WO2022245124A1 - Nouveau composé d'éthène et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement du cancer - Google Patents

Nouveau composé d'éthène et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement du cancer Download PDF

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WO2022245124A1
WO2022245124A1 PCT/KR2022/007099 KR2022007099W WO2022245124A1 WO 2022245124 A1 WO2022245124 A1 WO 2022245124A1 KR 2022007099 W KR2022007099 W KR 2022007099W WO 2022245124 A1 WO2022245124 A1 WO 2022245124A1
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compound
alkyl
cancer
alkoxy
pharmaceutically acceptable
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PCT/KR2022/007099
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Korean (ko)
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김진아
조성진
전용현
진정욱
황하영
이재언
정민선
이수정
안홍찬
황지선
최효정
권수경
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재단법인 대구경북첨단의료산업진흥재단
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Priority claimed from KR1020220060100A external-priority patent/KR102503296B1/ko
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Publication of WO2022245124A1 publication Critical patent/WO2022245124A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/495—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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to an ethene compound having a novel structure acting as an ERR ⁇ / ⁇ inverse agonist, a pharmaceutically acceptable salt thereof or an N-oxide thereof, and prevention of cancer containing the same as an active ingredient Or a pharmaceutical composition for treatment.
  • Estrogen-related receptors such as ERR ⁇ , ERR ⁇ , and ERR ⁇
  • ERRs Estrogen-related receptors
  • Many reports have described its biological role in regulating oxidative metabolism, energy expenditure and mitochondrial beta oxidation. Conventionally, it has been reported to exhibit antidiabetic effects such as alleviating hyperglycemia and insulin resistance by inhibiting the activity of ERR ⁇ and therapeutic effects of retinopathy.
  • ERR ⁇ / ⁇ in cancer development, such as breast, gastric, and prostate cancer.
  • Expression of ERR ⁇ is decreased in breast carcinoma compared to adjacent normal breast tissue, and upregulation of ERR ⁇ expression in breast cancer has been shown to be associated with breast cancer treatment.
  • the expression of ERR ⁇ in prostate cancer was higher than in benign cancer. According to these reports, ERR ⁇ / ⁇ can be considered as an attractive therapeutic target for various types of cancer. Accumulated research results have shown an important interaction between ERR ⁇ / ⁇ and cancer development, but there is still a need for research on anticancer agents that can selectively remove only cancer cells without affecting normal cells in the body. It is becoming.
  • the present inventors while conducting research to evaluate the therapeutic potential of ERR ⁇ / ⁇ in cancer, synthesized an ethene compound with a novel structure that has high biocompatibility, high selectivity, and can act as an orally bioavailable ERR ⁇ / ⁇ inverse agonist. And they confirmed that they can be used as new anticancer agents by showing anticancer effects in cancer, particularly intractable cancer models in vitro and in vivo, and completed the present invention.
  • An object of the present invention is to provide an ethene compound with a novel structure, a pharmaceutically acceptable salt thereof, or an N-oxide thereof capable of acting as an ERR ⁇ / ⁇ inverse agonist.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising the ethene compound, a pharmaceutically acceptable salt thereof, or an N-oxide thereof as an active ingredient.
  • Another object of the present invention is the ethene compound, a pharmaceutically acceptable salt thereof or an N-oxide thereof; And to provide a combination preparation for preventing or treating cancer containing an anticancer agent.
  • Another object of the present invention is to provide a method for treating cancer, comprising administering the ethene compound, a pharmaceutically acceptable salt thereof, or an N-oxide thereof to a subject or subject in need thereof.
  • Another object of the present invention is to provide the above ethene compound, a pharmaceutically acceptable salt thereof or an N-oxide thereof for use in the treatment of cancer.
  • Another object of the present invention is to provide the use of the ethene compound, its pharmaceutically acceptable salt or its N-oxide for use in the manufacture of a medicament for the treatment of cancer.
  • One aspect of the present invention provides an ethene compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof as a novel compound capable of acting as an ERR ⁇ / ⁇ inverse agonist:
  • R 1 is C1-C20 alkyl or C3-C20 cycloalkyl
  • R 2 is C1-C20 alkyl, halogen, C3-C20 cycloalkyl, -L a1 -R a1 , -NR a2 R a3 , nitro or cyano;
  • L a1 is O or S
  • R a1 is hydrogen, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 cycloalkyl, C1-C20 alkoxyC1-C20 alkyl, C1-C20 alkylthioC1-C20 alkyl or C1-C20 alkylcarbonyl;
  • R a2 and R a3 are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;
  • a 1 to A 4 are each independently CR a4 or N;
  • R a4 is hydrogen or hydroxy
  • R 3 is hydrogen, C1-C20 alkyl or C3-C20 cycloalkyl
  • L is CR a5 or N
  • R a5 is hydrogen or C1-C20 alkyl
  • n is an integer from 1 to 5, and when m is an integer of 2 or greater, R 2 may be the same or different;
  • n is an integer of 0 or 1;
  • the alkyl of R 2 and R 3 may be further substituted with one or more selected from the group consisting of halogen, C1-C20 alkyl, C1-C20 alkoxy, hydroxy, amino, mono- or di-C1-C20 alkylamino.
  • Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the ethene compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof as an active ingredient.
  • Another aspect of the present invention is an ethene compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof; And it provides a combination preparation for preventing or treating cancer containing an anticancer agent.
  • Another aspect of the present invention provides a method for treating cancer, comprising the step of administering the ethene compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof to a subject or subject in need thereof. .
  • Another aspect of the present invention provides an ethene compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof for use in the treatment of cancer.
  • Another aspect of the present invention provides a use of the ethene compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof for use in the preparation of a drug for cancer treatment.
  • the ethene compound of the present invention has high biocompatibility and high selectivity and can act as an orally bioavailable ERR ⁇ / ⁇ inverse agonist.
  • the ethene compound of the present invention can specifically induce apoptosis in cancer cell lines by acting as an ERR ⁇ / ⁇ inverse agonist without exhibiting toxicity to normal cells, it is effective against various cancer diseases caused by abnormal cell growth. It can be usefully used as an improvement, prevention, and treatment without side effects.
  • the pharmaceutical composition for preventing or treating cancer containing the ethene compound of the present invention as an active ingredient exhibits low cytotoxicity and selectively exhibits high inhibitory activity and antiproliferative effect on cancer cells, and thus is useful for preventing or treating cancer. can be used
  • the pharmaceutical composition for preventing or treating cancer containing the ethene compound of the present invention as an active ingredient is an intractable drug selected from the group consisting of ovarian cancer, prostate cancer, breast cancer, neuroblastoma, glioblastoma, anaplastic thyroid cancer, dedifferentiated thyroid cancer, and colorectal cancer. It can be usefully used for the prevention or treatment of cancer.
  • the ethene compound of the present invention can be used alone or in combination for the prevention or treatment of cancer.
  • a and B upregulated ERR ⁇ / ⁇ expression in colon cancer tissues (ERR ⁇ / ⁇ expression levels in normal and tumor tissues are determined). Western blot analysis was performed to do this);
  • Figures 2 to 6 show the inhibition of proliferation of compound 1 (DN203368)-treated colon cancer cells [( Figure 2) endogenous expression of ERR ⁇ / ⁇ in colon cancer cells, namely HCT116, RKO, SW480 and CT26 cells; (FIG. 3) Effect of compound 1 (DN203368) on the proliferation of normal cells including BJ and CHO cells; (FIG. 4) Effect of Compound 1 (DN203368) on proliferation of colon cancer cells; (FIG. 5) Normalized cell viability (%) of normal cell lines and colon cancer cells after compound 1 (DN203368) treatment; (FIG. 6) Concentration that induces 50% cell growth inhibition (GI 50 ) of colon cancer cells for Compound 1 (DN203368)].
  • FIG. 7 and 8 show a comparison of the proliferation inhibitory effects of existing anticancer drugs (oxaliplatin and 5-FU) and compound 1 (DN203368) in colon cancer cells [(FIG. 7) of oxaliplatin and compound 1 (DN203368) in colon cancer cells. antiproliferative effect; (FIG. 8) Proliferation inhibitory effect of 5-FU and Compound 1 (DN203368) in colon cancer cells].
