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WO2021162451A1 - Composition pharmaceutique pour la prévention ou le traitement du cancer, contenant des acides biliaires ou des dérivés de ceux-ci, composés à base de biguanide, et deux ou plus de deux types d'agents antiviraux en tant que principes actifs - Google Patents

Composition pharmaceutique pour la prévention ou le traitement du cancer, contenant des acides biliaires ou des dérivés de ceux-ci, composés à base de biguanide, et deux ou plus de deux types d'agents antiviraux en tant que principes actifs Download PDF

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WO2021162451A1
WO2021162451A1 PCT/KR2021/001785 KR2021001785W WO2021162451A1 WO 2021162451 A1 WO2021162451 A1 WO 2021162451A1 KR 2021001785 W KR2021001785 W KR 2021001785W WO 2021162451 A1 WO2021162451 A1 WO 2021162451A1
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carcinoma
adenocarcinoma
cancers
cancer
cell carcinoma
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Korean (ko)
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박수현
김샛별
김정훈
모영원
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Frontbio Inc
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Frontbio Inc
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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/395—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
    • A61K31/536—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 ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • 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 a pharmaceutical composition for preventing or treating cancer containing two or more of bile acids or derivatives thereof, biguanide-based compounds and antiviral agents as active ingredients.
  • the present invention is a bile acid or a derivative thereof, a biguanide-based compound, an antiviral agent, an antidepressant, a thiazolidinedione-based compound, and cancer prevention containing two or more of its pharmaceutically acceptable salts as an active ingredient or to a pharmaceutical composition for treatment.
  • Cancer is a disease caused by the uncontrolled growth of cells that can come into contact with tissues or other parts of the body and spread. have. Normal cells differentiate until they reach maturity and then replace damaged or dead cells as needed. Malignant tumor cells metastasize to other parts of the body through the bloodstream or lymphatic system, where they multiply and form new tumors.
  • cancer still seriously threatens human health worldwide.
  • the main cancer treatment methods include surgery, radiation therapy, hormone therapy, and chemotherapy, among which chemotherapy is a method of directly treating cancer or relieving symptoms using one or more anticancer drugs.
  • chemotherapeutic agents exhibit cytotoxicity to cancer cells by interfering with cancer cell division and metabolism, or by inhibiting the biosynthesis of nucleic acids or proteins.
  • these chemotherapeutic agents have a problem of causing serious side effects, such as a problem that cancer cells have resistance to an anticancer agent, and toxicity to normal tissues.
  • substances used as existing anticancer drugs affect cancer cells, but are also toxic to normal cells, causing various side effects in many cases. Therefore, there is a need for an anticancer therapeutic agent that does not have toxicity to normal cells, exhibits excellent toxicity selective only to cancer cells, and has excellent anticancer activity.
  • ursodeoxycholic acid has been reported to have anticancer effects in colon cancer
  • ursodeoxycholic acid and chenodeoxycholic acid derivatives have been reported to have anticancer effects in prostate cancer and breast cancer.
  • Biguanide drugs such as metformin, phenformin, buformin, or biguanide, inhibit glucose production in the liver and reduce glycolysis in peripheral blood vessels. It is still widely used as a treatment for type 2 diabetes. Metformin, phenformin, buformin, or biguanide activates AMPK (AMP-activated protein kinase), a key enzyme in metabolic regulation, to inhibit protein, lipid lipid, and glycogen synthesis and promote degradation. Inhibits the production of leptin and adiponectin. On the other hand, since activated AMPK inhibits cell regeneration, it inhibits cancer cell metabolism and inhibits cell division.
  • AMPK AMP-activated protein kinase
  • AMPK activation directly inhibits mTOR (mammalian target of rapamycin) and eventually inhibits protein synthesis, thereby inhibiting cancer cell proliferation.
  • metformin inhibits the growth of cancer cells by inhibiting the expression of angiogenesis promoters. Due to this anticancer mechanism, metformin and phenformin alone or in combination with other anticancer drugs have been tried in clinical trials of various types of cancer, but their therapeutic effects have been different, and they have not yet been approved as anticancer drugs due to various problems. is not in a state of
  • An antiviral agent is a drug that treats an infectious disease caused by a virus by weakening or eliminating the action of a virus that has invaded the human body. According to the mechanism of action, it can be classified into virus adhesion and penetration inhibitors and virus growth inhibitors. Most antiviral agents exhibit antiviral action by inhibiting various types of enzymes required for virus propagation.
  • HIV Human Immunodeficiency Virus
  • HIV-1 HIV type-1
  • type-2 HIV-2
  • AIDS acquired immunodeficiency syndrome
  • HIV is a retrovirus
  • the HIV replication cycle requires transcription of the viral RNA genome into DNA via reverse transcriptase.
  • compounds that inhibit the enzymatic action of HIV reverse transcriptase are being developed as HIV antiviral agents.
  • NRTI Nucleoside Reverse Transcriptase Inhibitor
  • NRTI Non nucleoside Reverse Transcriptase Inhibitor
  • FDA-approved NRTIs include zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil fumarate), emtricitabine, and tenofovir alafenamide fumarate.
  • NNRTI does not act as a terminator of viral DNA synthesis, but directly binds to a hydrophobic pocket near the active site of reverse transcriptase and inhibits enzymatic action by changing the structure of the enzyme.
  • FDA-approved NNRTIs include efavirenz, etravirine, nevirapine, doravirine, rilpivirine, and delavirdine.
  • Protease inhibitors are compounds that inhibit the enzyme that cleaves the precursor proteins of Gag and Gag-Pol contained in non-infectious virions and transforms them into infective mature viruses.
  • the enzyme plays a very important role in virus propagation and the size is very small (11 kDa), it was expected that resistance would be small, but resistance mutations occurred at a very high frequency. It is mainly used only for PIs include saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, atazanavir, and fosamprenavir. , tipranavir, and darunavir.
  • efavirenz has been reported to have an anticancer effect in glioblastoma, pancreatic cancer and ovarian cancer
  • etravirine has been reported to have an anticancer effect in ovarian cancer
  • nevirapine has an inhibitory effect on cancer cell metastasis in liver and thyroid cancer. It has been reported that the combination of nelfinavir, lopinavir and vincristine has an effect of reducing the viability of oral squamous cell carcinoma cells.
  • Antidepressants are drugs that improve depressive symptoms by regulating the imbalance of neurotransmitters (serotonin, norepinephrine, and dopamine) associated with depression.
  • Tricyclic antidepressants TCAs
  • monoamine oxidase It can be classified into inhibitors (monoamine oxidase inhibitors, MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and the like.
  • Tricyclic antidepressants block the reuptake of serotonin and norepinephrine at the nerve cell terminals, thereby increasing the concentration of neurotransmitters in the synapse, thereby improving the symptoms of depression.
  • These include clomipramine, imipramine, and amoxapine.
  • Selective serotonin reuptake inhibitors are substances that selectively block reuptake of serotonin at the nerve cell terminal and increase the concentration of serotonin in the synapse, thereby increasing the activity of serotonin and alleviating depressive symptoms.
  • Fluoxetine, paroxetine, Drugs such as fluvoxamine, sertraline, escitalopram, and vortioxetine are used for depression, obsessive-compulsive disorder, and premenstrual dysphoric disorder. Compared to tricyclic antidepressants, it is superior in side effects and safety, and is the most used antidepressant.
  • Thiazolidinediones (TZD)-based compounds that improve insulin action in muscle and fat as a type of diabetes treatment agent include pioglitazone and lobeglitazone.
  • Thiazolidinedione-based compounds and their compounds The anticancer effects of derivatives are being investigated. For example, it has been reported that pioglitazone has an anticancer effect in renal cancer.
  • the present inventors have researched to develop a combination of substances with more excellent anticancer effect, and as a result, a combination of a bile acid or a salt thereof and a biguanide-based compound, a biguanide-based compound and an antiviral agent, a bile acid, a biguanide-based compound And by revealing that the combination of antiviral agents, the combination of which an antidepressant or a thiazolidinedione-based compound is added shows a remarkable synergism in anticancer effect, it led to the invention of a new combination, combination or combination anticancer agent.
  • AMPK AMPactivated protein kinase
  • Piatkowska-Chmiel I Gawronska-Grzywacz M, et al. Pioglitazone as a modulator of the chemoresistance of renal cell adenocarcinoma to methotrexate. Oncol Rep. 2020 Mar;43(3):1019-1030. doi: 10.3892/or.2020.7482.
  • Substances used as existing anticancer drugs affect cancer cells, but they are also toxic to normal cells, for example, rapidly dividing normal cells, such as skin, mucous membranes, and blood cells, causing various side effects such as hair loss, diarrhea, and leukopenia.
  • cancer cells the expression of antiapoptotic proteins such as BCL-2 is increased or the expression of proapoptotic proteins such as BAX is suppressed. apoptosis) is often absent.
  • the expression of caspases is low or mutations in the caspase gene may appear.
  • cancer cells inhibit apoptosis by inhibiting mitochondrial outer membrane permeabilization (MOMP). Since apoptosis does not occur in many cancer cells, there is a problem that the therapeutic effect of many anticancer drugs that induce apoptosis does not appear.
