[산업상 이용 분야][Industrial use]
본 발명은 방사선 감작제용 파클리탁셀 유도체에 관한 것으로서, 더욱 상세하게는 방사선 치료에 유용한 방사선 감작제용 파클리탁셀 유도체에 관한 것이다.The present invention relates to paclitaxel derivatives for radiation sensitizers, and more particularly to paclitaxel derivatives for radiation sensitizers useful for radiation therapy.
[종래 기술][Prior art]
현재 악성 종양은 수술 요법, 방사선 치료 등의 국소 요법과 화학 요법 및 면역 요법 등의 전신 요법을 다양하게 조합하여 치료하고 있다. 이중에서 널리 사용되는 방법은 방사선 치료 요법으로, 이 방법은 방사선을 환자의 종양 조직 부위에 조사하여 통증없이 종양 조직을 파괴하는 요법으로 이 역시 단독으로 각종 암의 치료에 많이 사용되지 않고 여러 가지 화학 요법제와 병용하고 있는 실정이다. 방사선 요법과 화학 요법의 병용시 화학요법제의 경우는 화학요법제들 만을 이용할때보다 상당히 낮은 농도로 이용하는 것이 부작용을 최소화할 수 있다. 또한 근래에는 식도암 및 생존율의 연장을 가져온 연구 결과도 있다(Arch. Surg. 2001, 136: 737-743). 이와 같은 방사선 요법시의 화학요법제를 방사선 감작제(Radio-sensitizer)라고 하여, 이러한 감작제에 대한 연구가 많은 학자들에 의해 수행되어기존에 사용하고 있던 화학 요법제 중 일부가 방사선 감작제로 개발되었다.Currently, malignant tumors are treated by various combinations of local therapies such as surgery, radiation, and systemic therapies such as chemotherapy and immunotherapy. The most widely used method is radiation therapy, which is a method of destroying tumor tissue without pain by irradiating radiation on the area of tumor tissue of the patient, which is also not used alone in the treatment of various cancers. In combination with the therapy. In the case of the combination of radiation therapy and chemotherapy, chemotherapeutic agents can be used at a significantly lower concentration than chemotherapeutic agents alone to minimize side effects. There are also recent studies that have resulted in prolonged esophageal cancer and survival rates (Arch. Surg. 2001, 136: 737-743). Such chemotherapeutic agents in radiation therapy are called radio-sensitizers, and research on these sensitizers has been carried out by many scholars, and some of the conventional chemotherapy agents have been developed as radiation sensitizers. It became.
파클리탁셀은 기존 항암제와는 달리 유사 분열기의 암세포 분열을 억제함으로써 비교적 낮은 독성과 강력한 항암 작용으로 인하여 1990년대에 가장 널리 사용되는 항암제가 되었다. 이러한 파클리탁셀은 미국 식품 의약국(FDA)에 의해 1992년에 난소암, 1994년에 유방암에 탁월한 효능이 있음이 확인되어 사용이 허가된 이후, 1997년에는 카포시종양(Kaposis sarcoma) 치료에도 사용이 허가되었다. 이 외에도 간암, 폐암, 류마티스성 관절염, 알츠하이머 등의 치료 목적으로 적응증이 확대되고 있고 다른 여러 약물들과 복합 처방에 대한 임상 시험이 다각도로 진행 중에 있어 수요는 크게 늘어날 전망이다.Paclitaxel, unlike conventional anticancer drugs, became the most widely used anticancer drug in the 1990s due to its relatively low toxicity and potent anticancer activity by inhibiting mitotic cancer cell division. Paclitaxel was licensed for the treatment of Kaposi sarcoma in 1997 after it was approved by the US Food and Drug Administration (FDA) for ovarian cancer in 1992 and breast cancer in 1994. It became. In addition, indications are expanding for treatment of liver cancer, lung cancer, rheumatoid arthritis, Alzheimer's disease, etc., and clinical trials for various drugs and combination prescriptions are in progress.
현재 화학요법제로 사용되는 파클리탁셀(paclitaxel)의 경우는 물에 난용성인 물질로서 크로모퍼 이엘(cremophor-EL, polyoxyethylated castor oil) 또는 폴리소르베이트 등의 계면활성제와 함께 투여되고 있다. 예를 들어 현재 임상에 사용되고 있는 탁솔 주사제(Taxol, Bristol-Muers Squibb)는 49.7 퍼센트(v/v) 알코올 용액 1 밀리리터에 파클리탁셀 6 밀리그램과 계면활성제인 크레모퍼 이엘 527 밀리그램이 함유되어 있으며, 파클리탁셀 유도체인 도세탁셀을 제재화한 탁소테레 주사제(Taxotere, Rhone-Poulene Rorer) 13 퍼센트(w/w) 알코올 용액 1.83 밀리리터에 도세탁셀 20밀리그램과 계면활성제인 폴리소르베이트 80이 0.5 밀리리터 함유되어 있다.Paclitaxel, currently used as a chemotherapeutic agent, is poorly soluble in water and is administered with a surfactant such as chromophor-EL (polyoxyethylated castor oil) or polysorbate. For example, Taxol, Bristol-Muers Squibb, currently in clinical use, contains 6 milligrams of paclitaxel and 527 milligrams of surfactant Cremoperel in one milliliter of a 49.7 percent (v / v) alcohol solution. 1.83 milliliters of 13 percent (w / w) alcohol solution of Taxotere (Rhone-Poulene Rorer) formulated with indocetaxel contains 20 milligrams of docetaxel and 0.5 milliliter of polysorbate 80 surfactant.
