KR101360478B1 - 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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- KR101360478B1 KR101360478B1 KR1020120025591A KR20120025591A KR101360478B1 KR 101360478 B1 KR101360478 B1 KR 101360478B1 KR 1020120025591 A KR1020120025591 A KR 1020120025591A KR 20120025591 A KR20120025591 A KR 20120025591A KR 101360478 B1 KR101360478 B1 KR 101360478B1
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- cancer
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- ruthenium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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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) 또는 HCT-15(직장암) 세포의 증식을 낮은 마이크로몰 농도에서 억제하며, 세포 성장 사이클을 조절하는 세포사멸을 통하여 암 세포의 활성을 저해함으로써 뛰어난 항암활성을 나타내는 바, 암의 예방 및 치료에 유용하게 사용될 수 있다.The present invention relates to a novel quaternary arene-ruthenium compound or a pharmaceutically acceptable salt thereof, which inhibits proliferation of human SK-hep-1 (liver cancer) or HCT-15 (rectal cancer) cells at low micromolar concentrations. In addition, it shows excellent anticancer activity by inhibiting the activity of cancer cells through apoptosis that regulates the cell growth cycle, it can be usefully used for the prevention and treatment of 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 시스플라틴, 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, in particular cisplatin, carboplatin, and oxoplatin, despite their high toxicity and unnecessary neurological, liver, and kidney toxicity side effects ((a) Y. Jung and SJ Lippard, Chem. Rev., 2007, 107, 1387; (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. 이에 따라, 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. Accordingly, 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,
[화학식 2-1]
또는
[화학식 2-2]
이고,
상기 화학식 2-1 또는 화학식 2-2에서 A는 각각 독립적으로 OTf(trifluoromethylsulfonate)이며,
[화학식 3]
또는
[화학식 4]
이고,
In Formula 1,
[Formula 2-1]
or
[Formula 2-2]
ego,
In Formula 2-1 or Formula 2-2, A is independently OTf (trifluoromethylsulfonate),
(3)
or
[Chemical Formula 4]
ego,
상기 화학식 2-1 또는 화학식 2-2의 루테늄과 화학식 3 또는 화학식 4의 방향족 고리 내의 질소원자가 결합하여 화학식 1의 화합물을 형성한다.The ruthenium of Formula 2-1 or 2-2 and the nitrogen atom in the aromatic ring of Formula 3 or Formula 4 combine to form a compound of Formula 1.
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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) 또는 HCT-15(직장암) 세포의 증식을 낮은 마이크로몰 농도에서 억제하며, 세포 성장 사이클을 조절하는 세포사멸을 통하여 암 세포의 활성을 저해함으로써 뛰어난 항암활성을 나타내는 바, 암의 예방 및 치료에 유용하게 사용될 수 있다.The quaternary arene-ruthenium compound according to the present invention inhibits proliferation of human SK-hep-1 (liver cancer) or HCT-15 (rectal cancer) cells at low micromolar concentrations, and inhibits cancer through apoptosis that regulates cell growth cycle. By inhibiting the activity of the cell shows excellent anticancer activity, it can be usefully used for the prevention and treatment of cancer.
도 1은 비교예 1 내지 4, 실시예 1 내지 4 화합물의 제조 모식도이다.
도 2는 D1(a), 비교예 1(b) 비교예 2(c), 실시예 1(d) 및 실시예 2(e) 화합물의 1H NMR 스펙트럼이다.
도 3은 비교예 3의 화합물의 단결정에 대한 X-선 결정구조이다(초록색: 루테늄, 빨간색: 산소, 파란색: 질소 및 회색: 탄소).
도 4는 각 화합물(비교예 1 내지 4, 실시예 1 내지 4) 및 D1, D2, A1, A2, A3 A4에 대한 UV-vis 스펙트럼이다.
도 5는 비교예 1 내지 4 및 D1, D2, A1, A2에 대한 방출 스펙트럼이다.
도 6은 실시예 1 내지 4 및 A3, A4에 대한 방출 스펙트럼이다.
도 7은 실시예 1 내지 4 화합물에 대한 MTT 분석 결과 그래프이다. BRIEF DESCRIPTION OF THE DRAWINGS The manufacturing schematic diagram of the comparative example 1-4 and the Example 1-4 compound.
2 is a 1 H NMR spectrum of a compound of D1 (a), Comparative Example 1 (b), Comparative Example 2 (c), Example 1 (d), and Example 2 (e).
3 is an X-ray crystal structure of a single crystal of the compound of Comparative Example 3 (green: ruthenium, red: oxygen, blue: nitrogen, and gray: carbon).
4 is a UV-vis spectrum for each compound (Comparative Examples 1-4, Examples 1-4) and D1, D2, A1, A2, A3 A4.
5 are emission spectra for Comparative Examples 1-4 and D1, D2, A1, A2.
6 is emission spectra for Examples 1-4 and A3, A4.
7 is a graph of MTT analysis results for Examples 1 to 4 compounds.
