KR101713678B1 - Novel compounds and pharmaceutical composition for using anticancer drug containing thereof - Google Patents
Novel compounds and pharmaceutical composition for using anticancer drug containing thereof Download PDFInfo
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- KR101713678B1 KR101713678B1 KR1020150118738A KR20150118738A KR101713678B1 KR 101713678 B1 KR101713678 B1 KR 101713678B1 KR 1020150118738 A KR1020150118738 A KR 1020150118738A KR 20150118738 A KR20150118738 A KR 20150118738A KR 101713678 B1 KR101713678 B1 KR 101713678B1
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Abstract
The present invention relates to a novel compound of formula (I) and a pharmaceutical composition for an anticancer agent which has excellent anticancer effect comprising the compound.
The cancer which can be prevented or treated by the pharmaceutical composition of the present invention is a mammal such as a cervical cancer, a breast cancer, a stomach cancer, a brain cancer, a colon / rectum cancer, a pancreatic cancer, a colon cancer, a lung cancer, a skin cancer, a blood cancer, Gallbladder cancer, bladder cancer, kidney cancer, laryngeal cancer, pancreatic cancer, and liver cancer, and may include anticancer drugs and common pharmaceutical additives.
This compound can be used in all formulations such as tablets, powders, granules, injections, liquids and the like. The amount of the pharmaceutical composition of Compound 1 of the present invention may vary depending on the age, sex, To 1000 mg / kg may be administered once or several times a day.
Formula 1
Description
The present invention relates to a novel 4-ethyl-7- (2-fluoro-benzylsulfanyl) -2-methyl-1-thia-3b, 5,6-triaza- cyclopenta [a] indene (hereinafter referred to as DN10227) And a pharmaceutical composition for an anticancer agent containing the same.
Cancer is an incurable disease in humans, and despite its efforts for several decades, cancer remains a disease that occupies the first or second place of modern human death due to disease. Is growing.
Lung cancer is the number one cause of cancer deaths in Koreans. Avastin, Tarceva, Alimata, Gemzar and taxotere are the most common types of non-small cell lung cancer.
However, the combination of these therapies with existing chemotherapeutic agents prolongs the survival period, but the duration is short and the clinical efficacy is limited in several clinical trials targeting target therapies.
Moreover, fewer patients present with serious side effects, which are caused by the development of tolerance and the high costs associated with the use of targeted therapies.
Therefore, in order to solve the above problems, there is a need for a drug development and treatment strategy having a new drug mechanism.
Cancer cells promote the proliferation by enhancing biosynthesis through self-metabolizing programs. In this process, an enzyme called pyruvate kinase M2 (PKM2) plays an important role in regulating the cancer-specific metabolic program.
Taro Hitosugi (2009) and Stefano Elia (2008) have shown that PKM2 is a major marker for the growth of cancer cells such as prostate cancer cells, lung cancer cells, breast cancer cells, and leukemia.
PKM2 is an important enzyme that determines the rate-limiting response (the conversion of phosphoenolpyruvate to pyruvate) of the corresponding aerobic action and is over expressed in most cancer cells, but it is unusual that the enzyme activity as a pyruvate kinase of PKM2 is inhibited by the signaling pathway of cancer cells .
This inhibition of PKM2 activity may slow down the rate of action and cause glucose and sub-metabolism (eg, glucose-6-phosphate) bottlenecks, resulting in the accumulation of glucose metabolites and replacement of the pentose phosphate pathway (PPP) By pathways, macromolecules or antioxidants (such as NADPH) are produced to help cancer cells proliferate.
As a result of these studies, selective PKM2 activator is expected to be a new treatment method to overcome the limitation of existing anticancer drugs.
The inventors of the present invention have made efforts to develop a substance which inhibits PKM2 activity, and as a result, they have succeeded in confirming the structure of a novel compound of formula (I) having an activity against PKM2,
The present inventors have the compound of formula (1) subjected to a single dose administration toxicity in In vivo , the single-dose toxicity test at 2 g / kg was administered orally, but no toxicity was observed, and in In vitro results showed that normal cells did not show toxicity and toxicity was observed in cancer cells.
