WO2021162451A1 - Pharmaceutical composition for preventing or treating cancer, containing bile acids or derivatives thereof, biguanide-based compounds, and two or more kinds of antiviral agents as active ingredients - Google Patents

Pharmaceutical composition for preventing or treating cancer, containing bile acids or derivatives thereof, biguanide-based compounds, and two or more kinds of antiviral agents as active ingredients 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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French (fr)
Korean (ko)
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박수현
김샛별
김정훈
모영원
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(주)프론트바이오
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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.

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer, containing bile acids or derivatives thereof, biguanide-based compounds, and two or more kinds of antiviral agents as active ingredients. More specifically, 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 combination of a bile acid, a biguanide-based compound and an antiviral agent, and the foregoing combinations with an antidepressant or a thiazolidinedione-based compound added thereto each exhibit weak anticancer effects when administered singularly, but were found to exhibit a significantly high anticancer effect in various carcinomas when administered as a complex, mixed, or combined preparation. Accordingly, the complex, mixed, or combined preparations of the above compounds may be advantageously used for preventing or treating cancer.

Description

담즙산 또는 이의 유도체, 바이구아나이드 계열 화합물 및 항바이러스제 중 2종 이상을 유효성분으로 함유하는 암 예방 또는 치료용 약학적 조성물A pharmaceutical composition for preventing or treating cancer containing two or more kinds of bile acids or derivatives thereof, biguanide-based compounds and antiviral agents as active ingredients
본 발명은 담즙산 또는 이의 유도체, 바이구아나이드(biguanide) 계열 화합물 및 항바이러스제 중 2종 이상을 유효성분으로 함유하는 암 예방 또는 치료용 약학적 조성물에 관한 것이다. 또한, 본 발명은 담즙산 또는 이의 유도체, 바이구아나이드 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염 중 2종 이상을 유효성분으로 함유하는 암 예방 또는 치료용 약학적 조성물에 관한 것이다.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. In addition, 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.
암은 신체의 조직 또는 다른 부분에 접하여 퍼져나갈 수 있는 조절되지 않는 세포의 비정상적 성장에 의한 질환으로, 암세포는 암세포가 함께 덩어리화되어 있는 고형종양을 형성하거나 백혈병에서와 같이 분산된 세포로서 존재할 수 있다. 정상세포는 성숙될 때까지 분화하고 이후 필요에 따라서 손상되거나 죽은 세포를 교체하나, 암세포는 끊임없이 분화하여 결국 인근 세포를 밀어내고 다른 부분으로 퍼지게 되어 악성으로 불린다. 악성 종양 세포는 혈류 또는 림프계를 통해 신체의 다른 부분으로 전이되며, 여기에서 증식하고 새로운 종양을 형성한다.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.
암은 다양한 치료방법이 개발되었음에도 불구하고, 전 세계적으로 여전히 인간의 건강을 심각하게 위협하고 있다. 현재 주요 암 치료법으로는 외과적 수술, 방사선 치료, 호르몬 요법 및 화학 요법이 있으며, 그 중 화학 요법은 하나 이상의 항암제를 사용하여 암을 직접 치료하거나 증상을 완화시키는 방법이다. Despite the development of various treatment methods, cancer still seriously threatens human health worldwide. Currently, 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.
전통적인 화학 요법제는 암세포 분열 및 대사를 방해하거나, 핵산 또는 단백질의 생합성을 억제함으로써, 암 세포에 대한 세포독성을 나타내게 된다. 그러나 이러한 화학 요법제는 항암제에 대하여 암세포가 저항성을 가지게 되는 문제 및 정상 조직에 대해 독성을 나타내는 등 심각한 부작용을 초래하는 문제가 있다. 특히 기존 항암제로 사용되고 있는 물질은 암세포에도 영향을 미치지만 정상세포에도 독성을 미침으로써 다양한 부작용을 초래하고 있는 경우가 많다. 따라서 정상세포에는 독성을 미치지 않고 암세포에만 선택적인 우수한 독성을 나타내며 항암 활성이 우수한 항암 치료제가 필요하다.Traditional 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. However, 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. In particular, 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.
담즙산의 일종으로 콜산(cholic acid), 데옥시콜산(deoxycholic acid), 케노데옥시콜산(chenodeoxycholic acid), 우르소데옥시콜산(ursodeoxycholic acid), 리토콜산(lithocholic acid) 등이 있으며, 다양한 담즙산 및 이의 유도체들의 항암 효과가 검토되고 있다. 일예로 우르소데옥시콜산은 대장암에서 항암 효과가 있는 것으로 보고되었고, 우르소데옥시콜산 및 케노데옥시콜산 유도체는 전립선암, 유방암 등에서 항암 효과가 있는 것으로 보고되었다.As a kind of bile acid, there are cholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, etc., and various bile acids and Anticancer effects of its derivatives are being investigated. For example, ursodeoxycholic acid has been reported to have anticancer effects in colon cancer, and ursodeoxycholic acid and chenodeoxycholic acid derivatives have been reported to have anticancer effects in prostate cancer and breast cancer.
메트포르민(metformin), 펜포르민(phenformin), 부포르민(buformin) 또는 바이구아나이드(biguanide)는 같은 바이구아나이드(biguanide) 계열의 약물은 간에서 당의 생성을 저해하고 말초혈관에서 당사용을 촉진하는 제2형 당뇨병 치료제로 아직도 널리 사용되고 있다. 메트포르민, 펜포르민, 부포르민 또는 바이구아나이드는 대사조절의 핵심효소인 AMPK(AMP-activated protein kinase)를 활성화시켜 단백질, 지방 지질, 글리코겐 합성을 저해하고 분해를 촉진하며, 인슐린, IGF1, 렙틴, 아디포넥틴의 생성을 저해한다. 한편, 활성화된 AMPK는 세포의 재생을 억제하기 때문에 암세포의 대사를 저해하고, 세포분열을 저해한다. AMPK 활성화는 직접 mTOR(mammalian target of rapamycin)를 저해하여 결국에는 단백질합성을 저해함으로써 암세포의 증식을 억제한다. 특히, 메트포르민은 혈관형성촉진인자들의 발현을 저해함으로써 암세포의 성장을 억제하는 것으로 보고되어 있다. 이러한 항암기전으로 인해 메트포르민 및 펜포르민은 단독으로 또는 다른 항암제와의 조합으로 여러 종류의 암의 임상시험에 사용이 시도되었으나, 그 치료효과는 다르게 나타났으며, 아직 여러 문제로 항암제로 허가되지는 못한 상태이다.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 activation directly inhibits mTOR (mammalian target of rapamycin) and eventually inhibits protein synthesis, thereby inhibiting cancer cell proliferation. In particular, it has been reported that 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
항바이러스제는 인체에 침입한 바이러스의 작용을 약화 혹은 소멸시킴으로써 바이러스에 의한 감염질환을 치료하는 약물로, 바이러스의 증식을 억제하는 작용을 가진다. 작용기전에 따라 바이러스 부착 및 침투 억제제와 바이러스 증식 저해제로 분류할 수 있다. 대부분의 항바이러스제는 바이러스 증식에 필요한 여러 종류의 효소들을 저해하여 항바이러스 작용을 나타낸다.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.
인간 면역결핍 바이러스(Human Immunodeficiency Virus, HIV), 특히 HIV 유형-1(HIV-1) 및 유형-2(HIV-2)로 공지된 균주는 후천성 면역결핍 증후군(AIDS)으로 공지된 면역억제 질환과 병인학적으로 연결되어 왔다. HIV는 레트로바이러스이기 때문에, HIV 복제 주기는 역전사효소를 통한 바이러스 RNA 게놈의 DNA로의 전사를 필요로 한다. 또한, HIV 역전사효소의 효소 작용을 억제하는 화합물이 HIV 항바이러스제로 개발되고 있다.Human Immunodeficiency Virus (HIV), particularly the strains known as HIV type-1 (HIV-1) and type-2 (HIV-2), is associated with the immunosuppressive disease known as acquired immunodeficiency syndrome (AIDS) and have been etiologically linked. Because HIV is a retrovirus, the HIV replication cycle requires transcription of the viral RNA genome into DNA via reverse transcriptase. In addition, compounds that inhibit the enzymatic action of HIV reverse transcriptase are being developed as HIV antiviral agents.
HIV 역전사효소의 효소 작용을 억제하는 화합물로는 뉴클레오시드 계열 역전사효소 저해제(Nucleoside Reverse Transcriptase Inhibitor, NRTI) 계열 화합물과 비뉴클레오시드 역전사 저해제(Non nucleoside Reverse Transcriptase Inhibitor, NNRTI) 계열 화합물이 있다. NRTI는 주로 전구체로 복용하며, 이후 숙주 세포에 들어가 인산화되어 뉴클레오티드 형태로 변환되면서 약물로써 활성을 갖게 된다. NRTI는 공동적으로 뉴클레오시드의 당분자의 3-OH(수산화기)가 없기 때문에 바이러스의 DNA 합성과정에서 DNA 가닥에 끼어들어가 DNA 체인의 다음에 오는 뉴클레오티드와의 3'-5' 인산에스터 결합을 차단함으로써 DNA 합성을 종료시킨다. FDA 승인받은 NRTI로는 지도부딘(zidovudine), 디다노신(didanosine), 잘시타빈(zalcitabine), 스타부딘(stavudine), 라미부딘(lamivudine), 아바카비어(abacavir), 테노포비르 디소프록시 푸마레이트(tenofovir disoproxil fumarate), 엠트리시타빈(emtricitabine), 테노포비르 알라페나미드 푸마레이트(tenofovir alafenamide fumarate) 등이 있다. NNRTI는 NRTI와 다르게 바이러스 DNA 합성 종료자로서 역할하지 않고, 역전사 효소의 활성부위 근처의 소수성 낭(hydrophobic pocket)에 직접 결합하여 효소의 구조를 변화시킴으로써 효소작용을 억제한다. FDA 승인받은 NNRTI로는 에파비렌즈(efavirenz), 에트라비린(etravirine), 네비라핀(nevirapine), 도라비린(doravirine), 릴피비린(rilpivirine), 델라비르딘(delavirdine) 등이 있다.As a compound that inhibits the enzyme action of HIV reverse transcriptase, there are a Nucleoside Reverse Transcriptase Inhibitor (NRTI) family compound and a Non nucleoside Reverse Transcriptase Inhibitor (NNRTI) family compound. NRTI is mainly taken as a precursor, and then enters the host cell, is phosphorylated, and is converted into a nucleotide form and becomes active as a drug. Since NRTIs do not jointly have 3-OH (hydroxyl group) of the sugar molecule of the nucleoside, they intervene in the DNA strand during viral DNA synthesis and block the 3'-5' phosphate ester bond with the next nucleotide in the DNA chain. This terminates DNA synthesis. FDA-approved NRTIs include zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil fumarate), emtricitabine, and tenofovir alafenamide fumarate. Unlike NRTI, 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.
단백질분해효소 억제제(Protease inhibitors, PIs)는 감염력이 없는 비리온(virion)에 함유되어 있는 Gag와 Gag-Pol의 전구체 단백질을 절단시켜 감염력있는 성숙한 바이러스로 변화시켜주는 효소를 억제하는 화합물로, 초기에는 상기 효소가 바이러스 증식에 매우 중요한 역할을 하면서도 크기는 11 kDa로 매우 작아 내성 발생이 적을 것으로 기대했지만 내성 돌연변이가 매우 높은 빈도로 발생하여 현재는 3가지 항-HIV 약제를 투여하는 '칵테일 요법'에만 주로 사용된다. PIs로는 사퀴나비르(saquinavir), 리토나비르(ritonavir), 인디나비르(indinavir), 넬피나비르(nelfinavir), 암프레나비르(amprenavir), 아타자나비르(atazanavir), 포삼프레나비르(fosamprenavir), 티프라나비르(tipranavir), 다루나비르(darunavir) 등이 있다 Protease inhibitors (PIs) 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. In this study, although 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.
최근에는, 이들 항바이러스제의 항암 효과가 검토되고 있다. 일예로 에파비렌즈는 교모세포종, 췌장암 및 난소암에서 항암 효과가 있는 것으로 보고되었고, 에트라비린은 난소암에서 항암 효과가 있는 것으로 보고되었으며, 네비라핀은 간암 및 갑상선암에서 암세포 전이 억제 효과가 있는 것으로 보고되었고, 넬피나비르, 로피나비르 및 빈크리스틴(vincristine)의 조합이 경구 편평 상피암 세포의 생존력 감소 효과가 있는 것으로 보고되었다.In recent years, the anticancer effect of these antiviral agents is examined. For example, 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, and 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.
항우울제는 우울증과 관련된 신경전달물질(세로토닌(serotonin), 노르에피네프린(norepinephrine), 도파민(dopamine))의 불균형을 조절하여 우울 증상을 개선하는 약물로 삼환계 항우울제(tricyclic antidepressants, TCAs), 모노아민 산화효소 저해제(monoamine oxidase inhibitors, MAOIs), 선택적 세로토닌 재흡수 억제제(selective serotonin reuptake inhibitors, SSRIs), 세로토닌 노르에피네프린 재흡수 억제제(serotonin-norepinephrine reuptake inhibitors, SNRIs) 등으로 분류될 수 있다. 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.
삼환계 항우울제는 신경 세포 말단에서 세로토닌과 노르에피네프린의 재흡수를 차단하여 시냅스 내 신경전달물질의 농도를 증가시켜 우울 증상을 개선하는 물질로, 아미트리프틸린(amitriptyline), 노르트립틸린(nortriptyline), 클로미프라민(clomipramine), 이미프라민(imipramine), 아목사핀(amoxapine) 등이 있다.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.
선택적 세로토닌 재흡수 억제제는 신경세포 말단에서 선택적으로 세로토닌의 재흡수를 차단하여 시냅스 내 세로토닌의 농도를 증가시켜 세로토닌의 활성이 증가되어 우울증상이 완화되는 물질로, 플루옥세틴(fluoxetine), 파록세틴(paroxetine), 플루복사민(fluvoxamine), 설트랄린(sertraline), 에스시탈로프람(escitalopram), 보티옥세틴(vortioxetine) 등의 약물이 있으며 우울증, 강박 장애, 월경 전 불쾌장애 등에 사용된다. 삼환계 항우울제에 비해 부작용과 안전성 면에서 우수하여, 항우울제로 가장 많이 사용된다. 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.
최근에 이들 항우울제의 항암 효과가 검토되고 있다. 일예로 이미프라민의 소세포폐암에서 항암 효과가 있는 것으로 보고되었고, 플루옥세틴은 간세포암 및 비소세포폐암에서 항암 효과가 있는 것으로 보고되었다.Recently, the anticancer effect of these antidepressants has been studied. For example, it has been reported that imipramine has an anticancer effect in small cell lung cancer, and fluoxetine has been reported to have an anticancer effect in hepatocellular carcinoma and non-small cell lung cancer.
당뇨병 치료제의 일종으로 근육과 지방에서 인슐린 작용을 개선시키는 치아졸리딘디온(thiazolidinediones, TZD) 계열 화합물로 피오글리타존(pioglitazone), 로베글리타존(lobeglitazone) 등이 있으며, 치아졸리딘디온 계열 화합물 및 이의 유도체들의 항암효과가 검토되고 있다. 일예로 피오글리타존의 신장암에서 항암 효과가 있는 것으로 보고되었다.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.
이에 본 발명자들은 항암 효과가 보다 탁월한 물질 조합을 개발하기 위해 연구해온 결과, 담즙산 또는 이의 염 및 바이구아나이드 계열 화합물의 조합, 바이구아나이드 계열 화합물 및 항바이러스제의 조합, 담즙산, 바이구아나이드 계열 화합물 및 항바이러스제의 조합, 여기에 항우울제 또는 치아졸리딘디온 계열 화합물이 추가된 조합이 항암 효과에서 현저한 상승작용을 보인다는 점을 밝힘으로써, 새로운 혼합, 복합 또는 병용 항암제를 발명하기에 이르렀다.Accordingly, 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.
[선행기술문헌][Prior art literature]
[특허문헌][Patent Literature]
US 2014-0113930 A1 (2014.4.24)US 2014-0113930 A1 (2014.4.24)
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기존 항암제로 사용되고 있는 물질은 암세포에도 영향을 미치지만 정상세포, 예를 들어 빠르게 분열하는 정상세포인 피부, 점막, 혈액세포에도 독성을 미침으로써 탈모, 설사, 백혈구 감소증 등 다양한 부작용을 초래하고 있는 경우가 많다. 또한 많은 암세포에서 BCL-2와 같은 세포자살억제 단백질들(antiapoptotic proteins)의 발현이 증가되어 있거나, BAX와 같은 세포자살 촉진 단백질들(proapoptotic proteins)의 발현이 억제되는 등 정상세포와 달리 세포자살(apoptosis)이 결여되어 있는 경우가 많다. 그리고 암세포에서는 카스페이즈(caspases)의 발현이 낮거나 카스페이즈 유전자의 돌연변이가 나타나기도 한다. 경우에 따라서는 암세포는 미토콘드리아 외막 투과성(mitochondrial outer membrane permeabilization, MOMP)이 저해됨으로써 세포자살이 저해되기도 한다. 많은 암세포에서 이렇게 세포자살이 일어나지 않기 때문에 세포자살을 유발하는 많은 항암제의 치료효과가 나타나지 않는다는 문제점이 있다.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. there are many In addition, in many 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. In cancer cells, the expression of caspases is low or mutations in the caspase gene may appear. In some cases, 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.
따라서 정상세포에는 독성을 미치지 않고 암세포에만 선택적인 우수한 독성을 나타내면서도 항암 활성이 우수한 항암 치료제가 절실히 요구되고 있다.Therefore, there is an urgent need for an anticancer therapeutic agent that has excellent anticancer activity while exhibiting excellent toxicity selectively only to cancer cells without being toxic to normal cells.
본 발명은 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물이 정상세포에는 독성을 나타내지 않고, 암세포에 대해서는 현저히 우수한 항암효과를 나타낸다는 점을 발견하였으며, 상기 2종 이상의 화합물을 유효성분으로 함유하는, 암의 예방 또는 치료용 약학적 조성물을 제공함으로써 상기 과제를 해결하였다.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 The point that a pharmaceutical composition for the prevention or treatment of cancer containing two or more compounds selected from the group consisting of pharmaceutically acceptable salts as an active ingredient does not show toxicity to normal cells and exhibits a remarkably excellent anticancer effect on cancer cells Found, and solved the above problem by providing a pharmaceutical composition for the prevention or treatment of cancer, containing the two or more compounds as an active ingredient.
보다 구체적으로, 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제 1 성분; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제 2 성분을 유효성분으로 함유하는 약학적 조성물을 제공함으로써 상기 과제를 해결하였다.More specifically, as a complex, mixed, or combination preparation for use in the prevention or treatment of cancer, 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.
보다 구체적으로, 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제 1 성분; 및 항바이러스제를 포함하는 제 2 성분을 유효성분으로 함유하는 약학적 조성물을 제공함으로써 상기 과제를 해결하였다.More specifically, as a complex, mixed, or combination preparation for use in the prevention or treatment of cancer, 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.
보다 구체적으로, 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 항바이러스제를 포함하는 제 1 성분; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제 2 성분을 유효성분으로 함유하는 약학적 조성물을 제공함으로써 상기 과제를 해결하였다.More specifically, it is 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.
또한, 상기 제 1 성분; 제 2 성분; 및 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물을 포함하는 제 3 성분을 유효성분으로 함유하는 약학적 조성물을 제공함으로써 상기 과제를 해결하였다.In addition, 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.
본 발명의 일 양태에서 상기 담즙산 또는 담즙산 유도체는 콜산(cholic acid) 계열 화합물 또는 이의 유도체일 수 있고, 상기 콜산 계열 화합물 또는 이의 유도체는 콜산(cholic acid), 케노데옥시콜산(chenodeoxycholic acid), 데옥시콜산(deoxycholic acid), 우르소데옥시콜산(ursodeoxycholic acid), 리토콜산(lithocholic acid), 글리코콜산(glycocholic acid), 타우로콜산(taurocholic acid), 글리코케노데옥시콜산(glycochenodeoxycholic acid), 타우로케노데옥시콜산(taurochenodeoxycholic acid), 글리코데옥시콜산(glycodeoxycholic acid), 타우로데옥시콜산(taurodeoxycholic acid), 글리코우르소데옥시콜산(glycoursodeoxycholic acid), 타우로우르소데옥시콜산(tauroursodeoxycholic acid), 글리코리토콜산(glycolithocholic acid) 및 타우로리토콜산(taurolithocholic acid)으로 구성된 그룹에서 선택될 수 있다.In one embodiment of the present invention, 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.
또한, 상기 콜산 계열 화합물 또는 이의 유도체는 하기 화학식 1의 화합물일 수 있다:In addition, the cholic acid-based compound or a derivative thereof may be a compound of Formula 1 below:
[화학식 1][Formula 1]
Figure PCTKR2021001785-appb-img-000001
Figure PCTKR2021001785-appb-img-000001
[상기 식에서,[In the above formula,
R 1 및 R 2는 각각 독립적으로 H 또는 OH이고, R 3은 OH, NHCH 2COOH, 또는 NH(CH 2) 2SO 2OH이다.]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.]
본 발명의 일 양태에서, R 1은 H이고, R 2 및 R 3는 OH일 수 있고, R 1 및 R 3는 OH이고, R 2는 H일 수 있으며, R 1, R 2 및 R 3는 OH일 수 있고, R 1 및 R 2는 H이고, R 3는 OH일 수 있다.In one aspect of the present invention, 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, and R 1 , R 2 and R 3 may be OH, R 1 and R 2 may be H, and R 3 may be OH.
또한, R 1은 H, R 2는 OH, R 3는 NHCH 2COOH 또는 NH(CH 2) 2SO 2OH일 수 있고, R 1은 OH, R 2는 H, R 3는 NHCH 2COOH 또는 NH(CH 2) 2SO 2OH일 수 있으며, R 1 및 R 2는 OH이고, R 3는 NHCH 2COOH 또는 NH(CH 2) 2SO 2OH일 수 있고, R 1 및 R 2는 H이고, R 3는 NHCH 2COOH 또는 NH(CH 2) 2SO 2OH일 수 있다.In addition, 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.
보다 구체적으로, 상기 담즙산 또는 담즙산 유도체는 하기 화학식 2 내지 9의 화합물로 구성된 그룹에서 선택될 수 있다:More specifically, the bile acid or bile acid derivative may be selected from the group consisting of compounds of Formulas 2 to 9 below:
[화학식 2][Formula 2]
Figure PCTKR2021001785-appb-img-000002
Figure PCTKR2021001785-appb-img-000002
[상기 식에서, [In the above formula,
R은 COCH 3, COC 6H 5, CH 2C 6H 5 또는 CH 2OCH 3이다.]R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ]
[화학식 3][Formula 3]
Figure PCTKR2021001785-appb-img-000003
Figure PCTKR2021001785-appb-img-000003
[상기 식에서, [In the above formula,
R은 COCH 3, COC 6H 5, CH 2C 6H 5 또는 CH 2OCH 3이다.]R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ]
[화학식 4][Formula 4]
Figure PCTKR2021001785-appb-img-000004
Figure PCTKR2021001785-appb-img-000004
[상기 식에서, [In the above formula,
R은 H 또는 CN이다.]R is H or CN.]
[화학식 5][Formula 5]
Figure PCTKR2021001785-appb-img-000005
Figure PCTKR2021001785-appb-img-000005
[상기 식에서,[In the above formula,
R 1 및 R 2는 각각 독립적으로 H, CH 3CO 또는 CH 3SO 3이다.]R 1 and R 2 are each independently H, CH 3 CO or CH 3 SO 3 ]
[화학식 6][Formula 6]
Figure PCTKR2021001785-appb-img-000006
Figure PCTKR2021001785-appb-img-000006
[상기 식에서,[In the above formula,
R은 H, CH 3, CH 3CH 2 또는 CH 3CH 2CH 2CH 2이다.]R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ]
[화학식 7][Formula 7]
Figure PCTKR2021001785-appb-img-000007
Figure PCTKR2021001785-appb-img-000007
[상기 식에서,[In the above formula,
R은 H, CH 3CO 또는 CH 3SO 3이다.]R is H, CH 3 CO or CH 3 SO 3 ]
[화학식 8][Formula 8]
Figure PCTKR2021001785-appb-img-000008
Figure PCTKR2021001785-appb-img-000008
[상기 식에서,[In the above formula,
R은 H, CH 3, CH 3CH 2 또는 CH 3CH 2CH 2CH 2이다.]R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ]
[화학식 9][Formula 9]
Figure PCTKR2021001785-appb-img-000009
Figure PCTKR2021001785-appb-img-000009
[상기 식에서,[In the above formula,
R은 NH(CH 2) 2COOC 10H 14, NHCH(CH 2C 6H 5)COOC 4H 9 또는 NH(CH 2) 2COOC 4H 9이다.]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 ]
본 발명의 일 양태에서, 상기 바이구아나이드 계열 화합물은 메트포르민(metformin), 펜포르민(phenformin), 부포르민(buformin) 및 바이구아나이드(biguanide)로 구성된 그룹에서 선택되는 것일 수 있다.In one embodiment of the present invention, the biguanide-based compound may be selected from the group consisting of metformin, phenformin, buformin and biguanide.
본 발명의 일 양태에서, 상기 항바이러스제는 비뉴클레오시드 역전사 효소 억제제(NNRTIs; Non-nucleoside reverse-transcriptase inhibitors), 뉴클레오시드 역전사 효소 저해제(NRTIs; Nucleoside reverse-transcriptase inhibitors), 단백분해효소 억제제(PIs; Protease inhibitors), 통합효소억제제(INSTI; Integrase Strand Transfer Inhibitor), 융합 억제제, CCR 5(Chemokine (C-C motif) ligand 5) 억제제, 독감 치료제, 헤르페스 치료제, B형간염 치료제, C형간염 치료제, 면역 증강제, 면역반응 조절제 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있다.In one aspect of the present invention, 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.
