KR20210016103A - Novel compound for inducing degradation of alk protein and pharmaceutical composition for using in preventing or treating cancer containing the same as an active ingredient - Google Patents
Novel compound for inducing degradation of alk protein and pharmaceutical composition for using in preventing or treating cancer containing the same as an active ingredient Download PDFInfo
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Abstract
Description
본 발명은 역형성 림프종 키나아제(Anaplastic lymphoma kinase, ALK) 단백질의 분해를 유도하는 신규 화합물 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물에 관한 것이다. The present invention relates to a novel compound that induces the degradation of an anaplastic lymphoma kinase (ALK) protein, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.
단백질 분해 유도제 (Proteolysis Targeting Chimera, PROTAC) 기술은 약물로 표적 할 수 없는 대부분의 단백질 (undruggable protein)을 표적 할 수 있다. 또한, 상기 단백질 분해 유도제 기술은 질병의 원인이 되는 단백질을 분해하기 때문에 약물에 대한 내성 발생이 낮으며, 소량만으로 원인이 되는 단백질을 분해할 수 있으므로 기존 저분자화합물이 갖는 부작용을 해결할 수 있다. 또한, 상기 단백질 분해 유도제 기술은 새로운 신약개발 플랫폼 기술로서 주목 받고 있으며, E3 ligase 결합 모듈-연결체-표적 단백질 결합 모듈로 구성되며, 질병 유발 표적단백질의 유비퀴틴화 (ubiquitination)를 통해 생체 내 분해를 유도하는 기술이다. Proteolysis Targeting Chimera (PROTAC) technology can target most undruggable proteins that cannot be targeted by drugs. In addition, the protein degradation inducing agent technology has low resistance to drugs because it degrades the protein that causes disease, and can degrade the causative protein with only a small amount, thereby solving the side effects of existing low molecular weight compounds. In addition, the protein degradation inducing agent technology is attracting attention as a new drug development platform technology, and is composed of an E3 ligase binding module-connector-target protein binding module, and decomposes in vivo through ubiquitination of a disease-causing target protein. It is an inducing technique.
상기 단백질 분해 유도제 기술의 핵심은 세포내 존재하는 E3 ligase에 결합하는 리간드 확보 및 신규표적을 대상으로 이를 검증하는 것이다. 이러한 단백질 분해 유도제 (Proteolysis Targeting Chimera, PROTAC) 기술의 예로 하버드대학의 연구팀 (Bradner)은 CRBN E3 유비퀴틴 리가아제에 결합하는 리간드로 탈리도마이드를 사용하고 BRD4 저해제인 JQ1 화합물을 사용하여 백혈병 치료에 효과가 있는 물질 개발에 성공하였다. 또한 미국의 다국적 제약사를 중심으로 여러 바이오텍 (Arvinas, C4 therapeutics, KYMERA) 및 글로벌 제약사 간의 활발한 공동연구가 진행 중으로, Arvinas사는 전립선암 치료제로 AR degrader (ARV-110)를 개발하여 2019년 하반기에 임상시험을 실시예정으로 FDA로부터 임상 승인 허가를 받았다.The core of the technology of the proteolysis inducing agent is to secure a ligand that binds to E3 ligase present in cells and to verify it for new targets. As an example of such proteolysis inducer (Proteolysis Targeting Chimera, PROTAC) technology, a research team at Harvard University (Bradner) uses thalidomide as a ligand that binds to CRBN E3 ubiquitin ligase, and JQ1, a BRD4 inhibitor, is effective in treating leukemia. Succeeded in material development. In addition, active joint research between several biotechs (Arvinas, C4 therapeutics, KYMERA) and global pharmaceutical companies is underway, centering on multinational pharmaceutical companies in the United States, and Arvinas developed AR degrader (ARV-110) as a prostate cancer treatment and clinically conducted in the second half of 2019. The trial was scheduled and received approval for clinical approval from the FDA.
단백질 분해 유도제는 질병의 원인이 되는 단백질을 분해하기 때문에 약물에 대한 내성 발생이 낮고, 표적 단백질에 결합만 가능하다면 충분히 표적 단백질 분해가 가능하기 때문에 높은 활성이 필요하지 않은 특성을 가지고 있다. 또한, 상기 단백질 분해 유도제는 단잭질 분해가 이루어지고 난 후 다시 원래의 결합 가능한 형태로 돌아오기 때문에 catalytic 양으로 충분히 약물의 효과를 기대 할 수 있어 이는 기존 항암제 개발의 주류를 이루었던 항암 표적 치료제가 갖는 약물에 대한 내성이 빠르게 나타나, 투여 후 1년 이내에 약물 내성이 발생하여 약물의 효과를 낮추며, 치료효과를 보이기 위해서는 많은 양을 오랜 기간 투여해야 하는 단점을 극복할 수 있는 새로운 기술로 부각되어 지고 있다.Proteolysis inducers degrade the protein that causes disease, so the incidence of resistance to drugs is low, and if only binding to the target protein is possible, the target protein can be sufficiently degraded, so it has a property that does not require high activity. In addition, the proteolysis inducing agent returns to its original binding form after protein degradation is performed, so the effect of the drug can be expected with a catalytic amount, which is the mainstream anticancer drug development. Resistance to the drug is rapidly manifested, and drug resistance occurs within 1 year after administration, lowering the effect of the drug, and emerging as a new technology that can overcome the shortcomings of administering a large amount for a long period of time to show therapeutic effect. have.
약물 내성의 가장 큰 문제점으로 부각되고 있는 역형성 림프종 키나아제 (ALK, Anaplastic lymphoma kinase)는 인체의 여러 암 세포 종양에서 발견되어 오랜 기간동안 표적 항암제 개발의 주요 목표물로 연구되고 있는데, 역형성 림프종 키나아제 (ALK)가 활성화되면 티로신 키나아제는 비정상적으로 행동하게 되고, 이로부터 암이 유발된다. Anaplastic lymphoma kinase (ALK), which is emerging as the biggest problem in drug resistance, has been found in various cancer cell tumors in the human body and has been studied as a major target for the development of targeted anticancer drugs for a long time. When ALK) is activated, tyrosine kinase behaves abnormally, resulting in cancer.
