KR20030050504A - Novel 5'-deoxy-n-alkyloxycarbonyl-5-fluorocytosine-5'-amide derivatives, their preparation, and anticancer agent comprising the same - Google Patents

Abstract

PURPOSE: Provided are 5-fluorouracil(5-FU)derivatives which are represented by formula 1, and used as an anti-cancer drug with excellent potency. CONSTITUTION: A method of preparation of 5-fluorouracil(5-FU)derivatives comprises the steps of: making a compound of the formula(4a) by reaction of a compound of the formula(4b) with acetic anhydride or acetyl chloride under presence of a base; synthesizing a compound of the formula(2) by reacting the compound of the formula(4a) with the compound of the formula(5) and an additive; making a compound of the formula(1b) by reacting the compound of the formula(2) with that of the formula(3):R¬4OCOCl in the presence of a base; converting the compound of the formula(1b) to that of formula(1a) by reduction.

Description

Novel 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-amide derivative, preparation method thereof, and anticancer agent comprising the same as an active ingredient {NOVEL 5'-DEOXY-N-ALKYLOXYCARBONYL- 5-FLUOROCYTOSINE-5'-AMIDE DERIVATIVES, THEIR PREPARATION, AND ANTICANCER AGENT COMPRISING THE SAME}

The present invention relates to a novel 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-amide derivative, a preparation method thereof, and an anticancer agent comprising the same as an active ingredient, and more particularly. New 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-amide derivatives having excellent anticancer effect and can be usefully used as new anticancer agents, methods for preparing the same, and including the same as an active ingredient It is about anticancer agent.

Cancer, along with AIDS, is one of the incurable diseases that modern medicine remains to address. In Korea, the incidence of cancer is increasing year by year, and cancer is a major cause of death due to its low healing rate, and the type and frequency of cancer are increasing day by day due to changes in modern society. Although the world is making huge investments to cure cancer, no satisfactory treatment has yet been developed. Therefore, it is essential to develop a cancer drug having excellent drug efficacy and fewer side effects for more efficient and effective healing.

Currently, as a method used to treat cancer, local therapies such as surgery, radiation therapy, and systemic therapy such as chemotherapy and immunotherapy are used. Among them, chemotherapy is widely used for the treatment of various cancers, such as solid tumors that occur primarily in various organs for gastrointestinal, liver, lung, etc. have.

In addition, research on cancer has been carried out by many scholars from several points of view, including 5-Fluorouracil (5-FU), Methotrexate, Frutraful, Cisplatin, etc. In addition to the development of anticancer drugs, research is being continued on new anticancer drugs. However, no formulations have yet been developed that can cure completely safely.

Therefore, there is a growing interest in developing a new anticancer agent having low toxicity and excellent effect, and recently using a derivative of 5-fluorouracil (5-FU), a representative anticancer agent of pyrimidine nucleoside family, Anticancer drug research is actively being conducted. However, 5-FU, which is widely known as an anticancer agent, is used for the treatment of tumors by metabolizing and activating in cells to inhibit the synthesis of pyrimidine nucleotides.

Therefore, many researches are being conducted to reduce this, but some of the developed 5-FU derivatives are activated in the intestinal wall after oral administration and cause side effects such as amputation, diarrhea and abdominal pain.

Recently, N-alkyloxycarbonyl 5'-deoxy-5-fluorocytidine represented by the following general formula (I) in European Patent No. 602454, Japanese Patent Laid-Open No. 6-211891 and US Patent No. 5,472,949 Processes for preparing derivatives are described.

(Wherein R ^a is a saturated or unsaturated hydrocarbon, R ^b represents hydrogen or an atomic group and easily removable protecting group that can be easily hydrolyzed under physiological conditions)

Said document is characterized by the fact that the 4'- position of cytidine system is a methyl group. However, the derivatives are known to be activated by enzymes in the liver, not in the intestine, and the side effects are greatly reduced. However, the derivatives are not yet completely able to safely cure cancer.

