KR20220089327A - Novel quinazoline compounds and medical use thereof - Google Patents
Novel quinazoline compounds and medical use thereof Download PDFInfo
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- KR20220089327A KR20220089327A KR1020200179842A KR20200179842A KR20220089327A KR 20220089327 A KR20220089327 A KR 20220089327A KR 1020200179842 A KR1020200179842 A KR 1020200179842A KR 20200179842 A KR20200179842 A KR 20200179842A KR 20220089327 A KR20220089327 A KR 20220089327A
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- cancer
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- acceptable salt
- pharmaceutically acceptable
- cycloalkyl
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Abstract
본 발명은 신규한 퀴나졸린 화합물 및 이의 항암치료제 용도에 관한 것으로, 상기 신규한 퀴나졸린 화합물은 매우 적은 용량으로 종양 세포 사멸효과를 나타내었으며, 우수한 암 전이 억제 및 종양 성장 억제 효과를 나타내는 것이 확인됨에 따라, 상기 퀴나졸린 화합물을 유효성분으로 함유하는 조성물은 암질환 예방 및 치료를 위한 항암체료제로 제공될 수 있다.The present invention relates to a novel quinazoline compound and its use as an anticancer agent, and it was confirmed that the novel quinazoline compound exhibited a tumor cell killing effect at a very small dose, and exhibited excellent cancer metastasis and tumor growth inhibitory effects. Accordingly, the composition containing the quinazoline compound as an active ingredient may be provided as an anticancer agent for the prevention and treatment of cancer diseases.
Description
본 발명은 신규한 퀴나졸린 화합물 및 이의 항암치료제 용도에 관한 것이다.The present invention relates to a novel quinazoline compound and its use as an anticancer agent.
암이란 일반적으로 인체 조직을 이루고 있는 세포 주기에 이상이 생겨 세포가 정상적으로 분화하지 않고 세포분열을 계속하는 질환으로, 개시(initiation), 촉진(promotion) 및 진행(progression)의 세 단계를 거쳐 발생한다. 암의 원인은 환경이나 음식물 속에 포함된 발암 물질에 의해 정상적인 세포의 유전자나 암 억제 유전자에 돌연변이가 일어나고 이러한 세포들이 발암 물질의 계속적인 자극을 받으면서 비정상적으로 증식하여 암 조직을 형성하는 것으로 알려져 있으나, 암의 발생 원인에 대해서는 아직도 명확하게 밝혀진 바가 없다.Cancer is a disease in which cells do not differentiate normally due to an abnormality in the cell cycle constituting human tissue and continue to divide. Cancer occurs through three stages: initiation, promotion, and progression. . It is known that cancer is caused by mutations in genes or cancer suppressor genes of normal cells by carcinogens contained in the environment or food, and these cells proliferate abnormally and form cancerous tissues while receiving continuous stimulation from carcinogens. The cause of cancer has not yet been clearly elucidated.
암은 양성종양(benign tumor)과 악성종양(malignant tumor)로 구분되어지는데, 양성종양은 비교적 성장속도가 느리고 종양의 원발생 부위에서 다른 조직으로 이동되어지는 전이(metastasis)가 되지 않는 것에 반해 악성종양은 원발부를 떠나 다른 조직으로 침윤되어 빠르게 성장하는 특징을 가짐으로써 생명을 위협하며 사망에 이르는 아주 중요한 원인이 된다.Cancer is divided into benign tumors and malignant tumors. Benign tumors grow relatively slowly and do not metastasize from the original site of the tumor to other tissues, whereas malignant tumors. Tumors leave the primary part and invade other tissues and rapidly grow, so they are life-threatening and a very important cause of death.
이러한 암은 인류가 해결해야 할 난치병 중의 하나로, 전 세계적으로 이를 치유하기 위한 개발에 막대한 자본이 투자되고 있고, 의학 기술 또한 혁신적으로 발전하고 있음에도 불구하고, 암의 발생 및 암에 의한 사망은 계속 증가추세에 있다. 세계 보건 기구의 최근 통계 자료에 의하면 전세계적으로 연간 약 1천만 명 이상의 새로운 암 환자가 발생하는 것으로 알려져 있으며, 우리나라에서도 암은 가장 높은 사망원인으로 연간 약 십만명 이상이 진단되고, 약 6만명 이상이 암에 의해 사망하고 있다.Cancer is one of the incurable diseases that humanity needs to solve, and despite huge capital investment worldwide and innovative medical technology, the incidence of cancer and deaths due to cancer continue to increase. is in trend According to the latest statistical data of the World Health Organization, it is known that more than 10 million new cancer patients occur every year worldwide. dying of cancer
암의 치료를 위해서는 수술 요법, 방사선 치료 요법 및 화학요법 등이 사용되고 있으나 많은 연구에도 불구하고 암 환자 전체의 50% 이상이 결국 치유되지 못하고 사망하는 것으로 보고된다. 그에 따른 이유는 외과적으로 절제를 하였다 하더라도 미세하게 전이된 암 세포를 제거하지 못하여 암이 재발하거나, 다양한 항암제의 개발에도 불구하고 항암제를 이용한 암 치료 시, 항암제에 대한 암세포 사멸이 유도되지 않거나 초기에는 반응을 보여 종양이 줄어드는 듯 보이지만 치료도중이나 치료가 끝난 후 항암제에 대한 내성이 생긴 암세포들이 급격히 증식하기 때문이다.Surgical therapy, radiation therapy, and chemotherapy are used to treat cancer, but it is reported that more than 50% of all cancer patients eventually die without being cured, despite many studies. The reason for this is that even after surgical resection, the cancer recurs due to the failure to remove the microscopically metastasized cancer cells, or when cancer treatment using anti-cancer agents is used despite the development of various anti-cancer agents, the death of cancer cells is not induced or in the early stage. This is because the cancer cells that have developed resistance to chemotherapy rapidly proliferate during or after treatment, although the tumor appears to be shrinking due to the response to chemotherapy.
이렇듯, 암은 조기에 발견되지 못할 경우 완치가 거의 불가능하고, 병이 진전될수록 환자와 가족의 고통과 경제적 손실이 막대하며, 의료 보험의 재정고갈 등 사회적으로도 큰 비용을 초래한다는 점에서 암의 예방과 조기 치료의 중요성은 더욱 강조되고 있는 실정이다.As such, if cancer is not detected at an early stage, it is almost impossible to cure it, and as the disease progresses, the pain and economic loss for patients and families is enormous, and it causes great social costs such as financial exhaustion of medical insurance. The importance of prevention and early treatment is being emphasized more and more.
본 발명은 신규한 퀴나졸린 화합물을 제공하며, 상기 퀴나졸린 화합물을 유효성분으로 함유하는 조성물을 암전이 억제제 및 항암치료제로 제공하고자 한다.The present invention provides a novel quinazoline compound, and an object of the present invention is to provide a composition containing the quinazoline compound as an active ingredient as a cancer metastasis inhibitor and anticancer agent.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
A는 아릴, 헤테로아릴, (C3~C8)사이클로알킬 또는 헤테로(C3~C8)사이클로알킬 중에서 선택되며,A is selected from aryl, heteroaryl, (C3 to C8) cycloalkyl or hetero (C3 to C8) cycloalkyl,
R1과 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, (C3~C8)사이클로알킬, 할로, 트리플루로메틸 또는 트리플로로메톡시에서 선택되고, R 1 and R 2 may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy; ,
m은 1 내지 3의 정수이고, m is an integer from 1 to 3,
n은 0 내지 2의 정수임.n is an integer from 0 to 2.
본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 암질환 치료 또는 예방용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for treating or preventing cancer disease, comprising the compound or a pharmaceutically acceptable salt thereof.
본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 암질환 개선 또는 예방용 건강기능식품 조성물을 제공한다.The present invention provides a health functional food composition for improving or preventing cancer disease comprising the compound or a pharmaceutically acceptable salt thereof.
본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 암전이 억제용 약학조성물을 제공한다. The present invention provides a pharmaceutical composition for inhibiting cancer metastasis comprising the compound or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염과, 면역항암제를 포함하는 암질환 치료 또는 예방용 약학조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for treating or preventing cancer disease comprising the compound or a pharmaceutically acceptable salt thereof and an immuno-cancer agent.
본 발명에 따르면, 신규한 퀴나졸린 화합물은 매우 적은 용량으로 종양 세포 사멸효과를 나타내었으며, 우수한 암 전이 억제 및 종양 성장 억제 효과를 나타내는 것이 확인됨에 따라, 상기 퀴나졸린 화합물을 유효성분으로 함유하는 조성물은 암질환 예방 및 치료를 위한 항암체료제로 제공될 수 있다.According to the present invention, as it was confirmed that the novel quinazoline compound exhibited a tumor cell killing effect at a very small dose, and exhibited excellent cancer metastasis and tumor growth inhibitory effects, a composition containing the quinazoline compound as an active ingredient may be provided as an anticancer therapeutic agent for the prevention and treatment of cancer diseases.
