KR102701332B1 - Radiosensitizer for anti-cancer comprising pyrrolopyrimidin derivatives as active ingredient - Google Patents
Radiosensitizer for anti-cancer comprising pyrrolopyrimidin derivatives as active ingredient Download PDFInfo
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- KR102701332B1 KR102701332B1 KR1020210101254A KR20210101254A KR102701332B1 KR 102701332 B1 KR102701332 B1 KR 102701332B1 KR 1020210101254 A KR1020210101254 A KR 1020210101254A KR 20210101254 A KR20210101254 A KR 20210101254A KR 102701332 B1 KR102701332 B1 KR 102701332B1
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Abstract
본 발명은 피롤로피리미딘 유도체를 유효성분으로 함유하는 항암 방사선 치료 민감제에 관한 것으로, 상기 피롤로피리미딘 유도체는 방사선 조사에 병용하여 투여함으로써, 암세포의 세포주기를 교란하고, 암세포를 사멸하는 효과가 있으므로, 항암 방사선 치료 민감제로 유용하게 사용할 수 있다.The present invention relates to an anticancer radiotherapy sensitizer containing a pyrrolopyrimidine derivative as an active ingredient. Since the pyrrolopyrimidine derivative has the effect of disrupting the cell cycle of cancer cells and killing cancer cells when administered in combination with radiation exposure, it can be usefully used as an anticancer radiotherapy sensitizer.
Description
본 발명은 피롤로피리미딘 유도체를 유효성분으로 함유하는 항암 방사선 치료 민감제에 관한 것이다.The present invention relates to an anticancer radiotherapy sensitizer containing a pyrrolopyrimidine derivative as an active ingredient.
통계적으로 암 환자 중, 국내는 약 35%, 미국의 경우 약 50% 정도가 방사선 치료를 받고 있다. 국내에서 방사선 치료를 받는 암 환자의 수는 매년 증가하고 있어 암 치료에 있어 방사선 치료의 중요성이 크게 증가하고 있다. 일반적으로 방사선 치료가 적용되고 있는 암은 두경부암, 후두암, 자궁경부암, 인두암, 폐암, 뇌암, 유방암, 직장암 및 대장암 등이 있다. 이들 암종이 방사선 치료의 주요 대상이 될지라도, 방사선 치료에 대한 예후가 좋지 않은 경우도 빈번하므로 치료 효율을 높이기 위한 전략이 필요하다. Statistically, among cancer patients, about 35% in Korea and about 50% in the United States receive radiation therapy. The number of cancer patients receiving radiation therapy in Korea is increasing every year, and the importance of radiation therapy in cancer treatment is greatly increasing. Cancers that are generally treated with radiation therapy include head and neck cancer, laryngeal cancer, cervical cancer, pharynx cancer, lung cancer, brain cancer, breast cancer, rectal cancer, and colon cancer. Although these cancers are the main targets of radiation therapy, there are many cases where the prognosis for radiation therapy is poor, so a strategy to increase treatment efficiency is necessary.
또한, 방사선 치료에 대한 초기 효과가 좋을지라도 재발 또는 방사선에 저항성을 갖는 세포가 큰 문제가 될 수 있어, 이에 대한 대책을 세우는 것이 방사선 치료의 효율을 높이는데 중요하다. 암 세포에서 방사선 치료에 대한 감수성의 차이가 존재하므로 방사선 치료 전에 개인별로 방사선에 대한 감수성을 예측할 수 있거나 이를 증가시킬 수 있는 기술을 개발하면 맞춤형 치료를 제공할 수 있다.In addition, even if the initial effect of radiation therapy is good, relapse or cells that are resistant to radiation can be a big problem, so it is important to establish countermeasures for this to increase the effectiveness of radiation therapy. Since there are differences in the sensitivity to radiation therapy among cancer cells, if a technology is developed that can predict or increase the sensitivity to radiation for each individual before radiation therapy, customized treatment can be provided.
이에, 방사선 치료 전에 방사선에 대한 암 세포의 감수성을 알아보기 위해, 분리된 암 세포에 방사선을 조사한 후, 암 세포의 사멸 정도를 분석하는 방법이 필요하다. 알려져 있는 방법들 중 가장 직접적이고 이상적인 방법은 세포를 트립판 블루(trypan blue)등의 염색약으로 염색하고 현미경과 세포 수 측정기를 이용하여 살아있는 세포의 수를 세는 것이지만 이는 시간과 너무 많은 노력이 요구되며, 검체 수가 많을 경우에는 사용할 수가 없는 문제점이 있다. 조직학적 소견이나 병기가 같은 암 환자라 하더라도 방사선 감수성은 매우 다르며, 이에 영향을 주는 많은 인자들이 있는 것으로 알려져 있다. Therefore, in order to determine the sensitivity of cancer cells to radiation before radiation therapy, a method is needed to analyze the degree of cancer cell death after irradiating isolated cancer cells with radiation. The most direct and ideal method among the known methods is to stain cells with a dye such as trypan blue and count the number of living cells using a microscope and a cell counting device, but this requires too much time and effort, and has the problem that it cannot be used when there are many samples. Even for cancer patients with the same histological findings or stage, radiation sensitivity is very different, and it is known that there are many factors that affect this.
종양이 방사선 저항성을 가지게 되는 이유 중 가장 큰 요인으로 종양 세포의 내적인 방사선 감수성이다. 방사선에 조사된 암 세포는 복잡한 분자생물학적 변화에 의해 사멸하거나 회복 되는데 이러한 기전에 관여된 유전자와 단백질들이 밝혀졌으며, 밝혀진 모든 유전자나 단백질이 방사선 치료의 효과를 증진시킬 수 있는 표적이 될 수 있는 것으로 알려졌다(Park HJ., J Korean. Soc. Ther. Radiol. Oncol., 2004, 22:S6; Choi EK., J. Korean. Soc. Ther. Radiol. Oncol. 2004, 22:S7). The most important factor in why tumors become radioresistant is the intrinsic radiosensitivity of tumor cells. Cancer cells irradiated with radiation die or recover through complex molecular biological changes, and the genes and proteins involved in this mechanism have been identified, and it is known that all of the identified genes or proteins can be targets that can enhance the effectiveness of radiotherapy (Park HJ., J Korean. Soc. Ther. Radiol. Oncol., 2004, 22:S6; Choi EK., J Korean. Soc. Ther. Radiol. Oncol. 2004, 22:S7).
방사선 저항성에 대한 연구가 지속적으로 진행되었고 이들 연구는 방사선 저항성을 극복하기 위한 방사선 민감제의 개발에 기초가 되고 있다. 현재까지 밝혀진 방사선 저항성과 관련된 인자들로는 시클로옥시게나아제-2(Terakado N et al., Oral Oncol., 2004; 40:383-9), 상피세포 성장 인자 수용체(EGFR)(Milas Let al., Int J Radiat Oncol Biol Phys., 2004; 58(3); 966-71), 시클린 D1(Milas L et al., Int J Radiat Oncol Biol Phys., 2002; 52; 514-21), 인슐린-유사 성장인자 1 수용체(IGFBP-1 receptor), 망간 수퍼옥시드 디스뮤타아제 및 수르비빈(survivin) 등이 있다.Research on radioresistance has been continuously conducted, and these studies have become the basis for the development of radiosensitizers to overcome radioresistance. Factors related to radioresistance that have been discovered to date include cyclooxygenase-2 (Terakado N et al., Oral Oncol., 2004; 40:383-9), epidermal growth factor receptor (EGFR) (Milas Let et al., Int J Radiat Oncol Biol Phys., 2004; 58(3); 966-71), cyclin D1 (Milas L et al., Int J Radiat Oncol Biol Phys., 2002; 52; 514-21), insulin-like growth factor 1 receptor (IGFBP-1 receptor), manganese superoxide dismutase, and survivin.