이와 같이 일반적으로 파클리탁셀을 투여하기 위해서 사용되는 계면활성제인 크레모포 이엘 및 폴리소르베이트 성분은 일부 환자에게서 과민성 반응(Agents andactions 1982 12, 64-80)의 심각한 부작용을 유발하는 것으로 알려져 있다. 또한 크레모포 이엘과 같은 식물성 기름을 사용함에 따라 생체 이용율이 낮을 뿐만 아니라 과민성 반응(hypersensitive) 등의 부작용이 발생된다. 아울러, 주사제 개발에 알코올과 크로모퍼 이엘과 같은 점도가 매우 높은 물질(온도에 따라 고체인 물질)을 첨가하는 방법은 비경구적인 사용에 고려해야할 사항이다. 또한 알코올과 같은 유기 용매의 사용은 주사 부위에서의 용혈 현상과 국소 자극의 문제점이 있다.As such, the Cremopoel and Polysorbate components, which are generally used to administer paclitaxel, are known to cause serious side effects of hypersensitivity reactions (Agents and actions 1982 12, 64-80) in some patients. In addition, the use of vegetable oils such as cremopoiel not only has low bioavailability, but also causes side effects such as hypersensitive reaction. In addition, the addition of highly viscous materials (solid materials, depending on the temperature), such as alcohol and chromophorel, to the development of injections is a consideration for parenteral use. In addition, the use of organic solvents such as alcohol has problems of hemolysis and local irritation at the injection site.
이러한 이유들로 인해서, 최근 임상 실험 결과에서 파클리탁셀(탁솔)의 경우, 신경병증(neuropathy), 근증(myopathy), 근육톡(myalgia), 호중구감소증(neutopenia) 등의 부작용이 나타났으며, 도세탁셀(탁소티어(Taxotere))의 경우에는 구내염(stomatitis), 불쾌감(malaise) 등의 부작용이 나타났다.For these reasons, recent clinical trials have shown side effects such as neuropathy, myopathy, myalgia, and neutopenia in paclitaxel (taxol). Taxotere) had side effects such as stomatitis and malaise.
따라서 이러한 부작용을 줄이고 생체 이용율을 높이기 위해 세계 각지에서 파클리탁셀을 포함하는 수용성 화합물을 개발하기 위한 노력이 광범위하게 진행되고 있다. 그중에서도 폴리에틸렌글리콜을 이용한 화합물의 개발은 과학자들의 깊은 관심의 대상이며 많은 연구가 진행되고 있다. 최근 Greenwald(Enzon, Inc.) 등은 폴리에틸렌글리콜을 이용하여 여러 가지 파클리탁셀 유도체를 합성하였으며(미국 특허 제 5,614,549 호, 제 5,880,131 호 및 제 5,965,566 호), Desai(Vivorx, Inc.) 등 또한 폴리에틸렌글리콜을 이용한 수용성 유도체를 합성한바 있다(미국 특허 제 5,648,506 호). Chun Li(PG-TXL Company) 등은 파클리탁셀과 썩시닉 언하이드라이드(succinic anhydride)를 반응시켜 2'-썩시닐-파클리탁셀(2'-succinyl-paclitaxel)을 합성하고 여기에 메톡시폴리옥시에틸렌아민(methoxypolyoxyethylene amine)을 결합시켜 수용성 유도체를 합성한 바 있다(미국 특허 제 5,977,163 호).Therefore, in order to reduce these side effects and increase the bioavailability, efforts to develop water-soluble compounds including paclitaxel have been extensively performed all over the world. Among them, the development of compounds using polyethylene glycol is of great interest to scientists, and much research is being conducted. Recently, Greenwald (Enzon, Inc.) et al. Synthesized various paclitaxel derivatives using polyethylene glycol (US Pat. Nos. 5,614,549, 5,880,131 and 5,965,566), and Desai (Vivorx, Inc.) and others also used polyethylene glycol. A water soluble derivative used has been synthesized (US Pat. No. 5,648,506). Chun Li (PG-TXL Company) et al. Synthesizes 2'-succinyl-paclitaxel by reacting paclitaxel with succinic anhydride and adds methoxypolyoxyethyleneamine (methoxypolyoxyethylene amine) was combined to synthesize a water-soluble derivative (US Pat. No. 5,977,163).
그러나 지금까지 합성된 이러한 화합물들은 방사선 감작제가 아니라, 화학 요법으로 단독으로 사용되는 항암제로만 개발되었을 뿐, 악성 종양을 치료하기 위하여, 방사선 요법과 함께 사용되는 방사선 감작제로의 개발은 이루어지지 않았다.However, these compounds synthesized so far have not been developed as radiation sensitizers, but as anticancer agents used alone as chemotherapy, and have not been developed as radiation sensitizers used with radiation therapy to treat malignant tumors.
본 발명은 상술한 문제점을 해결하기 위한 것으로서, 본 발명의 목적은 방사선 치료 요법과 함께 사용되는 방사선 감작제용 파클리탁셀 유도체를 제공하는 것이다.The present invention has been made to solve the above problems, and an object of the present invention is to provide a paclitaxel derivative for radiation sensitizers to be used in combination with radiation therapy.
도 1은 본 발명의 실시예 2에 따라 제조된 7-모노메톡시폴리에틸렌글리콜 5000 썩시닐옥시메틸옥시카보닐 파클리탁셀의 항종양 효과 측정 결과를 나타낸 그래프.1 is a graph showing the anti-tumor effect measurement results of 7-monomethoxypolyethyleneglycol 5000 rosinyloxymethyloxycarbonyl paclitaxel prepared according to Example 2 of the present invention.
도 2는 본 발명의 실시예 2에 따라 제조된 7-모노메톡시폴리에틸렌글리콜 5000 썩시닐옥시메틸옥시카보닐 파클리탁셀의 방사선 감작 효과 측정 결과를 나타낸 그래프.Figure 2 is a graph showing the radiosensitization effect measurement results of 7-monomethoxypolyethyleneglycol 5000 rosinyloxymethyloxycarbonyl paclitaxel prepared according to Example 2 of the present invention.
도 3은 본 발명의 실시예 3에 따라 제조된 7-모노메톡시폴리에틸렌글리콜 20000 썩시닐옥시메틸옥시카보닐-파클리탁셀의 항종양 효과 측정 결과를 나타낸 그래프.Figure 3 is a graph showing the anti-tumor effect measurement results of 7-monomethoxypolyethyleneglycol 20000 Rosinyloxymethyloxycarbonyl-paclitaxel prepared according to Example 3 of the present invention.
도 4는 본 발명의 실시예 3에 따라 제조된 7-모노메톡시폴리에틸렌글리콜 20000 썩시닐옥시메틸옥시카보닐-파클리탁셀의 방사선 감작 효과 측정 결과를 나타낸 그래프.Figure 4 is a graph showing the radiosensitization effect measurement results of 7-monomethoxypolyethyleneglycol 20000 Rosinyloxymethyloxycarbonyl-paclitaxel prepared according to Example 3 of the present invention.