Therefore, in view of the above problems, the present invention is a novel 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-amide which is a novel compound having superior anticancer effects compared to conventional anticancer agents. It is an object to provide a derivative.

Another object of the present invention is to provide a method for preparing the novel 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-amide derivative.

Another object of the present invention is to use the novel 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-amide derivative, a pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient. It is to provide an anticancer agent comprising.

In order to achieve the above object, the present invention is a 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-amide derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, Or solvates thereof.

[Formula 1]

In which R is^Oneand R²Are each independently or simultaneously C_One-C₇Saturated or unsaturated hydrocarbons of; R³Are atomic groups and easily removable protecting groups which have a functional group such as hydrogen or acetyl to be easily hydrolyzed under physiological conditions; R⁴C₂-C₇Are saturated or unsaturated hydrocarbons.

In addition, the present invention

a) reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a base to prepare a compound of Formula 1b; And

b) reducing the compound of Formula 1b to prepare a compound of Formula 1a

It provides a method for producing a compound of Formula 1 comprising a.

[Formula 1a]

[Formula 1b]

[Formula 2]

[Formula 3]

R ⁴ OCOCl

In which R is^Oneand R²Are each independently or simultaneously C_One-C₇Saturated or unsaturated hydrocarbons of; R³Are atomic groups and easily removable protecting groups which have a functional group such as hydrogen or acetyl to be easily hydrolyzed under physiological conditions; R⁴C₂-C₇Are saturated or unsaturated hydrocarbons.

The present invention also provides an anticancer agent comprising the compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present inventors have conducted extensive research on a wide range of 5-FU series compounds and derivatives thereof to develop excellent anticancer agents. As a result, 5'-deoxy-N-alkyloxycarbonyl substituted with an amide instead of a methyl group at the 4'-position It was confirmed that the -5-fluorocytosine-5'-amide derivatives are excellent in anticancer effect, and completed the present invention.

Referring to the compound of Formula 1 of the present invention in more detail based on the preparation method as follows.

According to the present invention, the compound of Formula 1 is preferably a compound of Formula 1a wherein R ³ is hydrogen. The compound of Formula 1a is prepared by reducing the compound of Formula 1b through a deprotection reaction such as hydrolysis in the presence of a solvent, as shown in Scheme 1 below.

Scheme 1

Wherein R ¹ _, R ² _, R ³ and R ⁴ are each as defined above.

The compound of Formula 1b is prepared by reacting the compound of Formula 2 with the compound of Formula 3 in the presence of a base.

At this time, the compound of Formula 2 in the present invention is prepared through the following steps.

First, the present invention binds a compound of formula 7 with a compound of formula 8 in a solvent to prepare a compound of formula 6.

[Formula 6] [Formula 7]

[Formula 8]

R ¹ R ² NH

Wherein R ¹ and R ² are each independently or simultaneously a saturated or unsaturated hydrocarbon of C ₁ -C ₇ .

Next, the present invention is prepared by the deprotection reaction of the compound of formula 6 prepared above under an acid catalyst to prepare a compound of formula 4b.

[Formula 4b]

Next, the compound of formula 4b is reacted with acetic anhydride or acetyl chloride to prepare a compound of formula 4a.

[Formula 4a]

Thereafter, the compound of Formula 4a is reacted with a compound of Formula 5 and an additive to prepare a compound of Formula 2.

[Formula 5]

For example of the method for producing the compound of Formula 1 of the present invention, the following scheme 2, the following scheme 3 and the following scheme 4.

Scheme 2

Scheme 3

Scheme 4

Wherein R ⁴ is a C ₂ -C ₇ saturated or unsaturated hydrocarbon.

In Reaction Scheme 2, N-bromosuccinimide or N-chlorosuccinimide and an initiator are added to a compound of Formula 7 under carbon tetrachloride solvent to reflux, followed by C ₁ -C ₇ saturated or unsaturated hydrocarbon. By adding and stirring an amine, a compound of Formula 6 is prepared. The solvent may be carbon tetrachloride. The initiator may be azobis isobutyronitrile (AIBN), light and the like. The amount of the compound of Formula 8 is preferably used in 5 to 20 equivalents based on the compound of Formula 7. The amount of N-bromosuccinimide or N-chlorosuccinimide used is preferably 1 to 1.5 equivalents.