As a result, it was found that only the cancer cells were attacked, and the inhibition of the PKM2 signaling pathway in the cancer cells directly inhibited the proliferation of cancer cells. As a result, a comparative study of existing anticancer drugs and PKM2 activator And found that weight loss does not occur when the compound of the formula (1) is repeatedly administered during the administration of the anticancer agent, which is a disadvantage of the anticancer agent. Thus, the present invention has been completed
The present invention relates to a novel 4-Ethyl-7- (2-fluoro-benzylsulfanyl) -2-methyl-1-thia-3b, 5,6-triaza-cyclopenta [a] indene (DN10227) The present invention provides a pharmaceutical composition for an anticancer agent of the above compound having an activity of inhibiting PKM2 activity and exhibiting an excellent activity against anticancer activity.
The present invention provides a novel 4-ethyl-7- (2-fluoro-benzylsulfanyl) -2-methyl-1-thia-3b, 5,6- cyclopenta [a] indene (DN10227) compound, and the compound is pharmaceutically acceptable as a cancer treatment agent, and the present invention has been completed.
In the present invention, it was confirmed that the novel compound of formula (I) inhibits the signal transduction pathway directly related to the main factors regulating cancer cell proliferation, and thus Compound 1 was used as an anticancer agent.
In particular, it was confirmed that the compound of formula (I) inhibits the proliferation of cancer cells by inhibiting PKM2 signaling.
Cancers which can be prevented or treated by the pharmaceutical composition of the present invention include cancer such as cervical cancer, breast cancer, stomach cancer, brain cancer, colon / rectal cancer, pancreatic cancer, colon cancer, lung cancer, skin cancer, blood cancer, oral cancer, Cancer, thyroid cancer, gallbladder cancer, bladder cancer, kidney cancer, laryngeal cancer, pharyngitis and liver cancer.
In addition, the pharmaceutical composition of the present invention may further comprise an anticancer agent as an active ingredient, and the additional anticancer agent includes, for example, nitrogene mustard, imatinib, oxaliplatin, rituximab, elotinib, , Zetitib, vandetanib, nilotinib, semathanib, conservative nib, acacinib, cediranib, lestaurintinib, trastuzumab, gepetinib, bortezomib, suminitinib, Cetuximab, biscum alum, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramerstin, gemtuzumab ozogamicin, ibritumotemit, cetane, heptaplate, But are not limited to, laminin, laminin, laminin, laminin, laminin, laminin, laminin, laminin, laminin, laminin, laminin, laminin, laminin, aminolevulinic acid, amsacrine, alemtu zum, procarbazine, , Otterac , Azacytidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enocitabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, calmopar, ralitriptycide, docetaxel , Paclitaxel, irinotecan, bellotecan, topotecan, vinorelbine, etoposide, vincristine, vinblastine, tenifocide, doxorubicin, dirubicin, epirubicin, mitoxantrone, mitomycin, But are not limited to, doronobuchin, dactinomycin, pyra rubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, epidermal, iopospermide, cyclophosphamide, melaran, altretin, , Thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, xestan, aminoglutethimide, anagrelide, navelin, pradrazol, tamoxifen, toremifene, testolactone , Anastrozole, letrozole , Borozol, bicalutamide, rosmutin, chrysotanib and carmustine.
When this compound is applied to a pharmaceutical preparation, it corresponds to all formulations such as tablets, powders, granules, injections, and liquid preparations.
According to the present invention, the amount of the
Further, the dose of the
Accordingly, the dosage is not intended to limit the scope of the invention in any way.
The present invention provides a novel compound of formula (I) useful as an anticancer agent. As can be clearly seen from the examples, the compound of formula (1-ethyl-7- 1-thia-3b, 5,6-triaza-cyclopenta [a] indene) has excellent anticancer effect.
It also has the effect of preventing side effects of weight loss during chemotherapy.
1 is a synthesis step of DN10227.
2 shows the results of 1 H-NMR.
3 shows the results of 13 C-NMR.
FIG. 4 is a graph showing the result of selective activation of PKM2 by DN10227. FIG.
Figure 5 is a graph showing that DN10227 increases the initial rate of PKM2 activity by the substrate.
FIG. 6 is a graph (A) showing the morphological change of PKM2 by DN10227 and a graph (B) comparing pyruvate kinase activity.
FIG. 7 is a graph (A) showing intracellular PKM2 changes to tetrameric form by DN10227 and a graph (B) showing activation of pyruvate kinase.
Fig. 8 shows the result of evaluating the colony forming effect of DN10227 on lung cancer cell lines A549 and H460.