  • FIG. 9 and 10 show Compound 1 (DN203368)-mediated cell cycle arrest and induction of apoptosis in colon cancer cells [(Fig. 9) Cell cycle analysis in Compound 1 (DN203368)-treated HCT116, SW480 and RKO cells. graph showing; (FIG. 10) FACS analysis showing the percentage of apoptotic cells].
  • Figure 11 shows the induction of compound 1 (DN203368)-mediated caspase-3-dependent apoptosis through upregulation of p53 acetylation
  • A Expression level of ERR ⁇ / ⁇ in colon cancer cells after treatment with compound 1 (DN203368) ;
  • B Changes in expression of cell cycle related proteins in Compound 1 (DN203368)-treated colon cancer cells;
  • C Changes in apoptosis regulatory protein expression in Compound 1 (DN203368)-treated human colon cancer cells;
  • D expression levels of ERR ⁇ / ⁇ , cell cycle inhibition regulatory proteins and apoptosis regulatory proteins in compound 1 (DN203368)-treated mouse colon cancer cells;
  • E Time-dependent changes in apoptosis-related protein expression in 12 ⁇ M Compound 1 (DN203368)-treated HCT-116 cells].
  • Figure 12 shows the quantification of compound 1 (DN203368)-mediated induction of caspase 3-dependent apoptosis [(A) In vitro bioluminescence of time-dependent caspase-3 activation in compound 1 (DN203368)-treated colon cancer cells. signal quantification; (B) time-dependent cell viability in Compound 1 (DN203368)-treated colon cancer cells; (C) normalized caspase-3 activation in Compound 1 (DN203368)-treated colon cancer cells; (D) Inhibition of caspase-3 activation by Z-VAD treatment in compound 1 (DN203368)-treated HCT-116 cells (Z-VAD: pan-caspase inhibitor), caspase-3 activity shows viability CCK8 standardized with respect to the results of the assay].
  • Figure 13 shows the anti-tumor effect of compound 1 (DN203368) on colorectal cancer progression
  • HCT-116 tumor-bearing mice were randomly divided into three groups: group 1: vehicle, group 2: 5 mg/kg compound 1 (DN203368), and group 3: 10 mg/kg compound 1 (DN203368), and compound 1 (DN203368) was administered to mice via intraperitoneal injection once daily for 10 days;
  • Compound 1 (DN203368) was dose-dependently administered to mice via intraperitoneal injection.
  • RTV (tumor volume on day of measurement)/(tumor volume on day 0);
  • D Body weight measurement of HCT-116 tumor-bearing mice;
  • E Serum biochemical analysis of vehicle-treated and Compound 1 (DN203368)-treated mice].
  • Figure 14 shows the antitumor effect of Compound 1 (DN203368) on SW480 and RKO xenograft models of colorectal cancer
  • RTV (tumor volume on day of measurement)/(tumor volume on day 0);
  • D and E body weight measurements of SW480 or RKO tumor-bearing mice;
  • F Immunohistochemical staining with anti-cleaved caspase-3 and Ki-67 antibodies in compound 1 (DN203368)-treated SW480 tumor tissue;
  • G Immunohistochemical staining with anti-cleaved caspase-3 in Compound 1 (DN203368)-treated RKO tumor tissue].
  • Figure 15 shows the induction of potent antitumor effects after oral administration of Compound 1 (DN203368) in a colorectal cancer model
  • RTV (tumor volume on day of measurement)/(tumor volume on day 0);
  • C Body weight measurement of HCT-116 tumor-bearing mice;
  • D Evaluation of tumor volume in the CT26 xenograft model following oral administration of Compound 1 (DN203368);
  • E Weight measurement of CT26 tumor-bearing mice.
  • Figure 17 shows the inhibition of proliferation of Compound 1 (DN203368)-treated prostate cancer, ovarian cancer, breast cancer, neuroblastoma, undifferentiated and dedifferentiated thyroid cancer cells [(A) normal cells after treatment with Compound 1 (DN203368), prostate cancer, normalized cell viability (%) of ovarian cancer, breast cancer, and neuroblastoma; (B) Normalized cell viability (%) of undifferentiated and dedifferentiated thyroid carcinoma cells after compound 1 (DN203368) treatment].
  • A normal cells after treatment with Compound 1 (DN203368), prostate cancer, normalized cell viability (%) of ovarian cancer, breast cancer, and neuroblastoma
  • B Normalized cell viability (%) of undifferentiated and dedifferentiated thyroid carcinoma cells after compound 1 (DN203368) treatment.
  • Figure 18 shows the antitumor effect of Compound 1 (DN203368) on neuroblastoma and ovarian cancer models [(A) Relative tumor volume of BE2C xenograft mice treated with Compound 1 (DN203368) via intraperitoneal injection; (B) Relative tumor volume of A2780 xenograft mice after treatment with compound 1 (DN203368) via intraperitoneal injection].
  • Figure 19 shows the antitumor effect of Compound 1 (DN203368) on a breast cancer model [(A) tumor volume of MDA-MB231 xenograft mice after treatment with Compound 1 (DN203368) via intraperitoneal injection; (B) Tumor volume of MDA-MB231 orthotopic mice after treatment with compound 1 (DN203368) via intraperitoneal injection].
  • Figure 20 shows the antitumor effect of Compound 1 (DN203368) on a dedifferentiated thyroid carcinoma BHP103scp model [(A) Relative tumor volume of BHP103scp xenograft mice treated with Compound 1 (DN203368) via intraperitoneal injection; (B) Body weight measurement of BHP103scp tumor-bearing mice; (C) Immunohistochemical staining with anti-cleaved caspase-3 and Ki-67 antibodies in compound 1 (DN203368)-treated BHP103scp tumor tissue].
  • A Relative tumor volume of BHP103scp xenograft mice treated with Compound 1 (DN203368) via intraperitoneal injection
  • B Body weight measurement of BHP103scp tumor-bearing mice
  • C Immunohistochemical staining with anti-cleaved caspase-3 and Ki-67 antibodies in compound 1 (DN203368)-treated BHP103scp tumor tissue.
  • Figure 21 shows the inhibition of proliferation of Compound 12 (DN3317)-treated prostate cancer, ovarian cancer, glioblastoma and dedifferentiated thyroid cancer cells [normal cell lines after treatment with Compound 12 (DN3317) and prostate, ovarian cancer, glioblastoma and dedifferentiation Normalized cell viability (%) of thyroid cancer cells].
  • 22 to 24 are normalized cell viability (%) of colorectal cancer cells according to the combined administration of compound 1 (DN203368) and conventional anticancer drugs.
  • C A -C B means “more than A and less than B”
  • a to B means "more than A and less than B”.
  • alkyl refers to a monovalent straight-chain or branched saturated hydrocarbon radical composed of only carbon and hydrogen atoms.
  • the alkyl has 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 7 carbon atoms.
  • Examples of the alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethylhexyl, and the like.
  • cycloalkyl refers to a monovalent saturated carbocyclic radical composed of one or more rings.
  • examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • alkoxy refers to an -O-alkyl radical, where 'alkyl' is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.
  • alkylthio refers to an -S-alkyl radical, where 'alkyl' is as defined above. Specific examples include, but are not limited to, methylthio, ethylthio, isopropylthio, butylthio, isobutylthio, t-butylthio, and the like.
  • halo refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.
  • haloalkyl refers to an alkyl, alkoxy or alkylthio group in which one or more hydrogen atoms are substituted with halogen atoms, respectively, wherein alkyl, alkoxy, alkylthio and Halogen is as defined above.
  • haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, perfluoroethyl, etc.
  • haloalkoxy is fluoromethoxy, difluoromethyl oxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, perfluoroethoxy and the like
  • haloalkylthio is fluoromethylthio, difluoromethylthio, trifluoromethylthio, Fluoroethylthio, difluoroethylthio, perfluoroethylthio, etc. are mentioned.
  • aryl is an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, either singly or fused, each ring containing preferably 4 to 7, preferably 5 or 6, ring atoms. It includes a ring system, and even includes a form in which a plurality of aryls are connected by single bonds. Examples include, but are not limited to, phenyl, naphthyl, biphenyl, terphenyl, anthryl, fluorenyl, and the like.
