KR20090016794A - 1,3,5-triazinylthiocarborane derivatives, a process for the preparation thereof and a pharmaceutical composition comprisin g the same - Google Patents

Abstract

A 1,3,5-triazinylthiocarborane derivatives are provided to selectively accumulate the boron atom in the cancer cell, so that they are useful as boron neutron capture therapeutic agent for destroying the cancer cells by irradiating the thermal neutron. The 1,3,5-triazinylthiocarborane derivatives represented by the chemical formula(1), its isomer or pharmaceutically acceptable salts thereof are useful for treating cancer, wherein R is C1-C5 alkyl group having alkoxy group, C1-C5 alkyl group having alcohol group, or ortho-, meta- and para-carboran-1-yl thio group; and the vertex of the truncated icosahedron without the character indicates a B-H bond.

Description

1,3,5-triazineylthiocarborane derivatives, isomers thereof or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the same and methods for preparing the same approximately and a pharmaceutical composition comprisin g the same}

The present invention relates to a 1,3,5-triazineylthiocarborane derivative, an isomer thereof or a preparation method thereof, and a pharmaceutical composition comprising the same, and more particularly, to di (2-methoxyethyl) amino-1, 3,5-triazine-6-ylthiocarborane derivative or bis [{2,4-di (2-methoxyethyl) amino} -1,3,5-triazine-6-ylthio] carbonan Derivatives, methods for their preparation, and pharmaceutical compositions for boron neutron capture therapy comprising the same.

The cancer treatment technology that is attracting the most attention as one of human diseases today includes surgical methods such as surgery, medical methods such as drug administration, and radiation therapy by gamma irradiation. Such a cancer treatment method not only damages cancer cells but also normal cells around the cancer cells, and in the case of chemotherapy, there is a problem of generating cancer cells with resistance.

Therefore, recently, as a method of intensively irradiating a large amount of radiation where cancer cells have proliferated, a compound containing a specific element such as boron is selectively accumulated in cancer cells by using a suitable transport biochemical, and an appropriate amount of heat. A method of treating cancer by destroying only cancer cells with energy released from the nuclear fission by neutron irradiation to the cancer cell proliferation site to induce nuclear fission of the element has been attempted.

Such dual therapy is called neutron capture therapy (NCT), and in particular, the method using boron element is called boron neutron capture therapy (BNCT). The reagent used for this purpose is also called boron neutron capture therapy a gent (BNCT a gent).

Boron atoms found in nature exist in a ratio of about 81.17: 18.8 to two isotopes of ¹¹ B and ¹⁰ B. Among them, when the thermal neutrons are irradiated on the isotope ¹⁰ B, the boron atoms capture neutrons and then the nuclear decay of the boron atoms. Occurs, followed by energy that can destroy cancer cells.

Therefore, if the patient is irradiated with a boron ( ¹⁰ B) compound and the neutron is irradiated to the tumor site of the patient, the tumor cells become a key target of the neutrons, so that only tumor cells can be selectively and safely removed. . In order to achieve the desired effect, the boron accumulation selectivity of tumor tissue to normal tissue subjected to neutron irradiation should be as large as possible.

Inorganic boron compounds were used as the first generation boron neutron capture therapy, but there was a problem in the passage and toxicity of the cell membrane. However, with the successful treatment of glioblastoma, a type of brain cancer, using BSH (Na ₂ ¹⁰ B ₁₂ H ₁₁ SH, mercaptoborane), a second-generation boron neutron capture therapy, the concept of boron neutron capture therapy A new biography has emerged for the treatment of brain cancer. The combination of boron compounds found in the late 1950s and 1960s with bioactive materials with various biochemical pathways has enabled the selective accumulation of boron atoms in cancer cells. Examples of the boron compound is a bundle to three kinds of isomers of dicarboxylic bar represented by the formula - claw small - there is a dodecyl carborane (dicarba- closo -dodecarborane, carborane).

