KR102709756B1 - Phenylene dibenzamide based compounds and composition for preventing and treating cancer diseases comprising the same as effective ingredient - Google Patents
Phenylene dibenzamide based compounds and composition for preventing and treating cancer diseases comprising the same as effective ingredient Download PDFInfo
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- KR102709756B1 KR102709756B1 KR1020210048315A KR20210048315A KR102709756B1 KR 102709756 B1 KR102709756 B1 KR 102709756B1 KR 1020210048315 A KR1020210048315 A KR 1020210048315A KR 20210048315 A KR20210048315 A KR 20210048315A KR 102709756 B1 KR102709756 B1 KR 102709756B1
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- C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
본 발명은 하기 구조식 1로 표시되는 신규 화합물에 관한 것이다. 이에 의하여 헤지호그 신호전달 경로에서 GLI를 표적으로 하여 발현 및 활성을 제어함으로써 결과적으로 헤지호그 신호전달 경로를 억제할 수 있고, 토포이소머레이즈(topoisomerase) 억제제와 병용함으로써 GLI 발현 및 활성 억제능을 더욱 향상시킬 수 있고, 상기 신규 화합물들을 포함하는 라이브러리로부터 스크리닝된 화합물은 암질환 예방 또는 치료용으로 사용될 수 있다.
[구조식 1]
The present invention relates to a novel compound represented by the following structural formula 1. By this, the hedgehog signaling pathway can be inhibited by targeting GLI in the hedgehog signaling pathway and controlling its expression and activity, and by using it in combination with a topoisomerase inhibitor, the ability to inhibit GLI expression and activity can be further improved, and a compound screened from a library containing the novel compounds can be used for preventing or treating cancer.
[Structural formula 1]
Description
본 발명은 페닐렌 디벤즈아미드계 신규 화합물 및 이를 유효성분으로 포함하는 암질환 예방 또는 치료용 약제학적 조성물에 관한 것이다.The present invention relates to a novel phenylene dibenzamide compound and a pharmaceutical composition for preventing or treating cancer containing the same as an effective ingredient.
대장암은 현재 우리나라에서 전체 3번째의 높은 발생률을 가지고 있으며, 남자에서 2번째, 여자에서 3번째의 높은 발생률 가지며 그 발생률과 사망률이 계속 증가하고 있는 추세를 보인다. 또한 생활양식이 점차 서구화되어 가는 것을 고려하면 대장암의 증가는 더욱 가속화 될 것으로 예상되어 우리 사회에서 대장암에 대한 적극적 관심과 연구가 반드시 필요하다. 또한 대장암은 완치 후 재발률이 최대 50%에 이를 정도로 높아 그 위험률은 더 심각하다. 대장암은 외과적 근치 절제술이 치료의 원칙이고 조기 대장암일 경우에는 수술만으로 좋은 생존율이 기대된다. 암이 전이된 환자의 경우나 재발 또는 전이의 위험이 높은 환자의 경우에는 보조요법으로 이리노테칸(IRI), 옥살리플라틴(Oxaliplatin)과 같은 상대적으로 비 선택적인 세포독성의 약제들이 지금까지 대장암의 치료에 사용되었으며 이에 더하여 최근에는 선택적인 치료제로 알려진 세툭시맙(Cetuximab)이나 베바시주맙(Bevacizumab) 같은 약제들이 대장암 치료제로 사용되고 있다. 이제까지 대장암의 항암요법에 널리 쓰이는 약제는 대장암 세포뿐만 아니라 정상 세포도 죽임으로써 심각한 부작용을 초래하였으며, 암화 과정의 억제에 집중되어있기 때문에 실질적인 치료의 한계를 가지고 있다. 또한 선택적인 치료제로 알려진 표적항암제의 경우에는 항암제 내성이라는 큰 문제점을 가진다. 따라서 앞으로 개발이 될 약제들은 이러한 부작용을 최소화시키는 약제가 되어야 한다. 이러한 관점에서 효과적인 대장암 치료법 개발을 위해서는 대장암 발생의 분자생물학적 기전은 물론 다른 조직으로 전이 되는 과정에 나타나는 다양한 유전자 발현양상을 비교함과 동시에 그 역할을 규명함으로써 암화과정에 관련된 새로운 표적인자를 발굴하는 연구가 요구된다.Colon cancer currently has the third highest incidence rate in Korea, the second highest in men and the third highest in women, and its incidence and mortality rates are continuously increasing. In addition, considering the gradual westernization of lifestyles, the increase in colon cancer is expected to accelerate further, so active interest in and research on colon cancer in our society are absolutely necessary. In addition, colon cancer has a high recurrence rate of up to 50% after complete cure, making its risk even more serious. The principle of treatment for colon cancer is surgical radical resection, and in the case of early colon cancer, a good survival rate is expected with surgery alone. In the case of patients with metastatic cancer or patients with a high risk of recurrence or metastasis, relatively non-selective cytotoxic drugs such as irinotecan (IRI) and oxaliplatin have been used as adjuvant therapy for colon cancer. In addition, drugs known as selective agents such as cetuximab and bevacizumab have recently been used as colon cancer treatments. The drugs widely used in the treatment of colorectal cancer so far have caused serious side effects by killing not only colorectal cancer cells but also normal cells, and have limitations in practical treatment because they are focused on suppressing the carcinogenic process. In addition, targeted anticancer drugs known as selective treatment agents have a major problem called anticancer drug resistance. Therefore, drugs to be developed in the future should be drugs that minimize these side effects. From this perspective, in order to develop effective colorectal cancer treatment, research is required to discover new target factors related to the carcinogenic process by comparing the molecular biological mechanisms of colorectal cancer occurrence as well as the various gene expression patterns that appear in the process of metastasis to other tissues, and at the same time clarifying their roles.
한편, 헤지호그 신호전달 경로는 주변세포에 작용하여 발생 중 세포의 운명결정, 분화, 증식을 유도할 수 있다. 최근 헤지호그 신호전달 경로가 성인의 줄기세포유지에 관여하며, 필리스터홀 증후군(Pallister Hall syndrome), VATER 증후군 등의 각종 선천성질환, 속질모세포암, 폐암, 위암, 식도암, 췌장암 등의 암 발생에도 관여하는 것이 알려지면서 그 임상적 중요성이 부각되고 있다. 헤지호그/GLI 신호전달 경로가 돌연변이나 환경적 요인에 의해 과발현시 여러 종류의 암을 유발함이 여러 보고들에 의해 알려져 있다. (Yoo YA et al., Cancer Res 2011; 71: 7061-7070, Sun Q et al., Tumor Biol 2016; 37: 16215-16225). 헤지호그 신호 전달 체계는 암줄기 세포의 자기 복제에 필수적이기 때문에 대장암 치료의 새로운 표적으로 기대할 수 있다. 헤지호그 신호 전달 체계의 저해를 일반 항암제 치료와 병용하여 대장암의 암줄기 세포를 소멸시키는 것이 가능할 것으로 생각되고, 헤지호그 신호 전달 체계는 세포막에 있는 수용체인 Patched-1 (PTCH-1)에 헤지호그가 결합함으로써 시작된다. 참고로 이와 같은 헤지호그 신호전달 경로에 대한 개략도를 도 1에 나타내었다.Meanwhile, the Hedgehog signaling pathway can act on surrounding cells to induce cell fate determination, differentiation, and proliferation during development. Recently, the clinical importance of the Hedgehog signaling pathway has been highlighted as it has been known to be involved in the maintenance of stem cells in adults, various congenital diseases such as Pallister Hall syndrome and VATER syndrome, and the development of cancers such as medullary blastoma, lung cancer, gastric cancer, esophageal cancer, and pancreatic cancer. Several reports have shown that the Hedgehog/GLI signaling pathway induces various types of cancer when overexpressed due to mutations or environmental factors (Yoo YA et al., Cancer Res 2011; 71: 7061-7070, Sun Q et al., Tumor Biol 2016; 37: 16215-16225). Since the Hedgehog signaling system is essential for the self-renewal of cancer stem cells, it can be expected as a new target for the treatment of colon cancer. It is thought that inhibition of the hedgehog signaling pathway may be possible to eliminate cancer stem cells of colon cancer by combining it with general chemotherapy. The hedgehog signaling pathway is initiated by the binding of hedgehog to Patched-1 (PTCH-1), a receptor on the cell membrane. For reference, a schematic diagram of the hedgehog signaling pathway is shown in Fig. 1.
