KR101376403B1 - Novel Tetranuclear Arene-Ruthenium Compound and Parmaceutical Composition for Preventing or Treating Cancer Containing Thereof - Google Patents
Novel Tetranuclear Arene-Ruthenium Compound and Parmaceutical Composition for Preventing or Treating Cancer Containing Thereof Download PDFInfo
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- KR101376403B1 KR101376403B1 KR1020110093092A KR20110093092A KR101376403B1 KR 101376403 B1 KR101376403 B1 KR 101376403B1 KR 1020110093092 A KR1020110093092 A KR 1020110093092A KR 20110093092 A KR20110093092 A KR 20110093092A KR 101376403 B1 KR101376403 B1 KR 101376403B1
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- cancer
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- compound
- pharmaceutical composition
- ruthenium
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Abstract
본 발명은 신규한 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염에 관한 것으로, 이는 인간 SK-hep-1(간암), HeLa(난소암), HCT-15(직장암), A549(폐암), 및 MDA-MB-231(유방암) 세포의 증식을 낮은 마이크로몰 농도에서 억제하며, 세포 성장 사이클을 조절하는 세포사멸을 통하여 암 세포의 활성을 저해함으로써 뛰어난 항암활성을 나타내는 바, 간암, 난소암, 직장암, 폐암, 유방암 등의 암의 예방 및 치료에 유용하게 사용될 수 있다. The present invention relates to novel quaternary arene-ruthenium compounds or pharmaceutically acceptable salts thereof, which include human SK-hep-1 (liver cancer), HeLa (ovarian cancer), HCT-15 (rectal cancer), A549 (lung cancer) ), And inhibits the 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. It can be usefully used for the prevention and treatment of cancers such as cancer, rectal cancer, lung cancer, breast cancer.
Description
본 발명은 신규한 4핵 아렌-루테늄 화합물 또는 이의 약제학적으로 허용가능한 염, 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.
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.
금속약학 분야는 금속 기반 약물의 치료학적 적용 때문에 의약 화학의 중요한 새로운 분야로서 대두되었다((a) M. Mascini, G. Bagni, M. L. D. Pietro, M.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). 넓은 범위의 배위수로부터 3차원 공간에서유기 리간드의 재배열 및 조절가능한 금속 중심의 접근가능한 산화-환원상태는 의약 목적에 사용될 수 있는 반응성의 넓은 스펙트럼을 제공한다(U. Schatzschneider and N.Metzler-Nolte, Angew. Chem., Int. Ed., 2006, 45, 1504.). 백금 복합체 특히 시스플래틴, 카보플래틴, 및 옥소플래틴은 그들의 높은 독성 및 불필요한 신경, 간, 및 신장 독성 부작용에도 불구하고((a) Y. Jung and S. J. Lippard, Chem. Rev., 2007, 107, 1387; (b) C. Gianomenico and M. U. S. Christen, Patent 6413953, 2000), 현재 가장 효과적인 화학적 치료제로서 사용되고 있다((a) L. Kelland, Nat. Rev. Cancer, 2007, 7, 573; (b) J. Reedijk, Eur. J. Inorg. Chem., 2009, 1303). 그러나 백금계 약물과 관련된 높은 전신 독성 및 저항성 문제들은 대안적인 금속계 항종양제((a) C. H. A. Goss, W. Henderson, A. L. Wilkins and C. J. Evans, J. Organomet. Chem. 2003, 679, 194; (b) A. G. Quiroga and C. N. Ranninger, Coord. Chem. Rev. 2004, 248, 119; (c) W. Henderson, B. K. Nicholson and E. R. T. Tiekink, Inorg. Chim. Acta, 2006, 359, 2046) 및 더 안전하고 더욱 효과적인 치료제의 설계 및 약리학적 발전에 관심을 갖는 새시대를 열었다. 특히, 루테늄 복합체는 백금계 약물에 잘 반응하지 않는 종양에 있어서 저독성 및 고활성을 갖는 금속계 약물로 촉망받는 새로운 분류를 대표한다((a) C. G. Hartinger, S. Zorbas-Selfried, M.A. Jakupee, B. Kynast, H. Zorbas and B. K. Keppler, J. Inorg. Biochem. 2006, 100, 891; (b) Y. K. Yan, M. Melchart, A. Habtemariam and P. J. Sadler Chem. Commun., 2005, 4764). 두 루테늄 복합체, ImH[트랜스RuCl4(DMSO)Im]](NAMI-A) 및 KO1019가 임상 1상을 성공적으로 통과한 최초 1핵 루테늄계 항암 약물이다((a) J. M. Rademaker-Lakhai, D. Van Den Bongard, D. Pluim, J. H. Beijnen and J. H. M. Schellens, Clin. Cancer Res., 2004, 10, 3717; (b) M. Groessl, C. G. Hartinger, K. Polec-Pawlak, M. Jarosz, P. J. Dyson and B. K. Keppler, Chem. Biodiversity, 2008, 5, 1609.). 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.).