한편, 브로모도메인(BRD)-함유 단백질은 전사 활성화 동안 히스톤의 아세틸화된 라이신(KAc) 잔기의 인식을 위해 필수적인데, BRD는 다양한 종양유전자, 예컨대, c-Myc 및 Bcl-2의 전사를 조절한다. 따라서, BRD는 후성적세포 특징(epigenetic cell signature)에 있어서의 변화에 의해 특징화되는 다수의 질환 경로에 대한 약물 표적으로 부상하여 왔다. 지금까지, 단지 소수의 구조적으로 다양한 BRD 억제제가 보고되었으며, 이들 모두는 브로모도메인의 KAc 인식 부위 및 단백질의 브로모도메인 엑스트라 터미널(bromodomain extra terminal:BET)(BRD2, BRD3, BRD4, 및 BRDT) 패밀리의 KAc 인식 부위를 구체적으로 표적화하며, 각각은 2개의 탄뎀(tandem) BRD를 함유한다. BET-억제제는 광범위한 스펙트럼의 바람직한 생물학적 효과, 예컨대, 항암 및 소염특성을 발휘한다. 최근에, BET의 BRD는 다양한 키나제 억제제와 상호작용함이 밝혀졌다.Meanwhile, bromodomain (BRD)-containing proteins are essential for the recognition of acetylated lysine (KAc) residues of histones during transcriptional activation, and BRD regulates the transcription of various oncogenes, such as c-Myc and Bcl-2. Therefore, BRD has emerged as a drug target for a number of disease pathways characterized by changes in the epigenetic cell signature. To date, only a few structurally diverse BRD inhibitors have been reported, all of which specifically target the KAc recognition site of the bromodomain and the KAc recognition site of the bromodomain extra terminal (BET) family of proteins (BRD2, BRD3, BRD4, and BRDT), each containing two tandem BRDs. BET inhibitors exert a broad spectrum of desirable biological effects, such as anticancer and anti-inflammatory properties. Recently, the BRD of BET has been shown to interact with various kinase inhibitors.
본 발명자들은 방사선 치료에 대한 민감성을 증진시킬 수 있는 물질을 찾기 위해 노력하던 중, BRD4 억제 효과가 있는 피롤로피리미딘 유도체를 방사선과 병용처리 시에, 암 세포주의 세포주기를 변화시키고, 암의 크기를 감소시키는 것을 확인함으로써, 본 발명을 완성시켰다.The present inventors, while trying to find a substance capable of enhancing sensitivity to radiation therapy, completed the present invention by confirming that a pyrrolopyrimidine derivative having a BRD4 inhibitory effect, when used in combination with radiation, changes the cell cycle of a cancer cell line and reduces the size of cancer.
본 발명의 목적은 항암 방사선 치료 민감제를 제공하는 것이다.An object of the present invention is to provide an anticancer radiotherapy sensitizer.
본 발명의 다른 목적은 항암 보조제를 제공하는 것이다.Another object of the present invention is to provide an anticancer adjuvant.
상기 목적을 달성하기 위하여,To achieve the above purpose,
본 발명의 일 측면에 따라, 하기 화학식 1로 표시되는 화합물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항암 방사선 치료 민감제를 제공한다:According to one aspect of the present invention, there is provided an anticancer radiotherapy sensitizer comprising a compound represented by the following chemical formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[화학식 1][Chemical Formula 1]
. .
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 항암 보조제를 제공한다.According to another aspect of the present invention, an anticancer adjuvant containing a compound represented by the chemical formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is provided.
본 발명의 다른 측면에 따라, 암의 치료에 있어서의, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 항암 방사선 치료 민감제, 항암 보조제의 용도를 제공한다.According to another aspect of the present invention, there is provided a use of an anticancer radiotherapy sensitizer or anticancer adjuvant containing a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof in the treatment of cancer.
본 발명의 피롤로피리미딘 유도체는 방사선 조사에 병용하여 투여함으로써, 암세포의 세포주기를 교란하고, 암세포를 사멸하는 효과가 있으므로, 항암 방사선 치료 민감제로 유용하게 사용할 수 있다.The pyrrolopyrimidine derivative of the present invention can be usefully used as an anticancer radiotherapy sensitizer because it has the effect of disrupting the cell cycle of cancer cells and killing cancer cells when administered in combination with radiation exposure.
도 1은 인간 대장암 세포주인 HT29 세포에 대조군 또는 실시예 1 화합물을 처리한 후에 6 Gy의 방사선을 조사하고, 유세포분석기를 이용하여 세포주기 변화를 분석한 결과를 나타내는 그래프이다.
도 2는 인간 유방암 세포주인 HDA-MB-231 세포에 대조군 또는 실시예 1 화합물을 처리한 후에 4 Gy의 방사선을 조사하고, 유세포분석기를 이용하여 세포주기 변화를 분석한 결과를 나타내는 그래프이다.
도 3은 암컷 누드마우스에 인간 대장암 세포주인 HCT15 종양 세포를 이식하고, 약물투여 및/또는 방사선 조사를 수행한 후에, 경과한 날짜별로 종양의 크기를 측정한 결과를 나타내는 그래프이다.
도 4는 암컷 누드마우스에 인간 대장암 세포주인 HCT15 종양 세포를 이식하고, 약물투여 및/또는 방사선 조사를 수행한 후에, 경과한 날짜별로 누드마우스의 체중을 측정한 결과를 나타내는 그래프이다.Figure 1 is a graph showing the results of analyzing cell cycle changes using a flow cytometer after irradiating HT29 cells, a human colon cancer cell line, with 6 Gy of radiation after treating them with a control group or compound of Example 1.
Figure 2 is a graph showing the results of analyzing cell cycle changes using a flow cytometer after irradiating 4 Gy of radiation to HDA-MB-231 cells, a human breast cancer cell line, treated with a control or Example 1 compound.
Figure 3 is a graph showing the results of measuring the size of tumors by number of days after transplanting HCT15 tumor cells, a human colon cancer cell line, into female nude mice and administering drugs and/or radiation.
Figure 4 is a graph showing the results of measuring the body weight of nude mice by number of days after transplanting HCT15 tumor cells, a human colon cancer cell line, into female nude mice and administering drugs and/or radiation.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 측면은, 하기 화학식 1로 표시되는 화합물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항암 방사선 치료 민감제를 제공한다:One aspect of the present invention provides an anticancer radiotherapy sensitizer comprising a compound represented by the following chemical formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[화학식 1][Chemical Formula 1]
. .