보다 구체적으로, 상기 항바이러스제는 에파비렌즈(efavirenz), 에트라비린(etravirine), 네비라핀(nevirapine), 도라비린(doravirine), 릴피비린(rilpivirine), 델라비르딘(delavirdine), 지도부딘(zidovudine), 디다노신(didanosine), 잘시타빈(zalcitabine), 스타부딘(stavudine), 라미부딘(lamivudine), 아바카비어(abacavir), 테노포비르 디소프록시 푸마레이트(tenofovir disoproxil fumarate), 엠트리시타빈(emtricitabine), 테노포비르 알라페나미드 푸마레이트(tenofovir alafenamide fumarate), 사퀴나비르(saquinavir), 리토나비르(ritonavir), 인디나비르(indinavir), 넬피나비르(nelfinavir), 암프레나비르(amprenavir), 로비나비르(lopinavir), 아타자나비르(atazanavir), 포삼프레나비르(fosamprenavir), 티프라나비르(tipranavir), 다루나비르(darunavir), 코비시스타트(cobicistat), 돌루테그라비르(dolutegravir), 랄테그라비르(raltegravir), 엔푸버타이드(enfuvirtide), 마라비록(maraviroc), 엘비테그라비르(elvitegravir), 테노포비르 알라페나미드(tenofovir alafenamide), 테노포비르 디소프록실(tenofovir disoproxil), 아만타딘(amantadine), 리만타딘(rimantadine), 오셀타미비르(oseltamivir), 자나미비르(zanamivir), 페라미비르(peramivir), 발록사비르(baloxavir), 라니나미비어(laninamivir), 아시클로비르(aciclovir), 발라시클로비르(valaciclovir), 이독스우리딘(idoxuridine), 비다라빈(vidarabine), 펜시클로비르(penciclovir), 팜시클로비르(famciclovir), 트리플루리딘(trifluridine), 시도포비어(cidofovir), 포스카넷(foscarnet), 클레부딘(clevudine), 텔비부딘(telbivudine), 엔테카비르(entecavir), 아데포비르(adefovir), 베시포비르(besifovir), 페그인터페론 알파 2a(peginterferon-α-2a), 페그인터페론 알파 2b(peginterferon-α-2b), 리바비린(ribavirin), 보세프레비르(boceprevir), 다사부비르(dasabuvir), 다클라타스비르(daclatasvir), 아수나프레비르(asunaprevir), 소포스부비르(sofosbuvir), 엘바스비르(elbasvir), 그라조프레비르(grazoprevir), 글레카프레비르(glecaprevir), 피브렌타스비르(pibrentasvir), 옴비타스비르(ombitasvir), 파리타프레비르(paritaprevir), 인터페론알파 2a(interferon alfa-2a), 인터페론알파 2b(interferon alfa-2b) 및 이미퀴모드(imiquimod)로 구성된 그룹에서 선택된 1종 이상의 화합물일 수 있다.More specifically, 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, oseltamivir, zanamivir, peramivir, baloxavir, raninamivir, acyclo Aciclovir, valaciclovir, idoxuridine, vidarabine, penciclovir, famciclovir (fa) mciclovir, trifluridine, cidofovir, foscarnet, clevudine, telbivudine, entecavir, adefovir, besifovir (besifovir), peginterferon alpha 2a (peginterferon-α-2a), peginterferon alfa 2b (peginterferon-α-2b), ribavirin, boceprevir, dasabuvir, daclatas daclatasvir, asunaprevir, sofosbuvir, elbasvir, grazoprevir, glecaprevir, pibrentasvir , at least one selected from the group consisting of ombitasvir, paritaprevir, interferon alfa-2a, interferon alfa-2b, and imiquimod. It may be a compound.
본 발명의 일 양태에서, 상기 제 3 성분은 아미트리프틸린(amitriptyline), 노르트립틸린(nortriptyline), 클로미프라민(clomipramine), 이미프라민(imipramine), 아목사핀(amoxapine), 플루옥세틴(fluoxetine), 파록세틴(paroxetine), 플루복사민(fluvoxamine), 설트랄린(sertraline), 에스시탈로프람(escitalopram), 보티옥세틴(vortioxetine), 모클로베미드(moclobemide), 둘록세틴(duloxetine), 벤라팍신(venlafaxine), 데스벤라팍신(desbenlafaxine), 밀나시프란(milnacipran), 부프로피온(bupropion), 미르타자핀(mirtazapine), 트라조돈(trazodone), 티아넵틴(tianeptine), 피오글리타존(pioglitazone), 로베글리타존(lobeglitazone), 로시글리타존(rosiglitazone), 시글리타존(ciglitazone), 다르글리타존(darglitazone), 엔글리타존(englitazone), 네토글리타존(netoglitazone), 리보글리타존(rivoglitazone), 트로글리타존(troglitazone), 및 밸라글리타존(balaglitazone)으로 구성된 그룹에서 선택될 수 있다.In one embodiment of the present invention, 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.
본 발명의 일 양태에서, 상기 암은 (A) (1) 정위치 도관 암종(DCIS)(면포 암종, 사상, 유두, 미세유두), 침윤 도관 암종(IDC), 관 암종, 점액(콜로이드성) 암종, 유두 암종, 화생 암종 및 염증성 암종을 비롯한 도관 암종; (2) 정위치 소엽 암종(LCIS) 및 침윤성 소엽 암종을 비롯한 소엽 암종; 및 (3) 유두의 파제트 질환을 비롯한 유방 암; (B) (1) 자궁경부 상피내 종양(등급 I), 자궁경부 상피내 종양(등급 II), 자궁경부 상피내 종양(등급 III)(정위치 편평 세포 암종), 각화성 편평 세포 암종, 비각화성 편평 세포 암종, 사마귀모양암종, 정위치 선암종, 정위치 선암종, 자궁경내막 타입, 자궁내막양 선암종, 투명 세포 선암종, 선상피 암종, 선낭 암종, 소 세포 암종 및 미분화 암종을 비롯한 자궁경부의 암; (2) 자궁내막양 암종, 선암종, 선극세포종(편평 상피화생을 갖는 선암종), 선상피 암종(혼합 선암종 및 편평 세포 암종, 점액 선암종, 장액 선암종, 투명 세포 선암종, 편평 세포 선암종 및 미분화 선암종을 비롯한 자궁체의 암; (3) 장액성 낭선종, 장액 낭선종, 점액 낭선종, 점액 낭선종, 자궁내막양 종양, 자궁내막양 선암종, 투명 세포 종양, 투명 세포 낭선종 및 미분류 종양을 비롯한 난소의 암; (4) 편평 세포 암종 및 선암종을 비롯한 질의 암; 및 (5) 외음부 상피내 종양(등급 I), 외음부 상피내 종양(등급 II), 외음부 상피내 종양(등급 III)(정위치 편평 세포 암종); 편평 세포 암종, 사마귀모양암종, 음문의 파제트 질환, 선암종(NOS), 기저 세포 암종(NOS) 및 바르톨린선 암종을 비롯한 외음부의 암을 포함한 여성 생식계의 암; (C) (1) 편평 세포 암종을 비롯한 음경의 암; (2) 전립선의 선암종, 육종 및 이행 세포 암종을 비롯한 전립선의 암; (3) 정상피종 종양, 비정상피종 종양, 기형종, 배아 암종, 난황낭 종양 및 융모막암종을 비롯한 고환의 암을 포함한 남성 생식계의 암; (D) 육종(혈관육종, 섬유육종, 횡문근육종, 지방육종), 점액종, 횡문근종, 섬유종, 지방종 및 기형종을 비롯한 심장계의 암; (E) 후두의 편평 세포 암종, 원발성 흉막 중피종 및 인두의 편평 세포 암종을 비롯한 호흡계의 암; (F) 편평 세포 암종(표피모양 암종), 편평 세포 암종의 변형, 방추 세포 암종, 소 세포 암종, 기타 세포의 암종, 중간 세포 타입의 암종, 복합 귀리 세포 암종, 선암종, 세엽 선암종, 유두 선암종, 기관지폐포 암종, 점액 형성 고형 암종, 거대 세포 암종, 거대 세포 암종, 투명 세포 암종 및 육종을 비롯한 폐의 암; (G) (1) 원발성 선암종, 카르시노이드 종양 및 림프종을 비롯한 바터(Vater) 팽대부의 암; (2) 선암종, 편평 세포 암종 및 흑색종을 비롯한 항문관의 암; (3) 정위치 암종, 선암종, 유두 선암종, 선암종, 창자형, 점액 선암종, 투명 세포 선암종, 반지 세포 암종, 선상피 암종, 편평 세포 암종, 소 세포(귀리) 암종, 미분화 암종, 암종(NOS), 육종 및 카르시노이드 종양을 비롯한 간외 담관의 암; (4) 정위치 선암종, 선암종, 점액 선암종(콜로이드형; 50% 초과의 점액 암종), 반지 세포 암종(50% 초과의 반지 세포), 편평 세포(표피모양) 암종, 선상피 암종, 소 세포(귀리 세포) 암종, 미분화 암종, 암종(NOS), 육종, 림프종 및 카르시노이드 종양을 비롯한 결장 및 직장의 암; (5) 편평 세포 암종, 선암종, 평활근육종 및 림프종을 비롯한 식도의 암; (6) 선암종, 선암종, 창자형, 선상피 암종, 정위치 암종, 암종(NOS), 투명 세포 선암종, 점액 선암종, 유두 선암종, 반지 세포 암종, 소 세포(귀리 세포) 암종, 편평 세포 암종 및 미분화 암종을 비롯한 담낭의 암; (7) 편평 세포 암종을 비롯한 입술 및 구강의 암; (8) 간암(간세포 암종), 담관암종, 간모세포종, 혈관육종, 간세포 선종 및 혈관종을 비롯한 간의 암; (9) 관 세포 암종, 다형태 거대 세포 암종, 거대 세포 암종, 오스테오클라스토이드(osteoclastoid)형, 선암종, 선상피 암종, 점액(콜로이드) 암종, 낭선종, acinar 세포 암종, 유두 암종, 소 세포(귀리 세포) 암종, 혼합 세포형, 암종(NOS), 미분화 암종, 랑게르한스 도세포에서 발생하는 내분비 세포 종양 및 카르시노이드를 비롯한 외분비선 췌장의 암; (10) 세엽(샘꽈리) 세포 암종, 선낭 암종(원주종), 선암종, 편평 세포 암종, 다형태 선종에서의 암종(악성 혼합 종양), 점막표피모양 암종(잘 분화된 또는 낮은 등급) 및 점막표피모양 암종(불량하게 분화되거나 또는 높은 등급)을 비롯한 타액선의 암; (11) 선암종, 유두 선암종, 관상 선암종, 점액 선암종, 반지 세포 암종, 선상피 암종, 편평 세포 암종, 소 세포 암종, 미분화 암종, 림프종, 육종 및 카르시노이드 종양을 비롯한 위의 암; 및 (12) 선암종, 림프종, 카르시노이드 종양, 카포시 육종, 평활근종, 혈관종, 지방종, 신경섬유종증 및 섬유종을 비롯한 소장의 암을 포함한 위장관의 암; (H) (1) 신장 세포 암종, 벨리니 집합관의 암종, 선암종, 유두 암종, 관상 암종, 과립 세포 암종, 투명 세포 암종(신선암), 신장의 육종 및 신장모세포종을 비롯한 신장의 암; (2) 이행 세포 암종, 유두 이행 세포 암종, 편평 세포 암종 및 선암종을 비롯한 신우 및 요관의 암; (3) 이행 세포 암종, 편평 세포 암종 및 선암종을 비롯한 요도의 암; 및 (4) 정위치 암종, 이행 요로상피 세포 암종, 유두 이행 세포 암종, 편평 세포 암종, 선암종, 미분화를 비롯한 방광의 암을 포함한 비뇨기계의 암; (I) (1) (a) 골형성: 골육종; (b) 연골-형성: 연골육종 및 중간엽 연골육종; (c) 거대 세포 종양, 악성; (d) 유잉 육종; (e) 혈관 종양: 혈관내피종, 혈관주위세포종 및 혈관육종; (f) 결합 조직 종양: 섬유육종, 지방육종, 악성 간엽종 및 미분화 육종; 및 (g) 기타 종양: 척삭종 및 장골의 범랑종을 비롯한 골의 암; (2) 폐포 연질부 육종, 혈관육종, 상피모양 육종, 골외성 연골육종, 섬유육종, 평활근육종, 지방육종, 악성 섬유 조직구종, 악성 혈관주위세포종, 악성 간엽종, 악성 슈반세포종, 횡문근육종, 활액 육종 및 육종(NOS)을 비롯한 연조직의 암; (3) 두개골의 암(골종, 혈관종, 육아종, 황색종, 변형성 골염), 수막의 암(수막종, 수막육종, 신경교종증), 뇌의 암(별아교세포종, 속질모세포종, 신경아교종, 뇌실막세포종, 종자세포종(솔방울샘종), 다형성아교모세포종, 희소돌기아교세포종, 슈반세포종, 망막모세포종, 선천성 종양) 및 척수의 암(신경섬유종증, 수막종, 신경아교종, 육종)을 비롯한 신경계의 암; (4) 골수성 백혈병(급성 및 만성), 급성 림프모구 백혈병, 만성 림프구 백혈병, 골수증식 질환, 다발성 골수종; 골수형성이상 증후군), 호지킨병 및 비-호지킨 림프종(악성 림프종)을 비롯한 혈액암; (5) (a) 유두 암종(소포 부위의 것 포함), 소포 암종, 속질 암종 및 미분화(역형성) 암종을 비롯한 갑상선의 암; 및 (b) 교감신경모세포종, 교감신경원세포종, 악성 신경절신경종, 신경절교감신경모세포종 및 신경절신경종을 비롯한 신경모세포종을 포함하는 내분비계의 암; (6) 편평 세포 암종, 편평 세포 암종의 방추 세포 변형, 기저 세포 암종, 한선 또는 피지선으로부터 발생된 선암종 및 악성 흑색종을 비롯한 피부의 암; (7) (a) 결막의 암종을 비롯한 결막의 암; (b) 기저 세포 암종, 편평 세포 암종, 안검의 흑색종 및 피지 세포 암종을 비롯한 안검의 암; (c) 선암종, 선낭 암종, 다형태 선종에서의 암종, 점액표피모양 암종 및 편평 세포 암종을 비롯한 누선의 암; (d) 방추 세포 흑색종, 혼합 세포 흑색종 및 상피모양 세포 흑색종을 비롯한 포도막의 암; (e) 안와의 육종, 연조직 종양 및 골의 육종을 비롯한 안와의 암; 및 (f) 망막모세포종을 포함한 눈의 암을 포함한 근육, 골 및 연조직의 암으로 구성된 그룹에서 선택되는 것일 수 있다.In one aspect of the invention, 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, endometrial type, endometrioid adenocarcinomas, clear cell adenocarcinomas, glandular carcinomas, adenocystic carcinomas, small cell carcinomas and undifferentiated carcinomas; (2) uterus including endometrioid carcinoma, adenocarcinoma, adenoblastoma (adenocarcinoma with squamous metaplasia), glandular carcinoma (mixed adenocarcinoma and squamous cell carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, clear cell adenocarcinoma, squamous cell adenocarcinoma and undifferentiated adenocarcinoma) Cancers of the body: (3) cancers of the ovaries, including serous cystadenomas, serous cystadenomas, mucinous cystadenomas, mucinous cystadenomas, endometrioid tumors, endometrioid adenocarcinomas, clear cell tumors, clear cell cystadenomas and unclassified tumors; (4) squamous tumors; cancers of the vagina, including cell carcinoma and adenocarcinoma; and (5) vulvar intraepithelial tumors (grade I), vulvar intraepithelial tumors (grade II), vulvar intraepithelial tumors (grade III) (squamous cell carcinoma in situ); Cancers of the female reproductive system, including cancers of the vulva, including carcinoma, Paget's disease of the vulva, adenocarcinoma (NOS), basal cell carcinoma (NOS) and Bartholin's adenocarcinoma; (C) (1) cancer of the penis, including squamous cell carcinoma (2) cancers of the prostate, including adenocarcinomas, sarcomas, and transitional cell carcinomas of the prostate; (D) cancers of the heart system including sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; (E) squamous cell carcinoma of the larynx, primary pleura Cancers of the respiratory system, including mesothelioma and squamous cell carcinoma of the pharynx; Cancer of the lung, including complex oat cell carcinoma, adenocarcinoma, acinar adenocarcinoma, papillary adenocarcinoma, bronchoalveolar carcinoma, mucinous solid carcinoma, giant cell carcinoma, giant cell carcinoma, clear cell carcinoma and sarcoma; (G) (1) primary adenocarcinoma; Cancers of the ampulla of Vater, including carcinoid tumors and lymphomas; (2) cancers of the anal canal, including adenocarcinomas, squamous cell carcinomas and melanomas; (3) orthostatic carcinomas, adenocarcinomas, papillary carcinomas; Extrahepatic bile ducts including adenocarcinoma, adenocarcinoma, intestinal type, mucinous adenocarcinoma, clear cell adenocarcinoma, ring cell carcinoma, adenoid carcinoma, squamous cell carcinoma, small cell (oat) carcinoma, undifferentiated carcinoma, carcinoma (NOS), sarcoma and carcinoid tumor of cancer; (4) Orthostatic adenocarcinoma, adenocarcinoma, mucinous adenocarcinoma (colloidal; >50% mucinous carcinoma), ring cell carcinoma (greater than 50% of ring cells), squamous cell (epidermal) carcinoma, adenoid carcinoma, small cell (oat) cell) cancers of the colon and rectum, including carcinomas, undifferentiated carcinomas, carcinomas (NOS), sarcomas, lymphomas and carcinoid tumors; (5) cancers of the esophagus, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma and lymphoma; (6) adenocarcinoma, adenocarcinoma, bowel type, adenocarcinoma, orthotopic carcinoma, carcinoma (NOS), clear cell adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, ring cell carcinoma, small cell (oat cell) carcinoma, squamous cell carcinoma and undifferentiated carcinoma cancer of the gallbladder, including; (7) cancers of the lips and oral cavity, including squamous cell carcinoma; (8) cancers of the liver, including liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma; (9) ductal cell carcinoma, giant cell carcinoma multiforme, giant cell carcinoma, osteoclastoid type, adenocarcinoma, glandular carcinoma, mucinous (colloid) carcinoma, cystadenoma, acinar cell carcinoma, papillary carcinoma, small cell ( oat cells) carcinoma, mixed cell type, carcinoma (NOS), undifferentiated carcinoma, cancer of the exocrine pancreas including endocrine cell tumors arising from Langerhans islet cells and carcinoids; (10) acinar (acinar) cell carcinoma, adenocystic carcinoma (columoma), adenocarcinoma, squamous cell carcinoma, carcinoma in polymorphic adenoma (malignant mixed tumor), mucoepidermoid carcinoma (well-differentiated or low-grade) and mucosal cancers of the salivary glands, including epidermal carcinoma (poorly differentiated or high grade); (11) cancers of the stomach, including adenocarcinoma, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, ring cell carcinoma, adenoid carcinoma, squamous cell carcinoma, small cell carcinoma, undifferentiated carcinoma, lymphoma, sarcoma and carcinoid tumor; and (12) cancers of the gastrointestinal tract, including cancers of the small intestine, including adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibromatosis and fibroma; (H) (1) cancers of the kidney, including (1) renal cell carcinoma, carcinoma of the Bellini collecting duct, adenocarcinoma, papillary carcinoma, tubular carcinoma, granular cell carcinoma, clear cell carcinoma (renal cancer), sarcoma of the kidney and nephroblastoma; (2) cancers of the renal pelvis and ureter, including transitional cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma; (3) cancers of the urethra, including transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma; and (4) cancers of the urinary system, including cancers of the bladder, including orthotopic carcinoma, transitional urothelial cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, undifferentiated; (I) (1) (a) Osteogenesis: osteosarcoma; (b) cartilage-forming: chondrosarcoma and mesenchymal chondrosarcoma; (c) giant cell tumor, malignant; (d) Ewing's sarcoma; (e) vascular tumors: hemangioendothelioma, hemangiopericytoma and hemangiosarcoma; (f) connective tissue tumors: fibrosarcoma, liposarcoma, malignant mesenchymal and undifferentiated sarcoma; and (g) other tumors: cancers of the bone, including chordomas and erosions of the long bones; (2) alveolar soft sarcoma, angiosarcoma, epithelial sarcoma, extraosseous chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant hemangiopericytoma, malignant mesenchymal, malignant Schwanncytoma, rhabdomyosarcoma, cancers of soft tissues including synovial sarcoma and sarcoma (NOS); (3) Cancer of the skull (osteoma, hemangioma, granuloma, xanthomas, osteomyelitis), cancer of the meninges (meningoma, meningiosarcoma, gliomatosis), cancer of the brain (astrocytoma, meduloblastoma, glioma, ependymocytoma, seed) cancers of the nervous system, including cellomas (pineal adenoma), glioblastoma multiforme, oligodendrocytoma, Schwannoma, retinoblastoma, congenital tumors) and cancers of the spinal cord (neurofibromatosis, meningioma, glioma, sarcoma); (4) myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma; myelodysplastic syndrome), hematologic cancers including Hodgkin's disease and non-Hodgkin's lymphoma (malignant lymphoma); (5) (a) cancers of the thyroid gland, including papillary carcinomas (including those of the follicular region), follicular carcinomas, medullary carcinomas, and undifferentiated (anaplastic) carcinomas; and (b) cancers of the endocrine system, including neuroblastomas, including sympathoblastoma, sympathoblastoma, malignant ganglioneuroma, gangliosympathoblastoma and ganglioneuroma; (6) cancers of the skin, including squamous cell carcinoma, spindle cell deformation of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma arising from sweat glands or sebaceous glands, and malignant melanoma; (7) (a) cancer of the conjunctiva, including carcinoma of the conjunctiva; (b) cancers of the eyelids, including basal cell carcinoma, squamous cell carcinoma, melanoma of the eyelid and sebaceous cell carcinoma; (c) cancer of the lacrimal gland, including adenocarcinoma, adenocystic carcinoma, carcinoma in polymorphic adenoma, mucoepidermoid carcinoma and squamous cell carcinoma; (d) cancers of the uvea, including spindle cell melanoma, mixed cell melanoma and epithelial cell melanoma; (e) cancers of the orbit, including sarcomas of the orbit, soft tissue tumors, and sarcomas of the bone; And (f) it may be selected from the group consisting of cancers of muscle, bone and soft tissue, including cancer of the eye including retinoblastoma.
본 발명의 일 양태에서, 상기 약학적 조성물은 정제, 캡슐제, 주사제, 트로키제, 산제, 과립제, 액제, 현탁제, 내용액제, 유제, 시럽제, 좌제, 질정제, 및 환제로 구성된 그룹에서 선택되는 제형으로 제형화될 수 있다.In one embodiment of the present invention, 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
본 발명의 또 다른 양태에서, 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 포함하는 제제를 함유하는, 암의 예방 또는 치료용 복합, 혼합 또는 병용제 키트가 제공된다.In another embodiment of the present invention, 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.
보다 구체적으로, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제제; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제제를 함유하는, 복합, 혼합 또는 병용제 키트가 제공된다.More specifically, 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.
보다 구체적으로, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제제; 및 항바이러스제를 포함하는 제제를 함유하는, 복합, 혼합 또는 병용제 키트가 제공된다.More specifically, a preparation comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and an antiviral agent. Combination, combination or combination kits are provided.
보다 구체적으로, 항바이러스제를 포함하는 제제; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제제를 함유하는, 복합, 혼합 또는 병용제 키트가 제공된다.More specifically, a formulation comprising an antiviral agent; and a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof, is provided.
또한, 상기 제제; 및 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물을 포함하는 제제를 더 함유하는, 복합, 혼합 또는 병용제 키트가 제공된다.In addition, 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.
본 발명의 또 다른 양태에서, 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 약학적으로 유효한 양으로 개체에 복합, 혼합 또는 병용 투여하는 단계를 포함하는, 암의 예방 또는 치료방법이 제공된다.In another embodiment of the present invention, 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 There is provided a method for preventing or treating cancer, comprising the step of complex, mixed or co-administered to a subject in a pharmaceutically effective amount.
본 발명의 또 다른 양태에서, 암의 예방 및 치료용 약학적 조성물로 사용하기 위한 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 유효성분으로 함유하는 복합, 혼합 또는 병용제제의 용도가 제공된다.In another aspect of the present invention, 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 Provided is the use of a complex, mixed or combined preparation containing two or more compounds selected from the group consisting of acceptable salts as an active ingredient.
본 발명에서는 담즙산 또는 이의 염 및 바이구아나이드 계열 화합물의 조합, 바이구아나이드 계열 화합물 및 항바이러스제의 조합, 담즙산, 바이구아나이드 계열 화합물 및 항바이러스제의 조합, 여기에 항우울제 또는 치아졸리딘디온 계열 화합물이 추가된 조합이 각각을 단독으로 처리하였을 때에는 항암 효과가 미약하나, 복합, 혼합 또는 병용처리하는 경우 다양한 암종에서 현저히 높은 항암 효과가 나타나는바, 이를 유효성분으로 함유하는 약학적 조성물은 암 예방 또는 치료에 유용하게 사용될 수 있다. 또한 유효농도에서 정상세포에는 독성을 나타내지 않는바 부작용이 크게 감소되었으면서도 항암 효과는 우수한 항암제를 제공할 수 있다. In the present invention, 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 When this added combination is treated with each alone, 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. In addition, 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.
도 1a는 5 mM 메트포르민(metformin), 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트(sodium deoxycholate), 5 mM 메트포르민 + 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 유방암세포인 MCF-7 세포주에 24, 48, 72시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figure 1a shows 5 mM metformin, 0.01, 0.1, 1 and 10 μM sodium deoxycholate, 5 mM metformin + 0.01, 0.1, 1 and 10 μM 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;
파란색 막대 그래프(1): 5 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트(기타 파란색 막대 그래프)만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트);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 μM sodium deoxycholate (other blue bar graphs) were treated alone ;
붉은색 막대 그래프(2): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 24시간 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트); Red bar graph (2): 5 mM metformin plus 0.01, 0.1, 1, and 10 μM sodium deoxycholate in combination for 24 hours to inhibit growth of cancer cells (percentage);
녹색 막대 그래프(3): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 48시간 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트); 및Green bar graph (3): the degree of growth inhibition (percent) of cancer cells when 5 mM metformin and 0.01, 0.1, 1 and 10 μM sodium deoxycholate were co-treated for 48 hours; and
보라색 막대 그래프(4): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 72시간 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트).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 μM sodium deoxycholate were co-treated for 72 hours.
도 1b는 5 mM 메트포르민, 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트, 5 mM 메트포르민 + 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 WISH 정상 상피세포(primary epithelial cell)에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figure 1b shows WISH primary epithelial cells treated with 5 mM metformin, 0.01, 0.1, 1 and 10 μM sodium deoxycholate, 5 mM metformin + 0.01, 0.1, 1 and 10 μM sodium deoxycholate for 24 hours. This is a diagram showing the degree of growth inhibition (% growth inhibition);
파란색 막대 그래프(1): 5 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트(기타 파란색 막대 그래프)만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트); 및Blue 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 μM sodium deoxycholate (other blue bar graphs) were treated alone ; and
붉은색 막대 그래프(2): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트).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 μM sodium deoxycholate were co-treated.
도 2a 및 도 2b는 5 mM 메트포르민, 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트, 5 mM 메트포르민 + 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 췌장암 세포인 AsPC-1 세포주(도 2a) 및 MIA PaCa-2 세포주(도 2b)에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figures 2a and 2b show that 5 mM metformin, 0.01, 0.1, 1 and 10 μM sodium deoxycholate, 5 mM metformin + 0.01, 0.1, 1 and 10 μM 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;
파란색 막대 그래프(1): 5 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트(기타 파란색 막대 그래프)만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트); 및Blue 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 μM sodium deoxycholate (other blue bar graphs) were treated alone ; and
붉은색 막대 그래프(2): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트).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 μM sodium deoxycholate were co-treated.
도 3은 5 mM 메트포르민, 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트, 5 mM 메트포르민 + 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 전립선암 세포인 LNcaP 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;3 shows growth when 5 mM metformin, 0.01, 0.1, 1 and 10 μM sodium deoxycholate, 5 mM metformin + 0.01, 0.1, 1 and 10 μM sodium deoxycholate were treated in LNcaP cell lines, which are prostate cancer cells, for 24 hours. It is a diagram showing the degree of inhibition (% growth inhibition);
파란색 막대 그래프(1): 5 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트(기타 파란색 막대 그래프)만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트); 및Blue 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 μM sodium deoxycholate (other blue bar graphs) were treated alone ; and
붉은색 막대 그래프(2): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 소듐 데옥시콜레이트를 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트).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 μM sodium deoxycholate were co-treated.