다핵 약물 또한 치료가능한 종양의 범위를 증대시키기 위해 설계되었다. 많은 고분자 백금 화합물((a) Z. Yang, X. Wang, H. Diao, J. Zhang, H. Li, H. Sung and Z. Guo, Chem. Commun., 2007, 3453; (b) N. J. Wheate, A. I. Day, R. J. Blanch, A. P. Arnold, C. Cullinane and J. G. Collins, Chem. Commun., 2004, 1424), 예를 들면 고분자 링크된 디아미노사이클로헥실 금속 화학적 치료적(AP5346) 및 pt-배위된 고차분지구조를 갖는 폴리글리세롤 폴리머가 선택적 투과, 보유 효과(EPR)(Y. Matsumura and H. Maeda, Cancer. Res., 1986, 46, 6387.) 및 긴 범위 가닥간 및 가닥내 DNA 교차결합을 통해 약물이 선택적으로 암세포 내에서 축적하도록 하는 이들의 독특한 세포밖 환경 때문에 잠재적으로 타겟 특정형 종양 세포에 사용될 수 있을 것이다. 따라서, 다핵 금속-고분자 복합체 화합물에 대한 연구가 활발하게 이루어지고 있는 실정이다.
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.
본 발명은 다핵 금속-고분자 복합체의 일종인 신규한 4핵 아렌-루테늄 화합물 및 이의 항암 치료용 용도를 제공하고자 한다.
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.
상기 목적을 해결하기 위하여, 본 발명은 하기 화학식 1로 표시되는 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다. 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.
[화학식 1][Formula 1]
상기 화학식 1에서, In Formula 1,
는 The
[화학식 2](2)
이고, ego,
상기 화학식 2에서 In
A는 각각 독립적으로 OTf(trifluoromethylsulfonate), 니트레이트(NO3), OTs(톨루엔-4-설포네이트), OMs(메탄설포네이트), Cl, Br, I, BF4, PF6, ClO4, CH3COO, CF3COO 또는 CH3SO3이며, 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
[화학식 3](3)
또는 or
[화학식 4][Chemical Formula 4]
이고, ego,
상기 화학식 2의 루테늄과 화학식 3 또는 4의 방향족 고리 내의 질소원자가 결합하여 화학식 1의 화합물을 형성한다.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.
본 발명은 또한, 상기 신규한 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물을 제공한다.
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.
본 발명에 따른 4핵 아렌-루테늄 화합물은 인간 SK-hep-1(간암), HeLa(난소암), HCT-15(직장암), A549(폐암), 및 MDA-MB-231(유방암) 세포의 증식을 낮은 마이크로몰 농도에서 억제하며, 세포 성장 사이클을 조절하는 세포사멸을 통하여 암 세포의 활성을 저해함으로써 뛰어난 항암활성을 나타내는 바, 간암, 난소암, 직장암, 폐암, 유방암 등의 암의 예방 및 치료에 유용하게 사용될 수 있다.
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.
도 1은 비교예 1, 비교예 2 및 실시예 1의 화합물의 제조 모식도이다.
도 2는 비교예 1(a), 비교예 2(b) 및 실시예 1(c) 화합물의 1H NMR 스펙트럼이다.
도 3은 비교예 1(a), 비교예 2(b) 및 실시예 1(c) 화합물의 13C NMR 스펙트럼이다.
도 4는 비교예 1(a), 비교예 2(b) 및 실시예 1(c) 화합물의 화합물의 ESI 질량분석 스펙트럼이다
도 5는 비교예 1(a) 및 2(b) 화합물의 X-선 구조를 나타낸다(H 원자, 대응 음이온 및 용매 분자는 명확함을 위해 생략되었음).
도 6은 본 발명의 실시예 1 화합물의 A549 세포주에 대한 항암 효과를 나타내는 그래프이다.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.