도 5는 본 발명의 실시예 4에 따라 제조된 7-모노메톡시폴리에틸렌글리콜 5000 썩시닐옥시메틸옥시카보닐-파클리탁셀의 항종양 효과 측정 결과를 나타낸 그래프.Figure 5 is a graph showing the antitumor effect measurement results of 7-monomethoxypolyethyleneglycol 5000 rosinyloxymethyloxycarbonyl-paclitaxel prepared according to Example 4 of the present invention.
도 6은 본 발명의 실시예 4에 따라 제조된 7-모노메톡시폴리에틸렌글리콜 20000 썩시닐옥시메틸옥시카보닐-파클리탁셀의 방사선 감작 효과 측정 결과를 나타낸 그래프.Figure 6 is a graph showing the radiosensitization effect measurement results of 7-monomethoxypolyethyleneglycol 20000 Rosinyloxymethyloxycarbonyl-paclitaxel prepared according to Example 4 of the present invention.
상기 목적을 달성하기 위하여, 본 발명은 썩시닐옥시메틸옥시카보닐-파클리탁셀, 썩시닐옥시티오메틸옥시카보닐-파클리탁셀, 7-모노메톡시폴리에틸렌글리콜 5000 내지 20000 썩시닐옥시메틸옥시카보닐-파클리탁셀 및 7-모노메톡시폴리에틸렌글리콜 5000 내지 20000 썩시닐티오메틸옥시카보닐-파클리탁셀로 이루어진 군에서 선택되는 방사선 감작제용 파클리탁셀 유도체를 제공한다.In order to achieve the above object, the present invention provides a rosiniloxymethyloxycarbonyl-paclitaxel, a rosinyloxythiomethyloxycarbonyl-paclitaxel, 7-monomethoxypolyethylene glycol 5000 to 20000 rosinyloxymethyloxycarbonyl-paclitaxel And 7-monomethoxypolyethylene glycol 5000 to 20000 rosinylthiomethyloxycarbonyl-paclitaxel, to provide a paclitaxel derivative for radiation sensitizers.
이하 본 발명을 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 천연물의 일종인 파클리탁셀로부터 합성된 유도체로써, 체내에서 파클리탁셀로 전환되는 속도가 빠른 유도체를 방사선 감작제로 이용한 발명에 관한 것이다. 본 발명의 파클리탁셀 유도체는 방사선 치료시에 항종향 효과를 증진시키는 효과가 매우 우수한 화합물로써, 파클리탁셀을 투여하기 위해서 사용되는 계면활성제인 크레모포아 이엘 및 폴리소르베이트 성분으로부터 발생하는 문제점을 줄이기 위하여, 물에 용해성이 좋고 체내에서 가수분해 속도가 뛰어난 유도체이다.The present invention relates to a derivative synthesized from paclitaxel, which is a kind of natural product, using a derivative having a high rate of conversion into paclitaxel in the body as a radiation sensitizer. Paclitaxel derivative of the present invention is a compound having a very excellent effect of enhancing the anti-tumor effect during radiation treatment, in order to reduce the problems arising from the components of cremopoel and polysorbate, a surfactant used to administer paclitaxel, It is a derivative that has good solubility in water and excellent hydrolysis rate in the body.
이러한 특성을 갖는 본 발명의 방사선 감작제용 파클리탁셀 유도체는 썩시닐옥시메틸옥시카보닐-파클리탁셀(succinyloxymethyloxycarbonyl-paclitaxel), 썩시닐티오메틸옥시카보닐-파클리탁셀(succinylthiomethyloxycarbonyl-paclitaxel), 7-모노메톡시폴리에틸렌글리콜 5000 내지 20000 썩시닐옥시메틸옥시카보닐-파클리탁셀(7-monomethoxypolyethyleneglycol 5000-20000 succinyloxymethyloxycarbonyl-paclitaxel) 또는 7-모노메톡시폴리에틸렌글리콜 5000 내지 20000 썩시닐옥시티오메틸옥시카보닐-파클리탁셀(7-monomethoxypolyethyleneglycol 5000-20000 succinyloxythiomethyloxycarbonyl-paclitaxel)을 포함한다.The paclitaxel derivatives for radiation sensitizers of the present invention having these characteristics are rosinyloxymethyloxycarbonyl-paclitaxel, rosinylthiomethyloxycarbonyl-paclitaxel, and 7-monomethoxypolyethylene glycol 5000-20000 succinyloxymethyloxycarbonyl-paclitaxel (7-monomethoxypolyethyleneglycol 5000-20000 succinyloxymethyloxycarbonyl-paclitaxel) or 7-monomethoxypolyethyleneglycol 5000-20000 rotsinyloxythiomethyloxycarbonyl-paclitaxel (7-monomethoxypolyethyleneglycol 5000- 20000 succinyloxythiomethyloxycarbonyl-paclitaxel).
바람직한 방사선 감작제용 파클리탁셀 유도체는 썩시닐티오메틸옥시카보닐-파클리탁셀, 썩시닐옥시메틸옥시카보닐-파클리탁셀, 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐티오메틸옥시카보닐-파클리탁셀, 7-모노메톡시폴리에틸렌글리콜 20000 썩시닐티오메틸옥시카보닐-파클리탁셀, 7-모노메톡시폴리에틸렌글리콜 5000 썩시닐옥시메틸옥시카보닐-파클리탁셀이다.Preferred paclitaxel derivatives for radiation sensitizers are rosinylthiomethyloxycarbonyl-paclitaxel, rosinyloxymethyloxycarbonyl-paclitaxel, 7-monomethoxypolyethyleneglycol 5000-rotinylthiomethyloxycarbonyl-paclitaxel, 7-monome Methoxypolyethyleneglycol 20000 Rosinylthiomethyloxycarbonyl-paclitaxel, 7-monomethoxypolyethyleneglycol 5000 rosinyloxymethyloxycarbonyl-paclitaxel.
