KR101065865B1 - Method preparing complex compounds by the reaction of ge-132 with titanocene - Google Patents
Method preparing complex compounds by the reaction of ge-132 with titanocene Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 44
- KOMDZQSPRDYARS-UHFFFAOYSA-N cyclopenta-1,3-diene titanium Chemical compound [Ti].C1C=CC=C1.C1C=CC=C1 KOMDZQSPRDYARS-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 title description 9
- -1 germanium-titanocene Chemical compound 0.000 claims abstract description 38
- PKCYYRXPGMHIPO-UHFFFAOYSA-N 4-[[3-carboxypropyl(oxo)germyl]oxy-oxogermyl]butanoic acid Chemical compound OC(=O)CCC[Ge](=O)O[Ge](=O)CCCC(O)=O PKCYYRXPGMHIPO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002131 composite material Substances 0.000 claims abstract description 18
- 229910052732 germanium Inorganic materials 0.000 claims abstract description 8
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000002291 germanium compounds Chemical class 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- VEYLRWJOBBCNNK-UHFFFAOYSA-J germanium(4+) 2-hydroxypropane-1,2,3-tricarboxylate 2-hydroxypropanoate Chemical compound C(C(O)C)(=O)[O-].C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].[Ge+4] VEYLRWJOBBCNNK-UHFFFAOYSA-J 0.000 claims 1
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- 231100000957 no side effect Toxicity 0.000 abstract description 3
- 238000001243 protein synthesis Methods 0.000 abstract description 3
- 229960000074 biopharmaceutical Drugs 0.000 abstract description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 4
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- 238000002329 infrared spectrum Methods 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
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- 0 *NN[N+]([O-])OI(C1C=CC=C1)[I+](O[N+](NN*(ON=O)=O)[O-])IIC1C=CC=C1 Chemical compound *NN[N+]([O-])OI(C1C=CC=C1)[I+](O[N+](NN*(ON=O)=O)[O-])IIC1C=CC=C1 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- HVYWZJASVLEHGV-UHFFFAOYSA-N hydroxy(oxo)germane 2-hydroxypropane-1,2,3-tricarboxylic acid 2-hydroxypropanoic acid Chemical compound O[GeH]=O.CC(O)C(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O HVYWZJASVLEHGV-UHFFFAOYSA-N 0.000 description 1
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/30—Germanium compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/28—Titanium compounds
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Abstract
본 발명은 유기 게르마늄-티타노센 복합 화합물 및 이의 제조방법에 관한 것으로, 보다 상세하게는 비스-카복시에틸게르마늄 세스퀴옥사이드 및 티타노센을 반응시켜 제조되는 유기 게르마늄-티타노센 복합 화합물 및 이의 제조방법으로, 상기 유기 게르마늄-티타노센 복합 화합물은 종래의 합성약품에서는 찾아볼 수 없는 생리활성을 갖는 무독성의 유기 게르마늄을 이용함으로써 부작용이 없으며, 또한 정상세포보다 높은 단백질 합성능력을 나타내는 암세포에 대하여 선택적 독성을 갖는 항암제에 적용할 수 있어 생물의약 산업에 크게 기여할 것이다.The present invention relates to an organic germanium-titanocene composite compound and a method for preparing the same, and more particularly, to an organic germanium-titanocene composite compound prepared by reacting bis-carboxyethyl germanium sesquioxide and titanocene and a method for preparing the same. , The organic germanium-titanocene complex compound has no side effects by using a non-toxic organic germanium having a physiological activity not found in conventional synthetic drugs, and also has a selective toxicity to cancer cells showing higher protein synthesis capacity than normal cells It can be applied to anticancer drugs having a great contribution to the biopharmaceutical industry.
Description
본 발명은 유기 게르마늄-티타노센 복합 화합물 및 이의 제조방법에 관한 것으로, 보다 상세하게는 비스-카복시에틸게르마늄 세스퀴옥사이드 및 티타노센을 반응시켜 제조되는 유기 게르마늄-티타노센 복합 화합물 및 이의 제조방법에 관한 것이다.The present invention relates to an organic germanium-titanocene composite compound and a method for preparing the same, and more particularly to an organic germanium-titanocene composite compound prepared by reacting bis-carboxyethyl germanium sesquioxide and titanocene and a method for preparing the same. It is about.
