KR100707655B1 - Porphyrin Metal complex compound derivatives - Google Patents
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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Abstract
본 발명은 광역학 치료(Phothodynamic therapy) 및 광민감제(Photosensitizer)로서 유용한 하기 화학식 1로 표시되는 포르피린 가돌리늄 착화합물 유도체 또는 그것의 약제학적으로 허용 가능한 염을 함유하는 광역학적으로 고형암을 치료하기 위한 치료제 및 이의 신규한 제조 방법에 관한 것이다.
포르피린, PDT, 클로린, 페오피틴 a, 페오포바이드 a, 가돌리늄, 광역학 치료, 광역학진단, 광민감제
The present invention provides a therapeutic agent for treating photodynamically solid cancer containing a porphyrin gadolinium complex derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof useful as Phothodynamic therapy and a photosensitizer, and It relates to a novel production method thereof.
Porphyrin, PDT, chlorine, pheophytin a, pheophobide a, gadolinium, photodynamic therapy, photodynamic diagnosis, photosensitizer
Description
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본 발명은 광역학 치료법(PDT)에 사용되는 광민감성 물질로 유용한, 하기 화학식 1로 표시되는 포르피린 가돌리늄 착화합물 유도체 또는 이의 약제학적으로 허용 가능한 염을 함유하는 광역학적으로 고형암을 치료하기위한 치료제에 관한 것이다.The present invention relates to a therapeutic agent for treating photodynamically solid cancer containing a porphyrin gadolinium complex derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, which is useful as a photosensitive substance used in photodynamic therapy (PDT) will be.
광역학 치료법이란, 암세포나 각종 종양에 대한 선택성 및 광즘감성이 있는 광민감성 물질(photosensitizer)을 이용해 수술 없이 암 등의 난치병을 치료할 수 있는 기술의 하나로서, 화학요법제와 같은 부작용이 없는 일종의 근치법이다.Photodynamic therapy is a technique that can treat incurable diseases such as cancer without surgery by using photosensitizer, which is selective and photosensitive to cancer cells or various tumors, and is a kind of radical without the side effects like chemotherapy. It is a law.
상기 광민감성 물질을 예컨대, 정맥주사에 의해 대상자에 투여하고, 이에 적절한 광(light)을 조사함으로써, 여기된 광민감성 물질이 산소분자를 활성화시켜 단일항(singlet) 상태의 산소로 변환시키거나, 새로운 라디칼을 만들거나 혹은 새로운 화학종을 만들어 암세포나 각종 종양조직만을 선택적으로 공격, 궤멸시키는 것이다.By administering the photosensitive material to the subject, for example, by intravenous injection, and irradiating with appropriate light, the excited photosensitive material activates an oxygen molecule to convert it into a singlet oxygen, By creating new radicals or creating new species, selective attack and destruction of only cancer cells or various tumor tissues.
이러한 광민감성 물질로는 포르피린(porphyrin)류의 화합물이 대표적인데, 누에의 잠분이나 뽕잎, 녹조류 등에서 추출되는 포르피린계 화합물은 광민감성 물질로 사용하기에 적합한 분광학적 특성을 갖고 있고, 가장 중요한 성질은 비교적 세토투과력이 큰 적색광선(700-900nm)에 의해 전자 전이를 일으키는 성질과 그에 따른 3중항 여기상태를 효율적으로 생성할수 있다는 것이다.Such photosensitive materials are typical of porphyrin compounds. Porphyrin-based compounds extracted from silkworms, mulberry leaves, and green algae of silkworms have spectroscopic characteristics suitable for use as photosensitive materials. The red light beam (700-900 nm), which has relatively high seto-transmittance power, is capable of generating electron transitions and a triplet excited state accordingly.
광민감성 물질로서의 포르피린 유도체는 암세포나 종양조직에 선택적으로 침투, 축적될 뿐만 아니라 화합물의 특징상 형광이나 인광을 나타내므로 종양의 조기 진단으로 활용되기도 한다.Porphyrin derivatives as photosensitizers selectively penetrate and accumulate in cancer cells or tumor tissues, and are also used as early diagnosis of tumors because they exhibit fluorescence or phosphorescence due to the characteristics of the compounds.
