KR20220008474A - Method for preparing novel quinone-indolizine hybrid derivatives and anticancer composition containing the same - Google Patents
Method for preparing novel quinone-indolizine hybrid derivatives and anticancer composition containing the same Download PDFInfo
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Abstract
Description
본 발명은 새로운 퀴논-인돌리진 하이브리드 유도체 제조방법 및 이를 포함하는 항암제 조성물에 관한 것이다. The present invention relates to a novel quinone-indolizine hybrid derivative preparation method and an anticancer agent composition comprising the same.
퀴논(quinone)과 인돌리진(indolizine)은 다수의 생물학적 활성 천연 및 합성 제품에 자주 포함되는 두 가지 기본 화학 골격이다. 실제로, 각각의 코어는 치료 가능성을 갖는 많은 물질의 하부 구조로서 널리 사용되어왔다. 더욱이, 이들 2 개의 약동학(pharmacophores)으로 구성된 하이브리드 화합물은 항균 및 항암 활성을 포함하여 다양한 흥미로운 약리학적 활성을 갖는 것으로 알려져 있다. [비특허문헌 0001-0003]Quinone and indolizine are the two basic chemical backbones frequently included in many biologically active natural and synthetic products. Indeed, individual cores have been widely used as substructures of many materials with therapeutic potential. Moreover, hybrid compounds composed of these two pharmacokinetics are known to possess a variety of interesting pharmacological activities, including antibacterial and anticancer activities. [Non-patent document 0001-0003]
따라서, 이러한 하이브리드 모티프에 대한 많은 합성 접근법이 보고되었다. 예를 들어, 피리도[1,2-a]인돌-1,4-디온 유도체는 퀴논, 피리딘 및 아세틸렌 다이카복실레이트의 3 성분 커플링에 의해 접근되었고, 피리도[2,1-a]아이소인돌-7,10-디온(2)[비특허문헌 0004-0007]은 피리딘-유래 아조메틴(quine-derived azomethines)으로 퀴논의 1,3-이극성 고리 첨가에 의해 합성되었다. 두 경우 모두, 중심 피롤 고리는 환형을 통해 형성된다. 새로운 하이브리드 구조를 생성하려는 지속적인 노력의 일환으로, 본 발명자들은 신규한 퀴논-인돌리진 분자 하이브리드 구조가 N-치환된 피롤-2-카복스알데히드 및 퀴논의 고리를 통해 구축될 것이라고 추론했다. 기계적으로, 본 발명자들은 중앙 피리딘 고리가 도미노 마이클 첨가-분자 알돌-탈수-방향족 절차에 의해 형성될 것으로 예상하였다. 실제로, 이 아이디어는 온화한 조건 하에서 실현되었으며 이들 화합물 및 이들의 유도체의 생물학적 연구는 본 논문의 주제인 전립선암 및 구강 편평 상피암 세포에 대한 항암 효과를 나타냈다.Therefore, many synthetic approaches to these hybrid motifs have been reported. For example, pyrido[1,2-a]indole-1,4-dione derivatives were accessed by three-component coupling of quinone, pyridine and acetylene dicarboxylate, followed by pyrido[2,1-a]iso Indole-7,10-dione (2) [Non-Patent Document 0004-0007] was synthesized by 1,3-dipolar cycloaddition of quinone with pyridine-derived azomethines. In both cases, the central pyrrole ring is formed through the ring. In an ongoing effort to create new hybrid structures, the present inventors deduced that a novel quinone-indolizine molecular hybrid structure would be constructed via a ring of N-substituted pyrrole-2-carboxaldehyde and quinone. Mechanistically, we expected that the central pyridine ring would be formed by a domino Michael addition-molecular aldol-dehydration-aromatic procedure. Indeed, this idea was realized under mild conditions, and biological studies of these compounds and their derivatives showed anticancer effects on prostate cancer and oral squamous cell carcinoma, the subject of this paper.
남성의 암으로 인한 모든 사망의 약 6.6 %를 차지하는 전립선암은 남성의 암 관련 사망의 다섯 번째 주요 원인이다 [비특허문헌 0008]. 전이는 전립선암 진단 당시 환자의 약 5 %에서 발견되며 [비특허문헌 0009], 테스토스테론을 고갈시키고 안드로겐 수용체 신호 전달을 억제하는 조기 호르몬 요법은 대부분의 전립선암 환자에게 효과적이다. 그러나 여전히 ~20 %의 환자가 5 년 이내에 거세 저항성 전립선암 (CRPC)으로 발전한다 [비특허문헌 0010, 0011]. 구강암은 전 세계적으로 가장 흔한 악성 종양 중 하나이며, 이 중 90 %는 구강 편평 상피암 (OSCC)이다 [비특허문헌 0012, 0013]. 진단 및 치료 전략에서 상당한 진전이 있었지만 OSCC 환자의 5 년 생존율은, 주로 충분하지 않은 효능과 높은 전이율로 인해 낮게 유지된다 [비특허문헌 0014, 0015]. 따라서, 전립선암 및 구강 편평 상피암을 위한 새로운 치료제 개발이 시급하다.Prostate cancer, which accounts for about 6.6% of all cancer-related deaths in men, is the fifth leading cause of cancer-related deaths in men [Non-Patent Document 0008]. Metastasis is found in about 5% of patients at the time of diagnosis of prostate cancer [Non-Patent Document 0009], and early hormone therapy that depletes testosterone and inhibits androgen receptor signaling is effective for most prostate cancer patients. However, ~20% of patients still develop castration-resistant prostate cancer (CRPC) within 5 years [Non-Patent Documents 0010, 0011]. Oral cancer is one of the most common malignancies worldwide, and 90% of them are oral squamous cell carcinoma (OSCC) [Non-Patent Documents 0012, 0013]. Although significant progress has been made in diagnosis and treatment strategies, the 5-year survival rate of OSCC patients remains low, mainly due to insufficient efficacy and high metastasis rates [Non-Patent Documents 0014, 0015]. Therefore, there is an urgent need to develop new therapeutic agents for prostate cancer and oral squamous cell carcinoma.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로서, 본 발명자들은 항암을 목적으로 하는 전립선암 세포인 PC-3 세포와 구강 편평 상피암 세포인 CAL-27 세포를 억제하는 신규 물질을 찾고자 예의 연구한 결과, PC-3 및 CAL-27 세포의 성장과 이동을 억제하고 세포자멸사(apoptosis)를 일으키는 신규한 퀴논-인돌리진 하이브리드 유도체를 확인하고, 이에 기초하여 본 발명을 완성하게 되었다.The present invention was devised to solve the above problems, and the present inventors studied intensively to find new substances that inhibit PC-3 cells, which are prostate cancer cells, and CAL-27 cells, which are oral squamous cell carcinoma cells, for the purpose of anticancer. As a result, a novel quinone-indolizine hybrid derivative that inhibits the growth and migration of PC-3 and CAL-27 cells and causes apoptosis was identified, and based on this, the present invention was completed.
이에, 본 발명의 목적은, 전립선암 및 구강암 세포의 성장과 이동을 억제하고 세포자멸사(apoptosis)를 일으키는 신규한 퀴논-인돌리진 하이브리드 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel quinone-indolizine hybrid derivative or a pharmaceutically acceptable salt thereof that inhibits the growth and migration of prostate and oral cancer cells and causes apoptosis.
본 발명의 다른 목적은, 전립선암 및 구강암 세포의 성장과 이동을 억제하고 세포자멸사(apoptosis)를 일으키는 신규한 퀴논-인돌리진 하이브리드 유도체의 제조방법을 제공하는 것이다. Another object of the present invention is to provide a method for producing a novel quinone-indolizine hybrid derivative that inhibits the growth and migration of prostate and oral cancer cells and causes apoptosis.
본 발명의 또 다른 목적은, 상기 퀴논-인돌리진 하이브리드 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the quinone-indolizine hybrid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은, 상기 퀴논-인돌리진 하이브리드 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 전립선암 및 구강암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. Another object of the present invention is to provide a pharmaceutical composition for preventing or treating prostate cancer and oral cancer, comprising the quinone-indolizine hybrid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은, 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.In order to achieve the object of the present invention as described above, the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1은 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, C1-C4 알킬 에스터, 또는 나이트릴이고,R 1 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl ester, or nitrile,
R2는 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C3-C6 헤테로 고리 화합물이며,R 2 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 3 -C 6 heterocyclic compound,
R3 및 R4는 각각 독립적으로 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 또는 페닐이고,R 3 and R 4 are each independently hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or phenyl;
R5 및 R6는 각각 독립적으로 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 아릴, 페녹시, 또는 모폴리닐이거나,R 5 and R 6 are each independently hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, phenoxy, or morpholinyl;
R5 및 R6는 이들이 결합된 탄소 원자와 함께 연결되어 질소 원자를 하나 내지 둘 포함하거나 포함하지 않는 6 원자의 고리(ring)를 형성하며,R 5 and R 6 are joined together with the carbon atom to which they are attached to form a 6 membered ring with or without one or two nitrogen atoms,
R7은 수소, 할로겐, 하이드록시, C1-C4 알킬, 또는 C1-C4 알콕시이고,R 7 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
상기 화학식 1에서 실선과 점선의 이중선()으로 표현된 결합선은, 단일 탄소-탄소 결합, 또는 2중 탄소-탄소 결합을 나타낸다.In Formula 1, the double line of the solid line and the dotted line ( ) represents a single carbon-carbon bond or a double carbon-carbon bond.
또한, 본 발명은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 암의 예방 또는 치료용 약학적 조성물을 제공한다. In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 전립선암, 구강암의 예방 또는 치료용 약학적 조성물을 제공한다. In addition, the present invention provides a pharmaceutical composition for preventing or treating prostate cancer or oral cancer, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일 구현 예로서, 상기 조성물은 암세포의 성장과 이동을 억제하고 세포자멸사(apoptosis)를 일으킬 수 있다.In one embodiment of the present invention, the composition can inhibit the growth and migration of cancer cells and cause apoptosis.
본 발명에 따른 신규 퀴논-인돌리진 하이브리드 유도체 또는 이의 약학적으로 허용 가능한 염은 암세포의 성장과 이동을 억제하고 세포자멸사(apoptosis)를 일으키는 활성을 나타내는바, 상기 유도체를 포함하는 약학적 조성물은 암, 예컨대 전립선암, 구강암 등의 예방 및 치료에 유용하게 이용될 수 있을 것으로 기대된다.The novel quinone-indolizine hybrid derivative according to the present invention or a pharmaceutically acceptable salt thereof inhibits the growth and migration of cancer cells and exhibits activity causing apoptosis. , for example, is expected to be usefully used in the prevention and treatment of prostate cancer, oral cancer, and the like.
도 1은, 생리활성을 지니는 퀴논 및 인돌리진들의 화학식이다.
도 2는, 본 발명의 4s 화합물의 결정 구조이다.
도 3은, 본 발명의 4o 화합물의 PC-3 및 CAL-27 세포에서 세포 생존력 및 이동에 대한 효과 실험 결과를 나타낸 그래프이다(A: PC-3 세포를 72 시간 동안 지시 된 농도에서 4o로 배양, B-C: 스크래치 이동 분석을 PC-3 세포에서 수행, D: CAL-27 세포를 72 시간 동안 지시 된 농도에서 4o로 배양, E-F: 스크래치 이동 분석을 CAL-27 세포에서 수행, 스크래치 이동 분석은, 세포를 0.1, 0.3 및 1 μM의 4o로 처리하고 스크래치 후 0 시간 및 18 시간에 대표적인 이미지를 촬영함, 상처 봉합을 24 시간 동안 측정(평균 ± S.E., n = 3-4)).
도 4는, 본 발명의 4o 화합물의 PC-3 및 CAL-27 세포에서 Caspase-3 활성 및 PARP의 절단에 대한 효과 실험 결과를 나타낸 그래프이다(A-B: 세포를 24 시간 동안 1μM의 4o와 인큐베이션 한 다음, 2μM의 Caspase-3 기질 및 1μM Hoechst 33342 를 20 분 동안 처리함, 흰색 막대는 200 μm, C-D: 세포를 24 시간 동안 지시된 농도의 4o로 배양한 다음, 1 μM의 Caspase-3 기질을 30 분 동안 처리, Caspase-3 활성은 10 μM Ac-DEVD-CHO (평균 ± S.E., n = 3-4)에 의해 억제됨, E-F: 세포를 24 시간 동안 4o로 배양하였다. 웨스턴 블롯팅(western blotting)을 사용하여 PARP, 절단 PARP 및 β-액틴을 검출함, ** P<0.01, *** P<0.001).
도 5는, 도 3과 동일한 방법으로, 본 발명의 4s 화합물의 PC-3 및 CAL-27 세포에서 세포 생존력 및 이동에 대한 효과 실험 결과를 나타낸 그래프이다.
도 6은, 도 4와 동일한 방법으로, 본 발명의 4s 화합물의 PC-3 및 CAL-27 세포에서 Caspase-3 활성 및 PARP의 절단에 대한 효과 실험 결과를 나타낸 그래프이다.
도 7은, 도 3과 동일한 방법으로, 본 발명의 4p 화합물의 PC-3 및 CAL-27 세포에서 세포 생존력 및 이동에 대한 효과 실험 결과를 나타낸 그래프이다.
도 8은, 도 4와 동일한 방법으로, 본 발명의 4p 화합물의 PC-3 및 CAL-27 세포에서 Caspase-3 활성 및 PARP의 절단에 대한 효과 실험 결과를 나타낸 그래프이다.1 is a chemical formula of quinone and indolizine having physiological activity.
2 is a crystal structure of the 4s compound of the present invention.
3 is a graph showing the experimental results of the effect of the compound 4o of the present invention on cell viability and migration in PC-3 and CAL-27 cells (A: PC-3 cells were cultured at the indicated concentration at 4o for 72 hours) , BC: scratch migration assay performed on PC-3 cells, D: CAL-27 cells incubated at 4o at the indicated concentrations for 72 h, EF: scratch migration assay performed on CAL-27 cells, scratch migration assay is, Cells were treated with 0.1, 0.3 and 1 μM of 4o and representative images were taken at 0 and 18 hours post-scratch, wound closure was measured for 24 hours (mean ± SE, n = 3-4)).
