KR102605163B1 - Composition for preventing or treating brain cancer - Google Patents
Composition for preventing or treating brain cancer Download PDFInfo
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- KR102605163B1 KR102605163B1 KR1020210070823A KR20210070823A KR102605163B1 KR 102605163 B1 KR102605163 B1 KR 102605163B1 KR 1020210070823 A KR1020210070823 A KR 1020210070823A KR 20210070823 A KR20210070823 A KR 20210070823A KR 102605163 B1 KR102605163 B1 KR 102605163B1
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- cancer
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- alkyl
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
본 발명에서 제공하는 화합물은 브루톤 티로신 키나제(Bruton's tyrosine kinase; BTK) 억제제로서, 암 중에서도 특히 뇌암을 효과적으로 예방, 개선 또는 치료할 수 있다.The compound provided in the present invention is a Bruton's tyrosine kinase (BTK) inhibitor, and can effectively prevent, improve, or treat cancer, especially brain cancer.
Description
본 발명은 암 중에서도 특히 뇌암을 효과적으로 예방, 개선 또는 치료할 수 있는 조성물에 관한 것이다.The present invention relates to a composition that can effectively prevent, improve, or treat cancer, especially brain cancer.
암이란 개체의 필요에 따라 규칙적이고 절제 있는 증식과 억제를 할 수 있는 정상 세포와 달리 조직 내에서 필요한 상태를 무시하고 무제한의 증식을 하는 미분화 세포로 구성된 세포 덩어리로서 종양이라고도 한다. 이러한 무제한의 증식을 하는 암 세포는 주위의 조직으로 침투하고 더 심각한 경우는 신체의 다른 기관으로 전이가 되어 심각한 고통을 수반하고 결국 죽음을 초래하는 난치병이다.Cancer is also called a tumor, as it is a cell mass composed of undifferentiated cells that proliferate indefinitely, ignoring the necessary conditions within the tissue, unlike normal cells that can proliferate and suppress in a regular and controlled manner according to the individual's needs. Cancer cells that proliferate indefinitely infiltrate surrounding tissues and, in more serious cases, metastasize to other organs of the body, causing severe pain and ultimately death, making it an incurable disease.
미국 암 협회(American Cancer Society) 자료에 따르면 2007년 한해 세계적으로 새로이 암 진단을 받은 환자는 1200만 명 이상이며 사망자는 760만 명으로 매일 약 2만 명씩 암으로 사망하는 것으로 보고되었다. 우리나라의 경우 2006년 통계청 보고에 따르면 암으로 인한 사망이 사망원인 1위를 차지하였다. 따라서, 암 발생 및 투병으로 인한 정신적, 육체적 고통의 감소와 삶의 질 향상을 위해 치료 효과가 우수한 종양 치료제의 개발이 절실히 요구된다.According to data from the American Cancer Society, in 2007 alone, more than 12 million patients were newly diagnosed with cancer worldwide, and the number of deaths was 7.6 million, with approximately 20,000 people dying from cancer every day. In Korea, according to a 2006 report from the National Statistical Office, death due to cancer ranked first as the cause of death. Therefore, the development of tumor therapeutics with excellent therapeutic effects is urgently needed to reduce mental and physical pain caused by developing and fighting cancer and improve quality of life.
그러나 많은 노력에도 아직까지 정상 세포가 어떠한 기전을 거쳐 암 세포로 형질전환이 되는 지에 대해서는 정확하게 규명되지는 않았으나, 환경 요인, 화학 물질, 방사선, 바이러스 등 외적 요인 및 유전 인자, 면역학적 요인 등의 내적 요인 등이 복잡하게 얽혀 결과적으로 암이 발생한다. 암의 발생에 관련되는 유전자에는 종양형성 유전자(oncogenes)와 종양억제 유전자(tumor suppressor genes)가 있는데, 이들 사이의 균형이 위에서 설명한 내적 혹은 외적 요인들에 의해 무너질 때 암이 발생하게 된다.However, despite much effort, the exact mechanism by which normal cells are transformed into cancer cells has not yet been clearly identified. However, external factors such as environmental factors, chemicals, radiation, viruses, and internal factors such as genetic factors and immunological factors have not yet been identified. Cancer occurs as a result of a complex intertwining of factors. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, and cancer occurs when the balance between them is broken by the internal or external factors described above.
암은 혈액암과 고형암으로 크게 분류되며, 폐암, 위암, 유방암, 구강암, 간암, 자궁암, 식도암, 피부암 등 신체의 거의 모든 부위에서 발생하며, 이들의 치료방법으로 최근 글리벡 또는 허셉틴과 같은 소수의 표적 치료제가 특정암의 치료에 이용되고 있으나 현재까지는 수술이나 방사선 요법 및 세포증식을 억제하는 화학요법제를 이용한 항암제 치료가 주된 방법이다. 그러나 표적 치료제가 아니기 때문에 기존 화학요법제의 가장 큰 문제는 세포독성으로 인한 부작용과 약제 내성으로써, 항암제에 의한 초기의 성공적인 반응에도 불구하고 결국에는 치료가 실패하게 되는 주요 요인이다. 따라서, 이러한 화학요법제의 한계를 극복하기 위해서는 항암작용 기전이 명확한 표적 치료제 개발이 지속적으로 필요하다.Cancer is broadly classified into blood cancer and solid cancer, and occurs in almost all parts of the body, including lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer. Recently, a few targets such as Gleevec or Herceptin have been used as treatment methods for these cancers. Treatments are being used to treat certain cancers, but to date, surgery, radiation therapy, and anticancer treatment using chemotherapy agents that inhibit cell proliferation are the main methods. However, because they are not targeted treatments, the biggest problems with existing chemotherapy drugs are side effects due to cytotoxicity and drug resistance, which are major factors that ultimately cause treatment to fail despite an initial successful response to anticancer drugs. Therefore, in order to overcome the limitations of these chemotherapy drugs, the development of targeted treatments with a clear anticancer action mechanism is continuously needed.
한편, 신경교종(glioma)은 원발성 뇌 종양(primary brain tumor)의 60%를 차지하는 종양으로서, 발생 빈도가 높고 치료가 어려워, 현재까지도 방사선 치료 외엔 특별한 치료법이 없는 악성 종양에 해당한다. 그 중 가장 악성으로 분류되고 있는 교모세포종(glioblastoma, GBM)의 경우, 다른 암과 비교하였을 때 방사선 및 항암제 치료에 대한 저항성이 매우 높아 일단 진단되면 생존 기간이 1년에 불과하므로, 각 환자의 발생 기원과 과정에 대한 적절한 진단 및 이해가 중요하다.Meanwhile, glioma is a tumor that accounts for 60% of primary brain tumors. It is a malignant tumor that occurs frequently and is difficult to treat, and there is no specific treatment other than radiation therapy to date. Among them, glioblastoma (GBM), which is classified as the most malignant, has a very high resistance to radiation and anticancer drug treatment compared to other cancers, and once diagnosed, the survival period is only one year, so each patient's Proper diagnosis and understanding of the origin and course are important.
또한, 상기 뇌 종양의 경우, 뇌혈관 장벽(Brain Blood Barrier)이 존재하기 때문에 치료를 위한 약물 전달이 목적하는 뇌 부위로 전달되기 어려울 뿐만 아니라, 상대적으로 뇌신경 생물학에 대한 이해가 부족하여 치료제 개발이 활발하지 못한 것이 현실이다. 더욱이, 교모세포종은 다른 뇌 종양과 비교해볼 때 공격적 변이(aggressive variant)를 나타내어, 이를 빠른 시일 내에 치료하지 않으면 몇 주 이내에 치명적인 결과를 초래할 수 있다. In addition, in the case of brain tumors, not only is it difficult for drugs for treatment to be delivered to the target brain area due to the presence of the brain blood barrier, but also the development of treatments is difficult due to the relative lack of understanding of brain neurobiology. The reality is that it is not active. Moreover, compared to other brain tumors, glioblastoma shows an aggressive variant, which can lead to fatal results within a few weeks if not treated quickly.
따라서, 교모세포종의 치료에는 외과적 처치 이외에 방사선 치료 및 화학 약물 치료가 함께 수행되고 있으나, 상기 치료는 내성 변이의 발생, 종양줄기세포에 의한 재발 등의 원인으로 인하여 완벽한 치료법이 없다. 따라서, 보다 효과적으로 교모세포종을 치료할 수 있는 약물이 요구되고 있는 실정이다.Therefore, in the treatment of glioblastoma, in addition to surgical treatment, radiation therapy and chemical drug treatment are performed together. However, there is no perfect treatment due to causes such as the occurrence of resistance mutations and recurrence due to tumor stem cells. Therefore, there is a need for a drug that can more effectively treat glioblastoma.
본 발명의 일 목적은 암 중에서도 특히 뇌암을 예방, 개선 또는 치료할 수 있는 조성물을 제공하고자 한다. One object of the present invention is to provide a composition that can prevent, improve, or treat cancer, especially brain cancer.
본 발명의 다른 목적은 암 중에서도 특히 뇌암을 예방, 개선 또는 치료하기 위한 항암제의 감수성을 증진시킬 수 있는 조성물을 제공하고자 한다. Another object of the present invention is to provide a composition that can improve sensitivity to anticancer drugs for preventing, improving or treating brain cancer, especially brain cancer.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업계에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.
본 명세서에 사용되는 용어 '할로겐'은 다른 언급이 없으면, 플루오르, 염소, 브롬 또는 요오드를 의미한다. As used herein, the term 'halogen' means fluorine, chlorine, bromine or iodine, unless otherwise specified.
본 명세서에 사용되는 용어 'C1-6알킬'은 다른 언급이 없으면, 탄소수 1 내지 6개의 직쇄형 또는 분지형의 탄화수소 잔기를 의미한다. 이의 예로는 메틸, 에틸, 프로필, 이소프로필, n-부틸, sec-부틸, t-부틸, n-펜틸, n-헥실 등을 들 수 있으나, 이들로 제한되는 것은 아니다.As used herein, the term 'C 1-6 alkyl' means a straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.
본 명세서에 사용되는 용어 'C3-7사이클로알킬'은 다른 언급이 없으면, 탄소수 3 내지 7개의 고리형의 탄화수소 잔기를 의미한다. 이의 예로는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸 등을 들 수 있으나, 이들로 제한되는 것은 아니다.As used herein, the term 'C 3-7 cycloalkyl' refers to a cyclic hydrocarbon residue having 3 to 7 carbon atoms, unless otherwise specified. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
본 명세서에서 사용되는 용어 'C6~C14의 아릴'은 다른 언급이 없으면, 융합 또는 비-융합된 하나 이상의 방향족 고리를 갖는, 탄소수 6 내지 14개의 모노- 또는 폴리-시클릭 카르보시클릭 고리 시스템을 지칭하고, 아릴의 예로는 페닐, 나프틸, 테트라하이드로나프틸, 인데닐 및 안드라세닐 등을 들 수 있으나, 이들로 제한되는 것은 아니다.As used herein, the term 'aryl of C 6 to C 14 ', unless otherwise specified, refers to a mono- or poly-cyclic carbocyclic ring having 6 to 14 carbon atoms, having one or more aromatic rings that are fused or non-fused. Refers to a system, and examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, and andracenyl.
