KR20130029673A - Novel tetranuclear arene-ruthenium compound and parmaceutical composition for preventing or treating cancer containing thereof - Google Patents

Abstract

PURPOSE: A tetranuclear arene-ruthenium compound is provided to suppress proliferation of cancer cells at a low molar concentration and to suppress cancer cell activity through cell apoptosis. CONSTITUTION: A tetranuclear arene-ruthenium compound or a pharmaceutically acceptable salt thereof is denoted by chemical formula 1. In chemical formula 1, a vertical red line is denoted by chemical formula 2, wherein A is trifluoromethylsulfonate, nitrate(NO3), toluene-4-sulfonate, methane sulfonate, Cl, Br, I, BF4, PF6, ClO4, CH3COO, CF3COO, or CH3SO3; and a horizontal blue line is denoted by chemical formula 3 or 4.

Description

Novel Tetranuclear Arene-Ruthenium Compound and Parmaceutical Composition for Preventing or Treating Cancer Containing Thereof}

The present invention relates to a novel quaternary arene-ruthenium compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

The metalpharmaceutical field has emerged as an important new field of medicinal chemistry because of the therapeutic application of metal-based drugs ((a) M. Mascini, G. Bagni, M. L. D. Pietro, M.

Ravera, S. Baracco and D. Osella, Bio Metals, 2006, 19, 409; (b) T. W. Hambley, Dalton Trans., 2007, 4929). Rearrangement of organic ligands in a three-dimensional space from a wide range of coordination numbers and accessible redox states of the controllable metal centers provide a broad spectrum of reactivity that can be used for medical purposes (U. Schatzschneider and N. Metzler-). Nolte, Angew. Chem., Int. Ed., 2006, 45, 1504.). Platinum complexes, particularly cisplatin, carboplatin, and oxoplatin, despite their high toxicity and unnecessary neuronal, liver, and kidney toxicity side effects ((a) Y. Jung and SJ Lippard, Chem. Rev., 2007, (B) C. Gianomenico and MUS Christen, Patent 6413953, 2000), which are currently used as the most effective chemotherapeutic agents ((a) L. Kelland, Nat. Rev. Cancer, 2007, 7, 573; (b J. Reedijk, Eur. J. Inorg. Chem., 2009, 1303. However, the high systemic toxicity and resistance issues associated with platinum-based drugs include alternative metal-based antitumor agents ((a) CHA Goss, W. Henderson, AL Wilkins and CJ Evans, J. Organomet. Chem. 2003, 679, 194; (b ) AG Quiroga and CN Ranninger, Coord. Chem. Rev. 2004, 248, 119; (c) W. Henderson, BK Nicholson and ERT Tiekink, Inorg. Chim. Acta, 2006, 359, 2046) and more secure and more effective A new era has opened with interest in the design and pharmacological development of therapeutics. In particular, ruthenium complexes represent a new class of promising metal-based drugs with low toxicity and high activity in tumors that do not respond well to platinum-based drugs ((a) CG Hartinger, S. Zorbas-Selfried, MA Jakupee, B. Kynast, H. Zorbas and BK Keppler, J. Inorg.Biochem. 2006, 100, 891; (b) YK Yan, M. Melchart, A. Habte mariam and PJ Sadler Chem. Commun., 2005, 4764). Two ruthenium complexes, ImH [transRuCl4 (DMSO) Im]] (NAMI-A) and KO1019, are the first mononuclear ruthenium-based anticancer drugs that have successfully passed Phase I clinical trials ((a) JM Rademaker-Lakhai, D. Van Den Bongard, D. Pluim, JH Beijnen and JHM Schellens, Clin. Cancer Res., 2004, 10, 3717; (b) M. Groessl, CG Hartinger, K. Polec-Pawlak, M. Jarosz, PJ Dyson and BK Keppler , Chem. Biodiversity, 2008, 5, 1609.).