도 4a는 5 mM 메트포르민, 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산(ursodeoxycholic acid), 5 mM 메트포르민 + 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산을 유방암세포인 MCF-7 세포주에 24시간 처리하였을 때 성장억제 정도를 나타낸 도이다;Figure 4a shows that 5 mM metformin, 0.01, 0.1, 1 and 10 μM ursodeoxycholic acid, 5 mM metformin + 0.01, 0.1, 1 and 10 μM 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;
녹색 막대 그래프(3): 5 mM 메트포르민만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트);Green bar graph (3): the degree of growth inhibition (percent) of cancer cells when only 5 mM metformin was treated;
파란색 막대 그래프(1): 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트); 및Blue bar graph (1): the degree of growth inhibition (percent) of cancer cells when only 0.01, 0.1, 1 and 10 μM ursodeoxycholic acid were treated alone; and
붉은색 막대 그래프(2): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산을 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트).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 μM ursodeoxycholic acid were co-treated.
도 4b는 5 mM 메트포르민 + 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산을 WISH 정상 상피세포(primary epithelial cell)에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다.Figure 4b is a diagram showing the degree of growth inhibition (% growth inhibition) when 5 mM metformin + 0.01, 0.1, 1 and 10 μM ursodeoxycholic acid was treated in WISH normal epithelial cells (primary epithelial cells) for 24 hours.
도 5a 및 도 5b는 5 mM 메트포르민, 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산, 5 mM 메트포르민 + 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산을 췌장암 세포인 AsPC-1 세포주(도 5a) 및 MIA PaCa-2 세포주(도 5b)에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figures 5a and 5b show that 5 mM metformin, 0.01, 0.1, 1 and 10 μM ursodeoxycholic acid, 5 mM metformin + 0.01, 0.1, 1 and 10 μM 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;
녹색 막대 그래프(3): 5 mM 메트포르민만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트);Green bar graph (3): the degree of growth inhibition (percent) of cancer cells when only 5 mM metformin was treated;
파란색 막대 그래프(1): 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트); 및Blue bar graph (1): the degree of inhibition of cancer cell growth (percent) when only 0.01, 0.1, 1 and 10 μM ursodeoxycholic acid were treated alone; and
붉은색 막대 그래프(2): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산을 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트).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 μM ursodeoxycholic acid were co-treated.
도 6a 및 도 6b는 5 mM 메트포르민, 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산, 5 mM 메트포르민 + 0.01, 0.1, 1 및 10μM 우르소데옥시콜산을 전립선암 세포인 LNcaP 세포주(도 6a) 및 DU145 세포주(도 6b)에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figures 6a and 6b show that 5 mM metformin, 0.01, 0.1, 1 and 10 μM ursodeoxycholic acid, 5 mM metformin + 0.01, 0.1, 1 and 10 μM 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;
녹색 막대 그래프(3): 5 mM 메트포르민만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트);Green bar graph (3): the degree of growth inhibition (percent) of cancer cells when only 5 mM metformin was treated;
파란색 막대 그래프(1): 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산만을 단독 처리했을 때의 암세포의 성장억제 정도(퍼센트); 및Blue bar graph (1): the degree of inhibition of cancer cell growth (percent) when only 0.01, 0.1, 1 and 10 μM ursodeoxycholic acid were treated alone; and
붉은색 막대 그래프(2): 5 mM 메트포르민과 0.01, 0.1, 1 및 10 μM 우르소데옥시콜산을 병용 처리했을 때의 암세포의 성장억제 정도(퍼센트).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 μM ursodeoxycholic acid were co-treated.
도 7a는 5 mM 메트포르민, 1 및 2 μM 에파비렌즈(efavirenz), 5 mM 메트포르민 + 1 및 2 μM 에파비렌즈를 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figure 7a shows the extent of growth inhibition (% growth inhibition) when 5 mM metformin, 1 and 2 μM efavirenz, and 5 mM metformin + 1 and 2 μM efavirenz were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. ) is a diagram showing;
파란색 막대 그래프(1): 5 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 1 및 2 μM 에파비렌즈(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM efavirenz (other blue bar graphs) were treated alone; and
붉은색 막대 그래프(2): 5 mM 메트포르민과 1 및 2 μM 에파비렌즈를 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of inhibition of cancer cell growth (percent) when 5 mM metformin and 1 and 2 μM efavirenz were co-treated.
도 7b는 5 mM 메트포르민, 1 및 2 μM 에파비렌즈, 5 mM 메트포르민 + 1 및 2 μM 에파비렌즈를 사람 정상 상피세포(primary epithelial cell) WISH에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figure 7b shows the degree of growth inhibition (% growth inhibition) when 5 mM metformin, 1 and 2 μM efavirenz, 5 mM metformin + 1 and 2 μM efavirenz were treated with WISH for 24 hours. ) is a diagram showing;
파란색 막대 그래프(1): 5 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 1 및 2 μM 에파비렌즈(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM efavirenz (other blue bar graphs) were treated alone; and
붉은색 막대 그래프(2): 5 mM 메트포르민과 1 및 2 μM 에파비렌즈를 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of inhibition of cancer cell growth (percentage) when 5 mM metformin and 1 and 2 μM efavirenz were co-treated.
도 8은 1 mM 메트포르민, 0.1 및 1 μM 에트라비린(etravirine), 1 mM 메트포르민 + 0.1 및 1 μM 에트라비린을 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;FIG. 8 shows the degree of growth inhibition (% growth inhibition) when 1 mM metformin, 0.1 and 1 μM etravirine, 1 mM metformin + 0.1 and 1 μM etravirine were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. ) is a diagram showing;
파란색 막대 그래프(1): 1 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 0.1 및 1 μM 에트라비린(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM etravirine (other blue bar graphs) alone; and
붉은색 막대 그래프(2): 1 mM 메트포르민과 0.1 및 1 μM 에트라비린을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 0.1 and 1 μM etravirine were co-treated.
도 9는 1 mM 메트포르민, 0.1 및 1 μM 네비라핀(nevirapine), 1 mM 메트포르민 + 0.1 및 1 μM 네비라핀을 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;9 shows the degree of growth inhibition (% growth inhibition) when 1 mM metformin, 0.1 and 1 μM nevirapine, 1 mM metformin + 0.1 and 1 μM nevirapine were treated for 24 hours in the ASPC-1 cell line, which is pancreatic cancer cells. The diagram is shown;
파란색 막대 그래프(1): 1 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 0.1 및 1 μM 네비라핀(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM nevirapine (other blue bar graphs) alone; and
붉은색 막대 그래프(2): 1 mM 메트포르민과 0.1 및 1 μM 네비라핀을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of inhibition of cancer cell growth (percent) when 1 mM metformin and 0.1 and 1 μM nevirapine were co-treated.
도 10은 1 mM 메트포르민, 0.1 및 1 μM 라미부딘(lamivudine), 1 mM 메트포르민 + 0.1 및 1 μM 라미부딘을 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;10 is a diagram showing the degree of growth inhibition (% growth inhibition) when 1 mM metformin, 0.1 and 1 μM lamivudine, 1 mM metformin + 0.1 and 1 μM lamivudine were treated for 24 hours in the ASPC-1 cell line, which is pancreatic cancer cells. am;
파란색 막대 그래프(1): 1 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 0.1 및 1 μM 라미부딘(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM lamivudine (other blue bar graphs) alone; and
붉은색 막대 그래프(2): 1 mM 메트포르민과 0.1 및 1 μM 라미부딘을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 0.1 and 1 μM lamivudine were co-treated.
도 11은 1 mM 메트포르민, 0.1 및 1 μM 로피나비르(lopinavir), 1 mM 메트포르민 + 0.1 및 1 μM 로피나비르를 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;11 shows 1 mM metformin, 0.1 and 1 μM lopinavir, 1 mM metformin + 0.1 and 1 μM lopinavir in the ASPC-1 cell line, which is a pancreatic cancer cell, for 24 hours. The degree of growth inhibition (% growth inhibition) ) is a diagram showing;
파란색 막대 그래프(1): 1 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 0.1 및 1 μM 로피나비르(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM lopinavir (other blue bar graphs) alone; and
붉은색 막대 그래프(2): 1 mM 메트포르민과 0.1 및 1 μM 로피나비르를 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 0.1 and 1 μM lopinavir were co-treated.
도 12는 1 mM 메트포르민, 10, 20 및 40 μM 아타자나비르(atazanavir), 1 mM 메트포르민 + 10, 20 및 40 μM 아타자나비르를 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;12 shows the degree of growth inhibition when 1 mM metformin, 10, 20 and 40 μM atazanavir, and 1 mM metformin + 10, 20 and 40 μM atazanavir were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. (% growth inhibition) is a diagram showing;
파란색 막대 그래프(1): 1 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 10, 20 및 40 μM 아타자나비르(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM atazanavir (other blue bar graphs) alone; and
붉은색 막대 그래프(2): 1 mM 메트포르민과 10, 20 및 40 μM 아타자나비르를 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 10, 20, and 40 μM atazanavir were co-treated.
도 13은 1 mM 메트포르민, 10, 20 및 40 μM 다루나비르(darunavir), 1 mM 메트포르민 + 10, 20 및 40 μM 다루나비르를 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;13 shows the degree of growth inhibition when 1 mM metformin, 10, 20 and 40 μM darunavir, and 1 mM metformin + 10, 20 and 40 μM darunavir were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. (% growth inhibition) is a diagram showing;
파란색 막대 그래프(1): 1 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 10, 20 및 40 μM 다루나비르(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM darunavir (other blue bar graphs) alone; and
붉은색 막대 그래프(2): 1 mM 메트포르민과 10, 20 및 40 μM 다루나비르를 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 10, 20, and 40 μM darunavir were co-treated.
도 14는 1 mM 메트포르민, 10, 20 및 40 μM 리토나비르(ritonavir), 1 mM 메트포르민 + 10, 20 및 40 μM 리토나비르를 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;FIG. 14 shows the degree of growth inhibition when 1 mM metformin, 10, 20 and 40 μM ritonavir, and 1 mM metformin + 10, 20 and 40 μM ritonavir were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. (% growth inhibition) is a diagram showing;
파란색 막대 그래프(1): 1 mM 메트포르민(Control 오른쪽 파란색 막대 그래프) 또는 10, 20 및 40 μM 리토나비르(기타 파란색 막대 그래프)만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue 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 μM ritonavir (other blue bar graphs) alone; and
붉은색 막대 그래프(2): 1 mM 메트포르민과 10, 20 및 40 μM 리토나비르를 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 1 mM metformin and 10, 20, and 40 μM ritonavir were co-treated.
도 15는 2.5 mM 메트포르민, 2 μM 에파비렌즈 및 20 μM 우르소데옥시콜산(UDCA), 2.5 mM 메트포르민 + 2 μM 에파비렌즈 + 20 μM 우르소데옥시콜산을 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;15 shows 2.5 mM metformin, 2 μM efavirenz, 20 μM ursodeoxycholic acid (UDCA), 2.5 mM metformin + 2 μM efavirenz + 20 μM ursodeoxycholic acid in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. It is a diagram showing the degree of growth inhibition (% growth inhibition) when treated;
파란색 막대 그래프(1): 2.5 mM 메트포르민, 2 μM 에파비렌즈 또는 20 μM 우르소데옥시콜산만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue bar graph (1): the degree of cancer cell growth inhibition (percent) when only 2.5 mM metformin, 2 μM efavirenz, or 20 μM ursodeoxycholic acid was treated; and
붉은색 막대 그래프(2): 2.5 mM 메트포르민, 2 μM 에파비렌즈 및 20 μM 우르소데옥시콜산을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 2 μM efavirenz and 20 μM ursodeoxycholic acid were co-treated.
도 16은 2.5 mM 메트포르민, 2 μM 에파비렌즈 및 10 μM 피오글리타존(pioglitazone), 2.5 mM 메트포르민 + 2 μM 에파비렌즈 + 10 μM 피오글리타존을 췌장암세포인 ASPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;16 shows the degree of growth inhibition when 2.5 mM metformin, 2 μM efavirenz and 10 μM pioglitazone, 2.5 mM metformin + 2 μM efavirenz + 10 μM pioglitazone were treated in the ASPC-1 cell line, a pancreatic cancer cell, for 24 hours. (% growth inhibition) is a diagram showing;
파란색 막대 그래프(1): 2.5 mM 메트포르민, 2 μM 에파비렌즈 또는 10 μM 피오글리타존만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue bar graph (1): the degree of cancer cell growth inhibition (percent) when only 2.5 mM metformin, 2 μM efavirenz, or 10 μM pioglitazone was treated; and
붉은색 막대 그래프(2): 2.5 mM 메트포르민, 2 μM 에파비렌즈 및 10 μM 피오글리타존을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 2 μM efavirenz, and 10 μM pioglitazone were co-treated.
도 17은 2.5 mM 메트포르민, 2 μM 에파비렌즈 및 10 μM 피오글리타존, 2.5 mM 메트포르민 + 2 μM 에파비렌즈 + 10 μM 피오글리타존을 대장암세포인 HCT116 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;17 shows the degree of growth inhibition (% growth inhibition) when 2.5 mM metformin, 2 μM efavirenz and 10 μM pioglitazone, 2.5 mM metformin + 2 μM efavirenz + 10 μM pioglitazone were treated in HCT116 cell line, a colon cancer cell line for 24 hours. is a diagram showing;
파란색 막대 그래프(1): 2.5 mM 메트포르민, 2 μM 에파비렌즈 또는 10 μM 피오글리타존만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Blue bar graph (1): the degree of cancer cell growth inhibition (percent) when only 2.5 mM metformin, 2 μM efavirenz, or 10 μM pioglitazone was treated; and
붉은색 막대 그래프(2): 2.5 mM 메트포르민, 2 μM 에파비렌즈 및 10 μM 피오글리타존을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (2): the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 2 μM efavirenz, and 10 μM pioglitazone were co-treated.
도 18은 0.5 μM 에파비렌즈, 0.5 μM 플루옥세틴 및 200 μM 우르소데옥시콜산(UDCA), 0.5 μM 에파비렌즈 + 0.5 μM 플루옥세틴 + 200 μM 우르소데옥시콜산을 대장암세포인 HCT116 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figure 18 shows that 0.5 μM efavirenz, 0.5 μM fluoxetine and 200 μM ursodeoxycholic acid (UDCA), 0.5 μM efavirenz + 0.5 μM fluoxetine + 200 μM 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);
파란색 막대 그래프(1): 0.5 μM 에파비렌즈만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트);Blue bar graph (1): the degree of inhibition of cancer cell growth (percent) when only 0.5 μM efavirenz was treated;
초록색 막대 그래프(2): 0.5 μM 플루옥세틴만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트);Green bar graph (2): the degree of inhibition of cancer cell growth (percent) when 0.5 μM fluoxetine alone was treated;
노란색 막대 그래프(3): 200 μM우르소데옥시콜산만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Yellow bar graph (3): the degree of inhibition of cancer cell growth (percent) when only 200 μM ursodeoxycholic acid was treated; and
붉은색 막대 그래프(4): 0.5 μM 에파비렌즈, 0.5 μM 플루옥세틴 및 200 μM 우르소데옥시콜산을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (4): the degree of growth inhibition (percent) of cancer cells when 0.5 μM efavirenz, 0.5 μM fluoxetine and 200 μM ursodeoxycholic acid were co-treated.
도 19는 0.5 μM 에파비렌즈, 0.5 μM 플루옥세틴 및 200 μM 우르소데옥시콜산(UDCA), 0.5 μM 에파비렌즈 + 0.5 μM 플루옥세틴 + 200 μM 우르소데옥시콜산을 췌장암 세포인 AsPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;19 shows 0.5 μM efavirenz, 0.5 μM fluoxetine and 200 μM ursodeoxycholic acid (UDCA), 0.5 μM efavirenz + 0.5 μM fluoxetine + 200 μM ursodeoxycholic acid in the AsPC-1 cell line as pancreatic cancer cells for 24 hours. It is a diagram showing the degree of growth inhibition (% growth inhibition) when treated;
파란색 막대 그래프(1): 0.5 μM 에파비렌즈만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트);Blue bar graph (1): the degree of inhibition of cancer cell growth (percent) when only 0.5 μM efavirenz was treated;
초록색 막대 그래프(2): 0.5 μM 플루옥세틴만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트);Green bar graph (2): the degree of inhibition of cancer cell growth (percent) when 0.5 μM fluoxetine alone was treated;
노란색 막대 그래프(3): 200 μM 우르소데옥시콜산만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Yellow bar graph (3): the degree of inhibition of cancer cell growth (percent) when 200 μM ursodeoxycholic acid alone was treated; and
붉은색 막대 그래프(4): 0.5 μM 에파비렌즈, 0.5 μM 플루옥세틴 및 200 μM 우르소데옥시콜산을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (4): the degree of growth inhibition (percent) of cancer cells when 0.5 μM efavirenz, 0.5 μM fluoxetine and 200 μM ursodeoxycholic acid were co-treated.
도 20은 2.5 mM 메트포르민, 10 μM 피오글리타존 및 20 μM 우르소데옥시콜산(UDCA), 2.5 mM 메트포르민 + 10 μM 피오글리타존 + 20 μM 우르소데옥시콜산을 대장암세포인 HCT116 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figure 20 shows the degree of growth inhibition when 2.5 mM metformin, 10 μM pioglitazone and 20 μM ursodeoxycholic acid (UDCA), 2.5 mM metformin + 10 μM pioglitazone + 20 μM ursodeoxycholic acid were treated in HCT116 cell line, a colorectal cancer cell, for 24 hours. (% growth inhibition) is a diagram showing;
파란색 막대 그래프(1): 2.5 mM 메트포르민만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트);Blue bar graph (1): the degree of inhibition of cancer cell growth (percent) when only 2.5 mM metformin was treated;
초록색 막대 그래프(2): 10 μM 피오글리타존만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트);Green bar graph (2): the degree of inhibition of cancer cell growth (percent) when 10 μM pioglitazone alone was treated;
노란색 막대 그래프(3): 20 μM 우르소데옥시콜산만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Yellow bar graph (3): the degree of inhibition of cancer cell growth (percent) when only 20 μM ursodeoxycholic acid was treated; and
붉은색 막대 그래프(4): 2.5 mM 메트포르민, 10 μM 피오글리타존 및 20 μM 우르소데옥시콜산을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (4): the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 10 μM pioglitazone and 20 μM ursodeoxycholic acid were co-treated.
도 21은 2.5 mM 메트포르민, 10 μM 피오글리타존 및 20 μM 우르소데옥시콜산(UDCA), 2.5 mM 메트포르민 + 10 μM 피오글리타존 + 20 μM 우르소데옥시콜산을 췌장암 세포인 AsPC-1 세포주에 24시간 처리하였을 때 성장억제 정도(% growth inhibition)를 나타낸 도이다;Figure 21 shows growth when 2.5 mM metformin, 10 μM pioglitazone and 20 μM ursodeoxycholic acid (UDCA), 2.5 mM metformin + 10 μM pioglitazone + 20 μM 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);
파란색 막대 그래프(1): 2.5 mM 메트포르민만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트);Blue bar graph (1): the degree of inhibition of cancer cell growth (percent) when only 2.5 mM metformin was treated;
초록색 막대 그래프(2): 10 μM 피오글리타존만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트);Green bar graph (2): the degree of inhibition of cancer cell growth (percent) when 10 μM pioglitazone alone was treated;
노란색 막대 그래프(3): 20 μM 우르소데옥시콜산만을 단독으로 처리했을 때의 암세포 성장억제 정도(퍼센트); 및Yellow bar graph (3): the degree of inhibition of cancer cell growth (percent) when only 20 μM ursodeoxycholic acid was treated; and
붉은색 막대 그래프(4): 2.5 mM 메트포르민, 10 μM 피오글리타존 및 20 μM 우르소데옥시콜산을 병용처리했을 때의 암세포의 성장억제 정도(퍼센트).Red bar graph (4): the degree of growth inhibition (percent) of cancer cells when 2.5 mM metformin, 10 μM pioglitazone and 20 μM ursodeoxycholic acid were co-treated.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에서, "예방"은 조성물의 투여로 발병을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다. 또한, 본 발명에 있어서, "개선" 또는 "치료"란 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.In the present invention, "prevention" means any action that suppresses the onset or delays the onset by administration of the composition. In addition, in the present invention, "improvement" or "treatment" means any action in which the symptoms of the disease are improved or beneficially changed by administration of the composition.
본 발명에서, "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 일반적인 모든 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 조성물은 활성물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.In the present invention, "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. In addition, the composition may be administered by any device capable of transporting the active agent to a target cell.
본 발명은 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 유효성분으로 함유하는, 암의 예방 또는 치료용 약학적 조성물을 제공한다.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.
본 발명에 있어서, 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 암의 예방 또는 치료용 약학적 조성물은 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제 1 성분; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제 2 성분을 유효성분으로 함유할 수 있다.In the present invention, as a combination, mixture or combination preparation for use in the prevention or treatment of cancer, 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.
본 발명에 있어서, 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 암의 예방 또는 치료용 약학적 조성물은 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제 1 성분; 및 항바이러스제를 포함하는 제 2 성분을 유효성분으로 함유할 수 있다.In the present invention, as a combination, mixture or combination preparation for use in the prevention or treatment of cancer, 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.
본 발명에 있어서, 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 암의 예방 또는 치료용 약학적 조성물은 항바이러스제를 포함하는 제 1 성분; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제 2 성분을 유효성분으로 함유할 수 있다.In the present invention, as a complex, mixed, or combination preparation for use in the prevention or treatment of cancer, 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.
또한, 상기 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 암의 예방 또는 치료용 약학적 조성물은 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물을 포함하는 제 3 성분을 유효성분으로 더 함유할 수 있다. In addition, as a complex, mixed, or combination preparation for use in the prevention or treatment of cancer, 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.
본 발명에 따른 바이구아나이드 계열 화합물은 메트포르민(metfomrin), 펜포르민(phenformin), 부포르민(buformin) 및 바이구아나이드(biguanide)로 구성된 그룹에서 선택되는 것일 수 있다.The biguanide-based compound according to the present invention may be selected from the group consisting of metformin, phenformin, buformin and biguanide.
본 발명에서 메트포르민(metformin)은 다음 화학식 10의 화합물이다:In the present invention, metformin is a compound of formula (10):
[화학식 10][Formula 10]
Figure PCTKR2021001785-appb-img-000010
.
Figure PCTKR2021001785-appb-img-000010
.
본 발명에서 펜포르민(phenformin)은 다음 화학식 11의 화합물이다:In the present invention, phenformin is a compound of formula (11):
[화학식 11][Formula 11]
Figure PCTKR2021001785-appb-img-000011
.
Figure PCTKR2021001785-appb-img-000011
.
본 발명에서 부포르민(buformin)은 다음 화학식 12의 화합물이다:In the present invention, buformin is a compound of formula (12):
[화학식 12][Formula 12]
Figure PCTKR2021001785-appb-img-000012
.
Figure PCTKR2021001785-appb-img-000012
.
본 발명에서 바이구아나이드(biguanide)는 다음 화학식 13의 화합물이다:In the present invention, biguanide is a compound of the following formula (13):
[화학식 13][Formula 13]
Figure PCTKR2021001785-appb-img-000013
.
Figure PCTKR2021001785-appb-img-000013
.
또한, 본 발명에 따른 담즙산 또는 담즙산 유도체는 콜산(cholic acid) 계열 화합물 또는 이의 유도체일 수 있고, 상기 콜산 계열 화합물 또는 이의 유도체는 콜산(cholic acid), 케노데옥시콜산(chenodeoxycholic acid), 데옥시콜산(deoxycholic acid), 우르소데옥시콜산(ursodeoxycholic acid), 리토콜산(lithocholic acid), 글리코콜산(glycocholic acid), 타우로콜산(taurocholic acid), 글리코케노데옥시콜산(glycochenodeoxycholic acid), 타우로케노데옥시콜산(taurochenodeoxycholic acid), 글리코데옥시콜산(glycodeoxycholic acid), 타우로데옥시콜산(taurodeoxycholic acid), 글리코우르소데옥시콜산(glycoursodeoxycholic acid), 타우로우르소데옥시콜산(tauroursodeoxycholic acid), 글리코리토콜산(glycolithocholic acid) 및 타우로리토콜산(taurolithocholic acid)으로 구성된 그룹에서 선택될 수 있다.In addition, 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.
또한, 본 발명에 따른 콜산 계열 화합물 또는 이의 유도체는 하기 화학식 1의 화합물일 수 있다:In addition, the cholic acid-based compound or a derivative thereof according to the present invention may be a compound of Formula 1 below:
[화학식 1][Formula 1]
Figure PCTKR2021001785-appb-img-000014
Figure PCTKR2021001785-appb-img-000014
[상기 식에서,[In the above formula,
R 1 및 R 2는 각각 독립적으로 H 또는 OH이고, R 3은 OH, NHCH 2COOH, 또는 NH(CH 2) 2SO 2OH이다.]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.]
본 발명의 일 양태에서, R 1은 H이고, R 2 및 R 3는 OH일 수 있고, R 1 및 R 3는 OH이고, R 2는 H일 수 있으며, R 1, R 2 및 R 3는 OH일 수 있고, R 1 및 R 2는 H이고, R 3는 OH일 수 있다. In one aspect of the present invention, 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, and R 1 , R 2 and R 3 may be OH, R 1 and R 2 may be H, and R 3 may be OH.
또한, R 1은 H, R 2는 OH, R 3는 NHCH 2COOH 또는 NH(CH 2) 2SO 2OH일 수 있고, R 1은 OH, R 2는 H, R 3는 NHCH 2COOH 또는 NH(CH 2) 2SO 2OH일 수 있으며, R 1 및 R 2는 OH이고, R 3는 NHCH 2COOH 또는 NH(CH 2) 2SO 2OH일 수 있고, R 1 및 R 2는 H이고, R 3는 NHCH 2COOH 또는 NH(CH 2) 2SO 2OH일 수 있다.In addition, 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.
본 발명에서 콜산(cholic acid)은 다음 화학식 14의 화합물이다:In the present invention, cholic acid is a compound of the following formula (14):
[화학식 14][Formula 14]
Figure PCTKR2021001785-appb-img-000015
.
Figure PCTKR2021001785-appb-img-000015
.
본 발명에서 케노데옥시콜산(chenodeoxycholic acid)은 다음 화학식 15의 화합물이다:In the present invention, chenodeoxycholic acid is a compound of formula 15:
[화학식 15][Formula 15]
Figure PCTKR2021001785-appb-img-000016
.
Figure PCTKR2021001785-appb-img-000016
.
본 발명에서 데옥시콜산(deoxycholic acid)은 다음 화학식 16의 화합물이다:In the present invention, deoxycholic acid is a compound of formula 16:
[화학식 16][Formula 16]
Figure PCTKR2021001785-appb-img-000017
.
Figure PCTKR2021001785-appb-img-000017
.
본 발명에서 우르소데옥시콜산(ursodeoxycholic acid)은 화학식 17의 화합물이다:In the present invention, ursodeoxycholic acid is a compound of formula 17:
[화학식 17][Formula 17]
Figure PCTKR2021001785-appb-img-000018
.
Figure PCTKR2021001785-appb-img-000018
.
본 발명에서 리토콜산(lithocholic acid)은 화학식 18의 화합물이다:In the present invention, lithocholic acid is a compound of formula (18):
[화학식 18][Formula 18]
Figure PCTKR2021001785-appb-img-000019
.
Figure PCTKR2021001785-appb-img-000019
.
본 발명에서 글리코콜산(glycocholic acid)은 화학식 19의 화합물이다:In the present invention, glycocholic acid is a compound of formula 19:
[화학식 19][Formula 19]
Figure PCTKR2021001785-appb-img-000020
.
Figure PCTKR2021001785-appb-img-000020
.
본 발명에서 타우로콜산(taurocholic acid)은 화학식 20의 화합물이다:In the present invention, taurocholic acid is a compound of formula 20:
[화학식 20][Formula 20]
Figure PCTKR2021001785-appb-img-000021
.
Figure PCTKR2021001785-appb-img-000021
.
