Composition for inhibiting proliferation of cancer stem cells

Abstract

The purpose of the present invention is to provide an agent for inhibiting the proliferation of cancer stem cells, and to provide a composition and a method for treating cancer, inhibiting the recurrence of cancer, and inhibiting the metastasis of cancer. The purpose is achieved by a compound represented by general formula (I) (in the formula, R1 represents a chlorine atom or a bromine atom, R2 represents an alkyl group, and R3 represents an aryl group. ) A composition for inhibiting proliferation of cancer stem cells, which comprises, as an active ingredient, a triazolohalogenated pyrimidine compound represented by formula (1). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a composition for inhibiting the proliferation of cancer stem cells and a method for inhibiting the proliferation of cancer stem cells. Background Art

[0002] Cancer is the leading cause of death in Japan, and although many efforts have been made to develop treatments for cancer, cancer remains difficult to cure except for early-stage cancers that can be removed surgically.

[0003] It is reported that there are some cell groups (i.e., cancer stem cells) in cancer that have the same characteristics as normal stem cells and are related to the growth of cancer. In fact, complex tumor tissues are composed of cancer cells at various stages, from undifferentiated cells to highly differentiated cells. In other words, cancer stem cells present in tumor tissues constitute hierarchical tumor tissues by providing cancer cells with various characteristics (cancer stem cell hypothesis). In addition, it is reported that cancer stem cells are more resistant to anticancer drugs and radiation than other cancer cells, play an important role in the metastasis of cancer, and are considered to be the main reason why cancer recurs after retreating from existing anticancer drugs and radiotherapy.

[0004] Therefore, there is a need for therapeutic drugs that can inactivate cancer stem cells as a whole and thus not only cure cancer but also suppress recurrence and metastasis. In particular, great expectations are placed on brain tumors that are difficult to completely remove surgically.

[0005] However, there are only a few reports on compounds such as Dofequidar that are suggested to act on cancer stem cells (see Non-Patent Document 1), and no effective therapeutic drugs are known yet.

[0006] On the other hand, the inventors of the present application have studied triazolopyrimidine derivatives as compounds having antitumor effects (see Patent Document 1).

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: International Publication No. 2020 / 204024

[0010] Non-patent literature

[0011] Non-patent literature 1: Katayama R. et al., Cancer Science, Volume 100, Issue 11, p. 2060-2068, First published 11 October 2009 Summary of the invention

[0012] Problem that the invention aims to solve

[0013] The object of the present invention is to provide a drug that inhibits the proliferation of cancer stem cells, thereby providing a composition and method that can treat cancer, inhibit cancer recurrence, and inhibit cancer metastasis.

[0014] Solutions for solving problems

[0015] Therefore, according to a composition and method according to one embodiment of the present invention, the following scheme is provided:

[0016] [1] A composition for inhibiting the proliferation of cancer stem cells, comprising a triazolohalopyrimidine compound represented by the following general formula (I) as an active ingredient.

[0017]

[0018] (Where R 1 represents a chlorine atom or a bromine atom, R 2 represents an alkyl group, R 3 represents an aromatic group. )

[0019] [2] Use of the triazolohalopyrimidine compound represented by the general formula (I) for producing a composition for inhibiting the proliferation of cancer stem cells.

[0020] [3] A method for inhibiting the proliferation of cancer stem cells, comprising the step of contacting cancer stem cells with a triazolohalopyrimidine compound represented by the general formula (I).

[0021] [4] The composition according to [1], wherein the cancer stem cells are brain tumor stem cells.

[0022] [5] The composition according to [4], wherein the brain tumor stem cell is at least one brain tumor stem cell selected from the group consisting of glioma stem cells and glioblastoma stem cells.

[0023] [6] The composition according to [1] or [4], wherein the composition is used for treating cancer, inhibiting cancer recurrence, and inhibiting cancer metastasis.

[0024] [7] The composition according to [1], wherein R 1 is a chlorine atom, and / or said R 2 It is methyl.