본 발명은 하기 화학식 1로 표시되는 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다. The present invention provides a quaternary arene-ruthenium compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서, In Formula 1,
는 The
[화학식 2](2)
이고, ego,
상기 화학식 2에서 A는 각각 독립적으로 OTf(trifluoromethylsulfonate), 니트레이트(NO3), OTs(톨루엔-4-설포네이트), OMs(메탄설포네이트), Cl, Br, I, BF4, PF6, ClO4, CH3COO, CF3COO 또는 CH3SO3이며, In
는 The
[화학식 3](3)
또는 or
[화학식 4][Chemical Formula 4]
이고, ego,
상기 화학식 2의 루테늄과 화학식 3 또는 4의 방향족 고리 내의 질소원자가 결합하여 화학식 1의 화합물을 형성한다.The ruthenium of
상기 화학식 1로 표시되는 본 발명의 4핵 아렌-루테늄 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산 등을 사용할 수 있다. 바람직하게는 무기산으로는 염산, 유기산으로는 메탄설폰산을 사용할 수 있다.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. . As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.
또한, 본 발명의 상기 화학식 1로 표시되는 4핵 아렌-루테늄 화합물은 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함한다.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.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.
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. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.
본 발명에 따른 화학식 1의 4핵 아렌-루테늄 화합물은 아마이드 공여체인 화학식 3 또는 화학식 4의 화합물과 루테늄 트리플레이트 수용체인 화학식 2의 화합물을 1:1 비로 반응시킴으로서 용이하게 제조될 수 있으며, 상기 반응은 니트로메탄-메탄올 1:1 용액에서 이루어 질 수 있으나 이에 제한되는 것은 아니다. 상기 반응은 6 내지 15시간 동안 상온에서 교반 하에 일어날 수 있으며, 농축된 반응 혼합물에 디에틸 에테르를 첨가하면 순수한 자기집합된 화학식 1의 생성물이 초록색 고체로 형성된다. The quaternary arene-ruthenium compound of formula 1 according to the present invention can be easily prepared by reacting a compound of
상기와 같이 본 발명에 따라 제조된 신규한 4핵 아렌-루테늄 화합물은 제조 후, 적외선 분광법, 핵자기 공명 스펙트럼, 질량 분광법, 액체 크로마토그 래피법, X-선 구조결정법, 선광도 측정법 및 대표적인 화합물의 원소분석 계산치와 실측치의 비교에 의해 분자구조를 확인할 수 있다.
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.
또한 이하 실시예에서 확인할 수 있는 바와 같이, 본 발명에 따른 화학식 1의 4핵 아렌-루테늄 화합물은 인간 SK-hep-1(간암), HeLa(난소암), HCT-15(직장암), A549(폐암), 및 MDA-MB-231(유방암) 세포의 증식을 낮은 마이크로몰 농도에서 억제하며, 세포 성장 사이클을 조절하는 세포사멸을 통하여 암 세포의 활성을 저해함으로써 뛰어난 항암활성을 나타내는 바, 항암제의 유효성분으로 사용될 수 있다. 따라서 본 발명은 상기 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물, 항암제의 제조를 위한 상기 4핵 아렌-루테늄 화합물의 용도, 상기 4핵 아렌-루테늄 화합물을 대상체에 투여하는 단계를 포함하는 암의 치료 방법을 제공한다. 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.
본 발명의 한 구체예에서, 상기 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물은 약학 조성물 100 중량부에 대하여 상기 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 0.01 내지 90 중량부, 0.1 내지 90 중량부, 1 내지 90 중량부, 또는 10 내지 90 중량부로 포함할 수 있으나 이에 한정되는 것은 아니고, 환자의 상태 및 질환의 종류 및 진행 정도에 따라 달라질 수 있다.
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.
본 발명의 다른 구체예에서, 상기 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물은 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 보조제를 추가로 포함할 수 있다. 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.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.
Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin or the like in the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
본 발명의 또 다른 구체예에서, 상기 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물의 제형은 과립제, 산제, 피복정, 정제, 환제, 캡슐제, 좌제, 겔, 시럽, 즙, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택될 수 있다.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.
본 발명의 일실시예에 따르면 상기 약학 조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다. According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.
상기 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 1,000 mg/kg, 구체적으로는 0.1 내지 1,000 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.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. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.
In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.
본 발명의 또 다른 구체예에서, 상기 암은 간암, 난소암, 직장암, 폐암 또는 유방암일 수 있으나 이제 제한되는 것은 아니다.