노년인구의 증가와 환경악화로 인하여 세계 암발생률은 매년 5% 이상 증가하고 있고 1997년 통계에 의하면 암으로 사망한 사람이 600만 명으로 전세계 사망률의 12%에 달하고 있는 것으로 조사되고 있다.The global cancer incidence is increasing by more than 5% every year due to the increase in elderly population and environmental degradation. According to the 1997 statistics, 6 million people died of cancer, accounting for 12% of the global mortality rate.
대한민국의 경우에도, 통계에 의하면 매년 10만명 정도의 암환자가 새롭게 발생하고 5만 여명이 사망하며, 1997년 암환자는 12만 명으로서 남자는 위암(21%), 간암(12%), 폐암(11%)의 순서로, 여자는 자궁경부암(20%), 위암(16%), 유방암(13%)의 순서로 암환자가 발생하였고 매년 암환자 증가율이 10% 정도에 이르는 것으로 보고되고 있다.In South Korea, statistics show that 100,000 new cancer cases and 50,000 deaths occur each year. In 1997, 120,000 cancer patients were diagnosed with gastric cancer (21%), liver cancer (12%), and lung cancer (11). In women, cervical cancer (20%), gastric cancer (16%), and breast cancer (13%) occurred in the order of cancer patients.
현대의학의 대표적 암 치료법으로는 외과적 수술요법, 화학요법, 생물학적 요법 및 방사선요법 등을 들 수 있으며, 이들을 단독 혹은 병용으로 치료에 응용하고 있으나 아직 완벽한 치료법이 없는 상태이다. 따라서 암은 21세기 인간의 수명 연장을 위해 극복해야 할 최우선 과제의 하나로 인식되고 있다.Representative cancer treatments of modern medicine include surgical surgery, chemotherapy, biological therapy and radiotherapy, and these are applied alone or in combination, but there is no perfect treatment. Therefore, cancer is recognized as one of the top tasks to overcome in order to extend the life span of humans in the 21st century.
항암제란 암세포의 각종 대사경로에 작용하여 암세포에 대하여 세포독성(cytotoxicity)이나 성장억제효과(cytostatic effects)를 나타내는 약제를 총칭하는 것으로서, 지금까지 개발된 항암제는 그 작용기전과 화학구조에 따라 대사길항제, 식물성 알칼로이드, 국소이성질화효소 억제제(topoisomerase inhibitor), 알킬화제, 항암성 항생물질, 호르몬제, 기타 약제로 분류된다.An anticancer agent is a generic term for drugs that act on various metabolic pathways of cancer cells and exhibit cytotoxicity or cytostatic effects on cancer cells. The anticancer agents developed so far are metabolic antagonists depending on their mechanism of action and chemical structure. , Plant alkaloids, topoisomerase inhibitors, alkylating agents, anticancer antibiotics, hormones, and other drugs.
항암제들은 약제에 따라 세포내 표적이 다양한데, 세포의 DNA복제, 전사, 번역과정을 차단하거나 세포생존에 중요한 단백질의 작용을 방해하며, 이러한 세포 내 표적에의 영향은 이후 괴사(necrosis)나 자사(apoptosis)의 과정을 통해 암세포를 사멸시키게 된다. 일반적으로 이러한 항암제가 작용하는 대사경로는 암세포에만 특이한 것이 아니고 정상세포에도 동일하기 때문에 항암제 투여시에는 정상조직의 손상(즉, 독성)도 피할 수 없다.Anticancer drugs vary in intracellular targets, depending on the drug, blocking the DNA replication, transcription, and translation processes of the cell or disrupting the action of proteins important for cell survival. The effects on these intracellular targets are then necrotic or internal Apoptosis kills cancer cells. In general, the metabolic pathways in which these anticancer drugs work are not specific to cancer cells and are also the same for normal cells. Thus, when the anticancer drug is administered, normal tissue damage (ie, toxicity) is inevitable.
그러나, 암세포와 정상세포의 대사 사이에는 의미 있는 양적인 차이가 존재하고 이런 차이에 근거하여 항암제는 암조직에 보다 큰 독성을 나타내게 되는 것임으로, 이와 같은 항암제의 선택적 독성(selective toxicity)을 이용함으로써 임상적으로 항암화학요법이 가능한 것이다. 따라서 정상조직의 독성은 피하면서 암세포를 없앨 수 있는 특이적 치료효과지수(therapeutic index)가 클수록 보다 안전한 항암제라고 할 수 있다.However, there is a significant quantitative difference between the metabolism of cancer cells and normal cells, and based on these differences, anticancer drugs are more toxic to cancer tissues. Thus, by utilizing the selective toxicity of such anticancer drugs, Chemotherapy is possible. Therefore, the greater the specific therapeutic index (therapeutic index) that can eliminate cancer cells while avoiding the toxicity of normal tissue, the safer the cancer drug.