4 is a graph showing the experimental results of the effect of the compound 4o of the present invention on Caspase-3 activity and PARP cleavage in PC-3 and CAL-27 cells (AB: cells were incubated with 1 μM 4o for 24 hours Then, treated with 2 μM Caspase-3 substrate and 1 μM Hoechst 33342 for 20 min, white bars are 200 μm, CD: Cells were incubated at the indicated concentrations at 4o for 24 hours, followed by 1 μM Caspase-3 substrate Treatment for 30 min, Caspase-3 activity was inhibited by 10 μM Ac-DEVD-CHO (mean ± SE, n = 3-4), EF: cells were incubated at 4o for 24 h Western blotting ) to detect PARP, cleaved PARP and β-actin, **P<0.01, ***P<0.001).
5 is a graph showing the experimental results of the effect of the 4s compound of the present invention on cell viability and migration in PC-3 and CAL-27 cells in the same manner as in FIG. 3 .
6 is a graph showing the experimental results of the effect of the 4s compound of the present invention on Caspase-3 activity and PARP cleavage in PC-3 and CAL-27 cells in the same manner as in FIG. 4 .
7 is a graph showing the experimental results of the effect of the 4p compound of the present invention on cell viability and migration in PC-3 and CAL-27 cells in the same manner as in FIG. 3 .
8 is a graph showing the experimental results of the effect of the 4p compound of the present invention on Caspase-3 activity and PARP cleavage in PC-3 and CAL-27 cells in the same manner as in FIG. 4 .
이하, 본 발명을 상세히 설명하기로 한다.Hereinafter, the present invention will be described in detail.
본 발명은, 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a compound of
[화학식 1][Formula 1]
상기 화학식 1에서,In
R1은 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, C1-C4 알킬 에스터, 또는 나이트릴이고,R 1 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl ester, or nitrile,
R2는 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C3-C6 헤테로 고리 화합물이며,R 2 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 3 -C 6 heterocyclic compound,
R3 및 R4는 각각 독립적으로 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 또는 페닐이고,R 3 and R 4 are each independently hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or phenyl;
R5 및 R6는 각각 독립적으로 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 아릴, 페녹시, 또는 모폴리닐이거나,R 5 and R 6 are each independently hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, phenoxy, or morpholinyl;
R5 및 R6는 이들이 결합된 탄소 원자와 함께 연결되어 질소 원자를 하나 내지 둘 포함하거나 포함하지 않는 6 원자의 고리(ring)를 형성하며,R 5 and R 6 are joined together with the carbon atom to which they are attached to form a 6 membered ring with or without one or two nitrogen atoms,
R7은 수소, 할로겐, 하이드록시, C1-C4 알킬, 또는 C1-C4 알콕시이고,R 7 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
상기 화학식 1에서 실선과 점선의 이중선()으로 표현된 결합선은, 단일 탄소-탄소 결합, 또는 2중 탄소-탄소 결합을 나타낸다.In
"알킬"은 일반적으로 명시된 수의 탄소원자 (예컨대, 1 내지 12개의 탄소원자)를 갖는 선형 및 분지형 포화 탄화수소 기를 의미한다. 알킬기의 예는 제한 없이 메틸, 에틸, n-프로필, 아이소프로필, n-부틸, sec-부틸, 아이소부틸, tert-부틸, n-펜틸, n-헥실 및 n-헵틸 등을 포함한다. 알킬은 부착이 원자가 필요조건을 위반하지 않는다면 임의의 고리 원자에서 부모 기(parent group) 또는 기재(substrate)에 부착될 수 있다. 마찬가지로, 알킬기 또는 알케닐기는, 부착이 원자가 요구조건을 위반하지 않는다면 하나 이상의 비수소 치환기를 포함할 수 있다."Alkyl" refers generally to linear and branched saturated hydrocarbon groups having the specified number of carbon atoms (eg, from 1 to 12 carbon atoms). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and n-heptyl, and the like. Alkyl may be attached to a parent group or substrate at any ring atom provided that attachment does not violate valence requirements. Likewise, an alkyl or alkenyl group may contain one or more non-hydrogen substituents provided that attachment does not violate valence requirements.
"알콕시"는 산소와 결합된 알킬기이다. (R-O)알콕시기의 범위는 매우 크며, 메톡시, 에톡시, 프로폭시, 부톡시, 펜틸옥시, 헥실옥시가 있다."Alkoxy" is an alkyl group bonded to oxygen. The range of (R-O)alkoxy groups is very large and includes methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy.
"페닐"은 탄소와 수소로 이루어진 작용기로, 벤젠에서 수소 1개를 제거해 유도되는 치환기이다. 아릴기 중 가장 간단한 것이며, 약어로 -Ph로 표기할 수 있다. 매우 안정적이며, 많은 유기 화합물에서 발견된다. 가장 단순한 화합물은 페놀(C6H5OH)이다."Phenyl" is a functional group consisting of carbon and hydrogen, and is a substituent derived by removing one hydrogen from benzene. It is the simplest among the aryl groups, and can be expressed as -Ph as an abbreviation. It is very stable and is found in many organic compounds. The simplest compound is phenol (C 6 H 5 OH).
"할로겐"은 주기율표 17족에 속하는 원소들로, 최외각 전자 껍질에 전자가 7개 존재하기 때문에 다른 원소로부터 전자를 얻어 음이온이 되기 쉽다. 각 주기에서 비금속성이 가장 크고, 반응성이 크기 때문에 주로 다른 원소와 화합물의 형태로 존재한다. 불소, 염소, 브롬, 아이오딘 등이 있다."Halogen" is an element belonging to group 17 of the periodic table, and since there are 7 electrons in the outermost electron shell, it is easy to obtain electrons from other elements and become negative ions. It exists mainly in the form of other elements and compounds because of its high non-metallic properties and high reactivity in each cycle. These include fluorine, chlorine, bromine, and iodine.
"하이드록시"는 구조식이 -OH 으로 표시되는 작용기이다."Hydroxy" is a functional group whose structural formula is represented by -OH.
"알킬 에스터"는 -COOR과 같은 일반식을 가지며, 여기에서 R은 C1-C4 알킬을 나타낸다. 알킬 에스터는 예를 들어, 에틸 에스터 일 수 있다."Alkyl esters" have the general formula -COOR, wherein R represents C 1 -C 4 alkyl. The alkyl ester may be, for example, an ethyl ester.
"헤테로 고리 화합물"은 고리 화합물 중 고리를 이루는 원소가 2개 이상인 화합물이다.A "heterocyclic compound" is a compound in which two or more elements constituting a ring among ring compounds.
본 발명의 한 구체 예에서, 상기 화학식 1에서,In one embodiment of the present invention, in
R1은 수소, 할로겐, 또는 C1-C4 알킬 에스터이고,R 1 is hydrogen, halogen, or C 1 -C 4 alkyl ester,
R2는 C1-C4 알킬, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C5 헤테로 고리 화합물이며,R 2 is C 1 -C 4 alkyl, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 5 heterocyclic compound,
R3 및 R4는 각각 독립적으로 수소, 할로겐, C1-C4 알콕시, 또는 페닐이고,R 3 and R 4 are each independently hydrogen, halogen, C 1 -C 4 alkoxy, or phenyl;
R5 및 R6는 각각 독립적으로 수소, C1-C4 알콕시, 페녹시, 또는 모폴리닐이거나,R 5 and R 6 are each independently hydrogen, C 1 -C 4 alkoxy, phenoxy, or morpholinyl;
R5 및 R6는 이들이 결합된 탄소 원자와 함께 연결되어 6원의 탄화수소 화합물, 또는 방향족 헤테로 고리 화합물을 형성하며,R 5 and R 6 are joined together with the carbon atom to which they are attached to form a 6-membered hydrocarbon compound, or an aromatic heterocyclic compound,
R7은 수소, 또는 C1-C4 알킬이다.R 7 is hydrogen, or C 1 -C 4 alkyl.
본 발명의 다른 구체 예에서, 제 1항에 있어서,In another embodiment of the present invention, according to
상기 화학식 1의 화합물은 하기 화학식2의 구조를 갖는 것인 화합물일 수 있다.The compound of
[화학식 2][Formula 2]
상기 화학식 2에서,In
R1은 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, C1-C4 알킬 에스터, 또는 나이트릴이고,R 1 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl ester, or nitrile,
R2는 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C3-C6 헤테로 고리 화합물이며,R 2 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 3 -C 6 heterocyclic compound,
R7은 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 페닐, 또는 할로겐이고,R 7 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, or halogen,
R8은 수소, 할로겐, 하이드록시, C1-C4 알킬, 또는 C1-C4 알콕시이며,R 8 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
R9 및 R10은 각각 독립적으로 수소, 할로겐, 하이드록시, C1-C4 알킬, 또는 C1-C4 알콕시이고,R 9 and R 10 are each independently hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
여기에서 X 및 Y는 각각 독립적으로 질소, 또는 탄소이다.wherein X and Y are each independently nitrogen or carbon.
본 발명의 또 다른 구체 예에서, 상기 화학식 2에서,In another embodiment of the present invention, in
R1은 수소, 할로겐, 또는 C1-C4 알킬 에스터이고,R 1 is hydrogen, halogen, or C 1 -C 4 alkyl ester,
R2는 C1-C4 알킬, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C5 헤테로 고리 화합물이며,R 2 is C 1 -C 4 alkyl, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 5 heterocyclic compound,
R3 및 R4는 각각 독립적으로 수소, 할로겐, C1-C4 알콕시, 페닐, 또는 할로겐이고,R 3 and R 4 are each independently hydrogen, halogen, C 1 -C 4 alkoxy, phenyl, or halogen,
R7은 C1-C4 알킬, 또는 수소이며,R 7 is C 1 -C 4 alkyl, or hydrogen,
R8은 C1-C4 알콕시, 하이드록시, 또는 수소이고,R 8 is C 1 -C 4 alkoxy, hydroxy, or hydrogen,
R9 및 R10은 각각 독립적으로 C1-C4 알킬, 또는 수소이며,R 9 and R 10 are each independently C 1 -C 4 alkyl, or hydrogen,
여기에서 X 및 Y는 각각 독립적으로 질소, 또는 탄소이다.wherein X and Y are each independently nitrogen or carbon.
본 발명의 또 다른 구체 예에서, 상기 화학식 1에서,In another embodiment of the present invention, in
R1은 수소, 할로겐, 또는 C1-C4 알킬 에스터이고,R 1 is hydrogen, halogen, or C 1 -C 4 alkyl ester,
R2는 C1-C4 알킬, 하나 이상의 비수소치환기로 치환된 페닐, 또는 나프탈레닐이며,R 2 is C 1 -C 4 alkyl, phenyl substituted with one or more non-hydrogen substituents, or naphthalenyl;
R3 및 R4는 각각 독립적으로 수소, 할로겐, C1-C4 알콕시, 또는 페닐이고,R 3 and R 4 are each independently hydrogen, halogen, C 1 -C 4 alkoxy, or phenyl;
R5 및 R6는 각각 독립적으로 수소, C1-C4 알콕시, 페녹시, 또는 모폴리닐이며,R 5 and R 6 are each independently hydrogen, C 1 -C 4 alkoxy, phenoxy, or morpholinyl,
R7은 수소이다.R 7 is hydrogen.
본 발명의 또 다른 구체 예에서, R2는In another embodiment of the present invention, R 2 is
;;; ; ; ;
;;; ; ; ;
;;; ; ; ;
; 또는 일 수 있다. ; or can be
본 발명의 또 다른 구체 예에서, 상기 6원의 탄화수소 화합물은 벤젠, 또는 사이클로헥센일 수 있다.In another embodiment of the present invention, the 6-membered hydrocarbon compound may be benzene or cyclohexene.
본 발명의 또 다른 구체 예에서, 상기 방향족 헤테로 고리 화합물은 피리딘, 또는 피리미딘일 수 있다.In another embodiment of the present invention, the aromatic heterocyclic compound may be pyridine or pyrimidine.