본 명세서에 사용되는 용어 'C1-6알콕시'는 다른 언급이 없으면, 산소와 연결된 탄소수 1 내지 6개의 직쇄형 또는 분지형의 탄화수소 잔기를 의미한다. 이의 예로는 메톡시, 에톡시, 프로폭시, 이소부톡시, n-부톡시, sec-부톡시, t-부톡시, 펜톡시, 헥속시 등을 들 수 있으나, 이들로 제한되는 것은 아니다.As used herein, unless otherwise specified, the term 'C 1-6 alkoxy' refers to a straight-chain or branched hydrocarbon residue having 1 to 6 carbon atoms linked to oxygen. Examples thereof include methoxy, ethoxy, propoxy, isobutoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, hexoxy, etc., but are not limited thereto.
본 명세서에 사용되는 용어 'C1-6알킬렌'은 탄소수 1 내지 6개의 직쇄형 또는 분지형의 탄화수소 사슬로부터 유도되는 2가의 잔기를 의미한다. 상기 알킬의 예로는 메틸, 에틸, 프로필, 이소프로필, n-부틸, sec-부틸, t-부틸, n-펜틸 및 n-헥실 등을 들 수 있으나, 이들로 제한되는 것은 아니다.The term 'C 1-6 alkylene' used herein refers to a divalent residue derived from a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. Examples of the alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.
본 발명의 일 구현 예에 따르면, 브루톤 티로신 키나제(Bruton's tyrosine kinase; BTK) 억제제를 유효 성분으로 포함하는, 암의 예방, 개선 또는 치료용 약학적 조성물에 관한 것이다.According to one embodiment of the present invention, it relates to a pharmaceutical composition for preventing, improving, or treating cancer, comprising a Bruton's tyrosine kinase (BTK) inhibitor as an active ingredient.
본 발명의 다른 구현 예에 따르면, 브루톤 티로신 키나제(BTK) 억제제를 유효 성분으로 포함하는, 암의 침윤성 또는 전이성 억제용 약학적 조성물에 관한 것이다.According to another embodiment of the present invention, it relates to a pharmaceutical composition for inhibiting the invasiveness or metastasis of cancer, comprising a Bruton's tyrosine kinase (BTK) inhibitor as an active ingredient.
본 발명에서 상기 BTK 억제제로는 하기 화학식 1로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 광학이성질체, 수화물 및 용매화물로부터 선택되는 화합물일 수 있다:In the present invention, the BTK inhibitor may be a compound selected from compounds represented by the following formula (1), pharmaceutically acceptable salts, optical isomers, hydrates, and solvates thereof:
[화학식 1][Formula 1]
상기 화학식 1에서, In Formula 1,
R1 및 R2는 각각 독립적으로 수소, C1-6알킬 또는 C3-6사이클로알킬이고;R 1 and R 2 are each independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R3는 수소, C1-6알킬 또는 C1-6알케닐이며; R 3 is hydrogen, C 1-6 alkyl or C 1-6 alkenyl;
L1은 직접결합 또는 C1-6알킬렌이고;L 1 is a direct bond or C 1-6 alkylene;
m은 0 내지 2의 정수이며;m is an integer from 0 to 2;
n 및 p는 각각 독립적으로 0 내지 3의 정수이고; n and p are each independently integers from 0 to 3;
o는 0 내지 4의 정수이며;o is an integer from 0 to 4;
q는 0 내지 5의 정수이고; q is an integer from 0 to 5;
Ra, Rb, Rc 및 Rd 및 Re는 각각 독립적으로 할로겐, C1-6알킬, C3-6사이클로알킬기 및 C1-6알콕시로 이루어진 군에서 선택되며;Ra, Rb, Rc, Rd and Re are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 3-6 cycloalkyl group and C 1-6 alkoxy;
상기 R1 및 R2의 알킬 및 사이클로알킬과, R3의 알킬 및 알케닐과, L1의 알킬렌과, Ra, Rb, Rc 및 Rd 및 Re의 알킬, 사이클로알킬 및 알콕시는 각각 독립적으로 할로겐, C1-6알킬, C3-6사이클로알킬기 및 C6-14아릴로 이루어진 군에서 선택되는 1종 이상의 치환기에 의해 치환되거나 비치환될 수 있다. The alkyl and cycloalkyl of R 1 and R 2 , the alkyl and alkenyl of R 3 , the alkylene of L 1 , and the alkyl, cycloalkyl and alkoxy of Ra, Rb, Rc and Rd and Re are each independently halogen. , C 1-6 alkyl, C 3-6 cycloalkyl, and C 6-14 aryl.
본 발명에서 상기 R1 및 R2는 각각 독립적으로 수소 또는 C1-6알킬이거나 바람직하게는 수소일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, R 1 and R 2 may each independently be hydrogen or C 1-6 alkyl, or preferably hydrogen, but are not limited thereto.
본 발명에서 상기 R3는 C1-6알케닐일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, R 3 may be C 1-6 alkenyl, but is not limited thereto.
본 발명에서 상기 L1은 C1-6알킬렌일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, L 1 may be C 1-6 alkylene, but is not limited thereto.
본 발명에서 상기 m은 0 또는 1의 정수일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, m may be an integer of 0 or 1, but is not limited thereto.
본 발명에서 상기 n은 0 내지 2의 정수이거나 바람직하게는 0 또는 1의 정수일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, n may be an integer of 0 to 2, or preferably an integer of 0 or 1, but is not limited thereto.
본 발명에서 상기 o는 0 내지 2의 정수이거나 바람직하게는 0 또는 1의 정수일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, o may be an integer of 0 to 2, or preferably an integer of 0 or 1, but is not limited thereto.
본 발명에서 상기 p는 0 내지 2의 정수이거나 바람직하게는 0 또는 1의 정수일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, p may be an integer of 0 to 2, or preferably an integer of 0 or 1, but is not limited thereto.
본 발명에서 상기 Re는 C1-6알킬 또는 C1-6알콕시일 수 있거나 바람직하게는 C1-6알콕시일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, Re may be C 1-6 alkyl or C 1-6 alkoxy, or preferably C 1-6 alkoxy, but is not limited thereto.
본 발명에서 상기 화합물은 하기 화학식 2로 표시되는 화합물일 수 있으나, 이에 제한되는 것은 아니다:In the present invention, the compound may be a compound represented by the following formula (2), but is not limited thereto:
[화학식 2][Formula 2]
상기 화학식 2에서, In Formula 2,
R1, R2, R3, L1, m, n, o, p, q, Ra, Rb, Rc, Rd 및 Re 각각의 정의는 상기 화학식 1에서 정의된 바와 같다. The definitions of R 1 , R 2 , R 3 , L 1 , m, n, o, p, q, Ra, Rb, Rc, Rd and Re are as defined in Formula 1 above.
본 발명에서 상기 화합물은 하기 화학식 3으로 표시되는 화합물일 수 있으나, 이에 제한되는 것은 아니다:In the present invention, the compound may be a compound represented by the following formula (3), but is not limited thereto:
[화학식 3][Formula 3]
상기 화학식 3에서, In Formula 3 above,
R1, R2, L1, m, n, o, p, q, Ra, Rb, Rc, Rd 및 Re 각각의 정의는 상기 화학식 1에서 정의된 바와 같다. The definitions of R 1 , R 2 , L 1 , m, n, o, p, q, Ra, Rb, Rc, Rd and Re are as defined in Formula 1 above.
본 발명에서 상기 화합물은 하기 화학식 4로 표시되는 화합물일 수 있으나, 이에 제한되는 것은 아니다:In the present invention, the compound may be a compound represented by the following formula (4), but is not limited thereto:
[화학식 4][Formula 4]
상기 화학식 4에서, In Formula 4 above,
R1, R2, L1, q 및 Re 각각의 정의는 상기 화학식 1에서 정의된 바와 같다. The definitions of each of R 1 , R 2 , L 1 , q and Re are as defined in Formula 1 above.
본 발명에서 상기 화합물은 하기 화학식 5 또는 6으로 표시되는 화합물일 수 있으나, 이에 제한되는 것은 아니다:In the present invention, the compound may be a compound represented by the following formula 5 or 6, but is not limited thereto:
[화학식 5][Formula 5]
[화학식 6][Formula 6]
본 발명에서 상기 약학적으로 허용되는 염은, 의학적 적용에 적합한 것으로 당업자에 의해 일반적으로 간주되는 염(예를 들어 이러한 염이 상기 염으로 치료될 수 있는 대상체에게 유해하지 않기 때문임), 또는 각각의 치료 내에서 허용 가능한 부작용을 야기하는 염이다. 일반적으로, 상기 약학적으로 허용되는 염은 미국 식품 의약국(FDA), 유럽 의약청(EMA), 또는 일본 후생성의 의약품 의료기기 종합기구(PMDA)와 같은 규제 당국에 의해 허용되는 것으로 간주되는 염이다. 그러나, 본 발명은 원칙적으로, 예를 들어 본 발명에 따른 화합물 또는 그의 생리학적으로 작용성인 유도체의 제조에서의 중간체, 또는 본 발명에 따른 화합물의 약학적으로 허용되는 염 또는 그의 생리학적으로 작용성인 유도체의 제조에서의 중간체로서, 그 자체로는 약학적으로 허용되지 않는 본 발명에 따른 화합물의 염을 또한 포함한다. 상기 염은 수불용성 염을 포함하고, 특히, 수용성 염을 포함한다.Said pharmaceutically acceptable salts in the present invention may be salts generally considered by those skilled in the art to be suitable for medical applications (e.g. because such salts are not harmful to the subjects to be treated with said salts), or, respectively. It is a salt that causes acceptable side effects within the treatment of. Generally, the pharmaceutically acceptable salts are salts that are considered acceptable by regulatory authorities, such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceutical and Medical Device Agency (PMDA) of the Japanese Ministry of Health, Labor and Welfare. . However, the present invention in principle also provides, for example, intermediates in the preparation of the compounds according to the invention or physiologically functional derivatives thereof, or pharmaceutically acceptable salts of the compounds according to the invention or physiologically functional derivatives thereof. As intermediates in the preparation of derivatives, also include salts of the compounds according to the invention which are not pharmaceutically acceptable as such. The salts include water-insoluble salts and, in particular, water-soluble salts.