  • alkylcarbonyl radicals include, but are not limited to, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, propylcarbonyl, butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl, and the like.
  • alkylcarbonyloxy radicals include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, t-butylcarbonyloxy, and the like. However, it is not limited thereto.
  • amino means -NH 2
  • hydroxy means -OH
  • nitro means -NO 2
  • cyano means -CN
  • alkylamino refers to an amino radical in which one or two alkyls are substituted, and specific examples include methylamino (-NHMe), dimethylamino (-NMe 2 ), ethylamino (-NHEt), diethylamino (-NEt 2 ); and the like, but are not limited thereto.
  • the term "pharmaceutically acceptable” means that it exhibits characteristics that are not toxic to objects such as cells or humans exposed to the composition, and is suitable for use as a pharmaceutical preparation, and generally refers to such use. It is considered safe for such use and is officially approved by a national regulatory authority for such use or is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.
  • the term "pharmaceutically acceptable salt” is a concentration that has a relatively non-toxic and harmless effective effect on patients, and the side effects caused by the salt do not reduce the beneficial effects of the compound itself of the present invention. means any and all organic or inorganic addition salts of a compound.
  • pharmaceutically acceptable excipient and “pharmaceutically acceptable carrier” refer to a substance that aids administration of an active agent and absorption by a subject.
  • prevention refers to any activity that inhibits or delays the occurrence, spread, and recurrence of cancer.
  • the term “improvement” refers to any activity that at least reduces a parameter related to the condition being treated, for example, the severity of a symptom.
  • treatment refers to any activity that improves or beneficially changes the symptoms of cancer.
  • the term "individual” refers to all animals, including humans, who have or are likely to develop cancer.
  • the animal may be not only humans but also mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats that require treatment for similar symptoms, but are not limited thereto.
  • the term "administration” means introducing the pharmaceutical composition of the present invention to a subject by any appropriate method, and the administration route of the composition of the present invention is various oral or parenteral routes as long as it can reach the target tissue. can be administered through
  • the term "combined administration" can be achieved by administering the individual components of the therapy simultaneously, sequentially, or separately.
  • Combination treatment effect is obtained by administering two or more drugs simultaneously or sequentially, or by alternately administering them at regular or unspecified intervals.
  • efficacy measured by time to disease progression or survival can be defined as being therapeutically superior to and capable of providing a synergistic effect over the efficacy obtainable by administering one or the other of the components of the combination therapy at conventional doses.
  • the term "pharmaceutically effective amount” means an amount that is sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is dependent on the patient's gender, Factors including age, weight, health condition, type and severity of disease, activity of drug, sensitivity to drug, method of administration, time of administration, route of administration, and excretion rate, duration of treatment, combinations or drugs used concurrently, and other medical It can be readily determined by a person skilled in the art according to factors well known in the art.
  • the term "food” means meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcohol Beverages, vitamin complexes, health functional foods and health foods, etc., include all foods in a conventional sense.
  • the term "functional health food” refers to food manufactured and processed using raw materials or ingredients having useful functionalities for the human body according to the Act on Health Functional Foods No. 6727, and “functional” refers to the human body. It refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients for the structure and function of food or physiological functions.
  • acceptable food salt means a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.
  • the present invention provides an ethene compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof:
  • R 1 is C1-C20 alkyl or C3-C20 cycloalkyl
  • R 2 is C1-C20 alkyl, halogen, C3-C20 cycloalkyl, -L a1 -R a1 , -NR a2 R a3 , nitro or cyano;
  • L a1 is O or S
  • R a1 is hydrogen, C1-C20 alkyl, haloC1-C20 alkyl, C3-C20 cycloalkyl, C1-C20 alkoxyC1-C20 alkyl, C1-C20 alkylthioC1-C20 alkyl or C1-C20 alkylcarbonyl;
  • R a2 and R a3 are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;
  • a 1 to A 4 are each independently CR a4 or N;
  • R a4 is hydrogen or hydroxy
  • R 3 is hydrogen, C1-C20 alkyl or C3-C20 cycloalkyl
  • L is CR a5 or N
  • R a5 is hydrogen or C1-C20 alkyl
  • n is an integer from 1 to 5, and when m is an integer of 2 or greater, R 2 may be the same or different;
  • n is an integer of 0 or 1;
  • the alkyl of R 2 and R 3 may be further substituted with one or more selected from the group consisting of halogen, C1-C20 alkyl, C1-C20 alkoxy, hydroxy, amino, mono- or di-C1-C20 alkylamino.
  • the ethene compound of Chemical Formula 1 according to the present invention is a compound with a novel structure and can be used as an active ingredient for preventing or treating cancer by controlling the expression level of ERR ⁇ / ⁇ , which is overexpressed in cancer cells. That is, the ethene compound according to the present invention acts as an ERR ⁇ / ⁇ inverse agonist and can be useful as a target anticancer agent for cancer.
  • the ethene compound of the present invention has high biocompatibility and high selectivity, is orally bioavailable, and can induce apoptosis specifically only for cancer cell lines by acting as an ERR ⁇ / ⁇ inverse agonist without exhibiting toxicity to normal cells. Therefore, it can be usefully used as an effective preventive and therapeutic agent for cancer without side effects.
  • Cancer diseases that can be prevented, treated, or ameliorated by treatment with the ethene compound according to the present invention are intractable cancers, specifically ovarian cancer, prostate cancer, breast cancer, neuroblastoma, glioblastoma, undifferentiated thyroid cancer, dedifferentiated thyroid cancer, or colorectal cancer. etc. may be included.
  • the ethene compound according to the present invention reduces the viability of cancer cells, inhibits proliferation, Since apoptosis of cancer cells is increased, it was confirmed that the anticancer effect was excellent. Therefore, the ethene compound according to the present invention can be usefully used as an active ingredient of a pharmaceutical composition for preventing or treating cancer.
  • At least two of A 1 to A 4 may be CR a4 , the others may be CR a4 or N, and R a4 may be hydrogen or hydroxy.
  • the ethene compound may be represented by Chemical Formula 2 below.
  • R 1 , R 2 , R 3 , L, m and n are the same as defined in Formula 1;
  • a 1 is CH or N
  • a is an integer of 0 or 1;
  • R 2 is halogen, hydroxy, C1-C20 alkoxy, haloC1-C20 alkoxy, C1-C20 alkoxyC1-C20 alkoxy, C1-C20 alkylthioC1-C20 alkoxy, C1-C20 alkylcarbo yloxy, C1-C20 alkylthio, haloC1-C20 alkylthio, C1-C20 alkylcarbonylthio, -NR a2 R a3 , nitro or cyano; R a2 is hydrogen or C1-C20 alkyl; R a3 is C1-C20 alkyl; m may be an integer from 1 to 3.
  • R 1 is C1-C10 alkyl or C3-C10 cycloalkyl
  • R 2 is hydroxy, C1-C10 alkoxy, haloC1-C10 alkoxy, C1-C10 alkoxyC1-C10 alkoxy, C1-C10 alkylthioC1-C10 alkoxy, C1-C10 alkylcarbonyloxy, C1-C10 alkylthio, haloC1-C10 alkylthio, C1-C10 alkylcarbonylthio or -NR a2 R a3
  • R a2 is hydrogen or C1-C10 alkyl
  • R a3 is C1-C10 alkyl
  • R 3 is hydrogen or C1-C10 alkyl
  • L is CH or N
  • m is an integer from 1 to 3
  • n may be an integer of 0 or 1.
  • R 3 may be C1-C10 alkyl, more preferably branched C3-C7 alkyl, specifically isopropyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, s-pentyl, 3-pentyl or s-isopentyl.
  • the R 3 may be isopropyl.
  • the ethene compound according to an embodiment may be specifically represented by Chemical Formula 3, Chemical Formula 4, or Chemical Formula 5 below.