상기 화학식 1로 표시되는 화합물의 명칭은 2,6-디클로로-4-(4-(((1r,4r)-4-히드록시시클로헥실)아미노)-7H-피롤로[2,3-d]피리미딘-5-일)페놀이다.The name of the compound represented by the above chemical formula 1 is 2,6-dichloro-4-(4-(((1r,4r)-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol.
본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by the chemical formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, and the like; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids; and organic acids such as acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. The types of these pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Includes phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜셔 제조할 수 있다. The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt can be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving a compound in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering off the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as a metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable anion salt (e.g., silver nitrate).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 이성질체, 용매화물, 수화물 등을 모두 포함한다.Furthermore, the present invention includes not only the compound represented by the chemical formula 1 and a pharmaceutically acceptable salt thereof, but also isomers, solvates, hydrates, etc. that can be prepared therefrom.
용어 "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 이성질체에는 호변이성질체(tautomer) 등의 구조 이성질체와, 비대칭 탄소 중심을 가지는 R 또는 S 이성체, 기하이성질체(트랜스, 시스) 등의 입체 이성질체, 광학 이성질체(enantiomer)가 모두 포함된다. 이들 모든 이성체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.The term "isomer" means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but structurally or sterically different. Such isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers having an asymmetric carbon center, geometric isomers (trans, cis), and optical isomers (enantiomers). All of these isomers and mixtures thereof are also included in the scope of the present invention.
용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.The term "solvate" means a compound of the present invention or a salt thereof which contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include those which are volatile, non-toxic, and/or suitable for administration to humans.
용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecμLar force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 본 발명의 상기 화학식 1로 표시되는 화합물의 수화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 물을 포함할 수 있다. 상기 수화물은 1당량 이상, 바람직하게는, 1 당량 내지 5당량의 물을 함유할 수 있다. 이러한 수화물은 물 또는 물을 함유하는 용매로부터 본 발명의 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약제학적으로 허용 가능한 염을 결정화시켜 제조될 수 있다.The term "hydrate" means a compound of the present invention or a salt thereof, which contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound represented by the formula (1) of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain at least 1 equivalent, preferably, 1 to 5 equivalents of water. Such a hydrate can be prepared by crystallizing the compound represented by the formula (1) of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof, from water or a solvent containing water.
본 발명에 따른 상기 항암 방사선 치료 민감제에 있어서, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 보다 바람직하게는 비경구 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.In the anticancer radiotherapy sensitizer according to the present invention, the compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof can be administered in various oral and parenteral dosage forms at the time of clinical administration, and more preferably, it can be a parenteral dosage form. When formulating, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing one or more compounds with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 항암 방사선 치료 민감제는 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. An anticancer radiotherapy sensitizer comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.At this time, in order to formulate a formulation for parenteral administration, the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof is mixed with a stabilizer or buffer in water to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form. The composition may be sterilized and/or contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying promoters, salts for osmotic pressure control, and/or buffers, and other therapeutically useful substances, and may be formulated according to conventional methods such as mixing, granulating, or coating.
상기 민감제는 약제학적으로 유효한 양으로 투여될 수 있다. 이는 질환의 종류, 중증도, 약물의 활성, 약물에 대한 환자의 민감도, 투여 시간, 투여 경로, 치료기간, 동시에 사용되는 약물 등에 따라 달라질 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명에 따른 민감제에 포함되는 유효성분의 양은 0.0001 내지 100 ㎎/㎏, 구체적으로 0.001 내지 10 ㎎/㎏일 수 있다. 상기 투여는 하루에 1회 또는 수회일 수 있다.The above sensitizer can be administered in a pharmaceutically effective amount. This may vary depending on the type and severity of the disease, the activity of the drug, the patient's sensitivity to the drug, the administration time, the administration route, the treatment period, drugs used simultaneously, etc. However, for a desirable effect, the amount of the effective ingredient included in the sensitizer according to the present invention may be 0.0001 to 100 mg/kg, specifically 0.001 to 10 mg/kg. The administration may be once or several times a day.
상기 화합물은 방사선 조사에 의한 암세포의 사멸을 유도할 수 있다.The above compound can induce death of cancer cells by radiation exposure.
용어 "방사선 조사"는 악성 세포의 DNA를 손상시키는 국소 치료 방법을 의미한다. 정상 세포는 종양 세포에 비해 이런 손상을 수선하는 능력이 더 크다. 방사선 조사는 이런 차이를 이용하는 치료를 의미하며, 통상적으로 의미하는 방사선을 이용하여 치료하는 방법을 포함한다.The term "irradiation" refers to a local treatment method that damages the DNA of malignant cells. Normal cells have a greater ability to repair this damage than tumor cells. Irradiation refers to a treatment that takes advantage of this difference, and includes treatments using radiation as it is commonly meant.
방사선 조사는 국소 요법의 형태이므로, 일반적으로 부작용은 치료된 부위에 제한된다. 그러나 공통된 전신 증상으로서 피로감이 있다. 많은 유전적 요인들이 일부 환자에서 2차 암의 소인이 되는 것이 사실이지만, 방사선 또한 관련 위험의 증가에 기여한다. 본 발명에 따른 방사선 민감성 증가용 조성물은 방사선의 필요량을 감소시킴으로써 이러한 부작용을 줄일 수 있다. 또한, 방사선에 민감한 암세포뿐만 아니라, 방사선에 저항성이 있는 암세포에서도 방사선 민감도를 증가시킬 수 있다.Since radiation therapy is a form of local therapy, side effects are generally limited to the treated area. However, fatigue is a common systemic symptom. While it is true that many genetic factors predispose some patients to secondary cancer, radiation also contributes to the increased risk. The composition for increasing radiosensitivity according to the present invention can reduce these side effects by reducing the required dose of radiation. In addition, it can increase radiosensitivity not only in radiation-sensitive cancer cells but also in radiation-resistant cancer cells.
본 발명의 일 실험예에서, 실시예 1 화합물의 방사선 병용처리 시에는 실시예 1 화합물 단독 처리 또는 방사선 조사 시보다 누드마우스에 이식된 종양의 크기가 더 줄어들었음을 확인하였고, 이를 통해 본 발명에 따른 피롤로피리미딘 유도체가 방사선 치료 민감도 증가에 따른 암 치료 효과가 우수함을 알 수 있었다(실험예 4 및 도 3 참조).In one experimental example of the present invention, it was confirmed that when the compound of Example 1 was treated in combination with radiation, the size of the tumor transplanted into nude mice was reduced more than when the compound of Example 1 was treated alone or with radiation irradiation. Through this, it was found that the pyrrolopyrimidine derivative according to the present invention has an excellent cancer treatment effect due to increased sensitivity to radiation therapy (see Experimental Example 4 and FIG. 3).
상기 화합물은 BRD4를 억제할 수 있다.The above compound can inhibit BRD4.
본 발명의 일 실험예에서, AlphaLISA 방법을 사용함으로써 실시예 1 화합물이 BRD4 효소 억제효과가 우수함을 확인하였다(실험예 1 및 표 1 참조).In one experimental example of the present invention, it was confirmed that the compound of Example 1 had an excellent BRD4 enzyme inhibitory effect by using the AlphaLISA method (see Experimental Example 1 and Table 1).