본 발명의 또 다른 구체 예에서, R2는In another embodiment of the present invention, R 2 is
;;; ; ; ;
; 또는 일 수 있다. ; or can be
본 발명의 또 다른 구체 예에서, 화학식 1의 화합물은In another embodiment of the present invention, the compound of
5-벤조일벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4a);5-benzoylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4a);
5-(3-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4b);5-(3-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4b);
5-(4-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4c);5-(4-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4c);
5-(2,5-다이메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4d);5-(2,5-dimethoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4d);
5-(4-메틸벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4e);5-(4-methylbenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4e);
5-(2-나프토일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4f);5-(2-naphthoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4f);
5-([1,1'-바이페닐]-4-카보닐)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4g);5-([1,1'-biphenyl]-4-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4g);
5-(4-플루오로벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4h);5-(4-fluorobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4h);
5-(4-클로로벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4i);5-(4-chlorobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4i);
5-(4-브로모벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4j);5-(4-bromobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4j);
5-(푸란-2-카보닐)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4k);5-(furan-2-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4k);
5-아세틸벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4l);5-acetylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (41);
5-벤조일-7-하이드록시벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4m);5-benzoyl-7-hydroxybenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4m);
5-벤조일-7-메톡시벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4n);5-benzoyl-7-methoxybenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4n);
5-벤조일피롤로[1,2-b]아이소퀴놀린-6,9-디온(4o);5-benzoylpyrrolo[1,2-b]isoquinoline-6,9-dione (4o);
5-(4-클로로벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온(4p);5-(4-chlorobenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione (4p);
5-벤조일-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온(4q);5-benzoyl-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4q);
5-벤조일-7-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온(4q’);5-benzoyl-7-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4q');
5-(4-플루오로벤조일)-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온(4r);5-(4-fluorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4r);
5-(4-클로로벤조일)-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온(4s);5-(4-chlorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4s);
8-메톡시-5-(4-메톡시벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온(4t);8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione (4t);
5-(2-나프토일)-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온(4u);5-(2-naphthoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4u);
5-벤조일-7,8-다이메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온(4v);5-benzoyl-7,8-dimethoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4v);
11-벤조일인돌리지노[7,6-g]퀴놀린-5,12-디온(4w);11-benzoylindolizino[7,6-g]quinoline-5,12-dione (4w);
6-벤조일인돌리지노[6,7-g]퀴나졸린-5,12-디온(4x);6-benzoylindolizino[6,7-g]quinazoline-5,12-dione (4x);
5-벤조일-8-페녹시피롤로[1,2-b]아이소퀴놀린-6,9-디온(4y);5-benzoyl-8-phenoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4y);
5-벤조일-8-모폴리노피롤로[1,2-b]아이소퀴놀린-6,9-디온(4z);5-benzoyl-8-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione (4z);
5-벤조일-7-모폴리노피롤로[1,2-b]아이소퀴놀린-6,9-디온(4z’);5-benzoyl-7-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione (4z');
2-브로모-5-(4-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(4aa);2-bromo-5- (4-methoxybenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4aa);
2-브로모-8-메톡시-5-(4-메톡시벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온(4ab);2-bromo-8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione (4ab);
에틸5-(4-메톡시벤조일)-6,11-다이옥소-6,11-다이하이드로벤조[g]피롤로[1,2-b]아이소퀴놀린-2-카복실레이트(4ac);ethyl 5- (4-methoxybenzoyl)-6,11-dioxo-6,11-dihydrobenzo [g] pyrrolo [1,2-b] isoquinoline-2-carboxylate (4ac);
에틸8-메톡시-5-(4-메톡시벤조일)-6,9-다이옥소-6,9-다이하이드로피롤로[1,2-b]아이소퀴놀린-2-카복실레이트(4ad);ethyl8-methoxy-5-(4-methoxybenzoyl)-6,9-dioxo-6,9-dihydropyrrolo[1,2-b]isoquinoline-2-carboxylate (4ad);
5-(4-메톡시벤조일)-12-메틸벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(5);5-(4-methoxybenzoyl)-12-methylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (5);
5-벤조일-8,9-다이메틸-6a,7,10,10a-테트라하이드로벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(7); 또는5-benzoyl-8,9-dimethyl-6a,7,10,10a-tetrahydrobenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (7); or
5-벤조일-8,9-다이메틸벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온(9);인 화합물이다.5-benzoyl-8,9-dimethylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (9);
또한, 본 발명에서의 화합물은 하기 반응식 1에 표시된 바와 같이, 나프토퀴논과 3번 화합물을 이용하여 4번 화합물인 제 1항의 퀴논-인돌리진 하이브리드 유도체를 제조할 수 있으나, 이 예에 한정되는 것은 아니다.In addition, as shown in
[반응식 1] [Scheme 1]
한편, 본 발명의 상기 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다.Meanwhile, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt.
본 발명에서 사용되는 용어 "염"은 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 다이카복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 아이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 다이나이트로 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 또는 만델레이트를 포함한다.As used herein, the term "salt" is useful as an acid addition salt formed by a pharmaceutically acceptable free acid. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkandioates. It is obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda. Id, 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, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salt according to the invention is prepared by a conventional method, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt with a water-miscible organic solvent, for example methanol, ethanol, acetone or acetonitrile. can be manufactured. It can also be prepared by evaporating the solvent or excess acid from the mixture and drying the mixture, or by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수도 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. 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염 (예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
또한, 본 발명의 화합물은 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 이성질체, 수화물 및 용매화물을 모두 포함한다.In addition, the compound of the present invention includes all salts, isomers, hydrates and solvates that can be prepared by conventional methods as well as pharmaceutically acceptable salts.
하기 실시예에서 확인할 수 있는 바와 같이 화학식1의 화합물은 전립선암 및 구강암 세포의 성장과 이동을 억제하고 세포자멸사를 유발하는 목적으로 사용할 수 있다.As can be seen in the Examples below, the compound of
본 발명은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 전립선암 및 구강암의 예방 또는 치료용 약학적 조성물, 상기 질환의 치료를 위한 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염의 용도, 및 치료상 유효량의 상기 화학식 1의 화합물 또는 그의 약학적으로 허용가능한 염을 대상체에게 투여하는 것을 포함하는 상기 질환의 치료 방법을 제공한다.The present invention provides a pharmaceutical composition for the prevention or treatment of prostate cancer and oral cancer, comprising the compound of
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 전립선암 및 구강암을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term “prevention” refers to any action that suppresses or delays the onset of prostate and oral cancers by administration of the pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 전립선암 및 구강암에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term “treatment” refers to any action in which symptoms for prostate cancer and oral cancer are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
본 발명의 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. In this case, pharmaceutically acceptable carriers are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose. , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. may be additionally included in addition to the above components.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage may vary depending on the condition and weight of the patient, and the disease. Although it varies depending on the degree, drug form, administration route and time, it may be appropriately selected by those skilled in the art.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래 의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, drug activity, and type of the patient's disease; Sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including concurrent drugs and other factors well known in the medical field may be determined. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.0001 내지 1000mg, 바람직하게는 0.001 내지 500mg을 매일 또는 격일 투여하거나, 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient into the body, inactivation rate and excretion rate, disease type, and drugs used in combination, in general 0.0001 to 1000 mg, preferably 0.001 to 500 mg per 1 kg of body weight may be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, the severity of obesity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.In the present invention, "individual" refers to a subject in need of treatment for a disease, and more specifically, refers to mammals such as humans or non-human primates, mice, dogs, cats, horses and cattle. .
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.
<실시예 1> 화합물의 기본적인 합성 방법<Example 1> Basic method for synthesizing the compound
나프토퀴논 (27 mg, 0.17 mmol, 1.2 당량) 및 3a (30 mg, 0.14 mmol, 1 당량)의 혼합물이 포함된 EtOH (2.5mL)에 TEA (1 당량)를 실온에서 적가하였다. 가열멘틀을 사용하여 80 ℃에서 6 시간 동안 교반한 후, 반응 혼합물을 실온으로 냉각시켰다. 침전물을 흡인 여과하고, 헥산으로 세척하고, 건조시켜 적색 고체를 수득하였다. EtOH 여과액에 남아있는 생성물을 수득하기 위해; 여액을 감압하에 농축시키고 미정제 잔여물을 실리카겔 칼럼 크로마토그래피 (EtOAc/헥산 = 1 : 5)로 정제하여 추가의 생성물 4a를 수득하였다. 수율은 86 % (적색 고체, 42 mg)였다.To EtOH (2.5 mL) containing a mixture of naphthoquinone (27 mg, 0.17 mmol, 1.2 equiv) and 3a (30 mg, 0.14 mmol, 1 equiv) was added dropwise TEA (1 equiv) at room temperature. After stirring at 80° C. for 6 hours using a heating mantle, the reaction mixture was cooled to room temperature. The precipitate was filtered off with suction, washed with hexanes and dried to give a red solid. to obtain the product remaining in the EtOH filtrate; The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (EtOAc/hexanes=1:5) to give additional product 4a. The yield was 86% (red solid, 42 mg).
다음과 같이 스케일업하여 합성하였다.It was synthesized by scaling up as follows.
3a (1 g, 4.695 mmol), 나프토퀴논 (1.2 당량), 및 Et3N (1 당량)이 포함된 EtOH (20 mL) 혼합물을 80 ℃에서 10 시간 동안 교반 한 후, 반응 혼합물을 0 ℃로 냉각시켰다. 침전물을 흡인 여과하고, 헥산 (20 mL)으로 세척하고 건조시켜 적색 고체 (75 %)를 수득하였다. 여액을 감압하에 농축시키고 미정제 잔여물을 실리카겔 칼럼 크로마토그래피 (헥산 / EtOAc / CH2Cl2 = 10 : 1 : 2)로 정제하여 추가의 생성물 4a (10%)를 수득 하였다. 합한 수율은 85 % (적색 고체, 1.4 g)였다.A mixture of EtOH (20 mL) containing 3a (1 g, 4.695 mmol), naphthoquinone (1.2 equiv), and EtN (1 equiv) was stirred at 80 °C for 10 h, and then the reaction mixture was cooled to 0 °C. made it The precipitate was filtered off with suction, washed with hexanes (20 mL) and dried to give a red solid (75%). The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (hexane/EtOAc/CH 2 Cl 2 =10: 1: 2) to give additional product 4a (10%). The combined yield was 85% (red solid, 1.4 g).
상기 실시예 1의 방법으로 하기 실시예의 화합물들을 수득하였다. The compounds of Examples below were obtained by the method of Example 1.
<실시예 2> 5-벤조일벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4a)<Example 2> 5-benzoylbenzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4a)
Red solid (42 mg, 86%); mp: 233-234 °C; R f = 0.3 in 33% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.79 (t, J = 7.5 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 2.1 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 7.05 - 7.00 (m, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.3, 182.0, 181.0, 137.2, 134.9, 134.8, 134.7, 134.6, 134.1, 134.0, 133.2, 129.5, 128.7, 127.6 , 121.6, 121.0, 119.8, 117.5, 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C23H14NO3 352.0968, found 352.0970.Red solid (42 mg, 86%); mp: 233-234 °C; R f = 0.3 in 33% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 8.1 Hz) , 2H), 7.79 (t, J = 7.5 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H) ), 7.29 (d, J = 2.1 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 7.05 - 7.00 (m, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.3, 182.0, 181.0, 137.2, 134.9, 134.8, 134.7, 134.6, 134.1, 134.0, 133.2, 129.5, 128.7, 127.6 , 121.6, 121.0, 119.8, 117.5 , 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 23 H 14 NO 3 352.0968, found 352.0970.
<실시예 3> 5-(3-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4b)<Example 3> 5-(3-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4b)
Red solid (39 mg, 73%); mp: 284-285 °C; R f = 0.3 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.4 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.64 (s, 1H), 7.34-7.27 (m, 3H), 7.18 (d, J = 7.3 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J = 2.2 Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.0, 182.0, 180.9, 160.5, 137.1, 136.1, 134.8, 134.6, 134.1, 134.0, 133.1, 130.5, 127.6, 121.6, 121.5, 121.4, 120.9, 119.8, 117.4, 115.5, 112.3, 109.6, 55.6; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C24H16NO4 382.1074, found 382.1076.Red solid (39 mg, 73%); mp: 284-285 °C; R f = 0.3 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.4 Hz) , 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.64 (s, 1H), 7.34-7.27 (m, 3H), 7.18 (d, J = 7.3 Hz, 1H), 7.07 (s, 1H) , 7.02 (d, J = 2.2 Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.0, 182.0, 180.9, 160.5, 137.1, 136.1, 134.8, 134.6, 134.1, 134.0, 133.1, 130.5, 127.6, 121.6, 121.5, 121.4, 120.9, 119.8 , 117.4, 115.5, 112.3, 109.6, 55.6; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 24 H 16 NO 4 382.1074, found 382.1076.
<실시예 4> 5-(4-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4c)<Example 4> 5-(4-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4c)
Yellow solid (47 mg, 88 %); mp: 203-205 °C; R f = 0.3 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.79 (t, J = 7.4 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J = 3.6 Hz, 1H), 7.02 (d, J = 2.7 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 189.8, 182.0, 181.2, 165.0, 137.6, 134.8, 134.5, 134.3, 134.0, 133.1, 131.2, 128.0, 127.6, 121.5, 121.1, 119.7, 117.6, 115.2, 114.8, 109.6, 55.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C24H16NO4 382.1074, found 382.1072.Yellow solid (47 mg, 88%); mp: 203-205 °C; R f = 0.3 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.1 Hz) , 2H), 7.79 (t, J = 7.4 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.07 (d, J = 3.6 Hz, 1H), 7.02 (d) , J = 2.7 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 189.8, 182.0, 181.2, 165.0, 137.6, 134.8, 134.5, 134.3, 134.0, 133.1, 131.2, 128.0, 127.6, 121.5, 121.1, 119.7, 117.6, 115.2 , 114.8, 109.6, 55.8; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 24 H 16 NO 4 382.1074, found 382.1072.
<실시예 5> 5-(2,5-다이메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4d)<Example 5> 5- (2,5-dimethoxybenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4d)
Red solid (36 mg, 62%); mp: 237-239 °C; R f = 0.3 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.36 (d, J = 7.4 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.86 (s, 1H), 7.77 (t, J = 7.1 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.28 (s, 1H), 7.19 - 7.11 (m, 1H), 7.00 (d, J = 12.8 Hz, 2H), 6.81 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 3.19 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 188.8, 182.3, 181.4, 154.9, 154.4, 141.4, 134.9, 134.4, 134.3, 133.9, 133.0, 127.5, 124.9, 123.9, 121.4, 120.4, 119.2, 116.8, 114.5, 113.4, 113.2, 109.1, 56.71, 56.02; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C25H18NO5 412.1179, found 412.1183.Red solid (36 mg, 62%); mp: 237-239 °C; R f = 0.3 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (s, 1H), 8.36 (d, J = 7.4 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.86 (s, 1H), 7.77 (t, J = 7.1 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.28 (s, 1H), 7.19 - 7.11 (m, 1H), 7.00 (d, J = 12.8 Hz, 2H) , 6.81 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 3.19 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 188.8, 182.3, 181.4, 154.9, 154.4, 141.4, 134.9, 134.4, 134.3, 133.9, 133.0, 127.5, 124.9, 123.9, 121.4, 120.4, 119.2, 116.8 , 114.5, 113.4, 113.2, 109.1, 56.71, 56.02; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 25 H 18 NO 5 412.1179, found 412.1183.