헤지호그가 없는 경우에는 PTCH-1가 SMO(Smoothened)을 저해하고 있으므로, 이 신호전달 체계는 작동하는 않는다. 헤지호그(SHH)가 PTCH-1에 결합하면 SMO의 저해는 해제되고 SMO는 하류의 신호전달 체계를 통해 전사 인자인 GLI을 활성화하고 헤지호그 표적 유전자를 활성화된다. 헤지호그 신호전달은 암줄기 세포의 자기 복제와 증식을 제어하는 신호 전달 체계로 알려져 있고, 이러한 결과들은 헤지호그 신호전달 경로가 암화를 차단할 수 있는 새로운 타겟 치료법(therapy)으로서의 가능성을 제시한다. SHH/GLI 신호전달 경로를 차단하는 억제제(inhibitor)인 GANT61(GLI inhibitor) 처리 시 암세포의 성장이 억제된다고 알려져 있다. 헤지호그 신호 전달과 암의 발생 사이의 관련성에 대하여는 다양한 연구적 접근이 시도되고 있지만, GLI를 직접 표적하여 GLI의 발현 및 활성을 효과적으로 제어하는 억제제의 임상적 보고는 거의 알려진 바가 없다. 또한 헤지호그 저해제로서 진행성 기저 세포암에 허가된 Vismodegib (Erivedge) 캡슐이 있지만, 1개월분이 천만원을 넘는 고가로서 사용이 쉽지 않다.In the absence of Hedgehog, PTCH-1 inhibits SMO (Smoothened), so this signaling pathway does not work. When Hedgehog (SHH) binds to PTCH-1, the inhibition of SMO is released, and SMO activates the transcription factor GLI through the downstream signaling pathway, thereby activating Hedgehog target genes. Hedgehog signaling is known as a signaling pathway that controls the self-renewal and proliferation of cancer stem cells, and these results suggest the possibility that the Hedgehog signaling pathway may be a new targeted therapy that can block cancer. It is known that cancer cell growth is inhibited when treated with GANT61 (GLI inhibitor), an inhibitor that blocks the SHH/GLI signaling pathway. Although various research approaches have been attempted on the relationship between Hedgehog signaling and the occurrence of cancer, there are few clinical reports of inhibitors that directly target GLI and effectively control its expression and activity. There is also Vismodegib (Erivedge) capsules, which are approved for advanced basal cell carcinoma as hedgehog inhibitors, but they are expensive at over 10 million won per month, making them difficult to use.
암은 현재 전 세계적으로 가장 많은 사망자를 내는 질병 중 하나로서, 암 발생 연령은 점차 낮아지고 있는 반면 평균 수명은 점차 연장되고 있어 암 발생률은 더욱 증가할 것으로 전망되고 있으므로 암을 효과적으로 제어하는 새로운 억제제가 필요하다. 또한 암세포에서 기존의 항암제의 효과를 극대화 시킬 수 있는 병용 항암제의 탐구가 매우 중요해지고 있는 실정이다. 이에 헤지호그/GLI 신호전달을 효과적으로 억제하는 새로운 소분자 화합물을 개발하여, 이를 활용한 암의 예방 및 치료방법을 제시하고자 한다.Cancer is currently one of the most common diseases causing deaths worldwide. The age of cancer onset is gradually decreasing, while the average life expectancy is gradually increasing, so the cancer incidence rate is expected to increase further. Therefore, new inhibitors that effectively control cancer are needed. In addition, the exploration of combination anticancer agents that can maximize the effect of existing anticancer agents in cancer cells is becoming very important. Accordingly, we aim to develop a new small molecule compound that effectively inhibits Hedgehog/GLI signaling and suggest a method for preventing and treating cancer using it.
본 발명의 목적은 헤지호그 신호전달 경로에서 GLI를 표적으로 하여 발현 및 활성을 제어함으로써 결과적으로 헤지호그 신호전달 경로를 억제할 수 있고, 토포이소머레이즈(topoisomerase) 억제제와 병용함으로써 GLI 발현 및 활성 억제능을 더욱 향상시킬 수 있는 신규 화합물을 제공하는 데 있다.The purpose of the present invention is to provide a novel compound which can suppress the hedgehog signaling pathway by targeting GLI in the hedgehog signaling pathway and controlling its expression and activity, and which can further enhance the ability to suppress GLI expression and activity by using it in combination with a topoisomerase inhibitor.
본 발명의 다른 목적은 헤지호그 신호전달 경로에서 GLI를 표적으로 하여 발현 및 활성을 제어함으로써 결과적으로 헤지호그 신호전달 경로를 억제할 수 있고, 토포이소머레이즈(topoisomerase) 억제제와 병용함으로써 GLI 발현 및 활성 억제능을 더욱 향상시킬 수 있는 신규 화합물을 유효성분으로 포함하는 암질환 예방 또는 치료용 약제학적 조성물을 제공하는 데 있다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising a novel compound as an active ingredient, which can suppress the hedgehog signaling pathway by targeting GLI in the hedgehog signaling pathway and controlling its expression and activity, and can further enhance the ability to suppress GLI expression and activity by using it in combination with a topoisomerase inhibitor.
본 발명의 다른 또 하나의 목적은 헤지호그 신호전달 경로에서 GLI를 표적으로 하여 발현 및 활성을 제어함으로써 결과적으로 헤지호그 신호전달 경로를 억제할 수 있고, 토포이소머레이즈(topoisomerase) 억제제와 병용함으로써 GLI 발현 및 활성 억제능을 더욱 향상시킬 수 있는 신규 화합물의 스크리닝 방법을 제공하는 데 있다.Another object of the present invention is to provide a method for screening a novel compound that can suppress the hedgehog signaling pathway by targeting GLI in the hedgehog signaling pathway and controlling its expression and activity, and can further enhance the ability to suppress GLI expression and activity by using the compound in combination with a topoisomerase inhibitor.
본 발명의 일 측면에 따르면,According to one aspect of the present invention,
하기 구조식 1로 표시되는 화합물이 제공된다.A compound represented by the following structural formula 1 is provided.
[구조식 1][Structural formula 1]
구조식 1에서,In structural formula 1,
R1은 수소원자, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 시클로알킬기, 치환 또는 비치환된 C1 내지 C30 헤테로시클로알킬기, 치환 또는 비치환된 C6 내지 C30 아릴기, 또는 치환 또는 비치환된 C1 내지 C30 헤테로아릴기이고,R 1 is a hydrogen atom, a substituted or unsubstituted C1 to C30 alkoxy group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group,
R2는 수소원자, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 시클로알킬기, 치환 또는 비치환된 C1 내지 C30 헤테로시클로알킬기, 치환 또는 비치환된 C6 내지 C30 아릴기, 또는 치환 또는 비치환된 C1 내지 C30 헤테로아릴기이고, R 2 is a hydrogen atom, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group,
R3은 수소원자, 니트로기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 시클로알킬기, 치환 또는 비치환된 C1 내지 C30 헤테로시클로알킬기, 치환 또는 비치환된 C6 내지 C30 아릴기, 또는 치환 또는 비치환된 C1 내지 C30 헤테로아릴기이다.R 3 is a hydrogen atom, a nitro group, a substituted or unsubstituted C1 to C30 alkoxy group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group.
바람직하게는 상기 구조식 1에서,Preferably, in the structural formula 1 above,
R1은 C1 내지 C10 알콕시기, 또는 C1 내지 C10 알킬기이고,R 1 is a C1 to C10 alkoxy group or a C1 to C10 alkyl group,
R2는 수소원자, 또는 C1 내지 C10 알킬기이고,R 2 is a hydrogen atom or a C1 to C10 alkyl group,
R3은 니트로기, 또는 C1 내지 C10 알콕시기 일 수 있다.R 3 can be a nitro group or a C1 to C10 alkoxy group.
더욱 바람직하게는, 상기 구조식 1로 표시되는 화합물은 하기 구조식 2 또는 구조식 3으로 표시될 수 있다.More preferably, the compound represented by the structural formula 1 may be represented by the following structural formula 2 or structural formula 3.
[구조식 2][Structural formula 2]
[구조식 3][Structural formula 3]
구조식 2 또는 3에서,In structural formula 2 or 3,
R1은 C1 내지 C10 알콕시기, 또는 C1 내지 C10 알킬기이고,R 1 is a C1 to C10 alkoxy group or a C1 to C10 alkyl group,
R2는 수소원자, 또는 C1 내지 C10 알킬기이고,R 2 is a hydrogen atom or a C1 to C10 alkyl group,
R3은 니트로기, 또는 C1 내지 C10 알콕시기이다.R 3 is a nitro group or a C1 to C10 alkoxy group.