상기 화합물은 암세포의 세포주기를 교란시킬 수 있다.The above compounds can disrupt the cell cycle of cancer cells.
상기 암세포는 대장암세포 또는 유방암세포일 수 있다.The above cancer cells may be colon cancer cells or breast cancer cells.
본 발명의 실험예에서, 실시예 1 화합물을 인간 대장암 세포주 또는 인간 유방암 세포주에 처리한 후에 방사선을 조사하면 암세포의 세포주기가 교란되는 것을 확인하였다(실험예 2, 실험예 3, 도 1 및 도 2 참조).In an experimental example of the present invention, it was confirmed that when the compound of Example 1 was treated on a human colon cancer cell line or a human breast cancer cell line and then irradiated, the cell cycle of the cancer cells was disrupted (see Experimental Example 2, Experimental Example 3, and FIGS. 1 and 2).
상기 화합물은 암 치료 시 방사선 조사와 병용하여 투여될 수 있다.The above compound may be administered in combination with radiation therapy for the treatment of cancer.
용어 "병용하여 투여"는 다양한 종류의 암세포를 치료하는 항암 과정에서 방사선 조사를 함께 투여하는 것을 의미한다.The term "combination administration" refers to the co-administration of radiation therapy during the course of chemotherapy to treat different types of cancer cells.
상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 삼중음성유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.The above cancers are pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, The compound may be at least one selected from the group consisting of duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, triple-negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, pulmonary adenocarcinoma, lung cancer, pulmonary squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.
본 발명의 다른 측면은 상기 화학식 1로 표시되는 화합물, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 항암 보조제를 제공한다.Another aspect of the present invention provides an anticancer adjuvant containing a compound represented by the chemical formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화합물은 암 치료 시 방사선 조사와 병용하여 투여됨으로써 방사선 치료 민감도를 증가시킬 수 있다.The above compound can increase radiotherapy sensitivity when administered in combination with radiation therapy for cancer treatment.
상기 화합물은 암 치료 시 방사선 조사와 병용하여 투여될 수 있다.The above compound may be administered in combination with radiation therapy for the treatment of cancer.
상기 화합물은 방사선 치료 민감도를 증가시킬 수 있다.The above compounds may increase radiotherapy sensitivity.
상기 화합물 및 항암 보조제에 대한 기타 구체적인 설명은 상기 항암 방사선 치료 민감제의 구체적인 설명과 동일하다.Other specific descriptions of the above compounds and anticancer adjuvants are the same as the specific description of the above anticancer radiotherapy sensitizer.
상기 화합물은 BRD4를 억제할 수 있다.The above compound can inhibit BRD4.
본 발명의 일 실험예에서, AlphaLISA 방법을 사용함으로써 실시예 1 화합물이 BRD4 효소 억제효과가 우수함을 확인하였다(실험예 1 및 표 1 참조).In one experimental example of the present invention, it was confirmed that the compound of Example 1 had an excellent BRD4 enzyme inhibitory effect by using the AlphaLISA method (see Experimental Example 1 and Table 1).
본 발명의 다른 측면은, 암의 치료에 있어서의, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 항암 방사선 치료 민감제, 항암 보조제의 용도를 제공한다Another aspect of the present invention provides the use of an anticancer radiotherapy sensitizer or anticancer adjuvant containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof in the treatment of cancer.
본 발명의 다른 측면은, 항암 방사선 치료 민감제 또는 항암 보조제를 필요한 대상에게 투여하는 단계를 포함하는 암의 치료를 위한 방사선 병용처리 요법을 제공한다.Another aspect of the present invention provides a combination radiation therapy for the treatment of cancer, comprising administering to a subject in need thereof an anticancer radiosensitizer or an anticancer adjuvant.
이하, 본 발명을 하기 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by the following examples.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이들에 의하여 한정되는 것은 아니다.However, the following examples are only intended to illustrate the present invention, and the content of the present invention is not limited to these examples.
<< 실시예Example 1> 2,6-1> 2,6- 디클로로Dichloro -4-(4-(((-4-(4-((( 1r,4r1r,4r )-4-)-4- 히드록시시클로헥실Hydroxycyclohexyl )아미노)-7H-피롤로[2,3-d]피리미딘-5-일)페놀의 제조Preparation of )amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol
4-클로로-7H-피롤로[2,3-d]피리미딘 (2 g, 13.02 mmol)에 DMF (30 mL)를 넣고, 0℃에서 NBS (2.52 g, 14.24 mmol)를 넣었다. 혼합물을 상온에서 3시간 동안 교반 하였다. 반응이 완료된 후에, 용매를 고압 하에 제거해주고, 결과물을 물로 섞어 여과한 뒤, 헥산으로 씻어주고, 건조시켜 5-브로모-4-클로로-7H-피롤로[2,3-d]피리미딘 (2.66 g, 88%) 를 제조하였다.4-Chloro-7 H -pyrrolo[2,3- d ]pyrimidine (2 g, 13.02 mmol) was added to DMF (30 mL) and NBS (2.52 g, 14.24 mmol) was added at 0 °C. The mixture was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed under high pressure, and the resultant was mixed with water, filtered, washed with hexane, and dried to prepare 5-bromo-4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine (2.66 g, 88%).
1H NMR (DMSO, 300MHz): δ 7.81 (s, 1H), 8.76 (s, 1H), 5.02 (br s, 1H). 1H NMR (DMSO, 300MHz): δ 7.81 (s, 1H), 8.76 (s, 1H), 5.02 (br s, 1H).
DMF (10 mL) 에 녹여 있는 5-브로모-4-클로로-7H-피롤로[2,3-d]피리미딘 (1.2 g, 5.16 mmol) 에 NaH (0.41 g, 10.3 mmol)을 넣고, 0℃에서 30분 동안 교반 하였다. p-토실 클로라이드 (1.36 g, 7.16 mmol)를 넣어 준 후에, 혼합물을 상온에서 6시간 동안 교반하였다. 반응이 완료된 후에, 물을 넣고, 10분 동안 교반한 뒤, 결과물을 여과하여 수집하고, 건조하여 5-브로모-4-클로로-7-토실-7H-피롤로[2,3-d]피리미딘 (1.79 g, 90%)을 제조하였다.To 5-bromo-4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine (1.2 g, 5.16 mmol) dissolved in DMF (10 mL) was added NaH (0.41 g, 10.3 mmol) and stirred at 0 °C for 30 min. p-Tosyl chloride (1.36 g, 7.16 mmol) was added and the mixture was stirred at room temperature for 6 h. After the reaction was completed, water was added and stirred for 10 min. The resultant was collected by filtration and dried to prepare 5-bromo-4-chloro-7-tosyl-7 H -pyrrolo[2,3- d ]pyrimidine (1.79 g, 90%).
1H NMR (CDCl3, 300MHz): δ 8.76 (s, 1H), 8.09 (d, 2H, J = 8.1Hz), 7.54 (s, 1H), 7.34(d, 2H, J = 8.1Hz), 2.41 (s, 3H). 1H NMR (CDCl 3 , 300MHz): δ 8.76 (s, 1H), 8.09 (d, 2H, J = 8.1Hz), 7.54 (s, 1H), 7.34 (d, 2H, J = 8.1Hz), 2.41 (s, 3H).