Dicarba- closo -dodecaborane has a molecular formula of C ₂ B ₁₀ H ₁₂ , depending on the position of carbon 1,2-dicarba- closo -dodecaborane ( 1 , ortho-carborane), 1, there are 7-dicarboxylic bar-claw small-dodecyl carborane (2, meta-carborane), 1,12-dicarboxylic bar-claw small-dodecyl carborane (3-carborane or para). remind Vertices in the equation, not marked with letters at the corners of the icosahedron, represent BH bonds. The third-generation boron neutron capture therapy, represented by BPA (L-4-boronophenylalanine), an analog of tyrosine, has also been successful in clinical applications. At present, the development of boron chemistry and the development of biochemical metabolic pathways have been combined to develop the fourth generation of reagents aiming at high selective absorption of cancer cells and low toxicity to normal cells.

Therefore, there is a need for the continuous development of new boron neutron capture therapy with low toxicity and excellent selectivity of the accumulation of boron atoms in cancer cells.

It is an object of the present invention to provide di (2-methoxyethyl) amino-1,3,5-triazine-6-ylthiocarborane derivatives or isomers thereof and pharmaceutically acceptable salts thereof.

The present invention also provides bis [{2,4-di (2-methoxyethyl) amino} -1,3,5-triazine-6-ylthio] carborane derivative or isomer thereof and pharmaceutically acceptable thereof. It is another object to provide a process for the preparation of possible salts.

The present invention relates to di (2-methoxyethyl) amino-1,3,5-triazine-6-ylthiocarborane derivative or bis [{2,4-di (2-methoxyethyl) amino} -1, Another object is to provide a pharmaceutical composition comprising 3,5-triazine-6-ylthio] carborane derivative, an isomer thereof and a pharmaceutically acceptable salt thereof as an active ingredient, in particular, a pharmaceutical composition for anticancer drugs. .

The present invention for achieving the above object provides a 1,3,5-triazinylthiocarborane derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, characterized in that represented by the following formula (1).

[Formula 1]

(In Formula 1, R is an alkyl group of C _1-5 with an alkoxy, C alkyl group of _{1 to 5} with an alcohol, and an ortho, meta-, and para-carborane and Im-yl import the positive and twenty Vertices without icosahedron represent BH bonds.)

And it provides a 1,3,5-triazineylthiocarborane derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, characterized in that represented by the following formula (2).

[Formula 2]

(In the formula 2, R is an alkyl group, and vertex do not have a character of the regular icosahedron of C ₁ with an alkyl group, an alcohol of C _{1 ~ 5} alkoxy group with _1-5 are showing a BH bond.)

In particular, Formula 1,

1) 6- ( ortho -carbonan-1-ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine (6- o- carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine),

2) 6- ( meta -carbolan-1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine (6- m -carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine),

3) 6- ( para -carbolan-1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine (6- p- carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine),

4) 4,6-di ( ortho -carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di ( o -carboran -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine),

5) 4,6-di (2-methyl- ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di (2-methyl- o- carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5- triazine),

6) 4,6-di (2-phenyl- ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di It is preferably at least one selected from the group consisting of (2-phenyl- o- carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine.

And Formula 2,

7) 1,7-bis [{2,4-di (2-methoxyethyl) amino-triazine-6-yl} thio] - meta-carborane (1,7-bis [{2,4- di (2-methoxyethyl) amino} triazin-6-ylthio] -m -carborane),

8) 1,12-bis [{2,4-di (2-methoxyethyl) amino-triazine-6-yl} thio] - para-carborane (1,7-bis [{2,4- di (2-methoxyethyl) amino} triazin-6-ylthio] -p- carborane) is preferably at least one selected from the group consisting of.

In addition, the present invention provides a pharmaceutical composition for anticancer, wherein the 1,3,5-triazineylthiocarborane derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof is an active ingredient.

In particular, the anticancer pharmaceutical composition provides an anticancer pharmaceutical composition, which is used as a therapeutic agent for boron neutron capture.

In addition, ortho - carborane (1), meta -carborane (2) or para -carborane (3), chloro-1,3,5 triazine (4, 5), and sulfur as shown in Scheme 1 below. It provides a method for preparing a 1,3,5-triazinylthiocarborane derivative, an isomer thereof or an acceptable salt thereof, characterized in that each step comprises reacting while controlling the equivalent ratio.

Scheme 1

(R is C _{1 ~ 5} alkoxy C _{1 ~ 5} alkyl group, an alkyl group of C _{1 ~ 5} with an alcohol and with a group of the ortho -, meta-, or para-carborane and Im-yl import, R 'is Hydrogen, methyl, phenyl groups, and the vertexes of the icosahedron represent BH bonds.)

