KR101034351B1 - Pyridine derivatives or pharmaceutically acceptable salts thereof substituted with novel benzoxazoles, preparation methods thereof, and pharmaceutical compositions for the prevention and treatment of abnormal cell growth diseases containing the same as active ingredients - Google Patents
Pyridine derivatives or pharmaceutically acceptable salts thereof substituted with novel benzoxazoles, preparation methods thereof, and pharmaceutical compositions for the prevention and treatment of abnormal cell growth diseases containing the same as active ingredientsDownload PDFInfo
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- KR101034351B1 KR101034351B1KR1020080044485AKR20080044485AKR101034351B1KR 101034351 B1KR101034351 B1KR 101034351B1KR 1020080044485 AKR1020080044485 AKR 1020080044485AKR 20080044485 AKR20080044485 AKR 20080044485AKR 101034351 B1KR101034351 B1KR 101034351B1
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Abstract
Translated fromKorean
Description
Translated fromKorean신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pyridine derivative substituted with novel benzoxazole or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing and treating aberrant cell growth diseases containing the same as an active ingredient.
단백질 키나아제(PK)는 단백질의 티로신, 세린 및 트레오닌 잔사 상의 하이드록시 그룹의 인산화를 촉매하는 효소이다. 상기 단백질 키나아제는 세포 성장, 분화 및 증식을 야기하는 성장 인자 신호 전달에 중요한 역할을 하고, 따라서 단백질 키나아제의 활성은 세포 생명의 거의 모든 양태에 영향을 미친다.Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The protein kinases play an important role in the growth factor signal transduction that causes cell growth, differentiation and proliferation, and thus the activity of protein kinases affects almost all aspects of cell life.
단백질 키나아제의 돌연변이나 과발현에 의한 세포신호전달체계의 이상은 건선과 같이 비교적 생명에 위협적이지 않은 질환에서부터 암과 같은 독성(병원성) 질환에 걸친 기질(stroma) 질환에 밀접한 영향을 미친다.Aberrations in cellular signaling systems due to mutation or overexpression of protein kinases have a close effect on stroma diseases ranging from relatively non-life threatening diseases such as psoriasis to toxic (pathogenic) diseases such as cancer.
단백질 키나아제는 티로신 키나아제(TK) 및 세린-트레오닌 키나아제(STK)로 분류할 수 있다.Protein kinases can be classified into tyrosine kinases (TK) and serine-threonine kinases (STK).
티로신 키나아제의 활성의 주요 양태들 중의 하나는 이것이 성장 인자 수용체와 관련이 있다는 것이다. 성장 인자 수용체는 세포 표면 단백질로서, 성장 인자 리간드에 결합된 경우에는 성장 인자 수용체가 활성 형태로 전환되어 세포막의 내부 표면상의 단백질과 상호 작용하여, 상기 수용체와 기타 단백질의 티로신 잔사 상에서 인산화가 유발되고, 세포 내부에 각종 세포질성 시그널링 분자와의 복합체가 형성되어 궁극적으로는 수많은 세포 반응, 예를 들면, 세포 성장, 분화 및 증식, 세포외 미소환경에 대한 대사성 효과 발현 등이 나타난다(Schleessinger and Ullrich, Neuron. 1992 9, 303-391).One of the major aspects of the activity of tyrosine kinases is that it is associated with growth factor receptors. Growth factor receptors are cell surface proteins that, when bound to growth factor ligands, convert the growth factor receptors into active form and interact with proteins on the inner surface of the cell membrane, causing phosphorylation on tyrosine residues of these receptors and other proteins. In addition, complexes with various cytoplasmic signaling molecules are formed inside cells, resulting in numerous cellular reactions such as cell growth, differentiation and proliferation, and expression of metabolic effects on extracellular microenvironments (Schleessinger and Ullrich, Neuron. 1992 9, 303-391).
티로신 키나아제의 활성을 지닌 성장 인자 수용체는 수용체 티로신 키나아제(Receptor tyrosine kinase, RTK)로서 알려져 있다. 상기 수용체 티로신 키나아제는 다양한 생물학적 활성을 나타내는 큰 계열의 막관통(transmembrane)수용체를 포함한다.Growth factor receptors with tyrosine kinase activity are known as receptor tyrosine kinase (RTK). The receptor tyrosine kinases contain a large family of transmembrane receptors that exhibit a variety of biological activities.
종래에 19개 이상의 "HER RTK"로 명명되는 것과 같은 아계열의 수용체 티로 신 키나아제가 알려져 있고, 상기 HER RTK에는 상피 성장 인자 수용체(EGFR), HER2, HER3, HER4 등이 포함된다. 상기 수용체 티로신 키나아제는 세포외 글리코실화리간드 결합성 도메인, 막관통 도메인 및 단백질 상의 티로신 잔사를 인산화시킬 수 있는 세포내 세포질성 도메인으로 이루어진다.Subtype receptor tyrosine kinases such as those previously termed 19 or more "HER RTKs" are known, and the HER RTKs include epidermal growth factor receptors (EGFR), HER2, HER3, HER4 and the like. The receptor tyrosine kinase consists of an extracellular glycosylated ligand binding domain, a transmembrane domain and an intracellular cytoplasmic domain capable of phosphorylating tyrosine residues on proteins.
또한, 수용체 티로신 키나아제 아계열은 인슐린 수용체(IR), 인슐린 유사 성장 I 수용체(IGF-1R) 및 인슐린 수용체 관련 수용체(IRR)로 이루어진다. IR 및 IGF-IR은 인슐린, IGF-I 및IGF-II와 상호 작용하여, 세포막을 가로지르고 키나아제 도메인을 함유하는 2개의 β소단위체와 2개의 완전하게 세포외 글리코실화된 α소단위체의 이종사량체(heterotetramer)를 형성한다.The receptor tyrosine kinase subfamily also consists of insulin receptor (IR), insulin like growth I receptor (IGF-1R) and insulin receptor related receptor (IRR). IR and IGF-IR interact with insulin, IGF-I and IGF-II, resulting in heterologous doses of two β subunits and two completely extracellular glycosylated α subunits that cross the cell membrane and contain a kinase domain Forms a heterotetramer.
또한, 수용체 티로신 키나아제 아계열은 혈소판 유도된 성장 인자 수용체(PDGFR)로서 명명되는 PDGFRα, PDGFRβ, CSFIR, c-Kit 및 c-Fms을 포함한다. 상기 수용체는 가변수의 면역글로블린 유사 루프와 세포내 도메인으로 구성된 글리코실화 세포외 도메인으로 이루어진다. PDGFR 아계열과의 유사성으로 인해 상기 PDGFR 그룹에 포함되는 태아 간 키나아제(Flk) 수용체 아계열이 알려져 있다. 상기 Flk 아계열은 키나아제 삽입물 도메인-수용체 태아 간 키나아제-1(KDR/Flk-1), Flk-1R, Flk-1, Fms-유사 티로신 키나아제 1 또는 3(Flt-1 또는 Flt-3) 등으로 이루어진다.In addition, the receptor tyrosine kinase subfamily includes PDGFRα, PDGFRβ, CSFIR, c-Kit and c-Fms, which are termed platelet induced growth factor receptors (PDGFR). The receptor consists of a glycosylated extracellular domain consisting of a variable immunoglobulin-like loop and an intracellular domain. Due to its similarity to the PDGFR subfamily, fetal liver kinase (Flk) receptor subfamily belonging to the PDGFR group is known. The Flk subfamily is a kinase insert domain-receptor fetal liver kinase-1 (KDR / Flk-1), Flk-1R, Flk-1, Fms-like tyrosine kinase 1 or 3 (Flt-1 or Flt-3) and the like. Is done.
티로신 키나아제 성장 인자 수용체 계열로서 MET은 c-Met으로서 명명되고 사람 간세포 성장 인자 수용체 티로신 키나아제(hHGFR)로서 1차적 종양 성장 및 전이에 일정 역할을 하는 것으로 여겨지고 있다(Plowman et al.,DN&P, 1994, 7, 6, 334-339).As a family of tyrosine kinase growth factor receptors, MET is named c-Met and is believed to play a role in primary tumor growth and metastasis as human hepatocyte growth factor receptor tyrosine kinase (hHGFR) (Plowman et al., DN & P, 1994, 7, 6, 334-339).
수용체 티로신 키나아제 이외에도, 비수용체 티로신 키나아제 또는 세포성 티로신 키나아제(CTK)로 불리우는 특정 계열의 완전한 세포내 TK가 존재한다. 상기 비수용체 티로신 키나아제는 세포외 도메인과 막관통 도메인을 함유하지 않고, Src, Frk, Btk, Csk Abl, Zap70, Fes, Fak, Jak 및 Ack 아계열로 이루어진다. 이중 Src 아계열은 Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1(Aurora-B), AUR2(Aurora-A), AUR3(Aurora-C), Yrk 등을 포함한다(Bolen, Oncogene. 1993, 8, 2025-2031).In addition to receptor tyrosine kinases, there is a specific family of complete intracellular TKs called nonreceptor tyrosine kinases or cellular tyrosine kinases (CTKs). The non-receptor tyrosine kinase contains no extracellular and transmembrane domains and consists of the Src, Frk, Btk, Csk Abl, Zap70, Fes, Fak, Jak and Ack subfamily. Src subfamily includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1 (Aurora-B), AUR2 (Aurora-A), AUR3 (Aurora-C), Yrk, etc. (Bolen, Oncogene. 1993, 8, 2025-2031).
수용체 티로신 키나아제 및 비수용체 티로신 키나아제와 관련된 병원성 질환은 건선, 간경변, 당뇨병, 혈관형성, 재발 협착증, 안과질환, 류마티스성 관절염, 자가면역 질환, 죽상경화증, 신장 장애 등이 포함된다.Pathogenic diseases associated with receptor tyrosine kinases and non-receptor tyrosine kinases include psoriasis, cirrhosis, diabetes, angiogenesis, recurrent stenosis, ophthalmic diseases, rheumatoid arthritis, autoimmune diseases, atherosclerosis, kidney disorders and the like.
상기에서 살펴본 PK 중에서 Bcr-Abl, EGFR, VEGFR 등의 수용체 티로신 키나아제는 좋은 항암제 타겟으로 많이 연구되어 왔으며, 글리벡, 이레사 등의 항암제가 개발되어 시판되고 있다.Among the PKs described above, receptor tyrosine kinases such as Bcr-Abl, EGFR, and VEGFR have been studied as a good anticancer target, and anticancer agents such as Gleevec and Iresa have been developed and marketed.