본 발명에서 글리코케노데옥시콜산(glycochenodeoxycholic acid)은 화학식 21의 화합물이다:In the present invention, glycochenodeoxycholic acid is a compound of formula 21:
[화학식 21][Formula 21]
Figure PCTKR2021001785-appb-img-000022
.
Figure PCTKR2021001785-appb-img-000022
.
본 발명에서 타우로케노데옥시콜산(taurochenodeoxycholic acid)은 화학식 22의 화합물이다:In the present invention, taurochenodeoxycholic acid is a compound of formula 22:
[화학식 22][Formula 22]
Figure PCTKR2021001785-appb-img-000023
.
Figure PCTKR2021001785-appb-img-000023
.
본 발명에서 글리코데옥시콜산(glycodeoxycholic acid)은 화학식 23의 화합물이다:In the present invention, glycodeoxycholic acid is a compound of formula 23:
[화학식 23][Formula 23]
Figure PCTKR2021001785-appb-img-000024
.
Figure PCTKR2021001785-appb-img-000024
.
본 발명에서 타우로데옥시콜산(taurodeoxycholic acid)은 화학식 24의 화합물이다:In the present invention, taurodeoxycholic acid is a compound of formula 24:
[화학식 24][Formula 24]
Figure PCTKR2021001785-appb-img-000025
.
Figure PCTKR2021001785-appb-img-000025
.
본 발명에서 글리코우르소데옥시콜산(glycoursodeoxycholic acid)은 화학식 25의 화합물이다:In the present invention, glycoursodeoxycholic acid is a compound of formula 25:
[화학식 25][Formula 25]
Figure PCTKR2021001785-appb-img-000026
.
Figure PCTKR2021001785-appb-img-000026
.
본 발명에서 타우로우르소데옥시콜산(tauroursodeoxycholic acid)은 화학식 26의 화합물이다:In the present invention, tauroursodeoxycholic acid is a compound of formula 26:
[화학식 26][Formula 26]
Figure PCTKR2021001785-appb-img-000027
.
Figure PCTKR2021001785-appb-img-000027
.
본 발명에서 글리코리토콜산(glycolithocholic acid)은 화학식 27의 화합물이다:In the present invention, glycolithocholic acid is a compound of formula 27:
[화학식 27][Formula 27]
Figure PCTKR2021001785-appb-img-000028
.
Figure PCTKR2021001785-appb-img-000028
.
본 발명에서 타우로리토콜산(taurolithocholic acid)은 화학식 28의 화합물이다:In the present invention, taurolithocholic acid is a compound of formula 28:
[화학식 28][Formula 28]
Figure PCTKR2021001785-appb-img-000029
.
Figure PCTKR2021001785-appb-img-000029
.
또한, 본 발명에 따른 담즙산 또는 담즙산 유도체는 다음 화학식 2 내지 9의 화합물일 수 있으나, 이에 제한되지 않는다:In addition, the 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:
[화학식 2][Formula 2]
Figure PCTKR2021001785-appb-img-000030
,
Figure PCTKR2021001785-appb-img-000030
,
상기 식에서, In the above formula,
R은 COCH 3, COC 6H 5, CH 2C 6H 5 또는 CH 2OCH 3이다;R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ;
[화학식 3][Formula 3]
Figure PCTKR2021001785-appb-img-000031
,
Figure PCTKR2021001785-appb-img-000031
,
상기 식에서, In the above formula,
R은 COCH 3, COC 6H 5, CH 2C 6H 5 또는 CH 2OCH 3이다;R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ;
[화학식 4][Formula 4]
Figure PCTKR2021001785-appb-img-000032
,
Figure PCTKR2021001785-appb-img-000032
,
상기 식에서, In the above formula,
R은 H 또는 CN이다;R is H or CN;
[화학식 5][Formula 5]
Figure PCTKR2021001785-appb-img-000033
,
Figure PCTKR2021001785-appb-img-000033
,
상기 식에서,In the above formula,
R 1 및 R 2는 각각 독립적으로 H, CH 3CO 또는 CH 3SO 3이다;R 1 and R 2 are each independently H, CH 3 CO or CH 3 SO 3 ;
[화학식 6][Formula 6]
Figure PCTKR2021001785-appb-img-000034
,
Figure PCTKR2021001785-appb-img-000034
,
상기 식에서,In the above formula,
R은 H, CH 3, CH 3CH 2 또는 CH 3CH 2CH 2CH 2이다;R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ;
[화학식 7][Formula 7]
Figure PCTKR2021001785-appb-img-000035
,
Figure PCTKR2021001785-appb-img-000035
,
상기 식에서,In the above formula,
R은 H, CH 3CO 또는 CH 3SO 3이다;R is H, CH 3 CO or CH 3 SO 3 ;
[화학식 8][Formula 8]
Figure PCTKR2021001785-appb-img-000036
,
Figure PCTKR2021001785-appb-img-000036
,
상기 식에서,In the above formula,
R은 H, CH 3, CH 3CH 2 또는 CH 3CH 2CH 2CH 2이다;R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ;
[화학식 9][Formula 9]
Figure PCTKR2021001785-appb-img-000037
,
Figure PCTKR2021001785-appb-img-000037
,
상기 식에서,In the above formula,
R은 NH(CH 2) 2COOC 10H 14, NHCH(CH 2C 6H 5)COOC 4H 9 또는 NH(CH 2) 2COOC 4H 9이다.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 .
또한, 본 발명에 따른 항바이러스제는 비뉴클레오시드 역전사 효소 억제제(NNRTIs; Non-nucleoside reverse-transcriptase inhibitors) 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있고, 상기 NNRTI 계열 화합물 또는 이의 유도체는 에파비렌즈(efavirenz), 에트라비린(etravirine), 네비라핀(nevirapine), 도라비린(doravirine), 릴피비린(rilpivirine) 및 델라비르딘(delavirdine)으로 구성된 그룹에서 선택될 수 있다.In addition, 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.
또한, 본 발명에 따른 항바이러스제는 뉴클레오시드 역전사 효소 저해제(NRTIs; Nucleoside reverse-transcriptase inhibitors) 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있고, 상기 NRTI 계열 화합물 또는 이의 유도체는 지도부딘(zidovudine), 디다노신(didanosine), 잘시타빈(zalcitabine), 스타부딘(stavudine), 라미부딘(lamivudine), 아바카비어(abacavir), 테노포비르 디소프록시 푸마레이트(tenofovir disoproxil fumarate), 엠트리시타빈(emtricitabine) 및 테노포비르 알라페나미드 푸마레이트(tenofovir alafenamide fumarate)로 구성된 그룹에서 선택될 수 있다.In addition, 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. (zidovudine), didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil fumarate, emtricitabine (emtricitabine) and tenofovir alafenamide fumarate.
또한, 본 발명에 따른 항바이러스제는 단백분해효소 억제제(PIs; Protease inhibitors) 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있고, 상기 PI 계열 화합물 또는 이의 유도체는 단일제일 사퀴나비르(saquinavir), 리토나비르(ritonavir), 인디나비르(indinavir), 넬피나비르(nelfinavir), 암프레나비르(amprenavir), 로비나비르(lopinavir), 아타자나비르(atazanavir), 포삼프레나비르(fosamprenavir), 티프라나비르(tipranavir), 다루나비르(darunavir) 및 복합제인 아타자나비르+코비시스타트(cobicistat), 다루나비르+코비시스타트, 리토나비르+로피나비르로 구성된 그룹에서 선택될 수 있다.In addition, 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
또한, 본 발명에 따른 항바이러스제는 통합효소억제제(INSTI; Integrase Strand Transfer Inhibitor) 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있고, 상기 INSTI 계열 화합물 또는 이의 유도체는 돌루테그라비르(dolutegravir) 및 랄테그라비르(raltegravir)일 수 있다.In addition, 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.
또한, 본 발명에 따른 항바이러스제는 융합 억제제 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있고, 상기 융합 억제제는 엔푸버타이드(enfuvirtide)일 수 있다.In addition, 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.
또한, 본 발명에 따른 항바이러스제는 CCR 5(Chemokine (C-C motif) ligand 5) 억제제 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있고, 상기 CCR 5 억제 화합물 또는 이의 유도체는 단일제인 마라비록(maraviroc) 및 복합제인 코비시스타트/엘비테그라비르/엠트리시타빈/테노포비르 알라페나미드(cobicistat/elvitegravir/emtricitabine/Tenofovir alafenamide), 코비시스타트/엘비테그라비르/엠트리시타빈/테노포비르 디소프록실(cobicistat/Elvitegravir/emtricitabine/Tenofovir disoproxil) 및 아바카비르/돌루테그라비르/라미부딘(abacavir/dolutegravir/lamivudine)로 구성된 그룹에서 선택될 수 있다.In addition, 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. Although (maraviroc) and cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide (cobicistat/elvitegravir/emtricitabine/Tenofovir alafenamide), cobicistat/elvitegravir/emtricitabine/ tenofovir disoproxil (cobicistat/Elvitegravir/emtricitabine/Tenofovir disoproxil) and abacavir/dolutegravir/lamivudine (abacavir/dolutegravir/lamivudine).
또한, 본 발명에 따른 항바이러스제는 인플루엔자 A 및 인플루엔자 B 바이러스 감염의 치료에 사용되는 독감 치료제일 수 있고, 상기 독감 치료제는 탈피(uncoating) 저해제 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염인 아만타딘(amantadine), 리만타딘(rimantadine) 및 뉴라미니다아제 저해제(NAIs; Neuraminidase inhibitors) 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염인 오셀타미비르(oseltamivir), 자나미비르(zanamivir), 페라미비르(peramivir), 발록사비르(baloxavir) 및 라니나미비어(laninamivir)로 구성된 그룹에서 선택될 수 있다.In addition, 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. Amantadine, rimantadine, and neuraminidase inhibitors (NAIs) series compounds or derivatives thereof, or pharmaceutically acceptable salts thereof, oseltamivir, zanamivir, It may be selected from the group consisting of peramivir, baloxavir and laninamivir.
또한, 본 발명에 따른 항바이러스제는 단순 헤르페스바이러스(HSV; herpes simplex virus) 및 수두대상포진바이러스(VZV; varicella zoster virus) 감염의 치료에 사용되는 헤르페스 치료제일 수 있고, 상기 헤르페스 치료제는 아시클로비르(aciclovir), 발라시클로비르(valaciclovir), 이독스우리딘(idoxuridine), 비다라빈(vidarabine), 펜시클로비르(penciclovir), 팜시클로비르(famciclovir), 트리플루리딘(trifluridine), 시도포비어(cidofovir) 및 포스카넷(foscarnet)으로 구성된 그룹에서 선택될 수 있다.In addition, 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, and the herpes treatment agent is acyclovir. (aciclovir), valacyclovir, idoxuridine, vidarabine, penciclovir, famciclovir, trifluridine, cidofovir ( cidofovir) and foscarnet.
또한, 본 발명에 따른 항바이러스제는 B형간염 바이러스의 증식을 억제하여 염증 완화, 섬유화 방지 및 간경변증, 감세포암종 발생을 예방하는 B형간염 치료제일 수 있고, 상기 B형간염 치료제는 라미부딘(lamivudine), 클레부딘(clevudine), 텔비부딘(telbivudine), 엔테카비르(entecavir), 아데포비르(adefovir), 테노포비르 디소프록실(tenofovir disoproxil), 테노포비르 알라페나미드(tenofovir alafenamide) 및 베시포비르(besifovir)로 구성된 그룹에서 선택될 수 있다. 내성 발현시 다른 약제로 전환하거나 두 가지 약물의 병합 치료로 전환할 수 있다.In addition, 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.
또한, 본 발명에 따른 항바이러스제는 C형간염 바이러스의 증식을 억제하여 질병의 진행을 지연시키는 C형간염 치료제일 수 있고, 상기 C형간염 치료제는 사이토카인인 페그인터페론 알파 2a(peginterferon-α-2a) 및 페그인터페론 알파 2b(peginterferon-α-2b), 단백분해효소 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염인 리바비린(ribavirin), 바이러스 단백질에 작용하는 항바이러스제(DAA; Direct-acting antivirals) 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염으로 단일제인 보세프레비르(boceprevir), 다사부비르(dasabuvir), 다클라타스비르(daclatasvir), 아수나프레비르(asunaprevir), 소포스부비르(sofosbuvir) 및 복합제인 엘바스비르/그라조프레비르(elbasvir/grazoprevir), 글레카프레비르/피브렌타스비르(glecaprevir/pibrentasvir), 옴비타스비르/파리타프레비르/리토나비르(ombitasvir/paritaprevir/ritonavir)로 구성된 그룹에서 선택될 수 있다.In addition, 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, and the hepatitis C therapeutic agent is a cytokine peginterferon-α- 2a) and peginterferon alpha 2b (peginterferon-α-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 ( ombitasvir/paritaprevir/ritonavir).
또한, 본 발명에 따른 항바이러스제는 면역증강제(인터페론류) 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있고, 상기 면역증강제는 인터페론알파 2a(interferon alfa-2a), 인터페론알파 2b(interferon alfa-2b) 및 페그인터페론알파 2a(peginterferon-α-2a)로 구성된 그룹에서 선택될 수 있다.In addition, 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-α-2a).
또한, 본 발명에 따른 항바이러스제는 면역반응 조절제 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염일 수 있고, 상기 면역조절제는 이미퀴모드(imiquimod)로 구성된 그룹에서 선택될 수 있다.In addition, 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.
또한, 본 발명에 따른 항우울제는 삼환계 항우울제(tricyclic antidepressants, TCAs)일 수 있고, 상기 삼환계 항우울제는 아미트리프틸린(amitriptyline), 노르트립틸린(nortriptyline), 클로미프라민(clomipramine), 이미프라민(imipramine) 및 아목사핀(amoxapine)으로 구성된 그룹에서 선택될 수 있다.In addition, 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.
또한, 본 발명에 따른 항우울제는 선택적 세로토닌 재흡수 억제제(selective serotonin reuptake inhibitors, SSRIs)일 수 있고, 상기 선택적 세로토닌 재흡수 억제제는 플루옥세틴(fluoxetine), 파록세틴(paroxetine), 플루복사민(fluvoxamine), 설트랄린(sertraline), 에스시탈로프람(escitalopram) 및 보티옥세틴(vortioxetine)으로 구성된 그룹에서 선택될 수 있다.In addition, 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.
또한, 본 발명에 따른 항우울제는 모노아민 산화효소 억제제(Monoamine oxidase inhibitor; MAOI)일 수 있고, 상기 모노아민 산화효소 억제제는 모클로베미드(moclobemide)일 수 있다.In addition, the antidepressant according to the present invention may be a monoamine oxidase inhibitor (MAOI), and the monoamine oxidase inhibitor may be moclobemide.
또한, 본 발명에 따른 항우울제는 세로토닌 노르에피네프린 재흡수 억제제(serotonin-norepinephrine reuptake inhibitors; SNRIs)일 수 있고, 상기 세로토닌 노르에피네프린 재흡수 억제제는 둘록세틴(duloxetine), 벤라팍신(venlafaxine), 데스벤라팍신(desbenlafaxine), 밀나시프란(milnacipran) 및 항우울제인 부프로피온(bupropion), 미르타자핀(mirtazapine), 트라조돈(trazodone), 티아넵틴(tianeptine)으로 구성된 그룹에서 선택될 수 있다.In addition, 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.
또한, 본 발명에 따른 치아졸리딘디온(thiazolidinediones, TZD) 계열 화합물 또는 이의 유도체는 피오글리타존(pioglitazone), 로베글리타존(lobeglitazone), 로시글리타존(rosiglitazone), 시글리타존(ciglitazone), 다르글리타존(darglitazone), 엔글리타존(englitazone), 네토글리타존(netoglitazone), 리보글리타존(rivoglitazone), 트로글리타존(troglitazone), 및 밸라글리타존(balaglitazone)으로 구성된 그룹에서 선택될 수 있다.In addition, 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.
본 발명의 일 양태에서, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염의 농도는 0.1 mM 내지 100 mM일 수 있고, 담즙산, 이의 유도체 또는 이의 약학적으로 허용되는 염의 농도는 0.001 μM 내지 10 mM일 수 있으며, 항바이러스제는 0.001 μM 내지 10 mM일 수 있고, 항우울제는 0.001 μM 내지 10 mM일 수 있으며, 치아졸리딘디온 계열 화합물, 이의 유도체 또는 이의 약학적으로 허용되는 염은 0.001 μM 내지 10 mM일 수 있다.In one embodiment of the present invention, 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 μM to 10 mM may be, the antiviral agent may be 0.001 μM to 10 mM, the antidepressant may be 0.001 μM to 10 mM, and the thiazolidinedione-based compound, derivative or pharmaceutically acceptable salt thereof is 0.001 μM to 10 mM can be
본 발명의 일 양태에서, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염; 항바이러스제; 항우울제; 및 치아졸리딘디온 계열 화합물, 이의 유도체 또는 이의 약학적으로 허용되는 염 중 2종 이상의 화합물의 본 발명의 의약 중 함량은 제제 형태 등에 따라 적절히 선택될 수 있다.In one aspect of the present invention, 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.
본 발명의 일 양태에서, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염; 항바이러스제; 항우울제; 및 치아졸리딘디온 계열 화합물, 이의 유도체 또는 이의 약학적으로 허용되는 염 중 2종 이상의 화합물이 하나의 단일 제제로 제형화 되는 경우, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염의 함량은 전체 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.01 내지 약 90 wt% 이며, 바람직하게는 약 0.1 내지 약 90 wt%이고, 더 바람직하게는 약 0.1 내지 약 80 wt%이며, 보다 더 바람직하게는 약 0.1 내지 약 70 wt%이고, 담즙산, 이의 유도체 또는 이의 약학적으로 허용되는 염의 함량은 전체 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.01 내지 약 90 wt%이며, 바람직하게는 약 0.1 내지 약 80 wt%이고, 더 바람직하게는 약 0.1 내지 약 70 wt%이며, 보다 더 바람직하게는 약 0.1 내지 약 60 wt%이며, 항바이러스제의 함량은 전체 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.01 내지 약 90 wt%이며, 바람직하게는 약 0.1 내지 약 80 wt%이고, 더 바람직하게는 약 0.1 내지 약 70 wt%이며, 보다 더 바람직하게는 약 0.1 내지 약 60 wt%이고, 항우울제의 함량은 전체 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.01 내지 약 90 wt%이며, 바람직하게는 약 0.1 내지 약 80 wt%이고, 더 바람직하게는 약 0.1 내지 약 70 wt%이며, 보다 더 바람직하게는 약 0.1 내지 약 60 wt%이며, 치아졸리딘디온 계열 화합물, 이의 유도체 또는 이의 약학적으로 허용되는 염의 함량은 전체 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.01 내지 약 90 wt%이며, 바람직하게는 약 0.1 내지 약 80 wt%이고, 더 바람직하게는 약 0.1 내지 약 70 wt%이며, 보다 더 바람직하게는 약 0.1 내지 약 60 wt%이다.In one aspect of the present invention, a biguanide-based compound or a pharmaceutically acceptable salt thereof; bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; antiviral agents; antidepressants; And when two or more compounds of a thiazolidinedione-based compound, a derivative thereof, or a pharmaceutically acceptable salt thereof are formulated as one single formulation, 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. wt%, preferably from about 0.1 to about 80 wt%, more preferably from about 0.1 to about 70 wt%, even more preferably from about 0.1 to about 60 wt%, and 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 %.
한편, 하나의 단일 제제로 배합되는 경우에 있어서 본 발명의 의약 중 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염의 함량비는, 1 : 0.0000001 ~ 10 중량비로 배합될 수 있고, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 및 항바이러스제의 함량비는, 1 : 0.0000001 ~ 10 중량비로 배합될 수 있으며, 항바이러스제; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염의 함량비는, 1 : 0.0000001 ~ 10 중량비로 배합될 수 있다.On the other hand, 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.
또한, 하나의 단일 제제로 배합되는 경우에 있어서 본 발명의 의약 중 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염; 및 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물의 중량비는, 1 : 0.0000001 ~ 10 : 0.0000001 ~ 10 중량비로 배합될 수 있고, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 항바이러스제; 및 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물의 함량비는, 1 : 0.0000001 ~ 10 : 0.0000001 ~ 10 중량비로 배합될 수 있으며, 항바이러스제; 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염; 및 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물의 함량비는, 1 : 0.0000001 ~ 10 : 0.0000001 ~ 10 중량비로 배합될 수 있다.In addition, 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; 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, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof, 1: 0.0000001 to 10: 0.0000001 to 10 weight ratio may be combined.
또한, 하나의 단일 제제로 배합되는 경우에 있어서 본 발명의 의약 중 담체 등과 같은 첨가제의 함량은 가변적이기는 하나, 전체 제제에 대해 일반적으로 약 1 내지 약 99.00 wt%이고, 구체적으로 약 1 내지 약 90 wt%이며, 바람직하게는 약 10 내지 약 90 wt%이고, 더 바람직하게는 약 10 내지 80 wt%이며, 보다 더 바람직하게는 약 10 내지 약 70 wt%일 수 있다. In addition, in the case of combining as a single formulation, 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%.
본 발명의 일 양태에서, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염; 항바이러스제; 항우울제; 및 치아졸리딘디온 계열 화합물, 이의 유도체 또는 이의 약학적으로 허용되는 염 중 2종 이상의 화합물이 각각 따로 제제화 되어 병용되는 경우, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염의 함량은 그 함유 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.1 내지 약 99.99 wt%이며, 바람직하게는 약 0.1 내지 약 90 wt%이고, 더 바람직하게는 약 0.1 내지 약 80 wt%이며, 보다 더 바람직하게는 약 1 내지 약 80 wt%일 수 있고, 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염의 함량은 그 함유 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.1 내지 약 99.99 wt%이며, 바람직하게는 약 0.1 내지 약 90 wt%이고, 더 바람직하게는 약 0.1 내지 약 80 wt%이며, 보다 더 바람직하게는 약 1 내지 약 80 wt%일 수 있으며, 항바이러스제의 함량은 그 함유 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.1 내지 약 99.99 wt%이며, 바람직하게는 약 0.1 내지 약 90 wt%이고, 더 바람직하게는 약 0.1 내지 약 80 wt%이며, 보다 더 바람직하게는 약 1 내지 약 80 wt%일 수 있고, 항우울제의 함량은 그 함유 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.1 내지 약 99.99 wt%이며, 바람직하게는 약 0.1 내지 약 90 wt%이고, 더 바람직하게는 약 0.1 내지 약 80 wt%이며, 보다 더 바람직하게는 약 1 내지 약 80 wt%일 수 있으며, 치아졸리딘디온 계열 화합물, 이의 유도체 또는 이의 약학적으로 허용되는 염의 함량은 그 함유 제제에 대해 일반적으로 약 0.01 내지 약 99.99 wt%이고, 구체적으로 약 0.1 내지 약 99.99 wt%이며, 바람직하게는 약 0.1 내지 약 90 wt%이고, 더 바람직하게는 약 0.1 내지 약 80 wt%이며, 보다 더 바람직하게는 약 1 내지 약 80 wt%일 수 있다. In one aspect of the present invention, a biguanide-based compound or a pharmaceutically acceptable salt thereof; bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; antiviral agents; antidepressants; And when two or more compounds of a thiazolidinedione-based compound, a derivative thereof, or a pharmaceutically acceptable salt thereof are separately formulated and used together, 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 containing the same. about 99.99 wt%, preferably about 0.1 to about 90 wt%, more preferably about 0.1 to about 80 wt%, even more preferably about 1 to about 80 wt%, 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. , preferably from about 0.1 to about 90 wt%, more preferably from about 0.1 to about 80 wt%, and even more preferably from about 1 to about 80 wt%, a thiazolidinedione-based compound, its 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%.
한편, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염; 항바이러스제; 항우울제; 및 치아졸리딘디온 계열 화합물, 이의 유도체 또는 이의 약학적으로 허용되는 염 중 2종 이상의 화합물이 각각 따로 제제화되어 병용되는 경우, 담체 등과 같은 첨가제의 함량은 가변적이기는 하나, 각 함유 제제에 대해 일반적으로 약 1 내지 99.00 wt%이고, 구체적으로 약 1 내지 약 90 wt%이며, 바람직하게는 약 10 내지 약 90 wt%이고, 더 바람직하게는 약 10 내지 80 wt%이며, 보다 더 바람직하게는 약 10 내지 약 70 wt%일 수 있다.On the other hand, a biguanide-based compound or a pharmaceutically acceptable salt thereof; bile acids, bile acid derivatives or pharmaceutically acceptable salts thereof; antiviral agents; antidepressants; And when two or more compounds of a thiazolidinedione-based compound, a derivative thereof, or a pharmaceutically acceptable salt thereof are formulated separately and used together, 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 %.