보다 바람직한 방사선 감작제용 파클리탁셀 유도체는 7-모노메톡시폴리에틸렌 글리콜 5000 썩시닐티오메틸옥시카보닐-파클리탁셀, 7-모노메톡시폴리에틸렌글리콜 20000 썩시닐옥시메틸옥시카보닐-파클리탁셀 또는 7-모노메톡시폴리에틸렌글리콜 5000 썩시닐옥시메틸옥시카보닐-파클리탁셀이다.More preferred paclitaxel derivatives for radiation sensitizers are 7-monomethoxypolyethylene glycol 5000 rosinylthiomethyloxycarbonyl-paclitaxel, 7-monomethoxypolyethyleneglycol 20000 rosinyloxymethyloxycarbonyl-paclitaxel or 7-monomethoxypolyethylene Glycol 5000 rosinyloxymethyloxycarbonyl-paclitaxel.
본 발명의 방사선 감작제용 파클리탁셀의 대표적인 제조 방법은 7-클로로메틸옥시카보닐-파클리탁셀을 무수 벤젠, 톨루엔 또는 클로로벤제과 같은 용매에 녹인 후, 이 용액에 모노메톡시폴리에틸렌글리콜 5000-20000 썩시네이트, 또는 모노메톡시폴리에틸렌글리콜 5000-20000 썩시닐티오산을 첨가하여 반응 가속화 촉매. 염기 및 양이온 캡쳐(capture) 존재하에서 반응시킨다. 상기 반응 가속화 촉매로는 요오드 또는 요오드화 나트륨 등을 사용할 수 있고, 상기 염기로는 탄산칼륨, 탄산나트륨, 탄산수소나트륨, 탄산수소칼륨, 수산화나트륨 또는 수산화칼륨을 사용할 수 있고, 또한 상기 양이온 캡쳐로는 18-크라운-6-에테르와 같은 크라운 에테르를 사용할 수 있다.Representative method for producing paclitaxel for radiation sensitizer of the present invention is to dissolve 7-chloromethyloxycarbonyl-paclitaxel in a solvent such as anhydrous benzene, toluene or chlorobene, and then to this solution monomethoxypolyethylene glycol 5000-20000 lycinate, Or monomethoxypolyethyleneglycol 5000-20000 rosinylthioic acid, to accelerate the reaction. React in the presence of base and cation capture. As the reaction acceleration catalyst, iodine or sodium iodide may be used, and as the base, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide or potassium hydroxide may be used, and as the cation capture 18 Crown ethers such as -crown-6-ether can be used.
얻어진 생성물을 통상의 방법으로 감압 건조, 여과 공정 및 재결정 공정을 실시하여 목적 생성물을 제조한다.The obtained product is dried under reduced pressure, a filtration step and a recrystallization step in a conventional manner to prepare a desired product.
다음의 실시예는 본 발명의 대표적인 실시예에 의하여 더욱 구체적으로 설명되나, 본 발명이 이들 실시예에 의하여 어떤 식으로든 제한되는 것은 아니다.The following examples are described in more detail by representative examples of the present invention, but the present invention is not limited in any way by these examples.
(실시예 1) 7-클로로메틸옥시카보닐-파클리탁셀(7-Chloromethyloxycarbonyl paclitaxel)의 합성(1))Example 1 Synthesis of 7-Chloromethyloxycarbonyl paclitaxel (1)
파클리탁셀 500 mg (0.586 mmol)을 무수 디클로로메탄 10 ml에 녹였다. 이 용액에tert-부틸디메틸실릴 클로라이드 106.0mg (0.70mmole)와 이미다졸 71.8 mg(1.05 mmole)을N,N-디메틸포름아마이드 1 ml에 녹인 용액을 가한 후, 6시간 동안 교반하였다. 이 혼합물에 디클로로메탄 20 ml를 가하여 희석하고 5% 염산(HCl) 용액으로 2회, 물로 1회 세척하였다. 유기층을 무수 황산마그네슘으로 처리하여 함유한 수분을 제거한 다음 감압 건조하여 생성물 2'-(tert-부틸디메틸실릴)-파클리탁셀 [2'-(tert-Butyldimethylsilyl)- paclitaxel] 540 mg을 얻었다. 1H NMR (300 MHz, CDCl3) δ 0.10 (s, 3H, -CH3), 0.03 (s, 3H, -CH3), -0.02 (s, 3H, -CH3), -0.26 (s, 3H, -CH3)500 mg (0.586 mmol) of paclitaxel was dissolved in 10 ml of anhydrous dichloromethane. To this solution was addedtert - butyl dimethylsilyl chloride 106.0mg (0.70mmole) and 71.8 mg (1.05 mmole) imidazoleN, N - was added to the solution in 1 ml of dimethylformamide, and the mixture was stirred for 6 hours. To this mixture was added 20 ml of dichloromethane, diluted and washed twice with 5% hydrochloric acid (HCl) solution and once with water. The organic layer was treated with anhydrous magnesium sulfate to remove moisture, and then dried under reduced pressure to obtain 540 mg of product 2 '-(tert -butyldimethylsilyl) -paclitaxel [2'-(tert- Butyldimethylsilyl) -paclitaxel]. 1 H NMR (300 MHz, CDCl3 ) δ 0.10 (s, 3H, -CH3 ), 0.03 (s, 3H, -CH3 ), -0.02 (s, 3H, -CH3 ), -0.26 (s, 3H , -CH3 )