Figure 9 shows the results of evaluating the anti-cancer effect of DN10227 in the A549 xenograft model.
After confirming the structure of the compound which increases the inhibited PKM2 activity by computer simulation, the inventors of the present invention prepared the compound of the formula (1) as follows.
1. Intermediate compound (S-1) was prepared by reacting DMF with sodium azide (manufacturer: Aldich) and Methyl bromoacetate (manufacturer: TCI).
C 3 H 5 BrO 2 + NaN 3 → C 3 H 5 N 3 O 2 + NaBr
2. Sodium methoxide solution (manufacturer: TCI) was added to methanol, S-1 and 5-methyl-2-thiophenecarboxaldehyde (manufacturer: Aldrich) were slowly added in order and stirred.
After completion of the reaction, an aqueous NH 4 Cl solution was added and stirred, followed by filtration and lyophilization to obtain Intermediate Compound S-2.
C 3 H 5 N 3 O 2 + C 6 H 6 OS → C 9 H 9 N 3 O 2 S + H 2 O
3. S-2 compound was refluxed and stirred in toluene solution, and the resultant solid was filtered and freeze-dried to prepare Intermediate Compound S-3.
C 9 H 9 N 3 O 2 S → C 9 H 9 NO 2 S + N 2
4. The S-3 compound was added to the ethanol solution, and hydrazine hydrate (manufacturer: Aldrich) was added thereto, followed by reflux stirring, cooling, filtration under reduced pressure and freeze-drying to prepare Intermediate Compound S-4.
C 9 H 9 NO 2 S + N 2 H 4 → C 8 H 9 N 3 OS + CH 3 OH
5. S-4 compound was added to the DMF solution, Trimethyl orthopropionate (manufactured by TCI) was added, and the mixture was stirred under reflux, cooled at room temperature and freezing, cooled, and vacuum-dried to prepare Intermediate Compound S-5.
C 8 H 9 N 3 OS + C 6 H 14 O 3 ? C 11 H 11 N 3 OS + C 3 H 9 (OH) 3
6. S-5 compound was added to benzene solution, and Lawesson reagent (manufacturer: Aldrich) was added and refluxed and stirred.
After completion of the reaction, the reaction mixture was cooled at room temperature, washed with n-hexane, and lyophilized to obtain Intermediate Compound S-6.
C 11 H 11 N 3 OS + C 14 H 14 O 2 P 2 S 4 → C 11 H 11 N 3 S 2 + C 14 H 14 O 3 P 2 S 3
7. S-6 compound was added to the acetonitrile solution, potassium carbonate (manufacturer: Aldrich) and 18-crown-6 (manufacturer: Aldrich) were added in order, 2-Fluorobenzyl chloride (manufacturer: TCI) was added and the mixture was refluxed .
After completion of the reaction, the reaction mixture was cooled at room temperature, and methylene chloride was added thereto.
The reactants were filtered to remove impurities and remaining reagents that did not dissolve in methylene chloride.
After filtration, the filtrate was concentrated and the resulting solid was purified by column chromatography.
The mobile phase was Ethyl acetate: Hexane (5: 5) and the final compound was obtained.
C 11 H 11 N 3 S 2 + C 7 H 6 ClF -> C 18 H 16 FN 3 S 2 + HCl
As a result of NMR measurement, the obtained compound was confirmed to be a compound of formula (1) as shown in Figs. 2 and 3, and it was named DN10227.
The formula of the novel compound was C 18 H 16 FN 3 S 2 , MW was 357.47, and mp was 125 ° C.
The pharmaceutical composition comprising the compound of formula (I) of the present invention can be formulated into various oral or parenteral dosage forms.
Formulations for oral administration include, for example, tablets, capsules, etc. These formulations may contain, in addition to the active ingredient, a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, For example, silica, talc, stearic acid and its magnesium or calcium salt and / or polyethylene glycol).
Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain magnesium stearate, citric acid, silicon dioxide . A disintegrating or boiling mixture such as starch, agar, alginic acid or its sodium salt and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.
The formulations may be prepared by conventional mixing, granulating or coating methods.
A representative oral formulation can be prepared as follows.
DN10227 is dissolved in the pharmacopoeial alcohol, and then silicon dioxide, citric acid, magnesium stearate, corn starch and mannitol are added and granulated. After hot air drying, tablets can be made using a tablet machine.