또한, 항암제 타겟으로 연구되고 있는 RTK 중에서도 간세포 성장인자(Hepatocyte Growth Factor/Scatter Factor, HGF/SF) 수용체인 c-Met (Hepatocyte Growth Factor Receptor: HGFR)을 타겟으로 하는 항암제가 많이 개발 되고 있다(J. G. Christensen, J. Burrows et al., Cancer Letters, 2005, 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).In addition, among the RTKs being studied as anticancer drugs, many anticancer drugs targeting c-Met (Hepatocyte Growth Factor Receptor (HGFR)), a hepatocyte growth factor / scatter factor (HGF / SF) receptor, have been developed (JG). Christensen, J. Burrows et al., Cancer Letters, 2005, 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).
c-Met은 종양 형성, 증대된 세포 운동성 및 침입성 하에서의 종양 진행, 및 전이에 수반되는 폐암, 위암, 피부암, 신장암, 직장암, 췌장암 등의 많은 인간 암에서 과발현 또는 활성화되어 있다(J. G. Christensen et al., Cancer Letters, 2005, 225, 1-26; W. G. Jiang et al., Critical Reviews in Oncology/Hematology, 2005, 53, 35-69). c-Met 및 이의 리간드인 HGF는 많은 조직에서 발현되지만, 정상적으로는 주로 상피 및 간엽 기원의 세포 각각으로 한정되어 발현된다. c-Met 및 HGF/SF는 정상적인 포유동물의 발육에 필요하며, 세포 전이, 세포 증식 및 생존, 형태 형성성 분화 및 3-차원적 관상 구조물(신 세뇨관 세포, 선 형성 등)의 조직화에서 중요한 것으로 밝혀졌다. HGF/SF는 신생혈관생성 인자이며, 상피 세포에서의 c-Met 신호전달은 신생혈관생성에 필수적인 세포 반응(증식, 운동성, 침입성 등)을 유도한다.c-Met is overexpressed or activated in many human cancers, including lung cancer, gastric cancer, skin cancer, kidney cancer, rectal cancer, and pancreatic cancer, accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et. al., Cancer Letters, 2005, 225, 1-26; WG Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53, 35-69). c-Met and its ligand, HGF, are expressed in many tissues, but are normally limited to cells of epithelial and mesenchymal origin, respectively. c-Met and HGF / SF are necessary for the development of normal mammals and are important for cell metastasis, cell proliferation and survival, morphogenic differentiation and organization of three-dimensional coronary structures (neotubule cells, glandogenesis, etc.). Turned out. HGF / SF is an angiogenesis factor and c-Met signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) that are essential for angiogenesis.
또한 c-Met 및 이의 리간드인 HGF는 다양한 인간 암에서 증가된 수준으로 공-발현되는 것으로 밝혀졌다. 그러나, 수용체 및 리간드는 통상적으로 상이한 세포 유형에 의해 발현되기 때문에, c-Met 신호전달은 대부분 보편적으로 종양-기질 (tumor-stroma) 상호작용에 의해 조절된다.It has also been found that c-Met and its ligand, HGF, are co-expressed at increased levels in various human cancers. However, because receptors and ligands are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.
또한, c-Met의 유전자 증폭, 돌연변이 및 재배열이 다양한 인간 암에서 관찰되었다. c-Met 키나아제를 활성화시키는 생식계 돌연변이를 갖는 부류는 다중 신 장 종양 및 다른 조직의 종양에 걸리기 쉽다.In addition, gene amplification, mutations and rearrangements of c-Met have been observed in various human cancers. Classes with germline mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues.
c-Met 및/또는 HGF/SF의 발현은 상이한 유형의 암(폐, 결장, 유방, 전립선, 간, 췌장, 뇌, 신장, 난소, 위, 피부, 뼈 등의 암)의 질환 진행 상태와 연관되어 있으며, c-Met 또는 HGF/SF의 과발현은 폐, 간, 위 및 유방을 포함한 많은 주요 인간 암에서 나쁜 예후 및 질환 결과와 상관되는 것으로 밝혀졌다. 또한, c-Met은 췌장암, 신경교종 및 간세포암과 같은 성공적인 치료법이 없는 암에 직접 관련되어 있다고 보고되었으며, c-Met이 과발현되면서 ERBB3 신호전달체계 활성화로 야기된 폐암이 게피티니브(Gefitinib; 이레사(상품명:Irresa))에 내성을 갖게 된다고 보고되었다 (J. A. Engelman, K. Zejnullahu et. al. Science, 2007, 316, 1039-1043).Expression of c-Met and / or HGF / SF is associated with disease progression in different types of cancer (lungs, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin, bone, etc.) Overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers including lung, liver, stomach and breast. In addition, c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation due to overexpression of c-Met is Gefitinib (Gefitinib; It has been reported to be resistant to Irresa (JA Engelman, K. Zejnullahu et. Al. Science, 2007, 316, 1039-1043).
HGF/SF는 c-Met의 세포외 도메인에 결합하여 c-Met을 활성화시키며, c-Met의 활성화는 각각 Gab1 및 Grb2 매개된 PI3-키나제 및 Ras/MAPK 활성화를 통한 티로신 포스포릴화 및 다운스트림 시그널화를 이끌어, 세포 운동성 및 증식을 유도한다.HGF / SF binds to the extracellular domain of c-Met to activate c-Met, and activation of c-Met is tyrosine phosphorylation and downstream via Gab1 and Grb2-mediated PI3-kinase and Ras / MAPK activation, respectively. Signaling to induce cell motility and proliferation.
c-Met은 수용체 활성화, 형질전환 및 침습을 이끄는 다른 단백질과 상호작용하는 것으로 밝혀졌고, 또한 c-Met은 초점부착(focal adhesion)을 형성하는 α6β4 인테그린(Integrin:라미닌과 같은 세포외 기질(ECM) 성분에 대한 수용체)과 상호작용하여 HGF/SF 의존적 침습적 성장을 촉진하는 것으로 보고되었다.c-Met has been shown to interact with other proteins leading to receptor activation, transformation and invasion, and c-Met also has an extracellular matrix (ECM) such as α6β4 integrin (laminin) that forms focal adhesion. Has been reported to promote HGF / SF dependent invasive growth.
이에, 본 발명자들은 단백질 키나아제 억제제를 개발하기 위한 연구를 수행 하 던 중, 단백질 키나아제에 대한 우수한 저해 활성을 갖는 벤즈옥사졸로 치환된 피리딘 유도체가 이상 세포 성장의 치료에 유용한 c-Met과 같은 단백질 키나아제에 대한 억제효과를 나타내므로, 이상 세포 성장 질환의 예방 및 치료에 유용하게 사용될 수 있음을 알아내고 본 발명을 완성하였다.Therefore, the inventors of the present invention, while conducting research to develop a protein kinase inhibitor, a pyridine derivative substituted with benzoxazole having excellent inhibitory activity against protein kinase is useful for the treatment of abnormal cell growth, such as a protein kinase such as c-Met. Since the present invention has an inhibitory effect on the present invention, the present invention has been found to be useful for the prevention and treatment of abnormal cell growth diseases.
본 발명의 목적은 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 데 있다.It is an object of the present invention to provide a pyridine derivative or pharmaceutically acceptable salt thereof substituted with novel benzoxazole.
본 발명의 다른 목적은 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공하는 데 있다.Another object of the present invention is to provide a method for preparing a pyridine derivative or pharmaceutically acceptable salt thereof substituted with novel benzoxazole.
본 발명의 또 다른 목적은 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물을 제공하는 데 있다.Still another object of the present invention is to provide a pharmaceutical composition for preventing and treating aberrant cell growth disease, containing a pyridine derivative substituted with novel benzoxazole or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pyridine derivative substituted with novel benzoxazole or a pharmaceutically acceptable salt thereof, a method for preparing the same and a pharmaceutical composition for preventing and treating aberrant cell growth disease containing the same as an active ingredient. to provide.
본 발명에 따른 신규 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 단백질 키나아제에 대한 우수한 저해 활성을 나타내는바, 이상 세포 성장질환의 치료에 유용한 다양한 단백질 키나아제, 예를들면 c-Met에 대하여 우수한 억제효과를 나타내므로, 이상 세포 성장 질환의 예방 및 치료에 유용 하게 사용될 수 있다.The novel benzoxazole-substituted pyridine derivatives or pharmaceutically acceptable salts thereof according to the present invention exhibit excellent inhibitory activity against protein kinases, which are useful for the treatment of aberrant cell growth diseases, for example c-Met. Since it shows an excellent inhibitory effect on, it can be usefully used for the prevention and treatment of abnormal cell growth diseases.
이하, 본 발명을 상세하게 설명한다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.
본 발명은 하기 화학식 1로 표시되는 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a pyridine derivative or pharmaceutically acceptable salt thereof substituted with benzoxazole represented by the following formula (1).
(상기 화학식 1에서,(In the formula 1,
A는
여기서, 상기 X는 N, O 또는 CH이고;Wherein X is N, O or CH;
R1 및 R2는 각각 수소, 비치환 또는 치환된 C3~C8 시클로알킬, C5-C8 아릴, C5-C8 아릴 C3~C8 시클로알킬, C3~C8 헤테로시클로알킬 또는
이때 R3은 비치환 또는 치환된 C1-C6 직쇄 또는 측쇄 알킬, C1-C6 알콕시, C3~C8 시클로알킬, C5-C8 아릴, C5-C8 아릴 C3~C8 시클로알킬 또는 C3~C8 헤테로시클로알킬이며;Wherein R3 is unsubstituted or substituted C1 -C6 straight or branched alkyl, C1 -C6 alkoxy, C3 -C8 cycloalkyl, C5 -C8 aryl, C5 -C8 aryl C3- C8 cycloalkyl or C3 to C8 heterocycloalkyl;
상기 X가 O인 경우에는 R1은 X에 치환되지 않는다.)When X is O, R1 is not substituted in X.)
바람직하게 상기 A는
여기서, 상기 R1 및 R2는 각각 수소, 비치환 또는 치환된 C5~C6 시클로알킬, C5~C6 아릴, C5~C6 아릴 C5~C6 시클로알킬, C5~C6 헤테로시클로알킬 또는
이때 R3은 비치환 또는 치환된 C1-C6 직쇄 또는 측쇄 알킬, C1-C6 알콕시, C5~C6 시클로알킬, C5~C6 아릴, C5~C6 아릴 C5~C6 시클로알킬 또는 C5~C6 헤테로시클로알킬이다.Wherein R3 is unsubstituted or substituted C1 -C6 straight or branched alkyl, C1 -C6 alkoxy, C5 to C6 cycloalkyl, C5 to C6 aryl, C5 to C6 aryl C5 to C6 cycloalkyl or C5 to C6 heterocycloalkyl.
더욱 바람직하게, 상기 A는
여기서 R1 및 R2는 각각 수소,
본 발명의 화학식 1로 표시되는 벤즈옥사졸로 치환된 피리딘 유도체의 구체적인 화합물은 하기와 같다.Specific compounds of the pyridine derivative substituted with benzoxazole represented by the general formula (1) of the present invention are as follows.
1) 3-벤즈옥사졸릴-5-(4-(피페라진-1-일))피리딘-2-아민;1) 3-benzoxazolyl-5- (4- (piperazin-1-yl)) pyridin-2-amine;
2) 3-벤즈옥사졸릴-5-(4-(몰포린-4-일))피리딘-2-아민;2) 3-benzoxazolyl-5- (4- (morpholin-4-yl)) pyridin-2-amine;
3) 3-벤즈옥사졸릴-5-(에틸-3-피페리딘 카르복실레이트)피리딘-2-아민;3) 3-benzoxazolyl-5- (ethyl-3-piperidine carboxylate) pyridin-2-amine;
4) 3-벤즈옥사졸릴-5-{4-(1-3급 부톡시 카보닐-피페리딘-4-일카보닐)피페라진-1-일}피리딘-2-아민;4) 3-benzoxazolyl-5- {4- (tert-butoxy carbonyl-piperidin-4-ylcarbonyl) piperazin-1-yl} pyridin-2-amine;
5) 3-벤즈옥사졸릴-5-{4-(메톡시프로판올)피페라진-1-일}피리딘-2-아민;5) 3-benzoxazolyl-5- {4- (methoxypropanol) piperazin-1-yl} pyridin-2-amine;
6) 3-벤즈옥사졸릴-5-(4-벤조일-피페라진-1-일)피리딘-2-아민;6) 3-benzoxazolyl-5- (4-benzoyl-piperazin-1-yl) pyridin-2-amine;
7) 3-벤즈옥사졸릴-5-{4-(벤질카보닐)피페라진-1-일}피리딘-2-아민;7) 3-benzoxazolyl-5- {4- (benzylcarbonyl) piperazin-1-yl} pyridin-2-amine;
8) 3-벤즈옥사졸릴-5-(4-이소프로필-피페라진-1-일)피리딘-2-아민;8) 3-benzoxazolyl-5- (4-isopropyl-piperazin-1-yl) pyridin-2-amine;
9) 3-벤즈옥사졸릴-5-{4-(2-메틸-프로필카보닐)피페라진-1-일}피리딘-2-아민;9) 3-benzoxazolyl-5- {4- (2-methyl-propylcarbonyl) piperazin-1-yl} pyridin-2-amine;
10) 3-벤즈옥사졸릴-5-{4-피페리딘-4-일카보닐)피페라진-1-일}피리딘-2-아민;10) 3-benzoxazolyl-5- {4-piperidin-4-ylcarbonyl) piperazin-1-yl} pyridin-2-amine;
11) 3-벤즈옥사졸릴-5-{4-피페리딘-3-일카보닐)피페라진-1-일}피리딘-2-아민;11) 3-benzoxazolyl-5- {4-piperidin-3-ylcarbonyl) piperazin-1-yl} pyridin-2-amine;
12) 3-벤즈옥사졸릴-5-{3-피페리딘-4-일카보닐)피페라진-1-일}피리딘-2-아민;12) 3-benzoxazolyl-5- {3-piperidin-4-ylcarbonyl) piperazin-1-yl} pyridin-2-amine;
13) 3-벤즈옥사졸릴-5-(3-퀴놀린일)피리딘-2-아민; 및13) 3-benzoxazolyl-5- (3-quinolinyl) pyridin-2-amine; And
14) 3-벤즈옥사졸릴-5-(4-이소퀴놀린일)피리딘-2-아민.14) 3-benzoxazolyl-5- (4-isoquinolinyl) pyridin-2-amine.
