WO2019035522A1 - Composition for preventing or treating cancer containing triazolopyridine-based derivative as active ingredient - Google Patents
Composition for preventing or treating cancer containing triazolopyridine-based derivative as active ingredient Download PDFInfo
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- WO2019035522A1 WO2019035522A1 PCT/KR2018/002502 KR2018002502W WO2019035522A1 WO 2019035522 A1 WO2019035522 A1 WO 2019035522A1 KR 2018002502 W KR2018002502 W KR 2018002502W WO 2019035522 A1 WO2019035522 A1 WO 2019035522A1
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- WIPO (PCT)
- Prior art keywords
- cancer
- pyridin
- triazolo
- piperidine
- carboxamide
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- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- 229950002376 tirapazamine Drugs 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Images
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
Definitions
- the present invention relates to a pharmaceutical composition for preventing or treating cancer, a composition for promoting an anti-cancer effect, or a health food for cancer prevention or improvement, which comprises a triazolopyridine derivative as an active ingredient.
- Chemotherapy, surgery, and radiation therapy have been used to treat cancer.
- chemotherapy is the most commonly used method for treating cancer as an anticancer drug.
- Today, about 60 kinds of anticancer drugs are used in clinical practice.
- new anticancer drugs are being developed.
- most of the anticancer drugs currently used in clinical practice are accompanied by side effects such as nausea, vomiting, ulcers in the mouth and small intestine, diarrhea, hair loss, and bone marrow suppression in which production of blood active ingredients is decreased.
- side effects such as nausea, vomiting, ulcers in the mouth and small intestine, diarrhea, hair loss, and bone marrow suppression in which production of blood active ingredients is decreased.
- mitomycin-C is known to cause renal insufficiency
- adriamycin has a side effect such as bone marrow suppression.
- cisplatin which is the most useful anticancer drug developed so far, is widely used for the treatment of testicular cancer, ovarian cancer, lung cancer, head and neck cancer, bladder cancer, stomach cancer and cervical cancer, but hematopoietic toxicity such as anemia, vomiting, Such as kidney toxicity such as digestive tract toxicity, kidney tubular damage, hearing loss, internal electrolyte abnormality, shock, peripheral neuropathy, etc., have been a major problem. Therefore, it is urgently required to develop a novel anticancer drug having excellent safety.
- the radiation therapy sensitizers reported so far are mainly anticancer agents such as Taxol and cisplatin which can be used as radiation therapy sensitizers in solid tumors such as breast cancer, uterine cancer, lung cancer, stomach cancer and colon cancer have.
- tirapazamine is a radiotherapeutic effect enhancer that is not used as an anticancer agent but only for radiation therapy. However, it is effective only for hypoxic tumor cells. Because of the pressure inside the tumor due to hypoxic conditions, It is known that the radiation therapy sensitizers have a low effect on clinical radiotherapy and their use is limited since they have high side effects.
- the present invention aims to provide a composition for enhancing an anticancer therapy effect which can solve the side effects of conventional anticancer therapy or radiation therapy and improve the anticancer treatment effect.
- the present invention provides a triazolo pyridine-based derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
- R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,
- X may be any one selected from nitrogen and carbon.
- the present invention provides a pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a triazolo pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,
- X is any one selected from nitrogen and carbon.
- the present invention provides a composition for enhancing an anticancer effect comprising, as an active ingredient, a triazolo pyridine derivative represented by the general formula (1) or a pharmaceutically usable salt thereof.
- the present invention also provides a health food for preventing or ameliorating cancer comprising, as an active ingredient, a triazolopyridine-based derivative represented by the general formula (1) or a pharmaceutically usable salt thereof.
- the triazolo pyridine derivative represented by the formula (1) inhibits the enzyme activity of the tumor cell line and inhibits the expression of the tumor factor beta -catenin, thereby increasing the cancer cell death by apoptosis .
- An anticancer agent or a radiation irradiation the triazole pyridine derivative can be used as a pharmaceutical composition for preventing and treating cancer, a composition for enhancing the effect of an anticancer agent or a radiation therapy, or a composition for preventing or improving cancer It can be usefully used as a health functional food.
- FIG. 1 shows the result of confirming concentration-dependent inhibition of TNKS activity by treating Compound 1 or Compound 2, which is a triazolepyridine derivative, in a test tube by concentration.
- FIG. 2 shows the results of confirming inhibition of ⁇ -catenin protein expression and increase of tumor suppressor AXIN2, respectively, after treating Compound 1 or Compound 2, which is a triazolepyridine derivative, with DLD-1 colon cancer cells.
- FIG. 3 shows the results of confirming inhibition of expression of VEGF2 and Birc / Survivin, which are sub-genes of ⁇ -catenin, after treating DLD-1 colorectal cancer cells with Compound 1 or Compound 2, which is a triazolopyridine derivative.
- FIG. 4 shows the result of confirming cell viability after treatment of DLD-1 colon cancer cells in which APC (mutant adenomatous polyposis coli) gene was mutagenized with Compound 1 or Compound 2, which is a triazole pyridine derivative, upon irradiation.
- APC mutant adenomatous polyposis coli
- FIG. 5 shows the results of confirming the decrease in cell survival rate after the combination treatment of the anticancer agent 5-FU and the triazolepyridine derivative, Compound 1 or Compound 2, into two colon cancer cell lines mutated with the APC gene.
- FIG. 6 shows the results of confirming the decrease of CYR61 and CTGF, which are subgenera of tumor factor YAP / TAZ, after treatment of Compound 1 or Compound 2, which is a triazolo pyridine derivative, in DLD-1 colon cancer cell line.
- FIG. 7 shows the results of confirming the decrease in cell viability after treatment of SKMEL28 melanoma cell line and SKMEL28 cell line, which is a BRAF inhibitory anticancer drug, with the compound 1 or 2, which is a triazolopyridine derivative, at various concentrations.
- the present invention can provide a triazolo pyridine-based derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
- R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,
- X may be any one selected from nitrogen and carbon.
- R 1 and R 2 of the compound may be the same or different and are selected from the group consisting of CN, NO 2 , CF 3, and halogen, and X may be carbon.
- the above triazolo pyridine derivative may be obtained by reacting N - ([1,2,4,] triazolo [4,3- a] pyridin-3-yl) -1- (2-cyanophenyl) piperidine- (2, 3-a) pyridin-3-yl) -1- (2-nitrophenyl) piperidine-4-carboxamide, N- [1,2,4] triazolo [4,3-a] pyridin-3-yl) -1-phenylpiperidine-4-carboxamide, N- , [3-a] pyridin-3-yl) -1- (4-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-c] pyridin-4-yl) a] pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine-4-carboxamide, N- Pyridin-3-yl)
- the present invention can provide a pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a triazolo pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- R 1 and R 2 may be the same or different and each is selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl, and X may be any one selected from nitrogen and carbon.
- R 1 and R 2 of the compound may be the same or different and are selected from the group consisting of CN, NO 2 , CF 3, and halogen, and X may be carbon.
- the above triazolo pyridine derivative may be obtained by reacting N - ([1,2,4,] triazolo [4,3- a] pyridin-3-yl) -1- (2-cyanophenyl) piperidine- (2, 3-a) pyridin-3-yl) -1- (2-nitrophenyl) piperidine-4-carboxamide, N- [1,2,4] triazolo [4,3-a] pyridin-3-yl) -1-phenylpiperidine-4-carboxamide, N- , [3-a] pyridin-3-yl) -1- (4-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-c] pyridin-4-yl) a] pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine-4-carboxamide, N- Pyridin-3-yl)
- Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer, and rectal cancer.
- the triazolopyridine derivatives can be effectively used for the treatment of cancer cells in which ⁇ -catenin, which is a tumor factor, is overexpressed by inhibiting the activity of Tankyrase (TNKS) enzyme.
- TNKS Tankyrase
- the TNKS is a telomeric repeat binding factor 1 (TRF1) which is a double-stranded telomer repeat protein; Nuclear-Mitotic associated protein (NuMA), an essential protein in the mitotic spindle assembly; IRAP (aminopeptidase), an endogenous membrane protein involved in glucose uptake in response to insulin; And myeloid leukemia cell differentiation protein (Mcl-1), an apoptosis-promoting protein, and exhibits biological functions through their various interactions.
- TRF1 telomeric repeat binding factor 1
- NuMA nuclear-Mitotic associated protein
- IRAP aminopeptidase
- Mcl-1 myeloid leukemia cell differentiation protein
- the triazolo pyridine compounds 1-12 inhibited the activity of the TNKS-1 enzyme as shown in Table 1, while confirming that the PARP-1 activity was not inhibited, It was confirmed that the activity of the derivative was specific to the TNKS-1 enzyme.
- the triazolopyridine compounds 1 and 2 identified as TNKS enzyme activity inhibitors were treated with DLD-1 colon cancer cells mutated with the APC gene, and as a result, as shown in FIG. 2, , But the expression of AXIN2 protein was increased.
- the triazolepyridine derivative inhibited the activity of the Tankyrase (TNKS) enzyme and expressed ⁇ -catenin Can be provided as an anticancer agent that increases cancer cell death by apoptosis.
- the pharmaceutical composition for preventing or treating cancer which comprises the compound represented by Formula 1 or a pharmaceutically utilizable salt thereof as an active ingredient, may be administered orally, parenterally, , Pills, capsules, suppositories, gels, suspensions, emulsions, drops, or liquid preparations can be used.
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, disintegrant, sweetener, coating, swelling agent, lubricant, lubricant, flavoring agent, antioxidant, buffer, A dispersant, a surfactant, a binder, and a lubricant.
- carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
- Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
- the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
- As the suppository base witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
- the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.
- the preferred dosage of the compound represented by Formula 1 may vary depending on the condition and body weight of the subject, the type and degree of disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art.
- the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto.
- the administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
- the 'subject' may be a mammal including a human, but is not limited thereto.
- the present invention also provides a composition for enhancing an anticancer effect comprising a triazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the anticancer effect enhancing composition may be treated with an anticancer agent or radiation.
- the anticancer agent is selected from the group consisting of cisplatin, 5-fluorouracil, Paclitaxel, Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Actinomycin D, Teniposide, Etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin, and mitomycin, And C (mitomycin-C).
- the composition may comprise 1 to 99 parts by weight of an anticancer agent and 1 to 99 parts by weight of a triazolopyridine derivative represented by the general formula (1), based on 100 parts by weight of the total composition.
- composition for enhancing the anticancer effect may be used for the treatment of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, , Cancer of the larynx, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer and rectal cancer.
- the compound 1 and the compound 2 were treated with 20 ⁇ M of the DLD-1 colon cancer cells cultured, irradiated with 3 Gy of gamma irradiation, cultured for 3 days, As a result, when the triazolepyridine compound 1 or compound 2 was treated with irradiation with radiation as shown in Fig. 4, the survival rate of the cancer cells was confirmed to decrease.
- Compound 1 or Compound 2 was treated with DLT-1 cells and SW480 cells at a concentration of 20 ⁇ M for 48 hours in combination with 5-FU (10 ⁇ M), a colorectal cancer treatment anticancer agent, and MTT assay was performed to confirm cell viability
- 5-FU 10 ⁇ M
- MTT assay MTT assay
- the triazolopyridine compound when the triazolopyridine compound is treated with an anticancer agent or radiation, the triazolopyridine compound can be used as an anticancer agent adjuvant.
- the present invention also provides a health food for preventing or ameliorating cancer, which comprises a triazolopyridine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer, and rectal cancer.
- the health food may be used in combination with other food or food additives in addition to the triazolopyridine derivative represented by Formula 1 or its pharmaceutically usable salt, and may be suitably used according to a conventional method.
- the amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
- the effective dose of the compound contained in the above-mentioned health food may be used in accordance with the effective dose of the therapeutic agent, but may be less than the above range for health and hygiene purposes or for long-term intake for health control purposes, It is clear that the component can be used in an amount of more than the above range since there is no problem in terms of safety.
- the type of the health food includes meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.
- the present invention provides a triazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the triazolopyridine derivative or a pharmaceutically acceptable salt thereof is an in vitro
- the present invention provides a reagent composition for inhibiting the activity of a Tancirase enzyme activity, which is characterized by inhibiting the activity of the Tankyrase (TNKS) enzyme in the cell in vitro.
- Tancirase enzyme activity which is characterized by inhibiting the activity of the Tankyrase (TNKS) enzyme in the cell in vitro.