Hereinafter, prior to describing the present invention in detail, terms or words used in the present specification and claims should not be construed as being limited to ordinary or dictionary meanings, and the inventors explain their own invention in the best way. In order to properly define the concept of the term in order to be interpreted as meanings and concepts in accordance with the technical spirit of the present invention.

Therefore, the configurations shown in the embodiments described in the present specification are only one of the most preferred embodiments of the present invention, and do not represent all of the technical ideas of the present invention, and various equivalents may be substituted for them in the present application. It should be understood that there may be variations and examples.

Hereinafter, the present invention will be described in detail.

In the compound represented by Formula 1 or 2 of the present invention, more preferable specific examples are as follows.

1) 6- ( ortho -carbonan-1-ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine (6- o- carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine),

2) 6- ( meta -carbolan-1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine (6- m -carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine),

3) 6- ( para -carbolan-1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine (6- p- carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine),

4) 4,6-di ( ortho -carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di ( o -carboran -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine),

5) 4,6-di (2-methyl- ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di (2-methyl- o- carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5- triazine),

6) 4,6-di (2-phenyl- ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di (2-phenyl- o- carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5- triazine,

7) 1,7-bis [{2,4-di (2-methoxyethyl) amino-triazine-6-yl} thio] - meta-carborane (1,7-bis [{2,4- di (2-methoxyethyl) amino} triazin-6-ylthio] -m -carborane),

8) 1,12-bis [{2,4-di (2-methoxyethyl) amino-triazine-6-yl} thio] - para-carborane (1,7-bis [{2,4- di (2-methoxyethyl) amino} triazin-6-ylthio] -p -carborane)

The compounds represented by the formulas (1) and (2) of the present invention can be used in the form of pharmaceutically acceptable salts, and such salts include acid addition salts formed by pharmaceutically acceptable free acids.

The free acid may be an inorganic acid and an organic acid, and the inorganic acid may be hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid or phosphoric acid, and the organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, Can be used.

The present invention also provides a di (2-methoxyethyl) amino-1,3,5-triazine-6-ylthiocarborane derivative represented by Chemical Formulas 1 and 2 or bis [{2,4-di (2 -Methoxyethyl) amino} -1,3,5-triazine-6-ylthio] carborane derivative, or a method for preparing a salt thereof is provided.

The present invention also provides ortho - carborane (1) , meta -carborane (2) or para -carborane (3) as shown in Scheme 1 below with chloro-1,3,5triazine (4, 5) , and Di (2-methoxyethyl) amino-1,3,5-triazine-6-ylthiocarborane derivatives of formulas 1 and 2 or bis [{2,4-di (2) comprising reacting sulfur -Methoxyethyl) amino} -1,3,5-triazine-6-ylthio] carborane derivative, or a method for preparing a salt thereof is provided.

Scheme 1

R is C _1-5 alkoxy C _1-5 alkyl group having a group, an alkyl group of C _1-5 with an alcohol, and an ortho, meta-, or para-carborane and Im-yl import, R 'is hydrogen And a methyl, phenyl group, and a vertex without icosahedron represents a BH bond.

In Scheme 1, the reaction equivalence ratio of ortho - carborane (1) , meta -carborane (2) , and para -carborane (3) and chlorotriazine (4, 5) , sulfur, and butyllithium is controlled. The products of 1 and 2 can be prepared.

Specifically, in Scheme 1, 1 equivalent of ortho - carborane (1) , meta -carborane (2) , para -carborane ( 3) and chlorotriazine (4, 5) , 1 equivalent of butyllithium, And using 1 equivalent of sulfur to obtain the product of formula (1). Also , using 2 equivalents of ortho - carbonanol (1) , 1 equivalent of chlorotriazine (5) , 2 equivalents of butyllithium, and 2 equivalents of sulfur, the product of Formula 1 having two carbonylthio groups You can get it. Using 1 equivalent of meta -carborane (2) and para -carborane ( 3) , 2 equivalents of chlorotriazine (5) , 2 equivalents of butyllithium, and 2 equivalents of sulfur, the product of Formula 2 can be obtained. have.

In the production method according to the present invention, triazine ( 4, 5) used as the starting material of Scheme 1 is from 2,4,6-trichloro-1,3,5-triazine and the corresponding secondary amine compound, (Can. Pat. Appl. 97pp, (1997), Eur. Pat. Appl. 41pp, (1994)).