각각의 경우에, 당업자는 본 발명에 따른 특정 화합물 또는 그의 생리학적으로 작용성인 유도체가 염을 형성할 수 있는지 여부, 즉, 상기 본 발명에 따른 화합물 또는 그의 생리학적으로 작용성인 유도체가, 예를 들어 아미노 기, 카르복실산 기 등과 같은 전하를 띨 수 있는 기를 가지는지 여부를 쉽게 결정할 수 있다.In each case, the person skilled in the art will be able to determine whether a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming salts, i.e. whether the compound according to the invention or a physiologically functional derivative thereof is capable of forming salts, e.g. For example, it can be easily determined whether it has a group that can bear a charge, such as an amino group, a carboxylic acid group, etc.
본 발명의 화합물의 예시적인 염은 산 부가 염 또는 염기와의 염, 특히 약학적으로 허용되는 무기산 및 유기산 부가 염 및 약학에서 통상적으로 사용되는 염기와의 염이며, 이는 수불용성 또는 특히 수용성 산 부가 염이다. 본 발명의 화합물의 치환기에 따라 염기와의 염이 또한 적합할 수 있다. 산 부가 염은, 예를 들어, 본 발명의 화합물의 용액을 염산, 황산, 푸마르산, 말레산, 석신산, 아세트산, 벤조산, 시트르산, 타르타르산, 탄산 또는 인산과 같은 약학적으로 허용되는 산의 용액과 혼합함으로써 형성될 수 있다. 마찬가지로, 약학적으로 허용되는 염기 부가 염은 알칼리 금속염(예를 들어, 나트륨 또는 칼륨 염); 알칼리 토금속 염(예를 들어, 칼슘 또는 마그네슘 염); 및 적합한 유기 리간드로 형성된 염(예를 들어, 할라이드, 하이드록사이드, 카복실레이트, 설페이트, 포스페이트, 니트레이트, 알킬 설포네이트 및 아릴 설포네이트와 같은 반대 음이온을 사용하여 형성된 암모늄, 4차 암모늄 및 아민 양이온)을 포함할 수 있다. 약학적으로 허용되는 염의 예시적인 예로는 아세테이트, 아디페이트, 알기네이트, 아르기네이트, 아스코르베이트, 아스파테이트, 벤젠설포네이트, 벤조에이트, 바이카르보네이트, 바이설페이트, 바이타르트레이트, 보레이트, 브로마이드, 부티레이트, 칼슘 에데테이트, 캄포레이트, 캄포설포네이트, 캄실레이트, 카르보네이트, 클로라이드, 시트레이트, 디글루코네이트, 디하이드로클로라이드, 도데실설페이트, 에데테이트, 에디실레이트, 에탄설포네이트, 포르메이트, 푸마레이트, 갈락테이트, 갈락투로네이트, 글루코네이트, 글루타메이트, 글리세로포스페이트, 헤미설페이트, 헵타노에이트, 헥사노에이트, 헥실레소르시네이트, 하이드로브로마이드, 하이드로클로라이드, 하이드로요오다이드, 2-하이드록시-에탄설포네이트, 하이드록시나프토에이트, 요오다이드, 이소부티레이트, 이소티오네이트, 락테이트, 라우레이트, 라우릴 설페이트, 말레이트, 말레에이트, 말로네이트, 만델레이트, 메탄설포네이트(메실레이트), 메틸설페이트, 2-나프탈렌설포네이트, 니코티네이트, 니트레이트, 올레에이트, 옥살레이트, 팔미테이트, 판토테네이트, 펙티네이트, 퍼설페이트, 3-페닐프로피오네이트, 포스페이트/디포스페이트, 프탈레이트, 피크레이트, 피발레이트, 폴리갈락투로네이트, 프로피오네이트, 살리실레이트, 스테아레이트, 설페이트, 수베레이트, 석시네이트, 탄네이트, 타르트레이트, 토실레이트, 운데카노에이트, 발레레이트 등이 포함되지만 이로 한정되지 않는다.Exemplary salts of the compounds of the invention are acid addition salts or salts with bases, especially pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmaceuticals, which are water-insoluble or especially water-soluble acid addition salts. It's salt. Depending on the substituents of the compounds of the invention, salts with bases may also be suitable. Acid addition salts include, for example, a solution of a compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. It can be formed by mixing. Likewise, pharmaceutically acceptable base addition salts include alkali metal salts (eg, sodium or potassium salts); alkaline earth metal salts (eg, calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amines formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates). cations). Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, Bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecyl sulfate, edetate, edisylate, ethanesulfonate, Formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide. , 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, mandelate, methane. Sulfonate (mesylate), methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate. /diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, Includes, but is not limited to, valerate.
본 발명에서 약학적으로 허용되지 않으며, 예를 들어, 산업적 규모로 본 발명에 따른 화합물을 제조하는 동안 공정 생성물로서 수득될 수 있는 염이 또한 본 발명에 포함되고, 요망되는 경우, 이는 당업자에게 알려진 방법에 의해 약학적으로 허용되는 염으로 전환될 수 있다.Salts which are not pharmaceutically acceptable in the present invention and which can be obtained, for example, as process products during the production of the compounds according to the invention on an industrial scale, are also included in the present invention and, if desired, are known to the person skilled in the art. It can be converted into a pharmaceutically acceptable salt by a method.
한편, 본 발명에 따른 화합물들은 비대칭 탄소 중심을 가질 수 있으므로 R 또는 S 이성질체 또는 라세믹 화합물로서 존재할 수 있으며 이들 모든 광학이성질체 및 혼합물은 본 발명의 범위에 포함될 수 있다.Meanwhile, the compounds according to the present invention may have an asymmetric carbon center and therefore may exist as R or S isomers or racemic compounds, and all of these optical isomers and mixtures may be included within the scope of the present invention.
그 외에도, 본 발명의 화합물뿐만 아니라 그의 염은, 예를 들어 결정질 형태로 분리될 때, 다양한 양의 용매를 함유할 수 있다. 따라서, 본 발명의 화합물의 용매화물, 특히 수화물뿐만 아니라 본 발명의 화합물의 염의 용매화물, 특히 수화물이 본 발명의 범위에 포함될 수 있다. 더욱 특히, 본 발명은, 화학량론에 대하여 1개, 2개 또는 1/2개의 물 분자를 포함하는, 본 발명에 따른 화합물, 염 및/또는 생리학적으로 작용성인 유도체의 수화물을 포함할 수 있다.In addition, the compounds of the invention, as well as their salts, may contain varying amounts of solvent, for example when isolated in crystalline form. Accordingly, solvates, especially hydrates, of the compounds of the invention, as well as solvates, especially hydrates, of salts of the compounds of the invention may be included within the scope of the invention. More particularly, the present invention may comprise hydrates of the compounds, salts and/or physiologically functional derivatives according to the invention, which contain 1, 2 or 1/2 water molecules relative to stoichiometry. .
본 발명의 화합물을 사용하는 경우 암 세포 또는 암 줄기세포의 증식을 억제하여 암을 효과적으로 예방, 개선 또는 치료할 수 있을 뿐만 아니라, 상기한 암 세포 또는 암 줄기세포의 침윤성 또는 전이성 또한 효과적으로 억제할 수 있다. When the compound of the present invention is used, not only can it effectively prevent, improve, or treat cancer by inhibiting the proliferation of cancer cells or cancer stem cells, but it can also effectively inhibit the invasiveness or metastasis of the cancer cells or cancer stem cells. .
본 발명에서 상기 "암 줄기세포"란 줄기세포 특유의 능력인 자가재생이나 분화능력을 가지고 있는 포괄적인 의미의 암 세포를 의미한다. In the present invention, the term “cancer stem cells” refers to cancer cells in a comprehensive sense that have self-renewal or differentiation abilities, which are abilities unique to stem cells.
본 발명에서 상기 "암"은 포유류에서 전형적으로 조절되지 않는 세포 성장으로 특징지어진 생리적 상태를 나타내거나 가리킨다. In the present invention, the term “cancer” refers to or refers to a physiological condition typically characterized by uncontrolled cell growth in mammals.
본 발명에서 상기 암은 브루톤 타이로신 키나제(Bruton's tyrosine kinase; BTK)의 발현 수준이 정상 조직에 비하여 증가된 암일 수 있다. In the present invention, the cancer may be a cancer in which the expression level of Bruton's tyrosine kinase (BTK) is increased compared to normal tissue.
본 발명에서 상기 암은 그 발생 부위에 따라 뇌암, 유방암, 자궁암, 나팔관암, 난소암, 위암, 직장암, 대장암, 소장암, 직장암, 식도암, 임파선암, 담낭암, 폐암, 피부암, 신장암, 방광암, 혈액암, 췌장암, 전립선암, 갑상선암, 내분비선암, 구강암, 간암 등 일 수 있으나, 바람직하게는 뇌암일 수 있으며, 종양의 분화 및/또는 증식 등 암의 진행이 본 발명에서 기술하는 암 줄기세포에 의존적인 암의 종류라면 이에 제한되지 않는다.In the present invention, the cancer includes brain cancer, breast cancer, uterine cancer, fallopian tube cancer, ovarian cancer, stomach cancer, rectal cancer, colon cancer, small intestine cancer, rectal cancer, esophageal cancer, lymph node cancer, gallbladder cancer, lung cancer, skin cancer, kidney cancer, and bladder cancer depending on the site of occurrence. , blood cancer, pancreatic cancer, prostate cancer, thyroid cancer, endocrine cancer, oral cancer, liver cancer, etc., but preferably brain cancer, and the progression of the cancer, such as tumor differentiation and/or proliferation, is performed using the cancer stem cells described in the present invention. It is not limited to this if it is a type of cancer dependent on .
이러한 암 세포로 분화할 수 있는 암 줄기세포는 악성 종양 조직 내에 1 ~ 2% 정도로 존재하며 정상줄기세포의 특성인 자가복제 능력 (self-renewal)과 다른 세포로 분화할 수 있는 전분화능 (pluripotent)을 가지고 있으나 자가 조절 기능에 이상이 있어 세포분열 활성화로 세포 수를 증가하게 되고 스스로 악성 종양 세포로 분화하는 것으로 보고되었다. Cancer stem cells that can differentiate into these cancer cells exist in approximately 1 to 2% of malignant tumor tissues and have self-renewal ability, which is a characteristic of normal stem cells, and pluripotent ability to differentiate into other cells. However, it has been reported that due to abnormalities in self-regulatory function, the number of cells increases by activating cell division and they differentiate into malignant tumor cells on their own.