[0025] [8] The composition according to [1] or [7], wherein R 3 It is phenyl or substituted phenyl.

[0026] [9] The composition according to [8], wherein the substituted phenyl group is a halogen-substituted phenyl group.

[0027]

[10] The composition according to [9], wherein the substituted phenyl group is selected from the group consisting of bromophenyl groups, chlorophenyl groups, and dichlorophenyl groups.

[0028]

[11] The composition according to [8], wherein the substituted phenyl group is selected from the group consisting of hydroxyphenyl, nitrophenyl and cyanophenyl.

[0029] Effects of the Invention

[0030] The present invention can inhibit the proliferation of cancer stem cells, which was difficult in the past due to the drug resistance of cancer stem cells. In addition, by inhibiting the proliferation of cancer stem cells, the self-replication function and multi-differentiation function of cancer stem cells are lost, and the cancer stem cells are inactivated through this action, and the entire cancer is inevitably inactivated as a result, thereby not only curing cancer, but also preventing its recurrence and metastasis to other parts. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a graph showing the evaluation results of the cancer stem cell proliferation inhibitory effect as described in the Examples described below.

[0032] Figure 2 This is a graph showing the evaluation results of the cancer stem cell proliferation inhibitory effect as described in the Examples described below. DETAILED DESCRIPTION

[0033] Each embodiment of the present invention will be described in detail below, but the technical scope of the present invention is not limited to the matters of this project, and the present invention can adopt various embodiments as long as the object can be achieved.

[0034] Each term in the present specification is used with the meaning generally used by those skilled in the art unless otherwise specified, and should not be improperly interpreted as having a limiting meaning.

[0035] The term "content" in this specification is synonymous with concentration, and refers to the ratio (eg, mass %) of the amount (eg, mass) of a component relative to the total amount (eg, volume) of the drug.

[0036] "Including" means that elements other than the elements explicitly stated to be included can be added (which is synonymous with "at least including"), and includes "consisting of" and "consisting essentially of". That is, "comprising" means containing the elements explicitly stated to be included and any one or more elements, and means consisting of the elements explicitly stated, or consisting essentially of the elements explicitly stated. Examples of elements include restrictions such as ingredients, processes, conditions, and parameters.

[0037] The "to" in a numerical range refers to a range that includes the values ​​before and after it, for example: "0% to 100%" refers to a range of more than 0% and less than 100%. "Greater than" and "less than" do not include the value before it, and represent the lower limit and upper limit respectively, for example, "greater than 1" is a value greater than 1, and "less than 100" is a value less than 100.

[0038] The number of digits in an integer value is the same as the number of significant digits. For example, 1 has 1 significant digit, and 10 has 2 significant digits. In addition, for decimals, the number of digits after the decimal point is the same as the number of significant digits. For example, 0.1 has 1 significant digit, and 0.10 has 2 significant digits.

[0039] The cancers that are the subject of the present invention include so-called cancers, malignant tumors, and sarcomas, and examples thereof include breast cancers such as hormone receptor-positive breast cancer, HER2-positive breast cancer, triple-negative breast cancer, and hereditary breast cancer; gliomas (astrocytomas, oligodendrogliomas, anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic oligodendrogliomas, glioblastomas, etc.), primary central nervous system lymphomas, meningiomas, pituitary adenomas, schwannomas, craniopharyngiomas, and other brain tumors; prostate cancer; colorectal cancers such as adenocarcinomas, squamous cell carcinomas, and adenosquamous carcinomas; head and neck cancers such as head and neck squamous cell carcinomas; pancreatic cancers such as pancreatic ductal carcinomas and neuroendocrine carcinomas, etc. The present invention can be preferably used for cancers in areas that are difficult to completely remove by surgery, such as brain tumors, particularly highly malignant gliomas, and glioblastomas are preferred.

[0040] In this specification, "cancer stem cells" refer to cells that retain the ability to self-replicate and differentiate under appropriate conditions among cancer cells, and also include cancer stem-like cells. In addition, "cancer stem cells" are generally considered to be resistant to existing anticancer drugs.