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.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
하기의 실험예들은 본 발명에 따른 각각의 실시예에 공통적으로 적용되는 실험예를 제공하기 위한 것이다.The following experimental examples are intended to provide experimental examples that are commonly applied to each embodiment according to the present invention.
1. 일반 사항 1. General
본 실험에 사용된 아렌-류테늄 수용체 A1, A2(화학식2) 및 아마이드 공여체 L1(화학식 3), L2(화학식 4)는 종래 방법에 따라 제조하였다. 본 발명의 실시예에서 사용된 A1, A2, L1, L2 화학식의 구조는 도 1에 나타내었다. 중수소화 용매는 캠브릿지 동위원소 실험실(Andover, MA)에서 구입하였다. NMR 스펙트럼은 Bruker 300 MHz 스펙트로미터에서 기록되었다.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.
1H NMR 화학적 이동은 잔여 용매 신호에 상대적으로 기록되었다. 자기조립에 대한 질량 스펙트럼은 MassLynx 작동 시스템으로 전자스프레이 이온화를 이용한 Micromass Quattro II triple-quadrupole 질량 스펙트로미터상에서 기록되었다. 제조된 화합물의 단결정으로부터 회절 데이터를 거대분자 결정학 빔 라인 6B1, 포항 가속기 연구소(PAL)에서 100 K 에서 싱크로트론 방사선(λ = 0.90000 Å)을 이용한 ADSC 양자 210 CCD 회절미터상에서 수집하였다. 초기 데이터를 프로그램 HKL2000을 이용하여 가공 및 축소하였다. 구조는 직접적 방법에 의해 규명되었고, SHELXTL 프로그램 패키지에 있는 적절한 소프트웨어를 이용하여 F2상에 full-matrix least-squares refinement로 정련하였다. 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. 반응 모식도2. Schematic diagram of the reaction
아렌-류테늄 수용체 A1, A2(화학식2) 및 아마이드 공여체 L1(화학식3), L2(화학식 4)를 사용하여 비교예 1, 비교예 2 및 실시예 1의 화합물을 제조하였다. 이의 모식도를 도 1에 나타내었다. A1, A2의 루테늄이 L1 또는 L2의 피리딘의 질소 원자와 상호작용하여 4각 구조를 형성하게 된다.
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.
<< 비교예Comparative Example 1> A1 + 1> A1 + L1L1 화합물 제조 Compound manufacturing
아마이드 공여체인 L1 화합물 (2.42mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A1 (8.58 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 1.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 비교예 1 화합물의 노란 결정 분말을 얻었다 (수율 86%). 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%).
1H NMR [300 MHz, (CD3)2SO]: 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(CH3)2), 2.12 (s, 12H, CH3), 1.26 (d, J = 6.9Hz, 24H,CH(CH--3)2) (도 2a 참조); 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);
13C NMR[75 MHz, (CD3)2SO]: 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 (도 3a 참조) ; 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) (C72H76F12N8O24Ru4S4): 949.9 [M - 2OTf]2+; 583.8 [M - 3OTf]3+ (도 4a 참조, 빨간색: 이론치, 파란색: 실험치).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-선 결정구조는 도 5의 (a)에 나타내었다(초록색: 루테늄, 빨간색: 산소, 파란색: 질소 및 회색: 탄소).
X-ray crystal structure is shown in Fig. 5 (a) (green: ruthenium, red: oxygen, blue: nitrogen and gray: carbon).
<< 비교예Comparative Example 2> A1 + 2> A1 + L2L2 화합물 제조 Compound manufacturing
아마이드 공여체인 L2 화합물 (2.42mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A1 (8.58 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 1.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 비교예 2 화합물의 노란 결정 분말을 얻었다 (수율 82%). 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%).
1H NMR [300 MHz, (CD3)2SO]: 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(CH3)2), 2.12 (s, 12H, CH3), 1.30 (d, J = 6.9Hz, 24H,CH(CH3)-2) (도 2b 참조); 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);
13C NMR [75 MHz, (CD3)-2SO]: 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 (도 3b 참조); 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) (C72H76F12N8O24Ru4S4): 583.8 [M - 3OTf]3+(도 4b 참조, 빨간색: 이론치, 파란색: 실험치).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-선 결정구조는 도 5의 (b)에 나타내었다(초록색: 루테늄, 빨간색: 산소, 파란색: 질소 및 회색: 탄소).