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,
[화학식 2-1]
또는
[화학식 2-2]
이고,
상기 화학식 2-1 또는 화학식 2-2에서 A는 각각 독립적으로 OTf(trifluoromethylsulfonate)이며,
[화학식 3]
또는
[화학식 4]
이고,
In
[Formula 2-1]
or
[Formula 2-2]
ego,
In Formula 2-1 or Formula 2-2, A is independently OTf (trifluoromethylsulfonate),
(3)
or
[Chemical Formula 4]
ego,
상기 화학식 2-1 또는 화학식 2-2의 루테늄과 화학식 3 또는 화학식 4의 방향족 고리 내의 질소원자가 결합하여 화학식 1의 화합물을 형성한다. The ruthenium of Formula 2-1 or 2-2 and the nitrogen atom in the aromatic ring of Formula 3 or Formula 4 combine to form a compound of
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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
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
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
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 녹색 고체로 형성된다. The quaternary arene-ruthenium 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) 및 HCT-15(직장암) 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 tetranuclear arene-ruthenium compound of the formula (1) according to the present invention is characterized in that the proliferation of human SK-hep-1 (liver cancer) and HCT-15 (rectal cancer) cells at low micromolar concentrations. It inhibits and inhibits the activity of cancer cells through apoptosis that regulates the cell growth cycle, and thus can be used as an active ingredient of an anticancer agent. 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 한 구체예에서, 상기 암은 고형암일 수 있으며, 더욱 구체적으로 본 발명에 따른 화학식 1의 4핵 아렌-루테늄 화합물은 뇌종양(Brain tumor), 양성성상세포종 (Low- grade astrocytoma), 악성성상세포종 (High-grade astrocytoma), 뇌하수체 선종 (Pituitary adenoma), 뇌수막종 (Meningioma), 뇌림프종 (CNS lymphoma), 핍지교종 (Oligodendroglioma), 두개내인종 (Craniopharyngioma), 상의세포종 (Ependymoma), 뇌간종양 (Brain stem tumor), 두경부 종양(Head & Neck tumor), 후두암 (Larygeal cancer), 구인두암 (Oropgaryngeal cancer) , 비강/부비동암 (Nasal cavity/PNS tumor), 비인두암 (Nasopharyngeal tumor), 침샘암 (Salivary gland tumor), 하인두암 (Hypopharyngeal cancer), 갑상선암 (Thyroid cancer), 구강암 (Oral cavity tumor), 흉부종양(Chest Tumor), 소세포성 폐암 (Small cell lung cancer), 비소세포성 폐암 (Non small cell lung cancer), 흉선암 (Thymoma), 종격동 종양 (Mediastinal tumor), 식도암 (Esophageal cancer), 유방암 (Breast cancer), 남성유방암 (Male breast cancer), 복부종양 (Abdomen-pelvis tumor), 위암 (Stomach cancer) , 간암 (Hepatoma), 담낭암 (Gall bladder cancer), 담도암 (Billiary tract tumor), 췌장암 (pancreatic cancer), 소장암 (Small intestinal tumor), 대장(직장)암 (Large intestinal tumor), 항문암 (Anal cancer), 방광암 (Bladder cancer), 신장암 (Renal cell carcinoma), 남성생식기종양 (Male genital cancer), 음경(요도)암 (Penile cancer), 전립선암 (Prostatic cancer), 여성생식기종양 (Female genital cancer), 자궁경부암 (Cervix cancer), 자궁내막암 (Endometrial cancer), 난소암 (Ovarian cancer), 자궁육종 (Uterine sarcoma), 질암 (Vaginal cancer), 여성외부생식기암 (Vulva cancer), 여성요도암 (Urethral cancer) 또는 피부암 (Skin cancer)의 치료에 사용함이 바람직하다. 보다 더 바람직하게는 간암 또는 직장암의 치료에 사용될 수 있으나 이제 제한되는 것은 아니다.
In one embodiment of the present invention, the cancer may be a solid cancer, more specifically, the four-nuclear allen-ruthenium compound of
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, A3, A4 및 아마이드 공여체 D1, D2는 종래 방법에 따라 제조하였다. 중수소화 용매는 캠브릿지 동위원소 실험실(Andover, MA)에서 구입하였다. NMR 스펙트럼은 Bruker 300 MHz 스펙트로미터에서 기록되었다. The arene-ruthenium receptors A1, A2, A3, A4 and amide donors D1, D2 used in this experiment were prepared according to conventional methods. Deuterated solvents were purchased from Cambridge Isotope Laboratory (Andover, Mass.). NMR spectra were recorded on a
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. UV-Vis 스펙트럼은 Cary 100 Conc에 기록되었다. 형광 적정(Fluorescence titration) 연구는 HORIBA FluoroMax-4 형광강도계로 수행되었다. 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. UV-Vis spectra were recorded at Cary 100 Conc. Fluorescence titration studies were performed with a HORIBA FluoroMax-4 fluorometer.
2. X-선 구조 분석 2. X-ray structure analysis
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. 모든 비-수소 원자는 이방성으로 정련되었고, 수소 원자는 기하학상 이상적인 위치에 가해졌다. CCDC-841900에 본 실험에 필요한 결정학상의 보조 데이터가 개시되어 있고, 이는 www.ccdc.cam.ac.uk/conts/retrieving.html 또는 Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK 에서 무료로 얻을 수 있다. 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 to full-matrix least-squares refinement on F 2 using appropriate software in the SHELXTL program package. All non-hydrogen atoms were refined anisotropically, and hydrogen atoms were placed in ideal positions in geometry. CCDC-841900 discloses crystallographic ancillary data required for this experiment, which can be found at www.ccdc.cam.ac.uk/conts/retrieving.html or at Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK. You can get it for free.
3. 반응 모식도 및 일반 사항 3. Schematic and General Reaction
3-디피리딜 공여체인 D1 또는 D2 화합물 및 루테늄 트리플레이트 수용체 A1, A2, A3 또는 A4 화합물이 1:1 몰비로 혼합된 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 결정 분말을 얻었다 (수율 82%). A mixture of a 3-dipyridyl donor, a D1 or D2 compound and a ruthenium triflate receptor A1, A2, A3 or A4 compound in a 1: 1 molar ratio was added to a CH 3 NO 2 -CH 3 OH solution (1: 1, 2 mL ) And stirred at room temperature for 10 hours. Diethyl ether was added dropwise to give crystalline powder (yield 82%).
이의 모식도를 도 1에 나타내었다. A1 내지 A4의 루테늄이 D1 또는 D2의 피리딘의 질소 원자와 상호작용하여 4각 구조 화합물 8개(비교예 1 내지 4, 실시예 1 내지 4)를 형성하게 된다.
A schematic diagram thereof is shown in FIG. 1. Ruthenium of A1 to A4 interacts with the nitrogen atom of the pyridine of D1 or D2 to form eight tetrahedral compounds (Comparative Examples 1-4, Examples 1-4).
<< 비교예Comparative Example 1> A1 + 1> A1 + D1D1 화합물 제조 Compound manufacturing
디피리딜 공여체인 D1 화합물 (1.8 mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A1 (8.6 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 비교예 1 화합물의 노란 결정 분말을 얻었다 (수율 85%). A mixture of dipyridyl donor D1 compound (1.8 mg, 0.01 mmol) and ruthenium triflate receptor A1 (8.6 mg, 0.01 mmol) was dissolved in CH 3 NO 2 -CH 3 OH solution (1: 1, 2.0 mL) and 10 Stir at room temperature for hours. After diethyl ether was added dropwise, yellow crystal powder of the compound of Comparative Example 1 was obtained (yield 85%).
C72H72F12N4O20Ru4S4: C, 41.70; H, 3.50; N, 2.70. Found: C, 41.31; H, 3.83; N, 2.94.C 72 H 72 F 12 N 4 O 20 Ru 4 S 4 : C, 41.70; H, 3.50; N, 2.70. Found: C, 41.31; H, 3.83; N, 2.94.