본 발명의 상기 화학식 1로 표시되는 벤즈옥사졸로 치환된 피리딘 유도체는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 약학적으로 허용가능한 염이란 표현은 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1의 염기 화합물의 이로운 효능을 떨어뜨리지 않는 화학식 1의 염기 화합물의 어떠한 유기 또는 무기 부가염을 의미한다. 이들 염은 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 질산, 황산, 과염소산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초 산, 젖산, 말레산, 푸마린산, 글루콘산, 메탄설폰산, 글리콘산, 숙신산, 타타르산, 갈룩투론산, 엠본산, 글루탐산, 아스파르트산, 옥살산, (D) 또는 (L) 말산, 말레산, 메테인설폰산, 에테인설폰산, 4-톨루엔술폰산, 살리실산, 시트르산, 벤조산 또는 말론산 등을 사용할 수 있다. 또한, 이들 염은 알칼리 금속염(나트륨염, 칼륨염 등) 및 알칼리 토금속염(칼슘염, 마그네슘염 등) 등을 포함한다. 예를들면, 산부가염으로는 아세테이트, 아스파테이트, 벤즈에이트, 베실레이트, 바이카보네이트/카보네이트, 바이설페이트/설페이트, 보레이트, 캄실레이트, 시트레이트, 에디실레이트, 에실레이트, 포메이트, 퓨마레이트, 글루셉테이트, 글루코네이트, 글루큐로네이트, 헥사플루오로포스페이트, 하이벤제이트, 하이드로클로라이드/클로라이드, 하이드로브로마이드/브로마이드, 하이드로요오디드/요오디드, 이세티오네이트, 락테이트, 말레이트, 말리에이트, 말로네이트, 메실레이트, 메틸설페이트, 나프틸레이트, 2-나프실레이트, 니코티네이트, 나이트레이트, 오로테이트, 옥살레이트, 팔미테이트, 파모에이트, 포스페이트/수소 포스페이트/이수소 포스페이트, 사카레이트, 스테아레이트, 석시네이트, 타르트레이트, 토실레이트, 트리플루오로아세테이트, 알루미늄, 알기닌, 벤자틴, 칼슘, 콜린, 디에틸아민, 디올아민, 글라이신, 라이신, 마그네슘, 메글루민, 올아민, 칼륨, 나트륨, 트로메타민, 아연염 등이 포함될 수 있으며, 이들 중 하이드로클로라이드 또는 트리플루오로아세테이트가 바람직하다.Pyridine derivatives substituted with benzoxazole represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and acid salts formed by pharmaceutically acceptable free acid are useful as salts. Do. The expression pharmaceutically acceptable salt is a concentration that has a relatively nontoxic and harmless effect on the patient and that any side effects due to the salt do not degrade the beneficial efficacy of the base compound of formula 1, or Means inorganic addition salts. These salts may include inorganic acids and organic acids as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, and the like, and as organic acids, citric acid, acetic acid, lactic acid, maleic acid and fu Malic acid, gluconic acid, methanesulfonic acid, glyconic acid, succinic acid, tartaric acid, galluxuronic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethane Sulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid and the like can be used. These salts also include alkali metal salts (sodium salts, potassium salts, and the like), alkaline earth metal salts (calcium salts, magnesium salts, and the like) and the like. For example, acid addition salts include acetates, aspartates, benzates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, edisylates, ecylates, formates, fumarates, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / Chloride, Hydrobromide / Bromide, Hydroiodide / Iodide, Isetionate, Lactate, Maleate, Mali Eate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccha Laterate, stearate, succinate, tartrate, tosylate, trifluoroacete , Aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like. Heavy hydrochloride or trifluoroacetate are preferred.
또한, 본 발명의 상기 화학식 1로 표시되는 벤즈옥사졸로 치환된 피리딘 유 도체는 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 이성질체, 수화물 및 용매화물을 모두 포함한다.In addition, the pyridine derivative substituted with benzoxazole represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates, and solvates that can be prepared by conventional methods. do.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile and adding an excess of an organic acid or an inorganic acid. It can be prepared by adding an acidic aqueous solution of and then precipitating or crystallizing. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.
본 명세서에서 이성질체는 동일한 화학식 또는 분자식을 가지지만 광학적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미하며, 상기 이성질체 및 이들의 혼합물 역시 본 발명의 범위에 포함된다.Isomers herein means compounds of the present invention or salts thereof having the same chemical formula or molecular formula, but which are optically or sterically different, and such isomers and mixtures thereof are also included within the scope of the present invention.
또한, 본 발명은 상기 화학식 1로 표시되는 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 제조방법을 제공한다.In addition, the present invention provides a method for preparing a pyridine derivative or pharmaceutically acceptable salt thereof substituted with benzoxazole represented by Chemical Formula 1.
본 발명에 따른 상기 화학식 1의 화합물은 하기 반응식 1~5에 나타낸 바와 같은 방법으로 제조될 수 있다.The compound of Formula 1 according to the present invention may be prepared by a method as shown in Schemes 1 to 5 below.
이하, 상기 제조방법을 반응식을 이용하여 설명한다.Hereinafter, the above production method will be described using the reaction scheme.
제조방법 1Manufacturing Method 1
하기 반응식 1로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이 의 약학적으로 허용가능한 염은As represented by the following Scheme 1, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof
출발물질인 화학식 2의 화합물을 금속 존재 하에 화학식 3의 화합물과 반응시켜 화학식 4의 화합물을 제조하는 단계(단계 1); 및Preparing a compound of formula 4 by reacting the starting compound of formula 2 with the compound of formula 3 in the presence of a metal (step 1); And
상기 단계 1에서 제조된 화학식 4의 화합물을 탈보호반응시켜 화학식 1의 화합물을 제조하는 단계(단계 2)를 포함하는 제조방법에 의해 제조될 수 있다.The deprotection reaction of the compound of Chemical Formula 4 prepared in Step 1 may be prepared by a process comprising the step of preparing the compound of Chemical Formula 1 (step 2).
(상기 반응식 1에서,(In Scheme 1,
X, R1및 R2는 화학식 1에서 정의한 바와 같고, n은 1-3의 정수이고, 화학식 1a는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이며, NaOt-Bu: 나트륨 3차부톡사이드, BINAP: 2,2'-비스(디페닐포스피노)-1,1'바이나프틸, Pd2dba3: 트리스(디벤질리덴아세톤)이팔라듐(0), TFA: 트리플루오로아세트산을 의미한다)X, R1 and R2 are as defined in formula 1, n is an integer of 1-3, formula 1a is a derivative of formula 1 or a pharmaceutically acceptable salt thereof, NaOt-Bu: sodium tert-butoxide , BINAP: 2,2'-bis (diphenylphosphino) -1,1 'binaphthyl, Pd2 dba3 : tris (dibenzylideneacetone) ipalladium (0), TFA: trifluoroacetic acid do)
제조방법 2Manufacturing Method 2
하기 반응식 2로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 2 below, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof
화학식 1b의 화합물을 R3-CO2H 또는 R3-COCl과 반응시켜 화학식 5의 화합물을 제조하는 단계(단계 1); 및Reacting a compound of Formula 1b with R3 -CO2 H or R3 -COCl to prepare a compound of Formula 5 (step 1); And
상기 단계 1에서 제조된 화학식 5의 화합물을 탈보호반응시켜 화학식 1c의 화합물을 제조하는 단계(단계 2)를 포함하는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 5 prepared in Step 1 may be prepared by a method comprising the step of preparing a compound of Chemical Formula 1c (Step 2).
(상기 반응식 2에서,(In Scheme 2,
R3은 화학식 1에서 정의한 바와 같고, n은 1-3의 정수이고, 화학식 1b 및 1c는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, EDAC:1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염, Et3N:트리에틸아민, TFA: 트리플루오로아세트산을 의미한다)R3 is as defined in Formula 1, n is an integer of 1-3, Formulas 1b and 1c are derivatives of Formula 1 or a pharmaceutically acceptable salt thereof, and EDAC: 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride, Et3 N: triethylamine, TFA means trifluoroacetic acid)
제조방법 3Manufacturing Method 3
하기 반응식 3으로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 3 below, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof
화학식 6의 화합물을 염기성 처리시켜 화학식 7의 화합물을 제조하는 단계(단계 1);Basic treatment of the compound of formula 6 to prepare a compound of formula 7 (step 1);
상기 단계 1에서 제조된 화학식 7의 화합물을 직접 치환반응시키거나 중간체인 화학식 9의 화합물을 생성시킨 후에 치환반응시켜 화학식 8의 화합물을 제조하는 단계(단계 2); 및Preparing a compound of formula 8 by directly substituting the compound of formula 7 prepared in step 1 or generating a compound of formula 9 which is an intermediate (step 2); And
상기 단계 2에서 제조된 화학식 8의 화합물을 탈보호반응시켜 화학식 1d의 화합물을 제조하는 단계(단계 3)를 포함하는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 8 prepared in Step 2 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1d (step 3).
(상기 반응식 3에서,(In Scheme 3,
R3은 화학식 1에서 정의한 바와 같고, n은 1-3의 정수이고, 화학식 1d는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이고, EDAC, Et3N 및 TFA는 상기 반응식 2에서 정의한 바와 같다)R3 is as defined in Formula 1, n is an integer of 1-3, Formula 1d is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof, and EDAC, Et3 N and TFA are as defined in Scheme 2 above. same)
제조방법 4Manufacturing Method 4
하기 반응식 4로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 4 below, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof
화학식 2의 화합물과 화학식 10의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)을 수행하여 화학식 11의 화합물을 제조하는 단계(단계 1); 및Preparing a compound of Formula 11 by performing a Suzuki coupling reaction between a compound of Formula 2 and a compound of Formula 10 (step 1); And
상기 단계 1에서 제조된 화학식 11의 화합물을 탈보호반응시켜 화학식 1e의 화합물을 제조하는 단계(단계 2)를 포함하는 제조방법에 의해 제조될 수 있다.Deprotection of the compound of Chemical Formula 11 prepared in Step 1 may be prepared by a manufacturing method comprising the step of preparing a compound of Chemical Formula 1e (Step 2).