Multinuclear drugs are also designed to increase the range of treatable tumors. Many polymeric platinum compounds ((a) Z. Yang, X. Wang, H. Diao, J. Zhang, H. Li, H. Sung and Z. Guo, Chem. Commun., 2007, 3453; (b) NJ Wheate , AI Day, RJ Blanch, AP Arnold, C. Cullinane and JG Collins, Chem. Commun., 2004, 1424), for example polymer linked diaminocyclohexyl metal chemotherapeutic (AP5346) and pt-coordinated higher orders Branched polyglycerol polymers have a selective permeation, retention effect (EPR) (Y. Matsumura and H. Maeda, Cancer. Res., 1986, 46, 6387.) and long-range and intrastrand DNA crosslinking. Because of their unique extracellular environment that allows drugs to selectively accumulate in cancer cells, they could potentially be used for target specific tumor cells. Therefore, research on multinuclear metal-polymer complex compounds is being actively conducted.

The present invention seeks to provide a novel quaternary arene-ruthenium compound which is a kind of multinuclear metal-polymer complex and its use for anticancer treatment.

In order to solve the above object, the present invention provides a quaternary arene-ruthenium compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

는

The

[Formula 2]

이고,

ego,

In Chemical Formula 2

A is independently OTf (trifluoromethylsulfonate), nitrate (NO ₃ ), OTs (toluene-4-sulfonate), OMs (methanesulfonate), Cl, Br, I, BF ₄ , PF ₆ , ClO ₄ , CH ₃ COO, CF ₃ COO or CH ₃ SO ₃ ,

는

The

(3)

또는

or

[Formula 4]

이고,

ego,

The ruthenium of Formula 2 and the nitrogen atom in the aromatic ring of Formula 3 or 4 combine to form a compound of Formula 1.

The present invention also provides a pharmaceutical composition for the prophylaxis or treatment of cancer containing the novel 4-nuclear arene-ruthenium compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The quaternary arene-ruthenium compound according to the present invention is composed of human SK-hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 (lung cancer), and MDA-MB-231 (breast cancer) cells. It inhibits proliferation at low micromolar concentrations and inhibits the activity of cancer cells through apoptosis that regulates the cell growth cycle, thereby showing excellent anticancer activity. Prevention of cancers such as liver cancer, ovarian cancer, rectal cancer, lung cancer and breast cancer It can be usefully used for treatment.

1 is a manufacturing schematic diagram of a compound of Comparative Example 1, Comparative Example 2, and Example 1. FIG.
2 is a ¹ H NMR spectrum of a compound of Comparative Example 1 (a), Comparative Example 2 (b), and Example 1 (c).
3 is a ¹³ C NMR spectrum of a compound of Comparative Example 1 (a), Comparative Example 2 (b) and Example 1 (c).
4 is an ESI mass spectrometry spectrum of a compound of Comparative Example 1 (a), Comparative Example 2 (b) and Example 1 (c)
5 shows the X-ray structures of the compounds of Comparative Examples 1 (a) and 2 (b) (H atoms, corresponding anions and solvent molecules are omitted for clarity).
Figure 6 is a graph showing the anticancer effect of the A549 cell line of the compound of Example 1 of the present invention.

The present invention provides a quaternary arene-ruthenium compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

는

The

[Formula 2]

이고,

ego,

In Formula 2, A is independently OTf (trifluoromethylsulfonate), nitrate (NO ₃ ), OTs (toluene-4-sulfonate), OMs (methanesulfonate), Cl, Br, I, BF ₄ , PF ₆ , ClO ₄ , CH ₃ COO, CF ₃ COO or CH ₃ SO ₃ ,

는

The

(3)

또는

or

[Formula 4]

이고,

ego,

The ruthenium of Formula 2 and the nitrogen atom in the aromatic ring of Formula 3 or 4 combine to form a compound of Formula 1.

The quaternary arene-ruthenium compound of the present invention represented by Chemical Formula 1 may be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts. . The inorganic acid and organic acid may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. may be used as the inorganic acid. , Acetic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, and the like can be used. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.

In addition, the quaternary arene-ruthenium compound represented by Chemical Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.

The quaternary arene-ruthenium compound of formula 1 according to the present invention can be easily prepared by reacting a compound of formula 3 or formula 4, which is an amide donor, with a compound of formula 2, which is a ruthenium triflate receptor, in a 1: 1 ratio. May be made in a nitromethane-methanol 1: 1 solution, but is not limited thereto. The reaction can take place at room temperature for 6-15 hours under stirring, and the addition of diethyl ether to the concentrated reaction mixture results in the formation of pure self-assembled product of formula 1 as a green solid.