본 발명의 일 양태에서, 상기 암은 (A) (1) 정위치 도관 암종(DCIS)(면포 암종, 사상, 유두, 미세유두), 침윤 도관 암종(IDC), 관 암종, 점액(콜로이드성) 암종, 유두 암종, 화생 암종 및 염증성 암종을 비롯한 도관 암종; (2) 정위치 소엽 암종(LCIS) 및 침윤성 소엽 암종을 비롯한 소엽 암종; 및 (3) 유두의 파제트 질환을 비롯한 유방 암; (B) (1) 자궁경부 상피내 종양(등급 I), 자궁경부 상피내 종양(등급 II), 자궁경부 상피내 종양(등급 III)(정위치 편평 세포 암종), 각화성 편평 세포 암종, 비각화성 편평 세포 암종, 사마귀모양암종, 정위치 선암종, 정위치 선암종, 자궁경내막 타입, 자궁내막양 선암종, 투명 세포 선암종, 선상피 암종, 선낭 암종, 소 세포 암종 및 미분화 암종을 비롯한 자궁경부의 암; (2) 자궁내막양 암종, 선암종, 선극세포종(편평 상피화생을 갖는 선암종), 선상피 암종(혼합 선암종 및 편평 세포 암종, 점액 선암종, 장액 선암종, 투명 세포 선암종, 편평 세포 선암종 및 미분화 선암종을 비롯한 자궁체의 암; (3) 장액성 낭선종, 장액 낭선종, 점액 낭선종, 점액 낭선종, 자궁내막양 종양, 자궁내막양 선암종, 투명 세포 종양, 투명 세포 낭선종 및 미분류 종양을 비롯한 난소의 암; (4) 편평 세포 암종 및 선암종을 비롯한 질의 암; 및 (5) 외음부 상피내 종양(등급 I), 외음부 상피내 종양(등급 II), 외음부 상피내 종양(등급 III)(정위치 편평 세포 암종); 편평 세포 암종, 사마귀모양암종, 음문의 파제트 질환, 선암종(NOS), 기저 세포 암종(NOS) 및 바르톨린선 암종을 비롯한 외음부의 암을 포함한 여성 생식계의 암; (C) (1) 편평 세포 암종을 비롯한 음경의 암; (2) 전립선의 선암종, 육종 및 이행 세포 암종을 비롯한 전립선의 암; (3) 정상피종 종양, 비정상피종 종양, 기형종, 배아 암종, 난황낭 종양 및 융모막암종을 비롯한 고환의 암을 포함한 남성 생식계의 암; (D) 육종(혈관육종, 섬유육종, 횡문근육종, 지방육종), 점액종, 횡문근종, 섬유종, 지방종 및 기형종을 비롯한 심장계의 암; (E) 후두의 편평 세포 암종, 원발성 흉막 중피종 및 인두의 편평 세포 암종을 비롯한 호흡계의 암; (F) 편평 세포 암종(표피모양 암종), 편평 세포 암종의 변형, 방추 세포 암종, 소 세포 암종, 기타 세포의 암종, 중간 세포 타입의 암종, 복합 귀리 세포 암종, 선암종, 세엽 선암종, 유두 선암종, 기관지폐포 암종, 점액 형성 고형 암종, 거대 세포 암종, 거대 세포 암종, 투명 세포 암종 및 육종을 비롯한 폐의 암; (G) (1) 원발성 선암종, 카르시노이드 종양 및 림프종을 비롯한 바터(Vater) 팽대부의 암; (2) 선암종, 편평 세포 암종 및 흑색종을 비롯한 항문관의 암; (3) 정위치 암종, 선암종, 유두 선암종, 선암종, 창자형, 점액 선암종, 투명 세포 선암종, 반지 세포 암종, 선상피 암종, 편평 세포 암종, 소 세포(귀리) 암종, 미분화 암종, 암종(NOS), 육종 및 카르시노이드 종양을 비롯한 간외 담관의 암; (4) 정위치 선암종, 선암종, 점액 선암종(콜로이드형; 50% 초과의 점액 암종), 반지 세포 암종(50% 초과의 반지 세포), 편평 세포(표피모양) 암종, 선상피 암종, 소 세포(귀리 세포) 암종, 미분화 암종, 암종(NOS), 육종, 림프종 및 카르시노이드 종양을 비롯한 결장 및 직장의 암; (5) 편평 세포 암종, 선암종, 평활근육종 및 림프종을 비롯한 식도의 암; (6) 선암종, 선암종, 창자형, 선상피 암종, 정위치 암종, 암종(NOS), 투명 세포 선암종, 점액 선암종, 유두 선암종, 반지 세포 암종, 소 세포(귀리 세포) 암종, 편평 세포 암종 및 미분화 암종을 비롯한 담낭의 암; (7) 편평 세포 암종을 비롯한 입술 및 구강의 암; (8) 간암(간세포 암종), 담관암종, 간모세포종, 혈관육종, 간세포 선종 및 혈관종을 비롯한 간의 암; (9) 관 세포 암종, 다형태 거대 세포 암종, 거대 세포 암종, 오스테오클라스토이드(osteoclastoid)형, 선암종, 선상피 암종, 점액(콜로이드) 암종, 낭선종, acinar 세포 암종, 유두 암종, 소 세포(귀리 세포) 암종, 혼합 세포형, 암종(NOS), 미분화 암종, 랑게르한스 도세포에서 발생하는 내분비 세포 종양 및 카르시노이드를 비롯한 외분비선 췌장의 암; (10) 세엽(샘꽈리) 세포 암종, 선낭 암종(원주종), 선암종, 편평 세포 암종, 다형태 선종에서의 암종(악성 혼합 종양), 점막표피모양 암종(잘 분화된 또는 낮은 등급) 및 점막표피모양 암종(불량하게 분화되거나 또는 높은 등급)을 비롯한 타액선의 암; (11) 선암종, 유두 선암종, 관상 선암종, 점액 선암종, 반지 세포 암종, 선상피 암종, 편평 세포 암종, 소 세포 암종, 미분화 암종, 림프종, 육종 및 카르시노이드 종양을 비롯한 위의 암; 및 (12) 선암종, 림프종, 카르시노이드 종양, 카포시 육종, 평활근종, 혈관종, 지방종, 신경섬유종증 및 섬유종을 비롯한 소장의 암을 포함한 위장관의 암; (H) (1) 신장 세포 암종, 벨리니 집합관의 암종, 선암종, 유두 암종, 관상 암종, 과립 세포 암종, 투명 세포 암종(신선암), 신장의 육종 및 신장모세포종을 비롯한 신장의 암; (2) 이행 세포 암종, 유두 이행 세포 암종, 편평 세포 암종 및 선암종을 비롯한 신우 및 요관의 암; (3) 이행 세포 암종, 편평 세포 암종 및 선암종을 비롯한 요도의 암; 및 (4) 정위치 암종, 이행 요로상피 세포 암종, 유두 이행 세포 암종, 편평 세포 암종, 선암종, 미분화를 비롯한 방광의 암을 포함한 비뇨기계의 암; (I) (1) (a) 골형성: 골육종; (b) 연골-형성: 연골육종 및 중간엽 연골육종; (c) 거대 세포 종양, 악성; (d) 유잉 육종; (e) 혈관 종양: 혈관내피종, 혈관주위세포종 및 혈관육종; (f) 결합 조직 종양: 섬유육종, 지방육종, 악성 간엽종 및 미분화 육종; 및 (g) 기타 종양: 척삭종 및 장골의 범랑종을 비롯한 골의 암; (2) 폐포 연질부 육종, 혈관육종, 상피모양 육종, 골외성 연골육종, 섬유육종, 평활근육종, 지방육종, 악성 섬유 조직구종, 악성 혈관주위세포종, 악성 간엽종, 악성 슈반세포종, 횡문근육종, 활액 육종 및 육종(NOS)을 비롯한 연조직의 암; (3) 두개골의 암(골종, 혈관종, 육아종, 황색종, 변형성 골염), 수막의 암(수막종, 수막육종, 신경교종증), 뇌의 암(별아교세포종, 속질모세포종, 신경아교종, 뇌실막세포종, 종자세포종(솔방울샘종), 다형성아교모세포종, 희소돌기아교세포종, 슈반세포종, 망막모세포종, 선천성 종양) 및 척수의 암(신경섬유종증, 수막종, 신경아교종, 육종)을 비롯한 신경계의 암; (4) 골수성 백혈병(급성 및 만성), 급성 림프모구 백혈병, 만성 림프구 백혈병, 골수증식 질환, 다발성 골수종; 골수형성이상 증후군), 호지킨병 및 비-호지킨 림프종(악성 림프종)을 비롯한 혈액암; (5) (a) 유두 암종(소포 부위의 것 포함), 소포 암종, 속질 암종 및 미분화(역형성) 암종을 비롯한 갑상선의 암; 및 (b) 교감신경모세포종, 교감신경원세포종, 악성 신경절신경종, 신경절교감신경모세포종 및 신경절신경종을 비롯한 신경모세포종을 포함하는 내분비계의 암; (6) 편평 세포 암종, 편평 세포 암종의 방추 세포 변형, 기저 세포 암종, 한선 또는 피지선으로부터 발생된 선암종 및 악성 흑색종을 비롯한 피부의 암; (7) (a) 결막의 암종을 비롯한 결막의 암; (b) 기저 세포 암종, 편평 세포 암종, 안검의 흑색종 및 피지 세포 암종을 비롯한 안검의 암; (c) 선암종, 선낭 암종, 다형태 선종에서의 암종, 점액표피모양 암종 및 편평 세포 암종을 비롯한 누선의 암; (d) 방추 세포 흑색종, 혼합 세포 흑색종 및 상피모양 세포 흑색종을 비롯한 포도막의 암; (e) 안와의 육종, 연조직 종양 및 골의 육종을 비롯한 안와의 암; 및 (f) 망막모세포종을 포함한 눈의 암을 포함한 근육, 골 및 연조직의 암으로 구성된 그룹에서 선택될 수 있다.In one aspect of the invention, 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, endometrial type, endometrioid adenocarcinomas, clear cell adenocarcinomas, glandular carcinomas, adenocystic carcinomas, small cell carcinomas and undifferentiated carcinomas; (2) uterus including endometrioid carcinoma, adenocarcinoma, adenoblastoma (adenocarcinoma with squamous metaplasia), glandular carcinoma (mixed adenocarcinoma and squamous cell carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, clear cell adenocarcinoma, squamous cell adenocarcinoma and undifferentiated adenocarcinoma) Cancers of the body: (3) cancers of the ovaries, including serous cystadenomas, serous cystadenomas, mucinous cystadenomas, mucinous cystadenomas, endometrioid tumors, endometrioid adenocarcinomas, clear cell tumors, clear cell cystadenomas and unclassified tumors; (4) squamous tumors; cancers of the vagina, including cell carcinoma and adenocarcinoma; and (5) vulvar intraepithelial tumors (grade I), vulvar intraepithelial tumors (grade II), vulvar intraepithelial tumors (grade III) (squamous cell carcinoma in situ); Cancers of the female reproductive system, including cancers of the vulva, including carcinoma, Paget's disease of the vulva, adenocarcinoma (NOS), basal cell carcinoma (NOS) and Bartholin's adenocarcinoma; (C) (1) cancer of the penis, including squamous cell carcinoma (2) cancers of the prostate, including adenocarcinomas, sarcomas, and transitional cell carcinomas of the prostate; (D) cancers of the heart system including sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; (E) squamous cell carcinoma of the larynx, primary pleura Cancers of the respiratory system, including mesothelioma and squamous cell carcinoma of the pharynx; Cancer of the lung, including complex oat cell carcinoma, adenocarcinoma, acinar adenocarcinoma, papillary adenocarcinoma, bronchoalveolar carcinoma, mucinous solid carcinoma, giant cell carcinoma, giant cell carcinoma, clear cell carcinoma and sarcoma; (G) (1) primary adenocarcinoma; Cancers of the ampulla of Vater, including carcinoid tumors and lymphomas; (2) cancers of the anal canal, including adenocarcinomas, squamous cell carcinomas and melanomas; (3) orthostatic carcinomas, adenocarcinomas, papillary carcinomas; Extrahepatic bile ducts including adenocarcinoma, adenocarcinoma, intestinal type, mucinous adenocarcinoma, clear cell adenocarcinoma, ring cell carcinoma, adenoid carcinoma, squamous cell carcinoma, small cell (oat) carcinoma, undifferentiated carcinoma, carcinoma (NOS), sarcoma and carcinoid tumor of cancer; (4) Orthostatic adenocarcinoma, adenocarcinoma, mucinous adenocarcinoma (colloidal; >50% mucinous carcinoma), ring cell carcinoma (greater than 50% of ring cells), squamous cell (epidermal) carcinoma, adenoid carcinoma, small cell (oat) cell) cancers of the colon and rectum, including carcinomas, undifferentiated carcinomas, carcinomas (NOS), sarcomas, lymphomas and carcinoid tumors; (5) cancers of the esophagus, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma and lymphoma; (6) adenocarcinoma, adenocarcinoma, bowel type, adenocarcinoma, orthotopic carcinoma, carcinoma (NOS), clear cell adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, ring cell carcinoma, small cell (oat cell) carcinoma, squamous cell carcinoma and undifferentiated carcinoma cancer of the gallbladder, including; (7) cancers of the lips and oral cavity, including squamous cell carcinoma; (8) cancers of the liver, including liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma; (9) ductal cell carcinoma, giant cell carcinoma multiforme, giant cell carcinoma, osteoclastoid type, adenocarcinoma, glandular carcinoma, mucinous (colloid) carcinoma, cystadenoma, acinar cell carcinoma, papillary carcinoma, small cell ( oat cells) carcinoma, mixed cell type, carcinoma (NOS), undifferentiated carcinoma, cancer of the exocrine pancreas including endocrine cell tumors arising from Langerhans islet cells and carcinoids; (10) acinar (acinar) cell carcinoma, adenocystic carcinoma (columoma), adenocarcinoma, squamous cell carcinoma, carcinoma in polymorphic adenoma (malignant mixed tumor), mucoepidermoid carcinoma (well-differentiated or low-grade) and mucosal cancers of the salivary glands, including epidermal carcinoma (poorly differentiated or high grade); (11) cancers of the stomach, including adenocarcinoma, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, ring cell carcinoma, adenoid carcinoma, squamous cell carcinoma, small cell carcinoma, undifferentiated carcinoma, lymphoma, sarcoma and carcinoid tumor; and (12) cancers of the gastrointestinal tract, including cancers of the small intestine, including adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibromatosis and fibroma; (H) (1) cancers of the kidney, including (1) renal cell carcinoma, carcinoma of the Bellini collecting duct, adenocarcinoma, papillary carcinoma, tubular carcinoma, granular cell carcinoma, clear cell carcinoma (renal cancer), sarcoma of the kidney and nephroblastoma; (2) cancers of the renal pelvis and ureter, including transitional cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma; (3) cancers of the urethra, including transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma; and (4) cancers of the urinary system, including cancers of the bladder, including orthotopic carcinoma, transitional urothelial cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, undifferentiated; (I) (1) (a) Osteogenesis: osteosarcoma; (b) cartilage-forming: chondrosarcoma and mesenchymal chondrosarcoma; (c) giant cell tumor, malignant; (d) Ewing's sarcoma; (e) vascular tumors: hemangioendothelioma, hemangiopericytoma and hemangiosarcoma; (f) connective tissue tumors: fibrosarcoma, liposarcoma, malignant mesenchymal and undifferentiated sarcoma; and (g) other tumors: cancers of the bone, including chordomas and erosions of the long bones; (2) alveolar soft sarcoma, angiosarcoma, epithelial sarcoma, extraosseous chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant hemangiopericytoma, malignant mesenchymal, malignant Schwanncytoma, rhabdomyosarcoma, cancers of soft tissues including synovial sarcoma and sarcoma (NOS); (3) Cancer of the skull (osteoma, hemangioma, granuloma, xanthomas, osteomyelitis), cancer of the meninges (meningoma, meningiosarcoma, gliomatosis), cancer of the brain (astrocytoma, meduloblastoma, glioma, ependymocytoma, seed) cancers of the nervous system, including cellomas (pineal adenoma), glioblastoma multiforme, oligodendrocytoma, Schwannoma, retinoblastoma, congenital tumors) and cancers of the spinal cord (neurofibromatosis, meningioma, glioma, sarcoma); (4) myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma; myelodysplastic syndrome), hematologic cancers including Hodgkin's disease and non-Hodgkin's lymphoma (malignant lymphoma); (5) (a) cancers of the thyroid gland, including papillary carcinomas (including those of the follicular region), follicular carcinomas, medullary carcinomas, and undifferentiated (anaplastic) carcinomas; and (b) cancers of the endocrine system, including neuroblastomas, including sympathoblastoma, sympathoblastoma, malignant ganglioneuroma, gangliosympathoblastoma and ganglioneuroma; (6) cancers of the skin, including squamous cell carcinoma, spindle cell deformation of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma arising from sweat glands or sebaceous glands, and malignant melanoma; (7) (a) cancer of the conjunctiva, including carcinoma of the conjunctiva; (b) cancers of the eyelids, including basal cell carcinoma, squamous cell carcinoma, melanoma of the eyelid and sebaceous cell carcinoma; (c) cancer of the lacrimal gland, including adenocarcinoma, adenocystic carcinoma, carcinoma in polymorphic adenoma, mucoepidermoid carcinoma and squamous cell carcinoma; (d) cancers of the uvea, including spindle cell melanoma, mixed cell melanoma and epithelial cell melanoma; (e) cancers of the orbit, including sarcomas of the orbit, soft tissue tumors, and sarcomas of the bone; and (f) cancers of muscle, bone and soft tissue, including cancers of the eye, including retinoblastoma.
본 발명의 일 양태에서, 제제는 정제, 캡슐제, 주사제, 트로키제, 산제, 과립제, 액제, 현탁제, 내용액제, 유제, 시럽제, 좌제, 질정제 및 환제로 구성된 그룹에서 선택되는 제형으로 제형화될 수 있으나 이로 한정되지 않으며, 필요에 따라 적절한 제형으로 제형화가 가능하다.In one embodiment of the present invention, 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.
또한, 본 발명은 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 포함하는 제제를 함유하는, 암의 예방 또는 치료용 복합, 혼합 또는 병용제 키트를 제공한다.In addition, 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.
본 발명의 일 양태에서, 암의 예방 또는 치료용 복합, 혼합 또는 병용제 키트는 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제제; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제제를 함유할 수 있다.In one aspect of the present invention, 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.
본 발명의 일 양태에서, 암의 예방 또는 치료용 복합, 혼합 또는 병용제 키트는 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제제; 및 항바이러스제를 포함하는 제제를 함유할 수 있다.In one aspect of the present invention, 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.
본 발명의 일 양태에서, 암의 예방 또는 치료용 복합, 혼합 또는 병용제 키트는 항바이러스제를 포함하는 제제; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제제를 함유할 수 있다.In one aspect of the present invention, 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.
또한, 암의 예방 또는 치료용 복합, 혼합 또는 병용제 키트는 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물을 포함하는 제제를 더 함유할 수 있다.In addition, the 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.
본 발명의 일 양태에서, 담즙산, 담즙산 유도체, 바이구아나이드 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염, 이들의 함량, 함량비, 암에 대해서는 상기 암의 예방 또는 치료용 약학적 조성물에 대한 설명과 동일한 바, 구체적인 설명은 상기 내용을 원용한다.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.
본 발명에 따른 화합물은 약학적으로 허용되는 염의 형태로 사용될 수 있으며, 염으로는 약학적으로 허용되는 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, 하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다. 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. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Toxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 본 발명의 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한, 이 혼합물에서 용매나 과량의 산을 증발시켜서 건조하거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.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.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.In addition, 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. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. Also, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
본 발명에 따른 조성물을 제제화할 경우, 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.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.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.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. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions, or syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like.
비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and 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.
본 발명에 따른 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 배합된 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "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.
구체적으로, 본 발명에 따른 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.1 mg 내지 100 mg, 바람직하게는 0.5 mg 내지 10 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 질환의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, 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.
본 발명은 또한, 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 약학적으로 유효한 양으로 개체에 복합, 혼합 또는 병용 투여하는 단계를 포함하는, 암의 예방 또는 치료방법을 제공한다.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.
본 발명의 일 양태에서, 담즙산, 담즙산 유도체, 바이구아나이드 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물은, 혼합, 복합 또는 병용하여 암 치료를 필요로 하는 대상에게 투여된다. 보다 구체적으로, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제 1 성분; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제 2 성분이 혼합, 복합 또는 병용하여 암 치료를 필요로 하는 대상에게 투여된다. 또는, 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제 1 성분; 및 항바이러스제를 포함하는 제 2 성분이 혼합, 복합 또는 병용하여 암 치료를 필요로 하는 대상에게 투여된다. 또는, 항바이러스제를 포함하는 제 1 성분; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제 2 성분이 혼합, 복합 또는 병용하여 암 치료를 필요로 하는 대상에게 투여된다. 또는, 상기 제 1 성분; 제 2 성분; 및 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물을 포함하는 제 3 성분이 혼합, 복합 또는 병용하여 암 치료를 필요로 하는 대상에게 투여된다.In one embodiment of the present invention, 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. Or, 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. Or, 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. 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.
본 발명의 구체적인 실시예에서, 본 발명자들은 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 및 담즙산, 이의 유도체 또는 이의 약학적으로 허용되는 염의 복합, 혼합 또는 병용제제에 대한 항암 활성을 확인하기 위하여 유방암, 대장암, 폐암, 전립선암, 췌장암 및 정상세포에 바이구아나이드 계열 화합물인 메트포르민과 담즙산 또는 이의 약학적으로 허용되는 염인 소듐 데옥시콜레이트 또는 우르소데옥시콜산을 단독으로 처리하거나 복합, 혼합 또는 병용처리하여 MTT 분석을 수행한 결과, 정상세포에서는 아무 변화를 나타내지 않았지만 암세포에서는 성장억제 효과를 나타냄을 확인하였다. In a specific embodiment of the present invention, 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 As a result of performing MTT analysis by treating bile acid or a pharmaceutically acceptable salt thereof, 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
또한, 본 발명자들은 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 및 항바이러스제의 복합, 혼합 또는 병용제제에 대한 항암 활성을 확인하기 위하여 췌장암 및 정상세포에 바이구아나이드 계열 화합물인 메트포르민과 항바이러스제 NNRTI인 에파비렌즈, 에트라비린 및 네비라핀을 단독으로 처리하거나 복합, 혼합 또는 병용처리하여 MTT 분석을 수행한 결과, 정상세포에서는 아무 변화를 나타내지 않았지만 암세포에서는 성장억제 효과를 나타냄을 확인하였다. 또한, 메트포르민과 항바이러스제 NRTI인 라미부딘을 단독으로 처리하거나 복합, 혼합 또는 병용처리하여 MTT 분석을 수행한 결과, 정상세포에서는 아무 변화를 나타내지 않았지만 암세포에서는 성장억제 효과를 나타냄을 확인하였다. 또한, 메트포르민과 항바이러스제 PI인 로피나비르, 아타자나비르, 다루나비르 및 리토나비르를 단독으로 처리하거나 복합, 혼합 또는 병용처리하여 MTT 분석을 수행한 결과, 정상세포에서는 아무 변화를 나타내지 않았지만 암세포에서는 성장억제 효과를 나타냄을 확인하였다.In addition, 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. In addition, as a result of performing MTT analysis by treating metformin and the antiviral NRTI, lamivudine, alone, complex, mixed, or combined treatment, it was confirmed that it did not show any change in normal cells, but showed a growth inhibitory effect in cancer cells. In addition, as a result of performing MTT analysis by treating metformin and the antiviral agents PI, lopinavir, atazanavir, darunavir, and ritonavir alone, in combination, in combination, or in combination, there was no change in normal cells. It was confirmed that cancer cells exhibit a growth inhibitory effect.
또한, 본 발명자들은 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 항바이러스제; 및 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염의 복합, 혼합 또는 병용제제에 대한 항암 활성을 확인하기 위하여 췌장암 세포에 바이구아나이드 계열 화합물인 메트포르민, 항바이러스제 NNRTI인 에파비렌즈 및 담즙산인 우르소데옥시콜산을 단독으로 처리하거나 복합, 혼합 또는 병용처리하여 MTT 분석을 수행한 결과, 암세포에서 성장억제 효과를 나타냄을 확인하였다. In addition, 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. As a result of performing 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.
또한, 본 발명자들은 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 항바이러스제; 및 치아졸리딘디온 계열 화합물 또는 이의 약학적으로 허용되는 염의 복합, 혼합 또는 병용제제에 대한 항암 활성을 확인하기 위하여 메트포르민, 에파비렌즈 및 치아졸리딘디온 계열 화합물인 피오글리타존을 단독으로 처리하거나 복합, 혼합 또는 병용처리하여 MTT 분석을 수행한 결과, 암세포에서 성장억제 효과를 나타냄을 확인하였다.In addition, 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. As a result of performing the MTT analysis by mixing or co-treatment, it was confirmed that the growth inhibitory effect in cancer cells.
또한, 본 발명자들은 항바이러스제; 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염; 및 항우울제의 복합, 혼합 또는 병용제제에 대한 항암 활성을 확인하기 위하여 대장암 세포 및 췌장암 세포에 에파비렌즈, 플루옥세틴 및 우르소데옥시콜산을 단독으로 처리하거나 복합, 혼합 또는 병용처리하여 MTT 분석을 수행한 결과, 암세포에서 성장억제 효과를 나타냄을 확인하였다. In addition, 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.
또한, 본 발명자들은 바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염; 담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염; 및 치아졸리딘디온 계열 화합물 또는 이의 약학적으로 허용되는 염의 복합, 혼합 또는 병용제제에 대한 항암 활성을 확인하기 위하여 대장암 세포 및 췌장암 세포에 메트포르민, 피오글리타존 및 우르소데옥시콜산을 단독으로 처리하거나 복합, 혼합 또는 병용처리하여 MTT 분석을 수행한 결과, 암세포에서 성장억제 효과를 나타냄을 확인하였다. In addition, 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. , as a result of performing the MTT analysis by mixing or co-treatment, it was confirmed that the growth inhibitory effect in cancer cells.
더불어 각각을 단독으로 처리한 경우보다 복합, 혼합 또는 병용처리한 경우, 현저하게 높은 성장억제를 보여주는 상승효과(synergistic effect)가 나타남을 확인하였다.In addition, it was confirmed that a synergistic effect showing significantly higher growth inhibition was observed in the case of combined, mixed or combined treatment than when each treatment was performed alone.
본 발명에서 대상은 암 치료를 필요로 하는 포유동물이다. 일반적으로 대상은 인간 암 환자이다. 본 발명의 일 양태에서, 대상은 사람이 아닌 영장류와 같은 비인간 포유동물, 모델 시스템에 사용된 동물(예를 들어, 약제의 스크리닝, 특징화 및 평가에 사용되는 마우스 및 랫트) 및 그 밖의 포유동물, 예를 들어 토끼, 기니아피그, 햄스터, 개, 고양이, 침팬지, 고릴라, 원숭이와 같은 유인원류 동물일 수 있다.In the present invention, a subject is a mammal in need of cancer treatment. Typically the subject is a human cancer patient. In one aspect of the invention, 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.
본 발명의 일 양태에서, 상기 약학적 조성물은 암환자의 치료를 위하여 단독 또는 수술, 호르몬 치료, 약물 치료 및 생물학적 반응 조절제와 병행하여 사용될 수도 있다.In one embodiment of the present invention, 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.
또한, 본 발명은 암의 예방 및 치료용 약학적 조성물로 사용하기 위한 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물의 복합, 혼합 또는 병용제제 용도를 제공한다.In addition, 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. Provided is the use of a combination, mixture or combination formulation of two or more compounds selected from the group consisting of acceptable salts.
아울러, 본 발명은 암의 예방 및 개선용 건강식품으로 사용하기 위한 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물의 복합, 혼합 또는 병용제제의 용도를 제공한다.In addition, 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. Provided is the use of a combination, mixture or combination preparation of two or more compounds selected from the group consisting of acceptable salts.
이하 본 발명을 실시예를 통해 보다 상세히 설명한다. 다만 하기 실시예는 본 발명의 이해를 돕기 위한 것이지 본 발명의 권리범위를 이로 한정하는 것을 의도하지 않는다.Hereinafter, the present invention will be described in more detail through examples. However, the following examples are provided to help the understanding of the present invention and are not intended to limit the scope of the present invention.
<실시예 1> 바이구아나이드(biguanide) 계열 화합물 및 담즙산 염의 항암 활성 확인<Example 1> Confirmation of anticancer activity of biguanide-based compounds and bile salts
<1-1> 유방암에서 메트포르민(metformin) 및 소듐 데옥시콜레이트(sodium deoxycholate)의 항암 활성 확인<1-1> Confirmation of anticancer activity of metformin and sodium deoxycholate in breast cancer
메트포르민(metformin) 및 소듐 데옥시콜레이트(sodium deoxycholate)의 항암 활성을 알아보기 위하여, 유방암 세포에 메트포르민 및 소듐 데옥시콜레이트를 처리하고 MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of metformin and sodium deoxycholate, 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.
구체적으로, 유방암 세포주인 MCF-7 세포주를 100 mm culture dish에서 DMEM-10% FBS을 사용하여 5% CO 2, 37℃에서 배양하여, 96 well plate의 각 well에 20% confluence로 접종하고 24시간 배양하였다. 메트포르민을 5 mM 농도로, 소듐 데옥시콜레이트를 0.01, 0.1, 1 및 10 μM 농도로 단독 또는 병용 처리하고, CO 2 incubator에서 24, 48 또는 72시간 동안 배양하였다. 각 well에서 배양액을 제거하고, 새 배양액 100 μl을 가한 후, 10 μl의 12 mM MTT stock 용액(5 mg MTT/PBS)을 가하고 2시간 동안 37℃에서 배양하였다. 이후 반응정지용액인 SDS-HCl 용액(1 g SDS/10 ml 0.01 M HCl) 100 μl을 가하고 4시간 동안 37℃에서 배양하고, microplate leader를 사용하여 570 nM에서 OD를 측정하였다. 약물을 처리하지 않은 세포의 OD와 비교하여 % growth inhibition을 계산하였다(도 1a). 정상세포 대조군으로는 WISH(human normal epithelial cells) 세포주를 사용하여 상기에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 정상세포 대조군의 경우 약물을 처리하고 24시간 동안 배양하였다(도 1b).Specifically, 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 μM 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 μl of a new culture medium was added, and 10 μl of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 μl 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. 1a). As a normal cell control, WISH (human normal epithelial cells) cell line was used and MTT analysis was performed in the same manner as described above. In the case of a normal cell control group, the drug was treated and cultured for 24 hours (Fig. 1b).