  • MOMP mitochondrial outer membrane permeabilization
  • the present invention is a complex, mixed, or combination preparation for use in the prevention or treatment of cancer, including bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds and their compounds.
  • a first component comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and a second component including a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, thereby solving the above problem.
  • a first component comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; And by providing a pharmaceutical composition containing a second component comprising an antiviral agent as an active ingredient has solved the above problem.
  • a complex, mixed or combined preparation for use in the prevention or treatment of cancer comprising: a first component comprising an antiviral agent; and a second component including a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof as an active ingredient, thereby solving the above problem.
  • the first component a second component; and by providing a pharmaceutical composition containing as an active ingredient a third component comprising at least one compound selected from the group consisting of antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof, the above problems have been solved.
  • the bile acid or bile acid derivative may be a cholic acid-based compound or a derivative thereof, and the cholic acid-based compound or a derivative thereof is cholic acid, chenodeoxycholic acid, de Deoxycholic acid, ursodeoxycholic acid, lithocholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, tau taurochenodeoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, tauroursodeoxycholic acid, glyco It may be selected from the group consisting of lithocholic acid and taurolithocholic acid.
  • cholic acid-based compound or a derivative thereof may be a compound of Formula 1 below:
  • R 1 and R 2 are each independently H or OH, and R 3 is OH, NHCH 2 COOH, or NH(CH 2 ) 2 SO 2 OH.
  • R 1 may be H
  • R 2 and R 3 may be OH
  • R 1 and R 3 may be OH
  • R 2 may be H
  • R 1 , R 2 and R 3 may be OH
  • R 1 and R 2 may be H
  • R 3 may be OH
  • R 1 may be H
  • R 2 is OH
  • R 3 may be NHCH 2 COOH or NH(CH 2 ) 2 SO 2 OH
  • R 1 is OH
  • R 2 is H
  • R 3 is NHCH 2 COOH or NH (CH 2 ) 2 SO 2 OH
  • R 1 and R 2 are OH
  • R 3 can be NHCH 2 COOH or NH(CH 2 ) 2 SO 2 OH
  • R 1 and R 2 are H
  • R 3 may be NHCH 2 COOH or NH(CH 2 ) 2 SO 2 OH.
  • bile acid or bile acid derivative may be selected from the group consisting of compounds of Formulas 2 to 9 below:
  • R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ]
  • R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ]
  • R is H or CN.
  • R 1 and R 2 are each independently H, CH 3 CO or CH 3 SO 3 ]
  • R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ]
  • R is H, CH 3 CO or CH 3 SO 3 ]
  • R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ]
  • R is NH(CH 2 ) 2 COOC 10 H 14 , NHCH(CH 2 C 6 H 5 )COOC 4 H 9 or NH(CH 2 ) 2 COOC 4 H 9 ]
  • the biguanide-based compound may be selected from the group consisting of metformin, phenformin, buformin and biguanide.
  • the antiviral agent is non-nucleoside reverse-transcriptase inhibitors (NNRTIs; Non-nucleoside reverse-transcriptase inhibitors), nucleoside reverse-transcriptase inhibitors (NRTIs; Nucleoside reverse-transcriptase inhibitors), protease inhibitors ( PIs; Protease inhibitors), Integrase Strand Transfer Inhibitors (INSTIs), fusion inhibitors, CCR 5 (Chemokine (CC motif) ligand 5) inhibitors, Influenza treatment, Herpes treatment, Hepatitis B treatment, Hepatitis C treatment, It may be an immune enhancer, an immune response modulating compound or a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • NRTIs non-nucleoside reverse-transcriptase inhibitors
  • NRTIs nucleoside reverse-transcriptase inhibitors
  • protease inhibitors PIs
  • Protease inhibitors Protease inhibitors
  • the antiviral agent is efavirenz, etravirine, nevirapine, doravirine, rilpivirine, delavirdine, zidovudine. ), didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil fumarate, emtricitabine ), tenofovir alafenamide fumarate, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir , lopinavir, atazanavir, fosamprenavir, tipranavir, darunavir, cobicistat, dolutegravir , raltegravir, enfuvirtide, maraviroc, elvitegravir, tenofovir alafenamide, tenofovir disoproxil ), amantadine, rimantadine,
  • the third component is amitriptyline, nortriptyline, clomipramine, imipramine, amoxapine, fluoxetine (fluoxetine, paroxetine, fluvoxamine, sertraline, escitalopram, vortioxetine, moclobemide, duloxetine ), venlafaxine, desbenlafaxine, milnacipran, bupropion, mirtazapine, trazodone, tianeptine, pioglitazone, pioglitazone lobeglitazone, rosiglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, It may be selected from the group consisting of troglitazone, and balaglitazone.
  • the cancer is (A) (1) in-place ductal carcinoma (DCIS) (comedon carcinoma, filamentous, papillary, micropapillary), infiltrating ductal carcinoma (IDC), ductal carcinoma, mucinous (colloidal) ductal carcinomas, including carcinomas, papillary carcinomas, metaplastic carcinomas and inflammatory carcinomas; (2) lobular carcinomas, including in-situ lobular carcinoma (LCIS) and invasive lobular carcinoma; and (3) breast cancer, including Paget's disease of the nipples; (B) (1) cervical intraepithelial tumor (grade I), cervical intraepithelial tumor (grade II), cervical intraepithelial tumor (grade III) (orthostatic squamous cell carcinoma), keratogenic squamous cell carcinoma, non-keratinizing squamous cell cancers of the cervix, including carcinomas, warts, orthotopic adenocarcinomas, orthostatic adenocarcinomas,
  • DCIS in-
  • the pharmaceutical composition is selected from the group consisting of tablets, capsules, injections, troches, powders, granules, solutions, suspensions, internal solutions, emulsions, syrups, suppositories, vaginal tablets, and pills. It can be formulated in a form that is
  • two or more compounds selected from the group consisting of bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof A complex, mixed, or combination kit for the prevention or treatment of cancer, containing a formulation comprising a, is provided.
  • a preparation comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof, is provided.
  • a preparation comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and an antiviral agent.
  • Combination, combination or combination kits are provided.
  • a formulation comprising an antiviral agent; and a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof, is provided.
  • the agent; and an antidepressant, a thiazolidinedione-based compound, and a pharmaceutically acceptable salt thereof, further containing a formulation comprising at least one compound selected from the group consisting of, a combination, mixture or combination kit is provided.
  • two or more compounds selected from the group consisting of bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof comprising the step of complex, mixed or co-administered to a subject in a pharmaceutically effective amount.
  • bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceuticals thereof for use as a pharmaceutical composition for the prevention and treatment of cancer
  • a complex, mixed or combined preparation containing two or more compounds selected from the group consisting of acceptable salts as an active ingredient.
  • a combination of a bile acid or a salt thereof and a biguanide-based compound a combination of a biguanide-based compound and an antiviral agent, a bile acid, a biguanide-based compound and an antiviral agent, and an antidepressant or a thiazolidinedione-based compound
  • the anticancer effect is weak, but when combined, mixed or treated in combination, a significantly high anticancer effect is shown in various carcinomas. It can be usefully used for treatment.
  • it since it does not show toxicity to normal cells at an effective concentration, it can provide an anticancer agent with excellent anticancer effect while significantly reducing side effects.
  • Figure 1a shows 5 mM metformin, 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate, 5 mM metformin + 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate in breast cancer cells MCF-7 It is a diagram showing the degree of growth inhibition (% growth inhibition) when the cell line was treated for 24, 48, 72 hours;
  • Blue bar graph (1) Growth inhibition of cancer cells (percentage) when only 5 mM metformin (Control right blue bar graph) or 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate (other blue bar graphs) were treated alone ;
  • Red bar graph (2) 5 mM metformin plus 0.01, 0.1, 1, and 10 ⁇ M sodium deoxycholate in combination for 24 hours to inhibit growth of cancer cells (percentage);
  • Green bar graph (3) the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate were co-treated for 48 hours;
  • Purple bar graph (4) the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1, and 10 ⁇ M sodium deoxycholate were co-treated for 72 hours.
  • Figure 1b shows WISH primary epithelial cells treated with 5 mM metformin, 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate, 5 mM metformin + 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate for 24 hours.
  • This is a diagram showing the degree of growth inhibition (% growth inhibition);
  • Blue bar graph (1) Growth inhibition of cancer cells (percentage) when only 5 mM metformin (Control right blue bar graph) or 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate (other blue bar graphs) were treated alone ;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate were co-treated.
  • Figures 2a and 2b show that 5 mM metformin, 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate, 5 mM metformin + 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate were administered to the AsPC-1 cell line, which is a pancreatic cancer cell ( Figure 2a). ) and MIA PaCa-2 cell line (FIG. 2b) is a diagram showing the degree of growth inhibition (% growth inhibition) when treated for 24 hours;
  • Blue bar graph (1) Growth inhibition of cancer cells (percentage) when only 5 mM metformin (Control right blue bar graph) or 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate (other blue bar graphs) were treated alone ;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate were co-treated.