1997년 백혈병에서 암 줄기세포(cancer stem cell)의 존재가 밝혀진 이래로 (Blood, 1997), 유방암 (PNAS, 2003), 뇌종양 (Nature, 2004), 전립선암 (Cancer Res, 2005), 대장암 (Nature, 2007), 흑색종 (Nature, 2008)에서도 암 줄기세포가 존재한다는 증거들이 제시되었고. 종양에 포함되어있는 소수의 암 줄기세포가 종양의 악성화, 항암저항성 및 재발의 주된 원인으로 부각되었다.Since the existence of cancer stem cells was discovered in leukemia in 1997 (Blood, 1997), breast cancer (PNAS, 2003), brain tumor (Nature, 2004), prostate cancer (Cancer Res, 2005), and colon cancer (Nature) , 2007), and evidence that cancer stem cells exist in melanoma (Nature, 2008). A small number of cancer stem cells contained in tumors have emerged as the main cause of tumor malignancy, anticancer resistance, and recurrence.
암 줄기세포들은 다른 암 세포들과 구별되는 표지 인자(marker)가 존재하며, 암 줄기세포의 표지 인자(cancer stem cell marker)로는 하기 표 1과 같이 다양한 암 종 특이적인 암 줄기세포 표지 인자가 알려져 있다.Cancer stem cells have markers that distinguish them from other cancer cells, and various cancer type-specific cancer stem cell markers are known as cancer stem cell markers, as shown in Table 1 below. there is.
상기한 암 줄기세포들은 끊임없이 자기 재생(self-renewal)을 하며, 실험동물 모델에서 천개 미만의 적은 세포수로도 종양을 만들 수 있으며 악성 종양 세포로서의 능력을 보유하고 있다. 또한, 암 치료법인 항암제 치료와 방사선 치료에 놀라울 정도로 저항성을 가지고 있어, 암 줄기세포의 제거는 암 치료의 성패를 가늠할 수 있는 바로미터로 점차 인식되고 있다. 최근에는 수술, 방사선 치료, 항암화학요법 등 기존의 여러 치료방법을 이용해 암 세포들을 사멸시키더라도 암 줄기세포들을 모두 사멸시키지 못한다면 남아있는 암 줄기세포들로부터 다시 암이 재발할 수 있다는 것으로 인식되고 있다. 이러한 암의 재발을 방지하기 위하여 종양을 재생성할 수 있는 능력을 가진 암 줄기세포를 타겟으로 하는 화학요법 및 이를 바탕으로 암을 치료하고자 하는 치료프로토콜 개발에 관심이 높아지고 있다.The above-mentioned cancer stem cells continuously self-renew, can create tumors with less than a thousand cells in experimental animal models, and have the ability to act as malignant tumor cells. In addition, because they are surprisingly resistant to chemotherapy and radiation therapy, which are cancer treatments, removal of cancer stem cells is increasingly recognized as a barometer for measuring the success or failure of cancer treatment. Recently, it has been recognized that even if cancer cells are killed using various existing treatment methods such as surgery, radiation therapy, and chemotherapy, if all cancer stem cells cannot be killed, cancer may relapse from the remaining cancer stem cells. . In order to prevent recurrence of such cancer, interest is growing in the development of chemotherapy targeting cancer stem cells with the ability to regenerate tumors and treatment protocols to treat cancer based on this.
정상 조직에서의 줄기세포는 자가 재생 (self-renewal) 기전에 의해 세포 성장과 분화를 조절하지만, 암 줄기세포는 종양세포 주변의 종양 미세환경 인자에 영향을 받아 비정상적인 자가분열(Self-renewal) 및 유지(maintenance) 경로를 활성화하여 급격히 집적됨으로써 악성화되고 항암치료에 대한 저항성을 획득하게 되며 궁극적으로 암의 재발을 야기한다고 제시되고 있다. 그러나 아직까지 암 줄기세포의 집적 및 유지를 조절하는 종양 미세 환경 인자의 실체와 상호작용에 대한 구체적인 기전 연구는 진행되지 못하고 있다.Stem cells in normal tissues regulate cell growth and differentiation through self-renewal mechanisms, but cancer stem cells are affected by tumor microenvironment factors around tumor cells and undergo abnormal self-renewal and differentiation. It is suggested that by activating the maintenance pathway and rapidly accumulating, it becomes malignant, acquires resistance to anti-cancer treatment, and ultimately causes cancer recurrence. However, specific mechanistic research on the identity and interaction of tumor microenvironmental factors that regulate the accumulation and maintenance of cancer stem cells has not yet been conducted.
본 발명에서, "예방"은 본 발명의 약학적 조성물을 이용하여 암 증상을 차단하거나, 암 증상의 억제 또는 지연시키는 모든 행위라면 제한없이 포함할 수 있다. In the present invention, “prevention” may include without limitation any act of blocking, suppressing or delaying cancer symptoms using the pharmaceutical composition of the present invention.
본 발명에서, "개선" 또는 "치료"는 본 발명의 약학적 조성물을 조사하여 암 증상이 호전되거나 이롭게 되는 모든 행위라면 제한없이 포함할 수 있다. In the present invention, “improvement” or “treatment” may include, without limitation, any action in which cancer symptoms are improved or beneficial by irradiating the pharmaceutical composition of the present invention.
본 발명에 있어서, 상기 약학적 조성물은 캡슐, 정제, 과립, 주사제, 연고제, 분말 또는 음료 형태임을 특징으로 할 수 있으며, 상기 약학적 조성물은 인간을 대상으로 하는 것을 특징으로 할 수 있다. In the present invention, the pharmaceutical composition may be in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage, and the pharmaceutical composition may be intended for human subjects.
본 발명의 약학적 조성물은 이들로 한정되는 것은 아니지만, 각각 통상의 방법에 따라 산제, 과립제, 캡슐, 정제, 수성 현탁액 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 약학적 조성물은 약제적으로 허용 가능한 담체를 포함할 수 있다. 약제학적으로 허용되는 담체는 경구 투여 시에는 결합제, 활탁제, 붕해제, 부형제, 가용화제, 분산제, 안정화제, 현탁화제, 색소, 향료 등을 사용할 수 있으며, 주사제의 경우에는 완충제, 보존제, 무통화제, 가용화제, 등장제, 안정화제 등을 혼합하여 사용할 수 있으며, 국소투여용의 경우에는 기제, 부형제, 윤활제, 보존제 등을 사용할 수 있다. 본 발명의 약학적 조성물의 제형은 상술한 바와 같은 약제학적으로 허용되는 담체와 혼합하여 다양하게 제조될 수 있다. 예를 들어, 경구 투여시에는 정제, 트로키, 캡슐, 엘릭서(elixir), 서스펜션, 시럽, 웨이퍼 등의 형태로 제조할 수 있으며, 주사제의 경우에는 단위 투약 앰플 또는 다수회 투약 형태로 제조할 수 있다. 기타, 용액, 현탁액, 정제, 캡슐, 서방형 제제 등으로 제형할 수 있다.The pharmaceutical composition of the present invention is not limited to these, but can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods. You can. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc. for oral administration, and buffers, preservatives, and analgesics for injections. Topics, solubilizers, isotonic agents, stabilizers, etc. can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives, etc. can be used. The dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing it with a pharmaceutically acceptable carrier as described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it can be manufactured in the form of unit dosage ampoules or multiple dosage forms. there is. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, etc.
한편, 제제화에 적합한 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말디톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등이 사용될 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Meanwhile, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil may be used. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.
본 발명에 따른 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다. 경구 또는 비경구 투하가 바람직하다. The route of administration of the pharmaceutical composition according to the present invention is not limited to these, but is oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, and topical. , sublingual or rectal. Oral or parenteral administration is preferred.
본 발명에서, "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입기술을 포함한다. 본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다.As used herein, “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention can also be administered in the form of a suppository for rectal administration.
본 발명의 약학적 조성물은 사용된 특정 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 정식, 투여시간, 투여경로, 배출율, 약물 배합 및 예방 또는 치료될 특정 질환의 중증을 포함한 여러 요인에 따라 다양하게 변할 수 있고, 상기 약학적 조성물의 투여량은 환자의 상태, 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만 당업자에 의해 적절하게 선택될 수 있고, 1일 0.0001 내지 50mg/kg 또는 0.001 내지 50mg/kg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 본 발명에 따른 의약 조성물은 환제, 당의정, 캡슐, 액제, 겔, 시럽, 슬러리, 현탁제로 제형될 수 있다.The pharmaceutical composition of the present invention may vary depending on several factors, including the activity of the specific compound used, age, body weight, general health, gender, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. It can vary in various ways, and the dosage of the pharmaceutical composition varies depending on the patient's condition, weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art, and is 0.0001 to 50 mg/day. It can be administered in kg or 0.001 to 50 mg/kg. Administration may be administered once a day, or may be administered several times. The above dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as pills, dragees, capsules, solutions, gels, syrups, slurries, and suspensions.
본 발명에 따른 화합물을 이용하는 경우 암 세포 또는 암 줄기세포의 증식을 억제하고, 줄기세포능(stemness)을 억제하여, 암을 효과적으로 예방, 개선 또는 치료할 수 있을 뿐만 아니라, 더 나아가 상기 암 세포 또는 암 줄기세포의 침윤성 또는 전이성 또한 효과적으로 억제할 수 있다.When using the compound according to the present invention, not only can it effectively prevent, improve, or treat cancer by inhibiting the proliferation of cancer cells or cancer stem cells and suppressing stemness, but can also effectively prevent, improve, or treat cancer. The invasiveness or metastasis of stem cells can also be effectively inhibited.
도 1은 실험예 1에서 정상 뇌 조직 세포, 정상 성상 세포(NHA), 교모세포종 세포(GBM) 및 교모세포종 종양구 세포(TS)에서 BTK 발현 수준을 비교한 결과를 나타낸 것이다.
도 2는 실험예 1에서 다양한 교모세포종 종양구에 대하여 BTK 발현 수준을 비교한 결과를 나타낸 것이다.
도 3은 실험예 2에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 세포 생존율의 변화를 측정하여 그 결과를 그래프로 나타낸 것이다.
도 4는 실험예 2에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 ATP 수준의 변화를 측정하여 그 결과를 그래프로 나타낸 것이다.
도 5는 실험예 3에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 BTK 및 세포 증식 관련 마커의 발현 수준의 변화를 웨스턴 블럿으로 분석한 결과를 나타낸 것이다.
도 6은 실험예 4에서 교모세포종 종양구 TS13-30에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 세포를 현미경으로 관찰한 사진을 나타낸 것이다.
도 7은 실험예 4에서 교모세포종 종양구 TS13-64에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 세포를 현미경으로 관찰한 사진을 나타낸 것이다.
도 8은 실험예 4에서 교모세포종 종양구 TS15-88에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 세포를 현미경으로 관찰한 사진을 나타낸 것이다.
도 9는 실험예 4에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 신경구 형성능을 비교한 결과를 나타낸 것이다.
도 10은 실험예 4에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 종양구의 반경 변화를 비교한 결과를 나타낸 것이다.