- the present invention also relates to a method for inhibiting the activity of a cell's tryptase enzyme activity in vitro, comprising the step of treating a cancer cell with a triazolo pyridine derivative represented by the formula 1 or a pharmaceutically acceptable salt thereof Can be provided.
- the triazolepyridine derivative compounds 1 to 12 represented by the following Chemical Formulas 1 to 12, were synthesized as follows.
- the starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the same manner as in Scheme 1, by using an amide coupling reaction using dipyridinium chloride and halobutyl chloride in the presence of dichloromethane, 21 mg was obtained in a yield of 25%.
- the starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the presence of diisocyanate and HOCI in the presence of an amide coupling reaction to obtain Compound 25 mg was obtained in a yield of 29%.
- the starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the presence of diisocyanate and H < 22 mg was obtained in a yield of 25%.
- the starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound (3) in the form of an amide coupling reaction using diisocyanate and H < 24 mg was obtained in a yield of 28%.
- starting material (1) and carboxylic acid (2) were reacted with compound 10 (3) in the presence of triethylamine and dichloromethane as a solvent via an amide coupling reaction using edicyl chloride and H- Was obtained in a yield of about 23%.
- the starting material (1) and the carboxylic acid (4) are reacted with compound 11 (5) in the presence of triethylamine and dichloromethane as a solvent, using acetic acid chloride and HCl, 20 mg was obtained in a yield of about 26%.
- the starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound (12) (3) in the form of an amide coupling reaction using epichlorohydrin and H- 20 mg was obtained in a yield of 23%.
- PARP-1 colorimetric assay kit (Cat # 4677-096-K, Trevigen) was used to confirm that Compound 1 to Compound 12 could inhibit PARP (poly-ADP ribose polymerase) , RnD systmes) according to the manufacturer's instructions, and 1 ⁇ M olaparib was used as a positive control.
- TNKS and PARP inhibitory activities of the compounds 1 to 12 were confirmed as shown in Table 1.
- Triazolopyridine Compound 1 95.2 ⁇ 0.5 0 Triazolopyridine Compound 2 94.3 ⁇ 1.3 0 Triazolopyridine Compound 3 58.7 ⁇ 2.4 0 Triazolopyridine Compound 4 30.8 ⁇ 4.7 1.5 ⁇ 0.8 Triazolopyridine Compound 5 70.4 ⁇ 2.5 0 Triazolopyridine Compound 6 51.7 ⁇ 1.7 1.2 ⁇ 0.4 Triazolopyridine Compound 7 75.4 ⁇ 1.2 0 Triazolopyridine Compound 8 65.8 ⁇ 2.3 0.8 ⁇ 0.2 Triazolopyridine Compound 9 72.9 ⁇ 4.7 1.1 ⁇ 0.5 Triazolopyridine Compound 10 59.6 ⁇ 5.2 0.8 ⁇ 0.4 Triazolopyridine Compound 11 47.4 ⁇ 3.4 0.6 ⁇ 0.1 Triazolopyridine Compound 12 94.8 ⁇
- the triazolopyridine compounds 1 to 12 showed inhibition of the activity of the TNKS-1 enzyme as shown in Table 1, while the PARP-1 activity was not inhibited.
- the DLD-1, SW480 and SKMEL28 cell lines were purchased from the American Type Culture Collection (ATCC). The cells were treated with 10% fetal bovine serum (FBS) and 100 ⁇ g / ml streptomycin in DMEM medium (Dulbecco's modified Eagle's medium) and 100 units / ml penicillin were added and cultured at 5% CO 2 and 37 ° C, respectively.
- FBS fetal bovine serum
- DMEM medium Dulbecco's modified Eagle's medium
- the vemurafenib-resistant SKMEL28 cell line was treated with verumupenib 5 ⁇ M for one month and then treated with veraCloud 40% cell proliferation inhibitor.
- the triazolopyridine compounds 1 and 2 were confirmed by Western blotting to inhibit the expression of beta -catenin protein through TNKS inhibition and maintain the AXIN2 protein.
- DLD-1 colon cancer cells mutated with APC gene were treated with 10 ⁇ M of Compound 1 or Compound 2, respectively, and then cultured for 24 hours at 5% CO 2 and 37 ° C.
- the fractions were separated by performing electrophoresis using 10% gradient SDS-PAGE and transferred to a nitrocellulose membrane (BioRad, Hercules, CA, USA).
- the membrane was blocked with 5% skim milk and reacted with primary anti- ⁇ -catenin (USA) and anti-AXIN2 antibody (Cell signaling, USA), followed by horseradish peroxidase ) Conjugated anti-mouse IgG antibody (Santa Cruz Biotechnology, USA) and visualized using an ECL system (GE, USA).
- DLD-1 colon cancer cells mutated with APC gene were dispensed into 6 cm plates in a number of 5 ⁇ 10 5 , treated with 10 ⁇ M each of the compound 1 and the compound 2, and incubated for 8 hours under the conditions of 5% CO 2 and 37 ° C. Respectively.
- Real-time PCR was performed using Cosmogentec (Korea) oligomer capable of binding to the ⁇ -catenin sub-genes VEGF2 and Birc5 / Survivin and labeled with SYBR-Green / fluorescein qPCR master mix (Thermo Scientific, USA) followeded by measurement on a Lightcycler 96 Real-time PCR system (Roche Diagnostics, Germany).
- the cultured DLD-1 colorectal cancer cells were dispensed in a number of 3 ⁇ 10 3 cells on a 96-well cell culture plate, and the compound 1 and the compound 2 were treated at a concentration of 20 ⁇ M, irradiated with 3 Gy of gamma irradiation, 5% CO 2 and 37 ° C.
- MTT 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide
- the triazolopyridine compounds 1 and 2 can be used as a radiotherapy adjuvant which can increase the efficacy in radiotherapy.
- DLD-1 cells and SW480 cells cultured in the same manner as in Example 3 were treated with 20 ⁇ M of Compound 1 or Compound 2 in combination with 5-FU (10 ⁇ M), a colorectal cancer treatment anticancer, for 48 hours and MTT assay was performed Cell viability was analyzed.
- the triazolopyridine compound can be used as an anticancer agent adjuvant which can enhance the therapeutic effect of anticancer drugs.
- Example 5 Tumor factor Identification of anticancer effect in resistant cancer cells by inhibition of YAP activity
- TNKS activates the tumor factor YAP through Angiomotin. Therefore, in order to confirm the inhibitory effect of YAP / TAZ signaling by the TNKS inhibitor triazolopyridine compound, real-time PCR was performed in the same manner as in Example 2 Expression levels of YAP / TAZ subgenus CYR61 and CTGF were confirmed.
- the cell proliferation rate was decreased in the SKMEL28 cell line and the veramugenep resistant SKMEL28 cell line dependent on the compound 1 concentration.
- cell proliferation was further reduced in veromucennep resistant SKMEL28 cells than in SKMEL28 cells, and thus it was confirmed that the triazolopyridine compound of the present invention can be used as a highly effective anticancer agent.
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Abstract
The present invention relates to a composition for preventing or treating cancer containing a triazolopyridine-based derivative or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the triazolopyridine-based derivative inhibits tankyrase enzyme activity to suppress the expression of β-catenin, which is a tumor factor, thereby increasing cancer cell death by apoptosis. Due to exhibiting excellent survival rate reduction when used in combination with anti-cancer drugs or irradiation, the triazolopyridine-based derivative can be usefully used as a pharmaceutical composition for preventing and treating cancer, a composition for increasing the effect of radiation therapy, or a health functional food for preventing or improving cancer.
Description
본 발명은 트리아졸로피리딘계 유도체를 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물, 항암 효과 증진용 조성물 또는 암 예방 또는 개선용 건강식품에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating cancer, a composition for promoting an anti-cancer effect, or a health food for cancer prevention or improvement, which comprises a triazolopyridine derivative as an active ingredient.
현대 의학의 발달로 많은 질병이 치료 및 예방되고 있으나, 암은 여전히 치료하기 힘든 질병의 하나이다. 암은 현재 사망 원인 1위를 차지하고 있으며, 계속적으로 증가하는 추세이다.With the development of modern medicine, many diseases are being treated and prevented, but cancer is still one of the most difficult diseases to treat. Cancer is currently the number one cause of death, and it is increasing continuously.
암의 치료방법으로는 화학 요법, 수술 요법 및 방사선 치료 요법 등이 사용되고 있다. 이 중에서, 화학 요법은 항암제를 이용하는 방법으로서 암의 치료에 가장 많이 사용되고 있다. 오늘날에는 약 60 여종의 다양한 항암제가 임상에 사용되고 있으며, 암 발생 및 암세포의 특성에 대한 지식이 많이 알려짐에 따라 새로운 항암제가 계속 개발되고 있다. 그러나 현재 임상에서 사용되고 있는 항암제의 대부분은 오심, 구토, 구강 및 소장의 궤양, 설사, 탈모, 혈액 유효성분의 생산이 저하되는 골수 억제 등과 같은 부작용을 수반하는 경우가 많다. 예를 들어, 마이토마이신-C(mitomycin-C)는 신부전증, 아드리아마이신(adriamycin)은 골수억제작용 등의 부작용이 알려져 있다. 특히, 지금까지 개발된 항암제 중 가장 유용한 약제인 시스플라틴(cisplatin)은 고환암, 난소암, 폐암, 두경부암, 방광암, 위암 및 자궁경부암 등의 치료에 널리 사용되고 있으나, 빈혈 등의 조혈독성, 구토, 메스꺼움 등의 소화기 독성, 콩팥 세뇨관 손상 등의 신장독성, 난청, 체내 전해질 이상, 쇼크, 말초신경 이상 등과 같은 부작용의 발생이 큰 문제가 되고 있으므로, 안전성이 우수한 새로운 항암제의 개발이 절실히 요구되고 있다.Chemotherapy, surgery, and radiation therapy have been used to treat cancer. Of these, chemotherapy is the most commonly used method for treating cancer as an anticancer drug. Today, about 60 kinds of anticancer drugs are used in clinical practice. As knowledge of cancer development and characteristics of cancer cells is well known, new anticancer drugs are being developed. However, most of the anticancer drugs currently used in clinical practice are accompanied by side effects such as nausea, vomiting, ulcers in the mouth and small intestine, diarrhea, hair loss, and bone marrow suppression in which production of blood active ingredients is decreased. For example, mitomycin-C is known to cause renal insufficiency, and adriamycin has a side effect such as bone marrow suppression. In particular, cisplatin, which is the most useful anticancer drug developed so far, is widely used for the treatment of testicular cancer, ovarian cancer, lung cancer, head and neck cancer, bladder cancer, stomach cancer and cervical cancer, but hematopoietic toxicity such as anemia, vomiting, Such as kidney toxicity such as digestive tract toxicity, kidney tubular damage, hearing loss, internal electrolyte abnormality, shock, peripheral neuropathy, etc., have been a major problem. Therefore, it is urgently required to develop a novel anticancer drug having excellent safety.
또한, 방사선 치료를 받는 암 환자의 수가 매년 증가함에 따라, 암 치료에 있어 방사선 치료의 중요성도 증가하고 있다.In addition, as the number of cancer patients receiving radiation therapy increases year by year, the importance of radiation therapy for cancer treatment is also increasing.
그러나 암세포의 방사선 내성 획득, 고선량 방사선 치료시 정상 조직의 손상 등이 방사선 치료의 효율을 저하시키는 문제점으로 지적되어 왔다. 따라서 방사선 치료의 효율을 증진시키기 위한 방사선 치료 민감제에 대한 연구가 시도되고 있다.However, it has been pointed out that the acquisition of radiation resistance of cancer cells and the damage of normal tissues during high-dose radiation therapy have been pointed out as a problem of reducing the efficiency of radiation therapy. Therefore, studies on radiation therapy sensitizers to improve the efficiency of radiation therapy have been made.
현재까지 보고된 방사선 치료 민감제는 주로 항암제들로서, 예를 들어 택솔(Taxol)과 시스플라틴(cisplatin)이 유방암, 자궁암, 폐암, 위암, 대장암 등의 고형암에서 방사선 치료 민감제로 사용될 수 있다고 보고된 바 있다.The radiation therapy sensitizers reported so far are mainly anticancer agents such as Taxol and cisplatin which can be used as radiation therapy sensitizers in solid tumors such as breast cancer, uterine cancer, lung cancer, stomach cancer and colon cancer have.