1H NMR [300 MHz, (CD3)2CO]: δ (ppm) 8.48 (s, 4H, H4), 8.22 (d, J = 6.0 Hz, 4H, H1), 8.00 (d, J = 7.8 Hz, 4H, H3), 7.51 (m, 4H, H2), 6.18 (m, 8H, Hcym), 6.06(m, 8H, Hcym), 3.01 (sept, 4H, CH(CH3)2), 2.33 (s, 12H, CH3), 1.44 (dd, J = 6.9 Hz, J = 6.9 Hz, 24H, CH(CH3)2 ) (도 2b 참조). 1 H NMR [300 MHz, (CD 3 ) 2 CO]: δ (ppm) 8.48 (s, 4H, H 4 ), 8.22 (d, J = 6.0 Hz, 4H, H 1 ), 8.00 (d, J = 7.8 Hz, 4H, H 3 ), 7.51 (m, 4H, H 2 ), 6.18 (m, 8H, Hcym), 6.06 (m, 8H, Hcym), 3.01 (sept, 4H, CH (CH 3 ) 2 ) , 2.33 (s, 12H, CH 3 ), 1.44 (dd, J = 6.9 Hz, J = 6.9 Hz, 24H, CH (CH 3 ) 2 ) (See FIG. 2B).
13C NMR[75 MHz, (CD3)2CO]: δ (ppm) 172.0, 171.7, 156.4, 152.6, 143.3, 127.4, 122.3, 103.4, 98.7, 89.9, 83.6, 83.3, 82.9, 81.9, 31.9, 22.7, 22.5 18.1 13 C NMR [75 MHz, (CD 3 ) 2 CO]: δ (ppm) 172.0, 171.7, 156.4, 152.6, 143.3, 127.4, 122.3, 103.4, 98.7, 89.9, 83.6, 83.3, 82.9, 81.9, 31.9, 22.7 , 22.5 18.1
MS (ESI) (C72H72F12N4O20Ru4S4): 887.9 [M - 2OTf]2+; 542.4 [M - 3OTf]3+
MS (ESI) (C 72 H 72 F 12 N 4 O 20 Ru 4 S 4 ): 887.9 [M-2OTf] 2+ ; 542.4 [M-3OTf] 3+
<< 비교예Comparative Example 2> A2 + 2> A2 + D1D1 화합물 제조 Compound manufacturing
디피리딜 공여체인 D1 화합물 (1.8 mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A2 (9.1 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 비교예 2 화합물의 붉은 결정 분말을 얻었다 (수율 88%). A mixture of dipyridyl donor D1 compound (1.8 mg, 0.01 mmol) and ruthenium triflate receptor A2 (9.1 mg, 0.01 mmol) was dissolved in CH 3 NO 2 -CH 3 OH solution (1: 1, 2.0 mL) and 10 Stir at room temperature for hours. After diethyl ether was added dropwise, red crystal powder of the compound of Comparative Example 2 was obtained (yield 88%).
C80H76F12N4O20Ru4S4(C2H5)2O: C, 44.88; H, 3.86; N, 2.49. Found: C, 45.12; H, 3.78; N, 2.81.C 80 H 76 F 12 N 4 O 20 Ru 4 S 4 (C 2 H 5 ) 2 O: C, 44.88; H, 3.86; N, 2.49. Found: C, 45.12; H, 3.78; N, 2.81.
1H NMR [300 MHz, (CD3)2CO]: δ (ppm) 8.80 (s, 4H, H4), 8.19 (d, J = 6.0 Hz, 8H, H1 ,3), 7.60 (m, 4H, H2), 6.24 (br, 8H, Hcym), 6.08 (br, 8H, Hcym), 5.78 (s, 4H, Hbq), 3.0 (sept, 4H, CH(CH3)2), 2.22 (s, 12H, CH3), 1.35 (d, J = 6.9 Hz, 24H,CH(CH3)2) (도 2c 참조). 1 H NMR [300 MHz, (CD 3 ) 2 CO]: δ (ppm) 8.80 (s, 4H, H 4 ), 8.19 (d, J = 6.0 Hz, 8H, H 1 , 3 ), 7.60 (m, 4H, H 2 ), 6.24 (br, 8H, Hcym), 6.08 (br, 8H, Hcym), 5.78 (s, 4H, Hbq), 3.0 (sept, 4H, CH (CH 3 ) 2 ), 2.22 (s , 12H, CH 3 ), 1.35 (d, J = 6.9 Hz, 24H, CH (CH 3 ) 2 ) (see FIG. 2C).
13C NMR[75 MHz, (CD3)2CO]: δ (ppm) 184.0, 155.4, 142.2, 126.0, 123.4, 121.4, 119.2, 104.0, 101.6, 88.7, 83.7, 31.1, 21.5, 17.1 13 C NMR [75 MHz, (CD 3 ) 2 CO]: δ (ppm) 184.0, 155.4, 142.2, 126.0, 123.4, 121.4, 119.2, 104.0, 101.6, 88.7, 83.7, 31.1, 21.5, 17.1
MS (ESI) (C80H76F12N4O20Ru4S4): 937.9 [M - 2OTf]2+; 575.8 [M - 3OTf]3+
MS (ESI) (C 80 H 76 F 12 N 4 O 20 Ru 4 S 4 ): 937.9 [M-2OTf] 2+ ; 575.8 [M-3OTf] 3+
<< 실시예Example 1> A3 + 1> A3 + D1D1 화합물 제조 Compound manufacturing
디피리딜 공여체인 D1 화합물 (1.8 mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A3 (9.6 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 실시예 1 화합물의 녹색 결정 분말을 얻었다 (수율 87%). A mixture of dipyridyl donor D1 compound (1.8 mg, 0.01 mmol) and ruthenium triflate receptor A3 (9.6 mg, 0.01 mmol) was dissolved in CH 3 NO 2 -CH 3 OH solution (1: 1, 2.0 mL) and 10 Stir at room temperature for hours. Diethyl ether was added dropwise to give green crystal powder of Example 1 compound (yield 87%).
C88H80F12N4O20Ru4S4: C, 46.48; H, 3.55; N, 2.46. Found: C, 46.19; H, 3.70; N, 2.41.C 88 H 80 F 12 N 4 O 20 Ru 4 S 4 : C, 46.48; H, 3.55; N, 2.46. Found: C, 46.19; H, 3. 70; N, 2.41.
1H NMR [300 MHz, (CD3)2CO]: δ (ppm) 8.85 (s, 4H, H4), 8.56 (d, J = 6.0 Hz, 4H, H1), 8.07 (d, J = 7.8 Hz, 4H, H3), 7.53 (m, 4H, H2), 7.32 (s, 8H, Hnq), 6.05 (d, J = 6.3 Hz, 8H, Hcym), 5.85(d, J = 6.3 Hz, 8H, Hcym), 2.94 (sept, 4H, CH(CH3)2), 2.14 (s, 12H, CH3), 1.34 (d, J = 6.9 Hz, 24H,CH(CH3)2) (도 2d 참조). 1 H NMR [300 MHz, (CD 3 ) 2 CO]: δ (ppm) 8.85 (s, 4H, H 4 ), 8.56 (d, J = 6.0 Hz, 4H, H 1 ), 8.07 (d, J = 7.8 Hz, 4H, H 3 ), 7.53 (m, 4H, H 2 ), 7.32 (s, 8H, Hnq), 6.05 (d, J = 6.3 Hz, 8H, Hcym), 5.85 (d, J = 6.3 Hz , 8H, Hcym), 2.94 (sept, 4H, CH (CH 3 ) 2 ), 2.14 (s, 12H, CH 3 ), 1.34 (d, J = 6.9 Hz, 24H, CH (CH 3 ) 2 ) (Fig. 2d).