화이자(Pfizer)제약에서 암세포 종양원성 변이에 대한 선택적 억제제로 개발한 약물로, 소분자 티로신 인산화효소 억제제의 하나인 크리조티닙 (crizotinib, 화학식 I)이 역형성 림프종 키나아제(ALK) 저해제로써, 비소세포폐암의 치료에 효과가 있는 것으로 알려져 있으며, 2011년 FDA에서 신약으로 허가를 받았다. 또한 노바티스 (Novartis)사의 세리티비 (ceritinib, 화학식 II) 화합물이 승인되었고, 다수의 역형성 림프종 키나아제 (ALK) 저해제들의 임상 실험이 진행중이다. 하지만, 크리조티닙은 투여 1년 이내에 약물 내성이 발생하며, 다양한 변이를 갖는 것으로 나타났으며, 써리티닙의 경우 일부 내성 단백질의활성은 억제되지만, G1202R을 비롯한 몇몇 변이 단백질의활성 저해는 약한 것으로 알려져 있다. 또한 주가이 (Chugai Pharmaceutical CO.LTD)제약에서 개발한 ALK저해제인 알렉티닙 (Alectinib, 화학식 III) 의 경우 내성 단백질에 대한 효과가 우수하나 이 약물 역시 약물 내성이 발생하여 새로운 역형성 림프종 키나아제 치료제에 대한 꾸준한 요구가 있다: A drug developed by Pfizer Pharmaceuticals as a selective inhibitor for tumorigenic mutations in cancer cells, and crizotinib (formula I), one of the small molecule tyrosine kinase inhibitors, is an anaplastic lymphoma kinase (ALK) inhibitor. It is known to be effective in treating lung cancer, and it was approved as a new drug by the FDA in 2011. In addition, a compound of ceritinib (formula II) from Novartis has been approved, and clinical trials of a number of anaplastic lymphoma kinase (ALK) inhibitors are ongoing. However, crizotinib develops drug resistance within 1 year of administration and has been shown to have various mutations.In the case of Critinib, the activity of some resistant proteins is inhibited, but the inhibition of the activity of some mutant proteins including G1202R is weak. It is known. In addition, Alectinib (Formula III), an ALK inhibitor developed by Chugai Pharmaceutical CO.LTD, has an excellent effect on resistant proteins, but this drug also develops drug resistance and is therefore a new drug for anaplastic lymphoma kinase treatment. There is a steady demand:
<화학식 I><Formula I>
<화학식 II><Formula II>
<화학식 III><Formula III>
공개 특허 WO2017204445A2 에서는 ALK 저해제인 세리티닙(Certitinib) 과 기존에 단백질 분해 유도제 개발에 주로 쓰이고 있는 VHL 리간드 또는 CRBN 리간드 (탈리도마이드)를 링커를 통해 연결하여 신규 역형성 림프종 키나아제 (ALK)을 치료할 수 있는 PROTAC 물질을 개발하여 발표하였다 (화학식 IV)In the published patent WO2017204445A2, a new anaplastic lymphoma kinase (ALK) can be treated by linking the ALK inhibitor Certitinib and the VHL ligand or CRBN ligand (thalidomide), which are mainly used in the development of proteolysis inducing agents, through a linker. PROTAC material was developed and published (Formula IV)
<화학식 IV><Formula IV>
그러나 상기 기술한 특허에서 아릴알킬술폰 (aryl alkyl sulfone)으로 표시되는 -S(O)2-그룹은 대사 (metabolism)의 영향을 상대적으로 많이 받으며, 물에 대한 용해도가 상대적으로 낮아지는 경향을 보여 침착이나 엉김의 요소를 내포하고 있다. 이는 단백질 분해 유도체가 가지는 장점인 타깃 단백질의 분해 후 원래의 결합 가능한 형태로 돌아와 Catalytic cycle로 진행하는데 방해의 요소로 작용될 수 있다.However, in the above-described patent, the -S(O) 2 -group represented by aryl alkyl sulfone is relatively affected by metabolism, and solubility in water tends to be relatively low. It contains elements of calm or entanglement. This is an advantage of proteolytic derivatives, which can act as a factor in preventing the target protein from being decomposed and returned to its original form and proceeding to the catalytic cycle.
설폭시민(Sulfoximine,
따라서, 이와 같은 설폭시민을 이용한 역형성 림프종 키나아제(Anaplastic lymphoma kinase, ALK) 단백질의 분해 물질 개발 기술에 대한 관심이 커지고 있다.Accordingly, there is a growing interest in the development of a decomposition substance for anaplastic lymphoma kinase (ALK) protein using sulfoximine.
본 발명자들은 상기 문제점을 해결하기 위해 다각적으로 연구를 수행한 결과, 설폭시민기를 이용하여 역형성 림프종 키나아제(Anaplastic lymphoma kinase, ALK) 단백질의 분해를 유도하는 신규 화합물을 개발하였다.As a result of conducting various studies to solve the above problems, the present inventors have developed a novel compound that induces the degradation of anaplastic lymphoma kinase (ALK) protein using a sulfoximine group.
따라서, 본 발명의 목적은 역형성 림프종 키나아제 단백질의 분해를 유도하는 신규 화합물 및 이의 제조방법을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel compound that induces the degradation of an anaplastic lymphoma kinase protein and a method for preparing the same.
또한, 본 발명의 다른 목적은 상기 화합물을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK) 관련 질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다.In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating anaplastic lymphoma kinase (ALK) related diseases containing the compound as an active ingredient.
또한, 본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물을 제공하는 것이다.In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.
상기 목적을 달성하기 위해, 본 발명은 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용 가능한 염을 제공한다:In order to achieve the above object, the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
Linker는 -(CH2)-, -(C=O)-, -NH- 및 -O-로 이루어진 군으로부터 선택되는 1종 이상이 3 내지 10개 연결된 연결기이며,Linker is a linking group having 3 to 10 connected at least one selected from the group consisting of -(CH 2 )-, -(C=O)-, -NH- and -O-,
상기 연결기는 연속하여 -O-로 연결될 수 없고; 및 The linker cannot be connected in succession to -O-; And
Ligand는 
본 발명은 또한, (S1) Ligand-H로 표시되는 화합물과 Linker-X로 표시되는 화합물을 반응시켜 Ligand-Linker-Y로 표시되는 화합물을 제조하는 단계; 및The present invention also includes the steps of (S1) reacting a compound represented by Ligand-H with a compound represented by Linker-X to prepare a compound represented by Ligand-Linker-Y; And
(S2) 상기 Ligand-Linker-Y로 표시되는 화합물과 하기 화학식 2로 표시되는 화합물을 반응시키는 단계;(S2) reacting the compound represented by Ligand-Linker-Y with the compound represented by Formula 2 below;
를 포함하는, 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다;It provides a method for preparing the compound represented by Formula 1, including;
[화학식 2][Formula 2]
본 발명은 또한, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK) 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating anaplastic lymphoma kinase (ALK)-related diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 또한, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 또한, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK) 관련 질환의 예방 또는 개선용 건강기능식품을 제공한다.The present invention also provides a health functional food for preventing or improving anaplastic lymphoma kinase (ALK)-related diseases containing the compound represented by Formula 1, its optical isomer, or its pharmaceutically acceptable salt as an active ingredient. .
본 발명에 따른 화학식 1로 표시되는 화합물은 역형성 림프종 키나아제(ALK)를 억제하거나 분해시킬 수 있어, 역형성 림프종 키나아제(ALK) 관련 질환, 예를 들어, 암의 예방 또는 치료에 유용한 효과가 있다.The compound represented by Formula 1 according to the present invention can inhibit or degrade anaplastic lymphoma kinase (ALK), and thus has a useful effect in the prevention or treatment of anaplastic lymphoma kinase (ALK) related diseases such as cancer. .
도 1은 H3122가 이종이식된 SCID 마우스에 본 발명의 실시예 3 화합물을 투여한 뒤, 종양 부피의 변화를 나타낸 그래프이다. 1 is a graph showing changes in tumor volume after administration of the compound of Example 3 of the present invention to SCID mice xenografted with H3122.
이하, 본 발명에 대한 이해를 돕기 위하여 본 발명을 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail to aid understanding of the present invention.
본 명세서 및 청구범위에서 사용된 용어나 단어는 통상적이거나 사전적인 의미로 한정해서 해석되어서는 아니 되며, 발명자는 그 자신의 발명을 가장 최선의 방법으로 설명하기 위해 용어의 개념을 적절하게 정의할 수 있다는 원칙에 입각하여 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야만 한다.The terms or words used in the specification and claims should not be construed as being limited to their usual or dictionary meanings, and the inventor may appropriately define the concept of terms in order to describe his own invention in the best way. It should be interpreted as a meaning and concept consistent with the technical idea of the present invention based on the principle that there is.