X-ray crystal structure is shown in Figure 5 (b) (green: ruthenium, red: oxygen, blue: nitrogen and grey: carbon).
<< 실시예Example 1> A2+ 1> A2 + L1L1 화합물 제조 Compound manufacturing
아마이드 공여체인 L1 화합물(2.42mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A2 (8.58 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 1.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 실시예 1 화합물의 초록 결정 분말을 얻었다 (수율 85%). 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%).
1H NMR [300 MHz, (CD3)2CO]: 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(CH3)2), 2.17 (s, 12H, CH3), 1.36 (d, J = 6.9Hz, 24H,CH(CH3)2) (도 2c 참조); 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);
13C NMR [75 MHz, (CD3)2SO]: 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 (도 3c 참조); 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) (C88H84F12N8O24Ru4S4): 1050.1 [M - 2OTf]2+, 650.5 [M - 3OTf]3++(도 4c 참조, 빨간색: 이론치, 파란색: 실험치).
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).
<< 실험예Experimental Example 1> 암 세포 성장 저해 분석( 1> Cancer cell growth inhibition assay ( MTTMTT 분석) analysis)
본 발명의 화합물의 SK-hep-1(간암), HeLa(난소암), HCT-15(직장암), A549(폐암), 및 MDA-MB-231(유방암) 세포에 대한 성장 저해 분석 실험을 수행하였다.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.
구체적으로, 상술한 암 세포를 10% 열 비활성화 소 태아 혈청(FBS) 및 1% 페니실린 스트렙토마이신이 보충된 둘베코 변형 이글 배지(DMEM)에서 37 ℃ 및 5% CO2 하에서 배양하였다. 각 다른 세포들의 현탁액을 96 웰 플레이트에 5×104 세포수/웰 (90 μL/웰 및 10 μL 샘플)의 농도로 분주하였다. 다음으로 MTT를 인산 완충액(PBS, pH 7.2)에 용해시키고 여과시켜 5 mg/ml의 저장용액으로서 제조하였다. 대조군으로서 무처리, 실시예 1의 화합물 처리, 비교군 1, 2의 화합물 처리 및 종래 항암제로 사용되는 시스플라틴(cisplatin) 처리 후에 10 μL의 MTT 용액을 각 웰에 첨가하였다. 37 ℃ 및 5% CO2 하에서 4시간 동안 배양시킨 다음, 100 μL의 DMSO(디메틸설폭사이드)를 각 웰에 첨가하였다. 이후 상기 96 웰 플레이트를 효소 연결된 면역흡착제 분석법(ELISA) 리더기로 570 nm에서 흡광도를 읽음으로써 상기 화합물을 처리한 세포와 비처리한 세포의 흡광도의 비로부터 세포 생존도 및 생존한 세포의 백분율을 측정하였다.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
세포 성장 저해에 대한 IC50 값은 선형 회귀 함수를 사용하여 약물 농도의 로그에 대한 생존한 세포의 로그 백분율의 플롯(plot)을 피팅(fitting)함으로써 측정되었다.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.
결과를 표 1에 나타내었다. The results are shown in Table 1.
상기 표 1에 나타난 바와 같이, 비교예 1 및 2의 화합물은 암세포주에 항암 활성이 없는 것으로 나타난 반면, 본 발명에 따른 신규한 4핵 아렌-류테늄 나노 케이지 화합물(실시예 1)은 SK-hep-1(간암), HeLa(난소암), HCT-15(직장암), A549(폐암), 및 MDA-MB-231(유방암) 세포에 대하여 2.8 내지 10.2 μM의 IC50 값을 나타냄으로써 종래 항암제로 사용되는 시스플라틴과 동등 이상의 항암효과를 나타내었다. 특히 HCT-15 및 SK-hep-1 암 세포주에서 실시예 1의 화합물은 각각 IC50 값이 3.7μM 및 4.2 μM 로, 시스플라틴의 5.6 μM 및 6.3 μM보다 월등히 우수한 것으로 나타났다. 따라서 본 발명의 화합물은 직장암 및 간암에서 기존의 시스플라틴을 대체할 수 있는 우수한 항암제로 사용될 수 있을 것으로 판단된다.
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.