13C NMR[75 MHz, (CD3)2CO]: δ (ppm) 171.8, 155.4, 152.6, 143.1, 138.4, 126.7, 122.2, 112.2, 104.1, 101.5, 89.7, 85.9, 83.2, 31.5, 22.5, 17.4 13 C NMR [75 MHz, (CD 3 ) 2 CO]: δ (ppm) 171.8, 155.4, 152.6, 143.1, 138.4, 126.7, 122.2, 112.2, 104.1, 101.5, 89.7, 85.9, 83.2, 31.5, 22.5, 17.4
MS (ESI) (C88H80F12N4O20Ru4S4): 2125.1 [M - OTf ]+.
MS (ESI) (C 88 H 80 F 12 N 4 O 20 Ru 4 S 4 ): 2125.1 [M-OTf] + .
<< 실시예Example 2> A4 + 2> A4 + D1D1 화합물 제조 Compound manufacturing
디피리딜 공여체인 D1 화합물 (1.8 mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A4 (10.5 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 실시예 2 화합물의 녹색 결정 분말을 얻었다 (수율 92%). A mixture of dipyridyl donor D1 compound (1.8 mg, 0.01 mmol) and ruthenium triflate receptor A4 (10.5 mg, 0.01 mmol) was dissolved in CH 3 NO 2 -CH 3 OH solution (1: 1, 2.0 mL) and 10 Stir at room temperature for hours. Diethyl ether was added dropwise to give a green crystalline powder of Example 2 compound (yield 92%).
C104H88F12N4O20Ru4S4: C, 50.48; H, 3.58; N, 2.26. Found: C, 50.52; H, 3.45; N, 2.31.C 104 H 88 F 12 N 4 O 20 Ru 4 S 4 : C, 50.48; H, 3.58; N, 2.26. Found: C, 50.52; H, 3.45; N, 2.31.
1H NMR [300 MHz, (CD3)2CO]: δ (ppm) 9.01 (s, 4H, H4), 8.87 (m, 8H, Hnd), 8.63 (d, J = 6.0 Hz, 4H, H1), 7.93 (m, 12H, Hnd, H3), 7.36 (m, 4H, H2), 6.25 (d, J = 6.3 Hz, 8H, Hcym), 6.01 (d, J = 6.3 Hz, 8H, Hcym), 3.08 (sept, 4H, CH(CH3)2), 2.18 (s, 12H, CH3), 1.32 (d, J = 6.9 Hz, 24H,CH(CH3)2) (도 2e 참조). 1 H NMR [300 MHz, (CD 3 ) 2 CO]: δ (ppm) 9.01 (s, 4H, H 4 ), 8.87 (m, 8H, Hnd), 8.63 (d, J = 6.0 Hz, 4H, H 1 ), 7.93 (m, 12H, Hnd, H 3 ), 7.36 (m, 4H, H 2 ), 6.25 (d, J = 6.3 Hz, 8H, Hcym), 6.01 (d, J = 6.3 Hz, 8H, Hcym), 3.08 (sept, 4H, CH (CH 3 ) 2 ), 2.18 (s, 12H, CH 3 ), 1.32 (d, J = 6.9 Hz, 24H, CH (CH 3 ) 2 ) (see FIG. 2E) .
13C NMR[75 MHz, (CD3)2CO]: δ (ppm) 170.1, 155.6, 152.3, 143.2, 134.7, 134.1, 128.5, 126.5, 122.1, 107.8, 103.9, 101.9, 89.6, 86.0, 82.5, 31.7, 22.7, 17.9 13 C NMR [75 MHz, (CD 3 ) 2 CO]: δ (ppm) 170.1, 155.6, 152.3, 143.2, 134.7, 134.1, 128.5, 126.5, 122.1, 107.8, 103.9, 101.9, 89.6, 86.0, 82.5, 31.7 , 22.7, 17.9
MS (ESI) (C104H88F12N4O20Ru4S4): 2326.1 [M - OTf ]+.
MS (ESI) (C 104 H 88 F 12 N 4 O 20 Ru 4 S 4 ): 2326.1 [M-OTf] + .
<< 비교예Comparative Example 3> A1 + 3> A1 + D2D2 화합물 제조 Compound manufacturing
디피리딜 공여체인 D2 화합물 (2.0 mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A1 (8.6 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 비교예 3 화합물의 황갈색 결정 분말을 얻었다 (수율 84%). A mixture of dipyridyl donor D2 compound (2.0 mg, 0.01 mmol) and ruthenium triflate receptor A1 (8.6 mg, 0.01 mmol) was dissolved in CH 3 NO 2 -CH 3 OH solution (1: 1, 2.0 mL) and 10 Stir at room temperature for hours. After adding diethyl ether dropwise, yellowish brown crystalline powder of the compound of Comparative Example 3 was obtained (yield 84%).