[0041] In addition, unlike normal cells that lack telomerase, stem cells express telomerase. This is also true for cancer stem cells. Also, normal somatic cells lack telomerase, so their telomeres shorten with each cell division, but stem cells express telomerase, so their telomere length can be maintained.

[0042] In this specification, "cancer cell" without a modifier refers to cells including cancer stem cells and other cancer cells, and has the same meaning as cancer cells as a whole. Other cancer cells have the same meaning as cancer cells other than cancer stem cells.

[0043] In this specification, "inhibiting the proliferation of cancer stem cells" at least means that the number of live cells or the occupancy rate of cancer stem cells does not increase or decrease compared to the case where the composition is not applied, and as a result, includes inactivating cancer stem cells. Inactivation of cancer stem cells means that cancer stem cells substantially lose their self-replication and differentiation abilities, including the disappearance of the self-replication and differentiation abilities of cancer stem cells caused by the death of cancer stem cells and the disappearance of cancer stem cells themselves. Therefore, the case in which cancer stem cells are killed can be called a composition for promoting cell death of cancer stem cells; the case in which cancer stem cells disappear can be called a composition for eliminating cancer stem cells. In addition, cancer stem cells are more resistant to anticancer agents than cancer cells other than cancer stem cells. Therefore, if cancer stem cells are inactivated, the proliferation of cancer cells will inevitably be inhibited.

[0044] A composition for inhibiting cancer stem cell proliferation according to one embodiment of the present invention contains a triazolohalopyrimidine compound represented by the above-mentioned general formula (I) (hereinafter also referred to as "triazolohalopyrimidine compound (I)") as an active ingredient.

[0045] The method for inhibiting cancer stem cell proliferation according to one embodiment of the present invention can be carried out by contacting the triazolohalopyrimidine compound (I) with cancer stem cells. Since cancer stem cells cannot be distinguished from other cancer cells visually, selective contact is not practically possible, so in practice, the compound is contacted with cancer cells or cancerous areas.

[0046] The contact between the triazolohalopyrimidine compound (I) and cancer stem cells can usually be carried out by administering the composition for inhibiting the proliferation of cancer stem cells according to one embodiment of the present invention to a patient or a sick animal. Specifically, for example, the composition for inhibiting the proliferation of cancer stem cells according to one embodiment of the present invention can be administered orally, enterally, parenterally (intravenously, intravenously), topically (for external use, injected into the affected part, or placed in the affected part), or the like.

[0047] The dosage can be appropriately determined according to the route of administration, patient age, condition, body weight, etc. When the administration is non-local, such as oral, enteral, parenteral (intravenous injection, intravenous drip), the dosage of the triazolohalopyrimidine compound (I) can be selected from the range of 1 mg / kg to 10 mg / kg body weight per day. When the administration is local, the dosage can be selected from the range of 1 mg / kg to 10 mg / kg body weight per day for every 1 cm2 of the area in contact with the affected part. 2 1 mg to 100 mg per time or per 1 cm of the affected area 3 The dosage range is 1mg to 100mg per dose.

[0048] The individual who takes the composition for inhibiting cancer stem cell proliferation according to one embodiment of the present invention is not particularly limited, and examples thereof include animals, particularly mammals. Examples of mammals include humans, dogs, cats, cows, horses, pigs, sheep, etc., and humans are preferred.

[0049] The composition for inhibiting the growth of cancer stem cells of the present invention may be prepared using only the triazolohalopyrimidine compound (I), but is usually preferably used in the form of a composition containing a pharmaceutically acceptable carrier such as an excipient and other additives.

[0050] Examples of the carrier include solid carriers such as lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, magnesium stearate, lecithin, sodium chloride, polypheprosan 20, and the like; and liquid carriers such as glycerol, peanut oil, polyvinyl pyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, and water.