  • R 1 is C1-C10 alkyl or C3-C10 cycloalkyl
  • At least one of R 11 , R 12 and R 13 is hydroxy, C1-C10 alkoxy, haloC1-C10 alkoxy, C1-C10 alkoxyC1-C10 alkoxy, C1-C10 alkylcarbonyloxy, C1-C10 alkylthio, halo C1-C10 Alkylthio, C1-C10 Alkylcarbonylthio or diC1-C10 Alkylamino, the rest being hydrogen, hydroxy, C1-C10 Alkoxy, haloC1-C10 Alkoxy, C1-C10 AlkoxyC1-C10 Alkoxy, C1 -C10 alkylcarbonyloxy, C1-C10 alkylthio, haloC1-C10 alkylthio, C1-C10 alkylcarbonylthio or diC1-C10 alkylamino;
  • a is an integer of 0 or 1;
  • n is an integer of 0 or 1;
  • R 1 is C1-C7 alkyl or C3-C8 cycloalkyl; At least one of R 11 , R 12 and R 13 is hydroxy, C1-C7 alkoxy, C1-C7 alkylcarbonyloxy, C1-C7 alkylthio or diC1-C7 alkylamino, and the others are hydrogen, hydroxy, C1 -C7 alkoxy, C1-C7 alkylcarbonyloxy, C1-C7 alkylthio, or diC1-C7 alkylamino; a is an integer of 0 or 1; n may be an integer of 0 or 1.
  • R 11 is hydrogen
  • R 12 is hydrogen, hydroxy, C1-C7 alkoxy, C1-C7 alkylcarbonyloxy, C1-C7 alkylthio or diC1-C7 alkylamino
  • R 13 can be hydroxy, C1-C7 alkoxy, C1-C7 alkylcarbonyloxy, C1-C7 alkylthio or diC1-C7 alkylamino.
  • R 11 is hydroxy or C1-C7 alkoxy
  • R 12 is hydrogen
  • R 13 can be hydroxy, C1-C7 alkoxy, C1-C7 alkylcarbonyloxy, C1-C7 alkylthio or diC1-C7 alkylamino.
  • R 11 and R 13 are hydrogen;
  • R 12 can be hydroxy, C1-C7 alkoxy, C1-C7 alkylcarbonyloxy, C1-C7 alkylthio or diC1-C7 alkylamino.
  • R 1 may be C2-C5 alkyl or C3-C7 cycloalkyl, preferably C2-C4 alkyl or C3-C6 cycloalkyl.
  • R 1 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, s-pentyl, 3-pentyl, s-iso It may be pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and more specifically, R 1 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the ethene compound according to an embodiment may be at least one selected from the group of compounds below, but is not limited thereto.
  • the method for preparing an ethene compound according to an embodiment may be performed using a method known in the art or by appropriately changing it.
  • the reaction time in the preparation method of Chemical Formula 1 according to an embodiment of the present invention may vary depending on the type and amount of the reactant, solvent, and the reaction after confirming that the starting material is completely consumed through TLC, for example. complete the When the reaction is complete, the solvent may be distilled off under reduced pressure, and then the target product may be separated and purified through a conventional method such as column chromatography. Further details are described in the Examples below.
  • the present invention includes all of the above ethene compounds, pharmaceutically acceptable salts thereof, or N-oxides thereof, as well as possible prodrugs, hydrates and solvates that can be prepared therefrom.
  • the ethene compound of the present invention can be used in the form of prodrugs, hydrates, solvates, and pharmaceutically acceptable salts in order to improve absorption or solubility in vivo. and pharmaceutically acceptable salts are also within the scope of the present invention.
  • the ethene compound has a chiral carbon, stereoisomers thereof exist, and these stereoisomers are also included within the scope of the present invention.
  • the ethene compound of the present invention can be used in the form of a pharmaceutically acceptable salt
  • the pharmaceutically acceptable salt is a salt prepared according to a conventional method in the art, and the preparation method thereof is known to those skilled in the art.
  • the pharmaceutically acceptable salt includes, but is not limited to, pharmacologically or physiologically acceptable salts derived from free acids and bases.
  • Acid addition salts formed by pharmaceutically acceptable free acids include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, Fluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorb It is obtained from organic acids such as acid, carbonic acid, vanillic acid, and hydroiodic acid.
  • organic acids such as acid, carbonic acid, vanillic acid, and hydroiodic acid.
  • Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succi nate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxy Benzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesul
  • the acid addition salt can be prepared by a conventional method.
  • the ethene compound of the present invention is dissolved in a water-miscible organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and an organic or inorganic acid is added to form a precipitate.
  • a water-miscible organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc.
  • an organic or inorganic acid is added to form a precipitate. It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the ethene compound of the present invention in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved ethene compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the hydrate of the ethene compound of the present invention comprises a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces, or A pharmaceutically acceptable salt thereof is meant.
  • the solvate of the ethene compound of the present invention refers to the ethene compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Solvents that can be used include those that are volatile and non-toxic.
  • the ethene compound of the present invention is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, and then crystallized or recrystallized after adding a free acid or free base to obtain a solvent containing a hydrate Cargo can be formed. Therefore, the novel compounds of the present invention include stoichiometric solvates including hydrates in addition to compounds containing various amounts of water that can be prepared by methods such as lyophilization.
  • a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane
  • the ethene compounds of the present invention may have chiral centers and may exist as racemates, racemic mixtures, and individual enantiomers or diastereomers. These isomers can be separated or resolved by conventional methods and any desired isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis. All such isomeric forms and mixtures thereof are included within the scope of the present invention.
  • the ethene compound of the present invention may be administered in the form of a prodrug that is decomposed in the body of a human or animal to provide the ethene compound of the present invention as an active ingredient.
  • Prodrugs can be used to alter and/or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains suitable groups or substituents that can be derivatized to form prodrugs.
  • prodrug refers to a reaction that is hydrolyzed, oxidized, and subjected to other reactions under biological conditions (ex vivo or in vivo) to provide an active compound, particularly an ethene compound of the present invention.
  • prodrugs means a compound of the present invention capable of Examples of prodrugs are biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable compounds that are biohydrolyzed to produce the ethene compounds of the present invention, including biohydrolyzable moieties, such as ureides that can be biohydrolyzed, and phosphate analogues that can be biohydrolyzed, but in this specific embodiment is not limited to
  • the prodrug of a compound having a carboxylic functional group is a lower alkyl ester of a carboxylic acid.
  • Carboxyl esters are commonly formed by esterifying a portion of a carboxylic acid present in a molecule.
  • Prodrugs can be readily prepared using known methods.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the ethene compound of Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof as an active ingredient.
  • the pharmaceutical composition of the present invention can be used for the purpose of treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth.
  • Cancer diseases that can be prevented, treated, or alleviated by the treatment of the pharmaceutical composition of the present invention may be intractable cancers, specifically ovarian cancer, prostate cancer, breast cancer, neuroblastoma, glioblastoma, undifferentiated thyroid cancer, dedifferentiated thyroid cancer, colon cancer, etc. can
  • the ethene compound according to the present invention may be useful for treating or preventing various cancer diseases by inhibiting the proliferation of cancer cells by controlling the expression level of ERR ⁇ / ⁇ in cancer tissues such as colorectal cancer.
  • the pharmaceutical composition according to an embodiment further includes a conventional non-toxic pharmaceutically acceptable carrier and/or excipient in addition to the active ingredient, and is a conventional preparation in the pharmaceutical field, that is, a preparation for oral administration or a preparation for parenteral administration. It can be formulated as In addition, diluents such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be further included.
  • Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil, but is not limited thereto.
  • the pharmaceutical composition of the present invention can be formulated in various forms such as oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and injections of sterile injection solutions according to conventional methods according to the purpose of use. It can be formulated and used, and can be administered through various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like.
  • the formulation for oral administration may optionally be enteric coated, and may exhibit a delayed or sustained release through the enteric coating. That is, the preparation for oral administration may be a dosage form having an immediate or modified release pattern.
  • the formulation for parenteral administration may be a formulation having an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • composition of the present invention may further include fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like.
  • Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These formulations are commonly used fillers in addition to the above active ingredients
  • One or more diluents or excipients such as extenders, wetting agents, disintegrants, lubricants, binders, and surfactants may be used.
  • agar, starch, alginic acid or sodium salt thereof, calcium monohydrogen phosphate anhydrous salt, etc. may be used, and as the lubricant, silica, talc, stearic acid or magnesium salt or calcium salt thereof, polyethylene glycol, etc. may be used.
  • Magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low-substituted hydroxypropyl cellulose and the like may be used as the binder.
  • lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc. may be used as diluents, and in some cases, generally known boiling mixtures, absorbents, coloring agents, flavoring agents, sweetening agents, etc. may be used together.
  • preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions.
  • injectable esters such as ethyl oleate
  • a base for the suppository witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, etc. may be used.
  • the active ingredient may be mixed in water with a stabilizer or buffer to prepare a solution or suspension, which may be prepared in unit dosage form in an ampoule or vial.
  • the pharmaceutical composition of the present invention may be sterilized or may further contain adjuvants such as preservatives, stabilizers, thickeners, hydration agents or emulsifiers, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances. It may further contain, and may be formulated according to conventional methods such as dissolution, dispersion, mixing, granulation, gelation or coating.
  • the pharmaceutically effective amount of the ethene compound which is an active ingredient in the pharmaceutical composition of the present invention, depends on the patient's health condition, disease type, severity, drug activity, drug sensitivity, administration method, administration time, administration route, and excretion rate. , duration of treatment, factors including medications used in combination or co-administration, and other factors well known in the medical arts.
  • the effective amount of the ethene compound in the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, and body weight, and is generally about 0.001 to 500 mg/kg/day, preferably 0.01 to 100 mg. /kg/day, it can be administered daily or every other day or divided into once to several times a day. However, since it may increase or decrease depending on the route of administration, severity of disease, sex, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally, and the ethene compound according to the present invention enters the gastrointestinal tract by oral administration as an anticancer agent for oral administration to treat cancer, or, for example, It can be absorbed directly from the mouth into the bloodstream, such as by buccal or sublingual administration.
  • the present invention relates to an ethene compound of Formula 1, a pharmaceutically acceptable salt thereof, or an N-oxide thereof; And it provides a combination preparation for preventing or treating cancer containing an anticancer agent.
  • the pharmaceutical 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 single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the other therapeutic agent may mean a known anticancer agent.
  • anti-cancer agent refers to known drugs used in conventional cancer treatment that exhibit cytotoxicity or growth inhibitory effects on cancer cells by acting on various metabolic pathways of cancer cells. It may include both cytotoxic anticancer agents and targeted anticancer agents.
  • Cytotoxic anticancer agents refer to anticancer agents that inhibit the synthesis and division of DNA or RNA by intervening in the metabolic pathway of cancer cells, or induce cell death by damaging DNA itself. ), plant-derived alkaloids, topoisomerase inhibitors, alkylating agents, antineoplastic antibiotics, hormones and other drugs.
  • the topoisomerase inhibitor is a substance that exhibits an anticancer effect by interfering with the action of topoisomerase, an enzyme that regulates the double helix structure of DNA, for example, etoposide, epipodophyllotoxin ) or a combination thereof, but is not limited thereto.
  • the metabolic antagonist refers to a substance that inhibits the growth and proliferation of cells by antagonizing with an indispensable metabolite for the metabolism or growth of microorganisms or tumor cells.
  • the antimetabolite is, for example, metotrexate, pemetrexed, cladribine, fludarabine, mercaptopurine, 6-thioguanine , clofarabine, 5-azacytidine, cytarabine, decitabine, enocitabine, gimeracil, oteracil ), capecitabine, camofur, doxifluridine, gemcitabine, tegafur, 5-fluorouracil, or combinations thereof It may be, but is not limited thereto.
  • the plant-derived alkaloids refer to organic compounds containing basic nitrogen having a specific and strong physiological action on animals.
  • the plant-derived alkaloids are, for example, etoposide, docetaxel, paclitaxel, cabazitaxel, vinblastine, vincristine, vinorelbine , teniposide, trabectedin, or a combination thereof, but is not limited thereto.
  • the alkylating agent is a very reactive substance having the ability to introduce an alkyl group R-CH2 into a certain compound, and when applied to cells, it transforms the DNA structure and causes chain scission to exhibit anticancer and cytotoxic effects, Also called DNA-damaging agents.
  • the alkylating agent is, for example, oxaliplatin, bendamustine, chlorambucil, melphalan, busulfan, cyclophosphamide, ifosfamide ( ifosfamide, carmustine, lomustine, nimustine, ranimustine, dacarbaxine, temozolomide, thiotepa, or combinations thereof It may be, but is not limited thereto.
  • the anticancer antibiotic refers to an antibiotic that inhibits the proliferation of animal tumor cells and shows a life-sustaining effect on cancer-bearing animals.
  • the antitumor antibiotics include, for example, doxorubicin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitoxanthrone, It may be pirarubicin, bleomycin, ixabepilone, mitomycin C, or a combination thereof, but is not limited thereto.
  • the hormonal agents are meant to regulate, reduce, block or suppress hormonal effects that can promote cancer growth.
  • the hormonal agent is diethylstilbestrol, medroxyprogesterone, megesterol, fulvestrant, tamoxifen, toremifene, bicalutamide ), flutamide, anastrozole, exemestane, letrozole, buserelin, gosereline, leuprorelin, trypto It may be relin (triptorelin), aminoglutethimide (aminoglutethimide) or a combination thereof, but is not limited thereto.
  • Targeted anticancer agents refer to drugs that selectively attack only cancer cells by targeting proteins of specific parts of cancer cells different from normal cells, and include at least one selected from signal transduction pathway inhibitors, angiogenesis inhibitors, etc. can
  • Anticancer agents according to one embodiment, Afatinib, oxaliplatin, doxorubicin, paclitaxel, vincristine, daunorubicin, vinblastine, actinomycin-D, docetaxel, etoposide, teniposide, bisantrene, homoharringtonine, Gleevec (STI-571), Cisplatin, 5-fluorouracil (5-FU), Adriamycin, metotrexate, busulfan, chlorambucil, cyclophosphamide ), melphalan, nitrogen mustard, and nitrosourea.
  • Afatinib, oxaliplatin doxorubicin, paclitaxel, vincristine, daunorubicin, vinblastine, actinomycin-D, docetaxel, etoposide, teniposide, bisantrene, homoharringtonine, Gleevec (STI-571), Cisplatin, 5-fluorouracil
  • the anticancer agent may be at least one selected from afatinib, oxaliplatin, and 5-fluorouracil (5-FU).
  • the combination preparation according to the present invention can exhibit a remarkable synergistic effect by using the two components together, compared to the treatment effect of each component alone, for the treatment of cancer, prolonging the duration of the drug effect, extending the drug administration interval, or It is possible to reduce the total dose or number of administrations, and as a result, the survival rate and survival period of cancer patients can be extended and side effects can be significantly reduced.
  • the combination preparation of the present invention can exhibit significantly superior effects in preventing or treating cancer compared to conventional anticancer drug administration alone, and can more effectively inhibit, delay, or stop tumor growth without side effects.
  • the ethene compound according to the present invention not only exhibits an excellent anticancer effect when used alone, but also exhibits a higher synergistic effect when used in combination with an existing anticancer agent. have.
  • the present invention comprises the step of administering the ethene compound, its pharmaceutically acceptable salt or its N-oxide, or the pharmaceutical composition, or the combination preparation to a subject who has or is at risk of developing cancer.
  • a method for preventing or treating cancer is provided.
  • the present invention provides a health functional food composition for preventing or improving cancer, comprising the ethene compound of Formula 1, a food-acceptable salt thereof, or an N-oxide thereof as an active ingredient.
  • the food chemically acceptable salt is obtained by dissolving the ethene compound of the present invention into inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and p-toluenesulfonic acid, tartaric acid, formic acid, citric acid, It can be obtained by reaction with an organic carbonic acid such as acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid
  • sulfonic acids such as methanesulfonic
  • salts such as alkali metal salts such as ammonium salts, sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, dicyclohexylamine, N-methyl-D-glucamine , It may also be obtained by forming salts of organic bases such as tris (hydroxymethyl) methylamine, and amino acid salts such as arginine and lysine, but is not limited thereto.
  • the health functional food composition may be provided in the form of powder, granule, tablet, capsule, syrup or beverage, and the health functional food is used with other foods or food additives in addition to the ethene compound as an active ingredient, can be used appropriately.
  • the mixing amount of the active ingredient may be appropriately determined depending on the purpose of use thereof, for example, prevention, health or therapeutic treatment.
  • the health functional food composition includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts , organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like.
