Pharmaceutical composition for preventing or treating cancer comprising a naphthoquinone-based compound and an immune checkpoint inhibitor as active ingredients

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising a naphthoquinone-based compound as an active ingredient, and at least one selected from an immune checkpoint inhibitor and an immunogenic cell death inducer, and the pharmaceutical composition has a significantly stronger anticancer effect than when each preparation is applied alone. Therefore, in cancer cells where the anticancer effect is not significant when existing anticancer agents are applied alone, anticancer synergistic effects of inhibiting cancer cell growth and inhibiting cancer cell metastasis can be expected. Therefore, the composition comprising the naphthoquinone-based compound can be effectively used as a drug for preventing or treating cancer together with the immune checkpoint inhibitor and / or the immunogenic cell death inducer.

Description

Background Art

[0001] The present invention relates to a pharmaceutical composition for preventing or treating cancer, which comprises a naphthoquinone-based compound, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof or an isomer thereof as an active ingredient, and an immune checkpoint inhibitor and / or an immunogenic cell death (ICD) inducer.

[0002] Most human tumors escape the subject's immune surveillance and are therefore difficult to treat for reasons that include: 1) loss of cancer antigen expression, 2) a chronic inflammatory environment, 3) inhibition of T cell influx, 4) suppression of the antigen presenting capacity of dendritic cells by the cancer environment, and 5) the cancer immunosuppressive environment composed of immune checkpoints, immunosuppressive cytokines, and immunosuppressive cells, among others.

[0003] At the same time, the advantage of anticancer immunotherapy is that it uses the patient's own immune system to obtain long-term anti-tumor immunity with few side effects. The purpose of immunotherapy is to produce tumor-specific cytotoxic T lymphocytes (CTLs) that can recognize tumor cells or tumor antigens and eliminate tumor cells. That is, tumor antigen peptides are loaded into the major histocompatibility complex (MHC) and presented to T lymphocytes by tumor cells themselves or antigen-presenting cells to activate T lymphocytes and induce differentiation into CTLs and increase CTLs.

[0004] Recently, as a method for enhancing such anti-cancer immune responses and overcoming the immunosuppressive environment of some cancers, antibodies that inhibit immune checkpoints such as CTLA-4 and PD-1 are currently used clinically as anti-cancer agents. However, single anti-cancer immunotherapy using CTLA-4, PD-1 or PD-L1 inhibitors still has limitations, such as showing excellent effects only in specific cancers and showing therapeutic effects only in some patients (Korean Patent Publication No. 10-2020-0055116).

[0005] It is known that immune checkpoint inhibitors generally cause mild adverse reactions compared to existing cytotoxic anticancer agents or targeted therapeutics, but rarely cause fatal or permanent functional impairment, and may cause various autoimmune diseases due to their immunomodulatory effects. Among immune checkpoint inhibitors, CTLA-4 inhibitors are known to cause more adverse reactions than PD-1 inhibitors or PD-L1 inhibitors, and when CTLA-4 inhibitors and PD-1 inhibitors are used in combination, the frequency and severity of adverse reactions increase. Another problem is that when immune checkpoint inhibitors are used, not only good treatment responses are shown, but also excessive tumor progression may be caused in some patients, in which the disease condition rapidly worsens due to the sudden growth of tumors after the administration of immune checkpoint inhibitors.

[0006] As a strategy to overcome the limitations of immune checkpoint inhibitors, combined clinical trials with anticancer chemotherapy, radiotherapy and targeted therapeutic agents are being tried, which can promote the immunogenic cell death of tumor cells. Immunogenic cell death is a form of cell death in which dying cells can produce antigens in vivo to activate adaptive immunity. This immunogenic cell death can be induced by specific external stimuli such as anticancer agents or radiotherapy. Damage-associated molecular patterns (DAMPs) released by these stimulants are recognized by pathogen recognition receptors of innate or adaptive immune responses, and danger signals are delivered to the living body.

[0007] To date, six types of DAMPs (including calreticulin, ATP, high mobility group protein 1 (HMGB1), type 1 IFN, cancer cell-derived nucleic acids, and annexin A1) are known to be involved in immune-induced cell death. For example, DAMPs such as calreticulin, ATP, and HMGB1 are usually located in cells. When stimulants that promote immunogenic cell death of tumor cells are administered, new cancer antigens are exposed and DAMPs are released from cells. As a result, dendritic cells are attracted to tumor cells, which enhances the antigen presentation ability of dendritic cells, promotes the activation of T cells and infiltration into tumors, and may therefore increase the anti-tumor effects caused by immune checkpoint inhibitors (Guido Kroemer et al., Annu. Rev. Immunol., Vol. 31: pp. 51-72, 2013).

[0008] Summarize

[0009] Therefore, as a result of developing a composition and a method for treating cancer that can further effectively enhance the anti-cancer immune response, the present inventors have confirmed that naphthoquinone-based compounds exhibit excellent anti-cancer effects when administered together with immune checkpoint inhibitors and / or immunogenic cell death inducers, thereby completing the present invention.

[0010] One aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising as active ingredients: a naphthoquinone-based compound; and at least one selected from an immune checkpoint inhibitor and an immunogenic cell death inducer.

[0011] When the naphthoquinone-based compound according to the present invention is co-administered with an immune checkpoint inhibitor and / or an immunogenic cell death inducer, a significantly stronger anticancer effect is shown compared to the case where each component is administered alone. Therefore, even in cancer cells where the anticancer effect is not significant when an existing anticancer agent is administered alone, the effect of inhibiting cancer cell metastasis and inhibiting cancer cell growth can also be expected. Therefore, the composition comprising the naphthoquinone-based compound can be effectively used as a drug for preventing or treating cancer together with the immune checkpoint inhibitor and / or the immunogenic cell death inducer. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Exemplary embodiments may be understood in more detail from the following description taken in conjunction with the accompanying drawings, in which:

[0013] Figure 1 is a graph showing tumor size in a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / 5-FU: 5-fluorouracil / OX: oxaliplatin);

[0014] Figure 2 is a graph showing tumor size in a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-CTLA4: anti-CTLA4 antibody / 5-FU: 5-fluorouracil / OX: oxaliplatin);

[0015] Figure 3 is a graph showing tumor size in a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / anti-CTLA4: anti-CTLA4 antibody / 5-FU: 5-fluorouracil / OX: oxaliplatin);

[0016] Figure 4 is a graph showing tumor size in a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-LAG3: anti-LAG3 antibody / OX: oxaliplatin);

[0017] Figure 5 is a graph showing tumor size in a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody);

[0018] Figure 6 is a graph showing tumor size in a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / Rego: regorafenib);

[0019] Figure 7 is a graph showing tumor size in a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / Abe: abemaciclib);

[0020] Figure 8 is a graph showing tumor size in a colorectal cancer animal model (CT26) according to single administration or co-administration of each drug (Dun: dongnione / FOLFIRI: irinotecan+folinic acid+5-fluorouracil);

[0021] Fig. 9 is a graph showing tumor size in a colorectal cancer animal model (CT26) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody);

[0022] Fig.10 is a graph showing tumor size in a breast cancer animal model (4T1) according to single administration or co-administration of each drug (Dun: donidone / anti-CTLA4: anti-CTLA4 antibody / MIT: mitoxantrone);

[0023] Fig.11 is a graph showing tumor size in a breast cancer animal model (4T1) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / ADR: doxorubicin);

[0024] Fig.12 is a graph showing tumor size in a breast cancer animal model (4T1) according to the single administration or co-administration of each drug (Dun: donidone / ACP: doxorubicin+cyclophosphamide+paclitaxel);

[0025] Fig.13 is a graph showing tumor size in a breast cancer animal model (4T1) according to single or co-administration of each drug (Dun: donidone / TAC: docetaxel+adriamycin+cyclophosphamide);

[0026] Fig.14 is a graph showing tumor size in a breast cancer animal model (EMT6) according to single administration or co-administration of each drug (Dun: dongnidone / anti-CTLA4: anti-CTLA4 antibody / LAPA: lapatinib);

[0027] Fig.15 is a graph showing tumor size in a renal cancer animal model (RENCA) according to single administration or co-administration of each drug (Dun: donidone / anti-CTLA4: anti-CTLA4 antibody / EVE: everolimus);

[0028] Fig.16 is a graph showing the tumor size in a renal cancer animal model (RENCA) according to the single administration or co-administration of each drug (Dun: Dunidone / Sorafenib: Sorafenib);

[0029] Fig.17 is a graph showing the tumor size in a renal cancer animal model (RENCA) according to the single administration or co-administration of each drug (Dun: Dunidone / anti-CTLA4: anti-CTLA4 antibody / Sorafenib: Sorafenib);

[0030] Fig.18 is a graph showing tumor size in a renal cancer animal model (RENCA) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / EVE: everolimus);

[0031] Fig.19 is a graph showing the tumor size in a renal cancer animal model (RENCA) according to the single administration or co-administration of each drug (Dun: Dunidone / anti-CTLA4: anti-CTLA4 antibody / Sorafenib: Sorafenib);

[0032] Fig. 20 is a graph showing tumor size in a renal cancer animal model (RENCA) according to single administration or co-administration of each drug (Dun: donidone / anti-CTLA4: anti-CTLA4 antibody / VIS: velutipetide);

[0033] Fig.21 is a graph showing tumor size in a skin cancer animal model (B16F10) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-L1: anti-PD-L1 antibody);

[0034] Fig. 22 is a graph showing tumor size in a skin cancer animal model (B16F10) according to single administration or co-administration of each drug (Dun: dongnidone / anti-PD-L1: anti-PD-L1 antibody / PTX: paclitaxel);

[0035] Fig.23 is a graph showing the tumor size in a skin cancer animal model (B16F10) according to the single administration or co-administration of each drug (Dun: dongnidone / anti-CTLA4: anti-CTLA4 antibody / PTX: paclitaxel);

[0036] Fig.24is a graph showing the tumor size in a skin cancer animal model (B16F10) according to the single administration or co-administration of each drug (Dun: donidone / anti-CTLA4: anti-CTLA4 antibody / Rego: regorafenib);

[0037] Fig.25 is a graph showing the tumor size in a skin cancer animal model (B16F10) according to the single administration or co-administration of each drug (Dun. Dongnidone / anti-PD-1: anti-PD-1 antibody / VIS: Vitorinamide);

[0038] Fig.26 is a graph showing the tumor size in a skin cancer animal model (B16F10) according to the single administration or co-administration of each drug (Dun: donidone / EVE: everolimus);

[0039] Fig. 27 is a graph showing the tumor size in a skin cancer animal model (B16F10) according to the single administration or co-administration of each drug (Dun: dongnidone / anti-PD-1: anti-PD-1 antibody / EVE: everolimus);

[0040] Fig.28 is a graph showing tumor size in a liver cancer animal model (Hepa1-6) according to single administration or co-administration of each drug (Dun: dongnidone / anti-CTLA4: anti-CTLA4 antibody / SORA: sorafenib);

[0041] Fig.29 is a graph showing the tumor size in a liver cancer animal model (Hepa1-6) according to the single administration or co-administration of each drug (Dun: dongnione / anti-CTLA4: anti-CTLA4 antibody / EVE: everolimus);

[0042] Fig.30 is a graph showing tumor size in a lung cancer animal model (KLN205) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / CP: carboplatin + paclitaxel);

[0043] Fig.31 is a graph showing tumor size in a lung cancer animal model (LL / 2) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / CaPe: carboplatin + pemetrexed);

[0044] Fig.32is a photograph obtained by taking the amount of photon emission as the extent of tumor metastasis in a breast cancer metastasis animal model (4T1-luciferase) according to the single administration or co-administration of each drug (Dun: dongnidone / anti-CTLA4: anti-CTLA4 antibody / MIT: mitoxantrone / CTRL: control);

[0045] Fig.33 is a graph showing the survival rate of a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / anti-CTLA4: anti-CTLA4 antibody / 5-FU: 5-fluorouracil / OX: oxaliplatin);

[0046] Fig.34 is a graph showing the survival rate of a colorectal cancer animal model (MC38) according to single administration or co-administration of each drug (Dun: donidone / anti-PD-1: anti-PD-1 antibody / 5-FU: 5-fluorouracil);

[0047] Fig.35 Schematically shows the construction of a spontaneous non-small cell lung cancer model and the regimen of administering each drug alone or in combination (Dun: Dunidone / Anti-PD-1: Anti-PD-1 Antibody / Carboplatin: Carboplatin / Paclitaxel: Paclitaxel);