C76H72F12N4O20Ru4S4·2H2O: C, 42.30; H, 3.55; N, 2.60. Found: C, 41.88; H, 3.45; N, 2.39C 76 H 72 F 12 N 4 O 20 Ru 4 S 4 2H 2 O: C, 42.30; H, 3.55; N, 2.60. Found: C, 41.88; H, 3.45; N, 2.39
1H NMR [300 MHz, (CD3)2CO]: δ (ppm) 8.38 (m, 4H, H4), 8.17 (m, 4H, H1), 8.12 (m, 4H, H3), 7.52 (m, 4H, H2), 6.13 (m, 8H, Hcym), 5.99 (d, J = 6.0 Hz, 8H, Hcym), 2.96 (sept, 4H, CH(CH3)2), 2.31 (s, 12H, CH3), 1.38 (d, J = 6.0 Hz, 24H,CH(CH3)2) 1 H NMR [300 MHz, (CD 3 ) 2 CO]: δ (ppm) 8.38 (m, 4H, H 4 ), 8.17 (m, 4H, H 1 ), 8.12 (m, 4H, H 3 ), 7.52 (m, 4H, H 2 ), 6.13 (m, 8H, Hcym), 5.99 (d, J = 6.0 Hz, 8H, Hcym), 2.96 (sept, 4H, CH (CH 3 ) 2 ), 2.31 (s, 12H, CH 3 ), 1.38 (d, J = 6.0 Hz, 24H, CH (CH 3 ) 2 )
13C NMR[75 MHz, (CD3)2CO]: δ (ppm) 170.9, 155.1, 152.7, 143.3, 126.6, 120.4, 102.6, 82.1, 78.0, 31.0, 21.5, 17.1 13 C NMR [75 MHz, (CD 3 ) 2 CO]: δ (ppm) 170.9, 155.1, 152.7, 143.3, 126.6, 120.4, 102.6, 82.1, 78.0, 31.0, 21.5, 17.1
MS (ESI) (C76H72F12N4O20Ru4S4): 911.9 [M - 2OTf]2+, 558.4 [M - 3OTf]3+ MS (ESI) (C 76 H 72 F 12 N 4 O 20 Ru 4 S 4 ): 911.9 [M-2OTf] 2+ , 558.4 [M-3OTf] 3+
상기 비교예 3의 화합물의 X-선 회절 분석 결과를 이하의 표 1에 나타내었다. 표 1을 참조하면, 비교예 3의 화합물은 결정학적 반전 중심을 가진 4각 고리 구조를 가지고 있는 것을 알 수 있었다. 상기 비교예 3의 화합물의 단결정에 대해 X-선 결정구조는 도 3에 나타내었으며(초록색: 루테늄, 빨간색: 산소, 파란색: 질소 및 회색: 탄소), 결합 길이 및 결합각은 표 2에 나타내었다.X-ray diffraction analysis of the compound of Comparative Example 3 is shown in Table 1 below. Referring to Table 1, it was found that the compound of Comparative Example 3 has a tetragonal ring structure having a crystallographic inversion center. X-ray crystal structure of the single crystal of the compound of Comparative Example 3 is shown in Figure 3 (green: ruthenium, red: oxygen, blue: nitrogen and gray: carbon), bond length and bond angle are shown in Table 2 .
각각의 루비듐 센터는 p-cymene 리간드에 캡쳐되어 세 다리 피아노-스툴 형태를 취하고 있었다. 테트라덴테이트 디카볼실레이트 리간드는 두 루비듐을 연결하고 있었고, 마지막 루비듐 결합위치는 두 디루테늄 모이티를 연결하는 피리딜 리간드와 연결되어 있었다. 피리딘 고리는 다른 고리와 28.9° 의 각을 이루며 꼬여있었다. 평균 Ru-N 및 Ru-O 결합 거리는 각각 2.13 및 2.10 A로 나타났다. 수산화된 오각고리 킬레이트 고리의 두 산소 원자간의 평균 bite angle 은 80.9° 였다.
Each rubidium center was captured in a p-cymene ligand and took the form of a three-legged piano-stool. The tetradentate dicarbosilate ligand was linked to two rubidium and the last rubidium binding site was linked to a pyridyl ligand connecting two diruthenium moieties. The pyridine ring was twisted at an angle of 28.9 ° with the other ring. The average Ru-N and Ru-O bond distances were 2.13 and 2.10 A, respectively. The average bite angle between the two oxygen atoms in the hydroxylated pentacyclic chelate ring was 80.9 °.
<< 비교예Comparative Example 4> A2 + 4> A2 + D2D2 화합물 제조 Compound manufacturing
디피리딜 공여체인 D2 화합물 (2.0 mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A2 (9.1 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 비교예 4 화합물의 적색 결정 분말을 얻었다 (수율 89%). A mixture of dipyridyl donor D2 compound (2.0 mg, 0.01 mmol) and ruthenium triflate receptor A2 (9.1 mg, 0.01 mmol) was dissolved in CH 3 NO 2 -CH 3 OH solution (1: 1, 2.0 mL) and 10 Stir at room temperature for hours. Diethyl ether was added dropwise to give red crystalline powder of the compound of Comparative Example 4 (yield 89%).
C84H76F12N4O20Ru4S4: C, 45.40; H, 3.45; N, 2.52. Found: C, 45.13; H, 3.68; N, 2.71C 84 H 76 F 12 N 4 O 20 Ru 4 S 4 : C, 45.40; H, 3.45; N, 2.52. Found: C, 45.13; H, 3.68; N, 2.71
1H NMR [300 MHz, (CD3)2CO]: δ (ppm) 8.58 (s, 4H, H-4), 8.32 (m, 4H, H1), 8.26 (m, 4H, H3), 7.63 (m, 4H, H2), 6.27 (d, J = 6.0 Hz, 8H, Hcym), 6.07 (d, J = 6.3 Hz, 8H, Hcym), 5.78 (s, 4H, Hbq), 3.04 (sept, 4H, CH(CH3)2), 2.30 (s, 12H, CH3), 1.40 (d, J = 6.9 Hz, 24H, CH(CH3)2) 1 H NMR [300 MHz, (CD 3 ) 2 CO]: δ (ppm) 8.58 (s, 4H, H- 4 ), 8.32 (m, 4H, H 1 ), 8.26 (m, 4H, H 3 ), 7.63 (m, 4H, H 2 ), 6.27 (d, J = 6.0 Hz, 8H, Hcym), 6.07 (d, J = 6.3 Hz, 8H, Hcym), 5.78 (s, 4H, Hbq), 3.04 (sept , 4H, CH (CH 3 ) 2 ), 2.30 (s, 12H, CH 3 ), 1.40 (d, J = 6.9 Hz, 24H, CH (CH 3 ) 2 )
13C NMR[75 MHz, (CD3)2CO]: δ (ppm) 184.7, 157.0, 154.3, 143.7, 127.4, 121.2, 104.9, 102.7, 100.1, 84.6, 83.0, 78.6, 78.4, 32.2, 22.6, 18.3 13 C NMR [75 MHz, (CD 3 ) 2 CO]: δ (ppm) 184.7, 157.0, 154.3, 143.7, 127.4, 121.2, 104.9, 102.7, 100.1, 84.6, 83.0, 78.6, 78.4, 32.2, 22.6, 18.3
MS (ESI) (C84H76F12N4O20Ru4S4): 2072.4 [M - OTf]+, 592.0 [M - 3OTf]3+
MS (ESI) (C 84 H 76 F 12 N 4 O 20 Ru 4 S 4 ): 2072.4 [M-OTf] + , 592.0 [M-3OTf] 3+
<< 실시예Example 3> A3 + 3> A3 + D2D2 화합물 제조 Compound manufacturing
디피리딜 공여체인 D2 화합물 (2.0 mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A3 (9.6 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 실시예 3 화합물의 녹색 고체 분말을 얻었다 (수율 90%). A mixture of dipyridyl donor D2 compound (2.0 mg, 0.01 mmol) and ruthenium triflate receptor A3 (9.6 mg, 0.01 mmol) was dissolved in CH 3 NO 2 -CH 3 OH solution (1: 1, 2.0 mL) and 10 Stir at room temperature for hours. Diethyl ether was added dropwise to give a green solid powder of the compound of Example 3 (yield 90%).