Next, the compound of Formula 4b is prepared by subjecting the compound of Formula 6 to an deprotection reaction using an acid catalyst such as hydrochloric acid at room temperature to reflux conditions. Thereafter, an appropriate reagent may be added to the compound of Formula 4b in the presence of a suitable solvent and a base, followed by stirring at 0 ° C to room temperature to prepare a compound of Formula 4a. The solvent used a lot in the reaction is preferably pyridine or methylene chloride. It is preferable to use pyridine and triethylamine or diisopropylethylamine as the base. It is preferable to use acetic anhydride or acetyl chloride as the reagent. It is preferable that the usage-amount of the said base is 1-20 equivalent. It is preferable that the usage-amount of the said reagent is 1-10 equivalents.

In addition, the compound of Formula 2 used as the reactant of Scheme 4 can be easily prepared by the method of Scheme 3 above. According to the method of Scheme 3, the compound of Formula 2 may be prepared by stirring the compound of Formula 4a and trimethylsilylated compound of Formula 5 with an appropriate additive in the presence of an acetonitrile solvent at −50 ° C. to room temperature. It is preferable to use tin chloride (IV), iodotrimethylsilane or chlorotrimethylsilane / sodium iodide as the additive. The amount of the compound of Formula 5 is preferably used in 1 to 2 equivalents. It is preferable that the usage-amount of the said additive is 1-2 equivalents.

In addition, in Scheme 4, the compound of Formula 1b may be prepared by adding and stirring a suitable base to the compound of Formula 2 and the compound of Formula 3 in the presence of a solvent such as methylene chloride or pyridine. As the base, pyridine, triethylamine, diisopropylethylamine and the like can be used. The amount of the compound of Formula 3 is preferably used in 1 to 5 equivalents.

Next, the compound of formula 1a can be obtained by reducing the compound of formula 1b using sodium alkoxide or sodium hydroxide having 1 to 2 carbon atoms in the presence of an alcohol solvent such as methanol or ethanol.

In addition, the present invention may provide a pharmaceutical composition comprising the compound of Formula 1, a pharmaceutically acceptable salt thereof, or solvate thereof as an active ingredient. The pharmaceutical composition is preferably an anticancer agent.

The compounds of the present invention can be administered by various oral or parenteral methods. The pharmaceutical composition of the present invention may comprise a pharmacologically acceptable liquid or solid carrier.

The solid form preparations include powders, tablets, dispersible granules or capsules, among which solid dosage forms suitable for oral administration include tablets, powders or capsules. Suitable excipients may include diluents, flavors, solubilizers, lubricants, suspending agents, binders, and / or tableting agents. In the case of powders or capsules, the carrier may contain 5 to 70%, preferably 10 to 70%, of the finely divided active ingredient. Suitable solid carriers or excipients include corn starch, magnesium stearate, film, polyethylene glycol, talc, sugar, lactose, pectin, dextrin, starch, gelatin, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, titanium dioxide, low Melting point wax, cocoa butter and the like.

The preparations in liquid form may be solutions, suspensions or emulsions. For example, in the case of parenteral injection, water or a mixed solution of water-propylene glycol may be used, and such a solution is prepared such that isotonicity, pH, and the like are suitable for a biological system. Liquid formulations may also be formed from aqueous polyethyleneglycol solution. Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding the appropriate flavoring, coloring, stabilizing and thickening agents. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and known suspending agents.

Preferred pharmaceutical preparations are in unit dosage form. In such forms, the preparation is subdivided into unit dosage forms containing an appropriate amount of active ingredient. The unit dosage form can be a packaged preparation containing discrete amounts of the preparation, for example a packaged tablet, capsule or powder in a vial or ampoule.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are provided to aid the understanding of the present invention, and the scope of the present invention is not limited thereto.