[0048] Fig.36 Schematically shows the drug administration scheme for analyzing immune-related adverse events (irAEs) according to the single administration or co-administration of each drug (Dun: Dongnione / Icilimumab: Ipilimumab / αPD-1: anti-PD-1 antibody / anti-human IgG: anti-human IgG);

[0049] Fig.37 The incidence of cardiac hypertrophy as an adverse reaction according to single administration or co-administration of each drug is shown (anti-human IgG: anti-human IgG / Ipilimumab: ipilimumab / αPD-1: anti-PD-1 antibody / Dun: Dunidone);

[0050] Fig.38 The incidence of hepatitis as an adverse reaction according to single administration or co-administration of each drug is shown (anti-human IgG: anti-human IgG / Ipilimumab: ipilimumab / αPD-1: anti-PD-1 antibody / Dun: donidone / ALT: alanine aminotransferase / AST: aspartate aminotransferase);

[0051] Fig.39The incidence of pneumonitis as an adverse reaction according to single administration or co-administration of each drug is shown (anti-human IgG: anti-human IgG / Ipilimumab: Ipilimumab / αPD-1: anti-PD-1 antibody / Dun: Dunidene);

[0052] Fig.40 The incidence of pancytopenia as an adverse reaction according to single administration or co-administration of each drug is shown (Anti-human IgG: anti-human IgG / Ipilimumab: Ipilimumab / αPD-1: anti-PD-1 antibody / Dun: Dunone / WBC: white blood cell / Monocyte: monocyte / Lymphocyte: lymphocyte / HCT: hematocrit / RBC: red blood cell / Hemoglobin: hemoglobin);

[0053] Fig.41 The drug administration scheme for analyzing immune-related adverse events according to the co-administration of each drug is schematically shown. Here, the administration of cyclophosphamide is based on metronomic anticancer therapy (Dun: Dongnione / Ipilimumab: Ipilimumab / αPD-1: anti-PD-1 antibody / CTX: cyclophosphamide / anti-human IgG: anti-human IgG);

[0054] Fig.42 The incidence of heart failure as an adverse reaction according to co-administration of each drug is shown (anti-human IgG: anti-human IgG / Ip: ipilimumab / αPD-1: anti-PD-1 antibody / Dun: dunilone / CTX: cyclophosphamide / LVIDd: left ventricular end-diastolic diameter / LVID: left ventricular end-systolic diameter / Fraction Shortening: shortening fraction / EjectionFraction: ejection fraction);

[0055] Fig.43 The degree of ovarian size reduction as an adverse reaction according to co-administration of each drug is shown (anti-human IgG: anti-human IgG / Ipilimumab: Ipilimumab / αPD-1: anti-PD-1 antibody / Dun: Dun);

[0056] Fig.44 The incidence of pneumonitis as an adverse reaction according to co-administration of each drug is shown (anti-human IgG: anti-human IgG / Ipilimumab: Ipilimumab / αPD-1: anti-PD-1 antibody / Dun: Dunidene);

[0057] Fig.45 The incidence of nephritis as an adverse reaction according to co-administration of each drug is shown (anti-human IgG: anti-human IgG / Ipilimumab: Ipilimumab / αPD-1: anti-PD-1 antibody / Dun: Dunidone); and

[0058] Fig.46 The incidence of pancytopenia as an adverse reaction according to co-administration of each drug is shown (anti-human IgG: anti-human IgG / Ip: ipilimumab / αPD-1: anti-PD-1 antibody / CTX: cyclophosphamide / Dun: donidone / WBC: white blood cell / Lymphocyte: lymphocyte / Monocyte: monocyte / RBC: red blood cell / Hemoglobin: hemoglobin). DETAILED DESCRIPTION

[0059] The present invention will be described in detail below.

[0060] One aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising as active ingredients: a naphthoquinone-based compound; and at least one selected from an immune checkpoint inhibitor and an immunogenic cell death (ICD) inducer.

[0061] An embodiment of the pharmaceutical composition may include a naphthoquinone-based compound and an immune checkpoint inhibitor. In addition, an embodiment of the pharmaceutical composition may include a naphthoquinone-based compound and an immunogenic cell death inducer. In addition, an embodiment of the pharmaceutical composition may include a naphthoquinone-based compound, an immune checkpoint inhibitor, and an immunogenic cell death inducer.

[0062] It is known that the "naphthoquinone-based compound" contained as an active ingredient of the composition provided by the present invention can be used as a component of a drug for treating various diseases, including cancer, hearing loss, diabetes, etc. For example, U.S. Patent No. 5,969,163 discloses an anticancer composition comprising a naphthoquinone-based compound, and Korean Patent No. 1739361 discloses a composition for preventing or improving metabolic diseases and comprising a naphthoquinone-based compound. However, in the case where the naphthoquinone-based compound is administered alone as an anticancer agent, the naphthoquinone-based compound will not act as a targeted therapeutic agent, and therefore there is a problem that it is difficult to avoid drug resistance or side effects caused by cytotoxicity in order to advance the treatment to a dose that causes a significant anticancer effect.

[0063] Therefore, the present inventors have endeavored to discover anticancer drugs that exhibit synergistic anticancer effects even at low doses, and have thus confirmed that when two or three drugs are co-administered by mixing a naphthoquinone-based compound with an immune checkpoint inhibitor and / or an immunogenic cell death inducer, the effect of inhibiting cancer cell proliferation is significantly increased compared to the case where each substance is administered alone, thereby completing the present invention.

[0064] The composition may be a composition comprising a naphthoquinone-based compound and an immune checkpoint inhibitor. For example, the composition may include 1 to 5, 2 to 4 or 3 immune checkpoint inhibitors and naphthoquinone-based compounds as active ingredients. In addition, the composition may be a composition comprising a naphthoquinone-based compound and an immunogenic cell death inducer. For example, the composition may include 1 to 5, 2 to 4 or 3 immunogenic cell death inducers and naphthoquinone-based compounds as active ingredients. In addition, the composition may be a composition comprising a naphthoquinone-based compound, an immune checkpoint inhibitor and an immunogenic cell death inducer. For example, the composition may include 1 to 5, 2 to 4 or 3 immune checkpoint inhibitors and immunogenic cell death inducers, and naphthoquinone-based compounds as active ingredients.

[0065] The composition can be in the form of a composite dosage form in which a naphthoquinone-based compound is mixed with at least one selected from an immune checkpoint inhibitor and an immunogenic cell death inducer. For example, the composition can be a single dosage form made by mixing a naphthoquinone-based compound and an immune checkpoint inhibitor with a pharmaceutically acceptable adjuvant, diluent or carrier. In addition, the composition can be a single dosage form made by mixing a naphthoquinone-based compound and an immunogenic cell death inducer with a pharmaceutically acceptable adjuvant, diluent or carrier. In addition, the composition can be a single dosage form made by mixing a naphthoquinone-based compound, an immune checkpoint inhibitor and an immunogenic cell death inducer with a pharmaceutically acceptable adjuvant, diluent or carrier. Here, naphthoquinone-based compounds, immune checkpoint inhibitors and immunogenic cell death inducers can each be included in various components within the scope of the corresponding drug. In addition, a single dosage form can be administered together with a separate preparation containing another therapeutic agent as a dosage form separated from such a dosage form.

[0066] In addition, the composition can be a form in which a naphthoquinone-based compound and at least one selected from an immune checkpoint inhibitor and an immunogenic cell death inducer are prepared separately and applied simultaneously or sequentially. For example, naphthoquinone-based compounds and immune checkpoint inhibitors are provided as separate pharmaceutical dosage forms, and each preparation can be applied simultaneously or at different times. In addition, naphthoquinone-based compounds and immunogenic cell death inducers are provided as separate pharmaceutical dosage forms, and each preparation can be applied simultaneously or at different times. In addition, naphthoquinone-based compounds, immune checkpoint inhibitors, and immunogenic cell death inducers are all provided as separate pharmaceutical dosage forms, and each preparation can be applied simultaneously or at different times. Here, the various components of naphthoquinone-based compounds, immune checkpoint inhibitors, and immunogenic cell death inducers within the scope of the corresponding drugs can be prepared separately and applied simultaneously or sequentially, and can be applied once or multiple times.

[0067] For example, naphthoquinone-based compounds can be dosage forms for oral administration, and can be administered once a week to 7 times a week, 2 times a week to 5 times a week, or 3 times a week. In addition, immune checkpoint inhibitors can be dosage forms for intraperitoneal administration, and can be administered daily, at intervals of 2 days, 3 days, 4 days, 5 days or 6 days, or once a week to 3 times a week. In addition, immunogenic cell death inducers can be dosage forms for oral administration or intraperitoneal administration, and can be administered daily, at intervals of 2 days, 3 days, 4 days, 5 days or 6 days, or once a week to 3 times a week. Naphthoquinone-based compounds, immune checkpoint inhibitors and immunogenic cell death inducers can be administered independently according to the scheme of each substance.

[0068] In addition, the naphthoquinone-based compound and the immune checkpoint inhibitor can be co-administered at a weight ratio of 1,000: 1 to 1: 10, 500: 1 to 1: 1, 250: 1 to 5: 1, 200: 1 to 2.5: 1, or 100: 1. In addition, the naphthoquinone-based compound and the immunogenic cell death inducer can be co-administered at a weight ratio of 5: 1 to 1: 5, 3: 1 to 1: 3, 2: 1 to 1: 2, 3: 2 to 2: 3, or 1: 0.001 to 0.001: 1. For example, based on a single dose of the composition, the naphthoquinone-based compound, the immune checkpoint inhibitor, and the immunogenic cell death inducer can be co-administered in a weight ratio of 1:(0.001 to 500):(0.1 to 1,000), in a weight ratio of 1:(0.001 to 300):(0.1 to 500), or in a weight ratio of 1:(0.001 to 0.1):(0.2 to 5).

[0069] Naphthoquinone compounds

[0070] The naphthoquinone-based compound used as an active ingredient in the composition according to the present invention may be at least one selected from the compounds represented by Chemical Formula 1 to Chemical Formula 5, pharmaceutically acceptable salts thereof, prodrugs thereof, solvates thereof, or isomers thereof.

[0071]

[0072]

[0073] In Chemical Formulae 1 and 2, R1 to R6 are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, amino, substituted or unsubstituted C1-C 10 Alkylamino, substituted or unsubstituted C1-C 10 Dialkylamino, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C2-C 10 Alkynyl, substituted or unsubstituted C1-C10 Alkoxy, substituted or unsubstituted C1-C 10 Alkoxycarbonyl, substituted or unsubstituted C1-C 10 acyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted -(CH2) n -aryl, or may be a substituted or unsubstituted double bond or C3-C6 ring structure formed by two substituents connected to each other, and the ring structure may be a saturated structure, or a partially or completely unsaturated structure, wherein the substituent may be one or more selected from the group consisting of: hydroxyl, halogen, C1-C6 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkoxycarbonyl, C1-C 10 Alkylamino, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl; R7 to R 10 Each is independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, substituted or unsubstituted C1-C 10 Alkylamino, substituted or unsubstituted C1-C 10 Dialkylamino, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C2-C 10 Alkynyl, substituted or unsubstituted C1-C 10 Alkoxy, substituted or unsubstituted C1-C 10 Alkoxycarbonyl, substituted or unsubstituted C1-C 10 acyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted -(CH2) n -aryl, or may be a substituted or unsubstituted C3-C6 ring structure formed by two substituents connected to each other, and the ring structure may be a saturated structure, or a partially or completely unsaturated structure, wherein the substituent may be one or more selected from the group consisting of: hydroxyl, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C10 Alkoxy, C1-C 10 Alkoxycarbonyl, C1-C 10 Alkylamino, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl; X is O, S or NR′, wherein R′ is hydrogen or C1-C6 alkyl; Y is C, S, N or O, wherein when Y is S or O, R5 and R6 are not any substituents, and when Y is N, R5 is hydrogen or C1-C6 alkyl and R6 is not any substituent; m is 0 or 1, and when m is 0, adjacent carbon atoms of m are directly bonded to each other to form a cyclic structure; and n is an integer from 0 to 10.

[0074] Preferably, in Chemical Formulae 1 and 2, X may be O or S, and Y may be C or O.

[0075] As a preferred example, in Chemical Formulae 1 and 2, R1 to R6 may be each independently selected from the group consisting of hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C1-C 10 Alkoxy and -(CH2) n -phenyl, or may be a double bond or a C4-C6 ring structure formed by R1 and R4 or R2 and R3 connected to each other, wherein the substituent may be C1-C 10 alkyl.