C92H80F12N4O20Ru4S4·2H2O: C, 46.86; H, 3.59; N, 2.38. Found: C, 46.63; H, 3.72; N, 2.04.C 92 H 80 F 12 N 4 O 20 Ru 4 S 4 2H 2 O: C, 46.86; H, 3.59; N, 2.38. Found: C, 46.63; H, 3.72; N, 2.04.
1H NMR [300 MHz, (CD3)2CO]: δ (ppm) 8.72 (s, 4H, H4), 8.63 (m, 4H, H1), 8.12 (m, 4H, H3), 7.59 (m, 4H, H2), 7.25 (s, 4H, Hnq), 6.04 (d, J = 6.3 Hz, 8H, Hcym), 5.86 (d, J = 6.3 Hz, 8H, Hcym), 3.00 (sept, 4H, CH(CH3)2), 2.24 (s, 12H, CH3), 1.40 (d, J = 6.9 Hz, 24H,CH(CH3)2) 1 H NMR [300 MHz, (CD 3 ) 2 CO]: δ (ppm) 8.72 (s, 4H, H 4 ), 8.63 (m, 4H, H 1 ), 8.12 (m, 4H, H 3 ), 7.59 (m, 4H, H 2 ), 7.25 (s, 4H, Hnq), 6.04 (d, J = 6.3 Hz, 8H, Hcym), 5.86 (d, J = 6.3 Hz, 8H, Hcym), 3.00 (sept, 4H, CH (CH 3 ) 2 ), 2.24 (s, 12H, CH 3 ), 1.40 (d, J = 6.9 Hz, 24H, CH (CH 3 ) 2 )
13C NMR[75 MHz, (CD3)2CO]: δ (ppm) 172.0, 155.9, 153.7, 143.6, 138.6, 127.0, 121.0, 112.4, 104.7, 100.7, 85.1, 84.1, 78.7, 77.9, 31.6, 22.5, 17.4 13 C NMR [75 MHz, (CD 3 ) 2 CO]: δ (ppm) 172.0, 155.9, 153.7, 143.6, 138.6, 127.0, 121.0, 112.4, 104.7, 100.7, 85.1, 84.1, 78.7, 77.9, 31.6, 22.5 , 17.4
MS (ESI) (C92H80F12N4O20Ru4S4): 625.1 [M - 3OTf]3+
MS (ESI) (C 92 H 80 F 12 N 4 O 20 Ru 4 S 4 ): 625.1 [M-3OTf] 3+
<< 실시예Example 4> A4 + 4> A4 + D2D2 화합물 제조 Compound manufacturing
디피리딜 공여체인 D2 화합물 (2.0 mg, 0.01 mmol) 및 루테늄 트리플레이트 수용체 A4 (10.5 mg, 0.01 mmol) 혼합물을 CH3NO2-CH3OH 용액 (1:1, 2.0 mL)에 용해하고 10시간 동안 상온에서 교반하였다. 디에틸 에테르를 적가한 후 실시예 4 화합물의 녹색 고체 분말을 얻었다 (수율 90%). A mixture of dipyridyl donor D2 compound (2.0 mg, 0.01 mmol) and ruthenium triflate receptor A4 (10.5 mg, 0.01 mmol) was dissolved in CH 3 NO 2 -CH 3 OH solution (1: 1, 2.0 mL) and 10 Stir at room temperature for hours. Diethyl ether was added dropwise to give a green solid powder of the compound of Example 4 (yield 90%).
C108H88F12N4O20Ru4S4: C, 51.43; H, 3.52; N, 2.22. Found: C, 51.73; H, 3.81; N, 2.39C 108 H 88 F 12 N 4 O 20 Ru 4 S 4 : C, 51.43; H, 3.52; N, 2.22. Found: C, 51.73; H, 3.81; N, 2.39
1H NMR [300 MHz, (CD3)2CO]: δ (ppm) 8.90 (m, 8H, Hnd), 8.70 (m, 8H, H1, H4), 8.10 (m, 8H, Hnd), 7.75 (m, 4H, H3), 7.33 (m, 4H, H2), 6.25 (d, J = 6.3 Hz, 8H, Hcym), 6.02 (d, J = 6.0 Hz, 8H, Hcym), 3.14 (sept, 4H, CH(CH3)2), 2.25 (s, 12H, CH-3), 1.39 (d, J = 6.9 Hz, 24H,CH(CH3)2) 1 H NMR [300 MHz, (CD 3 ) 2 CO]: δ (ppm) 8.90 (m, 8H, Hnd), 8.70 (m, 8H, H 1 , H 4 ), 8.10 (m, 8H, Hnd), 7.75 (m, 4H, H 3 ), 7.33 (m, 4H, H 2 ), 6.25 (d, J = 6.3 Hz, 8H, Hcym), 6.02 (d, J = 6.0 Hz, 8H, Hcym), 3.14 (sept , 4H, CH (CH 3 ) 2 ), 2.25 (s, 12H, CH- 3 ), 1.39 (d, J = 6.9 Hz, 24H, CH (CH 3 ) 2 )
13C NMR[75 MHz, (CD3)2CO]: δ (ppm) 170.1, 155.4, 153.2, 143.2, 134.7, 134.1, 128.3, 126.8, 120.6, 107.8, 104.6, 100.9, 85.1, 83.3, 78.2, 31.5, 22.6, 17.8 13 C NMR [75 MHz, (CD 3 ) 2 CO]: δ (ppm) 170.1, 155.4, 153.2, 143.2, 134.7, 134.1, 128.3, 126.8, 120.6, 107.8, 104.6, 100.9, 85.1, 83.3, 78.2, 31.5 , 22.6, 17.8
MS (ESI) (C108H88F12N4O20Ru4S4): 1111.8 [M - 2OTf]2+, 692.0 [M - 3OTf]3+.
MS (ESI) (C 108 H 88 F 12 N 4 O 20 Ru 4 S 4 ): 1111.8 [M-2OTf] 2+ , 692.0 [M-3OTf] 3+ .