<실시예 6> 5-(4-메틸벤조일)벤조[<Example 6> 5- (4-methylbenzoyl) benzo [ gg ]피롤로[1,2-]pyrrolo[1,2- bb ]아이소퀴놀린-6,11-디온 (4e)]Isoquinoline-6,11-dione (4e)
Dark solid (48 mg, 94 %); mp: 239-241 °C; R f = 0.4 in 33% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.29 - 7.26 (m, 3H), 7.06 (d, J = 3.9 Hz, 1H), 7.01 - 6.99 (m, 1H), 2.41 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.9, 182.0, 181.1, 146.0, 137.4, 134.8, 134.5, 134.2, 134.0, 133.1, 132.4, 130.2, 130.2, 128.9, 127.6, 121.5, 121.0, 119.7, 117.5, 115.3, 109.6, 22.0; HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C24H15NNaO3 388.0944, found 388.0947.Dark solid (48 mg, 94%); mp: 239-241 °C; R f = 0.4 in 33% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.60 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 7.8 Hz) , 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.29 - 7.26 (m, 3H), 7.06 (d, J = 3.9 Hz, 1H), 7.01 - 6.99 (m, 1H), 2.41 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190.9, 182.0, 181.1, 146.0, 137.4, 134.8, 134.5, 134.2, 134.0, 133.1, 132.4, 130.2, 130.2, 128.9, 127.6, 121.5, 121.0, 119.7 , 117.5, 115.3, 109.6, 22.0; HRMS (ESI-QTOF) m/z [M+Na] + calcd for C 24 H 15 NNaO 3 388.0944, found 388.0947.
<실시예 7> 5-(2-나프토일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4f)<Example 7> 5-(2-naphthoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4f)
Red solid (51 mg, 90 %); mp: 242-243 °C; R f = 0.4 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.21-8.04 (m, 2H), 7.99 (d, J = 6.67Hz, 1H), 7.88 (d, J = 5.7 Hz, 1H), 7.85-7.70 (m, 2H), 7.67 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.33 (s, 1H), 7.08 (s, 1H), 7.01 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.2, 181.9, 181.0, 137.3, 136.5, 134.7, 134.5, 134.1, 133.9, 133.2, 132.7, 132.4, 130.8, 129.8, 129.6, 129.3, 128.0, 127.5, 127.1, 123.6, 121.6, 121.0, 119.8, 117.5, 115.6, 109.6; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C27H16NO3, 402.1125, found 402.1124.Red solid (51 mg, 90%); mp: 242-243 °C; R f = 0.4 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.21-8.04 (m, 2H), 7.99 (d, J = 6.67 Hz, 1H), 7.88 (d, J = 5.7 Hz, 1H), 7.85-7.70 (m, 2H), 7.67 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.33 (s, 1H) ), 7.08 (s, 1H), 7.01 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.2, 181.9, 181.0, 137.3, 136.5, 134.7, 134.5, 134.1, 133.9, 133.2, 132.7, 132.4, 130.8, 129.8, 129.6, 129.3, 128.0, 127.5 , 127.1, 123.6, 121.6, 121.0, 119.8, 117.5, 115.6, 109.6; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 27 H 16 NO 3, 402.1125, found 402.1124.
<실시예 8> 5-([1,1'-바이페닐]-4-카보닐)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4g)<Example 8> 5-([1,1'-biphenyl]-4-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4g)
Red solid (57 mg, 97%); mp: 260-262 °C; R f = 0.4 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.38 (d, J = 7.0 Hz, 1H), 8.17 (d, J = 7.0 Hz, 1H), 8.00 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 7.3 Hz, 3H), 7.59 (d, J = 6.5 Hz, 2H), 7.44 (d, J = 6.7 Hz, 2H), 7.40 (d, J = 6.5 Hz, 1H), 7.34 (s, 1H), 7.09 (s, 1H), 7.04 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.9, 182.1, 181.0, 147.5, 139.7, 137.2, 134.8, 134.6, 134.1, 134.0, 133.6, 133.2, 129.3, 129.1, 128.6, 128.2, 127.6, 127.4, 121.7, 121.0, 119.8, 117.5, 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C29H18NO3 428.1281, found 428.1283.Red solid (57 mg, 97%); mp: 260-262 °C; R f = 0.4 in 35% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.38 (d, J = 7.0 Hz, 1H), 8.17 (d, J = 7.0 Hz, 1H), 8.00 (d, J = 7.2 Hz) , 2H), 7.79 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 7.3 Hz, 3H), 7.59 (d, J = 6.5 Hz, 2H), 7.44 (d, J = 6.7 Hz, 2H) ), 7.40 (d, J = 6.5 Hz, 1H), 7.34 (s, 1H), 7.09 (s, 1H), 7.04 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190.9, 182.1, 181.0, 147.5, 139.7, 137.2, 134.8, 134.6, 134.1, 134.0, 133.6, 133.2, 129.3, 129.1, 128.6, 128.2, 127.6, 127.4 , 121.7, 121.0, 119.8, 117.5, 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 29 H 18 NO 3 428.1281, found 428.1283.
<실시예 9> 5-(4-플루오로벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4h)<Example 9> 5- (4-fluorobenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4h)
Red solid (50 mg, 96 %); mp: 229-231 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.97 - 7.90 (m, 2H), 7.78 (t, J = 7.4 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.26 (s, 1H), 7.15 (t, J = 8.2 Hz, 2H), 7.07 (d, J = 3.8 Hz, 1H), 7.02 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 189.7, 182.0, 180.9, 168.0, 165.4, 136.6, 134.7, 134.6, 134.0, 133.2, 131.5, 131.4, 127.6, 127.5, 121.7, 120.9, 119.9, 117.3, 116.9, 116.7, 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C23H13FNO3 370.0874, found 370.0873.Red solid (50 mg, 96%); mp: 229-231 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.97 - 7.90 (m, 2H) , 7.78 (t, J = 7.4 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.26 (s, 1H), 7.15 (t, J = 8.2 Hz, 2H), 7.07 (d, J = 3.8 Hz, 1H), 7.02 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 189.7, 182.0, 180.9, 168.0, 165.4, 136.6, 134.7, 134.6, 134.0, 133.2, 131.5, 131.4, 127.6, 127.5, 121.7, 120.9, 119.9, 117.3 , 116.9, 116.7, 115.5, 109.7; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 23 H 13 FNO 3 370.0874, found 370.0873.
<실시예 10> 5-(4-클로로벤조일)벤조[<Example 10> 5- (4-chlorobenzoyl) benzo [ gg ]피롤로[1,2-]pyrrolo[1,2- bb ]아이소퀴놀린-6,11-디온 (4i)]Isoquinoline-6,11-dione (4i)
Red solid (34 mg, 63 %); mp: 262-264 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.81 (td, J = 7.5, 1.2 Hz, 1H), 7.73 (td, J = 7.6, 1.1 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 3.7 Hz, 1H), 7.06 - 7.01 (m, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.1, 182.1, 180.9, 141.3, 136.5, 134.8, 134.7, 134.1, 134.0, 133.4, 133.2, 130.0, 129.9, 127.7, 127.6, 121.8, 121.0, 120.0, 117.3, 115.7, 109.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C23H13ClNO3 386.0578, found 386.0576.Red solid (34 mg, 63%); mp: 262-264 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 8.5 Hz) , 2H), 7.81 (td, J = 7.5, 1.2 Hz, 1H), 7.73 (td, J = 7.6, 1.1 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 3.7 Hz, 1H), 7.06 - 7.01 (m, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190.1, 182.1, 180.9, 141.3, 136.5, 134.8, 134.7, 134.1, 134.0, 133.4, 133.2, 130.0, 129.9, 127.7, 127.6, 121.8, 121.0, 120.0 , 117.3, 115.7, 109.8; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 23 H 13 ClNO 3 386.0578, found 386.0576.
<실시예 11> 5-(4-브로모벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4j)<Example 11> 5- (4-bromobenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4j)
Yellowish red solid (54 mg, 90 %); mp: 274-275 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.2 Hz, 3H), 7.71 (t, J = 7.5 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.26 (s, 1H), 7.08 (d, J = 3.9 Hz, 1H), 7.05 - 6.99 (m, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.3, 182.1, 180.8, 136.4, 134.8, 134.7, 134.1, 134.0, 133.7, 133.2, 132.8, 130.1, 130.0, 127.7, 127.6, 121.8, 120.9, 119.9, 117.3, 115.7, 109.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C23H13BrNO3 430.0073, found 430.0072.Yellowish red solid (54 mg, 90%); mp: 274-275 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.2 Hz) , 3H), 7.71 (t, J = 7.5 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.26 (s, 1H), 7.08 (d, J = 3.9 Hz, 1H), 7.05 - 6.99 (m, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190.3, 182.1, 180.8, 136.4, 134.8, 134.7, 134.1, 134.0, 133.7, 133.2, 132.8, 130.1, 130.0, 127.7, 127.6, 121.8, 120.9, 119.9 , 117.3, 115.7, 109.8; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 23 H 13 BrNO 3 430.0073, found 430.0072.
<실시예 12> 5-(푸란-2-카보닐)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4k)<Example 12> 5-(furan-2-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (4k)
Red solid (43 mg, 91 %); mp: 249-251 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.33 (d, J = 7.0 Hz, 1H), 8.16 (d, J = 7.0 Hz, 1H), 7.83-7.66 (m, 2H), 7.60 (s, 1H), 7.41 (s, 1H), 7.26 (s, 1H), 7.11-6.98 (m, 2H), 6.58 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 182.1, 180.9, 178.5, 151.7, 148.1, 135.5, 134.7, 134.6, 134.1, 134.0, 133.2, 127.6, 122.0, 120.9, 119.7, 119.6, 117.3, 115.8, 113.1, 109.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H12NO4 342.0761, found 342.0761.Red solid (43 mg, 91%); mp: 249-251 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (s, 1H), 8.33 (d, J = 7.0 Hz, 1H), 8.16 (d, J = 7.0 Hz, 1H), 7.83-7.66 (m, 2H) , 7.60 (s, 1H), 7.41 (s, 1H), 7.26 (s, 1H), 7.11-6.98 (m, 2H), 6.58 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 182.1, 180.9, 178.5, 151.7, 148.1, 135.5, 134.7, 134.6, 134.1, 134.0, 133.2, 127.6, 122.0, 120.9, 119.7, 119.6, 117.3, 115.8 , 113.1, 109.7; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 21 H 12 NO 4 342.0761, found 342.0761.
<실시예 13> 5-아세틸벤조[<Example 13> 5-acetylbenzo [ gg ]피롤로[1,2-]pyrrolo[1,2- bb ]아이소퀴놀린-6,11-디온]Isoquinoline-6,11-dione (4l)(4l)
Brown solid (28 mg, 70 %); mp: 203-205 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.35 (d, J = 6.6 Hz, 1H), 8.27 (d, J = 6.8 Hz, 1H), 7.85 - 7.74 (m, 2H), 7.40 (s, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 2.75 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 198.5, 182.6, 180.9, 138.8, 134.9, 134.7, 134.1, 133.2, 127.7, 127.5, 121.5, 120.9, 119.9, 116.5, 113.6, 109.8, 30.1; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C18H12NO3 290.0812, found 290.0814.Brown solid (28 mg, 70%); mp: 203-205 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.35 (d, J = 6.6 Hz, 1H), 8.27 (d, J = 6.8 Hz, 1H), 7.85 - 7.74 (m, 2H) , 7.40 (s, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 2.75 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 198.5, 182.6, 180.9, 138.8, 134.9, 134.7, 134.1, 133.2, 127.7, 127.5, 121.5, 120.9, 119.9, 116.5, 113.6, 109.8, 30.1; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 18 H 12 NO 3 290.0812, found 290.0814.
<실시예 14> 5-벤조일-7-하이드록시벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4m)<Example 14> 5-benzoyl-7-hydroxybenzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4m)
Red solid (27 mg, 53%, brsm 69%); mp: 245-247 °C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 13.06 (s, 1H), 8.64 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 1.2 Hz, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.33-7.27 (m, 2H), 7.12 (d, J = 4.1 Hz, 1H), 7.06-7.03 (m, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.0, 186.5, 181.4, 163.1, 137.4, 136.6, 134.9, 134.8, 134.1, 133.1, 129.5, 128.7, 124.5, 121.8, 120.5, 120.1, 119.6, 118.1, 117.4, 115.2, 110.5; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C23H14NO4 368.0917, found 368.0918.Red solid (27 mg, 53%, brsm 69%); mp: 245-247 °C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 13.06 (s, 1H), 8.64 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 1.2 Hz, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.33-7.27 (m, 2H), 7.12 (d, J = 4.1 Hz, 1H), 7.06-7.03 (m, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.0, 186.5, 181.4, 163.1, 137.4, 136.6, 134.9, 134.8, 134.1, 133.1, 129.5, 128.7, 124.5, 121.8, 120.5, 120.1, 119.6, 118.1 , 117.4, 115.2, 110.5; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 23 H 14 NO 4 368.0917, found 368.0918.
<실시예 15> 5-벤조일-7-메톡시벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4n)<Example 15> 5-benzoyl-7-methoxybenzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4n)
Red solid (52 mg, 97%); mp: 236-238 °C; R f = 0.2 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 8.1 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.32-7.19 (m, 2H), 7.04 (d, J = 3.7 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H); 13 C { 1 H} NMR (100 MHz, CDCl3) δ 191.4, 181.3, 181.2, 161.0, 137.0, 136.7, 135.5, 135.0, 134.4, 133.1, 129.3, 129.3, 128.9, 122.1, 121.0, 120.6, 120.1, 119.5, 117.8, 117.4, 117.3, 109.2, 56.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C24H16NO4 382.1074, found 382.1074.Red solid (52 mg, 97%); mp: 236-238 °C; R f = 0.2 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 8.1 Hz) , 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.32-7.19 (m, 2H), 7.04 (d, J = 3.7 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 3.91 (s, 3H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 191.4, 181.3, 181.2, 161.0, 137.0, 136.7, 135.5, 135.0, 134.4, 133.1, 129.3, 129.3, 128.9, 122.1, 121.0, 120.6, 120.1, 119.5 , 117.8, 117.4, 117.3, 109.2, 56.7; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 24 H 16 NO 4 382.1074, found 382.1074.