As described above, the novel 4-nuclear arene-ruthenium compound prepared according to the present invention may be prepared by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, ray photometry, and representative compounds. The molecular structure can be confirmed by comparing elemental analysis calculations with actual measurements.

In addition, as can be seen in the following examples, the quaternary arene-ruthenium compound of Chemical Formula 1 according to the present invention is human SK-hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 ( Lung cancer), and inhibits proliferation of MDA-MB-231 (breast cancer) cells at low micromolar concentrations and inhibits the activity of cancer cells through apoptosis that regulates cell growth cycle. Can be used as an active ingredient. Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer containing the tetranuclear arene-ruthenium compound or a pharmaceutically acceptable salt thereof as an active ingredient, the use of the tetranuclear arene-ruthenium compound for the manufacture of an anticancer agent, Provided is a method of treating cancer comprising administering to a subject a tetranuclear arene-ruthenium compound.

In one embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer containing the tetranuclear arene-ruthenium compound or a pharmaceutically acceptable salt thereof as an active ingredient is based on 100 parts by weight of the pharmaceutical composition of the tetranuclear arene- Ruthenium compound or a pharmaceutically acceptable salt thereof may include 0.01 to 90 parts by weight, 0.1 to 90 parts by weight, 1 to 90 parts by weight, or 10 to 90 parts by weight, but is not limited to the condition and disease of the patient It may vary depending on the type and degree of progress.

In another embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer containing the quaternary arene-ruthenium compound or a pharmaceutically acceptable salt thereof as an active ingredient includes a carrier, an excipient, a disintegrant, a sweetener, a coating agent, It may further comprise one or more adjuvants selected from the group consisting of swelling agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, bacteriostatics, diluents, dispersants, surfactants, binders and lubricants.

Specifically, the carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil can be used, and solid preparations for oral administration include tablets, pills, powders, granules, capsules. And the like, and such solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like in the composition. In addition to simple excipients, lubricants such as magnesium styrate and talc may also be used. Oral liquid preparations include suspensions, solvents, emulsions, syrups, and the like, and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. Witsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used as the base material of the suppository.

In another embodiment of the present invention, the formulation of the pharmaceutical composition for the prevention or treatment of cancer containing the 4-nuclear arene-ruthenium compound or a pharmaceutically acceptable salt thereof as an active ingredient is granules, powders, coated tablets, tablets, It may be selected from the group consisting of pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, drops or solutions.

According to one embodiment of the invention the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, nasal, inhaled, topical, rectal, oral, intraocular or intradermal Via the route can be administered to the subject in a conventional manner.

The preferred dosage of the pharmaceutical composition for preventing or treating cancer containing the tetranuclear arene-ruthenium compound or a pharmaceutically acceptable salt thereof as an active ingredient is a condition and weight of the patient, type and extent of disease, drug form, administration It may vary depending on the route and duration and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 1,000 mg / kg, specifically 0.1 to 1,000 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. Administration may be administered once a day or divided into several times, thereby not limiting the scope of the invention.

In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.

In another embodiment of the present invention, the cancer may be liver cancer, ovarian cancer, rectal cancer, lung cancer or breast cancer, but is not limited thereto.

Hereinafter, examples will be described in detail to help understand the present invention. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

The following experimental examples are intended to provide experimental examples that are commonly applied to each embodiment according to the present invention.

1. General

The arene-ruthenium receptors A1, A2 (Formula 2) and amide donors L1 (Formula 3) and L2 (Formula 4) used in this experiment were prepared according to conventional methods. The structure of the formula A1, A2, L1, L2 used in the embodiment of the present invention is shown in FIG. Deuterated solvents were purchased from Cambridge Isotope Laboratory (Andover, Mass.). NMR spectra were recorded on a Bruker 300 MHz spectrometer.

¹ H NMR chemical shifts were recorded relative to the residual solvent signal. Mass spectra for self-assembly were recorded on a Micromass Quattro II triple-quadrupole mass spectrometer using electron spray ionization with the MassLynx operating system. Diffraction data from single crystals of the prepared compounds were collected on ADSC quantum 210 CCD diffractometer using synchrotron radiation (λ = 0.90000 Hz) at 100 K in macromolecular crystallography beam line 6B1, Pohang Accelerator Laboratory (PAL). The initial data was processed and reduced using the program HKL2000. The structure was identified by direct method and refined with full-matrix least-squares refinement on F2 using the appropriate software in the SHELXTL program package.