더욱 더 바람직하게는, 상기 구조식 1로 표시되는 화합물은 하기 화합물 1 또는 화합물 2 일 수 있다.Even more preferably, the compound represented by the structural formula 1 may be compound 1 or compound 2 below.
[화합물 1][Compound 1]
[화합물 2][Compound 2]
본 발명의 다른 하나의 측면에 따르면,According to another aspect of the present invention,
하기 화합물 1 또는 화합물 2, 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 암질환 예방 또는 치료용 약제학적 조성물이 제공된다.A pharmaceutical composition for preventing or treating cancer, comprising compound 1 or compound 2, or a pharmaceutically acceptable salt thereof, as an active ingredient, is provided.
[화합물 1][Compound 1]
[화합물 2][Compound 2]
상기 암질환 예방 또는 치료용 약제학적 조성물은 토포이소머레이즈(topoisomerase) 억제제를 추가로 포함할 수 있다.The pharmaceutical composition for preventing or treating cancer may additionally contain a topoisomerase inhibitor.
상기 토포이소머레이즈 억제제는 이리노테칸(irinotecan), 토포테칸(topotecan), 및 벨로테칸(belotecan) 중에서 선택된 1종 이상일 수 있다.The above topoisomerase inhibitor may be at least one selected from irinotecan, topotecan, and belotecan.
상기 암질환은 대장암, 위암, 전립선암, 폐암, 췌장암, 기저세포암, 뇌암, 간암, 및 유방암 중에서 선택된 어느 하나일 수 있다.The above cancer disease may be any one selected from colon cancer, stomach cancer, prostate cancer, lung cancer, pancreatic cancer, basal cell carcinoma, brain cancer, liver cancer, and breast cancer.
바람직하게는, 상기 암질환은 대장암, 위암, 전립선암 및 폐암 중에서 선택된 어느 하나일 수 있다.Preferably, the cancer disease may be any one selected from colon cancer, stomach cancer, prostate cancer, and lung cancer.
상기 암질환 예방 또는 치료용 약제학적 조성물은 헤지호그 신호전달(hedgehog signaling) 저해용일 수 있다.The pharmaceutical composition for preventing or treating the above cancer disease may be for inhibiting hedgehog signaling.
상기 암질환 예방 또는 치료용 약제학적 조성물은 GLI 전사활성 억제용일 수 있다.The pharmaceutical composition for preventing or treating the above cancer disease may be for inhibiting GLI transcriptional activity.
본 발명의 다른 또 하나의 측면에 따르면,According to another aspect of the present invention,
GLI 리포터 NIH3t3 세포주를 N,N'-1,3-페닐렌 디벤즈아미드(N,N'-1,3-phenylene dibenzamide)계 화합물 라이브러리에 처리하는 단계를 포함하는 암질환 예방 또는 치료용 화합물의 스크리닝 방법이 제공된다.A method for screening for compounds for preventing or treating cancer is provided, comprising the step of treating a GLI reporter NIH3t3 cell line with a library of N,N'-1,3-phenylene dibenzamide compounds.
상기 GLI 리포터 NIH3t3 세포주는 GLI 발현량에 따라 제어되는 루시퍼레이즈 유전자(luciferase gene)를 포함할 수 있다.The above GLI reporter NIH3t3 cell line may contain a luciferase gene that is controlled by the amount of GLI expression.
상기 GLI 리포터 NIH3t3 세포주에서 리포터 활성에 대한 IC50값이 15μM 이하로 측정되는 화합물을 스크리닝할 수 있다.Compounds whose IC50 value for reporter activity in the above GLI reporter NIH3t3 cell line is measured to be 15 μM or less can be screened.
본 발명의 구조식 1로 표시되는 N,N'-1,3-페닐렌 디벤즈아미드(N,N'-1,3-phenylene dibenzamide)계 신규 화합물은 헤지호그 신호전달 경로에서 GLI를 표적으로 하여 발현 및 활성을 제어함으로써 결과적으로 헤지호그 신호전달 경로를 억제할 수 있고, 토포이소머레이즈(topoisomerase) 억제제와 병용함으로써 GLI 발현 및 활성 억제능을 더욱 향상시킬 수 있다.The novel N,N'-1,3-phenylene dibenzamide compound represented by structural formula 1 of the present invention can suppress the hedgehog signaling pathway by targeting GLI in the hedgehog signaling pathway and controlling its expression and activity, and can further enhance the ability to suppress GLI expression and activity by using it in combination with a topoisomerase inhibitor.
또한, 본 발명의 N,N'-1,3-페닐렌 디벤즈아미드(N,N'-1,3-phenylene dibenzamide)계 화합물 라이브러리에서 스크리닝한 GLI 전사활성 억제능이 높은 화합물 1 또는 화합물 2은 암질환 예방 또는 치료에 유용하고, 특히 토포이소머레이즈 억제제와 병용함으로써 암질환 예방 또는 치료에 시너지 효과를 나타낼 수 있다.In addition, compound 1 or compound 2 having a high GLI transcriptional activity inhibitory ability screened from the N,N'-1,3-phenylene dibenzamide compound library of the present invention is useful for preventing or treating cancer, and in particular, can exhibit a synergistic effect in preventing or treating cancer when used in combination with a topoisomerase inhibitor.
도 1은 헤지호그 신호전달 경로에 대한 개략도이다.
도 2는 실시예 1에 따른 GLI 전사 활성 억제능 확인 결과이다.
도 3은 실험예 1에 따른 정상 대장세포 및 대장암 세포주에서 헤지호그/GLI 발현 확인 결과이다.
도 4는 실험예 2의 헤지호그/GLI 억제제와 이리노테칸(IRI) 단독 처리에 따른 세포성장 측정 결과이다.
도 5는 실험예 2의 헤지호그/GLI 억제제와 이리노테칸(IRI) 병용 처리에 따른 세포성장 측정 결과이다.
도 6은 실험예 3의 헤지호그/GLI 억제제와 IRI 병용 처리 후 세포의 현미경 사진이다.
도 7은 실험예 3의 헤지호그/GLI 억제제와 IRI 병용 처리에 따른 유세포 분석(flow cytometry) 결과이다.
도 8은 실험예 3의 헤지호그/GLI 억제제와 IRI 병용 처리에 따른 세포사멸 단백질 발현 확인 결과이다.
도 9는 실험예 3에서 세포사멸의 효과가 카스페이스에 의존적인지 확인한 결과이다.
도 10은 실험예 3에서 위암 세포주, 전립선암 세포주 및 폐암 세포주에서 세포사멸 단백질 생성을 측정한 결과이다.
도 11은 실험예 4에서 헤지호그/GLI 억제제의 GLI1 단백질 억제 확인 결과이다.
도 12는 실험예 5에서 헤지호그/GLI 억제제의 세포사멸 단백질 확인 결과이다. Figure 1 is a schematic diagram of the hedgehog signaling pathway.
Figure 2 shows the results of confirming GLI transcription activity inhibition ability according to Example 1.
Figure 3 shows the results of confirming Hedgehog/GLI expression in normal colon cells and colon cancer cell lines according to Experimental Example 1.
Figure 4 shows the results of cell growth measurement according to treatment with hedgehog/GLI inhibitor and irinotecan (IRI) alone in Experimental Example 2.
Figure 5 shows the results of cell growth measurement according to combined treatment with hedgehog/GLI inhibitor and irinotecan (IRI) in Experimental Example 2.
Figure 6 is a microscopic photograph of cells after combined treatment with hedgehog/GLI inhibitor and IRI in Experimental Example 3.
Figure 7 shows the results of flow cytometry analysis according to combined treatment with hedgehog/GLI inhibitor and IRI in Experimental Example 3.
Figure 8 shows the results of confirming the expression of apoptotic proteins according to combined treatment with hedgehog/GLI inhibitor and IRI in Experimental Example 3.
Figure 9 shows the results of Experimental Example 3, which confirmed whether the effect of cell death was dependent on the spacer.
Figure 10 shows the results of measuring the production of apoptotic proteins in gastric cancer cell lines, prostate cancer cell lines, and lung cancer cell lines in Experimental Example 3.
Figure 11 shows the results of confirming GLI1 protein inhibition by hedgehog/GLI inhibitor in Experimental Example 4.
Figure 12 shows the results of confirming the apoptosis protein of the hedgehog/GLI inhibitor in Experimental Example 5.
본 발명은 다양한 변환을 가할 수 있고 여러 가지 실시예를 가질 수 있는 바, 특정 실시예들을 도면에 예시하고 상세한 설명에 상세하게 설명하고자 한다. 그러나, 이는 본 발명을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 본 발명의 사상 및 기술 범위에 포함되는 모든 변환, 균등물 내지 대체물을 포함하는 것으로 이해되어야 한다. 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.The present invention can be modified in various ways and has various embodiments, and specific embodiments are illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, and it should be understood that it includes all modifications, equivalents, and substitutes included in the spirit and technical scope of the present invention. In describing the present invention, if it is judged that a specific description of a related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.