(상기 반응식 4에서,(In Scheme 4,
A는 화학식 1에서 정의한 바와 같고, n은 1-3의 정수이고, 화학식 1e는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)A is as defined in formula 1, n is an integer of 1-3, formula 1e is a derivative of formula 1 or a pharmaceutically acceptable salt thereof)
제조방법 5Manufacturing Method 5
하기 반응식 5로 표시되는 바와 같이, 본 발명의 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은As represented by Scheme 5, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof
화학식 2의 화합물을 스즈키 커플링 반응(Suzuki coupling reaction)시켜 화학식 12의 중간체 화합물을 제조하는 단계(단계 1);Suzuki coupling reaction of a compound of Formula 2 to prepare an intermediate compound of Formula 12 (Step 1);
상기 단계 1에서 제조된 화학식 12의 화합물을 할로겐을 가지는 A 화합물과 스즈키 커플링 반응시켜 화학식 11의 화합물을 제조하는 단계(단계 2); 및Preparing a compound of Chemical Formula 11 by suzuki coupling reaction of the compound of Chemical Formula 12 prepared in step 1 with an A compound having halogen (step 2); And
상기 단계 2에서 제조된 화학식 11의 화합물을 탈보호반응시켜 화학식 1e의 화합물을 제조하는 단계(단계 3)를 포함하는 제조방법에 의해 제조될 수 있다.It may be prepared by a manufacturing method comprising the step (step 3) of preparing a compound of Formula 1e by deprotecting the compound of Formula 11 prepared in Step 2.
(상기 반응식 5에서,(In Scheme 5,
A는 화학식 1에서 정의한 바와 같고, n은 1-3의 정수이고, 화학식 1e는 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염이다)A is as defined in formula 1, n is an integer of 1-3, formula 1e is a derivative of formula 1 or a pharmaceutically acceptable salt thereof)
또한, 본 발명은 상기 화학식 1로 표시되는 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 이상세포 성장 질환의 예방 및 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for the prevention and treatment of aberrant cell growth diseases containing a pyridine derivative substituted with benzoxazole represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
이때, 상기 이상세포 성장 질환은 폐암, 뼈암, 췌장암, 피부암, 두경부암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 항문 주위 암, 위암, 결장암, 유방암, 자궁암, 나팔관 암, 자궁내막 암, 자궁경부암, 질암, 외음부암, 호지킨병, 식도암, 소장암, 내분비계암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신세포암, 신우암, 중추 신경계(CNS) 종양, 1차 CNS 림프종, 척수 종양, 뇌간 신경교종, 뇌하수체 선종 등이 바람직하다.At this time, the abnormal cell growth disease is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, perianal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrium Cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocyte lymphoma, Bladder cancer, kidney or ureter cancer, renal cell cancer, renal cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, and the like are preferred.
또한, 상기 이상세포 성장 질환은 건선, 양성 전립선 비대 또는 망막증인 것이 바람직하다.In addition, the abnormal cell growth disease is preferably psoriasis, benign prostatic hypertrophy or retinopathy.
나아가, 상기 이상세포 성장 질환은 양성 증식성 질환인 것이 바람직하며, 상기 양성 증식성 질환은 섬유선종, 경화성 선질환, 유두종 등이 바람직하다.Further, the abnormal cell growth disease is preferably a benign proliferative disease, the benign proliferative disease is preferably fibroadenoma, sclerotic gland disease, papilloma and the like.
상기 화학식 1로 표시되는 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염, 용매화물 및 수화물은 c-Met의 단백질 키나아제를 억제할 수 있다.A pyridine derivative substituted with benzoxazole represented by Formula 1 or a pharmaceutically acceptable salt, solvate and hydrate thereof may inhibit protein kinase of c-Met.
상기 단백질 키나아제 중 c-Met은 항암제 타겟으로 연구되고 있는 간세포 성장인자(HGF/SF) 수용체로서, 이를 타겟으로 하는 항암제가 많이 보고되어 있다(J. G. Christensen, J. Burrows et al., Cancer Letters, 2005, 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).Among the protein kinases, c-Met is a hepatocyte growth factor (HGF / SF) receptor that is being studied as an anticancer agent, and many anticancer agents targeting it have been reported (JG Christensen, J. Burrows et al., Cancer Letters, 2005). , 225, 1-26; WO 2004/076412; WO 2006/021881 A; WO 2006/021886; WO 2007/064797).
c-Met은 종양 형성, 증대된 세포 운동성 및 침입성 하에서의 종양 진행, 및 전이에 수반되는 폐암, 위암, 피부암, 신장암, 직장암, 췌장암 등의 많은 인간 암에서 과발현 또는 활성화되어 있다(J. G. Christensen et al., Cancer Letters, 2005, 225, 1-26; W. G. Jiang et al., Critical Reviews in Oncology/Hematology, 2005, 53, 35-69). c-Met 및 이의 리간드인 HGF는 많은 조직에서 발현되지만, 정상적으로는 주로 상피 및 간엽 기원의 세포 각각으로 한정되어 발현된다. c-Met 및 HGF/SF는 정상적인 포유동물의 발육에 필요하며, 세포 전이, 세포 증식 및 생존, 형태 형성성 분화 및 3-차원적 관상 구조물(신 세뇨관 세포, 선 형성 등)의 조직화에서 중요한 것으로 밝혀졌다. HGF/SF는 신생혈관생성 인자이며, 상피 세포에서의 c-Met 신호전달은 신생혈관생성에 필수적인 세포 반응(증식, 운동성, 침입성 등)을 유도한다.c-Met is overexpressed or activated in many human cancers, including lung cancer, gastric cancer, skin cancer, kidney cancer, rectal cancer, and pancreatic cancer, accompanied by tumor formation, increased cell motility and invasive tumor progression, and metastasis (JG Christensen et. al., Cancer Letters, 2005, 225, 1-26; WG Jiang et al., Critical Reviews in Oncology / Hematology, 2005, 53, 35-69). c-Met and its ligand, HGF, are expressed in many tissues, but are normally limited to cells of epithelial and mesenchymal origin, respectively. c-Met and HGF / SF are necessary for the development of normal mammals and are important for cell metastasis, cell proliferation and survival, morphogenic differentiation and organization of three-dimensional coronary structures (neotubule cells, glandogenesis, etc.). Turned out. HGF / SF is an angiogenesis factor and c-Met signaling in epithelial cells induces cellular responses (proliferation, motility, invasiveness, etc.) that are essential for angiogenesis.
또한 c-Met 및 이의 리간드인 HGF는 다양한 인간 암에서 증가된 수준으로 공-발현되는 것으로 밝혀졌다. 그러나, 수용체 및 리간드는 통상적으로 상이한 세포 유형에 의해 발현되기 때문에, c-Met 신호전달은 대부분 보편적으로 종양-기질(tumor-stroma) 상호작용에 의해 조절된다.It has also been found that c-Met and its ligand, HGF, are co-expressed at increased levels in various human cancers. However, because receptors and ligands are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma interactions.
또한, c-Met은 유전자 증폭, 돌연변이 및 재배열이 다양한 인간 암에서 관찰되었다. c-Met 키나아제를 활성화시키는 생식계 돌연변이를 갖는 부류는 다중 신장 종양 및 다른 조직의 종양에 걸리기 쉽다.In addition, c-Met has been observed in various human cancers with gene amplification, mutations and rearrangements. Classes with germline mutations that activate c-Met kinase are susceptible to multiple kidney tumors and tumors of other tissues.
c-Met 및/또는 HGF/SF의 발현은 상이한 유형의 암(폐, 결장, 유방, 전립선, 간, 췌장, 뇌, 신장, 난소, 위, 피부, 뼈 등의 암)의 질환 진행 상태와 연관되어 있으며, c-Met 또는 HGF/SF의 과발현은 폐, 간, 위 및 유방을 포함한 많은 주요 인간 암에서 나쁜 예후 및 질환 결과와 상관되는 것으로 밝혀졌다. 또한, c-Met은 췌장암, 신경교종 및 간세포암과 같은 성공적인 치료법이 없는 암에 직접 관련되어 있다고 보고되었으며, c-Met이 과발현되면서 ERBB3 신호전달체계 활성화로 야기된 폐암이 게피티니브(Gefitinib; 이레사(상품명:Irresa))에 내성을 갖게 된다고 보고되었다 (J. A. Engelman, K. Zejnullahu et. al. Science, 2007, 316, 1039-043).Expression of c-Met and / or HGF / SF is associated with disease progression in different types of cancer (lungs, colon, breast, prostate, liver, pancreas, brain, kidney, ovary, stomach, skin, bone, etc.) Overexpression of c-Met or HGF / SF has been found to correlate with poor prognosis and disease outcome in many major human cancers including lung, liver, stomach and breast. In addition, c-Met has been reported to be directly related to cancers without successful treatment such as pancreatic cancer, glioma and hepatocellular carcinoma, and lung cancer caused by ERBB3 signaling system activation due to overexpression of c-Met is Gefitinib (Gefitinib; It has been reported to be resistant to Irresa (JA Engelman, K. Zejnullahu et. Al. Science, 2007, 316, 1039-043).
본 발명에 따른 화학식 1의 유도체 또는 이의 약학적으로 허용가능한 염은 c-Met 키나아제 활성 실험에서 IC50가 20 μM 이하의 c-Met 키나아제 저해 활성을 갖는 결과를 나타내었다.The derivative of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof showed the result that the IC50 had a c-Met kinase inhibitory activity of 20 μM or less in the c-Met kinase activity experiment.
따라서, 본 발명에 따른 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적인 염을 유효성분으로 함유하는 약학적 조성물은 c-Met의 발현으로부터 유도되는 상술한 각종 암을 치료하는데 유용하게 사용될 수 있다.Therefore, the pharmaceutical composition containing a pyridine derivative substituted with benzoxazole according to the present invention or a pharmaceutical salt thereof as an active ingredient can be usefully used to treat various cancers described above derived from the expression of c-Met.
본 발명의 화합물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤 제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.The compounds of the present invention can be administered in various dosage forms, oral and parenteral, for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., which are commonly used, are used. It is manufactured by.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
또한, 본 발명의 화합물의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 일반적으로 약 0.001-100 mg/kg/일이며, 바람직하게는 0.01-35 mg/kg/일이다. 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.07-7000 mg/일이며, 바람직하게는 0.7-2500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내 지 수회로 분할 투여할 수도 있다.In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular time intervals as determined by the physician or pharmacist. Administration may be divided into exponential doses.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.
<<제조예Manufacturing example 1> (N-3급-부틸-3- 1> (N-tert-butyl-3-벤즈옥사졸릴Benzoxazolyl)-2-)-2-아미노피리딘Aminopyridine-5--5-보로닉산피나콜에스트의Of Voronic Pina Colest 제조 Produce
3급-부틸-3-벤즈옥사졸릴-5-브로모피리딘-2-아민(1 g), 칼륨아세테이트(1 g) 및 비스(피나콜레이트)디보론(1.25 g)을 디메틸술폭사이드 10 ㎖에 희석시킨 후 Pd(dppf)2Cl2(0.12 g)을 넣고 80 ℃에서 2시간 동안 질소 분위기 하에서 반응시켰다. 이후 실온으로 냉각시킨 후 셀라이트로 여과하고 여과액을 에틸아세테이트로 추출한 후 감압 증발시켰다. 잔사를 실리카 컬럼크로마토그래피(에틸아세테이트:n-헥산=1:15~1:8 농도구배)하여 목적화합물((N-3급-부틸-3-벤즈옥사졸릴)-2-아미노피리딘-5-보로닉산피나콜에스트)을 수득하였다(600 mg, 53.1%).Tert-Butyl-3-benzoxazolyl-5-bromopyridin-2-amine (1 g), potassium acetate (1 g) and bis (pinacholate) diboron (1.25 g) were added to 10 ml of dimethyl sulfoxide. After dilution, Pd (dppf) 2 Cl 2 (0.12 g) was added and reacted at 80 ° C. for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered through celite, the filtrate was extracted with ethyl acetate and evaporated under reduced pressure. The residue was purified by silica column chromatography (ethyl acetate: n-hexane = 1: 15 to 1: 8 concentration gradient) to obtain the target compound ((N-tert-butyl-3-benzoxazolyl) -2-aminopyridine-5-). to give the acid pinacol Boro Sbit) (600 mg, 53.1%) .