포르피린 관련기술로서, 미국 특허(U.S. Pat. Nos. 5,633,275,5,654,423,5,675,001,5,703,230 및 5,705,622)와 포토프린Ⅱ에 관한 미국 특허(U.S Pat. No, 4,882,234)의 물질은 이미 시장에 나와 있고 일부는 여러 임상단계에 올라 잇는 것으로 알려 지고 있는데, 상기 포토프린트Ⅱ는 헤마토포르피린(HpD)이 에스테르결합으로 연결된 여러 올리고머로 이루어진 혼합물이다.As a porphyrin-related technique, the materials of US Pat. Nos. 5,633,275,5,654,423,5,675,001,5,703,230 and 5,705,622 and US Pat. No. 4,882,234 on Photorin II are already on the market and some are It is known that it is in the clinical stage, and Photoprint II is a mixture of several oligomers in which hematoporphyrin (HpD) is linked by ester bonds.
또한, BPDMA(verteporphin, WO 97/29915)는 벤조포르피린 유도체로서 현재 피부암과 건선, 노인성 황반퇴화(AMD)에 특별한 효과가 있는 것으로 알려져 있고, 식도 및 기관지 암의 치료에 유용한 가능성이 타진되는 m-THPC(WO 97/48393)또는 모노아스피틸클로린(CA 2121716; JP 09071531)은 클로린 유도체들로서 클로린 유도체도 PDT에 효과적인 물질로서 다수가 특허파일에 등록되어 있는 상황이다.(WO 97/19081, WO 97/32885; EP 569113; U.S Pat. Nos. 5,587,394,5,648,485,5,693,632)In addition, BPDMA (verteporphin, WO 97/29915) is a benzoporphyrin derivative, currently known to have a particular effect on skin cancer, psoriasis, and age-related macular degeneration (AMD), and m- has been shown to be useful in the treatment of esophageal and bronchial cancer. THPC (WO 97/48393) or monoaspirylchlorine (CA 2121716; JP 09071531) are chlorine derivatives, and many of them are registered in the patent file as effective substances for PDT. (WO 97/19081, WO 97/32885; EP 569113; US Pat.Nos. 5,587,394,5,648,485,5,693,632)
이러한 포르피린계 화합물은 대부분이 메조-테트라페닐포르피린(TPP)의 유도체이거나 클로린계, 크로로필계,푸르푸린계, 베르딘, 딜스-알더 부가물 등이 주종을 이루며, 비 포르피린계 물질로는 5-아미노레블루산, 프탈로시아닌 등이 있다.Most of these porphyrin compounds are derivatives of meso-tetraphenylporphyrin (TPP) or chlorine, chlorophyll, purpurine, verdin, and Diels-Alder adducts. Aminoleblue acid, phthalocyanine, and the like.
여기서, 단일항 산소분자를 생성시키는 수율은 세포독성효과와 직접 관련이 있기 때문에, 단일항산소 생성에 대한 효율이 높으면 더욱 효과적인 세포독성효과를 나타낼수 있는 것이다.Here, since the yield of generating singlet oxygen molecules is directly related to the cytotoxic effect, the higher the efficiency for the production of singlet oxygen may be more effective cytotoxic effect.
이것은 인체잔류시간과 더불어 광역학치료에 아주 중요한 요소로서, 개선의 여지를 많이 남겨두고 있다고 볼 수 있다.This is a very important factor in photodynamic therapy along with human retention time, and it can be said that there is much room for improvement.
그런데, 광민감성 물질로서 현재 임상적으로 많이 사용되고 있는 상기 포토프린은, 광민감성 물질의 인체 체류시간이 길어 광독성이 큰 단점이 있으며, 양자수율 또한 개선의 여지가 많다.By the way, the photoprint which is currently used clinically as a photosensitive material has a long phototoxicity due to a long residence time of the photosensitive material, and has a lot of quantum yields.
따라서, 본 발명에서는, 상기 종래의 광민감성 물질의 단점을 개선한 것으 로, 유기합성을 통하여 얻어진 새로운 변형된 클로린계 물질로서, 기존의 포토프린보다 세포독성효과가 우수한 포르피린 착화합물 유도체 또는 이의 약제학적으로 허용 가능한 염을 제공하고자 한다.Accordingly, in the present invention, a novel modified chlorine-based material obtained through organic synthesis, which improves the disadvantages of the conventional photosensitive material, is a porphyrin complex derivative or a pharmaceutical thereof, which is superior in cytotoxic effect than the conventional photoprine. It is intended to provide acceptable salts.