이에 본 발명자들은 부작용이 없으며, 정상세포보다 높은 단백질 합성능력을 나타내는 암세포에 대하여 선택적 독성을 갖는 항암제의 개발을 위한 지속적인 연구를 수행하던 중 종래의 합성약품에서는 찾아볼 수 없는 생리활성을 갖는 무독성의 유기 게르마늄을 이용한 항암활성성분을 가지는 복합 화합물을 제조하고, 본 발명을 완성하였다.Accordingly, the present inventors have no side effects, and during the ongoing research for the development of anticancer drugs having selective toxicity against cancer cells showing higher protein synthesis ability than normal cells, the present inventors have no toxic activity which is not found in conventional synthetic drugs. A composite compound having an anticancer active ingredient using organic germanium was prepared, and the present invention was completed.
본 발명은 종래의 합성약품에서는 찾아볼 수 없는 생리활성을 갖는 무독성의 유기 게르마늄을 이용한 항암활성성분을 가지는 유기 게르마늄-티타노센 복합 화합물 및 이의 제조방법을 제공하기 위한 것이다.The present invention is to provide an organic germanium- titanocene complex compound having an anticancer active ingredient using non-toxic organic germanium having a physiological activity not found in conventional synthetic drugs and a method for producing the same.
본 발명은 비스-카복시에틸게르마늄 세스퀴옥사이드 및 티타노센을 반응시켜 제조되는 유기 게르마늄-티타노센 복합 화합물 및 이의 제조방법을 제공한다.The present invention provides an organic germanium-titanocene complex compound prepared by reacting bis-carboxyethyl germanium sesquioxide and titanocene and a method for preparing the same.
본 발명의 유기 게르마늄-티타노센 복합 화합물은 유기 게르마늄 화합물 및 티타노센이 1 : 0.1 내지 5의 중량비인 것을 특징으로 한다.The organic germanium-titanocene complex compound of the present invention is characterized in that the organic germanium compound and titanocene are in a weight ratio of 1: 0.1 to 5.
본 발명의 유기 게르마늄-티타노센 복합 화합물은 무 결정질의 하기 화학식 1로 표시되는 복합 화합물인 것을 특징으로 한다.The organic germanium-titanocene complex compound of the present invention is characterized in that it is a complex compound represented by the following formula (1) which is amorphous.
본 발명의 상기 유기 게르마늄 화합물은 하기 화학식 2로 표시되는 비스-카복시에틸게르마늄 세스퀴옥사이드인 것을 특징으로 한다.The organic germanium compound of the present invention is characterized in that the bis-carboxyethyl germanium sesquioxide represented by the following formula (2).
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 The present invention
1) 유기 게르마늄 화합물 용액을 준비하는 단계;1) preparing an organic germanium compound solution;
2) 티타노센 용액을 준비하는 단계; 및2) preparing a titanocene solution; And
3) 상기 2) 단계의 티타노센 용액에 상기 1) 단계의 유기 게르마늄 화합물 용액에 혼합하여 반응시키는 단계;3) mixing and reacting the titanocene solution of step 2) with the organic germanium compound solution of step 1);
를 포함하는, 상기 화학식 1로 표시되는 유기 게르마늄-티타노센 복합 화합물의 제조방법을 제공한다.It provides a method of producing an organic germanium- titanocene complex compound represented by the formula (1).
본 발명의 제조방법에 있어서, 상기 1) 단계의 유기 게르마늄 화합물 용액은 탄산나트륨 용액에 10 내지 40 중량%의 유기 게르마늄 화합물을 첨가하여 제조하는 것으로, 바람직하게는 15 내지 30 중량%를 포함한다.In the preparation method of the present invention, the organic germanium compound solution of step 1) is prepared by adding 10 to 40% by weight of the organic germanium compound to the sodium carbonate solution, preferably 15 to 30% by weight.
본 발명의 제조방법에 있어서, 상기 1) 단계의 상기 유기 게르마늄 화합물은 비스-카복시에틸게르마늄 세스퀴옥사이드, 스피로게르마늄 및 유산-구연산-게르마늄산 염 중에서 선택되는 어느 하나인 것을 특징으로 하며, 보다 바람직하게는 상기 화학식 2로 표시되는 비스-카복시에틸게르마늄 세스퀴옥사이드인 것을 특징으로 한다.In the production method of the present invention, the organic germanium compound of step 1) is characterized in that any one selected from bis- carboxyethyl germanium sesquioxide, spirogmanium and lactic acid-citric acid-germanic acid salt, more preferred It is characterized in that the bis- carboxyethyl germanium sesquioxide represented by the formula (2).