도 1은 화합물 12의 암전이 억제 효과를 확인한 결과로, 전이된 폐 조직에 존재하는 종양 수준을 확인한 결과이다.
도 2는 A549 비소세포성폐암 (NSCLC) 세포주에 의한 폐암 동물 모델에서 화합물 12의 종양 성장 억제 효과를 확인한 결과이다.1 is a result of confirming the cancer metastasis inhibitory effect of
2 is a result confirming the tumor growth inhibitory effect of
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공할 수 있다.The present invention may provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
A는 아릴, 헤테로아릴, (C3~C8)사이클로알킬 또는 헤테로(C3~C8)사이클로알킬 중에서 선택되며,A is selected from aryl, heteroaryl, (C3 to C8) cycloalkyl or hetero (C3 to C8) cycloalkyl,
R1과 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, (C3~C8)사이클로알킬, 할로, 트리플루로메틸 또는 트리플로로메톡시에서 선택되고, R 1 and R 2 may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy; ,
m은 1 내지 3의 정수이고, m is an integer from 1 to 3,
n은 0 내지 2의 정수임.n is an integer from 0 to 2.
상기 화합물은 A가 페닐, 질소를 포함한 (5환~6환)헤테로아릴, (C3~C8)사이클로알킬 또는 질소를 포함한 헤테로(C3~C8)사이클로알킬 중에서 선택되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염일 수 있다.The compound is a compound, characterized in that A is selected from phenyl, nitrogen-containing (5- to 6-ring) heteroaryl, (C3 to C8) cycloalkyl, or nitrogen-containing hetero (C3 to C8) cycloalkyl, or a pharmaceutical thereof It may be an acceptable salt.
상기 화합물은 하기 화학식 2로 표시되는 화합물인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염일 수 있다.The compound may be a compound characterized in that it is a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.
[화학식 2][Formula 2]
상기 화학식 2에서,In Formula 2,
R1과 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시,(C3~C8)사이클로알킬, 할로, 트리플루로메틸 또는 트리플로로메톡시에서 선택되고, n은 0 내지 2의 정수임.R 1 and R 2 may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy; , n is an integer from 0 to 2.
상기 화합물은 R1 또는 R2 중 어느 하나가 트리플루로메틸, 할로 또는 (C1~C4)알콕시이고, 다른 하나가 수소이며, n은 1인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염일 수 있다.The compound may be a compound or a pharmaceutically acceptable salt thereof, wherein any one of R 1 or R 2 is trifluoromethyl, halo or (C1-C4) alkoxy, the other is hydrogen, and n is 1. have.
본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 암질환 치료 또는 예방용 약학조성물을 제공할 수 있다.The present invention may provide a pharmaceutical composition for the treatment or prevention of cancer diseases comprising the compound or a pharmaceutically acceptable salt thereof.
상기 암질환은 유방암, 폐암, 위암, 간암, 혈액암, 뼈암, 췌장암, 피부암, 두경부암, 피부 또는 안구 흑색종, 자궁육종, 난소암, 직장암, 항문암, 대장암, 난관암, 자궁내막암, 자궁경부암, 소장암, 내분비암, 갑상선암, 부갑상선암, 신장암, 연조직종양, 요도암, 전립선암, 기관지암 및 골수암으로 이루어진 군에서 선택된 것일 수 있다.The cancer disease is breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colorectal cancer, fallopian tube cancer, endometrial cancer , cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, may be one selected from the group consisting of bronchial cancer and bone marrow cancer.
본 발명은 상기 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 암질환 개선 또는 예방용 건강기능식품 조성물을 제공할 수 있다.The present invention may provide a health functional food composition for improving or preventing cancer disease, comprising the compound or a pharmaceutically acceptable salt thereof.
본 발명은 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 암전이 억제용 약학조성물을 제공할 수 있다.The present invention may provide a pharmaceutical composition for inhibiting cancer metastasis comprising a compound or a pharmaceutically acceptable salt thereof.
일반적으로 암은 발생한 부위에 존재하는 원발암과 상기 발생 부위로부터 신체의 다른 부위로 퍼져나간 전이암으로 구분된다. 즉, "암 전이"는 악성 종양이 발병한 장기에서 떨어진 다른 조직으로 전파한 상태를 의미하며, 암세포가 혈액순환이나 림프순환을 통해 퍼져나가서 형성되는 것으로, 대개는 혈액순환을 타고 다른 장기로 옮겨간 후 새로운 종양으로 자라난 것이거나, 이와 달리 암세포가 이웃한 조직으로 직접 이동하여 형성되기도 한다. 본 발명에서 암 전이는 암세포가 이웃조직으로 직접 이동하고 침투하는 침윤(invasion)에 의한 암세포의 확산 및 암세포가 혈류를 타고 이동하여 물리적으로 원발암과는 인접하지 않은 장기에서 새로운 종양을 형성하는 전이(metastasis)를 모두 포함한다.In general, cancer is divided into primary cancer existing at the site of occurrence and metastatic cancer that has spread from the site of occurrence to other parts of the body. In other words, “cancer metastasis” refers to a state in which a malignant tumor has spread to other tissues away from the diseased organ, and cancer cells are formed by spreading through blood or lymphatic circulation, usually moving through blood circulation to other organs. It is a new tumor that grows after the liver, or is formed by cancer cells moving directly to neighboring tissues. In the present invention, cancer metastasis refers to the spread of cancer cells by invasion, in which cancer cells directly move and infiltrate into neighboring tissues, and metastasis in which cancer cells move through the bloodstream to form a new tumor in an organ that is not physically adjacent to the primary cancer. (metastasis) is included.
또한, 본 발명은 화합물 또는 이의 약학적으로 허용가능한 염과, 면역항암제를 포함하는 암질환 치료 또는 예방용 약학조성물을 제공할 수 있다.In addition, the present invention may provide a pharmaceutical composition for treating or preventing cancer disease, comprising a compound or a pharmaceutically acceptable salt thereof, and an immuno-cancer agent.
상기 면역항암제는 항-PD1, 항-PDL1, 항-CTLA4, 항-LAG3, 항-VISTA, 항-BTLA, 항-TIM3, 항-HVEM, 항-CD27, 항-CD137, 항-OX40, 항-CD28, 항-PDL2, 항-GITR, 항-ICOS, 항-SIRPα, 항-ILT2, 항-ILT3, 항-ILT4, 항-ILT5, 항-EGFR, 항-CD19 및 항-TIGIT로 이루어진 군으로부터 선택되는 1종 이상의 면역항암제인 것일 수 있으나, 이에 제한되는 것은 아니다.The immuno-cancer agent is anti-PD1, anti-PDL1, anti-CTLA4, anti-LAG3, anti-VISTA, anti-BTLA, anti-TIM3, anti-HVEM, anti-CD27, anti-CD137, anti-OX40, anti- selected from the group consisting of CD28, anti-PDL2, anti-GITR, anti-ICOS, anti-SIRPα, anti-ILT2, anti-ILT3, anti-ILT4, anti-ILT5, anti-EGFR, anti-CD19 and anti-TIGIT It may be one or more types of immuno-cancer drugs, but is not limited thereto.
본 발명의 한 구체예에서, 상기 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학조성물은 통상적인 방법에 따라 주사제, 과립제, 산제, 정제, 환제, 캡슐제, 좌제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다.In one embodiment of the present invention, the pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof is prepared according to a conventional method for injections, granules, powders, tablets, pills, capsules, suppositories, gels, suspensions, and emulsions. , any one formulation selected from the group consisting of drops or liquids may be used.
본 발명의 다른 구체예에서, 상기 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In another embodiment of the present invention, the pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof is a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant commonly used in the preparation of pharmaceutical compositions. , flavoring agents, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders and lubricants may further include one or more additives selected from the group consisting of.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specifically, carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil can be used, and solid preparations for oral administration include tablets, pills, powders, granules, and capsules. agent, and the like, and the solid preparation may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like in the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid preparations for oral use include suspensions, solutions, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included in addition to commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base material for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명의 일실시예에 따르면 상기 약학 조성물은 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to an embodiment of the present invention, the pharmaceutical composition is administered in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal routes. can be administered to the subject.
상기 화합물 또는 이의 약학적으로 허용가능한 염의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.A preferred dosage of the compound or a pharmaceutically acceptable salt thereof may vary depending on the condition and weight of the subject, the type and extent of the disease, the drug form, the route and duration of administration, and may be appropriately selected by those skilled in the art. According to an embodiment of the present invention, although not limited thereto, the daily dose may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or may be administered in several divided doses, thereby not limiting the scope of the present invention.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal including a human, but is not limited to these examples.