1H NMR (200 MHz, CDCl3) δ 9.04(s, 1H), 8.66 (s, 2H), 7.70-7.74 (m, 1H), 7.54-7.59(m, 1H), 7.33-7.37(m, 2H), 1.67(s, 9H), 1.38(s, 6H), 1.28(s, 6H).1 H NMR (200 MHz, CDCl3 ) δ 9.04 (s, 1H), 8.66 (s, 2H), 7.70-7.74 (m, 1H), 7.54-7.59 (m, 1H), 7.33-7.37 (m, 2H ), 1.67 (s, 9H), 1.38 (s, 6H), 1.28 (s, 6H).
<<실시예Example 1> 3- 1> 3-벤즈옥사졸릴Benzoxazolyl-5-(4-(피페라진-1-일))피리딘-2--5- (4- (piperazin-1-yl)) pyridine-2-아민의Amine삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt
단계 1: 3급-부틸-3-Step 1: tert-butyl-3-벤즈옥사졸릴Benzoxazolyl-5-(4-(4-3급--5- (4- (4-3 grade-부톡시카보닐피페라진Butoxycarbonylpiperazine-1-일)피리딘-2--1-yl) pyridine-2-아민의Amine 제조 Produce
제조방법 1의 방법을 이용하였다.The method of Preparation Method 1 was used.
3급-부틸-3-벤즈옥사졸릴-5-브로모피리딘-2-아민(500 mg)과 3급-부틸-1-피페라진카르복실레이트(400 mg)를 10 ㎖의 톨루엔에 희석시킨 후, 330 mg의 소디움 3차 부톡사이드 및 54 mg의 2,2'-비스(디페닐포스피노)-1,1'-바이나프틸(이하, BINAP)을 넣고 질소로 충전하였다. 상기 반응액에 트리스(디벤질리덴 아세톤)이팔라듐(0)(이하, Pd2dba3) 40 mg을 넣고 질소 분위기하에서 80 ℃에서 밤새 가열하였다. 이후, 실온으로 냉각하고 셀라이트로 여과하고 여과액을 감압 증발시켰다. 잔사를 실리카겔 칼럼크로마토그래피(에틸아세테이트:n-헥산=1:5)를 이용하여 정제 함으로써 목적화합물(3급-부틸-3-벤즈옥사졸릴-5-(4-(4-3급-부톡시카보닐피페라진-1-일)피리딘-2-아민)을 수득하였다(550 mg, 84.3%).Tert-butyl-3-benzoxazolyl-5-bromopyridin-2-amine (500 mg) and tert-butyl-1-piperazinecarboxylate (400 mg) were diluted in 10 ml of toluene. , 330 mg of sodium tert-butoxide and 54 mg of 2,2'-bis (diphenylphosphino) -1,1'-binaptyl (hereinafter referred to as BINAP) were charged with nitrogen. 40 mg of tris (dibenzylidene acetone) ipalladium (0) (hereinafter, Pd2 dba3 ) was added to the reaction solution, and the mixture was heated at 80 ° C. under nitrogen atmosphere overnight. Thereafter, the mixture was cooled to room temperature, filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 5) to obtain the target compound (tert-butyl-3-benzoxazolyl-5- (4- (4-tert-butoxy). Carbonylpiperazin-1-yl) pyridin-2-amine) was obtained (550 mg, 84.3%).
1H NMR (200 MHz, CDCl3) δ 8.45 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 7.33 (m, 2H), 3.60(s, 4H), 3.05(s, 4H), 1.58 (s, 9H), 1.49(s, 9H)1 H NMR (200 MHz, CDCl3 ) δ 8.45 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 7.33 (m, 2H), 3.60 (s, 4H), 3.05 (s, 4H), 1.58 (s, 9H), 1.49 (s, 9H)
단계 2: 3-Step 2: 3-벤즈옥사졸릴Benzoxazolyl-5-(4-(피페라진-1-일))피리딘-2--5- (4- (piperazin-1-yl)) pyridine-2-아민의Amine삼트리플루Samtriflu오로아세트산 염의 제조Preparation of Oroacetic Salt
상기 단계 1에서 제조된 3급-부틸-3-벤즈옥사졸릴-5-(4-(4-3급-부톡시카보닐피페라진-1-일)피리딘-2-아민(150 mg)을 트리플루오로아세트산(이하, TFA)(5 ㎖)에 용해시킨 후 60 ℃에서 12시간 동안 교반시켰다. 이후 반응물의 온도를 실온으로 낮추고 감압 농축하였다. 농축물에 에틸에테르를 넣고 30분 동안 교반시킨 후 여과하여 연두색 고체의 목적화합물(3-벤즈옥사졸릴-5-(4-(피페라진-1-일))피리딘-2-아민의 삼트리플루오로아세트산 염)을 수득하였다(180 mg, 85%).Tert-butyl-3-benzoxazolyl-5- (4- (4-tert-butoxycarbonylpiperazin-1-yl) pyridin-2-amine (150 mg) prepared in step 1 was After dissolving in fluoroacetic acid (hereinafter referred to as TFA) (5 mL), the mixture was stirred for 12 hours at 60 ° C. The reaction was then cooled to room temperature, concentrated under reduced pressure, ethyl ether was added to the concentrate, followed by stirring for 30 minutes. Filtration gave the desired compound as a pale green solid (the tritrifluoroacetic acid salt of 3-benzoxazolyl-5- (4- (piperazin-1-yl)) pyridin-2-amine) (180 mg, 85% ).
1H NMR (200 MHz, D2O) δ 8.70 (s, 1H), 7.76-7.92 (m, 3H), 7.57-7.63 (m, 2H), 3.58(m, 4H), 3.55(m, 4H)1 H NMR (200 MHz, D2 O) δ 8.70 (s, 1H), 7.76-7.92 (m, 3H), 7.57-7.63 (m, 2H), 3.58 (m, 4H), 3.55 (m, 4H)
<<실시예Example 2> 3- 2> 3-벤즈옥사졸릴Benzoxazolyl-5-(4-(-5- (4- (몰포린Morpholine-4-일))피리딘-2--4-yl)) pyridine-2-아민의Amine이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt
실시예 1에서 사용한 3급-부틸-1-피페라진카르복실레이트 대신 몰포린을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 수행하여 목적화합물(3-벤즈옥사졸릴-5-(4-(몰포린-4-일))피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(25 mg, 65.2%).Except for using morpholine instead of the tert-butyl-1-piperazinecarboxylate used in Example 1, and the target compound (3-benzoxazolyl-5- (4- ( Morpholin-4-yl)) itrifluoroacetic acid salt of pyridin-2-amine) (25 mg, 65.2%).
1H NMR (200 MHz, D2O) δ 8.49 (s, 1H), 7.85 (m, 1H), 7.46-7.83 (m, 4H), 3.94(m, 4H), 3.16(m, 4H)1 H NMR (200 MHz, D2 O) δ 8.49 (s, 1H), 7.85 (m, 1H), 7.46-7.83 (m, 4H), 3.94 (m, 4H), 3.16 (m, 4H)
<<실시예Example 3> 3- 3> 3-벤즈옥사졸릴Benzoxazolyl-5-(에틸-3-피페리딘-5- (ethyl-3-piperidine카르복실레이트Carboxylate)피리딘-2-Pyridine-2-아민의Amine이트리플루오로아세트산Ditrifluoroacetic acid 염의 제조 Preparation of Salt
실시예 1에서 사용한 3급-부틸-1-피페라진카르복실레이트 대신 에틸-3-피페리딘 카르복실레이트를 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 수행하여 목적화합물(3-벤즈옥사졸릴-5-(에틸-3-피페리딘 카르복실레이트)피리딘-2-아민의 이트리플루오로아세트산 염)을 얻었다(21 mg, 55.3%).Except for using the ethyl-3-piperidine carboxylate instead of the tert-butyl-1-piperazine carboxylate used in Example 1 and the target compound (3-benzoxa Ditrifluoroacetic acid salt of zolyl-5- (ethyl-3-piperidine carboxylate) pyridin-2-amine) was obtained (21 mg, 55.3%).
1H NMR (200 MHz, D2O) δ 8.48 (s, 1H), 7.81 (m, 1H), 7.65 (m, 1H), 7.47(m, 2H), 4.23(q, 2H), 3.46(m,1H), 3.11-3.29(m, 2H), 2.73-2.85(m, 2H), 1.71-2.03(m,4H), 1.36(t, 3H)1 H NMR (200 MHz, D2 O) δ 8.48 (s, 1H), 7.81 (m, 1H), 7.65 (m, 1H), 7.47 (m, 2H), 4.23 (q, 2H), 3.46 (m , 1H), 3.11-3.29 (m, 2H), 2.73-2.85 (m, 2H), 1.71-2.03 (m, 4H), 1.36 (t, 3H)
<<실시예Example 4> 3- 4> 3-벤즈옥사졸릴Benzoxazolyl-5-{4-(1-3급--5- {4- (1-3 grade-부톡시카보닐Butoxycarbonyl-피페리딘-4-Piperidine-4-일카보닐Ilcarbonyl)피페라진-1-일}피리딘-2-) Piperazin-1-yl} pyridine-2-아민의Amine 제조 Produce
제조방법 2의 방법을 이용하였다.The method of Preparation Method 2 was used.
실시예 1에서 제조된 3-벤즈옥사졸릴-5-(4-(피페라진-1-일))피리딘-2-아민(50 mg)과 1-(3급-부톡시카르보닐)-4-피페리딘카르복실산(58 mg)을 3 ㎖의 무수 메틸렌클로라이드에 희석하고 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염(이하, EDAC)(65 mg), 트리에틸아민(70 ㎖), 및 4-디메틸아미노피리딘(이하, DMAP)(5 mg)을 넣고 질소 분위기에서 2시간 동안 실온에서 교반시켰다. 이후 감압 증류한 후 잔사를 컬럼크로마토그래피(에틸아세테이트:n-헥산=1:1에서 100% 에틸아세테이트로 점차 변화시킴)하여 목적화합물(3-벤즈옥사졸릴-5-{4-(1-3급-부톡시카보닐-피페리딘-4-일카보닐)피페라진-1-일}피리딘-2-아민)을 수득하였다(65 mg, 76.4%).3-Benzoxazolyl-5- (4- (piperazin-1-yl)) pyridin-2-amine (50 mg) and 1- (tert-butoxycarbonyl) -4- prepared in Example 1 Piperidinecarboxylic acid (58 mg) was diluted in 3 ml of anhydrous methylene chloride and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (hereafter EDAC) (65 mg), triethylamine (70 mL), and 4-dimethylaminopyridine (hereinafter DMAP) (5 mg) were added thereto, and the mixture was stirred at room temperature for 2 hours in a nitrogen atmosphere. After distillation under reduced pressure, the residue was gradually purified by column chromatography (ethyl acetate: n-hexane = 1: 1 to 100% ethyl acetate) to obtain the title compound (3-benzoxazolyl-5- {4- (1-3). Tert-butoxycarbonyl-piperidin-4-ylcarbonyl) piperazin-1-yl} pyridin-2-amine) was obtained (65 mg, 76.4%).