  • it may contain fruit flesh for the manufacture of natural fruit juice, fruit juice beverages and vegetable beverages. These components may be used independently or in combination.
  • the health functional food may additionally contain food additives, and the suitability as a 'food additive' is determined according to the general rules of the Food Additive Code and general test methods approved by the Korea Food and Drug Administration unless otherwise specified. It is judged according to standards and standards.
  • Examples of items listed in the 'Food Additive Code' include chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, and guar gum, sodium L-glutamate Mixed formulations such as formulations, noodle-added alkalis, preservatives, and tar colorants may be mentioned.
  • chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid
  • natural additives such as dark pigment, licorice extract, crystalline cellulose, and guar gum
  • sodium L-glutamate Mixed formulations such as formulations, noodle-added alkalis, preservatives, and tar colorants may be mentioned.
  • the ethene compound contained in the health functional food composition can be used according to the effective dose of the pharmaceutical composition, but in the case of long-term intake for the purpose of health and hygiene or health control, it may be less than the above range. And, of course, the active ingredient can be used in an amount greater than the above range because there is no problem in terms of safety.
  • the health functional food composition is meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes It can be formulated into various formulations such as the like.
  • the present invention provides the ethene compound, a pharmaceutically acceptable salt thereof, or an N-oxide thereof for use in the treatment of cancer.
  • the present invention provides the use of the ethene compound, its pharmaceutically acceptable salt or its N-oxide for use in the manufacture of a medicament for the treatment of cancer.
  • Step 1 (E)-3-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl pivalate (b-1) manufacture of
  • Step 2 (E)-3-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenol ( One ) manufacture of
  • Step 1 Preparation of (E)-3-(2-cyclopropyl-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylvinyl)phenyl pivalate (b-2)
  • Step 2 (E)-3-(2-cyclopropyl-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylvinyl)phenol ( 2 ) manufacture of
  • Step 1 (E)-4-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl pivalate (b-3) manufacture of
  • Step 2 (E)-4-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenol ( 12 ) manufacture of
  • Step 1 Preparation of (E)-4-(2-cyclopropyl-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylvinyl)phenyl pivalate (b-4)
  • Step 2 (E)-4-(2-cyclopropyl-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylvinyl)phenol ( 13 ) manufacture of
  • Step 1 (E)-4-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3,3-dimethyl-2-phenylbut-1-en-1-yl)phenyl pivalate (b- 5)
  • Step 2 (E)-4-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3,3-dimethyl-2-phenylbut-1-en-1-yl)phenol ( 14 ) manufacture of
  • Step 1 (E)-3-(2-(3-hydroxyphenyl)-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methylbut-1-en-1-yl)phenyl pivalate ( Preparation of d-1)
  • Step 2 (E)-3,3'-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methylbut-1-ene-1,2-diyl)diphenol ( 9 ) manufacture of
  • Step 1 (E)-3-(2-(4-hydroxyphenyl)-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methylbut-1-en-1-yl)phenyl pivalate ( Preparation of d-2)
  • Step 2 (E)-3-(2-(4-hydroxyphenyl)-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methylbut-1-en-1-yl)phenol ( 10 ) manufacture of
  • Step 1 (Z)-4-(1-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl pivalate ( Preparation of f-1)
  • Step 2 (Z)-4-(1-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-3-methyl-2-phenylbut-1-en-1-yl)phenol ( 26 ) manufacture of
  • Step 1 (E)-tert-butyl 4-(4-(3-methyl-2-phenyl-1-(3-(pivaloyloxy)phenyl)but-1-en-1-yl)phenyl)piperazine-1- Preparation of carboxylate (f-2)
  • Example 1 except that compound e-2 was used instead of 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine 0.11 g (15%) of the target compound f-2 was obtained in the same manner as in step 1 of
  • Step 2 (E) -3- (3-methyl-2-phenyl-1- (4- (piperazin-1-yl) phenyl) but-1-en-1-yl) phenyl pivalate (f-3) Produce
  • Step 3 (E)-3-(3-methyl-2-phenyl-1-(4-(piperazin-1-yl)phenyl)but-1-en-1-yl)phenol ( 28 ) manufacture of
  • Step 1 (E)-tert-butyl 4-(4-(3-methyl-2-phenyl-1-(3-(pivaloyloxy)phenyl)but-1-en-1-yl)phenyl)piperidine-1- Preparation of carboxylate (g-1)
  • Example 1 except that compound e-3 was used instead of 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine 0.18 g (22%) of target compound g-1 was obtained in the same manner as in step 1 of
  • Step 2 (E)-3-(3-methyl-2-phenyl-1-(4-(piperidin-4-yl)phenyl)but-1-en-1-yl)phenyl pivalate (g-2) Produce
  • Step 3 (E)-3-(1-(4-(1-ethylpiperidin-4-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl pivalate (g-3) manufacture of
  • Step 4 (E)-3-(1-(4-(1-isopropylpiperidin-4-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenol ( 24 ) manufacture of
  • Step 1 (E)-tert-butyl 4-(4-(3-methyl-2-phenyl-1-(4-(pivaloyloxy)phenyl)but-1-en-1-yl)phenyl)piperidine-1- Preparation of carboxylate (h-1)
  • Step 2 (E) -4- (3-methyl-2-phenyl-1- (4- (piperidin-4-yl) phenyl) but-1-en-1-yl) phenyl pivalate (h-2) Produce
  • Step 3 (E)-4-(1-(4-(1-isopropylpiperidin-4-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl pivalate (h-3) manufacture of
  • Step 4 (E)-4-(1-(4-(1-isopropylpiperidin-4-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenol ( 25 ) manufacture of
  • Step 1 Preparation of (4-hydroxyphenyl)(4-(4-isopropylpiperazin-1-yl)phenyl)methanone (j-1)
  • Step 2 (E)-4-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylbut-1-en-1-yl)phenol ( 11 ) manufacture of
  • Step 1 Preparation of (4-(4-isopropylpiperazin-1-yl)phenyl)(4-methoxyphenyl)methanone (j-2)
  • Step 2 (E)-1-isopropyl-4-(4-(1-(4-methoxyphenyl)-4-methyl-2-phenylpent-1-en-1-yl)phenyl)piperazine ( 17 ) manufacture of
  • Step 1 Preparation of (4-(4-isopropylpiperazin-1-yl)phenyl)(4-(methylthio)phenyl)methanone (j-3)
  • Step 2 (E)-1-isopropyl-4-(4-(3-methyl-1-(4-(methylthio)phenyl)-2-phenylbut-1-en-1-yl)phenyl)piperazine ( 22 ) manufacture of
  • Step 1 Preparation of (4-(dimethylamino)phenyl)(4-(4-isopropylpiperazin-1-yl)phenyl)methanone (j-4)
  • Step 2 (Z)-4-(1-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-2-phenylbut-1-en-1-yl)-N,N-dimethylaniline ( 23 ) manufacture of
  • Step 1 (Z)-1-isopropyl-4-(2-methoxy-4-(1-(3-methoxyphenyl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl)piperazine (j -5)
  • Step 2 1-isopropyl-4-(2-methoxy-4-((Z)-1-(3-methoxyphenyl)-3-methyl-2-phenylbut-1-enyl)phenyl)piperazine (m-1) Produce
  • Step 3 (Z)-5-(1-(3-hydroxyphenyl)-3-methyl-2-phenylbut-1-en-1-yl)-2-(4-isopropylpiperazin-1-yl)phenol ( 29 ) manufacture of
  • the compound of the present invention was sequentially put into a 384 well plate so that the concentration was diluted by a factor of two. Then, GST-coupled ERR gamma LBD (ligand-binding domain) was added to a final concentration of 5 nM, and fluorescien-conjugated coacitivator PGC1a and Tb-a-GST antibody were added to a final concentration of 500 nM and 5 nM, respectively. After all reagents were added, the mixture was reacted while gently shaking at 20 ° C. for 1 hour, and the binding activity after the reaction was measured by TR-FRET method.
  • ERR gamma LBD ligand-binding domain
  • ERR alpha binding assay used ERR alpha LBD coupled with GST, and all other experimental methods were the same as those of ERR gamma binding assay.