본 발명은 광역학 치료법(PDT)에 사용되는 광민감성 물질로 유용한, 하기 화학식 1로 표시되는 포르피린 착화합물 유도체 또는 이의 약제학적으로 허용 가능한 염을 함유하는 광역학적으로 고형암을 치료하기위한 치료제에 관한 것이다.The present invention relates to a therapeutic agent for treating photodynamically solid cancer containing a porphyrin complex derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, which is useful as a photosensitive substance used in photodynamic therapy (PDT) .
본 발명의 화학식 1의 포르피린 유도체 또는 그 염은, 건조된 잠분 또는 녹조류로부터 유기용매(물, 클로로포름,알코올,아세톤)를 이용하여 페오피틴(pheophytin) a 또는 10-히드록시페오피틴 a를 추출하고, 관크로마토그래피, TLC 등으로 분리하며, 이들은 산 또는 염기의 존재하에서 실온 또는 환류의 조건에서 메탄올과 반응시켜 페오포바이드(pheophorbide)a 메틸에tm테르 또는 10-히드록시페오포바이드 a 메틸에스테르를 얻은 다음, 이를 출발물질로 사용하여 질소기류하에서 빛이 차단된 상태에서 반응시켜 얻는다.The porphyrin derivatives of the general formula (1) or salts thereof of the present invention may be prepared by using the organic solvent (water, chloroform, alcohol, acetone), Extraction, separation by tube chromatography, TLC and the like, which are reacted with methanol at room temperature or under reflux in the presence of acid or base to form pheophorbidea methylether or 10-hydroxyphenophosphide a Methyl esters are obtained, which are then used as starting materials and reacted under light blocking under a stream of nitrogen.
이하, 본 발명을 실시 예에 의거하여 보다 상세하게 설명하고자 하나, 이는 본 발명의 구성 및 작용의 이해를 돕기 위한 것일 뿐이며 본 발명의 범위가 이들 실시 예에 한정 되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only intended to help the understanding of the structure and operation of the present invention and the scope of the present invention is not limited to these examples.
[반응식 1] Scheme 1
구체적인 반응 공정을 실시예1에 나타내었다.The specific reaction process is shown in Example 1.
[실시예1]Example 1
50mL 반응용기에 페오피틴 a(화학식2) 60mg, 디클로로메탄 3mL과 디에틸렌글리콜 20mL를 넣고 교반한다.Into a 50 mL reaction vessel, add 60 mg of pheophytin a (Formula 2), 3 mL of dichloromethane, and 20 mL of diethylene glycol and stir.
여기서 황산 1mL를 가하고 23시간 교반한 후, 탄산수소나트륨 수용액을 넣는다.After adding 1 mL of sulfuric acid and stirring for 23 hours, an aqueous sodium hydrogen carbonate solution was added thereto.
클로로포름으로 추출하고 유기용매를 제거한 다음, 남아있는 고체를 관크로마토그래피법으로 분리하여 39mg의 원하는 화합물(화학식 3)을 얻는다.Extraction with chloroform, removal of the organic solvent, and separation of the remaining solid by column chromatography yielded 39 mg of the desired compound (Formula 3).
1H NMR(500 MHz CDCl3): δ 9.51 (s, 1H meso-H), 9.37 (s, 1H, meso-H), 8.56 (s, 1H, meso-H), 7.99 (dd, 1H), 6.29(d, 1H), 6.28 (s, 1H), 6.18 (d, 1H), 4.48-4.41 (m, 1H), 4.24-4.22 (m, 1H), 4.19-4.04 (m, 2H), 3.87(s, 3H), 3.71-3.66(m,2H), 3.68 (s, 3H), 3.64-3.42 (m, 6H), 3.40 (s, 3H), 3.22 (s, 3H), 2.68-2.15(m, 4H), 1.82 (d, 3H), 1.69 (t, 3H), 0.56 (br s, 1H), -1.61 (br s, 1H). 1 H NMR (500 MHz CDCl 3 ): δ 9.51 (s, 1H meso-H), 9.37 (s, 1H, meso-H), 8.56 (s, 1H, meso-H), 7.99 (dd, 1H), 6.29 (d, 1H), 6.28 (s, 1H), 6.18 (d, 1H), 4.48-4.41 (m, 1H), 4.24-4.22 (m, 1H), 4.19-4.04 (m, 2H), 3.87 ( s, 3H), 3.71-3.66 (m, 2H), 3.68 (s, 3H), 3.64-3.42 (m, 6H), 3.40 (s, 3H), 3.22 (s, 3H), 2.68-2.15 (m, 4H), 1.82 (d, 3H), 1.69 (t, 3H), 0.56 (br s, 1H), -1.61 (br s, 1H).