본 발명의 제조방법에 있어서, 상기 3) 단계는 테트라히드로푸란 100 중량부에 대하여, 유기 게르마늄 화합물 0.5 내지 10 중량부 및 티타노센 0.1 내지 5 중량부를 혼합하여 반응시키는 것을 특징으로 한다.In the preparation method of the present invention, the step 3) is characterized in that 0.5 to 10 parts by weight of the organic germanium compound and 0.1 to 5 parts by weight of titanocene are reacted with respect to 100 parts by weight of tetrahydrofuran.
보다 상세하게는 상기 테트라히드로푸란 용매는 티타노센을 용액화하기 위해 필요한 구성으로, 상기의 비율로 혼합되지 않을 경우에는 상기 화학식 1로 표시되는 유기 게르마늄-티타노센 복합 화합물이 제조되지 않을 뿐 아니라 유기 게르마늄 화합물 및 티타노센의 반응 시간이 길어지거나 반응이 일어나지 않는 문제점이 있다.More specifically, the tetrahydrofuran solvent is required to liquefy titanocene, and when not mixed in the above ratio, the organic germanium-titanocene complex compound represented by Chemical Formula 1 may not be prepared as well as organic. There is a problem that the reaction time of the germanium compound and titanocene becomes long or the reaction does not occur.
본 발명의 제조방법에 있어서, 상기 유기 게르마늄-티타노센 복합 화합물은 유기 게르마늄 화합물 및 티타노센이 1 : 0.1 내지 5의 중량비인 것을 특징으로 한다. 상기 유기 게르마늄 화합물 및 티타노센의 조성비는 종래의 합성약품에서는 찾아볼 수 없는 생리활성을 갖는 무독성의 유기 게르마늄을 이용한 항암활성성분을 가지는 복합 화합물을 제조하기 위한 본 발명의 목적에 아주 중요한 의미를 가진다.In the production method of the present invention, the organic germanium-titanocene complex compound is characterized in that the organic germanium compound and titanocene 1: 1 by weight of 0.1 to 5. The composition ratio of the organic germanium compound and titanocene has a very important meaning for the purpose of the present invention for preparing a complex compound having an anticancer active ingredient using a nontoxic organic germanium having a physiological activity not found in a conventional synthetic drug. .
본 발명의 제조방법에 있어서, 상기 3)단계의 유기 게르마늄 화합물과 티타노센의 반응은 7 내지 10일 동안 이루어질 수 있다.In the preparation method of the present invention, the reaction of the organic germanium compound and titanocene of step 3) may be performed for 7 to 10 days.
또한 상기 3)단계 후, 건조단계를 더 포함하며, 상기 건조는 크게 제한 받지 않으나, 80 내지 100 ℃에서 12 내지 24시간 건조할 수 있으며, 건조 후, 비활성 기체 분위기에서 밀폐하여 보관한다.In addition, after the step 3), further includes a drying step, the drying is not limited significantly, can be dried for 12 to 24 hours at 80 to 100 ℃, after drying, it is kept closed in an inert gas atmosphere.
본 발명에 따른 유기 게르마늄-티타노센 복합 화합물의 제조방법은 항암제로서 용도가 알려진 유기 게르마늄과 티타노센을 최적반응 조건과 반응인자 및 반응조를 통해 직접적으로 반응시켜 제조되는 것으로, 부산물의 최소화 및 고순도, 고수율의 복합 화합물을 효율적으로 제조할 수 있는 장점이 있다.The method for producing an organic germanium-titanocene complex compound according to the present invention is prepared by directly reacting organic germanium and titanocene, which are known for use as an anticancer agent, through optimum reaction conditions, reaction factors, and reactors, minimizing by-products and high purity, There is an advantage that can be efficiently produced a complex compound of high yield.
본 발명에 따른 유기 게르마늄-티타노센 복합 화합물은 종래의 합성약품에서는 찾아볼 수 없는 생리활성을 갖는 무독성의 유기 게르마늄을 이용함으로써 부작용이 없으며, 또한 정상세포보다 높은 단백질 합성능력을 나타내는 암세포에 대하여 선택적 독성을 갖는 항암제에 적용할 수 있어 생물의약 산업에 크게 기여할 것이다.The organic germanium-titanocene complex compound according to the present invention has no side effects by using non-toxic organic germanium having physiological activity not found in conventional synthetic drugs, and is selective for cancer cells showing higher protein synthesis ability than normal cells. It can be applied to toxic anticancer drugs, which will greatly contribute to the biopharmaceutical industry.