  • LNcaP cell lines which are prostate cancer cells, for 24 hours. It is a diagram showing the degree of inhibition (% growth inhibition);
  • Blue bar graph (1) Growth inhibition of cancer cells (percentage) when only 5 mM metformin (Control right blue bar graph) or 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate (other blue bar graphs) were treated alone ;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1 and 10 ⁇ M sodium deoxycholate were co-treated.
  • Figure 4a shows that 5 mM metformin, 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid, 5 mM metformin + 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid were administered to breast cancer cells in the MCF-7 cell line. It is a diagram showing the degree of growth inhibition when treated with time;
  • Green bar graph (3) the degree of growth inhibition (percent) of cancer cells when only 5 mM metformin was treated
  • Blue bar graph (1) the degree of growth inhibition (percent) of cancer cells when only 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid were treated alone;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1, and 10 ⁇ M ursodeoxycholic acid were co-treated.
  • Figure 4b is a diagram showing the degree of growth inhibition (% growth inhibition) when 5 mM metformin + 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid was treated in WISH normal epithelial cells (primary epithelial cells) for 24 hours.
  • Figures 5a and 5b show that 5 mM metformin, 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid, 5 mM metformin + 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid were administered to a pancreatic cancer cell AsPC-1 cell line ( Figure 5a). ) and MIA PaCa-2 cell line (FIG. 5b) is a diagram showing the degree of growth inhibition (% growth inhibition) when treated for 24 hours;
  • Green bar graph (3) the degree of growth inhibition (percent) of cancer cells when only 5 mM metformin was treated
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when only 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid were treated alone;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1, and 10 ⁇ M ursodeoxycholic acid were co-treated.
  • Figures 6a and 6b show that 5 mM metformin, 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid, 5 mM metformin + 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid were administered to prostate cancer cells in the LNcaP cell line (Fig. 6a) and It is a diagram showing the degree of growth inhibition (% growth inhibition) when treated with DU145 cell line (FIG. 6b) for 24 hours;
  • Green bar graph (3) the degree of growth inhibition (percent) of cancer cells when only 5 mM metformin was treated
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when only 0.01, 0.1, 1 and 10 ⁇ M ursodeoxycholic acid were treated alone;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1, and 10 ⁇ M ursodeoxycholic acid were co-treated.
  • Figure 7a shows the extent of growth inhibition (% growth inhibition) when 5 mM metformin, 1 and 2 ⁇ M efavirenz, and 5 mM metformin + 1 and 2 ⁇ M efavirenz were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. ) is a diagram showing;
  • Blue bar graph (1) the degree of cancer cell growth inhibition (percent) when only 5 mM metformin (Control right blue bar graph) or 1 and 2 ⁇ M efavirenz (other blue bar graphs) were treated alone;
  • Red bar graph (2) the degree of inhibition of cancer cell growth (percent) when 5 mM metformin and 1 and 2 ⁇ M efavirenz were co-treated.
  • Figure 7b shows the degree of growth inhibition (% growth inhibition) when 5 mM metformin, 1 and 2 ⁇ M efavirenz, 5 mM metformin + 1 and 2 ⁇ M efavirenz were treated with WISH for 24 hours. ) is a diagram showing;
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when only 5 mM metformin (Control right blue bar graph) or 1 and 2 ⁇ M efavirenz (other blue bar graphs) were treated alone;
  • Red bar graph (2) the degree of inhibition of cancer cell growth (percentage) when 5 mM metformin and 1 and 2 ⁇ M efavirenz were co-treated.
  • FIG. 8 shows the degree of growth inhibition (% growth inhibition) when 1 mM metformin, 0.1 and 1 ⁇ M etravirine, 1 mM metformin + 0.1 and 1 ⁇ M etravirine were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. ) is a diagram showing;
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when treated with either 1 mM metformin (Control right blue bar graph) or 0.1 and 1 ⁇ M etravirine (other blue bar graphs) alone;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 0.1 and 1 ⁇ M etravirine were co-treated.
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when treated with either 1 mM metformin (Control right blue bar graph) or 0.1 and 1 ⁇ M nevirapine (other blue bar graphs) alone;
  • Red bar graph (2) the degree of inhibition of cancer cell growth (percent) when 1 mM metformin and 0.1 and 1 ⁇ M nevirapine were co-treated.
  • FIG. 10 is a diagram showing the degree of growth inhibition (% growth inhibition) when 1 mM metformin, 0.1 and 1 ⁇ M lamivudine, 1 mM metformin + 0.1 and 1 ⁇ M lamivudine were treated for 24 hours in the ASPC-1 cell line, which is pancreatic cancer cells. am;
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when treated with either 1 mM metformin (Control right blue bar graph) or 0.1 and 1 ⁇ M lamivudine (other blue bar graphs) alone;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 0.1 and 1 ⁇ M lamivudine were co-treated.
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when treated with either 1 mM metformin (Control right blue bar graph) or 0.1 and 1 ⁇ M lopinavir (other blue bar graphs) alone;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 0.1 and 1 ⁇ M lopinavir were co-treated.
  • Blue bar graph (1) the degree of cancer cell growth inhibition (percent) when treated with either 1 mM metformin (Control right blue bar graph) or 10, 20, and 40 ⁇ M atazanavir (other blue bar graphs) alone;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 10, 20, and 40 ⁇ M atazanavir were co-treated.
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when treated with either 1 mM metformin (Control right blue bar graph) or 10, 20 and 40 ⁇ M darunavir (other blue bar graphs) alone; and
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 10, 20, and 40 ⁇ M darunavir were co-treated.
  • FIG. 14 shows the degree of growth inhibition when 1 mM metformin, 10, 20 and 40 ⁇ M ritonavir, and 1 mM metformin + 10, 20 and 40 ⁇ M ritonavir were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours.
  • (% growth inhibition) is a diagram showing;
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when treated with either 1 mM metformin (Control right blue bar graph) or 10, 20 and 40 ⁇ M ritonavir (other blue bar graphs) alone;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 10, 20, and 40 ⁇ M ritonavir were co-treated.
  • Blue bar graph (1) the degree of cancer cell growth inhibition (percent) when only 2.5 mM metformin, 2 ⁇ M efavirenz, or 20 ⁇ M ursodeoxycholic acid was treated;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 2 ⁇ M efavirenz and 20 ⁇ M ursodeoxycholic acid were co-treated.
  • Blue bar graph (1) the degree of cancer cell growth inhibition (percent) when only 2.5 mM metformin, 2 ⁇ M efavirenz, or 10 ⁇ M pioglitazone was treated;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 2 ⁇ M efavirenz, and 10 ⁇ M pioglitazone were co-treated.
  • 17 shows the degree of growth inhibition (% growth inhibition) when 2.5 mM metformin, 2 ⁇ M efavirenz and 10 ⁇ M pioglitazone, 2.5 mM metformin + 2 ⁇ M efavirenz + 10 ⁇ M pioglitazone were treated in HCT116 cell line, a colon cancer cell line for 24 hours. is a diagram showing;
  • Blue bar graph (1) the degree of cancer cell growth inhibition (percent) when only 2.5 mM metformin, 2 ⁇ M efavirenz, or 10 ⁇ M pioglitazone was treated;
  • Red bar graph (2) the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 2 ⁇ M efavirenz, and 10 ⁇ M pioglitazone were co-treated.
  • Figure 18 shows that 0.5 ⁇ M efavirenz, 0.5 ⁇ M fluoxetine and 200 ⁇ M ursodeoxycholic acid (UDCA), 0.5 ⁇ M efavirenz + 0.5 ⁇ M fluoxetine + 200 ⁇ M ursodeoxycholic acid were treated in HCT116 cell line, a colon cancer cell, for 24 hours. It is a diagram showing the degree of growth inhibition (% growth inhibition);
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when only 0.5 ⁇ M efavirenz was treated;
  • Green bar graph (2) the degree of inhibition of cancer cell growth (percent) when 0.5 ⁇ M fluoxetine alone was treated;
  • Yellow bar graph (3) the degree of inhibition of cancer cell growth (percent) when only 200 ⁇ M ursodeoxycholic acid was treated.
  • Red bar graph (4) the degree of growth inhibition (percent) of cancer cells when 0.5 ⁇ M efavirenz, 0.5 ⁇ M fluoxetine and 200 ⁇ M ursodeoxycholic acid were co-treated.
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when only 0.5 ⁇ M efavirenz was treated;
  • Green bar graph (2) the degree of inhibition of cancer cell growth (percent) when 0.5 ⁇ M fluoxetine alone was treated;
  • Yellow bar graph (3) the degree of inhibition of cancer cell growth (percent) when 200 ⁇ M ursodeoxycholic acid alone was treated.
  • Red bar graph (4) the degree of growth inhibition (percent) of cancer cells when 0.5 ⁇ M efavirenz, 0.5 ⁇ M fluoxetine and 200 ⁇ M ursodeoxycholic acid were co-treated.
  • Figure 20 shows the degree of growth inhibition when 2.5 mM metformin, 10 ⁇ M pioglitazone and 20 ⁇ M ursodeoxycholic acid (UDCA), 2.5 mM metformin + 10 ⁇ M pioglitazone + 20 ⁇ M ursodeoxycholic acid were treated in HCT116 cell line, a colorectal cancer cell, for 24 hours.