본 출원에서 사용한 용어는 단지 특정한 실시예를 설명하기 위해 사용된 것으로, 본 발명을 한정하려는 의도가 아니다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한, 복수의 표현을 포함한다. 본 출원에서, "포함하다" 또는 "가지다" 등의 용어는 명세서상에 기재된 특징, 숫자, 단계, 구성요소 또는 이들을 조합한 것이 존재함을 지정하려는 것이지, 하나 또는 그 이상의 다른 특징들이나 숫자, 단계, 구성요소 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다.The terminology used in this application is only used to describe specific embodiments and is not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly indicates otherwise. In this application, the terms "comprises" or "has" and the like are intended to specify the presence of a feature, number, step, component or combination thereof described in the specification, but should be understood to not preclude the possibility of the presence or addition of one or more other features, numbers, steps, components or combinations thereof.
본 발명에서 "치환된"이란 적어도 하나의 수소원자가 중수소, C1 내지 C30 알킬기, C3 내지 C30 시클로알킬기, C2 내지 C30 헤테로시클로알킬기, C1 내지 C30 할로겐화알킬기, C6 내지 C30 아릴기, C1 내지 C30 헤테로아릴기, C1 내지 C30 알콕시기, C3 내지 C30 시클로알콕시기, C1 내지 C30 헤테로시클로알콕시기, C2 내지 C30 알케닐기, C2 내지 C30 알키닐기, C6 내지 C30 아릴옥시기, C1 내지 C30 헤테로아릴옥시기, 실릴옥시기(-OSiH3), -OSiR1H2(R1은 C1 내지 C30 알킬기 또는 C6 내지 C30 아릴기), -OSiR1R2H(R1 및 R2는 각각 독립적으로 C1 내지 C30 알킬기 또는 C6 내지 C30 아릴기), -OSiR1R2R3, (R1, R2, 및 R3는 각각 독립적으로 C1 내지 C30 알킬기 또는 C6 내지 C30 아릴기), C1 내지 C30 아실기, C2 내지 C30 아실옥시기, C2 내지 C30 헤테로아릴옥시기, C1 내지 C30 술포닐기, C1 내지 C30 알킬티올기, C3 내지 C30 시클로알킬티올기, C1 내지 C30 헤테로시클로알킬티올기, C6 내지 C30 아릴티올기, C1 내지 C30 헤테로아릴티올기, C1 내지 C30 인산아마이드기, 실릴기(SiR1R2R3 )(R1, R2, 및 R3는 각각 독립적으로 수소 원자, C1 내지 C30 알킬기 또는 C6 내지 C30 아릴기), 아민기(-NRR')(여기에서, R 및 R'은 각각 독립적으로, 수소 원자, C1 내지 C30 알킬기, 및 C6 내지 C30 아릴기로 이루어진 군에서 선택되는 치환기임), 카르복실기, 할로겐기, 시아노기, 니트로기, 아조기, 및 하이드록시기로 이루어진 군에서 선택되는 치환기로 치환된 것을 의미한다.In the present invention, "substituted" means that at least one hydrogen atom is substituted with deuterium, a C1 to C30 alkyl group, a C3 to C30 cycloalkyl group, a C2 to C30 heterocycloalkyl group, a C1 to C30 halogenated alkyl group, a C6 to C30 aryl group, a C1 to C30 heteroaryl group, a C1 to C30 alkoxy group, a C3 to C30 cycloalkoxy group, a C1 to C30 heterocycloalkoxy group, a C2 to C30 alkenyl group, a C2 to C30 alkynyl group, a C6 to C30 aryloxy group, a C1 to C30 heteroaryloxy group, a silyloxy group (-OSiH 3 ), -OSiR 1 H 2 (R 1 is a C1 to C30 alkyl group or a C6 to C30 aryl group), -OSiR 1 R 2 H (R 1 and R 2 are each independently C1 to C30 alkyl group or C6 to C30 aryl group), -OSiR 1 R 2 R 3 , (R 1 , R 2 , and R 3 are each independently a C1 to C30 alkyl group or a C6 to C30 aryl group), a C1 to C30 acyl group, a C2 to C30 acyloxy group, a C2 to C30 heteroaryloxy group, a C1 to C30 sulfonyl group, a C1 to C30 alkylthiol group, a C3 to C30 cycloalkylthiol group, a C1 to C30 heterocycloalkylthiol group, a C6 to C30 arylthiol group, a C1 to C30 heteroarylthiol group, a C1 to C30 phosphoric acid amide group, a silyl group (SiR 1 R 2 R 3 ) (R 1 , R 2 , and R 3 are each independently a hydrogen atom, a C1 to C30 alkyl group Or a C6 to C30 aryl group), an amine group (-NRR') (wherein, R and R' are each independently a substituent selected from the group consisting of a hydrogen atom, a C1 to C30 alkyl group, and a C6 to C30 aryl group), a carboxyl group, a halogen group, a cyano group, a nitro group, an azo group, and a hydroxy group.
또한 상기 치환기 중 인접한 두 개의 치환기가 융합되어 포화 또는 불포화 고리를 형성할 수도 있다.Additionally, two adjacent substituents among the above substituents may be fused to form a saturated or unsaturated ring.
또한, 상기 "치환 또는 비치환된 C1 내지 C30 알킬기" 또는 "치환 또는 비치환된 C6 내지 C30 아릴기" 등에서의 상기 알킬기 또는 아릴기의 탄소수 범위는 상기 치환기가 치환된 부분을 고려하지 않고 비치환된 것으로 보았을 때의 알킬 부분 또는 아릴 부분을 구성하는 전체 탄소수를 의미하는 것이다. 예컨대, 파라 위치에 부틸기가 치환된 페닐기는 탄소수 4의 부틸기로 치환된 탄소수 6의 아릴기에 해당하는 것을 의미한다.In addition, the carbon number range of the alkyl group or aryl group in the above "substituted or unsubstituted C1 to C30 alkyl group" or "substituted or unsubstituted C6 to C30 aryl group" etc. means the total number of carbon atoms constituting the alkyl moiety or aryl moiety when the substituent is viewed as unsubstituted without considering the substituted portion. For example, a phenyl group substituted with a butyl group at the para position means an aryl group having 6 carbon atoms substituted with a butyl group having 4 carbon atoms.
본 명세서에서 "헤테로"란 별도의 정의가 없는 한, 하나의 작용기 내에 N, O, S 및 P로 이루어진 군에서 선택되는 헤테로 원자를 1 내지 4개 함유하고, 나머지는 탄소인 것을 의미한다.As used herein, unless otherwise defined, "hetero" means containing 1 to 4 heteroatoms selected from the group consisting of N, O, S, and P in one functional group, and the remainder being carbon.
본 명세서에서 "수소"란 별도의 정의가 없는 한, 일중수소, 이중수소, 또는 삼중수소를 의미한다. As used herein, “hydrogen” means monotium, dihydrogen, or tritium, unless otherwise defined.
본 명세서에서 "알킬(alkyl)기"란 별도의 정의가 없는 한, 지방족 탄화수소기를 의미한다. As used herein, “alkyl group” means an aliphatic hydrocarbon group unless otherwise defined.
알킬기는 어떠한 이중결합이나 삼중결합을 포함하고 있지 않은 "포화 알킬(saturated alkyl)기" 일 수 있다. An alkyl group may be a "saturated alkyl group" that does not contain any double or triple bonds.
알킬기는 적어도 하나의 이중결합 또는 삼중결합을 포함하고 있는 "불포화 알킬(unsaturated alkyl)기"일 수도 있다. The alkyl group may be an "unsaturated alkyl group" containing at least one double bond or triple bond.
포화이든 불포화이든 간에 알킬기는 분쇄형, 직쇄형 또는 환형일 수 있다. Alkyl groups, whether saturated or unsaturated, may be branched, straight-chain, or cyclic.
알킬기는 C1 내지 C30 알킬기일 수 있다. 보다 구체적으로 C1 내지 C20 알킬기, C1 내지 C10 알킬기 또는 C1 내지 C6 알킬기일 수도 있다.The alkyl group may be a C1 to C30 alkyl group. More specifically, it may be a C1 to C20 alkyl group, a C1 to C10 alkyl group, or a C1 to C6 alkyl group.