2'-(tert-부틸디메틸실릴)-파클리탁셀 540 mg(0.558 mmol)을 무수 디클로로메탄 10 ml에 녹였다. 이 용액에 클로로메틸클로로포메이트 107.9 mg(0.837 mmol)을 가하였다. 여기에 피리딘 91.4 mg(1.116 mmol)을 서서히 적가한 다음, 12시간 동안 교반하였다. 이 혼합물에 디클로로메탄 20 ml를 가하여 희석하고 5% 염산(HCl) 용액과 포화 중탄산나트륨 용액으로 세척하였다. 유기층을 모아 무수 황산마그네슘으로 처리하여 함유한 수분을 제거한 다음 감압 건조하여 생성물 572 mg (97%)을 얻었다. 1H NMR (300 MHz, CDCl3) δ 5.98 (d, 1H,J=6.48 Hz), 5.70 (m, 1H), 5.51 (d, 1H,J=6.48 Hz), 0.00 (s, 3H, -CH3), -0.01 (s, 3H, -CH3), -0.03 (s, 3H, -CH3), -0.30 (s, 3H, -CH3)540 mg (0.558 mmol) of 2 '-(tert -butyldimethylsilyl) -paclitaxel was dissolved in 10 ml of anhydrous dichloromethane. To this solution was added 107.9 mg (0.837 mmol) of chloromethylchloroformate. 91.4 mg (1.116 mmol) of pyridine was slowly added dropwise thereto, followed by stirring for 12 hours. 20 ml of dichloromethane was added to the mixture, diluted and washed with 5% hydrochloric acid (HCl) solution and saturated sodium bicarbonate solution. The organic layer was collected, treated with anhydrous magnesium sulfate to remove the contained water, and then dried under reduced pressure to obtain 572 mg (97%) of the product. 1 H NMR (300 MHz, CDCl3 ) δ 5.98 (d, 1H,J = 6.48 Hz), 5.70 (m, 1H), 5.51 (d, 1H,J = 6.48 Hz), 0.00 (s, 3H, -CH3 ), -0.01 (s, 3H, -CH3 ), -0.03 (s, 3H, -CH3 ), -0.30 (s, 3H, -CH3 )
2'-(tert-부틸디메틸실릴)-7-클로로메틸옥시카보닐-파클리탁셀 572 mg (0.54 mmol)을 아세토니트릴 10 ml에 녹였다. 이 용액에 아세토니트릴에 녹아 있는 1% 불화 수소산 10 ml를 혼합하였다. 이 혼합물을 30분 동안 교반한 다음 아세토니트릴을 감압 증류하여 제거하였다. 얻어진 잔류물을 디에틸에테르 30 ml에 녹이고 포화 중탄산나트륨 용액 및 증류수로 세척한 다음 무수 황산마그네슘으로 처리하여 함유한 수분을 제거한 후 감압 건조하여 생성물 7-클로로메틸옥시카보닐-파클리탁셀 456 mg(91%)을 얻었다. 1H NMR (300 MHz, CDCl3) δ 5.97 (d, 1H,J=6.47 Hz, OCOOCH2Cl), 5.51 (d, 1H,J=6.40 Hz, OCOOCH2Cl), 3.92 (d, 1H,J=6.77 Hz, 7-H); 13C NMR (75 MHz, CDCl3) δ 154.83 (OCOOCH2Cl)572 mg (0.54 mmol) of 2 '-(tert -butyldimethylsilyl) -7-chloromethyloxycarbonyl-paclitaxel was dissolved in 10 ml of acetonitrile. To this solution was mixed 10 ml of 1% hydrofluoric acid dissolved in acetonitrile. The mixture was stirred for 30 minutes and then the acetonitrile was distilled off under reduced pressure. The obtained residue was dissolved in 30 ml of diethyl ether, washed with saturated sodium bicarbonate solution and distilled water, and then treated with anhydrous magnesium sulfate to remove the contained water, and then dried under reduced pressure to give 456 mg (91 mg) of the product 7-chloromethyloxycarbonyl-paclitaxel. %) Was obtained. 1 H NMR (300 MHz, CDCl3 ) δ 5.97 (d, 1H,J = 6.47 Hz, OCOOCH2 Cl), 5.51 (d, 1H,J = 6.40 Hz, OCOOCH2 Cl), 3.92 (d, 1H,J = 6.77 Hz, 7-H); 13 C NMR (75 MHz, CDCl3 ) δ 154.83 (OC OOCH2 Cl)
(실시예 2) 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐옥시메틸옥시카보닐-파클리탁셀(7-mPEG 5000-succinyloxymethyloxycarbonyl-paclitaxel)의 합성Example 2 Synthesis of 7-monomethoxypolyethyleneglycol 5000-lycinyloxymethyloxycarbonyl-paclitaxel (7-mPEG 5000-succinyloxymethyloxycarbonyl-paclitaxel)
7-클로로메틸옥시카보닐-파클리탁셀 1g(1.057mmol)을 무수 벤젠 100㎖에 녹였다. 이 용액과 모노메톡시폴리에틸렌글리콜 5000-썩시네이트 5.285g(1.057mmol), 요오드화 나트륨 475mg(3.171mmol), 탄산칼륨 262.8mg(1.902mmol)및 18-크라운-6-에테르 195.5mg(0.739mmol)을 혼합하였다. 이 혼합물을 환류 하에서 36시간 동안 교반한 다음 벤젠을 감압 건조하여 제거하고 잔류물을 디클로로메탄 50ml에 용해하였다. 녹지 않은 물질을 여과하여 제거하였다. 유기층을 물로 2회 세척하고 분리한 유기층을 무수 황산 마그네슘으로 처리하여 함유한 수분을 제거한 후 감압건조한 다음 이소프로필 알콜에서 재결정하여 고형물을 얻었다. 상기 고형물을 분취용 고성능 크로마토그래피 장치(Prep. HPLC)를 이용하여 순수한 생성물 433mg(68%)을 얻었다.1 g (1.057 mmol) of 7-chloromethyloxycarbonyl-paclitaxel was dissolved in 100 mL of anhydrous benzene. This solution and 5.285 g (1.057 mmol) of monomethoxypolyethylene glycol 5000-resinate, 475 mg (3.171 mmol) of sodium iodide, 262.8 mg (1.902 mmol) of potassium carbonate and 195.5 mg (0.739 mmol) of 18-crown-6-ether Mixed. The mixture was stirred under reflux for 36 hours, then benzene was removed by drying under reduced pressure and the residue was dissolved in 50 ml of dichloromethane. Undissolved material was removed by filtration. The organic layer was washed twice with water, and the separated organic layer was treated with anhydrous magnesium sulfate to remove water, and then dried under reduced pressure and recrystallized from isopropyl alcohol to obtain a solid. The solid was obtained by using a preparative high performance chromatography device (Prep. HPLC) to obtain 433 mg (68%) of pure product.