또한 본 발명의 건강식품은 상기 화합물 또는 이의 약학적으로 허용가능한 염 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.In addition, the health food of the present invention is used together with other foods or food additives other than the compound or a pharmaceutically acceptable salt thereof, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be suitably determined according to the purpose of its use, for example, prophylactic, health or therapeutic treatment.
상기 건강식품에 함유된 화합물의 유효용량은 상기 치료제의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the compound contained in the health food can be used according to the effective dose of the therapeutic agent, but in the case of long-term intake for health and hygiene or health control, it may be less than or equal to the above range, It is clear that the ingredient can be used in an amount beyond the above range because there is no problem in terms of safety.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제등을 들 수 있다.The type of health food is not particularly limited, and examples include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples will be described in detail to help the understanding of the present invention. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.
<실시예> 화합물 합성<Example> Synthesis of compounds
실시예Example 1. 2-((3-(2-(사이클로헥-1-엔-1-일)에틸)-6,7-디메톡시-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((3-(2-(cyclohex-1-en-1-yl)ethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 1)]1. 2-((3-(2-(cyclohex-1-en-1-yl)ethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) Thio)-N-(4-ethylphenyl)butanamide [2-((3-(2-(cyclohex-1-en-1-yl)ethyl)-6,7-dimethoxy-4-oxo-3,4 -dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (Compound 1)]
단계 1) 6,7-디메톡시-2H-벤조[d][1,3]옥사진-2,4(1H)-디온 [6,7-dimethoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (중간체 1)]Step 1) 6,7-dimethoxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione [6,7-dimethoxy-2H-benzo[d][1,3] oxazine-2,4(1H)-dione (intermediate 1)]
[반응식 1][Scheme 1]
건조 THF (Tetrahydrofuran)에 용해시킨 2-아미노-4,5-디메톡시벤조익 산 (1.00 eq.) 용액에 비스(트리클로로메틸)카보네이트을 용해시킨 건조 THF 용액을 실온에서 2시간 동안 첨가하였다. 혼합물을 얼음물에 부어 현탁액을 생성하여 여과한 후 에테르로 세척하여 추가 정제 없이 고체 (중간체 1)를 얻었다. A dry THF solution of bis(trichloromethyl)carbonate was added to a solution of 2-amino-4,5-dimethoxybenzoic acid (1.00 eq.) dissolved in dry THF (Tetrahydrofuran) at room temperature for 2 hours. The mixture was poured into ice water to form a suspension, filtered, and washed with ether to obtain a solid (Intermediate 1) without further purification.
단계 2) 3-(2-(사이클로헥-1-엔-1-일)에틸)-2-멀캅토-6,7-디메톡시퀴나졸린-4(3H)-온 [3-(2-(cyclohex-1-en-1-yl)ethyl)-2-mercapto-6,7-dimethoxyquinazolin-4(3H)-one (중간체 3)]Step 2) 3-(2-(cyclohex-1-en-1-yl)ethyl)-2-mercapto-6,7-dimethoxyquinazolin-4(3H)-one [3-(2-( cyclohex-1-en-1-yl)ethyl)-2-mercapto-6,7-dimethoxyquinazolin-4(3H)-one (intermediate 3)]
[반응식 2][Scheme 2]
DMF에 중간체 1 (1.00 eq.)을 용해시킨 용액에 2-(사이클로헥-1-엔-1-일)에탄-1-아민 [2-(cyclohex-1-en-1-yl)ethan-1-amine, 1.50 eq.]을 실온에서 2시간 동안 반응이 완료될 때까지 첨가하였다. 2-(cyclohex-1-en-1-yl)ethan-1-amine [2-(cyclohex-1-en-1-yl)ethan-1 in a solution of Intermediate 1 (1.00 eq.) in DMF -amine, 1.50 eq.] was added at room temperature for 2 hours until the reaction was complete.
추가 정제없이 진공상태에서 용매를 제거하였다. 이후 2.20 eq. 포타슘 하이드록사이드 (potassium hydroxide) 물/에탄올 용액을 첨가한 다음 이황화탄소 (carbon disulfide, 4.00 eq.)를 첨가하였다.The solvent was removed in vacuo without further purification. After 2.20 eq. Potassium hydroxide water/ethanol solution was added and then carbon disulfide (4.00 eq.) was added.
반응 혼합물을 5시간 동안 60℃로 가열하고 1M HCl로 냉각시켜 백색 고체(중간체 3)를 얻었다. The reaction mixture was heated to 60° C. for 5 h and cooled with 1M HCl to give a white solid (Intermediate 3).
단계 3) 2-브로모-N-(4-에틸페닐)부탄아미드 [2-bromo-N-(4-ethylphenyl)butanamide (중간체 4)]Step 3) 2-bromo-N-(4-ethylphenyl)butanamide [2-bromo-N-(4-ethylphenyl)butanamide (Intermediate 4)]
[반응식 3][Scheme 3]
4-에틸아닐린 (4-ethylaniline, 1.00 eq.)을 용해시킨 건조 THF 용액에 TEA (1.20 eq.)를 0℃에서 첨가하고 5분간 교반한 다음, 2-브로모부타노일 브로마이드 [2-bromobutanoyl bromide, 1.20 eq.]를 0℃에서 한 방울씩 첨가하고 1시간 동안 교반한 후 25℃에 1시간 동안 교반하였다. 반응 혼합물을 얼음물로 냉각시키고 여과하여 백색 고체 (중간체 4)를 얻었다.TEA (1.20 eq.) was added to a dry THF solution in which 4-ethylaniline (4-ethylaniline, 1.00 eq.) was dissolved at 0° C., stirred for 5 minutes, and then 2-bromobutanoyl bromide [2-bromobutanoyl bromide] , 1.20 eq.] at 0 °C It was added dropwise and stirred for 1 hour, followed by stirring at 25° C. for 1 hour. The reaction mixture was cooled with ice water and filtered to give a white solid (Intermediate 4).
단계 4) 2-((3-(2-(사이클로헥-1-엔-1-일)에틸)-6,7-디메톡시-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((3-(2-(cyclohex-1-en-1-yl)ethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 1)]Step 4) 2-((3-(2-(cyclohex-1-en-1-yl)ethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl )thio)-N-(4-ethylphenyl)butanamide [2-((3-(2-(cyclohex-1-en-1-yl)ethyl)-6,7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (Compound 1)]
[반응식 4][Scheme 4]
중간체 3 및 중간체 4를 아세톤에 용해시키고 포타슘 카보네이트 (2.00 eq.)를 첨가하였다. 혼합물을 5시간 동안 가열하여 환류시킨 후 혼합물을 얼음물에 붓고 여과하여 백색 현탁액을 얻었다. 생성물을 실리카겔에 적재하고 플레쉬 컬럼 크로마토그래피로 정제하여 화합물 1을 얻었다.Intermediate 3 and Intermediate 4 were dissolved in acetone and potassium carbonate (2.00 eq.) was added. After heating the mixture to reflux for 5 hours, the mixture was poured into ice water and filtered to obtain a white suspension. The product was loaded on silica gel and purified by flash column chromatography to obtain compound 1.
1H NMR (400 MHz, CDCl3,) δ 9.82 (s, 1 H), 7.56 (s, 1 H), 7.34 (d, 2 H, J = 8.8 Hz), 7.06 (d, 2 H, J = 8.4 Hz), 7.00 (s, 1 H), 5.44 (m, 1 H), 4.46 (t, 1 H, J = 8.0 Hz), 4.16 (t, 2 H, J = 8.0 Hz), 4.00 (s, 3 H), 3.98 (s, 3 H), 2.55 (m, 2 H), 2.30 (m 3 H), 2.03 (m, 2 H), 1.91 (m, 3 H), 1.62 (m, 2 H), 1.52 (m, 2 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.9, 160.5, 156.2, 155.4, 148.7, 142.9, 140.2, 135.9, 133.8, 128.4, 124.2, 119.3, 112.7, 106.3, 105.5, 56.5, 56.4, 49.8, 44.2, 36.0, 28.4, 28.3, 25.3, 22.9, 22.8, 22.2, 15.8, 12.3; MS m/z (M+H)+: 536.25. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.82 (s, 1 H), 7.56 (s, 1 H), 7.34 (d, 2 H, J = 8.8 Hz), 7.06 (d, 2 H, J = 8.4 Hz), 7.00 (s, 1 H), 5.44 (m, 1 H), 4.46 (t, 1 H, J = 8.0 Hz), 4.16 (t, 2 H, J = 8.0 Hz), 4.00 (s, 3 H), 3.98 (s, 3 H), 2.55 (m, 2 H), 2.30 (m 3 H), 2.03 (m, 2 H), 1.91 (m, 3 H), 1.62 (m, 2 H) , 1.52 (m, 2 H), 1.16 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.9, 160.5, 156.2, 155.4, 148.7, 142.9, 140.2, 135.9, 133.8, 128.4, 124.2, 119.3, 112.7, 106.3, 105.5, 56.5, 56.4, 49.8, 44.2, 36.0, 28.4, 28.3, 25.3, 22.9, 22.8, 22.2, 15.8, 12.3; MS m/z (M+H) + : 536.25.