또한, 항암제로서의 성질은 지니지 않고 방사선 치료에만 사용되는 방사선 치료 효과 증진제로는 티라파자민(tirapazamine)이 있으나 저산소증의 종양세포에만 효과가 있으며, 저산소상태 특유의 종양 내부 압력 때문에 종양 조직 내부로의 약물전달이 미흡하여 임상적 방사선 치료에서 효과가 미약하다고 알려졌으며, 이들 방사선 치료 민감제들은 높은 부작용을 가지므로 그 사용이 제한적이라는 문제점이 있다. In addition, tirapazamine is a radiotherapeutic effect enhancer that is not used as an anticancer agent but only for radiation therapy. However, it is effective only for hypoxic tumor cells. Because of the pressure inside the tumor due to hypoxic conditions, It is known that the radiation therapy sensitizers have a low effect on clinical radiotherapy and their use is limited since they have high side effects.
암세포에 대한 방사선 치료시 감수성의 차이가 존재하지만, 상기 감수성을 증진시킬 수 있다면 환자에게 더 적은 양의 방사선을 조사하면서 동일한 치료 효과를 얻을 수 있으므로, 암 치료 효과를 보이며 방사선에 대한 암세포의 민감성을 증가시킬 수 있는 항암제의 개발이 필요하다.Although there is a difference in sensitivity in the radiation therapy for cancer cells, if the sensitivity can be enhanced, the same therapeutic effect can be obtained while irradiating a smaller amount of radiation to the patient. Therefore, the cancer treatment effect is exhibited and the sensitivity of cancer cells to radiation Cancer drugs that can increase cancer risk.
본 발명은 종래의 항암제 치료 또는 방사선 치료의 부작용을 해결하고, 항암 치료 효과를 향상시킬 수 있는 항암 치료 효과 증진용 조성물을 제공하고자 한다.Disclosure of the Invention The present invention aims to provide a composition for enhancing an anticancer therapy effect which can solve the side effects of conventional anticancer therapy or radiation therapy and improve the anticancer treatment effect.
본 발명은 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 제공한다.The present invention provides a triazolo pyridine-based derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
상기 화학식 1에 있어서, In Formula 1,
상기 R1 및 R2는 각각 동일하거나 다를 수 있으며, 수소, CN, NO2, CF3, 할로겐 및 아세틸에서 선택되고,R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,
상기 X는 질소 및 탄소에서 선택된 어느 하나일 수 있다.X may be any one selected from nitrogen and carbon.
본 발명은 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a triazolo pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
상기 화학식 1에 있어서, In Formula 1,
상기 R1 및 R2는 각각 동일하거나 다를 수 있으며, 수소, CN, NO2, CF3, 할로겐 및 아세틸에서 선택되고, R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,
상기 X는 질소 및 탄소에서 선택된 어느 하나임.And X is any one selected from nitrogen and carbon.
본 발명은 상기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 항암 효과 증진용 조성물을 제공한다.The present invention provides a composition for enhancing an anticancer effect comprising, as an active ingredient, a triazolo pyridine derivative represented by the general formula (1) or a pharmaceutically usable salt thereof.
또한, 본 발명은 상기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 개선용 건강식품을 제공한다.The present invention also provides a health food for preventing or ameliorating cancer comprising, as an active ingredient, a triazolopyridine-based derivative represented by the general formula (1) or a pharmaceutically usable salt thereof.
본 발명에 따르면, 화학식 1로 표시되는 트리아졸로피리딘계 유도체는 탄키라제 효소 활성을 저해하여 종양인자 β-카테닌(β-catenin) 발현을 억제시킴으로써 세포자살(apoptosis)에 의한 암세포 사멸을 증가시키며, 항암제 또는 방사선 조사와 병용 적용할 경우, 우수한 세포 생존율 감소가 나타남에 따라, 상기 트리아졸로피리딘계 유도체는 암 예방 및 치료용 약학조성물, 항암제 또는 방사선 치료 효과 증진용 조성물 또는, 암 예방 및 개선용 건강기능식품으로 유용하게 활용될 수 있다.According to the present invention, the triazolo pyridine derivative represented by the formula (1) inhibits the enzyme activity of the tumor cell line and inhibits the expression of the tumor factor beta -catenin, thereby increasing the cancer cell death by apoptosis , An anticancer agent or a radiation irradiation, the triazole pyridine derivative can be used as a pharmaceutical composition for preventing and treating cancer, a composition for enhancing the effect of an anticancer agent or a radiation therapy, or a composition for preventing or improving cancer It can be usefully used as a health functional food.
도 1은 시험관 내에서 트리아졸로피리딘 유도체인 화합물 1 또는 화합물 2를 농도별로 처리하여 농도의존적인 TNKS 활성 저해를 확인한 결과이다.FIG. 1 shows the result of confirming concentration-dependent inhibition of TNKS activity by treating Compound 1 or Compound 2, which is a triazolepyridine derivative, in a test tube by concentration.
도 2는 DLD-1 대장암세포에 트리아졸로피리딘 유도체인 화합물 1 또는 화합물 2를 각각 처리한 후 β-카테닌(β-catenin) 단백질 발현 억제와 종양억제인자 AXIN2 증가를 확인한 결과이다.FIG. 2 shows the results of confirming inhibition of β-catenin protein expression and increase of tumor suppressor AXIN2, respectively, after treating Compound 1 or Compound 2, which is a triazolepyridine derivative, with DLD-1 colon cancer cells.
도 3는 DLD-1 대장암 세포에 트리아졸로피리딘 유도체인 화합물 1 또는 화합물 2를 각각 처리한 후 β-카테닌(β-catenin)의 하위유전자인 VEGF2와 Birc/Survivin의 발현 억제를 확인한 결과이다.FIG. 3 shows the results of confirming inhibition of expression of VEGF2 and Birc / Survivin, which are sub-genes of β-catenin, after treating DLD-1 colorectal cancer cells with Compound 1 or Compound 2, which is a triazolopyridine derivative.
도 4는 APC(adenomatous polyposis coli) 유전자가 돌연변이되어 있는 DLD-1 대장암세포에 방사선 조사시 트리아졸로피리딘 유도체인 화합물 1 또는 화합물 2를 각각 병용 처리한 후 세포 생존율을 확인한 결과이다.FIG. 4 shows the result of confirming cell viability after treatment of DLD-1 colon cancer cells in which APC (mutant adenomatous polyposis coli) gene was mutagenized with Compound 1 or Compound 2, which is a triazole pyridine derivative, upon irradiation.
도 5은 APC 유전자가 돌연변이된 대장암 세포주 2종에 항암제 5-FU와 트리아졸로피리딘 유도체인 화합물 1 또는 화합물 2를 각각 병용 처리한 후 세포 생존율 감소를 확인한 결과이다.FIG. 5 shows the results of confirming the decrease in cell survival rate after the combination treatment of the anticancer agent 5-FU and the triazolepyridine derivative, Compound 1 or Compound 2, into two colon cancer cell lines mutated with the APC gene.
도 6은 DLD-1 대장암 세포주에 트리아졸로피리딘 유도체인 화합물 1 또는 화합물 2를 각각 처리 후 종양 인자 YAP/TAZ의 하위유전자인 CYR61 및 CTGF의 감소를 확인한 결과이다.FIG. 6 shows the results of confirming the decrease of CYR61 and CTGF, which are subgenera of tumor factor YAP / TAZ, after treatment of Compound 1 or Compound 2, which is a triazolo pyridine derivative, in DLD-1 colon cancer cell line.
도 7은 SKMEL28 흑색종 세포주와 BRAF 저해 항암제인 베무라페닙 내성이 생긴 SKMEL28 세포주에 트리아졸로피리딘 유도체인 화합물 1 또는 화합물 2를 농도별로 처리한 후 세포 생존율 감소를 확인한 결과이다.FIG. 7 shows the results of confirming the decrease in cell viability after treatment of SKMEL28 melanoma cell line and SKMEL28 cell line, which is a BRAF inhibitory anticancer drug, with the compound 1 or 2, which is a triazolopyridine derivative, at various concentrations.
본 발명은 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 제공할 수 있다.The present invention can provide a triazolo pyridine-based derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
상기 화학식 1에 있어서, In Formula 1,
상기 R1 및 R2는 각각 동일하거나 다를 수 있으며, 수소, CN, NO2, CF3, 할로겐 및 아세틸에서 선택되고,R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,
상기 X는 질소 및 탄소에서 선택된 어느 하나일 수 있다.X may be any one selected from nitrogen and carbon.
상기 화합물의 R1 및 R2는 각각 동일하거나 다를 수 있으며, CN, NO2, CF3 및 할로겐으로 이루어진 군에서 선택되고, 상기 X는 탄소일 수 있다.R 1 and R 2 of the compound may be the same or different and are selected from the group consisting of CN, NO 2 , CF 3, and halogen, and X may be carbon.
상기 트리아졸로피리딘계 유도체는 N-([1,2,4,]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-페닐피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로-4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-플루오로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-아세틸페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-클로로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(5-니트로피리딘-2-일)피페리딘-4-카르복사마이드 및 N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노-4-니트로페닐)피페리딘-4-카르복사마이드으로 이루어진 군에서 선택될 수 있다.The above triazolo pyridine derivative may be obtained by reacting N - ([1,2,4,] triazolo [4,3- a] pyridin-3-yl) -1- (2-cyanophenyl) piperidine- (2, 3-a) pyridin-3-yl) -1- (2-nitrophenyl) piperidine-4-carboxamide, N- [1,2,4] triazolo [4,3-a] pyridin-3-yl) -1-phenylpiperidine-4-carboxamide, N- , [3-a] pyridin-3-yl) -1- (4-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-c] pyridin-4-yl) a] pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine-4-carboxamide, N- Pyridin-3-yl) -1- (4-fluoro-2-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyrimidin-4-yl) Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3 Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) - 1 (4-cyanophenyl) piperidine- Carboxamide and N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) -1- 2-cyano-4-nitrophenyl) piperidine-4-carboxamide.
본 발명은 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공할 수 있다.The present invention can provide a pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a triazolo pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
상기 화학식 1에 있어서, In Formula 1,
상기 R1 및 R2는 각각 동일하거나 다를 수 있으며, 수소, CN, NO2, CF3, 할로겐 및 아세틸에서 선택되고, 상기 X는 질소 및 탄소에서 선택된 어느 하나일 수 있다.R 1 and R 2 may be the same or different and each is selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl, and X may be any one selected from nitrogen and carbon.
보다 상세하게는 상기 화합물의 R1 및 R2는 각각 동일하거나 다를 수 있으며, CN, NO2, CF3 및 할로겐으로 이루어진 군에서 선택되고, 상기 X는 탄소일 수 있다.More specifically, R 1 and R 2 of the compound may be the same or different and are selected from the group consisting of CN, NO 2 , CF 3, and halogen, and X may be carbon.
상기 트리아졸로피리딘계 유도체는 N-([1,2,4,]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-페닐피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로-4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-플루오로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-아세틸페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-클로로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(5-니트로피리딘-2-일)피페리딘-4-카르복사마이드 및 N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노-4-니트로페닐)피페리딘-4-카르복사마이드으로 이루어진 군에서 선택될 수 있다.The above triazolo pyridine derivative may be obtained by reacting N - ([1,2,4,] triazolo [4,3- a] pyridin-3-yl) -1- (2-cyanophenyl) piperidine- (2, 3-a) pyridin-3-yl) -1- (2-nitrophenyl) piperidine-4-carboxamide, N- [1,2,4] triazolo [4,3-a] pyridin-3-yl) -1-phenylpiperidine-4-carboxamide, N- , [3-a] pyridin-3-yl) -1- (4-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-c] pyridin-4-yl) a] pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine-4-carboxamide, N- Pyridin-3-yl) -1- (4-fluoro-2-nitrophenyl) piperidine-4-carboxamide, N- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyrimidin-4-yl) Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3 Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) - 1 (4-cyanophenyl) piperidine- Carboxamide and N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) -1- 2-cyano-4-nitrophenyl) piperidine-4-carboxamide.
상기 암은 폐암, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나일 수 있다.Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer, and rectal cancer.
보다 상세하게 상기 트리아졸로피리딘계 유도체는 탄키라제(Tankyrase, TNKS) 효소 활성을 저해하여 종양 인자인 β-카테닌(β-catenin)이 과발현된 암세포의 치료에 효과적으로 사용될 수 있다.More specifically, the triazolopyridine derivatives can be effectively used for the treatment of cancer cells in which β-catenin, which is a tumor factor, is overexpressed by inhibiting the activity of Tankyrase (TNKS) enzyme.