  • ERR beta binding assay GST-conjugated ERR alpha LBD was used at a final concentration of 10 nM and fluorescien-conjugated coacitivator PGC1a at a final concentration of 250 nM, and all other experimental methods were the same as those of the ERR gamma binding assay.
  • ER alpha binding assay GST-bound ER alpha LBD (ligand-binding domain) was added to a 384 well plate to which the compound of the present invention was added, to a final concentration of 7.3 nM.
  • fluorescien-conjugated coacitivator PGC1a and Tb-a-GST antibody were added at 250nM and 5nM, respectively, and beta-estradiol, an agonist, was added to a final concentration of 4nM. All subsequent experimental methods were identical to those of the ERR gamma binding assay.
  • AD293 was cultured for 24 hours in a 24 well plate using DMEM High Glucose (Hyclone, USA) culture medium supplemented with 0.5% FBS at a concentration of 9 ⁇ 10 4 cells/well. Replace with DMEM High Glucose medium supplemented with 10% FBS, mix Trans IT-LT1 transfection reagent (Mirus, USA), pCMX-Gal4-ERR ⁇ , pFR-luciferase reporter plasmid, and pCMV- ⁇ -gal and treat them together. time incubated. Thereafter, luciferase activity assay and ⁇ -gal assay were performed with the lysate obtained after treatment with the compound of the present invention for 24 hours, respectively. All results were derived from at least three independent and repeated experiments.
  • ERR ⁇ /ERR ⁇ binding assay (concentration: 10 ⁇ M) compound number Binding assay at 10 ⁇ M, (% of control) ERR ⁇ ERR ⁇ One 4.98 0 4 3.03 2.744 10 2.8 4.7 11 6.6 3.5 12 2.63 0 13 6.74 1.86 19 3.5 -9.0 20 2.1 -2.9 22 3.1 -2.0
  • ERR ⁇ /ERR ⁇ /ERR ⁇ binding assay and ERR ⁇ inverse agonist function assay (IC 50 ) compound number Binding Assay, IC 50 ( ⁇ M) functional assays, IC 50 ( ⁇ M) ERR ⁇ ERR ⁇ ERR ⁇ ER ⁇ ERR ⁇ One 0.023 0.850 0.033 0.730 0.010 12 0.021 >10 0.010 0.088 0.004 13 0.026 >10 0.018 0.165 0.005
  • the oral administration group is fasted one day before
  • blood is drawn 10 times from the jugular vein at 0.25, 0.5, 1, 4, 6, 8, 10, and 24 hours.
  • the amount of blood drawn once is 200ul.
  • a colorectal cancer data set obtained from the Oncomine database was used for ERR ⁇ / ⁇ gene analysis.
  • TMA tumor microarray
  • BC051110c tumor microarray
  • Representative areas of cancerous lesions were carefully selected from sections stained with hematoxylin and eosin, and two tissue cores (2 mm in diameter) were obtained from each paraffin block.
  • Immunohistochemical (IHC) staining of TMA was performed using anti-human ERR gamma (mouse monoclonal antibody; PP-H6812-00; dilution 1:100; R&D systems, Minneapolis, MN) and anti-human ERR beta (mouse monoclonal antibody). ;PP-H6707-00;dilution 1:100;R&D systems, Minneapolis, MN).
  • SPF Specific pathogen-free
  • 6-week-old male Balb/c nude mice and immunocompetent Balb/c mice were purchased from SLC, Inc. All animal experimental procedures were maintained and used in accordance with the Guidelines for Care and Use of Laboratory Animals of the Laboratory Animal Center Research Institute of Daegu Gyeongbuk Medical Innovation Foundation. Animal experiments were conducted after the approval of the Institutional Review Board for Ethics of Animal Experiments, Daegu Gyeongbuk Medical Innovation Foundation (approval number: DGMIF-19020701-00).
  • HCT-116, RKO, SW480, CT26, PC-3, A2780, MDA-MB231, MCF-7, BE2C, CAL62, BHT101, BHP103scp, BcPAP and Human fibroblast (BJ) cells were purchased from American Type Culture Collection (ATCC) did
  • A2780, HCT-116, RKO, CT26, PC3, MDA-MB231, MCF-7, BHP103scp and SW480 cells maintained in RPMI 1640 supplemented with 10% FBS (Gibco FBS; Thermo Fisher Scientific) and 1% streptomycin/penicillin It became.
  • BJ cells were cultured in high-glucose Dulbecco modified Eagle medium containing 10% fetal bovine serum (FBS) and 1% streptomycin/penicillin.
  • BE2C was maintained in DMEM:F-12 supplemented with 10% FBS and 1% streptomycin/penicillin.
  • CAL62 and BcPAP were maintained in DMEM supplemented with 10% FBS and 1% streptomycin/penicillin.
  • BHT101 was maintained in DMEM supplemented with 20% FBS and 1% streptomycin/penicillin. All cells were grown at 37°C and 5% CO 2 atmosphere. Mycoplasma testing was performed regularly monthly using the BioMycoX Mycoplasma PCR Detection Kit (CellSafe).
  • Cell viability was analyzed using Cell Counting Kit-8 (Dojindo molecular technologies, MD, USA). Each cell was seeded in a 96-well plate and treated with Compound 1 (DN203368) or Compound 12 (DN3317) at different concentrations. At the indicated time points, CCK-8 (10 ⁇ L/well) reagent was added to the cells, followed by further incubation at 37° C. for 90 minutes. Absorbance at 450 nm was measured using a plate reader (BioTek Instruments, Winooski, USA).
  • the cells were treated with Compound 1 (DN203368) for 24 hours in a 37°C, CO 2 incubator, and washed twice with PBS (phosphate-buffered saline).
  • Cell pellets were lysed using radioimmunoprecipitation assay (RIPA) buffer (Thermo Fisher Scientific, IL, USA) containing protease and phosphatase inhibitor cocktail kit (Thermo Fisher Scientific).
  • the lysed cells were briefly vortexed at intervals and then centrifuged at 13,000 xg at 4°C. Protein samples were quantified with a bicinchoninic acid (BCA) protein assay kit (Thermo Fisher Scientific).
  • BCA bicinchoninic acid
  • the primary antibodies used were as follows: ERR ⁇ (R&D systems), ERR ⁇ (R&D systems), PARP (Cell signaling; working dilution 1:1000), cleaved caspase3 (Cell signaling; dilution 1:1000), acetyl-p53 (Cell signaling; working dilution 1:1000).
  • the HRP-conjugated secondary antibodies used were: anti-mouse (Cell Signaling) and anti-rabbit (Cell Signaling).
  • caspase3/7 activity was measured using the luminescent Caspase-Glo3/7 (Promega) assay according to the manufacturer's instructions. That is, each of the HCT-116, SW480, and RKO cells were seeded in a white-walled 96-well culture plate at a density of 10 4 /well. Cells were treated at various time points after compound 1 (DN203368) treatment. After incubation, 100 ⁇ L Caspase-Glo3/7 reagent was added to each sample. The degree of luminescence was measured using IVIS Lumina III.
  • MDA-MB231 cells HCT116, RKO, SW480, CT26, BE2C, A2780, MDA-MB231 and BHP103scp were inoculated subcutaneously into mice at 2 ⁇ 10 6 each.
  • MDA-MB231 cells were injected into the mammary fat pad just below the nipple under anesthesia.
  • compound 1 DN203368 was administered intraperitoneally or orally once a day for 10 days.
  • Vehicle information is as follows: vehicle solution is 10% DMSO, 15% DW and 75% PEG (for intraperitoneal injection), 0.5% methyl cellulose solution (for oral administration).
  • Tumor size was measured with calipers at designated time points, and tumor volume (mm 3 ) was calculated using the formula below.
  • d and D are the shortest and longest diameters in mm, respectively.
  • Resected HCT116, RKO, SW480 and BHP103scp tumors were excised and fixed in 10% formalin for further experiments.
  • paraffin-embedded tissues were cut into sections according to standard H&E staining protocols. Paraffin-embedded sections of SW480, RKO, and BHP103scp tumor tissues, respectively, were deparaffinized, hydrated, and subjected to antigen retrieval for IHC staining. Endogenous peroxidase was inactivated by hydrogen peroxide for 10 minutes. Tumor tissue sections were mixed with rabbit monoclonal anti-Ki-67 (1:200, ab16667; Abcam) and rabbit polyclonal anti-cleaved caspase-3 (9661, #1:200 dilution, Cell Signaling, Boston, MA) according to the manufacturer's instructions. USA). A DAB detection kit (Pierce, Rockland, IL, USA) was used for visualization.