실시예 2. 2-((3-(2-사이클로헥실에틸)-6,7-디메톡시-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((3-(2-cyclohexylethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 2)] Example 2. 2-((3-(2-cyclohexylethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4- Ethylphenyl)butanamide [2-((3-(2-cyclohexylethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide ( compound 2)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-사이클로헥실에탄-2-아민 [2-cyclohexylethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 2를 얻었다.In step 2 of Example 1, 2-cyclohexylethan-2-amine [2-cyclohexylethan-1-amine] was used instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine, and in Example Steps 3 and 4 of 1 were repeated to obtain compound 2.
1H NMR (400 MHz, CDCl3,) δ 9.83 (s, 1 H), 7.55 (s, 1 H), 7.35 (d, 2 H, J = 8.0 Hz), 7.06 (d, 2 H, J = 8.8 Hz), 7.00 (s, 1 H), 4.45 (t, 1 H, J = 7.6 Hz), 4.11 (m, 2 H), 4.00 (s, 3 H), 3.97 (s, 3 H), 2.55 (m, 2 H), 2.28 (m 1 H), 1.90 (m, 1 H), 1.69 (m, 7 H), 1.40 (m, 1 H), 1.19 (m, 9 H), 0.99 (m, 2 H); 13C NMR (100 MHz, CDCl3,) δ 169.0, 160.6, 156.2, 155.4, 148.7, 142.9, 140.2, 136.0, 128.4, 119.3, 112.7, 106.3, 105.5, 56.5, 56.4, 49.7, 43.5, 35.9, 35.2, 33.0, 28.3, 26.5, 26.1, 23.0, 15.8, 12.3; MS m/z (M+H)+: 538.27. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.83 (s, 1 H), 7.55 (s, 1 H), 7.35 (d, 2 H, J = 8.0 Hz), 7.06 (d, 2 H, J = 8.8 Hz), 7.00 (s, 1 H), 4.45 (t, 1 H, J = 7.6 Hz), 4.11 (m, 2 H), 4.00 (s, 3 H), 3.97 (s, 3 H), 2.55 (m, 2 H), 2.28 (m 1 H), 1.90 (m, 1 H), 1.69 (m, 7 H), 1.40 (m, 1 H), 1.19 (m, 9 H), 0.99 (m, 2 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 169.0, 160.6, 156.2, 155.4, 148.7, 142.9, 140.2, 136.0, 128.4, 119.3, 112.7, 106.3, 105.5, 56.5, 56.4, 49.7, 43.5, 35.9, 35.2, 33.0, 28.3, 26.5, 26.1, 23.0, 15.8, 12.3; MS m/z (M+H) + : 538.27.
실시예 3. 2-((6,7-디메톡시-4-옥소-3-페네틸-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-4-oxo-3-phenethyl-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 3)]Example 3. 2-((6,7-dimethoxy-4-oxo-3-phenethyl-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide [2-((6,7-dimethoxy-4-oxo-3-phenethyl-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (Compound 3)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-페닐에탄-1-아민 [2-phenylethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 3을 얻었다.In step 2 of Example 1, 2-phenylethan-1-amine [2-phenylethan-1-amine] was used instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine, and Example 1 Steps 3 and 4 were repeated to obtain compound 3.
1H NMR (400 MHz, CDCl3,) δ 9.76 (s, 1 H), 7.59 (s, 1 H), 7.36 (d, 2 H, J = 8.8 Hz), 7.30 (m, 4 H), 7.21 (m, 1 H), 7.08 (d, 2 H, J = 8.4 Hz), 7.02 (s, 1 H), 4.46 (t, 1 H, J = 7.6 Hz), 4.30 (t, 2 H, J = 8.0 Hz), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.04 (m, 2 H), 2.56 (m 2 H), 2.30 (m, 1 H), 1.91 (m, 1 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.8, 160.6, 156.0, 155.5, 148.8, 143.0, 140.2, 137.6, 135.9, 129.0, 128.8, 128.4, 127.0, 119.3, 112.7, 106.3, 105.6, 56.5, 56.4, 49.9, 46.6, 34.1, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H)+: 532.22. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.76 (s, 1 H), 7.59 (s, 1 H), 7.36 (d, 2 H, J = 8.8 Hz), 7.30 (m, 4 H), 7.21 (m, 1 H), 7.08 (d, 2 H, J = 8.4 Hz), 7.02 (s, 1 H), 4.46 (t, 1 H, J = 7.6 Hz), 4.30 (t, 2 H, J = 7.6 Hz) 8.0 Hz), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.04 (m, 2 H), 2.56 (m 2 H), 2.30 (m, 1 H), 1.91 (m, 1 H) , 1.16 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.8, 160.6, 156.0, 155.5, 148.8, 143.0, 140.2, 137.6, 135.9, 129.0, 128.8, 128.4, 127.0, 119.3, 112.7, 106.3, 105.6, 56.5, 56.4, 49.9, 46.6, 34.1, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H) + : 532.22.
실시예 4. 2-((6,7-디메톡시-4-옥소-3-(2-(피페리딘-1-일)에틸)-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-4-oxo-3-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 4)]Example 4. 2-((6,7-dimethoxy-4-oxo-3-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio )-N-(4-ethylphenyl)butanamide [2-((6,7-dimethoxy-4-oxo-3-(2-(piperidin-1-yl)ethyl)-3,4-dihydroquinazolin-2- yl)thio)-N-(4-ethylphenyl)butanamide (compound 4)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(피페리딘-1-일)에탄-1-아민 [2-(piperidin-1-yl)ethan-1-amine을 사용하고 실시예 1의 단계 3과 4를 반복하여 목적 화합물을 얻었다.2-(piperidin-1-yl)ethan-1-amine [2-(piperidin-1) instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -yl)ethan-1-amine was used and steps 3 and 4 of Example 1 were repeated to obtain the target compound.
1H NMR (400 MHz, CDCl3,) δ 9.80 (s, 1 H), 7.54 (s, 1 H), 7.35 (d, 2 H, J = 8.8 Hz), 7.06 (d, 2 H, J = 8.8 Hz), 6.99 (s, 1 H), 4.45 (t, 1 H, J = 7.2 Hz), 4.28 (t, 2 H, J = 7.2 Hz), 4.00 (m, 3 H), 3.97 (s, 3 H), 2.68 (m, 2 H), 2.55 (m, 6 H), 2.28 (m 1 H), 1.90 (m, 1 H), 1.58 (m, 4 H), 1.41 (m, 2 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.9, 160.6, 156.2, 155.5, 148.8, 142.9, 140.2, 135.9, 128.4, 119.3, 112.6, 106.3, 105.6, 56.5, 56.4, 55.8, 54.8, 50.0, 42.5, 28.3, 25.8, 24.1, 23.0, 15.8, 12.3; MS m/z (M+H)+: 539.26. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.80 (s, 1 H), 7.54 (s, 1 H), 7.35 (d, 2 H, J = 8.8 Hz), 7.06 (d, 2 H, J = 8.8 Hz), 6.99 (s, 1 H), 4.45 (t, 1 H, J = 7.2 Hz), 4.28 (t, 2 H, J = 7.2 Hz), 4.00 (m, 3 H), 3.97 (s, 3 H), 2.68 (m, 2 H), 2.55 (m, 6 H), 2.28 (m 1 H), 1.90 (m, 1 H), 1.58 (m, 4 H), 1.41 (m, 2 H) , 1.16 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.9, 160.6, 156.2, 155.5, 148.8, 142.9, 140.2, 135.9, 128.4, 119.3, 112.6, 106.3, 105.6, 56.5, 56.4, 55.8, 54.8, 50.0, 42.5, 28.3, 25.8, 24.1, 23.0, 15.8, 12.3; MS m/z (M+H) + : 539.26.