1H NMR (200 MHz, CDCl3) δ 8.0 (s, 2H), 7.7 (m, 1H), 7.5 (m, 1H), 7.47(m, 2H), 6.9(brs, 2H), 4.17(m, 3H), 3.75(m,5H), 3.09(m, 4H), 2.85(m, 1H), 1.73(m,4H), 1.47(s, 9H)1 H NMR (200 MHz, CDCl3 ) δ 8.0 (s, 2H), 7.7 (m, 1H), 7.5 (m, 1H), 7.47 (m, 2H), 6.9 (brs, 2H), 4.17 (m, 3H), 3.75 (m, 5H), 3.09 (m, 4H), 2.85 (m, 1H), 1.73 (m, 4H), 1.47 (s, 9H)
<<실시예Example 5> 3- 5> 3-벤즈옥사졸릴Benzoxazolyl-5-{4-(-5- {4- (메톡시프로판올Methoxypropanol)피페라진-1-일}피리딘-2-아민의 제조Preparation of Piperazin-1-yl} pyridin-2-amine
실시예 4에서 사용한 1-(3급-부톡시카르보닐)-4-피페리딘카르복실산 대신 3-메톡시프로피온산을 사용한 것을 제외하고는 실시예 4의 방법과 동일한 방법으로 수행하여 목적화합물(3-벤즈옥사졸릴-5-{4-(메톡시프로판올)피페라진-1-일}피리딘-2-아민)을 수득하였다(15 mg, 75%).The target compound was prepared in the same manner as in Example 4, except that 3-methoxypropionic acid was used instead of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid used in Example 4. (3-benzoxazolyl-5- {4- (methoxypropanol) piperazin-1-yl} pyridin-2-amine) was obtained (15 mg, 75%).
1H NMR (200 MHz, CDCl3) δ 8.00-8.04 (m, 2H), 7.73-7.78 (m, 1H), 7.52-7.62(m, 1H), 7.35- 7.42(m,2H), 6.73(brs, 2H), 3.63- 3.85(m, 6H), 3.40(s,3H), 3.01(m, 4H), 2.69(t, 2H)1 H NMR (200 MHz, CDCl3 ) δ 8.00-8.04 (m, 2H), 7.73-7.78 (m, 1H), 7.52-7.62 (m, 1H), 7.35-7.42 (m, 2H), 6.73 (brs , 2H), 3.63- 3.85 (m, 6H), 3.40 (s, 3H), 3.01 (m, 4H), 2.69 (t, 2H)
<<실시예Example 6> 3- 6> 3-벤즈옥사졸릴Benzoxazolyl-5-(4--5- (4-벤조일Benzoyl-피페라진-1-일)피리딘-2-Piperazin-1-yl) pyridine-2-아민의Amine 제조 Produce
실시예 4에서 사용한 1-(3급-부톡시카르보닐)-4-피페리딘카르복실산 대신 벤조산을 사용한 것을 제외하고는 실시예 4의 방법과 동일한 방법으로 수행하여 목적화합물(3-벤즈옥사졸릴-5-(4-벤조일-피페라진-1-일)피리딘-2-아민)을 수득하였다(22 mg, 80%).Except for using benzoic acid instead of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid used in Example 4, and the target compound (3-benz Oxazolyl-5- (4-benzoyl-piperazin-1-yl) pyridin-2-amine) was obtained (22 mg, 80%).
1H NMR (200 MHz, CDCl3) δ 7.98-8.07 (m, 2H), 7.72-7.76 (m, 1H), 7.55-7.60(m, 1H), 7.34 -7.46(m,7H), 6.67(brs, 2H), 3.67- 3.94(m, 4H), 3.11(m,4H)1 H NMR (200 MHz, CDCl3 ) δ 7.98-8.07 (m, 2H), 7.72-7.76 (m, 1H), 7.55-7.60 (m, 1H), 7.34 -7.46 (m, 7H), 6.67 (brs , 2H), 3.67-3.94 (m, 4H), 3.11 (m, 4H)
<<실시예Example 7> 3- 7> 3-벤즈옥사졸릴Benzoxazolyl-5-{4-(-5- {4- (벤질카보닐Benzylcarbonyl)피페라진-1-일}피리딘-2-) Piperazin-1-yl} pyridine-2-아민의Amine 제조 Produce
실시예 4에서 사용한 1-(3급-부톡시카르보닐)-4-피페리딘카르복실산 대신 페닐아세트산을 사용한 것을 제외하고는 실시예 4의 방법과 동일한 방법으로 수행하여 목적화합물(3-벤즈옥사졸릴-5-{4-(벤질카보닐)피페라진-1-일}피리딘-2-아민)을 수득하였다(15 mg, 50%).Except for using phenyl acetic acid instead of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid used in Example 4 was carried out in the same manner as in Example 4 to obtain the target compound (3- Benzoxazolyl-5- {4- (benzylcarbonyl) piperazin-1-yl} pyridin-2-amine) was obtained (15 mg, 50%).
1H NMR (200 MHz, CDCl3) δ 7.90-7.98 (m, 2H), 7.70-7.75 (m, 1H), 7.54-7.58(m, 1H), 7.22 -7.38(m, 7H), 6.65(brs, 2H), 3.80-3.87(m, 4H), 3.63(m, 2H), 3.05(m, 2H), 2.89(m, 2H)1 H NMR (200 MHz, CDCl3 ) δ 7.90-7.98 (m, 2H), 7.70-7.75 (m, 1H), 7.54-7.58 (m, 1H), 7.22 -7.38 (m, 7H), 6.65 (brs , 2H), 3.80-3.87 (m, 4H), 3.63 (m, 2H), 3.05 (m, 2H), 2.89 (m, 2H)
<<실시예Example 8> 3-벤즈옥사졸릴-5-(4-이소프로필-피페라진-1-일)피리딘-2-아민의 제조 8> Preparation of 3-benzoxazolyl-5- (4-isopropyl-piperazin-1-yl) pyridin-2-amine
실시예 4에서 사용한 1-(3급-부톡시카르보닐)-4-피페리딘카르복실산 대신 이소부티르산을 사용한 것을 제외하고는 실시예 4의 방법과 동일한 방법으로 수행하여 목적화합물(3-벤즈옥사졸릴-5-(4-이소프로필-피페라진-1-일)피리딘-2-아민)을 수득하였다(12 mg, 45%).Except for using isobutyric acid in place of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid used in Example 4, and the target compound (3- Benzoxazolyl-5- (4-isopropyl-piperazin-1-yl) pyridin-2-amine) was obtained (12 mg, 45%).
1H NMR (200 MHz, CDCl3) δ 8.00 (s, 2H), 7.71-7.76 (m, 1H), 7.55-7.59(m, 1H), 7.31- 7.40(m, 2H), 6.99(brs, 2H), 3.71- 3.82(m, 4H), 3.08(m, 4H), 2.84(m, 1H), 1.19(d, 6H)1 H NMR (200 MHz, CDCl3 ) δ 8.00 (s, 2H), 7.71-7.76 (m, 1H), 7.55-7.59 (m, 1H), 7.31-7.40 (m, 2H), 6.99 (brs, 2H ), 3.71-3.82 (m, 4H), 3.08 (m, 4H), 2.84 (m, 1H), 1.19 (d, 6H)
<<실시예Example 9> 3- 9> 3-벤즈옥사졸릴Benzoxazolyl-5-{4-(2--5- {4- (2-메틸methyl--프로필카보닐Propyl Carbonyl)피페라진-1-일}피리딘-2-) Piperazin-1-yl} pyridine-2-아민의Amine 제조 Produce
실시예 4에서 사용한 1-(3급-부톡시카르보닐)-4-피페리딘카르복실산 대신 이 소발레르산을 사용한 것을 제외하고는 실시예 4의 방법과 동일한 방법으로 수행하여 목적화합물(3-벤즈옥사졸릴-5-{4-(2-메틸-프로필카보닐)피페라진-1-일}피리딘-2-아민)을 수득하였다(13 mg, 45%).The same procedure as in Example 4 was carried out except that sovaleric acid was used instead of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid used in Example 4. 3-benzoxazolyl-5- {4- (2-methyl-propylcarbonyl) piperazin-1-yl} pyridin-2-amine) was obtained (13 mg, 45%).
1H NMR (200 MHz, CDCl3) δ 7.97-8.05 (m, 2H), 7.71-7.76 (m, 1H), 7.55-7.59(m, 1H), 7.34- 7.40(m, 2H), 6.68(brs, 2H), 3.65- 3.86(m, 4H), 2.13-2.29(m, 3H), 2.84(m, 1H), 1.10(d, 6H)1 H NMR (200 MHz, CDCl3 ) δ 7.97-8.05 (m, 2H), 7.71-7.76 (m, 1H), 7.55-7.59 (m, 1H), 7.34-7.40 (m, 2H), 6.68 (brs , 2H), 3.65- 3.86 (m, 4H), 2.13-2.29 (m, 3H), 2.84 (m, 1H), 1.10 (d, 6H)
<<실시예Example 10> 3- 10> 3-벤즈옥사졸릴Benzoxazolyl-5-{4-피페리딘-4--5- {4-piperidine-4-일카보닐Ilcarbonyl)피페라진-1-일}피리딘-2-) Piperazin-1-yl} pyridine-2-아민의Amine삼트리플루오로아세트산Tritrifluoroacetic acid 염의 제조 Preparation of Salt
실시예 4에서 제조된 3-벤즈옥사졸릴-5-{4-(1-3급-부톡시카보닐-피페리딘-4-일카보닐)피페라진-1-일}피리딘-2-아민(25 mg)을 TFA 2 ㎖에 용해시킨 후 실온에서 밤새 교반시켰다. 이후 감압증류하고 잔사를 메틸렌클로라이드로 희석시킨 후 한번 더 감압 증발시킨 후 잔사에 무수 에테르 5 ㎖를 넣어 고체화시킨 후 여과하고 진공 건조하여 연두색 고체인 목적화합물(3-벤즈옥사졸릴-5-{4-피페리딘-4-일카보닐)피페라진-1-일}피리딘-2-아민의 삼트리플루오로아세트산 염)을 수득하였다(20 mg, 57 %).3-Benzoxazolyl-5- {4- (1 -tert-butoxycarbonyl-piperidin-4-ylcarbonyl) piperazin-1-yl} pyridin-2-amine prepared in Example 4 (25 mg) was dissolved in 2 ml of TFA and stirred overnight at room temperature. After distilling under reduced pressure, the residue was diluted with methylene chloride and evaporated once more under reduced pressure. The residue was solidified with 5 ml of anhydrous ether, filtered and dried in vacuo to yield the title compound as a light green solid (3-benzoxazolyl-5- {4 Tritrifluoroacetic acid salt of piperidin-4-ylcarbonyl) piperazin-1-yl} pyridin-2-amine) (20 mg, 57%).
1H NMR (200 MHz, D2O) δ 8.00-8.04 (s, 2H), 7.73-7.78 (m, 1H), 7.52-7.62(m, 1H), 7.35-7.42(m,2H), 4.17(m, 3H), 3.75(m,5H), 3.09(m, 4H), 2.85(m, 1H), 1.73(m,4H).1 H NMR (200 MHz, D2 O) δ 8.00-8.04 (s, 2H), 7.73-7.78 (m, 1H), 7.52-7.62 (m, 1H), 7.35-7.42 (m, 2H), 4.17 ( m, 3H), 3.75 (m, 5H), 3.09 (m, 4H), 2.85 (m, 1H), 1.73 (m, 4H).