[0051] For the composition for inhibiting cancer stem cell proliferation which is one of the embodiments of the present invention, its form, i.e., dosage form, can take any form, for example, when a solid carrier is used, examples include tablets, powders, granules, capsules, etc., and when a liquid carrier is used, examples include syrups, emulsions, creams, gels, pastes, and injections.

[0052] The active ingredient of the composition for inhibiting the proliferation of cancer stem cells in the present invention is the triazolohalopyrimidine compound (I) represented by the above-mentioned general formula (I).

[0053] R 1 It is a chlorine atom or a bromine atom, and is preferably a chlorine atom.

[0054] R 2 It is an alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. As the alkyl group, preferably, a C1-C4 alkyl group is used, and more preferably, a methyl group is used.

[0055] R 3 is an aryl group such as phenyl or substituted phenyl. Examples of the substituted phenyl include halogen-substituted phenyl groups such as fluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromophenyl, tribromophenyl, iodophenyl, fluorochlorophenyl, and bromochlorophenyl; hydroxy-substituted phenyl groups such as hydroxyphenyl, dihydroxyphenyl, and trihydroxyphenyl; amino-substituted phenyl groups such as aminophenyl, N-methylaminophenyl, diaminophenyl, and triaminophenyl; alkoxy-substituted phenyl groups such as methoxyphenyl, dimethoxyphenyl, ethoxyphenyl, propoxyphenyl, and methylenedioxyphenyl; nitro-substituted phenyl groups such as nitrophenyl and dinitrophenyl; and cyano-substituted phenyl groups such as cyanophenyl. Preferred examples include phenyl, fluorophenyl, chlorophenyl, bromophenyl, dichlorophenyl, difluorophenyl, dibromophenyl, hydroxyphenyl, aminophenyl, diaminophenyl, nitrophenyl, and cyanophenyl. More preferred examples include phenyl, fluorophenyl, chlorophenyl, bromophenyl, dichlorophenyl, difluorophenyl, dibromophenyl, hydroxyphenyl, aminophenyl, nitrophenyl, and cyanophenyl.

[0056] In a non-limiting embodiment of the present invention, examples of the triazolohalopyrimidine compound (I) include: 1 is a chlorine atom, R 2 is methyl, R 3 is a compound of halogen-substituted phenyl, hydroxy-substituted phenyl, amino-substituted phenyl, cyano-substituted phenyl or alkoxy-substituted phenyl, preferably R 1 is a chlorine atom, R 2 is methyl, R 3 The compound is phenyl, chlorophenyl, bromophenyl, dichlorophenyl, dibromophenyl, hydroxyphenyl, dihydroxyphenyl, cyanophenyl, methoxyphenyl or methylenedioxyphenyl.

[0057] Specifically, R 1 is a chlorine atom, R 2 is methyl, R 3 A compound in which R is a phenyl group; 1 is a chlorine atom, R 2 is methyl, R 3 A compound having a chlorophenyl group; R 1 is a chlorine atom, R 2 is methyl, R 3 A compound having a bromophenyl group; R 1 is a chlorine atom, R 2 is methyl, R 3 A compound having dichlorophenyl; R 1 is a chlorine atom, R 2 is methyl, R 3 A compound having a dibromophenyl group; R 1 is a chlorine atom, R 2 is methyl, R 3 A compound in which R is a hydroxyphenyl group; 1 is a chlorine atom, R 2 is methyl, R 3 The compound is a methoxyphenyl group; R 1 is a chlorine atom, R 2 is methyl, R 3 A compound which is methylenedioxyphenyl; R 1 is a chlorine atom, R 2 is methyl, R 3 A compound in which R is an aminophenyl group; 1 is a chlorine atom, R 2 is methyl, R 3 A compound having a cyanophenyl group; R 1 is a bromine atom, R 2 is methyl, R 3 A compound in which R is a phenyl group; 1 is a bromine atom, R 2 is methyl, R 3 A compound having a chlorophenyl group; R1 is a bromine atom, R 2 is methyl, R 3 A compound having a bromophenyl group; R 1 is a bromine atom, R 2 is methyl, R 3 A compound having dichlorophenyl; R 1 is a bromine atom, R 2 is methyl, R 3 A compound having a dibromophenyl group; R 1 is a bromine atom, R 2 is methyl, R 3 A compound in which R is a hydroxyphenyl group; 1 is a bromine atom, R 2 is methyl, R 3 The compound is a methoxyphenyl group; R 1 is a bromine atom, R 2 is methyl, R 3 A compound which is methylenedioxyphenyl; R 1 is a bromine atom, R 2 is methyl, R 3 The compound where R 1 is a bromine atom, R 2 is methyl, R 3 A cyanophenyl compound.