실시예 5. 2-((6,7-디메톡시-4-옥소-3-(2-피리딘-2-일)에틸)-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-4-oxo-3-(2-(pyridin-2-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 5)]Example 5. 2-((6,7-dimethoxy-4-oxo-3-(2-pyridin-2-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio)-N -(4-ethylphenyl)butanamide [2-((6,7-dimethoxy-4-oxo-3-(2-(pyridin-2-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio )-N-(4-ethylphenyl)butanamide (Compound 5)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(피리딘-2-일)에탄-1-아민 [2-(pyridin-2-yl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 5를 얻었다.2-(pyridin-2-yl)ethan-1-amine [2-(pyridin-2-yl) instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 ) ethan-1-amine] and repeating steps 3 and 4 of Example 1 to obtain
1H NMR (400 MHz, CDCl3,) δ 9.72 (s, 1 H), 8.50 (dd, 1 H, J = 8.4, 0.8 Hz), 7.57 (s, 1 H), 7.49 (td, 1 H, J = 7.6, 2.0 Hz), 7.34 (d, 2 H, J = 8.8 Hz), 7.13 (d, 1 H, J = 8.0 Hz), 7.08 (m, 3 H), 7.01 (s, 1 H), 5.48 (m, 3 H), 4.01 (s, 3 H), 3.99 (s, 1 H), 3.23 (t, 2 H, J = 7.6 Hz), 2.55 (m, 2 H), 2.23 (m, 1 H), 1.85 (m 1 H), 1.14 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.8, 160.6, 157.8, 156.3, 155.5, 149.6, 148.8, 143.0, 140.1, 136.5, 136.0, 128.4, 123.5, 121.9, 119.3, 112.7, 106.3, 105.6, 56.5, 56.4, 49.8, 44.9, 36.0, 28.3, 22.9, 15.8, 12.3; MS m/z (M+H)+: 533.22. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.72 (s, 1 H), 8.50 (dd, 1 H, J = 8.4, 0.8 Hz), 7.57 (s, 1 H), 7.49 (td, 1 H, J = 7.6, 2.0 Hz), 7.34 (d, 2 H, J = 8.8 Hz), 7.13 (d, 1 H, J = 8.0 Hz), 7.08 (m, 3 H), 7.01 (s, 1 H), 5.48 (m, 3 H), 4.01 (s, 3 H), 3.99 (s, 1 H), 3.23 (t, 2 H, J = 7.6 Hz), 2.55 (m, 2 H), 2.23 (m, 1 H), 1.85 (m 1 H), 1.14 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.8, 160.6, 157.8, 156.3, 155.5, 149.6, 148.8, 143.0, 140.1, 136.5, 136.0, 128.4, 123.5, 121.9, 119.3, 112.7, 106.3, 105.6, 56.5, 56.4, 49.8, 44.9, 36.0, 28.3, 22.9, 15.8, 12.3; MS m/z (M+H) + : 533.22.
실시예 6. 2-((6,7-디메톡시-4-옥소-3-(2-(피리딘-3-일)에틸)-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-4-oxo-3-(2-(pyridin-3-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 6)]Example 6. 2-((6,7-dimethoxy-4-oxo-3-(2-(pyridin-3-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(4-ethylphenyl)butanamide [2-((6,7-dimethoxy-4-oxo-3-(2-(pyridin-3-yl)ethyl)-3,4-dihydroquinazolin-2-yl) thio)-N-(4-ethylphenyl)butanamide (compound 6)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(피리딘-3-일)에탄-1-아민 [2-(pyridin-3-yl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 6을 얻었다.2-(pyridin-3-yl)ethan-1-amine [2-(pyridin-3-yl) instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 ) ethan-1-amine] and repeating steps 3 and 4 of Example 1 to obtain compound 6.
1H NMR (400 MHz, CDCl3,) δ 9.65 (s, 1 H), 8.53 (d, 1 H, J = 1.6 Hz), 8.46 (dd, 1 H, J = 8.4, 1.6 Hz), 7.61 (dt, 1 H, J = 8.0, 2.0 Hz), 7.56 (s, 1 H), 7.35 (dt, 2 H, J = 8.8, 2.0 Hz), 7.21 (dd, 1 H, J = 7.6, 4.0 Hz), 7.07 (d, 2 H, J = 8.8 Hz), 7.01 (s, 1 H), 4.45 (t, 1 H, J = 7.6 Hz), 4.30 (m, 2 H), 4.00 (s, 3 H), 3.99 (s, 3 H), 3.06 (m, 2 H), 2.55 (m, 2 H), 2.27 (m, 1 H), 1.15 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.6, 160.5, 155.68, 155.62, 150.2, 148.9, 148.5, 142.9, 140.3, 136.5, 135.8, 133.0, 128.4, 123.6, 119.3, 112.6, 106.3, 105.7, 56.5, 56.4, 50.0, 46.0, 31.3, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H)+: 533.22. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.65 (s, 1 H), 8.53 (d, 1 H, J = 1.6 Hz), 8.46 (dd, 1 H, J = 8.4, 1.6 Hz), 7.61 ( dt, 1 H, J = 8.0, 2.0 Hz), 7.56 (s, 1 H), 7.35 (dt, 2 H, J = 8.8, 2.0 Hz), 7.21 (dd, 1 H, J = 7.6, 4.0 Hz) , 7.07 (d, 2 H, J = 8.8 Hz), 7.01 (s, 1 H), 4.45 (t, 1 H, J = 7.6 Hz), 4.30 (m, 2 H), 4.00 (s, 3 H) , 3.99 (s, 3 H), 3.06 (m, 2 H), 2.55 (m, 2 H), 2.27 (m, 1 H), 1.15 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.6, 160.5, 155.68, 155.62, 150.2, 148.9, 148.5, 142.9, 140.3, 136.5, 135.8, 133.0, 128.4, 123.6, 119.3, 112.6, 106.3, 105.7, 56.5, 56.4, 50.0, 46.0, 31.3, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H) + : 533.22.
실시예 7. 2-((6,7-디메톡시-4-옥소-3-(2-(피리딘-4-일)에틸)-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-4-oxo-3-(2-(pyridin-4-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 7)]Example 7. 2-((6,7-dimethoxy-4-oxo-3-(2-(pyridin-4-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(4-ethylphenyl)butanamide [2-((6,7-dimethoxy-4-oxo-3-(2-(pyridin-4-yl)ethyl)-3,4-dihydroquinazolin-2-yl) thio)-N-(4-ethylphenyl)butanamide (compound 7)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(피리딘-4-일)에탄-1-아민 [2-(pyridin-4-yl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 7을 얻었다.2-(pyridin-4-yl)ethan-1-amine [2-(pyridin-4-yl) instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 ) ethan-1-amine] and repeating steps 3 and 4 of Example 1 to obtain
1H NMR (400 MHz, CDCl3,) δ 9.65 (s, 1 H), 8.53 (d, 2 H, J = 6.4 Hz), 7.56 (s, 1 H), 7.35 (d, 2 H, J = 8.8 Hz), 7.22 (d, 2 H, J = 6.4 Hz), 7.08 (d, 2 H, J = 8.4 Hz), 7.02 (s, 1 H), 4.47 (t, 1 H, J = 7.6 Hz), 4.32 (t, 2 H, J = 8.0 Hz), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.04 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.90 (m, 1 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.6, 160.5, 155.7, 150.2, 149.0, 146.4, 142.9, 140.3, 135.8, 128.5, 124.2, 119.3, 112.6, 106.2, 105.7, 56.6, 56.4, 49.9, 45.3, 33.4, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H)+: 533.22. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.65 (s, 1 H), 8.53 (d, 2 H, J = 6.4 Hz), 7.56 (s, 1 H), 7.35 (d, 2 H, J = 8.8 Hz), 7.22 (d, 2 H, J = 6.4 Hz), 7.08 (d, 2 H, J = 8.4 Hz), 7.02 (s, 1 H), 4.47 (t, 1 H, J = 7.6 Hz) , 4.32 (t, 2 H, J = 8.0 Hz), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.04 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.90 (m, 1 H), 1.16 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.6, 160.5, 155.7, 150.2, 149.0, 146.4, 142.9, 140.3, 135.8, 128.5, 124.2, 119.3, 112.6, 106.2, 105.7, 56.6, 56.4, 49.9, 45.3, 33.4, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H) + : 533.22.
실시예 8. N-(4-에틸페닐)-2-((3-(2-플루오로페네틸)-6,7-디메톡시-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)부탄아미드 [N-(4-ethylphenyl)-2-((3-(2-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanamide (화합물 8)]Example 8. N-(4-ethylphenyl)-2-((3-(2-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazoline-2- yl)thio)butanamide [N-(4-ethylphenyl)-2-((3-(2-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanamide (Compound 8)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(2-플루오로페닐)에탄-1-아민 [2-(2-fluorophenyl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 8을 얻었다.2-(2-fluorophenyl)ethan-1-amine [2-(2-fluorophenyl)ethan instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -1-amine] and repeating steps 3 and 4 of Example 1 to obtain compound 8.