  • (% growth inhibition) is a diagram showing;
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when only 2.5 mM metformin was treated;
  • Green bar graph (2) the degree of inhibition of cancer cell growth (percent) when 10 ⁇ M pioglitazone alone was treated;
  • Yellow bar graph (3) the degree of inhibition of cancer cell growth (percent) when only 20 ⁇ M ursodeoxycholic acid was treated.
  • Red bar graph (4) the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 10 ⁇ M pioglitazone and 20 ⁇ M ursodeoxycholic acid were co-treated.
  • Figure 21 shows growth when 2.5 mM metformin, 10 ⁇ M pioglitazone and 20 ⁇ M ursodeoxycholic acid (UDCA), 2.5 mM metformin + 10 ⁇ M pioglitazone + 20 ⁇ M ursodeoxycholic acid were treated in the AsPC-1 cell line as pancreatic cancer cells for 24 hours. It is a diagram showing the degree of inhibition (% growth inhibition);
  • Blue bar graph (1) the degree of inhibition of cancer cell growth (percent) when only 2.5 mM metformin was treated;
  • Green bar graph (2) the degree of inhibition of cancer cell growth (percent) when 10 ⁇ M pioglitazone alone was treated;
  • Yellow bar graph (3) the degree of inhibition of cancer cell growth (percent) when only 20 ⁇ M ursodeoxycholic acid was treated.
  • Red bar graph (4) the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 10 ⁇ M pioglitazone and 20 ⁇ M ursodeoxycholic acid were co-treated.
  • prevention means any action that suppresses the onset or delays the onset by administration of the composition.
  • improvement means any action in which the symptoms of the disease are improved or beneficially changed by administration of the composition.
  • administration means providing a predetermined substance to a patient by any suitable method, and the route of administration of the composition of the present invention is oral or parenteral through all common routes as long as it can reach the target tissue. may be administered.
  • the composition may be administered by any device capable of transporting the active agent to a target cell.
  • the present invention is a complex, mixed, or combination preparation for use in the prevention or treatment of cancer, including bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and compounds thereof It provides a pharmaceutical composition for preventing or treating cancer, containing two or more compounds selected from the group consisting of pharmaceutically acceptable salts as an active ingredient.
  • the pharmaceutical composition for the prevention or treatment of cancer is a first comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof. ingredient; and a second component including a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition for the prevention or treatment of cancer is a first comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof. ingredient; And it may contain a second component including an antiviral agent as an active ingredient.
  • the pharmaceutical composition for the prevention or treatment of cancer includes a first component comprising an antiviral agent; and a second component including a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition for the prevention or treatment of cancer is an antidepressant, a thiazolidinedione-based compound, and a pharmaceutically acceptable salt thereof from the group consisting of
  • a third component including at least one selected compound may be further contained as an active ingredient.
  • the biguanide-based compound according to the present invention may be selected from the group consisting of metformin, phenformin, buformin and biguanide.
  • metformin is a compound of formula (10):
  • phenformin is a compound of formula (11):
  • buformin is a compound of formula (12):
  • biguanide is a compound of the following formula (13):
  • the bile acid or bile acid derivative according to the present invention may be a cholic acid-based compound or a derivative thereof, and the cholic acid-based compound or a derivative thereof is cholic acid, chenodeoxycholic acid, deoxy Deoxycholic acid, ursodeoxycholic acid, lithocholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, tauroke taurochenodeoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, tauroursodeoxycholic acid, glycoside It may be selected from the group consisting of tocholic acid (glycolithocholic acid) and taurolithocholic acid.
  • cholic acid-based compound or a derivative thereof according to the present invention may be a compound of Formula 1 below:
  • R 1 and R 2 are each independently H or OH, and R 3 is OH, NHCH 2 COOH, or NH(CH 2 ) 2 SO 2 OH.
  • R 1 may be H
  • R 2 and R 3 may be OH
  • R 1 and R 3 may be OH
  • R 2 may be H
  • R 1 , R 2 and R 3 may be OH
  • R 1 and R 2 may be H
  • R 3 may be OH
  • R 1 may be H
  • R 2 is OH
  • R 3 may be NHCH 2 COOH or NH(CH 2 ) 2 SO 2 OH
  • R 1 is OH
  • R 2 is H
  • R 3 is NHCH 2 COOH or NH (CH 2 ) 2 SO 2 OH
  • R 1 and R 2 are OH
  • R 3 can be NHCH 2 COOH or NH(CH 2 ) 2 SO 2 OH
  • R 1 and R 2 are H
  • R 3 may be NHCH 2 COOH or NH(CH 2 ) 2 SO 2 OH.
  • cholic acid is a compound of the following formula (14):
  • chenodeoxycholic acid is a compound of formula 15:
  • deoxycholic acid is a compound of formula 16:
  • ursodeoxycholic acid is a compound of formula 17:
  • lithocholic acid is a compound of formula (18):
  • glycocholic acid is a compound of formula 19:
  • taurocholic acid is a compound of formula 20:
  • glycochenodeoxycholic acid is a compound of formula 21:
  • taurochenodeoxycholic acid is a compound of formula 22:
  • glycodeoxycholic acid is a compound of formula 23:
  • taurodeoxycholic acid is a compound of formula 24:
  • glycoursodeoxycholic acid is a compound of formula 25:
  • tauroursodeoxycholic acid is a compound of formula 26:
  • glycolithocholic acid is a compound of formula 27:
  • taurolithocholic acid is a compound of formula 28:
  • bile acid or bile acid derivative according to the present invention may be a compound of the following formulas 2 to 9, but is not limited thereto:
  • R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ;
  • R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ;
  • R is H or CN
  • R 1 and R 2 are each independently H, CH 3 CO or CH 3 SO 3 ;
  • R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ;
  • R is H, CH 3 CO or CH 3 SO 3 ;
  • R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ;
  • R is NH(CH 2 ) 2 COOC 10 H 14 , NHCH(CH 2 C 6 H 5 )COOC 4 H 9 or NH(CH 2 ) 2 COOC 4 H 9 .
  • the antiviral agent according to the present invention may be a non-nucleoside reverse-transcriptase inhibitor (NNRTIs) series compound or a derivative thereof, or a pharmaceutically acceptable salt thereof, and the NNRTI series compound or a derivative thereof may be selected from the group consisting of efavirenz, etravirine, nevirapine, doravirine, rilpivirine and delavirdine.
  • NRTIs non-nucleoside reverse-transcriptase inhibitor
  • the antiviral agent according to the present invention may be a nucleoside reverse-transcriptase inhibitors (NRTIs)-based compound or a derivative thereof, or a pharmaceutically acceptable salt thereof, and the NRTI-based compound or a derivative thereof is zidovudine.
  • NRTIs nucleoside reverse-transcriptase inhibitors
  • zidovudine didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil fumarate, emtricitabine (emtricitabine) and tenofovir alafenamide fumarate.
  • the antiviral agent according to the present invention may be a protease inhibitor (PIs)-based compound or a derivative thereof, or a pharmaceutically acceptable salt thereof, and the PI-based compound or derivative thereof is single-first saquinavir ( saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir ), tipranavir, darunavir and the combination drug atazanavir + cobicistat, darunavir + cobicistat, ritonavir + lopinavir can
  • PIs protease inhibitor
  • the antiviral agent according to the present invention may be an Integrase Strand Transfer Inhibitor (INSTI)-based compound or derivative thereof, or a pharmaceutically acceptable salt thereof, and the INSTI-based compound or derivative thereof is dolutegravir ( dolutegravir) and raltegravir.
  • INSTI Integrase Strand Transfer Inhibitor
  • the antiviral agent according to the present invention may be a fusion inhibitor-based compound or a derivative thereof, or a pharmaceutically acceptable salt thereof, and the fusion inhibitor may be enfuvirtide.
  • the antiviral agent according to the present invention may be a CCR 5 (Chemokine (CC motif) ligand 5) inhibitor-based compound or derivative thereof, or a pharmaceutically acceptable salt thereof, and the CCR 5 inhibitory compound or derivative thereof is a single agent.
  • CCR 5 Cosmetic (CC motif) ligand 5
  • cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide cobicistat/elvitegravir/emtricitabine/Tenofovir alafenamide
  • cobicistat/elvitegravir/emtricitabine/ tenofovir disoproxil cobicistat/Elvitegravir/emtricitabine/Tenofovir disoproxil
  • abacavir/dolutegravir/lamivudine abacavir/dolutegravir/lamivudine
  • the antiviral agent according to the present invention may be a flu therapeutic agent used for the treatment of influenza A and influenza B virus infection, and the flu therapeutic agent is an uncoating inhibitor-based compound or a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • the antiviral agent according to the present invention may be a herpes treatment agent used for the treatment of herpes simplex virus (HSV) and varicella zoster virus (VZV) infection
  • the herpes treatment agent is acyclovir. (aciclovir), valacyclovir, idoxuridine, vidarabine, penciclovir, famciclovir, trifluridine, cidofovir ( cidofovir) and foscarnet.
  • the antiviral agent according to the present invention may be a hepatitis B therapeutic agent that inhibits the proliferation of hepatitis B virus to relieve inflammation, prevent fibrosis, and prevent liver cirrhosis and sensitive cell carcinoma, and the hepatitis B therapeutic agent is lamivudine. ), clevudine, telbivudine, entecavir, adefovir, tenofovir disoproxil, tenofovir alafenamide and besifovir may be selected from the group consisting of besifovir. When resistance develops, it can be switched to another drug or to a combination treatment of the two drugs.