신규 화합물New compound
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용 가능한 염에 관한 것이다;The present invention relates to a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof;
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
Linker는 -(CH2)-, -(C=O)-, -NH- 및 -O-로 이루어진 군으로부터 선택되는 1종 이상이 3 내지 10개 연결된 연결기이며,Linker is a linking group having 3 to 10 connected at least one selected from the group consisting of -(CH 2 )-, -(C=O)-, -NH- and -O-,
상기 연결기는 연속하여 -O-로 연결될 수 없고; 및 The linker cannot be connected in succession to -O-; And
Ligand는 
또한, 상기 화학식 1에서 상기 Linker는 
또한, 상기 화학식 1로 표시되는 화합물은 하기 화합물로 이루어진 군으로부터 선택되는 어느 하나인 것일 수 있다:In addition, the compound represented by Formula 1 may be any one selected from the group consisting of the following compounds:
(1) 5-(4-(4-(5-클로로-4-((프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(4-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)부틸)-5-옥소펜탄아미드)5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-5-oxopentanamide);(1) 5-(4-(4-(5-chloro-4-((pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-ylamino)-5-isopropoxy- 2-methylphenyl)piperidin-1-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino) Butyl)-5-oxopentanamide)5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5 -isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)- 5-oxopentanamide);
(2) 5-(4-(4-((5-클로로-4-((프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(4-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)옥시)부틸)-5-옥소펜탄아미드(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)-5-oxopentanamide);(2) 5-(4-(4-((5-chloro-4-((pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopro Foxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- Yl)oxy)butyl)-5-oxopentanamide (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl) amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy )butyl)-5-oxopentanamide);
(3) 4-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(2-(2,6-이옥소피레피딘-3-일)-1,3-디옥소이소인돌린-4-일)부탄아미드(4-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide);(3) 4-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5 -Isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-ioxopyrepidine-3-yl)-1,3-dioxoisoindolin-4-yl )Butanamide (4-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide);
(4) 5-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(2-(2,6-이옥소피레피딘-3-일)-1,3-디옥소이소인돌린-4-일)-5-옥소펜탄아미드(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-5-oxopentanamide);(4) 5-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5 -Isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-ioxopyrepidine-3-yl)-1,3-dioxoisoindolin-4-yl )-5-oxopentanamide (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5- isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-5-oxopentanamide);
(5) 2-(2-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-2-옥소에톡시)-N-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아세타미드 (2-(2-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide);(5) 2-(2-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino )-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-4-yl)acetamide (2-(2-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin)) -2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin -4-yl)acetamide);
(6) (2R,4R)-1-((R)-2-(5-(4-(4-((5-클로로-4-((2-( 프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)펜탄아미도)-3,3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복사미드 ((2S,4R)-1-(2-(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamid); 및 (6) (2R,4R)-1-((R)-2-(5-(4-(4-((5-chloro-4-((2-( pro-2-yl-sulfonimidoyl )Phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hyd Roxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-(2-(5-(4-(4- ((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)pentanamido)-3 ,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamid); And
(7) (2S,4R)-1-((R)-2-(7-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-7-옥소헵탄아미도)-3,3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복스아미드.(7) (2S,4R)-1-((R)-2-(7-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl )Phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl) -4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.
신규 화합물의 제조방법Method for preparing a new compound
본 발명은 또한, 상기 화학식 1로 표시되는 화합물의 제조방법에 관한 것으로, (S1) Ligand-H로 표시되는 화합물과 Linker-X로 표시되는 화합물을 반응시켜 Ligand-Linker-Y로 표시되는 화합물을 제조하는 단계 (단계 1); 및 (S2) 상기 Ligand-Linker-Y로 표시되는 화합물과 하기 화학식 2로 표시되는 화합물을 반응시키는 단계 (단계 2);를 포함할 수 있으며, 상기 Ligand와 Linker는 상기 화학식 1에서 정의된 바와 같고; 및 X가 -CO2-tBu 인 경우 Y는 -CO2H이고, X가 Cl 또는 Br인 경우 Y는 I이다 (여기서, tBu는 tertiary-butyl이다):The present invention also relates to a method for preparing a compound represented by Formula 1, wherein (S1) a compound represented by Ligand-Linker-Y by reacting a compound represented by Ligand-H with a compound represented by Linker-X Manufacturing step (step 1); And (S2) reacting the compound represented by the Ligand-Linker-Y with the compound represented by the following Formula 2 (Step 2); wherein the Ligand and the Linker are as defined in Formula 1, ; And when X is -CO 2 -tBu, Y is -CO 2 H, and when X is Cl or Br, Y is I (where tBu is tertiary-butyl):
[화학식 2][Formula 2]
이하, 하기 반응식 1을 참조하여 상기 화학식 1로 표시되는 화합물의 제조방법을 보다 상세히 설명한다.Hereinafter, a method of preparing the compound represented by Formula 1 will be described in more detail with reference to Reaction Scheme 1 below.
[반응식 1][Scheme 1]
상기 반응식 1을 참조하면, 단계 1에서는 Ligand-H로 표시되는 화합물과 Linker-X로 표시되는 화합물을 반응시킬 수 있으며, 상기 반응에 의해, Ligand-Linker-Y로 표시되는 화합물을 제조할 수 있다. 일 예로, 상기 단계 1의 반응은 상기 Linker-X에 포함된 활성화기 (예를 들면 Carboxylic acid)와 Ligand-H (예를 들면 Amine기)를 서로 축합 반응 또는 SN2(Bimolecular Nucleophilic Substitution) 반응 등으로 연결하여 Ligand-Linker-Y를 제조하는 것을 의미한다.Referring to Scheme 1, in step 1, a compound represented by Ligand-H and a compound represented by Linker-X may be reacted, and a compound represented by Ligand-Linker-Y may be prepared by the above reaction. . For example, the reaction of Step 1 is a condensation reaction or SN2 (Bimolecular Nucleophilic Substitution) reaction of an activator (e.g., Carboxylic acid) and Ligand-H (e.g., Amine group) contained in the Linker-X. It means to connect and manufacture Ligand-Linker-Y.
또한, 상기 반응식 1의 단계 2에서는, 상기 Ligand-Linker-X로 표시되는 화합물의 링커의 길이를 늘려서, Ligand-Linker-Y로 표시되는 화합물로 제조할 수 있다.In addition, in step 2 of Scheme 1, the length of the linker of the compound represented by Ligand-Linker-X may be increased, thereby preparing a compound represented by Ligand-Linker-Y.
또한, 상기 반응식 1의 단계 2에서는 상기 Ligand-Linker-Y로 표시되는 화합물과 상기 화학식 2로 표시되는 화합물을 반응시켜, 화학식 1로 표시되는 화합물을 제조할 수 있다.In addition, in step 2 of Scheme 1, the compound represented by Formula 1 may be prepared by reacting the compound represented by Ligand-Linker-Y with the compound represented by Formula 2.
약학 조성물Pharmaceutical composition
본 발명은 또한, 상기 화학식 1로 표시되는 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 역형성 림프종 키나아제(ALK) 관련 질환의 예방 또는 치료용 약학 조성물에 관한 것이다. The present invention is also a pharmaceutical for the prevention or treatment of anaplastic lymphoma kinase (ALK)-related diseases containing a compound represented by Formula 1 represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient It relates to the composition.
본 발명은 또한, 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물이다.The present invention is also a pharmaceutical composition for the prevention or treatment of cancer containing a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화합물은 역형성 림프종 키나아제(ALK)를 억제하거나 분해하여 암을 예방 또는 치료할 수 있다.The compounds may inhibit or degrade anaplastic lymphoma kinase (ALK) to prevent or treat cancer.