<<실시예Example 11> 3- 11> 3-벤즈옥사졸릴Benzoxazolyl-5-{4-피페리딘-3--5- {4-piperidine-3-일카보닐Ilcarbonyl)피페라진-1-일}피리딘-2-) Piperazin-1-yl} pyridine-2-아민의Amine삼트리플루Samtriflu오로아세트산 염의 제조Preparation of Oroacetic Salt
실시예 1에서 제조된 3-벤즈옥사졸릴-5-(4-(피페라진-1-일))피리딘-2-아민(50 mg)과 1-3급-부톡시카르보닐-3-피페리딘카르보닉산(58 mg)을 EDAC(65 ㎖), 트리에틸아민(0.07 ㎖), DMAP(5 ㎖) 및 무수메틸렌클로라이드(3 ㎖)의 혼합용매에 넣고 반응시켜 3-벤즈옥사졸릴-5-{4-N-3급-부톡시카르보닐피페리딘-3-일카보닐)피페라진-1-일]피리딘-2-아민을 제조하였다. 생성물을 실리카 컬럼으로 정제한 후 TFA 5 ㎖에 용해시킨 후 밤새 교반시켰다. 이후 감압농축한 후 잔사에 무수 에테르 5 ㎖를 넣어 고체화시킨 후 여과하고 진공 건조하여 연두색 고체인 목적화합물(3-벤즈옥사졸릴-5-{4-피페리딘-3-일카보닐)피페라진-1-일}피리딘-2-아민의 삼트 리플루오로아세트산 염)을 수득하였다(32 mg, 47 %).3-Benzoxazolyl-5- (4- (piperazin-1-yl)) pyridin-2-amine (50 mg) and 1-3-butoxycarbonyl-3-piperier prepared in Example 1 Dicarbonic acid (58 mg) was added to a mixed solvent of EDAC (65 mL), triethylamine (0.07 mL), DMAP (5 mL) and anhydrous methylene chloride (3 mL), and reacted with 3-benzoxazolyl-5. -{4-N-tert-butoxycarbonylpiperidin-3-ylcarbonyl) piperazin-1-yl] pyridin-2-amine was prepared. The product was purified by silica column, dissolved in 5 ml of TFA and stirred overnight. After concentrating under reduced pressure, the residue was solidified by adding 5 ml of anhydrous ether, followed by filtration and drying in vacuo to give the title compound (3-benzoxazolyl-5- {4-piperidin-3-ylcarbonyl) piperazine as a light green solid. Tritrifluoroacetic acid salt of -1-yl} pyridin-2-amine) (32 mg, 47%).
1H NMR (200 MHz, D2O) δ 8.00-8.04 (s, 2H), 7.72-7.76 (m, 1H), 7.56-7.61(m, 1H), 7.35-7.42(m, 2H), 4.14(m, 2H), 3.78(m,4H), 3.08-3.14(m, 4H), 2.6-3.0(m, 3H), 1.6-2.0(m,6H)1 H NMR (200 MHz, D2 O) δ 8.00-8.04 (s, 2H), 7.72-7.76 (m, 1H), 7.56-7.61 (m, 1H), 7.35-7.42 (m, 2H), 4.14 ( m, 2H), 3.78 (m, 4H), 3.08-3.14 (m, 4H), 2.6-3.0 (m, 3H), 1.6-2.0 (m, 6H)
<<실시예Example 12> 3- 12> 3-벤즈옥사졸릴Benzoxazolyl-5-{3-피페리딘-4--5- {3-piperidine-4-일카보닐Ilcarbonyl)피페라진-1-일}피리딘-2-) Piperazin-1-yl} pyridine-2-아민의Amine트리플루오로아세트산Trifluoroacetic acid 염의 제조 Preparation of Salt
제조방법 3의 방법을 사용하였다.The method of Preparation Method 3 was used.
화학식 6의 화합물(50 mg)을 메탄올 2 ㎖에 용해시킨 후 리튬하이드록사이드 수화물(10 mg)을 넣고 밤새 교반시켰다. 이후 5% 염산용액으로 pH를 5로 조정한 후, 에틸아세테이트로 추출하고 감압건조 및 진공건조시켜 화학식 7의 화합물을 수득하였다(38 mg, 81.5%). 이후, 상기 화학식 7의 화합물에 1-3급-부톡시카르보닐피페라진(28 mg), EDAC(38 mg), 트리에틸아민(0.04 ㎖), DMAP(4 mg) 및 무수메틸렌클로라이드를 넣고 실온에서 2시간 동안 교반시켰다. 이후 용매를 감압증발시킨 후 잔사를 실리카 컬럼크로마토그래피(에틸아세테이트:n-헥산=1:1에서 100% 에틸아 세테이트로 농도구배)하여 화학식 8의 화합물을 수득하였다(41 mg, 75.9%). 수득한 화학식 8의 화합물을 3 ㎖의 TFA에 용해시킨 후 60 ℃로 밤새 가열하였다. 냉각후 생성물을 감압 농축시킨 후, 무수에테르 5 ㎖를 넣고 고체화시켰다. 이후 여과 및 진공 건조시켜 목적화합물(3-벤즈옥사졸릴-5-{3-피페리딘-4-일카보닐)피페라진-1-일}피리딘-2-아민의 트리플루오로아세트산 염)을 수득하였다(25 mg, 48.5%).Compound (50 mg) of Chemical Formula 6 was dissolved in 2 ml of methanol, and then lithium hydroxide hydrate (10 mg) was added thereto, followed by stirring overnight. After adjusting the pH to 5 with 5% hydrochloric acid solution, the mixture was extracted with ethyl acetate, dried under reduced pressure and vacuum dried to obtain a compound of formula 7 (38 mg, 81.5%). Then, 1-3-butoxycarbonylpiperazine (28 mg), EDAC (38 mg), triethylamine (0.04 mL), DMAP (4 mg) and anhydrous methylene chloride were added to the compound of Chemical Formula 7 at room temperature. Stirred for 2 h. After evaporating the solvent under reduced pressure, the residue was purified by silica column chromatography (ethyl acetate: n-hexane = 1: 1 to 100% ethyl acetate in concentration gradient) to obtain a compound of formula 8 (41 mg, 75.9%). . The obtained compound of formula 8 was dissolved in 3 ml of TFA and then heated to 60 ° C. overnight. After cooling, the product was concentrated under reduced pressure, and 5 ml of anhydrous ether was added to solidify. After filtration and vacuum drying, the target compound (trifluoroacetic acid salt of 3-benzoxazolyl-5- {3-piperidin-4-ylcarbonyl) piperazin-1-yl} pyridin-2-amine) was obtained. Obtained (25 mg, 48.5%).
1H NMR (200 MHz, D2O) δ 7.9(s, 1H), 8.37 (s, 1H), 7.78-7.81 (m, 1H), 7.46-7.61(m, 1H), 7.42-7.46(m, 2H), 3.75-3.9(m, 4H), 3.5(m,4H), 3.08-3.2(m, 4H), 2.6-3.0(m, 4H), 1.8-2.0(m,3H)1 H NMR (200 MHz, D2 O) δ 7.9 (s, 1H), 8.37 (s, 1H), 7.78-7.81 (m, 1H), 7.46-7.61 (m, 1H), 7.42-7.46 (m, 2H), 3.75-3.9 (m, 4H), 3.5 (m, 4H), 3.08-3.2 (m, 4H), 2.6-3.0 (m, 4H), 1.8-2.0 (m, 3H)
<<실시예Example 13> 3- 13> 3-벤즈옥사졸릴Benzoxazolyl-5-(3-퀴놀린일)피리딘-2--5- (3-quinolinyl) pyridine-2-아민의Amine트리플루오로아세트산Trifluoroacetic acid 염의 제조 Preparation of Salt
제조예 1에서 제조된 (N-3급-부틸-3-벤즈옥사졸릴)-2-아미노피리딘-5-보로닉산피나콜에스트(60 mg), 3-브로모퀴놀린(0.019 ㎖) 및 칼륨아세테이트(59 mg)를 디메틸술폭사이드(2 ㎖)에 용해시킨 후, [1,1-비스(디페닐포스피노)-페로센]디클로로팔라듐(Ⅱ)(이하, Pd(dppf)2Cl2)(8.6 mg)을 넣고 80 ℃에서 2시간 동안 질소 분위기 하에서 교반시켰다. 이후 실온으로 냉각시킨 다음 셀라이트로 여과하고 여과액을 에틸아세테이트로 추출한 후, 용매를 감압 증발시켰다. 잔사를 실리카 컬럼크로마토그래피(에틸아세테이트:n-헥산=1:6~1:1 농도구배)하여 3급-부틸-3-벤즈옥사졸릴-5-(3-퀴놀린일)피리딘-2-아민을 제조하였다(30 mg). 이후, 제조된 3급-부틸-3-벤즈옥사졸릴-5-(3-퀴놀린일)피리딘-2-아민을 2 ㎖의 TFA에 용해시킨 후, 60 ℃로 밤새 교반시켰다. 냉각후 생성물을 감압 농축시킨 후, 무수에테르 5 ㎖를 넣고 고체화시켰다. 이후 여과 및 진공 건조시켜 목적화합물(3-벤즈옥사졸릴-5-(3-퀴놀린일)피리딘-2-아민의 트리플루오로아세트산 염)을 수득하였다(25 mg, 73%).(N-tert-Butyl-3-benzoxazolyl) -2-aminopyridine-5-boronic acid pinacol est (60 mg), 3-bromoquinoline (0.019 mL) and potassium acetate prepared in Preparation Example 1 (59 mg) was dissolved in dimethyl sulfoxide (2 mL) and then [1,1-bis (diphenylphosphino) -ferrocene] dichloropalladium (II) (hereinafter Pd (dppf)2 Cl2 ) (8.6 mg) was added and stirred at 80 ° C. for 2 hours under a nitrogen atmosphere. Thereafter, the mixture was cooled to room temperature, filtered through celite, the filtrate was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by silica column chromatography (ethyl acetate: n-hexane = 1: 6 to 1: 1 gradient) to give tert-butyl-3-benzoxazolyl-5- (3-quinolinyl) pyridin-2-amine. Prepared (30 mg). Thereafter, the prepared tert-butyl-3-benzoxazolyl-5- (3-quinolinyl) pyridin-2-amine was dissolved in 2 mL of TFA, followed by stirring at 60 ° C. overnight. After cooling, the product was concentrated under reduced pressure, and 5 ml of anhydrous ether was added to solidify. Filtration and vacuum drying were then carried out to give the target compound (trifluoroacetic acid salt of 3-benzoxazolyl-5- (3-quinolinyl) pyridin-2-amine) (25 mg, 73%).
1H NMR (200 MHz, D2O) δ 9.2(s, 1H), 8.4-8.8 (m, 4H), 7.3-8.2(m, 7H).1 H NMR (200 MHz, D2 O) δ 9.2 (s, 1H), 8.4-8.8 (m, 4H), 7.3-8.2 (m, 7H).
<<실시예Example 14> 3- 14> 3-벤즈옥사졸릴Benzoxazolyl-5-(4-이소퀴놀린일)피리딘-2--5- (4-isoquinolinyl) pyridine-2-아민의Amine트리플루오로아세트산Trifluoroacetic acid 염의 제조 Preparation of Salt
실시예 13에서 사용한 3-브로모퀴놀린 대신 4-브로모이소퀴놀린을 사용한 것을 제외하고는 실시예 13의 방법과 동일한 방법으로 수행하여 목적화합물(3-벤즈옥사졸릴-5-(4-이소퀴놀린일)피리딘-2-아민의 트리플루오로아세트산 염)을 수득하였다(25 mg, 73%).Except for using 3-bromoquinoline used in Example 13, except that 4-bromoisoquinoline was used in the same manner as in Example 13 to the target compound (3-benzoxazolyl-5- (4-isoquinoline 1) trifluoroacetic acid salt of pyridin-2-amine) (25 mg, 73%).