2. Schematic diagram of the reaction

Compounds of Comparative Example 1, Comparative Example 2 and Example 1 were prepared using arene-ruthenium receptors A1, A2 (Formula 2) and amide donors L1 (Formula 3), L2 (Formula 4). A schematic diagram thereof is shown in FIG. 1. The ruthenium of A1, A2 interacts with the nitrogen atom of the pyridine of L1 or L2 to form a tetragonal structure.

< Comparative example  1> A1 + L1  Compound manufacturing

A mixture of the amide donor L1 compound (2.42 mg, 0.01 mmol) and ruthenium triflate receptor A1 (8.58 mg, 0.01 mmol) was dissolved in CH ₃ NO ₂ -CH ₃ OH solution (1: 1, 1.0 mL) and maintained for 10 hours. Stir at room temperature. After diethyl ether was added dropwise, yellow crystal powder of the compound of Comparative Example 1 was obtained (yield 86%).

¹ H NMR [300 MHz, (CD ₃ ) ₂ SO]: δ (ppm) 11.46 (s, NH), 7.86 (d, J = 6.9 Hz, 8H, Hα), 7.75 (d, J = 6.9 Hz, 8H , Hβ), 6.02 (d, J = 6.3 Hz, 8H, Hcym), 5.83 (d, J = 6.3 Hz, 8H, Hcym), 2.76 (sept, 4H, CH (CH ₃ ) ₂ ), 2.12 (s, 12H, CH ₃ ), 1.26 (d, J = 6.9 Hz, 24H, CH (CH− ₃ ) ₂ ) (see FIG. 2A);

¹³ C NMR [75 MHz, (CD ₃ ) ₂ SO]: δ (ppm) 170.2, 158.7, 153.3, 147.4, 116.1, 102.7, 98.9, 83.6, 81.0, 30.7, 21.9, 17.5 (see FIG. 3A);

MS (ESI) (C ₇₂ H ₇₆ F ₁₂ N ₈ O ₂₄ Ru ₄ S ₄ ): 949.9 [M-2OTf] ²⁺ ; 583.8 [M-3OTf] ³⁺ (see FIG. 4A, red: theoretical, blue: experimental).

X-ray crystal structure is shown in Fig. 5 (a) (green: ruthenium, red: oxygen, blue: nitrogen and gray: carbon).

< Comparative example  2> A1 + L2  Compound manufacturing

A mixture of the amide donor L2 compound (2.42 mg, 0.01 mmol) and ruthenium triflate receptor A1 (8.58 mg, 0.01 mmol) was dissolved in CH ₃ NO ₂ -CH ₃ OH solution (1: 1, 1.0 mL) and maintained for 10 hours. Stir at room temperature. After diethyl ether was added dropwise, yellow crystal powder of the compound of Comparative Example 2 was obtained (yield 82%).

¹ H NMR [300 MHz, (CD ₃ ) ₂ SO]: δ (ppm) 11.23 (s, NH), 8.50 (m, 4H, H1), 8.25 (s, 4H, H4), 7.60 (m, 4H, H2), 7.29 (m, 4H, H3), 6.00 (d, J = 6.3 Hz, 8H, Hcym), 5.87 (dd, J = 6.6 Hz, 3JH, H = 5.4 Hz, 8H, Hcym), 2.82 (sept , 4H, CH (CH ₃ ) ₂ ), 2.12 (s, 12H, CH ₃ ), 1.30 (d, J = 6.9 Hz, 24H, CH (CH ₃ ) _-2 ) (see FIG. 2B);

¹³ C NMR [75 MHz, (CD ₃ ) _-2 SO]: δ (ppm) 170.4, 158.2, 147.0, 135.7, 129.5, 126.1, 122.8, 100.6, 96.3, 82.4, 81.6, 30.6, 22.0, 17.6 (FIG. 3b Reference);

MS (ESI) (C ₇₂ H ₇₆ F ₁₂ N ₈ O ₂₄ Ru ₄ S ₄ ): 583.8 [M-3OTf] ³⁺ (see FIG. 4B, red: theoretical, blue: experimental).