상기 화학식 1 화합물의 함량은 상기 약학 조성물 전체 중량을 기준으로 0.05% 내지 95 중량%, 바람직하게는 5 내지 80 중량%, 보다 바람직하게는 10 내지 60 중량%일 수 있다. 상기 화학식 1 화합물의 함량이 상기 범위로 포함될 경우, 역형성 림프종 키나아제(ALK)의 억제 또는 분해 효과가 우수할 수 있다.The content of the compound of Formula 1 may be 0.05% to 95% by weight, preferably 5 to 80% by weight, more preferably 10 to 60% by weight, based on the total weight of the pharmaceutical composition. When the content of the compound of Formula 1 is included in the above range, the inhibitory or decomposing effect of anaplastic lymphoma kinase (ALK) may be excellent.
또한, 상기 암은 대장암, 간암, 위암, 유방암, 결장암, 골암, 췌장암, 두부 또는 경부암, 자궁암, 난소암, 직장암, 식도암, 소장암, 항문부근암, 결장암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병, 전립선암, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종 중추신경계 종양 및 백혈병으로 이루어진 군으로부터 선택되는 것일 수 있다.In addition, the cancer is colon cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, anal muscle cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, uterus It may be selected from the group consisting of cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor and leukemia.
본 발명의 약학 조성물은 단독으로 또는 1종 이상의 추가의 치료제와 함께 투여될 수 있다. "함께 투여" 또는 "조합 치료"는 본 발명의 약학 조성물 및 1종 이상의 추가의 치료제가 치료될 포유동물에게 동시에 투여되는 것을 의미한다. 함께 투여되는 경우, 이러한 성분들은 동일한 시간에 또는 상이한 시점에서 임의의 순서로 순차적으로 투여될 수 있다. 따라서, 각 성분은 별도로 투여될 수 있으나, 목적하는 치료 효과를 제공하도록 충분히 근접한 시간으로 투여될 수 있다.The pharmaceutical compositions of the present invention may be administered alone or in combination with one or more additional therapeutic agents. “Concurrent administration” or “combination therapy” means that the pharmaceutical composition of the present invention and one or more additional therapeutic agents are administered simultaneously to the mammal to be treated. When administered together, these components may be administered sequentially at the same time or at different time points in any order. Accordingly, each component may be administered separately, but may be administered in a sufficiently close time to provide the desired therapeutic effect.
예컨대, 본 발명의 약학 조성물과 함께 투여 될 수 있는 치료제로는, 면역 체계를 자극하는 치료제, 예를 들어, PD-1 길항제, PD-L1 길항제, CTLA-4 길항제, LAG-3 길항제, GITR 길항제, 및/또는 항-CD39 항체, 항-CD73 항체, 항-A2AR 항체를 투여하는 것을 포함한다. 또한, 세포신호전달 억제제(cell signal transduction inhibitors), 유사분열 저해제(mitosis inhibitors), 알킬화제(alkylating agents), 대사길항제(antimetabolites), 항생제(antibiotics), 성장인자 저해제(growth factor inhibitors), 세포주기 저해제(cell cycle inhibitors), 토포이소머라아제 저해제(topoisomerase inhibitors), 면역조절제 (immunoregulatory agent), 생물학적 반응조절제(biological reaction modifiers), 항호르몬제(antihormonal agents), 항안드로겐제(antiandrogen), 세포 분화/증식/생존 저해제(cell differentiation/proliferation/survival inhibitors), 세포자살 저해제(apoptosis inhibitors), 염증 저해제(inflammation inhibitors) 및 P-당단백 저해제(P-glycoprotein inhibitors)로 이루어진 군으로부터 선택될 수 있다.For example, as a therapeutic agent that can be administered with the pharmaceutical composition of the present invention, a therapeutic agent that stimulates the immune system, for example, a PD-1 antagonist, a PD-L1 antagonist, a CTLA-4 antagonist, a LAG-3 antagonist, a GITR antagonist , And/or an anti-CD39 antibody, an anti-CD73 antibody, an anti-A2AR antibody. In addition, cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, growth factor inhibitors, cell cycle inhibitors (cell cycle inhibitors), topoisomerase inhibitors, immunomodulators (immunoregulatory agents), biological reaction modifiers, antihormonal agents, antiandrogens, cell differentiation/ It may be selected from the group consisting of proliferation/survival inhibitors (cell differentiation/proliferation/survival inhibitors), apoptosis inhibitors, inflammation inhibitors, and P-glycoprotein inhibitors.
또한, 본 발명에 따른 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있는데, 일반적으로 몸무게가 70kg인 성인환자를 기준으로 할 때 0.01~1,000 mg/일이 바람직하며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수 있다.In addition, the dosage of the compound according to the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and degree of disease, and is generally 0.01 based on an adult patient weighing 70 kg. ~1,000 mg/day is preferred, and may be administered in divided doses from once a day to several times a day at regular intervals according to the judgment of a doctor or pharmacist.
또한, 본 발명의 약학 조성물은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하고, 여기에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제 또는 비경구투여용 제제로 제제화할 수 있다.In addition, the pharmaceutical composition of the present invention contains the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient are added to It can be formulated as a preparation for oral administration or parenteral administration such as a conventional preparation in the scientific field, for example, tablets, capsules, troches, solutions, and suspensions.
본 발명의 약제 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 포함될 수 있다. 예를 들면 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소디움 알진산염, 메틸셀룰로오스, 소디움 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다.Excipients that can be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, tonicity agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, rubber tragacanth, alginic acid, sodium Alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.
사용 가능한 주사용 담체의 예로는 증류수, 식염수, 포도당 용액, 유사-포도당 용액, 알코올류, 글리콜에테르(예, polyethylene glycol 400), 오일, 지방산, 지방산 에스테르, 글리세리드, 계면활성제, 현탁화제, 에멀젼화제 등을 들 수 있다.Examples of injectable carriers that can be used include distilled water, saline, glucose solutions, pseudo-glucose solutions, alcohols, glycol ethers (e.g. polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifying agents. And the like.
이하 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시하나, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 범주 및 기술사상 범위 내에서 다양한 변경 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변경 및 수정이 첨부된 특허청구범위에 속하는 것도 당연한 것이다.Hereinafter, preferred embodiments are presented to aid the understanding of the present invention, but the following examples are only illustrative of the present invention, and it is obvious to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention. It is natural that changes and modifications fall within the scope of the appended claims.
실시예 1: 5-(4-(4-(5-클로로-4-((프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(4-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)부틸)-5-옥소펜탄아미드(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-5-oxopentanamide)의 제조 Example 1 : 5-(4-(4-(5-chloro-4-((pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-ylamino)-5-isopropoxy -2-Methylphenyl)piperidin-1-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino )Butyl)-5-oxopentanamide (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)- 5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl) -5-oxopentanamide) preparation
[화학식 1-1][Formula 1-1]
단계 step 1: 51: 5 -(4-(4-((5--(4-(4-((5- 클로로Chloro -4-(2-(프로-2-일--4-(2-(Pro-2-yl- 설포니미도일Sulfonimidoil )) 페닐)아미노)피리미딘-2-일아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-5-옥소펜탄산(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentanoic acid )의 제조Phenyl)amino)pyrimidin-2-ylamino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentanoic acid (5-(4-(4-((5- Preparation of chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-5-oxopentanoic acid)
[반응식 2-1][Scheme 2-1]
상기 반응식 2-1에 따라, Reliable chem(중국)으로부터 구매한 화합물 1(0.5 g, 0.9 mmol)을 디클로로메탄 (15 mL)에 녹이고, 글루타르산 무수물 (0.112 g, 0.99 mmol)을 가하고 테트라에틸아민 (0.151 mL, 1.08 mmol) 및 0.1당량의 4-(N,N-디메틸아미노)피리딘 (DMAP)을 첨가하고 상온에서 8시간 동안 교반하였다. 반응 종결 후, 반응물은 디클로로메탄에 희석시킨 후, 물, 포화 염화암모늄 수용액 및 소금물로 세척 후, 유기층은 무수 황산마그네슘으로 건조시키고, 여과 및 감압 농축 후 컬럼분리정제를 통하여 목적 화합물인 화합물 2(0.46 g, 흰색 고체)를 수득하였다.According to Scheme 2-1, Compound 1 (0.5 g, 0.9 mmol) purchased from Reliable chem (China) was dissolved in dichloromethane (15 mL), glutaric anhydride (0.112 g, 0.99 mmol) was added, and tetraethyl Amine (0.151 mL, 1.08 mmol) and 0.1 equivalent of 4-(N,N-dimethylamino)pyridine (DMAP) were added, followed by stirring at room temperature for 8 hours. After completion of the reaction, the reaction product was diluted in dichloromethane, washed with water, saturated aqueous ammonium chloride solution, and brine, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then the target compound, Compound 2 ( 0.46 g, white solid) was obtained.