Also typical of parenteral administration formulations are isotonic aqueous solutions or suspensions which are suitable for injectable use.
In a typical parenteral formulation, an injection may be prepared as follows.
After dissolving DN10227 in pharmacopoeial alcohol, add
Hereinafter, the constitution of the present invention will be described in more detail with reference to the production method of the compound of the formula (1), the NMR analysis of the compound, and the experiment and examples, but the scope of the present invention is not limited by the following examples.
Step 1: 350 ml of DMF and 90.36 g of sodium azide (1.39 mol, manufacturer: Aldich) were added and stirred at room temperature.
Methyl bromoacetate (124 mL, 1.307 mol, manufacturer: TCI) was slowly added to the solution and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed several times with water to remove DMF, and the recovered organic solution was filtered and concentrated under reduced pressure to obtain 103.59 g of compound S-1.
Step 2: Add 600 mL of methanol and add 179 mL (895 mmol, manufacturer: TCI) of sodium methoxide 5M in MeOH slowly at 0 ° C.
103.09 g (895 mmol) of S-1 and 48.68 mL (447.5 mmol, manufacturer: Aldrich) of 5-methyl-2-thiophenecarboxaldehyde were slowly added in this order.
After the addition, the mixture was stirred at about 20 ° C for 18 hours. After completion, 800 mL of NH 4 Cl aqueous solution was added, and the mixture was stirred for 1 hour.
The product was filtered and lyophilized to obtain 67.59 g of the compound S-2.
Step 3: 250 mL of toluene and 67.59 g (302.75 mmol) of S-2 compound were added and the mixture was refluxed at 200 ° C for 1 hour.
The resulting solid was filtered and lyophilized to obtain 46.61 g of the compound S-3.
Step 4: 180 ml of ethanol and 46.61 g (238.7 mmol) of S-3 compound were added, 74.3 ml (238.7 mmol, manufactured by Aldrich) of hydrazine hydrate was added and the mixture was refluxed and stirred at 150 ° C for 17 hours. After completion of the reaction, the reaction mixture was cooled at room temperature and freezing for 1 hour, filtered under reduced pressure, and lyophilized to obtain 43.21 g of S-4.
Step 5: 230 mL of DMF and 43.21 g (221.3 mmol) of the S-4 compound were added and 34.4 mL (243.43 mmol, manufacturer: TCI) of trimethyl orthopropionate was added and refluxed at 200 ° C for 17 hours.
After completion of the reaction, the mixture was cooled at room temperature and freezing for 1 hour, filtered and vacuum dried to obtain 51.15 g of S-5.
Step 6: 450.1 mL of benzene and 51.15 g (219.25 mmol) of S-5 compound were added, and 44.34 g (109.62 mmol, Lawesson reagent, manufacturer: Aldrich) was added and the mixture was refluxed and stirred at 150 ° C for 18 hours.
After completion of the reaction, the reaction mixture was cooled at room temperature, washed with n-hexane, and lyophilized to obtain 46.92 g of the compound S-6.
Step 7: 264 g (188.16 mmol, manufactured by Aldrich) of potassium carbonate and 1.69 g (6.4 mmol, manufacturer: Aldrich) of 18-crown-6 were added in this order to a solution of 840 mL of acetonitrile and 46.92 g (188.16 mmol) of S- .
Then 23.04 mL (193.8 mmol, 2-Fluorobenzyl chloride, manufactured by TCI) was added and the mixture was refluxed and stirred at 150 ° C for 18 hours.
After completion of the reaction, the reaction mixture was cooled to room temperature, and methylene chloride was added thereto, followed by stirring for 1 hour.
The reactants were filtered to remove impurities and residual reagents that did not dissolve in methylene chloride.
After filtration, the filtrate was concentrated and the obtained solid was purified by column chromatography.
The mobile phase was Ethyl acetate: Hexane (5: 5) and 26.22 g of compound DN10227 (see also Fig. 1).
≪ NMR Analysis of Compound (1)
NMR analysis of
Analysis data results 1 H-NMR (500 MHz, DMSO) δ 7.60 ~ 7.57 (m, 1H), 7.40 (s, 1H), 7.35 ~ 7.31 (m, 1H), 7.23 ~ 7.19 (m, 1H), 7.17 13 C-NMR 125 (m, 2H), 4.63 (s, 2H), 4.63 (s, 2H), 3.27 128.9, 124.9, 124.9, 124.8, 124.0, 115.9, 115.7, 113.0, 97.3, 25.9, 25.8, 25.7, 17.2, and 10.2 ppm, respectively (see Figs. 2 and 3).