도 1은 본 발명에 따른 유기 게르마늄-티타노센 복합 화합물의 XRD 분석 결과를 나타낸 것이고,
도 2는 본 발명에 따른 유기 게르마늄-티타노센 복합 화합물을 주사전자현미경으로 관찰한 사진이며,
도 3은 본 발명에 따른 유기 게르마늄-티타노센 복합 화합물의 고체상태 13C NMR을 나타낸 것이고,
도 4는 본 발명에 따른 유기 게르마늄-티타노센 복합 화합물의 IR 스펙트럼을 나타낸 것이며,
도 5는 본 발명에 따른 유기 게르마늄-티타노센 복합 화합물의 열중량분석 결과를 나타낸 것이다.1 shows the results of XRD analysis of the organic germanium-titanocene complex compound according to the present invention,
2 is a photograph of an organic germanium-titanocene complex compound according to the present invention observed with a scanning electron microscope,
Figure 3 shows a solid state 13 C NMR of the organic germanium- titanocene complex compound according to the present invention,
Figure 4 shows the IR spectrum of the organic germanium- titanocene complex compound according to the present invention,
5 shows the results of thermogravimetric analysis of the organic germanium-titanocene complex compound according to the present invention.
이하, 본 발명의 내용을 실시예 및 시험예를 통하여 구체적으로 설명한다. 그러나, 이들은 본 발명을 보다 상세하게 설명하기 위한 일예일 뿐 본 발명의 권리범위가 이들에 의해 한정되는 것은 아니다.Hereinafter, the content of the present invention will be described in detail through examples and test examples. However, these are only examples for describing the present invention in more detail, and the scope of the present invention is not limited thereto.
[실시예][Example]
3차 증류수 1 mL에 탄산나트륨(Na2CO3) 0.125 g(1.18 mmol)을 넣고 교반하여 완전히 녹인 후, 상기 탄산나트륨 용액에 비스-카복시에틸게르마늄 세스퀴옥사이드(Ge-132; bis-carboxyethyl-germanium sesquioxide) 0.407 g(1.18 mmol)을 첨가하여 다시 완전히 녹을 때까지 교반하여 무색의 용액을 제조하였다.0.125 g (1.18 mmol) of sodium carbonate (Na 2 CO 3 ) was added to 1 mL of tertiary distilled water, followed by stirring to completely dissolve it. Then, bis-carboxyethyl germanium sesquioxide (Ge-132; bis-carboxyethyl-germanium sesquioxide) was added to the sodium carbonate solution. ) 0.407 g (1.18 mmol) was added and stirred until it completely dissolved, thereby preparing a colorless solution.
20 mL 테트라히드로푸란(THF; tetrahydrofuran) 용매에 티타노센(Cp2TiCl2) 0.145 g(0.582 mmol)을 넣고 교반하여 완전히 녹인 후, 상기 제조한 비스-카복시에틸게르마늄 세스퀴옥사이드 용액을 첨가하여 교반하여 반응시켰다.0.145 g (0.582 mmol) of titanocene (Cp 2 TiCl 2 ) was added to a 20 mL tetrahydrofuran (THF; tetrahydrofuran) solvent, and the mixture was completely dissolved. Then, the bis-carboxyethyl germanium sesquioxide solution prepared above was added and stirred. The reaction was carried out.
상기 반응은 비스-카복시에틸게르마늄 세스퀴옥사이드와 티타노센이 2 : 1 당량으로 혼합된 것으로, 반응이 진행되는 동안 용액은 주황색으로 변하고, 점차 색깔이 옅어지면서 주황색에서 노란색으로 변화한다. 상기 색의 변화는 30분 만에 이루어지며, 유지 시간은 일주일이다. The reaction is a mixture of bis-carboxyethylgermanium sesquioxide and titanocene in an amount of 2: 1 equivalents. During the reaction, the solution turns orange and gradually fades from orange to yellow. The color change takes place in 30 minutes and the retention time is one week.
상기 반응을 통하여 하기 화학식 1의 완전한 유기 게르마늄-티타노센 복합 화합물을 제조하기 위하여 3000 rpm 속도로 20분 동안 원심분리를 한 후, 3차 증류수로 3회 반복하여 세척하고 50℃ 진공오븐에서 12시간 건조하여 항암제를 수득하였다.In order to prepare the complete organic germanium-titanocene complex compound of Chemical Formula 1 through the reaction, centrifugation was performed at 3000 rpm for 20 minutes, and then washed three times with tertiary distilled water and washed 12 times in a 50 ° C. vacuum oven. It dried and obtained anticancer agent.