<실시예 16> 5-벤조일피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4o)<Example 16> 5-benzoylpyrrolo[1,2-b]isoquinoline-6,9-dione (4o)
3a (30 mg, 0.14 mmol) 및 1,4-벤조퀴논 (2.5 당량)이 포함된 CH3CN (7 mL) 혼합물에 Et3N (1 당량)을 실온에서 적가하였다. 실온에서 20 시간 동안 교반한 후, 반응 혼합물을 감압하에 농축하고 미정제 잔류물을 용리제로서 혼합 용매 (헥산 : EtOAc : CH2Cl2 = 3 : 1 : 2)를 갖는 실리카겔의 플러그를 통해 여과하여 극성 불순물을 제거하였다. 여액을 진공에서 농축시켜 미정제 잔류물을 수득하고, 이를 컬럼 크로마토그래피 (헥산 : EtOAc : CH2Cl2 = 6 : 1 : 2)로 정제하여 4o를 적색 고체로서 수득하였다 (28 mg, 67 %). mp: 238-239 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.64 (t, J = 7.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.12 - 6.93 (m, 4H), 6.83 (d, J = 10.4 Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.9, 183.3, 182.4, 141.1, 139.7, 136.9, 134.9, 134.7, 132.8, 129.4, 128.8, 128.7, 121.2, 120.0, 119.7, 117.9, 114.5, 110.4; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C19H12NO3 302.0812, found 302.0812. To a mixture of CH 3 CN (7 mL) containing 3a (30 mg, 0.14 mmol) and 1,4-benzoquinone (2.5 equiv) was added dropwise Et3N (1 equiv) at room temperature. After stirring at room temperature for 20 h, the reaction mixture was concentrated under reduced pressure and the crude residue was filtered through a plug of silica gel with a mixed solvent (hexane: EtOAc: CH 2 Cl 2 =3: 1: 2) as eluent. to remove polar impurities. The filtrate was concentrated in vacuo to give a crude residue, which was purified by column chromatography (hexane : EtOAc : CH 2 Cl 2 = 6 : 1 : 2) to give 4o as a red solid (28 mg, 67 %). ). mp: 238-239 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.64 (t, J = 7.0 Hz, 1H), 7.48 (t, J = 7.5 Hz) , 2H), 7.12 - 6.93 (m, 4H), 6.83 (d, J = 10.4 Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190.9, 183.3, 182.4, 141.1, 139.7, 136.9, 134.9, 134.7, 132.8, 129.4, 128.8, 128.7, 121.2, 120.0, 119.7, 117.9, 114.5, 110.4 ; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 19 H 12 NO 3 302.0812, found 302.0812.
<실시예 17> 5-(4-클로로벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4p)<Example 17> 5- (4-chlorobenzoyl) pyrrolo [1,2-b] isoquinoline-6,9-dione (4p)
Red Solid (19 mg, 46%); mp: 239-241 °C; R f = 0.3 in 25% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.80 (d, J = 7.1 Hz, 2H), 7.46 (d, J = 7.1 Hz, 2H), 7.26 (s, 1H), 7.08 (d, J = 3.5 Hz, 1H), 7.07-7.01 (m, 2H), 6.85 (dd, J = 10.4, 1.8 Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 189.8, 183.4, 182.3, 141.5, 141.3, 139.7, 136.2, 133.2, 132.8, 130.0, 129.9, 121.4, 120.0, 119.9, 117.8, 114.7, 110.6; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C19H11ClNO3 336.0422, found 336.0421.Red Solid (19 mg, 46%); mp: 239-241 °C; R f = 0.3 in 25% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 1H), 7.80 (d, J = 7.1 Hz, 2H), 7.46 (d, J = 7.1 Hz, 2H), 7.26 (s, 1H), 7.08 (d, J = 3.5 Hz, 1H), 7.07-7.01 (m, 2H), 6.85 (dd, J = 10.4, 1.8 Hz, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 189.8, 183.4, 182.3, 141.5, 141.3, 139.7, 136.2, 133.2, 132.8, 130.0, 129.9, 121.4, 120.0, 119.9, 117.8, 114.7, 110.6; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 19 H 11 ClNO 3 336.0422, found 336.0421.
<실시예 18> 5-벤조일-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4q) 및 5-벤조일-7-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4q’)<Example 18> 5-benzoyl-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4q) and 5-benzoyl-7-methoxypyrrolo[1,2-b]iso Quinoline-6,9-dione (4q')
4o (0.14 mmol)와 TEA (2 당량)이 포함된 MeOH (2 mL) 용액을 80 ℃에서 12 시간 동안 가열 한 후, 반응 혼합물을 실온으로 냉각시키고 감압 하에서 농축시켰다. 미정제 잔여물을 30 % EtOAc이 포함된 헥산 용매로 용리하는 칼럼 크로마토그래피로 정제하여 3 : 1의 비율로 4q '및 4q를 적색 고체로서 (42 mg, 전체 91 %)수득하였다(1H NMR의 적분 값에 의해 결정). 4q '에 대한 스펙트럼 데이터는 혼합물로부터 기록되었다.After heating a solution of 4o (0.14 mmol) in MeOH (2 mL) with TEA (2 eq) at 80 °C for 12 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by column chromatography eluting with a hexane solvent containing 30% EtOAc to obtain 4q' and 4q as red solids (42 mg, total 91%) in a 3:1 ratio ( 1 H NMR). determined by the integral value of ). Spectral data for 4q' was recorded from the mixture.
Red solid (44 mg, 94%); mp: 210-213 °C; R f = 0.2 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.62 (t, J = 7.1 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.26 (s, 1H), 7.05 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.06 (s, 1H), 3.86 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.0, 183.1, 177.4, 162.6, 135.8, 134.9, 134.6, 132.8, 129.3, 129.3, 128.6, 128.6, 122.0, 119.5, 119.2, 118.3, 114.4, 111.3, 110.8, 56.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H14NO4 332.0917, found 332.0922.Red solid (44 mg, 94%); mp: 210-213 °C; R f = 0.2 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (s, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.62 (t, J = 7.1 Hz, 1H), 7.46 (t, J = 7.5 Hz) , 2H), 7.26 (s, 1H), 7.05 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.06 (s, 1H), 3.86 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.0, 183.1, 177.4, 162.6, 135.8, 134.9, 134.6, 132.8, 129.3, 129.3, 128.6, 128.6, 122.0, 119.5, 119.2, 118.3, 114.4, 111.3 , 110.8, 56.7; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 20 H 14 NO 4 332.0917, found 332.0922.
Red solid (31.5 mg, 68%); R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.26 (s, 1H), 7.01 (d, J = 3.9 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.25 (s, 1H), 3.83 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.8, 182.6, 178.3, 161.3, 134.8, 134.7, 132.8, 129.4, 128.7, 122.0, 120.3, 120.3, 119.7, 117.5, 112.6, 112.5, 110.8, 109.8, 56.6; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H14NO4 332.0917, found 332.0911.Red solid (31.5 mg, 68%); R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 7.3 Hz) , 2H), 7.26 (s, 1H), 7.01 (d, J = 3.9 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.25 (s, 1H), 3.83 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190.8, 182.6, 178.3, 161.3, 134.8, 134.7, 132.8, 129.4, 128.7, 122.0, 120.3, 120.3, 119.7, 117.5, 112.6, 112.5, 110.8, 109.8 , 56.6; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 20 H 14 NO 4 332.0917, found 332.0911.
<실시예 19> 5-(4-플루오로벤조일)-8-메톡시피롤로[1,2-<Example 19> 5- (4-fluorobenzoyl) -8-methoxypyrrolo [1,2- bb ]아이소퀴놀린-6,9-디온 (4r)]Isoquinoline-6,9-dione (4r)
Red solid (45 mg, 93 %); mp: 260-262 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.94 - 7.82 (m, 2H), 7.25 (s, 1H), 7.14 (t, J = 8.1 Hz, 2H), 7.06 (d, J = 3.2 Hz, 1H), 6.98 (s, 1H), 6.06 (s, 1H), 3.87 (s, 3H); 13 C { 1 H} NMR (100 MHz, CDCl3) δ 189.5, 183.1, 177.3, 167.9, 165.4, 162.7, 135.3, 132.8, 131.5, 122.1, 119.6, 119.2, 118.2, 116.8, 116.6, 114.4, 111.3, 110.9, 56.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H13FNO4 350.0823, found 350.0827.Red solid (45 mg, 93%); mp: 260-262 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (s, 1H), 7.94 - 7.82 (m, 2H), 7.25 (s, 1H), 7.14 (t, J = 8.1 Hz, 2H), 7.06 (d, J = 3.2 Hz, 1H), 6.98 (s, 1H), 6.06 (s, 1H), 3.87 (s, 3H); 13 C { 1 H} NMR (100 MHz, CDCl 3 ) δ 189.5, 183.1, 177.3, 167.9, 165.4, 162.7, 135.3, 132.8, 131.5, 122.1, 119.6, 119.2, 118.2, 116.8, 116.6, 114.4, 111.3, 110.9 , 56.8; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 20 H 13 FNO 4 350.0823, found 350.0827.
<실시예 20> 5-(4-클로로벤조일)-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4s)<Example 20> 5-(4-chlorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4s)
Red solid (38 mg, 74 %); mp: 267-269°C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.07 (s, 1H), 6.98 (s, 1H), 6.06 (s, 1H), 3.88 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 189.9, 183.1, 177.3, 162.7, 141.2, 135.1, 133.4, 132.9, 129.9, 129.8, 122.1, 119.6, 119.2, 118.1, 114.6, 111.2, 110.9, 56.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H13ClNO4 366.0528, found 366.0530.Red solid (38 mg, 74%); mp: 267-269°C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.07 (s, 1H), 6.98 (s, 1H), 6.06 (s, 1H), 3.88 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 189.9, 183.1, 177.3, 162.7, 141.2, 135.1, 133.4, 132.9, 129.9, 129.8, 122.1, 119.6, 119.2, 118.1, 114.6, 111.2, 110.9, 56.8 ; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 20 H 13 ClNO 4 366.0528, found 366.0530.
<실시예 21> 8-메톡시-5-(4-메톡시벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4t)<Example 21> 8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione (4t)
Red solid (47 mg, 92 %); mp: 227-228 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J = 3.9 Hz, 1H), 6.98-6.90 (m, 3H), 6.07 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 189.5, 183.0, 177.5, 164.9, 162.5, 136.1, 132.7, 131.2, 128.0, 121.9, 119.4, 118.4, 114.7, 114.0, 111.5, 110.7, 56.7, 55.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H16NO5 362.1023, found 362.1027.Red solid (47 mg, 92%); mp: 227-228 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J = 3.9 Hz, 1H), 6.98 -6.90 (m, 3H), 6.07 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 189.5, 183.0, 177.5, 164.9, 162.5, 136.1, 132.7, 131.2, 128.0, 121.9, 119.4, 118.4, 114.7, 114.0, 111.5, 110.7, 56.7, 55.7 ; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 21 H 16 NO 5 362.1023, found 362.1027.
<실시예 22> 5-(2-나프토일)-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4u)<Example 22> 5-(2-naphthoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4u)
Red solid (51 mg, 95 %); mp: 278-279°C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.16 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.31 (s, 1H), 7.08 (d, J = 3.9 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.05 (s, 1H), 3.86 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.1, 183.1, 177.5, 162.6, 136.5, 135.9, 132.9, 132.7, 132.5, 130.7, 129.8, 129.6, 129.3, 128.1, 127.2, 123.6, 122.1, 119.5, 119.4, 118.4, 114.5, 111.4, 110.8, 56.7; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C24H16NO4 382.1074, found 382.1073.Red solid (51 mg, 95%); mp: 278-279°C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.16 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 1H), 7.31 (s) , 1H), 7.08 (d, J = 3.9 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.05 (s, 1H), 3.86 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.1, 183.1, 177.5, 162.6, 136.5, 135.9, 132.9, 132.7, 132.5, 130.7, 129.8, 129.6, 129.3, 128.1, 127.2, 123.6, 122.1, 119.5 , 119.4, 118.4, 114.5, 111.4, 110.8, 56.7; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 24 H 16 NO 4 382.1074, found 382.1073.
<실시예 23> 5-벤조일-7,8-다이메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4v)<Example 23> 5-benzoyl-7,8-dimethoxypyrrolo[1,2-b]isoquinoline-6,9-dione (4v)
Red solid (20 mg, 40%, brsm 82%); mp: 191-193°C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.21 (d, J = 2.7 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 6.99 - 6.87 (m, 1H), 4.14 (s, 3H), 3.96 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.9, 180.1, 179.3, 150.6, 148.6, 136.5, 134.8, 132.8, 129.4, 128.8, 120.8, 119.3, 119.0, 117.8, 113.4, 110.2, 61.5; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H16NO5 362.1023, found 362.1025.Red solid (20 mg, 40%, brsm 82%); mp: 191-193°C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz) , 2H), 7.21 (d, J = 2.7 Hz, 1H), 7.01 (d, J = 4.0 Hz, 1H), 6.99 - 6.87 (m, 1H), 4.14 (s, 3H), 3.96 (s, 3H) ; 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190.9, 180.1, 179.3, 150.6, 148.6, 136.5, 134.8, 132.8, 129.4, 128.8, 120.8, 119.3, 119.0, 117.8, 113.4, 110.2, 61.5; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 21 H 16 NO 5 362.1023, found 362.1025.
<실시예 24> 11-벤조일인돌리지노[7,6-g]퀴놀린-5,12-디온 (4w)<Example 24> 11-benzoyl indolizino [7,6-g] quinoline-5,12-dione (4w)
Red solid (37 mg, 76%); mp: 299-301 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.73 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 6.7 Hz, 2H), 7.65 (s, 2H), 7.50 (d, J = 6.8 Hz, 2H), 7.31 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 190.9, 181.5, 179.4, 155.5, 150.2, 137.5, 135.9, 135.0, 134.6, 133.2, 131.3, 129.6, 129.3, 128.7, 128.1, 127.7, 120.6, 120.3, 118.0, 114.7, 110.5; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C22H13N2O3 353.0921, found 353.0928.Red solid (37 mg, 76%); mp: 299-301 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 9.10 (s, 1H), 8.73 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 6.7 Hz, 2H), 7.65 (s, 2H), 7.50 (d, J = 6.8 Hz, 2H), 7.31 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190.9, 181.5, 179.4, 155.5, 150.2, 137.5, 135.9, 135.0, 134.6, 133.2, 131.3, 129.6, 129.3, 128.7, 128.1, 127.7, 120.6, 120.3 , 118.0, 114.7, 110.5; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 22 H 13 N 2 O 3 353.0921, found 353.0928.