As a result of analysis, the structure of
<Activity analysis of PKM2 (PKM2 activity assay)>
Kinase-Glo® kit (Promega) was used to investigate the effect of DN10227 on PKM2 activity.
PKM2 activator was dissolved in DMSO in a kinase enzyme buffer (50 mM Tris-HCl (pH 7.4), 100 mM KCl, 10 mM MgCl 2 , 0.5% BSA, 2 mM PEP, 2 mM ADP) and 0.2-0.5 nM pyruvate kinase protein. (0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, and 50 μM) at room temperature for 50 minutes.
The same amount of kinase glo- red reagent as that of the reaction solution was added, and the mixture was stirred for 10 minutes. Fluorescence signals were measured with an Infinite F200 pro apparatus.
(1) PKM2 selective activation of DN10227
The effect of DN10227 on PKM1 and PKM2 protein activation was investigated.
As a result, it was confirmed that DN10227 (0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50 μM) specifically activates PKM2 (see FIG.
(2) Change of PKM2 Km value by DN10227
In order to confirm the affinity of the protein and the substrate complex, the change of initial velocity (ν0) according to PEP concentration was measured.
DN10227 used in the experiment and 50 μM of the positive control group DASA-10 were used.
The Michaelis constant (Km) of the control group without PKM2 activator was 1.62 ± 0.24 mM, and the Km of DASA-10 and DN10227 were 0.54 ± 0.03 mM and 0.48 ± 0.05 mM, respectively.
Thus, the affinity of PKM2 and PEP was increased about 3-fold by DASA-10 and about 3.4-fold by DN10227 (see FIG. 5).
≪ Change of PKM2 form and activity >
(1) Enzyme based assay
Human recombinant PKM2 was used to determine the effect of FBP and DN10227 on changes in PKM2 (monomer-, dimer-, trimer-, and tetrameric form) and activity.
Control (1% DMSO) or 70 μM of each test substance was mixed with 3.5 μM PKM2 and reaction buffer [50 mM Tris-HCl (pH 7.4), 100 mM KCl, 10 mM MgCl 2 ] was added to a total reaction volume of 500 μ , And reacted at room temperature for 1 hour.
To confirm the morphology of the reaction protein, size exclusion chromatography was performed with FPLC equipped with an ENRich ™ SEC650 column (10 × 300 column, 24 ml, cat. # 780-1650) and 200 μl aliquots were obtained.
The amount of PKM2 in the fraction was confirmed by western blot.
Kinase-Glo® kit (Promega) was used to compare pyruvate kinase activity of the reaction solution.
The effect of DN10227 and FBP on the morphological changes of PKM2 showed that FBP converted the dimeric or monomeric form of PKM2 into tetrameric or trimeric form, but DN10227 showed much less change of morphology.
When FBP and DN10227 were treated together, they were more converted to the tetrameric or trimeric form of PKM2 than the group treated with FBP alone (see Fig. 6A).
The activity of pyruvate kinase in the reaction solution was increased by about 16 times and the activity of PKM2 which reacted with DN10227 increased 2.5 times compared to the control.
The activity of PKM2 treated with FBP and DN10227 was increased 25-fold, confirming the increased activity as compared to the single treatment group (see Fig. 6B).
PKM2 tetrameric form formation and pyruvate kinase activity in the enzyme - based assay were more clearly confirmed as PKM2 activator when treated with FBP than with DN10227 alone.
(2) Cell based assay
The effect of DN10227 on PKM2 morphology and activity changes in cancer cells was investigated.
A549 lung cancer cells were cultured, treated with 1 μM DN10227, cultured for 3 hours, and treated with 100 μM pervanadate (tyrosine phosphatase inhibitor) for 10 minutes.
The intracellular PKM2 protein is converted to a dimeric or monomeric form by pervanadate and its activity is inhibited.
After the reaction, cellular proteins were extracted using RIPA buffer and PKM2 activity was confirmed by Kinase-Glo® kit (Promega) in the extracted proteins.
After performing exclusion chromatography on cell proteins, 200 μl aliquots were taken and the amount of PKM2 in the aliquots was confirmed by western blotting.