  • the antiviral agent according to the present invention may be a hepatitis C therapeutic agent that delays the progression of a disease by inhibiting the proliferation of hepatitis C virus
  • the hepatitis C therapeutic agent is a cytokine peginterferon- ⁇ - 2a) and peginterferon alpha 2b (peginterferon- ⁇ -2b), a protease-based compound or a derivative thereof, or a pharmaceutically acceptable salt thereof, ribavirin, an antiviral agent acting on a viral protein (DAA; Direct-acting) antivirals) series compounds or derivatives thereof, or pharmaceutically acceptable salts thereof, which are single agents boceprevir, dasabuvir, daclatasvir, asunaprevir, sophos buvir (sofosbuvir) and combination drugs elbasvir/grazoprevir, glecaprevir/pibrentasvir, ombitasvir/paritaprevir/ritonavir ( omb
  • the antiviral agent according to the present invention may be an immune enhancing agent (interferon) series compound or a derivative thereof, or a pharmaceutically acceptable salt thereof, and the immune enhancing agent is interferon alpha 2a (interferon alfa-2a), interferon alpha 2b ( interferon alfa-2b) and peg interferon alpha 2a (peginterferon- ⁇ -2a).
  • interferon alpha 2a interferon alfa-2a
  • interferon alpha 2b interferon alfa-2b
  • peg interferon- ⁇ -2a peginterferon- ⁇ -2a
  • the antiviral agent according to the present invention may be an immune response modulator-based compound or a derivative thereof, or a pharmaceutically acceptable salt thereof, and the immunomodulatory agent may be selected from the group consisting of imiquimod.
  • the antidepressant according to the present invention may be tricyclic antidepressants (TCAs), and the tricyclic antidepressant is amitriptyline, nortriptyline, clomipramine, imipramine. It may be selected from the group consisting of (imipramine) and amoxapine.
  • TCAs tricyclic antidepressants
  • the antidepressant according to the present invention may be selective serotonin reuptake inhibitors (SSRIs), and the selective serotonin reuptake inhibitor is fluoxetine, paroxetine, fluvoxamine, It may be selected from the group consisting of sertraline, escitalopram and vortioxetine.
  • SSRIs selective serotonin reuptake inhibitors
  • the antidepressant according to the present invention may be a monoamine oxidase inhibitor (MAOI), and the monoamine oxidase inhibitor may be moclobemide.
  • MAOI monoamine oxidase inhibitor
  • the antidepressant according to the present invention may be serotonin-norepinephrine reuptake inhibitors (SNRIs), and the serotonin-norepinephrine reuptake inhibitors include duloxetine, venlafaxine, and desbenlafaxine. ), milnacipran and the antidepressant bupropion, mirtazapine, trazodone, and tianeptine.
  • SNRIs serotonin-norepinephrine reuptake inhibitors
  • the serotonin-norepinephrine reuptake inhibitors include duloxetine, venlafaxine, and desbenlafaxine.
  • milnacipran and the antidepressant bupropion mirtazapine, trazodone, and tianeptine.
  • the thiazolidinediones (TZD)-based compound or derivatives thereof according to the present invention are pioglitazone, lobeglitazone, rosiglitazone, ciglitazone, darglitazone. (darglitazone), englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone.
  • the concentration of the biguanide-based compound or a pharmaceutically acceptable salt thereof may be 0.1 mM to 100 mM, and the concentration of a bile acid, a derivative thereof, or a pharmaceutically acceptable salt thereof is 0.001 ⁇ M to 10 mM may be, the antiviral agent may be 0.001 ⁇ M to 10 mM, the antidepressant may be 0.001 ⁇ M to 10 mM, and the thiazolidinedione-based compound, derivative or pharmaceutically acceptable salt thereof is 0.001 ⁇ M to 10 mM can be
  • a biguanide-based compound or a pharmaceutically acceptable salt thereof bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; antiviral agents; antidepressants; and a thiazolidinedione-based compound, a derivative thereof, or a pharmaceutically acceptable salt thereof
  • the content of two or more compounds in the medicament of the present invention may be appropriately selected according to the form of the preparation.
  • a biguanide-based compound or a pharmaceutically acceptable salt thereof bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; antiviral agents; antidepressants;
  • the content of the biguanide-based compound or a pharmaceutically acceptable salt thereof is the total generally from about 0.01 to about 99.99 wt%, specifically from about 0.01 to about 90 wt%, preferably from about 0.1 to about 90 wt%, more preferably from about 0.1 to about 80 wt%, relative to the formulation; Even more preferably, the content is about 0.1 to about 70 wt%, and the content of the bile acid, its derivative, or a pharmaceutically acceptable salt thereof is generally about 0.01 to about 99.99 wt%, specifically about 0.01 to about 90 wt%, based on the total formulation.
  • the content of the antiviral agent is the total formulation is generally from about 0.01 to about 99.99 wt%, specifically from about 0.01 to about 90 wt%, preferably from about 0.1 to about 80 wt%, more preferably from about 0.1 to about 70 wt%, and more More preferably, it is about 0.1 to about 60 wt%, and the content of the antidepressant is generally about 0.01 to about 99.99 wt%, specifically about 0.01 to about 90 wt%, preferably about 0.1 to about 90 wt%, based on the total formulation.
  • 80 wt% more preferably about 0.1 to about 70 wt%, even more preferably about 0.1 to about 60 wt%, the content of the thiazolidinedione-based compound, derivative thereof, or pharmaceutically acceptable salt thereof Silver is generally from about 0.01 to about 99.99 wt%, specifically from about 0.01 to about 90 wt%, preferably from about 0.1 to about 80 wt%, more preferably from about 0.1 to about 70 wt%, based on the total formulation and more preferably preferably from about 0.1 to about 60 wt %.
  • a biguanide-based compound or a pharmaceutically acceptable salt thereof in the medicament of the present invention in the case of combining as a single agent, a biguanide-based compound or a pharmaceutically acceptable salt thereof in the medicament of the present invention; And the content ratio of bile acid, bile acid derivative, or a pharmaceutically acceptable salt thereof, 1: 0.0000001 to 10 weight ratio may be combined, a biguanide-based compound or a pharmaceutically acceptable salt thereof; And the content ratio of the antiviral agent, 1: 0.0000001 to 10 can be formulated in a weight ratio, antiviral agent; And the content ratio of bile acid, bile acid derivative, or a pharmaceutically acceptable salt thereof may be formulated in a weight ratio of 1: 0.0000001 to 10.
  • a biguanide-based compound or a pharmaceutically acceptable salt thereof in the medicament of the present invention bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; and the weight ratio of one or more compounds selected from the group consisting of antidepressants, thiazolidinedione-based compounds and pharmaceutically acceptable salts thereof, 1: 0.0000001 to 10: 0.0000001 to 10 weight ratios may be combined, and biguanide-based compounds compound or a pharmaceutically acceptable salt thereof; antiviral agents; And the content ratio of one or more compounds selected from the group consisting of antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof, 1: 0.0000001 to 10: 0.0000001 to 10 weight ratio may be combined, antiviral agents; bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; And the content ratio of one or more compounds selected from the group consisting of antidepressants, thiazol
  • the content of additives such as carriers in the medicament of the present invention is variable, but is generally from about 1 to about 99.00 wt% based on the total formulation, and specifically from about 1 to about 90 wt%, preferably about 10 to about 90 wt%, more preferably about 10 to 80 wt%, even more preferably about 10 to about 70 wt%.
  • a biguanide-based compound or a pharmaceutically acceptable salt thereof bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; antiviral agents; antidepressants;
  • the content of the biguanide-based compound or a pharmaceutically acceptable salt thereof is a formulation containing the same is generally from about 0.01 to about 99.99 wt%, specifically from about 0.1 to about 99.99 wt%, preferably from about 0.1 to about 90 wt%, more preferably from about 0.1 to about 80 wt%, and more More preferably, it may be about 1 to about 80 wt%, and the content of the bile acid, bile acid derivative, or pharmaceutically acceptable salt thereof is generally about 0.01 to about 99.99 wt%, specifically about 0.1 to about 99.99 wt%, based on the preparation
  • the content is generally from about 0.01 to about 99.99 wt%, specifically from about 0.1 to about 99.99 wt%, preferably from about 0.1 to about 90 wt%, and more preferably from about 0.1 to about 80 wt% relative to the formulation containing the same. wt%, and even more preferably, it may be about 1 to about 80 wt%, and the content of the antidepressant is generally about 0.01 to about 99.99 wt%, specifically about 0.1 to about 99.99 wt%, based on the formulation containing it.
  • the content of the derivative or pharmaceutically acceptable salt thereof is generally from about 0.01 to about 99.99 wt%, specifically from about 0.1 to about 99.99 wt%, preferably from about 0.1 to about 90 wt%, based on the formulation containing the derivative, more preferably It may be about 0.1 to about 80 wt%, and even more preferably about 1 to about 80 wt%.