[[ 시험예Test Example ]]
(1) X-선 (1) X-ray 회절무늬Diffraction pattern 측정 Measure
상기 실시예의 유기 게르마늄-티타노센 복합 화합물의 결정성을 확인하기 위해서 Rigaku사의 D/MAX Ultima Ⅲ X-선 회절분석기로 X-선 회절무늬를 측정하였다. In order to confirm the crystallinity of the organic germanium-titanocene composite compound of the above example, the X-ray diffraction pattern was measured by a D / MAX Ultima III X-ray diffractometer manufactured by Rigaku.
그 결과 도 1의 XRD분석에서도 확인할 수 있듯이, XRD스펙트럼에서 뚜렷한 결정성 피크가 검출되지 않는 것을 확인할 수 있었다. 상기의 결과에서 상기 실시예의 유기 게르마늄-티타노센 복합 화합물이 무 결정질(amorphous) 구조인 것을 확인할 수 있었고, 상기 무 결정질 구조가 3 내지 5°의 2θ값을 나타내는 것을 확인하였다.As a result, as can be seen from the XRD analysis of FIG. 1, it was confirmed that no distinct crystalline peak was detected in the XRD spectrum. From the above results, it was confirmed that the organic germanium-titanocene composite compound of the above example had an amorphous structure, and the amorphous structure had a 2θ value of 3 to 5 °.
상기 3 내지 5°의 2θ값은 비스-카복시에틸게르마늄 세스퀴옥사이드의 주 피크가 나타나는 부분이며, 넓게 분포된 20 내지 35°의 2θ값은 비스-카복시에틸게르마늄 세스퀴옥사이드와 티타노센의 피크가 겹쳐서 브로드하게 나타내는 부분으로서, 상기의 결과로부터 상기 실시예의 유기 게르마늄-티타노센 복합 화합물은 비스-카복시에틸게르마늄 세스퀴옥사이드와 티타노센이 서로 결합된 형태로 존재함을 알 수 있었다.The 2θ value of 3 to 5 ° is the portion where the main peak of bis-carboxyethyl germanium sesquioxide appears, and the widely distributed 2θ value of 20 to 35 ° is the peak of bis-carboxyethyl germanium sesquioxide and titanocene. As the overlapping part, the organic germanium-titanocene composite compound of the above example showed that the bis-carboxyethyl germanium sesquioxide and titanocene were present in the form of bonding with each other.
(2) 주사전자현미경 관찰(2) Scanning electron microscope
상기 실시예의 유기 게르마늄-티타노센 복합 화합물의 분말 입자크기 및 형태를 주사전자현미경(scanning electron microscopy, Hitachi S-4700)으로 관찰하였다.The powder particle size and shape of the organic germanium-titanocene composite compound of the above example were observed by scanning electron microscopy (Hitachi S-4700).
그 결과 도 2의 SEM 사진에서도 확인할 수 있듯이, 결정성을 보이는 비스-카복시에틸게르마늄 세스퀴옥사이드 및 티타노센과는 달리 상기 실시예의 유기 게르마늄-티타노센 복합 화합물의 입자는 뭉쳐있는 형태로 비교적 균일한 크기, 즉 400 내지 600 nm 입자크기의 구형임을 확인할 수 있었다.As a result, as can be seen in the SEM photograph of FIG. 2, unlike the bis-carboxyethyl germanium sesquioxide and titanocene showing crystallinity, the particles of the organic germanium-titanocene composite compound of the above example are agglomerated in a relatively uniform size. That is, it could be confirmed that the sphere size of 400 to 600 nm particle size.