The reaction of butyllithium with ortho - carborane (1) , meta -carborane (2) , and para -carborane (3) is carried out by known methods. (Haushalter, RC; Butler, WM; Rudolph, RWJ Am. Chem. Soc. 1981, 103 , 2620)

Reaction solvents in Scheme 1 include tetrahydrofuran (THF), N, N -dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dioxane, N, N -methylacetamide, benzene, toluene, xylene (xylene) may be used, and the reaction temperature may be performed at -20 ° C to reflux temperature. In addition, the reaction time is preferably carried out for a sufficient time, can be carried out for more than 24 hours. Butyl lithium may instead use primary butyl, secondary butyl, tertiary butyl and methyllithium and sodium hydride, potassium hydride, and lithium diisopropylamide.

In formula (I) and formula (2) in the production method according to the present invention, R is an alkyl group of C _{1 ~ 5} with an alkoxy group, an alkyl group of C _{1 ~ 5} with an alcohol, ortho, meta-, or para-carborane -1-ylthio, and the vertices without the letters of the icosahedron represent BH bonds.

In another aspect, the present invention provides a pharmaceutical composition for anticancer comprising a compound represented by Formula 1 and 4 or a salt thereof.

In addition, the compounds represented by Formulas 1 and 2 or pharmaceutically acceptable salts thereof may be mixed with a pharmaceutical carrier and any adjuvant, etc., to provide an anticancer pharmaceutical composition in which the mixture is in a herbal form.

The composition of the present invention can be usefully used as a boron neutron capture therapy that can effectively destroy cancer cells when irradiated with thermal neutrons by selectively accumulating boron atoms in cancer cells.

Derivatives and salts thereof of the present invention may be formulated into oral preparations such as granules, powders, solutions, tablets, capsules or dry syrups or parenteral preparations such as injections, but are not limited thereto. Preferably the compositions of the present invention are in the form of tablets or capsules or in the form of solutions or injections.

When formulating the derivative of the present invention and salts thereof, one or more diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used may be used. As the excipient, microcrystalline cellulose, lactose, low-substituted hydroxycellulose, and the like may be used, and as the disintegrant, sodium starch glycolate, calcium monohydrogen phosphate, and the like may be used. As the binder, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and the like may be used, and the lubricant may be selected from magnesium stearate, silicon dioxide, talc and the like.

In addition, when the derivative of the present invention and salts thereof are formulated as a liquid or injection, 10 to 40% of propylene glycol and sodium chloride in an amount sufficient to prevent hemolysis may be included if necessary.

Dosage of the derivative of the present invention and salts thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and once a day at regular intervals according to the judgment of the doctor or pharmacist It may be administered in several divided doses.

1,3,5-triazineylthiocarborane derivatives or isomers thereof and pharmaceutically acceptable salts thereof according to the present invention are not cytotoxic and exhibit high selective accumulation of boron atoms on cancer cells, thereby treating cancer. There is an effect that can be useful as a boron neutron capture therapy (BNCT a gent) for.

Hereinafter, the present invention will be described in more detail with reference to the following Examples, which are intended to illustrate the present invention, but are not intended to limit the present invention.

Example 1

6- ( ortho - carbonan -1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine

Under a dry nitrogen atmosphere, ortho - carborane (0.14 g, 1 mmol) was dissolved in dried tetrahydrofuran (15 mL), and 2.5 M normal butyllithium (0.4 mL) dissolved in normal hexane was maintained at -78 ° C. , 1 mmol) is added slowly. Stir for 45 min at -78 ° C until a white suspension. Sulfur (0.032 g, 1 mmol) was added thereto and stirred at -78 ° C for 45 minutes. To this compound 6-chloro-2,4-di (2-methoxyethyl) amino-1,3,5-triazine ( 4 , 0.37 g, 1 mmol) was added, followed by reflux for 24 hours and cooling. Excess water is added to the reaction mixture and the mixture is extracted with diethyl ether. The ether layer is washed with distilled water, dried over anhydrous sodium sulfate and concentrated, and then the residue is chromatographed to give 0.07 g (14%) of the title compound.

mp 94-96 ° C. IR (KBr) δ 2594 cm ⁻¹ .