<< 실험예Experimental Example 1> 1> UVUV -- VisVis 스펙트럼 분석 Spectrum analysis
비교예 1 내지 4, 실시예 1 내지 4 화합물의 UV-vis 스펙트럼이 메탄올 용액에서 측정되었고, 흡수 밴드를 표 3에 나타내었고, 각 화합물 및 D1, D2, A1, A2, A3 A4에 대한 UV-vis 스펙트럼을 도 4에 나타내었다. UV-vis spectra of the compounds of Comparative Examples 1 to 4 and Examples 1 to 4 were measured in methanol solution, the absorption bands are shown in Table 3, and UV- for each compound and D1, D2, A1, A2, A3 A4. The vis spectrum is shown in FIG. 4.
표 3 및 도 4를 참조하면, 모든 사각 화합물에서 관측되는 높은 에너지 밴드는 D1 및 D2 화합물에서도 관측됨을 알 수 있었다. 상기 밴드는 자가조립 과정에서 유지되는 ethynyl 백본의 π→π* 전이에 기인한 것으로 판단된다. 이핵 아렌-Ru 수용체는 또한 270-298nm 에서 높은 에너지 흡수 밴드를 보였으며, 또한 380-680 nm에서 넓고 낮은 에너지 흡수 밴드를 보였다. 상기 흡수밴드는 금속-리간드간 전하 이동 전이와 혼합된 분자내/분자간 π→π* 전이의 조합에 기인한 것으로 판단된다. 피리딜 공여체의 밴드와 함께, 이러한 아렌-Ru에 기초한 밴드는 자가 조립 후에도 관측되었으며, 이는 비교예 1 내지 4, 실시예 1 내지 4 화합물의 복잡한 흡수 매니폴드(manifolds)로 나타났다. Referring to Table 3 and Figure 4, it can be seen that the high energy bands observed in all the square compounds are also observed in the D1 and D2 compounds. The band is believed to be due to the π → π * transition of the ethynyl backbone maintained during self-assembly. The dinuclear arene-Ru receptor also showed high energy absorption bands at 270-298 nm and also wide and low energy absorption bands at 380-680 nm. The absorption band is believed to be due to the combination of intermetallic / molecular π → π * transitions mixed with the metal-ligand charge transfer transition. Together with the bands of the pyridyl donors, these arene-Ru based bands were observed even after self assembly, which resulted in complex absorption manifolds of the compounds of Comparative Examples 1-4, Examples 1-4.
사각 화합물 및 이의 전구체의 방출 데이터가 도 5 및 도 6에 요약되어 있다. D1의 스펙트럼(λex = 289 nm)은 371 nm에서 넓은 밴드를 보여준다. 유사한 밴드가 D2에서도 관측되었고, 그러나 D1 에 비해 확장된 π 시스템으로 인해 보다 긴 파장을 보인다. 이러한 넓은 피크는 360, 387 및 416 nm 로 특징지어진다. A1 및 A2 수용체는 411nm 부근에서 유사한 흡수 밴드를 보인다. Release data of the square compound and its precursors are summarized in FIGS. 5 and 6. The spectrum of D1 (λ ex = 289 nm) shows a wide band at 371 nm. Similar bands were observed in D2, but with longer wavelengths due to the extended π system compared to D1. These broad peaks are characterized by 360, 387 and 416 nm. The A1 and A2 receptors show similar absorption bands around 411 nm.
그러나, 도 6을 참조하면, A3 및 A4의 스펙트럼은 다르게 나타나는데, A3는 350nm 부근에서 단일 밴드를 보이는 반면, A4는 530 및 560 nm 에서 두 밴드를 보인다. However, referring to FIG. 6, the spectra of A3 and A4 appear differently, where A3 shows a single band around 350 nm, while A4 shows two bands at 530 and 560 nm.
사각 화합물인 비교예 1 및 비교예 3의 화합물은 각각 381 및 362nm에서 방출 밴드를 보인다(도 5의 A참조). 이러한 방출 밴드는 이와 유사한 방출 피크를 보이는 D1 및 D2에서 기인한 것으로 판단된다. 흥미롭게도, 비교예 1의 화합물은 미세하게 적색 편이되며 공여체 화합물과 유사한 방출 강도를 보였으나, 비교예 3의 화합물은 D2에 비해 소광된 강도를 보였다. 비교예 2 및 비교예 4의 화합물은 335 및 352nm(비교예 2) 및 335 및 345nm(비교예 4)에서 방출 밴드를 보였으며, 이는 D1 및 D2의 밴드보다 청색 편이된 파장에 해당한다(도 5의 B 참조). Compounds of Comparative Example 1 and Comparative Example 3, which are a square compound, exhibit emission bands at 381 and 362 nm, respectively (see FIG. 5A). This emission band is believed to be due to D1 and D2 showing similar emission peaks. Interestingly, the compound of Comparative Example 1 was slightly reddish and showed similar emission intensity as the donor compound, but the compound of Comparative Example 3 exhibited quenched strength compared to D2. The compounds of Comparative Examples 2 and 4 showed emission bands at 335 and 352 nm (Comparative Example 2) and 335 and 345 nm (Comparative Example 4), corresponding to wavelengths shifted blue than the bands of D1 and D2 (FIG. 5, see B).
또한 사각 화합물인 실시예 1 및 실시예 3의 화합물의 방출 밴드(λex = 330 nm)는 368, 399 및 432 nm(실시예 1) 및 368 및 399nm(실시예 3) 에서 나타났다(도 6의 A참조). 실시예 2 및 실시예 4의 화합물은 각각 527 및 560nm에서 방출 피크를 보였고, 이는 A4의 방출 강도보다 강하게 나타났다(도 6의 B 참조). 실시예 1, 2, 3, 4 의 화합물은 이들에 대응하는 아렌-Ru 전구체에 따라 모두 유사한 방출 특성을 공유하였고, 이에 따라 아렌-Ru 수용체가 방출 밴드의 주요하게 기여함을 알 수 있었다. 실시예 1, 2 및 비교예 1, 2 화합물은 실시예 3, 4 및 비교예 3, 4 화합물에 비해 보다 강한 밴드를 보였는데, 이는 실시예 3, 4 및 비교예 3, 4 화합물에서의 디에티닐디피리딜(diethynyldipyridyl) 리간드의 강한 컨쥬게이션이 자기-소광 효과를 촉진하고, 인접한 금속 사각 화합물의 분자간 π-π 스태킹(stacking)을 촉진하기 때문으로 판단된다.