(3) 고체 (3) solid 핵자기Nuclear magnetic 공명 측정 Resonance measurement
상기 실시예의 유기 게르마늄-티타노센 복합 화합물의 고체 상태를 확인하기 위하여, 200 MHz Solid-State NMR Spectrometer(Unity Solid Inova WB 200 MHz system, Varian)를 사용하여 13C NMR로 분석하였다. In order to confirm the solid state of the organic germanium-titanocene composite compound of the above example, it was analyzed by 13 C NMR using a 200 MHz Solid-State NMR Spectrometer (Unity
그 결과 도 3에서도 확인할 수 있듯이, 에틸기가 18.2와 29.3 ppm에서 관찰 되었고, 또한 카복실기 탄소 피크가 183.9 ppm에서 관찰되었다. 특히 81.0 ppm에서 시클로펜타디엔(Cp)의 탄소 피크를 관찰할 수 있었는데, 이는 비스-카복시에틸게르마늄 세스퀴옥사이드와 티타노센이 결합되어 있음을 확인한 결과이기도 하다.As a result, as can be seen in Figure 3, the ethyl group was observed at 18.2 and 29.3 ppm, the carboxyl carbon peak was also observed at 183.9 ppm. In particular, the carbon peak of cyclopentadiene (Cp) was observed at 81.0 ppm, which is also a result of confirming that bis-carboxyethyl germanium sesquioxide and titanocene are combined.
(4) (4) IRIR (( InfraredInfrared SpectrumSpectrum ) 스펙트럼 측정Spectral measurement
상기 실시예의 유기 게르마늄-티타노센 복합 화합물의 적외선 영역에서의 파장에 대한 특성을 조사하기 위하여 FT-IR(IR Prestige-21)을 사용하여 분석하였다.In order to investigate the characteristics of the organic germanium-titanocene composite compound of the above-described wavelength in the infrared region, it was analyzed using FT-IR (IR Prestige-21).
그 결과 도 4에서도 확인할 수 있듯이, 전형적인 티타노센의 시클로펜타디엔(Cp)의 3100 cm-1의 피크가 비스-카복시에틸게르마늄 세스퀴옥사이드와 결합해서 2900 cm-1로 이동했으며, 또한 비스-카복시에틸게르마늄 세스퀴옥사이드의 1700 cm-1의 카르복실기의 산소 피크도 1600 cm- 1이하로 이동한 것을 확인할 수 있다.As can be seen in FIG. 4, the peak of 3100 cm −1 of the typical titanocene cyclopentadiene (Cp) shifted to 2900 cm −1 in combination with bis-carboxyethylgermanium sesquioxide, and also bis-carboxy it can be confirmed that the movement to less than one-ethyl germanium sesquioxide oxygen peak 1600 cm even in the 1700 cm -1 of the carboxyl group.
그러나 상기 실시예의 유기 게르마늄-티타노센 복합 화합물의 IR 피크는 브로드하게 변하는 것을 확인할 수 있었다.However, it was confirmed that the IR peak of the organic germanium-titanocene complex compound of the above example was changed broadly.
상기의 결과로부터 실시예의 유기 게르마늄-티타노센 복합 화합물이 비스-카복시에틸게르마늄 세스퀴옥사이드와 티타노센이 서로 결합된 형태로 존재한다는 것을 IR을 통해 확인한 결과이기도 하다.From the above results, the organic germanium-titanocene composite compound of the example was also confirmed through IR that bis-carboxyethylgermanium sesquioxide and titanocene were present in the form of binding to each other.
(5) 열중량분석((5) thermogravimetric analysis TGATGA ;; ThermogravimetricThermogravimetric AnalysisAnalysis ))
상기 실시예의 유기 게르마늄-티타노센 복합 화합물을 TGA-50A(Shimadzu, Japan)을 이용하여 N2 분위기 하에서 10℃/min의 속도로 600℃까지 측정하여 열중량분석을 하였다. The embodiment of an organic germanium were a titanocene complex compound the TGA-50A (Shimadzu, Japan) for 10 ℃ / min measured by thermogravimetric analysis at a rate of up to 600 ℃ under N 2 atmosphere using.
그 결과 도 5에서도 확인할 수 있듯이, 티타노센의 경우 곡선이 심하게 변하면서 무게감소가 급격이 변하고 반면, 비스-카복시에틸게르마늄 세스퀴옥사이드의 경우 티타노센과는 달리 완만하게 변하기는 하지만 300℃ 근처에서 심하게 무게 감소가 일어나는 것을 확인할 수 있었다. As a result, as can be seen in Figure 5, in the case of titanocene, the curve is severely changed, the weight loss is sharply changed, while in the case of bis-carboxyethyl germanium sesquioxide, unlike titanocene, but slowly changes, it is severely weighted near 300 ℃ A decrease occurred.
그러나 실시예의 유기 게르마늄-티타노센 복합 화합물은 상기 두 경우의 분석결과를 합쳐놓은 곡선의 패턴으로 피크가 거의 완만하게 변하는 것을 확인할 수 있다. However, it can be seen that the organic germanium-titanocene composite compound of the example changes the peak almost smoothly by the pattern of the curve combining the analysis results of the two cases.