¹ H NMR (CDCl ₃ ) δ 3.33 (s, 12 H), 3.57 (t, J = 5.0 Hz, 8 H), 3.83 (t, J = 5.0 Hz, 8 H), 5.06 (s, 1 H) ppm .

¹³ C NMR (CDCl ₃ ) δ 48.3, 59.2, 62.9, 67.5, 70.4, 161.7, 175.6 ppm.

Example 2

6- ( meta -carborane-1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine

Under a dry nitrogen atmosphere, 2.5 M normal butyllithium (0.4 mL) dissolved in normal hexanes was dissolved in meta -carborane (0.14 g, 1 mmol) in dried tetrahydrofuran (15 mL) and maintained at -78 ° C. , 1 mmol) is added slowly. Stir for 45 min at -78 ° C until a white suspension. Sulfur (0.032 g, 1 mmol) was added thereto and stirred at -78 ° C for 45 minutes. Compound 6-chloro-2,4-di (2-methoxyethyl) -1,3,5-triazine ( 4 , 0.37 g, 1 mmol) was added thereto, and the mixture was cooled to reflux for 24 hours. Excess water is added to the reaction mixture and the mixture is extracted with diethyl ether. The ether layer was washed with distilled water, dried over anhydrous sodium sulfate and concentrated, and then the residue was separated by chromatography to give 0.08 g (17%) of the title compound.

mp 47-49 ° C. IR (KBr) δ 2610 cm ⁻¹ .

¹ H NMR (CDCl ₃ ) δ 3.33 (s, 1 H), 3.34-3031 (dd, J = 15.5 Hz, 12 H), 3.51-3.50 (m, 8 H), 3.75-3.70 (m, 8 H) ppm.

¹³ C NMR (CDCl ₃ ) δ 48.0, 58.9, 70.4, 71.5-71.4 (d), 162.8, 175.2 ppm.

Example 3

6- ( para -carbonan-1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine

Under a dry nitrogen atmosphere, para -carborane (0.14 g, 1 mmol) was dissolved in dried tetrahydrafuran (15 mL), followed by 2.5 M normal butyllithium (0.4 mL) dissolved in normal hexane at -78 ° C. , 1 mmol) is added slowly. Stir for 45 min at -78 ° C until a white suspension. Sulfur (0.032 g, 1 mmol) was added thereto and stirred at -78 ° C for 45 minutes. Compound 6-chloro-2,4-di (2-methoxyethyl) amino-1,3,5-triazine ( 4 , 0.37 g, 1 mmol) was added thereto, and the mixture was cooled to reflux for 24 hours. Excess water is added to the reaction mixture and extracted with diethyl ether. The ether layer was washed with distilled water, dried over anhydrous sodium sulfate and concentrated, and then the residue was separated by chromatography to give 0.09 g (11%) of the title compound.

mp 41-43 ° C. IR (KBr) δ 2617 cm ⁻¹ .

¹ H NMR (CDCl ₃ ) δ 3.39 (s, 1 H) 3.33-3.31 (td, J = 11.45 Hz, 12 H), 3.54-3.50 (m, 8 H), 3.77-3.69 (m, 8 H) ppm.

¹³ C NMR (CDCl ₃ ) δ 47.94-47.91 (d), 58.9, 70.4, 71.5, 77.6, 163.1, 175.2 ppm.

Example 4

4,6-di ( ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine

Under a dry nitrogen atmosphere, ortho - carborane (0.42 g, 3 mmol) was dissolved in dried tetrahydrofuran (15 mL), followed by 2.5 M normal butyllithium (1.2 mL) dissolved in normal hexane at -78 ° C. , 3 mmol) is added slowly. Stir for 45 min at -78 ° C until a white suspension. Sulfur (0.096 g, 23 mmol) was added thereto and stirred at -78 ° C for 45 minutes. 4,6-dichloro-2-di (2-methoxyethyl) amino-1,3,5-triazine ( 5 , 0.42 g, 1.5 mmol) was added thereto, followed by stirring at room temperature for 24 hours. Excess water is added to the reaction mixture and the mixture is extracted with diethyl ether. The ether layer is washed with distilled water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is then purified by chromatography to give 0.77 g (92%) of the title compound.

mp 112-114 ° C. IR (KBr) δ 2586 cm ⁻¹ .