[0076] As another preferred example, in Chemical Formulae 1 and 2, R7 to R 10 can be independently selected from the group consisting of hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C 10 Alkyl and substituted or unsubstituted C1-C 10 Alkoxy.

[0077] Among the compounds represented by Chemical Formula 1 or 2, preferred examples include: a compound represented by Chemical Formula 1-1 or 2-1, wherein X is O and Y is C; or a compound represented by Chemical Formula 1-2 or 2-2, wherein X is S.

[0078]

[0079] In these chemical formulas, R1 to R 10 , Y and m are as defined in Chemical Formulas 1 and 2.

[0080] As another preferred example, the compound represented by Chemical Formula 1 or 2 may be a compound represented by Chemical Formula 1-3 or 2-3, wherein m is 0, and adjacent carbon atoms are directly bonded to each other to form a cyclic structure (furan ring). Hereinafter, the compound is sometimes referred to as a "furan compound" or a "furano-o-naphthoquinone derivative".

[0081]

[0082]

[0083] In these chemical formulas, R1 to R4, R7 to R 10 and X are as defined in Chemical Formula 1.

[0084] In addition, the compound represented by Chemical Formula 1 or 2 may be a compound represented by Chemical Formula 1-4 or 2-4, wherein m is 1. Hereinafter, the compound is sometimes referred to as a "pyran compound" or a "pyrano-o-naphthoquinone derivative".

[0085]

[0086] In these chemical formulas, R1 to R 10 , X and Y are as defined in Chemical Formula 1.

[0087] As yet another preferred example, the compound represented by Chemical Formula 1 or 2 may be a compound represented by Chemical Formula 1-5 or 1-6, or a compound represented by Chemical Formula 2-5 or 2-6, wherein R7 and R8 are bonded to each other to form a ring structure.

[0088]

[0089]

[0090] In these formulas, R1 to R 10 , X, Y and m are as defined in Formula 1, and R 11 To R 18 Each is hydrogen, hydroxyl, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkoxycarbonyl, C1-C 10 Alkylamino, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl.

[0091] Preferably, R 11 To R 18can be independently hydrogen, hydroxyl, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C3-C8 cycloalkyl or phenyl.

[0092] Among the naphthoquinone-based compounds represented by Chemical Formula 1 or 2, particularly preferred examples include compounds in Table 1 below, but are not limited thereto.

[0093] [Table 1]

[0094]

[0095]

[0096]

[0097]

[0098] The naphthoquinone-based compound represented by Chemical Formula 1 or 2 used in the composition according to the present invention can be prepared by the method disclosed in International Publication Nos. WO 2006 / 088315 and WO 2006 / 020719, and can be prepared by other known methods and / or various methods based on the technology in the field of organic synthesis. Based on the above method, various derivatives can be synthesized using appropriate synthesis methods according to the type of substituents.

[0099] In addition, the naphthoquinone-based compound may include, as a component, a compound represented by Chemical Formula 3, a pharmaceutically acceptable salt thereof, a prodrug thereof, an isomer thereof, or a solvate thereof.

[0100]

[0101] In Chemical Formula 3, R1 and R2 are each independently hydrogen, halogen, substituted or unsubstituted C1-C 20 Alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C6-C 10 aryloxy, substituted or unsubstituted 5- to 10-membered heteroaryl, -NO2, -NR'1R'2, -NR'1(CO(O)R'2), -NR'1(C(O)NR'1R'2), -C(O)NR'1R'2, -CN, -SO(O)R'1, -SO(O)NR'1R'2, -NR'1(SO(O)R'2) or -CSNR'1R'2, or R1 and R2 may be bonded to each other to form a substituted or unsubstituted C6-C 10The cyclic structure of an aryl group, or the cyclic structure of a substituted or unsubstituted 5- to 10-membered heteroaryl group; wherein R'1 and R'2 are each independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C6-C 10 aryloxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted -(CR"1R"2) m′ -C6-C 10 Aryl or substituted or unsubstituted NR" i R″2; where R″ i R"1 and R"2 are each independently hydrogen or C1-C3 alkyl, or R"1 and R"2 may be bonded to each other to form a substituted or unsubstituted C6-C 10 R3, R4, R5 and R6 are each independently hydrogen, halogen, substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted C2-C 20 Olefins, substituted or unsubstituted C1-C 20 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C6-C 10 Aryloxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted --(CR′5R′6) m -C6-C 10 Aryl, substituted or unsubstituted -(CR′5R′6) m -C6-C 10 Aryloxy, substituted or unsubstituted -(CR′5R′6) m -5- to 10-membered heteroaryl, substituted or unsubstituted -(CR′5R′6) m -3- to 10-membered heterocycloalkyl, substituted or unsubstituted -(CR′5R′6) m -NR'3R'4, substituted or unsubstituted -(CR'5R'6) m -OR′3, -CO(O)R′3, -CONR′3R′4, -NR′3R′4, -NR′3(C(O)R′4), -SO(O)R′3, -SO(O)NR′3R′4, -NR′3(SO(O)R′4) or -CSNR′3R′4, or -CH2A when the compound represented by Chemical Formula 3 is “A”, or -A when the compound represented by Chemical Formula 3 is “A”; wherein R′3 and R′4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10Aryl, substituted or unsubstituted -(CH2) m -C6-C 10 Aryl, substituted or unsubstituted -(CH2) m -C6-C 10 aryloxy or -CO(O)R"3, or R'3 and R'4 may be bonded to each other to form a substituted or unsubstituted 3- to 10-membered heterocycloalkyl ring structure, or a substituted or unsubstituted 5- to 10-membered heteroaryl ring structure; R'5 and R'6 are each independently hydrogen or C1-C3 alkyl; and R"3 is C1-C6 alkyl; wherein the substituent is one or more selected from the group consisting of hydroxyl, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkoxycarbonyl, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl and 5- to 10-membered heteroaryl; provided that R3 and R4 are each independently C6-C 10 Aryl structures, excluding those wherein R4 and R6 are each independently C6-C 10 The structure of the aryl group, excluding the structure in which R4 is hydrogen, methyl, halogen-substituted methyl or piperidinylmethyl when R3 has the structure defined above, and excluding the structure in which R5 is phenyl; m and m' are each independently a natural number of 1 to 4; the heteroatom is one or more selected from N, O and S; X1, X2, X3 and X4 are each independently CH or N; and n is 0 or 1, and when n is 0, adjacent carbon atoms of n are directly bonded to each other to form a cyclic structure.

[0102] In a preferred example, the compound represented by Chemical Formula 3 may be a compound represented by Chemical Formula 3-1.

[0103]

[0104] In Chemical Formula 3-1, R1, R2, R4, R5, X1, X2, X3 and X4 are as defined in Chemical Formula 3.

[0105] Examples of the compound represented by Chemical Formula 3-1 include a compound represented by Chemical Formula 3-1-1, but the following compounds do not limit the present invention.

[0106]

[0107] In another preferred example, the compound represented by Chemical Formula 3 may be the compound represented by Chemical Formula 3-2 or the compound represented by Chemical Formula 3-3.

[0108]

[0109] In Chemical Formulae 3-2 and 3-3, R1 to R4, R6, x1, X2, X3 and X4 are as defined in Chemical Formula 3.

[0110] Specifically, in Chemical Formulas 3-2 and 3-3, R1 and R2 may each independently be hydrogen, halogen, substituted or unsubstituted C1-C 20 Alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, -NO2, -NR'1R'2, -NR'1(C(O)R'2), -NR'1(SO2R'2), -NR'1(CO2R'2), -NR'1(C(O)NR'1R'2), -COOR'1, -C(O)NR'1R'2 or -CN, or R1 and R2 may be bonded to each other to form a substituted or unsubstituted C6-C 10 The cyclic structure of an aryl group, or the cyclic structure of a substituted or unsubstituted 5- to 10-membered heteroaryl group, wherein R'1 and R'2 are each independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C 10 Aryl or substituted or unsubstituted -(CH2)m-C6-C 10 Aryl; wherein the substituent may be one or more selected from the group consisting of: hydroxyl, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkoxycarbonyl, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl and 5- to 10-membered heteroaryl.

[0111] More specifically, in Chemical Formulae 3-2 and 3-3, R1 and R2 may each independently be H, F, Cl, -NO2, NH2, -N(CH3)2, -NHCOCH3, -NHCOC3H5 or -NHCH2C6H5F, and X2 and X3 may each be CH.

[0112] Still more specifically, in Chemical Formulae 3-2 and 3-3, R1 and R2 are each independently H, F, Cl, -NO2, NH2, -N(CH3)2, -NHCOCH3, -NHCOC3H5 or -NHCH2C6H5F; X2 and X3 are each CH; R3 to R6 are each independently H, halogen, substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted -(CR′5R′6) m -C6-C 10 Aryl, substituted or unsubstituted -(CR′5R′6) m -C6-C 10 Aryloxy, substituted or unsubstituted -(CR′5R′6) m -5- to 10-membered heteroaryl, substituted or unsubstituted -(CR′5R′6) m -3- to 10-membered heterocycloalkyl, substituted or unsubstituted -(CHR′5) m -NR'3R'4, -CO(O)R'3, -CONR'3R'4, -NR'3R'4 or -NR'3(C(O)R'4), or -CH2A when the compound represented by Chemical Formula 3 is "A"; R4 is halogen, substituted or unsubstituted C2-C9 alkyl, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C6-C 10 aryloxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted -(CR′5R′6) m -C6-C 10 Aryl, substituted or unsubstituted -(CR′5R′6) m -C6-C 10 Aryloxy, substituted or unsubstituted -(CR′5R′6) m -5- to 10-membered heteroaryl, substituted or unsubstituted -(CHR′5) m -NR′3-C6-C 10 Aryl, substituted or unsubstituted -(CR′5R′6) m -3- to 10-membered heterocycloalkyl, substituted or unsubstituted -(CR′5R′6) m -NR'3R'4, substituted or unsubstituted -(CR'5R'6) m -OR′3 or -NR′3R′4, or -A when the compound represented by Chemical Formula 3 is "A"; wherein R′3 and R′4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted -(CH2)m -C6-C 10 Aryl, substituted or unsubstituted -(CH2) m -C6-C 10 aryloxy or -CO(O)R"3, or R'3 and R'4 may be bonded to each other to form a substituted or unsubstituted 3- to 10-membered heterocycloalkyl ring structure, or a substituted or unsubstituted 5- to 10-membered heteroaryl ring structure; R'5 and R'6 are each independently hydrogen or C1-C3 alkyl; R"3 is C1-C6 alkyl; wherein the substituent is one or more selected from the group consisting of hydroxyl, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkoxycarbonyl, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl group and 5- to 10-membered heteroaryl group; m is a natural number of 1 to 4; and the heteroatom may be one or more selected from N, O and S.

[0113] Still more specifically, in Chemical Formulae 3-2 and 3-3, R1 and R2 are each independently H, F, Cl, -NO2, NH2, -N(CH3)2, -NHCOCH3, -NHCOC3H5 or -NHCH2C6H5F; X2 and X3 are each CH; R3 and R6 are each independently H, halogen, substituted or unsubstituted C1-C9 alkyl, substituted or unsubstituted -(CH2) m -C6-C 10 Aryl, substituted or unsubstituted -(CH2) m -C6-C 10 Aryloxy, substituted or unsubstituted -(CHR′5) m -5- to 10-membered heteroaryl, substituted or unsubstituted -(CHR′5) m -3- to 10-membered heterocycloalkyl, substituted or unsubstituted -(CHR′5) m -NR'3R'4, -CO(O)R'3, -CONR'3R'4, -NR'3R'4 or -NR'3(C(O)R'4), or -CH2A when the compound represented by Chemical Formula 3 is "A"; R4 is halogen, substituted or unsubstituted C2-C9 alkyl, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C6-C 10aryloxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted -(CH2) m -C6-C 10 Aryl, substituted or unsubstituted -(CH2) m -C6-C 10 Aryloxy, substituted or unsubstituted -(CHR′5) m -5- to 10-membered heteroaryl, substituted or unsubstituted -(CHR′5) m -NR′3-C6-C 10 Aryl, substituted or unsubstituted -(CHR′5) m -3- to 10-membered heterocycloalkyl, substituted or unsubstituted -(CHR′5) m -NR'3R'4 or -NR'3R'4, or -A when the compound represented by Chemical Formula 3 is "A"; wherein R'3 and R'4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted -(CH2) m -C6-C 10 Aryl, substituted or unsubstituted -(CH2) m -C6-C 10 aryloxy or -COOC(CH3)3, or R'3 and R'4 may be bonded to each other to form a substituted or unsubstituted 3- to 10-membered heterocycloalkyl ring structure, or a substituted or unsubstituted 5- to 10-membered heteroaryl ring structure; R'5 is hydrogen or C1-C3 alkyl; wherein the substituent is one or more selected from the group consisting of hydroxyl, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkoxycarbonyl, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 aryl group and 5- to 10-membered heteroaryl group; m is a natural number of 1 to 4; and the heteroatom may be one or more selected from N, O and S.