예를 들어, C1 내지 C4 알킬기는 알킬쇄에 1 내지 4 개의 탄소원자, 즉, 알킬쇄는 메틸, 에틸, 프로필, 이소-프로필, n-부틸, iso-부틸, sec-부틸 및 t-부틸로 이루어진 군에서 선택됨을 나타낸다.For example, a C1 to C4 alkyl group indicates that the alkyl chain has 1 to 4 carbon atoms, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.
구체적인 예를 들어 상기 알킬기는 메틸기, 에틸기, 프로필기, 이소프로필기, 부틸기, 이소부틸기, t-부틸기, 펜틸기, 헥실기, 에테닐기, 프로페닐기, 부테닐기, 시클로프로필기, 시클로부틸기, 시클로펜틸기, 시클로헥실기 등을 의미한다.For example, the alkyl group refers to a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, a hexyl group, an ethenyl group, a propenyl group, a butenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
"시클로알킬(cycloalkyl)기"는 모노시클릭 또는 융합고리 폴리시클릭(즉, 탄소원자들의 인접한 쌍들을 나눠 가지는 고리) 작용기를 포함한다.A "cycloalkyl group" includes a monocyclic or fused ring polycyclic (i.e., a ring that shares adjacent pairs of carbon atoms) functional groups.
"헤테로시클로알킬(heterocycloalkyl)기"는 시클로알킬기 내에 N, O, S 및 P로 이루어진 군에서 선택되는 헤테로원자를 1 내지 4개 함유하고, 나머지는 탄소인 것을 의미한다. 상기 헤테로시클로알킬기가 융합된 고리(fused ring)인 경우, 융합된 고리 중 적어도 하나의 고리가 상기 헤테로 원자를 1 내지 4개 포함할 수 있다.A "heterocycloalkyl group" means a cycloalkyl group containing 1 to 4 heteroatoms selected from the group consisting of N, O, S, and P, and the remainder being carbon. When the heterocycloalkyl group is a fused ring, at least one ring among the fused rings may contain 1 to 4 of the heteroatoms.
"아릴(aryl)기"는 모노시클릭 또는 융합 고리 폴리시클릭(즉, 탄소원자들의 인접한 쌍들을 나눠 가지는 고리) 작용기를 포함한다. "Aryl" group includes monocyclic or fused ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) functional groups.
"헤테로아릴(heteroaryl)기"는 아릴기 내에 N, O, S 및 P로 이루어진 군에서 선택되는 헤테로원자를 1 내지 4개 함유하고, 나머지는 탄소인 것을 의미한다. 상기 헤테로아릴기가 융합된 고리(fused ring)인 경우, 융합된 고리 중 적어도 하나의 고리가 상기 헤테로 원자를 1 내지 4개 포함할 수 있다. A "heteroaryl group" means an aryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O, S, and P, and the remainder being carbon. When the heteroaryl group is a fused ring, at least one ring among the fused rings may contain 1 to 4 of the heteroatoms.
아릴기 및 헤테로아릴기에서 고리의 원자수는 탄소수 및 비탄소원자수의 합이다.In aryl and heteroaryl groups, the number of ring atoms is the sum of the number of carbon atoms and the number of non-carbon atoms.
본 명세서에서 "약제학적으로 허용가능한 염" 란 별도의 정의가 없는 한, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는, 화합물의 제형을 의미한다. 상기 약제학적으로 허용가능한 염은, 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어, 염산, 황산, 질산, 인산, 브롬화수소산, 요드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리신산 등과 같은 유기 카본산, 메탄설폰산, 에탄술폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 예를 들어, 약제학적으로 허용되는 카르복실산 염에는, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 금속염 또는 알칼리 토금속 염, 라이신, 아르기닌, 구아니딘 등의 아미노산 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸)메틸아민, 디에탄올아민, 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다. 본 발명에 따른 구조식 1, 2 또는 3의 화합물은 통상적인 방법에 의해 그것의 염으로 전환시킬 수도 있다.As used herein, "pharmaceutically acceptable salt", unless otherwise defined, means a formulation of a compound which does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutically acceptable salt includes acid addition salts formed by acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid, organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicyic acid, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound of structural formula 1, 2 or 3 according to the present invention can also be converted into its salt by a conventional method.
이하, 본 발명의 페닐렌 디벤즈아미드계 신규 화합물에 대해 설명하도록 한다.Hereinafter, the novel phenylene dibenzamide compound of the present invention will be described.
본 발명의 페닐렌 디벤즈아미드계 신규 화합물은 하기 구조식 1로 표시될 수 있다.The novel phenylene dibenzamide compound of the present invention can be represented by the following structural formula 1.
[구조식 1][Structural formula 1]
구조식 1에서,In structural formula 1,
R1은 수소원자, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 시클로알킬기, 치환 또는 비치환된 C1 내지 C30 헤테로시클로알킬기, 치환 또는 비치환된 C6 내지 C30 아릴기, 또는 치환 또는 비치환된 C1 내지 C30 헤테로아릴기이고,R 1 is a hydrogen atom, a substituted or unsubstituted C1 to C30 alkoxy group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group,
R2는 수소원자, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 시클로알킬기, 치환 또는 비치환된 C1 내지 C30 헤테로시클로알킬기, 치환 또는 비치환된 C6 내지 C30 아릴기, 또는 치환 또는 비치환된 C1 내지 C30 헤테로아릴기이고, R 2 is a hydrogen atom, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group,
R3은 수소원자, 니트로기, 치환 또는 비치환된 C1 내지 C30 알콕시기, 치환 또는 비치환된 C1 내지 C30 알킬기, 치환 또는 비치환된 C3 내지 C30 시클로알킬기, 치환 또는 비치환된 C1 내지 C30 헤테로시클로알킬기, 치환 또는 비치환된 C6 내지 C30 아릴기, 또는 치환 또는 비치환된 C1 내지 C30 헤테로아릴기이다.R 3 is a hydrogen atom, a nitro group, a substituted or unsubstituted C1 to C30 alkoxy group, a substituted or unsubstituted C1 to C30 alkyl group, a substituted or unsubstituted C3 to C30 cycloalkyl group, a substituted or unsubstituted C1 to C30 heterocycloalkyl group, a substituted or unsubstituted C6 to C30 aryl group, or a substituted or unsubstituted C1 to C30 heteroaryl group.
바람직하게는, 상기 구조식 1에서,Preferably, in the structural formula 1,
R1은 C1 내지 C10 알콕시기, 또는 C1 내지 C10 알킬기이고,R 1 is a C1 to C10 alkoxy group or a C1 to C10 alkyl group,
R2는 수소원자, 또는 C1 내지 C10 알킬기이고,R 2 is a hydrogen atom or a C1 to C10 alkyl group,
R3은 니트로기, 또는 C1 내지 C10 알콕시기일 수 있다.R 3 can be a nitro group or a C1 to C10 alkoxy group.
더욱 바람직하게는, 상기 구조식 1로 표시되는 화합물은 하기 구조식 2 또는 구조식 3으로 표시될 수 있다.More preferably, the compound represented by the structural formula 1 may be represented by the following structural formula 2 or structural formula 3.
[구조식 2][Structural formula 2]
[구조식 3][Structural formula 3]
구조식 2 또는 3에서,In structural formula 2 or 3,
R1은 C1 내지 C10 알콕시기, 또는 C1 내지 C10 알킬기이고,R 1 is a C1 to C10 alkoxy group or a C1 to C10 alkyl group,
R2는 수소원자, 또는 C1 내지 C10 알킬기이고,R 2 is a hydrogen atom or a C1 to C10 alkyl group,
R3은 니트로기, 또는 C1 내지 C10 알콕시기이다.R 3 is a nitro group or a C1 to C10 alkoxy group.
가장 바람직하게는, 상기 구조식 1로 표시되는 화합물은 하기 화합물 1 또는 화합물 2 일 수 있다.Most preferably, the compound represented by the structural formula 1 may be compound 1 or compound 2 below.
[화합물 1][Compound 1]
[화합물 2][Compound 2]
상기 구조식 1, 2 또는 3의 화합물이 광학 이성질체, 입체 이성질체, 위치 이성질체, 회전 이성질체 등과 같은 이성질체를 갖는 경우에는, 어느 쪽의 이성질체 및 이들의 혼합물도 상기 구조식 1, 2 또는 3의 화합물에 포함된다. 예를 들어, 구조식 2의 화합물이 광학 이성질체를 갖는 경우에는, 라세미체로부터 분할된 광학 이성질체도 구조식 2의 화합물에 포함된다. 이들의 이성질체는 그 자체로 공지된 합성 및 분리 방법(농축, 용매 추출, 칼럼 크로마토그래피, 재결정화 등)에 따라 각각의 단일 생성물로서 수득될 수 있다.When the compound of the structural formula 1, 2 or 3 has isomers such as optical isomers, stereoisomers, positional isomers, rotational isomers, etc., any of the isomers and mixtures thereof are included in the compound of the structural formula 1, 2 or 3. For example, when the compound of the structural formula 2 has optical isomers, optical isomers resolved from the racemate are also included in the compound of the structural formula 2. These isomers can be obtained as individual single products according to synthetic and separation methods known per se (concentration, solvent extraction, column chromatography, recrystallization, etc.).