1H NMR (400 MHz, CDCl3,) δ 9.71 (s, 1 H), 7.58 (s, 1 H), 7.34 (d, 2 H, J = 8.4 Hz), 7.17 (m, 2 H), 7.07 (d, 2 H, J = 8.0 Hz), 6.98 (m, 3 H), 4.42 (t, 1 H, J = 7.6 Hz), 4.33 (t, 2 H, J = 7.6 Hz), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.12 (m, 2 H), 2.56 (m, 2 H), 2.25 (m, 1 H), 1.87 (m, 1 H), 1.15 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.8, 160.6, 156.2, 155.5, 148.8, 142.9, 140.2, 136.0, 131.2 128.9, 128.8, 128.4, 124.5, 119.3, 115.6, 115.4, 112.6, 106.3, 105.6, 56.5, 56.4, 49.9, 45.1, 28.3, 27.7, 22.9, 15.8, 12.3; MS m/z (M+H)+: 522.18. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.71 (s, 1 H), 7.58 (s, 1 H), 7.34 (d, 2 H, J = 8.4 Hz), 7.17 (m, 2 H), 7.07 (d, 2 H, J = 8.0 Hz), 6.98 (m, 3 H), 4.42 (t, 1 H, J = 7.6 Hz), 4.33 (t, 2 H, J = 7.6 Hz), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.12 (m, 2 H), 2.56 (m, 2 H), 2.25 (m, 1 H), 1.87 (m, 1 H), 1.15 (m, 6 H) ); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.8, 160.6, 156.2, 155.5, 148.8, 142.9, 140.2, 136.0, 131.2 128.9, 128.8, 128.4, 124.5, 119.3, 115.6, 115.4, 112.6, 106.3, 105.6, 56.5 , 56.4, 49.9, 45.1, 28.3, 27.7, 22.9, 15.8, 12.3; MS m/z (M+H) + : 522.18.
실시예 9. N-(4-에틸페닐)-2-((3-(3-플루오로페네틸)-6,7-디메톡시-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)부탄아미드 [N-(4-ethylphenyl)-2-((3-(3-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanamide (화합물 9)]Example 9. N-(4-ethylphenyl)-2-((3-(3-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazoline-2- yl)thio)butanamide [N-(4-ethylphenyl)-2-((3-(3-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanamide (Compound 9)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(3-플루오오페닐)에탄-1-아민 [2-(3-fluorophenyl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 9를 얻었다.2-(3-fluorophenyl)ethan-1-amine [2-(3-fluorophenyl)ethan instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -1-amine] and repeating steps 3 and 4 of Example 1 to obtain compound 9.
1H NMR (400 MHz, CDCl3,) δ 9.71 (s, 1 H), 7.58 (s, 1 H), 7.35 (d, 2 H, J = 8.8 Hz), 7.25 (m, 1 H), 7.04 (m, 5 H), 6.91 (td, 1 H, J = 8.4, 2.0 Hz), 4.46 (t, 2 H, J = 8.0 Hz), 4.29 (m, 2 H), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.04 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.91 (m, 1 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.7, 164.2, 161.8, 160.5, 155.8, 155.6, 148.9, 142.9, 140.3, 140.0, 139.9, 135.9, 130.3, 130.2, 128.4, 124.6, 119.3, 116.0, 115.8, 114.0, 113.8, 112.6, 106.3, 105.7, 56.5, 56.4, 49.9, 46.2, 33.8, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H)+: 550.21. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.71 (s, 1 H), 7.58 (s, 1 H), 7.35 (d, 2 H, J = 8.8 Hz), 7.25 (m, 1 H), 7.04 (m, 5 H), 6.91 (td, 1 H, J = 8.4, 2.0 Hz), 4.46 (t, 2 H, J = 8.0 Hz), 4.29 (m, 2 H), 4.02 (s, 3 H) , 4.00 (s, 3 H), 3.04 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.91 (m, 1 H), 1.16 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.7, 164.2, 161.8, 160.5, 155.8, 155.6, 148.9, 142.9, 140.3, 140.0, 139.9, 135.9, 130.3, 130.2, 128.4, 124.6, 119.3, 116.0, 115.8, 114.0, 113.8, 112.6, 106.3, 105.7, 56.5, 56.4, 49.9, 46.2, 33.8, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H) + : 550.21.
실시예 10. N-(4-에틸페닐)-2-((3-(4-플루오로페네틸)-6,7-디메톡시-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)부탄아미드 [N-(4-ethylphenyl)-2-((3-(4-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanamide (화합물 10)]Example 10. N-(4-ethylphenyl)-2-((3-(4-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazoline-2- yl)thio)butanamide [N-(4-ethylphenyl)-2-((3-(4-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanamide (Compound 10)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(4-플루오로페닐)에탄-1-아민 [2-(4-fluorophenyl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 10을 얻었다.2-(4-fluorophenyl)ethan-1-amine [2-(4-fluorophenyl)ethan instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -1-amine] and repeating steps 3 and 4 of Example 1 to obtain
1H NMR (400 MHz, CDCl3,) δ 9.71 (s, 1 H), 7.35 (d, 2 H, J = 8.0 Hz), 7.24 (m, 2 H), 7.08 (d, 2 H, J = 8.0 Hz), 7.02 (s, 1 H), 6.97 (tt, 2 H, J = 8.4, 2.0 Hz), 4.46 (t, 1 H, J = 7.6 Hz), 4.27 (t, 2 H, J = 8.4 Hz), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.01 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.90 (m, 1 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.7, 160.5, 155.8, 155.6, 148.9, 142.9, 140.3, 135.9, 133.2, 130.5, 130.4, 128.4, 119.3, 115.7, 115.5, 112.6, 106.3, 105.7, 56.5, 56.4, 49.9, 46.5, 33.3, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H)+: 522.18. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.71 (s, 1 H), 7.35 (d, 2 H, J = 8.0 Hz), 7.24 (m, 2 H), 7.08 (d, 2 H, J = 8.0 Hz), 7.02 (s, 1 H), 6.97 (tt, 2 H, J = 8.4, 2.0 Hz), 4.46 (t, 1 H, J = 7.6 Hz), 4.27 (t, 2 H, J = 8.4) Hz), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.01 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.90 (m, 1 H) , 1.16 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.7, 160.5, 155.8, 155.6, 148.9, 142.9, 140.3, 135.9, 133.2, 130.5, 130.4, 128.4, 119.3, 115.7, 115.5, 112.6, 106.3, 105.7, 56.5, 56.4, 49.9, 46.5, 33.3, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H) + : 522.18.
실시예 11. 2-((6,7-디메톡시-4-옥소-3-(3-(트리플루오로메틸)페네틸)-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-4-oxo-3-(3-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 11)]Example 11. 2-((6,7-dimethoxy-4-oxo-3-(3-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(4-ethylphenyl)butanamide [2-((6,7-dimethoxy-4-oxo-3-(3-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N -(4-ethylphenyl)butanamide (Compound 11)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(3-(트리플루오로메틸)페닐)에탄-1-아민 [2-(3-(trifluoromethyl)phenyl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 목적 화합물을 얻었다.2-(3-(trifluoromethyl)phenyl)ethan-1-amine [2-(3) instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -(trifluoromethyl)phenyl)ethan-1-amine] was used, and steps 3 and 4 of Example 1 were repeated to obtain the target compound.
1H NMR (400 MHz, CDCl3,) δ 9.67 (s, 1 H), 7.58 (s, 1 H), 7.53 (s, 1 H), 7.48 (d, 2 H, J = 8.4 Hz), 7.40 (m, 1 H), 7.35 (d, 2 H, J = 8.4 Hz), 7.08 (d, 2 H, J = 8.8 Hz), 7.02 (s, 1 H), 4.46 (t, 1 H, J = 8.0 Hz), 4.31 (t, 2 H, J = 8.0 Hz), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.11 (m, 2 H), 2.56 (m, 2 H), 2.29 (m, 1 H), 1.90 (m, 1 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.7, 160.5, 155.6, 148.9, 142.9, 140.3, 138.4, 135.9, 132.4, 129.2, 128.4, 125.7, 123.9, 119.3, 112.6, 106.3, 105.7, 56.6, 56.4, 49.9, 46.1, 33.9, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H)+ calculated for C31H32F3N3O4S; 600.2139, found: 600.2165. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.67 (s, 1 H), 7.58 (s, 1 H), 7.53 (s, 1 H), 7.48 (d, 2 H, J = 8.4 Hz), 7.40 (m, 1 H), 7.35 (d, 2 H, J = 8.4 Hz), 7.08 (d, 2 H, J = 8.8 Hz), 7.02 (s, 1 H), 4.46 (t, 1 H, J = 8.0 Hz), 4.31 (t, 2 H, J = 8.0 Hz), 4.02 (s, 3 H), 4.00 (s, 3 H), 3.11 (m, 2 H), 2.56 (m, 2 H), 2.29 (m, 1 H), 1.90 (m, 1 H), 1.16 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.7, 160.5, 155.6, 148.9, 142.9, 140.3, 138.4, 135.9, 132.4, 129.2, 128.4, 125.7, 123.9, 119.3, 112.6, 106.3, 105.7, 56.6, 56.4, 49.9, 46.1, 33.9, 28.3, 23.0, 15.8, 12.3; MS m/z (M+H) + calculated for C 31 H 32 F 3 N 3 O 4 S; 600.2139, found: 600.2165.