[0114] In addition, more specifically, in Chemical Formulae 3-2 and 3-3, R3 and R6 are each independently H, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted -(CH2) m -C5-C6 aryl, substituted or unsubstituted -(CH2) m -C5-C6 aryloxy, substituted or unsubstituted -(CHR′5) m -C4-C6 heteroaryl, substituted or unsubstituted -(CHR'5) m-C4-C6 heterocycloalkyl, substituted or unsubstituted -(CHR'5) m -NR'3R'4 or -CO(O)R'3, or -CH2A when the compound represented by Chemical Formula 3 is "A"; wherein R'3 and R'4 are each independently hydrogen, C1-C5 alkyl or C3-C5 cycloalkyl, or R'3 and R'4 may be bonded to each other to form a substituted or unsubstituted 3- to 10-membered heterocycloalkyl ring structure; R'5 is H; the substituent is methyl, halogen or hydroxyl; and m may be 1 to 3. Still more specifically, the halogen may be fluorine or chlorine, and the aryl may be a C6 aryl.

[0115] In addition, more specifically, in Chemical Formulas 3-2 and 3-3, R4 is halogen, substituted or unsubstituted C2-C5 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 aryl, substituted or unsubstituted -(CH2) m -C5-C6 aryl, substituted or unsubstituted C6-C 10 Aryloxy, substituted or unsubstituted -(CH2) m -C5-C6 aryloxy, substituted or unsubstituted C5-C6 heteroaryl, substituted or unsubstituted -(CHR′5) m -C5-C6 heteroaryl, substituted or unsubstituted C4-C6 heterocycloalkyl, substituted or unsubstituted -(CHR′5) m -C3-C6 heterocycloalkyl, -NR'3R'4, substituted or unsubstituted -(CHR'5) m -NR'3-C5-C6 aryl or substituted or unsubstituted -(CHR'5) m -NR'3R'4, or -A when the compound represented by Chemical Formula 3 is "A"; R'3 and R'4 are each independently hydrogen, methyl, ethyl or -COOC(CH3)3, or R'3 and R'4 may be bonded to each other to form a substituted or unsubstituted C4-C6 heterocycloalkyl ring structure; R'5 is H, methyl, ethyl, propyl or butyl; the substituent is methyl, halogen or hydroxyl; and m may be 1 or 2. Still more specifically, the halogen may be fluorine, and the aryl may be a C6 aryl.

[0116] In addition, among the naphthoquinone-based compounds represented by Chemical Formula 3, particularly preferred examples include the following compounds, but are not limited thereto.

[0117]

[0118]

[0119] The naphthoquinone-based compound represented by Chemical Formula 3 used in the composition according to the present invention can be prepared by the method disclosed in Korean Patent No. 10-1739361, and can be prepared by other known methods and / or various methods based on the technology in the field of organic synthesis. Based on the above method, various derivatives can be synthesized using appropriate synthesis methods according to the type of substituents.

[0120] In addition, the naphthoquinone-based compound may include, as a component, a compound represented by Chemical Formula 4, a pharmaceutically acceptable salt thereof, a prodrug thereof, an isomer thereof, or a solvate thereof.

[0121]

[0122] In Chemical Formula 4, R1 and R2 are each independently hydrogen, a halogen atom, a hydroxyl group, a substituted or unsubstituted C1-C 20 Alkoxy, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C4-C 10 Aryl, substituted or unsubstituted C4-C 10 Aryloxy, substituted or unsubstituted C2-C 10 heteroaryl, -NO2, -NR'1R'2, -NR'1(CO(O)R'2), -NR'1(C(O)NR'1R'2), -CO(O)R'1, -C(O)NR'1R'2, -CN, -SO(O)R'1, -SO(O)NR'1R'2, -NR'1(SO(O)R'2) or -CSNR'1R'2, or R1 and R2 may be bonded to each other to form a substituted or unsubstituted C4-C 10 The cyclic structure of the aromatic group, or a substituted or unsubstituted C2-C 10 wherein R'1 and R'2 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C 10 Aryl, substituted or unsubstituted C4-C 10 Aryloxy, substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted -(CR"1R"2) m′ -C4-C 10 Aryl, substituted or unsubstituted -(CR"1R"2) m′ -C4-C 10 Heteroaryl or substituted or unsubstituted NR" i R"1 and R"2 are each independently hydrogen or C1-C3 alkyl, or R"1 and R"2 may be bonded to each other to form a substituted or unsubstituted C4-C 10 The cyclic structure of the aromatic group; R3 is hydrogen, hydroxyl, halogen atom, substituted or unsubstituted C1-C10 Alkyl, substituted or unsubstituted C2-C 20 Olefins, substituted or unsubstituted C1-C 20 Alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C a Heterocycloalkyl, substituted or unsubstituted C4-C 10 Aryl, substituted or unsubstituted C4-C 10 Aryloxy, substituted or unsubstituted C1-C 10 Heteroaryl, substituted or unsubstituted -(CR′5R′6) m -C4-C 10 Aryl, substituted or unsubstituted -(CR′5R′6)m-C4-C 10 Aryloxy, substituted or unsubstituted -(CR′5R′6) m -C1-C 10 Heteroaryl, substituted or unsubstituted -(CR′5R′6) m -NR'3R'4, substituted or unsubstituted -(CR'5R'6) m -C2-C 10 Heterocycloalkyl, substituted or unsubstituted -(CR'5R'6) m -OR'3, substituted or unsubstituted -(CR'5R'6) m (O)COR'3, -CO(O)R'3, -CONR'3R'4, -NR'3R'4 or -NR'3(C(O)R'4), or -CH2A when the compound represented by Chemical Formula 4 is "A", or -A when the compound represented by Chemical Formula 4 is "A"; wherein R'3 and R'4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C 10 Aryl, substituted or unsubstituted -(CR′5R′6) m -C4-C 10 Aryl, substituted or unsubstituted -(CR′5R′6) m -C4-C 1010 Aryloxy, substituted or unsubstituted -(CR′5R′6) m -C1-C 10 heteroaryl or -CO(O)R"'3, or R'3 and R'4 may be bonded to each other to form a substituted or unsubstituted C4-C 10 The ring structure of heterocycloalkyl, or substituted or unsubstituted C1-C 10The cyclic structure of the heteroaryl group; R'5 and R'6 are each independently hydrogen or C1-C3 alkyl; R"'3 is C1-C6 alkyl; wherein the substituent may be one or more selected from the group consisting of: hydroxyl, nitro group, halogen atom, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C4-C 10 Aryl and C5-C 10 heteroaryl; X1, X2, X3 and X4 are each independently CH or N; m and m' are each independently a natural number of 1 to 4; and the heteroatom is one or more selected from N, O and S.

[0123] In a preferred example, X1 and X2 are each independently CH, CO or N(R3′); wherein R3′ is hydrogen or a C1-C3 alkyl group; and X3 and X4 may each be CH.

[0124] In addition, R1 and R2 can each independently be hydrogen, a halogen atom, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH3, -NO2, -CN, -NR'1R'2 or -OH (wherein, R'1 and R'2 can each independently be hydrogen, a C1-C3 alkyl group, a substituted or unsubstituted -CH2-C4-C 10 Aryl, substituted or unsubstituted -C2H4-C4-C 10 Aryl or substituted or unsubstituted C2-C 10 heteroaryl group, and the substituent is a halogen atom).

[0125] Still more specifically, R1 and R2 may each independently be hydrogen, Cl, -NO2, -NH2 or -NR'1R'2 (wherein R'1 and R'2 are each independently hydrogen or a substituted or unsubstituted -CH2-C4-C6 aryl group, and the substituent is a halogen atom).

[0126] In addition, R3 is hydrogen, substituted or unsubstituted methyl, ethyl, n-butyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, substituted or unsubstituted C4-C8 aryl, substituted or unsubstituted C4-C8 aryloxy, substituted or unsubstituted C1-C8 heteroaryl, substituted or unsubstituted -(CR'5R'6)m-C4-C 10 Aryl, substituted or unsubstituted -(CR′5R′6) m -C4-C 10 Aryloxy, substituted or unsubstituted -(CR′5R′6) m -C1-C10 Heteroaryl, substituted or unsubstituted -(CR′5R′6) m -C4-C 10 Heterocycloalkyl or substituted or unsubstituted -(CH2) m -NR'5R'6; R'5 and R'6 are each independently hydrogen or C1-C3 alkyl, wherein the substituent may be one or more selected from the group consisting of: halogen atoms, hydroxyl groups, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10 Alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C4-C 10 Aryl and C5-C 10 heteroaryl; the heteroatom is N, O or S; and m can be a natural number of 1 to 4.

[0127] Still more specifically, R3 is hydrogen, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, substituted or unsubstituted C4-C8 aryl, substituted or unsubstituted C4-C8 aryloxy, substituted or unsubstituted -(CH2) m -C4-C 10 Heterocycloalkyl or substituted or unsubstituted -(CH2) m -NR′5R′6; and R′5 and R′6 are each independently hydrogen or C1-C3 alkyl, still more specifically, R3 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, neopentyl, phenyl or phenyl substituted by a halogen atom, and even more specifically, R3 can be methyl, isopropyl, tert-butyl, phenyl or neopentyl.

[0128] Furthermore, among the naphthoquinone-based compounds represented by Chemical Formula 4, particularly preferred examples include the following compounds, but are not limited thereto.

[0129]

[0130]

[0131] The naphthoquinone-based compound represented by Chemical Formula 4 used in the composition according to the present invention can be prepared by the method disclosed in Korean Patent No. 10-1644778, and can be prepared by other known methods and / or various methods based on techniques in the field of organic synthesis. Based on the above method, various derivatives can be synthesized using appropriate synthesis methods according to the types of substituents.

[0132] In addition, the naphthoquinone-based compound may include, as a component, the compound represented by Chemical Formula 5, a pharmaceutically acceptable salt thereof, a prodrug thereof, an isomer thereof, or a solvate thereof.

[0133]

[0134] In Chemical Formula 5, X1, X2, X3 and X4 are each independently selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and at least two of X1, X2, X3 and X4 are heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, provided that when X1 and X2 are each a carbon atom, X3 and X4 may not be nitrogen atoms at the same time; R1 is one or more selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, nitro, hydroxyl, cyano and -NR5R6; R2 is absent or selected from the group consisting of hydrogen, oxygen, alkyl, alkoxy, C 6-10 Aryl and heterocyclic groups, in which the alkyl group may be C 6-10 The heterocyclic group may be substituted by -C(O)R8; R3 is absent or selected from the group consisting of hydrogen, oxygen, halogen, alkyl, alkoxy, C 6-10 Aryl, heterocyclic, -SO2NR7R 12 、-NR9R 10 and -C(O)R 11 , wherein when the alkyl group is substituted, the substituent is selected from the group consisting of halogen, alkoxy, C 6-10 Aryl, C 6-10 Aryloxy, heterocyclic, -C(O)R8, R 12 C(O)O- and -NR 13 R 14 , and the heterocyclic group may be substituted by -C(O)R8; R4 is absent or selected from the group consisting of hydrogen, oxygen, alkyl, alkoxy, C 6-10 Aryl, C 6-10 Aryloxy, heterocyclic and -C(O)R 15 When the alkyl group is substituted, the substituent is selected from the group consisting of halogen, C 6-10 aryl, heterocyclic group and -C(O)R8, and the heterocyclic group may be substituted by -C(O)R8; R5 and R6 are each independently selected from the group consisting of hydrogen, alkyl and -C(O)R7; R7 and R 12 Each is an alkyl group; R 11 is a heterocyclic group or -NR 13 R 14 ; R 15 Alkyl, alkoxy, C 6-10 Aryloxy, heterocyclic or -NR 13 R 14 ; R9, R10 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, unsubstituted or halogen-substituted C 6-10 wherein the alkyl group is a straight or branched alkyl group having 1 to 10 carbon atoms or a cyclic alkyl group having 3 to 7 carbon atoms, the heterocyclic group is a 3- to 7-membered heterocyclic group having one or more heteroatoms in the ring, the one or more heteroatoms being selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, and when the aryl group is substituted, each of the substituents is one or more selected from the group consisting of halogen, C 1-6 Alkyl, halogen-substituted alkyl, and alkoxy; and is a single bond or a double bond, depending on R2, R3, R4, X1, X2, X3 and X4, provided that when X1 and X4 are each a carbon atom and X2 and X3 are each a nitrogen atom, one of R2 and R4 is not an alkyl, aryl or heterocyclic group, wherein when R2 is an alkyl, aryl or heterocyclic group, R4 is not -C(O)R 15 .