5-브로모-4-클로로-7-토실-7H-피롤로[2,3-d]피리미딘 (500 mg, 1.29 mmol)에 n-BuOH (10 mL)를 넣고, trans-4-아미노사이클로헥산-1-올 (223 mg, 1.94 mmol)을 넣고, DIPEA (2.58 mmol)을 넣었다. 혼합물을 110℃로 3시간 동안 가열하였다. 용매를 고압에서 제거하였고, 잔여물을 크로마토그래피를 통해 정제하여 (trans)-4-((5-브로모-7-토실-7H-피롤로[2,3-d]피리미딘-4-일)아미노)사이클로헥산-1-올 (540 mg, 90 %)을 제조하였다.5-Bromo-4-chloro-7-tosyl-7 H -pyrrolo[2,3- d ]pyrimidine (500 mg, 1.29 mmol) was added n-BuOH (10 mL), trans -4-aminocyclohexan-1-ol (223 mg, 1.94 mmol), and DIPEA (2.58 mmol). The mixture was heated to 110 °C for 3 h. The solvent was removed under pressure, and the residue was purified by chromatography to afford ( trans )-4-((5-bromo-7-tosyl-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)cyclohexan-1-ol (540 mg, 90%).
1H NMR (CDCl3, 300 MHz): δ 8.37 (s, 1H), 8.06 (d, 2H, J = 8.3Hz), 7.45 (s, 1H), 7.31 (d, 2H, J = 8.2 Hz), 5.87 (d, 1H), 4.12 (m, 1H), 3.70 (m, 1H), 2.40 (s, 3H), 2.16 (m, 2H), 2.03 (m, 2H), 1.54 (m, 2H), 1.31 (m, 2H). 1 H NMR (CDCl 3 , 300 MHz): δ 8.37 (s, 1H), 8.06 (d, 2H, J = 8.3 Hz), 7.45 (s, 1H), 7.31 (d, 2H, J = 8.2 Hz), 5.87 (d, 1H), 4.12 (m, 1H), 3.70 (m, 1H), 2.40 (s, 3H), 2.16 (m, 2H), 2.03 (m, 2H), 1.54 (m, 2H), 1.31 (m, 2H).
(trans)-4-((5-브로모-7-토실-7H-피롤로[2,3-d]피리미딘-4-일)아미노)사이클로헥산-1-올 (200 mg, 0.43 mmol), 2,6-디클로로-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보로렌-2-일)페놀 (0.86 mmol), Na2CO3 (0.86 mmol)과 다이옥산 (4 mL), 물 (1mL)를 마이크로웨이브 바이얼에 넣는다. 용매를 15분 동안 탈기체화를 시키고 Pd(PPh3)2Cl2 (10 mol %)를 넣고 80℃에서 30분간 마이크로웨이브를 조사하였다. 용액을 셀라이트층으로 여과하였고 여과액을 브라인 (10 mL x 5)로 씻어주고 유기층을 농축하여 크로마토그래피(10% 메탄올:디클로로메탄)를 수행하여 (trans)-2,6-디클로로-4-(4-((-4-하이드록시사이클로헥실)아미노)-7-토실-7H-피롤로[2,3-d] 피리미딘-5-일)페놀 (40%)을 제조하였다.( trans )-4-((5-bromo-7-tosyl-7H-pyrrolo[2,3- d ]pyrimidin-4-yl)amino)cyclohexan-1-ol (200 mg, 0.43 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxabororen-2-yl)phenol (0.86 mmol), Na 2 CO 3 (0.86 mmol), dioxane (4 mL), and water (1 mL) were placed in a microwave vial. The solvent was degassed for 15 min, Pd(PPh 3 ) 2 Cl 2 (10 mol %) was added, and microwaved at 80 °C for 30 min. The solution was filtered through a celite layer, the filtrate was washed with brine (10 mL x 5), and the organic layer was concentrated and chromatographed (10% methanol:dichloromethane) to prepare ( trans )-2,6-dichloro-4-(4-((-4-hydroxycyclohexyl)amino)-7-tosyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenol (40%).
1H NMR ( CDCl3, 300 MHz ): δ 8.46 (s, 1H), 8.11 (d, 2H, J = 8.36 Hz), 7.41 (s, 1H), 7.36 (s, 2H), 7.31 (d, 2H, J = 8.13 Hz), 6.03 (m, 1H), 4.71 (d, 1H), 4.09 (m, 1H), 3.63 (m, 1H), 2.41 (s, 3H), 2.05 (m, 2H), 1.89 (m, 2H), 1.40 (m, 2H), 1.10 (m, 2H). 1 H NMR ( CDCl 3 , 300 MHz): δ 8.46 (s, 1H), 8.11 (d, 2H, J = 8.36 Hz), 7.41 (s, 1H), 7.36 (s, 2H), 7.31 (d, 2H) , J = 8.13 Hz), 6.03 (m, 1H), 4.71 (d, 1H), 4.09 (m, 1H), 3.63 (m, 1H), 2.41 (s, 3H), 2.05 (m, 2H), 1.89 (m, 2H), 1.40 (m, 2H), 1.10 (m, 2H).
상기의 중간체인 (trans)-2,6-디클로로-4-(4-((-4-하이드록시사이클로헥실)아미노)-7-토실-7H-피롤로[2,3-d]피리미딘-5-일)페놀에 1M TBAF (in THF)를 넣고 상온에서 20시간 동안 교반하였다. 반응물을 감압하여 크로마토그래피(15% 메탄올:디클로로메탄 + 0.1% 암모니아수)를 수행하여 실시예 1의 화합물 (40%)을 제조하였다.1 M TBAF (in THF) was added to the above intermediate, ( trans )-2,6-dichloro-4-(4-((-4-hydroxycyclohexyl)amino)-7-tosyl-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)phenol, and stirred at room temperature for 20 hours. The reaction mixture was purified by depressurizing and chromatography (15% methanol:dichloromethane + 0.1% ammonia water) to produce the compound of Example 1 (40%).
1H NMR (DMSO-d6, 300 MHz): δ 11.82 (br s, 1H), 10.16 (br s, 1H), 8.17 (s, 1H), 7.42 (s, 2H), 7.29 (s, 1H), 5.27 (d, 1H), 4.54 (m, 1H), 4.01 (m, 1H), 3.43 (m, 1H), 1.95 (m, 2H), 1.76 (m, 2H), 1.40 (m, 2H), 1.20 (m, 4H). 1 H NMR (DMSO-d6, 300 MHz): δ 11.82 (br s, 1H), 10.16 (br s, 1H), 8.17 (s, 1H), 7.42 (s, 2H), 7.29 (s, 1H), 5.27 (d, 1H), 4.54 (m, 1H), 4.01 (m, 1H), 3.43 (m, 1H), 1.95 (m, 2H), 1.76 (m, 2H), 1.40 (m, 2H), 1.20 (m, 4H).