LC/MS (ESI) m/z 672.1 [M+H]+ LC/MS (ESI) m/z 672.1 [M+H] +
단계 2: 5-(4-(4-(5-클로로-4-((프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(4-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)부틸)-5-옥소펜탄아미드의 제조Step 2: 5-(4-(4-(5-chloro-4-((pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-ylamino)-5-isopropoxy- 2-methylphenyl)piperidin-1-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino) Preparation of butyl)-5-oxopentanamide
[반응식 2-2][Reaction Scheme 2-2]
상기 반응식 2-2에 따라, 상기 단계 1에서 제조한 화합물 2(40 mg, 0.06 mmol)를 디클로로메탄 (5 mL)에 녹인 후, Pure & applied science(중국) 에서 구매한 화합물 3(23.6 mg, 0.06 mmol), 벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스페이트(32.2 mg, 0.06 mmol) 및 트리에틸아민(22 uL, 0.16 mmol)을 첨가한 후, 상온에서 12시간 교반하였다. 반응이 완결되면, 반응물에 디클로로메탄 5ml를 추가하여 희석시키고, 물과 포화 소금물로 씻어주었다. 유기층은 무수 황산마그네슘으로 건조하고, 여과 및 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물 45mg을 연갈색의 고체로 수득하였다.According to Scheme 2-2, after dissolving Compound 2 (40 mg, 0.06 mmol) prepared in Step 1 in dichloromethane (5 mL), Compound 3 (23.6 mg, purchased from Pure & applied science (China)) 0.06 mmol), benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (32.2 mg, 0.06 mmol) and triethylamine (22 uL, 0.16 mmol) were added, and then at room temperature for 12 hours Stirred. When the reaction was completed, dichloromethane 5ml was added to the reaction mixture, diluted, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column separation to obtain 45 mg of the target compound as a light brown solid.
LC/MS (ESI) m/z 998.2 [M+H]+ LC/MS (ESI) m/z 998.2 [M+H] +
실시예Example 2: 5-(4-(4-((5-클로로-4-((프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(4-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)옥시)부틸)-5-옥소펜탄아미드(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)-5-oxopentanamide)의 제조2: 5-(4-(4-((5-chloro-4-((pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy -2-Methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) )Oxy)butyl)-5-oxopentanamide (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino) )-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy) butyl)-5-oxopentanamide)
[화학식 1-2][Formula 1-2]
단계 1Step 1
실시예 1의 단계 1과 동일한 방법으로 실시하여, 하기 반응식 3의 화합물 2를 제조하였다.In the same manner as in Step 1 of Example 1, compound 2 of Scheme 3 was prepared.
단계 2Step 2
[반응식 3][Scheme 3]
상기 반응식 3에 따라, 상기 단계 1에서 제조한 화합물 2 (40 mg, 0.06 mmol)를 디클로로메탄 (5 mL)에 녹인 후, Pure & applied science (중국)에서 구매한 화합물 4 (23.6 mg, 0.06 mmol), 벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스페이트 (32.2 mg, 0.06 mmol) 및 트리에틸아민 (22 uL, 0.16 mmol)을 첨가한 후, 상온에서 8시간 교반하였다. 반응이 완결되면, 반응물에 디클로로메탄 5ml를 추가하여 희석시키고, 물과 포화 소금물로 씻어주었다. 유기층은 무수 황산마그네슘으로 건조하고, 여과 및 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물 42mg을 연갈색의 고체로 수득하였다.According to Scheme 3, after dissolving Compound 2 (40 mg, 0.06 mmol) prepared in Step 1 in dichloromethane (5 mL), Compound 4 (23.6 mg, 0.06 mmol) purchased from Pure & applied science (China) ), benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (32.2 mg, 0.06 mmol) and triethylamine (22 uL, 0.16 mmol) were added, followed by stirring at room temperature for 8 hours. . When the reaction was completed, dichloromethane 5ml was added to the reaction mixture, diluted, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column separation to obtain 42 mg of the target compound as a light brown solid.
실시예Example 3: 4-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(2-(2,6-이옥소피레피딘-3-일)-1,3-디옥소이소인돌린-4-일)부탄아미드(4-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide)의 제조3: 4-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5- Isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-ioxopyrepidine-3-yl)-1,3-dioxoisoindolin-4-yl) Butanamide (4-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl ) Preparation of piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide)
[화학식 1-3][Formula 1-3]
[반응식 4][Scheme 4]
반응식 4에 따라, 상기 화합물 1(40mg)과 WO2017204445A2의 실시예 4(단계 1)에 따라 만든 5-브로포-N-(2-(2,6-이동소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)펜탄아미드인 화합물 5(31.2 mg, 0.072 mmol)를 N,N-디메틸포름아미드 (5 mL)에 녹이고 디이소프로필에틸아민 (32 uL, 0.18 mmol)을 첨가한 후, 100℃에서 12시간 교반하였다. 반응물을 디클로로메탄 10ml를 추가하여 희석시키고, 물과 포화 소금물로 3회 씻어주었다. 유기층은 무수 황산마그네슘으로 건조하고, 여과 및 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물 40mg을 연갈색의 고체로 수득하였다. According to Scheme 4, compound 1 (40 mg) and 5-brofo-N-(2-(2,6-isopiperidin-3-yl)-1 made according to Example 4 (step 1) of WO2017204445A2 ,3-dioxoisoindolin-4-yl)pentanamide compound 5 (31.2 mg, 0.072 mmol) was dissolved in N,N-dimethylformamide (5 mL) and diisopropylethylamine (32 uL, 0.18 mmol) After addition, the mixture was stirred at 100° C. for 12 hours. The reaction was diluted by adding 10 ml of dichloromethane, and washed three times with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column separation to obtain 40 mg of the target compound as a light brown solid.