실시예 12. 2-((6,7-디메톡시-4-옥소-3-(4-(트리플루오로메틸)페네틸)-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 12)]Example 12. 2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)- N-(4-ethylphenyl)butanamide [2-((6,7-dimethoxy-4-oxo-3-(4-(trifluoromethyl)phenethyl)-3,4-dihydroquinazolin-2-yl)thio)-N -(4-ethylphenyl)butanamide (Compound 12)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(4-(트리플루오로메틸)페닐)에탄-1-아민 [2-(4-(trifluoromethyl)phenyl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 12를 얻었다.2-(4-(trifluoromethyl)phenyl)ethan-1-amine [2-(4) instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -(trifluoromethyl)phenyl)ethan-1-amine] was used, and steps 3 and 4 of Example 1 were repeated to obtain
1H NMR (400 MHz, CDCl3,) δ 9.67 (s, 1 H), 7.56 (m, 3 H), 7.38 (m, 4 H), 7.05 (m, 3 H), 4.46 (t, 1 H, J = 7.6 Hz), 4.31 (m, 2 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.11 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.91 (m, 1 H), 1.15 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.7, 160.5, 155.7, 149.0, 142.9, 141.6, 140.3, 135.8, 129.3, 128.4, 125.77, 125.73, 119.3, 112.6, 106.3, 105.7, 56.5, 56.4, 50.0, 46.0, 34.0, 28.3, 23.0, 15.7, 12.3; MS m/z (M+H)+: 600.21. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.67 (s, 1 H), 7.56 (m, 3 H), 7.38 (m, 4 H), 7.05 (m, 3 H), 4.46 (t, 1 H) , J = 7.6 Hz), 4.31 (m, 2 H), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.11 (m, 2 H), 2.55 (m, 2 H), 2.29 (m , 1 H), 1.91 (m, 1 H), 1.15 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.7, 160.5, 155.7, 149.0, 142.9, 141.6, 140.3, 135.8, 129.3, 128.4, 125.77, 125.73, 119.3, 112.6, 106.3, 105.7, 56.5, 56.4, 50.0, 46.0, 34.0, 28.3, 23.0, 15.7, 12.3; MS m/z (M+H) + : 600.21.
실시예 13. 2-((6,7-디메톡시-3-(4-메톡시페네틸)-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-3-(4-methoxyphenethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 13)]Example 13. 2-((6,7-dimethoxy-3-(4-methoxyphenethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4 -Ethylphenyl)butanamide [2-((6,7-dimethoxy-3-(4-methoxyphenethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (Compound 13)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(4-메톡시페닐)에탄-1-아민 [2-(4-methoxyphenyl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 13을 얻었다.2-(4-methoxyphenyl)ethan-1-amine [2-(4-methoxyphenyl)ethan instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -1-amine] and repeating steps 3 and 4 of Example 1 to obtain compound 13.
1H NMR (400 MHz, CDCl3,) δ 9.77 (s, 1 H), 7.58 (s, 1 H), 7.35 (d, 2 H, J = 8.0 Hz), 7.20 (d, 2 H, J = 8.4 Hz), 7.07 (d, 2 H, J = 8.0 Hz), 7.01 (s, 1 H), 6.83 (d, 2 H, J = 8.0 Hz), 4.46 (t, 1 H, J = 7.6 Hz), 4.26 (t, 2 H, J = 8.0 Hz), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.75 (s, 3 H), 2.98 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.90 (m, 1 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.8, 160.6, 158.6, 156.0, 155.5, 148.8, 143.0, 140.2, 135.9, 130.0, 129.6, 128.4, 119.3, 114.2, 112.7, 106.3, 105.6, 56.5, 56.4, 56.3, 49.9, 46.8, 33.3, 28.3, 23.0, 15.8, 12.3; MS: 562.23. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.77 (s, 1 H), 7.58 (s, 1 H), 7.35 (d, 2 H, J = 8.0 Hz), 7.20 (d, 2 H, J = 8.4 Hz), 7.07 (d, 2 H, J = 8.0 Hz), 7.01 (s, 1 H), 6.83 (d, 2 H, J = 8.0 Hz), 4.46 (t, 1 H, J = 7.6 Hz) , 4.26 (t, 2 H, J = 8.0 Hz), 4.01 (s, 3 H), 4.00 (s, 3 H), 3.75 (s, 3 H), 2.98 (m, 2 H), 2.55 (m, 2 H), 2.29 (m, 1 H), 1.90 (m, 1 H), 1.16 (m, 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.8, 160.6, 158.6, 156.0, 155.5, 148.8, 143.0, 140.2, 135.9, 130.0, 129.6, 128.4, 119.3, 114.2, 112.7, 106.3, 105.6, 56.5, 56.4, 56.3, 49.9, 46.8, 33.3, 28.3, 23.0, 15.8, 12.3; MS: 562.23.
실시예 14. 2-((3-(사이클로헥실메틸)-6,7-디메톡시-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((3-(cyclohexylmethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 14)]Example 14. 2-((3-(cyclohexylmethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl )Butanamide [2-((3-(cyclohexylmethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (Compound 14)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 사이클로헥실메탄아민 (cyclohexylmethanamine)을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 14를 얻었다.Compound 14 by using cyclohexylmethanamine instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 and repeating steps 3 and 4 of Example 1 got
1H NMR (400 MHz, CDCl3,) δ 9.84 (s, 1 H), 7.56 (s, 1 H), 7.36 (d, 2 H, J = 8.8 Hz), 7.07 (d, 2 H, J = 8.8 Hz), 7.00 (s, 1 H), 4.45 (t, 2 H, J = 8.0 Hz), 3.99 (d, 8 H, J = 7.2 Hz), 2.55 (m, 2 H), 2.27 (m, 1 H), 1.91 (m, 2 H), 1.66 (m, 5 H), 1.16 (m, 11 H); 13C NMR (100 MHz, CDCl3,) δ 169.0, 161.1, 156.7, 155.4, 148.7, 142.8, 140.2, 136.0, 128.4, 119.3, 112.7, 106.5, 105.5, 56.5, 56.4, 50.6, 50.1, 37.3, 30.8, 28.3, 26.2, 25.8, 23.0, 15.8, 12.3; MS m/z (M+H)+: 524.25. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.84 (s, 1 H), 7.56 (s, 1 H), 7.36 (d, 2 H, J = 8.8 Hz), 7.07 (d, 2 H, J = 8.8 Hz), 7.00 (s, 1 H), 4.45 (t, 2 H, J = 8.0 Hz), 3.99 (d, 8 H, J = 7.2 Hz), 2.55 (m, 2 H), 2.27 (m, 1 H), 1.91 (m, 2 H), 1.66 (m, 5 H), 1.16 (m, 11 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 169.0, 161.1, 156.7, 155.4, 148.7, 142.8, 140.2, 136.0, 128.4, 119.3, 112.7, 106.5, 105.5, 56.5, 56.4, 50.6, 50.1, 37.3, 30.8, 28.3, 26.2, 25.8, 23.0, 15.8, 12.3; MS m/z (M+H) + : 524.25.
실시예 15. N-(4-에틸페닐)-2-((3-(2-플루오로페네틸)-6,7-디메톡시-4-옥소-3,4-디하이드로퀴나졸린-2-일)티오)부탄아미드 [N-(4-ethylphenyl)-2-((3-(2-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanamide (화합물 15)]Example 15. N-(4-ethylphenyl)-2-((3-(2-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazoline-2- yl)thio)butanamide [N-(4-ethylphenyl)-2-((3-(2-fluorophenethyl)-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)thio)butanamide (Compound 15)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(2-플루오로페닐)에탄-1-아민 [2-(2-fluorophenyl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 15를 얻었다.2-(2-fluorophenyl)ethan-1-amine [2-(2-fluorophenyl)ethan instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -1-amine] and repeating steps 3 and 4 of Example 1 to obtain compound 15.
1H NMR (400 MHz, CDCl3,) δ 9.69 (s, 1 H), 7.58 (s, 1 H), 7.32 (d, 2 H, J = 8.0 Hz), 7.17 (m, 1 H), 7.09 (d, 2 H, J = 8.4 Hz), 6.99 (m, 3 H), 4.34 (t, 2 H, J = 7.6 Hz), 3.99 (s, 6 H), 3.94 (s, 2 H), 3.12 (t, 2 H, J = 7.6 Hz), 2.56 (m, 2 H), 1.16 (t, 3 H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3,) δ 166.6, 160.6, 155.6, 148.9, 142.9, 140.4, 135.7, 131.3, 129.0, 128.9, 128.4, 124.4, 124.3, 119.5, 115.6, 115.4, 112.7, 106.3, 105.8, 56.6, 56.4, 45.2, 35.9, 28.3, 27.8, 15.7; MS m/z (M+H)+: 550.21. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.69 (s, 1 H), 7.58 (s, 1 H), 7.32 (d, 2 H, J = 8.0 Hz), 7.17 (m, 1 H), 7.09 (d, 2 H, J = 8.4 Hz), 6.99 (m, 3 H), 4.34 (t, 2 H, J = 7.6 Hz), 3.99 (s, 6 H), 3.94 (s, 2 H), 3.12 (t, 2 H, J = 7.6 Hz), 2.56 (m, 2 H), 1.16 (t, 3 H, J = 7.6 Hz); 13 C NMR (100 MHz, CDCl 3 ,) δ 166.6, 160.6, 155.6, 148.9, 142.9, 140.4, 135.7, 131.3, 129.0, 128.9, 128.4, 124.4, 124.3, 119.5, 115.6, 115.4, 112.7, 106.3, 105.8, 56.6, 56.4, 45.2, 35.9, 28.3, 27.8, 15.7; MS m/z (M+H) + : 550.21.