X-ray crystal structure is shown in Figure 5 (b) (green: ruthenium, red: oxygen, blue: nitrogen and grey: carbon).

< Example  1> A2 + L1  Compound manufacturing

A mixture of the amide donor L1 compound (2.42 mg, 0.01 mmol) and ruthenium triflate receptor A2 (8.58 mg, 0.01 mmol) was dissolved in CH ₃ NO ₂ -CH ₃ OH solution (1: 1, 1.0 mL) and maintained for 10 hours. Stir at room temperature. Diethyl ether was added dropwise to give a green crystal powder of Example 1 compound (yield 85%).

¹ H NMR [300 MHz, (CD ₃ ) ₂ CO]: δ (ppm) 10.71 (s, NH), 8.46 (d, J = 6.9 Hz, 8H, Hα), 7.93 (d, J = 6.9 Hz, 8H , Hβ), 7.28 (s, 8H, Hq), 5.96 (d, J = 6.3 Hz, 8H, Hcym), 5.76 (d, J = 6.3 Hz, 8H, Hcym), 2.93 (sept, 4H, CH (CH) ₃ ) ₂ ), 2.17 (s, 12H, CH ₃ ), 1.36 (d, J = 6.9 Hz, 24H, CH (CH ₃ ) ₂ ) (see FIG. 2C);

¹³ C NMR [75 MHz, (CD ₃ ) ₂ SO]: δ (ppm) 170.3, 158.3, 152.2, 146.9, 137.3, 115.9,110.9, 102.1, 99.2, 84.3, 82.2, 30.1, 21.9, 16.6 (see FIG. 3C) );

MS (ESI) (C ₈₈ H ₈₄ F ₁₂ N ₈ O ₂₄ Ru ₄ S ₄ ): 1050.1 [M-2OTf] ²⁺ , 650.5 [M-3OTf] ^{3 ++} (see FIG. 4C, red: theoretical, blue: Experimental value).

< Experimental Example  1> Cancer cell growth inhibition assay ( MTT  analysis)

The growth inhibition assay of the compounds of the present invention against SK-hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 (lung cancer) and MDA-MB-231 Respectively.

Specifically, the above-described cancer cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin streptomycin at 37 ° C and 5% CO ₂ . Suspensions of each other cells were dispensed in 96 well plates at a concentration of 5 × 10 ⁴ cell counts / well (90 μL / well and 10 μL samples). MTT was then dissolved in phosphate buffer (PBS, pH 7.2) and filtered to produce a 5 mg / ml stock solution. As a control, 10 μL of MTT solution was added to each well after treatment, compound treatment of Example 1, compound treatment of Comparative Groups 1 and 2, and cisplatin treatment used as conventional anticancer agents. After 4 hours of incubation at 37 ° C and 5% CO ₂ , 100 μL of DMSO (dimethylsulfoxide) was added to each well. The 96 well plate was then read by absorbance at 570 nm with an enzyme linked immunosorbent assay (ELISA) reader to determine cell viability and percentage of surviving cells from the ratio of absorbance of cells treated with the compound and untreated cells. It was.

IC50 values for cell growth inhibition were determined by fitting a plot of the log percentage of viable cells to the log of drug concentration using a linear regression function.

The results are shown in Table 1.

compound IC ₅₀ value (μM) SK-hep-1 HeLa HCT-15 A549 MDA-MB-231 Comparative Example 1 > 200 > 200 > 200 > 200 > 200 Comparative Example 2 > 200 > 200 > 200 > 200 > 200 Example 1 4.2 ± 0.11 10.2 ± 0.21 3.7 ± 0.10 3.2 ± 0.11 2.8 ± 0.03 Cisplatin 6.3 ± 0.06 10.5 ± 0.18 5.6 ± 0.09 2.4 ± 0.08 2.7 ± 0.05

As shown in Table 1, the compounds of Comparative Examples 1 and 2 were shown to have no anti-cancer activity in cancer cell lines, whereas the novel 4-nuclear arene-ruthenium nano-cage compound according to the present invention (Example 1) was SK- Hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 (lung cancer), and MDA-MB-231 (breast cancer) cells exhibit IC50 values of 2.8 to 10.2 μM for conventional anticancer agents. It showed an anticancer effect equivalent to that of cisplatin used. In particular, the compounds of Example 1 in the HCT-15 and SK-hep-1 cancer cell lines showed IC ₅₀ values of 3.7 μM and 4.2 μM, respectively, which were much better than 5.6 μM and 6.3 μM of cisplatin. Therefore, it is considered that the compound of the present invention can be used as an excellent anticancer agent that can replace the existing cisplatin in rectal cancer and liver cancer.