1H NMR (200 MHz, D2O) δ 8.7(s,2H), 8.0-8.6(m,6H), 7.4-7.9(m, 4H)1 H NMR (200 MHz, D2 O) δ 8.7 (s, 2H), 8.0-8.6 (m, 6H), 7.4-7.9 (m, 4H)
<<실험예Experimental Example 1> c- 1> c-MetMet키나아제Kinase 억제활성 실험 Inhibitory activity test
본 발명에 따른 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염의 이상세포의 증식억제활성을 세포단계에서 측정하기 위하여 하기와 같은 실험을 수행하였다.In order to determine the proliferation inhibitory activity of the abnormal cells of the pyridine derivative or pharmaceutically acceptable salt thereof substituted with benzoxazole according to the present invention, the following experiment was performed.
c-Met 키나아제에 대한 저해활성을 시간분해형광도(Time-resolved fluorescence, TRF)의 일종인 분리 증강된 란탄족플루오로 면역 분석(Dissociation Enhanced Lanthanide Fluoro Immuno Assay, DELFIA; Perkin Elmer)을 이용하여 분석하였다.Inhibitory activity against c-Met kinase was analyzed using Dissociation Enhanced Lanthanide Fluoro Immuno Assay (DELFIA; Perkin Elmer), a type of time-resolved fluorescence (TRF). It was.
그레이너 96웰 V형 바닥 플레이트에 시험화합물로서 실시예 4~6, 8~12에서 제조된 화합물 10 ㎕을 가하고 c-Met 효소를 섞은 티로신 키나아제 버퍼(20 ㎕)를 가한 후, 상기 효소 및 시험화합물을 15분 동안 혼합하여 배양하였다. 여기에 ATP용액(10 ㎕)을 가하여 상온에서 30분 동안 키나아제 반응을 시킨후, 50 mM 에틸렌다이아민테트라아세트산 용액(EDTA, 40 ㎕)을 가하여 반응을 중지시켰다. 스트렙트아비딘이 코팅된 플레이트에 반응물을 옮기고 진탕하에 배양하고 2시간 후 PBS-T 완충액(PBS 0.05% 트윈20)으로 3회 세척하였다.10 μl of the compound prepared in Examples 4 to 6 and 8 to 12 was added to the Greyner 96-well V-type bottom plate, and tyrosine kinase buffer (20 μl) mixed with c-Met enzyme was added. Compounds were incubated by mixing for 15 minutes. ATP solution (10 μl) was added thereto, followed by kinase reaction at room temperature for 30 minutes, and then 50 mM ethylenediaminetetraacetic acid solution (EDTA, 40 μl) was added to stop the reaction. The reactions were transferred to streptavidin-coated plates, incubated under shaking and washed three times with PBS-T buffer (PBS 0.05% Tween20) after 2 hours.
유로퓸이 붙은 항-포스포타이로신 항체를 1:2,500으로 희석시켜 웰 당 100 ㎕씩 가하고 진탕하에 배양하고 1시간 후, PBS-T 완충액(PBS 0.05% 트윈20)으로 5회 세척하였다.Europium-containing anti-phosphotyrosine antibody was diluted 1: 2,500, added to 100 μl per well, incubated under shaking, and washed 1 time with PBS-T buffer (PBS 0.05% Tween20).
개선제(enhancement solution, 100 ㎖)을 가하고 5분 동안 진탕배양한 후, 왈락 인비전 2103(Wallac Envision 2103) 기기로 615/665 nm의 파장 범위에서 판독하였다.Enhancement solution (100 mL) was added and shaken for 5 minutes, then read in a wavelength range of 615/665 nm with a Wallac Envision 2103 instrument.
상기 실험을 수행한 시험화합물의 IC50는 2개씩의 데이터 세트로 결정하였고 프리즘(버전 5.01, 그래프패드) 소프트웨어를 이용하여 구하였다.The IC50 of the test compound which carried out the experiment was determined by two data sets and was obtained using Prism (version 5.01, GraphPad) software.
c-Met 키나아제 효소활성을 50%로 감소시키는 상기 화합물의 IC50는 하기 표 1에 나타내었다.The IC50 of this compound which reduces c-Met kinase enzyme activity by 50% is shown in Table 1 below.
표 1에 나타낸 바와 같이, 본 발명에 따른 화합물(실시예 4~6, 8~12)의 IC50가 20 μM 이하로 측정되었으며, 이로부터 본 발명에 따른 벤즈옥사졸로 치환된 피리딘 유도체 또는 이의 약학적으로 허용가능한 염은 c-Met 키나아제에 대한 우수한 억제효과가 있음을 알 수 있다.As shown in Table 1, the IC50 of the compounds according to the present invention (Examples 4 to 6, 8 to 12) was measured at 20 μM or less, from which the pyridine derivatives or pharmaceutics thereof substituted with benzoxazoles according to the present invention. It can be seen that the acceptable salt has an excellent inhibitory effect on c-Met kinase.
하기에 본 발명의 조성물을 위한 제제예를 예시한다.Examples of formulations for the composition of the present invention are illustrated below.
<<제제예Formulation example 1> 약학적 제제의 제조 1> Preparation of Pharmaceutical Formulations
<1-1>산제의 제조<1-1>Preparationof powders
화학식 1의 벤즈옥사졸로 치환된 피리딘 유도체 2 g2 g of pyridine derivative substituted with benzoxazole of Formula 1
유당 1 g1 g lactose
상기의 성분을 혼합한 후, 기밀포에 충진하여 산제를 제조하였다.After mixing the above components, the airtight cloth was filled to prepare a powder.
<1-2> 정제의 제조<1-2> Preparation of Tablet
화학식 1의 벤즈옥사졸로 치환된 피리딘 유도체 100 ㎎100 mg of pyridine derivative substituted with benzoxazole of Formula 1
옥수수전분 100 ㎎Corn starch 100 mg
유 당 100 ㎎Lactose 100 mg
스테아린산 마그네슘 2 ㎎2 mg magnesium stearate
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
<1-3> 캡슐제의 제조<1-3> Preparation of Capsule
화학식 1의 벤즈옥사졸로 치환된 피리딘 유도체 100 ㎎100 mg of pyridine derivative substituted with benzoxazole of Formula 1
옥수수전분 100 ㎎Corn starch 100 mg
유 당 100 ㎎Lactose 100 mg
스테아린산 마그네슘 2 ㎎2 mg magnesium stearate
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
<1-4> 주사액제의 제조<1-4> Preparation of Injection Solution
화학식 1의 벤즈옥사졸로 치환된 피리딘 유도체 10 ㎍/㎖10 μg / ml pyridine derivative substituted with benzoxazole of formula (1)
묽은 염산 BP pH 3.5로 될 때까지Dilute hydrochloric acid BP until pH 3.5
주사용 염화나트륨 BP 최대 1 ㎖Injectable sodium chloride BP up to 1 ml
적당한 용적의 주사용 염화나트륨 BP 중에 본 발명에 따른 벤즈옥사졸로 치환된 피리딘 유도체를 용해시키고, 생성된 용액의 pH를 묽은 염산 BP를 사용하여 pH 3.5로 조절하고, 주사용 염화나트륨 BP를 사용하여 용적을 조절하고 충분히 혼합하였다. 용액을 투명 유리로 된 5 ㎖ 타입 I 앰플 중에 충전시키고, 유리를 용해시킴으로써 공기의 상부 격자하에 봉입시키고, 120 ℃에서 15 분 이상 오토클래이브시켜 살균하여 주사액제를 제조하였다.Dissolve the pyridine derivative substituted with benzoxazole according to the invention in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, and adjust the volume with sodium chloride BP for injection. Adjusted and mixed well. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.
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| KR1020080044485AKR101034351B1 (en) | 2008-05-14 | 2008-05-14 | Pyridine derivatives or pharmaceutically acceptable salts thereof substituted with novel benzoxazoles, preparation methods thereof, and pharmaceutical compositions for the prevention and treatment of abnormal cell growth diseases containing the same as active ingredients |
| PCT/KR2009/002536WO2009139576A2 (en) | 2008-05-14 | 2009-05-13 | Pyridine derivatives substituted with novel benzoxazoles or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical compositions containing the same as active ingredients for prevention and treatment of abnormal cell growth disease |
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| AR070317A1 (en) | 2008-02-06 | 2010-03-31 | Osi Pharm Inc | FURO (3,2-C) PIRIDINE AND HAVING (3,2-C) PIRIDINES |
| TW201718581A (en) | 2015-10-19 | 2017-06-01 | 英塞特公司 | Heterocyclic compounds as immunomodulators |
| SG11201804152RA (en)* | 2015-11-19 | 2018-06-28 | Incyte Corp | Heterocyclic compounds as immunomodulators |
| BR112018012756A2 (en) | 2015-12-22 | 2018-12-04 | Incyte Corp | heterocyclic compounds as immunomodulators |
| MA44860A (en) | 2016-05-06 | 2019-03-13 | Incyte Holdings Corp | HETEROCYCLIC COMPOUNDS USED AS IMMUNOMODULATORS |
| US20170342060A1 (en) | 2016-05-26 | 2017-11-30 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| SMT202200392T1 (en) | 2016-06-20 | 2022-11-18 | Incyte Corp | Heterocyclic compounds as immunomodulators |
| WO2018013789A1 (en) | 2016-07-14 | 2018-01-18 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| US20180057486A1 (en) | 2016-08-29 | 2018-03-01 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| MA47120A (en) | 2016-12-22 | 2021-04-28 | Incyte Corp | PYRIDINE DERIVATIVES USED AS IMMUNOMODULATORS |
| CN110582493B (en) | 2016-12-22 | 2024-03-08 | 因赛特公司 | Benzoxazole derivatives as immunomodulators |
| EP3558989B1 (en) | 2016-12-22 | 2021-04-14 | Incyte Corporation | Triazolo[1,5-a]pyridine derivatives as immunomodulators |
| WO2019161010A1 (en)* | 2018-02-16 | 2019-08-22 | Boehringer Ingelheim International Gmbh | Inhibitors of trpc6 |
| CA3095758A1 (en) | 2018-03-30 | 2019-10-03 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| SI4219492T1 (en) | 2018-05-11 | 2025-04-30 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| JP7665593B2 (en) | 2019-08-09 | 2025-04-21 | インサイト・コーポレイション | Salts of PD-1/PD-L1 inhibitors |
| BR112022005826A2 (en) | 2019-09-30 | 2022-06-21 | Incyte Corp | Pyrido[3,2-d]pyrimidine compounds as immunomodulators |
| US11866451B2 (en) | 2019-11-11 | 2024-01-09 | Incyte Corporation | Salts and crystalline forms of a PD-1/PD-L1 inhibitor |
| EP4196118A1 (en) | 2020-08-13 | 2023-06-21 | Boehringer Ingelheim International GmbH | Treatment of cognitive impairement associated with schizophrenia |
| CA3195702A1 (en) | 2020-10-13 | 2022-04-21 | Boehringer Ingelheim International Gmbh | Process of reworking |
| WO2022099018A1 (en) | 2020-11-06 | 2022-05-12 | Incyte Corporation | Process of preparing a pd-1/pd-l1 inhibitor |
| US11760756B2 (en) | 2020-11-06 | 2023-09-19 | Incyte Corporation | Crystalline form of a PD-1/PD-L1 inhibitor |
| JP2023548859A (en) | 2020-11-06 | 2023-11-21 | インサイト・コーポレイション | Process for making PD-1/PD-L1 inhibitors and their salts and crystalline forms |
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