  • a biguanide-based compound or a pharmaceutically acceptable salt thereof bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; antiviral agents; antidepressants;
  • the content of additives such as a carrier is variable, but generally for each containing formulation from about 1 to 99.00 wt%, specifically from about 1 to about 90 wt%, preferably from about 10 to about 90 wt%, more preferably from about 10 to 80 wt%, even more preferably from about 10 wt% to about 70 wt %.
  • the cancer is (A) (1) in-place ductal carcinoma (DCIS) (comedon carcinoma, filamentous, papillary, micropapillary), infiltrating ductal carcinoma (IDC), ductal carcinoma, mucinous (colloidal) ductal carcinomas, including carcinomas, papillary carcinomas, metaplastic carcinomas and inflammatory carcinomas; (2) lobular carcinomas, including in-situ lobular carcinoma (LCIS) and invasive lobular carcinoma; and (3) breast cancer, including Paget's disease of the nipples; (B) (1) cervical intraepithelial tumor (grade I), cervical intraepithelial tumor (grade II), cervical intraepithelial tumor (grade III) (orthostatic squamous cell carcinoma), keratogenic squamous cell carcinoma, non-keratinizing squamous cell cancers of the cervix, including carcinomas, warts, orthotopic adenocarcinomas, orthostatic adenocarcinomas,
  • DCIS in-
  • the formulation is a formulation selected from the group consisting of tablets, capsules, injections, troches, powders, granules, solutions, suspensions, internal solutions, emulsions, syrups, suppositories, vaginal tablets and pills. It may be formulated, but is not limited thereto, and may be formulated in an appropriate formulation if necessary.
  • the present invention provides two or more compounds selected from the group consisting of bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof. It provides a complex, mixed or combination kit for the prevention or treatment of cancer, containing a formulation comprising a.
  • the combination, mixed, or combination kit for the prevention or treatment of cancer is a formulation comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and a preparation comprising a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof.
  • the combination, mixed, or combination kit for the prevention or treatment of cancer is a formulation comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and an antiviral agent.
  • the combination, mixed or combination kit for the prevention or treatment of cancer includes a formulation comprising an antiviral agent; and a preparation comprising a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof.
  • combination, combination, or combination kit for the prevention or treatment of cancer may further contain a formulation comprising at least one compound selected from the group consisting of an antidepressant, a thiazolidinedione-based compound, and a pharmaceutically acceptable salt thereof. have.
  • bile acids in one aspect of the present invention, bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds and pharmaceutically acceptable salts thereof; Their content, content ratio, and cancer are the same as the description of the pharmaceutical composition for the prevention or treatment of cancer, and the specific description is incorporated herein by reference.
  • the compound according to the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda.
  • the acid addition salt according to the present invention is prepared by a conventional method, for example, by dissolving the compound of the present invention in an aqueous solution of an excess of acid, and dissolving the salt in a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation. It can also be prepared by evaporating the solvent or excess acid from the mixture to dryness, or by suction filtration of the precipitated salt.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt.
  • the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • composition according to the present invention When formulating the composition according to the present invention, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.
  • Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and such solid preparations include one or more compounds of the present invention with at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose or lactose or gelatin.
  • excipients for example, starch, calcium carbonate, water It is prepared by mixing sucrose or lactose or gelatin.
  • lubricants such as magnesium stearate talc are also used.
  • Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , sensitivity to drugs, administration time, administration route and excretion rate, duration of treatment, factors including concurrent drugs, and other factors well known in the medical field.
  • the composition of the present invention may be administered as individual combined therapeutic agents 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. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the compound according to the present invention may vary depending on the age, sex, and weight of the patient, and in general, 0.1 mg to 100 mg per kg body weight, preferably 0.5 mg to 10 mg per kg body weight, is administered daily or every other day Or it can be administered in divided doses 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
  • the present invention also provides two or more compounds selected from the group consisting of bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof. It provides a method for preventing or treating cancer, comprising the step of administering compound, mixed, or co-administered to a subject in a pharmaceutically effective amount.
  • two or more compounds selected from the group consisting of bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof are mixed, It is administered to a subject in need of cancer treatment in combination or in combination. More specifically, a first component comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and a second component including a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof is administered to a subject in need of cancer treatment by mixing, combining, or using the combination thereof.
  • a first component comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and a second component comprising an antiviral agent is administered to a subject in need of cancer treatment by mixing, combining, or in combination.
  • a first component comprising an antiviral agent; and a second component including a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof is administered to a subject in need of cancer treatment by mixing, combining, or using the combination thereof.
  • a second component or the first component; a second component; and a third component comprising at least one compound selected from the group consisting of an antidepressant, a thiazolidinedione-based compound, and a pharmaceutically acceptable salt thereof is administered to a subject in need of cancer treatment by mixing, combining, or in combination.
  • the present inventors a biguanide-based compound or a pharmaceutically acceptable salt thereof; And biguanide-based compound metformin in breast cancer, colon cancer, lung cancer, prostate cancer, pancreatic cancer and normal cells in order to confirm the anticancer activity of the combination, mixture or combination of bile acids, derivatives thereof, or pharmaceutically acceptable salts thereof
  • MTT analysis sodium deoxycholate or ursodeoxycholic acid alone, in combination, in combination, or in combination
  • MTT analysis showed no change in normal cells, but growth inhibitory effect in cancer cells. It was confirmed that the
  • the present inventors include a biguanide-based compound or a pharmaceutically acceptable salt thereof; And in order to confirm the anti-cancer activity of the combination, mixture, or combination of antiviral agents, pancreatic cancer and normal cells were treated with metformin, a biguanide-based compound, and efavirenz, etravirin, and nevirapine, which are antiviral agents NNRTI, alone or As a result of performing MTT analysis by compounding, mixing, or co-treatment, it was confirmed that no change was observed in normal cells, but a growth inhibitory effect was observed in cancer cells.
  • the present inventors include a biguanide-based compound or a pharmaceutically acceptable salt thereof; antiviral agents; and biguanide-based compound metformin, antiviral NNRTI efavirenz and bile acid ursode in pancreatic cancer cells in order to confirm anticancer activity against the complex, mixed, or combined preparation of bile acids, bile acid derivatives, or pharmaceutically acceptable salts thereof.
  • MTT analysis by treating oxycholic acid alone, complex, mixed, or combined treatment, it was confirmed that it exhibits a growth inhibitory effect in cancer cells.
  • the present inventors include a biguanide-based compound or a pharmaceutically acceptable salt thereof; antiviral agents; and pioglitazone, which is a thiazolidinedione-based compound or a thiazolidinedione-based compound, or a combination of metformin, efavirenz, and thiazolidinedione-based compound, in order to confirm the anticancer activity of the complex, mixed, or combined preparation thereof.
  • a biguanide-based compound or a pharmaceutically acceptable salt thereof antiviral agents
  • pioglitazone which is a thiazolidinedione-based compound or a thiazolidinedione-based compound, or a combination of metformin, efavirenz, and thiazolidinedione-based compound, in order to confirm the anticancer activity of the complex, mixed, or combined preparation thereof.
  • the present inventors antiviral agents; bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; And in order to confirm the anticancer activity for the complex, mixed, or combination of antidepressants, efavirenz, fluoxetine and ursodeoxycholic acid are treated alone or combined, mixed or combined to colorectal cancer cells and pancreatic cancer cells to perform MTT analysis As a result, it was confirmed that it exhibits a growth inhibitory effect in cancer cells.
  • the present inventors include a biguanide-based compound or a pharmaceutically acceptable salt thereof; bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; and metformin, pioglitazone and ursodeoxycholic acid alone or in combination with colorectal cancer cells and pancreatic cancer cells in order to confirm anticancer activity against the complex, mixed, or combined preparation of a thiazolidinedione-based compound or a pharmaceutically acceptable salt thereof.
  • MTT analysis by mixing or co-treatment
  • a subject is a mammal in need of cancer treatment.
  • the subject is a human cancer patient.
  • the subject is a non-human mammal, such as a non-human primate, animals used in model systems (eg, mice and rats used in the screening, characterization and evaluation of pharmaceuticals) and other mammals. , for example, rabbits, guinea pigs, hamsters, dogs, cats, chimpanzees, gorillas, ape such as monkeys.
  • the pharmaceutical composition may be used alone or in combination with surgery, hormone therapy, drug therapy, and biological response modifiers for the treatment of cancer patients.
  • the present invention provides bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceuticals thereof for use as pharmaceutical compositions for the prevention and treatment of cancer.
  • bile acids bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceuticals thereof for use as pharmaceutical compositions for the prevention and treatment of cancer.
  • a combination, mixture or combination formulation of two or more compounds selected from the group consisting of acceptable salts are examples of bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceuticals thereof for use as pharmaceutical compositions for the prevention and treatment of cancer.
  • a combination, mixture or combination formulation of two or more compounds selected from the group consisting of acceptable salts selected from the group consisting of acceptable salts.
  • the present invention provides a bile acid, a bile acid derivative, a biguanide-based compound, an antiviral agent, an antidepressant, a thiazolidinedione-based compound, and a pharmaceutical composition thereof for use as a health food for the prevention and improvement of cancer.
  • a combination, mixture or combination preparation of two or more compounds selected from the group consisting of acceptable salts are provided.