[0058] The triazolohalopyrimidine compound (I) may be in any form of a free form, a salt form or a hydrate form (including a hydrated salt). For example, as a salt form, examples include: inorganic acid salts such as hydrochloride, sulfate, and hydrobromide, organic acid salts such as oxalate, citrate, and malate, or ammonium salts, and pharmaceutically acceptable salts are particularly preferred.

[0059] The triazolohalopyrimidine compound (I) can be produced, for example, according to the following scheme by the method described in International Publication No. 2020 / 204024 (see Patent Document 1).

[0060]

[0061] The present invention will be specifically described below by way of examples, but the present invention is not limited to these examples, and the present invention can take various forms as long as the subject of the present invention can be achieved.

[0062] Example

[0063] [Manufacturing example]

[0064] A mixture of 4-thiothymine (compound 2) (1 g, 7.0 mmol) and hydrazine monohydrate (2 g, 40 mmol) was added to ethanol (8 ml) and subjected to a reaction under heating reflux for 10 minutes. The crystals precipitated after the reaction were filtered out. The obtained crystals were recrystallized with water to obtain colorless, needle-shaped crystals of 4-hydrazino-5-methylpyrimidine-2 (1 H )-ketone (compound 3a) (melting point (mp)>300°C).

[0065] 4-Hydrazino-5-methylpyrimidine-2(1 H A mixture of )-ketone (compound 3a) (4 mmol) and benzaldehydes (4.8 mmol) shown in Table 1 below was subjected to a reaction with stirring at room temperature for 0.5 to 2 hours. The crystals precipitated after the reaction were filtered out. The obtained crystals were recrystallized from ethanol to obtain 4-arylmethylenehydrazine-5-methylpyrimidine-2 (1 H )-ketone (compounds 4a~4g).

[0066] [Table 1]

[0067] Use Compounds Use of benzaldehyde Generated compounds Compound 3a Benzaldehyde Compound 4a Compound 3a 4-Nitrobenzaldehyde Compound 4b Compound 3a 3,4-Dinitrobenzaldehyde Compound 4c Compound 3a 4-Bromobenzaldehyde Compound 4d Compound 3a 4-Cyanobenzaldehyde Compound 4e Compound 3a 3,4-Dichlorobenzaldehyde Compound 4f Compound 3a 4-Hydroxybenzaldehyde Compound 4g

[0068] 4-Arylmethylenehydrazine-5-methylpyrimidine-2(1 H A mixture of )-ketone (compounds 4a to 4g) (1 mmol) and 70% nitric acid (0.1 ml, 1.1 mmol) was stirred under reflux for 1 hour. After the reaction, the solvent in the reaction product was distilled off under reduced pressure, treated with ethyl acetate, and then the precipitated solid was filtered. The precipitated solid was recrystallized from ethanol to obtain 2-aryl-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine-5(6 H )-ketone (compounds 5a~5g).

[0069] 2-Aryl-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine-5(6 HA mixture of )-ketone (compounds 5a~5g) (1.3mmol) and triethylamine (4ml) is subjected to a reaction under heating reflux overnight. After the reaction, water is added to the reaction product in small amounts gradually under ice cooling to decompose the unreacted phosphorus oxychloride in the reaction product. Next, the reaction product is subjected to an extraction treatment using dichloromethane, and the solvent is distilled off under reduced pressure to precipitate crystals. A small amount of ethanol is added to the precipitated crystals and the crystals are filtered to obtain 2-aryl-5-chloro-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine (triazolohalopyrimidine compounds (I)a~(I)g) corresponding to compounds 5a~5g. Triazolohalopyrimidine compounds (I)a~(I)g have the following general formula (I) structure (wherein, R 1 is a chlorine atom, R 2 Represents methyl, R 3 The melting points of the two compounds are shown in Table 2.