<실시예 25> 6-벤조일인돌리지노[6,7-g]퀴나졸린-5,12-디온 (4x)<Example 25> 6-benzoyl indolizino [6,7-g] quinazoline-5,12-dione (4x)
Red solid (15 mg, 30%, brsm 78%); mp: 334-335 °C; R f = 0.2 in 50% EtOAc in hexane; 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.45 (s, 1H), 8.69 (s, 1H), 7.93 (d, J = 6.9 Hz, 2H), 7.79-7.69 (m, 1H), 7.61-7.53 (m, 2H), 7.50 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H); 13 C{ 1 H} NMR (100 MHz, DMSO-d6) δ 190.4, 180.8, 178.9, 162.3, 157.7, 155.2, 136.1, 135.0, 134.1, 132.6, 129.5, 128.7, 126.6, 121.7, 121.1, 120.5, 118.2, 114.7, 110.9; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H12N3O3 354.0873, found 354.0879.Red solid (15 mg, 30%, brsm 78%); mp: 334-335 °C; R f = 0.2 in 50% EtOAc in hexane; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.69 (s, 1H), 9.45 (s, 1H), 8.69 (s, 1H), 7.93 (d, J = 6.9 Hz, 2H), 7.79-7.69 ( m, 1H), 7.61-7.53 (m, 2H), 7.50 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H); 13 C{ 1 H} NMR (100 MHz, DMSO-d 6 ) δ 190.4, 180.8, 178.9, 162.3, 157.7, 155.2, 136.1, 135.0, 134.1, 132.6, 129.5, 128.7, 126.6, 121.7, 121.1, 120.5, 118.2 , 114.7, 110.9; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 21 H 12 N 3 O 3 354.0873, found 354.0879.
<실시예 26> 5-벤조일-8-페녹시피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4y)<Example 26> 5-benzoyl-8-phenoxypyrrolo [1,2-b] isoquinoline-6,9-dione (4y)
Red solid (39 mg, 70%); mp: 213-214 °C; R f = 0.2 in 20% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.61 (t, J = 7.0 Hz, 1H), 7.49 - 7.37 (m, 4H), 7.31-7.26 (m, 2H), 7.14-7.06 (m, 3H), 7.01 - 6.98 (m, 1H), 5.84 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.0, 183.1, 177.2, 162.7, 152.8, 136.0, 134.9, 134.7, 132.9, 130.5, 130.5, 129.4, 128.6, 126.8, 122.1, 121.2, 119.6, 119.4, 118.5, 114.8, 114.4, 111.0; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C25H16NO4 394.1074, found 394.1076.Red solid (39 mg, 70%); mp: 213-214 °C; R f = 0.2 in 20% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (s, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.61 (t, J = 7.0 Hz, 1H), 7.49 - 7.37 (m, 4H) , 7.31-7.26 (m, 2H), 7.14-7.06 (m, 3H), 7.01 - 6.98 (m, 1H), 5.84 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.0, 183.1, 177.2, 162.7, 152.8, 136.0, 134.9, 134.7, 132.9, 130.5, 130.5, 129.4, 128.6, 126.8, 122.1, 121.2, 119.6, 119.4 , 118.5, 114.8, 114.4, 111.0; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 25 H 16 NO 4 394.1074, found 394.1076.
<실시예 27> 5-벤조일-8-모폴리노피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4z) 및 5-벤조일-7-모폴리노피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4z’)<Example 27> 5-benzoyl-8-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione (4z) and 5-benzoyl-7-morpholinopyrrolo[1,2-b ]Isoquinoline-6,9-dione (4z')
4o (0.14 mmol)이 포함된 CH3CN (2 mL) 용액에 모폴린 (0.28 mmol)을 실온에서 적가하였다. 실온에서 3 시간 동안 교반한 후, 반응 혼합물을 감압하에 농축하고, 40 % EtOAc이 포함된 헥산용매로 용리하는 칼럼 크로마토그래피로 정제하여 4z'및 4z(6 : 1의 비율로 별도로 분리, 49 mg, 전체 수율 91 %)를 수득하였다. 4z'는 TLC에서 4z보다 극성이 높다.To a solution of 4o (0.14 mmol) in CH 3 CN (2 mL) was added dropwise morpholine (0.28 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure and purified by column chromatography eluting with a hexane solvent containing 40% EtOAc to separate 4z' and 4z (6:1 ratio, 49 mg). , an overall yield of 91%) was obtained. 4z' is more polar than 4z in TLC.
Red solid (36 mg, 67%); mp: 194-196 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H), 7.24 (s, 1H), 7.02 (d, J = 3.9 Hz, 1H), 6.94 (dd, J = 2.6, 1.5 Hz, 1H), 5.91 (s, 1H), 3.85 (t, J = 4.2 Hz, 4H), 3.54 (d, J = 4.8 Hz, 4H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.4, 181.7, 180.0, 155.1, 135.3, 134.5, 134.4, 132.9, 129.3, 128.6, 121.9, 121.1, 119.0, 117.8, 114.9, 113.5, 110.0, 66.6, 49.3; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C23H19N2O4 387.1339, found 387.1339.Red solid (36 mg, 67%); mp: 194-196 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.2 Hz) , 2H), 7.24 (s, 1H), 7.02 (d, J = 3.9 Hz, 1H), 6.94 (dd, J = 2.6, 1.5 Hz, 1H), 5.91 (s, 1H), 3.85 (t, J = 4.2 Hz, 4H), 3.54 (d, J = 4.8 Hz, 4H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.4, 181.7, 180.0, 155.1, 135.3, 134.5, 134.4, 132.9, 129.3, 128.6, 121.9, 121.1, 119.0, 117.8, 114.9, 113.5, 110.0, 66.6 , 49.3; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 23 H 19 N 2 O 4 387.1339, found 387.1339.
Red solid (46 mg, 86%); mp: 181-182 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.64 (d, J = 5.9 Hz, 1H), 7.50 (d, J = 6.8 Hz, 2H), 7.16 (s, 1H), 6.94 (d, J = 4.3 Hz, 2H), 6.12 (s, 1H), 3.79-3.65 (m, 4H), 3.47-3.20 (m, 4H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.2, 181.7, 181.1, 154.3, 137.5, 134.8, 132.9, 129.5, 128.9, 120.4, 119.3, 119.2, 116.9, 116.1, 115.2, 108.9, 66.4, 49.2; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C23H19N2O4 387.1339, found 387.1339.Red solid (46 mg, 86%); mp: 181-182 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.64 (d, J = 5.9 Hz, 1H), 7.50 (d, J = 6.8 Hz) , 2H), 7.16 (s, 1H), 6.94 (d, J = 4.3 Hz, 2H), 6.12 (s, 1H), 3.79-3.65 (m, 4H), 3.47-3.20 (m, 4H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.2, 181.7, 181.1, 154.3, 137.5, 134.8, 132.9, 129.5, 128.9, 120.4, 119.3, 119.2, 116.9, 116.1, 115.2, 108.9, 66.4, 49.2 ; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 23 H 19 N 2 O 4 387.1339, found 387.1339.
<실시예 28> 2-브로모-5-(4-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (4aa)<Example 28> 2-bromo-5- (4-methoxybenzoyl) benzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (4aa)
Red solid (56 mg, 87%); mp: 234-235 °C; R f = 0.3 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.7 Hz, 2H), 7.80 (t, J = 7.5 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.06 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 3.87 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 189.2, 181.7, 180.9, 165.2, 138.8, 136.5, 134.7, 134.6, 134.3, 134.2, 133.3, 131.3, 127.7, 122.2, 119.9, 116.9, 115.4, 115.0, 111.0, 109.9, 55.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C24H15BrNO4 460.0179, found 460.0181.Red solid (56 mg, 87%); mp: 234-235 °C; R f = 0.3 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.7 Hz) , 2H), 7.80 (t, J = 7.5 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.28 (s, 1H), 7.06 (s, 1H), 6.97 (d, J = 8.4 Hz) , 2H), 3.87 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 189.2, 181.7, 180.9, 165.2, 138.8, 136.5, 134.7, 134.6, 134.3, 134.2, 133.3, 131.3, 127.7, 122.2, 119.9, 116.9, 115.4, 115.0 , 111.0, 109.9, 55.8; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 24 H 15 BrNO 4 460.0179, found 460.0181.
<실시예 29> 2-브로모-8-메톡시-5-(4-메톡시벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온 (4ab)<Example 29> 2-bromo-8-methoxy-5- (4-methoxybenzoyl) pyrrolo [1,2-b] isoquinoline-6,9-dione (4ab)
Red solid (52 mg, 85%); mp: 253-255 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.05 (s, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.08 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 188.9, 182.7, 177.4, 165.1, 162.3, 135.2, 133.0, 131.2, 127.8, 120.4, 120.2, 117.7, 114.9, 114.8, 111.9, 111.7, 109.4, 56.8, 55.8; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H15BrNO5 440.0128, found 440.0132.Red solid (52 mg, 85%); mp: 253-255 °C; R f = 0.2 in 40% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.05 (s, 1H), 6.95 (d, J = 8.0 Hz, 2H), 6.08 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 188.9, 182.7, 177.4, 165.1, 162.3, 135.2, 133.0, 131.2, 127.8, 120.4, 120.2, 117.7, 114.9, 114.8, 111.9, 111.7, 109.4, 56.8 , 55.8; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 21 H 15 BrNO 5 440.0128, found 440.0132.
<실시예 30> 에틸5-(4-메톡시벤조일)-6,11-다이옥소-6,11-다이하이드로벤조[g]피롤로[1,2-b]아이소퀴놀린-2-카복실레이트 (4ac)<Example 30> Ethyl 5- (4-methoxybenzoyl) -6,11-dioxo-6,11-dihydrobenzo [g] pyrrolo [1,2-b] isoquinoline-2-carboxylate ( 4ac)
Red solid (49 mg, 78%); mp: 313-315 °C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.87 - 7.78 (m, 1H), 7.76 (s, 2H), 7.44 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H), 4.38-4.26 (m, 2H), 3.87 (s, 3H), 1.35 (t, J = 6.4 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 189.1, 181.7, 180.8, 165.2, 163.4, 137.9, 134.9, 134.6, 134.4, 134.2, 133.1, 131.3, 127.8, 125.6, 122.8, 122.4, 119.8, 117.0, 116.5, 115.0, 109.8, 61.2, 55.8, 14.5; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C27H20NO6 454.1285, found 454.1289.Red solid (49 mg, 78%); mp: 313-315 °C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.6 Hz) , 2H), 7.87 - 7.78 (m, 1H), 7.76 (s, 2H), 7.44 (s, 1H), 6.97 (d, J = 8.0 Hz, 2H), 4.38-4.26 (m, 2H), 3.87 ( s, 3H), 1.35 (t, J = 6.4 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 189.1, 181.7, 180.8, 165.2, 163.4, 137.9, 134.9, 134.6, 134.4, 134.2, 133.1, 131.3, 127.8, 125.6, 122.8, 122.4, 119.8, 117.0 , 116.5, 115.0, 109.8, 61.2, 55.8, 14.5; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 27 H 20 NO 6 454.1285, found 454.1289.
<실시예 31> 에틸8-메톡시-5-(4-메톡시벤조일)-6,9-다이옥소-6,9-다이하이드로피롤로[1,2-b]아이소퀴놀린-2-카복실레이트 (4ad)<Example 31> Ethyl 8-methoxy-5-(4-methoxybenzoyl)-6,9-dioxo-6,9-dihydropyrrolo[1,2-b]isoquinoline-2-carboxylate (4ad)
Red solid (44 mg, 73%); mp: 319-321 °C; R f = 0.2 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.41 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.10 (s, 1H), 4.35-4.26 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 188.8, 182.5, 177.2, 165.1, 163.3, 162.4, 136.5, 132.7, 131.3, 127.9, 125.4, 123.0, 120.6, 120.5, 115.3, 114.8, 111.8, 110.8, 61.2, 56.8, 55.8, 14.5; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C24H20NO7 434.1234, found 434.1234.Red solid (44 mg, 73%); mp: 319-321 °C; R f = 0.2 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.41 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.10 (s, 1H), 4.35-4.26 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 188.8, 182.5, 177.2, 165.1, 163.3, 162.4, 136.5, 132.7, 131.3, 127.9, 125.4, 123.0, 120.6, 120.5, 115.3, 114.8, 111.8, 110.8, 61.2, 56.8, 55.8, 14.5; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 24 H 20 NO 7 434.1234, found 434.1234.
<실시예 32> 5-(4-메톡시벤조일)-12-메틸벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (5)<Example 32> 5-(4-methoxybenzoyl)-12-methylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (5)
Red solid (34 mg, 61%); mp: 196-197 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.78 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.26 (s, 1H), 7.14 (d, J = 4.1 Hz, 1H), 7.00 - 6.89 (m, 3H), 3.85 (s, 3H), 3.11 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 189.9, 183.4, 182.7, 164.7, 137.3, 136.7, 136.3, 134.7, 134.6, 133.4, 133.3, 131.1, 128.2, 127.5, 127.1, 118.7, 118.0, 117.6, 116.4, 114.8, 108.8, 55.7, 18.0; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C25H18NO4 396.1230, found 396.1229.Red solid (34 mg, 61%); mp: 196-197 °C; R f = 0.4 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.78 (t) , J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.26 (s, 1H), 7.14 (d, J = 4.1 Hz, 1H), 7.00 - 6.89 (m, 3H), 3.85 (s, 3H), 3.11 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 189.9, 183.4, 182.7, 164.7, 137.3, 136.7, 136.3, 134.7, 134.6, 133.4, 133.3, 131.1, 128.2, 127.5, 127.1, 118.7, 118.0, 117.6 , 116.4, 114.8, 108.8, 55.7, 18.0; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 25 H 18 NO 4 396.1230, found 396.1229.