그 결과, 도 1a 및 도 1b에 나타낸 바와 같이, 유방암 세포에 5 mM의 메트포르민 또는 0.01, 0.1, 1 및 10 μM의 소듐 데옥시콜레이트 각각을 단독으로 처리한 경우보다 5 mM의 메트포르민 및 0.01, 0.1, 1 및 10 μM의 소듐 데옥시콜레이트를 병용 처리한 경우 현저하게 높은 성장억제를 보여주는 상승 효과가 나타남을 확인하였다(도 1a). 반면, 5 mM의 메트포르민과 0.01, 0.1, 1 및 10 μM의 소듐 데옥시콜레이트를 사람의 정상 상피세포에 병용 처리하였을 때에는 성장억제 활성은 0-8%로 매우 약하게 나타나서 메트포르민과 소듐 데옥시콜레이트의 병용 처리가 암세포의 성장은 현저하게 억제하지만 정상세포에는 영향이 매우 적음을 확인하였다(도 1b).As a result, as shown in 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 μM 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 μM (Fig. 1a). On the other hand, when 5 mM metformin and 0.01, 0.1, 1, and 10 μM of sodium deoxycholate were co-treated with human normal epithelial cells, 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).
<1-2> 췌장암에서 메트포르민 및 소듐 데옥시콜레이트의 항암 활성 확인<1-2> Confirmation of anticancer activity of metformin and sodium deoxycholate in pancreatic cancer
메트포르민 및 소듐 데옥시콜레이트의 항암 활성을 알아보기 위하여, 췌장암 세포에 메트포르민 및 소듐 데옥시콜레이트를 처리하고 MTT 분석을 수행하여 성장억제를 확인하였다.In order to examine the anticancer activity of metformin and sodium deoxycholate, pancreatic cancer cells were treated with metformin and sodium deoxycholate and growth inhibition was confirmed by performing MTT analysis.
구체적으로, 췌장암 세포주인 AsPC-1 세포주(도 2a) 및 MIA PaCa-2 세포주(도 2b)를 이용하여 상기 실시예 <1-1>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다.Specifically, 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.
그 결과, 도 2a 및 도 2b에 나타낸 바와 같이, 췌장암 세포에 5 mM의 메트포르민 또는 0.01, 0.1, 1 및 10 μM의 소듐 데옥시콜레이트 각각을 단독으로 처리한 경우보다 5 mM의 메트포르민 및 0.01, 0.1, 1 및 10 μM의 소듐 데옥시콜레이트를 병용 처리한 경우 현저하게 높은 성장억제를 보여주는 상승 효과가 나타남을 확인하였다(도 2a 및 도 2b). As a result, as shown in Figures 2a and 2b, 5 mM metformin and 0.01, 0.1 than when 5 mM metformin or 0.01, 0.1, 1, and 10 μM of sodium deoxycholate were treated alone in pancreatic cancer cells. , 1 and 10 μM of sodium deoxycholate in combination treatment showed a synergistic effect showing a remarkably high growth inhibition ( FIGS. 2a and 2b ).
<1-3> 전립선암에서 메트포르민 및 소듐 데옥시콜레이트의 항암 활성 확인<1-3> Confirmation of anticancer activity of metformin and sodium deoxycholate in prostate cancer
메트포르민 및 소듐 데옥시콜레이트의 항암 활성을 알아보기 위하여, 전립선암 세포에 메트포르민 및 소듐 데옥시콜레이트를 처리하고 MTT 분석을 수행하여 성장억제를 확인하였다.In order to examine the anticancer activity of metformin and sodium deoxycholate, prostate cancer cells were treated with metformin and sodium deoxycholate, and growth inhibition was confirmed by performing MTT analysis.
구체적으로, 전립선암 세포주인 LNcaP 세포주를 이용하여 상기 실시예 <1-1>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 3).Specifically, 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).
그 결과, 도 3에 나타낸 바와 같이, 전립선암 세포에 5 mM의 메트포르민 또는 0.01, 0.1, 1 및 10 μM의 소듐 데옥시콜레이트 각각을 단독으로 처리한 경우보다 5 mM의 메트포르민 및 0.01, 0.1, 1 및 10 μM의 소듐 데옥시콜레이트를 병용 처리한 경우 현저하게 높은 성장억제를 보여주는 상승 효과가 나타남을 확인하였다(도 3). As a result, as shown in FIG. 3, 5 mM metformin and 0.01, 0.1, 1 compared to the case where prostate cancer cells were treated with 5 mM metformin or 0.01, 0.1, 1, and 10 μM of sodium deoxycholate alone. And it was confirmed that when 10 μM sodium deoxycholate was treated in combination, a synergistic effect showing significantly high growth inhibition was observed (FIG. 3).
상기 결과를 통해 메트포르민과 데옥시콜산(deoxycholic acid) 또는 이의 염은 병용처리 시에 정상세포의 성장에는 적은 영향을 미치면서 암세포 성장억제 활성에서는 보다 탁월한 효과를 나타내는 것을 확인하였다.Through the above results, it was confirmed that 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.
<실시예 2> 바이구아나이드(biguanide) 계열 화합물 및 담즙산의 항암 활성 확인<Example 2> Confirmation of anticancer activity of biguanide-based compounds and bile acids
<2-1> 유방암에서 메트포르민(metformin) 및 우르소데옥시콜산(ursodeoxycholic acid)의 항암 활성 확인<2-1> Confirmation of anticancer activity of metformin and ursodeoxycholic acid in breast cancer
메트포르민(metformin) 및 우르소데옥시콜산(ursodeoxycholic acid)의 항암 활성을 알아보기 위하여, 유방암 세포에 메트포르민 및 우르소데옥시콜산를 처리하고 MTT 분석을 수행하여 성장억제를 확인하였다.In order to examine the anticancer activity of metformin and ursodeoxycholic acid, growth inhibition was confirmed by treating breast cancer cells with metformin and ursodeoxycholic acid and performing MTT analysis.
구체적으로, 유방암 세포주인 MCF-7 세포주를 이용하여 상기 실시예 <1-1>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다(도 4a). 정상세포 대조군으로는 WISH(human normal epithelial cells) 세포주를 사용하였다. 또한, 정상세포 대조군의 경우 약물을 처리하고 24시간 동안 배양하였다(도 4b). Specifically, 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). As a normal cell control, WISH (human normal epithelial cells) cell line was used. In addition, in the case of a normal cell control group, the drug was treated and cultured for 24 hours (Fig. 4b).
그 결과, 도 4a 및 도 4b에 나타낸 바와 같이, 유방암 세포에 5 mM의 메트포르민 또는 0.01, 0.1, 1 및 10 μM의 우르소데옥시콜산 각각을 단독으로 처리한 경우보다 5 mM의 메트포르민 및 0.01, 0.1, 1 및 10 μM의 우르소데옥시콜산을 병용 처리한 경우 현저하게 높은 성장억제를 보여주는 상승 효과가 나타남을 확인하였다(도 4a). 반면, 5 mM의 메트포르민과 0.01, 0.1, 1 및 10 μM의 우르소데옥시콜산을 사람의 정상 상피세포에 병용 처리하였을 때에는 성장억제 활성은 0-8%로 매우 약하게 나타나서 메트포르민과 우르소데옥시콜산의 병용 처리가 암세포의 성장은 현저하게 억제하지만 정상세포에는 영향이 매우 적음을 확인하였다(도 4b).As a result, as shown in FIGS. 4A and 4B, 5 mM metformin and 0.01, 0.1 compared to the case where breast cancer cells were treated with 5 mM metformin or 0.01, 0.1, 1, and 10 μM ursodeoxycholic acid alone. , 1 and 10 μM of ursodeoxycholic acid in combination treatment showed a synergistic effect showing a significantly high growth inhibition (Fig. 4a). On the other hand, when 5 mM metformin and 0.01, 0.1, 1, and 10 μM of ursodeoxycholic acid were co-treated with human normal epithelial cells, 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. 4b).
<2-2> 췌장암에서 메트포르민 및 우르소데옥시콜산의 항암 활성 확인<2-2> Confirmation of anticancer activity of metformin and ursodeoxycholic acid in pancreatic cancer
메트포르민 및 우르소데옥시콜산의 항암 활성을 알아보기 위하여, 췌장암 세포에 메트포르민 및 우르소데옥시콜산을 처리하고 MTT 분석을 수행하여 성장억제를 확인하였다.In order to examine the anticancer activity of metformin and ursodeoxycholic acid, pancreatic cancer cells were treated with metformin and ursodeoxycholic acid and growth inhibition was confirmed by performing MTT analysis.
구체적으로, 췌장암 세포주인 AsPC-1 세포주(도 5a) 및 MIA PaCa-2 세포주(도 5b)를 이용하여 상기 실시예 <1-1>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다.Specifically, 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.
그 결과, 도 5a 및 도 5b에 나타낸 바와 같이, 췌장암 세포에 5 mM의 메트포르민 또는 0.01, 0.1, 1 및 10 μM의 우르소데옥시콜산 각각을 단독으로 처리한 경우보다 5 mM의 메트포르민 및 0.01, 0.1, 1 및 10 μM의 우르소데옥시콜산을 병용 처리한 경우 현저하게 높은 성장억제를 보여주는 상승 효과가 나타남을 확인하였다(도 5a 및 도 5b). As a result, as shown in Figures 5a and 5b, 5 mM metformin and 0.01, 0.1 than when 5 mM metformin or 0.01, 0.1, 1, and 10 μM of ursodeoxycholic acid were treated alone in pancreatic cancer cells. , 1 and 10 μM of ursodeoxycholic acid in combination treatment showed a synergistic effect showing a remarkably high growth inhibition ( FIGS. 5A and 5B ).
<2-3> 전립선암에서 메트포르민 및 소듐 우르소데옥시콜산의 항암 활성 확인<2-3> Confirmation of anticancer activity of metformin and sodium ursodeoxycholic acid in prostate cancer
메트포르민 및 우르소데옥시콜산의 항암 활성을 알아보기 위하여, 전립선암 세포에 메트포르민 및 우르소데옥시콜산을 처리하고 MTT 분석을 수행하여 성장억제를 확인하였다.In order to investigate the anticancer activity of metformin and ursodeoxycholic acid, prostate cancer cells were treated with metformin and ursodeoxycholic acid and growth inhibition was confirmed by performing MTT analysis.
구체적으로, 전립선암 세포주인 LNcaP 세포주(도 6a) 및 DU145 세포주(도 6b)를 이용하여 상기 실시예 <1-1>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다.Specifically, 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.
그 결과, 도 6a 및 도 6b에 나타낸 바와 같이, 전립선암 세포에 5 mM의 메트포르민 또는 0.01, 0.1, 1 및 10 μM의 우르소데옥시콜산 각각을 단독으로 처리한 경우보다 5 mM의 메트포르민 및 0.01, 0.1, 1 및 10 μM의 우르소데옥시콜산을 병용 처리한 경우 현저하게 높은 성장억제를 보여주는 상승 효과가 나타남을 확인하였다(도 6a 및 도 6b). As a result, as shown in 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 μM ursodeoxycholic acid alone. It was confirmed that 0.1, 1, and 10 μM of ursodeoxycholic acid in combination showed a synergistic effect showing significantly high growth inhibition ( FIGS. 6a and 6b ).
상기 결과를 통해 메트포르민과 우르소데옥시콜산 또는 이의 염은 병용처리 시에 정상세포의 성장에는 적은 영향을 미치면서 암세포 성장억제 활성에서는 보다 탁월한 효과를 나타내는 것을 확인하였다.Through the above results, it was confirmed that 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.
<실시예 3> 바이구아나이드(biguanide) 계열 화합물 및 항바이러스제 비뉴클레오시드 역전사 효소 억제제(NNRTIs; Non-nucleoside reverse-transcriptase inhibitors)의 항암 활성 확인<Example 3> Confirmation of anticancer activity of biguanide-based compounds and antiviral non-nucleoside reverse-transcriptase inhibitors (NNRTIs; Non-nucleoside reverse-transcriptase inhibitors)
<3-1> 췌장암에서 메트포르민 및 에파비렌즈(efavirenz)의 항암 활성 확인<3-1> Confirmation of anticancer activity of metformin and efavirenz in pancreatic cancer
바이구아나이드 계열 화합물 및 항바이러스제 NNRTI의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민 및 항바이러스제 NNRTI로 에파비렌즈를 처리하고 MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of the biguanide-based compound and the antiviral NNRTI, 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.
구체적으로, 췌장암 세포주인 ASPC-1 세포주를 100 mm 배양 접시(culture dish)에서 DMEM-10% FBS을 사용하여 5% CO 2, 37℃에서 배양한 후, 96 웰플레이트(well plate)의 각 웰에 20% 컨플루언스(confluence)로 접종하고 24시간 배양하였다. 메트포르민을 5 mM 농도로, 에파비렌즈를 1 및 2 μM 농도로 단독 또는 병용처리하고, CO 2 인큐베이터(incubator)에서 24시간 동안 배양하였다. 각 웰에서 배양액을 제거하고, 새 배양액 100 μl을 가한 후, 10 μl의 12 mM MTT 스탁(stock) 용액 (5 mg MTT/PBS)을 가하고 2시간 동안 37℃에서 배양하였다. 이후 반응정지용액인 SDS-HCl용액 (1 g SDS/10 ml 0.01 M HCl) 100 μl을 가하고 4시간 동안 37℃에서 배양하고, 마이크로플레이트 리더(microplate leader)를 사용하여 570 nM에서 OD를 측정하였다. 약물을 처리하지 않은 세포의 OD와 비교하여 % growth inhibition을 계산하였다(도 7a). 정상세포 대조군으로는 WISH 세포주(human normal epithelial cells)를 사용하여 상기에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 정상세포 대조군의 경우 약물을 처리하고 24시간 동안 배양하였다(도 7b).Specifically, the 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 μM 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 μl of a fresh culture medium was added, and 10 μl of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 μl 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. 7a). As a normal cell control, WISH cell line (human normal epithelial cells) was used and MTT analysis was performed in the same manner as described above. In the case of a normal cell control group, the drug was treated and cultured for 24 hours (FIG. 7b).
그 결과, 도 7a 및 도 7b에 나타낸 바와 같이, 췌장암 세포에 5 mM의 메트포르민 또는 1 및 2 μM의 에파비렌즈 각각을 단독으로 처리한 경우보다 5 mM의 메트포르민 및 1 및 2 μM의 에파비렌즈를 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 7a). 반면, 5 mM의 메트포르민 또는 1 및 2 μM의 에파비렌즈를 사람의 정상 상피세포에 병용처리하였을 때에는 성장억제 활성이 0-18%로 약하게 나타나서 메트포르민과 에파비렌즈의 병용처리가 암세포의 성장은 현저하게 억제하지만 정상세포에는 영향이 매우 적음을 확인하였다(도 7b).As a result, as shown in Figures 7a and 7b, 5 mM metformin and 1 and 2 μM efavirenz compared to the case where pancreatic cancer cells were treated with 5 mM metformin or 1 and 2 μM efavirenz alone, respectively. It was confirmed that a synergistic effect showing remarkably high growth inhibition was observed when co-treated with (FIG. 7a). On the other hand, when 5 mM metformin or 1 and 2 μM efavirenz were co-treated with normal human epithelial cells, the growth inhibitory activity was weak at 0-18%. Although it was significantly inhibited, it was confirmed that the effect on normal cells was very small (FIG. 7b).
<3-2> 췌장암에서 메트포르민 및 에트라비린(etravirine)의 항암 활성 확인<3-2> Confirmation of anticancer activity of metformin and etravirine in pancreatic cancer
바이구아나이드 계열 화합물 및 항바이러스제 NNRTI의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민 및 항바이러스제 NNRTI로 에트라비린을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of the biguanide-based compound and the antiviral agent NNRTI, 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.
구체적으로, 췌장암 세포주인 ASPC-1 세포주를 100 mm 배양 접시(culture dish)에서 DMEM-10% FBS을 사용하여 5% CO 2, 37℃에서 배양한 후, 96 웰플레이트(well plate)의 각 웰에 20% 컨플루언스(confluence)로 접종하고 24시간 배양하였다. 메트포르민을 1 mM 농도로, 에트라비린을 0.1 및 1 μM 농도로 단독 또는 병용처리하고, CO 2 인큐베이터(incubator)에서 24시간 동안 배양하였다. 각 웰에서 배양액을 제거하고, 새 배양액 100 μl을 가한 후, 10 μl의 12 mM MTT 스탁(stock) 용액 (5 mg MTT/PBS)을 가하고 2시간 동안 37℃에서 배양하였다. 이후 반응정지용액인 SDS-HCl용액 (1 g SDS/10 ml 0.01 M HCl) 100 μl을 가하고 4시간 동안 37℃에서 배양하고, 마이크로플레이트 리더(microplate leader)를 사용하여 570 nM에서 OD를 측정하였다. 약물을 처리하지 않은 세포의 OD와 비교하여 % growth inhibition을 계산하였다(도 8).Specifically, the 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 μM 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 μl of a fresh culture medium was added, and 10 μl of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 μl 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. 8).
그 결과, 도 8에 나타낸 바와 같이, 췌장암 세포에 1 mM의 메트포르민 또는 0.1 및 1 μM의 에트라비린 각각을 단독으로 처리한 경우보다 1 mM의 메트포르민 및 0.1 및 1 μM의 에트라비린을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 8).As a result, as shown in FIG. 8 , the combination treatment of 1 mM metformin and 0.1 and 1 μM of etravirin was compared with the case where pancreatic cancer cells were treated with either 1 mM metformin or 0.1 and 1 μM etravirin alone. In one case, it was confirmed that a synergistic effect showing significantly high growth inhibition appeared (FIG. 8).
<3-3> 췌장암에서 메트포르민 및 네비라핀(nevirapine)의 항암 활성 확인<3-3> Confirmation of anticancer activity of metformin and nevirapine in pancreatic cancer
바이구아나이드 계열 화합물 및 항바이러스제 NNRTI의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민 및 항바이러스제 NNRTI로 네비라핀을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to examine the anticancer activity of the biguanide-based compound and the antiviral agent NNRTI, 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.
구체적으로, 췌장암 세포주를 이용하여 상기 실시예 <3-2>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 9).Specifically, 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).
그 결과, 도 9에 나타낸 바와 같이 췌장암 세포에서 1 mM의 메트포르민 또는 0.1 내지 1 μM의 네비라핀 각각을 단독으로 처리한 경우보다 1 mM의 메트포르민 및 0.1 및 1 μM의 네비라핀을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 9).As a result, as shown in FIG. 9 , in pancreatic cancer cells, 1 mM metformin and 0.1 and 1 μM nevirapine were significantly more significant when treated in combination than when 1 mM metformin or 0.1 to 1 μM nevirapine was treated alone. It was confirmed that a synergistic effect showing high growth inhibition was observed (FIG. 9).
<실시예 4> 바이구아나이드(biguanide) 계열 화합물 및 항바이러스제 뉴클레오시드 역전사 효소 저해제(NRTIs; Nucleoside reverse-transcriptase inhibitors)의 항암 활성 확인<Example 4> Confirmation of anticancer activity of biguanide-based compounds and antiviral nucleoside reverse-transcriptase inhibitors (NRTIs; Nucleoside reverse-transcriptase inhibitors)
<4-1> 췌장암에서 메트포르민 및 라미부딘(lamivudine)의 항암 활성 확인<4-1> Confirmation of anticancer activity of metformin and lamivudine in pancreatic cancer
바이구아나이드 계열 화합물 및 항바이러스제 NRTI의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민 및 항바이러스제 NRTI로 라미부딘을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to examine the anticancer activity of the biguanide-based compound and the antiviral agent NRTI, 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. .
구체적으로, 췌장암 세포주를 이용하여 상기 실시예 <3-2>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 10).Specifically, 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).
그 결과, 도 10에 나타낸 바와 같이 췌장암 세포에서 1 mM의 메트포르민 또는 0.1 내지 1 μM의 라미부딘 각각을 단독으로 처리한 경우보다 1 mM의 메트포르민 및 0.1 및 1 μM의 라미부딘을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 10).As a result, as shown in FIG. 10 , in pancreatic cancer cells, 1 mM metformin and 0.1 and 1 μM lamivudine were significantly higher than when 1 mM metformin or 0.1 to 1 μM lamivudine was treated alone. It was confirmed that a synergistic effect showing growth inhibition appears ( FIG. 10 ).
<실시예 5> 바이구아나이드(biguanide) 계열 화합물 및 항바이러스제 단백분해효소 억제제(PIs; Protease inhibitors)의 항암 활성 확인<Example 5> Confirmation of anticancer activity of biguanide-based compounds and antiviral protease inhibitors (PIs; Protease inhibitors)
<5-1> 췌장암에서 메트포르민 및 로피나비르(lopinavir)의 항암 활성 확인<5-1> Confirmation of anticancer activity of metformin and lopinavir in pancreatic cancer
바이구아나이드 계열 화합물 및 항바이러스제 PI의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민 및 항바이러스제 PI로 로피나비르를 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of the biguanide-based compound and the antiviral agent PI, 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.
구체적으로, 췌장암 세포주를 이용하여 상기 실시예 <3-2>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 11).Specifically, 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).
그 결과, 도 11에 나타낸 바와 같이 췌장암 세포에서 1 mM의 메트포르민 또는 0.1 내지 1 μM의 로피나비르 각각을 단독으로 처리한 경우보다 1 mM의 메트포르민 및 0.1 및 1 μM의 로피나비르를 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 11).As a result, as shown in FIG. 11 , in pancreatic cancer cells, 1 mM metformin and 0.1 and 1 μM lopinavir were treated in combination than when 1 mM metformin or 0.1 to 1 μM lopinavir was treated alone. In this case, it was confirmed that a synergistic effect showing significantly high growth inhibition was observed (FIG. 11).
<5-2> 췌장암에서 메트포르민 및 아타자나비르(atazanavir)의 항암 활성 확인<5-2> Confirmation of anticancer activity of metformin and atazanavir in pancreatic cancer
바이구아나이드 계열 화합물 및 항바이러스제 PI의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민 및 항바이러스제 PI로 아타자나비르를 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of the biguanide-based compound and the antiviral agent PI, 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.
구체적으로, 췌장암 세포주인 ASPC-1 세포주를 100 mm 배양 접시(culture dish)에서 DMEM-10% FBS을 사용하여 5% CO 2, 37℃에서 배양한 후, 96 웰플레이트(well plate)의 각 웰에 20% 컨플루언스(confluence)로 접종하고 24시간 배양하였다. 메트포르민을 1 mM 농도로, 아타자나비르를 10, 20 및 40 μM 농도로 단독 또는 병용처리하고, CO 2 인큐베이터(incubator)에서 24시간 동안 배양하였다. 각 웰에서 배양액을 제거하고, 새 배양액 100 μl을 가한 후, 10 μl의 12 mM MTT 스탁(stock) 용액 (5 mg MTT/PBS)을 가하고 2시간 동안 37℃에서 배양하였다. 이후 반응정지용액인 SDS-HCl용액 (1 g SDS/10 ml 0.01 M HCl) 100 μl을 가하고 4시간 동안 37℃에서 배양하고, 마이크로플레이트 리더(microplate leader)를 사용하여 570 nM에서 OD를 측정하였다. 약물을 처리하지 않은 세포의 OD와 비교하여 % growth inhibition을 계산하였다(도 12).Specifically, the 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 μM 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 μl of a fresh culture medium was added, and 10 μl of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 μl of SDS-HCl solution (1 g SDS/10 ml 0.01 M HCl) as 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. 12).
그 결과, 도 12에 나타낸 바와 같이, 췌장암 세포에 1 mM의 메트포르민 또는 10, 20 및 40 μM의 아타자나비르 각각을 단독으로 처리한 경우보다 1 mM의 메트포르민 및 10, 20 및 40 μM의 아타자나비르를 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 12).As a result, as shown in FIG. 12, 1 mM metformin and 10, 20 and 40 μM of atazana were higher than when pancreatic cancer cells were treated with 1 mM metformin or 10, 20, and 40 μM of atazanavir alone. It was confirmed that a synergistic effect showing a remarkably high growth inhibition was observed when vir was treated in combination (FIG. 12).
<5-3> 췌장암에서 메트포르민 및 다루나비르(darunavir)의 항암 활성 확인<5-3> Confirmation of anticancer activity of metformin and darunavir in pancreatic cancer
바이구아나이드 계열 화합물 및 항바이러스제 PI의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민 및 항바이러스제 PI로 다루나비르를 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to examine the anticancer activity of the biguanide-based compound and the antiviral agent PI, 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.
구체적으로, 췌장암 세포주를 이용하여 상기 실시예 <5-2>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 13).Specifically, 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).
그 결과, 도 13에 나타낸 바와 같이, 췌장암 세포에 1 mM의 메트포르민 또는 10, 20 및 40 μM의 다루나비르 각각을 단독으로 처리한 경우보다 1 mM의 메트포르민 및 10, 20 및 40 μM의 다루나비르를 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 13).As a result, as shown in FIG. 13 , 1 mM metformin and 10, 20, and 40 μM darunavir at 1 mM metformin and 10, 20 and 40 μM darunavir, respectively, compared to the case where pancreatic cancer cells were treated with 1 mM metformin or 10, 20, and 40 μM darunavir alone It was confirmed that a synergistic effect showing a remarkably high growth inhibition was observed when le was co-treated (FIG. 13).
<5-4> 췌장암에서 메트포르민 및 리토나비르(ritonavir)의 항암 활성 확인<5-4> Confirmation of anticancer activity of metformin and ritonavir in pancreatic cancer
바이구아나이드 계열 화합물 및 항바이러스제 PI의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민 및 항바이러스제 PI로 리토나비르를 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to examine the anticancer activity of the biguanide-based compound and the antiviral agent PI, 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.
구체적으로, 췌장암 세포주를 이용하여 상기 실시예 <5-2>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 14).Specifically, 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).
그 결과, 도 14에 나타낸 바와 같이, 췌장암 세포에 1 mM의 메트포르민 또는 10, 20 및 40 μM의 리토나비르 각각을 단독으로 처리한 경우보다 1 mM의 메트포르민 및 10, 20 및 40 μM의 리토나비르를 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 14).As a result, as shown in FIG. 14 , 1 mM metformin and 10, 20 and 40 μM ritonavir were higher than when pancreatic cancer cells were treated with either 1 mM metformin or 10, 20, and 40 μM ritonavir alone. It was confirmed that a synergistic effect showing a remarkably high growth inhibition was observed when le was co-treated (FIG. 14).
<실시예 6> 바이구아나이드(biguanide) 계열 화합물, 항바이러스제 및 담즙산의 항암 활성 확인<Example 6> Confirmation of anticancer activity of biguanide-based compounds, antiviral agents and bile acids
<6-1> 췌장암에서 메트포르민, 에파비렌즈 및 우르소데옥시콜산의 항암 활성 확인<6-1> Confirmation of anticancer activity of metformin, efavirenz and ursodeoxycholic acid in pancreatic cancer
바이구아나이드 계열 화합물, 항바이러스제 및 담즙산의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민, 항바이러스제로 에파비렌즈 및 담즙산으로 우르소데옥시콜산을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of biguanide-based compounds, antiviral agents and bile acids, 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.