<< 실험예Experimental example 1> 1> BRD4BRD4 효소 억제효과 평가Enzyme inhibition effect evaluation
본 발명에 따른 실시예 화합물의 BRD4 효소 억제효과를 평가하기 위하여 하기와 같은 실험을 수행하였고, 그 결과를 하기 표 1에 나타내었다.In order to evaluate the BRD4 enzyme inhibitory effect of the example compound according to the present invention, the following experiment was performed, and the results are shown in Table 1 below.
AlphaLISA 방법을 사용하여 BRD4 효소 억제 효과를 평가하였다. 구체적으로, biotinylated histone peptide substrate 및 GST tagged BRD4 BD1 domain을 사용하였는데, BRD4 도메인은 acetylated histone substrate에 바인딩(binding)한다. GST tagged Brd4 및 biotinylated acetylated histone peptide를 억제제(inhibitor)와 함께 반응시킨 후, ALphaLISA GSH acceptor bead 및 AlphaScreen Streptavidin conjugated donor bead를 넣어서 바인딩(binding)시키고 Alpha count로 값을 읽었다.The BRD4 enzyme inhibition effect was evaluated using the AlphaLISA method. Specifically, biotinylated histone peptide substrate and GST tagged BRD4 BD1 domain were used, and the BRD4 domain binds to acetylated histone substrate. After reacting GST tagged Brd4 and biotinylated acetylated histone peptide with an inhibitor, binding was performed by adding ALphaLISA GSH acceptor beads and AlphaScreen Streptavidin conjugated donor beads, and the value was read by Alpha count.
(IC50; μM)BRD4 enzyme inhibitory assay
(IC 50 ; μM)
그 결과 상기 표 1에 나타난 바와 같이, 실시예 1에서 제조된 화합물이 BRD4 효소 활성 어세이 결과 8.50 μM의 IC50을 나타내어 BRD4 억제 효과를 나타냄을 확인하였다. As a result, as shown in Table 1 above, it was confirmed that the compound manufactured in Example 1 exhibited a BRD4 inhibitory effect, as shown in the BRD4 enzyme activity assay result of IC 50 of 8.50 μM.
<< 실험예Experimental example 2> 방사선 병용처리에 의한 세포주기 변화 유도 확인 12> Confirmation of cell cycle change induction by combined radiation treatment 1
본 발명에 따른 실시예 화합물의 방사선 병용처리에 의한 세포주기 변화 유도 효과를 평가하기 위하여 하기와 같은 실험을 수행하였고, 그 결과를 하기 도 1에 나타내었다. 방사선 조사는 세포 내 DNA의 손상을 유발함과 동시에 DNA 손상 회복기전을 활성화시키므로, DNA 손상이 복구되기 위한 세포주기의 정지 (Cell cycle arrest)를 유도한다. 따라서 방사선 치료 민감제의 개발을 위해서는 세포주기를 교란시키는 바이오 분자가 약물개발 표적이 될 수 있다.In order to evaluate the effect of inducing cell cycle changes by combined radiation treatment of the example compound according to the present invention, the following experiment was performed, and the results are shown in Fig. 1. Radiation exposure induces damage to DNA within cells and simultaneously activates DNA damage repair mechanisms, thereby inducing cell cycle arrest for DNA damage repair. Therefore, for the development of a radiation therapy sensitizer, biomolecules that disrupt the cell cycle can be drug development targets.
실시예 1 화합물이 세포주기의 변화를 유도하는지 확인하기 위해, 인간 대장암 세포주 HT29 세포에 DMSO만 넣은 대조군 또는 실시예 1 화합물을 각각 10 μM 농도로 처리한 후, 24시간 후에 6 Gy의 방사선을 조사하였다. 방사선 조사하고 24 시간 후에, 세포를 수집하여 PI로 염색한 다음 유세포분석기를 이용하여 세포주기를 분석하였다. To determine whether the compound of Example 1 induces changes in the cell cycle, human colon cancer cell line HT29 cells were treated with a control group containing only DMSO or the compound of Example 1 at a concentration of 10 μM, and then irradiated with 6 Gy after 24 hours. 24 hours after irradiation, the cells were collected, stained with PI, and then the cell cycle was analyzed using a flow cytometer.
그 결과 도 1에 나타난 바와 같이, M1은 sub-G1, M2는 G1, M3는 S, M4는 G2와 M을 합친 것을 의미하는데, 인간 대장암 세포주 HT29 세포에 실시예 1의 화합물을 처리하고 방사선을 조사하면 M4인 G2와 M 부분이 급격하게 증가하는 것을 확인하였다. 즉, 일반적으로 G2/M phase의 세포들이 방사선 치료에 민감하게 작용하는 것으로 알려져 있고, 실시예 1의 화합물과 방사선을 함께 인간 대장암 세포주 HT29 세포에 처리하면 G2/M arrest가 일어나게 되는 바, 실시예 1의 화합물은 인간 대장암 세포주에서 방사선 치료 민감성을 가지는 것을 의미한다. As a result, as shown in Fig. 1, M1 means sub-G1, M2 means G1, M3 means S, and M4 means the combination of G2 and M. When the human colon cancer cell line HT29 cells were treated with the compound of Example 1 and irradiated, it was confirmed that the G2 and M portions, which are M4, rapidly increased. That is, it is generally known that cells in the G2/M phase are sensitive to radiation therapy, and when the human colon cancer cell line HT29 cells are treated with the compound of Example 1 and radiation together, G2/M arrest occurs, which means that the compound of Example 1 has radiation therapy sensitivity in human colon cancer cell lines.
<< 실험예Experimental example 3> 방사선 병용처리에 의한 세포주기 변화 유도 확인 23> Confirmation of cell cycle change induction by combined radiation treatment 2
본 발명에 따른 실시예 화합물의 방사선 병용처리에 의한 세포주기 변화 유도 효과를 평가하기 위하여 하기와 같은 실험을 수행하였고, 그 결과를 하기 도 2에 나타내었다. 방사선 조사는 세포 내 DNA의 손상을 유발함과 동시에 DNA 손상 회복기전을 활성화시키므로, DNA 손상이 복구되기 위한 세포주기의 정지 (Cell cycle arrest)를 유도한다. 따라서 방사선 치료 민감제의 개발을 위해서는 세포주기를 교란시키는 바이오 분자가 약물개발 표적이 될 수 있다.In order to evaluate the effect of inducing cell cycle changes by combined radiation treatment of the example compound according to the present invention, the following experiment was performed, and the results are shown in Fig. 2. Radiation exposure induces damage to DNA within cells and simultaneously activates DNA damage repair mechanisms, thereby inducing cell cycle arrest for DNA damage repair. Therefore, for the development of a radiation therapy sensitizer, biomolecules that disrupt the cell cycle can be drug development targets.
실시예 1 화합물이 세포주기의 변화를 유도하는지 확인하기 위해, 인간 유방암 세포주 MDA-MB-231 세포에 대조군 또는 실시예 1 화합물을 각각 10 μM 농도로 처리한 후, 24시간 후에 4 Gy의 방사선을 조사하였다. 방사선 조사하고 24 시간 후에, 세포를 수집하여 PI로 염색한 다음 유세포분석기를 이용하여 세포주기를 분석하였다. To determine whether the compound of Example 1 induces changes in the cell cycle, human breast cancer cell line MDA-MB-231 cells were treated with the control or the compound of Example 1 at a concentration of 10 μM, respectively, and then irradiated with 4 Gy 24 hours later. 24 hours after irradiation, the cells were collected, stained with PI, and then the cell cycle was analyzed using a flow cytometer.