상기의 결과로부터 실시예의 유기 게르마늄-티타노센 복합 화합물은 300℃까지 무게 감소가 20% 밖에 일어나지 않았고, 600℃에서 10% 정도 아주 적은 감소가 일어남을 확인할 수 있었으며, 이는 상기 실시예의 유기 게르마늄-티타노센 복합 화합물이 매우 안정함을 확인한 결과이기도 하다.From the above results, the organic germanium-titanocene complex compound of Example showed a weight loss of only 20% up to 300 ° C., and a very small decrease of about 10% occurred at 600 ° C., which is the organic germanium-titano of the example. It is also the result of confirming that the sen complex compound is very stable.
Claims (6)
2) 티타노센 용액을 준비하는 단계; 및
3) 상기 2) 단계의 티타노센 용액에 상기 1) 단계의 유기 게르마늄 화합물 용액에 혼합하여 반응시키는 단계;
를 포함하는, 하기 화학식 1로 표시되는 유기 게르마늄-티타노센 복합 화합물의 제조방법.
2) preparing a titanocene solution; And
3) mixing and reacting the titanocene solution of step 2) with the organic germanium compound solution of step 1);
Method for producing an organic germanium- titanocene complex compound represented by the following formula (1) comprising a.
상기 1) 단계의 유기 게르마늄 화합물 용액은 탄산나트륨 용액에 10 내지 40 중량%의 유기 게르마늄 화합물을 첨가하여 제조하는 것을 특징으로 하는 유기 게르마늄-티타노센 복합 화합물의 제조방법.The method of claim 1,
The organic germanium compound solution of step 1) is prepared by adding 10 to 40% by weight of the organic germanium compound to sodium carbonate solution.
상기 1) 단계의 상기 유기 게르마늄 화합물은 비스-카복시에틸게르마늄 세스퀴옥사이드, 스피로게르마늄 및 유산-구연산-게르마늄산 염 중에서 선택되는 어느 하나인 것을 특징으로 유기 게르마늄-티타노센 복합 화합물의 제조방법.The method of claim 2,
The organic germanium compound of step 1) is a bis- carboxyethyl germanium sesquioxide, spiger germanium and lactic acid-citric acid-germanium salt of any one selected from the method of producing an organic germanium- titanocene composite compound.
상기 1) 단계의 상기 유기 게르마늄 화합물은 하기 화학식 2로 표시되는 비스-카복시에틸게르마늄 세스퀴옥사이드인 것을 특징으로 유기 게르마늄-티타노센 복합 화합물의 제조방법.
The organic germanium compound of step 1) is a bis-carboxyethyl germanium sesquioxide represented by the following formula (2) characterized in that the method for producing an organic germanium- titanocene composite compound.
상기 3) 단계는 테트라히드로푸란 100 중량부에 대하여, 유기 게르마늄 화합물 0.5 내지 10 중량부 및 티타노센 0.1 내지 5 중량부를 혼합하여 반응시키는 것을 특징으로 하는 유기 게르마늄-티타노센 복합 화합물의 제조방법.The method of claim 1,
The step 3) is a method for producing an organic germanium-titanocene complex compound, characterized in that the reaction mixture by mixing 0.5 to 10 parts by weight of organic germanium compound and 0.1 to 5 parts by weight of titanocene with respect to 100 parts by weight of tetrahydrofuran.
상기 유기 게르마늄-티타노센 복합 화합물은 유기 게르마늄 화합물 및 티타노센이 1 : 0.1 내지 5의 중량비인 것을 특징으로 하는 유기 게르마늄-티타노센 복합 화합물의 제조방법.The method according to any one of claims 1 to 5,
The organic germanium-titanocene composite compound is an organic germanium compound and titanocene 1: 1: 0.1 to 5 characterized in that the weight ratio of the organic germanium- titanocene composite compound.
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| JPH11292885A (en) | 1998-03-27 | 1999-10-26 | Rin Shusho | Production of chitosan organic germanium compound |
| KR100691745B1 (en) | 2006-03-23 | 2007-03-12 | 한국원자력연구소 | Technetium-99m labeled organic germanium nanocolloids, preparation method and use thereof |
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| JPH11292885A (en) | 1998-03-27 | 1999-10-26 | Rin Shusho | Production of chitosan organic germanium compound |
| KR100691745B1 (en) | 2006-03-23 | 2007-03-12 | 한국원자력연구소 | Technetium-99m labeled organic germanium nanocolloids, preparation method and use thereof |
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