1H NMR(300MHz, CDCl3) δ 4.39-3.38(m, mPEG), 5.88(d, 1H,J=5.85Hz, OCOOCH2O), 5.71(d, 1H,J=5.85 Hz, OCOOCH2O)1H NMR (300MHz, CDCl 3) δ 4.39-3.38 (m, mPEG), 5.88 (d, 1H, J = 5.85Hz, OCOO CH 2 O), 5.71 (d, 1H, J = 5.85 Hz, O C OOCH 2 O)
(실시예 3) 7-모노메톡시폴리에틸렌글리콜 20000-썩시닐옥시메틸옥시카보닐-파클리탁셀(7-mPEG 20000-succinyloxymethyloxycarbonyl-paclitaxel)의 합성Example 3 Synthesis of 7-monomethoxypolyethyleneglycol 20000-lycinyloxymethyloxycarbonyl-paclitaxel (7-mPEG 20000-succinyloxymethyloxycarbonyl-paclitaxel)
7-클로로메틸옥시카보닐 파클리탁셀(995mg, 1.050mmole)을 무수 벤젠 150ml에 용해하였다. 이 용액에 모노메톡시폴리에틸렌글리콜 20000-석시네이트(11.1g, 1.1 mmole), 요오드화 나트륨(472mg, 3.149mmole), 탄산칼륨(261mg, 1.888mmol), 및 18-크라운-6-에테르(396.5mg, 1.5mmole)를 가한 후 20시간 동안 환류시켰다. 반응 혼합물을 상온까지 냉각하고 무기물은 여과하여 거르고 여액은 감압 건조하였다. 잔류물을 메틸렌클로라이드/에테르에서 재결정하고, 얻어진 생성물을 분취용 고성능 크로마토그래피 장치(Prep. HPLC)를 이용하여 순수한 생성물 14.6g(66%)을 얻었다.7-chloromethyloxycarbonyl paclitaxel (995 mg, 1.050 mmol) was dissolved in 150 ml of anhydrous benzene. To this solution monomethoxypolyethyleneglycol 20000-succinate (11.1 g, 1.1 mmole), sodium iodide (472 mg, 3.149 mmol), potassium carbonate (261 mg, 1.888 mmol), and 18-crown-6-ether (396.5 mg, 1.5 mmol) was added and refluxed for 20 hours. The reaction mixture was cooled to room temperature, the inorganics were filtered off and the filtrate was dried under reduced pressure. The residue was recrystallized in methylene chloride / ether and the resulting product was obtained using 14.6 g (66%) of pure product using preparative high performance chromatography apparatus (Prep. HPLC).
1H NMR(300MHz, CDCl3) δ 4.21-3.37(m, mPEG), 5.89(d, 1H,J=5.78 Hz, OCOOCH2O); 5.74(d, 1H,J=5.78Hz, OCOOCH2O), 5.46(s, 1H, 2'-H)1 H NMR (300 MHz, CDCl3 ) δ 4.21-3.37 (m, mPEG), 5.89 (d, 1H,J = 5.78 Hz, OCOOCH2 O); 5.74 (d, 1H,J = 5.78 Hz, OCOOCH2 O), 5.46 (s, 1H, 2'-H)
(실시예 4) 7-모노메톡시폴리에틸렌 글리콜 5000-썩시닐티오메틸옥시카보닐-파클리탁셀(7-mPEG5000-succinylthiomethyloxy carbonyl-paclitaxel)의 합성Example 4 Synthesis of 7-monomethoxypolyethylene glycol 5000-lycinylthiomethyloxycarbonyl-paclitaxel (7-mPEG5000-succinylthiomethyloxy carbonyl-paclitaxel)
7-클로로메틸옥시카보닐-파클리탁셀(2g, 2.114mmole)을 무수 벤젠 100ml에 용해하였다. 이 용액과 모노메톡시폴리에틸렌글리콜 5000-썩시닐티오산(5.29g, 1.057mmole), 요오드화 나트륨(475mg, 3.171mmol), 탄산칼륨(262.8mg, 1.902mmole) 및 18-크라운-6-에테르(396.5mg, 1.5mmole)를 혼합하였다. 얻어진 혼합물을 환류 하에서 36시간 동안 교반한 다음 벤젠을 감압 건조하여 제거하고 잔류물을 디클로로메탄 50ml에 용해하였다. 녹지 않은 물질은 여과하여 제거하였다. 유기층을 물로 2회 세척하고 분리한 유기층을 무수 황산 마그네슘으로 처리하여 함유한 수분을 제거한 후, 감압 건조한 다음 이소프로필 알콜에서 재결정하여 고형물을 얻었다. 얻은 고형물을 분취용 고성능크로마토그래피 장치(Prep. HPLC)를 이용하여 순수한 생성물 9.2g(72%)을 얻었다.7-chloromethyloxycarbonyl-paclitaxel (2 g, 2.114 mmol) was dissolved in 100 ml of anhydrous benzene. This solution and monomethoxypolyethylene glycol 5000-lysinylthioic acid (5.29 g, 1.057 mmol), sodium iodide (475 mg, 3.171 mmol), potassium carbonate (262.8 mg, 1.902 mmol) and 18-crown-6-ether (396.5 mg) , 1.5mmole) was mixed. The resulting mixture was stirred under reflux for 36 hours and then benzene was removed by drying under reduced pressure and the residue was dissolved in 50 ml of dichloromethane. Undissolved material was removed by filtration. The organic layer was washed twice with water, and the separated organic layer was treated with anhydrous magnesium sulfate to remove the contained water, dried under reduced pressure and recrystallized from isopropyl alcohol to obtain a solid. The obtained solid was obtained by preparative high performance chromatography device (Prep. HPLC) to obtain 9.2 g (72%) of pure product.
1H NMR(300MHz, CDCl3) δ 4.39-3.38(m, mPEG), 5.98(d, 1H,J=5.85Hz, OCOOCH2S), 5.81(d, 1H,J=5.85Hz, OCOOCH2S), 5.44(s, 1H, 2H)1 H NMR (300 MHz, CDCl3 ) δ 4.39-3.38 (m, mPEG), 5.98 (d, 1H,J = 5.85 Hz, OCOOCH2 S), 5.81 (d, 1H,J = 5.85 Hz, OC OOCH2 S), 5.44 (s, 1 H, 2 H)
(실험예 1) 항종양 효과 측정Experimental Example 1 Antitumor Effect Measurement
상기 실시예 2-4의 방법으로 얻은 유도체, 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐옥시메틸옥시카보닐-파클리탁셀(실시예 2), 7-모노메톡시폴리에틸렌글리콜 20000-썩시닐옥시메틸옥시카보닐-파클리탁셀(실시예 3) 및 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐티오메틸옥시카보닐-파클리탁셀(실시예 4)의 항종양 효과의 측정은 다음과 같이 하였다.Derivative obtained by the method of Example 2-4, 7-monomethoxypolyethyleneglycol 5000-lysinyloxymethyloxycarbonyl-paclitaxel (Example 2), 7-monomethoxypolyethyleneglycol 20000-lycinyloxymethyloxy The antitumor effect of carbonyl-paclitaxel (Example 3) and 7-monomethoxypolyethyleneglycol 5000-rotinylthiomethyloxycarbonyl-paclitaxel (Example 4) was measured as follows.