그 결과 도 2에 나타난 바와 같이, M1은 sub-G1, M2는 G1, M3는 S, M4는 G2와 M을 합친 것을 의미하는데, 인간 유방암 세포주 MDA-MB-231 세포에 실시예 1의 화합물을 처리하고 방사선을 조사하면 M4인 G2와 M 부분이 급격하게 증가하는 것을 확인하였다. 즉, 일반적으로 G2/M phase의 세포들이 방사선 치료에 민감하게 작용하는 것으로 알려져 있고, 실시예 1의 화합물과 방사선을 함께 인간 유방암 세포주 MDA-MB-231 세포에 처리하면 G2/M arrest가 일어나게 되는 바, 실시예 1의 화합물은 인간 유방암 세포주에서 방사선 치료 민감성을 가지는 것을 의미한다. As a result, as shown in Fig. 2, M1 means sub-G1, M2 means G1, M3 means S, and M4 means the combination of G2 and M. When the human breast cancer cell line MDA-MB-231 cells were treated with the compound of Example 1 and irradiated, it was confirmed that the G2 and M portions, which are M4, rapidly increased. That is, it is generally known that cells in the G2/M phase are sensitive to radiation therapy, and when the human breast cancer cell line MDA-MB-231 cells are treated with the compound of Example 1 and radiation together, G2/M arrest occurs, which means that the compound of Example 1 has radiation sensitivity in human breast cancer cell lines.
<< 실험예Experimental example 4> 이식된 종양 크기 축소 확인4> Confirm reduction in transplanted tumor size
본 발명에 따른 실시예 화합물의 방사선 병용처리 시에, 방사선 치료 민감도 증가에 따른 암 치료 효과가 있는지를 평가하기 위하여 하기와 같은 실험을 수행하였고, 그 결과를 하기 도 3에 나타내었다.In order to evaluate whether there is a cancer treatment effect due to an increase in radiation therapy sensitivity when the example compound according to the present invention is used in combination with radiation, the following experiment was performed, and the results are shown in Figure 3 below.
본 실험예에서 이용한 누드마우스(BALB/c nu / nu , female)는 Charles River Japan, Inc.에서 구입하였으며, SPF(Specific Pathogen Free) 관리 하에서 사육, 실험하였다. 인간 대장암 세포주인 HCT15 세포주는 한국화학연구원에서 계대 유지한 것을 사용하였다.Nude mice (BALB/c nu / nu , female) used in this experiment were purchased from Charles River Japan, Inc., and were raised and tested under SPF (Specific Pathogen Free) management. The human colon cancer cell line, HCT15 cell line, was maintained through passage at the Korea Research Institute of Chemical Technology.
구입 후 실험실에 적응시킨 암컷 누드마우스의 오른쪽 뒷다리 피하에 인간 대장암 세포주인 HCT15 종양 세포(1x107 cells/mouse)를 이식한 뒤, 이식된 종양의 크기가 약 200 mm3에 도달하였을 때에 약물투여 및/또는 방사선 조사를 시작하였으며, 이때를 실험 1일차로 하였다. 상기 약물 투여 및/또는 방사선 조사는 표 2에 기재된 대로 그룹을(5 mice/group) 나누어 수행했는데, 구체적으로 대조군은 20% PEG400 및 3% Tween80 in DDW를 경구로 투여하였고, 동일 용매에 녹인 실시예 1(50mg/kg)를 경구로 1회 투여한 실험군, 상기와 같이 실시예 1을 투여하되 3시간 후 방사선을 약 1분간 1회 조사한 실험군을 두어 실험을 진행하였다. 그리고 또 다른 대조 실험군은 약물 투여 없이 방사선만 약 1분간 1회 조사하였다(표 2 참조). 표 2에서 p.o.는 경구 투여로 약물을 투여한 것을 의미하고, Schedule은 방사선 조사 횟수를 의미한다. After purchase, female nude mice that were acclimated to the laboratory were implanted with HCT15 tumor cells ( 1x107 cells/mouse), a human colon cancer cell line, subcutaneously under the right hind limb. When the size of the implanted tumor reached approximately 200 mm3 , drug administration and/or irradiation were started, which was defined as day 1 of the experiment. The drug administration and/or irradiation were performed by dividing the mice into groups (5 mice/group) as described in Table 2. Specifically, the control group was administered 20% PEG400 and 3% Tween80 in DDW orally, the experimental group was administered Example 1 (50 mg/kg) dissolved in the same solvent orally once, and the experimental group was administered Example 1 as described above but irradiated once for approximately 1 minute 3 hours later. In addition, another control experimental group was irradiated once for approximately 1 minute without drug administration (see Table 2). In Table 2, po means that the drug was administered orally, and Schedule means the number of times radiation was administered.
종양의 크기는 상술한 바와 같은 약물 투여 및/또는 방사선 조사 후에 2일 내지 3일마다 caliper를 이용하여, 종양의 직경(long diameter(a), short diameter(b))을 측정하고, 다음의 식에 따라 암의 크기를(volume, V) 측정하였다.Tumor size was measured using a caliper every 2 to 3 days after drug administration and/or radiation treatment as described above. The tumor diameter (long diameter (a), short diameter (b)) was measured, and the cancer volume (volume, V) was measured according to the following formula.
Volume (mm3) = a × b2 / 2 Volume (mm 3 ) = a × b 2 / 2
(control)Control group
(control)
p.o.
po
20% PEG 400 및
3% Tween 80
in DDW (용매)
20% PEG 400 and
3% Tween 80
in DDW (solvent)
50mg/kg (실시예 1)
50mg/kg (Example 1)
그 결과 도 3에 나타난 바와 같이, 용매만 투여한 대조군은 실험 39일차에 종양의 크기가 약 6000 mm3이었고, 방사선을 조사한 실험군은 실험 39일차에 종양의 크기가 2500 mm3로 대조군의 경우보다 줄어들었고, 실시예 1 처리 및 방사선 조사를 수행한 실험군의 경우는 1000 mm3로 방사선을 조사한 실험군보다도 현저하게 감소한 것을 확인하였다(도 3 참조).As a result, as shown in Fig. 3, the control group that was administered only the solvent had a tumor size of approximately 6000 mm 3 on the 39th day of the experiment, the experimental group that was irradiated had a tumor size of 2500 mm 3 on the 39th day of the experiment, which was smaller than the control group, and the experimental group that was treated with Example 1 and irradiated had a tumor size of 1000 mm 3 , which was significantly smaller than the experimental group that was irradiated (see Fig. 3).