< Experimental Example  2> Review of cytotoxicity for each ingredient

To determine the appropriate dosage, cytotoxicity was measured on the A549 cell line against the compound of Example 1, the reactant of Example 1, the arene-ruthenium receptor A2 compound and the amide donor L1 compound, and the results are shown in FIG. Indicated.

Referring to FIG. 6, the amide donor L1 compound showed no measurable IC ₅₀ value at 200 μM, but the A2 compound showed weak cytotoxic activity at high concentration of 200 μM. The compound of Example 1 showed at least 10-fold cytotoxic activity compared to the A2 compound.

Therefore, in view of the results for the compounds of Comparative Examples 1, 2 and Example 1, it was found that the length of the spacer is an important factor in the preparation of a compound having anticancer activity. The L1 compound, a biocompatible amide donor, had the synergistic effect of increasing cytotoxicity in combination with the A2 compound. The cytotoxicity of the compound of Example 1 is due to a function of inducing cell death by inhibiting cell function, and thus can be usefully used for the treatment of cancer by preventing cancer cell proliferation.

Meanwhile, the compound according to the present invention can be formulated into various forms depending on the purpose. The following examples illustrate some formulations containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example  1> tablet (direct pressure)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressed to prepare tablets.

< Formulation example  2> tablets (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The fine particles were pressed to prepare tablets.

< Formulation example  3> with powder Capsule

5.0 mg of the active ingredient was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was extruded through a hard No. 5 &lt; / RTI &gt; gelatin capsules.

< Formulation example  4> Injection

100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO _{4 12} H ₂ O and 2974 mg of distilled water were mixed. The mixed solution was filled in an ampoule made of transparent glass, sealed in an upper lattice by dissolving the glass, sterilized by autoclaving at 120 DEG C for 15 minutes or longer, and injected.

Having described the specific parts of the present invention in detail, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (6)

A quaternary arene-ruthenium compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Chemical Formula 1,

The
(2)

ego,
In Formula 2, A is independently OTf (trifluoromethylsulfonate), nitrate (NO ₃ ), OTs (toluene-4-sulfonate), OMs (methanesulfonate), Cl, Br, I, BF ₄ , PF ₆ , ClO ₄ , CH ₃ COO, CF ₃ COO or CH ₃ SO ₃ ,

The
(3)

or
[Chemical Formula 4]

ego,
The ruthenium of Formula 2 and the nitrogen atom in the aromatic ring of Formula 3 or 4 combine to form a compound of Formula 1.
A pharmaceutical composition for preventing or treating cancer, comprising the quaternary arene-ruthenium compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 2,
The quaternary arene-ruthenium compound or a pharmaceutically acceptable salt thereof is a pharmaceutical composition for preventing or treating cancer that exhibits anticancer activity through apoptosis of cancer cells.
The method of claim 2,
The pharmaceutical composition for the prevention or treatment of cancer may be a carrier, an excipient, a disintegrant, a sweetener, a coating agent, a swelling agent, a lubricant, a lubricant, a flavoring agent, an antioxidant, a buffer, a bacteriostatic agent, a diluent, a dispersant, a surfactant, Wherein the composition further comprises at least one adjuvant selected from the group consisting of:
The method of claim 2,
The pharmaceutical composition for preventing or treating cancer may be selected from the group consisting of granules, powders, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, Wherein the pharmaceutical composition is for preventing or treating cancer.
6. The method according to any one of claims 2 to 5,
The cancer is liver cancer, ovarian cancer, rectal cancer, lung cancer or breast cancer that is a pharmaceutical composition for the prevention or treatment of cancer.

Images