상기 TNKS는 이중-가닥 텔로머 반복 결합 단백질인 TRF1(telomeric repeat binding factor 1); 유사분열 방추 어셈블리(assembly)에서의 필수 단백질인 NuMA(NuclearMitotic associated protein); 인슐린에 대응한 글루코스 흡수에 관여하는 내재성 막 단백질인 IRAP(aminopeptidase); 및 세포자살(apoptosis)-촉진 단백질인 Mcl-1(myeloid leukemia cell differentiation protein)을 포함하는 몇몇의 결합 단백질 파트너를 가지며, 이들의 다양한 상호작용을 통해 생물학적 기능을 나타낸다.The TNKS is a telomeric repeat binding factor 1 (TRF1) which is a double-stranded telomer repeat protein; Nuclear-Mitotic associated protein (NuMA), an essential protein in the mitotic spindle assembly; IRAP (aminopeptidase), an endogenous membrane protein involved in glucose uptake in response to insulin; And myeloid leukemia cell differentiation protein (Mcl-1), an apoptosis-promoting protein, and exhibits biological functions through their various interactions.
본 발명의 일실시예에 따르면, 트리아졸로피리딘계 화합물 1 내지 12는 표 1과 같이 TNKS-1 효소의 활성을 억제시킨 반면, PARP-1 활성은 억제되지 않은 것을 확인함에 따라, 상기 트리아졸로피리딘계 유도체의 활성은 TNKS-1 효소에 특이적인 것을 확인할 수 있었다.According to one embodiment of the present invention, the triazolo pyridine compounds 1-12 inhibited the activity of the TNKS-1 enzyme as shown in Table 1, while confirming that the PARP-1 activity was not inhibited, It was confirmed that the activity of the derivative was specific to the TNKS-1 enzyme.
상기 결과로부터 TNKS 효소 활성 억제제로 확인된 트리아졸로피리딘계 화합물 1 및 화합물 2를 APC 유전자가 돌연변이된 DLD-1 대장암세포에 처리한 결과, 도 2와 같이 화합물 1 및 화합물 2에 의해 β-카테닌 단백질의 발현이 감소된 반면, AXIN2 단백질의 발현은 증가된 것을 확인함에 따라, 트리아졸로피리딘계 유도체는 탄키라제(Tankyrase, TNKS) 효소 활성을 저해하여 종양 인자인 β-카테닌(β-catenin) 발현을 억제시킴으로써, 세포자살(apoptosis)에 의한 암세포 사멸을 증가시키는 항암제로 제공될 수 있다.From the above results, the triazolopyridine compounds 1 and 2 identified as TNKS enzyme activity inhibitors were treated with DLD-1 colon cancer cells mutated with the APC gene, and as a result, as shown in FIG. 2, , But the expression of AXIN2 protein was increased. Thus, the triazolepyridine derivative inhibited the activity of the Tankyrase (TNKS) enzyme and expressed β-catenin Can be provided as an anticancer agent that increases cancer cell death by apoptosis.
본 발명의 한 구체예에서, 상기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물은 통상적인 방법에 따라 주사제, 과립제, 산제, 정제, 환제, 캡슐제, 좌제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다.In one embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer, which comprises the compound represented by Formula 1 or a pharmaceutically utilizable salt thereof as an active ingredient, may be administered orally, parenterally, , Pills, capsules, suppositories, gels, suspensions, emulsions, drops, or liquid preparations can be used.
본 발명의 다른 구체예에서, 상기 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In another embodiment of the present invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, disintegrant, sweetener, coating, swelling agent, lubricant, lubricant, flavoring agent, antioxidant, buffer, A dispersant, a surfactant, a binder, and a lubricant.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
본 발명의 일실시예에 따르면 상기 약학조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.
상기 화학식 1과 같이 표시되는 화합물의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The preferred dosage of the compound represented by Formula 1 may vary depending on the condition and body weight of the subject, the type and degree of disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.
또한, 본 발명은 상기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 항암 효과 증진용 조성물을 제공할 수 있다.The present invention also provides a composition for enhancing an anticancer effect comprising a triazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 항암 효과 증진용 조성물은 항암제 또는 방사선과 병용 처리될 수 있다.The anticancer effect enhancing composition may be treated with an anticancer agent or radiation.
상기 항암제는 시스플라틴(Cisplatin), 5-플루오로우라실(5-fluorouracil), 파클리탁셀(Paclitaxel), 독소루비신(Doxorubicin), 도노루비신(Daunorubicin), 빈블라스틴(Vinblastine), 빈크리스틴(Vincristine), 액티노마이신 D(Actinomycin D), 테니포사이드(Teniposide), 에토포사이드(Etoposide), 시클로포스파미드 (cyclophosphamide), 에피루비신(epirubicin), 아드리아마이신(adriamycin), 다우노마이신(daunomycin) 및 미토마이신-C(mitomycin-C)으로 이루어진 군에서 선택된 어느 하나 이상일 수 있다.The anticancer agent is selected from the group consisting of cisplatin, 5-fluorouracil, Paclitaxel, Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Actinomycin D, Teniposide, Etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin, and mitomycin, And C (mitomycin-C).
상기 조성물은 조성물 총 100 중량부에 대하여, 항암제 1 내지 99 중량부 및 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 1 내지 99 중량부를 포함할 수 있다.The composition may comprise 1 to 99 parts by weight of an anticancer agent and 1 to 99 parts by weight of a triazolopyridine derivative represented by the general formula (1), based on 100 parts by weight of the total composition.
상기 항암 효과 증진용 조성물은 폐암, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나의 암 질환에 대한 항암 효과를 증진시키는 것일 수 있다.The composition for enhancing the anticancer effect may be used for the treatment of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, , Cancer of the larynx, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer and rectal cancer.
본 발명의 다른 일실시예에 따르면, 배양된 DLD-1 대장암 세포에 상기 화합물 1 및 화합물 2를 20 μM 농도로 처리한 후 감마 방사선 3 Gy을 조사하고 3일 동안 배양한 후 세포생존율을 확인한 결과, 도 4와 같이 트리아졸로피리딘계 화합물 1 또는 화합물 2와 방사선 조사를 병용 처리한 경우, 암세포의 생존율 감소가 확인되었다. 또한, 상기 화합물 1 또는 화합물 2를 20 μM 농도로 DLD-1 세포와 SW480 세포에 대장암치료 항암제인 5-FU (10 μM)와 48시간 동안 병용 처리하고 MTT 시험법을 수행하여 세포 생존율을 확인한 결과, 도 5와 같이 항암제인 5-FU을 단독 처리한 대조군보다 5-FU와 화합물 1 및 화합물 2를 병용 투여한 실험군의 세포 증식 억제 효과가 각각 2배 및 1.5배 이상 증가한 것을 확인할 수 있다. According to another embodiment of the present invention, the compound 1 and the compound 2 were treated with 20 μM of the DLD-1 colon cancer cells cultured, irradiated with 3 Gy of gamma irradiation, cultured for 3 days, As a result, when the triazolepyridine compound 1 or compound 2 was treated with irradiation with radiation as shown in Fig. 4, the survival rate of the cancer cells was confirmed to decrease. In addition, Compound 1 or Compound 2 was treated with DLT-1 cells and SW480 cells at a concentration of 20 μM for 48 hours in combination with 5-FU (10 μM), a colorectal cancer treatment anticancer agent, and MTT assay was performed to confirm cell viability As a result, the cell proliferation inhibitory effects of 5-FU and Compound 1 and Compound 2 in the experimental group treated with 5-FU alone and 5-FU alone were increased by 2-fold and 1.5-fold, respectively, as shown in FIG.
상기 결과로부터 상기 트리아졸로피리딘계 화합물은 항암제 또는 방사선과 병용 처리될 경우, 항암 치료 효과를 상승시키는 것으로 확인됨에 따라, 상기 트리아졸로피리딘계 화합물은 항암제 보조제로 사용이 가능하다.From the above results, it was confirmed that when the triazolopyridine compound is treated with an anticancer agent or radiation, the triazolopyridine compound can be used as an anticancer agent adjuvant.
또한, 본 발명은 상기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 개선용 건강식품을 제공할 수 있다.The present invention also provides a health food for preventing or ameliorating cancer, which comprises a triazolopyridine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 암은 폐암, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나일 수 있다.Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer, and rectal cancer.
상기 건강식품은 상기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 이용가능한 염 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.The health food may be used in combination with other food or food additives in addition to the triazolopyridine derivative represented by Formula 1 or its pharmaceutically usable salt, and may be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
상기 건강식품에 함유된 화합물의 유효용량은 상기 치료제의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the compound contained in the above-mentioned health food may be used in accordance with the effective dose of the therapeutic agent, but may be less than the above range for health and hygiene purposes or for long-term intake for health control purposes, It is clear that the component can be used in an amount of more than the above range since there is no problem in terms of safety.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제등을 들 수 있다.There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.
또한, 본 발명은 상기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하며, 상기 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염은 생체 외(in vitro)에서 세포의 탄키라제(Tankyrase, TNKS) 효소 활성을 억제하는 것을 특징으로 하는 탄키라제 효소 활성을 억제하는 것을 특징으로 하는 탄키라제 효소 활성 억제용 시약조성물을 제공할 수 있다.Also, the present invention provides a triazolopyridine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the triazolopyridine derivative or a pharmaceutically acceptable salt thereof is an in vitro ( the present invention provides a reagent composition for inhibiting the activity of a Tancirase enzyme activity, which is characterized by inhibiting the activity of the Tankyrase (TNKS) enzyme in the cell in vitro.
또한, 본 발명은 암세포에 상기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 처리하는 단계를 포함하는 생체 외(in vitro)에서 세포의 탄키라제 효소 활성 억제방법을 제공할 수 있다.The present invention also relates to a method for inhibiting the activity of a cell's tryptase enzyme activity in vitro, comprising the step of treating a cancer cell with a triazolo pyridine derivative represented by the formula 1 or a pharmaceutically acceptable salt thereof Can be provided.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
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합성예Synthetic example
1> 1>
트리아졸로피리딘계Triazolopyridine-based
유도체 합성 Derivative synthesis
하기 화학식 1 내지 화학식 12와 같은 트리아졸로피리딘계 유도체 화합물 1 내지 화합물 12를 하기와 같이 합성하였다.The triazolepyridine derivative compounds 1 to 12, represented by the following Chemical Formulas 1 to 12, were synthesized as follows.
1. N-(1. N- (
[1,2,4,]트리아졸로[4,3-a]피리딘[1,2,4] triazolo [4,3-a] pyridine
-3-일)-1-(2-Yl) -1- (2-
시아노페닐Cyanophenyl
)피페리딘-4-카르복사마이드 {N-() Piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(2-cyanophenyl)piperidine-4-carboxamide; 화합물 1}) -1- (2-cyanophenyl) piperidine-4-carboxamide; Compound 1}
[반응식 1][Reaction Scheme 1]
상기 반응식 1과 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 1(3)을 약 25%의 수율로 21mg 얻었다. The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the same manner as in Scheme 1, by using an amide coupling reaction using dipyridinium chloride and halobutyl chloride in the presence of dichloromethane, 21 mg was obtained in a yield of 25%.
1H NMR (DMSO-d6, 400 MHz): δ 10.96 (1H, s), 7.96 (1H, d, J = 8.0Hz), 7.73 (1H, m), 7.61 (1H, t, J = 8.0Hz), 7.4 (1H, ddd, J = 12.0, 4.0 and 0.8Hz), 7.22 (1H, d, J = 8.0Hz), 7.11 (1H, t, J = 8.0Hz), 6.99 (1H, t, J= 6.0Hz), 3.58 (2H, d, J=12.0Hz), 2.91 (2H, t, J = 12.0Hz), 2.50 (1H, m) 2.10 (2H, d, J = 12.0Hz), 1.91 (2H, t, J = 6.0Hz) (1H, s), 7.96 (1H, d, J = 8.0 Hz), 7.73 (1H, t, J = 8.0 Hz), 7.4 (1H, ddd, J = 12.0, 4.0 and 0.8 Hz), 7.22 D, J = 12.0 Hz), 2.91 (2H, t, J = 12.0 Hz), 2.50 (1H, J = 6.0 Hz)
2. N-(2. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(2-Yl) -1- (2-
니트로페닐Nitrophenyl
)피페리딘-4-카르복사마이드 {N-() Piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(2-nitrophenyl)piperidine-4-carboxamide; 화합물 2}) -1- (2-nitrophenyl) piperidine-4-carboxamide; Compound 2}
[반응식 2][Reaction Scheme 2]
상기 반응식 2와 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에서 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 2(3)를 약 29%의 수율로 25mg 얻었다.The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the presence of diisocyanate and HOCI in the presence of an amide coupling reaction to obtain Compound 25 mg was obtained in a yield of 29%.