상기 결과는 방사선 조사 시에 암 치료 효과가 있으나, 실시예 1의 방사선 병용처리 시에는 방사선 치료 민감도 증가에 의해 방사선 조사 시보다 더 우수한 암 치료 효과가 있음을 나타낸다. 이를 통해, 본 발명에 따른 피롤로피리미딘 유도체가 방사선 치료 민감도 증가에 따른 암 치료 효과가 있으므로, 항암 방사선 치료 민감제로 유용하게 사용할 수 있음을 알 수 있다.The above results show that although there is a cancer treatment effect when irradiated, the cancer treatment effect is more excellent than when irradiated when combined with radiation treatment in Example 1 due to the increase in radiotherapy sensitivity. Through this, it can be seen that the pyrrolopyrimidine derivative according to the present invention has a cancer treatment effect due to the increase in radiotherapy sensitivity, and therefore can be usefully used as an anticancer radiotherapy sensitizer.
<< 실험예Experimental example 5> 누드마우스 체중 변화 측정5> Measuring nude mouse weight changes
본 발명에 따른 실시예 화합물의 방사선 병용처리 시에, 누드마우스 체중 변화를 확인하기 위하여 하기와 같은 실험을 수행하였고, 그 결과를 하기 도 4에 나타내었다.In order to confirm the change in body weight of nude mice when the compound of the present invention is combined with radiation, the following experiment was performed, and the results are shown in Figure 4 below.
본 실험예에서 이용한 누드마우스(BALB/c nu / nu , female)는 Charles River Japan, Inc.에서 구입하였으며, SPF(Specific Pathogen Free) 관리 하에서 사육, 실험하였다. 인간 대장암 세포주인 HCT15 세포주는 한국화학연구원에서 계대 유지한 것을 사용하였다. Nude mice (BALB/c nu / nu , female) used in this experiment were purchased from Charles River Japan, Inc., and were raised and tested under SPF (Specific Pathogen Free) management. The human colon cancer cell line, HCT15 cell line, was maintained through passage at the Korea Research Institute of Chemical Technology.
구입 후 실험실에 적응시킨 암컷 누드마우스의 오른쪽 뒷다리 피하에 인간 대장암 세포주인 HCT15 종양 세포(1x107 cells/mouse)를 이식한 뒤, 이식된 종양의 크기가 약 330 mm3에 도달하였을 때에 약물투여 및 방사선 치료를 시작하였으며, 이때를 실험 1일차로 하였다. 상기 약물 투여는 상기 표 2에 기재된 대로 수행했는데, 구체적으로 대조군(5 mice/group)은 20% PEG400 및 3% Tween80 in DDW를 경구로 투여하였고, 동일 용매에 녹인 실시예 1(20mg/kg)를 경구로 1회 투여한 실험군, 상기와 같이 실시예 1을 투여하되 3시간 후 방사선을 약 1분간 1회 조사한 실험군을 두어 실험을 진행하였다. 그리고 또 다른 대조 실험군은 약물 투여 없이 방사선만 약 1분간 1회 조사하였다.After purchase, human colon cancer cell line HCT15 tumor cells ( 1x107 cells/mouse) were transplanted under the skin of the right hind leg of female nude mice that had been acclimated to the laboratory. When the size of the transplanted tumor reached approximately 330 mm3 , drug administration and radiation therapy were started, which was designated as the first day of the experiment. The drug administration was performed as described in Table 2 above. Specifically, the control group (5 mice/group) was orally administered 20% PEG400 and 3% Tween80 in DDW, an experimental group was orally administered Example 1 (20 mg/kg) dissolved in the same solvent once, and an experimental group was administered Example 1 as described above but irradiated once for approximately 1 minute after 3 hours. In addition, another control experimental group was irradiated once for approximately 1 minute without drug administration.
약물투여 및/또는 방사선 조사로 인한 누드마우스의 체중 변화를 확인하기 위하여, 실험에 사용한 누드마우스의 체중은 약물 투여 및/또는 방사선 조사를 수행한 날로부터 2일 내지 3일 간격으로 동물용 저울 (AND balance)을 이용하여 체중을 측정하였다. 실험 1일차의 체중 (Wo)과 실험 n일차의 체중 (Wn)을 측정하여, 각각의 대조군(Wc)과 실험군(Wt)의 평균값을 구하였다.To determine the change in body weight of nude mice due to drug administration and/or irradiation, the body weights of nude mice used in the experiment were measured using an animal scale (AND balance) at intervals of 2 to 3 days from the day of drug administration and/or irradiation. The body weight on day 1 of the experiment (Wo) and the body weight on day n of the experiment (Wn) were measured, and the average values of each control group (Wc) and experimental group (Wt) were obtained.
그 결과 도 4에 나타난 바와 같이, 20% PEG400 및 3% Tween80 in DDW를 경구로 투여한 대조군(5 mice/group)과 동일 용매에 녹인 실시예 1(20mg/kg)를 경구로 1회 투여한 실험군의 39일차의 평균 체중의 차이가 없었고, 약물 투여 없이 방사선만 약 1분간 1회 조사한 대조군과 실시예 1을 투여하되 3시간 후 방사선을 약 1분간 1회 조사한 실험군 간의 비교에서도 유의한 체중 차이를 보이지 않았다. As a result, as shown in Fig. 4, there was no difference in the average body weight on the 39th day between the control group (5 mice/group) orally administered 20% PEG400 and 3% Tween80 in DDW and the experimental group orally administered Example 1 (20 mg/kg) dissolved in the same solvent once. In addition, there was no significant difference in body weight in the comparison between the control group that was irradiated once for about 1 minute without drug administration and the experimental group that was administered Example 1 but irradiated once for about 1 minute 3 hours later.
상기와 같은 결과에 따라, 실시예 1의 화합물을 처리시 체중에 영향이 없음을 확인하였는 바, 부작용없이 사용 가능함을 의미한다. According to the results above, it was confirmed that there was no effect on body weight when treating with the compound of Example 1, which means that it can be used without side effects.
Claims (8)
[화학식 1]
.
A pharmaceutical composition for enhancing anticancer radiotherapy sensitivity, comprising a compound represented by the following chemical formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
.
상기 화합물은 방사선 조사에 의한 암세포의 사멸을 유도하는 것을 특징으로 하는, 항암 방사선 치료 민감 증진용 약학적 조성물.
In the first paragraph,
A pharmaceutical composition for enhancing anticancer radiotherapy sensitivity, characterized in that the compound induces death of cancer cells by radiation exposure.
상기 화합물은 BRD4를 억제하는 것을 특징으로 하는, 항암 방사선 치료 민감 증진용 약학적 조성물.
In the first paragraph,
A pharmaceutical composition for enhancing anticancer radiotherapy sensitivity, characterized in that the compound inhibits BRD4.
상기 화합물은 암 치료 시 방사선 조사와 병용하여 투여됨으로써 방사선 치료 민감도를 증가시키는 것을 특징으로 하는, 항암 방사선 치료 민감 증진용 약학적 조성물.
In the first paragraph,
A pharmaceutical composition for enhancing anticancer radiotherapy sensitivity, characterized in that the compound increases radiotherapy sensitivity by being administered in combination with radiation irradiation during cancer treatment.
상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 삼중음성유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 것을 특징으로 하는, 항암 방사선 치료 민감 증진용 약학적 조성물.In paragraph 4,
The above cancers are pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, An anticancer radiation therapy characterized by being at least one selected from the group consisting of duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, triple-negative breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, pulmonary adenocarcinoma, lung cancer, pulmonary squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. A pharmaceutical composition for enhancing therapeutic sensitivity.
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