LC/MS (ESI) m/z 899.3 [M+H]+ LC/MS (ESI) m/z 899.3 [M+H] +
실시예Example 4: 5-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(2-(2,6-이옥소피레피딘-3-일)-1,3-디옥소이소인돌린-4-일)-5-옥소펜탄아미드 (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-5-oxopentanamide)의 제조4: 5-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5- Isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-ioxopyrepidine-3-yl)-1,3-dioxoisoindolin-4-yl) -5-Oxopentanamide (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy Preparation of -2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-5-oxopentanamide)
[화학식 4-1][Formula 4-1]
[반응식 5][Scheme 5]
상기 반응식 5에 따라, 상기 화합물 1(20mg)과 WO2017204445A2의 실시예 5(단계 1)에서 제조된 5-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-5-옥소펜탄산인 화합물 6 (10 mg, 0.026 mmol)을 클로로메탄 (4 mL)에 녹이고 벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스페이트 (11.8 mg, 0.031 mmol), 디이소프로필에틸아민 (6.7 uL, 0.039 mmol)을 첨가한 후, 상온에서 교반하였다. 반응물을 디클로메탄 10ml를 추가하여 희석시키고, 물과 포화 소금물로 3회 씻어주었다. 유기층은 무수 황산마그네슘으로 건조하고, 여과 및 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물 16mg을 연갈색의 고체로 수득하였다.According to
LC/MS (ESI) m/z 927.2 [M+H]+ LC/MS (ESI) m/z 927.2 [M+H] +
실시예Example 5: 2-(2-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-2-옥소에톡시)-N-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아세타미드 (2-(2-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide)의 제조5: 2-(2-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino) -5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindolin-4-yl)acetamide (2-(2-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-)) 2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- Preparation of 4-yl)acetamide)
[화학식 5][Formula 5]
[반응식 6][Scheme 6]
상기 반응식 6에 따라, 상기 화합물 1(40mg)과 WO2017204445A2의 실시예 6(단계 1)에서 제조된 2-(2-((2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아미노)-2-옥소에톡시)아세트산인 화합물 7(10 mg, 0.026 mmol)을 클로로메탄 (4 mL)에 녹이고 벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스페이트 (11.8 mg, 0.031 mmol), 디이소프로필에틸아민 (6.7 uL, 0.039 mmol)을 첨가한 후, 상온에서 교반하였다. 반응물을 디클로로메탄 10ml를 추가하여 희석시키고, 물과 포화 소금물로 3회 씻어주었다. 유기층은 무수 황산마그네슘으로 건조한 후, 여과 및 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물 26mg을 연갈색의 고체로 수득하였다.According to Scheme 6, the compound 1 (40 mg) and 2-(2-((2,6-dioxopiperidin-3-yl)-1,3- prepared in Example 6 (step 1) of WO2017204445A2) Dioxoisoindolin-4-yl)amino)-2-oxoethoxy)acetic acid compound 7 (10 mg, 0.026 mmol) was dissolved in chloromethane (4 mL) and benzotriazol-1-yloxy) tripyrroli Dinophosphonium hexafluorophosphate (11.8 mg, 0.031 mmol) and diisopropylethylamine (6.7 uL, 0.039 mmol) were added, followed by stirring at room temperature. The reaction was diluted by adding 10 ml of dichloromethane, and washed three times with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column separation to obtain 26 mg of the target compound as a light brown solid.
LC/MS (ESI) m/z 928.4 [M+H]+ LC/MS (ESI) m/z 928.4 [M+H] +
실시예Example 6: (6: ( 2R,4R2R,4R )-1-((R)-2-(5-(4-(4-((5-)-1-((R)-2-(5-(4-(4-((5- 클로로Chloro -4-((2-( 프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)펜탄아미도)-3,3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복사미드 ((2S,4R)-1-(2-(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamid)의 제조-4-((2-(Pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl )Pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S ,4R)-1-(2-(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)- 5-isopropoxy-2-methylphenyl)piperidin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamid) Manufacture of
[화학식 1-6][Formula 1-6]
단계 1: (Step 1: ( 2S,4R2S,4R )-1-((R)-2-(5-)-1-((R)-2-(5- 브로모펜탄아미도Bromopentanamido )-3,3-)-3,3- 디메틸부탄오일Dimethylbutane oil )-4-히드록시-N-(4-(4-)-4-hydroxy-N-(4-(4- 메틸티아졸Methylthiazole -5-일)-5 days) 벤질benzyl )) 피롤리딘Pyrrolidine -2--2- 카르복사미드의Carboxamide 제조 Produce
[반응식 7-1][Scheme 7-1]
반응식 7-1에 따라, (2R,4R)-1-((R)-2-아미노-3,3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복사미드 염산을 디클로로메탄에 녹이고 5-브포모펜탄오일 클로라이드과 디이소프로필에틸아민을 첨가 후 상온에서 교반하였다. 반응이 종결되고, 반응물은 디클로로메탄으로 희석하고 물과 소금물로 씻어준 후, 유기층은 무수 황산마그네슘으로 건조한 후, 여과 및 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물인 화합물 8을 제조하였다.According to Scheme 7-1, (2R,4R)-1-((R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloric acid was dissolved in dichloromethane, 5-bromopentanoyl chloride and diisopropylethylamine were added, followed by stirring at room temperature. After the reaction was completed, the reaction product was diluted with dichloromethane, washed with water and brine, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then the target compound, Compound 8, was prepared through column separation and purification.
1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 7.39-7.29 (m, 4H), 6.11 (d, J = 8.7 Hz, 1H), 4.73 (t, J = 8.0 Hz, 1H), 4.61-4.48 (m, 3H), 4.35-4.30 (m, 1H), 4.08 (d, J = 11 Hz, 1H), 3.71-3.64 (m, 1H), 3.62-3.59 (m, 1H), 3.39 (t, J = 6.5 Hz, 2H), 3.15-3.10 (m, 3H), 3.01 (s, 1H), 2.61-2.57 (m, 1H), 2.55 (s, 3H), 2.24 (t, J = 7.1 Hz, 2H), 2.16-2.09 (m, 1H), 1.84-1.71 (m, 8H), 0.93 (s, 9H)) 1 H NMR (300 MHz, CDCl 3 ) δ 8.68 (s, 1H), 7.39-7.29 (m, 4H), 6.11 (d, J = 8.7 Hz, 1H), 4.73 (t, J = 8.0 Hz, 1H) , 4.61-4.48 (m, 3H), 4.35-4.30 (m, 1H), 4.08 (d, J = 11 Hz, 1H), 3.71-3.64 (m, 1H), 3.62-3.59 (m, 1H), 3.39 (t, J = 6.5 Hz, 2H), 3.15-3.10 (m, 3H), 3.01 (s, 1H), 2.61-2.57 (m, 1H), 2.55 (s, 3H), 2.24 (t, J = 7.1 Hz, 2H), 2.16-2.09 (m, 1H), 1.84-1.71 (m, 8H), 0.93 (s, 9H))
단계 2Step 2
[반응식 7-2][Reaction Scheme 7-2]
반응식 7-2에 따라, 상기 화합물 1(40mg)과 상기 단계 1에서 제조된 화합물 8 (42 mg, 0.026 mmol)을 클로로메탄(4 mL)에 녹이고 벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스페이트(11.8 mg, 0.031 mmol), 디이소프로필에틸아민(6.7 uL, 0.039 mmol)을 첨가한 후, 상온에서 교반하였다. 반응물을 디클로메탄 10ml를 추가하여 희석시키고, 물과 포화 소금물로 3회 씻어주었다. 유기층은 무수 황산마그네슘으로 건조한 후, 여과, 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물 38mg을 미색의 고체로 수득하였다.According to Scheme 7-2, compound 1 (40 mg) and compound 8 (42 mg, 0.026 mmol) prepared in step 1 were dissolved in chloromethane (4 mL), and benzotriazol-1-yloxy) tripyrroli Dinophosphonium hexafluorophosphate (11.8 mg, 0.031 mmol) and diisopropylethylamine (6.7 uL, 0.039 mmol) were added, followed by stirring at room temperature. The reaction was diluted by adding 10 ml of dichloromethane, and washed three times with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column separation to obtain 38 mg of the target compound as an off-white solid.