1H NMR (DMSO-d6, 400 MHz): δ 10.95 (1H, s), 7.95 (1H, d, J = 8.0Hz), 7.81 (1H, dd, J = 8.0 and 4.0Hz), 7.75 (1H, d, J = 8.0Hz), 7.59 (1H, td, J = 8.0, and 4.0Hz), 7.38 (2H, m), 7.13 (1H, t, J = 8.0Hz), 7.00 (1H, t, J = 4.0Hz), 3.27 (2H, d, J = 12.0Hz), 2.91 (2H, t, J = 12.0Hz), 2.71 (1H, m), 2.03 (2H, d, J = 12.0Hz), 1.85 (2H, m) 1 H NMR (DMSO-d6, 400 MHz): δ 10.95 (1H, s), 7.95 (1H, d, J = 8.0Hz), 7.81 (1H, dd, J = 8.0 and 4.0Hz), 7.75 (1H, t, J = 8.0 Hz), 7.59 (1H, td, J = 8.0, and 4.0 Hz), 7.38 (2H, d, J = 12.0 Hz), 2.85 (2H, t, J = , m)
3. N-(3. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-Yl) -1-
페닐피페리딘Phenylpiperidine
-4--4-
카르복사마이드Carboxamide
{N-( {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-)-One-
phenylpiperidine페 phenylpiperidine
-4-carboxamide; 화합물 3}-4-carboxamide; Compound 3}
[반응식 3][Reaction Scheme 3]
상기 반응식 3과 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 다이클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 3(3)을 약 28%의 수율로 24mg 얻었다. The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the same manner as in Scheme 3 to give compound 3 (3) in an amide coupling reaction using dipyridinium chloride and H + 24 mg was obtained in a yield of about 28%.
1H NMR (CDCl3-d, 400 MHz): δ 11.65 (1H, s), 7.91 (1H, d, J = 4.0Hz), 7.67 (1H, d, J = 8.0Hz), 7.27 (3H, m), 6.97 (2H, d, J = 8.0Hz), 6.9 (2H, m), 3.76 (2H, dt, J=11.0 and 3.1Hz), 2.9 (3H, td, J=10.0 and 3.2Hz), 2.19 (2H, dd, J=14.0 and 2.0Hz), 2.07(2H, ddd, J=24.0, 12.0 and 4.0Hz) 1 H NMR (CDCl 3 -d, 400 MHz): δ 11.65 (1H, s), 7.91 (1H, d, J = 4.0Hz), 7.67 (1H, d, J = 8.0Hz), 7.27 (3H, m (2H, d, J = 8.0 Hz), 6.97 (2H, d, J = 8.0 Hz) (2H, dd, J = 14.0 and 2.0 Hz), 2.07 (2H, ddd, J = 24.0, 12.0 and 4.0 Hz)
4. N-(4. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(4-Yl) -1- (4-
니트로페닐Nitrophenyl
)피페리딘-4-카르복사마이드 {N-() Piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(4-nitrophenyl)piperidine-4-carboxamide; 화합물 4}) -1- (4-nitrophenyl) piperidine-4-carboxamide; Compound 4}
[반응식 4][Reaction Scheme 4]
상기 반응식 4와 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 4(3)을 약 25%의 수율로 22mg 얻었다.The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the presence of diisocyanate and H < 22 mg was obtained in a yield of 25%.
1H NMR (DMSO-d6, 400 MHz): δ 10.96 (1H, s), 8.06 (2H, d, J = 8.0Hz), 7.93 (1H, d, J = 4.0Hz), 7.74 (1H, d, J = 8.0Hz), 7.39 (1H, ddd, J = 8.4, 6.6 and 1.8Hz), 7.07 (2H, d, J = 8.0Hz), 6.97 (1H, t, J = 6.0Hz), 4.13 (2H, d, J = 12.0Hz), 3.14 (2H, t, J = 12.0Hz), 2.89 (1H, m), 2.05 (2H, d, J = 12.0Hz), 1.75 (2H, m) 1 H NMR (DMSO-d6, 400 MHz): δ 10.96 (1H, s), 8.06 (2H, d, J = 8.0Hz), 7.93 (1H, d, J = 4.0Hz), 7.74 (1H, d, J = 8.0 Hz), 7.39 (1H, ddd, J = 8.4, 6.6 and 1.8 Hz), 7.07 d, J = 12.0 Hz), 3.14 (2H, t, J = 12.0 Hz), 2.89 (1H, m), 2.05
5. N-(5. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(2-니트로-4-(Yl) -1- (2-nitro-4- (
트리플루오로메틸Trifluoromethyl
)페닐)피페리딘-4-카르복사마이드 {N-() Phenyl) piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carboxamide; 화합물 5}) -1- (2-nitro-4- (trifluoromethyl) phenyl) piperidine-4-carboxamide; Compound 5}
[반응식 5][Reaction Scheme 5]
상기 반응식 5와 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 5(3)을 약 27%의 수율로 28mg 얻었다.The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent in the same manner as in Scheme 5 to give compound (3) in the form of an amide coupling reaction using edicyl chloride and H- 28 mg was obtained in a yield of 27%.
1H NMR (DMSO-d6, 400 MHz): δ 10.97 (1H, s), 8.16 (1H, d, J = 4.0Hz), 7.87 (1H, d, J = 4.0Hz), 7.85 (1H, d, J = 2.0Hz), 7.75 (1H, dt, J = 10.6 and 0.4Hz), 7.49 (1H, d, J = 8.0Hz), 7.40 (1H, ddd, J = 10.2, 6.0 and 1.4Hz), 6.99 (1H, td, J = 7.5, 7.5 and 3.2Hz), 3.43 (2H, d, J = 16.0Hz), 3.07 (2H, t, J = 12.0Hz), 2.79 (1H, m), 2.05 (2H, d, J = 12.0Hz), 1.85 (2H, t, J = 12.0Hz) 1 H NMR (DMSO-d6, 400 MHz): δ 10.97 (1H, s), 8.16 (1H, d, J = 4.0Hz), 7.87 (1H, d, J = 4.0Hz), 7.85 (1H, d, J = 2.0 Hz), 7.75 (1H, dt, J = 10.6 and 0.4 Hz), 7.49 (1H, d, J = 8.0 Hz), 7.40 T, J = 7.5, 7.5 and 3.2 Hz), 3.43 (2H, d, J = 16.0 Hz), 3.07 (2H, t, J = 12.0 Hz), 2.79 , J = 12.0 Hz), 1.85 (2H, t, J = 12.0 Hz)
6. N-(6. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(4-(Yl) -1- (4- (
트리플루오로메틸Trifluoromethyl
)페닐)피페리딘-4-카르복사마이드 {N-() Phenyl) piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(4-(trifluoromethyl)phenyl)piperidine-4-carboxamide; 화합물 6}) -1- (4- (trifluoromethyl) phenyl) piperidine-4-carboxamide; Compound 6}
[반응식 6][Reaction Scheme 6]
상기 반응식 6과 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 6(3)을 약 27%의 수율로 24mg 얻었다.As shown in Scheme 6, the starting material (1) and carboxylic acid (2) are reacted with triethylamine and dichloromethane in the presence of dichloromethane, 24 mg was obtained in a yield of 27%.
1H NMR (DMSO-d6, 400 MHz): δ 10.94 (1H, s), 7.93 (1H, d, J = 8.0Hz), 7.74 (1H, d, J = 12.0Hz), 7.50 (2H, d, J = 12.0Hz), 7.39 (1H, t, J = 8.0Hz), 7.10 (2H, d, J = 8.0Hz), 6.97 (1H, t, J = 6.0Hz), 3.97 (2H, d, J = 16.0Hz), 2.95 (2H, t, J = 12.0Hz), 2.81 (1H, m), 2.02 (2H, d, J = 12.0Hz), 1.76 (2H, m) 1 H NMR (DMSO-d6, 400 MHz): δ 10.94 (1H, s), 7.93 (1H, d, J = 8.0Hz), 7.74 (1H, d, J = 12.0Hz), 7.50 (2H, d, D, J = 8.0 Hz), 6.97 (1H, t, J = 6.0 Hz), 3.97 (2H, M, 2.02 (2H, d, J = 12.0 Hz), 1.76 (2H, m)
7. N-(7. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(4-Yl) -1- (4-
플루오로Fluoro
-2--2-
니트로페닐Nitrophenyl
)피페리딘-4-카르복사마이드 {N-() Piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(4-fluoro-2-nitrophenyl)piperidine-4-carboxamide; 화합물 7}) -1- (4-fluoro-2-nitrophenyl) piperidine-4-carboxamide; Compound 7}
[반응식 7][Reaction Scheme 7]
상기 반응식 7과 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 7(3)을 약 27%의 수율로 28mg 얻었다.As shown in Scheme 7, starting compound (1) and carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound (3) in the form of an amide coupling reaction using epidichloride and H 28 mg was obtained in a yield of 27%.
1H NMR (DMSO-d6, 400 MHz): δ 10.94 (1H, s), 7.94 (1H, d, J = 4.0Hz), 7.83 (1H, dd, J = 8.0 and 4.0Hz), 7.75 (1H, d, J = 8.0Hz), 7.52 (2H, m), 7.40 (1H, dd, J = 12.0 and 6.0Hz), 6.99 (1H, t, J = 8.0Hz), 3.20 (2H, d, J = 12.0Hz), 2.88 (2H, t, J = 12.0Hz), 2.69 (1H, m), 2.03 (2H, d, J = 8.0Hz), 1.82 (2H, m) 1 H NMR (DMSO-d6, 400 MHz): δ 10.94 (1H, s), 7.94 (1H, d, J = 4.0Hz), 7.83 (1H, dd, J = 8.0 and 4.0Hz), 7.75 (1H, d, J = 8.0 Hz), 7.52 (2H, m), 7.40 (1H, dd, J = 12.0 and 6.0 Hz), 6.99 (2H, m), 2.03 (2H, d, J = 8.0Hz), 2.82
8. N-(8. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(4-Yl) -1- (4-
아세틸페닐Acetylphenyl
)피페리딘-4-카르복사마이드 {N-() Piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(4-acetylphenyl)piperidine-4-carboxamide; 화합물 8}) -1- (4-acetylphenyl) piperidine-4-carboxamide; Compound 8}
[반응식 8][Reaction Scheme 8]
상기 반응식 8과 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 8(3)을 약 28%의 수율로 24mg 얻었다.The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound (3) in the form of an amide coupling reaction using diisocyanate and H < 24 mg was obtained in a yield of 28%.
1H NMR (DMSO-d6, 400 MHz): δ 10.95 (1H, s), 7.93 (1H, d, J = 8.0Hz), 7.81 (2H, d, J = 8.0Hz), 7.74 (1H, d, J = 12.0Hz), 7.39 (1H, ddd, J = 8.4, 6.4 and 1.6Hz), 6.99 (3H, m), 4.04 (2H, d, J = 12.0Hz), 3.00 (2H, t, J = 12.0Hz), 2.84 (1H, m), 2.45 (3H, s), 2.02 (2H, d, J = 12.0Hz), 1.74 (2H, m) 1 H NMR (DMSO-d6, 400 MHz): δ 10.95 (1H, s), 7.93 (1H, d, J = 8.0Hz), 7.81 (2H, d, J = 8.0Hz), 7.74 (1H, d, J = 12.0 Hz), 7.39 (1H, ddd, J = 8.4, 6.4 and 1.6 Hz), 6.99 (3H, m), 4.04 M), 2.45 (3H, s), 2.02 (2H, d, J = 12.0 Hz), 1.74
9. N-(9. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(4-Yl) -1- (4-
클로로Chloro
-2--2-
니트로페닐Nitrophenyl
)피페리딘-4-카르복사마이드 {N-() Piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(4-) -1- (4-
chlorochloro
-2-nitrophenyl)piperidine-4-carboxamide; 화합물 9}-2-nitrophenyl) piperidine-4-carboxamide; Compound 9}
[반응식 9][Reaction Scheme 9]
상기 반응식 9와 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 9(3)을 약 26%의 수율로 28mg 얻었다.The starting material (1) and carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound 9 (3) as an amide coupling reaction using epithichlorohydrate and H < 28 mg was obtained in a yield of 26%.