동물은 수컷 비이 디이 에프 1(BDF1) 마우스(Charles River, Japan) 6주령을 사용하였다. 이식 세포주는 엘 1210(L1210) 혈액암 세포주를 이용하였다. 엘 1210 1 ×106개를 비디이에프 1 마우스의 뒷 다리에 이식하여 종양의 크기가 150㎣가 된 후부터 실시예 2 내지 4의 유도체, 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐옥시메틸옥시카보닐-파클리탁셀(실시예 2), 7-모노메톡시폴리에틸렌글리콜 20000-썩시닐옥시메틸옥시카보닐-파클리탁셀(실시예 3) 및 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐티오메틸옥시카보닐-파클리탁셀(실시예 4)을 각각 12 및 6 마이크로그램의 농도로 매일 5회 투여하여 종양 크기의 변화를 측정하였다(J. Med. Chem 1996, 39: 424-431). 그 결과를 하기 표 1에 나타내었다.Animals were 6 weeks old male BD1 mice (Charles River, Japan). Transplantation cell lines were L 1210 (L1210) hematologic cancer cell line. The derivatives of Examples 2 to 4, 7-monomethoxypolyethyleneglycol 5000-rotynyloxymethyloxycarbo, after implantation of6 L 1210 1 × 106 cells into the hind legs of BD1 mice and the tumor size reached 150 mm 3 Nyl-paclitaxel (Example 2), 7-monomethoxypolyethyleneglycol 20000-lycinyloxymethyloxycarbonyl-paclitaxel (Example 3) and 7-monomethoxypolyethyleneglycol 5000-rotinylthiomethyloxycarbonyl- Paclitaxel (Example 4) was administered five times daily at concentrations of 12 and 6 micrograms, respectively, to determine the change in tumor size (J. Med. Chem 1996, 39: 424-431). The results are shown in Table 1 below.
반복 측정한 결과, 상기 표 1에 나타낸 것과 같이, 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐옥시메틸옥시카보닐-파클리탁셀(실시예 2), 7-모노메톡시폴리에틸렌글리콜 20000-썩시닐옥시메틸옥시카보닐-파클리탁셀(실시예 3) 및 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐티오메틸옥시카보닐-파클리탁셀(실시예 4)은 기존의 파클리탁셀과 동등한 정도의 항종양 효과를 나타냈다.As a result of repeated measurements, as shown in Table 1 above, 7-monomethoxypolyethyleneglycol 5000-lysinyloxymethyloxycarbonyl-paclitaxel (Example 2), 7-monomethoxypolyethyleneglycol 20000-lycinyloxymethyl Oxycarbonyl-paclitaxel (Example 3) and 7-monomethoxypolyethyleneglycol 5000-rosinylthiomethyloxycarbonyl-paclitaxel (Example 4) showed antitumor effects equivalent to that of conventional paclitaxel.
(실험예 2) 방사선 감작 효과 측정Experimental Example 2 Measurement of Radiation Sensitization Effect
상기 실시예 2-4의 방법으로 얻은 유도체, 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐옥시메틸옥시카보닐-파클리탁셀(실시예 2), 7-모노메톡시폴리에틸렌글리콜 20000-썩시닐옥시메틸옥시카보닐-파클리탁셀(실시예 3) 및 7-모노메톡시폴리에틸렌글리콜 5000-썩시닐티오메틸옥시카보닐-파클리탁셀(실시예 4)의 방사선 감작 효과를 측정하기 위하여 사람의 종양 세포를 이용하였다. 이때 사람의 암세포는A549(폐암)와 SK-OV-3(난소암)으로 하였다.Derivative obtained by the method of Example 2-4, 7-monomethoxypolyethyleneglycol 5000-lysinyloxymethyloxycarbonyl-paclitaxel (Example 2), 7-monomethoxypolyethyleneglycol 20000-lycinyloxymethyloxy Human tumor cells were used to measure the radiosensitizing effects of carbonyl-paclitaxel (Example 3) and 7-monomethoxypolyethyleneglycol 5000-rosinylthiomethyloxycarbonyl-paclitaxel (Example 4). Human cancer cells were A549 (lung cancer) and SK-OV-3 (ovarian cancer).
먼저 종양 세포를 37℃, 5% CO2항온항습기에서 배양했으며, 이때 사용한 배지는 RPMI 1640을 기본 배지로 하여 10% 우태아 혈청을 첨가하였다. 방사선 감작 효과를 측정하기 위하여 대수 증식기에 있는 암세포를 4-웰 플레이트의 한 웰당 5 × 103세포가 되도록 분주하여 24시간 예비 배양한 후, 실시예로부터 조제된 유도체 각각에 48시간 동안 노출시키고, 노출을 종료한 후, 자외선 5 및 10 그레이(Gy)를 조사하였다. 방사선 조사 후, 즉시 새로운 배지로 교체하여 5일간 배양하여, 증식 저해 정도를 SRB 어세이를 이용하여 측정하였다. 방사선 미처리 대조군은 유도체 각각을 48시간 처리한 후, 새로운 배지로 교체하여 5일간 배양하였고, 유도체 미처리 대조군 즉, 방사선 단독 처리군은 생리 식염수를 48시간 처리후, 방사선을 조사하여 새로운 배지로 교체후 5일간 배양하여 증식 저해 정도를 SRB 어세이로 측정하였다(Anti-Cancer Drugs, 1995, 6: 115-123).Tumor cells were first cultured in a 37 ° C., 5% CO2 thermohygrostat, at which time 10% fetal calf serum was added using RPMI 1640 as a basal medium. To measure the radiosensitizing effect, cancer cells in the logarithmic proliferative phase were aliquoted to 5 x 103 cells per well of a 4-well plate, pre-cultured for 24 hours, and then exposed to each of the derivatives prepared from the examples for 48 hours, After the exposure was completed, ultraviolet rays 5 and 10 gray (Gy) were irradiated. Immediately after irradiation, the cells were replaced with fresh medium and cultured for 5 days, and the extent of inhibition of proliferation was measured using an SRB assay. The untreated control group was treated for 48 hours after each derivative was replaced with fresh medium and cultured for 5 days. The untreated derivative, that is, the radiation alone group, was treated with physiological saline for 48 hours and then irradiated with fresh medium. The extent of inhibition of proliferation was measured by incubation for 5 days (Anti-Cancer Drugs, 1995, 6: 115-123).