[0135] In a preferred example, the compound represented by Chemical Formula 5 may be a compound in which X1 and X4 are carbon atoms and X2 and X3 are nitrogen atoms. Here, in Chemical Formula 5, R2 is absent or is an alkyl group, an alkoxy group or a C 6-10 Aryl, R3 is absent or is hydrogen, alkyl or C 6-10 Aryl, R4 is absent or is oxygen, alkyl or alkoxy, wherein one of R2 and R4 is not alkyl or aryl, and when the alkyl or aryl is substituted, the substituent is as defined above.

[0136] In another preferred example, the compound represented by Chemical Formula 5 may be a compound in which X1 and X3 are carbon atoms and X2 and X4 are nitrogen atoms. Here, in Chemical Formula 5, R2 may not exist or may be an alkyl group, and R3 may be selected from the group consisting of halogen, alkyl, alkoxy, C 6-10 aryl and heterocyclic groups, and R4 may be absent or may be selected from the group consisting of hydrogen, alkyl, C 6-10 Aryl, C 6-10 Aryloxy, heterocyclic and -C(O)R 15 Here, when R 15 When the alkyl, aryl or heterocyclic group is substituted, the substituent is as defined above.

[0137] In another preferred example, the compound represented by Chemical Formula 5 may be a compound in which X1 and X3 are carbon atoms, X2 is a nitrogen atom, and X4 is a sulfur atom. Here, in Chemical Formula 5, R2 and R4 are absent, R3 is an alkyl group or a C 6-10 Aryl, wherein when the alkyl or aryl group is substituted, the substituent is as defined above.

[0138] In another preferred example, the compound represented by Chemical Formula 5 may be a compound in which X1 and X3 are carbon atoms, and one of X2 and X4 is a nitrogen atom and the other is an oxygen atom. Here, in Chemical Formula 5, R2 is absent, and R3 is oxygen, an alkyl group, or a C6- 10 aryl, and R4 is absent or is hydrogen or alkyl, wherein when the alkyl or aryl is substituted, the substituent is as defined above.

[0139] In another preferred example, the compound represented by Chemical Formula 5 may be a compound in which X2, X3 and X4 are nitrogen atoms. Here, in Chemical Formula 5, R2 is absent or is an alkyl group or a heterocyclic group, and R3 is absent or is selected from the group consisting of: an alkyl group, a C 6-10 Aryl, heterocyclic, -SO2R7, -NR9R 10 and -C(O)R 11 , and R4 is absent or selected from the group consisting of: alkyl, heterocyclyl and -C(O)R 15 Here, when R7, R9, R 10 , R 11 or R 15 When the alkyl, aryl or heterocyclic group is substituted, the substituent is as defined above.

[0140] In yet another preferred example, the compound represented by Chemical Formula 5 may be a compound in which X2 and X3 are carbon atoms and X1 and X4 are nitrogen atoms. 6-10 aryl, and R3 and R4 are absent, wherein when the aryl is substituted, the substituents are as defined above.

[0141] Among the naphthoquinone-based compounds represented by Chemical Formula 5, particularly preferred examples include compounds in the following Table 2, but are not limited thereto.

[0142] [Table 2]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] The naphthoquinone-based compound represented by Chemical Formula 5 used in the composition according to the present invention can be prepared by the method disclosed in Korean Patent Publication No. 10-2247694, and can be prepared by other known methods and / or various methods based on the technology in the field of organic synthesis. Based on the above method, various derivatives can be synthesized using appropriate synthesis methods according to the type of substituents.

[0152] As used herein, the term "alkyl" refers to an atomic group that does not have an unsaturated group and contains carbon and hydrogen. The alkyl atomic group can be straight chain (linear) or branched (branched). Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, etc., but are not limited thereto. C1-C 10 Alkyl is an alkyl group having 1 to 10 carbon atoms in the main chain of a straight or branched alkyl group. The alkyl group may be optionally substituted. When the alkyl group is substituted, the alkyl group may be substituted with 4 or fewer substituents at any particular bonding point (at any specified carbon atom). At the same time, the alkyl group is substituted with an alkyl group, which is used synonymously with "branched alkyl group".

[0153] The term "alkenyl" refers to an unsaturated aliphatic group similar to an alkyl in length and substitutability but comprising one or more carbon-carbon double bonds. For example, "alkenyl" includes a straight chain alkenyl group (for example, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl), a branched chain alkenyl group and a cycloalkenyl group (for example, cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl). In addition, "alkenyl" may also include an alkenyl group comprising oxygen, nitrogen, sulphur or phosphorus atoms of one or more carbon atoms of a substituted hydrocarbon backbone. In a specific example, a straight chain or branched chain alkenyl group may have 6 or less carbon atoms in the main chain (for example, C2-C6 for a straight chain alkenyl group, and C3-C6 for a branched chain alkenyl group). Similarly, a cycloalkenyl group may have 3 to 8 carbon atoms in a ring structure, and more preferably has 5 or 6 carbon atoms.

[0154] The term "alkynyl" refers to an unsaturated aliphatic group similar to an alkyl group in length and substitutability but comprising one or more carbon-carbon triple bonds. For example, "alkynyl" includes a straight chain alkynyl group (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl or decynyl) and a branched chain alkynyl group (including an alkynyl group substituted with an alkyl or alkenyl group). In addition, "alkynyl" may also include an alkynyl group comprising oxygen, nitrogen, sulfur or phosphorus atoms that replace one or more carbon atoms of a hydrocarbon backbone. In a specific example, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in the backbone (e.g., C2-C6 for a straight chain alkynyl group, and C3-C6 for a branched chain alkynyl group).

[0155] When the alkyl, alkynyl and alkenyl groups are each substituted, the substituents may be, for example, hydroxy, carboxylate, oxo, halogen (e.g., F, Cl, Br or I), C1-C6 haloalkyl (e.g., CCl3 or CF3), carbamoyl (-NHCOOR or -OCONHR), urea (-NHCONHR), thiol, cyano, nitro, amino, amido, C1-C6 alkyl ... 10 Alkylthio, C6-C 10 Arylthio, C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 10 Aryloxy, C1-C 10 Alkylcarbonyloxy, C6-C 10 Arylcarbonyloxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, aminocarbonyl, C1-C 10 Alkylcarbonyl, C3-C8 cycloalkylcarbonyl, 3- to 10-membered heterocycloalkylcarbonyl, C6-C 10 Arylcarbonyl, C6-C 10 Aryloxycarbonyl, C1-C 10 Alkoxycarbonyl, C3-C8 cycloalkoxycarbonyl, 3- to 10-membered heterocycloalkoxycarbonyl, C1-C 10 Alkylsulfonyl, C6-C 10 Arylsulfonyl, C1-C 10 Alkylamino, 3-membered to 10-membered heterocycloalkyl, 5-membered to 10-membered heteroaryl, and the like.

[0156] Preferably, the substituents may be selected from hydroxyl, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C 10Alkoxycarbonyl, C1-C 10 Alkylamino, C3-C8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C 10 one or more of an aryl group and a 5- to 10-membered heteroaryl group.

[0157] The term "cycloalkyl" refers to an alkyl group containing 3 to 15 carbon atoms, preferably 3 to 8 carbon atoms, and having no alternating or resonant double bonds between the carbon atoms. The cycloalkyl group may contain 1 to 4 rings. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like. Exemplary substituents of the cycloalkyl group may be halogen, C1-C 10 Alkyl, C1-C 10 Alkoxy, amino, nitro, cyano, mercapto, C1-C 10 Alkylthio, etc.

[0158] The term "heterocycloalkyl" refers to a substitution product in which the carbon atoms in the ring are replaced by heteroatoms such as nitrogen, sulfur or oxygen, and refers to a saturated or unsaturated 7- to 10-membered bicyclic heterocycle or a stable non-aromatic 3- to 8-membered monocyclic heterocycle, and can form additional rings by fusion, spiro or crosslinking between these rings. Each heterocycle is composed of one or more carbon atoms and one to four heteroatoms. Heterocycloalkyl can be bonded to any bridged ring that produces a stable structure. Its preferred examples include furans, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isothiazole, triazole, thiadiazole, pyrans, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine and triazine, but are not limited thereto.

[0159] The term "aryl" refers to an aromatic substituent having at least one ring with a shared π electron system, and includes carbocyclic aryls (e.g., phenyl) and heterocyclic aryls (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. The aryl group may be a carbocyclic ring, or may optionally contain 1 to 4 heteroatoms (e.g., nitrogen, sulfur, or oxygen) in the aromatic ring, and such aryl groups are also referred to as "heteroaryl".

[0160] Examples of the aryl or heteroaryl group include phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolyl, isothiazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, triazinyl, quinazolinyl, thiazolyl, benzothiophenyl, furanyl, imidazolyl and thienyl, but are not limited thereto.

[0161] The cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be optionally substituted, and examples of substituents include hydroxy, halogen, mercapto, cyano, nitro, amino, amido, C1-C 10 Alkylthio, C6-C 10Arylthio, C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 10 Aryloxy, C1-C 10 Alkylcarbonyloxy, C6-C 10 Arylcarbonyloxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 10 Aryl, carboxylate, aminocarbonyl, C1-C 10 Alkylcarbonyl, C3-C8 cycloalkylcarbonyl, 3- to 10-membered heterocycloalkylcarbonyl, C6-C 10 Arylcarbonyl, C6-C 10 Aryloxycarbonyl, C1-C 10 Alkoxycarbonyl, C3-C8 cycloalkoxycarbonyl, 3- to 10-membered heterocycloalkoxycarbonyl, C6-C 10 Aryloxycarbonyl, C1-C 10 Alkylsulfonyl, C1-C 10 Alkylamino, C6-C 10 arylsulfonyl, 3-membered to 10-membered heterocycloalkyl, and 5-membered to 10-membered heteroaryl, but are not limited thereto.

[0162] Additionally, the heterocycloalkyl and heteroaryl groups have 1 to 3 heteroatoms selected from the group consisting of N, O and S.

[0163] The scope of the active ingredient contained in the composition according to the present invention includes all of the naphthoquinone-based compound, its pharmaceutically acceptable salt, its prodrug, its solvate or its isomer. Unless otherwise specified in this specification, the term "naphthoquinone-based compound" can be used as a concept including all of the compound itself, its pharmaceutically acceptable salt, its prodrug, its solvate and its isomer.

[0164] As used herein, the term "pharmaceutically acceptable salt" refers to a compound dosage form that does not cause severe irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutically acceptable salt includes an acid addition salt formed by an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, and examples of the acid include: inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid or hydroiodic acid; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid or salicylic acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Meanwhile, examples of base addition salts include alkali metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine or guanidine; and organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline or triethylamine. As used herein, naphthoquinone-based compounds can be converted into their salts by conventional methods.

[0165] The term "prodrug" refers to a substance that is converted into a parent drug in vivo. Prodrugs are easier to use than parent drugs, and are therefore frequently used. For example, prodrugs can obtain physiological activity by oral administration, but parent drugs may not be. Compared with parent drugs, prodrugs may also have improved solubility in pharmaceutical compositions. For example, prodrugs are such compounds: their water solubility is not conducive to mobility, but once they enter cells (water solubility is favorable in cells), they are metabolically hydrolyzed into carboxylic acids as activators, and prodrugs are administered as esters that promote cell membrane penetration. Another example of prodrugs can be a short peptide (polyamino acid) bonded to an acidic group, which is converted by metabolism to expose the active site of the peptide. Prodrugs according to the present invention include compounds described in International Publication No. WO 2006 / 020719, but are not limited to these compounds.

[0166] As used herein, the term "solvate" refers to a compound according to the invention or a salt thereof, which contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include volatile, non-toxic and / or solvents suitable for human administration, and when the solvent is water, the solvate refers to a hydrate.