1H NMR (DMSO-d6, 400 MHz): δ 10.95 (1H, s), 7.95 (2H, m), 7.75 (1H, d, J = 8.0Hz), 7.65 (1H, dd, J = 12.0 and 8.0Hz), 7.39 (2H, m), 6.99 (1H, t, J = 8.0Hz), 3.26 (2H, d, J = 12.0Hz), 2.92 (2H, t, J = 12.0Hz), 2.72 (1H, m), 2.03 (2H, d, J = 8.0Hz), 1.83 (2H, m) 1 H NMR (DMSO-d6, 400 MHz): δ 10.95 (1H, s), 7.95 (2H, m), 7.75 (1H, d, J = 8.0Hz), 7.65 (1H, dd, J = 12.0 and 8.0 (2H, t, J = 12.0 Hz), 2.72 (1H, d, J = m), 2.03 (2H, d, J = 8.0 Hz), 1.83 (2H, m)
10. N-(10. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(4-Yl) -1- (4-
시아노페닐Cyanophenyl
)피페리딘-4-카르복사마이드 {N-() Piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(4-cyanophenyl)piperidine-4-carboxamide; 화합물 10}) -1- (4-cyanophenyl) piperidine-4-carboxamide; Compound 10}
[반응식 10][Reaction Scheme 10]
상기 반응식 10과 같이, 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드, 에이치오비티를 이용하여 아마이드 커플링 반응을 통하여 화합물 10(3)을 약 23%의 수율로 20mg을 얻었다.As shown in Scheme 10, starting material (1) and carboxylic acid (2) were reacted with compound 10 (3) in the presence of triethylamine and dichloromethane as a solvent via an amide coupling reaction using edicyl chloride and H- Was obtained in a yield of about 23%.
1H NMR (DMSO-d6, 400MHz): δ 10,94(1H, s), 7.93(1H, d, J=8.0Hz), 7.74(1H, d, J=8.0Hz), 7.58(1H, d, J=8.0Hz), 7.39(1H, dd, J=8.0 and 8.0Hz), 7.06(2H, d, J=8.0Hz), 6.97(1H, m), 4.03(2H, d, J=12.0Hz), 3.01(2H, m), 2.83(1H, m), 2.02(2H, d, J=16Hz), 1.73(2H, m) 1 H NMR (DMSO-d6, 400MHz): δ 10,94 (1H, s), 7.93 (1H, d, J = 8.0Hz), 7.74 (1H, d, J = 8.0Hz), 7.58 (1H, d (2H, d, J = 8.0 Hz), 7.39 (1H, dd, J = 8.0 and 8.0 Hz), 7.06 ), 3.01 (2H, m), 2.83 (1H, m), 2.02 (2H,
11. N-(11. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(5-Yl) -1- (5-
니트로피리딘Nitropyridine
-2-일)피페리딘-4-카르복사마이드 {N-(-2-yl) piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(5-nitropyridin-2-yl)piperidine-4-carboxamide; 화합물 11}) -1- (5-nitropyridin-2-yl) piperidine-4-carboxamide; Compound 11}
[반응식 11][Reaction Scheme 11]
상기 반응식 11과 같이 출발물질(1)과 카르복실산(4)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드, 에이치오비티를 이용하여 아마이드 커플링 반응을 통하여 화합물 11(5)를 약 26%의 수율로 20mg을 얻었다.The starting material (1) and the carboxylic acid (4) are reacted with compound 11 (5) in the presence of triethylamine and dichloromethane as a solvent, using acetic acid chloride and HCl, 20 mg was obtained in a yield of about 26%.
1H NMR (DMSO-d6, 400MHz): δ 10,97(1H, s), 8.98(1H, d, J=2.0Hz), 8.23(1H, dd, J=2.0 and 4.0Hz), 7.94(1H, d, J=8.0Hz), 7.74(1H, d, J=8.0Hz), 7.39(1H, dd, J=2.0 and 8.0Hz), 6.99(2H, m), 4.59(2H, d, J=12.0Hz), 3.22(2H, m), 2.94(1H, m), 2.08(2H, d, J=12.0Hz), 1.70(2H, m) 1 H NMR (DMSO-d6, 400MHz): δ 10,97 (1H, s), 8.98 (1H, d, J = 2.0Hz), 8.23 (1H, dd, J = 2.0 and 4.0Hz), 7.94 (1H d, J = 8.0 Hz), 7.74 (1H, d, J = 8.0 Hz), 7.39 M), 2.08 (2H, d, J = 12.0 Hz), 1.70 (2H, m)
12. N-(12. N- (
[1,2,4]트리아졸로[4,3-a]피리딘[L, 2,4] triazolo [4,3-a] pyridine
-3-일)-1-(2-Yl) -1- (2-
시아노Cyano
-4--4-
니트로페닐Nitrophenyl
)피페리딘-4-카르복사마이드 {N-() Piperidine-4-carboxamide {N- (
[1,2,4]triazolo[4,3-a]pyridin[1,2,4] triazolo [4,3-a] pyridine
-3--3-
ylyl
)-1-(2-) -1- (2-
cyanocyano
-4-nitrophenyl)piperidine-4-carboxamide; 화합물 12}-4-nitrophenyl) piperidine-4-carboxamide; Compound 12}
[반응식 12][Reaction Scheme 12]
상기 반응식 12와 같이 출발물질(1)과 카르복실산(2)를 트리에틸아민과 용매인 디클로로메탄 존재하에 이디씨클로라이드 및 에이치오비티를 이용하여 아마이드 커플링 반응으로 화합물 12(3)을 약 23%의 수율로 20mg 얻었다. The starting material (1) and the carboxylic acid (2) are reacted with triethylamine and dichloromethane as a solvent to give compound (12) (3) in the form of an amide coupling reaction using epichlorohydrin and H- 20 mg was obtained in a yield of 23%.
1H NMR (DMSO-d6, 400 MHz): δ 11.00 (1H, s), 8.54 (1H, d, J = 4.0Hz), 8.3 (1H, dd, J = 10.0 and 2.0Hz), 7.96 (1H, d, J=4.0Hz), 7.75 (1H, d, J = 8.0Hz), 7.39 (1H, ddd, J=6.6, 4.0 and 1.4Hz), 7.30 (1H, d, J = 12.0Hz), 6.98 (1H, t, J= 6.0Hz), 4.05 (2H, d, J=12.0Hz), 3.25 (2H, t, J = 12.0Hz), 2.87 (1H, m), 2.13 (2H, d, J = 12.0Hz), 1.885 (2H, d, J = 12.0Hz) 1 H NMR (DMSO-d6, 400 MHz): δ 11.00 (1H, s), 8.54 (1H, d, J = 4.0Hz), 8.3 (1H, dd, J = 10.0 and 2.0Hz), 7.96 (1H, d, J = 4.0 Hz), 7.75 (1H, d, J = 8.0 Hz), 7.39 (1H, ddd, J = 6.6, 4.0 and 1.4 Hz) D, J = 12.0 Hz), 3.25 (2H, t, J = 12.0 Hz), 2.87 (1H, m), 2.13 Hz), 1.885 (2H, d, J = 12.0 Hz)
<실시예 1> 탄키라제(TNKS) 효소 활성 억제 효과 확인Example 1 Confirmation of Inhibitory Effect of Tanzirase (TNKS) Enzyme Activity
상기 트리아졸로피리딘계 유도체 화합물 1 내지 화합물 12가 탄키라제(TNKS) 효소 활성을 억제할 수 있는지 확인하기 위해, 탄키라제-1 비색 활성 분석 키트(Tankyrase 1 colorimetric activity assay kit, Cat# 4500-192-K, Trevigen, RnD systems, 미국)를 이용하여 제조사의 지침에 따라 수행하였으며, 양성대조군으로 2-(4-트리플루오로메틸-페닐)-3,5,7,8-테트라하이드로-티오피라노[4,3-d]피리미딘-4-온 {2-(4-(trifluoromethyl-phenyl)-3,5,7,8-tetradihydro-thiopyrano[4,3-d]pyrimidin-4-one, XAV939}을 사용하였다.(Tankyrase 1 colorimetric activity assay kit, Cat # 4500-K) was used to confirm that the triazolo pyridine derivative compounds 1 to 12 can inhibit the activity of the enzyme tyrosylase (TNKS) (4-trifluoromethyl-phenyl) -3,5,7,8-tetrahydro-thiophene was used as a positive control. 4,3-d] pyrimidin-4-one < / RTI > , XAV939} was used.
또한, 화합물 1 내지 화합물 12가 PARP(poly-ADP ribose polymerase) 효소 활성을 억제할 수 있는지 확인하기 위해, PARP-1 비색 분석 키트(PARP-1 colorimetric assay kit, Cat# 4677-096-K, Trevigen, RnD systmes)를 이용하여 제조사의 지침에 따라 측정하여 확인하였으며, 양성대조군으로 올라파립(Olaparib) 1μM을 사용하였다.PARP-1 colorimetric assay kit (Cat # 4677-096-K, Trevigen) was used to confirm that Compound 1 to Compound 12 could inhibit PARP (poly-ADP ribose polymerase) , RnD systmes) according to the manufacturer's instructions, and 1 μM olaparib was used as a positive control.
그 결과, 표 1과 같이 화합물 1 내지 화합물 12의 TNKS 및 PARP 억제 활성을 확인할 수 있었다.As a result, TNKS and PARP inhibitory activities of the compounds 1 to 12 were confirmed as shown in Table 1.
TNKS-1 억제능TNKS-1 inhibition (대조군 0% 대비)(Compared to 0% in the control group) | PARP 억제능PARP inhibition | |
농도(μM)Concentration (μM) | 1010 | 1010 |
트리아졸로피리딘 Triazolopyridine 화합물 1Compound 1 | 95.2±0.595.2 ± 0.5 | 00 |
트리아졸로피리딘 |
94.3±1.394.3 ± 1.3 | 00 |
트리아졸로피리딘 Triazolopyridine 화합물 3Compound 3 | 58.7±2.458.7 ± 2.4 | 00 |
트리아졸로피리딘 Triazolopyridine 화합물 4Compound 4 | 30.8±4.730.8 ± 4.7 | 1.5±0.81.5 ± 0.8 |
트리아졸로피리딘 |
70.4±2.570.4 ± 2.5 | 00 |
트리아졸로피리딘 |
51.7±1.751.7 ± 1.7 | 1.2±0.41.2 ± 0.4 |
트리아졸로피리딘 Triazolopyridine 화합물 7Compound 7 | 75.4±1.275.4 ± 1.2 | 00 |
트리아졸로피리딘 |
65.8±2.365.8 ± 2.3 | 0.8±0.20.8 ± 0.2 |
트리아졸로피리딘 Triazolopyridine 화합물 9Compound 9 | 72.9±4.772.9 ± 4.7 | 1.1±0.51.1 ± 0.5 |
트리아졸로피리딘 |
59.6±5.259.6 ± 5.2 | 0.8±0.40.8 ± 0.4 |
트리아졸로피리딘 Triazolopyridine 화합물 11Compound 11 | 47.4±3.447.4 ± 3.4 | 0.6±0.10.6 ± 0.1 |
트리아졸로피리딘 |
94.8±0.894.8 ± 0.8 | 00 |
대조군인 XAV939(10μM)는 TNKS-1 효소 활성을 약 96% 저해하였으며, 올라파립(10μM)은 PARP 효소 활성을 98% 저해하였다. 한편, 트리아졸로피리딘계 화합물 1 내지 12는 상기 표 1과 같이 TNKS-1 효소의 활성 억제를 나타낸 반면, PARP-1 활성은 억제되지 않았다. The control group, XAV939 (10 μM), inhibited the activity of TNKS-1 enzyme by about 96% and Olafalp (10 μM) inhibited PARP enzyme activity by 98%. On the other hand, the triazolopyridine compounds 1 to 12 showed inhibition of the activity of the TNKS-1 enzyme as shown in Table 1, while the PARP-1 activity was not inhibited.
상기 결과로부터 트리아졸로피리딘계 유도체의 활성은 TNKS-1 효소에 특이적인 것을 확인할 수 있었다.From the above results, it was confirmed that the activity of the triazolopyridine derivative was specific to the TNKS-1 enzyme.