구체적으로, 췌장암 세포주인 ASPC-1 세포주를 100 mm 배양 접시(culture dish)에서 DMEM-10% FBS을 사용하여 5% CO 2, 37℃에서 배양한 후, 96 웰플레이트(well plate)의 각 웰에 20% 컨플루언스(confluence)로 접종하고 24시간 배양하였다. 메트포르민을 2.5 mM 농도로, 에파비렌즈를 2 μM 농도로, 우르소데옥시콜산을 20 μM 농도로 단독 또는 병용처리하고, CO 2 인큐베이터(incubator)에서 24시간 동안 배양하였다. 각 웰에서 배양액을 제거하고, 새 배양액 100 μl을 가한 후, 10 μl의 12 mM MTT 스탁(stock) 용액 (5 mg MTT/PBS)을 가하고 2시간 동안 37℃에서 배양하였다. 이후 반응정지용액인 SDS-HCl용액 (1 g SDS/10 ml 0.01 M HCl) 100 μl을 가하고 4시간 동안 37℃에서 배양하고, 마이크로플레이트 리더(microplate leader)를 사용하여 570 nM에서 OD를 측정하였다. 약물을 처리하지 않은 세포의 OD와 비교하여 % growth inhibition을 계산하였다(도 15).Specifically, the 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 μM, and ursodeoxycholic acid at a concentration of 20 μM 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 μl of a fresh culture medium was added, and 10 μl of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 μl 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).
그 결과, 도 15에 나타낸 바와 같이, 췌장암 세포에 2.5 mM의 메트포르민, 2 μM의 에파비렌즈 또는 20 μM의 우르소데옥시콜산 각각을 단독으로 처리한 경우보다 2.5 mM의 메트포르민, 2 μM의 에파비렌즈 및 20 μM의 우르소데옥시콜산을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 15).As a result, as shown in FIG. 15 , 2.5 mM metformin, 2 μM efavirex, 2.5 mM metformin, 2 μM efavirex compared to the case where pancreatic cancer cells were treated with 2.5 mM metformin, 2 μM efavirenz, or 20 μM ursodeoxycholic acid alone. When the lens and 20 μM of ursodeoxycholic acid were co-treated, it was confirmed that a synergistic effect showing a remarkably high growth inhibition was observed (FIG. 15).
<실시예 7> 바이구아나이드(biguanide) 계열 화합물, 항바이러스제 및 치아졸리딘디온 계열 화합물의 항암 활성 확인<Example 7> Confirmation of anticancer activity of biguanide-based compounds, antiviral agents and thiazolidinedione-based compounds
<7-1> 췌장암에서 메트포르민, 에파비렌즈 및 피오글리타존(pioglitazone)의 항암 활성 확인<7-1> Confirmation of anticancer activity of metformin, efavirenz and pioglitazone in pancreatic cancer
바이구아나이드 계열 화합물, 항바이러스제 및 치아졸리딘디온 계열 화합물의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민, 항바이러스제로 에파비렌즈 및 치아졸리딘디온 계열 화합물로 피오글리타존을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.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.
구체적으로, 췌장암 세포주인 ASPC-1 세포주를 100 mm 배양 접시(culture dish)에서 DMEM-10% FBS을 사용하여 5% CO 2, 37℃에서 배양한 후, 96 웰플레이트(well plate)의 각 웰에 20% 컨플루언스(confluence)로 접종하고 24시간 배양하였다. 메트포르민을 2.5 mM 농도로, 에파비렌즈를 2 μM 농도로, 피오글리타존을 10 μM 농도로 단독 또는 병용처리하고, CO 2 인큐베이터(incubator)에서 24시간 동안 배양하였다. 각 웰에서 배양액을 제거하고, 새 배양액 100 μl을 가한 후, 10 μl의 12 mM MTT 스탁(stock) 용액 (5 mg MTT/PBS)을 가하고 2시간 동안 37℃에서 배양하였다. 이후 반응정지용액인 SDS-HCl용액 (1 g SDS/10 ml 0.01 M HCl) 100 μl을 가하고 4시간 동안 37℃에서 배양하고, 마이크로플레이트 리더(microplate leader)를 사용하여 570 nM에서 OD를 측정하였다. 약물을 처리하지 않은 세포의 OD와 비교하여 % growth inhibition을 계산하였다(도 16).Specifically, the 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 μM, and pioglitazone at a concentration of 10 μM 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 μl of a fresh culture medium was added, and 10 μl of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 μl 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).
그 결과, 도 16에 나타낸 바와 같이, 췌장암 세포에 2.5 mM의 메트포르민, 2 μM의 에파비렌즈 또는 10 μM의 피오글리타존 각각을 단독으로 처리한 경우보다 2.5 mM의 메트포르민, 2 μM의 에파비렌즈 및 10 μM의 피오글리타존을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 16).As a result, as shown in FIG. 16 , 2.5 mM of metformin, 2 μM of efavirenz and 10 When pioglitazone of μM was co-treated, it was confirmed that a synergistic effect showing a remarkably high growth inhibition was observed (FIG. 16).
<7-2> 대장암에서 메트포르민, 에파비렌즈 및 피오글리타존의 항암 활성 확인<7-2> Confirmation of anticancer activity of metformin, efavirenz and pioglitazone in colorectal cancer
바이구아나이드 계열 화합물, 항바이러스제 및 치아졸리딘디온 계열 화합물의 항암 활성을 알아보기 위하여, 대장암 세포에 바이구아나이드 계열 화합물로 메트포르민, 항바이러스제로 에파비렌즈 및 치아졸리딘디온 계열 화합물로 피오글리타존을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.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.
구체적으로, 대장암 세포주 HCT116 세포를 이용하여 상기 실시예 <7-1>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 17).Specifically, 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).
그 결과, 도 17에 나타낸 바와 같이, 대장암 세포에 2.5 mM의 메트포르민, 2 μM의 에파비렌즈 또는 10 μM의 피오글리타존 각각을 단독으로 처리한 경우보다 2.5 mM의 메트포르민, 2 μM의 에파비렌즈 및 10 μM의 피오글리타존을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 17).As a result, as shown in FIG. 17, colorectal cancer cells were treated with 2.5 mM metformin, 2 µM efavirenz, or 10 µM pioglitazone alone, respectively. When 10 μM of pioglitazone was co-treated, it was confirmed that a synergistic effect showing significantly high growth inhibition was observed (FIG. 17).
<실시예 8> 항바이러스제, 항우울제 및 담즙산의 항암 활성 확인<Example 8> Confirmation of anticancer activity of antiviral agents, antidepressants and bile acids
<8-1> 대장암에서 에파비렌즈, 플루옥세틴 및 우르소데옥시콜산의 항암 활성 확인<8-1> Confirmation of anticancer activity of efavirenz, fluoxetine and ursodeoxycholic acid in colorectal cancer
항바이러스제, 항우울제 및 담즙산의 항암 활성을 알아보기 위하여, 대장암 세포에 항바이러스제로 에파비렌즈, 항우울제로 플루옥세틴 및 담즙산으로 우르소데옥시콜산을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of antiviral agents, antidepressants and bile acids, colorectal cancer cells were treated with efavirenz as an antiviral agent, fluoxetine as an antidepressant, and ursodeoxycholic acid with bile acid, and growth inhibition was obtained by performing MTT analysis. Confirmed.
구체적으로, 대장암 세포주인 HCT116 세포주를 100 mm 배양 접시(culture dish)에서 DMEM-10% FBS을 사용하여 5% CO 2, 37℃에서 배양한 후, 96 웰플레이트(well plate)의 각 웰에 20% 컨플루언스(confluence)로 접종하고 24시간 배양하였다. 에파비렌즈를 0.5 μM 농도로, 플루옥세틴을 0.5 μM 농도로, 우르소데옥시콜산을 200 μM 농도로 단독 또는 병용처리하고, CO 2 인큐베이터(incubator)에서 24시간 동안 배양하였다. 각 웰에서 배양액을 제거하고, 새 배양액 100 μl을 가한 후, 10 μl의 12 mM MTT 스탁(stock) 용액 (5 mg MTT/PBS)을 가하고 2시간 동안 37℃에서 배양하였다. 이후 반응정지용액인 SDS-HCl용액 (1 g SDS/10 ml 0.01 M HCl) 100 μl을 가하고 4시간 동안 37℃에서 배양하고, 마이크로플레이트 리더(microplate leader)를 사용하여 570 nM에서 OD를 측정하였다. 약물을 처리하지 않은 세포의 OD와 비교하여 % growth inhibition을 계산하였다(도 18).Specifically, 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 μM, fluoxetine at a concentration of 0.5 μM, and ursodeoxycholic acid at a concentration of 200 μM alone or in combination, and incubated in a CO 2 incubator for 24 hours. The culture medium was removed from each well, 100 μl of a fresh culture medium was added, and 10 μl of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 μl 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).
그 결과, 도 18에 나타낸 바와 같이, 대장암 세포에 0.5 μM의 에파비렌즈, 0.5 μM의 플루옥세틴 또는 200 μM의 우르소데옥시콜산 각각을 단독으로 처리한 경우보다 0.5 μM의 에파비렌즈, 0.5 μM의 플루옥세틴 및 200 μM의 우르소데옥시콜산을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 18).As a result, as shown in FIG. 18 , 0.5 µM efavirenz, 0.5 µM colorectal cancer cells were treated with 0.5 µM efavirenz, 0.5 µM fluoxetine, or 200 µM ursodeoxycholic acid alone, respectively. When fluoxetine of and 200 μM of ursodeoxycholic acid were co-treated, it was confirmed that a synergistic effect showing significantly high growth inhibition appeared (FIG. 18).
<8-2> 췌장암에서 에파비렌즈, 플루옥세틴 및 우르소데옥시콜산의 항암 활성 확인<8-2> Confirmation of anticancer activity of efavirenz, fluoxetine and ursodeoxycholic acid in pancreatic cancer
항바이러스제, 항우울제 및 담즙산의 항암 활성을 알아보기 위하여, 췌장암 세포에 항바이러스제로 에파비렌즈, 항우울제로 플루옥세틴 및 담즙산으로 우르소데옥시콜산을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of antiviral agents, antidepressants and bile acids, 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.
구체적으로, 췌장암 세포주 ASPC-1 세포를 이용하여 상기 실시예 <8-1>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 19).Specifically, 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).
그 결과, 도 19에 나타낸 바와 같이, 췌장암 세포에 0.5 μM의 에파비렌즈, 0.5 μM의 플루옥세틴 또는 200 μM의 우르소데옥시콜산 각각을 단독으로 처리한 경우보다 0.5 μM의 에파비렌즈, 0.5 μM의 플루옥세틴 및 200 μM의 우르소데옥시콜산을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 19).As a result, as shown in FIG. 19, 0.5 μM of efavirenz and 0.5 μM of efavirenz and 0.5 μM of pancreatic cancer cells were treated alone than when 0.5 μM of efavirenz, 0.5 μM of fluoxetine, or 200 μM of ursodeoxycholic acid were treated alone. When fluoxetine and 200 μM of ursodeoxycholic acid were co-treated, it was confirmed that a synergistic effect showing a remarkably high growth inhibition appeared (FIG. 19).
<실시예 9> 바이구아나이드(biguanide) 계열 화합물, 치아졸리딘디온 계열 화합물 및 담즙산의 항암 활성 확인<Example 9> Confirmation of anticancer activity of biguanide-based compounds, thiazolidinedione-based compounds and bile acids
<9-1> 대장암에서 메트포르민, 피오글리타존 및 우르소데옥시콜산의 항암 활성 확인<9-1> Confirmation of anticancer activity of metformin, pioglitazone and ursodeoxycholic acid in colorectal cancer
바이구아나이드 계열 화합물, 치아졸리딘디온 계열 화합물 및 담즙산의 항암 활성을 알아보기 위하여, 대장암 세포에 바이구아나이드 계열 화합물로 메트포르민, 치아졸리딘디온 계열 화합물로 피오글리타존 및 담즙산으로 우르소데옥시콜산을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of biguanide-based compounds, 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.
구체적으로, 대장암 세포주인 HCT116 세포주를 100 mm 배양 접시(culture dish)에서 DMEM-10% FBS을 사용하여 5% CO 2, 37℃에서 배양한 후, 96 웰플레이트(well plate)의 각 웰에 20% 컨플루언스(confluence)로 접종하고 24시간 배양하였다. 메트포르민을 2.5 mM 농도로, 피오글리타존을 10 μM 농도로, 우르소데옥시콜산을 20 μM 농도로 단독 또는 병용처리하고, CO 2 인큐베이터(incubator)에서 24시간 동안 배양하였다. 각 웰에서 배양액을 제거하고, 새 배양액 100 μl을 가한 후, 10 μl의 12 mM MTT 스탁(stock) 용액 (5 mg MTT/PBS)을 가하고 2시간 동안 37℃에서 배양하였다. 이후 반응정지용액인 SDS-HCl용액 (1 g SDS/10 ml 0.01 M HCl) 100 μl을 가하고 4시간 동안 37℃에서 배양하고, 마이크로플레이트 리더(microplate leader)를 사용하여 570 nM에서 OD를 측정하였다. 약물을 처리하지 않은 세포의 OD와 비교하여 % growth inhibition을 계산하였다(도 20).Specifically, 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 μM, and ursodeoxycholic acid at a concentration of 20 μM 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 μl of a fresh culture medium was added, and 10 μl of a 12 mM MTT stock solution (5 mg MTT/PBS) was added and incubated at 37° C. for 2 hours. Then, 100 μl 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).
그 결과, 도 20에 나타낸 바와 같이, 대장암 세포에 2.5 mM의 메트포르민, 10 μM의 피오글리타존 또는 20 μM의 우르소데옥시콜산 각각을 단독으로 처리한 경우보다 2.5 mM의 메트포르민, 10 μM의 피오글리타존 및 20 μM의 우르소데옥시콜산을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 20).As a result, as shown in FIG. 20 , 2.5 mM of metformin, 10 μM of pioglitazone and 20 It was confirmed that a synergistic effect showing a remarkably high growth inhibition was confirmed when the μM ursodeoxycholic acid was co-treated (FIG. 20).
<9-2> 췌장암에서 메트포르민, 피오글리타존 및 우르소데옥시콜산의 항암 활성 확인<9-2> Confirmation of anticancer activity of metformin, pioglitazone and ursodeoxycholic acid in pancreatic cancer
바이구아나이드 계열 화합물, 치아졸리딘디온 계열 화합물 및 담즙산의 항암 활성을 알아보기 위하여, 췌장암 세포에 바이구아나이드 계열 화합물로 메트포르민, 치아졸리딘디온 계열 화합물로 피오글리타존 및 담즙산으로 우르소데옥시콜산을 처리하고 MTT 분석을 수행하여 성장억제(growth inhibition)를 확인하였다.In order to investigate the anticancer activity of biguanide-based compounds, thiazolidinedione-based compounds and bile acids, 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.
구체적으로, 췌장암 세포주 ASPC-1 세포를 이용하여 상기 실시예 <9-1>에 기재된 방법과 동일한 방법으로 MTT 분석을 수행하였다. 이때 약물을 처리하고 24시간 동안 배양하였다(도 21).Specifically, 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).
그 결과, 도 21에 나타낸 바와 같이, 췌장암 세포에 2.5 mM의 메트포르민, 10 μM의 피오글리타존 또는 20 μM의 우르소데옥시콜산 각각을 단독으로 처리한 경우보다 2.5 mM의 메트포르민, 10 μM의 피오글리타존 및 20 μM의 우르소데옥시콜산을 병용처리한 경우 현저하게 높은 성장억제를 보여주는 상승효과가 나타남을 확인하였다(도 21).As a result, as shown in FIG. 21 , 2.5 mM of metformin, 10 μM of pioglitazone, and 20 μM of 2.5 mM metformin, 10 μM of pioglitazone, and 20 μM of pancreatic cancer cells were compared with the case of treating pancreatic cancer cells alone with 2.5 mM of metformin, 10 μM of pioglitazone, or 20 μM of ursodeoxycholic acid alone. When ursodeoxycholic acid of ursodeoxycholic acid was co-treated, it was confirmed that a synergistic effect showing a remarkably high growth inhibition was observed (FIG. 21).
결론적으로 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염 중 2종의 화합물 조합으로 바이구아나이드 계열 화합물과 담즙산, 이의 유도체 또는 담즙산 염의 조합, 또는 바이구아나이드 계열 화합물과 항바이러스의 조합을 병용처리 시 정상세포의 성장에는 적은 영향을 미치면서 여러 종류의 암세포에서는 탁월한 암세포 성장억제 효과를 보여주었다.In conclusion, 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.
또한, 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염 중 3종의 화합물 조합으로 바이구아나이드 계열 화합물, 항바이러스제 및 담즙산의 조합, 바이구아나이드 계열 화합물, 항바이러스제 및 치아졸리딘디온 계열 화합물의 조합, 항바이러스제, 항우울제 및 담즙산의 조합, 또는 바이구아나이드 계열 화합물, 치아졸리딘디온 계열 화합물 및 담즙산의 조합을 병용처리 시 정상세포의 성장에는 적은 영향을 미치면서 여러 종류의 암세포에서는 탁월한 암세포 성장억제 효과를 보여주었다.In addition, 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.
따라서, 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염 중 2종 이상의 화합물은 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서, 암의 예방 또는 치료용 약학적 조성물의 유효성분으로 유용하게 이용될 수 있다.Accordingly, 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. As 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.
본 발명은 담즙산 또는 이의 유도체, 바이구아나이드(biguanide) 계열 화합물 및 항바이러스제 중 2종 이상을 유효성분으로 함유하는 암 예방 또는 치료용 약학적 조성물에 관한 것으로, 부작용이 적고 항암 효과가 우수하여 암 예방 또는 치료에 유용하게 사용될 수 있다. 또한, 본 발명은 담즙산 또는 이의 유도체, 바이구아나이드 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염 중 2종 이상을 유효성분으로 함유하는 암 예방 또는 치료용 약학적 조성물에 관한 것으로, 부작용이 적고 항암 효과가 우수하여 암 예방 또는 치료에 유용하게 사용될 수 있다. 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. In addition, 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 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.

Claims (24)

  1. 암의 예방 또는 치료에 사용하기 위한 복합, 혼합 또는 병용제제로서,As a combination, combination or combination preparation for use in the prevention or treatment of cancer,
    담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 유효성분으로 함유하는, Contains 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 as active ingredients doing,
    암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer.
  2. 제1항에 있어서,According to claim 1,
    바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제 1 성분; 및 A first component comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and
    담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제 2 성분을 유효성분으로 함유하는, 약학적 조성물.A pharmaceutical composition comprising a second component comprising a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof as an active ingredient.
  3. 제1항에 있어서,According to claim 1,
    바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제 1 성분; 및 A first component comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and
    항바이러스제를 포함하는 제 2 성분을 유효성분으로 함유하는, 약학적 조성물.A pharmaceutical composition comprising a second component comprising an antiviral agent as an active ingredient.
  4. 제1항에 있어서,According to claim 1,
    항바이러스제를 포함하는 제 1 성분; 및 a first component comprising an antiviral agent; and
    담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제 2 성분을 유효성분으로 함유하는, 약학적 조성물.A pharmaceutical composition comprising a second component comprising a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 제2항 내지 제4항 중 어느 한 항에 있어서,5. The method according to any one of claims 2 to 4,
    항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물을 포함하는 제 3 성분이 유효성분으로 더 추가되는 것인, 약학적 조성물.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 further added as an active ingredient, a pharmaceutical composition.
  6. 제1항에 있어서, 담즙산 또는 담즙산 유도체는 콜산(cholic acid) 계열 화합물 또는 이의 유도체인, 약학적 조성물.The pharmaceutical composition according to claim 1, wherein the bile acid or the bile acid derivative is a cholic acid-based compound or a derivative thereof.
  7. 제6항에 있어서, 7. The method of claim 6,
    콜산(cholic acid) 계열 화합물 또는 이의 유도체는 콜산(cholic acid), 케노데옥시콜산(chenodeoxycholic acid), 데옥시콜산(deoxycholic acid), 우르소데옥시콜산(ursodeoxycholic acid), 리토콜산(lithocholic acid), 글리코콜산(glycocholic acid), 타우로콜산(taurocholic acid), 글리코케노데옥시콜산(Glycochenodeoxycholic acid), 글리코데옥시콜산(glycodeoxycholic acid), 타우로데옥시콜산(taurodeoxycholic acid), 글리코우르소데옥시콜산(glycoursodeoxycholic acid), 타우로우르소데옥시콜산(tauroursodeoxycholic acid), 글리코리토콜산(glycolithocholic acid) 및 타우로리토콜산(taurolithocholic acid)으로 구성된 그룹에서 선택되는 것인, 약학적 조성물.Cholic acid-based compounds or derivatives thereof include cholic acid, chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid, and lithocholic acid. , glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid (glycoursodeoxycholic acid), tauroursodeoxycholic acid (tauroursodeoxycholic acid), glycolithocholic acid (glycolithocholic acid) and taurolithocholic acid (taurolithocholic acid) that is selected from the group consisting of, the pharmaceutical composition.
  8. 제6항에 있어서, 7. The method of claim 6,
    콜산 계열 화합물 또는 이의 유도체는 하기 화학식 1의 화합물인, 약학적 조성물:The cholic acid-based compound or derivative thereof is a compound of Formula 1 below, a pharmaceutical composition:
    [화학식 1][Formula 1]
    Figure PCTKR2021001785-appb-img-000038
    Figure PCTKR2021001785-appb-img-000038
    [상기 식에서,[In the above formula,
    R 1 및 R 2는 각각 독립적으로 H 또는 OH이고, R 3은 OH, NHCH 2COOH, 또는 NH(CH 2) 2SO 2OH이다.]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.]
  9. 제8항에 있어서, 9. The method of claim 8,
    R 1은 H이고, R 2 및 R 3는 OH;R 1 is H, R 2 and R 3 are OH;
    R 1 및 R 3는 OH이고, R 2는 H;R 1 and R 3 are OH, R 2 is H;
    R 1, R 2 및 R 3는 OH; 또는R 1 , R 2 and R 3 are OH; or
    R 1 및 R 2는 H이고, R 3는 OH인 것인, 약학적 조성물.R 1 and R 2 are H and R 3 is OH.
  10. 제8항에 있어서, 9. The method of claim 8,
    R 1은 H, R 2는 OH, R 3는 NHCH 2COOH, 또는 NH(CH 2) 2SO 2OH;R 1 is H, R 2 is OH, R 3 is NHCH 2 COOH, or NH(CH 2 ) 2 SO 2 OH;
    R 1은 OH, R 2는 H, R 3는 NHCH 2COOH, 또는 NH(CH 2) 2SO 2OH;R 1 is OH, R 2 is H, R 3 is NHCH 2 COOH, or NH(CH 2 ) 2 SO 2 OH;
    R 1 및 R 2는 OH이고, R 3는 NHCH 2COOH, 또는 NH(CH 2) 2SO 2OH; 또는R 1 and R 2 are OH and R 3 is NHCH 2 COOH, or NH(CH 2 ) 2 SO 2 OH; or
    R 1 및 R 2는 H이고, R 3는 NHCH 2COOH, 또는 NH(CH 2) 2SO 2OH인 것인, 약학적 조성물.R 1 and R 2 are H, and R 3 is NHCH 2 COOH, or NH(CH 2 ) 2 SO 2 OH.
  11. 제1항에 있어서, According to claim 1,
    담즙산 또는 담즙산 유도체는 하기 화학식 2 내지 9의 화합물로 이루어진 그룹에서 선택되는 것인, 약학적 조성물:A pharmaceutical composition, wherein the bile acid or bile acid derivative is selected from the group consisting of compounds of formulas 2 to 9:
    [화학식 2][Formula 2]
    Figure PCTKR2021001785-appb-img-000039
    Figure PCTKR2021001785-appb-img-000039
    [상기 식에서, [In the above formula,
    R은 COCH 3, COC 6H 5, CH 2C 6H 5 또는 CH 2OCH 3이다.]R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ]
    [화학식 3][Formula 3]
    Figure PCTKR2021001785-appb-img-000040
    Figure PCTKR2021001785-appb-img-000040
    [상기 식에서, [In the above formula,
    R은 COCH 3, COC 6H 5, CH 2C 6H 5 또는 CH 2OCH 3이다.]R is COCH 3 , COC 6 H 5 , CH 2 C 6 H 5 or CH 2 OCH 3 ]
    [화학식 4][Formula 4]
    Figure PCTKR2021001785-appb-img-000041
    Figure PCTKR2021001785-appb-img-000041
    [상기 식에서, [In the above formula,
    R은 H 또는 CN이다.]R is H or CN.]
    [화학식 5][Formula 5]
    Figure PCTKR2021001785-appb-img-000042
    Figure PCTKR2021001785-appb-img-000042
    [상기 식에서,[In the above formula,
    R 1 및 R 2는 각각 독립적으로 H, CH 3CO 또는 CH 3SO 3이다.]R 1 and R 2 are each independently H, CH 3 CO or CH 3 SO 3 ]
    [화학식 6][Formula 6]
    Figure PCTKR2021001785-appb-img-000043
    Figure PCTKR2021001785-appb-img-000043
    [상기 식에서,[In the above formula,
    R은 H, CH 3, CH 3CH 2 또는 CH 3CH 2CH 2CH 2이다.]R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ]
    [화학식 7][Formula 7]
    Figure PCTKR2021001785-appb-img-000044
    Figure PCTKR2021001785-appb-img-000044
    [상기 식에서,[In the above formula,
    R은 H, CH 3CO 또는 CH 3SO 3이다.]R is H, CH 3 CO or CH 3 SO 3 ]
    [화학식 8][Formula 8]
    Figure PCTKR2021001785-appb-img-000045
    Figure PCTKR2021001785-appb-img-000045
    [상기 식에서,[In the above formula,
    R은 H, CH 3, CH 3CH 2 또는 CH 3CH 2CH 2CH 2이다.]R is H, CH 3 , CH 3 CH 2 or CH 3 CH 2 CH 2 CH 2 ]
    [화학식 9][Formula 9]
    Figure PCTKR2021001785-appb-img-000046
    Figure PCTKR2021001785-appb-img-000046
    [상기 식에서,[In the above formula,
    R은 NH(CH 2) 2COOC 10H 14, NHCH(CH 2C 6H 5)COOC 4H 9 또는 NH(CH 2) 2COOC 4H 9이다.]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 ]
  12. 제1항에 있어서,According to claim 1,
    바이구아나이드 계열 화합물은 메트포르민(metformin), 펜포르민(phenformin), 부포르민(buformin) 및 바이구아나이드(biguanide)로 구성된 그룹에서 선택되는 것인, 약학적 조성물.The biguanide-based compound is selected from the group consisting of metformin, phenformin, buformin and biguanide, a pharmaceutical composition.
  13. 제1항에 있어서,According to claim 1,
    항바이러스제는 비뉴클레오시드 역전사 효소 억제제(NNRTIs; Non-nucleoside reverse-transcriptase inhibitors), 뉴클레오시드 역전사 효소 저해제(NRTIs; Nucleoside reverse-transcriptase inhibitors), 단백분해효소 억제제(PIs; Protease inhibitors), 통합효소억제제(INSTI; Integrase Strand Transfer Inhibitor), 융합 억제제, CCR 5(Chemokine (C-C motif) ligand 5) 억제제, 독감 치료제, 헤르페스 치료제, B형간염 치료제, C형간염 치료제, 면역 증강제, 면역반응 조절제 계열 화합물 또는 이의 유도체, 또는 이의 약학적으로 허용되는 염인, 약학적 조성물.Antiviral agents include non-nucleoside reverse-transcriptase inhibitors (NNRTIs), nucleoside reverse-transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and integrase inhibitors. Inhibitor (INSTI; Integrase Strand Transfer Inhibitor), fusion inhibitor, CCR 5 (Chemokine (CC motif) ligand 5) inhibitor, flu treatment, herpes treatment, hepatitis B treatment, hepatitis C treatment, immune enhancer, immune response modulator-type compound Or a derivative thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition.