LC/MS (ESI) m/z 1069.2 [M+H]+ LC/MS (ESI) m/z 1069.2 [M+H] +
실시예Example 7: (2S,4R)-1-((R)-2-(7-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-7-옥소헵탄아미도)-3,3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복스아미드의 제조7: (2S,4R)-1-((R)-2-(7-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl))) Phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)- Preparation of 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
[화학식 1-7][Formula 1-7]
단계1Step 1 : : terttert -부틸 7-(((R)-1-((2R,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)아미노)-7-옥소헵타노에이트 ((2S,4R)-1-(2-(7-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)의 제조-Butyl 7-(((R)-1-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine- 1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate ((2S,4R)-1-(2-(7-(4-(4- ((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido )-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)
[반응식 8-1][Scheme 8-1]
반응식 8-1에 따라, (2R,4R)-1-((R)-2-아미노-3,3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복사미드 염산 (0.1 g, 0.232 mmol)을 디클로로메탄 (5 mL)에 녹이고, 7-(tert-부톡시)-7-옥소헵탄산 (0.065 g, 0.279 mmol), 1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸로[4,5-b]피리딘늄 3-옥시드 헥사플루오로포스페이트 (0.115 g, 0.302 mmol), 디이소프로필에틸아민 (0.061 mL, 348 mmol)을 첨가한 후 상온에서 6시간 교반하였다. 반응이 종결되고, 반응물은 디클로로메탄으로 희석하고 물과 소금물로 씻어주었다. 유기층은 무수 황산마그네슘으로 건조한 후, 여과, 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물인 화합물 9(0.152 g, 무색 젤)를 제조하였다.According to Scheme 8-1, (2R,4R)-1-((R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloric acid (0.1 g, 0.232 mmol) is dissolved in dichloromethane (5 mL), and 7-(tert-butoxy)-7-oxoheptanoic acid (0.065 g , 0.279 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.115 g, 0.302 mmol) After adding diisopropylethylamine (0.061 mL, 348 mmol), the mixture was stirred at room temperature for 6 hours. When the reaction was completed, the reaction product was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column separation to prepare compound 9 (0.152 g, colorless gel).
단계 step 2: 72: 7 -(((R)-1-((-(((R)-1-(( 2R,4R2R,4R )-4-히드록시-2-((4-(4-)-4-hydroxy-2-((4-(4- 메틸티아졸Methylthiazole -5-일)-5 days) 벤질benzyl ) ) 카바모일Carbamoyl )) 피롤리딘Pyrrolidine -1-일)-3,3-디메틸-1--1-yl)-3,3-dimethyl-1- 옥소부탄Oxobutane -2-일)아미노)-7--2-yl)amino)-7- 옥소헵탄산의Oxoheptanoic acid 제조 Produce
[반응식 8-2] [Scheme 8-2]
반응식 8-2에 따라, tert-부틸 7-(((R)-1-((2R,4R)-4-히드록시-2-((4-(4-메틸티아졸-5-일)벤질)카바모일)피롤리딘-1-일)-3,3-디메틸-1-옥소부탄-2-일)아미노)-7-옥소헵타노에이트(0.16 g, 0.232 mmol)를 20% 트리플루오로아세트산/디클로로메탄 (5 mL)에 녹인 후, 상온에서 8시간 교반하였다. 여과, 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물 (0.125 g, 흰색 고체)을 제조하였다.According to Scheme 8-2, tert-butyl 7-(((R)-1-((2R,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl) )Carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate (0.16 g, 0.232 mmol) in 20% trifluoro After dissolving in acetic acid/dichloromethane (5 mL), the mixture was stirred at room temperature for 8 hours. After filtration and concentration under reduced pressure, the target compound (0.125 g, white solid) was prepared through column separation and purification.
단계 3Step 3
[반응식 8-3][Scheme 8-3]
반응식 8-3에 따라, 상기 화합물 1(40mg)과 상기 단계 2에서 제조된 화합물 9(48mg)를 디클로로메탄 (4 mL)에 녹이고 벤조트리아졸-1-일옥시)트리피롤리디노포스포늄 헥사플루오로포스페이트 (32.63 mg, 0.086 mmol), 디이소프로필에틸아민 (14 uL, 0.108 mmol)을 첨가한 후, 상온에서 16시간 교반하였다. 반응이 완결되면, 반응물은 디클로로메탄 10ml로 희석시키고, 물과 소금물로 씻어주었다. 유기층은 무수 황산마그네슘으로 건조한 후, 여과, 감압 농축 후 컬럼 분리 정제를 통하여 목적 화합물을 25mg제조하였다.According to Scheme 8-3, compound 1 (40 mg) and compound 9 (48 mg) prepared in step 2 were dissolved in dichloromethane (4 mL), and benzotriazol-1-yloxy) tripyrrolidinophosphonium hexa After adding fluorophosphate (32.63 mg, 0.086 mmol) and diisopropylethylamine (14 uL, 0.108 mmol), the mixture was stirred at room temperature for 16 hours. When the reaction was complete, the reaction product was diluted with 10 ml of dichloromethane and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column separation to prepare 25 mg of the target compound.
LC/MS (ESI) m/z 1112.3 [M+H]+ LC/MS (ESI) m/z 1112.3 [M+H] +
실험예Experimental example 1: One: In In vivovivo 암 성장 억제활성 평가 Evaluation of cancer growth inhibitory activity
본 발명에 따른 화합물의 암 성장 억제활성 평가를 수행하기 위해, 다음과 같이 실험하였다.In order to evaluate the cancer growth inhibitory activity of the compound according to the present invention, the following experiment was performed.
H3122 이종이식 모델을 사용한 SCID(severe combined immunodeficiency mouse) 마우스를 대조군과 실험군을 나누어, 상기 실험군에는 본 발명에 따른 실시예 3 화합물을 복강주입하여 실험하였고, 그 결과를 도 1에 나타내었다. 이때, 하나의 대조군 또는 실험군에 포함되는 마우스는 8마리로 하였다. Severe combined immunodeficiency mouse (SCID) mice using the H3122 xenograft model were divided into a control group and an experimental group, and the experimental group was intraperitoneally injected with the compound of Example 3 according to the present invention, and the results are shown in FIG. At this time, the number of mice included in one control or experimental group was 8 mice.
도 1은 H3122가 이종이식된 SCID 마우스에 본 발명의 실시예 3 화합물을 투여한 뒤, 종양 부피의 변화를 나타낸 그래프이다. 1 is a graph showing changes in tumor volume after administration of the compound of Example 3 of the present invention to SCID mice xenografted with H3122.
상기 그래프에서 대조군 및 각 실험군은 하기 표 2에 나타난 바와 같다.In the graph, the control group and each experimental group are as shown in Table 2 below.
도 1을 살펴보면, 본 발명에 따른 실시예 3 화합물을 투여한 실험군은 투여 경과일이 흐름에 따라 종양 크기가 발달되지 않고 유지되거나 줄어드는 것을 확인할 수 있다.Referring to FIG. 1, it can be seen that in the experimental group to which the compound of Example 3 according to the present invention was administered, the tumor size did not develop, but maintained or decreased as the administration elapsed day.
따라서, 본 발명에 따른 화합물은 상기 실험예 3에서 확인되는 바와 같이, 암 성장 억제 활성을 갖는 것으로 확인되어, 이를 함유하는 약학 조성물로서 암의 예방 및 치료에 유용하게 사용될 수 있음을 알 수 있다.Therefore, as confirmed in Experimental Example 3, the compound according to the present invention was confirmed to have cancer growth inhibitory activity, and as a pharmaceutical composition containing the same, it can be seen that it can be usefully used in the prevention and treatment of cancer.