또한, 가장 활성이 좋은 것으로 확인된 화합물 1 및 화합물 2를 대상으로 TNKS-1 활성 50% 저해농도를 표 2와 같이 확인하였다.In addition, Compound 1 and Compound 2, which were found to have the highest activity, were tested for inhibition concentration of TNKS-1 activity of 50% as shown in Table 2.
TNKS -1 활성 50% 저해 농도 (μM) (IC50) TNKS -1 activity 50% inhibitory concentration (μM) (IC 50 ) | |
트리아졸로피리딘 Triazolopyridine 화합물 1Compound 1 | 0.7600.760 |
트리아졸로피리딘 |
0.8630.863 |
<실시예 2> β-카테닌 발현 억제 효과 확인<Example 2> Confirmation of β-catenin expression inhibitory effect
1. 세포준비1. Cell preparation
DLD-1, SW480 및 SKMEL28 세포주는 ATCC(American Type CultureCollection)로부터 구매하였다. DLD-1 및 SW480 세포는 DMEM(Dulbecco's modified Eagle's medium) 배지로, SKMEL28 세포는 MEM 배지에 각각 10% 소태아혈청(fetal bovine serum, FBS) 및 100 ㎍/ml 스트렙토마이신(streptomycin)과 100 unit/ml 페니실린(penicillin)을 첨가하여 5% CO2 및 37℃ 조건하에서 각각 배양하였다.The DLD-1, SW480 and SKMEL28 cell lines were purchased from the American Type Culture Collection (ATCC). The cells were treated with 10% fetal bovine serum (FBS) and 100 μg / ml streptomycin in DMEM medium (Dulbecco's modified Eagle's medium) and 100 units / ml penicillin were added and cultured at 5% CO 2 and 37 ° C, respectively.
베라무페닙(vemurafenib) 내성 SKMEL28 세포주는 베라무페닙 5 μM을 한 달간 지속적으로 처리한 후 베라무페닙 처리 시 40% 세포증식이 억제되는 세포주를 사용하였다. The vemurafenib-resistant SKMEL28 cell line was treated with verumupenib 5 μM for one month and then treated with verapunem 40% cell proliferation inhibitor.
2. β-카테닌 발현 억제 확인2. Confirmation of inhibition of β-catenin expression
상기 트리아졸로피리딘계 화합물 1 및 화합물 2이 TNKS 억제를 통하여 β-카테닌 단백질 발현을 억제시키고, AXIN2 단백질을 유지시킬 수 있는지 웨스턴 블롯을 통해 확인하였다.The triazolopyridine compounds 1 and 2 were confirmed by Western blotting to inhibit the expression of beta -catenin protein through TNKS inhibition and maintain the AXIN2 protein.
먼저, APC 유전자가 돌연변이된 DLD-1 대장암세포에 화합물 1 또는 화합물 2를 각각 10μM 처리한 후, 5% CO2 및 37℃ 조건하에 24시간 배양하였다. First, DLD-1 colon cancer cells mutated with APC gene were treated with 10 μM of Compound 1 or Compound 2, respectively, and then cultured for 24 hours at 5% CO 2 and 37 ° C.
그 후, 화합물 1 또는 화합물 2가 처리된 세포를 수득하고 당분야에서 통상적으로 이용되는 방법으로 세포질 분획을 얻었다.Cells treated with Compound 1 or Compound 2 were then obtained and a cytoplasmic fraction was obtained by a method commonly used in the art.
상기 분획을 10% 구배 SDS-PAGE를 이용한 전기영동을 수행하여 분리하고, 니트로셀룰로오즈 막(BioRad, Hercules, CA, USA)으로 옮겼다. 상기 막을 5% 탈지유로 블로킹(blocking)시킨 후, 일차 항체로 항-β-카테닌(Cell signaling, 미국) 및 항-AXIN2 항체(Cell signaling, 미국)를 반응시킨 후 호스래디쉬 퍼옥시다아제(horseradish peroxidase) 접합 항-쥐 IgG 항체(Santa Cruz Biotechnology, 미국)로 항온 반응시킨 후 ECL 시스템(GE, 미국)을 이용하여 시각화하였다.The fractions were separated by performing electrophoresis using 10% gradient SDS-PAGE and transferred to a nitrocellulose membrane (BioRad, Hercules, CA, USA). The membrane was blocked with 5% skim milk and reacted with primary anti-β-catenin (USA) and anti-AXIN2 antibody (Cell signaling, USA), followed by horseradish peroxidase ) Conjugated anti-mouse IgG antibody (Santa Cruz Biotechnology, USA) and visualized using an ECL system (GE, USA).
그 결과, 도 2와 같이 TNKS 억제제인 화합물 1 및 화합물 2에 의해 β-카테닌 단백질의 발현이 감소된 반면, AXIN2 단백질은 증가된 것을 확인할 수 있었다.As a result, as shown in FIG. 2, the expression of the β-catenin protein was decreased by the TNKS inhibitors, Compound 1 and Compound 2, while the AXIN2 protein was increased.
3. β-카테닌 하위 유전자 발현 억제 확인3. Confirmation of β-catenin sub-gene expression inhibition
APC 유전자가 돌연변이된 DLD-1 대장암 세포를 5 × 105의 개수로 6cm 플레이트에 분주하고, 상기 화합물 1 및 화합물 2를 각각 10μM 처리한 후, 5% CO2 및 37℃ 조건하에 8시간 배양하였다.DLD-1 colon cancer cells mutated with APC gene were dispensed into 6 cm plates in a number of 5 × 10 5 , treated with 10 μM each of the compound 1 and the compound 2, and incubated for 8 hours under the conditions of 5% CO 2 and 37 ° C. Respectively.
화합물 1 또는 화합물 2가 처리된 세포를 수득한 후 RNeasy kit (Qiagen, 미국)을 이용하여 총 RNA는 추출하였고, M-MLV reverse transcriptase (Enzynomics, 한국)이용하여 cDNA 합성하였다. 실시간 PCR는 β-카테닌의 하위 유전자 VEGF2와 Birc5/Survivin에 결합가능한 올리고머를 Cosmogentec (한국)에서 합성하고 이를 SYBR-Green/fluorescein qPCR master mix (Thermo Scientific, 미국)로 표지한 후 제조사의 가이드라인에 따라 Lightcycler 96 Real-time PCR system (RocheDiagnositics, 독일)에서 측정하였다. Total RNA was extracted using RNeasy kit (Qiagen, USA) after obtaining Compound 1 or Compound 2-treated cells, and cDNA was synthesized using M-MLV reverse transcriptase (Enzynomics, Korea). Real-time PCR was performed using Cosmogentec (Korea) oligomer capable of binding to the β-catenin sub-genes VEGF2 and Birc5 / Survivin and labeled with SYBR-Green / fluorescein qPCR master mix (Thermo Scientific, USA) Followed by measurement on a Lightcycler 96 Real-time PCR system (Roche Diagnostics, Germany).
그 결과, 도 3과 같이 화합물 1 또는 화합물 2 처리된 세포에서 VEGF2와 Birc5/Survivin 발현이 현저하게 감소하는 것을 확인할 수 있었다.As a result, it was confirmed that expression of VEGF2 and Birc5 / Survivin was remarkably decreased in the cells treated with Compound 1 or Compound 2 as shown in Fig.
<실시예 3> 방사선 조사 병용처리에 따른 항암 효과 확인<Example 3> Confirmation of anticancer effect by treatment with radiation irradiation
배양된 DLD-1 대장암 세포를 3 × 103의 개수로 96-웰 세포배양 플레이트에 분주하고, 상기 화합물 1 및 화합물 2를 20 μM 농도로 처리한 후 감마 방사선 3 Gy을 조사하고 3일 동안 5% CO2 및 37℃ 조건에서 배양하였다. The cultured DLD-1 colorectal cancer cells were dispensed in a number of 3 × 10 3 cells on a 96-well cell culture plate, and the compound 1 and the compound 2 were treated at a concentration of 20 μM, irradiated with 3 Gy of gamma irradiation, 5% CO 2 and 37 ° C.
그 후, 0.5 mg/mL의 MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) 용액을 각각의 웰에 첨가하고 37℃에서 3시간 추가 배양하였다. 배양이 끝난 후 상등액을 제거하고 형성된 포르마잔(formazan) 결정을 DMSO에 용해시킨 후 분광분석계(랩시스템즈, 미국)를 이용하여 590nm에서 측정하였다. 대조군에는 DMSO를 처리하였으며, 세포생존율은 100%에 대한 상대적인 증식율로 나타내었다.Then, 0.5 mg / mL MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) solution was added to each well and further incubated at 37 ° C for 3 hours. After the incubation, the supernatant was removed and the formazan crystals formed were dissolved in DMSO and measured at 590 nm using a spectrophotometer (Lap Systems, USA). The control group was treated with DMSO and the cell viability was expressed as the relative growth rate relative to 100%.
그 결과, 도 4와 같이 20 μM 농도의 트리아졸로피리딘계 화합물 1 또는 화합물 2와 방사선 조사를 병용 처리한 경우, 각각 생존능이 감소하는 것을 확인할 수 있었다. As a result, it was confirmed that when the triazolepyridine compound 1 or compound 2 with a concentration of 20 [mu] M was treated with irradiation with radiation as shown in Fig. 4, the viability decreased.
상기 결과로부터 트리아졸로피리딘계 화합물 1 및 화합물 2는 방사선 치료시 효과를 상승시킬 수 있는 방사선 치료 보조제로 사용 가능한 것이 확인되었다.From the above results, it was confirmed that the triazolopyridine compounds 1 and 2 can be used as a radiotherapy adjuvant which can increase the efficacy in radiotherapy.
<실시예 4> 항암제 병용 처리에 따른 항암 효과 확인Example 4 Confirmation of Anti-Cancer Effect by Combination Treatment with Anticancer Agent
상기 실시예 3과 같이 배양한 DLD-1 세포와 SW480 세포에 20 μM의 화합물 1 또는 화합물 2를 대장암치료 항암제인 5-FU (10 μM)와 48시간 동안 병용 처리하고 MTT 시험법을 수행하여 세포 생존율을 분석하였다.DLD-1 cells and SW480 cells cultured in the same manner as in Example 3 were treated with 20 μM of Compound 1 or Compound 2 in combination with 5-FU (10 μM), a colorectal cancer treatment anticancer, for 48 hours and MTT assay was performed Cell viability was analyzed.
그 결과, 도 5와 같이 항암제인 5-FU을 단독 처리한 대조군보다 5-FU와 화합물 1 및 화합물 2를 병용 투여한 실험군의 세포 증식 억제 효과가 각각 2배 및 1.5배 이상 증가한 것을 확인할 수 있다. As a result, as shown in FIG. 5, it was confirmed that the cell proliferation inhibitory effects of the experimental group in which 5-FU and Compound 1 and Compound 2 were administered in combination were 2-fold and 1.5-fold higher, respectively, than those in the control group in which 5-FU alone was treated .
상기 결과로부터 상기 트리아졸로피리딘계 화합물은 항암제 치료 효과를 상승시킬 수 있는 항암제 보조제로 사용 가능한 것이 확인되었다.From the above results, it was confirmed that the triazolopyridine compound can be used as an anticancer agent adjuvant which can enhance the therapeutic effect of anticancer drugs.
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실시예Example
5> 5>
종양인자Tumor factor
YAP 활성 저해에 따른 내성암세포에서의 항암 효과 확인 Identification of anticancer effect in resistant cancer cells by inhibition of YAP activity
1. YAP/TAZ 신호전달 억제 효과 확인1. Confirmation of inhibition of YAP / TAZ signaling
TNKS는 Angiomotin을 통해 종양인자 YAP를 활성화시키는 것으로 확인됨에 따라, TNKS 억제제인 트리아졸로피리딘 화합물에 의한 YAP/TAZ 신호전달 억제효과를 확인하기 위해, 상기 실시예 2와 같은 방법으로 실시간 PCR을 수행하여 YAP/TAZ 하위 유전자인 CYR61 및 CTGF의 발현 수준을 확인하였다.It was confirmed that TNKS activates the tumor factor YAP through Angiomotin. Therefore, in order to confirm the inhibitory effect of YAP / TAZ signaling by the TNKS inhibitor triazolopyridine compound, real-time PCR was performed in the same manner as in Example 2 Expression levels of YAP / TAZ subgenus CYR61 and CTGF were confirmed.