[0167] The term "isomer" refers to a compound according to the invention or a salt thereof, which has the same chemical formula or molecular formula, but is optically or sterically different. For example, a compound according to the invention may have a chiral carbon center and may therefore exist as an R or S isomer, a racemic compound, a single enantiomer or a mixture thereof, or a single diastereomer or a mixture thereof, and all such stereoisomers and mixtures thereof may fall within the scope of the invention.

[0168] Immune checkpoint inhibitors

[0169] As used herein, the term "immune checkpoint" refers to an intracellular signaling system that maintains self-tolerance and protects tissues from excessive immune responses that cause damage. Immune checkpoint proteins are cell membrane proteins that regulate immune checkpoints and can inhibit the differentiation, proliferation, and activity of immune cells. Specifically, immune checkpoint proteins are expressed in activated T cells and have the effect of reducing the proliferation, cytokine secretion, and cytotoxicity of T cells and inhibiting the excessive activity of T cells. Some immune checkpoints are known to be one of the main mechanisms for tumor cells to induce immune escape. Therefore, "immune checkpoint inhibitors" target immune checkpoint proteins and inhibit or block immune checkpoints to increase T cell activation, thereby enhancing anti-tumor immunity and showing anti-cancer effects. In addition to having fewer side effects (such as vomiting, hair loss) and greater therapeutic effects compared to typical cytotoxic anticancer agents, it is known that immune checkpoint inhibitors have a sustained therapeutic effect even after drug administration stops because they use an immune response system with excellent memory ability.

[0170] Specifically, the immune checkpoint inhibitor can target any one of the immune checkpoints selected from the group consisting of cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), lymphocyte activation gene 3 (LAG3), B7-H3 (CD276), B7-H4 (VTCN1; T cell activation inhibitor 1 containing V-set domain), herpes virus entry mediator (HVEM), killer cell immunoglobulin-like receptor (KIR), OX40 (CD134, TNFRSF4; TNF receptor superfamily member 4), IgG, indoleamine-2,3-dioxygenase 1 (IDO-1), indoleamine-2,3-dioxygenase 2 (IDO-2), carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), B and T lymphocyte attenuator (BTLA), OX40 ligand (OX40L), T cell membrane protein 3 (TIM3), galectin 9 (GAL9), V-domain Ig inhibitor of T cell activation (VISTA), T cell immunoglobulin and ITIM domain (TIGIT), and combinations thereof. Immune checkpoint inhibitors can be purchased from conventional manufacturers and the like and then used, or can be prepared according to known production methods and then used.

[0171] As used herein, an immune checkpoint inhibitor may be an antibody, such as a monoclonal antibody, that binds to a protein of a cancer cell and may inhibit an immune checkpoint to induce a response in which T cells kill the cancer cell.

[0172] In one embodiment, the immune checkpoint inhibitor can be any one selected from the following: anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-LAG3 antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-HVEM antibody, anti-KIR antibody, anti-OX40 antibody, anti-IgG antibody, anti-IDO-1 antibody, anti-IDO-2 antibody, anti-CEACAM1 antibody, anti-BTLA antibody, anti-OX40L antibody, anti-TIM3 antibody, anti-GAL9 antibody, anti-VISTA antibody, anti-TIGIT antibody, and combinations thereof.

[0173] Specifically, the immune checkpoint inhibitor can be any one selected from the group consisting of: anti-CTLA4 antibody, its antigen-binding fragment or variant thereof; anti-PD-L1 antibody, its antigen-binding fragment or variant thereof; anti-PD-1 antibody, its antigen-binding fragment or variant thereof; anti-LAG3 antibody, its antigen-binding fragment or variant thereof; and combinations thereof.

[0174] As used herein, the term "cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)" is also referred to as CD152, and CTLA-4 is expressed on the membrane surface of activated T cells. CTLA-4 binds to CD80 (B7-1) and CD86 (B7-2) of antigen-presenting cells to inhibit the activity of T cells. CTLA-4 inhibitors may be ipilimumab. and tremelimumab.

[0175] As used herein, the term "programmed death ligand 1 (PD-L1)" is also known as CD274 or B7-H1, and refers to a protein present on the surface of cancer cells or in hematopoietic cells. PD-L1 on the surface of cancer cells can bind to PD-1 on the surface of T cells. PD-L1 inhibitors can be, for example, atezolizumab, avelumab, or Durvalumab KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0176] As used herein, the term "programmed cell death protein 1 (PD-1)" is also known as CD279 and refers to a protein expressed on the surface of activated T cells. PD-1 reacts with proteins PD-L1 (B7-H1) and PD-L2 (B7-DC) present on the surface of cancer cells to inhibit T cell receptor (TCR) and CD28-mediated T cell activation and the production of growth factors and cytokines, thereby inducing negative signal transduction. PD-1 inhibitors are, for example, pembrolizumab MK-3475, nivolumab Cimiprilimab JTX-4014, spartalizumab, carrelizumab, sintilimab, tislelizumab, toripalimab, dotalimumab, INCMGA00012, AMP-224, and AMP-514.

[0177] As used herein, the term "lymphocyte activation gene 3 (LAG3)" is also referred to as CD223, and LAG3 binds to major histocompatibility complex (MHC) class II to inhibit the proliferation and activity of T cells. LAG3 inhibitors may be IMP321, relalizumab, and GSK2831781.

[0178] In one embodiment of the present invention, a composition comprising a naphthoquinone-based compound and an immune checkpoint inhibitor is provided, and the combination has an excellent effect of inhibiting cancer cell proliferation compared to the case where each component is administered alone. For example, the naphthoquinone-based compound can be compound No. 2 of Table 1 (Dongnione; 2,3,3-trimethyl-2H-benzo[g][1]benzofuran-4,5-dione), and the immune checkpoint inhibitor can be any one selected from the group consisting of the following items: anti-CTLA4 antibodies, anti-PD-L1 antibodies, anti-PD-1 antibodies, anti-LAG3 antibodies, and combinations thereof.

[0179] "Dongnione" is a naphthoquinone-based compound and is divided into two structures: α-dongnione (2,3-dihydro-2,3,3-trimethylnaphtho[1,2-b]furan-4,9-dione) and dongnione (2,3-dihydro-2,3,3-trimethylnaphtho[1,2-b]furan-4,5-dione). In addition, dongnione is obtained from the leaves of Streptocarpus dunnii that grows naturally in South America, or from several species of caltrops. According to the pharmacological effects of dongnione reported so far, dongnione is reported to increase NQO1 (NAD(P)H:quinone oxidoreductase 1) enzyme activity to induce NAD in cells + etc., and by deacetylase (such as using NAD + As a coenzyme, Sirtuin 1 is activated, which effectively prevents and treats small intestinal mucosal damage caused by anticancer agents and acute pancreatitis caused by alcohol, gallstones in the pancreatic duct, etc. (Pandit et al., Biochem Biophys Res Commun, 2015, Vol. 467: pp. 697-703; Shen et al., Sci Rep, 2017, Vol. 7: p. 3006). In addition, U.S. Patent No. 9,066,922 B2 discloses that dongnidone can be used to prevent and treat obesity, diabetes, metabolic syndrome, neurodegenerative diseases or mitochondrial dysfunction-related diseases.

[0180] Immunogenic cell death inducers

[0181] As used herein, the term "immunogenic cell death" refers to a type of cell death caused by cell proliferation inhibitors (such as oxaliplatin, cyclophosphamide, paclitaxel and docetaxel) or radiotherapy and photodynamic therapy. Immunogenic cell death is different from typical cell death, and the immunogenic cell death of cancer cells can induce an effective anti-cancer immune response through the activation of dendritic cells and the subsequent activation of specific T cell responses. Substances that induce immunogenic cell death are called immunogenic cell death inducers. Kroemer et al. have well summarized the details of immunogenic cell death and immunogenic cell death inducers (Annu. Rev. Immunol., Vol. 31: pp. 51-72, 2013). This document is hereby incorporated by reference in its entirety.

[0182] The immunogenic cell death inducing agent used as an active ingredient in the composition according to the present invention can be a general anticancer agent and / or a targeted anticancer agent that attacks only cancer cells through respective cancer-specific molecular targets. Specifically, the immunogenic cell death inducing agent can be an anthracycline anticancer agent, a taxane anticancer agent, an anti-EGFR antibody, a BK channel agonist, bortezomib, a cardiac glycoside, a cyclophosphamide anticancer agent, a GADD34 / PP1 inhibitor, LV-tSMAC, measles virus or oxaliplatin. An anthracycline anticancer agent can be daunorubicin, doxorubicin, epirubicin, idarubicin, pixantrone, sarubicin or valrubicin, a taxane anticancer agent can be paclitaxel or docetaxel, and an anti-EGFR antibody can be cetuximab.

[0183] In a more specific example, the immunogenic cell death inducing agent can be any one selected from the group consisting of capecitabine, 5-fluorouracil, thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbine, gemcitabine, pemetrexed, doxorubicin, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide, tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, temozolomide, carmustine, lomustine, epirubicin, eribulin, toremifene, goserelin, megestrol acetate, vinblastine, bendamustine, thiotepa, bleomycin, topotecan, folinic acid, trifluridine, tipizil dapoxetine, mitoxantrone, mitomycin C, aldesleukin, temsirolimus, everolimus, nitrogen mustard, methotrexate, pemetrexed, trastuzumab, bevacizumab, cetuximab, aflibercept, pertuzumab, ramucirumab, pantumumab, nivolumab, necituzumab, pembrolizumab, obinutuzumab, ofatumumab, erlotinib, gefitinib, sorafenib, lapatinib, denosib, palbociclib, regorafenib, imatinib, sunitinib, axitinib, pazopanib, afatinib, ceritinib, crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, procarbazine, abemaciclib, velutuzumab, and combinations thereof.

[0184] In one embodiment of the present invention, a composition comprising a naphthoquinone-based compound and an immunogenic cell death inducer is provided, and the combination has an excellent effect of inhibiting cancer cell proliferation compared to the case where each component is applied alone. For example, the naphthoquinone-based compound can be compound No. 2 (Dongnione) in Table 1, and the immunogenic cell death inducer can be any one selected from the group consisting of the following items: 5-fluorouracil, oxaliplatin, paclitaxel, irinotecan, folinic acid, doxorubicin, docetaxel, cyclophosphamide, mitoxantrone, everolimus, gefitinib, sorafenib, denosyl, regorafenib, afatinib, carboplatin, abemaciclib, velutase, lapatinib, pemetrexed and a combination thereof.

[0185] In addition, in one embodiment of the present invention, a composition for co-administration is provided, which is used for treating cancer and comprises a naphthoquinone-based compound, an immune checkpoint inhibitor, and an immunogenic cell death inducer.

[0186] For example, the naphthoquinone-based compound may be Compound No. 2 of Table 1 (donone).

[0187] In addition, immune checkpoint inhibitors can be any one selected from the following items: anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-LAG3 antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-HVEM antibody, anti-KIR antibody, anti-OX40 antibody, anti-IgG antibody, anti-IDO-1 antibody, anti-IDO-2 antibody, anti-CEACAM1 antibody, anti-BTLA antibody, anti-OX40L antibody, anti-TIM3 antibody, anti-GAL9 antibody, anti-VISTA antibody, anti-TIGIT antibody and their combination. Preferably, immune checkpoint inhibitors can be any one selected from the group consisting of the following items: anti-CTLA4 antibody, anti-PD-L1 antibody, anti-PD-1 antibody, anti-LAG3 antibody and their combination.

[0188] In addition, the immunogenic cell death inducing agent may be any one selected from the group consisting of capecitabine, 5-fluorouracil, thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbine, gemcitabine, pemetrexed, doxorubicin, etoposide, vincristine, cytarabine, cyclophosphamide, ifosfamide, tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, temozolomide, carmustine, lomustine, epirubicin, eribulin, toremifene, goserelin, megestrol acetate, vinblastine, bendamustine, thiotepa, bleomycin, topotecan, folinic acid, trifluridine, tipiprimidine, m Toxantrone, mitomycin C, aldesleukin, temsirolimus, everolimus, nitrogen mustard, methotrexate, pemetrexed, trastuzumab, bevacizumab, cetuximab, aflibercept, pertuzumab, ramucirumab, pantumumab, nivolumab, necituzumab, pembrolizumab, obinutuzumab, ofatumumab, erlotinib, gefitinib, sorafenib, lapatinib, denosib, palbociclib, regorafenib, imatinib, sunitinib, axitinib, pazopanib, afatinib, ceritinib, crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, procarbazine, abemaciclib, velutuzumab, and combinations thereof. Preferably, the immunogenic cell death inducer can be any one selected from the group consisting of 5-fluorouracil, oxaliplatin, paclitaxel, irinotecan, folinic acid, doxorubicin, docetaxel, cyclophosphamide, mitoxantrone, everolimus, gefitinib, sorafenib, denocillib, regorafenib, afatinib, carboplatin, abemaciclib, velutipet, and combinations thereof.