  • breast cancer cells were treated with metformin and sodium deoxycholate and MTT (3-(4,5-dimethylthiazol-2-yl)-2 ,5-diphenyltetrazolium bromide) analysis was performed to confirm growth inhibition.
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2 ,5-diphenyltetrazolium bromide
  • the breast cancer cell line MCF-7 cell line was cultured in a 100 mm culture dish using DMEM-10% FBS at 5% CO 2 , 37° C., and inoculated at 20% confluence in each well of a 96 well plate for 24 hours. cultured. Metformin at a concentration of 5 mM, sodium deoxycholate at concentrations of 0.01, 0.1, 1 and 10 ⁇ M alone or in combination were treated, and incubated in a CO 2 incubator for 24, 48 or 72 hours. The culture medium was removed from each well, 100 ⁇ l of a new culture medium was added, and 10 ⁇ l of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours.
  • FIGS. 1A and 1B 5 mM metformin and 0.01, 0.1 compared to when breast cancer cells were treated with 5 mM metformin or 0.01, 0.1, 1, and 10 ⁇ M sodium deoxycholate alone, respectively. , it was confirmed that the synergistic effect showing a significantly high growth inhibition when treated with sodium deoxycholate of 1 and 10 ⁇ M (Fig. 1a).
  • the growth inhibitory activity was very weak at 0-8%. It was confirmed that the combined treatment significantly inhibited the growth of cancer cells, but had very little effect on normal cells (Fig. 1b).
  • pancreatic cancer cells were treated with metformin and sodium deoxycholate and growth inhibition was confirmed by performing MTT analysis.
  • Example ⁇ 1-1> MTT analysis was performed in the same manner as described in Example ⁇ 1-1> using the AsPC-1 cell line (FIG. 2A) and the MIA PaCa-2 cell line (FIG. 2B), which are pancreatic cancer cell lines. At this time, the drug was treated and incubated for 24 hours.
  • prostate cancer cells were treated with metformin and sodium deoxycholate, and growth inhibition was confirmed by performing MTT analysis.
  • Example ⁇ 1-1> MTT analysis was performed using the LNcaP cell line, which is a prostate cancer cell line, in the same manner as in Example ⁇ 1-1>. At this time, the drug was treated and cultured for 24 hours (FIG. 3).
  • metformin and deoxycholic acid or a salt thereof exhibited a more excellent effect in inhibiting cancer cell growth while having little effect on the growth of normal cells when treated in combination.
  • MTT analysis was performed using the breast cancer cell line, MCF-7 cell line, in the same manner as in Example ⁇ 1-1> (FIG. 4a).
  • WISH human normal epithelial cells
  • Fig. 4b the drug was treated and cultured for 24 hours.
  • pancreatic cancer cells were treated with metformin and ursodeoxycholic acid and growth inhibition was confirmed by performing MTT analysis.
  • MTT analysis was performed using the AsPC-1 cell line (FIG. 5a) and the MIA PaCa-2 cell line (FIG. 5b), which are pancreatic cancer cell lines, in the same manner as in Example ⁇ 1-1>. At this time, the drug was treated and incubated for 24 hours.
  • prostate cancer cells were treated with metformin and ursodeoxycholic acid and growth inhibition was confirmed by performing MTT analysis.
  • Example ⁇ 1-1> MTT analysis was performed in the same manner as in Example ⁇ 1-1> using the LNcaP cell line (FIG. 6a) and the DU145 cell line (FIG. 6b), which are prostate cancer cell lines. At this time, the drug was treated and incubated for 24 hours.
  • FIGS. 6A and 6B 5 mM metformin and 0.01, 5 mM metformin and 0.01, respectively, compared to the case of treating prostate cancer cells with 5 mM metformin or 0.01, 0.1, 1, and 10 ⁇ M ursodeoxycholic acid alone. It was confirmed that 0.1, 1, and 10 ⁇ M of ursodeoxycholic acid in combination showed a synergistic effect showing significantly high growth inhibition ( FIGS. 6a and 6b ).
  • metformin and ursodeoxycholic acid or a salt thereof exhibited a more excellent effect in inhibiting cancer cell growth while having little effect on the growth of normal cells when treated in combination.
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound and efavirenz with the antiviral NNRTI, and MTT (3-(4,5-dimethylthiazol-2) -yl)-2,5-diphenyltetrazolium bromide) analysis was performed to confirm growth inhibition.
  • pancreatic cancer cell line ASPC-1 cell line was cultured in a 100 mm culture dish using DMEM-10% FBS at 5% CO 2 , 37° C., and then each well of a 96 well plate. Inoculated to 20% confluence (confluence) and cultured for 24 hours. Metformin at a concentration of 5 mM, efavirenz at a concentration of 1 and 2 ⁇ M alone or in combination were treated, and incubated in a CO 2 incubator for 24 hours. The culture medium was removed from each well, 100 ⁇ l of a fresh culture medium was added, and 10 ⁇ l of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours.
  • SDS-HCl solution (1 g SDS/10 ml 0.01 M HCl), which is a reaction stop solution, was added and incubated at 37° C. for 4 hours, and the OD was measured at 570 nM using a microplate leader. . % growth inhibition was calculated by comparing the OD of the cells not treated with the drug (Fig. 7a).
  • WISH cell line human normal epithelial cells
  • MTT analysis was performed in the same manner as described above.
  • the drug was treated and cultured for 24 hours (FIG. 7b).
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound and ettravirin as the antiviral agent NNRTI, followed by MTT analysis to obtain growth inhibition. Confirmed.
  • pancreatic cancer cell line ASPC-1 cell line was cultured in a 100 mm culture dish using DMEM-10% FBS at 5% CO 2 , 37° C., and then each well of a 96 well plate. Inoculated to 20% confluence (confluence) and cultured for 24 hours. Metformin at a concentration of 1 mM, ettravirin at a concentration of 0.1 and 1 ⁇ M alone or in combination were treated, and incubated in a CO 2 incubator for 24 hours. The culture medium was removed from each well, 100 ⁇ l of a fresh culture medium was added, and 10 ⁇ l of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours.
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound and nevirapine with the antiviral agent NNRTI, and MTT analysis was performed to confirm growth inhibition. did.
  • MTT analysis was performed using the pancreatic cancer cell line in the same manner as described in Example ⁇ 3-2>. At this time, the drug was treated and cultured for 24 hours (FIG. 9).
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound and lamivudine as the antiviral agent NRTI, and MTT analysis was performed to confirm growth inhibition. .
  • MTT analysis was performed using the pancreatic cancer cell line in the same manner as described in Example ⁇ 3-2>. At this time, the drug was treated and cultured for 24 hours (FIG. 10).
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound and lopinavir with the antiviral agent PI, followed by MTT analysis to obtain growth inhibition. Confirmed.
  • MTT analysis was performed using the pancreatic cancer cell line in the same manner as described in Example ⁇ 3-2>. At this time, the drug was treated and cultured for 24 hours (FIG. 11).
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound and atazanavir with the antiviral agent PI, followed by MTT analysis to obtain growth inhibition. Confirmed.
  • pancreatic cancer cell line ASPC-1 cell line was cultured in a 100 mm culture dish using DMEM-10% FBS at 5% CO 2 , 37° C., and then each well of a 96 well plate. Inoculated to 20% confluence (confluence) and cultured for 24 hours. Metformin at a concentration of 1 mM and atazanavir at a concentration of 10, 20 and 40 ⁇ M alone or in combination were treated, and incubated in a CO 2 incubator for 24 hours. The culture medium was removed from each well, 100 ⁇ l of a fresh culture medium was added, and 10 ⁇ l of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours.
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound and darunavir with the antiviral agent PI, followed by MTT analysis to obtain growth inhibition. Confirmed.
  • MTT analysis was performed using the pancreatic cancer cell line in the same manner as described in Example ⁇ 5-2>. At this time, the drug was treated and cultured for 24 hours (FIG. 13).
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound and ritonavir with the antiviral agent PI, followed by MTT analysis to obtain growth inhibition. Confirmed.
  • MTT analysis was performed using the pancreatic cancer cell line in the same manner as described in Example ⁇ 5-2>. At this time, the drug was treated and cultured for 24 hours (FIG. 14).
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound, efavirenz as an antiviral agent, and ursodeoxycholic acid with bile acid, followed by MTT analysis. Growth inhibition was confirmed.
  • pancreatic cancer cell line ASPC-1 cell line was cultured in a 100 mm culture dish using DMEM-10% FBS at 5% CO 2 , 37° C., and then each well of a 96 well plate. Inoculated to 20% confluence (confluence) and cultured for 24 hours. Metformin at a concentration of 2.5 mM, efavirenz at a concentration of 2 ⁇ M, and ursodeoxycholic acid at a concentration of 20 ⁇ M were treated alone or in combination, and incubated in a CO 2 incubator for 24 hours.
  • the culture medium was removed from each well, 100 ⁇ l of a fresh culture medium was added, and 10 ⁇ l of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 ⁇ l of SDS-HCl solution (1 g SDS/10 ml 0.01 M HCl), which is a reaction stop solution, was added and incubated at 37° C. for 4 hours, and the OD was measured at 570 nM using a microplate leader. . % growth inhibition was calculated by comparing the OD of the cells not treated with the drug (FIG. 15).