[0070]

[0071] [Table 2]

[0072]

[0073] In the step of obtaining compound (I)a from compound 5a, the same operation as in the production of compound (I)a is carried out except that phosphorus oxybromide is used instead of phosphorus oxychloride to obtain 2-phenyl-5-bromo-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine (compound (I)h).

[0074] In the step of obtaining compound (I)d from compound 5d, the same operation as in the production of compound (I)d was carried out except that phosphorus oxybromide was used instead of phosphorus oxychloride to obtain 2-(4-bromophenyl)-5-bromo-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine (compound (I)i).

[0075] [Test Example 1]

[0076] The growth inhibitory effect of the triazolohalopyrimidine compound on cancer stem cells was evaluated as follows.

[0077] The growth inhibitory effect of the triazolohalopyrimidine compound on cancer stem cells was evaluated using commercially available anticancer agents and known compounds known to have antitumor effects.

[0078] 12037NS was used as cancer stem cells. 12037NS was isolated and purified according to the method described in Nature 432, No. 18, 396-401 (2004). 12037NS cells are susceptible to cytotoxicity from DMSO (dimethyl sulfoxide) used to dilute the test compound. Therefore, DMSO was used as a control.

[0079] (Cancer Stem Cells)

[0080] The cancer stem cells used were cultured cancer stem cells 12037NS. 12037NS was obtained by isolating and culturing glioblastoma stem cells according to the method described in Nature, 432. No. 18, 396-401.

[0081] (Test method)

[0082] Cancer stem cells (12037NS) were cultured in Dulbecco's modified Eagle's medium (DMEM) at a rate of 3.0 × 10 3 Cells / well were seeded in 96-well plates.

[0083] The test compounds shown in Table 3 were diluted with DMSO and then further diluted with PBS (phosphate buffered saline) to prepare test solutions. The test solutions were added to each well at a final concentration of 10 μM. As a control, DMSO was added to the well at a final concentration of 0.1% (v / v).

[0084] The culture plate to which the test solution had been added was incubated at 37°C and 5% CO2 for 3 days.

[0085] After the incubation, water-soluble tetrazolium salt WST-8 (color developing reagent of Cell Counting Kit-8; manufactured by Dojindo Chemical Laboratories) was added to each well at 10 μL / well, and the cells were incubated at 37° C. and 5% CO 2 for 2 hours.

[0086] The absorbance of the culture solution in each well of the culture plate after incubation at a wavelength of 450 nm is measured. In addition, WST-8 is reduced by intracellular dehydrogenase to generate water-soluble formazan. By measuring the absorbance of the formazan at 450 nm, the number of viable cells can be counted.

[0087] The survival rate of cancer stem cells was determined by comparing the counted number of viable cells with the number of cells inoculated. The survival rate of cancer stem cells for each test compound is shown in Table 3 and Figure 1 .

[0088] [Table 3]

[0089] category Test compound Survival rate (%) Comparison 1 DM SO 100 Example 1 Triazolohalopyrimidine compound (I) d 1 Example 2 Triazolohalopyrimidine compound (I)f 2 Comparative Example 1 Triazolopyrimidine compound 5d 90 Comparative Example 2 Triazolopyrimidine compound 5f 70 Comparative Example 3 5-Fluorouracil 80 Comparative Example 4 Temozolomide 65

[0090] In Table 3, the meanings of the test compounds are as follows.