도 11은 실험예 5에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 줄기세포능 관련 마커의 발현 수준의 변화를 웨스턴 블럿으로 분석한 결과를 나타낸 것이다.
도 12는 실험예 6에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 세포의 침윤성 변화를 현미경으로 관찰한 사진을 나타낸 것이다.
도 13은 실험예 6에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 처리 시간에 따른 세포의 침윤 면적의 변화를 비교한 결과를 나타낸 것이다.
도 14는 실험예 7에서 교모세포종 종양구(TS13-30, TS13-64 및 TS15-88)에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리하고, 대조군으로는 이브루티닙(Ibrutinib)을 처리한 뒤 침윤성 관련 마커의 발현 수준의 변화를 웨스턴 블럿으로 분석한 결과를 나타낸 것이다.
도 15는 실험예 8에서 교모세포종 종양구 TS13-30의 정위 이식 마우스 모델에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물, 대조군으로는 이브루티닙(Ibrutinib)을 투여한 뒤 시간에 따른 종양 크기 변화를 관찰한 사진을 나타낸 것이다.
도 16은 실험예 8에서 교모세포종 종양구 TS13-30의 정위 이식 마우스 모델에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물, 대조군으로는 이브루티닙(Ibrutinib)을 투여한 뒤 각 처리에 따른 마우스의 생존 기간의 변화를 분석한 결과를 나타낸 것이다.Figure 1 shows the results of comparing BTK expression levels in normal brain tissue cells, normal astrocytes (NHA), glioblastoma cells (GBM), and glioblastoma tumor sphere cells (TS) in Experimental Example 1.
Figure 2 shows the results of comparing BTK expression levels for various glioblastoma tumors in Experimental Example 1.
Figure 3 shows that in Experimental Example 2, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) was processed, the change in cell viability was measured, and the results were presented in a graph.
Figure 4 shows that in Experimental Example 2, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) was processed, the change in ATP level was measured, and the results were displayed in a graph.
Figure 5 shows that in Experimental Example 3, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) shows the results of analysis by Western blot of changes in the expression levels of BTK and cell proliferation-related markers after treatment.
Figure 6 shows that in Experimental Example 4, glioblastoma tumor cells TS13-30 were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib was treated and the cells were observed under a microscope. It shows a photo.
Figure 7 shows that in Experimental Example 4, glioblastoma tumor cells TS13-64 were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib was treated and the cells were observed under a microscope. It shows a photo.
Figure 8 shows that in Experimental Example 4, glioblastoma tumor cells TS15-88 were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib was treated and the cells were observed under a microscope. It shows a photo.
Figure 9 shows that in Experimental Example 4, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) shows the results of comparing the neurosphere formation ability after processing.
Figure 10 shows that in Experimental Example 4, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) shows the results of comparing the change in radius of the tumor sphere after processing.
Figure 11 shows that in Experimental Example 5, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) shows the results of analyzing the changes in expression levels of stem cell potency-related markers after treatment with Western blot.
Figure 12 shows that in Experimental Example 6, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) shows a photo of changes in cell invasiveness observed under a microscope after treatment.
Figure 13 shows that in Experimental Example 6, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) shows the results of comparing the change in cell invasion area according to the treatment time.
Figure 14 shows that in Experimental Example 7, glioblastoma tumor cells (TS13-30, TS13-64, and TS15-88) were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and as a control group, Ibrutinib ) shows the results of analyzing the changes in expression levels of invasiveness-related markers by Western blotting.
Figure 15 is a graph over time after administration of the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and Ibrutinib as a control group, to the orthotopic transplantation mouse model of glioblastoma tumor cells TS13-30 in Experimental Example 8. This photo shows changes in tumor size.
Figure 16 shows the administration of the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2, and Ibrutinib as a control group to the orthotopic transplantation mouse model of glioblastoma tumor cells TS13-30 in Experimental Example 8, followed by each treatment. This shows the results of analyzing changes in the survival period of mice.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
[제조예 1] SPA8007 화합물(아크릴산 2-[6-아미노-5-(6-벤질옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터)의 준비[Preparation Example 1] SPA8007 compound (acrylic acid 2-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester) preparation of
3,5-다이클로로-2-나이트로피리딘을 K2CO3, 톨루엔, 60 ℃ 조건에서 10시간 동안 6-(벤질옥시)-1,2,3,4-테트라하이드로아이소퀴놀린과 반응한 후, K2CO3, DMSO, 18-crown-6, 100 ℃ 조건에서 10시간 동안 카테콜과 반응하고, 상온에서 TEA, DCM 조건 하에 1시간 동안 아크릴로일클로라이드와 반응하였다. 그 다음 SnCl2ㆍ2H2O, EtOH를 이용하여 상온에서 1시간 동안 반응시켜 나이트로그룹을 아민으로 전환하여 상기 화학식 5로 표시되는 아크릴산 2-[6-아미노-5-(6-벤질옥시-3,4-다이하이드로-1H-아이소퀴놀린-2-일)피리딘-3-일옥시]페닐 에스터(Acrylic acid 2-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin-2-yl)pyridin-3-yloxy]phenyl ester)를 제조하였다.3,5-Dichloro-2-nitropyridine was reacted with 6-(benzyloxy)-1,2,3,4-tetrahydroisoquinoline under conditions of K 2 CO 3 , toluene, and 60°C for 10 hours. , K 2 CO 3 , DMSO, 18-crown-6, reacted with catechol at 100°C for 10 hours, and reacted with acryloyl chloride at room temperature under TEA and DCM conditions for 1 hour. Next, the nitro group was converted to an amine by reacting with SnCl 2 .2H2O and EtOH at room temperature for 1 hour to produce acrylic acid 2-[6-amino-5-(6-benzyloxy-3, 4-dihydro-1H-isoquinolin-2-yl) pyridin-3-yloxy] phenyl ester (Acrylic acid 2-[6-amino-5-(6-benzyloxy-3,4-dihydro-1H-isoquinolin- 2-yl)pyridin-3-yloxy]phenyl ester) was prepared.
아이보리색 고체 (수율 23%); IR (neat, cm-1) 2980.65, 2888.60,1735.13, 1610.91, 1461.97, 1380.75, 1239.82, 1150.48, 1015.44, 969.35; 1H NMR (500 MHz, CDCl3) δ 7.68 (1H, d, J = 2.5 Hz), 7.42 (2H, d, J = 7.5 Hz), 7.38 (2H, t, J = 7.5 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.15 (2H, t, J = 7.5Hz), 7.07(1H, t, J = 7.5 Hz), 7.01 (1H, d, J = 2.5 Hz), 6.97 (1H, d, J = 8.5 Hz), 6.88(1H, d, J = 8.0 Hz), 6.81-6.77 (2H, m), 6.57 (1H, dd, J = 1.0, 17.0 Hz), 6.31(1H, dd, J = 10.5, 17.0 Hz), 5.98 (1H, dd, J = 1.0, 10.5 Hz), 5.04 (2H, s), 4.72 (2H, br s), 3.98 (2H, s), 3.17 (2H, t, J = 5.5 Hz), 2.95 (2H, t, J = 5.5 Hz); 13C NMR (500 MHz, CDCl3) δ 164.1, 159.8, 157.6, 154.5, 151.4, 150.2, 145.7, 140.7, 137.2, 135.1, 135.1, 133.7, 132.9, 130.2, 128.7, 128.1, 127.5, 127.5, 127.1, 126.9, 123.6, 123.2, 119.8, 117.9, 114.7, 113.2, 70.2, 52.7, 48.7, 30.0; LCMS (ESI) m/z calcd for C30H27N3O4, 493.20; Found 494.20 [M + H]+Ivory solid (yield 23%); IR (neat, cm-1) 2980.65, 2888.60,1735.13, 1610.91, 1461.97, 1380.75, 1239.82, 1150.48, 1015.44, 969.35; 1H NMR (500 MHz, CDCl3) δ 7.68 (1H, d, J = 2.5 Hz), 7.42 (2H, d, J = 7.5 Hz), 7.38 (2H, t, J = 7.5 Hz), 7.31 (1H, t , J = 7.5 Hz), 7.15 (2H, t, J = 7.5 Hz), 7.07 (1H, t, J = 7.5 Hz), 7.01 (1H, d, J = 2.5 Hz), 6.97 (1H, d, J = 8.5 Hz), 6.88(1H, d, J = 8.0 Hz), 6.81-6.77 (2H, m), 6.57 (1H, dd, J = 1.0, 17.0 Hz), 6.31(1H, dd, J = 10.5, 17.0 Hz), 5.98 (1H, dd, J = 1.0, 10.5 Hz), 5.04 (2H, s), 4.72 (2H, br s), 3.98 (2H, s), 3.17 (2H, t, J = 5.5 Hz) ), 2.95 (2H, t, J = 5.5 Hz); 13C NMR (500 MHz, CDCl3) δ 164.1, 159.8, 157.6, 154.5, 151.4, 150.2, 145.7, 140.7, 137.2, 135.1, 135.1, 133.7, 132.9, 130.2, 128. 7, 128.1, 127.5, 127.5, 127.1, 126.9, 123.6 , 123.2, 119.8, 117.9, 114.7, 113.2, 70.2, 52.7, 48.7, 30.0; LCMS (ESI) m/z calcd for C 30 H 27 N 3 O 4 , 493.20; Found 494.20 [M + H]+
[제조예 2] SPA8009 화합물(아크릴산 3-{6-아미노-5-[6-(4-메톡시벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터)의 준비[Preparation Example 2] SPA8009 compound (acrylic acid 3-{6-amino-5-[6-(4-methoxybenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3- Preparation of monooxy}phenyl ester)
3,5-다이클로로-2-나이트로피리딘을 K2CO3, 톨루엔, 60 ℃ 조건에서 10시간 동안 6-((4-메톡시벤질)옥시)-1,2,3,4-테트라하이드로아이소퀴놀린과 반응한 후, K2CO3, DMSO, 18-crown-6, 100 ℃ 조건에서 10시간 동안 레조르시놀과 반응하고, 상온에서 TEA, DCM 조건 하에 1시간 동안 아크릴로일클로라이드와 반응하였다. 그 다음 SnCl2ㆍ2H2O, EtOH를 이용하여 상온에서 1시간 동안 반응시켜 나이트로그룹을 아민으로 전환하여 상기 화학식 6으로 표시되는 아크릴산 3-{6-아미노-5-[6-(4-메톡시벤질옥시)-3,4-다이하이드로-1H-아이소퀴놀린-2-일]피리딘-3-일옥시}페닐 에스터(Acrylic acid 3-{6-amino-5-[6-(4-methoxybenzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenylester)를 제조하였다.3,5-Dichloro-2-nitropyridine was reacted with 6-((4-methoxybenzyl)oxy)-1,2,3,4-tetrahydro for 10 hours under the conditions of K 2 CO 3 , toluene, and 60°C. After reacting with isoquinoline, reacting with resorcinol for 10 hours under the conditions of K 2 CO 3 , DMSO, 18-crown-6, 100 ℃, and reacting with acryloyl chloride for 1 hour under the conditions of TEA and DCM at room temperature. did. Next, the nitro group is converted to an amine by reacting at room temperature for 1 hour using SnCl 2 ㆍ2H2O and EtOH to form acrylic acid 3-{6-amino-5-[6-(4-methoxy) represented by Chemical Formula 6. Benzyloxy)-3,4-dihydro-1H-isoquinolin-2-yl] pyridin-3-yloxy} phenyl ester (Acrylic acid 3-{6-amino-5-[6-(4-methoxybenzyloxy)- 3,4-dihydro-1H-isoquinolin-2-yl]pyridin-3-yloxy}phenylester) was prepared.