  • antiviral agents and thiazolidinedione-based compounds In order to examine the anticancer activity of biguanide-based compounds, antiviral agents and thiazolidinedione-based compounds, metformin as a biguanide-based compound, efavirenz as an antiviral agent, and pioglitazone as a thiazolidinedione-based compound were administered to pancreatic cancer cells. treatment and MTT analysis was performed to confirm growth inhibition.
  • pancreatic cancer cell line ASPC-1 cell line was cultured in a 100 mm culture dish using DMEM-10% FBS at 5% CO 2 , 37° C., and then each well of a 96 well plate. Inoculated to 20% confluence (confluence) and cultured for 24 hours. Metformin at a concentration of 2.5 mM, efavirenz at a concentration of 2 ⁇ M, and pioglitazone at a concentration of 10 ⁇ M were treated alone or in combination, and incubated in a CO 2 incubator for 24 hours.
  • the culture medium was removed from each well, 100 ⁇ l of a fresh culture medium was added, and 10 ⁇ l of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 ⁇ l of SDS-HCl solution (1 g SDS/10 ml 0.01 M HCl), which is a reaction stop solution, was added and incubated at 37° C. for 4 hours, and the OD was measured at 570 nM using a microplate leader. . % growth inhibition was calculated by comparing the OD of the cells not treated with the drug (FIG. 16).
  • antiviral agents and thiazolidinedione-based compounds In order to investigate the anticancer activity of biguanide-based compounds, antiviral agents and thiazolidinedione-based compounds, metformin as a biguanide-based compound in colon cancer cells, efavirenz as an antiviral agent, and pioglitazone as a thiazolidinedione-based compound was treated and MTT analysis was performed to confirm growth inhibition.
  • MTT analysis was performed using the colon cancer cell line HCT116 cells in the same manner as in Example ⁇ 7-1>. At this time, the drug was treated and cultured for 24 hours (FIG. 17).
  • colorectal cancer cells were treated with 2.5 mM metformin, 2 ⁇ M efavirenz, or 10 ⁇ M pioglitazone alone, respectively.
  • 10 ⁇ M of pioglitazone was co-treated, it was confirmed that a synergistic effect showing significantly high growth inhibition was observed (FIG. 17).
  • the colon cancer cell line HCT116 cell line was cultured in a 100 mm culture dish using DMEM-10% FBS at 5% CO 2 , 37° C., and then in each well of a 96 well plate. Inoculated to 20% confluence (confluence) and cultured for 24 hours. Efavirens was treated at a concentration of 0.5 ⁇ M, fluoxetine at a concentration of 0.5 ⁇ M, and ursodeoxycholic acid at a concentration of 200 ⁇ M alone or in combination, and incubated in a CO 2 incubator for 24 hours.
  • the culture medium was removed from each well, 100 ⁇ l of a fresh culture medium was added, and 10 ⁇ l of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 ⁇ l of SDS-HCl solution (1 g SDS/10 ml 0.01 M HCl), which is a reaction stop solution, was added and incubated at 37° C. for 4 hours, and the OD was measured at 570 nM using a microplate leader. . % growth inhibition was calculated by comparing the OD of the cells not treated with the drug (FIG. 18).
  • 0.5 ⁇ M efavirenz, 0.5 ⁇ M colorectal cancer cells were treated with 0.5 ⁇ M efavirenz, 0.5 ⁇ M fluoxetine, or 200 ⁇ M ursodeoxycholic acid alone, respectively.
  • fluoxetine of and 200 ⁇ M of ursodeoxycholic acid were co-treated, it was confirmed that a synergistic effect showing significantly high growth inhibition appeared (FIG. 18).
  • pancreatic cancer cells were treated with efavirenz as an antiviral agent, fluoxetine as an antidepressant, and ursodeoxycholic acid with bile acid, and growth inhibition was confirmed by performing MTT analysis. did.
  • MTT analysis was performed using the pancreatic cancer cell line ASPC-1 cells in the same manner as in Example ⁇ 8-1>. At this time, the drug was treated and cultured for 24 hours (FIG. 19).
  • thiazolidinedione-based compounds and bile acids metformin as a biguanide-based compound, pioglitazone as a thiazolidinedione-based compound, and ursodeoxycholic acid as a bile acid were administered to colon cancer cells. treatment and MTT analysis was performed to confirm growth inhibition.
  • the colon cancer cell line HCT116 cell line was cultured in a 100 mm culture dish using DMEM-10% FBS at 5% CO 2 , 37° C., and then in each well of a 96 well plate. Inoculated to 20% confluence (confluence) and cultured for 24 hours. Metformin at a concentration of 2.5 mM, pioglitazone at a concentration of 10 ⁇ M, and ursodeoxycholic acid at a concentration of 20 ⁇ M were treated alone or in combination, and incubated in a CO 2 incubator for 24 hours.
  • the culture medium was removed from each well, 100 ⁇ l of a fresh culture medium was added, and 10 ⁇ l of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 ⁇ l of SDS-HCl solution (1 g SDS/10 ml 0.01 M HCl), which is a reaction stop solution, was added and incubated at 37° C. for 4 hours, and the OD was measured at 570 nM using a microplate leader. . % growth inhibition was calculated by comparing the OD of the cells not treated with the drug (FIG. 20).
  • pancreatic cancer cells were treated with metformin as a biguanide-based compound, pioglitazone as a thiazolidinedione-based compound, and ursodeoxycholic acid as a bile acid. and MTT analysis was performed to confirm growth inhibition.
  • MTT analysis was performed using the pancreatic cancer cell line ASPC-1 cells in the same manner as in Example ⁇ 9-1>. At this time, the drug was treated and cultured for 24 hours (FIG. 21).
  • a combination of two compounds among bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof, a biguanide-based compound and a bile acid When a combination of its derivatives or bile salts, or a combination of a biguanide-based compound and an antiviral, was treated in combination, it had little effect on the growth of normal cells, and showed excellent cancer cell growth inhibitory effects in various types of cancer cells.
  • a biguanide-based compound an antiviral agent as a combination of three compounds among bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof and a combination of a bile acid, a biguanide-based compound, an antiviral and a thiazolidinedione-based compound, an antiviral, an antidepressant and a bile acid, or a biguanide-based compound, a thiazolidinedione-based compound and a bile acid
  • the combination treatment showed an excellent cancer cell growth inhibitory effect on several types of cancer cells while having little effect on the growth of normal cells.
  • two or more compounds of bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof are used for the prevention or treatment of cancer.
  • a combination, mixture, or combination preparation it may be usefully used as an active ingredient in a pharmaceutical composition for the prevention or treatment of cancer.
  • the present invention relates to a pharmaceutical composition for preventing or treating cancer containing two or more of bile acids or derivatives thereof, biguanide-based compounds and antiviral agents as active ingredients. It can be usefully used for prevention or treatment.
  • the present invention is a bile acid or a derivative thereof, a biguanide-based compound, an antiviral agent, an antidepressant, a thiazolidinedione-based compound, and cancer prevention containing two or more of its pharmaceutically acceptable salts as an active ingredient
  • it relates to a pharmaceutical composition for treatment, which has few side effects and excellent anticancer effect, and thus can be usefully used for preventing or treating cancer.

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement du cancer, contenant des acides biliaires ou des dérivés de ces derniers, des composés à base de biguanide et deux ou plus de deux types d'agents antiviraux en tant que principes actifs. Plus spécifiquement, une combinaison d'un acide biliaire ou d'un sel de celui-ci et d'un composé à base de biguanide, une combinaison d'un composé à base de biguanide et d'un agent antiviral, une combinaison d'un acide biliaire, d'un composé à base de biguanide et d'un agent antiviral, et les combinaisons susmentionnées avec un antidépresseur ou un composé à base de thiazolidinédione ajouté à celui-ci présentent chacune des effets anticancéreux faibles lorsqu'elles sont administrées de manière singulière, mais ont démontré présenter un effet anticancéreux significativement élevé dans divers carcinomes lorsqu'elles sont administrées sous la forme d'une préparation complexe, mélangée, ou combinée. Par conséquent, les préparations complexes, mélangées ou combinées des composés ci-dessus peuvent être avantageusement utilisées pour prévenir ou traiter le cancer.
PCT/KR2021/001785 2020-02-13 2021-02-10 Composition pharmaceutique pour la prévention ou le traitement du cancer, contenant des acides biliaires ou des dérivés de ceux-ci, composés à base de biguanide, et deux ou plus de deux types d'agents antiviraux en tant que principes actifs Ceased WO2021162451A1 (fr)

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CN116942676A (zh) * 2023-07-17 2023-10-27 郑州大学 Baloxavir在制备抗肿瘤药物中的应用
CN116808176A (zh) * 2023-08-30 2023-09-29 上海彗天锦泽生物医学科技有限公司 一种基于免疫检查点阻断的抗肿瘤药物组合物及其应用
CN116808176B (zh) * 2023-08-30 2023-12-05 上海彗天锦泽生物医学科技有限公司 一种基于免疫检查点阻断的抗肿瘤药物组合物及其应用

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