WO2019035522A1 - Composition pour prévenir ou traiter le cancer, contenant un dérivé à base de triazolopyridine comme principe actif - Google Patents

Composition pour prévenir ou traiter le cancer, contenant un dérivé à base de triazolopyridine comme principe actif Download PDF

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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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cancer
pyridin
triazolo
piperidine
carboxamide
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Korean (ko)
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안지연
송지영
남기엽
유화니
정인성
황상구
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한국원자력의학원
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Priority to DE112018004197.2T priority Critical patent/DE112018004197T5/de
Priority to GB2001444.5A priority patent/GB2579480B/en
Publication of WO2019035522A1 publication Critical patent/WO2019035522A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • 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
    • 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
    • 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

La présente invention concerne une composition pour prévenir ou traiter le cancer contenant comme principe actif un dérivé à base de triazolopyridine ou un sel pharmaceutiquement acceptable de ce dernier, le dérivé à base de triazolopyridine inhibant l'activité enzymatique de la tankyrase ce qui conduit à l'inhibition de l'expression de la β-caténine, laquelle est un facteur tumoral, permettant ainsi d'augmenter la mort des cellules cancéreuses par apoptose. Du fait qu'il présente une excellente réduction du taux de survie lorsqu'il est utilisé en association avec des médicaments anticancéreux ou une irradiation, le dérivé à base de triazolopyridine peut être utilisé utilement en tant que composition pharmaceutique pour la prévention et le traitement du cancer, en tant que composition pour augmenter l'effet d'une radiothérapie, ou comme aliment fonctionnel pour la santé pour prévenir ou améliorer le cancer.
PCT/KR2018/002502 2017-08-16 2018-02-28 Composition pour prévenir ou traiter le cancer, contenant un dérivé à base de triazolopyridine comme principe actif WO2019035522A1 (fr)

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DE112018004197.2T DE112018004197T5 (de) 2017-08-16 2018-02-28 Zusammensetzung zur prävention oder behandlung von krebs, beinhaltend triazolpyridin-basiertes derivat als wirkstoff
GB2001444.5A GB2579480B (en) 2017-08-16 2018-02-28 Composition for preventing or treating cancer containing Triazolopyridine-based derivative as active ingredient

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WO2020212895A1 (fr) * 2019-04-16 2020-10-22 Vince Grolmusz Procédé et appareil permettant de faciliter la liaison de la protéine gap à la protéine ras mutante par des agents moléculaires pour le traitement de cancers liés à une mutation ras

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KR20230072623A (ko) * 2021-11-18 2023-05-25 한국원자력의학원 탄키라제 억제용 화합물 및 이의 의학적 용도

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JP6428114B2 (ja) 2014-09-30 2018-11-28 ブラザー工業株式会社 液体消費装置
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WO2015143380A1 (fr) * 2014-03-20 2015-09-24 Samumed, Llc Indazole-3-carboxamides 5-substitués, et préparation et utilisation de ceux-ci

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020212895A1 (fr) * 2019-04-16 2020-10-22 Vince Grolmusz Procédé et appareil permettant de faciliter la liaison de la protéine gap à la protéine ras mutante par des agents moléculaires pour le traitement de cancers liés à une mutation ras

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GB202001444D0 (en) 2020-03-18
GB2579480B (en) 2022-04-27

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