¹ H NMR (CDCl ₃ ) δ 3.26 (s, 6 H), 3.50 (t, J = 5.0 Hz, 4 H), 3.77 (t, J = 5.0 Hz, 4 H), 5.00 (s, 2 H) ppm .

¹³ C NMR (CDCl ₃ ) δ 48.3, 59.2, 62.9, 67.5, 70.4, 161.7, 175.6 ppm.

Example 5

4,6-di (2-methyl- ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine

In a dry nitrogen atmosphere, 2-Methyl- ortho - carbonanol (0.42 g, 3 mmol) was dissolved in dried tetrahydrofuran (15 mL), and 2.5 M normal butyl dissolved in normal hexane was maintained at -78 ° C. Lithium (1.2 mL, 3 mmol) is added slowly. Stir for 45 min at -78 ° C until a white suspension. Sulfur (0.096 g, 3 mmol) was added thereto and stirred at -78 ° C for 45 minutes. Compound 4,6-dichloro-2-di (2-methoxyethyl) -1,3,5-triazine ( 5 , 0.42 g, 1.5 mmol) was added thereto, followed by stirring at room temperature for 24 hours. Excess water is added to the reaction mixture and the mixture is extracted with diethyl ether. The ether layer was washed with distilled water, dried over anhydrous sodium sulfate and concentrated, and then the residue was separated by chromatography to give 0.54 g (62%) of the title compound.

mp 138-139 ° C. IR (KBr) δ 2590 cm ⁻¹ .

¹ H NMR (CDCl ₃ ) δ 2.1 (s, 6 H), 3.95 (t, J = 5.5 Hz, 4 H), 3.61 (t, J = 5.5 Hz, 4 H), 3.36 (s, 6 H) ppm .

¹³ C NMR (CDCl ₃ ) δ 24.1, 48.7, 59.1, 71.1, 75.3, 80.1, 161.9, 174.8 ppm.

Example 6

4,6-di (2-phenyl- ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine

Under a dry nitrogen atmosphere, 2.5 M normal butyllithium dissolved in normal hexane after dissolving phenyl- ortho - carbonanol (0.22 g, 1 mmol) in dried tetrahydrofuran (15 mL) was maintained at -78 ° C. 0.4 mL, 1 mmol) is added slowly. Stir for 45 min at -78 ° C until a white suspension. Sulfur (0.032 g, 1 mmol) was added thereto and stirred at -78 ° C for 45 minutes. Compound 4,6-dichloro-3-di (2-methoxyethyl) amino-1,3,5-triazine ( 5 , 0.14 g, 0.5 mmol) was added thereto, followed by stirring at room temperature for 24 hours. Excess water is added to the reaction mixture and the mixture is extracted with diethyl ether. The ether layer was washed with distilled water, dried over anhydrous sodium sulfate and concentrated, and then the residue was separated by chromatography to give 0.11 g (31%) of the title compound.

mp 51-52 ° C. IR (KBr) δ 2592 cm ⁻¹ .

¹ H NMR (CDCl ₃ ) δ 3.39 (s, 6 H), 3.64 (t, J = 5.5 Hz, 4 H), 3.95 (t, J = 5.5 Hz, 4 H), 7.33 (t, J = 7.3 Hz , 2H), 7.43 (t, J = 7.8 Hz, 4H), 7.51 (d, J = 7.3 Hz, 4H) ppm.

¹³ C NMR (CDCl ₃ ) δ 48.3, 59.1, 71.1, 79.8, 89.1, 128.7, 130.8, 131.0, 131.6, 161.9, 174.8 ppm.

Example 7

1,7-bis [{2,4-di (2-methoxyethyl) amino-triazine-6-yl} thio] - meta-carborane

Under a dry nitrogen atmosphere, 2.5 M normal butyllithium (1.2 mL) dissolved in normal hexanes was dissolved in meta -carborane (0.14 g, 1 mmol) in dried tetrahydrofuran (15 mL) and maintained at -78 ° C. , 3 mmol) is added slowly. Stir for 45 min at -78 ° C until a white suspension. Sulfur (0.064 g, 2 mmol) was added thereto and stirred at -78 ° C for 45 minutes. Compound 6-chloro-2,4-di (2-methoxyethyl) amino-1,3,5-triazine ( 4 , 0.74 g, 2 mmol) was added thereto, followed by reflux cooling for 24 hours. Excess water is added to the reaction mixture and the mixture is extracted with diethyl ether. The ether layer is washed with distilled water, dried over anhydrous sodium sulfate and concentrated, and then the residue is separated by chromatography to give 0.22 g (13%) of the title compound.