이하, 본 발명의 암질환 예방 또는 치료용 약제학적 조성물에 대해 설명하도록 한다.Hereinafter, the pharmaceutical composition for preventing or treating cancer of the present invention will be described.
본 발명의 암질환 예방 또는 치료용 약제학적 조성물은 하기 화합물 1 또는 화합물 2, 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함한다.The pharmaceutical composition for preventing or treating cancer of the present invention contains compound 1 or compound 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.
[화합물 1][Compound 1]
[화합물 2][Compound 2]
바람직하게는, 암질환 예방 또는 치료용 약제학적 조성물은 국소이성질화효소(topoisomerase) 억제제를 추가로 포함할 수 있다.Preferably, the pharmaceutical composition for preventing or treating cancer may additionally comprise a topoisomerase inhibitor.
상기 국소이성질화효소 억제제는 이리노테칸(irinotecan), 토포테칸(topotecan), 및 벨로테칸(belotecan) 중에서 선택된 1종 이상인 것이 바람직하고, 더욱 바람직하게는 이리노테칸 일 수 있다.The above-mentioned local isomerase inhibitor is preferably at least one selected from irinotecan, topotecan, and belotecan, and more preferably irinotecan.
상기 암질환은 대장암, 위암, 전립선암, 폐암, 췌장암, 기저세포암, 뇌암, 간암, 및 유방암 중에서 선택된 어느 하나일 수 있으나 본 발명의 범위가 여기에 한정되지 않는다. 바람직하게는, 상기 암질환은 대장암, 위암, 전립선암 및 폐암 중에서 선택된 어느 하나일 수 있다.The cancer disease may be any one selected from colon cancer, stomach cancer, prostate cancer, lung cancer, pancreatic cancer, basal cell carcinoma, brain cancer, liver cancer, and breast cancer, but the scope of the present invention is not limited thereto. Preferably, the cancer disease may be any one selected from colon cancer, stomach cancer, prostate cancer, and lung cancer.
상기 암질환 예방 또는 치료용 약제학적 조성물은 헤지호그 신호전달(hedgehog signaling) 저해용인 것을 특징으로 한다. 여기서 헤지호그 신호전달의 저해는 GLI 전사활성 억제에 따라 구현될 수 있다.The pharmaceutical composition for preventing or treating the above cancer disease is characterized by inhibiting hedgehog signaling. Here, inhibition of hedgehog signaling can be implemented by suppressing GLI transcriptional activity.
본 발명의 약제학적 조성물은 상기 유효 성분 이외에 약학으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.The pharmaceutical composition of the present invention can be prepared using, in addition to the above-mentioned effective ingredient, a pharmaceutically suitable and physiologically acceptable excipient, and the excipient may include an excipient, a disintegrant, a sweetener, a binder, a coating agent, a swelling agent, a lubricant, a glidant, or a flavoring agent.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효 성분 이외에 추가로 약학으로 허용 가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.The above pharmaceutical composition may be preferably formulated as a pharmaceutical composition by additionally including one or more pharmaceutically acceptable carriers in addition to the effective ingredients described above for administration.
상기 약제학적 조성물의 제제 형태는 액제, 시럽, 즙, 현탁제, 유제, 점적제 또는 등이 될 수 있다. 예를 들어, 또한, 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연 당, 옥수수 감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성 검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐 아세테이트, 소듐 클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸 셀룰로스, 아가, 벤토니트, 잔탄 검 등을 포함한다. 본 발명의 약제학적 조성물은 경피 투여에 의하는 것이 바람직하다.The formulation form of the pharmaceutical composition may be a solution, syrup, juice, suspension, emulsion, drop or the like. For example, also, if necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracheacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The pharmaceutical composition of the present invention is preferably administered transdermally.
이하, 본 발명의 암질환 예방 또는 치료용 화합물의 스크리닝 방법에 대해 설명하도록 한다.Hereinafter, a screening method for a compound for preventing or treating cancer of the present invention will be described.
본 발명의 암질환 예방 또는 치료용 화합물의 스크리닝 방법은 GLI 리포터 NIH3t3 세포주를 N,N'-1,3-페닐렌 디벤즈아미드(N,N'-1,3-phenylene dibenzamide)계 화합물 라이브러리에 처리하는 단계를 포함한다.The method for screening a compound for preventing or treating cancer of the present invention comprises the step of treating a GLI reporter NIH3t3 cell line with a library of N,N'-1,3-phenylene dibenzamide compounds.
상기 GLI 리포터 NIH3t3 세포주는 GLI 발현량에 따라 제어되는 루시퍼레이즈 유전자(luciferase gene)를 포함할 수 있다.The above GLI reporter NIH3t3 cell line may contain a luciferase gene that is controlled by the amount of GLI expression.
상기 GLI 리포터 NIH3t3 세포주에서 리포터 활성에 대한 IC50값이 15μM 이하로 측정되는 화합물을 스크리닝하는 것이 바람직하고, 더욱 바람직하게는 13μM 이하, 더욱 더 바람직하게는 11μM 이하로 측정되는 화합물을 스크리닝할 수 있다.It is preferable to screen compounds having an IC50 value of 15 μM or less for reporter activity in the above GLI reporter NIH3t3 cell line, more preferably 13 μM or less, and even more preferably 11 μM or less.
이에 따라 스크리닝된 화합물은 하기 화합물 1 및 화합물 2를 포함할 수 있다.Accordingly, the screened compounds may include the following compounds 1 and 2.
[화합물 1][Compound 1]
[화합물 2][Compound 2]
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시하나, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 범주 및 기술사상 범위 내에서 다양한 변경 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속하는 것도 당연한 것이다.Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only illustrative of the present invention, and it will be apparent to those skilled in the art that various changes and modifications are possible within the scope and technical idea of the present invention, and it is natural that such changes and modifications fall within the scope of the appended patent claims.
[실시예] [Example]
실시예 1: 화합물 1 및 화합물 2의 스크리닝Example 1: Screening of compounds 1 and 2
하기 화합물 A(N,N'-1,3-phenylene dibenzamide)과 같은 코어 구조에 다양한 치환기를 도입한 라이브러리를 이용하여, GLI 전사 억제능 IC50값을 측정하여 그 값이 낮게 측정된 화합물 1과 화합물 2를 스크리닝하였다.Using a library in which various substituents were introduced into the core structure, such as compound A (N,N'-1,3-phenylene dibenzamide), the IC50 values of GLI transcription inhibition ability were measured, and compounds 1 and 2, which were measured to have low values, were screened.
구체적으로, NIH3t3-GLI 루시퍼레이즈(luciferase) 세포에서 상기 라이브러리의 화합물들에 대하여 GLI 전사 활성을 저해 정도를 확인하기 위한 GLI 루시퍼레이즈 분석(luciferase assay)를 수행하였다. 먼저, 96웰 플레이트에 NIH3t3-GLI 루시퍼레이즈 세포를 2.5x104 시딩(seeding) 한 후, 7시간 후 리간드(ligand)인 1 μM N-SHH 펩파이드(peptide)를 처리하였다. 오버나이트 후에 상기 화합물들을 농도별 (0~50 μM)로 처리 후 7시간 뒤에 루시퍼레이즈 키트(luciferase kit)를 사용하여 GLI 전사 활성 억제능을 확인하고, 그 결과를 도 2에 나타내었다. Specifically, a GLI luciferase assay was performed to confirm the degree of inhibition of GLI transcriptional activity by compounds of the library in NIH3t3-GLI luciferase cells. First, 2.5x10 4 NIH3t3-GLI luciferase cells were seeded in a 96-well plate, and 7 hours later, 1 μM N-SHH peptide, a ligand, was treated. After overnight treatment with the compounds at various concentrations (0 to 50 μM), the GLI transcriptional activity inhibition ability was confirmed using a luciferase kit after 7 hours, and the results are shown in Fig. 2.