[0189] The cancer that can be prevented or treated with the composition according to the present invention can be any one selected from the group consisting of liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, small intestine cancer, rectal cancer, perianal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, lymph node cancer, bladder cancer, gallbladder cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, adenocarcinoma, chronic or acute leukemia, lymphocytic lymphoma, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal cord tumors, brain stem gliomas, pituitary adenomas, and combinations thereof, but are not limited thereto.

[0190] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising a naphthoquinone-based compound as an active ingredient, wherein the naphthoquinone-based compound is used in combination with at least one selected from an immune checkpoint inhibitor and an immunogenic cell death inducer. In other words, the naphthoquinone-based compound can be used in combination with an immune checkpoint inhibitor and / or an immunogenic cell death inducer to prevent or treat cancer.

[0191] Here, for the description of the naphthoquinone-based compound, the immune checkpoint inhibitor, and the immunogenic cell death inducer, reference is made to the above description.

[0192] Specifically, for the purpose of preventing or treating cancer, the naphthoquinone-based compound can be used in the form of a combination drug in which the naphthoquinone-based compound is mixed with at least one selected from an immune checkpoint inhibitor and an immunogenic cell death inducer, or can be used in a form in which the naphthoquinone-based compound and at least one selected from an immune checkpoint inhibitor and an immunogenic cell death inducer are formulated and administered simultaneously or sequentially.

[0193] For example, naphthoquinone-based compounds can be dosage forms for oral administration, and can be applied once a week to 7 times a week, 2 times a week to 5 times a week, or 3 times a week.Here, naphthoquinone-based compounds can be used in combination with immune checkpoint inhibitors, which are dosage forms for intraperitoneal administration, and the immune checkpoint inhibitors can be applied daily, at intervals of 2 days, 3 days, 4 days, 5 days or 6 days, or once a week to 3 times a week.In addition, naphthoquinone-based compounds can be used in combination with immunogenic cell death inducers, which are dosage forms for intraperitoneal administration or oral administration, and the immunogenic cell death inducers can be applied daily, at intervals of 2 days, 3 days, 4 days, 5 days or 6 days, or once a week to 3 times a week.According to the scheme of each substance, naphthoquinone-based compounds can be applied independently of immune checkpoint inhibitors and / or immunogenic cell death inducers.

[0194] In addition, based on a single dose, the naphthoquinone-based compound, the immune checkpoint inhibitor and the immunogenic cell death inducer can be co-administered in a weight ratio of 1: (0.001 to 500): (0.1 to 1,000), a weight ratio of 1: (0.001 to 300): (0.1 to 500), or a weight ratio of 1: (0.001 to 0.1): (0.2 to 5). For example, the naphthoquinone-based compound and the immune checkpoint inhibitor can be co-administered in a weight ratio of 1,000: 1 to 1: 10, 500: 1 to 1: 1, 250: 1 to 5: 1, 200: 1 to 2.5: 1, or 100: 1. Additionally, the naphthoquinone-based compound and the immunogenic cell death inducer may be co-administered in a weight ratio of 5:1 to 1:5, 3:1 to 1:3, 2:1 to 1:2, 3:2 to 2:3, or 1:0.001 to 0.001:1.

[0195] The pharmaceutical composition for preventing or treating cancer according to the present invention can be prepared into the dosage form for oral administration, and can be orally administered. The example of the dosage form for oral administration includes tablets, pills, hard / soft capsules, liquid medicines, suspensions, emulsifiers, syrups, granules and elixirs, and such dosage forms also include diluents (for example, lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine) and lubricants (for example, silicon dioxide, talcum, stearic acid and its magnesium salt or calcium salt, and / or polyethylene glycol) in addition to active ingredients. Tablets may also include adhesives such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and may optionally include disintegrants or effervescent mixtures such as starch, agar and alginic acid or its sodium salt, and / or absorbents, coloring agents, flavoring agents and sweeteners.

[0196] In addition, the pharmaceutical composition for preventing or treating cancer according to the present invention can be administered parenterally, and the parenteral administration is carried out by a method for injecting a subcutaneous injection, an intravenous injection, an intramuscular injection or an intrathoracic injection. Here, in order to be formulated into a dosage form for parenteral administration, a pharmaceutical composition comprising a naphthoquinone-based compound as an active ingredient and a stabilizer or a buffer can be mixed with water to prepare a solution or suspension, and the solution or suspension can be prepared into an ampoule or a vial unit administration form. The composition can be sterile and / or can include adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, or salts and / or buffers for regulating osmotic pressure, and other therapeutically useful substances. In addition, the composition can be prepared according to conventional methods such as mixing, granulation or coating. In the same way, naphthoquinone-based compounds and immune checkpoint inhibitors and / or immunogenic cell death inducers can be prepared together or separately, and can be applied simultaneously or sequentially.

[0197] In another aspect of the present invention, a method for preventing or treating cancer is provided, the method comprising administering to a subject a pharmaceutical composition comprising a naphthoquinone-based compound and at least one selected from an immune checkpoint inhibitor (ICI) and an immunogenic cell death (ICD) inducer.

[0198] Specifically, the pharmaceutical composition may include a naphthoquinone-based compound and an immune checkpoint inhibitor. In addition, the pharmaceutical composition may include a naphthoquinone-based compound and an immunogenic cell death inducer. In addition, the pharmaceutical composition may include a naphthoquinone-based compound, an immune checkpoint inhibitor, and an immunogenic cell death inducer.

[0199] The naphthoquinone-based compound, immune checkpoint inhibitor, immunogenic cell death inducer, and administration are as described above.

[0200] The term "prevention" refers to any action of inhibiting the occurrence of cancer or delaying the onset of cancer by administering a pharmaceutical composition. The term "treatment" refers to any action of improving or beneficially changing the symptoms of cancer by administering a pharmaceutical composition.

[0201] The pharmaceutical composition according to the present invention may be used to treat any one or more cancers selected from the group consisting of colorectal cancer, breast cancer, kidney cancer, skin cancer (melanoma), liver cancer and lung cancer, but is not limited thereto.

[0202] More specifically, when the cancer is colorectal cancer, for example, the combined use of donidone as a naphthoquinone-based compound, anti-PD-1 antibody and / or anti-CTLA4 antibody as immune checkpoint inhibitors, and regorafenib as an immunogenic cell death inducer or a combination drug of oxaliplatin and 5-fluorouracil can have a significant effect on the tumor growth inhibition rate.

[0203] When the cancer is breast cancer, for example, the combined use of dongnione as a naphthoquinone-based compound, anti-PD-1 antibody or anti-CTLA4 antibody as an immune checkpoint inhibitor, and mitoxantrone or lapatinib as an immunogenic cell death inducer can produce a significant effect on the tumor growth inhibition rate.

[0204] When the cancer is renal cancer, for example, the combined use of dongnione as a naphthoquinone-based compound, anti-PD-1 antibody or anti-CTLA4 antibody as an immune checkpoint inhibitor, and everolimus, sorafenib or velutipet as an immunogenic cell death inducer can produce a significant effect on the tumor growth inhibition rate.

[0205] When the cancer is skin cancer, for example, the combined use of dongnione as a naphthoquinone-based compound, anti-PD-L1 antibody, anti-PD-1 antibody or anti-CTLA4 antibody as an immune checkpoint inhibitor, and paclitaxel, regorafenib, velutipet or everolimus as an immunogenic cell death inducer can produce a significant effect on the tumor growth inhibition rate.

[0206] When the cancer is liver cancer, for example, the combined use of dongnione as a naphthoquinone-based compound, anti-CTLA4 antibody as an immune checkpoint inhibitor, and sorafenib or everolimus as an immunogenic cell death inducer can produce a significant effect on the tumor growth inhibition rate.

[0207] When the cancer is lung cancer, for example, the combined use of dongnione as a naphthoquinone-based compound, an anti-PD-1 antibody as an immune checkpoint inhibitor, and a combination drug of carboplatin and pemetrexed as an immunogenic cell death inducer can produce a significant effect on the tumor growth inhibition rate.

[0208] The pharmaceutical composition according to the present invention can be administered to a patient in a therapeutically effective amount or in a pharmaceutically effective amount.

[0209] Here, "therapeutically effective amount" or "pharmaceutically effective amount" is an amount of a compound or composition that is effective for preventing or treating a target disease, and refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and without causing side effects. The level of an effective amount can be determined based on factors including the patient's health status, the type of disease, severity, drug activity, sensitivity to the drug, administration method, administration time, administration route, excretion rate, duration of treatment, drugs used in combination or simultaneously, and other factors well known in the medical field.

[0210] The subject can be a mammal such as a human, cow, horse, pig, dog, sheep, goat or cat. The subject can be a patient suffering from cancer such as liver cancer, stomach cancer, colon cancer, breast cancer or lung cancer, or a subject who is more likely to suffer from cancer.

[0211] In another aspect of the present invention, a use of a composition for preparing a pharmaceutical composition for preventing or treating cancer is provided, wherein the composition comprises a naphthoquinone-based compound and at least one selected from an immune checkpoint inhibitor (ICI) and an immunogenic cell death (ICD) inducer.

[0212] Another aspect of the present invention provides a use of a composition for preventing or treating cancer, wherein the composition comprises a naphthoquinone-based compound and at least one selected from an immune checkpoint inhibitor (ICI) and an immunogenic cell death (ICD) inducer.

[0213] The naphthoquinone-based compound, immune checkpoint inhibitor and immunogenic cell death inducer are as described above.

[0214] Hereinafter, the present invention will be described in detail with reference to the following examples. Herein, the following examples are only used to exemplarily describe the present invention, and the content of the present invention is not limited by the following examples.

[0215] Example 1. Tumor Proliferation Assessment

[0216] Example 1.1. Preparation and evaluation of tumor implantation animal model

[0217] All mice used in the experiments were housed in a sterile animal room with a constant temperature (22°C to 26°C) and constant humidity (55% to 60%), and were acclimatized for 1 week with adequate supply of typical solid feed (Samtako Co., Korea) and water before being used. All experiments were performed in accordance with the Laboratory Animal Care and Use Committee of Wonkwang University in accordance with the Laboratory Animal Care and Use Committee's ethical regulations, after obtaining approval from the Laboratory Animal Care and Use Committee.

[0218] 7-week-old BALB / c or C57BL / 6 mice were used and subcutaneously inoculated into the mice using a 1 mL insulin syringe within 30 minutes after mixing mouse cancer cells with 0.2 mL of PBS. Information on animal models for each cancer type is shown in Table 3 below.

[0219] [Table 3]

[0220]

[0221]

[0222] After subcutaneous implantation of cancer cell lines, when the tumor size reached 50 mm 3 Up to 100mm 3 The volume of the tumors produced after inoculation was measured at 3-day intervals using a caliper (mm 3), use the formula length × width / 2 to calculate, and then compare the results.

[0223] Example 1.2. Evaluation of tumor proliferation according to single administration and co-administration of each drug

[0224] Dongnione (2,3,3-trimethyl-2H-benzo[g][1]benzofuran-4,5-dione) represented by the following structural formula is used as the naphthoquinone-based compound (C 15 H 14 O3, 242.274 g / mol):

[0225]

[0226] In addition, each drug was administered alone or in combination according to the administration schedule listed in Table 4 to Table 34 below, and then the tumor volume was measured according to the tumor proliferation evaluation method described in Example 1.1, and the tumor growth inhibition rate was calculated based on these tumor volumes (TGI (%) = (Vc-Vt) / Vc×100 (%); Vc: tumor volume of the control group, Vt: tumor volume of the experimental group), and the results are shown in the tables and Figures 1 to 31 shown.