그 결과, 도 6과 같이 화합물 1 또는 화합물 2가 처리된 세포에서는 CYR61 및 CTGF의 발현이 현저하게 감소된 것을 확인할 수 있었다.As a result, it was confirmed that the expression of CYR61 and CTGF was markedly decreased in the cells treated with Compound 1 or Compound 2 as shown in Fig.
상기 결과로부터 트리아졸로피리딘 화합물은 YAP/TAZ 종양인자를 표적할 수 있음이 확인되었다.From these results, it was confirmed that the triazolopyridine compound can target YAP / TAZ tumor factor.
2. 내성암 세포에서 항암제와 병용처리에 따른 항암 효과 확인2. Identification of anticancer effects of anti-cancer drugs and anti-cancer drugs in resistant cancer cells
B-RAF 저해 항암제 베라무페닙(PLX4032)이 YAP/TAZ 신호전달에 관여하는 것으로 보고됨(EMBO J. 2016;35(5):462)에 따라, 앞선 실험에서 배양된 SKMEL28 흑색종 세포와 베라무페닙 내성 SKMEL28 세포에 10 μM, 20 μM 및 30 μM 농도의 화합물 1 또는 vemurafenib 10 μM 및 20 μM을 각각 처리한 후, MTT 시험법을 통하여 세포 생존율을 분석하였다.According to EMBO J. 2016; 35 (5): 462), the B-RAF inhibiting anticancer drug verapunem (PLX4032) is reported to be involved in YAP / TAZ signaling. SKMEL28 melanoma cells cultured in the above- Mucopenib resistant SKMEL28 cells were treated with 10 μM, 20 μM and 30 μM of compound 1 or vemurafenib 10 μM and 20 μM, respectively, and cell viability was analyzed by MTT assay.
그 결과, 도 7와 같이 SKMEL28 세포주와 베라무페닙 내성 SKMEL28 세포에서 화합물 1 농도 의존적으로 세포증식율이 감소하였다. 특히 SKMEL28 세포보다 베라무페닙 내성 SKMEL28 세포에서 세포증식이 더욱 감소하는 것이 확인됨에 따라, 본 발명의 트리아졸로피리딘 화합물은 매우 효과적인 항암제로 사용될 수 있음이 확인되었다.As a result, as shown in FIG. 7, the cell proliferation rate was decreased in the SKMEL28 cell line and the veramugenep resistant SKMEL28 cell line dependent on the compound 1 concentration. In particular, it was confirmed that cell proliferation was further reduced in veromucennep resistant SKMEL28 cells than in SKMEL28 cells, and thus it was confirmed that the triazolopyridine compound of the present invention can be used as a highly effective anticancer agent.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (15)
- 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염.A triazolopyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.[화학식 1][Chemical Formula 1]상기 화학식 1에 있어서, In Formula 1,상기 R1 및 R2는 각각 동일하거나 다를 수 있으며, 수소, CN, NO2, CF3, 할로겐 및 아세틸에서 선택되고,R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,상기 X는 질소 및 탄소에서 선택된 어느 하나임.And X is any one selected from nitrogen and carbon.
- 청구항 1에 있어서, 상기 화합물의 R1 및 R2는 각각 동일하거나 다를 수 있으며, CN, NO2, CF3 및 할로겐으로 이루어진 군에서 선택되고, The compound according to claim 1, wherein R 1 and R 2 of the compound may be the same or different and are selected from the group consisting of CN, NO 2 , CF 3 and halogen,상기 X는 탄소인 것을 특징으로 하는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염.Wherein X is carbon, or a pharmaceutically acceptable salt thereof.
- 청구항 1에 있어서, 상기 트리아졸로피리딘계 유도체는 N-([1,2,4,]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-페닐피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로-4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-플루오로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-아세틸페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-클로로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(5-니트로피리딘-2-일)피페리딘-4-카르복사마이드 및 N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노-4-니트로페닐)피페리딘-4-카르복사마이드으로 이루어진 군에서 선택되는 것을 특징으로 하는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염.[2] The compound according to claim 1, wherein the triazolo pyridine derivative is N - ([1,2,4,] triazolo [4,3-a] pyridin- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) -1- (2-nitrophenyl) piperidine- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) N, N ' - [[1,2,4] triazolo [4,3-a] pyridin- Pyridine-4-carboxamide, N - ([l, 2,4] triazolyl) (4,3-a) pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine- 4-carboxamide, N - ([l, 2,4] triazolo [4,3-a] pyridin- , 3-a] pyridin-3-yl) -1- (4-acetylphenyl) piperidine- (4-chloro-2-nitrophenyl) piperidine-4-carboxamide, N - ([ (4,3-a) pyridin-3-yl) -1- (4-cyanophenyl) piperidine- a] pyridin-3-yl) -1- (5-nitropyridin-2-yl) piperidine- Pyridin-3-yl) -1- (2-cyano-4-nitrophenyl) piperidine-4-carboxamide or a pharmacologically acceptable derivative thereof Possible salts.
- 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물.1. A pharmaceutical composition for preventing or treating cancer comprising, as an active ingredient, a triazolo pyridine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.[화학식 1][Chemical Formula 1]상기 화학식 1에 있어서, In Formula 1,상기 R1 및 R2는 각각 동일하거나 다를 수 있으며, 수소, CN, NO2, CF3, 할로겐 및 아세틸에서 선택되고,R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,상기 X는 질소 및 탄소에서 선택된 어느 하나임.And X is any one selected from nitrogen and carbon.
- 청구항 4에 있어서, 상기 화합물의 R1 및 R2는 각각 동일하거나 다를 수 있으며, CN, NO2, CF3 및 할로겐으로 이루어진 군에서 선택되고, 5. The compound of claim 4, wherein R 1 and R 2 of the compound may be the same or different and are selected from the group consisting of CN, NO 2 , CF 3 and halogen,상기 X는 탄소인 것을 특징으로 하는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물.Wherein X is carbon, or a pharmaceutically acceptable salt thereof, as an active ingredient.
- 청구항 4에 있어서, 상기 트리아졸로피리딘계 유도체는 N-([1,2,4,]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-페닐피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-니트로-4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-(트리플루오로메틸)페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-플루오로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-아세틸페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-클로로-2-니트로페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(4-시아노페닐)피페리딘-4-카르복사마이드, N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(5-니트로피리딘-2-일)피페리딘-4-카르복사마이드 및 N-([1,2,4]트리아졸로[4,3-a]피리딘-3-일)-1-(2-시아노-4-니트로페닐)피페리딘-4-카르복사마이드으로 이루어진 군에서 선택되는 것을 특징으로 하는 암 예방 또는 치료용 약학조성물.[5] The method according to claim 4, wherein the triazolo pyridine derivative is at least one selected from the group consisting of N - ([1,2,4,] triazolo [4,3-a] pyridin- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) -1- (2-nitrophenyl) piperidine- Carboxamide, N - ([1,2,4] triazolo [4,3-a] pyridin-3-yl) N, N ' - [[1,2,4] triazolo [4,3-a] pyridin- Pyridine-4-carboxamide, N - ([l, 2,4] triazolyl) (4,3-a) pyridin-3-yl) -1- (4- (trifluoromethyl) phenyl) piperidine- 4-carboxamide, N - ([l, 2,4] triazolo [4,3-a] pyridin- , 3-a] pyridin-3-yl) -1- (4-acetylphenyl) piperidine- (4-chloro-2-nitrophenyl) piperidine-4-carboxamide, N - ([ (4,3-a) pyridin-3-yl) -1- (4-cyanophenyl) piperidine- a] pyridin-3-yl) -1- (5-nitropyridin-2-yl) piperidine- Pyridin-3-yl) -1- (2-cyano-4-nitrophenyl) piperidine-4-carboxamide.
- 청구항 4에 있어서, 상기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체는 탄키라제(Tankyrase, TNKS) 효소 활성을 저해하는 것을 특징으로 하는 암 예방 또는 치료용 약학조성물.[Claim 4] The pharmaceutical composition for preventing or treating cancer according to claim 4, wherein the triazolo pyridine derivative represented by Formula 1 inhibits the enzyme activity of Tankyrase (TNKS).
- 청구항 4에 있어서, 상기 암은 폐암, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나인 것을 특징으로 하는 암 예방 또는 치료용 약학조성물.The method of claim 4, wherein the cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, Wherein the composition is any one selected from the group consisting of brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer and rectal cancer.
- 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 항암 효과 증진용 조성물.1. A composition for enhancing an anticancer effect comprising, as an active ingredient, a triazolopyridine derivative represented by the following formula (1) or a pharmaceutically usable salt thereof.[화학식 1][Chemical Formula 1]상기 화학식 1에 있어서, In Formula 1,상기 R1 및 R2는 각각 동일하거나 다를 수 있으며, 수소, CN, NO2, CF3, 할로겐 및 아세틸에서 선택되고,R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,상기 X는 질소 및 탄소에서 선택된 어느 하나임.And X is any one selected from nitrogen and carbon.
- 청구항 9에 있어서, 상기 항암 효과 증진용 조성물은 항암제 또는 방사선과 병용 처리되는 것을 특징으로 하는 항암 효과 증진용 조성물.[Claim 12] The composition for promoting anti-cancer activity according to claim 9, wherein the anti-cancer effect enhancing composition is treated with an anti-cancer agent or radiation.
- 청구항 10에 있어서, 상기 항암제는 시스플라틴(Cisplatin), 5-플루오로우라실(5-fluorouracil), 파클리탁셀(Paclitaxel), 독소루비신(Doxorubicin), 도노루비신(Daunorubicin), 빈블라스틴(Vinblastine), 빈크리스틴(Vincristine), 액티노마이신 D(Actinomycin D), 테니포사이드(Teniposide), 에토포사이드(Etoposide), 시클로포스파미드 (cyclophosphamide), 에피루비신(epirubicin), 아드리아마이신(adriamycin), 다우노마이신(daunomycin) 및 미토마이신-C(mitomycin-C)으로 이루어진 군에서 선택된 어느 하나 이상인 것을 특징으로 하는 항암 효과 증진용 조성물.[Claim 11] The method of claim 10, wherein the anticancer agent is selected from the group consisting of cisplatin, 5-fluorouracil, Paclitaxel, Doxorubicin, Daunorubicin, Vinblastine, (Vincristine), Actinomycin D, Teniposide, Etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin, daunomycin, and mitomycin-C. < RTI ID = 0.0 > 25. < / RTI >
- 청구항 9에 있어서, 상기 조성물은 조성물 총 100 중량부에 대하여, 항암제 1 내지 99 중량부 및 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 1 내지 99 중량부를 포함하는 것을 특징으로 하는 항암 효과 증진용 조성물.[Claim 11] The anticancer composition according to claim 9, wherein the composition comprises 1 to 99 parts by weight of an anticancer agent and 1 to 99 parts by weight of a triazolopyridine derivative represented by the following formula .
- 청구항 9에 있어서, 상기 항암 효과 증진용 조성물은 폐암, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나의 암 질환에 대한 항암 효과를 증진시키는 것을 특징으로 하는 항암 효과 증진용 조성물.[12] The composition according to claim 9, wherein the composition for enhancing the anti-cancer effect is selected from lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, The present invention provides an anticancer effect enhancing anticancer effect for cancer diseases selected from the group consisting of cancer, breast cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer and rectal cancer / RTI >
- 하기 화학식 1과 같이 표시되는 트리아졸로피리딘계 유도체 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 개선용 건강식품.1. A health food for preventing or ameliorating cancer comprising, as an active ingredient, a triazolopyridine derivative represented by the following formula (1) or a pharmaceutically usable salt thereof:[화학식 1][Chemical Formula 1]상기 화학식 1에 있어서, In Formula 1,상기 R1 및 R2는 각각 동일하거나 다를 수 있으며, 수소, CN, NO2, CF3, 할로겐 및 아세틸에서 선택되고,R 1 and R 2 may be the same or different and are selected from hydrogen, CN, NO 2 , CF 3 , halogen and acetyl,상기 X는 질소 및 탄소에서 선택된 어느 하나임.And X is any one selected from nitrogen and carbon.
- 청구항 14에 있어서, 상기 암은 폐암, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나인 것을 특징으로 하는 암 예방 또는 개선용 건강식품.15. The method of claim 14, wherein the cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, Wherein the composition is any one selected from the group consisting of brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer, kidney cancer, blood cancer and rectal cancer.
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