<< 실험예Experimental Example 2> 각 성분별 세포독성 검토 2> Review of cytotoxicity for each ingredient
적합한 투여량을 결정하기 위해, A549 세포주를 대상으로 실시예 1의 화합물, 실시예 1의 반응물인 아렌-루테늄 수용체 A2 화합물 및 아마이드 공여체인 L1 화합물에 대하여 세포독성을 측정하였고, 결과를 도 6에 나타내었다. 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.
도 6을 참조하면, 아마이드 공여체인 L1 화합물은 측정 가능한 IC50 값이 200 μM에서도 관찰되지 않았으나, A2 화합물은 높은 농도인 200 μM에서는 약한 세포 독성 활성을 보였다. 실시예 1의 화합물은 A2 화합물에 비해 10배 이상의 세포독성 활성을 보였다. 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.
따라서, 상기 비교예 1, 2 및 실시예 1 화합물에 대한 결과에 비추어 보면, 스페이서의 길이가 항암 활성이 있는 화합물의 제조에 있어 중요한 인자임을 알 수 있었다. 생체적합성 아마이드 공여체인 L1 화합물은 A2 화합물과 결합하여 세포독성을 증가시키는 시너지 효과를 내었다. 상기 실시예 1 화합물의 세포독성은 세포 기능을 저해하여 세포 사멸을 유도하는 기능에 기인한 것이며, 이를 통해 암세포 증식을 막아 암의 치료에 유용하게 사용될 수 있다.
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.
한편, 본 발명에 따른 상기 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.
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.
<< 제제예Formulation example 1> 정제(직접 가압) 1> tablet (direct pressure)
활성성분 5.0㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 제조하였다.
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.
<< 제제예Formulation example 2> 정제(습식 조립) 2> tablets (wet assembly)
활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 제조하였다.
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
<< 제제예Formulation example 3> 분말과 3> with powder 캡슐제Capsule
활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 혼합하였다. 상기 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 넣어 캡슐제를 제조하였다.
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 < / RTI > gelatin capsules.
<< 제제예Formulation example 4> 주사제 4> Injection
활성성분 100 mg, 만니톨 180 mg, Na2HPO412H2O 26 mg 및 증류수 2974 mg를 혼합하였다. 상기 혼합 용액을 투명 유리로 된 앰틀 중에 충전시키고, 유리를 용해시킴으로써 상부 격자하에 봉입시키고, 120 ℃에서 15분 이상 오토클레이브시켜 살균하여 주사제를 제조하였다.
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.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시예일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (6)
[화학식 1]
상기 화학식 1에서, 상기 A는 OTf(trifluoromethylsulfonate)이고,
는
[화학식 2]
이고,
상기 화학식 2에서 A가 제거된 것이고, 상기 A는 OTf(trifluoromethylsulfonate)이고,
는
[화학식 3]
이고,
상기 화학식 2에서 A가 제거된 루테늄과 화학식 3의 방향족 고리 내의 질소원자가 결합하여 화학식 1의 화합물을 형성함.
A pharmaceutical composition for the prophylaxis or treatment of cancer diseases selected from liver cancer or rectal cancer, containing a 4-nuclear arene-ruthenium compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
In Formula 1, A is trifluoromethylsulfonate (OTf),
The
(2)
ego,
In Formula 2, A is removed, and A is trifluoromethylsulfonate (OTf),
The
(3)
ego,
In Formula 2, ruthenium from which A is removed and a nitrogen atom in the aromatic ring of Formula 3 combine to form a compound of Formula 1.
상기 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염은 암 세포의 세포사멸을 통하여 항암활성을 나타내는 것인 암질환의 예방 또는 치료용 약학 조성물.
3. 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 diseases that exhibit anticancer activity through apoptosis of cancer cells.
상기 약학 조성물은 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 보조제를 추가로 포함하는 것인 암질환의 예방 또는 치료용 약학 조성물.
3. The method of claim 2,
The pharmaceutical composition is one selected from the group consisting of carriers, excipients, disintegrants, sweeteners, coatings, expanding agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders and lubricants A pharmaceutical composition for preventing or treating cancer diseases, further comprising the above adjuvant.
상기 약학 조성물의 제형은 과립제, 산제, 피복정, 정제, 환제, 캡슐제, 좌제, 겔, 시럽, 즙, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택되는 것을 특징으로 하는 암질환의 예방 또는 치료용 약학 조성물.
3. The method of claim 2,
Formulation of the pharmaceutical composition is selected from the group consisting of granules, powders, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, drops or solutions Prophylactic or therapeutic pharmaceutical composition.
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