이에 따르면, 코어 구조인 화합물 A의 경우 GLI 전사 억제능 IC50값이 농도 50 μM까지 측정이 되지 않았으며, 화합물 1과 화합물 2의 IC50값은 각각 10.04μM, 10.15μM로 억제능이 매우 우수한 것으로 나타났다.Accordingly, for compound A, which is the core structure, the IC50 value of GLI transcription inhibition ability was not measured up to a concentration of 50 μM, and the IC50 values of compounds 1 and 2 were 10.04 μM and 10.15 μM, respectively, showing excellent inhibition ability.
[화합물 A][Compound A]
[화합물 1][Compound 1]
[화합물 2][Compound 2]
[실험예][Experimental example]
실험예 1: 정상 대장세포 및 대장암 세포주에서 헤지호그/GLI 발현 확인Experimental Example 1: Confirmation of Hedgehog/GLI expression in normal colon cells and colon cancer cell lines
화합물의 헤지호그/GLI 억제 효과를 확인하기에 앞서 정상 대장세포 (CCD-18Co), 대장암 세포주 (DLD-1, HT29, HCT116)의 헤지호그/GLI 단백질 레벨 확인하기 위하여 대장암 세포를 시딩한 후, 다음날 용균(cell lysate)하여 웨스턴 블로팅하고, GLI1 발현을 확인하였다. 이에 따른 결과를 도 3에 나타내었다.Prior to confirming the hedgehog/GLI inhibitory effect of the compound, the hedgehog/GLI protein levels of normal colon cells (CCD-18Co) and colon cancer cell lines (DLD-1, HT29, HCT116) were confirmed by seeding colon cancer cells, and the next day, cell lysates were collected and Western blotting was performed to confirm GLI1 expression. The results are shown in Fig. 3.
이에 따르면, 정상 대장 세포인 CCD-18Co와 대장암 세포주인 DLD-1에서 GLI1의 발현이 낮았으며, HCT116, HT29 대장암 세포주에서는 GLI1의 발현이 높은 것을 확인 할 수 있었다.According to this, the expression of GLI1 was low in normal colon cells, CCD-18Co, and colon cancer cell line, DLD-1, and the expression of GLI1 was high in colon cancer cell lines, HCT116 and HT29.
실험예 2: 헤지호그/GLI 억제제와 이리노테칸(IRI) 단독 및 병용 처리에 따른 세포성장 측정Experimental Example 2: Measurement of cell growth following treatment with hedgehog/GLI inhibitors and irinotecan (IRI) alone and in combination
정상 대장세포 (CCD-18Co), 대장암 세포주 (DLD-1, HT29, HCT116)를 96웰 플레이트에 시딩한 후, 다음 날 실시예 1에 따라 스크리닝된 헤지호그/GLI 억제제인 화합물 1 또는 이리노테칸(IRI)을 농도별로 단독 처리하고 24시간 후에 WST-1 용액에 넣어 3시간 반응 후 450nm에서 흡광도를 측정하여 세포 성장을 확인하고 그 결과를 도 4에 나타내었다. 이에 따르면, 대장 정상세포에서는 크게 세포 성장이 억제되지 않았고, 대장암 세포주에서는 IRI와 헤지호그/GLI 억제제인 화합물 1에 의한 세포 성장이 억제되는 것을 확인할 수 있었다.Normal colon cells (CCD-18Co) and colon cancer cell lines (DLD-1, HT29, HCT116) were seeded in a 96-well plate, and the following day, compound 1 or irinotecan (IRI), a hedgehog/GLI inhibitor screened according to Example 1, were treated alone at various concentrations, and 24 hours later, they were placed in a WST-1 solution, reacted for 3 hours, and then the absorbance was measured at 450 nm to confirm cell growth, and the results are shown in Fig. 4. According to this, cell growth was not significantly inhibited in normal colon cells, while it was confirmed that cell growth was inhibited in colon cancer cell lines by IRI and the hedgehog/GLI inhibitor compound 1.
한편 정상 대장세포(CCD-18Co), 대장암 세포주 (DLD-1, HT29, HCT116)를 96웰 플레이트에 시딩한 후, 다음 날 화합물 1(10 μM 또는 20 μM) 처리하고 1시간 뒤에 IRI(10 μM 또는 20 μM)처리하였으며, 24시간 후에 WST-1 용액을 넣어 3시간 반응 후 450nm에서 흡광도를 측정하여 세포 성장을 확인하고 그 결과를 도 5에 나타내었다. 이에 따르면, 화합물 1과 이리노테칸을 병용 처리한 경우 대장 정상세포에서는 영향이 없었고, GLI1의 발현이 낮은 DLD-1 세포에서도 유의적인 세포 성장 억제의 효과가 나타나지 않았다. 이에 반해, GLI1의 발현이 높은 HCT116 및 HT29 세포에서는 단독 처리 보다 두 성분을 병용 처리하였을 때 세포 성장이 통계적으로 유의하게 현저히 감소하는 것으로 나타났다.Meanwhile, normal colon cells (CCD-18Co) and colon cancer cell lines (DLD-1, HT29, HCT116) were seeded in 96-well plates, treated with compound 1 (10 μM or 20 μM) the next day, and IRI (10 μM or 20 μM) 1 hour later. After 24 hours, WST-1 solution was added, and after 3 hours of reaction, absorbance was measured at 450 nm to check cell growth, and the results are shown in Fig. 5. According to this, when compound 1 and irinotecan were treated together, there was no effect on normal colon cells, and in DLD-1 cells with low GLI1 expression, no significant cell growth inhibition effect was observed. In contrast, in HCT116 and HT29 cells with high GLI1 expression, cell growth was statistically significantly reduced when the two components were treated together compared to when they were treated alone.
실험예 3: 헤지호그/GLI 억제제와 IRI 병용 처리에 따른 세포 사멸 효과 확인Experimental Example 3: Confirmation of cell death effect by combined treatment with hedgehog/GLI inhibitor and IRI
먼저 대장암 세포주(HT29)를 시딩한 후 화합물 1을 10μM 처리하고 1시간 후에 이리노테칸(IRI)을 10μM을 병용 처리한 24시간 후에 세포의 상태(cell morphology)를 현미경을 통해 확인한 결과를 도 6에 나타내었다. 이에 따르면, 하나의 성분을 단독 처리한 것에 비해 두 성분을 병용 처리 한 군에서 세포 사멸 효과가 큰 것으로 확인되었다.First, colon cancer cell lines (HT29) were seeded, then treated with 10 μM compound 1 for 1 hour and then irinotecan (IRI) was co-treated with 10 μM. The cell morphology was checked under a microscope 24 hours later. The results are shown in Fig. 6. According to this, it was confirmed that the cell death effect was greater in the group treated with the two components together than in the group treated with one component alone.
또한, 대장암 세포주(HT29)를 시딩한 후 화합물 1을 10μM 또는 20μM 처리하고 1시간 후에 이리노테칸(IRI) 10μM 또는 20μM를 병용 처리하고, 24시간 후에 셀을 수득하여 Annexin V-FITC, PI(propidium iodide)를 염색하고 유세포 분석(flow cytometry)을 통해 세포 사멸 (apoptosis)을 분석하였으며, 그 분석 결과를 도 7에 나타내었다. 또한, 상기 결과에 따라 약물의 병용 처리에 대한 효과를 Compusyn program을 통해 수치로 계산함으로써 콤비네이션 인덱스(combination index)를 구하고 그 결과를 아래의 표 1에 정리하였다. 이에 따르면, 두 성분을 병용 처리한 군에서 세포 사멸의 시너지 효과가 나타남을 확인할 수 있었다.In addition, after seeding the colon cancer cell line (HT29), compound 1 was treated at 10 μM or 20 μM, and irinotecan (IRI) was co-treated after 1 hour at 10 μM or 20 μM, and the cells were harvested after 24 hours, stained with Annexin V-FITC and PI (propidium iodide), and apoptosis was analyzed through flow cytometry, and the results of the analysis are shown in Fig. 7. In addition, based on the results above, the effect of the combination treatment of the drugs was numerically calculated using the Compusyn program to obtain the combination index, and the results are summarized in Table 1 below. According to this, it was confirmed that a synergistic effect of apoptosis was shown in the group treated with the two components in combination.
한편, 웨스턴 블로팅(Western blotting)을 통해 세포사멸 단백질의 발현을 확인한 결과를 도 8에 나타내었다. 이에 따르면, 약물의 단독 처리군 보다 화합물 1과 IRI의 병용 처리군에서 c-PARP, c-카스페이스 3, 8, 9 및 활성이 증가하는 것을 확인하였다.Meanwhile, the results of confirming the expression of apoptotic proteins through Western blotting are shown in Fig. 8. According to this, it was confirmed that c-PARP, c-caspace 3, 8, and 9 activity increased in the combined treatment group of compound 1 and IRI compared to the group treated with either drug alone.