IR (KBr) δ 2615 cm ^-1 .

¹ H NMR (CDCl ₃ ) δ 3.34-3,31 (dd, J = 13.6 Hz, 12 H), 3.53-3.49 (m, 8 H), 3.76-3.68 (m, 8 H) ppm.

¹³ C NMR (CDCl ₃ ) δ 47.8, 58.9, 70.5, 71.6, 163.1, 175.3 ppm.

Example 8

1,12-bis [{2,4-di (2-methoxyethyl) amino} triazine-6-ylthio] -para -carbonan

Under a dry nitrogen atmosphere, para -carborane (0.14 g, 1 mmol) was dissolved in dried tetrahydrofuran (15 mL), and 2.5 M normal butyllithium (1.2 mL) dissolved in normal hexane was maintained at -78 ° C. , 3 mmol) is added slowly. Stir for 45 min at -78 ° C until a white suspension. Sulfur (0.064 g, 2 mmol) was added thereto and stirred at -78 ° C for 45 minutes. Compound 6-chloro-2,4-di (2-methoxyethyl) amino-1,3,5-triazine ( 4 , 0.74 g, 2 mmol) was added thereto, and the mixture was cooled to reflux for 24 hours. Excess water is added to the reaction mixture and the mixture is extracted with diethyl ether. The ether layer is washed with distilled water, dried over anhydrous sodium sulfate and concentrated, and then the residue is separated by chromatography to give 0.20 g (12%) of the title compound.

mp 77-78 ° C. IR (KBr) δ 2625 cm ⁻¹ .

¹ H NMR (CDCl ₃ ) δ 3.34-3,31 (dd, J = 13.7 Hz, 12 H), 3.52-3.49 (m, 8 H), 3.76-3.70 (m, 8 H) ppm.

¹³ C NMR (CDCl ₃ ) δ 47.9, 58.9, 70.4, 71.6-71.5 (d), 163.1, 175.3 ppm.

Experimental Example 1 Cytotoxicity Experiment

A solution of 200 mg of the compound prepared in Examples 1 and 4 in 1.0 ml of DMSO was diluted with culture solution (Ea gle's MEM; Ea gle's Minimum Essential Medium) (10% FCS (Fetal Calf Serum)) to dissolve 2000 ppm of the solution. Prepared. In a culture dish (Falcon 3072; 92-well), B-16 melanoma cells (B-16 melanoma cells, mouse melanoma cells) (1 × 10 ⁴ cells / well) were treated with boron at various concentrations (1-100 ppm). The culture containing the compound was incubated in five dishes for 3 days in a CO ₂ incubator at 37 ℃. DMSO is known to be nontoxic at concentrations below 0.5%, and experimentally confirmed that DMSO is not toxic at the above concentrations. The cultures were removed and the cells washed three times with phosphate buffer, followed by staining with crystal violet (0.4% solution of methyl alcohol) and counting the cells with a microplate reading device. The results obtained are shown as the concentration of 50% cells survived (IC ₅₀ ), the results are shown in Table 1.

TABLE 1 Cytotoxicity (IC ₅₀ ) and boron uptake rate for B-16 melanoma cells

compound Chemical formula IC ₅₀ (M) Boron uptake rate (μBB / 10 ⁶ cells)    Example 1

6.32 × 10 ^-5 (± 0.65)    0.34 ± 0.049   Example 4

  > 100   0.12 ± 0.0028 Positive Control Substance (BPA) C ₉ H ₁₂ BNO ₄ 4.49 × 10 ^-5 0.083 ± 0.012

Experimental Example 2 Boron Absorption of B-16 Melanoma Cells

B-16 melanoma cells were cultured in Falcon dishes (150 mmf). After confirming that the melanoma cells were sufficiently grown in a dish (3.0 × 10 ⁶ cells / dish), they were incubated for 3 hours in an Eagle-MEM medium containing BPA containing 10.8 ppm boron and the compounds prepared in Examples 1 and 4. The cultured cells were washed three times with PBS (-), and the absorbed boron concentration was measured using ICP-AES (Shimadzu, ICP-100-III). Each experiment was repeated three times, the average boron absorption is shown in Table 1 above.