또한, 본 발명에 따른 화학식 1로 표시되는 화합물은 역형성 림프종 키나제(ALK)를 억제하거나 분해시킬 수 있어, 역형성 림프종 키나제(ALK) 관련 질환, 예를 들어 암의 예방 및 치료에 유용한 효과가 있음을 알 수 있다.In addition, the compound represented by Formula 1 according to the present invention can inhibit or degrade anaplastic lymphoma kinase (ALK), so it has a useful effect in the prevention and treatment of anaplastic lymphoma kinase (ALK) related diseases, such as cancer. You can see that there is.
Claims (8)
[화학식 1]
상기 화학식 1에서,
Linker는 -(CH2)-, -(C=O)-, -NH- 및 -O-로 이루어진 군으로부터 선택되는 1종 이상이 3 내지 10개 연결된 연결기이며,
상기 연결기는 연속하여 -O-로 연결될 수 없고; 및
Ligand는
[Formula 1]
In Formula 1,
Linker is a linking group having 3 to 10 connected at least one selected from the group consisting of -(CH 2 )-, -(C=O)-, -NH- and -O-,
The linker cannot be connected in succession to -O-; And
Ligand is
상기 Linker는
The Linker is
상기 화학식 1로 표시되는 화합물은 하기 화합물로 이루어진 군으로부터 선택되는 어느 하나인 것인, 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용 가능한 염:
(1) 5-(4-(4-(5-클로로-4-((프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(4-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일아미노)부틸)-5-옥소펜탄아미드 (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-5-oxopentanamide);
(2) 5-(4-(4-((5-클로로-4-((프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(4-((2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)옥시)부틸)-5-옥소펜탄아미드(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)-5-oxopentanamide);
(3) 4-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(2-(2,6-이옥소피레피딘-3-일)-1,3-디옥소이소인돌린-4-일)부탄아미드(4-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide);
(4) 5-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-N-(2-(2,6-이옥소피레피딘-3-일)-1,3-디옥소이소인돌린-4-일)-5-옥소펜탄아미드 (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-5-oxopentanamide);
(5) 2-(2-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-2-옥소에톡시)-N-(2-(2,6-디옥소피페리딘-3-일)-1,3-디옥소이소인돌린-4-일)아세타미드 (2-(2-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide);
(6) (2R,4R)-1-((R)-2-(5-(4-(4-((5-클로로-4-((2-( 프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)펜탄아미도)-3,3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복사미드 ((2S,4R)-1-(2-(5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamid); 및
(7) (2S,4R)-1-((R)-2-(7-(4-(4-((5-클로로-4-((2-(프로-2-일-설포니미도일)페닐)아미노)피리미딘-2-일)아미노)-5-이소프로폭시-2-메틸페닐)피페리딘-1-일)-7-옥소헵탄아미도)-3,3-디메틸부탄오일)-4-히드록시-N-(4-(4-메틸티아졸-5-일)벤질)피롤리딘-2-카르복스아미드.The method of claim 1,
The compound represented by Formula 1 is any one selected from the group consisting of the following compounds, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(1) 5-(4-(4-(5-chloro-4-((pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-ylamino)-5-isopropoxy- 2-methylphenyl)piperidin-1-yl)-N-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino) Butyl)-5-oxopentanamide (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5 -isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)- 5-oxopentanamide);
(2) 5-(4-(4-((5-chloro-4-((pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopro Foxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- Yl)oxy)butyl)-5-oxopentanamide (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl) amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy )butyl)-5-oxopentanamide);
(3) 4-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5 -Isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-ioxopyrepidine-3-yl)-1,3-dioxoisoindolin-4-yl )Butanamide (4-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2- methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide);
(4) 5-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5 -Isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-ioxopyrepidine-3-yl)-1,3-dioxoisoindolin-4-yl )-5-oxopentanamide (5-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5- isopropoxy-2-methylphenyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-5-oxopentanamide);
(5) 2-(2-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino )-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-4-yl)acetamide (2-(2-(4-(4-((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin)) -2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin -4-yl)acetamide);
(6) (2R,4R)-1-((R)-2-(5-(4-(4-((5-chloro-4-((2-( pro-2-yl-sulfonimidoyl )Phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hyd Roxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((2S,4R)-1-(2-(5-(4-(4- ((5-chloro-4-((2-(propan-2-ylsulfonimidoyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)pentanamido)-3 ,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamid); And
(7) (2S,4R)-1-((R)-2-(7-(4-(4-((5-chloro-4-((2-(pro-2-yl-sulfonimidoyl )Phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl) -4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.
(S2) 상기 Ligand-Linker-Y로 표시되는 화합물과 하기 화학식 2로 표시되는 화합물을 반응시키는 단계;
를 포함하되,
상기 Ligand와 Linker는 상기 화학식 1에서 정의된 바와 같고,
상기 X가 -CO2-tBu 인 경우 Y는 -CO2H이고, X가 Cl 또는 Br인 경우 Y는 I인,
제1항의 화학식 1로 표시되는 화합물의 제조방법:
[화학식 2]
(S2) reacting the compound represented by the Ligand-Linker-Y with the compound represented by the following formula (2);
Including,
The Ligand and Linker are as defined in Formula 1,
When X is -CO 2 -tBu, Y is -CO 2 H, and when X is Cl or Br, Y is I,
A method for preparing a compound represented by Formula 1 of claim 1:
[Formula 2]
상기 화합물은 역형성 림프종 키나아제(ALK)를 억제하거나 분해하여 암을 예방 또는 치료하는 것인, 약학 조성물.The method of claim 6,
The compound is to prevent or treat cancer by inhibiting or degrading anaplastic lymphoma kinase (ALK), a pharmaceutical composition.
상기 암은 대장암, 간암, 위암, 유방암, 결장암, 골암, 췌장암, 두부 또는 경부암, 자궁암, 난소암, 직장암, 식도암, 소장암, 항문부근암, 결장암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병, 전립선암, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 중추신경계 종양 및 백혈병으로 이루어진 군으로부터 선택되는 것인, 약학 조성물.
The method of claim 6,
The cancer is colorectal cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or neck cancer, uterine cancer, ovarian cancer, rectal cancer, esophageal cancer, small intestine cancer, muscle cancer of the anus, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma , Vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, prostate cancer, bladder cancer, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system tumor and leukemia.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022242725A1 (en) * | 2021-05-19 | 2022-11-24 | 和径医药科技（上海）有限公司 | Class of novel protein degradation agents and application thereof |
| CN116888108A (en) * | 2021-03-19 | 2023-10-13 | 上海齐鲁制药研究中心有限公司 | Novel EGFR degradation agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017204445A2 (en) | 2016-05-24 | 2017-11-30 | 한국화학연구원 | Pharmaceutical composition inducing decomposition of alk protein, and pharmaceutical composition for cancer prevention or treatment containing same as active component |
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| WO2017204445A2 (en) | 2016-05-24 | 2017-11-30 | 한국화학연구원 | Pharmaceutical composition inducing decomposition of alk protein, and pharmaceutical composition for cancer prevention or treatment containing same as active component |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116888108A (en) * | 2021-03-19 | 2023-10-13 | 上海齐鲁制药研究中心有限公司 | Novel EGFR degradation agent |
| CN116888108B (en) * | 2021-03-19 | 2024-04-19 | 上海齐鲁制药研究中心有限公司 | Novel EGFR degradation agent |
| WO2022242725A1 (en) * | 2021-05-19 | 2022-11-24 | 和径医药科技（上海）有限公司 | Class of novel protein degradation agents and application thereof |
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