[0227] [Table 4]

[0228]

[0229]

[0230] [Table 5]

[0231]

[0232] [Table 6]

[0233]

[0234]

[0235] [Table 7]

[0236]

[0237] [Table 8]

[0238]

[0239] [Table 9]

[0240]

[0241]

[0242] [Table 10]

[0243]

[0244] [Table 11]

[0245]

[0246] [Table 12]

[0247]

[0248]

[0249] [Table 13]

[0250]

[0251] [Table 14]

[0252]

[0253]

[0254] [Table 15]

[0255]

[0256] [Table 16]

[0257]

[0258] [Table 17]

[0259]

[0260]

[0261] [Table 18]

[0262]

[0263] [Table 19]

[0264]

[0265] [Table 20]

[0266]

[0267]

[0268] [Table 21]

[0269]

[0270] [Table 22]

[0271]

[0272] [Table 23]

[0273]

[0274]

[0275] [Table 24]

[0276]

[0277] [Table 25]

[0278]

[0279] [Table 26]

[0280]

[0281] [Table 27]

[0282]

[0283] [Table 28]

[0284]

[0285] [Table 29]

[0286]

[0287] [Table 30]

[0288]

[0289] [Table 31]

[0290]

[0291] [Table 32]

[0292]

[0293] [Table 33]

[0294]

[0295] [Table 34]

[0296]

[0297]

[0298] Refer to Tables 4 to 34 and Figures 1 to 31, it was confirmed that when naphthoquinone-based compounds were administered in combination with immune checkpoint inhibitors and / or immunogenic cell death inducers, the effect of inhibiting cancer cell proliferation was significantly better than when each substance was administered alone.

[0299] Example 2. Analysis of tumor metastasis

[0300] Example 2.1. Preparation of tumor metastasis animal model and tumor metastasis analysis method

[0301] The mouse breast cancer cell line 4T1-Luc (2.5×10 6 cells) were implanted into the mammary fat pad of BALB / c mice, and when the tumor size reached 150 mm 3 Up to 200mm 3 The tumor was removed by surgical resection at the time of the operation. The administration of the drug was started from the day after the tumor resection operation, and the extent of cancer metastasis was measured by measuring the amount of photon emission at intervals of 1 week from the 3rd day after the tumor resection operation.

[0302] Example 2.2. Evaluation of tumor metastasis according to single administration and co-administration of each drug

[0303] After the individual or co-administration of each drug according to the administration schedule listed in Table 35 below, the photon emission amount (multiple) was measured on the 17th day according to the tumor metastasis evaluation method described in Example 2.1, and the results are shown in Tables 35 and Fig.32 shown.

[0304] [Table 35]

[0305]

[0306] Refer to Table 35 and Fig.32 , confirmed that when a naphthoquinone-based compound was administered in combination with an immune checkpoint inhibitor, or when a naphthoquinone-based compound and an immunogenic cell death inducer and an immune checkpoint inhibitor, that is, these three substances were co-administered, cancer cell metastasis was significantly reduced compared to the case where each substance was administered alone.

[0307] Example 3. Survival rate analysis

[0308] Example 3.1. Survival rate analysis method

[0309] After subcutaneous implantation of cancer cell lines, the survival rate was measured by recording the number of mice that died in each group every day. The measurement of the survival rate was carried out until all mice in all groups died or all mice in the control group died. The mean survival days were calculated by using the survival rate to obtain a survival curve.

[0310] Example 3.2. Survival rate analysis according to single administration and co-administration of each drug

[0311] After the individual or co-administration of each drug according to the administration regimen listed in Table 36 and Table 37 below, the survival rate and the average survival days were calculated according to the survival rate analysis method described in Example 3.1, and the results are shown in Table 36 and Table 37 and Fig.33 and Fig.34 shown.

[0312] [Table 36]

[0313]

[0314] [Table 37]

[0315]

[0316]

[0317] Refer to Table 36 and Table 37 and Fig.33 and 34 It can be seen that when the naphthoquinone-based compounds were administered alone, the effect of improving the survival rate of mice was not significant, but when the naphthoquinone-based compounds were administered in combination with immune checkpoint inhibitors and immunogenic cell death inducers, the survival rate and average survival days of mice were significantly increased.

[0318] Example 4. Assessment of tumor proliferation using genetically engineered mouse models (GEMM)

[0319] Example 4.1. Construction of spontaneous non-small cell lung cancer model and drug administration

[0320] Conditional mutant mice with Ras activation and p53 mutation were constructed by crossing conditional K-Ras activation mutation-genetically engineered mice with conditional p53 mutation-genetically engineered mice (Kras LSL-G12D / + ;Trp53 flox / flox mice), and then an adenovirus into which the Cre gene was introduced (Ad5-CMV-Cre; 2.5×10 7PFU / infectious unit) was instilled into the lungs through the trachea to induce a spontaneous non-small cell lung cancer model. After 12 weeks of inducing Cre protein expression using adenoviral vectors, the development of cancer in the lungs of mice was examined by micro-CT imaging. The experimental groups were set as control group, Dongnidone (40 mg / kg) administration group, carboplatin (25 mg / kg) + paclitaxel (10 mg / kg) administration group, carboplatin (25 mg / kg) + paclitaxel (10 mg / kg) + Dongnidone (40 mg / kg) administration group, anti-PD-1 antibody (200 μg / head) administration group The mice were divided into the drug group, the anti-PD-1 antibody (200 μg / head) + Dongnidone (40 mg / kg) administration group, the carboplatin (25 mg / kg) + paclitaxel (10 mg / kg) + anti-PD-1 antibody (200 μg / head) administration group and the carboplatin (25 mg / kg) + paclitaxel (10 mg / kg) + anti-PD-1 antibody (200 μg / head) + Dongnidone (40 mg / kg) administration group, and then the drug administration was started (see Table 38).

[0321] Example 4.2. Tumor proliferation analysis according to single administration and co-administration of each drug

[0322] According to the following table 38 and Fig.35 After single administration or co-administration of each drug according to the administration regimen listed in , the tumor growth rate of each group compared with that before drug administration was measured by micro CT imaging at week 6, and the results are summarized in Table 39.

[0323] [Table 38]

[0324]

[0325]

[0326] [Table 39]

[0327]

[0328] Example 5. Analysis of immune-related adverse events (irAEs) according to administration of anticancer agents

[0329] Example 5.1. Analysis of adverse reactions according to the administration of immune checkpoint inhibitors

[0330] Immune checkpoint inhibitors are known to cause milder adverse reactions than existing cytotoxic anticancer agents, but may rarely cause fatal or permanent functional impairment. Fig.36 Each drug was administered alone or in combination according to the administration regimen listed in , and then the adverse reactions of each organ were analyzed, and the results were shown as follows Figures 37 to 40 shown.

[0331] [Table 40]

[0332]

[0333] refer to Figures 37 to 40 , it can be seen that in the myocardial hypertrophy corresponding to the adverse reactions induced by the administration of immune checkpoint inhibitors ( Fig.37 ),hepatitis( Fig.38 ),pneumonia( Fig.39 ) and pancytopenia ( Fig.40 ), the incidence of such adverse reactions was significantly reduced by the single or co-administration of naphthoquinone-based compounds.

[0334] Example 5.2. Analysis of adverse reactions according to the administration of immune checkpoint inhibitors and immunogenic cell death inducers

[0335] The adverse reactions to each organ caused by the administration of immune checkpoint inhibitors and existing chemical anticancer agents accompanied by various immune-related adverse reactions were analyzed. According to the following Table 41 and Fig.41 After the administration of each drug alone or in combination according to the administration regimen listed in , the adverse reactions in each organ were analyzed, and the results were as follows: Figure 42 to Figure 46 Here, in order to minimize the side effects of existing chemical anticancer drugs, metronomic anticancer therapy (metronomic treatment) in which low doses of anticancer drugs are regularly administered is being performed.

[0336] [Table 41]

[0337]

[0338] refer to Fig.42 Fig.46 , it can be seen that in heart failure ( Fig.42 ), decreased ovarian size ( Fig.43 ),pneumonia( Fig.44 )、Nephritis( Fig.45 ) and pancytopenia ( Fig.46 ), the incidence of such adverse reactions was significantly reduced by co-administration of naphthoquinone-based compounds.

[0339] Example 6. Analysis of immunogenic cell death of tumor cells

[0340] Example 6.1. Immunogenic Cell Death Assay

[0341] Calreticulin is one of the most important molecules in the process of immunogenic cell death. When calreticulin appears on the tumor cell membrane, a strong signal can be generated for phagocytes including dendritic cells to cause phagocytes to attack dying tumor cells. This is the most important "eat me" signal for immune cells. Whether the anticancer agent used in the present invention induces immunogenic cell death is evaluated by quantitative changes in calreticulin expressed on the surface of cancer cells after treatment with anticancer agents. Single cells isolated from tumors were incubated with anti-calreticulin antibodies (ratio of 1:50) as primary antibodies at 4°C for 30 minutes and then washed twice with PBS. After washing, the cells were stained with AlexaFluor488 anti-goat IgG antibodies (ratio of 1:500) as secondary antibodies, then fixed with a fixative, and the level of calreticulin (ecto-CRT) expressed on the cell surface was observed using a flow cytometer. The expression of calreticulin increased by 20% or more compared to the control group and was considered to induce immunogenic cell death.

[0342] [Table 42]

[0343]

[0344] Referring to Table 42, it was confirmed that the anticancer agents used in the present invention increased the expression rate of calreticulin on the cell surface of various cancers. Therefore, it can be seen that immunogenic cell death is induced by various anticancer agents used in the present invention.

Claims

1. A pharmaceutical composition for preventing or treating cancer, comprising as an active ingredient: Dongnione (2,3,3-trimethyl-2H-benzo[g][1]benzofuran-4,5-dione); and At least one selected from immune checkpoint inhibitors (ICIs) and immunogenic cell death (ICD) inducers, wherein the immune checkpoint inhibitor comprises any one selected from the following group: anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-LAG3 antibody and a combination thereof, The immunogenic cell death inducer comprises any one selected from the following group: oxaliplatin, regorafenib, abemaciclib, irinotecan, folinic acid, lapatinib, everolimus, sorafenib, velutrinib, carboplatin, pemetrexed and a combination thereof.

2. The pharmaceutical composition according to claim 1, wherein the composition comprises the dongnidone, the immune checkpoint inhibitor and the immunogenic cell death inducer as active ingredients.

3. The pharmaceutical composition according to claim 1, wherein the composition is in the form of a composite dosage form in which the dongnidone is mixed with at least one selected from the immune checkpoint inhibitor and the immunogenic cell death inducer.

4. The pharmaceutical composition according to claim 1, wherein the composition is in a form in which the dongnidone and at least one selected from the immune checkpoint inhibitor and the immunogenic cell death inducer are separately formulated and administered simultaneously or sequentially.

5. The pharmaceutical composition according to claim 1, wherein the donidone is administered orally, and the immune checkpoint inhibitor and the immunogenic cell death inducer are administered intravenously, orally or intraperitoneally.

6. The pharmaceutical composition according to claim 1, wherein Based on a single dose of the composition, the dongnione and the immune checkpoint inhibitor are co-administered in a weight ratio of 1:0.001 to 1:0.1, and the dongnione and the immunogenic cell death inducer are co-administered in a weight ratio of 1:0.2 to 1:

5.

7. The pharmaceutical composition according to claim 1, wherein the immune checkpoint inhibitor comprises two different types of immune checkpoint inhibitors.

8. The pharmaceutical composition of claim 1, wherein the immunogenic cell death inducers comprise two different types of immunogenic cell death inducers.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the cancer is any one selected from the group consisting of liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, small intestine cancer, rectal cancer, perianal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, lymph node cancer, bladder cancer, gallbladder cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, adenocarcinoma, chronic or acute leukemia, lymphocytic lymphoma, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphomas, spinal cord tumors, brain stem gliomas, pituitary adenomas, and combinations thereof.

10. A composition for use in the preparation of a drug for preventing or treating cancer, wherein the composition comprises dongnidone and at least one selected from an immune checkpoint inhibitor (ICI) and an immunogenic cell death (ICD) inducer, wherein the immune checkpoint inhibitor comprises any one selected from the following group: anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-LAG3 antibody and a combination thereof, The immunogenic cell death inducer comprises any one selected from the following group: oxaliplatin, regorafenib, abemaciclib, irinotecan, folinic acid, lapatinib, everolimus, sorafenib, velutrinib, carboplatin, pemetrexed and a combination thereof.

11. The use according to claim 10, wherein the cancer is any one selected from the group consisting of liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, small intestine cancer, rectal cancer, perianal cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, lymph node cancer, bladder cancer, gallbladder cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, adenocarcinoma, chronic or acute leukemia, lymphocytic lymphoma, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphomas, spinal cord tumors, brain stem gliomas, pituitary adenomas, and combinations thereof.

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