실시예 16. 2-((6,7-디메톡시-4-옥소-3-(2-(피롤리딘-1-일)에틸)-3,4-디하이드로퀴나졸린-2-일)티오)-N-(4-에틸페닐)부탄아미드 [2-((6,7-dimethoxy-4-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(4-ethylphenyl)butanamide (화합물 16)]Example 16. 2-((6,7-dimethoxy-4-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinazolin-2-yl)thio )-N-(4-ethylphenyl)butanamide [2-((6,7-dimethoxy-4-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydroquinazolin-2- yl)thio)-N-(4-ethylphenyl)butanamide (compound 16)]
실시예 1의 단계 2에서 2-(사이클로헥-1-엔-1-일)에탄-1-아민 대신 2-(피롤리딘-1-일)에탄-1-아민 [2-(pyrrolidin-1-yl)ethan-1-amine]을 사용하고 실시예 1의 단계 3과 4를 반복하여 화합물 16을 얻었다.2-(pyrrolidin-1-yl)ethan-1-amine [2-(pyrrolidin-1) instead of 2-(cyclohex-1-en-1-yl)ethan-1-amine in step 2 of Example 1 -yl)ethan-1-amine] and repeating steps 3 and 4 of Example 1 to obtain compound 16.
1H NMR (400 MHz, CDCl3,) δ 9.79 (s, 1 H), 7.56 (s, 1 H), 7.34 (d, 2 H, J = 8.4 Hz), 7.07 (d, 2 H, J = 8.4 Hz), 6.99 (s, 1 H), 4.45 (t, 1 H, J = 7.6 Hz), 4.29 (m, 2 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 2.81 (m, 2 H), 2.63 (m, 4 H), 2.55 (m, 2 H), 2.28 (m, 1 H), 1.91 (m, 1 H), 1.78 (m, 4 H), 1.16 (m, 6 H); 13C NMR (100 MHz, CDCl3,) δ 168.9, 160.6, 156.2, 155.5, 148.8, 142.9, 140.2, 135.9, 128.4, 119.3, 112.7, 106.4, 105.6, 56.5, 56.4, 54.4, 53.2, 50.0, 44.1, 28.3, 23.6, 23.0, 15.7, 12.3; MS m/z (M+H)+: 525.25. 1 H NMR (400 MHz, CDCl 3 ,) δ 9.79 (s, 1 H), 7.56 (s, 1 H), 7.34 (d, 2 H, J = 8.4 Hz), 7.07 (d, 2 H, J = 8.4 Hz), 6.99 (s, 1 H), 4.45 (t, 1 H, J = 7.6 Hz), 4.29 (m, 2 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 2.81 (m, 2 H), 2.63 (m, 4 H), 2.55 (m, 2 H), 2.28 (m, 1 H), 1.91 (m, 1 H), 1.78 (m, 4 H), 1.16 (m , 6 H); 13 C NMR (100 MHz, CDCl 3 ,) δ 168.9, 160.6, 156.2, 155.5, 148.8, 142.9, 140.2, 135.9, 128.4, 119.3, 112.7, 106.4, 105.6, 56.5, 56.4, 54.4, 53.2, 50.0, 44.1, 28.3, 23.6, 23.0, 15.7, 12.3; MS m/z (M+H) + : 525.25.
<실험예 1> 암세포에 대한 증식억제<Experimental Example 1> Inhibition of proliferation of cancer cells
폐암세포주 A549 및 NCI-H460을 이용하여 앞서 합성된 화합물들의 세포활성을 확인하기 위해, 세포 생존도를 확인하고 세포활성 50% 억제를 나타내는 농도를 IC50 값을 확인하였다.In order to confirm the cellular activity of the previously synthesized compounds using lung cancer cell lines A549 and NCI-H460, the cell viability was checked and the IC 50 value of the concentration showing 50% inhibition of the cellular activity was confirmed.
각 세포를 96 웰 플레이트에 적정한 세포수로 분주하였고 (A549 및 NCI-H460 각각 3,000 cells), 각 화합물을 농도별로 처리 후 48시간 동안 추가로 세포 배양한 후 EZ-cytox (EZ-1000, DOGEN)를 처리하여 세포 생존도 (cell viability)를 계산하여 IC50 값을 얻었다.Each cell was seeded in an appropriate number of cells in a 96-well plate (3,000 cells each for A549 and NCI-H460), and after treatment with each compound at each concentration, the cells were further cultured for 48 hours, followed by EZ-cytox (EZ-1000, DOGEN) was treated to calculate cell viability to obtain an IC 50 value.
그 결과, 표 1과 같이 폐암 세포에서 화합물 12의 IC50 값이 10μM 이하로 가장 낮은 것을 확인할 수 있었다.As a result, as shown in Table 1, it was confirmed that the IC 50 value of
<실험예 2> in vivo 항암 효과 확인<Experimental Example 2> Confirmation of in vivo anticancer effect
1. 폐암 전이 모델에서 전이 억제 효과 확인1. Confirmation of metastasis inhibition effect in lung cancer metastasis model
앞서 합성된 화합물 중 가장 우수한 IC50 값을 나타낸 화합물 12의 암 전이 억제 효과를 확인하기 위해, 마우스 폐 암 (LLC, Lewis lung carcinoma) 전이 모델을 사용하였다. ICR 마우스에 Lewis lung carcinoma cell를 4 × 105 세포로 주사한 후 화합물 12를 0.1 및 0.5 mg/kg 농도로 주 2회씩 4주간 정맥 내 (IV) 투여하였다.In order to confirm the cancer metastasis inhibitory effect of
그 결과, 도 1과 같이 화합물 12가 투여된 마우스 실험군에서 대조군과 비교하여 폐종양이 유의하게 감소한 것을 확인할 수 있었다. As a result, as shown in FIG. 1 , it was confirmed that lung tumors were significantly reduced in the mouse experimental group administered with
2. A549 비소세포성폐암 (NSCLC) 세포주에 의한 폐암 모델에서 항암 효과 확인2. Confirmation of anticancer effect in lung cancer model by A549 non-small cell lung cancer (NSCLC) cell line
앞선 실험과 동일한 방법으로 A549 비소세포성폐암 (NSCLC) 세포주를 누드 마우스에 이식하여 종양을 형성시킨 폐암 마우스 모델에서 화합물 12의 항암 효과를 확인하였다. The anticancer effect of
그 결과, 도 2와 같이 대조군과 비교하여 화합물 12가 투여된 마우스 실험군에서 폐 종양의 무게가 현저하게 감소된 것을 확인할 수 있었다.As a result, as shown in FIG. 2 , it was confirmed that the weight of the lung tumor was significantly reduced in the mouse experimental group administered with
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As described above in detail a specific part of the present invention, for those of ordinary skill in the art, it is clear that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (10)
[화학식 1]
상기 화학식 1에서,
A는 아릴, 헤테로아릴, (C3~C8)사이클로알킬 또는 헤테로(C3~C8)사이클로알킬 중에서 선택되며,
R1과 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시, (C3~C8)사이클로알킬, 할로, 트리플루로메틸 또는 트리플로로메톡시에서 선택되고,
m은 1 내지 3의 정수이고,
n은 0 내지 2의 정수임.A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Formula 1,
A is selected from aryl, heteroaryl, (C3 to C8) cycloalkyl or hetero (C3 to C8) cycloalkyl,
R 1 and R 2 may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy; ,
m is an integer from 1 to 3,
n is an integer from 0 to 2.
[화학식 2]
상기 화학식 2에서,
R1과 R2는 각각 동일하거나 다를 수 있고, 수소, (C1~C4)알킬, (C1~C4)알콕시,(C3~C8)사이클로알킬, 할로, 트리플루로메틸 또는 트리플로로메톡시에서 선택되고, n은 0 내지 2의 정수임.The method according to claim 2, wherein the compound is a compound represented by the following formula (2), or a pharmaceutically acceptable salt thereof, characterized in that:
[Formula 2]
In Formula 2,
R 1 and R 2 may each be the same or different, and are selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C8)cycloalkyl, halo, trifluoromethyl or trifluoromethoxy; , n is an integer from 0 to 2.
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