  • ERR ⁇ / ⁇ expression In order to investigate the clinical correlation between ERR ⁇ / ⁇ expression and colorectal cancer carcinogenesis, we analyzed ERR ⁇ / ⁇ expression in colorectal cancer patients using the Oncomine database. Higher levels were found in tissues.
  • a commercial tumor microarray (BC051110c, containing 12 normal tissues and 108 tumor tissues) obtained from colorectal cancer patients was used to determine the difference in ERR ⁇ / ⁇ protein expression between human colorectal cancer and normal colorectal tissues.
  • TMA tissue microarray
  • colorectal cancer tissue showed a higher level of ERR ⁇ / ⁇ expression than normal tissue (FIG. 1C).
  • ERR ⁇ / ⁇ is related to the pathophysiological characteristics of colorectal cancer, confirming that ERR ⁇ / ⁇ is a promising therapeutic target for colorectal cancer in vivo.
  • Oxaliplatin and 5-fluorouracil (5-FU) are widely applied alone or in combination with other treatments as first-line treatments for colorectal cancer cells.
  • the antiproliferative effect in cells treated with Compound 1 (DN203368) was higher than that in cells treated with conventional anticancer drugs oxaliplatin or 5-FU (FIG. 7). and Figure 8).
  • p21 binds to cyclin E/Cdk2 and cyclin D/Cdk4 complexes to induce cell cycle G1-phase arrest, and downregulation of CDK4 and cyclin D1 was confirmed in Compound 1 (DN203368)-treated cells.
  • Apoptosis-related proteins were further identified in Compound 1 (DN203368)-treated colon cancer cells.
  • Bcl-2 anti-apoptotic protein
  • Compound 1 (DN203368) showed an increase in BID (proapoptotic protein).
  • compound 1 (DN203368) treatment resulted in a dose-dependent increase in cleaved caspase 3 and cleaved PARP.
  • a time-dependent decrease in Bcl-2 as well as an increase in cleaved caspase 3 and cleaved PARP1 were confirmed in Compound 1 (DN203368)-treated HCT116 cells (Fig. 11E).
  • compound 1 (DN203368) was administered to each tumor-bearing mouse via intraperitoneal injection every day for 10 days.
  • the antitumor effect was first found with a significant difference on day 4 and continued until day 18 (FIG. 14B).
  • RKO xenografts significant inhibition of tumor growth was found in compound 1 (DN203368)-treated mice on day 6 after treatment, and anti-tumor effect was also found on day 16 (FIG. 14C). Abnormal behavior and weight loss were not found during administration of Compound 1 (DN203368) (Fig.
  • SW480 and RKO tumors were excised after in vivo treatment, and immunohistochemical analysis was performed to determine tumor cell proliferation and cleaved caspase-3 levels.
  • FIG. 14F immunohistochemistry using the Ki-67 antibody as a tumor cell proliferation marker showed higher expression in vehicle-treated SW480 tumors than in Compound 1 (DN203368)-treated SW480 tumors.
  • Immunohistochemical staining using a cleaved caspase-3 antibody showed a greater increase in expression in Compound 1 (DN203368)-treated tumors than vehicle-treated tumors (FIG. 14 F and G). From this, it was confirmed that Compound 1 (DN203368) can be used as an anticancer agent for treating colon cancer.
  • FIG. 15 In order to confirm the antitumor effect of compound 1 (DN203368) on colon cancer through oral administration, an experiment was conducted using a colon cancer model including HCT-116 and CT26 cells as shown in FIG. 15 .
  • Tumor-bearing mice were administered 10 mg/kg Compound 1 (DN203368) via oral administration once a day for 10 days.
  • FIG. 15B oral administration of Compound 1 (DN203368) successfully induced an antitumor effect in HCT-116 xenografts, and a significant difference was first observed on day 13 after treatment.
  • CT26 tumor growth was significantly inhibited in Compound 1 (DN203368)-treated mice, whereas it was not observed in vehicle-treated mice (Fig. 15D).
  • cancer cells other than colorectal cancer namely prostate cancer (PC-3), ovarian cancer (A2780), breast cancer (MDA-MB231, MCF-7), neuroblastoma (BE2C), undifferentiated and dedifferentiated thyroid cancer (CAL62, BHT101, BHP103scp, The inhibitory effect of Compound 1 (DN203368) on the proliferation of BcPAP) cells was investigated.
  • the results of the CCK-8 assay showed that Compound 1 (DN203368) induced dose-dependent inhibition of proliferation of prostate, ovarian, breast, neuroblastoma, undifferentiated and dedifferentiated thyroid cancer cells (FIG. 17A and B). However, no anti-proliferative effect was observed in normal cells such as fibroblasts (BJ cells) and epithelial cells (CHO cells) (FIGS. 3 and 17A). From the above results, the selective cytotoxicity of Compound 1 (DN203368) in cells of prostate cancer, ovarian cancer, breast cancer, neuroblastoma, and undifferentiated and dedifferentiated thyroid cancer cells was confirmed.
  • Compound 1 (DN203368) was administered to each tumor-bearing mouse via intraperitoneal injection every day for 14 days. The antitumor effect was confirmed from the 14th day and continued until the 30th day, and significance was also confirmed (FIG. 18A).
  • Compound 1 (DN203368) was administered to each tumor-bearing mouse via intraperitoneal injection daily for 14 days.
  • (DN203368)-treated mice tumor growth inhibition was found to be significant, and the anti-tumor effect was consistently found even on day 16 (FIG. 18B).
  • Compound 1 (DN203368) was administered to each tumor-bearing mouse via intraperitoneal injection every day for 14 days. On day 15 after treatment, tumor growth inhibition was found in compound 1 (DN203368)-treated mice, and anti-tumor effect was also found on day 23, and significance was also confirmed (FIG. 19A).
  • Compound 1 (DN203368) was administered to each tumor-bearing mouse via intraperitoneal injection every day for 14 days. On day 3 after treatment, significant inhibition of tumor growth was found in Compound 1 (DN203368)-treated mice, and antitumor effect was also found on day 23 (FIG. 19B).
  • Compound 1 (DN203368) was administered to tumor-bearing mice via intraperitoneal injection every day for 14 days. On day 8 after treatment, significant inhibition of tumor growth was found in Compound 1 (DN203368)-treated mice, and antitumor effect was also found on day 14 (Fig. 20A). Abnormal behavior and weight loss were not found during administration of Compound 1 (DN203368) (FIG. 20B). BHP103scp tumors were excised after in vivo treatment, and immunohistochemical analysis was performed to determine tumor cell proliferation and cleaved caspase-3 levels. As shown in FIG.
  • Compound 1 can be used as an anticancer agent for treating various intractable cancers such as colorectal cancer, neuroblastoma, ovarian cancer, breast cancer, and dedifferentiated thyroid cancer.
  • the inhibitory effect of Compound 12 (DN3317) on the proliferation of prostate cancer (PC-3), ovarian cancer (A2780), glioblastoma (U87MG) and dedifferentiated thyroid cancer (BHP103scp, BcPAP) cells was investigated.
  • the ethene compound according to the present invention since the ethene compound according to the present invention selectively exhibits high inhibitory activity and antiproliferative effect on cancer cells, it can be usefully used for preventing or treating cancer.
  • the survival rate of cancer cells can be significantly reduced compared to when each is used alone, and the antiproliferative effect can be maintained over a long period of time.

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Abstract

La présente invention concerne un composé éthène dans une nouvelle structure, un sel pharmaceutiquement acceptable de celui-ci, ou un N-oxyde de celui-ci, qui agissent chacun en tant qu'agoniste inverse du récepteur β/γ (ERRβ/γ) associé aux œstrogènes, et une composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement du cancer.
PCT/KR2022/007099 2021-05-18 2022-05-18 Nouveau composé d'éthène et composition pharmaceutique le comprenant en tant que principe actif pour la prévention ou le traitement du cancer WO2022245124A1 (fr)

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