노란색 고체 (수율 42%); IR (neat, cm-1) 3345.48, 2980.40, 2970.51, 2930.34, 1740.92, 1609.63, 1513.79, 1462.81, 1400.63, 1379.59, 1304.07, 1241.82, 1153.82, 1025.10, 1001.88; 1H NMR (500 MHz, CDCl3) δ 7.70 (1H, d, J = 2.5 Hz), 7.33 (2H, d, J = 8.5 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.03 (1H, d, J = 2.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.82-6.77 (3H, m), 6.76 (1H, d, J = 2.0 Hz), 6.73 (1H, t, J = 2.5 Hz), 6.57 (1H, dd, J = 1.0, 17.5 Hz), 6.27 (1H, dd, J = 10.5, 17.5 Hz), 5.98 (1H, dd, J = 1.0, 10.5 Hz), 4.95 (2H, s), 4.82 (2H, br s), 4.00 (2H, s), 3.78 (3H, s), 3.18 (2H, t, J = 6.0 Hz), 2.95 (2H, t, J = 6.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.8, 159.6, 157.7, 151.7, 151.7, 145.0, 135.3, 135.1, 134.4, 132.9, 130.2, 129.3, 129.2, 127.9, 127.5, 126.8, 120.6, 115.6, 114.8, 114.2, 114.2, 113.3, 110.4, 70.0, 55.5, 52.8, 48.8, 29.9; LCMS (ESI) m/z calcd for C31H29N3O5, 523.21; Found 524.22 [M + H]+.Yellow solid (42% yield); IR (neat, cm-1) 3345.48, 2980.40, 2970.51, 2930.34, 1740.92, 1609.63, 1513.79, 1462.81, 1400.63, 1379.59, 1304.07, 1241.82, 1153 .82, 1025.10, 1001.88; 1H NMR (500 MHz, CDCl3) δ 7.70 (1H, d, J = 2.5 Hz), 7.33 (2H, d, J = 8.5 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.03 (1H, d) , J = 2.5 Hz), 6.96 (1H, d, J = 8.5 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.82-6.77 (3H, m), 6.76 (1H, d, J = 2.0 Hz) ), 6.73 (1H, t, J = 2.5 Hz), 6.57 (1H, dd, J = 1.0, 17.5 Hz), 6.27 (1H, dd, J = 10.5, 17.5 Hz), 5.98 (1H, dd, J = 1.0, 10.5 Hz), 4.95 (2H, s), 4.82 (2H, br s), 4.00 (2H, s), 3.78 (3H, s), 3.18 (2H, t, J = 6.0 Hz), 2.95 (2H) , t, J = 6.0 Hz); 13C NMR (500 MHz, CDCl3) δ 164.4, 159.8, 159.6, 157.7, 151.7, 151.7, 145.0, 135.3, 135.1, 134.4, 132.9, 130.2, 129.3, 129.2, 127. 9, 127.5, 126.8, 120.6, 115.6, 114.8, 114.2 , 114.2, 113.3, 110.4, 70.0, 55.5, 52.8, 48.8, 29.9; LCMS (ESI) m/z calcd for C 31 H 29 N 3 O 5 , 523.21; Found 524.22 [M + H]+.
[실험예 1] 교모세포종에서의 BTK 발현 수준의 확인[Experimental Example 1] Confirmation of BTK expression level in glioblastoma
정상 뇌 조직 세포, 정상 성상 세포(NHA), 교모세포종 세포(GBM) 및 교모세포종 종양구 세포(TS)를 준비한 뒤, 마이크로어레이를 통해 이들 세포에서의 BTK 발현 수준을 측정하여 그 결과를 도 1에 나타내었다. 또한, 다양한 종류의 교모세포종 종양구에 대하여도 BTK 발현 수준을 측정하여 그 결과를 도 2에 나타내었다.After preparing normal brain tissue cells, normal astrocytes (NHA), glioblastoma cells (GBM), and glioblastoma tumor sphere cells (TS), the BTK expression level in these cells was measured through microarray, and the results are shown in Figure 1 shown in In addition, BTK expression levels were measured for various types of glioblastoma tumor cells, and the results are shown in Figure 2.
도 1에서 보는 바와 같이, 정상 뇌 조직 세포에 비하여 교모세포종 세포에서는 BTK 발현 수준이 증가되어 있는 것을 확인할 수 있었다. As shown in Figure 1, it was confirmed that the expression level of BTK was increased in glioblastoma cells compared to normal brain tissue cells.
또한, 도 2에서 보는 바와 같이 교모세포종 종양구 중에서도 TS13-30에서 BTK 발현 수준이 매우 증가되어 있는 것을 확인할 수 있었다. In addition, as shown in Figure 2, it was confirmed that the BTK expression level was greatly increased in TS13-30 among glioblastoma tumor cells.
이하의 실험에서는 BTK 발현이 높은 TS13-30과, 일반적으로 실험에 많이 사용되는 TS15-88 및 TS13-64를 사용하였다. In the following experiments, TS13-30, which has high BTK expression, and TS15-88 and TS13-64, which are commonly used in experiments, were used.
[실험예 2] 교모세포종의 사멸 효과 확인[Experimental Example 2] Confirmation of the killing effect of glioblastoma
흑색 또는 백색의 96 웰 플레이트의 각각의 웰에 완전 배지(100 μl)를 사용하여 TS13-30, TS13-64 및 TS15-88을 각각 104개의 세포로 접종하였다. 상기 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 50 μl의 완전 배지에 희석하여 5, 10, 15, 20, 50 또는 100 μl의 완전 배지에 희석하여 각 웰에 처리하였다. 72시간 배양 후 백색의 96 웰 플레이트에 세포 계수 키트 8(Cell Counting Kit 8)을 사용하여 WST를 측정하여 그 결과를 도 3에 나타내었다. 흑색의 96 웰 플레이트에 CellTiter-Glo® 발광 세포 생존율 어쎄이 키트(Luminescent Cell Viability Assay kit)를 사용하여 ATP를 측정하여 그 결과를 도 4에 나타내었다. 단, 양성 대조군으로는 BTK 억제제인 이브루티닙(Ibrutinib)을 사용하였다. Each well of a black or white 96 well plate was inoculated with 10 4 cells each of TS13-30, TS13-64, and TS15-88 using complete medium (100 μl). The SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 were diluted in 50 μl of complete medium and then diluted in 5, 10, 15, 20, 50, or 100 μl of complete medium and treated in each well. After 72 hours of incubation, WST was measured using Cell Counting Kit 8 in a white 96-well plate, and the results are shown in Figure 3. ATP was measured using the CellTiter-Glo® Luminescent Cell Viability Assay kit in a black 96-well plate, and the results are shown in Figure 4. However, Ibrutinib, a BTK inhibitor, was used as a positive control.
도 3에서 보는 바와 같이, 교모세포종 종양구에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 경우 농도 의존적으로 세포 사멸율이 증가하는 것을 확인할 수 있었고, TS13-30, TS13-64 및 TS15-88 종양구 모두에서 우수한 사멸 효과를 보였지만, 특히 BTK 발현이 높은 TS13-30 종양구에 대한 사멸 효과가 현저히 뛰어난 것을 볼 수 있었다. As shown in Figure 3, when glioblastoma tumor spheres were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, it was confirmed that the cell death rate increased in a concentration-dependent manner, and TS13-30 , it showed an excellent killing effect on both TS13-64 and TS15-88 tumor spheres, but in particular, the killing effect on TS13-30 tumor spheres with high BTK expression was seen to be significantly superior.
또한, 도 4에서 보는 바와 같이, 교모세포종 종양구에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 경우 농도 의존적으로 ATP 수준이 감소하는 것을 확인할 수 있었고, TS13-30, TS13-64 및 TS15-88 종양구 모두에서 ATP 수준의 감소 효과를 보였지만, 특히 BTK 발현이 높은 TS13-30 종양구에 대한 ATP 수준의 억제 효과가 현저히 뛰어난 것을 볼 수 있었다.In addition, as shown in Figure 4, when glioblastoma tumor spheres were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, it was confirmed that the ATP level decreased in a concentration-dependent manner, and TS13- 30, Both TS13-64 and TS15-88 tumors showed a reduction in ATP levels, but the inhibitory effect on ATP levels was particularly outstanding for TS13-30 tumors with high BTK expression.
[실험예 3] BTK 및 세포 증식 관련 마커의 발현 수준의 변화 확인[Experimental Example 3] Confirmation of changes in expression levels of BTK and cell proliferation-related markers
교모세포종 종양구 TS13-30, TS13-64 및 TS15-88에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 각각 10 μM의 농도로 처리한 뒤 세포 용해물(cell lysates)을 10% 트리스-글리세린 겔(Tris-glycine gels)에서 SDS-PAGE를 진행하였다. 전기 영동된 단백질은 니트로셀룰로스 막(nitrocellulose membranes)에 옮겨지고, p-BTK (Cell Signaling Technology); BTK (Cell Signaling Technology); p-mTOR (Cell Signaling Technology); mTOR (Cell Signaling Technology); p-AKT (Cell Signaling Technology); AKT (Cell Signaling Technology); GAPDH (Santa Cruz Biotechnology)의 1차 항체를 처리하였다. 2차 항체를 처리한 후, 웨스턴 라이트닝 플러스-강화된 화학발광 시약(Western Lightning Plus-enhanced chemiluminescence reagent (PerkinElmer, Waltham))과 함께 호스래디시 페록시다제-결합된(horseradish peroxidase-conjugated) IgG (Santa Cruz Biotechnology)를 처리하였다. ImageQuant LAS 4000 mini (GE Healthcare Life Sciences)로 이미지 촬영을 하여 그 결과를 도 5에 나타내었다. 단, 양성 대조군으로는 BTK 억제제인 이브루티닙(Ibrutinib)을 사용하였다.Glioblastoma tumor cells TS13-30, TS13-64, and TS15-88 were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 at a concentration of 10 μM, and then the cell lysates were washed with 10% Tris. -SDS-PAGE was performed on glycerin gels (Tris-glycine gels). Electrophoresed proteins were transferred to nitrocellulose membranes, p-BTK (Cell Signaling Technology); BTK (Cell Signaling Technology); p-mTOR (Cell Signaling Technology); mTOR (Cell Signaling Technology); p-AKT (Cell Signaling Technology); AKT (Cell Signaling Technology); Primary antibody from GAPDH (Santa Cruz Biotechnology) was used. After secondary antibody treatment, horseradish peroxidase-conjugated IgG (Santa) was incubated with Western Lightning Plus-enhanced chemiluminescence reagent (PerkinElmer, Waltham). Cruz Biotechnology). Images were captured with ImageQuant LAS 4000 mini (GE Healthcare Life Sciences), and the results are shown in Figure 5. However, Ibrutinib, a BTK inhibitor, was used as a positive control.