In addition, the emission bands (λ ex = 330 nm) of the compounds of Examples 1 and 3, which are quadrangular compounds, were shown at 368, 399 and 432 nm (Example 1) and 368 and 399 nm (Example 3). A). The compounds of Examples 2 and 4 showed emission peaks at 527 and 560 nm, respectively, which were stronger than the emission intensity of A4 (see FIG. 6B). The compounds of Examples 1, 2, 3, and 4 all shared similar emission characteristics according to their corresponding arene-Ru precursors, and thus it was found that the arene-Ru receptors contributed mainly to the release band. Examples 1 and 2 and Comparative Examples 1 and 2 showed stronger bands compared to Examples 3 and 4 and Comparative Examples 3 and 4, which resulted in dies in Examples 3 and 4 and Comparative Examples 3 and 4 It is believed that the strong conjugation of the diethynyldipyridyl ligand promotes self-quenching effect and promotes intermolecular π-π stacking of adjacent metal square compounds.
<< 실험예Experimental Example 2> 암 세포 성장 저해 분석( 2> cancer cell growth inhibition assay ( MTTMTT 분석) analysis)
본 발명의 화합물 및 D1, D2 화합물의 SK-hep-1(간암) 및 HCT-15(직장암) 세포에 대한 성장 저해 분석 실험을 수행하였다.Growth inhibition assays for SK-hep-1 (liver cancer) and HCT-15 (rectal cancer) cells of the compounds of the invention and D1, D2 compounds were performed.
보다 구체적으로, 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. 실시예 1 내지 4, 비교예 1 내지 4의 화합물 처리, D1, D2 의 화합물 처리, 종래 항암제로 사용되는 시스플라틴(cisplatin) 및 독소루비신(doxorubicin)을 각각 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.More specifically, cancer cells were cultured at 37 ° C. and 5% CO 2 in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% heat inactivated fetal bovine serum (FBS) and 1% penicillin streptomycin. 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. 10 μL of MTT solution was added to each well after treatment of the compounds of Examples 1 to 4, the compounds of Comparative Examples 1 to 4, the treatment of the compounds of D1 and D2, cisplatin and doxorubicin, which are conventionally used as anticancer agents. It was. 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.
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.IC 50 values for cell growth inhibition were determined by fitting a plot of the log percentage of surviving cells to the log of drug concentration using a linear regression function.
결과를 표 4 및 도 7에 나타내었다.The results are shown in Table 4 and FIG.
표 4를 참조하면, D1, D2 및 비교예 1, 2 화합물은 항암 활성이 없는 것으로 나타났다 (IC50 > 200 μM). 또한 비교예 3 및 4 화합물은 IC50 값이 50 내지 70 μM 로 매우 낮은 항암 활성을 보였다. 실시예 1 (IC50 = 6.97 및 7.46 μM), 실시예 2 (IC50 = 29.53 및 39.45 μM), 실시예 3 (IC50 = 9.60 및 10.66 μM), 실시예 4 (IC50 = 16.32 및 17.68 μM) 화합물은 모두 시스플라틴 및 독소루비신과 유사한 우수한 항암 활성을 보였다(도 7 참조). 따라서 본 발명의 화합물은 직장암 및 간암에서 기존의 시스플라틴을 대체할 수 있는 우수한 항암제로 사용될 수 있을 것으로 판단된다. 또한 세포 사멸 과정에서, 시스플라틴은 G2-phase에서의 세포 성장을 억제하는 반면, 아렌-루테늄 기초한 금속 화합물은 G1 phase 에서의 세포 성장을 억제하는 바, 본 발명의 화합물은 시스플라틴과 별도로 암세포 증식을 막아 암의 치료에 유용하게 사용될 수 있을 것으로 판단된다.
Referring to Table 4, D1, D2 and Comparative Examples 1 and 2 compounds were found to have no anticancer activity (IC 50 > 200 μM). In addition, Comparative Examples 3 and 4 compound is IC 50 Values of 50 to 70 μM showed very low anticancer activity. Examples 1 (IC50 = 6.97 and 7.46 μM), Example 2 (IC50 = 29.53 and 39.45 μM), Example 3 (IC50 = 9.60 and 10.66 μM), Example 4 (IC50 = 16.32 and 17.68 μM) It showed good anticancer activity similar to cisplatin and doxorubicin (see FIG. 7). 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. In addition, in the process of cell death, cisplatin inhibits cell growth in the G2-phase, whereas the aren-ruthenium-based metal compound inhibits cell growth in the G1 phase. The compound of the present invention prevents cancer cell proliferation separately from cisplatin. It is considered that it can be usefully used for the treatment of cancer.
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 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.
<< 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.
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 (7)
[화학식 1]
상기 화학식 1에서,
[화학식 2-1]
또는
[화학식 2-2]
이고,
상기 화학식 2-1 또는 화학식 2-2에서 A는 각각 독립적으로 OTf(trifluoromethylsulfonate)이며,
[화학식 3]
또는
[화학식 4]
이고,
상기 화학식 2-1 또는 화학식 2-2의 루테늄과 화학식 3 또는 화학식 4의 방향족 고리 내의 질소원자가 결합하여 화학식 1의 화합물을 형성함.
A quaternary arene-ruthenium compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
In Formula 1,
[Formula 2-1]
or
[Formula 2-2]
ego,
In Formula 2-1 or Formula 2-2, A is independently OTf (trifluoromethylsulfonate),
(3)
or
[Chemical Formula 4]
ego,
The ruthenium of Formula 2-1 or Formula 2-2 and the nitrogen atom in the aromatic ring of Formula 3 or Formula 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.
상기 4핵 아렌-루테늄 화합물 또는 이의 약학적으로 허용가능한 염은 암 세포의 세포사멸을 통하여 항암활성을 나타내는 것인 암의 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 that exhibits anticancer activity through apoptosis of cancer cells.
상기 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 포함하는 것인 암의 예방 또는 치료용 약학 조성물.
3. 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:
상기 암의 예방 또는 치료용 약학 조성물의 제형은 과립제, 산제, 피복정, 정제, 환제, 캡슐제, 좌제, 겔, 시럽, 즙, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택되는 것을 특징으로 하는 암의 예방 또는 치료용 약학 조성물.
3. 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.
상기 암은 고형암인 것인 암의 예방 또는 치료용 약학 조성물.
6. The method according to any one of claims 2 to 5,
Wherein said cancer is a solid cancer.
상기 고형암은 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강/부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 구강암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 직장암, 항문암, 방광암, 신장암, 남성생식기종양, 음경암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암 또는 피부암인 것인 암의 예방 또는 치료용 약학 조성물.
The method according to claim 6,
The solid tumor may be selected from the group consisting of brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial lesion, ependymoma, brain tumor, head and neck tumor, laryngeal cancer, Cancer, breast cancer, breast cancer, gastric cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small bowel cancer, pancreatic cancer, breast cancer, pancreatic cancer, cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non- Ovarian cancer, uterine sarcoma, vaginal cancer, female germ cell cancer, female urethral cancer, colon cancer, colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, Or skin cancer. ≪ / RTI >
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