EXAMPLE

Example 1

(Preparation of methyl-2,3-O-isopropylidene-D-erythrose 4- (N, N-diethyl) amide (R ¹ = R ² = ethyl, compound 6))

To 1 g (4.95 mmol) of methyl-2,3-O-isopropylidene-D-erythrose aldehyde (Compound 7) in the presence of nitrogen, 10 ml of carbon tetrachloride and 1 equivalent of N-bromosuccinimide, 0.05 equivalent of AIBN After refluxing for 30 minutes, 10 equivalents of diethylamine (Compound 8a) was added thereto, stirred, extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, filtered through distillation under reduced pressure, and then purified by silica gel column chromatography. 780 mg (58% yield) of the title compound were obtained.

¹ H NMR (CDCl ₃ , ppm) δ 5.42 (d, 1H), 5.01 (d, 1H), 4.53 (dd, 1H), 4.43 (dd, 1H), 3.35 (s, 3H), 3.24 (q, 4H ), 1.45 (s, 3H), 1.40 (s, 3H), 1.20 (t, 6H)

Example 2

(Preparation of D-erythrose 1,2,3-tri-O-acetyl-4- (N, N-diethyl) amide (R ¹ = R ² = ethyl, R ³ = acetyl, compound 4a))

Methyl-2,3-O-isopropylidene-D-erythrose 4- (N, N-diethyl) amide (R ¹ = R ² = ethyl, compound 6) 520 mg (1.90 mmol) in water 6 ml and 0.6 ml of 1N aqueous hydrochloric acid solution were added thereto, stirred at 80 to 120 ° C. for 2 hours, neutralized with 1N aqueous sodium hydroxide solution, and concentrated by distillation under reduced pressure. 6 ml of pyridine was added to dissolve it, 2 ml of acetic anhydride was added thereto, stirred at room temperature for 9 hours, 15 ml of water was added thereto, extracted three times with 20 ml of chloroform, dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Concentration and purification through silica gel column chromatography gave 605 mg (yield 92%) of the title compound.

¹ H NMR (CDCl ₃ , ppm) δ 6.81 (d, 1H), 5.50 (dd, 1H), 5.28 (d, 1H), 5.13 (dd, 1H), 3.26 (q, 4H), 2.04 (s, 3H ), 2.02 (s, 3H), 2.01 (s, 3H), 1.20 (t, 6H)

Example 3

(5'-deoxy-2 ', 3'-di-O-acetyl-5-fluorocytosine-5'-(N, N-diethyl) amide (R ¹ = R ² = ethyl, R ³ = Acetyl, preparation of compound 2))

510 mg (1.48 mmol) of D-erythrose 1,2,3-tri-O-acetyl-4- (N, N-diethyl) amide in the presence of nitrogen (R ¹ = R ² = ethyl, R ³ To acetyl, compound 4a) was added trimethylsilylated 5-fluorocytosine (compound 5) and 8 ml of acetonitrile prepared from 330 mg of 5-fluorocytosine. 0.3 ml of tin (IV) chloride was added dropwise thereto at -30 to 0 DEG C, and stirred at room temperature for 4 to 8 hours. Then, an aqueous solution of sodium bicarbonate was added, extracted three times with 20 ml of ethyl acetylate, and dried and filtered over anhydrous magnesium sulfate. After distillation under reduced pressure, the mixture was purified by silica gel column chromatography to obtain 480 mg (yield 82%) of the title compound.

¹ H NMR (CDCl ₃ , ppm) 57.25 (d, 1H), 6.44 (1H, d), 5.53 (1H, dd), 5.28 (d, 1H), 5.12 (1H, dd), 3.24 (q, 4H), 2.06 (s, 3H), 2.04 (s, 3H), 1.22 (t, 6H)

Example 4

(5'-deoxy-2 ', 3'-di-O-acetyl-5-fluoro-N ^4- (pentyloxycarbonyl) -cytosine-5'-(N, N-diethyl) amide ( R ¹ = R ² = ethyl, R ³ = acetyl, R ⁴ = pentyl, preparation of compound 1b-1)