[반응식 2]Scheme 2
구체적인 반응 공정을 실시예2에 나타내었다.The specific reaction process is shown in Example 2.
[실시예2]Example 2
50mL 반응용기에 메틸페오포바이드 a 메틸에스테르(화학식 3) 50mg, 메탄올 20mL, 3N 농도의 KOH 수용액 5mL 를 넣고 10시간 동안 가열 한 후 상온으로 냉각 한다. 반응액에 무수 황산마그네슘으로 수분을 제거하고 여과한다. 여액을 농축하고 클로로포름 10mL, 메탄올 10mL, 가돌리니움(Ⅲ) 클로라이드 40mg 를 넣고 상온에서 5시간 동안 반응하였다. 반응액의 용매를 제거한 후 남은 물질을 관크로마토그래피로 분리 하여 목적하는 화합물(화학식 1)을 18mg 얻었다.Into a 50 mL reaction vessel, 50 mg of methyl pheophobide a methyl ester (Chemical Formula 3), 20 mL of methanol, and 5 mL of 3N KOH aqueous solution were heated for 10 hours, and then cooled to room temperature. The reaction solution is dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, 10 mL of chloroform, 10 mL of methanol, and 40 mg of gadolinium (III) chloride were added thereto, and the mixture was reacted at room temperature for 5 hours. After removing the solvent of the reaction solution, the remaining material was separated by column chromatography to obtain 18 mg of the target compound (Formula 1).
1H NMR(500 MHz CD3OD): δ 9.74 (s, 1H meso-H), 9.54 (s, 1H, meso-H), 9.06 (s, 1H, meso-H), 8.01 (dd, 1H), 6.24 (d, 1H), 5.98 (d, 1H), 5.24 (m, 1H), 4.48 (m, 1H) ,3.70 (m, 2H), 3.69 (s, 3H), 3.65-3.43 (m, 6H), 3.42(s, 3H), 3.24 (s, 3H), 2.70-2.24 (m, 4H), 1.85 (d, 3H), 1.65 (t, 3H) 1 H NMR (500 MHz CD 3 OD): δ 9.74 (s, 1H meso -H), 9.54 (s, 1H, meso -H), 9.06 (s, 1H, meso -H), 8.01 (dd, 1H) , 6.24 (d, 1H), 5.98 (d, 1H), 5.24 (m, 1H), 4.48 (m, 1H), 3.70 (m, 2H), 3.69 (s, 3H), 3.65-3.43 (m, 6H ), 3.42 (s, 3H), 3.24 (s, 3H), 2.70-2.24 (m, 4H), 1.85 (d, 3H), 1.65 (t, 3H)
[실시예3]Example 3
(동물시험)(Animal test)
상기 화학식1의 화합물을 이용하여 동물시험을 실시하되, 현재 유통되고 있는 포토젬(photogem, 상품명-포토트린)을 대조군으로 사용하였다. 먼저, 유방암 세포(EMT6 : 1 x 106 cell/kg)과 주사용 증류수로 희석한 포토젬(각 마우스 당 2mg/kg)을 정맥 주사하였다. 주사 3시간 후 마우스를 마취시켜 할로겐 램프를 이용하여 1.2 J로 조사하고 2∼3일 간격으로 캘리퍼를 이용하여 종양의 크기를 측정하였다. 아래 도면1은 화학식1로 처리된 EMT6 세포에 의해 종양이 유발된 BALB/c 마우스의 종양 억제를 나타낸 도표로서, 본 발명의 광민감성 물질로 처리한 군은 대조군 및 포토프린(포토젬) 처리군과 비교하여, 처리 시간이 경과하면서 EMT6 세포의 종양성장율이 현저히 줄어 들었다.Animal tests were performed using the compound of Formula 1, but photogem (trade name-Phototrin), which is currently distributed, was used as a control. First, intravenous injections of breast cancer cells (EMT6: 1 × 10 6 cells / kg) and photogem (2 mg / kg for each mouse) diluted with distilled water for injection were performed. Three hours after injection, the mice were anesthetized, irradiated with 1.2 J using a halogen lamp, and tumor size was measured using calipers every two to three days. 1 is a diagram showing tumor suppression of tumor-induced BALB / c mice by EMT6 cells treated with Formula 1, wherein the group treated with the photosensitive material of the present invention is a control group and a photoprin (photogem) treated group. Compared with the treatment time, the tumor growth rate of EMT6 cells was significantly reduced.