또한, 화합물 1과 IRI 처리에 대한 세포사멸의 효과가 카스페이스에 의존적(caspase-dependent)인지 확인하기 위하여 대장암 세포주 HT29 세포를 시딩한 후 24시간 후에 카스페이스 억제제(caspase inhibitor)인 z-vad-fmk를 전처리한 30분 후 화합물 1을 10μM 처리하고 1시간 후 IRI를 10μM 병용 처리하였다. 이후 24시간 후에 셀을 수득하여 웨스턴 블로팅을 수행하여 세포사멸 단백질의 발현을 분석하고 그 결과를 도 9에 나타내었다. 이에 따르면, 카스페이스 억제제와 함께 화합물 1과 IRI을 병용처리한 군에서 세포사멸이 억제되는 것으로 보아 카스페이스에 의존적으로 세포사멸이 일어나는 것을 확인할 수 있었다.In addition, to confirm whether the apoptotic effect of compound 1 and IRI treatment is caspase-dependent, colon cancer cell line HT29 cells were seeded, and 24 hours later, the caspase inhibitor z-vad-fmk was pretreated, 30 minutes later, compound 1 was treated at 10 μM, and 1 hour later, IRI was co-treated at 10 μM. After 24 hours, cells were harvested and Western blotting was performed to analyze the expression of apoptotic proteins, and the results are shown in Fig. 9. According to this, it was confirmed that apoptosis occurred in a caspase-dependent manner, as apoptosis was inhibited in the group treated with compound 1 and IRI together with the caspase inhibitor.
또한, 상기 방법과 동일한 방법으로 위암 세포주인 AGS(a)와 전립선암 세포주인 DU145(b), 폐암 세포주 A549(c)에서 세포사멸 단백질 생성을 측정한 결과를 도 10에 나타내었다. 이에 따르면, 약물의 단독처리 보다 병용 처리할 때 세포 사멸 단백질인 c-PARP가 증가하는 것을 확인하였다.In addition, the results of measuring the production of apoptotic proteins in the gastric cancer cell line AGS (a), the prostate cancer cell line DU145 (b), and the lung cancer cell line A549 (c) using the same method as above are shown in Fig. 10. According to this, it was confirmed that the apoptotic protein c-PARP increased when the drugs were used in combination rather than when they were used alone.
실험예 4: 헤지호그/GLI 억제제의 GLI1 단백질 억제 확인Experimental Example 4: Confirmation of GLI1 protein inhibition by hedgehog/GLI inhibitor
대장암 세포주인 HT29 및 HCT116세포을 시딩한 후 24시간 후에 화합물 1을 농도별(0, 10, 20 μM) 처리하고, 24시간 후에 세포를 수득하여 웨스턴 블로팅을 수행하여 GLI1의 단백질 발현을 측정하였고 그 결과를 도 11에 나타내었다. 이에 따르면, 화합물 1의 처리에 의하여 GLI1 단백질 발현이 감소하는 것을 확인하였다.After seeding HT29 and HCT116 cells, which are colon cancer cell lines, the cells were treated with compound 1 at various concentrations (0, 10, 20 μM) 24 hours later, and the cells were harvested 24 hours later to measure the protein expression of GLI1 by performing Western blotting, and the results are shown in Fig. 11. According to this, it was confirmed that GLI1 protein expression was reduced by treatment with compound 1.
실험예 5: 헤지호그/GLI 억제제의 세포사멸 단백질 확인Experimental Example 5: Identification of Apoptotic Proteins by Hedgehog/GLI Inhibitors
헤지호그/GLI억제제인 화합물 1이 항암제인 IRI의 효능을 증진시키는 이유를 확인하기 위해 화합물 1을 농도별(0, 10, 20 μM) 처리하여 세포사멸 관련 단백질 DR5, DR4, Bim, Noxa, Puma, Bid, Bcl-xL, XIAP, Survivin의 발현을 웨스팅 블로팅에 의하여 확인하고 그 결과를 도 12에 나타내었다. 이에 따르면, 세포사멸을 매개하는 수용체인 사멸 수용체(death receptor) DR5가 화합물 1의 처리에 의해 증가되는 것을 확인하였다. 즉, 화합물 1이 DR5를 증가시켜 IRI의 세포 사멸 효능을 증가시키는 것을 알 수 있다.To confirm the reason why compound 1, a hedgehog/GLI inhibitor, enhances the efficacy of IRI, an anticancer agent, compound 1 was treated at various concentrations (0, 10, 20 μM), and the expression of apoptosis-related proteins DR5, DR4, Bim, Noxa, Puma, Bid, Bcl-xL, XIAP, and Survivin was confirmed by western blotting, and the results are shown in Fig. 12. According to this, it was confirmed that death receptor DR5, a receptor that mediates apoptosis, was increased by treatment with compound 1. In other words, it can be seen that compound 1 increases DR5 and thereby increases the apoptotic efficacy of IRI.
이상, 본 발명의 실시예들에 대하여 설명하였으나, 해당 기술 분야에서 통상의 지식을 가진 자라면 특허청구범위에 기재된 본 발명의 사상으로부터 벗어나지 않는 범위 내에서, 구성 요소의 부가, 변경, 삭제 또는 추가 등에 의해 본 발명을 다양하게 수정 및 변경시킬 수 있을 것이며, 이 또한 본 발명의 권리범위 내에 포함된다고 할 것이다.Above, the embodiments of the present invention have been described, but those skilled in the art will be able to modify and change the present invention in various ways by adding, changing, deleting or adding components, etc., within the scope that does not depart from the spirit of the present invention described in the claims, and this will also be considered to be included within the scope of the rights of the present invention.
Claims (14)
상기 화합물 1 또는 화합물 2는 GLI를 표적으로 하여 발현 및 활성을 억제하는 GLI 억제용이고, GLI 억제에 따라 헤지호그 신호전달 경로를 억제하는 것을 특징으로 하는 대장암, 위암, 전립선암 및 폐암 중에서 선택된 어느 하나의 암질환 예방 또는 치료용 약제학적 조성물.
[화합물 1]
[화합물 2]
Comprising compound 1 or compound 2, or a pharmaceutically acceptable salt thereof, as an active ingredient,
A pharmaceutical composition for preventing or treating any one cancer disease selected from colon cancer, gastric cancer, prostate cancer, and lung cancer, wherein the compound 1 or compound 2 is a GLI inhibitor that targets GLI and inhibits its expression and activity, and inhibits the hedgehog signaling pathway according to GLI inhibition.
[Compound 1]
[Compound 2]
상기 암질환 예방 또는 치료용 약제학적 조성물은 토포이소머레이즈(topoisomerase) 억제제를 추가로 포함하는 것을 특징으로 하는 것을 특징으로 하는 암질환 예방 또는 치료용 약제학적 조성물.In paragraph 5,
A pharmaceutical composition for preventing or treating cancer, characterized in that the pharmaceutical composition for preventing or treating cancer further comprises a topoisomerase inhibitor.
상기 토포이소머레이즈 억제제는 이리노테칸(irinotecan), 토포테칸(topotecan), 및 벨로테칸(belotecan) 중에서 선택된 1종 이상인 것을 특징으로 하는 암질환 예방 또는 치료용 약제학적 조성물.In Article 6,
A pharmaceutical composition for preventing or treating cancer, characterized in that the topoisomerase inhibitor is at least one selected from irinotecan, topotecan, and belotecan.
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| KR1020210048315A KR102709756B1 (en) | 2020-05-29 | 2021-04-14 | Phenylene dibenzamide based compounds and composition for preventing and treating cancer diseases comprising the same as effective ingredient |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004032716A2 (en) * | 2002-10-08 | 2004-04-22 | Massachusetts Institute Of Technology | Compounds for modulation of cholesterol transport |
| WO2005033288A2 (en) * | 2003-09-29 | 2005-04-14 | The Johns Hopkins University | Hedgehog pathway antagonists |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS50105558A (en) * | 1973-12-19 | 1975-08-20 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004032716A2 (en) * | 2002-10-08 | 2004-04-22 | Massachusetts Institute Of Technology | Compounds for modulation of cholesterol transport |
| WO2005033288A2 (en) * | 2003-09-29 | 2005-04-14 | The Johns Hopkins University | Hedgehog pathway antagonists |
Non-Patent Citations (1)
| Title |
|---|
| Bin Yang 등, Bioorg. Med. Chem. Lett. Vol.22, 2012, pp.4907-4911. 1부* |
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| KR20210147876A (en) | 2021-12-07 |
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