도 5에서 보는 바와 같이, 교모세포종 종양구에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 경우 BTK 수준과 세포 증식에 관련된 마커의 발현 수준이 모두 감소한 것을 확인할 수 있었다. As shown in Figure 5, when glioblastoma tumor cells were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, it was confirmed that both the BTK level and the expression level of markers related to cell proliferation were reduced. there was.
[실험예 4] 줄기세포능의 억제 확인[Experimental Example 4] Confirmation of inhibition of stem cell function
96 웰 플레이트를 사용하여 교모세포종 종양구 TS13-30, TS13-64 및 TS15-88를 10 단일 세포/웰로 접종하였다. 세포를 9.6 X 103개로 계수하여 1 ml로 희석한 뒤 9.6 X 103 세포/ml의 세포 100 μl (9.6 X 102개 세포)와 배지 9.6 ml을 섞어 10 세포/100 μl로 만들어 주었다. 96 웰에 웰당 100 μl씩 넣고 가장자리 웰에 증류수 200 μl씩 넣었다. 오버나이트(overnight) 후 약물을 알맞은 용액에 녹여서 분취(aliquot) 해놓았다. 약물을 농도에 맞게 희석하여 50 μl씩 각 웰에 넣었다. 각 처리 후 세포를 촬영한 사진을 도 6 내지 8에 나타내었다. 또한, 신경구 형성능은 총 웰당 스피어가 형성된 웰의 비율로 측정하여 그 결과를 도 9에 나타내었다. 이때 스피어가 형성된 웰을 양성(positive), 스피어가 형성되지 않은 웰을 음성(negative)으로 측정하였다. 각 처리 후 스피어의 크기 변화는 스피어의 반경으로 측정하여 그 결과는 도 10에 나타내었다. 단, 양성 대조군으로는 BTK 억제제인 이브루티닙(Ibrutinib)을 사용하였다.Glioblastoma tumor spheres TS13-30, TS13-64 and TS15-88 were seeded at 10 single cells/well using a 96 well plate. Cells were counted at 9.6 100 μl per well was added to 96 wells, and 200 μl of distilled water was added to the edge wells. After overnight, the drug was dissolved in an appropriate solution and aliquoted. The drug was diluted to the appropriate concentration and 50 μl was added to each well. Pictures taken of cells after each treatment are shown in Figures 6 to 8. In addition, neurosphere formation ability was measured as the ratio of wells in which spheres were formed per total wells, and the results are shown in Figure 9. At this time, wells in which spheres were formed were measured as positive, and wells in which spheres were not formed were measured as negative. The change in size of the sphere after each treatment was measured by the radius of the sphere, and the results are shown in Figure 10. However, Ibrutinib, a BTK inhibitor, was used as a positive control.
도 6 내지 8에서 보는 바와 같이, 교모세포종 종양구에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 경우 세포의 크기가 현저히 감소하는 것을 볼 수 있었다. As shown in Figures 6 to 8, when glioblastoma tumor spheres were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, the size of the cells was seen to be significantly reduced.
또한, 도 9 및 10에서 보는 바와 같이 각 교모세포종 종양구에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 결과 스피어의 형성능이 감소하고, 스피어의 크기가 현저히 감소한 것을 확인할 수 있었다. In addition, as shown in Figures 9 and 10, as a result of treating each glioblastoma tumor sphere with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, the ability to form spheres was reduced, and the size of the spheres was significantly reduced. could be confirmed.
[실험예 5] 줄기세포능 관련 마커의 발현 수준의 변화 확인[Experimental Example 5] Confirmation of changes in expression levels of stem cell function-related markers
교모세포종 종양구 TS13-30, TS13-64 및 TS15-88에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 각각 10 μM의 농도로 처리한 뒤 세포 용해물(cell lysates)을 10% 트리스-글리세린 겔(Tris-glycine gels)에서 SDS-PAGE를 진행하였다. 전기 영동된 단백질은 니트로셀룰로스 막(nitrocellulose membranes)에 옮겨지고, CD133 (Cell Signaling Technology); Sox2 (Abcam); PDPN (Santa Cruz Biotechnology); Oct3/4 (Santa Cruz Biotechnology); Nestin (Abcam); GAPDH (Santa Cruz Biotechnology)의 1차 항체를 처리하였다. 2차 항체를 처리한 후 웨스턴 라이트닝 플러스-강화된 화학발광 시약(Western Lightning Plus-enhanced chemiluminescence reagent (PerkinElmer, Waltham))과 함께 호스래디시 페록시다제-결합된(horseradish peroxidase-conjugated) IgG (Santa Cruz Biotechnology)를 처리하였다. ImageQuant LAS 4000 mini (GE Healthcare Life Sciences)로 이미지 촬영을 하여 그 결과를 도 11에 나타내었다. 단, 양성 대조군으로는 BTK 억제제인 이브루티닙(Ibrutinib)을 사용하였다.Glioblastoma tumor cells TS13-30, TS13-64, and TS15-88 were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 at a concentration of 10 μM, and then the cell lysates were washed with 10% Tris. -SDS-PAGE was performed on glycerin gels (Tris-glycine gels). Electrophoresed proteins were transferred to nitrocellulose membranes, CD133 (Cell Signaling Technology); Sox2 (Abcam); PDPN (Santa Cruz Biotechnology); Oct3/4 (Santa Cruz Biotechnology); Nestin (Abcam); Primary antibody from GAPDH (Santa Cruz Biotechnology) was used. After secondary antibody treatment, horseradish peroxidase-conjugated IgG (Santa Cruz) was incubated with Western Lightning Plus-enhanced chemiluminescence reagent (PerkinElmer, Waltham). Biotechnology) was processed. Images were captured with ImageQuant LAS 4000 mini (GE Healthcare Life Sciences), and the results are shown in Figure 11. However, Ibrutinib, a BTK inhibitor, was used as a positive control.
도 11에서 보는 바와 같이, 교모세포종 종양구에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 경우 줄기세포능과 관련된 마커의 발현 수준이 모두 감소한 것을 확인할 수 있었다. As shown in Figure 11, when glioblastoma tumor spheres were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, it was confirmed that the expression levels of markers related to stem cell function were all reduced.
[실험예 6] 침윤성의 변화 확인[Experimental Example 6] Confirmation of change in invasiveness
96 웰 플레이트에 마트리겔, 콜라겐 I형(Corning Incorporated), 및 TS 완전 배지를 채우고 각 웰에 교모세포종 종양구 TS13-30, TS13-64 또는 TS15-88의 한 개의 세포를 접종하였다. 매트릭스가 적당히 굳으면 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 10 μM의 농도가 되도록 용해시킨 TS 완전 배지를 첨가하여 72 시간 동안 관찰한 뒤 상기 화합물 첨가 전과 비교하여 침윤 면적의 변화를 측정해 그 결과를 도 12 및 13에 나타내었다. 단, 양성 대조군으로는 BTK 억제제인 이브루티닙(Ibrutinib)을 사용하였다.A 96-well plate was filled with Matrigel, collagen type I (Corning Incorporated), and TS complete medium, and one cell of glioblastoma tumor cell TS13-30, TS13-64, or TS15-88 was inoculated into each well. When the matrix is sufficiently hardened, TS complete medium in which the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 are dissolved to a concentration of 10 μM is added, observed for 72 hours, and the change in infiltration area is compared to before adding the compound. The measurements were made and the results are shown in Figures 12 and 13. However, Ibrutinib, a BTK inhibitor, was used as a positive control.
도 12 및 13에서 보는 바와 같이, 교모세포종 종양구에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 경우 상기 종양구의 침윤성이 현저히 감소한 것을 확인할 수 있었다. As shown in Figures 12 and 13, when glioblastoma tumor spheres were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, it was confirmed that the invasiveness of the tumor spheres was significantly reduced.
[실험예 7] 침윤성 관련 마커의 발현 수준의 변화 확인[Experimental Example 7] Confirmation of changes in expression levels of invasiveness-related markers
교모세포종 종양구 TS13-30, TS13-64 및 TS15-88에 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 각각 10 μM의 농도로 처리한 뒤 세포 용해물(cell lysates)을 10% 트리스-글리세린 겔(Tris-glycine gels)에서 SDS-PAGE를 진행하였다. 전기 영동된 단백질은 니트로셀룰로스 막(nitrocellulose membranes)에 옮겨지고, β-catenin (BD Biosciences); N-cadherin (R&D Systems); Zeb1 (Sigma-Aldrich); CD44 (Cell Signaling Technology); GAPDH (Santa Cruz Biotechnology)의 1차 항체를 처리하였다. 2차 항체를 처리한 후 웨스턴 라이트닝 플러스-강화된 화학발광 시약(Western Lightning Plus-enhanced chemiluminescence reagent (PerkinElmer, Waltham))과 함께 호스래디시 페록시다제-결합된(horseradish peroxidase-conjugated) IgG (Santa Cruz Biotechnology)를 처리하였다. ImageQuant LAS 4000 mini (GE Healthcare Life Sciences)로 이미지 촬영을 하여 그 결과를 도 14에 나타내었다. 단, 양성 대조군으로는 BTK 억제제인 이브루티닙(Ibrutinib)을 사용하였다.Glioblastoma tumor cells TS13-30, TS13-64, and TS15-88 were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 at a concentration of 10 μM, and then the cell lysates were washed with 10% Tris. -SDS-PAGE was performed on glycerin gels (Tris-glycine gels). Electrophoresed proteins were transferred to nitrocellulose membranes, and β-catenin (BD Biosciences); N-cadherin (R&D Systems); Zeb1 (Sigma-Aldrich); CD44 (Cell Signaling Technology); Primary antibody from GAPDH (Santa Cruz Biotechnology) was used. After secondary antibody treatment, horseradish peroxidase-conjugated IgG (Santa Cruz) was incubated with Western Lightning Plus-enhanced chemiluminescence reagent (PerkinElmer, Waltham). Biotechnology) was processed. Images were captured with ImageQuant LAS 4000 mini (GE Healthcare Life Sciences), and the results are shown in Figure 14. However, Ibrutinib, a BTK inhibitor, was used as a positive control.