5'-deoxy-2 ', 3'-di-O-acetyl-5-fluorocytosine-5'-(N, N-diethyl) amide (R ¹ = R ² = ethyl, R ³ = acetyl , Compound 2) 3 ml of methylene chloride and 0.3 ml of pyridine were added to 155 mg (0.392 mmol), and 70 mg of pentyl chloroformate (compound 3) was added dropwise at 0 ° C., stirred at room temperature for 30 minutes, and then an aqueous solution of sodium hydrogen carbonate was added. Then, the mixture was extracted three times with 20 ml of methylene chloride, dried over anhydrous magnesium sulfate, filtered and concentrated by distillation under reduced pressure, and purified by silica gel column chromatography to obtain 170 mg (yield 85%) of the title compound.

¹ H NMR (CDCl ₃ , ppm) δ 11.45 (br.s, 1H), 7.20 (d, 1H), 6.31 (d, 1H), 5.43 (m, 1H), 5.26 (d, 1H), 5.13 (m , 2H), 4.26 (t, 2H), 3.25 (q, 4H), 2.10 (s, 3H), 2.05 (s, 3H), 1.60-1.25 (m, 6H), 1.19 (t, 6H), 0.99 ( t, 3H)

Example 5

(5'-deoxy-5-fluoro-N ^4- (pentyloxycarbonyl) -cytosine-5 '-(N, N-diethyl) amide (R ¹ = R ² = ethyl, R ⁴ = pentyl , Compound 1a-1))

5'-deoxy-2 ', 3'-di-O-acetyl-5-fluoro-N ^4- (pentyloxycarbonyl) -cytosine-5'-(N, N-diethyl) amide (R ¹ = R ² = ethyl, R ³ = acetyl, R ⁴ = pentyl, compound 1-b1) 5 ml of methanol was dissolved in 165 mg (0.324 mmol), and 3 ml of 1N sodium methoxide was added and stirred for 1 hour. It was then neutralized with 1N hydrochloric acid, and concentrated by distillation under reduced pressure. To this was added 5 ml of water, extracted with methylene chloride / methanol (95/5) solution several times, dried over anhydrous magnesium sulfate, filtered and concentrated by distillation under reduced pressure, and recrystallized with ethyl acetylate (103 mg ( Yield 75%).

¹ H NMR (CD ₃ OD, ppm) δ 7.15 (d, 1H), 5.93 (d, 1H), 4.77 (d, 1H), 4.28 (m, 1H), 4.24 (t, 2H), 3.88 (m, 1H), 3.24 (q, 4H), 1.60-1.25 (m, 6H), 1.20 (t, 6H), 0.98 (t, 3H)

Example 6

(5'-deoxy-2 ', 3'-di-O-acetyl-5-fluoro-N ^4- (allyloxycarbonyl) -cytosine-5'-(N, N-diethyl) amide ( R ¹ = R ² = ethyl, R ³ = acetyl, R ⁴ = allyl, preparation of compound 1b-2))

Prepared in the same manner as in Example 4, except that 66 mg of allyl chloroformate (Compound 3) was added instead of pentyl chloroformate to obtain 158 mg (yield 81%) of the title compound.

Example 7

(5'-deoxy-5-fluoro-N ^4- (allyloxycarbonyl) -cytosine-5 '-(N, N-diethyl) amide (R ¹ = R ² = ethyl, R ⁴ = allyl , Compound 1a-2)

Prepared in the same manner as in Example 5, but using Compound 1b-2 prepared in Example 6 instead of Compound 1b-1 prepared in Example 4, 83 mg (yield 66%) of the title compound were obtained.