PKM2 of A549 cells was converted to dimeric form and monomeric form by pervanadate, and inhibited the activity of pervandate by 1 μM DN10227 and maintained the tetrameric PKM2 form (see FIG. 7A).
Evaluation of pyruvate kinase activity of A549 cell protein revealed that the PKM2 activity was reduced by about 35% in pervanadate treatment but increased by about 90% in 1 μM DN10227 than in the control group (see FIG. 7B).
DN10227 inhibited pervanadate activity and produced tetrameric PKM2 and increased PKM2 activity.
< In vitro assay >
Two types of human-derived lung cancer cells (A549, H460) were subcultured in a 6-well plate for 10 days in CO 2 Incubator (37 ° C, 5.0%) to induce colony formation. DN10227 was treated twice a week Colony formation inhibitory effect was confirmed.
FIG. 8 is a graph showing the effect of inhibiting colony formation by staining cells with
DN10227 inhibited colony formation up to 0.1 - 30 μM in a concentration dependent manner, and
< In vivo assay >
Six-week-old BALB / c nude female mice were purchased and stabilized, and human-induced lung cancer cells, A549, were injected subcutaneously into RPMI-1640 medium and matrigel at 5 × 10 6 cells / mouse.
When the size of the tumor reached 100 mm 3 on average, drug treatment was started. DN10227 was suspended in 0.5% methylcellulose (1,500 cP) aqueous solution and the drug was administered orally five times a week for a certain period of time.
Cisplatin and DN10227 10 mg / kg ip were administered at the same rate with DMSO: EtOH: PEG400: Cremophor EL: water = 7.5: 54: 25: 12.5: 50 (vehicle)
As a result of observing the weight change of mice during the drug administration period, no change in body weight was observed after administration of DN10227 oral or intraperitoneal administration group, but 10% body weight of
Was the size of the mouse tumors for drug administration period, the measurement results in the control group was 95.1 ± 15.3mm 3 to 977.7 ± 193.3mm 3 increased tumor size, 447.6 ± 36.8mm 3 cisplatin 1mg / kg intraperitoneally administered at 95.0 ± 15.1mm 3 And 54.2%, respectively.
In the 10 mg / kg peritoneal administration group of DN10227, 43.7% of the anticancer efficacy was confirmed from 94.4 ± 17.5 mm 3 to 550.0 ± 78.9 mm 3 , and the oral administration group of
The mice were weighed and weighed. The results were as follows: the
As described above, the compound of the formula (I) of the present invention has anticancer activity in the same category without weight loss compared to the conventional anticancer drug cisplatin, and it has excellent anticancer effect pharmaceutical composition with less side effect than existing anticancer drugs. .
The composition for the anticancer drug of the present invention has been specifically described, and the composition of the other additives is a general matter in the technical field, and a description thereof has been omitted, and such a configuration is within the scope of the present invention, It is to be understood that the invention is not limited thereto.
Claims (6)
[Chemical Formula 1]
The cancer is selected from the group consisting of cervical cancer, breast cancer, gastric cancer, brain cancer, colon / rectal cancer, pancreatic cancer, colon cancer, lung cancer, skin cancer, blood cancer, oral cancer, prostate cancer, ovarian cancer, thyroid cancer, gall bladder cancer, Or a pharmaceutically acceptable salt thereof.
Wherein the pharmaceutical composition is in the form of an oral or parenteral pharmaceutical preparation.
Wherein the activity of the inhibited PKM2 is increased.
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Citations (2)
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EP0713876A1 (en) | 1994-11-24 | 1996-05-29 | Wakamoto Pharmaceutical Co., Ltd. | Triazine derivative, chymase activity inhibitor and nitric oxide production inhibitor |
WO2010042867A2 (en) | 2008-10-09 | 2010-04-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Activators of human pyruvate kinase |
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EP0713876A1 (en) | 1994-11-24 | 1996-05-29 | Wakamoto Pharmaceutical Co., Ltd. | Triazine derivative, chymase activity inhibitor and nitric oxide production inhibitor |
WO2010042867A2 (en) | 2008-10-09 | 2010-04-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Activators of human pyruvate kinase |
Non-Patent Citations (2)
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Chemical Abstract 화합물, STN express, RN 892087-54-6 (Entered STN: 2006.07.11.)* |
Journal of Combinatorial Chemistry, 2007, 9(1), 96-106 |
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