<실시예 33> 5-벤조일-8,9-다이메틸-6a,7,10,10a-테트라하이드로벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (7)<Example 33> 5-benzoyl-8,9-dimethyl-6a,7,10,10a-tetrahydrobenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione (7)
4o (0.14 mmol) 및 2,3-다이메틸-1,3-부타디엔 (2 당량, 0.28 mmol)이 포함된 EtOH (2 mL) 용액을 60 ℃에서 18 시간 동안 교반한 후, 상온으로 냉각시켰다. 침전물을 여과하고 헥산으로 세척하여 7을 황색 고체로서 수득하였다 (51 mg, 96 %).A solution of 4o (0.14 mmol) and 2,3-dimethyl-1,3-butadiene (2 equiv, 0.28 mmol) in EtOH (2 mL) was stirred at 60 °C for 18 hours, and then cooled to room temperature. The precipitate was filtered and washed with hexanes to give 7 as a yellow solid (51 mg, 96%).
Yellow solid (51 mg, 96%); mp: 200-201 °C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.26 (s, 1H), 7.01 (s, 2H), 3.32-3.35 (m, 2H), 2.58 - 2.32 (m, 2H), 2.21 - 1.94 (m, 2H), 1.62 (s, 3H), 1.58 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.4, 135.7, 134.9, 134.7, 133.2, 129.4, 128.6, 123.5, 121.2, 120.6, 119.5, 116.8, 108.5, 47.2, 46.6, 30.7, 30.3, 19.1, 19.0; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C25H22NO3 384.1594, found 384.1591.Yellow solid (51 mg, 96%); mp: 200-201 °C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.5 Hz) , 2H), 7.26 (s, 1H), 7.01 (s, 2H), 3.32-3.35 (m, 2H), 2.58 - 2.32 (m, 2H), 2.21 - 1.94 (m, 2H), 1.62 (s, 3H) ), 1.58 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.4, 135.7, 134.9, 134.7, 133.2, 129.4, 128.6, 123.5, 121.2, 120.6, 119.5, 116.8, 108.5, 47.2, 46.6, 30.7, 30.3, 19.1 , 19.0; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 25 H 22 NO 3 384.1594, found 384.1591.
<실시예 34> 5-벤조일-8,9-다이메틸벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온 (9)<Example 34> 5-benzoyl-8,9-dimethylbenzo [g] pyrrolo [1,2-b] isoquinoline-6,11-dione (9)
3a (0.14 mmol), 8 (1.2 당량) 및 트리에틸아민 (2 당량)이 포함된 EtOH (2 mL) 용액을 70 ℃에서 5 시간 동안 교반한 후, 반응 혼합물을 농축시키고, 20 % EtOAc를 포함하는 헥산용매를 사용하여, 용리를 이용한 칼럼 크로마토그래피에 의해 정제하여 9를 적색 고체로서 수득하였다 (50 mg, 94 %).A solution of 3a (0.14 mmol), 8 (1.2 equiv) and triethylamine (2 equiv) in EtOH (2 mL) was stirred at 70 °C for 5 h, then the reaction mixture was concentrated, containing 20% EtOAc Purification by column chromatography using elution using a hexane solvent to give 9 as a red solid (50 mg, 94 %).
Yellow solid (50 mg, 94%); mp: 299-300 °C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.07 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.88 (s, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.5 Hz, 3H), 7.03 (d, J = 3.8 Hz, 1H), 7.01 - 6.96 (m, 1H), 2.40 (s, 3H), 2.33 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 191.4, 182.1, 181.2, 144.7, 144.0, 136.9, 135.0, 134.6, 133.1, 132.7, 132.0, 129.4, 128.6, 128.5, 121.3, 119.5, 117.2, 115.8, 109.3, 20.4, 20.3; HRMS (ESI-QTOF) m/z [M+H]+ calcd for C25H18NO3 380.1281, found 380.1280.Yellow solid (50 mg, 94%); mp: 299-300 °C; R f = 0.3 in 30% EtOAc in hexane; 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (s, 1H), 8.07 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.88 (s, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.5 Hz, 3H), 7.03 (d, J = 3.8 Hz, 1H), 7.01 - 6.96 (m, 1H), 2.40 (s, 3H), 2.33 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 191.4, 182.1, 181.2, 144.7, 144.0, 136.9, 135.0, 134.6, 133.1, 132.7, 132.0, 129.4, 128.6, 128.5, 121.3, 119.5, 117.2, 115.8 , 109.3, 20.4, 20.3; HRMS (ESI-QTOF) m/z [M+H] + calcd for C 25 H 18 NO 3 380.1281, found 380.1280.
실험예 1. 생물학적 평가 방법 및 조건Experimental Example 1. Biological evaluation method and conditions
세포 독성 분석(Cytotoxicity assay)Cytotoxicity assay
CellTiter 96® AQueous One Solution 세포 증식 분석 키트 (Promega)를 MTS 분석에 사용했다. PC-3 및 CAL-27 세포를 2% FBS를 함유하는 배양 배지와 함께 1.0*103의 밀도로 96-웰 세포 배양 플레이트에 분주하였다. 화합물을 24 시간마다 72 시간 동안 처리하였다. MTS 용액을 각 웰에 적용하고 1 시간 동안 배양하였다. 490 nm에서의 흡광도는 Infinite M200 마이크로 플레이트 리더 (Tecan)를 사용하여 측정되었다. 절차를 3 회 반복하고 모든 데이터를 평균 ± SEM으로 제시하였다.CellTiter 96® AQueous One Solution Cell Proliferation Assay Kit (Promega) was used for MTS analysis. PC-3 and CAL-27 cells were seeded in a 96-well cell culture plate at a density of 1.0*10 3 together with a culture medium containing 2% FBS. Compounds were treated every 24 hours for 72 hours. MTS solution was applied to each well and incubated for 1 hour. Absorbance at 490 nm was measured using an Infinite M200 microplate reader (Tecan). The procedure was repeated 3 times and all data are presented as mean±SEM.
체외 스크래치 상처 분석(In vitro scratch wound assay)In vitro scratch wound assay
PC-3 및 CAL-27 세포를 96-웰 플레이트에서 배양하여 100% 합류에 도달하였다. 상처 부위를 만들기 위해 96-웰 상처 제조기(MI: Essen BioScience)가 사용되었다. 상처 생성 후, 각 웰을 무 혈청 배지로 2 회 세척하고 2% FBS가 보충된 배양 배지와 함께 배양하였다. 상처의 이미지는 IncuCyte ZOOM (Essen BioScience, MI)을 사용하여 촬영하였고, 상처 치유의 백분율은 IncuCyte 소프트웨어로 분석되었다.PC-3 and CAL-27 cells were cultured in 96-well plates to reach 100% confluence. A 96-well wound machine (MI: Essen BioScience) was used to make the wound site. After wounding, each well was washed twice with serum-free medium and incubated with culture medium supplemented with 2% FBS. Images of wounds were taken using an IncuCyte ZOOM (Essen BioScience, MI), and the percentage of wound healing was analyzed with IncuCyte software.
Caspase-3 활성 분석(Caspase-3 activity assay)Caspase-3 activity assay
PC-3 및 CAL-27을 96-웰 배양 플레이트에 시딩하여 대략 30 % 합류에 도달시켰다. 시험 화합물을 24 시간 동안 처리하였다. 배양 배지를 1 μM의 카스파 제 3 기질, NucView 488 또는 Caspase-3 억제제를 함유하는 포스페이트 완충 식염수 (PBS)로 대체하고 실온에서 30 분 동안 배양하였다. 1 μM Hoechst 33342로 염색한 후 NucView 488 및 Hoechst 33342의 형광 강도를 FLUOstar Omega microplate reader (BMG Labtech)로 측정하고 Lionheart FX automated live cell microscope (BioTek)로 형광 이미지를 촬영했다.PC-3 and CAL-27 were seeded into 96-well culture plates to reach approximately 30% confluence. Test compounds were treated for 24 hours. The culture medium was replaced with phosphate buffered saline (PBS) containing 1 μM of
웨스턴 블롯 분석(Western blot analysis)Western blot analysis
웨스턴 블롯에 대한 샘플 제조는 알려진 방법으로 수행되었다 [PLoS One, 11 (2016) e0155771.]. 수득 된 단백질 샘플을 4-12 % 트리스-글리신 프리캐스트 겔 (KOMA BIOTECH)에 의해 분리하고, PVDF 막으로 옮겼다. 이어서, 5 % 소 혈청 알부민 (BSA)이 포함된, 0.1 % 트윈 20 (TBST)이 보충된 트리스 완충 식염수로 막을 1 시간 동안 차단시켰다. 이어서 막을 항-ANO1 항체 (Abcam), 항-절단 PARP (BD Biosciences) 및 베타-액틴 (Santa Cruz Biotechnology)을 포함하는 1 차 항체와 함께 인큐베이션 한 후, HRP-접합된 항 2 차 IgG 항체(Enzo life science)와 인큐베이션 하였다. 마지막으로, 화학 발광 단백질 검출은 ECL 플러스 웨스턴 블로팅 검출 시스템 (GE Healthcare)을 사용하여 수행되었다.Sample preparation for Western blot was performed by known methods [PLoS One, 11 (2016) e0155771.]. The obtained protein sample was separated by 4-12% Tris-Glycine precast gel (KOMA BIOTECH) and transferred to PVDF membrane. The membrane was then blocked with Tris-buffered saline supplemented with 0.1% Tween 20 (TBST) with 5% bovine serum albumin (BSA) for 1 h. The membrane was then incubated with primary antibodies comprising anti-ANO1 antibody (Abcam), anti-cleavage PARP (BD Biosciences) and beta-actin (Santa Cruz Biotechnology) followed by HRP-conjugated anti-secondary IgG antibody (Enzo). life science) and incubated. Finally, chemiluminescent protein detection was performed using an ECL plus Western blotting detection system (GE Healthcare).
실험예 2. 본 발명에 따른 화합물의 세포 독성 및 IC50 값Experimental Example 2. Cytotoxicity and IC50 value of the compound according to the present invention
본 발명에 따른 하기 표 1의 퀴논-인돌리진 하이브리드 유도체 처리에 의한 PC-3 및 CAL-27 억제 효력을 측정하였다. The inhibitory effect of PC-3 and CAL-27 by treatment with the quinone-indolizine hybrid derivative of Table 1 below according to the present invention was measured.
실험예 3. PC-3 및 CAL-27 세포에서 세포 생존성, 세포 이동 및 세포예정사(Apoptosis)에 대한 퀴논-인돌리진 하이브리드 유도체의 효과Experimental Example 3. Effect of quinone-indolizine hybrid derivatives on cell viability, cell migration and apoptosis in PC-3 and CAL-27 cells
PC-3 및 CAL-27 세포에서 4o의 항암 효과를 조사하였다. 도 3에 도시 된 바와 같이, 4o는 각각 0.11 ± 0.05 μM 및 0.12 ± 0.04 μM의 IC50 값으로 PC-3 및 CAL-27 세포의 세포 생존력을 강력하게 억제하였다. 또한, 4o는 용량 의존적 방식으로 PC-3 및 CAL-27 세포의 세포 이동을 유의하게 억제하였다. 4o가 PC-3 및 CAL-27 세포에서 세포예정사를 유도하는지 여부를 조사하기 위해, Caspase-3 활성 및 PARP 절단에 대한 4o의 효과를 조사하였다. 플루오로제닉 Caspase-3-기질로 세포를 염색함으로써 Caspase-3 활성을 평가하였다. 4o는 PC-3 및 CAL-27 세포에서 용량-의존적 방식으로 Caspase-3 활성을 유의하게 증가시켰고, Caspase-3의 4o-유도된 활성화는 Caspase-3 의 특이적 억제제인 Ac-DEVD-CHO에 의해 완전히 차단되었다 (그림 4A-4D). PARP 절단에 대한 4o의 효과를 관찰하기 위해, 면역블롯팅(immunoblotting)을 PC-3 및 CAL-27 세포에서 수행하였다. 절단된 PARP의 수준은 PC-3 및 CAL-27 세포에서 4o만큼 유의하게 증가되었다 (도 4E 및 4F).The anticancer effect of 4o was investigated in PC-3 and CAL-27 cells. As shown in Fig. 3, 4o strongly inhibited the cell viability of PC-3 and CAL-27 cells with IC50 values of 0.11 ± 0.05 μM and 0.12 ± 0.04 μM, respectively. In addition, 4o significantly inhibited cell migration of PC-3 and CAL-27 cells in a dose-dependent manner. To investigate whether 4o induces apoptosis in PC-3 and CAL-27 cells, the effect of 4o on Caspase-3 activity and PARP cleavage was investigated. Caspase-3 activity was assessed by staining the cells with a fluorogenic Caspase-3-substrate. 4o significantly increased Caspase-3 activity in a dose-dependent manner in PC-3 and CAL-27 cells, and 4o -induced activation of Caspase-3 was inhibited by Ac-DEVD-CHO, a specific inhibitor of Caspase-3. was completely blocked (Fig. 4A-4D). To observe the effect of 4o on PARP cleavage, immunoblotting was performed on PC-3 and CAL-27 cells. The level of cleaved PARP was significantly increased by 4o in PC-3 and CAL-27 cells ( FIGS. 4E and 4F ).