[0091] DMSO: Control

[0092] Triazolohalopyrimidine compound (I) d: 2-(4-bromophenyl)-5-chloro-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine

[0093] Triazolohalopyrimidine compound (I)f: 2-(3,4-dichlorophenyl)-5-chloro-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine

[0094] Triazolohalopyrimidine compound (I) g: 2-(4-hydroxyphenyl)-5-chloro-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine

[0095] Triazolopyrimidine compound 5d: 2-(4-bromophenyl)-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine-5(6 H )-ketone

[0096] Triazolopyrimidine compound 5f: 2-(3,4-dichlorophenyl)-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine-5(6 H )-ketone

[0097] 5-Fluorouracil: a commercially available anticancer agent

[0098] Temozolomide: a commercially available anticancer agent

[0099] As shown in Table 3 and Figure 1 As shown, the survival rate of cancer stem cells of triazolopyrimidine compounds 5d and 5f is at least 70%, while that of the corresponding triazolohalopyrimidine compounds (I)d and (I)f is less than 2%. In addition, the cancer stem cell proliferation inhibitory effect of triazolohalopyrimidine compounds (I)d and (I)f is significantly better than that of commercially available anticancer agents.

[0100] [Test Example 2]

[0101] In the same manner as in [Test Example 1], the survival rate of cancer stem cells was determined for the test compounds shown in Table 4. The survival rate of cancer stem cells for each test compound is shown in Table 4 and Figure 2 It should be noted that the triazolohalopyrimidine compound (I)g refers to 2-(4-hydroxyphenyl)-5-chloro-8-methyl[1,2,4]triazolo[1,5-c]pyrimidine.

[0102] [Table 4]

[0103] category Test compound Survival rate (%) Comparison 2 DMSO 100 Example 3 Triazolohalopyrimidine compound (I) 45 Comparative Example 5 Temozolomide 75

[0104] As shown in Table 4 and Figure 2 As shown, the survival rate of cancer stem cells of triazolohalopyrimidine compound (I) g was 45%, indicating an excellent cancer stem cell proliferation inhibitory effect.

[0105] As described above, the triazolohalopyrimidine compound (I) according to one embodiment of the present invention exhibits a proliferation inhibitory effect on cancer stem cells.

[0106] Industrial Applicability

[0107] According to the present invention, by using the triazolohalopyrimidine compound represented by the above general formula (I) as an active ingredient, the proliferation of cancer cells can be inhibited, thereby enabling the treatment of cancer, the inhibition of cancer recurrence and the inhibition of cancer metastasis. In particular, it can be applied to cancers in areas that are difficult to completely remove by surgery, such as brain tumors, especially highly malignant gliomas, especially glioblastomas. Therefore, it is useful for the individual who takes it, and can be used as a medicine that contributes to the health and welfare of such an individual who takes it.

Claims

1. A composition for inhibiting the proliferation of cancer stem cells, comprising a triazolohalopyrimidine compound represented by the following general formula (I) as an active ingredient, In the formula, R 1 represents a chlorine atom or a bromine atom, R 2 represents an alkyl group, R 3 It represents an aryl group.

2. The composition according to claim 1, wherein Cancer stem cells are brain tumor stem cells.

3. The composition according to claim 2, wherein The brain tumor stem cell is at least one brain tumor stem cell selected from the group consisting of glioma stem cells and glioblastoma stem cells.

4. The composition according to claim 1, wherein The composition is used for treating cancer, inhibiting the recurrence of cancer and inhibiting the metastasis of cancer.

5. The composition according to claim 1, wherein The R 1 is a chlorine atom, and / or said R 2 It is methyl.

6. The composition according to claim 1 or 5, wherein The R 3 It is phenyl or substituted phenyl.

7. The composition according to claim 6, wherein The substituted phenyl group is a halogen-substituted phenyl group.

8. The composition according to claim 7, wherein The substituted phenyl group is selected from the group consisting of bromophenyl, chlorophenyl and dichlorophenyl.

9. The composition according to claim 6, wherein The substituted phenyl group is selected from the group consisting of hydroxyphenyl, nitrophenyl and cyanophenyl.

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