As shown in Table 1, the compound according to the present invention was confirmed that the boron uptake rate for B-16 melanoma cancer cells is higher than the conventional BPA nutrient capture therapy BPA.

Thus, di (2-methoxyethyl) amino-1,3,5-triazine-6-ylthiocarborane derivative or bis [{2,4-di (2-methoxyethyl) amino} according to the present invention It can be seen that the -1,3,5-triazine-6-ylthio] carborane derivatives or isomers thereof and pharmaceutically acceptable salts thereof exhibit high selective accumulation of boron atoms on B-16 melanoma cancer cells. have.

Claims (8)

A 1,3,5-triazineylthiocarborane derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is represented by the following Chemical Formula 1. [Formula 1]

(In Formula 1, R is an alkyl group of C _1-5 with an alkoxy, C alkyl group of _{1 to 5} with an alcohol, and an ortho, meta-, and para-carborane and Im-yl import the positive and twenty Vertices without icosahedron represent BH bonds.) A 1,3,5-triazinylthiocarborane derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, which is represented by the following Chemical Formula 2. [Formula 2]

(In the formula 2, R is an alkyl group, and vertex do not have a character of the regular icosahedron of C ₁ with an alkyl group, an alcohol of C _{1 ~ 5} alkoxy group with _1-5 shows a BH bond.) The method of claim 1, Formula 1, 1) 6- ( ortho -carbonan-1-ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine (6- o- carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine), 2) 6- ( meta -carbolan-1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine (6- m -carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine), 3) 6- ( para -carbolan-1-ylthio) -2,4-bis [di (2-methoxyethyl) amino] -1,3,5-triazine (6- p- carboran-1 -ylthio) -2,4-bis {di (2-methoxyethyl) amino} -1,3,5-triazine), 4) 4,6-di ( ortho -carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di ( o -carboran -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine), 5) 4,6-di (2-methyl- ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di (2-methyl- o- carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5- triazine), 6) 4,6-di (2-phenyl- ortho - carbonan -1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5-triazine (4,6-di (2-phenyl- o- carboran-1-ylthio) -2-di (2-methoxyethyl) amino-1,3,5- triazine and at least one selected from the group consisting of 1,3,5- Triazineylthiocarborane derivatives, isomers thereof or pharmaceutically acceptable salts thereof. The method of claim 2, Formula 2, 7) 1,7-bis [{2,4-di (2-methoxyethyl) amino-triazine-6-yl} thio] - meta-carborane (1,7-bis [{2,4- di (2-methoxyethyl) amino} triazin-6-ylthio] -m -carborane), 8) 1,12-bis [{2,4-di (2-methoxyethyl) amino-triazine-6-yl} thio] - para-carborane (1,7-bis [{2,4- di (2-methoxyethyl) amino} triazin-6-ylthio] -p -carborane) 1,3,5-triazineylthiocarborane derivative, isomer thereof or pharmaceutical composition thereof, characterized in that at least one selected from the group consisting of Acceptable salts by use. The anticancer pharmaceutical composition according to any one of claims 1 to 4, wherein the 1,3,5-triazineylthiocarborane derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof is an active ingredient. The method of claim 5, The pharmaceutical composition for anticancer, characterized in that the anticancer pharmaceutical composition is used as a boron neutron capture therapy. As shown in Scheme 1, ortho - carborane (1), meta -carborane (2) or para -carborane (3) is equivalent to chloro-1,3,5 triazine (4, 5) and sulfur, respectively. Method for preparing a 1,3,5-triazineylthiocarborane derivative, an isomer thereof or an acceptable salt thereof, characterized in that it comprises the step of reacting while controlling. Scheme 1

(R is C _{1 ~ 5} alkoxy C _{1 ~ 5} alkyl group, an alkyl group of C _{1 ~ 5} with an alcohol and with a group of the ortho -, meta-, or para-carborane and Im-yl import, R 'is Hydrogen, methyl, phenyl groups, and the vertexes of the icosahedron represent BH bonds.) An anticancer comprising preparing the 1,3,5-triazineylthiocarborane derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof prepared according to claim 7, in admixture with a pharmaceutical carrier and any adjuvant. Method for preparing a pharmaceutical composition.