A (ko) * 2020-03-03 2021-09-13 웰마커바이오 주식회사 Kras 돌연변이 및 활성화된 ron이 존재하는 암의 예방 또는 치료용 약학 조성물

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