Example 8

(Measurement of anticancer effect of derivatives)

Capecitabine = 5'-deoxy-5-fluoro showing the best results among the 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytidine derivatives disclosed in European Patent No. 602454. -N ^4- (pentyloxycarbonyl) cytidine (R ^a = pentyl, R ^b = hydrogen compound of formula 2)] as a control agent, the compounds according to the invention 5'deoxy-5-fluoro- In order to determine the anticancer activity of N ^4- (alkyloxycarbonyl) -cytosine-5 '-(N, N-diethyl) amide, cytotoxicity against human cancer cells was measured. Human cancer cells were compared using A549 (lung cancer), HCT15 (colon cancer), SK-OV-3 (ovarian cancer), and SK-MEL-2 (skin cancer).

First, the cancer cells were incubated at 37 ° C. in a 5% CO ₂ thermohygrostat, and the medium used was 10% fetal calf serum using RPMI as a medium. In order to measure the cytotoxic activity, the cancer cells in the logarithmic phase were cultured at 2-5 x 10 ⁴ cells per well of a 96-well plate and incubated for 24 hours, followed by capecitabine and 5'deoxy-5-fluoro. A sample solution of stepwise dilutions of -N ^4- (alkyloxycarbonyl) -cytosine-5 '-(N, N-diethyl) amide was added and incubated for 72 hours. 20 μl of MTT reaction solution dissolved in physiological saline at a concentration of 5 mg / ml in each well of the cultured plate was incubated for 4 hours, and the formed formazan crystals were dissolved in dimethyl sulfoxide (DMSO). The viable cell number was measured by measuring the absorbance of each well at a wavelength of 540 nm. When the absorbance of the wells containing only cells containing no cells was 0% and the absorbance of the wells without the sample was 100%, the concentration showing 50% absorbance was calculated as the IC ₅₀ value of each anticancer agent. The results are shown in Table 1.

Inhibitory Concentration on Cancer Cell Lines (IC ₅₀ , μg / mL) Concentration (μg / ml) A549 SK-OV-3 HCT15 SK-MEL2 Capecitabine 8.8 23.8 13.9 23.0 Example 5 (Compound 1a-1) 1.0 0.99 0.99 0.95 Example 7 (Compound 1a-2) 1.0 0.91 0.71 0.86

As shown in Table 1, it was confirmed that the compound of Formula 1 according to the present invention has a good anticancer activity of about 0.7 ~ 1.0 ㎍ / ml for each cancer cell, this value is better than the control drug It can be seen that.

As described above, the compound of Formula 1 according to the present invention has a very good anticancer effect and less toxic, and thus an anticancer agent including it as an active ingredient may be used more effectively than a conventional anticancer agent.

Claims (6)

5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-amide derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, or solvate thereof: [Formula 1] In which R is^Oneand R²Are each independently or simultaneously C_One-C₇Saturated or unsaturated hydrocarbons of; R³Are atomic groups and easily removable protecting groups which have a functional group such as hydrogen or acetyl to be easily hydrolyzed under physiological conditions; R⁴C₂-C₇Are saturated or unsaturated hydrocarbons. a) reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a base to prepare a compound of Formula 1b; And b) reducing the compound of Formula 1b to prepare a compound of Formula 1a Method for producing a compound of claim 1 comprising: [Formula 1a] [Formula 1b] [Formula 2] [Formula 3] R ⁴ OCOCl In which R is^Oneand R²Are each independently or simultaneously C_One-C₇Saturated or unsaturated hydrocarbons of; R³Are atomic groups and easily removable protecting groups which have a functional group such as hydrogen or acetyl to be easily hydrolyzed under physiological conditions; R⁴C₂-C₇Are saturated or unsaturated hydrocarbons. According to claim 2, wherein the compound of formula 2 of step a) a) reacting a compound of formula 4b with acetic anhydride or acetyl chloride in the presence of a base to prepare a compound of formula 4a; And b) a method of preparing a compound prepared by a method comprising the step of reacting the compound of Formula 4a with a compound of Formula 5 and an additive: [Formula 4a] [Formula 4b] [Formula 5] The method of claim 2 or 3, Wherein said base is pyridine, triethylamine, or diisopropylethylamine. The method of claim 3, wherein The additive of d) is tin chloride (IV), iodotrimethylsilane or chlorotrimethylsilane / sodium iodide. An anticancer agent comprising the compound of claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.