또한 PC-3 및 CAL-27 세포에서 4s의 항암 효과를 조사했다. 도 5에 도시 된 바와 같이, 4s는 각각 0.07 ± 0.04 μM 및 0.11 ± 0.03 μM 의 IC50 값으로 PC-3 및 CAL-27 세포의 세포 생존력을 유의하게 억제하였다. 또한, 4s는 용량 의존적 방식으로 PC-3 및 CAL-27 세포의 세포 이동을 강력하게 억제하였다. 4s가 PC-3 및 CAL-27 세포에서 세포예정사를 유도하는지 여부를 조사하기 위해, Caspase-3 활성 및 PARP 절단에 대한 4s의 효과가 관찰되었다. 4s는 PC-3 및 CAL-27 세포에서 용량-의존적 방식으로 Caspase-3 활성을 유의하게 증가시켰고, Caspase-3의 4s-유도된 활성화는 Ac-DEVD-CHO에 의해 완전히 차단되었다 (도 6A-6D). 또한, 절단된 PARP의 수준은 PC-3 및 CAL-27 세포에서 4s 만큼 유의하게 증가하였다 (도 6E 및 6F).We also investigated the anticancer effect of 4s in PC-3 and CAL-27 cells. As shown in Fig. 5, 4s significantly inhibited the cell viability of PC-3 and CAL-27 cells with IC50 values of 0.07 ± 0.04 μM and 0.11 ± 0.03 μM, respectively. In addition, 4s strongly inhibited cell migration of PC-3 and CAL-27 cells in a dose-dependent manner. To investigate whether 4s induces apoptosis in PC-3 and CAL-27 cells, the effect of 4s on Caspase-3 activity and PARP cleavage was observed. 4s significantly increased Caspase-3 activity in a dose-dependent manner in PC-3 and CAL-27 cells, and 4s -induced activation of Caspase-3 was completely blocked by Ac-DEVD-CHO (Fig. 6A- 6D). In addition, the level of cleaved PARP was significantly increased by 4s in PC-3 and CAL-27 cells ( FIGS. 6E and 6F ).
도 7에 도시 된 바와 같이, 4p는 각각 24.0 ± 8.0 및 27.6 ± 6.9 nM의 IC50 값으로 PC-3 및 CAL-27 세포의 세포 생존력을 유의하게 억제하였다. 또한, 4p는 용량 의존적 방식으로 PC-3 및 CAL-27 세포의 세포 이동을 강력하게 억제하였다. 4p가 PC-3 및 CAL-27 세포에서 세포예정사를 유도하는지 여부를 조사하기 위해, Caspase-3 활성 및 PARP 절단에 대한 4p의 효과가 관찰되었다. 플루오로제닉 Caspase-3 기질로 세포를 염색함으로써 Caspase-3 활성을 측정하였다 (도 8A 및 8B). 특히, 0.3 μM 4p는 PC-3 및 CAL-27 세포에서 ~8 배까지 Caspase-3 활성을 증가 시켰고, Caspase-3의 4p-유도된 활성화는 Ac-DEVD-CHO에 의해 완전히 차단되었다 (도 8C 및 8D). 또한, 절단된 PARP의 수준은 PC-3 및 CAL-27 세포에서 4p만큼 유의하게 증가하였다 (도 8E 및 8F).As shown in Fig. 7, 4p significantly inhibited the cell viability of PC-3 and CAL-27 cells with IC50 values of 24.0 ± 8.0 and 27.6 ± 6.9 nM, respectively. In addition, 4p strongly inhibited cell migration of PC-3 and CAL-27 cells in a dose-dependent manner. To investigate whether 4p induces apoptosis in PC-3 and CAL-27 cells, the effect of 4p on Caspase-3 activity and PARP cleavage was observed. Caspase-3 activity was measured by staining the cells with a fluorogenic Caspase-3 substrate ( FIGS. 8A and 8B ). In particular, 0.3
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.
Claims (13)
[화학식 1]
상기 화학식 1에서,
R1은 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, C1-C4 알킬 에스터, 또는 나이트릴이고,
R2는 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C3-C6 헤테로 고리 화합물이며,
R3 및 R4는 각각 독립적으로 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 또는 페닐이고,
R5 및 R6는 각각 독립적으로 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 아릴, 페녹시, 또는 모폴리닐이거나,
R5 및 R6는 이들이 결합된 탄소 원자와 함께 연결되어 질소 원자를 하나 내지 둘 포함하거나 포함하지 않는 6 원자의 고리(ring)를 형성하며,
R7은 수소, 할로겐, 하이드록시, C1-C4 알킬, 또는 C1-C4 알콕시이고,
상기 화학식 1에서 실선과 점선의 이중선()으로 표현된 결합선은, 단일 탄소-탄소 결합 또는 2중 탄소-탄소 결합을 나타낸다.A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Formula 1,
R 1 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl ester, or nitrile,
R 2 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 3 -C 6 heterocyclic compound,
R 3 and R 4 are each independently hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or phenyl;
R 5 and R 6 are each independently hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, phenoxy, or morpholinyl;
R 5 and R 6 are joined together with the carbon atom to which they are attached to form a 6 membered ring with or without one or two nitrogen atoms,
R 7 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
In Formula 1, the double line of the solid line and the dotted line ( ) represents a single carbon-carbon bond or a double carbon-carbon bond.
상기 화학식 1에서,
R1은 수소, 할로겐, 또는 C1-C4 알킬 에스터이고,
R2는 C1-C4 알킬, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C5 헤테로 고리 화합물이며,
R3 및 R4는 각각 독립적으로 수소, 할로겐, C1-C4 알콕시, 또는 페닐이고,
R5 및 R6는 각각 독립적으로 수소, C1-C4 알콕시, 페녹시, 또는 모폴리닐이거나,
R5 및 R6는 이들이 결합된 탄소 원자와 함께 연결되어 6원의 탄화수소 화합물, 또는 방향족 헤테로 고리 화합물을 형성하며,
R7은 수소, 또는 C1-C4 알킬이다.The method of claim 1,
In Formula 1,
R 1 is hydrogen, halogen, or C 1 -C 4 alkyl ester,
R 2 is C 1 -C 4 alkyl, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 5 heterocyclic compound,
R 3 and R 4 are each independently hydrogen, halogen, C 1 -C 4 alkoxy, or phenyl;
R 5 and R 6 are each independently hydrogen, C 1 -C 4 alkoxy, phenoxy, or morpholinyl;
R 5 and R 6 are joined together with the carbon atom to which they are attached to form a 6-membered hydrocarbon compound, or an aromatic heterocyclic compound,
R 7 is hydrogen, or C 1 -C 4 alkyl.
상기 화학식 1의 화합물은 하기 화학식2의 구조를 갖는 것인 화합물:
[화학식 2]
상기 화학식 2에서,
R1은 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, C1-C4 알킬 에스터, 또는 나이트릴이고,
R2는 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C3-C6 헤테로 고리 화합물이며,
R7은 수소, 할로겐, 하이드록시, C1-C4 알킬, C1-C4 알콕시, 페닐, 또는 할로겐이고,
R8은 수소, 할로겐, 하이드록시, C1-C4 알킬, 또는 C1-C4 알콕시이며,
R9 및 R10은 각각 독립적으로 수소, 할로겐, 하이드록시, C1-C4 알킬, 또는 C1-C4 알콕시이고,
여기에서 X 및 Y는 각각 독립적으로 질소, 또는 탄소이다.The method of claim 1,
The compound of Formula 1 is a compound having a structure of Formula 2 below:
[Formula 2]
In Formula 2,
R 1 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl ester, or nitrile,
R 2 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 3 -C 6 heterocyclic compound,
R 7 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl, or halogen,
R 8 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
R 9 and R 10 are each independently hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
wherein X and Y are each independently nitrogen or carbon.
상기 화학식 2에서,
R1은 수소, 할로겐, 또는 C1-C4 알킬 에스터이고,
R2는 C1-C4 알킬, 하나 이상의 비수소치환기로 치환된 페닐, 나프탈레닐, 또는 C5 헤테로 고리 화합물이며,
R3 및 R4는 각각 독립적으로 수소, 할로겐, C1-C4 알콕시, 페닐, 또는 할로겐이고,
R7은 C1-C4 알킬, 또는 수소이며,
R8은 C1-C4 알콕시, 하이드록시, 또는 수소이고,
R9 및 R10은 각각 독립적으로 C1-C4 알킬, 또는 수소이며,
여기에서 X 및 Y는 각각 독립적으로 질소, 또는 탄소이다.4. The method of claim 3,
In Formula 2,
R 1 is hydrogen, halogen, or C 1 -C 4 alkyl ester,
R 2 is C 1 -C 4 alkyl, phenyl substituted with one or more non-hydrogen substituents, naphthalenyl, or C 5 heterocyclic compound,
R 3 and R 4 are each independently hydrogen, halogen, C 1 -C 4 alkoxy, phenyl, or halogen,
R 7 is C 1 -C 4 alkyl, or hydrogen,
R 8 is C 1 -C 4 alkoxy, hydroxy, or hydrogen,
R 9 and R 10 are each independently C 1 -C 4 alkyl, or hydrogen,
wherein X and Y are each independently nitrogen or carbon.
상기 화학식 1에서,
R1은 수소, 할로겐, 또는 C1-C4 알킬 에스터이고,
R2는 C1-C4 알킬, 하나 이상의 비수소치환기로 치환된 페닐, 또는 나프탈레닐이며,
R3 및 R4는 각각 독립적으로 수소, 할로겐, C1-C4 알콕시, 또는 페닐이고,
R5 및 R6는 각각 독립적으로 수소, C1-C4 알콕시, 페녹시, 또는 모폴리닐이며,
R7은 수소이다.The method of claim 1,
In Formula 1,
R 1 is hydrogen, halogen, or C 1 -C 4 alkyl ester,
R 2 is C 1 -C 4 alkyl, phenyl substituted with one or more non-hydrogen substituents, or naphthalenyl;
R 3 and R 4 are each independently hydrogen, halogen, C 1 -C 4 alkoxy, or phenyl;
R 5 and R 6 are each independently hydrogen, C 1 -C 4 alkoxy, phenoxy, or morpholinyl,
R 7 is hydrogen.
R2는
;;;
;;;
;;;
; 또는 인 화합물.4. The method of claim 1 to 3,
R 2 is
; ; ;
; ; ;
; ; ;
; or phosphorus compound.
상기 6원의 탄화수소 화합물은 벤젠, 또는 사이클로헥센인 화합물.3. The method of claim 2,
The 6-membered hydrocarbon compound is benzene or cyclohexene.
상기 방향족 헤테로 고리 화합물은 피리딘, 또는 피리미딘인 화합물.3. The method of claim 2,
The aromatic heterocyclic compound is a pyridine or pyrimidine compound.
R2는
;;;
; 또는 인 화합물.6. The method of claim 5,
R 2 is
; ; ;
; or phosphorus compound.
상기 화학식 1의 화합물은,
5-벤조일벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(3-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(4-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(2,5-다이메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(4-메틸벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(2-나프토일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-([1,1'-바이페닐]-4-카보닐)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(4-플루오로벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(4-클로로벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(4-브로모벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-(푸란-2-카보닐)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-아세틸벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-벤조일-7-하이드록시벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-벤조일-7-메톡시벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-벤조일피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-(4-클로로벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-벤조일-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-벤조일-7-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-(4-플루오로벤조일)-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-(4-클로로벤조일)-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온;
8-메톡시-5-(4-메톡시벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-(2-나프토일)-8-메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-벤조일-7,8-다이메톡시피롤로[1,2-b]아이소퀴놀린-6,9-디온;
11-벤조일인돌리지노[7,6-g]퀴놀린-5,12-디온;
6-벤조일인돌리지노[6,7-g]퀴나졸린-5,12-디온;
5-벤조일-8-페녹시피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-벤조일-8-모폴리노피롤로[1,2-b]아이소퀴놀린-6,9-디온;
5-벤조일-7-모폴리노피롤로[1,2-b]아이소퀴놀린-6,9-디온;
2-브로모-5-(4-메톡시벤조일)벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
2-브로모-8-메톡시-5-(4-메톡시벤조일)피롤로[1,2-b]아이소퀴놀린-6,9-디온;
에틸5-(4-메톡시벤조일)-6,11-다이옥소-6,11-다이하이드로벤조[g]피롤로[1,2-b]아이소퀴놀린-2-카복실레이트;
에틸8-메톡시-5-(4-메톡시벤조일)-6,9-다이옥소-6,9-다이하이드로피롤로[1,2-b]아이소퀴놀린-2-카복실레이트;
5-(4-메톡시벤조일)-12-메틸벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;
5-벤조일-8,9-다이메틸-6a,7,10,10a-테트라하이드로벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온; 또는
5-벤조일-8,9-다이메틸벤조[g]피롤로[1,2-b]아이소퀴놀린-6,11-디온;인 화합물.The method of claim 1,
The compound of Formula 1 is,
5-benzoylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(3-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(2,5-dimethoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-methylbenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(2-naphthoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-([1,1'-biphenyl]-4-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-fluorobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-chlorobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(4-bromobenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-(furan-2-carbonyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-acetylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-benzoyl-7-hydroxybenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-benzoyl-7-methoxybenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-benzoylpyrrolo[1,2-b]isoquinoline-6,9-dione;
5-(4-chlorobenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-7-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-(4-fluorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-(4-chlorobenzoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione;
5-(2-naphthoyl)-8-methoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-7,8-dimethoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
11-benzoylindolizino[7,6-g]quinoline-5,12-dione;
6-benzoylindolizino[6,7-g]quinazoline-5,12-dione;
5-benzoyl-8-phenoxypyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-8-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione;
5-benzoyl-7-morpholinopyrrolo[1,2-b]isoquinoline-6,9-dione;
2-bromo-5-(4-methoxybenzoyl)benzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
2-bromo-8-methoxy-5-(4-methoxybenzoyl)pyrrolo[1,2-b]isoquinoline-6,9-dione;
ethyl5-(4-methoxybenzoyl)-6,11-dioxo-6,11-dihydrobenzo[g]pyrrolo[1,2-b]isoquinoline-2-carboxylate;
ethyl8-methoxy-5-(4-methoxybenzoyl)-6,9-dioxo-6,9-dihydropyrrolo[1,2-b]isoquinoline-2-carboxylate;
5-(4-methoxybenzoyl)-12-methylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione;
5-benzoyl-8,9-dimethyl-6a,7,10,10a-tetrahydrobenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione; or
5-benzoyl-8,9-dimethylbenzo[g]pyrrolo[1,2-b]isoquinoline-6,11-dione; phosphorus compound.
상기 암은 전립선암인, 약학적 조성물. 12. The method of claim 11
The cancer is prostate cancer, pharmaceutical composition.
상기 암은 구강암인, 약학적 조성물.12. The method of claim 11
The cancer is oral cancer, pharmaceutical composition.
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