도 14에서 보는 바와 같이, 교모세포종 종양구에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 경우 침윤성과 관련된 마커의 발현 수준이 모두 감소한 것을 확인할 수 있었다. As shown in Figure 14, when glioblastoma tumor spheres were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, it was confirmed that the expression levels of markers related to invasiveness were all reduced.
[실험예 8] 인-비보에서의 종양 억제 효과 확인[Experimental Example 8] Confirmation of tumor suppression effect in vivo
수컷의 무흉선 누드 마우스(6주령; Central Lab. Animal Inc.)를 사용하여 실험하며 실험 전 1주간 빛, 온도, 습도가 조절되고 멸균된 상태에서 순화 기간을 가졌다. 교모세포종 종양구 TS13-30 (마우스 당 5X105 세포)를 마우스의 우측 전두엽에 가이드-스크류 시스템을 사용하여 4.5 mm 깊이에 이식하였다. 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 50mg/kg의 용량으로 IP(intraperitoneal) 투여하며 동물 체중의 최대치에서 15% 이상 감소하게 되면 안락사를 진행하였다. 각 처리에 따른 마우스의 종양의 크기 변화를 확인하여 그 결과를 도 15에 나타내었고, 각 처리에 따른 마우스의 생존 기간을 비교하여 그 결과를 도 16에 나타내었다. 단, 양성 대조군으로는 BTK 억제제인 이브루티닙(Ibrutinib)을 사용하였다.Male athymic nude mice (6 weeks old; Central Lab. Animal Inc.) were used for the experiment, and light, temperature, and humidity were controlled for one week before the experiment, and an acclimatization period was conducted under sterilized conditions. Glioblastoma tumor spheres TS13-30 ( 5 The SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 were administered intraperitoneally (IP) at a dose of 50 mg/kg, and when the animal's body weight decreased by more than 15% from the maximum, euthanasia was performed. Changes in tumor size in mice according to each treatment were confirmed and the results are shown in Figure 15. Survival periods of mice according to each treatment were compared and the results are shown in Figure 16. However, Ibrutinib, a BTK inhibitor, was used as a positive control.
도 16에서 보는 바와 같이, 교모세포종 정위이식 마우스에 본 발명에 따르는 제조예 1의 SPA8007 화합물과 제조예 2의 SPA8009 화합물을 처리한 경우 마우스의 생존 기간이 현저히 증가하여 치료 효과가 있음을 알 수 있었고, 특히 제조예 2의 SPA8009 화합물을 처리한 경우 인-비보에서 치료 효과가 매우 뛰어남을 알 수 있었다.As shown in Figure 16, when glioblastoma orthotopic transplantation mice were treated with the SPA8007 compound of Preparation Example 1 and the SPA8009 compound of Preparation Example 2 according to the present invention, the survival period of the mouse was significantly increased, indicating a therapeutic effect. , In particular, when treated with the SPA8009 compound of Preparation Example 2, it was found that the treatment effect was very excellent in vivo.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (13)
[화학식 1]
상기 화학식 1에서,
R1 및 R2는 각각 독립적으로 수소, C1-6알킬 또는 C3-6사이클로알킬이고;
R3는 수소, C1-6알킬 또는 C1-6알케닐이며;
L1은 직접결합 또는 C1-6알킬렌이고;
m은 0 내지 2의 정수이며;
n 및 p는 각각 독립적으로 0 내지 3의 정수이고;
o는 0 내지 4의 정수이며;
q는 0 내지 5의 정수이고;
Ra, Rb, Rc 및 Rd 및 Re는 각각 독립적으로 할로겐, C1-6알킬, C3-6사이클로알킬기 및 C1-6알콕시로 이루어진 군에서 선택되며;
상기 R1 및 R2의 알킬 및 사이클로알킬과, R3의 알킬 및 알케닐과, L1의 알킬렌과, Ra, Rb, Rc 및 Rd 및 Re의 알킬, 사이클로알킬 및 알콕시는 각각 독립적으로 할로겐, C1-6알킬, C3-6사이클로알킬기 및 C6-14아릴로 이루어진 군에서 선택되는 1종 이상의 치환기에 의해 치환되거나 비치환될 수 있다.A pharmaceutical composition for the prevention or treatment of brain cancer comprising as an active ingredient a compound selected from the following formula (1), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
[Formula 1]
In Formula 1,
R 1 and R 2 are each independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 3 is hydrogen, C 1-6 alkyl or C 1-6 alkenyl;
L 1 is a direct bond or C 1-6 alkylene;
m is an integer from 0 to 2;
n and p are each independently integers from 0 to 3;
o is an integer from 0 to 4;
q is an integer from 0 to 5;
Ra, Rb, Rc, Rd and Re are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 3-6 cycloalkyl group and C 1-6 alkoxy;
The alkyl and cycloalkyl of R 1 and R 2 , the alkyl and alkenyl of R 3 , the alkylene of L 1 , and the alkyl, cycloalkyl and alkoxy of Ra, Rb, Rc and Rd and Re are each independently halogen. , C 1-6 alkyl, C 3-6 cycloalkyl, and C 6-14 aryl.
상기 R1 및 R2는 각각 독립적으로 수소 또는 C1-6알킬인, 약학적 조성물. According to paragraph 1,
The pharmaceutical composition wherein R 1 and R 2 are each independently hydrogen or C 1-6 alkyl.
상기 R3는 C1-6알케닐인, 약학적 조성물. According to paragraph 1,
The pharmaceutical composition wherein R 3 is C 1-6 alkenyl.
상기 L1은 C1-6알킬렌인, 약학적 조성물. According to paragraph 1,
The pharmaceutical composition wherein L 1 is C 1-6 alkylene.
상기 Re는 C1-6알킬 또는 C1-6알콕시인, 약학적 조성물. According to paragraph 1,
The pharmaceutical composition wherein Re is C 1-6 alkyl or C 1-6 alkoxy.
상기 화합물은 하기 화학식 2로 표시되는 화합물인, 약학적 조성물:
[화학식 2]
상기 화학식 2에서,
R1, R2, R3, L1, m, n, o, p, q, Ra, Rb, Rc, Rd 및 Re 각각의 정의는 제1항에서 정의된 바와 같다. According to paragraph 1,
A pharmaceutical composition, wherein the compound is a compound represented by the following formula (2):
[Formula 2]
In Formula 2,
The definitions of R 1 , R 2 , R 3 , L 1 , m, n, o, p, q, Ra, Rb, Rc, Rd and Re are as defined in paragraph 1.
상기 화합물은 하기 화학식 3으로 표시되는 화합물인, 약학적 조성물:
[화학식 3]
상기 화학식 3에서,
R1, R2, L1, m, n, o, p, q, Ra, Rb, Rc, Rd 및 Re 각각의 정의는 제1항에서 정의된 바와 같다. According to paragraph 1,
A pharmaceutical composition, wherein the compound is a compound represented by the following formula (3):
[Formula 3]
In Formula 3 above,
The definitions of R 1 , R 2 , L 1 , m, n, o, p, q, Ra, Rb, Rc, Rd and Re are as defined in paragraph 1.
상기 화합물은 하기 화학식 4로 표시되는 화합물인, 약학적 조성물:
[화학식 4]
상기 화학식 4에서,
R1, R2, L1, q 및 Re 각각의 정의는 제1항에서 정의된 바와 같다. According to paragraph 1,
A pharmaceutical composition, wherein the compound is a compound represented by the following formula (4):
[Formula 4]
In Formula 4 above,
The definitions of R 1 , R 2 , L 1 , q and Re respectively are as defined in paragraph 1.
상기 화합물은 하기 화학식 5 또는 6으로 표시되는 화합물인, 약학적 조성물:
[화학식 5]
[화학식 6]
According to paragraph 1,
A pharmaceutical composition wherein the compound is a compound represented by the following formula (5) or (6):
[Formula 5]
[Formula 6]
[화학식 1]
상기 화학식 1에서,
R1 및 R2는 각각 독립적으로 수소, C1-6알킬 또는 C3-6사이클로알킬이고;
R3는 수소, C1-6알킬 또는 C1-6알케닐이며;
L1은 직접결합 또는 C1-6알킬렌이고;
m은 0 내지 2의 정수이며;
n 및 p는 각각 독립적으로 0 내지 3의 정수이고;
o는 0 내지 4의 정수이며;
q는 0 내지 5의 정수이고;
Ra, Rb, Rc 및 Rd 및 Re는 각각 독립적으로 할로겐, C1-6알킬, C3-6사이클로알킬기 및 C1-6알콕시로 이루어진 군에서 선택되며;
상기 R1 및 R2의 알킬 및 사이클로알킬과, R3의 알킬 및 알케닐과, L1의 알킬렌과, Ra, Rb, Rc 및 Rd 및 Re의 알킬, 사이클로알킬 및 알콕시는 각각 독립적으로 할로겐, C1-6알킬, C3-6사이클로알킬기 및 C6-14아릴로 이루어진 군에서 선택되는 1종 이상의 치환기에 의해 치환되거나 비치환될 수 있다.A pharmaceutical composition for inhibiting the invasiveness or metastasis of brain cancer, comprising as an active ingredient a compound selected from the group consisting of a compound represented by the following formula (1), a pharmaceutically acceptable salt, optical isomer, hydrate and solvate thereof:
[Formula 1]
In Formula 1,
R 1 and R 2 are each independently hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 3 is hydrogen, C 1-6 alkyl or C 1-6 alkenyl;
L 1 is a direct bond or C 1-6 alkylene;
m is an integer from 0 to 2;
n and p are each independently integers from 0 to 3;
o is an integer from 0 to 4;
q is an integer from 0 to 5;
Ra, Rb, Rc, Rd and Re are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 3-6 cycloalkyl group and C 1-6 alkoxy;
The alkyl and cycloalkyl of R 1 and R 2 , the alkyl and alkenyl of R 3 , the alkylene of L 1 , and the alkyl, cycloalkyl and alkoxy of Ra, Rb, Rc and Rd and Re are each independently halogen. , C 1-6 alkyl, C 3-6 cycloalkyl, and C 6-14 aryl.
상기 화합물은 하기 화학식 5 또는 6으로 표시되는 화합물인, 약학적 조성물:
[화학식 5]
[화학식 6]
According to clause 11,
A pharmaceutical composition wherein the compound is a compound represented by the following formula (5) or (6):
[Formula 5]
[Formula 6]
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Caldwell, R. D. 등, Journal of Medicinal Chemistry, 2019, 제62권, 페이지 7643-7655 |
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