[실시예4]Example 4
(in vitro)(in vitro)
유방암 세포(EMT6)를 배양하여(배양배지 ; DMEM + 10％ FBS + 100U ㎍ streptomycin) 실험에 사용하였다. 세포를 상기 배지에서 배양한 후 0.25％ 트립신 - EDTA를 처리하여 세포를 수거 한 후 트립판 블루를 이용하여 세포를 개수한다. 2x105 cell/ml의 농도로 세포를 35 mm culture dish에 3 ml 첨가하여 24시간동안 5％ CO2 배양기에서 배양하여 모든 세포가 dish에 단층이 되게한다. DMF에 용해한 화학식1의 물질을 여러 농도로 희석하여 35 nm culture dish에 첨가하였다. 이 때, DMF 에 의한 효과를 배제하기위하여 사용한 DMF 농도는 0.5％를 넘지 않았다. 광민감성 물질을 세포에 첨가하고 1시간 후, 할로겐 램프를 이용하여 1.2 J의 세기로 빛을 조사하였다. 빛을 조사한 다음, culture dish를 배양기로 옮겨 배양하였다.Breast cancer cells (EMT6) were cultured (culture medium; DMEM + 10% FBS + 100 U μg streptomycin) and used for the experiment. After culturing the cells in the medium, the cells are harvested by treatment with 0.25% Trypsin-EDTA and the cells are counted using trypan blue. Add 3 ml of cells to a 35 mm culture dish at a concentration of 2x10 5 cell / ml and incubate in a 5% CO 2 incubator for 24 hours so that all cells are monolayer in the dish. The substance of Formula 1 dissolved in DMF was diluted to various concentrations and added to a 35 nm culture dish. At this time, the DMF concentration used to exclude the effect by DMF did not exceed 0.5%. One hour after the addition of the photosensitive material to the cells, light was irradiated at a intensity of 1.2 J using a halogen lamp. After irradiating with light, the culture dish was transferred to the incubator and cultured.
아래 도면2는 세포 사멸의 기전을 연구하기 위하여 Annexin V/PI 염색을 실시한 결과가 나타나 있으며, 도면에서와 같이, 대조군에서는 90％이상이 생존해 있는 반면, PDT 처리군(0.4 ㎍/hr)에서는 50∼60％ 이상 고사(cell apoptosis)됨으로써 EMT6 세포가 사멸되고 있음을 확인 할 수 있다.Figure 2 below shows the results of staining Annexin V / PI to study the mechanism of cell death. As shown in the figure, 90% or more survived in the control group, while in PDT treated group (0.4 μg / hr) It can be confirmed that EMT6 cells are killed by 50 to 60% or more of apoptosis.
이상 설명한 바와 같이, 본 발명의 화학식 1의 포르피린 금속 착화합물 유도체 또는 이의 약제학적으로 허용 가능한 염을 함유하는 광역학적으로 고형암을 치료하기위한 치료제로써, 기존의 광민감성 물질의 단점을 개선한 것으로, 단일항 상태의 산소를 생성시키는 양자수율이 우수하고 물리적 안정성이 좋으며, 기존의 포토프린보다 세포독성효과가 우수하여 관련 분야에의 이용 및 응용이 가능하다 하겠다.As described above, a therapeutic agent for treating photodynamically solid cancer containing the porphyrin metal complex derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof, which improves the disadvantage of the conventional photosensitive material, It has excellent quantum yield, good physical stability, and superior cytotoxic effect than conventional photoprin, which can be used and applied in related fields.
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| KR101288461B1 (en) | 2009-06-26 | 2013-07-26 | 주식회사 진코스 | Anticancer chemotherapeutic agent-chlorin derivative conjugate, a photosensitizer comprising the same, and a composition for treatment of cancer comprising the same |
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| KR20070010257A (en) | 2007-01-24 |
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