실시예 2 내지 4의 파클리탁셀 유도체에 48시간 노출시킨 종양 세포의 생존율과, 노출을 종료한 후, 120시간 후(회복시간, 노출 종료부터 120시간 후)의 생존율을 측정하여, 그 결과를 도 1(실시예 2), 도 3(실시예 3) 및 도 5(실시예 4)에 각각 나타내었다. 도 1, 3 및 5에서, □는 A549 종양 세포에 대한 결과이고, ○는 SK-OV-3 종양 세포에 대한 결과이다. 도 1, 3 및 5에서, (0)은 노출 종료시간을 말하고, (120)은 회복 시간 (0) 노출 종료시간 후부터 120시간 후를 말한다.The survival rate of the tumor cells exposed to the paclitaxel derivatives of Examples 2 to 48 for 48 hours and the survival rate after 120 hours (recovery time, 120 hours after the end of the exposure) after the exposure was measured and the results are shown in FIG. 1. (Example 2), FIG. 3 (Example 3) and FIG. 5 (Example 4) are shown, respectively. 1, 3 and 5, □ is the result for A549 tumor cells, and ○ is the result for SK-OV-3 tumor cells. 1, 3 and 5, (0) refers to the exposure end time, and 120 refers to the recovery time (0) 120 hours after the exposure end time.
아울러, 실시예 2 내지 4의 파클리탁셀 유도체에 노출시키고, 방사선을 조사한 후의 종양 세포의 생존율을 측정하여 그 결과를 도 2(실시예 2), 도 4(실시에 3) 및 도 6(실시예 4) 각각 나타내었다. 도 2, 4 및 6에서, □는 방사선만 조사한 A549 종양 세포에 대한 결과이고, ○는 방사선만 조사한 SK-OV-3 종양 세포에 대한 결과이고, ■는 실시예의 파클리탁셀 유도체(0.029㎍)와 방사선 조사를 함께 사용한 A549 종양 세포 결과이고, ●는 실시예의 파클리탁셀 유도체(0.029㎍)와 방사선 조사를 함께 사용한 SK-OV-3 종양 세포에 대한 결과이다.In addition, the survival rate of the tumor cells after exposure to the paclitaxel derivatives of Examples 2 to 4 was measured, and the results are shown in FIGS. 2 (Example 2), 4 (Example 3) and 6 (Example 4). ) Respectively. 2, 4 and 6, □ is the result for radiation irradiated A549 tumor cells, ○ is the radiation only result for SK-OV-3 tumor cells irradiated, ■ is the paclitaxel derivative (0.029 µg) of the Example and radiation The result was A549 tumor cell using a combination of irradiation, and ● are the results for SK-OV-3 tumor cells using a combination of paclitaxel derivative (0.029 µg) and irradiation in Example.
도 1 내지 6에 나타낸 것과 같이, 실시예 2 내지 4의 파클리탁셀 유도체와 방사선 조사를 함께 실시한 것이 파클리탁셀 유도체만 사용한 것과 방사선만 조사한 것에 비하여 항종양 효과가 현저하게 큼을 알 수 있다. 특히, 실시예 2 내지 4의 경우에는 0.029 마이크로그램과 같이 낮은 농도 처리시 방사선 5 그레이 조사 상태에서 방사선 단독 및 유도체 단독 처리군에 비하여 뛰어난 항종양 효과를 나타내었다.As shown in Figs. 1 to 6, it can be seen that the anti-tumor effect of the paclitaxel derivatives of the Examples 2 to 4 together with the irradiation was significantly greater than that of the paclitaxel derivative alone and the radiation alone. In particular, in the case of Examples 2 to 4 showed an excellent anti-tumor effect compared to the radiation alone and derivative alone treatment group in the radiation 5 gray irradiation state at a low concentration treatment such as 0.029 microgram.
본 발명의 방사선 감작제는 방사선과 병용하여 종양 치료시 뛰어난 항종양 효과를 나타낸다.Radiation sensitizers of the present invention exhibit excellent antitumor effects in the treatment of tumors in combination with radiation.
| Application Number | Priority Date | Filing Date | Title |
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| KR1020010079093AKR20030049023A (en) | 2001-12-13 | 2001-12-13 | Paclitaxel derivatives for radio-sensitizer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH08337589A (en)* | 1995-06-06 | 1996-12-24 | Bristol Myers Squibb Co | Prodrug of pacrytaxel derivative |
| KR20000067033A (en)* | 1996-03-12 | 2000-11-15 | 왈라스 시드니, 리 춘, 양 데이비드 제이, 유 동-황 | Water Soluble Paclitaxel Prodrug |
| KR20010100902A (en)* | 2000-04-15 | 2001-11-14 | 조병욱 | Aqueous-prodrug compound comprising moiety of paclitaxelor derivatives thereof, method of preparing same and pharmaceutical composition comprising same |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08337589A (en)* | 1995-06-06 | 1996-12-24 | Bristol Myers Squibb Co | Prodrug of pacrytaxel derivative |
| KR20000067033A (en)* | 1996-03-12 | 2000-11-15 | 왈라스 시드니, 리 춘, 양 데이비드 제이, 유 동-황 | Water Soluble Paclitaxel Prodrug |
| KR20010100902A (en)* | 2000-04-15 | 2001-11-14 | 조병욱 | Aqueous-prodrug compound comprising moiety of paclitaxelor derivatives thereof, method of preparing same and pharmaceutical composition comprising same |
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