  14. 제13항에 있어서, 14. The method of claim 13,
    항바이러스제는 에파비렌즈(efavirenz), 에트라비린(etravirine), 네비라핀(nevirapine), 도라비린(doravirine), 릴피비린(rilpivirine), 델라비르딘(delavirdine), 지도부딘(zidovudine), 디다노신(didanosine), 잘시타빈(zalcitabine), 스타부딘(stavudine), 라미부딘(lamivudine), 아바카비어(abacavir), 테노포비르 디소프록시 푸마레이트(tenofovir disoproxil fumarate), 엠트리시타빈(emtricitabine), 테노포비르 알라페나미드 푸마레이트(tenofovir alafenamide fumarate), 사퀴나비르(saquinavir), 리토나비르(ritonavir), 인디나비르(indinavir), 넬피나비르(nelfinavir), 암프레나비르(amprenavir), 로비나비르(lopinavir), 아타자나비르(atazanavir), 포삼프레나비르(fosamprenavir), 티프라나비르(tipranavir), 다루나비르(darunavir), 코비시스타트(cobicistat), 돌루테그라비르(dolutegravir), 랄테그라비르(raltegravir), 엔푸버타이드(enfuvirtide), 마라비록(maraviroc), 엘비테그라비르(elvitegravir), 테노포비르 알라페나미드(tenofovir alafenamide), 테노포비르 디소프록실(tenofovir disoproxil), 아만타딘(amantadine), 리만타딘(rimantadine), 오셀타미비르(oseltamivir), 자나미비르(zanamivir), 페라미비르(peramivir), 발록사비르(baloxavir), 라니나미비어(laninamivir), 아시클로비르(aciclovir), 발라시클로비르(valaciclovir), 이독스우리딘(idoxuridine), 비다라빈(vidarabine), 펜시클로비르(penciclovir), 팜시클로비르(famciclovir), 트리플루리딘(trifluridine), 시도포비어(cidofovir), 포스카넷(foscarnet), 클레부딘(clevudine), 텔비부딘(telbivudine), 엔테카비르(entecavir), 아데포비르(adefovir), 베시포비르(besifovir), 페그인터페론 알파 2a(peginterferon-α-2a), 페그인터페론 알파 2b(peginterferon-α-2b), 리바비린(ribavirin), 보세프레비르(boceprevir), 다사부비르(dasabuvir), 다클라타스비르(daclatasvir), 아수나프레비르(asunaprevir), 소포스부비르(sofosbuvir), 엘바스비르(elbasvir), 그라조프레비르(grazoprevir), 글레카프레비르(glecaprevir), 피브렌타스비르(pibrentasvir), 옴비타스비르(ombitasvir), 파리타프레비르(paritaprevir), 인터페론알파 2a(interferon alfa-2a), 인터페론알파 2b(interferon alfa-2b) 및 이미퀴모드(imiquimod)로 구성된 그룹에서 선택된 1종 이상의 화합물인, 약학적 조성물.Antiviral drugs include efavirenz, etravirine, nevirapine, doravirine, rilpivirine, delavirdine, zidovudine, didanosine ( didanosine), zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil fumarate, emtricitabine, tenofovir alafenamide fumarate, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, robinavir ( lopinavir), atazanavir, fosamprenavir, tipranavir, darunavir, cobicistat, dolutegravir, raltegravir (raltegravir), enfuvirtide, maraviroc, elvitegravir, tenofovir alafenamide, tenofovir disoproxil, amantadine ), rimantadine, oseltamivir, zanamivir, peramivir, baloxavir, laninamivir, acyclovir, valaciclovir, idoxuridine, vidarabine, penciclovir, famciclovir, Trifluridine, cidofovir, foscarnet, clevudine, telbivudine, entecavir, adefovir, besifovir , peginterferon alfa 2a (peginterferon-α-2a), peginterferon alfa 2b (peginterferon-α-2b), ribavirin, boceprevir, dasabuvir, daclatasvir ), asunaprevir, sofosbuvir, elbasvir, grazoprevir, glecaprevir, pibrentasvir, ombitas At least one compound selected from the group consisting of ombitasvir, paritaprevir, interferon alfa-2a, interferon alfa-2b and imiquimod, pharmaceutical composition.
  15. 제5항에 있어서, 6. The method of claim 5,
    제 3 성분은 아미트리프틸린(amitriptyline), 노르트립틸린(nortriptyline), 클로미프라민(clomipramine), 이미프라민(imipramine), 아목사핀(amoxapine), 플루옥세틴(fluoxetine), 파록세틴(paroxetine), 플루복사민(fluvoxamine), 설트랄린(sertraline), 에스시탈로프람(escitalopram), 보티옥세틴(vortioxetine), 모클로베미드(moclobemide), 둘록세틴(duloxetine), 벤라팍신(venlafaxine), 데스벤라팍신(desbenlafaxine), 밀나시프란(milnacipran), 부프로피온(bupropion), 미르타자핀(mirtazapine), 트라조돈(trazodone), 티아넵틴(tianeptine), 피오글리타존(pioglitazone), 로베글리타존(lobeglitazone), 로시글리타존(rosiglitazone), 시글리타존(ciglitazone), 다르글리타존(darglitazone), 엔글리타존(englitazone), 네토글리타존(netoglitazone), 리보글리타존(rivoglitazone), 트로글리타존(troglitazone), 및 밸라글리타존(balaglitazone)으로 구성된 그룹에서 선택되는 것인, 약학적 조성물.The third ingredient is amitriptyline, nortriptyline, clomipramine, imipramine, amoxapine, fluoxetine, paroxetine, fluvoxamine, sertraline, escitalopram, vortioxetine, moclobemide, duloxetine, venlafaxine, des Venlafaxine, milnacipran, bupropion, mirtazapine, trazodone, tianeptine, pioglitazone, lobeglitazone, lobeglitazone (rosiglitazone), ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and ballagl Which is selected from the group consisting of litazone (balaglitazone), a pharmaceutical composition.
  16. 제1항에 있어서,According to claim 1,
    암은 (A) (1) 정위치 도관 암종(DCIS)(면포 암종, 사상, 유두, 미세유두), 침윤 도관 암종(IDC), 관 암종, 점액(콜로이드성) 암종, 유두 암종, 화생 암종 및 염증성 암종을 비롯한 도관 암종; (2) 정위치 소엽 암종(LCIS) 및 침윤성 소엽 암종을 비롯한 소엽 암종; 및 (3) 유두의 파제트 질환을 비롯한 유방 암; (B) (1) 자궁경부 상피내 종양(등급 I), 자궁경부 상피내 종양(등급 II), 자궁경부 상피내 종양(등급 III)(정위치 편평 세포 암종), 각화성 편평 세포 암종, 비각화성 편평 세포 암종, 사마귀모양암종, 정위치 선암종, 정위치 선암종, 자궁경내막 타입, 자궁내막양 선암종, 투명 세포 선암종, 선상피 암종, 선낭 암종, 소 세포 암종 및 미분화 암종을 비롯한 자궁경부의 암; (2) 자궁내막양 암종, 선암종, 선극세포종(편평 상피화생을 갖는 선암종), 선상피 암종(혼합 선암종 및 편평 세포 암종, 점액 선암종, 장액 선암종, 투명 세포 선암종, 편평 세포 선암종 및 미분화 선암종을 비롯한 자궁체의 암; (3) 장액성 낭선종, 장액 낭선종, 점액 낭선종, 점액 낭선종, 자궁내막양 종양, 자궁내막양 선암종, 투명 세포 종양, 투명 세포 낭선종 및 미분류 종양을 비롯한 난소의 암; (4) 편평 세포 암종 및 선암종을 비롯한 질의 암; 및 (5) 외음부 상피내 종양(등급 I), 외음부 상피내 종양(등급 II), 외음부 상피내 종양(등급 III)(정위치 편평 세포 암종); 편평 세포 암종, 사마귀모양암종, 음문의 파제트 질환, 선암종(NOS), 기저 세포 암종(NOS) 및 바르톨린선 암종을 비롯한 외음부의 암을 포함한 여성 생식계의 암; (C) (1) 편평 세포 암종을 비롯한 음경의 암; (2) 전립선의 선암종, 육종 및 이행 세포 암종을 비롯한 전립선의 암; (3) 정상피종 종양, 비정상피종 종양, 기형종, 배아 암종, 난황낭 종양 및 융모막암종을 비롯한 고환의 암을 포함한 남성 생식계의 암; (D) 육종(혈관육종, 섬유육종, 횡문근육종, 지방육종), 점액종, 횡문근종, 섬유종, 지방종 및 기형종을 비롯한 심장계의 암; (E) 후두의 편평 세포 암종, 원발성 흉막 중피종 및 인두의 편평 세포 암종을 비롯한 호흡계의 암; (F) 편평 세포 암종(표피모양 암종), 편평 세포 암종의 변형, 방추 세포 암종, 소 세포 암종, 기타 세포의 암종, 중간 세포 타입의 암종, 복합 귀리 세포 암종, 선암종, 세엽 선암종, 유두 선암종, 기관지폐포 암종, 점액 형성 고형 암종, 거대 세포 암종, 거대 세포 암종, 투명 세포 암종 및 육종을 비롯한 폐의 암; (G) (1) 원발성 선암종, 카르시노이드 종양 및 림프종을 비롯한 바터(Vater) 팽대부의 암; (2) 선암종, 편평 세포 암종 및 흑색종을 비롯한 항문관의 암; (3) 정위치 암종, 선암종, 유두 선암종, 선암종, 창자형, 점액 선암종, 투명 세포 선암종, 반지 세포 암종, 선상피 암종, 편평 세포 암종, 소 세포(귀리) 암종, 미분화 암종, 암종(NOS), 육종 및 카르시노이드 종양을 비롯한 간외 담관의 암; (4) 정위치 선암종, 선암종, 점액 선암종(콜로이드형; 50% 초과의 점액 암종), 반지 세포 암종(50% 초과의 반지 세포), 편평 세포(표피모양) 암종, 선상피 암종, 소 세포(귀리 세포) 암종, 미분화 암종, 암종(NOS), 육종, 림프종 및 카르시노이드 종양을 비롯한 결장 및 직장의 암; (5) 편평 세포 암종, 선암종, 평활근육종 및 림프종을 비롯한 식도의 암; (6) 선암종, 선암종, 창자형, 선상피 암종, 정위치 암종, 암종(NOS), 투명 세포 선암종, 점액 선암종, 유두 선암종, 반지 세포 암종, 소 세포(귀리 세포) 암종, 편평 세포 암종 및 미분화 암종을 비롯한 담낭의 암; (7) 편평 세포 암종을 비롯한 입술 및 구강의 암; (8) 간암(간세포 암종), 담관암종, 간모세포종, 혈관육종, 간세포 선종 및 혈관종을 비롯한 간의 암; (9) 관 세포 암종, 다형태 거대 세포 암종, 거대 세포 암종, 오스테오클라스토이드(osteoclastoid)형, 선암종, 선상피 암종, 점액(콜로이드) 암종, 낭선종, acinar 세포 암종, 유두 암종, 소 세포(귀리 세포) 암종, 혼합 세포형, 암종(NOS), 미분화 암종, 랑게르한스 도세포에서 발생하는 내분비 세포 종양 및 카르시노이드를 비롯한 외분비선 췌장의 암; (10) 세엽(샘꽈리) 세포 암종, 선낭 암종(원주종), 선암종, 편평 세포 암종, 다형태 선종에서의 암종(악성 혼합 종양), 점막표피모양 암종(잘 분화된 또는 낮은 등급) 및 점막표피모양 암종(불량하게 분화되거나 또는 높은 등급)을 비롯한 타액선의 암; (11) 선암종, 유두 선암종, 관상 선암종, 점액 선암종, 반지 세포 암종, 선상피 암종, 편평 세포 암종, 소 세포 암종, 미분화 암종, 림프종, 육종 및 카르시노이드 종양을 비롯한 위의 암; 및 (12) 선암종, 림프종, 카르시노이드 종양, 카포시 육종, 평활근종, 혈관종, 지방종, 신경섬유종증 및 섬유종을 비롯한 소장의 암을 포함한 위장관의 암; (H) (1) 신장 세포 암종, 벨리니 집합관의 암종, 선암종, 유두 암종, 관상 암종, 과립 세포 암종, 투명 세포 암종(신선암), 신장의 육종 및 신장모세포종을 비롯한 신장의 암; (2) 이행 세포 암종, 유두 이행 세포 암종, 편평 세포 암종 및 선암종을 비롯한 신우 및 요관의 암; (3) 이행 세포 암종, 편평 세포 암종 및 선암종을 비롯한 요도의 암; 및 (4) 정위치 암종, 이행 요로상피 세포 암종, 유두 이행 세포 암종, 편평 세포 암종, 선암종, 미분화를 비롯한 방광의 암을 포함한 비뇨기계의 암; (I) (1) (a) 골형성: 골육종; (b) 연골-형성: 연골육종 및 중간엽 연골육종; (c) 거대 세포 종양, 악성; (d) 유잉 육종; (e) 혈관 종양: 혈관내피종, 혈관주위세포종 및 혈관육종; (f) 결합 조직 종양: 섬유육종, 지방육종, 악성 간엽종 및 미분화 육종; 및 (g) 기타 종양: 척삭종 및 장골의 범랑종을 비롯한 골의 암; (2) 폐포 연질부 육종, 혈관육종, 상피모양 육종, 골외성 연골육종, 섬유육종, 평활근육종, 지방육종, 악성 섬유 조직구종, 악성 혈관주위세포종, 악성 간엽종, 악성 슈반세포종, 횡문근육종, 활액 육종 및 육종(NOS)을 비롯한 연조직의 암; (3) 두개골의 암(골종, 혈관종, 육아종, 황색종, 변형성 골염), 수막의 암(수막종, 수막육종, 신경교종증), 뇌의 암(별아교세포종, 속질모세포종, 신경아교종, 뇌실막세포종, 종자세포종(솔방울샘종), 다형성아교모세포종, 희소돌기아교세포종, 슈반세포종, 망막모세포종, 선천성 종양) 및 척수의 암(신경섬유종증, 수막종, 신경아교종, 육종)을 비롯한 신경계의 암; (4) 골수성 백혈병(급성 및 만성), 급성 림프모구 백혈병, 만성 림프구 백혈병, 골수증식 질환, 다발성 골수종; 골수형성이상 증후군), 호지킨병 및 비-호지킨 림프종(악성 림프종)을 비롯한 혈액암; (5) (a) 유두 암종(소포 부위의 것 포함), 소포 암종, 속질 암종 및 미분화(역형성) 암종을 비롯한 갑상선의 암; 및 (b) 교감신경모세포종, 교감신경원세포종, 악성 신경절신경종, 신경절교감신경모세포종 및 신경절신경종을 비롯한 신경모세포종을 포함하는 내분비계의 암; (6) 편평 세포 암종, 편평 세포 암종의 방추 세포 변형, 기저 세포 암종, 한선 또는 피지선으로부터 발생된 선암종 및 악성 흑색종을 비롯한 피부의 암; (7) (a) 결막의 암종을 비롯한 결막의 암; (b) 기저 세포 암종, 편평 세포 암종, 안검의 흑색종 및 피지 세포 암종을 비롯한 안검의 암; (c) 선암종, 선낭 암종, 다형태 선종에서의 암종, 점액표피모양 암종 및 편평 세포 암종을 비롯한 누선의 암; (d) 방추 세포 흑색종, 혼합 세포 흑색종 및 상피모양 세포 흑색종을 비롯한 포도막의 암; (e) 안와의 육종, 연조직 종양 및 골의 육종을 비롯한 안와의 암; 및 (f) 망막모세포종을 포함한 눈의 암을 포함한 근육, 골 및 연조직의 암으로 구성된 그룹에서 선택되는 것인, 약학적 조성물.Cancers include: (A) (1) orthostatic ductal carcinoma (DCIS) (comedonal carcinoma, filamentous, papillary, micropapillary), infiltrating ductal carcinoma (IDC), ductal carcinoma, mucinous (colloidal) carcinoma, papillary carcinoma, metaplastic carcinoma and ductal carcinoma, including inflammatory carcinoma; (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, endometrial type, endometrioid adenocarcinomas, clear cell adenocarcinomas, glandular carcinomas, adenocystic carcinomas, small cell carcinomas and undifferentiated carcinomas; (2) uterus including endometrioid carcinoma, adenocarcinoma, adenoblastoma (adenocarcinoma with squamous metaplasia), glandular carcinoma (mixed adenocarcinoma and squamous cell carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, clear cell adenocarcinoma, squamous cell adenocarcinoma and undifferentiated adenocarcinoma) Cancers of the body: (3) cancers of the ovaries, including serous cystadenomas, serous cystadenomas, mucinous cystadenomas, mucinous cystadenomas, endometrioid tumors, endometrioid adenocarcinomas, clear cell tumors, clear cell cystadenomas and unclassified tumors; (4) squamous tumors; cancers of the vagina, including cell carcinoma and adenocarcinoma; and (5) vulvar intraepithelial tumors (grade I), vulvar intraepithelial tumors (grade II), vulvar intraepithelial tumors (grade III) (squamous cell carcinoma in situ); Cancers of the female reproductive system, including cancers of the vulva, including carcinoma, Paget's disease of the vulva, adenocarcinoma (NOS), basal cell carcinoma (NOS) and Bartholin's adenocarcinoma; (C) (1) cancer of the penis, including squamous cell carcinoma (2) cancers of the prostate, including adenocarcinomas, sarcomas, and transitional cell carcinomas of the prostate; (D) cancers of the heart system including sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; (E) squamous cell carcinoma of the larynx, primary pleura Cancers of the respiratory system, including mesothelioma and squamous cell carcinoma of the pharynx; Cancer of the lung, including complex oat cell carcinoma, adenocarcinoma, acinar adenocarcinoma, papillary adenocarcinoma, bronchoalveolar carcinoma, mucinous solid carcinoma, giant cell carcinoma, giant cell carcinoma, clear cell carcinoma and sarcoma; (G) (1) primary adenocarcinoma; Cancers of the ampulla of Vater, including carcinoid tumors and lymphomas; (2) cancers of the anal canal, including adenocarcinomas, squamous cell carcinomas and melanomas; (3) orthostatic carcinomas, adenocarcinomas, papillary carcinomas; Extrahepatic bile ducts including adenocarcinoma, adenocarcinoma, intestinal type, mucinous adenocarcinoma, clear cell adenocarcinoma, ring cell carcinoma, adenoid carcinoma, squamous cell carcinoma, small cell (oat) carcinoma, undifferentiated carcinoma, carcinoma (NOS), sarcoma and carcinoid tumor of cancer; (4) Orthostatic adenocarcinoma, adenocarcinoma, mucinous adenocarcinoma (colloidal; >50% mucinous carcinoma), ring cell carcinoma (greater than 50% of ring cells), squamous cell (epidermal) carcinoma, adenoid carcinoma, small cell (oat) cell) cancers of the colon and rectum, including carcinomas, undifferentiated carcinomas, carcinomas (NOS), sarcomas, lymphomas and carcinoid tumors; (5) cancers of the esophagus, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma and lymphoma; (6) adenocarcinoma, adenocarcinoma, bowel type, adenocarcinoma, orthotopic carcinoma, carcinoma (NOS), clear cell adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, ring cell carcinoma, small cell (oat cell) carcinoma, squamous cell carcinoma and undifferentiated carcinoma cancer of the gallbladder, including; (7) cancers of the lips and oral cavity, including squamous cell carcinoma; (8) cancers of the liver, including liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma; (9) ductal cell carcinoma, giant cell carcinoma multiforme, giant cell carcinoma, osteoclastoid type, adenocarcinoma, glandular carcinoma, mucinous (colloid) carcinoma, cystadenoma, acinar cell carcinoma, papillary carcinoma, small cell ( oat cells) carcinoma, mixed cell type, carcinoma (NOS), undifferentiated carcinoma, cancer of the exocrine pancreas including endocrine cell tumors arising from Langerhans islet cells and carcinoids; (10) acinar (acinar) cell carcinoma, adenocystic carcinoma (columoma), adenocarcinoma, squamous cell carcinoma, carcinoma in polymorphic adenoma (malignant mixed tumor), mucoepidermoid carcinoma (well-differentiated or low-grade) and mucosal cancers of the salivary glands, including epidermal carcinoma (poorly differentiated or high grade); (11) cancers of the stomach, including adenocarcinoma, papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, ring cell carcinoma, adenoid carcinoma, squamous cell carcinoma, small cell carcinoma, undifferentiated carcinoma, lymphoma, sarcoma and carcinoid tumor; and (12) cancers of the gastrointestinal tract, including cancers of the small intestine, including adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibromatosis and fibroma; (H) (1) cancers of the kidney, including (1) renal cell carcinoma, carcinoma of the Bellini collecting duct, adenocarcinoma, papillary carcinoma, tubular carcinoma, granular cell carcinoma, clear cell carcinoma (renal cancer), sarcoma of the kidney and nephroblastoma; (2) cancers of the renal pelvis and ureter, including transitional cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma; (3) cancers of the urethra, including transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma; and (4) cancers of the urinary system, including cancers of the bladder, including orthotopic carcinoma, transitional urothelial cell carcinoma, papillary transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, undifferentiated; (I) (1) (a) Osteogenesis: osteosarcoma; (b) cartilage-forming: chondrosarcoma and mesenchymal chondrosarcoma; (c) giant cell tumor, malignant; (d) Ewing's sarcoma; (e) vascular tumors: hemangioendothelioma, hemangiopericytoma and hemangiosarcoma; (f) connective tissue tumors: fibrosarcoma, liposarcoma, malignant mesenchymal and undifferentiated sarcoma; and (g) other tumors: cancers of the bone, including chordomas and erosions of the long bones; (2) alveolar soft sarcoma, angiosarcoma, epithelial sarcoma, extraosseous chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant hemangiopericytoma, malignant mesenchymal, malignant Schwanncytoma, rhabdomyosarcoma, cancers of soft tissues including synovial sarcoma and sarcoma (NOS); (3) Cancer of the skull (osteoma, hemangioma, granuloma, xanthomas, osteomyelitis), cancer of the meninges (meningoma, meningiosarcoma, gliomatosis), cancer of the brain (astrocytoma, meduloblastoma, glioma, ependymocytoma, seed) cancers of the nervous system, including cellomas (pineal adenoma), glioblastoma multiforme, oligodendrocytoma, Schwannoma, retinoblastoma, congenital tumors) and cancers of the spinal cord (neurofibromatosis, meningioma, glioma, sarcoma); (4) myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma; myelodysplastic syndrome), hematologic cancers including Hodgkin's disease and non-Hodgkin's lymphoma (malignant lymphoma); (5) (a) cancers of the thyroid gland, including papillary carcinomas (including those of the follicular region), follicular carcinomas, medullary carcinomas, and undifferentiated (anaplastic) carcinomas; and (b) cancers of the endocrine system, including neuroblastomas, including sympathoblastoma, sympathoblastoma, malignant ganglioneuroma, gangliosympathoblastoma and ganglioneuroma; (6) cancers of the skin, including squamous cell carcinoma, spindle cell deformation of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma arising from sweat glands or sebaceous glands, and malignant melanoma; (7) (a) cancer of the conjunctiva, including carcinoma of the conjunctiva; (b) cancers of the eyelids, including basal cell carcinoma, squamous cell carcinoma, melanoma of the eyelid and sebaceous cell carcinoma; (c) cancer of the lacrimal gland, including adenocarcinoma, adenocystic carcinoma, carcinoma in polymorphic adenoma, mucoepidermoid carcinoma and squamous cell carcinoma; (d) cancers of the uvea, including spindle cell melanoma, mixed cell melanoma and epithelial cell melanoma; (e) cancers of the orbit, including sarcomas of the orbit, soft tissue tumors, and sarcomas of the bone; and (f) cancer of the muscle, bone and soft tissue, including cancer of the eye, including retinoblastoma.
  17. 제1항에 있어서,According to claim 1,
    약학적 조성물은 정제, 캡슐제, 주사제, 트로키제, 산제, 과립제, 액제, 현탁제, 내용액제, 유제, 시럽제, 좌제, 질정제, 및 환제로 구성된 그룹에서 선택되는 제형으로 제형화되는, 약학적 조성물.The pharmaceutical composition is formulated in a dosage form selected from the group consisting of tablets, capsules, injections, troches, powders, granules, solutions, suspensions, internal solutions, emulsions, syrups, suppositories, vaginal tablets, and pills. enemy composition.
  18. 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 포함하는 제제를 함유하는,A preparation containing 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,
    암의 예방 또는 치료용 복합, 혼합 또는 병용제 키트.Combination, combination or combination kits for the prevention or treatment of cancer.
  19. 제18항에 있어서,19. The method of claim 18,
    바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제제; 및A preparation comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and
    담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제제를 함유하는, 복합, 혼합 또는 병용제 키트.A combination, mixture or combination kit containing a preparation comprising a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof.
  20. 제18항에 있어서,19. The method of claim 18,
    바이구아나이드 계열 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 제제; 및 A preparation comprising a biguanide-based compound or a pharmaceutically acceptable salt thereof; and
    항바이러스제를 포함하는 제제를 함유하는, 복합, 혼합 또는 병용제 키트.A combination, combination or combination kit containing a formulation comprising an antiviral agent.
  21. 제18항에 있어서,19. The method of claim 18,
    항바이러스제를 포함하는 제제; 및 formulations comprising antiviral agents; and
    담즙산, 담즙산 유도체 또는 이의 약학적으로 허용되는 염을 포함하는 제제를 함유하는, 복합, 혼합 또는 병용제 키트.A combination, mixture or combination kit containing a preparation comprising a bile acid, a bile acid derivative, or a pharmaceutically acceptable salt thereof.
  22. 제19항 내지 제21항 중 어느 한 항에 있어서,22. The method according to any one of claims 19 to 21,
    항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 1종 이상의 화합물을 포함하는 제제가 더 추가되는 것인, 복합, 혼합 또는 병용제 키트.An antidepressant, a thiazolidinedione-based compound, and a formulation comprising at least one compound selected from the group consisting of pharmaceutically acceptable salts thereof is further added, a complex, mixed, or combination kit.
  23. 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온(thiazolidinedione) 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 약학적으로 유효한 양으로 개체에 복합, 혼합 또는 병용 투여하는 단계를 포함하는, 암의 예방 또는 치료방법.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 pharmaceutically effective A method for preventing or treating cancer, comprising the step of administering complex, mixed or co-administered amounts to a subject.
  24. 암의 예방 및 치료용 약학적 조성물로 사용하기 위한 담즙산, 담즙산 유도체, 바이구아나이드(biguanide) 계열 화합물, 항바이러스제, 항우울제, 치아졸리딘디온 계열 화합물 및 이의 약학적으로 허용되는 염으로 구성된 그룹에서 선택된 2종 이상의 화합물을 유효성분으로 함유하는 복합, 혼합 또는 병용제제의 용도.From the group consisting of bile acids, bile acid derivatives, biguanide-based compounds, antiviral agents, antidepressants, thiazolidinedione-based compounds, and pharmaceutically acceptable salts thereof for use as a pharmaceutical composition for the prevention and treatment of cancer Use of a complex, mixed or combined preparation containing two or more selected compounds as active ingredients.
PCT/KR2021/001785 2020-02-13 2021-02-10 Pharmaceutical composition for preventing or treating cancer, containing bile acids or derivatives thereof, biguanide-based compounds, and two or more kinds of antiviral agents as active ingredients WO2021162451A1 (en)

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